The lHlealtl Consequences of SMOICING A Reference Edition Selected Chapters From 1971 Through 1975 Reports With Cumulative Index For All Reports 1964-1975 U.S. Department of Health, Education, and Welfare Public Health Service Center for Disease Control Atlanta, Georgia 30333 THE HEALTH CONSEQUENCES OF SMOKING A Reference Edition Selected Chapters From 1971 Through 1975 Reports With Cumulative Index For Al Reports 1964-1975 U.S. Department of Health, Education, and Welfare Public Health Service Canter for Disease Contrci Atlanta, Georgia 30333 1976 HEW Publication No. (CDC) 78-8357 October 1977 @onorable Thomas P. O'Neill Speaker of the House of Representatives Washington, D.C. 20515 Dear Mr. Speaker: As required by Section 8(a) of the Public Health Cigarette Smoking Act of 1969 (Public Law 91-222), enclosed is the 1976 Report to Congress on the Health Consequences of Smoking. This year‘s report includes the "Bibliography on Smoking and Health - 1975," the offictal abstract bulletin of the National Clearinghouse for Smoking and Health, Bureau of Health Education, Center for Disease Control, Public Health Service. It presents the scientific information published since last year's report to Congress. Also part of this year's report is “The Health Consequences of Smoking, a Reference Edition," a compilation of selected chapters from previous reports to Congress. This reference edition was prepared to emphasize the fact that the major health risks from smoking are known and that recent scientific information refines the understanding of these relationships. Without doubt, cigarette smoking is a cause of cardiovascular disease, various types of cancer, and respira-~ tory disease. Its toll im illness and premature death is needless and preventable. - Because of ny strong commitment in reducing the morbidity and mortality which result from smoking, the Department is conducting a major review of its programs in this field in order to introduce administrative and legislative proposals to combat this problem. Sincerely, Joseph A. Califano, Jr. Enclosure PREFACE ie health consequences of cigarette smoking are well established’ ad have been clearly understood for several years. The causal re- ionships between cigarette smoking and an excess risk of devel- ding cardiovascular disease, respiratory tract cancers, and chronic structive lung disease, as well as the risk to the fetus, are well Peumented and accepted by the scientific and health communities. r the past several years, new additions to the literature have bstantiated these risks and further explained the mechanisms which smoking produces disease, disability, and death; however, search has identified no new major health risks, Therefore, it ems appropriate at this time to prepare a reference document viewing the full range of health hazards due to smoking. is reference report consists of selected chapters from previous ports to the U.S. Congress which present summations of the own health hazards from smoking. Because the 197] report was review of all information on smoking and health at that time, © chapters were included from reports prior to that time. This tference, coupled from the annual Bibliography on Smoking and Lalth, represents a complete description of major smoking and alth information. € scientific evidence is clear and unavoidable, and the important k now is to convert this knowledge into programs for reducing d eliminating the Preventable death and disability related to the oking habit. Theodore Cooper, M_D. Assistant Secretary for Health TABLE OF CONTENTS Page PREFACE ......0. 00.0000 ee nee iii TABLE OF CONTENTS .........-2-..020 00002 eee eee eee v PREVIOUS PUBLIC HEALTH SERVICE REPORTS ON SMOKING AND HEALTH......2..--02.2-2-0.2--02--000055 Vii ACKNOWLEDGEMENTS .........2-.002 20 ee eee eens ix CHAPTER 1 Overview (1975 Report) ......0000 020 c eee eee 1 CHAPTER 2 Cardiovascular Disease... 2.2.0.0... 0-0 ee eee eee 9 Part 1 (1971 Report, Chapter 2) ...............--. ll Part 2 (1975 Report, Chapter 1) ...............-.. 131 CHAPTER 3 Chronic Obstructive Bronchopulmonary Disease (1971 Report, Chapter 3) ........0..2.2---00008- 161 CHAPTER 4 Cancer (1971 Report, Chapter4) ...........---04- 257 CHAPTER 5 Pregnancy (1973 Report, Chapter 4) ...........---.- 4}i CHAPTER 6 Peptic Ulcer Disease (1973 Report, Chapter 5)......... 465 CHAPTER7 Involuntary Smoking (1975 Report, Chapter 4) ........ 479 CHAPTER 8 Allergy (1972 Report, Chapter 7) ...-......------. 509 CHAPTER 9 Tobacco Amblyopia (1971 Report, Chapter7) ........ 527 CHAPTER 10 Pipes and Cigars (1973 Report, Chapter6) .........-. 535 CHAPTER 11 Exercise Performance (1973 Report, Chapter 7)......-- 607 CHAPTER 12 Harmful Constituents of Cigarette Smoke . (1972 Report, Chapter9) ........-----------5+-- 621 INDEX This Report... 2.2022 ce ee ee ee ee 635 CUMULATIVE INDEX (1964 - 1975) 22.0.2. eee ee eee 000 Previous Public Health Service Reports on Smoking and Health Reviews of the scentific evidence linking smoking to health effects began in 1964 with Smoking and Health, Report of the Advisory Committee to the Surgeon General of the Public Health Service or as subsequently referred to “the Surgeon General’s Report.” After this report, Public Law 89-92 was passed requiring supplemental reports to Congress on this subject. In compliance, three reports were submitted: 1. The Health Consequences of Smoking, A Public Health Service Review: 1967. 2. The Health Consequences of Smoking, 1968 Supplement to the 1967 PHS Review. 3. The Health Consequences of Smoking, 1969 Supplement to the 1967 PHS Review. In April 1970, Public Law 91-222 amended the previous law and called for an updated report on the health effects of smoking no later than January 1, 1971, with annual reports thereafter. The Health Consequences of Smoking, A Report of the Surgeon General: 1971, a comprehensive review of all the scientific literature available to the National Clearinghouse for Smoking and Health and with emphasis on the most recent additions to the literature was that updated report. Since then, the following annual reports on the health consequences of smoking have been submitted: 1. The Health Consequences of Smoking, A Report of the Surgeon- General, 1972. 2. The Health Consequences of Smoking, 1973. 3. The Health Consequences of Smoking, 1974. 4. The Health Consequences of Smoking, 1975. Each report since the original “Surgeon General’s Report” has reviewed the scientific literature relevant to the association between smoking and vii cardiovascular diseases, non-neoplastic bronchopulmonary diseases, and cancer. Smoking as related to the following diseases and conditions has been reviewed periodically in the reports: Pregnancy (1967, 1969, 1971, 1972, 1973) Peptic Ulcer Disease (1967, 1971, 1972, 1973) Public Exposure to Air Pollution from Tobacco Smoke (1972, 1975) Noncancerous Oral Disease ( 1969) Tobacco Amblyopia (1971) Allergy (1972) Harmful Constituents of Cigarette Smoke (1972) Exercise Performance (1973) Pipe and Cigar Smoking (1973) Overview: The Health Consequences of Smoking (1975) ACKNOWLEDGMENTS Preparation of this reference edition, The Health Consequences of Smoking, was the responsibility of the National Clearinghouse for Smoking and Health; Charles A. Althafer, Acting Director; David M. Burns, Medical Staff Director; Priscilla B. Holman, Technical Editor; Donald R. Shopland, Technical In- formation Officer. Individual chapters comprising this reference volume are from reports which were prepared under the direction of Daniel Horn, Ph.D., Director of the Clearinghouse,-currently on assignment to the World Health Organization. The following persons served as medical staff directors or consultants for the preparation of the reports whose chapters are included in this reference edi- tion: Elvin E. Adams, M.D.; Daniel P. Asnes, M.D.; David M. Burns, M.D.; David G. Cook, M.D.; John H. Holbrook, M.D.; Paul Schneiderman, M.D.; and H. Stephen Williams, M.D. The following persons provided assistance and advice for the preparation of reports whose chapters are included in this reference edition. Reviewers! Anderson, William H., M.D. — Chief, Pulmonary Disease Section, University of Louisville, School of Medicine, Louisville, KY. Anthonisen, Nicholas, R., M.D., Ph.D. — Director, Respiratory Division for the Health Sciences Center, Winnipeg General Hospital, Winnipeg, Canada. Auerbach, Oscar, M.D. — Senior Medical Investigator, Veterans Hospital, East Orange, NJ. Ayres, Stephen M., M.D. — Professor and Chairman, Department of Internal Medicine, St. Louis University Medical School, St. Louis, MO. Baker, Carl, M.D. — Director, Program Policy Staff, Health Resources Ad- ministration, U.S. Department of Health, Education, and Welfare, Wash- ington, D.C. tBellet, SamueJ, M.D. — Director, Division of Cardiology, Philadelphia General Hospital, Philadelphia, PA. : , — Bing, Richard J., M.D. ~ Visiting Associate in Biomedical Engineering, California Institute of Technology, Pasadena, CA. Bock, Fred G., Ph.D. — Director, Orchard Park Laboratories, Roswell Park Memorial Institute, Orchard Park, NY. Boren, Hollis, M.D. — Professor of Medicine, University of South Florida Medical Center, Tampa, FL. Boutwell, Roswell K., M.D. — Professor of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI. Bross, Irwin, M.D. — Director of Biostatistics, Roswell Park Memorial Institute, Buffalo, NY. 1 Current addresses. t Deceased. ix Cooper, Theodore, M.D. — Assistant Secretary for Health, U.S. Department of Heaith, Education and Welfare, Washington, DC. Cornfield, Jerome — Research Professor of Biostatistics, University of Pittsburgh Graduate School of Public Health, Biostatistics Project, Bethesda, MD. Earl, Christopher J., M.D. — National Hospital, London, England. Epstein, Frederick H., M.D. — University of Zurich, Zurich, Switzerland. Falk, Hans L., Ph.D. — Associate Director for Program, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. Farr, Richard, M.D. — Director, Department of Medicine, Section of Allergy and Clinical Immunology, National Jewish Hospital and Research Center, Denver, CO. Ferris, Benjamin G., Jr., M.D. — Professor, Department of Physiology, Harvard School of Public Heaith, Boston, MA. Finklea, John F., M.D. — Director, National Institute for Occupational Safety and Health, Center for Disease Control, Public Health Service, U.S. Department of Health, Education and Welfare, Rockville, MD. Fitzpatrick, Mark J., M.D., M.P.H. — Fairhaven Medical Associates, Inc., Fairhaven, MA. Frazier, Todd M. — Assistant Director, Harvard Center for Community Health and Medical Care, Harvard School of Public Health, Boston, MA. Freston, James, M.D. — Associate Professor of Medicine; Chairman, Divisions of Gastroenterology and Clinical Pharmacology, University of Utah Medicai School, Salt Lake City, UT. Goldsmith, John R_, M.D. — Medical Epidemiologist, Epidemiological Studies Laboratory, California State Department of Health, Berkeley, CA. Gori, Gio B., Ph.D. — Deputy Director, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD. Hanna, Michael G., Jr., Ph.D. — Director of Basic Research, Frederick Cancer Research Center, Frederick, MD. Harkavy, Joseph, M.D. — Clinical Professor of Medicine (Emeritus), the Mount Sinai Medical School of the University of New York, New York, NY. Harke, H. -P.. Ph.D, — Forschunginstitut der Cigarettenindustrie, e.V., Hamburg, Germany. Higgins, fan T, T., M.D., F.R.C.P. — Professor, Department of Epidemiotogy, University of Michigan School of Public Health, Ann Arbor, MI. Hoffmann, Dietrich, Ph.D. ~ Member, and Chief, Division of Environmental Carcinogenesis, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, NY. Israel, Robert A, — Acting Deputy Director, National Center for Health Statistics, Public Health Service, U.S. Department of Health, Education, and Welfare, Rockville, MD. ee Current addresses. Deceased. Jennings, Michael, M.D. — Epidemic Intelligence Service, Center for Disease Control located at Ohio Department of Health, Columbus, OH. Keller, Andrew Z., D.M.D., M.P.H. — Chief, Research in Geographic Epidemiology, Medical Research Service, Veterans Administration Centra! Office, Washington, DC. Kirsner, Joseph, M.D. — Professor of Medicine, University of Chicago School of Medicine, Chicago, IL. Knox, David L., M.D. — Associate Professor, The Wilmer Opthalmological Institute, The Johns Hopkins University Schoo! of Medicine, Baltimore, MD. — Kolbye, Albert C., Jr., M.D., J.D. — Director, Office of Sciences, Bureau of Foods, Food and Drug Administration, U.S. Department of Health, Education and Welfare, Washington, DC. Kotin, Paul, M.D. — Senior Vice President of Health, Safety, and Environ- ment Division, Johns-Manville Company, Denver, CO. Krumholz, Richard A., M.D. — Medical Director, Institute of Respiratory Diseases, Kettering Medical Center, Kettering, OH. Lenfant, Claude, J.M., M.D., — Director, Division of Lung Diseases, National Heart and Lung Institute, National Institutes of Health, Bethesda, MD. Liebow, Averill A., M.D. — Professor and Chairman, Department of Pathology, University of California at San Diego, LaJolla, CA. Lilienfeld, Abraham, M.D. — University Distinguished Service Professor of Epidemiology, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD. Lowell, Francis C., M.D. — Chief, Allergy Unit, Massachusetts General Hospital, Boston, MA. MacMahon, Brian, M.D. — Professor, Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA. McLean, Ross, M.D. — Professor of Medicine and Chief of Pulmonary Services, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC. McMillan, Gardner C., M.D. — Assistant Director for the Etiology of Arteriosclerosis and Hypertension, National Heart and Lung Institute, National Institutes of Health, Bethesda, MD. . . =: Manning, Kathleen M., R.N. — Department of Staff Development, Boston City Hospital, Boston, MA. Meyer, Mary B., Mrs. — Assistant Professor of Epidemiology, The Johns Hopkins University, Baltimore, MD. Mitchell, Roger S., M.D. — Chief of Staff, Veterans Administration Hospital, Denver, CO. Murphy, Edmond A., M.D. — Professor of Medicine and Biostatistics, The Johns Hopkins University, Baltimore, MD. Nettesheim, Paul, M.D. — Group Leader, Respiratory Carcinogenesis Group, Biology Division, Oak Ridge National Laboratory, Oak Ridge, TN. Teurrent addresses. t Deceased. xi Newill, Vaun A., M.D. — Executive Office of the President, Office of Science and Technolagy, Washington, DC. Paffenbarger, Ralph S., Jr., M.D. — Epidemiologist, California State Depart- ment of Health, Berkeley, CA. Parker, Charles W., M.D. — Professor of Internal Medicine, Division of Immunology, Washington University Medical School, St. Louis, MO. Peters, John M., M.D, — Associate Professor of Occupational Medicine, Harvard University School of Public Health, Boston, MA. Peterson, William F.. M.D. — Chairman, Department of Obstetrics and Gynecology, Washington Hospital Center, Washington, DC. Petty, Thomas L., M.D. ~— Professor of Medicine; Head, Director of Pulmonary Medicine, University of Colorado Medica! Center, Denver, CO. Rall, David P., M.D. — Director, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. Rauscher, Frank J., M.D. — Director, National Cancer Program, National Cancer Institute, Nationa! Institutes of Health, Bethesda, MD. Reinke, William A., Ph.D. — Professor, Department of International Health, The Johns Hopkins University, Baltimore, MD. Renzetti, Attilio D. Jr., M.D. — Professor of Medicine, and Head, Pulmonary Disease Division, The University of Utah Medical Center, Salt Lake City, UT. Ringler, Robert L., Ph.D. — Deputy Director, National Heart and Lung Institute, National Institutes of Health, Bethesda, MD. Robins, Morton, M.D. Health Consultant, Westat, Inc., Rockville, MD. Saffiotti, Umberto, M.D. — Associate Director, Carcinogenesis Program, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD. Schuman, Leonard M., M.D. — Professor and Head, Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, MN. Shimkin, Michael B., M.D. — Professor of Community Medicine and Oncology, School of Medicine, University of California at San Diego, LaJolla, CA, Stamler, Jeremiah, M.D. — Professor and Chairman, Community Health and Preventive Medicine and Dingman Professor of Cardiology, Northwestern University Medical School, Chicago, IL: . Underwood, Paul B., Jr., M.D. — Professor, Department of Obstetrics and Gynecology, and Director of Gynecologic Oncology, University of South Carolina Medical School, Charleston, SC. Van Duuren, Benjamin L., M.D. — Professor of Environmental! Medicine, Institute of Environmental Medicine, New York University Medical Center, New York, NY. Victor, Maurice, M.D. — Professor, Department Head, Neurology, Case Western Reserve, Cleveland, OH. Wynder, Ernest L., M.D. — President and Medical Director, American Health Foundation, New York, NY. ee Icurrent addresses. tDeceasea. xii The following staff persons at the National Clearinghouse for Smoking and Health or at the Center for Disease Control contributed to the preparation of one or more reports whose chapters are included in this report: Richard H. Amacher, Elaine Bratic, Marjorie L. Brighman, Kathryn Carlyste, Emil Corwin, Winthrop N. Davey, M.D., Lillian Davis, Mary E. Dement, Julia M. Fuller, Sandy Harris, Annabel W. Hecht, Gertrude Herrin. Priscilla B. Holman, Robert S. Hutchins, Theresa Klotz, Jennie M. Jennings. Nancy S. Johnston, Sanda Lager, Seth N. Leibler, Ed. D., Rosalie Levine. Mary Mitchell, Dan Nemzer, Mildred Ritchie, James A. Robertson, Donald R. Shopland, Kathleen H. Smith, Elsie Van Valkenburg, and Richard W. White. xiii Chapter 1 Overview — The Health Consequences of Smoking Source: 1975 Report, Overview — The Health Consequences of Smoking, pages 1 - 8. OVERVIEW — HEALTH CONSEQUENCES OF SMOKING The statement, ‘Warning: The Surgeon General Has Determined That Cigarette Smoking fs Dangerous to Your Health,”’ has been required by law on cigarette packaging since 1970 as a part of the Public Health Cigarette Smoking Act of 1969. This Act was a response by the U.S. Congress to the scientific information on the health consequences of cigarette smoking summarized in reports then available (the Surgeon General’s Report of 1964 and the subsequent 1967, 1968, and 1969 PHS Health Consequences of Smoking). This Act was passed because a series of important questions concerning cigarette smoking and health had been answered. The following discussion summarizes the basic questions, the methodology used to determine the answers, and the answers themselves. The initial question to be answered concerning the health consequences of smoking was “Are there any harmful health effects of smoking cigarettes?” The answer to this question was provided in two ways. First, it was demonstrated that some diseases occurred more frequently in smokers than in nonsmokers. Second, a causal relationship was established between smoking and these diseases. Concern about the possible health effects of smoking started when scientists began looking for an explanation to account for the rapidly increasing death rate from lung cancer. The early retrospec- tive studies showed a link between lung cancer and smoking. The first prospective studies, however, found that only one-eighth of the excess overall mortality found among smokers could be accounted for by lung cancer; the rest was largely due to coronary heart disease, chronic respiratory disease, and other forms of cancer. They also found that the effect on overall mortality was largely confined to cigarette smokers rather than the users of other forms of tobacco. However, demonstrating an association by statistical probability is not enough to establish the causal nature of a relationship. Determining that the association between smoking and excess death rates is cause and effect was a judgment made after a number of criteria had been met, no one of which by itself is sufficient to make this judgment. These criteria as listed in the Surgcon General’s 3 Advisory Committee Report (1964) were the consistency, Strength, specificity, temporal relationship, and coherence of the association. In addition, convincing theories about the mechanisms whereby smoking contributes to the various diseases responsible for the excess mortality among cigarette smokers were developed from the evidence on the biochemical, cytologic, pathologic, and pathophysiologic effects of cigarette smoking, thereby providing the necessary support for the decision that the relationship was causal. The most important specific health consequence of cigarette smoking in terms of the number of people affected is the development of premature coronary heart disease (CHD). Both Prospective and retrospective studies clearly established that cigarette smokers have a greater risk of death due to CHD and have a higher prevalence of CHD than nonsmokers. Long-term. followup of healthy populations has confirmed that a Cigarette smoker is more likely to have a myocardial infarction and to die from CHD than a nonsmoker. Cigarette smoking has been shown to be one of the elevated senim cholesterol). Autopsy studies have shown that persons who smoked cigarettes have more severe coronary athero- sclerosis than persons who did not smoke. Physiologic studies and animal experiments have indicated several mechanisms whereby these effects can take place. cancer than smokers of nonfilter cigarettes, but the risk remains well above that for nonsmokers. The risk of developing cancer of the larynx, pharynx, oral cavity, esophagus, Pancreas, and urinary bladder. was also found to be significantly higher in cigarette smokers than in nonsmokers. Pipe and cigar smokers were found to have Pharynx, larynx, and esophagus when compared to nonsmokers. Fewer Pipe and cigar smokers than cigarette smokers report that they inhale. As a result lungs of pipe and cigar smokers receive much less 4 exposure to smoke than the lungs of cigarette smokers. This is probably the primary reason for the lower incidence of cancer of the lung for pipe and cigar smokers compared to cigarette smokers. Women have had far lower rates of lung cancer than men. This has been attributed to the fact that fewer women than men smoke and the fact that women smokers generally select filter and low tar and nicotine cigarettes. However, the percentage of women smokers in the United States has increased steadily in the last 30 years, and since 1955 the death rates from lung cancer in women have increased proportionately more rapidly than the rates for men, reflecting this increased proportion of women smokers. The tar from cigarette smoke has been found to induce malignant changes in the skin and respiratory tract of experimental animals, and a number of specific chemical compounds contained in cigarette smoke were established as potent carcinogens or co-carcino- gens. Malignant changes including carcinoma in situ were found in the larynx and in the sputum exfoliative cytology. of experimental animals exposed to cigarette smoke. Nonmalignant respiratory disease is a third area of smoking- induced morbidity and mortality. Cigarette smokers have been shown to have more frequent minor respiratory infections, miss more days from work due to respiratory iliness, and report symptoms of cough and sputum production more frequently than nonsmokers. Retrospective and prospective studies with long-term followup have found that cigarette smoking is the primary factor in the develop- ment of chronic bronchitis and emphysema in the United States. Cigarette smokers have also been found to be more likely to have abnormalities of pulmonary function and have higher death rates from respiratory diseases than nonsmokers. Data from autopsy studies have shown that cigarette smokers were more likely to have the macroscopic changes of emphysema, and that these changes are closely related to the number of cigarettes smoked per day. Mucous cell hyperplasia has been found more often in cigarette smokers. Cigarette smoke also inhibits the ciliary motion responsible for cleansing the respiratory tract. An additional area of health concern has been the effect of cigarette smoking during pregnancy. Mothers who smoke cigarettes during the last two trimesters of their pregnancy have been found to have babies with a lower average birth weight than nonsmoking mothers. In addition cigarette smoking mothers had a higher risk of having a stillborn child, and their infants had higher late fetal and 5 neonatal death rates. There are some data to show that these risks due to cigarette smoking are even greater in women who have a high risk pregnancy for other reasons. These effects may occur because carbon monoxide passes freely across the placenta and is readily bound by fetal hemoglobin, thereby decreasing the oxygen carrying capacity of fetal blood. Having established that cigarette smoking is a significant causal factor in a number of serious disease processes, two additional questions became important. They are “Can the health consequences to the individual be averted by stopping smoking or by changing the cigarette,”’ and “What are the overall public health consequences of cessation and of the changes made in cigarettes?” The first question is the simpler of the two to answer. In the individual, cessation of cigarette smoking results in a rapid decline of the carbon monoxide level in the blood over the first 12 hours. Symptoms of cough, sputum production, and shortness of breath usually improve over the next few weeks. A woman who stops smoking by the fourth month of her pregnancy has no increased risk of stillbirth or perinatal death in her infant related to smoking. The deterioration in pulmonary function tests that occurs in some smokers becomes less rapid than that of continuing smokers. The death rates from ischemic heart disease, chronic bronchitis, and emphysema also become less than those of the continuing smoker. The risk of developing cancer of the lung, larynx, and oral cavity declines relative to the continuing smoker in the first few years after cessation and 10 to 15 years after stopping smoking approximates that of nonsmokers. A smoker who switches to filter cigarettes and has smoked them for 10 years or longer has a lower risk of developing lung cancer than a smoker who continues to smoke nonfilter cigarettes. The risk to a filter cigarette smoker, however, still remains well above that of a nonsmoker. The public health benefits of cessation are more difficult to determine than the effects of cessation on the individual. Just as Cause-specific death rates have reflected the effect of cigarette smoking on certain diseases, they should also reflect any substantial benefits to be gained by cessation or reduction in cigarette smoking. Several factors combined to produce a reduction in per capita dosage of tobacco exposure in the United States for the years 1966-1970. First, per capita consumption of cigarettes declined from 4,287 cigarettes per person in 1966 to 3,985 in 1970. Second, during this period there was a slow but significant decrease in the average tar and nicotine content of cigarettes as well as a decrease in the amount of 6 tobacco contained in the average cigarette. The decline in per capita consumption during those years occurred in the face of a substantial increase in the proportion of young women becoming smokers as compared to women of previous generations and ‘so reflected predominantly a decrease in cigarette consumption by men. Since 1970, although the per capita consumption of cigarettes has increased, the average levels of tar and nicotine have continued to decline, making it more difficult to predict what has happened to per capita dosage. Examination of cause-specific death rates for the period of this declining per capita consumption reveals that there was a downturn in the male death rate from ischemic heart disease beginning in 1966 which reversed the upward trend that had occurred over the previous two decades. This decline in the death rate from ischemic heart disease has not occurred in women. The male death rate from chronic bronchitis has also been declining since 1967, and the male death rate for emphysema has declined since 1968 when it was first recorded as a separate category. Female death rates for these two diseases have not shown these trends. Despite the impressive coincidences of the decline in deatn rates among males occurring at the same time that there was a decline in per capita cigarette consumption, it is impossible to be certain of the exact cause of the decline in the death rates. These diseases are influenced by a variety of factors in addition to cigarette smoking such as blood pressure and air pollution. Some of these factors have also been subject to major control efforts which may have contributed to the decline in the death rates. In addition, there have been therapeutic advances in the treatment of these problems which may also have helped lower the death rates. A decline in male death rates from lung cancer should also follow the decline in per capita consumption. This rate would not be influenced as much by changes in other etiologic factors or changes in therapy because cigarette smoking causes from 85 to 90 percent of all lung cancer and there have been no major improvments in survival due to changes in therapy. With lung cancer, however, two additional considerations must be kept in mind. A decline in death rates from lung cancer would be expected to lag several years behind a decline in per capita consumption. In addition, the decline in consumption and switch to low tar and nicotine cigarettes occurred 7 predominantly in the younger age groups where death rates from lung cancer are low. For these reasons, it is necessary to look at lung cancer death rates by age group rather than total lung cancer death rates. The lung cancer rates by age groups for 197] suggest a decline in the lung cancer rates for the younger males (under 45), but the confidence limits on these trends at present remain wide enough that it is impossible to say whether this is a real decline or merely a leveling off. The national health statistics broken down by 5-year age groups are currently available only through 1971. The data by age group from a few more years will be necessary to determine whether the changes in smoking behavior which have taken place have reversed the trend of the preceding 40 years of continually increasing lung cancer rates in men. In 1971, the last year for which detailed mortality statistics are available, the accumulated exposure to cigarettes reached its peak among men bor between 1915 and 1919, a group then in their early 50’s. Cumulative exposure has continued to decline with each successive 5-year birth cohort born since then. The trends of the last few years offer some hope that the peak of the “lung cancer epidemic,” as some have termed this phenomenon, may have been reached with this group and that future years will show a slow but consistent decline. Chapter 2 Cardiovascular Diseases Part f Part I Sources: Part 1-— 1971 Raport, Chapter 2, pages 15 - 174. Part 11 — 1975 Revort, Chapter 1, pages 9 - 38. Chapter 2 Cardiovascular Diseases Part I Contenis Introduction The Effect of Cessation 9 i Cigarette Smoking on Coronary « Heart Disease The Constitutional Hypothesis AG Autopsy Studies Relating (Smoking, | Atherosclerosis, and | ~ Sudden CHD Death 48 Experimental Studies Concerning the - ‘Relationship of | Coronary Heart Disease and Smoking .....2222.20 2080, 52 Cardiovascular Effects of Cigarette Smoke and Nicotine ......, TE 2: Deane . Coronary Blood Flow °. 2/0/8034 -ha3iaubr sot! 3 5 Cardiovascular Effects of Carbon Monoxide . Bae Effects of Smoking on the Formation of Atherosclerotic ae Lesions .....0 200. ives ies. we hee pg 59 The Effect of Smoking on Serum Lipid Levels The Effect of Smoking on Thrombosis .. abl Other Areas of Investigation. erreres Cerebrovascular Disease <.°. need. SEO A A: os al ob Nonsyphilitic Aortic Aneurysm . we LE Hon Peripheral Arteriosclerosis we ah Experimental Evidence.” Thromboangiitis Obliterans .” Summary and Conclusions ae, i ‘Coronary Heart Disease ..........-......2........ 70 Cerebrovascular Disease ............0.0.0-20...... 71 Nonsyphilitic Aortic Aneurysm .................... 71 Peripheral Vascular Disease ......2......0.2.02... 71 References.....020..... ws s SURE eee eeee see cee eee eee 71 FIGURES 1. National Cooperative Pooling Project, Inter-Society Com- ..° mission for Heart Disease Resources 2000 vse etiecrey 19 a Risk of coronary heart disease “(2 years) according to. . a ~ cigarette smoking habit and presence of “predisposing . factors” (men 30-59 at entry). Framingham Heart AStudy 00 ISLA cenee 20 3. Estimated coronary heart disease death ratios i in a 17-51 year follow-up, and frequencies of paired combinations of six high-risk characteristics in n college, for all ages atdeath 1.0.0.0... 0... bebe aces wa lee we wheel... 21 4. Relationship between smoking status and serum choles- ~ terol level at initial examination, and incidence of clin- ical coronary heart disease in men originally age 40-59 ’. free of definite CHD. Peoples Gas Light and Coke Company Study, 1958-1962...... “nee be tec eee aeeee _ 39 5. Average annual incidence of first myocardial infarction a among men in relation to overall physical activity, — class, and smoking habits _(age- adjusted | rates per 1,000) . rpeiitiertyechscnuy tigen tts feu - : “LIST OF TABLES» . - (A indicates tables located i in Appendix at end of Chapter) ort an 5° 1. Sudden death and acute mortality with first major. coronary episodes ..0ish.levSccsves: paver 19 2. Coronary heart disease mortality ratios related to smoking—prospective studies’. pidge. Pig 89 .22 3. Sudden death from coronary heart aie related to ~. ' smoking . vee cee bees SACI ee Voi ee6r 3. A 26 4. Coronary heart disease morbidity | as Ebene to 65567} smoking. 2.02... see eee ee cere eee ee tene : Sis en,28, 5. Coronary heart disease morbidity as yelated to smok- | fer “ J ing—-angina pectoris—prospective studies V2.7 yd 33 A6. Coronary heart disease morbidity | and mortality— en -r .. yetrospective studies ....0.0..00 0000270. ” aE Bg A7. Differences in serum lipids between smokers and non- eg 0000) ) 6 REEL oT Og ry we LIST OF TABLES (CONT.) (A indicates tables located in Appendix at end of Chapury Page A 8. ‘Blood pressure differences between smokers and non- 7 smokers 2... cos Sa ee ee a ese oles Net. oa dae 99 , 9. Death rates from coronary heart disease, by systolic fAS - blood pressure: ILWU mortality study, 1951-1961 38 10. Death rates from coronary heart disease, by diastolic (51:5 °*i blood pressure: ILWU mortality study, 1951-1961 _ 38 11. Death rates from coronary heart disease, among hy-. ay, - 12. Death rates from coronary heart disease among men‘ without abnormalities related to cardiopulmonary - ‘diseases by weight classification in 1951: ILWU . mortality study, 1951-1961. - arrin tometer dsr Al 13. Death rates from coronary heart disease, by electro- : cardiographic findings in 1951: ILWU mortality Study, 1951-1961... 1.0.0... ce eee eee eee eee 41 14, 1958 status with respect to heart rate, blood pressure, cigarette smoking, and ten-year mortality rates, by cause (1,329 men originally age 40-59 and free of definite coronary heart disease) Peoples Gas Com- pany Study, 1958-1968............+-+ e+e eeee 41 15. The effect of the cessation of cigarette smoking on the , incidence of CHD .......--.. 2 0c e eee eee etre 42 16. Annual probability of death from coronary heart dis- ease, in current and discontinued smokers, by age, maximum amount smoked, and age started smoking 42 Al7. Incidence of new coronary heart disease by smoking category and behavior type for men 39-49 years Of AGE Lecce eee ee eee erent terre reetttes “101 A18. Incidence of new coronary heart disease by smoking category and behavior type for men 50-58 years se “of age .....- Jicicsceeee+-+-ss eee ao obead —102 19. Autopsy studies of atherosclerosis cece cee eens a 49 A 20. Experiments concerning the effects of smoking and nicotine on animal cardiovascular function ...... ~ 103 A 21. Experiments concerning the effects of smoking and _ nicotine on the cardiovascular system of humans. 109 A22. Experiments concerning the effect of nicotine or smoking on catecholamine levels ...-.--- aeseceee +115 ‘A 23. Experiments concerning the atherogenic effect of ; nicotine administration. ......---e-ereeree eres “116 15 LIST OF TABLES (CONT.) (A indicates tales located in Appendix at end of Chapter) Page 24. Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia . 60 425. Experiments coricerning the effect of smoking and nicotine upon blood lipids (Human Studies) +. bootde 119 A 25a. Experiments concerning the effect of smoking and’ E08 nicotine upon blood lipids (Animal Studies) ..: <4% _ 123 4 26. Experiments concerning the effect ‘of. carbon amon- $e & oxide exposure upon blood lipids. a out vr 2-125 4 27. Smoking and thrombosis ..02°22: ; 28. Deaths from cerebrovascular. “disease. related to. Gare smoking. ossiece. ol fas eer 2 TS ete wa 64 29. Deaths from nonsyphilitic aortic aneurysm related to A 30. Experiments concerning the effect. of. ‘Ricotine. and. j pe smoking upon the > peripheral vascular system .. 4; 1 POG 260L TH in vonank. ed adi? ede erg Fe . os ts Cenk ra Sup Shy Lyaey 02-8 pgm jens a Ge : 2. ne ait i we eos ; hae . tote ae duce 2H ay S503 : esrb re : 19, ari! lesia™ : i ofa ‘be fai139h09- -Errasnis SgxG AoA Ble: 7 sfimcl: piadog?- no INTRODUCTION Coronary Heart Disease (CHD) cuts short the lives of many men in the Western World in their prime productive years. More Americans die from heart disease than from any other disease. In 1967, in this country, a total of 345,154 men and 227,999 women were classified as dying of arteriosclerotic heart disease (ASHD) (196), a. category which consists largely of what is commonly called CHD. During the years, from 1950 to 1967, the age-adjusted ' death rate from ASHD increased 15.1 percent (196, 197). ‘Besides the many deaths attributed to CHD, much morbidity results from this disease, The National Health Examination Sur- - vey of 1960-1962 estimated that 3.1 million American adults, ages 18 to 79, had definite CHD and 2.4 million had suspect CHD, together representing about 5 percent of the population. It was further estimated that of Americans under age 65, almost 1.8 mil- lion had definite CHD and 1.6 million had suspect CHD (195). - There are several manifestations of CHD, all related in part to the basic process of severe atherosclerosis, a disease of arteries in which fatty materials (lipids) accumulate in the form of plaques in the walls of medium and large arteries. This process, as it occurs in the coronary arteries, leads to stiffening of the wall and narrow- ing of the lumen which, when severe, result in a diminution in the: blood supply to the cardiac muscle. Angina pectoris, a major mani- festation of CHD, results from diminution in blood supply relative to the needs of the myocardium. If the blood supply to a portion of the myocardium is completely obstructed, due for example to the formation of a thrombus at the site of atherosclerotic narrowing, necrosis or death of a portion of heart muscle may occur.-This occurrence is known as a myocardial infarction. In many cases, a disturbance of cardiac rhythm occurs at the time of thrombosis, and the patient may die immediately. It is estimated that approxi- mately 25 percent of patients suffering coronary artery occlusion die within the first three hours following the occlusion (table 1) (88). Not infrequently, sudden death occurs in patients with severe coronary atherosclerosis but without a demonstrable arterial occlu- sion. In these cases, it is thought that the meager blood flow to a portion of the myocardium becomes so diminished with respect to cardiac needs as to lead to a fatal arrhythmia, as well as to, per- haps, a myocardial infarction. gyl7 vel te et GARETTE SMOKING(S) AT ENTRY—WITH CONTROL Of SERUM CHOLESTEROL (C) AND DIASTOLIC BLOOD PRESSURE (H)—-AND TEN YEAR INCIDENCE oo ino MORTALITY RATER 7,594 WHITE MALES AGE 30-59 AT ENTRY, POOLING PROJECT / ‘ web rho i RATE bet 2) i © FIRST MAJOR -, RATE - _ ALL CHD DEATHS”. 2” v wee ‘ ryt a $2" PER 1000779 *__ PER 1,000 . ~ nt {> 15O— em ha Se i oie 7 ye Va aha erg] BES-< t wD > qure. ADS “yey » » = >a ac os JCtH oR 8 fYCORH 840 ‘<: C+H bs 3 os ‘ONLY “+ ONLY OR StH™ - SC+H be . MB wn > Q 4 oO a a Qo nn w o z t ame 3 yom “iC NUMBER 28). 97 SD 2 al (Ree OF EVENTS Och OS Se an . “ Qo NUMBER 1,249° 01a Sy! OT 984 595 OF MEN” : i ot : — moe eae oo Dee EEE a ‘ ui Natlonal Cooperative Pooling Project; smoking status at entry and 10-year age-adjusted rates per 1,000 men for first major coronary event (Incting nonfatal MI, gs fatal MI, and sudden death due to CHD) and any coronary death. U.S. white males age 30-59 at entry. All rates age-adjusted by 10-year age groups to the U.S, S white male Fopuiaton 1960, Graphs present rates for noncigaratte vs, cigarette smokers at entry with simultaneous control of blood pressure and serum cho- lesterol level. For this latter anatysis, the following cutting points were used: iu .. (a) Cigarette smoking S$ —any use at entry “e want i (y) Serum cholesterol: Co 250 mg/d. we 7 : hoy PR ee oy ay Spt (¢) Diastolic blood pressure H ~— = 90 mm. Hg. Slo me Ry fh 2 2 ‘ rent ee Te Ry “ct = SOURCE: Inter-Soclety Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88). SIP. . cholesterol level. (a) Cigarette smoking—S-any use at entry (b) Serum cholesterol—C-2250 mg./dl. ~”(e) Diastolic blood Pressure—H-290 mm, Hg. ..Floure 1—National Cooperative. Pooling Project; smoking status at entry and 10-year age-adjusted rates per 1,000 men for ¥ first major coronary event (includes nonfatal MI, fatal MI, and sudden death due to CHD) and any coronary death. U.S. white males age 30-59 at entry. All rates age-adjusted by 10 year age groups to the U.S. white male population 1960, . - Graphs present rates for noncigarette vs, cigarette smokers at entry with simultaneous control of blood pressure and serum For this latter analysis, the following cutting points were used: ! TABLE i Sudden death and acute mortality ‘pith firat major’ coronary “episodes ©’ me * Author, year, « Proportion per ; 5. within 8 hours of onset - 28 Association, “. Ten-year - ae ‘data from the Albany civil servant, Chicago Number and mot - is Number « 1,000 events . country, - typeof. Data - : wus of { (ascaleulatedon . - “3 . reference cca, Population . collection « . Event “et events =} the basis of age- “> Comment : ” " be i adjusted rates) me am * Pooling , ;, 1,694 males. Medical exam- All first major coronary a \- vee Data from the Poollng Project, Council on hie Project, ~ ‘ty Males 30-59 inationand episodes, nonfatal and fatal, 60h oT. * Epidemiology, American Heart Association, < American’ o7. yearsofage. | follow-up. , Budden death (death 4 ‘Ro a national cooperative project for pooling . Heart a atentry, - 2H ” of acute illness) ae? All acute deaths with first episodes. “1970, U.S.A. 4 (38), r -experience. | “ ce Bounce, Inter-Soclety Commission for Heart Disease Resources (88), is pe i Representative references include: lor 95, 148, 177) and others lsted ag te a 6a-6k fn Inter-Society Commission ‘or Heart Disease Resources report, Cg Le Peoples Gas Co., Chicago Western Electric Co., Framingham Community, Los Angeles civil servant, Minneapolis-St. Paul busincas } = ‘ men, and other prospective epidemiologie : studies of adult cardiovascular disease in the United States. ots ee BY we acl Ss aot re wk CIGARETTE SMOKING: 2° 0 vss) [LJ] None -. wo Bet L- >? PKG. IDAY 8 MORBIOITY RATIO 8 T _ ANY ONE PREDISPOSING FACTORS (CHOLESTEROL * 250, HYPERTENSION, DIABETES) *SIGNIFICANTLY DIFFERENT FROM “NONSMOKER™ P<.05 . moi 3 ? Ficure 2—Risk of coronary heart disease (12 years) according to cigarette smoking habit and presence of PL factors” (men 30-59 at takes Framingham Heart Study. : | . Be, : Source: Kannel, W. B., et al. (94). i. ee _ s s . a) oo. oe : Do Numerous epidemiological studies have indicated that cigarette smokers have increased mortality ratios for CHD; that is, cigarette smokers show significantly increased death rates compared with nonsmokers (table 2). The risk incurred by cigarette smoking in- creases with increasing dosage and, as measured by mortality _ ratios, is more marked for men in the younger age groups, under age 60, although the absolute increment in death rates experienced by smokers over that of nonsmokers continues to increase with increasing age. Table 2 lists the mortality ratios found in the major _ studies. Certain of these studies, including those at Framingham, © _ Massachusetts, the Health Insurance Plan of New York City (HIP), and at Tecumseh, Michigan, have analyzed morbidity as well as mortality from CHD and have indicated that the risk of developing fatal and nonfatal CHD is greater among cigarette smokers than among nonsmokers (tables 3 and 4). Conflicting evidence has been published concerning the relationship of ciga- rette smoking and the incidence of angina pectoris. While some 20 . Me sport —A ms Yetci2e A 3 nes Vetci29 —8 Height <2 8 3 2 Toa a ag spn tere tece ee Dy : : ~ 245 14 Q 386 i uaz a 6} if, . [33 232 227 , a [| d Mo sport--A 3 Sys. BP 1304 —B Le. ~ ; BE at 2 Ak , 321 2 ae 491 5 7 6 t ae Ee 201 a °? . i Cigarettes —A No tport —A ” Sys. BP 130-4 i 3] Sy. BP 130 8 Heirnic6s —B 7 Heightces —B 8 s Ss S ne 8 & " S : Le x 14 1.3 - > Lo | 238 10 feos} og | 3” x 1 442 s10 < 324 90 }]1265| [49 5 B44 239 2 52 5 0 L ° : Le wees 2 Cigarettes “—A No apart —A . Sys. BP 1304 —A % oa] eight <68 —8 Parent dead —B | Parent deed (--8 > 3 2 te 2.5 we - P73] “ . 7s 7 i “wo 2 2.0 . 1.8 69 2 2] oe 96 . 1 ois wel} 077 1a —--} 183 eo . a Lt . no | 277 1.0 100 f2aztf 1.0) [ogs weg 1 199 735 is 1.5 346 || 4681 soy 33 T}ias6!| 25 509] | 487 B 39 237 ee 875 253 1182 La 0 i ot . Cigarettes, —A nes eanci29 A Height<68 3] Parent deed —B S*dYC Sys. BP 2304. —B «YC Pavan dead tab gett . pts : 7 : : 1A - a 19 : 4 . 76 1.3 124 1.0 [307 } 2? | 02 1000 149 2 99 232 _ was || 52 || 402 1 {189 ]] a 1071 1119 | | 294 0 A- AF AS AE AR AP AR AE B— e— B+ B+ s— e— 8+ Be " B-* a : , PRESENCE (+) OR ABSENCE (—) OF CHARACTERISTICS (A or B) ~ -- —- Top numbers in bars are CHD decedents with paired combinations of characteristics; bottoms aumbers, : ~ 5 ate subjects with combinations. . Bhi Me Lote on Dit as xX OF ar OF a res eR Beng BRE Ficure 3—Estimated coronary heart disease death ratios in a 17-51 year - follow-up, and frequencies of paired combinations of six high-risk charac- _ teristics in college, for all ages at death. eT RGek Sage tee stp s inf) _ Source: Paffenbarger, R 8., et al. (146). Tas_e 2.—Coronary heart disease mortality (Actual number of deaths : {SM = Smokers Author, a oo. son : country, Noe a Cigarettes /day t reference population sone ; Hammond 187,783 Questin- Pay Bast Ns ....../5£1.00 (709) and white males naireand «- ---- pov All smokers .1.70 (3361) *(p<0.001) - Horn, in @ states - follow-up vt - (192) + . ~ 1958, * 50-69 years of death . (864) © As. : - U.S.A. of age. ““ eertificate, _ (604) - . fe) = + (77,78). eas op tt 3 (118) ‘| Doyle . 2282 males, Detailed - 10 ce 98 NS ...025...1.00 (20) a _ etal, 1. Fram | |! medical 25: te Allamokers .2.40 (73) 8 1964, «|. ingham, °-.examina- =? {ote <20 ....2-5.2.00 (17) 1 otk USA. |: 3062yearms tion and : a 7 20 .. oo (54). cof age. follow-up. PB op cl pd 20-2... 3.80 ! hae 1,913 males, wah Chips Sec woken. * Albany, ages fet 29-55 years oe ma ee fo of age. Meee aa ooh Doll and Approuzi- Question- 10 1,376 NS ......-- 1.00 : . Hid, mately naire and : Allsmokers .1.35 : * 1964, 41,000 }. follow-up aa 1-14 ....1.29 . og Z Great male British of death Cobra 18-24 ....1.27 fo. Britain physicians. certificate. ae «>26 ..2....-1-43 02 0; (50). : Pe : . Btrobel 3,149 male —- Question- 9 162 NS ........ 1.00 oo and Gsell Swiss phy- naire and : pon: : fear “ 1965 sicians. follow-up ean 1.4, 37200 2 ..--- 21,48 7" Switzer- of death "320 2.22216 ° land BG certificate. : : (180). : fon - ae LoS - Best, Approxi- Question- 2,000 NS ......-. 1.00 1966 mately ~. naire and i= + Allsmokers .1.60 (1380) Canada 78,000 follow-up ~S10 2..22...1.686 (337) (25). male Cana- of death : 1.58 (766) dian. certificate. 1.78 (217) = veterans, 0°" + be eeppret Kahn U.S. male Question- 8% 10,890 NS ........ 1.00 (2997) . 1966 veterans naire and . Allsmokers .1.74 (4150) U.S.A. 2,265,674 “follow-up 2. 0 89 (489 OP (93). person , ofdesth fh 10-20 ......1.78 (2102) 1° . ; : . “years. . _ -- certificate. & 21-39 - 1225-184 (1292) z Peery St peer ye e898 “2.00 (266) _ 3, Hirayama, 265,118 Trained in- NS ........1.00 (17) +s - 1967, Japanese | terviewers (69) wale Japan adultsover — and follow- . 9 * (84). age 40, up of death ‘ ~. * ‘certificate. Kannel 5,127 males = Medical ex- 12 62 NS ..0..2..1.00 (27) etal, and females amination -- 8 gMs20 1.2.20 (25); (><0.05) 1968, age 30-59. and Coa - an _ vs U.S.A. POatd og gd follow-up. : (%). : fA ae mie yt 2 Unless otherwise specified, disparities between the total number of deaths : and the som of the individual smoking categories are due to the exchosion of either occasional, miscellaneous, mixed, or ex-emokers. ‘ : _ gis 22 ratios related to smoking—prospective studies shown in parentheses}* NS = Nonamokers} - ., : _ oe a . . mi Cigars, pipes _ ° SO A ge variation : 7 3us =" Comments : oie aad sb le : a. a Cigarea UP SOSb |. BSD 60-45 65-48 toad bevel NS. .1,00 ONS ool lees. 1.00 (90) 1.00 (142) 1.00 (204) 1.00 (273). we SM. .1.28 (420). Allsmokers 1.93 (765) 1.85 (962) 1.66 (921) 1.41 (718) |, Pipes 10 88 (386) 1.88 (50) 1.7 (49) 1.27 (68) | NS..1.00 ~ "10-20 +2.00 (213) 2.04 (258) 1.91 (235) 1.58 (158) SM..1.03 (312) >20 > 2.51 (203) 2.47 (199) 1.92 (129) 1.86 (78) 3 odie bs + : : Data apply . . oe . ae only to males ~ aged 40-49 - 7 and free . oy ,_ of CHD at . entry. NS : " inelude pipe, Soot ee an eet erm se ete wens cmmene ss mers 7 ~.. Clgar and , - “"-* ex-amokers, SS-45 -, 65-84 65-85 ff se > 1.00 1.00 . ° 1.40 1.71 mo . . 1.73 12700 t ane 1.92 1.58 oa NS. .1,00 Ltr . BM. 1.45 Ss wee - us Cigara . . 30-49 50-69 70 and over NS. .1,00 NS .... 1.00 1.00 8M..0.98 (16) <10 . 1.66 (220) 1.71 (99) Pipes 10-20 ......- 1.45 (115) 1.67 (557) 1,29 (94) N8. .1.00 >20 ...-.... 1.85 (65) 1.76 (184) 1.73 (28) SM..0.96 (95) . . Cigars mo, : or a: NB. .1.00 ob east t , 3M..1.06 (623), 4 . whew Pipes Be Ld . dsr DASARI PE oe NB. .1.00 Dele EMS os TD fa tet 18: 3M. .1.08 (3868) . 2 a ye ee eee . ee ae ~ ere - a Prelimin- . . * Sash fite+ ~~ ayy report, 7 zp” values specified only for those provided by authors. ite ; oy ar ~ : z Ge ane oe foe ao at ab ads my wee Bot Aft Sele gc inh Oe aatsiz to, TABLE 2.—Coronary heart disease mortality ratios (Actual number of deaths {SM = Smokers Author, year, | Number and y Follow- Number . tee eoantry, typeof Data “ep - of or Clgarcties/day reference population collection (years) deaths [ woe ee eae Hammond 358,534 _ Question- ; 5 at B19 and mates <)"*-netreangd 2°37 oNS Garfinkel, 445,878 ‘follow-up * " [1 1969, females “7 of death : 15S kz 3 ba ct “10-19 age 40-79 ‘enka AG gag "18 spate tee he ge eet ars aye. 7 certificate. boo x? aera Laiyotes fa8S Sao ays pny Paffenbsar- 50,000 male Baseline 17-51 1,146 NS ger and _ former . interview —.,----matehed 3M (885) {p<0.01) Wing stodents. and exam- tVicwith +--+, . 1969 ination and eo: 2992 °°. te vere cao U.S.A. _ follow-up [*Seontrola > --9- - Gt (4) by death ave cab, oe certificate, “a ° Paffenbar- 3,263 male Initial multi. 16 ~ 21 NSand<20 2.00 (137) oe geretal, longshore phasic SM>20 ....2.08 (15a) (S900) 1970, men 85-64 screening i. . ne U.B.A, years of and follow- . (164). age. up of death certificate, Taylor - 2,571 male —s Interviews B 74600 ONS C...L...1.00 (4) ea etal, railroad and regular ae S20 NOT (20) es 1970, . employees follow-up itis te PRO ce, 3.60 (22) “3 U.S.A. 40-59 years os exam- | ; faye eed (143). of age at ination, |: vie entry. ° Weir and $8,153 Call- Question- BS 1,718 NS .........1.00 Dunn, fornia male naire and oC Allsmokers .1.60 1970, workers follow-up +10 2.0.....1.89 U.B.AL 85-64 years of death 20 2... 1.67 (905). of age at certificate, >80 .....0.. La entry. Pooling 1,427 white Medieslex- 10 = 289 NS ......... 1.00 (27) ~ Project, males amination (84) American 30-59 years and . (86) Heart of age at follow-up. (68) Associe- entry, 9 -—---— : ton, ° 1970, . ’ U.B.A. : Le (se). ar - - 1 Unless otherwise specified, dis Gnd the sum of the individus] of ether Occasfqnal, miscellaneous, mix 24 amoking parities between the tots! number of deathe categories are due to the exclusion ed, or ex-smokers. “> Fare related to smoking—prospective atudies (cont.) shown in parentheses}I ces“ * NS = Nonsmokers] --~ ~* - ~ 7 til ve Coat. aes mw. PTRSdE . Cigars, pipes _ Age variation — woe _ - Comments PBN tt tegen Males ~- sos E"" *Based on oe 40-09 970-79 "69 deaths. - 1.00 "Loo -. i 1.48 ‘aye : “1.820 -— Bal” + 2.40 1.91 1.49 2.79 1.79 LAT Females pT ern 1.00 1.00 1.00 1.15 1.04 0.76 237 1.79 0.98 2.68 . 2.08 1.27 woe 3.13 202 ke ee “10-19 20-30 __.. D4 ween me Ob SESE SSBB em NS ...,.....1.00 1.00. 1.00 : (p<0.01) SM ...... 180 (88) 1. 60 (163) ‘120 (134) 5 ; : gre? : 7Y _85-09 _..- NS includes ~~ ee SESE 45-56 55-84 . NS . - 1.00 1.00 17 1,00 ters 2> pipes and Mood x10 . 2.05 hap. La: tat heselgars at ‘ tee +20 3.17 166 > 126 -tishity BM incladés | - +++ ©3830 . 3.83 $660 ix C186 - rock 4 ex-smokers.- re $18 AZ ee AZ at ae eae All ......- 5. 6.24 295 | 1856 . 2 124 aes es - 1.00 (27) So LE ra fate a - tad ~ lg go (aay aR rs _. - ‘ : 4 ot att arew- * ‘eeitiss pasty, eek oe ab acy our wre 5 hal tae neds, 2a a TaBLe 3.—Sudden death from coronary (Mortality ratios—actual number Author year, Number end Date Follow-up Numbe: country, typeof collection years “of , reference Population deaths Pooling 7,427 white Medical 10 145 Project, males 30-59 examination American Heart years of age and Association, atentry. follow-up. 1970, U.S.A. (88). TasLe 4.—Coronary heart disease (Risk ratios—actual number of CHD (SM = Smokers NS = Nonsmokers PROSPECTIVE STUDIES Author, year, Number and a Follow- Number of country, eo collection ap incidents Ci ettes/d. reference population years ee Doyle 2,282 males Detailed 10 243 myo- NS ............ 1.00 (52) etal, Framingham, medica] cardial All amokers ....2.36(191) . 1964, 30-62 years examina- infare- <20 -1.98 (44) USA. of age. tion and ‘tions and 20 2... 2.05 (64) (84). 1,913 males follow-up. CHD >20 3.04 (83) Albany, deaths, 39-55 years of age. Stamler 1,329 CHD- Interview 4 46 CHD NS 2.2.22... 1.00 (2) etal, free male and examin- <10 cigarettes. 2.92 (6) 1966, employees of ation with <5 cigars... } ° U.S.A. Peoples Gas cUnic <5 pipes..... (177). Company follow-up. 10-19 cigarettes.3.67 (8) 40-59 years >20 cigarettes. 3.83 (29) of age. > 5 cigars.... > & pipes..... Epetein, 6,565 male Initial 4 96 male, Males 1967, and female medical 92 female _ 40-59 UB.A. residents examina- CHD in- NS ...es eee eee 1.00 (1) (e@1), of Tecumseh, tion and eluding EX .... -.-6.63 (10) Mich. repeat deaths, Cigarettes .....5.20 (36) follow-up angina, and Females examina- myocardial NS aoa dO (22) tions. infarctions, EX .......... ~-0.89 (3) Cigarettes .....1.02 (14) 3 Unless otherwise specified, disparities between the total number of mant!- festations and the sum of the Individua] smoking categories are due to the exclusion of cither occasional, misceDaneous, mixed, or ex-smokers, 26 heart disease related to smoking of deaths shown [n parentheses) Comment Cigarettes/day Never smoked ........... 1.00 (15) S10 oo... eee -1.90 (23) 20 eee cee ee 90 (50) P20 Loe eee eee 8,36 (44) See table 1 for description of Pooling Project. morbidity as related to smoking manifestations shown in Parentheses)! EX = Ex-amokers} PROSPECTIVE STUDIES—Continued Pipes, cigars Comments Data include CHD deaths, only on males 40-49 years of age and free of CHD on entry. NS includes pipes, cigars, and ex-smokers. NS includes ex-smokers. Includes all CHD. Males—Continued Males Reexamination 60 and over 40-59 of patients 1.00 (7) SM +++ -1.80(2) was spread L27(11) 60 and over over 114-6-year 1.96(23) SM... .0.86 (6) period, but Pemales—Continued data are re- 1.00(47) ported in 1.41 (6) terms of 0.42 (2) 4-year inci- dence rates. Actual number of CHD inci- dents derived from data on incidence and total in smok- ing class, 27 TABLE 4.—Coronary heart disease (Risk ratios—actual number of CHD (SM = Smokers PROSPECTIVE STUDIES NS = Nonamokers Apthor, Number and Data Follow- Number of country, = typeof collection up incidents Cigarettes/day reference population years Jenkins, 3,182 males Initial ayy 104 myo- NS oo... 6222100 (22) etal, 39-59 years medical cardial EX oe. 2.47 (15) 1968, of age at examina- infarctlons. Current .. --2.78 (68) U.S.A. entry. tion and O-l5/day .. ~$1.39 (45) (90). follow-up 16 2.00221 3.08 (89) by repeat examina- tions. Kannel, 5,127 males Medical 12 228 myo- Myocardial Infarction etal, and females examination cardial Males 1968, 80-59 years and follow- infarc- NS wo... pa eneee 1.00 (21) U.S.A. of age. up. tions. All SM ........1.61(153) (94). 280 CHD. Heavy SM ....1.85 (59) Risk of CHD (overall) Males NS .. ++--1.00 (61) 1-10 .. --1.34 (25) 11-20 ........2. 1.80 (90) 20 2.00... 2.41 (76) Shapiro 110,000 male Baseline med- 3 Total Males etal, and female feal inter- unspecl- NS ............ 1.00 1869, eDrollees view and fled. All current ....2.14 U.S.A. of Heakh examination cigarettes (p<0.01) (178), Insurance and regular <20 Lee. 1.50 Plan of follow-up. 20 ........0., 233} Greater >40 0 22. 8.96 New York CHIP) 25-64 years of age. Keys 9,186 males Interviews 5 65 deaths. NS, EX 1970 in & coun- and regu- 80 myocar- (SM <20) ...1.00(306) Yugo- tries 40-59 lar follow- dial in- AU current alavia yearsof up examina- farctions. (20). 2.2. ..1.81(108) Pintand age at entry. tion by 128 angina Italy local pectoris. Nether- physicians 155 other lands _ Greece £428 total. (112). * Unless otherwise specified featations and the som of exclusion of either occasi 28 » disparities between the total number of mani- the individual amoking categories are due to the onal, miacellaneous, mixed, or ex-smokers, morbidity as related to smoking (cont.) manifestations shown in parentheses)! EX = Ex-smokers] PROSPECTIVE STUDIES—Continued Pipes, cigars Age variatfon Comments tinecludes non- (p<0.001) _ $9-h9 50-59 smokers and NS8......1.00 (4) 1.00 (6) ex-smokers. (p<0.001) Current 4.23(85) 2.28(83) NS inchuides (comparing former pipe O15 and 16+) and cigar smokers. Myocardial infarction-—Continued Females 1.00(31) 1.71 (23) Risk of CHD (overall)—Continued Females 1.00 (89) 0.86 (18) 1.29 (18) 0.93 (3) Females Males only Males Females Total myo- 1.00 NS ......1.00 S5-44 45-54 55-64 35-44 45-54 55-64 cardial in- 2.00 SM ......1.82 1.00 1,00 1.00 1.00 1.00 1.00 farction in- (p>0.01) (p<0.08) 2.47 3.06 1.69 2.26 2.87 1,80 cludes those 0.52 2.16 1.82 dead within wat 3.04 $29 1.81 126 281 1.65 48 hours. 5.92 10.09 7.69 5.80 20.26 11.79 4.07 NS include ex-smokers. Includes all CHD incidence includiag EKG diagnoses. Covers all countries in- vestigated except U.S.A. t Difference between total CHD and the sum of smoking groups is due to difference in figures presented by ‘authors. 29 TABLE 4.—Coronary heart disease (Risk ratios—actual number of CHD [SM = Smokers NS = Nonsmokers PROSPECTIVE STUDIES Author, year, Number and Data Follow- Number of country, tyne of collection up incidents Cigarettes/day reference population years Taylor, 2,571 male Interviews 6 46 deatha. NS and EX ....3.00 (62) etal. railroad and regu- 33 myocar- All current ....1.77(150) 1970 emphyees lar follow- dial-in- U.S.A. 40-59 up examina- farctions. (183). years of tion. 78 angina age at pectoris. entry. 66 other CHD, 212 total. Dayton 422 male U.S. Interviews upto8 27 sudden <0 2-2 ese... 1.00 (26) etal, veterans par- and routine deaths. 10-20 ..........1.04 (22) 1970, ticipatiog as follow-up 44 definite >20 ..........-).17 (13) U.S.A. controls in a examina- Myocardial (48,49). clinical trial of tions, infarctions. adiet high in unsatu- rated fat. Dunn 13,148 male Data only uptol4 Totalun- etal, patients in on new specified. 1970 Periodic heatth incidents U.S.A. examination extracted (55). clinics. from clinic records. Pooling 1,427 white Medical 10 538 Project, males 30-59 examination Includes Never emoked ..1,00 (63) American years of and follow- fatal and <10 .. 165 (72) Heart age atentry. up. nonfatal 20. - -2.08 (205) Association myocardial >20 ....----40. 3.28 (164) 1970, infarction U.S.A. and audden (an). death. Pauletal, 1,989 Western Sereening 1963, _Electrie Co. examination Coronary U.S.A. male workers and eases (£7) (148). participating history. 23° in a prospec- 2 tive stody 9 for 4% years. 6 47 3 9 3 Uniess otherwise specified, disparities between the total number of mani- festations and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. 30 morbidity as related to smoking (cont.) manifestations shown in parentheses)? : EX = Ex-smokers} - ' PROSPECTIVE STUDIES—Continued want ak - = Soke ae “Age variation . 3 “ Comments " Pipes , cigars vy {> ANI CHD oP including EKG diagnoses. - aoe a A abe? fst CoP Aha ONG SK 2 OO edaelyo Gt lt Nodataon Catgio Stans oom Bt nel Perinat: by cane . Stas ee bitty 4 parotaad group. wa e yy te i coeds - Clb dont : coast ; . tee tts 20-39. $0-49 50-59 t Includes oe ‘ ee how oe - NS, EX, and wot ae » SM 1.00(25) 1.00(125) 1,00(157) <20 cigarettes ‘ . . tHigh ert. th day. one ‘ - : SM 2.17(10) 0.90 (31) 1.41 (53) $220 ciga- r ty, cee ey ate ee be a. rettes/day. ; “ oe cee eee ns Includes all fag moma uo o CHD but 2 pon oe Sigcre JD. exeludes : . diese} foe Te death, ~ ‘ oo " ~ “ ‘ No data avail- bbe cla te ER vk to ae able comparing ~ 7 wry toe rey ba ai . . smokers and . , nonsmokers. “+ 1.00(53) 1.25 (54) 88 developed ’ elinica) - coronary | ° disease, a 47 angine 7 pectoris, 28 myocardial - . a infarction, ct Veni ue a7) t. 13 deaths CHD, ae Dt, studies have shown an increased risk of this manifestation among smokers, others have not (see table 5). From these longitudinal studies, it has become increasingly clear that cigarette smoking is one of several risk factors for CHD and that it exerts both an independent effect and an effect in conjunc- tion with the other risk factors. The basic concept may he ex- pressed as follows: The more risk factors a given individual has, the greater the chance of his developing CHD. The importance of the constellation of coronary risk factors which include cigarette smoking, high blood pressure, and high serum cholesterol in pre- , dicting the risk for CHD is illustrated in figures 1 through 3. Other risk factors are included in certain of these figures and are dis- cussed below. Knowledge of the effects of cigarette smoke on the cardiovascu- lar system has developed concurrently with the knowledge derived from the epidemiological studies. Nicotine, as well as cigarette smoke, has been shown to increase heart rate, stroke volume, and blood pressure, all most probably secondary to the promotion of catecholamine release from the adrenal gland and other chromaffin tissue. This release of catecholamines is also considered to be the cause of the rise in serum free fatty acids observed upon the in- halation of cigarette smoke. Studies concerning the effect of nico- tine on cardiac rhythm have also suggested that smoking might contribute to sudden death from ventricular fibrillation. In addition, research efforts have also been directed toward the effects of smoking on blood clotting and thrombosis; since many eases of sudden death and myocardial infarction are associated with thrombosis in a diseased coronary artery branch. Cigarette smoking may be associated with increased platelet aggregation in vitro and thus might play a role in the development of such throm- bi or platelet plugs in vivo, oO Other mechanisms have been investigated. Because cigarette smoking has been shown in some studies to be related to the prev- alence of angina pectoris as well as to the incidence of myocardial infarction, it has been suggested that smoking enhances the de- velopment of atherosclerotic lesions. Autopsy and experimental ' Btudies have shown that cigarette smoking plays a role in athero- - enesis. The administration of nicotine has been observed to in- crease the severity of cholesterol-induced atherosclerotic lesions in experimental animals. Attention is presently being given to carbon monoxide, which is present in cigarette smoke in such concentra- tions as to cause carboxyhemoglobin concentrations in the blood of smokers as high as 10 percent. Based on research in animals, it is reasonable to conclude that the atherosclerotic Process may be enhanced, in part, by the relative arterial hypoxemia in cigarette 32 ana ts TABLE 5.—Coronary heart disease morbidity as related to smoking—angina pectoris—prospective studies Kore Moe . : (Risk ratlos—actual number of CHD manifestations shown in parentheses)! te co Moy Vos: 7 [SM = Smokers NS = Nonsmokers} te nee Author, . . year, Number and .\ Data -, Follow-up Number Cigars - ” wy +) country, ° typeof *. collection > years of Cigarettes/day . and pipes wy a Age variation me Commenta | reference Population —“ ‘incidents —° : Ft : Ce Doyle 2,282 males, Detalled 10 BL ONS eee e eae 1.00 (80) el . cn NS include ex. etal., Framingham, - medical Ao, AM vice ce cee ceaee _e Oo(S1) 7 03 ” smokers and 1964, "80-82 years SS examinations Lek 80 sees even ees oLDT (IB) | a. ws SEs pipe and "OR USAN of age. wand) nah 20 ev eeeeseveees 0.09(18) ° Peet Re ORL ! elgar 5, (8S). 1,018 males, follow-up. % PLD cece cece eevee oDIB(1B) _- poe M ea Lr emokers. | 3 Albany, ‘.. m 7 : or i * ; o =f 39-55 years | a _ a we : Vorpou ; . of age, wr re ey ts Py : pee te eG mel . ron my ~"Jenkine 3,182 males Initial medical = 44g Be NS eee B00 (8), - NS Include : etal, .. aged $9-59 ©: examination - ’ All current , t-- former pipe 35 1968, atentry, 3 te and follow. - cigarettes .......1.44(16) | - 3 and cigar te USAS “. up by repeat» ©. csi PIE eee OSM) BS. < wmokers, 4 HOV. Fee \ examina- r wo 7 a eh Te NE tion, a ‘Kannel — 5,127 males _ Medical 12 - 107 Males , en andfemales -: examination =, 3: > NS tepeeeeee eens T00(16) . . ok woe! le " years of age ) and follow. - cote) we Heavy SM, >20 : : aw . 30-59 = : ’ cigarettes ........2.06(17) - ty 3 : - : - Females re : “4 i oe, vs NS cseeeeserereeee00(68) eS * 4 seh ME * Cigarette SM ....,.0.66(16) 7 02 . pee ie ; -Bhaplre 110,000 male Baseline er | Total Males Females Males . ., Males t(p<0.01) etal.) and female ia medieal ; \ Unepees NS .....46,.1,00 1.00 NS. ..1,00 Sk, Ba oe Uhh 45-84 88-84 (0 <0.05) iS rN “interview tice ae “s ffied Current a 7 SMELL. Ns uv aede lave i100 5 1.00 + 1.00 NS Include 5 New York City’: and examina. ee . Clgarettes {191 00-120 | Current clarettes 7.3.40 51.87 2.06 ex-amokers. v: HIP 85-64 ton and kg SMO eee BA 1200 KAO seeceeveepee e238 IMO LBA pox veare ofage regular os * 4d ee} 320°, >40 chenee tsi 1610. 15258 6.15 oe Lo —_ follow-up,” . ‘ “oy ” Females’ e . gel Poa I. a . : ae NS: beecuechech. “41.00 1.00 1.00" " wor ing nt SA AE ee - . mony ee = Current siearettee 1.88 C167 0.97 |: vom POSE Dee on Pos oe SAD eevee ee eee VelOT LOS 7 1L04- : ' PhO eecceerenee es — 412 ~ Unless otherwise specified, disparities between the. total number of . to the exclualon of either occasional, miscellaneous, mixed, or ex-amokers. “ .' Waanifestations and the sum of the Individual smoking categories are due smokers caused by the increased carboxyhemoglobin level. With respect to the acute event of myocardial infarction, atten- tion has been focused on the role of nicotine. Nicotine stimulates the myocardium, increasing its oxygen demand. Other experiments have demonstrated that in the face of diminished coronary flow ‘(due to partial occlusion from severe atherosclerosis in man or to partial mechanical obstruction in the animal), nicotine does not lead to an increase in coronary blood flow as seen in the normal individual. These effects exaggerate the oxygen deficit when the supply of oxygen has already been decreased by the presence of carboxyhemoglobin. Thus, a marked imbalance between oxygen demand (which has been increased) and oxygen supply (which has been decreased) is created by the inhalation of CO and nico- tine. This imbalance may contribute to acute coronary insufficiency and myocardial infarction. — EPIDEMIOLOGICAL STUDIES Numerous epidemiological studies, both retrospective and pros- pective, have been carried out in various countries in order to iden- tify the risk factors associated with the development of coronary heart disease (CHD). Many of these studies have included smok- ing as one of the variables investigated. Tables 2 to 4 present the major findings. | CORONARY HEART DISEASE MORTALITY Table 2 lists the various prospective studies concerning the rela- tion of CHD mortality and smoking. These studies demonstrate the dose-related effect of cigarette smoking on the risk of developing CHD. For example, the Dorn Study of U.S. Veterans as reported by Kahn (93) reveals progressively increasing mortality ratios, from 1.39 for those smoking 1 to 9 cigarettes per day to 2.00 for those smoking more than 39 cigarettes per day. Although the data are not detailed in the accompanying tables, several of these stud- ies have also shown that increased rates of CHD mortality are associated with increased cigarette dosage, as measured by the degree of inhalation and the age at which smoking began. Although not as striking, the data for females reveal the same trends. : In most studies, the smokers’ increased risk of dying from CHD appears to be limited mainly to those who smoke cigarettes. Some studies that have investigated other forms of smoking have shown much smaller increases in risk for pipe and cigar smokers when compared to nonsmokers. However, the recent study by Shapiro, et al. (172) of a large population enrolled in the Health Insurance Plan (HIP) of New York City showed a significantly increased 34. risk for the development of myocardial infarction and rapidly fatal myocardial infarction for a group consisting of both pipe and cigar smokers. _ Table 3 details the findings of the American Heart Association Pooling Project on sudden death. The Pooling Project, a national cooperative project of the AHA Council on Epidemiology, is de scribed in table 1 (88). Cigarette smokers in the 30 to 59 year age group incurred a risk of sudden death from CHD substantially greater than that of nonsmokers. Pipe and cigar smokers were observed to show a risk slightly greater than that of nonsmokers (table 3)... . The relative risk of CHD mortality is greatest among cigarette smokers (as well as among those with other risk factors) in the younger age groups and decreases among the elderly. In table 2, Hammond and Horn found that for those smoking more than one pack per day, the risk is 2.51 in the 50 to 54 year age group and 1.56 in the 65 to 69 year age group. Although the relative risk for CHD among smokers decreases in the older age groups, the actual number of excess deaths among smokers continues to climb since the differences in death rates between smokers and nonsmok- “ers continue to rise. Coronary HEART DISEASE MorBipiry Tables 4 and 5 list the prospective studies carried on in a num- ber of countries to identify the risk of CHD morbidity incurred by smoking. Here, CHD morbidity includes myocardial infarction as well as angina pectoris. Certain studies, notably those of Doyle, et al. (54), Keys, et al. (711), and Taylor, et al. (188) include a number of CHD deaths in their data that could not be separated out ‘using the information provided in their respective reports. As noted in the discussion on CHD mortality, the CHD risk ratio increases significantly as the number of cigarettes smoked per day increases. Similarly, the HIP data of Shapiro, et al. (172) show that the elevated morbidity ratios declined with increasing age as has been shown for mortality ratios. — A recent monograph edited by Keys (111) dealt with the 5-year CHD incidence in males age 40 to 59 from seven countries. As Summarized in table 4, cigarette smoking was found to be associ- ated with an increased incidence of CHD in the U.S. railroad worker population, 2,571 individuals (183). None of the differences in ratio between smokers and nonsmokers was statistically signifi- cant for the 13 other population samples which varied in size from 505 to 982 individuals, from the five other countries. (Smoking was not considered in the two Japanese populations.) When more cases 35 become available to provide greater statistical stability to the rates, this intercultural comparison should prove illuminating. The results of those studies which have separated out angina pectoris as a manifestation of CHD are presented in table 5. Doyle, et al. (54) found no relationship between this manifestation of CHD and cigarette smoking. Both Jenkins, et al. (90) and Kannel, et al. (94) observed increased risk ratios among male cigarette smokers although these’ differences were not statistically signifi- cant. More recently, Shapiro, et al. (172) found a significantly increased risk for angina among their male cigarette smokers as well as increasing risk ratios with increasing dosage among both males and females, particularly in the ‘younger age groups. A variety of hypothetical explanations have been advanced to account for this seeming contradiction. Among these are the relatively small number of cases, the difficulties associated with the definitive diagnosis of the syndrome, and differences in the methods of clas- sifying those cases of angina pectoris which are followed by mvo- cardial infarction. RETROSPECTIVE STUDIES Table A6 presents data from the various retrospective studies of CHD prevalence. Most of these are case-control studies and show an increased percentage of smokers among those with clinical CHD when compared with a selected control population, usually without apparent CHD. Two of these studies include data on mortality. THE INTERACTION OF CIGARETTE SMOKING AND OTHER CHD Risk FActTors ‘The preceding section has reviewed the epidemiologic evidence which supports the judgment that cigarette smoking is a signifi- cant risk factor in the development of CHD. Many of the studies discussed above have identified a number of biochemical, physio- logical, and environmental factors, other than cigarette smoking, which also increase the risk of developing CHD. These risk factors include elevated serum lipids ( particularly serum cholesterol) and hypertension, which, with cigarette smoking, are considered to be of greatest importance. Other factors are obesity, physical inac- tivity, elevated resting heart rate, diabetes (as well as asympto- matic hyperglycemia), electrocardiographic ‘abnormalities, and a positive family history of premature CHD (88). A number of these studies have also found that these factors, when present in the same individual, exert a combined effect on the risk of developing CHD. Figures 1 through 8 depict this inter- action of risk factors. As may be noted in Figures 1 and 2, the 36 additional factor of smoking greatly increases the risk of develop- ing CHD among those people already at high risk because of other factors. Furthermore, these studies have shown that the effect of smok- ing on the risk of developing CHD is statistically independent of the other risk factors. That is, when the effect of the other factors is statistically controlled, smoking continues to exert a significant effect on increasing the risk of developing and dying from CHD. Smoking and Serum Lipids The interaction of smoking and serum lipid levels in the develop- ment of CHD should be considered in the light of information con- cerning the relationship of smoking to serum lipid levels. Table AT presents studies which deal with the association between smoking and lipids, notably cholestervl, triglycerides, and lipoproteins (con- cerned with lipid transport). While some of the studies have indi- cated that smokers show increased serum levels of these lipid con- stituents, others have not. The populations investigated and the methods of the various studies show significant variation. This lack of comparability makes interpretation of the findings difficult. It is clear, however, that in the presence of high serum choles- terol, cigarette smoking increases the risk of. CHD. Figure 4 de- picts the data from the Chicago Peoples Gas, Light and Coke Com- pany study which show that smoking greatly increases the risk of CHD in each of the cholesterol groups. Smoking and Hypertension Some epidemiological studies have indicated that smokers tend to have lower mean systolic and/or diastolic blood pressures than nonsmokers, while other studies have not found this to be the case. (table A&). Reid, et al. (155), in a study of 1,300 British and American postal workers, found that the blood pressure difference between the smoking and nonsmoking groups was eliminated after. controlling for body weight. Tables 9 through 11, derived from the study by Borhani, et al. (27), demonstrate the following associations: That for both smok- ers and nonsmokers, the risk of dying from CHD increases with increasing diastolic or systolic pressure, and that the risk of mor- tality from CHD is higher among smokers than among nonsmokers in each blood pressure group. Cigarette smoking, therefore, has been shown to elevate CHD mortality independently both of its effect on blood pressure and of the effect of hypertension on CHD. Smoking and Physical Inactivity The recent study by Shapiro, et al. (172) of more than 110,000 37 TABLE 9.—Death rates from coronary heart disease, by systolic blood j pressure: a ILWU mortality study 1951-61 x on those 4 “(Coronary heart disease as classified under ISC Code 426) . . Smokers Nousmokers rage My de bo. 7 “ "12 Bystolle blood = Person-years Death - Person-years Death ~ -.* Age group 7 } Pressure in 1951 0 of obeervation rate? of chservation rete? M656 eeepc 170 ret) » 180-149 160-169 >170 :~ 3 p<0.026. #p<0.01 - ? TABLE 10. “Death rates from coronary heart disease, by diastolic blood pressure: ILWU mortality study, 1951-61 eee he oe, (Coronary heart disease as classified under ISC Code ¢20) a ease 4. Smokers : Nonsztwokers : . Diastolic blood Person-years Death Person-years Death ‘ pressure in 1861 of observation rate) of observation rated <80 (4h + «4,627 vals 26 (re | 80-89 ye, 221B a1 _ 2947 gs so 99 BR BR OT 32 D100 of dag cist gs vo 2020 2 er fT) 100 ope 869 oa 163 7 S54 . wet 3 Rate per 10,000 person-years of observation. 2 p<0.05. 2 p<0.01. —— a + Source: Borbani, N.O., etal. (27). ave . letn, ote FA le they aig TABLE rH —Death rates from ‘coronary heart disease, among hypertensives ond nonhypertensives: ILWU mortality study, 1951-61 2 . . (Coronary heart disease as classified under ISC Code 420) : oe vp Bes . Smokers . . Nonsmeokers T4nie eee cee peter: Blood pressure * Person-years ” Death Pereon-years Age group status? _ (Le of observation ‘rate? - of observation Hypertensives -.-- Nonhypertensives . Hypertensives ..- Nonbypertensives 1 According to the WHO recommendation, the following cut-off points are recommended for the Sefinition of hypertension: ° (1) Normotension—below 140/60 mm. Hg. * (2) Hypertension—aystolic blood pressure 160 mm. He. or over, or diastolic 95 ram. Hg. or over, or both. - (3) Borderline—the residual category. In this analbsis, Normotensives and Borderiincs were combined and the population | was ercuped into ‘Nonhypertensires" a and 3) and “Hrpertensives’ q). ae _ oe . to, 3 Rate per 10,000 person-years ¢ of obeervatioa. . ein tea : oS , - ay 5 p<0.01. : . ons iBe asset toe : od rs a “3 pn Souacz: Borhanl, N. O., et al (27). . . " lene 4. ‘Ne hmebe we £0 AS sie ist fo "Ss: gadZ 3 wed ybite.s ae 2st est 2 38 INCIDENCE PER 1,000 MEN 30-—- 70-— ALL NON NON NON SMOKERS SMOKERS SMOKERS SMOKERS SMOKERS SMOKERS <225 225-274 2754 225 225-274 2754+ CHD 46° 1 5 2 3 16 12 K 1329° 187 235 7 336 317 151 AGE 49 49 50 51 50 49 50 SYSTOLIC = 134 133 136 139 131 133 135 PRESSURE . WEIGHT 1.16 1.19 1.21 Lig Li 115 Ly RATIO Ficure 4—-Relationship between smoking status and serum cholesterol level at initial examination, and incidence of clinical coronary heart disease in men originally age 40-59, free of definite CHD, and followed subsequently without systematic intervention, Peoples Gas Light and Coke Company study, 1958-1962. *For 34 men, no information on smoking status was available; one of these men had a coronary episode. Source: Stamler, J., et al. (177)- persons participating in the Health Insurance Plan of New York City has further identified and elaborated upon the interaction of the various risk factors. Physical inactivity, both in employment and during leisure time, was found to be a potent risk factor for _the development of CHD, particularly for rapidly fatal myocardial infarction. Figure 5 depicts the effect which smoking exerts on CHD In combination with physical inactivity. Of note, also, is the observa- tion that within each activity grouping, smoking greatly increases tne risk of myocardial infarction, thus exerting an independent ect. Smoking and Obesity The analysis by Truett, et al. (190) of the risk factor data from the Framingham study revealed that weight, while a significant risk factor, had a considerably smaller effect on CHD incidence than serum cholesterol, cigarette smoking, or elevated blood pres- sure. The results concerning the interaction of smoking and obesity from the San Francisco longshoremen study are shown in table 12. 39 10.89 U0 ¢ 10.0 - 9.0 - Not b> wi n Bo 48 hes. 5.72 g ($7) 70 F NONCIQARETTE SMOKERS i 6.33 2 gol 5.78 7 60 bk i 3.76 § 4.0} (47) 4.48 3.03 . 166, 77 peed _ within 48 brs, ey 20 - 7 2.34 (218) 2.57 oF 1.30 en a 7 0.0L Least More Least More active active active active Note: Both for clgerstta smokers and noncigerette smokers differences betwaen rates among the feat more active men are statistically significant for totel Mi and rapidly fatet Mis at the 0.99 confidence « For other Mis the difference is statistically significant onty for the nonsmokers (confidence level 0.95). Ficurr 5—Average annual incidence of first myocardial infarction among men in relation to overall physical activity class and smoking habits (age-ad- justed rates per 1,000) (Actual number of deatha or myocardial Infarctions area represented by figures in parentheses) Source: Shapiro, 8., et al. (172). This table shows that cigarette smokers in the 65 to 64 year age Sroup were observed to have higher CHD death rates than non- smokers in all welght categories. Similar findings, although not in all weight groups, were observed for the 45 to 54 year age group. Cigarette smoking is thus shown to be a CHD risk factor indepen- dent of body weight. 40 TABLE 12.—Death rates from coronary heart disease among men unthout abnormalities related to cardiopulmonary diseases by weight classification in 1951: ILWU mortality stuly, 1951-61 (Coronary heart disease as classified under ISC Code 420) Smokers Nonsmokers Weight Person-years . Death Person-years Death Age group classification ! of observation rate = of observation rate? 45-84 2. Not overweight _ 388 21 279 1 Slightly overweight 962 28 1,096 0 Moderately overweight 1,383 28 1,574 28 Markedly overweight 1,055 22 1,797 o 53-44 -..-..... Not overweight 222 43 247 e Slightly overweight 536 15 “606 36 Moderately overweight 855 103 1,320 711 Markedly overweight 735 88 1,653 112 *The four classes are defined in the text. 7 Rate per 10,000 person-years of observation. 3p<0.01. Source: Borhani, N. O., et al. (27). TABLE 13.—Death rates from coronary heart disease, by electrocardiographic findings in 1951: ILWU mortality study, 1951-61 (Caronary heart disease as classified under TSC Code 420) Smokers Nonamokers Electrocardiographic Person-years Death Person-years Death Age group findings in 1951 of observation rate? of observation rate? 45-84 ......... Abnormal wen cece eee eee 586 102 1,020 39 Normal ............... _ 4,454 38 6,134 “15 55-64 22.2... Abnormal ............. 683 223 1,143 96 Normal ............... 3,031 86 6,478 731 1 Rate per 10,000 Person-years of observation, 7p<0_005. Source: Borhani, N. O., et al (27). TABLE 14.—1958 status with respect to heart rate, blood pressure, cigarette smoking, and 10-year mortality rates, by cause (1,829 men originally age 40-59 and free of definite coronary heart disease) Peoples Gas Co. Study, 1958-68 1958 risk factor status Ten-year mortality, 1958-68 Heart Cigarette Diastolic Number All causes . CHD” rate smoking pressure of men Number Rate Number Rate NH NH NH 378 20 148.3 5 112.0 H NH NE - 46 6 114.9 8 70.8 NH NH H 107 “4 118.3 6 “51.8 H NH H 30 8 221.6 3 52.0 NH H NH 491 87 116.8 19 38.9 H HR NH 127 22 VLI 8 62.3 NH H H 103 22 190.4 6 55.0 H H H 44 1s 265.4 ‘6 949 All 1,325 162 118.2 65 39.4 * Rate per thousand. All rates are age-adjusted by S-year age groups to U.S. male popalation, 1960.. High (H): Heart rate 280; 210 elgarettes per dey: diastolic blood pressure 290 mm. Hg. NH is not high, ie., below specified cutting points. 3 No smoking data available on 4 of the 1,329 men, Source: Berkson, D. M., et al. (£3). 41 TABLE 15.—The effect of the cessation of cigarette smoking on the incidence of CHD (Incidence ratios—actual number of cases or events are shown in parentheses) Author, year, country, Results Comments reference AU myocardial AU CHD events infarction Jenkins Never smoked eee eee eens 1.00(80) 1.00(21} etal, Current 1968 elgarette amokers ....... -2.36 (84) 2.78 (68) U.S_A. Former (90). cigarette smokers ....... -2.18 (19) 2.47 (15) Death from CHD Smoked >#0 Smoked 1-19 cigarettes/day cigarettes/day Hammond Never and Garfinkel, smoked regularly ...... 1.00 (1,841) 1.00(1,841) Male data only 1969, Current US.A. cigarette amokers .......1.90(1,063) 2.55 (2,822) (78). Stopped pack/day .. -- -1.65(34) 1.65 (72) for description Association TE pack/day ........22.2..1.70(86) 2.08 (205) of Pooling 1970, > pack/day ..............3.00(68) 3.28 (154) Project. U.S.A. Ex-mokers ......2.....004 0,80(19) 1.25 (51) (88). TABLE 16.—Annual probability of death from coronary heart disease, in current and discontinued smokers, by age, mazimum amount smoked, and age started smoking Age started smoking 15-18 20-24 Discontinued Discontinued Maximum daily Current for five or Current for five or Age ber of cign- smokers more years amokers more years nrettes smoked (Probability X10 *) BEA . ° 501 — 501 _— 10-20 798 BEE 811 551 21-39 969 766 872 698 €5-T4) 2... wees o 1,015 —_—_ 1,018 — 10-20 1,801 1,169 1,478 1,218 21-39 1,710 1334 1,578 1,098 * For are group 65-74, probabilities for discontinued smokers are for 10 or more years of dis continuence since data for the 5-0 year discontinuance group are not given. Source: Cornfield, J., Mitebell, 8. (48). Based on data derived from Kahn, H. A. (#5). 42 Smoking and Electrecardiographic Abnormalities Electrocardiographic (ECG) abnormalities such as T-wave and ST-segment changes as well as a number of arrhythmias are use- ful indicators of CHD and may, therefore, be predictive of the development of clinically over’ CHD manifestations. The results summarized in table 13, from the prospective study by Borhani, et al. (27), reflect the joint predictive value of smoking and ECG abnormalities on the death rate from CHD. Smoking and Heart Rate Recent analysis by Berkson, et al. (23) of the data derived from the Chicago Peoples Gas, Light and Coke Company study of middle-aged men revealed that resting heart rates of 80 or greater were associated with an increase in the risk of death from CHD. These authors found that this association was independent of the other major coronary risk factors. Table 14 presents the interaction between smoking, blood pres- sure, and elevated heart rate in increasing the risk of CHD mor- tality. This study shows that cigarette smoking increases CHD risk in the presence of elevated heart rate as well as in its absence. THE EFFECT OF CESSATION OF CIGARETTE SMOKING ON CORONARY HEART DISEASE A number of epidemiological studies have been concerned with the CHD incidence and mortality among ex-cigarette smokers as compared with current smokers (51, 76, 88, 90, 98, 172). These studies are listed in table 15. Table 16 presents the data derived by Cornfield and Mitchell (45) from the Dorn Study of U.S. Veterans (93). Ex-cigarette smokers show a reduced risk of both myocardial infarction and death from CHD relative to that of continuing ciga- rette smokers. The Pooling Project (88) and the Western Collab- orative Study Group (192) which adjusted for the other risk fac- tors of elevated serum cholesterol and blood pressure observed this relationship. Hammond and Garfinkel (76) noted that cessation of smoking is accompanied by a relative decrease in risk of death from CHD within 1 year after stopping. This decreased risk of CHD among ex-smokers further strength- ens the relationship between smoking and CHD. It must be noted, however, that the group of ex-smokers is composed of individuals who have stopped smoking for a variety of reasons. Those who stop because of ill health and the presence of symptoms are gen- erally at high risk and can bias the group results in one direction; 43 those healthy persons who stop as part of a general concern about their health and may adopt a number of self-protective health prac- tices are generally at low risk and can bias the group results in the other direction. Therefore, ex-smokers as a group are not fully representative of the entire population of smokers and may have limited value in predicting what would happen if large numbers of cigarette smokers stopped smoking purely for self-protection. Cer- tain incidence studies, such as the Pooling Project (88), were initi- ated with only clinically healthy individuals. The data from such studies, as well as those from the British physicians study, contain ex-smoker data less influenced by these biases. Fletcher and Horn (68) have recently presented data derived from the British physicians study of Doll and Hill. Over the past 10-15 years, cigarette smoking rates among British physicians have declined significantly in comparison with those of the general British population. The information presented by these authors concerning all cardiovascular diseases showed that for individuals between the ages of 35 and 64, the age-adjusted death rate for CHD declined by 6 percent among physicians and rose by 10 percent among the male population of England and Wales during the period from 1953-57 to 1961-65, THE CONSTITUTIONAL HYPOTHESIS The effect of smoking on the incidence of CHD has been found to be independent of the influence of the other CHD risk factors. When such risk factors ag high serum cholesterol (177), increased blood pressure (27), elevated resting heart rate (23), physical in- activity (172), obesity (27), and electrocardiographic abnormali- ties (27) have been controlled, cigarette smokers still show higher rates of CHD than nonsmokers. It has been suggested by some (89, 1 70) that the relationship between cigarette smoking and CHD has a constitutional basis. That is people with certain constitutional make-ups are more likely to develop CHD, and the same people are more likely to smoke cigarettes. This hypothesis maintains that the relationship between cigarette smoking and CHD is thus largely fortuitous and that the significant relationships are between the genetic make-up of the individual and CHD and between the genetic make-up of the indi- vidual and hia becoming a cigarette smoker. Two sets of epidemio- logic data bear on this hypothesis. It has been maintained that People with a certain temperament are more likely to smoke and also more likely to develop CHD. These characteristics have been demonstrated for those with the 44 Type A behavior pattern of Rosenmann, et al. (159) which is characterized by competitiveness, excessive drive, and an enhanced sense of time urgency. The prospective study organized by the Western Collaborative Group indicates that individuals who ex- hibit this type of personality are more likely to have or develop CHD than those without it (Type B), whether or not they smoke. When the incidence rates of CHD are analyzed with respect to smoking and personality types (tables A17, A18), it is noted that in both Type A and Type B individuals the incidence of CHD is greater among cigarette smokers than among nonsmokers. This research indicates that both personality type, as measured in these studies, and cigarette smoking contribute independently as risk factors to the development of CHD. To what extent such behavior patterns are determined constitutionally or represent acquired characteristics is still open to question. The other type of research designed to study the genetic hypoth- esis has made use of data from registries of twins. Cederlof, et al. (37, 38, 39, 40) have utilized the Twin Registries of Sweden and the Veterans Follow-Up Agency of the U.S. National Academy of Sciences-National Research Council to investigate the relative contributions of heredity and smoking to cardiovascular and bron- chopulmonary symptom prevalence. Data obtained by mailed ques- tionnaires were analyzed for the following characteristics: zy- gosity of the same-sex twin pair, urban-rural residence differences, smoking concordance, and history of various symptoms. Compari- sons were made between smoking discordant monozygotic (iden- tical) pairs and smoking discordant dizygotic (fraternal) pairs, and between unmatched twin pairs and matched twin pairs. Smok- ing discordance has been defined somewhat differently in various reports but, in general, describes twin pairs in which the smoking’ habits differ between the two members of the same twin pai: Analyzing the data obtained from 9,319 Swedish twin pairs (72.3 percent of the possible respondents), Cederlof, et al. ($9) found that respiratory symptoms were more common among smok- ers in both the unmatched and matched smoking discordant twin pair groups. The authors analyzed the data in two distinct man-' ners. Group A analysis, which did not control for genetic factors utilized two groups; the first composed of all the firstborn, and the second of those listed second on the birth certificates. Group B analysis utilized MZ and DZ twin pairs which were discordant for smoking, thereby controlling genetic factors. “Angina pectoris,” a8 defined by a certain pattern of responses to the questionnaire, was found to be more prevalent among smokers in Group A, but this” @ifference was not present when the data from Group B were an- alyzed. Males in the first group exhibited a “hypermorbidity ratio” 45 of 1.6, while those in the second group were found to have one of approximately 1.1. The authors concluded that this difference be- tween the two groups provides better support for the importance of constitutional factors as against the importance of cigarette smoking in the development of angina pectoris. A similar study was done using the responses of 4,379 U.S. Vet- eran twin pairs (approximately 60 percent of estimated available total) who completed the mailed questionnaires (88). Cederlof, et al. found a significantly increased prevalence of chest pain and “angina pectoris” among smokers when Group A’ was analyzed. Analysis of the smoking-discordant matched twin pairs (Group B) revealed no association between smoking and cardiovascular symp- toms among the monozygotic pairs. The dizygotic pair data did show a slight association. The authors concluded that this lack of association among the monozygotes and its presence among the dizygotes and unmatched pairs strengthens the case for a constitu- tional hypothesis. A major problem in these studies is the small number of cases available and, therefore, the statistical instability of the results. In the Swedish study, among the 274 monozygotes, only 19 smokers and 16 nonsmokers were classified as having angina pectoris while among the 733 dizygotes, 25 smokers and 25 nonsmokers were so classified. In neither group was the difference between the prev- alence ratios found in the Group A analysis and that in the Group B analysis of statistical significance. Analysis of the data on women shows a similar lack of significance. Similar criticisms may be made of the study which utilized the U.S. Veteran Twin Registry. In that study, the authors observed that the difference in the prevalence of angina pectoris between the low-cigarette-exposure and high-cigarette-exposure dizygotic groups was not present among the monozygotes. The authors ques- tioned whether the excess morbidity associated with cigarette smoking found in the dizygotic group was causal as it was not pos- sible to reproduce the association when studying monozygotic smoking-discordant twin pairs. As noted above, the numbers in this study are also gmail so that the differences in rates do not approach statistical significance. _ Libblin (188) has questioned the value of a mailed questionnaire to diagnose heart disease. The questionnaire as originally con- structed was used and validated by interview technique alone (157, 158). Cederlof, et al. (40) conducted a study to determine the validity of this questionnaire as a mailed instrument by personally interviewing and examining 170 of the twin pairs who had replied. Of the eight males who were diagnosed as having “angina pectoris” by the questionnaire. four were found to be free of symptoms on 46 clinical examination, while among 204 responding negatively, two were found to have angina by clinical criteria. None of the 11 women who were diagnosed as positive by questionnaire was found to be clinically affected, and of the 136 reporting as negative, three had symptoms of angina pectoris. Other major difficulties associated with these studies include the problems of using prevalence data in the investigation of a disease (CHD) from which a significant number of those affected die shortly after the onset of symptoms, the inclusion of ex-smokers in the smoking population, and the low numbers of heavy cigarette smokers in the Swedish population. In general, the problems of using twin registries to study the etiology of cardiovascular disease with mortality and morbidity ratios in the neighborhood of 2 to 1 are much more difficult than in studying the etiology of bronchopulmonary disease in which the relationships are of the order of magnitude of 4 to 1. More recently, Friberg, et al. (69) reported on mortality data from the Swedish Twin Registry. The authors suggested that part of the increased mortality observed among smokers when com- pared with nonsmokers was not due to smoking per se but to fac- tors associated with smoking. The very small numbers of total deaths presently available (47 deaths among 706 dizygotic pairs and 13 deaths among 246 monozygotic pairs) do not provide a sta- tistically stable base for deriving any conclusions at the present time. Hauge, et al. (81) have recently reported on the influence of smoking on the morbidity and mortality observed in the Danish Twin Register. Among 762 monozygotic and same-sexed dizygotic twin pairs, angina pectoris was found to be significantly more fre- quent in those cotwins with a higher consumption of tobacco than m those with a lower or no consumption. A similar tendency was observed for myocardial infarctions but was not of statistical significance. _ Seltzer, who has been a proponent of the constitutional hypothe- #18, In a recent review of some of the experimental, clinical, and “Pathological data relating smoking and CHD, concluded that the evidencé from these areas has not “reasonably substantiated” the “hypothesis” of the acute effect of cigarette smoking on the coro- nary circulation, nor has the chronic effect of cigarette smoking on the cardiovascular system been shown to be a “clear” and con- sistent one (170). His views are contrary to those of most re- searchers in this field. Although the data from the twin studies are inconclusive with regard to a role for genetic factors in heart disease, it would be surprising if genetic factors did not play such a role. It is open to 47 question whether findings from twin Studies can be used to distin- guish between the hypothesis that genetic factors govern the level of host susceptibility or resistance to the effects of an exogenous influence such as cigarette smoking and the hypothesis that genetic factors “cause” both heart disease and smoking. AUTOPSY STUDIES RELATING SMOKING, ATHEROSCLEROSIS, AND SUDDEN CHD DEATH A number of researchers have investigated the cigarette smoking habits and the cardiovascular pathology of those individuals dying suddenly from CHD and of large populations of individuals with and without histories of overt CHD. Spain and Bradess (175) recently analyzed the smoking habits of 189 individuals who died suddenly and unexpectedly, apparently from the first acute clinical episodes of CHD. The authors noted a close correlation of a history of cigarette smoking with this type of sudden death and also with shorter survival times following the acute episode. This association was strongest in those persons under 50 years of age. The authors also observed that those Surviving very short pe- riods of time showed a notable lack of intracoronary artery throm- bi at autopsy and that the frequency of thrombi present increased with increasing survival time. They suggested that thrombi found at autopsy may be the result rather than the cause of certain instances of myocardial infarction, Particularly of lesions showing subendocardial necrosis. This finding is of significance in the study of the effect of smoking on myocardial metabolism and oxygen supply and demand rather than on thrombus or platelet plug formation. While the autopsy study of Spain and Bradess (175) concerned sudden death among smokers, other autopsy studies from various dilov, ét al, (73), Sackett, et al. (165 ), and Strong, et al. (182) found that aortic and coronary atherosclerosis were more common and more severe among smokers than among nonsmokers. Auerbach, et al. (12) noted that this relationship persisted when the cases Were matched for both age and cause of death or when the follow- ing cases were excluded ; Men with a history of diabetes ; men who had died of any type of heart disease; and men whose hearts weighed 400 grams, or more. Sackett, et al. (165) found that the 48 64 TABLE 19.—Autopsy studies of atherosclerosis (Figures {n parentheses are number of individuals In that smoking category)! NS = nonsmokers} (SM = smokers Cigarettes per day Conclusions Comments Severity of aortic ecleroes Above average Average NB ovissecerees 9.9 (161) 60.2 S20 ceceeenees 1926152) 63.2 20-30 ..ccceuns 26.4(288) 62.5 80 cee neue f26.1 (199) 61.8 Below average 29.8 17.8 Mi $13.6 The authors conclude that in 60 percent of cases, the degree of asclerosls at autopsy was commen- surate with age of patient, regardless of smoking habita, In the remaining 40 percent there {fs ev!- dence that cigarette smoking may be asso- elated with an abovee average degree of sortie sclerosis, Smoking data unavailable for 120 cases, Each aorta specimen given an “atherosclerotic age” by comparison with a standard, If “athero- sclerotic age’ was found to be 10 years more than real age, the sorta was sald to show above. average aclercals, tp<0.001 comparing 9.9 with 26.1 and 29.8 with 18.6, Author, year, Autopay Data country, population collection reference Witens 989 consecutive Routine clinical and Plair, male autopsies records of 1962, at New York previous and USA, City VA present (88). hospitals. admiastons. Averbach, 1,872 autopsies Interview with etal, of male next of kin, 1986, patients in” U.B.AY, Orange, New (12), Jersey, VA hospital for whom smoking . habit data were _ available and who d{d not have overt CHD at death, Degree of coronary artery atherosclerosis (overall age- The authors conclude that adjusted results) No athero- : _acleroria’ = SUght NS veeeee e668 (68) --5e 57.8 Current elgarette <20 0.64 2.6(189) 80.9 20-89. 4.0.8 (299) 19.7 40 04605 .0.6 (144) 18.1 1 Unless otherwise specified, disparities between the total number of in- dividuala and the sum of the individual amoking categories are due to the exclusion of either occasional, talacellaneous, mixed, or ex-amokers, ‘Moderate Advanced | 21.8 87.8 ant 35.4 15.8 20.2” 87.4 45.9 + the percentage of men with an advanced degree of coronary atherosclerosls was higher among elga- ~ rette smokers than among nonsmokers and that the percentage Increased with amount of cigarette | smoking. This relation- ship persisted even when cases were matched for age and cause of death. os TABLE 19.—Autopsy studies of atherosclerosis (cont.) (Migores {n parentheses are number of individuals in that smoking category)? (SM = smokers NBS = nonsmokers) deathe 1956-1064 exclusive of 81 male pipe and clgar smoker and 65 income plete files. ‘Unless otherwise specified, disparities between the total number of Ine dividuals and the gum of the Individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-amokers. Aothor, year, Autopsy Data ~ ; gentry, population | collection Cigarettes per day Conchusions Comments Avtandiloy, 259 male and Not specified, Comparative eise of mean area of atherosclerottc legtiona The author concludes that Causes of death 96-athero- 1965, 141 female but there were: in inner coat of coronary arteries, the worst changes were sclerotic, 102-accldental, Ruaala autopsles. 180 SM and Right coronary artery Left coronary artery « found In the left and 202-varlous diseases. (18). 220 NS, SM NS right coronary arteries {T-test for significance 30=39 ... $15.5 (80) 1.3 (82) with less severe changes of difference between 40-49 .. $28.6(94) ° 13.6(27) in elreumflex artery means js significant 50-50 .. £86.3(89) 14.8 (89) and aorts. at p<0.05 level, 60-69 .. $81.91 32) 23.8 (86) 10-78 ., 41.9(18) 31.7 (86) Sackett, 893 total, Patient The resulta concerning aortic atheroaclerosis are given in The authors conclude that eal, | including 483 interview on form of figure presentation of ridit-analysis. among males, “.., @ 1963, male and 450 admission. large increase In the U.B.A. female (white) severity of aortic athero- (188), patients autop- sclerosis occurred in the nied at Roswell groups uslng either clea. Park Memorial rettes only or both clga- Hospital. rettes and alcohol aa Represents all compared with the group ualng neither clgarettes nor alcohol... there was only a small and statistically insignificant difference between the group using cigarettes alone and the group using both cigarettes and alcohol,. ooo The severity of aortic atheroscleroels increased with Increasing use of cigarettes, when measured both by In« tenalty and by duration of amoking. TS TABLE 19.—Autopay studies of atherosclerosis (cont.) (Figures in parentheses are number of individuals in that amoking category)! (SM = smokers NS = nonsmokers) Author, Auto Dat county, population collection Cigarettes per day Conclusions Comments reference Viel 1,150 males Interview with The resulta concerning Internal fibrous streaks and fatty The authors conclude that; etal, and 290 relatives, plaques in the left anterior descending coronary artery ‘No relationship be- 1968 females who are reported in graphic form only, An examination of tween atherosclerotic Chile died violently this data indicates that the moderate and heavy smokers lesions and the use of (£00) in 1961-1964, appeared to show consistently higher Percentages of tobacco was discernible,” Smoking infore diseased areas than the nonsmokers. But the atatement mation avall- of the authors implies that these differences were not able only on statistically significant when subjected to an analysis 566 males, of variance. Strong 747 males 20- Interview with Basal Group (excluding diseases related to emoking or The authors concludethat:; This report concerns only et al, 64 years of next of kin CHD), Mean percentage of coronary artery internal : “Atberoselerotle {n- ages 25-44. 1969 age autopaled within 8 weeks surface involved with raised lesions (number of cases). volvement of aorta and No data on statletical UBLA, betwen 1963- of death, White coronary arteries le significance provided. (188) 1866 at Charity 25-34 S554 45-55 55-84 greatest in heavy Hospital in NS Nec eecscsereaeereee 2 (8) 19(14) 20 (6) 80(11) smokers and least in New Orleans, 1-24 cigarettes/day .,.. 9(14) 17(10). 26(16) 89 (7) nonsmokers.” >26 cigarettes/day .,,.12 (9) 81014) 26(25) 89(20) Negro NS ce cccceeeeeee eee ACMA) 8 (8) 16CLL) 17 (14) 1-24 ciwarettes/day ...°. (39) 11(81) 14(80) 28(22) >25 clearettes/day eee17(10) 14017) 29(12) 16 (41) 1 Unless otherwise 3 ecified, disparities between the total number of in. dividuals and the sum of the Individual amoking categories are due to the exclusion of either occasional, miscellaneo us, mixed, or ex-smokers. severity of aortic atherosclerosis, as measured both by intensity and duration, increased with increasing use of cigarettes and that this dose-relationship persisted when the patients were matched for the consumption of alcohol. On the other hand, Viel, et al. (200) concluded from their study of accidental deaths in Chile that “no relationship between atherosclerotic lesions and the use of tobacco was discernible.” Examination of the data (provided in graph form only) indicates that heavy smokers showed consistently higher percentages of diseased areas than nonsmokers, but appar- ently these differences were not statistically significant when sub- jected to an analysis of variance. Thus, in addition to the acute effects which smoking exerts on cardiovascular physiology, cigarette smoking is associated with a significant increase in atherosclerosis. EXPERIMENTAL STUDIES CONCERNING THE RELATIONSHIP OF CORONARY HEART DISEASE AND SMOKING Several areas of interest in cardiovascular pathophysiology have been investigated in the search for the mechanisms by which ciga- rette smoking contributes to cardiovascular disease, particularly coronary artery disease. Previous Public Health Service Reviews (191, 192, 198, 198) have described in detail and commented on the results of experiments by many teams of researchers. Central to the discussion which follows is a concept of cardiac physiology which provides a framework for analysis and under- standing of the varied research. That concept concerns the dynamic balance between myocardial oxygen need and supply. CARDIOVASCULAR EFFECTS OF CIGARETTE SMOKE AND NICOTINE The inhalation of tobacco smoke or the parenteral administra- tion of nicotine has been found by many researchers to be asso- ciated with a number of specific acute cardiovascular resporises, These responses have been observed in human as well as animal Subjects, including increased heart rate, blood pressure, cardiac output, stroke volume, velocity of contraction, myocardial contrac- tile force, myocardial oxygen consumption, arrhythmia formation, and electrocardiographic or ballistocardiographic changes (tables A20 to A22). The effect of these responses on coronary blood flow will be discussed in a following section. That the acute effects observed following the inhalation of ciga- rette smoke are due primarily to the nicotine present in the smoke may be seen in the results of a number of experiments. In humans, Irving and Yamamota (89) and Von Ahn (202) duplicated the 52 effects of cigarette smoking by the administration of nicotine intra- venously. Similar results in animals were noted by Kien and Sherrod (112). ‘The mechanism by which cigarette smoke and hence nicotine in- duces these changes has been of interest to numerous investigators. Nicotine has long been known as a stimulator of both sympathetic and parasympathetic ganglia. Research has centered, therefore, on the function of catecholamines, mainly epinephrine and norepi- nephrine, as mediators, of these responses. Using isolated rabbit atrial myocardium, Burn and Rand (85) noted that the prior ad- ministration of reserpine to the perfusate blocked the increased rate and amplitude of contraction seen following the administra- tion of nicotine. West, et al. (208) showed that the in vivo cardiac stimulating effect of nicotine was blocked by tetraethylammonium chloride. Leaders and Long (125), Romero and Talesnik (156), and, more recently, Ross and Blesa (160) have all demonstrated this blockade in animals using agents such as pentolinium, hexa- methonium, guanethidine, and reserpine. More direct evidence of the catecholamine-releasing effect of nicotine has been found by Watts (203) and Westfall, et al. (209, 210, 211) (table A22). Among animal subjects, nicotine adminis- tration and the inhalation of the smoke of standard cigarettes caused significant increases in peripheral arterial epinephrine lev- els, while cornsilk cigarette smoke inhalation evoked no such change. In humans, cigarette smoking was found to be associated with a significant increase in urinary epinephrine excretion. The source of these nicotine-released catecholamines, particu- larly those which mediate the immediate and local cardiac re- sponses to intracoronary injections of nicotine, is felt to be the myocardial chromaffin tissue (35, 160). The more widespread effects are most probably mediated by hormones released from the adrenal gland. According to recent research of Saphir and Rapaport, catechol- amine release may not be the sole mediator of these responses (166). These investigators reported that intra-arterial injections of nicotine into the mesenteric circulation of cats were followed within 1 to 2 seconds by enhanced myocardial performance, in- creased left ventricular systolic pressure, and increased systemic resistance. Sectioning of the mesenteric afferent nerves led to a diminished response. The authors concluded that the cardiovascu- lar response to nicotine may also be neurogenic in nature. Nadeau and James (142) injected nicotine directly into the sinus node artery of dogs and noted an initial bradycardia, due probably to direct vagal stimulation, followed by tachycardia, due probably to catecholamine release. 53 That the presence of nicotine may predispose the myocardium, particularly a hypoxic or previously damaged myocardium, to ar- rhythmia formation is suggested by the research of Balazs, et al. (16), Bellet, et al. (27), and Greenspan, et al. (74). Balazs pro- duced myocardial lesions in dogs either by pretreatment with iso- proterenol or jigation of the anterior descending coronary artery. It was found that while normal animals did not develop arrhy- thmias upon challenge with smal} doses of intravenous nicotine, the animals with damaged myocardiums responded with increased arrhythmia formation shortly after their spontaneous arrhythmias had ceased. More recently, Bellet, et al. (20) studied the effect of cigarette smoke inhalation on the ventricular fibrillation threshold in anesthetized dogs. They observed a statistically significant de- crease in the threshold following smoke inhalation. Greenspan, et al. (74), using isolated dog right ventricular myocardium, ob- served that nicotine perfusion increased the automaticity of the Purkinje fibers system and decreased the conduction velocity. The authors consider that these two nicotine-induced effects probably predispose the myocardium to the initiation of arrhythmias. CORONARY BLoop FLOW Studies in animals and humans (tables A20, A21) have noted alterations in coronary blood flow (CBF) following the inhalation of cigarette smoke or the administration of nicotine. Generally, exposure of the normal subject to these agents results in an in- crease in flow. Kien and Sherrod (112), Leb, et al. (126), Ross and Blesa (160), Travell, et al. (189), and West et al. (208), working with normal animals, and Bargeron, et al. (17), working with normal humans, have demonstrated this response. As with the other cardiac responses to the administration of nicotine, it has been found that the augmentation in CBF is most probably due to the release of catecholamines. Using instantaneous coronary arte- ria] flow measurement in dogs, Ross and Blesa (160) were able to reproduce the effects of intracoronary nicotine with the adminis- tration of epinephrine and were able to block the response to nico- tine by pretreatment with pentolinium. The direct action of catecholamines on the coronary arteries may not, however, be solely responsible for the increase in CBF geen with cigarette smoking and intravenous nicotine administra- tion. It appears that the catecholamine-induced increase in myo- cardial work and therefore in myocardial oxygen requirement is a prerequisite for the increase in CBF. Kien and Sherrod (112), using tracheostomized dogs, found that without blood pressure and cardiac output changes CBF did not increase following either the inhalation of cigarette smoke or the administration of nicotine 54 intravenously, although CBF did increase following such changes. Recent work by Leb, et al. (126) has utilized Rb** as a radioactive marker in order to distinguish capillary flow from overall total CBF. The authors consider that this capillary flow represents that portion of CBF which is effectively involved in nutrient and oxygen exchange. The researchers observed that the increase in effective coronary flow was almost proportional to the nicotine- induced increase in myocardial oxygen consumption. However, the increase in total coronary flow which may be due to increased myocardial shunting was far in excess. Thus, the increased work evoked by the effect of nicotine on the myocardium may induce local hormonal release in the myocardium and coronary vessels leading to coronary vasodilatation and increased CBF. This homeostatic response to increased work appears to be fully effective only in the subjects with normal coronary arteries. Bellet, et al. (22), working with normal dogs and dogs that had under- gone either coronary artery ligation or artificially-induced coro- nary artery narrowing, noled that the increase in CBF following the intravenous administration of nicotine was significantly less among the animals with coronary insufficiency. Work with humans discussed above has revealed a similar increase in CBF with smok- ing in normals. Regan, et al. (154) studied seven men with EKG- proven myocardial infarction and observed that cigarette smoke evoked slight increases in myocardial oxygen consumption in only three patients and caused no overall rise in CBF. A number of other investigators have noted that patients with overt CHD do not respond to the stimulus of cigarette smoke ag readily as do normals (67, 149, 164). Thus, patients with compromised coronary circulation may not be capable of increasing their coronary flow in the face of the in- creased demands of a myocardium stimulated by nicotine or ciga- ‘rette smoke. In the normal state, the heart responds to increased oxygen demands by increasing coronary flow because even at rest oxygen extraction is almost at a maxima] level. Any further in- crease in extraction may produce coronary sinus pO, values incom- patible with proper tissue oxygenation. CARDIOVASCULAR EFFECTS OF CARBON MoNOxDE Carbon monoxide (CO) is a colorless and odorless gas, low levels of which have significant effects on human and animal physi- ology which are just now beginning to be understood. According ‘to Wynder and Hoffmann (215), it is present in cigarette smoke in concentrations of approximately 2.9 to5.1 percent, The concen- tration of CO in smoke is subject to many factors, among them 55 the type of tobacco and the porosity of cigarette paper. The con- centration of CO in smoke has been found to increase significantly toward the last puffs of the cigarette. According to Chevalier, et al. (41), a concentration of approxi- mately 4 percent CO in cigarette smoke will produce alveolar levels éf around 0.04 percent which, equilibrated with hemoglobin, result in carboxyhemoglobin (COHb) concentrations of from 3 to 10 per- cent. A number of investigators have compared COHb levels in smokers and nonsmokers. Goldsmith and Landaw (73) reported the analysis of expired air samples obtained from 3,311 Jongshore- men, Using a regression analysis, they calculated the concentra- tion of COHb and found that nonsmokers showed levels of 1.2 per- cent while those smoking over 2 packs per day had levels of 6.8 percent and that smokers of lesser amounts had intermediate levels. Occupational exposure accounted for the mean nonsmokers’ level being over 1.0 percent, an unusual finding in comparison with other studies. Kjeldsen (113) interviewed and obtained blood samples from 934 CHD-free smokers and nonsmokers. The mean COHb level for 196 nonsmokers was 0.4 percent while all inhaling smokers had a mean level of 7.3 percent. All 416 cigarette smokers, regardless of inhalation or amount smoked, showed a mean level of 4.0 percent. Carbon monoxide has many varied and significant effects on human physiology. An overall review of these effects may be found fn a discussion by Lilienthal (127) or more recently in an exten- sive review by the United States Public Health Service National Air Pollution Control Administration (194). Apart from its effects on respiratory and circulatory function, CO has been found to affect certain central nervous system functions adversely. These effecta are probably due to interference by CO with the proper oxygenation and oxidative metabolism of the tissue in question. CO interferes with oxygen transport in a variety of ways. First, the affinity of hemoglobin for CO is approximately 200 times greater than its affinity for oxygen, and thus CO can easily dis- place oxygen from hemoglobin. Second, CO shifts the oxyhemo- globin dissociation curve. By increasing the avidity with which oxygen is bound by hemoglobin, CO interferes with O, release at the tissue level. This is of greatest importance at the tissue level where the oxygen content of the capillary blood has been reduced to approximately 40 percent saturation. Here the shift can sub- stantially decrease the oxygen tension supplying the tissues. Third, and of more recent note, is the possible interference by CO with the homeostatic mechanism by which 2, 3-diphosphogly- cerate (2, 3~DPG) controls the affinity of hemoglobin for oxygen. Bunn and Jandl ($4) have recently reviewed the various experi- 56 ments concerning this glycolytic intermediate. The question of whether the low levels of CO present in the blood of smokers can affect this homeostasis is presently under investigation (29, 143), and firm conclusions cannot be drawn at this time. Apart from its effect on hemoglobin affinity, CO appears to induce arterial hypoxemia, and this may act as an additional cause of tissue hypoxia. Ayres, et al. (14, 15) observed unexpectedly that exposure of individuals to CO sufficient to ‘raise their levels of COHb to between 5 and 10 percent was associated with a signifi- cant fall in arterial pO Greater fall in venous pO; was noted, but this was considered secondary to increased tissue extraction. In a recent article, Brody and Coburn (30) suggested that this COHb-induced arterial hypoxemia was due to the interaction of a number of factors. These authors noted that in the presence of veno-arterial shunts or of an imbalance in the ventilation-perfu- sion ratio, the shift in the oxyhemoglobin dissociation curve in- creased the alveolar-arterial O, gradient and resulted in arterial hypoxemia. The presence of shunts as small as 2 percent of cardiac output as well as of approximately 10 percent COHb was found to cause an increase in the gradient. Such ventilation-perfusion (V/Q) abnormalities have recently been noted even in asymp- fomatic smokers (see Chapter on Chronic Obstructive Broncho- pulmonary Disease). The increased levels of COHb found in the blood of smokers may interact with these V/Q abnormalities to further decrease available oxygen. In normal individuals, coronary flow can increase to meet the increased oxygen demands of a stressed myocardium (as that under nicotine stimulation), while in individuals with severe CHD coronary flow cannot respond as readily. In such cases, myocardial oxygen extraction must be increased above the almost maximal extraction found at rest. Any interference with arterial oxygen levels or hemoglobin affinity could very well decrease available oxygen supplies below the level required for proper tissue func- tion. That this occurs is suggested by the experiments discussed. below. Chevalier, et al. (41) exposed 10 young nonsmokers to CO con- centrations sufficient to induce COHb levels of approximately 4 percent. Taking measurements from blood specimens obtained at cardiac catheterization under resting and exercise conditions, the authors noted that the ratio of oxygen debt to oxygen uptake in- creased significantly under conditions of increased COHb. Accord- ing to the investigators this implied that the same work was being done at a greater metabolic cost. These same authors (121, 122) had previously noted similar findings among smokers and observed 57 that cessation of smoking was associated with a significant im- provement in oxygen debt accumulation. More recent work by Ayres, et al. (15) has focused on the dif- ference in response to CO exposure between 7 normals and 4 pa- tients suffering from CHD (proven arteriographically) . The induc~ tion of a COHb concentration of approximately 9 percent in the normals was followed by an increase in coronary blood flow, a decrease in hemoglobin-oxygen percent extraction and no change in myocardial oxygen consumption, coronary sinus oxygen tension, ‘and lactate and pyruvate extraction ratios. The induction of simi- Jar COWb levels in the CHD patients was followed by no change in coronary blood flow, a decrease in the hemoglobin-oxygen ex- traction ratio, and no change in myocardial oxygen consumption. However, these patients did manifest a decrease in coronary sinus pO, as well as a decrease in lactate and pyruvate extraction. The latter measures indicate that the myocardium was functioning under hypoxic conditions. Because the coronary flow could not in- crease and because the myocardium could not extract O, from HbO, which was under the influence of CO, coronary sinus oxygen tension decreased to a point which could inactivate certain oxida- tive enzyme processes. Thus, the myocardial function of persons with CHD may be unable to compensate for the stresses induced by smoking. Although COHb levels resulting from the CO present in the atmosphere during periods of high air pollution are much lower than those due to the inhalation of cigarette smoke, these concen- trations of COHb might contribute to the manifestations of CHD. Cohen, et al. (44) studied the case fatality rates for patients ad- mitted to 35 Los Angeles area hospitals with myocardial infarction in relation to atmospheric CO pollution. The authors observed an increased MI case fatality rate in areas of increased pollution, and then only during periods of relatively increased CO pollution. An area of interest which has been discussed in previous reports concerns the presence of hydrogen cyanide in tobacco smoke. According to Wynder and Hoffmann (215), the amount present ranges from 11 to 32 micrograms HCN per puff. It is known that & significant amount of this material jg detoxified to thiocyanate and excreted as such in the urine or saliva. However, cyanide is a potent inhibitor of oxidative metabolism. Such inhibition of myo- cardial oxidative metabolism may be of importance when combined with the other factors mentioned above which tend to decrease the oxygen supply available and increase the need for oxygen on the part of the myocardium. 58 EFFECTS OF SMOKING ON THE FORMATION OF ATHEROSCLEROTIC LESIONS A number of autopsy studies have demonstrated a significant association between cigarette smoking and the presence of aortic and coronary artery atherosclerosis, even in men without a his- tory of clinical CHD. The possible pathophysiologic mechanisms for the atherogenic influence of cigarette smoking are discussed in this section. A number of investigators have studied the effect of nicotine administration, either subcutaneously or intravenously, upon athe- rosclerotic changes in the aorta and coronary arteries of animals (table A23). When administered alone, nicotine induces certain necrotic changes in the arterial wall. However, in combination with the administration of increased amounts of cholesterol in the diet, nicotine aggravates either subendothelial fibrosis (75) or definite atheromatous lesions (46, 75, 80, 180, 178). Studies by Choi (42) and by Wenzel, et al. (207) did not demonstrate this synergism between cholesterol and nicotine. The other major cigarette smoke component under discussion in this chapter, carbon monoxide, has also been recently implicated in atherogenesis. Table 24 presents the studies which have related exposure to CO in combination with increased dietary cholesterol to both macroscopic and microscopic aortic and coronary athero- matosis. Astrup, et al. (10) exposed cholesterol-fed rabbits to CO continually over a period of up to 10 weeks. The experimental group showed increased aortic atheromatosis over that shown by the control group, also cholesterol-fed. Kjeldsen, et al. (174) observed that exposure of rabbits to increased oxygen concentra- tions significantly reduced the amount of cholesterol-induced atheromatosis in rabbits. Most recently, Webster, et al. (204) have extended this research to primates. These investigators found that cholesterol-fed squirrel monkeys developed significantly more coronary artery atherosclerosis when exposed intermittently to CO over a 7-month period than when exposed only to room air. Recent discussion has centered on the mechanisms whereby CO can induce these changes (9, 212). Astrup (9), referring to pre- vious experiments in humans which had shown increased vascular permeability for albumin upon chronic exposure to CO (11), con- siders it likely that this increase in permeability allows for in- creased filtration of lipoproteins into arterial walls. This, he con- siders, is a primary cause of intima] and medial lipid accumulation and, therefore, of atherosclerosis. Another point of view has been stressed by Whereat (212), who considers the filtration theory to be an inadequate hypothesis for 59 TABLE 24.~—Experimenta concerning the atherogenic effect of carbon monoxide Author, year, eountry, reference Number and type of animal Procedure exposure and hypoxia Resulta Astrup etal, 1967 Denmark (10), 24 female alblno rabbits, Kjeldsen etal, 1968, Denmark (217), 24 castrated male albino rabbits, Kjeldsen etal, 1069, Denmark (114), Webster etal., 1970, U.S.A. (204). 24 castrated male albino rabbits, 22 female aquirre] monkeys, Regular diet plus 2 percent tholestero!: I. (12) control IL (12) continual exposure to carbon monoxide: 0.017 percent for 8 weeks, 0,085 percent for 2 weeks, Regular diet plua 2 percent cholesterol; I, (12) contro}, TH, (2) continua, sapusure, to hypoxia: 10 percent-0, for 6 weeks, 9 percent 0, for 2 weeka, Regular diet plus 2 percent cholesterol: TI. (12) control, IL, (12) exposure to 28 percent 05 for 10 weeks, Diet containing 0.8 percent cholesterol and 25 percent fat: I. (10) control, Tl. (12) experimentally exposed to 200-800 p.p.m. carbon monoxide for 20 houra per week for q Months, The experimental group exposed to carbon monoxide showed increased macro- and microscopi¢e aortic atheromatoats over that shown by eontrol animals, Micro~ scopic examination revealed {ntivnal Upold deposition LUmited fn penetration by the Interval elastic membrane. Coronary veesels were found to show similar changes, Carboxyhemoglobin (COHb) levels averaged S19 percent during the firat 8 weeks and 83 percent during the final 2 weeks, The experimental Broup exposed to hypoxia ahowed Increased Mmacroscople aortle atheromatosia over that shown by control animals, Microscopie examination re- vealed more intimal and subintimal Upid deposition tn the aortas of the exposed rabbits than In those of the nonexposed. The total amount of cholesterol! de posited In the aortas of the experimental group was three times higher than in those of the contro! group, Maoroscopieally, the experimental group showed changes, Microscopically, Intimal pid deposition. significantly fewer atheromatous the experimental group showed algnificantly less aortic The experimental group exposed to carbon monaxide showed &@ greater mean per centage of coronary arteries with atheroaclerotle lesfons and more lumen oce}us ston among the affected arteries, There were algnificantly more CO-treated monkeys than control monkeys having 85 percent or more apperent athero- sclerotic stenoals among the affected arteries. Aortic atherosclerosis was appar ently not aggravated by exposure to CO, COHb levels at the end of each expoeure perlod averaged 18-26 percent during the final 24 weeks of the experiment. mural lipid accumulation. The author notes that when the oxida- tion of the pyridine nucleotide, nicotinamideadenine dinucleotide (NAD), is impaired, the reduced form of this nucleotide (NADH) provides an essential factor for fatty acid synthesis. Fatty acid synthesis in the aorta and heart is carried out by mitochondrial enzymes whose hydrogen donor is NADH. Substances which slow or impair the reoxidation of this compound tend to increase mito- chondrial fatty acid synthesis (and decrease fatty acid utilization) in the arterial wall. Carbon monoxide prevents this oxidation proc- ess both directly and indirectly. Indirectly, it decreases the oxygen available for diffusion into the tissue. Directly, carbon monoxide can stall the process of NADH oxidation by combining with cyto- chrome oxidase. Further research is required into this problem, particularly in view of the fact that cyanide is also a respiratory chain inhibitor and thus may also adversely affect arterial wall fat metabolism. THE EFFECT OF SMOKING ON SERUM Lipm LEVELS In the discussion concerning the epidemiological aspects of CHD, it was noted that increased serum cholesterol was. 2 significant risk factor for the development of overt CHD. Serum triglycerides have also been related to CHD incidence. Of concern also is the immediate effect which cigarette smoking has upon blood lipid levels. The studies concerning this immediate effect are presented in tables A25 and A 25a. The table is divided into a section concern- ing studies on humans (table A25) and one concerning studies utilizing animals or in vitro systems (table A 25a). Although no consistent response was noted for serum cholesterol, serum fre¢ fatty acids were found consistently to rise following smoking, As with other cardiovascular reactions to nicotine and smoking, it appears that the fatty acid response is also mediated by catechol- amine release. This relationship has been observed in a number of experiments by Kershbaum, et al. (105, 106, 108, 109, 110) and Klensch (118). That nicotine is primarily responsible for this rise may be seen by reference to the study by Kershbaum, et al. (105) in which lettuce-leaf cigarettes of minimal nicotine content had a negligible effect upon serum free fatty acids in comparison with that of regular cigarettes. While attention has been centered upon nicotine as the agent inducing the immediate increase in serum lipids, recent studies have been concerned with the effect of chronic exposure to carbon monoxide on serum lipid metabolism. These studies are listed in table A26. Among rabbits fed increased amounts of cholesterol, 61 the authors observed significant increases in cholesterol and tri- glyceride concentrations in those exposed to CO versus those maintained in a normal atmosphere. THE EFFECT OF SMOKING ON THROMBOSIS In the study of CHD, a number of investigators have turned their attention to thrombosis because myocardial infarction and sudden coronary death frequently result from thrombotic events. A thrombus may be of either gross or microscopic dimensions, and a minute thrombus at a strategic site may precipitate a fatal-ar- rhythmia. However, thrombotic and prethrombotic states are dif- ficult to detect except when gross, and the emphasis has been pri- marily on factors which can be studied conveniently. Coagulation is now thought to have a secondary role in the consolidation of an arterial thrombus and little if any in initiating the process. The prime mechanism in thrombogenesis appears to be the reaction of the platelet. Severa] papers have been written about platelet re- activity in vitro but few about the effect of smoking on platelet behavior in vivo. The assay of fibrinolysis, which may also be im- portant, has received scanty treatment. The relevant studies are listed in table A27. Many of these are discussed in the 1968 sup- plement (192) and by Murphy (140). Corroborative data are still inconclusive as to whether smoking shortens platelet survival. OTHER AREAS OF INVESTIGATION Certain other aspects of cardiovascular pathophysiology may be of importance in the relationship of smoking to CHD. Glucose me- tabolism and insulin response, when altered, may alter myocardial response. This topic has been covered in detail in the 1968 Supple- ment to the Health Consequences of Smoking (192). Also, varia- tions in. blood hemoglobin and hematocrit may adversely affect coronary blood flow. A number of studies showing a possible rela- tionship of smoking to hemoconcentration have been reviewed pre— viously (197, 192), and the reader is referred to those discussions. CEREBROVASCULAR DISEASE The term cerebrovascular disease (CVD) refers toa number of erent types of vascular lesions affecting the central nervous system: subarachnoid hemorrhage, cerebral hemorrhage, cerebral embolism, and thrombosis (ICD Codes 330 to 334). In 1967 in the United States; a total of 93,071 males and 109,113 females were listed as dying from CVD as the underlying cause (196). Epidemiological studies indicate that cigarette smoking is asso- 62 ciated with increased mortality from cerebrovascular disease, whether CVD is listed as the underlying or as a contributory cause of death. Table 28 presents the results of the seven major epidemi- ological studies. The smoking of pipes and cigars does not appear to increase significantly the risk of dying from CVD. The impor- tance of high blood pressure and diabetes as risk factors for mor- tality from CVD has recently been noted by Hammond and Gar- finkel (76). The data from their study, as presented in table 28, also indicate that the mortality ratio for cigarette smokers is greater for persons under 75 years of age than for older individuals. Many of the pathophysiological considerations discussed in the sections concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction. In a study reported by Kuhn (123), 20 habitual smokers re- frained from smoking for one-half day, and base line retrograde brachiocerebra!l angiograms were taken; they then smoked one cigarette, inhaling deeply, and had repeat angiograms. Those over 60 years of age failed to have significant acceleration of flow as demonstrated in carbon dioxide inhalation experiments. More recently, Miyazaki (132) studied the effect of smoking on the cerebral circulation of 12 moderate/heavy cigarette smokers a8 measured indirectly using an ultrasonic Doppler technique to record internal carotid artery flow. Measurements were made be- fore and after ordinary smoking and showed an increase in cere- bral blood flow and a decrease in cerebral vascular resistance in all subjects. No significant difference in response was observed between the 4 younger and 8 older (over 60 years of age) subjects. More research is needed to clarify the role of cigarette smoking in the acute pathogenesis of CVD manifestations. However, the chronic effect of smoking upon the cerebral circulation (particu- larly its extracranial portion) is likely to be similar to the effect of smoking upon the aortic and coronary atherosclerosis, NON-SYPHILITIC AORTIC ANEURYSM Aortic aneurysm is an uncommon but not rare cause of death. In 1967 in the United States, a total of 8,448 men and 3,173 women were listed ag dying from aortic aneurysm as the underlying cause (196). Cigarette smoking appears to increase the risk of dying from this disease, perhaps by promoting the atherosclerotic proc- @ss which underlies this type of aneurysm. As illustrated in table 29, the mortality ratios for cigarette smokers are high relative to other cardiovascular diseases in which smoking increases the risk, and the risk increases in proportion to the amount smoked. 63 49 TABLE 28.Deaths from cerebrovascular disease related to smoking (Mortality ratios—actual number of deaths shown in parentheses)? NS = nonsmokers) (SM = smokers PROSPECTIVE STUDIES 1 Unless otherwise epecified, disparities between the total number of deaths and the sum of the individual smoking categories are due to either occasional, miscellaneous, mixed, or exegmokers, the exclusion of Number of Anthog, : Follow. deaths due Pipes year, Number and Data ‘up «6 toOVDas Clgarettes per day and Age variation: Comments country, type of collection Yeara underlying elgars reference population cause Hammond 187,783 white Questionnaire 344 1,060 NS ...,....3.00 (164) t(p<0.01), and Horn, males ing and follow. Cigarettes 1958, states 50-69 up of death SM ....,.¢2.80 (656) U.S.A... years of age, certificate, OtherSM ,.1.26 (880) (77, 78), Cigarettes only <10 o....0..024 (41) 10-20 .....53,44 (140) P20 cerca 146 (83) Doll and Approximately Questionnaire 10 605 NS .......,.1.00 Bil, 41,000 male and follow. AN SM ......1.06 1964, British up of death All Great physicians, certificate, elgarette © 1.12 Britatn 1-140 00.0. 50.10 (80). 16-24 205..61,09 25 ARE Kanne} 8,127 males Medical 12 W°ONS oo... + 1.00 (8) Data apply only etal, and females examination Heavy SM to males 30-89 1985 30-59 years and follows (>20) ..,.3,28 (8) years of age U.S.A, of age. up. atentry. (96), Data apply only to cerebral} Infarction, TABLE 28.—Deaths from cerebrovascular disease related to emoking (cont.) (Mortality ratloe—actual number of deaths shown In parentheses)! {SM = emokera NS = nonsmokers) PROSPECTIVE STUDIES Number of Anuthor, deaths due Pipes year, Number and Data Follow. underlying Cigarettes per day and Age variation Comments country, type of collection ap years to CVD as cigars - reference population cause Kahn, U.8. male Questionnalre 8% 2,008 NS wise eeeed O00 (614) Pipes 1966, veterans and follow. All 8M. .1.08 (82) U.S.A, 2,265,674 up of death current ....1.80(1,894) NS ..1.00(614) (9s). person certificate, Current Cigare years. cigarettes ..1.52 (692) NS ..1.00(614) 1-9 .....,. 0.61 (88) SM ..1,08 (185) 10-20) .4...4.42 (925) 21-89) 4....3.70 (215) S39 sce aeee 1.59 (87) Hammond 858,584 males Questlonnaire 6 4,099 Current {Based on only and 445,875 and follow- regular Males 5-9 deaths. Garfinkel, females 40-79 up of death eigaretta 40-49 80-59 80-68 = TO-79 1989, years of age certificate, Never U.S.A. atentry, amoked = 1.00 1.00 1.00 1,00 (76). WO cee BD 1.95 1,80 0.95 10-19 .....2,14 1480 Lda 0.92 20-89 0 221 2.08 1.62° 1.22 “S400 200 1 64 2.40 172 = 0.68 Females Never amoked = 1,00 1.00 1.06 1.00 1-8 0610. 1,80 1,26 1,26 0.88 10-19 ..,..2.60 2.70 2.45 40,57 20-89 .....2.90 2.87 1,88 1,28 >40 .....f5.70 8.52 — — 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual amoking categories are due to the exclusion of elther occaslonal, miscellaneous, mixed, or ex-emokera. TABLE 28.—Deaths from cerebrovascular disease related to smoking (cont.) (Mortality ratios—actual number of deaths shown In parentheses) SM = Smokers, NS = Nonamokers, PROSPECTIVE STUDIES Paffene 3,268 male Initial multi. 16 87 NSand barger, Jongshoremen phasle 20 ee N00 (42) etal. 85-64 years Bereening P20 veces ee eLlS (25) 1970 of age ln and follow. U.S.A. 1951, up of death (145). certificate, RETROSPECTIVE STUDY Paffen- 50,000 male = Initial college Death Rates barger University entrance Cases (158) Controls (618) and atudents medical ex. SM cee ee cee ee senses eee 48,0 81.8 (p<0.01) Willams followed up aminations Cigarette SM >10 per day . 20.9 14.2 (p<0.01) 1967 to 50 years. with follow. USB.A, up of death (148), certificate, Controls— surviving classmates age-matched, The 63 deaths from occlusive atroke contributed to the statistical alge nificance, The 95 deaths from hemorrhagic atroke showed no statlatical significance ag asingle group, 1 Unless otherwise specifi and the sum of the individ either occasional, miscellan ed, disparities between the total number of deaths ual smoking categories are due to the exclusion of eous, mixed, or ez-amokers, £9 TABLE 29.—Deatha from nonsyphilitie aortic aneuryemrelated to amoking—prospective studies (Mortality ratlos—actual number of deaths shown in parentheses)! (SM = Smokers NS = Nonsmokers} A tan Number and Data Follow-up Number country, type of collection years of Cigarettes per day Pipes Cigars Commenta reference Population deaths Hammond 187,783 white Questionnaire 314 68 NS .,.......1.00(25) (expected) and Horn, males in and follow-up SM o..44455.2.72 (68) (p<0.006) 1988, states 60-69 of death U.S.A. years of age. certificate. (77,78). Kahn, U.S. male Questionnaire 84 491 NS viceeceeeesee eee 200 (58) NS ..1,00(58) NS ..1.00(58) 1966, veterans and follow-up Current cigarettes ....5.24(234) SM ..1.13 (8) SM ..2,06(24) U.S.A. 2,265,674 of death 1-9 cigarettes/day ...2.12 (13) (8s), person years. certificate. W020 cuvsc rene ence ee B53 (124) 21-89 i cece eee ene 695 (76) DID ec e eee ene ee ee eo T26 (17) Hammond $58,534 males Questionnalre 6 837 NS vee ee ee ene 100 Data apply only and 445,875 females and follow-up M9 cee ee ne 262 to males 50-69 Garfinkel, 40-79 years of of death 10~19 cee ae ee BBS years of age. 1969, age at entry. certificate. 20-39 eee te aa 5d U.S.A, DAD vce e ena e oe B.00 (78). Weir and 68,183 California Questionnaire 6-8 BL ONS cece ence ee 00 SM Include Dunn, maale workers and follow-up AML cee ce cence ae S64 ex-emokers, 1970, 85-64 years of of death SLO Loe ue cece ZAd NS include pipe U.S.A. age at entry. certificate, H20 vec ee eee 288 and cigar (208), E90 cave eens ee 2.54 smokers, 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the {ndlvidual categories are due to the exclusion of elther occasional, miscellaneous, mixed, or ex-smokers, PERIPHERAL ARTERIOSCLEROSIS Peripheral arteriosclerosis represents the effects on the vascu- lature of the extremities of the pathophysiologic processes which produce coronary and aortic atherosclerosis. A number of studies have been concerned with smoking as a risk facter in the develop- ment of this disease. Kannel, et al. (95) observed, in the Framing- ham study, that diabetes mellitus and elevated serum cholesterol, as well as cigarette smoking, were also risk factors in the develop- ment of peripheral vascular disease. Juergens, et al. (92) reviewed the records of and contacted 478 male patients with arteriosclerosis obliterans (a severe form of peripheral arteriosclerosis), who had been patients at the Mayo Clinic between 1939 and 1948. The diagnosis of this condition was based upon certain clinical criteria: the presence of intermittent claudication, the marked diminution or absence of lower extremity arterial pulsations, and objective trophic manifestations of per- ipheral limb ischemia. Smoking information was available on 401 patients. These patients were compared with a control group of 350 Mayo Clinic patients of similar age who showed no clinical evidence of vascular disease. It was found, for males under the age of 60, that 2.5 percent of the cases and 25 percent of the con- trols were nonsmokers. However, no difference was noted between the percentages of heavy smokers in each group. The authors also implicated high blood pressure and elevated serum cholesterol as risk factors in the occurrence of this disease. Begg (19) noted similar findings in a study of 294 male patients with intermittent claudication who were patients at the Western Infirmary in Glasgow, Scotland. In comparing the smoking his- tories of 100 patients with this complaint with those of 116 healthy male controls, the author found that 1 percent of the patients and 21 percent of the controls had never smoked. A total of 42 percent of the patients smoked more than 20 cigarettes per day while only 24 percent of the controls had a similar history of heavy smoking. The author concluded that smoking, while not a prime cause of peripheral arterial disease, is a significant cofactor in its develop- ment in almost all cases. The author also noted obesity, high blood pressure, and elevated serum cholesterol as risk factors. Schwartz, et al. (168) compared the prevalence of risk factors in four groups of subjects: 141 cases with arteriosclerotic disease of the lower limbs, 551 cases with coronary arteriosclerosis, 58 cases with both conditions, and finally an indefinite number of control individuals who had been hospitalized for injuries. The in- vestigators reported that certain risk factors, including hyper- cholesterolemia, hypertension, and cigarette smoking, were signifi- 68 cant in both coronary and lower limb arteriosclerosis. The authors noted that the inhalation of cigarette smoke appeared to be an important risk factor for coronary arteriosclerosis up to age 55 while in arteriosclerosis of the lower extremities, inhalation ap- peared to increase the risk even in the older age groups. Widmer, et al. (213) compared 277 male patients with arterial occlusion of the limbs as demonstrated by aortography or oscillog- raphy with 2,082 men demonstrated by oscillography to be free of arterial disease. The authors found that cigarette smoking, parti- cularly heavy smoking, was significantly more frequent among the cases with arterial occlusion than among the controls. Increased beta-lipoproteins and systolic hypertension were also found to be more common among the cases. EXPERIMENTAL EVIDENCE A number of experimenters have investigated the acute effects of smoking or nicotine upon the peripheral circulatory system. These investigators, as listed in table A30, have measured effects in terms of alterations in skin temperature and blood flow as meas- ured by plethysmography, radioactive iodinated albumin clear- ance, or radiosodium clearance from the skin. The majority of these studies have shown significant decreases in peripheral blood flow and skin temperature upon smoking, particularly in persons without manifest peripheral vascular disease, The study of Freund and Ward (68) demonstrates the difference in peripheral vascular reactivity found between normals and patients with arterioscle- rotic changes in the vessels of their extremities. The work of Strémblad (181) on blockade of this response with automatic sys- tem blockers indicates that the reactivity of these vessels is sec- ondary to the local release of catecholamines. Most probably, the degenerative changes associated with this disease create a stiffen- ing of the vessel wall and prevent rapid alteration, particularly dilatation, in response to the catecholamines liberated by smoking or nicotine. THROMBOANGIITIS OBLITERANS Thromboangiitis obliterans (Buerger’s Disease) (TAO) is an uncommon obstructive vasculitis primarily involving the arteries and veins of the extremities. Severely affected patients may even lose their limbs secondary to ischemic changes. Much discussion has centered upon the question as to whether this disease is a clin- ical and pathological entity separate from, peripheral arterioscle- rosis. McKusick, et al. (128) consider it to be a distinct entity 69 while Eisen (57) concludes that TAO is the acute inflammatory phase of severe arteriosclerosis. Clinically, it has been shown that smoking aggravates this dis- ease and cessation of smoking frequently aids in complete or par- tial remission. Razdan, et al. (153) and Brown, et al. (32) found very few nonsmokers in groups of patients diagnosed as having typical TAO. A recent study from Israel (16) involved a case- contro] comparison of 46 patients with TAO and 32 matched con- trols. Although the controls were found to smoke less per day than the patients, this difference was not found to be statistically sig- nificant. However, 100 percent of the smoking patients and only 72 percent of the smoking controls were inhalers, a difference sig- nificant at the 0.02 level. CARDIOVASCULAR DISEASES SUMMARY AND CONCLUSIONS CORONARY HEART DISEASE 1. Data from numerous prospective and retrospective studies confirm the judgment that cigarette smoking is a significant risk factor contributing to the development of coronary heart disease including fatal CHD and its most severe expression, sudden and unexpected death. The risk of CHD incurred by smokers of pipes and cigars is appreciably less than that by cigarette smokers. 2. Analysis of other factors associated with CHD (high serum cholesterol, high blood pressure, and physical inactivity) shows that cigarette smoking operates independently of these other fac- tors and can act jointly with certain of them to increase the risk of CHD appreciably. 3. There is evidence that cigarette smoking may accelerate tne pathophysiological changes of pre-existing coronary heart disease and therefore contributes to sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking ig associated with a significant increase in atherosclerosis of the aorta and coro- nary arteries. 5. The cessation of smoking is associated with a decreased risk of death from CHD. 6. Experimental studies in animals and humans suggest that cigarette smoking may contribute to the development of CHD and/ or its manifestations by one or more of the following mechanisms: a. Cigarette smoking, by contributing to the release of catechol- amines, causes increased myocardial wall tension, contraction 70 velocity, and heart rate, and thereby increases the work of the heart and the myocardial demand for oxygen and other nutrients. b. Among individuals with coronary atherosclerosis, cigarette smoking appears to create an imbalance between the increased needs of the myocardium and an insufficient increase in coro- nary blood flow and oxygenation. ec. Carboxyhemoglobin, formed from the inhaled carbon mon- oxide, diminishes the availability of oxygen to the myocardium and may also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hypoxemia, thus reducing the amount of oxygen available to the myocardium. e. Cigarette smoking may cause an increase in platelet adhesive- ness which might contribute to acute thrombus formation. CEREBROVASCULAR DISEASE 1. Data from numerous prospective studies indicate that ciga- rette smoking is associated with increased mortality from cerebro- vascular disease. 2. Experimental evidence concerning the relationship of smok- ing and cerebrovascular disease is at present insufficient to allow for conclusions concerning pathogenesis. However, some of the pathophysiological considerations discussed concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction. NON-SYPHILITIC AORTIC ANEURYSM Cigarette smoking has been observed to increase the risk of dying from nonsyphilitic aortic aneurysm. PERIPHERAL VASCULAR DISEASE 1. Data from a number of retrospective studies have indicated that cigarette smoking is a likely risk factor in the development of peripheral vascular disease. Cigarette smoking also appears to be a factor in the aggravation of peripheral vascular disease. 2. 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G0 or over + G4R (431) 61.8 (327) (not significant) {60). male noneCHD Controls: Alluges » GOK 66.3 (p<0.06) patients, wame year of udmis- sion age matched, Mills and 474 white male Undefined. 40-49 50-59 60-69 7Oorover 40-49 50-59 60-69 70 or over Porter, coronary deaths. (58) (135) (153) (130) (216) (188) (id) (83) 1967, Controls: 606 NS tenaee LTA 6.66 18.30 35.84 19.91 24,47 35.09 64,12 U.S.A, white males, Allcigarettes os... ees 83.93 82,23 45.02 18.44 70,83 89.94 43.86 16.47 (isi), Pipes, cigars 8.93 HLL 32.68 47.70 9.26 16.47 21.05 25.41 Buechley Males reporting Question- 20.4 (23) NS veneers AZL(BE) etal. CHD to California natre and . GLY (69) M20 ee eee AGT (56) 1958, Health Survey interview. 18.5 (21) seeve ee Lh6 (14) U.S.A. with matched (39). controls from Bame survey (included those surviving first myocardial infarction). 06 TABLE A6.—Coronary heart discase morbidity and mortality—retrospective studies (cont.) (SM = Smokers (Actual number of cases shown in parentheses)? NS = Nensmokers EX = Ex-smokers]} Author, year, Number and Data country, type of collection Cases (percent) Controls (percent} Comments reference Dopulation Russek and 97 male and 3 Interviews Tobacco waaye>9u cigurettcs/day Patients Zohman, female coronary by 70 percent. 35 percent. included 99 1958, patients, Controls: authors, with classical USA. 100 healthy controls myocardial (169), of similar age, infarction sex, occupation, and li with and ethnic origin. Angina pectoris. Spain and 269 males identified 3,000 males NS... 8000 (BL) 29,0 (172) Nathan, as having CHD by in New <40/day seen 29.0 (7B) 33.0 (870) 1961, physicalexumination York City >40/day ....,....13.0 (93) 9.0 (234) (p<0.06) U.S.A. and history. Controls: interes EX ooe cece 14.0 (99) 14.0 (361) (176). 2,637/3,000 males Viewed and Cigar, pipe .......14.0 (38) 16.0 (400) identified as examined Total wo... 100,0(269) 100.0( 2,637) not having CHD by medical group. Muleahy and 400 ma‘-s less than Interview, Matca Males Control smoking Hickey, 60 years of age with . 4.60 (18) 18,2(110) data obtnined 1967 elussical CHD. Data \ . 90.76 (363) 70,6 (427) from estimnted Treland compared with male ties 4.75 (19) 11.2 (68) amoking habits (35,146). population con. » 100,00 (400) 100.0(605) of Irish sumption figures. population of same age group. Schwartz 612 male patients Interview, Average amount 18.8 (p<0.0001) Data apply only to etal, with angina or laboratory, per day as 6.0 those under $5 1966, myocardial and cigarettes ...,,. 18.6 yeurs of age. France infarction, cliniealexs ANISM ,.... (169). 612 age-matched aminations, Inhalers ......... »69.0 controls, 45,0(p<0,00001) 16 TABLE AG.—Coronary heart discase morbidity and mortality—retrospective studies (cont.) {Actual number of cases shown In parentheses)? (SM = Smokers NS = Nonamokera EX = Ex-smokeras] Author, year, Number and Data country, type of collection Cases (percent) Controls (percent) Comments reference population Villiger and 100 casey with Hospital Malea(7%) Femalea(23) Malea(72) Females (28) Theye are not pure Heyden- recent myocardial history or NS viccece scene Servet e ewe res 6.94 Wd $26.0 82.1 amoking classes. Stucky, infarctions, interview, Cigarettes... cece cece eseneaee 66.7 28.6 45.8 14.3 tip<0.01) 1966, 72 malex, 28 females, 1-19 cigarettca/day ............, 1B. 10.7 23.6 10.7 Swit- 100 age-matched >20 79 $22.2 36 ger. controls (72 male Cigar, pipe 27.8 oe land industrial EX $16.3 3.6 (201). employees and 28 females in hospital for other dingnoses), Dorken, 205 males up to 44 Death cer- NS wiv... 1.0 (2) 18.4 (76) Ex-samokers listed 1967, years of age with tificate re- Cigarette Unita under nonsmokers, Germany myocardial infarc- view. In- 1-5 usec eee eee. 1B (38) 10.4 (43) Smoking information (52). tion or sudden terview of WO-18 o....5260...92.2 (62) 46.5 (192) available only on death (139 deceased, patient 20-30 2 ....06605..43,8 (84) 22.5 (93) 199/205. These 66 living). Controls or kin. 8B eee eee eee 21.8 (42) 22 (9) cigarette categories —Hamburg age- 100.0(193) . 100.0(413) include nvined ov cigar matched citizens * (only 28 were mixed (62 were mixed or smokers recaleuinated selected randomly, or cigar smokers) cigar smokers) as tu number of ciga- rettus. No patients or controls smoked pipes exclusively. Dorken, 33 females up to Death cer- Cigarettes per day 1967, 44 years of age tificates, DO eerseaeeee eee BL (2) 63.2(84) (p<0.001) Germany with myocardial inter. 1-5 . 17,3 (23) (53). infarction or sudden views, 6-15 - 48.5 (16) 16.5 (22) death. Controls—133 20-380... cee. 39.4 (13} 8.0 (4) formales 27-44 years >36 G1 (2) of age from clinic without CVD or lung cancer, Z6 TABLE AG.—Coronary heart disease morbidity and mortality—retrospective studies (cont.) (SM = Smokers (Actual number of cases shown in parentheses)? NS = Nonsmokers EX = Ex-smokers] Author, year, Number and Data country, type of collection Cases (percent) Controls (percent) Comments reference population Hyams 79 males surviving Interviews NS voce e cece eee 10.1 (9) 21.0 (33) etal, myocardial infarc by trained 1-9 cigarettes 1967, tion. 157 ages personnel, per day 10,5 (13) Japan matched controls 10-15 2.0... 33.9 (42) (87), hospitalized for non- 16-20 J... cee ae 26.8 (32) CVD but include 21-44... 17.7 (22) hypertensive disease, D836 w... 12.2 (15) ALL SM vo ees 200.0 (Th) 100.0(124) Mulcahy 100 female patients Hospital SM vevec cess eee 83.0 (69) 45.6 (261) Smoking on controls etal, Jess than 60 years interviews. NS . 33.0 (33) 45.3 (259) obtained from 1967, of age admitted to EX w.eceaaee > 400 (4) 9.1 ($2) stulistics of Treland hospital with CHD. Total ..... 100.0(100) 100.0 (572) emoking in (137) Trish Repubtic, Sudden death not ineluded, Stejfa, 70 male and Direct Prevalence of risk factors Authors then fullowed 1967, female patients interviews. Angina patients Control group the 70 puticnts for Poland with recent onset 60.0 3 years and noted (179). exertional angina 48.1¢p>0.1) that smoking signifi- pectoris, 54 controls cantly influenced of same age, the incidence of coronary occlusion, Schimmler 503 males with Hospital NS reves 90 (44) 26.0(187) (p<0.001) etal, healed myocardial interviews, EX ......... ..12,0 (59) 20.0(142) (p<0.001) 1968, infarctions. 714 male Cigar, pipe ...... 12.0 (62) 14.0 (77) Germany controls of same age <19 cigarettes ~ .25,0(129) 14.0(101) (n<0.001) (267). without detectable 20 ccc ee ee 42.0 (209) 29,0(207) (p<0.001) heart disease. Total .,..,100,0(503) 100.0(714) oO We TABLE AG.—Coronary heart disease morbidily anid nrortality—retrospective atudies (cont.) (Actual number of casey shown in parenthoves) + {SM = Smokers NS = Nonsmokers EX = Exeamokers} Author, year, Number and Data country, type of collection Cases (percent) Controls (percent) Comments teference population Hoodetal., 230 males surviving Interview ' (230) (865) 1969, early first myocardia) and exam- Never smoked ....1.75 24.2 Sweden infarction, Controls: ination. EX before (85). 855 randomly selected infarction ...... 1.75 , 19.7 males 50 years of EX after age. infarction .....29.1 <6 cigarettes ...28.3 27.4 >15 cigarettes ...22.6 20,0 All cece cee eee 80.0 47.4 Pipe .........00, 16.5 8.8 Jouve 1,229 CHD patients: Interview. 43.0 13.0(p<0.0001) etal, 802 males, 427 1969, females. Controls: France 743 individuals of (91). both sexes; age, aex, and social class matched, Kastl, 275 male railway Interview NS wee trae 20.0 (65) 29.8 (82) 1969, employees up to 65 and exe 2-20 cigarettes or Germany years of age sur- amina- up to 6 cigars.. ..92.0 (88) 63.3 (82) (92). viving myocardial tion. >20 cigarettes or infarction. 275 con- >6 cigars, .......48.0(192) 6.9 (19) trol employees with minor circulatory disturbances, Unless otherwise specified, disparities between the total number of cases and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers, 76 TABLE A7,—Differences in serum lipids between smokers and nonsmokers (Actual number of individuals shown in parentheses)! [SM = Smokers NS = Nonsmokers] Author, year, Number and country, type of Results Comments reference population Gofman 401 male Difference between SA and NS tSf refers to Svedberg etal, employecs Ages 20~29 Ages 30-39 Ageas0-59 flotation units of 1955, 20-59 years Lipid: (NS 55, SM 37) (NS 66, SM 67) (NS 17, SM 44) centrifuged Jipoproteing, U.S.A, of age. St 0-12 +s $59.9 p0.00l +19.9 p0.0s + 39 p<0.05 (72£), Sf 12-20 > $+ 9.4 poo.ool + 5.4 pco.0s — 3.5 p<0.05 Sf 20-100 + $20.0 p0.025 + 9.1 p<0.05 + 8.5 p0.05 Sf 100-400 - +15.8 p0.025 +121 po0.0s — 4.5 pf0.05 Cholesterol » $212 p0.0s + 9,0 pco.0s — 4.8 p<0.05 Thomas, 521 medical Serum cholecaterol mg, percent 1958, students. NS (264) SM (257) U.S.A. Observed/Expected Obeerved/Expeeted (185). <250 170/157 149/161.6 >250 Se Cree eee eae es 87/$9.6 115/102.4 Chi Square Value = 5.2 p<0.025 Dawber 2,253 males Scrum cholesterol mg. percent The authors conclude that etal., participating 29-h4 45-59 there is evidence of a 1959, inthe Framingham NS bee 216.1 (149) 228,3(131) gradient of cholesterol with U.S.A. study 29-59 All cigarettes 224.8 (874) 229.5 (589) increasing amount of cigarctle (47), years of age. sees 2IT.4 (75) 229.1 (76) smoking in younger men, \ soe 2201 (194) 230.1 (96) 226.8(651) 227,8(350) 229.0(114) 258.5 (68) 2149(128) 227.1 (166) Karvonen 526 males in Serum cholesterol my. percent The authors slate that no etal, various Weat Finland Rust Finland Heloinki trend was note mssocinting 1959, becupntions NS ieee c cect eee te ner yenes 208,0(64) 226.0 (39) 235.1 (62) increasing aniwunt smoked with Finland 20-59 yours SM Cece treet ences QAR COED 249.7(103) 257.8(166) increasing serum cholestero}, (97), of age, although smokers and nonsmokers did have different overall levels S6 TABLE A7.—Differcnces in serum lipids between smokers and nonsmokers (cont.) (Actual number of individuals shown in parentheses)! {SM = Smokers NS = Nonsmokers] Author, year, Number and country, type of NResulty Comments reference population Acheson 221 randomly Mean aerum cholesterol Mean Beta/Alpha and Jessap, chosen pensioners mg. percent Upoprotein ratio 16! 65-85 years of NS ccc eee cette ete ve es 2440638) 2.0(36) Ireland age, Secigavettes/day oo... .c ce cece eee eres 201(12) 20012) (fh). VD cece cece ee eter renee 213 (94) 1.9(33) 20 eee etree eter tener neces 201639) 1.9 (35) P30 ete teense eee 206 (8) 1.8 (8) Bronte Approximately Cholestcral mg. percent Retu/ Alpha Upoprotein ratio No data given on numbers in Stewart, G00 healthy 25-39 40-55 25-39 40-55 each group, 1961, mules 25~55 tA tk A BE A E A E tA—Afriean, South years of age, NS ww... eee. 179 197 222 0 246 249 3.34 3.76 4.69 tE—European, Alrion “Heuvy' SM... 1K6 220 204 236 3.82 4.40 4.07 5.40 (gst) Kontlinen, 314 male military Scrum cholesterol Serum phospholipids No serum lipid differences 162, reeruity 18-25 mg. pereent mg, percent found omong the various Finland years of age. NS ccc ee eee CUS) eee eee eens 200.8 218.0 smoking groups, (1g), (Cigarettes per day) 1-10 (83)..........,5.. 200.8 222.3 11-19 terete cece CBA ee eee ONS 224.7 Pk cette eee eee (G2). ...., cercese 202.3 210.6 Blumstrand and Lundman, 1s, Sweidlen (26). 76 munuzygolice twin pairs and KT dizygotic twin pairs obtained from Swedish Twin Registry. I, Monozygutes discordant for smoking: Smokers showed slightly lower levels of cholesterol, triglycerides, and phospholipids than nonsmokers, If. Dizygotes discordant for smoking: Smokers showed significantly higher levels of phospholipids. No differences for cholesterol and triglycerides. The authors conclude from the differing MZ and DZ results that constitutional factors are probably more important than amoking in determining lipid levels. 96 Tape A7.—Differences in serum lipids between smokers and nonsmokers (cont.) {Actual number of individuals shown in parentheses}? {SM = Smukers NS = Nonsmokers} Autbor, year, Number and country, type of Results Commenta reference population Fidanza Vo male prigoners Serum choleaterol mg. percent No statistically algnificant etal, 34-69 years of Ages C39 40-49 50-59 60-69 differences found between 166, ake. NS lisse cseee eee . 195 (12) 189 (10) 176 (7) SM and NS, Traly “LW cigarettes/dsy cic vcse evens 208(8) 201(16) 202(13) 195 (10) (62). D>20 cigarettes/day ....sseeeeeaes 197 (6) 175 (7) 171 (7) Serum triglyceridce mg, percent NS cicaev eee renee $4.7 9 85.0 <20 cigarettes/day 84.6 99.4 101.9 89.8 >20 cigarettes/day 91.0 86.0 65.7 Kedra and 200 clinically Serum cholesterol Phospholiptda Total lipida Serum cholesterol also noted Dmowski, henlthy males mg. percent mg. pereent mg. percent to increase with increasing 1966, 20-50 years of NS(100) ....... eee 170.2 268.1 1,234.8 intensity and duration of Poland ue. SM 100) vscsevevees ze} POOL asa.ge P7006 vasa} PSO0L smoking. (9s), Heta-lpoproteins Total futty acids percent of total mg, percent tipoprotcine NS(100) ..cceee eves YTS 43.1 SM 100) .eccese eee woof PSO. wat p 10 cigarettes/day 240.0 (166) 180.0 £6 TaBLe A7.—Differences in serum lipids between smokers and nonsmokers (cont.) (Actual number of individuals shown in parentheses)?! {SM = Smckers NS = Nonsmokers) Author, year, Number and country, type of Results Comments reference population Higgins 5,030 male und Males Females and Kjelsterg, fomale residents NS icc ee cere renee 209.9 (360) 210.1 (1,439) 1967, uf Tecumsch, Cigorette .i.cseuee Se ceec cere ev cveeeneeee 212,602,426) 212.4 (910) U.S.A, Michigan, 16-79 (8d), years of age. Pincherly 2,000 men Percentage with serum = The authors noted that amokers and Wright, participating in Serum cholesterol cholesterol >270 showed significantly bigher 1967, executive health mg, percent mg. percent {p<0,001) aerum cholesterol England examinations NS (677) 236.2 19.0 levels than nonsmokers, (150). 28-70 years of Ex-smoker (388) ...-....0-.55 oe 246.0 28.0 age. 1-19 cigarettes/day (424) oo. cc cee eee ee 239.2 24.0 >20 cigarettes/day (SLL)... cece eee eee 249.4 30.0 Van Buchem, 918 randomly chosen Serum cholesterol The authors found no 1967, males 40-5Y yoars 0-209 mg, percent 210-249 mg. percent 3250 mg, percent correlation between smoking Netherlands of age for entry NS icseccecceveecevecee 22.4 (32) 14.0 (44) 14.2 (41) and serum cholesterol levels. (199), into prospective CigaretteSM ......... 71.6 (184) 67,.8(213) 68.2(197) study. Other wecseweeee 16.0 (41) 18.2 (67) 17.6 (61) Buyle et al. 1,104 male factory Serum cholestera Scrum Beta-lipoprotein Beta-lipoproteina were found 1968, . employees 20-64 mg. percent mg. percent to inerease with age, but U.S.A. yenrs of age. NS ccs ec ceca ee cece neers veces 243(519) 0.925 smokers had higher levels P28), SM cece eect e ne asi tste) f b<0.005 asi} P<0.001 than nonsmokers at all ages. Caganova 49 males living Serum cholesteral Serum Beta-lipoprotein etal, in youth hostel, mg. percent mg. percent 1968, 21.6 average axe, NS(34) cee eae e eee Devens 188.20 359.80 Czechoslovakia SM (15) cece ccvcc een eunceseauns 214.20) ¥<0.025 1a2toy P<0.001 (36). Beta/alpha lipoprotein ratio NS(94) .... oe ‘ SM (15) 86 TABLE A7.—Differences in serum lipids between smokers and nonsmokera (cont.) (Actual number of individuals shown in parentheses)! {SM = Smokers NS = Nonemokers] Author, year, Number and country, type of Resulta Comments refcrence population Modzclewskt 140 males 20-68 Serum-cholesterol Serum Seta-lipoproteine Serwm free fatty acids and Malee, years of age, NS (20) p<0.01 NS p<0.01 NS pool 196, Heavy amokers Heavy umukers lleavy smokers Poland | (28), Kjeldsen, 934 employees of Serum choleaterol mg. percent 1969, various firms NS (196) 236 Denmark in Copenhagen, SM (738) 2a P<0.01 (413). Potner 4 male and Scrum cholesterol Serum triglycerides Total Phospholipide Significant figures refer to and Billimoria, female healthy : | mg. percent mg. pereent mg. percent heavy smokers as compared 1970, volunteers 19-30 NS(20) wc... cc ceee) 196.3 68.6 193.4 with nonsmokers. England years of age. Light SM(17)0...., 0 1721 68.4 188.9 (151). ver 7.3 iGlgarettes/day) Heavy SM(27) «2... 200.0 pc0.06 87.6 p>0.05 215.0 p<0.001 (Over 22.5 1Uniess otherwise specifi and the eum of the indiv} of elther occasional, cigarettes/day) ed, disparities between the total number of cases dual smoking categories are due to the exclusion miscellaneous, mixed, or ex-amokers, 66 TABLE A8.—Blood pressure differences between smokers and nonsmokers (Actual number of individuals ahown in parentheses)? (SM = Smokers NS = Nonsmokers) Author, year, countty, Number and type Results Commenta reference of population Dawber etal., 1,253 male Systolic blood preasure No association found 1969, U.S.A, and female Agee 29-44 45-59 between aystolic blood (47). residents NS(19) ec ce cee et eee eeee renee nnre weseee 138.8 143.0 pressure and amoking, of Framingham. Cigarettes(874)) wo... : . vee 182.5 140.3 S1LOCTE) vce ce cee ee 194.2 144.0 10-19(434) ........, 129.4 141.6 20~39(651) oe eee ee 132.2 138.9 PAOCIMA) oseee eee ee ve 136.1 141.6 Pipe and cigar (128) 135.0 141.9 Edwarda et al., 1,737 male Proportion of males with “Hypertension” (2200/2100 mm, Hg.) 1969, England patients of NS woes. 27.2 percent (161) (86). general prac- Cigarettes 20.5 percent (780) titioners over Pipe ieee e ccc ecce en neueeves 23.9 percent (341) 60 years of age, Karvonen et a}., 625 males in Systolic blood pressure No duta on pipe and 1959, Finland various regions Weat Finland Laat Finland Helainks cigar smokers, No (97), of Finland NS .,, 139.2 (64) 142.6 (39) 132.8 (62) statistical significance 20-59 years of SM . 133,2(91) 135.4 (103) 129,8(166) noted. age. Diastolic blood pressure NS sees 84,7 86.8 89.6 81.9 84d 86.8 Clark et al., 1,859 male civil Mean syatolic Mean diastolic Nonsmoker and smoker 1967, U.S.A. servants, blood-preagure blood-pressure groups were of similar (43). NS (728) © 137.0 83.9 average age, SM (407) iat (p=0.05) east (p350.06) OoT TABLE A8.—Blood pressure differences between smokers and nonsmokers (cont.) (Actual number of individuals shown in parentheses)? (SM = Smokers NS = Nonsmokers)} Author; year, country, Namber and type ' Results Comments reference of population Higgine and 5,030 male and Age adjusted Age adjusted Kjelsburg, female residents mean eyatotic blood pressure mean diastolic blood preasure 1967, U.S.A. of Tecumseh, Michigan, Males Females Males Females (a3), 16-79 years of age, NS ........187.8 (360) 84.5 (1439) 186.6 (960) 82,1(1439) (p<0.001) Clemrette 2960411426) 81.4 (810) 131.6 (1426) 79.0 (910) pe. Reid et al., 676 male British Mean eyatolic blood preasure The author did note 1967, England and 625 male (adjusted for difference in weight) AMcan diastolic blood pressurc SM-NS blood presaure dif. (155), American postal UK ULS.A. UK U.S.A, ferences prior to workers 40-59 NS .......128.2 (45) 124.8 (80) 79,3 81.0 controfling for weight, years of age. 1-14 gramg 130.2 (27) 183.0 (60) 79.4 82.1 but not after auch control. 16-24 grams 128.6 (232) 127.7 (169) 78.6 11.3 >25 grams 127.9 (70) 128.1 (218) 17.6 WA All amounts 129.1 (519) 128.6 (447) 78.7 78 Tibblin, 1967, 895 males in Blood pressure 215-145/ 150-170/ Numbers in parenthcses Sweden Goteborg, Sweden, 110/370 (89) 75-95 (468) 100—110(220) > 175/>115(78) represent total in blood (187), bor in 1913, NS wee ee cece eae see TBO 23.0 25.5 34.7 pressure group. I-14 cigarettes ...........29.2 29.2 25.5 18.7 The author noted >16 cigarettes .......,...28.1 20.9 15.5 17.3 a stepwive decrease with Pipeandcigar .,.......,,11.2 86 10.0 4.0 level of blood pressure _ As smoking increased. ‘Unless otherwise specified, disparities between the total number of in- dividuals and the aum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokera. TOT TABLE A17,.—Incidence of new coronary heart disease by smokin (Numbers in parentheses are number of CHD cases in each subgroup) g category and behavior type for men 39-49 years of age Smoking group Former Current and Cigarettes Behavior Never cigarette former pipe type smoked smokers and cigar only 1-16 16-25 26 and over Total Ca 15.3(5) 13.8 (7) 1.3(1) 1.6(1) 15.8 (15) 14.9(16) 9.3( 46) |: . 1.3(2) 6.1 (3) 2.2(2) 7.3(4) 3.1 (3) 49 (4) 3.3(18) Total 2.9(7) 9.1(10) 1.8(3) 4.9(5) 9.3(18) 10.4(20) 6.2(63) Analysis of variance table Source Sum of squares dt. Mean square F Pp Within cells ...... Cenc e rete e cena 69.471 2,245 0.026 oe oe Regression on age ......... 0.458 1 0.458 17.296 0.002 Between smoking froups? 0.504 5 0.101 3.81 0.002 Between behavior types? .... breve eee 0.329 1 0.329 12.43 0.001 Interaction oo... cee eee cee 0.396 5 0.079 2.99 0.011 ‘Rates are age-adjusted annual incidence per 1,000 men. > Mean squares for “between smoking groups” and “between behavior types" are each computed eliminating the general mean and the other main effect but ignoring interaction, thus yielding an estima fect unconfounded by other significant main effects, Source: Jenkins, C. D. et al. (90), te of each main ef- zot TABLE A18.—Incidence of new coronary heart disease by (Numbers in parentheses are number of CHD cases In each subgroup) Smoking group smoking category and behavior type for men 50-59 years of age Former Current and Cigarettes Behavior Never cigarette former pipe type amoked smokers and cigar only 1-16 16-25 26 and over Total Ace eee e ete eeneees 112.4(5) 18.6 (8) 21.8 (8) 16.4(6) 21.5 (9) 30.0(14) 20,4 (49) |: sores 10,064) 6.11) 8.4 (3) 4.7(1) 21.1 (7) 19,1 (5) 12.0(21) Tota) . eee 12.109) 14,.2(9) 14,.9(t1) 11,5 (6) 21.3(16) 26.0(19) 16.8 (70) Analysis of variance table Source Sum of squares df. Mean square F Pp Within cells ............00, 63.627 oil 0.070 we we Regression on age ............. 0.177 1 0.177 2.54 Ol Between amoking groups? , 0.522 5 0.104 1.496 0.188 Between behavior types? ., 0.296 1 0.296 4.24 0.040 Interaction ........, Cece eer eae 0.129 5 0.026 0.37 0.870 t Rates are age-adjusted annual incidence per 1,000 men. 1Mean squares for “between smoking groups” and “between behavior types’ are each computed eliminating the general mean and the other main fect unconfounded by other significant main effecta. Source: Jenkins, C. D, et al. (90), > effect but ignoring interaction, thus yielding an estimate of each main cf- £OT TABLE A20.—Ezperiments concerning the effects of smoking and nicotine on animal cardiovascular function Author, year, Number and Smoking Heart Blood Cardiac Coronary country, tyne of procedure rate pressure oulput blocd Commenta reference population flow Bellet 39 experiments Inhalation Definite Definite Coronary artery ligation increased the frequency etal., on dogs which of tobacco increase. inerease. of nicutine-induced severe arrhythmias: thege 1941, had undergune amokein became less evident with increasing time since U.S.A. coronary chamber. ligation. (21), artery liga. Nicotine Definite Definite tlon up to intravenous increase, increase, 45 days before. 0.2-1.2 ma./ke, Burn and 10 rabbita, Experimental Tvoluted utrial specimen showed increnacd rate and Rand, OB experimental, antinal pres lnvrenoed amplitude of contractions with admins JGR, beeomtrad, trented with Jutrutlon Of nicutlve propurtlonal to pretreat England feolaled atria, Intraperitoneal ment, These renetlona were blocked by renerpine, (35). nicotine and and the authors consider nicutine effects to be the atria of mediated by catechulamine release frum chro- both groups muffin store in myocardium, exciged and perfused with nicotine. Westetal., 33 normal Coronary Definite I. Myocardial contractility increased 40-90 per- 1958, adult mongrel intra. increase cent in 16/15 animals tested accumpanicd by U.S.A. dogs. arterial (systolic), ST segment depression and T-wave inversion (203), nicotine: and blocked by tetracthylammounium chloride, I. 0.2-2.2 Il, Coronary blood flow increased 19 pereent upon ug./kg. lett circumflex artery injection; coronary blood Il. 0.04-} flow showed no change upon left anterior dee ug. /ke. scending artery injection, 64 obscrvationg on 10 dogg. (Tetracthylammonium chloride blocked CUF {ne crease.) The authors found no evidence of coronary vaso- conatriction in these healthy animals. yout TaBLe A20—Experiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) Author, year, Number and Smoking Heart Blood Cardiac Coronary country, typeof procedure rate pressure output blood Comments reference population flaw Forte 27 observas Intravenous Definite No change. No significant change In either left ventricular etal, tions on 8 nicotine up initial work or myocardial oxygen extraction. 1960, dogs. to 21.5 mg. increase U.S.A. given as 5-15 then (65). ug./kg./ decroase, minute. Kien and 21 adult dogs Cigarette Definite Definite Increase Effects of cigarette smoke were duplicated by In- Sherrod, smoke under increase. increase. following travenoug nicotine and epinephrine. 1960, positive increase During cigarette amoke inhalation, it was noted U.S.A. pressure via in blood that without blood pressure or output changes, (112). tracheostomy, pressure coronary blood flow did not {ncrense and tbat Nicotine 20 and cardiac while adverse EKG changes were noted they cor- uag./kg. intra- output. related morc closely with decrensed cardiac oxy- venously. gen utilization than with actual cardiac work, Epinephrine § ug./kg. intra venously, Travell 14 normal Intravenous Definite Nicotineeinduced coronary blood fow and heart etal, rabbits and nicotine increase tate increase in the atherosclerotic animals re 1960, 16 rabbits 0.01-0.1 mg. in normals. quired 10 times and 2 times, respectively, the US.A, with severe amounts required in the normel animals. (189), cholesterol- induced athero- Sclerosis. sot TaBLD A20.—Experiments concerning the effect 8 of smoking and nicotine on animal cardiovascular function (cont.) Author, year, Number and Smoking coutry, typeof procedure Comments reference population Bellet T. 10 normal dogs Intravenous 1. 128 percent The authors noted that: et al., TL. 9 dogs at nicotine, increase 1, The response of coronary blood flow to nico- 1962, varying ins 20 ug./kg./ TL. 82.5 percent tine resembled that of anoxemia in the pres- U.S.A, tervals fol- minute for increase ence of coronary insufficiency, (22). lowing coro- 15-20 minutes. TIT, 83.3 percent 2. The greater the induced coronary impairment nary artery increase the smaller the increment in coronary blood ligation. flow. IL, 7 dogs with varying grades of artifcially- induced coroe nary artery narrowing. Leaders 15 adult Left anterior Nicotine and norepinephrine both increased coro and mongrel descending nary vascular resistance and myocardial contrac: Long, dogs, intracoronary tile force (the former measured by a constant. 1962, injection of volume variable-pressure system). The action of U.S.A, nicotine or nicotine was blocked by pretreatment with hex- (125). norepinephrine, amethonium, pentolinium, reserpine, or guane thidine. Larson 13 adult Intravenous Definite Definite Systemic vascular resistance and pulmonary artery etal., mongrel nicotine, increase, increase, and left atrial pressures showed biphasic rev 1965, dogs. 0.02 mg./keg./ sponses of increase fullowed by decrease. ULS.A, minute for (424), 10-12 minutes. got TaBLp A20.—Ezperimente concerning the effects of smoking and nicotine on animal cardiovascular function (cont.) Smoking Procedure Comments I, Cigarette smoke inhalation to isolated left lower lobe and then blood perfused coronary arteries. 11. Cigarctte smoke to rest of lung and then blood passed to general circulation. IL. Nicotine perfused directly into left coronary artery. 1, No change in coronary vascular resistance. II, 5/6 showed increase in coronary vaaculor resistance due, according to the author, to general sympathetic nervous system stimulation. IL. 4/5 showed increase in coronary vascular resistance, The authors con- clude that the cardiag effects of tobacco arise almost entirely from the extracardiac actions of smoking inatead of the direct response of the heart, Author, year, Number and country, type of reference population Folle 7 dogs of 30 investigated etal, (Remainder experienced 1966, catheterization failures). U.S.A, (64). Nadeau and 26 dogs James, 1967, U.S.A. (142). Nicotine 0.01-10.0 ug, into sinus node artery. Heart rate showed initial slowing (due probably to vagal stimulation) fol- lowed by acceleration (due probably to vagal paralysis and catecholamine release). No systemic blood pressure changes noted, Romero and 16 experiments Talesnik, on isolated 1967, cat heart, U.S.A, (156), Puri 22 mongrel dogs etal, 1968, U.S.A. lise). Nicotine in varying doses in perfusate of coronary arteries. I. (414) Intravenous nicotine 50 ue./kg./minute for 3-4 minutes UW, (8) Propranoio) pretreat- ment, then 50 ug./kg./minute nicotine for 3-4 minutes Over 5 wg. of nicutine was found to produce an initial bradycordin asso- ciated with increased curonary flow, followed by prolonged tachycardia with an initial deersase in coronary bloud flow followed by a prolonged increase, Pretreatment with hexamethonium or reserpine prevented both the myocardial stimulation and the increase in coronary blood fluw. The authors consider the action uf nicotine to be o combination of a direct vasocunstrictive effect and an indirect catechalamine-releasing vasudiluting effoet, I, Nicotine produced a definite increase in the force and velivity of left ventricular contraction. IE. Pretreatment with propranolol produced (relative to results of Group I): (a) A further increase in left ventricular ayatolic pressure. {b) A decrense in velocity of shortening. (ce) A significant increase in left ventricular end-diastolic pressure, The authors conclude that propranolol probably impaira the norepinephrine like effects of nicotine on the myocardium while enhancing ita peripheral vasonressor effects, LOT TaBip A20.—Experiments concerning the effecte of smoking and nicotine on animal cardiovascular function (cont.) Comments Author, year, Number and Smoking country, type of procedure reference population Balazs Beagle dogs with lesions I, Normals (3-6 per experiment); etal, induced in myocardium by (a) 4 ug./kg. intravenous 1969, either: (1) Isoproterenol nicotine, (b) 40 ug./kg. U.S.A. pretreatment, or (2) intravenous nicotine. (16), ligation of the anterior IL. Experimental (3), 4 ug./kg. descending coronary artery, intravenous nicotine I. (a) No evidence of arrhythmias; (b) A single or a few ectople beats in 2/3 normal dogs. JL. Extrasystoles noted in 2/3 animals during the firat day after cessation of the arrhythmia induced by the lesion alone, but not therenfter, These and nicotine-induced arrhythmias were of a short duration. Greenspan Cardiac muscle isolated from = Nicotine 2-100 ug./ec. in Nicotine perfusion produced: etal. the right ventricle of 10 Tyrode’s solution perfusate. (1) An increase {n myocardial contractile force apparently independent 1969, adult dogs. of adrenergic innervation. U.S.A, (2) An increased automaticity of the Purkinje fiber system apparently (74). due to release of catecholamines from chromaffin tissuc stures, {3) A decrease in conduction velocity. The authors conclude that the latter two effects probably predispose to are rhythmia formation. Saphir and 88 mongrel cats Nicotine 6-12 we./kg. injected I. Mesenteric injection of nicotine was followed with 1-2 seconds by: Rapaport, intraarterially to mesenteric (a) Increased left ventricular systolic preasure (LVSP), 1969, circulation. {b) Increased systemic resistance, U.S.A. (c) Enhanced myocardial performance. (168). Il, Left ventricular injection of nicotine was followed by: (a) Increased LVSP. (b) Bradycardia. (c) Enhanced myocardial performance greater than that seen in mesenteric-injected group, ILI. Pretreatment with phenoxybenzamine diminished the increase in LYSP while propranolol pretreatment diminished the enhancement of my- ocardial perfurmance while LVSP still showed a aignificant incrensc, IV. Mesenteric sympathetic nerve section led to a diminished reaponse. The authors conelude that the cardiovascular responses to nicotine may be neurogenic in nature with receptors distributed in certain abdominal arterica, gor TABLE A20,—Experiments concerning the effects of smoking and nicotine on animal cardiovascular funetion (cont.) Author, year, Number and Smoking country, type of procedure Comments reference Population Leb et al., 12 mongrel dogs and Nicotine 100 xg./keg. for Effective Corunary Flow (ECF) ig that part of the totul coronary flow 1970, CBF measured with use of 2 minute intravenously, (TCF) which ig ‘effectively’ involved in nutrient exchange. U.S.A, Rb? and digital counter. Nicotine injection waa followed by; (126). (1) 96,6 percent increase in TCF. (2) G1. percent Increase in ECF, (3) 73.1 percent increase in myocardial oxygen consumption and analyala revealed that capillary flow increased almost proportionately to mye ocardial oxygen consumption whereas the increase in TCF was far in excess. (4) Definite increases in cardiac output, heart rate, left ventricular work, and oortic pressure, Ross and 10 dogs undergoing Nicotine 10-100 ug. intra- Nicotine injection was followed by: Blesa, instantancous coronary coronary injection, {1) Increased contractile force, 1970, arterial flow measurement, (2) Decreased myocardial contraction time, U.S.A. (3) Decreased time necessary to reach peak tension. (160). (4) Decreased total stroke systolic CBF, (5) Incroayed tutal stroke diastolic CBF, (6) Increased total stroke CBF. (1) Changes similar to intraarterial epinephrine. (8) Changes blocked by pentolinium pretreatment, (9) No change in heart rate or blood pressure. The authors conclude that catecholemines released from the ventricular myocardium mediated these responses to nicotine. 60T TABLE A2i.—Experiments concerning the effects of smoking. and nicotine on the cardi ovascular system of humans A veer Number and Smoking Heart Blood Electrocardiogram Coronary country, typeof procedure rate pressure ballistocardiugrany blood Comments reference population flow Russek 1, 28 healthy Latandard and 1 I. Increase. Increase. EKG: Denicotinized ciga- etal., male amokers denicotinized 1, 16/28 showed rettes evoked changes 1955, 21-60 years cigarette. Bignificant of a lesser degree U.S.A. of age (aver- changes. in normals and CHD (16a), age 42). IL. No sig- subjects, but in the IL. 87 male patients Il. Increase. Increase. nificant Jatter group there witb overt changes, was no significant clinical CHD BCG: difference between 42-70 years of toou.. these changes. age (average TI, 18/37 showed 4), 6 were significant nonsmokers. change. Bargeron 14 of 30 healthy l cigarette Insignificant Increase. Definite Coronary voacular etal, adult male vol- inhaled at increase. increase, resistance fell 1967, unteer smokers intervals of significantly. U.S.A. and nonsmokers 20 seconds. Myocardial 0, (17). who underwent successful catheterization 18-63 yeare of age. usage underwent no significant change. Pyruvate extraction fell slightly. Authors conaider lack of increase in heart rate as due to baseline apprehensive tachycardia. ot TABLE A21l.—Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) ae Number and Smoking Heart Blood Electrocardiogram Stroke Cardiac Coronary country, type of procedure rate Pressure bailistocardiogram volume output blood Commenta reference population flow Regan T males with 2 atandard Definite Definite Increase. No signi- Myocardial 0, consump: etal, history of cigarettes in increase, increase. ficant tion rose glightly in 1960, EKG-proven 25 minutes change, Youtof7. ULS.A. myocardial inbaled at The author considers (154). infarction minute that the EKG changes undergoing intervals. noted on smoking are cardiac ca- probably due less to theterization, decreased coronary, blood flow than to increased workload {oxygen need) where oxygen aupply docs not increase, Noted no evidence of myocardial tuchemia during amoking. Thomasand 113 clinically One atandard Definite Definite Definite Definite Pulse pressure showed Murphy, healthy young cigarette increase, increase, increase. increase, a decreuse, 1960, males. smoked at Smokers responded US.A. own pace. slightly but signi (186), ficantly more actively than non- smokers. BCG changes were increasingly common with increasing age, weight, and serum cholesterol. +t eas Taste A2l.—Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) rene Number and Smoking Heart Blood Electrocardiogram Stroke Cardiac Coronary country, type of procedure rate pressure ballistocardiogram volume output blood Comments reference population flow - Von Abn, The author Cigarette Increase, EKG: Slight ST EKG changes more 1960, reviews & smoking. segment prominent in young, Sweden series of depression clinically healthy (202), experiments and T-wave subjects than In performed flaltening, older, habituat between amokery, Intra- 1944-1954. venous nicutine and smoking showed identical cardios vascular effects. Smoking elicited angina pectoris in a number of CHD patierts, Irving and 5 normal males, (a) Sham smoking. (a) No No change. {a) Nochange. No change. Cardiac output Yuomamoto, 15 patients with change, measured by dye 1963, diseases not dee (b)} Non-inhalation (b} No No change, (v) No change, No change. dilution technique. England fined, 19-66 years amoking. change. (89). ofage,allmod- (c) 2 standard {c) Definite Widened (c)} Definite Definite erate-heavy cigarettes in increase. pulse, increase, increase, cigarette smokers, 10 minutes. pressure. {d) Nicotine 0.6 (d) Definite Definite {d} Definite Definite mg. intra- increase, increase. increase, change. venoualy, att TABLE A2lL.—Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Avner Number and Smoking Heart Blood Electrocardiogram Stroke Cardiac Coronary country, type of procedure rate pressure ballistocardiogram volume output blood Comments reference population flow Pentecost I, }4 volunteers Single cigarette Definite Definite 1.10 27 percent and with clinical smoked at own increase increase percent increase. Shilling- CHD, 18/14 rate in 6-7 in all in all increase, ford, smokers, minutes, groups, groups, Tu64, average age U.S.A. 39.5. (149). II. & patients II. Inter- Interme- with angina mediate diate pectoris, all change. change. smokers, aves rage age 43.4. IIL. 14 patients HL. 8 per- 1 percent with history of cent increase. definite myos decrease. cardial infarce tion, all smok- ers average age 64.1, Froukl 6 male and 3 2 standard Definite No signifi- No signifi- The author contrasts eval, female patients cigarettes in increase cunt changes cant this response with 1965, with healed 10 minutes at at rest atrestor changes that Been among U.S.A, myocardial infarc- rest and under and at during at rest or healthy young (B7), tion 48-69 years graded exercise, exercise. exercise, during individuals. of age 2/8 non- exercise. smokers. TABLE AZ1L.—Eaperiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author, yenr, Number and Smoking Heart Blood Elpetrocardiogrum Stroke Cardiae Coronary country, type of procedure rate pressure ballistucardiogrium volume output blood Comments reference populntian flow Sen Gupta 6 healthy male luntipped Increase Increase No change. and Ghosh, nonsmukera, cigurette in in all in all 1967, 8 henlthy mate 6-7 minutes. groups. groups, 6/8 showed ST India smokers. changes. Ci7r), 6 paticnty with Allshowed ST CHD, nensmokers. and T-wave 5 patients with changes. CHD, smokers. All showed ST 36-64 years of age, and T-wave changes. Aronow 10 male patients l standard high Definite Definite Product of systolic et al, with classical Nicotine ciga- increase. increase. blood pressure and 1968, angina pectoris. retteinS heart rate showed a ULS.A. 32-59 years of age minutes. significant increase’ (5). on smoking while le ventricular ejection time values did not. All patients developed angina more rupidly under a constant exercise toad if they had amoked before exerciaing, + Kerriyan 24 male and 1 2 filtered clau- Delite Definite Carding The Jocrense in etal, femnle healthy rettes In 16 Inereuse inevearne Index, curdiae fadex, heart 1068, smokers, average minutes with under under reat Deflutte rate, and bluod ULS.A, ane, 46, meunures taken rent and gad exerelay Inereune prensure during (102). Smale and 2 ulrestaond during exercing conditions, under rest exercise with amokh female henlthy exercise, conditiongs. and whe the sum uf auch nonamokera, exerclse increases aceon with £TT averoge age 33, conditions, amoking or exerciae avpurately. Neither greup uhowed increasva In perl- pheowd veascuter revintance, VTT TaBLE A2l—Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author, , year, , Number and Smoking Heart Blood Electrocardiogram Stroke Cardiac Coronary country, type of procedure rate pressure ballistocardiogram volume output blood Comments reference population flow Allison 30 healthy male 2 standard ciga- Definite Increase. Increase fol- Definite decrease in and Roth, subjects. rettes smoked increase. lowed by pulmonary blood 1969, 19~59 years of in 12-16 minute decrease volume as indicated U.S.A. age. period, within 20 by impedance methods (ne minutes. of thoracic pulse volume, Aronowand 10 male patients 1 low nicotine Definite Definite All patients developed Swanson, with classical cigarette in increase, increase. angina sooner if 1969, angina pectoris. & minutes. they amoked before U.S.A. 32-59 years of exercising, (7), age. Aronow and 10 male patients 1 non-nicotine No change. No change. No difference noted Swanson, with classical cigarette in in time or onset 1969, angina pectoris. 5 minutes. of exercise-induced U.S.A, 32-59 years of angina between (6). age, amoking and non- smoking procedures, Marshal) 42 normotensive 3/dofonestandard Insignificant Insignificant Blood pressure response etal, healthy male cigarette, increase. increase. to cold pressor tcst 1969, prisoners noted to be greater in U.S.A. 18-50 years of (129), age. 13 nonsmokers. 16 moderate amokers. 13 heavy smokers, heavy amokers. Presyncopal reactions to 40 degree bead-up tilt more frequent in smokers. STt TABLE A22,.—Exzperiments concerning the effect of nicotine or amoking on catecholamine levels Author, year, Number and country, type of Procedure Resulus reference subject Watts, 11 dogs 0.02-0.60 mg/kg. Nicotine administration waa associated with algnificant Increases In peripheral arterial 1960, nicotine intravenously. epinephrine levely. Ganglionle blocking agents provented this effect. U.S.A. (£03). Westfall 22 mongrel doga Cigarette amoking via Regular cigarette amoke evoked a statistically significant increase in adrenal vein, and Watts, tracheal cannula; vena cava, and femoral artery levels of epinephrine, Cornsilk cigarette amuke evoked 1963, 1 cigarctte/8 minutes no change, U.S.A. for 36 minutes, (210), Westfall 21 male volunteers 3 cigarettes smoked in Smoking at rate noted for 214 hours evoked a significant Snerenee In urinary epines and Watta, approximately 25 40 minutes. phrine, but not norepinephrine levels. 1964, years of age; U.S.A. 11 nonsmokers, (21t), 10 smokers, Westfalletal., 1966, U.S.A. (£03). Mongrrel dogs Standard cigarette smoke exposure via endotracheal tube. Smoke inhalation every third inspiration for 3 minutes. Smoke inhalation evoked a rise In cardiac cutput, stroke volume, blood pressure, and plasmn catecholamine levels. Pretreatment with propranolol diminished the cardiac output and atroke volume responses but increased the blood pressure rcsnonse—the latter effect due to the release of alpha-receptor activity by beta-Llockade. STT Author, year, Taste A23.—Experiments concerning the atherogenic effect of nicotine administration Resulta country, Number and type Procedure reference of animal Adler et al, Rabbits Nicotine 1.5 mg. intravenously in 6 percent The authors noted an artcrionecrosis of the aorta, affecting mainly the 1906, solution 6 of 7 daya per week for more than inner muscular layers. Macroscopically, early changes consisted of U.S.A, 4 months. small sreas of calcarcous ridging and aneurysmal dilatation without (2). notable fatty’ degeneration or intimal discontinuity. Microscopically, early changes appeared in the muscle cells of the media, and “chalky” deposits were noted between the elastic fibers. Hueper, I. 6mongrel dogs. Nicotine subcutaneously. Increasing dosage up J. 4/6 animals died of infection and showed marked edema and focal 1943, up to 2.5 cc. of 3 percent solution for 1 hyalinization of the media of the aorta and large clustic artvrics. U.S.A. month, 2/6 animals were sacrificed and showed thickening and hynliniza- (8¢). tion of the walls of the coronary arteries and edema of the media ag well as endothelial proliferation of other arterics, II. 60 rats. Increasing doses up to ice. of 1 percent Il. Much less aortic involvement than that found in the dogs: infre- solution for 1 month. quent arteriolar changes consisting of fibrosia and thickening ot the media. Maslova, Rabbits I. (10) Nicotine subcutaneously 1 percent I. Aortic wall--acute swelling of elastic fibers with focal fragmenta 1956, solution 0.2 cc. daily for 115 days. tion and partial disintegration—no intimal fat deposits seen. USSR Coronary vessels—thickening of the vessel wall—no fat deposits. (130). I, (14) Nicotine plus 0.2 grams cholesterol If. Aorta—“'massive’’ deposits of ‘‘cholesteral” in the intima and vasa per day, vasorum with “loosening” of the nurtic wall. Coronary vessely— the larger vessels showed moderate fat deposition and the smaller veasels showed swelling of the elastica. ITT, (10) Cholesterol only. HI. Aorta--isolated lipid depusition in the arch and ascending portiuns only. Coronary vessels—no fat depusition. Czochra- Rabbits T, (10) 1.0 g, cholesterol/dsy for 100 Index of aortic lesion density (cholesterol infiltration): Lyganowicz days. I, 2.5, etal, Il, (10) Cholesterol plus 0.0015 g. nicotine/ IL 3.4. 1969, day intravenously, USA, III. (4) Nicotine only. IIt, No aortic lesions noted. (46), itt Author, ycar, TABLE A23,—-Experiments concerning the atherogenic effect of ricotine administration (cont.) country, Number and type Procedure Resulty reference of animal Wenzelet al, Rabbits 1. (12) Control untreated. General findings: Marked aortic pathologic involvement was noted in all 1959, U.S.A. (127), Thienes 1960, U.S.A. (184). Grosgogeat et al., 1965, France (75). Newborn rats and mice, Male rabbits Tl. (12) Control diet plus l percent cholesterol and 5 percent cottonseed oil added. III. (12) Control dict plus oral nicotine 2.28 mg./ke./day. IV, (12) Regimen II plus oral nicotine 2,28 me./ke./day. V. (12) Regimen If plus oral nicotine 1.42 mg./kg./day. Vi. (12) Regimen IT plus oral nicotine 0.57 mg./kg./day. Nicotine subcutancously up to 5 mg./kg. twice daily by the end of 1 month, Animals autopsied at 1 year, I. (10) Nicotine subcutaneously 0.76 me./day, (10) Controls—saline injected. Sacrificed at from 20-120 days. If. (27) Sume ans Group 1. (27) Controls~-saline injected, Sacrificed ut 90 days, TH (66) Nicotine subcutaneously Ob 1G mug. /day. Sacrificnt nt dO days, IV. (24) Nicotine subcutancously 0.75 my./duy. (24) Controls—~snline injected. One-half of cach group ate cholesterol- enriched diet (0.5-1.0 percent choles- terol added). Sacrificed at 60 days. cholesterol-treated groups; however, no difference was noted hebween Group Tf. and Groups IV., V., and VI. Cardiac histopathology: 1, No change. Il, Advanced atherosclerotic changes in the subendocardinl vessels. TIL. Thickening and fibrosis of coronary artery small branches. IV.-WI. More severe changes with greater fatty metamorphosis ond actual early myocardial necrosis, but no dose-dependent ef- fects observed. No arterial pathology noted. Medial degeneration seen more {requaitly in controls, Suggests that older animals ve used. Significant differences in aortic subendothclial fibrusis between control and experimental groups noted only in TI] and IV. In group IV, the nicotinestreated group showed more severe changes. 8TTt TABLE A23.—Experiments concerning the atherogenic effect of nicotine administration (cont.) Author, year, country, Number and type Procedure Results reference of animal Hase et al,, Male rabbits Nicotine Diet Vitamin D 1966, I. (8) Control Control Control I, Infrequent medial calcific disease without Mpid localization, U.S.A, I. (7) Control Cholesterol Cuntrol II. No medial calcific disease but frequent intimal atheroma formation, (80). Ill. (14) Nicotine Control Control MT, Rare calcific medial degeneration; no intimal athcromatous discase. IV, (15) Nicotine Cholesterol Control IV, The Jargest number of atheromatous lesions. Vv. (9) Control Cholesterol Vitamin D V. No medial calcific disease. VIL (14) Nicotine Cholesterol Vitamin D VI. Consistent medial calcific digease. (Sacrificed at various times) Control—no treatment. Nicotine—subcutaneous injections in oil— increasing amounts 2 times per week. Vitamin D—subcutaneous injections up to 6-8 x 1H TU, Cholesterol~250-500 mg. cholesterol added per 100 g. diet, Choi, Albino rabbits I, Nicotine 1-5 mg./kg./day intraperi. I. Increasing nicotine dosages were associated with decreased atheroma 1967, toneally. formation (findings not statistically significant). Korea Cholesterol 1 g./day (in varying Il, Nicotine ulone produced no atheroma formation but was asgsociated (42). combinations with controls), with the presence of aortic medial calcification und endothelial Il. Nicotine alone. hyperplasia, UI, Cholesterol alone. (Sacrificed at 60 days) IT. Cholesterol alone was associated with a definite increase in atheroma formation. Stefanovich Female albino J. (10) Diet supple- Percent of aortic In both stuck and cholesterol-fed animals, nicotine was also noted to etal, rabbits, mented with 2.0 surface tnvolved increase aortic triglyceride content and to decrease aortic free cho- 1969, percent choles- with lesterol content, U.S.A. terol. Nicotine ine atheroucterosia (478), tramuscularly 1. 9.4 2.78 mg./ke./day, It. 5.7 5/7 days. ME O14 | TI. (10) Cholesterol ly. } only, IIl. (10) Nicotine only. IV. (10) Control. 611 TABLE A25.—Experiments concerning the effect of smoking and nicotine upon blood Npids (Human Studics} Author, year, Number and Smoking Plasma free Serum Serum country, type of procedure fatty acids cholesterol — triglycerides Other Commenta reference poputation Page 13 male und 2 nonfillered No change. Serum lipoproteins etal, 7 female cigarettes No change (10 subjects), 1950, luburatury in 10 minutes ULS.A. workers and blood (147). 17-51 years levels of uge. measured over 30- minute period. Kershbaum 31 mate I. 17 atibjects Afean rine No change. No change, The outhors consider the in- etalk, patients or smoked 2 Tul pFa/h. crease amoung controls to be MGT, atull 16-72 nou-filer TH. 9.8 phy /h. due to fasting. U.S.A. years of age, clparcttes Ill. 272-2,404 (104). Tnormuls, in 10 akash. 7 CHD, minutes. 17 other Il. 9 controls. modical IH. Gaubjects dingnoses, smoked 6 elyarcttes in 40 minutes, Kershbaum — I. 17 male LoL Wh, Mean riac No difference found between re etal, rationts 2 non-filter 1. 858 pEq./L, sults following inhalation or s962, with healed cigarettes in HL, $20 wEq./L. noninhalation, ULS.A. myocnurdial 10 minutes. TEL. 292 pEq/t, Stutiatically ainnificant difference (£Us), infuretions. 1V, No smoking. VY. 20 wEq./L. fuund betwem increwica in Groups IT and JP ond HI. 16 non-CID Group 1, patients, Hl. 0 normals, IV. 33 normals. OcT TABLE A26.—Lxperiments conccrning the effect af smoking and nicotine upon (Human Studies) ISM = Smokers NS = Nonsmokers) blood lipids (cont.) Author, year, Number and country, type of reference population Smoking procedure Plasma free Serum falty acids cholesterol Serum triglycerides Other Comments Kershbaum etal, 1963, ULS.A, (lay), 11 narmal patients, 9 standard cignrettes in 3 hours. Samples at 10, 20, and 40 minutes of smoking neriod, Definite increase at start of smoking period, 3 patients with trime- thaphan cumphor- sulfonate (Arfonad) pretreatment and 8 formerly adrenalectos mized patients showed either minimal or no elevation. Both free and total urinary catecholamines increased wilh smoking and the author considers them ag mediators of the PPA incrense. Konttinen 40 healthy anid moderate iealmi, smokers 3, 19-20 years Finland afage, Cis), Fed at fat menl and then 20 were allowed to smoke cigarettes of known-nicotine contont over 6 hour period (approximately 23 ciwarettes cansumed). NS—definite therease mt 6 hours. SM—~delinite No change in cither kroup, increase ut 6 hours. NS—definite increase at 2 hours. SM-—slight increase at? hours, Kedra S37 male and etal, 5 fomaly 1OGS, medical Poland students (rar). 22-23 years of age. 3 cignrettes smoked in rapid succession and sumplog taken at 10 and 30 minutes, MN No change. No change, Beta-lipoproteins defi. nite increase. LéT TAULE AZG.—Laepertments concerning (he effect af smoking and nicotine upon blood lipids (cunt) (Hinman Studies) Author, year, Number and Smoking Plisma free Serum Serum country, type of pracedure fatty acids cholesterol triglycerides Other Comments reference population Frankl S mate and 1 2 standard No change. Subjects were in nonfasting, etal, fernale cigarettes nonhasal xtate, 1966, hentthy jaded ina U.S.A, amokira 10 minutes, (Ge), 2429 year of uge, Kerahbaum 43 normal male 1. Terminal Tl. Indefinite Cie smoking dn Ll subjects etal, heavy cigarette segment of inrrense, showed on intermediate Ine 1966, or cigar cigar in 20 V]. Definite crease in the excretion of US.A,. amokers, minutes—15 increase. urinary catecholamingys ag (106). 21-46 years subjects. II. Increase with compared to that with ciga- of age, Il. 3 cigarettes inhalation rette smoking. in 20 minutes greater than 15 subjects with none (including 6 inhalation from group I), in every Hil. Cigarette subject, inhalation or noninhalation 6 subjects, Klensch, 56 observations 1 standard Definite Indefinite increase in venous 1966, on student cignrette increoge, epinephrine levels, Germany smokers 20-24 in 4 minutes, (178), years of age, FFA measured at 16-25 minutes. Author, yenr, country, reference Murchison and Fyfe, 1966, Scotland (139). Kershbaum etal, 1967, U.S.A. (105), a TABLE A25.—Experiments concerning the effect of smuking and nicotine upon blood lipids (cont.) Number and tyne of population B male and 4 female mod- erate smokers with various disenses 37- 67 years of age. normal heavy cigarette amokers 28-45 years of age. Smoking procedure 2 cigarettes in 15 minutes, I, Lit-ciga- rettes, Il. Unlit-cigas rettes, Various types of cigarettes of known nicotine content. Plasma {ree fatty acidy I. Definite increase. Il. No change. Regular cigarettes, filter cigarettes, charcaal-Alter cigarettes, pipe tobacco plus cignrettes all showed similar increase in FFA, Lettuce leaf cigarettes had negligible effect. (ifuman Studies) Comments Both regular and sham smokers sbowed significant increases in concentration of serum oleic acid and significant decreases in conccutration of serum palinitic acid. Both catecholamine and nicotine excretion rates showed responses to the various ciga- vettes similar to that of the FFA response. TABLE A25a.—Experiments concerning the effcet of smoking and nicotine upon blood lipids (Animal Studies) ANIMAL AND IN VITRO STUDIES Author, Number yenr, and Smoking Plasma free Serum Serum country, type of procedure fatty acida cholesterol triglycerides Other Comments reference population Wenzreland 48 male Beckloff, New 1968, Zealand U.S.A, while (208). rabbits, Kershbaum 6 mongrel etal., dogs. 1961, ULS.A, (104). Kershbaum 20 adult etal, mongrel 1965, dogu. U.S.A. (107). I. Untreated control— 12 subjects, If. Resrular dict plus 0.1 percent cholesterol— 12 subjects. If, Regular diet plus 2.28 mg./kg./day nicotine In water—12 subjecta. 1V. Diet plue— (a) 0.1 percent cholesterol (b) 2.28 mg./kg./day nicotine in water 12 subjects. Intravenous infusion of 20 mg./kg. nicotine in 20 minutes. I. 9 received IM nicotine dnily for 6 weeks: up to l mg./kg. TL. & placebo injection. Ili. 6 control. Definite increase in 13/15 observations, T. Significant increase in 8/9 dogs, If. No change. Ill. No change. Group Iland IV showed an im- mediate ine ¢reasc in plasma cholestore}) and phospholipids with @ level- with a leveling of response at 4 weeks. Group IV showed a further in- crease at &-12 week period, No change in uny group. The authors consider an e+ evated cholesterol/ phos- pholipid ratio to be a notable indication of atheroxenic susceptibility. The cuncomitant inereage in phospholipids with the cholesterul may negate the importance of nico- tineinduced hypercho- lestcrolemia as an atherogenic stimulus. “ZT TABLE A26a.—Eaperiments concerning the effect of smoking and nicotine upon blood lipids (cont.) (Animal Studies) ANIMAL AND IN VITRO STUDIES Author, Number year, and Smoking Serum Plasma free Serum country, type of Procedure trighycevides fatty acids cholestero] Other Comments reference population Kershbaum 28 adult Intravenous infusion of nicotine, No change, The authors report on the etal, mongrel results of the use of ne 1966, dogs, thalide (an Beta-adrenere U.S.A, gic blocker), phenoxy (108). Kershbaum Sprague- Nicotine perfusion. etal, Dawley 1967, rat U.S.A, fat-pad (#10), tissue, benzamine, and chlure Promazine to block the FFA yespunse to nicotine, Only nethntide was sues cessful and this consti tutes an indiention that Nicotine stiniulates Beta. adrenergic receptors to release catecholamines which, in turn, stimulate the release of FFA. Although nicotine perfusion was not associated with FRA release from fat tise sue, epinephrine did produce a gixnifieant ine ereose in PRA rvicnse. The authors conclude that the sympathetic nervous system mediates the FRA respanse to nicotine in the intact animal, Sct Authur, yen, country, reference Kjeldsen ond Damenard L9GR, Denmark (115). Namber and type of population R mate students 23-27 youry of age. Smoking procedure five daily onehall hour exposures to 0,5 pereent CO for 8-10 days. Overall mean COHDb resulting was 12.5 percent. No Table A2G.—Kxperiments concerning the effect of carbon monowide exposure upon blood lipids Rerults significant changes in total fatty acidy, phospholipids, or triglycerides. Cholestevel showed a significant inereuse only during the Inst do days of exposure. Kjeldsen, 1969, Denmark Chiyy. Kjeldsen, 13, Denmark (fie). 72 female nlbing rabbite: 1. Regulor diet, 24 atl jee ta. Th. Reyuilay diet plus 2 percent choles- terol, 24 subjects, VW, Regeatar diet plus 2 percent choles- terol, 24 subjects. 24 casteated ovale albino rabbits. Roymbar dict plus 2 pereont cholesteral 1, 12 control and 12 exposed to wrndually increasing CO conmentrations (0.015 40 pereent) over Bh daewerk peviud. HL. 12 control and 12 exposed to 0,020 percent CO for os days. HI. 12 control and 12 exposed to to 0.020 pereent CO for T weeks, then 0,046 percent GO for 3 weeks, Vf controfand 12 maintained at 10 pereontasxyyen levels for t weoks, Chen 9 percent for 2 weeks. Hd ~ Serum. cholesterol concentrations vose rapidly and then remained slightly above control values fay the deweek periad, WAC SS days, Che scrum cholesteral concentration da the exposed group wien Zhe (ios that in Qhe central geoap, Sorutn cholesterol concentrations amobg thoge exposal were signilieantly higher than those in the control group fov & weeks of the lOewerk period. Serum. cholesterol and triglyceride concentratiuns rose to significantly higher levels during S of the 8 weeks. No changes noted in serum phaipbolipads. 9ceT TABLE A27.—Smoking and thrombosis Author, Whole Partial Recalcified year Number and Experl- blood Pro» thrombo- — plasma Pintelet Platelet Platelet Platelet country, type of mental clotting thrombin — plastin clotting adhesive. count survival turnover Other Comments reference population conditions ? time time lime time Tess Black- 16 adult 12 individuals Plasma burn achizo- smoked 2 atypven etal, phrenic high. time 1959, patienta, & nicotine (+) U.S.A. university atandard (¥5). students, all brand smokers, cigarettes, Mustard = 7 white males Compared Platelet and with vither after clumping Murphy, CVDor periods of time 1963, COrD, all abstinence (-) (—) (-) (—) (-) (+) (+) (4) U.S.A, heavy or continua- decrease increase (£40), smokers 35- tion of 72 years of smoking. axe, Ambrus 20 healthy Deep inhala- Thromboplaatin 2 students and mute non- lion of one yeneration became ill. Mink, smuking nonfiltered (~) (—} (~) (+) (-) time Results 1964, medical cigarette, - increase (-) reflect U.S.A, students <30 dala on 19. (4). years of age, Ashby 27 male 13 controls Increase of etal, medical measured at subjects 1965, students and 2 separate sereater Treland hospital times 14 Chin that (a), staff subjects (+) of controls members, measured inerense ae pe O01, before and after smuking 2 cigarettes in 20 minutes, Let Author, TABLE A2ZT.—Smoking and th runtbusts (cont.) OT ft ee Whole Partial feendeiied year, Number and Experi. blood Peo- thrombi. plasina Platelet Platelet Platelet Platelet country, typeof mental clotting thrombin plastin elotting adhesives out survival turnover Other Comimenty Seference | ovulation eonditingwey time —_.. time ae time ue Gare Nem a ne . Se eee ee ne Sogunt HL observations Smoked 2 thks Mibrivotyaia Wet. tint on male Aveta or (+f) tobacco Joshi, smoker al] 2 btrig or dee rene wrapgecck fey Tbh, revular chewed { {~-) {-) (+) (fe) fabaece tadla tobacen Vetel nut Inereane lowe, (17g), Uyera, guid in? minutes, Engel- ~~ 40 male and 2 ‘ciknretteg Oe es Chandler berg, 20 feninle in 20 {in uttro) 1064, hoxpital pus minutes, thrombosin USA, tients, alt lime (48), smokom 17- + GK yours of decrease tee, Kodra 30 male and 4 cigarettes ~~ —~ ~ ~~ Thrombin and 11 female in) hour. tone Korolku, smokers and (x) (-—) {-+b) (xt) 165, 44 male und dlecvense decrouse deerense Poland 26 fomale (10n), nonsmokery 18-25 years of age, Murchi- 8 males and Z cigarettes t Smoking both son 4 female in 15 lit and unlit and patients minutes, cigarettes Fyfe, with lit or unlit (t) (+) enused a rise 1966, various cigarettes, increase in platelet Scotland diseases, all adhesiveness (239). heavy which the smokers 37- authors 67 years corre|nted of uge. with rine in plasma none esterified fatty neida. 8cl TaBLE A27.—Smoking and thrombosis (cort.) Author, Whole Partial Recalcified year, Number and Experi- blood Pro- thrombo — plasma Platelet Platelet Platelet Platelet country, type of mental clotting thrombin plastin clotting sdhesive. count survival turnover Other Comments reference population conditiona! time time time time ness Glynn 20 male and J cigarettes Platelet Smokers found etal, 17 femole in 30 acrotinin to have a 1966, smokers and minutes, {~) (—) Kreater Cunada 9 male and Platelet tendency for (71). 21 female adenosine plutelet nonsmuokera nucleotide aggregation 17-76 years (~) than none of age, smokers. Engelberg 94 male and 1 cigarette Thrombue No relation and 53 female in 5 minutes. formation found with Futter- patients and time incrvaye in man, medical (+) free fatty 1967, house staff. decrease acidy. ULS.A. (59). Murphy, Literature Platelet 1968, review with adherence to U.S.A, summary of (+) (4) (+) vascular (140). data and increase increase decrease endothelium conclusions. (+) increase Pibrinolyaia {) decrease Thrombua formation time (4+) decrease t t Symbols: + = Definite effect. —=Noeffect, = = Questionable effect, 1 Results, Meusured before and after amoking procedure noted, unicss otherwise stated, conyern specific cougwation teat as TABLE A30.—Experiments concerning the effect of nicotine and smoking upon the peripheral vascular system Author, year country, reference Moyer and Maddock, 20 subjects (including heavy smokers) were studied for the effects of 1940, U.S.A. (154). the following procedures on skin temperature: the inhalation of a lit cigarette, inhalation through an empty paper tube, or the ad- ministration of 1 mg. nicotine intravenously. All subjects responded with decveased cutaneous temperature following the smoking and nicotine procedures, No changes were noted following sham smoking. Mulinos and Shulman, A number of experimental groups, each consisting of 6-17 persons, 1940, U.S.A. (198). were studied for the effects of deep breathing and cigarette smoking on skin temperature and digit or Jimb plethysmography. The au- thors concluded that deep breathing alone could account for the changes in tempevature and blood flow noted upon smoking and noted that denicotinized cigarettes evoked the same or greater vasoconstriction as that noted folluwing the smoking of a standard cigarette. 50 young male smokers were studied with plethysmography before and after the normal and rapid inhalation of a standard cigarette. The author noted that rapid inhalation was associated with a pro- longed decrease in extremity blood flow while a more natural rate of inhalation was followed by a momentary decrease in flow. The author considered the former reaction to represent the pharmacolo~ gic effect of the smoke and the latter ta represent the physiologic response to deep breathing, as the natural inhalation of an unlit cigarette produced the same transient decrease in flow as did the natural inhalation of the lit cigarette. Sbephberd, 1951, Treland (273). Friedei}, 1953, 52 male and 48 female young smokers and nonsmokers were studied U.S A_ 79). for the effects of smoking on hand blood volume as measured by the use of radioactive iodinated albumin. The inhalation of un- filtered cigarettes was associated with an average decrease in hand blood volume of 19 percent in men and 33 percent in women; while filtered cigarettes showed respective decreases of JL percent and 21 percent. Strombiad, 1959, 11 male and female subjects (smokers and nonsmokers) were studied Sweden (121). for the effect of the intra-arterial administration of nicotine (bra- chial artery) on blood flow to the hand as measured by venous occlusion plethysmography. Increasing doses of nicotine were asso- ciated with increasing numbers of individuals manifesting vaso- constriction. The vasoconstrictive effects of nicotine were abolished by the prior administration of either hexamethonium or pentojinium. Bamett and Boake 9 male patients with intermittent claudication (7 were heavy smokers) 1960 Australia (18). were studied for the effect of smoking on blood flow to the leg as measured by venous occlusion plethysmography. Smoking an un- filtered cigarette was found not te produce any consistent changes in blood flow to the calf or foot of the affected leg, Freund and Ward, 15 male prison inmates (Jess than 35 years of age} and 14 male 1966. U.S.A. (63). patients with peripheral vascular disease (approximately 65 yeara of age) were studied for the effect of smoking on digital circulation as measured by skin temperature, plethysmography, and radiosodium clearance from the skin. Smoking was found to adversely affect the first and third measures in a significant manner (while plethys- mogvapnic values were variable) only in the healthy prisoners and not at all in the patient group. 100 normal individusls underwent 425 experimental procedures con- cerning the effect of smoking on the pevipheral cireulation. Smok- ing was found to be associsted with a dezrease in extremity skin Roth and Schick, 1360, U.S.A. (161). temperature. 129 TaBLe A30.—Experiments concerning the effect of nicotine and smoking upon the peripheral vascular system (cont.) Author, year, country, reference B males (18-32 years of age) were studied for the effect of intra- venous ‘nicotine on extremity temperature and blood flow. Intra- venous nicotine was found to evoke a decrease in skin temperature while increasing muscle blood flow. The former effect began sooner and lasted longer than the latter. Rottenstein et al., 1960, U.S.A. (162). Allison and Roth, 30 healthy individuals (19-59 years of age) were studied for the effect 1969, U.S.A. (8). of smoking two cigarettes on extremity pulse volumes and skin temperature. Smoking was found to be associated with a 2-6 per- cent decrease in skin temperature and a 45-50 percent decrease in blood pulse volumes to segments of the finger, calf, and toe. 130 Chapter 2 Cardiovascular Diseases Part H 131 CONTENTS Page Coronary Heart Disease(CHD) ........02202.......-....-..... 135 Introduction»... 2... ee 135 Cigarette Smoking as a Major Risk Factor for Coronary Heart Disease 22.2.2... .0000............. 136 Cigarette Smoking in Relation to Other Risk Factors for Coronary Heart Disease .........2.......... 137 Hypertension... 2... 2... eee 137 Coffee Drinking ~. 0.2.0 00000002.......-0222.. 141 Ventricular Premature Beats .................... 142 Carbon Monoxide... 20. ee ee ee. 142 Introduction... 2... ee 142 Sources of Carbon Monoxide Exposure and Human Absorption ....................-.-2..-.. 143 Effects on Healthy Individuals 2.2. ..0002000000........ 148 Effects on Persons With Atherosclerotic Cardiovascular Disease... 0 ee 149 Studies on the Pathogenesis of Cardiovascular Disease. ee 150 Nicotine 2.2... ee ee 151 Acrolein 2... ee ee eee 15l Cerebrovascular Disease... 2... 0. ee 151 Effects of Smoking on the Coagulation System ................... 154 Summary of Recent Cardiovascular Findings ..........22.....0.... 155 Bibliography 2.0... eee eee 156 133 List of Tables Table 1. — Age-standardized blood pressure changes (mm Hg) at followup for continuing cigarette smokers and quitters according to weight changes .......0......0.00.. Table 2. ~ Number of subjects who had developed hypertension at followup for continuing cigarette smokers and quilters 2. ee ee ee Table 3. — Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by sex and race ........2..0.... Table 4. — Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by employment status... 2.2.0.2... Table 5. ~ Median percent carboxyhemoglobin (COHb) saturation and 90 percent range for smokers and nonsmokers by location 2.2... ... 2000000000000. eee ee eee Table 6. — Mean percent carboxyhemoglobin (COHb) saturation in cigarette smokers | hour after last cigarette... 2. .000002. Table 7. — Age-standardized death rates and mortality ratios for cerebral vascular lesions for men and women by type of smoking (lifetime history) and age at start of study 2.2... 0. ee eee 134 CORONARY HEART DISEASE (CHD) introduction Coronary Heart Disease (CHD) is the most frequent cause of death in the United States and is the most important single cause of excess mortality among cigarette smokers. The evidence relating smoking to CHD has been reviewed in previous reports on the health consequences of smoking (6/, 62, 63, 64, 65, 66, 67, 68). The following is a bnef summary of the relationships between smoking and CHD presented in these reports. Cigarette smoking, hypertension, and elevated serum cholesterol are the major alterable risk factors for myocardial infarction and death from CHD. Cigarette smoking acts both independently as a risk factor and synergistically with the other CHD risk factors. The magnitude of the risk increases directly with the amount smoked. The excess risk of CHD among smokers has been demonstrated in some Asian, Black, and Caucasian populations and is proportionately greater for younger men, especially those below age 50. Cessation of cigarette smoking results in a reduced mortality rate from CHD compared with the mortality rate for those who continue to smoke. Pipe and cigar smokers have a slightly higher risk of death from CHD than nonsmokers, but they incur a much lower risk than ciga- rette smokers. This has been attributed to the lower levels of inhala- tion that characterize most pipe and cigar smoking. Data from autopsy studies have shown coronary atherosclerosis to be more frequent and more extensive in cigarette smokers than in nonsmokers, and experimental work in humans and animals has suggested several mechanisms by which smoking may influence the’ development of atherosclerosis and CHD. The formation of carboxy- hemoglobin, release of catecholamines, creation of an imbalance between myocardial oxygen supply and demand, and increased platelet adhesiveness leading to thrombus formation have all been demonstrated in smokers and proposed as explanations for the excess CHD mortality and morbidity among smokers. 135 Cigarette Smoking as a Major Risk Factor for Coronary Heart Disease The evidence establishing smoking as a major risk factor in CHD has been reviewed in previous reports (6/, 62. 63, 64, 63, 66. 67, 68). During the last year new epidemiologic data have been published on the relationship between coronary artery disease and smoking. Bengtsson (9, 70) studied the smoking habits of women with myocardial infarction (MI) in Goteborg, Sweden. He found that smoking was significantly more common ina group of 46 women (80 percent smokers), ages 50-54, who had a myocardial infarction than in a control group of 578 healthy nonhospitalized women (37.2 percent smokers). Other investigators examined the effect of cigarette smoking on survival of people with acute myocardial infarction. In a study of 400 patients with documented myocardial infarction who survived to be admitted to a coronary care unit, Helmers (26, 27, 28) found no significant difference between the percentages of smokers and nonsmokers among survivors studied after the first 24 hours, from 2 days until discharge, and from discharge to 3 years. Reynertson and Tzagournis (52), in a 5-year prospective study of 137 patients with documented CHD at age 50 or less, were also unable to find any relationship between CHD mortality rates and smoking habits. Smoking habits after entrance into the study were also considered and again no difference in mortality rates was found. The Coronary Drug Project (/7) found an effect of cigarette smoking on mortality after myocardial infarction. This group studied 2,789 men ages 30-64 years for 3 years after myocardial infarction and found a statistically significant correlation between cigarette smoking determined 3 months after a myocardial infarction and mortality (¢-value of 2.94). None of these studies (/7, 26, 27, 28, 52) were able to examine the smoking habits of the group of people who die suddenly as a first manifestation of CHD, and therefore may have excluded that group in which there is the highest excess mortality due to cigarette smoking (3/). Additional data from the Swedish twin study of Friberg, et al. (23) have been reported. They found an excess CHD mortality among smokers in dizygotic twins with different degrees of smoking, but no similar excess in monozygotic twins. Although the numbers were [oo small to be significant, the authors suggest that this tends to support the theory that both smoking and CHD are constitutionally 136 determined. These data must be viewed with caution. however, since the difference was demonstrable only in the older age group (born 1901 - 1910). When the younger age group (born 191} - 1925) was considered, no excess CHD mortality was seen in the dizygotic group but a small excess was noted in the monozygotic group (three CHD deaths in the high smoking group and one in the low smoking group). Also the difference in cigarette consumption between the Ingh and low smoking groups was relatively small (seven cigarettes per day). Consequently, data from this study are not sufficient to warrant the conclusion that both smoking and excess CHD mortality are constitutionally determined rather than smoking being a cause-of the excess CHD mortality. Cigarette Smoking in Relation to Other Risk Factors for Coronary Heart Disease Cigarette smoking, elevated serum cholesterol, and elevated blood pressure are generally accepted as the three major modifiable risk factors for CHD. However, there is less agreement concerning other CHD risk factors — obesity, physical inactivity, diabetes mellitus. elevated resting heart rate, psychologic type A behavior, etc. The following studies present recent evidence on the relation- ships between smoking and hypertension, coffee drinking, and ventricular premature beats. Ay pertension Results from several studies have shown that smokers on the average have slightly lower blood pressure than nonsmokers. Some investigators have attributed this finding to the fact that smokers on the average weigh slightly less than nonsmokers. Three current studies (24, 36, 55) discuss this relationship. Gyntelberg and Meyer (24), based on their evaluation of 5,249 men ages 40-59, were of the opinion that lower blood pressure in smokers could not be accounted for by differences in weight, age, or physical fitness. Kesteloot and Van Houte (36), in a study of 42,804 men, performed a multiple regression analysis on age, weight, and height and found that cigarette smokers had lower blood pressure than nonsmokers; however, when they inchided serum cholesterol values in the analysis, the ditference in blood pressure was reduced to approxi- mately | mm Hg. Although this difference was statistically signifi- cant based on the large population, the actual difference in blood pressure was too small to be of clinical importance. 137 Seltzer (55) studied 794 men selected for their initial good health and normal blood pressure (below 140 systolic and 90 diastolic) and followed them for changes in cigarette smoking habits, weight, and blood pressure. During the 5-year period of the study 104 men gave up smoking. For every age group except those over 55, there was a significantly greater weight gain (8 ib) among the “quitters” than among the continuing smokers (3.5 Ib). Blood pressure increased 4 mm Hg systolic and 2.5 mm Hg diastolic in the quitters with no change in systolic and a slight reduction in diastolic (-1.1 mm Hg) in persons who continued to smoke. In order to examine blood pressure changes in relation to weight change, both continuing smokers and quitters were grouped according to their weight changes during the period of study (Table 1). The most significant finding was an increase in the systolic blood pressure (+1.77 mm Hg) among the quitters even in that group with significant weight loss. In contrast, the continuing smokers with significant weight loss had a decline in systolic blood pressure (-3.28 mm Hg). Diastolic blood pressure in quitters showed an increase with weight gain and no change with weight loss, while continuing smokers showed a decrease in diastolic pressure with weight loss and no change with weight gain. The data on subjects whose blood pressure had increased to hypertensive levels (systolic > 150 and diastolic > 95) were evaluated, and it was found that quitters had a much higher frequency of becoming hypertensive than continuing smokers (Table 2). Seltzer, in interpreting these data, suggested that cigarette smoking tends to inhibit blood pressure increases, with only minimal pressure rises occurring even in instances of substantial weight gain. When this inhibiting effect of cigarette smoking is removed as in the case of the quitters, sharp rises in blood pressure become evident. He cautioned, however, that the development of hypertension in some quitters may have been responsible for decisions to lose weight and that his data do not allow an evaluation of the degree of blood pressure changes according to how recently cigarettes were given up. The results of the ischemic heart disease study by Kahn, et al. (34) raise additional questions about Seltzer’s data. Kahn followed 10,000 Israeli male civil service employees for 5 years to determine what factors were associated with an increased incidence of hypertension. He presented no data concerning persons who stopped smoking, but he did show that the incidence of hypertension increased with age and that the age-adjusted incidence of hyper- tension in smokers was over twice that of nonsmokers (76.9/ 1000 for smokers versus 35.4/1000 for nonsmokers). Seltzer reported no 138 6eT TABLE 1. ~ Age-standardized blood pressure changes (mm Hg)! at followup for continuing cigarette smokers and quitters according to weight changes Weight Change (LB) Significant No Significant Moderate Significant Smoking Class Wt Loss Wt Change Wt Gain Wt Gain tb Ib tb Ih No. 25 to -§ No. -4to+4 No. +5 to +12 No. +13 to +30 Mean systolic BP changes; Continuing smokers 32 ~4.00 84 ~1.$2 7 2.85 24 1.50 Quitters 13 1.77 27 2.22 27 4.04 32 3.69 Mean diastolic BP changes: Continuing smokers 32 -3,28 84 - =2.04 71 0.73 24 ~0.04 Quitters 13 -0.31 27 —1.96 27 4.30 32 3.94 ‘Standardized on basis of age distribution of current cigarette smokers, Source: Seltzer, CC, (55). OovTt TABLE 2, — Number of subjects who had developed hypertension at followup for continuing cigarette smokers and quitters Blood pressure Continuing cigarette smokers Quitters levels Number Percent Number Percent Systolic blood pressure 150+ 6 2.8 9 87 Systolic blood pressure 160+ 2 0.9 5 4.8 Diastolic blood pressure 95+ 3 14 5 4.8 Source: Seltzer, C.C. (55). data on the incidence of hypertension in nonsmokers, and the age distnbution for his group of smokers (the onginal source of the quitters) is heavily weighted toward younger age groups (with only 33 of 214 men age SO years or over). According to Kahn’s data, this age group would be expected to have a lower incidence of hypertension, and, in fact, Seltzer found only small numbers of men who developed hypertension (eight with diastolic hypertension) (Table 2). Making interpretations based on such small numbers is hazardous; for example, the difference between current smokers and quitters in the incidence of diastolic hypertension could have been produced by only three men quitting smoking because they developed hypertension. Coffee Drinking The Boston Collaborative Drug Study (/2) recently reported a correlation between coffee drinking (> 6 cups per day) and myocardial infarction that persisted after controlling for the effect of cigarette smoking. This was a retrospective study of 276 patients with a hospital discharge diagnosis of myocardial infarction and 1,104 age, sex, and hospital-matched controls discharged with other diagnoses. In addition to the usual limitations of retrospective studies, this study has several characteristics that make interpretation difficult. In controlling for the effect of cigarette smoking, the investigators divided the smokers into those who smoked one pack or less per day and those who smoked more than one pack per day. Because cigarette consumption is highly correlated with coffee consumption (29, 39), it can be expected that within such broad smoking categories those who were heavy coffee drinkers tended to be heavier smokers than those who consumed smaller amounts of coffee. It is also possible that the hospitalized controls represented persons who drank less coffee than the general population because of serious chronic illnesses. These characteristics of the study design do not allow firm conclusions to be made concerning the extent to which the relationship between coffee drinking and myocardial infarction is independent of the relationship of both variables to cigarette smoking. The question of the independent nature of this relationship is also dealt with in a prospective study by Klatsky, et al. (39) of 464 patients with myocardial infarction who previously had had multi- phasic health checkups. Both ordinary controls and CHD risk factor-matched controls were drawn from 250,000 people who had undergone the same multiphasic health checkups. The investigators did not find an independent correlation between coffee drinking and myocardial infarction when risk-matched controls were used. 141 The Framingham Study (18) recently published data on coffee drinking based on a {2-year followup of 5,209 men and women ages 30-62. An increased risk cf death from all causes was demonstrated in coffee drinkers, but this relationship was accounted for by the associ- ation between coffee consumption and cigarette smoking. No association between coffee drinking and myocardial infarction OT between coffee drinking and the development of CHD, stroke, or intermittent claudication was demonstrated. Heyden, et al. (29) also found no relationship between excessive coffee consumption (> 5 cups per day) and atherosclerotic vascular disease. Ventricular Premature Beats Ventricular premature beats have been shown to be a risk factor for sudden death from CHD. Vedin, et al. (69), ina study of 793 men in Goteborg, Sweden, examined the frequency of rhythm and conduction disturbances at rest and during exercise. They found no statistically significant correlation between cigarette smoking habits and the presence of supraventricular or ventricular premature beats at rest or during exercise. CARBON MONOXIDE Introduction Carbon monoxide has long been recognized as a dangerous gas, but until recently concentrations which produced carboxyhemo- globin levels below 15S to 20 percent were thought to have little effect on humans. Currently there is considerable interest in determining the effect of chronic exposure to low levels of carbon monoxide (65, 66, 67, 68). Carbon monoxide is present in concentrations of | to5 percent of the gaseous phase of cigarette smoke (J, 45). The concentration varies with temperature of combustion as well as with factors which control the oxygen supply such as the porosity of the paper and packing of the tobacco. The amount of carbon monoxide produced increases as the cigarette burns down. Carboxyhemoglobin levels in smokers vary from 2 to 15 percent depending on the amount smoked, degree of inhalation, and the time elapsed since smoking the last cigarette. Carbon monoxide, which has 230 times the affinity of oxygen for hemogtobin, impairs oxygen transportation in at least two ways: 142 First, it competes with oxygen for hemoglobin binding sites. Second. it increases the affinity of the remaining hemoglobin for oxygen. thereby requiring a larger gradient in Po2 between the blood and tissue to deliver a given amount of oxygen; this increased gradient is usually produced by a lowering of the tissue Po2. Carbon monoxide also binds to other heme-containing pig- ments, most notably myoglobin, for which it has even a greater affinity than for hemoglobin under conditions of low Po2. The significance of this binding is unclear, but may be important in tissues, such as the heart muscle, which have both high oxygen requirements and large amounts of myoglobin. Sources of Carbon Monoxide Exposure and Human Absorption Several researchers (13, 32, 35, 57, 60, 70) have estimated the relative contribution of cigarette smoking and air pollution to the human carbon monoxide burden as measured by carboxyhemoglobin levels (COHb). Kahn, et al. (35), in a study of 16,649 blood donors. determined that smoking was the most important contributing factor, followed by industrial work exposure. Nonsmoking industrial workers had COHb levels of 1.38 percent, and nonsmokers without industrial exposure had levels of .78 percent. Cigarette smokers, on the other hand, had very high levels. Smokers with industrial exposure had levels of 5.01 percent, while smokers without industrial exposure had levels of 4.44 percent (Tables 3 and 4). Stewart, et al. (57) found similar results in a nationwide survey of blood donors and noted marked vanation in mean COHb levels in residents of different cities measured at different times of the year (Table 5). However, in all areas, smokers still had COHb levels two to three times higher than nonsmokers and had increasing COHb levels with increasing level of cigarette consumption (Table 6). Similar findings were reported by Torbati, et al (60) in a study of 500 male Israeli blood donors. Nonsmoking workers exposed to automobile exhaust — London taxi drivers (32) and garage and service station operators (/3) — have higher baseline levels of carboxyhemoglobin than nonsmokers of the general population. But even in these high exposure occupations smokers have markedly higher COHb levels (8.1 and 10.8 percent) than nonsmokers (6.3 and 5.5 percent). An extreme is represented by New York City tunnel workers who are exposed to an average of 63 ppm CO with peak exposure levels as high as 217 ppm CO: cigarette smokers still maintained much higher COHb levels (5.01 percent) than nonsmokers (2.93 percent) (8). 143 9oT TABLE 3. — Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by sex and race Total Sample Nonsmokers Smokers! No. X +S No. X +Sz No. X + Sx Total Sample 16,649 2.30 £0.02 10,157 0.85 +0.01 6,492 4.58 £0.03 Male 10,542 2.66 40.03 5,888 1.00 £0.01 4,654 4.76 + 0.04 Female 6,107 1.68 + 0.03 4,269 0.64 +00) 1,838 4.10 + 0.06 White 15,167 2.28 £0.02 9,474 0.85 £0.01 5,693 4.66 40.04 Male 9,669 2.65 £0.03 5,508 1.00 40.01 4,161 4.83+0.04 Female 5,498 1.63+0.03 3,966 0.64 +001 1,532 4.19 + 0.06 Black 1,429 2.59 + 0.06 641 0.86 + 0.03 788 4.00 t 0.08 Male 829 2.91 £0.10 347 1.07 £0.05 482 4.244 0.10 Female 600 2.15 £0.09 294 0.62 +0.04 306 3.63 40.12 1 smokers are defined as those who smoked on the day of giving blood. NOTE. — X = mean percent; Sy* standard error of mean percent. Source: Kahn, A., et al. (35). TABLE 4, ~ Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by employment status Nonsmokers Smokers! No. Xs: No, X tS Persons employed 8.478 0.89 + 0.0) 5,962 V6OUb OUI Chissed ats industrial workers! 1,523 1.38 + 0.04 1,738 5.01 t 0.06 Classed as workers other than industrial 6,955 0.78+0.01 4,224 4.44 + O04 Persons not employed 1,678 0.63 + 0.02 531 4247041 cvT Nodustrial workers are employed in either durable or nondurable goods manufacturing (craftsmen, Operatives, or laborers). Smokers are defined us those who smoked on the day of giving blood. NOTE. ~ X= mean percent; Sz 5 Standard error of nivan Percent, Source: Kahn, A., et al. (35). 97T TABLE 5. — Median percent carboxyhemoglobin (COHb) saturation and 90 percent range for smokers and nonsmokers by location Cigarette Smokers | Nonsmokers - Location | Median Range | Median Range Anchorage 4.7 0.9 - 9.5 1.5 0.6 -- 3.2 Chicago 5.8. 2.0 - 9.9 17 10-32 Denver 5.5 2.0 - 9.8 2.0 0.9 -3.7 Detroit 5.6 1.6 - 10.4 1.6 0.7 - 2.7 Honolulu 49 : 1.6 - 9.0 1.4 0.7 = 2.5 Houston 3.2 1.0 -7.8 1.2 0.6 - 3.5 Los Angeles 6.2 2.0 - 10.3 1.8 1.0 ~ 3.0 Miami $.0 12+ 9.7 1.2 0.4 ~ 3.0 Milwaukee 4.2 1.0 - 8.9 1.2 0.5 - 2.5 New Orleans 5.5 2.0 - 9.6 1.6 1.0 - 3.0 New York 4.8 12-91 4,2 0.6 - 2.5 Phoenix 4.1 0.9 - 8.7 1.2 0.8 - 2.8 St. Louis 5.) "17-922 1.4 0.9 - 2.1 Salt Lake City S.1 15-9.5 1.2 0.6 + 2.5 San Francisco 5.4 1.6 - 9.8 1.8 O8 - 2.7 Seattle 5.7 1.7 - 9.6 1.5 Q.8 - 2.7 Vermont, New Hampshire 4.8 1.4 - 9.0 1.2 0.8 = 2.1 Washington, DC 4.9 12-84 ‘ 1.2 0.6 ~ 2.5 | VT Source: Stewart, R.D., et al. (57). L4T TA BLE 6, ~ Mean percent carboxyhem oglobin (COND) saturation in cigarette smokers | hour after last cigarette Packs of Cigarettes Smoked Per day Location Nonsmoker <¥% Yael 1 I% 2 Milwaukee 1.3 3,0 4,2 5.3 6.2 4,7 New Hampshire, Vermont 1.4 3.3 4.4 5.7 6.7 5.3 New York City 1.4 3.1 4.3 4.7 5.8 6.3 Washington, DC 1.4 3.8 4.6 5.2 5.8 6.6 Los Angeles 2.0 4.0 5.2 6.0 7.4 7.5 Chicago 2.0 4.8 5.4 6.3 7 7 Source: Stewart, R.D., et al . (57), Studies on the CO burden of each cigarette have determined the body burden of CO per cigarette to be 7.10-8.66 ml (49). and the increase in COHb Jevel produced by smoking one cigarette to be .94 to 1.6 percent after 12 hours of abstinence (40, 53). The half-life for the washout of CO in healthy college smokers (40) was calculated to be from 3 to 5 hours. Effects on Healthy Individuals Several studies have been published on the effects of carbon monoxide on healthy individuals. Small doses of CO (COrb levels 2.4-5.4 percent) were found to have no effect on heart rate (56). Raven, et al. (5/), ina study of young men exposed during exercise on a treadmill to 50 ppm CO (COHDb levels 2.5 percent in nonsmokers and 4.1 in smokers), found no decrease in maximum aerobic capacity when the subjects were tested at 25°C. Ina similar experiment conducted at 35°C by the same researchers (20), there was a decrease in maximum aerobic capacity in nonsmokers exposed to 50 ppm CO, but not in smokers despite an increase in the carboxyhemoglobin levels of 1.5 percent in both groups. They postulated a possible physiologic adaptation of smokers to carbon monoxide. Ekblom and Huot (22) studied five young men who inhaled CO to reach given COHb tevels. They reported that as COHb levels increased, there was a decrease in maximal oxygen uptake and lower heart rates at maximal treadmill exercise. Sagone, et al. (54), in a study of 9 cigarette smokers and 18 nonsmokers ages 20-32, showed significantly higher values for COHb, red cell mass, hemoglobin, and hematocrit in the smokers. Levels of 2,3 DPG were unaltered while oxyhemoglobin affinity P50 and ATP levels were significantly lower in the smokers. The three smokers with highest red cell mass had normal arterial blood gases and one smoker had very high values of red cell mass which returned to normal after he stopped smoking. The authors interpret these data.as evidence of tissue hypoxia. Millar and Gregory (43), in a study of both fresh heparinized blood and ACD-stored blood from a blood bank, showed a reduction in the oxygen carrying capacity of up to 10 percent in the blood of cigarette smokes, this reduction persisted for the full 21-day storage life of blood bank blood. Cole, et al. (16), in a study of pregnant women, found COHb levels in the fetus to be 1.8 times 4s great as those in the 148 simultaneously measured blood of the mother. Fetal blood was exposed to carbon monoxide in vitro, and fetal hemoglobin was found to have a shift of the oxvhemoglobin disassociation curve to the left as occurs with adult hemoglobin. The higher fetal COHb levels were attributed to the lower fetal Poz and a resultant decrease in the ability of oxygen to compete for the fetal hemoglobin. It was felt by the authors that the high COHb levels may be responsible for the lower birth weight of infants born to mothers who smoke. Effects on Persons with Atherosclerotic Cardiovascular Disease Aronow and Isbell (5) and Anderson, et al. (/) have shown a decrease in the mean duration of exercise before the onset of pain in patients with angina pectoris exposed to low levels of carbon monoxide (50 and 100 ppm). Carboxyhemoglobin levels were significantly elevated (2.9 percent after 50 ppm; 4.5 percent after 100 ppm) and the systolic blood pressure, heart rate, and product of systolic blood pressure times heart rate (a measure of cardiac work) were all significantly lower at onset of angina pectoris. In a continuation of this work, Aronow, et al. (2, 3) studied eight patients during two separate cardiac catheterizations, one during which each patient smoked three cigarettes and one during which each patient inhaled carbon monoxide until the maximal coronary sinus COHb level equalled that produced by smoking during the first catheterization. All eight had angiographically demonstrated CHD (> 75 percent obstruction of at least one coronary artery). Smoking increased the systolic and diastolic blood pressure, heart rate. left ventricular end-diastolic pressure (LVEDP), and coronary sinus, arterial, and venous CO levels. No changes were noted in left ventricular contractility (dp/dt), aortic systolic ejection period, or cardiac index, and decreases were found in stroke index and coronary sinus, arterial, and venous Po. When carbon monoxide was inhaled, increased LVEDP and coronary sinus, arterial, and venous CO levels were noted; there were no changes in systolic and diastolic blood pressure, heart rate, or systolic ejection period; and decreases in left ventricular dp/dt, stroke index, cardiac index and coronary sinus. arterial, and venous Poz were found. These data suggest that carbon monoxide has a negative inotropic effect on myocardial tissue resulting in the decrease in contractility (dp/dt) and stroke index. When the positive effect of nicotine on contrac- tility and heart rate is added by cigarette smoking, the net effect is increased cardiac work for the same cardiac output. In the heart with 149 coronary artery disease there is a greatly restricted capacity to increase blood flow in response to this increase in cardiac work. The result is early cardiac decompensation manifested by elevation in LVEDP and angina pectoris. Aronow, et al. have also shown decreased exercise time prior to onset of angina pectoris in persons exercised after riding for 90 minutes on the Los Angeles Freeway (4). In a related study, they demonstrated a decrease in exercise time before claudication in a group of patients with intermittent claudication who were exposed to 50 ppm CO (6). Studies on the Pathogenesis of Cardiovascular Disease In a review of some of their work on carbon monoxide, Astrup and Kjeldsen (7) noted that in cholesterol-fed rabbits exposed to 170 ppm carbon monoxide for 7 weeks (COHb 16 percent) and then to 340 ppm for 2 weeks, the cholesterol content of the aorta was 2.5 times higher than that of cholesterol-fed, air breathing controls. Groups of cholesterol-fed rabbits intermittently exposed to carbon monoxide for 12 or 4 hours per day produced three- to fivefold increases in the cholesterol content of their aortas. Cholesterol-fed rabbits made hypoxic at 10 and 16 percent oxygen had 3 to 3.5 times the aortic cholesterol content, while those exposed to 26 and 28 percent oxygen had a considerable decrease in cholesterol accumulation. Theodore, et al. (98) studied the aortas of monkeys, baboons, dogs, rats, and mice fed a normal diet but exposed to very high levels of CO (COHb levels 33 percent) and found no atheromatous changes in their aortas. Further work by Astrup and Kieldsen (38) revealed that in rab- bits fed normal diets but exposed to 180 ppm carbon monoxide for 2 . weeks, there were local areas in their hearts of partial or total necrosis © of myofibrils; in the arteries there was endothelial swelling, formation of subendothelial edema, and degeneration of the myocytes. When the aortas of these rabbits were examined (37), the luminal coats showed pronounced changes characterized by severe edematous reaction with extensive swelling and formation of subendothelial blisters and plaques. The authors postulate that carbon monoxide increases endothelial permeability to albumin which results in formation of edema leading to changes indistinguishable from early atherosclerosis. 150 Evidence that this mechanism may occur in humans ts provided by the findings of Paring (50) who showed an increased trans- capillary escape rate for 131 [- labeled albumin in humans exposed to 43 percent CO (COHb 20 percent) for 3 to 5 hours. but not in those made hypoxic to an altitude of 4300 meters (hemoglobin 75 percent saturated). By exposing rabbits to different concentrations of carbon monoxide (50, 100, and 180 ppm) for varying periods (.5, 2. 4, 8, 24, and 48 hours), Thomsen and Kjeldsen (59) were able to show a threshold ot 100 ppm of CO for myocardial damage. The demonstra- tion of damage at this level of CO (COHb 8-10 percent) is possibly explained by the ratio of carboxymyoglobin to carboxyhemoglobin which is about 2 to 1 in myocardium at ambient Poz2. Thus,a COHb level of 10 percent would be accompanied by a carboxymyo- globin level of 30 percent in heart muscle. This ratio is even greater under hypoxic conditions with a ratio of 6 to I when the arterial Pa» is below 40 mm Hg (/5). Nicotine In a study of the effects of smoking cigarettes with low and high nicotine content, Hill and Wynder (30) noted increasing serum epinephrine levels with increasing nicotine content of the smoke. but serum norepinephrine levels were unchanged. However. increasing serum epinephrine levels with increasing number of low nicotine content cigarettes smoked were also noted. , Acrolein Egle and Hudgins (21) did inhalation studies with acrolein on rats. Inhalation of this aldehyde at concentrations below those encountered in cigarette smoke resulted in a significant increase in blood pressure and heart rate in rats. CEREBROVASCULAR DISEASE There has been conflicting evidence on whether there is an increased risk of cerebrovascular disease due to smoking (6/, 62, 63, 64, 65, 66, 67, 68). A prospective study by Paffenbarger, et al. (48) of 3,991 longshoremen followed for 18 years showed no correlation between fatal strokes and smoking. However, both the Dom study of 151 US. veterans (33) and Hammond's study of one million men and women (25) showed a small but significant increase in the death rates from cerebrovascular disease among cigarette smokers. The Framing- ham 18-year followup of men ages 45 to $4 (42) and Paffenbarger’s study of men who entered Harvard between 1916 and 1940 (49) also showed an excess risk of cerebrovascular disease associated with cigarette smoking. Two recent studies provided more data on this topic. Ostfeld. et al. (46, 47), in a study of 2,748 peaple ages 65-74 receiving old age assistance in Cook County, Hlinois, were unable to find any relation between cigarette smoking habits at the start of the study and incidence of new strokes or prevalence of transient ischemic attacks. Nomura, et al. (44), in a study of the population of Washington County, Maryland, ages 25 and older, were unable to find any relation between cigarette smoking and either mortality or morbidity from stroke. Nomura noted that “in atherosclerotic strokes the Framingham study and Paffenbarger’s investigation of former college students included a great percentage of stroke cases under the age of 55. Because these two studies found an association between cigarette smoking and atherosclerotic strokes and the present study did not, it may be that the association is age-dependent.” Hammond (25) provides some data which may clarify this relationship. Analysis of his data shows that the difference between cerebrovascular death rates in cigarette smokers and nonsmokers increases as persons get older except in males ages 75-84 (Table 7), indicating that the excess death rates associated with cigarette smoking increase with advancing age. The ratio of the death rates for smokers and nonsmokers (mortality ratio), however, decreases with age. reflecting the fact that cerebrovascular disease death rates attributable to other causes increase with age more rapidly than death rates attributable to smoking. Cigarette smoking may well be a risk factor for stroke at all ages, but other causes of strokes become proportionally so important in older age groups that in studies not. based on very large populations the risk due to cigarette smoking is" masked by the large total number of strokes due to other causes. 152 est TABLE 7. — Age-standardized deaths rates and mortality ratios for cerebral vascular lesions for men and women by wpe of smoking (lifetime history) and age at start of study Type of Smoking Age Groups 45-54 55-64 65-74 78-84 CVL Death Rates per 100,000 Person-Years Men Never sinoked regularly 28 92 349 1,358 Pipe, cigar 25 100 369 1,371 Cigarette and other 28 129 361 990 Cigarette only 42 130 477 1,168 Total 35 116 391 1,272 Women Never smoked regularly 18 $7 eae 1,082 Cigurette 38 88 315 1,277 Total 25 64 238 1,091 CVL Mortality Ratios Men Never smoked regularly 1.00 1.00 1.00 1.00 Pipe, cigur 0.89 1.09 1.06 1.01 Cigarette and other 1.00 1.40 1.03 0.73 Cigurette only 1.50 14 1.37 0.86 Women Never smoked regularly 1.00 1.00 1.00 1.00 Cigarette 2.11 1.54 1.38 1.48 NOTE. ~ CVL = Cerebral vascular lesions, EFFECTS OF SMOKING ON THE COAGULATION SYSTEM Several studies have contributed to an understanding of the role of smoking in thrombogenesis. Levine (4/), ina controlled double blind study, showed that smoking a single cigarette increased the platelet’s response {0 a standard aggregating stimulus (ADP). This phenomenon did not occur when lettuce leaf cigarettes were smoked and was independent of a rise in free fatty acids in the plasma. The author postulates that this may be due to increasing epinephrine levels. These data may have relevance for two other studies. In the clinical _ trial of the possible prevention of heart attack by hyperlipidemic drugs in Newcastle, England, (19) it was found that cigarette smokers were at increased risk of sudden death. This increased msk was not present in smokers treated with clofibrate. However, the researchers were unable to relate this reduction in risk to any etfect of clofibrate on serum lipids. Recently Carvalho, et al. (14) evaluated 29 patients with familial hyperbetalipoproteinemia and noted that their platelets had an increased sensitivity [to aggregating stimuli (ADP). Treatment with clofibrate returned the ADP sensitivity to normal without significantly altering serum lipids. This demonstrated effect of clofibrate may provide some insight into the Newcastle study. The reduction in the excess risk of sudden death could be due to a clofibrate induced reversal of increased sensitivity to aggregating stimuli produced by smoking. 154 SUMMARY OF RECENT CARDIOVASCULAR FINDINGS 1. Data from one recent incidence study suggest that cigarette smokers are more likely to develop hypertension than are nonsmokers. There is some evidence that suggests that stopping smoking may be accompanied by a rise in blood pressure. 2. Cigarette smoking has been shown to be the major source of elevated carboxyhemoglobin levels, with occupational exposure and air pollution being far less important in most circumstances. Carboxyhemoglobin levels in cigarette smokers are two to three times the levels in nonsmokers and increase with the amounts smoked. 3. 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Smoking and carboxyhemoglobin in the St. Louis Metropolitan population. Theoretical and empirical considerations. Archives of Environmental Health 29(3): 136-142, September 1974. Chapter 3 Chronic Obstructive Bronchopulmonary Disease Source: 1971 Report, Chapter 3, pages 135 - 230. 16) Contents Introduction. 2.0000 oc eee eens Epidemiological Studies.............2.. 0200202 ee eee COPD Mortality..........0.......00 2022 COPD Morbidity.................2...22-2000 08> - Ventilatory Function. ............0. 00000 e eevee eee Genetic Factors......... 0.00. cee eee eee Alpha,-antitrypsin 2.2.2.0... 0.200 2c eee ee eee Air Pollution............. 2.0000 eee ccc eee eee Occupational Hazards.......... 0.000. Cadmium... 0... ee ee eee ene Pathological Studies ........ 0.0.0 c cee ee ee eee Experimental Studies ........2. 0.000000 2 eee eee eee Animal Studies ..........-ccccce eee cee c scenes Studies in Humans ............ 20000 cece ee ee eee Studies Concerning Pulmonary Clearance .......... Overall Clearance .......... 2.00.22: e ee eee Ciliary Function .......-....022 202-00 eee eee Phagocytosis... 0.0.0... ccc ee ee ee eee Studies Concerning the Surfactant System ......... Other Respiratory Disorders ..............-0 00042 eeeee Infectious Respiratory Diseases ..............2+-+-- Postoperative Complications ................-+0--- Summary and Conclusions .............0220 0c eee eee References 0... 0.0 cc eee ee eens FIGURES 1. Percent of lung sections with Grade IV or V fibrosis ... 2. Percent of lung sections with Grade II or IJJ emphysema LIST OF TABLES (A indicates tables located in appendix at end of chapter) 1. Chronic obstructive bronchopulmonary disease mor- tality ratios... 0... ee eee eeee 187 188 168 163 AIO. 11. 12. Al3. Ald. Alb. Al6. AlT, 164 LIST OF TABLES (Continued) (A indicates tables located in appendix at end of chapter) . Smoking and chronic obstructive pulmonary disease symptoms—percent prevalence. .--+--serrrrrttt . Smoking and ventilatory function ..------s-+70077 4. Glossary of terms used in tables and text on smoking and ventilatory function....---.eeeer ttt Cessation of smoking and human pulmonary function . Epidemiological] studies concerning the relationship of air pollution, social class, and smoking to chronic. obstructive bronchopulmonary disease (COPD). .- . Epidemiological studies concerning the relationship of occupational exposure and smoking to chronic obstructive bronchopulmonary disease... --- eee te Studies concerning the relation of human pulmonary histology and smoking .-.e-serer ct Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheobronchial tree and pulmonary parenchyma of animals ...---- e077" Experiments concerning the effect of the chronic in- halation of NO, upon the tracheobronchial tree and pulmonary parenchyma of animals ..---- tees Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function. . Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance. ...--- Experiments concerning the effect of cigarette smoke or its constituents upon ciliary function ..------+ Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tension ..--- Studies concerning the relationship of smoking to in- fectious respiratory disease in humans ..-+-+---7* Complications developing in the postoperative period in patients undergoing abdominal operations - Lee Arterial oxygen saturation before and after operation Page 221 232 241 175 242 244 181 185 246 192 196 247 251 252 256 256 INTRODUCTION Chronic obstructive bronchopulmonary disease (COPD) is char- acterized by chronic obstruction to airflow within the lings. The term COPD refers to three common respiratory aiJments; namely, chronic bronchitis, pulmonary emphysema, and reversible obstruc- tive lung disease (bronchial asthma) .* Chronic bronchitis has been defined as the chronic or recurrent excessive mucus secretion of the bronchial tree. It is characterized by cough with the production of sputum on most days for at least three months in the year during at least two consecutive years (217). Pulmonary emphysema is that anatomically defined condition of the iung characterized by an abnormal, permanent increase in the size of the distal air spaces (beyond the termina! bronchiole) ac- companied by destructive changes (217). Patients can suffer from both of these conditions simultaneously. The symptoms as well as the abnormalities in pulmonary function observed in the presence of the two ailments may be quite similar. Patients with chronic bronchitis suffer from productive cough with or without dyspnea (breathlessness both at rest or on exertion) while pulmonary emphysema is characterized mainly by dyspnea. COPD comprises a spectrum of clinical manifestations; thus, it is frequently difficult to determine whether a particular patient is suffering from one of the two specified diseases alone or which one predominates when both are thought to be present. COPD is responsible for significant mortality in the United States. In 1967, a total of 21,507 men and 3,885 women were re- corded as dying from chronic bronchitis and emphysema (221). This figure does not include a sizable number of individuals for whom COPD was a contributory cause of death. During the past two decades, a major increase has taken plage in the mortality from COPD in the United States. In 1949, the death rate from COPD was 2.1 per 100,000 resident population, while in 1960 it was 6.0 (222), and in 1967, 12.9 (221). Although * Because mortality from bronchial asthma does not appear to be related to cigarette smoking, the term COPD will be used henceforth to refer only to chronic bronchitis and pulmonary emphysema. Exacerbation of preexisting bronchial asthma has been observed among cigarette smokers. Further elaboration of this question may be found in a previous Public Health Service Review (#23). 165 much of this rise is probably due to changes in certification and recording methods as well as to an increased interest on the part of the medical community, an appreciable proportion is also gen- erally accepted as reflecting a real increase in disease. Similar in- creases over the past 20 to 30 years have also been observed in Canada (7) and in Israel (54). The lack of a similar increase in Great Britain, a country with an extremely high rate of COPD, may be the result of a number of factors including improved therapy and decreased air pollution. Moreover, it is also likely that the diagnosis of COPD has been made more commonly and ac- curately in Great Britain for a longer time than in the United States, or elsewhere. Furthermore, the British definitions of bron- chitis and emphysema have differed in the past from those used in the United States. The mortality from and prevalence of COPD is probably under- estimated. In a study of death certificates, Moriyama, et al. (170) reported that COPD is often omitted as a contributing cause of death. In a study of more than 350 autopsies, Mitchell, et al. (169) noted that the disease often goes unreported and that emphysema was occasionally found unassociated with severe clinical airway obstruction. Hepper, et al. (110) observed that ventilatory test re- sults were abnormal in 10 percent of 714 patients in whom no symptoms, signs, or past history of pulmonary disease were noted. They concluded that severe degrees of ventilatory impairment may be undetected by history and physical examination alone. Boushy, et al. (40) evaluated clinical symptoms, physiologic measurements of airway obstruction, and morphologic bronchial and parenchymal changes in 90 males with bronchogenic carcinoma. The authors found that when either clinical, physiologic, or pathologic evidence of COPD was used alone, one-third to one-fourth of the patients were considered normal, but when all three criteria were used to- gether, only one patient was free of COPD. The importance of COPD as a contributing cause of mortality is now beginning to be more fully recognized. ; Clinicians have long observed that the majority of their patients suffering from COPD were cigarette smokers (1, 150). Epidemio- logical studies have validated this impression by indicating that cigarette smokers are at a much greater risk of developing or dying from this disease and that the risk increases with increased dosage of cigarette smoke, reaching in the smoker of two packs or more a day a level as high as 18 times that of the nonsmokers (132). The salutary effect of giving up smoking has also been borne out by clinical observation and epidemiological studies. In a number of studies, smokers were found to suffer more fre- quently than nonsmokers from pulmonary symptoms including 166 cough, cough with production of phlegm, and dyspnea. By a variety of pulmonary function tests, emokers were shown to have dimin- ished function as compared to nonsmokers and also to have a steeper slope of the expected decline of function with age. Tests of ventilation/perfusion relationships in the lung have revealed ab- normal function in smokers. Autopsy studies have indicated that smokers dying of causes other than COPD have significantly more changes characteristic of emphysema than nonsmokers. Several recent studies have validated the clinical impression that among patients who undergo surgery, cigarette smokers run a greater risk of developing complications in the post-operative period than nonsmokers. Abundant experimental evidence of the role of smoking in bronchopulmonary disease has been obtained from experiments employing animals and tissue and cell cultures. Recent work has demonstrated, in dogs trained to inhale cigarette smoke through a tracheostoma, that emphysema, pulmonary fibrosis, and other path- ologie changes in the pulmonary parenchyma and bronchi develop and that these changes are proportional] to the total dosage of cig- arette smoke inhaled. In vivo and in vitro studies have shown that whole cigarette smoke, or certain fractions thereof, inhibit cilary activity of the bronchial epithelium, adversely affect the mucous sheath, and inhibit the phagocytic activity of the pulmonary alveolar macrophage. These abnormalities lead to retarded clear- ance of inhaled foreign matter including infectious agents from the lungs, thus predisposing the individual to respiratory infec- tions, Evidence also exists that pulmonary surfactant may be ad- versely affected by cigarette smoke. The convergence of these lines of evidence, which will be de- scribed in more detail in the body of this chapter, leads to the judgment that cigarette smoking is the most important cause of COPD in man. EPIDEMIOLOGICAL STUDIES COPD MORTALITY Numerous epidemiological studies, based on a variety of pop- ulations and carried on in a number of countries, have investi- gated the association between cigarette smoking and COPD. They have shown a greatly increased mortality and morbidity from COPD among smokers as compared to nonsmokers. Results from the major prospective studies relating smoking and COPD mortal- ity are presented in table 1. The majority of the studies separate 167 89T TABLE 1,—Chronic obstructive bronchopulmonary disease mortality ratios {Actual number of deaths shown in parentheses)?! SM = Smokers, PROSPECTIVE STUDIES NS = Nonsmokers see Number and Data Followeup Number Cigurcttes/day Chronic country, type of collection years of deaths pipes, cigars bronchitis Empbysema Other reference population Hammond 187,783 white Questionnaire 344 338 Cigarcttes and males in 9 and follow-up SM ,.....308 NS .......4,00 (30) Horn, states 50-69 of desth NS ...... 30 <10 ..,....8,67 (10) 1988, years of age. certificate, 10-20 + -3.00 (67) U.S.A, P20 ...ee, 3.64 (40) (105). Alo. . 2,85 (231) Pipes NS «1.00 (30) SM o......8.77 (23) Cigare NS ......1,00 (90) SM ......4.29 (18) Doll and Approximately Questionnaire 10 292 Cigarctics Cigurettes Hill 41,000 male and follow-up Chronic NS oo... 1.00 NS ow... 1.00 1964 British of death bronchitis - 1-144... 6.80 Te-l4....0.65 Great physicians. certificate, Wi 15-24 ...12.80 15-24 .,1,08 Britain Other D282... 24,20 Dib... 0.68 (70). 181 AN .....11.60 Al... 0.81 Pipes and Pipes and Cigara Ciyare SM ..... 63.00 SM... 0,78 69T TADLE L=Chronie obstructive brouchopulnumary disease mortality ratios (cunt) (Actual number of deaths shown i parentheses)! SM 2 Smokers. NS =: Nuonsmokers Author, year, Number and Data Follow-up Number Cigarcttes/day Chronic country, type of collection years of deaths pipes, cigars bronchitis Emphysema Other reference Population PROSPECTIVE STUDIES Best, Approximately Questionnaire 6 124 Cigarctics Cigarcttys 1966, 78,000 male and follaw-up NS ..,,..1.00 NS .......1.00 Conada Canadian of death <0 1 ...67.02 (17) <10 1... 4 BL (9) (90), veterans. certificate, 10-20) .,.13.65(49) 10-20) ..,..6.12(21) 220 ..,.44.69(12) >20 vee. 6.93 (7) All o.....10.42(78) All 60... 585 (87) Pipea Pipes SM o...,..2.11 (5) SM oo......0,.75 (2) Cigars Cloara SM ow... 3.87 (1) SM .4.....3.83 (1) Hammond, 440,568 males Interviews by 4 389 Males 1966, 52.671 ACS volun. SM ....,.369 NS ....,..1,00 (20) U.S.A. fomales teers, NS ......20 SM (age (103), 35-44 yearg 45-64), .6.65(194) of agein SM (age 25 states. 65-79) .11.41(175) Kahn, U.S. male Questionnaire 84 Bronchitte NS ......1.00 (91) Current ciga- Current ciga- 1966, veterans and SM .......64 ASM -» 6,49 (348) rettes only retlea only U.S.A, 2,265,674 follow-up NS ....,..13 Current cigas NS ......1,00(14) NS .......1,00 (18) (182), Person years, of death Emphysema rettes .10.08(229) 1-9 ween 8,63 (5) 1-9 ..,..6.33 (10) certificate, SM ......284 Pipes 10-20 ....4.51(22) 10-20 2... 14.04 (93) NS .......18 SM ....,.2.36 (9) 21-39) 14, .4.87(12) 21-39 ...17.04 (62) Cigars 239° .....8.81 (4) 239, 25.34 (17) SM ......0.79 (6) Alt ++ 4.49 (43) Al ..0...14.170186) oLt TANLE 1.—Chronic o hstruetive Gronchopilaco ery disease niu ltt Ponumber of deathe shown $n parentheses) § lity ration (cont) (Actua SM Siokers Nu Nonarniok evi arene eigenen nme tet ane EEE SS SS en Author, year, Number and Data Follow-up Number Ciynrettes/day Chronke epuntry, type of collection yeurs of denths pipes, cignrs bronchitis Emphysema 0 reference population a PROSPECTIVE STUDY Weirand 68,163 males Questionnaire 5-8 58 Cigarettes Dunn, in various and NS 1.00 1970, occupations follow-up mid. 8.18 USA, In California, of death H20 eee 11.80 (225). certificate. P30 vee 20.86 All 12.33 RETROSPECTIVE STUDY Wicken, 1,189 males. Personal inter- 1,188 obtoined Ciyarcttca 1966, view with retrospec- only North- relatives of tively. NS oe B00 (124) ern individuals SM ....1,064 Ve1O vee 2-95 (245) Ireland listed on NS... 124 11-22... -9.43(900) (227). death 73... Ad (168) register, Mixed SM 1... 2.55 (62) 1 Unless otherwise specified, disparities between the and the sum of the individual smoking categories ar total number of deaths e due to the exclusion Tipes or cigars SM of either occasional, miscellaneous, 2NS includes pipe and cigur amokers; . 1.84 (289) mixed, or ex-smokers. SM includes exesmokers. the findings for chronic bronchitis and emphysema. Such specific grouping of the mortality data should be viewed with some reser- vations in the light of the difficulties mentioned above in dis- tinguishing the two diseases clinically. _ The dose relationship of increased mortality ratios with increased consumption of cigarettes is indicated by the results of all the studies which present rates for different levels of smoking. Kahn (132), for instance, noted that those smoking only 1 to 9 cigarettes per day incurred an emphysema mortality ratio of 5.33 while those smoking over 39 per day incurred one of 25.34. Pipe and cigar smokers were found in some studies to have slightly elevated mor- tality ratios in comparison with nonsmokers although other studies did not show this. The risk of dying from COPD among cigar and pipe smokers appears to be much less than that incurred by cigarette smokers but may be somewhat greater than that among nonsmokers (table 1). The effect of stopping smoking on COPD mortality is reflected in the results of Doll and Hill (70, 71) in their study of British physi- cians. They found that during the years immediately following cessation of smoking, mortality ratios remained elevated and did not begin to decline below the level of continuing smokers until nearly a decade later. This delay in response is probably due to two factors: the presence in the ex-smokers’ group of many who quit for reasons of ill health and the long-term effects of cigarette smoke on the respiratory tree, some of which are irreversible. Kahn (1/32) also noted that the age-specific mortality ratios for ex-smokers were Jower than those for continuing smokers of cor- responding amounts of cigarettes. A better estimate of the potential effect of stopping smoking on COPD mortality can be gained by studying the death rates in a population in which a high proportion of smokers have stopped smoking to protect their health rather than as a response to ill health. Among doctors age 35-64 in England and Wales, many of whom have stopped smoking cigarettes, there was a 24 percent_ reduction in bronchitis mortality between 1953-57 and 1961-65, as compared with a reduction of only 4 percent in al] men of the same age in England and Wales, among whom there was no reduc- tion of cigarette smoking. (84). COPD MorsiDITY Many investigators have studied the prevalence of bronchopul- monary symptoms (including those of chronic nonspecific respira- tory disease) among smokers and nonsmokers. These studies are outlined in table A2. Their results indicate that the cigarette 171 smoker is much more likely to suffer from respiratory symptoms such as cough, sputum production, and dyspnea than is the non- smoker. Such symptoms, particularly cough and sputum produc- tion, increase with increasing dosage of cigarette smoke. Table A2 also shows that pipe and cigar smokers experience COPD symptoms more frequently than nonsmokers although not to the degree found in cigarette smokers. These morbidity findings are similar to the mortality findings presented above. Similarly, cessation of cigarette smoking has been shown to be associated with a decrease in symptom prevalence. Mitchell, et al. (168) studied 60 patients who succeeded in stopping smoking and 84 continuing smokers. Among the ex-smokers, more than 70 per- cent reported improvement in their cough while less than 5 percent of the continuing smokers did so. Wynder, et al. (237) followed 224 ex-smokers of cigarettes and noted that 77 percent reported cessation of persistent cough and an additional 17 percent reported definite improvement. Hammond (102) reported similar results concerning cough and shortness of breath in a study of a large group of ex-smokers. VENTILATORY FUNCTION Another type of quantification of the effects of smoking on the bronchopulmonary system has been obtained by those groups of investigators who have studied pulmonary function in various groups. Results are presented in table A3, and a glossary of the terms used in the various tests is presented in table A4. The pa- rameters investigated have included maximal breathing capacity (maximal voluntary ventilation), expiratory flow rates, forced expiratory volume, and vital capacity. Although certain of these parameters appear to be more sensitive measures of pulmonary dysfunction than others, the overwhelming majority of these stud- ies have shown diminished function among smokers. An increase in the expected age-diminution rate in smokers has been observed in those studies which employed either repeated examinations oF examinations at many different age levels. Higgins, et al. (117) da nine-year follow-up examination of 385 male residents of a British industrial town who were age 55-64 at the beginning of the study. Among the survivors who were tested initially and nine years later, the average decline in FEV,.;; Was smallest in non- smokers, slightly greater in ex-smokers, and greatest in smokers. As with COPD mortality and symptom prevalence, the impairment of pulmonary function shows a dose-relationship with increasing amounts of cigarettes smoked. conducte 172 The data contained in table A3 provide two different kinds of information. The majority of the studies were conducted on un- selected populations, which probably include a number of individ- uals with clinically manifest COPD. Therefore, these studies re- flect the prevalence of COPD-related dysfunction (as determined by pulmonary function tests) in relation to smoking. However, some studies of younger individuals have revealed that pulmonary function tests are abnormal in clinically asymptomatic smokers. Krumbholz, et al. (240) and Rankin, et al. (189) have shown that pulmonary diffusing capacity is impaired in young asymptomatic smokers when compared with age-matched nonsmokers. Similar impairment in other pulmonary function tests was noted by Peters and Ferris (182, 183) in an asymptomatie college-age proup and by Zwi, et al. (241) and Krumholz, et al. (140, 142) in groups of young asymptomatic physicians and medical] students. Several investigators have employed tests which measure the relationship of ventilation and perfusion (V/Q relationships) in the various pulmonary segments. These tests are predicated on observations that some segments of the lung may be relatively under or overperfused and that, likewise, segments may be under or overventilated. Anthonisen, et al. (10) investigated pulmonary function in 10 male smokers with clinically mild chronic bronchitis, all of whom had smoked cigarettes for at least 20 years. Regional pulmonary function was studied using radioactive xenon. Despite the fact that overall pulmonary function was nearly normal in sev- eral patients, all had depressed V/Q ratios in some lung regions with the basal areas being those most commonly affected. The au- thors suggested that significant disease in the peripheral airways may exist in patients whose chronic bronchitis is clinically mild and who show no present impairment of ventilatory capacity. The radioactive xenon test may reveal severe compromise of local gas exchange when usual studies of ventilatory capacity do not reveal any impairment. Similar results concerning peripheral airway ob struction in bronchitic patients with normal, or only minimally in- creased pulmonary resistance, have been observed by Woolcock, et al. (234). These authors also noted that their patients demon- strated frequency-dependent compliance Which was unaffected by the administration of bronchodilator aerosols. Strieder, et al. (214) have recently investigated the mechanism of postural hypoxemia in 24 asymptomatic smokers and non-- smokers. They found that standard ventilatory tests and lung vol- umes were normal in both the smoking and nonsmoking groups. However, the arterial pO* measured in the supine position was significantly lower among the smokers and alveolar-arterial oxygen gradients, while breathing room air, were larger in smokers than in 173 nonsmokers (more so in the supine than in the erect position). The increase in alveolar-arterial O. gradients was greater for heavy than for light smokers. The authors concluded that maldistribution of ventilation and perfusion accounted for the observed hypoxemia. They also felt that this mild diffuse airway disease among asympto- matic smokers is physiologically significant mainly because of in- volvement of small bronchi, as expressed by maldistribution unac- companied by gross airway obstruction. A similar ventilatory distribution abnormality among smokers has also been observed by Ross, et al. (198) with the mcre severe alterations found in the long-term smokers. Although of concern in the consideration of COPD, such dis- turbances of the V/Q relationship may also have adverse effects upon cardiac function depending upon the level of hypoxemia (219). The discussion in the section on Coronary Heart Disease noted that carbon monoxide has adverse effects on both oxygen transport and alveolar-arterial exchange as well as on oxygen debt developed with exercise (50). Further research 1s needed on the joint effect of these pulmonary and carbon monoxide induced hypoxemic influences. A number of other studies have provided further evidence con- cerning the adverse effect of smoking on ventilatory function. Table 5 presents those experiments which deal with the effect of cessation of smoking on pulmonary function. Among the param- eters which have been noted to improve after stopping smoking are: diffusing capacity, compliance, resistance, maximal breathing capacity, and forced expiratory volumes. These parameters showed improvement within 3 to 4 weeks after cessation of smoking. GENETIC FACTORS Recent interest has been shown in the possible contribution of genetic factors to the pathogenesis of COPD. Earlier studies (127, 147) had noted the existence of kindreds with high incidences of chronic bronchitis, emphysema, or both diseases. In addition to the presence of genetic susceptibility, Larson, et al. (147) also observed that all but one of the 11 symptomatic individuals in their two kindreds were smokers. They postulated that the susceptibility of some smokers to develop emphysema may be, at least partially, genetically detemined. More recently, Larson, et al. (248) studied 156 relatives of COPD patients and 86 control individuals. The subjects underwent pul- monary function testing, including forced expiratory volume and residual volume/total lung capacity measurements. The authors observed that pulmonary function abnormalities were most prev- alent among the relatives who smoked and least prevalent among 174 CLT TABLE 5.—~Cessation of smoking and human pulmonary function’ Author, year, Number and country, typeof Results Comments reference population Krumbolz 10 physicians Following 3 wecka abstinence Following 6 wecks abstinence (6 eubjecta only)t ft All subjects were DS pack etal, 25-33 years Lung volumes—no significant change. Lung volumes; per year emokers, 1965, of age, Peak expiratory flow rate—incrense Inspiratory reserve volume—inerease (p<0.05), USA, (p<0.01), Functional residunt capacity—increase (p<0,05). (14t), Maximal breathing cnpacity—increase (p<0.02), Mean diffusing capacity: Mean diffusing caparity~no change, Resting—~Iinerease (p<0.02) Exercise—no change. Compliance—increased in 6/8 tested. Compliance—continued to show increase. Wilhelmsen, 16 smokers. Value prior to cessation Valuc after cessation Significance Mean duration of the non 1967, (43.7 mean Vital capacity wee 4.50 4.57 Not significant. smoking period wos 40 U.S.A. age), PEV) gy cceteeeeee eens 3.38 3.52 p<0.05, days, (230), FEV, )/FVC vee TED 76.8 Not significant. PEFR ow. eee 697 7.45 Not significant. MEFR 50% ..........3,81 3.93 Not significant. MEFR 256 ..........1.82 1.50 p<0.05, Inspiratory resistance .2,07 1.43 poo.02s. Expiratory resistance .2.80 2.04 p40 cigarcttes/day 2.3 Megahed 50 male patients Mucous gland hypertrophy etal, with chronic Percent 1967, bronchitis under- NS coc c eee e eae vee eens 29 (2/7) Egypt going bronchial SM 11 Garin t (p<0.02) (163), biopsy and Invage. €8t TABLE 8.—Studies concerning the relation of human pulmonary histology and smoking (cont.) (Actual number of deaths shown in parentheses) SM = Smokers, NS = Nonsmokers Author, year, Number and country, type of Results Comments reference population Auerbach 662 males au- Deproc of trachcal and bronchial arteriolar thickening etal, topsied at East (by peroantege of smokers} 1968, Orange VA 0.00.3 0.5-0.9 LOLA 1.51.9 U.S.A, Hospital. Never smoked (122) ccc. ccee ce ceceeereeee 4601 39.3 13.3 13 (14). <20 cigarettes/day (120) 2... ccc ceseeaee UL7 22.0 33.6 28.4 20-40 cigarettes/day (254) .. » 6,0 8.6 37.4 40.9 DAO cigarcttes/day (66) .... ccc ccs eee aaes 1.3 1.4 31.5 45.3 ‘Numerous experiments detailing changes in bronchial epithelium are detailed tnbularly in the Cancer chapter, EXPERIMENTAL STUDIES ANIMAL STUDIES A number of investigators have studied the effect of the inhala- tion of cigarette smoke on the macroscopic and microscopic struc- ture of the tracheobronchial tree and pulmonary parenchyma of animals. Studies dealing with metaplasia and cellular atypism of the trachea and bronchi are listed in table A16 of the cancer chap- ter. Studies more directly concerned with the pathology of COPD are listed in table 9. They show that cigarette smoke exposure is associated with changes similar to those found in humans with COPD, i.e., bronchitis, parenchymal disruption, alveolar septal rupture, alveolar space dilatation, and the loss of cilia and ciliated cells in the bronchial mucosa. The investigations of Auerbach and his coworkers (10, 16, 88) have demonstrated by the use of both light and electron microscopy that dogs who inhale cigarette smoke through tracheostomas de- velop progressively more severe lesions of the bronchi and paren- chyma with increased exposure to cigarette smoke. In electron microscopic studies of specimens taken from the lungs of dogs thus exposed to cigarette smoke, the following changes were observed : In 5 dogs sacrificed after only 44 days of smoking exposure, there was a proliferation of goblet cells as well as a partial loss of cilia in the lining cells, and in 5 dogs sacrificed after 420 days or more of exposure, the number of cell layers in the bronchial epithelium was found to be twice that of the nonsmoking dogs. Goblet cells and ciliated columnar cells were no longer present ; instead, the surface was lined with columnar and cuboidal cells with stubby projections in place of cilia. Mitotic figures were frequently observed in the basal cells. These findings may be relevant to carcinogenesis as well as to the development of COPD. In a long-term experiment, carried out by the same group, dogs doses of cigarette smoke. Details of the experimental procedure have been outlined in the section on Pul- monary Carcinogenesis. The animals were separated into non- smoker, filter-tip cigarette, nonfilter-light, and nonfilter-heavy ex- posure groups. The dogs were “smoked” for 873 days, or approxl- mately 29 months. The animals which died during the experiment and the animals sacrificed after day 875 were examined for pul- . monary parenchymal changes as well as for bronchial epithelial alterations. As seen in figures 1 and 2, dose-related pathological changes, including fibrosis and emphysema, were found in the lung parenchyma of the exposed dogs. These changes were similar to those seen in the lungs of humans with COPD. were exposed to varying 184 S8T TABLE 9,.—Experiments concerning the effect of the inhalation of cigarette smoke upon the tracheo-bronchial tree and pulmonary parenchyma of animals (Actual number of animals shuwn in parentheses) Author, A. Type of year, Animal exposure country, and B. Duration Results reference strain C. Material Leuchten- 603 CF, A. Inhalation, Number of mice showing specified changea berger, female mice. B. Up to 8 cigas Number Number etal, rettes/day for Months of of No Mild Severe bronchitis 1960, up to 2 years, exposure cigarettes mice change bronchitta with atypiem U.S.A, C. Cigarette smoke, 0 0 150 146 2 2 (no atypism) {1S2), 1-3 100-200 36 20 9 7 4-8 260-500 36 19 10 1 9-29 600-1600 34 19 7 8 1-23 26-1526 161 88 33 30 Hotlund 60 rabbits, A. Inhalation, Cytoloyy of trachcobronchial mucosa etal, B. Up tw 20 ciga- Generalized Generalized 1963, rettes/day for Normal Focal hyperplasis Ayperplasia cnt phyacma (123), 2-5. Controls va (30)21/30 6/30 3/30 1/30 C. "Normal ciga- Exposed sree (80) 7/30 10/30 9/30 11/30 rette smoke’, Hernandez Adult Grey- A, Inhalation. Mean Mean etal, bound L. Twice daily/ Number of “number of parenchymal Groups Wi86 dogs, 5 per week, sections nignths digruptwnu/doy compared Pevalue U.S.A. C. Cigarette I, Controls (8) 112 we 0.7150 l-Ull ingigniticant (fir). smoke, Il. All exposed sae (15) 205 10,50 0.9583 Tl-} hisigniticant Il. Exposed <1 year... (7) 98 4.60 0.6423 IH-1V p <0.05 IV, Exposed >l year ....., (8) 107 W474 3.2350 1V-I p<0,02 98T TabpLe 9.—Experiments concerning the effect of the inhalation of etgarette smoke npon parenchyma of animals’ (cont.) (Actual number of animals shown in porenthesea) the tracheo-bronchial tree and pubnonary Author, A. Tyne of year, Animal exposure country, and B. Duration Results reference strain C. Material Auerbach Beagle dogs. A. Active inhalation Controls ....(10)—No evidence of pulmonary fibrosis or septal rupture. etal, vin tracheostomy, Exposed .U0)-Rarly (sacrificed): 1967, B. Up to 12 cigarettes t. Alvevlar apace dilatation. U.S.A. per day for up 2. Padelike attachments to alveolar septa. (15,16). to 423 days, Medium exposurc: Septal wall thickening. C. Cigarette smoke. Lateat crposure; 1, Focal subpleural pulmonary fibrosis. 2 Ruptured alveolar septa, 3. Granulomata. Frasea Beagle dogs. A, Active inhalation Electron microscopic results: etal, Via tracheostomy. After 44 days — Increased number uf goblet eclis. 1968, B, Up to 12 cigarettes Decreased number of cilia un surface lining cells. U.S.A. per day fur up After 420 days— Increased number of epithelia! cell Jayers. (88). to 423 days. Loss vf ciliated columnar cells. s Numerous experiments detail C. Cigarette amoke. ing changes in bronchial e Frequent interruptions in basement membrane. pithelium are detailed tabularly in the Cancer Chapter. 100 91.7 80-— wn b z 9 Be oO uw 60-- n g z 5 L a a o wp 40f- z a oO ond ul L a 20h—- 12.9 y 5.7 BOPUTS PREG 0 0.0 URS GROUP N: GROUP F: GROUP L: GROUP H: NONSMCKING FILTER-TIP NO FILTER NO FILTER ('% as many cigarettes) as Group H Ficure 1.—Percent of lung sections with grade IV or V fibrosis. Sources: Hammond, et al. (104). Several investigative groups have exposed rodents to various ambient concentrations of nitrogen dioxide over prolonged periods of time. This gas is found in cigarette smoke and in some indus- trially polluted air. The results of these studies are outlined in table A10. It is clear that chronie exposure to low levels of NO, is capable of inducing lesions in the bronchial tree although the rela- tionship between these changes, cigarette smoking, and the devel- opment of COPD remains to be determined. Rosenkrantz, et al. (196, 197) have recently undertaken experi- ments dealing with pulmonary cellular metabolism. They exposed Swiss albino mice to cigarette smoke or its vapor phase for varying lengths of time. On autopsy, animals exposed to cigarette smoke showed elevations in the levels of lung DNA, lactate, and glycogen which the authors conclude reflect hyperplasia and macrophage infiltration. Similarly, a dose-related increase in lung hydroxypro- line was observed. This was considered to be due to increased fi- broblastic collagen synthesis. 187 100 sof o z 3 5 - o ul ° 60 oa z 2 a - o - z ial 40r- a « pers a GROUP N: GROUP F: GROUP L: GROUP H: NONSMOKING FILTER-TIP NO FILTER NO FILTER CA as many cigarettes) as Group H FIGURE 2.—Percent of lung sections with grade If or HT emphysema. Sources Hammond, et al. (104). Aviado and coworkers have performed a series of experiments on live animals and in heart-lung preparations to study the effect of cigarette smoke on pulmonary physiology and structure (18, 19, 20, 21, 22,179, 180, 199, 200, 201, 202). The authors observed that cigarette smoke causes acute bronchoconstriction both by the re- lease of histamine and the stimulation of parasympathetic nerve pathways in the lung. Bronchial arteria] injections of nicotine were found to cause reactions similar to those observed after cigarette smoke inhalation. The bronchoconstriction was usually followed by bronchodilatation which the authors attributed to sympathetic stimulation. As mentioned in the Chapter on Cardiovascular Dis- eases, nicotine has been shown to induce the release of catechola- mines. Experiments by Aviado and coworkers as well as other authors (66, 99) using guinea pigs showed that exposure to cigarette smoke was associated with increased bronchopulmonary resistance and decreased pulmonary compliance. The authors related these changes to the bronchoconstriction of terminal ventilatory ‘units. 188 Similar experiments in dogs showed that the increase in resistance following either cigarette smoke exposure or intravenous nicotine could be blocked by pretreatment with atropine. As a parasympa- thetic blocker, atropine would decrease the acute bronchoconstric- tive phase. Most recently, Aviado and his colleagues (20, 130) have at- tempted to induce physiologic and anatomic changes similar to those found in the lungs of patients with emphysema. They ex- posed male rats to cigarette smoke, the introduction of the enzyme papain, as well as to partial tracheal ligation. In 10 rats exposed to cigarette smoke twice daily for 30 minutes over a period of 10 weeks, no changes in pulmonary compliance or resistance were noted. Also, no abnormal histological changes were observed in the group exposed only to cigarette smoke. However, animals who underwent tracheal ligation as well as smoke exposure showed in- creased numbers of enlarged air spaces and increased pulmonary resistance when compared with animals who underwent only tracheal ligation. STUDIES IN HUMANS The acute effects of cigarette smoke inhalation on bronchopul- monary function in man have been investigated by a number of workers. The results of these studies are presented in table 11. The majority of studies, particularly the more recent ones, found that the inhalation of cigarette smoke is associated with an acute in- crease in pulmonary resistance and a decrease in pulmonary com- pliance. Chapman (48) also observed decreases in pulmonary dif- fusing capacity and arterial O. tension. Chiang and Wang (51) noted changes in nitrogen washout time and alveolar dilution fac- tor, alterations which reflect impaired alveolar ventilation and gas mixing. James (131) examined the effect of prior smoking on the mul- tiple breath nitrogen washout test in 41 pneumoconiotic miners and 2 normal young males. Prior smoking of a cigarette in the subject’s- normal manner was found to adversely affect the indices of dis- tribution in 20 percent of the miners and in all of the 5 normals who smoked within one hour of testing. The author suggests that smoking be prohibited prior to any series of pulmonary function studies. Anderson and Williams (9) studied the acute effect of cigarette smoke inhalation upon the ventilation-perfusion (V/Q) measure- ments in the lung in normals and in patients with COPD. Cigarette smoking was observed to cause acute changes in the V/Q measure- ments, and the COPD patients were found to be particularly Hable to these changes. 189 Finally, Robertson, et al. (194) studied the effect of unfiltered and filtered cigarette smoke and cigar smoke upon bronchial re- activity in 19 of the most reactive persons in a group of 91 heavy smokers. They observed that bronchial reactivity was significantly reduced by increasing the retention efficiency of the filter and that reactivity to inhaled cigar tobacco was no less than that to cigarette smoke. They concluded that differences in inhalation account for the difference in COPD prevalence observed between cigarette and cigar smokers. SruDIES CONCERNING PULMONARY CLEARANCE Overall Clearance The ability of the !ung to rid itself of inhaled particles that can- not be easily exhaled is dependent upon a number of physiologic mechanisms including ciliary activity, the mucous sheath, and the pulmonary alveolar macrophage. Studies concerning the effect of human cigarette smoking and the exposure of animals to cigarette smoke on this clearance system are presented in table A13. LaBelle, et al. (145) and Bair and Dilley (23) observed no change in clear- ance following the exposure of rats, rabbits, or dogs to cigarette smoke. The latter authors noted, however, that normal clearance rates obtained prior to smoking were too low to reflect any sig- nificant change except complete cessation. Albert, et al. (3) exposed donkeys to cigarette smoke via nasal catheter and observed impairment of clearance times. Holma (125) obtained similar results in rabbits. In a related study, Albert, et al. (2) studied the bronchial clear- ance times of 9 nonsmokers and 14 cigarette smokers in a total pop- ulation of 36 subjects. The rates of bronchial clearance were slower on the average in the cigarette smokers when compared with the nonsmokers, although a wide variation was present in each group. In relation to their study mentioned above, they also noted that the shape of the whole lung clearance curves seen in smokers (with markedly prolonged 50 percent clearance times) was similar to that developed in the donkey following acute exposures to sulfur dioxide or cigarette smoke. Ciliary Function Numerous experiments have shown that cigarette smoke or cer- tain constituents of cigarette smoke adversely affect and can even bring about a cessation of ciliary activity in respiratory epithelium in vivo and in vitro in cultures of ciliated microorganisms. The re- sults of a number of these experiments are presented in table 12. 190 Ciliary activity has been shown to be affected by particulate matter as well as by the gas phase components of cigarette smoke. The rel- ative importance of these two large classes of components of smoke in producing ciliastasis is presently a matter of some discussion. Dalhamn and Rylander (68, 64) consider the particulate phase to be of greater importance while Battista and Kensler (28, 29) con- chide that gas phase components are more important in the induc- tion of cillastasis. , Studies investigating the effect of cigarette smoke on the morphology of the tracheobronchial tree in animals have noted a decrease or absence in the number of cilia in smoke-exposed ani- mals. Recently, Kennedy and Elliot (734) studied the effect of the direct exposure of cigarette smoke upon the electron microscopic structure of protozoan mitochondria. After 42 minutes of exposure to mainstream smoke, they noted destruction of the internal mem- brane structure of the mitochondria. Thus, cigarette smoke has been shown to be toxic to ciliary func- tion by pathological (including electron microscopic) and physio- logical methods. Phagocytosis The effect of cigarette smoke upon pulmonary alveolar phago- cytosis, one part of the clearance mechanism, has been studied by several authors. Masin and Masin (162) observed increased varia- tion in the size of lipid inclusions in sputum macrophages obtained from smokers as compared to those obtained from nonsmokers. They attributed these differences to a combined effect of irritation of the alveolar lining, increased turnover of alveolar cells, and in- creased injury to the macrophages. Green and Carolin (96) noted that cigarette smoke inhibited the ability of rabbit alveolar macro- phages to clear cultures of S. aureus. This effect was noticeably reduced by filtration. Similarly, Yeager (239) exposed rabbit alveolar macrophages which had been induced by Af. bovis to cigar= ette smoke and observed a dose-dependent decrease in protein syn- thesis. This alteration occurred at smoke solution concentrations that did not affect cell viability. The alteration was only partly re- versible and was due mainly to gas phase components, Myrvik and Evans (175) observed similar protein synthesis alterations in macrophages exposed to NO;. Roque and Pickren (195) obtained alveolar macrophages at thoracotomy from 17 smokers and 4 nonsmokers, They found a decrease in the activity of oxidoreductases and hydrolases in the macrophages of smokers. The reduction in the enzymatic activity was directly proportional to the amount of stored fluorescent ma- terial present in the macrophages. This materia] was thought to 191 Z6L TABLE 11.—Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function Author, A. Method } year, Number and B, Material? country, type of C, Duration of Resulta Comments reference population smoking Bickerman J. 66 male and A. Pulmonary Vital capacity (VC) Maximal breathing capacity 9/91 patients showed and 26 female function, I. 10/91 decrease. 10/81 docrease. VC increase due to Barach, patients B. 3 cigarettes, Il. No significant change. No significant change. clearance of secre- 1984, with chronic C. 30 minutes, tions, All mild or U.S.A. nontuberculous modcrate smokers. CSE). respiratory discuses (avernge age 50). II, 20 male and 1 female normal sub- jecta (average age 20). Eich, I. 31 patients with A. Esophageal balloon Mean airway reafetance Mean airway compliance etal, obstructive technique to 1, Statiutically elynificant No change. 1967, pulinonary measure pulmonary Incrouse, U.S.A, emphysema, complinnee ond Il, No change. No change. (78), UW, 14 normal resistance. Hil, No change, No change. subjects, B, lelgarette. III. & patients with C. Undefined, respiratory complaints. All habitual smokers. TABLE 11,—L'vperiments concerning the acute effect of cigarette smoke inhal atton on human pulmonary function (cont.) Author, A. Method! year, Number and B. Material? country, typeof C, Duration of Results Comments reference population smoking Attinger 1. 20 normal A. Esophngal balloon I, No change. No change. etal, subjects technique to measure 1958, (10 Sm, pulmonary compliance U.S.A, 10 NS). and resistance. (23). I]. 34 pationts with B. 1~4 cigarettes, If. Expiratory resistance rose No change. various diseases: 9 rheumatic heart diseases, 8 pul- monary emphy- seman, 7 asthma, 5 pulmonary fibrosis, 5 undefined, C. 10 minute interval between vigarettes, significantly only among Patients with emphysema, Motley and Kuzman, 1988, U.S.A. (174). Nadel and Comroe, 1961, U.S.A, (176), 125 males and 16 females (24-70 years of age—normals and patients), I, 22 patients with cardiopulmonary discase—all smokers, IT, 36 normals (21 smokers, 15 nonsmokers). A. Pulmonary function. B. 2 cigarettes. C. Undefinet. A. Body plethy- smography, I B. 15 puffs. C. 5 minutes, I. 41 smokers (8 normals, 33 patients with cardio- pulmonary discase), Airway conductance/thoracte gas volume 18/22 significant decrease (inhibited by pretreatment Pulmonary compliance Significant decroase after smoking. with isoproterenol acrosul), 31/36 significant decrease isoproterenal avrosal). (inhibited by pretreatment with Various groups of normals and cardios pulmonary pationts showed litth or no change in arterial po, during exercise and at reat follows ING Cigarette smoke inhalution, Nicotine bitartrate aerosol evoked no change. Cor vot TABLE L1.—Kperiments concerning thy acute effuct of cigarette nnake infalation an dieman pudmarary fretion (cont) Author, A, Method? year, Number and N. Material? country, type ol C, Duratlon of Result Comments reference population smoking Shmonmson, I, male and 7 A. Pulmonary Afcun FEV, Mean FEV 4 No algnificant chanwens W062, femole normale funeton, (imedintely after) (45 minute tater) oburrved tn Eb /P YC, Bweden, (most amokern), ood clwaretde, 1. Slwalilcant decrease. No slgnitlennt decrease. (t07). TE, 16 arate wud t C. 6-6 minutes H. Sleniflcant decrease, SlgnsAMeant decrense, female pulmonary per cignrette, discuse patient (moat smokers). Zamel Tr. Omaleandé A. Body picthye Airway resistance etal, female nonsmokers. amography. 1. Significant increase, 1063, Il. 6 male and 6 B. l cigarette, I. Significant Increase, England, female smokers C, Undefined, (240), (18-32 years of age.) Chapmon, I. 12 normal A. Pulmonary function 1. All showed a decrease tn diffusing eapacity, 1965, volunteers Arteriul blood IL 4/6—wignificant decrease in arterial 0, tension, Ireland (all smokers). atudies. No change in vital capacity or FEV. (48). Il. 6 paticonta with B. 1 cigarette, chronic non- C. Undefined. apecilic lung disease, McDermott I, 32 normals. A. Body plethy- Mean airway restetance Light smokere showed and II, 28 with chronle smography, I, Significant increase. greater changes than Collins, bronchitia B. Cigarette. I]. Significant increase. heavy smokers, 1966, (All ciga- C. Undefined. Wales rette smokers (160), 35-60 years of age.) TABLE 11.—Experiments concerning the acute eff ect of cigarette smoke inhalation on human pulmonary function (cont.) Author, A. Method} year, Number and B. Material? country, type of C, Duration of Results Commenta reference population smoking Millerand 10 normal A. Esophageal bailoon Dynamic Ingpiratory and Sproule, cigarette technique. FEV) 5 compliance expiratory reatatance 1966, smokers B. 1 cigarette. No significant Significant Significant ULS.A, (40 years C. One inhalation change decrease, incrense (166). of age}. every 30-60 seconds, Sterling, 11 normal adults A. Body plethy- Airway resistance 1067, (8 smokers, smography. Significant increaso (Return England 3 nonsmokers). B. 16 inbalationa. to normal in $0 minutes). (212). C. 6 minutes. Chiang and 7 male normal A, Pulmonary function Nitrogen washout Lung clearance Alveolar dilution All lung volumes, Wang, nonsmokers Nitrogen washout. time index factor exeept for residual 1970, {18-43 years B. 2 cigarettes. Significant Significant Significant volume showed no Formosa of age). C. Undefined. increase. increase. ducreuse. significant change. (61). No significant change in any of the flow rates. Guyatt 710 subjects; A. Body plethy- Bronchoconatriction On the averuge, non- etal, 608 smoked amography. Significant increase with amoking. smokers and cx-smokort 1970, between meas- B. l cigarette. showed bronchudilation England ures 202 C. Undefined. and smokers showed (100), did not smoke. 1 All the experiments listed concern studies of pulmonary function be- fore and after smoking the epecified number of cigarettes (unlesa other- wise specified). bronchoconstrictivn. The wuthors postulate that the rewult omong nonsmokers is duo to the release of adrenal hovmones in these sub- jects. 96T TABLE 12.—Ezperiments concerning the effect o f cigurette smoke on human and animal pulmonary clearance Author, year, country, Subjects Method Results Commenta reference Laurenti Swiss-Webster Mice exposed to Significant increase in S. aureus retention in mice exposed to: etal, male mice. aerosol of S. aurcus (a) hypoxia—retention ratio 2.5 (10 percent 04). 19638, and sacrificed at (b) cigarette smoke—retention ritio 4.6. ULS.A. intervals following (149), exposure to various stimuli. LaBelle Albino female Silver judide or 17-30 hours uf exposure to cigarette smoke coused no change In pulmonary etal. rabbits. colloidal gold clearance ag comparad with controly breathing room air. 1966, intratracheally, ULS.A. (£45). Bair and Sprague-Dawley Radioactive aerosol. Acute exposure to cigarette smoke had no gross effect on clearance. Chronic Dilley, female rata, exposure to cigurette smoke (up to 18-20 cigarettes/7 bour day/6 day week 1967, male beagle dogs. Radioactive aerosol, for up to 420 days) had no observable effects. The authors noted, however, U.S.A, that normal clearance rates were too low to reflect anything but complete (23). cessation. 50 percent 90 percent t Approximate values. clearance clearunce Noneold nonsmokers Albert 36 subjects Radioactive tagged Number of Average time time had 60 percent times etal, undergoing 117 Fed, particles subjects age (minutca) (minutes) over 200 minutes or 1969, experiments. measured with Nonsmokers ..seesereeeerene 9 28 88 357 90 percent times over U.S.A, Scintillation All smokers M4 33 192 $496 600 minutes while (2). counter, 20+29 cigarettes/day .sereeees 1 29 191 4519 6/14 smokers exceeded 30-40 cignrettes/day .....-. oe q 36 163 {ATA both these limits. Uranium miners oo... seen eee 3 62 310 £380 Cigar and pipe smokers 4 46 81 376 Emphysema patients ....+-. 0+ 2 66 330 676 Lot TABLE 12.—-Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance (cont.) Author, year, country, Subjects Method Results Comments reference Albert Donkeys exposed Radioactive tagged Average Trachaeltranait Those donkeys exposed etal, to cigarette Fed, particles number time to the greatest 1969, amoke by nasal measured with cigarettes in Percent clearance Halftime clearance amount of smoke U.S.A. catheter. Scintillation g-hour period Control Cigarette Control Cigarette Control Cigarette showed residual (S), counter. 18-24 58 69 1.2 1.9 0.6 1.2 impairment of 36 58 64 1.0 34 0.4 5.8 clearance for at least 2 monthy after acute exposure, Holma, Rabbits Cr*! monodisperse Exposure to fresh cigarette smoke (1.5 cc. puffs, 40 pulfs/8 minutes) caused 1969, (anesthetized). polystyrene a ‘significant’ increase in lung retention 10 minutes following cesyation of USA, aerosol, exposure. (125). originate in tobacco smoke. The authors suggested that the tobacco smoke may have induced abnormalities in the mitochondria of the macrophage. In a study of pulmonary macrophages harvested by endobronchial lavage from smokers and nonsmokers, Pratt, et al. (187) observed that the macrophages of smokers contained an ab- normal pigment. These studies indicate that the function of pulmonary clearance carried on by the macrophage and ciliary systems is adversely af- fected by cigarette smoke. STUDIES CONCERNING THE SURFACTANT SYSTEM The surfactant system of the lung consists of various biologically active compounds such as phospholipids and mucopolysaccharides which are present in the alveolar lining. Norma] pulmonary func- tion is influenced and partly determined by the integrity of this system (203). The purpose of the surfactant system is to main- tain the proper amount of surface tension in the alveoli so that the expansion and contraction of the alveoli are facilitated. Studies concerning the effect of cigarette smoke upon the sur- factant system and the surface tension of the pulmonary alveoli are presented in table Al4. Exposure of rat and dog lung extracts to cigaretie smoke has been found to induce a notable decrease in the maximal surface tension demonstrated by the extracts (94, 165, 224). Cook and Webb (57) observed that surfactant activity was diminished in smokers and in patients with pulmonary disease when compared with healthy nonsmokers. Scarpelli (203) ina recent review, concluded that the lowering of maximal surface tension by cigarette smoke has been demon- strated reasonably well. The relationship of these findings to the pathogenesis of emphysema is unclear at this time. OTHER RESPIRATORY DISORDERS INFECTIOUS RESPIRATORY DISEASES Several studies have examined the question of whether ciga- rette smokers are at an increased risk of developing infectious res- piratory and bronchopulmonary disease. Table Al5 presents a summary of these studies. Lowe (157) observed an excess of smokers among 705 tuberculosis patients, but Brown and Campbell (48) in a similar study found that the difference was not present when the cases and controls were matched for alcohol intake. More recent studies have been concerned with the frequency of upper respiratory infections among groups of smokers and nonsmokers. A number of investigators (108, 181, 183) have reported increased 198 rates of respiratory illnesses among smokers, Finklea, et al. (83) studied a male college population (prospectively) during the 196869 influenza epidemic. They found that smokers of all amounts experienced more clinical ilIness than did nonsmokers and that this relation was dose-dependent. Similarly, smokers required more bed rest than nonsmokers. A survey conducted by the National Center for Health Statistics (220), involving approximately 134,000 persons, showed that male cigarette smokers reported 54 percent more cases of acute bron- chitis than males who had never smoked cigarettes, while female smokers reported 74 percent more acute bronchitis than did females who had never smoked. Male cigarette smokers reported 22 percent more cases of influenza than did males who had never smoked cigar- ettes, while the female smokers reported an excess of 9 percent. Experimental evidence in support of this relationship has been noted by Spurgash, et al. (211). Mice were challenged with Klebsiella pneumoniae or Diploecoceus pneumoniae before or after a single exposure to cigarette smoke. They observed that those ani- mals exposed to smoke exhibited a decrease in resistance to respira- tory infection, as shown by an increase in mortality and a decrease in survival time. Preexposure to cigarette smoke was found to have no significant effect on resistance of mice to influenza infection initiated by aerosol exposure. However, exposure of infected mice to smoke resulted in significantly higher mortality, thus suggest- ing that cigarette smoke can aggravate an existing respiratory viral infection. In the light of the experimental evidence presented above con- cerning the effect of cigarette smoke on pulmonary clearance, phagocytosis, and ciliary function, it seems reasonable to conclude that such changes in tracheobronchial physiologic function would predispose a person to respiratory infections or aggravate already existing ones. : Further evidence is derived from the work of Henry, et al. (109) and Ehrlich, et al. (75). These investigators exposed squirrel monkeys to atmospheres containing 10 and 5 p.p.m. of nitrogen dioxide. They observed that this exposure increased the suscepti- bility of the animals to airborne Klebsiella pneumoniae as demon- strated by increased mortality and reduced Jung clearance of viable bacteria. Infectious challenge with influenza virus 24 hours before exposure to 10 p.p-m, was fatal to all monkeys within three days. Infected controls showed symptoms of viral infection but did not succumb to the infection. The extent to which the various oxides of nitrogen present in cigarette smoke contribute to the increased sus- ceptibility to respiratory disease noted in smokers is presently undefined. 199 POSTOPERATIVE COMPLICATIONS Several studies have been published which examine the questions of whether smokers run an increased risk of developing postopera- tive pulmonary complications over nonsmokers undergoing similar operations. Morton (173) reported on a study of more than 1,100 patients undergoing abdominal operations in which he found that cigarette and mixed smokers were significantly more likely to develop bron- chitis, bronchopneumonia, or atelectasis during the postoperative period than nonsmokers (table Al6). Wiklander and Norlin (229) examined the incidence of post- operative complications in 200 patients undergoing laparotomy in the winter months when it was expected that pulmonary comphi- cations would be at their maximum. These authors found no sig- nificant differences between the frequency of complications in smokers and nonsmokers. No information about the definition of a smoker and no data on dosage of tobacco smoke were reported. Piper (186) observed the prevalence of postoperative pulmonary complications in 150 patients undergoing laparotomy. Of the total sample, 66.7 percent developed pulmonary complications during the first postoperative week, All patients considered in the statis- tical analysis as having pulmonary complications had radiographic evidence of disease. Of the cigarette smokers, 73.5 percent had complications as compared to 55.5 percent of the nonsmokers. When the smokers were divided according to dosage, heavy smok- ers being those consuming more than 10 cigarettes per day for the previous six months, 55 percent of light smokers and 88 percent of heavy smokers were considered to have postoperative compli- cations. Piper also reported that stopping smoking for up to four days preoperatively had no apparent effect on the incidence of complications. Wightman (228) reported on the incidence of postoperative pul- monary complications in 455 patients undergoing abdominal oper- ations and in 330 patients undergoing other operations. Of the cigarette smokers, 14.8 percent developed complications as com- pared to 6.3 percent of the nonsmokers. The substantial difference between these figures and those of Piper (186) is due to the latter’s use of radiographic criteria alone. Wightman utilized only clinical criteria. Morton (172) has recently reported a study of postoperative hypoxemia in 10 patients, 5 of whom were cigarette smokers. Four of the smokers had chronic bronchitis. He found that the smokers had a more pronounced decrease in arterial oxygen saturation, per- sisting into the second postoperative day (table A17)- 200 In summary, the majority of studies so far reported indicate that cigarette smokers run a higher risk of developing postopera- tive pulmonary complications than do nonsmokers, corroborating a long-held clinical impression. The risk of developing such com- plications appears to increase with increasing dosage of cigarette smoke. SUMMARY AND CONCLUSIONS 1. Cigarette smoking is the most important cause of chronic ob- structive bronchopulmonary disease in the United States. Ciga- rette smoking increases the risk of dying from pulmonary emphy- sema and chronic bronchitis. Cigarette smokers show an increased prevalence of respiratory symptoms, including cough, sputum pro- duction, and breathlessness, when compared with nonsmokers. Ventilatory function is de¢reased in smokers when compared with nonsmokers. 2. Cigarette smoking does not appear to be related to death from bronchial asthma although it may increase the frequency and se- verity of asthmatic attacks in patients already suffering from this disease. 8. The risk of developing or dying from COPD among pipe and/ or cigar smokers is probably higher than that among nonsmokers while clearly less than that among cigarette smokers. 4. Ex-cigarette smokers have lower death rates from COPD than do continuing smokers. The cessation of cigarette smoking is associated with improvement in ventilatory function and with a decrease in pulmonary symptom prevalence. 5. Young, relatively asymptomatic, cigarette smokers show measurably altered ventilatory function when compared with non- smokers of the same age. 6. For the bulk of the population of the United States, the im- portance of cigarette smoking as a cause of COPD is much greater than that of atmospheric pollution or occupational exposure. How- ever, exposure to excessive atmospheric pollution or dusty occupa- tional materials, and cigarette smoking may act jointly to produce greater COPD morbidity and mortality. 7. The results of experiments in both animals and humans have demonstrated that the inhalation of cigarette smoke is associated with acute and chronic changes in ventilatory function and pul- monary histology. Cigarette smoking has been shown to alter the mechanism of pulmonary clearance and adversely affect cillary function. 8. Pathological studies have shown that cigarette smokers who die of diseases other than COPD have histologic changes charac- 201 teristic of COPD in the bronchial tree and pulmonary parenchyma more frequently than do nonsmokers. 9. Respiratory infections are more prevalent and severe among cigarette smokers, particularly heavy smokers, than among nonsmokers. 10. Cigarette smokers appear to develop postoperative pulmo- nary complications more frequently than nonsmokers. CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE REFERENCES (1) AssoTt, O. A., Hopkins, W. A., VAN FLEIT, W. E., Rosinson, J. S. A new approach to pulmonary emphysema. Thorax 8: 116-132, 1953. (2) ALBERT, R. E., LIPPMANN, M., Briscoe, W. The characteristics of bron- chial clearance in humans and the effects of cigarette smoking. Archives of Environmental Health 18(5) : 738-755, May 1969. ALBERT, R. E., SPIEGELMAN, J. R., SHATSKY, S., LIPPMANN, M. 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American Review of Respiratory Dis- eases 89(1): 73-81, January 1964. 217 BRONCHOPULMONARY APPENDIX TABLES 219 Tez TABLE A2.,—Smoking and chronic obstructive pulmonary disease symptoms'—percent prevalence (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokera. NS = Nonsmokers. EX <= Ex-smokers, Author, year, Number and Breathlessness . country, type of Cough Sputum production or dyspnea Chest illnesses Other Cominents reference Population Short 2,031 male and NS....... 16 (496) NS .........10,9 Chest ilincases etal, female ineurance SM ....... 6.4(1,293) SM o..e. ee 18.0 ay yepre- 1939, policy holders, sented by USA, frequent (£06), colds, Oswald 3,602 male and Chronic Bronchitts Chronic and 2,242 female Malces brunchitis Medvei, clerical NS .......16.8 (474) defined ly 1956, workers 40-65 SM .......18.4 (1,940) habitual England years of age. Females cough and (178). NS ..,.,..121 (619) aputunt SM .......18.8 (879) production. Phillips 1,274 male NS....... 2,0 (461) etal, factory workers SM .......61.0 (823) 1956, without overt U.S.A. pulmonary (185), disenge or heart failure. Higgins 301 male and Cough and aputum Chronic Bronchitis 1957, 280 female Malee Males Males Males England rural dwellers NS vw, TL (28) NS vice eeeeee TE NS oo. 86 NS ciseeee 26 (212). 25-74 years of SM .4.......63.9 (222) SM ......0..-998 SM... WL SMM 6... 99 age, Females Females Females Females NS ....ece.. 4B C176) ONS cee 216 NS occa BT ONS cecsees 34 SM ow. ce ee kT (93) SM eee OT SM rece ae 15.2 SMM ......, 8.6 CCS TABLE A2,—Smoking and chronic obstructive pu (Numbers in parentheses represent total nu SM = Smokers. NS = Nonsmokers. bnonary, discase symiptonis'—percent prevalence (cont.) mber of individuals in particular smoking group) EX = Ex-smokers. Author, Number and Breathiesaness contr, type of Cough Sputum production or dyspnea Chest illnesses Other Comments reference population Higgins 94 males and Females Males Males Chronic bronchitis and 92 females Cough and aputum NS .cccc coe ee 893 NS... 0.0 Mates Cochran, randomly chosen NS vo. cee ee (6) SM vice eee ee 293 SM ...., 16.0 NS visee es 0.0 1958, (members of an SM .........24.0 (75) Females Fematea SM ....--- 67 England agricultural NS occccceas Gl (64) NS. vee eee ABB NSO. 10,9 Females (1th). community.} SM occ cc cee BO (20) SM Lecce ce ee 2000 SM ..... 10.0 NS .,..... 0.0 SM ....e- 60 Edwards 1,737 male out= Chronic bronchitis etal., patients on NS ..c0ee-16.6 (181) 1959, lists of Cigarettes 29.7 (779) England general prac- i- 9 2.23.4 (236) (74). titionera >60 10-19 31.2 (969) years of age. >20 . 33.7 (175) Pipe . 18.5 (349) Flick 222 male NS ....5.510,0 (61) NS....... 28.0 (49) NS ..... 30.0 (47) and patients not SM .,...,-56.0 (157) SM........,66.0 (166) SM ...,.,. 60.0(13B) Paton, suffering from 1959, overt cardiae ULS.A, pulmonary (86). didease, 20-90 yenra of age. Wigwins 716 males in Cough and aputum Chronie bronchitis etal, various SM visveaeee Ti (8B) NS... ee cesses DA NS weeee Td SM weeee 143 1968, occupations NS o0.00255.36,8 (B75) SM vce ee eee 248 SM voce. 20.2 NS ...... 35 England 25-64 years (116), of age. ce TAULE A2.—Smoking and chronic obstructive pulmonary disease symplons'—percent prevalence (cont.) (Numbers in parentheses represent totel number of individuals in particular smoking group) SM = Smokers. NS = Nunsmokers. EX =: Ex-smokers. Author, year, Number and Breathlessness country, tyne of Cough Sputum production or dyspnea Chest illnesses Other Comments refrrence population Higgins, 393 males in Cough and sputum Chronic bronchitia Chronic 1959, Vurious NS ........ 62 (33) NS .......6.6. 18.2 NS eee 30 NS ...... 0.0 bronchitis Englond occupations \+14g./day 9.7 (173) \-14g./day 30.1 l-ld4g./day 23.7 1-14 g./day 13.9 defined as (113). 65-64 years >15 wees 42,3 (142) Dis ......... 338 15 ........,23.9 DIB ..... 17.6 persistent of age. sputum and at tenst ] chest Hinesy in past d yours. Tobneco ram equivalents. are: Lcigarette rz. ld ywram, Locigar cs 2-0 Krams, lpipen 1-05 grams, Liebeschuetz,147 male NS ...... (52) 1053, soldiers SM oo... (83) England 20~30 years (1568), of age. Ashford eee a vere Respiratory symptoms Respiratory 1801, ' NS cere 103 (677) Bymptuma— ‘England EX ....6.19.8 9 (123) “bronchitis Un), Cigarettes 21.1 (1,504) and/or Pipeonly 36.1 (202) asthma’. No Cigarettes doge rela- and pipe 37,1 (90) tionship —— ANSM .. 21.7 (8,214) found. 720 TABLE AZ.—Smoking and chronte obstructive pulmonary disease aymptoms'—-percent prevalence (curt.) (Numbers in parentheses represent total numbe r of judividualy in particular smoking group) SM = Smokera. NS = Nonamokers. VX cz Ex-amokers. Author, yeur, Number and Breathlessness country, type of Cough Sputum production or dyapnea Chest illnesses Other Comments reference population Bower, 96 male and NS .....0. 4b (49) NS vices 204 NS ....6 OAT Chest inese— 1961, 71 female SM vcccee 27.6 (16) SM eee 34.2 SM ......88.2 chent colda U.S.A. bank employees Pipe, cigar =.. (18) Pipe, elgar 16.4 Pipe, elgor during cach (41). 40-70 yonrs 62.9 of Inst & of ue. wihrtess. Fietchor and 863 mate London NS cscveeee ae (80) NS viceeceees OF NS p.cceeeree 8 NS ..ceee 48 Tinker, transport l-la4g./dny 16.8 (106) t-l4g-/day ..20.9 Ieldg./doy .. 8.2 1-14 g./day 1061, employees DIB cures 27.8 (116) Pls rene BOD DIG ...ee reer 86 8.2 England 40-00 years DIB 4.6 107 (85), ofuge. Read 170 male and Males and 132 female NS v..caeee 44 Selby, individuals SM .......,.28.1 1961, interviewed EX woe... 21.2 Australia in an out- Femalca (191), patient NS ...-.0-- 49 clinic (not SM... 18.6 all patients), Balebum 1,451 male NS ........40,.2 (268) NS wccee eee » 14.0 NS vciceeee ee 9.8 etal, Ught SM ....,...,23.3 (1,198) SM oo... 804 SM voc eevee AAS 1062, industry <1 packs 20 3.1132) 60.0 (4) Ferris 542 male and Chronic bronchitis Age-specific and 625 female Males rates. Andergon, residents of NS ...se. 13.8 (125) 1962, New Hampshire EX .......11,9 (77) ULS.A. town chosen Cigarettes 40.9 (340) (81). by randum 1-10 ..,..29.8 sumpling of 11-20 .,..,.34.2 census. 21-30 ..,.,.42.3 31-40 .0.. 62.1 Dal ow.’ 76.3 Females NS vi.eee GA (878) EX .....,.10,8 (37) Cigarettes 19.8 (208) 1-10 .....43,1 11-20 .....22.2 21-30 vo... 6. 31-40 .....27.3 >4l 92¢ TABLE A2.—Smoking and chronic obstructive pulmo (Numbers In parentheses represent total num NS = Nonsmokers. SM = Smokers. nary disease symptoms'—percent prevalence (cont.) ber of individuals in particular smoking group) EX = Ex-smokera. A on Number snd Breathlessness country, typeof Cough Sputum production or dyapnes Other Comments reference population Goldsmith $,381 active Respiratory etal, or retired conditions 1962, longshoremen, NS vince) B14 (744) U.S.A. Moderate/heavy (95). amokers 43,0 (1,288) Coates 1,842 male and Cough and chronic phlegm Current etal, 242 female NS ....0,2 (147) NS... 147 NS ovis 40 amoking 1965, Detroit post 1-14 ...12.7 (266) (not sig.) 1-14 .28.2(p<0.001) 1-14 ,.... 5-3(motalg.) data. U.S.A. office 15-24 ...27.5 (402) (p<0.001) 15-24 30,7 (p<0.001) 16-24 ....17.2(p<0.001) (53). employees. >26 ....36.4 (170) (p 0.001) >25 . 94,1 (p0.001) 326 coos 26.8(p<0,001) Deane 608 tele Persistent cough, NS includes etal, phone phlegm, dyspnea ex-smokers, 1965, company NS .....-. 4:6 (200) pipe, and U.S.A. workers. Current cigarette cigar (67), smokera 16.9 (808) amukers. Huht, 653 male and Malee Males Matlee Chronic bronchilis Ex-gsmokers 1966, 823 female NS teres AL (122) NS .... 15.6 Males represent Finland residents of EX vice. 8.5 (141) EX. 2 24,8 NS voc. 67 those who (126). a Finnish 1-14 ...,.,31.5 (108) d-ddo cea +. 26.0 EX ....+.-16.3 have communal 18-24 veces 40.8 (191) 15-24 weveeeee 26.2 1-14 ,..,.38.0 stupped region, D250 .4602.42.4 (85) eb ee ae 31.8 1b-24 0. Add sinoking 40-64 years Females Pematee 325 4. 400 for more of age. NS ...eeee 46 (709) NS van 29.2 Females than 1 EX veeeeeee 13.3 (30) EX .....8s 683.3 NS vice, 46 month. W140 0....104 (17) V-1d veveaeee 14.3 EX v.05, 189 Dyspnea 16-24 54... .43.0 (6) 15-24 15-24 I-14 ....104 Grade I DOB weecee ve GL) 88 57.0 >? } veseeees 14.0 -2 Sis t oo. B10 only. Lee TABLE A2,.—Smoking and chronic obstructive pulmonary discase syniplonsg'—percent prevalence (cunt.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokers. NS = Nonsmokers. EX = Ex-smokers. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other Comments reference population Wynder 316 male New York City etal, patients in NS vec 14.0 (44) 1966 New York City Pipe, cigar 33.0 (54) ULS.A. and 315 male Cigarettes: (288). patients in 1-10 .,.45.0 (44) California. 10-20 ...46.0 (88) 20 ....67.0 (86) California NS ....eee 22.0 (69) Pipe, cigar 30.0 (32) Cigarettes; 1-10 ...45.0 (64) 10-20 ...74.0 (91) >20 ....74.0 (69) Freour 1,055 randomly Clinteal aigne of etal, chosen males in bronchitis and 1966 Bordeaux 30-70 reaptratory France years of age, fnauficteney (92). NS ......254 (45) SM ...... 64.4 0 (478) Haynes, 179 male Average number of Henvy etal., Preparatory gcvere respiratory smuokepe 1966 school illucasca per 10 more than ULS.A. students students (adjuated 10 ciga- (108). 14-19 yeara foruye) reltes of age. NS oa... O96 per day. Allsmokers 2,30 Heavy SM 3.34 Bec TABLE A2.—Smoking and chronic obstructive pulmonary disease symptoms'—percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular smoking group) SM = Smokera. NS = Nonamokers. EX = Ex-smokers. Author, year, Number and Breathblesaness country, type of Cough Sputum production or dyapnes Chest illnesses Other Commenta reference population Densen 6,218 male Postal Poatal Postal Dyapnes etal. and 7,291 NS cecveee 7.0 (908) 13.1 19.8 represented 1967, female postal Pipe, clyar 12.4 (628) 17.4 24.8 by Grade IL U.S.A. and transit Clgarettes only, (68). workers. only ....27,0(2,687) 28.9 81.7 Transit Tranast Transit NS wees 6.4(1,012) 95 11.7 Pipe, cigar 10.6 (766) 14.1 14.2 Cigarettes only ....28,.6(8,745) 23.7 21.9 Higgins 926 white — NS .......16.4 (162) NS cccceeere ee 6.0 etal. male real- (SM .......47.2 (618) ban SM vvcreeeee 107 1968, dents of EX ...06..19.3 (144) EX wiceseeyeee 28.6 EX ......0-...16,8 ULS.A. Marion (218). County, Weat Virginia, 26-69 years of age. Holland 9,786 male Malca Fematcs Males Females and and female NS veveese 3.8(1,000) $.2(3,137) 24 2. Eilott, school SM v.eee ee 6.9(1,098) 6.3 (554) 6.1 8.3 1068, children, EX wiceaes 2.9(1,782) 4.3(1,161) 38 42 England <1 cigarette/day - 5.8 (876) 5.8 (ift). 1-2 ...., + 6.5 (417) 8.4 B-4 ceca wren anes » 6.60124) 8.1 DE vivifererceccceeees ween eee 99 (142) 18.3 62 TABLE A2.—Smoking and chronic obstructive pulmonary disease symptoms'—percent prevalence (cont) (Numbers in parentheses represent tu SM = Smokers. NS = Nonsmokers. tal number of individuals in particular smoking group) EX = Ex-smokera. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other Comments _teference population Gandevia 762 male and Males Productive 1969 1,304 female NS weve 10.9 (234) cough upon Australia patienty SM woes. 61,3 (628) request. (93), from 13 general Femalca practices NS w..aeee 10.5 (867) in all parts of SM o..4,..,87.4 (447) Australia. Rimington 41,729 male Age-adjusted total Cigarette 1969 und 22,295 prevalenec of dosage England fomale persons chronic bronchitis Rradient (193). participating Males signifiennt in mass NS . 6.2 (9,055) to pO.001. miniature EX ...c.0, 9.8 (6,610) radiography Pipe ..... 9.0 (2,921) screening, Cigarcttes . (23,243) 9 vere. OA 10-19 1... 16.0 >20 1.1... 20,6 Females NS woes 3,412,361) EX ...... 3.8 (959) Pipe .... 00 Cigarcttes (8,986) 1-9 4... 6.1 Wilhelmsen 313 males 10-19... 10.6 >20 11... 18.5 Chronte bronchitis et al., 60-54 years NS ...... 1.0 {88) 1969, of age randomly EX ......5 3.0 (67) Sweden sampled from 1-14 grams/ (281), population day ... 8.0 (94) of Guteborg. D168 oe. 17.0 (64) Oc? Tanie A2.—Smoking and chronic obstructive pulmonary disease symptoms'—percent prevalence (cont.) (Numbers in parentheses represent total number of individuals in particular amoking group) SM = Smokers. NS = Nonsmckers. EX = Ex-smokers. Author, year, Number and Breathlessness country, type of Cough Sputum production or dyspnea Chest illnesses Other Commenta reference population Lambert 9,975 male Peraistent cough and phicgm and and female Males Reid, responders Age Age Age Age 1070, to a postal 35-465 45-55 55-05 65-09 England aurvey NS visee 7(227) 6(200) Wd) 7 (61) (t4¢). (4,088 males EX ..... 7(308) 11 (358) 15(336) 18(148) and 5,287 20 6... 16 (621) 22 (488) 30(490) 37 (139) females 20) ......29 (191) 24 (204) 32(149) 38 (37) 36-60 years D20. ..,.27(148) 28 (136) 42(121) 26 (12) of age). Femalce NS .,... 3(600) 4(637) 6 (926) 6 (21) EX . 3(127) 8(128) 7 (94) 7 (Al) <20 « 9(602) 13 (472) 16 (306) 11 (66) 200 2.....16(128) 27 (122) 31 (77) wa (7) >20 = ..,.23 (22) 26 (39) 43° (7) we GQ) Lefeoe 310 male Age-atandardizcd rates Excluded from and physicians of chronic reapiratory ex-amokers Wonnacott, in London disease are those 1970, and Ontario, NS ceccesrees 1.0 (88) clgurette Canada 25-74 years EX viscreeees 6.0 (61) smokers who (151), of age. SM veveeee es 84.0 (101) now smoke Pipe, cigar = ..12,0 (83) pipes or cigars. ‘Data collected by either direct interview, questionnaire, review of medical records and/or medical examination. TE? TABLE A2a,—Smoking and chronic obstrnetive pulmonary discase (Numbers In parentheses represent total numbe SM = Smokers, symploms'—percent prevalence r of individualy in particuar smoking group) NS = Nonsmokers, EX = Ex-gymokers. Author, year, Number ond country, tyne of Cough Bronchitis Comments reference popuation Cederlof 9,319 twin Observed/ Observed Explanation of analyses for All exeamokers included etal, pairs expected Hypermorbidity czpected Hypermorbidity respiratory symptom with smokers. 1966, Tegistered Group A: cases ratio eaaca ralio prevalence: MZ—monorygotic Sweden in Sweden Males vee SOB/IELY 2.6 157/60.8 3.1 Group A analysis—using each paira (46), of 12,889 Females ..... 136/ 49.4 2.8 43/11.2 3.8 firstborn twin as one group DZ—dizygotle pairs available, Group B SM/NS5: in an unmatched relationship Author concludes that MZ Males .... 14.6/7,7 1.9 6.6/ Li 6.0 (274) to cach secondborn twin, aince hypermorbidity Females ... 13,6/7.6 1.8 3.0/ 2.3 1.33 (264) Group B analysis—using each for smoking persists DZMales .... 12.8/5.5 2,26 4.5/ 1.8 2.64(733) twin set ay matched pair, in smoking-discordant Females .., 14.6/6.7 2.57 6.5/ 1.8 3.0 (663) All comparisons in Groups A MZ population, a and B are between smoking casual relationship of discordant pairs. amoking and brancho- pulmonary symptoms is suppuited. Cederlof 4,379 twin Prevalence of respiratory eymptoms No ex-smokers included etal, pairs (all Group A in Group B analysis, 1963, U.S. veterans) NS . 4.3 1.6 Group A=as above, The authors conclude ULS.A. in U.S. 1-10 6.4 2.4 Group B—as above, that the data indiente (45). National 11-39 16.3 8.0 a strong probability Academy of >31 tee 27,7 16.8 of a cnusal connection Sciences Twin Pipe, cigar ....,., mM 2.7 with smoking, Even Registry (of Group B: NS SM NS SM these symptoms, 9,000 avial- MZ 5.4 1.8 48 however, acem to be able), DZ 9.8 1.6 a1 influenced by genctic factora. ‘Data collected by either direct interview, questionnaire, review of medical records and/or medical examination, CES TABLE A3.—Smoking and ventilatory function (Numbers in parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers. SM = Smokers, EX = Ex-smokers. Author, year, Number and country, type of MBC EFR FEV veo Miscellaneous Commenta roference population Chivers, 463 male Height-in-inches {Mean EPR 1969, employees Cigaorettes/day: 64" oe" 68'' vo" in liters England of alkaline OB wc... rn ». $97 (28) 91 (35) 108 (81) 101(21) per minute, (Se). industry 6-20 .eieeee ee teeeeee se, 89(50) 88 (75) 101 (112) 109 (76) Regresylun plant. Ped ie eee eevee eee sy 63 (6) 88.6 (9) 92.5 (9) 118(12) analysis of data revealed a significant re lationship between smoking and de creosing function, Higgina 173 maleg 28~$4 55-64 FEV, 5 expreuacd etal, in various NS 145 (56) 101 (29) a9 mean indirect 1969, occupations EX 143 (31) 89 (62) MBC, England (25-34 and 1-14 grams (136), 66-64 years -140(193) 87(157) of age). 215 grams 1183 (89) 80(186) Wilson 28 male : RV/TLC et al., residents of NS..... 6.59 (14)NS ...,.., 21a 1960 Dallas, SM... 44d CLO SM Le, 227.01 U.S.A, Texas, (232), former tural dwellers; matched for body surface, age, and height. Feo (Numbers In parentheses represent total number of individuals in particular amoking group) TaBLy A3.—Smoking and ventilatory function (cont.) NS = Nonamokers, SM = Smokers, EX = Ex-smokera. Author, year, Number and . country, type of MBC EFR FEV vc Miscellaneous Comments reference population Ashford 4,014 male FEV 1,4 Data represent etal, coal workers Age: NS SM resulta after 1961, at 3 Scottish <21-30 4.00(103) 3,96(280) correction for Scotland collieries. 21-30 .3.86(182) 3.77(655) sitting height, (iz), 31-40 .8.44(188) 3.88(777) 5M includes pipe 41-60 .3,04(110) 2.96(755) amoker, 61-60 .2.71(102) 2.56(610) Data on ex-smoker >60 ...2,88 (42) 2,21(287) not Included, FEV, , found significant; lower for SMtban Ns. Fletcher 363 male Mean peak EFR and London NS .....,.. 570 (80) Tinker, transport 1-14 grams 837 (168) 1961, employecs, >165 grams 828(116) ~ England EX ........ 555 (61) (85). Franklin 213 male FEV; 5 FEV, 5 FEV 5 59 Heavy amoker and factory 0:75 0.75 representa an Lowell, workerg Heavy 2,670 3,014 2,710 Light .. 3,703 (69) amount equal 1961, 40-60 years Light 12,489 72,656 42,284 Heavy ,38,578(104) to or mure USA, of age, than 30 pack (87), years, VEZ TABLE A3.—Smoking NS = Nonamokers. anid ventilatory function (cont.) (Numbers In parentheses represent total number of individuals in EX = bx-amokers, SM = Smokers, particular amoking group) Author, year, Number and country, typeof EFR FEV ve Miscellancous Comments reference population Balchum 1,451 male MMEFR Data fur; MMEPR etal, employces NS ....... 16.8 (38) 7.8(19) Kiven ay percent 1962, in Pack/year: of individuals U.S.A. California 10 years » $24.90 (28) . between amokera and nonsmokers. Gee TABLE A3.—Smoking and ventilatory function (cont.) NS = Nonsmokers, SM = Smokers, EX = Ex-wmokers. (Numbers In parentheses represent total number of individuals in particular amoking group) Author, year, Number and country, typeof EFR FEV ve Miscellaneous Commenta reference population Revotskle 1,130 male FEV, 4 Data preaented etal, and 1,818 Males Females in terma of 1962, female NS ..,..0.88 (65) 0.98(255) ratio of U.S.A, residents in Cigarettes/day: observed to (208), Framing- 1-10 .0.97 (80) 0.99 (92) predicted ham par. 10-29 .0.01(168) 0.03(157) valuca, ticipating >30 = ..0.90 (81) 0.01 (22) in the pro- spective Btudy. Krumholz 18 physicians MEFR Mean D etal., 24-37 years NS .i...... 880 (9) NS e 1964, of age. SM ........ 2690 (9) Rest ....5556.36 291 uae Exerciae: . 2minutes ..50 4) 4minutes ..50 148 3 minutes post exercise 39 186 2wi 20 medical MMEFR Authors found etal, students or e+e 187 (10) 4.84 8.77 a significant difference 1964, graduate 6624193 (10) 15.09 16.53 between SM and U.S.A, physicians, NS for RV/TLC, (£41), compliance, and non : elastic realstance, Coates 1,842 male FEV, , Timed VC! FEV, /¥C et al., and 242 Age: NS >25cig/day NS >#5/day NS" >25/day 1965, female post 40-44 22,99(186) 2.85 (69) 3.89 3.86 30.77 0.74 U-S.A, office 45-49 92.96(170) 2.64 (42) 3.92 3.83 40.74 0.70 (53). employees 50-54 42.76(115) 2.62 (22) 8.71 3.74 10.74 0.70 > 40 years 55-59 32.64 (64) 2.44 (18) 3.54 9 8.61 50.74 0.68 of age. GO-64 32.35 (53) 2.30 (8) 3.30 3.33 10.72 0.70 9t7¢ TabLp A8.—Smoking and ventilatory function (cont.) (Numbers In parentheses represent total number of individuals in particular amoking group) NS = Nonsmokers, SM = Smokers, EX = Ex-amokers, Author, year, Number and country, type of MBC EFR FEV vc Miscellancous Comments reference population Huhtl, 668 male PEFRt FEV, ¢ Foreed VCt Pipe and cigar 1968, and 628 Males Females Males "Females Males Femalee ainukers nab Finland female NS viccccseesreven eens 669 (122) 410(700) 3.48 2.42 4.40 8.18 inchided, (188). realdents EX veseeeee soeernoevens BELCLEL) 403 (30) 8.89 2.82 dct 8.10 { Ditference ofarural Ciyarettes/day: between NS and region in V-Vd iceceeeeen nes = 518 (108) 431 (97) 8.17 2.74 4.40 3.53 De/doy by Finland, VB—24 ccc cee ee seen eae B9T(I91) 8.90 4.61 elynifeant fur DUB ececrcneeesessee BM (a6) 431) 208 2.82 tact 5.50 46-49, 60-64 age groups. t Trend je not atatisticnlly significant. Krumhols 20 male Pulmonary compliance Mean body surface etal, medical NS vcceeeees :0.241(10) area for 2 groups 1968, atudenta or SM cseer eee f0.1977(10) was not signifi- ULS_A. graduate Compliance/FRC cantly different. (148), physicians, NS vcesece ee 0.064 Smokers are those SM vce ee 70,042 with equal to or greater than 5 pack year history. Rankin 125 roales NS ... 118.1 (68) FEV, 5 D D_/ NS includes pipe etal, withouta. SM ...2111.7 (67) NS ccecceuse 66 6406.6 NS $1 ‘ alveolar and ciguy smokers 10665, past SM vevevevee A L027 SM 126.9 volume 8nd ex-smokera of U.S.A. history oo 822 grenter than 1 (180), of respira. 5496 pack year, tory ‘ D, values have disease \ 20-63 years been corrected of age. for COVb. LEC TABLE A3.—Smoking and ventilatory function (cont.) (Numbers {n parentheses represent total number of individuals in particular smoking group) NS = Nonsmokers, SM = Smokers, EX = Ex-smokers. Author, year, Number and country, type of MBC EFR . FEV veo Miscellaneous Comments reference population Edelman 410 male FEV, 4 Vital capacity Ex-eamokeva of etal, community NS ........ 164(182) 7,89 2.83 4.93 cigarettes only. 1966, dwellers Current Difference signifi- U.S.A, 20-103 cigarette cant between NS (72), years of amokers. .*161(118) 7.36 42.64 94,74 and current age. EX v.cscce. UBT (98) 8.09 2.80 4.77 cigarette amokers Pipe, cigar .. 167 (47) 8.20 2.91 5.08 atpco.ol, Peters 124 male MEFR FEV 14 FEV, J/Ve Heavy smoker refers and college age NS .....6..710.28 (41) 4.68 287.6 to greater than Ferris, students, Moderate . 10.06 (84) 4.59 85.8 or equal to 4 1967, Heavy ..... 9.64 (20) 4.43 83.9 pack years. U.S.A. EX ....... 9.48 (10) QTd 83.2 Moderate ainoker (182), includes plpe and elgar omckers, Difference between NS and henvy emoker is significant, Higgins 926 white FEV etal, male ie . NS ........ 8,64(160) 1968, residents EX ........, 8.25 (143) U.S.A, of Marion Cigarette SM 8.48 (511) (148), County, 1-14 ....... 8.67 (88) West 16-24 0 ...... 8.57 (278) Virginia, P25 wo... .s.. 8.80 (150) 20-69 years of age. Ber TABLE A3.—Smoking and ventilatory function (cont.) (Numbers in parentheses represent total numbe NS = Nonsmokers, SM <= Smokers, EX = Ex-smokers. r of individuals in particular smoking group) Author, year, Number and country, type of MBC EFR FEV ve Miscellancous Comments reference population Sluis- 633 white 85-45 45-54 >55 FEV 19 lcigarctte = Cremer male NS voce 553 (106) 527(101} 444(27) 35-44 45-54 DoS l gram. and factory Grams/day: 3.70 3.22 2.76 1 ounce tobacco = Sichel, workers 1-14 657 (26) 519 (17) 410 (7) 3.64 3.31 2.24 26 grams. 1968, over 36 15-24 ....0e- 632 (94) 446 (35) 401413) 3.66 2.94 2.28 lcigar = 2105 South years of > 1528 (66) 494 (32) $380(10) 3.54 3.05 $2.12 grams. Africa age, ¢ Derived slopes (208). found signifie cantly different from 0. Stanescu 87 male bus FEV 54 Nitrogen gradient etal. drivers; Younger “Older Younger Older Younger Older 1968, 27 aged NS vues 4,470(14) 3,310 (40) 5,126 4,290 1,63 2.49 Rumania 20-25, 60 SM .....'4,500(13) 43,200 (20) 15,285 14,290 11.47 83.97 (#12), aged 40-60, all without respiratory symptoms. Densen 5,287 male FEV) 4 FEV expressed as etal., postal and Postal standardized for 1969, 7,213 male White Non-white specified postal U.S.A, transit NS oc cecseeeeee iv evte sees seeenenterseee 8:29 (686) 3.05 (204) and transit (69). workers in Allcigarette oo... ..cccee seer renee ee renee 3.11 (2,340) 2.04 (768) workers at age New York 25 grams/day oe. cece cece e eee eee 3.14 (1,292) 2.95 (699) 45 and at sitting City. 225 grams/day 3.06 (1,038) 2.93 (161) height of 35 Transit inches. . White Nonewhite Includes mixed NS civecccvccsenccest eres ners ee etnes 7 3.39 (620) 3.08 (298) amokers. Allcigarette ........ Devan eee eens veaaee 3,11 (2,941) 2,99 (1,041) <25 grams/day vee 8.16 (1,929) 3.00 (B91) Beeb gramsa/day ....cc cece eee vee er eeeeees 902 (1,011) 2.968 (149) 6£2 TABLE A38.—Smoking and ventilutory function (cont.) NS = Nonsmokers. (Numbers in parentheses represent totul number of individuals { SM = Smokers, n particular smoking group) EX cs Ex-smokerg. Author, year, Number and country, type of EFR FEV ve Miscellaneous Comments reference population Rankin 60 male FEV, FEV expressed aa etal., and 10 NS ree f97 5 (12) Percent of 1969, female SM » 78.4 (58) predicted value Australia patients for age, aex, (190), with chronic and height. alcoholism 26-66 years of age. Wilhelmsen 313 male PEFR FEV, 4 ve 1963 values only. etal, residents NS woe, Pian ee ee teen es 525 (88) B17 4.83 1969, of Géteburg EX ccc cece eee aee 639 (67) 3.65 ANT Sweden 50-54 years I-ld grams/day .00............, 521 (94) 3,62 4.83 (231), of age. P16 grams/doy 2... eee ee 492(64) 3.39 4.56 Lefeoe 310 mule MMFR FEV, 5 MMEFR hag been and physicians NS ....... 4,09 (88) 3.39 standardized for Wonna- of London, Cigarette oge and height. cott, Ontario, smokers. 3.64 (101) 3.11 1970, EX ..... ’ 3.99 (61) 3.38 Cannda Pipe, cigar 4.17 (33) 3.17 (154), Ove TABLE A3,—Smoking and ventilatory function (cont.) (Numbers in parentheses represent total number of Individuals In particular amoking group) NS = Nonsmokers. SM = Smokers, EX = Ex-amokers, Author, year, country, FEV Miscellaneous Comments reference Lundman, 87 MZ and FEV.) N, washout gradient MZ = monozygotle. 1966, 62 DZ twin lenif " DZ = dizygotic. Sweden pairs aclected 8 Br ce umohine dh dant Slanifcant dinerences The author concludes that the degree of ventilation as measured by Ny (158), from Swedlah ng aiscordan ween smo ng a washout was correlated with cigarette consumption, The FEV, 0 : twin pairs found for: cordant twin pairs : : Twin-Pair was significantly lower for amokera and there was & correlation Regletry, 1. Group A MZ males found for: with cigarette consumption and females, Group B DZ males. . 2, Group B DZ males, 8 Group A DZ males. Not significant (difference or trend), 5 p<0.06 > p<0.01 #p0.008 "n<0.001 Explanation of analyses for respiratory symptom prevalence: Group A analysis—vaing each firatborn twin as one group in an unmatched relationship to each secondborn twin. Group B analyals~-using each twin set as matcbed pair. All comparisons in Group A and B are between amoking-discor dant pairs. T?Z2 Tape A4.—Glossary of terms used in tables and text on smoking and ventilatory function Symbol Term Volume or rate Definition MDC. ....00.. Muxlmal breathing Litera. cicsereee Sean cseceses The maximal volume of gas that can be breathed jn one minute. capacity. MVV......... Maximal voluntary ventilation. EFR... eee Explratory flow rate.......c0c0. Ldters/minute. occ rceeveereeenee Rate of flow for a specified portion of a forced explration (MMEFR—rate PEFR......., Peak expiratory flow rate, of flow measured for middie half of FVC). MEFR,......- Maximal expiratory flow rate, MMEFR.,..... Maximal midexpiratory flow rate, FEV. .-.ees Forced expiratory Liters. .........00. . rer Volume expired within a specified time interval. (FEV, p—~volume expired volume. in first second of expiration.) VCO. cece ee Vital capacity. ..... CoceccecceceKtOPS. ccc cceccaceecevveerveress Maximal volume of a gag that can be expelled from the lungs by forecful FVC......... Forced vital capacity. effort following & maximal expiration. FEV /VOG.... Forced expiratory Percent... ccc. cece ee eae teseees MWolume of forced expiration (in time specified) related to vital capacity, volume/vital capacity. De teseeeeees Pulmonary diffusing ml/min/mmHg The ability of a chosen gas to pass from the alveolus to within the pulmonary capacity. capillary. N, washout... Nitrogen washout Exponential The stepwise pulmonary alveolar clearance of a gas. (Slope of curve dependa gradient. curve, upon the uniformity and adequacy of ventilation of all parta of the lung.) It may be done as a single—or multiple—breath procedure. Compliance. 0.0... eee ceee eee Liters/OCMHQ0. cs cseeaseereesee Volume change of the lung produced by a unit pressure change. RV oo cece eens Residual volume... ..ecce eee eee Uiters.... 0... cece eee sacevveaeee Wolume of gas remaining in the lungs at the end of a maximal expiration. TLC. ccc eae Total lung capacity. ......cceaee Giters. ccc cee eee veeeress Volume of gas contained in the lungs at the end of a maximal inspiration. FRC,....,..,. Functional residual Liters. ..cscecssceevesaeeecessss Volume of gas remaining in the lunga at the resting expiratory level. capacity, Liters... cee ee eee eee Volume of gas contained in pulmonary alveoll. Aleveolar volum@....cs.ceeaeee i Source: Coniroc, J. et al. (58) Tas_e A6.—Epidemiological studies concerning the relationship of air pollution, social class, and smoking to chronic obstructive bronchopulmonary disease (COPD) Author, year, Number and type country, of population Results reference Higgins, 301 males and Male data only (170): 1957, 280 femajes (a) The frequency of recurrent chest illnesses was bigh- England living in 2 er in the more polluted region but the prevalence of (iz). separate other respiratory symptoms and mean values were districts. similar. (45-64 years (b) Significant difference observed In COPD mortality of age.) rate. College of 187 males and (a) Male urban inbabitants manifested almost twice the General 782 females prevalence of chronic bronchitis as rural males; this Practi- 45-64 years of difference could not be explained on the basis of tioners, age from smoking habits. . 1961, medical doctors’ {b) No significant urban/rural differences noted for England case lists. PEFR. (55). (ce) No significant urban/rural differences noted for COPD symptoms among females. Ferris and 1,219 males and Following adjustment for differences in smoking habits, no significant differences in chronic bronchitis were observed Anderson, females living 1962, in 3 different among the 3 pollution areas. ULS.A. areas of 1 New (41). Hampshire town, Mork, 339 male trapsport The excess prevalence of serious respiratory symptoms (dy- 1962, employees from spnea, wheezing) and PEFR dysfunction among London U.S.A. London and Transport employees was only partly eliminated after (172)- Norway. standardization for smoking, and the author suggests that this is due to differences in air pollution levels. Schoettlin, 2,622 -males (a) No positive correlation found between ehronic respira- 1962, 45-15 years tory illness and city size. U.S.A. of age. (b) A positive correlation was found between chronic res- (£04). piratory illness and cigarette smoking (particularly du- ration). Anderson 118 residents of Berlin, New Hampshire, has higher so, and particulate air etal., Berlin, N-H., and pollution levels and the higher respiratory disease preva- 1965, 918 residents of Jence rates among its residents were not accounted for Canada Chilliwack, by age differences, but were accounted for after stan- (8). Canada. dardization for smoking habits (except that PEFR and FEV, 4 dysfunction was more prevalent in New Hamp- shire, and the authors suggest that this difference re- flects air pollution differences). Holland 676 male transport {a) London employees manifested a greater prevalence of and employees in COPD symptoms and PEFR dysfunction than did the Reid, London and rural rural employees. 1966, England. (b) Smoking habit differences alone were not sufficient to England explain this difference in COPD manifestations. (124). (c) Both groups manifested pulmonary dysfunction cor- related with tobacco consumption. Bates 216 hospitalized Winnipeg (cleanest of all areas in SO, and industrial etal, veterans from dustfall) residents manifested decreased prevalence of 1966, various areas of chest illnesses, Jess severe grades of dyspnea, and less Canada Canada (all sputum volume produced when compared to residents of (27). standardized for all other areas. age, tobacco consumption, and occupation). 242 TABLE A6.—Epidemiological studies concerning the relationship of air pollution, social class, and smoking to chronic obstructive bronchopulmonary disease (COPD) (cont.) Author, year, country, reference Ashley, 1969, England (12). Holland etal, 1969, England (£22). Winkelstein and Kantor, 1969, U.S.A. (233), Cooley and Reid. 1970, England (58). Lambert and Reid, 1970, England (246). Number and type of population Standardized mortality ratios for males (1958-63) for 53 boroughs with air pollution indexes. 10,971 children over 11 years of age in 4 areas. 842 females over 25 years of age in various regions of Buffalo. 10,887 children 6-10 years of age from con- trasting urban and rural areas. 9,975 males and females responding to questionnaire survey. Results Positive correlations: (a} Smoke concentration and bronchitis mortality. {b) So, and smoke concentration and bronchitis mor- tality and social class. (ce) Pollution and social class. Factors affecting prevalence of respiratory symptoms: (a) Smoking—highly significant association. (b) Area of residence (pollution)—significant association except for periods of cough and phlegm lasting more than 3 weeks. (c) Social class, age, sex—no association noted. (a) The increased prevalence of respiratory symptoms could not be explained by social class differences. (b) No overall association noted between productive cough and air pollution. Illnesses considered included chronic cough, past bronchi blocked nose. (a) Every geographic area showed 4 clear gradient of in- creasing illness prevalence with decreasing social class. (b) Social classes 1, II, and III showed no urban/rural gradient while IV and V showed a clear excess in fre- quency of chest illnesses among urban residents over rural residents. (a) The trend of increasing prevalence of bronchitic symp- toms from rural to urban respondents was not negated by adjustment for smoking differences. (b) After adjustment for age and smoking habits, male respondents manifested a clear correlation of persistent cough and phlegm prevalence with increasing air polu- tion. Correlation was not as striking in females. {c) Although the proportionate rise in symptom preva~ lence increased with air pollution similarly in each smok- ing group, the absolute differences in morbidity risk in- creased with increased cigarette consumption, suggesting synergistic influences of cigarette smoking and air pollu- tion. (d) In the absence of cigarette smoking, the correlation. between the prevalence of persistent cough and phlegm and air pollution was slight. 1 See Glossary of Terms: Bronchopulmonary table A4. 243 TABLE A7.—Epidemiological studies concerning the relationship of occupational exposure and smoking to chronic obstructive bronchopulmonary discase Author, year, Number and country, typeof Results reference population Higgioas 185 males Miners showed increased symptom prevalence (breathless~ etal (84 nonminers, ness, cough, sputum). 1956,° 101 miners) Miners showed increased prevalence of chronic bronchitis. England without pneumo Miners showed decreased MBC.? C119). caniosis. Differences in smoking between the two groups did not ac- count for above differences. Phillips 1,274 males None of the industrial environments were associated with etal, factory employees an increased prevalence of chronic cough. 1956, {coke and Cigarette smoking and age were directly correlated with U.S.A. electrolytic increased prevalence of chronic cough. (185). process). Higgias 325 males 25-34 Miners as compared to workers in non-dusty occupations: etal, years of age and 25-34 years of age—significantly incrensed prevalence of 1959, 401 males 66-64 chronic bronchitis and MBC abnormalities. England years of age in 65-64 years of age—tess significantly increased prevalence (116). various occupa- of chronic bronchitis and MBC abnormalities than in tions. 25-34 years of age group. No smoking information available. Chivers, 463 males in No significant differences in PEFR?) between dusty and 1959, non-dusty and non-dusty groups. Emgland dusty occupations Cigarette smoking (especially in those >40 years of age) (52). (lime and soda was associated with decreased PEFR values. ash exposure). Higgins 300 male miners Miners showed increased prevalence of symptoms and de and and 300 male creased MBC values which remained even after standard- Cochrane, nonminers 35-64 ization for smoking habits. 1961, years of age. Total dust exposure was not directly correlated with these England findings. q1is). - Wives of miners showed similar symptom and test changes as compared with wives of nonminers. Brinkman 1,317 males 40-65 Increased silica exposure was associated with an increased and years of age prevalence of chronic bronchitis. Coates, with various Highest prevalence of chronic bronchitis was noted in the 1962, silica exposure non-exposed group; and this group was. noted to have U.S.A. histories. the highest number of smokers and highest consumption. (42). Hyatt 267 male miners Increased history of underground work was associated with etal, and ex-miners an increased bronchopulmonary symptom prevalence and 1964, 45-55 years decreased pulmonary function values. U.S.A. of age. The impairment of pulmonary function sssoctated with (128). underground work was separate from effect of smoking; but smoking and underground work did show additive effects. Elwood 2.628 male and Preparing room workers who manifested byssinosis symp- etal, female flax toms also showed an increased prevalence of chronic 1965, workers over 35 bronchitis independent of age or smoking when compared Ireland years of age. with non-preparing room workers. (77). Female workers manifested a significant association be- tween byssinosis symptoms and smoking while male work- ers did not. Sluis-Cremer 827 miners and Those smokers exposed to gold mine dust manifested more etal, nonminers over symptoms of COPD? than did non-dust exposed smokers, 1967, 35 years of age. while prevalence of symptoms, among nonsmokers, was South Africa similar for the two groups, (209). Vs TasBie A7.—Epidemiological studies concerning the relationship of occupattonal exposure and smoking to chronic obstructive bronchopulmonary disease (cont.) Autbor, year, Number and country, type of Results reference population Stuis-Cremer 827 miners and etal. 1967, South Africa (209). (cont.) nonminers over 35 years of age. The dose relationship of cigarettes and COPD?! symptoms was mutch more noticeable among those exposed to dust. The authors stressed the synergistic actions of cigarette smoking and dust exposure. Boubuys 455 male cotton Those exposed to dust manifested a significantly greater etal, textile workers prevalence of byssinosis symptoms than nonexposed. 1969, (214 exposed to Smokers manifested a significantly greater prevalence of U.S.A. dust in carding byssinosis symptoms than nonsmokers. (79). and epinning No significant differences in Monday morning FEV? values rooms, 241 not were observed between smokers and nonsmokers. exposed). Prevalence of byssinosis symptoms did not show any re- lationship to length of employment. Bouhuys 216 male hemp Hemp workers (especially the older ones) were noted to etal, workers and 247 have different smoking habits from contral group—fewer 1969, workers in other heavy smokers, more light smokers, more ex-smokers due ULS.A, industries in to doctor’s orders. (38). same region, Aged 20-49 — a. No difference in FEV, values - between 20-69 years controls and hemp workers in any smok- of age. ing category. . b. No difference in FEV, values between men in different smoking categories. Aged 50-69 — 3. Hemp workers manifested decreased FEV, values in all smoking groups except for heaviest smokers. Ex-smok- ers had lowest FEV, 5 values. b. Those smoking most had lower FEV, , values as compared with light and non- smokers. The authors conclude that: There appears to be no synergism between smoking and hemp exposure as to effect on FEV, although the selection process whereby those with symptoms have a greater tendency to stop smoking may obscure such a relationship. Chester 139 male chlorine Chlorine-exposed group manifested no difference in symp- etal. plant workers toms and a decreased MBC value when compared with 1969, ($5 with history non-exposed group. U.S.A. of severe ex- Smokers in chlorine-ex posed group had significantlh de (49). posure). creased MBC and FEV values as compared with non- smokers in non-exposed group. Greenberg 121 workers in Sensitized group manifested Jower FEV, /FVCt values et al, washing powder as compared with nonsensitized group even after smok- 1970, factory (48 found ing habits were controlled for. England to be sensitized (97). to product, 73 not). Tokuhata 801 male miners Increased mine exposure was associated with residual vol- etal, ume and FEV abnormalities even after adjustments for 1970, age and smoking. U'S.A. A systematic exposure-impairment relationship wag noted (218). only among smokers while relatively few nonsmokers showed COPD impairment, Smoking miners manifested more X-ray alterations and COPD symptoms than nonsmokers, regardless of num- ber of years of underground exposure. 1 See Glossary of Terms in Bronchopuimonary table Ad. 245 Tas_e A10.—Experiments upon the tracheobronchial tree and pulmonary parenchyma of animals concerning the effect of the chronic inhalation of NOx Author, year, country, Animal Results reference Freeman Sprague-Dawley 25 p-p.m.: and rats. {a) after 37-41 days—-moderate hypertrophy and hyper Haydon, plasia of bronchial and bronchiolar epithelium. 1964 (b) after 146-157 daye—(1) Advanced hypertrophy and U.S.A. hyperplasia of bronchial and (90). bronchiolar epithelium. (2) Increased lung volume. (3) Proliferation of connective tissue. Haydon Sprague-Dawley 12.5 p.p.m. to death: etal, rats. (a) Hypertrophy and occasiona) metaplasia of bronchial 1965 and bronchiolar epithelium. ULS.A. (b) Increase in number of actively secreting goblet cells. (107). Haydon Albino rabbits. 8-12 p.p.m. for 4 montha: etal, (a2) Abnormal dilatation of peripheral air spaces. 1967 {b) Decreased density of alveolar walls, U.S.A. (c) Hypertrophy and hyperplasia of bronchial epithelium (108). (especially terminal bronchiolar). {d) Increase in size of alveolar ducts. (e) Increased elastic tissue staining. {f) Increased alveolar size. Freeman Sprague-Dawley 0.8 p.p.m.-2 p.p.m. for entire lifespan: etal, rats. (a) Alveolar distention. 1968, (b) Reduction in number of cilfa. U.S.A. {¢) Epithelial inactivity (“dormancy”). (91). Freeman Sprague-Dawley 18 p.p.m. etal., rats. (a) 5 days—terminal bronchiolar epithelial hypertrophy. 1968, : {b) 4 weeks—(1) Widespread bronchiolar epithelial hy- U~S.A. pertrophy. (89). (2) Non-necrotizing emphysema. Blair Female Swiss 0.5 p.p-m.: etal. Albino mice. (a) 6 hours/day for 3 months—pneumonitis. 1969, (b) 24 hours/day for 3 montbs—(1) Respiratory bronchi- US.A. * olar obstruction. (32). Kleinerman, 1970, U.S.A. (1gsa). 246 Male Syrian Golden hamsters. (2) Alveolar expansion and bronchiolar inflammation con- sistent with early focal emphysema. 100 p.p.m. for 54 hours: {a) thymidine autoradiography—intense burst of prolif- eration of epithelium returning to normal in 4 days (more persistent distally). (b) electron microscope—(1) Decreased number of se- eretory cells + secretory granules, (2) Increased number of lyso- somal structures. (3) No change ia number of ciliated cells. TARLE A13.—Experiments concerning the effect of cigarette smoke or its constituents upon ciliary function Author, year, country, System Method ? Resuits reference Mendenhall fn vttro: Cigarette smoke Controls—ciliary activity Cepressed spprox and Calf trachea. by direct apphi- mately 4 percent. Shreeve, cation or in Experimental— pe eeeweee 53 ULS.A. Cellulose acetate filter ....- beeen eeeee --» 46 (45). Carbon cellulose acetate filler -----++-+0> 30 Dalbamn, In vivo: Cigarette smoke. Mean number of puffs required to produce 1966, Cat trachea. ciliastisis ~~ Sweden No filter -- 91 (60). Charcoal filter -.-.-.---22 0-220 rrere «eeee 170 Commercial cellulose acetate filter ....---- 194 Charcoal and acetate filter .-.------ weeee B12 Cambridge filter ....------er errr ret --- 600 Kensler In vivo: Cigarette smoke Rabbit trachea—Tota!l smoke condensate of 4 and Rabbit and components cigarettes, gas phase condensate of 7 cigs- Battista, trachea, in Tyrode’s rettes caused similar ciliastasis. 1966, ecattrachea, solution. Other species—All found sensitive to cilisatatic U.S.A. dog trachea, components of cigarette smoke. Bulk of ac- (155). roonkey tivity noted in gas phase (HCH, formaHe- trachea, hyde, acrolein). rat tracker. 248 TABLE A13.—Experiments concerning the effect of cigarette smoke or tts constituents upon ciliary function (cont.) Author, year, country, System Method * Results reference Dalhamn In vivo: Cellulose acetate. Increased amounts of tar were sssociated with and Cat trachea. filter cigurettes decrensed number of puffs required to inhibit Rylander, with varying ciliary activity. 1967, amounts of Sweden tar’ but simi- (63). jar gas phases. Daibamna In vivo: Unfiltered and Whole smoke found to be markedly more toxic and Cat trachea. Cambridge-filter to ciliary activity than volatile (gas) phase Rylander, cigarettes. at lower dosages (puff volume). This di%er- 1968, ence diminishes with increasing puff volume. Sweden (64). Kaminski In vivo: Whole and filtered Wet chamber adsorption significantly reduced etal., Cat trachea. cigarette smoke the ciliastatic activity of whole smoke, but 1968, exposed or unex- did not affect the ciliastatic activity of smoke U.S.A, posed to “wet previously filtered by Cambridge or charcoal (133). chamber” made filters. to stimulate oral mucoss and saliva. Krahl In vivor Cigarette smoke Significant ciliastasis, reversible. and Common disso)ved in Bulmash, mollusk sea water, 1968, ciliated U-S.A. epithelium. (138). Battists In vitro: Cigarette smoke The authors observed that: and Chicken or HCN in (1) The more diluted amoke required more Kenaler, tracheal Tyrode's puffs to cause ciliastasis. 19790, epithelium. solution, (2) Activated charcoal filtered smoke was U.S.A. less ciliastatic than cellulose acetate filtered (£8). smoke and also contained Jess HCN and acrolein. (3) HCN alone was ciliastatic but recovery was more rapid than after cigarette smoke alone. They conclude that the gas phase components are more related to ciliastasis (sa particulate matter is not significantly decreased by char- coal filtration while HCN and acrolein are)- Battista In vivo: Cigarette smoke. The authors observed that: and Hen trachea. {1) Whole smoke acutely depressed ciliary Kensler, activity in 4-6 puffs. 1970, (2) Gas phase was only slightly less depres- U.S.A. sant than whole smoke. (29). (3) Chronic exposure (1 cigarette/day for 32 days) to smoke resulted in no apparent permanent defect in ciliary activity (2+ though mucous production was signifi- cantly increased). 249 TaBpLe Al3.—Experiments concerning the effect of cigarette smoke or its constituents upon ciliary function (cont.) Autbor, year, country. System Method ? Results reference Dalhamn In vivo: Unfiltered cigarette Average number of puis required to arrest and Cat trachea. and cigar smoke. ciliary activity Rylander, Cigarette smoke ...---- 73 1970, Cigar smoke ....- 0-005 ag iPooon) Sweden The authors note that cimar smoke is of a (65). different pH and that it contains more iso- prene, acetone, toluene, and acetonitrile. Kennedy In vivo: Mainstream Electron microscopic observations: and Protozoan cigarette smoke. (1) After 7 minutes exposure—alteration of Eliiott, (ciliated) - mitochondrial structure. 1970, (2) After 42 minutes exposure—destruction U.S.A. of internal mitochondrial membrane struc- (134). ture. (3) Gas phase alone, while ciliatoxic, did cause mitochondrial swelling but no dis- ruption of membrane structure. 1 Unless otherwise stated, method entailed the direct observation of ciliary activity using markers. 250 TS¢ Taste Al4.—Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tenston Author, year, country, System Method Results reference Miller and Rat lung extracts Cigarette smoke: (1) Exposure to cigarette smoke wag nasoctated with decreased surface tenalon in lung extract. Bondurant, {1) Applied to (2) Surfoce tension of rats (lung extracts) exposed to’ cigarette smoke waa decreadcd 1962, extract. as compared with those not exposed, U.S.A. (2) Exposure (168) of rats. Cook 40 subjects undergoing Surface tension and Webb bronchoscopy: valuce of aurfactant 1966, 14 normal 20 100 Stability index (reflects ? Values algnificantly U.S.A. 7 nonsmokers with percent percent surfactant activity) different from (57) pulmonary disease area area values of normals 19 smokers with and Normal ...esereee 6.5 60.0 1.61 at p<0.02 level, without pulmonary Pulmonary dincase. pationts caeeee $17.0 $60.0 1.00 Chronic smokers .. 16.7 61.0 1.04 Giammona In vitro: Exposed to In vitro: 1967, Surfactant motcrial cigureltte Exponure to clanrette smoke wos associated with w significant decrease in maximn) surface U.S.A. induced from dogs smoke for tenpion, (94) and rats. 3 hours/duy Inatyo: In vivo: for up to Dogs and cats (expored for 1 week)}—no sixnificant change. Dogs, cats, and 3 weeks. Guinen pigs (exposed for 4 weeks) —significant decrense in muximal surface tension. gulnca pigs. Webb, Bronchial Direct Surface tenaion values of surfactant etal. washing, exposure to £0 pereent 100 pereent Ue, from cigarette smoke. Number arca areca Stability index S.A, dog lungs. Control .....6.. 1 ; ; . (2h Smoke on 10 serpincoane {53} (eco. 034 ZSt TaBLp Al6.—Studies concerning the relationship of amoking to infectious (Actual number of cases shown in parentheses) SM = Smokers NS =: Nonamokers respiratory digease in humans Author, year, Number and Data country, type of collection - Results Comments reference population Mills, 118 male and Hospital Cases Controle The author stated that 1980, female patients Interview. Mean age csseececeeecreeeees aneeee ees 43.6 49.6 there was a U.S.A. with pneumonia NS cseeee seoe veers beeeeeennes tae 16,26 26.24 significant uifference (187). and 472 bealtby Cigarettes only cceeesereeeeee surest oe 63.86 62.93 in tobacco usage individuals from Mixed v.cceceeee cece eree tee teeees . 21.19 22.46 between the “random” sample. two groups. Lowe, 520 male and Interview by Males Females Cigarette smokers 1966, 185 female trained Casce Controle Coace Controla include pipe smokers. England tuberculosis social NS iceevree eee peeneenane , 2.6 8.1 37.3 614 The author noted a (157). patients and 419 worker. Cigarettes/day: 1-9 ...05, 9.2 12.9 20,5 26.7 significant deficiency male and 249 10-19 seers eee Vea 38.1 35.6 30.8 20.6 of non- and light female control 20-29 ve rereeeee teens 29.4 27.4 smokers and an outpatients. 30-39 rare eeeee sees 11.3 9.3 11.4 2.4 excess of heavy DAD cece ee eee beveneee 9.4 6.7 smokers among the cnges Dowling, Individuals Interview and Exposed to placebo Exposcd to infectious agent No atatiatically etal, exposed to medical Percent Percent significant 1967, “Snfectious examination. developing developing differences U.S.A. eold agent” Number “eald" Number ‘eold” noted. (7£). and placebo, NS veesee an a M11 10 328 34 SM wee eae veeeeene 18 4 249 36 €SZ Tanie Alb.—Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.) (Actual number of cases shown in parentheses) SM = Smokers NS = Nonsmokera Author, year, Number and Data country, typeof collection Results Comments reference population Boake, Parents of Interview Number of No statistically 1968, 59 families, Person- respiratory Ilinesses/ significant U.S.A, years tlnessea = person-years differences (33). NS co cseer vere recaee seveeeee (24) 120 624 6.2 noted. Cigarettes/day: 1-10 .,....0., (18) 99 529 5.3 W-20 vee eee Sav eenaee (26) 108 436 48 >20 oe . 9 424 4.3 Pipe, cigar 12 804 42 Sbah Tuberculosis Survey, X-ray, Tuberculous Normal or t Numbers In etal, {natitute and by X-ray nontuberculous parentheses 1969, employees, interview. NS beers ete eee et eeee t10 (19.7) 178 (168.3) represent figures India SM bene v eee e eet enens 36 (26.3) 215 (224.7) “expected” by use of (£08). 2x2contingency table. Tuberculous employees wero found to have significantly Cower nonsmokers and more amokers. 7S¢ TABLE Alb.—~Studies concerning the relationship of smoking to infectious respiratory discase in humans (covt.) (Actual number of enses shown in parentheses) SM = Smokers NS = Nonsmokers Author, year, Number and country, type of Data reference population collection Results Comments Brown 306 male und Interview Smoking habite prior to diagnogts Data presented only etal, female Tuberculous paticnte Controls on Queensland 1961, tuberculosis (percent) (percent) sample. Australia clinic NS Fest eee ce eect cesses sees 91 19.9 The authors noted G). patients, Cigarettes/day: 1-9 10.6 15.4 that the 221 male and 10-19 443 19.5 significant difference female 20-29 26.3 25.8 between the outpatients. 30-39 1.2 6.4 patients and DIO cee eevee cece tees aes eans 6.2 9.1 controls was not Pipes ieee ese cece eee eee 5.9 4.6 present when the groups were matched for alcohol intake. Haynes 191 male Interview Average number of respiratory illnessee/10 students etal, prep school (adjusted for age) 1966, students, All severe lower U.S.A. All All severe or combined (108). respiratory respiratory reapiratory episodes episodes cptsodes NS (99) vee eee c cece eee 111 1.6 0.36 SM (92) tee 20.2 6.7 3.34 Parnell 47 smoking- Interview Median number of Wncases/student The authors noted eal,, nonsmoker palra and health Au All that these 1966 of student nurses service respiratory other differences were Canada matched for age records. diseascat incasce statistically (281), and parents’ NS (AT) ccc ccc eters neces 2.08 2.99 significant. occupational SM (47) icc e cece reece eae 2.64 5.00 { Particularly class. trachcitis, bronchitis, and pneumonia. SSC TABLE (Actual number of casey shown in parentheses) SM = Smokers NS = Nonsmokery Alb.—Studics concerning the relationship of smoking to infectious respiratory discase in humans (cont.) Author, year, Number and Data country, tyne of collection Results Commenta reference population Peters 1,496 Harvard Medical history, Number of visite to student health untt for respiratory illness/atudent + p<0.001. etal., and chart review, (comnion colds, pharyngitts, bronchitis, laryngitis, 1967, 370 Radcliffe and preumonia~not allergic rhinitia) U.S.A, students. questionnaire, Harvard Radeliffe (183), NS 1.44 (771) 1.44 (193) SM $2.27 (726) 2.27 (177) <2 years smoked . 2,00 3-4 2.30 >5 2.60 Finklea 1,811 male Questionnaire Heavy smokers--21 percent more clinical jInesses than nonsmokera; The authors also etal, college prior to 20 percent more requiring bed rest than nonsmokers noted that: 1969 students. A, /HK/68 Light smokers—10 percent more clinical [!lnesses than nonsmokers: (a) Smokers U.S.A. epidemic and 7 percent more requiring bed reat than nonsmokers exhibited (83). follow-up on serologic morbidity, evidence of increased aubclinical A,/HK/68 infection. (b) There wna no difference in the vaccination slatus between amokers and nonsmokers, Taste Al6.—Complications developing in the postoperative period tn patients undergoing abdominal operations Men over 20 Percent Percent broncho- Pereent Group Cases chest Percent pneumonia total clear bronchitis and complication atelectasis rate Smokers . 2... 2.2.20 eee ee eee 300 417 63.0 5.3 58.3 Light Smokers .. 180 68.4 27.7 3.9 31.6 Nonsmokergs ....-..--0-0-00- 66 92.5 6.0 1.5 TB Women over 20 Smokers oo... eee eee eee ee 23 39.1 43.5 17.4 60.9 Light Smokers ..........--- 62 WS 20.9 1.6 22.5 Nonsmokers ......06--0-0--% 518 88.8 8.1 3.1 112 Source: Morton, H. J. V. (473) TABLE AlT7.—-Arterial oxygen saturation before and after operation Arterial oxygen saturation (percentage) Case Before Group number operation Day l Day 2 Day 3 1 94 93 94 2 94 93 94 - Nonsmokers ......--- 2-0 eee cree ee 3 96 93 go4 a 4 95 90 a¢ as & 94 90 93 a. 6 95 91 89 91 7 92 89 81 89 Smokers 2... 2.6.0 e cece eee ee eee 8 91 89 85 89 9 93 91 88 92 10 90 87 88 92 Source: Morton, A. (172). 256 Chapter 4 Cancer Source: 1971 Report, Chapter 4, pages 231 - 384, 257 Contents Introduction .........0 cece eee eee ete Lung Cancer .....----e eee eee eee eet ern eettee Epidemiological Studies ......5.----- 0-222 eee ereee Prospective Studies .......-. 2. ee eee eee reese Retrospective Studies ......--- +e eee reece eres Lung Cancer Trends in Other Countries .........--- Histology of Lung Tumors......-..--- esse ee eer eet Lung Cancer Relationships in Women .....-.-.--+-+- Lung Cancer, the Urban Factor, and Air Pollution. ... Lung Cancer and Occupational Hazards ......------ Uranium Mining ........--200ee eee eer eres Other Occupations........-¢ See eee eee eee eeee Nickel... .....2 cece cece cee eee eect eens AsbestoS. 0... ccc eee cee eee ete een aetee AYSONIC. 0 ec ee te eee eters Chromium. ......--00+ cece e seer reeset erete Pathological Studies. ........- +--+ ee eee er eee ret Pulmonary Carcinogenesis ....--6---+ eee ee ere eee General Aspects of Carcinogenesis .........---+ Polynuclear Aromatic Hydrocarbons .....-- Nitrosamine Compounds. .......------++++-: Pesticides and Fungicides.........-..-++-- Radioactive Isotopes .....--- e+e eer eeeee Inhibitors of Ciliary Movement ......-.--- Experimenta! Studies ...-..----++-20 rr rreeee Skin Painting and Subcutaneous Injection. a Tissue and Organ Culture .......----++--> Tracheobronchial Implantation and Instillation ......-.+------eee rere Inhalation ...----- ee eee cree teeter tets Reduction in Tumorigenicity ......--+++--+ Summary and Conclusions ...-.---++-+re er errtett Cancer of the Larynx ....---- eee erect Epidemiological Studies .-.------+++++ sre rrertrtts Pathological Study ....2------ seer cee rere rrnte Experimental Study ...-.-----++++eeereertrst Summary and Conclusions .......---++--+errrertte Oral Cancer ....-.-0-ce cece eee eset eeenereressts Epidemiological Studies ....-.----+-+++serrrrtrtte Experimental Studies ......-----++e++eeerrerctttt Summary and Conclusions .....--.+++-+++serrttrte Cancer of the Esophagus ..-.------+--rrercrctr tt Epidemiological Studies ....---- eee eect ttre Pathological Study ....--.-+-+seeereerrrrrttt Experimental Studies .....--+-+---+errrtrettrte Stummary and.Conclusions .---++++---+sssrrertrts Cancer of the Urinary Bladder and Kidney .......-+---+5 Epidemiological Studies (Bladder) ....-----+--+++>> Epidemiological Studies (Kidney) ...------ eee ree Experimental Studies ....-------++ssrecrrrcrrtt Summary and Conclusions ...-----+++++eesrertttt Cancer of the Pancreas .....----++rerrrrserrrr Summary and Conclusions ....----ssserrrrrrrtt References ..-.----e+ eects eee e eee eee ee eerntee peo me GO OO A3. A4. 10. 260 FIGURES _ Lung cancer, Finland and Norway ..------sre errr? _ Percent of smoking dogs with tumors ..------r errs . Percent of lung lobes with tumors in smoking dogs ....- _ Effects of chronic cigarette smoke inhalation on the hamster larynX .....- cece erect LIST OF TABLES Lung cancer mortality ratios ....-----+ee rere Lung cancer mortality ratios for males by duration of cigarette smoking ..-----+see erect Outline of methods used in retrospective studies of smoking in relation to lung cancer ..-.--++--00 Group characteristics in retrospective studies on lung cancer and tobacco use ..------rree rt Annual means of total lung cancer mortality and sex ratios for selected periods in Finland and Norway Epidemiologic and pathologic investigations concern- ing smoking and histology of lung cancer ..----- Grouping of pulmonary carcinomas ..----+es-+e0 Tumor prevalence among males and females 35-69 years of age, by type of tumor and smoking category .---- eee eee rect Epidemiologic investigations concerning the relation- ship of lung cancer to smoking, air pollution, and urban or rural residence ...---++sssec rrr Pathologic and cytologic findings in the tracheo- bronchial tree of smokers and nonsmokers .....-- 271 300 300 310 267 270 349 355 272, 273 360 276 279 285 il. Al2. A138. Al4. Alb. Al6. V7. 18. 19. 20. LIST OF TABLES (Continued) (A indicates tables located in appendix at end of chapter) Identified or suspected tumorigenetic agents in cigarette smoke .......---5 +2202 eee crete Autopsy studies concerning the presence of radio- activity in the lungs of smokers .:....-----+-++- Experiments concerning the effects of the skin paint- ing or subcutaneous injection of cigarette smoke condensate or its constituents upon animals ....- Experiments concerning the effect of cigarette smoke or its constituents on tissue and organ cultures .. Experiments concerning the effect of the instillation or implantation of cigarette smoke or its constitu- ents into the tracheobronchial tree of animals .... Experiments concerning the effect of the mhalation of cigarette smoke or its constituents upon the respiratory tract of animals ....-...----++ee88 Data on pedigreed male beagle dogs of groups F, L, H, hand N .......- ee eee eee eee eerste Summary of principal cause of death (days No. 57 through No, 875) in dogs of groups F, L, H, hand N Data on dogs with lung tumors indicating type of tumor and lobe in which the tumor was found ...- Laryngeal cancer mortality ratios —- prospective studies . oc. cece eee eee eee ete teense A21l. Outline of retrospective studies of tobacco use and cancer of the larynx .....-.----2 eer cere etree A22. Summary of results of retrospective studies of tobacco A23. A24. 26. 27. A28. A28a. use and cancer of the larynx ........--+---+--+5- Number and percent distribution by relative fre- quency of atypical nuclei among true vocal cord cells, of men classified by smoking category ..... Number and percent distribution, by highest num- ber of cell rows in the basal layer of the true vocal cord, of men classified by smoking category. ....- Deposition of '*C-labeled smoke particles in particu- lar regions of the respiratory tract ........---- Classification of the five registered stages of epithe- lial changes at the larynx .......-----2+.-++0-- Oral cancer mortality ratios—prospective studies. : Outline of retrospective studies of tobacco use and cancer of the oral cavity .........--.20 22-2 eee Summary of results of retrospective studies of smok- ing by type and oral cancer of the detailed sites. . Page 291 361 363 369 372 375 296 297 298 304 380 384 385 386 308 309 312 387 394 261 A35a. 36. 262 LIST OF TABLES (Continued) (A indicates tables located in appendix at end of chapter) Experimenta] studies concerning oral carcino- QONESIS 2. eee eee eee Esophageal cancer mortality ratios—prospective studieS 2.0... ee ee eee eens Summary of methods used in retrospective studies of tobacco use and cancer of the esophagus ...... Summary of results of retrospective studies of to- bacco use and cancer of the esophagus ......... Atypical nuclei in basal cells of epithelium of esoph- agus of males, by smoking habits and age ...... Atypical nuclei in basal cells of epithelium of esoph- agus of males, by amount of smoking and age .... Kidney and urinary bladder cancer-—prospective studieS 0... eee ee ee eet ees Summary of methods used in retrospective studies of smoking and cancer of the bladder ............ Summary of results of retrospective studies of smok- ing and cancer of the bladder ................. Pancreatic cancer mortality ratios—prospective studies 2.2... ee ee ee eee Page 397 316 401 404 405 406 320 407 409 324 INTRODUCTION During the early years of this century, a number of pathologists and clinicians reported a dramatic increase in the incidence of lung cancer. Autopsy studies and studies of lung cancer death rates re- vealed a significant increase beginning prior to World War J and continuing during the ensuing years. This epidemic of lung cancer continues to the present day, with nearly 60,000 deaths expected from this disease in the United States during 1970. Beginning in the 1920's, a number of reports appeared which suggested a relationship between lung cancer and tobacco smoking (4, 203, 278). Since that time, many clinical and epidemiological studies have been published which confirm this relationship. The 1964 Report (291) contains a thorough review and analysis of the data available at that time as well as an excellent discussion of the considerations necessary for their evaluation. Major epidemiological studies have demonstrated that smokers have greatly increased risks of dying from lung cancer compared to nonsmokers. An increased risk of lung cancer has been found for every type of smoking habit investigated, but two character- istics of the risk are particularly evident: The risk is much greater for cigarette smokers than for smokers of pipes and cigars, and among cigarette smokers a dose relationship exists. That is, the more one smokes, as. measured by total pack-years of smoking, present level of smoking, degree of inhalation, or age at start of smoking, the greater is the risk. It has also been shown that the risk of lung cancer among ex-smokers decreases with time almost to the level of nonsmokers; the time required is dependent on the degree of exposure prior to cessation. Pathologists have found that the squamous cell or epidermoid form of lung cancer is the most prevalent one in cigarette smoking populations and that this form accounts for a major portion of the rise in lung cancer deaths (154). Such studies have also indi- cated a lower prevalence among smokers for oat-cell and adeno- carcinomas of the lung than for the squamous form, but in most studies a higher frequency of these tumors is found among smokers than among nonsmokers. Smoking has been implicated in the development of other types of cancer in humans. Among these is cancer of the larynx. A num- 263 ber of epidemiological studies have demonstrated increased mor- tality rates for laryngeal cancer in smokers, particularly cigarette smokers, compared with nonsmokers. Autopsy studies have re- vealed that a clear dose-relationship exists between smoking and the development of cellular changes in the larynx, including carci- noma in situ. Cancers of the mouth and oropharynx have been found to be more common among users of all types of tobacco than among abstainers. Although smoking is a definite risk factor in the de- velopment of malignant lesions of the oral cavity and pharynx, its relative contribution in conjunction with other factors such as poor nutrition and alcohol consumption has not been fully clarified. Similarly, although smokers are more likely to develop carci- noma of the esophagus than nonsmokers, the relative additional contribution of smoking in conjunction with nutritional factors and alcohol consumption requires clarification. Smokers have been found to be more at risk for the development of cancer of the urinary bladder than are nonsmokers, and there is evidence to suggest that some smoking-induced abnormal meta- bolic product or abnormal concentration of a metabolic product may be responsible for this increased risk. In addition, cancer of the kidney is apparently more common in smokers than in non- smokers, but the epidemiologic evidence for this relationship is not as definite as for bladder cancer. Epidemiological studies have indicated an association between smoking and cancer of the pancreas. The significance of this rela- tionship is unclear at this time. Experimental studies have demonstrated the carcinogenicity of the condensate of tobacco smoke, or “tar.” This material, when painted on the skin of animals, leads to the development of squam- ous cell tumors of the skin. Researchers have shown that this condensate contains substances known as carcinogens, capable of inducing cancers. Among these earcinogens are several chemicals which have been identified as tumor initiators, that is, compounds which initiate changes in target cells and also tumor promoters, or compounds which promote the neoplastic development of initi- ated cells. Other, as yet unidentified, factors are presumably also involved because the sum of the carcinogenic effects of the known agents does not equal that of cigarette smoke condensate. Numerous experiments have been performed in which whole cigarette smoke, filtered smoke, or certain constituents of smoke, such as the “tar,” are administered by varying methods to animals or to tissue and cell cultures in order to investigate the neoplastic- inducing properties of cigarette smoke. Particular difficulty has been encountered in experiments which have attempted to deliver 764. whole cigarette smoke to the larynx and into the lungs of experi- mental animals. This has resulted in the use of other methods such as the implanting of pellets containing suspected carcinogens and the instilling into the trachea of suspected carcinogens as such, or adsorbed onto fine inert particulate matter as a carrier. The dif- ficulty with the inhalation studies has been twofold. First, the animals, particularly the smaller species such as the rat, frequently die from the acute toxic effects of the nicotine and carbon monoxide in the tobacco smoke. Second, the upper respiratory tract of experi- mental animals, particularly the nose, is much different from anal- ogous human structures, resulting in a more efficient filtration of smoke in the upper respiratory tract. Nevertheless, in rodents and canines, progressive changes apparently indicative of ultimate neo- plastic transformation have been identified in the respiratory tract. Recently, two studies in different species and in different target organs have been reported concerning the development of early in- vasive cancer following the prolonged inhalation of cigarette smoke: Auerbach and his coworkers (11) trained dogs to inhale cigarette- smoke through a tracheostoma. After approximately 29 months of daily exposure, these investigators found a number of cancers of the lung. Dontenwill (76) in the second of these two studies, exposed ham- sters to the passive inhalation of cigarette smoke over varying and prolonged periods of time. He observed the development of pre- malignant changes and, ultimately, invasive squamous cell cancer of the larynx. LUNG CANCER Cancer of the lung in the United States accounted for 45,383 deaths among males and 9,024 deaths among females in 1967 (289). It is presently estimated that approximately 60,000 people will die of lung cancer during 1970. The alarming epidemic of lung cancer is a relatively recent phenomenon. Death rates for lung cancer (ICD Codes 162, 163) rose from 5.6 (per 100,000 resident population per year) in 1989 to 27.5 in 1967 (289, 290). This rapid increase followed the in- creased use of cigarettes among the United States population. The increase has occurred principally among males, although more re- cently females have shown a similar rising pattern. The converging evidence for the conclusion that cigarette smok- ing is the major cause of lung cancer is derived from varied types of research including epidemiological, pathological, and laboratory Investigations. 265 EPIDEMIOLOGICAL STUDIES Numerous epidemiological studies, both retrospective and pros- pective, have been carried out in different parts of the world to investigate the relationship between smoking and cancer of the lung. These studies are outlined in tables 1, 2, A3, and A4. Prospective Studtes The major prospective studies concerning the relationship of gmoking and lung cancer are presented in table .1. In all, these investigations have studied more than a million persons from a number of different populations for up to 10 years. These studies show increased lung cancer mortality ratios for cigarette smokers of all amounts ranging from 7.61 to 14.20 among male smokers as compared to nonsmoking males. The one major prospective study of female cigarette smokers reveals an overall mortality ratio of 2.20 (118). Also uniformly present in these studies is a dose-related increase in the mortality from lung cancer with increasing amounts of cigar- ettes smoked per day. Other measures of exposure show similar trends. Hammond (118) reported increased mortality ratios asso- ciated with increased inhalation (table 1) as well as with increased duration of smoking (table 2). Ex-smokers show significantly lower lung cancer death. rates than continuing smokers. In their study of more than 40,000 British physicians, Doll and Hill (74, 75) noted a decrease in lung cancer mortality rates with increasing time since smoking stopped (table 1). During the past 20 years, half of all the physicians in Britain who used to smoke cigarettes have stopped smoking. While the death rates from lung cancer rose by 7 percent among all men from England and Wales during the period from 1953-57 through 1961— 65, the rates for male doctors of the same ages fell by 38 percent (96). Pipe and cigar smokers have been shown in the prospective stud- ies to have lung cancer mortality rates higher than those of mon- smokers, although these are generally substantially lower than those of cigarette smokers (table 1). Retrospective Studies More than 30 retrospective (case-control) studies have been re- ported concerning the relationship of smoking and lung cancer. These studies are outlined in tables A3 and A4. Table A4 presents the percent of nonsmokers and of heavy smokers among both cases and controls as well as the relative risk ratios for all smokers. 266 L£9¢ TABLE 1.—Lung cancer mortality ralios (Actual number of deaths shown in Parentheses)? SM = Smokers. NS = Nonsmokera, Prospective studies Author, Number year, and type collection Follow- Number Regular cigarette Pipe country, of Da up of smoking only cigar Inbalation Exemokers Comments reference population years deaths (cigarettes/day) Hammond 187,783 Question- 3% 448 Pipe No data Bronchogenia 341/448 and white Naire and SM. 443 NS ..,., 1,00 (15) NS « 1.00 (16) (Exzeluding adenocarcinoma) dentha with Horn, males interview. NS. 15 <10 .... 8.00 (24) SM . 2.67 (18) Never smoked ......... 1.00 microscopic 1968, in9 10-20 ...10.50 (84) Cigar Previously <1 pack/day proof, Ins USA States >20 ....23.40(117) NS - 1.00 (16) Continuing sree 16,94 cludes those (120) ages AN ....410.73(397) SM... 100 (7) Duration 10 years ., 1.61 amokers who Previoualy >1 pack/day also smoked Continuing ...,....... 46.21 Pipes and Duration 10 years ..17.79 without microscopic proof, Dolland Approxi- Question- 10 212 NS » 1,00 (3) Pipeand Cigar No dota Cigarette amokers Hill, mately naire and SM . 209 1-14 + 8.14 (22) NS.... 1.00 (3) NS wwe. eee eeee 1,00 (3) 1964, 41,000 followup NS . 8 15-24 ...19.86 (53) Grams/day Continuing cere eee 18.29 (124) Great male of death >25 +692.43 (67) 1-14.. 6.00 (12) Duration 25..,13.71 (3) cessativun] 10-20 yeara . 2.67 (3) >20 years =, 2.72 (2) Best, Approxis Question- 6 331 NS + 100 (7) Pine No data t Refers 1966, mately naire and TSM . 324 <10 + 10.00 (57) NS ....1.00 (7) NS voce cece eee 100 (7) to cure 1966, 78,000 followup NS. 7 10-20 .,.16.41(204) SM ....4.35 (18) Ex-amokera of rent Canada male of death £00 ....97.31 (63) Cigar cigurettes only + 606 (18) cignrette (#1), Canadian certificate. All wun. 14,20(245) NS ....1.00 (7) amokers velcrang, SM ..,..2.94 (2) only. 897 TABLE 1.—Lung cancer mortality ratios (cont.) (Actual number of deatha shown in parentheses}? SM = Smokers. NS = Nonsmokers. Prospective studies Author, Number year, andtype Data Follows Number Regular cigarette Pipe country, of collection up of smoking only elgar Inhalation Exsmokers Comments reference population years deaths (clgarettes/day) Kabn U.S. male Question. gy 1,256 Pipe (Dorm), veterans nalre and BM .1,178 NS ..... 1.00 (78) NS ....1.00 (78) No data 1966, 2,265,674 followup NS. 7B 1-9 1... 5.49 (45) SM ..,.1.84 (17) NS viceeveeeees 2600 (78) U.S.A. person of death 10-20 ... 9.94 (808) Cigar Number of cigarettes/day: (236), years. certificate. 21-89 .,.17.41(818) NS ..,.1.00 (78) WD vreeeeeeeee 0.95 (4) >89 ....28.93 (82) SM ,...1.69 (8) 10-20 .......-. 8.48 (89) Al .....12.14(749) Pipe and cigar Z1-89 cree ee es 9.88 (BT) NB ....1.00 (78) S80 cece ee eres 8.24 (19) SM ....1.66 (20) Hammond,440,558 Interviews 4 Males Current cigarettes Pipe Males ICD code 1966, males by ACS 1,159 only NS .,..1.00 (49) NS .....06. 2.00 (49) 162 only, U.S.A. 62,674 volunteers. SM .1,110 Males SM ,...2.24 (21) Slight ...... 8.42(120) (11a). females NS. 49 NS ..... 1.00 (49) Cigar Moderate ...11.48 (811) 85-84 Females 1-9 1... 4.60 (26) NS ....1.00 (49) Deep .......14,81(141) years of 188 1019 ... 7.48 (82) SM ....1.85 (22) Females age in 25 SM, 8% 20-89 ,..18.14(381) Pipe and cigar NS ...c...- 1.00(102) States, NS. 102 >40 ....16.61 (82) NS ....1,00 (49) Slight ...... 1.78 (25) All ..... 9,20(719) SM ....0.90 (11) Moderate Femalea — Deep \ 7+ B70 (45) NS ..... 1.00(102) 1-19 ..., 1.06 (20) >20 .... 4.76 (50) All vices 2.20 (81) 692 TABLE 1.—Lung cancer mortality ratios (cont.) (Actual number of deaths shown in parentheses)? SM = Smokers. NS = Nonamokers. Prospective studies Author, Number Follow- year, and type Data up Number Regular cigarette Pipe eountry, of eollection years of smoking only cigar Inhalation Examokers Comnients reference population deaths (cigarettes/day ) Buell 69,868 Question= 3 304 NS . 1.00 etal, American naire and <20 1... 2.30 1967, Legion- followup 20... 3.60 USA, naires of death >20 .... 4.90 (49), 36-76 certificate. years of age and older. Hirayama, 265,118 Trained 1% 48 NS ..... 1,00 (3) Preliminary 1967, maleand PHS SM. 40 1-24 .. 2,69 (29) report. Japan female nurse >25 . 668 (6) (185), adulta interview 40 years and fol- ofageand lowup of older. death certificate. Welrand 68,153 Question- 5-8 868 NS .... 1,00 NS Include Dunn, males in naire and +10 1... 8,72 pipe and 1970, varlous followup +20 1... 8.05 clgar U.S.A. oecupae of death >30 .,., 9.06 amokers (506). tlona in ' certificate. AN uo... 7.64 SM Include California, ex-emokera. 1 Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or exsmokers. TABLE 2.—Lung cancer mortality ratios for males by duration of cigarette smoking (Actual number of deaths are shown in parentheses) Age began cigarette smoking 35-64 65-459 10-84 35-84 25 or older 2.17 (6) 3.39 (12) 3.38 (3) 321 (20) 2024.6 eee rere -+ §.83 (31) Zi.11 (72) 12.11 (7) 9.72(116) YHS-19 wee eee . 8.71 (112) 13.06 (176) 19.37 (27) 12.81(315) CUB cee eee ere wee 12.80 (35) 18.81 (57) 16.76 (9) 16.10¢101) SOURCE: Hammond,E. C. (118). These smoker-nonsmoker risk ratios range from 1.2 to 36.0 for males and from 0.2 to 5.3 for females. Although not presented in tabular form, the data concerning lung cancer and pipe or cigar smoking are similar to those found by the prospective studies mentioned above. However, a study by Abelin and Gsell (1) conducted on a rural Swiss population noted that an increased risk of lung cancer was present among heavy cigar and pipe smokers (as well as cigarette smokers) to a greater degree than previously reported. The authors suggest that their findings might be due to differences in either the amount smoked or the car- cinogenicity of Swiss and German cigars. The difference might also be explained by the greater use and more frequent inhalation of small cigars in Switzerland as compared to other countries where large cigars are more commonly smoked but rarely inhaled. Kreyberg (154), ina review of 887 cases of lung cancer in Norway, noted that pipe smokers showed an increased risk of lung cancer, although this risk was substantially lower than that for cigarette smokers. LUNG CANCER TRENDS IN OTHER COUNTRIES Several studies of particular interest are those in which the changing mortality from lung cancer has been investigated in countries in which cigarette smoking has become popular and wide- spread only in recent years. In those countries where accurate statistics for lung cancer mortality are available for both the pre- smoking and post-smoking periods, long-term trends can be studied in some detail. Two such studies have dealt with lung cancer mortality trends in Iceland. Dungal (83) noted in 1950 that lung cancer was a rare disease in Iceland and felt that this rarity could be explained by the relatively late onset of heavy tobacco smoking in the Icelandic population when compared to that of Great Britain and Finland. He observed that the annual per capita consumption of tobacco did not reach one pound in Iceland until 1945, while Great Britain and Finland passed that amount before 1920. In 1967, Thorarinsson, et al. (276) noted a sharp rise in the incidence of lung cancer in Ice- 270 60—~ ee Fintand Pd Cy ce Be mem Norwazy 50— 40-4 304 20—4 6—4 Annual Death Rate per 100,000 = 7 - 7 - - 1934-36 1939-41 1944-46 1949-51 1954-56 1959-61 1963-64 Calendar Years Figure 1.—Lung cancer, Finland and Norway. Source: Kreyberg, L. (154). land after 1950 and found a correlation between that increase and the increasing sale of cigarettes in that country. Kreyberg (154) analyzed the lung cancer death rates of both Norway and Finland in relation to the use of tobacco in those two countries over the past 100 years. Figure 1 shows the substantial difference in lung cancer mortality between the two countries. Kreyberg observed that cigarettes came into use in Norway in 1886 while the Finnish population (more closely allied to Russia socio- economically) was consuming more than 100 million cigarettes per year during the decade of the 1880's, Cigarettes remained scarce in Norway until after World War I, and this 30-year lag in consump- 271 TABLE 5.—Annual means of total lung cancer mortality and sex ratios for selected periods in Finland and Norway Finland Norwey Year ~~ TT Moles Females Males Females LOIEBB wo eee ee ere ree 192 33 34 30 Sex ratio ...---.5 essere 68:1 Lisl Oy <3) es 1,319 121 355 19 Sex ratio ....--.e eee cere 10.921 46:1 Source: Kreyberg, L. (154). tion behind that of Finland is reflected in a similar lag in total lung cancer mortality and sex ratios (table 5). HistroLocy of LUNG TUMORS A number of investigators have focused their interest upon the relationship of cigarette smoking to the varied histology of lung tumors. The major histological types of lung cancer include squa- mous cell (epidermoid) carcinoma, smal] and large cell anaplastic carcinomas, adenocarcinoma (including bronchiolar and alveolar types), and undifferentiated carcinoma (153). A review of these studies (table 6) indicates a closer relationship between cigarette smoking and epidermoid carcinoma than between cigarette smok- ing and adenocarcinoma (42, 113). The work of Kreyberg (153) in Norway, over the past 20 years, provides evidence of a specific histologic relationship. This inves- tigator noted that a clearer association is obtained if the various types of pulmonary carcinomas are grouped. Table A7 presents his groupings of the specific histologic types. Using this classification as a basis for analysis of lung cancer gex-ratios in Norway, Kreyberg has observed that Group I carcinomas are significantly more frequent among males while Group II carcinomas show an approximately equal distribution among males and females. The author considers the recent rise in lung cancer in Norway to be a reflection of the increased prevalence of Group I carcinomas. Fable 8 presents a summary of Kreyberg’s investigation concerning 793 male and female cases of lung cancer. Among both males and fe- males, the risk ratio among smokers is substantially higher for Group I types than for those of Group II. However, adenocarcinoma among males shows a risk ratio of 2.9, signifying a relationship with smoking. Kreyberg attributes the lower rates noted among females to their significantly lower consumption of tobacco in all orms, 272 £L2 TABLE 6,—'pidemiologic and pathologic inveatigations concerning amuking and the hiatolugy of lung cancer (Actual number of cases shown in parentheses) Author, Number of year, persons and country, caso aciection Resulta Comments reforence method Wynder 644 autopsics on Percent oases by histologic type and smoking Atatory The percentage of chain and males with Al lung cancers other than smokers in the general Graham, confirmed adenocarcinoma (605) Adenocarcinoma (39) population (7.6) wag 1950, lung cancer. Nonsmokers ci sccseccecseeveevteeeeees 1.3 10.3 significantly Joss than U.S.A. Light cigarette amokers .. 2.3 VT among the patients with (316), Moderate wo... .. eee there, 10.1 16.4 adenocarcinoma. The HEavy ice cece ccc ec enc ee ee ereerens 30.2 88.5 authors refrained from Excessive (oo... ccc caevte ere cenenaaeeae 30.9 10.3 making any definite CHAIN ccc cece cence eter entrees . 20.3 18.7 conclusions due to the {nauMelent number of cases, Doll 916 male and 79 Percent patients with lung cancer by average amount amoked daily over 10 ycara No ataltlstically and female cascs Males algnificant difference Hii, with histologically Oat-ecll or was found between 1962, confirmed Epidermoid (475) anaplastio ($03) Adonocarcinoma (#3) the amounts amuked by England lung cancer, Nonamokerg....... Q2 (1) 0.7 (2) 6.1 (2) the patients in the (78), Smokers: different histological <6 clgarettes/day .. 2.9 (14) 8.9 (12) 6.1 (2) groups. Number of 6-14 $6.6 (109) 86.3(110) 21.2 (7) proven adenocarcinoniag 16-26 36.8 (175) 34.7(106) 48.5(16) toa amall for >26 24,4 (116) 24.4 (74) 18.2 (6) conclusions, Females Oat-cell or Epidermoid (18) anaplastic ($8) Adenocarcinoma (10) Males—105 unclassified Nonsmokers 61.2 (11) 31.6(12) 50.0 (6) tumors, Smokers: Females—13 unclassified <5 cigarettes/day .. 66 (1) 15.8 (6) 20.0 (2) tumors. 6-14 seen 22.2 (4) 23.7 (9) 10.0 (1) 15-25 5.6 (1) 18,4 (7) eee eb. 6.6 (1) 10.6 (4) 20.0 (2) 9LE TABLE 6. E’pide miologic and pathologic investigations concerning emoking and the histolog (Actual number of cases shown in parentheses) y of lung ecaricer’ (cont.) Author, Number of year, persons and country, case aclection Results Comments reference method Breslow 498 male and 25 Percent of patienta with specific lung cancers by tobacco usage during the 20 years prior to study Nonsmokers tuclude pipe etal., female cases and cigar amokers only. 1964, with histologically All lung cancers other than The authors conclude USA proven lung alcnocarcinoma Adenocarcinoma Controle that cigarette smoking (i2). cancer. (472) (518) appeore ty ulfyct the 618 age and Nonsmokers reer eeeeenee penne nene 5.8 24.4 develupment of aex-matebed Cigarctte smokers .....6. Levee ere nenee 94.1 76.6 epithelial carcinoma controls. more than that of adenocarcinoma. Schwartz 430 male and Percent of amokera by Aistologic type and emoking history etal., female cases 1957, with hlatologleally Epidermoid Anaplastic Unknown types Cylindrical + Difference France confirmed Jung Cases ... 96.0 87.0 100.0 significant (#67). cancer, 4 matched Controls 79.0t 83.0t 96.0 at px0.05 level. control groups. Heenszel 168 female Relative risk for apecified tumore (emokers/nonemokers)} 134 cases with final etal, cases of histological 1958, lung cancer, Group I (Kreyberg) Adenocarcinoma determination. U.S.A. Adjusted for age and occupation. wieeveeee cues 3.0¢ 1.19 t Difference from (119). unity significant at peo.o1 Haenszel 2,191 male Standardised mortality ratios Cases obtained from a and cases of 10 percent sample of Shimkin, lung cancer Epidermoid and wniifferentiated Jung cancer deaths in 1962, with adequate carcinomas Adenocarcinoma —=o- S.A, during 1968. U.S.A. biytulogic data. White males total .....-- Leen e ee enter net e aes . 100 100 The suthory noted an (112). Never smoked «... 6 18 absence of important Ex-amokers ws... 34 46 differentials by || <2 nock/day 123 a hintulogic type. 4 CDT pack/day versveeeeeeee ee 4g SLe TaBLe 6.—Epidemiologic and pathologic investigations concerning smoking and the histology of lung cancer’ (cont.) (Actunl number of cases shown in parenthoscs) Author, Number of yerr, persons and country, case aclectlon Results Commenta reference method Cohen 417 male and Percent cases by Atatulogtc type and amoking history The authora oluo and female cases of (number of emokers) Noted that: Hossain, lung cancer with 1, Adenocarcinumas 1966, histologic Squamous Undifferentiated Adenocarcinoma Alveolar were 214-3 times U.S.A. diagnosis 1939-63 Nonsmokers ......... 10 (3) 10.0 (17) 23.0 (8) 20,0(1) more common in women (58). at one hospital. Smokers 89.0(183) 90.0(146) 60.0(20) 2. Only l percent of Kreyberg Group | cuaey Were nonsmokers. Ashley 442 male and Percent casce by hiatulopic type and emoking history The authors noted that and female couva of Cigarette smoking Davies, histoloyically Undifferontiated Squamous Adenocarcinom apjears to be as 1967, diagnosed Nonsmokers vie... ss csess 2.8 (4) 2.5 (6) 3.4 (2) strongly related to England lung cancer. PIPE ve eeeee eee eeese ees 9.9 (14) 9.9 (24) 17) adenocarcinoma as to (6), Cigaretle oo... ccc eee 87.3(124) 87.6(211) 94,9(56) the other 2 types. ClO/day we. cee eee 14.1 (20) 22.4 (64) 22.0(13) Agbley’s data on total 10-20 0, 33.6 (48) 41.6 (100) 33.9(20) number of cigarette 21-30 12,0 (17) 21.6 (62) 16.9 (10) smokers are 31-40 14.1 (20) 12.9 (31) 8.6 (5) inconsistent with >40 7A (10) 6.2 (16) 6.1 (3) his breakdown of amokery into groups based on number of cigurctlos smoked per duy, Ormos 118 male and Percent cases by histologic type and amoking Atetory The author nuted that etal, female cases of the amall number of 1969, histologically Group! Group and largocell carcinomas — cuyey ntluws for ne Hungary Proven lung Nonamokers 11. sieve eevee seers eee 24.0 (18) s6.u CO) definite concluyions, (204). cancer with Smokers 79.0 (68) 64.0(16) adequate smoking information, 1 Data obtained frum putlent interview and other sources. 9172 TABLE 8.—Tumor prevalence among males and females 85-69 years of age, by type of tumor and emoking category (Smokers constituted 86 percent of populations studied) Smoking category Expected Risk number tatio Sex and type of tumor Smoking Non- among Among Total all methods amokers emokers? smokers Males Epidermoid carcinoma ..ccccnscsnre ree sre erent eee e teenies beeeeres 434 431 3 17.0 25.4 Small cell anaplastic carcinoma ......56, wee see cee eee eens 117 116 1 8.7 20.4 Adenocarcinoma cecccseeee eee e eee teeeee 88 83 6 28.3 2,9 Brenchiololalveular carcinoma ...ccsece eee te os . dees vues os saee sone Carcinoid wise eee ee Veve vet estnaesestvsssssee : 46 $9 q $9.7 1.0 Bronchial gland Cumor ...icee creer ree eens . cane Total ccc ccc e eee etre teen e nee teen e eee RE EER EES wees 685 669 16 90.7 TA Females Epidermoid carcinoma co.cc ccs ccc c neers ese cee weeeenneneees seeene an 12 8 3 16 12.0 Small cell anaplastic carcinoma wecseiereeseneeeeenee Leneee pevtaee 8 6 3 16 6.6 Adenocarcinoma seen eee teees Sao ren teens cane 56 14 42 10.6 1.3 Bronchiolol-alveolar carcinoma@ voces ee cere ene beeen ee beet eveerrane wees ve wae vane us Carcinoid ...ceceaee eee Arn beter weenie 32 q 25 6.3 ML Bronchial gland tumor ....... pee e teem ent eee eee te sees Total ccc ccc cen cree se eee e rere aee rasta ree trier teehee ene teaee 108 35 13 18.3 1.9 ‘Number that would be expected if incidence rate among smokers were equal to that of nonsmokers. Source: Kreyberg, L. (154) LUNG CANCER RELATIONSHIPS IN WOMEN Lung cancer death rates for women are presently much lower than the corresponding rates for men. In addition, it has been ob- served that among certain strains of mice exposed to carcinogenic agents, the male animals show a greater tendency to develop lung tumors than do the females (200, 207) although there are strains for which this is apparently not so. The extent of the influence of endocrine factors in the sex variation in the incidence of lung tumors is unknown. As of 1967 in the United States, women accounted for only about one-sixth of the total deaths from lung cancer (289). However, the lung cancer death rate in women has risen by over 400 percent in the past 40 years. From 1950 to 1967 alone, the rate per 100,000 population doubled, increasing from 4.5 to 8.9 (289, 290). A number of retrospective studies concerning lung cancer and cigarette smoking among women have found that the difference in the prevalence of lung cancer between males and females is ac- counted for principally by those tumors classified as Kreyberg’s 311). These, as was noted above, are the tumors, par- ticularly in males, which show the closest relationship with smok- ing. Haenszel, et al. (113), in a study of 158 women with lung cancer, observed that the sex differential for lung cancer death rates diminishes, but does not fully disappear when only non- smokers are considered. Hammond (118) found that the death rate for lung cancer in hat higher than for nonsmoking fe- le rates was much a substantial Group I (154, nonsmoking males was somew males. However, the difference in male-fema greater when smokers were compared. It appears that part of the difference in death rates between male smokers and fe- male smokers can be explained mainly by differences in their smok- ing habits. These differences in smoking habits between males and females are of two types. First, overall consumption among females is still significantly lower than that among males. In 1966 (281), 30 per- cent of males reported that they had never smoked while for fe- males the corresponding figure was 59 percent. This study also — noted that nearly three times as Many males as females reported consuming more than 20 cigarettes per day. Second, it has been shown that women smoke differently than men (803) : They begin smoking later than men (114) and do not smoke cigarettes as close to the end, where proportionally more nicotine and “tar” are in- haled. Women smoke more filter-tip and “low tar and nicotine” cigarettes than men. Furthermore, cigarette smoking still tends to be heavily concentrated among women under the age at which lung cancer is most likely to occur. 277 Finally, analysis of the ratio of male and female Jung cancer death rates (283, 284, 285, 286, 287, 288, 289, 290) reveals that since 1960 this ratio has shown a steady decline, reflecting the greater relative rise in mortality from lung cancer in the female population. Lune CANCER, THE URBAN FACTOR, AND AIR POLLUTION A number of studies have been concerned with the relative influ- ences of smoking, urban residence, and air pollution in the etiology of lung cancer. Table 9 lists studies performed in the United States, Great Britain, and Japan which have dealt with this question. Kotin and Falk (249, 150) and more recently the Royal College of Physi- cians (228) have reviewed the literature concerning the influence of atmospheric and environmental factors in the pathogenesis of lung cancer. The studies listed-in table 9 show a number of important trends. Lung cancer death rates are found to be higher among urban popu- lations than among rural populations. It is not known to what ex- tent this urban factor in the etiology of lung cancer. is due to differences in the levels of air pollution. Other factors associated with urban residence which may influence the etiology of lung cancer are: differences in smoking habits between the two popula- tions, occupational differences, and possible differences in the re- porting of lung cancer deaths (228). The studies also uniformly show that within each urban/rural grouping, lung cancer death rates increase with increased smoking. Whether air pollution acts with cigarette smoking to influence lung cancer death rates in a combined manner is presently unclear (112, 126, 264, 265), and the evidence concerning a separate role of air pollution in the etiology of lung cancer is still inconclusive (228). The recent report of the Royal College of Physicians on air pollu- tion and health (228) concluded that ‘the study of time trends in the death rates of lung cancer in urban areas demonstrates the ribution of the overwhelming effect of cigarette smoking on the dist disease. Indeed, only the detailed surveys that have taken individual smoking histories into account have succeeded in separating the f the ‘urban factor’ on the over- relatively very smal] influence 0 riding effect of cigarette smoking in the development of cancer of the lung.” 278 622 TABLE 9.—Lpidemiologic investigations concerning the relationship of lung cancer to 7 gy g { Pp g smoking, air pollution, and urban or rural residence (Actual number of deaths shown in parentheses) Author, Population year, atudied and Country, method of Results Comments reference data collection Dol, Estimated death rates Lung cancer mortality (1950) per 1,000 Authors noted that 1963, from jung cancer Maics Females Nonamokera — eatirnutes are based on England in English London Otherurban Rural London Othcrurban Rural Allarcas very few deaths. (70), population and Age: among nonsmokers 26-44 ....,. 0.126 0.095 0.070 0.028 0.028 0.012 0.020 obtained from 48-64 ....., 1.572 1.264 0.861 0.194 0.162 0.120 0.090 general regiater, 65-74 2... 3.124 2.006 1.164 0.440 0.326 0.288 1219 Stocks and Death rates in Male lung cancer death rates 1952-44 (per 100,000) ages 54-74 The authors noted the Campbell, England and upward gradicnt among 1956, Northern Wales. Rural (68) Mized (118) Urban (589) nonsmokers, pipe England Review of patient Nonamokers .......... 14 oe 131 smokers and Wight (265), chartor interview Pipe ........., tee 41 26 143 cigarette smokers and the with kin or Cigarettes: Light ......:c:ceccuccecenaees 87 163 297 lack of asimilar physicians, Moderate ........ 00ers 183 132 287 gradicnt among Heavy cocci cecececcc cee aeenes 363 303 304 moderate and heavy cigarette smokers, Hammond 187,783 white males Age standardized death ratca due to bronchogenic carcinoma (males) Data excluded and Horn, in 9 states, adenocarcinoma. when 1868, Questionnatre Suburb City of City of standardized for age and U.S.A. and interview. Rural ortown 10,000-50,000 >60,000 amoking, rural rate waa (120). Nonsmokers ....... beeen nae 4.7 (2) 8.8 (8) 14.7 (4) atill noted to be 26 Cigarette smokers ....,.., 66.2(62) 71,7 (67) 70.9 (59) 85.2 (83) percent legs than urban, O8z TADLE 9.—Epidemiologic investigations concernt gmoking, air pollution, and urban or rural residence (cont.) (Actual number of deaths shown in parentheses) ng the relationship of lung cancer to Author, Population year, studied and Country, method of Results Comments reference data collection Haenszel 10 percent of all Age and amoking-standardized lung cancer mortality ratios Standardized Mortality etal, white male lung (epidermoid and undifferentiated carcinomas only) Ratio = 100 for U.S. 1962, cancer deaths in white males age 36 and U.S.A. U.S.A. for 1958 Metropolitan counties Nonmetropolitan counties over In 1958, The authors (112), for whom next of 350,000 sess eee ved l9 2,500-50,000 ....,-90 also noted"... joint kin or physiciang 10,000-50,000 .....-0-- 151 Rural nonfarm ....74 effects of residence and supplied smoking 2,500-10,000 ..rceeeeeee 39 Farm cee ABT smoking historics in the data. 2,191 cases schedule of lung-cancer with adequate rates far greater than information. those expected on the assumption of additivity of the separate effects..." Doll 41,000 male British Standardized death rates for lung cancer The authors noted that and Hid, physiciana, 1964, anne ; rural mortality data England follow-up of death Nonsmok Conurbation(49) Large Towns ($4) Small Towna (32) Rural (18) were affected hy a a weninerve oy smokers ...e. eee 0.03 0.00 OAL ‘ 0.12 significant number of . garette smokers: city residenta 1-14 0.48 0.32 0.87 0.52 retiring to the country. 15-24 1.31 1.88 1.06 1,16 >25 1.90 4.43 2.20 LAT wien. hate male and . Lung cancer death rate per 100,000—-age- and amoking-atandardized Total number of denthy Northem deaths over 3 Inner Out 1 noted under methud of Ireland years ofa ‘ t Belfast B ‘fea ne on Urban Small data colloction include (308), veuiaiar, Persoval east china atiacunaaha Towns Rural 954 controls. aa or. ersonal Males... 167 (241) 139 (167) 135 (46) 118 (186) 137 (26) 47(149) nterviews with Females 22 (38) 17 (24) 12 (6) 23 (35) 22 (6) 12 (43) kin or physicians, T8C TABLE 9.—Epidemiologic investigations concerning the relationship of lung cancer to emoking, air pollution, and urban or rural residence (cont) (Actual number of deaths shown In parentheses) Author, Population year, atudied and Country, method of Results Comments reference data collection Buell 804 Jung caneer Age-adjusted lung cancer death rates per 100,000 man yeara and mortality ratios The authors noted the lack etal, deatha among of death-rate diffcrence 1967, American San Franctaco/ All other between Los Angeles and U.S.A, Legionnaires Los Angeles San Diego California countiss San Francisco regions 449). aged 25 and over. Rate Ratio Rate Ratio Rate Ratio and concluded that Questionnairesto Nonsmokers .....ccceeeeeee . 28.1 2.6 43.0 3.9 11.2 1.0 photochemical amog fa next of kin. Smokers: : not related to 1 pack/day: <40 years of age ....... poets eenee 17 880 1.6 12.5 BOBO ccc ccc etre ere rer cere ee eees 63 3,027 4.6 17.4 GOOD cicsreceee veupee panes 84 4,186 6.9 20.5 DT0 cece cere eee teen net ee ences 16 766 9.8 23.7 Cross 140 persons Percent acctions showing changes in branchial epithelium (number of ecctions) {| The authors noted etal,, autopsied at Squamous Atypical Carcinoma that the differs 1961, Towa City Normal Hyperplasia metaplasia metaplasia tn attu Carcinoma ence between ULS.A. Veterans Nonsmokerw (81) cecceeeses G1 (062) 36 (137) 8 (33) t15 (68) - vane smokers and non. (64). Hospital Smokers (109) crvseesaver es 44(670) 43(562) 16 (197) 20(263) 1(12) 2.6(34) amokers was on whom etatlatically smoking alyuificant. data was available. L£8¢ TABLE 10,—Pathologic and cytologic findings in the tracheo-bronchial tree of smokers and nonsmokers (cont.) (Actual number of coseas ahown in parentheses) Author, Number of year, cases and country, method of TResulta Comments reference selection Averbach 12 autopsicd Number of Percent acctiona Percent scctions Percent sectiona Each ex-smoker etal, former ciga- acctions of with etlia abeent with some atypi- with 50 percent matched with s 1362, rette smoker bronchial and entirely cal ecle and atypical cells current smoker U.S.A. who had been Number epithelium alypteal cella cilia abeent andciliapresent plus never-smoker (4), amoking for Nonsmokers sae 12 3,156 0.0 O.4 0.5 for age, occupa- 2:10 years Ex-smokers oe 42 3,436 0.2 0.9 2.5 tion, and resi- and had Current amokers .... 12 3,537 8.0 19.0 $0.8 dence, There was ceased an average of 226 years ago. 60.4 acctiona per subject and none had Icas than 18 sections. 882 TABLE 10,—-Pathologic and cytologic findings in the trachco-bronchial tree of amokers and nonsmokers (cont.) (Actual number of cases shown In parentheses) Autbor, Number of year, eascs and country, method of Teeaults Cumments reference selection Auerbach 466 male and Percent eece Perecnt secs Percent sec- Major findings etal., 802 female Number of tions with tions with tions with 50 noted: 1962, smokers and acetions of eilia obacnt tomeatypi percent atynical Urbun nonsmokers ULS.A. nonsmokers bronchial and entirely cal cells and ecllg and showed more (43). autopsied and Number epithelium atypical cella cilia abeent cilia present lesion than rural. matched for Males: Both Ieslons and age, occu- Nonsmokers ........-5. 47 2,346 te O14 0.7 atypleal nuclel pation, and Cigarette amokers ....,, 76 3,393 6.9 21.2 18.5 were much legs residence, Females: we frequent In none Nonsmokera ..ceseeeees 47 2,879 . 01 0.6 emokers and less Cigarette smokers ....., 76 3,607 2.5 18.8 62.6 frequent In pipe Males: and cigar smokers Nonsmokerg ....ess.s0. 85 1,706 os 0.2 0.5 than in cigarette Cigar smokers ... . 85 1,733 0.8 10.0 10.7 smokers, Cigarette amokers ...... 35 1,526 12.8 27.3 83.1 67.1% of cases hud 50-66 sections 81.5% of cases had 40-49 sections 9.3% of casca had 30-89 acctiona 4.6% of cases had 16~29 sections Robbins, 103 studenta Percent in each cytologic class Smokera defined a8 1966, 17-24 years Slightly Moderately Strongly those having con- U.S.A, of age who : Normal atypical atypical atypical sumed 210 ciga- (222), underwent Nonsmokers (45) .oscceeveevseaes 1. 86.7 44 8.9 we rettes a day for merosol Smokers (58) .. 85.2 32.8 10,8 1.7 zh year. sputum | Induction. #87 TABLE 10,—-Pathologic and cytologic findings in the tracheo-bronchial tree of smokers and nonsmokera (cont,) (Actual number of cascy ahown in parentheses) Author, Number of year, caoxes and country, method of Results Comments reference selection Maltoni 1,000 healthy Number Percont showing metaplasia etal., matics who Oy vee eee ee 294 41,16 1968, underwent Smokers: Italy sputum 1-30 clgarcttes/day 189 47.09 (182). induction, M-20 vs. 886 61.43 21-80 ....0, bee enas 93 61.29 280 eee eee . 39 60.23 Nasiell, 60 nonsmoking Sputum cytologic changes Percent with t Regarded by 1968, vutpatients, Porcent Percent with atypical author as “real Sweden 398 umokera Number Males Mean age metaplasia metaplasiat premalignant (198). participating Nonamokers ..........,. » 60 , 42 67.1 18 change,” in general Smokers ......, reeeeenes 898 73 45.6 62 health exam- ination who underwent sputum induction. Spain . 157 males and Number Percent with metaplasia The authors found etal., 78 females Males; no evidence of 1970, autopsied fo). Nonsmokers 36 60.0 carcinoma in eity U.S.A. lowing sudden Ex-smokers 21 67.7 or prencoplaatic (258). or accidental 1 pack ...,. Teese ees Senet beeen tence Nee vaes beeen aeruce ‘ 68 73.5 whom smok- Females: ing data were Nonsmokers 34 84.2 available (ex <1 pack ...., oe 18 33.3 amokers ex- >1 pack 26 46.1 cluded from female data). In order to facilitate understanding of the relationships of the various compounds to one another, the third column presents the presently understood relative importance of each of the various groups of compounds. These compounds have been tested only in animals or tissue cultures, and it should be stressed that the rela- tive importance of one compound may not be the same in man as it ig in animals. Table 11 is divided into two major sections. The first section details those compounds which are considered to be or are suspected of being cancer initiators. These are compounds which induce irreversible changes in responsive cells. In the second section are listed those compounds which are considered to be or are suspected of being tumor promoters. These compounds promote the malig- nant reproduction of cells in which neoplastic changes have been initiated. A number of these initiators may also act as complete carcinogens in their own right. The evidence concerning the two stage initiation-promotion mechanism is still rather limited for respiratory tract carcinogenesis. The polynuclear aromatic hydrocarbons (PAH) listed are pres- ently considered to play a very significant role in pulmonary car- cinogenesis due to tobacco smoking. These compounds act as tumor initiators or complete carcinogens. The particular role of these agents in environmental and occupational carcinogenesis has been reviewed by Falk, et al. (93). That such hydrocarbons are pro- duced from tobacco during human smoking has been shown by Kiryu and Kuratsune (146). These authors reported the presence of benz{aJanthracene, chrysene, benzo[a]pyrene, and benzo- [b]fluoranthene in the ‘tar’ produced by normal smoking and measured in either filters or stubs. Two hydrocarbons which have frequently appeared in the litera- ture on experimental tobaceo carcinogenesis may not actually be present in tobacco smoke. They have been used as representatives of carcinogenic PAH, a class which includes many constituents that have been identified in cigarette smoke condensate. They” are 7,12-dimethylbenz[aJanthracene and 3-methylcholanthrene and have been frequently used as tumor initiators or complete carcino- gens, particularly in skin painting and tracheal implantation experiments. The nitrosamine compounds listed are potent carcinogens affect- ing many organ systems, including the respiratory tract (188, 189). Magee and Barnes (181) have presented a detailed account of experiments in this area. Nitrosamines have been identified in trace amounts in tobacco “tar’’ and the conditions required for their formation (the presence of secondary amines and nitric oxide) are 290 TABLE 11.—Identified or suspected tumorigenic agents in cigarette smoke* Components Eatimated concentra- tion in 100 cigarettes (85 mm. non filter) Presently understood relative importance in experimental tobacco carcinogenesis I. Complete carcinogens and tumor initiators: Polynuclear aromatic hydrocarbons I. Benzo(a)pyrene 2. Dibenz(a,h)anthracene 3. Benzo(b) fluoranthene 4. Benzo{j) fluoranthene 5. Dibenzo(a,i) pyrene 6. Benz{s) anthracene 1. Chrynene 8. Indeno(1,2,3-cd) pyrene 9. Benzo(c)phenanthrene? 10. Methylbenzo(a) pyrenes 11. Methyichrysenes N-heterocyclic hydrocarbons ...----+-++++> 3. Dibenz{a,h)acridine .-.- 2. Dibenz(a,j) acridine 3. TH-dibenzo(¢,g) carbazole N-nitrosamines? .. 1. Dimethylnitrosamine 2. Diethylnitrosamine 3. Methyl-n-butyinitrosamine 4. Nitrosopyrrolidine 5. Nitrosopiperidine Epoxides, peroxy compounds, and lactones: lL. Epoxides 2. Peroxides 3. Lactones a. g-Levantenolide b. p-Levantenolide N-aikyl-heterocyclics: 1. I-metbylindole Pesticides and fungicides :*¢ 1.TDE .... 2.0,p-DDD .- 3. DDT ...- : 4. Maleic hydrazide ...-------eeer cnt Beta-naphthylamine ..-------serereretttt Polonium 210 22-6... eee eee ttt Nickel compounds ...-.---+-serertrrrre 1-2 0.01 1.0 0.07 1-10 No data Present Present 10-100 10-100 10-100 10-100 1-50 picocuries Tumor initiators. Tumor initiators. Suspected carcinogens of possible importance (presence in fresh smoke possible) . Certain of these compounds are known carcinogens; presence in amoke condensate not established. Possible initiator. No essential contribution suspected. Suspected bladder carcinogen; of doubtful significance at reported levels. Of some importance only in the case of relatively high concen- tration, but not important at reported levels. Suspected carcinogens of some importarce. 291 TABLE 11.—Identified or suspected tumorigenic agents in cigarette smoke? (cont.) Estimated concentra- tion in 100 Presently understood relative Components cigarettes importance in experimental (85 mm. tobacco carcinogeness nonfiiter} Il. Tumor promoting agents: Neutral promoters (polymers) Nodata Of possible importance, (unknown strictures.) Volatile phenols ....------- eee e erect 20-30 mg. Of possible importance. 1. Phenol 2. Cresol Nonvolatile fatty acids -...-+---- reer certt 20-100 mg. Of minor importance. 1. Stearic acid 2. Oleic acid N-alkyl heterocyclics: Of possible importance. 1. @-methylearbazole «1... eee eee Present 1 Modified and expanded from (3519, 320) with reference to (5%, 40, 89, 111, 129, £02, 262, 209, 294, 295). 2 Has not been tested as an initiator, but is a known complete carcinogen. 3 See Neurath, (202). *See (111, 128). found in tobacco smoke (38). However, nitrosamines may be arti- facts dependent on the method of smoke collection (201). Neurath (202) considers the nitrosamines listed in table 11 as being present in fresh cigarette smoke (253, 254). However, con- clusive confirmation of their presence in fresh smoke is not available (38, 188, 155, 319). Certain of the pesticides and fungicides presently in use on tobacco have been found to be carcinogenic (91, 273, 280). A num- ber of these, such as DDT, are now being phased out of regular domestic use. The compounds listed have been shown to be present in trace amounts in mainstream tobacco smoke (1171, 1 28) . A recent, extensive review by Guthrie (171) provides more detailed informa- tion concerning these agents. Radioactive isotopes can be found in tobaeco and tobacco smoke (105). Potassium-40, while present in tobacco leaf, is not trans- mitted in any substantial amount to mainstream smoke (230). Polonium-210 (Po.,.), however, is transmitted into the mainstream smoke (94, 123, 142, 145, 215, 217). A number of autopsy studies (table A12) have shown that the bronchial epithelium of smokers contains significantly more Pozo than that of nonsmokers. Little, et al. (172, 173, 174) have also noted that the concentration of polonium was markedly higher at sites of bronchial bifurcation. These authors stress the importance of this finding for pulmonary carcinogenesis by noting that bronchogenic carcinomas are fre- 292 quently located at bifurcations and that the polonium levels which they found in those regions probably have biologic significance (216). Other investigators (123, 217) have not observed this excess at bifurcations, and in a recent discussion Wynder and Hoff- mann (320) concluded that it appears unlikely that Po.,,. in the amounts present in cigarette smoke plays a role in tobacco car- cinogenesis. Although not listed as a separate group, there are a number of agents in cigarette smoke which are potent inhibitors of ciliary movement. Their importance in carcinogenesis derives from the increased amount of time which they afford the known carcinogens to be present on the surface of the bronchial epithelium. These inhibitors include volatile aldehydes, hydrogen cyanide, nitrogen oxides, volatile phenols, and certain volatile acids such as formic and acetic (129). Experimental Studies In some respects, the animal and tissue culture studies detailed below apply to neoplastic transformations, not only in the lung but in other tissues in which tobacco smoke, particularly cigarette smoke, is believed to play a role. These general experiments will be presented here, however, with the experiments which bear on lung tissue directly. Skin Painting and Subcutaneous Injection Numerous animal studies on rats, mice, and rabbits, have been performed utilizing known carcinogens, whole tobacco “tar,” and various tobacco condensate subfractions, or compounds known to be present in tobacco smoke. These experiments involve the single or repeated painting of shaved or unshaved anima] skin. A selected number of these studies is presented in table A13. Numerous other studies, performed prior to and following 1953, are reviewed by Wynder and Hoffmann (319). . The skin painting method is still considered to be a valid pro- cedure for the identification of agents suspected of participating in pulmonary carcinogenesis, as well as for the quantification of the reduction in tumorgenicity of specific agents. Tissue and Organ Culture The exposure of tissue and organ cultures to cigarette smoke, its condensates, or its constituent compounds has been shown to sig- nificantly alter patterns of cell growth and reproduction. Table A14 presents an outline of these experiments. Once again, less severe effects have been noted when filtered smoke was used (165). 293 Tracheobronchial Implantation and Instillation More complex experiments concerning the carcinogenicity of cigarette and tobacco smoke are represented by those which involve the direct implantation, instillation, or fixation of suspected ma- terials into the tracheobronchial tree of animals. Certain of these experiments are outlined in table A15, Recent reviews by Saffiotti (233, 234) Laskin, et al. (159), and Montesano, et al. (189) as well as that by Wynder and Hoffmann (319) provide more detailed and extensive accounts of these experiments. Of note among the results outlined in this table are the following: The enhanced carcinogenicity found when benzofal]pyrene (B[{a]lP) js combined with a carrier such as hematite dust (235), and the definite increase in bronchial epithelial preneoplastic and neo- plastic changes among dogs treated with smoke condensate as com- pared with those undergoing only physical bronchial stimulation (224). Inhalation Various species, including mice, rats, hamsters, and dogs, have been exposed to cigarette smoke or aerosols of its constituents. These inhalation experiments are outlined in table A16. It must be noted that the majority of the studies listed involve the passive inhalation of the material presented usually in a chamber. Active inhalation experiments, exemplified by the work of Rockey and Speer (223) and Auerbach and his colleagues (11, 119) involved animals which were trained to inhale voluntarily, thus more closely simulating human smoking. Results of note among these experiments include the following: Miihlbock (195) observed that cigarette smoke inhalation en- hances the already substantial rate of spontaneous alveolar cell carcinoma formation in hybrid mice, and various investigators in- duced adenomas in experimental animals (108, 168, 206). Harris and Negroni (121) found that exposure to cigarette smoke achieved some enhancement of adenocarcinoma formation in mice but did not observe proven squamous cell carcinoma, Some of their mice had also been exposed to Swine influenza virus aerosol. In a related study, Boren (32) exposed hamsters to cigarette smoke at set inter- vals over a 48-hour period. The author observed alterations in pul- monary cell kinetics (the pattern of DNA synthesis) as demon- strated by H*-thymidine autoradiography. The pattern of the label- ing response to cigarette smoke was significantly different from that of the response to high oxygen concentrations. Auerbach, et al. (11) have reported the development of early 294 invasive squamous cell bronchogenic carcinoma in dogs following a period of direct inhalation of cigarette smoke. These investiga- tors trained beagle dogs to inhale cigarette smoke through a tracheostoma (50) and divided the animals into groups according to dosage as detailed in table 17. A number of dogs died during the course of the experiment which ran for 875 days, or approximately 29 months. The causes of death are Hsted in table 18. All of the remaining dogs, with the exception of group “h” (high exposure, heavy weight), were sacrificed shortly after day 875; the survivors among the heavier dogs are continuing to smoke. Examination of the respiratory tree of the animals revealed a number of tumors (table 19). Most of these were similar to the type of tumor which in man is referred to as bronchiolo-alveolar. This tumor arises in the bronchiolar and alveolar epithelium and tends to be multicentric. Two striking characteristics of these bronchiolo- alveolar tumors were the existence of a histologic spectrum (from a tumor resembling the benign condition of adenosis to frankly malignant tumors with invasion of the pleura and surrounding parenchyma) and the marked tendency to squamous change. Inva- sive bronchiolo-alveolar tumors were found in 12 dogs in the group which had been exposed to the largest dosage of cigarette smoke. Several had tumors of more than one category. Ten of these dogs had invasive bronchiolo-alveolar tumors which did not extend into the pleura, one dog had an invasive bronchiolo-alveolar tumor which extended to the pleura, and four had invasive bronchiolo- alveolar tumors extending into the pleura beyond the pleural- pulmonary junctions. In addition, two bronchogenic squamous cell carcinomas were found in this group (table 19). The dosage de- pendence of tumor formation is shown in figures 2 and 3. Major findings of the study were twofold. First, that smoking filter-tip cigarettes was less harmful, both in terms of pulmonary parenchymal damage and lung tumors, than smoking identical cigarettes without filters. This supports the generally held view that total particulate matter is a meaningful indicator of the car- cinogenic potential of a cigarette. Second, lung cancer of two types found in man was produced by the inhalation of cigarette smoke. Two of the dogs were found to have early invasive squamous cell carcinoma of the bronchus, and both belonged to the high-dosage group. These carcinomas were indistinguishable from early invasive squamous cell carcinomas found in the bronchial] tubes of human beings who smoke cigarettes. The majority of tumors found in the dogs were of a bronchiolo-alveolar type, which although not as common as squamous cell cancer in man, is not rare in humans. This type is often included in the category of adenocarcinoma. A number of studies have shown an excess of these tumors among 295 962 TABLE 17.—Data on pedigrecd male beagle dogs of groupa F, L, H,h,andN (Some of the figures apply only to doga surviving 876 days or longer) No Filter fitee iter filter Nonamokers ¢ rou group oe sroup g 7 Pp ; N Number of dogs on day No. 67* ..... vase neeeee an ‘ 12 12 24 $8 8 Welght at start (day No.1) mean weight (pounds) ...... 25.0 25.1 26.0 819 30.7 Cigarettes per dog in 875 dayp corse ever eee ences tees 6,143 3,103 6,129 6,129 none Mean number of cigarettes per day .... beens 7.02 3.64 1.0 7.0 Equivalent number of cigarettes per day for 150 pound man 42,1 21.2 42.0 32.9 — Type of cigarettes :? Milligrams of tar per cigarette ...., 17.8 34.8 34.8 84.8 ne Milligrams of nicotine per cigarette .... 117 1.86 1.85 1.85 —_ Total dosage in 875 days: Grams of tar per dog voce cece eee eeerene cea eeneenee 109.3 103.5 207.8 207.8 _ Grams of nicotine per dog occ. cece cece reece een eee : TAY 6.56 11,12 1412 — Dosage in 875 days relative to starting weight: Grams tar/pounds weight ........ denen bene eeenee . 4.37 4,12 8.81 6.81 — Grams nicotine/pounds weight .......0005 Reine) 0.29 0.22 0.44 0.35 — 1 The smoking dogs were divided into groups F, L, H, and b on day No, 57. 2 Doge of groupa L, H, and b amoked filter-tip cigarettes during a training period at the start of the exper! Sounce: Adapted from Hammond, E. C. et al. (119). tment, but smoked nonfilter cigarettes thereafter. L672 TABLE 18.—Summary of principal cause of death (days No. 57 through No. 875) in dogs of groups F, L, H, h, and N (Each death classified according to most severe condition—some doga dicd of a combination of causes listed) Filter No No No tip filter filter filter Nonsmokers Principal cause of death Group Group Group Group Group F L H N Pulmonary emphysema and fibrosis .........00.005 seneee _ ~ 2 _ _- Cor pulmonale (pulmonary emphysema and fibrosis with right heart enlargement) _— —_ 8 6 _ Pulmonary infarction ........05 1 1 2 5 _ Bronchonneumonia a _ a 1 _ Aapiration of food .. 1 1 - ~~ - Uncertain .,...... _— _ 2 1 _ Number of deaths ....... sae 2 2 12 12 _ Number surviving 875 days 10 10 12 26 8 Total number of dogs ..... 12 12 24 a8 8 Source: Hammond, E. C. et al. (£18), B6c TABLE 19.—Data on dogs with lung tumors indicating type of tumor and lobe in which the tumor was found Early squamous Group Day of Nusper ace Lobes with bronchbiolo-alveolar tumors cell bronchial death cigarettes (years) Non-invasive Tuvagive carcinoma Group N (nonsmokers) .+.ee> eens eee ely 904a _ 5.1 LA _ _ N 904b _ 4.9 RA - _ Group F (filter-tip) sect nensereeeeenee 8788 6,161 6.1 LA _- _ F 8798 6,170 47 LA - _ F 8850 6,224 5.2 LA _ _ F 890a 6,269 54 LA - _ Group L (no filter} ..ceaeenae seveee steels 347 1,055 3.8 LA, LC = _— L 812 2,847 5.1 RA - _ L 8760 3,103 BL LA, RA _ _ L 8778 3,107 6.2 LA, LC _ _ L 882a 3,127 8.2 LA, LD - _ L ROGa 3,183 6.3 LA, RD _ - iL Bue S196 G4 LA _ 7 Group H (no filter) cccsescereer reece eee ell 136 BiK 26 RE _ ~— YW 269 Vai dat LA, RA, RD - _ H 063 3.404 47 LD, RA _ - Il 716 4,089 6.0 te LA _ H 783 6,050 3.8 Rl LA, RA, RD - H 160 G.OBS 2 LA -- _ H 86K 6,970 $3 LA _ - H s7ha GLY 4.9 ae LA, LD, RA _ H HT? 7a G,134 64 oe LA LALB H Sika 6,147 6.3 RA LA _ H 882n 6,183 6.4 LA _ _ H Sh3u 6,192 4.7 RA, RD, RI LA -- H 8850 6,210 6.0 os LA, RA LMU H 8890 6,246 6.0 oe LA -— H 8908 6,255 4.9 LA _— _ H 8920 6,273 6.7 LC, RA _ a H 8o2b 6,273 5.3 oe LA, RA _ H 8970 6,318 5.2 RA a - H ROTb 6,318 4.6 Lc LA _ 66¢ TABLE 19.—Data on dogs with lung tumors indicating type of twmor and lobe in which the tumor was found (cont.) Number Age at Early squamous Group Day of of death Lobes with bronchiolo-alveolar tumors cell bronchial death cigarettes (years) Non-invasive Invasive carcinoma Grouph (no filter) .....c.ae, pe eeee ene BD 606 3,769 46 LA _ _ h 626 3,928 44 we LA, RI _ b 649 4,143 5.0 RI LA, RA _ h 794 5,400 B.1 LA, RA _ _ LA, left apical lobe; LC, left cardiac; LD left diaphragmatic; RA, right spical; RC, right cardiac; RI, right intermediate; RD, right diaphragmatic: LABB, left apical branch bronchus; LMB, left main bronchus. For smoking dogs, the day of death indicates the number of days since start of smoking. The letter “a” or “b” follows the day of death sacrificed after day #875. Source: Auerbach, O. etal. (11), of dogs ao b 79.2 . a 58.3 Oo 60 ° a Done seen te uw ° L e - : ry r 2 40+ 3 tl “3 “ 4 i ot GROUP N: GROUP F: GROUP L: GROUP H: NONSMOKING FILTER-TIP NO FILTER NO FILTER OA as many cigarettes) as Group H TUMORS 2 4 7 19 DOGS 8 12 i2 24 Ficure 2.—Percent of smoking dogs with tumors. Source: Adapted from Auerbach, O., et al. (11). 60 + o . ad a ° + 40} = ° k 5 5 S 20.8 a 2 20 14.3 4.8 we TERY 3.6 2, 4 0 rs fa . el GROUP N: GROUP F: | GROUP L: GROUP H: NONSMOKERS FILTER-TIP NO FILTER NO FILTER CA as many cigarettes) as Group H TUMORS 2 A 32 35 LOBES 56 B4 84 168 Ficure 3.—Percent of lung lobes with tumors in smoking dogs. Source: Adapted from Auerbach, O., et al. (11). 300 cigarette smokers (6, 42, 112), but the magnitude of this relation- ship is not as great as that with squamous cell cancer in man. Reduction in Tumorigenicity The importance of reducing total particulate matter in cigarette smoke is reflected in the dose-dependent results of the Auerbach- Hammond study. A major objective of experimental tobacco car- cinogenesis must be the reduction in the tumorigenicity of cigarette smoke and other tobacco products. In a recent article (320), Wynder and Hoffmann have reviewed the various methods applied to achieve this goal. Among these methods are the modification of the tobacco itself, the modification of the conditions of tobacco pyrolysis, the use of additives, and the use of filters. The use of filters should produce a reduction of particulate matter as well as of gas phase components. Bross (44) studied 974 cases of lung cancer at Roswell Park Memorial Institute and concluded that smokers who switched to filter cigarettes showed a decreased risk of developing lung cancer. However, even after switching, heavy smokers were still found to have a mortality risk five times that of nonsmokers. More recently, Wynder, et al. (324) reported on an interview study of 350 patients with histologically confirmed lung cancer and 552 age and sex-matched controls. They found that subjects who had switched from nonfilter to filter cigarettes ten or more years prior to the study incurred a lower relative risk of lung cancer at all consumption levels than that incurred by those who continued to smoke nonfilter cigarettes, The authors suggest that this difference in relative risk may be due to the lower “tar” content in filter cigarette smoke. Prospective studies concerning the effects of filter cigarette smoking are presently being conducted. Apart from variations in “tar” exposure due to filtration, it appears that different patterns of smoking result in the inhalation of varied amounts of “tar.” Graham, et al. (103) simulated dif- ferent inhalation patterns with the use of an analytic smoking ma-~ ~ chine. He found that smoking a given number of puffs over a long period of time results in greater “tar” retrieval than smoking them over a short period. Also, he observed that taking most of the puffs at the end of the cigarette results in the highest retrieval while taking most at the beginning results in the smallest retrieval. Complementing these observations is the same author’s case/con- trol study (102) of 183 men with lung cancer and 161 men with diseases not related to tobacco smoking. He found that the lung cancer patients had significantly greater high “tar” yield cigarette smoking patterns than the controls. The risk of lung cancer was found to increase with the increase in mean number of puffs per 301 cigarette, the average length of time taken to smeke wo cigarette (except in the highest number of puffs category), wid the Taking of more puffs at the end of the cigarette. These findings, and those of the study of Averbrehy, 4 eh ELLY, add further support to the dose-response relationsh*: Between ung, cancer and total cigarette smoke condensate €Xposire.. SUMMARY AND CONCLUSIONS 1. Epidemiological evidence derived from a numer ei PrSaset- tive and retrospective studies coupled with experimminé zd! path: ological evidence confirm the conclusion that cigarette: smoking; is: the main cause of lung cancer in men. These studies seseuk titae che risk of developing lung cancer increases with the nuzd y of. cigar: ettes smoked per day, the duration of smoking, ant aeler miga- tion, and diminishes with cessation of smoking. 2. Cigarette smoking is a cause of lung cancer sen ceorpere leat accounts for a smaller proportion of cases than in rvs “S2e moc tality rates for women who smoke, although signdiwads hégier than for female nonsmokers, are lower than for mex win smoke. This difference may be at least partially attributed to differenve 12 exposure; such as, the use of fewer cigarettes per diy the use. of filtered and low “‘tar” cigarettes, and lower Jevels af inhalation. Nevertheless, even when women are compared wit men who: an- parently have similar levels of exposure to cigarette: smoke; the mortality ratios appear to be lower in women. 3 The risk of developing lung cancer among pie. andor cigar smokers is higher than for nonsmokers but significr2tayy ippsen than. for cigarette smokers. 4. The risk of developing lung cancer appears to@higher among smokers who smoke high “tar” cigarettes or smoke Gr suv a. mare ner as to produce higher levels of “tar” in the inhazd! smoke. 5. Ex-cigarette smokers have significantly lower deatir rates for lung cancer than continuing smokers. There is evidence to support the view that cessation of smoking by large numkevs: af uigarette smokers would be followed by lower lung cancer dpath: nates. 6. Increased death rates from Jung cancer have teen sbserved among urban populations when compared with pepuiatans from. rural environments. The evidence concerning the rule. ef sir peliv- tion in the etiology of lung cancer is presently incommusive. Facters such as occupational and smoking habit difference: mayr ad8G. con- tribute to the urban-rural difference observed. Detaed. epidemic- logic surveys have shown that the urban factor exexts 2 small influence compared to the overriding effect of cigavede smoking in the development of lung cancer. 302 7. Certain occupational exposures have been found to be asso- ciated with an increased risk of dying from lung cancer, Cigarette smoking interacts with these exposures in the pathogenesis of lung cancer so as to produce very much higher lung cancer death rates in those cigarette smokers who are also exposed to such substances. 8. Experimental studies on animals utilizing skin painting, tracheal instillation or implantation, and inhalation of cigarette smoke or its component compounds, have confirmed the presence of complete carcinogens as wel] as tumor initiators and promoters in tobacco smoke. Lung cancer has been found in dogs exposed to the inhalation of cigarette smoke over a period of more than two years. CANCER OF THE LARYNX Cancer of the larynx is a disease which predominantly affects males in the 55 to 70 year age group. In 1967, a total of 2,468 males and 329 females died of laryngeal cancer in the United States. With the development and application of more effective therapy during the past 30 years, the death rate for cancer of the larynx appears to be dropping slightly (282, 289); however, the incidence con- tinues to rise. Figures from the Connecticut Cancer Registry (88) show that the age-adjusted incidence per 100,000 population of cancer of the larynx for males rose from 3.0 in 1950 to 5.6 in 1961. EPIDEMIOLOGICAL STUDIES A number of epidemiological studies have investigated the rela- tionship between smoking habits and the development of cancer of the larynx. The major prospective studies, as outlined in table 20, show that smokers of cigarettes run an approximately six-to- tenfold risk of dying from this form of cancer as compared to non- smokers. Smokers of pipes and cigars incur a three-to-sevenfold risk. The retrospective studies listed in table A21 uniformly show fewer nonsmokers and more smokers among cases with cancer of the larynx than among matched controls. Table A22 summarizes— - the relative risk ratios derived from the retrospective studies. The wide variation is due to a number of factors, including type of popu- lation and interview technique. But, in general, the magnitude of most of these ratios is of the same order as in the prospective studies. Wynder, et al. (312) have distinguished between cancer of the intrinsic and extrinsic larynx. Tumors arising on the vocal cords are classified as intrinsic and constitute approximately 70 percent of the lesions, The extrinsic larynx is composed of those sections of the larynx excluding the vocal cords and may also be referred to as 303 HOE TABLE 20.—Laryngeal cancer mortality ratios (Actual number of denths shown in parentheses)?! SM = Smokers. NS = Nonsmokers. Prospective atudics Number Autbor, of year, Number and Data Follow. laryngeal Cigarcttes/day Pipes, clgars Comments country, type of collection un cancer reference population years denths Hammond 187,783 white Questionnaire 3M 24 Chyarette smokera 17/24, Cigar Data referring to mortality and males 60-69 and follow- \ SM ..24 3/24 ratio Included cancer of Norn, years of age up of death NS .. 0 Mixed esophagus and mouth, 1958, {n 9 states. certificate, 4/24 ULS.A, (120), Doll and Approximately Questionnaire 10 16 All amokera by amount Pipeand cigart + Includes data on ex- Rill, 41,000 male and follow- SM ,.16 in grama NS .... 1,00 smokers of pipes and cigars, 1964, British up of death NS .. 0 NS vivseeece nee ne SM .... 5.00 No NS died of laryngeo- Great physicians, certificate. 1-14 . « 1.00 tracheal cancer, therefore Britain 16-24 pereceeeee 1,00 1-14 gram SM act oa 1.00 (76), OG eee e seen 7.60 standard, Data combine laryngeal and tracheal carcinoma. Kahn U.S. male Questlonnalre By 54 NS oe. eee eae 1.00 (8) Pipe Refers to current cigarette (Dorn), veterana, and follow- SM ..61 | +» 827 (1) NS .... 1.00 (3) smokers only. 1966, 2,265,674 up of death NS .. 3 10-20. .. 8.45(10) SM ....10.83 (6) ULS.A, person years, certificate, 21-39 «28.62(11} Pipe and cigar (139), >, 1.18.85 (3) NS... 1.00 (8) All viv ceec ev eenes 9.95(28) SM ..,. 7.28¢11) Hammond, 440,558 males Interviews 4 57 NS ocisceeeeeeeaee 1,00 (8) Pipeand cigar Male data only. 1966, 562,671 fo by ACS SM ..B4 SM (age 45-64) ., 6.09(82) NS .... 1,00 (8) Pipe and cigar data refer to U.S.A. males 35-84 volunteers, NS .. 3 | SM (oge 65-79) .. 8.99(18) SM ..,. 8.87 (4) males 66-84 yoarp of age. (118), years of age in 25 states, SOE TABLE 20.—Laryngeal cancer mortality ratios (cont.) (Actual number of deaths shown in parentheses)? SM = Smokers, NS = Nonsmokers, Prospective studies Number Author, of year, Number and Data Follow. laryngeal Clgarettes/day Pipes, cigars Comments country, tyne of collection up eancer reference population years deaths Weir and 68,153 males Questionnaire 5-8 1k NS icceee ee ee eee OS No nonamokers died of Dunn, in various and follow- SM ..11 SLO Lis eeeee sees 1,00 lurynucal carcinumna, 1970, occupations up of death NS .. 0 20 ieee ee 6.99 therefore £10 amoher set U.S.A, in California. certificate. P90 eee eee eee B84 as 1,00 atundard, (306), NS includes plpe and clyar smokers, SA includes ex-amokers. ' Unless otherwise specified, disparities between the total number of deatha and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-amokers. the hypopharynx. These authors noted that the percentage of heavy smokers among the patients with cancer of both the extrinsic and intrinsic larynx was significantly greater than that among controls. However, it 1s of interest that the excess risk of laryngéa] cancer among cigar and pipe smokers in this study could be attributed to the extrinsic laryngeal group. As in studies of oral cancer, it appears that alcohol consumption should also be taken into account in studies of Jaryngeal cancer. Wynder, et al. (312) reported a significantly increased risk of extrinsic cancer among those with alcohol intake above 7 ounces of whiskey per day. With less than this amount, no increased risk was evident. Schwartz, et al. (248), noted no effect in relation to alcohol intake. Further research into the interaction of these two variables is necessary. PATHOLOGICAL STUDY Auerbach, et al. (9) studied histological changes in the larynges of 942 men, age 21 to 95, who were autopsied at a single hospital between 1964 and 1967. Cases of primary cancer of the larynx were excluded from the study. Smoking histories for all cases were obtained from family members of the deceased by trained inter- viewers. The randomized histological sections were graded by one observer. Tables A23 and A24 summarize the findings in the true vocal cord. Of the men who never smoked, 75 percent had no cells with atypical nuclei, only 4.5 percent had sections with areas con- taining 60 to 69 percent of cells with atypical nuclei, and none had a higher percentage. The 116 ex-smokers had laryngeal histology similar to that of the nonsmokers, as far as atypical nuclei were concerned. However, disintegrating nuclei were found in 40.5 per- cent of the ex-cigarette smokers and in only 0.4 percent of the remaining cases. Only one of the 94 cigar and/or pipe smokers had no atypical cells. Three had carcinoma in situ, and one case had a section showing early Invasive primary carcinoma. The highest percentage of atypical cells was found among the cigarette smokers. The proportion of cases with a high degree of cellular change increased with increased daily smoking. None of the pack-or-more-a-day smokers was free of atypical nuclei in the laryngeal epithelium. Of those who smoked two or more packs per day, 85 percent had lesions with 60 percent or more atypical cells as compared to 4 percent of the nonsmokers. Between 10 and 18 percent of the cigarette smokers had areas of carcinoma in situ, and 4 of the 644 cases showed early microscopic invasion. The thickness of the basal level of the true vocal cord was also directly related to the amount smoked. 306 EXPERIMENTAL STUDY Dontenwill (76) has recently reported the development of an effective and practicable method by which small rodents (ham- sters, rats, mice) can be exposed to long-term passive inhalation of cigarette smoke in a manner which circumvents the fatal effects of acute toxicity which ruined earlier attempts but allows for a dosage of smoke great enough to induce the development of chronic patho- logical changes. The Syrian Golden hamster was found to be the most suitable species for such inhalation experiments for several reasons: its resistance to pulmonary infections, its resistance to the effects of nicotine as compared to that of rats or certain strains of mice, and, especially, its susceptibility to develop tracheobronchial cancers after treatment with carcinogens, in contrast to its almost total freedom from the spontaneous development of these tumors. Dontenwill demonstrated that the concentration of deposited cigarette smoke was greatest in the hamster’s larynx as compared to the other portions of the exposed respiratory tract (table 25), and that the laryngeal epithelium was the tissue which underwent the greatest smoke-induced histological changes. In studying the changes in the larynx, the author differentiated five stages of epithelial change, using as his reference the Atlas of Tumor Pathology of the Armed Forces Institute of Pathology (5). Table 26, quoted by Dontenwill, describes the five types of change. They range from benign, such as epithelial hyperplasia, to pre- malignant, exemplified by pseudoepitheliomatous leukoplakia, The results of the inhalation experiment are presented in figure 4 in which a dosage-related increase in the severity of the epithelial changes is represented in graphic form. The author also reported, and depicted with photomicrographs, the finding of an early inva- sive squamous cell carcinoma. This form of cancer is the predomi- nant type involving the human larynx. SUMMARY AND CONCLUSIONS 1. Epidemiological, experimental, and pathological studies sup-— port the conclusion that cigarette smoking is a significant factor in the causation of cancer of the larynx. The risk of developing laryngeal cancer among cigarette smokers as well as pipe and/or cigar smokers is significantly higher than among nonsmokers. The magnitude of the risk for pipe and cigar smokers is about the same order as that for cigarette smokers, or possibly slightly lower. 2. Experimental exposure to the passive inhalation of cigarette “. smoke has been observed to produce premalignant and malignant changes in the larynx of hamsters. 307 TABLE 25.—Deposition of C-labeled smoke particles in particular regions of the respiratory tract* Traced Traced Estimated Deposition Proportional deposition radio- radio- of areaofthe in relation Organ activity Organ activity particles respiratory to the (nCi) (nCi) (%) tract proportional area Head and palate ... 6-12 Head, palate 5.5 37.4 Tongue ..-.------- 0.41 Oralcavity 16 10.9 in total. Larynx .....------ 0.39 0.1-0.3 X561-187 Trachea .....--.-- 0.26 7.6 (traced) 5L.7 0.6 X62.3 Lungs ...-.------- 6.95 1000 Xl Total ......- 14.12 714.7 100.0 1 Cigarettes labeled with 11C_1-n-hexadecan; data represent calculated from surface distribution in the head. 2 The value of 14.7 contains 0.58 nanocuries as estimated from mean values from 10 animals, quantity of deposition in the nontraced oral cavity regions (calculated as to proportiona) area}. Sounce: Dontenwill, W. (76)- 368 60€ TABLE 26,—-Classification of the five registered stages of epithelial changes at the larynx’? Dyskeratogis (pre+ mature atypical Acanthosis (thicken- Hy perkeratosss Parakeratosis (ine cornification : Stage ing of stratum increased complete cornifica- changes in the Mitosis spinosum multi- cornification tion of nuclelin nucleus prolifera. cellular layer) (stratum corneum) the stratum comeum) tion 7 {pe basal ayar) 1, Pachydermia (epithelial hyperplasia) ........ Leeeaee + + t t t 2. Leucoplakia ........, ees sees tases at ee nes + + t t t 3. Verrucous leucoplakia .........000. Feb eeeeaee teens + + + t z 4. Papillomatous leucoplakia 0.0... ...ccsaes cece, vteee + t t ++ t 5. Pseudoenitheliomatous leucoplakia pee eey yyy Seeeaey + + + p+ + Symbols: t+ = negative; t=ominimal; += weak; +-+ = medium: +++ = atrong. 7From Atlas of Tumor Pathology of the Armed Forces Institute of Pathology. Source: Adapted from Dontenwill, W. (78), TOTAL 146 34 as as | 6 10 { 7 12 4 5 17 4 | ° . eoue ye o° ° ose ee eene je oeenle lee le jee eesion . ee en . . HISTOLOGY Pa%s%e te e é peee 2 4 6 8 10 12 14 16 18 20 22—> 23 SMOKE EXPOSURE, months e =ONE ANIMAL 6 =ANIMAL LIVING O=LARYNX CANNIBALIZED Ficure 4._Effects of chronic cigarette smoke inhalation on the hamster larynx. Review of the results of the inhalation experiments: number of smoke-ex- posed animals with and without changes in the larynx, duration of smoke exposure, and number of animals still alive. Source: Dontenwill, W. (76). ORAL CANCER The cancers included in this category are those of the lips, tongue, floor of the mouth, hard and soft palate, gingiva, alveolar mucosa, buccal mucosa, and oropharyns. It is estimated that 15,000 of these cancers will be diagnosed in the United States in 1970, accounting for about 2.5 percent of the estimated 600,000 malignant neo- plasms reported (289). A variety of histological types of malig- nant neoplasms can affect these tissues, but squamous cell car- cinoma is by far the predominant type, accounting for about 90 percent of the cancers. The incidence of and mortality from oral cancers has remained steady over the past 20 to 30 years. The Connecticut Cancer Reg- istry (88), which is a fairly reliable index of incidence, noted that the incidence among males remained between 15.8 and 16.3 per 100,000 population during the years from 1950-1961, Examination of mortality rates over the past 20 to 30 years (282, 289) reveals a similar constancy. The apparent lack of change in mortality from oral cancer in 310 contrast to the sharp increase that took place in lung cancer rates in those years is probably due to several of the following factors. First, pipe and cigar smohing are both significantly related to can- cer of the oral cavity, and the increase in cigarette smoking among men, noted between 1920 and 1955, has been, to a large degree, accompanied by corresponding reductions in the use of pipes and cigars. Second, aside from the various changes which the Interna- tional Classification of Diseases (ICD) had undergone during that period, the diseases discussed above are recorded in ICD Codes 140-148 which include some neoplasms not found to be related to the use of tobacco. The various sites of cancer themselves do not contribute equally to the overall rate and are subject to widely dif- ferent cure rates, so that their contributions to the total incidence rate is different from their contribution to the overall mortality rate from oral cancer. Although more than 20,000 cancers of the oral cavity were estimated as newly diagnosed in 1967, the total number of individuals recorded as dying from oral cancer during that year was only 6,718 (289). Ora] cancer occurs predominantly in people of the middle and older age groups. More than 90 percent of all oral cancers occur in persons over age 45, with the average age at time of diagnosis approximating 60. Although the majority of oral cancers occur in men, there is recent evidence that the ratio of males affected to females affected is decreasing (257). EPIDEMIOLOGICAL STUDIES The use of tobacco in various forms has been associated with the development of cancer of the ora] cavity and pharynx. The studies in this area of concern are truly international, many having been carried out in Asian nutions as well as in the West. The major prospective epidemiological studies have found in- creased rates of these cancers for cigarette smokers as well as for pipe and cigar smokers (see table 27). Pipe smoking, per se, has_ _ long been recognized as a cause of lip cancer (291). The methodol” ~ ogy and results of the numerous retrospective studies are sum- marized in tables A28 and A28a. These studies almost uniformly show significant relationships between the various forms of tobacco use and crnecrs of the oral cavity and pharynx. Studies in Asian notions have examined the prevalence or inci- dence of premaliynant change, such as oral leukoplakia, as well as that of cancer of the oral cavity. In many of these studies, forms of tobacco use not prevalent in Western countries have been investi- gated, including reverse smoking (in which the lighted end of the cigarette is kept in the mouth close to the palate) and the chewing 311 ZTE TABLE 27.—Oral cancer mortality ratios—prospective studies (Actual number of deaths shown in parentheses) NS = Nonsmokers. SM< Smokers, Author year, Number and Data Follow- Number country, type of collection up years of Cigarettes Pipes, clgars Comments reference population deaths Hammond = 187,783 white Questionnaire M4 56 20/56 Pipe Mixed Data referring to mortality and males in 9 and follow-up 1SM. GL 5/56 21/66 ratlo do not include cancer of Norn, States 60-69 of death NS. ..3 Cigar larynx and esophagua, 1968, yeors of age, certificate, 6/66 ft Excludes two oceanlonal U.S.A, only emoubess, (180), Dol} and Approximately Questlonnatre 10 19 Allamokera by amount Pipe and cigar No NS dhed of oral cancer, Hall, 41,000 male and follow-up SM ..19 in graeme NS ovisseee 1.00 therefore 1-14 gram 1964, British of death NS 6.0 NG cicccerceeveee —_ SM... seee 1.00 smoker act as 1.00 Great physiclana, certificate. 1-4 veeaee 1,00 standard. Britain 16-24 saves 0.25 (74). >25 . 5.25 Kahn U.S. male Questionnaire 84 61 NS wee ee eee 2,00(11) Pipe Data do not Include pharynx, (Dorn), veterans, and follow-up SM ..50 tCigs/day 1-9 .... 0.86 (1) NS ....... 2.00(41) f Refers to current clgarctte 1966, 2,265,674 of denth NS wi 10~20 . 2.93(13) SM oo... 3.12 (4) smokers only. ULS.A. person years, certificate, ZN-39 cece av eevee TOA (20) Cigar (139). >49 -. 673 (3) NS w..eaee 1.00(41) AN teens » 4.00(397) SM wi.ccaee GUE (9) Hammond, 440,468 males Interviews by 4 05 NS ova. eeee receaes 1.00 (7) ¢ Plpe and/or 1 Male data only. Pipe and 1966, 562,671 fomalea ACS volunteers SM ..BB OSM (nage 46-64) ..,. 9.00(63) chuar. clyor data refer to nmintes USA, SG-84 yours of NS ..7 SM (age 65-10) .. 2.93(26) NS ....e. 21,00 (7) 6b-B4 yours of axe. (41s), age in 26 States. ‘ SM oo... e, 4.9416) Welrand 68,163 males Questionnaire 6-8 19 1.00 SM Includes ex-amokers, Dunn, in various and follow-up .. 3.69 NS includes plpe and 1070, occupations of death 2117 elgar smokers, ULS.A, in California. certificate. 5.52 (906), . 2,96 of “pan” or “Nass,” which are mixtures of tobacco with either betel nut or lime ash, and other ingredients (241, 255, 256). Snuff dipping, a habit in which snuff is placed in the gum and retained there for prolonged periods, has also been associated with the development of oral cancer (198, 210), as has the chewing of tobacco (124, 193, 241, 298). ‘The risk of developing a second primary mouth or throat cancer, aftér the recognition of the first primary cancer, has been found to be greater in continuing smokers than in those who quit smok- ing. All of the patients studied by Moore (190) were asymptomatic for at least three years following the treatment of the first cancer. Of the 117 patients with adequate smoking histories, only 4 of 43 (9 percent) who quit smoking developed a new primary cancer. On the other hand, 27 of 74 (36 percent) who continued to smoke developed a second primary cancer. However, a study by Castigliano (53) of patients treated for oral cancer did not show a greater risk of a second primary among continuing smokers. In this study, 5 of 26 (19 percent) of those patients who did not quit smoking developed a second primary cancer as compared to 9 of 51 (18 percent) of those who did quit. The rate of quitting smoking in the two studies is markedly dif- ferent (36 percent in the Moore study and 62 percent in the Casti- gliano study). From the data presented in the two papers, it is not possible to evaluate the other significant ways in which the pop- ulations may have differed. Keller (140) studied 408 males with histologically confirmed Squamous cell cancer of the mouth or pharynx. This author dealt with the question of recurrent tumors in a somewhat different manner. The patients were observed for the development of a sec- ond or third primary cancer at an anatomically discrete site of the mouth and pharynx within a median period of three years after the first cancer. He found that a second or third cancer (termed a coexisting cancer) developed in 28 of the 408 cases. Among these 28 cases with 33 coexisting neoplasms, 21.7 percent were heavy — - smokers, but among their matched controls, there were no heavy smokers. Coexisting cancers were most commonly found on the soft palate, an anatomical site that is in dire¢t contact with the main- stream of tobacco smoke. More recently, Wynder, et al. (315) studied 63 male and 23 female patients with multiple primary cancers of the mouth and pharynx. They observed that heavy smoking prior to the develop- ment of the oral cancer was associated with a greater likelihood of developing a second primary. Also, continued smoking after the first primary was found to have a significant association with the occurrence of a sé€cond primary. 313 With or without smoking, use of alcohol appears to contribute to the development of oral cancer (124, 140, 183, 297, 322). In a study of male vetérans, Keller (150) found that heavy smoking and heavy drinking were associated with cancer of the mouth and pharynx. No studies are presently available which determine the relative contributions and possible interactions of heavy smoking, heavy drinking, and concurrent nutritional deficiencies in the etiol- ogy of these cancers. EXPERIMENTAL STUDIES In 1964, the Advisory Committee to the Surgeon General on Smoking and Health (291) reported that cigarette smoke and ciga- rette smoke condensates had failed to produce cancer when applied to the oral cavity of mice and rabbits or to the palate of hamsters and that the oral mucosa appears to be resistant in general to can- cer induction even when highly active carcinogens such as benzo- [aJpyrene are applied. Some of the difficulties in experimental de- sign were attributed to the fact that mechanical factors, such a3 secretion of saliva, interfere with the retention of applied carcino- genic agents on the tissues of the oral cavity and pharynx. Positive results with certain carcinogens have, however, been obtained in the hamster cheek pouch, but it has also been pointed out that the cheek pouch lacks salivary glands and that its structure and func- tion differ from those of the oral mucosa. The majority of these studies are outlined in table A293. Although cigarette smoke condensate acts as a complete carcino- gen on mouse skin, the work of several authors (319) supports the concept that cigarette smoke contains cancer promoters that may be of special importance, particularly in oral carcinogenesis. Elzay (90) has reported that whole cigarette smoke is a promoting agent for the hamster cheek pouch. More importantly, regarding the chewing of tobacco, Bock, et al. (27,30), Van Duuren, et al. (294), and Wynder and Hoffmann (321) have shown that unburned to- bacco products contain tumor promoters that might contribute to the promoting activity of the smoke. . Roth, et al. (226, 227) have shown that the dye-binding capacity of the DNA of oral epithelial cells is significantly enhanced in cigarette smokers in contrast to nonsmokers, probably reflecting an increase in the DNA content of oral epithelial cells in smokers. Smokers had values of dye-binding capacity intermediate between nonsmokers and 21 patients with proven oral cancer. Those smok- ers who refrained from smoking for up to six months showed a significant decrease toward more normal! values. 314 SUMMARY AND CONCLUSIONS 1. Epidemiological and experimental studies contribute to the conclusion that smoking is a significant factor in the development of cancer of the oral cavity and that pipe smoking, alone or in conjunction with other forms of tobacco use, is causally related to cancer of the lip. 2. Experimental studies suggest that tobacco extracts and tobacco smoke contain initiators and promoters of cancerous changes in the oral cavity. CANCER OF THE ESOPHAGUS Esophageal cancer accounted for 4,306 deaths among American males in 1967 and 1,321 deaths among females. The death rate from esophageal cancer has remained relatively constant since 1949. EPIDEMIOLOGICAL STUDIES The major prospective epidemiological] studies (table 30) have indicated a significant relationship between smoking and esopha- geal cancer. Overall mortality ratios for male cigarette smokers range from 1.74 to 6.17. There are insufficient data concerning females for establishing firm conclusions. A number of retrospective studies concerning the relationship of smoking and esophageal cancer are outlined in table A351 and A31a. Smokers incur risk ratios ranging from 1.3 to 6.6 when compared with nonsmokers. As in studies of oral cancer, the effect of alcohol consumption must be taken into account in studies of esophageal cancer. Because a relationship between alcohol consumption and tobacco use is known to exist, Wynder and Bross (310) analyzed the association between tobacco consumption and esophageal cancer after adjust- ing for alcohol intake. They found that in the absence of alcohol - consumption, there was no association between the use of tobacco and esophageal cancer but that in the presence of alcohol consump- tion, an increasing relative risk with increasing number of ciga- rettes smoked was apparent, as well as an association between cigar and pipe smoking and esophageal cancer. More recently, Takano, et al. (272), ina retrospective study of 200 patients with esophageal carcinoma, found an increased risk with smoking which was magnified by increased alcoho] consump- tion. Martinez (183) analyzed the association of tobacco usage and esophageal cancer after controlling for age, sex, and alcohol consumption. Increasing relative risks with increasing tobacco use 315 gtt TABLE 30.—E'sophageal cancer mortality rattos—prospective studies {Actual number of deaths shown in parentheses}? SM = Smokers. NS = Nonamokers. Author, Number of year, Number and Data Follow- esophageal country, typeof collection up years cancer Cigarettes/day Pipes, cigars Comments reference population deaths Hammond 187,783 white Questionnaire 3Y, 34 Cigarette smokers Pipe Mixed Data referring to and males ing and follow-up NS ... 1 16/33. 2/33 elgarette mortality ratios Horn, States 60-69 of death SM... 433 Cigar smokers included cancer 1958, years of age. certificate. 2/38 13/33 of mouth U.S.A. and larynx. (220). Doll and Approximately Questionnaire 10 29 All emokers by amount t+Pipe and cigar tIncludes ex- Hill, 41,000 male and follow-up in grams NS ..., 1,00 amokers of pipe 1964, British of death NS w...se 1,00 SMo.... 2.00 and cigars. Great physicians. certificate, 25 1.1... 6.00 All seers 3,00 Kahn U.S. male Questionnaire 84 lili NS ...... 1,00(12) Pipe } Refers to (Dorn), vetevang and follow-up NS ... 41 t1-9 ~ 1.76 (2) 1.99 (3) cigarette 1966, 2,265,674 of death SM ...100 1O-19 0... 4.71 (18) Cigar amoking U.S.A. person years. certificate. 20-39) ....11.60(24) §.33(12) only. (199). 25, « 7.65 (3) All ...... 6.17(47) Hammond, 440,558 males Interviews by 4 46 NS ...... 1.00 (6) Pipe and Cigar 1966, 662,671 females ACS volunteerg, NS... 6 SM (age NS .... 1.00 U.S.A, 35-84 years of SM ... 40 45-64). 4,17(82) SM .... 397(14) (218). age in 25 States. SM (age 65-79) . 1,74 (8) LTE TABLE 30.—KHsophagcal cancer mortality ratios—prospective studies (cont.) (Actual number of deaths shown in parentheses) SM= Smokers, NS = Nonsmokers, Author year, Number and Dato Follow- country, type of collection up years Comments reference population Hirnyama, 265,118 male Trained PHS 144 SM... 21 NS ...... 1,00(p<0.01) Refers to all 1967, and female nurse inter- SM ve. ee. 2.47 (21) forms of Japan adults 40 view and smoking. (285), years of age follow-up and older, of death certificate, Weir and 68,163 males Questionnaire 6-8 32 NS ......- 1.00 NS includes pipe Dunn, in various and follow-up zh1d .. 1.27 and cigar 1970, occupations of death +20 «. 1,69 smokers. . U.S.A. in California. certificate. >30 » 1.82 (306), All vaseens 1.82 ‘Unless otherwise specified, disparities between the total number of deaths and the sum of the individual amoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or exesmokers, were noted. The consumption of very hot beverages was also found to be related to the development of esophageal cancer. PATHOLOGICAL STUDY Autopsy studies of smokers as compared with nonsmokers, spe- cifically observing the pathological changes in esophageal tissue, have been performed by Auerbach, etal. (15). A microscopic study was made of 12,598 sections of esophageal autopsy tissue from 1,268 men who died from causes other than esophageal cancer. The findings were strikingly similar to the abnormalities generally ac- cepted as representing premalignant tissue changes in the respira- tory tract epithelium. Esophageal epithelial cells with atypical nuclei (having an irregular distribution of chromatin) were found far more frequently in cigarette smokers than in nonsmokers. Basal cel] hyperplasia and hyperactive glands were also found more fre- quently in cigarette smokers than in nonsmokers. An increase in frequency with amount of cigarette smoking was noted for both epithelial cells with atypical nuclei and basal cell hyperplasia. Tables A32 and A33 summarize these findings. EXPERIMENTAL STUDIES Kuratsune, et al. (156) investigated the possibility that the car- cinogens known to be present in tobacco smoke could penetrate the esophageal epithelium more readily if dissolved in aqueous ethanol. Mice were exposed to several compounds by esophageal intubation. Tissues were then removed and studied by fluorescence microscopy. Deeper penetration and a different distribution were found when B{a]P was dissolved in aqueous ethanol as compared to B[a]P in olive oil. It was also found that benzo[a]anthracene and fluoran- thene dissolved in ethanol solution or aqueous caffeine solution could penetrate the epithelium of the esophagus. Horie, et al. (132) reported on the development of 10 papillomas and one squamous cell carcinoma of the esophagus in a group of 63 mice periodically forced to drink a solution of benzo[a]pyrene dissolved in diluted ethanol. Twenty-six papillomas and one squam- ous cell carcinoma also developed in a group of 63 mice to which 4-nitroquinoline 1-oxide was administered in the same way. None of the 67 control animals given only diluted ethanol developed neoplasms. Several other authors have reported nitrosamine-induced esopha- geal cancer in experimental animals (56, 79, 89, 81). As noted above, the presence of nitrosamines in cigarette smoke is still a subject of debate. 318 SUMMARY AND CONCLUSIONS 1. Epidemiological studies have demonstrated that cigarette smoking is associated with the development of cancer of the esopha- gus. The risk of developing esophageal cancer among pipe and/or cigar smokers jis greater than that for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly lower. 2. Epidemiological studies have also indicated an association be- tween esophageal cancer and alcohol consumption and tthat alcohol consumption may interact with cigarette smoking. This combina- tion of exposures is associated with especially high rates of cancer of the esophagus. CANCER OF THE URINARY BLADDER AND KIDNEY ISPIDEMIOLOGICAL STUDIES (BLADDER) Cancer of the urinary bladder accounted for 6,019 deaths among American males and 2,743 deaths among American females in 1967 (289). Incidence rates have increased from 1949 to 1962 (88), but the death rates from bladder cancer have remained relatively stable during that period. Improvemenis in early diagnosis and therapy may have masked the increasing incidence of this disease. A number of epidemiological studies have indicated that smokers have an increased risk of contracting or of dying from bladder cancer (see tables 34 and A35). Certain of these studies include kidney cancer mortality in the results. The major prospective stud- ies, with the exception of that of British physicians, have shown bladder cancer mortality ratios among cigarette smokers ranging from 1.40 to 2.89. Smokers of more than 1 pack per day were shown to incur ratios of 3.42 to 5.41. The study by Doll and Hill (74, 75) of British physicians, on the other hand, reports death rates for smokers to be lower than those of nonsmokers based on 38 bladder cancer deaths. The mortality ratios for pipe or cigar smokers aré= -< substantially lower than those among cigarette smokers. Pipe smokers were shown by both Hammond and Horn (120) and Kahn (129) to incur ratios approximating 1.20. Retrospective studies (table A35a) have also shown an inereased proportion of smokers among bladder cancer patients when com- pared with matched controls. Relative risk ratios for bladder can- cer among smokers range from 1.0 to 7.3 among all smokers and up to 10.3 among heavy smokers of all types. 319 Oce Taste 34.—Kidney and urinary bladder cancer—prospective studies—Mortality ratios (Actual number of deathy shown in parentheses)! NS = Nonsmokers. SM = Smokers. Author, year, Number and Data Follows Number country, type of collection up yeara of Cigarette/day Pipe, cigar Kidney Bladder Comments reference population deaths . Hammond — 187,783 white Questionnaire 31% 287 NS .... 1,00(98) Pipe Data Include paticnta and mates in 9 and <10 .,, 2.00(14) NS ...1,00(38) dying of prostatic Horn, States. interview, SM .249 10-20 .. 2.00(42) SM ...1.17(21) carcinoma. 1954, NS .. 38 = >20 » 3.42 (4h) Cigar Data refer to U.S.A, NS ...1.00(38) microscopically (129). SM ...1.06 (39) proven carcinomas. Doll and Approximately Questionnaire 10 38 NS ...1,00 AILSM by Hill, 41,000 male and follow. SM ...0.4t amount in grame 1964, British up of death NS ...1,00 Great physicions. certificate. 1-14 .,0.69 Britain 16-24 ..0.65 (74), D25 .. 0.76 All ....0.71 Best, Approximately Questionnaire 10 114. ONS . 1,00 Pipe Refers to 1966, 78,000 male and follow. <10 . 1.33(29) NS ...2.00 genitourinary Canada Canadian up of death 10-20 .. 1.44(57) SM ...0.56(10) CANCCTB 83 B {@r). veterans, certificate. 20)... 1.43(15) Cigar group. All . 1.40020) NS ...1,00 SM ...1.16 (3) Hammond, 440,554 mules Interviews by 4 Bladder Cigarettes Cigarettes Male data only, 1966, 662,671 ACS 138 NS vives cree eee 500 (22) 1.00(23) Bladder Includes ULS.A. females volunteers, SM (115 SM (age 45-64) 9 ...1.42(54) 2.00 (69) other urinary (428). 35-84 years NS .. 23 SM (nge 65-79) ...1,57(28) 2.96 (66) tract cancers, of age in 25 Kidney States. 404 SM. 82 NS .. 22 TABLE 34.—Aidney and urinary bladder cancer—prospective studics—Mortality ratios (cont.) (Actual number of deaths shown In parentheses)?! Ns = Nonsemokera. SM = Smokers, eral Number and Data Follow- Number country, type of collection up years of Cigarette/day Pipe, cigar Kidney Bladder Commenta reference population deaths Kahn U.S. male Questionnaire 814 Bladder NS vw... ».1,00(39) 1.00(62) Bladder includes (Dorn), veterans and follow. 224 Pipe . . 232 (6) 1.20 (8) other urinary 1966, 2,266,674 up of death SM (172 Cigar wo. cece esas 0.77 (6) 0.94 (10) tract cancers. U.S.A. person certificate. NS .. 52 Cigarettes/day! (139), years. Kidney 1-9 vane O97 (4) 1.10 (6) 141 10-19 + h34 (24) 1.03 (37) SM ..102 20-39 ~ 1.68 (16) 9.20 (34) NS ., 39 >39 ae 76 (6) 2.62 (6) All seen D406 446) 2.15 (82) Hirayama, 266,118 male Trained PHS wy, SM 6 NS .,.. 1,00 Diadder cancer only, 1967, and female nurse inter- SM ....10.00 (6) Refera to all Japan adults 40 view and forms of amoking, (125). years of age follow-up and older, of death certificate. Weir and 68,153 males Questionnaire 6-8 Bladder NS ...1.00 NS ...1.00 SM include ex- Dunn, in various and follow- 27 +10 ..0.86 #10 ...1,52 amokera. 1970, occupations up of death Kidney *20 .,3.30 420 ...2.81 NS include pipe ULS.A, in California. certificate, 27 >30 = ..2.57 >20 ...6.41 and cigar (306), Alb ...2.46 All ....2.89 amokers, ‘Unless otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exclusion of either occasional, miscellaneous, mixed, or ex-smokers. [ce EPIDEMIOLOGICAL STUDIES (KIDNEY) A total of 5,894 Americans died of cancer of the kidney during 1967. A relationship between smoking and this type of cancer has been suggested by several epidemiological studies. The three major studies which separately examine the relationship of kidney cancer to smoking (table 34), namely those of Hammond (118), Kahn (139), and Weir and Dunn (806), have shown mortality ratios for all cigarette smokers to range from 1.42 to 2.46. Retrospective studies by Bennington, et al. (78, 19) have indicated a significant association between all forms of smoking and renal adenoma and adenocarcinoma. EXPERIMENTAL STUDIES Numerous experiments have been undertaken by many investi- gators to elucidate the relationship of tobacco smoking to bladder carcinogenesis. The two areas of major concern have centered upon the presence of a known bladder carcinogen, beta naphthylamine, in cigarette smoke and the presence of abnormal tryptophan me- tabolism in patients with bladder cancer. By virtue of data gathered concerning industrial exposure of workers, beta naphthylamine has long been known as a blacder carcinogen. Complementing such data was the work of Hueper, et al. (136) who subjected mongre] dogs to daily subcutaneous injeéc- tions and oral administration of commercial beta naphthylamine. Thirteen of the 16 animals developed bladder papillomas and car- cinomas of the bladder. Saffiotti, et al. (236) fed hamsters a diet containing up to 1.0 percent beta naphthylamine and observed that 18 of 39 animals developed bladder tumors, almost all typical tran- sitional cell carcinomas. More recently, Conzelman, et al. (39) ad- ministered beta naphthylamine to 24 rhesus monkeys for more than 30 months. Transitional cell carcinomas of the urinary blad- der were induced in 9 of the animals, and a dose-response relation- ship was apparent, Pailer, et al. (207) and Miller and Stedman (185) failed to find this amine in cigarette smoke. However, more recently, Hoffmann, et al. (127) identified it in cigarette smoke. The authors, noting the minute quantity present in each cigarette (2.2 x 1U-g), hesi- tated to attach a biological significance to the finding. Of more recent interest have been the metabolites of tryptophan present in certain patients with bladder cancer. A number of nor- mal and abnormal metabolites of tryptophan have been found to be carcinogenic when tested by implantation in the bladders of mice. These include 3-hydroxykynurenine (OHKy), 3-hydroxyanthranilic 322 acid (OHA), 3-hydroxy-2-amino-acetophenone (all orthoamino- phenols), the 8-methy] ether of xanthurenic acid (CHXa), xanthu- renic acid (Xa), L-kynurenine (Ky), quinaldic acid, and 3-meth- oxyanthranilic acid (SCHOA) (2, 36, 37, 39, 47, 48). OHKy and OHA are frequently present in human urine, as Is kynurenic acid (KyA). Certain investigators have concentrated their attention on the presence of abnormal tryptophan metabolites and increased amounts of normal tryptophan metabolites in the urine of patients with bladder cancer as compared with selected controls (1, 40, 46, 97, 148, 214, 243, 329). These authors have observed the increased excretion of Ky, KyA, OHKy, anthranilic acid, OHA, and acetylky- nurenine in such patients. Yoshida, et al. (329), in a recent study concerning the relationship between tryptophan metabolism and heterotopic recurrences of human urinary bladder tumors, reported that those patients with recurrences showed abnormal metabolite excretion more often than those without recurrences. The relationship of smoking to these biochemical findings is presently uncertain. Kerr, et al. (143), in 30 experiments on 3 smokers and 3 nonsmokers who were given large doses of trypto- phan, found that smoking increased the urinary excretion of OHKy and OHA and decreased that of N’methylnicotinamide (an end product of tryptophan metabolism). Kerr concluded that smoking interferes with the normal metabolism of tryptophan. Recently, Brown, et al. (45) studied 15 adults under smoking and abstinence conditions and found that except for the basal excretion of acetylky- hurenine, tryptophan metabolite excretion did not change with smoking or cessation. The authors also compared 13 nonsmokers and 17 regular cigarette smokers under basal and tryptophan- loaded conditions. No differences were observed in the excretion of the measured tryptophan metabolites. However, due to its instabil- ity, OHA was not measured. The authors concluded that the rela- tionship of smoking to urinary bladder cancer was probably not via - its effect on the kynurenine pathway of tryptophan metabolism. Another experimental approach to the relationship of smoking and urinary bladder cancer is reflected in the work of Schlegel, et al. (234, 245). The authors observed an elevated concentration of certain ortho-amincphenols in the urine of bladder cancer patients and cigarette smokers, when compared with nonsmokers (244). More recently (245), the same group compared the chemilumines- cence of the urines of smokers, nonsmokers, and bladder tumor patients. They noted that nonsmokers showed the lowest level of luminescence (which they relate to the presence of aromatic hydro- carbons) and the bladder tumor patients the highest level. The norma] cigarette smokers’ level was found to be intermediate. 323 VrAs TABLE 36.—Pancreatic cancer mortality ratios—prospective studies (Actual number of deaths shown in parentheses)? SM = Smokers. NS = Nonsmokers. Author, year, Number and Data Follow-up Number Comments country, type of collection years of deaths Cigarettes Pipes, cigars population sae ~ Best, Approximately Questlonnaire & SM oo... 35 Current (ciparettce only) Piper 1966, 78,000 ninte and follow-up NS ..... 1.00 NS ..1,00 Canada Canaan of death <0 so, 1400 (5) SM ..2.60 (6) (et), vetorana, cortificnte, 10-20 1.96 (16) Cigars >20 « 2.37 (7) NS ..1,00 SM ..2.69 (1) Hammond 440,558 males Interviews by 4 962. NS ..... 1.00 (29) Male data only. 1966 662,671 females ACS SM ...233 SM (age U.S.A. U5-b4A yoars volunteers. NS . 29 45-64) 2.69 (168) (118). of age in 26 SM (age States. 65-79) 2.17 (75) Kahn U.S. male Questionnaire 8h 344. NS ..,.. 4.00 (88) Pipea } Refers to current smokers (Dorn) veterans, and follow-up {SM ...256 1-9 4... 0.87 (8) NS ..1.60(88) of all types. 1966 2,265,674 of death NS . 88 10-20 ... 1.93 (65) SM ..0.74 (8) U.S.A. person years. certificate, 21-89 2... 2.18 (43) Cigare (£39), >39 » 1.87 (7) NS ..1.00(88) All vo... 1,84(125) SM ..1.52(27) Both NS ..1.00(88) SM ..0.93(13) Hirsyama, 265,118 mole Trained PHS Wy SM ... 14 NS wi... 1.00 1967, and female nurse inter: SM .....16.56 (14) } (e<0.01) Japan adults 40 view and (125), yeors of age follow-up of and older. death certificate, Weir and 64,15: males Questionnaire 5+8 SM... TA NS wooo. 1.00 SM inchides ex-smokers, Dunn, in various and follow-up 10 ..., 2.94 NS inchides pipe and cigar 1970, occupations of death 20 1... 2.45 smokers. U.S.A. in California, certifiente. D>A0 144 (206), All vases 2.43 TUniess otherwise specified, disparities between the total number of deaths and the sum of the individual smoking categories are due to the exe clusion of either oecasional, miscellaneous, mixed, or ex-smokers. At present, no definite conclusions can be drawn concerning the interrelationships of bladder cancer, abnormal tryptophan metab- olism, and tobacco smoking. Further study is required in this and the other areas of bladder cancer pathophysiology. SUMMARY AND CONCLUSIONS 1. Epidemiological studies have demonstrated an association of cigarette smoking with cancer of the urinary bladder among men. The association of tobacce usage and cancer of the kidney is less clear-cut. 2. 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Schoniger, (avernge age 53.0), Contrula; Questlounatre sent to 700. 1943, Ciermany (age). Potter and M 43 male patients over 40 years of 3,847 patients of same group with diagnoses Coses and controls interviewed Jn clinics. Tully, Age. other than cancer. 1945, U.S.A, (fie), Wansink, M 134 male cline patients with 100 normal mon of sume age groups ws coses, Cases: Interviewed In clinic. 1Od8, lung cuncer, , Controls; Nut stuted. Nether- lunds (Sus). Sehrek etal, M 82 male lung cancer casea atnong 522 miscellaneous tumors other than lung, Smoking habits recorded during routine hos- 1950, 6,003 patients recorded, 1941- larynx, pharynx, or lip. pital interview. U.S.A. 48, (246). . Mills and M 444 respiratory cancer decedents. 430 sample of residents matched by age in Cases: Relatives queried by mail question- Porter, Columbus, Ohio, from census tracts strati« naire or personal visit. 1950, fied by degree of air pollution, Controls: House-to-house Interviews. U.S.A (186) OSE Author, year, country, reference Levin et al, 1950, U.S.A. (169). Wynder and Graham, 1950, U.S.A. (316). McConnell et o)., 1952, England, (280). Doll! and Hill, 1952, Great Britain (73). Sadowsky et al., 1963, U.S.A. (232), TABLE A3.—Outline of methods used in retros Sex of CBRBCS M M-F M-F M-F Number of persons Cases 236 cancer hospital patients with diagnosed lung cancer, 606 hospital and private lung cancer patients in many cities. 100 tung cancer patients, un- selected, in 3 hospitals in Liv- erpool area, 1,465 patients with lung cancer in hospitals of several cities. 477 patients with lung cancer in hospitals in 4 states. and method of selection Controls 48) patients in same hospital with nonma- jignant diagnoses. 780 patients of several hospitals with disg- noses other than lung cancer. 200 inpatients of snme hospitals, matched by age and sex, without cancer. 1,465 patients in same hospitals, matched by sex and age group; some wilh cancer of other sites, some without cancer. 616 patients in same hospitals with illnesses other than cancer. pective studies of smoking in relation to lung cancer (cont.) Collection of datu Casey and Contrels: Routine clinical history tuken before diagnosis, Nearly all data by personal interview; a few cases by questionnaire; a few frum inti mate acquaintances. Some interviews with knowledge or presumption of diognosis, some with none. 595 diagnosed by tissue examination, ning by sputum, and one by pleural fluid examination, Personal interviews by the authors of both cages and controls. Personal interviews of cases and controls by almoners. Porsonal questioning by trained interviewers. TSE TABLE A—Ontline of methods used in retrospective studics of smoking in rel Authur, year, country, reference Sex of cases Wynder and M Cornfield, 1953, U.S.A, (314), Koulumies, 1953, Finland C4Sty, M-F Lickint, 1963, Germany (170). M-F Breslow etal, 1064, U.S.A. (42), Watson and Grell, ” M 1954, Switzerland (107), Number of porsons Cases 63 physicians reported in AMA Journal ag dying of cancer of the lung. 812 lung cancer patients ding- nosed at one hospital. 246 lung cancer patients in a number of hospitals and clinics. 618 Jung cancer patients in Mt California hospitals, 801 patients at Memorial Hospi- tal with lung cancer. 135 men with diagnosis of bron- chial carcinoma. and method of selectiun Controls 133 physicians of same group dying of can- cer of certain other sites. 300 mule outpatients of same hospital over 40 years of age. 2,002 sample of persons without cancer liy- ing in the same area and of the same sex and age range ay cases. G1H patients admitted to same hospitals about the same time, for conditiona other than enncer or chest digcuge, mutched for race, sex, und age group, 468 patients of same clinic period with diagnoses cancer. during same other than lung 185 similar hospital patients with dingnoses other thun hing cancer, and of the same BR, ation to lung cancer (cunt.) Collection of data Mail questionnaire to eatates of decedents, Cases and controla questioned about amuking habits when taking case histurics, 361 di- Agnoges confirmed histologically; 494 ding noses confirmed by clinical, operative data. X-ray, and Personal interviews by ataff members of cu- operating hospitals and clinics. Cusea and controls interviewers, samc person, trained palr by the questloned by cach matched The 769 consecutive patients of case and control groups were tuestioned by the same trained interviewer. Control group includes patienty with oral and esophageal cancer and bronchitis. Personal interviows, all by the game persun. ZSE TABLE AS Outline of methods used in retrospective studies of smoleing in relation to hou cancer (cunt.) Author, yenr, Sex of Number of persons and methud of selection country, cnges -—--- Collection of data reference Cases Controls Randig, M-F 44R lung enncer patients in a h12 patients with other dingnoses, matched Controls were interviewed at about the same 134, nutnber of West Rerlin hospi- fay aie. time as the cuses, ench case-control palr Germany tats, by the same physician, (293), Wyner etal, F 105 patients with lung cancer in 1,801 patients at Memorial Center with tue Cases: Personal interview or questionnaire 1956, yeveral New York City hospi- mors of sites ather than respiratory or mailed tu cluse relatives or friends. U.S.A. tals. upper alimentary, Controls: Personal interview. (str), Segi ct al, M-F 207 patients with lung cancer in 5,035 patients {vee of cancer in 420 Jocal Cusex and controls by personal Interview 1957, 33 hospitals in all parts of health centers, selected to approximate using long questionnaire on occupational Japan the country. the sex and axe distributions uf cuses. and medical histury and living habits. (250), Mills and M-F 578 residents of defined areas $310 population sample approximately pro- Cases: From death certificates, hospital rece Porter, dying of respiratory cancer. bortivonal to casea ag rewards ureas of resis ords, and close relatives or fricnads. 157, dence, and 10 years or more in the area, Controls: Persunal home visita or telepbone U.S.A. calls, usually interviewing housewife. (487). Stocks, M-F 2,356 patients suffering from or 2,382 unselected patients of the same area Cases: Histories tuken at the hospital from 1957, dying with lung cancer within admitted fur conditions other than cancer. relatives by health visitors. England certain orcas, Controls: Personal Interview in hospital. (264), Schwartz and M 602 patients with bronchopul- L204 patients (3 groups) in same hospitals Personal interviews in the hospital: cascs Denoix, monary cancer in hospitals, with other cancer, with nonmalignant ill- and controls at about the same time by 1967, tess, and accident cases, mutched by age France (247), Kroup, the same interviewer. Taste A3.—Oulline of methods used in retrospective studies of smoking in relation to lung cancer (cont) Author, year, Sex of Number of persons and method ef sclection country, eoacy Collection of data reference Cases Controls Hacnazel and F 168 lung cancer patients avnil- 339 patients in same hospital and service at Personal interviews by resident, medical so. Shimkin, able for interview in 20 has» xame time, next older and next younger cinl worker, or clinle seerclury. 196K, pitaly, than ench cue. U.S.A. (iis), Lombard and M 600 men dying of lung cancer, 4,238 controls in 7 groups inchiding volun Personal Interviews by trained workers. Snegireff, microscopleally confirmed. teers, huspital and elinle patients, random 1069, population sample, and hovse-do-house sure U.S.A, vey samples. (176). Pernu, M-F 1,€06 respiratory cancer patients 1,773 concer-free persons recruited by Parish Cases: From case hiytorics or mailed ques- 1960, in 4 hospitals and from cuncer Sisterg of 2 institutey in all parts of the tionnaires. Finland registry. country, Controls: Questionnnires distributed by Tar (298). ish Sisters. Haenszel M 2,191 sample of 10 percent of 31,616 random sample from Current Popu- Cuses: By mail from certifying physicians etal, white male lung cancer deaths lution Survey, and family informants. 1962, in the U.S.A. in 1988, Controls: Persons) interview by censug wniue ULS.A. mornlors, (ile), Lancaster, M 238 hospital patients with Jung 476 in 2 groups, 1 with other cancer, 1 with Personal interviews of bath eases ond cone 1962, cancer. some uther disease, matched by sex and trols in haypitals, Australia BEG, (153). Hoensze) and F 749 sample of 10 percent of 34,339 random sample from Current Popula- Cases: By mail from certifying physiciang Toecuber, white female lung cancer deaths tion Survey used to estimate population and family informants. 1964, in the U.S.A. in 1968 and buse. Controls: Personal interview by census enu- U.S.A. 1969, merators, (115), “St TABLE A3.—Oxtline of methods used in retrospective studies of smoking in relation to lung cancer (cont.) Author, year, country, reference Sex.of Number of persana and method of aclection cascs Cases Controls Collection of data Wieken, 1966, Northern Ireland (903), M-F 964 patients with primary Jung 954 age and sex-matched controls from same cancer. locale and deceased from nonrespiratory disenuca, Interviews with relatives. Gelfand ct ab, JGR, Rhodesla (9¥). M 32 patlenta with bronchogenic 82 ae ntl nexematehed pattents cuncur, Monpltallzatlon titerviews. Hitosugi, 19Gs, Japan (126), M.-F 185 pationty with Jung cancer 491 pertona sex-matched from almilar alr pollution regions, Cases? Hospital interviews. Controls: Interviews by trained public health nurscs, Brodyhaw and Schontund, 1969, South Africa (Natal) (47). M 45 Zulu patients with lung can- S41 Zulu patients without lung cancer, cer, Interviewed by trained African social worker, Ormus et al, 1969, Hungary (204). M-F 118 patients with lung cancer, 3,089 control persuns without data on health history. Cases: Datu derived from enae histories und interviews with relatives, Controls: Interviews with a random saniple of troin passengers. Wynder, et al, 1970 U.S.A, (S24). M-F 240 patients with Kreyberg Type 480 oge and sex-matched patients I lung concer. Hospitalization interview, GSE TaBre Ad.—Group characteristics in retrospective etudies on ling cancer and tobacco use SM = Smokers. NS =: Nonsmokers, Males Females Author, Cases Controls Cases Controls year, Relative Relative Comments reference Percent Percent Pereent Percent risk Pereent Percent Percent Pereent — risk none heavy non- heavy ratio none hea non heavy ratio Number smokers smokers) Number smokers smokerst SM:NS? Number smokers smokers! Number amokers smokers! SM;NS? Muller, &G 35 65.1 86 16.3 36.0 75.4 (*) (4) (4) (*) () (4) 1939 (196). Schairer and 93 3.2 31.2 270 16.9 9.3 26.7 (9 io) 9 (4) (9 (9) ... 1G female Schoniger, cases nat 1943 (242), analyzed. Potter and 43 7.0 30.2 2,804 26.0 23.0 U1 (4) (9 (4) Cy) (4) (*) Tully, M945 (292), Wassink, 134 4.8 54,8 100 19.2 19.2 4.7 (4) (4) (*) (1) (*) {4} ve. Percentages 1948 (904), estimated from chart. Schrek et al, K2 14.6 18.3 522 23.9 9.2 1.8 (*) (4) (') (4) (4) (4) L950 (246), Milla and 444 72 430 30.6 6.7 (4) (4) (4) (*) (4) (4) Purter, 1950 (46), Levin et al., 246 16.8 481 21,7 1.6 (4) (*) (4) (4) (*) {') vee Quantity 1050 C477), amouhked not considered, Wynder and G05 1.3 $1.2 780 14.6 19,1 13.0 40 57,5 25.0 552 79.6 1.2 2.9 Graham, 1950 (316). gst TAULE Ad.—Group characteristics tn retrospective studies an Qui SM = Smokers. NS 2s Nonumokers. cancer und tobacce use (cortt.) Males Femites Author, Cases Controls : Cases Controls ; your, ~ Relative Retative Comments reference Percent Percent Percent Percent visk Percent = Pereent Percent Pereent =o risk none heavy non- heavy ratio none heavy non- heavy ratio Number smokers smokers’ Number smokers smokers! SM:NS? Number smukers smokerst Number amokers smokers! SM:NS? McConnell Ou 3.4 38.5 186 6.5 23.2 1,2 1 ST. 14 78.6 2.8 eval, 1952 (180). Doll and Hill 1,957 0.5 25.1 1,357 45 13.4 9.4 108 37.0 1 108 54.6 0.9 2.1.00 Porcentige 1962 (79). “heavy” atmmukers, vniderstated, Sadowsky 477 38 G15 2 3.9 (*) {*) (4) (4) (4) (4) Gradient etal, with amount 1953 (292), smoked. Wynder and 63 4 C76 133 20.6 29,3 36.1 (*) (4) (*') () (*) (*) Cornfield, 1953 (srs), Koulumies 12 0.6 58.9 300 18.0 25.0 36.0 os (4) (*) (4) 1954 (fo). Lickint 224 1.8 35.8 1,000 16.0 4.8 310-4 22 G40 4.6 1,002 90.4 O1 5.3 ~ 1953 (870). . Breslow el ab, 493 a7 TA 518 10.8 42.7 4.2 A954 (an), Watson and 265 1 m4 287 01 61.6 5.6 6 oH 28 1H 42.0 bok ° Cunte, 1954 (305), Gxell, Wo Q,7 Gs.1 Wah 16.0 14.0 _— “GR ~ Cy ~— “| yy ~ Oyo (ty Oo 1054 (107), LS TABLE A4.—Group characteristics in retrospective stiudics on lang cancer and tobacco use (cont.) SM = Smukers, NS = Nonsmokers. Males Females Author, Cases Controls Chacs Controls yeur, an en te ee ee -— Kelutive--- a ee ee ne ne te ee Relative Comments reference Bereent | Pereent Perernt Percent risk Pereent Percent Percent Percent — risk Num. vole henvy none heavy ratio Num- none heavy hone heavy rala ber smokers oxmokers! Number smokers amokers! SMiNS? ber amokers gyimokers! Number smokers smokers! SM:INS? Randig, 415 1.2 34,2 381 5.8 17.9 55.1 33 51.6 3.0 131 70.3 0 2.2 1054 (278), Wynder etal, (4) (*) () (*) (‘) (4) 105 66.2 16.2 1,304 66.0 3.4 14 ASG (att). Segietal, 166 ' 2,124 ‘ a Quantities 1U67 (250), amohest stated UY AVE only, Diterences are tatoo eally sidnitiennt, Mills and 484 ad 26.0 1,588 27.6 5.3 4.2 o4 83.0 4.3 3,722 13.3 0.5 0.6 Percent “heavy' Porter, amuhers uridine 1957 stated. Only (187), S0l; survey VOspoase WMOENS female coses, Stocks, 2,101 19 28.2 6,960 8.7 22.3 4.9 255 57.6 17.2 3,402 68.6 10.7 LG 1037 (268). Schwartz and — 602 1.0 58.2 1,204 2.5 36.2 10.4 (4) (4) () () ) () Denoix, WOT (247), Hacnszeland (4) (4) (4) () ) ) 15x 51.9 HG 339 69.6 8.2 1 _ Shimkin, 1958 (738), BSE TABLE A4.—Group characteristics in retrospective stiulics on lung cancer and tobacco use (cont.) SM = Smokers. NS = Nonsmokers. Males Females Author, Cases Controls Cases Controls . year, Relative Relative Comments reference Percent Percent Percent Percent risk Percent Percent Percent Percent risk Num- none heavy none envy ratio non- heavy none heavy ratio ber smokers smokers! Number smokers smokers! SM:NS? Number smokers smokers! Number smokers smokers! SM:NS? Lombard and 500 1.6 ne 4,238 11.0 19 (9 rem) i) () (4) (4) Authurs' Snegireff, culeulations for 1959 (176). heusy smoking Daseibun lifetime number of packs of cigarettes, Pernu, 1,477 6.6 34,5 713 37.2 20.8 8.4 129 35.9 c6.4 1,060 91.6 | 0.7 1,9 Quantities 1960 (2f2), wiven only in Kran per day. Haenszel 2,191 3.4 41.9 () 16.2 12.0 6.2 (4) (4) (4) (4) @) “4 vee) Population etal, sample of 1962 (y22)}. 31,510 used ag Dase. Not a cages control study. Lancaster, 238 2.5 86.1 476 20,1 912 9.8 (*‘) (4) (*) (4) (+) (4) 1962 (159). Haenszeland — (‘) (9 () () () (4) . 749 60.9 IS rc) 67.3 2.5 1.3 Population Taeuber, 1964 (175). gample of Sa, 330 aed as base. Not a case-cantral study, 6SE Taw yy Ad—-Clroup characteristies in tetraspective stidies on hang eameer wud tohaces se (cont) SM = Smokers, NS. Nonsmokers, Males Females Author, Cases Controls Cases Controls year, Relative Relative Cunmments reference Pereent. Pereent Percent Percent risk Pereent Percent Percent Percent — risk Num. none heavy nuns heavy ratio none heavy none henvy ratia ber smokers smokers! Number smokers smokers! SM:NS* Number smokers smokers! Number smokers smokers! SM:NS? Wicken, Od 4.0 40.0 803 14.0 22.0 3.8 151 5x0 29.0 161 80.0 17.0 2.9 Heavy sinokers— 1966 (708). renter Chr 28 on stny. Gelfand et ul., 32 6.3 see 32 63.0 sae 525.3 (") (4) i) () () (") W968 (94). Hlitosugi, 124 5.6 67.8 1,839 13.2 66.0 2.6 61 84.1 6.6 2,362 80,5 2.9 2.30 Air pollution 19GR (225), found to have no effeel on Vung vapeu yates of one smokers. Peavy emoherss oreite trthan la day, Bradshaw and = 45 0.0 bes 34l 31.7 on bes () (9 (y (y (4) ay - Schanland, 1969 (41). Ormos otal, os 15 68.5 1,811 42.9 38.9 9.3 a4 OGM uo 1,278 B17 9.1 0.2 Heavy smokers 1uGd (204), greater thin 15 aday. Wynderetol, 210 1.4 67.5 420 21.0 40.9 220.8 30 16.7 44.0 132 57.6 23.3 6.78 leavy V970 (334). : amukers— greater than 20 w day, ’ For this table, heavy smokers nre defined as those smoking 20 or more 2 Based upon fewer than $ cuse nonsmokers. Cigaretles per day, unless otherwise stated, Does not apply. + Computed according to method of Corntleljl, J. (61). TABLE A7.—Grouping of pulmonary carcinomas Group I: A. Epidermoid carcinoma. B. Smali cell anaplastic carcinoma (“oat-cell” carcinoma). Group II: A. Adenocarcinoma. B. Bronchiolo-alveolar cell carcinoma. €. Carcinoid tumor. D. Mucous gland tumor. Extra (not included in I and If): A. Large cell undifferentiated carcinoma. B. Combined epidermoid and adenocarcinoma. Unsuitable for diagnosis. Source: Kreyberg, L. (1535). 360 T9E Author, your, country, reference Little et al, 1964, ULS.A. (173). TABLE Number CASCS NS woe eee eee eee B SM ceereeeeveeae 12 NS = Nonamukers. SM = Smokeru. Results Po! levels in various tiesuce (pe/g tissue) Peribronchia! Bronchial lymph nodes Lung (average) epithelium 0.011 0.001-2 negligible 0.011 0.008 0,028-1,25 Al2.—Autopsy studica concerning the presence of radiouctivity in the lungs of smokers Comments Vertebral bodics, renal cortex, spleen, and urinary bladder showed no differences, Hill, 1965, ULS.A. (129), NS vicceceeeereeee 6 EC) a | Mean Pot! levela in various tissucs (pe/kg tiaaue) Bronchial tree Alveolac Total lung Liver Kidney al 3.4 3.2 14.8 18.0 13 9.9 8.6 20,0 20.6 The authors found no excessive concentrations at bronchial bifurca tions. Little et al., 1965, U.S.A. (174), Po?!l® levela in various epithelial tiasuc regions of lung (pe/g)t Site: Mainstem bronchus ooo... cc cece eee e ee eee rr eee neste Lobar bronchus wi. see ese aee Basal segmental bronchus Upper segmentul bifurcation Lower segmental bifurcation The autharg noted con. aiderable interpersunal variation but did lind a trend relationship be» tween increnusel daily consumption and ine ereased Bot!" Jevely in hung parenchynia, No guch relationship waa noted for uge of indi- vidual ut death or for fotal puck-yeurs, +Smokery only. Z9L TABLE A12.—Autopsy studies concerning the presence of radioactivity in the lungs of smokera (cont,) NS = Nonsmokers. SM == Smokers. Author, year, Number country, of Results Comments reference cases Ferriand Mean Pot! levels in various tisaues (pe/g wet tieeve) Baratta, Lung Liver Kidney 1966, NS cicceseeees ee sll 0.031 0.103 0.080 U.S.A. (95). SM vec scsseacene ed 0,066 0.125 0.070 Rajewsky and Moan Pot! levela tn various tiaauer (pe/7) ¢Data not given. Smokers Stablhofen, Lung parenchyma Bronchial tree Bronchial btfureation were considered those 1966, 0.0025 0.0020 6.0012 using more than 1 pack Germany (217). 0,0078 0.0077 0.0047 a day, The authors noted that thelr figures were cone aiderably smaller than those of Little et al. (173, 174) and alyo digagreed with thelr data on bifurcation. Little and Radford, 1967, U.S.A. (178). SM cee c cee ee en 25 Pipe veveserseeres & Ex-cigarette ...... 1 Never wcccsevecune 8 Mean Pot! levels in various epithelial tissues (pe/g wet tiseue) Bronchial wall and gubmucosa sissseecrerseseneeceeeeerernserse 0,008 Bronchial epithelium: Trachea .....e been center euane ve cee eet teeeeeresnseesneeees O120 Lobar bronchi ......0..-.-eaaee vceeene cerreeveseerenere O90 Segmental bifurcation ..csseccecenecccerceceereeteresnes ese ce 4,600 £9€ TABLE Al3.—Experiments concerning the effects of the skin painting or subcutancous injection of cigarette smoke condensate or its constituents upon animals Author, A. Method, year, Animal B, Frequency and/ country, and or duration, Results Comments reference strain Cc. Material Wynder Car, mice A. Painting shaved skin. Percent animals with: ¢ Number in paren- etal, LB. 3/week fur 2 years. Treatment: Papillomaat Cancert thesis represents 1963, C, Whole cigarette smoke 'Tar’ alone $9.0(81) 44.0(81) total in that U.S.A. condensate in acetone. “Tar and croton oil .. 42.0(31) 9.7(31) experimental group. (317). Croton oil once/week. Acetone alone . (30) (30) Skin-painting Acetone and croton oil (14) (14) experimenta prior to 1953 are fully detoital in tab- ular form in this article. Passey 5 different A. Painting unshaven No malignant tumore noted in cither group. etal, mouse skin. Papilloma noted on one animal (in whole “tar group) which later regressed. 1955, straing B. 2/week for 9 England (4102). months. (209). C. Whole “tar” or neutral fraction. Orretal., Mice of 2 A. Painting skin. Number animala with? 1985, stroing. B. 1 or 2/week for Treatment; Papillomas England VR months. Nenzpyrene 1/week fullowed 4/20 at 18 months (separate greup received only (205). C. 20 pereent cigarette by “tar' 2/week. henzpyrene and showed no tumors). “tar’’ in acetone, 0.38 percent benzpyrene, “Tar’ nlone O7OU at dX months. HOF TaBLe A1l3.—Eaperiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.) Author, Animal A. Method, year, and B. Frequency and/ country, strain or duration, Results Comments reference C. Material Wynder Mice of 4 A. Painting shaved skin. Strain Papilomas Carcinomas No tumors noted with etal, separate B. 3/week for 80 days. 10/89 2/89 acetune alone. 1965, atrains. C. Whole condensate 22/86 12/86 Stressed U.S.A. in acetone. differences in (348). susceptibility of strain. Hamer and Outbred A. Painting unshaved Treatment: Papillomas Woodbouse, albino skin. "Tar? 2/week oo... cece eee 1/60 1966, atrain B, Varied for 18 months. “Tar and croton oil I/week. ......, 2/30 ULS.A, tice. C, Whole ‘‘tar'’/acetone, B(a)P 3 times then ‘tar’ 2/week ..... 4/30 (126). benzpyrene {B(a)P), Bnd P B times cece eee ee eee 0/30 croton oll. Sugiura, Rockland A. Painting unshaved Paptllomae Carcinomas 1966, Swiss skin. 16/44 12/44 {anly 44/60 U.S.A. albino B. 8/week fur 2 yenra. lived froin (266). mice (60). ©. Whole ‘tar’, 368-696 Unya). Graham Albino New A. Printing shaved akin. Treatment: Papillomas Carcinomas The suthors review etal, Zealand B. 3/week for 6 years. Condensate ooccccscceseeerecceueavnee 4l/at 6/4t previous experiments 1957, rabbits. C. Whole condensate. Condensate and eruton oi! 1/week. 10/10 2/10 with rabbits in U.S.A, Crotun ail and acetone 1/week. 0/3 0/3 tabulur form, (101), Acetone T/week vcssscce cet renee anes 0/7 0/7 ‘ Guerin and Mice A. Palnting neck skin, Original mumber Survivora Pupillomas Sarcomas ¢ Control group. Curin, (Pasteur DB. 2/week for D1 your. {C. 42 wi... , ol O/iL 0/51 t Experimental group, a wlruin,) C. Whole condensate. PELOT2 vee 220 10/220 6/220 SA, (108), S9E TABLE Al3,—Experiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or ils constituents upon animals (cont.) Author, Animal A. Method, year, an R. Frequency and/ country, wtrain or duration, Reaults Comments reference C. Material Wynder Swiss mice A. Painting skin. Pereent Percent etal, B. Varicd for 12 Treatment; Number papillomas carcinomas 1957, months, 5/ week 50 12.0 8.0 U.S.A. C. Whole condensate 3/week 50 38.0 16.0 ($23), in acetone. 2/week 40 10,0 3.0 1/week 40 6.0 Wynder and CAF, or A. Painting shaved skin. Percent Percent Swiss mice noted Wright Swiss B. 3/week for lifespan. Treatment CAF,: Number papillomaa carcinomas to be more sus- 1957, mice. C. Whole ‘tar’ or nicotine Whole “tar’ ...,...... 0c. ce, 30 53.0 27.0 ceptible. USA free tar” derived Nicotine free “tar ....... 40 73,0 26.0 Majority of carcino. ($28) from pipe and Cigarette “tar" ceeers 30 30.0 30.0 Bena noted to be cigarette tobacco. Pipe ‘tar’ oo... ccc 30 60.0 20.0 in neutral fraction Treatment Swiss: of condensate. Whole “tar’ oo... .c. cece 30 §3.0 10.0 Nicotine free “tar ........... 40 43.0 20.0 Cignorette ‘tor’ ...,.......,, , 30 63.0 33.0 Pipe “tar cee 39 63.0 60.0 Gelihorn, Paris RII A. Painting shaved skin. Treatment: Papillomas Carcinomas 1958, mice B. Varied for 1-2 years, Benzpyrene (twice only) .........05, 20/529 5/629 U.S.A. C. “Tar’' in acetone, Croton oi] (5/6 week) 4/26 0/26 (99), benzpyrene, “Tar (5/6 week) 3/559 2/559 croton oil. Acetone (3/0 week) .o....... cece, 0/30 0/30 “Tar” and croton oil (5/6 week) 10/175 0/175 Bock and Swiss A. Painting skin. Pereent Moore, female B. 8/week for lifespan. Group: Number living at 6 montha Skin tumoraat C4 weeks 1959, mice C. Whole condensate Painted oo. cc ees cce cece cee 49 13.0 U.S.A. irradiation, Painted and irradiated ......... 65 44.0 (23). Irradiated oo... cee eee eee 36 99€ TABLE Al3.—-Experiments concerning the effects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.) Author, Animal A. Method, year, and B. Frequency and/ country, atraoin or duration, Results Comments reforenee C. Material Druckrey, Rata A. Subcutaneous Group: Surconiad t Control group. 1961, injection, tc... bev eeaye 1/75 P Experimental group, Germany RB. i/week for 60 weeks. tke.. sae en 16/76 (78), C. Smoke condensate in tricaprytin and alevhol. Bock et al., ICR Swiss A. Painting shaved skin. Survtviug Percent Percent Skin 1962, mice B. 10/week for 1 year, Treatment: at ig weeks Skin cancer neoplasia U.S.A. C. Cigarette “tar”, Standard cigarette ............ 24/30 25.9 54.0 ($2), Standard cigarette ....e..c. cee 21/30 5.0 57.0 Standard cigarette 18/30 33.0 44.0 Standard cigarette 13./30 23.0 62.0 Filter cigarette 30/30 TO 27.0 Filter elgarette 30/30 3.0 23.0 Acetone only eas 66/06 tee toe Control cecsesaerereeee eevee 65/65 Roe, Albino mice A. Painting shaved akin. Treatment: Survivors Percent akin tumore Author canchiuded 1062, B, 3/week for 84 wecks. “Tar and 0.025 mg. BlabP wi... 26 12.0 thal cigarette U.S.A. C. Whole emoke "tar" “Tar” and 0.06mg. B(a)P ....., 15 27.0 amoke contaln (285). with added B(a) P "Tar and 0.25 mg. Bla)P ....., 15 13.0 cocarcinoxens, in acetone. “Tor and 1.25 mg. B(a)P ...... 4 64.0 Bla) P 1.25 mg. .......0, Torres ld he Druckrey and Rats A. Subcutaneous Treatment (BP mg./week): Sarcomas Schildbach, injection. BD cece eee b eee eee ene en te eens 26/30 1963, B. 1/week for 700 daya. 10... 14/40 Germany C. Benzpyrene in 3 8/50 (82), tricaprylin. — (solvent) 2/75 L9E TABLE Al3.—Ewperiments concerning the effects of the skin painting or subcutancous injection of cigarette snioke condensate or its constituents upon animals (cont.) Author, A. Method, year, Animal B. Frequency and/ country, and or duration, Results Comments reference strain C. Material Homburger CAF, mice A. Painting ahaved skin. Complete Perecnt Percent etal, B, 2-3/week for 2 years, Condensate; autopsics Papillumas Carcinomae 1963, C. Various tobacco Pipe tobacco 77 35.0 15.0 U.S.A. condensates in Cigar tobacco ud 27.5 16.0 (282), acetone. Cigarette tohacco ., 82 27.0 16.0 Benzpyrene ....... tae 54 10.0 20.0 Acetone only wise ecee eee ee G2 Bock etal, Swiss ICR A. Palnting clipped skin. Percent Perecnt 1965, mice B. 10/week for 11 weeks. Percent concentration of tar gurptineg Percent cancer and U.S.A. C. Various smoke {type cigarette): Ti weeks cancer papilloma (£2). condenaates in 9.2 (standard) vc... eee 96.0 30.0 67.0 acetone, 8.3 (standard) ven eeedeeee 93.0 27.0 67.0 7.9 (English standard) ........ 90.0 24.0 88.0 BT (King) fee cee eee 100.0 24.0 69.0 4.0 (filter) 98.0 9.0 36.0 4.4 (filter) 100.0 10.0 41.0 2.5 (filter) 97.0 4.0 16.0 Acetone contro] tee 94.0 Untreated control 100.0 Van Duuren Swiss ICR/ A. Painting shaved akin, Cumulative number of mice with t 7,12-dimethyl- etal, Ha mice B, Initiating agent once Initiator Promoter Payillomaa Carcinomas bend{a)anthracenc, 1966, Promoter 3/week for DMBA ...Ether tobacco lenf extract 4/20 0/20 U.S.A, 12-14 montha. O ....... Ether tobacco lenf extract a 0/20 0/20 (206), C. DMBAT, tobacco DMBA ...Choloroform tobaceu tenf extract ......ee 1/20 0/20 extracts ciga~ © ....,., Cholorefurm tobaceo leaf extract ss... 0/20 0/20 rette "tar’’ DMBA .,.Cigarette “tar” eee eae 11/20 4/20 O ......, Cigarette “tar'! 0/20 0/20 Occ ACOLONG eee cece cece cect nena 0/20 0/20 89E TABLE Al3.—2Haperiments concerning the effects of the skin painting or subcutancous injection of cigarctte smoke condensate or ita constituents upon animals (cont.) Author, A. Method yeor, Animal B. Frequency and/ country, an or duration, Results Comments reference strain C. Material Munozetal., Swiss ICR/ A. Painting shaved skin, Dark tobacco ‘'tar” At risk Tumore Carcinomas The authors noted 1968, 4a mice B, Varied, 4.0 percent 81 50 7 a shortened latent ULS.A. C. Tar’ from dark - $.0 percent rare i 46 16 period for dark and (Colombian) and Light tobacco tar: tubacco. Colombia light (U.S.A.) 4.0 percent 95 26 6 (197), tobaccos. 8.0 percent 98 64 20 Acetone ....45 91 0 0 Davies and Albino A. Painting shaved skin, Percent of carcinoma-bearing animals at 116 weckes The authors concluded Day, mice LB. Varied regimen, Treatment: (actual number of animals in porentheacs) that the lack of 1969, C. Cigarette and soo mg. 150 mg. 75 mo. $7.5 mg. difference in ree Great cigar condensate, Standard cigarette ......., 20.1(29} 13.2 (10) 0.7 (1) we sults from the Arst Britain Cigar ieee eee o 27.139) 1nd (6) 2.1(3) and third groups (65). Cigar tobacco cigarette... .. 13.9(10) oe oe under treatment suxweats that the Increased tumori- genicity of clyar tobaceo is tue to physical processing (actors, 69€ TaBLE Al4.—Experimenta concerning the effect of cigarette smoke or its constituents on tissue and organ cultures Author, year, Tissue or country, organ culture Material/delivery Results reference Bouchard Mouse tung. Tobacco amoke condensate Increased number of mitotic abnormalities in the treated cultures; particularly in and May, perfusion for 24 hours the first 5-10 days after grafting. 1960, France (35). Japan (18). Thayer and Kenaler, 1964, U.S.A. (275). Berwald and Israel (£0). Crocker et al., 1965, U.S.A. (83), Diamond, 1966, ULS.A. (68), Human fetal lung. KB mammalian tumor cells. SWR mice and golden hamster embryvs, Suckling rat trachea in organ culture. Varivus con- tinuous cell strains (mammalian). and aubsequent grafting under renal capsule of mice. Direct exposure to emoke from: a. Whole cigarettes, b. Tabacco alone. c. Paper alone. Cigarette smoke condensate applica- tion; filtered and unfiltered cigarettes. Direct application of benzo(a)pyrene (B(s)P). Application of B(a)P in acetone, Application of (a) P in either dimethylsulfuxide (DMSO) or paraffin. Paper smoke induced the most severe changes, consisting of cytoplasmic varu- olization and nuclear pyknosis. Also noted were a decrease in the mitotic index and an increase in abnormal divisions, more so with paper. amoke than with the other two. Significant growth inhibition was shown in unfiltered smoke, Cytotoxic compo~ nents were noted in both the gas and particulate phases. Benzo(a)pyrene caused increased cell transformation as manifeuted by: a. Hereditary random growth pattern. b. Progressive growth as tumors after subcutaneous injection into adults. c, Ability to grow continuously in culture. Treated cultures revenled cellular metaplasia, bagsnl cell hyperplasia, jucresagat mitotic rate, and increased H-thymidine incorporation proportional to the eun- centration of material and duration of application, Inhibition of cell growth. OLE TabLe Al4.—Experiments concerning the cffect of cigarette smoke or its constituents on tissue and organ cullurca (cont.) Author, year, country, reference Tlasue or organ culture Materlal/delivery Results Borenfreund et al., 1966, Hamster luhg tipaue, Application of B(a)P in either a. Increased appearance of new small chromosomes and telocentric chromosomca, b. Increased ability to grow in hamater cheek pouch and there become spindle- U.S.A. (f8). DMSO or dimethyl- cell sarcomay. formamide. Guimard, Chicken embryo Application of Increased mitotic activity and increased incidence of anomalous mitoses. 1966, muscular tobacco extract. France (£10), explants. Lasnitzkl, Mice neonatal Application of a hy- 4. Incrensed busnl cell hyperplasia and pleomorphism of newly formed cella. 1968, trachea. drocarbon-enriched b. Increased eplthelial mitosis. England (160), fraction of whale amoke condensate, Lasnitzki, 1968, England (161). Human fetal lung in organ culture, Application of a hy- drocarbon-enriched fraction of whole smoke condensate. a. CelluJar enlargement and promotion of growth of new bronchi, b. Increased mitoses, bronchial epithelial hyperplasia, and squamous mctaplnsia. c. Inhibition of stromal growth, Chan et al., Mouse Jung Application of a. Cellular disorganization, 1969, bud embryonic B(a)P in DMSO, b. Cellular pyknosis; nuclear shape and size Irregularitics, U.S.A. (54). cultures, c. Increased epithelial mitotic rate and decreased mesenchymal mitotic rate in thogye cultures exposed to B(a)P versus those exposed to pyrene or DMSO. Leuchtenberger Mouse lung Exposure to fresh amoke: and and kidney a. Unfiltered. a. Decreased RNA production, pyknosis, and death of cells. Leuchtenberger, tissue and b. Activated b, Similar results, but changes were of minimal severity. 1969, organ cultures. charcoal filter. Switzerland (165), ce. Cigarette or elgar tobacco, c. Similar effects as group a., but lesa severe. TLE TABLE Al4.—Ezperinents concerning the effect of cigarette smoke or its constituents on tissue and organ cultures (cont.) Author, year, country, reference Crocker, 1970, ULS.A. (62). Tissue or organ culture Various organ cultures: a. Whole suck ling hamster tracheas. b. Whole bron- chial tubes from late fetal dogs and monkeys, Muterial/delivery Application of B(a)P in serum, Results Squamous metaplasia; frequent pleomorphic cells; dedifercntiation of eplthellum (inhibited by Vitumin A). cle TaBLe AlS.—Experiments concerning the effect of the instillation or implantation of cigarette smoke or its constituents into the tracheobronchial tree of animals Author, A. Method year, Animal B. Frequency and/ country, and or duration Results reference strain C. Material Blacklock, CB white A. Injection into 3,4-benzpyrene: Number with tumora/numbecr exposed 1957, rata. lung parenchyma a, 3 mg. in olive oi! 6/6 sarcoma. Great by thoracotomy. b. Shing. in olive oil with dead Th bacilll 2/4 sarcoma, 4/8 squamous cell carcinoma, Britain B. Once. e, 6.75 mg. in cholesterol pellet 1/8 squamous eell carcinoma. (8s). C. 3,4-benzpyrene Cigarette “tar: in olive oil, a. In olive oil 0/10, : with dead Tb b. In olive oil with dead Tb bacilil 1/8 surcoma, t/8 squamous cell carcinoma. bacilli or in Controls: cholesterol, a. 0.15 ec. olive oil 0/4, cigarette ‘“‘tar’’. b. 0.15 cc. olive oi! with dead Tb bacilli O/4, c. Cholesterol pellets O/4, Della Porta Syrian golden A. Direct tracheal Number of etal, hamsters. instilllation. hamatcra with 1968, B. Weekly up to Survivors at 20 tracheobronchisl U.S.A, 45 weeks. weeks/original carcinomas (67), C. 1 percent 7,12-dime- Material: Weeks number expoued at death thylbenz(a)anthra- 4, DMBA 50 yr./week ....es 45 10/20 2 cene (DMBA), b. "Tar" 200 pe. /week tenes 32 11/2i _ cigarette ‘tar’ c. DMBA FO yx./week oo... 12 9/20 - concentrate, then ‘‘tar'’ 200. RP WOK Core ceevees 30 _ _ d. DMBA 100 ype./week .... 17 1/20 4 e. DMBA 100 ye./week \ and ‘tar’ 500 b 20 9/20 3 pe /week visu. teeeeee el Rigdon, White Pekin A. Intratracheal No neoplastic changes noted in either the experimental or control groups, 1960, ducks. injection, ULS.A. Controls: 99 B. Daily for 721 days. (ef7), Experimental C. Tobacco condensate group: 62 lin liquid petrolatum. CLE TABLE Al$.—Experiments concerning the effect of the instillation or implantation of cigarette smoke or tts constituents dito the tracheobronchial tree of animals (cont.) Author, A. Method yoar, Animal B. Frequency and/ country, and oe duration Results reference strain C. Mnteriat Blacklock, CL white rata. A. Inoculation at Number Percent with 1961, thoracotomy, of rats malignant tumore Great B, Once and sacrificed Controls ..., cece scenes pet easever esses eae 276 1,5 (1 carcinoma, 3 warcomas),. Britain at] week-2 years, Cigarette condenante 72 T1.1 (6 carcinomas, 2 sarcomas), (25), C, Cigarette tubacco Eucerin alone 44 2.3 (1 sarcoma), amoke condensate in eucerin, Herrold and Syvian golden A. Intyatracheal Number of Number with Number of tracheoe Dunham, hamsters, inoculation, Material: hamatera tunora bronchial tumors 1462, B. 0.6 cc./week for Ba) in Tween60 ... 6 3 & (3 papillomas, 2 carcinonina). U.S.A, 5/6 months. Bta)P in Tween60!l 6 9 (4 papillomas, & carcinomas), (ree), C. Benzo(a)pyrene Tweendd 6 0 _ in Tween60 B(u)P in olive oil 6 0 ~ or olive vil. Otivevil woo... 6 0 _ Rockey etal, Dogg. A, Bronchial inoculation Squamous 1962, or stimulation, Pree metaplasia U.S.A. B. 3-5 times/week Number Invasive Carcinomas cancerous with atypicad inflam. (224). for up to § Procedure: of doga carcinoma in atty changes changes mation years. Controls ......,, 27 _- _ _- 6 a4 C. Cigarette smoke Manipulation of condensate. bronchus .,.., 25 _ - _ 7 26 Smoke condensate 130 1 3 25 98 128 Tipton and Mongrel dogs. A. Bronchial Rapid induction of squamous metaplasia in condensute-exposed animals. No tabular Crocker, Contro] group and inoculation. data is presented, 1964, experimental B. Daily for 8 days. U,S.A. gEroup—19, C, Cigarette smoke (277), condengate. PLE TABLE Al5.—Experiments concerning the effect of the instillation or implantation of cigarette smoke or its constituents into the tracheobronchial tree of animals (cont.) Author, A, Method year, Animal B. Frequeney and/ country, and or duration Results reference atrain C. Material SaMiottletal., Syrian golden A. Intratracheal Percent tumor. 1966, hamsters. Inoculation. Number of bearing of Total Total number ULS.A. B. Weekly for 15 weeks. Number autopsiad: tumor-bearing aurvivore at number of respiratory (257), C. B(a)P (3 mg.) animals 15 weceka of tumore tract cancera attached to fine Male ...., ete a eens 23 15 109.0 24 18 hematite duat, Female .......,, ceee TT Mt 100.0 \7 16 Kuschner, Hamsters. A. Wire mesh pellet Number of Number of 10638, implantation survivors/original animale with U.S.A, into bronchus. Implant: number in proup lung cancer (157), B. Lifetime, Wire mesh only vice ceccceceeccevecvece . 34/35 _ C. Bia)P, MCA ice ceca e eae 88/91 43 methylcholan- BEB) P eect eee e cece ee ener veuaens 89/91 67 threne (MCA). SaMiottiet al, Syrian golden A. Intratracheal Number of 1968, hamsters, inoculation. hamatcra with U.S.A, B. Weekly for 15 Number autopsied reaptratory (235), weeks, Tnoculate: tract tumors C. B(a)P attached Control FOE ee eet et eee tenet nnens 176 ~ toa fine B(a)Pin hematite ., fens 55 35 hematite dust. Hematite only tae 41 _ Borisyuk, Wistar rats, A. Intratracheal Number final/ Duration of 1969, intubation. tnittal inoculation Russia B. Monthly up to Tnoculate: (monthe) (94), 10 months, Controls eee s seca eeceesecs 11/20 12 C, Cigarette “tar”, Unfractionated ‘tar’ 24/200 10 Denicotinized “tar! oc. ccc s ee eee ee 9/45 8 (1/8 metaplasia) Neutral “tar fraction 14/100 8 (2/14 carcinomas, 1 ‘This group also received one Injection of urethane intraperitonealls, VS papillary adenoma), SLE TABLE Al6.—Exrperiments concerning the effect of the inhulation of cigarette smoke or tts constituents upon the respiratory tract of animals (Figures in parentheses represent total pumber survivors in specific group) Author, year, Animal A. Type of exposure country, and RK. Duration Results Comments reference atrain C. Material Lorenz ctal., Strain A mice: A. Chamber, E. Nu increase in tumor formation over that noted in controls, This strain of mice docs 1948, tC. 97, B, Up to 693 hours. haves hereditary U.S.A. (177). TE, 97. C. Cignrette smoke, tendency to tumor formation. 1C. Control. * TE. Experimental. Essenberg, Strain A mice: A. Chamber, Percent of lung tumors No epidermoid cancer 1962, C. 32. B. 12 hours per day C. 59.4 (19) noted; papillury U.S.A. (92), E, 36. for t year. E.. 91.3 (23) adenocarcinoma was C. Cigarette smoke. most common Percentage difference is significant at PSOUt bevel. Mihlbock, Hybrid (020x A. Chamber, Percent with alveolur carcinomas No other type of 1955, DBA) mice: B. 2 hours per day for Cc. 31.0 lung tumors were Netherlands C. 32, up to 684 days. E. 79.0 found, (195), E. 29. C. Cigarette smoke. Leuchtenberger CF, albino mice: A. Chamber, 29 of the experimental mice showed: etal, C. and E. 276, B. To 8 cigarettes 15 busal cell hyperplasia, 1958, per day from 44 atypical basal cell hyperplasia. ULS.A. (166), 11-201 daya, 7 dysplasia, C. Cigarette smoke, 2 aquamous cell metaplasia. Guerin, IC and Wistar A. Chamber, Percentage of rate with pulmonary tumors 1969, strain rats, B. 45 minutes C. 2.4 percent of 39 survivors, France (108), C. 40. per day from E. §.1 percent of 68 survivora, E. 100. 2-6 months. C. Cigarette amoke. 9LE TABLE Al16,—Eaperiments concerning the effect of the inhul or tts constituents upun the respiratury tract of a (Figures in parentheses re atlun of cigarette smoke nimals (cont.) present total number gurvivorys in specific wroup) Author, year, Animal A. Type of exposure country, and MW, Duration Results Comments reference strain C. Material Leuchtenberger = Female CF, mice: A, Chamber, Number with etal, C. 243. LB. 4-6 cigarettes scverc bronchitia; 1960, E. 360. per day for 1 Expoaure peribronchitis; U.S.A. (167), month to 2 years, Number Numther of length atypical eyithe- C. Cigarette smoke, of mice eiparcttea (monthe) Ual proliferation MA, 25-1,526 1-23 30 50 0 0 2 a6 100- 290 1-3 q 36 250- 600 4-8 1 34 600-1,600 9-23 a Stow... 100- 400 3- 6 4 63 100- 400 3-6 17 Leuchtenberger Female CF, mice: A, Chamber, Number Percent of mice Presence uf tumora etal, C, 166, B. 14-8 cigarettes of mice Expoeure with pulmonary showed an age- 1960, E. 231, per day for ezamined (daya) adenomatous tumors relutionship ULS.A. (16a) 17-600 dnys. x1 0 56 independent of C. Cigarette smoke, 0) 17. 99 41 amuking exposure, 35 100-109 a7 re 200. 600 68 {tu, 1063, Albino mice, A. Chamber, Number Ezpomre Number with Germuny C. 60, B. Approximately of mice None. lung tumors (208), EL 180. 12 clawrettes per eramined Varying 3 pulmonary adenomas. day for varying Cc. 80 up to 24 21 pulmonary adenomas. intervals, E. 189 munths, 2 epithelial carelnumas. C. Cigarette smoke, LLe TanLe Al6.—Experiments concerning the effect of the inhalation of cigarette smoke or ite constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total number survivors in specific group) Author, year, * Animal A. Type of exposure country, and B. Duration Results Comments reference atrain C. Material Dontenwill and Golden hamaters, A, Chamber. Number of Daily MET des = desquama- Wiebecke, Cc — B. Up to 4 cigarettes ansmale average Hiatologie tive metaplasia. 1866, E. 320 per day for up dead at exposure findinge in MET bronch = bron- Germany to 2 years. 540 daya (etgaretica) dead animale chial papillary (77). C, Cigarette smoke. 40 1 8/ 40 MET des metaplasia. 40 2 8/ 40 MET des PAP trach = tracheal 80 1-2 44/ 80 MET des (3 MET papillomata or bronch, 2 PAP trach) intense trucheal 143 1-4 67/143 MET des (18 MET metaplasia. bronch, 8 PAP trach) Leuchtenberger CF, mice, A. Chamber, Marked tEpithelial tissues and B. Up to 1,000 hours. tranayression of these animals Leuchten- C, Cigarette smoke, Marked squamous Marked of lung showed an increased berger 1966, expogure to in- cell metaplasia dysplasia porenchyma frequency of cellular Switzerland fluenza virus (percent) (percent) (percent) atypism. The (164). (PR8). Controls (100): authors concluded Male _ _ _ that PRS influenzu Female ...., _ _- _ virus May act ng ou Smoke exposed (59): cofactor in malix- Male _ 6.0 3.0 nant tran:iformation, Female . _ _ - Virus exposed (59): Male ....... 11,0 21.0 13.0 Female ..... _ _ 5.0 Smoke and virus exposed (68): Male 9.0 43.0 $18.0 Female 29.0 64.0 $33.0 BZe TABLE AlG.—Ezperiments conecrning the effect of the inhalation of cigarette smoke or ity constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total number survivers in specific wroup) Author, year, Animal A. Type of expopure country, and B, Duration Rewults Comments reference strain C. Material Rockey and Mongrel dogs: A. Tracheal fenestra- : Squamous tCurcinoma tn ait Speer, Cc. li. tion (20). Hyperplasia metaplu- noted in & separate 1966, E. 19. Nostril inhala- with aia with Pre- Carcis sites in this U.S.A. (223). tion (9). Inflam. atypical atypicul cancerous nome animal. B. Tracheal fenestra- mation features features changes fatty tion—284 treat- Controls (ir). 8 1 1 0 9 ment days. Tracheal Nostril inhalation— fenestra- 180 treatment tien (10)... 10 5 6 1 tl iluys. Nosteil ine C. Cigarette smoke. hajation (9). 6 0 0 0 0 Auerbach Bengle dogs: A. Tracheostoma, Controls, experimental: etal, C. 10 (2 with B. Upto le No histologig change in bronchial epithelium: 1967, tracheustoma). cignrettes per a, 1 animal died at 24 days and no histologic change noted. U.S.A. (10), E, 10. day for up b. 5 animals sacrificed at 421 dayg und nuclear atypism to 421 days. noted in all. C. Cigaretre smoke. c. 2 animals died at 229 and 278 days and nuclear atypism wag noted but of lesser severity than in those sacrificed at 421 days. Harvis and CSTBL mice: A. Chamber. Number of This strain of mice Negroni, Cc, 200. B, Smoke—12 ciga- Treatment Number lung carcinomas is noted for ite 1967, E. 1,437. yettes per 20 Controls c.ece eee vues tae 200 Q lack of spontancous England mice for 12 Influenza aerosol alone ...-- 682 16 lung tumor formation, (f2t). minutes every Benzpyrene acrosal Animals exposed to other day for (4 exposures) aan 200 2 cigarette smuke lifetime. Smoking ..eeeeee i 200 8 (all adeno- shawad no hy pers C. Cigarette smoke, carcinomas) pinstic epithe lial influenza virus Influenza and benzpyrene ... 200 a chankes such as aerosyl, benz Influenza and smoking ...-> 155 3 those noted by pyrene aerosol, Leuchtenberger. TaBLeE Al6.—Experiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals (cont.) (Figures in parentheses represent total] number survivors in specific group) 6LE Author, year, Animal A. Type of exposure country, and B. Duration Results Commenta reference strain C. Material Wynder et al,, Male C57BL6 A. Chamber. Conclusions: t tResults not provided 1968, mice: B. Up to 315 No squamous cell respiratory cancer noted. This is attributed in tabular form. U.S.A. ($27). C. and E.— cigarettes. to the limitation of inhalation time (CO and nicotine acute morethan 40. C. Cigarette smoke, effects) and to the anatomically and physiologically intricate nitrogen dioxide, nasal passage defense system. volatile acids Exposure to cigarette smoke, NO. or volatile acide and alde and aldehydes hydes leads to reactive hyperplasia and metaplasia, beth of fuund in ciga- which were noted to be reversible. rette smoke, Swine influenzu virus exposure produced hyperplastic and swine influenza metaplastic effects which could not be enhanced by subse- virus, quent exposure tu cixarette smoke. Laskin et al., Rats; A. Chamber. Squamoua cell 1970, C, 45. B. 1 hour per day Exposure Number corcinomas U.S.A. (159). E, 3. for up to Atmosphere controls ...... 3 0/ 3 690 days. Atmosphere plus benzo(a)- C. Benzo(a) pyrene PYrene eXPOSuTE ov... ee 21 2/21 aerosol, SQ, SO. controls voces eee eee 3 o/ 3 atmosphere SO, lus benzo (ade ” (3.5 p.p.m.). PY TEN’ Exposure vos reene 21 6/21 lfammond Beagle dogs, See text Seo text. etal, 1970, U.S.A, (119), Ost TABLE A21,—Outline of retrospective studies of tobaceo use and cancer of the larynx Author, year, Cases Controls country, Collection of data reference Sex Number Method of selection Number Method of sclection Sehrek et nb, M. Ts Referrals from V.A, hospitals in “entire 522 From yame set of referrals, patients Random sampie of 6,003 1950, midwest” to VA. Cancer Center, Hines, with tumorg other than lip, lung, Jar. admissions; questivis USA, Ga). THingis, shuring 1942-44; patients with ynx-pharynx: naires from Hines re luvynx-pharynx tumors clinically or his- forrals for 1942-4¢; tulogically diagnosed: records included Pereent Percent smoking history. Nonsmokers oo... cee eee eee UBT Nongmokera op .. cc eae eee eee 23.9 Cigarcttes cise ee cere eee 19,5 Cigarettes oe. cece e ce eee a ee B92 Cigars cece cece eee ST Cire cece cece een eee 10.0 Pipes cece eee cee eee 6.8 Piped coe cece cen eae viene 11.6 Valko, M-F 226 Clinic patients with cancer of the larynx: 108 Clinic putients of same age group with Medical histury and ques- 1952, other diagnoses: tlonnaire in elinde, Crochoslovakia Percent Percent (292). Nonsmokers ........e cece eee 75 Nonsmokers v.cccscssseee eee 22.2 Cigarettes oo... eee ee B32 Cigars voice cece eevee 4.4 PIPES vise ccs e eect eee 10.6 Sadowsky et al, M. 273 White male admissions to hospitals in 615 From same set of admissions, patients Sample of 2,605 out of 1953, New York City, Missouri, New Orleans, with illnesses other than cancer: 2,847 interviews (in+ ULS.A. (232). Chicagu; pationts with dingnused laryn- cluding smoking his- geal tumors, 1938-43: tory} by trained lay Pereent Percent interviewers. Nonsmokers 4.0 Nonsmokera vec ccc e ae ee eee 13.2 Cigarettes only - 60.1 Cigarettes unly 53.3 Cigars only 2.2 Cigars only . 3.4 Pipe only 48 Pipeonly oo... cc, cee 7.0 Some combination + 28.9 Sume combination .......... 23.1 Tse TABLE A2l.--Outline of retrospective studies of tobacco use and cancer of the larynz (cont.) Author, year, Cases Controls country, Collection of data reforence Sex Number Method of selection Number Method of selection Blimilein, M. 241 Clinic patients with cancer of larynx: 200 Patients with no laryngeal disease: Personal history taken In 1985, Percent Percent clinic. Patients and Germany Nonsmokers 0.8 Nonsmokers . » 18.0 controls over 40 years (26). Heavy amokers .. 19.3 Heavy smokers 43 of age. Inhalers oc. e eee ee eee eee 96.0 Inhalers... cece eee er ee eenre 17.0 Wynder etal, M. 209 White male inpatients Memorial Cancer 209 Pationts with other than epidermoid Trained lay interviewers. 1956, Research Center during 1952 to 1954, enncer, individually matched controls U.S.A. (812), with benign or malignant epidermoid in same institutions: tumors of larynx: Percent Percent Nonsmokers cs .cevesn eee eeee 0.5 Nonsmokere oss csserreeeenee 10.5 Cigarettes oo cce ner eee eee eee 86.0 Cigorettes co.cc cssseeeeecneee 73.7 Cigars eee 7.6 Cigars voce cence eee e ee eeaee 10.1 Pipes voce cece erences : 5.0 Pipes occ ceeeeeceeeresennee 3.8 Cigars/pipea vscsssrseseeeeee 1.0 Cigars/pipes wo. cree eee bree 19 Wynder etal, M. 122 Laryngeal enncer patients at Tata Mem- 132 Controls individually matched as for Interviews for smoking Wung, orinl Hospital, 1962-b4: U.S.A, dutu ubove: and medical histories, Indian (912). Percent Percent Nonsmokers occ cveereee eee ee VG Nonsmokers csccsseveaee vee 30.3 Ridis . 78.8 Hidig vo cc cc eevee cee cere ewes €2.1 Cigarettes 8.3 CHgAvettes cece cere rece eee 4B Hookah oo... vee 16 Hookah ccc cec eee rer eee eee 0.8 Chilum wu... .eeeee bene ee 0.8 Chilum ce ccc ce eee certs 2.3 Schwartz et al, M, 121 Patients hospitalized from 1954 through 242 Same time and sources; patients hospital- Cases and controls indi- 1957, 1956 with laryngen! cancer, in Paris ized for non-cancerous conditions or vidually matched within France (248). and other large cities: trauma: institutions; cach mem- Percent Percent ber of a set questioned Smokers 96 Smokers (p0.05) - sae cones 84 by the saine trained Iny Inhalers . 58 Inhalers (p<0.05) .iceeceees 47 interviewer. Roll their own cigarettes .... 44 : Roll their own elgarettes .... 31 c8e TABLE A21.—Outline of retrospective studies of tobacco use and cancer of the laryna (cont.) Author, year, Cases Controls country, Collection of data reference Sex 9 Number Method of selection Number Method of selection Wynder ctal., M. 60 Patients at Radiumhemmet with squam- 271 Patients from same source and time, By trained Jay inter- 1957, ous-cell cancer of larynx, from 1952 with cancer other than squamous-cell viewers in hospital. Sweden (22), through 1955; of larynx: Percent Percent Nonsmokeras ....... cea seuss 5 Nonsmokera .......-.0005 . 2 Cignrettes oo... 0c... .ccaeaee 47 Cigarettes 36 Cigars 7 Cigars ....... 3 Pipes 16 Pipes ...,, 16 Mixed been eee tere recess 1 Mixed 13 Wynder etal., M. 142 Clinic patients in Havana during 1956-57, 220 Same source and time; apparently pa- Interview of paticnts 1958, F. 32 with histulogically diagnosed epider. 214 tients with cancers other thon lurynx, in clinic, Cuba (325). moid cancer of larynx. lung, or oral cavity, matched for age: Percent Percent Male Female Male Femate Nonsmokers ..,...... 1 13 Nonsmokers ...,.... 16 66 Cigarettes cee 62 72 Cigarettes .......,0, 45 27 Cigors ..........,a.0, 20 6 Cigars wo... cc... ee, 22 6 Pipes coe cece cece aes 1 .. Pipes vvcs see ecacce ee 1 Mixed seas 36 9 Mixed 16 Dutta-Choudhuri M-F 582 Patients in Calcuttn cancer hospita) dur- 288 Not specified Tobacco histurics ub- etal., ing 1950-54, with laryngeal tumor diag tained during 1961-64, 1959, nosed and confirmed by biupsy or smear: apparently by inter- India (86), Percent Pereent viewer. Nonusers Tereees - 141 Nonusers cee ve tener sees ALF Cigarettes or bidi .. 17.8 Cigarettes or bidi beeeeee 2.1 Chew vo.ccsecccceeeeaes . 3.1 Chew 3.8 Both 6.0 Both EBe Author, yer, country, reference TABLE A2L—Ontline of retrospective studics of tobacco use and cancer of the laryne ( Cases cont.) Controls Sex Number Method of selection Collection of duta Number Method of selection Staszewski, M. UT Patients admitted to chronic disease hos gi2 Pationts admitted during 1957 and 1958 Author interviewed pa- 1960, KF. WW pital during 157 ond 196K with histos 1,813 to chronic disease center for cancer- tients auspected of Jung Poland (259). Jogically confirmed squanious-cell care vus and noncancerous conditions pre- cancer for amoking cinoma uf the larynx: sumably not related to tobacca cone history and background, sumption: Percent Percent Nonsmokers ...- cere 05 Nonsmokers oo. ..e eee ee reves 173 Cigurettes only . 87.9 Cigarettes only wees G06 Pipes and/or cigars .... 1.9 Pipes and/or cigars weeee DAA “Heavy smokers ..... BRA “Heuvy smokere” .. 49,0 Inhalers 0.0... : Inhalers ......0 eee . 66.8 Female smokers Female smokers... 8.4 Rozenbilds, M. 19} Patients admitted to 3 major hospitnis No controls. Futient interviews. 1967, F 21 with cancer of larynx and hypopharynx: Australia Pereent (az9), Nonsmckers pe. cece eee eee » 8 Smokers viceeec sere e ences YR Heavy smokers .....e-s-seeee 30 Terracol et al,, M. 961 Private service and clinic patients of ENT No controls. Patient interviews. (N67, hospital: France Percent (7a), Nonsmoker$ .s.ece ce eee eee ee VR Smokera veseeee ects ce eeeeees BIG Svoboda, M. 205 Patients admitted to a regional hospital 320 Male controls Cases; patient interviews. 196K, F, 1 over a period of G yenrs all confirmed Controls: not stated. Czechoslovakia histologically: Percent (271). Percent Nonsmokers viccee cece ere es 220 Nonsmokers vise e cece cere ees 2,98 Cigarettes (approximately) 9. 71.0 CigBrettes crecure reece ereee 94.63 Pipes (approximately) c.ceee 7-0 Pipes cise eev sees event 2.44 TABLE A22.—Srmmary of results of retrospective studies of tahacco use and canecr of the laruns (Figures in parentheses represent ratios based on tess than 5 case nonsmokers.) Relative risk ratio} all smokers to nonsmokers Investigator reference Schrek et al. US.A. (246) sees 2.0 Valke, Crechostavakia ¢292) tee vee 3.5 Sadowsky et al. ULS.A. (232) De ee ee eee eee eee ee 37 Rlumlein. Germany (26) ...0..0..0-.02-.0-- Be ee ee ee ee ee 27.5 Wynder ct al, ULS.N. 23.6 Wrynderet al, Indian (srt) 0. 22 eee 3.1 Schwartz etal, France (239) 4.6 Woaniter et akh, Sweden ¢ 6.0 Worden en uh, Cabs (625 0 ce eee (18.9) (males only) a-Choudhburi et aby India Ox6> Dat (40.0) {males only) 8.3 row shi, Poland wy Meedwadea, Ceeehoslavaktia O22 2p 00 ee eee eee > Computed according ta method of Cornfield, J. (61). 384 CE TABLE A23.—Number and percent distribution by relative frequency of atypical nuclei among true vocal cord cells, of men classified by smoking category (100 percent atypical celly defined ay curcinoma) Current cigarette smukery Pereent Never smoked Ex-cignarette Cigar/pipe Less than 1 1-2 packs Dor more atypical nuclei regularly smokers amokers pack u duy odnay packs adny Nume Pere Non Pere Num- Pere Num- Pere Num- Pere Num-+ Jer ber cent ber cont ber cent ber cont ber cont ber cent rr LMM 100.0 116 100.0 94 100.0 125 100.0 yzy 100.0 190 100.0 None co.cc cee eee beeen bene 66 75.0 KG Taal J 1 1 Al 0 - 0 _ Tass than 50)... x 9.4 14 12.1 4 4.3 25 20.0 4 4.2 0 _ 4) - Sth 10 11,4 Va 11.2 G0 63.0 54 43.2 BT 26,4 oo 16.3 60 fy 4 4.5 1 a 23 24.5 2) 16.8 116 34.3 718 29.4 70 79 0 -- 2 1.47 9 9.6 9 7.2 44 1a4 38 du 0 KU XY u _ 0 _ 2 2.1 2 Lf ty 5,K i 6.4 sh SEY 0 - 0 ~— 1 ld 0 a § 1G 0 7- hau: Carcinoma tn atta... eee ee 0 _ v ~ 3 3.2 Mg thar b2 15.% 35 1H 4 Invasive carcinomn v.cceeee eee 0 7 0 -_ ! a os 2 fo 2 1 Source: Auerbach, O. et al. (4), 98E TABLE A24.—Number and percent distribution, by highest number of cell rows tn the basal layer of the true vocal cord, of men classified by smoking category Current cigarette smokers Number of Never smoked Ex-clgarctte Cigar/pipe Less than 1 1-2 packs 2 or more cell rows regularly smokers smokers pack a day a day pucks aday Num- Per- Num- Per- Num- Per- Num. — Per- Nume = Pere Num- Jiere ber cont ber cent ber cent ber cent ber cent ber cent Total veeseee Cee eee eee ena RR 100.0 116 100.0 04 100.0 125 100.0 329 100.0 190 100.0 Less than & cell rows ......- veveeee OO 34,1 7 6.0 4 4.3 3 24 1 0.3 0 bee Sceurows Lies cee reece eters 29 33.0 27 23,3 20 21.3 27 21.6 38 11.6 2 10.6 6eellrows . & 9.1 1S 12.9 15 6.0 25 20.0 61 18.4 24 12.6 Tecell rows 6 6.8 12 10.3 18 19.1 12 9.6 38 11,6 19 10.0 8 cell rows 8 9.1 Va 12.1 9 9.6 13 10.4 30 9.1 2 12.1 9 cell rows 1 Ll 7 6.0 q V4 6 4.8 26 79 14 V4 10 or more cell rows § 6.8 34 29.4 21 22.3 a9 31.2 145 44 90 474 Souree: Auerbach, O. et al. (9). L8E TABLE A28.—Outline of retrospective studies of tobacco ise and cancer of the oral cavity (Dota obtnined from patient interview and atber sources} Authar, year, Cases Control country, ee — Comments reference Sex Number Method of selection Number Method of selection Hardeys, M. 526 Series uf clinic patients with epithelioma 500 Series of clinic patients without epithe- 1920, r. iat of the lip: lioma of the lip: U.S.A. (43). Percent Percent Tobacco users 80.5 Tobacey user$ wee eee eee ee TBE Smokers... 6. cee eee ee 15.1 Smokers » 75,2 Cigarettes 2... cece eee 0.9 Cigarettes .. 444 Chewers 24.0 Chewers .....0, «. lad Pipes 69.0 Pipes . 28.6 CIBATS Lele eee eee 38.5 Cigars 44.0 Ebenius, M. 439 Clinic patients with cancer of the lip: 300 Not defined. } Estimate of prevalence 1943, ¥, 33 of use. Sweden (87). Percent Pereent Male Female Male Female Tobacco users ........ 79.7 —_ Tobacco users. ...+-+ G87 _ Tobacco users Tobacco users oe... Ot? (all pines) . oo BT6 Pipes cece cvareee creas 22,9 _ Pipes occ. ccecrceev ees 61,8 _ Chew or useanuff .,... 60.7 - Chew or use snuff .... 47.4 ~ Cigars and cignrettea .. 92,5 _— Cigars and cigarettes .. 12.9 _ Levin et al., M. 143 Cancer Institute patients with cancer of 51 Cancer Institute patients with non-can- 1950, the lip: cer diseases of same site: ULS.A. (169). Percent Percent Smokers » 84.5 Smoker8S veces vervceeeeeeeee 74.0 Cigarettes ........ ~- 45.3 CIOrOUlCS eevee eee rece eee 43.0 PIPOS cece eee ccc cee een r anes 48.1 PIPES cece cece eee ee er ete e ey 90.7 Cigars . 26.5 CIBATS Loic cece eter eee 34.9 88E Tape AZB—Oulline of retrospective studies of fobaces use and cancer of the oral cavity (cont) (Data obtained from patient ipterview and other svurces } Author, year, eountry, wee : sen veference Sex Nunber Cases Method of seleetion Mills and Porter, M. bed Deaths Crom enneer of ornt eavity in Cine yaa Sample of population of Columbus, Ohiu, 1uSu, eiinali and Delroit, Ta0-45 and ldo- in same proportion of color, sex, wnd ALS AL GEXA). 40 respectively: ARE usd dn cases: Prreent Percent Cignretios ainly 3n5 Cigarettes only 1. Od Vives, Cigitis, or Pipes, cigars, ar combinations 51K combiontions 207 Moureet ab, M his Patients over 50 yours old sinee LOL with 4S Patients of same ue groups with les Vu, concer of oval eavity: ign oral lesions ar benign surgical ILS. A Chet), conditions: Perera Percent Chewers 3S.U Chewers .occcee ec ceeeeee 31.6 Pipes beeen 42.U Pipes Coven ere ects e tee ATA Cisars and elgarettes oad Ciynys and cigurettes co. .6... O2.5 Sadowsky et ad, M. yas Hospital pationts with Hp, oral, andl phir. Oy Patients with iliness other than eatecer: ay yates eaueer, DEES dt: Perveut USA. (ate), Pirveent Ciarethes atly Cove Oh Cisruret tes andy wet Chpar sadly oc. cee eee Chin culy 1.0 Vippronty oc. o. eee ae seu TAh Wipes onty sca. Vow Misedo oo. oc... , ee Miseul IN Sunkhyvi etal, M. WT Hospitnt patients with mameer of oral cave “ERM Ttospatad patients with alisenses ather 1OGh, Yr, st ty nue peburyaies wae Chi cunests Trin (Zor). Percent . Barvent Male Pemate Matte Be meale Smoke andehew 6.0... 38.8 8.7 Smoke and chew 2 Smokeonly o.......... 40.7 6.2 Smoke andy cc BOLO Chew only V7 re Chewonky co.cc. cece ORT Neither 27 250 Neither vee ATS Controly Number Method of selection Cumments Smoking: bs of bidia eng Loth cases anil controls. 68E TABLE AQ8.—Outline of retrospective studies of fohiaeco use and cancer of the oral cartty (Data obtained from patient interview and other sources) (cont.) Author, yeur, Cases Controls country, - Comments reference Sex Number Method of selection Number Method of selection Ledermiann, M. 2a Patients with cancer of oral cavity and 62 Patients with cancer of skin, bone, and Differences between cases 1095, pharynx: muscle: and controls for both France (fie). Percent Pereent high and low alcohol in- Nonsmokers oo... eee eee ee 46 Nonsmokerg cece ee eee cere 47.2 take ore insignificant >20 cigaretics perday 1.6... 23.4 >20 cigarettes perday ....., 18.6 when smoking ta con- trolled. Woyiiler etal, 43 Patients with cancer of ora) cavity: 207 Patients with cancer of other sites and 157, F. 16 232 benign diseases: ULS.A, (398). Pereent Percent Male Female Male Femule Nonsmokerg oo... eee 3 47 Nonsmukers .eee.eeer 10 70 CigNyS ccc ee ee eee eee 20 _- CiRATS oe cee eee 13 _ Pipes Me M _ Pipes Dene ee ere 6 _ Mined vis .ce esr eee ee x ~- Mined occ. ce ee eee eee 8 _ CHOW Cie 7 _ Chew eee eee R _ Cipnyettes cc... 2... AT 58 Cignrettes cee 68 40 DNS cigarettes SSD viscuretten per day tees eee eee 29 _— perdny cece eee 17 -- Dh cigarettes “SYH cigarettes per day co.cc cere Md per day me i Schwart, etad, M, wae Hospital patients with cancer of oral cay- GOx Hospital pationty with nun-cancer iil. 1957, ity and pharynx: nesa and nccident cases, matched by Vranee (258). age: Pereent Pereent Nonsmokers Sete eee 16.4 Nonsmokers occ csc eee eee es 234 Cigarettes only oc. cece eee ee GR. Cigarettes only cece e ieee eee O82 Pipesonly .. Pipes only ccc cceeerceeeeeees 30 O6€ Taney A28—Oxtline of retrospective studies af tabaces use and caneer of the oval cavity (eons) (Data obtiined from: patient interview and other sources) Author, year, Cases Controls country, - Comments reference Sex | Number Method of selection Number Method of selection Wyniler etal, M. 17s Hospital clinic patients with cancer of 220 Patients in same clinics with non-emalix- . 1957, F, 3d oral cavity and pharynx: MM nant conslitions, matched by sex anil Cuba (925), Ree: Pereent Percent Male Female Male Female Nonamokersy ......... 4 a4 Nonamokers oo... ..05 16 ch Cigarettes Cigarettes predominantly oo... 45 GL predominantly ...... 45 17 Cigars predominantly. 33 MW Cigars predansinantly . 22 4 Wynder et al, M. 115 Male pationta with cancer of oral cavity V5 Mole pationty in same hospital with cane Alcohol data sisnilteant 1957, and pharynx: cer of sites other than oral, pharynx, only for hypopharynx, Sweden ($22 faryns, lung, esophugus, breast: Pereent Péreent Cigarettes oo... cece 36.5 Cigarcttes 36 Cigara ......., Dever eee nee 13.0 Cigars 9 Pipes ccc ccc cece cee eee eee 22.2 Pipes, 16 Mixed .....0.., . 15,7 Mixed co.cc cece eee eee eee ee 18 Peacock et al., M. 25 Hospital patients with oral cancer: 74 Pationts in same hospital without oral 1960, F, 20 92 cancer and 117 male and 100 female U.S.A. (210). Out-prtionts, randomly selected. Pereent 32.6 percent of first group, and 43.3 pers Chewed or used snuff over 20 cent of secund group ehewed or used yenrs (all patients) seve 55.6 snuff over 20 yearn. Staszewski, M. BRS Male patients with oral cancer: 912 Male patients with other enancerous and 1960, Pereent non-canceruus conditions: Poland (259). Nonsmokers 2.4.0.0... wee BT Percent “Heavy” smoking index ...... 72.8 Nomamokergs eecc ccc en eee VES Cigarettes only 72.3 “Heavy” smoking index ..... 49.0 Pipes and/or cigars 12.8 Cigarettes only ............, 60.5 Pipes and/or cigarg ws... eee . T6E Author, yuar, country, TABLE A28.—Outline of retrospective studies of tobacco use and cancer of the oral cavity (Data chtained from patient interviews und other saurees) Controls (cont.) Comments reference Sex Number Method of selection Method of selection Vogler etal., M. 1B8 Clinic patients with cancer of lip and oral Pationta of same clinic with other can- t Due to varying tabular 1962, F. 92 cavily: nonematgnant conditions: treatment of duta, per- U.S.A. (298), Percent centages of tobacco Male Female usera are not al} bused Chewers o.......0.5..992.9 _ Percent on the same number of Excessive chewerg .... 22.9 _ Male Female CHSCs. Snuffdippera ........ 0 72.0 Snuff dippers voces. wee $6.1 Excessive anuff dippera ......eceee, om 413 Tobacco users » 90.0 99.0 Tobaceo users oc... 66.0 66.0 Vineent and M. 66 Successive patients with lesions of buccal patients attending gastroin- Male patients used cone Marchetta, F, 16 cavity and oropharynx: testinul clinic, ageemateched; afdcrubly more alevhol 1963, Percent than male controls. U.S.A. (297), Oral Oro- Data refers to all forme Males: Cavity pharynz Percent of smoking expressed Nonsmokers ,......., 3.0 _ 27.0 og Cigarette equivalent. <20 cigarettes Cigarctle equivalents: . verday ........0... 18.3 15.1 24.0 lcigar = & ciyarcttes > 20 cigarettes l pipe = 2 cigarettes perday ..........5. 787 9 84.9 49.0 t BN=Detel nut. Females: Nonsmokera ......... 85.5 28.6 82,0 <20 cigarettes Per day veecseeesae _ 8.0 >20 cigarettes perday ............ 44.6 Wd 10.9 Z6E TABLE A28,—Outline of retrospective studies of tobacco use and cancer of the oral cavity (cont.) (Data obtained from paticnt interview and other sources) Author, year, Cases Controls country, Comments reference Sex Number Method of selection Number Method of selection Shanta and M. 552 Patients with oral and pharyngeal cancer 300 Controls residing in Krisbnamurthi, F. 206 (unsure of confirmation): 100 same area matched 1964, Percent for age, sex, and India (256). Buccal Anterior Posterior class: Males: Lip mucosa tongue tongue Pharynz Males No tobacco habit .... _ 2.0 1.2 2.0 5.3 39.1 Smokers .......,... 60,0 45.7 66.6 76.0 12.8 52.7 Number of cases .... (12) (293) (69) (48) (130) (300) Females: Femalca No tobacco habit ..., 14,3 11.0 33.3 _ 40.0 88.8 Smokers wi. csavaees _ 47 5.5 _ 8.8 _ Number of cases .... (7) (152) (18) (4) (25) (100) Wahi etal, M. 589 Patients with oral and pharyngeal cor- 689 Patients matched for age, sex, religion, 1965, F. 232 cinoma: 232 and social class. India ($02). Perecnt Percent Nonsmokerg ....... ee ccaeee 9.62 66.5 Smokers wi... cece eens sevee 17,05 21.2 Chewers (Betel nut) ........, 95.44 69 Both vissesscseceeeve veeevene 87,88 6.4 Hirayama, M. 369 Patients with oral and pharyngeal carci- 277 Patients with other (unspecified) dise Found only a suggestive 1966, F. 176 noma: 163 eases: association between Central and Percent Percent aleohol-drinking and South East Male Female Male Female oral cancer in none Asia (124). Nonusers ......-..005 1.6 2.5 17.0 33.0 chewers only. Smokers ...........08 VA 2.5 23.8 12 t BN-Hetel nut. Smokers, tBN and tobneco chewers .... 46.7 6.6 24,9 1.8 £6€ TABLE A28.—Outline of retrospective studies of tobacco use and cancer of the oral cavity (cont.) (Date obtained from patient interview and other sources) Author, yeur, Cases Controls country, Comments reference Sex Number Method of selection Number Method of selection Keller, M 408 Patients with squamous cell carcinoma of 408 Next male patient admitted to same hos- Excessive nleohol con. 1967, oral cavity and oropharynx confirmed Pital within 5 year age range, sumption noted for U.S.A. (140). histologically. Three New York City VA cases involving floor, Hospitals 1953-63: mesopharynx, and Percent tongue. Nonusers 14.2 Findings indicate the Cigarettes §6.4(p<0.0001) association of heavy Pi? only ra . 2.9 drinking with cancer Cigaronly ......,. Chee eee 6.9 6.1 independent of the amount of tobucco used. Martinez, M. Patients with epidermoid carcinoma of 345 116 male and 38 female hospital or clinic Cases found to conguine 1969, F. 38 oral cavity and pharynx: 114 pationts without cancer: 330 male and more alcoholic hevers Puerto Rieo 76 female residents of sume region, axes than controls, (143). age and aex matched, Percent Perecent Nonsmokers seen . 37 19.2 Heavy tobacco users . 24.8 12.2 (p<0.0001) Keller, M. 304 Patients with primary basal or squamous dod Patients from same hospital matched for 1970, cell carcinoma of lip: Sge and race, U.S.A. (144), Pereent Nonsmokers oo... .... cece say 1.3 Cigarettesonly .......... 00, 60.2 Pipeonly ...ccceee eee seee 6.0 Pipe, other ...0.000000...,, oe 6.3 Percent 16.6(p<0.001) 52.8 a4 0.4 (p _ 1960, Poland (260), —_———_. Schwartz et al,, 3.0 17.0 Totalaumount amoked 39.0 38.0 6.6 _ 1961, daily (cigarettes) France (249), 16, 16.0 Wynder and Bross, American males 6.0 16.0 48.0 33.0 ~ _ 3.4 44 1961, U.S.A. and American females 41.0 78.0 27.0 16.0 _ ~ a 3.2 India (370), Indian males 13.0 28.0 - - _ _ 2.6 - Indian females 78.0 94.0 - - _ _ 4.5 _ Takano etal., 17.0 23.0 _ _ - _ 1.3 - 1963, Japan (272), Bradshaw and Schonland, 18.3 31.7 31.6 69 ~ — 2.6 Mal 1969, South Africa (41). Martinez, 1969, 14.0 23.6 79 4.6 _ _ eB 3.6 Puerto Rico (183). SO” TABLE A32,—Atypical nuclei in basal cells of epithelium of esophagus of males, by smoking habits and age TSections with some epithelium present. Souree: Auerbach, O. et al (75), Never smoked Current regularly Cigarettes Ex-cigarettes Pipe, cigar Other Atypical nuclei Num- Per. Num- Per- Num- Pers Num- Per. Num- ber cent ber cent ber cent ber cent ber A. All men: Number men pecans 9t _ 779 _- 18 _— 89 od 62 Total sections! te 187 100.0 6,762 100.0 1,586 100.0 766 100.0 622 No atypical nuclei 733 93.1 167 2.5 770 48.5 ag 6.9 198 Sume but <60 percent atypical 52 6.6 5,389 79.8 165 44.3 Obs OY ai? G0 percent aur morentypical ......0, 2 0.3 1,196 int bl 3.2 25 33 10 B. Men under age 50: Number men 26 ~~ 236 —_ on — 9 —~ 1 Total sections 223 100.0 2,039 100.0 254 100.0 17 t0u.0 83 No atypical nuclei soeeeneeer 190 85.2 TM b4 56 21.7 1 1.3 4 Some but <60 percent atypical ...., 33 14.8 1,853 9U.0 105 75.6 74 96.1 46 60 percent or more atypical ~ — 135 6.6 7 2.7 2 2.6 3 C. Men aged 50-69: Number men 44 — 445 _ 109 — 3R — 34 Total sections oc... viee cece aes 379 100.0 3,553 100.0 953 100.0 310 100.0 265 No atypical nuclei eee ee 37 98.4 $3 22 461 48.4 37 41.9 74 Some but <60 percent atypical ....,, 4 ht 2,915 75.6 462 dtd 261 84.2 178 60 percent or more atypical 2 0.5 855 22.2 40 4,2 12 3.9 4 D. Men aged 70 or older: Number men .. 21 —_ UN ~- ad — 42 ~~ a4 Tota! sections Pees eee eee eee ee 185 100.0 K4G 100.0 S75 100.0 379 100.0 213 No atypient nuctei bette eee 170 91.9 V3 1S 268 oT4 1S 4.0 M7 Some but <60 percent atypical » 15 8.1 621 74.0 IR 415 353 oa 95 G0 percent or more atypical - _ 206 24.5 4 Mt iM 249 3 100.0 bo.8 6&7 100.0 28.9 69.5 1.6 100.0 Gay 14 907 TABLE A33.—Atypical nuclei in basal cells of eptthelion of esophagus of males, by amaunt uf sntoking and age Current cigarette smok ers Never smoked regularly <1 pack 1-2 packs >2 packs Cells with atypical nuclei Number Percent Number Percent Number Pereent Nionber A. Allages o........0.. 0, Seay 91 ee 179 _ 413 _ 187 _ Tutatsections! oo... eect e eee 187 100.0 1,544 100.0 3,629 100.0 1,679 100.0 No atypical nuclei oo... 0... cece, 183 93.1 89 5.8 39 hl 39 25 Some but <60 percent atypical ...., 62 6.6 1,341 86.8 2,957 81.5 1,091 69.1 CO percent or more atypical ........ 2 0.3 114 7.4 633 17,4 449 2K.4 B. Men under nage 50: Number men ce cccccceec cesses cease 26 vee 9 _ M2 _ 55 _ Total sections t Severe en eeneees 223 100.0 433 100.0 3,1u9 100.0 457 100.0 Nontypical nuclei ssc ccece cee eee ee 190 85.2 48 Mal 2) Lx 2 0.4 Srme but 60 percent atypienl oo... 33 14.8 382 RK.2 1,049 93.2 Sho a6 fl percent ay more atypical ooo... sae an 3 0.7 69 5,0 73 16.U C. Men aged 60-69; Number men See tee eee eae 44 ee 92 ~ 240 _ Wi - Trtal sections ! Pete eee eee 379 100.0 789 100.9 2.416 100.0 948 luu.d Neatypleal nuchi ...c css ccc sees 373 98.4 30 3.8 1K 0. 45 47 Some but £60 pereont atypleal oo... 4 Ml 604 87.9 1,607 15.9 ol GSK HU percent or nore atypient oy... .. , 2 0.6 65 8.3 491 23.2 209 Sho D. Mou aged Fo on older: Number men ooo. cee ee reece 2h ee aS -- ai _ 19 : Total sections) cece ee cevaes 188 100.0 322 100.0 gas 100.0 17s 100.0 Noatypical nuclei oo... ceca 170 91.9 M1 34 _ _ 2 Lt Some but £60 pereent atypical 2... 15 Bl 265 82.3 261 76.9 uh O47 GU peveent or more atypical ......., tee sae 46 14.3 xs a4. WG dau ‘Sections with some epithelium present, Souree: Auerbach, O. et al, (15). L09 TABLE A86.—Summary of methods used in retrospective studios of smoking aad enneer af the bladder Author, year, Cases Contras country, ee ee ee . wee ee wee ee wee ee — ro reference Sex Number Method of selection whey Method of selection Lilienfeld ct ab, M. 821 Admissions to Roswell Park Memorial Institute, RAT Nou disease patients, 1956, 3045-55 over 45 years of age, U.S.A. (171), rr. lt Same as mules lou Renin bladder conditions. RYT No disease pationts, Schwartz et al., M. 218 Admissions to hospitals in Paris and a few 24 Healthy individuals admitted to same hospitntt 1961, large provincial cities since 1954, because of work or trafic accident, matched France (249), hy & year age geraup. Lockwood, M. 282 All bladder tumors reported to Danish Cancer Qa2 A. From clection rolls matched with cases e+ 1961, KF, Register during 142-50 and living at time ST cording ta sex, age, morital status, ocrupa- Denmark (175), of interview in Copenharen and Fredericks. tion, and residence. burg. (Includes bludder papillomas). BR. Ancther contrul group obtained from game ple of Danish Marhidity Survey (1402, 1953, and VI54) compared with respect te smoke ing histories. Wynder, M. 200 First phase: luo 1963, By 50 Admission te several hospitals in’ New ny Admission ta same hospitals Cexetuded cancer U.S.A. (326), York City during January 1957-Devem- uf respiratory system, upper alimentary tract, ber 1160, myocnvdiol infwretion) matehed by sex and Second phase; are. M. 100 Admission tu same hospitals during 1007, oa Some ous above, K 20 Zo Cobb and Angell, M. 136 Patients udmitted to VA Hospital in Seattle 44a 120 patients with cancer of sigmoid colon, 122 1965, U.S.A. (87), 1951-61, Patients with nun-enceplastic pulmonary dis- vase, 807 TABLE A86.—Summary of methods used in retrospective studies of smoking and cancer of the bladder (cont.) Author, yenur, Crues Controla cauntry, 7 reference Sex Number Method of selection Number Method of actection Stoszewski, M, 150 Patients with histologically confirmed bladder Th0 Undetined source age-matched. 1968, carcinoma, Poland (26!), Deeley and Cuhen, M. 127 Patienta with histologically confirmed bladder 127 Patients in same hospital with nun-cancerous 1966, earcinoma, or pulmunary disease matched for age. Engtand (6¢), Yoshida ct al, M. 163 Patienty with bladder cancer, 163 "Comparison cases.” 1968, F. 29 69 - Japan ($90). Kida ct al, M. 8B Admissions to 18 hospitals in North Fukuoka Ry Sclected from patients hospltalized in aame re- 1968, F, 26 prefecture, 26 yegion for non-urinary allments and age Japan (144). matched Dunham et al., M. 334 Admissions to New Orleans hospitals with his- 350 Admissions to same hospitals with non-ncoplas- 1968, KF, 189 tologic diagnosis of bladder carcinoma, \7T tic diseases and discases unrelated to genl- U.S.A. (85). tourinary tract. Anthony and Thomas, M. Sst Patients with papilloma and cancer of bladder 275 1970, England (9). at Leeds betweeen 1968-67. Surgical patients without cancer previously In« terviewed for lung cancer study, 604 TABLE ASba.——Summary of results of retrospective studies of smoking and cancer of the bladder Percent elgoretios Relative riek ratio: Author, Percent nonamokers Percent heavy smokers amuked All amokers to nonsmokers year, country, All Heavy Cigarette Comments reference Sex Casea Controls Cases Controls Canes Controls smokers amokers amokers Lilienfeld ct al., M. 16.0 29.0 61.0 44.0 2.8 see 247 Cigarette and other. 1966, F, 87.0 83.0 14 ene vee U.S.A, (971), Schwartz et al, M. 11.0 20.0 : 83.0 70.0 2 , 2.2 Cigarette only. 1961, France (£49). Lockwood, M. 0.0 13.4 30.0 16.0 30.0 18.0 1.6 3.0 3.0 Cigarettes main mode of 1961, F. 56.0 66.0 4.0 4.0 sae see 1.5 1.2 sae smoking. Denmark (178). Wynder ct al,, M. 7.0 18.0 47.0 23.0 85.0 63.0 2.9 5.2 3.3 Phases A and B com- 1963, F. 61.0 86.0 6.0 tee vee vee 8.9 tee aoe bined, ULS.A. (526), Cobb and Ansell, M, 4.6 25.8 79.4 43.3 vee see 1.3 10.3 1965, ULS.A, (67), Staszewski, M. 6.7 16.0 86.7 65.7 87.1 72.2 2.7 8.1 2.9 Cigarettes only. 1966, Polnnd (£61). Deeley and Cohen, M. 24 UA tee see es 3.1 tee see 1956, England (66). OV TABLE A35a,—Summary of results of retrospective studics of smoking and cancer of the bladder (cont.) Percent cigarettes Relative risk rattle: Author, Percent nonsmokers Percent heavy smokers smoked All emokers to nonsmokers year, country, All Heavy Cixarctte Comments reference Sex Cases Contrlos Cases Controls Casue Controls smokcra smokers amokers Yoshida ctal., M. 8.0 22.7 43.4 35,0 — _ 34 3.7 - 1968, F, 62.1 86.4 — _ — _ —_ ~ ~ Janon (330), Kida et al., M. 11.0 11.0 32.0 29.0 _ _ 1.0 _ _ 1068, KF, 16.0 21.0 _ o - _ 4 ~ ~ Japan (144), Dunham etal, M. 8.6 14.5 — ~ 49.4 48.4 1.8 _- 1.8 Clgarettcs only. 1968, F. 62.2 61.5 _ - 32.0 28.2 1.0 - Ma U.S.A. (85), Anthony and F, 6.3 6.3 _ _ 36.5 29.1 1.0 _ 1.3 Cigarettes only. Thomas, More than 15 a diy. 1970, England (8). Chapter 5 Pregnancy Source: 1973 Report, Chapter 4, pages 97 - 149. 411 Contents Introduction 2... 0.0.0.0. 0 0.0002 eee eee Smoking and Birth Weight Epidemiological Studies Cigarette Smoking and the Low-Birth-Weight Infant ..... Evidence for a Causal Association Between Cigarette Smoking and Small-for-Dates Infants ...........-. Evidence for an {Indirect Association Between Ciga- rette Smoking and Smali-for-Dates Infants ......... Experimental Studies Studies in Animals Tobacco Smoke .. 1.2.22... eee ee eee Nicotine .. 2... 2 ee ee ee Carbon Monoxide... 2.2.0.0... 002020220 eee eee Polycyclic Hydrocarbons .. 2... 2.2.26. -+0 ee eee Studies in Humans Carbon Monoxide .. 2.2.02. ee ee ee ee ees Polycyclic Hydrocarbons .......-..-.0202-0-00-- Vitamin By, and Cyanide Detoxification ...........- Vitamin 2. eee Possible Mechanisms 2.00 0 ee Timing of the Influence of Cigarette Smoking on Birth Weight 0.202... ee ee ees Site of Action at the Tissue and Cellular Level .......... Significance of the Association .. 2.2... eee ee eee ee Birth Weight Summary 2... ee Cigarette Smoking and Fetal and Infant Mortality Introduction . 2000 ce eee Spontaneous Abortion 00... ee eee Spontaneous Abortion Summary .-.-..-------+-+--- Srillbirth 000 0 te eee Stillbirth Summary .......---.2- 020+ er eee ee cee Late Fetaland Neonatal Deaths .......-..00002222 02% Epidemiological Studies... 2-2-2. - 22-0 - ee ee ee eee ee Comparisons of the Mortality Risks of Low- Birth-Weight Infants Born to Smokers and Nonsmokers .....0.------- 22 eee eee eee Recent Studies ........---.-- De eee eee Analysis of Previously Reported Studies .....-.----- Factors Which Influence Perinatal Mortality Other Than Smoking ...--.--...-.- 000 eee eee 413 Page 417 419 420 424 Experimental Studies Studiesin Animals .....----- 02-20 fete 446 Studiesin Humans ....-.------- 0800 e rrr 447 Significance of the Association... 2. +222 ser rrr ttt 447 Cigratte Smoking and Infant Mortality - Cont. Late Fetal and Neonatal Death Summary ..------ +--+ e000 448 Sex Ratio ..-- eee eet teeter sss 449 Summary... 000000 cece terres tts 449 Congenital Malformations ©... - +++ +2 ser ctr errr 450 Congenital Malformation SUMMANY oo ee 451 Lactation Introduction... 00-0 eters 452 Epidemiological Studies... 62-0000 c ttre srt 452 Experimental Studies... 0000 cer r errr rss ett 452 Studies in Animals Nicotine ...- 2-22 - cee te eet 452 Influence on the Lactation Process ....----- 2 eect 452 Presence of Nicotine in the Milk ..-.---- +e eect 2. 453 Evidence for an Effect Upon the Nursing Off- spring... eee ttt 453 Nitrosamines ....---- 20-2 ¢ cece eter tr 453 Studies in Humans Nicotine and/or Tobacco Smoke ..---- +--+ e src 453 Influence on the Lactation Process -.-- +--+ 7s 5 rr cts 453 Presence of Nicotine in the Milk 2.2.6.2 26-25 s ee 454 Evidence for a Clinical Effect Upon the Off- Od 454 Vitamin ....-- eect cette 455 Lactation Summary ...- 0-000 ccc 455 Preeclampsia... 2-2-0 456 Summary 200-00 e cette tts 456 References ...--ece creer trees ttt rss 456 414 List of Figures Figure 1.—-Mean birth weight for week of cestation according to maternal smoking habit: control week singletons..___.__- Figure 2.—Percentage distribution by birth weight of infants of mothers who did not smoke during pregnancy and of those who smoked 1 pack of cigarettes or more per day_...-____. Figure 3.—Percentage of pregnancies with infant weighing less than 2,500 grams, by cigarette smoking category____.__22_- Figure 4.—Average birth weight by maternal smoking habit (a) before current pregnancy and (b) during current preg- Figure 5.—Percent of low birth weight white infants by smok- ing status of their mothers._....-2--- Figure 6.—Neonatal mortality rates among single white births in hospitals (by detailed birth weight and specified gestation groups: United States)... Figure 7.—Perinatal mortality rate per 1,000 total births by cigarette smoking category_.._.-----6 ee List of Tables Table 1.—Infant birth weight by maternal and paternal smok- ing habits. _____. eee Table 2.—Effect of carbon monoxide exposure of pregnant rabbits on birth weight-_-00--28 Table 3.—Comparison of the perinatal mortality for infants weighing less than 2,500 grams, of smokers and nonsmokers. Table 4.—Effect of carbon monoxide exposure of pregnant rab- bits on birth weight and neonatal mortality... 22 8. Table 5.—Proportion of male infants delivered to smoking and nonsmoking mothers.-_..-.----2 ee Table 6.— Relative risk of congenital malformation for infants of cigarette smokers and nonsmokers, comparing available studies with regard to study design, study population, sample size, number of infants with malformations, and definition of malformation... 22222! Pace 418 419 422 424 427 442 443 425 431 441 447 450 415 Introduction Cigarette smoking is a common habit among women of child-bearing age in the United States. In 1970, approximately one-third of Amer- ican women of child-bearing age were cigarette smokers. The percent- age of U.S. women who smoked throughout pregnancy 1s not definitely known, but is presumably lower. probably in the neighborhood of 20 to 25 percent. With a large fetal population at potential, but prevent- able, risk, the relationship between cigarette smoking and the out- come of preenancy has been the focus of considerable and continuing research. Every investigator who has examined the relationship has confirmed that the infants of women who smoke during pregnancy have a lower average birth weight than the infants of women who do not smoke during pregnancy. Much evidence indicates that cigarette smoking during pregnancy causes this reduction in infant birth weight. Several investigators have demonstrated that the fetal and neonatal mortality rate is sienifcantly higher for the infants of smokers than for the infants of nonsmokers: other investigators have not found higher mor- tality for smokers’ in fants. Studies of the association between maternal cigarette smoking and congenital malformations have produced con- flicting results. The following is a review of work previously reported and recent studies which bear on the relationships bet ween cigarette smoking and different outcomes of pregnancy. In addition, the chapter includes a review of the relationship between cigarette smoking and lactation. Smoking and Birth Weight E' pidemiolo gical St urdiEs” CIGARETTE SMOKING AND THE Low-Birre-Wericur INFant In 1957. Simpson (90), using 2 retrospective study design. deter- mined that among 7.499 women in San Bernardino Connty. Calif. the delivery of infants weishing less than 2,500 grams was nearly twice as 417 frequent among cigarette smokers as among nonsmokers. Subsequently, Lowe (46) studied 2.042 women in Birmingham, England, and dem- onstrated in his retrospective study that the infants of smoking mothers were delivered only slightly earlier (14 days on the average) than those of nonsmokers. He further noted that for gestations of 260 days and over, the infants of smokers were consistently lighter in weight during each week of gestation than those of the nonsmokers. This finding has heen confirmed since, and figure 1 from the British Perinatal Mortality Study (73) provides illustration of this relationship. Given the nearly constant disparity present between the birth weights of the infants of smokers and nonsmokers for gestations of 260 days and over, but absent prior to that time, and given the similar birth weights of infants of nonsmokers and of women who gave up smoking early in pregnancy and did not begin to smoke again, Lowe inferred that the influence of smoking upon birth weight might lie mainly in the later months of pregnancy. He emphasized the tentative nature of this conclusion, since the number of infants with a gestation of less than 260 days and the number of women who gave up smoking early in the pregnancy and did not begin to smoke again were both smal]. Figure 1.—Mean birth weight for week of gestation according to maternal smok- ing habit: control week singletons.’ 3650 - ® 125 _— __ a 0-7-7 OF 3400 g x “or E & 115 7 Non- on or 3150 £ o smokers -7 4 to c oe & = 105 f 7 2 & J. Smokers + 2900 & = & : id = L Cc 5 95 LA 4 2650 § = yo = 85 67 4 2400 75 4 4 ‘ 4 1 ro 2150 36 37 38 39 40 41 42 43+ Gestation in completed weeks 7 This term refers to singleton births In England, Scotland, and Wales occurring during the week of March 3-9, 1958, which are included in the Perinatal! Mortality Survey. These comprise 97 percent of ali births notified in Engtand and Wales or registered in- Scotland during this weak. SOURCE: Butler, N. R., Alberman, E. D. (13). 418 Lowe found that the infants whose mothers smoked throughout pregnancy weighed, on the average, 170 grams less than those whose mothers did not smoke. In addition, he noted that the entire distribu- tion of weights of infants of smokers was shifted to the left (toward lower weights) relative to that for the infants of nonsmokers. This finding, too, has been confirmed by other investigators. Figure 2 offers an iNustration from MacMahon, et al. (49). Given that the infants of smokers and nonsmokers differed only slightly with respect to the duration of gestation, Lowe concluded that the lower birth weight of smokers’ infants must be attributed to a direct retardation of fetal growth. In other words, on the basis of his data, the infants of smokers were emall-for-dates rather than truly premature. Many investigators have subsequently confirmed this point (72, 14, 20, 35, 65, 78, 85, 113). Buncher (72), ina study of 49.897 births among U.S. naval wives, in the same population studied by Underwood, et al. (700), found that the infants of smokers were, on the average, de- livered only 1 day earlier than those of nonsmokers. This finding accounted for only 10 percent of the discrepancy in birth weight be- tween the two groups of infants. The remainder of the studies resulted im the detection of either similar variations in gestational length or no average difference. In a recent study, Muleahy and Murphy (56), Figure 2,—Percentage distribution by birth weight of infants of mothers who did not smoke during pregnancy and of those who smoked 1 pack of cigarettes or more per day. INFANT WEIGHT ANO PARENTAL SMOKING HABITS TT ey 10 4 —— Nonsmokers Smokers BEL 4 o Cc BSF 7 4-L “4 2 4 0 ed I ray 4 5 6 7 8 9 10 11 BIRTH WEIGHT (SCALE IN POUNDS; INTERVALS OF 4 OZ.) SOURCE: MacMahon, et al. (49). 419 in « sample of 5,099 Irish mothers, concluded that although the babies born to cigarette smokers were delivered slightly earher than those of nonsmokers, independent of age and parity, the direct effect of smoking in retarding fetal growth was more significant. The following points, based upon the results from many different studies, can be made about the relationship between cigarette smoking during pregnancy and lower infant birth weight: 1. Women who smoke cigarettes during pregnancy have a higher proportion of low-birth-weight infants than do nonsmokers. This excess of low-birth-weight infants among cigarette smokers pre- dominantly consists of infants who are sinall-for-gestational age rather than gestationally premature. 2. The entire distribution of birth weights of the infants of ciga- rette smokers is shifted toward lower weights compared to the birth weights of the infants of nonsmokers. 3. The birth weights of the infants of cigarette smokers are con- sistently lighter than those of the infants of nonsmokers when the birth weights of the two sets of infants are compared within groups of similar gestational age beyond the 36th week of gestation. The results of the studies which have been considered so far identify a relationship between cigarette smoking and lower infant birth weight and illustrate some aspects of that relationship, but do not indicate whether the association is causal or indirect. The succeeding two sections of this chapter contain evaluations of the available evi- dence which bears upon the nature of the association between cigar- ette smoking during pregnancy and the incidence of small-for-dates in fants. Eviwence ror a Cacsa. Association BeTwren CicareTre SMOKING AND Sm 4uu-ror-Dates Ixrants Evidence previously reviewed in the 1971 and 1972 reports on the health consequences of smoking (/01, 102). suggests that cigarette smoking is causally associated with the delivery of small-for-dates infants. The following is a summary of this evidence: 1. The results from all 30 studies in which the relationship between smoking and birth weight was examined have demonstrated a strong association between maternal cigarette smoking and delivery of low- birth-weight infants. On the average. the smoker has nearly twice the risk of delivering a low-birth-weight infant as that of a nonsmoker 420 (3, 13, 17, 20, 25, 29, 35, 42, 43, 46, 47, 49, 47, 58, 59, 65, 70, 72, 73, 77,78, 80, 83, 85, 90, 95, 99, 100, 113, 118). 2. The strong association between cigarette smoking and the de- livery of small-for-dates infants first demonstrated with results from studies of retrospective design (3, 13, 17, 35, 46, 47, 49, 57, 58, 59, 65, 70,72, 73, 77, 80, 85, 90, 95, 99, 100, 118) has been repeatedly confirmed subsequently by data from studies of prospective design (20, 25, 29, 42, 43, 78,83, 113). 3. A strong dose-response relationship has been established between cigarette smoking and the incidence of low-birth-weight infants (25, 43, 46,49, 100, 113). 4. When a variety of known or suspected factors which also exert an influence upon birth weight have been controlled for, cigarette smok- ing has always been shown to be independently related to low birth weight (1, 13,25, 43, 46, 73,78, 83). 5. The association has been demonstrated tn many different coun- tries, among different races and cultures, and in different geographical settings (13, 17, 25, 29, 36. 42. 43,59, 78, 78, 80, 113). 6. Previous smoking does not appear fo influence birth weight if the mother gives up the habit prior to the start of her pregnancy (24, 46.49.13). 7. The infants of smokers experience an necelerated growth rate during the first 6 months after delivery, compared to infants of nonsmokers. This finding is compatible with viewing birth as the re- moval of the smoker's infant from a toxic intlience (83). 8. Data from experiments in animals have documented that ¢x- posure to tobacco smoke or soine of its ingredients results in the delivery of low-birth-weight off NX 3.0 fF 2.0 F XXRXR\RARARRYYAL MOY 0.0 21 pack per day per day ER&&aaw Nonsmoker Number of infants weighing <2,500 grams: 1,3 1,186 793 8 Total births: 28,358 15,328 6,581 (P <0.001) SOURCE: Ontario Department of Health (66). 422 Rantakallio (76) carried out a prospective study of 11,905 single births in Finland. Cigarette smoking mothers had sinificantly more infants weighing less than 2,500 grams than did nonsmokers (P30_.----------------- 1,570 3, 182 213 1,330 3, 393 3 ene t Nonsmoker niitus smoker. Source: Undenvood, ct al. (199). Yerushalmy (727) pointed out that other investigators had found” marked differences between smokers and nonsmokers. In his own study. he found Chat nonsmokers used contraceptives significantly more frequently than did smokers. Moreover, a significantly higher proportion of smokers drank cotfec, beer, and whiskey. However, he did not adjust for these variables in his analysis of the association between cigarette smoking and lower infant birth weight. Other im- vestigaters have also found differences between smokers and non- smokers. Forexample, Frazier. et al. (29) found significant differences in the distribution of parity, work history, education, and‘ psycho- 425 somatic complaint score between smokers and nonsmokers. However, when smokers were compared with nonsmokers of the same parity, education, work history, and psychosomatic complaint seore. cigarette smokers still had a significantly higher proportion of smal] infants than did nonsmokers. .\s previously mentioned, whenever other factors known or suspected to influence birth weight have been controlled, cigarette smoking has always been demonstrated to have an inde- pendent and significant effect. Ounsted (49) offered evidence that the best predictor of the birth weight of a mother’s future offspring was the birth weight of her previous children. Herriott, et al. (35) found prematurity rates for previous pregnancies among smokers to be markedly higher than among nonsmokers, independent of parity, height, and social class. Evidently a woman whose previous infants have been small tends to continue to have relatively smaller than average infants in subsequent pregnancies. The question is. will those infants be even smaller than expected tf she smokes? Goldstein, et al. (28). in a comprehensive review, proposed a research design in which a woman would serve as her own contro] to compare outcomes of pregnancies during which she smoked with those during which she did not with consideration of the effect of parity on the outcome. Yerushalmy (772) has recently tested this type of research design. using data from his Oakland Growth Study. With information on the age at which a woman began to smoke cigarettes, her smoking status during the pregnancy actually studied, her prior reproductive experience, and the outcome of her present pregnancy, the author compared the outcomes of pregnancy during periods of smoking and nonsmoking using the woman as her own control. As the author noted, “If smoking causes the increase in Jow-birth-weight infants, then the incidence of low birth weight for infants born to smoking mothers during the period before they acquired the smoking habit. should be relatively low. If, on the other hand, the high incidence of low birth weight is due to the smoker, then it should be high for infants of future smokers also when they were born before their mothers started to smoke.” Yerushalmy then proceeded to compare the reproductive experiences of four groups of women: (a) Those who smoked in none of their ‘pregnancies, (b) those who smoked in all of their pregnancies, (c) those who were smoking now but previously had not smoked during some pregnancies (future smokers), and (d) those who were ex- smokers now but had previously smoked during some pregnancies. These outcomes are shown in figure 5. The incidence of low-birth- weight infants in the pregnancies of the future smokers. before they started to smoke, was similar to that for women who smoked in every pregnancy, which was significantly higher than that of infants from 426 mothers who had never smoked. Ie also noted that ex-smokers, during the period before they quit, gave birth to relatively few low-birth- weight infants; the imcidence was significantly lower than for mothers who smoked during all of their pregnanctes. He concluded that the findings cannot be eastly reconciled with a cause-ctfect basis for smok- ing and birth weight. He said, “Rather the evidence appears to support the hypothesis that the higher incidence of low-birth-weight infants is due to the smoker, not the smoking.” There are several considerations which limit the interpretations which can be drawn from this study. The information on smoking behavior of the women during past pregnancies was apparently de- rived from the woman's age when she began to smoke, her smoking behavior early in the study pregnancy, and the age at which she had her prior pregnancies. Thus, if the woman reported that she began smoking at a certain age, and that she was still smoking at the time of the study. it was apparently inferred that she had smoked during all of her pregnancies. Since no questions were specifically asked about actual smoking behavior during each previous pregnancy, it is possible that the woman indeed had not smoked during every pregnancy or that the amount or way she smoked had differed from current smoking Figure 5.—Percent of tow birth weight white infants by smoking status of their mothers. Gravidas’ smoking habits Percent low birth weight infants in previous pregnancies Nonsmoker 7 (during alt pregnancies) | 2,529 Nonsmoker |° (future smoker) 9.5 210 Smoker a |" + (during all pregnancies) a 2,076 Smoker ee (future ex-smoker) 6.0 | 651 Percent “Difference is statistically significant (P <0.01). **Difference is Statistically significant (P <0.02). SOURCE: Adapted from Yerushalmy, 3. (112). 427 habits. This would be important to know given the strong dose- response relationship which has been established between cigarette smoking and low birth weight, and would tend to make the reproduc- tive outcomes for ex-smokers similar to those of nonsmokers, and diferent from those of women who smoked in all pregnancies. For ex-smokers, the age at which smoking began was not elicited. Hence, some of the infants of ex-smokers may have been born before their mothers acquired the smoking habit. This would also tend to make the reproductive experiences of ex-smokers more like those of nonsmokers and different from those of women who smoked in all pregnancies. No direct adjustment for age, parity, and other variables was reported, although Yerushalmy stated that the study population was limited to the births that occurred to women at age 25 years or less. He noted that, “In order to adjust for parity, the same comparisons were performed for firstborn infants only. The numbers were reduced considerably, but the same tendencies as found above were noted.” However, no data were presented. Primiparous births and births in teenagers are strongly associated with the delivery of low-birth-weight infants. If the pregnancies which occurred among future smokers included a predominance of very young women and primiparous births, the reproductive experiences of future smokers would tend to be similar to those of women who smoked during all pregnancies, and diiferent from those of nonsmokers. In the absence of more precise information on actual smoking behavior during pregnancy and more rigorous adjustment for maternal age, this study does not provide a critical test of the hypothesis that it is the smoking during pregnancy which is responsible for the high proportion of small-for-dates in- fants born to women who smoke. Experimental Studies Sropres IN ANIMALS Tobacco Smoke Several investigators have demonstrated that exposure of pregnant rats or rabbits to tobacco smoke leads to a reduction of birth weight in the offspring, as compared to controls (23, 87, 117). Younoszai, et al. (117) reported data from studies in rats which indicated that some agent present in cigarette smoke other than nicotine was responsible for the reduction in birth weight observed. The authors suggested that carbon monoxide might also not be responsible for the retardation of 428 fetal growth; however, the evidence presented was inadequate to support a firm conclusion. Haworth and Ford (33) recently extended the experiments of Younoszai. A group of pregnant rats was exposed to cigarette tobacco smoke for 6 to 8 minutes, five times a day, from days 3 to 20 of ges- tation. These rats were compared with another group whose food intake was restricted to the amount actually consumed by the tobacco- exposed rats, and both were compared to a well-fed control group. The animals in both experiments were killed on the 2ist day of gestation, and weights of the entire body, the liver, and the kidney of each fetus were recorded. The total average fetal weight of the group exposed to tobacco smoke was significantly lower than that of both the food-restricted and control groups. The fetal weights of the latter two groups were quite similar. Protein and DNA analyses were performed separately on the entire forebrains and hindbrains of the fetuses and on the entire carcass. Both DNA and protein were sig- nificantly and proportionately reduced in the carcass and hindbrains of the animals exposed to tobacco smoke. This implies that cell number was reduced and cell size was normal, and suggests that the exposure to tobaceo smoke either inhibited cellular proliferation or accelerated cellular destruction. Nicotine Several workers have demonstrated that chronic injections of large doses of nicotine into pregnant rats resulted in a reduction of birth weight of the offspring (7, 8, 9, 23, 40). Other investigators have de- termined that tritium-labelled nicotine injected into pregnant rabbits and C"-labelled nicotine injected into pregnant mice crossed the placenta to the developing embryo and fetus (89, 98). Kirschbaum, et al. (47) found no significant acute effects of small doses of nicotine, injected intravenously into near-term sheep, on blood gas composition, pH, blood pressure, or heart rate in either the ewes or their fetuses. The authors concluded that the influence of maternal smoking upon. the fetus must result from chronic effects or through the effects “of other variables which they did not study. Recently, Suzuki, et al. (94) evaluated the short-term effects of in- jected nicotine on the cardiovascular performance, acid-base status, and oxygenation of pregnant female Rhesus monkeys and their infants during the second half of gestation using the mothers as their own controls. Nicotine was administered either as a single intravenous dose of 0.5 to 1.0 mg. or as a continuous infusion of 100 pg./kg. over 495-028 O--73-——-9 429 a 20-minute period. The injection of nicotine in the larger, single dose into the mother produced a rise in maternal blood pressure and a fall in maternal heart rate, and an immediate fall in both fetal blood pressure and fetal heart rate followed by persistent hypotension and tachycardia in the fetus. Subsequent to the injection of 1.0 mg./kg. of nicotine into pregnant monkeys, in a single dose, significant changes in the arterial blood of the older fetuses included a fall in pH, a rise in base deficit, and a fall in oxygen tension. Carbon dioxide tension remained unchanged. Nicotine injected directly into the fetus prompted an immediate rise in fetal blood pressure and a fall in fetal heart rate. These responses were similar to those previously seen in the mothers following a direct injection of nicotine. The changes were more prominent in older rather than in younger fetuses. The authors sum- marized their findings by stating that: (a) fetuses in different ges- tational stages are differentially responsive to a given dose of nico- tine, probably because of the different stages of development of the autonomic nervous system; (b) diminished intervillous space per- fusion resulting from vasoconstriction in the uterine circulation ap- pears to be mainly responsible for the fetal asphyxta following the injection into the mother, because fetal hypotension and bradycardia were not preceded by the transient hypertension seen following the direct administration of nicotine to the fetus; (c) the differences be- tween the results obtained by Kirschbaum and by Suzuki, et al. may reflect either the considerable dosage differences or species differences; and (d) the doses which the authors employed were much larger than those which a human mother would absorb from usual cigarette smok- ing, but that differences in tolerance to nicotine between the Rhesus monkey and humans would imply that the dosages were, in fact, com- parable and that, “Hence, it can be envisaged that the concentration of nicotine which could be reached in the organism of a smoking mother would reduce oxygen availability to the fetus.” Carbon Monoxide Longo (45) has reviewed the work of several investigators which has demonstrated the transplacental passage of carbon monoxide from mother to fetus in animals. A recent study which related CO to birth weight was published by Astrup (2). He found that continuous ex- posure throughout gestation of pregnant rabbits to different levels of ambient carbon monoxide resulted in a statistically significant dose- related reduction in birth weight (table 2). The actual significance level was not reported. 430 TABLE 2.—Effect of carbon monoride erposure of pregnant rabbits on birth weight Group 1, Group 2, Group 3, 0 percent § to 10 percent 16 10 14 percent COHb COokib Colib Number of pregnant rabbits__________ 17 14 17 Total number of babies_._.-.... 116 S1 123 Average weight of babies in grams_____ 53.7 51.0 44.7 Source: Astrup, P. (£). Polycyclic Hydrocarbons Polycyclic aromatic hydrocarbons (PAH) such as benzo(a)pyrene (BAP) are constituents of cigarette smoke which have been impli- cated in the generation of cancers in many animal species (711). No studies presently available relate benzo(a)pyrene to a reduction in birth weight of exposed offspring. Evidence suggests, however, that BAP does reach and cross the placenta. Aryl hydrocarbon hydroxylase (AHH) is a part of the cytochrome P-450- containing microsomal enzyme system, present in many tissues of different species. This enzyme system is induced to hydroxylate polycyclic aromatic hydro- carbons after exposure of cells to PAH. Several investigators have utilized the inducibility of the enzyme system to demonstrate indirectly that benzo(a)pyrene and other polycyclic hydrocarbons reach the placenta and fetus. Welch, et al. (208) extended this work by administering the poly- cyclic hydrocarbon, 3-methylcholanthrene (8-MC), to rats during late gestation. The metabolism of benzo(a) pyrene was studied in vivo (1s- ing tritium-labelled benzo(a)pyrene) and in vitro. AHH activity was increased in fetal livers to adult levels by pretreatment with 3-MC Since a relatively high dose of polycyclic hydrocarbon was required to stimulate enzyme activity in the fetus, compared to the dose which stimulated placental enzyme activity, the authors suggested that the placenta may protect the fetus from exposure to polycyclic hydro- carbons. However, immaturity of the fetal enzyme system might also account for its apparent relative insensitivity to polycyclic hydro- carbons. Therefore, an exposure of the fetus to levels of poly- cyclic hydrocarbon similar to those experienced by the mother cannot be ruled out by the available data. 431 Schlede and Merker (86) have studied the effect of benzo(a) pyrene administration on aryl hydrocarbon hydroxylase activity in Che mater- nal liver, placenta, and fetus of the rat during the latter half of gestation. The pregnant animals were treated with large oral doses of benzo(a)pyrene 24 hours prior to sacrifice. Control rats had no detectable levels of aryl hydrocarbon hydroxylase in their placentas. Treatment with benzo(a) pyrene resulted in barely detectable placental levels on gestation day 13, but steadily rising values until day 15, and then constant levels thereafter. No activity was detected in the fetuses of untreated controls. In the treated animals, the fetal enzyme activity rose steadily from the 13th to the 18th day of gestation. The authors concluded that the stimulatory effect of benzo(a)pyrene treatment on aryl hydrocarbon hydroxylase activity in the fetus demonstrates that benzo(a)pyrene readily crosses the rat placenta. Srupres 1 Huxrans Carbon Monoxide Smokers and their newborn infants have significantly elevated levels of carbon monoxide as compared with nonsmokers and their infants (31, 34, 88, 116). Recently, Baribaud, et al. (5) studied 50 nonsmokers and 27 cigarette smokers and their newborns. All smokers inhaled. The authors found that the mean level of CO content in the blood of non- smokers was 0.211 volumes percent compared with 0.672 volumes per- cent in the blood of smokers. The values for blood samples from the umbilical cords of their newborns were 0.352 and 0.949 volumes per- cent, respectively. Moreover, a definite dose relationship was found between CO levels and number of cigarettes smoked. Younoszai, et al. (716) found, in addition to elevated carboxyhemo- globin levels among the infants of smoking mothers, significant elevation of mean capillary hemotocrits and significant reduction of standard bicarbonate levels, as compared to the infants of nonsmoking mothers. Since no evidence for nicotine effects upon blood glucose, serum FFA levels, or urinary catecholamines, or for hypoxia was present, they concluded that the higher hematocrit levels in the infants of smoking mothers may have represented a compensatory response to the decreased oxygen-carrying capacity of the blood due to the presence of carboxyhemoglobin. Longo (44) pointed out that a level of 9 percent carboxyhemoglobin in the fetus is the equivalent of a 41 percent decrease in fetal blood flow or fetal hemoglobin concentration. In reviewing the studies of CO levels in human mothers and their newborns, he made the follow- 432 ing comments: “These samples were obtained at the time of vaginal delivery or Cesarean section and may not accurately reflect the normal values of (COHb), for several reasons. The number of cigarettes smoked by the mothers during labor may be less than their normal consumption and was not specified in these studies. The blood sam- ples were collected at varying time periods following the cessation of smoking. In addition, many of the samples were probably taken early in the day before COHb levels had built up to the levels reached after prolonged periods of smoking. Thus actual levels of (COHb) » and (COHb)r may be higher than the reported values.” Polycyclic Hydrocarbons The results of several studies concur that cigarette smoking is strongly associated with the induction of aryl hydrocarbon hydrox- ylase in the human placenta (18, 38, 61, 99, 109). This finding implies that benzo(a)pyrene or other polycyclic hydrocarbons reach the placenta. To date, evidence to support the passage of polycyclic hydro- carbons through the placenta to the human fetus has not been published. Vitamin B,. and Cyanide Detoxification McGarry and Andrews (48) determined serum vitamin B,, levels in 826 women at their first prenatal clinic visit. They found that the serum levels for smokers were significantly lower than for nonsmokers. After adjustment for gestational age, parity, social class, hemoglobin level, hypertension, and maternal weight, smokers stil] had signifi- cantly lower levels of Bie. They also found a direct, statistically sig- nificant dose-response relationship between cigarettes smoked and serum vitamin By,» level. They again confirmed the relationship be- tween smoking and low birth weight. The authors suggested that the lowered vitamin B,, levels reflect a disorder of cyanide detoxification. Cyanide is a demonstrable ingredient in cigarette smoke (29, 60, 62, 64,68, 74,91). Vitamin C Venulet (105, 106, 107) has demonstrated that the vitamin C level is significantly lower in the serum of women who smoke cigarettes during pregnancy, compared to values for their nonsmoking counter- parts. Possible Mechanisms The following mechanisms have been proposed for the production of low birth weight and other unfavorable outcomes of pregnancy following exposure to cigarette smoke: 433 1, A direct toxic influence of constituents of cigarette smoke upon the fetus (2, 5, 50, 51, 117). - Decreased placental perfusion (94). 3. Decreased maternal appetite and diminished maternal weight gain with secondary effects upon the fetus (6, 33, 36, 65, 75, 99- 17). . A direct effect upon the placenta (36, 57, 65, 110). . An oxytocic effect on uterine activity (44). . A disturbance of vitamin B,, metabolism (48). . A disturbance of vitamin C metabolism (703, 106, 107). to “Tm On He Of the potential mechanisms, available evidence suggests that neither decreased maternal appetite and decreased maternal weight gain nor a direct effect upon the placenta are responsible for a sig- nificant reduction in birth weight. Existing evidence does not permit firm conclusions concerning the relative significance of the remaining mechanisms. Timing of the Influence of Cigarette Smoking on Birth Weight Several investigators have published results which bear on the time period during which exposure to cigarette smoke most affects fetal growth. Lowe (46) and Zabriskie (/18) have offered evidence which suggests that cigarette smoking influences fetal growth most during the second half of pregnancy. Butler, et al. (15) found that the birth weights of infants of women who did not smoke after the fourth month of pregnancy were essentially the same as those of the infants of nonsmokers. This implies that the influence is most probably exerted after the fourth month of pregnancy. Herriott, et. al. (35), however, found that women in lower socioeconomic classes who gave up smoking early in pregnancy tended to have intermediate weight babies as com- pared with nonsmokers and persistent smokers, but his numbers of women were small and the results were not statistically significant. Underwood, et al. (100) found that cigarette smoking in any single trimester was associated with a lower birth weight of the infant, although the difference between the birth weights of infants of women who smoked only during a single trimester and infants of non- smokers was not statistically significant because of small numbers. Several investigators have detected a nearly constant difference be- tween the birth weights of the infants of smokers and nonsmokers, delivered during the last month of pregnancy, following gestations of comparable length {fig. 1, (7/)]. Although this observation is 434 compatible with the suggestion that the influence of cigarette smoking upon the fetus occurs prior to the last month of pregnancy, it is based upon data derived from cross-sectional rather than longitudinal studies. The results of many human epidemiological studies sugeest that maternal smoking prior to pregnancy does not influence fetal weight gain (15, 25, 46, 49, 113). Site of Action at the Tissue and Cellular Level The use of labelled nicotine (98) and the preparations of autoradio- grams have permitted the localization of nicotine within the tissues of the fetus and mother. Tjalve, et al. (98) found high levels of nico- tine in the respiratory tract, adrenal, kidney, and intestine of 16- to 18- day mice fetuses. The use of other labelled constituents during various parts of gestation might further the understanding of how certain ingredients in cigarette smoke produce an impact upon birth weight. Haworth and Ford (33) have reported data which suggest that the reduction of birth weight of rat fetuses caused by the action of the ingredient.(s) of tobacco smoke results from a reduction in cell number, but not in cell size. Significance of the Association Among all women in the United States, cigarette smokers are nearly twice as likely to deliver low-birth-weight infants as are non- smokers. Assuming that 20 percent of pregnant women in the United States smoked cigarettes through the entire pregnancy (extrapolated from data on changes in smoking behavior during pregnancy collected for the British Perinatal Mortality Study), taking into account the apparently different risks of delivering a small-for-dates infant for— . Caucasian and non-Caucasian women who smoke during pregnancy, and considering the number of infants with a birth weight less than 2,500 grams born to Caucasian and non-Caucasian women, an excess of nearly 43,000 occurred in the 286,000 low-birth-weight infants among the 3,500,000 infants born in the United States in 1968, because of the increased risk among women who smoke of having small-for- dates infants. Since neonatal mortality is higher for low-birth-weigth infants, with gestational age held constant, the excess of small-for-dates infants among smoking mothers would imply a significant excess mortality risk as well. 435 Birth Weight Summary A causal association between cigarette smoking and fetal growth retardation is supported by the following evidence: 1. The resulte of all 42 studies in which the relationship between smoking and birth weight was examined have demonstrated a strong association between cigarette smoking and delivery of small-for-dates infants. On the average, the smoker has nearly twice the risk of delivering a low-birth-weight infant as tpat of a nonsmoker. _ This association has been confirmed by both retrospective and prospective study designs. A strong dose-response relationship has been established between cigarette smoking and the incidence of low-birth-weight infants. Available evidence suggests that the effect of smoking upon fetal growth reflects the number of cigarettes smoked daily during a pregnancy, and not the cumulative effect of cigarette smoking which occurred before the pregnancy began. . When a variety of known or suspected factors which also exert an influence upon birth weight have been controlled for, cigarette smoking has consistently been shown to be independently related to low birth weight. _ The association has been found in many different countries, among different populations, and in a variety of geographical settings. . New evidence suggests that if a woman gives up smoking by the fourth month of pregnancy, her risk of delivering a low-birth- weight infant is similar to that of a nonsmoker. _ The infants of smokers experience a transient acceleration of growth rate during the first 6 months after delivery, compared to infants of nonsmokers. This finding is compatible with viewing birth as the removal of the smoker’s infant from a toxic influence. . The results of experiments in animals have shown that exposure to tobacco smoke or some of its ingred{ents results in the delivery of low-birth-weight offspring. New evidence demonstrates that chronic exposure of rabbits to carbon monoxide during gestation results in a dose-related reduction in the birth weight of their offspring. . Data from studies in humans have demonstrated that smokers’ fetuses are exposed directly to agents within tobacco smoke, such as carbon monoxide, at levels comparable to those which have been shown to produce low-birth-weight offspring in animals. 436 Cigarette Smoking and Fetal and Infant Mortality Introduction Several previous studies ofthe relationship between cigarette smok- ing and higher fetal and infant mortality among the infants of smokers have been reviewed in the 1971 and 1972 reports on the health con- sequences of smoking (/0/, 102). In many of these studies, the authors combined two or more categories of fetal and infant mortality. Differ- ent mortality outcomes, such as spontaneous abortion, stillbirth, and neonatal death, are influenced by different sets of factors. Among other factors, the frequency of abortion is influenced by congenital infections, hormonal deficiencies, and cervical incompetency. In addi- tion to other factors, the frequency of stillbirth is influenced by pre- mature separation of the placenta, uterine inertia, and dystocia. Along with other factors, the frequency of neonatal death is influenced by gestational maturity, birth injucies, and delivery room and nursery care. Separate analysis of the relationship of cigarette smoking to each different mortality outcome, with control of the unique set of factors which influences it, may facilitate understanding of the relationship. Spontaneous Abortion Previous epidemiological and experimental studies of the relation- ship between spontaneous abortion and cigarette smoking reviewed in the 1971 and 1972 reports on the health consequences of smoking (J01, 102) form the basis of the following statements: The results of several studies, both retrospective and prospective, have demonstrated a statistically significant association between ma- ternal cigarette smoking and spontaneous abortion (43, 65, 70, 99, 118). Data from some of these studies have documented a strong dose- response relationship between the number of cigarettes smoked and_ the incidence of spontaneous abortions (70, 99, 178). In general, vari- ables other than cigarette smoking (e.g., maternal age, parity, health, desire for the pregnancy, and use of medication), which may influence the incidence of spontaneous abortions, have not been controlled. The results of the one study, in which adjustment for the woman’s desire for the pregnancy was performed, indicated that after such adjust- ment cigarette smoking during the pregnancy retained an association with spontaneous abortion of borderline significance (43). The time period during which cigarette smoking might exert an influence on the incidence of spontaneous abortions has not been determined. Abor- 437 tions have been produced in animals only with large doses of nicotine (23, 96, 104); the relevance of these studies for humans is uncertain. SpoxtTaNEocs ABORTION SUMMARY Although several investigators have found a significantly higher, dose-related incidence of spontaneous abortion among cigarette smokers as compared to nonsmokers, the lack of control of significant variables other than cigarette smoking does not permit a firm con- clusion to be drawn about the nature of the relationship. Stillbirth Epidemiological studies of the association between cigarette smok- ing and stillbirth previously reviewed in the 1971 and 1972 reports on the health consequences of smoking (101, 102) form the basis for the following statements: In one group of retrospective and prospective studies, a higher still- birth rate was found for the infants of smokers as compared ta those of nonsmokers (14, 25, $3). In another group of retrospective and prospective studies, no significant difference was detected in the still- birth rate among the infants of smokers and nonsmokers (/6, 20, 85, 99, - 100). Differences in study size, numbers of cigarettes smoked, or the presence or absence of control of variables, such as age and parity, which may influence stillbirth rates, were probably not sufficient to explain the differences in results obtained. Several recent epidemiological studies have added to our under- standing of the relationship between cigarette smoking and stillbirth. Niswander and Gordon (63) have reported data from 39,215 preg- nancies followed prospectively and collected between 1959 and 1966 at 12 university hospitals in the United States. A random sample of women who presented to hospital prenatal clinics were enrolled in the study. The authors reported no increase in stillbirths among white smokers as compared with white nonsmokers. A higher incidence of stillbirths was found among black women who smoked than among nonsmoking black women. and a dose-response relationship with 5 suggested, although the findings did not attain statistical significance. The results were not adjusted for other vari- ables. Rush and Kass (82) found, in a prospective study of 3,296 City Hospital, a nonsignificant Increase in cigarettes smoked wa pregnancies at Boston 438 stillbirths among white women who smoked, but a statistically signifi- cant increase in stillbirths among black women who smoked (P<0.02). These findings are consistent with those previously outlned by Frazier, et al. (25) and Underwood, et al. (99). Rumeau-Roquette (8/), in a prospective study of 4,824 pregnancies in Paris, demonstrated that the risk of stillbirth was significantly higher for cigarette smokers than for nonsmokers (P<0.001). The authors also presented evidence that a woman with either a previous stillbirth or at least one prior infant weighing less than 2,500 grams at birth was significantly more likely to have a future stillborn infant than a woman without such an obstetrical history. After previous obstetrical history was controlled, smokers still retained a statistically significant increased risk of subsequent stillbirth as compared to non- smokers (P<0.01). Of further interest was the finding that among women who previously had delivered only living infants, weighing over 2,500 grams, cigarette smoking had no influence on the stillbirth rate. Previous experimental studies were reviewed in the 1971 and 1972 reports on the health consequences of smoking (7/01, 102). The authors demonstrated that exposure of pregnant rabbits to tobacco smoke and pregnant rats te large doses of injected nicotine resulted in a signifi- cant increase in stillbirths (7, 8, 23, 87). STILLBIRTH SUMMARY 1. The results of recent studies suggest that cigarette smoking is most strongly associated with a higher stillbirth rate among women who possess less favorable socioeconomic surroundings or an unfavorable previous obstetrical history. In the United States, black women have higher stillbirth rates than white women. The finding that cigarette smoking is associated with an even greater difference between the stillbirth rates of the two groups merits special attention. These findings may provide at least a partial | explanation for the lack of a significant difference in stillbirth rates between smokers and nonsmokers, which some investigators have found. 2. The results of experiments in animals demonstrate that exposure to tobacco smoke and some of its ingredients, such as nicotine, can result ina significant increase in stillbirth rate. 439 Late Fetal and Neonatal Deaths Considerable variation has occurred in the definition of the study population among the studies in which the relationship of cigarette smoking to fetal mortality (other than abortion) and early infant mortality was examined. The most commonly identified study popula- tions have been perinatal deaths, neonatal deaths, and late fetal plus neonatal deaths. Perinatal deaths are a combination of late fetal deaths (ie., stillborn infants) and deaths occurring within the first week of life. Neonatal deaths include all deaths of liveborn infants within the first 28 days of life. EpPipeMIOLOGICAL STUDIES Most of the earlier epidemiological studies of the association between cigarette smoking and late fetal plus neonatal mortality were reviewed in the 1971 and 1972 reports on the health consequences of smoking (101, 102). A review of previously unreported studies (67, 76), as well as reexamination of previously cited studies, forms the basis of the following statements: The results of several prospective and retrospective studies indicate a statistically significant higher late fetal and/or neonatal mortality for the infants of smokers compared to those of nonsmokers (/4. 17, 25, 43). The results of other prospective and retrospective studies iden- tified no significant difference in the mortality rates between the in- fants of smokers and nonsmokers (20, 65, 72, 85, 100, 115). If mortality rates were compared for those infants of smokers and nonsmokers weighing less than 2.500 grams, the infants of nonsmokers apparently had a considerably higher risk than did those of smokers. The results of recent studies, coupled with a critical review of the design and analysis of previous studies, and a reexamination of exist- ing data, may provide at least a partial explanation of discrepancies between the results of previous studies. Comparisons of the Mortality Risks of Low-Birth-Weight Infants Born to Smokers and Nonsmokers The perinatal mortality risk for infants weighing Jess than 2.500 grams appears to be lower for those infants born to women who smoke during pregnancy than for those born to nonsmokers (table 440 3). However, available evidence shows that cigarette smokers’ infants tend to be small-for-gestational age rather than gestationally pre- mature. Hence, within a given birth weight group, the infants of smokers are, on the average, gestationally more mature than those of nonsmokers. Data collected by the National Center for Health Sta- tistics (403) demonstrate that within a given birth weight group, the more gestationally mature an infant, the lower is its mortality risk (fig. 6). Thus, the difference in perinatal mortality risks experienced by the infants of cigarette smokers and nonsmokers, within comparable birth weight classes, reflects the facts that the two sets of infants are not of the same average gestational age, and that gestational age is a major factor influencing late fetal and neonatal mortality. An accu- rate estimate of comparative mortality risks for the infants of cig- arette smokers and nonsmokers requires adjustment for gestational age. For infants of comparable gestational age, lower birth weight is as- sociated with higher mortality (fig. 6). Since infants of cigarette smokers have, on the average, lower birth weights than the infants of nonsmokers, within groups of comparable gestational age, cigarette smokers’ infants should experience higher mortality rates than non- smokers’ infants of similar gestational ages. In a recent review, Meyer and Comstock (45/) provided a more extensive discussion of these points. TaBLe 3.—Compartson of the perinatal mortality for infants weighing less than 2,500 grams, of smokers and nonsmokers Perinatal mortality rate (deaths per 1,000 live births) Auther, reference Smokers Nonsmokers Underwood, et al. (100)_._.._.-.2-- 2-2-2 ++ 187 269 Ontario Department of Health (67)_....---_--- 232 300 Kullander and Kallen (43)_.......-..--------- 129 139 Rantakallio (76)_..-..---. 2-2 eee ee 288 344 Yerushalmy ! (112): Black women_______.._.---------------- 114 202 White women__.__..__-..--------------- 114 218 Butler and Alberman (14)______.-_.---------- 269 284 1 Reported neonatal mortality rates only. 441 Figure 6.—Neonatal mortality rates among single white births in nospitals (by detailed birth weight and specified gestation groups: United States). JANUARY 1 TO MARCH 31, 1950 400 ~ ~~ 200 \ © 28-31 weeks % Ne “ ~A 2? 100 . aa “ 32-35 x 80 }-—_ * “XN oa * weeks o *. 2 60 . = . °o ° “ ° 40 *. ct ~ . o + a . oc 20 *, . . * . ‘* J . . ‘. 10 “s . . . ee tf 4 1 1 _ti. i 4 lo ol ho to do to A ob DS Om HO OF HO os Hy RO ON NH MRE RO on an AN NA NN NN ONO mo BIRTH WEIGHT (in grams) SOURCE: U.S. Public Health Service, National Center for Health Statistics (103). Recent Studies The Ontario Perinatal Mortality Study (66, 67) was conducted among 10 teaching hospitals during 1960 and 1961. In this retrospec- tive study of 51.490 pregnancies, a statistically significant increase in the perinatal mortality rate was demonstrated for smokers’ in- fants as compared with those of nonsmokers; the infants of smokers experienced an overall relative risk of 1.27 (P?<0.001). Moreover, the investigators found a statistically significant dose-response relationship between the amount of cigarettes smoked and the perinatal mortality rate (P<0.001) (fig. 7). 442 Figure 7.—Perinatal mortality rate per 1,000 total! births by cigarette smoking category. wn = 40} = 2 33.4 2 cH oO 6 307 27.7 CL) 5 23.2 0 Q 2 7 C4) C4) 2 99 |b CH C4) 2 Cd CL) a & Cd) = i1o0f i. cy 4 a £ 5 Lo C4 Oy oO. OL, 0 LZ) 4 4 Nonsmoker <1 pack of =21 pack of cigarettes cigarettes per day per day Number of perinatal deaths: 659 425 220 Total births: 28,358 15,328 6,581 (P <0.001) SOURCE: Ontarfo Department of Health (66). Recently Butler, et al. (75) further analyzed the British Perinatal Mortality Study. They found a highly significant association between maternal smoking after the fourth month of pregnancy and both late fetal and neonatal deaths. Infants of smokers had an increase in the late fetal mortality rate of 30 percent, and an increase in the neo- natal mortality rate of 26 percent, compared to the infants of non- smokers. The overall mortality ratio of late fetal plus neonatal deaths was 1.28 (P<0.001). Given the large number of women in the study, and the significant changes in smoking behavior which occurred, they found it possible to consider the effect of a change in smoking 443 behavior between the beginning of pregnancy and the fourth monn on late fetal and neonatal mortality. A statistically significant and dose-related increase in mortality occurred among the infants of mothers who continued to smoke after the fourth month of pregnancy, as compared with the infants of nonsmokers and those of women who smoked prior to the pregnancy but gave up smoking by the fourth month of gestation. Niswander and Gordon (63) reported data from the prospective Collaborative Perinatal Study of the National Institute of Neurologi- cal Disease and Stroke. The 39,215 pregnancies registered at 12 uni- versity hospitals in the United States were almost equally divided between black and white women. They found a nonsignificant increase in perinatal mortality among the infants of white smokers as compared to those of white nonsmokers; the overall mortality ratio was 1.13 (P>0.1). The infants of black smokers, however, had a significantly higher mortality risk than did those of black nonsmokers; the mor- tality ratio was 1.18 (P<0.02). Moreover, a definite dose-response re- lationship between cigarettes smoked by pregnant mothers and mortality risk was shown for black infants. Black women were noted to smoke significantly fewer cigarettes, on the average, than white women. Rush and Kass (82) found, in a prospective study of 3.276 preg- nancies followed at Boston City Hospital, a nonsignificant increase in late fetal plus neonatal mortality rate among the infants of white women who smoked as compared to those of white nonsmokers. How- ever, the infants of black women who smoked had a statistically sig- nificant increase in mortality rate compared to the infants of black nonsmokers (P<0.01). The overall mortality ratio for black women who smoked was 1.86. The difference in frequency of stillbirth among the infants of smokers and nonsmokers was the primary factor which contributed to the significance of the difference in mortality rates. Analysis of Previously Reported Studies Previously reported studies can be divided into two groups: A group in which the late fetal plus neonatal mortality rates for infants born to cigarette smokers were significantly higher than those for the infants born to nonsmokers, and a group in which no significant differences were detected in the mortality rates for the infants born to smokers and nonsmokers. The results of several studies (14, 17, 25, 42, 43, 55, 84, 92) yielded mortality ratios ranging from 1.38 to 1.78. The results of other studies (20, 65, 76, 85, 100, 115) yielded mortality ratios ranging from 1.01 to 1.66. Both groups contained retrospective and prospective studies of comparable size. The two groups did differ 44h significantly, however, with regard to control of variables other than cigarette smoking which infuence perinatal mortality. Factors Which Influence Perinatal Mortality Other Than Smoking Butler and Alberman (/3), on data from the British Perinatal Mortality Study, employed a logit transformation analysis of variance, and demonstrated that maternal height, age, parity, social class, and severe preeclampsia all had a significant independent effect on late fetal and neonatal mortality. Rumeau-Roquette (8/) provided evi- dence that a previous stillbirth or low-birth-weight infant significantly increased the risk of a future stillbirth. Meyer and Comstock (5/) provided examples of how the differential distribution of smoking and other factors which are related to perinatal mortality, in a population of women, can bias data (e.g., black women have higher perinatal mortality rates than do white women, but black women smoke less than white women do. Hence, nonsmokers will tend to include more black women. and smokers more white women. This will tend to reduce anv differences between the groups in mortality rates.) Meyer and Comstock concluded, “Comparisons of mortality rates of smokers” and nonsmokers’ babies should be made within subgroups according to parity, socioeconomic status, and other appropriate risk factors, and not separated by birth weight.” In three of the studies in which a significantly higher mortality risk was demonstrated for the infants of smokers, adjustment for other variables was performed. The results indicated that, after such ad- justment, a significant independent association between cigarette smoking and infant mortality persisted (73 and 15, 17, 81). Of the studies which revealed no significant increase in mortality risks for smokers’ infants, one (7/15) controlled for race alone. Hence, at least part of the discrepancy in results between the two groups of studies may be explained by a lack of control of variables other than smoking. Another possible, at least partial, explanation of the discrepancy _ in results obtained by the two sets of studies is that cigarette smoke ~ may be more harmful to the fetuses of certain women than others. Several developing lines of evidence suggest that. this may be the case: 1. Cigarette smoking and socioeconomic background. Butler. et al. (15) noted that when data from the British Perinatal Mortality Study are grouped by social class of the mother’s husband, the late fetal plus neonatal mortality ratio for infants of smokers and nonsmokers in the upper social classes T and II is 1.10; the mortality ratio for the entire sample was 1.28. Rush and Kass (82) reviewed tho British Perinatal Mortality Study, along with several other studies, and noted that all have shown the strongest association between excess infant mortality and cigarette smoking among the infants of those 495-028 O—73——10 445 mothers with lower socioeconomic status. Comstock and Lundin (76) found excess mortality among smokers’ infants almost entirely con- fined to those whose fathers had a grammar school education or less. Several of the studies which revealed no significant difference in mor- tality among the infants of smokers and nonsmokers were conducted in predominately middle class populations (20, 100, 115). 2. Cigarette smoking and previous obstetrical experience. Peterson, et al. (72) had rigid criteria for entry into his study population of 7,740 women. He included only those women who pre- viously had healthy infants with a birth weight greater than 2,500 grams. He found a significant decrease in birth weight among smokers’ infants, but no significant increase in mortality rates. Rumeau- Roquette (87) found that among women who previously had delivered only healthy infants weighing more than 2,500 grams, cigarette smok- ing was not associated with an increased risk of stillbirth ; among those women with a previous stillbirth, smoking was significantly associated with increased risk of a future stillbirth. 3. Cigarette smoking and genetic differences. The consistent finding that the mortality risk for the infants of black smokers is higher than the risk for the infants of white smokers, even when the socioeconomic background for both is ostensibly similar, suggests that genetic factors also may interact with smoking to pro- duce enhanced risk (82, 99, 115). Available evidence suggests that if those women, who are already likely to have small infants for reasons other than smoking, smoke during pregnancy, their infants will be most unfavorably affected. This means that the women in the United States whose infants will be most affected by cigarette smoking are those who have an unfavor- able socioeconomic situation, have a history of previously unsuccessful pregnancies, and are black. EXvERIMENTAL STUDIES Studies in Animals Studies previously reviewed in the 1971 and 1972 reports on the health consequences of smoking (/01, 102) demonstrate that exposure of rabbits and rats to tobacco smoke and to injections of large doses of nicotine resulted in significantly increased late fetal and neonatal mortality. Astrup (2) has recently studied the effect of continuous exposure of pregnant rabbits to carbon monoxide on stillbirth rates. He found a significantly higher. dose-related incidence of stillbirths and deaths within the first 24 hours of life among the offspring of the experimental rabbits (table 4)- 446 TasLe 4.-Eyfect of carbon monoride erposure of pregnant rabbits on birth weight and neonatal mortality Group 1, Group 2, Group 3, O percent 8 to tO percent 16 to 18 percent COUb COlIb Colin Number of pregnant rabbits__.---.----- 17 14 17 Total number of babies_.......--------- 116 8k 123 Stillborn and babies died within first 24 hours____.__-___-------------+------ iy 78 144 (P<0.001) 11 percent. 110 percent. 136 percent. Bource: Astrup, P. (2). Studies in Humans Some investigators have examined the causes of death among the infants of smokers as compared with those of nonsmokers. Comstock, et.al. (77) found that infants of smokers died more frequently of as- phyxia, atelectasis, and immaturity. Kullander and Kallen (43) found abruptio placentae significantly increased as a cause of death among smokers’ infants. Butler and Alberman (74) found httle difference in the death rates for the infants of smokers and nonsmokers from iso- immunization and malformations, but higher rates were found for smokers’ infants in the groups in which death occurred before or dur- ing labor, or in which death resulted from massive pulmonary hemor- rhage, or pulmonary infection. As the authors noted, “The latter three are conditions known to be associated with small-for-dates babies.” They pointed out that distribution of causes of death in the smoking group could be accounted for almost entirely by the excess of low-birth-. weight babies. This supports the conclusion that the mechanism which affects birth weight also influences mortality. SIGNIFICANCE OF THE ASSOCIATION The following calculation is offered to give some idea of the order of magnitude of increased late fetal and neonatal mortality associated with cigarette smoking during pregnancy. If women who smoked dur- 447 ing pregnancy in the United States had an elevation in risk of 28 per- cent for late fetal and neonatal mortality. as demonstrated by Butler. et al. (15) for Britain, Scotland, and Wales, and if 20 percent of pregnant women smoked throughout the prernaney,' the higher risk of stillbirth and neonatal death for the infants of mothers who smoke cigarettes during pregnancy would account for approximately 4,600 of the 87,263 stillbirth and neonatal deaths in the United States in 1963. A Late Ferra, anp Neonata, Deatn Susr1ary strong, probably causal association between cigarette smoking and higher late fetal and infant mortality among smokers’ infants is supported by the following evidence: 1. Twelve retrospective and prospective studies have revealed a sta- tistically significant relationship between cigarette smoking and an elevated mortality risk among the infants of smokers. In three of these studies, of sufficient size to permit adjustment for other risk factors, a highly significant independent association between smokng and mortality was established. Part of the discrepancy in results between these studies and those in which a significant association between smoking and infant mortality was not dem- onstrated may be explained by a lack of adjustment for risk fac- tors other than smoking. - Evidence is converging to suggest that cigarette smoking may be more harmful to the infants of some women than others; this may also, in part, explain the discrepancies between the results of the studies in which a significantly higher mortality risk was shown for the infants of smokers compared to those of nonsmokers and the results of those studies in which significant differences in mortality risk were not found. - Within groups of similar birth weight, the infants of nonsmokers appear to have a higher mortality risk than do the infants of ciga- rette smokers. This results from the fact that the infants of non- smokers within such similar birth weight proups are on the average gestationally less mature than the infants of cigarette smokers. Available evidence indicates that within groups of sim- ilar gestational age, infants of lower birth weight experience a higher mortality risk. Since the infants of cigarette smokers are 2 Based on extrapolation of data on smoking behavior change during pregnancy from the British Pertnatal Mortality Study, which probably yields a conservative estimate. 448 small-for-gestational age, one should expect that if the infants of cigarette smokers and nonsmokers are compared within similar gestational age classes, the infants of cigarette smokers would have the higher mortality rate. The results of recent studies have documented a statistically sig- nificant dose-response relationship between the number or amount of cigarettes smoked and late fetal and neonatal mortality. New data suggest that if a woman gives up smoking by the fourth month of pregnancy, she will have the same risk of incurring & fetal or neonatal loss as a nonsmoker. Available evidence strongly supports cigarette smoking as one cause of fetal growth retardation. The causes of excess deaths among the infants of smokers are those associated with small- for-dates babies. Data from experiments in animals have demonstrated that expo- sure to tobacco smoke or some of its ingredients, such as nicotine or carbon monoxide, results in a significant increase in Jate fetal and or neonatal deaths. The results of studies in humans have shown that the fetus of a smoking mother may be directly exposed to agents such as carbon monoxide within tobacco smoke, at levels comparable to those which have been shown to produce stilJbirth in experimental animals. Sex Ratio Although a number of small studies have found a slight, usually statistically nonsignificant, increase in the proportion of female infants born to smokers, the three largest studies of Underwood, ct al. (48,505 pregnancies), Butler (15,791 pregnancies), and MacMahon (12,155 pregnancies) have found similar infant sex ratios among both smok- ing and nonsmoking mothers, with the expected slight excess of males among each (table 5). Summary Available evidence strongly indicates that maternal cigarette smok- ing dogs not influence the sex ratio of newborn infants. 449 Tasie 5.—Proportion of male infants delivered to smoking and non- smoking mothers Proportion of rosie infaots Author, reference Pregnancies ———--______—_ cputennes Smokers Nom smokers Underwood, et al. (100)__..---.-------- 48, 505 . 518 -519 None. Butler and Alberman (14)_.-__--------- 15, 791 . 518 . 516 Do. MacMahon, et al. (49)_._.-------------- 12, 155 . al3 ~al2 Do. Kulander and Kallen (43)__..--------- 6, 363 ~ 515 501 Do. Reinke and Henderson '(78)___--------- 3, 156 . 498 517 Do. Frazier, et al.' (26)-.....--------------- 2,915 - 472 - 505 Do. (P> 0.05) Kizer (42)._...----------------------- 2, 095 . 502 .493 None. Herriott, et al. (36)__------------------ 2,745 . 492 ~ 517 Do. Ravenholt, et al (77)_--.--------------- 2, 052 . 501 .533 P<0.05 Lowe (46)_._.------------------------ 2, 042 . 532 .529 None. Russell, et al. (83)__.__----------------- 2, G02 . 513 . 512 Do. ’ Black women. Congenital Malformations Previous epidemiological studies which examined the relationship between cigarette smoking and congenital malformations were re- viewed in the 1971 and 1972 reports on the health consequences of smoking (107, 102). Recently, the authors of the Ontario Perinatal Mortality Study (66, 67), a retrospective study of 51,490 births, re- ported no difference in malformation rate for the infants of smokers— and nonsmokers. The various studies of the association between ciga- rette smoking and congenital malformation have differed significantly with regard to study design, the type of population sampled, sample size and number of infants with malformations, the definition of mal- formation, and results (table 6). Previous experimental work was reviewed in the 1971 and 1972 reports on the health consequences of smoking (101, 102). The chick embryo has been employed in recent studies. The direct application of nicotine to the émbryo results in cephalic hematomas (26), malforma- tions of the cervical vertebrae (93), and anomalies of the heart (27), depending upon dose of nicotine and period of incubation in which exposure occurs. Anomalies of the limbs of chicken embryos can also be induced by exposure of the egg to high Jevels of carbon monox- ide (4). 450 Tas_e 6.—Relative risk of congenital malformation for infants of cigarette smokers and nonsmokers, comparing available studies with regard to study design, study population, sample size, number of infants unth malformations, and definition of malformation Infants Relative Author, Study design Study population Sample with risk Definition of reference size moalfor- SMjNS malformations mations Lowe (46). ...---- Retrospective. Stillborn plus 24-hour 2, 2 2 1.34 Major. deaths. Comstock, et al. ._--- do......2-- Neonatal deaths_..-.-_ 236 37 31) Major, cause of (17). death. Yerushalmy (172). Prospective... Infants less than 695 59 .67 Mafor. 2,500 g. Ontario Depart- Retruspective. Stillbom plus Ist- 51, 490 1, 744 .97 ment of Health week deaths plus (67). surviving infants. Butlersnd Al- 9 ____. do___....-. Stlborn plus neo- 7,123 1,382 1.19 Major, cause of berman (/4). natal deaths. death. {a) Stillborn plus neo- 137 43 1.25 natal deaths plus remainder of desths to ago 1. (b) Surviving infants 4,903 700 1.06 to age l. (a) 1 Etitborn plus 17,418 86 1.55 @). neonatal deaths & and desths to age 7,! sur- vivors ? to age 7. (b) Neonatal deaths ! 7, 822 204 1.07) @). {3-moath study). Major and minor malformations. EKoullander and Prospective. __ Estien (43). Fedrtck, et al. Retrospective. (24). * Aulopsy-proven congenital cardiac malformation. *Ctinically determined congenital heart disease. Congenital Malformation Summary Given the considerable variation in study design, study population, sample size, number of affected infants, definition of malformation, and results, no conclusions can be drawn about any relationship between maternal cigarette smoking and congenital malformation at the present time. 451 Lactation Introduction The following section is a review of available evidence which bears upon any interaction between cigarette smoking and lactation. Empha- sis is placed upon the relationship of cigarette smoking to the quantity of milk produced, to the presence of constituents of cigarette smoke within the milk, and to effects upon the nursing infant mediated through changes in either the quantity of milk available or the sub- stances within the milk. Epidemiological Studies Underwood, et al. (99), in a study of 2,000 women from various social and economic strata, observed a definite but statistically insig- nificant trend toward more frequent inadequacy of breast milk pro- duction among those smoking mothers who attempted to nurse compared to nonsmokers. Mills (52), in a study of 520 women. found that among women who indicated either a desire to nurse or no desire to nurse yet continued to nurse beyond 10 days, and who had delivered their first live-born infant, the average period of nursing for mothers who smoked was significantly shorter than for nonsmokers. Moreover, among the 24 mothers who had given up smoking during at least the final 3 months of their pregnancies, the average length of nursing was identical to that of the nonsmokers. There was no significant difference between smokers and nonsmokers with regard to complete inability to nurse their offspring. This study is difficult to interpret because the author did not determine the reason(s) for the discontinuation of nursing among the women. Experimental Studies Sropis iN ANIMALS Nicotine Influence on the Lactation Process ; Blake and Sawyer (11) studied the influence of subcutaneously injected nicotine (4 mg. total over a 5-minute period) upon lactation in the rat. They found that nicotine inhibited the suckling-induced 452 rise in prolactin. No effect of injected nicotine was demonstrated for oxytocin secretion since milk release was not. blocked. Wilson (210) examined the effects of nicotine supplied through drinking water (0.5, 1.0. and 2.0 mg. daily) on the weight gain of nursing rats. Apparently, the nicotine had been available throughout gestation as well, because the author commented on a reduction in litter size among the experimental groups, more or less proportionate to the dose of nicotine; hence, a prenatal effect could not. have been dis- tinguished froma postnatal one. Average birth weight was similar for experimental and control groups. No difference in weight gain was seen for any of the groups. The lack of impact on birth weight suggests that dose was lower than that used in other studies. Presence of Nicotine in the Milk Hatcher and Crosby (32), using a frog bioassay, reported traces of nicotine in cow's milk 24 hours after the intramuscular injection of 5.0 mg./kg. and 5 hours after the injection of 0.5 mg./kg- Evidence for an Effect Upon the Nursing Offspring Hatcher and Crosby (32). found that 0.5 mg./kg. nicotine injected into nursing cats had no apparent harmful effect upon the kittens. Apparently 4.0 mg./kg. suppressed lactation. Kittens fed the milk from the cow which had been injected with 5.0 mg./kg. nicotine were also apparently unaffected. Nitrosamines Mohr (53) found that diethyInitrosamine and dibuty]Initrosamine, when administered to lactating hamsters, were associated with the development of typical tracheal papillary tumors in the young, sug- gesting passage of these compounds in‘the milk. Although diethyl- nitrosamine and dibutyInitrosamine have not been identified in ciga- rette smoke, many N-nitrosamines are potent carcinogens, and some of them are present in cigarette smoke (37, 79). Sropres In Hustans Nicotine and/or Tobacco Smoke Influence on the Lactation Process Emanuel (22) noted no reduction in milk production among 10 wet nurses who were encouraged to smoke seven to 15 cigarettes daily; 453 some were observed to inhale the smoke. Hatcher and Crosby (32) noted that after a mother smoked seven cigarettes within 2 hours, it was difficult to obtain a specimen of breast milk. Perlman, et al. (77) found that of 55 women smokers with an adequate milk supply at the beginning of his study, 11 (20 percent) of the women had an inade- quate supply at the time of discharge from the hospital. No relation- ship was reported between the number of cigarettes smoked and the likelihood of developing an inadequate milk supply. The authors’ im- pression was that there was no greater proportion with an inadequate milk supply among smokers than among nonsmokers, but no cor- roborating data were supplied. Presence of Nicotine in the Milk Hatcher and Crosby (32) found, using a frog bioassay, that the milk of a woman collected after she had smoked seven cigarettes in 2 hours contained approximately 0.6 mg./liter nicotine. Emanuel (22), using a leech bioassay, studied excretion of nicotine in the milk of wet nurses who were encouraged to smoke for the experiment. After the subjects had smoked six to 15 cigarettes over a 1- to 2-hour period, the author found nicotine in their milk 4 to 5 hours after smoking, with a maximum concentration of 0.03 mg./liter. Bisdom (10) demonstrated nicotine in the milk of a mother who smoked 20 cigarettes a day. Thompson (97) found approximately 0.1 mg./liter of nicotine in the milk of a mother who smoked nine cigarettes a day (plus three pipe- fuls). Perlman, et al. (7/), using a Daphnia bioassay, demonstrated nicotine in the milk of all women who smoked in their study. Moreover, they found a direct dose-relationship between concentration of nicotine and the number of cigarettes smoked. No comment is made by the authors on the possible inaccuracy introduced by examining only the residual milk following nursing, but it is well known that the composi- tion of the fore milk and hind milk is different and perhaps the concentration of nicotine also differs. Evidence for a Clinical Effect Upon the Offspring Emanuel (22) noted that among the infants in his study, loose stools were observed only in the one whose wet nurse had smoked 20 ciga- rettes in the previous 4 hours. Bisdom (10) observed a case of “nico- tine poisoning” in a 6-week-old infant whose mother smoked 20 ciga- rettes a day. The symptoms included : restlessness, vomiting, diarrhea, and tachycardia. Nicotine was demonstrated in the milk, and the symptoms abated when smoking was stopped. Greiner (30) also de- scribed a case of possible nicotine poisoning in a 3-week-old nursling 454 whose mother smoked 35 to 40 cigarettes a day. The symptoms included yomiting and loose stools. Following the curtailment of smoking, the symptoms gradually abated over a 3-day period. Perlman, et al. (77) noted no effect of smoking on the weight vain of the infants of the smokers In their study. Furthermore, no untoward symptoms were observed. They therefore doubted an effect of smoking on Jactation. They noted that the dose received by the infants was beneath the toxic level as computed from adult experience. and this accorded with their clinical observations. The fact that they admitted to the study only women with an apparently adequate milk supply may have affected their results. The authors suggested that perhaps the lack of effect of smoking upon lactation might represent the development of tolerance to nicotine, as both the mother and the offspring had been exposed throughout the pregnancy. VITAMIN C Venulet (105, 106, 107), in a series of studies, demonstrated that the level of vitamin C was reduced in the milk of smoking mothers as compared with nonsmokers. The clinical significance of this observa- tion has not been evaluated. Lactation Summary 1. The two pertinent epidemiological studies suggest a possible in- fluence of smoking upon the adequacy of milk supply However, with only Hmited numbers of women and without control of other potentially significant variables, no conclusions can be drawn. 2. Studies in rats have demonstrated that nicotine ean interfere with suckling-induced rise in prolactin. The relevance for humans is uncertain. 3. Evidence exists that nicotine passes into breast milk. No clear evidence for an acute effect upon the nursing infant is available. Potential chronic effects have not been studied. 4. New evidence from experiments with mice suggests that nitros- antines, known carcinogens, pass through the milk to suckling youn. 455 Preeclampsia Previous epidemiological studies of the relationship between cig- arette smoking and preeclampsia were reviewed in the 1971 and 1972 reports on the health consequences of smoking (/01, 102) and form the basis of the following statements: The results of several large prospective and retrospective studies indicate a statistically significant lower incidence of preeclampsia among smoking women (14, 43, 100). The results of one large retro- spective study demonstrated a significant inverse relationship between the incidence of preeclampsia and the number of cigarettes smoked (100). When other risk factors, such as parity, social class, maternal weight before the pregnancy, and maternal weight gain during the pregnancy were controlled, smoking women retained a significantly decreased risk of preeclampsia (2/). The lower risk of preeclampsia for cigarette smoking women has been demonstrated in Britain and Scotland (14, 21, 46. 83), The United States (100, 118), Venezuela (42), and Sweden (43). If a maternal smoker does develop preeclamp- sia, however, available data suggest that her infant has a higher mor- tality risk than does the infant of a nonsmoker with preeclampsia (21, 83). Summary 1. Available evidence indicates that maternal cigarette smokers have a significantly lower risk of developing preeclampsia as compared to nonsmokers. 9. If a woman who smokes cigarettes during pregnancy does develop preeclampsia, her infant has a higher mortality risk than the infant of anonsmoker with preeclampsia. Pregnancy References (1) ApennarHy, J. R., Gseensess, B. G., Werrs, H. B., FRAZIER, T. M. Smoking as an independent variable in a multiple regression analysis upon birth weight and gestation. American Journal of Public Health and the Nation’s Health 56(4) : 626-633, April 1966. (2) Asrrup, P. 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Obstetrics and Gynecology 21(4) 1405-411, April 1963. 463 Chapter 6 Peptic Ulcer Disease Source: 1973 Report, Chapter 5, pages 151 - 164. 465 Contents Page Introduction__._. 22222-2222 469 Epidemiological and Clinical Studies_..._.._._.__..__..___. 469 Experimental Studies Gastric Secretion...___.. 2.2222 471 Pancreatic Secretion___._.- 2.222 473 Summary of Recent Peptic Ulcer Disease Findings. _________ 476 References... _.-----2- 2-2 477 List of Figures Figure 1.—Gastric ulcer mortality ratios of Japanese (men and women combined) by age at initiation of cigarette smoking (1966-70)___ ee 470 Figure 2.—Effect of cigarette smoking on volume of secretin- stimulated pancreatic secretion in humans___...__________ 474 Figure 3.—Effect of cigarette smoking on secretin-stimulated pancreatic bicarbonate output in humans________.._______ 475 467 Introduction Previous epidemiological and expermmental studies of the relation- ship between cigarette smoking and peptic ulcer disease were reviewed in the 1971 and 1972 reports on the health consequences of smoking (17, 18) and form the basis of the following summary : The results of epidemiological studies indicate that cigarette smok- ing males have an increased prevalence of peptic ulcer disease and a ereater mortality from peptic ulcer as compared to nonsmoking males. Among males, the association between cigarette smoking and peptic ulcer disease is stronger for gastric than for duodenal ulcer, but sig- nificant for both. For males, cigarette smoking appears to reduce the effectiveness of standard peptic ulcer treatment and to slow the rate of peptic ulcer healing. The relationship between cigarette smoking and the prevalence of and mortality from peptic ulcer disease is less clear for females than for males. Experimental studies of the effect of cigarette smoking in man, and of the effect of injection and infusion of nicotine in animals, on gastric secretion and motility have produced conflicting results. In dogs, an infusion of nicotine has been found to inhibit pancreatic and hepatic bicarbonate secretion, thus demonstrating a possible link between cigarette smoking and duodenal ulcer. Recently, additional epidemiological, clinical, autopsy, and experi- mental studies have confirmed the association between cigarette smok- ing and gastric ulcer mortality and have clarified a mechanism through which cigarette smoking might be linked to duodenal ulcer. Epidemiological and Clinical Studies Previous studies of the relationship between peptic ulcer disease and cigarette smoking have been conducted in predominantly white, West- erm populations. A large prospective epidemiological study is currently being conducted in Japan. From this study, Hirayama (6) reported 5-vear followup data on 265,118 men and women, aged 40 years and older, representing 91 to 99 percent of the total population in the area of the 29 health districts in which the study was conducted. Both male 469 and female cigarette smokers experienced higher death rates from gastric ulcer as compared with nonsmokers. The mortality ratio for cigarette smokers was 1.81 for males (P<0.001) and 2.15 for females (P<0.05). The mortality ratio for smokers (males and females com- bined) was dose-dependent as measured by age at initiation of smoking (fig. 1). The results of this study, in the context of the genetic and cul- tural differences between Japanese and Western populations, provide a significant confirmation of the association between cigarette smoking and gastric ulcer mortality. Figure 1.—Gastric ulcer mortality ratios of Japanese (men and women combined) by age at initiation of cigarette smoking (1966-1970). Fao | 1.59 ee Y wot 2 MA VA AAA 2 Nonsmoker >25 24 <1g9 Age at initiatlon of cigarette smoking (years) SOURCE: Hirayama, T. (6). 470 Alp, et al. (7) conducted a retrospective survey of 638 patients, admitted to two -Lustralian teaching hospitals between 1954 and 1963, with chronic gastric ulcer confirmed by roentgenographic, endoscopic, or surgical examination. The findings in the patients were compared with information available about the South Australian population obtained at census in 1954 and 1961, and with a control group of 233 subjects matched for age and sex with the ulcer patients. Cigarette use, a family history of peptic ulcer, domestic stress, and aspirin and alcohol intake occurred significantly more frequently among ulcer patients. Alp, et al. (2) found that after surgical treatment, recurrence of the ulcer was significantly more likely to recur among those patients who continued to smoke, drink, and use aspirin (P<0.001). Fingerland, et al. (5) compared the autopsy findings from 765 males with their smoking history. The autopsies were performed without selection during 1965 and 1966 at the University of Hradec Kralové, Czechoslovakia. Peptic ulcer was significantly more frequent among male ex-smokers and male lifelong smokers than among male non- smokers (P<0.02). Among males, a dose-response relationship was found between estimated total cigarette consumption and the presence of peptic ulcer at autopsy. Cooper and Tolins (4) reported results from a retrospective study of the relationship between cigarette smoking and postoperative com- plications among 2,988 males, admitted to 19 Veterans Administration hospitals, for the surgical treatment of duodenal ulcer. Smoking his- tory was obtained for 1,441 of the men, and of these 273 were non- smokers, 1,018 smoked cigarettes only, and 93 smoked cigarettes plus a pipe and/or cigars. The authors found no evidence of an association between either the number of cigarettes smoked per day, or the number of years of cigarette smoking, and postoperative complications, opera- tive mortality, or length of hospital stay. They emphasized that their results must be viewed with considerable caution and listed several potential sources of bias. In addition, they noted, “* * * that these results apply only to the immediate postoperative findings and do not apply to the long-range effects of smoking upon the patient after surgery for duodenal ulcer disease.” Experimental Studies Gastric Secretion Srcpres is Homans Morales, et al. (10, 11) studied the effect of cigarette smoking on gastric secretion in a group of 312 patients. The patients included 138 471 with duodenal ulcer, 93 with gastric ulcer, and 81 with other gastro- intestinal disorders, who served as controls. Cigarette smoking was significantly more frequent among the patients with peptic ulcer than among the controls. The chronic effect of smoking on gastric secretion was quite variable. Male smokers among the controls and in the group with duodenal ulcers had a significantly increased baseline acid output as compared with nonsmokers in the same groups (P<0.05). After a subcutaneous injection of histamine, only the group of male smokers with gastric ulcers had a significant increase in acid output over the values obtained for nonsmokers in the same group (P<0.05). Among the smokers in the control group, the relationship between gastric acid output and the number of cigarettes smoked daily was dose dependent. No such rela- tionship was obtained for either of the two groups with peptic ulcers. In these experiments, the acute effect of smoking on gastric secre- tion was slight. In one set of experiments, a group of eight smokers served as its own control. The smoking of two cigarettes prior to collection of gastric juice had no significant effect on acid output as compared to baseline values. After smoking two cigarettes and also receiving a subcutaneous injection of histamine, the patients experi- enced no significant change in gastric acid output as compared to baseline values; 21 male patients, including members from the groups with ulcers and controls, smoked one cigarette 1 hour after an intra- venous infusion of histamine. A transient depression of gastric acid output was noted as compared with the values obtained from nine patients who did not smoke. Srupies 1n Animas Konturek, et al. (8) studied the effect of intravenous infusion of nicotine on the formation of acute, experimental duodenal ulcers in cats. The authors infused nicotine intravenously in doses comparable to the smoking of four, eight, and 16 cigarettes per hour into cats in whom near maximal gastric acid output had been stimulated with intravenous pentagastrin. The investigators found that nicotine in the two lower doses had no effect upon the gastric acid output stimulated by pentagastrin, but that the highest dose produced a significant de- crease in response, due to a fall in both volume and acid concentration. Nicotine alone failed to alter a negligible basal gastric secretion. In control animals (pentagastrin alone), duodenal ulcers were found in eight of 10 animals. Nicotine at the two lower doses, in combination with pentagastrin, produced ulcers in all 26 animals. At the inter- mediate dose of nicotine, the mean ulcer area was twice that found in 472 the control group. At the highest dose of nicotine. peptic wleers ap- peared in only two of six animals and the area of ulcer was reduced compared to controls. Shaikh, et al. (74) studied the acute and chronic effects of sub- cutaneously injected nicotine on gastric secretion in rats. Under basal conditions, the volume of gastric secretion was initially depressed, then stimulated, and depressed again as the dose of nicotine was increased. Acid output was decreased over the entire range of nicotine dosage. Pepsin output reflected a similar triphasic response to in- creasing nicotine doses as did gastric secretory volume. In the absence of nicotine, pentagastrin stimulated gastric volume, acid, and pepsin output. The injection of nicotine, in increasing doses, administered simultaneously with pentagastrin, resulted in a gradual decrease in response for all parameters. Volume of gastric juice, acid output, and pepsin output were all increased significantly by chronic exposure to nicotine alone. Based on an average smoking dose of nicotine, the dose of nicotine employed in the chronic experiments corresponded to the smoking of three to five cigarettes per day. Thompson, et al. (76) extended the study of rats described above by studying the effects of chronic nicotine injections in vagotomized rats and rats with discrete lesions in the hypothalamus. In sham- operated animals, chronic nicotine injections significantly increased baseline volume of gastric juice, acid output, and pepsin output. Fol- lowing vagotomy, the nicotine response was completely suppressed. Caudal hypothalamic lesions did not influence the response to nicotine in the presence of intact vagus nerves. Anterior hypothalamic lesions, ranging from the anterior hypothalamic area to the ventromedial hypothalamus, blocked the nicotine-induced gastric secretory stimula- tion in the presence of intact vagi. The authors concluded that chronic nicotine-induced gastric secretory stimulation is mediated via anterior hypothalamic activation and intact vagus nerves. ‘The importance of local effects remained uncertain. Pancreatic Secretion Srupres 1x HuMANS Bynum, et al. (3) studied the effect of cigarette smoking upon pan- creatic secretion in 23 healthy young males and females. Five control male nonsmokers were compared with seven male and two female light smokers (less than one pack of cigarettes per day for less than 3 years) and eight male and one female heavy smokers (more than one pack of 473 cigarettes per day for more than 3 years). Pancreatic secretion was measured by the double secretin test, using Boots secretin. The experi- ment was divided into two parts for the smokers: A basal collection period and an experimental period during which the subjects smoked seven nonfiltered cigarettes at the rate of four per hour. Light smokers had basal values for pancreatic secretory yolume and bicarbonate out- put in response to secretin which were not significantly different from controls. After the subjects had smoked, significant depression of both pancreatic volume and bicarbonate output was noted (P<.001). Heavy smokers had basal values that were significantly less than in the control subjects (P<0.01). Smoking, however, did not further depress the response to secretin (figs. 2 and 3). Solomon and Jacobsen (15) reviewed some possible mechanisms whereby the increased prevalence and mortality from duodenal ulcer among cigarette smokers might be produced. They concluded that evidence from studies in animals, coupled with the findings of Bynum, et al. (3), supported the hypothesis that the mechanism active in humans involves impaired neutralization of acid secondary to the inhibition of pancreatic bicarbonate secretion. Figure 2.-—Effect of cigarette smoking on volume of secretin-stimulated pancre- atic secretion in humans. 3.0 a 2.4 Mean volume 2.5 of 1.9° 2.0 pancreatic 2.0 fluid in 1.5% milliliters 1.5 per kilogram body weight 1.0 0.5 ° % 2 ¢ 2 2 Cc wo Qo £3 eS PS Po £5 E = SX E 3 E os £ s — “5 Zee Eo zeu E? 50 at or ne an > =z aD bo a s a a x Zz 1 Significantly different from nonsmoking test within group of light smokers (P <0.001). * Significantly different from nonsmoking controls (P <90.01). SOURCE: Bynum, et al. (3). 474 Figure 3.—Effect of cigarette smoking on secretin-stimulated pancreatic bicar- bonate output in humans. 12 11.5 10 8.4 8.1 Mean hourly 8 7.1? output of ————_ 6 5.5% miltiequiva- 4 lents per hour 2 O I bo 2 2 ¥ ad Cou o o o oa Se PS BS mS 2S Ea SEZE =% E ez t& Ze e8 226 84 229 288 9° we a= A> ae = B&B mo a S | a r x 1 Significantly different from nonsmoking test within group of light smokers (P_ <0.001). 1 Significantly different from nonsmoking controls (P <0.01). SOURCE: Bynum, et al. (3). Srupres IN ANIMALS Konturek, et al. (7) extended his research on the mechanism of nicotine-induced inhibition of pancreatic secretion in the dog, using the design previously employed (9). Infused secretin alone led to a sustained increase in pancreatic bicarbonate output. Intravenous nico- tine, at all four doses of infused secretin, produced a significant in- hibition of pancreatic volume and bicarbonate output (P<0.05). Infused nicotine appeared to inhibit competitively the effect of secre- tin on pancreatic secretion of fluid and bicarbonate. Topical (intraduo- denal) nicotine failed to affect significantly the response to infused secretin. Stimulation of endogenous secretin by an acid infusion into the duodenum produced the expected pancreatic secretory response. Nicotine either applied to the duodenal mucosa or injected intra- venously significantly inhibited the pancreatic secretory response to endogenous secretin. Nicotine had no significant effect on total pancrea- tic protein output. Nicotine did not alter the cholecystokinin-induced stimulation of pancreatic secretion. The authors concluded that nico- tine may inhibit pancreatic secretion of fluid and bicarbonate both 475 hy by a direct effect on pancreatic secretory mechanisms, acting as a com- petitive inhibitor of secretin, and by a secondary effect on the duodenal mucosa, depressing the endogenous release of secretin by acid. . Robert (/2) studied the potentiation of active duodenal ulcers by nicotine administration in the rat. Subcutaneous infusion of pentagas- trin and carbachol resulted in the dose-dependent formation of duo- denal ulcers within 24 hours. Nicotine alone produced no ulcers. Increasing doses of subcutaneously infused nicotine, in combination with the other two agents, resulted in a steadily increasing dose-related incidence and severity of the duodenal ulcers. Robert noted that Konturek, et al. (9) found that nicotine inhibited pancreatic and biliary bicarbonate secretion in dogs, and that Thompson, et al. (Z6) found that acute doses of nicotine in rats either depressed or did not alter gastric secretion. He concluded that the most probable mechanism by which nicotine potentiated acute duodenal ulcer formation in the rat was via a Suppression of pancreatic secretion. Robert, et al. (23) further tested this hypothesis by infusing acid via the esophagus of rats in doses found to cause duodenal ulcers in one-third of the experimental animals. One group of rats also received a subcutaneous infusion of nicotine. Another received nicotine, but. only water was infused via the esophagus; 31 percent of the animals receiving acid but no nicotine had duodenal ulcers; 93 percent of the nicotine-acid group had duodenal ulcers, while none of the nicotine- water group had ulcers. The ulcers in the nicotine-acid group were more numerous, extensive, and deeper than those in the animals which received acid alone. Summary of Recent Peptic Ulcer Disease Findings In addition to the findings relating cigarette smoking to peptic ulcer dlisease, summarized in previous reports on the health consequences of smoking (17, 78) and cited in the introduction to this chapter, recent studies have contributed further to our understanding of the association : 1. The finding of a significant dose-related excess mortality from gastric ulcers among both male and female Japanese cigarette smnokers, in a large prospective study, and in the context of the genetic and cultural differences between the Japanese and pre- viously investigated Western populations, confirms and extends the association between cigarette smoking and gastric ulcer mortality. 476 2. Data from experiments in several different animal species sug- gest that nicotine potentiates acute duodenal ulcer formation by means of inhibition of pancreatic bicarbonate output. Cigarette smoking has been demonstrated to inhibit pancreatic bicarbonate secretion in healthy young men and women. % Peptic Ulcer Disease References (1) Ace, M. H., Hiszrop, I. G., Grant, A. K. Gastric ulcer in South Australla, 1954-63. L. Epidemfological factors, Medical Journal of Australia 2(24): 1128-1132, Dec. 12, 1970. (2) Aur, M. H., Hiscop, I. G., Grant, A. K, Gastric ulcer in South Australia, 1954-63. 2. Symptomatology and response to treatment, Medical Journal of Australia 1(7) : 372-374, Feb. 13, 1971. (3) Brynux, T. E., SoLomon, T. E., Jounson, L. R., Jacosson, FE. D. Inhibition of pancreatic secretion in man by cigarette smoking. Gut 13(5) : 361-365, May 1972. (4) Coores, P., Totins, S. H. Relationship between smoking history and compl- cations immediately following surgery for duodenal ulcer. Mount Sinai Journal of Medicine 39(3) : 287-292, May—June 1972. (3) Fexcrerianp, A., Husak, T., BenpLova, J. Contribution to the investigation of the effect of cigarette smoking. Sbornik Vedeckych Praci Lekarske Fakulty Karlovy University v Hradcit Krélové 14(2) : 221-234, 1971. (6) Hrrayvama, T. Smoking in relation to the death rates of 265,118 men and women in Japan. A report of 5 years of followup, Presented at the Amer- ican Cancer Society’s l4th Science Writers’ Seminar, Clearwater Beach, Fia., Mar. 27, 1972, 15 pp. {7} Kontures, 8. J., Dare, J., Jaconson, E, D., Jounson, lL. R. Mechanisms of nicotine-induced inhibition of pancreatic secretion of bicarbonate in the dog. Gastroenterology 62(3) : 425-429, 1872. (8) Kontousnex, S. J, Rapecus, T., THos, P., Dempinsxy, A., Jacosson, B.D. Effects of nicotine on gastric secretion and ulcer formation in cats. Pro- ceedings of the Society for Experimental Biology and Medicine 138(2): 674-674, November 1971. (9) Kostrurex, 8. J., Soromon, T. E.. McCerront, W. G., Jonnson, L. B, Jacosson, E. D. Effects of nicotine on gastrointestinal secretions. Gastro- enteroclogy 60(6) : 1098-1105, June 1971. (10) Monares, A., Suva, S., Atcarpe, J., WAISSBLUTH, J., Ramos, J., Bey, ., Sanz, R. Cigarrillo y secrecion gastrica. I. Analisis de la secrecl6n- gdstrica en pacientes digestivos fumudores y no fumadores. (Cigarettes and gastric secretion, I. Analysis of gastric secretion in smoking and non- smoking ulcer patients.) Revista Medica de Chile 990(4) : 271-274, April 1971. (11) Mozares, A, Sriva, S., Osonio, G., ALcaLpy, J, WatsssLutn, J. Cigarrillo y secrecion gastrica. II. Efecto del cigarriilo sobre la secreci6n g&strica. (Cigarettes and gastric secretion. II. Effect of cigarettes on gastric secre tion.) Revista Medica de Chile 99(4) : 275-279, April 1971. 495-028 O -73—__12 477 (35) (14) (15) (16) (17) (78) 478 Roseat, A. Potentiation, by nicotine, of duodenal ulcers in the rat. Pro- ceedings of the Society for Experimental Biology and Medicine 139 1): 319-322, January 1972. Ropert, A., Stowe, D. F., Nezamis, J. E. Possible relationship between smoking and peptic ulcer. Nature 233 (5320) : 497-498, Oct. 15, 1971. SHAIKH, M. 1, THompson, J. H., Aures, D, Acute and chronic effects of nicotine on rat gastric secretion. Proceedings of the Western Pharma- ecology Society 13: 178-184, 1970. SoLtowon, T. E., Jacosson, E. D. Cigarette smoking and duodenal-ulcer dis- ease. New England Journal of Medicine 286(22) : 1212-1213, June 1, 1972. Trowrson, J. H., Georce, R., ANGULO, M. Some effects of nicotine on gastric secretion in rats. Proceedings of the Western Pharmacology Society 14:173-177, 1971. U.S. Punric HEALTH SEgvice, The Health Consequences of Smoking. A Re- port of the Surgeon General : 1971. U.S. Department of Health, Education, apd Welfare. Washington, DHEW Publication No. (HSM) 71-7513, 1971, 458 pp. U.S. Poesric Heatrn Service. The Health Consequences of Smoking. A Report of the Surgeon General : 1972. U.S, Department of Health, Educa- tion, and Welfare. Washington, DHEW Publication No. (HSM) 72-6516, 1972, 158 pp. Chapter 7 Involuntary Smoking Source: 1975 Report, Chapter 4, pages 83-112. 479 Contents Page Introduction ....000..0-2 00002 483 Constituents of Tobacco Smoke .......-----+- eee eters 484 Carbon Monoxide .....0.-00 02 c eee 486 Nicotine .. 2... eee 493 Other Substances .. 0... 2.62 eee eee eee 494 Effects of Exposure to Cigarette Smoke -......-.--0-+---+-22055- 494 Cardiovascular Effects of Involuntary Smoking .....--------- 494 Effects of Carbon Monoxide on Psychomotor Tests ....------- 495 Pathologic Effects of Exposure to Cigarette Smoke .......----. 495 Summary of Involuntary Smoking Findings ........--------+++-- 504 Bibliography .....-..--.-202 020 tteeeee 505 481 List of Tables Table 1.—-Comparison of mainstream and sidestream cigarette smoke ...... we ee eee eee eee 485 Table 2.-Measurements of constituents released by the combustion of tobacco products in various situations Table 3.—Median percent carboxyhemoglobin (COHb) saturation and 90 percent range for nonsmoker by location 2.2.2... eee 492 Table 4.—Effects of carbon monoxide on psychomotor functions 2.2.0... 00 000.0. cee eee eee ene Lee 496-497 Table 5.—Admission rates (per 100 infants) by diagnosis, birth weight, and maternal smoking 2.20... 0.0.0. 0.2 ee te eee 500 Table 6.—Pneumonia and bronchitis in the first S years of life by parents’ smoking habit and morning phlegm .... 2.0.2.0... 00000 eee eee eee 502 482 INTRODUCTION The effects of smoking on the smoker have been extensively studied, but the effects of tobacco smoke on nonsmokers have received much less attention. The 1972 Health Consequences of Smoking (49) reviewed the effects of public exposure to the air pollution resulting from tobacco smoke. This exposure has been called “passive smoking” by many authors, but will be referred to in this report as “Involuntary Smoking.” The term involuntary smoking will be used to mean the inhalation of tobacco combustion products from smoke-filled atmospheres by the nonsmoker. This type of exposure is, in a sense, “smoking” because it provides exposure to many of the same constituents of tobacco smoke that voluntary smokers experience. It is also “involuntary” because the exposure occurs as an unavoidable consequence of breathing in a smoke-filled environment. The chemical constituents found in an atmosphere filled with tobacco smoke are derived from two sources — mainstream and sidestream smoke. Mainstream smoke emerges from the tobacco product after being drawn through the tobacco during puffing. Sidestream smoke rises from the buming cone of tobacco. Main- stream and sidestream smoke contribute different concentrations of many substances to the atmosphere for several reasons: Different amounts of tobacco are consumed in the production of mainstream and sidestream smoke; the temperature of combustion differs for tobacco during puffing or while smouldering; and certain substances are partially absorbed from the mainstream smoke by the smoker. The amount of a substance absorbed by the smoker depends on the characteristics of the substance and the depth of inhalation by the smoker. As discussed in the 1972 Report, when the smoker does not inhale the smoke into his lungs, the smoke he exhales contains less than half its original amount of water-soluble volatile compounds, four-fifths of the orginal: nonwatersoluble compounds and particulate matter, and almost all of the carbon monoxide (/5). When the smoker inhales the mainstream smoke, he exhales into the= atmosphere less than one-seventh of the amount of volatile and particulate substances that were originally present in the smoke and also reduces the exhaled CO to less than half its original concentra- tion (J6). As a result, different concentrations of substances are found in exhaled mainstream smoke depending on the tobacco product, composition of the tobacco, and degree of inhalation by the smoker. 483 Several minor symptoms (conjunctival irritation, dry throat. etc.) are caused by levels of cigarette smoke encountered in everyday life, and serious allergic-like reactions to cigarette smoke may occur in some sensitive individuals. A major concern, however, about atmospheric contamination by cigarette smoke has been due to the production of significant levels of carbon monoxide. Cigarette smoking in poorly ventilated enclosed spaces may generate carbon monoxide levels above the acceptable 8-hour industrial exposure limits (SO ppm) — set by the American Conference of Govemment Industrial Hygienists (/). Exposure to this level of carbon monoxide even for short periods of time has been shown to reduce significantly the exercise tolerance of some persons with symptomatic cardio- vascular disease. There is also some evidence that prolonged exposure to this level of carbon monoxide in combination with a high cholesterol diet can enhance experimental atherosclerosis in animals (Chapter |, Cardiovascular Diseases). In the present chapter, the effects of cigarette smoke on the environment and on the nonsmoker in that environment will be examined by reviewing data on (1) the constituents of cigarette smoke measured under various conditions, and (2) the physiologic effects of this “‘involuntary smoking” on individuals. CONSTITUENTS OF TOBACCO SMOKE In a recent workshop on the effects of environmental tobacco smoke on the nonsmoker (4/), Corn (/4) presented a compilation adapted from Hoegg (32) of some of the substances in mainstream cigarette smoke and the ratio of sidestream to mainstream levels for some of these substances (Table 1). The actual numerical value of the sidestream to mainstream concentration ratio will vary with different types of tobacco tested, but Table | gives values generally consistent with those found by others (34, 42). Many of these substances including nicotine and carbon monoxide are found in much higher concentrations in sidestream smoke than in mainstream smoke, establishing that the smoke exposure received by both the smoker and nonsmoker due to breathing in a smoke-filled environment differs qualitatively as well as quantitatively from the smoke exposure received by the smoker who inhales through a lighted cigarette. A more comprehensive recent review of the constituents of mainstream and sidestream smoke has also been provided by Schmeltz, et al. (42) and Johnson, et al. (34). 484 S8y TABLE 1. — Comparison of mainstream and sidestream cigarette smoke!* Ratio Compound Mainstream Sidestream Sidestream/ Comment (mg/cig) (mg/cig) Mainstream A General characteristics Duration of smoke production 20 see S81) sec 27 Tobaceo burnt 347 411 1.2 Particulates, no. per cigarette 1.05 X Jol? 3.5 x 10!? 33 B Particulate phase 2Tar (chloroform extract) 20.8 44.1 2.1 10.2 34.5 3.4 Filter cigarette Nicotine 0.92 1.69 1.8 0.46 1.27 2.8 Filter cigarette Benzo(a)pyrene 3.5 xX 105 13.5 x 1075 37 Pyrene 13x 1075 39 x 1075 3.0 Total phenols ‘ 0.228 0.603 2.6 Cadinium 12.5 x 1078 45 x 1075 3.6 Cc Gases and vapors Water 7.5 298 39.7 3.5 mg of Mainstream and 5.5 my of Sidestreany in particulate phase, rest in vapor phase Ammonia 0.16 7.4 46 Carbon mondyide 31.4 148 4.7 Carbon dioxide 63.5 79,5 1.3 Oxides of Nitrogen 0.014 0.051 3.6 ‘ Adupted from Hoegg, UR. (31, 32). 2 Wor 3s mil puff volume, 2 sec puff dur ation, one puff per minute and 23 or 30 mm butt length and 10 percent tobacco moisture, Source: Corn, M. (14), A number of other researchers have attempted to measure the levels of some of the substances in cigurette smoke encountered in everyday situations (Table 2). They have also tried to determine the factors controlling the atmospheric concentrations of these substances as well as the amount absorbed by nonsmokers under these conditions. Carbon monoxide, nicotine, benzo(a)pyrene, acrolein, and acetaldehyde have been of particular concern. Carbon Monoxide Levels of carbon monoxide (CO), a major product of tobacco combustion, have been studied in a variety of situations, and concentrations ranging from 2 to 110 ppm have been measured (Table 2). The major determinants of the CO levels in these situations are size of the space in which the smoking occurs (dilution of CO), the number and type of tobacco products smoked (CO production), and the amount and effectiveness of ventilation (CO removal). The type of tobacco product smoked is important as a determinant of CO exposure because it has been found that mainstream smoke from regular and small cigars contains more CO pre puff and per gram of tobacco burned than filtered or unfiltered cigarettes (8). This greater production of CO by cigars was confirmed by Harke (23). He measured the CO produced by 42 cigarettes, 9 cigars, and 9 pipefuls of tobacco, each product evaluated separately but under the same room conditions. The cigars produced the highest CO level (60 ppm). In addition to the effect of type of tobacco product on CO levels. data on the effects of room size, amount of tobacco burned, and ventilation are included in Table 2. Only under conditions of unusually heavy smoking and poor ventilation did CO levels exceed the maximum permissible, 8-hour industrial exposure limit of 50 ppm CO (7); however, even in cases where the ventilation was adequate, the measured CO levels did exceed the maximum acceptable ambient level of 9 ppm (/8). Harke (27) also showed that in small enclosed ventilated spaces (an automobile) the CO level is determined more by the number of cigarettes being smoked at one given time than by the cumulative number of cigarettes that have been smoked; also the CO level decreases rapidly once the smoking stops. 486 £84 Ne Ae gh a TABLE 2, — Measurements Of CONSTANT Fated by the | Cig = cigarettes; — = unknown: TPM = total particulate matter] combustion oP tobacce products in various sittiations Reference, Location, and Amount of Dimensions If Known Ventilation Tobacco Burned Constituents Harke, HL-P., et al. (27) Mid-size European car, None 9 cig 30 ppm CO engine off, in wind tunnel at $0 km/hr Air jets open & 6 cig 20 ppm CO wind speed blower off Air jets open & 6 cig 10 ppm CO blower on Mid-size European car, None 9 cig 110 ppm CO engine off, in wind tunnel at zero km/hr None 6 cig 80 ppm C wind speed Air jets open & 6 cig 8-10 ppm CO blower on Harke, H.-P., Peters, H. (28) Car in traffic None 4 cig 21.4 ppm CO Stch, M. (45) None 10 cig in 1 hr 90 ppm CO, Smokers 10% COMb Car, engine off— 2.09 m Seif, HEL (gay Intercity buses 15 air changes per hr 23 cig (burning continuausly) 3 cig (burning continuously) Nonsmokers % COUb 33 ppm CO (at driver's sea) 18 ppm CO (at driver's seat) 887 TABLE 2. ~ Measurements of constituents released by the combustion of tobacco products in various situations ~ Continued Reference, Location, and Dimensions If Known U.S. Dept. Transportation, etal. (48) Airplane flights: Overseas—100% filled Domestic—66% filled Cano, J.P., et al. (22) Submarines—66 m3 Godin, G, et al. (27) Ferry boat compartments: Smoking Nonsmoking Theater: Foyer Auditorium Bridge, D.P., Corn, M. (7) Party rooms: 145 m3 101 m3 [ Cig = cigarettes; ~ = unknown; TPM = total particulate matter] Ventilation 15-20 air changes per hr do. Yes 7 air changes per hr I] 10.6 air changes per hr Amount of Tobacco Burned 157 cig per day 94-103 cig per day SO cig & 17 cigarsin 1.5 hr 63 cig & 10 cigars in 1.5 hr Constituents 2-5 ppm CO, <,120 mg/m? TPM <2 ppm CO, <.120 mg/m? TPM <40 ppm CO, 32 ug/m> Nicotine <40 ppm CO, 15-35 ug/m3 Nicotine 18.4 +8.7 ppm CO 3.022.4 ppm CO 3.440.8 ppm CO 1,420.8 ppm CO 7 ppm Co 9 ppm CO 687 TABLE 2. — Measurements of constituents released by the combustion of tobacco products in various situations — Continued [ Cig = cigarettes; — = unknown; TPM = total particulate matter] Reference, Location, and Dimensions If Known Harke, H.-P, et al. (25) Room--38.2 m Harke, H.-P. (24) Office Bldg Office Bldg Room=78,3 m3 Harke, H.-P., (23) Room-57 m3 Ventilation None Air conditioned Not air conditioned None 7,2 air changes per hr 8.4 air changes per hr None 7.2 alr changes per hr None 7.2 air changes per hr Amount of Tobacco Burned 30 cig per 13 min (by machine) 5 cig per 13 min (by machine) 3 smokers 42cig (by machine) 42 cig do. 42 cig do. 9 cigars do. 9 cigars do. 9 pipes do. 9 pipes do. Constituents 64 ppm CO, 510 ug/m3 Nicotine .46 mg/m~ Acrolein 6.5 mg/m? Acetaldehy de 11.5 ppm CO, 60 g/m? Nicotine, 07 mg/m? Acrolcin, 1,3 me/m3 Acetaldehyde <5 ppm CO <5 ppm CO 15.6 ppin CO 50 ppm CO, 530 g/m? Nicotine 10 ppm CO, 120 ugim3 Nicotine <10 ppm CO, <100 ugim? Nicotine 60 ppm CO, 1040 ugim3 Nicotine 20 ppm CO, 420 ug/in? Nicotine 10 ppm CO, $20 ug/m? Nicotine <10 ppm CO, <100 g/m? Nicotine O64 TABLE 2. — Afeasurements of constituents released by Reference, Location, and Dimensions If Known Harke, H.-P. (23) Room—170 m3 Anderson, G., Dalhamn, T. (3) Room-- 80 m3 Russell, MOALTL, et al. (40) Room -43 m4 humisen, Hh, Hffenberger, FE. (fu) Room 93 m3 Movge URL, 22) Sealed test chamber-25 m3 [ Cig = cigarettes: Ventilation None 1.2 air changes per hr 2.3 air changes per hr 6.4 air changes per hr None None None Amount ot Tobacco Burned 105 cig 107 cig 101 cig 46 cig & 3 pipefuls 80 cig & 2 cigars per hr 62 vig in 2 hrs 4 cig 8 cig 16 cig 24 cig the combustion of tobaceo producis in various situartions — Continued — = unknown, TPM = total particulate matter | Constituents 30 ppm CO, Smokers 7.84% COD Nonsmokers 2.1% CONb SppmCO, Smokers 5.8% COD Nonsmokers 1.347 CONb 75 ppm CO, Smokers 5.0% COHb Nonsmokers $.6% COHDb 4.5 ppm CO, 377 up/m? Nicoting, 3.0 mg/m3 TPM 38 ppm CO, Smokers 9.64% COHb Nonsmokers 2.6% COUb ‘ 80 ppm CO, $200 xe/m3 Nicotine 12,2 ppm CO, 2,28 mefins TPM 25.6 ppm CO, 5,39 my/ins PPM 47.0 ppm CO, ELT mess rest 69.8 ppm CO, 16.65 mys TPM One must be careful when using the levels recorded in Table 2 as measures Of individual exposure because the CO levels were usually measured at points several feet from the nearest smoker and probably would have been higher if measured at points correspond- ing to the position of a person sitting next to someone actively smoking (/7, 35). In addition. it is the CO absorbed by the bodv that causes the harmful effects and not that which is measured in the atmosphere. This absorption can vary trom individual to individual, depending on factors such as duration of exposure, volume of air breathed per minute, and cardio-respiratory function. Several investigators have tried to detennine the amount of carbon monoxide absorbed in involuntary smoking situations by measuring changes in carboxyhemoglobin levels in’ nonsmokers exposed to cigarette smoke-filled environments. Anderson and Dalhamn (3) were unable to find any change in the COHb levels of nonsmokers in a well ventilated room where the CO level was 4.5 ppm. When Harke (23) studied nonsmokers under similar conditions (good ventilation and less than 5 ppm CO), he was able to show an increase in COHb level from 1.1 to 1.6 percent: without ventilation the CO levels rose to 30 ppm and the COHb level increased trom .9 to 2.1 percent in 2 hours. Russell, et al. (40) also found that COHb levels increased from 1.6 to 2.6 percent in nonsmokers exposed to a smoke-filled room where the CO level was measured at 38 ppm: however, he cautioned that nearly all persons in the room felt that the conditions were worse than those experienced in most social situations. Stewart, et al. (46) measured COHb levels in a group of nonsmoking blood donors from several cies and found that 45 percent exceeded the Clean Air Act's Quality Standard of 1.5 percent with the 90 percent range as high as 3.7 percent for individual cities (Table 3). These levels represent the total CO exposure from all sources, involuntary smoking, and other sources of pollution as well as establishing the levels which would be added to any new involuntary smoking ex posure. Increases in the COHb levels of this magnitude are probably functionally insignificant in the healthy adult, but in persons with angina pectoris, any reduction of OXygen-carrying capacity is of great importance. In this disease, the volume of blood able to be pumped through the diseased coronary artery is already unable to meet the demands of the heart muscle under exercise stress. Aronow, et al. (4) examined the effect of exposure to carbon monoxide on persons with angina pectoris. They exercised Persons with angina 491 C69 TABLE 3. — Median percent carboxyhemoglobin (COHb) saturation and 90 percent range for nonsmokers by location | Sonmsen Woof erect, Location Nonsmokers With COHDb Median Range > 1.5% Anchorage 1.5 0.6 - 3.2 152 $6 Chicago 1.7 103.2 401 74 Denver 2.0 0.9 ~ 3,7 744 76 Detroit 1.6 0.7 — 2.7 1,172 42 Honolulu 1.4 0.7 ~2.5 $03 39 Houston 1,2 0.6 — 3.5 240 30 Los Angeles 1.8 1.0 - 3.0 2,886 76 Miami 1,2 0.4 ~ 3.0 398 33 Milwaukee 1,2 0.5 -— 2.5 2,720 26 New Orleans 1.6 1.0 - 3.0 159 $9 New York 1,2 0.6 ~2.5 2,291 35 Phoenix 1.2 0.5 -2.5 147 24 St. Louis 1.4 0.9 ~ 2,1 67) 35 Salt Lake City 1.2 0.6 ~ 2.5 544 27 San Francisco 1.5 0.8 - 2.7 660 61 Seattle 1,5 0.8 - 2.7 535 55 Vermont, New Hampshire 1,2 0.8 ~ 2.1 959 18 1.2 0.6 — 2.5 850 35 Washington, D.C. ic Source; ' Stewart, R.D., et al . (46). pectoris before and after exposure to carbon monoxide. The average amount of exercise that was able to be performed before a person developed chest pain was significantly shortened from 226.7 seconds before exposure to 187.6 seconds after CO exposure. This change occurred after a 2-hour exposure to 50 ppm CO and with an increase in COHb level from 1.03 percent to 2.68 percent: these COHb levels are within the range produced by involuntary smoking. These data indicate that exposure to CO at levels found in some involuntary smoking situations may well have a significant impact on the functional capacity of persons with angina pectoris. Carbon monoxide has also been shown to decrease cardiac contractility in persons with coronary heart disease at COHb levels similar to those produced due to involuntary smoking situations (5). It is reasonable to assume that any significant CO exposure to the diseased heart reduces its functional reserve. Nicotine Nicotine in the atmosphere differs from CO in that it tends to settle out of the air with or without ventilation (thereby decreasing its atmospheric concentration), whereas the CO level will remain constant until the CO is removed. The concentrations of both substances are decreased substantially by ventilation. As can be seen from data in Table 2, under conditions of adequate ventilation neither exceeds the maximum threshold limit values for industrial exposure (nicotine, 500 yg/m3; CO, 50 ppm, /): whereas in conditions without ventilation, smoking produces very high con- centrations of both (nicotine, up to 1,040 pe/m3:CO, 110 ppm). Nicotine in the environment is of concern because nicotine absorbed by cigarette smokers is felt to be one factor contributing to the development of atherosclerotic cardiovascular disease. Several researchers have attempted to measure the amount of nicotine absorbed by nonsmokers in involuntary smoking situations. Cano, ef~ ” al. (7/7) studied urinary excretion of nicotine by persons on a submarine. Despite very low levels measured in the air (15 to 32 ve/m3), nonsmokers did show a small rise in nicotine excretion; however, the amount excreted was still less than | percent of the amount excreted by smokers. Harke (23) measured nicotine and its metabolite cotinine in the urine of smokers and nonsmokers exposed to a smoke-filled environment and reported that nonsmokers excreted less than |] percent of the amount of nicotine and cotinine excreted by smokers. He feels that at this low level of absorption nicotine is unlikely to be a hazard to the nonsmoker. 493 Other Substances In two. studies environmental levels of the experimental carcinogen benzo(a)pyrene were measured. Galuskinova (20) found levels of benzo(ajpyrene from 2.82 to l44 mgm? in smoky restaurants, but it is not clear how much of this was due to cooking snd how much was due to smoking. In a study of the concentration of benzo(a)pyrene in the atmosphere of airplanes (48). only a fraction of a microgram per cubic meter was detected. The effect of chronic exposure to very low levels of this carcinogen lias not been established for humans. Acrolein and acetaldehyde have also been measured in smoke- filled rooms (25, Table 2) and may contribute to the eye irritation commonly experienced in these situations. EFFECTS OF EXPOSURE TO CIGARETTE SMOKE Cardiovascular Effects of Involuntary Smoking The effects of cigarette smoking on the cardiovascular system of the smoker are well established, but very little is Known about the cardiovascular response of the nonsmoker to cigarette smoke. Harke and Bleichert (26) studied 18 adults (11 smokers and 7 nonsmokers) in a room 170 m3 large in which [50 ciguretfes were smoked or allowed to burn in ashtrays for 30 minutes. They noted that the subjects who smoked during the experiment had a significant lowering of skin temperature and a rise in blood pressure. Non- smokers who were exposed to the same smoke-contaminated environment showed no change in either of these parameters. Luquette. et al. (06) performed a similar experiment with 40 children exposed alternately to smoke-contaminated and clean atmospheres, but otherwise under identical experimental conditions. They found that exposure to the smoke caused increases in heart rate (5 beats per minute) and in systolic (4 mm He) and diastolic (5 mm Hg) blood pressure. The differences in results between these studies may be due, in part, to the age of the subjects — i.e,. children may be more sensitive to the cardiovascular effects of involuntary smoking than adults, or the increase in heart rate and blood pressure muy be due to a difference between children and adults im the psychologic response to being ina smoke-tilled atmosphere. 494 Effects of Carbon Monoxide on Psychomotor Tests Carbon monoxide from tobscco smoke. automobile exhaust. and industrial pollution is an important component of air pollution. There has been some concern over the effect of relatively low levels of carbon monoxide on psychomotor functions (the ubilitv. to perceive and react to stimuli). especially those functions related to driving an automobile (Table 4). Carbon monoxide levels occasionally reached in some involun- tary smoking situations result in measurable cognitive and motor effects, but these effects generally are measurable only at the threshold of stimuli perception. One study (Wright. et al.. (50)) found that the safe driving habits measured on a driving simulator did not improve as much with practice in a group exposed to CO as did the habits of a control group. Another study (37) with a different experimental design but at the same levels of CO did not find any effect on complex psychomotor activity such as driving a car. Thus, the role of CO alone in motor vehicle accidents remains unclear. The effect on judgement and reactions of CO in combina- tion with factors such as fatigue and alcohol. conditions known to influence judgement and reaction time, has not been determined. Pathologic Effects of Exposure to Cigarette Smoke The effect of involuntary smoking on an individual is deter- mined not only by the qualitative and quantitative aspects of the smoke-filled environment, but also largely by the characteristics of the individual. Reactions may vary with age as well as with the sensitivity of an individual to the components of tobacco smoke. The severity of possible effects range from minor eye and throat irritations experienced by most people in smoke-filled rooms, to the anginal attacks of some persons with cardiovascular disease. The minor symptomatic irritation experienced by nonsmokers in a smoke-filled environment is influenced by the humidity of the air as well as the concentration of irritating substances found in the atmosphere. Johansson and Ronge (33) have shown that irritation due to cigarette smoke is maximal in warm, dry air and decreases with a small rise in relative humidity. A change from acceptable to unpleasant was reported at 4.7 me/m3 of particulate matter for nonsmokers and eye irritation was noted at 9 mg/m} for both smokers and nonsmokers. The authors concluded that a ventilation rate of 12 m3/hr/cig was necessary to avoid eye irritation and 50 m3 /hr/cig was necessary to avoid unpleasant odors. 495 967 TABLE 4.— Effects of carbon monoxide on Psychomotor functions co COllb Reference Test or level level Measurement (ppm) (Percent) Effect McFarland, R.A. Ability of drivers to stay 6 None (37) between two-lane markers I None while being permitted only 17 None brief glimpses of the road Ray, A.M., Reaction time to 10 Prolonged Rockwell, T.H. Car tuillights (39) McFarland, R.A. Performance of two tasks at 700 17 None (38) same time Dark adaptation and glare 700 17 None recovery Peripheral vision at 10. 700 17 None and 30° Peripheral vision at 20° 700 17 Decreased Depth perception 700 17 None Stewart, R.D., et al. Time perception 500 20 None (47) | TABLE 4, — Effects of carbon monoxide on psychomotor functions — Continued co CONb Test or level fevel Reference Measurement ppm (Percent) Effect Fodor, G.G,, Atlontiveness ta SQ x 5 hes, 2-8 Decreased Winneke, G, wuditory stimuli (79) Mheker fusion SOx 5 firs. 2-5 No change Apeed of motor performance SOx 5 Ins. 2-5 No change Perception of complex SUX 5 hrs. 2-5 Improved Vistal patterns Schulte, JU. Cognitive function 100 5 Decreased (43) Reaction time 20 No change Bender, W., etal. Threshold for temporal 100 7.25 Raised (6) resolution of visual stimuli Manual dexterity too 7.25 Decreased Learning meaningless syllables 100 7,25 Decreased Retention of 10 syllables 100 7.25 No change for | hr Groll-Knupp, E., et al, Attentiveness lo auditory SU Deterioration af (22 stinvali $0 ppm. worse at 100 100 ppim, worst 150 at lS ppm Wright, G., et al, Reaction time 6.3 Prolonged ($0) Glare recovery 6.3 Prolonged Careful driving habits 6.3 Failure to improve with practice Two government sponsored studies have attempted to evaluate the degree of minor irritation due to cigarette smoke experienced by bus and plane passengers. The U.S. Department of Transportation (44) studied the environment on two ventilated buses - one with simulated unrestricted smoking and another with simulated smoking limited to the rear 20 percent of the seats. In one bus. hghted cigarettes were placed at every olher seat (23 cigarettes) to simulate a bus filled with smokers. In the other bus, cigarettes were placed only in the rear 20 percent of the bus (five cigarettes) to simulate a bus where smoking was limited to the rear 20 percent of the seats. When smoking was limited, the CO level at the driver's seat was only 18 ppm (ambient air 13> ppm) compared to the fevel of 33 ppm (ambient air 7 ppm) measured in the unrestricted smoking situation. Four of the six subjects seated in the bus reported eve irritation during the unrestricted smoking simulation. None of the six subjects reported any eye irritation in the restricted smoking situation (not even those seated in the rear 20 percent of the bus). Several Federal agencies (48) cooperated to survey the symp- toms experienced by travelers on both military and commercial aircraft. They distributed a questionnaire to passengers on 20 military and 8 commercial flights; 57 percent of the passengers on the military fights and 45 percent of the passengers on the commercial flights were smokers. The planes were well ventilated and CO levels were always below 5 ppm with low levels of other pollutants as well. In spite of the Jow fevel of measurable pollution, over 60 percent of the nonsmoking passengers and 15 to 22 percent of the smokers reported being annoyed by the other passengers’ smoking. Seventy-three percent of the nonsmoking passengers on the commercial flights and 62 percent of the nonsmoking passengers on the military flights suggested that some remedial action be taken; 84 percent of those suggesting remedial action felt that segregating the smokers from nonsmokers would be a Satisfactory solution. These feelings were even more prevalent among those nonsmokers who had a history of respiratory disease. Children have been found to have a higher meidence of respiratory infections than adults and are thought to be more sensitive to the effects of air pollution due to their greater minute ventilation per body weight than adults. Several researchers have investigated the effects of parental smoking on the health of children. Cameron, et al. conducted two tclephone surveys of Detroit families to determine the relationship between children’s respiratory illness and parental smoking habits. In the first survey (4) they found a statistically significant relationship between the prevalence of 498 children’s respiratory infection and parental smoking habits only when all children under 16 were considered ¢not when only those under 9 or under 5 were considered). [In a larger survey of the same city (/9) they found a relationship between parental smoking and prevalence of respiratory illness in the 1Q- to 1G-vear age eroup and in the birth to 5-year age group. Neither study controlled for smoking by the children which might be a factor in the 1O- to 16-year age group or for socioeconomic status which has an effect an both smoking habits and illness. However, the data Were consistent with a higher prevalence of respiratory disease in families where there are smokers than in nonsmoking families. Colley (72) also found a relationship between parental smoking habits and the prevalence of respiratory illness in the children. He found an even stronger relationship between Parental cough and phlegm production and respiratory infections in children. He postulates this latter relationship to result from the greater infec- tivity of these parents due to their cough and phlegm production. The relationship between parental cigarette smoking and respiratory infection in’ their children would then occur because cigarette smoking caused the parents fo cough and produce phlegm and would not be indicative of a direct effect of cigarette smoke-filled air on the children. Harlap and Davies (29) studied infant admissions to Hadassah Hospital in West Jerusalem and found a telationship between admissions for bronchitis and pneumonia in the first year of life and maternal smoking habits during pregnancy. Data on materna! smoking habits after the birth of the child were not obtained, but it can be assumed that most of the mothers who smoked during preenancy continued to smoke during the first year of the infant’s life. A relationship between infant admission and maternal smoking habits was demonstrable only between the sixth and ninth months of infant life and was more pronounced during the winter months (when the effect of cigarette smoke on the indoor environment would be greatest). Mothers who smoke during pregnancy are known to have infants with a lower average birth weight than the infants of nonsmoking mothers. The relationship between maternal smoking and their infants’ admission to the hospital found in this Study was greater for: low birth weight infants, but was also found for normal birth weight infants (Table 5) (29). Harlap-and Davies (29) demonstrated a dose-response relationship for maternal smoking and infant admission for bronchitis and pneumonia, however, they also found 4 relationship between maternal smoking and infant admis- sions for Poisoning and injuries. This may indicate a bias in the study 499 00s TABLE S.- Admission rates (per 100 infants) by diagnosis, birth weight, and maternal smoking Birth weight (g) Total Diagnosis <2,999 3,000 - 3,499 3,800+ (including unknown) 5 NS S NS S NS S NS (297) (2,326) (415) (4,098) (264) (3,195) (986) (9,686) Bronchitis and pneumonia 19.2 12.3 9.6 8.2 12.1 9.0 13.1 9.8 All other 22.6 19.9 14.5 14.6 1§.2 13.3 16.9 15.5 Total 41.8 32.2 24.1 22.8 27.3 22.3 30.0 24.9 NOTE. — S=Smokers; NS=Nonsmokers. Source: Harlap, S., Davies, A.M. (29). due to relationships which may exist between smoking and factors such as parental neglect or socioeconomic class. In addition. hospital admission rates may not be an accurate index of infant morbidity. Colley, et al. (73) studied the incidence of pneumonia and bronchitis in 2,205 children over the first 5 years of life in relation to the smoking habits of both parents. They found that a relationship between parental smoking habits and respiratory infection in children occurred only during the first vears of life (Table 6). They also showed a relationship between parental cough and phlezm production and infant infection (Table 6) which was found to be independent of the effect of parental smoking habits. The relation- ship between parental smoking and infant infection was greater when both parents smoked and increased with Increasing number of cigarettes smoked per day. The relationship persisted after social class and birth weight had been controlled for. Thus, respiratory infections during the first year of life are closely related to smoking habits independent of parental symptoms, social class, and birth weight. Because of the dose-response relation- ship between parental smoking and infant respiratory infection established by Colley, et al. (/3), it is reasonable to suspect that cigarette smoke in the atmosphere of the home may be the cause of these infections: however, other factors such as parental neglect may also play arole. The above studies examined the effects of involuntary smoking on relatively healthy people. A substantial proportion of the U.S. population suffers from chronic cardiovascular and pulmonary diseases, however, and they represent the segment of the population most seriously jeopardized by conditions found in involuntary smoking situations. In Chapter | of. this report (Cardiovascular Diseases) evidence was presented which showed that levels of CO sometimes experienced in smoke-filled environments (SO ppm) are. _ capable of significantly decreasing the exercise tolerance of persons with angina pectoris and intermittent claudication. In addition, these levels of CO have been shown to decrease cardiac contractility and to raise left’ ventricular end-diastolic pressure (an indication of heart failure) in persons with cardiovascular disease. Persons with chronic bronchitis and emphysema have consider- able excess mortality under conditions of severe air pollution. In smoke-tilled environments levels of CO and several other pollutants may be as high or higher than occur during air pollution emergencies. The effects of short-term exposure of persons with chronic obstnic- 501 cOS TABLE 6. — Pneumonia and bronchitis in the first 5 years of life by parents’ smoking habit and morning phlegm Annual incidence of pneumonia and bronchitis per 100 chitdren (Absolute numbers in parentheses) | Both ex-smokers Yearat Both nonsmokers One smoker Both smokers or one ex smoke All Followup or smoking habit changed N O/B N O/B N 0/B N O/B N O/B 1 7.6 10.3 10.4 14.8 15.3 23.0 8.2 13.2 10.1 16.7 (343) (29) (424) (128) (339) (139) (546) (129) (1,652) (425) 2 8.1 8.3 7A 18.5 4.7 9.2 6.5 10.7 7.4 11.3 (322) (36) (365) (129) (286) (152) (599) (159) (1,872) (476) 3 6.9 8.1 10.5 9.4 719 11.0 8.2 11.6 8.4 10.6 (305) (37) (353) (107) (242) (154) (665) (173) (1,561) (471) 4 8.0 Hl 75 10.8 7.6 11.6 8.2 9.1 7.9 10.3 (287) (36) (306) (102) (236) (121) (695) (187) (1,824) (446) S 6.7 14.7 5.6 9.4 3.9 10.6 6.4 7.3 3.9 9.) (285) (34) (267) (107) (208) (132) (737) (219) (1,497) (492) NOTE, — Neneither with winter morning phiegm, O/B=one or both with winter morning phlegm. Source: Colley, J.R.T., et al. (23). tive bronchopulmonary disease (COPD) to these conditions have not been evaluated. Persons with COPD are also possibly at increased risk to CO exposure because of their low alveolar Po>. Due to the reduced amount of oxygen available to compete with the CO for hemoglobin binding sites, these persons might experience a carboxy- hemoglobin to oxyhemoglobin ratio higher than those in healthy subjects under the same conditions of CO exposure. The retention of CO may also be prolonged due to both this increased binding of CO to hemoglobin under low alveolar Po, and decreased ventilatory capacity to excrete CO. In summary, the effects of cigarette smoke on healthy nonsmokers consists mainly of minor eye and throat irritation. However, people with certain heart and lung diseases (angina pectoris, COPD, allergic asthma) may suffer exacerbations of their symptoms as a result of exposure to tobacco smoke-filled environ- ments. These effects are dependent on the degree of individual exposure to cigarette smoke which is determined by proximity to the source of the tobacco smoke, the type and amount of tobacco product smoked, conditions of room size and ventilation as well as the amount of time the individual spends in the smoke-filled environment, and his physiologic condition at the time of exposure. 503 SUMMARY 1. Tobacco smoke can be a significant source of atmospheric pollution in enclosed areas. Occasionally under conditions of heavy smoking and poor ventilation, the maximum limit for an 8-hour work exposure to carbon monoxide (50 ppm) may be exceeded. The upper limit for CO in ambient air (9 ppm) may be exceeded even in cases where ventilation is adequate. For an individual located close to a cigarette that is being smoked by someone else. the pollution exposure may be greater than would be expected from atmospheric measurements. 2. Carbon monoxide, at levels occasionally found in cigarette smoke-filled environments, has been shown to produce slight deterioration in some tests of psychomotor performance, especially attentiveness and cognitive function. [t is unclear whether these levels impair complex psychomotor activities such as driving a car. The effects produced by CO may become important when added to factors such as fatigue and alcohol which are known to have an effect on the ability to operate a motor vehicle. 3. Unrestricted smoking on buses and planes is reported to be annoying to the majority of nonsmoking passengers, even under conditions of adequate ventilation. 4. Children of parents who smoke are more likely to have bronchitis and pneumonia during the first year of life, and this is probably at least partly due to their being exposed to cigarette smoke in the atmosphere. 5. Levels of carbon monoxide commonly found in cigarette smoke-filled environments have been shown to decrease the exercise tolerance of patients with angina pectoris. 10 13 14 BIBLIOGRAPHY AMERICAN CONFERENCE OF GOVERNMENT INDUSTRIAL HYGENISTS. TLVs® threshold Inmit values for chemical substances in workroom air adopted by the American conference of government industrial hygienists for 1973. Journal of Occupational Medicine 16(1): 39-49, January 1974. ANDERSON, E. W.. ANDELMAN, R.J., STRAUCH, J. M., FORTUIN, N.J.. KNEL- SON, J. H. Effect of low-level carbon monoxide exposure on onset and duration of angina pectoris. A study of ten patients with ischemic heart disease. Annals of Internal Medicine 79(1): 46-50, July 1973. ANDERSON, G., DALHAMN, T. 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September 1973. 507 48 U.S. DEPARTMENT OF TRANSPORTATION, FEDERAL AVIATION ADMINIS- TRATION, U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH. Health aspects of smoking in transport atrcraft. Rockville. Md. AD-736997, December 1971, 85 pp. 49 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of the Surgeon General: 1972. U.S. Department of Health, Education, and Welfare. Washington, DHEW Publication No. (HSM) 72-6516, 1972, 158 pp. SO WRIGHT, G., RANDELL, P., SHEPHARD, R. J. Carbon monoxide and driving skills. Archives of Environmental Health 27(6): 349-354, December 1973. 508 Chapter 8 Allergy Source: 1972 Report, Chapter 7, pages 99 - 116. 509 Contents Page Introduction 2... ....... 0.000. cece cece cece cece eee 513 Antigenic Properties 2.0.0... 0 cece cece ec cee cece 514 Skin Testing 2.0.0.0... ccc cece ce ccc cece cececeuee 515 Additional Immunological Effects ................0... 517 Effect on the Immune Response ..............0000000- 518 Irritant and Pharmacologic Effects ................... 519 Clinical Allergy 2.0... 0000... cc ccc ccc ccc cence cee eeecs 520 Summary ................0.0005. bee tence eee 521 References 0.0... cece ete eee cence nee 522 511 INTRODUCTION As early as 1886 reference was made to an entity called “tobacco asthma” (64). Subsequently, controversy has arisen over whether tobacco smoking causes clinical allergy (61) and whether such tobacco allergy is associated with the major smoking-related dis- eases (25, 69). In 1957, Silvette, et al. (64) reviewed more than 100 papers con- cerned with “the immunological aspects of tobacco and smoking.” They concluded that inadequate animal studies had been performed in this area. Referring to clinical studies, they observed: “... virtu- ally all reported clinical investigation has been limited to determi- nations of cutaneous sensitivity to tobacco extracts; and it must be regretfully admitted that much of this published work is equivocal, uncritical, and inadequately controlled.” Such criticism is also applicable to many studies published since then. . Epidemiologic studies designed to determine the prevalence of tobacco allergy have not been carried out; hence, it is difficult to evaluate the magnitude of the problem. Allergy may be defined as a specific alteration in response medi- ated by an antigen-antibody reaction. When a hereditary suscepti- bility to allergic illness is present, the term atopy is used. For ex- ample, hay fever and asthma are atopic diseases. There is no single test or observation which can be used to de- termine whether a substance may be responsible for allergic dis- ease; however, fulfillment of the following criteria constitutes evi- dence for such a relationship: 1. Demonstration that the substance is antigenic, i.e., capable of stimulating the production of antibody and then reacting with the antibody. 2. Demonstration that, upon exposure to the substance, signs and symptoms simulating an allergie reaction are elicited which disappear upon its removal. 3. Demonstration that the immunologic event is related to the - clinical event. Recent advances in the understanding of immunological reactions as well as in the methodology of immunology are now being applied 513 to problems of clinical allergy. For example, Ishizaka (87), using radioimmunoelectrophoresis, recently reported that the so-called “allergic antibody” (reagin, skin-sensitizing antibody (SSA), atopic antibody) belongs to a new class of immunoglobulins, IgE. Although the skin test remains a simple and definitive method of demonstrating reagins in the allergic patient, there are many vari- ables involved in this technique which must be carefully weighed when interpreting test results. In the area of tobacco skin testing, such variables include: differences in antigenic content of the test extract, differences in route of administration, and heterogeneity of test groups. ANTIGENIC PROPERTIES Tobacco leaf contains a complex mixture of chemical components including: celluloses, starches, proteins, sugars, alkaloids, pectic substances, hydrocarbons, phenols, fatty acids, isoprenoids, sterols, and inorganic minerals (69). Theoretically, relatively few of these substances should be antigenic. Tobacco extracts of different compo- sition result from differences in tobacco types and species, process- ing of tobacco, and preparation of the extract. Harkavy (26) has shown in some patients a differential skin reactivity to extracts from different types of tobacco. Coltoiu, et al. (9) reported that 13 different antigens capable of inducing precipitins in rabbits have been isolated from tobacco pollen. Chu, et al. (7) prepared aqueous extracts of five commercial tobacco products which stimulated anti- body formation in rabbits. The antigens contained in the extracts included both proteins and polysaccharides and had molecular weights ranging from 20,000 to 60,000. Silvette, et al. (64) reviewed several papers dealing with the immunology of nicotine and concluded that nicotine was nonanti- genic. Harkavy (25), who performed some of the earliest studies on the antigenicity of nicotine, could not exclude the possibility that nicotine may act as a hapten. A hapten is a compound which, -al- though not antigenic by itself, reacts with antibody and conveys antigenic specificity when combined with another compound. With pyrolysis many of the tobacco constituents undergo reac- tions involving oxidation, dehydrogenation, cracking, rearrange- ment, and condensation (69). Many new compounds are formed. Pipes (51) demonstrated, through exhaustion of passive transfer reactivity in skin sites, that allergy to tobacco smoke in man is dis- tinct from that of allergy to tobacco leaf. Tobacco smoke exhausted reactivity in sites injected with tobacco smoke sensitized serum; reactivity was reduced but not exhausted with tobacco extract. The converse was true with passive transfer sites of tobacco-sensitized serum; tobacco extracts abolished allergic reactivity. whereas to- 514 bacco smoke extract produced a diminution but not total exhaustion. He concluded that it would be useful to test human subjects for both tobacco leaf and tobacco smoke sensitivity. Kreis, et al. (39) have speculated that tobacco Jeaf antigenicity may be lost with pyrolysis. Coltoiu, et al. (9) recently emphasized the importance of remov- ing all irritants from test extracts. In a clinical setting, allergy to tobacco additives such as menthol has also been suspected (47). SKIN TESTING {ntracutaneous injection of test antigen is a widely used method of skin testing. Patch tests have also been used in cases of suspected contact dermatitis. Rosen (54) has observed that skin testing does not accurately duplicate the most common route of exposure to tobacco, i.e., tobacco smoke inhalation. For those involved in the production of tobacco products, inhalation of tobacco dust or direct contact with tobacco may play important roles in sensitization (9). The extensive literature on cutaneous sensitivity to tobacco ex- tracts includes comparisons of the prevalence of positive skin reac- tions in different groups, such as “normal” nonsmoking adults (17, 68), “normal” smokers (17, 33), allergic patients (59, 76), children (41, 50), tobacco workers (6,9), and patients with specific diseases, e.g., thromboangiitis obliterans (28, 7%). Harkavy reported on tobacco skin reactions in several different groups of patients (30). Many of the apparently discordant results in some of these reports can be traced to failure to compare similar populations or to control for differences in the test antigen or in the method of testing. Sulzberger (66) studied the different types of skin reactions pro- duced by intracutaneous injection of denicotinized tobacco extract. Three types of positive skin responses were observed: eczematous reactions; immediate wheal-and-flare reactions; and late reactions, probably of the tuberculin type. The wheal-and-flare response has been by far the predominant type (42). This immediate wheal-and-flare response is a specific immune-re- action (64) largely mediated by IgE. Patterson (48) recently pro- posed a simplified model explaining the mechanism of action of the akin sensitizing antibody (SSA). “Subsequent to stimulation of the animal by antigen, SSA are produced by cells of the lymphoid sys- tem possibly located in the alimentary and-respiratory tract. ... The SSA so produced are secreted in such a way that they reach the cir- culation, where circulating cells, predominantly basophilic leuko- cytes, are sensitized by attachment of the SSA to the cell surface. In addition, the SSA also leave the vascular compartment and sen- sitize mediator-releasing cells in tissues. The tissue cells are pri- marily mast cells...The immediate-type allergic reaction occurs 515 when antigen is introduced into the individual sensitized by SSA, either by transfer of antigenic molecules through the respiratory or alimentary mucosal surface or by injection into the skin or vascular system. The antigens reach the antibody on the surface of the mast cellg and initiate the intracellular events that result in mediator re- lease from the cells.” The actions of these mediators include smooth muscle contraction, vasodilation, and increased capillary permeabil- ity which can produce such clinical pictures as hay fever, asthma, and generalized anaphylaxis. Until recently, direct skin testing and the passive transfer test (Prausnitz-Kiistner reaction) were the only methods of studying IgE mediated responses. In the passive transfer test, serum from an allergic patient is injected into the skin of a normal subject. After a suitable interval the antigen is injected into the prepared site and adjacent normal skin. In a positive response, cutaneous reactivity is transferred to the normal subject at the injection site. The absence of a positive response in nearby normal skin excludes nonspecific irritation as a cause of the response and shows that the normal subject is not himself allergic to the antigen. Harkavy and Witebsky (84) found and selectively absorbed tobacco reagins in patients showing multiple sensitivities. This se- lective absorption documented the immunologic mechanism of the skin reaction. Passive transfer of the SSA was also reported by Peshkin and Landay (50) and by Lima and Rocha (41). Lowell (48) stated, “The individual possessing skin-sensitizing antibody to the tobacco extract may be regarded ag unequivocally allergic to the extract....”” Despite the inability of Sulzberger and Feit (67) to demonstrate tobacco reagins in their skin test positive patients, several investigators have found them (26, 50, 75). Harkavy (23) biopsied urticarial wheals after intradermal injec- tion of tobacco extract and found a local eosinophilia. He felt that this helped confirm the allergic mechanism of the positive skin test. He also biopsied the site of a delayed skin reaction to tobacco and found an eczematous type of response. The delayed type hypersensitivity reaction is manifested by in-_ duration and erythema developing within 24 to 48 hours after injec- tion of antigen. The absence of response in the first 6 to 8 hours after exposure to antigen helps exclude an’ Arthus reaction, which is also a slowly evolving allergic response. Serum antibodies are not involved in the initiation of delayed type hypersensitivity ; rather, the initial step is thought to involve interaction of antigen and spec- ialized lymphocytes (10, 11). Contact dermatitis is thought to be very nearly a pure type, delayed hypersensitivity reaction (10, 11). The foregoing discussion has highlighted the studies concerning cutaneous sensitivity to tobacco extracts. Despite the complexities and contradictions, numerous workers agree that tobacco extract 516 (leaf or smoke) is antigenic and can sensitize (2, 7, 9, 18, 26, 48, 50, 52, 64, 66, 76). Silvette, et al. (64) concluded, “It is, indeed, beyond question that allergy to tobacco extracts, presumably atopic in na- ture, is an established fact. ...” Lowell (43) observed that, in most instances, skin reactivity to an extract of tobacco actually means the presence of allergy in some degree to something in the extract. Armen and Cohen (2), Harkavy and Perlman (82), and Popescu, et al. (52) observed that tobacco extract is weakly antigenic. Armen and Cohen (2) were able to sensitize rabbits to tobacco proteins only after absorbing the pro- tein to aluminum hydroxide, which served as an adjuvant. Even though a positive skin test to tobacco extract may be due to a specific allergic reaction, the interpretation of such a positive test in a given patient or group of patients poses problems, since sen- sitivity to a battery of antigens has been demonstrated in individ- uals who are entirely free from allergic symptoms upon exposure to the antigens. Rosen (54) stated that this lack of correlation be- tween positive skin tests and clinical symptoms is greater for to- bacco than for other antigens such as pollens, dusts, and feathers. He and others have emphasized that the skin test has value only when correlated with clinical evidence. : Analysis of skin test studies in nonsmokers (64) shows that ap- proximately 15 percent of such “healthy” individuals give positive reactions to tobacco extracts. Some studies of smokers reporting a 30 percent or more prevalence of skin sensitivity to tobacco ex- tract (98, 48) have considered patients with multiple sensitivities, including that to tobacco. Atopic individuals have been noted to have a greater prevalence of skin sensitivity to tobacco than non~ atopics (64); hence, in some studies an excess of atopic patients may account for a substantial part of the elevated prevalence of tobacco skin sensitivity reported for smokers. Several workers have sought to use the skin test as a screening device for indicating an unusual susceptibility to the adverse effects of tobacco. DeCrinis, et al. (13), Fontana (17), and Redisch (53) have reported that patients with positive skin tests to tobacco €x- tracts were more likely to have an adverse vascular response to tobacco as indicated by a fall in peripheral skin temperature on smoking. More recent studies have shown that a decrease in skin temperature with smoking is a reproducible response to nicotine found in “normal” individuals and does not appear to be confined to a specific group of smokers (1, 56, 70). ADDITIONAL IMMUNOLOGICAL EFFECTS Additional evidence is available to support the view that tobacco induces immunologic changes in man and animals. Armen and 517 Cohen (2), Chu, et al. (7), Harkavy and Perlman ($1), and Zuss- man (76) induced precipitin formation in animals sensitized to tobacco extract. Kreis, et al. (89) studied precipitation reactions in 651 hospitalized patients, many of whom were suffering from tu- berculosis or lung cancer. A precipitation reaction between the pa- tients’ sera and a commercial tobacco extract was found in 62.6 per- cent of the patients. Chu, et al. (7), using the same antigens as those employed to stimulate precipitin formation in rabbits, found serum antibodies in 40 percent of a group of smokers which precipi- tated specificially with the tobacco antigens. Only 7 percent of a group of nonsmokers demonstrated these antibodies, Savel (59) studied eight nonsmoking, allergic individuals who developed immediate upper respiratory discomfort after being ex- posed to cigarette smoke. As measured by the uptake of tritiated thymidine, the lymphocytes of these individuals were stimulated by cigarette smoke, while ‘‘normal” lymphocytes were depressed. The author stated that the correlation of this test with specific forms of clinical allergy remains uncertain. Some investigators have observed abnormal laboratory test re- sults in smokers as compared to nonsmokers, which may indicate an allergic response in the former group. Schoen and Pizer (60) de- scribed a smoking woman who demonstrated a striking blood eosino- philia while smoking cigarettes. Upon cessation of smoking, the eosinophil count returned promptly to normal levels. Resumption of smoking was associated with a return of the eosinophilia. Heiskell, et al. (86) found a significant increase in C-reactive protein and an abnormal seroflocculant for ethyl choledienate in smokers as com- pared to nonsmokers. Plasma histaminase levels were reported by Kameswaran, et al. (88) to be elevated in smokers. Experimental animal sensitization to tobacco was reported by Friedlander, et al. (19) in male rats. Harkavy (29) confirmed these results in male rats and also obtained positive Schultz-Dale reac- tions in the sensitized animals; however, female rats failed to dem- onstrate this sensitization. Harkavy (24) reported cardiac histo- logical abnormalities in three rabbits sensitized with denicotinized © tobacco extracts. The abnormalities found in the three rabbits, re- spectively, included: intimal proliferation, focal fragmentation of the internal elastic membrane, and loss of smooth muscle fibers in the media of a branch of a coronary artery; focal intimal prolifera- tion and fibrinoid alterations in the media of a small coronary ves- sel; and a focus of myocardial fibrosis and necrosis. EFFECT ON THE IMMUNE RESPONSE The effect of tobacco on the immune response has received some attention. Early studies in rabbits suggested that tobacco smoke re- 518 tarded the production of agglutinins in rabbits immunized against typhoid (14). A variety of observations indicate that ingestion of antigenic material by the macrophage may be an essential step in the immune response (3). Bruni (5) found that cigarette smoke suppressed phagocytosis in rabbits. Green and Carolin (20) performed t7 vitro studies in rabbit alveolar macrophages and observed that cigarette smoke inhibited the capacity of these cells to inactivate bacteria. Harris, et al. ($5) reported no differences in the phagocytic ability of macrophages taken from human smokers and nonsmokers, but he also concluded that his data neither contradicted nor supported Green’s work. Cohen and Cline (8), while noting that macrophages from smokers had normal phagocytic capacity, demonstrated sub- optimal macrophage function in an environment of low O, tension, a state found more frequently in smokers than nonsmokers. Max- well, et al. (45), using guinea pigs, found that smoke exerted no effect on phagocytosis; nevertheless, smoke seemed to impair the phagocytes’ ability to inactivate bacteria. Nicotine has been shown by Meyer, et al. (46) to exert a depressant effect on sheep pulmo- nary alveolar macrophage respiration and ATPase activity. Re- cently, Yeager (74) reported that water soluble constituents of cigarette smoke depress protein-synthesis in rabbit alveolar macro- phages in vitro. Lewis, et al. (40) found that cigarette smoking had a suppressive action on secretory IgA production in normal subjects but not in subjects with chronic respiratory disorders. Vos-Brat and Rumke (71) recently reported that IgG serum concentrations and the re- sponse of lymphocytes to phytohemagglutinin were significantly lower in smokers than nonsmokers. A number of investigators have reported increased rates of res- piratory illnesses among cigarette smokers (70). Finklea, et al. (16) studied antibody response in 289 volunteers after the 1968 Hong Kong influenza epidemic. They reported a significant decrease among cigarette smokers in the persistence of hemagglutination in- hibition antibody after natural infection or vaccination with A, . antigens. They postulated that this antibody deficit among cigarette mowers might be related to increased illness during influenza out- reaks. IRRITANT AND PHARMACOLOGIC EFFECTS As Lowell (43) has emphasized, the pharmacologic, irritant, and allergic effects of tobacco are difficult to distinguish. Acrolein and acetaldehyde are potent irritants found in tobacco smoke, which, as demonstrated in animal studies, are capable of releasing chemical mediators such as histamine (58). The inhalation of tobacco smoke 519 causes bronchial constriction, mucus hypersecretion, and ciliary stasis (57) in man, all of which can contribute to a clinical picture indistinguishable from an allergic reaction. Several authors (44, 61, 63) share Sherman’s (62) view that “... tobacco smoke is an im- portant secondary factor in precipitating allergic symptoms through its action as a nonspecific irritant.” Speer (65) recently compared the subjective responses of two groups of nonsmokers to tobacco smoke exposure. One group of 191 patients suffered from documented allergies. In one-sixth of these ‘ patients a positive skin test to tobacco extract was found, but only a few patients were seen with objective symptoms which could be traced to tobacco smoke. The other group of 250 patients had no history of allergy and was studied by questionnaire only. Eye irrita- tion, nasal symptoms, headache, and cough were common in both groups. Speer concluded that these effects of tobacco smoke were irritative rather than allergic in origin. The data presented in this study demonstrate that tobacco smoke can contribute to the dis- comfort of many individuals; they do not rule out a possible con- tribution from allergic reactions. Harkavy (80) cited experimental data distinguishing allergic effects from pharmacologic effects of smoking such as increased heart rate and decreased skin temperature. Additional studies are needed to separate the pharmacologic, ir- ritant, and allergic effects of tobacco smoke. CLINICAL ALLERGY It is important to understand what role tobacco and tobacco smoke may play in clinical allergy because many individuals are exposed to them in varying concentrations throughout the year. A variety of conditions have been ascribed to allergic manifesta- tions toward tobacco leaf or smoke including: asthma, rhinitis, urticaria, angioneurotic edema (giant hives), contact dermatitis, Migraine headache, gastrointestinal symptoms, and various cardio~ . vascular disturbances (64) ; however, some case reports are lacking in documentation (4, 49). A small group of patients having cutane- Ous sensitivity to tobacco and showing complete disappearance of symptoms when free from exposure to tobacco were reported by Rosen and Levy (55). Included in this group were cases of asthma and urticaria. . Studies of atopic individuals have revealed a group of nonsmoking patients with cutaneous sensitivity to tobacco who developed clinical symptoms upon exposure to tobacco smoke (59, 76). In none of these studies (54, 59,76) have detailed immunologic investigations, attempting to link clinical and immunologic events, been performed. Lowel} (438) reviewed case reports of contact dermatitis to to- 520 bacco among tobacco workers and noted that because of “...the small proportion of exposed individuals who develop such lesions, and the tendency for it to clear completely when contact with tobacco is avoided and to return on reexposure, an allergic cause in certain instances would appear to be highly probable.” Recently, case re- ports have appeared identifying tobacco smoke and tobacco smoke residue as causes of contact dermatitis (6, 12, 72). Harkavy’s (28) early reports of a greater number of reactors to tobacco extract among patients with thromboangiitis obliterans (TAQ) than among controls drew attention to the cardiovascular system as a possible “susceptible” organ for allergic reactions (15). Harkavy continues to be a strong proponent of the role of tobacco allergy in a wide range of cardiovascular abnormalities, including coronary artery disease (21, 22, 25, 27, $1, 82). This view on tobacco allergy as one of the etiological factors in coronary heart disease (CHD) has not received much attention. Silvette, et al. (64) reviewed reports (28, 83, 66, 68,73) on the prevalence of skin sensitivity in patients with TAO as compared to controls and cited possible reasons for a higher prevalence of posi- tive skin tests to tobacco in these patients. In general, the evidence relating TAO to tobacco allergy is incon- clusive. SUMMARY 1. Tobacco leaf, tobacco pollen, and tobacco smoke are antigenic in man and animals. 2. (a) Skin sensitizing antibodies specific for tobacco antigens have been found frequently in smokers and nonsmokers. They appear to occur more often in allergic individuals. Precipitating antibodies specific for tobacco antigens have also been found in both smokers and nonsmokers, (b) A delayed type of hypersensitivity to tobacco has been demonstrated in man. (c) Tobacco may exert an adverse effect on protective mecha- nisms of the immune system in man and animals. 3. (a) Tobacco smoke can contribute to the discomfort of many individuals. It exerts complex pharmacologic, irritative, and allergic effects, the clinical manifestations of which may be indistinguishable from one another. (b) Exposure to tobacco smoke may produce exacerbation ol allergic symptoms in nonsmokers who are suffering from allergies of diverse causes. 4. Little is known about the pathogenesis of tobacco allergy and its possible relationship to other smoking-related diseases. 521 (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) 122 ALLERGY REFERENCES ALLISON, R. D., Roru, G. M. Central and peripheral vascular effects during cigarette smoking. Archives of Environmental Health 19(2): 189-198, August 1969. ARMEN, R. N., CoHEN, S. The effect of forced inhalation of tobacco smoke on the electrocardiogram of normal and tobacco-sensitized rab- bits. Diseases of the Chest 35(6): 663-676, June 1959. AUSTEN, K. F. Disorders due to hypersensitivity and altered immune response. IN: Wintrobe, M. M., Thorn, G. W., Adams, R. D., Bennett, LL., Jr., Braunwald, E., Isselbacher, K. J., Petersdorf, R. G. (Editors). Harrison’s Principles of Internal Medicine. Sixth Edition. New York, McGraw-Hill Book Company, 1970. p. 342. Buve, J. A. Cigarette asthma and tobacco allergy. Annals of Allergy 28(3): 110-115, March 1970. Brunt, A. Influenza dell’avvelenamento da fumo di tabacco sulla fago- citosi. (Effect _of tobacco smoke poisoning on phagocytosis.) Speri- mentale 85: 523-543, 1931. CHANIAL, G., JosePH, J., CoLIn, L., Ducraux, C. Les dermites chez les travailleurs du tabac (A propos de 9 observations). (Dermatitis in tobacco workers. Nine observations.) Bulletin de la Société Francaise de Dermatologie et de Syphiligraphie 77 (2) : 281-283, July 1970. Cuu, Y. M., PARLEtT, R. C., Wricut, G. L., Jk. A preliminary investi- gation of some immunologic aspects of tobacco use. American Review of Respiratory Disease 102(1): 118-123, July 1970. CoueEN, A. B., CLINE, M. J. The human alveolar macrophage: Isolation, cultivation in vitre, and studies of morphologic and functional char- acteristics. The Journal of Clinical Investigation 50(7): 1390-1398, July 1971. Cottorvu, A., Mateescu, D., Lege, V. Consideratii privind sensibilizarea la tatun. (Considerations concerning sensitization to tobacco.) Viata Medicala 16(1): 29-37, January 1969. Coomss, R. R. A. The basic types of allergic reactivity producing disease, Triangle 9(2): 43-46, 1969. Coomps, R. R. A., Geis, P. G. H. Classification of allergic reactions re- sponsible for clinical hypersensitivity and disease. Chapter 20. IN: Gell, P.G.H., Coombs, R.R.A. (Editors). Clinical Aspects of Immu- nology. Second Edition. Philadelphia, F. A. Davis Company, 1968. pp. 575-596. Cori, F. E., DeGarA, P. F. Vesiculobullous dermatitis from tobacco smoke. Journal of the American Medical Association 193 (5): 391-392, August 2, 1965. - DeCrinis, K., Repisca, W., FoNTANA, V., Lewis, A., SULZBERGER, M. B., Steere, J. M. Vascular responses to smoking tobacco compared with responses to skin testing of tobacco extracts. Annals of Internal Medicine 52(5): 1035-1041, May 1960. Donzeu.i, F. Influenza sulle agglutinine dell’avvelenamento da fumo di tabacco. (Effect of tobacco smoke poisoning on agglutinins.) Gior- nale di Batteriologia e Immunologia 11: 1012-1018, 1933. Ferstt, A. Die bedeutung der tabakrauchallergie bei erkrankungen des Gafasssystems. (The importance of allergy to tobacco in diseases of the vascular system.) Weiner Zeitschrift fiir Innere Medizin und Thre Grenzgebiete 43: 455-458, 1962. FINKLEA, J. F., HASSELBLAD, V., RiccaN, W. B., NeLson, W. C., Ham- MER, D. I, Newry, V. A. Cigarette smoking and hemagglutination (17) (18) (79) (20) (21) (22) (25) (24) (25) (26) (27) (28) (29) (50) ($1) ($2) (53) ($4) (35) inhibition response to influenza after natural disease and immuniza- tion. American Review of Respiratory Disease 104(3) : 368-376, Sep- tember 1971. FonTANA, V. J. Tobacco hypersensitivity. Annals of the New York Academy of Sciences 90(1) : 138-141, September 27, 1960. Fontana, V. J., Repiscn, W., Nemm, R. L., SMiry, M. K., DeECRINIS, K., SULZBERGER, M. B. Studies in tobacco hypersensitivity. HI. Reac- tions to skin tests and peripheral vascular responses. Journal of Allergy 30(3): 241-249, May—June 1959. FRIEDLANDER, M., SILBERT, S., LASKEY, N. Toe lesions following tobacco injections in rats. Proceedings of the Society for Experimenta] Biology and Medicine 34: 156-157, 1936. GREEN, G. M., Carorin, D. The depressant effect of cigarette smoke on the in vitro antibacterial activity of alveolar macrophages. New England Journal of Medicine 276: 422-427, February 23, 1967. Harkavy, J. Cardiac manifestations due to hypersensitivity. Annals of Allergy 28(6): 242-251, June 1970. HarkKavy, J. Cardiovascular manifestations due to hypersensitivity. New York State Journal of Medicine 69(21): 2757-2765, November 1, 1969. Haxrxavy, J. Hypersensitiveness to tobacco and biopsy studies of skin reactions in vascular disease. Journal of Allergy 9:475-488, 1938. Harkavy, J. Tobacco allergy. Chapter 13. IN: Vascular Allergy and its Systemic Manifestations. Washington, Butterworths, 1963. pp. 101-116. Harxavy, J. Tobacco allergy in cardiovascular disease: A review. Annals of Allergy 26(8): 447-459, August 1968. Harwavy, J. Tobacco allergy in vascular diseases. Review of Allergy and Applied Immunology 11: 189-212, March 1957. Harkavy, J. Tobacco sensitiveness in angina pectoris and coronary artery disease. Proceedings of the Society for Experimental Biology and Medicine 30: 683-684, 1933. Harkavy, J. Tobacco sensitiveness in thromboangiitis obliterans, mi- grating phlebitis and coronary artery disease. Bulletin of the New York Academy of Medicine 9: 318-322, 1933. Harkavy, J. Tobacco sensitization in rats, Journal of Allergy 9: 275- 277, 1938. HAarkavy, J. Tobacco skin reactions and their clinical significance. The Journal of Investigative Dermatclogy 2: 257-279, 1939. HARKAVY, J., PERLMAN, E. Tobacco allergy in coronary artery disease. Annals of the New York Academy of Sciences 90(1): 327-332, Sep- tember 27, 1960. Harkavy, J., PeRLMAN, E. Tobacco allergy in coronary artery disease. New York State Journal of Medicine 64(11) : 1287-1296, June 1, 1964. Harkavy, J., RoMANOFF, A. Skin reactions to tobacco and other aller- gens in normal men and women smokers. Journal of Allergy 6: 62- 10, 1934. Harkavy, J., WiTessky, E. Studies of specificity in multiple hyper- sensitiveness by quantitative titration and absorption of reagins. Journal of Allergy 6: 437-447, 1935. Harris, J. 0., Swenson, E. W., JoHNson, J. E. II. Human alveolar macrophages: Comparison of phagocytic ability, glucose utilization, and ultrastructure in smokers and nonsmokers. The Journal of Clini- cal Investigation 49: 2086-2096, 1970. 523 (36) (37) (38) (39) (49) (47) (42) (43) (44) (45) (46) (47) (48) (49) (50) (51) (52) 524 Heisxe, C. L., Mirver, J. N., Avoricg, H. J., Carpenter, C. M. Smok- ing and serologic abnormalities. Journal of the American Medical Association 181(8): 674-677, August 25, 1962. IsHIZAKA, K. The identification and significance of Gamma E. Hospital Practice: 70-81, September 1969. KAMESWARAN, L., KANAKAMBAL, K., VIJAYASEKARAN, V. Studies on plasma histaminase levels in normal and allergic individuals. Indian Journal of Physiology and Pharmacology 12(4): 159-165, October 1968. Kreis, B., PELTIER, A., FourNaup, S., Dupin-Girop, 5. Reaction de precipitation entre certains serums humains et des extraits solubles de tabac. (Precipitation reaction between certain human sera and soluble tobacco extracts.) Annales de Medecine Interne 121(4) : 437- 440, April 1970. Lewis, D. M., Lapp, N. LeR., BURRELL, R. Quantitation of secretory immunoglobulin A in chronic pulmonary disease. American Review of Respiratory Disease 101(1): 55-61, January 1970. Lima, A. O., Rocua, G. Cutaneous reactions to tobacco antigen in aller- gic and nonallergic children. Annals of Allergy 7(4): 528-531, July- August 1949. Lounsgury, J. B., OUGHTERSON, A. W. Specificity of tobacco antigen. Yale Journal of Biology and Medicine 7(4) : 305-316, March 1935. LoweLL, F. C. Allergy. IN: Wynder, E. (Editor). The Biologic Effects of Tobacco. Boston, Little, Brown, and Company, 1955. pp. 151-170. Maurer, M. L., Span, W. C. The allergic response to tobacco. Journal of the American Geriatric Society 2: 278-283, 1954. MAXWELL, K. W., Maxcus, S., RENZETTI, A. C., Jn. 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Chapter 9 Tobacco Amblyopia Source: 1971 Report, Chaprer 7, pages 431 - 438. 527 Summary and conclusions References ............. Contents 529 TOBACCO AMBLYOPIA Tobacco amblyopia (tobacco-aleohol amblyopia) is that syn- drome of visual failure occurring in association with the use of tobacco, with or without the concurrent use of alcohol, and with or without concurrent nutritional deficits. The disease has a subacute onset, leading to a loss of visual acuity and color perception (12). It is characterized by centrocecal scotomas which are bilateral but not necessarily symmetrical and which have sloping diffuse edges and by the presence of nuclei of denser visual loss within the large scotomas (22, 23). Such visual impairment is not unique to tobacco amblyopia, as it is also seen in neurodegenerative disorders, such as Leber’s hereditary optic atrophy (7, 25). Clinical information on tobacco amblyopia has appeared in nu- merous articles throughout the past century. This information has been reviewed by Silvette, et al. (17) and, more recently, by Dunphy (5). Pure tobacco amblyopia (TA), that is amblyopia unassociated with excessive alcohol intake or the exposure to other toxins, is rarely seen in the United States today (12). Walsh, et al. (23) have observed that when TA is found it is usually present in association with nutritional or idiopathic vitamin deficiencies. Victor (22) recently observed that the type of visual defect seen in tobacco amblyopia may be found in clinical circumstances in which tobacco Is clearly not a causative factor. He questions whether TA is distinguishable from other forms of amblyopia. The prevalence of this disorder has been variously estimated in the past at from 0.5 to 1.5 percent of all eye clinic patients (20, 23). However, currently in the United States, it appears to be a rare condition. Silvette, et al. (17) have observed that the incidence of tobacco amblyopia appears to have decreased substantially during the past decades. Other authors (3, 15) have also commented on this trend. Although reference has been made to the increased fre- quency of certain types of tobacco usage in patients with this dis- order, adequate population studies with proper controls have yet to be performed. The association of this disorder with the use of tobacco is strengthened by the frequent clinical observations of improvement following the cessation of smoking although improve- ment has been noted by some to occur without cessation. Research into the pathogenesis of tobacco amblyopia has cen- 531 tered upon the interrelationships of cyanide metabolism, vitamin B,2, and other vitamin deficiencies. Three reviews of this material have recently appeared (7, 12, 22). Numerous studies reviewed in these articles suggest that tobacco amblyopia may result from the incomplete detoxification of the cyanide present in tobacco smoke. This failure of detoxification may stem from or be intensified by inadequate dietary intake of necessary nutritional factors. This may be the reason for the association of this disorder with exces- sive alcohol intake and with its related nutritional deficits (2, 4, 6, 8,9, 10, 11, 13,14, 16, 18, 19, 21, 24, 26, 27,28). SUMMARY AND CONCLUSIONS Tobacco amblvopia is presently a rare disorder in the United States. The evidence suggests that this disorder is related to nutri- tional or idiopathic deficiencies in certain detoxification mechan- isms, particularly in handling the cyanide component of tobacco smoke. REFERENCES (1) CANADIAN MEDICAL ASSOCIATION JOURNAL. Tobacco amblyopia. (Edi- torial) Canadian Medical Association Journal 102(4): 420, February 28, 1970. (2) CursHoi, IL. A., BRONTE-StEwart, J., FOULDS, W.S. Hydroxocobalamin versus cyanocobalamin in the treatment of tobacco amblyopia. Lancet 2(7513): 450-451, August 26, 1967. (3) Daxrsy, P. W., Wicson, J. Cyanide, smoking, and tobacco amblyopia. Observations on the cyanide content of tobacco smoke. British Journal of Ophthalmology 51(5) : 336-338, May 1967. (4) Drexrus, P. M. Blood transketolase levels in tobacco-alcohol amblyopia Archives of Ophthalmology 74(5): 617-620, November 4965. (5) Duxpny, E. B. Alcohot and tobacco amblyopia: A historical survey. American Journal of Ophthalmology 68(4): 569-578, October 1969. (6) Fou.ps, W. S., BRonTe-STewaRT, J. M., CuisHo_M, I. A. Serum thio- cyanate concentrations in tobacco amblyopia. Nature 218(5141) : 586, May 11, 1968. Foutps, W. S., Cant, J. S., CH1sHoim, YT. A., BRONTE-STEWART, d., Witson, J. Hydroxocobalamin in the treatment of Leber’s hereditary optic atrophy. Lancet 1(7548) : 896-897, April 27, 1968. Fouups, W. S., CuisHoi, I. A., BRonTe-Stewakrr, J., Witson, T. M. Vitamin B,., absorption in tobacco amblyopia. British Journal of Ophthalmology 53(6) : 393-397, June 1969. Founps, W. S., CHISHOLM, I. A., BRONTE-STEWART, J., Wrison, T. M. The optic neuropathy of pernicious anemia. Archives of Ophthalmol- ogy &2(4) : 427-432, October 1969. FREEMAN, A. G., HEATON, J. M. The aetiology of retrobulbar neuritis in 908-911, April 29, (7) (8) (9) (10) Addisonian pernicious anaemia. Lancet 1(7183) : 1961. 532 (11) Heaton, J. M., McCormicn, A. J. A., FREEMAN, A. G. Tobacco amblyo- pia: A clinical manifestation of vitamin-B,, deficiency. Lancet 2(7041) : 286-290, August 9, 1958. (12) Knox, D. L. Neuro-ophthalmology. Archives of Ophthalmology 83(1): 103-127, January 1970. (13) LinpstRanp, K., WiLson, J., MattHews, D. M. Chromatography and microbiological assay of vitamin B,, in smokers. British Medical Journal 2 (5520) : 988-990, October 22, 1966. (14) Linnett, J. C., Smitu, A. D. M., Smitu, C. L., WILson, J., MATTHEWS, D. M. Effects of smoking on metabolism and excretion of vitamin B,,. British Medical Journal 2(5599) : 215-216, April 27, 1968. (15) Scuepens, C. L. Is tobacco amblyopia a deficiency disease— Transactions of the Ophthalmological Society of the United Kingdom 66: 309-331, 1946. (16) ScHieverseIn, H., WERLE, E., Scnurz, E. K., BAUMEISTER, R. The influ- ence of tobacco smoke and nicotine on thiocyanate metabolism. Naunyn-Schmiedebergs Archiv fiir Pharmakologie und Experimentelle Pathologie 262(3) : 358-365, February 5, 1969. (17) Siverre, H., Haac, H. B., Larson, P. S. Tobacco amblyopia. The evolu- tion and natural history of a “tobaccogenic” disease. American Journal of Ophthalmology 50(1): 71-100, January 1960. (18) Snuts, A. D. M. Retrobulbar neuritis in Addisonian pernicious anae- mia. (Letter) Lancet 1(7184): 1001-1002, May 6, 1961. (19) SMirH, A. D. M., Duckett, S. Cyanide, vitamine B,,, experimental demyelination and tobacco amblyopia. British Journal of Experimen- tal Pathology 46(6) : 615-622, December 1965. (20) Traquair, H. M. Toxic amblyopia, including retrobulbar neuritis. Trans- actions of the Ophthalmological Society of the United Kingdom 50: 351-385, 1930. (21) Victor, M. Tobacco-alcohol amblyopia. A critique of current concepts of this disorder, with special reference to the role of nutritional deficiency in its causation. Archives of Ophthalmology 70(3): 313-318, Septem- ber 1963. (22) Vicror, M. Tobacco amblyopia, cyanide poisoning and vitamin B,, de- ficiency. A critique of current concepts. Chapter 3. IN: Smith, J. L. (Editor) Neuro-Ophthlamology. Symposium of the University of Miami and the Bascom Palmer Eye Institute. Hallandale, Florida, Huffman Publishing Co., 1970. pp. 33-48. - (23) Watsu, F. B., Hoyt, W. F. (Editors) Neurotoxic substances affecting the visual and ocular motor systems. Chapter 15: IN: Clinical Neuro- Ophthalmology, Volume 3, 3rd Edition. Baltimore, The Williams & Wilkins Company, 1969. pp. 2613-2616. (24) WAaTSON-WILLIAMS, E. J., BoTtoMtey, A. C., AInLEY, R. G., PHILLIPS, C. I. Absorption of vitamin B,. in tobacco amblyopia. British Journal of Ophthalmology 53(8) : 549-552, August 1969. (25) Witson, J. Leber’s hereditary optic atrophy: A possible defect of cya- nide metabolism. Clinical Science 29(3): 505-515, December 1965. (26) Witson, J., MartrHews, D. M. Metabolic inter-relationships between cyanide, thiocyanate and vitamin B,, in smokers and nonsmokers. Clinical Science 31(1): 1-7, January 1966. 533 (27) Wokes, F., Picarp, C. W. The role of vitamin B,. in human nutrition. Clinical Nutrition 3(5) : 383-390, September-October 1955. (28) Wynoer, E. L., HOFFMANN, ID. Certain constituents of tobacco products. Chapter 8. K. Vapor phase af tobacco smoke. IN: Wrynder, E. L., Hoffmann, P. (Editors). Tobacco and Tobaceo Smoke. Studies in Ex- perimental Carcinogenesis, New York, Academic Press, 1967. pp. 451-453. 534 Chapter 10 Pipes and Cigars Source: 1973 Report, Chapter 6, pages 165 - 236. 535 Contents Introduction _.....222-2 2.22 The Prevalence of Pipe, Cigar, and Cigarette Usage._________ The Definition and Processing of Cigars, Cigarettes, and Pipe Tobaccos...-._-- 222-22 eee Mortality Overall Mortality........22..2222.- 2-2 Mortality and Dose-Response Relationships Amount Smoked___-_- 2 2-222 Inhalation.-.__-_ 2-222 List of Figures Figure 1.—Inhalation among pipe smokers by age... Figure 2.—Inhalation among cigar smokers by age—Ham- mond___ 2222 Page S41 543 545 547 549 550 553 559 559 560 561 563 567 373 5890 580 585 592 592 599 600 554 555 555 Figure 5.—Percent distribution of 130 brands of cigarettes and 25 brands of little cigars by nicotine content._...._.-____- List of Tables Table 1.—Percent distribution of U.S. males aged 21 and older by type of tobacco used for the years 1964, 1966, and 1970__ Table 2.—Percent distribution of U.S. males by type of tobacco used and age for 1970__.____.__.____-. 2222 ee. Table 3.—Percent distribution of British males aged 25 and older by type of tobacco used for the years 1965, 1968, and Table 4.—Amounts of several components of 1 gram of par- ticulate material from mainstream smoke of tobacco prod- Table 5.—A comparison of several chemical compounds found in the mainstream smoke of cigars, pipes, and cigarettes____ Table 6.—Mortality ratios for total deaths by type of smoking (males only). ....2222 22-2 ee Table 7.—Mortality ratios for total deaths of cigar and pipe smokers by amount smoked—Hammond and Horn_______- Table 8.—Mortality ratios for total deaths of cigar and pipe smokers. by amount smoked—Best_..._-.__.____-_.___.__. Table 9.—Mortality ratios for total deaths of cigar and pipe smokers by age and amount smoked—-Kahn_.____________ Table 10.—Mortality ratios for total deaths of cigar and pipe smokers by amount smoked—Hammond__._____________. Table 11.—The extent of inhaling pipes, cigars, and cigarettes by British males aged 16 and over in 1968 and 1971_______ Table 12.—Inhalation among cigar, pipe, and cigerette smokers by age—Doll and Hill__-..-- 28 Table 13.—Mortality ratios for total deaths of cigar and pipe smokers by age and inhalation—Hammond._____________. Table 14.—Percentage of British male cigar smokers who re- ported inhaling a lot or a fair amount by type of product smoked... Table 15.—Percentage of individuals reporting inhalation of “almost every puff” of tobacco smoke by current and pre- vious tobacco usage and type of tobacco used____.________ Table !6.—Percentage of British males who reported inhaling a lot or fair amount of cigar smoke by current and previous tobacco usage and type of tobacco previously smoked (1968) _- 22. 538 Page 596 543 544 544 547 548 550 551 551 552 552 556 556 557. 557 558 558 Table 17.—Extent of reported inhalation of cigar smoke by British male cigar smokers who were ex-cigarette smokers in 1968, analyzed by extent of reported inhalation of cigarette smoke when previously smoking cigarettes__~.------------- Table 18.—Mortality ratios for total cancer deaths in cigar and pipe smokers. A summary of prospective epidemiological studieS.._..._------------- eee ee eee Table 19.—Relative risk of Jip cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies... -_-----------------------7-77-7577 Table 20.—Mortality ratios for oral cancer in cigar and pipe smokers. A summary of prospective epidemiological studies- - Table 21.—Relative risk of oral cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A sum- mary of retrospective studies- - ~~ ----------------r--7 777 Table 22.—-Mortality ratios for cancer of the larynx in cigar and pipe smokers. A summary of prospective epidemiological studieS._..___-----e ne eee ener Table 23.—Relative risk of cancer of the larynx for men, com- paring cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies__.___---------------- Table 24.—Mortality ratios for cancer of the esophagus in cigar and pipe smokers. A summary of prospective epidemio- logical studies....------------------------070 rrr Table 25.—Relative risk of cancer of the esophagus for mep, comparing cigar, pipe, and cigarette smokers with non- smokers. A summary of retrospective studies_.._~---------- Table 26.—-Mortality ratios for lung cancer deaths in male cigar and pipe smokers. A summary of prospective studies. .-- Table 27.—Lung cancer death rates for cigar and pipe smokers by amount smoked—Doll and Hill_._-__.--------------- Table 28.—Lung cancer mortality ratios for cigar and pipe smokers by amount smoked—Kahn-_-_-.--------------7-- Table 29.—Relative risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies._------------------7777 Table 30.—Changes in bronchial epithelium of male cigar, pipe, and cigarette smokers as compared to nonsmokers- - - - Table 31.—Tumorigenic activity of cigar, pipe, and cigarette smoke condensates in skin painting experiments on animals _- Table 32.—Mortality ratios for cardiovascular deaths in male cigar and pipe smokers. A summary of prospective epi- demiological studies_.--.-----------------77 77007077707 Page 559 559 562 563 564 566 568 570 571 574 574 575 576 579 583 586 539 Page Table 33.— Mortality ratios for chronic obstructive pulmonary deaths in male cigar and pipe smokers. A summary of pros- pective epidemiological studies..-...-.----. 589 Table 34.—Prevalence of respiratory symptoms and illness by type of smoking.____. 222 ee 590 Table 35.—Pulmonary function values for cigar and pipe smokers as compared to nonsmokers.....-.-...-.. 591 Table 36.—Mortality ratios for peptic ulcer disease in male cigar and pipe smokers. Summary of prospective studies. __ 592 Table 37.—Shipment of small and large cigars destined for domestic consumption (1970, 1971, 1972)_...- 597 Table 38.-—Selected compounds in mainstream smoke... _. 598 Table 39.—The pH of the mainstream smoke of selected tobacco products. _-___.___..- ee 538 540 Introduction This chapter is a review of the epidemiological, pathological, and experimental data on the health consequences of smoking cigars and pipes, alone, together, and in varicus combinations with cigarettes. Previous reviews on the health consequences of smoking have dealt primarily with cigarette smoking. Although some of the material on pipes and cigars presented in this chapter has been presented in previ- ous reports of the Surgeon General, this is the first attempt to summa- rize what is known about the health effects of pipe and cigar smoking. Since the use of pipes and cigars is limited almost exclusively to men in the United States, only data on men are included in this review. The influence of pipe and cigar smoking on health is determined by examining the overall and specific mortality and morbidity ex- perienced by users of these forms of tobacco compared to nonsmokers. Epidemilogical evidence suggests that individuals who limit their smoking to only pipes or cigars have overall mortality rates that are slightly higher than nonsmokers. For certain specific causes of death, however, pipe and cigar smokers experience mortality rates that are as great as or exceed those experienced by cigarette smokers. This analysis becomes more complex when combinations of smoking forms are examined. The overall mortality rates of those who smoke pipes, cigars, or both in combination with cigarettes appear to be inter- mediate between the high mortality rates of cigarette smokers and the lower rates of those who smoke only pipes or cigars. This might seem to suggest that smoking pipes or cigars in combination with ciga- rettes diminishes the harmful effects of cigarette smoking. However, an analysis of mortality associated with smoking combinations of ciga- rettes, pipes, and cigars should be standardized for the level of con- sumption of each of the products smoked in terms of the amount smoked, duration of smoking, and the depth and degree of inhalation. For example, cigar smokers who also smoke a pack of cigarettes a day might be expected to have mortality rates somewhat higher than those who smoke only cigarettes at the level of a pack a day, assuming that both groups smoke their cigarettes in the same way. Mixed smokers who inhale pipe or cigar smoke in a manner similar to the way they smoke cigarettes might be expected to have higher mortality rates than mixed smokers who do not inhale their cigars and pipes and also 541 resist inhaling their cigarettes. Unfortunately, little of the published material on mixed cigarette, pipe, and cigar smoking contains these types of analvses or controls. -\ paradox seems to exist. bet ween the mortality rates of ex-smokers of pipes and cigars and ex-smokers of cigarettes. Ex-cigarette smokers experience a relative decline in overall and certain specific causes of mortality following cessation. This decline is important but indirect evidence that cigarette smoking is a major cause of the elevated mor- tality rates experienced by current cigarette smokers. In contrast to this finding, several prospective epidemiological investigations, Hammond and Horn (40), Best (9), Kahn (50), and Hammond (38), have reported higher death rates for ex-pipe and ex-cigar smokers than for current pipe and cigar smokers. This phenomenon was ana- lyzed by Hammond and Garfinkel (39). The development of il health often results in a cigarette smoker giving up the habit, reducing his daily tobacco consumption, switching to pipes or cigars, or choosing a cigarette low in tar and nicotine. In many instances, a smoking- related disease is the cause of ill health. Thus, the group of ex-smokers includes some people who.are ill from smoking-related diseases, and death rates are high among persons in ill health. As a result, ex-cigarette smokers initially have higher overall and specific mortality rates than continuing cigarette smokers, but be- cause of the relative decrease in mortality that occurs in those who quit smoking for reasons other than ill health, and because of the dwindling number of ill ex-smokers, a relative decrease in mortality is observed (within a few years) following cessation of cigarette smoking. The beneficial effects of cessation would be obvious sooner were it not for the high mortality rates of those who quit smoking for reasons of illness. A similar principle operates for ex-pipe and ex- cigar smokers, but because of the lower initial risk of smoking these forms and therefore the smaller margin of benefit following cessation, the effect produced by the ill ex-smokers creates a larger and more Persistent impact on the mortality rates than is seen in cigarette smoking. _ For the above reasons a bias is introduced into the mortality rates of current smokers and ex-smokers of pipes and cigars, so that a more accurate picture of mortality might be obtained by combining the ex-smokers with the current smokers and looking at the resultant mortality experience, Because of a lack of data that would allow a precise analysis of mortality among ex-pipe and ex-cigar smokers, a detailed analysis of these groups could not be undertaken in this review. . For each specific cause of death, tables have been prepared which summarize the mortality and relative risk ratios reported in the major 542 prospective and retrospective studies which contained information about pipe and cigar smokers. The smoking categories used include: cigar only, pipe only, total pipe and cigar, cigarette only, and mixed. The total pipe and cigar category includes: those who smoke pipes only, cigars only, and pipes and cigars. The mixed category includes: those who smoke cigarettes and cigars; cigarettes and pipes; and cigarettes, pipes, and cigars. Mortality and relative risk ratios were _ calculated relative to nonsmokers. The Prevalence of Pipe, Cigar, and Cigarette Usage The prevalence of pipe, cigar, and cigarette smoking in the United States was estimated by the National Clearinghouse for Smoking and Health from population surveys conducted in 1964, 1966, and 1970 (98, 99, 100). In each survey, about 2,500 interviews were conducted on a national probability sample stratified by type of population and geographic area. The use of these products among adults aged 21 and older is summarized in tables 1 and 2. The prevalence of pipe, cigar, and cigarette smoking in Great Britain for the years 1965, 1968, and 1971 is presented in tables. Tape 1.—Percent distribution of U.S. male smokers aged 21 and older by type of tobacco used for the years 1964, 1966, and 1970 Forms used 1064 1964 1970 (percent) (percent) (percent) 1. Cigar only. __--------------------00 0077 6.38 5.5 5.6 2. Pipe only____--------------+-----777777 1.7 3.0 3.6 3. Pipe and cigar--.-.---------------77-777 3.9 49 44 4. Cigarette only_.-------------------7777> 28. 6 31.2 25.9 5. Cigarette and cigar._------------------7- 11.3 9.9 6.6 6. Cigarette and pipe. --------------------- 5.3 4.9 5.3 7. Cigarette, pipe, and cigar. -.------------- 7.7 6.3 46 8. Nonsmoker_...----------------7-7 777777 34.7 34.3 44.0 oo Total. ._---------------- 7-7-0007 100. 0 100. 0 100. 0 a Number of persons in sample-~------------- 2, 389 2, 679 2, 861 Total pipe users (2+3+ 647)_-------------- 18. 7 9. 2 17.9 Total cigar users (1+34+547)-------------- 29.9 26.7 21.2 Total cigarette users (4454+647)_---------- 529 52. 4 42.3 Source. U8. Department of Health, Education, and Welfare (98, 09, 100). 543 TABLE 2.—Percent distribution of U.S. male smokers by type of tobac- co used and age for 1970 Age groups Forms used 21 to 34 Btow 4to5t SStoGd 65to7S + 1. Cigar only_..-------------- 3.7 6.5 4.7 6.7 9.3 2. Pipe only_.---------------- 4.3 3.5 3.0 3.2 3.6 3. Pipe and cigar__.-.--------- 3.8 3.3 5. 2 4.4 6.9 4. Cigarette only._.._--------- 28. 8 29. 0 27.1 24.3 13. 6 5. Cigarette and cigar__..------ 6.8 10. 4 5.5 5. 2 4.2 6. Cigarette and pipe_--------- 6.6 4.4 5. 6 4.0 3.8 7. Cigarette, pipe, and cigar---- 5.8 48 5.0 4.0 14 §. Nonsmoker._-.------------- 40. 2 38. 1 43.9 48. 2 57. 2 Total___..------------- 100.0 100.0 100.0 100.0 100. 0 Number of persons in sample--- 1, 009 528 523 405 388 Total pipe users_.------------- 20. 5 16.0 18. 8 15. 6 15. 7 Total cigar users_.------------ 20. 1 25. 0 20. 4 20. 3 21.8 Total cigarette users_--------- 48.1 48. 6 43.3 37.5 23. 0 Bource: U.S. Department of Health, Education, and Welfare (/00). TABLE 3.—Percent distribution of British male smokers aged 25 and older by type of tobacco used for the years 1965, 1968, and 1971 Forms used 1963 1968 1971 1. Cigars only_..-.---------------------+-- 1.9 2.8 3.3 2. Pipe only----------------------------7- 3.1 5.6 5.9 3. Cigarettes only. __.__------------------- 46. 8 A5. 7 40.8 4, Cigarettes and pipe. -------------------- 8.0 7.0 6.1 5. Mixed smokers. __._-------------------- 7.5 9.1 8.4 6. Nonsmokers_..._----------------------- 30. 7 29. 9 35. 4 Total.__._.---------------------- 77> 100. 0 100. 0 106. 0 ee Number of persons in sample-- - ------------ 3, 576 3, 566 3, 594 i Total pipe users-_.------------------------- 13.9 14.3 13. 3 Total cigar. __---------------------------- 9.0 11.7 11.3 67.6 67. 6 61.6 Total cigarette Source: Todd 544 .G. F. (95). The Definition and Processing of Cigars, Cigarettes, and Pipe Tobaccos Cigarettes The U.S. Government has defined tobacco products for tax pur- poses. Cigarettes are defined as “(1) Any roll of tobacco wrapped in paper or in any substance not containing tobacco, and (2) any roll of tobacco wrapped in any substance containing tobacco which, because of its appearance, the type of tobacco used in the filler, or its packaging and labeling, is likely to be offered to, or purchased by, consumers 88 a cigarette described in subparagraph (1).” Cigarettes are further classified by size, but virtually all cigarettes sold in the United States are “small cigarettes” which by definition weigh “not more than 3 pounds per thousand” which is not more than 1.361 grams per cigarette (96). ‘American brands of cigarettes contain blends of different grades of Virginia, Burley, Maryland, and oriental tobaccos. Several varieties of cigarette tobaccos are flue-cured. In this process, tobacco leaves are cured in closed barns where the temperature is progressively raised over a period of several days. This results in “color setting,” fixing, and drying of the leaf. The most conspicuous change is the conversion of starch into simpler sugars and suppression of oxidative reactions. Flue-cured tobaccos produce an acidic smoke of light aroma (35, 112). Cigars Cigars have been defined for tax purposes as: “Any roll of tobacco wrapped in leaf tobacco or in any substance containing tobacco (other than any roll of tobacco which is a cigarette within the meaning of subparagraph (2) of the definition for cigarette)” (172). In order to clarify the meaning of “substance containing tobacco” the Treasury department has stated that, “The wrapper must (1) contain a signifi- cant proportion of natural tobacco; (2) be within the range of colors normally found in natural leaf tobacco; (3) have some of the other characteristics of the tobaccos from which produced; e.g., nicotine content, pH, taste, and aroma; and (4) not be so changed in the reconstitution process that it loses all the tobacco characteristics” (102). Further, “To be a cigar, the filler must be substantially of tobaccos unlike those in ordinary cigarettes and must not have any added flavoring which would cause the product to have the taste or aroma generally attributed to cigarettes. The fact that a product does 545 not resemble a cigarette (such as manv large cigars do not) and has a distinctive cigar taste and aroma is of considerable significance in making this determination” (762). Cigars are also classified by size. “Small cigars” weigh not more than 3 pounds per thousand and “large cigars” weigh more than 3 pounds per thousand. “Large cigars” are further divided into seven classes for tax purposes based on the retail price intended by the manufacturer for such cigars (96). Cigars are made of filler, binder, and wrapper tobaccos. Most cigar tobaccos are air-cured and then fermented. More recently, reconsti- tuted cigar tobaccos have been used as wrapper, binder, or both. Cigars are either hand-rolled or machine made. Some brands of small cigars are manufactured on regular cigarette making machines. The aging and fermentation processes used in cigar tobacco production produce chemical catalytic, enzymatic. or bacterial transformations as evi- denced by increased temperature, oxygen utilization, and carbon dioxide generation within fermenting cigar tobaccos. In this complex process, up to 20 percent of the dry weight of the leaf is lost through decreases in the concentration of the most readily fermentable ma- terials such as carbohydrates, proteins. and alkaloids. The flavor and aroma of cigar tobaccos are in large measure the results of precisely controlled treatment during the fermentation process (35, 96, 112). Pipe Tobaccos The definition of pipe tobacco used by the U.S. Government was repealed in 1966 and there is no Federal tax on pipe tobaccos. The most popular pipe tobaccos are made of Burley; however, many pipe tobaccos are blends of different types of tobacco. A few contain a significant proportion of midrib parts that are crushed between rollers. “Saucing” material, or casings containing licorice, sweetening agents, sugars, and other flavoring materials are added to improve the flavor, . aroma, and smoke taste. These additives modify the characteristics — of smoke components (112). Conclusion Because of the unique curing and processing methods used in the production of cigar and pipe tobaccos. significant physical and chemi- cal differences exist between pipe and cigar tobaccos and those used in 546 cigarettes. The extent to which these changes may alter the health consequences of smoking pipes and cigars can best be estimated by an analysis of the potentially harmful chemical constitutents found in the smoke of these tobaccos. the tumorigenic activity of smoke conden- sates in experimental animals, and a review of the epidemiological data which has accumulated on the health etfects of pipe and agar smoking. Chemical Analysis of Cigar Smoke Only a few studies have been conducted that compare the chemical constituents of cigar smoke with those found in cigarette smoke. Hoffmann, et al. (43) compared the yields of several chemical com- ponents in the smoke from a plain 85 mm. cigarette, two types of cigars, and a pipe. The particulate matter, nicotine, benzo(a) pyrene, and phenols were determined quantitatively in the smoke of these tobacco products. One cigar tested was a 135-mm.-long, 7.8-g., U.S.- made cigar. The other was a handmade Havana cigar 147 mm. long weighing 8.6 g. The relative content of nicotine in the particulate matter produced by the cigars was similar to that of the cigarette tars. The benzo(a)pyrene and phenol concentrations in the cigar condensate was two to three times greater than in cigarette “tar” (table 4). Kuhn (58) compared the alkaloid and phenol content in conden- sates from an 80-mm. Bright-blend cigarette sold commercially in Austria with that obtained from 103-mm. cigars. These were tested Amounts of several components of 1 g. of perticulate material TABLE 4. from mainstream smoke of tobacco products Tobacco product ! - Standard 85 mm. 83mm. Compound U.S. Havana pipe Cigarette plain U.S. plain U.S. cigar A cigar B tobacco tabscco cigarette cigarette (b} (b) in pipe in pipe (a) (b) (bd) Nicotine (mg.)---------- 46.2 63. 6 56. 1 61.0 65. 9 774 Benzo(a)pyrene (yg.)- --- 3.9 3.6 6.0 3.6 1.2 1.3 Phenol (mg.)_----------- 8.2 67 15.0 7.3 2.9 4.1 »+Cresol (mg.)_-~------- 1.6 1.7 1.9 La .6 8 n+ p-Cresol (mg.)-_----- 4.8 3.8 5.6 34 L4 1.9 n+p-Ethylphenol (mg.)-- 1. i 1.5 i 1.3 .7 7 4 Smoking conditions: (a) 1 pul per minute, duration 2 sec., puff volume 35 ml. (b) 2 putts per minute, duration 2sec., put volume 335 ml. Source: Hoffmann, et al. (43). 547 with and without the use of a cellulose acetate filter. The concentra- tions of total alkaloids and phenol in the cigar smoke condensate were essentially the same as in the cigarette condensate, but pyridine values were about 214 times higher in the cigar condensate. Campbell and Lindsey (/7) measured the polycyclic hydrocarbon levels in the smoke of a small popular-type cigar 8.8 cm. long, weighing 1.9 g. Significant quantities of anthracene, pyrene, fluoranthene, and benzo(a)pyrene were detected in the unsmoked cigar tobacco, in con- centrations much greater than those found in Virginia cigarettes but of the same order as those found in some pipe tobaccos. The smoking process contributed considerably to the hydrocarbon content of the smoke. Table 5 compares the concentrations in the mainstream smoke of cigarettes, cigars, and pipes of four hydrocarbons frequently found in condensates. The authors reported that the mainstream smoke from a popular brand of small cigar contained the polycyclic aromatic hydrocarbons; acenaphthylene, phenanthrene, anthracene, pyrene, fluoranthene, and benzo(a) pyrene. The concentrations of these hydro- carbons in the mainstream smoke were greater than those found in Virginia cigarette smoke. Osman, et al. (69) analyzed the volatile phenol content of cigar smoke collected from a 7-g. American-made cigar with domestic filler. After quantitative analysis of phenol, cresols, xylenols, and meta and para ethyl phenol, the authors concluded that the levels-of these com- pounds were generally similar to those reported for cigarette smoke. Osman and Barson (68) also analyzed cigar smoke for benzene, toluene. ethyl benzene, m-, p-, and o-xylene, m- and p-ethyltoluene, 1.2,4-trimethylbenzene, and dipentene, and generally found levels within the range of those previously reported for cigarette condensates. In summary. available evidence suggests that cigar smoke contains many of the same chemical constituents, including nicotine and other alkaloids, phenols, and polycyclic aromatic hydrocarbons as are found TasLe 5.—A comparison of several chemical compounds found in the mainstream smoke of cigars, pipes, and cigarettes Micrograms per 100 g. of tobacco consumed Compound Cigars Pipes ! Cigarettes Acenaphthylene___------------------------ 1.6 29. 1 5.0 Anthracene____--_--------------------- 7" 11.9 110. 0 10.9 Pyrene_____-------------------- 7-00-00 17.6 75. 5 12.5 3.4 8. 5: .9 ‘This Is alight pipe tobacco. Bource: Campbell, J. M., Lindsey, A. J.a7). 548 in cigarette smoke. Most of these compounds are found in concentra- tions which equal or exceed levels found in cigarette “tar.” A more complete picture of the carcinogenic potential of cigar “tars” is ob- tained from experimental data in animals. Mortality Overall Mortality Several large prospective studies have examined the health conse- quences of various forms of smoking. The results of these investiga- tions have been reviewed in previous reports of the Surgeon General in which the major emphasis has been on cigarette smoking and its effect on overall and specific mortality and morbidity. The following pages present a current review of the health consequences of smoking pipes and cigars. Data from the prospective investigations of Dunn, et al. (3/), Buell, et al. (26), Hirayama (42), and Weir and Dunn (705) are not cited, because in these studies a separate category for pipe and cigar smokers was not established. The smoking habits and mortality experience of 187,783 white men between the ages of 50 and 69 who were followed for 44 months were reported by Hammond and Horn (41). The overall mortality rates of men who smoked pipes or cigars were slightly higher than the rates of men who never smoked. The overall mortality rate of cigar smokers was shghtly higher than that of pipe smokers. In a study of 41,000 British physicians, Doll and Hill (26, 27) re- ported the overall mortality of pipe and cigar smokers as being only 1 percent greater than that among nonsmokers. Best: (9), in a study of 78,000 Canadian veterans, reported overall mortality rates of pipe and cigar smokers slightly above those of nonsmokers. Kahn (50) exam- ined the death rates and smoking habits of more than 293,000 U.S. veterans and Hammond (38) examined the smoking habits of and mortality rates experienced by 440,559 men. In these studies, pipe _ smokers experienced mortality rates similar to those of men who never smoked regularly, whereas cigar smokers had death rates somewhat higher than men who never smoked regularly. Table 6 summarizes the results of these five studies. Thus, data from the major prospective epidemiological studies demonstrate that the use of pipes and cigars results in a small but defi- nite increase in overall mortality. Cigar smokers have somewhat higher death rates than pipe smokers, and mixed smokers who use cigarettes in addition to pipes and cigars appear to experience an inter- mediate level of mortality that approaches the mortality experience of cigarette smokers. 495-023 O—73-——_13 549 TasLe 6.—Mortality ratios for total deaths by type of smoking (nales only) Smoking type Author, reference Non- Cigar Pipe Cigsr Cigarette Cizarette Mixed Cigarette smoker only only and and cigar and pipe {cizsrette only pipe and other) Hammond and Horn ! (40)_-- 1.00 1.22 1.12 14.10 1. 36 1. 50 1. 43 1. 68 Doli and Hill (26)_..------ 1.00 .-.. ---. LOL --.---) ------- Lit 1. 238 Best (9)__-.---- 1.00 1.06 21.05 .98 1. 22 1. 26 1.13 1.54 Kahn (60)------ 1.00 1.10 1.07 1.08 -_-.-. ------- 1.51 1. 84 Hammond? (38) __.------ 1.00 21.25 1.19 LOL --_--- ------- 1. 57 1. 86 5 Only mortality ratios for ages 50 to 69 are presented. 1 Only mortality ratios for ages 55 to 64 are presented. ’ Mortality and Dose-Response Relationships A consistent association exists between overall mortality and the total dose of smoke a cigarette smoker receives. The methods most frequently used to measure dosage of tobacco products are: Amount smoked, degree of inhalation, duration of smoking experience, age at initiation, and the amount of tar in a given tobacco product. For cigarette smokers, the higher the dose as measured by any of these parameters, the greater the mortality. The significance of the small increase in overall mortality that occurs for the entire group of pipe and cigar smokers can be analyzed by examining the mortality of subgroups defined by similar measures of dosage as used in the study of cigarette smokers. AMOUNT SMOKED Hammond and Horn (40) reported an increase in the overall mor- tality of pipe and cigar smokers with an increase in the amount smoked. Individuals who smoked more than four cigars a day or more than 10 pipefuls a day had death rates significantly higher than men who never smoked (P<0.05 for cigar smokers and P<0.05 for pipe smokers) (table 7), Cigar and pipe users who smoked less than this amount experienced an overall mortality similar to men who never 550 smoked. The study of Canadian veterans (9) also contained evidence of a dose-response in mortality by amount smoked for cigar smokers. No dose-response relationship was observed among pipe smokers (table 8). Kahn (50) reported a consistent increase in overall mortality with an increase in the amount smoked for both pipe and cigar smokers (table 9). Hammond (38) found no consistent relationship between overall mortality and the number of cigars or pipefuls smoked (table 10). Tase 7.—Mortality ratios for total deaths of cigar and pipe smokers by amount smoked— Hammond and Horn Number of deaths Amount smoked Observed Expected Mortality ratio Nonsmoker.......-_-_------------------ 1, 664 1, 664 1. 00 Cigar only: Total... ---- 2 - ee 653 598 1. 09 1 to 4 cigars... 2-22 ee 410 400 1. 03 > 4 cigars. 222-222 eee eee 229 185 1. 24 Pipe only: Total_____----- 2 ---- 609 560 1.09 1 to 10 pipefuls.______- Lene ene ee- 391 374 1. 05 > 10 pipefuls__-.- 22 ee 204 172 1.19 8ource: Hammond, E.C., Horn, D. (40). Tas_Le 8.—Mortality ratios for total deaths of cigar and pipe smokers by amount smoked—Best Number of deaths Amount smoked Observed Expected Mortality ratio Nonsmoker______.____.....__-_---e eee eee ee ee eee 1. 00 Cigar only: : Total..____._.-.---.----------- 90 82. 07 1.10 1 to 2 cigars__.________.._------ 64 56. 05 1.44 3 to 10 cigars_.._____._-.------- 23 19. 40 1.19 > 10 cigars... ----- 1 1. 59 . 63 Pipe only: Total. 22. eee 570 566. 99 1. 00 1 to 10 pipefuls_.._.___.--------- 374 370. 09 1.01 10 to 20 pipefuls_____._.-------- 141 140. 84 1. 00 > 20 pipefuls___.__.._..-------- 36 35. 90 1.00 Source: Best, E. W. BR. (#). 551 The above evidence suggests that a dose-response relationship may exist between the number of cigars and pipefuls smoked and overall mortality. However, because of the high-mortality rate of ex-smokers of cigars and pipes, it is difficult to interpret the data presented with- out including this group with the continuing smokers. Without data which examines patterns of both daily rate of smoking and inhalation at various age levels, no firm conclusions can be drawn as to the nature of this dosage relationship. TABLE 9.—Mortality ratios for total deaths of cigar and pipe smokers by age and amount smoked—Kahn Mortality ratio, age Amount smoked 55 to 64 63 to 74 Nonsmoker___...__----------------------------- 1. 00 1. 00 Cigar only: Total___. 22-2 1. OL 1. 08 1 to 4 cigars per day.____.__-_-__.----------- . 89 1. 00 5 to 8 cigars per day_._______-----_---------- 1. 14 1. 23 >8 cigars per day_._._..._------------------ 1.65 1. 28 Pipe only: Total___ 22-2 ee -- 1. 08 1. 06 1 to 4 pipefuls per day_____-__--------------- 1. 16 -91 5 to 19 pipefuls per day__.__-.--------------- 1. 04 1.10 1.18 >19 pipefuls per day__...------------------- ---------- Bource: Kahn, H. A. (50}. TasLE 10.—Mortality ratios for total deaths of cigar and pipe smokers by amount smoked—Hammond Amonant smoked Mortality Amount smoked Mortality ratlo ratlo 1. 00} Current pipe smokers: Nonsmoker__._------------- Current cigar smokers: Total_....--------------- 1. 04 Total_.____-__.__--------- 1. 09 1 to 9 pipefuls per day_.__- 1. 08 1 to 4 cigars per day_._-_-- 1. 03 >9 pipefuls per day_.----- . 92 > 4 cigars per day.....---- 1.18 Source: Hammand, B.C. (98). 552 INHALATION Inhalation of tobacco smoke directly exposes the bronchi and the lungs to smoke and results in the absorption of the soluble constituents of the gas and particulate phases Without inhalation tobacco smoke only reaches the oral cavity and the upper digestive and respiratory tracts and does not reach the lungs where further direct effects and systemic absorption of various chemical compounds can occur. Although the smoker has some voluntary control over the inhalation of smoke, the physical and chemical properties of tobacco smoke to a degree determine its acceptability and “inhalability.” The condensate of pipe and cigar smoke is generally found to be alkaline when the pH is measured by suspending a Cambridge filter in CO,-free water. Cigarette condensate is slightly acidic as measured by this method. Since alkaline smoke is more irritating to the respira- tory tract, it has been assumed that the more alkaline smoke of pipes and cigars was in part responsible for the lower levels of inhalation reported by pipe and cigar smokers. Brunnemann and Hoffmann (/5) have analyzed the pH of whole, mainstream smoke of cigarettes and cigars on a pull-by-puff basis using a pH electrode suspended in main- stream smoke. Smoke from several U.S. brands of cigarettes was found to be acidic throughout the entire length of the cigarette. Of interest was the finding that cigar smoke also had an acidic pH for the first two-thirds of the cigar and became alkaline only in the last 20 to 40 percent of the puffs from the cigar. Available epidemiological evidence indicates that most cigar smokers do not inhale the smoke and most cigarette smokers do. The fact that smoke from the first half or more of a cigar is acidic, near the range of pH values commonly found in cigarette smoke, and becomes alkaline only toward the end of the cigar might suggest that the pH of the smoke of a tobacco product may not be the only factor that influences inhalation patterns. Per- haps “tar” and nicotine levels as well as the concentration of other “irritating” chemicals also affect the degree to which a tobacco smoke will be inhaled. Nicotine is rapidly absorbed into the blood stream from the lungs when tobacco smoke is inhaled. The amount of nicotine absorbed from the lungs is primarily a function of the nicotine concentration in the smoke and the depth of inhalation. Some nicotine may also be ab- sorbed through the mucous membranes of the mouth. This is more likely to occur under alkaline conditions when nicotine is unprotonated (3, 15, 79). This suggests that cigar smokers may be able to absorb some nicotine through the oral cavity without having to inhale, par- ticularly during the time that the smoke from the cigar is alkaline. 553 With the development of sensitive measures of serum nicotine levels (48) the extent to which nicotine is absorbed through the membranes of the mouth in pipe and cigar smokers can be more accurately determined. Inhalation patterns of smokers were determined in several of the large prospective and some of the retrospective epidemiological studies. Inhalation was usually determined by the administration of a ques- tionnaire that required a subjective evaluation of one’s own patterns of inhalation. Although the accuracy of these questionnaires has not been confirmed by an objective measure of inhalation, such as carboxy- hemoglobin or serum nicotine levels, their reliability is supported by mortality data which demonstrate higher overall and specific death rates with self-reported increases in the depth of inhalation. Doll and Hill (26) and Hammond (38) presented information on inhalation patterns of pipe, cigar, and cigarette smokers (figs. 1, 2, 3, and table 12). Some 80 to 90 percent of cigarette smokers reported inhaling, with the majority of individuals inhaling moderately or deeply, whereas most pipe and cigar smokers denied inhaling at all. Pipe smokers reported slightly more inhalation than cigar smokers. For each type of smoking, less inhalation was reported by older smokers. This change may represent less awareness of inhalation, differences in smoking habits of successive cohorts of smokers, or it may reflect the operation of selective factors which favor survival of noninhalers, The Tobacco Research Council of the United Kingdom has, since 1957, periodically reported the use of tobacco products by the British. Figure 1.—Inhalation among pipe smokers by age. No inhalation Some inhalation Age SOURCE: Hammond, E. C. (38). 554 Figure 2.—Inhalation among cigar smokers by age—Hammond. No inhalation Some 185 inhalation 26.4 22.9 17.1 13.7 . Age 40 50 60 70 80 SQURCE: Hammond, E. C. (38). Figure 3.—Depth of inhalation among cigarette smokers by age.—Hammond. None Slight inhalation Moderate inhalation 41.1 31.9 Deep i i 29.1 inhalation 23.9 17.4 121 oD 4 Age 40 SOURCE: Hammond, E. C. (38). 50 60 70 8&0 Recent reports edited by Todd have contained data on the inhalation pattern of cigar, pipe, and cigarette smokers (92, 93, 94). Table 11 shows that most cigarette smokers inhale a “lot” of “fair amount” whereas most pipe and cigar smokers do not inhale at all or “just a little.” Little change is observed in the inhalation patterns of.a given product since 1968. , Best (9) reported inhalation data among male cigarette smokers by smoking intensity and age group, but did not report the inhalation 555 patterns of pipe and cigar smokers. The overall mortality rates of current pipe smokers who inhaled at least slightly were reported by Hammond (38) as being somewhat higher than for men who never smoked regularly. The overall mortality rates of current cigar smokers who reported inhaling at least slightly were appreciably higher than for men who never smoked regularly (table 13). Available evidence indicates that cigarette smokers inhale smoke to a greater degree than smokers of cigars or pipes. Once a smoker has learned to inhale cigarettes, however, there appears to be a tendency to also inhale the smoke of other tobacco products. For cigars, this is evidently true whether one smokes both cigarettes and cigars or switches from cigarettes to cigars (tables 14, 15, 16). Bross and Tidings (14) examined the inhalation patterns of smokers of large cigars, cigarettes, and those who switched from one tobacco product to another (table 15). Nearly 75 percent of those who were currently smoking only cigarettes reported inhaling “almost every puff” and only 7 percent never inhaled. The opposite was true for per- sons who had always smoked only cigars among whom 4 percent re- TapLe 11.—-The extent of inhaling pipes, cigars, and cigarettes by British males aged 16 and over in 1968 and 1971 Tobacco product Cigars Pipes Cigarettes Amount of inhalation 1968 1971 1968 1971 1958 1971 Inhale a lot_._.___._.-------------- 23 19 8 8 47 47 Inhale a fair amount.__.------------ 16 19 10 8 3k 30 Inhale just a little.___...----------- 27 27 24 26 13 15 Do not inhale at all.__.-_----------- 34 35 59 58 9 8 Total___.___--.-------------- 100 100 100 100 100 100 Source: Todd, G. F. (93, 94). TapLe 12.—Inhalation among cigar, pipe, and cigarette smokers by age—Doll and Hill Percentage of Inhalers, age Smoking type tow Btu 45tabi SStosd G5to 74 > Cigar and pipe---------------- 12.00 1000 7.00 5.00 4.00 4. 00 Mixed (cigarette and other)..... 74.00 60.00 47. 00 36.00 30.00 26.00 Cigarette only.--.------------ 90.00 85.00 75.00 66.00 58. 00 41.00 Source: Doll, R., Hil, A. B. (£6). 556 ported inhaling almost every puff and 89 percent said they never inhaled. Cigar smokers who also smoked cigarettes reported inter- mediate levels of inhalation between the cigar only and cigarette only categories. Inhalation patterns were similar whether the individual continued to smoke both products, stopped smoking cigarettes but continued smoking cigars, or stopped smoking cigarettes and switched to cigars. In all three groups, about 20 percent reported inhaling “almost every puff.” This suggests that once an individual’s inhalation patterns are established on cigarettes, he may be more likely to inhale cigar smoke if he switches to cigars, or uses both cigars and cigarettes, than the cigar smoker who has not smoked cigarettes. Todd (93) reported similar data for a sample of smokers in the United Kingdom (table 16). The prevalence of inhaling a “lot” or “fair amount” of smoke was highest among cigarette smokers who were currently smoking cigarettes (77 percent) and lowest among current cigar smokers who had previously smoked only cigars or pipes (18 percent). Individuals who switched from cigarettes to cigars main- TaBLe 13.—Mortality ratios for total deaths of cigar and pipe smokers by age and inhalation—-Hammond Mortality ratfo, age Inhalation 45 to 64 85 to 84 Nonsmoker___._____-_2 eee eee ee 1. 00 1. 00 Cigar only: Total... oe eee 1. 09 . 98 No inhalation.___-___ eee 1.02 .9l Some inhalation.___________.__.________--______. 1. 28 1. 37 Pipe only: Total. oe ee pepe eee eee 1. 04 - 95 No inhalation__.-._-__.____._________.-__-.-_-__- . 98 . 87 Some inhalation._._______________.______-- ee 1. 21 Lit Bource: Hammond, E. C. (38). TABLE 14.—Percentage of British male cigar smokers who reported inhaling a lot or a fair amount by type of product smoked 1968 1971 Type of product Number of Percent Number of Percent individuals individuals Cigars only___._____2_ 222-2 2-2 706 =. 23.0 11 27.0 Cigars and cigarettes-._____..--_--_ 1,193 42.0 277 44.0 Cigars and pipes._--. 22.22 -- 596 35.0 109 32. 0 Cigars, cigarettes, and pipes________.. 26 «52.0 15 32.0 Bource: Todd, G. F. (83, 84). 557 tained somewhat higher levels of cigar smoke inhalation than those cigar smokers who had never smoked cigarettes (30 percent). Todd (93) examined further the relationship between the inhalation of cigarette and cigar smoke. In general, cigarette smokers who switched to cigars were much less likely to report inhaling cigar smoke than cigarette smoke; however, those who in the past reported inhaling cigarette smoke a “lot” or “fair amount” were much more likely to report inhaling cigar smoke to the same degree than those ex- cigarette smokers who in the past did not inhale the smoke of their cigarettes (table 17). TasLe 15.—Percentage of individuals reporting inhalation of “almost every puff” of tobacco smoke by current and previous tobacco usage and type of tobacco used Confidence Type of tobacco smoked Number Percen- Umits of Type inhaled tae —_-—_—_—_—- Current usage Previous usage patients {nhsled Lower Upper Cigarettes only_... Cigarettes only____ 2,359 Cigarette... 74.8 73.1 76.6 Cigars only_______ Cigars only______ 649 Cigars_____ 45 3.0 60 Cigarettes and Cigarettes and 520 ____. do... _ 20.4 105 28.0 cigars. cigars. . Cigars... 22.22. Cigarettes and 93 ____. do_____ 13.3 90 30.0 cigars. None__.. 2-22. Cigarettes and 186 _____ do_____ 215 17.8 24.2 cigars. Cigars.__.2_2 22 Cigarettes only ____ 64 Le do__... 17.2 16.0 28.0 Bource: Bross, I. D.J., Tidings, J. (14). TasLe 16.—Percentage of British males who reported inhaling a lot or fair amount of cigar smoke by current and previous tobacco usage and type of tobacco previously smoked (1963) Type of tobacco smoked Number of Percentage individuals Type inhaled Inhaled ~ Current usage Previous usage Cigarettes only_.____ | Cigarettes only______ 2,586 Cigarette_____ 77.7 Cigars only___________ Nonsmoker_________ 306 Cigars_______ 18.0 Cigars only..____-____ Cigarettes only_______ 321 LLL do___.__. 30. 0 8ource: Todd, G. F. (94). 558 TABLE 17.—Extent of reported inhalation of cigar smoke by British male cigar smokers who were ex-cigarette smokers in 1568, analyzed by extent of reported inhalation of cigarette smoke when previously smoking cigarettes Extent of inhaling cigars Extent of inhaling cigarettes Inhale a lot Inhale a little or fair amount or not at all Percent Peoveent Inhale a lot or fair amount_.__.__._..-.___.______. 44.0 5. 0 Inhale a little or not at all..--_-_-- ee 56. 0 95. 0 Total. ___.2 eee 100. 0 100. 0 Sample size_____-.--_-_. 2222-2 244 56 Source: Todd, G. F. (gn). Specific Causes of Mortality Cancer Several prospective epidemiological studies have shown a signifi- cantly higher overall cancer mortality among pipe and cigar smokers compared to the cancer mortality of nonsmokers (table 18). Pipe and cigar smokers have much higher rates of cancer at certain sites than at others. The upper airway and upper digestive tracts appear to be the most likely target organs. The relationship of pipe and cigar smoking to the development of specific cancers is detailed in the following sections. TABLE 18.—Mortality ratios for total cancer deaths in cigar and pipe smokers. A summary of prospective epidemiological studies Author, reference Nonsmoker Type of smoking Pipeonly Total pipe Cigarette Hammond and Hom (40)___- Best (9)________ Hammond (88)____--_._____ Kabn (60)______.2____-__- 1. 00 1. 00 1.00 1. 00 and cigar only 1.44 22 LL -ee 1.97 1.38 ~.-L_--- 2. 06 wee eeee 1. 21 1. 76 1. 25 1.25 2. 21 559 Cancer of the Lip Approximately 1,500 new cases of cancer of the lip are reported each year. Because of the possibility of early detection and surgical accessibility of cancers in this area, there are less than 200 deaths from cancer of the lip each year in the United States. Some of the earliest scientific investigations exploring the association between tobacco use and disease examined the smoking patterns of individuals with cancer of the lip. Broders (73) in 1920 examined the smoking habits of patients in a retrospective study of 526 cases of epithelioma of the hp and 500 controls. Of the cancer cases, 59 percent smoked pipes, whereas this was true for only 28 percent of the controls. No association was found between cigar or cigarette smoking and cancer of the lip. In a restrospective study of 439 clinic patients with cancer of the Jip and 300 controls conducted in Sweden, Ebenius (32) reported a significant association between pipe smoking and cancer of the lip. A total of 61.8 percent of the lip cancer cases smoked pipes, while only 22.9 percent of the controls smoked pipes. No association was found between the use of cigarettes, cigars, or chewing tobacco and cancer of the lip. In other retrospective studies, Levin, et al. (60) reviewed a series of 143 cases of cancer of the lip, and Sadowsky, et al. (77) reviewed 571 cases of cancer of the lip. In both studies, a strong association was found between pipe smoking and cancer of the lip. No significant association was found between the use of tobacco in ether forms and cancer at this site. In a study of environmental factors in cancer of the upper alimen- tary tract, Wynder, et al. (413) found an association between pipe smoking, cigarette smoking, and cancer of the lip. There were only 15 cases of cancer of the lip in this study. Staszewski (87) examined the smoking habits of 394 men with carcinoma or precancerous lesions of the lips. An association was found between the smoking of pipes and cigars and cancer of the lip, but this was only of doubtful significance. A significant association was found between the use of cigarettes and cancer of the hp. Keller (51) conducted a study of lip cancers in which he considered a number of factors including histologic types, survival, race, occupa- tions, habits, and associated diseases. A total of 304 patients with primary basal cell or squamous cell carcinoma of the lip and 304 controls from the same hospital matched for age and race were con- sidered in this series. A significant association was found between smoking in all forms and combinations and carcinoma of the lip. It was also found that increasing age and outdoor occupations with exposure to the sun were equally significant factors in the etiology of lip cancer. 560 In summary. it appears that there are several factors involved in the etiology of cancer of the lip. Among the various forms of tobacco use, pipe smoking either alone or in combination with other forms of smoking seems to be a cause of cancer of the hip. Table 19 summarizes the results of these retrospective studies. Oral Cancer The lips, oral cavity, and pharynx are the first tissues exposed to tobacco smoke drawn in through the mouth. Variations in inhalation during the smoking of various tobacco products result in different pat- terns of distribution of smoke throughout the respiratory tree. How- ever, the oral cavity and adjacent tissues are the sites most consistently exposed to tobacco smoke. For this reason, differences in inhalation should result in less variation in exposure to tobacco smoke for these sites than for the lower trachea and the lung. The inherent carcinogen- icity of pipe, cigar, and cigarette smoke is most reliably compared at those tissue sites where dosage and exposure to tobacco smoke are most nearly equal. Data from the epidemiological studies suggest that little difference exists between the smoking of cigarettes, pipes, or cigars and the risk of developing oral cancer. Hammond and Horn (40) examined the association between smok- ing in various forms and cancer of the combined sites of lip, mouth, pharynx, larynx, and esophagus. The mortality ratios were 5.00 for cigar smokers, 3.50 for pipe smokers, and 5.06 for cigarette smokers compared to nonsmokers. All the deaths from cancer of the lip, oral cav- ity, and pharynx reported by Doll and Hill (26) occurred in smokers. The death rates from cancer at these sites were 0.04 per 1,000 for pipe and cigar smokers, 0.10 per 1,000 for mixed smokers, and 0.05 per 1,000 for cigarette smokers. A fairly detailed analysis of oral cancer was pre- sented by Kahn (50) who differentiated between cancer of the oral cavity and cancer of the pharynx. The mortality ratios for oral cancers were 1.00 for those who never smoked, 3.89 for all pipe and cigar smokers, and 4.09 for cigarette smokers. A further breakdown of the pipe and cigar smokers demonstrated a mortality ratio of 4.11 for cigar smokers, 3.12 for pipe smokers, and 4.20 for smokers of pipes and cigars. For cancer of the pharynx, the mortality ratios were 1.00 for those who never smoked, 3.06 for all pipe and cigar smokers, and 12.5 for cigarette smokers. No deaths occurred among those who smoked only cigars. The mortality ratio was 1.98 for pipe smokers and 7.76 for smokers of pipes and cigars. Hammond (38) combined cancers of the hip, oral cavity, and pharynx. The pipe and cigar smokers had a mortality ratio of 4.94 and the cigarette smokers a mortality ratio of 9.90 compared to nonsmokers. 561 29S Tale 19.—Melative risk of lip cancer for men, comparing cigar, pipe, and ciyarette smokers with nongsmokerstel summary of retrospective studies Rolutive rlak cally nnd percentage of cases and coutruls by typeof sucking Author, referenicy Number Nonsmoker Ciguronly Plpvonly Total pipe Cigarette Mired and clyor only Broders (13): Relative risk... 2222.8. 1.0 0.8 4.3 ...0...-. O _.-...-e- Casts. .... 202-2 eee ee eee §37 Percent cayes._..--.---. 7 19 [ ) Lo oleae ee Controls... eee eee eee eee 500 Percent controly....2.... 4 16 6 Lee ee eee 2600 Lotte eee Ebenius (32): Relative risk....-...22.-- 1.0 7 4.1 0.5 Llo. tee eee e eee Cuscs_ oo... eee eee eee ee 439 Percent cases-.....2---- 49 6 41 4 nen e cee e ewes Controls. oo... eee eee ee eee 300 Percent controls.......2- 65 12 13 1000 Loe eee wee ee eee Levin, et al. (G0): Relative risko..0 22 leek 1.0 1.9 2.9 ...-0---e | Cases. oe ae eae eee ee eee ee 143 Percent cases... 2.22200. 15 27 48 Lac eee ee 450 Le eee Controlg.o22 22 22e eee eee eee 554 Percent controly....2222- 22 20 24 eee e eee 460 Lee eee Sadowsky, et al. (77): Ielative riskoo.c.eeele 1.0 Li 4.3 2.6 L4 0. 4 Causes. ... 0 0.0 ee eee eee eee 571 Percent cases... eee. ee 8 2 18 6 44 22 Controly. 22222 ee eee eee G15 Percent controlg..2. 2222. 13 3 7 4 53 19 Wynder,! et al. (178): Relative riskoo. leek 0 8 | ar 1.0 2.2 Cases... ...... 00 eee eee eee 14 Poreent cases...2--- 2... 0 7 290 faa a eee 36 29 Controls... 2.2.2.0 22--- eee 115 Percent controls.....222- 24 9 16 Ltt... 36 13 Staszewski (87): Relative risk. oe 1.0 coe lle 2.1 2.4 ..2------ Cases... 2.022222 eee euee eee 394 Percent cases__....---..- Gee ennece anceeee 12 1 an Controls.....2 2... .00 0 eee 912 Percent controls___-_-- 2. . 130 Leelee eee eee i a Keller: (61): Relative risk__-- 00.00 1.0 14 4.0 2.6 Cases- 220... ee eee een e neces 301 Percent cases_..2.22. 7 eee 7 2 6 1 60 6 Controlg....0.020-0--002------ 265 Percent controlg_.....-_- 17 4 3 0 53 0 § Percentage based on loss than 20 pationts. Rutlus: relative to cighretto smokors, These studies are summarized in table 20. They demonstrate that smokers experience a large and Significant risk of developing cancer of the oral cavity compared to nonsmokers. This risk seems to be about the same for all smokers whether an individual uses a Pipe, cigar, or cigarette, A number of retrospective studies have examined the relationship between smoking in various forms and cancer of the oral cavity. The results of these studies are presented in table 21. Some of the variations in relative risk of developing oral cancer observed in the retrospective studies is probably due to the Jack of a uniform definition of oral cancer by anatomical site and the various means used in selecting and defin- ing cases and controls. It appears, however, that a significant risk of developing oral cancer exists for smokers compared to nonsmokers and this risk is similar for smokers of pipes, cigars, and cigarettes. Several epidemiological investigations have demonstrated an asso- ciation between the combined use of aleohol and tobacco and the development of oral cancer. A few of these studies (52, 62, 63, 109) contain data on pipe and cigar smokers. Heavy smoking and heavy drinking are associated with higher rates of oral cancer than are seen with either habit alone. TABLE 20.—AMfortality ratios for oral cancer in cigar and pipe smokers. A summary of prospective epidemiological studies Smoking type Author, reference Non- Cigar Pi Total pipe Cigarette Mixed smoker only only and cigar only Hammond and Horn'(40)_ 1.00 5.00 3.50 _______. 5.06 _____2. Doll and Hill? (26, 27)-__ 000 ---- 22. LLL Lee 0. 80 1. 00 2. 00 Hammond (88)..___.___. 1,00 .---2 8. LLL 4.94 3990 .._.___L Kahn (60): Oral #_ 2-2 1.00 4.11 3. 12 3. 89 4.09 .-_. LLL Pharynx_._.-_._ 1,00 ___.____ 8 3.06 12.54 ___.. LL ' Combines data for oral, larynx, and esopbagus. 1 Rauos: relative to cigarette smokers. » Mortallty ratics for ages 45 to & only are presented. 4 Excludes pharynx. Cancer of the Larynx The larynx is situated at the upper end of the trachea. Because of its proximity to the oral cavity, the larynx probably has a similar exposure to smoke drawn through the mouth as the buccal cavity and pharynx. Tobacco smoke that is not inhaled may still reach ag far as the larynx and upper trachea. Pipe and cigar smokers develop cancer of the larynx at rates comparable to those of cigarette smokers. These 563 79S TABLE 21.—Relative risk of oral cancer for men, comparing cigar, pipe, and cigarette smokers uith nonsmokers. A summary of retrospective sludtes Relative risk ratio wid percentage of cases and controls by typo of smoking Author, reference Number Nonamoker Clyurouly Pipeonly Totul plpo — Clyurette Mirod and clyur only Mills and Porter (65): Relative risk.....__.. 008. LO eee Leelee 7.0 41 cele. Cases__ 2-2. eee eee 124 Percent cases_____.-_22.. 10 nee eee ee Lee eae 55 3600 eee eee Controls... 2.0.02 0 eee eee 185 Percent controls.__....... 88 Lee tle eee 30 820 eee Sadowsky, et al. (77): Relative risk_.....2.2 0. 1,0 2.0 re 14 2.1 Cases... 22.2222 e eee eee 1,136 Percent cases_......-_... 4 18 Leelee 42 28 Controls....222202. beeen n eee 615 Percent controls.._....._. 13 3 TO eee 53 23 Schwartz, et al. (83): Relative risk__.-.... 08. 10 .2lle Lele 16 wo... lle 16 Lele “Cases. lll. 332 Percent cases..._.._..... 160 Leelee 3 Leelee i Controls.......2222 0.20022. 608 Percent controls....___... 23 17 8 Leelee 58 ok. wae Wynder, et al. (109): Relative risk_...2.2_2.2.. 1.0 3.6 i 3.0 3.3 Cases... 22. eee eee 543 Percent cases_.____...... 20 Vb Lee 57 8 Controls... 0.02.2 eel 207 Percent controls..._..._.. 10 13 G6 Leelee. 63 8 Wynder, et al. (113): Relative risk_......-..0.- 10 17 a: 1,2 14 Cases. eel 115 Percent cases___...__ 8. 23 13 20 Ll. 37 16 Controls... ee. 115 Percent controls..___._... 26 9 16 eee ee 36 13 S9S Wynder, ct al. (116): ~ Cases. oo. eee eee eee 178 : Controls. .... cee cee eee 220 Pernu (73): r LO 1, 400 [ Controls......022 eee eee 713 = Staszewski (87): Cases... 0. ee - eee 383 Controls... 912 Keller (62): Cases... eee eee 408 Controls....02 22... 408 Martinez (62): Cases... eee eee 170 Controls... eee 510 Martinez ! (63): Cases. 2... e eee 346 Controls......0.2....-00-- 8. 346 1.0 12 22 'This study combines data for oral caucer and cancer of the esophagus, rates are several times the rates of nonsmokers. The similarity of the mortality ratios of cancer of the larynx for smoking in various fomns suggests that the carcinogenic potentials of the smoke from cigars, pipes, and cigarettes are quite alike at this site. Several of the prospective epidemiological studies include data on deaths from cancer of the larynx for pipe and cigar smokers as well as for cigarette smokers. Hammond and Horn (40) combined data for cancer of the larynx with cancer of the esophagus and oral cavity. The mortality ratios compared to nonsmokers were 5.00 for cigar smokers, 3.50 for pipe smokers, and 5.06 for cigarette smokers. There were no deaths from carcinoma of larynx among nonsmokers in the study of British physicians by Doll and Hill (26) ; however, the death rate for cancer of the larynx among pipe and cigar smokers was 0.10 per 1,000 while the death rate for cigarette smokers was 0.05 per 1,000. Kahn (50) reported mortality ratios for cancer of the larynx of 10.33 for cigar smokers, 9.44 for pipe and cigar smokers, 7.28 for al] pipe and cigar categories combined, and 9.95 for cigarette smokers. No deaths from cancer of the larynx occurred in pipe smokers. Hammond (38) reported a mortality ratio of 3.37 for all pipe and cigar smokers and a mortality ratio of 6.09 for cigarette smokers in the age category 45 to 64. These studies are, summarized in table 22. Several retrospective studies have examined the smoking habits of patients with cancer of the larynx and appropriately matched controls. The small number of pipe and cigar smokers in each study results in relative risk ratios that are quite unstable; however, it appears that pipe and cigar smokers experience a risk of developing cancer of the larynx that is similar to the risk observed among cigarette smokers (table 18). Tas.e 22.—Mortality ratios for cancer of the larynz in cigar and pipe smokers. A summary of prospective epidemiological studies Smoking type Author, reference Non- Cigaronly Pipeonly Total Pipe Cigarette Mixed smoker and cigar only Hammond and Horm ! (40)_ 22 1. 00 5. 00 3.50 2.2L 5.06 -_.. Doll and Hill? (26, £7)... 0.00 _...... _.__.. 2. 00 1. 00 0. 60 Hammond (38)__________ 100 2222. LLL. 3.37 36.09 Kahn (60)_._-.---_ 100 1033 __ 7. 28 9.95 -. LLL 1 Combines data for oral, larynx, and eso bagus. ? Ratios: relauve to cigarette smokers. P * Only mortality ratios far Bges 45 Co 64 are presented. 566 Wynder, et al. (708, 1/3) distinguished between intrinsic and ex- trinsic larynx cancers. For smokers the relative msk of developing cancer of the intrinsic larynx was similar to the relative risk of lung cancer whereas the relative risk of developing extrinsic larynx cancer was more like the relative risk of cancer of the upper digestive tract. Histologic changes of the larynx in relation to smoking in various forms were described by Auerbach, et al. (5). Microscopic sections of the larynx from 942 subjects were examined for the presence of atypical nuclei and proliferation of cell rows. Sections were taken | from four separate areas of the larynx in each case. Among those who smoked cigars and pipes but not cigarettes, only 1 percent had no atypical cells and more than 75 percent of the subjects had lesions with 50 to 69 percent atypical cells. Four of the cigar and pipe smokers had carcinoma in situ and in one of these four cases early invasion was seen in three of the sections. Of those who never smoked regu- larly, 75 percent had no atypical cells. The cigar and pipe smokers had a similar percentage of cells with atypical nuclei as cigarette smokers who smoked one to two packs per day. With respect to the prolifera- tion of cell rows in the basal layer of the true vocal cord, the least proportion of .cases with eight or more cell rows was found in men who never smoked, and the greatest proportion was found in heavy cigarette smokers. Pipe and cigar smokers had a distribution of cell rows that was comparable to that of cigarette smokers who consumed about a pack a day. Several retrospective studies have reported an association between the combined use of tobacco and alcohol and cancer of the larynx. A study by Wynder, et al. (£08) included some information on pipe and cigar smoking in relation to drinking habits and the development of cancer of the larynx, but because of the limited number of pipe and cigar smoking subjects this relationship could not be adequately determined. Cancer of the Esophagus The esophagus is not directly exposed to tobacco smoke drawn into_ . the mouth; however, the esophagus does have contact with that portion ~ of tobacco smoke that is condensed on the mucous membranes of the mouth and pharynx and then swallowed. The esophagus is also ex- posed to a portion of tobacco smoke that is deposited in the mucus cleared from the lung by the ciliary mechanism or by coughing. Varia- tions in inhalation of a tobacco product may not appreciably alter the exposure the esophagus receives from smoke dissolved in mucus and saliva. This suggestion receives support from the prospective and retrospective epidemiological studies which demonstrate similar mor- tality rates for cancer of the esophagus in smokers of cigars, pipes, and cigarettes. 567 89S TABLE 23.—Relative risk of cancer of the larynx for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies Relative risk ratio and percentage of cases and controls by type of smoking Author, reference Number Nonsmokor Cigar only Pipe only Total pips Clearatte Mired and clgar only Schrek, et al. (81): Relative risk... 22.208. 1.0 0 Ld celle 23 celle Cases. _ 2. eel 73 Percent caseg___.__.___- 14 0 To eke eee 80 Lee Controls... 2 ee 522 Percent controls..___._._ 24 10 Vb cell 1) Sadowsky, et al. (77): Relative risk....2-2.0 oo. 1.0 2,2 23 Lo... 3.7 4.1 Cases... 2.22 eel 273 Percent cases___.._.._.. 2 GB nee ate 60 29 Controls._....2220 ee 615 Percent controls..._..... 13 3 Fo eee 53 23 Wynder, et al. (108): Relative risk... 2.008. 1.0 15.5 27,7 ll 24.6 2 lle ASOS- eee elle 209 Percent cases.__-._. 8. 5 8 5 1 8B Lee Controls._....22- 22 209 Percent controls......_.. 1] 10 4 (. Wynder, et al. (113): Relative risk_..2. 20008. 1.0 9.7 4.5 woe 6.3 6.3 Cases... 60 Percent cases..._...___. 5 17 Wo Leelee 47 17 Controls_....2 0. e el 271 Percent controls_.._.._.. 24 9 Wo Leelee 36 13 Wynder, et al. (116): Relative risk.....20 8. 1.0 14.5 16.0 .... lll le 22.0 16. 0 Cases... eee 142 Percent cases....__...._ 1 20 bee 62 16 Controls... eo oo 220 Percent controls.....__.. 16 22 Yo eel 45 16 69S Pernu (78): Relative risk... 02222. Percent cases In the prospective epidemiological studies, cigar, pipe, and cigarette smokers all had similar mortality ratios from cancer of the esophagus. Hammond and Horn (40) combined the categories of carcinoma of the esophagus, larynx, pharynx, oral cavity, and lip and described mortality ratios of 5.00 for cigar smokers, 3.50 for pipe smokers, and 5.06 for cigarette smokers. Doll and Hill (26) reported an esophageal sancer mortality ratio of 2.0 for pipe and cigar smokers, 4.8 for mised smokers, and 1.5 for cigarette smokers. Kahn (50) reported the fol- lowing mortality ratios for smoking in various forms compared to non- smokers: cigar only, 5.33; pipe only, 1.99; pipe and cigar, 4.17; all pipes and cigars combined, 4.05; and cigarettes only, 6.17. The results of these prospective studies are summarized in table 24, Several retrospective investigations have also examined the associa- tion between smoking in various forms and cancer of the esophagus. These studies have been summarized in table 25. The evidence sug- gests that cigar, pipe, and cigarette smokers develop cancer of the esophagus at rates substantially higher than those seen in nonsmokers, and that little difference exists between these rates observed in smokers of pipes and cigars and cigarettes. Histologic changes in the esophagus in relation to smoking in vari- ous forms were investigated by Auerbach, et al. (7), who looked for atypical nuclei, disintegrating nuclei, hyperplasia, and hyperactive esophageal glands. A total of 12,598 sections were made from tissues obtained from 1,268 subjects. For each of the parameters investigated, pipe and cigar smokers demonstrated significantly more abnormal histologic changes than nonsmokers; however, these changes were not as severe or as frequent. as those seen in cigarette smokers. Several retrospective studies conducted in the United States and other countries have examined the synergistic roles of tobacco use and heavy alcohol intake on the development of cancer of the esophagus. Four of these investigations contain data on pipe and cigar smoking (72, 62, 63, 107). It appears that smoking in any form in combination with heavy drinking results in especially high rates of cancer of the esophagus. TaBLe 24.—Mortality ratios for cancer of the esophagus in cigar and pipe smokers. A summary of prospective epidemiological studies Smoking type Author, reference Non- Clear Pi Total Cigarette smoker only only Pipe and only Mixed cigar Hammond and Horn! (40) _ 1.00 5. 00 3.50 -._- Le 5.06 __.222 Doll and Hill (26, 27). 1.00 -22--222 LL 2. 00 1.50 4. 80 Hammond (38)_._.______ 100-2222 LLL 3.97 74.17 _._____. Kahn (60)___-.-___. 1. 00 5. 33 1.99 4.05 6.17 _L.- Le ' Combines data for oral, larynx, and esophagus. 1 Mortality ratio for ages 45 to 64. P . 570 TLS TAaune 25.—Nelative risk of cancer of the esophagus for men, comparing cigar, pipe, and cigarette smokers with nonsmokers, ‘l swonmary of retrospective studies Relatlvo risk ratio and percentage of cases and controls by typo of smoking Author, reference Number Nonsinukee Clyar only — Pipe only Total plpo — Ctynretto Misod ond cipar only Sadowsky, et al. (77); Relative risk...--- 28 10 4.8 3.8 5.1 3, 8 3.3 Cases... 2. eel. 104 Percent cases..-..2 2 2. 4 5 8 6 60 18 Controls.....0222200..-00 8. 615 Percent controls...._.... 13 3 7 4 53 19 Wynder, et al. (113); Relative risk_-.20. 0. 1,0 31 21 ce. e lee 2.6 4 Cases_- 2... ee 39 Percent cases... 8] 13 15 18 wee ° 3 Controls... eee 115 Percent controls.....__.. 24 9 WW lee 13 Pernu (78): Relative risk.-...- 0-2 .. 10 Leelee 3.0 lel le. 27 5.9 Cases... eee 202 Percent casegs_....__. 8. Wo elle. TO ee aee eee 59 18 Controls__... 2.2 - 713 Percent controls__..._..- 39) le 6 Leet eee 50 7 Schwartz, et al. (84) Relative risk_..-2 020028. |) 2.6 ... 2 ll ll. 11.7 8.6 Cusos. ee eel 249 Percent cases__.__..._.- 2 Leelee 2 Leelee 88 7 Controls... 2.2 eee 249 Percent controls__..._.._. Wo eel Tease eens 67, 7 Wynder and Bross (107): Relative risk... 2008 - 1.0 3.6 9.0 6.0 2.8 3.7 Cases... 2222.2 eee 150 Percent casey__...00.0.. 5 19 9 4 51 I Controlg._oe ee 150 Percent controls....-.._. 15 16 3 2 59 9 cls Tasie 25—Relative risk of cancer of the esophagus for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies —Continued Rolatlve risk ratio and porcentago of cnses and controls by type of smoking Author reference Number Nonsmoker Cigaronly Plpeonly Total pips Clyarotte Mixed and cigar only Bradshaw and Schonland (12): Relative risk............ 10 ...-.-2e- 4.8 os. -2ee 2.3 ..--..-.- Cases_.-2.------- en eee ee eee 117 Percent cases.......---- | 4.00 Lol ellen 63 oleate eeee Controlg..__.-22 2-2. ee eee 366 Percent controls.....-.-- 320 eee ene 1B keene 58 wee ee eee Martinez (62): Relative risk... .- 22228. 1.0 2.0 pec ne cee eee 1.5 2, 2 Cases... eee wwe wee ee eee 120 Percent cases......----- 8 9 Leen ee teen eee 31 43 Controls... 2-2 oe eee ene 360 Percent controls......... 14 Beene ee eee eee 34 34 Martinez ! (68): Relative risk.......--... 1.0 2,0 2.8 we------ 1,7 2.5 Cases...-.-------------0e--- 346 Percent cases......--..- 21 10 15 eee 34 34 Controls... 22-2. ee nncee ee nne 346 ‘Percent controls__....2. 22 9 Lo teen eee 36 25 1 This study combines data for oral cancer and cancer of the esophagus. Lung Cancer Abundant evidence has accumulated from epidemiological, experi- mental, and autopsy studies establishing that cigarette smoking is the major cause of lung cancer. Several prospective epidemiological studies have demonstrated higher lung cancer mortality ratios for pipe and cigar smokers than for nonsmokers, but the risk of developing lung cancer for pipe and cigar smokers is less than for cigarette smokers. Table 26 presents a summary of these prospective studies. Dose- response relationships such as those that helped demonstrate the nature of the association between cigarette use and lung cancer could not be as thoroughly studied for pipe and cigar smokers because of the rela- tively few smokers in these categories. Although the number of deaths were few, Doll and Hill (26) reported increased death rates from lung cancer for pipe and cigar smokers with increasing tobacco consump- tion (table 27). Kahn (50) also demonstrated a dose-response relation- ship for lung cancer by the amount smoked (table 28). A few of the retrospective studies contained enough smokers to allow an examination of dose-response relationships for pipe and cigar smok- ing and lung cancer (J, 61, 74, 77). An increased risk of developing lung cancer was demonstrated with the increased use of pipes and cigars as measured by amount smoked and inhalation. The retrospec- tive investigation of Abelin and Gsell (1) is of particular interest. The smoking habits of 118 male patients with cancer of the lung from a rural area of Switzerland were compared with those reported in a sur- vey of all male inhabitants of a town in the same region. About 20 percent of the population of this area were regular cigar smokers, the most popular cigar being the Stiimpen, a small Swiss-made machine- manufactured cigar cut at both ends with an average weight of 4.5 g. In this investigation, cigar smokers experienced a risk of developing lung cancer that was similar to the risk of cigarette smokers. A dose- response relationship was demonstrated for inhalation and amount smoked. These data suggest that the heavy smoking of certain cigars may result in a risk of lung cancer that is similar to that experienced by cigarette smokers. Several pathologists have reported histologic changes in the bronchial epithelium in relation to smoking in various forms. Knudt- son (57) examined the bronchial mucosa of 150 lungs removed at au- topsy and correlated the histologic changes noted with the history of smoking, age, occupation, and residence. Specimens obtained from the six cigar and pipe smokers demonstrated basal cell hyperplasia; however, there was no squamous or atypical proliferative metaplasia as 18 frequently seen in the heavy cigarette smokers. Sanderud (78) examined histologic sections from the bronchial tree of 100 male autopsy cases for the presence of squamous epithelial 573 metaplasia. In this study, 39 percent of the population were non- smokers, 20 percent were pipe smokers, and 38 percent smoked cig- arettes. A total of 80 percent of the pipe smokers and cigarette smokers demonstrated squamous metaplasia of the bronchial tree, whereas only 54 percent of the nonsmokers had this abnormality. Auerbach, et al. (6) examined 36,340 histologic sections obtained from 1,522 white adults for various epithelial lesions including: presence or absence of ciliated cells, thickness or number of cell rows, atypical nuclei, and the proportion of cells of various types. The pathologic findings in the bronchial epithelium of pipe and cigar smokers are compared to those found in nonsmokers and cigarette smokers (table 25). Pipe and cigar smokers had abnormalities that were intermediate between those of nonsmokers and cigarette smokers, although cigar smokers had pathologic changes that in some categories approached the changes seen in cigarette smokers. TaBLe 26.—AMortality ratios for lung cancer deaths in male cigar and pipe smokers. A summary of prospective studies Type of smoking Author, reference Non- Cigar Pipe Total pipe Cigarette Mixed smoker only only and cigar ouly Hammond and Horn (40). 1. 00 3. 35 8.50 ..2 2 8. 23. 12 19. 71 Doll and Hill (26, 27).... 1.00 _...._.. __._.. 6.14 13.29 7. 43 Best (9)_-22 2222 1. 00 2. 94 435 -. 1 __. 14.91 __.. LLL Hammond (88)___._.._._ 1. 00 1. 85 2. 24 1.97 9. 20 7.39 Kahn (60)___. 1. 00 1. 59 1. 84 1. 67 12.14 _-_ ole TABLE 27.—Lung cancer death rates for cigar and pipe smokers by amount smoked—Doll and Hill Smoking type Death rate per 100 Number of deaths Nonsmoker_______._-.__-_-___. 0. O7 3 Cigar and pipe: ltol4g. perday___.--.-. oe. - 42 12 15 to 24 g. perday____.-__... - 45 6 >24 g.perday__.__-.- - 96 3 Cigarette only._.---- - 96 143 Sources: Doll, R., Hill, A. B. (28). 574 TaBLe 28.—Lung cancer mortality ratios for cigar and pipe smokers by amount smoked— Kahn Smoking types Mortality ratlo Number of deaths Nonsmoker__..._...----------------+-------- 1. 00 78 Cigar smokers: <5 cigars per day_____-__.-------------- 1.14 12 5 to & cigars per day.____.-_-.----------- 2. 64 il >8 cigars per day____-.----------------- 2. 07 2 Pipe smokers: <5 pipefuls per day___.--_-------------- -T7 2 5 to 19 pipefuls per day.._-.------------- 2.¢ 12 >19 pipefuls per day..--.--------------- 2.47 3 Cigar and pipe: 8 or less cigars, 19 or less pipefuls._...---- 1. 62 18 >8 cigars, >19 pipefuls_....--.---------- 2.19 2 Source: Kahn, H. A. (50). 575 9LS Tanue 29.—Relatine risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A sums mary of retrospective studies Relative tisk ratto and Porcentage of cases and controls by typo of smoking Author, reference Numbor Nonsmoker Cigar only Plpeonly Total Pips = Clgnrotts Mixed and clgar only Levin, et al. (60); Relative risk..... 82 1.0 0.7 0.8 ..lL lll. 21 el. Cases... 2. 236 = Percent cases_.._.. 15 ll 40 Leelee 66 Lele. Controls__.2... eae eee ceeeuee 481 Percent controls... _. 22 23 2 le 4400 ell. Schrek, et al. (81); Relative risk.3002 28. 1.0 6 07 lle | ns Cases... 82 Percent cases......0. = 15 4 8 Leelee eee Bk Controls... 522 Percent controls__...___. 22 23 VW eee 1! ee Wynder and Graham (111) Relative risk...9..0 | 1.0 5. 1 3.6 2... 15.7 Joelle Cases... 22. 605 Percent cases__.....___ | 1 4 $0 eee BL eel. Controls... eee 780 Percent controls......._- 15 8 V2 lle 65 Lele Doll and Hill (26): Relative risk.---. 00 1.0 welll BL eee l.. 96 oe ll Bees 8 1,357 Percent cases___.... ne 4 lll T4 0 ell Controls..... 2 1,357 Percent controls_....-_ G8 Lele TO eect eee 69 eee Koulumies (66): Relative risk...02. 00 | al 9.6 -oel ll. 29.3 222 lll Cases... 2.22. 812 Percent cases._..... 6. 6 Lele 2 ell TT lee Controls... 2.222 300 Percent controls......__. Wo Le 6 Leelee M6 eel Sadowsky, et al. (77) Relative risk... 8.088. 1.0 2.4 14 ll 3.7 5.6 Cases... 22... 477 Percent cases....00. 68 4 2 3 lle, 57 3h Controls...02 222 fpeeeeee 615 Percent controls...... 13 3 7 knell. 53 19 LZL¢ Wynder and Cornfield (110): Cases. 22... eee Cases. eee Cases. 2.2... teen Cases_ 2. Schwartz and Denoix (82) ; Cases Lombard and Snogireff (61); Cases 13.5 96 78 89 78 95 75 50 82S TABLE 29.—Relative risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A sum- mary of retrospective studies—Continued Rolativo risk ratio and percentage of casos and controls by typo of smoking Author, reference Number Nonsmoker Cigar only Pipsonly Total pipe Clgaretta Mixod ond cigar only Wicken (106): ‘Relative risk... 000 | LO eee Ll. 2.2 4.3 4.2 Cases... eee 803 Percent cases.__._..____ 4 lle eee loll. 10 78 7 Controls... eee 803 Percent controls.......__ ee 16 64 6 Abelin and Gsell (1): Relative risk... 20. 1.0 30.7 21.8 39. 9 31.0 24.7 Cases... 118 Percent cases.._....___| 2 28 7 58 25 24 Controls... 2... 524 Percent controls......._. 35 19 6 31 17 10 Wynder, et al. (116): Relative risk... 008. LO wee. lle 2.0 a Cases--- 2. ee 210 Percent cases__._.. 2. 8 eee tlle 5 920 Lee Controls... ee 420 Percent controls......... 21 eee ele 15 AT leas 62S TABLE 30.—Changes in bronchial epithelium of male cigar, pipe, and cigarette smokers as compared to nonsmokers Percont sectiona Percent 3 plus Percent Percent Group Number of Sections with with epithelial callrows with atypical cells Total byperplasta and subjects epithellum loslons cilia present sections goblet calls tao ginods Ist set (none vs. pipe vs. cigarette—matched on 1:1 basis): Nonsmoker_....-----------e2---- ee ee ee 20 985 21.7 11.2 2. 6 1, 031 10. 3 Pipe only-_... 2-2 eee ee eee eee eee eee 20 924 65.5 38, 1 37.0 979 35. 9 Cigarette only_-_--.------------------- 20 914 96. 8 88. 6 95. 2 982 72.1 2d set (none vs. pipe vs. cigarette—matched on frequency basis): Nonsmoker...-------------------- eee ee 25 1, 246 22.9 13. 4 7 1, 277 11.5 Pipe only.......---------------- eee 25 1, 164 68. 7 38.7 38. 2 1, 247 37.9 Cigarette only_..----------------- eee 25 1, 126 96.3 88. 7 89.5 1, 237 75.5 3d set (none vs. cigar vg. cigarette); Nonsmoker_.--.----------+--+---e eee 35 1, 706 27.4 12.7 .8 1, 748 15.3 Cigar only......--2----.----------- eee 35 1, 733 90. 8 40. 0 73.6 1, 828 52.5 Cigarette only.......-..--------------- 35 1, 526 99. 0 92.7 97.8 1, 693 80. 2 Source: Auerbach et al. (8). Tumorigenic Activity The tumorigenic activity of tobacco smoke can be modified in botha quantitative and qualitative sense. Physical or chemical changes in tobacco that result in a reduction of total particulate matter upon combusion of a given quantity of tobacco may result in a reduction of carcinogenic potential. Such factors as tobacco selection, treatment, blending, cut, end additives may quantitatively alter tar production. Wrapper porosity and filtration may also affect tar production. Quantitative changes in the tumorigenic activity of tobacco tar on a gram-for-gram basis can be produced by the selection and treatment of tobacco, the use of additives or tobacco sheets, or adjustments in the cut and packing density. Combustion temperature can also produce quantitative changes in the particulate matter of tobacco smoke. Although high-temperature burning produces less particulate matter in the smcke, it appears that tumorigenic components occur in higher concentration when tobacco is pyrolized at temperatures higher than 700° centigrade (34). Cigars, pipes, and cigarettes are similar in that they are smoked orally and have a common site of introduction to the body. The tissues of the mouth, larynx, pharynx, and esophagus appear to receive ap- proximately equal exposure to the smoke of these products. Inhalation causes smoke to be drawn deeply into the lungs and also allows for systemic absorption of certain constituents of tobacco smoke which then can be carried further to other organs. Pipe tobacco and cigars vary from cigarettes in a number of charac- teristics that can produce both quantitative and qualitative changes in the total particulate matter produced by their combustion. Experi mental evidence suggests that although there is some difference in the amount and quality of tar produced by cigars, this cannot account for the reduced mortality observed in cigar smokers compared to cigarette smokers. Experimental Studies Several experimental investigations have been conducted to examine the relative tumorigenic activity of tobacco smoke condensates obtained _ from cigarettes, cigars, and pipes. Most of these studies were standard- ized in an attempt to make the results of the cigar and pipe experiments more directly comparable with the cigarette data and most used the shaved skin of mice for the application of tar. Tars from cigars, pipes, and cigarettes were usually applied on an equal weight basis so that qualitative differences in the tars could be determined. In several ex- periments, the nicotine was extracted from the pipe and cigar conden- sates in an attempt to reduce the acute toxic effects that resulted in animals from the high concentrations of nicotine frequently found in these products. 580 Wynder and Wright (717) examined the differences in tumorigenic activity of pipe and cigarette condensates. Tars were obtained by the smoking of a popular brand of king-size cigarettes and the same ciga- rette tobacco smoked in 12 standard-grade briar bowl pipes. Both the cigarettes and pipes were puffed three times a minute with a 2-second putf and a 35-ml. volume. Both the cigarettes and pipes attained similar maximum combustion zone temperatures; however, the use of cigarette tobacco in the pipe resulted in a combustion chamber temperature that averaged about 150° centigrade higher than temperatures achieved when pipe tobacco was used. Chemical fractionation was accomplished and equal concentrations of the neutral fraction were applied in three weekly applications to the shaved skin of CAF, and Swiss mice. The results indicate that neutral tar obtained from cigarette tobacco smoked in pipes is more active than that obtained in the usual manner from cigarettes. About twice as many cancers were obtained in both the CAF, and the Swiss mice, and the latent period was about 2 months shorter. Extending these data, Croninger, et al. (20) examined the biologic activity of tars obtained from cigars, pipes, and cigarettes, Each form of tobacco was smoked as it was manufactured in a manner to simulate human smoking or to maintain tobacco combustion. The whole tar was applied in dilutions of one-to-one and one-to-two with acetone to the shaved backs of female CAF, and female Swiss mice using three applications each week for the life-span of the animal. The nicotine was extracted from the pipe and cigar condensates to reduce the acute toxicity of the solutions. The Swiss mice. pipe, cigar, and cigarette tars produced both benign and malignant tumors. The incidence rates of malignant tumors given as percents were: 44, 41, and 37, respectively. These results suggested a somewhat higher degree of carcinogenic activity for cigar and pipe tars than for cigarette tar. Similar results were reported by Kensler (53) who applied conden- Sates obtained from cigars and cigarettes to the shaved skin of mice. The incidence of papillomas produced by cigar smoke concentrate was no different from that of the cigarette smoke condensate. Similarly, there was no difference between cigar and cigarette smoke condensates when carcinoma incidences were conipared. Homburger, et al. (45) prepared tars from cigar, pipe, and cigarette tobaccos that were smoked in the form of cigarettes. In this way, all tobaccos were smoked in an identical manner and uniform combustion temperatures were achieved. Because of this standardization, differ- ences in tumor yield could be attributed to tobacco blend and not the manner in which the tars were prepared. The whole tars were diluted one-to-one with acetone and applied to the shaved skin of CAF, mice three times a week for the lifespan of the test animal. Skin cancers Were produced more quickly with pipe and cigar smoke condensates than with cigarette smoke condensates. This suggests that the smoking 425-028 O—73-_15 581 of pipe and cigar tobaccos in the form of cigarettes does not alter the condensates to any significant degree. Davies and Day (22) prepared tars from small cigars especially manufactured from a composite blend of cigar tobacco representing small cigar brands smoked in the United Kingdom, cigarettes espe- cially manufactured from the same tobacco used for the cigars de- scribed above, and plain cigarettes especially manufactured from a composite blend of flue-cured tobacco representing the major plain cigarette brands smoked in the United Kingdom. The whole tar was diluted to four concentration levels and applied to the shaved backs of female albino mice for their lifespan using four dosing regimens. A statistically significant increase in mouse skin carcinogenicity was shown with the cigar smoke condensate compared with the tars obtained from either fiue-cured or cigar tobacco cigarettes. These results are consistent with those of the previously reported investigations. The effect of curing on carcinogenicity was examined by Roe, et al. (76). Bright tobacco grown in Mexico was either flue-cured or air- cured and bulk fermented. Both flue-cured and air-cured tobaccos were made into cigarettes standardized for draw resistance and were smoked under similar conditions. Condensates from these cigarettes were ap- plied to mouse skin three times each week in an acetone solution. The development of skin tumors was higher in mice treated with the flue- cured condensate than in mice treated with the air-cured condensate (P<0.01). The difference may have been due to the use of equal — weights of condensate rather than the use of extracts from an equal number of cigarettes. The air-cured cigarettes produced a greater weight of condensate than did the flue-cured cigarettes. A chemical analysis of the two tobaccos and two condensates revealed only small differences in composition. Evidently air curing of Bright tobacco in the method used is not associated with a loss of reducing sugars. A more detailed analysis of these experimental studies is presented in table 31. These experimental data suggest that cigar and pipe tobacco con- densates have a carcinogenic potential that is comparable to cigarette condensates. This is supported by human epidemiological data for those sites ex posed equally to the smoke of cigars, pipes, and cigarettes. The partially alkaline smoke derived from pipes and cigars is gen- erally not inhaled, and as a result there appears to be a lower level of exposure of the lungs and other systems to the harmful properties of pipe and cigar smoke than occurs with cigarette smoking. It is antic- ipated that modifications in pipe tobacco or cigars which would result in a product that was more readily inhalable would eventually result in elevated mortality from cancer of the lung, bronchitis and emphy- sema, arteriosclerotic cardiovascular diseases, and the other condi- tions which have been clearly associated with cigarette smoking. 582 8S TABLE 31.—T'umorigenic activity of cigar, pipe, and cigaretle smoke condensates in skin painting experiments on animals {[Key: A= Mothod, B=Froquoncy. CDuratlon, D=Matertal.] Porcent Author, reference Animal Activity Treatmoat Numbor nea enna Papitlomas Carcinomas Wynder and CAF, and A. Painting shaved skin, CAF: Wright Swiss mice, B, 3 times a week, Pipe (cigarette tobacco)... 2. 30 GO 20 (117). C. Lifespan (24 months), Cigarette... 22 eee 30 30 3 D. Neutral fraction tar from Swiss: cigarettes and cigarette Pipe (cigarette tobacco)__.._- 30 63 50 tobacco smoked in pipes. Cigarette... 2 30 63 33 Croninger, et Female Swiss A. Painting shaved skin, Cigar, nicotine free (1:1)... 46 65 4i al. (£0). mice, B. 3 times a week. Pipe, nicotine free (1 eel 45 71 44 C. Lifespan. Cigar (1:2). 22 e 78 83 18 D. Whole tar diluted in Pipe, nicotine free (1 1) &9 30 16 acetone. Cigarette (lil). ee eel 86 47 37 Acctone controly.. 2 2222... 8 23 0 0 Kensler (68)_.. Swiss mice.._... A. Painting shaved skin. Cigar tar (J) 100 mg. per week__ 100 42 41 B. 3 times a week, Cigarette tar (G) 100 mg. per 100 40 28 C. Lifespan. week, D. Whole tar diluted in Cigarette tar (E) 100 mg. per 100 34 34 acetone. week. 98S TABLE 31.—Tumorigenic activity of cigar, pipe, and cigarette smoke condensates in skin painting experiments on animals—Continued (Key: A» Mothod, B= Frequoucy, C= Duration. D =Matortal.] Porcent Author, reference Anima! Activity Treatment Number Papillomas Carcinomas Homburger, et CAF, mice___..- A. Painting shaved skin, Cigar tobacco cigarettes 165 mg. 100 37.5 19 al. (44). B. 2 to 3 times a week. | per week. C. Lifespan (2 years), Pipe tobacco cigarettes ! 64 mg. 100 23 20 D. Whole tar diluted 50 per- per week. cent in acctone, Cigarettes } 62 mg. per week.__. 100 15 23 Acctone controls... ....20220--- 100 0 0 Davies and Female albino A. Painting shaved skin. Cigars, small 83 mm. long 150 144 44 27 Day (£8). mice. B. Varied. per week. C. 116 weeks, Cigar tobacco cigarettes 150 72 32 14 D, Whole tar in 150 mg. per week. acctone, Cigarettes 150 per week... _- 144 28 13 Roe, et al. Female Swiss A, Painting shaved skin. Flue-cured Bright tobacco 180 400 52 30 (76). mice. B. 3 times a week. mg. per week, C. Lifespan. Air-cured Bright tobacco 180 400 68 23 D. Whole tar diluted in mg, per week, acetone, Acctone controls 0.75 cc. per 400 1.3 0. 5 week, 1 Clygur, plpo, and clgarotto tobacco smokod us clgaretios at similar combustion tomporaturey, CarpiovAsCULAR DiszasEs The majority of deaths in the United States each year are due to cardiovascular diseases. Cigarette smoking has been identified as a major risk factor for the development of coronary heart disease (CHD). However, pipe and cigar smokers experience only a small increase in mortality from coronary heart disease above the rates of nonsmokers. Cigarette smokers have higher death rates from cerebro- vascular disease than nonsmokers, whereas pipe and cigar smokers have cerebrovascular death rates that are only slightly above the rates of nonsmokers. Table 32 summarizes the major prospective epidemiologi- cal investigations that examined the association of smoking in various forms and total cardiovascular diseases, coronary heart disease, and cerebrovascular disease. Doll and Hill. (28), Best (9), and Kahn (50) examined dose-response relationships for pipe and cigar smokers and. reported a slight increase in mortality from coronary heart disease with an increase in the number of cigars or pipefuls smoked. Other prospective epidemiological studies have also examined the relationship of smoking in various forms to coronary heart disease and related risk factors. Jenkins, et al. (49) in the Western Collaborative Group Study of coronary heart disease, reported an incidence of coro- nary heart disease in men aged 50 to 59 who were pipe and cigar smok- ers that was intermediate between the rates seen in cigarette smokers and nonsmokers. No increase in incidence of coronary heart disease was seen among the pipe and cigar smokers in the younger age groups. Shapiro, et al. (8d), in a study of the health insurance plan (HIP) population, reported incidence rates for myocardial infarction, angina pectoris, and possible MI, in pipe and cigar smokers that were similar to the incidence rates seen in cigarette smokers. These rates were con- siderably higher than those of nonsmokers. Data from the pooling project (47) suggested that the incidence of CHD deaths, sudden death, and the first major coronary event in pipe and cigar smokers was intermediate between the incidence experienced by cigarette smok- ers and nonsmokers. In contrast to these-studies, Doyle, et al. (30) reported no increase in CHD deaths, myocardial infarction, or angina pectoris in pipe and cigar smokers over the rates of nonsmokers in the ~ Framingham study. The retrospective studies of Mills and Porter (64), Villiger and Hevden-Stucky (704), Schimmler, et al. (80), and Hood, et al. (46) contained data suggesting that pipe and cigar smokers experience mortality rates from coronary heart disease that are essentially similar to those experienced by cigarette smokers. The retrospective study of Spain and Nathan (8¢) reported lower rates of coronary heart dis- ease in all smoking categories than were found in nonsmokers. Van Buchem (703) and Dawber, et al. (23) examined serum choles- terol levels in groups of individuals classified according to smoking 585 habits. In these two studies, pipe and cigar smokers had serum choles- terol levels that were nearly identical with the levels found in nonsmokers. Tibblin (97) and Dawber, et al. (23) investigated the effect of smok- ing on blood pressure. The proportion of smokers decreased in proups with higher blood pressures, although this was not as dramatic for pipe and cigar smokers as it was for cigarette smokers. In an experimental study using anesthetized dogs, Kershbaum and Bellet (54, 55) examined the effects of inhaled and noninhaled ciga- rette, cigar, and pipe smoke on serum free fatty acid levels and urinary catecholamine and nicotine excretion. In this study, inhalation of to- bacco smoke from all these sources resulted in similar increases in serum free fatty acids and in catecholamine and nicotine excretion. TABLE 32.—Mortality ratios for cardiovascular deaths in male cigar and pipe smokers. A summary of Prospective epidemiological studies Type of smoking Author, reference Category Non- Clpar PI Total Clga- smoker only only pipe and rette only Mixed cigar Hammond and Cardiovascular 1.00 1.26 1.07 _____. 157 _LLL__ Horn (40). total. Coronary.__.___ 100 128 £03 ______ 1.70 2. Cerebrovascular_____ 1.00 1.31 1.23 1 | 1.30 2.2L. Doll and Hill Cardiovascular 100-2022 LLlL le 0.99 1.26 1.13 (26, 27). total. Coronary_..___.___. 1.00 22-0 oo. 94 123 1.18 Cerebrovascular. ____ 100-22. LL lle -95 113 97 Best (9)__._._ Cardiovascular 1.00 £14 -95 _ Le 1.52 ___.o total. Coronary._________. 1. 00 99 1.00 _____. 1.60 _..___ Cerebrovascular__ --- 100 1.28 85 22 ~ 83 2. LL Hammond ! Cardiovascular 1.00 -_-.. lll. 1.06 1.90 ______ (38). total. Coronary_____._____. 100 135 21.19 |__| 184 1.58 Cerebrovascular_____ 1.00 2020 2 1.09 1. 1.40 Kahn (60)____ Cardiovascular 100 105 £06 105 1 752 ee total Coronary eae ee eee 1.00 104 108 1.05 1.74 LLL Cerebrovascular. ____ 1.00 108 109 106 1.52 __.___ ' Mortality ratios for ages 33 to 64 only are presented. Curonxic Oxstrective Pcusox ary Disease (COPD) Chronic bronchitis and pulmonary emphysema account for most of the morbidity and mortality from chronic respiratory disease in the United States. Cigarette smokers have higher death rates from these 586 diseases and have more pulmonary symptoms and impaired pul- monary function than nonsmokers. Cigarette smokers also have more frequent and more severe respiratory infections than nonsmokers. The relationship between smoking pipes and cigars and these diseases is summarized in this chapter. The major prospective epidemiological studies are summarized in table 33. In a retrospective study of 1,189 males and matched controls in Northern Ireland, Wicken (406) investigated smoking in various forms and mortality from bronchitis. ‘Che relative risk ratios com- pared to nonsmokers for mortality from chronic bronchitis were 1.98 for all smokers, 1.55 for pipe and cigar smokers, 2.95 for cigarette smokers, and 1.49 for mixed smokers. From a review of these prospective and retrospective studies, it appears that pipe and cigar smokers experience mortality rates from bronchitis and emphysema that are higher than the rates of non- smokers. Although these morality rates approach those of cigarette smokers, in most instances they are intermediate between the rates of cigarette smokers and nonsmokers. Pipe and cigar smokers have significantly more respiratory symp- toms and illnesses than nonsmokers. Those studies which contain data on pipe and cigar smoking as related to respiratory symptoms are summarized in table 34. , Only a few studies have examined pulmonary function in pipe and cigar smokers. There appears to be little difference in pulmonary func- tion values for pipe and cigar smokers as compared to nonsmokers (table 35). Naeye (67) conducted an autopsy study on 322 Appalachian coal workers who were classified according to the type of coal mined and tobacco usage. Emphysema was slightly greater in cigarette smokers, as were anatomic evidences of chronic bronchitis and bronchiolitis. Those changes found in pipe and cigar smokers were intermediate between those of cigarette smoking miners and nonsmoking miners. Changes in pulmonary histology in relation to smoking habits and age were examined by Auerbach, et al. (8). Fibrosis, alveolar rupture, thickening of the walls of small arteries, and thickening of the walls of the pulmonary arterioles were found to be highly related to the smoking habits of the 1,340 male subjects examined, The 91 pipe and cigar smokers over the age of 60 were found to have somewhat more alveolar rupture than the men of the same age distribution who never smoked regularly. However, pipe and cigar smokers as a group had far less rupture than cigarette smokers. The same relations as described above were found for fibrosis, thickening of the walls of the arterioles and small arteries, and padlike attachinents to the alveolar septums. Tobacco smoke has been shown experimentally to have a ciliostatic effect on the respiratory epithelium. The interval between puffs, the 587 amount of volatile and particulate compounds in the smoke, and the exposure volume have been shown to influence the toxic effect of tobacco smoke. Dalhamn and Rylander (27) exposed the upper trachea of anesthetized cats to the smoke of cigarettes and cigars, observing the effect on ciliary activity through an incident-light microscope. A chemical analysis of the gas and particulate phases revealed that the cigar smoke was more alkaline and, in general, contained higher concentrations of isoprene, acetone, acetonitrile, toluene, and total particulate matter compared to cigarette smoke. The average number of puffs required to arrest ciliary activity was found to be 73 for the cigarette smoke and 114 for the cigar smoke. The difference is statisti- cally significant (P <0.01). Of the two smokes, the smoke with the highest concentration of volatile compounds was found to be the least ciliostatic. This suggests that the degree of ciliotoxicity of a smoke is not necessarily correlated to the level of one or several of the substances found in the smoke. Passey, et al. (70.71, 72) studied the effect of smoke from flue-cured cigarette tobacco cigarettes and air-cured cigar tobacco cigarettes on the respiratory system of rats. In two separate but similar experi- ments, a total of 48 animals were exposed to English cigarette tobacco smoke, 48 were exposed to air-cured cigar tobacco smoke, and 12 were exposed to an air-cured Burley tobacco smoke. The rats in groups were exposed to the specific smoke in a smoke-filled cabinet. Animals ex- posed to the smoke. from air-cured tobaccos remained healthy through- out the experiments, even at high levels of smoke exposure. The three deaths that occurred within this group were from nonrespiratory causes. In both experiments, the rats exposed to cigarette tobacco smoke began to die within 1 or 2 months, and in each experiment most of the animals died within a week or two of the first deaths. At autopsy the rats exposed to flue-cured tobacco smoke on gross examination were found to have greatly enlarged lungs, the trachea was often full of mucus, and there was evidence of pneumonia. On microscopic examina- tion it was found that the trachea and bronchi contained purulent cellular exudates, evidence of metaplastic changes, an absence of cilia, and goblet cell hpyerplasia. Typically, the cause of death was a lobar or bronchopneumonia. The author concluded that, “the smokes of flue- cured tobaccos are more dangerous to man and to animals than those of air-cured tobaccos.” 588 Unfortunately, few details were published concerning the method used to expose the animals to the different types of smoke. The fre- quency and duration of exposure were not specified. and the extent of actual inhalation of smoke by the different groups of rats was either not determined or not reported. It is also difficult to determine the effect of smoke exposure on the frequency and severity of respiratory infections when animals are exposed to smoke in groups where common exposure occurs. The rat strain used was not identified, but it was noted that animals appeared to suffer from an endemic rat. bron- chiectasis. It is not known to what extent epidemics of respiratory infections occurred among these animals. Because of these difficulties, no firm conclusion can be drawn concerning the effect of smoking flue- cured or air-cured tobaccos on the incidence of respiratory infections in rats. TABLE 33. —Mortality ratios for chronic obstructive pulmonary deaths im male cigar and pipe smokers. A summary of prospective epidemio- logical studies Type of smoking Author, reference Category Non- Cigar P Total Cigs- smoker only only pipe and rette only Mixed cigar Hammond and COPD total._______ 1.00 829 L777 LL 2.85 .__..e Horn (40). Emphysema__.---2. 2222 22-2. Lee Le. Le Bronchitis.-.--.---22 22. 28 nee ee Doll and Hill COPD total. 22-22 ee ee ee ee (26, 27). Emphysema__.-.2-- _222 22-2. @2-e ee Le Bronchitis.._______. 1.00 _.2 0) LLL Le 4.00 7.00 6.67 Best (9)... COPD total... 2-22. Lee. ee eee ee Emphysema_______. 1.00 3.33 .75 ____. 5.85 22 _ Bronchitis._._._____ 1.00 3.57 2.11 _____ 11.42 _____. Hammond ($8).. COPD total_._-..-. 222. 22-2. eee eee 8 Emphysema________ 1.00 L202. LLL 1.37 '°655 _._.2- Bronchitis_._-....222 _-2. © Le pene eee Kahn (60)______ COPD total._______ 100 .79 2.36 .99 1008 ______ Emphysema________ 100 £24 2.13 1.31 1417 _____. Bronchitis..._______ 1.00 21.17 1.28 1.17 449 | ' Only mortality ratios for ages 55 to 64 re presented. 495-028 O—73-—_16 589 TasLe 34.—Prevalence of respiratory symptoms and illness by type of smoking Percent prevalence Autbor, reference Number and type of Tiinass population Noo- Total Cigs- smoker pipe and rette Mixed cigar only Boake (10)_._ Parents of 59 Cough__..2-2 2. 32 32 48... families. Sputum 24 15 20 _-.-- production. Chest iliness______ 5 4 nn Edwarda, et 1,737 male Chronic bronchitis. 17 19 31 14 al. (38). outpatients. Ashford, et 4,014 male Bronchitis________ IO '35 21 37 al. (4). workers in 3. Pneumoconiosis___. 1k 6134 14 2 Scottish collieries. Bower ({f1)__. 95 male bank Cough... 2 Le 0 0 29 __LL_e employees. Sputum 8 15 33 .__L_. production. Wheeze._.__-.___. & 31 33 LL. Chest iliness._____ 15 54 40 _____. Wynder, etal. 315 male pa- Cough (New 14 33 56 51 (114). tients in York). New York Cough 22 30 67 66 and 315 male (California). patients in Influenza (New ll 21 24 2 LLL California. York). influenza 28 24 3b LLL. (California). Chest illness 9 10 12 LLL. (New York). Chest illness 7 6 WLLL (California). Densen, et al. 5,287 male Persistent cough. . 7 11 25 22 (24). postal and Persistent 11 16 26 LL 7,213 male sputum transit production. workers in Dyspnea___.______ 16 19 26 _.__L- New York Wheeze___._-._-_- 14 21 32 Le City. Chest illness______ 13 16 18 ___L_. Cederlof, et 4,379 twin pairs, Cough. 22.22 Le 4 7 WF _ 1. al. (18). all U.S. Prolonged cough... 2 4 lE Llllle veterans. Bronchitis. _._.._- 2 3 10 _.. LL. Rimington 41,729 male Chronic bronchitis. 5 1g | (78). volunteers. 590 TABLE 34.— Prevalence of respiratory symptoms and illness by type of smoking—Continued Percent prevalence Autbor, references Number and type of Tiness population Noo- Total Ciga- smoker pipe and rette Mired cigar only Comstock, et 670 male tele- Persistent cough. _ 10 16 41 _.2LL. al. (19). phone Persistent 13 20 cn employees. sputum. Dyspnea___.____. 33 39 44 28. Chest illness in 14 18 20 _____- past 3 years. Lefcoe and 310 male phy- Chronic respira- 9 18 44 _ Wonnacott Sicians in tory disease. (69). London, Chronic bronchitis_ 1 12 34 _..__. Ontario. Obstructive lung 1 3 4 Lie. disease, Asthma____.____. 7 3 6 .. 2 - Rhonchi.....---.- oO 3 9__--L. 1 Figures for pipe only. TABLE 35.—Pulmonary function values for cigar and pipe smokers as compared to nonsmokers Type of smoking Auther, reference Number and type Function of population Non- Total pipe Cigarette Mized smoker and cigar only Ashford, et 4,014 male FEV, 0..----- 3.39 12,59 3.14 2.62 al. (4). workers in 3 Scottish collieries. Goldsmith, 3,311 active Puffmeter__.. 313.63 299.26 303.44 _..__- et al. (37). or retired FEV).0-_.---- 2.99 2. 80 2.91 2. LL longshore- TVC_.._____- 3. 87 3. 68 3.88 --- 22 men. _ Comstock, 670 male FEV, .c._-_--- 3.12 3. 26 2.82 ...-- et al. (19). telephone employees. Lefcoe and 310 male FEV, .9-__---- 3. 39 3.17 31D Lee Wonnacott physicians MMFR liters 4.09 4.17 3.64 -.---- (89). in London, per second. Ontario. 5 Figures for pipe only. 591 GASTROINTESTINAL D1soRDERS Cigarette smokers have an increased prevalence of peptic ulcer disease and a greater peptic ulcer mortality ratio than is found in nonsmokers. These relationships are stronger for gastric ulcer than for duodenal ulcer. Cigarette smoking appears to reduce the effective- ness of standard peptic ulcer treatment regimens and slows the rate of ulcer healing. Cigar and pipe smokers experience higher death rates from peptic ulcer disease than nonsmokers. These rates are higher for gastric ulcers than for duodenal ulcers but are somewhat less than those rates experienced by cigarette smokers, Table 31 presents the mortality ratios for ulcer disease in cigar and pipe smokers as reported in the prospective epidemiological studies. Retrospective or cross-sectional studies by Trowell (95), Allibone and Flint (2), Doll, et al. (29), and Edwards, et al. (33) contain data on ulcer disease in pipe smokers as well as cigarette smokers. No association was found between pipe smoking and ulcer disease in these investigations. Tas_Le 36.—Afortality ratios for peptic ulcer disease in male cigar and pipe smokers. Summary of prospective studies Type of smoking Author, reference Tiiness Total Cigs- Non- Cigar Pipe pipe rette Mixed smoker only only and only cigar Hammond and Ducdenal ulcer_..... 1.00 0.25 1.67 ..-__- 2.16 _-.--- liorn (40). Doll and Hill Gastric ulcer__...__. 1.00 -...- -.--- 4.00 7.00 5.30 (26, 27). Hammond (38).. Gastric ulcer_..----- 1.00 __--- ----- 2.04 2.95 ____-- Duodenal ulcer_____- 1.00 ___.. ----- 92 2.86 __---- Kahn (60)___..- Gastric ulcer___.---- 1.00 2.90 2.84 2.48 4.13 _.._-- Duodenal ulcer. __--- 1.00 1.58 1.59 1.39 2.98 -_.__- Little Cigars In the past year, several new brands of little cigars (weighing 3 poundsor less per 1,000) have appeared on the national market. These cigarette-sized products are manufactured, packaged, advertised, and sold in a manner similar to cigarettes, Little cigars enjoy several legal advantages over cigarettes: They have access to television advertising ; they are taxed by the Federal Government and by most States, at much lower rates than cigarettes, resulting in a significant price advantage; 592 and they do not carry the warning label required on cigarette pack- ages and in cigarette advertising. A market appears to be developing for these products, as there has recently been a sharp increase in the shipment of little cigars destined for domestic consumption (table 37). It is important to estimate the potential public health impact of these little cigars. An adequate epidemiological evaluation of the ef- fect of Jittle cigar smoking on health could take 10 or 15 years and is probablv an impractical consideration ; however, a review of the epide- miological, autopsy, and experimental data concerning the health con- sequences of cigarette, pipe, and cigar smoking summarized in this and previous reports 19 helpful in considering the potential impact on health of smoking little cigars. An analysis of the chemical constit- uents suggests that both cigarettes and cigars contain similar com- pounds in similar concentrations. Two exceptions are reducing sugars, which are not found in quantity in the fermented tobaccos commonly used in cigars, and the pH of the inhaled smoke. The pH of the smoke from U.S. commercial cigarettes is below 6.2 from the first to the last puff, whereas the smoke from the last half of a cigar may reach as high as pH 8 to 9. With increasing pH, nicotine is increasingly present in the smoke as the free base. Skin painting experiments in mice indicate that tumor yields with cigar or pipe “tars” are nearly identical with those obtained with cigarettes “tars”. In addition, the epidemiological data suggest that depth of inhalation probably accounts for the fact that cigarettes are so much more harmful than cigars and pipes in con- tributing to the development of lung cancer, coronary heart disease, and nonneoplastic respiratory disease. For such diseases as cancer of the oral cavity, larynx, and esophagus, where smoke from cigars, pipes, and cigarettes is available to the target organ at comparable levels, the mortality ratios are very similar for all three forms of tobacco use. Several factors, including “tar,” nicotine, and the pH of the smoke, probably operate to influence inhalation patterns of smokers. The relative contribution of individual factors to the inhalability of a tobacco product has not been determined. Smoking those brands of little cigars which can be inhaled by a significant portion of the population in a manner similar to the pres— ent use of cigarettes would probably result in an increased risk of de- veloping those pulmonary and cardiovascular diseases which have been associated with cigarette smoking. On the other hand, smoking those little cigars which are used like most large cigars whereby the smoke is rarely inhaled would probably result in lower rates of those pulmonary and cardiovascular diseases than would be found among cigarette smokers, Only a limited analysis is available comparing the chemical com- pounds found in little cigars, cigarettes, and large cigars. The FTC analyzed the tar and nicotine content of all the little cigars (24) and cigarettes (97) currently available on the market. Little cigars have 593 generally a higher “tar” and nicotine level than cigarettes, although considerable overlap results in some little cigar brands having “tar” and nicotine levels comparable to those of some brands of cigarettes (figs. £ and 5). Hoffmann and Wynder (44) recently compared three brands of little cigars with an unfiltered cigarette, a filtered cigarette, and a large cigar. They measured a number of smoke constituents, in- cluding: “tar,” nicotine, carbon monoxide, carbon dioxide, reducing sugars, hydrogen cyanide, acetaldehyde, acrolein, pyridines, phenols, benz(a)anthracene, and benzo(a)pyrene (table 32). Cigarette A was the Kentucky reference cigarette, cigarette B was a popular brand of filter cigarette. Cigar A was an 85 mm, little cigar, cigar B was an 85 mm. little cigar, cigar C was a 95 mm. small cigar, and cigar D was a 112 mm. popular brand of medium sized cigar. The smoke pH was analyzed puff by puff (table 39). Cigarette smoke was found to be acidic (pH less than 7) for the entire cigarette. The smoke from little cigars became alkaline only in the last puff or two, whereas about the last 40 percent of the puffs from the larger cigar were alkaline. Although the pH of the total condensate obtained from cigarettes is usually acidic and the total condensate obtained from cigars is usually alkaline, the above data indicate that smoke pH of tobacco products changes during the combustion process. Smoke from large cigars may be acidic during the first portion of the smoke and not become alkaline until the last half of the cigar is smoked. Brunnemann and Hoffmann (7/5), using the same techniques de- scribed above, examined the effect of 60 leaf constituents on smoke pH. For several varieties of cigarette tobacco, they found a high correlation between the total aklaloid and nitrogen content and smoke pH. Stalk position also affected smoke pH. Tobacco leaves near the top of the plant, which contain high levels of tar and nicotine, yielded a smoke with a much higher pH than leaves lower on the plant. At present it is not known to what extent these factors influence the pH of the smoke of tobaccos commonly used in cigars or how these kinds of pH changes influence the inhalability of tobacco smoke. The inhalation of smoke, however, appears to be the most important factor determining the impact a cigar will have on overall health. Those physical and chemical characteristics of a tobacco product which most influence inhalation of tobacco smoke have not been accurately determincd. Nevertheless, it appears likely that the smoke of some brands of cigars may be compatible with inhalation by a sig- nificant portion of the smoking population, since: (2) Little cigars have tar and nicotine levels which, in some brands, are similar to the levels found in cigarettes, and (6) the pH of the smoke of some little cigar brands is acidic for the major portion of the little cigar and becomes alkaline only in the last puff or two. 594 It is reasonable to conclude that smoking little cigars may result in health effects similar to those associated with smoking cigarettes if little cigars are smoked in amounts and with patterns of inhalation similar to those used by cigarette smokers, for the reasons cited nbove, and these additional reasons: (a) In those little cigars for which pre- liminary data are available, the concentrations of carbon monoxide, hydrogen cyanide, acetaldehyde, acrolein, pyridine, phenol, and poly- cyclic hydrocarbon levels are comparable to those found in cigarettes: (4) cigarette smokers who switch to cigars appear to be more likely to inhale cigar smoke than cigar smokers who have always smoked cigars (14); and (c) cigarette smokers who switch to little cigars may be inclined to use them as they did cigarettés because of the physical similarities between the little cigars and cigarettes, including their size and shape, the number in a package, the burning rate, and the time it takes to smoke them. Figure 4.—Percent distribution of 130 brands of cigarettes and 25 brands of little cigars by “tar’’ content. 50 f ast 7) [Cigarettes Z 77] 40} 35} 4 . 30} q | 7] Soa = D 4 60 S 25} A 5 3 é | 20+ 1 15} I 4 10 J 5 i] g olf —n Mg. ‘tar’ 0 0 0 16.0 8.0 32.0 32.0 0 8.0 4.0 Cigarettes O4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 Little Cigars 3.1 3.1 10.0 46.2 23.1 10.0 3.9 0.8 9 0 SOURCE: U.S. Department of Health, Education, and Welfare (97) and Federal Trades Commission (34). 595 Figure 5.—Percent distribution of 130 brands of cigarettes and 25 brands of little cigars by nicotine content. 50 Cigarettes » Little Cigaee 40 7] 2 Y = 3 Y 2 30 3° iY) e? Z @ 20 , @ 15 g 10 4 5 | Y ota al. 2 & 8s & & @ © & © F 4 ; > ; > “ “ “ “ nN nN ee i 8 si 22 284 a8 2228 Sd a 0 ~m <+ m n o n ) 2 , oO gu oo 4 § ¢ 4a aa <§ Sd oO o S 2 ° ° ° 2 ° 4 ee ° 3 8 + 8 £ & ¥ OOS o & eS SOURCE: US. Department of Health, Education, and Welfare (97) and Fedaral Trade Com- mission (34). 596 Tasie 37.—Shipment of small and large cigars destined for domestic consumption (1970, 1971, 1972) Year 1970 1971 1072 Small cigars January.-220 02 58, 328, 520 85, 753, 780 123, 477, 550 February....---_) 63, 431, 580 72, 092, 205 179, 817, 839 March. .-22- 222 85, 881, 860 46, 542, 800 198, 165, 593 Aprile. 101, 613, 500 59, 059, 920 125, 335, 740 May_.--- 2 81, 093, 180 93, 237, 473 159, 334, 565 June... 82, 471, 120 94, 560, 140 180, 582, 243 Subtotal__._. 472, 819, 760 451, 246, 318 966, 713, 530 July. 62, 143, 140 70, 332, 500 127, 713, 320 August... 22-2 68, 220, 365 127, 709, 310 670, 936, 869 September_.____._____ 79, 101, 045 95, 027, 340 422, 534, 705 October___..-_- 90, 752, 880 109, 567, 900 708, 116, 830 November___.____-______ 64, 290, 600 106, 666, 107 551, 326, 888 December__.____._._ 8, 63, 806, 010 123, 809, 553 485, 587, 014 Subtotal... oo. 428, 314, 040 633, 112, 710 2, 966, 215, 626 Yearly total... 901, 133, 800 1, 084, 359, 028 3, 932, 929, 156 Large cigars 573, 039, 120 586, 810, 844 665, 998, 099 655, 850, 213 670, 064, 933 692, 436, 529 534, 565, 488 562, 414, 577 654, 827, 796 554, 242, 048 719, 489, 529 578, 501, 068 January... 581, 742, OOL February...--.. 595, 249, 522 March____.._---_ 629, 977, 375 April.” 652, 800, 200 May____.--2- 748, 040, 796 June_.----e ee, 644, 539, 031 Subtotal. | 3, 852, 348, 925 July. 647, 397, 547 August.____ ween elle 673, 082, 971 September... | a 721, 561, 449 October._2- 797, 601, 253 November_...0 696, 526, 464 December_.__..--. 596, 244, 159 Subtotal... | 4, 132, 413, 843 Yearly total. __ 8, 084, 762, 763 Boures: 0.8. Department of the Treasury (101). 3, 844, 199, 738 619, 838, 386 662, 970, 148 680, 476, 418 679, 420, 968 742, 948, 802 516, 879, 415 3, 902, 534, 137 7, 746, 733, 875 3, 604, 040, 506 520, 873, 339 682, 331, 630 594, 843, 957 693, 150, 668- 650, 746, 540 437, 429, 996 3, 579, 356, 130 7, 183, 396, 636 597 TaBLe 38.—Selected compounds in mainstream smoke Smske compound Cigarette A Cigarette 3B Little Littles Small (nonaiter) (filter) cigar A clear B ciaar C “Tar, milligram per cigarette___ 36. t 20, 3 17.4 31.8 40.6 Nicotine, milligram per cigarette - 2.7 14 -6 1.8 3.1 Carbon monoxide, volume per- cent.._-_.._.--------------- 4.6 4.5 5. 3 Mi 7.7 Carbon dioxide, volume percent__ 9.4 9.6 8.3 13. 2 12.7 Reducing sugars, percent of tobacco weight__._-_.-_----- 9.3 7.9 L5 2.9 2.7 Hydrogen cyanide, microgram per Cigarette__.__----.-.-.-- 536.0 361.0 381.0 697.0 1,029.0 Acetaldehyde, microgram per Cigarette_...__.------------- 770.0 774.0 630.0 1,238.0 1,150.0 Acrolein, microgram per cigar- ette._. eee eee 105. 0 71.0 41.0 54.0 66. 0 Total pyridines, micrograms per Cigarette... _..- 2-2-2 ------ 82.8 27.3 58. 0 85. 3 80. 3 Phenol, microgram per cigsrette_. 124.2 33. 0 35.1 63.4 94.1 Benz(s)anthracene, nanogram per cigarette__ 22-2 2 -- 74.0 31.0 34.0 25.0 39. 0 Benzo(s)pyrene, nanogram per cigsrette_.--- ee 47.0 20.0 18. 0 22.0 30. 0 Source: Hoffmann, D., Wynder, E. L. (44). TasLe 39.—The pH of the mainstream smoke of selected tobacco products {Numbers fu parentheses Indicate number of last puff.] Average pH CizarettoA Cigarette B Little Little Small Cigar D (nonfilter) (filter) cigar A clgar B cigac C 3d puff_____ 6.19 6.15 6. 44 6. 55 6. 53 6. 47 5th puff__.. 6.14 6. 12 6. 34 6. 46 6.49 _LiL--.- 7th puff... 6.09 6. 01 7.03 6. 51 6.56 _L_Lee- 9th puff___._ 6.02 5.83 __.-.--- 6. 98 6. 59 6. 27 13th puff... 2-2-e eee eee ee eee eee eee eee we ++ --- 6. 39 18th puff ee eee eee eee eee eee 6. 41 23d puff... -----e-- eee eee eee eee eee eee eee 6. 81 28th puff..§ 8 eee eee eee nee 7. 22 33d puff..-2 Lee eee eee eee eee eee eee 7. 53 38th puff..8 22 eee eee eee eee eee 7. 78 Last puff_.. 5.96(11) 5.76(10) 7.73 (8) 7.25(10) 7.11(41) 7. 96(43) Source: Hoffmann, D., Wynder, FB. L. (44). 598 Conclusions Pipe and cigar smokers in the United States as a group experience overall mortality rates that are slightly higher than those of nonsmok- ers, but these rates are substantially lower than those of cigarette smokers. This appears to be due to the fact that the total exposure to smoke that a pipe or cigar smoker receives from these products is relatively low. The typical cigar smoker smokes fewer than five cigars a day and the typical pipe smoker smokes less than 20 pipefuls a day. Most pipe and cigar smokers report that they do not inhale the smoke. Those who do inhale, inhale infrequently and only slightly. As a result, the harmful effects of cigar and pipe smoking appear to be largely limited to increased death rates from cancer at those sites which are exposed to the smoke of these products. Mortality rates from cancer of the oral cavity, intrinsic and extrinsic larynx, pharynx, and esophagus are approximately equal in users of cigars, pipes, and ciga- rettes. Inhalation is evidently not necessary to expose these sites to tobacco smoke. Although these are serious forms of cancer, they account for only about 5 percent of the cancer mortality among men. Coronary heart disease, lung cancer, emphysema, chronic bronchitis, cancer of the pancreas, and cancer of the urinary bladder are diseases which are clearly associated with cigarette smoking, but for cigar and pipe smokers death rates from these diseases are not greatly elevated above the rates of nonsmokers. These diseases seem to depend on mod- erate to deep inhalation to bring the smoke into direct contact with the issue at risk or to allow certain constituents, such as carbon mon- oxide, to be systematically absorbed through the lungs or to affect the temporal patterns of absorption of other constituents such as nicotine that can be absorbed either through the oral mucosa or through the lungs. Evidence from countries where smokers tend to consume more cigars and inhale them to a greater degree than in the United States indicates that rates of lung cancer become elevated to levels approach- ing those of cigarette smokers. Available data on the chemical constituents of cigar, pipe, and cigaretta smoke suggest that there are marked similarities in the cam-= position of these products. Pipe and cigar smoke, however, tends to be more alkaline than cigarette smoke, and fermented tobaccos com- monly used in pipes and cigars contain less reducing sugars than the rapidly dried varieties commonly used in cigarettes. Experimental evidence suggests that little difference exists between the tumorigenic activities of tars obtained from cigar or cigarette 599 tobaccos. Malignant skin tumors appear somewhat more rapidly and in larger numbers in animals whose skin has been painted with cigar tars than in those animals painted with cigarette tars. 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Summary. __ 222 609 Introduction Although it has long been held by athletes and coaches that cigarette smoking is associated with “shortness of wind” and impaired perform- ance, until recently there has been little scientific evidence to support this view. In the past few years, a variety of studies have appeared dealing with the effect of cigarette smoking on the response of man to exercise. The following is a review of these studies. Age, sex, training, health, weight, and other factors are known to influence exercise performance. Because most of the investigations were carried out in healthy, young male volunteers, the groups were quite comparable with regard to age, sex, and health; however, weight, training, and other factors were often inadequately controlled. Furthermore, problems in study design and statistical analysis mit the value of several of these studies. ~ Many forms of exercise were performed in these experiments, in- cluding: pedaling a bicycle ergometer, running on a treadmill, running on a track, swimming, step climbing, gripping a hand dynamometer, and doing several different exercise activities as part of a battery of tests. Small to maximum amounts of work were carried out in the various studies revewed. Studies of Smokers Most of the studies of habitual cigarette smokers followed a similar format with respect to smoking: (2) The subjects refrained from smoking for a few hours prior to testing, and (5) two test runs were. performed, one without smoking and one in which smoking imme- diately preceded the exercise or was incorporated with the exercise protocol. Several investigators (7, 15, 28) studied the effect of smoking on maximum grip strength. Willgoose (28) reported a greater mean per- cent recovery of grip strength after the nonsmoking trial than after the smoking trial. Kay and Karpovich (/5) and Anderson and Brown (7) all followed a protocol similar to that of Wullgoose except that they randomized the smoking and nonsmoking trials, and substituted 611 a “placebo” cigarette for the nonsmoking trial. In neither of these studies were statistically significant differences observed between the grip scores for the smoking and nonsmoking trials. Reeves and Morehouse (24) administered a battery of tests to 15 colleges students. The tests were: A tapping test, a strength test. 2 jumping test, and the short form of the Harvard step test. No statis- tically significant differences in performance were noted under con- ditions of smoking or nonsmoking. A total of 32 college students from intermediate swimming classes abstained from smoking for 15 minutes, 2 hours, and 12 hours in astudy conducted by Pleasants, et al. (23). Following the abstinence, they swam distances of 100 and 200 yards. Although actual swimming times were not published, the authors reported no statistically significant differences between the mean swimming times after the different periods of abstinence for either distance. In 1946, Juurup and Muido (13) carried out several experiments in which three young cigarette smokers exercised on a Krogh’s bi- eycle ergometer. Smoking was found to increase the pulse rate at rest as well as during exercise. Although the effect. was less con- sistent than on the heart rate, smoking was also associated with elevated blood pressure. Smoking had no effect on oxygen consump- tion. Henry and Fitzhenry (/2), in 1949, using the bicycle ergometer, also found that smoking exerted no effect on oxygen consumption. In the same year, Karpovich and Hale (14) studied bicycle ergometer performance in eight young men. In all subjects, the average riding time was better in nonsmoking tests than in smoking tests; how- ever, the results were statistically significant for only three of the eight subjects. Kerrigan, et al. (16) more recently measured direct, arterial blood pressure, heart rate, and cardiac output in 25 habitual smokers at rest and after exercise. Smoking two cigarettes produced statistically significant (P<0.01) increases in cardiac index, heart rate, and arter- ial mean pressure compared to the immediately preceding control period. Exercise after smoking resulted in an increase in cardiac in- dex over ejther the resting period or the exercise period which fol- lowed abstinence; the resultant cardiac index appeared to be approxi- mately the sum of the exercise and smoking effects. Exercise tests preceded by smoking were also associated wtih significantly higher (P.<0.01) and more prolonged elevations of blood pressure than those not preceded by smoking. In the study by Goldbarg, et al. (/7) of nine habitual smokers performing submaximal exercise on a bicycle ergometer, cardiovas- cular responses were measured via pulmonary and subclavian artery catheters. At rest, after smoking, the mean cardiac index and mean heart rate increased. During successively increasing levels of exercise, the heart rate was greater and stroke index lower than values for 612 comparable work before smoking. The net etfect of smoking was to decrease the effiicency of the heart during exercise in the upright position by causing a smaller stroke volume and a higher heart rate. Rode and Shephard (26) investigated near maximal treadmill exer- cise performance in six habitual smokers. A l-day abstinence from cigarette smoking was associated with a 13- to 79-percent decrease in the oxygen cost of breathing. Abstinence was also followed by a slow- ing of the heart rate and a decrease in expiratory minute volume after exercise. The study of Krumholz, et al. (78) is different from those cited pre- viously in that bicycle ergometer exercise performance was measured in habitual smokers both before and after 3 to 6 weeks of abstinence. Among the 10 subjects who abstained from smoking for 3 weeks, there was a statistically significant (P<0.05) decrease in heart rate, oxygen debt, and ratio of oxygen debt to total increase in oxygen uptake pro- duced by the 5 minutes of exercise. Using a “double 9-inch progressive step test” Rode and Shephard (25) studied several hundred participants of a smoking withdrawal clinic at the time of entry and at a 1-year followup. Among those who returned for the followup and who gave up smoking, absolute aerobic power increased insignificantly ; however, the relative aerobic power diminished in both sexes among those who quit smoking because of the weight gain experienced. Studies Comparing Smokers to Nousmokers Athletic Performance In 1968 Cooper, et al. (6) evaluated 419 airmen during their initial 6 weeks on active duty in the USAF. A 12-minute maximum running test was performed at least 1 hour after cigarette smoking. The mean distance covered in 12 minutes by the nonsmokers was significantly greater (P<0.05) than that covered by the smokers at the beginning, the middle, and the end of training. All categories of smokers and non- smokers improved their performance at the end of training; however, the maximum change in performance of those smoking 10 to 30 cig- arettes per day was significantly (P<0.001) less than that of non- smokers. : David (7) administered a battery of tests to 88 military personnel, aged 19 to 39 years. A 1-mile run was included in the testing, and cig- arette smoking was associated with a significant decrease in perform- ‘ince in this event. 613 Some 45 special forces soldiers were investigated at sea level and 13,000 feet above sea level by Fine (8). The subjects were randomly assigned to a placebo group or an acetazolamide treated group. Cig- arette smoking was positively correlated to decrements in 600-yard running performance from sea level to altitude in both groups. Pleasants (22) studied 106 students from intermediate university swimming classes. Swimming times were measured for 100- and 200- yard distances before and after training and for 800-yard distances after training. The mean swimming times of nonsmokers were less than those of smokers in six of seven listed categories, but these dif- ferences were not statistically significant. Bicycle Ergometer Performance Chevalier, et al. (5) investigated cardiovascular parameters in 32 young physicians after a standard 5-minute ergometer test. Oxygen debt accumulation among smokers was significantly (P<0.01) greater than among nonsmokers. The heart rate at rest and 3 minutes after exercise was significantly (P<0.02) faster in smokers than in non- smokers. Using a 5-minute ergometer test, 18 housestaff physicians, half of whom smoked, were investigated by Krumholz, et al. (27). They noted the following: Oxygen debt accumulation after exercise was signifi- cantly (P<0.02) greater in smokers than non-smokers, the ratio of the oxygen debt to total increased oxygen uptake during exercise was sig- nificantly (P<0.001) greater in smokers than in nonsmokers, and the diffusing capacity at rest and with exercise was significantly (P<0.05) decreased in smokers compared to nonsmokers. Kerrigan, et al. (16) studied cardiovascular parameters in smokers and nonsmokers at rest, during, and after a 5-minute bicycle ergometer ride. Cardiac index and blood pressure values obtained during exercise performed immediately after smoking were greater than those found in nonsmokers performing the same exercise. Similarly, heart rate and blood pressure remained elevated for longer periods in those who exercised immediately after smoking than in nonsmokers performing the same task. Aerobic capacity scores were examined in 60 university student, vol- unteers by Peterson and Kelley (29). Subjects worked at submaximal levels on a bicycle ergometer before, during, and after a training program. At all of these intervals, nonsmokers had significantly (P<0.05) higher mean aerobic capacity scores than smokers. Both groups increased their aerobic capacity during training but non- smokers consistently performed better throughout training. 614 Treadmill Performance In 1960 Blackburn, ct al. (4) carried out several measurements of cardiovascular function after different amounts of treadmill exercise were performed by 233 professional men, 159 university students, and 414 railroad workers. The differences between the smokers and non- smokers were of small magnitude. Basal oxygen consumption was slightly higher in smokers than in nonsmokers. Also. resting pulse rates were higher in smokers of most groups. Cooper, et al. (6) studied 47 out of 419 airmen with treadmill test- ing. Cardiopulmonary indices measured on the treadmill, including maximum indices, were comparable in smokers and nonsmokers ex- cept for a significant (P<0.01) reduction in the maximum minute volume among the smokers. A total of 277 prospective Canadian firemen performed the Balke- Ware test of work capacity in treadmill studies carried out by Glass- ford and Howell (40). The mean performance scores of nonsmokers were significantly (P<0.01) greater than those of smokers. The effect of vitamin C supplementation on treadmill exercise per- formance was investigated in 40 male volunteers by Bailey, et al. (2). Significant differences in oxygen utilization and ventilatory function between smokers and nonsmokers were noted in only two of the 24 separate analyses of variance performed. Maximal oxygen intake during treadmill exercise was examined by McDonough, et al. (29) in 86 healthy, middle-aged male volunteers. Cigarette smoking was one of six variables which together provided a multiple correlation coefficient of 0.73. Performance in Other Tests of Fitness When physical fitness tests were administered to 88 military per- sonnel by David (7), cigarette smoking was found to be associated with a significant (P?<0,001) decrease in performance in the dodge and jump test, and a significant (P.<0.02) decrease in performance in the crawling test. Using a step test, a breath holding test. and an ergometer test, Franks (9) examined 58 middle-aged men. Nonsmokers were able to hold their breath longer and had greater vital capacity residual after the step test than the smokers. In 1971, Wysokinski (29) studied 200 young Polish soldiers using Letunov’s test which included 20 knee-bending exercises, a fast run for 20 seconds. and a run for 3 minutes. Cigarette smoking was associated with a signifteant (P<0.01) reduction in the vital capacity and a 615 marked rise in the pulse rate at rest and after exercise. Intense exer- cise also caused a greater rise in the systolic blood pressure in smokers than in nonsmokers. Discussion Most of the studies in habitual cigarette smokers compared exercise performance in “smoking” and “nonsmoking” runs after only a few hours of abstinence. In some studies, smoking adversely affected per- formance (11, 13, 14, 16, 18, 26, 28), while in others it did not (J, 12, 16, 28, 24). Some of these apparently discrepant results are due to dif- ferences in methodology and in amounts and types of work performed. In all of the more recent studies of habitual smokers in which moderate to near maximal amounts of work were performed and sophisticated measurements of oxygen transport and cardiopulmonary function were made, impairment of function during smoking trials was found (11, 16, 18, 26). The data of Krumholz, et al. (78) also raise the question of whether residual effects of cigarette smoking influence “nonsmoking” trials per- formed after a few hours of abstinence; they found statistically sig- nificant decreases in heart rate and oxygen debt produced by exercise after 3 weeks of cessation. The work of Rode and Shephard (25) suggests that physical fitness improves with cessation, but this improvement may be negated if the subject gains a substantial amount of weight after giving up smoking. Several investigators compared exercise performance or postexer- cise cardiopulmonary function of smokers to nonsmokers. Although only minor differences between smokers and nonsmokers were found in a few of these studies (3, 4, 22), in most of them (5, 6, 7, 8, 10, 16, 17, 20,29) the performance or function of the nonsmokers was better than that of the smokers. Both nonsmokers and smokers improved their performance with training, but nonsmokers maintained their ad- vantage throughout training (6, 20). Biomechanisms The cited studies indicate that cigarette smoking exerts its adverse effect on exercise performance through several mechanisms. Cigarette smoking appears to impair cardiac performance during exercise by increasing the heart rate and exerting a variable effect on cardiac 616 output (4, 11, 13, 76, 18, 26, 29). Cigarette smoking is associated with an increased oxygen debt after exercise (5, 18). Also, one study indi- cated that the oxygen cost of hyperventilation was greater among smokers than among nonsmokers (26). Some of these adverse effects of smoking on oxidative metabolism are mediated by the elevated carboxyhemoglobin levels found in smokers. CO exerts these effects through one or more of the following mechanisms: (a) Reduction of the amount of hemoglobin available for oxygen transport, (8) shift of the oxygen-hemoglobin dissociation curve to the left with consequent interference in oxygen release at the tissue level, (c) induction of arterial hypoxemia, and {@) possible interference with the homeostatic mechanism by which 2,3,DPG controls the affinity of hemoglobin for oxygen (27). Because carboxy- hemoglobin has a half life in the body of at least 3 to 4 hours, its influ- ence may still be measurable several hours after abstinence from smoking (27). A recent investigation of maximal muscular exercise during CO in- tosication in five male volunteers demonstrated reduced maximal O, consumption in spite of a much higher heart rate and a relative hyper- ventilation (27). Astrand and Redahl (2) commented recently on the adverse effect of cigarette smoking on oxygen transport: “All other factors being equal, a reduction in the oxygen-transporting capacity is associated with a corresponding reduction in physical performance capacity dur- ing heavy or maximal work * * *, Because a regular physical train- ing program only increases the maximal oxygen uptake by some 10 to 20 percent, a 5- to 10-percent reduction in maximal aerobic power due to smoking may play a significant role in many types of athletic events and in very heavy work.” Other studies cited in this review document the adverse effect of smoking on pulmonary diffusing capacity (78) and on pulmonary function with exercise (6, 29). Summary Clinical studies in healthy, young men have shown that cigarette smoking impairs exercise performance, especially for many types of athletic events and activities involving maximal work capacity. Some of these effects are mediated by reduced oxygen transport and reduced cardiac and pulmonary function. 617 Exercise Performance References (1) Anpensoy, J. M., Brown, C. W. A. study of the effects of smoking upon grip strength and recuperation from local muscular fatigue. Research Quar- terly 22(1) : 102-108, March 1951. (2) Asrganp, P.-O., Ropagar, K. Factors affecting performance. In: Textbook of Work Physiology. New York, McGraw-Hill Book Co., 1970, 689 pp. ($) Bamey, D. A., Carron, A. V., Treece, R. G. Weanez H. J. Vitamin C supplementation related to physiological response to exercise in smoking and nonsmoking subjects. American Journal of Clinical Nutrition 23(7): 905-912, July 1970. (4) Bracxsurn, H., Brozex, J., Taytor, WH. L. Common circulatory measure- ments in smokers and nonsmokers. Circulation 22: 1112-1124, December 1960. . (5) Crevarier, R. B., Bowes, J. A., Bonpurant, S., Ross, J. C. Cireulatory and ventilatory effects of exercise in smokers and nonsmokers. Journal of Applied Physiology 18(2) : 357-360, March 1963. (6) Coorrs, K. H., Gry, G. O., Borrenserc, R. A. Effects of cigarette smoking on endurance performance. Journal of the American Medical Association 203 (3) : 189-192, Jan. 15, 1963. (7) Davin, K. H. Age, cigarette smoking, and tests of physical fitness. Journal of Applied Psychology 52(4): 296-298, August 1968 (8) Fine, B. J. Personality traits as related to symptomatology and running performance at altitude under normal and drug (acetazoleamide) condi- tions. Perceptual and Motor Skills 27: 975-990, 1968. : (9) Frangs, B. D. Smoking and selected cardiovascular-respiratory measures. Research Quarterly 41 (2) : 140-144, May 1970. (10) GLassrorp, R. G., Hower, M. L. Smoking and physical fitness: A prelim- inary report. Canadian Family Physician 15(10): 60-62, October 1969. (11) Gotpparc, A. N., Krone, R. J., RESNEKov, L. Effects of cigarette smoking on hemodynamics at rest and during exercise. I. Normal subjects. Chest 60(6) : 531-536, December 1971. (72) Henry, F. M., FrrzHenry, J. R. Oxygen metabolism of moderate exercise, with some observations on the effects of tobacco smoking. Journal of Applied Physiology 2: 464-468, Febrna ry 1950. (13) Juurup, A, Mutpo, L. On acute effects of cigarette smoking on oxygen consumption, pulse rate, breathing rate and blood pressure in working organisms. Acta Physiologica Scandinavica 11: 48-60, 1946. (74) Karpovicnr, P. V., Hate, C. J. Tobaceo smoking and physical performance. Journal of Applied Physiology 3: 616-621, April 1951. (is) Kay, H. W., Karpovicn, P. V. Effect of smoking upon recuperation fronj lo: cal muscular fatigue. Research Quarterly 20: 250-256, 1949. (76) Kerrican, R., Jain, A. C., Dore, J. T. The circulatory response to ciga- rette smoking at rest and after exercise. American Journal of the Medi- cal Sciences 255: 113-119, February 1968. (17) Kxumuotrz, R. A., CHEVALIER, R. B., Ross, J. C. Cardiopulmonary function in young smokers. A comparison of pulmonary function measurements and some cardiopulmonary responses to exércise between a group of young smokers and a comparable group of nonsmokers. Annals of Internal Medi- cine 60(4) : 603-610, April 1964. (18) KeumHotz, R. A., CHEVALIER, R. B., Ross, J. C. Changes in cardfopul- monary functions related to abstinence from smoking. Studies in young cigarette smokers at rest and exercise at 3 and 6 weeks of abstinence, Annals of Internat Medicine 62(2) : 197-207, February 1965. 618 (19) McDoxotag, J. R., Kususs, F., Bruce, R. A. Variations in maximal oxygen intake with physical activity {02 middleaged men. Circulation 41(5) : 743-751, May 1970. (20) Pererson, F. J., Ketrey, D. L. The effect of clgarette smoking upon the acquisition of physical fitness during training as measured by aerobdic capacity. Journal of the American College Health Association 17(3): 250-234, February 1969. (21) Prmxar, F.. Dusarprn, J., Denoanne, R., Petit, J. M. Muscular exercise during intoxication by carbon monoxide. Journal of Applied Physiology 31(4) : 573-575, October 1971. (22) Preasants, F., Jr. Pretraining and post-training swimming endurance of smokers and nonsmokers. Research Quarterly 40(4) : 779-782, 1969. (23) Preasants, F., Jr., Gauoan, J., Raturr, J. W., Ir. Effects of short periods of abstinence from cigarette smoking on swimming endurance of chronic smokers. Research Quarterly 38(3) : 474-479, 1966. (24) Reeves, W. E., MoreHoussr, L. E. The acute effect of smoking upon the physi- eal performance of habitual smokers. Research Quarterly 21: 245-248 1950. (25) Rope, A, SHEpHagpD, R. J. Smoking withdrawal and changes of cardiores- piratory fitness, American Review of Respiratory Disease 104(6) : 933- 935, December 1971. (26) Ropz, A., Soernarp, R. J. The influence of cigarette smoking upon the oxy- gen cost of breathing in near-maximal exercise. Medicine and Science in Sports 3(2) : 51-55, summer 1971. (27) U.S. Posric Bearrna Service. The Health Consequences of Smoking. A Re- port of the Surgeon General: 1972. U.S. Department of Health, Education, and Welfare. Washington, DHEW Publication No. (HSM) 72-7516, 1972, 158 pp. (28) Wrixcoose, C. E. Tobacco smoking, strength, and muscular endurance. Re- search Quarterly 18: 219-225, 1947. (29) Wrsoxrsxi, Z. Effects of tobacco smoking on certain parameters reflecting the condition of the circulatory system at rest and during exercise. Polish Medical Science and History 14(2) : 73-76, April 1971. 619 Chapter 12 Harmful Constituents of Cigarette Smoke Sourca: 1972 Report, Chapter 9, pages 137 - 150. 621 Contents Page The Dose Relationship ...20..002 625 References .. 2.0.0... eee eee, 630 LIST OF TABLES Table 1—Compounds in cigarette smoke judged most likely to contribute to the health hazards of smoking .......... 627 Table 2.—Compounds in cigarette smoke judged as probable contributors to the health hazards of smoking ........., 628 Table 3.—Compounds in cigarette smoke judged as suspected contributors to the health hazards of smoking .......... 629 623 HARMFUL CONSTITUENTS OF CIGARETTE SMOKE* Cigarette smoke contains a large number and a wide variety of compounds which may result in complex and multiple pathophysio- logical effects on various tissues and organ systems. Although the constituents of cigarette smoke are usually divided for convenience into the two categories of particulate and gas phases,** many of them exist in a distribution equilibrium, that is, they are present partially in the gas phase and partially in the particulate phase. This review concerns itself with judgments concerning the harmful constituents of cigarette smoke whether these are found primarily in the gas phase or in the particulate phase. Constituents of cigarette smoke may enter the body by a variety of routes. Theoretically, the route of entry and subsequent absorp- tion could affect the degree to which various organs are subjected to specific cigarette smoke constituents. Some constituents, par- ticularly the water soluble components of the gas phase, may be absorbed by the nasal and oropharyngeal mucous membranes, or may be dissolved in the saliva and swallowed, thus allowing for pos- sible gastric or intestinal absorption. Other constituents are ab- sorbed along the tracheobronchial tree, and the distance which they reach before being absorbed or deposited depends on such factors as the depth of inhalation and the particle size. The absorption of gases in the tracheobronchial tree appears to be in part dependent on the adsorption of gases to particulate matter. Another factor affecting the route and degree of absorption is the adequacy of pulmonary clearance by which constituents deposited or dissolved in the mucous sheath are delivered to the pharynx and then usually swallowed. Of the hundreds of compounds identified in cigarette smoke, some occur in the smoke in concentrations which may be considered suf- ficient to present hazards to health. Other compounds appear in * This report attempts to summarize the areas of general consensus reached in a special one- day conference of experts in this field which met in June 1970. This is not to imply that there was unanimous agrcement on all statements contained herein. A Hat of participants in the meet- ing appears in the Acknowledgments. ** It should be noted that there is, at present, no available instrumentation permitting the separation and individual collection of the particulate and gas phases which duplicates the precise physicochemical conditions prevailing in cigarette amoke as it is inhaled. A widely ac- cepted arbitrary distinction between the two phases is as follows: If &0 percent or more of s given conatituent is retained on « Cambridge filter (CM-113) during atandardized machine smok- ing of a cigarette, then the compound is considered to belong to the particulate phase: if on the other hand more than 50 percent of the compound passes through tbe Cambridge fiter under these conditions, then the constituent is considered to belong to the gas phase. 625 borderline concentrations. Still others, although potentially harm- ful, are probably not present in sufficient concentrations to con- tribute to the hazard, and some may be hazardous only when they interact with other substances in the smoke. Substances and classes of substances in cigarette smoke which have been judged to contribute to the hazard of cigarette smoking have been classified into three priority groups. Those compounds which are judged most likely to contribute to the health hazards of smoking are listed in table 1. Additional substances which probably contribute to the health hazards of smoking are listed in table 2. Those compounds which are suspected contributors to the health hazards of smoking in the concentrations in which they are present in tobacco smoke are listed in table 3. Many other constituents of tobacco smoke are considered to be toxic under some conditions but probably do not present a health hazard in the concentrations in which they are generally found in cigarette smoke; these are not listed. This listing is not presented as final, and may be subject to modification as more information becomes available.* In 1966, the Public Health Service prepared a technical report on “tar” and nicotine (60). Tobacco “tar” is the name given to the ag- gregate of particulate matter in cigarette smoke after subtracting nicotine and moisture. In that report it was stated: “It ig clear that the overall risk associated with cigarette smoking increases as the average number of cigarettes con- sumed per day increases. In the studies which have reported other measures of exposure such as pack-years, degree of in- halation, and maximum level of cigarette consumption, the same type of relationship holds.” Individuals may differ in their inherent susceptibility to diseases in which cigarette smoking plays a role and differ in their exposure to other factors which may increase the likelihood of these diseases. Within these groups of varying risk, the degree of exposure to ciga- rette smoke appears to be the most critical factor for the develop- ment of smoking related disease. Therefore, the general statement that the lower the dosage the lower the risk is the most useful guide available. It was also stated that: “It is possible for a cigarette to be altered in such a way that its ‘tar’ and nicotine content is reduced but certain other harmful effects, for example the effect of the gaseous phase, may be increased. Although this is a theoretical possibility, © Subsequent to the conference on which this report was based, several studies were published reporting the presence of N-nitrosamines in cigarette smoke. Since these substances are-accepted as carcinogens in experimental animals, they represent another portion of the “tar” which probably contributes to the total bealth hazard (18, 24). 626 there is no evidence that this has occurred to any serious degree.” The consensus is that there is inadequate evidence to support a change in that view at the present time. In addition, it was concluded that “the preponderance of scientific evidence strongly suggests that the lower the ‘tar’ and nicotine con- tent of cigarette smoke, the less harmful would be the effect.” Sev- eral studies reported since that time have added strong support to this position. The present review is an attempt to identify those constituents of the ‘‘tar” as well as those constituents considered part of the gas phase which are most likely to contribute to the health hazards from cigarette smoking. TABLE 1.—Compounds in cigarette smoke judged most likely to con- tribute to the health hazards of smoking. Primary phase Concentration in classification cigarette smoke G—ges Cam pound microgramsa/cigsrette P—particulate References Carbon Monoxide 6,240-21,<00 G (i, 10, 23, 26, 29, 34, 35, 37, 42, 46, 49, 61, 63) Nicotine 200-2,400 P (9) tTar” - 3,000-33,000 P (9) 1*“Tar” ta defined as the total particulate matter collected by a Cambridge filter (CM-113) after subtracting moisture apd nicotine and includes the class of compounds known as polycyclic aromatic hydrocarbons (PAH). PAH are generally accepted as being responsible for a sub- stantial portion of the carcinogenic activity of the total “tar.” Although ‘‘tar’ from different elgarettes varies in its carcinogenic potential as measured by the bioassay methods in current use, it remains the most practical single “indicator” of total carcinogenic potential. Special mention should be made of Beta Naphthyleamine which is a known human urinary bladder car- cloogen for which there is no known safe level of exposure and which has been reported present {n tobacco smoke in very Jow concentrations (16, 28, 30) (0.022 xem./cigarette). It is recognized that the substances in cigarette smoke may inter- act so that the combined pathological effects of several substances . may be quite different from the sum of their effects produced in isolation. An example of this type of interaction might be the car- cinogenic effects of tobacco “tar’”’ as a result of the combined action of cancer initiating, cancer promoting, and cancer accelerating agents in producing the total effect. Such interactions theoretically could take place among substances within the gas phase, or sub- stances within the particulate phase, or between constituents of the gas phase and constituents of the particulate phase. In the absence of data which identify the interactions of cigarette smoke compo- nents, judgments concerning the action or identification of harmful substances in Cigarette smoke have, of necessity, been made pri- 627 TABLE 2.—Compounds in cigarette smoke judged as probable con- tributors to the health hazards of smoking. Primary phase Concentration in classification cigarette smoke G—gas Compound micrograms/cigarette P—particulate References Acrolein 45-140 G (12, 20, 21, 27, 36, 43, 45) Cresol (all isomers) 68-97 P (20, 40) Hydrocyanic Acid 100-400 G (26, 38, 43, 45, 46, 49,53) Nitric Oxide 0-600 G (1, 3, 15, 40, 42, 44, 57) Nitrogen Dioxide 0-10 G (1, 40, 44, 57) Phenol 9-202 P (7, 19, 20, 32, 50, 52) marily on the basis of the action of the individual substances. Never- theless, experimental evaluation of modified cigarette smoke should be designed to take into account the possibility of such interaction. Until there is a better understanding of the relative importance of the interaction of the constituents of cigarette smoke in the de- velopment of the diseases associated with cigarette smoking, it will be difficult to assess the significance of the reduction or elimination of one or several of the constituents named in this report. However, it is reasonable to take the position that unless there is positive in- formation to the contrary, cigarettes in which overall “tar” and nicotine levels have been reduced present to the smoker lower con- centrations of the harmful substances in the particulate phase. Hf, at the same time, significant reductions are made in those gas phase constituents which also contribute to the hazards of smoking, the resulting product should be less hazardous to health.* The consensus is that a progressive and simultaneous reduction of all substances considered likely to be involved in the health haz- ards of smoking should be encouraged as the most promising step available at the present time towards the development of a less haz- ardous cigarette. Primary emphasis should be given to the reduc- tion of the three substances or classes of substances named in the first table, and as a second priority to the reduction of those sub- stances or classes of substances in the second table before reducing © An alternative point af view held by some ia that smoking behavior is a reaponse to the need to reach a certain nicotine fevel and that lowering the amount of nicotine available from a cigarette may result in an increase in the nomber of cigarettes smoked, the depth of inhalation, or the number of puffs in order to maintaln an accustomed level. Such an increase in smoking might result in an increased inhalation of other hazardous substances in the smoke, thereby potentially nezating the effect of reducing the amount available in each cigarette. 628 TABLE 3.—Compounds in cigarette smoke judged as suspected con- tributors to the health hazards of smoking. Primary phase Concentration in classification cigarette smoke G—gas Compound micrograms/cigerette P—particulate References Acetaldehyde 180-1,440 G (4, 21, 27, 36, 43, 45, 48, 49, 53, 59) Acetone 88-650 G (12, 21, 27, 36, 43, 45, 48, 49, 53) Acetonitrile 140-200 G (12, 43) Acrylonitrile 10-15 G (12, 43) Ammonia 60-330 G (2, 22, 40, 41, 43, 64) Benzene 12-100 G (il, 12, 25, 43, 45, 49, 53) 2,3-Butadione 43-200 G (43, 46, 49, 53) Butylamine 3 P (31, 40, 41) ? Carbon Dioxide 23,100-78,300 G (1, 10, 15, 23, 26, 29,34, 35, 42, 46, 49, 63) Crotononitrile 4 G (43) Dimethylamine 10-11 P (31, 40, 41) DDT 0-0.77 P (17, 39, 54) Endrin 0.06 P (14) Ethylamine 10-11 G (22, 31, 40, 41) Formaldehyde 20-41 G (4, 36, 43, 48, 53) Furfural 45-110 P (4, 13, 36) Hydrogen Sulphide 12-35 G (10, 43, 51, 58) Hydroquinone - 83 P (6, 7) Methacrolein 9-11 G (12, 43) Methy! Alcohol 90-300 G (12, 21, 43, 46, 49) - Methylamine 20-22 G (22, 31, 40, 41) Nickel compounds 0-—0.58 P (5, 8, 47, 55, 56) Pyridine 25-218 P (40, 62) ‘CO, is included because of the hazard it may represent to those with CO, retention, such as those with advanced COPD. those named in the third table. In addition to the epidemiological and pathological data gained from human studies, it is important to develop better bioassay systems to evaluate cigarettes modified by these general guidelines. 629 It should again be emphasized that, in addition to the variation in chemical properties of the cigarette being smoked, procedures within the control of the individual smoker such as how many ciga- rettes he smokes, how far down he smokes the cigarette, and how frequently and deeply he inhales are critical factors in determining how much of the harmful substances which can be produced by the burning cigarette is given the opportunity to injure him. 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Abstracts of 21st Tobacco Chemists’ Research Con- ference, Durham, N.C., October 19-20, 1967. p. 14. 634 INDEX Abortion effect of maternal smoking, 437, 438 Acenaphthylene in cigar, pipe, and cigarette smoke, 548 Acttaldehyde levels, effects of room size, amount of tabsacco burned, and = ventilauon, 487-490, 494 as suspected contributor to health haz- ards of smoking, 629 Acetone as suspected contributor to heaith hazards of smoking, 629 Acetonitrile as suspected contributor to health hazards of smoking, 629 Acrolein effects of inhalation of, in rats, 151 as irritant in tobacco smoke, 511 levels, effects of room size, amount of tobacco burned, and venulation, 487-490, 494 as probable contributor to health haz- ards of smoking, 628 Acryloniuie as suspected contributor to health hazards of smoking, 629 Adenocarcinoma prevalence in male and female smokers and nonsmokers, 276 relationship of cigarette smoking to, 272-275, 322 Adenoma papillary, induction in rats by exposure to cigarette tars, 374 pulmonary, induction in mice by ctga- rette smoke inhalation, 375 renal, relationship of smoking to, 322 Adrenal glands catecholamine release from, nicotine effects on, 32 Advisory Committee on Smoking: and Health report on cigarette smoke and conden- sates effects on oral cavity of animals, 314 Acrobic capacity effect of cessation of smoking, 613 effecy of exercise and smoking, 613,614 “Age atypical nuclei in esophageal epithelium arranged by smoking and, 405-406 effects on CHD, 23-35 Air pollution as cause of COPD, 178, 201, 242-243 in etiology of lung neoplasms, 302 and human CO burden, 142 relationship of lung neoplasms, smoking and place of residence, 278-281 summary of recent findings, 564 Aicohol ethanol, penetrabihty of dissolved benzo(a)pyrene im mice esophageal epithehum, 319 Alcohol consumption effect. on esophaeceal neoplasms in smokers, 315, 319 effect on laryngeal neoplasms in tobacco users, 306 effect on tobacco amblyopia, 531-532 and heavy smoking, effect on oral neoplasms, 314 smoking and, in esophageal neoplasm etiology, 64,66, 67,570 smoking and, im laryngeal neoplasm etiology, 567 smoking and, in oral neoplasm etiology, 563 smoking and, in neoplasm development, 570 Alcoholism patients, smoking and venulatory func- tion in, 239 Allergy effect on cardiovascular abnormalities, 521 tobacco and, $13-521 tobacco smoke irritants and, 520 Alpha-l-antitrypsin deficiency COPD predisposition from, 176 determination using immunoelectro- phoresis, 177 in emphysema etiology, 520 smoking and, 520 Amblyopia, tobacco alcohol consumption effect on, 531-532 characterization of, 531 incidence of 531 American Heart Association pooling project on CHD, 19, 24, 26, 35 Ammonia as suspected contributor to health hazards of smoking, 629 Angina pectoris effects of increased carboxyhemogiobin levels, in passive smokers, 491, 497 incidence in pipe and cigar smokers, 485 Animals a : esophageal neoplasms in, induction by nitrosamines, 318 respiratory tract of, neoplastic changes following cigarette smoke inhalation, 264-265 skin of, carcinogenicity of tobacco tars, 264, 293 Anthracene in cigar, pipe, and cigarette smoke, 548 Anthranilic acid, 3-hydroxy- urinary excretion of, smoking effects on, 322 635 Antigen-antibody reactions abergy and, 513-517 smokers vs. nonsmokers, §15,521 tobacco and, S 14-517 Aortic aneurysm smoking and, 63, 67, TN Aromatic compounds carcinogenic = propertues in cigarette smoke from, 290, 293 detection in urine using chemilumines- cence technique, 323 Aromatic hydrocarbons, polycyclic effect during pregnancy in laboratory animals, 431,432 maternalfetal exchange and, 433 Anhythmias formation in nicotine stimulated damaged myocardium, 54 Arsenic lung neoplasm mortality in smelter workers exposed to, 283 respiratory tract carcinoma in workers exposed to, 282, 283 Arteries aneurysm in aortic, cigarette smoking effects on, 63,67, 71 atherosclerotic, increased by Cigarette smoking, 59 flow of carotid, cigarette smoking effects on, 63 occlusions of, cigarette smoking effects on, 69 watls of, mechanism of Lipoprotein infiltration, 59 walls of, nicotine-induced necrosis, 59 Artenosclerasis in aotta and coronary arteries, Cigarette smoking effects on, 4}, 48-52 development of, carbon monoxide ef- fects on, 59 development of, effects of nicotme on, 34 lesion development in, smoking enhance- ment, 32 peripheral, cigarette smoking effects on, 68-69 see also Cardiovascular diseases; Coro- nary diseases Ary} hydrocarbon hydroxylase effect of benzo(a)pyrene in pregnant rats, 433 Asa Central and Southeast, relationship of tobacco use and neoplasms of oral cavity, 392 Asthma bronchial, cigarette smoking effects on, 201 Atherosclerosis aortic, long term smoking effects, 48-52 Athletic performance running, effect of smoking, 613,614 smokers vs. nonsmokers, 613, 614 swimming, effect of smoking, 614 Atropine effects on bronchoconstriction in dogs, 189 636 Australia COPD morbidity in smokers 0, 229 laryngeal neoplasms in, relauonshp to tobacco use, 383 lung neoplasms in, retrospective studies of, 353 Bacterna effect of cigarette smoke on action of macrophages on, 191 pneumonia, mice resistance following cigarette inhalation, 199 Benz(e)acephenanthrylene carcinogenic $= properties in cigarette smoke from, 290, 291 Benz(a)anthracene alcoholic solution of, penetrability of mice esophageal epithelium, 3 18 Benz(a)anthracene, 7,1 2-dimethyl! carcinoma induction in hamsters Follow- ing instillation of, 372 skin painting with, papilloma and carcinoma induction in mice by, 367 Benzene as suspected contributor to health hazards of smoking, 629 Benzo(j)fluoranthene carcinogenic properties in cigarette smoke from, 291 Benzo(c)phenanthrene carcinogenic properties in cigarette smoke from, 291 Benzof{a)pyrene alcoholic solution of, penetration of mice esophageal epithelium, 318 carcinogenic properties in cigarette smoke from, 290, 291 carcinogenicity of, in relation to asbestos in hamsters, 283 in cigar, pipe, and cigarette smoke, 491, 492 detoxification by lung aryl] hydroxylase, 283 effects during pregnancy in laboratory animals, 431,432 effects of instillation or implantation in animal tracheobronchial tee, 372-373 effects on animal tissue and organ cultures in, 369-371 effects with influenza virus on cigarette inhalation by mice, 378 levels, effects of room size, amount of tobacco bumed, and ventilation, 487-490, 494 sarcoma induction in rats following instillation of, 372 skin painting with, papilloma induction in mice by, 363-364 Betel nut chewing oral neoplasms from, 392, 395-396 Bicarbonate in pancreatic secretions, effect of smok- ing, 473,474 Bicycle ergometer performance cardiovascular parameters in smokers vs. nonsmokers, 612414 Buth weight effect cf maternal smoking, 417-428, 433436 effect of maternal smoking before and during current pregnancy by cigarette consumpuon, 421423 effect of maternal smoking dumnng previous pregnancies, 426-428 effect of paternal smoking, 424, 425 effect of tobacco smoke, nicoune, or carbon monoxide in laboratory animals, 428432 gestation duration in smokers vs. non- smokers, 417420 mortality risk of low birth weight infants of smoking vs. nonsmoking mothers, 440-446 timing of influence of smoking, 434,435 Bladder neoplasms frequency in smokers vs. nonsmokers, 264, 319-321 mortality rates, 319, 320 relationship of cigarette smoking to, 325 retrospective studies of, and smoking, 319, 407-410 and tryptophan metabolites in unne, 322-323 Blood cholesterol fevels and coronary disease, 17-18, 19-20, 39 effect of carbon monoxide in rabbits, 150 effect of smoking, 37, 39 effect of smoking in peripheral vascular disease, 68 and hypertension, in smokers vs. non- smokers, 137 in pipe and cigar smokers, 585,586 in smokers vs. nonsmokers, 94-98 Blood circulation effect of variations in hemoglobin and hemat, 62 Blood coagulation etfect of smoking, 32 Blood lipids etfect of smoking, 61-62, L19-124 smokers vs. nonsmokers, 37 Blood platelets effect of smoking, 62,71 Blood pressure coronary disease and smoking, 39, 43 diastolic, cigarette smoking effects, 19 diastolic, in smokers with CHD, 17-18, 20, 38 effect of exercise and smoking, 612, 614-416 effect of nicotine, 32 effect of pipe and cigar smoking, 586 high risk in mortality from CVD, 63 hypertensive vs. nonhypertensive, mor- tality rates of CHD in, 38 tisk factors in artenosclerosis obliterans, 68 in smokers, nonsmokers, and ex- smokers, 137-139 in smokers vs. nonsmokers, 37, 38, 99-100 systole, mortality from elevated, with CHD, 38 Body weight and hypertension, m= snokers, non- smokers, and ex-smokers, 137-139 Bradycardia . development in dogs given nxoune, 53 Bronchial epithehum histological changes in cigar, pipe, cigarette smokers vs. nonsmokers, $73,574,579 Bronchitis development in infants of mateznal smokers, 499 incidence in children of parental smokers, 501, 502 mortality ratios in male pipe and cigar smokers, 587, 589 in passive smokers, summary of recent findings, 504 prevalence in pipe and cigar smokers, §90, S91 Bronchitis, chronic definition of, 165 mortality in cigarette smokers, 201 mortality rates, 165 smokers vs. nonsmokers, 221-231 Bronchopneumonia development in degs following cigarette smoke inhalation, 297 Bronchopulmonary diseases, chronic ob- structive air pollution relationship in, 178, 242-243 characterization of, 165 Cigarette smoking effects on develop- ment, 20] . genetic factors in pathogenesis of, 174, 176-178, 231 increased prevalence of heterozygotes in, 177-178 mortality rates, 165-171 mortality rates in pipe, cizar, and Cigarette smokers, 201 mortality ratios in male pipe and cigar smokers, 586, 587,589 2,3-Butadione as suspected contributor to health hazards of smoking, 629 Buty lamine as suspected contributor to health hazards of smoking, 629 Butylaminc, N-methylnitroso suspected carcinogenic properties in cigarette smoke from, 291 Cadmium in cigarette smoke, relation to patho- genesis of emphysema, 180 Canada COPD morbidity of smokers in, 230 infectious respiratory disease in, relation- ship to smoking, 254 kidney and bladder neoplasms in smokers in, 320 mortality sates from COPD, 165-167, wm mortality ratios from COPD, L169 637 mortality ratios in smokers and non- smokers fram pancreauc neoplasms, 324 thrombosis in, smoking relationship, 128 Canadian veterans study jung neoplasm mortality ratios 1n, smokers vs. nonsmokers, 267 Carbazole, 9anethyt possible importance In tobacco carcino- genesis, 292 Carbon-14 labeled smoke particulate deposition in hamster respuatory tract, 307-308 Carbon dioxide as suspected contnbutor to health hazards of smoking, 629 Carbon monoxide cholesterol levels in rabbits, after ex- posure to, 150 and decrease in exercise ume before claudication, 150 effect during pregnancy in laboratory anumals, 430, 431,446, 447 effect on aortas in animals, 150 effect on birth weight and neonatal mortality in anmats, 447 effect on cholesterol-fed rabbits. 6142 elfect on healthy smokers vs. non- smokers, 148 effect on human physiology, 56-58 effect on myocardium, 151 exposure to, and human absorption, 143-150 as most likely contibuter to health hazards of smoking, 627 summary of previous findings on rela- tionship to passive smoking, 483, 484,504 summary of recent findings, 155 from tobacco smoke, effects on psycho- motor performance, including atten- tiveness and cognition function, 495-497 Carbon monoxide levels in cigarette smoke, 55 effect of room size, amount of tobacco burned and ventilation, 486-591 effect on exercise performance, 493 from smokers in buses and planes, 498 - Carboxy hemoglobin formation in blood of smokers, 56, 71 Carboxy hemoglobin levels in cigarette smokers, one hour after last cigarette, 147, 148 and CO burden m= smokers vs. non- smokers, 147, 148 effect on CO absorption, in passive smokers, 591, 592 effect. on exercise performance, 493, 616,617 in fetuses, 148,149 in neonates of smoking mothers, 432, 433 in smokers vs. nonsmokers, by sex, face, employment status or urban location, 144-146 summary of recent findings, 155 in workers exposed to exhaust gases, 143 638 Carcinogenesss effect of tobacco curing methods, 582 Carcinogens action on oral cavity, effect of saliva, 314 cigar, pipe, and cigarette smoke conden- sate, in skin painting experiments in animals, 580-584 listing of, in cigarette smoke, 291-292 tobacco smoke constituents as, 580-584 Carcinoid tumor prevalence in male and female smokers and nonsmokers, 276 Carcinoma formation following animal skin painting with smoke condensates, 363-368 induction in rats exposed to cigarette tars, 374 undifferentiated, relationship to ciga- rette smoking, 274-275 Carcinoma, alveolar cell induction in mice by cigarette smoke inhalation, 375 Carcinoma, anaplastic prevalence in-male and female snokers and nonsmokers, 276 Carcinoma, bronchogenic development in dogs following cigarette smoke inhalation, 295, 298-29? mortality from, relationships to smo k- ing,-au pollution and residence, 279 mortality in smoking vs. ne- smoking asbestos workers, 283 Carcinoma, epidermoid mortality from, relationship to smoking, air poliution and residence, 280 prevalence in male and female smokers and nonsmokers, 276 relationship of cigarette“ smoking to, 272-275 Carcinoma, epithelial induction in mice by cigarette smoke inhalation, 376 Carcinoma, oat cell relationship of cigarette smoking to, 273 Carcinoma, squamous cell development in mice drinking alcoholic benzo(a)pyrene, 3 18 in oral cavity, relationship to tobacco use, 392-393 Carcinoma, tracheobronchial induction in hamsters by cigarette smoke _ instillation, 372-373 Cardiac index effect of exercise and smoking, 6124614 Cardiovascular diseases atherosclerotic, effects of CO, 149, 150 mortality ratios in male pipe and cigar smokers, 585, 586 pathogenesis of, 150.151 summary of prospective epidemiologicat studies for cigar and pipe smoker, $86 see also Arteriosclerosis Cardiovascular system effect of cigarette smoke on, 52-54, 103-114 effect of nicotine on, $2-54, 103-114 Catecholamine levels effect of cigar, pipe, and cigarette smoke in dogs, 586 Catecholamines etfect of nicotine on release of, 32,53, tis effect on blood circulation in coronary astenes, 54 Cats cardiovascular function in, smoking and nicotine effects on, 106, 107 ciliary function in, effect of cigarette smoke on, 248-250 lungs of, cigarette onoke effect on surfactant activity, 251 Cattle cilary function in, effect of cigarene smoke on, 247 Central nervous system effect of carbon monoxide in smoke on, 56 Cerebrovascular diseases definition of, 62 epidemiological studies, 149, 150 mortality rates by age, sex and smoking classification, 15} moraiity rates, smokers vs. nonsmokers, 62-466 mertality ratios in pipe and cigar smokers, $85, 586 Cessation of smoking compared benefits in cigarette vs. pipe/- cizar smokers, 542,543 effect an absolute aerobic power, 613 effect on COPD development, 166 effect on COPD development in Bntish physicians, 168 effect on COPD morbidity and mor- tahty, 201 effect on COPD morbidity in smokers vs. nonsmokers, [72 eifect on coronary disease mortality rate, 28, 42-44, 102 effect on infant birth weight, 421423, 426-428 improvements in respiratory system, $74,175 relation to incidence of CHD, 28, 4244, 102 Chest illnesses prevalence of, in pipe and cigar smokers, 590, 591 Chickens ciliary function in, effect of cigarette smoke on, 249 effect of cigarette smoke on embryos, 370 Children of smokers, incidence of pneumonia and bronchttis, SOL, $02 of smokers, prevalence of respuatory symptoms, 501,502 Chile atherosclerosis autopsy studies in, §1,52 Cholesterot rabbits fed, ~arbon monoxide effects on, 6142 synergstic relationship of carbon mon- oxde in coronary atheromatosis, 59 Chromium lung neoplasn mortality from, 283-284 respiratory Uact Carcinoma m Workers exposed to, 282 Chrysene carcinogenicity, as component of ciga- rette smoke, 29) Cigarettes definition and processing. $45 development of esophageal neoplasms, 319 similarities with little cigars, $94,595 tar and nicotine content, 626, 627 tar levels of, relationship to lung neoplasm development, 301, 302 Cigarettes, filter summary of previous findings, 4 Cigars definition and processing, 545,546 Cigars, little chemical composition of, 594, $95,598 evaluation of potential public health impact, 592-598 shipment for domestic consumption (1970-1972), 592-594, 597 similarity to cigarettes, 594, 59S sugar and pH differences with large cigars and cigarettes, 592-594 tar and nicotine content, 594-596, 598 Ciliary activity effect of pipe/cigar smoke vs. cigarette smoke in cats, 587, $88 Clofibrate and reduction in risk of sudden death in cigarette smokers, 154 Coffee drinking myocaidisl infarclion, smoking and, in smokers vs. nonsmokers, 141, 142 Combustion temperature effect on tumorigenic activity of pipe and cigarette tobacco, 580, 581 Congenital malformations maternal smoking and, 450, 451 Connecticut Cancer Registry figures on age-adjusted larynx neoplasm incidence, 303 figures on incidence of oral neoplasms, 310 Constitutional hypothesis relationship to CHD and smoking, 4445, 101-102 Cornsilk smoking, tack of arterial epinephrine level increase, $3 Coronary diseases age-adjusted rates in smokers, 19 arterjosclerotic, mortality rates in US., 17 atherosclerosis, effects of smoking on, 59 blood pressure of smokers vs. non- smokers, 39,43 carbon dioxide effects on oxygen uptake in, 58 death ratios of paired combinations of high risk, 21 effect of coffee drinking and cigarette smoking, 142 epidemiological studies, 136, 137 incidence and mortality rates in former smokers, 42, 43-44 incidence in pipe and cigar smokers, 585, 586 infarction in NYC pipe and cigar smokers, 28, 34-35 infarction, relationship to physical act- ivity, smokers vs. nonsmokers, 40 morbidity, relationship of smoking to, 28-31, 33, 35, 89-93 mortality and morbidity retrospective studies, 36, 89-93 mortality rates in hypertensives vs. nonhypertensives, 38 mortality rates in obese vs. nonobese, 41 mortality rates in smokers vs. non- smokers, 17-18, 20, 22-25 mortabty rates in, with increased carbon monoxide, 58 mortality rates of cigarette smokers from, AHA pooling project, 24, 26, 35 mortality rates of paired combinations of high risk, 21 mortality rates of U.S. veterans, 22, 34 mortality rates, relationship to electro- cardiographic findings, 38 mortality ratios in pipe and = cigar smokers, 585, 586 nicotine effect on coronary blood flow in, 54 relationship of blood pressure and smoking, 41, 43 relationship of heart rate and smoking, 41,43 relationship of physical activity and smoking, 37, 39, 40 relationship of triglycerides to, 61 relationship to constitutional makeup and smoking, 44-45, 101-102 relationship to ECG abnormalities and smoking, 41,43 relationship to obesity and smoking, 39-41 risk factors, 19-20, 36-37 smokers’ age effects on development, 23, 35 in smokers with predisposing factors, 20 sudden death, and smoking, 48 summary of previous findings, 4, 7 see also Arteriosclerosis; Myocardial in- farct Cough of parental smokers, and respiratory symptoms in children, 499, 501 prevalence in pipe and cigar snokers, 590, 591 Cresols in cigar, pipe, and cigarette smoke, 547 as probable contributors to health hazards of smoking, 628 suspected carcinogenic agent of cigarette smoke, 292 Crotononitrile as suspected contributor to health hazards of smoking, 629 Cuba laryngeal neoplasms in, relationship to tobacco use, 382 640 ora] neoplasms in, relationship of tobac- co use, 390 Cyanides detoufication, m pregnant smokers vs. nonsmokers, 433 in tobacco amblyopia etiology, 531-532 Czechoslovakia laryngeal neoplasms in, relationship to tobacco use, 380, 383 serum bpid difference in smokers vs. nonsmokers, 97 DDT as suspected contributor to heaun hazards of smoking, 629 Deaths, sudden . incidence in pipe and cigar smokers, 585 reduction of risk of, in cigarette smokers, using clofibrate, 154 Denmark atherogenic effect of carbon monoxide and hypoxia, 60 ' bladder neoplasms in, methods and results in retrospective studies of smoking and, 407, 409 carbon monoaide effects on human blood lipids in, 125 carbon monoxide effects on rabbit blood tipidsin, 125 serum Lipid differences in smokers vs. nonsmokers in, 98 twins in, angina pectoris in smokers vs. nonsmokers, 47 Dermatitis among tobacco workers, 52} Diabetes mellitus effect on CHD in smokers, 20 relationship with cigarette smoking in peripheral vascular disease, 68 tisk in mortalicy from CVD, 67 Dibenz(a h)acndine cascinogenic properties in cigarettc smoke from, 29} Dibenz(aj)acridine carcinogenic properties in cigarette smoke from, 291 Diethylnitrosamine suspected carcinogenic properties in cigarette smoke from, 291 Dimethylamine — as suspected contnbuter to health hazards of smoking, 629 Dimethyinivosamine suspected caremogenic properties in cigarette smoke from, 291 2,3-Diphosphogly cerate effects of carbon monoxide ou, $6.57 DNA increases in smokers’ oral epithelial cells, 314 levels in mouse Jung exposed to Cigarette smoke, 187 Dogs atherogenic effects of nicotine m, 116 bladder neoplasms in, fed 2-naphthy- lamine, 322 bradycardia and tachycardia in, follow- ing nicotine injection, 53-54 bronchogenic carcinoma induction in, from cigarette smoke inhalation, 295, 296 cigarette smoke institlation or implan- tation effects on tracheobronchial trce of 294,373 death in, causes trom cigarette smoke inhalation, 297 effect of cigarette smoke on pulmonary clearance in, 190, 196 fetal bronchial tubes of, effect of cigarette smoke on, 37) lung neoplasms following cigarette smoke inhalation, 265, 303 lung neoplasms in, types and lobes where found, 295, 298-299 lungs of. cigarette smoke effects on surfactant activity, 198,251 myocardium, nicotine effects on, 54 neoplasin development in sinoking, per- centages of, 300 pulmonary histological changes in ciga- rette smoke inhaling, 184. 185-186 respiratory tract’ of, cigaretic smoke inhajation effects on, 294, 378, 379 smoke-induced bronchoconstreuon in, atropine effects, 189 smoking and nicotine cffects an blood lipids in, £23-124 sinoking and nicaline ctfeets on cardio- vawular function in, 103-108 \inoking and nicotine cfferts on catecho- luring levels ing 115 Donkeys elfeect of civarette smoke on pulmonary clearance in, 190, 197 Ducks eigaretle smoke instillation of implan- tation offeeis an tracheebronchial free at, 372 Deuodenub ulcers mortality mos in male cigar and pipe smokers. 592 nicotine induced, in cats, 472,473 Potepcrutive compliciuions in sinokers vs. nonsmokers, 471 petentiating action af nicetine, in animals, 475-477 prevalence in smoker, mechanikm of action, 474 Dust exposure COPD development from, 179, 244 Dyspnea Prevalence ins cigar and pipe smokers, $90, 591 Veypi relationship of human pulmonary histo- foxy and smoking in, 189 Plevtrocardhosrams abnormubties, and CHD, 38.41.43 effect of smoking, 41,43 Mlectrophoresis uc in’ determining serum level of alpha-lanttrypsn, 177 Uniphysema alple:-L-antitrypsin deficiency and, 176, 177 definition of, 165 development in dogs following cigarette smoke inhalation, 297 development of, relation of cadmium in” smoke to, 180 grade JI or Il, smokers vs. nonsmokers, 188 incidence in cigar/pipe smoking coal miners vs. cigarette smokers and nonsmokers, 587 mortality, effect of cigarette smoking on. 20) mortality rates, 165 mortality ratios, in male pipe and cigar smokers, 587, 589 summary of previous findings on rela- tionship to smoking, 5, 7 Endrin as suspected contributor to health hazards of smoking, 629 Enzymes activity, effect of smoking, 9t aryl hydroxylase, effect of nickel in cigarctte smoke on induction, 283 Epidemiological studies cerebrovascular dpcase and smoking, 151.152 coronary diseases and smoking. 136, 137 peptic ulcer and smoking, 181-183 Epinephrine effect of nicotine. 151 levels in arteries. cigarette smoking effects on, $3 Epitheliomas of lip. relationship of tobacco uye with, 387 Cpoxides suspected carcinogenic ugents in ciga- rete sinoke, 291 Esophageal epithelium atypical nuclei in) basal cells, male smokers. 318. 405-496 Esophageal neoplasms alcohol consumption and smoking im, $70 frequency in smokers vs. nonsmokers, 264 induction in anunals by nitrosamine, 318 methods and results of retrospective studies of lobseco use in, 315. 401-404 mortality rates, 315 mortality ratios for cigar, pipe, and cigareue smokers va. nonsmokers. 567,870 mortality ratios in, 315-337 relative risk in cigar. pipe, and cizaretle smokers vs. wonsmokers, 567, 570-872 smoking in chology of, 319 summary of retroypective studies, 571, $72 Esophagus histofovical chines in cicar. pipe. and Cigarette smokers vs. nonsmokers. 570 Exercise on bicyck ergometer, effect of smoking, 612,613 cardiac index, effect of smoking, 612, 613 effect of smoking and smoking absu- nence. 611,642,616, 617 effects of CO exposure und increased carboayhemoglobin levels, 491, 493 influencing factors, 641,616,617 summary of findings and mechanism of action, 616,617 - on treadmill, effect of smoking, 613, 615 Ex-smokers atypical nuclei in esophageal epithelium in male, 405-406 effects of cessation on body weight, blood pressure, and hypenenson development, 138-141 low buth weight infants of, 426-428 mortality rates in, COPD, 201 mortality rates in, coronary discaxt, 4244 mortalty rates in, coronary disease, cigarette vs. pipe/cigar smokers, $42-543 mortality rutes im, lung neoplasms, 302 mortally ratios an, Jung ncophisms, 267-268 summary of previous findings on health consequences Of cessation, 6 Eye irritation effects of exposure lo cigarette smoke, in passive smokers, 495, 496 Fatty acid levels effect of cigar, pipe, and cigarette smoke in dogs, 586 tise in, after smoking, 32,61 in smokers vs. nonsmokers, 98 Fatty acids suspected carcinogenic agents of ciga- rette smoke, 292 Fetal death effect of maternal smoking, 437-449 epidemiological studies, in snoken vs. nonsmokers, 440-446 Filters advantages in reduction of particulates, 295,30) Finland blood pressure differences in smokers vs. nonvmokers, 99 COPD morbidity in smokers, 226 lung neoplasm mortality in, relationship to lobacco use, 271, 272 lung neoplasms in, retrospective study of, methods, 353, 353 serum lipid differences in smokers vs. nonsmokers in, 94.95 smoking and nicotine effects on human blood lipids, 120 Fitness tests smokers vs. nonamoken, 615 Ttuoranthene aluoholic solution of, penetrability of csophagceal epithchum, 318 642 Formaldehyde as suspected contndutor to health hazards of smoking, 629 Formosa acute effect of cigarette wnoke on human pulmonary function in, 195 Framingham Study effect of coffee drinking on mortality in smokers vs. nonsmokers, 142 France bladder neoplasms in, methods and results in retrospective studies of smoking, 407-409 CHD mortality and morbidity in, 90,93 Cigarette smoke effects on animal tissue in, 369,370,375 COPD mortality of smokers in, 227 esophageal neoplasms in, retrospective studies of tobacco use, 404 laryngeal neoplasms in, relationship to tobacco use, 381, 383 lung neoptasms in, methods of retrospec- live study of smoking in, 352 oral neoplasms in, relationship of tobac- co use and, 389 Fungicides concentration in cigarette smoke, 29], 292 Furfural as suspected contributor to health hazards of smoking, 629 Gas phase, cigurette smoke harmful constituents in, 627 Gastric secretion effect of nicotine in laboratory animals. 472,473 effect of smuking in ulcer patients, 471. 472 Gastrointestinal disorders prevalence in cigarette and pipe/cigar smokers, S92 Genetic factors COPD pathogenesis and, 174, 176-178. 231 twin studies, effects of smoking, 45-48, 95 ° Germany CHD morbidity and mortality in, 91-92, 93 cigarette smoke inhalation cffects on animal respiratory tract in, 376 laryngeal neoplasms in, relationship to tobacco use, 381 lung neoplasms in, methods of retrospec- tive study of smoking in, 349, 351. 352 ' polonium-210 levels in Jungs of smokers in, 362 smoking and nicotine cffects on human blood lipids, 121 Gestational ace effect on perinatal mortality rates in smoking vs. nonsmoking mothcrs, 440446 and low-birth-weight infants, effcet of mafernal smoking, 417420 Glossary terms used in smoking and ventilatory function, 241 Giucose metabolism and insulin response, alteration effects on myocardial response, 62 Glycogen levels in mice lung exposed to cigarette smake, 187 Graphite respiratory tract carcinoma in workers exposed to, 282 Grip strength effect of smoking, 611, 612 Guanethidine blockage of nicotine cardiac stimulation by, 53 Guinea pigs lung neoplasm development following chronic nickel carbonyl or dust inhalation, 282 lungs of, cigarette smoke effects on surfactant activity, 28t lespisatory changes in, exposed to cigarette smoke, 188 Hamsters benzo(a)pyrene inhalation by, effect of asbestos dust on carcinoma induc- tion, 188 bladder neoplasms in, fed 2-naphthy- lamine, 322 cigarette smoke instillation or implan- tation effects on tracheobronchial tree of, 294,372-374 ~ larynx of, effect of cigarette smoke inhalation on, 307, 310 lung and embryos, effects of cigarette smoke tars on, 369-370 pulmonary changes from chronic nitro- gen dioxide inhalation, 246 respiratory tract of, C-14 labeled particu- lates deposition in, 307-308 respiratory tract of, cigarette smoke inhalation effects on, 294, 377 Health Insurance Plan myocardial infarction in pipe and cigar smokers under, 28, 34-35 Heart effect of nicotine, 32 Heart rate effect of exercise and smoking, 6124616 effect of smoking and coronary disease, 41,43 Hematite dust, respiratory tract neoplasms in hamsters exposed to, 374 Hematocrit variations in, effect on coronary blood flow, 62 Hemoglobin affinity for oxygen, CO effects on 2,3-diphosphoglycerate control of, 56-57 variations in, effect on coronary blood flow, 62 Heterocyche compounds carcinogenic properties in cigarette smoke, 290, 291 Hexamethonium blockage of nicotine cardiac stimulation by, 53 Hookahs smokers of, laryngeal neoplasm induc- tion in, 382 Humidity and pathologic effects of exposure to cigarette smoke, 495 Hungary methods used for retrospective studies of lung neoplasms in, 354 Hydrocyanie acid as probable contnbutor to health haz- ards of smoking, 628 Hydrogen cyanide in cigarette smoke, effects on body oxidative metabolism, 58 Hydrogen sulfide as suspected contributor to health hazards of smoking, 629 Hydroquinone as suspected contributor to health hazards of smoking, 629 3-Hy droxykynurenine excretion of, smoking effects on, 322 Hydroxyproline level in mice lung exposed to cigarette smoke, 187 Hypertension smoking effects in, 137-141 summary of recent lindings, 155 Hy poxemia carbon dioxide effects on, 57,71 Hypoxia aortic atheromatosis development in rabbits exposed ta, 60 postoperative, in smokers, 200, 256 postural, mechanism in asymptomatic smokers vs. nonsmokers, 173 tissue, carbon monoxide effects on, 57 Iceland lung neoplasms in, relationship to tobacco smoking, 270 Indeno(1,2,3