The Health Consequences Of Smoking CHRONIC OBSTRUCTIVE LUNG DISEASE a report of the Surgeon General 1984 we SERVIC ge L = ty, © U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES z Public Health Service Fr Office on Smoking and Health , Rockville, Maryland 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 THE SECRETARY OF HEALTH AND HUMAN SERVICES WASHINGTON. OC 20701 The Honorable Thomas P. C'Neill, Jr. Speaker of the House of Representatives Washington, D.C. 20515 Bear Mr. Speaker: It is a pleasure to transmit to the Congress the Surgeon General's Report on the Health Consequences of Smoking, as mandated by Section 8(a) of the Public Health Cigarette Smoking Act of 1969. This is the Public Health Services't 16th report on this topic anc, like all of the earlier Reports, it identifies cigarette smoking as the chief preventable cause of death and disability in our society. The enclosed report deals with the relationship between smok- ing and those disease conditions described as chronic obstructive lung disease, particularly chronic bronchitis and emphysema. These diseases significantly increase patient loads in hospitals and other health care facilities and escalate this Nation's health care costs, including expenditures under the Medicaid and Medicare programs. This report indicates that chronic obstructive lung diseases can be reduced and, in the case of emphysema, almost eradicated, if individuals stop cigarette smoking. Moreover, stopping smok- ing also would prevent the enormous suffering and human loss now well-known to be associated with smoking. This Department has a strong and ongoing commitment to its programmatic and research efforts in the field of disease preven- tion. In our view, it is essential to apprise individuals of the consequences of smoking. A central part of our efforts is to identify ways to help smokers quit smoking, and to encourage individuals, particularly the youth of this country, not to begin smoking. Sincerely, a ow, Marggret M. Heckler Seerftary Enclosure THE SECRETARY OF HEALTH AND HUMAN SERVICES WASHENGTON OC 20201 The Honorable George Bush President of the Senate Washington, D.C. 20616 Dear Mr. President: It is a pleasure to transmit to the Congress the Surprean General's Report on the Health Consequences of Smoking, as mandated by Section 8(a) of thea Publin Health Cirerette Smoking Act of 1969. This is the Public Health Services’ 16th report or this topic and, like ail of the ezrlier Peports, it identifies cigarette smoking as the chief preventable cause of death enc disability in our society. The enclosed report deals with the relationship setweer sroy- ing and those disease conditions described as chronic obstructive lung disease, particularly chronic brorchitis and emphysema. These diseases significantly increase patient loads in hospi and other health care facilities and esealete this Naticn's health care costs, including expenditures under the Medicaid and Medicare programs. This report indicates that chronic obstructive lung diseases can be reduced and, in the case of emphysema, almost eradicated, if individuals stop cigarette smoking. Moreover, stcpning srck- ing also would prevent the enormous suffering and human toss now well-known to be asscciated with smoking. This Department has a strong and ongoing commitment to its programmatic and research efforts in the field cf disease preven- tion. In our view, it is essential to apprise individurls of the consequences of smoking. A central part of our efforts is to identify ways to help smokers quit smoking, and to encourage individuals, particularly the youth of this country, not to beri: smoking. Sincerely, Enclosure FOREWORD The 1984 Report on the Health Consequences of Smoking consti- tutes a state-of-the-art review of the information currently available regarding the occurrence and etiology of chronic obstructive lung diseases. Traditionally, chronic bronchitis and emphysema have been subsumed under the term chronic obstructive lung diseases (COLD). It is now recognized that COLD comprises three separate, but often interconnected, disease processes: (1) chronic mucus hypersecretion, resulting in chronic cough and phlegm production; (2) airway thickening and narrowing with expiratory airflow obstruction; and (3) emphysema, which is an abnormal dilation of the distal airspaces along with destruction of alveolar walls. The last two conditions can develop into symptomatic ventilatory limitation. Although there were scientific reports of a link between cigarette smoking and respiratory symptoms as early as 1870, it was not until the comprehensive review in the first Report of the Advisory Committee to the Surgeon General in 1964 that the nature of the observed association was officially recognized by the Public Health Service. At that time the committee concluded that Cigarette smoking is the most important of the causes of chronic bronchitis in the United States and increases the risk of dying from chronic bronchitis and emphysema. A relationship exists between cigarette smoking and emphysema, but it has not been established that the relationship is causal. On the basis of the evidence reviewed in this volume, we are now able to reach a much stronger conclusion: Cigarette smoking is the major cause of chronic obstructive lung disease in the United States for both men and women. The contribution of cigarette smoking to chronic obstructive lung disease morbidity and mortality far outweighs all other factors. The Importance of Chronic Obstructive Lung Disease Previous Reports on the health consequences of smoking empha- Sized the impact of cigarette smoking on mortality from smoking- related disease. It is estimated that more than 60,000 Americans died last year owing to chronic obstructive respiratory conditions vii (chronic bronchitis, emphysema, and COLD and allied conditions). From available epidemiologic and clinical evidence, it may be reasonably estimated that approximately 80 to 90 percent of these are attributable to smoking. Over 50,000 of the COLD deaths can therefore be considered preventable and premature because these individuals would not have died of COLD if they had not smoked. While smoking-related COLD mortality is less than estimates for smoking-related deaths due to coronary heart disease (170,000) and those due to cancer (130,000), it nonetheless represents a significant number of excess deaths. COLD morbidity has a greater impact upon society than COLD mortality. Death from COLD usually occurs only after an extended period of disability, and many individuals with disability from COLD will die from other causes before the disease progresses to a degree of severity likely to cause death. The progressive loss of lung function that characterizes COLD can lead to severe shortness of breath, limiting the activity level. In recognizing the morbidity associated with these diseases, it is important to realize that the frequency of activity limitation with COLD exceeds that reported for any other major disease category. In 1979, 52 percent of individuals with emphysema reported that it limited their activity; 27 percent said it resulted in one or more bed days that year; and 73 percent reported at least one visit to a doctor during the preceding year due to emphysema. Forty percent more people with emphysema than with heart conditions reported limitation of activity. More recently, the National Center for Health Statistics has estimated that over 10 million Americans suffer from either chronic bronchitis or emphyse- ma. The Changing Pattern of Mortality The 1980 and 1982 Surgeon General’s Reports (The Health Consequences of Smoking for Women and The Health Consequences of Smoking: Cancer) reported a rapidly increasing rate of lung cancer among women compared with the rate for men. As this Report documents, the mortality ratio between men and women for COLD is also narrowing. In just 10 years, while total deaths from COLD increased from 33,000 in 1970 to 53,000 in 1980, the male-to-female ratio narrowed from 4.3:1 in 1970 to 2.3:1 in 1980. This epidemic increase in COLD among women reflects their later uptake of smoking when compared with men. Findings of the 1984 Report The mortality ratios for COLD in cigarette smokers compared with nonsmokers are as large as or larger than for lung cancer, the viii disease most people usually associate with smoking. In heavy smokers, this risk can be as much as 30 times the risk in nonsmokers. Perhaps even more important, in studies of cross- sections of U.S. populations, cigarette smoking behavior is often the only significant predictor for COLD. Even after 30 years of intensive investigation, only cigarette smoking and o,-antiprotease deficiency have been established as being able to cause COLD in the absence of other agents. The decline in lung function with age is steeper in smokers than in nonsmokers, and the rate of decline increases with an increasing number of cigarettes smoked per day. This excess decline in lung function in smokers reflects the progressive lung damage that can eventually lead to symptoms of COLD and ultimately death. Therefore, it is not surprising that the risk of death from COLD increases with an earlier age of smoking initiation, number of cigarettes smoked per day, and deep inhalation of the smoke. Abnormal lung function can be demonstrated in some cigarette smokers within a few years of smoking initiation. These changes initially reflect inflammation in the small airways of the lung and may reverse with cessation. Beginning in their late twenties, some smokers start to develop abnormal measures of expiratory airflow, an excess decline in lung function that continues as long as they continue to smoke. Some of these smokers will develop enough functional loss to become symptomatic, and some of those who become symptomatic will develop enough functional loss to die of COLD. When the smoker quits, the rate of functional decline slows, but there is little evidence to suggest that the smoker can regain the function that has been lost. We are also beginning to understand that the impact of cigarette smoke on the lung is not limited to the active smoker. Children of smoking parents have an increased risk of bronchitis and pneumonia early in life, and seem to have a small, but measurable, difference in the growth of lung function. One of the major advances described in this volume is in the understanding of the mechanisms by which cigarette smoking causes COLD, particularly emphysema. There is now a clear, plausible explanation of how emphysema might result from cigarette smoking. The inflammatory response to cigarette smoke results in an in- creased number of inflammatory cells being present in the lungs of cigarette smokers. These cells can increase the amount of elastase in the lung, and elastase is capable of degrading elastin, one of the structural elements of the lung. In addition, cigarette smoke is capable of oxidative inactivation of a,-antiprotease, a protein capable of blocking the action of elastase. The net result is an excess of elastase activity, degradation of elastin in the lung, destruction of alveolar walls, and the development of emphysema. ix Research scientists continue to expand our understanding of the process by which cigarettes damage the lung, but the important public health focus must shift to how to prevent children from becoming cigarette smokers and how to help those who now smoke to quit. Helping Smokers Quit Smokers can realize a substantial health benefit from quitting smoking, no matter how long they have smoked. As this Report states, sufficient evidence now exists to document lung function improvement in smokers who have quit. Ex-smokers can look forward to improved future health, avoiding long-term and possibly severe disability, or even death, from COLD. Two chapters in this Report summarize research studies using two vastly different cessation approaches. One focuses on the role of physicians in assisting patient populations to quit smoking; the other looks at communitywide intervention programs. Both can have a significant impact on reducing the number of smokers in our population. In January of this year, the Food and Drug Administration approved a nicotine chewing gum that physicians can prescribe for their patients as an aid to cessation. Studies have shown encouraging results when the gum is used as part of a complete behavior modification program. It must be cautioned, however, that nicotine chewing gum is not a magic cure. Smokers must be strongly motivated to quit or they are unlikely to meet with long-term success. Public Attitudes and Knowledge In 1981, a Federal Trade Commission staff report on cigarette advertising revealed that a sizable portion of the population is not aware of the link between cigarette smoking and chronic bronchitis and emphysema. The report cited a 1980 Roper survey finding that 59 percent of the population, including 63 percent of smokers, did not know that smoking causes most cases of emphysema. Over a third of the general population and almost 40 percent of smokers do not know that smoking causes many cases. It is quite clear that physicians and other health professionals must redouble their efforts to persuade more smokers to quit. As in previous years, I call upon all segments of the health care communi- ty to provide assistance and encouragement in whatever way possible to reduce the health impact of cigarette smoking on our society, by helping their patients to quit smoking and by encouraging our young people not to take up the habit. It is only through efforts x such as these that we can reduce our country’s terrible burden of disability and death due to cigarette smoking. Edward N. Brandt, Jr., M.D. Assistant Secretary for Health xi PREFACE This Report The Health Consequences of Smoking: Chronic Ob- structive Lung Disease completes an examination by the Public Health Service of the three principal disease entities associated with cigarette smoking. In 1982, the Service presented an in-depth review of tobacco’s relationship to cancer, and in 1983, a review of its relationship to cardiovascular disease. This 1984 Report evaluates the contribution that tobacco makes to the suffering and premature deaths due to the chronic obstructive lung diseases, including emphysema and chronic bronchitis. Cigarette smoking is causally related to chronic obstructive lung disease, just as it is to cancer and coronary heart disease; severe emphysema would be rare were it not for cigarette smoking. The evidence presented in this Report supports my judgment and the judgment of five preceding Surgeons General that cigarette smoking is the chief, single, avoidable cause of death in our society and the most important public health issue of our time. This Report, as were all previous Surgeon General’s Reports dealing with cigarette smoking, is the work of many experts both within and outside the Federal establishment. To these authors, editors, and reviewers I again express my great respect and sincere thanks. C. Everett Koop, M.D. Surgeon General xill ACKNOWLEDGMENTS This Report was prepared by the Department of Health and Human Services under the general editorship of the Office on Smoking and Health, Joanne Luoto, M.D., M.P.H., Director. Manag- ing Editor was Donald R. Shopland, Technical Information Officer, Office on Smoking and Health. Senior scientific editor was David M. Burns, M.D., Assistant Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California at San Diego, San Diego, Califor- nia. Consulting scientific editors were John H. Holbrook, M.D., Associate Professor of Internal Medicine, University of Utah Medi- cal Center, Salt Lake City, Utah; and Ellen R. Gritz, Ph.D., Director, Macomber-Murphy Cancer Prevention Program, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California. The editors wish to acknowledge their grateful appreciation to the National Heart, Lung, and Blood Institute, Claude Lenfant, M.D., Director, for the Institute’s invaluable assistance in the compilation of this volume. The following individuals prepared draft chapters or portions of the Report: Brenda E. Barry, Ph.D., Research Associate, Environmental Science and Physiology, Harvard School of Public Health, Boston, Massa- chusetts Richard A. Bordow, M.D., Associate Director of Respiratory Medi- cine, Brookside Hospital, San Pablo, California, and Assistant Clinical Professor of Medicine, University of California at San Francisco, San Francisco, California Joseph D. Brain, Sc.D., Professor of Physiology and Director, Respiratory Biology Program, Harvard School of Public Health, Boston, Massachusetts o A. Sonia Buist, M.D., Professor of Medicine, Department of Medicine, Oregon Health Sciences University, Portland, Oregon Louis Diamond, Ph.D., Professor and Dirextor-of the Pharmacody- namics and Toxicology Division, University of Kentucky College of Pharmacy, Lexington, Kentucky XV Terence A. Drizd, Statistician, Medical Statistics Branch, Division of Health Examination Statistics, National Center for Health Statis- tics, Public Health Service, Department of Health and Human Services, Hyattsville, Maryland Millicent W. Higgins, M.D., Professor of Epidemiology and Professor of Internal Medicine, Department of Epidemiology, The University of Michigan School of Public Health, Ann Arbor, Michigan Gary W. Hunninghake, M.D., Director, Pulmonary Disease Division and Professor, Department of Internal Medicine, The University of Iowa Hospitals and Clinics, Iowa City, Iowa Philip Kimbel, M.D., Chairman, Department of Medicine, The Graduate Hospital, Philadelphia, Pennsylvania Edgar C. Kimmel, Pharmacodynamics and Toxicology Division, University of Kentucky College of Pharmacy, Lexington, Ken- tucky Charles Kuhn, M.D., Department of Pathology, Jewish Hospital at Washington University Medical Center, St. Louis, Missouri Alfred L. McAlister, Ph.D., The University of Texas Health Science Center at Houston, Houston, Texas John McCarren, M.D., Division of Pulmonary and Critical Care Medicine, University of California at San Diego, San Diego, California Linda L. Pederson, Ph.D., Department of Epidemiology and Biosta- tistics, University of Western Ontario, London, Ontario, Canada John A. Pierce, M.D., Department of Medicine, Washington Univer- sity Medical Center, St. Louis, Missouri Jonathan M. Samet, M.D., Associate Professor of Medicine, The University of New Mexico School of Medicine, Albuquerque, New Mexico Robert M. Senior, M.D., Professor of Medicine, Respiratory and Critical Care Division, Jewish Hospital at Washington University Medical Center, St. Louis, Missouri Frank E. Speizer, M.D., Associate Professor of Medicine, Harvard Medical School, and Associate Chief, Channing Laboratory, Brig- ham and Women’s Hospital, Boston, Massachusetts Ira B. Tager, M.D., M.P.H., Division of Infectious Disease, Beth Israel Hospital and Channing Laboratory, Brigham and Women’s Hospi- tal, and Assistant Professor of Medicine, Harvard Medical School, Boston, Massachusetts William M. Thurlbeck, M.D., F.R.C.P(C), Professor of Pathology, Department of Pathology, The University of British Columbia, Vancouver, British Columbia, Canada Martin J. Tobin, M.D., M.R.C.P.L., Assistant Professor of Medicine, Division of Pulmonary Medicine, Department of Internal Medi- cine, The University of Texas Health Science Center at Houston, Houston, Texas Xvi Adam Wanner, M.D., Professor of Medicine and Chief, Division of Pulmonary Diseases, University of Miami School of Medicine, Miami Beach, Florida Scott T. Weiss, M.D., M.S., Associate Chief, Pulmonary Division, Beth Israel Hospital, and Assistant Professor of Medicine, Har- vard Medical School, Boston, Massachusetts The editors acknowledge with gratitude the following distin- guished scientists, physicians, and others who lent their support in the development of this Report by coordinating manuscript prepara- tion, contributing critical reviews of the manuscript, or assisting in other ways. Oscar Auerbach, M.D., Senior Medical Investigator, Veterans Ad- ministration Medical Center, East Orange, New Jersey John Bailar III, M.D., Ph.D., Office of the Assistant Secretary of Health, Office of Disease Prevention and Health Promotion, Washington, D.C. David V. Bates, M.D., F.R.C.P.(C), Professor of Medicine, Department of Health Care and Epidemiology, The University of British Columbia, Vancouver, British Columbia, Canada Benjamin Burrows, M.D., Division of Respiratory Science, University of Arizona College of Medicine, Tucson, Arizona Jacqueline Coalson, Professor of Pathology, School of Medicine, University of Texas at San Antonio, San Antonio, Texas Allen B. Cohen, M.D., Ph.D., Executive Associate Director and Professor of Medicine, The University of Texas Health Center at Tyler, Tyler, Texas Manuel G. Cosio, M.D., Director, Pulmonary Laboratories, Royal Victoria Hospital, Montreal, Quebec, Canada Manning Feinleib, M.D., Dr.P.H., Director, National Center for Health Statistics, Public Health Service, Department of Health and Human Services, Hyattsville, Maryland Benjamin G. Ferris, Jr., M.D., Professor of Environmental Health and Safety, Department of Physiology, Harvard School of Public Health, Boston, Massachusetts Gareth M. Green, M.D., Professor and Chairman, Department of Environmental Health Sciences, The Johns Hopkins University School of Hygiene and Public Health, Baltimore, Maryland Clarence A. Guenter, M.D., F.R.C.P.(C), Professor and Head, Depart- ment of Medicine, The University of Calgary Foothills Hospital, Calgary, Alberta, Canada Ian T. T. Higgins, M.D., Professor of Epidemiology, Department of Epidemiology, The University of Michigan School of Public Health, Ann Arbor, Michigan John R. Hughes, M.D., Assistant Professor, Department of Psychia- try, University of Minnesota, Minneapolis, Minnesota Xvli Suzanne S. Hurd, Ph.D., Director, Division of Lung Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Roland H. Ingram, Jr., M.D., Director, Respiratory Division, Brig- ham and Women’s Hospital, and Parker B. Francis Professor of Medicine, Harvard Medical School, Boston, Massachusetts Aaron Janoff, Ph.D., Professor and Experimental Pathologist, De- partment of Pathology, School of Medicine and University Hospi- tal, State University of New York at Stony Brook, Stony Brook, New York Lynn T. Kozlowski, Ph.D., Scientist, Clinical Institute of the Addic- tion Research Foundation, Toronto, Ontario, Canada Claude Lenfant, M.D., Director, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Peter T. Macklem, M.D., F.R.S.C., Physician-in-Chief, Royal Victoria Hospital, and Professor and Chairman, Department of Medicine, McGill University, Montreal, Quebec, Canada James O. Mason, M.D., Director, Centers for Disease Control, Atlanta, Georgia Kenneth M. Moser, M.D., Professor of Medicine and Director, Division of Pulmonary and Critical Care Medicine, School of Medicine, University of California at San Diego, San Diego, California C. Tracy Orleans, Ph.D., Division of Psychosomatic Medicine, Department of Psychiatry, Duke University Medical Center, Durham, North Carolina Terry F. Pechacek, Ph.D., Assistant Professor, Division of Epidemiol- ogy, School of Public Health, University of Minnesota, Minneapo- lis, Minnesota Solbert Permutt, M.D., Professor of Medicine, Department of Medi- cine, Division of Pulmonary Medicine, The Johns Hopkins Univer- sity School of Medicine, Baltimore, Maryland Chery] L. Perry, Ph.D., Assistant Professor, Division of Epidemiolo- gy, School of Public Health, University of Minnesota, Minneapolis, Minnesota Richard Peto, M.A., M.Sec., LC.R.S., Clinical Trial Service Unit, Radcliffe Infirmary, University of Oxford, Oxford, England Thomas L. Petty, M.D., Professor of Medicine, and Director, Webb Waring Lung Institute, University of Colorado Health Sciences Center, Denver, Colorado James L. Repace, Office of Policy Analysis, U.S. Environmental Protection Agency, Washington, D.C. Attilio D. Renzetti, Jr.. M.D., University of Utah Medical Center, Salt Lake City, Utah John Repine, M.D., Webb Waring Lung Institute, Denver, Colorado xviii Eugene Rogot, Statistician, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland Marvin A. Sackner, M.D., Director, Medical Services, Mount Sinai Medical Center, and Professor of Medicine, University of Miami School of Medicine, Miami Beach, Florida Roy J. Shephard, M.D., Ph.D., Director of School of Physical and Health Education, University of Toronto, Toronto, Ontario, Cana- da Gordon L. Snider, M.D., Professor of Medicine and Director, Pulmo- nary Center, Boston University School of Medicine, Boston, Massachusetts Donald F. Tierney, M.D., Department of Medicine, School of Medi- cine, Center for the Health Sciences, University of California at Los Angeles, Los Angeles, California Nicholas J. Wald, M.R.C.P., F.F.C.M., Professor, Department of Environmental and Preventive Medicine, The Medical College of St. Bartholomew’s Hospital, University of London, London, Eng- land James B. Wyngaarden, M.D., Director, National Institutes of Health, Bethesda, Maryland The editors also acknowledge the contributions of the following staff members and others who assisted in the preparation of this Report. Erica W. Adams, Copy Editor, Information Programs Division, Informatics General Corporation, Rockville, Maryland Richard H. Amacher, Director, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland John L. Bagrosky, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Richard J. Bast, Medical Translation Consultant, Information Pro- grams Division, Informatics General Corporation, Rockville, Mary- land Charles A. Brown, Programmer, Data Processing Services, Informat- ics General Corporation, Rockville, Maryland Clarice D. Brown, Bio-Statistician and Epidemiologist, Office on Smoking and Health, Rockville, Maryland Joanna B. Crichton, Copy Editor, Clearinghouse Projects Depart- ment, Informatics General Corporation, Rockville, Maryland Alicia Doherty, Information Specialist, Clearinghouse Projects De- partment, Informatics General Corporation, Rockville, Maryland Danny A. Goodman, Information Specialist, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land XIX Kit Hagner, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Rebecca C. Harmon, Publications Manager, Information Programs Division, Informatics General Corporation, Rockville, Maryland Karen Harris, Clerk-Typist, Office on Smoking and Health, Rock- ville, Maryland Douglas M. Hayes, Publications Systems Supervisor, Publishing Services Division, Informatics General Corporation, Riverdale, Maryland Patricia E. Healy, Technical Information Clerk, Office on Smoking and Health, Rockville, Maryland Shirley K. Hickman, Data Entry Operator, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Margaret H. Hindman, Publications Specialist, Information Pro- grams Division, Informatics General Corporation, Rockville, Mary- land Robert S. Hutchings, Associate Director for Information and Pro- gram Development, Office on Smoking and Health, Rockville, Maryland Leena Kang, Data Entry Operator, Clearinghouse Projects Depart- ment, Informatics General Corporation, Rockville, Maryland Margaret E. Ketterman, Public Information and Publications Spe- cialist, Office on Smoking and Health, Rockville, Maryland Julie Kurz, Graphic Artist, Information Programs Division, Infor- matics General Corporation, Rockville, Maryland Roberta L. Litvinsky, Secretary, Office on Smoking and Health, Rockville, Maryland William R. Lynn, Program Operations Technical Assistance Officer, Office on Smoking and Health, Rockville, Maryland Edward W. Maibach, Health Promotion Specialist, Informatics General Corporation, Rockville, Maryland Dixie P. McGough, Publications Specialist, Information Programs Division, Informatics General Corporation, Rockville, Maryland Patricia A. Mentzer, Data Entry Operator, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Kurt D. Mulholland, Graphic Artist, Information Programs Division, Informatics General Corporation, Rockville, Maryland Judy Murphy, Writer-Editor, Office on Smoking and Health, Rock- ville, Maryland Sally L. Nalley, Secretary, Office on Smoking and Health, Rockville, Maryland Ruth C. Palmer, Secretary, Office on Smoking and Health, Rockville, Maryland XX Raymond K. Poole, Production Coordinator, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Roberta A. Roeder, Secretary, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland Anne C. Ryon, Copy Editor, Information Programs Division, Infor- matics General Corporation, Rockville, Maryland Linda R. Sexton, Information Specialist, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Mary- land Linda R. Spiegelman, Administrative Officer, Office on Smoking and Health, Rockville, Maryland Evelyn L. Swarr, Administrative Secretary, Data Processing Ser- vices, Informatics General Corporation, Rockville, Maryland Karen Weil Swetlow, Copy Editor, Clearinghouse Projects Depart- ment, Informatics General Corporation, Rockville, Maryland Debra C. Tate, Publications Systems Specialist, Publishing Services Division, Informatics General Corporation, Riverdale, Maryland Jerry W. Vaughn, Development Technician, University of California at San Diego, San Diego, California Jill Vejnoska, Writer-Editor, Information Programs Division, Infor- matics General Corporation, Rockville, Maryland Aileen L. Walsh, Secretary, Clearinghouse Projects Department, Informatics General Corporation, Rockville, Maryland Dee Whitley, Computer Operator, Data Processing Services, Infor- matics General Corporation, Rockville, Maryland Louise Wiseman, Technical Information Specialist, Office on Smok- ing and Health, Rockville, Maryland Pamela Zuniga, Secretary, University of California at San Diego, San Diego, California Xxi TABLE OF CONTENTS Foreword 2.0.00... cccccccce cece cence tenet ee ee enna eet eeeeeeet et nae sens vii Preface .........c ccc ccce cece cece eee e eee ene e tds eee e nee een nee EE xili Acknowledgments ..............ccceeeeeee eect cette eee eee eea sean ns XV 1. Introduction, Overview, and Conclusions ................. 1 2. Effect of Cigarette Smoke Exposure on Measures of Chronic Obstructive Lung Disease Morbidity ......... 17 3. Mortality From Chronic Obstructive Lung Disease Due to Cigarette Smoking ..................:cce pees ee ee es 185 4. Pathology of Lung Disease Related to Smoking..... 219 5. Mechanisms by Which Cigarette Smoke Alters the Structure and Function of the Lung................... 251 6. Low Yield Cigarettes and Their Role in Chronic Ob- structive Lung Disease.............. 20. .ccc sees eee e ee eee enes 329 7. Passive Smoking ..................ccccsccceeceeeeeeeee eee enees 361 8. Deposition and Toxicity of Tobacco Smoke in the LUNG... cece cece cece eee ee eee e seen enced teat eae ee tes eneee ees 413 9. Role of the Physician in Smoking Cessation......... 451 10. Community Studies of Smoking Cessation and Preven- THOT oo cece cece ccc cee e cette eee rect eee eee eee ne eeee een eeen ent eaeees 499 1s 6 (=>: 535 Xxili CHAPTER 1. INTRODUCTION, OVERVIEW, AND CONCLUSIONS CONTENTS Introduction Organization and Development of the 1984 Report Historical Perspective ‘Overview Conclusions of the 1984 Report COLD Morbidity COLD Mortality Pathology of Cigarette-Induced Disease Mechanisms of COLD Low Tar and Nicotine Cigarettes Passive Smoking Deposition and Toxicity of Tobacco Smoke in the Lung Role of the Physician in Smoking Cessation Community Studies of Smoking Cessation and Prevention Introduction Organization and Development of the 1984 Report Each year the Office on Smoking and Health (OSH), working in close collaboration with scientists, researchers, and others, compiles the annual Surgeon General’s Report The Health Consequences of Smoking for submission to the US. Congress as part of the Department’s responsibility to report new and current information on the topic as required under Public Law 91-222. This Report is the third to examine in detail specific disease entities related to smoking. The 1982 Report was a comprehensive assessment of the relationship between tobacco use and various cancers, and the 1983 Report examined this relationship for cardiovascular diseases. The 1984 volume represents a state-of-the-art comprehensive review of tobacco use and the development of chronic obstructive lung diseases. The scientific content of this Report is the work of experts in the field of chronic obstructive lung disease research both within the Department of Health and Human Services and from outside the Federal Government. Individual manuscripts were written by ex- perts who are nationally and internationally recognized for their scientific understanding of the etiology of chronic obstructive lung diseases, particularly the relationship with cigarette use. Manuscripts received from authors were extensively reviewed by numerous outside experts familiar with these specific areas. The entire Report was then submitted to a broad-based panel of 11 distinguished lung disease experts and to experts within the U.S. Public Health Service for their review and comments. The 1984 Report includes a Foreword by the Assistant Secretary for Health of the Department of Health and Human Services and a Preface by the Surgeon General of the U.S. Public Health Service. The body of the Report consists of 10 chapters, as follows: e Chapter 1. Introduction, Overview, and Conclusions e Chapter 2. Effect of Cigarette Smoke Exposure on Mea- sures of Chronic Obstructive Lung Disease Morbidity e Chapter 3. Mortality From Chronic Obstructive Lung Dis- ease Due to Cigarette Smoking e Chapter 4. Pathology of Lung Disease Related to Smoking e Chapter 5. Mechanisms by Which Cigarette Smoke Alters the Structure and Function of the Lung e Chapter 6. Low Yield Cigarettes and Their Role in Chronic Obstructive Lung Disease Passive Smoking Deposition and Toxicity of Tobacco Smoke in the Lung e Chapter @ Chapter on e Chapter 9. Role of the Physician in Smoking Cessation e@ Chapter 10. Community Studies of Smoking Cessation and Prevention Historical Perspective The relationship between cigarette smoking and chronic obstruc- tive lung disease (COLD) was among the first recognized and is now the best understood of the diseases caused by smoking. Sigmund reported as early as 1870 that heavy smokers suffered “affections” of the nose, mouth, and throat more frequently and in a more virulent fashion. In 1897, Mendelssohn reported the incidence of “affections” of the respiratory tract to be 60 percent greater in smokers than in nonsmokers, as well as somewhat greater in those who inhaled compared with smokers who did not inhale. Overview Scientists from a variety of disciplines have investigated the role of cigarette smoking in the development of COLD; today we can trace the progressive decline in lung function in smokers with increasing smoke exposure, describe the concurrent pathologic changes, demon- strate that both COLD prevalence and COLD death are limited largely to smokers, and describe in detail a plausible mechanism by which cigarette smoking can lead to the development of emphysema. Some gaps in the understanding of the details of this process may still exist, but the experimental and epidemiologic evidence leaves no room for reasonable doubt on the fundamental issue: cigarette smoking is the major cause of COLD in the United States. The earliest recognized response to cigarette smoke is an increase in airway resistance that occurs with the inhalation of smoke by the smoker. This increase in resistance is a response to the irritants in the smoke, as is coughing, which is more frequent in smokers than in nonsmokers, even among adolescents. By the time smokers become young adults, a substantial proportion of them will have developed pathologic changes in their small airways. These abnormalities are demonstrable using a variety of physiologic tests, and are a result of pathologic changes or inflammation in the airways less than 2 mm in diameter. Part of this small airways response, but perhaps a later manifestation of it, is the development of smooth muscle hypertro- phy, goblet cell hyperplasia, and mild peribronchiolar fibrosis. The prevalence of abnormalities on tests of small airways function increases as these young smokers grow older, and is greater in heavy smokers than in light smokers. While it is clear that changes in the small airways represent an early response to cigarette smoking and that they are a significant finding in the pathophysiology of COLD, it is not clear that abnormal function of the small airways, per se, is 6 useful as a marker for identifying who will progress to develop symptomatic COLD. It may identify a large group of smokers who manifest an irritant response to smoke in the small airways, of whom only a subset actually develop symptomatic airflow obstruc- tion. Measurable differences in tests of expiratory airflow exist between smokers and nonsmokers after age 25. Smokers as a group have a more rapid decline in FEV, with age than that observed in nonsmokers, and the decline is even greater among heavy smokers. However, this increased rate of decline in lung function is not distributed evenly, even among smokers with similar smoking histories. Some smokers have a far more rapid decline than the average smoker, and clearly those individuals who have developed symptomatic chronic airflow obstruction have had a larger total decline in lung function than the average smoker. This has led to the suggestion that individuals with a particularly rapid decline in FEV, early in life may represent a group especially susceptible to the later development of symptomatic COLD. The nature of this susceptibility remains unclear, but differences in depth or pattern of inhalation, variations in the cellular and biochemical response of the lung to smoke, differences in immune or repair mechanisms, and childhood infections or exposure to environmental tobacco smoke as a child have been suggested as potential factors. The accumulation of lung damage, marked by the excess decline in FEV, and other measures of expiratory airflow, can lead to shortness of breath and other symptoms that characterize clinically significant COLD. These symptoms can result in disability due to ventilatory limitation and may vary from patient to patient in severity and duration. Many patients with clinically disabling COLD die with the disease rather than because of it. Death from COLD usually results only after extensive lung damage and commonly occurs because of failure of the severely damaged lungs to maintain adequate gas exchange. The cessation of cigarette smoking has a substantial salutary impact on the incidence and progression of COLD. Cigarette smokers who quit prior to developing abnormal lung function are unlikely to go on to develop ventilatory limitation; when the abnormalities are demonstrable only on tests of small airways function, cessation often results in a reversal of these changes and a return to normal function. The presence of significant fixed reduction in measures of expiratory airflow usually reflects the presence of substantial lung damage. Cessation of smoking at this stage of COLD results in a slowing in the rate of decline in lung function with age, in comparison with that in continuing smokers. After a period of cessation, this rate of decline in function may approximate the rate found in nonsmokers, but there is little evidence to suggest that 7 those who quit are able to regain their prior excess functional loss. Therefore, those who quit continue to have reduced lung function when compared with those who have never smoked, but their lung function begins to decline less rapidly with age when compared to the lung function of those who continue to smoke. The importance of cigarette smoking as a causative factor in COLD is emphasized by cross-sectional studies of populations in the United States where often the only major predictor for developing or dying of COLD is smoking behavior. In the absence of cigarette smoking, clinically significant COLD is rare. As the smoker enters the sixth decade of life, pathologically definable pulmonary emphysema begins to become evident. In older age groups, mild to moderate emphysema is present in most smokers and is rare in nonsmokers. Once again, however, only a small percentage of smokers develop severe emphysema; this minority includes a disproportionate number of heavy smokers. A mechanism for smoking-induced emphysematous lung injury has been proposed and continues to evolve as our understanding of cellular and biochemical responses of the lung increases. Emphyse- ma can be produced by the presence of excessive amounts of elastase (an enzyme capable of degrading the structural elements of lung tissue) or by the absence of a,-antiprotease (a protein that inhibits the action of elastase). As part of the inflammatory response to cigarette smoke, an increased number of inflammatory cells are present in the lungs of smokers; these cells may result in an increased amount of elastase being present in the lung. In addition, cigarette smoke can oxidize the a,-antiprotease in the lung, further contributing to the imbalance between levels of elastase and levels of a,-antiprotease. The net result can be excess elastase activity, leading to degradation of elastin in the lung, destruction of alveolar walls, and development of emphysema. The text of this Report discusses in detail the relationship of cigarette smoking to COLD morbidity and mortality, the pathology of smoking-induced COLD, some of the mechanisms by which smoking results in COLD, the impact on the lung of low tar and nicotine cigarettes and of involuntary smoke exposure, the deposi- tion and toxicology of tobacco smoke, and the role of the physician and of community intervention programs in smoking cessation. The overall conclusion of this Report is clear: Cigarette smoking is the major cause of chronic obstructive lung disease in the United States for both men and women. The contribution of cigarette smoking to chronic obstructive lung disease morbidi- ty and mortality far outweighs all other factors. 8 Conclusions of the 1984 Report COLD Morbidity 1. 6. Cigaretie smoking is the major cause of COLD morbidity in the United States; 80 to 90 percent of COLD in the United States is attributable to cigarette smoking. .In population-based studies in the United States, cigarette smoking behavior is often the only significant predictor for the development of COLD. Other factors improve the predictive equation only slightly, even in those populations where they have been found to exert a statistically significant effect. .In spite of over 30 years of intensive investigation, only cigarette smoking and a,-antiprotease deficiency (a rare genet- ic defect) are established causes of clinically significant COLD in the absence of other agents. . Within a few years after beginning to smoke, smokers experi- ence a higher prevalence of abnormal function in the small airways than nonsmokers. The prevalence of abnormal small airways function increases with age and the duration of the smoking habit, and is greater in heavy smokers than in light smokers. These abnormalities in function reflect inflammatory changes in the small airways and often reverse with the cessation of smoking. . Both male and female smokers develop abnormalities in the small airways, but the data are not sufficient to define possible sex-related differences in this response. It seems likely, how- ever, that the contribution of sex differences is small when age and smoking exposure are taken into account. There is, as yet, inadequate information to allow a firm conclusion to be drawn about the predictive value of the tests of small airways function in identifying the susceptible smoker who will progress to clinical airflow obstruction. . Smokers of both sexes have a higher prevalence of cough and phlegm production than nonsmokers. This prevalence in- creases with an increasing number of cigarettes smoked per day and decreases with the cessation of smoking. . Differences between smokers and nonsmokers in measures of expiratory airflow are demonstrable by young adulthood and increase with number of cigarettes smoked per day. . The rate of decline in measures of expiratory airflow with increasing age is steeper for smokers than for nonsmokers; it is also steeper for heavy smokers than for light smokers. After the cessation of smoking, the rate of decline of lung function with increasing age appears to slow to approximately that seen in nonsmokers of the same age. Only a minority of smokers will develop clinically significant COLD, and this group will have 9 480-144 0 - 85 = 2 demonstrated a more extensive decline in lung function than the average smoker. The data are not yet available to determine whether a rapid decline in lung function early in life defines the subgroup of smokers who are susceptible to developing COLD. 10. Clinically significant degrees of emphysema occur almost exclusively in cigarette smokers or individuals with genetic homozygous o,-antiprotease deficiency. The severity of em- physema among smokers increases with the number of ciga- rettes smoked per day and the duration of the smoking habit. COLD Mortality 10 1 . Data from both prospective and retrospective studies consis- tently demonstrate a uniform increase in mortality from COLD for cigarette smokers compared with nonsmokers. Cigarette smoking is the major cause of COLD mortality for both men and women in the United States. . The death rate from COLD is greater for men than for women, most likely reflecting the differences in lifetime smoking patterns, such as a smaller percentage of women smoking in past decades, and their smoking fewer cigarettes, inhaling less deeply, and beginning to smoke later in life. . Differences in lifetime smoking behavior are less marked for younger age cohorts of smokers. The ratio of male to female mortality from COLD is decreasing because of a more rapid rise in mortality from COLD among women. .The dose of tobacco exposure as measured by number of cigarettes or duration of habit strongly affects the risk for death from COLD in both men and women. Similarly, people who inhale deeply experience an even higher risk for mortality from COLD than those who do not inhale. . Cessation of smoking leads eventually to a decreased risk of mortality from COLD compared with that of continuing smokers. The residual excess risk of death for the ex-smoker is directly proportional to the overal! lifetime exposure to ciga- rette smoke and to the total number of years since one quit smoking. However, the risk of COLD mortality among former smokers does not decline to equal that of the never smoker even after 20 years of cessation. 6. Several prospective epidemiologic studies examined the rela- tionship between pipe and cigar smoking and mortality from COLD. Pipe smokers and cigar smokers also experience higher mortality from COLD compared with nonsmokers; however, the risk is less than that for cigarette smokers. 7. There are substantial worldwide differences in mortality from COLD. Some of these differences are due to variations in terminology and in death certification in various countries. Emigrant studies suggest that ethnic background is not the major determinant for mortality risk due to COLD. Pathology of Cigarette-Induced Disease 1. Smoking induces changes in multiple areas of the lung, and the effects in the different areas may be independent of each other. In the bronchi (the large airways), smoking results in a modest increase in size of the tracheobronchial glands, associated with an increase in secretion of mucus, and in an increased number of goblet cells. 2. In the small airways (conducting airways 2 or 3 mm or less in diameter consisting of the smallest bronchi and bronchioles) a number of lesions are apparent. The initial response to smoking is probably inflammation, with associated ulceration and squamous metaplasia. Fibrosis, increased muscle mass, narrowing of the airways, and an increase in the number of goblet cells follow. 3. Inflammation appears to be the major determinant of small airways dysfunction and may be reversible after cessation of smoking. 4. The most obvious difference between smokers and nonsmokers is respiratory bronchiolitis. This lesion may be an important cause of abnormalities in tests of small airways function, and may be involved in the pathogenesis of centrilobular emphyse- ma. The severity of emphysema is clearly associated with smoking, and severe emphysema is confined largely to smok- ers. Mechanisms of COLD 1. Increased numbers of inflammatory cells are found in the lungs of cigarette smokers. These cells include macrophages and, probably, neutrophils, both of which can release elastase in the lung. 2. Human neutrophil elastase produces emphysema when in- stilled into animal lungs. 3. Alpha,-antiprotease inhibits the action of elastase, and a very small number of people with a homozygous deficiency of a,- antiprotease are at increased risk of developing emphysema. The a,-antiprotease activity has been shown to be reduced in the bronchoalveolar fluids obtained from cigarette smokers and from rats exposed to cigarette smoke. 4. The protease-antiprotease hypothesis suggests that emphyse- ma results when there is excess elastase activity as the result of increased concentrations of inflammatory cells in the lung 11 Low 12 and of decreased levels of a,-antiprotease secondary to oxida- tion by cigarette smoke. . Cigarette smokers have been shown to have a more rapid fall in antibody levels following immunization for influenza than nonsmokers. Whole cigarette smoke has been shown to depress the number of antibody-forming cells in the spleens of experi- mental animals. . Cigarette smoke produces structural and functional abnormali- ties in the airway mucociliary system. . Short-term exposure to cigarette smoke causes ciliostasis in vitro, but has inconsistent effects on mucociliary function in man. Long-term exposure to cigarette smoke consistently causes an impairment of mucociliary clearance. This impair- ment is associated with epithelial lesions, mucus hypersecre- tion, and ciliary dysfunction. . Chronic bronchitis in smokers and ex-smokers is characterized by an impairment of mucociliary clearance. . Both the particulate phase and the gas phase of cigarette smoke are ciliotoxic. Tar and Nicotine Cigarettes . The recommendation for those who cannot quit to switch to smoking cigarette brands with low tar and nicotine yields, as determined by a smoking-machine, is based on the assumption that this switch will result in a reduction in the exposure of the lung to these toxic substances. The design of the cigarette has markedly changed in recent years, and this may have resulted in machine-measured tar and nicotine yields that do not reflect the real dose to the smoker. .Smoking-machines that take into account compensatory changes in smoking behavior are needed. The assays could. provide both an average and a range of tar and nicotine yields produced by different individual patterns of smoking. . Although a reduction in cigarette tar content appears to reduce the risk of cough and mucus hypersecretion, the risk of shortness of breath and airflow obstruction may not be reduced. Evidence is unavailable on the relative risks of developing COLD consequent to smoking cigarettes with the very low tar and nicotine yields of current and recently marketed brands. . Smokers who switch from higher to lower yield cigarettes show compensatory changes in smoking behavior: the number of puffs per cigarette is variably increased and puff volume is almost universally increased, although the number of ciga- rettes smoked per day and inhalation volume are generally unchanged. Full compensation of dose for cigarettes with lower yields is generally not achieved. 5. Nicotine has long been regarded as the primary reinforcer of cigarette smoking, but tar content may also be important in determining smoking behavior. 6. Depth and duration of inhalation are among the most impor- tant factors in determining the relative concentration of smoke constituents that reach the lung. Considerable interindividual variation exists between smokers with respect to the volume and duration of inhalation. This variation is likely to be an important factor in determining the varying susceptibility of smokers to the development of lung disease. 7. Production of low tar and nicotine cigarettes has progressed beyond simple reduction in tobacco content. Additives such as artificial tobacco substitutes and flavoring extracts have been used. The identity, chemical composition, and adverse biologi- cal potential of these additives are unknown at present. Passive Smoking 1. Cigarette smoke can make a significant, measurable contribu- tion to the level of indoor air pollution at levels of smoking and ventilation that are common in the indoor environment. 2. Nonsmokers who report exposure to environmental tobacco smoke have higher levels of urinary cotinine, a metabolite of nicotine, than those who do not report such exposure. 3. Cigarette smoke in the air can produce an increase in both subjective and objective measures of eye irritation. Further, some studies suggest that high levels of involuntary smoke exposure might produce small changes in pulmonary function in normal subjects. 4. The children of smoking parents have an increased prevalence of reported respiratory symptoms, and have an increased frequency of bronchitis and pneumonia early in life. 5. The children of smoking parents appear to have measurable but small differences in tests of pulmonary function when compared with children of nonsmoking parents. The signifi- cance of this finding to the future development of lung disease is unknown. 6. Two studies have reported differences in measures of lung function in older populations between subjects chronically exposed to involuntary smoking and those who were not. This difference was not found in a younger and possibly less exposed population. 7. The limited existing data yield conflicting results concerning the relationship between passive smoke exposure and pulmo- nary function changes in patients with asthma. 13 Deposition and Toxicity of Tobacco Smoke in the Lung 1 .The mass median aerodynamic diameter of the particles in cigarette smoke has been measured to average approximately 0.46 um, and particulate concentrations have been shown to range frorn 0.3 x 10° to 3.3 x 10° per milliliter. . The particulate concentration of the smoke increases as the cigarette is more completely smoked. . Particles in the size range of cigarette smoke will deposit both in the airways and in alveoli; models predict that 30 to 40 percent of the particles within the size range present in cigarette smoke will deposit in alveolar regions and 5 to 10 percent will deposit in the tracheobronchial region. . Acute exposure to cigarette smoke results in an increase in airway resistance in both animals and humans. . Exposure to cigarette smoke results in an increase in pulmo- nary epithelial permeability in both humans and animals. . Cigarette smoke has been shown to impair elastin synthesis in vitro and elastin repair in vivo in experimental animals (elastin is a vital structural element of pulmonary tissue). Role of the Physician in Smoking Cessation 14 1. At least 70 percent of North Americans see a physician once a year. Thus, an estimated 38 million of the 54 million adults in the United States who smoke cigarettes could be reached annually with a smoking cessation message by their physician. . Current smoking prevalence among physicians in the United States is estimated at 10 percent. . While the majority of persons who smoke feel that physician advice to quit or cut down would be influential, there is a disparity between physicians’ and patients’ estimates of cessa- tion counseling, with physician advice being reported by only approximately 25 percent of current smokers. . Studies of routine (minimal) advice to quit smoking delivered by general practitioners have shown sustained quit rates of approximately 5 percent. Followup discussions enhance the effects of physician advice. .A median of 20 percent of pregnant women who smoke quit spontaneously during pregnancy. That proportion can be doubled by an intervention consisting of health education, behavioral strategies, and multiple contacts. . Large controlled trials of cardiovascular risk reduction have demonstrated that counseling on individual specific risk fac- tors, including smoking cessation techniques, can be effective. .Studies of pulmonary and cardiac patients indicate that severity of illness is positively related to increased compliance in smoking cessation. Survivors of a myocardial infarction have smoking cessation rates averaging 50 percent. 8. Nicotine chewing gum has been developed as a pharmacologi- cal aid to smoking cessation, primarily to alleviate withdrawal symptoms. Cessation studies conducted in offices of physicians who prescribe the gum have produced mixed results, however, with outcome depending on motivation and intensity of adjunc- tive support or followup. 9. Physician-assisted intervention quit rates vary according to the type of intervention, provider performance, and patient group. In general, quit rates in recent research appear to be lower than in older studies. Community Studies of Smoking Cessation and Prevention 1.Community studies of smoking cessation and prevention are becoming an established paradigm for public health action research. Such studies emphasize large-scale delivery systems, such as the mass media, and include community organization programs seeking to stimulate interpersonal communication in ways that are feasible on a large-scale basis. 2. Although there are methodological limitations to nearly all communitywide studies, the results yield fairly consistent positive results, indicating that large-scale programs to reduce smoking can be effective in whole populations. Person-to- person communication appears to be a necessary part of a successful community program to reduce smoking. 3. Further research is needed, with both improved methodology and more emphasis on low socioeconomic status groups that have not yet shown population trends toward reduced smoking. 4. Several promising directions for research are clear, but the most important future trends will be toward the establishment of smoking reduction programs within existing health services, the combination of chronic disease prevention with mental health promotion via mass media and community intervention, and the development of social policy to establish integrated strategies for smoking cessation and prevention. 15 CHAPTER 2. EFFECT OF CIGARETTE SMOKE EXPOSURE ON MEASURES OF CHRONIC OBSTRUCTIVE LUNG DISEASE MORBIDITY 17 CONTENTS Introduction Early Changes in Response to Cigarette Smoking Acute Response to Cigarette Smoke Chronic Response to Cigarette Smoke Smoking and Tests of Small Airways Function in Population Studies Dose-Response Relationship Between Amount Smoked and Small Airways Dysfunction How Soon Do Changes in Small Airways Function Occur? Male-Female Differences in the Responses of the Small Airways to Cigarette Smoking Effect of Smoking Cessation on Small Airways Function Relationship Between Small Airways Disease and Chronic Airflow Obstruction Summary Chronic Mucus Hypersecretion Introduction Measurement of Cough and Phlegm in Epidemiologic Studies Prevalence of Cough and Phlegm Relationship of Cough and Phlegm to Smoking Effects of Smoking Cessation Dose-Response Relationships Relationship of Cough and Phlegm to Sex and Age Relationship of Cough and Phlegm to Airflow Obstruction Summary Chronic Airflow Obstruction Introduction Prevalence of Airflow Obstruction Determinants of Airflow Obstruction Introduction Cigarette Smoking and Chronic Airflow Obstruction 19 Dose-Response Relationships Factors Other Than Cigarette Smoking ABH Secretor Status Air Pollution Airways Hyperreactivity Alcohol Consumption Atopy Childhood Respiratory Illness Familial Factors Occupation Passive Exposure to Tobacco Smoke Respiratory Illnesses Socioeconomic Status Development of Airflow Obstruction Summary Emphysema Introduction Definition of Emphysema Types of Emphysema Detection of Emphysema Quantification of Emphysema Pulmonary Function in Emphysema Mechanical Properties of the Lungs in Emphysema Aging and Lung Structure Emphysema and Cigarette Smoking Observations in People Studies Using Post-Mortem Material Dose-Response Relationships Studies of Alphai-Proteinase-Inhibitor-Deficient Individuals Homozygous Deficient—PiZZ Heterozygous Deficient—PiMZ Observations in Experimental Animals Summary Summary and Conclusions Appendix Tables References 20 INTRODUCTION This chapter describes the sequential development of smoking- induced chronic lung disease, traced from the early structural changes limited to the small airways to the severe and widespread changes involving the small airways, large airways, and lung parenchyma. Chronic obstructive lung disease (COLD) develops relatively slowly, and the progression of lung injury and alterations in function can be followed using an individual smoker’s symptoms and performance on a variety of pulmonary function tests. Early in the duration of the smoking behavior, a person may be asymptomat- ic, but often there are abnormalities demonstrable in the small airways that probably represent an inflammatory response to the constituents of cigarette smoke. Later, usually after 20 or more years of smoking, a constellation of symptoms and functional changes may develop, particularly in heavy smokers and in those who will later develop clinically significant COLD. The clinical picture of cigarette- induced chronic lung injury includes three Separate, but often interconnected, disease processes. They are (1) chronic mucus hypersecretion (cough and phiegm), (2) airway narrowing with expiratory airflow obstruction, and (3) abnormal dilation of the distal airspaces with destruction of alveolar walls (emphysema). Patients with severe COLD commonly have some degree of all three pro- cesses, but individual patients vary significantly in the relative contribution of the processes to their overall disease state. Some alteration in lung structure or function is demonstrable in the majority of long-term smokers, but only a minority of smokers will develop clinically limiting COLD, In fact, only 10 to 15 percent of smokers will develop moderate or severe airflow obstruction (Bates 1973; Fletcher et al. 1976). This chapter details the relationship between cigarette smoking and morbidity from COLD. The relationship of cigarette smoking to changes in the small airways is described first, followed by discussion of the role of smoking to chronic mucus hypersecretion, chronic airflow obstruction, and emphysema. 21 EARLY CHANGES IN RESPONSE TO CIGARETTE SMOKING The tests of small airways function were developed in the late 1960s and early 1970s, and grew out of a series of studies calling attention to the functional importance of disease in the small airways. Macklem and Mead (1967) predicted that there could be considerable peripheral airway obstruction that might influence the distribution of ventilation but would have little effect on lung mechanisms; subsequently, Anthonisen et al. (1968) and Ingram and Schilder (1967) demonstrated the existence of early functional changes in smokers. These investigators showed that in a group of patients with clinically mild chronic bronchitis and normal lung function measured by spirometric tests, all had abnormalities of regional gas exchange, as determined by Xenon!33. They attributed this finding to peripheral airway disease and suggested that the functionally important lesion in chronic bronchitis may be in the small airways. Brown and coworkers (1969), using excised lobes of dog and pig lung, demonstrated that considerable obstruction may be present in the airways smaller than 2 mm with little or no effect on overall pulmonary resistance. Hogg and coworkers (1968), using a retrograde catheter technique, measured central and peripheral airway resistance in excised normal and emphysematous human lungs and found that the peripheral airway resistance (accounting for only 25 percent of total airway resistance in the normal lungs (Macklem and Mead 1967)) was greatly increased in the lungs with emphysema. In an early structure-function correlation study, these investigators correlated the physiologic findings with histologic and bronchographic evidence of mucus plugging and narrowing and obliteration of small airways. Woolcock and coworkers (1969) report- ed that a group of bronchitic subjects with normal responses to routine lung function tests (lung volumes, flow rates, and diffusing capacity) demonstrated a decrease in the dynamic-to-static compli- ance ratio with increasing breathing frequency. These studies provided clear evidence that there can be measurable obstruction in airways 2 mm in diameter or smaller with little or perhaps no detectable influence on total airway resistance, and, therefore, on lung function measured by conventional tests such as lung volumes, spirometry, and diffusing capacity. With the concept of small airways disease firmly established, a number of new tests considered capable of detecting the abnormality were introduced, along with reinterpretation of existing tests. The new measures included frequency dependence of compliance, the single breath Ne test for the measurement of closing volumes (closing volume as a percent of vital capacity [CV/VC%] and closing capacity as a percent of total lung capacity [CC/TLC%)]), the slope of the alveolar plateau, maximal expiratory flow volume (MEFV) curves using gases of different-densities, and moment analysis of the forced 22 expiration. The measurements obtained from the MEFV curve, breathing gases of different densities, are (a) the difference in maximal flow at 50 and 75 percent of the forced vital capacity — breathing air and breathing a helium-oxygen (HeQ2) mixture (AVimaxson and AV75«), and (b) a measurement of the lung volume at which the air and HeO: curves cross, the volume of isoflow (VisoV). Tests already in common use included the volume—time curve (the spirogram) and the MEFV curve breathing air. The measurements obtained from standard tests that were thought to be sensitive to mild airflow obstruction are (a) from the spirogram, the forced expiratory flow between 75 and 85 percent of the forced vital capacity (FEF 75-850); and (b) from the MEFV curve: maximal flow at 50 and 75 percent of the forced vital capacity, Vmax 50% and Wmax 75%. The important question of structure-function correlation in tests of small airways function has received much attention over the past 5 years, and has been addressed via a series of attempts to correlate physiologic tests with the actual structural changes observed in lobes or lungs obtained at thoracotomy or post mortem. Fulmer and coworkers (1977) correlated measurements of dynamic compliance with measurements of small airway diameter obtained from lung biopsies in patients with idiopathic pulmonary fibrosis. These investigators demonstrated a highly significant correlation between dynamic compliance and an overall] estimate of small airways diameter. Cosio and coworkers (1978) and Berend et al. (1979) did pulmonary function tests before lung resection and correlated the function tests with morphologic abnormalities that divided the subjects into four groups based on increasing degree of pathologic change. They found that an index of overall histologic small airways disease could be related to CC/TLC, VisoV, and the slope of the alveolar plateau of the single breath No» test (Figure 1); inflammation, fibrosis, and Squamous metaplasia were the most important lesions. The impor- tant conclusions that can be drawn from this study are that abnormalities of both spirometry and the special tests of small airways function are associated with structural changes in the peripheral airways, and that inflammation is the most important cause of obstruction to flow in small airways dysfunction. Berend and coworkers (1979) noted a significant relationship between narrowing of the peripheral airways and CV/VC and FEF %575%. In contrast to the study of Cosio et al. (1978), the slope of the alveolar plateau did not correlate with peripheral airway narrowing, and the volume of isoflow was essentially useless because of its high variability. They found that the FEV, was also related to peripheral airway narrowing. Berend (1982) has recently provided new information by reanalysis and expansion of his earlier study. In measurements of small and 23 Smoking index FEV,/FVC MMF RV cig/yr percent predicted percent predicted 10 120 200 “lect I eat 07 ie 7 | “r 06 ° 40 100 | 200 O5 4k a 20 A 4 cc Viso¥ AN2/L AVmaxso o wo ea 4 roi 200 * os eo | i 300 a 400 120 190 s 300 160 - 80 r 200 140 l 200 60 I 120 I 100 I 1ooF T 20 ef 100 a dos Oh 1 4 | Percent predicted tol wow I oW Wl wv iow WoW 1 wom wv Pathology groups FIGURE 1.—Comparison of increasing small airways disease (Groups I to IV) to smoking index and various pulmonary function tests, by mean + S.E. *P <0.05. **P <0.01. SOURCE: Cosio et al. (1978). TABLE 1.—Correlation coefficients (r) between morphologic variables and tests of pulmonary function Slope FEV, MMFR V0 Ri phase ITI CV/VC Ti CO Bronchiolar diameter 0.28 0.37 0.48' = 0.36 —0.06 —0.03 0.20 Total path score —0.39 -0.42' —0.48! 0.03 0.22 0.30 _ Inflammation score —0.557 -046' -0.41 0.17 0.61? 0.50! _ Reid index -050' -041 -0.34 0.31 0.06 0.07 = ~—0.37 Emphysema 0.33 -0.45' -0.43 0.28 0.45 0.19 -0.72 'P<0.06. *P<0.01. *P<0.001. large airway lesions, he found that inflammation correlates best with the slope of the alveolar plateau, FEV:, CV/VC, and the FEF 25-75% (Table 1). Petty and coworkers (1981) studied a younger group of subjects (average age, 32) who came to autopsy. They found that inflamma- 24 tion and increased muscle in the small airways correlate with CC/TLC and that the slope of the alveolar plateau correlates with inflammation, increased muscle in the small airways, and increased intraluminal cells and mucus. Berend and Thurlbeck (1982) obtained volume-pressure and MEFYV curves with air and HeOzin 25 excised human lungs obtained at autopsy from nonhospitalized patients (age 57, +13 years) who died suddenly from nonrespiratory causes. The emphysema grade was measured, and the total pathological score was determined from four variables: inflammation, smooth muscle hyperplasia, fibrosis, and pigmentation. Correlations were then made between the mea- surements obtained from the MEFV curves with air and HeQ2 and the morphology. A significant correlation was obtained between maximal flow (Vmax) and the inflammation score, fibrosis score, and emphysema grade. Small airways dimensions correlated poorly with Vinax 75% and Vinax 50%, and VisoV showed no significant correlation with any small airways measurement or score. Cosio and coworkers (1980) have also studied lungs obtained at autopsy, but did not attempt to provide structure—function correla- tion. They examined the lungs of smokers and nonsmokers and showed that structural changes in the small airways are more severe in smokers than in nonsmokers, with the main lesions being inflammation, goblet cell metaplasia, and hypertrophied muscle. In smokers, all the airways less than 2 mm were about equally involved. This study used slightly older subjects than an earlier study by the same investigators. In the earlier study, goblet cell metaplasia, increased smooth muscle, and airway narrowing were not observed, suggesting that perhaps these lesions are a later stage in the evolution of the response to injury in the small airways. In another study of lungs obtained at autopsy, Salmon and coworkers (1982) correlated morphologic measurements of the cen- tral and peripheral airways and the alveolar surface-to-volume ratio with the slope of the alveolar plateau measured in the lung post mortem. They found a significant inverse correlation between the slope of the alveolar plateau and the peripheral airway diameter, but no significant relationship between the slope of the alveolar plateau and the alveolar-to-surface volume ratio, once age had been con- trolled. They concluded from these findings that the slope of the alveolar plateau does indeed assess the properties of the peripheral airways. Mink and Wood (1980) performed physiologic studies on the lungs of six men (average age, 66 years) who died of atherosclerotic heart disease. Morphometrics were performed on one lung of each of two of the subjects. The physiologic studies involved ventilating a lung through a main-stem bronchus in a volume displacement plethysmo- graph with two catheters placed to record pressure: one in the lower 25 lobe to measure lateral bronchial pressure and the other within the plethysmograph to record pleural surface pressure. MEFV curves were obtained in lungs ventilated with either air or a HeO2 mixture. They found that an abnormal response to breathing HeQ: is not necessarily indicative of either airway or parenchymal disease, and concluded that the ability of the HeOs breathing to discriminate between normal and obstructed peripheral airways is affected by large between-subject variation in normal maximal flow, which is probably due to normal variation in the caliber of the central airways. They therefore questioned the use of MEFV curves breath- ing air and HeQ:2 as a means of distinguishing between peripheral and central airflow obstruction or as a means of identifying mild airflow obstruction due to structural changes in the small airways. A similar conclusion was reached by MacNee and coworkers (1983). These structure-function correlation studies have provided fairly convincing evidence that at least some of the tests purported to measure small airways function can indeed identify structural changes in the small airways. These changes appear initially to involve macrophage accumulation around respiratory bronchioles, with subsequent development of epithelial abnormalities in the terminal bronchioles. With cumulative injury over a long period, chronic inflammation leads to fibrosis and perhaps to an increase in the amount of smooth muscle. These are strictly airway lesions. The alveolar wall destruction of emphysema is not as clearly related to the tests of small airways function (Petty et al. 1981). Acute Response to Cigarette Smoke Before the tests of small airways function were introduced in the late sixties and early seventies, it was established that smoking a cigarette results in an immediate increase in airway resistance and a decrease in expiratory flow (Attinger et al. 1958; Chiang and Wang 1970; Clarke et al. 1970; Nadel and Comroe 1961; Robertson et al. 1969; Simonsson 1962; Zamel et al. 1963; Sterling 1967). It was thought that this response is mediated by the vagus nerve, and may be suppressed by isoproterenol and atropine (Nadel and Comroe 1961; Sterling 1967; Zamel et al. 1963). Using the MEF'V curve and closing volume, Da Silva and Hamosh (1973) showed a decrease in the maximum expiratory flow at 50 percent of the vital capacity, with the MEFV curve assuming a concave shape in 21 subjects immediately following cigarette smok- ing. Sobol et al. (1977) found the greatest change following smoking in airway resistance and specific conductance, with significant but lesser changes in the l-second forced expiratory volume (FEV)), the forced expiratory flow over the middle half of the forced vital capacity (FEF 25-75%), and the ratio of FEV: to the forced vital capacity (FVC), FEVi/FVC. Neither study found a change in closing volume. 26 From this limited information, it can be reasonably concluded that the large airways, rather than the small airways, respoud acutoly ta the inhalation of cigarette smoke. Chronic Response to Cigarette Smoke In the late 1800s, Mendelssohn (1897) repurted that srnoking had: deleterious effect on the respiratory system. The ea) Iv stud hampered by the lack of sensitive physiologic tests of lung function and relied heavily on differences between smokers and nonsmokers in the prevalence of respiratory symptoms. Confirmation of the structural basis of excessive respiratory symptoms seen in the smokers came from the classic paper by Reid in 1954, in whicl, she described the pathology of chronic bronchitis (Reid 1954). Ventilato- ry limitation usually occurs late in the course of COLD. In centrost. the inflammatory response of the small airways is demane:- i ts relatively early in life in cigarette smokers. es were Smoking and Tests of Small Airways Function in Poprthation Studies A large number of studies using tests of small airways functicn have been conducted over the past 15 years in groups and popula- tions of various sizes, ages, and other characteristics. In some of these studies, the investigators have developed their own normal test ranges from a group of asymptomatic nonsmokers, but the normal ranges obtained by others (Buist and Ross 1973a, b:; McCarthy et al. 1972; Collins et al. 1973) have been more commonly used. In one of the earliest reported studies using the single breath Ne test, Buist and coworkers (Buist and Ross 1973b; Buist et al. 1973) examined 1,073 persons attending a screening center, of whom 524 were current cigarette smokers. Among the smokers, an abnormal CV/VC was found in 35 percent, an abnormal CC/TLC in 44 percent, and an abnormal slope of the alveolar plateau in 47 percent. When the three measurements obtained from the single breath Nz test were taken in conjunction, 64 percent of the smokers and 61 percent of the ex-smokers had an abnormal test result. In contrast, only 11 percent of the smokers had an abnormal FEV and 21 percent had an abnormal FEF2575%. This study suggested that the prevalence of measurable small airways dysfunction among cigarette smokers exceeds 50 percent. It must be kept in mind, however, that this study was carried out in a screening center and was therefore presumably biased toward a high disease prevalence. A collaborative study was conducted in three North American cities (Montreal and Winnipeg, Canada, and Portland, Oregon)(Buist et al. 1979a) to avoid the pitfall of using a biased volunteer population. Random population samples were used in two of the 27 cities and a random sample of a working population in the third. Only people aged 25 to 54 were studied. Among the nonsmokers in each of the three cities, the age-related regressions for the single breath Ne variables (CV/VC, CC/TLC, and the slope of the alveolar plateau) and for FEV:/FVC had very similar slopes. As a result, a combined set of reference values was derived and used for compari- son with the smokers and ex-smokers. No single test consistently showed the greatest prevalence of abnormality among the three cities. The slope of the alveolar plateau was abnormal most often in the women who smoked, and the CC/TLC was abnormal most often in the men who smoked. However, the prevalence of abnormalities was considerably lower than that reported in the screening center population study described above. Among the smokers for the three cities combined, CV/VC was abnormal in 17 percent of the men and in 26 percent of the women, CC/TLC was abnormal in 32 percent of the men and in 29 percent of the women, and the slope of the alveolar plateau was abnormal in 13 percent of the men and in 37 percent of the women. In comparison, the FEV:/FVC ratio was abnormal in 7 percent of the men who smoked and in 25 percent of the women who smoked. In another large-scale study, Knudson and Lebowitz (1977) used the single breath Nz test in a random, stratified, cluster sample of 1,900 white, non-Mexican-American residents of Tucson, Arizona. These investigators established their own reference values from the asymptomatic nonsmokers, and then compared their smokers to the reference values. Figure 2 reveals the prevalence of an abnormal test result in three groups: normals, asymptomatic smokers, and symp- tomatic subjects (a group comprised largely of smokers). For the V max 75% and slope of phase III as well as for combined parameters of the MEF'V curve and single breath Ne test, asymptomatic smokers had approximately twice the prevalence of abnormal test results compared with the normal nonsmoking population. When the analysis was limited to the population aged 25 to 54, the results were even more striking. Of the asymptomatic smokers, 21.5 percent had an abnormal Vmax 75%, and 33.9 percent had some abnormality on either the single breath Netest or the MEFV curve. Manfreda and coworkers (1978) studied population samples strati- fied by sex, age, and smoking habits from a rural community (Portage la Prairie) and an urban community (Charleswood) in Manitoba. They tested 246 persons in Portage la Prairie and 256 subjects in Charleswood. Reference values for asymptomatic non- smokers were established for the single breath Ne test variables and for FEVi/FVC and RV/TLC. In both communities, the slope of the alveolar plateau was abnormal! (more than 2 SD from the mean) more often in smokers than in nonsmokers in both sexes (Figure 3). 28 1 | Normal subjects EZ} 1! Asymptomatic smokers 35 4 [24 1 Symptomatic subjects 3 30 4 Cc 8 26 & & & 204 a § € 155 5 a © 3 4 = 10 D oO 5 a 54 V+Vmaxrs Slope FEV, CV/VO% Phase fi! FEV,/FVG CC/TLO% (Nz) V¥4+Vmaxso Phase lil V4 V¥ max7s (Na) Single sensitive test Combined parameters FIGURE 2.—The relative sensitivity in three adult groups of a single sensitive test and of combined measurements for maximal expiratory flow volume (MEFV) versus closing volume (CV) NOTE: I = normal; II = asymptomatic smokers; III = symptomatic subjects SOURCE: Knudson and Lebowitz (1977). Detels and coworkers (1979) studied population samples in two California communities, one being exposed to photochemi- cal/oxidant pollutants (3,465 subjects). They used the single breath N2 test, but measured the change in Ne concentration between 750 and 1,250 cm? of expired air (ANovs0-1250) rather than the more traditional way of looking at the slope of the alveolar plateau. They found that the mean values for ANo750-1250) and CV/VC were consistently higher for smokers than for nonsmokers. Tockman and coworkers (1976) studied two groups of subjects selected from the Baltimore metropolitan area and not known to have disease. One group consisted of neighborhood control subjects participating in an epidemiologic study of obstructive pulmonary disease, and the other consisted of teachers in the Baltimore public schools who volunteered for a study of health and disease. Of the 133 subjects studied, 78 were smokers and 55 were nonsmokers. The investigators analyzed their data in a slightly different way from the approach used in the studies described above, in that they looked for differences between the age-related regression equations for the various tests in smokers and nonsmokers. They found significant differences between the adjusted mean smoker and nonsmoker 29 : EE] Portage ia Prairie d © charleswood Bercentad PY%TLO CV % VCE CC%TLE Slope ltl FEV, %FVC FiGURE 3.—Prevalence of lung function abnormalities among smokers in an urban and a rural community SOUCRL EB: Monfreda et at L978 values, but no differences associated with age for CC/TLC, the slope of the alveolar plateau, RV/TLC, the steady state diffusing capacity, and the number of respiratory symptoms. Differences between smoker and nonsmoker mean values and an increasing difference between smokers and nonsmokers with increasing age were found for the FEV., FEF 25-75%, Vmax 50, and moment analysis. The research- ers suggest that the first group of tests may measure an all-or-none response that occurs relatively soon after the onset of smoking and is not affected by duration of smoking, and that the second group of tests may measure the effect of continued smoking, thus reflecting the increasing abnormality associated with longer exposure. This theory should be tested as part of an evaluation of the predictive vaiue of small airways function. Nemery and coworkers (1981) used the single breath N> test and MEF'V curves to study a group of 272 European blue-collar workers, aged 45 to 55, from a steel plant near Brussels, Belgium. They first abtained reference values from their asymptomatic nonsmokers and iefined their limit of normality as the 95th percentile for each of the tests. CC/TLC and the slope of the alveolar plateau had the highest prevalence of abnormality among the smokers (47 and 44 percent, Me respectively), followed by CV/VC% (34 percent), Vinax 75% (33 percent), and Vmax 50% (30 percent). When the indices derived from the single breath Ne test were combined, 60 percent of their smokers had an abnormality in one or more of the measurements obtained from the test, whereas 52 percent had an abnormality in one or more measurements obtained from the forced expiratory maneuver. They pointed out that combining the measurements obtained from a test increases its sensitivity but decreases its specificity. In addition to the studies described above, which involved fairly large population groups, numerous studies have been carried out in smaller groups (McCarthy et al. 1972; Stanescu et al 1973; Gelb and Zamel 1973; Cochrane et al. 1974; Abboud and Morton 1975; Marcq and Minette 1976). These studies have also found the measurements obtained from the single breath N2 test and MEFV curve to be abnormal more often among smokers than among nonsmokers. There have been very few published studies using MEFV curves with air and HeO: in reasonably large population groups. This is probably because the test is more difficult to perform than the single breath Nz test or the forced expiration maneuver, and because of the wide range of within-individual and between-individual variability associated with these tests. Lam and coworkers (1981) obtained spirometry and MEFV curves with air and HeQ: in 423 subjects participating in epidemiologic health surveys in British Columbia. The subjects consisted of four groups: nonsmokers and smokers not exposed to air pollutants at work, and nonsmoking and smoking grain elevator workers. Reference values were established from the 78 healthy, asymptomatic nonsmokers who were not exposed to any air pollutant at work. They found that in the subjects not exposed to air pollutants at work, Vinexs0 was the best test for discriminating the effects of cigarette smoking, but AWmax so and VisoV were not significantly different between the smokers and the nonsmokers. Interestingly, the FEV: was the best discriminator of the effect. of grain dust, and there was poor concordance among the FEVi, Vmax 50 and AVmaxso, and VisoV, They concluded that a comparison of MEFV curves breathing air and HeQ; is less helpful than the standard MEF'V curves in distinguishing the effects of smoking and the effects of exposure to an air pollutant. A careful evaluation of moment analysis in a reasonably large population group of adults has not been published. The limited information in the literature comes from studies of small groups of children (Neuberger et al. 1976; Liang et al. 1979; MacFie et al. 1979) and adults (Permutt and Menkes 1979; MacFie et al. 1979). These preliminary studies look promising, but a more extensive evaluation of the technique in carefully chosen population groups must be carried out before conclusions are reached on the value of this approach. Moment analysis is particularly sensitive to changes in 31 the terminal part of the forced expiratory spirogram, which is particularly sensitive to an artifact in the MEFV curve when volume is measured by a spirometer at the mouth rather than by plethys- mography. This artifact relates to the fact that there are volume changes due to gas compression that are measured by plethysmogra- phy but not by a spirometer at the mouth. The appropriate method to measure volume in moment analysis is by plethysmography, but very few such measurements have been made, most measurements having been made by spirometry. The magnitude of the resulting error has not been assessed. In summary, the prevalence of abnormalities observed in any group of smokers depends on the age and characteristics of the group (how they were selected), on the reference values used (external reference values or reference values obtained from the population under study), and the cutoff used to define abnormality. However, this prevalence is uniformly higher in smoking than in nonsmoking populations. In a randomly selected sample of the general population below age 55, at least a third (and usually more) of the smokers can be classified as having small airways dysfunction. Dose-Response Relationship Between Amount Smoked and Small Airways Dysfunction In general, population-based studies involving adults of all ages with a reasonable range of cigarette consumption consistently show a fairly strong dose-response relationship between the number of cigarettes smoked and the degree of impairment. Burrows and coworkers (1977a), studying a randomly stratified cluster sample of Tucson, Arizona, households comprised of 2,360 white, non-Mexican-American adults over age 14, found a highly significant quantitative relationship between pack-years of smoking and functional impairment, as measured by Vmax 75%, FEV: percent predicted, and FEV:/FVC percent. The shift in the mean FEV: percent predicted and the distribution of the FEV: percent predicted with increasing cigarette consumption is illustrated in Figure 4. Buist and coworkers found a positive correlation between total cigarette consumption and the frequency of abnormalities in tests of small airways function in 524 smokers attending an emphysema screening center. However, tests of significance were not reported in the description of the relationship between pack-years and CV/VC and CC/TLC (Buist et al. 1973). Tests of significance were reported in the description of the relationship between the slope of the alveolar plateau and cigarette consumption (Buist and Ross 1973b); no clear relationship between daily cigarette consumption and an abnormal slope of the alveolar plateau was found. Among women who smoked more than 20 cigarettes a day, however, the prevalence of an abnormal slope of the alveolar plateau was significantly increased; 32 -1S.D. Mean +18.D. 0 pack-years (945) 2 0-20 pack-years (578) 20 of 0 Cc & 3 f 3 21-40 pack-years (277) 20 4 3 | o 0-4 [| g pT < 0 8 41-60 pack-years (/59) 4 3 a 2-4 ma 0-4 61+ pack-years (700) 4 2044 “Lot 0 40 60 80 100 120 140 160 Percent predicted FEV, FIGURE 4.—Percentage distribution of predicted forced expiratory volume in 1-second (FEV;) values in subjects with varying pack-years of smoking * Subjects with "respiratory trouble” before age 16 are excluded. NOTE: Means, medians, and +1 standard deviation of the data for each group are shown in the abscissae. SOURCE: Burrows et al. (1977a). among men, a significant increase was found only for those who smoked more than 40 cigarettes a day. Somewhat similar conclusions were reached by Tockman and coworkers (1976) in their study of healthy Baltimore residents. These investigators found that the CC/TLC, the slope of the alveolar plateau, RV/TLC, the steady state diffusing capacity, and respira- tory symptoms were significantly different between smokers and nonsmokers, but there were no significant age-related differences for these variables. In contrast, tests of forced expiration (FEV:/FVC, Vmax 50, and moment analysis) showed both differences between smokers and nonsmokers and increasing smoker versus nonsmoker differences with increasing age. These investigators interpreted their findings as suggesting that the tests of small airways function measure an all-or-none response that occurs at the onset of smoking but is not affected by duration of smoking. They proposed that the 33 measurements obtained from a forced expiration maneuver probably measure the effects of continued smoking and reflect increasing abnormality associated with longer duration of smoking. In their study of population samples in Manitoba, Manfreda and coworkers (1978) found a significant relationship between the current number of cigarettes smoked per day and the slope of the alveolar plateau and CC/TLC in both sexes and RV/TLC in women. These investigators found that an index of lifetime exposure to smoke had no effect after accounting for the effect of current smoking. Among all the lung function measurements, smoking status accounted for the largest proportion of variance due to the three smoking variables (smoker versus nonsmoker, number of cigarettes smoked per day, and lifetime amount smoked). They interpreted this finding as suggesting that responses on these lung function tests are related more to whether one does or does not smoke than to the amounts smoked. Buist and coworkers, in the three-city collaborative study de- scribed earlier (Buist et al. 1979a), considered the effect of smoking in two ways, first by means of multiple regression analysis using age and cigarette-years data from both smokers and nonsmokers. Using the pooled data from the three cities, they found that cigarette consumption had a significant effect on the CC/TLC, CV/VC, the slope of the alveolar plateau, and FEV:/FVC (only in women). In this analysis, the effect of aging was considerably greater than the effect of smoking. The second approach involved data only from smokers, and a linear regression of the percentage of the predicted value for each variable on cigarette-years was obtained. A significant regres- sion occurred in only one-third of the city/sex groups, and in each case the regression coefficients were very small. They concluded that a dose effect was not apparent when smokers only were considered, using both cigarettes per day and years smoked as indicators of cigarette consumption. They interpreted these findings similarly to Manfreda and coworkers (1978): it could be smoking itself and not the quantity of cigarettes smoked that is the crucial factor in the development of early functional impairment. The researchers sug- gest that absence of a clear-cut dose-response relationship in this study may also have resulted from the limited age range (25 to 54 years) and the relatively few heavy smokers in the study. They also speculate that the single breath Nztest variables, especially the slope of the alveolar plateau, may be so “sensitive” that they reflect an on- off effect of smoking rather than cumulative damage. Dosman and coworkers (1976) looked for a dose-response relation- ship in 49 smokers, aged 28 to 67, of whom 60 percent were attending a smoking cessation clinic. They found a significant relationship between a smoking index (cigarettes per day x years smoked) and VisoV and Vinax so. They did not find a significant relationship 34 between symptoms and frequency dependence of compliance, CC/TLC, the slope of the alveolar plateau, or Vmax 50 (Figure 5). Beck and coworkers (1981, 1982), in a cross-sectional study of three communities (Lebanon and Ansonia, Connecticut, and Winnsboro, South Carolina) sought a dose-response relationship in 1,209 smok- ers. Dividing the sample into light smokers (1 to 20 cigarettes/day) and heavy smokers (>20 cigarettes/day), they found a trend of increasing dysfunction across smoking categories that was evident as early as age group 15 to 24 for both men and women. A difference between men and women occurred in terms of the relationship between residual lung function (observed—predicted FEV) and pack- years of smoking. In male smokers, the combination of number of cigarettes smoked per day and duration of smoking was the best indicator of loss in lung function, as measured by residual lung function (FEV:, Vinax sow, and Wiss). For women smokers, pack-years best explained lung function loss as measured by residual lung function. These investigators thus found a very definite dose—re- sponse relationship between the amount smoked and lung function loss. They do point out, however, that smoking variables and age accounted only for up to 15 percent of the variation in residual lung function. In summary, the data suggest a dose-response relationship between number of cigarettes smoked per day and the prevalence of abnormal results on tests of small airways function. That is, heavy smokers are more likely to have abnormal small airways function than light smokers. However, there is only a weak relationship between the degree of abnormality in small airways function and the number of cigarettes smoked per day or pack-years of smoking. In contrast, tests obtained from the forced expiration maneuver have a stronger dose-response relationship. This is consistent with the theory that cigarette smoking induces an inflammatory response in the small airways and that. this response is more likely to happen in heavy smokers, as measured by sensitive measures of small airways function such as the single breath nitrogen test. The extent of chronic airway disease that reflects the dose and duration of the smoking habit is better measured by changes in the forced expirato- ry maneuver. How Soon Do Changes in Small Airway Function Occur? The first study to look at the prevalence of abnormalities on tests of small airways function by age in a large group of smokers was reported by Buist and coworkers (1973a). These investigators found that abnormalities of small airways function could be detected before age 30 by means of the single breath No test, with CV/VC discriminating best between smokers and nonsmokers in the age decade of the twenties (Figure 6). 35 160 7 . A . 120 ; . : Cdyn « 100 ; } , . ns Cst 7 ' I t : (908PM) 80 fF § . ° 1 40 + i ah. 4. 4 L . . . 300 » 8 PF a, . . . 3 as Visov 200 F ! 8 ft i Percent predicted . Q i ° e 100 - 7 . 2 e . ‘ . 0 4 1 4 4 2 120 r . c AV maxso 80 t . : i j ' Percent preuicted : . ns 40 F ° . * j 3 : > . : : 0 4. in. in. a 4. Q 1 2 3 4 Symptoms score 500 - o Slope phase ill 400 F . Percent predicted 300 . e . ns 200 F t ’ i ‘ : 100 + 1 r } 3 ‘ 0 i i i 4 de. 180 fF . E 160 F CC 140 F : : . ns Percent predicted 429 - : § 3 J ’ 100 : ° ! : : a0 i 4 iL ale, 4 F 150 [ . 7 ‘ . 28 . . = V maxso 100 F 1 ‘ - 2 : : p< .05 Percent predicted ‘ & 1 . © FG he 50 J- . § . 0 1 1 i 1 0 1 2 3 4 Symptoms score FIGURE 5.—A composite of six tests plotted against symptoms score SOURCE: Dosman et al. (1976). 36 [J 284 Nonsmokers EE) 524 Smokers 80 TT 1 Py 268 Ex-smokers e 60 & 4 L 46 E 43 - 43 44 5 40- os fas 4 5 Th bd 36 ° m Bo or be o E ne “ 20 + aps pope 18 L ae os 4 : ap ops of 0°00 é Se is ne on 0 N= 7 3. 43° 20 30 26 3v §1 63 80 66 64 32 21.4113 7 81 94 126 143 65 14 <20 20-29 30-39 40-49 50-59 60-69 70-79 +80 Age (years) FIGURE 6.—Prevalence of abnormal closing volume/ vital capacity ratios in nonsmokers, smokers, and ex-smokers, by age decade SOURCE: Buist et al. (1973). In their cross-sectional survey of residents in three separate communities in Connecticut and South Carolina, Beck and cowork- ers (1981, 1982) found that the age of onset of abnormalities in lung function may occur as early as age 15 to 24. Their approach used residual lung function (observed-predicted value) for FEV, Vinax 50%, and Vmax 75%, With a negative residual indicating an observed value below prediction. Negative residuals for all three measurements began to occur in women in the age group 15 to 24 (Figure 7). Significant differences among smoking categories—nonsmokers, ex- smokers, light smokers (1 to 20 cigarettes/day), and heavy smokers (>20 cigarettes/day)—were seen for Vmax sox and Vmax 735% in women aged 15 to 24 and for FEV: in age group 25 to 34 (Figure 8). In male smokers, negative residuals began to occur for all three measure- ments in the age 25 to 34 group. Significant differences among the smoking categories were seen for FEV: in the 35 to 44 age group and for Vex sox and Vmax 75% in the 45 to 54 age group. Seely and coworkers (1971) found lower values for Vmax sox and Vinx 75% in a group of high school students with 1 to 5 years of smoking experience. These differences were significant in boys who smoked more than 15 cigarettes per day and in girls who smoked more than 10 cigarettes per day. Significant differences between the smokers and nonsmokers were not found for FEV}. Dosman and coworkers (1981) studied 1,202 adults, aged 25 to 59, living in Humboldt, Saskatchewan. Among smokers in the 25 to 29 37 Oe 01 0 _~ ~O1 eg s = 02 lu Le “93 0.4 -0.5 06 Age 7-14 15-24 Women (n =2,623) L. CI Nonsmokers EE3 Ex-smokers i. Light smokers (1-20 cigarettes/day) ei Heavy smokers (.- 20 cigarettes/day) _ ° No observations 25-34 35-44 45-54 55-64 654 DAAAAAAAAAAAN BAA AAA AASAAAAAN PLATS AAA FIGURE 7.—Mean residual FEV: in women, by smoking status and age SOURCE: Beck et al, (1981) 0.2 0.1 QO 0.1 0.2 0.3 r FEV, (liters} 05 -0.6 0.7 O08 0.4 ba be ha 5 = 5 r Le 3 3 a A he A 4 2 7 g A 4 1 8 s e KH A kad a ’ 4 , 4 g s A 3 g s oe g g @ eH A He Men (n = 2,067) 3 3 2 g s CC) Nonsmokers Cs g Ca) €x-smokers Z GB Light smokers (1-20 cigarettes/day) Z 1M ea Age 7-14 15-24 25-34 35-44 45-54 55-64 65+ Heavy smokers ( > 20 cigarettes/day) No observations FIGURE 8.-—-Mean residual FEV: in men, by smoking status and age SOURCE: Beck et al. (2981). age group, 14.9 percent of the women and 18.5 percent of the men had an abnormal test value for the slope of the alveolar plateau, for CV/VC, or for both. Comparable rates of abnormality for FEVi/FVC 38 were 2.1 percent in women and 5.6 percent in men. For both the slope of the alveolar plateau and CV/ VC, the prevalence of abnormal test value increased steadily with increasing age, so that 63.6 percent of the female smokers aged 55 to 59 and 46.2 percent of the male smokers aged 55 to 59 had abnormal values. Comparable rates for an abnormal FEV:/FVC were 4.5 and 19.2 percent in the women and men, respectively. Walter and coworkers (1979) studied 102 Indian male medical students in their late teens and early twenties. Of the 102 subjects, 60 were nonsmokers, 23 were light smokers (lifetime total of < 10,000 cigarettes), and 19 were heavy smokers (lifetime total of >10,000 cigarettes). The researchers compared mean pulmonary function values obtained from the. spirograms across the smoking categories. There was a consistent trend for all the lung function variables examined (FEF 20-30%, FEF 35-65%, FEF 020%, FEF 80-90%, FEF 25-75%, and FEV:/FVC),with the highest mean values being seen in the nonsmokers, intermediate values in the light smokers, and the lowest values in the heavy smokers. There were no significant differences among the three groups in height and weight. No information was given in this report about the type of cigarettes smoked. The consistency of results from the studies attempting to define the age of onset of measurable abnormalities in tests of small airways function is striking. Even though statistical significance was not always found, the trend is clear and provides strong evidence that measurable abnormalities of small airways function do occur in some smokers within a few years of smoking onset. Male-Female Differences in the Responses of the Small Airways to Cigarette Smoking When looking at variations between the sexes in response to cigarette smoking, one must take into account possible differences in the manner in which cigarettes are smoked, in the amount smoked, and in environmental exposures that may interact with smoking. Most investigators have found little or no difference based on sex for the relationship between the various tests of small airways function and age in nonsmokers. Thus, a difference between the sexes in response to smoking, if it exists, probably represents a true biological difference in the effect of smoking on lung function or variations in exposure dose resulting from method of smoking or amount smoked. Unfortunately, the information available in the literature about sex-related differences in small airways response to cigarette smok- ing is scanty and conflicting. Manfreda and coworkers (1978) found a higher prevalence of abnormality in tests of small airways function among male smokers than among female smokers in their study of two communities in Manitoba. The opposite finding has been 39 reported by Buist and coworkers (Buist and Ross 1973a, b; Buist et al. 1973, 1979a) in their studies of a screening center population and of population samples and groups in Montreal, Winnipeg, and Port- land. It is quite possible that selection bias in the screening center study limits the ability to extrapolate this study to the general population. The three-cities study, however, did not suffer from that flaw, and showed clear differences (women higher than men) in the prevalence of abnormalities of CV/VC and the slope of the alveolar plateau. The prevalence of abnormality of CC/TLC, on the other hand, was slightly higher in male smokers than in female smokers (32 and 29 percent, respectively). A surprising finding was that the prevalence of FEV:/FVC abnormality was considerably higher among women who smoked than among men who smoked (25 and 7 percent, respectively). At this point, a generalization is not yet possible on sex-related differences in the response of the small airways to cigarette smoking. However, it seems likely that the contribution of sex difference is relatively small once age and dose are taken into account. Effect of Smoking Cessation on Small Airway Function The correlation between abnormalities in tests of small airway function and the pathologic changes of inflammation of the small airways suggests that cessation of smoking may lead to a return toward normal in these tests. A number of authors have examined changes in tests of small airways function in cigarette smokers who have quit. Ingram and O’Cain (1971) examined six smokers with an abnormal frequency dependence of compliance who quit smoking. After 1 to 8 weeks of cessation, values in all six returned to the normal range. Bode et al. (1975) examined 10 subjects aged 29 to 61 with normal FEV: values while they were active smokers and again 6 to 14 months after they had stopped smoking. Static volume pressure curves, slope of phase III, and forced expiratory flow rates on air were unchanged by cessation. However, the maximum expiratory flow rates with helium at 50 and 25 percent of the vital capacity increased, and the volume of isoflow and closing volume decreased. McCarthy et al. (1976) followed 131 smokers aged 17 to 66 who volunteered to attend a smoking cessation clinic. Cessation resulted in a significant reduction in the closing capacity (CC/TLC%) and the slope of phase III within 25 to 48 weeks in the 15 persons who were able to abstain from cigarettes completely. Buist et al. (1976) followed a group of 25 cigarette smokers who attended a smoking cessation clinic and found that cessation resulted in significant improvements in the closing volume (CV/VC%), closing capacity (CC/TLC%), and the slope of the alveolar plateau (phase IID at 6 and 12 months following cessation. 40 cvsvc CC/TLC AN,/L Percent predicted Quitters —77* Smokers Months after clinic FIGURE 9.—Mean values for the ratio of closing volume to vital capacity (CV/VO), of closing capacity to total lung capacity (CC/TLC), and slope of phase III of the single breath Nz test (ANe/L), expressed as a percentage of predicted value (12, 13) in 15 quitters and 42 smokers, during 30 months after two smoking cessation clinics * A significant difference from the initial value at p< 0.05. NOTE: Data from 3-month followup of the 1973 clinic and 4-month followup of the 1975 clinic have been combined, as have 6-month and 8 month data for the 1973 clinic. SOURCE: Buist et al. (1979a). This study was expanded using a second group of subjects (Buist et al. 1979b) and a 30-month followup. Once again, the three parame- ters of the single breath No test showed improvement in smokers who quit; this improvement continued for 6 to 8 months, and then leveled off (Figure 9). In addition, the values for the single breath Ne test in those who quit returned to the levels predicted for nonsmokers, suggesting that the changes in the small airways can be substantial- ly reversed with cessation. Bake et al. (1977) also showed an improvement in the slope of phase III following cessation in a small group who were followed for 5 months. In summary, abnormalities in the small airways are substantially reversible in smokers who have not developed significant chronic airflow obstruction. This suggests that the inflammatory response in the small airways, which may be the earliest change induced by smoking, is also a change that reverses with the cessation of chronic exposure to the irritants in cigarette smoke. 41 480-144 0 - g5 - 3 Relationship Between Small Airways Disease and Chronic Airflow Obstruction There is no question that the information obtained over the past 15 years from studies of small airways function has helped to describe more accurately the natural history of chronic airflow obstruction. The practical question of the place of tests of small airways function in clinical practice has not yet been resolved, and will not be fully answered until longitudinal studies using the tests have been completed. The important issue to be addressed is whether the tests of small airways function can be be used to identify the smoker who will progress to develop irreversible airflow obstruction. This question can be answered satisfactorily only by following a fairly large group of smokers prospectively over a period of time long enough for some of the smokers to develop an abnormal! FEV:. If the tests of small airways function can be used alone, or in conjunction with other qualitative or quantitative data about risk factors, they will clearly be useful to the practicing physician. If they are too sensitive or have a poor predictive value, their use will be more limited. Buist and coworkers (1984) determined the positive and negative predictive value of tests of small airways function in their study of two cohorts followed prospectively over a 7- to 11-year period. They found that the positive and negative predictive values of the tests of small airways function varied greatly between the cohorts, largely because of the different ages and prevalences of an abnormal FEV; between the cohorts. They concluded that significant associations existed between the single breath Nz test variables and spirometric variables in smokers, but the weakness of these associations and the high misclassification rates suggest that small airways disease does not necessarily lead to clinical airflow obstruction. Over a period of 8 years, Marazzini and coworkers (Marazzini et al. 1977, 1981) followed a group of 69 asymptomatic workers in an iron foundry (49 smokers, 20 nonsmokers) living in the same area. They found that 39 percent of the smokers and 15 percent of the nonsmokers, initially diagnosed as having peripheral airways dis- ease, developed central airways obstruction (defined as 1 or more of the vital capacity (VC), FEV: or FEV.i/VC being more than 15 percent different from normal) within the 8-year followup. An indirect way to assess the predictive value of the tests of small airways function was proposed by Tattersall and coworkers (1978). These investigators proposed that any valid test of chronic airflow obstruction must yield results that are systematically worse in middle-aged smokers than in middle-aged nonsmokers, and that such a test should also correlate with the FEV: in middle-aged smokers. Using these criteria in a cross-sectional study of a sample of working 42 men in West London, they concluded that the most informative and repeatable tests were Vmax 75% and the slope of the alveolar plateau. Nemery and coworkers (1981) addressed the question of the significance of tests of small airways function in their study of 2,072 blue-collar workers, aged 45 to 55, from a steel plant near Brussels. They found that smokers with an abnormal CC/TLC or slope of the alveolar plateau and a normal FEVi/FVC had a significantly lower FEV:/(height)’ than subjects with normal CC/TLC and slope of the alveolar plateau. They interpret their data as suggesting that smokers with small airways dysfunction experience a more rapid decline in FEV: than smokers without small airways dysfunction, leading to a higher susceptibility to long-term smoking effects in the former group. The opposite conclusion was reached by Fletcher (1976), wh» examined the relationship between CV/VC, the slope of the alveolar plateau, and FEV in 200 male smokers aged 40 to 55. In this group, he found a relatively poor correlation between FEV; and the single breath Ne variables. There is thus, as yet, inadequate information to allow a firm conclusion to be drawn about the predictive value of the tests of small airways function in identifying the susceptible smoker who is going to progress toward clinical airflow obstruction. The tests of small airways function are probably abnormal for many years before the FEV: becomes abnormal in those smokers who go on to develop airflow obstruction. However, many smokers with abnormal tests of small airways function may never develop clinically significant airflow obstruction. Therefore, functional changes in the small airways may not always be related to the widespread alveolar destruction seen in smokers or to the development of clinical airflow obstruction. It may be that varying degrees of inflammation and fibrosis occur in virtually all smokers, and that there is something very different about the smokers who develop extensive airway or emphysematous changes. Summary A number of tests have been developed that can identify small airways dysfunction in individuals with normal lung volumes and standard measures of forced expiratory airflow. These tests correlate well with the presence of pathologic changes in the airways 2 mm or less in diameter, particularly with peribronchiolar inflammation. Cigarette smokers have a significantly higher frequency of abnormal tests of small airways function. Heavy smokers have a greater prevalence of small airways dysfunction than light smokers, but there is only a weak dose-response relationship between numbers of cigarettes smoked per day or duration of smoking and the extent of small airways dysfunction. This suggests that the response of the 43 small airways may be an “all or nothing” inflammatory response to cigarette smoke irritants rather than a progressive response repre- senting a cumulative injury. Cessation of cigarette smoking results in significant improvement in small airways function, which in those smokers without evidence of chronic airflow obstruction, may return to normal. The relationship between changes in the small airways and the development of chronic airflow obstruction remains unclear. It seems likely that those smokers who will go on to develop ventilatory limitation will have abnormal small airways function before the FEV: becomes abnormal, but many smokers with small airways dysfunction may never progress to significant airflow obstruction. Therefore, the usefulness of tests of small airways function for identifying those who will develop ventilatory limitation remains to be established. 44 CHRONIC MUCUS HYPERSECRETION Introduction The association of cigarette smoking and chronic cough was recognized by the general public in the term “smokers cough” well before the demonstration of this association in epidemiologic studies. Cough is the symptom most frequently experienced by smokers, and it is often accompanied by excess mucus secretion resulting in phlegm production or a “productive” cough. Chronic bronchitis was defined by the Ciba Foundation Guest Symposium report (1959) as “the condition of subjects with chronic or recurrent excess mucus secretion into the bronchial tree.” The position was taken that any production of sputum was abnormal, and chronic was defined as “occurring on most days for at least 3 months of the year for at least 2 successive years.” Also, the sputum production could not be on the basis of specific diseases such as tuberculosis, bronchiectasis, or lung cancer. Measurement of Cough and Phlegm in Epidemiologic Studies The increasing use of standardized questionnaires in interviews to ascertain the presence of cough, phlegm, or other symptoms of respiratory disease has improved the quality of measurements of prevalence and incidence of these symptoms and the validity of comparisons within and between studies. Similar attention has been given to developing questions about smoking habits, including questions about the type and number of cigarettes used at the time of interview and in the past. The first British Medical Research Council (BMRC) questionnaire published in 1960 (Medical Research Council 1960) had been tested, revised, modified, and extended, and many studies have resulted from its widespread use. However, difficulties in using this questionnaire in epidemiological studies of populations in the United States and the desire to collect additional information led to modification in individual studies and to a loss of comparabili- ty between studies. This motivated the American Thoracic Society and the Division of Lung Diseases of the National Heart, Lung, and Blood Institute to establish the Epidemiology Standardization Project. Extensive methodological studies were done, standardized questionnaires were developed, and techniques for measuring pulmo- nary function and evaluating chest radiographs were proposed (Ferris 1978). Samet (1978) has reviewed the history of the develop- ment of respiratory symptom questionnaires. Although many inves- tigators now use the methods advocated by the BMRC or the Epidemiology Standardization Project, several of the studies re- viewed in this chapter of the Report are based on other, nonstandard questionnaires. A comparison between studies of different popula- 45 tions, or the same population studied at different times, must be made cautiously and only after careful consideration of technical and methodological issues. Low rates of participation and use of unrepresentative samples may cause biased estimates of the frequen- cy and distribution of symptoms. Attitudes toward smoking have changed, and comparisons of questionnaire responses and objective measurements of smoking habits indicate that at least in some situations, less reliance can now be placed on answers to questions about smoking habits (MRFIT Research Group 1982). Estimates of prevalence and incidence of respiratory symptoms are imprecise, and too much importance should not be attached to relatively small differences in rates of reporting cough and phlegm. Each author’s criteria for detecting the presence of cough or phlegm should be considered, especially when combinations of symptoms or diagnostic labels such as chronic bronchitis or mucus hypersecretion are used. Notwithstanding methodological differences, however, consistent patterns or trends found in many studies indicate that the associa- tions between smoking and chronic mucus hypersecretion are real and that the findings are widely applicable. Prevalence of Cough and Phlegm Unpublished data from the National Center for Health Statistics estimate that there were almost 8 million persons with chronic bronchitis in the United States in 1981 (3.4 million men, 4.5 million women). This is probably an underestimate of the true frequency of cough and phlegm in the population, since people who had these symptoms were not counted as chronic bronchitics unless they responded affirmatively to the question about bronchitis. On the other hand, some cases of acute bronchitis may have been included incorrectly and inflated the estimate. The apparently higher preva- lence rates of chronic bronchitis in women than in men in the National Health Interview Surveys in 1970 and 1979 (3.4 and 3.7 percent for women in 1970 and 1979, respectively, and 3.1 and 3.2 percent for men in 1970 and 1979) are probably due to ascertainment being less complete for men (USDHEW 1980b). Prevalence rates of chronic bronchitis ranged from 4.2 percent at ages under 17 years to 2.7 percent at 17 to 44 years, 3.6 percent at 45 to 64, and 4.5 percent at ages over 65 years. The high rate in the youngest group is presumably because of the inclusion of cases of acute bronchitis. Standard questions about chronic cough were asked in the National Health and Nutrition Examination Surveys (NHANES) of representative samples of the U.S. population. Some supplementary questions were asked about phlegm and other respiratory symptoms, and these data are presented in the appendix to this chapter. Prevalence rates of diagnosed chronic cough in 18- to 74-year-old participants in NHANES 1 (1971-1975) were 3 percent for men and 2 . 46 40 [ | Women 3h.t 30-4 Percent Never Former Current Light Moderate Heavy Smoked Smoker Smoker Smoker Smoker Smoker FIGURE 10.—Percentage of recurring persistent cough attacks by sex and smoking status for adults 25-74, United States, 1971-1975 NOTE: Light smoker: 1~14 cigarettes per day Moderate smoker: 15-24 Cigarettes per day Heavy smoker: > 25 cigarettes per day SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey NHANES |) percent for women; they increased with age from 1 percent at 18 to 24 years to 6 percent at 65 to 74 years for men, and from 1 percent at 18 to 24 years to 3 percent at 65 to 74 years for women (National Center for Health Statistics, unpublished data). The prevalence of self-reported recurring persistent cough by smoking status for men and women of different ages is presented in the appendix and in Figure 10 based on NHANES 1. For the entire NHANES population, the prevalence of the persistent cough in- creased threefold in male smokers and twofold in female smokers compared with nonsmokers (Figure 10), and the prevalence of cough increased with increasing cigarette consumption in both men and women. Relationship of Cough and Phlegm to Smoking Relationships between smoking and cough or phlegm are strong and consistent; they have been amply documented and are judged to be causal (USPHS 1964, 1971; USDHEW 1979: USDHHS 1980a, 1981). Associations between smoking and cough or sputum are apparent in the recent studies listed in Tables 2 and 3 and are illustrated in Figures 11 and 12. Although cough, phlegm, and 47 chronic bronchitis occur in nonsmokers, prevalence rates are consis- tently higher in cigarette smokers. The excess prevalence of cough and phlegm in cigarette smokers increases with the amount smoked (see below). The frequency of reporting cough and phlegm is at least twice as high for smokers as for nonsmokers except in some groups with minimal exposure. Differences in prevalence rates between smokers and nonsmokers tend to be greater at older ages among men, whereas differences in rates between smoking and nonsmoking women tend to be as great or greater at younger ages (Tables 2 and 3). Rates are not given for pipe or cigar smokers in most of these studies, presumably because the numbers of such smokers were too small for reliable rates; male pipe smokers and cigar smokers in Tecumseh reported cough and phlegm more frequently than nonsmokers or ex-smokers, but less frequently than cigarette smokers (Higgins et al. 1977). Individual studies have evaluated other factors as well as smoking, but smoking has been judged the most important determinant of symptom prevalence (Fletcher et al. 1976; Ferris et al. 1976; Kiernan et al. 1976; Bouhuys 1977; Higgins et al. 1977). Consideration of evidence from many different studies has led to the conclusion that cigarette smoking is the overwhelmingly most important cause of cough, sputum, chronic bronchitis, and mucus hypersecretion (Speiz- er and Tager 1979; USDHHS 1980b). Effects of Smoking Cessation Cross-sectional information on ex-smokers suggests that stopping smoking is followed by a reduction in cough and phlegm because symptoms are less prevalent than in current smokers, but these symptoms are generally mere prevalent in ex-smokers than in lifelong nonsmokers (Huhti et al. 1978; Guisvik 1979; Park 1981; Schenker et al. 1982). However, the differences between ex-smokers and nonsmokers were either very small or absent in the studies reported by Higgins et al. (1977) and Manfreda et al. (1978). The longitudinal studies cited in Table 3 strengthen the evidence from cross-sectional studies that cigarette smoking causes cough and phlegm. Prevalence rates were higher at followup examinations in persons who started to smoke after being nonsmokers at a previous examination (Kiernan et al. 1976; Leeder et al. 1977). Rates of reporting cough or phlegm decreased in smokers who stopped smoking in two British studies (Kiernan et al. 1976; Leeder et al. 1977) and in populations in the United States (Ferris et al. 1976; Friedman et al. 1980; Beck et al. 1982). Many people who stop smoking report a rapid reduction in cough and phlegm. Although remission of symptoms occurs in some persistent smokers, remission rates are generally higher and incidence rates lower in those who quit than in those who continue to smoke. 48 6h TABLE 2.—Prevalence (percent) of cough, phlegm, and other symptoms for nonsmokers (NS), smokers (SM), and ex-smokers (EX), cross-sectional studies Author, year, country Population Cough Phlegm Other Comments Tager and 507 residents, Chronic bronchitis Chronic bronchitis (cough and Speizer, aged 15-65+, Men Phlegm >3 mos/yr for 2 years); 1976, U.S. East Boston NS 7.0 no age trend for either sex after SM (pack-years) adjusting for smoking; prevalence 1-5 8.7 greater for men than women at 5-10 25.0 each age; significant increase in 10-20 28.6 chronic bronchitis with increased >20 47.5 lifetime cigarette consumption for current smokers, but not Women ex-smokers NS 46 SM (pack-years) 1-5 143 5-10 91 10-20 20.8 >20 30.0 og TABLE 2.—Continued Author, year, country Population Cough Phlegm Other Comments Dean et al., 6,277 men and Morning cough Bronchitis syndrome Bronchitis syndrome (cough and 1978 6,459 women, Men phiegm 3 mos/yr, shortness of United Kingdom aged 37-67, NS 12.5 NS 11.4 NS 3.5 breath); significant increase of all England, SM (filter) SM (filter) SM (filter) symptoms with age; prevalence of Scotland, and 1-7 19.6 144 5.1 cough, phlegm, and wheeze Wales 8-12 32.8 20.8 86 increased with number of 13-17 36.3 25.4 9.4 cigarettes smoked; filter vs. 18-22 44.0 26.9 85 nonfilter cigarette effects 23-27 50.6 34.2 10 small, nonsignificant for most 28-32 56.8 34.5 8.7 symptoms 334 §2.1 28.4 13.8 Women NS 98 NS 75 NS 25 SM (filter) SM (filter) SM (filter) 1-7 16.9 13.8 3.8 8-12 25.8 16.6 42 13-17 29.6 16.6 5.1 18-22 45.1 25.8 10.6 23+ 56.6 34.3 12.0 Tg TABLE 2.—Continued Author, year, country Population Cough Phlegm Other Comments Higgins et al., 4,699 men and Chronic bronchitis Chronic bronchitis (cough and 1977, women, aged Men phlegm >3 mo/yr); chronic US. 20-74, Tecumseh NS 5.1 bronchitis increased with age EX 26 for male smokers; no age trend 5M apparent for male or female <20/day 13.4 nonsmokers; dose-response > 20/day 29.9 relationship between chronic Pipe/cigar 8.4 bronchitis and cigarette smoking (age adjusted) Women NS 35 EX 47 SM < 20/day 48 > 20/day 15.3 as TABLE 2.—Continued Author, year, country Population Cough Phlegm Other Comments Lebowitz and 2,857 men and Chronic cough and/or phlegm Male prevalence consistently Burrows, women, aged 14-96, Men greater than female only in older 1977, US. Tucaon NS 10.3 age groups; frequency of SM (pack years) symptoms increased with age; <6 29.0 impossible to distinquish effects 6-20 35.8 of aging and increased duration 21-40 47.9 of smoking 41+ 61.1 Women NS 12.1 SM (pack-years) <6 21.0 6-20 33.1 21-40 40.5 41+ 60.4 &¢ TABLE 2.—Continued Author, year, country Population Cough Phlegm Other Comments Bland et al., 6,320 first-year Morning cough Breathlessness No questions on phlegm; child’s 1978, secondary school Boys Boys smoking habits more important Great Britain children, NS 3.1 NS 12 than parents’ smoking habits; Derbyshire SM once 29 SM once 14 Parents’ smoking habits Occas. 4.0 Occas. 22 independently related to most 1 per wk. 19.2 1 per wk 35 symptom frequencies for boys and girls Girls Girls NS 18 NS 7 SM once 45 SM once 22 Occas. 6.0 Occas. 29 1 per wk. 13.5 lperwk. 40 Cough at other times Boys NS 20 SM once 27 Occas, 34 1 per wk. 47 Girls NS 19 SM once 30 Occas. 35 1 per wk. 47 ¥S TABLE 2.—Continued Author, year, country Population Cough Phlegm Other Comments Huhti et al., 1,162 men, All day in winter All day in winter Chronic bronchitis For total group, significant 1978, aged 25-65, Age NS NS Age NS increase with age of cough, Finland Hankasalmi 25-39 2 5 25-39 9 phlegm, and severe breathlese- 40-49 2 2 40-49 2 ness; for nonsmokers, signficant 50-59 5 8 50-59 15 increase with age for phlegm 60-69 4 7 60-69 19 and breathlessness only Age EX EX EX 25-39 = 11 25-39 11 40-49 - 10 40-49 14 50-59 4 8 50-59 ll 60-69 12 18 60-69 28 Age SM SM SM 1-14 g/day 26-39 9 14 25-39 29 40-49 19 29 40-49 39 50-59 19 24 50-59 31 60-69 30 7 60-69 39 SM 15-24 g/day 25-39 13 40-49 45 50-59 46 60-69 46 SM >25 g/day 25-39 50 40-49 63 50-59 57 60-69 53 g¢ TABLE 2.—Continued Author, year, country Population Cough Phlegm Other Comments Manfreda et al., 273 men and 229 Most days >3 mo/yr Most days >3 mo/yr Wheeze apart from colds No consistent difference in 1978 women, aged Men symptom prevalence for two Canada 24-55, two CH* PLP* CH PLP CH PLP communities; higher prevalence communities NS 8.3 4.0 NS _ 4.0 NS 4.2 8.0 of cough, phlegm, and wheeze in Manitoba EX 8.1 29 EX 108 5.7 EX 108 14.3 among smokers than SM 25.4 31.5 SM 169 247 SM 268 31.5 nonsmokers or ex-smokers; * CH=Charleswood Women ** PLP=Portage la Prairie NS — 40 NS — 4.0 NS 35 8.0 Ex — 10.0 EX — 5.0 EX 121 20.0 SM 203 31.7 SM 102 26.4 SM 254 302 TABLE 2.—Continued Author, year, country Population Cough Phlegm Other Comments Rawbone et al., 10,498 secondary A little most days With colds Frequent colds * EXPER (ex-emokers and 1978, echool children, Age NS NS NS experimental smokers combined); Great Britain aged 11-17, li 64 22.8 36.0 sex differences not significant; Hounslow 13 16.7 25.3 32.3 nonstandard questions; higher 15 13.4 24.5 34.3 symptom prevalence in younger EXPER * EXPER EXPER children not explained 11 20.5 32.3 42.2 13 173 31.2 36.1 15 11.3 29.6 36.3 SM SM SM ll 24.3 56.1 51.1 13 25.9 49.6 50.4 15 27.4 53.6 39.8 A little every day NS 11 13 13 42 15 47 EXPER 11 70 13 47 15 3.5 SM 11 29.2 13 17.8 15 13.4 Lg TABLE 2.—Continued Author, year, country Population Cough Phiegm Other Comments Bouhuys et al., 7,203 residents, Usual cough Smoking significantly associated 1979, aged 7-65+, LE* AN** WIt with cough, phlegm, wheeze, and US. three communities Men dyspnea; prevalence increased NS 8 100 15 significantly with age, slightly SM 27 324 higher in urban community; Women women had lower prevalence of NS 7 12 9 phlegm and higher prevalence of SM 13 17 uw dyspnea than men * LE= Lebanon ** AN= Ansonia t WI = Winnsboro Burghard et. al., 29,138 students, Morning Breathlessness Prevalence of symptoms increased 1979, aged 14-18, NS 13.7 NS 14.1 with increasing cigarette France Bas-Rhin Department SM 25.7 SM 22.2 consumption; girls had higher Day or night prevalence of respiratory NS 16.9 symptoms for each smoking SM 29.1 category Chronic NS 2.7 SM 6.6 g¢ TABLE 2.—Continued Author, year, country Population Cough Phlegm Other Comments Gulsvik, 19,988 people, Morning cough When coughing Cough and phlegm periods Cough and phlegm increased more 1979, aged 15-70, NS ll NS 10 NS 6 with age for smokers (10-19 Norway Oslo EX 15 EX 18 EX 8 cig/day) than nonsmokers; no SM 36 SM 28 SM 16 significant relationship between Daytime cough age and prevalence of periods of NS 4 cough and/or phlegm; EX 7 dose-response relationship SM 16 between number of cigarettes and ugh 3 mos/yr symptoms reported; data not NS 3 given EX 5 SM 14 Liard et al., 899 men and women, Men Respiratory symptoms (cough and/or 1980, aged 20-60+, NS 16.0 phlegm 3 mos/yr. for 2 years); not a France (av. 39), Paris SM 25.4 random sample; male and female Women smokers had similar symptom NS 8.1 prevalence; female nonsmokers had SM 26.5 lower prevalence 6¢ TABLE 2.—Continued Author, year, country Population Cough Phlegm Other Comments Park, 856 university Morning Morning Breathlessness on exertion Symptom prevalences apparently 1981, men and women, NS 16.0 NS 20.1 NS 23.2 not age-adjusted; significance Korea aged 18-29, EX 31.3 EX 22.9 EX 25.0 levels not reported; nonstand- Seoul SM 34.0 SM 26.1 SM 29.7 ard questions; symptoms current Daytime Daytime NS 42 NS 2.1 EX 83 EX 146 SM 109 SM 12.0 Nightime Nightime NS 13.5 NS 73 EX 18.8 EX 10.4 SM 19.9 SM 13.2 Neukirch et al., 2,266 secondary Usual cough and/or phlegm 21.8% of boys, 32.2% of girls 1982, school students, Boys were current smokers; girl France aged < 11->18 NS 26.1 smbdkers had higher symptom (mean 14.9), SM 34.9 prevalence than boys if total Paris Girls lifetime cigarettes > 4,000; results NS 26.9 probably not age adjusted SM 44.7 Schenker et al., 5,686 women, Chronic cough Chronic phlegm Wheeze most days or nights Cough and phlegm most strongly 1982, aged 17-74 (mean NS 5.6 NS 45 NS 7.2 related to current cigarettes/day: US. 44.6), western EX 75 EX 6.7 EX 8.3 tar content had independent Pennsylvania, SM SM SM effects; age effect seen for telephone interviews 1-14 91 1~14 72 1-14 14.4 nonsmokers, but not current 15-24 17.0 15-24 16.7 15-24 18.5 smokers; symptom 25+ 31.8 25+ 24.8 254 28.0 prevalences age adjusted TABLE 3.—Prevalence (percent of cough, phlegm, and other symptoms for nonsmokers (NS), smokers (SM), and ex-smokers (EX), longitudinal studies Author, year, country Population Smoking habits Symptoms Comments Ferris et al., 1,201 men and Cough Phiegm 72.3% of men, 78.4% of 1976, women, aged 25-74 1973 1967 1973 1967 1973 women followed up; 1973, US. in 1961, Berlin Men symptom prevalences, age New Hampshire NS 6.0 85 89 76 adjusted to compare with 1967, EX 20.5 9.7 23.3 159 showed little change SM 1-14 22.2 25.5 17.9 275 15-24 35.4 26.5 31.8 30.0 25-34 26.1 25.7 33.8 32.4 35+ 50.6 56.4 37.1 519 Women . NS 44 - 6.2 81 14 EX 3.2 5.2 73 10.1 SM 1-14 10.7 10.0 11.6 98 15-24 19.5 16.3 218 98 25-34 27.2 16.1 22.5 218 35+ 44.7 31.0 43.1 41.2 Kiernan et al., 2,738 men and Cough day or night in winter Effects of chest illness before age 1976, women, aged 25, born 1966 1971 1966 1971 2, father’s vocation, and current Great Britain in 1946, exams in NS NS 55 49 smoking significant; air pollution 1966 and 1971 NS SM 72 9.6° effect not significant; current SM SM 143 18.5* smoking had largest effects SM EX 9.2 5.8 * Prevalence, 1966 vs. 1972, p <0.05 TABLE 3.—Continued Author, year, country Population Smoking habits Symptoms Comments Leeder et al., 2,130 fathers, Cough/phlegm prevalence range In male ex-smokers, prevalence 1977, mean age 31.0+6.1, Men of cough/phlegm decreased Great Britain 2,148 mothers, 1st period 2nd _ period Ist 3-yr period 2nd 3-yr period over time; no significant mean age 27.9+5.3, NS NS 8.6-9.6 9.2-11.1 change in prevalence in female children born NS SM 48-16.9 13.3-20.5 ex-smokers, but numbers 1963-1965, SM SM 25.6-30.2 30.8-34.0 were small London, 6 year SM EX 21.8-25.3 §.8-20.7 followup Women NS NS 49- 68 5.8 7.3 NS SM 8.2-10.2 13.3-18.4 SM SM 16.3-22.4 23.0-28.4 SM EX 4.1-22.5 12.2-14.3 Woolf and Zamel, 302 women, aged Cough and/or phlegm Breathlessness 60% followed up; all subjects 1980, 25-54 at initial Ist exam Final exam lst exam Final exam maintained consistent smoking Canada atudy, 5-year NS 10 14 10 5 habits for 5 years followup EX 3 13 18 8 SM 56 54 25 21 69 TABLE 3.—Continued Author, year, country Population Smoking habits Symptoms Comments Beck et al., 1,262 white Usual cough Usual phlegm 55% followed up; health indices 1982, residents, aged 7-55+, 1972 1978 1972 1978 1972 1978 of respondents and non- US. Lebanon, Connect- Men respondents similar; symptom icut, exams in NS NS 5 2 7 3 prevalence tended to decline, but 1972 and 1978 NS SM 0 0 0 4 few changes were significant, SM SM 23 21 22 26 * Prevalence, 1972 vs. 1978, SM EX 25 2° 18 8 p <05 EX EX 7 6 12 15 Women NS NS 7 4 5 6 NS SM 0 0 0 9 SM SM 20 14 15 ll SM EX 28 12 8 EX EX 10 4 1 Ex-smokers urrently 1-20/day 60+ C] Never smoked Pp a 3 Currently > 20/day 45-59 Women 30-44 15-29 Age 85 + BO 4 75 70 4 65 + 60 55 50 4 45 yp 40 35+ 30 ah 25 > 20 + 1S 104 S+ QO Men 3044 15-29 Age [ 85 5 80 4 75 4 70 + 60 + rg o ° Lrg 2 e w 2 Lr > we = y ¢ “= NN N = = Percent prevalence 65 + FIGURE 11.—Prevalence of chronic cough and/or chronic sputum among samples of men and women in Tucson, Arizona SOURCE: Lebowitz and Burrows (1977). Dose-Response Relationships The most common measures of dose are the number of cigarettes currently smoked per day and the pack-years of cigarette consump- tion; the latter estimates lifetime exposure by integrating the number of cigarettes smoked (by pack) and the duration of cigarette use. Errors of memory compromise the accuracy of retrospective information, which may also be biased by differential recall in those 63 50.0 = >20 10-19 400 ~ Smokers Cigarettes/day o 1-9 Ss 300-4 5 5 € 2 200 =£ a e Ex-smokers 10.0 —4 © Nonsmokers 0.0 T | t 18-23 24-27 28-32 233 Tar (mg/cigarette) FIGURE 12.—Percentage of smokers with phlegm production (adjusted for age), according to tar yield of cigarettes SOURCE: Higenbottam et al. (1980). with and without smoking-related symptoms or diseases. Even accurate reports of current smoking habits fail to take into account all the sources of variation in exposure associated with the material used in cigarette manufacture or generated in the burning of cigarettes. The dose of noxious materials received is also influenced by human behavior, including the number, volume, and timing of puffs taken with each cigarette; retention of smoke in the mouth; depth of inhalation; disposition of the cigarette between puffs; and other aspects of smoking style that are not reproduced by the smoking-machines used to measure tar and nicotine yield. Prevalence rates of cough or phlegm, or both, generally increase as the number of cigarettes smoked per day increases. The trends illustrated in Figures 11 and 12 were present in both sexes and all age groups (Lebowitz and Burrows 1977; Dean et al. 1978; Higgins et al. 1977; Huhti et al. 1978; Higenbottam et al. 1980; Schenker et al. 1982), Bland et al. (1978) found a dose-response relationship in secondary school children, among whom rates of reporting cough were higher in those who smoked most, even though levels of cigarette consumption were generally reported to be low. At the other extreme of the age range the trend is also apparent, even though symptomatic smokers are more likely than asymptomatic smokers to stop smoking or to reduce their cigarette consumption 64 (Higgins 1974; Fletcher 1976). Symptoms were more prevalent among heavier smokers of filter cigarettes as well as of nonfilter cigarettes (Dean et al. 1971). Prevalence rates of cough, phlegm, chronic bronchitis, and mucus hypersecretion show a similar pattern of association with pack-years of exposure (Tager and Speizer 1976; Lebowitz and Burrows 1977). Rates of incidence and remission observed in longitudinal studies add further support to the strong evidence that respiratory symptoms increase as exposure to cigarette smoke increases (Table 3). In their study of more than 18,000 male civil servants in London, Higenbottam and colleagues (1980) found that the percentage of smokers who produced phlegm increased with increased daily cigarette consumption and also with increasing tar content of cigarettes among those who smoked less than 20 cigarettes a day. Symptoms were prevalent about equally among smokers of 20 or more cigarettes per day, regardless of the tar yield of the brands they used (Figure 12). Schenker et al. (1982) reported the relationship of tar content of cigarettes to respiratory symptoms in a cross-sectional telephone survey of 5,686 adult women in rural Pennsylvania. The risk of chronic cough and phlegm was more strongly affected by the number of cigarettes smoked per day than by tar content. Cough and phlegm were reported least often by never smokers and with increasing frequency as the number of cigarettes smoked per day increased. Tar content of cigarettes was significantly associated with symptoms of chronic cough and phlegm—especially cough—and its effects were independent of the number of cigarettes smoked per day in a multiple logistic analysis. The risk (relative odds) of chronic cough for smokers of high tar cigarettes (20 or more mg) was approximately twice that for smokers of an equivalent number of low tar cigarettes (10 or less mg). A limitation of this cross-sectional study was the determination of tar content for current cigarettes only, rather than for lifetime smoking habits. Although the apparent relationship between tar content and symptoms could have been caused by changes in smoking habits, this was considered unlikely because symptomatic smokers tend to reduce their consumption of cigarettes more than asymptomatic smokers (Fletcher et al. 1976) and may also switch to low yield cigarettes. In this situation, any reported effect of tar content on symptoms would be an underestimate. In summary, the prevalence of symptoms increases with dose of smoke exposure, when dose is measured by number of cigarettes smoked per day or tar content of the cigarette smoked. Relationship of Cough and Phlegm to Sex and Age Prevalence rates of cough and phlegm ascertained in epidemiologi- cal studies generally increase with age and are higher in men than 65 in women, as shown in Figure 11 and Tables 2 and 3. Rates also vary with smoking habits. Rates in nonsmokers better clarify associations of symptoms with age and sex than do rates in smokers, since they are less confounded by variations in exposure to cigarette smoke. However, recent evidence linking passive smoking with increased prevalence of respiratory symptoms suggests that rates in nonsmok- ers may be in excess of those that would be found in a population compietely free of exposure to cigarette smoke (Lefcoe et al. 1983; Weiss et al. 1983). Rates of reporting cough or phlegm or both were roughly equal in nonsmoking men and women in several cross-sectional studies (Bland et al. 1978; Higgins et al. 1977; Lebowitz and Burrows 1977; Manfreda et al. 1978; Neukirch et al. 1982; Rawbone et al. 1978). Rates were higher in nonsmoking men in some populations (Dean et al. 1977; Liard et al. 1980; Tager and Speizer 1976). Bouhuys et al. (1979) found no sex difference in the prevalence of cough, but a higher rate of reporting phlegm in male nonsmokers (Table 2). In most of these studies, the rates were not corrected for exposures to other respiratory irritants in the workplace or in the general environment. In general, symptoms are more prevalent in male smokers than in female smokers (Table 3). However, differences in prevalence rates between the sexes are generally smaller or absent when comparisons are made between men and women who smoke similar numbers of cigarettes. Lebowitz and Burrows (1977) found that the excess prevalence of symptoms in male smokers compared with female smokers tended to be greatest at older ages, where there are also the greatest differences in smoking behavior. Men in these birth cohorts tend to have begun smoking earlier in life, smoke more cigarettes per day, inhale more deeply, and smoke higher tar and nicotine or unfiltered cigarettes. Two studies from France, Burghard et al. (1979) and Neukirch et al. (1982), concentrated on high school students. In general, the prevalence of smoking was similar for both boys and girls for the two studies, although the Neukirch group found a somewhat higher rate among the girls (46 percent versus 39 percent). Slightly more boys than girls, however, smoked more than 10 cigarettes per day. In these two studies, the prevalence of symptoms was higher among female smokers than among male smokers. These data suggest that the past differences in prevalence of symptoms between the sexes is largely attributable to differences in cigarette consumption. These differences were substantial in the past, and are still present among older adults, whereas current smoking practices are about the same in male and female adoles- cents and young adults. Prevalence rates of cough, phlegm, and chronic bronchitis in- creased with increasing age in the U.S. population samples studied 66 by the National Center for Health Statistics (1981) and in several of the cross-sectional studies cited in Table 2. However, differences in rates of reporting symptoms among people of different ages may relate to effects of aging, differences in current exposures, or differences in exposure to cigarette smoke or other noxious agents in the past. It is therefore difficult or impossible to use cross-sectional data to separate effects of aging from effects of duration, dose, and nature of cigarette smoke exposure throughout life. Longitudinal studies provide information on time trends, both in exposure and in onset and course of disease. Nevertheless, conclusions may be incorrect if people who drop out of longitudinal studies are different from those who continue to participate. Prevalence of symptoms increased with increasing age among men in cross-sectional data from Tucson (Figure 11), but the trend was more apparent among smokers and ex-smokers than among non- smokers. However, Lebowitz and Burrows (1977) could not distin- guish between an association caused by increasing age and an association due to increasing duration of exposure to cigarette smoke in smokers because the two were so highly correlated. Among women, symptoms were reported more frequently at ages 30 to 44 than at ages 15 to 29 (except by ex-smokers), but prevalence rates were essentially the same for the three groups over age 30. Higgins et al. (1977) found that there was no increase in cough and phlegm with increasing age in male or female nonsmokers in Tecumseh (Michigan), whereas prevalence rates increased with increasing age in male smokers. The pattern in female smokers was similar to that in Tucson and showed an increase with age up to age 30 or 40, but rates declined with increasing age after age 50. The extent to which these patterns related to amount smoked or duration of smoking was not reported, but these older birth cohorts of women probably began to smoke later in life and smoked fewer cigarettes per day, according to national smoking survey data. In other cross-sectional studies cited in Table 2, symptom preva- lence increased with age in the populations studied (Bouhuys et al. 1979; Dean et al. 1977; Gulsvik 1979; Huhti et al. 1978; Tager and Speizer 1976), but the trend was noted by Gulsvik to be less in nonsmokers. Huhti et al. found a significant increase with age among nonsmokers for phlegm and dyspnea only. Schenker et al. (1982) observed a trend for nonsmokers but not for smokers, and Tager and Speizer found that adjusting for smoking eliminated the trend with age. Prevalence rates of cough and phlegm on two occasions 3 to 6 years apart are shown in Table 3 for five recent longitudinal studies of populations in the United States, Canada, and Great Britain. Kiernan et al. (1976), Leeder et al. (1977), Woolf and Zamel (1980), and Beck et al. (1982) found little change in the prevalence of 67 symptoms among continuing nonsmokers during the followup inter- val of up to 6 years. The rates among nonsmokers reported by Ferris et al. (1976) are similar on the two occasions, but symptoms were presented by smoking habits at followup only, and any effect of age was deliberately adjusted out because the authors’ purpose was to evaluate effects of changes in smoking, changes in pollution, and trends over time independent of changes in age. Cough and phlegm appeared to be more frequent at followup in the persistent smokers studied by Kiernan et al. (1976) and Leeder et al. (1977), and about the same in women studied by Woolf and Zamel (1980) and in men studied by Beck et al. (1982). However, rates were slightly lower at followup in the female smokers followed by Beck. Even though starting to smoke or quitting can be eliminated as the explanation for increases or decreases in symptom prevalence over the course of these studies, it is possible that changes in the number or type of cigarettes smoked by persistent smokers influenced the prevalence of symptoms. The duration of followup in all these studies was relatively brief, and it is still difficult to distinguish between effects of aging and effects of duration, amount, and nature of exposure to cigarette smoke in smokers, even when major changes in smoking behavior are controlled. However, available data suggest that age itself is not the major factor responsible for differences in the frequency or distribution of symptoms in populations of nonsmokers and smokers. Relationship of Cough and Phlegm to Airflow Obstruction Many cross-sectional studies have found associations between cough, phlegm, chronic bronchitis, or mucus hypersecretion and reduced levels of pulmonary function. The forced expiratory volume at 1 second (FEV) has been measured in most clinical studies and in nearly all epidemiological studies, and mean levels of FEV: are generally slightly lower in groups of people who report respiratory symptoms (USPHS 1964, 1971; USDHEW 1979; USDHHS 1980a, 1981). Recent studies have compared other measures of pulmonary function in people with and without symptoms and have provided longitudinal data on pulmonary function for symptomatic and asymptomatic smokers and nonsmokers. Attention has been given to understanding the natural history of chronic airways obstruction and the interrelationships of respiratory symptoms, levels and rates of decline of pulmonary function, and their independent and interrelated associations with cigarette smoking. Several investiga- tors have emphasized the desirability of identifying in advance those smokers who will develop severe COLD; symptoms and other characteristics have been evaluated as potential predictors of morbidity or mortality from COLD. 68 Fletcher and colleagues ( 1976) found that the age—height standard- ized FEV at the initial survey of their population of working men in London was inversely related to the volume of sputum produced in the first hour after getting up. The regression of FEV; on age, given height, was steeper for symptomatic cigarette smokers than for asymptomatic smokers or nonsmokers. However, the authors cau- tion that men may develop symptoms as they age and change from one regression slope to the other. Burrows et al. (1977a) found that an index of cough or sputum was related to FEV: percent predicted when pack-years of smoking were controlled in a multiple regression analysis. Regressions of FEV, percent predicted on pack-years are shown for people with and without chronic cough and sputum in Figure 13; the intercept at 0 pack-years was lower and the decline in FEV; with increasing pack- years was significantly greater for those with chronic cough and sputum than for those with no cough or sputum. The authors calculated that values of FEV: were lower by about 10 percent in people with cough and sputum, regardless of smoking habits, and that values declined by about 4 percent of predicted for each 10 pack- years of smoking in people with cough and sputum and by about 2 percent in subjects without productive cough. There was a signifi- cant relationship between FEV; and pack-years of smoking in asymptomatic smokers in this population. A weaker relationship between cough and sputum and Vmax was also found to be independent of pack-years of smoking; however, prediction equations for flow rates have been revised substantially (Knudsen 1983), and the extent to which relationships between the revised flow rates and pack-years of smoking differ in symptomatic and asymptomatic subjects has not been reported. Dosman et al. (1976) found poor correlations between respiratory symptoms and dynamic lung compliance, closing volume, closing capacity, slope of phase III, and helium flow-volume curves in a study of 49 smokers and 60 nonsmokers who were recruited from a smoking cessation clinic, a personnel department, and the staff of a laboratory. In their community-based studies of children and adults, Bouhuys and colleagues (1977) studied relationships between respiratory symptoms and loss of lung function in smokers and nonsmokers. They found that residual values (observed-predicted) of FVC, FEV), PEF, MEF ‘sox, and MEF 2% were not significantly different in people with no symptoms or only one symptom when analyses were done separately for adult white male smokers and nonsmokers. When a Symptom score was used to combine information on usual cough, usual phlegm, wheeze, and dyspnea, decrements in lung function were greatest among those with most symptoms. 69 No cough or A sputum (n= 1,492) Total population without chronic cough and chronic sputum (n = 1,803) Percent FEV, 80 =4 70 4 Subjects with chronic cough and chronic 5 sputum (n = 247) 0 v T T T 20 40 60 80 Pack-years Figure 13.—Percentage distribution of predicted forced expiratory volume in 1 second (FEV:) versus pack-year of cigarettes smoked, by cough and sputum history SOURCE: Burrows et al. (1977a). In a study (Detels et al. 1982) designed to assess the relative sensitivity and specificity of symptoms, the flow-volume curve (FV), the single breath nitrogen test (SBNT), and specific airway conduc- tance (Scaw) for identifying COLD were compared with the FEVi/FVC ratio and with one another in 1,201 residents of Los Angeles 25 to 29 years old. The tests were done in 1978-1979 at a followup examination of a previously defined cohort. Prevalence rates of cough and sputum were 9 percent in never smokers, 26 70 percent in current smokers, and 33 percent in smokers of 20 or more cigarettes a day. Prevalence rates of an abnormal FEV:/FVC ratio in these groups were 8, 23, and 33 percent, respectively (the FEV:/FVC ratio was considered abnormal if it was below the 95th percentile for never smokers without a history of respiratory illness). The research- ers found that there was very little overlap between the presence of productive cough and abnormal tests, and that none of the tests of function showed reasonable concordance with this symptom. Lack of reasonable concordance meant that none of the other tests were abnormal in 50 percent or more of the individuals with productive cough. In this study, the FEV:/FVC ratio was used as the standard against which the sensitivities of the other tests were judged; the sensitivity of the FEV:/FVC itself was evaluated by its agreement with those tests found to be sensitive in the study. The lack of an independent method for identifying COLD, the cross-sectional na- ture of these data, and the way in which analyses were done restrict the ability to make biological inferences about the independence of the effects of cigarette smoking that lead to cough and sputum or to chronic airflow limitation. However, the authors note their findings are consistent with the hypothesis that effects of smoking on cough and sputum are independent of effects on airflow limitation. Insights into the course and pathogenesis of COLD have been developed by Fletcher and his colleagues from observations made during their 8-year longitudinal studies of levels and rates of decline in lung function in middle-aged working men in London (Fletcher 1976; Fletcher et al. 1976). These investigators found that various measures of sputum production were correlated with FEV: standard- ized for height and age, and that this correlation was weakened only slightly by adjusting for smoking habits. The researchers maintained that the association between sputum production and pulmonary function could be due entirely to a common causation. Some men with mucus hypersecretion had normal FEV;; conversely, some men with airflow obstruction did not report phlegm. Nevertheless, the relationship between phlegm and reduced FEV: was strong enough to give rise to an estimated reduction in FEV) of about 0.1 liters for every ml of sputum expectorated in the first hour after getting up. However, because decline in FEV; (FEV: slope) was not related to measures of sputum production when level of FEV; and smoking habits were controlled, the researchers concluded that mucus hypersecretion is not a cause of accelerated decline in FEV}. Furthermore, there was no evidence that short-term changes in sputum production were associated with short-term changes in FEV:. The researchers concluded that the association between expectoration and reduced FEV; is caused by the increased suscepti- bility of some people to both expectoration and excessive loss of FEV; when they are exposed to cigarette smoke or, presumably, to 71 other noxious materials. This study has made important contribu- tions to understanding the natural history of chronic bronchitis and emphysema, but the duration of followup was only 8 years, the men were 30 to 59 years of age at the start of the study, and their mean age was 51 years at the midpoint. Similar studies of younger men and women and observations over longer periods of time are needed to extend these findings. Johnston et al. (1976) found that sputum volume was not related to decline in FEV: in a 10-year followup study of chronic bronchitic patients. There was no difference in sputum volume between patients whose FEV: fell by more than 33 percent and controls (matched on initial FEV: ) whose FEV: did not fall. Furthermore, sputum volume was reduced in response to stopping smoking or to antibiotic treatment, whereas rate of decline of FEV: was unaffected. In this and other studies (Higgins et al. 1970; Fletcher et al. 1976; Peto et al. 1983) FEV: was strongly predictive of morbidity and mortality, whereas respiratory symptoms were not. Woolf and Zamel (1980) studied “normal” employed women aged 25 to 54 in a longitudinal study designed to identify smokers at increased risk of developing COLD. Ventilatory function was mea- sured at the beginning and at the end of a 5-year period during which smoking habits and symptoms were ascertained annually. Differences between initial and followup values of pulmonary function tests were expressed as a percentage of the initial value and compared in persistent nonsmokers and persistent smokers who either consistently reported or consistently denied cough or sputum. The decline in FEV:, FEVi/FVC, and FEF275% was greater in symptomatic smokers than in asymptomatic nonsmokers, but not significantly different in asymptomatic smokers compared with either nonsmokers or symptomatic smokers. The average number of cigarettes smoked during the course of the study was greater for smokers with cough and sputum. Change in FEF25-75% was evaluated in individual smokers, and no association was detected between cough and sputum and percentage change in this measure of lung function. The investigators identified one group of smokers whose decline in FEF2s-75%, was similar to that in nonsmoking women and another group with a greater decline; cigarette consumption was similar in the two groups. The investigators concluded that individu- al susceptibility is an important determinant of the effect of cigarette smoking, because some women develop symptoms and others remain symptomless but experience rapid worsening of ventilatory function. However, they noted a tendency for both cough and sputum and rapid worsening of ventilatory function to coexist. The number of women in some groups was very small, and the measure of decline in lung function used by these researchers does not take into account regression to the mean or assess absolute 72 reduction; those with smaller initial values will have greater percentage reductions for a constant absolute reduction in function. Followup studies at 10 and 15 years of the Tecumseh, Michigan, population showed that incidence rates of obstructive airways disease were higher in men and women who reported cough, phlegm, or both symptoms (chronic bronchitis) at entry compared with those who denied these symptoms (Figure 14) (Higgins et al. 1982). Both cough and chronic bronchitis were significant predictors of obstruc- tive airways disease in men even when smoking habits were controlled in multiple logistic analyses. However, respiratory symp- toms were poorer predictors of impaired pulmonary function at followup than were smoking habits and baseline levels of lung function. In a multiple logistic model with age, smoking habits, and level of lung function as risk factors, over 60 percent of the 10-year incidence cases developed among men and women in the top 10 percent of the risk distribution, whereas only 36 percent of incidence cases were in the top decile of risk when cough, rather than FEV, was used as a risk factor (Higgins 1984). Summary Cigarette smoking is associated with respiratory symptoms, in- cluding mucus hypersecretion, and with prevalence and incidence of COLD manifested by irreversibly impaired pulmonary function. While some smokers develop both conditions, and those with cough and phlegm are at increased risk of developing airways obstruction, the conditions can occur separately by mechanisms that are imper- fectly understood but appear to be different. The excess risk of reduced FEV: or COLD in symptomatic smokers compared with asymptomatic smokers may be a reflection of increased susceptibili- ty in some individuals. However, it may also be a measure of increased dose of cigarette smoke, in that smokers who report cough and phlegm tend to smoke more heavily than smokers who deny these symptoms, and measures such as numbers of cigarettes smoked per day are not precise enough to control adequately for the amount of smoke exposure. The rate, number, and volume of puffing as well as the depth of inhalation can vary substantially between smokers and are important additional measures of cigarette smoke exposure dose. 73 4380-144 0 - 85 - 4 a“ g Q Cc re S Oo ~ 2 5 z £ 8 g 6 a t y —€ ¢« ANY i ge 2 c= Coa a = —_—_——_— [ « oO 8 —_— 4. + io OQ uw ° 2 £ Q ¢c e a KX Cc ° £ Oo Phiegm Men Cough 18 107 54 0 incidence of obstructive airways disease (percent) FIGURE 14.—Age-adjusted 15-year incidence of obstructive airways disease, by cough, phlegm, and chronic bronchitis status at entry to the study, Tecumseh, ages 16 to 64, 1962-1979 SOURCE: Higgins et al. (1982) 74 CHRONIC AIRFLOW OBSTRUCTION Introduction Airflow obstruction is the physiological consequence of disease processes that narrow the airway. In asthma the obstruction is reversible with pharmacologic bronchodilation, whereas the obstruc- tion associated with airways damage and emphysema is often not reversible. The terminology with regard to permanent airflow obstruction has varied. The 1958 Ciba Foundation Guest Symposium proposed “generalized obstructive Jung disease,” which was subdivid- ed into “asthma” and “irreversible or persistent obstructive lung disease” (1959); in the 1962 recommendations of the American Thoracic Society, “chronic obstructive bronchitis” was the only definition that mentioned abnormality of expiratory flow (American Thoracic Society 1962). In 1975, a joint committee of the American College of Chest Physicians and the American Thoracic Society recommended the term “chronic obstructive pulmonary disease” ‘American College of Chest Physicians and American Thoracic Society 1975). Thurlbeck (1976, 1977) has advocated the use of “chronic airflow obstruction,” a functionally based definition that does not specify the underlying disease processes. Previous Reports of the Surgeon General have used varying terminology, including “chronic bronchopulmonary disease” in 1964, “chronic obstructive bronchopulmonary disease” in 1971, and “chronic obstructive lung disease” in 1979 (USPHS 1964, 1971; USDHEW 1979). These definitions, however, cannot be readily applied to identify specific populations. Physiologists, epidemiologists, and clinicians often use differing approaches in determining whether airflow obstruction is present (Fletcher 1978). Physiologists, with the capability for making sophisticated laboratory measurements of airflow obstruction, may regard subtle early abnormalities of flow as definitive. In the community, epidemiologists have generally used spirometry as the primary method for assessing airflow obstruction. For epidemiologic purposes, airflow obstruction is usually defined by a forced expiratory volume in 1 second (FEV)) less than a particular level after standardization for sex, age, and height, or by a ratio of the FEV: to the forced vital capacity (FVC) below a specified value. Tests of forced exhalation, such as the FEV 1, have the advantage of sensitivity to abnormalities of both the lung parenchyma and the airways (Mead 1979). Clinicians are more likely to detect and diagnose airflow obstruction when it is advanced and symptomatic. As would be anticipated, the differing approaches of physiologists, epidemiologists, and clinicians may lead to differing estimates of the frequency of airflow obstruction. The natural history of chronic airflow obstruction in adults has been partially described by several recent prospective investigations: n ‘ or Howard (1970), Bates (19733, Sharp et al. (1973), Fletcher et al. (1976), Fletcher and Peto (1977), Bosse et al. (1981), Beck et al. (1982), and Clement and van de Woestijne (1982). Although these investigations did not characterize the course of airflow obstruction across the entire human lifespan, the results provide a conceptual model for considering its development (Figure 15). Ventilatory function, gener- ally measured by the FEVi, increases during childhood and reaches a maximum level during early adulthood (Cotes 1979; Knudson et al. 1983). From this peak; the FEV: gradually and progressively declines with age. In people who develop airflow obstruction, a similar gradual loss of function occurs, but at a more rapid rate (Fletcher et al. 1976; Speizer and Tager 1979). Continued excessive loss of FEV: eventually results in symptomatic airflow obstruction when ventila- tory function reaches a level at which activities are limited and dyspnea occurs. Evaluation by a physician for symptoms may lead to a clinical diagnosis at this point in the natural history of the disease process. This model may not satisfactorily describe the development of airflow obstruction in all individuals (Burrows 1981), but the accumulating evidence, reviewed below, indicates that a sustained excessive loss of ventilatory function most often leads to the development of clinically important chronic airflow obstruction. In the conceptual model (Figure 15), there are three different measures of the frequency of airflow obstruction in a particular population: the prevalence of reduced ventilatory function as measured by the FEV:, the FEV:/FVC ratio, or other physiological parameters; the prevalence of physician-diagnosed airflow obstruc- tion; and the frequency of excessive functional loss in a population followed over time. The first two measures can be determined from a single cross-sectional survey, whereas the third requires longitudinal observation. At present, scant data are available for the third category. The prevalence of physician-confirmed airflow obstruction is determined not only by the proportion of affected people in the population, but also by the patterns of medical care access and usage and the diagnostic practices of individual physicians. Furthermore, the clinical labels applied by physicians to people with airflow obstruction are variable and may include “chronic bronchitis,” “emphysema,” “COLD,” and other terms. Thus, estimates of disease prevalence based on reported physician diagnoses may differ from those derived from physiological assessment. Prevalence of Airflow Obstruction Numerous populations throughout the world have been surveyed to assess the prevalence of airflow obstruction (Stuart-Harris 1968a, 1968b; Higgins 1974). Most often, the investigative techniques have included a respiratory symptoms questionnaire and measurement of pulmonary function, generally with a spirometer or peak flow meter. 76 34 N, A Normal FEV, (ters) SX. \ Xu. 25 35 45 55 65 76 Years FIGURE 15.—Decline of FEV; at normal rate (solid line) and at an accelerated rate (dashed line) NOTE: A: person who has attained a “normal” maximal FEV, during lung growth and development; B: person whose maximal FEV; has been reduced by childhood respiratory infection. SOURCE: Samet et al. (1983), The latter technique has the disadvantage of effort dependence. Early recognition of the potential problem of observer bias led to the development of standardized methods (Cochrane et al. 1951; Higgins 1974; Ferris 1978). Thus, most investigators throughout the world have used the British Medical Research Council questionnaire in the original form or with some modifications (Samet 1978). Standardiza- tion has been less uniform for lung function measurements, but minor variations in procedures would not introduce important differences in disease prevalence among the various populations examined. Although many different populations have been surveyed since the 1950s, surprisingly few published reports provide data concern- ing the prevalence of airflow obstruction in the general population 77 (Tables 4 and 5). Comparisons among the available studies are limited by varying methodologies and inconsistent approaches in calculating rates. For example, only crude rates are available in some reports, and reference populations for age standardization also vary. The investigations summarized in Tables 4 and 5 were selected because they offer estimates of the prevalence of airflow obstruction in defined community-based samples. Those reports that describe mean levels of lung function parameters but not their distributions were excluded. Investigations of specific occupational groups were also excluded because prevalence estimates based on such popula- tions may be biased by the overrepresentation of healthy persons (Monson 1980) and workplace exposures may have affected the frequency of disease. For the United States, the available information spans the time period 1961 to 1979 and covers most geographic regions (Table 4). Regardless of the definition, it is apparent that airflow obstruction is common among aduits in the United States. A higher proportion of men than women is affected, and the prevalence increases with age (Ferris and Anderson 1962; USPHS 1973; Lebowitz et al. 1975; Detels et al. 1979; Samet et al. 1982). Few minority populations have been studied. In New Mexico, Hispanic whites had a lower prevalence of physician-diagnosed current chronic bronchitis or emphysema than non-Hispanic whites (Samet et al. 1982). Although blacks have been included in several surveys (Bouhuys et al. 1979), prevalence estimates for this racial group have not been published. The available data (Table 4) do not permit a satisfactory assessment of changes in prevalence rates with time over the years 1961 to 1979. The National Health and Nutrition Examination Surveys (NHANES 1) included spirometry in their evaluation of a represen- tative sample of the U.S. population. The numerical values for these measures are reported by age, sex, and smoking status for the white population in the tables in the appendix to this chapter. The changes in mean values of these measures between age groups are also presented for white male and female smokers and nonsmokers in Figures 16 through 23. Differences between smokers and nonsmok- ers are evident for each of these spirometric measures. These differences are portrayed for successive age groups at one point in time, and therefore cannot be used to describe the changes with age or smoking status that one would expect in an individual or copulation followed sequentially. These data represent only those people in the study population who were willing and physically able to maximally exert themselves on the various spirometry tests. Others were disqualified by the examining physician because of existing medical conditions. The sampling nonresponse was higher among segments of tne population expected to perform less well on the test. including necple with existing airflow limitation. Therefore, TABLE 4.—Prevalence of indices of airflow obstruction in selected U.S. adult populations Author, year of study, location, reference Number and type of population Index Prevalence (per 100) Higgins and Kjelaberg, 1959-1960, Tecumseh, Michigan (1967) 4,500 men and women, 20 years or older, community sample Emphysema based on physician history and examination Higgins, 1962-1979, Tecumseh, Michigan (1983) 4,916, 4,443, and 4,930 men and women, 16 to 74 years old, in 1962-65, 1967-69, 1978-79 Obstructive airways disease: FEV, less than 65% predicted, and FEV,/FVC ratio less than 80% Ferris and Anderson, 1961, Berlin, New Hampehire (1962) 1,167 men and women, community sample Irreversible obstructive lung disease, including wheezing, dyspnea, or FEV,/FVC ratio less than 60% Mueller et al., 1967, Glen- wood Springs, Colorado (1971) US. Public Health Service, 1970, United States (1973) 609 men and women, community sample 116,000 men and women, nationwide sample Chronic airway obstruction: FEV,/FVC ratio less than 60% Presence of the condition during the previous year Men 4.1! Women Li! Men Women 1962-65 48? 25? 1967-69 3.7? 14? 197& 79 3.7? 2.2? Men 8.6! Women Blt Men 13.2! Women 1.5) Chronic bronchitis Men 3.1! Women 3.4! Emphysema Men 1.0! Women 0.3 TABLE 4.—Continued Author, year of study, location, reference Number and type of population Index Prevalence (per 100) Lebowitz et al., 1972-1973, Tucson, Arizona (1975) 3,805 men and women, adults and children, community sample Physician-confirmed illness, current Men over 44 years Knudson et al., 1972-1973, Tucson, Arizona (1976) 3,805 men and women, adults and children, community sample FEV, and FEV,/FVC ratio lower than 95th percentile for “normal” Detels et al., 1973-1974, Burbank and Lancaster, California (1979) 3,465 and 4,509 men and women, in Burbank and Lancaster, respectively, community samples FEV, less than 50% of predicted value Tager et al., 1973-1974, East Boston, Massachusetts (1978) 1,770 men and women, community sample of index subjects and their relatives FEV, less than 65% of predicted Ferris et al., 1974-1977, six cities in the US. (1979) 7,909 men and women, community sampie FEV,/FVC less than, equal to 60% Chronic bronchitis 10.2 Emphysema 13.3! Women over 44 years Chronic bronchitis 9.0! Emphysema 4.3! Asymptomatic cigarette smokers FEV, 78° FEV,/FVC 8.1! Lancaster 18-59 yrs 0.8? 60 yrs 6.5° Burbank 18-59 yrs 1.0? 60 yrs 6.2? Men 56! Women 3.47 Men 5.0' Women 19° T8 TABLE 4.—Continued Author, year of study, location, reference Number and type of population Index Prevalence (per 100) Non-Hispanic whites Samet et al., 1978-1979, 1,722 men and women, Physician-diagnosed current Men 3.6? Albuquerque, New Mexico community sample chronic bronchitis or Women 3.4 (1982) emphysema Hispanic whites Men 0.8? Women 1.8? ‘Crude rate. ” Age-adjusted rate. * Age and sex-adjusted rate. os TABLE 5.—Prevalence of indices of airflow obstruction in selected adult non-U.S. populations Author, year of study, location, reference Number and type of population Index Prevalence (per 100) Anderson et al., 1963, Chilliwack, British Columbia (1965) 558 men and women, community sample Obstructive lung disease, including wheezing, dyspnea, or FEV,/FVC ratio less than 60% FEV,/FVC ratio less than 60% Mimica, 1969, Croatia, Yugoslavia (/975) 4,214 men and women, samples of six communities FEV,/FVC ratio less than 60% Sawicki, 1968, Krakow, Poland (1977) 4,355 men and women, community sample FEV,/FVC ratio less than 60% Huhti et al., 1968-1970, Hankasalmi, Finland (1978) 1,162 men, community sample FEV,/FVC ratio less than 60% Brown and Gajdusek, year not stated, Western Caroline Islands (1978) 240 men and women, community sample Chronic obstructive airway disease: clinical and spiro- metric criteria Anderson, year not stated, Lufa, Papua New Guinea (1979) 770 men and women, 25 years or older, community sample FEV,/FVC ratio less than 60% Men 12.6! Women 87! Men 7.3! Women 3.5! Men 8.3! Women 1.9' Men 7.0! Women 5.0' Men 76! Men and women 79! Men 9.01 Women 3.6! ‘Crude rate. the estimated means are probably overestimates of the true popula- tion values. Nevertheless, the figures clearly portray the magnitude of the effect that smoking exerts on expiratorv flow rates in a national population sample. Airflow obstruction is also prevalent outside the United States (Table 5). The disease can be identified in both technologically advanced and less developed populations. As in the United States, in other countries the prevalence of airflow obstruction is higher among men than among wamen. Determinants of Airflow Obstructior Introduction Current understanding of the natural history of airflow obstruc- tion suggests that risk factors operative during both childhood and adulthood may influence the development of disease. In the concep- tual model proposed in Figure 15, childhood factors might increase the risk of airflow obstruction by lowering the maximum FEV; attained during lung growth and development, by predisposing to increased FEV: decline during adulthood, or by both mechanisms (Speizer and Tager 1979). During adulthood, in the model of Figure 15, risk factors for airflow obstruction must increase the rate at which lung function deteriorates. Many endogenous and exogenous determinants of the develop- ment of airflow obstruction have been postulated (Tables 6 and 7). However, in spite of over 30 years of intensive investigation, the available data are definitive only for cigarette smoking and for a,- antitrypsin deficiency (Speizer and Tager 1979; USDHHS 1980). Cigarette Smoking and Chronic Airflow Obstruction In nearly every population studied worldwide, cigarette smoking is the predominant determinant for the prevalence of airflow obstruc- tion (Tables 8, 9, and 10). The uncommon exceptions primarily involve populations in whom severe chest infections or wood smoke exposure may have an etiological role (Wooicock et al. 1973: Anderson 1979a). The relationship between cigarette smoking and airflow obstruction has been variably described in the published reports. In some, the prevalence of airflow obstruction has been considered; in others, mean values of lung function parameters have been compared across categories of smoking use. In several more recent analyses, multiple regression or other multivariate tech- niques have been used for more careful characterization of dose- response relationships. Because the epidemiologic criteria for airflow obstruction are gencrally based on the FEV), this section focuses on studies that have included measurernents of this parameter. The selected studies involve community samoles (Tubles & and 9) and 4500-4404 Men 4000 -4 ~~ ! 4037 ~~ | 3500 E ec 3000-4 a | 3 | = i ~ ' 2738 ~~~ 2500 -~ ws ~~ i 2222 2000 "| | — Never smokers 1500 ; --- Current cigarette smokers 0 —- ; ro 25-34 35-44 45-54 55-64 65-74 Age qroup 3500 - ; Women E c a o = ro “ T ~ T ~ T 7 25-34 35-44 45-54 55-64 65-74 Age group FIGURE 16.—Mean FEV; for white persons by smoking status, sex, and age, United States, 1971-1975 NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey ‘NHANES 1). 84 8000-7874 ee 7715 Men 7500-+ seal 7606 a 7262 oN. x NN 7000 ~ se — — ne ‘ 6848 >. SA 6543 5500— N SN A ae é SN 8097 < 6000-< 6130 ~~ xs ~ > se 3 ~ 5500— “N 5567* N ‘\ 5000 -- a \, \ 4500 — \ —— Never smokers X 4000 4 ~—- Current cigarette smokers 4199 : Op Ta pe Poe eee 25-34 35-44 45-54 55-64 65-74 Age group 6000—~ 5847 Women 5500 — E 5000 | c | g . = 4s00-| NL 4331 i | 4000 \ i ~ NN ~ 5 00 3627

. 2500 -- se ~N ~N “N ' N 2000 -- “s : ~-- Never smokers 1889 ~—- Current cigarette smokers 1600 ~ Or i ae on 25-34 35-44 45-54 55-64 65-74 Age group gas 4000-5 Se a Women 873 Oo a 3500-- ae ~ 3634 Te oN, att0 mS F170 33257 ~— = 3000-- ~ 2886 = se ae 5 x me a ae 2410 = 2500-- 2604 See ~ 2361 2000-- me 1965 1500 -- (het - 7 . mo . 25-34 35-44 45-54 55-64 65-74 Age group FIGURE 18.—Mean flow at 50 percent of FVC for white persons by smoking status, sex, and age, United States, 1971-1975 NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey SOURCE: National Center for Health Statistics Unpublished data from the first National Health Nutrition and Examination Survey (NHANES Li 86 | Men | 2065 2000 + = 1500 - c a 2 ! = 1000— ~ 795 — 500 —~— Never smokers ae —-- Current cigarette smokers 350 0 T “4 ee ee oo 25-34 35-44 48-54 55-64 65-74 Age group 2000 Women 1500 E § 1000 vo = 500 Q T T T T a 1 25-34 35-44 45-54 55-64 65-74 Age group FIGURE 19.—Mean flow at 75 percent of FVC for white persons by smoking status, sex, and age, United States, 1971-1975 NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. SOURCE: Nationa] Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). 87 Men 85 + 80.7 BO 78.8 ae 77.5 = 9.2 OT ee 75.8 © 75 wee 73. s 75.9 ~~ ~~~ 8s ad 73.0 ~~~~~2 1 704 ~~ 70.6 ~~~. 664 —— Never smokers 67.0 ~~~ Current cigarette smokers a Qo T T T T TO 25-34 35-44 48-54 55-64 65-74 Age group 90 7 Women 85 + 804 z § 757 oo = 705 65 LA 0 4 T T T T T 25-34 35-44 45-54 55-64 65-74 Age group FIGURE 20.—Mean FEV1/FVC ratio for white persons by smoking status, sex, and age, United States, 1971-1975 NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). 85 4500-5 Men 4000 -> 3500 — 3188 = 3000 — E ae 2734 Cc 3 = 2500-- ~~ ~ 2314 251s ad 2000 ~ os 2085 ~~~ SL . 1500 ~ oS ~+— Never smokers 1422 --~- Current cigarette smokers 1000 — oi, } a wo ee 25-34 35-44 45-54 55-64 65-74 Age group 3500 7 3357 Women E c © o 2 Oo — Sanne ea T T T q 25-34 35-44 45-54 55-64 65-74 Age group FIGURE 21.—Mean MMEF for white persons by smoking status, sex, and age, United States, 1971-1975 NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). 89 9000 + Men 8500 ~ | 8000 4 | | 7500 4 | 7000-| = . ~—___8526 = 6500- 6758 ~. o ~~ ® ~~ = *A 6000 SS | \, 5834°.. 5500-4 ‘ ! N \ \ 5000 4 \, ‘ 4500 ~ —— Never smokers ‘\ ' -—~ Current cigarette smokers 4341 4000 + L o-t T 7 7 T 7 7 a 7 >> rn — rn 25-34 35-44 45-54 55-64 65-74 Age group 5991 5 6000 > = 923 Women 5947 > 5500 ~ 5000 -- = 4500 ~ c a » 2 4000 - 3500 3000 - 2500 0° : anne 25 34 35-44 45-54 55-64 65-74 Age group FIGURE 22.—Mean MEFR for white persons by smoking status, sex, and age, United States, 1971-1975 NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). 90 5500 ] Men 5000 -4 ! => 4500-— = 500 ; < oO a = 4000-—- 4500 + | ~ | —-N ~ lever smokers 3925 ‘ —-- Current cigarette smokers 3000 4 25-34 35-44 45-54 55-64 65-74 Age group Women E Cc ° 2 LL 2603 2533 9 y 7 ee Ts ee rns ee ae 25-34 35-44 45-54 55-64 65-74 Age group FIGURE 23.—Mean forced vital capacity for white persons by smoking status, sex, and age, United States, 1971-1975 NOTE: Values adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). 91 ‘ABLE 6.~Postulaied risk factors for airflow obstruction during childhood Active cigarette smoking Air pollution. indoor and outdoor Airways hyperreactivity Atopy Familial factors Passive expcsare to tobacco smoke Respiratory illnesses Socioeconomic .tatus ABLE 7.—Moerindity USTABLISHED Risk FACEORS FOR AIRFLOW OBSTRUCTION DURING ADULTHOOD Active cigarette smoking Alpha,-antitrypsin deficiency PUTATIVE RISK } A: TORS FOR AIRFLOW OBSTRUCTION DURING ADULTHOOD ABH secretor status Air pollution Airways hyperreactivity Alcohol consumption Atopy Childhood respiratory illnesses Familial factors Occupation Passive exposure to tobacco smoke Respiratory illnesses Socioeconomic status occupational groups (Table 10) with exposures that have little or no effect on lung function. The selected studies are all cross sectional in design and thus describe the relationship between cigarette smoking and lung function level at only a single point in time. Investigations in the United States, spanning the time period 1958 to 1977, convincingly demonstrate that cigarette smoking is a strong determinant of FEV: level and the prevalence of airflow obstruction (Table 8). In every population for which prevalence data are available, airflow obstruction is more common among smokers than among nonsmokers (Mueller et al. 1971; Knudson et al. 1976; Detels et al. 1979; Rokaw et al. 1980). In fact, in a multivariate analysis of determinants of airflow obstruction in East Boston, lifetime cigarette consumption was the only statistically significant predictor (Tager et al. 1978). Data from populations outside the United States (Table 9) and from a variety of occupational groups (Table 10) confirm the importance of cigarette smoking. Effects of cigarette smoking on FEV) level have been readily demonstrated in employed populations 92 £6 TABLE 8.—Association between cigarette smoking and FEV, Author, year of study, location, reference Ashley et al., 1958, Framingham, Massachusetts, (1975) Number and type of population 1,238 men and women, 37 to 69 years of age level in selected U.S. adult populations Findings By linear regression, significant decline of FEV 1/FVC ratio with pack-years of cigarette consumption in men; similar decline demonstrated in women, but not significant for all age groupe Age-adjusted mean FEV, (liters) Higgins and Kjelsberg 1959. 5,140 men and women, Men Women 1960, Tecumseh, Michigan 16 to 79 years of age Nonsmokers 3.32 2.34 (1967) Ex-smokers 3.31 2.34 Current smokers 3.12 2.28 arena Mean FEV, (liters) Higgins et al., 1963, Marion 926 white men, 20 Nonsmokers 3.64 County, West Virginia to 69 years of age Ex-smokers 3.25 (1968a} Current smokers 1-14/day 3.67 15-24/day 3.51 2 25/day 3.30 Mean normalized FEV, score Higgins et al, 1962-1965, 4,669 men and women, Men Women Tecumseh, "fichigan (1977) 20 to 74 years of age Nonsmokers 10.2 10.1 Ex-smokers 9.9 10.0 Current smokers < 20/day 98 99 2 20/day 95 96 eG TABLE 8.—Continued Author, year of study, jocalion, reference Number and type of population Findings Mueller et al. 19€7, Glenwood, Colorado (1970 Ferrix et al., 1967, Berlin, New Hampshire (1973) Burrows et al., 1972-1972, Tucson, Arizona (1977 Knudson et al., 1972-1973, Tucson, Arizona (1976) 609 men and women, 20 to 69 years of age 848 men and women, 30 to 80 years of age 2,368 men and women, above 14 years of age 2,735 men and women, all ages Prevalence of FEV, /FVC< 60% Men Women Nonsmokers 3 1 Current smokers 1g 2 By multiple regression, in men and women, FEV, drops by 0.01 liters for each cigarette smoked per day By multiple regression analysis, FEV, drops by 0.31 and 0.24 percent of predicted value per pack-year of smoking in men and women, respectively Prevalence (%) of abnormal FEV, and/or FEV,/FVC . Asymptomatic nonsmokers 83 Asymptomatic smokers 13.3 Tager and Speizer, 1973-1974, East Boston, Massachusetts (1978) Tager et al., 1973-1974, East Boston, Massachusetts (1979) Beck et al, 1972-1974, Lebanon and Ansonia, Con- necticut, Winnsboro, South Carolina (1987) 633 men and women, 15+ years of age 1,251 men and women, 4,690 men and women, 7+ years of age By multiple regression, in men and women, significant reduction of an FEV, score with increasing lifetime consumption, and in smokers compared with nonsmokers By multiple logistic analysis, lifetime cigarette consumption only significant predictor of airflow obstruction, defined as FEV, less than 65% predicted By multiple regression analysis, significant dose-response relationships of adjusted residual FEV, with measures of cigarette smoking: duration, pack-years, and cigarettes per day S6 TABLE 8.—Continued Author, year of study, location, reference Ferris et al., 1974-1977, U.S. communities (1979) Number and type of population 8,480 men and women, 25 to 74 years of age Findings Mean residual FEV, (liters) after correction for height and age Lifetime packs Men Women None 0.25 0.06 < 3,000 0.21 0.04 3,000-8,999 0.01 0.05 | 9,000--17,999 0.19 0.20 > 18,000 0.45 ~0.28 Detels et al., Rokaw et al., 1973-1975, Burbank, Lan- caster, Long Beach, California (Detels et al., 1979, Rokaw et al., 1980) Approximately 8,000 men and women, 18 years or older Prevalence (%) of FEV, below 75% predicted, age and sex-adjusted Never smoked Current smoker 18-59 years old Burbank 6.6 12.5 Lancaster 3.4 6.6 Long Beach 5.3 10.0 >60 years old Burbank 15.9 23.5 Lancaster 13.4 217 96 TABLE 9.—Association between cigarette smoking and lung function in selected non-U.S. populations Author, year of study, location, reference Number and type of population Findings Higgins, 1956, Vale of Glamorgan, Wales (1957) 581 men and women, 25 to 74 years of age Ir men, reduced peak flow rates and indirect maximum voluntary ventilation in smokers compared with nonsmokers; no effect of smoking in women Higgins et al., 1957 Stavely, England (1959) 776 men, aged 25 to 34 and 55 to 64 Mean indirect maximal breath capacity (liters) 25 to 34 yrs 55 to 64 yrs Nonsmokers 145 101 Ex-smokers 143 89 Current smokers Light 140 87 Heavy 133 80 Higgins et al., 1968, Rhondda Fach, Wales (1961) 537 men, aged 35 to 64, and 173 women, aged 55 to 64 Mean indirect maximal breathing capacity (liters), men Miners Nonminers Nonsmokers 93.1 114.6 Ex-smokers 93.6 105.9 Current smokers Light 89.0 104.1 Heavy 88.3 99.4 No effect of smoking in women 16 TABLE 9.—Continued Author, year of study, location, reference Number and type of population Findings College of General Practitioners, 1958, Britain (1962) 787 men and 782 women, aged 40 to 64 Age-adjusted mean PEFR! (liters/minute) Men Women Nonsmokers 448 318 Ex-smokers 4l7 300 Current smokers 1-14/day 412 314 15-24/day 399 310 > 25/day 398 265 Sluis-Cremer and Sichel, 1962-1963, Carletonville, South Africa (1968) Huhti, 1961, Harjavalta, Finland (1967) Wilhelmsen et al., 1963, Goteborg, Sweden (7969) 533 men, 35 years or older 420 men, 608 women, aged 40 to 64 339 men, aged 50 Reduced FEV, and PEFR! with increased tobacco consumption All women, nonsmokers; in men, reduced FEV, and PEFR' in smokers compared with nonsmokers Mean FEV, (liters) Nonsmokers 3.72 Ex-smokers 371 Current smokers 1-14 g/day 3.58 > 15 g/day 3.36 Huhti et al., 1968-1970, Hankasalmi, Finland (1978) 1,162 men, aged 25 to 69 Reduced FEV, in smokers compared with nonsmokers; increased prevalence of FEV,/FVC ratio less than 60% in smokers 2 TABLE 9.—Continued Author, year of study, location, reference Number and type of population Findings Mimics, 1969, Croatia, Yugoslavia (1975) 4,214 men and women, 35 to 54 years of age Mean FEV, (liters) Men Women Nonsmokers 3.58 2.62 Ex-smokers 3.57 2.70 Current smokers Light 3.42 2.64 Heavy 3.42 2.60 Neri et al, 1969-1973, Sudbury and Ottawa, Canada (1975) 5,488 men and women, 14 years of age or older Declining ratio of FEV,/FVC with number of cigarettes smoked daily Manfreda et al. 1974, Portage la Prairie and Charleswood, Canada (1978) 502 men and women, 25 to 55 years of age Significant regression of FEV,/FVC ratio on number of cigarettes smoked daily Anderson, year not stated, Karkar Island, Papua New Guinea (1976) 548 men and women, 25 years of age or older Age and height-adjusted mean FEV, (liters) Anderson, year not stated, Lufa, Papua New Guinea (1979) 733 men and women 25 years of age or older Men Women Nonsmokers 2.56 2.13 Smokers 2.40 2.01 Age and height-adjusted mean FEV, (liters) Men Women Nonsmoker 2.58 2.36 Ex-smoker 2.62 2.27 Occasional 2.57 2.29 Regular 2.63 2.43 ' Peak expiratory flow rate 66 TABLE 10.—Association between groups Author, year of study, location, reference Sharp et al., 1960-1961, Chicago, U.S. (1965) Fletcher et al., 1961, London, England (1976) tt Goldsmith et al. 1961, San ‘Francisco, U.S. (1962) cigarette smoking and lung function level in selected occupational Number and type of population 1,887 men, aged 43 to 58 years, employed at an electronics plant 1,136 men aged 30 to 59, employed at bank or in maintenance of transporiation equipment 3,311 longshoremen Findings Mean FEV, (liters) Nonsmokers Smokers one pack per day Adjusted FEV, (iters) Nonsmokers Ex-amokers Current smokers 1-4 cigarettes/day 5-14 cigarettes/day 15-24 cigarettes/day 225 cigarettes/day Mean FEV, percent of predicted value Never smokers Ex-mokers Current smokers 10 cigarettes/day 11-39 cigarettes/day > 40 cigarettes/day 100 97 93 93 OOT TABLE 10.—Continued Author, year of study, location, reference Number and type of population Balchum et al., 1961, Loe Angeles, U.S. (1962) 1,456 men employed in various industries Findings Prevalence (per 100) of FEV,/FVC ratio less than 70 percent Nonsmokers 76 Smokers 18.8 Coates et al., 1962, Detroit, US. (1965) 1,584 male and female postal employees, Reduced FEV, and FEV,/FVC ratio in smokers of 25 or more cigarettes daily compared with nonsmokers aged 40 or older Densen et al., 1961-1963, New 12,500 males employed Age- and height-adjusted FEV, (liters) York City, U.S. (1969 as postal or transit workers Postal workers Transit workers White Nonwhite White Nonwhite Nonsmokers 3.29 3.05 3.39 3.08 Cigarette smokers <25 g per day 3.14 2.95 3.15 3.00 > 25 g per day 3.06 2.93 3.02 2.95 Bandé et al., 1960-1975, Belgium (1980) Comstock et al., 1962-1963 and 1967, U.S. and Japan (1973) 7,123 male military personnel, a few over age 45 Three cross-sectional studies of men working for telephone company; U.S.—1,302 and 1,194 subjects, aged 40 to 65, 6% in study; Japan—592 subjects, aged 40 to 60 By multiple regression, in cross-sectional analysis, significant effect of smoking on FEV, level after age 35 Mean FEV, level as percent predicted US. Japan Study 1 Study 2 Cigarettes per day None 106 103 99 1-14 104 101 100 15-24 98 92 98 > 25 95 93 99 tor TABLE 10.—Continued Author, year of study, location, reference Khosla, 1964, Port Talbot, Number and type of population 7,701 males employees Findings Adjusted mean FEV, level (liters) United Kingdom (1971) in the steel industry Never smokers 3.70 Current smokers <15 cigarettes/day 3.57 15-24 cigarettes/day 3.48 25-34 cigarettes/day 3.41 > 35 cigarettes/day 3.37 Schlesinger et al., 1968, 4,331 male civil servants, Mean value of the FEV,/FVC ratio Israel (1972) aged 45 or older Nonsmokers 76.0 Ex-smokers 74.3 Current smokers 1-19 cigarettes/day 73.9 2 20 cigarettes/day 72.7 Kesteloot et al., 1968-1969, Belgium (1976) O'Donnel] and de Hamel, 1969- 1970, New Zealand (1976) Linn et al., 1973, San Fran- cisco and Los Angeles, US. (1976) Endelman et al., year not stated, Baltimore, U.S. (1966) 4,961 males in the Belgian military, aged 15 to 59 1,079 male public servants, up to age 65 644 male and female office workers, aged 17 to 60 410 male volunteers, aged 20 to 103 By multiple regression, FEV, reduced by 0.14 liters in smokers of 1-19 cigarettes daily and by 0.23 liters in smokers of 20 or more daily Reduced mean FEV, in smokers of 10 or more cigarettes daily; increased prevalence of FEV, below 80 percent of predicted in smokers of more than two packs daily By analysis of covariance, significant reduction of FEV, smokers compared with nonsmokers By partial regression analysis, significant reduction of FEV, in current and former cigarette smokers in cOT TABLE 10.-—-Continued Author, year of study, Number and type location, reference of population Findings Woolf and Suero, year not 298 female volunteers Adjusted mean levels stated, Toronto (1971) employed at commercial FEV, FEV,/FVC ratio firms, aged 25~54 Nonsmokers 2.65 86.7 Ex-smokers 2.64 85.0 Current smokers 70 cigarettes/week 2.63 85.2 71-140 cigarettes/week 2.50 85.1 > 140 cigarettes/week 2.45 84.1 Krumholz and Hedrick, year 227 male executives, Mean values not stated, Dayton, US. aged 35-64, selected (1973) to include nonsmokers FEV, FEV,/FVC (n= 136) and long- Nonsmokers 3.80 77.3 term amokers (n=91) Smokers 3.42 73.6 Grimes and Hanes, year not 1,059 male and By multiple regression, significant reduction of FEV, level stated, Los Angeles, US. (1973) Lefcoe and Wonnacott, year not stated, western Ontario, Canada (1974) Higgenbottam et al, year not stated, London, England (1980) female insurance company employees 1,072 males in four occupational groups 18,403 male civil servants, aged 40 to 64 in male smokers but not in female smokers By multiple regression, significant reduction of FEV, in current cigarette smokers Reduced FEV, in cigarette smokers compared with nonsmokers, increased effect with increasing daily amount in current smokers (Table 10), even though people with symptomatic airflow obstruction may be likely to retire from their jobs. Recently, predictors of the incidence of airflow obstruction have been examined with multivariate techniques in data from popula- tion samples in Tecumseh, Michigan (Higgins et al. 1982), and in Tucson, Arizona (Lebowitz et al. 1984). In Tecumseh, the strongest predictors of airflow obstruction (defined as an FEV; less than 65 percent of predicted) were age, the number of cigarettes smoked daily, changing smoking habits, and the initial FEV; level (Higgins et al. 1982). The addition of other variables to the predictive model did not greatly improve its validity. In Tucson, these same variables, along with certain symptoms and illnesses, and skin test reactivity were significant predictors (Lebowitz et al. 1984). During the 10 years of followup of a population sample in Finland, incidence cases of chronic airflow obstruction (defined as FEV:/FVC ratio less than 60 percent) were observed only in those who continued to smoke (Huhti and Ikkala 1980). These studies of incidence highlight the importance of cigarette smoking in the etiology of airflow obstruc- tion; new cases are rare among nonsmokers. Dose-Response Relationships Dose-response relationships between FEV; level and the amount of cigarette smoking have been described with simple descriptive statistics and further characterized by multiple regression analysis. In cross-sectional data, the FEV; level varies inversely with the amount smoked. Although the variation in mean FEV; levels among strata of smoking appears clinically unimportant, the distributions of values in smokers and nonsmokers are quite different (Figure 4). Cigarette smokers more often have abnormal lung function, regard- less of the criteria applied to the population (Mueller et al. 1971: Knudson et al. 1976; Burrows et al. 1977a; Detels et al. 1979; Rokaw et al. 1980; Beck et al. 1981). This increased prevalence of abnormal function is a result of the skewed distribution of function in smokers, with a subgroup of the smokers showing a large decline rather than the entire group shifting by a small amount (Figure 4). As noted in this reference, however, there are decreasing numbers of smokers with FEV, above the mean for nonsmokers as pack-years increase, suggesting that all smokers are probably somewhat affected, even though only a minority eventually develop clinically significant airflow limitation. In several populations, the relationship between cigarette smoking and FEV; level has been examined in greater detail. Burrows et al. (1977a) used linear multiple regression analysis to examine the relationship between cigarette smoking and ventilatory function ina population sample in Tucson, Arizona. Pack-years, a cumulative- dose measure, was the strongest predictor of FEV; level among the 103 smoking variables considered. In currently smoking men and women, the FEV; declined by approximately 0.25 percent of the predicted value for each pack-year of cigarette smoking; the effect was of a similar magnitude in ex-smokers. Using data from three separate U.S. communities, Beck and colleagues (1981) assessed the importance of six separate smoking variables: amount smoked daily, use of filters, inhalation, age started, age stopped for ex-smokers, and cumulative pack-years. For the FEV, the strongest predictors in male current smokers were the duration of smoking and the amount smoked; in female current smokers, only pack-year was statistically significant. The number of years of cessation was associated with FEV: in male but not in female ex-smokers. However, in both the multiple regression analysis reported by Beck et al. (1981) and that reported by Burrows et al. (1977a), the measured cigarette smoke variables accounted for only about 15 percent of the variation of age- and height-adjusted FEV; levels. Unmeasured aspects of cigarette smoking, other environmental exposures, and the characteristics of the smokers must contribute to the unexplained variation. A role for the type of cigarette smoked has not yet been established (USDHHS 1981), and the impact of differences in depth or pattern of inhalation and other aspects of the pattern of smoking remains to be investigated; they are discussed in more detail in the chapter on low tar and low nicotine cigarettes. Further studies of these aspects of cigarette smoking are needed to monitor the consequences of changing cigarettes. Factors Other Than Cigarette Smoking A number of risk factors other than cigarette smoking have been postulated as contributing to the development of airflow obstruction (Table 7). Of these, a definite role for a,-antitrypsin deficiency has been established, but only the small number of persons with homozygous deficiency incur markedly increased risk (Morse 1978). The current hypotheses on susceptibility to cigarette smoke postu- late roles for childhood respiratory illnesses (USDHEW 1979; Burrows and Taussig 1980; Samet et al. 1983), for endogenously determined hypersensitivity of the lung, and for other genetic and familial factors (Speizer and Tager 1979; USDHHS 1980a). At present, these hypotheses remain largely untested. The data are similarly incomplete at present for the other factors listed as putative risk factors in Table 7. The status of each is briefly reviewed below. ABH Secretor Status Secretion of ABH antigens is a genetically determined trait that follows an autosomal dominant inheritance pattern; approximately 104 70 to 80 percent of the population excrete antigen into the body fluids (Cohen et al. 1980a). In a genetic-epidemiology study in Baltimore, Maryland (Cohen et al. 1980a), ABH nonsecretors had lower levels of FEVi/FVC ratio and a higher proportion with FEV:/FVC ratio below 69 percent. Studies in France (Kauffmann et al. 1982a, 1983) and in England (Haines et al. 1982) have confirmed reduced expiratory flow rates in ABH nonsecretors. In contrast, ABH secretor status did not predict the development of obstructive airways disease in the Tecumseh, Michigan, population (Higgins et al. 1982). Air Pollution Although exposure to air pollution at high levels may exacerbate the clinical condition of persons with chronic lung disease, a causal role for air pollution in the development of airflow obstruction has not been established (Tager and Speizer 1979; USDHHS 1980b). However, smoking is the major predictor for chronic airflow obstruction in areas of high as well as low atmospheric air pollution. Airways Hyperreactivity Orie and colleagues in the Netherlands (Orie et al. 1960) speculat- ed that bronchial hyperreactivity and allergy may predispose to asthma and chronic bronchitis. Findings from two small longitudinal studies have suggested that airways reactivity may influence indi- vidual susceptibility to cigarette smoke. Barter and colleagues followed 56 patients with mild chronic bronchitis during a 5-year period (Barter et al. 1974; Barter and Campbell 1976). The rate of decline of FEV: increased with the degree of airways reactivity, as measured by reversibility with isoproterenol or responsiveness to methacholine. Britt et al. (1980) measured change of FEV: in 20 young adult male relatives of patients with chronic obstructive pulmonary disease. The decline of FEV: was approximately five times larger in the nine subjects with a positive methacholine challenge test. In patients with clinically diagnosed airflow obstruc- tion, airways reactivity is also associated with more rapid decline of lung function (Kanner et al. 1979). Because airway reactivity would affect the FEV, directly as well as possibly influence the susceptibili- ty to smoke, it is difficult to ascertain from these data whether the relationship between airway reactivity and COLD is direct or spurious. Alcohol Consumption The epidemiological data on alcohol consumption are conflicting. A study of former alcoholics demonstrated an excess prevalence of lung function abnormalities, including airflow obstruction (Emergil 105 480-144 0 - B85 -~ 5 and Sobol 1977). In the Tucson population, alcohol consumption was a significant predictor of ventilatory function after the effect of smoking was controlled (Lebowitz 1981). The findings of an investiga- tion in Yugoslavia were similar (Saric et al. 1977). However, two large U.S. investigations did not demonstrate adverse effects of alcohol intake (Cohen et al. 1980b; Sparrow et al. 1983a). Atopy Cross-sectional data from the Tucson population suggest increased susceptibility to cigarette smoke in atopic people (Burrows et al. 1976). In subjects aged 15 to 54, the prevalence of an FEV:/FVC ratio below 90 percent of predicted value increased with skin test reactivity among both smokers and nonsmokers. Subsequent reports from this same study have not confirmed an overall relationship between FEV: level and atopy, but indicate that atopy may predis- pose to airflow obstruction in a subset of the population (Burrows et al. 1977a, 1983). Burrows and coworkers (1981) also reported an increased level of IgE in smokers independent of their allergy skin test reactions, and the interrelationship of these factors is currently being examined. Childhood Respiratory Iliness In a longitudinal investigation of 792 English working men, Fletcher and coworkers (Fletcher et al. 1976) found a cross-sectional association between childhood illness history and FEV: level. The decline of FEV; level during the study’s longitudinal phase was not correlated with childhood illness variables. In contrast, analyses of cross-sectional data from a population sample in Tucson suggested that childhood respiratory illnesses may increase susceptibility to cigarette smoke (Burrows et al. 1977b). In this population, people with a history of respiratory trouble before age 16 demonstrated excessive decline of ventilatory function with increasing age and with increasing cigarette consumption. Familial Factors Familial aggregation of lung function level, adjusted for age, height, and sex, has been demonstrated in populations in the United States and elsewhere (Higgins and Keller 1975; Tager et al. 1976; Schilling et al. 1977; Mueller et al. 1980). However, a recent report suggests that the familial aggregation of lung function may be a reflection of the familial aggregation of body habitus (Lebowitz et al. 1984). Relatively modest correlations of FEV: level have been demonstrated between siblings and between parent-child pairs. The role of familial factors is further supported by investigations demonstrating increased prevalence of airflow obstruction in rela- 106 tives of diseased subjects (Kueppers et al. 1977; Tager et al. 1978; Cohen 1980). This familial factor cannot be explained by familial resemblance of a.,-antitrypsin phenotype or of ABH secretor status (Kueppers et al. 1977; Cohen 1980). In the Tecumseh population, however, family history of airflow obstruction did not predict the incidence of this disease. The results of twin studies are also consistent with genetic influences on FEV; level and suggest that genetic factors may influence susceptibility to cigarette smoke (Webster et al. 1979; Hankins et al. 1982; Hubert et al. 1982). Occupation Several population-based investigations suggest that occupational exposures other than those recognized as causing lung injury may have some effect on lung function level. In Tecumseh, mean age and height-adjusted FEV scores in men were highest in farmers and lowest in laborers; the differences were not explained by smoking and were present in nonsmokers (Higgins et al. 1977). Similarly, in Tucson, men reporting employment in certain high risk industries or exposure to specific harmful agents had a higher prevalence of abnormal lung function (Lebowitz 1977a). In a Norwegian case— control study, men employed in workplaces characterized as polluted were at increased risk for clinically diagnosed emphysema (Kjuus et al. 1981). Longitudinal studies of industrial populations also show that occupational exposures may increase the rate of decline of FEV: (Jedrychowski 1979; Kauffmann et al. 1982b; Diem et al. 1982). For example, Kauffmann et al. (1982b) found that FEV, change during a 12-year period varied with job exposures in an employed industrial population. Effects of dust, gas, and heat were present, as was evidence for a dose-response relationship between increasing exposure and a greater rate of decline. In these studies, however, smoking effects were generally much greater than the occupational effects. Passive Exposure to Tobacco Smoke Passive exposure is discussed in detail elsewhere in this Report. Respiratory Ilinesses In an 8-year followup study of London men, chest infections were not associated with a rate of FEV; decline (Fletcher et al. 1976). The findings of several smaller longitudinal studies were similarly negative with regard to respiratory infection (Howard 1970; John- ston et al. 1976). It is now apparent that mucus hypersecretion and airflow obstruction are separate pathophysiological entities that have a common cause—cigarette smoking (Fletcher et al. 1976; Peto et al. 1983). 107 Socioeconomic Status Weak effects of socioeconomic status on lung function level have been demonstrated in community samples in Tecumseh (Higgins et al. 1977) and in Tucson (Lebowitz 1977b). In both populations, lung function appeared to be influenced independently by socioeconomic status indicators, even after controlling for cigarette smoking. In the Tecumseh study, FEV1 increased slightly with increasing income and education level (Higgins et al. 1977); in the Tucson study, the proportion of people with an abnormal FEV: varied in a similar pattern with these indices (Lebowitz 1977a). Effects of socioeconomic status were present in nonsmokers in both investigations. Stebbings (1971), in a sample of nonsmokers in Hagerstown, Maryland, also demonstrated an association between lung function level and socioeconomic status. In summary, there is evidence that a number of factors other than cigarette smoke may influence lung function, but the influence of these factors is small relative to the effect of smoking, and the major question is whether they can influence susceptibility to cigarette- induced lung injury rather than whether they, of themselves, result in lung disease in nonsmokers. Development of Airflow Obstruction At this time, the natural history of airflow obstruction has been only partially described; a population has not yet been followed from childhood to the development of airflow obstruction during adult- hood. However, the available data from separate investigations cover the entire course of the disease and support the conceptual model proposed in Figure 15. With aging, measures of function begin to deteriorate after age 25 to 30. In nonsmokers without respiratory disease, cross-sectional data generally show that the FEV; declines by 20 to 30 ml per year (Dickman et al. 1969; Morris et al. 1971; Cotes 1979; Crapo et al. 1981). Longitudinal data have been confirmatory (Tables 11 and 12). For example, Tockman (1979) measured the FEV: loss during an 8- year period in 399 male nonsmokers. In most, the FEV: declined at 25 ml annually; a few, with an initial FEV: lower than 2.5 1, lost 34 ml annually. Sufficient excessive loss leads to the development of airflow obstruction. However, many questions remain unanswered concern- ing this process of functional deterioriation. It is unclear whether the loss always occurs uniformly or if it develops in stages with intermittent and relatively steep declines (Bates 1979; Burrows 1981). The concept that the decline is nearly always gradual receives strong support from the findings of the 8-year longitudinal study conducted by Fletcher and coworkers (1976). In this investigation of 108 60T TABLE 11.—Association between cigarette smoking and longitudinal change in lung function in selected population samples Author, years of study, location, reference Number and type of population Findings Higgins and Oldham, 1954-1959 Rhondda Fach, Wales (1962) 253 male miners, ex- miners, and nonmining controls Annual decline of indirect maximal breathing capacity (liters/min) Miners, ex-miners Controls without pneumoconiosis Nonsmokers 16 0.8 Ex-smokers 0.7 1.8 Current smokers 1-14 g/day 13 17 > 15g/day 1.6 2.2 Ashley et al., 1958-1968, Framingham, U.S. (1975) 399 men and 636 women, aged 37 to 69 in 1958 10-year change in FEV,/FVC ratio (age-standardized to overall distribution for each sex) Higgins et al., 1957-1966, tavely, England (1968b) 594 men, aged 25-34 or 55-64 in 1957 Men Women Nonsmokers 0.21 -3.6 Continued smokers -13 —41 Stopped, 1958-1968 0.51 —4.6 Annual decline of FEV75, (ml/year) by age and smoking in 1957 25-34 yrs 55-64 yrs Nonsmokers 21 32 Ex-smokers 29 44 Current smokers 1-14g/day 37 54 > 15g/day 38 37 OTT TABLE 11.—Continued Author, years of study, location, reference Number and type of population Findings Huhti and Ikkala, 1961-1971, 492 men and 671 women, Annual decline of FEV, (ml/year) Harjavalta, Finland (/980) aged 40 to 64 in 1961 Men Women Nonsmokers 33 27 Ex-smokers 45 27 Continued smokers 44 39 Stopped, 1961-1971 51 35 Wilhelmsen et al., 1963-1967, 313 men, aged 50 Annual decline of FEV, (ml/year) Goteborg, Sweden (1969) in 1963 Nonsmokers 43 Ex-smokers 33 Current smokers 1-14g/day 70 > l5g/day 70 Stopped, 1963-1967 40 TIT ee WV eee eee Author, years of study, location, reference Oxhoj et al. 1963-1973, Goteborg, Sweden (same popu- lation as Wilhelmsen et al. 1969) (1976) Number and type of population 269 men, aged 50 in 1963 Findi Annual decline of FEV, (mi/year) Nonsmokers Ex-smokers Current smokers Stopped, 1963-1973 40 37 58 49 Van der Lende et al., 894 men and women, Mean annual decline of FEV, Viaardingen, 1967-1978, and aged 25 and older Unadjusted Adjusted Vlagtwedde, 1967-1976, Nonsmokers 13.3 16.6 Netherlands (/98/) Ex-smokers 15.8 13.4 Pipe/cigar 24.4 22.6 « 4 g/cig 3.6 8.7 5-14 gicig 22.2 20.9 15-24 g/cig 31.4 28.2 > 25 g/cig 35.8 34.0 Krzyzanowski, 1968-1973, 2,572 men and women, Annual decline of FEV, (ml/year) Cracow, Poland (/980) aged 19 to 70 Men Women Nonsmokers 56 44 Continued smokers 73 53 alt TABLE 12.—Association between cigarette smoking and longitudinal change in lung function in selected occupational or other groups Author, years of study, location, reference Number and type of population Findings Comstock et al., 1962-1963 to 1967 or 1969, various locations 670 male telephone company employees, Decline in FEV, (liters) between surveys US. (1970) aged 40 to 65 Nonsmokers 0.28 Ex-smokers 0.17 All smokers 0.41 Howard, 1956 ta 1967, 159 male employees of Annual decline in FEV:s« (ml/year) Sheffield, England |/970) an engineering works Nonsmokers 0.036 Ex-smokers 0.025 Current smokers 0.031 DeMeyere and Vuyisteek, 1967 to 1970, Ghent, Belgium (/97/) 627 male railroad workshop employees Annual decline in FEV, (ml/year) Nonsmokers Ex-smokers Current smokers 1-14 g/day >15 g/day Stopped, 1961-1971 SRR RS €IT TABLE 12.—Continued Author, years of study, location, reference Number and type of population Findings Fletcher et al., 1961 to 1969, London, England (1976) Kauffmann et al., 1960 to 1972, Paris, France (1979) Jedrychowski, 1968 to 1973, Cracow. Poland (1979) Poukkula et al., 1967 to 1977, Oulu, Finland (7982) 792 male transport maintenance or bank workers, aged 30 to 59 at entry 575 male factory workers, aged 30 to 54 in 1960 186 male employees of a fertilizer factory 659 male pulp mill employees, aged 18 to 64 in 1967 Annual decline of FEV, (ml/year) Nonsmokers Ex-smokers Continued smokers <5 cigs/day 5-15 cigs/day 15-25 cigs/day >25 cigs/day Annual decline of FEV, (ml/year), adjusted for initial level Nonsmokers Ex-smokers Current smokers «15 g/day > 15 g/day S-year decline of FEV, as percent of mean, by 1973 smoking Nonsmokers Ex-smokers Current smokers Annual decline of FEV, (ml/year) Nonsmokers Ex-smokers Continued smokers Stopped, 1967-1977 36 31 44 46 54 54 40 44 46 51 3 5 7 37 39 49 48 ry ¥ TABLE 12.—Continued Author, years of study, location, reference Number and type of population Findings Woolf and Zamel. vears not given, Toronto, Canada (/980) 302 female volunteers, aged 25 to 54 at entry 5-year change in FEV, as percent of initial value Nonsmokers Lb Ex-smokers 0.8 Smokers < 70 cigs/week 0.4 71-140 cigs/week ‘, 3.65 140 cigs/week at Bosse et al., 1963-1968 to 1969-1974. Boston, U.S. (1981) 850 male volunteers Annual decline of FEV, (ml/year), adjusted for age and initial level Nonsmokers 0.053 Ex-smokers 0.057 Current smokers 0.085 Love and Miller. 1957 to 1973 taverage followup, 11 years), United Kingdom (/982) 1,677 male coalminers ll-year decline in FEV, (liters) Nonsmokers 0.41 Ex-smokers 0.48 Intermittent smokers 0.52 Current smokers 0.53 792 employed men, the individual patterns of temporal change of the FEV; were strongly variable, but the loss generally occurred gradually. Fletcher et al. further demonstrated that FEV; level correlated with FEV; slope, a finding that they termed the “horse- racing effect.” Correlation between slope and level would be antici- pated, if functional loss occurs gradually. This correlation has important implications for intervention; those losing FEV: more rapidly should become identifiable early as they develop a reduced FEV; level. Other studies, however, do not agree with either the pattern of FEV decline or the “horse-racing” effect. Rapid declines to levels compatible with clinical disease or followed by a prolonged plateau have been described (Howard and Astin 1969; Howard 1970; Johnston et al. 1976). In a followup study of Canadian men with chronic bronchitis, steep declines of FEV, without subsequent improvement were frequently observed (Bates 1973). Additionally, correlation of FEV, level and slope has been found in most other longitudinal investigations (Howard 1970; Petty et al. 1976; Huhti and Ikkala 1980; Bosse et al. 1981; Clement and van de Woestijne 1982; Kauffmann et al. 1982b), but not in all (Barter et al. 1974; Krzyzanowski 1980). Another unanswered question concerning functional deterioration is whether gradual decline occurs in a linear or a nonlinear fashion (Fletcher et al. 1976). Sufficient numbers of people have not yet been followed to distinguish alternative patterns, although the available data indicate acceleration of the decline with aging (Emergil et al. 1971; Fletcher et al. 1976). In spite of these uncertainties concerning the development of airflow obstruction, the available data indict cigarette smoking as the primary risk factor for excessive loss of FEV: (Tables 11 and 12). The findings in both general population samples (Table 11) and occupational and volunteer cohorts (Table 12) have been similar. Recent reports from Belgium (Bande et al. 1980; Clement and van de Woestijne 1982) and from Connecticut (Beck et al. 1982), not readily summarized in tabular form, also described a strong effect of smoking on FEV; decline. A few studies have not shown increased loss in cigarette smokers (Howard 1970; De Meyere and Vuylsteek 1971). Even in people with clinically diagnosed airflow obstruction, continued smoking maintains the excess decline of FEV, (Hughes et al. 1982), although not all findings are consistent (Ogilvie et al. 1973; Johnston et al. 1976). Dose-response relationships have been found in many investiga- tions between the amount smoked during followup and the FEV, decline (Tables 11 and 12). The reported increases from the lowest to the highest smoking categories range up to 10 to 15 ml annually. Although this additional loss in heavier smokers appears small, if sustained for long periods of time it would shorten the time interval 115 Never smoked or not susceptible to smoke ~“ a 1 Smoked FEV, (percent of value at age 25) 50 4 regularly an ~. ~— Stopped at 45 susceptible to ~ its effects swQ Disability ~ mr rw ee Qe LLL UN 25 7 “SS Stopped at 65 Death Sn ee. -M. LL o T ¥ tT T T T T T ¥ T 25 50 75 Age (years) FIGURE 24.—Risks for men with varying susceptibility to cigarette smoke and consequences of smoking cessation NOTE: + = death. SOURCE: Fletcher and Peto (1977). to the development of functional impairment. So far, favorable effects of filter tip smoking and declining tar content on the rate of decline have not been shown (Fletcher et al. 1976; Sparrow et al. 1983b). Generally, sustained smokers experience a greater loss than those who stop during followup. In the study by Fletcher et al. (1976) of London men, subjects who stopped smoking at the beginning of the followup period lost FEV: at the same rate as never smokers. The results of two U.S. studies of ex-smokers are similar (Bosse et al. 1981; Beck et al. 1982). This reduced loss in ex-smokers emphasizes the importance of active smoking and the immediate benefits of smoking cessation (Figure 24). Smokers with reduced FEV; may be protected from developing clinically significant loss by timely smoking cessation (Fletcher and Peto 1977). The distribution of FEV; decline has been characterized and described for some populations, including patient groups (Burrows and Earle 1969; Howard 1974; Barter et al. 1974), population samples (Milne 1978), and occupational cohorts (Howard 1970; Fletcher et al. 1976). Similar data are also available for the mid-maximum expira- tory flow, another measure of ventilatory function (Bates 1973; Woolf and Zamel 1980). In each of these investigations, the distribu- tion of FEV: decline is unimodal (Figure 25); that is, a distinct population with more rapid decline is not sharply separated from those with lesser rates. The modes and medians of the distributions 116 80 4 Mean ro F © Smokers r: 60 J Nonsmokers and Ah ex-smokers 7 eed 40 + 30 — Number of men (total 792) 20 ~ T q v v F -160 -140 -120 -100 -80 -60 40 -20 0 +20 FIGURE 25.—Distribution of 8-year FEV; slope in 792 London men SOURCE: Fletcher et al. (1976). are generally negative, but some subjects have had positive slopes during the relatively brief followup period of investigations conduct- ed up to this time. The distributions tend to be skewed by subjects losing FEV: more rapidly. The proportion of cigarette smokers is increased among those in the tail of excess loss (Figure 25). For example, Clement and van de Woestijne (1982) examined subjects with excess FEV, decline in a prospective study of 2,406 members of the Belgian Air Force. Losses beyond those expected from nonsmokers affected 6 percent of nonsmokers, 7.5 percent of light smokers (< 20 cigarettes/day), and 12 percent of heavy smokers (> 20 cigarettes/day). The shape of the distribution of FEV) decline has important implications for the development of airflow obstruction. Smokers are not sharply separated from nonsmokers (Figure 25), but more often lose FEV) at a rapid rate. Because of this spectrum of severity, not al] smokers develop significant airflow obstruction. Although the fac- tors that lead to excessive loss in individual smokers remain uncertain, they may include differences in the pattern of smoking. It is apparent, however, that this susceptible minority can be protected by smoking cessation. 117 summary During the 20 years that have elapsed since the 1964 Surgeon General’s Report, the relationship between cigarette smoking and airflow obstruction has been intensively investigated. Surveys of community samples and other groups have established that airflow obstruction is a common condition in the United States and elsewhere. In some populations, as high as 10 percent of adults are affected. Determinants of lung function level and of the prevalence of airflow obstruction have now been examined in many populations throughout the world. Cigarette smoking is the strongest predictor of abnormal measures of ventilatory function. A causal relationship between cigarette smoking and airflow obstruction is supported by the consistency of the many published reports, the strength of the association, and the evidence for dose-response. Many risk factors for airflow obstruction other than cigarette smoking have been postulated, including other harmful environmen- tal exposures and the inherent susceptibility of the smoker. Homozy- gous a,-antitrypsin deficiency can explain only a minute proportion of the disease burden. The development of airflow obstruction by only a minority of smokers indicates that the interaction of smoking with other factors may influence the risk for specific smokers. Current research emphasizes the potential roles of childhood respira- tory illness and airways hyperresponsiveness. Longitudinal studies have now partially described the prolonged natural history of airflow obstruction. Excessive loss of ventilatory function, beyond that expected from aging alone, results in the development of disease in cigarette smokers. Only a susceptible minority of cigarette smokers lose function at a rate that will eventually cause clinically significant impairment. For this group, timely smoking cessation can prevent the development of disease. 118 EMPHYSEMA Introduction Pulmonary emphysema is frequently present in the lungs of individuals with chronic obstructive lung disease. This section has three purposes: (1) to review the definition, types, and quantification of emphysema; (2) to summarize the physiological and radiographic feature of emphysema: and (3) to discuss critically the relationship of smoking to emphysema, based upon observations in people and in experimental animals. Current concepts of the pathogenesis of emphysema are reviewed elsewhere. Definition of Emphysema The generally accepted definition of emphysema is an anatomic condition of the lung characterized by abnormal dilation of air spaces distal to the terminal bronchioles accompanied by destruction of air space walls (American Thoracic Society 1962: Heard et al. 1979). Difficulties with this definition have been discussed by Thurlbeck (1983). Normal air space dimensions have not been determined, and criteria of destruction have not been defined. These limitations hamper attempts to investigate the earliest lesions of emphysema and the subtle effects of environmental agents on lung structure. Types of Emphysema British pathologists pointed out in the forties and fifties that emphysematous lesions in certain people involved the respiratory bronchioles, which appeared as grossly enlarged airspaces in the center of the primary lung lobules surrounded by normal lung. In other individuals, the alveolar ducts were involved early, and even mild involvement appeared grossly as a coarsening of the architec- ture of the entire lobule. They designated the two polar patterns of emphysema as centrilobular emphysema (CLE) and panlobular emphysema (PLE) (Heppleston and Leopold 1961), Many lungs either show both types of emphysema or are unclassifiable. Of 122 lungs with emphysema examined by one pulmonary pathologist, 73 were _considered mixed or unclassifiable and 49 were clearly CLE or PLE (Mitchell et al. 1970). When the agreement of three pathologists was required, only 27 of the original 122 lungs remained classifiable and 95 were mixed or could not be classified. There were no Statistically significant differences between the groups classified as PLE or CLE in any clinical variables. The only nonsmokers in either group had CLE, and the proportion of light smokers (less than 25 pack-years) was very similar between groups. In this study and others (Anderson and Foraker 1973), CLE was most severe in the upper lobes and PLE was uniformly distributed. According to Thurlbeck (1976), a common 119 combination is CLE in the upper lobes and PLE in the lower lobes; where lobectomies are used for correlation, typing of emphysema is therefore a particularly empty exercise. When emphysema is far advanced, it is often impossible to recognize the site of the initial involvement. Thus, it is not clear whether the differences in prevalence of CLE and PLE are real or represent differences in interpretation by different observers. Several localized types of emphysema occur in areas around scar tissue (paracicatricial), along interlobar and interlobular septa (paraseptal), and as bullous lesions (which represent the most advanced and extreme distortion of normal lung structure). Bullous deformities occur with any type of emphysema, including CLE and PLE. Occasionally, bullous lesions occupy huge intrapulmonary volumes, Detection of Emphysema The detection of emphysema requires suitably prepared lung specimens. At a minimum, this means the lung must be fixed in inflation (Thurlbeck 1964). Fume fixation or fixation by instillation of liquid fixative through the airways is satisfactory, but for optimal evaluation of the latter group, barium impregnation or paper- mounted whole-lung sections should be used. Because lungs with emphysema frequently also have some degree of intrinsic airways disease, the severity of emphysema and the clinical state of the patient may not correlate directly. Pathologists can easily recognize mild degrees of emphysema that are rarely associated with clinical disability. Quantification of Emphysema There are a number of techniques for quantifying the volume of lung involved with “obvious” emphysema that are adequately reproducible and correlate well with one another (Thurlbeck 1976; Bignon 1976). Semi-quantitative or subjective scoring methods as well as point counting have been used. These approaches all require lungs inflated to a relevant volume, usually one approximating total lung capacity during life. This can be achieved by a distending pressure of 25 cm H:20 (Thurlbeck 1979; Berend et al. 1980). In the scoring method, the lung is divided into a number of units and the severity of emphysema in each unit is scored (mild, moderate, or severe receive 1, 2, or 3 points, respectively). The scores for each unit are summed to give a total score for the lung (Ryder et al. 1969). Alternatively, lung slices may be matched by visual comparison to a set of graded standards to achieve an emphysema score (Thurlbeck et al. 1970). These methods include both severity and extent of emphysema, and although they involve subjective judgments, they have proved to be remarkably reproducible. 120 In the point counting approach, regularly spaced points are superimposed on a lung slice. Each point is recorded as falling on normal parenchyma, emphysematous parenchyma, or nonparenchy- ma (conducting airways or vessels). The volume proportion of emphysematous lung is recorded. This method can be objective (e.g., if an emphysematous space is taken to be one greater than 1 mm in diameter), but it includes only extent and not severity of emphyse- ma. Morphometric methods carried out on histologic sections, exempli- fied by the mean linear intercept (Lm) (Thurlbeck 1967a, b), are strictly objective, but they require careful attention to problems of sampling and are time consuming and insensitive to focal disease. For measurements of the Lm, histologic sections are made of blocks selected by stratified random sampling. The average distance between alveolar walls is determined from the number of intersec- tions of alveolar walls with a line of known length. The internal surface area of the lung can be calculated when the volume of the lung is known (Hasleton 1972). Pulmonary Function in Emphysema Because unequivocal proof of the presence of emphysema requires direct examination of lung tissue, the strategies used to characterize the pulmonary function abnormalities associated with emphysema have either involved comparison of functional data collected during life with autopsy or surgical material or have used measurements made exclusively on post-mortem specimens. Two important conclu- sions from these studies should be noted at the outset. First, impaired air flow during maximal expiratory maneuvers, as reflect- ed in reduced values for the FEV, FEVi«, and FEFs75%, is neither sensitive nor specific for emphysema. It is possible to have severe emphysema without clinical obstructive lung disease (Thurlbeck 1977). It is also possible to have severe chronic obstructive lung disease without having emphysema, even though most patients with advanced chronic obstructive lung disease have some degree of emphysema (Mitchell et al. 1976). Second, none of the tests used to identify early obstructive lung disease, such as closing volume, the single breath Ne curve, or frequency dependence of compliance, distinguish diminished elastic recoil that may be related to emphyse- ma (see below) from increased resistance in small airways (Buist and Ducic 1979). Even the determination of density dependence of maximum expiratory airflow, once felt to be specific for detecting abnormalities in the caliber of small airways, is not immune to the effects of lung elastic recoil. A decreased effect on maximal expiratory air flow of using low density gas can be caused by decreased elastic recoil (Gelb and Zamel 1981). 121 Pulmonary function testing of individuals with proven emphyse- ma often shows increases of residual volume, functional residual capacity, and total lung capacity and decreases of maximal expirato- ry air flow (Boushy et al. 1971; Park et al. 1970; reviewed in Kidokoro et al. 1977). However, because individuals with emphysema commonly also have intrinsic airway disease (Cosio et al. 1978) affecting the results of these pulmonary function tests in the same direction as emphysema, it is clear that these tests are not specific for emphysema. Accordingly, there has been interest in other, more distinctive tests. Among readily applicable tests, the diffusing capacity has proved to be directly related to the extent of emphyse- ma (Park et al. 1970; Boushy et al. 1971; Berend et al. 1979), presumably reflecting a diminution of internal surface area avail- able for gas exchange. The usefulness of the diffusing capacity to identify and estimate emphysema is limited, however, because the measurement is not sensitive to low grades of emphysema (Symonds et al. 1974) or specific for emphysema. Moreover, the results must be interpreted carefully in smokers because the values for diffusing capacity are lower than in nonsmokers, and the difference extends even to young smokers who are not likely to have emphysema (Enjeti et al. 1978; Miller et al. 1983). Mechanical Properties of the Lungs in Emphysema Measurements of the pressure-volume characteristics of the lung have generally been regarded as a reliable means of physiologically detecting and quantifying emphysema because (a) patients with emphysema often have increased lung distensibility and correspond- ingly low transpulmonary pressures (loss of elastic recoil) and (b) the severity of emphysema has seemed to correlate with the change in elastic recoil. It has also been assumed that the regions of lung with emphysema are the cause of the decreased lung elastic recoil, an assumption that appears reasonable because elastic recoil results in part from surface forces at the air-liquid interface and there is less surface area in emphysema. Recent observations challenge these concepts. Berend and Thurl- beck (1982), using lungs obtained post mortem, could not demon- strate a relationship between indices of lung elasticity and the grade of emphysema in 48 lungs ranging in grade from 2 to 80 (on a scale of 100), and observed (Berend et al. 1981) in emphysematous lungs that the relative increase in compliance of the lower lobes was greater than the upper lobes, even though the emphysema was worse in the upper lobes. Others have also reported poor correlations between emphysema and elastic recoil. Silvers et al. (1980) found decreased elastic recoil and increased total lung capacity in excised human lungs with minimal emphysema, and Schuyler et al. (1978) noted in hamsters given small doses of elastase intravenously that there was 122 decreased lung elastic recoil at low lung volumes, although the lungs did not show morphometric changes. Guenter et al. (1981) noted that mild emphysema produced by pepsin caused greater changes in lung elasticity than similar degrees of lung destruction produced by endotoxin-induced repetitive leukocyte sequestration. They suggest- ed that these differences may be due to differences in the location of the connective tissue injury within the lung. Even among those who have reported an association between emphysema and elastic recoil, the correlations have been best when the emphysema was severe (Greaves and Colebatch 1980). Pare et al. (1982) found a correlation between emphysema grade and elastic properties of the lungs in 55 persons; however, in 5 whose surgically removed lung tissue received emphysema scores between 20 and 70 (out of a maximum of 100), the elastic properties of the lungs tested preoperatively were indistinguishable from normal. While such discrepancies probably reflect the limitations of relating the overall elastic properties of both lungs to the morphology of a single lobe, it must also be recognized that the sensitivity of the pressure-volume diagram is limited, since a narrow range of pressure (to 20 cm H20) depicts the average retractive force from millions of air spaces and the connective tissue network of the lung. From these recent findings it must be concluded that the relationship between elastic recoil and morphologic measures of emphysema is not highly predictable, and that the decrease of elastic recoil and increase of total lung capacity commonly seen in emphysematous lungs may not result entirely from abnormal mechanical properties in the areas showing emphysema. The mechanical abnormalities may also derive from areas that appear normal, although the possible reasons for this are obscure (reviewed by Thurlbeck 1983). An alternate explanation for this discordance between elastic recoil and morphologic emphysema may be the problems of sampling and grading intrinsic to these morphologic measures. The work of Michaels et al. (1979) introduces a further complexity to the use of pressure-volume curves as an indicator of emphysema. They found that inhalation of a bronchodilator shifted the curve of smokers in the direction of increased compliance, but had no effect in nonsmokers (Figure 26). Cessation of smoking had the same effect as a bronchodilator. These results were interpreted as indicating that smoking causes some peripheral airway units to constrict and become effectively closed. Thus, pressure-volume studies to detect early changes compatible with emphysema in smokers may give false negative results unless accompanied by studies with bronchodi- lators. 123 en 80 = = 74 8 a z z 3 60 4 O--O Smokers @——@ > Smokers B.D. O--O Nonsmokers . @——® Nonsmokers p B.D. 50 =—d a 4 0 T T t v 4 8 12 16 P(stathomH,0 FIGURE 26.—The effect of nebulized bronchodilator on the pressure-volume characteristics of the lungs in 19 smokers (6 men and 13 women) and 16 nonsmokers (9 men and 7 women) NOTE: The mean age was approximately 40 years (range, 19 to 56) and smokers used approximately 30 cigarettes per day. Male smokers showed borderline significant differences in indices of expiratory airflow and single breath Nz test data as compared with the male nonsmokers, but there was no difference in these tests between female smokers and nonsmokers. As shown, smokers had significantly less elastic recoil than nonsmokers. After the bronchodilator, the difference between smokers and nonsmokers increased further, particularly at high lung volume. B.D. = broncodilator; % pred. TLC = percent predicted total lung capacity; P(stat) = transpulmonary pressure. * p< 0.05; ** p< 0.01; *** p< 0.005. SOURCE: Michaels et al. (1979). Aging and Lung Structure With advancing age, structural and functional changes occur in the lungs of virtually all adults, even those who have no known exposure to specific inhalants through occupation or personal habits (Fishman 1982; Campbell and Lefrak 1983). The elastic recoil of the lungs declines with aging, and the residual volume to total lung capacity ratio increases. These changes are seen even in people who have never smoked, do not have signs or symptoms of cardiorespira- tory disease, and have the normal (MM) phenotype of a,-antiprotein- 124 ase (Knudson et al. 1977). Also with aging, the average distance between alveolar walls increases (Thurlbeck 1967a; Hasleton 1972), the proportion of lung volume that is composed of alveoli decreases, and the proportion of alveolar ducts increases (Ryan et al. 1965). Whether the differences in the lungs that occur with aging are a consequence only of the passage of time or are the result of subtle environmental insults summed over many years is unanswerable. They are “normal” or “abnormal” depending on whether one regards “normal” as a statistical concept or as the optimal state for the tissue. In either case, the aging lung has some features similar to emphysema. Age changes alone will not, however, contribute to or obscure the diagnosis of centrilobular emphysema, which involves mainly respiratory bronchioles, recognized macroscopically as focal lesions against a background of normal lung. The age changes may overlap with early panlobular emphysema (Anderson et al. 1970). However, since smokers usually die at an earlier age than nonsmok- ers, aging cannot account for the differences observed between the lungs of smokers and nonsmokers at autopsy. Emphysema and Cigarette Smoking Studies of people and of experimental animals conclusively link cigarette smoking to the development and extent of emphysema. This information is summarized in the following discussion. Observations in People Post-mortem material, used to approach the problem in the 1960s and 1970s, clearly established an association between smoking and emphysema. Post-mortem lung tissue has continued to be used to study emphysema, but the main goal of recent studies has been to identify those physiologic features that correlate with emphysema rather than to quantify the relationship between smoking and emphysema. Studies of emphysema using surgically removed lung tissue, a more recent approach to studying emphysema, have aimed mainly at elucidating the physiology of the emphysematous lung. The results of these studies have involved smokers almost exclusive- ly because of the rarity of emphysema in nonsmokers. Studies Using Post-Mortem Material A number of studies have examined the relationship between cigarette smoking and emphysema (Anderson et al. 1964, 1966; Thurlbeck 1963; Thurlbeck et al. 1974; Ryder et al. 1971; Auerbach et al. 1972, 1974; Spain et al. 1973). These data emphasize that not only is cigarette smoking closely associated with the development and extent of emphysema, but also it is extremely rare for the forms 125 of emphysema found in patients with COLD to be present to a significant degree in nonsmokers. Thurlbeck (1963) reported 19 patients who had severe emphysema at autopsy. All 19 were cigarette smokers, in contrast to 18 smokers out of 38 patients who did not have significant emphysema at autopsy. Anderson et al. (1964) conducted a more systematic evaluation of the relationship between cigarette smoking and the degree of emphysema at autopsy. They found that 12 of 23 patients without emphysema were cigarette smokers, whereas 55 of 84 with mild emphysema, 30 of 33 with moderate emphysema, and 14 of 15 with severe emphysema were cigarette smokers. Petty et al. (1967) reported similar findings, with 6 of 57 patients with moderate emphysema at autopsy being nonsmokers and only 1 of 61 patients with severe emphysema being a nonsmoker. Ryder et al. (1971) found that of 21 patients whose lungs showed more than 25 percent emphysema, only 1 was a nonsmoker. Thurlbeck et al. (1974) examined the relationship of age to extent of emphysema in smokers compared with nonsmokers in the combined autopsy populations of the teaching hospitals in three separate cities. The severity of emphysema was quantified using a panel grading method, with a score under 25 representing mild emphysema. They found that the degree of emphysema increased slightly in nonsmokers beginning in the fifth decade and reached an average score of 10 to 15 in men and 4 to 6 in women by the eighth and ninth decades. In contrast, male smokers had an average score of 25 to 30 by the seventh decade and maintained this level for the next two decades. Sutinen et al. (1978) (Table 13) examined the relationship between prevalence and extent of emphysema and duration of the smoking habit. As would be expected from previous studies, moderate or severe emphysematous changes were limited to smokers. However, these changes were also limited to those smokers who had smoked for 20 or more years, and severe emphysema was reported only in those who had smoked for 40 years or more. These data, coupled with that of Thurlbeck et al. (1974) describing only mild emphysematous changes in nonsmokers with advancing age, suggest that emphyse- ma is a late pathologic change in cigarette-induced lung disease. This correlates well with the clinical experience of severe emphysema being rare prior to the fifth decade. It also suggests that cessation, even among middle-aged smokers, may have substantial impact on emphysema morbidity and mortality. Dose-Response Relationships Some studies have reported the extent of emphysematous change in smokers of different numbers of cigarettes per day. Spain et al. (1973) examined the lungs of 134 subjects who died suddenly and 126 TABLE 13.—Correlation between the severity of emphysema at autopsy and total smoking duration Prevalence of emphysema (percent) by total smoking years Grade of emphysema 0 1-19 20-39 40 or more Total No emphysema 61.6 81.6 21.2 8.8 43.1 Mild (grades 5 to 20) 38.4 15.4 69.7 50.0 45.8 Moderate (grades 30 to 50) - - 9.1 26.5 78 Severe (grade 60 or more) - ~ - 14.7 3.3 All grades 38.4 15.4 78.8 918 56.9 Total number 73 13 33 34 153 NOTE: P < 0,005: X? test, with groups of moderate and severe emphysema and of smoking times 1-19 and 20— 39 years combined. SOURCE: Sutinen et al. (1978) who had no previous history of lung disease. They found emphysema- tous changes greater than grade 20 (mild emphysema) in 10 percent of nonsmokers, 36 percent of smokers of less than one pack per day, and 39 percent of smokers of more than one pack. A much larger study was conducted by Auerbach et al. (1972, 1974), who examined whole lung sections from 1,443 men and 388 women autopsied between 1963 and 1970. Table 14 describes the relationship of age, smoking habits, and degree of emphysema graded on a scale of 0 to 9, with 9 representing severe emphysema. It is clear that severe emphysema is limited to smokers, and that the severity of emphysematous change at autopsy increases with in- creasing number of cigarettes smoked per day during life. This study also found that almost all (94.5 percent) smokers of more than one pack per day had some degree of emphysema (slight, moderate, advanced, or far advanced) (Table 15). In contrast, 93.8 percent of nonsmokers had either none or minimal emphysema. This evidence would suggest that emphysematous change is a nearly universal phenomenon in heavy smokers, but is rare in nonsmokers, and that it is the large ventilatory reserve of the lungs that restricts clinically manifest disease to those individuals with far advanced emphysema. Similar results were reported in a more limited number of autopsies done on female smokers (Auerbach et al. 1974) (Table 16). A study of microscopic lung sections from the autopsies of 1,436 men and 388 women was also reported by Auerbach et al. (1974), and closely paralleled the results of the whole lung study. However, they also reported the results in smokers who had quit for more than or less than 10 years prior to death (Table 17). The degree of emphysematous change was still related to the amount smoked, but 127 TABLE 14.—Degree of emphysema in current smokers? and in nonsmokers, according to age groups Subjects Current Age Degree of who never pipe or Current cigarette group emphysema smoked cigar smokerst regularly smokers —_ hot ota lt 1 2t 2+ ¢ 0-60.75 5a 1s 12 3 2 = 1 1.75 2 ll 4 9 24 4 2.2.75 1 2 Ww 130 56 < 60 33.95 1 5 12 50 3& 4475 4 8 7 5 6.75 4 5 7 9.00 3 1 Totals 55 31 23 45 221 112 Mean 0.10 0.83 1.29 2.37 2.56 2.86 SD 0.04 0.13 0.26 0.16 0.07 0.10 0.0.75 35 Wv 4 ~ - 1-1.75 1 x 1 - 4 1 2-2.75 2 3 4 5 37 23 60-69 343.75 2 2 2 9 42 24 44.75 1 3 1h 9 5-675 1 8 1 7-9.00 1 5 4 Totals 40 30 12 19 107 62 Mean 0.39 0.95 1.90 3.59 3.39 3.37 SD 0.13 0.16 0.34 0.35 0.15 0.20 0-0.75 68 2k 2 . . 1-1.75 4 28 10 8 2 2 2 2.74 i 2 13 23 40 9 70 or 3-38.75 4 8 5 10 38 8 older 44.75 2 i 7 ll 7 54.75 1 2 9 3 7- 9.00 1 12 5 Totals R] 82 3h 51 112 44 Mean 0.50 1.66 2.15 2.98 3.68 3.91 sD 0.39 OA] O17 0.20 0.17 0.27 * Subjects who smoked regularly up to time of terminal itlness +Packages- day SOURCE: Auerbach et al. (1972). was less in those who had quit for more than 10 years prior to death, suggesting that the cessation of smoking results in a slowing of the 128 TABLE 15.—Age-standardized percentage distribution of male subjects in each of four smoking categories, according to degree of emphysema Subjects Current Degree of who never pipe or Current emphysema smoked cigar cigarette regularly smokers smokers (%) to) ry " i+ * 0-0,.75 (none) ao.u 46.5 13.1 0.3 4-1.75 (minimal) 38 33.0 16.4 5.2 2-2.75 (slight) 3.38 13.0 33.7 12.6 3-3.75 {moderate} 29 63 25.1 32.7 4$-9.00 (advanced to far advanced} ( 12 Wt 19.2 Totals 1000 100.0 100.0 100.0 *Packages day. SOURCE: Auerbach et al. (1972) TABLE 16.—Means of the numerical values given lung sections at autopsy of femaie current smokers, standardized for age Subjects who Current cigarette never smoked smokers regularly <1 Pk. >1 Pk. _ Number of subjects 252 33 64 Emphysema 0.05 1.37 1.70 Fibrosis 0.37 2.89 3.46 Thickening of arterioles 0.06 1.26 1.57 Thickening of arteries 0.01 0.40 0.64 NOTE: Numerical values were determined by rating each lung section on scales of 0-4 for emphysema and thickening of the arterioles, 0-7 for fibrosis, and 0-3 for thickening of the arteries. SOURCE: Auerbach et al. (1974). rate of progression of emphysematous change in those who quit compared with those who continue to smoke. Studies of Alphas-Proteinase-Inhibitor-Deficient Individuals The deficiency of a,-proteinase inhibitor is an experiment of nature with broad implications for understanding the pathogenesis of emphysema (Idell and Cohen 1983). Discovery of homozygous- deficient subjects (type PiZZ) with only 10 percent of normal plasma 129 TABLE 17.—Means of the numerical values given lung sections at autopsy of male former cigarette smokers, standardized for age Never smoked regularly Stopped >10 years Stopped <10 years Formerly smoked <1 Pack >1 Pack <1 Pack >1 Pack Number of 175 35 66 51 131 subjects Emphysema 0.09 0.24 0.70 1.08 1.69 Fibrosis 0.40 114 1.74 2.44 3.30 Thickening of 0.10 0.57 0.93 1.25 1.59 arterioles Thickening of 0.02 0.04 0.16 0.36 0.61 arteries NOTE: Numerical values for each finding were determined by rating each lung section on scales of 0-4 for emphysema and thickening of the arterioles, 0-7 for fibrosis, and 0-3 for thickening of the arteries. SOURCE: Auerbach et al. (1974). proteinase inhibitory activity and the demonstration of the frequent early development of emphysema in such subjects (Orell and Mazodier 1972) called attention to the critical step of fibrous tissue proteolysis in the remodeling of lung structure. It also pointed to at least one potential explanation for the variability in extent of emphysema among smokers. Together with data from animal experiments, the discovery of the PiZZ defect and its association with emphysema has led to general acceptance of a theory of imbalance between the extracellular levels of proteinase and proteinase inhibitor in the lung as the cause of panacinar emphysema in subjects with this deficiency. The patho- genetic lessons learned from a,-proteinase-inhibitor deficiency also afford plausible explanations for other forms of emphysema, espe- cially emphysema associated with cigarette smoking. Homozygous Deficient—PiZZ In his classic description of the severe (PiZZ) deficiency of the a,- proteinase inhibitor, Eriksson (1965) did not indicate an effect. of cigarette smoking on the development of emphysema. Later studies, however, did recognize smoking as a potential aggravating factor (Kueppers and Black 1974, Larsson 1978) and reported that PiZZ persons who smoked cigarettes were destined to experience shortness of breath 10 to 15 years earlier (Figure 27) and to die sooner than PiZZ persons who did not smoke (Figure 28). 130 Men Women Smokers Nonsmokers Smokers Nonsmokers 704 e - ° 7 3 ° e r e 60 4 e = eae ° _ e eo 7 { ° r & oe =~ ce egge —_eo—— o D 8 } e e g 4 = bs tt «4 t i fi | 83. ° 4 ees — 30 4 a r— 4 ee = e e 20 + oe oe t 4 e — FIGURE 27.—Age at onset of dyspnea in 169 PiZZ individuals separated according to sex and smoking history NOTE: The horizontal lines show the median values. The difference between nonsmokers and smokers was highly significant for both sexes and was 13 and 15 years for men and women, respectively. SOURCE: Larsson ‘1978). More recent studies, however, have shown considerable variation in the rate of decline of lung function among middle-aged PiZZ adults (Buist et al. 1983). In a comparison of 22 persons with PiZZ phenotype who had never smoked with 36 PiZZ smokers, Black and Kueppers (1978) found variability in symptoms and lung function abnormalities in both groups. Smokers generally sought medical attention earlier, and those who reached the older age groups, such as 60 to 69, had smoked less and started to smoke later in life. There was overlap in these characteristics between the age groups, however, and some smokers did live into the 50 to 69 age range. In this analysis, the correlations between pulmonary function test abnormalities and pack-years of cigarette smoking were small. The British Thoracic Society, in a multicentered study of PiZZ individuals (Tobin et al. 1983), reported an association between 131 @ Smoking PiZ men and women 1.0 J O Nonsmoking PiZ men and women S os A All Swedish women 2 & Ali Swedish men a 4 6 z 06 + a g —_ a & © 04 44 > 3 = J § g 02 TTT TTT rh lt 20 30 40 50 60 70 80 90 100 Age (in years) FIGURE 28.—The cumulative probability of survival, given that 20 years of age is reached, in smoking and nonsmoking Swedish PiZZ individuals, compared with all Swedish men and women NOTE: Survival was higher for PiZZ nonsmokers than for PiZZ smokers in both sexes above age 35. SOURCE: Larsson (1978). cigarette smoking and the onset of pulmonary symptoms and deterioration of lung function, but demonstrated no significant correlation between the quantity of tobacco consumed and the extent of pulmonary dysfunction. A notable finding in this study, applicable to other studies of the natural history of disease related to ai- proteinase-inhibitor deficiency, was the impressive difference be- tween individuals found because of medical complaints (index cases) and those detected by surveys (nonindex cases). Nonindex cases had better pulmonary function and survived longer than index cases, irrespective of other variables such as age and smoking history. The distinction between these two categories of subjects suggests the importance of factors besides the PiZZ phenotype in the development of symptomatic lung disease in PiZZ persons. PiZZ individuals who smoke increase their risk for early onset of symptomatic chronic obstructive lung disease and for a shortened lifespan, compared with nonsmoking PiZZ individuals. However, pulmonary function data have shown only limited differences in diffusing capacity and elastic recoil between the smokers and the nonsmokers (Black and Kueppers 1978). 132 Heterozygous Deficient—PiMZ The PiMZ phenotype of a,-antiproteinase inhibitor occurs in approximately 3 percent of the population. Because of the high frequency of emphysema in PiZZ persons, it is important to establish whether PiMZ individuals also have an increased risk of emphysema and chronic obstructive lung disease. From the unpredictability of obstructive lung disease even among those with the PiZZ phenotype, however, one might expect difficulty in discerning the effect of the PiMZ phenotype. Among adults with symptomatic chronic obstructive lung disease, the PiMZ phenotype is more prevalent than expected (Mittman 1978). It is uncertain whether this means of subject identification is appropriate, as was noted concerning index and nonindex PiZZ individuals. Madison et al. (1981) emphasized the complexity of this issue by noting that the PiMZ phenotype was only one of several factors that appeared to be related to the risk of obstructive lung disease. Other factors identified as relevant included smoking, a family history of lung diseases, and being male. From studies of children and young adults it is evident that the PiMZ phenotype does not strongly predispose to chronic pulmonary disease. Thus, PiMZ children (Buist et al. 1980) failed to show any early changes of lung dysfunction analogous to what has been observed in some young PiZZ individuals; PiMZ adults below the age of 40 had the same results by spirometry and the single breath No test as PiMM individuals matched for smoking history (Buist et al. 1979b). Numerous studies involving older subjects indicate that PiMZ individuals preserve their lung function, as measured by spirometry, compared with controls matched for smoking (Tattersall et al. 1979, de Hamel and Carrell 1981). The elastic properties of the lungs may be different in PiMZ persons, but if there are differences, they are small. Larsson et al. (1977) reported that 50-year-old PiMZ men who smoked had reduced elastic recoil at total lung capacity compared with PiMZ nonsmokers, even though they had no evidence of impaired air flow. The PiMZ nonsmokers were indistinguishable from PiMM nonsmokers. Tattersall et al. (1979) also found no effect upon airflow in PiMZ middle-aged men, and a statistically nonsignif- icant decrease in elastic recoil. Using an index of the slope of the pressure-volume curve, Knudson and Kaltenborn (1981) found no significant reduction in elastic recoil of PiMZ subjects compared with matched PiM controls. There is little direct information about the occurrence of emphyse- ma among PiMZ individuals. In an autopsy study, Eriksson et al. (1975) found emphysema among 13 of 26 subjects with diastase- resistant PAS-positive inclusions in the liver, compared with an incidence of emphysema of only 18 percent in the controls. Although 133 these findings suggest an increased occurrence of emphysema with the PiMZ phenotype, this study should be interpreted cautiously because the smoking histories of the subjects and the quantification of the emphysema were not included. Moreover, the significance of the PAS-positive inclusions is not certain, because one recent study found that such inclusions represented immunoreactive a,-protein- ase inhibitor in only half of the tissue studied (Qizilbash and Young- Pong 1983). It may be concluded from the studies involving a,-proteinase- inhibitor-deficient people that for those with the PiMZ phenotype, smoking has not been shown to promote a greater risk of emphysema than it does in PiMM persons. In the rare individual with PiZZ, the risk of emphysema is extremely high in both smokers and nonsmok- ers, but PiZZ smokers experience an earlier onset and more severe chronic obstructive lung disease than PiZZ nonsmokers. Observations in Experimental Animals Experimental animals have been subjected to cigarette smoke to examine whether changes typical of emphysema result. As noted below, it appears that cigarette smoke exposure can produce emphysematous-like changes in the lungs under experimental conditions, but the exposure must be quite prolonged and intense, or additional factors must be employed to “sensitize” the lungs to the effects of cigarette smoke. Pioneering studies in dogs exposed to cigarette smoke, by Hernan- dez et al. (1966) and by Auerbach et al. (1967), indicated effects consistent with emphysema, but these reports did not include quantitative morphology or data about the mechanical properties of the lungs. Moreoever, the exposures may have created problems of hypoxemia and infection that may have influenced the responses to cigarette smoke. Contrary to these findings, in later studies, beagles that inhaled cigarettes by face mask in four sessions per day for up to 1 year—an inhalation sufficient to raise the blood carboxyhemoglo- bin saturation to 5.4 + 0.9 percent—had no statistically significant changes in mean linear intercept or internal surface area, although their large airways showed epithelial cell hyperplasia, proliferation of goblet cells, and peribronchial inflammation (Park et al. 1977). Recently, Hoidal and Niewoehner (1983) presented data suggesting that cigarette smoke may be an important cofactor in the develop- ment of elastase-induced emphysema. They found that inhalation of cigarette smoke led to severe emphysema in hamsters if used in conjunction with doses of elastase that did not produce emphysema when used alone. In this study, hamsters were exposed to cigarette smoke for 15 minute periods, six times per day, 6 days per week for 7 weeks in standardized chambers. The animals were challenged with small doses of elastase given intratracheally; controls consisted of 134 animals given either elastase or smoke exposure or neither. Animals receiving only smoke or only elastase showed no changes of mean linear intercept or volume—pressure relationship of the excised lungs, compared with animals given neither elastase nor smoke exposure. The combinations of smoking followed by elastase or smoking both before and after elastase produced statistically signifi- cant increases of mean linear intercept, displacement upward and to the left of the volume—pressure curves (Figure 29), and marked emphysema by light microscopy of inflation-fixed lungs. The mecha- nism of the synergism between elastase and smoking was not elucidated. One possibility considered was that cigarette smoke impaired the repair mechanism normally triggered by elastase exposure, a possibility supported by Osman et al. (1982), who found that hamsters exposed to cigarette smoke after intratracheal elas- tase did not show the heightened lung elastin synthesis typically seen after lung injury produced by elastase. Summary Clinically significant degrees of emphysematous lung destruction are commonly present in individuals with COLD. Severe emphysema occurs almost exclusively in cigarette smokers and those with homozygous a,-antitrypsin deficiency. The extent of emphysematous change increases with increasing numbers of cigarettes smoked per day and with the duration of the smoking habit. While clinically significant emphysema is limited to a minority of those who smoke, most heavy smokers have some degree of emphysematous change by the sixth decade of life. Individuals with homozygous a,-antitrypsin deficiency have an exceptionally high risk of developing emphysema. This risk is present for both smokers and nonsmokers, but smokers with a.- antiprotease deficiency develop clinical symptoms earlier in life. It is unclear whether individuals with heterozygous antiprotease pheno- types are at increased risk of developing COLD. Summary and Conclusions 1. Cigarette smoking is the major cause of COLD morbidity in the United States; 80 to 90 percent of COLD in the United States is attributable to cigarette smoking. 2.In population-based studies in the United States, cigarette smoking behavior is often the only significant predictor for the development of COLD. Other factors improve the predictive equation only slightly, even in those populations where they have been found to exert a statistically significant effect. 3.In spite of over 30 years of intensive investigation, only cigarette smoking and a,-antiprotease deficiency (a rare genet- 135 120 F—- * i f 100 [- S80 F rz oD Ke a — & 2 2 60 - oa > mn Cc 3 | @ Nosmoke, no elastase O Continuous smoke, no elastase 40 Hl No smoke. elastase C) Post-elastase smoke s & Pre-elastase smoke A Continuous smoke, elastase 20 p- ,05 compared with * No smoke, no elastase L r l i 1 | 5 10 15 20 25 30 Pressure (cmH,O) FIGURE 29.—The effects of combining cigarette smoking and elastase upon the pressure-volume characteristics of the lungs of experimental animals NOTE: The in vitro measurements of lung volume are shown as percentage of predicted total lung capacity (TLC) relative to transpulmonary pressure of hamster lungs following in vivo exposure to various combinations of cigarette smoke and intratracheally administered pancreatic elastase. Values are the mean + SEM of measurements made during deflation The animals that smoked and then received elastase (Pre-Elastase Smoke) and those that smoked both before and after elastase (Continous Smoke, Elastase) had significant changes in the elastic properties of the lungs. There were no changes from control if elastase or smoking were used separately or when smoking occurred only after elastase. SOURCE: Hoidal and Niewoehner (1983). ic defect) are established causes of clinically significant COLD in the absence of other agents. 4. Within a few years after beginning to smoke, smokers experi- ence a higher prevalence of abnormal function in the small airways than nonsmokers. The prevalence of abnormal small airways function increases with age and the duration of the 136 10. smoking habit, and is greater in heavy smokers than in light smokers. These abnormalities in function reflect inflammatory changes in the small airways and often reverse with the cessation of smoking. Both male and female smokers develop abnormalities in the small airways, but the data are not sufficient to define possible sex-related differences in this response. It seems likely, how- ever, that the contribution of sex differences is small when age and smoking exposure are taken into account. _There is, as yet, inadequate information to allow a firm conclusion to be drawn about the predictive value of the tests of small airways function in identifying the susceptible smoker who will progress to clinical airflow obstruction. _Smokers of both sexes have a higher prevalence of cough and phlegm production than nonsmokers. This prevalence in- creases with an increasing number of cigarettes smoked per day and decreases with the cessation of smoking. Differences between smokers and nonsmokers in measures of expiratory airflow are demonstrable by young adulthood and increase with number of cigarettes smoked per day. The rate of decline in measures of expiratory airflow with increasing age is steeper for smokers than for nonsmokers; it is also steeper for heavy smokers than for light smokers. After the cessation of smoking, the rate of decline of lung function with increasing age appears to slow to approximately that seen in nonsmokers of the same age. Only a minority of smokers will develop clinically significant COLD, and this group will have demonstrated a more extensive decline in lung function than the average smoker. The data are not yet available to determine whether a rapid decline in lung function early in life defines the subgroup of smokers who are susceptible to developing COLD. Clinically significant degrees of emphysema occur almost exclusively in cigarette smokers or individuals with genetic homozygous a,-antiprotease deficiency. The severity of em- physema among smokers increases with the number of ciga- rettes smoked per day and the duration of the smoking habit. 137 Appendix Tables 6ET a+swrases ue—easv, lor white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexes Men Women Cigarette smoking status (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Never smokers 25-74 3140! 21' 3669' 39! 2664! 19! 25-34 6733 394 3607 791 51 2633 130 4404 584 63 4099 264 3095 372 26 35-44 5278 291 3171 607 49 1669 81 3742 591 73 3609 210 2907 397 40 45-54 4942 353 2840 594 35 1206 85 3487 626 72 3736 268 2631 401 29 55-64 3660 251 2511 589 31 880 59 3215 531 81 2781 192 2289 401 29 65-74 2875 235 2148 549 36 481 43 2856 627 96 2394 192 2006 402 36 Ex-smokers 25-74 3112 24 3623 37 2651 28 25-34 2811 160 3677 810 80 1359 66 4303 627 92 1452 94 3091 441 55 35-44 3086 171 3566 767 69 1828 94 4013 643 70 1258 77 2916 361 44 45-54 3323 213 3155 742 65 2345 143 3414 683 69 978 70 2535 454 65 55-64 2669 181 2845 693 63 1826 130 3087 649 63 843 §1 2319 456 90 65-74 1769 157 2388 686 66 1270 121 2533 699 78 499 36 2020 487 92 Smokers 25-74 2878 20 3281 32 2514 27 , 2-34 8885 487 3567 752 44 4792 239 4037 639 51 4093 248 3018 435 41 3444“ 5849 320 3166 655 47 3027 158 3507 639 71 2822 162 2800 439 43 45-54 5606 374 2761 623 37 2743 182 3126 579 49 2863 192 2411 437 40 55-64 3251 192 2416 631 50 1700 108 2738 632 63 1551 84 2064 400 50 65-74 933 84 2071 653 86 534 56 2222 556 79 400 28 1869 714 155 OvT TABLE A.—Continued Both sexes Men Women Cigarette smoking or status (by age) N n Mean SD SE N hn Mean sD SE N Dn Mean SD SE Light smokers 25-74 2951 38 3311 57 2626 52 25-34 2162 113 3425 650 97 879 43 3914 508 102 1283 70 3089 508 88 35-44 1267 72 3106 618 93 308 17 3775? 515 139 859 55 2891 479 83 45-54 1090 76 2683 490 73 383 24 3009 409 95 707 52 2507 437 76 55-64 1043 57 2408 573 83 313 18 2919? 660 150 730 39 2190 350 62 65-74 304 21 2150 137 185 131 Bl 2222? 426 130 172 10 2095? 901-305 Moderate smokers 25-74 2878 23 3335 40 2466 25 25-34 4269 235 3671 810 60 2534 123 4136 684 69 1735 112 2991 393 51 35-44 2413 130 3217 646 68 1214 66 3593 624 99 1199 64 2836 395 47 45-54 2715 179 2679 634 53 1145 15 3106 622 719 1570 104 2368 429 51 55-64 1287 82 2406 589 68 690 45 2776 455 60 597 37 1977 408 10 65-74 464 4 2023 609 105 261 28 2279 572 126 203 16 1693? 484 «124 Heavy smokers 25-74 2785 32 3202 52 2409 38 25-34 QAIT 136 3514 699 70 1363 72 3927 597 82 1054 64 2979 393 80 35-44 2148 116 3143 684 val 1505 75 3382 646 89 643 41 2582 373 64 45-54 1779 118 2930 649 70 1193 82 3184 579 15 586 36 24h 440 92 55-64 922 53 2440 741 118 697 45 2619 737 133 224 8 1883? 398 «121 65-74 154 18 20387 606 151 130 16 2096? 638 172 24 2 1733? 215 150 NOTE: N = weighted population estimate in thousands; | Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. * Does not meet standards of reliability. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). n = number of people in sample; SD = standard deviation; SE = standard error. Trl TABLE B.—Flow at 25 percent of FVC for white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexes Men Women Cigarette smoking status (by age) N n Mean SD SE N no Mean SD SE N n Mean SD SE Never smokers 25-74 6253" 47' 7261' 91' 5343! 36! 25-34 6733 394 6639 1591 98 2633 130 7871 1513 157 4099 264 5847 1042 89 35-44 5278 291 6377 1484 114 1669 81 7715 1545 176 3609 210 §758 952 80 45-54 4942 353 5742 1586 90 1206 85 7262 1796 213 3736 268 5252 1141 70 55-64 3660 251 5368 1397 101 880 59 6543 1593 265 2781 192 4996 1091 83 65-74 2875 235 4626 1576 102 481 43 6097 1961 298 2394 192 4331 1303 108 Ex-smokers 25-74 6093 62 7095 107 5188 67 25-34 2811 160 6835 1855 203 1359 66 8042 1715 285 1452 94 5705 1126 165 35-44 3086 171 7020 2041 176 1828 94 7956 2059 232 1258 77 5659 965 116 45-54 3323 213 6270 1896 164 2345 143 6765 1919 185 978 70 5084 1176 151 55-64 2669 181 5783 1764 144 1826 130 6261 1820 160 843 51 4749 1058 197 65-74 1769 157 4918 1948 207 1270 121 5194 2091 265 499 36 4213 1278 197 Smokers 25-74 5647 47 6362 88 5002 52 25-34 8885 487 6760 1694 102 4792 239 7606 1663 126 4093 248 5769 1081 83 35-44 5849 320 6157 1740 123 3027 158 6848 1875 180 2822 162 5415 1200 102 45-54 5606 374 5471 1658 92 2743 182 6130 1783 137 2863 192 4840 1233 106 55-64 3251 192 §123 1815 132 1700 108 5567 2041 223 1551 84 4636 1372 169 65-74 933 84 3954 1586 181 534 56 4199 1745 238 400 28 3627 1274 255 ol TABLE B.—Continued Both sexes Men Women Cigarette smoking ~ status (by age) N nh Mean SD SE N n Mean sD SE N n Mean sD SE Light smokers 25-74 5834 91 6569 142 5171 112 25-34 2162 113 6549 1652 209 879 43 1688 1690 293 1283 70 5769 1071 140 35-44 1267 72 6045 1481 211 308 17 7250? 1634 369 959 55 5658 1193 188 45-54 1090 76 5545 1476 217 383 24 6373 1572 311 707 52 5096 1203-193 55-64 1043 57 5222 1534 238 313 18 6096? 1616 399 730 39 4849 1333 249 65-74 304 21 3779 1272 345 131 ll 3742? 1279 482 172 10 i? 1266 489 Moderate smokers 25-74 5661 66 6430 118 4967 76 25-34 4269 235 6909 1719 136 2534 123 7647 1667 164 1735 112 5831 1120-132 35-44 2413 130 6384 1786 194 1214 66 7348 1738 236 1199 64 5408 1212 =—-:170 45-54 2715 179 5269 1490 i 1145 75 5821 1661 183 1570 104 4867 1202137 55-64 1287 82 5065 1787 202 690 45 5576 1897 334 597 37 4475 1439-265 65-74 464 44 3950 1717 304 261 28 4356 1892 404 203 16 3427? 1285 = 319 Heavy smokers 25-74 5485 85 6219 151 4822 ll 25-34 QA1T 136 6691 1659 166 1363 12 7468 1640 225 1054 64 5685 1018 =: 17€ 35-44 2148 116 5964 1815 198 1505 15 6363 1902 261 41 5031 1084 186€ 45-54 1779 118 5712 1940 207 1193 82 6326 1920 251 586 36 4458 1257-266 55-64 922 53 5090 2117 321 697 45 §322 2288 434 224 8 4370? 1202-355 65-74 154 18 4155? 1653 401 130 16 4180? 1758 463 24 2 40237 904 = 626 NOTE: N = Weighted population estimate, in thousands; n = number of people in sample; SD = standard devia ' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. * Does not meet standards of reliability. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and E: tion; SE = standard error. ‘xamination Survey (NHANES 1). ert TABLE C.—Flow at 50 percent of FVC for white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexes Men Women Cigarette smoking status (by age) N n Mean SD SE N n Mean sD SE N n Mean SD SE Never smokers 25-74 3743' 38! 4083' 86! 3342! 34! 25-34 6733 394 4381 1194 69 2633 130 4998 1255 128 4099 264 3984 963 78 35-44 5278 291 3904 1164 84 1669 81 4315 1221 152 3609 210 3713 989 91 45-54 4942 353 3366 1212 84 1206 85 3972 1287 150 3736 268 3170 1119 90 55-64 3660 251 3090 1087 74 880 59 3736 1220 180 2781 192 2886 955 72 65-74 2875 235 2535 1045 3 481 43 3157 1060 174 2394 192 2410 996 84 Ex-smokers 25-74 3579 59 4188 67 3123 81 25-34 2811 160 4329 1292 120 1359 66 5029 1243 195 1452 94 3674 949 114 35-44 3086 171 4249 1384 129 1828 94 4702 1410 180 1258 77 3590 1037 160 45-54 3323 213 3474 1404 114 2345 143 3749 1428 143 978 70 2816 1091 147 55-64 2669 181 3110 1411 118 1826 130 3294 1362 127 843 51 271 1432 293 65-74 1769 157 2524 1296 121 1270 121 2578 1364 153 499 36 2384 1092 167 Smokers 25-74 3169 39 3475 59 2892 54 25-34 8885 487 4126 1268 74 4792 239 4546 1296 103 4093 248 3634 1037 90 35-44 5849 320 3552 1298 87 3027 158 3764 1399 140 2822 162 3325 1137 98 45-54 5606 374 2924 1208 76 2743 182 3257 1278 92 2863 192 2604 1040 94 55-64 3251 192 2587 1248 107 1700 108 2793 1364 148 1561 84 2361 1062 144 65-74 933 84 1922 1220 159 534 56 1889 1174 175 400 2B 1965 1279 252 Per TABLE C.—Continued Both sexes Men Women Cigarette smoking — status (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Light smokers 25-74 3313 14 3676 110 2984 102 25-34 2162 113 3964 1230 169 879 43 4617 1248 222 1283 70 3516 994 162 35-44 1267 72 3630 1076 151 308 \7 4190? 943 226 959 55 3450 1054 168 45-54 1090 76 2911 864 107 383 24 3150 969 197 707 52 2781 711 103 55-64 1043 57 2756 1375 205 313 18 3542? 1643 395 730 39 2420 1080 =. 200 65-74 304 21 2056 1252 292 131 11 1706" 883 366 172 10 23217 1415425 Moderate smokers 25-74 3207 57 3561 79 2888 71 25-34 4269 235 4246 1239 96 2534 123 4640 1297 126 1735 112 3671 872 47 35-44 2413 130 3781 1182 124 1214 66 4039 1198 171 1199 64 3520 1107 142 45-54 27115 179 2775 1205 111 1145 15 3079 1243 124 1570 104 2553 1125 140 55-64 1287 82 2665 1186 167 690 45 2873 1191 207 597 37 2425 11340245 65-74 464 44 1881 1239 218 261 28 2131 1316 279 203 16 1558? 1047-266 Heavy smokers 25-74 3043 68 3283 92 2828 110 25-34 2417 136 4067 1333 153 1363 72 4326 1305 197 1054 64 3733 1295247 35-44 2148 116 3239 1469 166 1505 15 3456 1550 227 643 41 2731 1103 185 45-54 1779 118 3152 1355 147 1193 82 3458 1377 168 586 36 2526 1062 9-222 55-64 922 53 2286 1123 173 697 45 2379 1222 221 224 8 1997? 651 232 66-74 154 18 1760? 1113 285 130 16 1559* 1059 274 2A 2 2834" 703 490 NOTE: N = weighted population estimate, in thousands; n = number of people in sample, ‘ Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. * Does not meet standards of reliability. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). SD = standard deviation; SE = standard error. SFI TABLE D.—Flow at 75 percent of FVC for white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexes Men Women Cigarette smoking status (by age) N a Mean sD SE N Qo Mean SD SE N n Mean sD SE Never smokers 25-74 1230! 28° 1329° 42! 1073" 24! 25-34 6733 394 1776 714 52 2633 130 2065 649 72 4099 264 1590 691 62 35-44 5278 291 1277 621 49 1669 81 1478 843 129 3609 210 1184 456 32 45-54 4942 353 1044 636 44 1206 85 1184 664 74 3736 268 999 620 53 55-64 3660 251 7137 611 36 880 59 978 612 83 2781 192 661 449 34 65-74 2875 235 609 463 32 481 43 795 408 64 2394 192 572 465 38 Ex-smokers 25-74 1152 29 1403 41 992 37 25-34 2811 160 1695 678 61 1359 66 1925 664 109 1452 94 1480 616 72 35-44 3086 171 1460 664 62 1828 94 1623 693 92 1258 71 1224 538 59 45-54 3323 213 1026 625 48 2345 143 1148 666 59 978 70 134 378 53 55-64 2669 181 134 541 54 1826 130 178 446 41 43 51 638 694 156 65-74 1769 157 588 506 43 1270 121 592 516 47 499 36 578 481 87 Smokers 25-74 967 22 1053 29 889 34 25-34 8885 487 1530 688 41 4792 239 1665 655 60 4093 248 1373 692 65 35-44 5849 320 1062 552 34 3027 158 1134 599 57 2822 162 985 486 35 45-54 5606 374 778 511 31 2743 182 866 530 41 2863 192 693 478 43 55-64 3251 192 631 536 42 1700 108 113 580 63 1551 84 541 468 56 65-74 933 84 452 689 100 534 56 350 445 77 400 2 588 901 199 OFT TABLE D.—Continued Both sexes Men Women Cigarette smoking status (by age) N D Mean sD SE N n Mean SD SE N n Mean SD SE Light smokers 25-74 1049 44 1120 64 985 67 25-34 2162 113 1480 679 94 879 43 1647 606 113 1283 70 1366 703 127 35-44 1267 72 1122 534 63 308 17 1294? 484 101 959 55 1067 537 73 45-54 1090 76 837 431 57 383 24 840 500 137 707 52 836 388 42 55-64 1043 57 706 540 85 313 18 931? 652 182 730 39 609 450 88 65-74 304 21 660 1040 264 131 11 393? 587 231 172 10 864? 1244 414 Moderate smokers 25-74 970 28 1107 41 846 32 25-34 4269 235 1603 685 57 2534 123 1755 686 82 1735 112 1382 620 16 35-44 2413 130 1134 499 62 1214 66 1265 517 78 1199 64 1000 443 58 45-54 2715 179 TT 480 49 1145 15 801 416 47 1570 104 656 514 67 55-64 1287 82 643 598 72 690 45 184 637 119 597 37 481 503 69 65-74 464 44 373 366 68 261 28 381 375 85 203 16 363? 353-103 Heavy smokers 25-74 882 47 956 38 815 82 25-34 2417 136 1447 689 95 1363 12 1503 593 101 1054 64 1874 790 172 35-44 2148 6 940 595 63 1505 75 995 647 85 643 41 Bil 422 69 45-54 1779 118 836 589 57 1193 82 941 624 3 586 36 620 438 19 55-64 922 53 529 410 57 697 45 545 416 62 224 8 479? 388 160 65-74 154 18 2977 453 112 130 16 2587 408 98 24 2 505? 6038 420 NOTE: N = weighted population estimate, in thousands, ' Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. * Does not meet standards of reliability. n = number of people in sample; SD = standard deviation; SE = standard error. SOURCE: National Center for Health Statistics. Unpublished data from the firat National Health Nutrition and Examination Survey (NHANES 1). LPT TABLE E.—FEV,/FVC ratio for white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexes Men Women Cigarette smoking status (by age) N n Mean sD SE N n Mean SD SE N n Mean sD SE Never smokers 25-74 79.17 0.21' T79' 0.34! 80.2! 0.23! 25-34 6733 394 82.5 6.08 0.34 2633 130 80.7 5.91 0.69 4039 264 83.6 5.93 0.44 35-44 5278 291 80.3 §.67 0.37 1669 81 78.8 5.25 0.64 3609 210 80.9 5.73 0.45 45-54 4942 353 78.7 5.84 0.38 1206 85 775 5.95 0.77 3736 268 79.0 5.75 0.41 55-64 3660 251 77.6 §.03 0.35 880 59 75.8 5.13 0.81 2781 192 78.2 4.85 0.39 65-74 2875 235 76.5 6.41 0.52 481 43 73.5 7.59 1.14 2394 152 77.0 5.97 0.55 £x-smokers 25-74 117 0.30 76.6 0.44 78.7 0.41 25-34 2811 160 817 §.92 0.53 1359 66 80.9 5.94 0.94 1452 94 82.4 5.81 0.78 35-44 3086 171 79.5 6.26 0.56 1828 94 78.8 6.78 0.83 1258 7 80.4 5.26 0.69 45-64 3323 213 76.2 6.58 0.50 2345 143 159 7.10 0.66 978 70 77.0 5.04 0.69 55-64 2669 181 13.7 7.79 0.70 1826 130 72.7 8.07 0.79 843 51 76.0 6.60 1.36 65-74 1769 157 715 9.34 1.05 1270 121 70.0 9.83 1.20 499 36 75.3 6.58 1.05 Smokers 25-74 75.9 0.26 74.0 0.36 715 0.39 25-34 8885 487 80.3 6.78 0.38 4792 239 79.2 6.50 0.52 4093 248 817 6.85 0.61 35-44 5849 320 16.7 7.28 0.46 3027 158 75.3 7.92 0.71 2822 162 78.2 6.16 0.47 45-54 5606 374 74.2 7.05 0.41 2743 182 73.0 7.55 0.59 2863 192 75.4 6.32 0.52 55-64 3251 192 73.1 8.73 0.59 1700 108 70.6 9.59 1.03 1551 84 76.0 6.61 0.75 65-74 933 84 69.8 9.40 1.44 534 56 67.0 8.94 1.54 400 28 73.6 8.67 2.09 SPI TABLE E.—Continued Both sexes Men Women Cigarette smoking status (by age) N n Mean sD SE N a Mean sD SE N n Mean SD SE Light smokers 25-74 77.3 0.47 75.7 0.76 78.7 0.60 25-34 2162 113 80.9 7.43 0.84 879 43 80.3 7.10 1.11 1283 10 81.4 7.62 1.30 35-44 1267 72 78.4 6.18 0.79 308 17 771? 6.14 1.54 959 55 78.8 6.13 1.30 45-54 1090 16 76.5 4.94 0.66 383 24 751 6.06 1.58 107 52 W713 4.01 0.54 55-64 1043 57 76.9 7.06 0.97 313 18 74.8? 9.00 2.25 730 39 178 5.81 0.87 65-74 304 21 71.4 10.59 2.65 131 ll 64.67 10.84 47 172 10 765° 6.90 2.64 Moderate smokers 25-74 758 0.36 74.6 0.48 169 0.47 25-34 4269 235 80.4 6.36 0.53 2534 123 79.3 6.29 0.70 1735 112 81.9 6.16 0.73 35-44 2413 130 T19 6.18 0.65 1214 66 T1.3 6.61 0.85 1199 64 78.6 5.64 0.77 45-54 2715 179 13.6 7.48 0.69 1145 vii) 113 7.87 0.96 1570 104 75.3 6.67 0.80 55-64 1287 82 13.2 7.46 0.81 690 45 721 8.00 1.38 §97 37 743 658 1.07 65-74 464 44 69.3 8.30 1.48 261 28 68.4 7.63 1.58 203 16 70.4? 8.98 2.42 Heavy smokers 25-74 15.1 0.58 728 0.57 772 1.06 25-34 2417 136 79.1 6.85 0.73 1363 72 78.0 6.33 0.89 1054 64 819 6.90 1.16 35-44 2148 116 74.2 8.24 0.92 1505 15 13.3 8.68 1.21 643 41 16.2 6.64 1.15 45-54 1779 118 13.7 721 0.74 1193 82 74.0 1.34 0.86 586 36 73.2 6.91 1.30 55-64 922 53 68.9 10.08 1.42 697 45 67.1 10.09 1.81 22A 8 74.63 7.63 2.40 65-74 154 18 68.0? 9.78 2.65 130 16 65.9* 8.75 2.42 2A 2 79.4% 6.66 4.63 NOTE: N = weighted population estimate, in thousands; n = * Adjusted by the direct method to reflect the age distribution o 1 Does not meet standards of reliability. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). number of people in sample; SD = standard deviation; SE = standard error. f the U.S. population at the midpoint of the survey. 6FT TABLE F.—MMEF for white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexes Men Women Cigarette smoking status (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Never smokers 25-74 3020! 29" 3392' 52! 2684" 26 25-34 6733 394 3748 1023 64 2633 130 4357 1008 106 4199 264 3357 820 58 35-44 5278 291 3140 827 58 1669 81 3501 911 106 3609 210 2973 727 58 45-54 4942 353 2724 837 50 1206 85 3198 1021 119 3736 268 2572 703 48 55-64 3660 251 2301 730 43 880 59 2734 763 104 2781 192 2164 663 51 65-74 2875 235 1891 679 51 481 43 2314 827 130 2394 192 1806 611 56 Ex-mokers 25-74 2910 41 3324 66 2537 51 25-34 2811 160 3753 1066 102 1359 66 4321 1014 162 1452 54 3222 809 =: 108 35-44 3086 171 3500 1165 106 1828 94 3882 1237 157 1258 17 2944 765 104 45-54 3323 213 2800 1111 91 2345 143 3021 1171 114 978 70 2270 714 = 102 55-64 2669 181 2318 948 15 1826 130 2463 953 87 843 51 2005 857 ~—s-180 65-74 1769 157 1826 873 82 1270 121 1865 922 99 499 36 1728 7230115 Smokers 25-74 2553 31 2786 49 2343 41 25-34 8885 437 3512 1069 66 4792 239 3857 1101 93 4093 248 3109 872 17 35-44 5849 320 2850 970 65 3027 158 3033 1073 107 2822 162 2654 800 63 45-54 5606 374 2283 896 54 2743 182 2511 1007 78 2863 192 2065 709 66 55-64 3251 192 1955 854 67 1700 108 2065 985 106 1551 &4 1813 654 18 65-74 933 84 1474 831 118 534 56 1422 677 104 400 28 1545 995 220 OST TABLE F.—Continued Both sexes Men Women Cigarette smoking status (by age) N n Mean sD SE N n Mean sD SE N n Mean SD SE Light smokers 25-74 2736 57 2985 93 2510 71 25-34 2162 113 3457 1034 144 879 43 3923 1044 196 1283 10 3137 807 153 35-44 1267 72 2936 839 110 308 Vi 3400? 760 184 959 55 2787 808 124 45-54 1090 76 2334 641 84 383 24 2521 806 173 707 52 2232 502 68 55-64 1043 57 2252 894 124 313 18 2694* 1239 321 730 39 2063 605 87 65-74 304 21 1667 1023 257 131 li 13397 568 238 172 10 1917? 1206 404 Moderate smokers 25-74 2542 41 2848 64 2266 40 25-34 4269 235 3605 1106 93 2534 23 3960 1132 123 1735 112 3087 828 98 35-44 2413 130 2993 907 99 1214 66 3257 968 145 1199 64 2725 152 92 45-54 2715 179 2169 823 74 1145 15 2345 891 92 1570 104 2041 144 95 55-64 1287 82 1894 811 103 690 45 2144 848 162 597 87 1604 655 106 65-74 464 44 1395 738 126 261 28 1535 746 159 203 16 1214? 687 157 Heavy smokers 25-74 2404 53 2620 72 2210 87 25-34 2417 136 3389 1018 120 1363 72 3614 1045 167 1054 64 3122 911 187 35-44 2148 116 2628 1063 119 1505 15 2177 1144 157 643 41 2280 735 123 45-54 1779 118 2421 1087 125 1193 82 2663 1145 150 536 36 1926 786 = «185 55-64 922 53 1706 164 166 697 45 1754 828 136 224 8 1557? 439 s:169 65-74 154 18 1313* 591 151 130 16 1247? 601 160 24 2 1665? 369257 NOTE: N = weighted population estimate, in thousands; n = number of people in sample; SD = standard deviation; SE = standard error. ' Adjusted by the direct method to reflect the age distribution o! * Does not meet standards of reliability. SOURCE: National Center for Health Statistica. Unpub! {the U.S. population at the midpoint of the survey. lished data from the first National Health Nutrition and Examination Survey (NHANES }). TST TABLE G.—MEFR for white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexes Men Women Cigarette smoking status (by age) N n Mean SD SE N n Mean SD SE N n Mean SD SE Never smokers 25-74 6545' 62! 7894! 114! 5327 ' 41! 25-34 5733 394 7103 1895 123 2633 130 8833 1551 167 4099 264 5991 1081 94 35-44 5278 291 6744 1774 144 1669 81 8519 1710 223 3609 210 5923 1058 103 45-54 4942 353 5887 1825 110 1206 85 7805 2106 268 3736 268 5268 1185 86 55-64 3660 251 §280 1559 98 880 59 6722 1527 228 2781 192 4824 1264 98 65-74 2855 234 4317 1776 112 472 42 6526 1863 289 2394 192 3882 1394 118 Ex-smokers 25-74 6453 72 7809 120 5229 83 25-34 2811 160 7521 2246 232 1359. 66 9184 1911 295 1452 94 5964 1153 167 35-44 3086 171 7554 2241 212 1828 94 8789 2006 239 1258 77 5759 1017 131 45-54 3323 213 6773 2056 202 2345 143 7451 1901 213 978 70 5146 1398 191 55-64 2669 181 5944 2002 194 1826 130 6532 1997 220 843 51 4671 1297 245 65-74 1769 157 4986 2187 221 1270 121 5425 2267 280 499 36 3867 1463 220 Smokers 25-74 5914 52 7041 96 4897 55 25-34 8885 487 7393 2019 122 4792 239 8629 1728 133 4093 248 5847 1216 101 35-44 5849 320 6712 1974 152 3027 158 7780 1922 211 2822 162 5566 1256 94 45-54 5606 374 5762 1864 104 2743 182 5758 1819 137 2863 192 4807 1332 3 55-64 3251 192 5030 1952 147 1700 108 5834 2022 211 1551 84 4149 1421 171 65-74 933 84 3753 1862 216 534 56 4341 1961 260 400 28 2969 1373 263 = TABLE G.—Continued c Both sexes Men Women Cigarette smoking status (by age) N n Mean sD SE N n Mean SD SE N n Mean SD SE Light smokers 25-74 6068 104 7085 177 5150 114 25-34 2162 113 7006 1792 233 879 43 8347 1559 246 1283 70 6088 1294 193 35-44 1267 72 6450 1784 275 308 17 8275? 1918 530 959 55 5864 1270 =—-:192 45-54 1090 76 5656 1632 232 383 24 6718 1445 269 707 52 5080 1425-249 55-64 1043 57 4979 1611 240 313 18 6142? 1903 478 730 39 4482 1154-208 65-74 304 21 3585 1295 350 131 ll 4054" 1318 457 172 10 3228? 1157-388 Moderate smokers 25-74 5921 76 7165 120 4798 89 25-34 4269 235 7616 2146 154 2534 123 8755 1864 176 1735 112 5952 1263-164 35-44 2413 130 6819 1992 230 1214 66 8112 1734 264 1199 64 5511 1241 150 45-54 2715 179 5513 1755 137 1145 75 6533 1799 181 1570 104 4769 1286 = «144 55-64 1287 82 5100 1996 243 690 45 6122 1687 261 597 37 3917 1640 =. 299 65-74 464 44 3701 2084 373 261 28 4495 2122 466 203 16 2681? 1512 376 Heavy smokers 25-74 5755 98 6902 155 4720 5 25-34 2417 136 7356 1925 204 1363 72 8573 1544 192 1054 64 5781 1010 + =170 35-44 2148 116 6751 2053 223 1505 75 7412 1995 289 643 41 5205 1164 196 45-54 1779 118 6167 2034 214 1193 82 6945 1909 239 586 36 4581 1280-254 55-64 922 53 4989 2221 366 697 45 5410 2285 433 224 8 3679* 1327-395 65-74 154 18 4136? 2060 496 130 16 42497 2187 571 24 2 3535? 964671 NOTE: N = weighted population estimate, in th ds; n = of people in ple; SD = standard deviation; SE = standard error. * Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. * Does not meet standards of reliability. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES }). esl TABLE H.—Forced vital capacity for white adults, by smoking status, sex, and age, United States, 1971-1975 Both sexes Men Women Cigarette smoking status (by age) N n Mean SD SE N n Mean sD SE N n Mean SD SE Never smokers 25-74 3978' 29! 4708! 52! 3320! 24! 25-34 6733 394 4403 1052 67 2633 130 5480 759 89 4099 264 3712 464 32 35-44 5278 291 3972 814 65 1669 81 4761 759 98 3609 210 3607 530 54 45-54 4942 353 3624 782 45 1206 85 4506 795 92 3736 268 3340 522 39 55-54 3660 251 3252 820 47 880 59 4265 758 123 2780 192 2932 526 38 65-74 2875 235 2815 719 48 481 43 3867 774 127 2394 192 2603 482 43 Ex-emokers 25-74 3996 30 4703 46 3357 32 25-34 2811 150 4522 1043 101 1359 66 5335 816 118 1452 94 3760 §33 68 35-44 3086 171 4500 972 91 1828 94 5096 153 86 1258 77 3633 450 49 45-54 3323 213 4143 915 78 2345 143 4499 796 76 978 70 3291 543 79 55-64 2669 181 3862 898 94 1826 130 4239 786 95 843 61 3044 489 79 65-74 1769 157 3335 864 86 1270 121 3594 821 92 499 36 2675 568 99 Smokers 25-74 3790 26 4405 38 3236 35 25-34 8885 487 4464 977 55 4792 239 5111 784 59 4093 248 3707 539 50 35-44 5849 320 4146 851 59 3027 158 4665 750 81 2822 162 3588 546 55 45-54 5606 374 3731 814 49 2743 182 4284 678 65 2863 192 3202 §32 45 55-64 3251 192 3315 845 66 1700 108 3866 730 71 1551 84 2712 467 59 65-74 933 84 2985 870 118 534 56 3325 747 117 400 2 2533 815 85 PST TABLE H.—Continued Both sexes Men Women Cigarette smoking status (by age) N n Mean SD SE N D Mean SD SE N n Mean SD SE Light smokers 25-74 3824 54 4358 81 3342 64 25-34 2162 113 4260 857 116 879 43 4892 641 118 1283 70 3828 705 118 35-44 1267 72 3986 875 135 308 17 49227 768 235 959 55 3686 671 119 45-54 1090 76 3521 680 103 383 24 4022 555 155 707 52 3249 580 107 55-64 1043 57 3135 704 108 313 18 3866? 636 141 730 39 2822 457 87 65-74 304 21 3042 917 237 131 11 3470? 555 159 172 10 2717? 1001 347 Moderate smokers 25-74 3789 30 4454 50 3190 38 25-34 4269 235 4584 1020 74 2534 23 5217 793 80 1735 112 3660 447 55 35-44 2413 130 4145 846 90 1214 66 4671 812 125 1199 64 3612 457 66 45-54 2715 179 3658 852 73 1145 75 4357 737 111 1570 104 3147 521 57 55-64 1287 82 3312 854 99 690 45 3881 696 89 597 37 2654 453 80 65-74 464 44 2928 820 149 261 28 3327 734 172 203 16 2414? 614 173 Heavy smokers 25-74 3710 43 4364 61 3120 54 25-34 2417 136 4440 968 91 1363 72 5055 818 102 1054 64 3644 404 69 35-44 2148 116 4244 832 82 1505 75 4609 679 94 643 41 3392 440 3 45-54 1779 118 3971 758 81 1193 82 4304 638 84 586 36 3292 480 95 55-64 922 53 3524 928 151 697 45 3851 798 142 224 8 2508 ? 438 143 65-74 154 18 3036? 938 240 130 16 3189? 925 252 24 2 2223? 472 328 NOTE: N = weighted population estimate, in thousands; n = number of people in sample; SD = standard deviation; SE = standard error. ‘ Adjusted by the direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. * Does not meet standards of reliability. SOURCE: National Center for Health Statistica. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). SCT TABLE I.—Recurring persistent cough attacks for adults, by sex, age, States, 1971-1975 and smoking status, United Men Women Smoking status Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 25-34 P 3.2 44 6.7 76 5.7 V7 4.4 6.0 84 5.7 TA 15.2 SE 1.85 2.23 1.57 4.01 1.98 2.79 1.21 2.48 1.63 1.92 2.27 4.93 n 168 78 327 72 160 94 399 121 367 119 164 81 N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393 35-44 P 49 8.0 13.8 9.0 5.9 22.1 5.4 5.0 89 2.3 8.0 25.8 SE 2.59 3.47 3.17 6.39 2.69 6.40 1.60 2.46 1.89 1.21 2.85 7.37 n 101 117 226 33 93 100 310 107 270 103 114 51 N 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799 45-54 Py 43 9.2 10.3 6.4 12.0 10.6 49 3.0 11.5 78 99 218 SE 1.61 2.28 2.07 2.73 3.65 3.53 1.55 1.97 2.16 2.61 2.99 4.04 n 114 204 296 61 122 112 435 101 329 109 163 57 N 1568 3290 4282 810 1705 1745 5989 1458 4800 1497 2413 890 55-64 P 11 146 20.5 2.4 14.4 25.9 6.8 9.9 15.7 6.4 14.8 50.1 SE 1.06 3.21 3.27 8.88 4.33 5.87 1.65 3.35 3.46 3.17 3.93 1568 a 94 192 205 50 91 64 394 86 178 76 82 20 N 1320 2791 2990 708 1305 976 5599 1501 3014 1268 1369 378 TABLE I.—Continued Men Women Smoking status Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 65-74 P 15 175 23.7 3.6 34.4 25.4 8.7 5.4 23.1 17.2 24.8 59.9? SE 3.16 3.44 4.55 2.31 6.90 10.1 1.52 2.85 4.93 6.05 8.02 22.37 n 98 232 135 39 60 35 461 61 83 46 32 5 N 864 2232 1199 318 574 295 5487 958 952 523 362 66 25-74 P? 3.9 96 13.4 10.2 12.0 16.7 5.7 5.8 12.4 V1 11.6 31.1 SE! 0.92 151 1.30 2.22 1.66 2.31 0.66 1.25 1.19 1.32 1.84 5.63 NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands. ‘ Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. * Does not meet standards of reliability. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). TABLE J.—Three-week periods of increased cough or phlegm for adults, by sex, age, and smoking status, United States, 1971-1975 Women Smoking status Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 25-34 P 69 2.9 72 69 79 6.5 42 5.6 10.7 5.4 ill 18.0 SE 2.39 1.67 1.83 4.04 2.63 2.33 1.07 2.39 1.91 2.05 2.97 5.18 n 168 78 327 72 160 94 399 121 367 119 164 81 N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393 35-44 P 6.0 3.3 5.2 12 3.9 76 3.8 19 B.1 5.1 10.9 8.3 SE 2.43 1.98 1.68 1.20 2.08 2.86 1.54 1.37 2.01 1.89 3.67 4.20 n 101 117 226 33 93 100 310 107 270 103 114 51 N 2114 2384 4412 614 1769 2229 5197 1771 4563 1776 1968 799 45-54 P 17 3.9 6.3 0.3 5.5 98 3.5 6.1 10.8 84 8.4 216 SE 1.24 1.82 1.72 0.32 2.10 3.66 1.00 2.39 2.14 2.93 2.72 6.49 n 114 204 296 61 122 112 435 101 329 109 163 57 N 1568 3290 4282 810 1706 1745 5989 1458 4800 1497 2413 890 55-64 P 12 2.9 114 6.8 10.2 16.2 6.6 13.7 14.7 7.0 13.1 46.2 SE 0.91 1.33 2.61 4.00 4.07 5.39 1.63 4.88 3.57 3.44 3.96 16.61 n 94 192 205 50 91 64 394 86 178 16 82 20 N 1320 2791 2990 708 1305 976 5599 1501 3014 1268 1369 378 TABLE J.—Continued Men Smoking status Women Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 65-74 P 75 45 12.0 3.3 14.2 175 5.1 9.1 115 2.6 26.4 0.07 SE 3.10 1.38 4.11 2.55 6.01 10.31 1.25 3.47 4.24 2.55 9.80 0.0 n 98 232 135 39 60 35 461 81 83 46 32 5 N 864 2232 1199 318 574 295 5487 958 952 523 362 66 25-74 P! 46 3.4 79 3.8 76 10.5 45 69 11.0 5.9 12.9 19.5 SE! 1.04 0.93 1.02 1.43 1.31 2.04 0.63 1.34 1.26 1.18 1.84 3.86 NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands. 1 Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. ? Does not meet standards of reliability. SOURCE: National! Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). 6ST TABLE K.—Shortness of breath for adults, by sex, age, and smoking status, United States, 1971-1975 Men Women Smoking status Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 25-34 P 5.6 15.2 23.3 10.0 23.1 33.6 14.4 17.9 31.0 30.9 20.1 515 SE 1.99 4.97 3.20 3.81 4.01 7.21 1.92 494 3.17 5.65 3.56 7.48 n 168 78 327 72 160 94 399 121 367 119 164 81 N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393 35-44 P 17.1 19.9 22.9 15.6 15.9 31.2 22.5 26.5 39.0 36.4 45.3 30.3 SE 4.62 4.89 3.26 7.08 4.71 5.46 2.42 5.32 4.62 5.48 7.07 7.08 n 101 117 226 33 93 100 310 107 270 103 114 51 N 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799 45-54 P 19.3 27.2 35.5 25.4 34.9 413 28.1 32.5 42.5 30.3 48.1 47.9 SE 4.07 3.58 2.99 6.35 4.64 5.40 2.85 6.05 3.93 5.01 4.95 7.57 n 114 204 296 61 122 2 435 101 329 109 163 57 N 1568 3290 4282 810 1706 1745 5989 1458 4800 1497 2413 890 55-64 P 25.6 31.3 42.2 37.7 42.4 45.2 38.0 56.8 39.0 29.8 43.1 54.6 SE 5.79 3.94 4.37 9.57 6.14 6.39 2.94 6.24 4.60 6.85 6.06 16.51 n 94 192 205 50 91 64 394 86 178 76 82 20 N 1320 2791 2990 708 1305 9761 5599 1501 3014 1268 1369 378 i > Q TABLE K.—Continued Men Women Smoking status Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 65-74 P 27.0 45.8 41.7 26.7 42.4 54.4 416 32.3 43.2 48.6 40.0 17.4? SE 5.46 4.05 4.59 787 6.86 9.12 2.92 5.63 6.70 9.64 10.85 16.12 n 98 232 135 39 60 35 461 81 83 46 32 5 N 864 2232 1199 318 574 295 5487 958 952 523 362 66 25-74 P! 17.1 25.2 31.4 21.5 29.9 39.2 270 31.8 38.2 34.1 38.2 42.4 SE! 1.89 2.38 1.75 2.84 2.31 2.74 1.27 2.82 2.08 2.59 2.88 5.07 NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands. ‘ Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. * Doss not meet standards of reliability. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). 19T TABLE L.—Wheezy chest sounds of adults, by sex, age, and smoking status, United States, 1971-1975 Men Women Smoking status Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 25-34 P 2.7 13.0 15.0 11.5 12.6 22.0 7.6 11.6 17.5 12.9 14.8 29.5 SE 1.17 4,67 2.42 4.43 2.72 6.14 1.46 3.54 2.33 3.13 2.94 6.13 n 168 78 327 72 160 94 399 121 367 119 164 81 N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393 35-44 P 14.0 51 18.4 13.6 12.3 25.2 19 VT 16.4 99 219 179 SE 4.72 2.12 3.28 6.14 4.03 5.61 1.83 2.98 2.56 3.77 4.53 4.89 n 101 117 226 33 93 100 310 107 270 103 114 51 N 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799 45-54 P 43 12.3 18.8 10.2 23.2 18.7 8.5 5.3 22.7 12.9 24.1 35.7 SE 1.97 2.60 2.60 3.99 4.05 4.13 1.39 1.82 2.98 3.59 4.37 6.24 n 114 204 296 61 122 112 435 101 329 109 163 57 N 1568 3290 4282 810 1706 1745 5989 1458 4800 1497 2413 890 55-64 P 12.0 13.6 25.9 29.9 26.6 22.1 12.7 22.0 27.3 19.5 31.0 40.0 SE 4.24 2.50 4.46 9.22 5.87 6.10 2.09 5.93 3.64 4.98 5.21 14.00 n 94 192 205 50 91 64 394 86 178 76 82 20 N 1320 2791 2990 708 1305 976 5599 1501 3014 1268 1369 378 bt TABLE L.—Continued Men Women Smoking status Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 65-74 P 5.0 20.7 33.1 34.7 31.6 35.6 15.1 215 28.6 34.6 18.1 39.0? SE 2.04 3.00 5.25 10.10 747 9.91 2.16 4.78 5.60 8.99 6.69 21.96 n 98 232 135 39 60 35 461 81 83 46 32 5 N 864 2232 1199 318 574 295 5487 958 952 523 362 66 25-74 P! 74 12.1 20.6 176 19.6 23.5 98 12.6 21.7 16.4 21.7 31.6 SE’ 1.33 1.83 1.42 2.68 1.98 2.69 0.82 1.68 1.49 2.01 1.88 4.80 NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands. ‘ Adjusted by direct method to reflect the age distribution of the U.S. "Does not meet standards of reliability. population at the midpoint of the survey. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). egt TABLE M.—Diminished or absent breath sounds of adults, by sex, age, and smoking status, United States, 1971-1975 Smoking status Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 25-34 P 18 0.0 0.3 04 0.0 0.7 0.1 0.0 0.6 0.3 0.0 2.2 SE 1.76 0.0 0.21 0.36 0.0 0.71 0.07 0.0 0.51 0.31 0.0 2.21 n 168 78 327 72 160 94 399 121 367 119 164 81 N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393 35-44 P 0.6 0.5 0.6 0.0 0.7 0.6 0.3 0.2 2.3 0.4 3.4 3.5 SE 0.61 0.47 0.55 0.0 0.73 0.57 0.26 0.22 1.58 0.44 3.33 3.39 n 101 17 226 33 93 100 310 107 270 103 1l4 51 N 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799 45-54 P 0.7 10 5.9 0.4 9.8 47 0.8 2.4 14 10 1.6 15 SE 0.55 0.53 al 0.41 3.33 2.64 0.64 1.87 0.56 0.36 0.82 1.24 n 114 204 296 61 122 112 435 101 329 109 163 57 N 1568 3290 4282 810 1706 1745 5989 1458 4800 1497 2413 890 55-64 P 25 5.7 12.4 8.4 13.0 14.4 0.8 41 3.36 2.7 3.9 35 SE 2.12 1.66 3.15 4.75 4.57 4.99 0.53 2.51 1.44 1.82 2.40 3.55 n 94 192 205 50 91 64 394 86 178 76 82 20 N 1320 2791 2990 708 1305 976 5599 1501 3014 1268 1369 378 TABLE M.—Continued Men Women Smoking status Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 65-74 P 88 97 179 13.9 25.2 88 24 45 2.7 3.3 2.3 0.0? SE 3.53 2.57 3.76 8.10 5.86 45 0.81 2.63 1.58 2.34 2.27 0.0 n 98 232 135 39 60 35 461 81 83 46 32 5 N 864 2232 1199 318 574 295 5487 958 952 523 362 66 25-74 Pp! 2.2 2.44 58 3.3 15 5.0 0.7 19 19 1.32 21 23 SE' 0.72 0.46 0.95 1.33 1.47 1.06 0.20 0.71 0.46 0.49 0.88 1.16 NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands. ‘ Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. * Does not meet standards of reliability. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). got TABLE N.—Wheeze of adults, by sex, age, and smoking status, United States, 1971-1975 Men Women Smoking status Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 25-34 P 0.0 12 17 11 16 2.2 0.4 0.0 0.7 0.0 13 0.0 SE 0.0 124 0.77 1.06 1.25 1.28 0.29 0.0 0.37 0.0 0.79 0.0 n 168 78 327 72 160 94 399 121 367 119 164 81 N 3319 1593 6608 1383 3335 1875 6416 1873 6304 2239 2642 1393 35-44 P 0.0 1.0 13 0.0 0.9 2.1 0.3 0.0 3.2 0.0 3.6 96 SE 0.0 0.75 0.67 0.0 0.89 1.22 0.26 0.0 1.28 0.0 1.50 4.97 a 101 117 226 33 93 100 310 107 270 103 114 51 N 2114 2384 4412 614 1769 2029 5197 1771 4563 1776 1968 799 45-54 P 0.0 1.2 25 0.0 45 18 0.3 0.0 24 08 3.3 2.5 SE 0.0 1.02 0.93 0.0 2.13 1.27 0.33 0.0 0.94 0.78 1.40 1.76 n 114 204 296 61 122 112 435 101 329 109 163 57 N 1568 3290 4282 810 1706 1745 5989 1458 4800 1497 2413 890 55-64 P 0.0 0.4 5.6 23 3.3 10.9 0.1 0.0 1.7 08 14 58 SE 0.0 0.37 1.76 1.95 1.69 4.48 0.05 0.0 0.95 0.77 1.18 5.78 n 94 192 205 50 91 64 394 86 178 76 82 20 N 1320 2791 2990 708 1305 976 5599 1501 3014 1268 1369 378 i TABLE N.—Continued Men Smoking status Smoking status Never Former Current Light Moderate Heavy Never Former Current Light Moderate Heavy 65-74 P 2.6 10.0 0.0 114 18.4 1.0 19 3.6 2.7 16 20.9? SE 0.0 lll 3.75 0.0 5.27 10.98 0.56 1.85 2.14 2.66 1.64 18.53 n 98 232 135 39 60 35 46] 81 83 46 32 5 N 864 2232 1199 318 574 295 5487 958 952 523 362 66 25-74 Pp! 0.0 1.2 3.4 0.7 3.5 55 0.4 0.2 2.1 0.7 2.3 6.3 SE 0.0 0.46 0.71 0.46 0.92 1.65 0.14 0.25 0.45 0.41 0.48 2.79 NOTE: P = proportion; SE = standard error; n = number of people in sample; N = weighted population estimate, in thousands. ‘ Adjusted by direct method to reflect the age distribution of the U.S. population at the midpoint of the survey. ? Does not meet standards of reliability. SOURCE: National Center for Health Statistics. Unpublished data from the first National Health Nutrition and Examination Survey (NHANES 1). References ABBOUD, R.T., MORTON, J.W. Comparison of maximal mid-expiratory flow, flow volume curves, and nitrogen closing volumes in patients with mild airway obstruction. American Review of Respiratory Disease 111(4): 405-417, April 1975. AMERICAN COLLEGE OF CHEST PHYSICIANS-AMERICAN THORACIC SOCI- ETY. 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MORTALITY FROM CHRONIC OBSTRUCTIVE LUNG DISEASE DUE TO CIGARETTE SMOKING 185 CONTENTS Introduction COLD Mortality Patterns in the United States Prospective Studies The British Doctors Study The American Cancer Society 25-State Study The U.S. Veterans Study The Canadian Veterans Study The American Cancer Society 9-State Study California Men in Various Occupations The Swedish Study The Japanese Study of 29 Health Districts Cigarette Smoking and Overall COLD Mortality Retrospective Studies Male and Female Differences in COLD Mortality Amount Smoked and Mortality From COLD Inhalational Practice and Mortality From COLD Age of Initiation and COLD Mortality Smoking Cessation and COLD Mortality Pipe and Cigar Smoking Mortality From COLD International Comparison of COLD Death Rates a Smoking Habits: The Emigrant Studies COLD Mortality Among Populations With Low S Rates Summary and Conclusions References Introduction The chronic obstructive lung diseases (COLD) that are causally related to cigarette smoking are chronic bronchitis, emphysema, and chronic obstructive pulmonary disease and allied conditions without mention of asthma, bronchitis, or emphysema. The last classification was introduced by the National Center for Health Statistics in response to the changes that occurred in the late 1960s in patterns of reporting causes of death on death certificates. During this period, physicians increasingly recorded deaths as due to “chronic obstruc- tive lung disease” rather than the more specific categories of “emphysema” or “chronic bronchitis” (NCHS 1982). Because of this shift in patterns of reporting, and in recognition of the difficulty of clinically separating these categories from one another as a cause of death, the discussion in this chapter combines all of these categories for analysis, where possible, which should result in a more complete description of death rates from COLD. COLD Mortality Patterns in the United States The three chronic obstructive lung diseases related to smoking may account for almost 62,000 deaths in 1983, compared with 56,920 deaths in 1982, according to provisional mortality data recently published by the National Center for Health Statistics. This data is based on a 10 percent sample of all death certificates for the 12- month period ending in November (NCHS 1984). This is a dramatic increase from 1970, when slightly over 33,000 deaths were attributed to COLD. Complete mortality data are available through 1980, and Table 1 presents the numbers of male and female deaths from COLD for 1970, 1975, and 1980. In addition to the relatively rapid rise in COLD deaths during these years, there was also a shift in the male to female ratio of these deaths. In 1970 male deaths outnumbered female deaths by a ratio of 4.3 to 1. By 1980 this ratio had declined to 2.36. The age-adjusted death rates for COLD during the years 1960 through 1980 are presented in Figure 1 for white men, white women, and men and women of other races. As described in the previous chapter, however, COLD is a slowly progressive disease, and death from COLD usually occurs only after extensive damage has devel- oped in the diseased lungs. Many individuals with COLD will die with their disease rather than because of it, and even those who do die of COLD are usually symptomatic for an extended period of time prior to death. Therefore, death rate data may not accurately reflect the true prevalence or incidence of COLD in the U.S. population. In addition, COLD is often not recorded as a cause of death in hospital records 189 TABLE 1.—Number of and ratio of male to female chronic obstructive lung disease (COLD) deaths for three time periods, United States 1970 1975 1980 Cause of death Men Women Men Women Men Women Chronic bronchitis 4,282 1,564 3,260 1,452 2,380 1,348 Emphysema 18,901 3,820 14,849 3,946 10,133 3,744 COLD and allied conditions 3,601 848 13,411 4,182 24,820 10,734 Total COLD deaths 26,784 6,227 31,520 9,580 37,333 15,826 M:F ratio 4.30 3.29 2.36 SOURCE: National Center for Health Statistics (1982, and unpublished mortality data). 30- a5 wuire 3 S 20 o oS S OTHERS a «1 5F id a. ded a x 10 WHITE? 4 5b OTHER i i i J 1960 1965 1970 1975 1980 YEAR FIGURE 1.—Age-adjusted COLD mortality rates for whites and nonwhites in the United States, 1960-1980 SOURCE: National Center for Health Statistics (1982, and unpublished data). (Moriyama et al. 1966) or on death certificates (Mitchell et al. 1968), even though it may have played an important role in a person’s death. In a recent prospective study, nearly half of the excess mortality associated with significantly lowered FEV, was attributed to other causes (Peto et al. 1983). Relatively advanced lung disease (as judged by pathologic examination) may also exist without clinical 190 recognition because of the lung’s large ventilatory reserve (Mitchell et al. 1968; Hepper et al. 1969). A joint committee of the American College of Chest Physicians and the American Thoracic Society (ACCP-ATS 1975) has developed standardized definitions of these conditions that may improve the accuracy of mortality reporting in the future. As discussed in the chapter on morbidity in this Report, COLD in an individual is usually a combination of mucus hypersecretion, airway narrowing, and emphysema. The extent of damage represent- ed by each of these three processes can vary substantially from individual to individual, both in the absolute magnitude of the damage and in the proportional contribution of each of these three components. The majority of those with smoking-induced lung damage do not have enough damage to result in clinically significant disease, and only some of those with clinically significant disease have damage to the lung that results in death from COLD. The progressive loss of FEV, in smokers described in the preceding chapter is one measure of the extent and progression of lung damage, and individuals with a markedly reduced FEV, are far more likely to die of COLD (Peto et al. 1983). These deaths commonly occur secondary to the failure of these severely damaged lungs to carry out the gas exchange required for survival. Because death from COLD is the end result of lung damage accumulated over many years, these deaths would be expected to occur disproportionately in the older age groups; therefore, the presentation of a single age-adjusted death rate might not reflect a true picture of the changes in this disease with time. Figure 2 presents the age-specific death rates in 1977 for COLD in the different sexes and racial groups. Death rates increase rapidly over the age of 45, and this increase is particularly dramatic over the age of 65. In addition, the bulk of the difference between white men and men of other races, evident in Figure 2, occurs in those over age 65. Indeed, the COLD death rates for nonwhite men are actually higher than that for white men under age 55. The examination of age-specific death rates over time also presents a somewhat different picture from that presented by the age- adjusted numbers in Figure 1. The age-adjusted rates for white men in Figure 1 seem to have changed only slightly between 1968 and 1980. However, when the age-specific rates for the years 1968 and 1977 are examined (Figure 3), this apparent stability can be seen to be a product of counterbalancing trends in those under and over 65 years of age. The death rates from COLD declined in white men under age 65 between 1968 and 1977, but COLD death rates increased in white men over age 65 during the same years; this increase was particularly dramatic in those over age 75. 191 WHITES 400 oS © 300 fom] oS a a ws 200+ OTHERS. << Cc roy WHITES OTHER 25-34 35-44 46-54 55-64 65-74 75-84 85+ AGE FIGURE 2.—Age-specific COLD mortality rates for whites and nonwhites in the United States, 1977 SOURCE: National Center for Health Statistics (1982). Figure 4 presents the age-specific COLD mortality rates for white women in 1960, 1968, and 1977. As with the male rates, the female COLD death rates rise rapidly with age, but they are substantially lower than the male rates. In contrast with the male rates, however, the white female death rates increased steadily with time from 1960 through 1977 both above and below age 65. In each of the age groups over the age of 45, where significant numbers of COLD deaths would be expected, there was a steady increase in rates from 1960 to 1968 and from 1968 to 1977. As is discussed later in this chapter, these differences between men and women over time are consistent with their differences in smoking behavior. The effect of the normal aging process on the lung is small, rarely limits maximal exercise, and never results in ventilatory failure. Therefore, death from chronic obstructive lung disease is never a natural part of the aging process; it is the result of an infectious or other disease process or of the cumulative damage of environmental respiratory toxins. The most important of these toxins in the United States is cigarette smoke. 192 1977 400+ S © 300+ 1968 So So oc La a mw 200+ < co 100} 1960 25-34 35-44 45-54 55-64 65-74 75-84 85+ AGE FIGURE 3.—Age-specific COLD mortality rates for white men in the United States, 1960, 1968, and 1977 SOURCE: National Center for Health Statistics (1982). In spite of the large ventilatory reserve possessed by the lung, death from COLD is a major cause of U.S. mortality. This mortality is closely linked to cigarette smoking and has been examined extensively. Figure 5 shows the differences in COLD death rates for smokers and nonsmokers at different ages. From the rarity of COLD death in nonsmokers and the magnitude of the increased risk associated with smoking, it is clear that the overwhelming impor- tance of cigarette smoking as a determinant of abnormal lung function demonstrated in the previous chapter is matched by the importance of cigarette smoking as a determinant of death from COLD. Examination of the death rates from COLD in smokers and nonsmokers suggests that from 85 to 90 percent of the COLD deaths in the United States can be attributed to cigarette smoking. Prospective Studies The relationship between smoking and death from COLD has been evaluated in a large number of prospective mortality studies. There are eight major prospective studies of the disease consequences of smoking. They involve large numbers of smokers and nonsmokers 193 1977 80+ 7O-+ 1968 60} 50+ 40+ 1960 RATE PER 100,000 20+ 10+ L L. 1. —4 25-34 35-44 45-54 55-64 65-74 75-84 86+ AGE FIGURE 4.—Age-specific COLD mortality rates for white women in the United States, 1960, 1968, and 1977 SOURCE: Nationa! Center for Health Statistics (1982) and have examined the death rates from COLD in both groups. These studies cumulatively represent more than 17 million person- years of observation and over 330,000 deaths. The size of the populations studied allows a detailed examination of the relationship between smoking and death rates. The characteristics of the populations studied are summarized in Table 2 and are briefly reviewed here. The British Doctors Study The British doctors study (Doll and Hill 1954, 1956, 1964a, 1964b, 1966; Doll and Peto 1976, 1977; Doll and Pike 1972; Doll et al. 1980) of 40,000 male and female physicians in Britain was the first prospective study and is the longest running. Deaths from chronic bronchitis and emphysema were combined. Deaths from cor pulmo- nale (i.e., heart failure secondary to lung disease) were separately analyzed by smoking category and probably include some deaths from chronic bronchitis and emphysema. 194 450 Smoker 400 oo LY S 300 so : & | ~ | o | & | 2 200 1 = i 100 Nonsmoker o 4 + eS | 35-44 45-54 55-64 65-74 75-84 Age Group FIGURE 5.—Death rate for bronchitis, emphysema, or both, per 100,000 population, by age and smoking status', U.S. veterans study, 16-year followup ‘Smoker is defined as al! people who smoke cigarettes and those who have ever smoked other tobacco products SOURCE: Adapted from Rogot and Murray (1980) The American Cancer Society 25-State Study The American Cancer Society 25-State study (Hammond 1965, 1966; Hammond and Garfinkel 1969; Hammond et al. 1976; Lee and Garfinkel 1981) represents the largest investigation. Deaths from emphysema were separately analyzed by smoking habit; deaths from cor pulmonale were also separately recorded. The U.S. Veterans Study The mortality experience of approximately 294,000 U.S. veterans who held U.S. Government life insurance policies in December 1953 was examined in the U.S. veterans study (Dorn 1959; Kahn 1966; Rogot 1974a, b; Rogot and Murray 1980). Deaths from COLD were recorded as “bronchitis and/or emphysema”; “bronchitis, underlying or contributory”; and “emphysema without bronchitis.” The Canadian Veterans Study Initiated in 1955 by the Canadian Department of National Health and Welfare, the Canadian veterans study (Best 1966; Best et al. 1961) included 78,000 men and 14,000 women. Over the next 6 years of followup, there were 9,491 male and 1,794 female deaths. The cause of death in most of these cases was confirmed by autopsy. 195 96T TABLE 2 .— Outline of eight major prospective studies Doll Weir Cedertof : Dorn Best . Authors mul Hammond Kahn Hirayama Jone Hammond Dunn Friberg Peto t Walker Horn Linden Hrubec Pike Breslow Lorich Males and Total population . . Probability California British females US of Canadian White males in sample of Subjects doctors n veterans = healt " various the 3 distnets in pensioners nine States occupations Swedish States Japan Pe population Population size 40,000 1,000,000 230,000 265,000 92,000 187,000 68,000 55,000 Females 6,000 562,671 300,000 1.93 > 300,000 10.93 California men Nonsmoker? 1.00 Emphysema in various About '. pk 8.18 occupations About 1 pk 11.80 About 11, pk 20.86 American Cancer Nonsmoker 1.00 All pulmonary Society 1-9 1.67 diseases other 9-State 10-20 3.00 than cancer? 20+ 3.64 ‘Data for the Japanese study are for lifetime exposure by > total number of cigarettes consumed. ? Nonsmoker in the California occupations study also includes > smokers of pipes and cigars. * Pneumonia, influenza, TB, asthma, bronchitis, lung abscess, etc. 202 Maile and Female Differences in COLD Mortality Mortality data presented by the National Center for Health Statistics indicate that in 1980 the number of deaths from COLD was 2.36 times higher among men than among women (9th ICDA nos. 490, 491, 492, and 494-496). In the prospective studies reviewed above, it is also apparent that the relative risk for death from COLD was greater for male smokers than for female smokers, although both male and female smokers exhibited a greater risk than nonsmokers for death from COLD. These differences are most likely a consequence of differences in male and female smoking patterns. The women in these studies tended to smoke fewer cigarettes, inhale less deeply, and begin smoking later in life than the men. They more frequently smoked filtered and low tar and nicotine cigarettes and had less occupational exposure to pulmonary irritants than men. These differences in mortality from COLD are narrowing because of a more rapid rise in female mortality from COLD (see Table 1). Figures 6 and 7 help to explain the male-female differences in COLD mortality ratios in the prospective mortality studies and in U.S. COLD death rates. The figures are descriptions of the preva- lence of cigarette smoking in successive 10-year birth cohorts of men and women as those cohorts progressed through the years 1900-1980 (Harris 1983). Examination of these figures revealed several impor- tant findings. Relatively few women took up smoking prior to 1930. The heaviest smoking cohorts of men have a prevalence of over 70 percent compared with 45 percent of women, and the male cohorts with these peak prevalences are older than the female cohorts. However, as discussed earlier, the incremental and progressive nature of cigarette-induced lung injury results in both prevalence and duration of cigarette smoking having an impact on COLD death rates. Therefore, in examining Figures 6 and 7 it is important to consider the span of years of a given prevalence of smoking maintained by a given birth cohort as well as the peak prevalence achieved by that cohort. The COLD death rates should then be proportional to the area under the prevalence curve described by each cohort, rather than to the peak of that curve. A careful examination of Figure 6 reveals that the area under the prevalence curve for the cohort born between 1921 and 1930 is less than the area under the curve for the cohort born between 1911 and 1920, in spite of their similar peak prevalences. This difference is due to the more rapid decline in prevalence with age in the 1921 to 1930 cohort. Similarly, the cohort born between 1901 and 1910 partially compensates for a peak prevalence that is lower than the 1911 to 1920 cohort by having a somewhat a broader base. Each of the cohorts born prior to 1900 have substantially smaller areas under their curves than those born during the first three decades of this century. These differences in prevalence are reflected in the changes 203 1910 1920 1930 1940 1950 1960 1970 T T T T T “tT T 8 Men 1921-30 1900 1910 1920 1930 1940 1950 1960 1970 1960 FIGURE 6.—Prevalence of cigarette smoking among successive birth cohorts of men, 1900-1980, derived from smoking histories in the National Health Interview Survey (HIS) SOURCE: Harris 1963. in age-specific death rates portrayed in Figure 8 and Table 5. The oldest age group (75-84) continues to show a rapid rise in COLD death rates as those birth cohorts with increasing prevalence and duration of smoking move into this age range. In the age range 65-74 the rates rose rapidly from 1960 through the mid 1970s, but seem to be leveling off, consistent with the fact that this age group is now made up entirely of men born after 1900. In the age range 55-64 the rates suggest a slight downturn beginning in the mid 1970s, coincident with the entry of the 1921 to 1930 birth cohort into this age group. The numbers for the age range 45-54 are too small to 204 1910 1920 1930 1940 1950 1960 1970 T T T T T T T 1931-40 Women 1921-30 _ 44 o 1 1 0 1900 1910 1920 1930 1940 1950 1960 1970 1980 Year FIGURE 7.—Prevalence of cigarette smoking among successive birth cohorts of women, 1900-1980, derived from smoking histories in the National Health Interview Survey (HIS) SOURCE: Harris 1983. permit firm conclusions, but also suggest that a downturn in rates occurred in this group in the late 1960s. A close examination of Figures 6 and 7 also offers an explanation of the differences in mortality ratios for men and women observed in the prospective studies. COLD is a slow, progressive disease, and death from COLD usually results only after extensive lung damage has occurred. The fact that death from COLD is unusual prior to age 45 reflects, in part, the 30 or more years required for cigarette smoke to damage enough lung to result in death. The substantial ventilato- ry reserve of the lung allows a significant amount of damage to exist in a person without symptomatic limitation or risk of death from COLD. The prospective mortality studies were conducted in the 1950s and 1960s, a point in time approximately 30 years after the beginning of the rise in smoking prevalence among women demon- strated in Figure 7. Even the older cohorts, where significant mortality might be expected, had begun smoking largely after 1930, and therefore had a shorter duration of smoke exposure than the men born in the same years. This shorter duration of the smoking habit, together with the previously described tendency of women to 205 75-84 400+ Oo S 2 300F 7 ao a E 200 b 65-74 Cc 100 ee 55-64 - = —— 45-54, 1960 1965 1970 1975 YEAR FIGURE 8.—Age-specific COLD mortality rates for white men in the United States, 1960-1977 NOTE: ICDA Nos. 490-492 and 519.3. SOURCE: National Center for Health Statistics (1982). smoke fewer cigarettes per day and to inhale less deeply, would be expected to result in less cumulative lung damage at any given age. This difference in extent of lung damage could explain the difference in COLD mortality ratios between men and women observed in the prospective mortality studies. The British doctors study examined the risk of COLD death for male and female physicians who smoked similar numbers of cigarettes per day (Table 4), and the mortality ratios were similar for similar numbers of cigarettes smoked per day. In summary, data from the prospective studies indicate that the relative risk of death from COLD is greater for male smokers than for female smokers. These differences are most likely a consequence of differences in female smoking patterns. Women tend to smoke fewer cigarettes, inhale less deeply, and begin to smoke later in life than men. These differences in mortality from COLD are narrowing because of a more rapid rise in female mortality from COLD than in male COLD mortality. This reflects the narrowing in differences between male and female smoking patterns and the rising preva- lence of female smokers in successive cohorts born between 1920 and 206 TABLE 5.—Age-specific COLD death rates per 100,000 population Age Year 45-54 55-65 65-74 75-84 1960 8.6 36.1 82.9 101.8 1961 7.6 38.7 87.9 1118 1962 9.6 44.2 107.2 136.7 1963 117 52.3 131.2 169.6 1964 12.1 51.8 131.6 181.9 1965 12.4 57.8 153.6 216.6 1966 12.4 61.9 161.9 244.8 1967 12.4 61.2 164.8 248.6 1968 13.1 7.4 186.7 286.5 1969 13.9 7.5 189.5 294.3 1970 13.6 68.1 196.5 311.5 1971 13.5 67.4 195.6 327.4 1972 13.0 67.7 204.8 351.4 1973 12.7 69.9 210.1 378.4 1974 12.8 64.8 204.8 380.4 1975 11.9 64.7 207.6 399.7 1976 12.2 64.0 210.7 419.7 1977 11.4 60.1 206.1 431.5 SOURCE: National Center for Health Statistics (1982). 1950. These data are ominous for women, portending a rising mortality from COLD over the next decades. Amount Smoked and Mortality From COLD Six of the major prospective studies evaluated the influence of different smoking levels on mortality from COLD. These studies employed a variety of measures of tobacco exposure, including number of cigarettes smoked per day, grams of tobacco smoked, and total number of cigarettes smoked in a lifetime. The data, presented in Table 4, show a gradient in risk for mortality from COLD as the number of cigarettes smoked per day increases and as the cumula- tive number of lifetime cigarettes smoked increases. In the U:S. veterans study, smokers of two packs or more per day had 22 times the risk of COLD death of nonsmokers. Furthermore, mortality ratios between the two followup periods for bronchitis and emphyse- ma actually increased overall and by the amount smoked (Figure 9). The authors noted that this was the only major disease of those associated with cigarette smoking that showed such an increase, suggesting that mortality ratios have been increasing over time at all levels of smoking. In the British and Japanese studies, women smokers at the highest levels exhibited a 32- and an 11-fold higher risk for death from COLD (respectively) than their nonsmoking counterparts. The variability in COLD mortality ratios noted in 207 21.98 q 20 | 7 81/2 years @ 16 years 17.45 Mortality ratio Nonsmoker All cigarette 1-9 10-20 21-39 240 smokers Cigarettes smoked per day FIGURE 9.—Bronchitis and emphysema for male smokers number of cigarettes smoked per day, US. veterans study, 8’/,-year and 16-year followup Table 3 is much less evident when the mortality ratios are presented. by amount smoked. In summary, the degree of tobacco exposure strongly affects the risk for death from COLD in men and in women. This clearcut dose-— response relationship enhances the strength of the causal relation- ship between smoking and COLD. Inhalational Practice and Mortality From COLD The inhalation of tobacco smoke is the major mechanism whereby. bronchial and alveolar tissues are exposed to the potentially damaging effects of tobacco smoke. In the British doctors study, subjects who acknowledged inhaling exhibited a 1.53-fold higher risk for COLD death as compared with those who stated they did not. inhale (see Table 6). However, all smokers, regardless of their. inhalational practice, exhibited higher risk for COLD mortality than did nonsmokers. In the retrospective study from northeast England (Dean et al. 1977, 1978), the risk among men for mortality from chronic bronchitis steadily declined with a decrease in the depth of inhala- tion (Table 7). Among women, the risk for mortality from chronic bronchitis was lower for all other groups than for those who stated they “inhaled a lot.” 208 TABLE 6.—COLD mortality by inhalation practice, British doctors study, men Annualized death rate per Risk in inhalers Number of 100,000 men responding compared with unity Cause of death deaths to question: do you inhale? in noninhalers Chronic bronchitis Yes No and emphysema and 71 89 58 1.53 pulmonary heart disease Table 7.—Relative risk for mortality by depth of inhalation, 1963-1972, second retrospective mortality study in northeast England Relative risk for chronic bronchitis Depth of inhalation Men Women A lot (base) 1.00 1.00 A fair amount 0.98 0.54 A little 0.62 0.41 None 0.58 0.58 SOURCE: Dean et al. (1977, 1978. Results from prospective mortality studies comparing COLD death rates by inhalation are identical to those observed in the morbidity studies, which have consistently shown that COLD is more prevalent among inhalers than noninhalers (Ferris et al. 1972; Comstock et al. 1970; Rimington 1974). These data suggest that inhalational practice affects the risk of mortality from COLD. People who inhale deeply experience a higher risk for mortality from COLD than people who do not inhale. Regardless of their inhalational practice, however, smokers still experience higher rates of death from COLD than nonsmokers. Age of Initiation and COLD Mortality Another indicator of exposure to tobacco smoke that may influ- ence risk for mortality from COLD is the age of initiation of smoking. If their smoking habits are otherwise similar, people who take up smoking at a younger age have a greater total exposure to tobacco smoke than those who take up smoking later in life, and might be expected to experience greater adverse consequences from smoking. In the Japanese prospective study (Hirayama 1981), men who began to smoke before the age of 19 exhibited slightly higher mortality ratios for emphysema than did men who began to smoke after the 209 TABLE 8.—Number of deaths from chronic bronchitis, emphysema, and pulmonary heart disease in ex- cigarette smokers, by years of cessation, versus number of deaths in lifelong nonsmokers, British doctors study Number of deaths in ex-smokers, divided by Number of deaths number expected in lifelong smokers in nonsmokers Years of cessation 0* <6 5-9 10-14 >14 35.6 34.2 477 7.3 8.1 2 * Current smokers age of 20. In the retrospective study from northeast England (Dean et al. 1977, 1978), the relative risk for death from chronic bronchitis among men who began to smoke after the age of 25 was 60 percent of that of men who began to smoke between the ages of 15 and 19. Among women in the same study who began to smoke between the ages of 15 and 19, the relative risk for death from chronic bronchitis was 1.28-fold higher than for women who began to smoke after age - 25; however, the number of deaths was small. Smoking Cessation and COLD Mortality The effects of smoking cessation on mortality from COLD were examined in the British doctors study and the U.S. veterans study. In the British doctors study, men who quit smoking experienced no change in mortality from COLD in the first 4 years and a rise in the next 5 years; presumably, this is related to the presence of many _ people in this group who quit smoking for health reasons (Table 8). Thereafter, ex-smokers experienced lower death rates from COLD, although their rates were still higher than those of the nonsmokers. Female ex-smokers also experienced lower mortality rates than current smokers, but the rates in ex-smokers were still higher than those in nonsmokers. In the U.S. veterans study, ex-smokers who had quit for reasons other than ill health experienced lower mortality rates for COLD than did current smokers. However, the benefit of cessation upon risk for mortality was heavily dependent upon the prior level of smoking and the length of time of cessation. These data are presented in Table 9. Ex-smokers who had smoked less than 10 cigarettes per day had a 1.64-fold higher risk for mortality from COLD than nonsmokers; in contrast, ex-smokers who smoked more than 39 cigarettes per day had a 9.91-fold higher rate of death from COLD than nonsmokers. For any given number of cigarettes smoked 210 TABLE 9.—Mortality ratios for bronchitis and emphysema in nonsmokers and in ex-smokers and current smokers by number of cigarettes smoked daily and number of years of cessation, U.S. veterans study Cigarettes/day Smoking status 0 <10 10-20 21-39 >39 Nonsmoker 1.00 — _ _ — Ex-smoker _— 1.64 5.35 7.68 9.91 Current smoker _— 4.84 11.23 17.45 21.98 Years of cessation Current Nonsmoker smoker <5 5-9 10-14 15-20 >20 1.00 12.07 11.66 14.35 10.19 5.66 2.64 per day, however, ex-smokers had a lower risk than current smokers. As in the British study, mortality ratios initially increased over the first 9 years of cessation. After the first 9 years, mortality ratios for ex-smokers fell, but never reached the level of the nonsmoker. Two studies have evaluated mortality rates from COLD among physicians, a group among whom many quit smoking to protect their health. Fletcher and Horn (1970) assessed the mortality rates from bronchitis among physicians in England and Wales. Among doctors aged 35 to 64, there was a 24 percent reduction in bronchitis mortality between 1953-1957 and 1961-1965, as compared with a reduction of only 4 percent in the national bronchitis mortality rates for men of the same age in England and Wales. Enstrom (1983) assessed mortality trends from COLD in a cohort of 10,130 physi- cians in California. The standardized mortality ratio for bronchitis, emphysema, and asthma among male California physicians relative to American white men declined from 62 during the period 1950 to 1959 to 35 during the period 1970 to 1979. In summary, cessation of smoking leads to a decreased risk for mortality from COLD as compared with that of current smokers. The residual risk of death for the ex-smoker is determined by the person’s prior smoking status and the number of years of cessation. However, the residual risk remains larger than that of the nonsmok- er, presumably because of the presence of irreversible lung damage acquired during prior smoking. Pipe and Cigar Smoking Mortality From COLD Several of the prospective epidemiological studies examined the relationship between pipe and cigar smoking and mortality from COLD. The data from these studies indicate that pipe smokers and 211 TABLE 10.—COLD mortality ratios in male pipe and cigar smokers, prospective studies Type of smoking Total Non- Cigar Pipe pipe and Cigarette Study Category smoker only only cigar only Mixed American Cancer COLD total 1.00 1.29 177 2.85 Society 9-State Emphysema Bronchitis British doctors COLD total 1.00 9.33 24.67 11.33 Emphysema Bronchitis 1.00 4.00 7.00 6.67 Canadian veterans COLD total Emphysema 1.00 3.33 15 5.85 Bronchitis 1.00 3.57 2.11 11.42 American Cancer COLD total Society 25-State Emphysema 1.00 1.37 6.55* Bronchitis US. veterans COLD total 1.00 .79 2.36 39 10.08 (8.5-year Emphysema 1.00 1.24 2.13 1.31 14.17 followup) Bronchitis 1.00 117 1.28 117 4.49 U.S. veterans COLD total 1.00 0.84? 1.443 4.75 (16-year Bronchitis, followup) emphysema 1.00 2.53% 13.13* ' Mortality ratios for agea 55 to 64 only are presented. * Pure cigar. > Pure pipe. * Pure cigarette. cigar smokers also experience higher mortality from COLD as compared with nonsmokers. However, the risk of dying from COLD is less than that of current cigarette smokers (Table 10). International Comparison of COLD Death Rates and Smoking Habits: The Emigrant Studies Reid (1971) reported that age-adjusted mortality rates from chronic nonspecific lung disease among British citizens varied with migration patterns. British men living in the United Kingdom had a chronic, nonspecific lung disease death rate of 125 per 100,000, whereas migrants to the United States experienced a mortality rate of only 24 per 100,000, which is similar to the rate found in the US. population. Differences in cigarette smoking and air pollution were identified as the major factors contributing to the real excess in bronchitis morbidity experienced by the British in the United: Kingdom. Rogot (1978) conducted a study of British and Norwegian emigrants to the United States. The mortality rate from chronic nonspecific lung disease (CNSLD) in Great Britain is about fivefold 212 that in the United States, whereas the mortality rate from CNSLD in Norway is slightly lower than that in the United States. In contrast, the British migrant rates were about equal to those of native-born Americans and the Norwegian migrant rates were the lowest. Mortality rates for CNSLD were higher for smokers than for nonsmokers in all groups. These data suggest that ethnic origin plays a minor role, if any, in determining COLD risk. Regardless of country of origin, these studies indicate that tobacco smokers experience higher mortality rates for COLD than do nonsmokers. COLD Mortality Among Populations With Low Smoking Rates Numerous studies have reported that certain population groups who traditionally abstain from cigarette smoking for religious or other reasons have lower mortality rates from those diseases traditionally related to tobacco use. The 1982 and 1983 Reports of the Surgeon General, The Health Consequences of Smoking (USDHHS 1982, 1983), extensively reviewed this phenomenon as it relates to cancer and cardiovascular diseases among Mormons, Seventh Day Adventists, and others. Because Amish are seen as strict and fundamentalist in outlook, it is assumed that their use of tobacco is severely restricted. While cigarettes are largely considered taboo, pipe and cigar smoking and tobacco chewing are widespread (Hostetler 1968). Hamman et al. (1981) examined the major causes of death in Old Order Amish people in three settlements in Indiana, Ohio, and Pennsylvania to determine if their lifestyle altered their mortality risk compared with neighboring non-Amish. Mortality ratios from all respiratory diseases were significantly lower by over 80 percent in Amish men 40 to 69 years old, and by 50 percent in those 70 and older. In the chronic pulmonary disease categories including emphysema, bronchitis, and asthma, only one Amish male death occurred, whereas approximately 23 were expected. The pattern of mortality *-om chronic respiratory diseases was similar for Amish women. Summary and Conclusions 1. Data from both prospective and retrospective studies consis- tently demonstrate a uniform increase in mortality from COLD for cigarette smokers compared with nonsmokers. Cigarette smoking is the major cause of COLD mortality for both men and women in the United States. 2. The death rate from COLD is greater for men than for women, most likely reflecting the differences in lifetime smoking patterns, such as a smaller percentage of women smoking in 213 214 past decades, and their smoking fewer cigarettes, inhaling less deeply, and beginning to smoke later in life. _ Differences in lifetime smoking behavior are less marked for younger age cohorts of smokers. The ratio of male to female mortality from COLD is decreasing because of a more rapid rise in mortality from COLD among women. -The dose of tobacco exposure as measured by number of cigarettes or duration of habit strongly affects the risk for death from COLD in both men and women. Similarly, people who inhale deeply experience an even higher risk for mortality from COLD than those who do not inhale. Cessation of smoking eventually leads to a decreased risk of mortality from COLD compared with that of continuing / smokers. The residual excess risk of death for the ex-smoker is directly proportional to the overall lifetime exposure to ciga- rette smoke and to the total number of years since one quit smoking. However, the risk of COLD mortality among former smokers does not decline to equal that of the never smoker even after 20 years of cessation. . Several prospective epidemiologic studies examined the rela- tionship between pipe and cigar smoking and mortality from COLD. 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PATHOLOGY OF LUNG DISEASE RELATED TO SMOKING 219 CONTENTS Introduction Lesions Associated With Chronic Airflow Obstruction Central Airways Mucus Other Abnormalities of Central Airways Peripheral (Small) Airways General Review Smoking and Lesions of Peripheral (Small) Airways Vascular Lesions Related to Smoking Emphysema Definition Classification Proxima] Acinar Emphysema Panacinar (Panlobular) Emphysema Distal (Paraseptal) Acinar Emphysema Irregular Emphysema Tobacco Smoking and Emphysema Summary and Conclusions References 221 Introduction It is usual to think of chronic airflow obstruction as being caused by airway narrowing or loss of airflow driving pressure—the elastic recoil of the lung (Macklem 1971)—or both. Lesions of the airways are often divided into those of the “large airways” and those of the “small airways.” The reasons for this division are both historical and conceptual. Hogg et al. (1968) showed that in patients with chronic obstructive lung disease (COLD) the major site of airway obstruction lay in airways that were peripheral to the wedged catheter that the researchers used to partition airway resistance. The catheter was wedged in airways 2 or 3 mm in diameter, and thus the airways peripheral to the catheter included the smallest bronchi (airways with cartilage in their walls) and bronchioles (conducting airways without cartilage in their walls). Since both bronchi and bronchioles were involved, Hogg and associates used the term “small airways” to describe them, which has since become a popular term. Conceptual- ly, lesions of airways may consist of an intraluminal component (mucus) or a mural component. Most of the mucus in the airways is thought to be secreted by the tracheobronchial submucosal glands (Reid 1960); these are mainly confined to airways more than 2 or 3 mm in diameter, or large airways. Because of the documented association between chronic productive cough and airflow obstruc- tion (Fletcher et al. 1959), for a long time it was thought by many that intraluminal mucus was a major source of chronic airflow obstruction. Thus, the notion developed, without proper substantia- tion, that central airways obstruction was due to intraluminal mucus and peripheral airway obstruction was due to inflammation and narrowing. It is also true that many have equated emphysema with loss of elastic recoil, but when this has been examined in vivo (Park et al. 1970; Boushy et al. 1970; Gelb et al. 1973; Berend et al. 1979; Pare et al. 1982) or in excised lungs (Berend et al. 1980; Silvers et al. 1980), the association has not been close, with some notable exceptions (Niewoehner et al. 1975; Greaves and Colebatch 1980). Thurlbeck (1983) reviewed the evidence and argued that loss of recoil in emphysematous lungs may not be due to the lesions of emphyse- ma per se but to defects in apparently morphologically normal intervening lung tissue. The classical approach to considering the different sites of flow obstruction is used in this chapter to analyze the relationship between smoking and the morphologic lesions associated with chronic airflow obstruction in humans. Lesions of the large airways (bronchi) are discussed first, followed by small airways, and then by alveolated structures. It has very recently become apparent that it is important to include respiratory bronchiolitis as well as emphysema in the last category (Wright et al., in press); this issue is discussed in the paragraphs on peripheral (small) airways. Definitions and a brief 223 review of the diseases involved are provided. This chapter attempts to present the morphologic changes associated with chronic obstruc- tive lung disease. The detailed epidemiologic and experimental evidence relating cigarette smoking and COLD are presented elsewhere in this Report. Lesions Associated With Chronic Airflow Obstruction Central Airways Mucus It is convenient to discuss intraluminal mucus and increased tracheobronchial mucus gland size together, because they are - thought to be related (Reid 1960). Chronic bronchitis is defined as - “the condition of subjects with chronic or recurrent excess mucus secretion into the bronchial tree” (Ciba Foundation Guest Sympo- - sium 1959). Because there is no way to accurately measure the amount of mucus secreted into the bronchi, the empirical approach was taken that production of any sputum was abnormal. Chronic was defined as “occurring on most days for at least 3 months of the year for at least 2 successive years” (Ciba Foundation Guest Symposium 1959). A further qualification was that such sputum production should not be on the basis of specific diseases such as tuberculosis, bronchiectasis, or lung cancer. The initial step was to correlate chronic bronchitis, as defined above, with lesions in the central airways. This was first done by Reid (1960), who assessed gland size by comparing the thickness of the submucosal bronchial mucus glands in histologic sections to the” thickness of the bronchial wall. The latter was defined as the- distance from the basement membrane of the epithelium to the- inner periochondrium. This measurement is now known as the Reid Index. This increase has been confirmed by several observers (Thurlbeck et al. 1963; Thurlbeck and Angus 1964; Mitchell et al. 1966; MacKenzie et al. 1969; Scott 1973), but not by all (Bath and Yates 1968; Karpick et al. 1970). An important observation was that there was a distinct overlap in the value of the Reid Index between bronchitics and nonbronchitics (Thurlbeck and Angus 1964) as opposed to Reid’s 1960 finding that there were two completely separate groups. In practical terms, this meant that the Reid Index had limitations in predicting the presence or absence of chronic bronchitis. More important, it suggested a broad border between’ health (nonbronchitis) and disease (bronchitis). For a variety of technical reasons (Jamal et al., in press), the Reid Index is a difficult measurement to use; thus, other measurements of mucus gland size" were developed. The most popular was the volume density of mucus glands, i.e., the ratio of area of mucus glands to area of the entire bronchial wall as seen on histologic slides (Hale et al. 1968; Dunnill 224 et al. 1969; Takizawa and Thurlbeck 1971; Oberholzer et al. 1978). Other methods included absolute gland size (Restrepo and Heard 1963; Bedrossian et al. 1971) and a radial intercept method (Alli 1975). The size of the acini (tubules) of mucus glands, the number per unit area, and the ratio of mucus to serous tubules have also been used (Reid 1960). The Reid Index, the volume density of mucus glands, and the ratio of mucus to serous acini have been examined in smokers and nonsmokers; the results are shown in Table 1. When one considers the overwhelming association between smoking and chronic bronchi- tis in living subjects, differences in mucus gland size are insignifi- cant. For example, three laboratories (Reid 1960; Thurlbeck et al. 1963; Thurlbeck and Angus 1964; Scott 1973) have found a difference in Reid Index between smokers and nonsmokers; two have not (Bath and Yates 1968; Hayes 1969). The results from volume density of mucus glands are clearer—Ryder et al. (1971) found a higher volume density of mucus glands in both male and female subjects. In populations of mixed sex, Cosio et al. (1980) and Pratt et al. (1980) found a higher volume density of glands, but Sobonya and Kleiner- man (1972) and Scott (1973) did not. When observers have expressed their morphologic findings as either “normal” or “abnormal” (using different criteria), the smokers have been significantly abnormal in all the studies (Field et al. 1966; Megahed et al. 1967; Petty et al. 1967; Vargha 1969). The balance of the evidence is that there is an increase in mucus gland size in smokers. The discrepancy between the clinical and the morphologic findings may reflect several factors: the wide variation in mucus gland size in normal subjects, the difficulties in measuring the Reid Index and volume density of mucus glands, the different ways in which the cases have been collected, and the errors inherent in assessing smoking histories- from analysis of charts; also, the fact that mucus glands can enlarge terminally (Helgason et al. 1970) might obscure true differences between the two groups. In addition, submucosal gland enlargement is a nonspecific change that can also occur in pneumoconiosis and cystic fibrosis. Mucus is also secreted by goblet cells, most of which are in the major airways. Pratt et al. (1980) showed that goblet cells constituted 10.7 percent of the cells in the central airways of nonsmoking nontextile workers and 20.4 percent in smoking nontextile workers. Interestingly, they found an 18 percent frequency of goblet cells in nonsmoking textile workers; the frequency was about the same in smokers, whether or not they were textile workers. Other Abnormalities of Central Airways A variety of other changes have been described in the central airways in patients with chronic airflow obstruction, including 225 TABLE 1.—Comparison of mucus gland size in smokers and nonsmokers Findings in smoking category Assessment of Light and mucus gland Non- moderate Heavy enlargement Author smokers Smokers smokers smokers Reid index Reid (1960) 0.46 0.43 Thurlbeck et al. (1963) 0.43 0.50 0.45 0.53 Thurlbeck and Angus (1964) 0.44 0.49 Bath and Yates (1968) 0.45 0.49 Hayes (1969) 0.32 0.33 Scott (1973) 0.41 0.46 Mucus gland Ryder et al. (1971) (men) 14.5% 17.8% proportion Ryder et al. (1971) (women) 14.5% 17.1% Sobonya and Kleinerman (1972) 11.2% 10.7% Scott (1973) 14.1% 14.4% Cosio et al. (1980) Increased Pratt et al. (1980) 9.3% 12.6% Frequency of cases Field et al. (1966) (men) 12% 37% with MGH? expressed Field et al. (1966) (women) 18% 26% as a percentage of § Megahed et al. (1967) 14% 61% cases in the group _—~ Petty et al. (1967) 8.8% 37% Vargha (1969) 18% 44% *MGH = Mucus gland hypertrophy. inflammation and edema of the wall (Reid 1954), increase in bronchial smooth muscle (Hossain and Heard 1970; Takizawa and Thurlbeck 1971), and diminished cartilage, which is related more to emphysema than to chronic bronchitis (Thurlbeck et al. 1974a). Peripheral (Small) Airways General Review As indicated, it was as recent as 1968 that the obstruction in patients with chronic airflow obstruction was conclusively shown to be due mainly to lesions in airways less than 2 or 3 mm in diameter. However, abnormalities in these airways had long been recognized. Indeed, Laennec (1962) pointed out in 1826 that air remained trapped in emphysematous lungs even when the major bronchi had been opened, and he reasoned that the source of the air-trapping was obstruction in the airways peripheral to the opened ones. Since then, numerous descriptions have been made of the peripheral airways in severe chronic airflow obstruction (see Table 2). Smokers were not compared with nonsmokers in any of these series. The probable reason is that for a long time it was thought that bronchiolitis was an infective complication of chronic bronchitis. Only very recently, and from studies in patients with mild chronic airflow obstruction, 226 has the link between smoking and peripheral airway lesions become established. Hogg et al. (1968) not only found that the peripheral airways were the site of airflow obstruction in patients with severe disease, but also observed that peripheral airways contributed only about 15 percent of resistance to flow in normal lungs. It followed that considerable disease could be present in these peripheral airways without airway resistance being measurably increased. It was reasoned also that standard tests of expiratory function, such as the FEV; and the FEF25-75, might not be abnormal in the presence of significant disease. Thus a variety of “tests of small airway function” were devised; these evolved to the single breath nitrogen washout test and to flow volume studies, in some instances comparing the effect of breathing helium mixtures with the effect of breathing room air. It soon became apparent that these tests could be abnormal when the FEV was greater than the 80 percent predicted and that tests of small airway function could return to normal after cessation of smoking (Buist et al. 1976, 1979; Beck et al. 1981; Bouse et al. 1981). The term “small airways disease” was and is often applied to these abnormalities. It then became of interest to determine what the lesions in the airways were. Long before this, Reid (1955) had studied nine lungs resected from patients with chronic bronchitis and two lungs from chronic bronchitics obtained at autopsy. She found excess intraluminal mucus and narrowing and obliteration of airways, as assessed subjectively. Because the surgical patients also had lung cancer, most likely they were chronic smokers. Matsuba and Thurlbeck (1973) compared the airways of chronic bronchitics to those of nonbronchitics in nonemphysematous lungs. All the bron- chitics were smokers and two nonbronchitics were smokers. Morpho- metrically, they found obvious narrowing of airways less than 2 mm in diameter, which also contained excess mucus. The important study by Cosio et al. (1978), using surgically resected lungs, showed for the first time that abnormal tests of small airway function were related to abnormal morphology. There were 34 smokers and 2 nonsmokers in their group. A variety of abnormali- ties were observed, including inflammation, squamous cell metapla- sia, ulceration, fibrosis, pigmentation, and increased muscle. They developed a score that summed the observed lesions (the total pathology score), and divided their patients into four groups on the basis of this score. They showed that as the total pathology score increased, tests of small airway function (single breath nitrogen test and flows on air and helium mixtures) deteriorated, as did standard tests of pulmonary function such as the FEV: and FEF 25-75. The data concerning smoking are hard to interpret, but the smoking index (number of cigarettes smoked per day times number of years smoked) increased from groups I| to III and was similar in groups III 227 TABLE 2.—Occurrence of lesions of peripheral airways in patients with severe chronic airflow obstruction Authors Disease investigated Abnormalities found Laennec (1962) Emphysema Obstruction to flow in peripheral airways Spain and Kaufman Emphysema Mural inflammation and fibrosis (1953) Reid (1954) Leopold and Gough (1957) McLean (1958) Anderson and Foraker (1962) Pratt et al. (1965) Anderson and Foraker (1967) Hogg et al. (1968) Mitchell et al. (1968) Bignon et al. (1969, 1970) Karpick et al. (1970) Linhartova et al. (1971) Matsuba and Thurlbeck (1972) Linhartova et al. (1973, 1974, 1977) Scott and Steiner (1975) Scott (1976) Mitchell et al. (1976) Chronic bronchitis Centrilobular emphysema Emphysema Emphysema Centrilobular emphysema Emphysema Emphysema with severe chronic airflow obstruction Chronic airflow obatruction and severe emphysema Cor pulmonale and centrilobular emphysema Respiratory failure Emphysema Severe emphysema and chronic airflow limitation Emphysema Cor pulmonale Chronic airflow obstruction Chronic airflow obstruction obstruction of bronchioles Bronchiolitis, bronchiolar oblit- eration, and mucus plugging Inflammation, fibrosis with narrowing of 60% of bronchioles supplying centrilobular space Inflammation of proximal res- piratory bronchioles, mucus plugging, and loss of bronchioles Collapse of bronchioles due to loss of alveolar attachments Loss or distortion of the radial support of bronchioles Loss of bronchioles in patients under age 70 Inflammation and fibrosis of bronchi and bronchioles and mucus plugging Inflammation, atrophy, goblet cell metaplasia, squamous metaplasia, and mucus plugs in bronchioles Inflammatory narrowing and fibrosis, loss of bronchioles, and mucus plugging Goblet cell metaplasia Plugging of bronchioles with inflammatory cells and mucus Loss of lumen of airways less than 2 mm in diameter due primarily to narrowing and mucus plugs Distortion, tortuosity, and irregular narrowing of bronchioles Lack of filling bronchioles of less than 1 mm Loss of airway lumen Chronic inflammation (r=0.48), narrowing (0.29), fibrosis (0.27), goblet cel] metaplasia (0.24), and fewer smal] airways (-0.18) 228 and IV. The lesions that were different in group II from lesions in group I were squamous cell metaplasia, inflammation, and fibrosis. Fibrosis and squamous cell metaplasia increased steadily from groups I to III. Increased muscle and goblet cell metaplasia occurred only in group IV. One extrapolation of these data is that inflamma- tion in the peripheral airways is the initial event produced in response to cigarette smoke. This inflammation leads to, or is associated with, squamous metaplasia and mural fibrosis. Goblet cell metaplasia and increase in muscle subsequently occur and are associated with decrements of function. Berend et al. (1979) did a similar study on 21 smokers and 1 nonsmoker, and added the important information that airway narrowing occurred and was associated with abnormalities of the single breath nitrogen washout test and the FEF2575. The data were reanalyzed subsequently (Berend et al. 1981b) and showed that inflammation was the lesion associated with the most abnormalities in tests of expiratory function. Airway inflammation was significant- ly related to abnormalities of the FEV:, FEF 25-75, slope of phase ITI of the single breath nitrogen test, and closing volume expressed as a percentage of vital capacity. The authors also noted that as the total pathology score got worse, the airways diminished in caliber in surgically derived lungs, but not in autopsy lungs. They noted that airway caliber was larger in autopsy lungs than surgical lungs, and suggested that this represented functional narrowing due to in- creased muscle tone, which was caused by release of mediators affecting the muscle directly or reflexly. Studies of lungs at autopsy have shown correlations between airway lesions and abnormal tests of function. Petty et al. (1980, 1982) have shown that correlations exist between inflammation, and increased muscle and elevations in the closing capacity; that occlusion of airways by cells and mucus, inflammation, and in- creased airway muscle are related to abnormalities of the slope of phase III of the nitrogen washout; that airway narrowing is closely related to the FEVi, FEF 25-15, and slightly less well related to closing capacity. Similarly, Berend et al. (198la) showed an association between post-mortem closing capacity and both peripheral airways inflammation and a total pathology score. Decrease in maximum flow at a transpulmonary pressure of 5 cm H2O was related to inflammation and the total pathology score, but not as well related to airway narrowing (Berend and Thurlbeck 1982). Morphologic abnormalities similar to those found in autopsy lungs have been found in surgically excised lungs derived almost entirely from smokers, and these in turn have been related to abnormal tests of small airway function. 229 Smoking and Lesions of Peripheral (Small) Airways An increase in goblet cells was the first abnormality of peripheral airways noted in smokers. The observation was made in bituminous coal workers. In nonsmokers, about 0.66 percent of peripheral airway cells were found to be goblet cells; in smokers, this rose to about 1.0 percent (Naeye et al 1971). The critical observation, both factually and conceptually, was that of Niewoehner et al. (1974). In an autopsy study of men under the age of 40 who died suddenly elsewhere than in the hospital, they compared lesions of bronchioles and respiratory bronchioles (airways with both nonrespiratory epithelium and alveoli in their walls) in smokers and nonsmokers. Emphysematous lungs were excluded, and the smoking history was obtained by personal interview with close relatives, using a standard questionnaire. The researchers found that intraluminal mucus, mural edema, peribronchiolar pigment, peribronchiolar fibrosis, denuded epithelium, mural inflammatory cells, and respiratory bronchiolitis were more severe in the smokers. The last three were significantly different statistically. They empha- sized the importance of respiratory bronchiolitis, which consisted of aggregates of brown macrophages in and around the first and second order respiratory bronchioles and was associated with edema, fibrosis, and epithelial hyperplasia in adjacent bronchioles and alveolar walls. Bronchiolitis was found in all of the smokers, but in only 5 of the 20 nonsmokers, and it was the lesion that showed the greatest difference between smokers and nonsmokers. Since respira- tory bronchiolitis was found in precisely the same regions where - centrilobular emphysema is found in subjects 20 years older, the - researchers suggested that this lesion might evolve into emphysema. This observation fits well the proteolytic—antiproteolytic hypothesis of the pathogenesis of emphysema. Ebert and Terracio (1975) compared the peripheral airways in resected lungs of 22 smokers and 3 nonsmokers and found that the number of Clara cells (the tall nonciliated airway cells thought to be secretory, although the nature of their secretion is not completely certain) was diminished, as assessed subjectively, and the number of goblet cells was increased, as assessed quantitatively. Two laboratories have concentrated on the association between smoking and lesions of vessels as well as of airways. One has used autopsy-derived lungs (Cosio et al. 1980; Hale et al 1980); the other, surgically excised lungs (Wright et al. 1983a, b, in press). The first material has the advantage that the entire lung can be examined, - but has the disadvantage that agonal changes may affect the airway; the second has the advantage that agonal changes are absent and structure-functional studies can be done, but has the serious disadvantage that usually only a part of the lung is examined. Because of the wide variation in severity of emphysema from lobe to 230 lobe, emphysema in the whole lung cannot be assessed from a single lobe. Also, airway inflammation may not be evenly distributed through the airways (Berend 1981; Hale et al. 1980). Cosio et al. (1980) studied 14 nonsmokers with an average age of 71.6 years and 25 long-term smokers with an average age of 58.4 years. The total pathology score was significantly higher in the smokers; in them, but not in the nonsmokers, the total pathology score was significantly related to age. Respiratory bronchiolitis was more common in the smokers, and of the components of the total pathology score, goblet cell metaplasia (p <0.001), inflammation of the bronchiolar wall (p <0.01), and smooth muscle hypertrophy (p <0.05) were significantly more abnormal in the smokers. Smokers had an excess of airways less than 400 y in diameter, also related to the total pathology score. Because goblet cell metaplasia and increased smooth muscle were not significantly increased in the researchers’ previous study of young smokers (Niewoehner et al. 1974), they concluded that these lesions were a late complication of cigarette smoking. They noted that there was a considerable similarity of all lesions of both smokers and nonsmokers, and felt that this indicated the existence of other causes of small airway lesions. They also made the interesting suggestion that the relation- ship between the total pathology score and the proportion of airways less than 400 p in diameter might indicate a predisposition of subjects with small airways to develop peripheral airway lesions. Wright et al. (1983b) studied 9 nonsmokers, 51 current smokers, 18 ex-smokers who had quit less than 2 years, and 19 ex-smokers who had quit more than 2 years. The only lesion of the bronchioles that distinguished the nonsmokers from the smokers and the long-term ex-smokers was goblet cell metaplasia, although there were obvious differences in pulmonary function among these groups. The signifi- cance of goblet cell metaplasia may be related to mucus production in airways not usually lined by mucus. There is evidence that they are lined by surfactant. If this is displaced by mucus with a higher surface tension it will produce narrowing difficult to detect by standard morphological methods. Respiratory bronchiolitis was more severe in the smokers and ex-smokers than in the nonsmokers. No differences were noted between the ex-smokers and smokers. This study has recently been extended (Wright et al., in press), and correlations between both bronchiolar inflammation and respiratory bronchiolitis and the FEV: were evident. When the FEV; was greater than the 80 percent predicted, the most important determinant of abnormalities of tests of small airway function was respiratory bronchiolitis. Thus, respiratory bronchiolitis may not only represent a stage in the pathogenesis of centrilobular emphysema, but also result in abnormalities of the single breath nitrogen test and other tests of small airway function. 231 It is not certain why cessation of smoking results in improvement - of lung function. The most likely reversible parameter is inflamma- tion; the lack of difference between nonsmokers and the other groups in the study by Wright et al. (1983b) is very surprising in view of the observations of Niewohner et al. (1974) and Cosio et al. (1980), but may be due to the very small number of nonsmokers studied and the fact that the nonsmokers had lung lesions for which resection was performed. An additional factor is the use of lobes in the study, which in the small group of normals may produce distortions in the data because of lobar variations in the total pathology score. Vascular Lesions Related to Smoking At first sight it may appear surprising that vascular lesions are detectable in asymptomatic smokers or those with only mild or moderate chronic airflow obstruction. On reflection, this could be anticipated. Severe chronic airflow obstruction, usually related to smoking, is often accompanied by pulmonary artery hypertension; mild chronic airflow obstruction might be associated with mild pulmonary artery hypertension and vascular lesions. The first study (Hale et al. 1980) involved the same cases reported by Cosio et al. (1980). They found that the smokers had an increased number of arteries less than 200 » in diameter and also an increased medial and intimal thickness of the pulmonary arteries. The intimal thickness was increased more in those vessels of less than 200 p in diameter. Both intimal and medial thickness were directly related to the total pathology score. Wright et al. (1983a) found an increase in the vessel area from an average of 0.12 mm? in nonsmokers to approximately 0.3 mm? in smokers. Intimal area expressed as a proportion of vessel area increased; there was an absolute increase of the medial area, but no proportional change. The adventitial area also increased in absolute terms, but the adventitial proportional area was decreased and was related to the pulmonary wedge pressure. Pulmonary artery pressures were norma! at rest, but abnormal and reversible by oxygen on exercise in the smokers with the worst airway inflammation and emphysema. Emphysema Of the lesions associated with chronic airflow obstruction, em- physema has been the one most clearly associated with tobacco smoking. There are several different types of emphysema, however, and cigarette smoking has not been clearly linked to, or examined in, all forms of the disorder. Therefore, the definition and classification of emphysema are reviewed before discussing the association be- tween smoking and emphysema. 232 AS Alveolus AD RB, RB, TB —$ > FIGURE 1.—Components of the acinus NOTE: TB: terminal bronchiole; RB), RBz, RBs: the three orders of respiratory bronchioles; AD: alveolar duct: AS: alveolar sac. SOURCE: Thurlbeck (1976). Definition Emphysema is defined as an abnormal enlargement of the air spaces of the lung accompanied by destruction of alveolar walls (World Health Organization 1961; American Thoracic Society 1962). Thus, emphysema is a disorder of anatomy, and one must know the appropriate normal anatomy in order to understand the pathology of emphysema. The structure involved is the acinus, the unit gas- exchanging structure of that part of the lung containing alveoli. The last purely conducting airway is the terminal bronchiole; structures distal to it constitute the acinus. The acinus is a complex unit, but a simplified model will suffice (Figure 1). The structures immediately before the terminal bronchiole are the respiratory bronchioles, which, as indicated previously, have both alveoli and nonalveolated epithelium forming their walls; thus, respiratory bronchioles both conduct and exchange gas. Proceeding distally, progressively more alveoli appear in the walls of respiratory bronchioles, of which there are three orders in the usual model of the acinus. Alveolar ducts succeed respiratory bronchioles, and their walls are entirely alveo- lated. Alveolar ducts lead into alveolar sacs, the terminal respiratory structures, which are likewise completely alveolated. Classification Emphysema is classified by the way it involves the acinus, and four forms of emphysema are usually recognized (Thurlbeck 1976): (1) proximal acinar emphysema, (2) panacinar (panlobular) emphyse- 233 480-144 0 - 85 - 9 ma, (3) distal (paraseptal) acinar emphysema, and (4) irregular emphysema. Proximal Acinar Emphysema In proximal acinar emphysema, the respiratory bronchioles are selectively or dominantly involved. Emphysema involving the proxi- mal part of the acinus is found in two different circumstances— centrilobular emphysema and focal emphysema. Proximal acinar emphysema is the common form of nonindustrial emphysema and is associated with inflammation of the distal airways (Leopold and Gough 1957) and of the walls of emphysema- tous spaces. This form of emphysema is usually referred to as centrilobular emphysema (Figure 2) because the lesions lie close to _ the center of the secondary lobules. The emphysematous spaces are found more frequently in the upper zones of the lungs, and centrilobular emphysema is usually more severe there (Thurlbeck 1963a). Involvement of the lung is characteristically quite uneven; some respiratory bronchioles are spared or slightly involved, whereas others close by may be severely affected, producing large emphysematous spaces. Centrilobular emphysema is frequently associated with chronic bronchitis, and is the form of emphysema most commonly encountered in patients with symptomatic chronic airflow obstruction. Focal emphysema, or simple pneumoconiosis of coalworkers, also involves the proximal part of the acinus. It can be distinguished from centrilobular emphysema in that there is always a heavy deposit of coal around the emphysematous spaces, the enlargement of respira- tory bronchioles is usually moderate, and the process is more uniform through the lung. Simple pneumoconiosis is usually associ- ated with only mild impairment of function, producing only minor abnormalities of gas exchange (Morgan and Seaton 1975). Panacinar (Panlobular) Emphysema In panacinar or panlobular emphysema, there is more or less uniform involvement of the acinus (Figure 3). Controversy exists concerning the distinction between centrilobular and panacinar emphysema; some believe them to be different conditions (Anderson and Foraker 1973), but others believe them to have the same clinical and functional associations (Mitchell et al. 1970). The reason for this - disagreement is discussed below. Four different associations of panacinar emphysema are described (Thurlbeck 1976), each with its specific clinicopathologic associations. This view is not shared by all, however. The classical association of panacinar emphysema is with a,- antitrypsin deficiency (Eriksson 1965), most commonly with the PiZ 234 inflamed FIGURE 2.—Centrilobular emphysema NOTE: See footnote to Figure 1 for defini tions SOURCE: Thurlbeck (1976). Septum FIGURE 3.—Panlobular emphysema NOTE: See footnote to Figure | for de finitions. SOURCE: Thurlbeck (1976), 235 phenotype. It is probable that other forms of Pi-associated emphyse- ma, such as PiSZ, are also panacinar in type. Familial emphysema unassociated with a,-antiprotease deficiency has been shown to be panacinar (Martelli et al. 1974). Familial emphysema is characteris- tically worse in the lower zones of the lung. Severe, pure panacinar emphysema is uncommon. Localized panacinar emphysema is found fairly frequently at autopsy (Thurlbeck 1963a). It is found more commonly in older people and is usually not associated with clinical evidence of chronic airflow obstruction. Under these circumstances, it is more frequent in the lower and anterior parts of the lung. It may represent a focal exaggeration of the aging process in the lung, which includes a well documented set of changes (Thurlbeck 1976), including changes in the shape of the lung with an increase in anteroposterior diameter, loss of volume density of alveolar walls, increase in the distance between alveolar walls, decrease of alveolar surface area, increase in volume density of alveolar ducts, and decrease of volume density of — alveoli. The reason for referring to these changes with age as the “aging lung” rather than “senile emphysema” is that it is a normal change, affecting virtually all people. The definiticn of emphysema requires that the enlargment and destruction of respiratory tissue be abnormal; therefore, it is probably inappropriate to categorize these changes as emphysema. Bronchial and bronchiolar obliteration may be associated with panacinar emphysema. Most commonly it is associated with Swyer- James (1953) or MacLeod’s (1954) syndrome of unilateral pulmonary hyperlucency, in which one lung or a major portion of the lung is unduly transradiant. The involved region or regions of the lung characteristically trap air on expiration so that the mediastinum then moves to the unaffected side. The syndrome is usually due to severe acute bronchitis and bronchiolitis in childhood, resulting in obliteration of airways. A detailed study of the lung parenchyma in cases of unilateral pulmonary transradiancy has never been reported, but it seems likely that emphysema may not be present in the affected lung tissue. However, when emphysema is present, it is panacinar in type. Panacinar emphysema may be found in the lower zones of the lung in patients with upper zonal centrilobular emphysema. The combi- nation of the two forms of emphysema is probably the classical ~ finding in patients with severe chronic airflow obstruction, and it is also one reason for the controversy concerning similarities or differences between centrilobular and panacinar emphysema. Tran- sitions, real or imagined, may be apparent between the upper zonal - centrilobular emphysematous spaces and lower zonal panacinar emphysema in this situation. Some believe the transitions are real, and maintain that centrilobular emphysema has progressed to 236 FIGURE 4.—Distal or paraseptal acinar emphysema NOTE: See footnote to Figure 1 for definitions. SOURCE: Thurlbeck (1976). Panacinar emphysema and that these lungs should be classified as examples of centrilobular emphysema. Others feel that it is panaci- nar emphysema, and thus the same lung may be classified different- ly. Distal (Paraseptal) Acinar Emphysema Distal (paraseptal) acinar emphysema is the third generally recognized form of emphysema. In this form, the alveolar ducts and Sacs are predominantly involved, and there may be substantial associated fibrosis (Figure 4). Since the distal acinus abuts on pleura, vessels, airways, and lobular septa, the emphysema is worse in these regions. The occurrence of distal acinar emphysema along the lobular septa had led to the term “paraseptal emphysema.” A characteristic clinical association of distal acinar emphysema is spontaneous pneumothorax of young adults (Edge et al. 1966), rregular Emphysema In irregular emph ysema, the acinus is irregularly enlarged {Figure »). It is nearly always associated with scarring. It may be the most ‘ommon form of emphysema, because nearly all lungs on close ‘xamination will disclose a scar associated with emphysema. The najority of these examples of irregular emphysema are unassociated vith symptoms. 237 AB 18 ' Me AY FIGURE 5.—Irregular emphysema NOTE: See footnote to Figure 1 for definitions. SOURCE: Thurlbeck (1976). Tobacco Smoking and Emphysema The apparently neat and orderly classification described above and the classical examples of emphysema illustrated in original articles and monographs should not obscure the lack of agreement between expert observers in the classification of severely emphysematous lungs (Thurlbeck et al. 1968, Mitchell et al. 1970). Severe emphyse- ma is usually atypical in morphology, and often more than one type - of emphysema is present. It might be more rational to speak of “end stage emphysema” when describing an extensively damaged lung, - rather than attempting to fit all of the damage under one classifica- tion. These differences in classification may lead to differing assess- ments of degrees of association between smoking and individual forms of emphysema. For example, Anderson and Foraker (1973) , found that all of their 21 patients with centrilobular emphysema were cigarette smokers, whereas 8 of the 17 patients with panacinar emphysema were cigarette smokers. Contrarily, Mitchell et al. (1970) found that 20 of their 21 patients with centrilobular emphysema were cigarette smokers and all 6 of their patients with panacinar emphysema were cigarette smokers. Including all of the different abnormalities described above under the single term “emphysema” may lead to confusion about the relationship between smoking and emphysema. Each of the different forms of emphysema may have different etiologies; while cigarette smoking is clearly implicated in the etiology of centrilobular emphysema (Mitchell et al. 1970, Anderson and Foraker 1973), it may not play a role in irregular or distal acinar emphysema and is 238 clearly not implicated in the etiology of unilateral pulmonary transradiancy. Another problem is the sensitivity with which emphysema is recognized. Thurlbeck (1976) reviewed the incidence of emphysema found at autopsy in 28 series. An extremely wide variation has been recorded, including three series with an incidence of 100 percent. The variation in incidence probably represents the care with which the lung is examined and the threshold for defining emphysema being present as much as a true difference in incidence. It is not relevant to the present discussion whether rare or unusual disease processes can cause abnormal enlargement of the air spaces or whether, after careful and exhaustive search, all lungs demonstrate minute areas of focal enlargement. The lung has substantial ventilatory reserve; therefore, what is significant is not the presence or absence of any emphysema, but rather the extent or severity of the emphysematous change in the lung. What is both clear and relevant to the present discussion is that the relationship between smoking and emphysema represents an association between smoking and the severity of emphysema, and that the relationship is between smoking and those forms of emphysema commonly found in patients with COLD. In 1963, clinicopathologic findings (Thurlbeck 1963b) in a group of patients dying at the Massachusetts General Hospital showed that 18 of 38 patients without emphysema were cigarette smokers, whereas all of the 19 patients with severe emphysema were cigarette smokers. A formal study of the relationship between emphysema and smoking was first made by Anderson et al. (1964), who showed that one-third of patients without emphysema, 19 of 37 patients with mild emphysema, 19 of 23 patients with moderate emphysema, and all 6 patients with severe emphysema were smokers. In 1966, an extended study (Anderson et al. 1966) found in the four groups, respectively, that 12 of 33 patients, 58 of 84 patients, 30 of 33 patients, and 14 of 15 patients were smokers. Mitchell et al. (1964) found 62 smokers among 85 patients with no or mild emphysema and 39 smokers among 40 patients with moderate or severe emphysema. These researchers also extended their series (Petty et al. 1967) and found 6 nonsmokers among 57 patients with moderate emphysema and 1 nonsmoker among 61 patients with severe emphysema. A very dramatic difference was shown between smokers and nonsmokers by Ryder et al. (1971). Figures 6 and 7 indicate very graphically the rarity of emphysema of even moderate severity in nonsmokers and the high incidence of emphysema in smokers over 50 years of age. Of the 21 patients in their series whose lungs had a more than 25 percent involvement by emphysema, only 1 was a nonsmoker. 239 Nonsmokers 70 50 4 40 4 Percentage volume of emphysema 30 ~ 20 4 . . 10— * 88. «8 ae ‘ o oo ones “e2 rt? Anon fBeisede of s l q l ( | U T T T 10 20 30 40 50 60 70 80 90 Age {in years) FIGURE 6.—Percentage of lung occupied by emphysema in nonsmokers SOURCE: Ryder et al. (1971) Only a small effect of smoking was noted in coal miners by Naeye et al. (1971), an increase from 24.3 percent of the lung involved in nonsmokers to 30 percent in smokers. A much greater effect of smoking was noted by Auerbach et al. (1972), who studied lungs from 2,613 autopsies and were able to obtain smoking histories in 1,831 of the patients. They found that 10 percent of male patients who had not smoked had emphysema; this percentage rose to 53.5 percent for pipe smokers and cigar smokers, 86.9 percent for smokers of less than a pack per day, and 99.7 percent for smokers of more than a pack per day. Of the 130 patients with severe emphysema, 126 smoked more than a pack a day, 2 smoked less than a pack, 2 were pipe or cigar smokers, and none were nonsmokers. Their findings were subsequently extended and confirmed by histologic examina- tion of these lungs (Auerbach et al. 1974). Findings in women were similar. Spain et al. (1973) studied lungs from 134 persons who died suddenly and unexpectedly and who had no previous known pulmonary disease. In men, they found an incidence of emphysema of more than grade 20 (mild emphysema) of 10 percent in nonsmok- ers, 36 percent in smokers of less than a pack per day, and 39 percent 240 Smokers 7c ° 60 “4 oO E *. ° 2 50 ° = 40 3 4 z " 3 ° ° ° § 304 ° i ° & * g . 5 ° e o 20 + s 8 10 ° *e ° _° e o*f . * % ye ee e ee ce ad ? oe at 3 068 tye 8 " . Age (in years} FIGURE 7.—Percentage of lung occupied by emphysema in smokers SOURCE: Ryder et al. (1971). in smokers of more than a pack. In women the incidences in the same categories were 0, 17, and 23 percent, respectively. Bonfiglio and Schenk (1974) found that the diagnosis of emphysema was made in 40 percent of autopsy protocols from smokers and in 12 percent from nonsmokers. Using the autopsy populations of teaching hospitals in three separate cities, Thurlbeck et al. (1974b) reported the average emphysema score per decade for male and female nonsmokers (Figure 8) and for male and female smokers combined with ex- smokers (Figure 9). The severity of emphysema is expressed using the panel grading method (Thurlbeck et al. 1970). With this method, a score of up to 25 is “mild emphysema.” As Figure 8 indicates, in nonsmokers there is an increasing average severity of emphysema with age, starting in the fifth decade, reaching an average score in the eighth and ninth decades of 10 to 15 in men and 4 to 6 in women. There is a dramatic difference in male heavy smokers and ex- smokers, for whom the average score of 25 to 30 in the seventh decade is maintained for the next two decades. The number of heavy smoking and ex-smoking women is very small, and the effects in 241 - @D nannowo oO ao Ss ovr Gr ®ro Boe cE 66 DBD = ak Soa < nn @ONG& bo i! | Ly ooor® tod wo oor 2 + NN + c oO N= oO D — S * oo 2 —_T 7 T BeBe _ wT Oo © N + cS az nN aq - 7 #833 = Score A ao; {+f ~ ar 7a® wr wo ovr nm = N nwaod orn o wm oOo - + t - |r & ole dr = — T T ¥ T x Qo oO N wt nN N - - Score FIGURE 8.—Average emphysema score in male and female nonsmokers in Montreal, Cardiff, and Malmo, by decade NOTE: All: The average for the three cities. SOURCE: Thurlbeck et al. (1974b). 242 f - oa | oom >= a ! & + : & 2 ses s f= : . . -— ON zosdc yy © bos \ bo: . ; | . so | a ™ i soy 1 ' oy | SN q “oY Lowe « wow = ~ KR SA SG ™e ee vs 7 oe thos i S f 5 : € Lio - {o- 2 i = r T t T T 1 2 = 2 © «2 ° N wt © 2 a 9 Do E = » + z ret nN = gy & ot Q Oo 2 Score feittawsw 7 18 23 9 50 244 16 4 8 0 T nN a 56 5 48 4 40 4 Score FIGURE 9.—Average emphysema score in male and female heavy cigarette smokers (>pack per day) and ex-smokers, by decade NOTE: All: The average for the three cities SOURCE: Thurlbeck et al. (1974b) women are more modest, with an average emphysema score of 8 to 12 from the sixth to the ninth decade. Pratt et al. (1980) studied the effect of smoking on cotton textile workers and on workers not exposed to cotton. They found that the incidence of centrilobular emphysema was 6.7 percent in non- smoking non-cotton-textile workers, 6.9 percent in nonsmoking cotton-textile workers, 26.5 percent in smoking non-cotton-textile workers, and 26.2 percent in smoking cotton-textile workers. The variation in the incidence of centrilobular emphysema involving more than 25 percent of the lung was even more dramatic—1.1, 0.4, 11.0, and 12.6 percent for the respective categories. Thus, despite the limitations in interpretation of the types of emphysema and in recognition of the presence of emphysema, the association between smoking and emphysema—particularly severe emphysema—is overwhelming. In the various series referred to, of the 227 patients with severe emphysema, only 3 were nonsmokers. Summary and Conclusions 1. Smoking induces changes in multiple areas of the lung, and the effects in the different areas may be independent of each other. In the bronchi (the large airways), smoking results in a modest increase in size of the tracheobronchial glands, associated with an increase in secretion of mucus, and in an increased number of goblet cells. 2. In the small airways (conducting airways 2 or 3 mm or less in diameter consisting of the smallest bronchi and bronchioles) a number of lesions are apparent. The initial response to smoking is probably inflammation, with associated ulceration and squamous metaplasia. Fibrosis, increased muscle mass, narrowing of the airways, and an increase in the number of goblet cells follow. 3. Inflammation appears to be the major determinant of small airways dysfunction and may be reversible after cessation of smoking. 4. The most obvious difference between smokers and nonsmokers is respiratory bronchiolitis. This lesion may be an important cause of abnormalities in tests of small airways function, and may be involved in the pathogenesis of centrilobular emphyse- ma. 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WRIGHT, J.L., LAWSON, L.M., PARE, P.D., KENNEDY, S., WIGGS, B., HOGG, J.C. Pulmonary function and peripheral airways disease. American Review of Respira- tory Disease, in press. WRIGHT, J.L., LAWSON, L.M., PARE, P.D., WIGGS, B.J., KENNEDY, S., HOGG, J.C. Morphology of peripheral airways in current smokers and ex-smokers. - American Review of Respiratory Disease 127(4): 474-477, April 1983b. 250 CHAPTER 5. MECHANISMS BY WHICH CIGARETTE SMOKE ALTERS THE STRUCTURE AND FUNCTION OF THE LUNG 251 CONTENTS EFFECT OF CIGARETTE SMOKING ON INFLAMMATORY AND IMMUNE PROCESSES IN THE LUNG Introduction Effect of Smoking on Numbers and Types of Inflammatory Cells Effect of Smoking on the Morphology and Function of Inflammatory Cells Emphysema Populations Deficient in Alpha,-antitrypsin Alpha,-antitrypsin Proteolytic Enzymes Inducing Emphysematous Change Papain Pancreatic Elastase Polymorphonuclear Leukocyte Elastase Alveolar Macrophage Elastase Protease-Antiprotease Hypothesis Increased Elastase Owing io the Cellular Response to Smoke Number of Cells Elastase Content Release Proximity Milieu Decreased Antiprotease Owing to Oxidation Explanation for Upper Lobe Distribution Animal Models of Emphysema Spontaneous Emphysema Experimentally Induced Emphysema Oxides of Nitrogen Cadmium Salts Cigarette Smoke 253 The Effects of Smoking on Cellular and Immune Defense Mechanisms In Vitro Effects of Cigarette Smoke on Inflammatory and Immune Effector Cells The Effect of Cigarette Smoke on A Production ntibody EFFECTS OF CIGARETTE SMOKE ON AIRWAY MUCOCILIARY FUNCTION Introduction Normal Mucociliary Function Cilia Mucus Mucociliary Interaction Effects of Cigarette Smoke on Mucociliary Function Short-Term Exposure Cilia Mucus Mucociliary Interaction Long-Term Exposure Cilia Mucus Mucociliary Interaction Fractionation and Filtering of Effects of Filters Cigarette Smoke Mucociliary Function in Chronic Bronchitis Cilia Mucus Mucociliary Interaction Summary and Conclusions References 254 EFFECT OF CIGARETTE SMOKING ON INFLAMMATORY AND IMMUNE PROCESSES IN THE LUNG Cigarette smoke is a complex mixture of several thousand different constituents that may produce physiologic and pathologic changes. This discussion focuses on the cellular and immune responses of the lung to cigarette smoke, the mechanism by which smoking can cause emphysema, and the impact of smoking on mucociliary clearance. The last 20 years have witnessed dramatical- ly increased understanding of cigarette-induced lung injury, particu- larly emphysema, thus enhancing our understanding of the process by which cigarette smoking can lead to emphysema. Introduction Inhalation of cigarette smoke markedly alters the inflammatory and immune processes in the lung, leading to increases in the total number of inflammatory cells and to changes in cell type and function. These effects of cigarette smoke on lung inflammatory cells may play a role in decreased pulmonary host defenses against various microorganisms and the development of lung cancer, chronic bronchitis, and pulmonary emphysema (USPHS 1971, 1972, 1973, 1974, 1975; USDHHS 1981). Effect of Smoking on Numbers and Types of Inflammatory Cells One of the most consistently observed effects of cigarette smoking on the lung is a marked increase in the numbers of inflammatory cells, especially at sites of disease. Increased numbers of inflammato- ry cells have been seen in pathological studies of the lungs of cigarette smokers, as well as in lungs of animals exposed to cigarette smoke. In addition, increased numbers of inflammatory cells occur in bronchoalveolar lavage fluid of cigarette smokers and in lavage fluid of animals exposed to cigarette smoke. Spain and Kaufman (1953) noted inflammatory changes in the lung bronchi of cigarette smokers. Later, Anderson and Foraker (1961) described the presence of an alveolitis, and McLean (1959) described the presence of a bronchiolitis in these patients. In an autopsy study of patients with early emphysema (McLaughlin and Tueller 1971), numerous abnormal, brownish-pigmented alveolar macrophages were found in adjacent, otherwise intact parenchyma, but none were found in normal lungs. Identical pigmented macro- phages were found in the sputum of patients obtained from apparently healthy cigarette smokers. The frequency of occurrence of these macrophages in the tissue appeared to be related to the 255 number of cigarettes consumed. Niewoehner et al. (1974) evaluated the lungs of young smokers and controls of comparable age from a population that had experienced sudden nonhospital deaths. In smokers, a characteristic lesion occurred in the form of respiratory bronchiolitis associated with clusters of pigmented alveolar macro- phages. This lesion was present in the lungs of all smokers studied, but was rarely seen in nonsmokers. Lungs of smokers also showed small, but significant, increases in mural inflammatory cells and denuded epithelium in the membranous bronchioles as compared with controls. The researchers suggested that this respiratory bronchiolitis may be a precursor of emphysema and may be responsible for the subtle functional abnormalities that are observed in young smokers. Mitchell et al. (1976) also noted the presence of significant amounts of inflammation in the small airways of cigarette smoker lungs, and Cosio et al. (1978) suggested that the primary lesion in the small airways was a progressive inflammatory reaction, leading to fibrosis with connective tissue deposition in the airway walls. These lesions were closely correlated with abnormali- ties in pulmonary function. As noted above, most early investigators concentrated on the role of the increased numbers of pigmented alveolar macrophages present at disease sites in cigarette smokers. These pigmented macrophages, because of their numbers and prominent coloration on histologic sections, were initially the sole focus of research on the inflammatory response in these patients. More recently, however, Ludwig et al. (1983) evaluated the relationship between cigarette smoking and the accumulation of neutrophils in the lungs of smoking and nonsmoking humans. Human lungs were obtained from autopsies of 10 cigarette smokers and 5 nonsmokers who experienced nonhospital death. These studies indicated a marked increase in neutrophil infiltration in the lungs of cigarette smokers compared with nonsmokers, and identified the site of the accumulation as the alveolar septa. Neutrophils were found in the alveolar walls of smokers both with and without emphysema. The researchers con- cluded that a marked neutrophil accumulation occurs in the lungs of cigarette smokers, that it precedes the development of emphysema, and that it continues once emphysema is established. They further suggested that the neutrophils may play a role in the destruction of the alveolar septa of the lungs in cigarette smokers. The presence of increased numbers of neutrophils in cigarette smokers’ lungs has also been documented by extracting inflammatory cells from open lung biopsies of smokers and nonsmokers (Hunninghake and Crystal 1983). A higher percentage of these inflammatory cells were neutrophils in smokers compared with nonsmokers. Finally, the association between cigarette smoking and increased numbers of inflammatory cells, including neutrophils, at disease sites has also 256 been confirmed in numerous animal studies (Frasca et al. 1971; Dahlgren et al. 1972; Rylander 1974, Park et al. 1977). Increased numbers of inflammatory cells in the lungs of smokers, as compared with nonsmokers, have also been observed by all investigators performing bronchoalveolar lavage studies (Davis et al. 1976; Demarest et al. 1979; Harris et al. 1970, 1975; Hunninghake et al. 1979a, 1980a; Hunninghake and Crystal 1983; Hunninghake and Gadek 1981-1982; Hunninghake and Moseley, in press; Reynolds et al. 1977; Reynolds and Newball 1974, 1976; Rodriquez et al. 1977; Warr et al. 1976, 1977; Warr and Martin 1974, 1978). Such increases have been detected additionally in lavage fluid of animals chronical- ly exposed to cigarette smoke (Davies et al. 1977; Flint et al. 1971; Holt et al. 1973). The majority of these studies have demonstrated increases in both the number of macrophages and the number of neutrophils, although Hoidal and Niewoehner (1982) found increases only in the former. The presence of neutrophils in the lungs of cigarette smokers is of interest because these cells contain elastase, an enzyme believed to be important in the pathogenesis of emphysema (Lieberman 1976; Karlinsky and Snider 1978; Kuhn and Senior 1978; Carp and Janoff 1978; Snider and Korthy 1978; Schuyler et al 1978; Janoff et al. 19717; Hunninghake et al. 1979a; Hunninghake and Crystal 1983; Hun- ninghake and Gadek 1981-1982, Hunninghake and Mosley 1984; Laurell and Eriksson 1963). Alveolar macrophages have also been implicated as a source of an elastase-like metalloprotease (Harris et al. 1975; Rodriguez et al. 1977). This enzyme is not inhibited by alpha,-antitrypsin (a, AT) (Banda and Werb 1981), the major anti- elastase in the lower respiratory tract (Gadek et al. 1981). Although macrophages are clearly present in large numbers in the alveolar structures of smokers (Niewoehner et al. 1974; Harris et al. 1975), several lines of evidence suggest that neutrophils may play a significant and perhaps more important role in increasing the elastase burden of the lungs. First, neutrophils store and release significantly more elastase than do alveolar macrophages (Barrett 1977; Rodriguez et al. 1977; Levine et al. 1976). Comparative estimates of elastase production by human neutrophils and alveolar macrophages suggest that neutro- phils are at least 1,000 times more potent elastase producers (Janoff et al. 1979). Second, although alveolar macrophages of cigarette smokers have been shown to release elastase in vitro (Rodriguez et al. 1977), it is not clear whether the elastase was produced by these cells or was secreted by other types of cells, such as neutrophils, and subsequent- ly ingested by the macrophages (Janoff et al. 1977). In this regard, recent studies by Campbell et al. (1979) and McGowan et al. (1983) have shown that alveolar macrophages are capable of phagocytosing 257 neutrophil elastase via a receptor-mediated mechanism; some of the elastase remains enzymatically active for up to 48 hours. These findings suggest that alveolar macrophages may, in fact, be capable of both decreasing and increasing the protease burden of the lung. Third, once a neutrophil has left its vascular space, its lifespan is only a few hours; when the neutrophil dies, it may release at least a portion of its preformed enzymes, including elastase. Thus, when a neutrophil is present within a tissue, it is possible that the tissue will be exposed not only to the elastase secreted by the neutrophil while it is functional, but also to the elastase stored by the neutrophil and released when the neutrophil disintegrates. In this context, the finding that neutrophils represent only a small percentage of all inflammatory and immune effector cells in the smoker’s lungs would not preclude the smoker’s exposure to a large chronic burden of neutrophil elastase. In contrast, the alveolar macrophage has a half- life of months to years (Thomas et al. 1976), and it stores little, if any, elastase (Rodriguez et al. 1977; Levine et al. 1976). Macrophages may also play an important role in this process by secreting a potent chemotactic factor for neutrophils (Hunninghake and Crystal 1983). This hypothesis is supported by the following observation: alveolar macrophages of cigarette smokers spontaneous- ly release a chemotactic factor for neutrophils, whereas alveolar macrophages of nonsmokers do not. In addition, in vitro exposure to cigarette smoke particulates results in the release of a chemotactic factor from the alveolar macrophages of nonsmokers. The migration of neutrophils to the lung in response to the chemotactic factor may be augmented by factors in cigarette smoke. In this regard, McCusk- er et al. (1983) have shown that nicotine is a potent chemokinetic factor for neutrophils, enhancing the migration of these cells to other chemotactic factors. Once neutrophils are present in the lung, they may release elastase, because both cigarette smoke (Blue and Janoff 1978) and the macrophage-derived chemotactic factor stimu- late these cells to release the enzyme (Gadek et al. 1979a, b). The postulated release of elastase by neutrophils could also partly explain how the number of macrophages are increased in this disorder. Fragments of elastin (which are probably generated by the release of neutrophil elastase at sites of disease activity) are potent chemoattractants for blood monocytes, the precursors of alveolar macrophages (Senior et al. 1980; Hunninghake et al. 1981). These fragments of elastin possess no chemotactic activity for neutrophils. Effect of Smoking on the Morphology and Function of Inflammatory Cells No size differences have been observed between alveolar macro- phages from smokers and those from nonsmokers when the cells are 258 fixed in suspension immediately after bronchoalveolar lavage (Table 1). Harris and coworkers (1970) observed a mean size of 23.3 ~m (range, 10 to 47 pm) for nonsmokers and 26.4 pm (range, 12 to 53 pm) for smokers. Reynolds and Newball (1974), using similar methods, did not find any size differences between smoker and nonsmoker alveolar macrophages. The morphology of smoker macrophages clearly differs, however, from that of nonsmokers (Table 1). Macrophages of smokers show increased numbers of large lysosomes, phagolysosomes, endoplasmic reticulum, ribosomes, and Golgi vesicles (Golde 1977; McLemore et al. 1977; Martin 1973; Warr and Martin 1978; Rasp et al. 1978; Pratt et al. 1971; Brody and Craighead 1975). These findings are generally associated with activated mononuclear phagocytes, and these macro- phages have probably become activated by the ingestion of the particulates present in cigarette smoke. Smoker macrophages have pigmented inclusions that appear to have platelike or needlelike configurations when seen by electronmicroscopy (Golde 1977; Warr and Martin 1978; Pratt et al. 1971; Brody and Craighead 1975). Studies of the nature of these inclusions by X-ray analysis suggest they may be, at least in part, particulates of aluminum silicate (Brody and Craighead 1975). Together with in vitro studies showing that alveolar macrophages are activated following phagocytosis of particulates (Hunninghake et al. 1980a), these findings are compat- ible with the notion that macrophages of smokers are activated in vivo. Alveolar macrophages from cigarette smokers have an increased ability to generate superoxide anion (Hoidal et al. 1979a, 1980, 1981), the functional effects of which include an increased capacity to kill lung fibroblasts. These observations suggest that alveolar macro- phages from cigarette smokers are increasingly able to injure lung parenchymal cells, and that they may contribute to the observed loss of lung cells in the alveoli of patients with pulmonary emphysema. A variety of other effector functions of smokers’ alveolar macro- phages have also been evaluated (Table 1). Alveolar macrophages from cigarette smokers appear to have a normal or increased ability to migrate in response to chemotactic factors (Demarest et al. 1979; Warr and Martin 1974). They differ, however, from normal alveolar macrophages in several other respects: for example, increased glucose utilization has been reported in some studies (Harris et al. 1970), but was normal in others (Hoidal et al. 1979a). Oxygen consumption has been reported to be normal (Hoidal et al. 1979a), but the protein content of these cells has been increased (Harris et al. 1975; Warr and Martin 1978). Alveolar macrophages from smokers release less PGE, and thromboxane B, than normal macrophages (Laviolette et al. 1981), suggesting that cigarette smoking induces a lesion in phospholipid hydrolysis or the mecha- 259 TABLE 1.—Cigarette-smoking- induced abnormalities in the inflammatory and immune effector systems > within human alveolar structures Parameter Findings in smokers Cell types present Total number of cells Percent polymorphonuclear leukocytes Percent T lymphocytes Percent B lymphocytes Lymphocyte function Response to mitogens Macrophage structure Diameter Ruffling of cell surface Number and size of cytoplasmic structures Abnormal cytoplasmic inclusions Macrophage properties and function Surface receptors jgG-Fe C3b Phagocytosis and killing of microorganisms Bacteria Fungi Effector and accessory cell function responsiveness to chemotactic factors Casein Activated serum Function as accessory cell to lymphocytes Responsiveness to MIF Production of neutrophil chemotactic factor Secretion of superoxide anion Secretion of elastase Release of prostaglandin E, and thromboxane B, Miscellaneous properties and function Glucose utilization Oxygen consumption Protein content Content of various enzymes Elastase Acid protease Neutral protease Esterase Acid phosphatase B-glucuronidase Lysozyme Aryl hydrocarbon hydroxylase Angiotensin-converting enzyme Spreading and adherence properties Pinocytosis Content of a,-antiproteinase Increased Increased Increased or normal Normal Decreased Normal Decreased Increased Pigmented inclusions, particulates with plate or needle-like configuration, presence of aluminum silicate Normal Decreased Normal or decreased Normal Increased Normal Decreased Decreased Increased Increased Increased Decreased Increased or normal Normal Increased Increased Increased Normal Increased Increased Increased Normal or increased Increased Increased Increased in presence of serum. decreased nylon adherence Decreased Increased SOURCE: Adapted from Hunninghake et al. ‘19791. 260 nism regulating hydrolysis. Smoker macrophages also appear to have increased amounts of various enzymes, including acid protease (Harris et al. 1975), neutral protease (Harris et al. 1975), esterase ~ (Harris et al. 1975), acid phosphatase (Martin 1973), angiotensin- converting enzyme (Hinman et al. 1979), B-glucuronidase (Martin 1973), lysozyme (Martin 1973), and arylhydrocarbon hydrolase (Cantrell et al. 1973; Harris et al. 1978; McLemore et al. 1977b, c, 1978; McLemore and Martin 1977). The functional significance of increased amounts of these enzymes is not entirely clear. In addition to its effects on the inflammatory and immune effector cells in the lung, cigarette smoke may also affect the composition of epithelial surface fluid. For example, some investigators have found that the amount of immunoglobulin G (IgG) present in lavage fluid is increased (Reynolds and Newball 1974); others have noted normal levels (Warr et al. 1977). Interestingly, cigarette smoking appears to cause a significant decrease in the secretory component of immuno- globulin A (IgA) in the lavage fluid of some people who smoke cigarettes (Merrill et al. 1980). This effect most likely indicates a subtle injury to the epithelium of the lung that produces this factor. The only additional factors that have been reported to be abnormal in lavage fluid of cigarette smokers are an increase in the amounts of fibronectin (Villiger et al. 1981) and a decrease in the function, but not the amount, of a,AT (Gadek et al. 1979; Janoff et al. 1979). This latter finding has been disputed by others (Stone et al. 1983). Emphysema A number of lines of evidence link the cellular changes described above with the development of emphysema. They include observa- tions in populations deficient in a, AT, in animal models of emphyse- ma, and most important, in human cigarette smokers. Populations Deficient in Alpha, -antitrypsin Eriksson (1965) described the characteristic features of a,AT- deficiency-associated lung disease. Approximately 60 percent of affected individuals develop symptoms of airways obstruction by age 40, and 90 percent by age 50. Excluding the influence of cigarette smoking, there is no sexual predominance of disease. Kueppers and Black (1974) found that dyspnea occurred a decade earlier in cigarette smokers (35 years in smokers versus 44 years in nonsmok- ers), and estimated that 70 to 80 percent of all PiZZ persons (where Pi= protease inhibitor) will develop lung disease. Larsson (1978) has projected that nearly 60 percent of PiZZ people will ultimately die of lung-related disease. Orell and Mazodier (1972) reviewed the morphologic features of a,AT-deficiency-associated emphysema and found primarily the 261 panacinar or panlobular form. Emphysematous lesions may be distributed uniformly throughout the lungs (Orell and Mazodier 1972), but frequently show a predominant lower lobe distribution (Greenberg et al 1973). In people genetically deficient in a, AT, the increased numbers of inflammatory cells found in the lungs of smokers probably present an increased elastase burden to the lung and magnify the protease— antiprotease imbalance. This may explain the deleterious effects of cigarette smoke in this population. Kueppers and Black (1974) reviewed data on the impact of cigarette smoking in people severely deficient in a,AT and concluded that, in addition to experiencing earlier onset of respiratory symptoms and pulmonary function abnormalities, cigarette smokers die at an earlier age from respira- tory failure than similiarly afflicted nonsmokers. The increased prevalence of emphysema in populations deficient in a, AT, plus the exacerbation of this lung disease by smoking, suggests that protease— antiprotease imbalance may also play a role in the development of emphysema by smokers who are not deficient in a,AT. This suggestion has resulted in a substantial body of research that has characterized a, AT, defined the nature of elastase-induced emphyse- ma, and clarified and supported the protease-antiprotease hypothe- sis of cigarette-induced emphysematous lung injury. Alpha,-antitrypsin The deficient constituent of o,-globulin was initially described by Schultze et al. (1955) as a,-3,5-glycoprotein but later renamed o- antitrypsin (a,AT) when it was found to inhibit trypsin activity (Schultze et al. 1962). Subsequently, a, AT has been shown to inhibit a variety of proteolytic enzymes including neutrophil elastase (Ohlsson 1971), neutrophil collagenase (Tokoro et al. 1972; Ohlsson 1971), cathepsin-G (Travis et al. 1978), chymotrypsin (Travis et al. 1978; Rimon et al. 1966), plasmin (Rimon et al. 1966), thrombin (Rimon et al. 1966), Hageman factor cofactor (Crawford and Ogston 1974), coagulation factor XI (Heck and Kaplan 1974), acrosin and kallikrein (Fritz et al. 1972a, b), urokinase (Crawford and Ogston 1974; Clemmensen and Christensen 1976), and renin (Scharpe et al. 1976). Although the range of proteases inhibited by a,AT appears broad, the association rate constants of these enzymes for a,AT differ (leukocyte elastase > chymotrypsin > cathepsin-G > trypsin > plasmin > thrombin) (Beatty et al. 1980), and the inhibitory role of a, AT against enzymes with low association rate constants, such as trypsin, may be negligible. The names a,-protease inhibitor or o1- proteinase inhibitor better describe this broader range of inhibitory functions and are preferred by some authors. In deference to historical usage and in accord with the recommendations of the 262 Nomenclature Meeting for this substance (Cox et al. 1983), the name a, AT has been retained in this discussion. The inhibitor a, AT is a polymorphic plasma protein (Fagerhol and Cox 1981; Cox and Celhoffer 1974; Cox et al. 1980; Cox 1981; Fagerhol and Braend 1965) encoded by two codominant autosomal alleles and inherited as a single Mendelian trait. The basal serum concentration is genetically determined (Eriksson 1964; Kueppers et al. 1964; Fagerhol and Gedde-Dahl 1969; Talamo et al. 1966). More than 31 allelic variants or Pi types (where Pi, or protease inhibitor, is the symbol assigned the genetic locus of the a,AT allele) have been identified (Cox and Celhoffer 1974; Cox et al. 1980; Cox 1981). The variants are designated by capital letters, B through Z, correspond- ing to their approximate electrophoretic mobility, relative to the anode, in acid starch gel electrophoresis or their relative positions on polyacrylamide isoelectric focusing. New variants are named accord- ing to the conventions established by the Fifth International Workshop on Gene Mapping and the Nomenclature Meeting for a,AT (Cox et al. 1980). The M allele (PiM) has a gene frequency of about 0.9 and is the most common Pi type in all populations tested (Kueppers 1978). The a,AT serum concentration in PiMM homozygotes is between 1.3 and 2.2 g/liter (depending on the method of measurement and the purity of standard) (Kueppers 1968; Jeppsson et al. 1978a) and, by conven- tion, defines normal. Pi types with decreased circulating levels of a,AT include (serum concentration expressed as percent normal) null 0% (Feldman et al. 1975; Talamo et al. 1973), Mmalton and Mduarte 12% (Cox 1976; Lieberman et al. 1976), Z 15% (Laurell and Eriksson 1963; Fagerhol and Laurell 1970), P 30% (Fagerhol and Hauge 1969), S 60% (Fagerhol 1969), and I 68% (Arnaud et al. 1978). PiZ was the first variant recognized (Laurell and Eriksson 1963) and is the Pi type most frequently associated with a serum deficiency of a,AT (Kueppers 1978). Its allele frequency varies markedly between different ethnic and racial groups. In the United States, the allele frequency is greater than 0.010 in whites but nearly zero in blacks (Kueppers 1978). Approximately 1 in 2,000 whites is homozy- gous for the Z gene (Laurell and Sveger 1975). Although a decrease in hepatic synthesis is probably the major mechanism for quantitatively significant reductions in serum a, AT, the factors that modulate such synthesis are only partially under- stood (Morse 1978). Impaired hepatic secretion, as evidenced by the presence of intrahepatic cytoplasmic inclusions containing accumu- lations of o,AT polypeptides (Blenkensopp and Haffenden 1977), occurs in persons with the PiZ genotype. It is uncertain if these intrahepatic inclusions exert a negative feedback inhibition on the hepatocyte and thereby retard biosynthesis of a,AT. Intrahepatic inclusions are not found with the S and null Pi types (Carrell et al. 263 1982), suggesting that decreased synthesis, independent of impaired secretion, iS primarily responsible for the reduced serum levels of a, AT. Catabolic studies of the PiM and PiZ proteins have identified similar half-lives in the circulation, 6 to 7 days and 5 days, respectively (Laurell et al. 1977; Jeppsson et al. 1978b). It is therefore unlikely that accelerated peripheral catabolism contributes signifi- cantly to serum deficiencies in a, AT. In addition to quantitative deficiencies in serum a, AT, a reduction in serum inhibitory capacity could also result from a loss in the functional activity of o,AT. Most genetic variants, however, are functionally equivalent to normal a, AT (PiMM) in their capacities to inhibit both trypsin and elastin (Billingsley and Cox 1982). The inhibitor a,AT is a low molecular weight (51,000 daltons) (Mega et al. 1980; Carrell et al. 1981; Chan et al. 1976; Pannell et al. 1974; Jeppsson et al. 1978) protein comprised of a single polypeptide chain containing 394 amino acid residues. Three carbohydrate side chains are attached, each containing terminal sialic acid residues (Mega et al. 1980; Carrell et al. 1981). The a, AT reacts stoichiometri- cally with free protease in a ratio of 1:1; one mole of a, AT inhibits one mole of protease and yields a stable complex (Cohen 1979). An in vitro study (James and Cohen 1978) found, however, that complete inhibition of elastase requires molar ratios of a,AT to elastase greater than 22:1. This phenomenon may be explained by elastase having two major sites of attack on a,AT. Attack against one site leads toa conformational change in a,AT and inhibition of elastase, whereas attack against the other site results in cleavage and inactivation of a,AT. The a,AT-protease complexes that form during protease inhibition are not reutilized by the body (Balldin et al. 1978), and the body supplies of a,AT are replenished via de novo synthesis by the liver. In addition to hepatic biosynthesis, a,AT is synthesized by at least two other endogenous sources. Both human peripheral lymphocytes - and rat alveolar macrophages have been shown to synthesize a,AT. - Ikuta et al. (1982) demonstrated that concanavalin A-stimulated monocytes interact with human peripheral lymphocytes, causing a threefold increase in a, AT synthesis. White et al. (1981) cultured rat alveolar macrophages and recovered newly synthesized radio-labeled (35S)a,AT from the cell culture medium. Macrophages and lympho- cytes, by virtue of their close physical proximity to the sites of connective tissue injury, may play a significant role in defense against proteolytic destruction. The physiologic significance of extrahepatic synthesis of a, AT remains speculative, however. While certain chemical and physiological aspects of a,AT are clear, the exact biochemical mechanism by which it causes protease inhibition is uncertain. It is generally agreed that the reactive center - of a,AT is located on a single serine-methionine segment peptide - 264 bond on the carboxyl-terminal end (Carrell et al. 1982; Kurachi et al. 1981). Proteolytic Enzymes Inducing Emphysematous Change Proteolytic enzymes have been a major focus of investigation following the demonstration by Gross et al. (1965) of papain’s ability to induce emphysematous changes in rats. Papain Papain, a proteolytic enzyme with a broad range of substrate specificities (Bergmann and Fruton 1941; Kimmel and Smith 1953), reproducibly causes emphysema-like lesions in a variety of experi- mental animals following aerosolization or intracheal instillation (Gross et al. 1965; Palecek et al. 1967; Goldring et al. 1968; Caldwell 1971; Pushpakom et al. 1970; Marco et al. 1969). A number of studies have helped to clarify the critical importance of elastolysis in papain-induced emphysema. Snider et al. (1974) tested amorphous and crystalline forms of papain and found that the emphysema-inducing properties of these preparations were directly proportional to their abilities to degrade and solubilize elastin. Heat inactivation of papain destroyed its emphysema-inducing capabilities. Similarly, intratracheal pretreat- ment of hamsters with human «,AT, an inhibitor of papain elastolytic activity, ameliorates papain-induced emphysematous changes (Martorana and Share 1976). Furthermore, Blackwood et al. (1973) showed that the elastolytic activities of several microbial enzymes, rather than their nonspecific protease activities, correlate best with the enzyme’s ability to induce emphysematous changes following intravenous administration to rats. Snider et al. (1977) showed that enzymes lacking elastolytic activity, such as collagenase or trypsin, do not produce emphysema in hamsters. Whereas these studies support the notion that the early histologic changes induced by papain are a direct consequence of its elastolytic activity, they do not preclude the possibility that endogenous factors ‘may contribute to subsequent disease progression. Snider and Sherter (1977) noted a gradual increase in static lung volumes in hamsters following a single intratracheal injection of pancreatic elastase. Stone et al. (1979) followed the fate of tritium-labeled pancreatic elastase and found that enzymatically active prepara- tions are retained longer within the lung than inactive preparations, and that 4C-guanidated elastase remains bound to lung matrix for at least 96 hours. This suggests that tissue-bound elastase may continue to digest elastin for extended periods of time. Martorana et al. (1982) found no progression in the mean linear intercept measurements or internal surface areas in the lungs of papain-treated dogs between 3 265 480-144 0 - 85 - 10 and 6 months after treatment. However, the mean pulmonary arterial pressure and pulmonary arteriolar resistance did increase during this interval. Papain-treated animals exhibit the expected physiologic changes of emphysema: increased RV, FRC, and TLC, decreased elastic recoil, increased static lung compliance at middle and low lung volumes, and reduced diffusing capacity (DLcoVA and DLco) (Caldwell 1971; Pushpakom et al. 1970; Marco et al. 1969; Giles et al. 1970; Johanson and Pierce 1973). Studies by Kobrle et al. (1982) have shown that following papain administration the elastic fibers are disrupted and that the elastin content of the lung initially decreases, but later returns to normal after a period of accelerated synthesis. The newly synthesized fibers are disordered; however (Kuhn and Senior 1978; Kuhn and Starcher 1980). Pancreatic Elastase The ability of porcine pancreatic elastase to rapidly hydrolyze insoluble elastin (Partridge and Davis 1955) and its commercial availability in a highly purified crystalline form have led to its extensive use as an experimental agent for inducing emphysema in animals (Karlinsky and Snider 1978). Lesions resembling human panacinar emphysema can be induced in hamsters within 2 hours of intratracheal instillation of pancreatic elastase (Kaplan et al. 1973). The severity of the lesions, as assessed by histologic or physiologic criteria, is dose related (Raub et al. 1982), with adult animals being more susceptible to pancreatic elastase than young animals (Lucey and Clark 1982). Within a few hours of intratracheal instillation in hamsters, hemorrhagic lesions develop and an influx of polymorpho- nuclear leukocytes is seen (Hayes et al. 1975; Kuhn and Tavassoli 1976). Digestion of elastin fibers is apparent in the pleura and in the alveolar walls by 4 hours, but is more extensive at 24 and 48 hours - (Kuhn et al. 1976). By day 4, there is a diminution in the number of polymorphonuclear leukocytes (PMNs), but many macrophages remain (Morris et al. 1981). The hemorrhage and cellular infiltration resolves within 3 weeks, and the ensuing lesions resemble panacinar emphysema (Kuhn et al. 1976). Over 95 percent of the detectable urinary excretion of desmosine and isodesmosine, amino acid markers of in vivo elastolysis, appears within 2 days of elastase instillation; only small amounts can be detected by day 3 (Goldstein and Starcher 1977). Kucich et al. (1980) developed a hemagglutina- tion inhibition assay to measure elastin-derived peptides in serum, and found that elastin-derived peptides could be detected in the serum of dogs for a period of 12 days following administration of a 25 to 50 mg dose of porcine pancreatic elastase and for 40 days following a 100 mg dose. Janoff et al. (1983b) found increases in urinary desmosine excretion during the first 48 hours following endobronchi- 266 al instillation of pancreatic elastase to sheep; increases in mean linear intercepts and decreases in lung ventilation and perfusion were found after 4 weeks. All changes correlated positively with the elastase dose. Studies have shown a decrease in the lung elastin content within the first 24 hours of intratracheal injection of elastase (Kuhn et al. 1976; Ip et al. 1980; Goldstein and Starcher 1977). Physiologic studies (Snider and Sherter 1977; Snider et al. 1977) of experimental animals after pancreatic elastase administra- tion have shown increases in the lung compliances and in the volume of air within the lungs at specified transpulmonary pressures (25 and -~20 cm H?°). These physiologic alterations appear to progress in severity for about 26 weeks following exposure to elastase (Snider and Sherter 1977). In spite of substantial experimental verification of ability of pancreatic elastase to induce emphysematous changes in animals following intratracheal instillation, there is little evidence implicat- ing endogenous pancreatic elastase in the pathogenesis of pulmonary emphysema in humans. A serine endopeptidase of pancreatic origin (elastase 2) has been shown to circulate in human blood (Geokas et al. 1977). However, the enzyme is rapidly bound to serum irhibitors a,AT and a2-macroglobulin (a,M) and inactivated (Gustavsson et al. 1980). Although a,M-elastase complexes retain enzymatic activity against low molecular weight synthetic elastin substrates (N-succi- ny]-L-alanyl-L-alany]-L-alanine-4-nitroanilide) (Twumasi and Liener 1977; Barrett and Starkey 1973); high molecular weight proteins such as elastin are prevented from reaching the enzyme and are not hydrolyzed (Barrett and Starkey 1973). Attempts to induce emphysematous changes via the intravenous injection of elastase have met with limited success. Hamsters injected intravenously with nonfatal doses of pancreatic elastase fail to show histologic changes characteristic of emphysema (Schuyler et al. 1978) and do not manifest detectable reductions in lung elastin (Ip et al. 1980). However, elastic recoil is lost at low lung volumes (Schuyler et al. 1978). Fierer et al. (1976) has noted enlargements in the airspaces of rats treated intravenously with large doses (330 UV) of pancreatic elastase. They also found increases in the mean linear intercepts and rarefication of the amorphous components of elastin within the lungs. It is doubtful, however, if proportionally similar intravenous levels of pancreatic elastase occur in humans with pulmonary emphysema. Polymorphonuclear Leukocyte Elastase Polymorphonuclear leukocytes (PMN) appear to be a more plausi- ble source of endogenous elastase in the human lung than the pancreas, and are more likely to be incriminated in the pathogenesis of naturally occurring pulmonary emphysema. PMNs contain elasto- 267 lytic enzymes (Janoff 1973; Ohlsson and Ohlsson 1974; Rindler- Ludwig et al. 1974) that can be released in active form within the lung. Experimental studies have clearly demonstrated the ability of PMN elastase to degrade lung elastin and to induce emphysematous lesions in animals. Marco et al. (1971) and Mass et al. (1972) induced experimental emphysema in dogs by the administration of aerosolized crude leukocyte homogenates. Using purified human leukocyte elastase, Janoff et al. (1977) demonstrated the ability of the enzyme to digest dog lung elastin in vitro and to cause significant dilation of terminal respiratory structures when instilled into isolated perfused dog lungs. The in vivo intratracheal instillation of human leukocyte elastase in dogs produces foci of alveolar destruction within 90 minutes of administration (Janoff et al. 1977). Senior et al. (1977) studied the effects of intratracheally injected human leukocyte elastase on hamsters and found a reduction in lung elastin in treated animals, as well as mild patchy airspace dilation. Sloan et al. (1981) were able to show that purified dog leukocyte elastase could also produce emphysematous lesions in dogs when instilled endobronchi- ally. Guenter et al. (1981) developed a dog model of experimentally induced emphysema that avoided the necessity of intratracheal instillation of enzymes. They repetitively injected E. coli endotoxin intravenously, thereby inducing extensive leukocyte sequestration within the lungs of the dogs. A previous study had shown that the sequestered cells degranulate and disintegrate within the vascular bed (Coalson et al. 1970). Histologic studies of these dogs revealed mild airspace destruction and prominent intra-alveolar fenestra- tions. Alveolar Macrophage Elastase In a widely cited article (Mass et a). 1972), dog alveolar macro- phage homogenates (obtained by the method of Brain 1970), adminis- tered to two mongrel dogs produced “some dilatation and nonuni- formity in the size of the airspaces accompanied by some alveolar wall destruction” in one of the dogs. The other dog showed no evidence of emphysema. In spite of the paucity of animal data, the pulmonary alveolar macrophage (PAM) has been the focus of much investigation. Both experimental and clinical evidence is available that implicates this cell in the pathogenesis of pulmonary emphysema. Two possible mechanisms by which macrophages may mediate tissue injury are being actively studied. One mechanism involves the release of elastolytic enzymes followed by unrestrained proteolysis. The second mechanism involves either a direct or an indirect injury 268 following the release of toxic forms of partially reduced oxygen such as superoxide anions, hydroxy] radicals, and hydrogen peroxide. The ability of human alveolar macrophages to synthesize and secrete an elastolytic enzyme distinct from PMN elastase is the subject of controversy. Although human alveolar macrophages have been shown to synthesize a metalloprotease distinct from the serine protease (elastase) of the PMNs (DeCremoux et al. 1978), its hydrolytic activity against insoluble elastin substrate has not been conclusively demonstrated (Hinman et al. 1980; Levine et al. 1976). Interpretation of the observation that human alveolar macrophages raised in cell culture systems secrete an enzyme with true elastolytic activity against insoluble elastin (Rodriguez et al. 1977; DeCremoux et al. 1978) is complicated by the fact that alveolar macrophages bind and internalize PMN elastase (Campbell and Greco 1982; White et al. 1982; Campbell and Wald 1983). Hinman et al. (1980) detected a calcium-dependent metalloprotease in the culture medium and in the cell lysates of human alveolar macrophages and _ initially demonstrated elastolytic activity against synthetic elastin substrate and soluble elastin by both the culture medium fluid and the cell lysates. However, after 3 and 5 days of culture, no detectable activity against insoluble elastin was evident. The authors calculated that the initial elastolytic activity observed could be quantitatively explained by PMN contamination. The recognition that human alveolar macrophages internalize human PMN elastase (Campbell and Greco 1982; White et al. 1982: Campbell et al. 1979; Campbell and Wald 1983) and that the internalized PMN elastase retains enzymatic activity for at least 48 hours (McGowan et al. 1983) suggests an alternative explanation. Green et al. (1979) subcultured human alveolar macrophages for 3 months and found measurable elastase activity against solubilized elastin during the entire period. They concluded that the elastase activity appeared to be synthesized continuously rather than being internalized from external sources. In summary, human alveolar macrophages release elastolytic enzymes capable of digesting connective tissue. Whether the elastase released by these cells represents an enzyme synthesized de novo or a previously internalized PMN elastase is uncertain and requires further study. Human alveolar macrophages, especially from cigarette smokers, secrete highly reactive oxygen species (Hoidal et al. 1979a) that are capable of directly injuring endothelial cells (Sacks et al. 1978) and ibroblasts (Hoidal et al. 1981) and of inactivating a,AT (Carp and fanoff 1979, Janoff 1979a). Whole cigarette smoke inhibits PMN chemotaxis in vitro in a dose- ependent manner (Bridges et al. 1977). However, when alveolar 1acrophages are exposed to cigarette smoke either in vitro or in 269 vivo, they release a PMN chemotaxic factor (Hunninghake et al. 1980c) (see above). Protease-Antiprotease Hypothesis The protease-antiprotease hypothesis proposes that enzymatic digestion of lung parenchyma occurs as a direct consequence of a genetic or acquired imbalance of the protease—antiprotease system and that the subsequent repair of connective tissue is unable to return the structures to normal. This hypothesis derives principally from two observations: (1) people genetically deficient in a,AT (Laurell and Eriksson 1963), the major antielastase of the lower respiratory tract of humans (Gadek et al. 1981a), are at greatly increased risk of developing pulmonary emphysema, and (2) proteo- lytic enzymes produce physiologic and anatomic lesions resembling emphysema when administered to experimental animals (Gross et al. 1965). Attempts to integrate the clearly established relationship of cigarette smoking and pulmonary emphysema with the protease— antiprotease hypothesis have led investigators to search for ways in which smoking perturbs this balance. Increased Elastase Owing to the Cellular Response to Smoke At least five variables, aside from the genetically determined level of antiprotease activity, could influence the elastase burden of the lungs. These variables include (1) an increase in the number of elastase-containing cells within the lung, (2) an increase in the quantity of prepackaged or newly synthesized elastase per cell, (3) the quantity of elastase released from the cells, (4) the proximity of the elastase to suitable substrate, and (5) the extracellular milieu (i.e., pH, ionic strength, and factors such as platelet factor 4). Number of Cells As discussed earlier, the human cigarette smoker has increased numbers of alveolar macrophages in the bronchoalveolar lavages compared with nonsmokers (Rodriguez et al. 1977; Harris et al. 1975; Reynolds and Newball 1974, Hoidal and Niewoehner 1982). Holt and Keast (1973b) found sustained elevations of pulmonary macrophages in mice exposed to cigarette smoke. Cigarette smoke has been shown to recruit PMNs into the airways (Kilburn and McKenzie 1975; Rylander 1974) and to induce alveolar macrophages to release a chemotactic factor for PMNs (Hunninghake et al. 1980c). The circulating PMNs are reported to be increased in cigarette smokers (Corre et al. 1971; Galdston et al. 1977). Hunninghake et al. (1980c) and Reynolds and Newball (1974) found increased numbers of PMNs in the lavage fluid of smokers, but Hoidal and Niewoehner (1982) reported similar numbers of PMNs in the lavages of cigarette 270 smokers and nonsmokers. Hunninghake and Crystal (1983) obtained isolated cell suspensions from the bronchoalveolar lavage fluids and from open lung biopsies of nonsmokers and cigarette smokers with both normal lung parenchyma and sarcoidosis. They found a significantly increased number of neutrophils and macrophages in the lavage fluid and in the biopsy specimens from cigarette smokers as compared with nonsmokers, both in patients with normal lung parenchyma and in those with sarcoidosis. Elastase Content Harris et al. (1975) found an increase in the elastase-like esterase and protease activity of macrophages obtained from smokers as compared with nonsmokers. Galdston et al. (1977) found the PMN elastase levels of circulating PMNs to be elevated in patients with chronic obstructive lung disease and suggested that the intracellular elastase levels may be genetically determined (Galdston et al. 1973). Other investigators (Lam et al. 1979; Rodriquez et al. 1979) reported similar findings, but Kramps et al. (1980) failed to find any correlation between the PMN elastase levels and obstructive lung disease in PiZZ patients, although they did note a difference in PiMM patients. Lonky et al. (1980) demonstrated that dogs infected with Type 3 pneumococcus had increased PMN elastase-like esterase activity within their cells, suggesting an acute phase reaction. Release A variety of mechanisms may lead to the extracellular release of lysosomal contents. These include cell lysis, regurgitation during phagocytosis, reverse endocytosis, humoral mediation, and cytocha- lasin B treatment of cells (Klebanoff and Clark 1978). Wright and Gallin (1979) showed that migration of PMNs is associated with the leakage of various enzymes. Sandhaus (1983) found that migrating human neutrophils degrade elastin in vitro in the presence or absence of human a,AT. A similar mechanism may occur during neutrophil migration in vivo. Hutchison et al. (1980) found that the soluble fraction of cigarette smoke suppressed the release of lysoso- mal enzymes (acid phosphatase and acid ribonuclease) from PMNs obtained from healthy persons, but not from the PMNs of emphy- sematous patients. Blue and Janoff (1978) demonstrated that the water-insoluble fraction of cigarette smoke has a cytotoxic effect on PMNs in vitro and causes them to release their lysosomal contents, including beta-glucuronidase, acid phosphatase, and elastase. Eliraz et al. (1977) found that canine alveolar macrophages and PMNs, when stimulated with the water-soluble fraction of cigarette smoke, secrete elastase. Abboud et al. (1983), however, compared the release of elastase and B-glucoaminodase from PMNs obtained from ciga- 271 rette smokers and with that from nonsmokers and found no differences. In vitro stimulation of these cells by 2ither phagocytosis or chemotactic polypeptides did not alter the results. These research- ers concluded that chronic smoking does not affect neutrophil elastase release in vitro and that among smokers there is no significant relationship between in vitro neutrophil elastase release and abnormalities in lung function. They speculated that some of the differences between studies may be related to experimental condi- tions, such as the concentrations of cigarette smoke. Because the mechanisms involved in the release of intracellular contents are complex and the representativeness of in vitro condi- tions to in vivo events is uncertain, definite conclusions await further studies. Proximity Elastolytic activity is conditioned by the absorption of elastase onto elastin substrate (Robert and Robert 1970); the adsorption, in turn, results from the electrostatic attraction between negatively charged carboxylate groups of elastin and positively charged groups of elastase (Hall and Czerkowski 1961; Gertler 1971). Campbell et al. (1982) found that a,AT has less inhibitory activity against PMN elastase derived from cells in contact with substrate than against ~ PMN elastase free in solution. They reasoned that the partial exclusion of protease inhibitors from the PMN-connective tissue interface may account for this phenomena and may be an important factor in elastase-mediated injury. Focusing more on the macroenvi- ronment within the lung, Janoff et al. (1983c) found that the bronchoalveolar lavage fluids of young asymptomatic cigarette smokers contain significantly more elastase activity than the lavage fluids from nonsmokers. Kucich et al. (1983) found that the serum lung elastin-derived peptides were elevated in some smokers and most patients with COLD, suggesting that elastolysis may be taking place in smokers and COLD patients. Milieu A number of in vitro experiments have examined the chemical and physical conditions that modify neutrophil elastase kinetics. Lesti- enne and Bieth (1980) demonstrated that human leukocyte elastase activity is activated in the presence of substrate excess, hydrophobic solvents, and increasing ionic strength. The adsorption of sodium dodecyl sulfate (SDS), a hydrophobic, anionic ligand, onto the surface of elastin enhances the elastolytic activity of pancreatic elastase (Kagan et al. 1972). Lonky et al. (1978) showed that platelet factor 4 (PF,) in physiologic concentrations is capable of in vitro stimulation of human neutrophil elastase (HLE) against lung elastin. Low doses - 272 of HLE instilled intratracheally in hamsters failed to induce physiologic, morphologic, or biochemical changes, but following the addition of PF,, a significant injury was evident, and the elastin content of the lung was lowered by 20 percent (Lonky et al. 1978). Boudier et al. (1981) demonstrated that human leukocyte cathepsin- G, an enzyme in the azurophilic granules that possesses little intrinsic elastolytic activity, stimulates the rate of solubilization of human lung elastin by HLE. The elastolytic activity increased by more than five times the HLE rate when the HLFE-cathepsin-G mixture was present in equimolar concentrations. The relevance of these findings to the physiologic conditions that prevail in vivo requires further study. Laurent et al. (1983) recently discovered that the water-soluble components of filtered cigarette smoke suppress, in a dose-dependent manner, the lysy] oxidase-catalyzed oxidation of the epsilon-amino groups of lysine residues in tropoelastin. This step is essential for the formation of covalent cross-links between neighboring elastin poly- peptide chains that, in turn, are necessary for norma] elastic strength within the lung. Decreased Antiprotease Owing to Oxidation A comprehensive review of the role of oxidative processes in emphysema has recently been published by Janoff et al. (1983a). In vitro studies have revealed that oxidants such as chloramine T (Abrams et al. 1981) or ozone (Johnson 1980) cause a loss in the inhibitory capacity of a, AT for neutrophil elastase. The mechanism of inactivation has been identified as the oxidation of methionine and tyrosine residues (Johnson and Travis 1979; Cohen 1979; Carp and Janoff 1978) within the a,AT molecule. Chloramine T, when administered differentially to dogs, reduces EIC > TIC of serum and also results in emphysema (Abrams et al. 1981). Cigarette smoke is also known to contain oxidants (Stedman 1968; Pryor et al. 1983). Aqueous solutions of cigarette smoke reduce the elastase inhibitory capacity of human serum (Carp and Janoff 1978) and result in less binding of elastase to a,AT in vitro (Carp and Janoff 1978). Some investigators have found that the a,AT activity is reduced in the lavage fluids (BALF) obtained from human cigarette smokers and from rats exposed to cigarette smoke (Gadek et al. 1979; Carp et al. 1982: Janoff et al. 1979a). Stone et al. (1983) reported similar levels of functional a,-antitrypsin in the bronchoalveolar lavage fluids of human smokers and nonsmokers. Janoff and Chan (1984) have suggested that this difference in results may reflect the timing of the lavage in these studies, as rats chronically exposed to cigarette smoke had rapid inactivation of a,-antitrypsin following smoke exposure, but also had a more rapid recovery of a,-antitrypsin activity than did rats acutely exposed to smoke. Stone et al. also 273 recognized that their study may not have detected a reduction in alpha,-antitrypsin activity if it was accompanied by a rapid recovery to normal levels. Methionine sulfoxide peptide reductase, an enzyme present in human PMNs, can reactivate a,AT oxidized by chlora- mine T or by the myeloperoxidase system, but «,AT exposed to cigarette smoke plus peroxide (Carp et al. 1983) has been shown to be either resistant to reactivation by the myeloperoxidase system (Carp et al. 1983) or incompletely reactivated (James et al. 1984). Human ceruloplasmin has been shown to prevent myeloperoxi- dase mediated oxidation of a,AT under specified conditions of pH and solvency (Taylor and Oey 1982), although the role played by ceruloplasmin in limiting oxidation by phagocytes in vivo is unclear. Taylor et al. (1983) examined plasma and leukocyte lysosomal samples from a group of COLD patients and measured the ability of these samples to inhibit lipid peroxidation. While they reasoned that inhibitors of peroxidation could protect a,AT from inactivation by neutralizing lipid free radicals, they found that inhibition required factors from both plasma and lysosomal extracts and that the factor was not ceruloplasmin. Two of ten emphysematous patients had reduced plasma factor activity, and one of these patients also had reduced lysosomal factor. Controls had normal values for both of these factors. Galdston et al. (1984) examined serum ceruloplasmin concentra- tions and antioxidant activity in male and female smokers. Smokers of both sexes had higher serum ceruloplasmin concentrations than did nonsmokers; women in both smoking categories had higher concentrations than their male counterparts. Serum antioxidant activity showed a significant positive correlation with serum cerulo- plasmin levels; however, for comparable ceruloplasmin concentra- tions, serum antioxidant activity was significantly lower in smokers than in nonsmokers of both sexes. The researchers suggest that - cigarette smoking may cause partial inactivation of serum antioxi- dant activity that is accompanied by an insufficient increase in ceruloplasmin concentration. Endogenous phagocytes are also capable of generating oxidants (Babior 1978; Klebanoff and Clark 1978). The phagocytic enzyme myeloperoxidase, in the presence of hydrogen peroxide and halide ions, oxidatively inactivates a,AT (Matheson et al. 1979, 1981). Smoking, as described above, elevates the oxidative metabolism in lung macrophages (Hoidal and Niewoehner 1982; Fox et al. 1979; 1980; 1981). Thus, it is clear that the oxidants present in cigarette smoke and the lung macrophages of smokers can inactivate a,AT. This inactiva- tion, coupled with the increased elastase burden that may result from the inflammatory cell response of the lung to smoke, could tip 274 the balance of the protease—antiprotease system in the direction of elastin degradation. Explanation for Upper Lobe Distribution In accord with the protease—antiprotease hypothesis, emphysema- tous lesions result from the unrestrained proteolytic digestion of connective tissue elements. The regional distribution of lesions within the lung is thought to be conditioned by both biochemical and physiological variables. The predilection of lower lobe involvement in persons with a,AT deficiency is hypothesized to result from an increased number of elastase-containing cells because of the higher vascular perfusion to this area in erect man. This excess could occur because of the deposition of senescent leukocytes in these areas of higher blood flow (Guenter et al. 1981). In addition, inhaled particulates preferentially deposit in the lower lobes (Milic-Emili et al. 1966; Dollfuss et al. 1967), and the leukocytes release their enzyme extracellularly during the ingestion of these particulates. Because of the genetic deficiency of a,AT, the proteolytic activity is unopposed and destruction occurs. The predominance of upper lobe lesions in cigarette smokers with normal systemic levels of a,AT is again thought to result from variations of ventilation and perfusion within the lung (Cockcroft and Horne 1982). However, in normal individuals the proteolytic activity due to the excess particulate deposition in the bases is inhibited by a,AT that is replenished by the increased vascular perfusion also occurring in the bases. The upper lobes, although less well ventilated than the lower lobes, nevertheless have higher ventilation:perfusion ratios because of the proportionately greater fall in perfusion. The oxidative inactivation of a,AT by cigarette smoke in the upper lobes therefore may not be compensated by vascular repletion of the inactivated a,AT, and an imbalance of protease-antiprotease may occur. The upper lobe injury may then be magnified by mechanical stresses caused secondary to the negative intrapleural pressures generated by gravitational forces in erect man (West 1971). Animal Models of Emphysema Spontaneous Emphysema Emphysema occurs spontaneously in animals in forms resembling the types seen in human disease (Karlinsky and Snider 1978). However, the low incidence and unpredictable occurrence of disease in animals greatly limit their utility as experimental models. tho =] or Experimentaily Induced Emphysema A number of insults, including oxides of nitrogen, cadmium salts, whole cigarette smoke, ozone exposure, and proteolytic enzymes, have been used to induce or augment emphysematous lesions in a variety of experimental animals. The reader interested in a compre- hensive review of this topic is referred to the well-documented article by Karlinsky and Snider (1978). The evidence for each of these insults, as they pertain to cigarette smoke, is reviewed below. Oxides of Nitrogen Oxides of nitrogen, present in the gas phase of smoke, appear to induce or potentiate emphysema-like lesions in some animals (Karlinsky and Snider 1978). Nitrogen dioxide (NO,) exposure causes airway narrowing and an increase in the proteolytic burden within the lungs of experimental animals. Airway narrowing is postulated as a contributing factor in the pathogenesis of pulmonary emphysema (Juhos et al. 1980): Following exposure to NO., rats develop bronchiolar stenosis. The nitrogen dioxide exposure also induces an influx of alveolar macro- phages (AM) and polymorphonuclear leukocytes (PMNs) (cells known to contain proteolytic enzymes) into the lungs (Juhos et al. 1980). Kleinerman et al. (1982) demonstrated an increased number of alveolar macrophages and PMNs in lung lavages from hamsters exposed to NO,. Although there is no detectable increase in the elastolytic activity from lung lavages of NO.-exposed animals, the cell-free culture medium from macrophage cultures of NO,-exposed animals does show a twofold to fivefold increase in elastolytic activity during the first 2 weeks of exposure (Kleinerman et al. 1982). Nitrogen dioxide exposure has not been shown to cause alveolar septal disruption, an essential feature of centrilobular emphysema, but it does result in a significant reduction in the internal surface area in the lungs of hamsters exposed for 12 to 14 months (Kleinerman and Niewoehner 1973). Cadmium Salts Animals exposed to cadmium, a constituent found in the particu-- late phase of cigarette smoke, develop a number of histologic and- biochemical changes that may lead to emphysematous lesions. Exposed animals develop pulmonary edema, vascular congestion, intraparenchymal hemorrhages, and a loss of Type I pneumocytes (Palmer et al. 1975; Strauss et al. 1976), and PMNs and mononuclear cells influx into the lungs (Snider et al. 1973). The animals develop acute peribronchial damage followed by the accumulation of granu- lation tissue near the respiratory bronchioles, thickened alveolar 276 septa, and distortion and distention of neighboring alveoli (Snider et al. 1973). These histologic changes are more suggestive of the scar or paracicatricial form of emphysema than the centrilobular form reported in some industrial workers exposed to CdCl, (Princi 1947). This disparity in response to CdCl, could be related to species differences or the interaction of CdCl, with other factors. When hamsters are exposed to CdCl, plus beta-amino proprioni- trile (B-APN), an inhibitor of lysyl oxidase, they develop thin-walled subpleural bullae and airspace enlargements resembling panlobular emphysema (Niewoehner and Hoidal 1982). The mean linear dis- tance between alveolar intercepts is significantly increased; pres- sure—-volume studies show overinflation and increased compliance of the lungs (Niewoehner and Hoidal 1982). This study suggests that CdCl., perhaps in conjunction with some other as yet undetermined agent, may be important in the pathogenesis of pulmonary emphyse- ma. The fact that CdCl, is a constituent of cigarette smoke (Randi et al. 1969) lends support to this hypothesis. Cigarette Smoke Cigarette smoking has been clearly identified as a major causal factor in the development of pulmonary emphysema in humans (Auerbach et al. 1972; 1974; Petty et al. 1967; Andersen et al. 1967; Niewoehner et al. 1974; USDHEW 1979). However, an animal model for the development of emphysema using the inhalation of cigarette smoke alone has not been convincingly demonstrated. Parenchymal disruption resembling human emphysema has been reported in some dogs following prolonged cigarette exposure, but this histologic pattern is not uniformly present (Hernandez et al. 1966; Auerbach et al. 1967a; Zwicker et al. 1978). This difficulty in developing an animal model for cigarette-induced emphysema may relate to the reluctance of animals to inhale smoke and the relatively long duration of exposure required to produce emphysema in humans. However, it may also result from the need for a combination or sequence of effects to induce emphysematous change. That is, an increased elastase burden might be necessary (secondary to the cellular response to smoke) before the oxidant damage of smoke to a,AT, or to repair mechanisms, results in emphysema. Hoidal and Niewoehner (1983) examined this question in hamsters exposed to low doses of smoke and elastase. Neither exposure alone resulted in significant emphysematous change, but the combined exposure did cause change. This suggests that an increased elastase burden may be a precondition for smoking- induced emphysematous lung injury, and may also explain the long exposure period required in humans prior to the demonstration of an increased prevalence of emphysema in smokers. 277 Experimental studies have shown that cigarette smoke can induce a number of cellular, biochemical, and metabolic changes within the lungs that may be causally related to the development of emphyse- ma. Macrophages and leukocytes, cells known to contain proteolytic enzymes, are recruited to the lungs of hamsters (Kilburn and McKenzie 1975) and guinea pigs (Flint et al. 1971) following exposure to cigarette smoke, thereby increasing the proteolytic burden of the lungs. Conversely, the a,AT activity decreases in rats after inhala- tion of cigarette smoke (Janoff et al. 1979a). The increased proteolyt- ic burden within the lungs coupled with the concomitant diminu- tion in inhibitory capacity tends to create a protease—-antiprotease imbalance and a situation whereby unrestrained connective tissue destruction may occur. The Effects of Smoking on Cellular and Immune Defense Mechanisms There are important functional differences between macrophages from smokers and those from nonsmokers (Table 1). For example, Warr and Martin (1977) demonstrated that receptors for the third component of complement (C3b) are decreased in number or function on the surface of smokers’ alveolar macrophages. The receptors for- the Fe portion of IgG, however, are normal on these cells (Warr and Martin 1977). An important function of the C3b receptor is to augment the attachment and phagocytosis of microorganisms and particulates by the macrophages. It is not clear whether this subtle defect in cell function results in a significant alteration in phagocyto- sis or clearance of particulates or microorganisms by these cells. In this regard, the phagocytosis and killing of a variety of microorga- nisms by smokers’ alveolar macrophages have been shown to be normal by Harris et al. (1970) and Cohen and Cline (1977). One report by Martin and Warr (1977), however, suggests that the capacity of alveolar macrophages to kill bacteria is decreased in smokers. The observation that human alveolar macrophages from cigarette smokers function normally to kill microorganisms appears to differ, at first glance, from a number of animal studies demonstrating that the capacity of alveolar macrophages to phagocytose and kill- bacteria is impaired following exposure to cigarette smoke (Holt and Keast 1973; Rylander 1971, 1973). In these animal studies, there was an initial decrease in the numbers of alveolar macrophages and a decrease in their bactericidal function following exposure to ciga- rette smoke. With prolonged exposure, however, the number of - macrophages increased and their ability to kill microorganisms returned to normal (Rylander 1973, 1974). These observations suggest that cigarette smoke, initially, is toxic to alveolar macro- 278 phages. However, it is likely that the macrophages, with time, adapt to the presence of cigarette smoke. In addition, a subpopulation of macrophages that are more resistant to cigarette smoke may increase in number in the lung. The macrophages isolated from the lungs of smokers resemble those isolated from animals following prolonged exposure to cigarette smoke. The acute effects of cigarette smoking on the number and functions of alveolar macrophages in man has not been systematically evaluated. Alveolar macrophages of cigarette smokers appear to interact in an abnormal fashion with lymphocytes (Table 1). In this regard, the alveolar macrophages from cigarette smokers function poorly as accessory cells in presenting antigen to autologous lymphocytes (Laughter et al. 1977). This latter defect may be further magnified by the observation that lymphocytes from cigarette smokers also respond poorly to mitogens (Neher 1974; Daniele et al. 1977). Additional evidence for an abnormal interaction of macrophages and lymphocytes in lungs of cigarette smokers is a decreased response of alveolar macrophages to the lymphokine, macrophage migration inhibitory factor (Warr 1979). These observations suggest that cigarette smoking may have broad effects on the ability of the lung to generate a cellular immune response. In Vitro Effects of Cigarette Smoke on Inflammatory and Immune Effector Cells The most readily demonstrable effect of cigarette smoke, in vitro; is a decrease in cell viability (Holt et al. 1974; Holt and Keast 1973; Nulsen et al. 1974; Weissbecker et al. 1969). At relatively low concentrations, cigarette smoke and its constituents rapidly kill alveolar and peritoneal macrophages in vitro. Lymphocytes and polymorphonuclear leukocytes are also very susceptible to these agents (Holt et al. 1974; Blue and Janoff 1978). When sublethal amounts of cigarette smoke are employed, a number of metabolic and functional changes occur in macrophages. Phagocytosis is depressed, as is the function of a number of macrophage enzymes (Vassallo et al. 1973; Green 1968a, b, c, 1969, 1970; Green and Carolin 1966, 1967; Green et al. 1977; Powell and Green 1971; Hurst and Coffin 1971). In addition; protein synthesis is also depressed (Yeager 1969; Low 1974), and stimulatory effects have been noted. While cigarette smoke depresses phagocytosis and intracellular killing, nitrogen dioxide increases the metabolic activi- ty of macrophages (Vassallo et al. 1973). Similar effects have been observed under some conditions with cigarette smoke (Holt and Keast 1973; Leuchtenberger and Leuchtenberger 1971). Results from a number of investigators suggest that the balance between stimula- tion and inhibition of macrophage activity is determined by dosage, with stimulation occurring at low exposure levels and inhibition at 279 higher concentrations (Holt and Keast 1973; Lentz and DiLuzio 1974; York et al. 1973). The most potent stimulation occurs after prolonged exposure to low levels of the agent. These in vitro effects of cigarette smoke are also seen acutely in vivo following exposure to smoke. The immediate effect of exposure to cigarette smoke, and to agents present in the smoke, is a decrease in viability of the pulmonary alveolar macrophages (Holt and Keast 1973a, b; Rylander 1971, 1973; Coffin et al. 1968; Dowell et al. 1970; Holt and Nulsen 1975; Gardner et al. 1969). Although not well studied, it is also likely that cigarette smoke is toxic to polymorpho- nuclear leukocytes (Blue and Janoff 1978). In support of these observations are studies demonstrating that acute exposure of — experimental animals to tobacco smoke, or to components of cigarette smoke, also lowers their resistance to bacterial infection (Rylander 1969, 1971; Acton and Myrick 1972; Gardner et al. 1969; Goldstein et al. 1971; Huber and LaForce 1971; Huber et al. 1971). - Short-term exposure to components of cigarette smoke, particularly nitrogen oxide, has also reduced resistance to viral infection, - probably by inhibiting interferon production by macrophages (Va- land et al. 1970). As noted above, these in vitro and acute in vivo effects of cigarette smoke are not seen following long-term in vivo exposure in animals; very little work has been done on the effects of cigarette smoke in vitro, using human cells. However, several studies have shown that cigarette smoking and nicotine, at levels compara- ble to those encountered in the circulation of smokers, produce a slight but significant depression of PHA-stimulated DNA synthesis in human peripheral blood lymphocytes (Neher 1974; Silverman et al. 1975; Vos-Brat and Rumke 1969). The Effect of Cigarette Smoke on Antibody Production The available data on antibody production in human smokers suggest that cigarette smoking may depress these responses. The production of antibodies was investigated in a large study involving influenza vaccination. Smokers in the population exhibited in- creased susceptibility to infection during an influenza outbreak (Finklea et al. 1969, 1971). Prior to immunization with influenza vaccine, smokers exhibited significantly lower titers of specific antibodies than did nonsmokers. Immediately following vaccination of both groups, the smokers developed levels of antibodies compara- ble to those of nonsmokers. However, the antibody titer in the smokers fell below their nonsmoking counterparts within a few weeks, and by a year after vaccination the smokers exhibited markedly depressed levels of circulating antibodies. The capacity of cigarette smoking to alter antibody production was also studied by evaluating the capacity of a fetus to stimulate lymphocytotoxic antibodies against HLA antigens in the mother 280 (Nyman 1974). Sera from a large number of pregnant women were tested for the presence of lymphocytotoxic antibodies against a 48- donor panel. The smokers exhibited a significantly lower incidence of these antibodies than did nonsmokers, and the divergence between groups increased with the number of deliveries. Infections during pregnancy were observed significantly more often in the smokers in this trial. In several animal models, acute exposure to whole cigarette smoke or components of cigarette smoke depressed the numbers of anti- body-forming cells in the spleen and the serum levels of antibodies in animals exposed to a variety of antigens (Miller and Zarkower 1974, Zarkower and Marges 1972; Zarkower et al. 1970). The depression was greatest when the antigen was administered by an aerosol (rather than by systemic inoculation), indicating that smoke appears to exert an effect close to the point of entry. Prolonged exposure ultimately resulted in severe depression both in local and in systemic antibody responses (Esber et al. 1973; Holt et al. 1976; Thomas et al. 1973, 1974a, 1974b, 1975). Although it is tempting to relate these abnormalities in immune response to the known association between cigarette smoking and increased incidence of upper respiratory infection, it is not clear whether the subtle defects in immune functions can entirely account for the infections present in cigarette smokers. Clearance of bacteria from the respiratory tract is a complex process that involves interplay between a variety of different mechanisms, only some of which include the function of alveolar macrophages and the capacity of the lung to mount cellular and humoral immune responses. Other abnormalities present in cigarette smokers that could account for this increased incidence of infection include a markedly abnormal tracheal bronchial clearance of particulates and an increased adherence of bacteria to airway epithelium (reviewed in USPHS 1971, 1973, 1974). 281 EFFECTS OF CIGARETTE SMOKE ON AIRWAY MUCOCILIARY FUNCTION Introduction There is extensive literature on the effects of cigarette smoke on mucociliary clearance in the airways, with the majority of the reports appearing between 1965 and 1975. Different experimental approaches have been used, including in vivo measurement of mucociliary function in animal models and in human subjects. The results of some of these studies have been contradictory, presumably because of differences in experimental technique or the influence on mucociliary function of factors other than cigarette smoking. For example, tracheal mucociliary transport appears to decline with age in normal subjects (Goodman et al. 1978), an important phenomenon to consider when assessing the effects of long-term cigarette smok- ing. Another complicating factor is the clearly demonstrated impair- ment of mucociliary function produced by chronic bronchitis even in nonsmokers, such as in patients with cystic fibrosis (Wood et al. 1975) or immunoglobin deficiency (Mossberg et al. 1982). Therefore, it is difficult to seperate the direct effects of cigarette smoke on mucociliary function from those of smoking-associated chronic bronchitis. Finally, in vitro bioassays for ciliotoxicity may not reliably reflect the effects of cigarette smoke on the mucociliary apparatus in the intact airways. Thus, Dalhamn et al. (1967) found that smoke produced by cigarettes containing a high concentration of hydrogen cyanide was more ciliotoxic in vitro than that produced by cigarettes containing a low concentration of hydrogen cyanide, and the two types of cigarettes caused a comparable reduction of mucus transport in vivo. This review is divided into three parts. The first part summarizes the normal structure and function of the mucociliary system in the airways. The second part deals with the direct effects of short-term and long-term cigarette smoke exposure on mucociliary function, and the third part discusses mucociliary function in chronic bronchi- tis. Normal Mucociliary Function The principal function of the airway mucociliary system is its contribution to host defenses. This is accomplished by physical removal of inhaled foreign material from the ciliated airways by mucous transport and by biochemical and immunological processes that protect against invasion of the mucosa by infectious agents. Normal mucociliary clearance depends upon an optimal interaction between cilia and mucus. 283 - Cilia The respiratory mucosa from the proximal trachea to the terminal bronchioles consists of a pseudostratified epithelium with cilia protruding from the luminal surface of columnar cells (Figure 1). The larynx contains a mucus-secreting squamous epithelium over most of its surface, and cilia are present only in the posterior commissure (Wanner 1977). The major cell types in the respiratory mucosa are basal cells, intermediate cells, nonciliated columnar cells, ciliated columnar cells, and goblet cells. In the larger airways, the major part of the epithelial surface is ciliated. The ratio of ciliated columnar cells to goblet cells is approximately 5:1 in the trachea, with a relative decrease in the number of both cell types toward the peripheral airways. The surface of each ciliated columnar cell contains approximately 200 cilia with an average length of 6 4m and diameter of 0.2 um. Both ciliated and nonciliated columnar cells are characterized by microvilli on their luminal surface. These measure 0.3 um in length and 0.1 pm in diameter. The ultrastruc- ture of cilia in lower animals and mammals is remarkably similar. Each cilium contains longitudinal microtubules that appear to represent contractile elements. Two single microtubules form a central core, and nine microtubules with a doublet structure are erranged in a circular fashion in the periphery of the cilium. A basal body in the apex of the cell corresponds to each cilium. Circular and radial bridges have been demonstrated between the peripheral microtubules and between the peripheral and central microtubules. These bridges (dynein arms, nexin links, radial spokes) appear to be crucial for ciliary bending. Mucus Respiratory secretions consist of mucus produced by submucosal glands and goblet cells and tissue fluid. The total volume of all mucus-producing structures has been estimated at approximately 4 ml in human lungs; submucosal glands make up most of this volume (Wanner 1977). The submucosal glands are under parasympathetic nervous control, with an estimated daily volume of respiratory secretions between 10 and 100 ml. Human respiratory secretions - contain approximately 95 percent water. The rest consists of micromolecules (electrolytes and amino acids) and macromolecules (lipids, carbohydrates, nucleic acid, mucins, immunoglobulins, en- zymes, and albumin). In situ, the respiratory secretions take the form of two layers, i.e., periciliary fluid (sol phase), and mucus (gel phase), as shown in Figure 1. Mucus has been clearly identified as the product of submucosal glands and goblet cells; the origin of the periciliary fluid has not been definitely established, although transepithelial water transport appears to be the most likely source. In central airways, the mucus layer is 5 to 10 4m deep and may be 284 oS | FIGURE 1.—Schematic representation of normal mucosa (central airway) with the components of the mucociliary apparatus NOTE: From top (airway lumen) to bottom, note mucus layer, periciliary fluid layer, epithelium with a predominance of ciliated columnar cells and an interspersed goblet cell, basement membrane, and submucosal gland. SOURCE: Wanner (1979). discontinuous. In peripheral airways where submucosal glands are absent and goblet cells are rare, mucus is either absent or present only in small quantities. Regeneration of injured ciliated respiratory epithelium takes approximately 2 weeks in animals; the exact regeneration time of damaged human tracheobronchial ciliated epithelium is not known (Wanner 1977). It appears that regeneration does not begin until 2 to 3 days following mechanical injury. Mucociliary Interaction Mucociliary interaction depends on ciliary activity, the rheologic properties and depth of the mucus layer, and the depth of the periciliary fluid layer. The viscoelastic properties of mucus are determined by its biochemical characteristics (disulfide cross-linking and hydrogen bonding between glycoprotein molecules and water) (Wanner 1977). Cilia beat in one plane, with a fast effective stroke (power stroke) in the cephalad direction and a recovery stroke that is two to three times slower. Adenosine triphosphate has been identi- fied as the energy source for ciliary bending. In mammals, the average normal ciliary beat frequency is approximately 1,000 beats per minute, with coordinated motion in adjacent cilia on an individual cell and in cilia of adjacent cells. This interciliated 285 TABLE 2.—Measurement of airway mucociliary function in humans Method Reference Clearance of inhaled radioactive Morrow et al. (1967) aerosols from the lungs Transport of discrete markers Friedman et al. (1977) Sackner et al. (1973) Central airway clearance of inhaled Yeates et al. (1975) boli of radioactive microspheres pattern of motion by which adjacent cilia beat one after another to generate a wave of ciliary motion is called metachronism. The “normal” thickness of the periciliary fluid layer is less than, or at best equal to, the length of the ciliar shafts, which measure approximately 6 pm in the central airways. The luminal surface of the mucus layer appears smooth, whereas the surface in contact with the cilia is irregular, and the mucus penetrates between the ciliary shafts. This penetration and the claw-like projections at the cilia tips may further facilitate the mechanical interaction between cilia and mucus. In the trachea, the “normal” surface mucus transport velocity is between 5 and 20 mm per minute depending upon the method of measurement. Mucous transport velocity decreases toward the peripheral airways. The three principal methods for the measurement of tracheobron- chial mucociliary function in humans are listed in Table 2. All of these have been used in studies of the effects of cigarette smoke on mucociliary function. Theoretically, mucociliary dysfunction can result from alterations in ciliary beat frequency and coordination, the quantity and visco- elastic properties of mucus, and the thickness of the periciliary fluid layer. In addition, focal destruction of the respiratory epithelium, producing areas without cilia or mucus, is also associated with impaired or absent mucociliary transport. Effects of Cigarette Smoke on Mucociliary Function The irritant effects of cigarette smoke on mucociliary clearance were recognized by Mendenhall and Shreeve (1937). They observed a decrease in the transport rate of carmine particles on the mucosa of excised cat tracheas after bringing them in contact with cigarette smoke, either directly or by dissolving it in the solution in which the tracheas were immersed (Mendenhall and Shreeve 1937, 1940). These early findings were confirmed by Hilding (1956) and Dalhamn 286 (1959) approximately 25 years ago. Since then, investigations to assess the effects of cigarette smoke on ciliary activity and mucocili- ary transport have proliferated. Because cigarette smoke can impair mucociliary transport by interfering with ciliary activity or mucus secretion, the studies relating to these two component functions are discussed separately and are complemented by a review of experi- ments involving mucociliary transport, the ultimate expression of mucociliary function. The effects of cigarette smoke on mucociliary function have been extensively studied in vitro, in intact animal models, and in human subjects. Comparison among the results of these experimental approaches is difficult, as there are major differences in inhalation patterns even between animal models and human subjects. Cigarette smoke is modified during its passage through the upper airways, and this may vary depending upon the mode of inhalation. By using smoke produced by radio-tracer spiked cigarettes, it has been shown that mice, who are obligatory nose breathers, retain 50 percent of the inhaled radioactivity in the nasal passages, 20 percent in the ijungs, and the rest in the esophagus, stomach, and other organs (Page et al. 1973). Using artificial airways to bypass the nasopharynx in experimental animals eliminates the problem of nasal cigarette smoke absorption, but also prevents the oral modification of ciga- rette smoke that is a typical feature of human smoking. In subjects inhaling cigarette smoke from a smoke dosage apparatus that delivers standard puffs, 86 to 99 percent of most components of gas and particulate phases of cigarette smoke are retained, with the exception of carbon monoxide (CO), of which only 54 percent is retained (Dalhamn et al. 1968). Much of the smoke appears to be retained in the mouth. In human subjects who hold cigarette smoke in their mouth for 2 seconds, 60 percent of the water-soluble components of the gas phase, 20 percent of the water-insoluble components of the gas phase, and 16 percent of particulate matter are absorbed or retained in the upper airways (Frances et al. 1970; Stupfel et al. 1974). This marked modification of cigarette smoke might decrease its ciliotoxic effect in the lower airways. Passing unfiltered cigarette smoke through a chamber with wet surfaces before bringing it in contact with ciliated epithelium decreased the cilioinhibitory capacity of the cigarette smoke (Kaminski et al. 1968). When filtered cigarette smoke was used, the wet surfaces had no additional effect on ciliotoxicity, indicating that the mucosa of the upper airway may serve as a filter (Kaminski et al. 1969). Similar observations have been made when cigarette smoke was passed through a water trap (Albert et al. 1969). Because of the differences in inhalation pattern between humans and animals, it might be argued that nasal mucociliary function should be measured to assess the effects of inhaled cigarette smoke 287 TABLE 3.—Effects of cigarette smoke on airway mucociliary system Impaired mucociliary Exposure Ciliary dysfunction Mucus hypersecretion clearance Short term Yes ? ? Long term Yes Yes Yes in animal models. However, it has been clearly shown that nasal mucociliary transport is not a good marker of tracheobronchial mucociliary transport because of differential responses at the two sites. For example, exposure to the whole cigarette smoke of up to 30 cigarettes does not impair nasal mucociliary transport in donkeys (Frances et al. 1970), whereas the same number of cigarettes clearly alters tracheobronchial deposition and clearance of radioactive aerosols (Albert et al, 1969). Likewise, Hilding (1965) has concluded from his studies that the nose is not an acceptable organ for the study of the effects of cigarette smoke on mucociliary transport. Realizing the problems with experimental models of ciliary function in response to cigarette smoke inhalation, Dalhamn (1969) postulated that a proper experimental design should fulfill the following requirements: (1) the exposure pattern and level of cigarette smoke inhalation should simulate that of natural smoking in human subjects, (2) cigarette smoke should be delivered in air and not as an aqueous solution, (3) the components of inhaled cigarette smoke should be analyzed, and (4) exposure should be of long duration. Although these criteria are obviously not met by many of the studies quoted in this review, understanding these principles allows a more critical assessment of the reported results as shown in Table 3. Short-Term Exposure The effects of short-term cigarette smoke exposure on the mor- phology of the respiratory mucosa have not been investigated in man. Cigarette smoke residue has been shown to cause ciliary damage in cultured rabbit tracheal epithelium with a contact-time- dependent effect (Kennedy and Allen 1979). The most consistent abnormalities were cellular desquamation and alterations in mito- chrondria, cilia, and microvilli, some of which occurred as early as 1 hour after exposure commenced. Cytotoxicity has also been observed after short-term exposure of _ ciliated epithelium to aqueous extracts of cigarette smoke conden- sate in vitro (Donnelly 1969), but it is difficult to extrapolate data from these in vitro studies to the in vivo conditions that occur during cigarette smoking. 288 Cilta With a few exceptions, e.g., Proetz (1939), most investigators have demonstrated an irritant effect of smoke on ciliated epithelium, usually characterized by ciliostasis. Residues of cigarette smoke passed through an aqueous medium have been shown to produce ciliostasis in protozoa (Weiss and Weiss 1964; Wang 1963) and in fragments of human respiratory epithelium (Ballenger 1960). In fragments of rat trachea, brief exposure to whole cigarette smoke appears to elicit a biphasic response, with a short period of stimulation during 1 to 2 minutes followed by a marked decrease in ciliary beat frequency (Guillerm et al. 1961, 1972). In an excised rabbit trachea model, 71 1-m) puffs or 35 10-m] puffs of whole cigarette smoke were necessary to produce ciliostasis; similar relationships were demonstrated in the tracheas of living cats (Dalhamn 1970; Dalhamn et al. 1968). Several investigators have established a stimulus—response relationship between dilutions of aqueous cigarette smoke extract and the time of exposure required for total stoppage of ciliary beat frequency in different experimental models (Donnelly 1969, 1972; Das et al. 1970; Donnelly et al. 1981). The mechanism by which cigarette smoke acutely depresses ciliary function is not clearly known, but may involve enzyme inhibition of adenylate kinase, thereby reducing adenosine triphosphate (ATP), the energy source for ciliary bending (Mattenheimer and Mohr 1975; Schabort 1967). Ciliary function in response to short-term cigarette smoke inhalation has not been studied in man. Mucus Very little is known about the quantity and rheologic properties of airway secretions after short-term cigarette smoke exposure. A brief exposure of slugs to cigarette smoke has been reported to stimulate the production of mucus containing an increased number of acid glycoprotein fibers (Wilde 1981). The significance of this observation with respect to the human respiratory tract is not clear, except that an increased number of acid glycoprotein fibers has also been demonstrated in sputum obtained from cigarette smokers. Mucociliary Interaction Using a variety of different techniques in animal experiments, ciliary dysfunction and impairment of mucociliary transport by short-term exposure to cigarette smoke have been demonstrated in rats (Iravani 1972; Dalhamn 1964; Ferin et al. 1966), rabbits (Dalhamn 1964; Holma 1969), cats (Carson et al. 1966; Dalhamn 1964, 1969: Kaminski et al. 1968), dogs (Guillerm et al. 1972; Sakakura and Proctor 1972; Isawa et al. 1980), donkeys (Albert et al. 1974, 1969), chickens,-and sheep (Stupfel et al. 1974). A few reports 289 have not demonstrated that short-term exposure to smoke depresses mucociliary function in animal models (La Belle et al. 1966; Bair and Dilley 1967). The reasons for the discrepancy between these and the previously listed studies are not clear, but may be related to methodology and dose of exposure. Stimulus response curves be- tween dose of cigarette smoke and the degree of mucociliary inhibition have been shown in airways of chickens and dogs (Battista and Kensler 1970b; Sakakura and Proctor 1972; Isawa et al. 1980). In one study, for example, 9 puffs of nonfiltered cigarette smoke had variable effects on tracheal mucociliary transport in intact dogs, but tracheal mucociliary transport was consistently inhibited by 12 puffs (Sakakura and Proctor 1972). Likewise, the number of 4-second exposures to cigarette smoke (separated by 1 minute) required to reduce mucus transport in intact chicken tracheas by more than 90 percent has been shown to increase with increasing dilutions (from 50 to 3 percent) of smoke in air (Battista and Kensler 1970b). Measurements of mucociliary clearance in man immediately after smoking one or more cigarettes have shown conflicting results, with either increased (Albert et al. 1973; Camner et al. 1971; Albert et al. - 1975; Camner and Philipson 1971, 1974), inconsistent, or unchanged rates (Yeates et al. 1975; Pavia et al. 1971; Goodman et al. 1978) or - decreased (Nakhosteen et al. 1982) rates. Transient effects on mucociliary clearance have been reported in both smokers and nonsmokers (Hilding 1956; Pavia et al. 1971). Such differences between human subjects may reflect a difference in the dose and inhalation pattern of cigarette smoke. Long-Term Exposure In dogs inhaling cigarette smoke through a tracheostomy, histolog- ic changes have been observed in the bronchi after 229 to 421 days of exposure (Auerbach et al. 1967b). These changes consisted of epithelial hyperplasia, decreased number of ciliated cells, and areas of squamous metaplasia. This may be criticized as a poor model of cigarette smoking in humans because the upper airway, which absorbs part of the smoke and decreases its toxicity, is bypassed. The irritant effect of cigarette smoke on the tracheobronchial mucosa could be enhanced in this model. However, inflammatory changes in the airways have also been observed in animals that inhaled cigarette smoke via their upper airways (Leuchtenberger et al. 1958; Rylander 1974; Mattenheimer and Mohr 1975; Park et al. 1977; Basrur and Basrur 1976; Jones et al. 1973; Iravani 1973). Various types of lesions have been observed, including tracheal and bronchial epithelial hyperplasia (Park et al. 1977; Frasca et al. 1974), goblet cell proliferation and submucosal gland hypertrophy (Jones et al. 1973; Park et al. 1977), bronchiolar metaplasia of mucus-secreting cells (Basrur and Basrur 1976), increased quantities of airway mucus 290 that appear to be adherent to submucosal gland openings (Iravani 1973), and a decreased number of ciliated epithelial cells (Basrur and Harada 1979). One study suggested a dose-dependence of the mucosal lesions when comparing hamsters exposed to either four cigarettes per day or eight cigarettes per day for 2 weeks (Basrur and Basrur 1976). The pathologic changes produced by long-term cigarette smoke exposure appear to be reversible if the exposure time is not excessive. Thus, inflammatory changes in the airways of hamsters exposed to cigarette smoke for 4 weeks showed marked reversibility with a recovery time of several weeks (Basrur and Harada 1979). The histologic changes in the airways of cigarette smokers are similar to those produced by cigarette smoke in animal models, and consist of varying degrees of denudation of the ciliated epithelium, an increase in the number of goblet cells, submucosal gland hypertrophy, and squamous metaplasia (Regland et al. 1976; Jones 1981). Morphometric studies have demonstrated an increased quan- tity of mucus in the airway lumen without histologic evidence of coexistent emphysema or a history of obstructive lung disease, whereas this is not observed in the lungs of healthy nonsmokers (Niewoehner et al. 1974; Matsuba and Thurlbeck 1971). Electron microscopic examination of ciliated epithelium in surgical lung specimens obtained from cigarette smokers has revealed ciliary abnormalities consisting of compound cilia, single axoneme, intra- cyctoplasmic microtubular doublets, and cilia within periciliary sheaths (McDowell et al. 1976). If bronchial biopsy material is used to detect ciliary abnormality in cigarette smokers, the results must be interpreted with caution, for a single biopsy may be misleading owing to the focal nature of the lesions (Fox et al. 1981). The morphologic changes of the respiratory mucosa in animals exposed to cigarette smoke for prolonged periods and in human cigarette smokers strongly suggests the presence of mucociliary dysfunction. This has been clearly demonstrated, particularly with respect to the production and clearance of mucus. Cilia Ciliary function after long-term cigarette smoke exposure has not been extensively studied. Iravani and Melville (1974) demonstrated a decrease in ciliary beat frequency in the airways of hamsters exposed to cigarette smoke for 1 year; however, in rats also exposed for 1 year under almost identical conditions, ciliary frequency was generally increased, although there were zones of ciliary inactivity or discoordination. A sustained inhibition of adenylate kinase activity in ciliated tracheal cells of hamsters exposed to cigarette smoke for up to 9 months has also been reported (Mattenheimer and Mohr 1975). Because inhibition of this enzyme leads to a decreased generation of adenosine triphosphate. the energy source of ciliary 291 bending, a decreased ciliary activity might be expected (Mattenheim- er and Mohr 1975). Mucus Mucus hypersecretion has been clearly demonstrated in the airways of several animal species exposed to cigarette smoke for prolonged periods of time (Battista and Kensler 1970a; Iravani and Melville 1974). Rheologic measurements of airway mucus have not been reported in such animal experiments, but biochemical analysis has revealed the presence of serum proteins that might have cilioinhibitory effect (Dalhamn and Pira 1979; Battista 1980). Mucus hypersecretion may occur as early as 1 month after beginning a smoke inhalation equivalent to as little as one cigarette per day (Battista and Kensler 1970a). Rheologic and biochemical examina- tions of airway secretions in healthy smokers have not been carried out, primarily because these subjects do not have a productive cough. Once a smoker develops chronic productive cough, he or she is no longer considered healthy, but by definition, has chronic bronchitis. Mucociliary Interaction Long-term effects of cigarette smoke on airway mucociliary transport have been studied in different animal species. In purebred beagle dogs exposed to cigarette smoke (100 cigarettes per week) for 13.5 months via a mask that administered cigarette smoke through both the mouth and the nose for 1.5 hours twice daily, tracheal mucus transport rate was decreased to approximately 30 percent of that observed in control animals (Wanner et al. 1973). Pulmonary function did not differ significantly between the two groups. It has subsequently been shown that the abnormality in mucociliary transport in beagles may already be present after 6 months of cigarette smoke exposure (Park et al. 1977). An impairment of mucociliary clearance with long-term cigarette smoke exposure has also been demonstrated in rabbits, guinea pigs, rats, and chickens (Okajima 1971; Rylander 1971b; Iravani and Melville 1974; Battista and Kensler 1970a). In some of those experiments, impaired mucoci- liary clearance was already observed 4 weeks after the beginning of exposure. The long-term effects of cigarette smoking on mucociliary function in human subjects has been investigated by aerosol clearance techniques and discrete marker transport techniques. Some of the investigators using radioactive aerosols demonstrated no abnormali- ty of overall clearance in habitual cigarette smokers, particularly in those who already may have had symptoms of chronic bronchitis (Sanchiz et al. 1972; Yeates et al. 1975; Pavia et al. 1970; Pavia and Thomson 1970). However, the deposition of the inhaled radioactive 292 aerosol is more central in normal smokers and in patients with chronic bronchitis than in nonsmokers (Lippman et al. 1970). Because clearance is faster in central airways than in peripheral airways, this centralization of aerosol deposition may compensate for the overall decrease in mucociliary clearance. Investigations that have related mucociliary clearance to deposition pattern have generally found an impairment of mucociliary clearance in cigarette smokers (Lourenco et al. 1971; Camner et al. 1973a; Camner and Philipson 1972, 1974). Camner and Philipson (1972), in a study of 10 pairs of twins discordant for cigarette smoking, showed a significant- ly lower average clearance rate in smokers compared with nonsmok- ers; in 5 pairs clearance was slower in the smoker than in the nonsmoker, whereas in the remaining 5 pairs there was no differ- ence. Analysis of regional clearance has produced further evidence that overall clearance of inhaled radioactive aerosols may fail to detect an abnormality in mucociliary clearance. Thus, Bohning and co-workers (1975) studied the deposition and clearance of 7 ym diameter particles in the tracheobronchial tree of six pairs of monozygotic twins, four of whom were discordant for cigarette smoking. They found comparable overall mucociliary clearance in the smoking and nonsmoking pairs, but more central deposition and slower central clearance in the smokers. Others have reported an impairment of peripheral mucociliary clearance and alveolar clear- ance as well (Matthys et al. 1983; Cohn et al. 1979). Discrete particle techniques involving either bronchoscopy or radiography have been used to assess mucus transport in central airways, notably the trachea. Most investigators have reported a decrease of tracheal mucus velocity in healthy smokers, with values ranging between 20 percent and 80 percent of those of nonsmoking controls (Goodman et al. 1978; Toomes et al. 1981; Nakhosteen et al. 1982). The bulk of the evidence indicates that long-term cigarette smoking alters mucociliary transport mechanisms and that these changes can occur as early as 1 year after smoking onset. Partial recovery of mucociliary transport has been observed in cigarette smokers after cessation for 3 months or more, but not after 1 week of cessation (Camner et al. 1973). These observations have also been supported by animal experiments (Albert et al. 1971). Fractionation and Filtering of Cigarette Smoke Whole cigarette smoke is composed of volatile elements and particulate matter, and it has become customary to distinguish between the gas phase and the particulate phase. The gas phase, by definition, consists of the components that remain after cigarette smoke has been “effectively” filtered by passing it through appropri- ate filters (Dalhamn 1966; Kensler and Battista 1963; Falk et al. 293 1959). The major constituents of the particulate phase are nicotine, phenols, hydrocarbons, aldehydes and ketones, organic acids, and alcohols. Although 95 percent of the gas phase (approximately 300 ml per cigarette).congists of combustion precucts and admixed air (nitrogen, oxygen, carbon dioxide, carbon monoxide) in concentra- tions that do not affect mucociliary transport, some trace gases are important (Battista et al. 1962). These include nitrogen dioxide, ammonia, cyanides, aldehydes, ketones, acrolein, and acids. As is shown below, some controversies still remain about whether the gas phase or the particulate phase of cigarette smoke is primarily responsible for its depressant effect on mucociliary activity. This problem is relevant when comparing the effects on mucociliary clearance of low tar versus high tar cigarettes, low nicotine versus high nicotine cigarettes, and filtered versus nonfiltered cigarettes. Dalhamn (1966) reviewed the controversy over the separate effects of the gas and the particulate phases of cigarette smoke on mucociliary function. In protozoa, both phases of cigarette smoke have been shown to possess ciliotoxic properties (Kennedy and Elliott 1970). Falk and associates (1959) reported that exposure to whole cigarette smoke for 30 seconds resulted in a biphasic response, with an initial stimulation, followed by depression with a minimum value at about 15 minutes and a tendency toward recovery 45 minutes after exposure. Removal of the particulate matter in cigarette smoke by passing it through filters decreased its depressant effect on mucus transport, indicating that the major effect on mucociliary clearance was related to the particulate phase. Similar observations have been made by others (Rylander 1970; Falk et al. 1959). In contrast, Kensler and Battista (1963) incriminated the gas phase of cigarette smoke; they exposed strips of rabbit trachea to smoke from different cigarettes for 12 seconds and identified various gas phase constituents as having a depressant effect on mucus transport. These findings have also been confirmed by others in in vitro and in in vivo animal experiments (Kensler and Battista 1963; Hee and Guillerm 1973; Dalhamn 1956; Albert et al. 1974; Carson et al. 1966). The most comprehensive study of individual gas and semivolatile constituents of cigarette smoke has been conducted by Petterson et al. (1982). Using chicken tracheal organ cultures, they showed that at a 5 mm concentration, 36 percent of 316 different compounds caused ciliostasis after 15 seconds of exposure, but 50 percent were without effect after an exposure time of 60 seconds. On the basis of this criterion of separation, either alkylated phenylethers, benzoni- triles, benzaldehydes, benzenes, napthalenes and indoles, or a-satu- rated, B-unsaturated ketones and aldehydes, or aliphatic alcohols, aldehydes, acids, and nitrates were found to be ciliotoxic. Inactive compounds included benzoic acids, esters, polyaromatic hydrocar- 294 bons, amines, and N-heterocycles (except indoles). With respect to aldehydes, the time to ciliostasis on tissues of rabbit trachea has been reported shortest for formaldehyde, followed by acetaldehyde, acrolein, crotonaldehyde, and methacrolein. The ciliotoxic effects of aldehydes have been confirmed by others using different experimen- tal approaches (Guillerm et al. 1968; Hee and Guillerm 1973; Kensler and Battista 1963). It has also been shown that acute acrolein inhalation causes denudation of ciliated cells, goblet cell discharge, exfoliation of surface epithelial cells, and infiltration of inflammatory cells in the lower airways of several different mam- mals (Dahlgren et al. 1972). Another volatile constituent of cigarette smoke with marked cilioinhibitory effects is hydrogen cyanide (Wynder et al. 1965a). Weissbecker et al. (1971) used a different approach to assess the effects of several volatile cigarette smoke constituents on mucocili- ary transport in the cat trachea. The addition of individual volatile cigarette smoke components (isoprene, nitric oxide, and nitrogen dioxide) to carbon-filtered cigarette smoke either aggravated the impairment of tracheal mucus velocity produced by the filtered smoke or abolished the protection afforded by the carbon filter. When these constituents were added to whole cigarette smoke, no further impairment of mucus transport velocity was observed, indicating a saturation by whole cigarette smoke of receptors responsible for mucociliary depression. A direct relation has been reported between tar content and the ciliotoxic effect of cigarette smoke (Dalhamn and Rylander 1967; Falk et al. 1959). However, Falk and associates (1959) found no difference between low tar and high tar cigarette residues with regard to in vitro mucociliary transport. The effects of nicotine on mucociliary transport are also controversial, although more investi- gators have demonstrated a lack of effect (Falk et al. 1959; Guillerm et al. 1972; Rakieten et al. 1952; Donnelly 1972) than a depression of mucociliary transport (Carson et al. 1966). Indeed, a biphasic dose- dependence has been suggested, with stimulation at lower concentra- tions and depression at higher concentrations (Tsuchiya and Kensler 1959). The stimulation of mucociliary function may be related to stimulation of nicotinic ganglionic receptors causing cholinergic ciliostimulation. This is based on the observation that the stimulat- ing effect of nicotine-containing cigarettes on the metachronal wave frequency in the maxillary sinus of anesthetized rabbits is blocked by atropine and hexamethonium (Hybbinette 1982). Among the different cigarette tobacco additives, menthol does not interfere with mucociliary transport (Rakieten et al. 1952). With respect to phenols, one investigator has reported that the ciliotoxici- ty of cigarette smoke produced by freeze-dried tobacco is the same as that produced by conventionally cured tobacco although the former 295 contains less phenol (Enzell et al. 1971). On the other hand, phenols - have been shown to impair mucociliary activity and mucus transport both in vitro (Dalhamn and Lagerstedt 1966; Bernfeld et al. 1964; Dalhamn 1968) and in vivo (Dalhamn 1968). Dalhamn and associates (Dalhamn and Lagerstedt 1966; Dalhamn 1968) have even attempted to relate the toxicity of various phenols to their boiling points. Addition of the anti-inflammatory agents phenylvinyloxadiozole and phenylmethyloxadiozole to tobacco has been shown to reduce the ciliotoxicity of tobacco smoke (Dalhamn and Rylander 1971; Rylan- der 1971b; Dalhamn 1969), and treatment of rats undergoing long- term exposure to tobacco smoke with phenylmethyloxadiozole has been shown to protect the animals against the cigarette-smoke- induced increase in the number of goblet cells in the respiratory mucosa (Jones et al. 1973). : It can be concluded from these studies that both the particulate - phase and the gaseous phase of cigarette smoke impair mucociliary function, that a large number of volatile components are ciliotoxic, that nicotine may or may not contribute to ciliotoxicity, and that the additive phenol is ciliotoxic, but the anti-inflammatory agents phenylmethyloxadiozole and phenylvinyloxadiozole afford partial protection against the deleterious effects of cigarette smoke. The - mechanisms by which the various constituents of cigarette smoke interfere with mucociliary transport are unknown. On the basis of experiments in the fresh water mussel, it has been suggested that - ciliotoxicity depends on their pH in solution (Wynder et al. 1963). It - should be noted, however, that such in vitro experiments requiring an aqueous medium do not necessarily reflect the type of exposure occurring in smokers in whom contact between cigarette smoke and — the ciliated epithelium is made by impingement or bypass. Effects of Filters Because the toxic effect of cigarette smoke on mucociliary trans- port mechanisms seems to reside both in the gas phase and in the particulate phase, the filtering of cigarette smoke before inhalation may be protective. It has been clearly shown that a longer exposure ~ time is needed for ciliostasis to occur with smoke from filtered cigarettes than from unfiltered cigarettes, with respect to both ciliary activity in vitro and mucociliary transport in vivo (Dalhamn - and Rylander 1964; Dalhamn 1964). Four major types of filters have been evaluated: cellulose acetate (Cambridge filter), charcoal, glass fiber, and aqua. The histologic - changes in the airways of guinea pigs exposed to unfiltered cigarette smoke for 4 to 8 weeks were not seen when cigarette smoke was passed through a Cambridge filter (Rylander 1974). Likewise, - Kaminski and coworkers (1968) have shown that cellulose-acetate filters provide protection for the mucociliary activity in the cat 296 trachea. Similar results have been obtained in other experiments involving in vitro and in vivo systems (Dalhamn and Rylander 1968: Donnelly 1972; Wynder et al. 1965b), and cellulose-acetate filters have been found to reduce the inhibitory effect of cigarette smoke on tracheal epithelial adenylate kinase activity in hamsters exposed for 1 to 5 days (Mattenheimer and Mohr 1975). Charcoal filters are also capable of reducing the ciliotoxicity of cigarette smoke (Kaminski et al. 1968; Kensler and Battista 1963; Battista and Kensler 1970a, b). In one study involving cat tracheas, short-term exposure to a standardized dose of cigarette smoke decreased particle transport rates by 50 percent when unfiltered smoke was used, by 40 percent when the cigarette smoke was passed through a cellulose-acetate filter, and by 20 percent when a carbon-cellulose filter was used (Carson et al. 1966). In another comparison of different studies, a charcoal filter was more effective than a cellulose-acetate filter in reducing the metachronal wave frequency and mucus transport of the eulamellibranch gill in vitro (Wynder et al. 1965b). Glass-fiber and aqua filters were generally less effective (Isawa et al. 1980; Wynder et al. 1965b). As expected, better protection might be provided by combined filters because they remove components of the particulate and the gaseous phase of cigarette smoke more effectively. Thus, a combina- tion of cellulose-acetate and charcoal filter has been found to be more effective than either filter alone (Dalhamn 1966; Wynder et al. 1965b). Mucociliary Function in Chronic Bronchitis Since chronic bronchitis is defined clinically as chronic productive cough rather than by clearly defined morphologic or functional abnormalities (American Thoracic Society 1962), some of the previ- ously reviewed studies of mucociliary function in cigarette smokers may have included patients with chronic bronchitis as well. Con- versely, most patients with chronic bronchitis are cigarette smokers or have been cigarette smokers in the past. Although it is very difficult to separate the direct effects of cigarette smoke on mucocili- ary transport from those related to the pathophysiologic changes of chronic bronchitis, the discussion herein is limited to mucociliary function in chronic bronchitis without considering the direct effects of cigarette smoke on the mucosa. The histologic changes of the mucociliary apparatus in chronic bronchitis include hypertrophy and hyperplasia of the submucosal glands, an increase in the number and distribution of goblet cells, and goblet cell metaplasia in smaller airways (Reid 1967). In addition, atrophy of the columnar epithelium (Wright and Stuart 1965) and spotty squamous metaplasia (Kleinerman and Boren 1974) 297 480-144 0 - 85 - 11 have been reported. A decrease in both the number of ciliated cells and the mean ciliary length has been noted in the larger airways in patients with chronic bronchitis (Wanner 1977), and electron micro- scopic examinations of the airway epithelium show subtle abnormal- ities in bronchial biopsy material (Miskovitz et al. 1974). Auerbach and associates (1962), in a large post-mortem study of cigarette smokers, reported epithelial lesions with loss of cilia in up to 30 percent of random sections, compared with approximately 15 percent of sections from nonsmokers. These ultrastructural changes consisted of swelling and serration of the epithelium with transfor- mation of the goblet cell granules. The capsule surrounding the cilia was irregular, with areas of breakage and outward projections; some cilia showed fibrillar degeneration or were fused to form compound cilia. The presence of visible respiratory secretions is a frequent endoscopic finding in patients with chronic bronchitis, and increased amount of bronchial secretions can be seen on pathologic sections of the lung (Kleinerman and Boren 1974; Hogg et al. 1968). Thus, the morphologic changes of chronic bronchitis involve both the ciliary apparatus and the mucus-producing structures. Cilia In vitro examination of ciliated lower airway epithelial cells obtained from chronic bronchitis patients by brushing has failed to reveal an abnormality in beat frequency (Yager et al. 1980). However, in vitro study of ciliary function is of limited informative value since the ciliated cells are suspended in an artificial medium and are not exposed to their natural milieu. This may explain the discrepancy between this study and one reported by Iravani and Van As (1972), in which ciliary motion was observed in vivo with an incident light technique. In the carefully dissected tracheobronchial tree of rats with experimental chronic bronchitis, the ciliary system showed discoordination and zonal akinesia. In addition, reversals of transport direction, whirlpool formations, and inactive zones without ciliary motion as large as 2 mm by several hundred ym were seen. Mucus The distribution, amount, and rheologic properties of mucus within the airways have not been studied in chronic bronchitis, but extensive literature exists on the biochemistry (Boat and Mathews 1973) and rheology of expectorated sputum from patients with chronic bronchitis. These results must be interpreted with caution, partly because of contamination with saliva and the rapid physical alteration of expectorated sputum, and partly because normal respiratory secretions for comparison are virtually impossible to obtain. Mucoid sputum of patients with chronic bronchitis is 298 biochemically similar to sputum of normal subjects induced by hypertonic saline aerosol, with the exception of a slightly higher fucose and neuraminic acid content in the former (Lopata et al. 1974). In purulent sputum from these patients, biochemical changes typical of inflammatory conditions (increases in the dry weight and deoxyribonucleic acid content and increased cross-linking by hydro- gen bonding) were observed. Reid (1968) showed that the neuraminic acid content of sputum is increased in chronic bronchitis, suggesting augmented secretion by the mucus-producing structures. This find- ing is supported by histochemical studies indicating distended acini of the submucosal glands in patients with chronic bronchitis compared with normal subjects, along with an increase in the volume of both the acid and the neutral mucopolysaccharide-produc- ing acini (Reid 1968). Impaired mucus transport in chronic bronchitis may, in part, be related to the rheologic abnormalities of respiratory secretions. Deviation from the ideal ratio between viscosity and elasticity may prevent an optimal interaction between cilia and mucus, thereby decreasing mucus transport rates (Dulfano and Adler 1975; Adler and Dulfano 1976). Higher values of sputum viscosity and lower values of sputum elasticity have been observed during exacerbations of chronic bronchitis than during clinical stability (Dulfano et al. 1971). In addition, purulent sputum has a higher viscosity than mucoid sputum (Charman and Reid 1972; Mitchell-Heggs et al. 1974), suggesting a relationship between the concentration of certain mucus constituents and mucus rheology. Indeed, examination of sputum obtained from patients with chronic bronchitis has shown positive correlations between protein content (particularly IgA) and mucus glycoprotein content on the one hand and viscosity on the other (Harbitz et al. 1980; Lopez-Vidriero and Reid 1978). That altered rheologic properties of airway secretions play a role in abnormal mucociliary clearance has been suggested by an observed relationship between in vivo mucociliary clearance, in vitro trans- portability of expectorated sputum (using the frog palate), and the viscoelastic properties of sputum (Puchelle et al. 1980). Mucociliary Interaction Mucus transport has been studied either by directly or indirectly observing the motion of discrete particles placed on the tracheal mucosa (Santa Cruz et al. 1974; Goodman et al. 1978) or by the deposition pattern and clearance rates of inpaled radioactive aero- . sols (Lourenco 1970; Camner et al. 1973a, b; Luchsinger et al. 1968; Patrick and Stirling 1977; Dulfano et al. 1971). In one study, a marked slacking of tracheal mucus velocity sas found in 15 patients with chronic bronchitis who were between 57 and 71 years of age (Santa Cruz et al. 1974). Clinical examination and pulmonary 299 (mm . min) TRACHEAL NUCOCILIARY TRANSPORT VELOCITY FIGURE 2.—Comparison of mean (S.E. in bracket) tracheal mucociliary transport velocity among young nonsmokers (n=10), elderly nonsmokers (n=7), healthy young ex-smokers (n=9), healthy young smokers (n=15), and patients with chronic bronchitis (n=14) SOURCE: Goodman et al. (1978). function tests diagnosed these patients as having both chronic bronchitis and emphysema. Mucociliary clearance of inhaled aero- sols is also altered in patients with chronic bronchitis. The clearance of inhaled particles from the lung is influenced by the deposition pattern, which in turn depends on particle size and flow regime in the airways. Clearance rates, therefore, can be interpreted only if particle deposition is carefully monitored (Pircher et al. 1965; Lopez- Vidriero 1973). Coughing, which is difficult to control in such patients, may also contribute to the clearance of particles (Toigo et al. 1963). For these reasons, it is not surprising that mucociliary clearance has been reported to be increased (Muller et al. 1975; Luchsinger et al. 1968), normal (Thomson and Short 1969), or decreased (Lourenco 1970; Camner et al. 1973a, b; Tiogo et al. 1963; Mossberg and Camner 1980; Agnew et al. 1982) in patients with chronic bronchitis. Once a subject has developed chronic bronchitis, cessation of smoking does not reverse the effect on mucociliary function, and a similar impairment of mucociliary transport has been reported in smokers and ex-smokers with this disorder (Agnew et al. 1982; Santa Cruz et al. 1974; Goodman et al. 1978). Persistence of mucociliary 300 dysfunction in patients with chronic bronchitis after cessation of smoking has also been reported in a small prospective study (Camner et al. 1973b). Thus, both patients with chronic bronchitis and healthy smokers exhibit an impaired mucociliary function. However, the magnitude of the impairment is not the same as suggested by Goodman et al. (1978), who demonstrated a greater impairment of tracheal mucocili- ary transport rates in smokers and nonsmokers with chronic bronchitis than in healthy smokers (Figure 2). The consequences of airway mucociliary dysfunction have not been satisfactorily examined, but may include increased susceptibili- ty to respiratory infections, airflow obstruction by excessive airway secretions, and increased risk of carcinogenesis resulting from prolonged contact between inhaled carcinogens and the respiratory epithelium (Matthys et al. 1983; Hilding 1957; Moersch and McDon- ald 1953). Summary and Conclusions 1. Increased numbers of inflammatory cells are found in the lungs of cigarette smokers. These cells include macrophages and, probably, neutrophils, both of which can release elastase in the lung. 2.Human neutrophil elastase produces emphysema when in- stilled into animal lungs. 3. Alpha,-antiprotease inhibits the action of elastase, and a very small number of people with a homozygous deficiency of a,- antiprotease are at increased risk of developing emphysema. The a,-antiprotease activity has been shown to be reduced in the bronchoalveolar fluids obtained from cigarette smokers and from rats exposed to cigarette smoke. 4. The protease-antiprotease hypothesis suggests that emphyse- ma results when there is excess elastase activity as the result of increased concentrations of inflammatory cells in the lung and of decreased levels of a,-antiprotease secondary to oxida- tion by cigarette smoke. 5. Cigarette smokers have been shown to have a more rapid fall in antibody levels following immunization for influenza than nonsmokers. Whole cigarette smoke has been shown to depress the number of antibody-forming cells in the spleens of experi- mental animals. 6. Cigarette smoke produces structural and functional abnormali- ties in the airway mucociliary system. 7. Short-term exposure to cigarette smoke causes ciliostasis in vitro, but has inconsistent effects on mucociliary function in man. 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Archives of Pathology and Laboratory Medicine 102(12): 623-628, © December 1978. 328 CHAPTER 6. LOW YIELD 480-144 0 - 85 - 12 CIGARETTES AND THEIR ROLE IN CHRONIC OBSTRUCTIVE LUNG DISEASE 329 CONTENTS Introduction Problems of Measurement by Machine Effect of Low Tar and Nicotine Cigarettes on Cough and Phlegm Production and Development of Chronic Obstructive Lung Disease Epidemiologic Studies Mechanisms of Lung Damage Variation in Smoking Pattern With Switching to Low Tar and Nicotine Cigarettes Smoking Behavior Carbon Monoxide Uptake Nicotine Uptake Role of Tar Content Variations in Pattern of Cigarette Smoke Inhalation Use of Additives in Low Tar and Nicotine Cigarettes Research Recommendations Summary and Conclusions References 331 Introduction Following the initial reports in the early 1950s linking cigarette smoke with lung cancer, the pathogenic role of cigarette tar content received considerable emphasis. Because the tar fraction of the smoke contained the bulk of the carcinogenic effect of whole smoke, and because lung cancer risk was closely related to other measures of total smoke exposure (number of cigarettes smoked per day, depth of inhalation, etc.), it was suggested that risk might be related to the amount of tar generated by different cigarettes. This prompted health authorities to advise smokers who were unable to quite smoking to switch to low tar cigarettes (U.S. Senate 1967; Health Department of the United Kingdom 1976). To facilitate this process, the Federal Trade Commission published smoking-machine assays of the tar and nicotine yield of different cigarette brands (Pillsbury et al. 1969). This approach to low tar and nicotine cigarettes was based on the assumption that smoking lower yielding brands, as deter- mined by a smoking-machine, would result in a proportional reduction in the lung’s exposure to these toxic substances. This approach to “safer” cigarette smoking has been promoted by the tobacco industry and apparently accepted by the smoking public, as evidenced by the escalation in sales of low tar and nicotine cigarettes. However, there is increasing evidence that this concept of a “less hazardous” cigarette is misleading; although definitive studies are still awaited, it appears that switching from regular to low tar and nicotine cigarettes may not substantially reduce the risk of chronic airflow obstruction. Problems of Measurement by Machine The first step in evaluating the relative health risks of different cigarettes is to establish some standardized measure of the toxic substances in different cigarettes in order to facilitate comparison. Quantifying each of the several thousand constituents of cigarette smoke for each brand of cigarette, and assessing the changes in these constituents as the manufacturing and agricultural processes change, would be a truly herculean task; therefore, a more modest goal of quantifying tar and nicotine yields was accepted. To date, the yields determined by the Federal Trade Commission have been the most widely adopted. These measurements are obtained with a laboratory smoking-machine, which consists of a syringe pump that takes a 35 ml bell-shaped puff from a cigarette, over a 2-second period, once per minute until a predetermined butt length is reached, either 23 mm for nonfiltered cigarettes or 3 mm longer than the filter overwrap for filter-tipped cigarettes (Pillsbury et al. 1969). These parameters are based on observations of smoking patterns in seven subjects in Europe in 1933 (Kozlowski 1983). Today’s cigarette 333 is markedly different from that smoked in 1967 when these parameters were established, yet the same parameters are still employed. Measurements obtained using these parameters indicate a marked - reduction in the tar and nicotine yield of cigarettes over the last decade (Figure 1). In addition to the actual tar and nicotine yield of the tobacco, the yield measured by a smoking-machine is influenced by many factors, including cigarette length and diameter, porosity of the cigarette paper, presence of a ventilated or an unventilated filter, butt length, number of puffs, interpuff interval, puff volume, puff duration, puff pressure profile, and frequency of puffing at different stages of cigarette consumption. The number of puffs is important in determining the tar yield of a cigarette, and the number of puffs taken from some brands with the official smoking-- machine has significantly declined in recent years (Kozlowski 1981). Since puffs are taken at 1-minute intervals, a more rapidly burning cigarette will have a smaller number of puffs. The burning time of the cigarette is determined by porosity of the cigarette paper, the. amount of tobacco in the cigarette, and the diameter of the cigarette column. In a survey of Canadian cigarettes between 1969 and 1974, Kozlowski et al. (1980b) noted a significant reduction in the number- of puffs taken in the official assays over this time period, which was strongly correlated with a reduction in tar yield. Omission of the last. few puffs can markedly affect tar yield, because tar delivery. increases with each puff, and the last few puffs from a cigarette can contain twice as much tar as the first few puffs (Wiley and Wickham 1974). Currently published yields do not indicate the number of puffs taken, which may range from 7 to 12 and may result in a marked. variation of the tar yield. Ventilated cigarette filters, which cause inhaled smoke to be. diluted with air, are one of the major methods of achieving low tar yields (Gori and Lynch 1978). Cigarettes with ventilated filters constituted about 25 percent of all cigarette sales in the United States in 1979 (Hoffmann et al. 1980). During systematic interviews, Kozlowski et al. (1980a) found that from 32 to 69 percent of low tar. smokers block these filter perforations with their fingers or lips, a feature unaccounted for by smoking-machines. This hole blocking increased the yield of toxic products by 59 to 293 percent. : If a person smokes a cigarette in a manner identical to the smoking-machine, the delivery of tar and nicotine to the mouth will be the same as that estimated by the machine. Human smoking patterns are diverse, however, and show considerable variation from the machine parameters; puff volumes range from less than 20 ml to more than 90 ml (Tobin and Sackner 1982), compared with the fixed 35 ml volume employed by the machine. Differences in puff profile from the bell-shaped puff used by the machine also alter cigarette 334 Tar mg Nicotine mg 40.0 40 T\ 35.0 \ 35 300 20 wo 25.0 x 25 \ \ an 20.0 4 2.0 \ Nicotine PN 15.0 Ps 15 ~ y —— \Y ~ Ty~. NN ad ~~ ~ 10.0 Sat 10 5.0 0.5 00 0.0 1950 1955 1960 1965 1970 1975 1980 FIGURE 1.—USS. sales-weighted average tar and nicotine yields SOURCE: American Cancer Society (1981). yield. Numerous studies indicate that smokers compensate for lower yielding cigarettes by altering their style of smoking. For each different cigarette brand, smokers may have a different smoking sattern. To provide more meaningful information, smoking-ma- shines should be designed to reproduce variations in the manner of smoking each cigarette brand, and their assays should provide both in average and a range of tar and nicotine yields depending on the ndividual pattern of smoking (USDHHS 1981). Many investigators have examined the relationship between the nachine-determined nicotine yield of a cigarette and the concentra- ion of nicotine or its metabolites in blood or urine. A fair correlation vas observed in some studies (Goldfarb et al. 1976; Herning et al. 983), but most studies have revealed a poor correlation (Russell et 1. 1975, 1980; Sutton 1982; Feyerabend 1982; Benowitz et al. 1983). Aachine-determined nicotine yield accounts for only from 4 (Russell t al. 1980) to 25 percent (Herning et al. 1983) of the variation in leod nicotine concentration, whereas 50 to 60 percent of the ifferences in blood nicotine levels are attributable to individual 335 smoking behavior. The overriding importance of the pattern of smoking in determining nicotine delivery from a cigarette was underlined in a recent study demonstrating that the nicotine content of the unburned tobacco was similar for cigarettes with high and low nicotine yields determined by smoking-machine assays (Benowitz et al. 1983). The concept of providing the smoker with information on cigarette yield need not be abandoned. Smoking-machines can be designed tc control the puff number, puff volume, puff pressure profile, puff duration, puff interval, butt length, position of the cigarette during and between puffs, and “restricted” or “free” smoking, i.e., whether the butt end is closed or open (Creighton and Lewis (1978a, b). These parameters should be determined and used to obtain an average and a range of yields for each brand. Measurement of cigarette yield should include assays not only of tar and nicotine but also of carbon monoxide and other toxic substances, because compensatory smok- ing behavior may alter the exposure to each substance beyond that expected on the basis of tar and nicotine delivery. Effect of Low Tar and Nicotine Cigarettes on Cough and Phiegm Production and Development of Chronic Obstructive Lung Disease Cigarette smokers account for the vast majority of deaths from chronic obstructive lung disease (COLD) (Peto et al. 1983), and the relative risk for the effects of smoking on mortality from COLD is even greater than that for lung cancer (see the chapter on Mortality in this Report). Chronic obstructive lung disease in smokers may take the following three forms: (1) cough and mucus hypersecretion, (2) airway obstruction, and (3) emphysema. Frequently the three components coexist, as all are related to cigarette smoking, but the agents in cigarette smoke responsible for each type of lung injury may be different. Over the past 25 years, considerable progress has been made in our understanding of the role of cigarette smoking in the pathogenesis and natural history of COLD, but most of the available data have not related lung function to cigarette yield. Epidemiologic Studies The cardinal importance of cigarette smoking in the pathogenesis of COLD has been repeatedly documented, and generally the severity of disease increases with increasing cigarette consumption (Ferris et al. 1976). Because of this dose-response relationship, it has been hoped that a reduction in cigarette yield by filtration or other means would reduce the risk of disease (Gori 1976). Available epidemiologic studies of the effect of low yield cigarettes on the development of COLD have shown variable results, which reflects 336 marked differences between the studies in terms of the population studied, sample size, variation in cigarette brands, reference period of the study, criteria of respiratory involvement, and type of statistical analysis, and whether the study was of a cross-sectional or a longitudinal design. Separating the studies by the three compo- nents of smoking-induced COLD indicates that there is a growing body of data on the effect of cigarette yield on the development of mucus hypersecretion and airway obstruction, but currently no information on the development of emphysema. Several studies have examined the effect of cigarette yield on respiratory symptoms and have observed a relationship between reduction in cigarette yield and the prevalence of cough (Comstock et al. 1970; Freedman and Fletcher 1976; Fletcher et al. 1976; Dean et al. 1978; Schenker et al. 1982) and phlegm production (Comstock et al. 1970; Rimington 1972; Hawthorne and Fry 1978; Higenbottam et al. 1980b). Tar yield was not defined in some of these earlier studies (Comstock et al. 1970; Rimington 1972; Dean et al. 1978; Hawthorne and Fry 1978), but instead a comparison was made between smokers of plain cigarettes and smokers of filter-tipped cigarettes. The tar yield was specified in some studies: in the recent study by Schenker et al. (1982) it ranged from 0.4 to 28 mg; in the studies by Freedman and Fletcher (1976), from 17 to 20 mg; and in the studies by Higenbottam et al. (1980b), from 18 to more than 33 ing, higher than that observed in many of today’s cigarettes. In a cross-sectional survey of over 18,000 men (Higenbottam et al. 1980b), the beneficial effect of low tar cigarettes on phlegm production was lost when subjects smoked 20 or more cigarettes per day, as their prevalence of phlegm production increased to that observed in higher tar cigarette smokers. In contrast, in another cross-sectional study of 5,686 women (Schenker et al. 1982), cigarette tar content was a significant risk factor for chronic cough and of borderline significance for phlegm production; this effect of cigarette tar content was indepen- dent of the number of cigarettes smoked per day. Chronic cough or phlegm production was approximately twice as common in smokers of high tar (at least 20 mg) cigarettes as it was in low tar (less than 10 mg) smokers. In the latter study, however, multiple logistic regres- sion analysis indicated that the risk of chronic cough and phlegm production is more strongly affected by daily cigarette consumption than by tar content: these symptoms were 4.5 times more common in smokers of 25 or more cigarettes per day than in smokers of less than 15 cigarettes per day. A small number of studies have examined the importance of cigarette yield on change in pulmonary function. In a prospective study of 680 men, Comstock et al. (1970) noted that smokers of plain cigarettes, compared with smokers of filter-tipped cigarettes, had a lower FEV, at entry into the study. Followup measurements showed 337 3.5 —___._™~_ tot 9 Cigarettes 30 —_— 30 smoked per day FEV, (/1 25 2.0 T T T 1 18-23 24-27 28-32 +33 Tar per cigarette (mq) FIGURE 2.—Relationship between mean FEV; of asymptomatic smokers (adjusted for height and weight) and tar yield of cigarettes, by number of cigarettes smoked per day SOURCE: Higenbottam et al. (1980b). a greater mean reduction of FEV: in users of filter-tips, so that the reduction was similar in the two groups after 5 to 6 years of followup. Unfortunately, the variance of the data was not stated, and tests of statistical significance were not performed. In another longitudinal survey of 1,355 men, Sparrow et al. (1983) determined the effect of cigarette tar content, which ranged from less than 16 mg to more than 22 mg, on pulmonary function. Multiple regression analysis indicated that tar content did not significantly influence baseline spirometry or repeat measurements after 5 years of followup. Cross- sectional epidemiologic surveys also indicate no relationship be- tween abnormal pulmonary function and the use of filter-tipped versus plain cigarettes (Beck et al. 1981) or cigarette tar content (Higenbottam et al. 1980b) (Figure 2). Interpretation of these studies as evidence that cigarette tar and nicotine yield is not an important factor in the development of COLD is premature. First, cross-sectional studies are limited in their capability of defining the natural history of a disease. Second, COLD has a very slow progress, and Fletcher et al. (1976) suggest that a span of approximately 8 years is necessary to establish rates of change of spirometric values with sufficient confidence even to distinguish between smokers and nonsmokers. Third, we have no information on the baseline pulmonary function of smokers at the time they choose between high or low tar and nicotine cigarettes. Significant differences in pulmonary function have been observed between young adults who decide to smoke and those who avoid cigarette smoking (Tashkin et al. 1983), and it is possible that similar 338 function differences may exist in subjects who choose between high or low tar and nicotine cigarettes. Fourth, the yield of tar and nicotine used in many of these studies does not lie in the same range as that produced by many of today’s cigarettes. However, the possibility that cigarette tar content is related to the development of cough and phlegm, but not of dyspnea or airflow obstruction, is consistent with current concepts of COLD. In a study of 792 men followed over an 8-year period, Fletcher et al. (1976) observed that cigarette smokers were susceptible to two distinct chronic lung diseases—mucus hypersecretion and chronic airflow obstruction. This has recently been confirmed in a large prospective study (Peto et al. 1983) of 2,728 men, followed over 20 to 25 years, which showed that the risk of death from COLD was strongly correlated with initial degree of airflow obstruction, but bore no relationship to initial mucus hypersecretion. Given the evidence that mucus hypersecretion may depend on the tar fraction of cigarette smoke, while development of airflow obstruction is more closely linked to the tumber of cigarettes smoked, Higenbottam et al. (1980b) reasoned that these differences might be due to a reduction in the particulate phase products, without a decrease in the gas phase products, in the low tar cigarettes. They hypothesized that tar droplets and soluble gases, such as sulfur dioxide and hydrogen cyanide, are more likely to be deposited or absorbed in the large airways where mucus is produced. The smaller airways, the earliest site of airflow obstruction, are exposed to a lower concentration of tar, but to a full concentration of insoluble gases such as nitrogen dioxide and ozone. This line of reasoning is in agreement with several studies showing a reduction in lung cancer with the use of low tar and nicotine cigarettes (Wynder et al. 1970; Lee and Garfinkel 1981; Rimington 1981; Hammond et al. 1976). The tar fraction is the component of cigarette smoke particularly linked with the development of both lung cancer and mucus hypersecretion. Although clinicians have long linked chronic bronchitis (mucus hypersecretion) with emphyse- ma, recent evidence indicates that mucus hypersecretion is not predictive of airflow obstruction, but is significantly greater in those smokers who develop lung cancer (Peto et al. 1983). Mechanisms of Lung Damage Studies of the mechanism of cigarette-smoke-induced lung damage have contributed significantly to the present understanding of COLD. Cigarette smoke may initiate and aggravate lung injury by a number of mechanisms and may also interfere with the lungs’ defense responses. These mechanisms include the protease-insd'bitor imbalance theo- ry for the pathogenesis of emphysema whereby alveolar wall 339 digestion results from an excess of proteases, a deficiency of their inhibitors, or a combination of both factors (see the chapter on Mechanisms in this Report). The sources of endogenous proteases include polymorphonuclear neutrophils and alveolar macrophages, both of which are found in increased number in the lungs of cigarette smokers. Protease release from both macrophages and neutrophils is increased in the presence of cigarette smoke (Rodriquez et al. 1977; Blue and Janoff 1978). In health, proteases are continually inhibited by au-antitrypsin, whereas proteases cause unimpeded digestion of lung tissue in patients with aantitrypsin deficiency, with a markedly increased risk of emphysema. In addition to increasing the protease burden, cigarette smoke causes a functional inhibition of an- - antitrypsin through the action of oxidants in cigarette smoke (Janoff © et al. 1979). The relative potency of smoke from cigarettes of varying tar and nicotine yields in stimulating protease production and release and in inhibiting o1-antitrypsin has received scant scientific investigation. - Travis et al. (1980) tested the effect of both filtered and unfiltered cigarette smoke on the elastase inhibitory activity of oi-antitrypsin. Filtered smoke reduced elastase inhibitory activity by 3 percent, and a 19 percent reduction was observed with unfiltered smoke; the tar content of the respective smokes was not stated. The researchers reasoned that this small in vitro effect would be greatly magnified by in vivo conditions in the lung, particularly through its huge surface area. In addition to examining the effect of filters, Cohen and James (1982) recently examined the effect of tar and nicotine content on the . elastase inhibitory capacity of ai-antitrypsin. The oxidant capacity of © cigarette smoke was also examined using a chromogenic electron donor. Aqueous condensates of cigarette smoke were obtained from a variety of brands ranging in tar content from about 1 mg to more than 20 mg. Reported tar and nicotine content correlated well with the amount of measured oxidants and the ability of a brand to reduce . the elastase inhibitory capacity of a:-antitrypsin. Filters were found to remove 73 percent of the oxidants from the aqueous smoke solutions. While these findings suggest that low tar and nicotine or filter-tipped cigarettes could reduce a smoker’s predisposition to enzymatic lung damage and consequent COLD, it should be noted that neither study examined the effect of lower yield cigarettes on protease production. Morosco and Gueringer (1979) demonstrated a greater increase in elastase in dogs exposed to high nicotine cigarette smoke compared with low nicotine cigarette smoke. More important, these studies have not taken into account the compensatory changes in smoking pattern likely to result with lower yield cigarettes. The airway response to acute exposure to cigarette smoke has been examined by several investigators employing spirometry (Da Silva and Hamosh 1981), body plethysmograph (Nadel and Comroe 1961),_ 340 and breathing pattern analysis (Tobin et al. 1982a). Airway narrow- ing has been consistently observed by some investigators (Nadel and Comroe 1961; Sterling 1967; Tobin et al. 1982a), but others report a variable response (Higenbottam et al. 1980a; Rees et al. 1982). In some studies, the acute airway response was unrelated to cigarette yield (Higenbottam et al. 1980a), but in most investigations (Robert- son et al. 1969; Tobin et al. 1982a: Rees et al. 1982), smoking a low tar or filter-tipped cigarette induced less acute bronchoconstriction. The acute airway response is probably localized to the larger alrways, as acute cigarette exposure resulted in no change in the nitrogen washout test of small airway function (Da Silva and Hamosh 1973; Tobin et al. 1982a). These observations on the relative bronchocon- strictor response of various types of cigarettes may be important in our understanding of why some smoking novitiates persist with the habit despite the initial unpleasant reactions (Tashkin et al. 1983), but it is unlikely that repeated episodes of smoking-induced acute airway narrowing finally result in COLD. Future studies examining the mechanism of smoking-induced lung injury must not only take into account the range of cigarette yields, as determined by a smoking-machine, but also consider variations in smoking behavior. Puff volumes may vary considerably with nomin- al cigarette tar and nicotine content, thus altering the relative amount of various toxic substances yielded by different cigarettes. Similarly, inhalation profiles are of a diverse nature (Tobin et al. 1982b) and are likely to significantly alter the distribution, penetra- tion, and retention of cigarette smoke constituents in the lungs. Variation in Smoking Pattern With Switching to Low Tar and Nicotine Cigarettes Low tar and nicotine cigarettes have gained considerable populari- ty among the smoking public, partly on the premise that a reduction in the nominal tar and nicotine yield results in a proportional reduction in the health hazards of cigarette smoking. The validity of this approach to cigarette smoking is contingent on the accuracy of smoking-machines in reflecting the actual manner of puffing and also on the smoker not altering smoking behavior to compensate for variations in nominal tar and nicotine content. Should smokers develop compensatory alterations in their smoking behavior, this would not only reduce the relevance of the smoking-machine assays but might also alter the proportionate delivery of the different toxic substances in cigarette smoke and expose the smoker to concentra- tions beyond those predicted by the smoking-machine. 34] Smoking Behavior Nearly 40 years ago, Finnegan et al. (1945) studied the effect of alterations in cigarette nicotine content on smoking behavior and noted no change in cigarette consumption. It is only in the last decade, with the increasing popularity of low tar and nicotine cigarettes, however, that this question has attracted significant interest. The results of 38 studies examining alterations in smoking behavior with a reduction in cigarette yield are shown in Table 1. Considerable differences can be observed between the studies, partly reflecting variations in the level of cigarette yield reduction, alterations in other cigarette constituents, type and duration of - switching procedure, parameters evaluated, and techniques used in their measurement. Most studies agree that smokers rarely increase their daily cigarette consumption upon switching from higher to lower yield brands. Reports are almost equally divided as to whether a smoker increases the number of puffs per cigarette or shows no change on switching to a lower yielding brand. There is an almost unanimous consensus that smokers take a larger puff volume from a lower yielding brand. Studies of puff volume also indicate huge variation between individual subjects (Guillerm and Radziszewski 1978; Hern- - ing et al. 1981; Tobin and Sackner 1982; Herning et al. 1983) and that considerable increases in puff volume may occur on switching from a higher to a lower yielding brand, with certain subjects increasing their puff volume by up to 75 percent (Tobin and Sackner 1982). This compensatory increase in puff volume may be observed within a single experimental session (Tobin and Sackner 1982) and maintained over several weeks (Rawbone et al. 1978; Stepney 1981). Full compensation for a lower yielding cigarette is generally not achieved by smokers taking a large puff volume (Rawbone et al. 1978; Herning et al. 1981; Tobin and Sackner 1982). Instrumentation is required to quantitatively assess the pattern of smoking, but it is important to realize that such instrumentation may, in itself, alter usual smoking behavior. Puff volume has been almost universally measured by using a specialized cigarette holder incorporating different flowmeter designs (Frith 1971, Adams 1977; Rawbone et al. 1978). These devices consist of two tubes connected to a pressure transducer that measures the pressure drop across a small resistance (a filter insert) in the holder; the flow measured is . integrated to obtain volume. Use of a cigarette holder has been shown to increase the rate of puffing and puff volume, compared with measurements made with the cheek inductive plethysmogra- phy coil (Tobin and Sackner 1982). Unlike the compensatory increases in puff volume, measurements of the subsequent inhalation volume—which includes the volume of smoke mixed with air inhaled into the lung—have shown no change 342 PE TABLE 1.—Effect of smoking low yield cigarettes on smoking pattern CO parameters Nicotine parameters Number Number Volume Duration Relationship Nicotine/cotinine | Mouth Relationship Reference Experimental of cigs of Puff of of Expired to level exposure to First author year design smoked puffs/cig volume inhalation inhalation COHb COQ nominal yield (blood/urine/saliva) index normal yield Finnegan 1945 cs NC Ashton 1970 VCF t t Poor Frith 1971 cs f Cohen 1971 cS NC Poor Russell 1973 cS t | Good Turner 1974 CS J /NC Poor Russell 1975 CS t {¢NC Poor Goldfarb 1976 cs t | Good Forbes 1976 cs | Good Adams 1977 cs NC NC NC Wald 1977 SVS t Sutton 1978 VCF NC | Poor \ Fair Rawbone 1978 CS NC ; NC ‘ Poor Schulz 1978 cs NC t Creighton 1978a,b 8 , Adams 1978 CS j t Guilerm 1978 CS t NC NC t Poor Jarvik 1978 cs ' ' Ashton 1979 CS NC , Poor ‘ ‘ Poor Garfinkel 1979 SVS NC Hill 1980 cs NC Poor 7 Good Robinson 1980 SVS i Good Russell 1980 SVS NC Poor Henningfield 1980 VCF NC t t NC Wald 1980 SVS t pre TABLE 1.—Continued CO parameters Nicotine parameters Number Number Volume Duration Relationship Nicotine/cotinine © Mouth Relationship Reference Experimental of cigs of Puff of of Expired to level exposure to First author year design smoked puffs/cig volume inhalation inhalation COHb CO nominal yield (blood/urine/saliva) index normal yield Herning 1981 cs NC t t Wald 1981 SVS NC ' Poor Stepney 1981 cs NC t t t Fair | | Jaffe 1981 SVS NC/{ NC Poor Tobin 1982 CS NC t NC NC Battig 1982 SVS NC ' NC Sutton 1982 SVS ' Good Poor Griffiths 1981 cs NC t Jaffe 1982 cs NC/t NC Poor Feyerabend 1982 SVS Poor Herning 1983 cs Fur Benowitz 1983 SVS NOTE: CS - controlled switching; VCF = variable cigarette filters; SVS - spontaneous voluntary switching, NC = no change; f — increase, | = decrease; CO = carbon monoxide. on switching to a low yield cigarette. Likewise, in one short-term study (Tobin and Sackner 1982), duration of inhalation showed no relationship to nominal cigarette yield. Perhaps compensatory changes in inhalation parameters require a longer period of time than puff volume does. Measurement of carboxyhemoglobin (COHb) concentration has been proposed as an index of the pattern of inhalation (Wald et al. 1975, 1978). While COHb provides valuable information on the amount of carbon monoxide absorbed from the lung during compen- satory alterations in smoking behavior, it is an indirect index and provides complementary information on cigarette smoke inhalation rather than replacing direct measurements of the volume of inhalation. Carbon Monoxide Uptake Unlike tar and nicotine, which are present in the particulate phase, carbon monoxide (CO) is a constituent of the vapor phase of cigarette smoke. For this reason, cigarettes purported to produce a low tar and nicotine yield may not necessarily provide a lower yield of carbon monoxide. Compared with tar and nicotine yield, carbon monoxide yield is more dependent on cigarette design, including such features as paper porosity and perforations in the filter tips. These factors regulate the dilution of smoke with air and the burning profile of the cigarette, and thus can significantly reduce carbon monoxide yield. Wald (1976) showed that the carbon monox- ide yield of filter-tipped cigarettes was 28 percent higher than that of plain cigarettes, although the average nicotine yield was lower in the filter-tipped cigarettes. He reasoned that smoke passing through a cigarette is diluted by air entering through the porous cigarette paper. However, the filter of filter-tipped cigarettes is surrounded by relatively nonporous paper, resulting in a higher content of carbon monoxide exiting from the proximal cigarette end. Perforations in the filter tip circumvent this problem and significantly reduce carbon monoxide yield (Hoffmann et al. 1980; Wald and Smith 1973). Many investigators have measured COHb or carbon monoxide concentration in expired gas following cigarette smoking and compared the levels achieved in smoking brands with different nominal yields (see Table 1). An increase, decrease, or no change in carbon monoxide intake has been observed, depending on relative differences in cigarette design and experimental procedure. As expected, unventilated filter-tipped cigarettes produced higher COHb levels than those observed with unfiltered cigarettes (Wald et al. 1977). This is in agreement with information provided by smoking-machine assays (Wald et al. 1973), but the use of ventilated filter-tipped cigarettes may produce COHb levels similar to those observed with unfiltered cigarettes despite lower carbon monoxide 345 yields on smoking-machine assay (Wald et al. 1977). Comparison of cigarettes with a marked difference in nominal carbon monoxide yield usually results in a lower COHb level when the lower yielding brand is being smoked (Russell et al. 1973; Turner et al. 1974; Sutton et al. 1978; Ashton et al. 1979); but over the range of different carbon . monoxide yields there is a poor correlation between levels of COHb and measured carbon monoxide yield. Similar information has been observed using expired carbon monoxide concentrations. Nicotine Uptake It has been long considered that nicotine might serve as a primary reinforcer of cigarette smoking and that smokers might adjust their smoking behavior to regulate their level of nicotine intake. Several investigators have measured the blood, urinary, or salivary levels of nicotine or its major metabolite cotinine during the smoking of cigarettes of varying nominal nicotine yields (see Table 1). A reduction in blood (Russell et al. 1975; Sutton et al. 1978; Ashton et al. 1979; Hill and Marquardt 1980) and urinary (Goldfarb et al. 1976; Ashton et al. 1979; Stepney 1981) nicotine levels or in plasma (Hill and Marquardt 1980; Stepney et al. 1981) and urinary (Ashton et al. 1979; Hill and Marquardt 1980) cotinine levels has generally been observed on switching to a cigarette with a lower nominal nicotine yield. However, smokers show variable degrees of compensation for the lower yield, as there is generally a poor relationship between nominal nicotine yield and measured blood nicotine levels (Russell et al. 1980; Sutton et al. 1982; Feyerabend et al. 1982; Benowitz et al. - 1983). Relating nominal nicotine yield and blood nicotine levels, Ashton et al. (1979) estimated that smokers compensated for about two- thirds of the difference in nominal yields when they switched from - medium nicotine cigarettes to high or low nicotine brands. Using a stepwise multiple regression analysis of nicotine yield and blood nicotine concentration, Russell et al. (1980) observed a significant, but very weak, correlation (r=0.21) between the two measurements, but the nominal nicotine yield of the cigarettes accounted for only 4.4 percent of the variability in blood nicotine concentrations. The use of absolute rather than logarithmic analysis in this study has been criticized (Kozlowski et al. 1982; Herning et al. 1983), and the criticism involved the problems of trying to predict doses to individuals rather than the dose to groups. In another study using log-linear regression analysis (Herning et al. 1983), a better correla- ~ tion was observed between nominal nicotine yield and the increasing blood nicotine after smoking (r=0.5), but this study used Kentucky reference cigarettes rather than commercial brands, and these low yield cigarettes have less nicotine in the unburned tobacco than commercial low yield brands. Such a relationship still accounted for 346 only 25 percent of the individual differences in blood nicotine levels, whereas 50 to 60 percent was accounted for by individual differences in smoking behavior (Herning et al. 1983). Additional information on compensatory alterations in nicotine intake has been provided by studying the mouth exposure index, which is calculated from analysis of cigarette butts for nicotine content and a knowledge of the retention efficiency of the filter tip (Ashton and Watson 1970). Because the amount of nicotine retained by a filter is proportional to the amount that passes through, it is possible to estimate the amount of nicotine presented to the smoker from the nicotine content of the filter. Results using this index have revealed a greater variation between individual studies (see Table 1) than observed with blood nicotine measurements. This may be related to the fact that filter efficiency is usually determined by a machine, but retention of nicotine is also dependent on the way the cigarette is smoked; therefore, the retention efficiency of the filter may vary between smokers. Role of Tar Content The observations that smokers adapt their smoking behavior according to the nicotine delivery of a cigarette and that raany of the toxic effects of smoking appear to be related to tar rather than nicotine content has led to the suggestion that altering the tar to nicotine ratio might produce a cigarette less hazardous to health (Russell 1976; Stepney 1981). A cigarette with a medium nicotine, low tar, and low carbon monoxide yield might be advantageous. While nicotine has been the component most extensively studied, it may not be the only substance responsible for the addictive power of tobacco. It is not possible to separate the effects of tar and nicotine in most studies, as their respective yields usually show a very close correlation. Using research cigarettes providing three different yields of nicotine and two different yields of tar, Goldfarb et al. (1976) found evidence of compensation for nicotine but not for tar content. The authors urged cautious interpretation of the results because of the limited range of tar yields examined. Examining a large number of subjects smoking cigarettes of varying tar and nicotine yield, Wald et al. (1981) found that both tar and nicotine were significantly related to blood COHb, taken as an index of cigarette smoke inhalation. Two- way analysis of variance of the data indicated that after allowing for the effect of either tar or nicotine yield, the COHb index was no longer significantly influenced by the other. A cross-over study of medium tar smokers who were switched to low nicotine, low tar cigarettes and medium nicotine, low tar cigarettes has been reported by Stepney (1981). While the intake of carbon monoxide was least with the medium nicotine, low tar cigarette, the mouth exposure 347 index to tar was similar among the brands. Indeed, the pattern of smoking adopted by the subjects was more effective in reducing the difference in tar delivery between the cigarettes than in compensat- ing for nicotine delivery. Further evidence indicating the importance of cigarette tar delivery in. determining smoking behavior was reported by Sutton et al. (1982). Using multiple regression analysis, they observed that when nicotine yield was controlled, smokers of lower tar cigarettes had higher blood nicotine levels than smokers of higher tar cigarettes, indicating that they inhaled a greater volume of smoke. In contrast, when tar yield was controlled, smokers of lower nicotine cigarettes had lower blood nicotine concentrations than smokers of higher nicotine cigarettes, indicating that they inhaled less smoke. These results suggest some compensation for tar over and above any compensation for nicotine. It may be that ncenpharmacologic, sensory stimulation by factors such as the flavor of cigarette smoke may be more important than nicotine in determining smoking behavior. These new observations, especially on the role of tar delivery, require further investigation. Most published research consists of controlled switching experiments in which the subject smokes cigarettes of varying yields (see Table 1). Further studies of smoking behavior in sukjects who have voluntarily chosen cigarettes of different yields are needed. The absence of an acceptable, palatable “standard” research cigarette continues to be an impediment to - research in this area. Variations in Pattern of Cigarette Smoke Inhalation While cigarette smoking is the single most important factor in the development of COLD, the majority of smokers never develop clinically significant airflow obstruction (Fletcher et al. 1976). Despite the clear dose-response relationship between number of cigarettes smoked and death from COLD, attempts at identifying the individual susceptible smoker on the basis of number of cigarettes smoked have had very limited success. Another approach to identifying the susceptible smoker is to study the manner of smoking, as this is probably a major determinant of the lung’s exposure to cigarette smoke. Cigarette smoking consists of two phases: initially, the smoker takes a puff into the mouth, and after a variable 1 to 4 second pause, the smoke mixed with air is inhaled into the lungs (Rawbone et al. 1978; Higenbottam et al. 1980a; Tobin and Sackner 1982). Individual differences in the pattern of cigarette smoking such as the size of the puff volume, the duration of holding the smoke in the oral cavity before inhalation, and the depth and duration of inhalation are among the important factors determining the relative concentration of smoke constituents 348 that reach the lung. Despite its significance in determining the distribution and deposition of cigarette smoke, the mode of inhala- tion following the puff has received scant scientific investigation. A number of epidemiologic studies have examined the relationship between cigarette smoke inhalation, based on the smoker’s subjec- tive estimation, and the severity of pulmonary disease. Results of these studies are conflicting; some investigators repcrted an associa- tion between smoke inhalation and the presence of mucus hyperse- cretion (Rimington 1974; Schenker et al. 1982; Dean et al. 1978) and decline in pulmonary function (Ferris et al. 1976; Bosse et al. 1975), and others observed no relationship between inhalation and pulmo- nary dysfunction (Beck et al. 1981; Schenker et al. 1982). The inconsistencies in these epidemiologic studies may be due to the smokers’ inability to accurately describe their inhalation pattern. There are three reports of the relationship between subjective estimations of cigarette smoke inhalation and direct objective measurement. Rawbone et al. (1978) found that the rating on a visual analog scale was a good predictor of inhalation volume (r=0.65). Conversely, Tobin et al. (1982a) noted no relationship between inhalation volume and the smoker’s perception of depth of inhalation, indicated on a visual analog scale (r—0.04); a similar finding was reported by Adams et al. (1983) (r~0.04). Standardizing the inhaled volume for vital capacity did not improve the relation- ship. Other investigators using measurements of COHb observed a weak relationship between self-estimated inhalation and COHb concentration (Stepney 1982; Wald et al. 1978). Measurements of COHb reflect the amount of cigarette smoke absorbed by the lung. In addition to being affected by the depth of inhalation, COHb concentration is influenced by the varying carbon monoxide yields of different cigarettes, the number of puffs per cigarette, puff volume, pulmonary function—particularly diffusing capacity and alveolar ventilation—and hemoglobin concentration (Wald et al. 1978: Ric- kert et al. 1980). Therefore, it yields valuable complementary information, but it does not provide a direct measure of the pattern of inhalation (Tobin et al. 1982a; Guyatt et al. 1983). Direct measurements of the pattern of cigarette smoke inhalation have been reported for a small number of smokers. Initially, the puff from the cigarette is taken into the mouth, and after a variable pause of 1 to 4 seconds, it is inhaled into the lungs (Rawbone et al. 1978; Higenbottaim et al. 1980a; Tobin and Sackner 1982; Tobin et al. 1982a; Adams et al. 1983). Higenbotiam et al.(1980a) reasoned that this pause, while holding the smoke in the mouth, minimized the irritant qualities cf cigarette smoke. In a group of five subjects who were requested to inhale smoke directly into®keir lungs, without an intervening pause in the mouth, consistent acute airway narrowing was observed. In contrast, smokers adopting the usual two-phase 349 smoking pattern showed a variable airway response. The authors suggested that buccal absorption of water-soluble compounds, such as sulfur dioxide and acrolein, together with precipitation of tar, minimized the irritating qualities of cigarette smoke. They observed no relationship between the acute airway response and amount of smoke inhaled in the regular two-phase smokers, although there appeared to be a relationship in those directly inhaling smoke into their lungs. However, there is a marked discrepancy in the inhala- tion volumes reported in this study compared with the values reported in other studies of cigarette smoke inhalation, probably due to the inaccuracy of the magnetometers employed for the measure- ments; therefore, a statement regarding the relationship between depth of smoke inhalation and the acute airway response may be misleading. The report that acute airway narrowing is uncommon after cigarette smoking is in disagreement with the findings of several investigators who have observed bronchoconstriction to be a common phenomenon after acute smoke exposure (Nadel and Comroe 1961; Sterling 1967; Da Silva and Hamosh 1981; Tobin et al. 1982a); however, it is certainly plausible that the response is greater in smokers who inhale smoke directly into the lungs than in two-phase smokers. The frequency of direct inhalation of cigarette smoke into the lungs is unknown. In a small study of 10 smokers, Tobin and Sackner (1982) observed 1 subject who showed an approximately 50 ml expansion of the abdominal compartment simultaneously with taking the puff from the cigarette. Adams et al. (1983) studied the relationship between puffing, cigarette smoke inhalation, and partitioning of airflow between the nose and mouth in 10 smokers. After taking the puff into the mouth, two subjects actively exhaled 80 ml and 200 ml volumes, respective- ly, before the subsequent inhalation. In this situation, the volumes of smoke might be expelled from the mouth, and little, if any, would be available for subsequent inhalation into the lungs. The frequency of this smoking pattern was not given, but another report from the same laboratory (Rawbone et al. 1978) indicated that it was uncommon. There was marked intersubject variation in the parti- tioning of airflow between the nose and mouth during smoking, with four subjects inhaling almost exclusively through the mouth, four inhaling predominantly through the nose, and the other two demonstrating both patterns of inhalation. The importance of factors in determining whether cigarette smoke is inhaled as a bolus followed by a subsequent “chaser” of air or is evenly distributed throughout the inhaled volume of air remains to be determined. Considerable discrepancies exist between published reports of the volume of air mixed with smoke that is inhaled into the lungs, with reported mean inhalation volumes of 34 to 152 ml (Higenbottam et 350 30 Sum 20 Putt Putt Volume (liters) v c t Puff Putt 1 id i Lt 1 jt i 1 10 20 30 40 50 60 Seconds FIGURE 3.—Pattern of inhalation of cigarette smoke mixed with air, in two smokers SOURCE: Modified from Tobin et al. (1982b). al. 1980a), 450 to 485 ml (Guillerm and Radziszewski 1978), 389 to 1,136 ml (Adams et al. 1983), 750 to 2,000 ml (Rawbone et al. 1978), and 170 to 1,970 ml (Tobin et al. 1982b). A major factor in the discrepancies between these studies is probably the inaccuracies inherent in some of the methods employed in the measurements, as discussed by Tobin and Sackner (1982). When inhalation volumes are standardized for body size by relating them to vital capacity, marked interindividual variation is still observed (Figure 3), with inhalation- al volumes ranging from 9 to 47 percent of the vital capacity and a group mean value of 20 percent (Tobin et al. 1982b). Smokers show considerable variation in inhaled volumes while smoking a single cigarette. The volume of inhalation bears no relationship to cigarette consumption in terms of pack-years (Tobin et al. 1982b). Similarly, duration of inhalation shows considerable variation between sub- jects, with mean individual values ranging from 1.7 to 7.3 seconds (Adams et al. 1983; Tobin et al. 1982b). Repeat measurements at intervals of up to 10 months apart indicate that individual subjects tend to maintain a fairly constant inhalation volume, duration of inhalation, and associated breathhold time (Tobin et al. 1982b; Adams et al. 1983). 351 The pattern of cigarette smoking shows a wide degree of intersub- ject variability, including differences in the number of puffs, puff volume, holding pause in the mouth, exhalation of smoke from the mouth before inhalation, partitioning of airflow between the nose and mouth, and volume and duration of inhalation. Given this degree of variation, it is not surprising that smokers might show wide differences in their individual susceptibilities to lung injury. In a study relating inhalation volume—standardized for vital capaci- ty—to the time-volume and flow-volume components of a forced vital capacity maneuver, no significant correlation was observed (Tobin et al. 1982b). Although this lack of a relationship might be interpreted as indicating that the pattern of smoking is unimportant in the development of lung disease, it may also reflect the fact that pulmonary function was normal or near normal in the majority of subjects and that the study was of a cross-sectional design. Use of Additives in Low Tar and Nicotine Cigarettes The nominal tar and nicotine yield of cigarettes has continually decreased since the time of the initial reports linking smoking with lung cancer (USDHHS 1981). In 1954, the average tar yield per cigarette was 38 mg, and in 1980 it was less than 14 mg. Initially, tar reduction was achieved by decreasing the cigarette tobacco content or removing tar by smoke filtration, both of which probably resulted in a lower smoke exposure. Since 1971, the reduction in tar yield has exceeded the relative reduction in the weight of tobacco per cigarette; this difference has increased since 1975 (USDHHS 1981). Manufacturing technology has progressed beyond simple reduction in tobacco content: the yield and composition of smoke can be modified by genetic modification of the tobacco leaf (Tso 1972a), changes in its cultivation and processing (Tso 1972b), changes in the porosity of cigarette paper, and alterations in filter design (Kozlow- ski et al. 1980b). When initially introduced, lower yield cigarettes lacked palatabili- ty and acceptability. Advertisements for the current low tar and nicotine cigarettes emphasize their flavor, presumably achieved by the use of additives in the processing of the tobacco. Additives employed may include artificial tobacco substitutes (Freedman and Fletcher 1976), flavor extracts of tobacco and other plants, exogenous enzymes, powdered cocoa (Gori 1977), and other synthetic flavoring substances. Perhaps more additives are being used in the new lower tar and nicotine cigarettes than in the older brands, and new agents may also be in use. Some of the substances, such as powdered cocoa, have been shown to further increase the carcinogenicity of tar (Gori 1977), and others may result in increased or new and different health risks. The pyrolytic products of these additive agents may 352 produce novel toxic constituents. A characterization of the chemical composition and adverse biologic potential of these additives is urgently required, but is currently impossible because cigarette companies are not required to reveal what additives they employ in the manufacture of tobacco (USDHHS 1981). No government agency is empowered with supervisory authority in the manufacture of tobacco products. With this lack of basic information and the usually prolonged latent period before manifestation of the adverse effects of smoking, it is likely that a long time period will elapse before we know the hazards of the new cigarettes in current use. Research Recommendations 1. Longitudinal epidemiologic studies are needed to determine the risk for pulmonary symptoms and dysfunction in smokers of cigarettes with the low tar and nicotine yields found in currently popular brands. 2. Further research is needed to determine the relative potency of high and low tar and nicotine cigarettes in inducing elastase release and producing functional inhibition of ai-antitrypsin activity. 3. Development of an animal model of cigarette-smoke-induced emphysema would be advantageous in determining the relative risk of lung injury of cigarettes of different composition. 4. More information is required on the smoking behavior of smokers who have voluntarily switched from high to low tar and nicotine cigarettes. 5. The role of cigarette tar, as opposed to nicotine content, in determining smoking behavior needs to be defined. 6. Standard research cigarettes of varying tar and nicotine contents that are palatable and acceptable to smokers need to be developed. 7.The role of variation in smoking behavior in determining susceptibility to lung injury needs to be defined. Studies are required to determine the effect of smoking patterns on the distribution and penetration of the smoke aerosol into the lung. 8. More information is needed on the composition and adverse biologic effects of flavor additives in cigarettes and their pyrolytic products. Summary and Conclusions 1. The recommendation for those who cannot quit to switch to smoking cigarette brands with low tar and nicotine yields, as determined by a smoking-machine, is based on the assumption that this switch will result in a reduction in the exposure of the 353 354 lung to these toxic substances. The design of the cigarette has markedly changed in recent years, and this may have resulted in machine-measured tar and nicotine yields that do not reflect the real dose to the smoker. .Smoking-machines that take into account compensatory changes in smoking behavior are needed. The assays could provide both an average and a range of tar and nicotine yields produced by different individual patterns of smoking. ._ Although a reduction in cigarette tar content appears to reduce the risk of cough and mucus hypersecretion, the risk of shortness of breath and airflow obstruction may not be reduced. Evidence is unavailable on the relative risks of developing COLD consequent to smoking cigarettes with the very low tar and nicotine yields of current and recently marketed brands. _ Smokers who switch from higher to lower yield cigarettes show compensatory changes in smoking behavior: the number of puffs per cigarette is variably increased and puff volume is almost universally increased, although the number of ciga- rettes smoked per day and inhalation volume are generally unchanged. Full compensation of dose for cigarettes with lower yields is generally not achieved. Nicotine has long been regarded as the primary reinforcer of cigarette smoking, but tar content may also be important in determining smoking behavior. . Depth and duration of inhalation are among the most impor- tant factors in determining the relative concentration of smoke constituents that reach the lung. 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PASSIVE SMOKING 361 480-144 0 - 85 - 13 CONTENTS Introduction Differences in Composition of Sidestream Smoke and Mainstream Smoke Measurement of Exposure Acute Physiologic Response of the Airway to Smoke in the Environment Symptomatic Responses to Chronic Passive Cigarette Smoke Exposure in Healthy Subjects Respiratory Infections in Children of Smoking Parents Pulmonary Function in Children of Smoking Parents Pulmonary Function in Adults Exposed to Involuntary Cigarette Smoke The Effect of Passive Smoke Exposure on People With Allergies, Asthma, and COLD Summary and Conclusions References 363 Introduction This chapter explores recent data that relate involuntary cigarette smoke exposure to the occurrence of physiologic changes, symptoms, and diseases in nonsmoking adults and children. Health effects related to fetal exposure in utero, a subject that has been extensively studied, are not discussed, although instances where such exposure may relate to potential development are pointed out. The interested reader is referred to several excellent recent reviews for a more complete treatment of this issue (USDHEW 1979; USDHHS 1980; Abel 1980; Weinberger and Weiss 1981). Differences in Composition of Sidestream Smoke and Mainstream Smoke Involuntary (passive) smoking is defined as the exposure of nonsmokers to tobacco combustion products from the smoking of others. Analysis of the health effects of passive smoking requires not only some knowledge of the constituents of tobacco smoke, but also some quantitation of tobacco smoke exposure. Tobacco smoke in the environment is derived from two sources: mainstream smoke and sidestream smoke. Mainstream smoke emerges into the environment after having first been drawn through the cigarette, which filters some of the active constituents. The smoke is then filtered by the smoker’s own lungs, and exhaled. Sidestream smoke arises from the burning end of the cigarette and enters directly into the environ- ment. Differences in the temperature of combustion, the degree of filtration, and the amount of tobacco consumed all lead to marked differences in the concentration of the constituents of mainstream smoke and sidestream smoke (USDHEW 1979; Sterling et al. 1982; Brunneman et al. 1978; National Academy of Sciences 1981; Rylander et al. 1984). Many potentially toxic gas phase constituents are present in higher concentration in sidestream smoke than in mainstream smoke (Brunneman et al. 1978) (Table 1), and nearly 85 percent of the smoke in a room results from sidestream smoke. Smaller amounts of smoke are contributed to the environment from the nonburning end of the cigarette by diffusion through the paper wrapping and by the smoke exhaled by the smoker. Therefore, both active and passive smokers may be similarly exposed to sidestream smoke. Mainstream smoke is inhaled directly into the lungs and is diluted only by the volume of air breathed in by the smoker when he or she inhales. Sidestream smoke is generally diluted in a considera- bly larger volume of air. Thus, passive smokers are subjected to a quantitatively smaller and qualitatively different smoke exposure than active smokers. The quantification of the exposure of a passive smoker to these sidestream smoke constituents is often difficult. Factors such as the type and number of cigarettes burned, the size of 365 the room, the ventilation rate, and the smoke residence time are all important variables in determining levels of exposure. Thus, no single variable accurately characterizes exposure to smoke constitu- ents. Repace and Lowrey (1980, 1982, 1983) have shown that, to a reasonable approximation, exposure to the particulate phase is predicted by the ratio of the smoker density to the effective ventilation rate of the area in which the smokers are located. Measurement of Exposure Levels of indoor byproducts of tobacco smoke, with measurements made under realistic exposure conditions, are presented in Table 2. Among the constituents that have been measured, nitrogen oxide, carbon monoxide, nicotine and respirable particulates, nitrosamines, and aldehydes have been shown to be significantly elevated indoors as a result of cigarette smoking. Nitrogen oxide is rapidly oxidized to nitrogen dioxide (NOz) in air, and reaches equilibrium with outdoor levels of NOz, provided there are suitable air exchange rates and no other indoor sources, such as a gas stove. The particulate concentra- tion indoors clearly increases with increasing numbers of smokers, although the background level is determined by the outdoor level. The conclusions from the few studies that actually measure ventila- tion rates during exposure suggest that under “normal” air circula- tion conditions, carbon monoxide (CO) levels will be relatively low, but still may exceed the ambient air quality standard of 9 ppm (NIOSH 1971). However, even modest reductions in ventilation rates can lead to CO accumulation. A variety of measures have been utilized to quantify the nonsmok- er’s exposure to tobacco smoke. No single measure has been uniformly accepted as characterizing the level of smoke. Nicotine is the most tobacco-specific of these measures, but it is relatively complicated and expensive to measure and settles out of the air with the particulate phase, making it a poor measure of gas phase constituents. In addition, nicotine may rapidly deposit on surfaces and subsequently evaporate into the environment (Rylander et al. 1984), making it a poor measure of acute smoke exposure levels. Measurements of total particulate matter are a broader measure of smoke exposure, particularly if the measurements are limited to particles in the respirable range and to environments without other major sources of respirable particles. The smoke particles also settle out of the air and therefore may not reflect the levels of gas phase constituents, and a wide variety of other dusts may contribute particulates to the air, particularly in the occupational setting. A number of authors have measured levels of CO. This measurement is relatively simple and a measure of absorption (carboxyhemoglobin) 366 L9E TABLE 1.—Ratio of selected constituents in sidestream smoke (SS) to mainstream smoke (MS) Gas phase constituents MS SS/MS ratio Particulate phase constituents MS SS/MS ratio Carbon dioxide 20-60 mg 8.1 Tar 1-40 mg 1.3 Carbon monoxide 10-20 mg 25 Water 14 mg 24 Methane 1.3 mg 3.1 Toluene 108 pg 5.6 Acetylene 27 wg 08 Phenol 20-150 pg 2.6 Ammonia 80 pg 73.0 Methylnaphthalene 2.2 ug 28 Hydrogen cyanide 430 pg 0.25 Pyrene 50-200 pg 3.6 Methylfuran 20 pe 3.4 Benzofa}pyrene 20-40 pg 3.4 Acetonitrile 120 pg 39 Aniline 360 pg 30 Pyridine 32 ug 10.0 Nicotine 1.0-2.5 mg 2.7 Dimethylnitrosamine 10-65 yg 52.0 2-Naphthylamine 2 ng 39 Adapted from U.S. Department of Health, Education, and Welfare (1979). 898 TABLE 2a.—Acrolein measured under realistic conditions Levels Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range Badre et al. Cafes Varied Not given 100 mL samples 0.03-0.10 mg/m* (1978) Room 18 smokers Not given 100 mL samples 0.185 mg/m* Hospital lobby 12 to 30 smokers Not given 100 mL samples 0.02 mg/m* 2 train compartments 2 to 3 emokers Not given 100 mL samples 0.02-0.12 mg/m? Car 3 smokers Natural, open 100 mL samples 0.03 mg/m* 2 smokers Natural, closed 100 mL samples 0.30 mg/m* Fischer et al. Restaurant 50-80/470 m?® Mechanical 27 x 30 min samples 7 ppb (1978) and Restaurant 60-100/440 m? Natural 29 x 30 min samples 8 ppb Weber et al. Bar 30-40/50 m* Natural, open 28 x 30 min samples 10 ppb (1979) Cafeteria 80-150/574 m? 11 changes/hr 24 x 30 min samples 6 ppb (5 ppb nonsmoking section) 69€ TABLE 2b.—Aromatic hydrocarbons measured under realistic conditions Levels Nonsmoking controls Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range Mean Range Benzene (mg/m*) Badre et al. Cafes Varied Not given 100 mL samples 0.05-0.15 (1978) Room 18 smokers Not given 100 mL samples 0.109 Train compartments 2 to 3 smokers Not given 100 mL samples 0.02-0.10 Car 3 smokers Natural, open 100 mL samples 0.04 2 smokers Natural, closed 100 mL samples 0.15 Toulene (mg/m°) _ Cafes Varied Not given 100 mL samples 0.04~1.04 Room 18 smokers Not given 100 mL samples 0.215 Train compartments 2 to 3 smokers Not given 100 mL samples 1.87 Car 2 smokers Natural, closed 100 mL samples 0.50 Benzofa}pyrene (ng/m’) Elliott and Rowe Arena 8,647-10,786 people Mechanical Not given TA (1975) 12,000-12,844 people Mechanical Not given 99 13,000-14,277 people Mechanical Not given 21.7 Separate non- 0.69 activity days Galuskinova Restaurant Not given Not given 20 days in summer 6.2 (1964) 18 days in the fall 28.2-144 OLE TABLE 2b.—Continued Levels Nonsmoking controls Type of Monitoring Study premises Occupancy Ventilation conditions Range Mean Range Just et al. Coffee houses Not given Not given 6 hr continuous 0.25-10.1 4.0-9.3 (outdoors) (1972) Benzofelpyrene (ng/m*) 3.3-23.4 3.0-5.1 (outdoors) Bei hi lene (ng/m* 5.9-10.5 6.9-13.8 (outdoors) Perylene (ng/m?) 0.7-1.3 0.1-1.7 (outdoors) Pyrene (ng/m’) 4.1-9.4 2.8-7.0 (outdoors) Anthanthrene (ng/m‘) 05-19 0.5-1.8 (outdoors) Coronene (ng/m’) 0.5-1.2 10-28 Phenols (1/m*) TAALS Benzofalpyrene (ng/m’) Perry (1973) 14 public places Not given Not given Samples, 5 outdoor < 20-760 < 20-43 locations TLE TABLE 2c.—Carbon monoxide measured under realistic conditions Levels (ppm) Nonsmoking controls (ppm) Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range Mean Range Badre et al. 6 cafes Varied Not given 20 min samples 2-23 (outdoors) 0-15 (1978) Room 18 smokers Not given 20 min samples 50 0 (outdoors) Hospital lobby 12 to 30 smokers Not given 20 min samples 5 2 train 2 to 3 smokers Not given 20 min samples 45 compartments Car 3 smokers Natural, open 20 min samples 14 0 (outdoors) 2 smokers Natural, closed 20 min samples 20 0 (outdoors) Cano et al. Submarines 157 cigarettes Yes <40 ppm (1970) 66 m’ per day 94-103 cigarettes Yes <40 ppm per day Chappell and 10 offices Not given Values not 17 x 23 min 25 + 10 1.54.5 25 + 10 15-45 Parker given samples (outdoors) (1977) 15 restaurants Not given Values not 17 x 23 min 40+ 25 1.0-9.5 25+ 15 1.0-5.0 given samples (outdoors) 14 nightclubs Not given Values not 19 x 23 min 13.0 + 7.0 3.0-29.0 3.0 + 2.0 1.0-5.0 and taverns given samples (outdoors) Tavern Not given Artificial 16 x 23 min 85 samples None 2x 23 min 35 (peak) samples Offices 1440 ft? Natural, open 2-3 min samples 10.0 (peak) 30 min after 1.0 smoking oLe TABLE 2c.—Continued Levels (ppm) Nonsmoking controls (ppm) Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range Mean Range Coburn et al. Rooms Not given Not given Not given 4.3-9.0 (1965) Nonsmokers’ rooms 2.2 + 0.98 0.44.5 Cuddeback Tavern 1 10-294 people 6 changes/hr 8 hr continuous 11.5 10-12 2 (outdoors) et al. 2 hr after smoking ~l (1976) Tavern 2 Not given 1-2 changes/hr 8 hr continuous 17 ~3-22 Values not given 2 hr after smoking ~12 Values not given US. Dept. of 18 military 165-219 people Mechanical 6-7 hr continuous <25 Transportation planes (1971 8 domestic 27-113 people Mechanical 1'/,-2", br <2 planes continuous Elliott and Arena | 11,806 people Mechanical Not given 9.0 3.0 (nonactivity day) Rowe Arena 2 2,000 people Natural Not given 25.0 3.0 (nonactivity day) (1975¢ Nonsmoking 9.0 arena Fischer et al. Restaurant 50-80/470 m? Mechanical 27 x 30 min 5.1 2.1-9.9 4.8 (outdoors) (1978) and samples Weber et al. Restaurant 60-100/440 m? Natural 29 x 30 min 2.6 1.4-3.4 1.5 (outdoors) (1979) samples Bar 30-40/50 m’ Natural, open 28 x 30 min 48 2.4-9.6 1.7 (outdoors) samples Cafeteria 80-150/574 m* 11 changes/hr 24 x 30 min 1.2 0.7-1.7 0.4 (outdoors) Nonsmoking 0.5 0.3-0.8 room Godin et al. Ferryboat Not given Not given 11 grab samples 18.4 + 87 3.0 + 2.4 (nonsmoking room) (1972) Theater foyer Not given Not given Grab samples 34+ 08 1.4 + 0.8 (auditorium) TABLE 2c.—Continued Levels (ppm) Nonsmoking controls (ppm) Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range Mean Range Harke Offices ~72 m? 236 m*/hr 30 min samples <25-46 (1974a) Offices ~78 m? Natural 30 min samples <25-9.0 Harke and Car 2 smokers Natural Samples 42 (peak) (Nonsmoking runs) Peters (4 cigs) 13.5 (peak) (19745 Mechanical Samples 32 (peak) (Nonsmoking runs) 15.0 (peak) Harmeen and Train 1-18 smokers Natural Not given 0-40 Effenberger (1957 Perry 14 public Not given Not given One grab sample <10 1973) places Portheine Rooms Not given Not given Not given 5-25 t197)8 Sebben et al. 9 nightclubs Not given Varied 77 x 1 min 13.4 65-419 (1977 samples Outdoors 9.2 3.0-35.0 14 restauranta Not given Not given Spot checks 99 + 55 Values not given 45 restaurants Not given Not given Spot checks 82 4 22 7.1 + 1.7 (outdoors) 33 stores Not given Not given Spot checks 10.0 + 4.2 115 + 69 (outdoors) 3 hospital Not given Not given Spot checks 438 Values not given lobbies ELE PLE TABLE 2c.—Continued Levels (ppm) Nonsmoking controls (ppm) Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range Mean Range Seiff Intercity bus Not given 15 changes/hr, 33 ppm (1973) 23 cigarettes burning continuously 3 cigarettes 18 ppm burning continuously Slavin and 2 conference Not given 8 changes/hr Continuous, 8 (peak) 1-2 (separate Hertz rooms morning nonsmoking day) (1975) 6 changes/hr Continuous, 10 (peak) 1-2 (separate morning nonsmoking day) Szadkowski 25 offices Not given Not given Continuous 2.78 + 1.42 259 + 2.23 et al. (separate nonsmoking (1976) offices) «Three cigarettes and one cigar smoked in 20 minutes. >The Drager tube used is accurate only within + 25 percent. ©The MSA Monitaire Sampler used is accurate only within + 25 percent. 4 About 40 cigarettes/day were smoked. * About 70 cigarettes/day were smoked. Four filter cigarettes were smoked. © No experimental deacription given. wo <1 on TABLE 2d.—Nicotine measured under realistic conditions Nonsmoking Levels (ug/m?) controls Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range Mean Range Badre et al. 6 cafes Varied Not given 50 min sample 25-52 (1978) Room 18 smokers Not given 50 min sample 500 Hoapital lobby 12 to 30 smokers Not given 50 min sample 37 2 train compartments 2 to 3 smokers Not given 50 min sample 36-50 Car 3 smokers Natural, open 50 min sample Natural, closed 50 min sample 1010 Cano et al. Submarines 157 cigarettes Yes 32 pg/m? (1970) 66m‘ per day 94-103 cigarettes Yes 15-35 g/m? per day _Harmsen and Train Not given Natural, closed 30-45 min 07.-3.1 ‘ Effenberger samples (1967) Hinds and First Train Not given Not given 2’, hr samples 49 Values not given (1975) Bus Not given Not given 2 hr samples 6.3 Values not given Bus waiting room Not given Not given 2, hr samples 1.0 Values not given Airline waiting room Not given Not given 2%, hr samples 3.1 Values not given Restaurant Not given Not given 2", hr samples 5.2 Values not given Cocktail lounge Not given Not given 2, hr samples 10.3 Values not given Student lounge Not given Not given 2‘, hr samples 28 Values not given Weber and Fischer 44 offices Varied Varied 140 x 3 hr 0.9 + 19 13.8 (peak) Values not given (1980 samples * Background levels have been subtracted. ‘Control values (unoccupied rooms) have been subtracted. OLE TABLE 2e.—Nitrogen oxides measured under realistic conditions Nonsmoking Levels controls (ppb) Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range Mean Range Fischer et al. Restaurant 50-80/470 m? Mechanical 27 x 30 min NO,: 76 59-105 63 (outdoors) (1978) and samples NO: 120 36-218 115 (outdoors) Weber et al. Restaurant 60-100/440 m? Natural 29 x 30 min NO,: 63 24-99 50 (outdoors) (1979) samples NO: 80 14-21 11 (utdoors) Bar 3040/50 m? Natural, 28 x 30 min NO, 21 1-61 48 (outdoors) open samples NO: 195 66-414 44 (outdoors) Cafeteria 80-150/574 m? 11 changes/hr 24 x 30 min NO,: 58 35-103 34 (outdoors) samples NO: 9 2-38 4 (outdoors) Other—non- NO,: 27 15-44 smokers room NO: 5 2-9 Weber and 44 offices Varied Varied 348-354 NO,: 24 + 22 115 (peak) Values not given Fischer samples (1980) NO: 32 + 60 280 (peak) Values not given "Control values (unoccupied rooms) have been subtracted. LLE TABLE 2f.—Nitrosamines measured under realistic conditions Levels (ng/L) Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range N-Nitrosdimethylamine Brunneman and Train bar car Not given Mechanical 90 min continuous 0.13 Hoffmann Train bar car Not given Natural 90 min continuous 0.11 (1978) Brunneman et al. (1977) Bar Not given Not given 3 hr continuous 0.24 Sports hall Not given Not given 3 hr continuous 0.09 Betting parlor Not given Not given 90 min continuous 0.05 Discotheque Not given Not given 2%, hr continuous 0.09 Bank Not given Not given 5 hr continuous 0.01 House Not given Not given 4 hr continuous < 0.005 House Not given Not given 4 hr continuous < 0.003 BLE TABLE 2g.—Particulates measured under realistic conditions Nonsmoking Occupancy Monitoring Levels (ug/m*) controls (ug/m*) Type of (active smokers conditions OTT ee Study premises per 100 m*) Ventilation (min) Mean Std. dev. Mean Std. dev. Repace and Cocktail party 0.75 Natural 15 351 + 38 24 Lowrey Lodge hall 1.26 Mechanical 50 697 + B 60' (1980) Bar and grill 1.78 Mechanical 18 589 + 28 63' Firehouse bingo 2.77 Mechanical 16 417 + 63 51' Pizzeria 2.94 Mechanical 32 414 + 58 40! Bar/cocktail lounge 3.24 Mechanical 26 334 + 120 50! Church bingo game 0.47 Mechanical 42 279 + 18 30 Inn 0.74 Mechanical 12 239 + #9 22" Bowling alley 1.53 Mechanical 20 202 + 19 491 Hoepital waiting room 2.15 Mechanical 12 187 + 52 58! Shopping plaza restaurant Sample 1 0.18 Mechanical 18 153 + 8 59! Sample 2 0.18 Mechanical 18 163 + 4 36! Barbeque restaurant 0.89 Mechanical 10 136 + 17 40' Sandwich restaurant A Smoking section 0.29 Mechanical 20 110 + % 40' Nonsmoking section 0 Mechanical 20 55 + 5 30 Fast-food restaurant 0.42 Mechanical 40 109 + 38 24! Sports arena 0.09? Mechanical 12 94 + 13 55! Neighborhood restaurant/bar 0.40 Mechanical 12 93 + 55! Hotel bar 0.59 Mechanical 12 93 + 2 30 Sandwich restaurant B Smoking section 0.13 Mechanical 8 8 + 7 55 Nonsmoking section 0 Mechanical 21 51 Roadside restaurant 1.12 Mechanical (9.5 ach *) 18 107¢ 30 Conference room 3.54 Mechanical (4.3 ach *) 6 19474 55 6LE TABLE 2g.—Continued Nonsmoking Occupancy Monitoring Levels (ug/m*) controls (ug/m *) Type of (active smokers conditions Study premises per 100 m*) Ventilation (min) Mean Std. dev. Mean Std. dev. Repace and Dinner theater 0.14 Mechanical 44 145 + 43 47 +10 Lowrey Reception hall 1.19 Mechanical 20 31 + 30 33? (1982) Bingo hall 0.93? Natural 2 1140 40! 0.93? Mechanical (1.39 ach?) 6 443° 40! ‘Sequential outdoor measurement (5 minute average). * Estimated. * Air changes per hour. * Equilibrium level as determined from concentration va. time curve. C3E TABLE 2g.—Continued Levels (yg/m*) Nonsmoking controls (yg/m°*) Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range Mean Range Cuddleback et al. Tavern Not given 6 changes/hr 4x 8hr 310 233-346 (1976) continuous Tavern Not given 1-2 changes/hr 8 hr continuous 986 U.S. Dept. of 18 military planes 165-219 people Mechanical 72 x 67 hr < 10-120 Transportation samples (197) 8 domestic planes 27-113 people Mechanical 2 x 1%-2"%, hr Not given samples Dockery and Residences Not given Varied 24 hr samples 32 Spengler (198D) Elliott and Arena 1 11,806 people Mechanical During activities 323 42 (nonactivity day) Rowe Arena 2 2,000 people Natural During activities 620 92 (nonactivity day) (1975) Arena 3 (smoking 11,000 people Mechanical During activities 148 71 (nonactivity day) prohibited) Harmsen and Trains 15-120 people Natural Not given 46-440 Effenberger particles/em* (1957) Nonsmokers’ cars 20-75 particles/cm* Just et al. 4 coffee houses Not given Not given 6 hr averages 1150 500-1900 570 (outdoors) 100-1900 (1972) Neal et al. Hospital unit Not given Mechanical 48 hr samples 21 + 14 3-58 73 + 25 (1978) Hospital unit Not given Mechanical 48 hr samples 40 + 21 13-79 72 + 25 T8€ TABLE 2g.—Continued Levels (ug/m?) Nonsmoking controls (ug/m*) Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range Mean Range Spengler et al. Residences 2+ smokers Natural 24 hr samples 70 + 43 21 + 12 (outdoors) (1981) 1 smoker Natural 24 hr samples 37 + 15 21 + 12 (outdoors) Weber and 44 offices Varied Natural and 429 x 2 min 133 + 130! 962' (peak) Fischer (1981) mechanical samples Quant et al. Office No. 1 0.62? Mechanical Five 10 hr workday 45 39.54 5-15 (1982) Office No. 2 0.68? Mechanical averages; continuous 45 37-50 15-20 Office No. 3 1.46? Mechanical monitoring 68 42-89 15--20 Brunekreef and 26 houses 1-3 smokers Natural 2 mo averages 153* 60-340 55 20-90 Boleij (1982) ‘Values above background. * Habitual smokers per 100 m *. * Weighted mean G8E TABLE 2h.—Residuals measured under realistic conditions Nonsmoking Levels controls Type of Monitoring Study premises Occupancy Ventilation conditions Mean Range Mean Range Acetone (mg/m'*) Badre et al. 6 cafes Varied Not given 100 mL samples 0.91-5.88 (1978 Room 18 smokers Not given 100 mL samples 0.51 Hospital lobby 12 to 30 smokers Not given 100 mL samples 1.16 2 train 2 or 3 smokers Not given 100 mL samples 0.36-0.75 compartments Car 3 smokers Natural, open 100 mL samples 0.32 Car 2 smokers Natural, closed 100 mL samples 1.20 Sulfates (ug/m*) Dockery and Residences Not given Varied 24 hr samples 481 Spengler (1981) Sulfur dioxide (ppb) Fischer et al. Restaurant 50-80/470 m* Mechanical 27 x 30 min samples 20 9-32 12 ppb (1978) Restaurant 60-100/440 m’ Natural 29 x 30 min samples 13 5-18 6 Bar 30-40/50 m* Natural, open 28 x 30 min samples 30 13-75 8 Cafeteria 80-150/574 m* 11 ch/hr 24 xX 30 min samples 15 1-27 12 Other nonsmokers’ 7 3-13 room Just et al. 4 coffee houses Not given Not given 6 hr continuous 12.0-15.3 (1972) « See original paper for nine other residuals. is also readily available. CO reflects the gas phase components of smoke and thus may not reflect the levels of particulate phase constituents. There are also a number of other CO sources in addition to cigarettes, both in the external environment (e.g., automobiles) and in the indoor environment (e.g., gas stoves). As a result, even the subtraction of external atmospheric levels may not entirely eliminate the contribution of other sources of CO to the indoor environment. Given these problems, use of several of these measures, or the tailoring of the measurement to the phenomenon being measured, seems appropriate. The measurement of total particulate matter may be a reasonable indicator of exposure to the particulate phase of smoke, once the measurement is limited to respirable particulates and once background levels with the same level of activity, but without smoke, are subtracted. Relatively precise methods have been developed to predict the levels of exposure to carbon monoxide (Jones and Fagan 1975; Coburn et al. 1965) and total particulate matter (Repace and Lowrey 1980) that would be expected in rooms of different size and ventilation with different rates of smoking. Stewart et al. (1974), using blood donors, found the median blood carboxyhemoglobin level for smokers and nonsmokers in selected populations to be 5.0 and 1.2 percent, respectively. This corresponds to a steady state ambient CO level of 7 ppm, which represents a combination of atmospheric pollution from cigarette smoke and the background level of urban pollution and is consistent with the levels described in Table 2. Exposure levels to carbon monoxide are highly dependent on ventilation, occupancy, smoking rates, and background levels in the ambient air. The half life of carboxyhemoglobin is approximately 4 hours, making blood carboxyhemoglobin a useful biologic monitor of acute exposure to passive smoking, but one that does not provide useful data for chronic exposure. Assessment of chronic exposure with a biologic marker requires the ability to measure some accumulating product of smoke. To date, substances such as cotinine (Matsukura et al. 1979; Langone et al. 1973; Williams et al. 1979; Feyerabend and Russell 1980; Russell et al. 1982), thiocyanate (Bottoms et al. 1982; Cohen and Bartsch 1980), and polonium-210 (Radford and Hunt 1964; Little and McGendy 1966) have been measured in active smokers. Plasma and urinary nicotine, plasma and urinary cotinine, and salivary nicotine and cotinine have been reported in nonsmokers exposed to tobacco smoke (Jarvis and Russell 1984; Russell and Feyerabend 1975; Feyerbend et al. 1982). Of these measures, it would appear that urinary cotinine offers the most promise as an index of exposure. However, there are no published data using these measures as biologic markers of chronic involuntary smoke exposure. 383 In contrast to physiologic investigations, epidemiologic studies have used the number of smokers in the home or in the working environment as the principal exposure variable. These relatively crude indices, in general, ignore time spent with the smoker and the environmental factors known to influence ambient smoke concentra- tion noted above. In summary, involuntary smoking research deals with an expo- sure that is qualitatively and quantitatively different from that of active smoking. Adequate characterization of passive exposure in both epidemiologic and physiologic studies is substantially more difficult for involuntary exposure than for active smoking exposure. While the active smoker’s total current cigarette consumption is relatively easily quantitated, the lower dose and greater influence of - ventilation and ambient environment for involuntary smoke expo- sure makes assessment of exposure one of the most important methodologic issues of this research. Clearly, a biologic marker of chronic exposure that reflects the amount of tobacco smoke to which nonsmoking persons are exposed would be a useful tool. In addition, carefully formulated questionnaires quantifying passive smoking are also necessary, and may prove equally valid for assessing exposure. No single index has yet been accepted by all investigators, and comparison between studies remains difficult. However, Repace and Lowrey (1983) have estimated that the nonsmoking population may | be exposed to from 0 to 14 mg of tar per day, with an average expo- sure of 1.43 mg per day. Acute Physiologic Response of the Airway to Smoke in the Environment Relatively little acute exposure data exist concerning the effects of passive inhalation of cigarette smoke on pulmonary function (Table 3). The data that are available have been obtained in exposure - chambers under carefully monitored and controlled circumstances - (Pimm et al. 1978; Shephard et al. 1979; Dahms et al. 1981). Pimm and colleagues (1978) exposed nonsmoking adults to smoke in an exposure chamber. Relatively constant levels of carbon monoxide (approximately 24 parts per million) were achieved in the chamber during involuntary smoking. Peak blood carboxyhemoglo- bin levels were always less than 1 percent in subjects before smoke exposure, but were significantly greater during the study exposure. Lung volumes, flow volume curves, and heart rate were measured for all subjects. Measurements were made at rest and following exercise under control conditions and smoke-exposure conditions. Flow at 25 percent of the vital capacity decreased significantly with smoke exposure at rest in men and with exercise in women. The magnitude of the change was small: a 7 percent decrease in flow in 384 G8E TABLE 3. —Acute effects on pulmonary function of passive exposure to cigarette smoke Study Type of exposure Magnitude of exposure Effects Comments Pimm et al. Chamber 14.6 m? with Peak [CO] ~ 24 ppm; Men: 5% increase FRC, Nonsmokers, average age of (1978) sparse furniture; smoking particulates >4 mg/m? 11% increase RV, 4% men = 22.7, women = 21.9; machine in room decrease Vnax25 during sham exposure as control exercise Women: 7% decrease V maxzs post exercise; no effects on VC, TLC, FVC, FEV,, maxi0) Shepard et al. As above Low exposure: peak [CO] ~ Low exposure: 3% decrease Nonsmokers; average age of (1979) 20 ppm, particulates ~ FEV,, 4% decrease Vioasso, men = 23, women = 25; mg/m*; high exposure: (CO] 5% decrease Viexs with sham exposure as control; ~ 31 ppm exercise; no increased effect subjects estimated to have with high exposure inhaled ~ 1/2 cigarette/2 hours Dahms et al. Chamber 30 m'; climate Room levels not measured: 0.9% increase in FVC, 10 nonsmckers; age range (1981) controlled estimated at peak (CO] ~ 5.2% increase in FEV,, 24-53 years; not blinded: no 20 ppm 2.2% increase in FEF 25-75 at 1 hour sham exposure men and 14 percent in women. No other consistent changes in lung function were observed. Shepard and coworkers (1979) utilized a similar crossover design in a chamber of exactly the same size as Pimm’s. Their results were almost identical, with a small (3 to 4 percent) decrease in FVC, FEV, Vmaxso, and Vmax. They concluded that these changes were of the magnitude anticipated from an exposure of less than 1/2 cigarette in 2 hours (the exposure anticipated for a passive smoker). Dahms et al. (1981) used a slightly larger chamber with an estimated peak CO level of approximately 20 parts per million. They found no change in FVC, FEV, or FEF2s5-75 after 1 hour of exposure in normal subjects. This experiment was not blinded and had no sham exposure. The data from these studies suggest that involuntary smoke exposure can probably produce measurable, albeit small, changes in the airways of normal individuals. This response is consistent with the acute response to the inhalation of cigarette smoke by the active - smoker, and it is not surprising that high dose involuntary exposure to tobacco smoke might produce similar results. The magnitude of these changes is small, even at moderate to high exposure levels, and - it is unlikely that this change in airflow per se results in symptoms, however, it may be only one manifestation of a broader irritant - response to smoke in nonsmokers. Symptomatic Responses to Chronic Passive Cigarette Smoke Exposure in Healthy Subjects Eye irritation is the most common complaint experienced by - normal people acutely exposed to cigarette smoke. In one study, 69 percent of subjects reported ever experiencing this symptom (Speer 1968). Headache, nasal irritation, and cough were reported by approximately one-third of the subjects in this and other investiga- tions (Weber and Hertz 1976; Slavin and Hertz 1975). Several factors - may alter the prevalence of irritant symptoms, including the amount of smoking, the size of the area involved, the humidity and temperature of ambient air, and the extent of ventilation (Johansson 1976). No longitudinal studies of these irritant effects (e.g., develop- ment of increased sensitivity or tolerance) have been reported. Weber (1984) has examined the effect of dose and duration of exposure to environmental tobacco smoke on subjective reporting of eye irritation and objective measurement of eye blink rate. Figure 1 reveals that both eye irritation and blink rate increase with increasing dose of smoke exposure, and that substantial subjective irritation and objective increase in blink rate occur at levels of smoke exposure (CO levels of 20 to 24 ppm) equivalent to those used to evaluate pulmonary function changes in response to environmen- 386 eye Irritation eye blink rate/min very strong 5 7— eye irritation index r 80 leseseeee eye biink rate - strong a> 60 medium 304 - 40 weak 27 - 20 none tT Ff T T T T , 0 QO 10 2c min FOU q tT q q co 1 11 22 32 42 43 ppm ct q qt q T 4 NO 0.08 0.42 0.77 1.11 1.45 1.50 ppm t q T } T q HCHO 0.03 0.18 0.32 0.47 0.62 0.64 ppm i q q i qT J acrolein 0 0.05 0.11 0.16 0.20 0.20 ppm rT number of cig. 0 10 20 FIGURE 1.—-Mean subjective eye irritation, mean eye blink rate, and concentrations of some pollutants during continuous smoke production in an unventilated climatic chamber NOTE: Thirty-three subjects; ventilation rate 0.01 h'; eye irritation index calculated from the answers to four questions concerning eye irritation; 0 min = measurement before smoke production. SOURCE: Weber (1984). tal tobacco smoke exposure. Both irritation and blink rate increase with duration of exposure to environmental tobacco smoke (Figures 2 and 3). After 60 minutes of exposure, distinct changes are evident in level of irritation with a smoke exposure of 1.3 ppm CO, and the blink rate increased with smoke exposures as low as 2.5 ppm CO. These levels of smoke exposure (1.3 to 2.5 ppm CO) are well within those measured under realistic conditions (see Table 1). Therefore, it is possible to demonstrate an objective irritant response in normal subjects at levels of smoke exposure substantially lower than the levels where an airway response (also presumably an irritant response) has been demonstrated. Whether this difference represents a difference in threshold for irritation in the eye and airway or a limitation in the ability to measure subtle changes in the airway is uncertain. 387 eye irritation index 35 fo 10 ppm Lf ue 5 ppm 2- foe ¢ 2.5 ppm {fv / 7 / _.--7 1.3 ppm peneeriscnneamenecananents control 7 ES T T T T 1 0 20 40 60 exposure min FIGURE 2.—Subjective eye irritation due to environmenta tobacco smoke, related to smoke concentratio and duration of exposure NOTE: CO values are levels during smoke production minus background level before smoke production; 32 t subjects; 0 min = measurements before smoke production. SOURCE: Weber (1984). Chronic respiratory symptoms have been reported most common in children. Studies from several different countries (Table 4) ha shown a positive relationship between parental cigarette smoki:; and the reporting of the symptoms of chronic cough, chronic phlegi and persistent wheeze (Colley et al. 1974; Bland et al. 1978; Lebow: and Burrows 1976; Weiss et al. 1980; Ware et al. 1984; Schilling et : 1977; Kasuga et al. 1979; Schenker et al. 1983). Some of these studi may be confounded by an increased reporting of symptoms in t child by parents who smoke and have symptoms (Colley et al. 19” Bland et al. 1978; Kasuga et al. 1979) or by the child’s own smoki habits (Colley et al. 1974; Bland et al. 1978; Kasuga et al. 1979). N all studies show statistical significance for all symptoms (Lebow and Burrows 1976; Schilling et al. 1977; Schenker et al. 198 However, a consistent finding in all reported data is an increase symptoms with an increased number of smoking parents in t 388 eye blink rate/min 40- 35-4 aT“ _7 10 ppm / \2 / 30-7 J / a wot 5 ppm 25 / Yo ~~ — le v7 7 / 2.5 ppm 20- - 1.3 ppm vat geceteteceveeeeneeeese control way Oe 4 ot i T T T T tT 0 20 40 60 exposure min FIGURE 3.—Effects of environmental tobacco smoke on eye blink rate NOTE: CO values are levels during smoke production minus background level before smoke production: 32 to 43 subjects; 0 min = measurements before smoke production. SOURCE: Weber (1984). home. This effect persists after controlling for parental cough and is most marked in the first year of life. British researchers, studying a birth cohort, demonstrated an increased incidence of wheezing over a 5-year period among nonasth- matic children who had two parents who smoked. However, when examined by logistic regression, parental smoking was not a significant predictor of occurrence of wheeze or the future occur- rence of asthma (Bland et al. 1978). Ina subgroup of the cohort—861 children of asymptomatic parents, Leeder and colleagues (1976a) found no significant trend in asthma—wheeze symptoms with in- creasing levels of parental smoking over a 5-year period. In a study of 650 children aged 5 to 10 years (Weiss et al. 1980), a significant trend in the reported prevalence of chronic wheezing with current parental smoking was found; the rates were 1.85 percent, 6.85 percent, and 11.8 percent for zero, one smoking parent, and two smoking parents, respectively. Although the data given are for all 389 O6E TABLE 4. —Respiratory symptoms in children in relation to involuntary smoke exposure Rates per 100 by Respiratory number of smoking parents Study Subjects symptoms or illness 0 1 2 Comment Colley et al. 2,426 children, aged 6-14, Chronic cough assessed by 156 17.7 222 Trend significant; possible that (1974) England questionnaire completed by symptoms in parents could result parent in reporting bias; active smoking in children could also bias results; bias unlikely to explain full effect of trend Bland et al. 3,105 children, aged 12-13, who Cough during day or at night 164 190 235 Self-reported symptoms and (1978) did not admit to ever smoking smoking history collected cigarettes, England Morning cough 15 2.8 2.9 simultaneously from children; difference between morning and daytime cough suggested as different diseases, but could be difference in exposure, in that exposure more likely in daytime than when asleep Weiss et al. 650 children, aged 5-9, United Chronic cough and phlegm 17 27 3.4 Trend not significant (1980) States Persistent wheeze 18 68 118 Trend significant Ware et al. 8,528 children, aged 5-9, with Chronic cough 17 84 106 Adjusted for age, sex, and city (1984) two parents of known smoking cohort effects; significant trends status, six U.S. cities Persistent wheeze 99 110 131 166 TABLE 4.—Continued Rates per 100 by Respiratory number of smoking parents Study Subjects symptoms or illness 0 1 2 Comment Dodge 628 children, grades 3-4, in Wheeze 276 279 40.0 All trends significant; some of (1982) two-parent households; effect might relate to parental questionnaire response of Phlegm 64 109 120 symptoms, but not likely to parents, United States influence trends Cough 146 230 278 Schenker et al. 4,071 children, aged 5-14, in Chronic cough 6.3 70 8.3 None of these rates significant; (1983) western Pennsylvania data not adjusted for parental Chronic phlegm 4.1 48 4.0 symptoms Persistent wheeze 7.2 V4 5.4 Never Parent smoking smoking Lebowitz and 1,252 children, <16 years Persistent cough 3.7 7.2 Higher rates in symptomatic Burrows old, United States households with trends persisting, (1976) Persistent phlegm 10 12.8 but not significant for asymptomatic households Wheeze 23.4 24.1 Schilling et al. 816 children, age 7+, United Cough, phlegm, wheeze No significant Specific data not provided (1977) States effect Kasuga et al. 1,937 children, aged 6-11, Wheeze, asthma Increased prevalence in families Data adjusted for distance of (1979) Japan with a heavy smoker (>21 home from main traffic, highway cig/day); leas clear effect in family with a light smoker (< 21 cig/day) households, when the analysis was restricted to those households where neither parent reported symptoms, the results were identical, suggesting that in this population, significant reporting bias was not responsible for the observed results. Lebowitz and Burrows (1976), in a group of 463 current-smoking and never-smoking households with children below age 15, found trends—but no statistically significant differences—for a variety of symptoms, including wheeze most days, in households with smokers. In the same study, among 849 house- - holds with older children and adults, there were no significant differences for any symptom prevalence between current-smoking and never-smoking household members. In a general population study, Schilling et al. (1977) reported no association between wheeze and involuntary smoking. A preliminary report from one of the largest studies currently under way (Speizer et al. 1980) indicated no association of persistent wheeze with the presence of smoking in the household for approxi- mately 8,000 children aged 6 to 11 in six communities. However, subsequent analyses of these same cohorts with the addition of approximately 2,000 more children and a more detailed assessment of the smoking behavior of each parent revealed a positive relation- ship that increased with the amount of maternal smoking and was only modestly affected by taking into account the parents’ own - symptoms (Ware et al. 1984). Dodge (1982), studying third and fourth grade children, found that symptoms, including wheeze, were related to both the presence of symptoms in the parents and the number of smokers in the household. The gradient of the wheeze effect persisted even after excluding the potential effect of reporting bias by symptomatic parents. Few data are available on the level of exposure necessary to produce symptoms or on the implication of these symptoms for future lung growth and development. No data are currently available on the relationship of passive smoking to other putative risk factors for wheezing such as atopy, respiratory infection, and increased levels of airways responsiveness, nor are sufficient data available to estimate whether these early exposures affect the occurrence of respiratory disease later in life. The characteristics of the child who may be susceptible to this type of exposure are unknown. However, the data are sufficiently consistent to suggest that pediatricians should routinely inquire about smoking habits of parents when caring for children with chronic or recurrent respiratory symptoms and illnesses. It would also be prudent to advise parents of children who are suffering from recurrent respira- tory illnesses or persistent wheeze or asthma not to smoke. 392 Respiratory Infections in Children of Smoking Parents Bronchitis and pneumonia and other lower respiratory illnesses are significantly more common in the first year of life in children who have one or two smoking parents (Table 5). Bonham and Wilson (1981) showed that in 1970 the majority of homes with children under 17 years of age had at least one smoker. Thus, passive smoking by children, even in early childhood, is widespread. Harlap and Davies (1974) studied 10,672 births in Israel between 1965 and 1968 and observed that infants whose mothers said they smoked (as determined at a prenatal visit) experienced a 27.5 percent greater hospital admission rate for pneumonia and bronchitis than children of nonsmoking mothers. In addition, they demonstrated a dose— response relationship between the amount of maternal smoking and the number of hospital admissions for these conditions. It should be noted that the mothers were reporting prenatal smoking and not postnatal smoking for the first year of life. British investigators studying live births between 1963 and 1965 in London also observed an increased frequency of bronchitis and pneumonia in the first year of life associated with involuntary smoking that did not carry over to years 2 to 5 (Colley et al. 1974). This effect was independent of parents’ own symptoms and increased with the amount of smoking by parents. Bronchitis and pneumonia also increased with an increased number of siblings, and this was not controlled in the analysis. Fergusson et al. (1981), studied 1,265 New Zealand children from birth to age 3. They demonstrated an increase in both bronchitis and pneumonia and lower respiratory illness during the first 2 years of life in children whose mothers smoked. Corrections for maternal age, family size, and socioeconomic status did not affect the linear relationship between the degree of maternal smoking and the rate of respiratory illness. This effect declined with the increasing age of the child. Leeder and colleagues (1976b) studied a British cohort of children born between 1963 and 1965 and demonstrated that parental cigarette smoking was associated significantly with bronchitis and pneumonia during the first year of life. A dose-response association persisted after correction for parental respiratory symptoms, sex of the child, number of siblings, and a history of respiratory illness in the siblings. Pullan and Hey (1982) studied children who were hospitalized with documented respiratory syncytial virus (RSV) infection in infancy. They found a significant difference in the smoking habits of mothers at the time of the infection, compared with children hospitalized for other illnesses—including respiratory diseases for which RSV infec- tion was not documented. These children reported an excess occurrence of wheeze and asthma and had lower levels of pulmonary 393 “~AB8N-144 0 - R25 - 14 PEE TABLE 5.—Early childhood respiratory illness and involuntary cigarette smoking Study Subjects Findings Illness rates per 100 Comments By cigarettes per day 0 1-10 11-20 -H+ Harlap and 10,672 births, 1965-1968, Hospitalized for 9.5 10.8 16.2 31.7 Smoking history obtained Davies West Jerusalem, Israel bronchitis/pneumonia in first antenatally; maternal smoking (1974) year of life only RR'=1.38 Colley? 2,205 births, 1963-1965, Questionnaire on 76 4 itd 182 = Asymptomatic parents (1974) London, England bronchitis/pneumonia in firet 10.3 15.1 14.5 23.2 = Symptomatic parents year of life Neither controlied for number RR=1.73 for one parent smoker of siblings or sex of smokers RR=2.60 for two parent smokers Fergusson et al. 1,265 births, 4 months, Questionnaires on doctor or 7.0 12.8 13.4 Maternal Combined effect significant for (1981) 1977, Christchurch, New hospital visits for only maternal smoking in first year Zealand bronchitis/pneumonia; check 70 46 88 Paternal of life only by hogpital records only Assessment at 4 months, 1, 2, and 3 years RR=2.04 if mother smoked By number of smoking parents 0 1 2 Ware et al. 8,528 children, aged 5-9, Respiratory illness in last year 12.9 13.7 14.8 Adjusted for age, sex, and city (1984) with two parents of known cohort effect; significant trends smoking status, six U.S. cities S6E TABLE 5.—Continued Study Subjects Findings Illness rates per 100 Comments Said et al. 3,920 children, aged 10-20, Tonsillectomy and/or 28.2 414 50.9 Self-reporting by children; not (1978) France adenoidectomy, generally clear that smoking habits of before age 5, as indicator of parents at time of reporting frequent respiratory tract directly related to exposure infection approximately 10+ years earlier Schenker et al. 4,071 children, aged 5-14, Chest illness before age 2 6.7 79 11.5 Trends for both significant (1983) western Pennsylvania Chest illness >3 days in past 88 118 13.6 year Cameron et al. 158 children, aged 6-9, Respiratory illness with 1.33 74 Illness reporting not verified; (1969) parents completed telephone restricted activity and/or not clear how reporting adult questionnaire, United States medical consultation in last was related to child year Leeder et al. 2,149 infants, born 1963- RR ~ 2.0 for infants with two Not provided Parents answered for children, (1976a, b) 1965, Harrow, England smoking parents but response bias seems unlikely because effects were observed for infants of asymptomatic parents; effects of maternal vs. paternal smoking not investigated Sims et al. 35 children hospitalized Borderline significant increase Not provided No significant effect for (1978) with RSV bronchiolitis, in maternal smoking during paternal smoking, average 35 controls, England first year of life RR=2.65 amount smoked greater for parents of cases than for controls 968 TABLE 5.—Continued Study Subjects Findings Tliness rates per 100 Comments Rantakallio 1,821 children of smoking Significant increase in Not provided Prospective followup of doctor (1978) mothers, hospitalization for respiratory visits, hospitalizations, deaths 1,823 children of illness during first 5 years of up to age 5; only maternal nonsmoking mothers life smoking evaluated RR=1.74 Pullan and Hey 130 children admitted to Significant effect of maternal Not provided (1982) hospital during first year of (RR=1.96) and paternal life with RSV infection, 111 nonhospitalized controls (RR=1.53) smoking at time of study; significant maternal effect of smoking during first year of life (RR=1.55) ’ Relative risk for children of smoking mothers versus children of king mothers * These data are considered in a more expanded analysis provided by Leeder et al. (1976). Jeulated from published data provided by J.M. Samet, M.D. function that persisted to age 10. The authors could not distinguish between the possibilities that infection caused damage that persisted and affected the maturation of the lung or that these children were already more susceptible to severe RSV infection. Greenberg et al. (1984) examined the tobacco smoke exposure of infants in the first year of life by measuring urinary cotinine-to-creatinine ratios. They found that infants of mothers who smoked had a ratio of 351 ng per mg, as contrasted with a ratio of 4 ng per mg in infants of mothers who did not smoke. Breast-fed infants were excluded because of the presence of nicotine in the breast milk of mothers who smoke. A dose-response relationship was present between the cotinine-to- creatinine ratio and the reported level of maternal smoking in the previous 24 hours. This study suggests that infants of mothers who smoke absorb measurable amounts of the smoke from this environ- mental exposure. Rantakallio (1978) studied over 3,600 children for 5 years, half of whom had mothers who smoked and half of whom did not. Children of mothers who smoked had a 70 percent greater chance of being hospitalized for a respiratory illness than children of nonsmoking mothers. Some of these studies may be confounded by the increased reporting of symptoms in the child by parents who smoke and have symptoms (Cameron et al. 1969: Said et al. 1978; Leeder et al. 1976b), but in those studies in which parental symptoms were controlled, the effects persisted. Other studies may be influenced by the child’s own smoking habits (Said et al. 1978), although the majority of research examined children in an age range in which smoking would be unlikely. In summary, several studies Suggest important increases in severe respiratory illnesses, particularly in the very young (less than 2 years old) children of smoking parents. Young children may repre- sent a more susceptible population for adverse effects of involuntary smoking than older children and adults. The amount of time spent with active smokers, particularly by children under 2 years of age with smoking mothers, may be an important factor. How in utero exposure influences this risk is unknown. Pulmonary Function in Children of Smoking Parents In recent years, a number of studies have examined the relation- ship of parental cigarette smoking to pulmonary function in children (Table 6). The majority of these studies have been cross sectional (Tager et al. 1979; Weiss et al. 1980; Vedal et al., in press; Burchfiel et al., 1983; Tashkin et al. 1983; Hasselblad et al. 1981: Ware et al. 1984) and have demonstrated decreases in level of pulmonary function (FEVo75, FEV), FEF»2.75, and flows at low lung volumes) in 397 children of smoking mothers compared with children of nonsmoking mothers. In some studies, there seems to be a dose-response relationship (Tager et al. 1979; Weiss et al. 1980); i.e., the greater the number of smokers in the home, the lower the level of function. When analyzed by multiple regression techniques, maternal smoking has the greatest impact (as would be expected from the greater contact time with the child), and a dose-response relationship with the amount smoked seems to exist (Weiss et al. 1980; Tager et al. 1979; Ware et al. 1984; Vedal et al., in press). Younger children seem to be more adversely affected than older children (Tager et al. 1979; Weiss et al. 1980), and clearly there is an added effect in older children if they themselves smoke (Tager et al. 1979). Tager and colleagues (1983) followed 1,156 children for 7 years to determine the effect of maternal smoking on growth of pulmonary function in children. After correcting for previous level of FEV:, age, height, personal cigarette smoking, and correlation between moth- er’s and child’s pulmonary function, maternal smoking was associ- ated with a reduced rate of annual increase in FEV: and FEF 2-75. The magnitude of the effect was consistent with a 3 to 5 percent decrease in expected lung growth due to the maternal smoking effect, constant over the time period of the study. Because so few mothers changed their smoking habits, the study did not attempt to differen- tiate between postnatal and in utero effects of involuntary smoke exposure. Ware et al. (1984) followed 10,106 white children for two successive annual examinations. The FEV, was 0.6 percent lower in the children of smoking mothers at the first examination and 0.9 percent lower at the second examination. These differences were statistically significant, but represent very small absolute differences. In this study, and in the other studies that show smal] changes in pulmonary function, it is not clear whether these changes represent small changes occurring uniformly among the children of smoking mothers or somewhat larger changes occurring in a small subpopula- tion of susceptible children. The available data demonstrate that maternal smoking affects lung function in young children. However, the absolute magnitude of the difference in lung function is small; it is unlikely that this small difference, per se, is of functional significance. The concern generat- ed by the demonstration of even small differences is directed at the future lung function of those children, particularly if they become active cigarette smokers as adults. The possibility that this differ- ence in lung function may result from pathophysiologic mechanisms similar to those present in active smokers raises the concern that these children may be “sensitized” to smoke at an early age, and that this “sensitization” may result in a more rapid decline in lung 398 66E TABLE 6.—Pulmonary function in children exposed to involuntary smoking Study Subjects Pulmonary function measure Outcome Comments Schilling et al. (1977) Tager et al. (1979) Weise et al. (1980) Vedal et al. (in press) Lebowitz and Burrows (1976) 816 children, aged 7-17, Connecticut and South Carolina 444 children, aged 5-19, East Boston, Massachusetts 650 children, aged 5-9, East Boston, Massachusetts 4,000 children, aged 6-13 271 households with complete histories of parents’ smoking and of pulmonary function of children > age 6, Tucson, Arizona FEV, as percent predicted MMEF in standard deviation unite MMEF in standard deviation units FEV25, FVC, Vinasso, Vmmax75, Vrnaxo0 FEV,, FVC, Vinexs0, Vmax75 derived from MEF, V curves, expressed as standard deviation units No effect of parental smoking Significant effect of parental smoking Significant effect of parental smoking FVC positively associated, flows negatively associated No effect of parental smoking No control for sibehip size or correlation of siblings’ pulmonary function; when analysis restricted to children who never smoked, Vmexso significantly less in children with smoking mothers Analysis controlled for sibehip size and correlation of siblings’ pulmonary function Analysis controlled for sibship size and correlation of siblings’ pulmonary function Flows dose-response with amount smoked by mother Suggestion that real differences in indoor levels of exposure compared with more northerly climates may be occurring OOF TABLE 6.—Continued Study Subjects Pulmonary function measure Outcome Comments Dodge (1982) 558 children, aged 8-10, Arizona FEV, by age change FEV,/H* per year No effect of parental smoking Potential bias in participation rates; cross-sectional data not controlled for children’s height; annual change in FEV,/H®* at ages 8, 9, and 11 consistently greater in nonsmoking households than in two-parent smoking households; statistical test not significant, however Tager et al. (19839) Burchfiel et al. (1983) Tashkin et al. (1983) Hasselblad et al. (198) 1,156 children, aged 5-19 at initial survey, East Boston, Massachusetts 4,378 children, aged 0-19, Tecumseh, Michigan 1,070 nonsmoking, nonasthmatic children, Los Angeles 16,689 children, aged 5-17, seven geographic regions, United States FEV,, FEF 25-75 FVC, FEV,, Vmaxso Vraax, Vmax75, Vmax2s, FEF 25-75 FEV7s as percent predicted Significant decreased rate of growth in FEV, and FEF2s5-75 for children of smoking mothers Decreased FEV, and FVC for boys and Vwuazso for girls with increased number of smoking parents Decreased Vinex, Vmax2s for boys and FEF275, Vinas7s for girls with at least a smoking mother Significant effect of maternal smoking, but not paternal smoking 1-year followup; no effect of paternal smoking; maximum effect of maternal smoking on fully developed lung not more than 4 or 5 percent Abetract; no distinction between effects of maternal and paternal smoking; effects most prominent for boys and youngest age groups No effect of paternal smoking Large number of children excluded because of invalid pulmonary function data or missing parental smoking data TOV TABLE 6.—Continued Study Subjects Pulmonary function messure Outcome Comments Speizer et al. 8,120 children, aged 6-10, FVC and FEV, as percent No effect for FEV, or FVC Recent analysis of this cohort (1980) in six US. cities predicted demonstrated an effect for FVC and FEV, Ware et al. 10,000 children, aged 6-11, FEV, and FVC FVC positively associated with FEV, dose-response with (1984) in six US. cities smoking, FEV, negatively associated amount smoked by mother function as adults, particularly if they become smoking adults. NO data are currently available to establish the role, if any, of the small physiologic changes in children on the development of adult obstruc- tive lung disease. Pulmonary Function in Adults Exposed to involuntary Cigarette Smoke White and Froeb (1980) reported on 2,100 asymptomatic adults drawn from a population about to enter a physical fitness program. They demonstrated statistically significant decreases in FEV: and MMEF as a percent of predicted in nonsmokers exposed to tobacco smoke in the work environment compared with nonexposed workers. The decrement was comparable to that seen in smokers inhaling 1 to 10 cigarettes per day. However, the absolute magnitude of the difference in mean levels of function in the smoke-exposed and unexposed groups was quite small: 160 ml (5.5 percent) for FEV: and 465 ml/sec (13.5 percent) for MMEF. Carbon monoxide levels were measured in the workplace and ranged from 3.1 to 25.8 ppm. The population was self-selected, response was related to current work- place exposure and did not account for people who changed jobs, and it is unclear how the ex-smokers in the population were handled in the analysis. Comstock et al. (1981) examined 1,724 subjects drawn from two separate studies in Washington County, Maryland. They found no statistically significant greater risk of having an FEV: less than 80 percent of predicted in male nonsmokers exposed to wives’ cigarette smoke at home. Schilling et al, (1977) did not find an effect of passive smoking exposure in adults. Both of these studies included adults in their samples who were relatively young and generally would not have had a long-term passive exposure in adult life. This point was brought out by a recently reported large study from France. Kauffmann et al. (1983) reported on a seven-city investigation in which a total of 7,818 adults were studied. In a subsample of 1,985 nonsmoking women aged 25 to 29, in which 58 percent were exposed to smoking husbands, there was a significant difference in level of MMEF between truly nonsmoking women and women of comparable ages exposed to passive smoking. This effect did not become apparent until age 40. These changes were small, and although not adjusted for differences in body size, may suggest a possible effect of long-term exposure in adult life. The physiologic and clinical significance of these small changes in pulmonary function in adults remains to be determined. In addition, variables such as ventilation, room size, number of rooms in the home, duration of contact with the active smoker, and number of cigarettes smoked could significantly influence total exposure and 402 need to be explored more fully. Differences in these exposure variables and the characterization of exposure may explain some of the differences in these study results (Table 7). The Effect of Passive Smoke Exposure on People With Allergies, Asthma, and COLD There are very limited data on the effects of passive smoke exposure in patients with preexisting pulmonary disease, and the available data are conflicting. Clinical studies have suggested a relationship between respiratory symptoms in asthmatics and expo- sure to parental cigarette smoke, but methodologic problems compli- cate the interpretation of the limited available data. O’Connel! and Logan (1974) identified 37 asthmatic children who were “bothered” by parental cigarette smoke. Parents of 20 of the children stopped smoking and 18 (90 percent) of the 20 children had an improvement in symptoms. The control group consisted of 15 children (2 were not followed up) whose parents did not stop smoking. Only 4 (27 percent) of the children in the control group improved. The self-selection of those parents who quit, subjective criteria for improvement, and an unclear duration of followup limit the interpretation of this data. Gortmaker and coworkers (1982) studied two populations of children aged newborn to 17 years. They found a significant association between parental reporting of chil- dren’s asthma and maternal smoking. Maternal smoking alone was associated with approximately 20 percent of all asthma. The effect persisted when age and sex of the child, allergies, and family income and education were controlled in the analysis. No control was attempted for the children’s own smoking habits or for increased reporting of symptoms in children of symptomatic parents. Other population-based studies (Lebowitz and Burrows 1976; Speizer et al. 1980; Schilling et al. 1977) have not shown such results. Dahms et al. (1981) studied 10 patients with bronchial asthma and 10 normal subjects passively exposed to smoke in an environmental chamber. Pulmonary function was measured at 15-minute intervals for 1 hour after smoke exposure. Blood carboxyhemoglobin levels were measured before and after the 1-hour exposure. Carboxyhemo- globin levels in subjects with asthma increased from 0.82 to 1.20 percent. In normal subjects the increase was from 0.62 to 1.05 percent. The increases in carboxyhemoglobin in the two study groups were not significantly different. Asthmatic subjects had a decrease in forced vital capacity (FVC), forced expiratory volume in 1 second (FEV:),and maximum mid expiratory flow rate (MMEF) to a level significantly different from their preexposure values. The decreases in asthmatic subjects were present at 15 minutes, but worsened over the course of the hour to approximately 75 percent of 403 OP TABLE 7.—Pulmonary function in adults exposed to involuntary smoking Study Subjects Pulmonary function measure Outcome Comments White and Froeb 2,100 adults, San Diego, FVC, FEV,, and MMF as Significant effect of office Potential bias in selection, (1980) California percent predicted exposure to involuntary assessed only current smoke cigarette smoke exposure Comstock et al. 1,724 adulta, Washington FEV, as percent predicted No effect of wives’ smoking Includes adults aged 20+ (198D) County, Maryland on husbands’ pulmonary function Kauffmann et al. 7,818 adults, seven French FEV,, FVC, and MMEF Significant effect in wives Not adjusted for height, (1983) cities, selected subgroups of smoking husbands in all dose-response to amount of measures; significant only husbands’ smoking for for MMEF in husbands of MMEF in wives, no effect smoking wives below age 40 the preexposure values. Normal subjects had no change in pulmo- nary function with this level of exposure. In this study, subjects were not blinded as to the exposure and were selected because of complaints about smoke sensitivity. Shephard et al. (1979), in a very similar experiment, subjected 14 asthmatic subjects to a 2-hour cigarette smoke exposure in a closed room (14.6 m‘). The carbon monoxide levels (24 ppm) were similar to those predicted in the study of Dahms and coworkers. No blood carboxyhemoglobin levels were measured. Subjects were randomized and blinded to sham (no smoke) and smoke exposure and tested on two separate occasions. Data were expressed as a percentage change from the sham exposure. No significant changes in FVC or FEV: were observed between sham and smoke exposure periods, although 5 of 12 subjects did report wheezing or tightness in the chest on the day of smoke exposure. The limited existing data yield conflicting results concerning the relationship between passive smoke exposure and symptoms in patients with known pulmonary disease. Further study of this important question is warranted. Summary and Conclusions 1. Cigarette smoke can make a significant, measurable contribu- tion to the level of indoor air pollution at levels of smoking and ventilation that are common in the indoor environment. 2. Nonsmokers who report exposure to environmental tobacco smoke have higher levels of urinary cotinine, a metabolite of nicotine, than those who do not report such exposure. 3. Cigarette smoke in the air can produce an increase in both subjective and objective measures of eye irritation. Further, some studies suggest that high levels of involuntary smoke exposure might produce small changes in pulmonary function in norma! subjects. 4. The children of smoking parents have an increased prevalence of reported respiratory symptoms, and have an increased frequency of bronchitis and pneumonia early in life. 5. The children of smoking parents appear to have measurable but small differences in tests of pulmonary function when compared with children of nonsmoking parents. The signifi- cance of this finding to the future development of lung disease is unknown. §. Two studies have reported differences in measures of lung function in older populations between subjects chronically exposed to involuntary smoking and those who were not. This difference was not found in a younger and possibly less exposed population. 405 eld conflicting results concerning 7. The limited existing data yi ke exposure and pulmo- the relationship between passive smo nary function changes in patients with asthma. 406 References ABEL, E.L. Smoking during pregnancy: A review of effects on growth and develop- ment of offspring. 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International Archives of Occupational and Environmental Health 47(3): 209-221, 1980. WEBER, A., FISCHER, T., GRANDJEAN, E. Passive smoking in experimental and field conditions. Environmental Research 20: 205-216, 1979. WEBER, A., JERMINI, C., GRANDJEAN, E. Irritating effects on man of air pollution due to cigarette smoke. American Journal of Public Health 66(7): 672-676, July 1976. WEINBERGER, S.E., WEISS, S.T. Pulmonary diseases. In: Burrow, G.N., Ferris, T.F. (Editors), Medical Complications During Pregnancy. 2nd Edition. Philadelphia, WB. Saunders, 1981, pp. 405-434. 411 WEISS, S.T., TAGER, LB., SPEIZER, F.E., ROSNER, B. Persistent wheeze. Its relation to respiratory illness, cigarette smoking, and level of pulmonary function in a population sample of children. American Review of Respiratory Disease 122(5): 697-707, November 1980. WHITE, J.R., FROEB, HF. Small-airways dysfunction in nonsmokers chronically exnosed to tobacco smoke. 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DEPOSITION AND TOXICITY OF TOBACCO SMOKE IN THE LUNG 413 CONTENTS CIGARETTE SMOKE DEPOSITION IN THE LUNG Introduction Characterization of an Aerosol Characterization of Cigarette Smoke Aerosols Factors That Affect Particulate Deposition Deposition of Cigarette Smoke Particulates Particulate Retention in the Lung Passive Smoking Conclusions CIGARETTE SMOKE TOXICOLOGY Introduction Preliminary Considerations Effects on Airway Function and Ventilation Human Studies Animal Studies Effects on Permeability of the Pulmonary Epithelium Human Studies Animal Studies Effects on Mucociliary Structure and Function Effects on Cells Human Studies Animal Studies Effects on Protease Inhibitors Human Studies Animal Studies Effects on Lung Tissue Repair Mechanisms Human Studies Animal Studies ee Summary and Conclusions ee References 415 CIGARETTE SMOKE DEPOSITION IN THE LUNG Introduction Previous Reports of the Surgeon General on the health conse- quences of smoking have focused on characterizing and quantifying responses to the inhalation of cigarette smoke. Typically, dose is given in terms of packs per day or cumulative pack years. However, a more accurate description of dose would include how much smoke is inspired into the respiratory tract, how much is deposited and fails to exit with the expired air, and the fate of the deposited smoke. A commonly held fallacy is that “living in New York is like smoking two packs per day.” Is the amount of particles produced by smoking comparable to that encountered in urban air pollution? A person who smokes two packs of cigarettes per day with an average tar rating of 20 mg per cigarette would breathe in 800 mg of material per day, or 292 g of tar per year. A reasonable value for urban air would be 100 wg, or 0.1 mg per cubic meter. The average person breathes approximately 20,000 liters, or 20 cubic meters, of air per day. Thus, 2 mg of material per day, or 0.73 g of particulate per year, would be inspired. At the outset, it is evident that the amount of smoke entering the lungs is considerably greater than the amount of particulates from air pollution. This chapter emphasizes the size and aerodynamic properties of smoke and relates them to the fraction of the inspired smoke that deposits in the lungs. Also considered is where the smoke deposits, and its possible fate is described. The particulate phase of cigarette smoke, commonly known as tar, is inhaled as an aerosol into a smoker’s respiratory tract. An aerosol is defined as a suspension of solid or liquid particles in a gas (Hinds 1982). In the case of cigarette smoke, the aerosol contains ambient air as well as the gases, liquids, and solids produced during tobacco combustion. The particulates include a wide variety of organic and metallic compounds, many of which are toxic to lung tissues. Hydrocarbons, aldehydes, ketones, organic acids, alcohols, nicotine, and phenols are among them. Metallic compounds such as radioac- ive lead and polonium are also present. The gas phase is also ‘complex; in addition to the nitrogen and oxygen in the air, ‘onsiderable amounts of carbon dioxide and carbon monoxide are resent, and also significant amounts of cyanides, acrolein, nitrogen xides, and ammonia. The precise quantitative composition of the obacco smoke varies with many different factors, including the type f tobacco plant grown, the soil used to grow the plant, the method of uring the leaves, the temperature of combustion during smoking, nd the composition and physical properties of the cigarette paper 417 and other additives. As the cigarette butt length decreases, many substances that have previously condensed on the remaining tobacco are revaporized. Generally, as butt length shortens, the smoke from the cigarette contains an increasing concentration of these sub- stances. Most of these constituents in smoke are toxic to lung tissues. Their toxicity extends from impairment of mucociliary transport, critical for clearing particles from the lungs, to carcinogenic and cocarcinogenic activities (Wynder and Hoffmann 1979; Battista 1976). To understand where the numerous particulates in cigarette smoke deposit in the lungs and how they are removed is important for determining the pathologic effects of chronic cigarette smoking. Characterization of an Aerosol To predict the deposition patterns of any aerosol, such as cigarette smoke, it is necessary to know the size, shape, and density of the individual particles or droplets. Describing the distribution of particle diameters is essential. It is convenient to describe particle size aS an aerodynamic diameter rather than as an actual particle size based on optical measurements, because the former is a better predictor of aerodynamic behavior (Hinds 1982). Aerodynamic diameter is defined as the diameter of a sphere of unit density that has the same settling velocity as the particle being measured. This may be expressed as a count median aerodynamic diameter (CMAD) and a mass median aerodynamic diameter (MMAD). These are, respectively, the diameters for which half of the number or mass of the particles are less than that diameter and half are more. Characterization of Cigarette Smoke Aerosols The particulates in cigarette smoke ‘have been measured by several investigators using a variety of analytical devices. Because of different apparatus and different methods of smoke generation and dilution, results vary but are reasonably consistent. McCusker et al. (1983) used a device called the single particle aerodynamic relaxa- tion time (SPART) analyzer to determine the size of particulates from several brands of cigarettes, with and without filters. The mass - median aerodynamic diameter (MMAD) for all brands averaged approximately 0.46 pm; it was not markedly different when the - filters were removed. These measurements showed that, even with a filter, billions of particles are present in an average 35 ml puff of cigarette smoke generated by an automatic smoking-machine. Par- ticulate concentrations per ml ranged from 0.3 x 109 to 3.3 x 10°, depending on whether the cigarettes were rated ultra-low, low, or medium in tar content. The reduced particulate concentration reported for low tar cigarettes results principally from filter ~ 418 efficiency and air dilution of the smoke. When the specially designed filters were removed or the vent holes were covered, as could be accomplished by the smoker’s fingers, particulate concentrations per milliliter increased to levels comparable to that for higher tar content cigarettes. Hinds (1978) compared the particulate size distribution in ciga- rette smoke using an aerosol centrifuge and a cascade impactor. Although these devices are based upon different physical principles, Hinds found that the results were comparable. The MMAD values ranged from 0.37 to 0.52 ym. Variations depended primarily upon the dilution of the smoke. The MMAD and concentration values reported by Hinds and coworkers (1983) were similar to those reported by Keith and Derrick (1960), who used a specially modified centrifuge, called a conifuge, to analyze cigarette smoke. Particulate analysis by a light scattering photometer yielded an MMAD of 0.29 yum and particulate concentrations of 3 x 10!° per ml (Okada and Matsunuma 1974). Carter and Hasegawa (1975) “fixed” cigarette particulates with methyl cyanoacrylate, a method that may produce artifacts, and measured a mean diameter of 0.48 ym from electron micrographs of the particulates. Earlier methods of measurement were based upon the collection of smoke particulates on various surfaces. Harris (1960) reported a range of 0.16 to 0.54 ym from a replica of cigarette smoke particulates that included a correction for droplet-spreading during sample preparation. Langer and Fisher (1956) found a median range of 0.6 um, but made no correction for droplet-spreading during sample collection. Time and concentration are important modifiers of tobacco smoke. Cigarette smoke aerosols contain volatile components, and evapora- tion gradually reduces particle diameters. It is also true that with the extremely high particle concentrations encountered in main- stream smoke, the aerosol can agglomerate rapidly because nearby particles collide with each other and coalesce. If smoke is cooled (reducing the vapor pressure of the volatile components) and diluted (reducing the probability of particle collisions) the particle size will be more stable. Thus, it is difficult to reliably measure the size and concentration of particles in cigarette smoke produced under realis- tic experimental conditions. The size and concentration of the particulates are also affected by the decreasing length of a cigarette as it is smoked. McCusker et al. (1983) found the particulate concentration to be 67 percent greater in the last three puffs of a filtered cigarette than in the first three. Ishizu et al. (1978) also reported that particulate concentrations in unfiltered cigarettes increased and that the mean geometric diame- ter of the particles decreased with decreasing cigarette length. They attributed the former effect to the decreased filtration by the tobacco column and the latter effect to the shorter length traveled by the 419 particles to reach the butt end and, hence, the decreased time for particulate coagulation. In addition, their results illustrate that filters may trap the larger particles and generate more uniform aerosols; McCusker et al. (1983) noted no change in MMAD between the first and last three puffs of filtered cigarettes. Ishizu et al. (1978) also reported that larger puff volumes decreased the average particulate diameters. This can affect interpretation of experimental data in that standard cigarette smoking-machines draw 35 ml puff volumes, whereas Hinds et al. (1983) reported that 54 ml was the average puff volume measured in smoking subjects. Particle size is a critical factor in determining what fraction of the particles that enter the respiratory tract will deposit there and fail to exit with the expired air, as well as where they will deposit. Submicrometric particles will deposit not only in small and large airways, but also in alveoli. Breathing pattern is also important (see review by Brain and Valberg 1979). Large tidal volumes will favor alveolar deposition. Higher inspiratory flows will promote deposition at bifurcations. Breath-holding is important, because the greater the elapsed time before the next expiration, the higher the fraction deposited (collection efficiency). Individual anatomic differences may influence the amount and distribution of deposited particles. The cross-section of airways will influence the linear velocity of the inspired air. Increasing alveolar size decreases alveolar deposition. Factors That Affect Particulate Deposition A typical puff volume is approximately 30 to 70 ml. It is usually inspired with a volume of ambient air that is one to two times the normal tidal volume. Particle size not only can change in experimen- tal equipment as described above, but also may change within the human respiratory tract. After a volume of smoke is drawn into the mouth and upper respiratory tract of a smoker, it may be retained in that humidified air before deep inhalation. Here too, the particulates can change in size through coagulation or evaporation. They can also grow because of the particulates’ affinity for water, termed hygroscopicity (Davies 1974; Hiller 1982b). Other aspects of each smoker’s behavior may also influence dose. Most manufacturers achieve low tar yields by the use of ventilated cigarette holders; this causes the inhaled smoke to be diluted with air. However, 32 to 69 percent of interviewed smokers of “low” tar cigarettes reported that they blocked these filter preparations with their fingers or lips. This causes dramatic increases in the amount of tar and nicotine in a way not predicted by studies using smoking-machines (Kozlowski et al. 1980). 420 Such individual differences in cigarette use as well as other strategies designed to increase the inhalation of tar and nicotine probably account for the poor correlation between the machine- determined nicotine yield of a cigarette and the concentration of nicotine or its metabolites in blood or urine (Russell et al. 1975, 1980, Sutton et al. 1982; Feyerabend et al. 1982; Benowitz et al. 1983). For example, Herning and coworkers (1981) demonstrated that when low nicotine cigarettes are used, most smokers compensate by increasing the puff volume. In addition, Tobin and Sackner (1982) reported that some subjects increase their puff volume by up to 70 percent after switching to low tar cigarettes. In some instances, this compensatory increase occurred during a single experimental session. In contrast, a few smokers may reduce smoke deposition in their lungs by retaining the smoke in their mouth for several seconds before inhaling it. Stupfel and Mordelet-Dambrine (1974) showed that if a smoker holds the smoke in his mouth for 2 seconds, 16 percent of the particulate matter is removed. Also, 60 percent of the water-soluble components of the gas phase are absorbed by the upper airways. Chronic smoking also causes alterations in lung structure that affect deposition patterns. Sanchis et al. (1971) studied the deposition of an aerosol of radioactively labeled albumin inhaled by smokers and nonsmokers. They found less aerosol deposition in the alveolar region of smokers than of nonsmokers and suggested that the difference may be the result of alterations in the small airways produced by chronic smoking. Similar results were reported for hamsters exposed to cigarette smoke for 3 weeks prior to a single exposure of radioactively labeled cigarette smoke (Reznik and Samek 1980). More labeled smoke concentrate was found in the lungs of hamsters not previously exposed to cigarette smoke. The rate and pattern of breathing can also affect the total dose of cigarette particulates deposited in the lungs. Dennis (1971) reported that exercise increased the percent deposition of two experimentally generated aerosols in human subjects. Increased deposition was also measured in exercising hamsters that inhaled a radiolabeled aerosol (Harbison and Brain 1983). These results are most relevant to those who smoke when ventilation is increased while working or shortly after a period of exercise. Deposition of Cigarette Smoke Particulates The factors discussed in the previous section illustrate that experimental measurements of the size and concentration of ciga- rette aerosols are insufficient for the prediction of deposition patterns. Cigarette smoke is a mutable aerosol, which complicates the collection of accurate and reproducible data regarding its particulate composition. In addition, alterations in respiratory 421 structure and respiratory rate can affect the deposition of particu- lates. These complexities stress the importance of actual measure- ment of the regional deposition of cigarette smoke particulates in human lungs. However, few data have been published on this important area, despite the prevalence of smoking and its impact on human health. Most of the available information on the deposition of cigarette smoke particulates is based upon theoretical or physical models of the lungs and measurements of differences in the concentration of aerosol between inhaled air and exhaled air. A model to predict the percent deposition of particles based upon MMAD was presented by the Task Group on Lung Dynamics of the International Commission on Radiological Protection (1966). The respiratory tract was divided into three main regions: nasopharynx, trachea and bronchi, and alveoli. In conjunction with estimates of particulate clearance, deposition calculations were made for these regions at three different inhalation volumes. This model suggests that 30 to 40 percent of the particles within the size range present in cigarette smoke will deposit in the alveolar region and 5 to 10 percent will deposit in the tracheobronchial region. This model also emphasizes the impact of particle solubility on the total integrated dose over time. Brain and Valberg (1974) developed convenient nomograms and a computer program to demonstrate how particle solubility and particle size significantly affect the net amount of particulates retained in the lungs. Aerosol deposition has also been studied in airway casts. Physical models of the upper airways of human lungs have been made by a double casting technique in order to study particulate deposition at several airway generations (Schlesinger and Lippmann 1972). Lungs obtained at autopsy were filled with wax or alloy. When these materials became solid, the tissue was removed and the casts were coated with silicon rubber or latex. The wax or alloy was then melted and removed, leaving 4 cast of the original airways. Different flow rates and particulate sizes were used to study deposition patterns. Schlesinger and Lippman (1978) reported a correlation between the deposition sites of test aerosols in the lung casts and the most common sites of origin of bronchogenic carcinoma in humans. Both occurred preferentially at bifurcations. Martonen and Lowe (1983) added an oropharyngeal compartment and a replica cast of the larynx to the tracheobronchial casts in order to better simulate air flow patterns in the upper respiratory tract. They used these models to evaluate the amount of cigarette smoke condensate deposited in the airways at different flow rates. More condensate was present at branching regions, especially at carinal ridges. Aerosol was also deposited preferentially along posterior airway walls. Most experiments designed to determine aerosol deposition in human subjects measure differences in aerosol concentration before 422 and after inhalation. Hinds and associates (1983) measured the percent mass of inhaled tobacco smoke particulates that deposited in male and female smokers. A transducer placed in the filter of a smoked cigarette relayed information to an automatic smoking- machine to duplicate inhaled puff volume. This method was used to produce a more natural smoking pattern. Comparisons were then made between particulate mass concentrations in the machine- generated smoke and the amount of smoke actually exhaled by the smoker. With these measurements, a 57 percent deposition of particulate mass was seen in men. This was greater than the significant 40 percent collection efficiency measured in women (p<0.01). No data regarding particulate size or deposition sites were reported. Hiller and coworkers (1982b) also measured the deposition fraction of an aerosol containing three different sizes of polystyrene latex spheres in nonsmoking humans. They measured a 10 percent deposition for 0.6 pm (MMAD) spheres, which is similar to the results of Davies et al. (1972) and Muir and Davies (1967) using 0.5 um aerosols and of Heyder et al. (1973) using aerosols with a 0.2 to 1.0 pm range. The size ranges of these aerosols are comparable to those experimentally measured in cigarette smoke, as previously discussed. These percentages are lower than those observed by Hinds et al. (1983), probably reflecting differences in breathing patterns. The measurements of Hinds et al. (1983) were made with realistic breathing patterns used during smoking; the other investigators had used normal breathing patterns. Increased breath-holding following inspiration probably accounts for the enhanced collection efficien- cies. Particulate Retention in the Lung The amount of particulates retained in the lung at different times following the inhalation of an aerosol such as cigarette smoke depends upon the balance between the amount that deposits in the respiratory tract and the efficiency of the lung clearance mecha- nisms in the airways and alveoli. Particles depositing in the airways are entrained in the mucus layer lining these passages. This layer is swept toward the mouth by the action of ciliated cells and eventually swallowed. Macrophages present in the airways may also phagocy- tose deposited particulates and are also carried toward the mouth by the mucociliary transport system. Particulates reaching the alveolar region—those that are usually smaller than several micrometers in size—are soon engulfed by alveolar macrophages. These cells gradu- ally migrate toward the airways and exit the lung via the mucocili- ary escalator. Dissolution is also an important clearance mechanism for soluble particles. Clearance mechanisms are a dynamic compo- nent of normal lung function and operate to keep the lung sterile. 423 Lung disease and cigarette smoking itself can affect particulate clearance and retention in smokers’ lungs. Previous studies have shown that smokers have different aerosol deposition patterns and slower clearance rates than nonsmokers (Albert et al. 1969; Cohen et al. 1979; Sanchis et al. 1971). These alterations in clearance are, in part, caused by components in cigarette smoke that are ciliotoxic (Battista 1976) and impair phagocytosis by alveolar macrophages (Ferin et al. 1965). Clearance mechanisms in smokers may be further compromised by lung diseases, such as emphysema and fibrosis, and by exposure to air pollutants. Oxidants in photochemical smog, such as ozone and nitrogen oxides, are toxic to ciliated cells and macrophages (Bils and Christie 1980). Measurements of retention of cigarette particulates in the lungs over time are difficult to estimate from data obtained with airway casts or from differences in the aerosol concentration of inhaled and exhaled smoke because these methods do not take clearance mechanisms into account. Unfortunately, few data are available regarding the actual retention and sites of deposition of cigarette smoke particulates in either humans or animals. The most accurate method is quantification of particulate deposits in individual pieces of tissue dissected from the lung. Impossible in living animals, this is a tedious procedure with animal lungs or human material obtained at surgery or autopsy and is especially difficult with large jungs. Little et al. (1965) examined lungs from humans at autopsy and suggested a correlation between the sites of bronchogenic carcinoma in the lungs of smokers with the deposition of polonium?®, a radioactive component of cigarette smoke. Resnik and Samek (1980) used a radioactive marker to study the retention of smoke in hamster lungs. They exposed hamsters to the smoke from cigarettes containing a labeled component in the tobacco and then measured the amount of radioactivity present in different lobes. They found that more radioactivity was present in the lung tissue of hamsters not previously exposed to unlabeled cigarette smoke. However, the clearance of the labeled component from the lungs was slower in the group previously exposed to smoke. There are problems with using - animal models for smoke uptake. Most rodents are obligatory nose breathers, and significant fractions of the smoke may be taken up as it passes through the upper airways. Page et al. (1973) studied mice using radiolabeled cigarettes. They found that 50 percent of the deposited smoke was recovered from the nasal passages. About 30 percent was recovered from the esophagus, stomach, and other - organs, and only 20 percent was present in the lungs. Exposing animals via a tracheostomy avoids this excessive and unnatural deposition in the nose, but it bypasses the mouth and larynx, which may remove some particles during smoking in man. 424 Passive Smoking Recently concern has increased regarding the health effects of cigarette smoke inhaled by nonsmokers, a phenomenon called passive smoking. The smoke is composed of that exhaled by the smoker and the sidestream smoke produced by the burning cigarette between inhalations. The concentration of respirable particulates in areas where there are smokers can range from 100 to 700 pg/m?. This is up to 25 times higher than that found in nonsmoking areas (Repace and Lowrey 1980). Using mean deposition values of 11 and 70 percent for the passive smoker and the active smoker, respective- ly, from the data presented by Hiller et al. (1982), the deposition would be approximately 0.55 mg for a nonsmoker over an 8-hour day in a room with 500 pg/m of smoke. In comparison, a smoker would deposit approximately 400 mg of tar in his or her lungs if he or she smoked two packs of cigarettes with an average tar rating of 20 mg per cigarette during the same time period. As has been discussed earlier, the rate and pattern of breathing can also affect the total dose of cigarette particulates deposited in the lungs. Although the amount of smoke depositing in the lungs of nonsmokers during passive smoking is small compared to that encountered by the active smoker, large numbers of people are involved. In the United States in 1979, 36.9 percent of men and 28.2 percent of women were current smokers (USDHEW 1980). Conclusions Cigarette smoke is the most important cause of chronic obstructive lung disease. This significant response is matched by the significant dose of toxic particulates received by the respiratory tract of smokers. The particle size of cigarette smoke is so small that little protection is offered by the filtering capacity of the upper airways. Cigarette smoke penetrates deep into the lungs and reaches the small airways and alveoli. The fraction of the smoke deposited is high because most smokers employ some breath-holding following inhalation of a puff. Their attempt to enhance deposition of smoke is successful, resulting in increased lung burdens of toxic smoke products. 425 480-144 0 - 85 - 15 CIGARETTE SMOKE TOXICOLOGY Introduction The inhalation toxicity of tobacco smoke has become one of the major public health problems of the 20th century. The chemical complexity of tobacco smoke confounds the task of identifying its toxic constituents. Tobacco smoke is comprised of thousands of chemical components arising primarily from volatilization and pyrolysis of the tobacco leaf (Stedman 1968; Green 1977). The chemical gamut runs from traces of elemental metals, such as cadmium, to nonvolatile whole tobacco leaf components that have escaped degradation during the burning process (USDHHS 1981). Approximately 90 percent of the individual constitutents are organic compounds associated with both the particulate phase and the gas phase (Guerin 1980). It is not surprising that chronic inhalational exposure to this diverse mixture of potentially bioactive compounds can evoke a wide variety of toxicologic responses. Over the years, scientific and public concern has centered primarily on the carcino- genic and atherogenic effects of tobacco smoke. In contrast, relative- ly little is known about the involvement of tobacco smoke constitu- ents in the pathogenesis of chronic obstructive lung disease (COLD) (USDHHS 1981). For the most part, smoke constituent toxicity studies, both epidemiologic (Dean et al. 1977; Higenbottam et al. 1980) and toxicologic (Walker et al. 1978; Lewis et al. 1979, Coggins et al. 1980), have been confined to a comparison of the varying amounts of particulate matter or tar delivered by smoke. In studies of this nature, attempts have been made to distinguish between the relative toxicities of the vapor phase and the particulate phase of tobacco smoke. The general conclusion reached is that gas phase components that penetrate to the small airways and alveoli may play a significant role in the production of peripheral airway and parenchy- mal diseases such as emphysema, whereas particulate phase compo- nents that deposit in larger airways may play a role in the development of disorders of the more proximal airways such as chronic bronchitis (USDHHS 1981). This generalization may not always hold, however. For example, in a review of the effects of smoking on mucociliary clearance, Newhouse (1977) noted consider- able disagreement among investigators with regard to whether the vapor phase or the particulate phase was the major factor in smoke- induced dysfunction of the mucociliary transport system. Also, Coggins and associates (1980) observed an increase in both peripher- al and central airway goblet cell number in rats after exposure to tobacco smoke from which most of the vapor phase had been removed. Cohen and James (1982) found that the level of oxidants in tobacco smoke (oxidants have been implicated in the pathogenesis of 426 emphysema) correlated with the amount of particulate matter in smoke from various brands of cigarettes. At present, therefore, attempts to associate a specific toxicologic response solely with either the vapor phase or the particulate phase of tobacco smoke are not recommended. Because so little is known regarding the role of specific constitu- ents or phases of tobacco smoke in the pathogenesis of COLD, this section of the Report is organized on the basis of specific insults to the respiratory system that may be brought on by exposure to whole tobacco smoke and that may lead to structural and functional changes within the lung. Included, as available information permits, are data on the known contribution of individual smoke constituents or phases to a specific insult. Human and animal studies are described separately to provide a perspective on the extent to which animal research has verified or extended clinical research and vice versa. Preliminary Considerations Tobacco smoking is generally accepted as the major cause of COLD (USDHEW 1979; USDHHS 1981). COLD is often subdivided into three categories: (1) uncomplicated bronchitis, characterized by mucus hypersecretion and cough, (2) chronic bronchitis with bronchi- olar inflammation and obstruction of distal airways, and (3) pulmo- nary emphysema, characterized by distal air space enlargement with loss of alveolar interstitium. These three pathologic conditions are often considered collectively within the context of COLD because they can coexist in the lungs of smokers and because signs and symptoms associated with one condition may presage the develop- ment of another. Effects on Airway Function and Ventilation Human Studies Cigarette smoke appears to have both chronic and acute effects on airway function. In adults, smoking over a period of years leads to narrowing of and histopathologic abnormalities in small airways (Ingram and O’Cain 1971; Cosio et al. 1980; Suzuki et al. 1983). Even in teenagers, regular smoking for 1 to 5 years is sufficient to cause demonstrable changes in tests of small airway function in some smokers (Seely et al. 1971); the lungs of young cigarette smokers who die suddenly show definite pathologic changes in the peripheral airways (Niewoehner et al. 1974). The acute response to cigarette smoke has been reported to involve large airways, small airways, or both. Costello and associates (1975), in a study of asymptomatic smokers and nonsmokers, found that 427 tests of small airway function (maximum expiratory flow volume curves, closing volume, and frequency dependence of compliance) were unaltered after smoking one cigarette, however, specific airways conductance, 4 measure of large airway function, fell significantly in both groups. Essentially the same results were obtained by Gelb and associates (1979), who reported a decrease in airways conductance but little or no change in volume of isoflow (another test of small airway function) in healthy nonsmokers after smoking one cigarette. Likewise, McCarthy and colleagues (1976), using several different tests, found no evidence for an acute effect of intensive cigarette smoking on small airways, but did demonstrate increased large airways resistance. The decrease in conductance caused by cigarette smoke has been shown to occur within 7 or 8 seconds of a single inhalation (Rees et al. 1982), and filtration seems to reduce the degree of bronchoconstriction (Da Silva and Hamosh 1980). Irritant effects of tobacco smoke are not limited to the particulate phase, because exposure to oxides of nitrogen at levels present in cigarette smoke also can precipitate acute bronchospasm (Tate 1977). Nicotine does not appear to be responsible for the acute bronchoconstriction that accompanies cigarette smoking (Nadel and Comroe 1961). Zuskin and coworkers (1974) showed that in healthy human subjects, smoking one or two cigarettes decreased flow rates on maximum and partial flow-volume curves, and concluded that smoking causes acute narrowing of small airways. Da Silva and Hamosh (1973) and Sobol and colleagues (1977) measured airways conductance, as well as maximum mid-expiratory flow rates, and concluded that both large and small airways are probably affected by the acute inhalation of cigarette smoke. Though the bronchoconstrictive response to cigarette smoke has most often been attributed to a cholinergic reflex originating with stimulation of irritant receptors in the airways, there are data suggesting that histamine may also be involved. Walter and Walter (1982b) found a significant increase in the number of degranulated basophils in the blood of smokers 10 minutes after smoking compared with just before smoking. There is also some evidence to indicate that smokers may differ from nonsmokers in their respon- siveness to inhaled histamine (Brown et al. 1977; Gerrard et al. 1980) as well as methacholine (Malo et al. 1982; Kabiraj et al. 1982; Buczko et al. 1984), but smoking immediately prior to an inhalation test does not appear to affect bronchial responsiveness to either histamine or methacholine (McIntyre et al. 1982). Asthmatic subjects have a greater than normal susceptibility to the bronchoconstrictive effects of cigarette smoke when the smoke is - actively inhaled. The question whether tobacco smoke plays a role in 428 allergic asthma has yet to be resolved completely (\USDHEW 1979; Shephard 1982; Burrows et al. 1984). Animal Studies Binns and Wilton (1978) studied the acute ventilatory response to cigarette smoke in rats. They found that within the first 3 minutes after initiation of smoke exposure, tidal volume fell to 80 percent of the preexposure level, then rose to 160 percent after 9 minutes of exposure; respiratory rate dropped to 40 percent of the preexposure level within 1 minute and remained there for the duration of the exposure period. There was no adaptation of the acute ventilatory response after 4 weeks of daily smoke exposures. In a similar study, Coggins and associates (1982) found that rats exposed to a relatively low dose of cigarette smoke demonstrated a persistent depression in tidal volume and breathing frequency, whereas animals exposed to a relatively high dose exhibited an increase in tidal volume with no change in frequency. Acute airway responses to cigarette smoke have not been studied as extensively in animals as they have been in man. Experiments in anesthetized dogs (Aviado and Palecek 1967), rabbits (Sellick and Widdicombe 1971), and cats (Boushey et al. 1972) indicate that acute smoke exposure elicits reflex bronchoconstriction. There also ‘s evidence from experiments with isolated monkey lungs that smoke exposures stimulate histamine release (Walter and Walter 1982a). Histamine appears to be responsible, at least in part, for mediating che increase in collateral resistance in dogs following administration of cigarette smoke (Gertner et al. 1982). The chronic effects of cigarette smoking on pulmonary function in logs were studied by Park and coworkers (1977). Active inhalation of 100 and 200 puffs of diluted (1:4) smoke 5 days per week for periods of 6 months and 1 year, respectively, did not produce any noteworthy changes in pulmonary function. The effects of chronic cigarette moke exposure on ventilation in rats were studied by Loscutoff and ‘oworkers (1982). Animals exposed for up to 24 months to cigarette moke containing various amounts of tar and nicotine were found to ave higher tidal volumes and lower respiratory rates than sham- ‘xposed animals. The most pronounced changes were seen in nimals exposed to smoke from low tar, high nicotine cigarettes. listopathologic examination of lungs taken from these animals evealed primarily granulomatous lesions with no evidence of mphysematous changes (Wehner et al. 1981). Roehrs and colleagues 1981) used operant conditioning techniques to get baboons to smoke 0 cigarettes per day for 3 years. Measurements of lung volumes, ompliance, and expiratory flow showed no differences between moking animals and sham animals, but airway reactivity to inhaled iethacholine was decreased in animals that had smoked. Subse- 429 quently, Wallis and associates (1982) reported that both acute and chronic imbalation of nicotine mimicked this effect of cigarette smoke on bronchial reactivity in baboons. Effects on Permeability of the Pulmonary Epithelium The pulmonary epithelium functions to protect underlying struc- tures from injuricus agents deposited in the airway lumen. Cigarette smoke has been shown to diminish this protective function by increasing epithelial permeability in all regions of the tracheobron- chial tree (Simani et al. 1974). In the airways, irritant receptors located just beneath epithelial tight junctions are more accessible following exposure to tobacco smoke. Stimulation of these receptors is thought to initiate rapid changes in ventilation and to induce bronchoconstriction (Widdicombe 1977). Likewise, mast celis, a source of potent bronchoconstrictive mediators, become more accessi- ble to inhaled toxicants after smoke exposure (Guerzon et al. 1979). In the alveolar region, an increase in epithelial permeability may promote the transfer of noxious smoke constituents and endogenous proteases to the interstitium, thereby facilitating disruption of alveolar septa. Human Studies Subepithelial structures of the lung are important targets for smoke-induced injury, and research has shown that tobacco smoke alters epithelial permeability to allow offending agents to gain access to these structures. Minty and colleagues (1981) showed that, compared with nonsmokers, smokers had significantly shorter half- time lung clearance as measured with inhaled radiolabeled aerosols. After cessation of smoking, half-time clearance increased, but at 21 - days it was still significantly less than that reported in nonsmokers. Using similar techniques, Kennedy and colleagues (1984) compared pulmonary epithelial permeability and bronchial reactivity to in- - haled histamine in smokers and nonsmokers. These researchers found increased permeability in smokers, but could find no evidence of increased reactivity. Although the mechanism by which cigarette smoke induces an increase in alveolar epithelial permeability is not fully understood, it has been suggested that carbon monoxide may play an important role, with possible additional contributions from nicotine and oxides of nitrogen (Jones et al. 1980). Animal Studies In studies of rabbit tracheal rings exposed in vitro, just a few puffs of diluted cigarette smoke have caused ultrastructural changes in tracheal epithelial cells and an increase in the size of intracellular spaces, but junctional complexes between cells remain intact (Davies 430 and Kistler 1975). Boucher and associates !1980) found that, com- pared with controls, guinea pigs exposed to 100 or more puffs of cigarette smoke exhibited a significantly faster transfer rate for horseradish peroxidase across tracheal epithelium. These animals also demonstrated a progressive disruption of epithelial tight junctions as a function of the dose of tobacco smoke. Hulbert and associates (1981) reported that smoke-induced increases in guinea pig airway permeability were transient, reaching maximum levels at 30 minutes after acute exposure to 100 puffs and returning to control levels 12 hours later. Gordon and associates (1983) reported that acute exposure (48 hours) of hamsters to NO: caused a marked increase in bronchiolar and alveolar epithelial permeability to horseradish peroxidase. Restoration of the epithelial barrier was noted 48 hours after exposure in these animals. Ranga and associates (1980) demonstrated a similar increase in guinea pig tracheal epithelial permeability upon exposure to NO» for 14 days. Effects on Mucociliary Structure and Function The mucociliary system provides the lung with one of its most effective lines of defense against inhaled pollutants. Disruption of this system enables pollutants to remain in contact with the respiratory membranes for prolonged periods and increases the risk of toxic damage. Tobacco smoke can adversely affect mucociliary function by increasing the amount or viscosity of respiratory tract secretions or by depressing ciliary activity directly (Newhouse 1977; Wanner 1977). Effects on Cells: Pulmonary Alveolar Macrophages and Polymorphonuclear Leukocytes Pulmonary emphysema is believed to result from the slow degradation of the elastin framework of lung parenchyma! tissue. Degradation of elastin is most likely initiated by elastolytic enzymes released locally in the lung and not adequately inhibited by endogenous antiproteases. Recent studies of the effects of cigarette smoke on these cellular sources of elastolytic enzymes have provided additional insights into the relationships between smoking and pulmonary emphysema. (See chapter 5) Human Studies Normally, pulmonary alveolar macrophages (PAMs) function as 4 defense mechanism against particulate material deposited on the respiratory surfaces of the lung. However, cigarette smoke can induce a number of changes in PAMs that may promote excessive degradation of native lung tissue. For example, PAMs from smokers 431 have elevated elastase levels, and these cells may secrete elastase in vitro (Harris et al. 1975; Rodriguez et al. 1977; Hinman et al. 1980). Further, PAMs from smokers have been shown in vitro and in vivo to bind and internalize elastase released from polymorphonuclear leukocytes (PMNs) (Campbell et al. 1979; White et al. 1982). It has been suggested that during the phagocytosis of smoke particulates by PAMs, elastolytic enzymes may be released into extracellular spaces (Hocking and Golde 1979; Brain 1980; Kuhn and Senior 1978). Numerous investigators have reported significantly greater yields of PAMs from the lungs of smokers compared with nonsmokers (Green et al. 1977; Roth et al. 1981, Hoidal and Niewoehner 1982). The effects of smoking on PAM mobility are unclear. Some researchers have reported a significant increase in chemotactic migration of PAMs from smokers versus PAMs from nonsmokers (Warr and Martin 1974), but others have been unable to observe such an effect (Demarest et al. 1979). Macrophages from smokers exhibit various morphologic, metabol- ic, and functional abnormalities. Structural changes noted in the PAMs of smokers include a slight increase in cellular diameter, the presence of “smokers inclusions” consisting predominantly of kaolin- ite particles (which have been shown to be cytotoxic to human PAMs in vitro (Green et al. 1977)) and increased numbers of lysosomes and phagolysosomes (Brody and Craighead 1975). Perturbations in sever- al metabolic pathways have been observed in PAMs from smokers, and acrolein in smoke has been implicated in this toxicity (Green et al. 1977; Laviolette et al. 1981). The production of superoxide radicals and hydrogen peroxide (H,0,), both of which inhibit lung antiproteases, has been reported to be enhanced in the PAMs of smokers (Hoidal et al. 1981). Smokers’ PAMs have also been shown to release chemotactic substances for PMNs (Gadek et al. 1978; Hunninghake et al. 1980). Additionally, there is evidence suggesting that PAMs from smokers secrete factors that promote the release of elastases from PMNs (Cohen et al. 1982). As with PAMs, PMNs have been found in elevated numbers in the lungs of smokers (Reynolds and Newball 1975; Hunninghake et al. 1980a; Hunninghake and Crystal 1983). Exposure of PMNs to cigarette smoke condensate in vitro has been shown to promote the release of elastolytic enzymes (Blue and Janoff 1978). Hutchison and coworkers (1980) found that the particulate phase of cigarette smoke stimulated the release of lysosomal enzymes from human PMNs, but they did not quantitate this release specifically for elastases. A recent study by Totti and colleagues (1984) showed that nicotine was chemotactic for human PMNs and that it enhanced PMN responsive- ness to other chemotactic factors. These results are in contrast with a previous study by Bridges and coworkers (1977) showing that nicotine, when used in higher concentrations than those employed 432 by Totti and colleagues, inhibited the chemotactic response of PMNs to casein. In a preliminary laboratory study, Janoff and colleagues (1983) found that smokers have elevated levels of PMN elastase in their lung fluids compared with nonsmokers. This finding is of particular interest in that human PMN elastase has been shown to induce emphysema in animals (Janoff et al. 1977; Senior et al. 1977; Snider et al. 1984). There is also evidence that cigarette smoke alters PMN metabolism in such a way as to favor the release of toxic oxygen metabolites. PMNs from smokers with an elevated white blood cell count show a marked increase in the release of superoxide anions compared with PMNs from nonsmokers or with PMNs from smokers with a normal white cell count (Ludwig and Hoidal 1982). These unstable oxygen metabolites have harmful effects on various cells and tissues in vivo and in vitro (Sachs et al. 1978; Fridovich 1978), and are capable of injuring phagocytes and promoting the release of proteolytic enzymes (Hoidal and Niewoehner 1982). Oxidants derived from PMNs are also capable of inactivating lung antiproteases in vitro; this may be yet another mechanism by which smoke-affected PMNs contribute to the development of emphysema (Zaslow et al. 1983). Animal Studies Laboratory animal studies of the effects of cigarette smoke on lung free-cell population and integrity have yielded results similar to those obtained from human studies. Recruitment of PAMs to the lungs following cigarette smoke exposure has been demonstrated in a number of animal species, including mice (Matulionis and Traurig 1977; Guarneri 1977); hamsters (Hoidal and Niewoehner 1982), and monkeys (DeLucia and Bryant 1980). In the rat, PAM recruitment in response to smoke exposure appears variable. In two relatively similar studies, one group of investigators (Drath et al. 1978) found a depression in the number of PAMs in the lungs of rats exposed to smoke for 30 days, whereas another group (Walker et al. 1978) reported a significant increase in the number of PAMs after 6 weeks of smoke exposure. Several authors have described the effects of cigarette smoke exposure on the morphology of rat PAMs. Observed changes include increases in PAM size, lipid vacuoles, and lysosomes, as well as the presence of “smokers inclusions” (Walker et al. 1978; Davies et al. 1978; Lewis et al. 1979). Cigarette smoke exposure of mice induces a similar pattern of morphological changes in PAMs (Matulionis 1977). Alterations of PAM phagocytic capacity have been demonstrated in animals exposed to cigarette smoke. Fogelmark and colleagues (1980) reported a dose-related increase in the rate of phagocytosis of fungal spores in vitro by PAMs from hamsters and rats that had 433 been exposed to cigarette smoke. The ability of rats to mobilize PAMs in response to a bacterial challenge does not appear to be altered by cigarette smoke exposure (Guarneri 1977), nor is there a significant effect upon PAM phagocytosis of Staphylococcus aureus in rats after 30 days of smoke exposure (Drath et al. 1981). Macrophages from mice exposed to cigarette smoke for 4 weeks secrete significantly higher amounts of elastase than PAMs from controls. However, it is not known whether this effect is due to the stimulation of resident macrophages or to the recruitment of a highly exudative population of macrophages to the lungs (White et al. 1979). A number of metabolic abnormalities have been noted in PAMs from smoke-exposed animals (Low et al. 1977). Among these is an increase in oxidative metabolism resulting in an increased produc- tion of superoxide anions. Hoidal and Niewoehner (1982) showed that enhanced oxidative metabolism in hamster PAMs was dimin- ished if the particulates were filtered from the smoke. However, other workers (Drath et al. 1981) studying smoke enhancement of rat PAM oxidative metabolism have attributed this effect to the vapor phase of smoke. In another study of PAM oxidative metabolism in rats exposed to cigarette smoke for 180. days (Huber et al. 1980), it was reported that metabolism was activated after 30 days, and at the same time PAM superoxide dismutase (an enzyme that detoxifies superoxide radical) activity was depressed by 30 percent. Animal PAMs, like human PAMs, can secrete PMN-directed chemotactic factor in response to various stimuli. For example, Gadek and colleagues (1980) demonstrated that noninfectious partic- ulate material stimulated the release of PMN-specific chemotactic factor from guinea pig PAMs. Perhaps tobacco smoke particulates might evoke a similar response. Owing to the ease with which PMNs can be harvested from peripheral blood, most research concerning the effects of tobacco smoke on PMNs has been conducted using human cells. In one laboratory study, hamsters exposed to cigarette smoke for 2, 8, and 20 hours showed a progressive recruitment of PMNs to the lungs. Control saline aerosol and filtered smoke did not stimulate recruit- ment of PMNs, suggesting that this effect of cigarette smoke resides in the particulate phase (Kilburn and McKenzie 1975). Effects on Protease Inhibitors In addition to efforts to characterize the effects of tobacco smoke on cellular sources of elastolytic enzymes, considerable research has gone into delineating the effects of tobacco smoke on the protease ~ inhibitor defense mechanism in the lungs. While several protease inhibitors have been identified, a,-protease inhibitor (a,Pi) is consid- 434 ered to be the most important in neutralizing the effects of elastase (Gadek et al. 1981). Chemical oxidants are known to inactivate a,Pi and diminish its capacity to inhibit elastase both in vitro and in vivo (Abrams et al. 1980). Cigarette smcke is an abundant source of chemical oxidants that can exert the same effect on a,Pi and therebv reduce lung defenses against endogencus elastases. Human Studies The toxic effect of tobacco smoke on protease inhibitors has been demonstrated in a variety of experimental situations. Janoff and Carp (1977) reported that tobacco smoke condensate suppressed the inhibitory action of human serum, purified «,Pi, and bronchopul:no- nary lavage fluids on both porcine snd hu:nen elastase. The suppression of human serum elastuse ‘ishibitory capacity by smoke condensate solutions in vitro has also been demcastrated by others ‘Ohlsson et al. 1980). Comparison of the protease inhibitory capacity of serum sarnples from smokers and nonsmokers has revealed a significant depression in smokers that is correlated with smoking history ‘Chowdhury 1981; Chowdhury et al. 1982). The latter studies also reported that the depression of serum protease inhibitors was related to an effect of smoke on the inhibitors per se. and not to a decrease in serum antiprotease concentration. Still, the effect of tobacco smoke on serum and lung lavage fluid antiprotease concentration and activity remains controversial. Several investigators have reported that smokers have elevated serum protease inhibitor levels (Rees et al. 1975; Ashley et al. 1980); others (Olsen et al. 1975: Warr et al. 1977). like Chowdhury and colleagues, have shown no difference in serum or lavage fluid protease inhibitor concentrations between smokers and nonsmokers. Gadek and associates (1979) compared «,Pi activity of lung lavage fluids taken from smokers and nonsmokers and found that smokers had a twofold depression of functional a,Pi activity. The activity of a, Pi in this study was tested against porcine pancreatic elastase. Ina similar study (Carp et al. 1982), in which human neutrophil elastase was used, bronchoalveolar lavage fluids obtained from smokers had 40 percent less a,Pi activity than fluids from nonsmokers. However, Stone and colleagues (1983) found that smokers’ bronchoalveolar lavage fluids did not exhibit decreased functional «Pi activity when tested against either porcine pancreatic elastase or human neutro- phil elastase, and suggested that increased elastase derived from neutrophils may be the main factor in the genesis of emphysema in smokers. Smokers may have a functional deficiency in bronchial mucus protease inhibitor (BMPi) activity. A comparison of BMP: obtained from tracheal aspirates of smokers with BMPi from nonsmokers 435 revealed that smokers’ BMPi was 20 percent less active against PMN elastase than nonsmokers’ BMPi (Carp and Janoff 1980a). Specific cigarette smoke constituents that may be responsible for the inactivation of lung protease inhibitors have not been identified. Nicotine and acrolein were studied for their ability to suppress a,Pi activity and were found to be ineffective (Janoff and Carp 1977). Several studies have shown that oxidizing compounds such as chloramine-T and N-chlorosuccinimide can oxidize methionine groups on 0,Pi and reduce its activity against porcine pancreatic and human PMN elastases (Cohen 1979: Johnson and Travis 1979; Satoh et al. 1979: Abrams et al. 1980; Beatty et al. 1980). This has led to the current belief that oxidants in cigarette smoke may be involved in the inactivation of protease inhibitors (Janoff et al. 1983). In addition to free radicals (Pryor 1980), cigarette smoke contains oxides of nitrogen possessing their own free radical properties and able to react with olefins in the gas phase or with peroxides to generate potent oxy-radicals (Dooley and Pryor 1982; Pryor et al. 1983). As mentioned previously, smoke condensate solution suppresses the elastase inhibitory capacity of serum a,Pi in vitro. This suppression can be prevented by the incorporation of phenolic antioxidants into the test media (Carp and Janoff 1978). Similarly, BMPi suppression by smoke condensate can be prevented by antioxidants (Carp and Janoff 1980a). Cohen and James (1982) used o-dianisidine oxidation to quantify the levels of oxidants in tobacco smoke condensates from various brands of cigarettes and found that oxidant levels correlated with capacity to suppress a,Pi deactivation of elastase. Further, this study provided evidence that peroxides and superoxide anions were responsible for the loss of a,Pi activity, because inclusion of catalase and superoxide dismutase in the test system reduced smoke condensate effects on a,Pi activity. Bron- choalveolar fluid from smokers contains some amount of oxidant- inactivated a,Pi, as evidenced by the presence of methionine sulfoxide residues (Carp et al. 1982). in addition to the numerous oxidizing agents present in cigarette smoke, byproducts of smoke-stimulated phagocyte metabolism repre- sent another potential source of oxidants capable of inactivating lung protease inhibitors. Carp and Janoff (1979) demonstrated that phagocytosing human PMNs produce activated oxygen species that diminish the elastase inhibitory capacity of human serum and pure a,Pi in vitro. These workers presented evidence to show that hydroxy! radicals resulting from the reaction between superoxide anions and H,O,2 were responsible for this effect. The inactivation of a,Pi by a myeloperoxidase-mediated reaction was also described in the study, which concurs with other studies demonstrating that purified myeloperoxidase, in conjunction with H.O, and a halide ion, can inactivate a,Pi in vitro (Matheson et al. 1979, 1981). Further 436 work has shown that activation of human blood monocytes, PMNs, and PAMs by use of a membrane-perturbing agent (as opposed to phagocytosis) results in the release of superoxide anions and H,O, and the suppression of serum elastase inhibitory capacity (Carp and Janoff 1980b). Clark and colleagues (1981) have demonstrated that the myeloperoxidase-H,O,-halide system from chemically stimulated PMNs oxidizes a,Pi in vitro. Similar evidence ascribing inactivation of BMPi to the myeloperoxidase-H,O,-halide system has been reported (Carp and Janoff 1980a). In the studies noted above, phagocyte-derived oxidants were shown to be capable of inactivating a,Pi when porcine pancreatic elastase was used as the substrate. These findings were recently extended to include the more pathophys- iologically relevant protease, human neutrophil elastase (Zaslow et al. 1983). Little is known about in vivo inactivation of protease inhibitors by phagocyte-derived oxidants, other than that inactive a,Pi (in the oxidized state) has been found in the synovial fluid of patients with inflamed joints (Wong and Travis 1980). The extent to which oxidants from stimulated phagocytes play a role in the suppression of lung a,Pi activity in smokers is at present unknown. Animal Studies Although most of what is known about cigarette-smoke-induced oxidant injury to lung protease inhibitors has been derived from human studies, some work has gone into the effects of cigarette smoke on lung protease inhibitors in laboratory animals. It has been demonstrated that very brief exposure of rats to cigarette smoke can cause a significant reduction in the elastase inhibitory capacity of a,Pi obtained from lung lavage fluid (Janoff et al. 1979). Very likely this toxic effect of cigarette smoke is caused by oxidant damage to protease inhibitors, because treatment of the lavage fluid with a reducing agent partially restored normal elastase inhibitory capaci- ty and because animals rendered oxidant tolerant by preexposure to ozone did not exhibit a significant reduction in a,Pi activity following exposure to cigarette smoke. Effects on Lung Tissue Repair Mechanisms A preponderance of the research to elucidate mechanisms by which cigarette smoking induces emphysema has focused on the factors that initiate lung tissue degradation. Recent studies suggest, however, that the increased risk of emphysema associated with cigarette smoking may be due partially to the effects of smoke on lung repair mechanisms. 437 Human Studies For the most part, work concerning the effects of cigarette smoke on jung repair mechanisms has been conducted in experimental animals. It has been shown, however, that cigarette smoke contains an inhibitor that can prevent the cross-linking of human fibrin polymers and thereby impede normal tissue repair (Galanakis et al. 1982). Smoke and smoke constituents have also been shown to induce membrane damage in human lung fibroblasts (Thelestam et al. 1980). Of 464 smoke constituents tested, approximately 25 percent caused membrane damage. The most active constituents were amines, strong acids, and alkylated phenols; nitriles and polycyclic aromatic hydrocarbons were inactive. Animal Studies Cigarette smoke has been shown to affect elastin synthesis in vitro and elastin repair in vivo. Laurent and coworkers (1983) determined the effect of solutions of smoke condensate on elastogenesis in vitro by measuring the formation of desmosine (one of the major cross- linking amino acids of elastin) during conversion of tropoelastin to elastin. Using a cell-free system of purified tropoelastin from chick embryo aorta or porcine aorta and lysyl oxidase purified from chick embryo or bovine lung, these investigators found that desmosine synthesis was inhibited from 80 to 90 percent in the presence of an aqueous solution of the gas phase of cigarette smoke. Elastin repair in vivo has been reported to be retarded by tobacco smoke. Osman and colleagues (1982) showed that hamsters with elastase-induced lung injury resynthesized elastin at a reduced rate if they were exposed to six or seven puffs of whole cigarette smoke hourly for 8 hours per day during the repair period. Summary and Conclusions 1. The mass median aerodynamic diameter of the particles in cigarette smoke has been measured to average approximately 0.46 pm, and particulate concentrations have been shown to range from 0.3 x 10° to 3.3 x 10° per milliliter. 2. The particulate concentration of the smoke increases as the cigarette is more completely smoked. 3 Particles in the size range of cigarette smoke will deposit both in the airways and in alveoli; models predict that 30 to 40 percent of the particles within the size range present in cigarette smoke will deposit in alveolar regions and 5 to 10 percent will deposit in the tracheobronchial region. 4. 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