The Health

Consequences

of SMOKING

A PUBLIC HEALTH SERVICE REVIEW : 1967

 

 

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
i, &, Public Health Service
Public Health Service Publication No. 1696

 

For sale by the Superintendent of Documents, U.S. Government Printing Office
Washington, D.C. 20802 - Price 60 cents
Foreword

The Federal Cigarette Labeling and Advertising Act of 1965 (Pub-
lic Law 89-92) requires that the Secretary of Health, Education, and
Welfare submit regular reports to the Congress on the health conse-
quences of smoking, together with any legislative recommendations
he may wish to make. €

This 1967 Surgeon General’s Report was prepared to provide the
Secretary and the public with a review of the research findings which
have taken place in smoking and health in the approximately 314 years
which have elapsed since the Surgeon General’s Advisory Committee
issued its monumental 1964 report. Part I of this document was in-
cluded as part of the Secretary’s 1967 Report which he sent to Congress
in July 1967. Part II, which provides detailed discussions of the re-
lationship of smoking to specific diseases, is issued here for the first
time.

The 1967 report represents a review of more than 2,000 research
studies published since the 1964 report. These additional studies con-
firm and strengthen the conclusion of the Surgeon General’s Advisory
Committee that: “Cigarette smoking is a health hazard of sufficient
importance in the United States to warrant appropriate remedial
action.”

In a separate section of this report, acknowledgments have been
made for the help of numerous scientists both within and outside the
Public Health Service, who participated in the preparation of this
report. These include the 10 distinguished scientists who made up the
Surgeon General’s 1964 Advisory Committee, all of whom were kind
enough to review part I of the 1967 report before its publication. A
special word of thanks is due Leonard M. Schuman, M.D., one of the
1964. committee members, who advised the staff in the final editing of

the entire document.

SURGEON GENERAL.
Table of Contents

Introduction__-_------------------------------
Smoking and Overall Mortality ----------------
Some General Considerations - - ------------
Smoking and Overall Morbidity--.-------------
Smoking and Cardiovascular Diseases. -- ------
Smoking and Chronic Bronchopulmonary Dis-
eases (Non-neoplastic) - ---------------------
Smoking and Cancer-.------------------------
Other Conditions and Areas of Research. - ------
Cited References- .---------------------------
II. Technical Reports on the Relationship of Smoking to
Specific Disease Categories---------------------+
Chapter 1. Smoking and Cardiovascular Diseases_

2. Smoking and Chronic Bronchopul-

monary Diseases (Non-neoplastic) .

3. Smoking and Cancer- --------------

4. Other Conditions and Areas of Re-
Acknowledgments

Responsible for the preparation of this report was the National
Clearinghouse for Smoking and Health, Daniel Horn, Ph. D., director.

Staff director for this report was Albert C. Kolbye, Jr., M.D., M.P.H.,
LL.B.

The professional staff has had the assistance and advice of a number
of experts in the scientific and technical fields in and outside govern-
ment. The staff gratefully acknowledges their contributions, often
made at considerable sacrifice of time from their own professional
duties. Although space does not permit a listing of all those who have
participated in this project, the staff wishes to express appreciation
for their cooperation and help. Special thanks are due the following:

ABINANTI, Francis R., D.V.M., Po. D.—Chief, Virology and Rickettsiology
Branch, Extramural Program, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Bethesda, Md.

AMES, Bruce N., M.D.—Laboratory of Molecular Biology, National Institutes
of Health, Bethesda, Md.

AREND, WitLt1amM P., M.D.—Medical consultant, Stroke Section, Heart Disease
Control Program, National Center for Chronic Disease Control, U.S.P.HLS.,
Arlington, Va.

AUERBACH, Oscak, M.D.—Senior medical investigator, Veterans Administration
Hospital, East Orange, N.J.

AxELEop, Davin, M.D.—-Medical consultant, Laboratory of Biology of Viruses,
National Institutes of Health, Bethesda, Md.

Ayes, SrepHen M., M.D.—Director, Cardiopulmonary Laboratory, Saint Vin-
cent’s Hospital and Medical Center of New York, New York, N.Y.

Ayres, WILLIAM R., M.D.—Medical officer, Heart Disease Control Program, Na-
tional Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

BALLENGER, JOHN J., M.D.—Head, Department of Otolaryngology, Evanston Hos-
pital, Evanston, IL

Berenpes, Hernz, W., M.D.—Chief, National Institute of Neurological Diseases
and Blindness, Perinatal Research Branch, National Institutes of Health,
Bethesda, Md.

Bere, Gorpon W.—Statistician, Operational Studies Section, Cancer Control Pro-
gram, National Center for Chronic Disease Control, U.S.P.ELS., Arlington, Va.

Ber.ines, Ropeer, M.D.—Director, Office of Director of Research, National Heart
Institute, National Institutes of Health, Bethesda, Md.

Bine, Ricuarp J., M.D.—Professor and chairman, Department of Medicine,
Wayne State University, Detroit, Mich.

Bress, Stuart R., M.D.—Medical consultant, Heart Disease Control Program,
National Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va.
Boren, Horzis, M.D.—-Clinical investigator, Veterans Administration Hospital,
Denver, Colo. : .

Carrot, BENJAMIN E.—Biometric Branch, National Cancer Institute, National
Institutes of Health, Bethesda, Md.

CHADWICK, DonaLD R., M.D.—Director, National Center for Chronic Disease
Control, U.S.P.H.S., Arlington, Va.

DE LA PUENTE, JosePH L.—Chief, statistical methods, Cancer Control Program,
National Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

Deyxin, DANIEL, M.D.—Assistant professor of medicine, Harvard Medical School,
Boston, Mass.

Dozss, GeoraE, M.D.—-Associate chief, Division of Scientific Opinions, Federal
Trade Commission, Washington, D.C.

Doytrsz, JosrrH, M.D.—Director, Cardiovascular Health Center, Albany Medical
College, Union University, Albany, N.Y.

HastTMan, Nicotas J., M.D.—Professor emeritus of obstetrics, Johns Hopkins
Hospital, Woman’s Clinic, Baltimore, Md.

Eprstemn, Freperick H., M.D.—-Professor, University of Michigan School of Public
Health, Department of Epidemiology, Ann Arbor, Mich.

Exzicu, 8S. Paut, Jr., M.D.—Deputy chief, Heart Disease Control Program, Na-
tional Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

Evans, Rogert, Ph. D.—-Department of Sociology, University of Wisconsin,
Madison, Wis.

Fax, Hans L., Ph. D.—Associate scientific director for carcinogenesis, National
Cancer Institute, National Institutes of Health, Bethesda, Md.

Ferris, BENJAMIN G., Jr., M.D.—Professor, Department of Physiology, Harvard
School of Public Health, Harvard University, Boston, Mass.

Fox, Bernarp H., Ph. D.—Acting Chief, Experimental Research Branch, Injury
Control Program, National Center for Urban and Industrial Health, U.S.P.HLS.,
Arlington, Va.

Fox, Samvuszt M., III., M.D.—Chief, Heart Disease Control Program, National
Center for Chronic Disease Control, U.S.P.HLS., Arlington, Va. .

GITTLEsOoHN, ALLAN, Ph. D.—Professor, Johns Hopkins School of Public Health
and Hygiene, Johns Hopkins University, Baltimore, Md.

Gop, Ronatp J.—Statistician, Operational Studies Section, Cancer Control Pro-
gram, National Center for Chronic Disease Control, U.S.P.HLS., Arlington, Va.

HaENszEL, WILLIAM M.—Chief, Biometry Branch, National Cancer Institute,
National Institutes of Health, Bethesda, Md.

HAprrin, Max, Ph. D.—Assistant chief, Biometrics Research Branch, National
Institutes of Health, Bethesda, Md.

Hammonp, E. Cuyter, Sc. D.—Vice president, epidemiology and statistical re-
search, American Cancer Society, New York, N.Y.

HaskeEL., WirrxzaM L., Ph. D.—Physical activity consultant, Heart Disease Con-
trol Program, National Center for Chronic Disease Control, U.S.P.H.S., Ariing-
ton, Va.

Hayes, Ricrarp, D.D.S.—Assistant to the chief, cancer detection, Cancer Control
Program, National Center for Chronic Disease Control, U.S.P.H.S., Arling-
ton, Va.

HEINZELMAN, FRep, Ph. D.—Research psychologist, Heart Disease Control Pro-
gram, Natfonal Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

Hess, CATHERINE B., M.D.—Assistant to the chief, Cancer Control Program, Na-
tional Center for Chronic Disease Control, U.S.P,H.S., Arlington, Va.

Hicorns, I. I. T., M.D.—Professor, University of Michigan School of Public
Health, Department of Epidemiology, Ann Arbor, Mich.
HorrMaNn, Dieteton, M.D.—Associate member, environmental carcinogenesis,
Sloan-Kettering Institute for Cancer Research, New York, N.Y. ,

Imsoven, C. A., Jr., M.D.—Chief, Chronic Respiratory Disease Control Program,
National Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

IsxRant, AtsmrT P.—Chief, Epidemiclogy and Surveillance Branch, Injury
Control Program, National Center for Urban and Industrial Health, U.8.P.EL8.,
Arlington, Va.

KANNEL, WILLIAM B., M.D.— Associate medical director, National Heart Institute,
Harvard Medical School, Boston, Mass.

Kenner, Hargis, M.D.—Medical consultant, Heart Disease Control Program,
National Center for Chronic Disease Control, U.S.P.H.S8., Arlington, Va.

Ko.syE, Susannan M.—Scientist, Chevy Chase, Md.

Korin, Pavt, M.D.—Director, National Environmental Health Sciences Center,
Research Triangle Park, N.C.

Kevunorr, Dean B.—Statistician, Biometrics Section, National Heart Institute,
National Institutes of Health, Bethesda, Md.

LANDAU, EMANUEL, Ph. D.—Statistical advisor, Office of the Director, National
Center for Air Pollution Control, U.S.P.H.S., Washington, D.C.

Lecator, Marvin S., M.D.-—Chief, Cell Biology Branch, Division of Nutrition,
Food and Drug Administration, Washington, D.C.

LeMaIsTrE, CHaRLes A., M.D.—vVice chancellor of health affairs, Office of the

_ Chancellor, University of Texas, Austin, Tex.

LILIENFELD, ABRAHAM, M.D.—Professor, Johns Hopkins School of Hygiene and
Public Health, Baltimore, Md.

Loncrn, Huseet, M.D.—Office of associate director for collaborative studies,
National Heart Institute, National Institutes of Health, Bethesda, Md.

Loupon, R. G., M.D.—Professor, Department of Internal Medicine, University
of Texas, Dallas, Tex. :

MaRLAND, Riowarp E., Ph. D.—Injury Control Program, National Center for
Urban and Industrial Health, U.S.P.H.S., Arlington, Va.

MoLean, Ross, M.D.—Professor of medicine (pulmonary disease), Emory Uni-
versity, School of Medicine, Atlanta, Ga.

Morrison, BayagD H., Ph. D.—Office of the Director, National Cancer Institute,
National Institutes of Health, Bethesda, Md.

Mount, Frank W., M.D.—Deputy chief, Ohronic Respiratory Disease Control
Program, U.S.P.H.S., Arlington, Va.

Morpuy, EpMonp A., M.D.— Associate professor, University of Colorado Medical
Center, medicine and biostatistics, Denver, Colo.

PETERSON, WILLIAM F., M.D.—Chief, Obstetrics and Gynecology Service, USAF
Hospital Andrews, MSHCB, Andrews Air Force Base, Washington, D.C.

Petty, THomas L., M.D.—Assistant professor of medicine, University of Colo-
rado Medical Center, Denver, Colo.

Rosrns, Morton—Chief, program evaluation and project design, Heart Disease
Control Program, National Center for Chronic Disease Control, U.S.P.ELS.,
Arlington, Va.

Ross, Wittzam L., M.D.—Chief, Cancer Control Program, National Center for
Chronic Disease Control, U.S.P.H.S., Arlington, Va.

ScuuMan, Leonagp M., M.D.—Professor of epidemiology, University of Minne-
sota, School of Public Health, Minneapolis, Minn.

Scuwartz, J. Tueoporr, M.D.—Section head, Epidemiology Branch, National
Institute of Neurological Diseases and Blindness, National Institutes of Health,
Bethesda, Md.
Suear, Murray J., Ph. D.—Special advisor, Office of the Director, National
Cancer Institute, National Institutes of Health, Bethesda, Md.

Smwe1, James 8S., M.D.—Chief, Field Staff, Coordination and Development Section,
Heart Disease Control Program, National Center for Chronic Disease Control,
U.S.P.H.S., Arlington, Va. ;

STEINKE, Wirt1am, M.D.—Medical officer, Heart Disease Control Program, Na-
tional Center for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

Srxone, Jack, M.D.—Chairman of Department of Pathology, Louisiana State
University, School of Medicine, New Orleans, La.

Tom, THomas J.—Statistician, Heart Disease Control Program, National Center
for Chronic Disease Control, U.S.P.H.S., Arlington, Va.

UNpERWoop, Paul, M.D.—<Asesistant professor of obstetrics and gynecology,
University of South Carolina Medical School, Department of Obstetrics and
Gynecology, Charleston, S.C.

Wesrura, Enwin, M.D.—Chief, Applied Physiology Laboratory, Heart Disease
Control Program, National Center for Chronic Disease Control, U.8.P.HLS.,
Arlington, Va.

Wairr, EvisaH L.—Acting Director, Division of Health Interview Statistics,
National Center for Health Statistics, U.S.P.HLS., Washington, D.C.

Wootsry, Turoporr D.—Deputy director, Office of the Center Director, National
Center for Health Statistics, U.S.P.HLS., Washington, D.C.

Wyrwoer, Denest L., M.D.—Associate member, Sloan-Kettering Institute for Tech-
nology, New York, N.Y.

YARMOLINSKY, MICHAEL, M.D.—Research chemist, Laboratory of Molecular
Biology, National Institutes of Health, Bethesda, Md. ,

ZUKEL, Wu1aM J., M.D.—Associate Director for Collaborative Studies, National
Heart Institute, National Institutes of Health, Bethesda, Md.

The following professional staff of the National Clearinghouse for
Smoking and Health contributed to the preparation of this report:
Robert F. Clarke, Ph. D., Emil Corwin, Robert S. Hutchings, Selwyn
Waingrow, and David G. Wember, MD.
PART 1

 

Current Information on the
Health Consequences of
Smoking
introduction

 

r January 1964, an Advisory Committee appointed by the Surgeon
General of the Public Health Service issued its report (74) on the
relationship between smoking and health.* The conclusions of that
Committee were summed up in the sentence: “Cigarette smoking is a
health hazard of sufficient importance in the United States to warrant
appropriate remedial action.”

In the 314 years since the publication of that report, an unprece-
dented amount of pertinent research has been completed, continued,
or initiated in this country and abroad under the sponsorship of
governments, universities, industry groups, and other entities. This
research has been reviewed and no evidence has been revealed which
brings into question the conclusions of the 1964 report. On the con-
trary, the research studies published since 1964 have strengthened
those conclusions and have extended in some important respects our
knowledge of the health consequences of smoking.

The present state of knowledge of these health consequences can,
in the judgment vof the Public Health Service, be summarized as
follows:

1. Cigarette smokers have substantially higher rates of death
and disability than their nonsmoking counterparts in the popu-
lation. This means that cigarette smokers tend to die at earlier
ages and experience more days of disability than comparable
nonsmokers.

2. A substantial portion of earlier deaths and excess disability
would not have occurred if those affected had never smoked.

3. If it were not for cigarette smoking, practically none of the
earlier deaths from lung cancer would have occurred; nor a sub-
stantial portion of the earlier deaths from chronic bronchopul-
monary diseases (commonly diagnosed as chronic bronchitis or
pulmonary emphysema or both); nor a portion of the earlier
deaths of cardiovascular origin. Excess disability from chronic
pulmonary and cardiovascular diseases would also be less.

*“Smoking and Health. Report of the Advisory Committee to the Surgeon
General of the Public Health Service.” It is frequently referred to in this manu-
script as “the Surgeon General’s 1964 Report.”
4. Cessation or appreciable reduction of cigarette smoking
could delay or avert a substantial portion of deaths which occur
from lung cancer, a substantial portion of the earlier deaths and
excess disability from chronic bronchopulmonary diseases, and a
portion of the earlier deaths and excess disability of cardiovas-
cular origin.

NATURE OF RECENT RESEARCH FINDINGS

Since the Surgeon General’s Report was published in January 1964,
there has been a proliferation of additional studies and reports on
smoking research. In the 12 years preceding that report, some 3,000
articles were published reporting research ; since 1964, there have been
more than 2,000 additional studies.

These studies have helped to clarify the role that age plays in the
relationship of smoking to health; the similarities and differences in
the ways in which men and women are affected by smoking; and the
influences and effects of stopping smoking, particularly in the case of
lung cancer where there is significant data to show that sharp reduc-
tions in lung cancer deaths follow closely reductions: in cigarette
smoking. The studies also suggest the importance of a variety of
measures of exposure; add substantial new information on the magni-
tude of the morbidity problem associated with smoking; and provide
more adequate data upon which to base estimates of the magnitude
of the mortality problem.

Historically, concern about the effects of smoking began with ob-
servations of the extremely high frequency with which lung cancer
patients were identified as cigarette smokers. These observations took
on a fuller meaning with the first publication of the prospective studies
in 1954 when higher overall death rates among cigarette smokers
were identified. The rates were found to exceed the difference that
could be accounted for by lung cancer alone. Until that time, the
possibility remained that although more cigarette smokers appeared to
suffer from lung cancer, if there were no significant excess overall
mortality, some other cause or causes of mortality would have had to
be underrepresented among cigarette smokers.

The Surgeon General’s 1964 Report concluded that cigarette smokers
do have higher death rates than their nonsmoking counterparts. This
has changed the emphasis of the present problem away from the ques-
tion “does cigarette smoking cause disease?” to the more precise
questions of :

1. How much mortality and excess disability are associated with
smoking?
2. How much of this early mortality and excess disability would
not have occurred if people had not taken up cigarette smoking?

3. How much of this early mortality and excess disability
could be averted by the cessation or reduction of cigarette
smoking ?

4, What are the biomechanisms whereby these effects take place
and what are the critical factors in these mechanisms?

To answer these questions one must not only study the details of
the relationship of overall mortality with cigarette smoking, one must
also turn to the specific causes of death and disability and to other
kinds of evidence.

The research carried on since 1964 is of three principal varieties:
Epidemiological studies, especially those which involve surveys of
large portions of the population; a health survey which has revealed
new information about the relation between smoking and illness; and
a vast amount of experimental, clinical, pathological, and behavioral
research which adds to the understanding of the precise ways in which
smoking affects the body, plus other closely related or peripheral
information. ;

In the area of morbidity or illness, the primary addition to our
knowledge is from “Cigarette Smoking and Health Characteristics,”
a report (16) of the National Center for Health Statistics on the
frequency of illness among smokers and nonsmokers in a large proba-
bility sample of the U.S. population. Regarding epidemiological data,
new reports from four of the major population studies have been
published since 1964:

1. The Dorn study of smoking and mortality among U.S. vet-
erans (73).

2. Hammond’s study on smoking in relation to the death rates
of 1 million men and women in 25 States (17).

3. The Doll and Hill study on the mortality of British physi-
cians in relation to smoking (8,9, 10).

4. A Canadian Smoking and Health Study of Canadian pen-
sioners, including veterans and dependents (7).

The principal features of the additional data provided by these
four studies are: (1) The extension of the time period of followup,
(2) the additional data available for specific age groups among men,
and (8) the inclusion of substantial data on women. In all, the pro-
spective study reports now available are based on more than 108,000
deaths, an increase of about 43,000 deaths over the 65,023 summarized

in the 1964 report. About 19,000 of these additional deaths were among
women.
THE NATURE OF THIS REPORT

This report which provides a summary of current information on the
health consequences of smoking, is based on the review of the research
reports which have become available since the study of the Surgeon
General’s Advisory Committee was released. Public Health Service
staff members consulted the literature and requested additional infor-
mation or interpretations of the published data from the research
scientists when needed. During this review a complete bibliography,
containing some 5,700 citations, was compiled; it is now in manu-
script form and will be published shortly (29). ,

The advice and comments of experts within the Public Health Serv-
ice, particularly the Bureau of Disease Prevention and Environmental
Control and the National Institutes of Health, as well as of specialists
outside the Public Health Service, were solicited especially on matters
involving judgment and evaluation.

The general criteria used by the Surgeon General’s Committee hav
been followed. First, epidemiological data were evaluated to determine
whether an association exists. In judging the significance of the as-
sociation, its consistency, strength, specificity, temporal relationship,
and coherence were utilized. The convergence of evidence from animal
experiments, clinical and autopsy studies, and population studies re-
mains the essential basis for evaluation of the significance of the
associations identified.

This report presents, under the following headings, the major find-
ings of research studies published in the past 3 to 4 years:

1. Smoking and Overall Mortality.
. Smoking and Overall Morbidity.
3. Smoking and Cardiovascular Diseases.
4, Smoking and Chronic Bronchopulmonary Diseases (Non-neo-
plastic).
5. Smoking and Cancer.
6. Other Conditions and Research Areas.

Each of these sections is introduced by pertinent conclusions from
the Surgeon General’s 1964 Report, which are followed by discussion
and conclusions of the present study.
Smoking and Overall Mortality

 

ConcuusIons oF THE SuRGEON GeEnzERAL’s 1964 Report

CIGARETTE smoking is associated with a 70-percent increase in
the age-specific death rates of males, and to a lesser extent with in-
creased death rates of females. The total number of excess deaths
causally related to cigarette smoking in the U.S. population cannot
be accurately estimated. In view of the continuing an mounting evi-
dence from many sources, it is the judgment of the Committee that
cigarette smoking contributes substantially to mortality from certain
specific diseases and to the overall death rate.

In general, the greater the number of cigarettes smoked daily, the
higher the death rate. For men who smoke fewer than 10 cigarettes
a day, according to the seven prospective studies, the death rate from
all causes is about 40 percent higher than for nonsmokers. For those
who smoke from 10 to 19 cigarettes a day, it is about 70 percent higher
than for nonsmokers; for those who smoke 20 to 39 a day, 90 percent
higher; and for those who smoke 40 or more, it is 120 percent higher.

igarette smokers who stopped smoking before enrolling in the
seven studies have a death rate about 40 percent higher than non-
smokers, as against 70 percent higher for current cigarette smokers.
Men who began smoking before age 20 have a substantially higher
death rate than those who began after age 25. Compared with non-
smokers, the mortality risk of cigarette smokers, after adjustments for
differences in age, increases with duration of smoking (number of
years), and is higher in those who stopped after age 55 than for those
who stopped at an earlier age.

In two studies which recorded the degree of inhalation, the mortality
ratio for a given amount of smoking was greater for inhalers than for
noninhalers.

The ratio of death rates of smokers to that of nonsmokers is highest
at, he earlier ages (40-50) represented in these studies, and deciines
with inc .

Possible relationships of death rates to other forms of tobacco use
were also investigated * * *. The death rates for men smoking less
than 5 cigars a day are about the same as for nonsmokers. For men
smoking more than 5 cigars daily, death rates are slightly higher.
There is some indication that these higher death rates occur primaril
in men who have been smoking more than 30 years and who inhale
the smoke to some d . The death rates for pipe smokers are little
if at all higher than for nonsmokers, even for men who smoke 10 or
more pipefuls a day and for men who have smoked pipes more than

years.

271-394 O—67———2 7
CURRENT INFORMATION, 1967

The primary addition to knowledge in the areas of smoking and
overall mortality comes from the four major population studies. Ad-
ditional periods of followup have provided a broader base from which
it becomes possible to estimate the excess deaths related to cigarette
smoking in the U.S. population and from which firmer conclusions
may be drawn as to the role of various exposure factors in the associa-
tions found.

The contributions since 1964 of each of the four population studies
to the relation of smoking and overall mortality, as summarized by the
authors, are set forth below.

Sroupy or U.S. Vererans

(An 8% year followup of 293,658 persons holding U.S. Government
life insurance policies. Commonly referred to as the Dorn Study after
the late Dr. Harold F. Dorn. The most recent report is by Kahn (13).)

“* * * the increased mortality risk associated with cigarette smok-
ing was found to be higher in the more recent calendar time period
than in the initial years of the study.

“* * * mortality ratios of current cigarette smokers compared with
those who have never smoked are 1.7 for death from all causes, 10.9
for lung cancer, 12.2 for emphysema without bronchitis, and 1.6 for
coronary heart disease. Paralysis agitans was the only cause of death
associated with significantly lower mortality for smokers than for
nonsmokers.

“For all categories of current smokers, risk was related to amount
smoked. The risk for cigarette smokers was much greater than that for
pipe or cigar smokers. Current smokers of cigarettes, cigars, or pipes
experienced a mortality risk significantly greater than that for non-
smokers if they smoked more than four pipes or four cigars daily or
more than an occasional cigarette.

“There was a positive relationship between duration of cigarette
smoking and mortality risk from all causes of death for at least some
classifications of smokers.

“* * * probabilities of death for ex-smokers of cigarettes revealed a
downward trend in risk as duration of time discontinued increased,
when other variables—age began smoking, amount smoked, and cur-
rent age—were controlled * * *. The data can be regarded as evidence
against the constitutional hypothesis.”

Calculations are presented to note that observations made during
the study suggest the possibility that data from respondents (those
who answered the smoking questionnaire) may in fact underestimate
the risk associated with smoking. The Surgeon General’s 1964 Report
had considered the possibility that differences between respondents
and nonrespondents to the questionnaire might have introduced a
bias and had attempted to calculate a maximum estimate of that
bias.

Srupy or Men anp WoMEN rn 25 States

(This report is based on 3,764,571 person-years of experience and 43,221
deaths occurring among 1,003,229 subjects—440,558 men and 562,671
women—between the ages of 35 and 84 from October 1, 1959, to Feb-_
ruary 15, 1960, when they enrolled in a prospective study and answered
detailed questionnaires including questions on their smoking habits.
Hammond. (11).) .

“Death rates of both men and women were higher. among subjects
with a history of cigarette smoking than among those who never
smoked regularly. ,

“Death rates of current cigarette smokers increased with number of
cigarettes smoked per day and degree of inhalation.

“Death rates were higher among current cigarette smokers starting
the habit at a young age than among those starting the habit later in
life. Among both men and women, the difference between the death
rates of cigarette smokers and nonsmokers increased with age.

“Among men, the death rates for ex-cigarette smokers were lower
than for men currently smoking cigarettes when they enrolled in the
study. Death rates of ex-cigarette smokers decreased with the length
of time since they last smoked cigarettes.

“* * * Total death rates and death rates from most of the common
diseases occurring in both sexes were higher in men than women,
were higher in men who never smoked regularly than in women who
never smoked regularly, and were far higher in men with a history
of cigarette smoking than in women with a history of regular cigarette
smoking.

“The difference between the death rates of subjects with a history
of cigarette smoking and subjects who never smoked regularly was
far greater among men than women. Female cigarette smokers (as
a group) have been far less exposed to cigarette smoke than male
cigarette smokers of the same ages, as judged by number of cigarettes
smoked per day, degree of inhalation, and the number of years they
have smoked. Many female cigarette smokers smoke only a few
cigarettes a day, do not inhale, and have been smoking for only a
few years; their death rates are about the same as the death rates of
women who never smoked regularly.”

Srupy or Brrmss Pxysicians

(The mortality of nearly 41,000 men and women in the medical profes-
sion in the United Kingdom has been followed for 12 years. During the
first 10 years 4,597 of the men and 366 of the women died. These deaths
were analyzed in relation to smoking habits reported by doctors in reply
to a questionnaire sent to them in 1961—both sexes—and again in 1957,
men, and 1960, women. Doll and Hill (8, 9).)

«“* * * An association with smoking is found, in differing degrees,
in men for seven causes of death [which accounted for 39 percent of
the death rate]—namely, cancer of the lung, cancers of the upper
respiratory and digestive tracts, chronic bronchitis, pulmonary tuber-
culosis, coronary disease without hypertension, peptic ulcer, and
cirrhosis of the liver and alcoholism. No association is found with the
remaining 61 percent of the death rate, and this includes such major
causes as other forms of cancer, cerebrovascular accidents, hyperten-
sion, myocardial degeneration, suicide, and accidents.

“In women, the few deaths at present available show an association
only between smoking and cancer of the lung.

«* * * Tf the excess deaths in smokers under the age of 65 years
from (a) cancer of the lung, (6) chronic bronchitis and emphysema,
(c) coronary thrombosis without hypertension be taken as attributable
to their cigarette smoking, then the total mortality from all causes at
ages 45-64 years is increased thereby by approximately 50 percent.”

The report states: “One of the striking characteristics of British
mortality in the last half-century has been the lack of improvement
in the death rate of-men in middle life. In cigarette smoking may lie
one prominent cause.”

Srupy or Canaptan PENSIONERS

(The purpose of the study was to investigate the relationships between
residence, occupation, smoking habits, and mortality from chronic
diseases particularly lung cancer. It was initiated by a questionnaire
which was sent to Canadian veteran pension recipients during the
period September 1965 through June 1956.

Returns from 78,000 men, and 14,000 women, mostly widows, were
analyzed. The men were mainly World War I and World War IT vet-
erans, but some Boer War and Korean War veterans, as well as some
non-veteran pension recipients were included. The age of most of the
men at the beginning of the study ranged from 30 to 90 years and the ©
distribution was characterized by the ages of men eligible for service
in the two World Wars.

_For each respondent dying between July 1, 1956, and June 80, 1962,
the cause of death was related to information on his questionnaire
about age, history of smoking habits, residence and occupation.
Among the respondents during the 6 years of followup there were 9,491
deaths of males, and 1,794 deaths of females which were analyzed
(1).)

“Current cigarette smokers had a death rate for overall mortality
54 percent higher than that of nonsmokers * * * Ex-cigarette smok-

10
ers had a comparatively lower rate, which was still 36 percent above
the rate for nonsmokers * * * Men smoking combinations of ciga-
rettes plus cigars and/or pipe also had elevated death rates for overall
mortality, but these were not elevated to the same extent as those of
men smoking only cigarettes.

' “The death rates for overall mortality of pipe smokers and cigar
smokers were not appreciably different from those of nonsmokers.

“For cigarette smokers as compared to nonsmokers, overall mor-
tality ratios were elevated after 5 years of smoking at any time in
their life and remained elevated as long as they continued to smoke
cigarettes. -

‘Male current cigarette smokers who inhaled had a death rate for
overall mortality 52 percent higher than that of those who did not
inhale.

“An urban/rural comparison was made between males of equivalent
cigarette smoking habits and nonsmokers. It was found that the
death rate for overall mortality of urban dwellers (persons with
a history of 5 years or more of city residence) was 12 percent higher
than that for rural dwellers of comparable smoking habits.

“Respondents were classified into occupational groups based on
their history of occupation. No evidence was found in this study of
clear-cut associations between cause of death and occupation. Further,
occupation did not appear to modify the established association of
cigarette smokers with death rates in excess of those of nonsmokers.”

SOME GENERAL CONSIDERATIONS

The problem of how best to measure the relationship between smok-
ing and mortality has been discussed in the Surgeon General’s 1964
Report as well as in some of the prospective study reports. As the
amount of data available increases, the person-years of observations
in the many population subgroups that are worth examining increases
so that stable rates may be computed and compared. A brief discussion
of three measures of comparison available and their utility seems
desirable as confusion frequently arises over these measures.

1. Mortality Ratios: Obtained by dividing the death rate for
a classification of smokers by the death rate of a comparable
group of nonsmokers.

2. Differences in Mortality Rates: Obtained by subtracting
from the death rate for smokers, the death rate of a comparable
group of nonsmokers.

3. Excess Deaths: Obtained by subtracting from the number
of deaths occurring in a group of smokers, the number of deaths

i
which would have occurred if that group of smokers had ex-
perienced the same mortality rates as a comparable group of
nonsmokers. In the example which follows this has been reported
as a percentage of all deaths in the appropriate age group.

Table 1 presents in summary form all three measures for five age
_ groups of men from both the U.S. veterans study and Hammond’s
study and for the same age groups of women from the latter study.

The statistics were derived from the cited publications to provide
reasonable comparability and may vary slightly from the figures
combined in other ways. Also it should be noted that the age groups
are not defined identically and the experience reported covers some-
what different time periods. The smoking group analyzed is “cur-
rent cigarette smokers,” i.e., those who were smoking at the time of
enrollment into the study, and the comparison group is “never smoked
regularly,” i.e., those who had never been regular smokers of any
form of tobacco.

The number of deaths in each age-sex group is given to indicate
the relative stability of the figures in that column. The data in the
veterans study are largely concentrated in age groups 55-64 and
65-74. In Hammond’s study, age group 35-44 is less stable than the
succeeding groups both for men and for women.

1. Mortality Ratioe—For men, these are at their highest in
age group 45-54, diminishing in each subsequent decade. In both
studies mortality ratios appear to be somewhat lower in the preceding
decade 35-44. However, with the smaller numbers of cases available
in that age group, it may be that selective factors contribute to the
finding. For women the mortality ratios are much smaller than for
men, although the same pattern is suggested. In general, a mortality
ratio has been considered to reflect the degree to which a classifica-
tion variable identifies or may account for variations in death rates.
As such, it is a measure of relative risk which indicates the importance
of that variable relative to uncontrolled variables—an indicator of
potential biological significance.

2. Differences in Mortality Rates——These increase consistently
with increasing age in all three study groups, except for the oldest
age group in women where there is practically no difference in the
rates for smokers and nonsmokers. Differences between smokers’ rates
and nonsmokers’ rates are much smaller for women than for men,
as are the death rates themselves for men and women classified simi-
larly with respect to smoking. This measure reflects the added proba-
bility of death in a 1-year period for the smoker over that for the non-
smoker. As such it is a measure of personal health significance, a. means
for the individual to estimate the added risk to which he is exposed.

12
Tas_e 1.—Comparison of 3 measures of relationship between cigarette
smoking and overall death rates by age and sex as derived from 2
major prospective studies (11, 13)*

 

 

 

Age
3-44 | 45-54 55-04 5-74 | 75-84
U.S. VETERANS: MEN
Total deaths_.._..._.__.-_.. 383 366 | 13, 840 | 17, 550 | 1, 932
Death rates per 100,000:
Never smoked regularly___..--. 127 264] 1,056 | 2,411 | 6, 214
Current cigarette smokers... .._ 232 728 1,819 | 4,032 | 8, 471
Mortality ratio #__._... 222222 L 1. 83 2. 76 172 167] 136
Difference in death rates per
100,000 *_ 2-2 -- eee 105 464 763 | 1,621 | 2, 257
Excess deaths as percentage of
total 4__---_- 2.2 33 483 21 17 8
HamMuonp Men
Total deaths.__........-.--. 631 | 5,297 | 8,427 | 8,125 | 3,968
Death rates per 100,000:
Never smoked regularly__.__..- 210 406 | 1,202 3, 168 | 7, 863
Current cigarette smokers... ... 397 925 | 2,202 | 4,788 | 9, 674
Mortality ratio?_..--..-..- 22 -__.- 189; 228 1.83] 151 1. 23
Difference in death rates per
100,000 *__.---- eee 187 519 | 1,000] 1,620 | 1,811
Excess deaths as percentage of
total #__--.2 2 ee 33 38 25 13 4
HamMonp WomMEN
Total deaths.....__.__.._--. 727 | 2,826 | 3,915 | 5,115 | 4, 188
Death rates per 100,000:
Never smoked regularly... _..__- 165 304 698 | 1,913 | 5,914
Current cigarette smokers ___-__- 186 384 838 | 2,229 | 5, 846
Mortality ratio ?_..............2-.. 1.13 | 126 1. 20 117 . 99
Difference in death rates per
100,000 3___-22. 22 21 80 140 316 68
Excess deaths as percentage of
total #_ 2 eee 5 9 4 2 |.-----

 

 

 

 

 

 

‘ These figures are derived from the references. 5 year age groups were combined directly from the reported
statistics without adjustment to any standard population.

2 Mortality ratios—Death rate for current cigarette emokera divided by death rate for those who never smoked
regularly.

5 Difference in death rates— Death rate for current cigarette smokere rainus death rete for those who never smoked
regularly.

4 Excess deaths among current cigarette smokers (1.e., additional deaths that occurred among current
cigarette smokers per year above those which would have occurred if smokers bad the same death rates as
those who never smoked regularly). This is expressed as a percentage of elf deaths occurring in that age-sex
group.

13
3. Ewcess Deaths as a Percentage of Total Deaths—As with mor-
tality ratios, this statistic appears to be highest in the age group 45-54
where it reaches 43 percent in one group of men and 38 percent in
the other. Hammond’s data by 5-year age groups show the highest
rate at ages 45-49, where it is 44 percent. Reviewing both study groups
it appears that for men between the ages of 35 and 60 approximately
one-third of all deaths that occur are excess deaths in the sense that
they would not have occurred as early as they did if cigarette smokers
had the same death rates as the nonsmoking group. For women, the
percentage is much lower, reaching a peak of 9 percent of all deaths
in age group 45-54. It should be noted that this measure not only de-
pends on the differences in death rates between the smokers and the
nonsmokers, but also on the proportion of smokers in the group. Thus,
even with a large difference in rates between smokers and nonsmokers,
a population with very few smokers would have very few excess
deaths. This measure is therefore an indicator of the public health
significance of the differences found since it measures the number of
people affected and therefore the magnitude of the problem for society
asa whole.

Once the magnitude of the excess-is identified the problem becomes
one of determining (1) how much of the excess would not have oc-
curred if it had not been for cigarette smoking and (2) how much
would have occurred anyhow. It should be noted that much of the ex-
cess has already been identified as belonging in the first category. Of
the remainder, little of the excess has been clearly identified as belong-
ing in the second category—that is, not caused by smoking. With most
of that remainder there is uncertainty as to the category in which it
belongs.

Measures or ExPosuRE

Studies involving smoking, whether epidemiological or behavioral,
have been concerned with measures of exposure to tobacco smoke. For
the most part, these studies have been restricted principally to the in-
dex of number of cigarettes smoked over a specified period of time,
usually an “average day.” The heavy reliance on numbers of cigarettes
alone as a measure has produced important findings but it has possi-
bly obscured others. The new reports on the prospective studies have
provided a substantial amount of data to support the concept that
many elements should enter into an overall measure of exposure. Such
factors as age at beginning smoking, duration of smoking, and inhala-
tion have all shown some independent contributions to the overall
- effect, along with numbers of cigarettes. A recent report (72) has at-
tempted to develop a more adequate measure of exposure in which
various individual components of dosage would be combined to form
composite scores.

14
A dosage score was developed as a function of the average number
of cigarettes smoked per day, the “tar” (smoke solids minus moisture)
rating of the brand of cigarette smoked, and the portion of the ciga-
rette actually smoked. In addition, questions on both depth and fre-
quency of inhalation were developed. Normative data have been ob-
tained from a national survey sample of smokers. In general, although
the various measures reflecting exposure are interrelated, there are
many individuals with high exposure on one measure but low ex-
posure on another. Furthermore, there are systematic differences in
some of these measures of dosage between men and women, between
heavy and light smokers (by the usual criterion of numbers of ciga-
rettes), etc. The existence of a dose-response relationship between ex-
posure to cigarette smoke and the risks most clearly associated with
cigarette smoking is now generally accepted.

Wynder and Hoffmann (20) have shown in laboratory experiments
with animals that the tumorigenicity of cigarette smoke can be
reduced by alteration in the cigarette which reduces the “tar” and nico-
tine content. They use the term “indicator” for “tar” and nicotine con-
tent (the two measures tend to be used jointly since when one is high
the other tends to be high unless the nicotine has been removed in
processing), or other measures which reflect this type of relationship,
lacking the identification of specific agents which are responsible for
the effect. Bock, Moore, and Clark (2) have independently shown a
similar variation in carcinogenic activity of tobacco “tar” obtained
from different types of cigarettes.

The preponderance of scientific evidence strongly suggests that the
“tar” and nicotine content of cigarette smoke is a meaningful factor in
the measurement of dosage.

CESSATION OF SMOKING

The cessation of smoking is, of course, an extreme example of the
reduction of dosage. Data from the prospective studies show a reduc-
tion in both overall mortality and mortality from specific diseases
among those who have stopped smoking when compared with those
persons who continue to smoke. This finding has been somewhat ob-
scured by the fact that ill health is a frequent cause of giving up
smoking so that death rates and disability rates for ex-smokers as a
group tend to be high for an initial period of time following cessation.

In this connection, the Study of British Physicians shows that
among the total group of physicians in the study (smokers, ex-
smokers, and those who never smoked, combined) there was a reduc-
tion in the standardized lung cancer death rate from 0.69 per 1,000
in the first 5 years of the study (1951-56) to 0.64 per 1,000 in the sec-
ond 5 years of the study (1956-61). This reduction occurred during

15
the time when there was also a substantial drop in cigarette smoking
among physicians in general, and during the time that lung cancer
rates were rising in the male population of Great Britain, This situa-
tion is not unlike that of a controlled cessation experiment in which
the effect of giving up smoking is judged by the mortality results in
an entire population in which the giving up of smoking is common
as against another population in which it is not common. A more recent
report by Doll (7) suggests that this trend is becoming more marked
as the rate of smoking among British physicians decreases and the
length of the cessation period increases.

These findings are shown in Table 2, which has been derived from
Doll’s report (7). The lung cancer death rate among men in England
and Wales increased from 1.49 per 1,000 in the period 1954-57 to 1.86
per 1,000 in the period 1962-64, a rise of 25 percent. At the same time,
the lung cancer death rate for British physicians dropped from 1.09
per 1,000 in the first period to 0.76 per 1,000 in the second period, a
reduction of 30 percent. This reduction in death rates from lung can-
cer among all physicians is larger than would have been anticipated
from examining only the experience of those physicians who had
stopped smoking before the study began and indicates that the ex-
perience of ex-smokers in prospective studies probably understates
the benefits of giving up smoking.

With these findings the case for cigarette smoking as the principal
cause of lung cancer is overwhelming. The reduction of rates experi-
enced in ex-smokers as compared with continuing smokers is clearly
shown in the case of lung cancer to be a reflection of a significant
change in risk. Since the concern that selective bias might have ac-
counted for the earlier findings has been contraindicated, a stronger
case can now be made for interpreting reduced rates of overall mor-
tality for those who give up smoking as also reflecting a direct altera-
tion of risk compared to those who continue to smoke.

There are no adequate data to evaluate the benefit of reductions in
exposure that are more modest than those achieved by complete cessa-
tion, although it seems reasonable to assume that a substantial reduc-
tion in exposure is likely to be accompanied by some reduction in risk
relative to those who do not reduce their exposure.

16
TABLE 2.—Changes in the lung cancer death rate in male British phy-
stcians (age 35-84) compared with changes in the rates for the male
population of England and Wales for 3 time intervals between 1954

and 1964 (7)

 

 

 

Lang cancer death rates per 1,000
Time period per
Men in © British
Wi physicians
1954 to 1957__._-----_-_--- eee 1, 49 1.09
1958 to 1961_--.--- 2 ee 1.71 - 83
1962 to 1964___--._---2 2 eee 1. 86 . 76
Percentage change:
Ist to 2nd period__--____-.--.------------.. +15 —24
2nd to 3rd period_-___._...--..---.-- 2. -___- +9 —8s
Ist to 3rd period__-......-.-.---22--- --- eee +25 —30

 

 

 

17
Smoking and Overall Morbidity

 

T THE TIME of the Surgeon General’s 1964 Report there was no
A information available on the overall disability associated with
smoking. To investigate the relationship between smoking and mor-
bidity, the National Center for Health Statistics of the Public Health
Service introduced questions about cigarette smoking into its National
Health Survey, beginning in July 1964. This Survey is a continuing
study conducted since 1957.

In carrying on this Survey, interviewers each year visit 42,000 fami-
lies (selected as a probability sample of the civilian, noninstitutional
population of the United States) and question them about illness, dis-
ability, and days absent from work because of illness, as well as the
nature of the illness. In the year ending in June 1965, they inquired
(after all other questions about health had been asked) about the smok-
ing habits of persons in the family who were 17 years of age or over.

The National Health Survey is concerned with three overall meas-
ures of the impact of illness. ,

1. Days Lost From Work.—These are days absent from job or busi-
ness because of illness or injury. They apply only to those persons
who are currently employed and are therefore heavily concentrated in
age groups 17-64.

2. Bed Days.—These are days when the person is sufficiently ill or
disabled so as to spend all or most of the day in bed, either at home
or in a hospital. All days spent as a hospital patient are included.

3. Days of Restricted Activity—These are days when a person cuts
down his usual activities for most of a day because of an illness or
an injury. Days lost from work because of illness and bed days are, of
course, counted as days of restricted activity. This represents the most
general measure of disability available in the United States today.

Table 3 summarizes the findings in a form similar to that used for
summarizing the overall mortality utilizing three measures of mor-
bidity effect: Morbidity ratios, differences in rates, and excess days of
disability.

19
TaBLe 3.—Comparison of 3 measures of relationship between cigarette
smoking and 8 types of disability days by age and sez as derived from
the National Health Survey (16)

 

 

 

Male Female
17-44 | 45-64 | Sand | 17-44 | 45-64 | 65 and
over over
Worx-Loss Days

Estimated total days (millions) _____ 112 | 127 21 80 55 4
Rate: !

Never smoked cigarettes. ___.. 3.4/ 5.61 9.8 | 4.5 5.3 5.0

History of cigarette smoking___.| 4.4 | 8.5 98) 6.5 6.9 ?)
Morbidity ratio #_.....-.....____- 1.3] 15] 10] L4/ 13] &®
Difference in morbidity rates !4..__| 1.0] 2.9 0 2.0 1.6 ?)
Excess days as percentage of total 5_ 20 28 0 18 11 @)

Restrictep Activiry Days
Estimated total days (millions) _-___ 305 | 386 | 271 | 543 | 469 395
Rate: !

Never smoked cigarettes_..____ 7.5 | 15.0 | 32.9 | 13.3 | 22.6] 40.1

History of cigarette smoking_--} 10.6 | 22.9 | 37.9 | 17.8 | 25.3 | 44.8
Morbidity ratio *__...2.2.222 2-21. 14] 1.5) 1.2 1.3; 1.1 11
Difference in morbidity rates }4...._| 3.1 7.9) 5.0] 4.5 |] 2.7 4.7
Excess days as percentage of total #_ 23 28 8 14 5 2

Bev Days

Estimated total days (millions) -____- 111 118 | 100 | 210) 168 146
Rate: !

Never smoked cigarettes... .___ 2.7| 46(/138.4) 5.4] 80] 15.1

History of cigarette smoking_..| 3.9 | 6.9 | 13.0] 6.7 | 9.2 15.2
Morbidity ratio #_..-.-.---- 2222 1.4] 1.5] .97 | 127) L1 1.0
Difference in morbidity rates!4.....| 1.2] 2.3 |-—0.4 13 1.2 0.1
Excess days as percentage of total °_ 23 28; —1 10 6 0

 

 

 

 

 

 

 

1 Rate is defined as “‘days per person per year.’

2 Based on too few smokers for stable rates.

3 Morbidity Ratios—Morbidity rate for cigarette smokers divided by morbidity rate for those who never emoked
cigarettes.

‘ Difference in Morbidity Rates—Morbidity rate for cigarette emokers minus morbidity rate for those who
never smoked cigarettes.

5 Excess deaths among cigarette smokers (i.c., additional days of disability that occur among cigarette
smokers per year above those which would have occurred if smokers had the same rates as those who never
smoked cigarettes). This is expressed as a percentage of all disability days occurring in that age-sex group.

Days Lost From Work

For those with a history of cigarette smoking, classified by heaviest
amount smoked, the average number of days was 7 percent higher for
men and 15 percent higher for women who had smoked less than 11
cigarettes per day; 33 percent higher for men and 60 percent higher

20
for women who had smoked 11-20 cigarettes per day ; 48 percent higher
for men and 79 percent higher for.women who had smoked 21-40
cigarettes per day; and 83 percent higher for men and 140 percent
higher for women who had smoked more than 40 cigarettes per day.
The relationships expressed by all three measures are somewhat higher
among men aged 45-64 than among men aged 17-44, but lower among
women aged 45-64 than among women aged 17-44. In the survey year,
there were an estimated 399 million workdays lost in the United States
because of illness. A total of 77 million days, or 19 percent, were excess
workdays lost because of the higher rates which exist among persons
who have ever smoked cigarettes as compared to those who never
smoked. This excess loss is highest in men 45-64 where it represents
28 percent of all days lost.
Brep Days

For those with a history of cigarette smoking, classified by heaviest
amount smoked, the average number of days was 10 percent higher
for men and 4 percent lower for women who had smoked less than 11
cigarettes per day; 22 percent higher for men and 17 percent higher
for women who had smoked 11-20 cigarettes per day ; 22 percent high-
er for men and 57 percent higher for women who had smoked 21-40
cigarettes per day; and 53 percent higher for men and 192 percent
higher for women who had smoked more than 40 cigarettes per day.
Relationships with smoking are higher for men than for women for
all three measures except for age 17-44 in which the differences in mor-
bidity rates betwéen smokers and nonsmokers are about the same. For
the entire population 17 years of age and older there were an estimated
853 million bed-days in the survey year. A total of 88 million of these
days, or 10 percent, were “excess” days lost because of the higher rates
which exist among persons who have ever smoked cigarettes as com-
pared to those who never smoked. Excess days as a percentage of total
bed-days is highest for men aged 45-64, where it is 28 percent.

Days or Restricrep Activity

For those with a history of cigarette smoking classified by heaviest
amount smoked, the average number of days was 12 percent higher
for men and 4 percent higher for women who had smoked less than
11 cigarettes per day; 32 percent higher for men and 22 percent for
women who had smoked 11-20 cigarettes per day; 39 percent higher
for men and 48 percent higher for women who had smoked 21-40
cigarettes per day; and 81 percent higher for men and 146 percent
higher for women who had smoked more than 40 cigarettes per day.
Again rates are higher for men than for women in all three measures
except for age group 17-44, in which differences in morbidity rates
are higher for women. There were an estimated 2,369 million such days

21
in the survey year; 306 million, or 18 percent, were excess days lost
because of the higher rates which exist among persons who have ever
smoked cigarettes as compared to those who never smoked. Excess
days as a percentage total restricted activity days was highest in men
aged 45-64.

To help evaluate these general indices of morbidity as measured by
various kinds of disability days it is necessary to turn to the conditions
which are reported more frequently by cigarette smokers than by non-
smokers. Since these are either self-reports or reports made by a re-
sponsible member of the household for others in the household, the
diagnostic accuracy of the reports is obviously less than one could ob-
tain from direct. medical examination. Nevertheless, the bulk of the
reports on chronic conditions reflect what a physician has previously
told the patient or the family with regard to a diagnosis of the
condition.

Chronic conditions (one or more) are reported by 11 percent more
of the men and 9 percent more of the women who have ever smoked
cigarettes than by those who have never smoked. cigarettes. This is
especially high in those who have reported their highest consumption
rate to have been over two packs a day (32 percent higher for men
and 43 percent higher for women). At the lower levels of consumption
the rates reported are 21 percent and 25 percent higher for those
smoking 21-40 cigarettes per day, but only 6 percent higher for men
and 7 percent higher for women for those smoking 11-20 cigarettes per
day and only 1 percent higher for both men and women who have
never smoked more than 10 cigarettes per day. The differences are
especially marked among present smokers of more than two packs per
day whose rate of reporting three or more chronic conditions is 73
percent higher for men and 148 percent higher for women than for
those who have never smoked cigarettes.

Applying differences in prevalence rates to the entire U.S. popula-
tion 17 years of age and over yields the estimate that there are approxi-
mately 11 million more cases of chronic illness annually than there
would be if all people had the same rate of:sickness as those who had
never smoked cigarettes. A large portion of these are accounted for by
conditions classified as “chronic bronchitis and emphysema,” “heart
conditions,” “peptic ulcers,” and “sinusitis.” AJI but the last of these
have previously shown substantially higher mortality rates among
cigarette smokers. Sinusitis, being a nonfatal condition, has not been
identified in the studies of mortality previously reported. The “heart
condition” relationship is most marked in the category “arteriosclero-
tic heart disease including coronary disease.”

The age-adjusted incidence rate of acute conditions for persons who
had ever smoked was 14 percent higher among men and 21 percent
higher among women than the rates for “never smokers.” However,

22
particular caution must be taken in interpreting the results relating
specific acute conditions to cigarette smoking because of the relatively
large sampling error connected with the estimates for the several types
of acute conditions.

Since the National Health Survey is not a prospective study, it does
not identify the rate at which various types of morbidity develop in
comparable groups of smokers and nonsmokers, but reports the recent
existence of such disability. Therefore, the findings are much more
significant when they support relationships previously identified than
when new relationships are identified. It should not be surprising that
causes of mortality which are associated with cigarette smoking have
a counterpart in disease or disability associated with smoking.

As the primary source of data in the United States on disability,
the Survey report, being based on a national probability sample,
provides a solid base for estimating the excess overall disability asso-
ciated with cigarette smoking.

HIGHLIGHTS OF CURRENT INFORMATION ON OVERALL
MORTALITY AND MORBIDITY

1. The previous conclusions with respect to the association between
smoking and mortality are both confirmed and strengthened by the
recent reports. The added period of followup and analysis of deaths
of nonrespondents as well as of respondents in the Dorn Study sug-
gests that the earlier reports may have understated the relationship.

2. More information is now available for specific age groups than
previously. A comparison of three ways of measuring the relationship
indicates that cigarette smoking is most important among men aged
45 to 54 both in terms of mortality ratios and excess deaths expressed
as a percentage of total deaths. Nevertheless, although both of these
measures decline with advancing age, the increment added to the
death rate, which reflects one’s personal chances of being affected,
continues to increase with age. For men between the ages of 35 and 59,
the excess deaths among current cigarette smokers account for one
out of every three deaths at these ages. For women, with their lower
overall exposure to cigarettes, the comparable figure is about one
death out of every 14 at ages 35 to 59.

3. Women who smoke cigarettes show significantly elevated death
rates over those who have never smoked regularly. The magnitude
of the relationship varies with several measures of dosage. By and
large the same overall relationships between smoking and mortality
are observed for women as had previously been reported for men, but
at a lower level. Not only are the death rates for men who have never
smoked regularly higher than those for women who have never smoked

271-304 O—87-—-3 23
regularly, but the effect of smoking as measured either by differences
in death rates or by mortality ratios is greater for men than for
women. At least part of this can be accounted for by the lower ex-
posure of female cigarette smokers whether measured by number of
cigarettes, duration of smoking, or degree of inhalation.

4. Previous findings on the lower death rates among those who
have discontinued cigarette smoking are confirmed and strengthened
by the additional data reviewed. Kahn’s analysis of ex-smokers in the
U.S. veterans study—controlling for age at which they began smoking,
amount smoked, and current age—reveals a downward trend in risk
relative to those who continued to smoke as the duration of time dis-
continued increases. The British physician study, in which a downward
trend is reported in lung cancer death rates for the entire group
(smokers, ex-smokers, and those who never smoked, combined) along
with a very sharp reduction in cigarette smoking by the physicians, is
the best available example of a controlled cessation experiment with
reduction of risks resulting from reduction of smoking. The findings
of this report support the view that epidemiological data showing
lower death rates among former smokers than among continuing
smokers cannot be dismissed as due to selective bias and that the bene-
fits of giving up smoking have probably been understated.

5. Cigarette smokers have higher rates of disability than non-
smokers, whether measured by days lost from work among the em-
ployed population, by days spent ill in bed, or by the most general
measure—days of “restricted activity” due to illness or injury. Data
from the National Health Survey provide a base for estimating that in
1 year in the United States an additional 77 million man-days were
lost from work, an additional 88 million man-days were spent ill in
bed, and an additional 306 million man-days of restricted activity were
experienced because cigarette smokers have higher disability rates than
nonsmokers. For men age 45 to 64, 28 percent of the disability days
experienced represent the excess associated with cigarette smoking.
Smoking and Cardiovascular Diseases

 

ConcLuUsIONS OF THE SuRGEON GENERAL’s 1964 Report

Male cigarette smokers have a higher death rate from coronary
artery disease than nonsmoking males, but it is not clear that the
association has causal significance.

CURRENT INFORMATION, 1967

Important additional epidemiological information from five pros-
pective mortality studies confirms that cigarette smokers have sub-
stantially higher death rates from coronary heart disease than do
nonsmokers. This is true for both men and women although the
relationships are less marked in women. Cigarette smoking also
markedly increases an individual’s susceptibility to earlier death from
coronary disease. In general, mortality rates increase with increasing
amounts smoked.

Cessation of cigarette smoking is followed by a reduction in the
risk of coronary heart disease mortality relative to those who con-
tinued to smoke. Epidemiological evidence indicates that there is
little risk of coronary heart disease associated with cigar and/or pipe
smoking.

The Surgeon General’s 1964 Report indicated a median mortality
ratio of 1.7 for current cigarette smokers, with a range from 1.5 to 2.0.
Additional evidence from the Hammond study (11) indicates that
young smokers between the ages of 45 and 54 have the highest mortality
ratios—three times as great for men, and twice as great for women if
they smoke 10 or more cigarettes per day, as compared with non-
smokers. In general, the mortality ratio shows the most marked in-
creases with increasing amount smoked for the ages under 65. While
the cigarette smokers older than 65 have lower mortality ratios than
those under 65, the public health significance of the relationship in
the older population is substantial because of the large numbers of
people over 65 who die of coronary heart disease. Studies of U.S.
veterans (13), Canadian pensioners (7), British physicians (8, 9, 70),

25
and California longshoremen (3) also provide extensive additional
information about coronary heart disease in male cigarette smokers as
compared to nonsmokers, supporting the above statements as they
pertain to men.

The study of British physicians (8, 9, 10) suggests that male
cigarette smokers have the largest increase in risk for death certi-
fied to coronary thrombosis—a subcategory of coronary heart disease
describing acute coronary events, frequently occlusive, causing myo-
cardial infarction. For that subcategory, the mortality ratio is also
largest for the younger age groups 35-54. .

Prospective morbidity studies confirm the relationships between
cigarette smoking and coronary heart disease. These studies also
provide the opportunity to evaluate the effect of smoking independ-
ently and in combination with other known “risk factors,” such as
high blood pressure and high serum cholesterol that are also impor-
tant in the pathogenesis of coronary heart disease. It has been demon-
strated that cigarette smoking not only operates as an independent
“risk factor” but that it may combine with other “risk factors” to pro-
duce even greater effects on cardiovascular health.

Other types of evidence have also been presented to confirm the
epidemiologic evidence. Autopsy studies show that cigarette smokers
have a much greater frequency of advanced coronary arteriosclerosis
than do nonsmokers. Clinical and experimental studies demonstrate
that smoking produces abnormalities of cardiovascular physiology
that may help to explain the mechanisms of how, smoking may pro-
duce earlier death from coronary heart disease.

Human and experimental studies indicate that the nicotine ab-
sorbed from smoking may cause an increase in the myocardial tissue
demand for oxygen yet at the same time the carbon monoxide absorbed
from smoking may cause a decrease in the supply of available oxygen
from the blood necessary to meet the increased myocardial tissue
demand. Studies indicate that some persons who already have pre-
existing coronary heart disease, not necessarily clinically obvious,
may be especially susceptible to the adverse physiological effects of
smoking. Evidence also indicates that important differences may
exist between normal individuals and those with coronary heart dis-
ease in their ability to increase coronary blood flow to compensate for
increased myocardial tissue oxygen demand. Smoking apparently can
accelerate thrombus formation of human blood, suggesting another
possible mechanism whereby smoking might increase the mortality
from coronary heart disease, especially those acute coronary events
certified as “coronary thrombosis.”

The convergence of many types of evidence—epidemiological, ex-
perimental, pathological, and clinical—strongly suggests that ciga-
rette smoking can cause death from coronary heart disease. These

26
biomechanisms may help to explain why cigarette smokers have such
an increased risk of developing coronary heart disease and of dying
from it.

An increasing amount of evidence has been accumulated in the past
few years relating the development of clinical cerebrovascular disease
to cigarette smoking. Most of this information has come from mor-
tality studies (27, 18), both retrospective and prospective, which
show that both male and female smokers of cigarettes under the age
of 75, as compared to nonsmokers, have higher death rates from cere-
brovascular disease designated as the underlying cause of death on
their death certificates. This may be especially true for younger ciga-
rette smokers age 45-54 where males had death rates about 50 percent
higher than nonsmoking males, and females had death rates about 100
percent higher than nonsmoking females. Under age 75, mortality
ratios for stroke increase as the number of cigarettes smoked increases.
No association has been shown for those aged 75 and over.

The new epidemiological evidence, then, indicates that cigarette
smoking may be more closely associated with cerebrovascular disease
than previously indicated in the population between the ages of 45 and
74 years. If cerebrovascular thrombosis (thrombotic brain infarction)
accounts for this association, it is possible that some of the considera-
tions of how cigarette smoking may produce coronary thrombosis also
apply to the pathogenesis of cerebrovascular disease. Further research
is essential to understand the relationships which exist between ciga-
rette smoking and cerebrovascular disease.

Additional epidemiological evidence from prospective mortality
studies provides confirmation that cigarette smoking is associated with
increased death rates from aortic aneurysm (nonsyphilitic), for both
men and women. In one study of male smokers an increase in death
rates was noted with increases in amount smoked.

HIGHLIGHTS OF CURRENT INFORMATION

1. Additional evidence not only confirms the fact that cigarette
smokers have increased death rates from coronary heart disease, but
also suggests how these deaths may be caused by cigarette smoking.
There is an increasing convergence of many types of evidence concern-
ing cigarette smoking and coronary heart disease which strongly sug-
gests that cigarette smoking can cause death from coronary heart
disease.

2. Cigarette smoking males have a higher coronary heart disease
death rate than nonsmoking males. This death rate may, on the aver-
age, be 70 percent greater, and, in some, even 200 percent greater or

27
more in the presence of other known “risk factors” for coronary heart
disease. Female cigarette smokers also have higher coronary heart
disease death rates than do nonsmoking females, although not as high
as that for males. In general, the death rates from this disease increase
with amounts smoked. Cessation of cigarette smoking is followed by
a reduction in the risk of dying from coronary heart disease when
compared with the risk incurred by those who continue to smoke.

3. A greater frequency of advanced coronary arteriosclerosis is
noted in male cigarette smokers, especially in those who smoke heavily.

4. Additional evidence strengthens the association between cigarette
smoking and cerebrovascular disease, and suggests that some of the
pathogenetic considerations pertinent to coronary heart disease may
also apply to cerebrovascular disease.

28
Smoking and Chronic Bronchopulmonary
Diseases (Non-Neoplastic)

 

Conciusions oF THE SURGEON Generav’s 1964 Report

1. 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. .

9. A relationship exists between pulmonary emphysema and cig-
arette smoking but it has not been established that the relationship 1s
causal. The smoking of cigarettes is associated with an increased risk
of dying from pulmonary emphysema. ; .

3. For the bulk of the population of the United States, the impor-
tance of cigarette smoking as a cause of chronic bronchopulmonary
disease is much greater than that of atmospheric pollution or occupa-
tional exposures.

4, Cough, sputum production, or the two combined are consistently
more frequent among cigarette smokers than among nonsmokers.

5. Cigarette smoking is associated with a reduction in ventilatory
function. Among males, cigarette smokers have a greater prevalence
of breathlessness than nonsmokers.

6. Cigarette smoking does not appear to cause asthma.

7. Although death certification shows that cigarette smokers have
a moderately increased risk of death from influenza and pneumonia,
an association of cigarette smoking and infectious diseases is not other-
wise substantiated.

CURRENT INFORMATION, 1967

Additional evidence from the four major prospective studies indi-
cates that cigarette smokers have a markedly increased risk of dying
from chronic bronchitis and pulmonary emphysema. The range of
risk varies for cigarette smokers between three and 20 times the mor-
tality rates for nonsmokers, and depends in part on the total amount
smoked and the age group studied. Female cigarette smokers have
similarly increased mortality risks although somewhat lower than
those for males. Cessation of cigarette smoking is followed by a lower
mortality risk relative to those who continue to smoke. Generally, pipe

29
and cigar smokers are much less affected than cigarette smokers by
these diseases.

Problems of nomenclature and diagnosis make satisfactory differ-
entiation of chronic bronchitis from pulmonary emphysema. difficult
when considering the epidemiologic data. Nevertheless autopsy studies
support the relationship between smoking and mortality. In addition,
recent information from morbidity studies indicates that smoking is
associated with symptoms of chronic bronchopulmonary disease. Even
relatively young cigarette smokers show increased respiratory symp-
toms and decreased ventilatory function. Cessation of smoking is
usually followed by improvement of these characteristics. Although
some individuals may have an increased susceptibility to respiratory
disease, studies of twin-pairs in Sweden (4, 5, 6, 14)—in which one
twin is a smoker and the other is not—show that those who smoke have
a much greater frequency of respiratory symptoms and abnormalities
of ventilatory function than do their nonsmoking twins. This dem-
onstrates that cigarette smoking is of greater importance than hered-
itary and constitutional factors in the pathogenesis of chronic bron-
chopulmonary disease. Similarly, occupational exposures and air
pollution may also cause respiratory disease, but cigarette smoking is
of much greater importance.

Additional clinical and experimental laboratory evidence confirms
the fact that constituents in tobacco smoke are harmful to the bronchial
mucosa of the respiratory tract. Bronchial changes have been produced
in experimental animals exposed to cigarette smoke.

It is suspected that smoking has a direct toxic effect upon the alveo-
lar tissue of human lungs, in which case this effect might be important
in the pathogenesis of many though not all cases of human pulmonary
emphysema. Additional indirect evidence exists to substantiate this
suspected toxic effect, but additional research is needed to confirm or
deny the presence of the effect. However, the presently available evi-
dence (epidemiological, clinical, pathological, and experimental)
strongly suggests that cigarette smoking may well play an important
pathogenic role in many, although not necessarily all, cases of pul-
monary emphysema. The fact that other causes of pulmonary emphy-
sema exist does not detract from the validity of this inference.

Additional evidence strongly supports the conclusion in the Surgeon
General’s 1964 Report 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.
HIGHLIGHTS OF CURRENT INFORMATION

1. New date confirm and to some extent strengthen the conclu-
sions of the Surgeon General’s 1964 Report.

9, Cigarette smoking is the most important of the causes of chronic
non-neoplastic bronchopulmonary diseases in the United States. It
greatly increases the risk of dying not only from both chronic bron-
chitis but also from pulmonary emphysema.

3. Cessation of smoking is followed by a reduction in mortality from
chronic bronchopulmonary disease relative to the mortality of those
who continue to smoke.

4, Even relatively young cigarette smokers frequently have demon-
strable respiratory symptoms and reduction in ventilatory function.

31
Smoking and Cancer

 

CoNCLUSIONS OF THE SuRGEON GENERAL’s 1964 Rerorr

Lung Cancer

1. Cigarette smoking is causally related to lung cancer in men; the
magnitude of the effect of cigarette smoking far outweighs all other
factors. The data for women, though less extensive, point in the same
direction.

2. The risk of developing lung cancer increases with duration of
smoking and the number of cigarettes smoked per day, and is dimin-
ished by discontinuing smoking.

3. The risk of developing cancer of the lung for the combined group
of pipe smokers, cigar smokers, and pipe and cigar smokers is greater
than for nonsmokers, but much less than for cigarette smokers.
The data are insufficient to warrant a conclusion for each group
individually.

Oral Cancer

1. The causal relationship of the smoking of pipes to the develop-
ment of cancer of the lip appears to be established.

2, Although there are suggestions of relationships between cancer
of other specific sites of the oral cavity and the several forms of tobacco
use, their causal implications cannot at present be stated.

Laryngeal Cancer

Evaluation of the evidence leads to the judgment that cigarette

smoking is a significant factor in the causation of laryngeal cancer in
the male.

Esophageal Cancer

The evidence on the tobacco-esophageal cancer relationship supports
the belief that an association exists. However, the data are not ade-
quate to decide whether the relationship is causal.

Cancer of Urinary Bladder

Available data suggest an association between cigarette smoking
and urinary bladder cancer in the male but are not sufficient to sup-
port judgment on the causal significance of this association.

Stomach Cancer

No relationship has been established between tobacco use and
stomach cancer.

338
CURRENT INFORMATION, 1967

Additional chemical, experimental, pathological, and epidemiolog-
ical evidence has been reported that substantiates the conclusions of
the Surgeon General’s 1964 Report concerning the various sites of
cancer that were shown to be associated with or caused by smoking.

Luna Cancer

Deaths from lung cancer in the United States are continuing to rise
rapidly. Epidemiological evidence concerning cigarette smoking and
lung cancer has confirmed positive relationships with increasing num-
bers of cigarettes smoked, with increasing duration, and with decreas-
ing age of initiation of the habit. Male cigarette smokers of less than
one pack a day have mortality ratios as high as 10 and smokers of more
than one pack a day have mortality ratios as high as 30.

There is a much smaller increase of the lung cancer death rates
associated with pipe and/or cigar smoking than with cigarette
smoking.

Additional evidence provides specific information on the increased
mortality ratios of female cigarette smokers. These have significantly
elevated mortality ratios ranging as high as 5 for the groups with
greatest exposure. Lung cancer rates appear to be somewhat lower
for women who have never smoked regularly than for men who have
never smoked regularly. The mortality rates for women who smoke,
although significantly higher than for nonsmokers, are lower than
for men who smoke. How much of this is due to lower exposure to
cigarettes and how much to other factors cannot be determined from
the data available.

Ex-cigarette smokers are shown to have significantly lower death
rates compared with those who continue to smoke. As discussed under
the general topic of cessation earlier in this report, the finding of re-
duced lung cancer rates in the population of British physicians (8, 9,
10) over a period of time in which the proportion of cigarette smokers
was dropping significantly can be interpreted as similar to a con-
trolled cessation experiment and provides critical confirmation of the
judgment that cigarette smoking is the major cause of lung cancer
and that sharp reductions can occur in the risk from lung cancer with
the cessation of smoking.

Additional information is available concerning the presence of
known or suspected carcinogens in tobacco smoke. It has been reported
that the “tar” and nicotine content of cigarette smoke* tends to reflect
the tumorigenicity of this smoke, and that a reduction of the “tar” and

* The phrase “ ‘tar’ and nicotine” is used here as a general indicator of total
particulate matter in cigarette smoke.

34
nicotine content is accompanied by a reduction in the tumorigenicity.
Research is needed to identify and separate the tumor-initiating and
tumor-promoting agents in tobacco smoke and to elucidate their inter-
actions in the pathogenesis of cancer. Similarly, while additional data
are available concerning experimental carcinogenesis, it is not yet
certain that the typical characteristics of human squamous-cell lung
cancer, with invasion and metastasis, have been experimentally pro-
duced by tobacco smoke in animals. It should be noted that this may
never be achieved not only because it may not be possible to duplicate
man’s smoking action for anatomic and physiologic reasons but also
because of species’ differences in cellular response.

There is evidence that certain other exposures, for example, occupa-
tional exposures to asbestos and uranium ore may interact with the
cigarette effect to produce an enhancement of the tumor-producing
effect. There is also information to indicate that the occurrence of
second primary lung cancers in smokers may be more frequent than
previously indicated.

OraL CANCER

Substantial mortality ratios are found for cancers of the buccal
cavity and pharynx. Mortality ratios for cancer of the pharynx are
especially high. There is some evidence implicating alcohol and/or
dietary deficiencies in some of these sites. With the exception of the
pipe-lip cancer relations there are too few cases related to the indi-.
vidual parts of the buccal cavity to evaluate each independently, and
data are inadequate on the interaction of smoking with other factors.
Although all forms of smoking have high mortality ratios with these
sites, mortality ratios for those smoking cigarettes appear to be some-
what higher than for those smoking pipes and cigars, especially in
the case of cancer of the pharynx.

LaryNnceaL CANCER

Continued evidence from the prospective studies supports the exist-
ence of a high laryngeal cancer mortality ratio for pipe and cigar
smokers as well as for cigarette smokers. Data on the smoking habits
of patients treated for buccal cancer subsequent to their therapy sug-
gests that continuing to smoke after therapy may increase the likelli-
hood of an independent laryngeal cancer. The epidemiological evi-
dence supports the previous conclusion that cigarette smoking is a
significant factor in the causation of cancer of the larynx.

EsopHaGEAL CANCER

Additional data from the prospective studies confirm the high
mortality ratio previously found for smokers of all forms of tobacco.

35
Autopsy studies of smokers compared with nonsmokers specifically
observing pathological changes in esophageal tissue have been reported
from both smokers and nonsmokers who died from causes other than
esophageal cancer. The findings were similar to the abnormalities
generally accepted as representing premalignant tissue changes of
the epithelium of the respiratory tract; that is, epithelial cells with
atypical nuclei were found far more frequently in cigarette smokers
than in nonsmokers. Tissue sections with basal cell hyperplasia were
also found more frequently in cigarette smokers and, as with the
atypical nuclei, these findings increased with amount of cigarette
smoking. Additional data to evaluate the relative importance of smok-
ing and alcohol, independently and jointly, would help clarify the
significance of these findings.

Urinary Briapper Cancer

The Dorn (73) and the Hammond (11) studies both show mortality
ratios over 2.0 for smokers of over 20 cigarettes a day, but the Doll-Hill
study (8, 9), based on only 38 deaths, shows no apparent relation-
ship. Two retrospective studies have shown significantly higher pro-
portions of smokers among patients than among controls. Small scale
metabolic studies suggest that cigarette smoking may block the normal
metabolism of tryptophan, which would lead to the accumulation of
carcinogenic metabolites in the urine. Further studies to verify this
finding and studies analyzing changes in the bladder tissue of smokers
as compared with nonsmokers would be helpful in arriving at a judg-
ment of the significance of the elevated death rates found in smokers
in the largest of the prospective studies.

Sromacn anp Pancreatic Cancer

Epidemiological evidence does not show a significant relationship
between smoking and stomach cancer. An association between ciga-
rette smoking and pancreatic cancer is implied, but the significance
of this association is not clear at the present time.

HIGHLIGHTS OF CURRENT INFORMATION

Lune Cancer

1. Additional epidemiological, pathological, and experimental data
not only confirm the conclusions of the Surgeon General’s 1964 Report
regarding lung cancer in men but strengthen the causal relationship
of smoking to lung cancer in women.

36
9. Cessation of cigarette smoking sharply reduces the risk of dying
from lung cancer relative to the risk of those who continue.

3, Although additional experimental studies substantiate previous
experimental data, additional research is needed to specify the tumor-
initiating and tumor-promoting agents in tobacco smoke and to elu-
cidate the basic mechanisms of the pathogenesis of lung cancer.

LaryNcEAL CANCER

The conclusion of the Surgeon General’s 1964 Report that cigarette
smoking is a significant factor in the causation of laryngeal cancer in
the male is supported by additional epidemiological evidence.

Otuer CANCERS

Additional evidence supports the conclusions of the Surgeon Gen-
cral’s 1964 Report and indicates a strong association between various
forms of smoking and cancers of the buccal cavity, pharynx, and
esophagus. In the absence of further information concerning the in-
teraction of smoking with other factors known or suspected as causa-
tive agents, further conclusions cannot be made at this time, although
causative relationship seems likely.

Additional epidemiological, clinical, and experimental data
strengthen the association between cigarette smoking and cancer of
the urinary bladder, but the presently available data are insufficient
to infer that the relationship is causal.

37
Other Conditions and Areas of Research

 

ConcLusions or THE SurGEON Generat’s 1964 Report

Peptic Uleer

Epidemiological studies indicate an association between cigarette
smoking and peptic ulcer which is greater for gastric than for duodenal
ulcer.

Tobacco Amblyopia

Tobacco amblyopia {dimness of vision unexplained by an organic
lesion] has been related to pipe and cigar smo. by clinical impres-
sions. The association has not been substantiated by epidemiological
or experimental studies.
Cirrhosis of the Liver

Increased mortality of smokers from cirrhosis of the liver has been
shown in the prospective studies. The data are not sufficient to support
a direct or casual association.
Maternal Smoking and Infant Birth Weight

Women who smoke cigarettes during pregnancy tend to have babies
of lower birth weight. Information is lacking on the mechanism
by which this decrease in birth weight is produced. It is not known
whether this decrease in birth weight has any influence on the bio-
logical fitness of the newborn.

Psychosocial Aspects

The overwhelming evidence points to the conclusion that smoking—
its beginning, habituation, and occasional discontinuation—is to a
large extent psychologically and socially determined. This does not
rule out physiological factors, especially in respect to habituation, nor
the existence of predisposing constitutional or heredity factors.

CURRENT INFORMATION, 1967

By and large the contributions to knowledge in this area of varied
considerations have been meager, although a number of investigations

271-394 O—67—_4 39
on one or another aspect of the problem of smoking and varied health
consequences have been undertaken.

Prrric Uncer

The relationship between cigarette smoking and death rates from
peptic ulcer, especially gastric ulcer, is confirmed. In addition, mor-
bidity data suggest a similar relationship exists with the prevalence
of reported disease from this cause.

Tosacco AMBLYOPIA

Tobacco amblyopia is now believed to be a manifestation of nutri-
tional amblyopia, which is aggravated by the inhalation of tobacco
smoke. Various vitamin B factor deficiencies may be involved and
there is evidence to suggest that chronic low vitamin B,, levels may
potentiate the toxic effects of cyanide in tobacco smoke.

CIRRHOSIS OF THE LIVER

Increased mortality of smokers from cirrhosis of the liver is found
in the prospective studies. This has generally been thought to be
largely secondary to an association between smoking and heavy con-
sumption of alcohol. Published data are inadequate to test this
interpretation.

MarernaL SmMoKING AND Inrant BirtuH WErIcHT

Further studies have confirmed the fact that women who smoke
during pregnancy tend to have babies of lower birth weight, but
data are lacking to determine either the mechanism or the significance
of this finding.

PsycHosociaL ASPECTS

There has been a sharp increase in the attention devoted to be-
havioral research since the Surgeon General’s Report. A number of
new concepts have been developed and more sophisticated multivariate
approaches are being used. However, because of the recency of these
studies very little in the way of findings has been published on which
firm conclusions may be based.
(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

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Beat, E. W. R. A Canadian study of smoking and health. Ottawa, De-
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Boox, F. G., Moorr, G. E., Crarx, P. C. Carcinogenic activity of cigarette
smoke condensate. III. Biological activity of refined tar from several
types of cigarettes. Journal of the National Cancer Institute (Washing-
ton) 34(4) : 481-493, April 1965.

Borwant, N. O., Hecuter, H. H., Barstow, R. Report of a 10-year followup
study of the San Francisco longshoremen. Mortality from coronary heart
disease and from all causes. Journal of Chronic Diseases (St. Louis) 16:
1251-1266, 1963.

Cevertor, R. Urban factor and prevalence of respiratory symptoms and
“angina pectoris.” A study of 9,168 twin pairs with the aid of mailed
questionnaires. Archives of Environmental Health (Chicago) 13(6) :
743-748, December 1966.

CepER.or, R., Frere, L., Jonsson, E., Kats, L. Morbidity among monzy-
gotic twins. Archives of Environmental Health (Chicago) 10(2) : 346-350,
February 1965.

Cepentor, R., Ferprra, L., Jonsson, E., Kars, L. Respiratory symptoms
and “angina pectoris” in twins with reference to smoking habits. An
epidemiological study with mailed questionnaire. Archives of Environ-
mental Health (Chicago) 13(6) : 726-737, December 1966.

Dott, R. Cancer bronchique et tabac. Bronches (Paris) 16(5) : 313-324,
September—October 1966.

Dox, R., Hm, A. B. Mortality in relation to smoking: 10 years’ observa-
tions of British doctors. (Part 1.) British Medical Journal (London)
1(5395) : 1899-1410, May 30, 1964.

Dott, R., Hx, A. B. Mortality in relation to smoking: 10 years’ observa-
tions of British doctors. (Concluded.) British Medical Journal (London)
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Dott, R., Hm, A. B. Mortality of British doctors in relation to smoking:
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demiological Approaches to the Study of Cancer and Other Chronic
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Hamwonp, BH. C. Smoking in relation to the death rates of 1 million men
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Study of Cancer and Other Diseases. Bethesda, U.S. Public Health Service,
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Hoen, D., Ixarp, F., Watncrow, S. Dosage patterns of cigarette smoking
in American adults. American Journal of Public Health and the Nation’s
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Kaun, H. A. The Dorn study of smoking and mortality among U.S. veterans:
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LunpMan, T. Smoking in relation to coronary heart disease and lung func.
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PART Il

 

Technical Reports on the
| Relationship of Smoking
to Specific Disease Categories
CHAPTER 1

 

Smoking and Cardiovascular Diseases

CONTENTS

Page
Smoking and Coronary Heart Disease...................... 47
Coronary Heart Disease Mortality.................... 47
Coronary Heart Disease Morbidity.................... 53
Manifestations of Coronary Heart Disease.............. 58
Cardiovascular Response to Smoking and/or Nicotine... . 60
Coronary Blood Flow in Normal Subjects.......... 60

Coronary Blood Flow in Subjects With Coronary
Heart Disease...........- 0... cece cece eee eens 61
Carbon Monoxide Effect....................0000- _ 62
Studies on Jn Vitro Thrombus Formation. ......... 64
Autopsy Studies............ 0.0.0 c cee eee eee eee eee eee 65
Smoking and Cerebrovascular Disease..................... 66
Smoking and Aortic Aneurysm......................02.005 69
Cited References.........0... 0.00 cece eee eee ene e ee eeees 69
Supplemental References. ............... 02. ee eee eee 76
SMOKING AND CORONARY HEART DISEASE

Coronary Heart Disease Mortatrry *

The relative importance of the association between cigarette smoking
and coronary heart disease (CHD) as compared to the association of
smoking with other diseases was previously described in the introduc-
tion to chapter 11 of the Surgeon General’s 1964 Report.

In the United States more persons die from coronary heart disease
than from any other single cause; and this most common form of fatal
cardiovascular disease accounts for a greater percentage of excess
deaths among cigarette smokers than do deaths from lung cancer. In
1964, there were 1,798,000 deaths from all causes, of which almost
545,500 or 30.3 percent, were due to atherosclerotic heart disease,
including coronary heart disease. Table 1 gives the 1964 death rates for
coronary heart disease per 100,000 persons by age and sex:

TasLE 1.—1964 death rates for coronary heart disease per 100,000

 

 

persons by age and sex
Allages | 25-34 35-44 45-54 55-64 65-74 75-64 85+
Both Sexes_.| 285.1} 6.9 | 53.2 | 205.8 | 576.3 |1, 384.9 |2, 957. 7 |6, 882. 9
Males_.-._- 354.2 | 11.0] 90.9 | 341.3 | 889. 8 |1, 942. 4 |3, 623. 0 17, 409. 4
Females..._| 218.5 3.0) 17.4 76. 8 | 286. 4 926. 5 |2, 464. 0 16, 559. 0

 

 

 

 

 

 

 

 

 

Source: National Center for Health Statistics (97).

These data illustrate the dramatic increases in the risk of death
from coronary heart disease as age advances. For males the rates
among persons over the age of 45 appear to double from one decade
to the next; among females the increased risk of death with advancing
age is more dramatic—a threefold increase every 10 years. Of perhaps
greater importance are the relatively low death rates among females,
particularly below the age of 65, compared to males of comparable
age. The mortality differential between the sexes becomes less as age
advances; under 45 years of age the coronary death rate among men
is five times as high as among women and in the 75-84 year age group
itis only about 1.5 times as high.

The Surgeon General’s 1964 Report determined a median mortality
ratio (99) (pp. 109-110) for coronary heart disease of male current
cigarette smokers of 1.7. Since this report, five large prospective

* All death rates throughout this chapter are per 100,000 population, unless
otherwise indicated.
47
studies of smoking and mortality have been updated on the basis of
longer periods of observation on each study subject. Current findings
are therefore more definitive and permit more detailed analysis of
the interrelationship of cigarette smoking to other significant variables
such as age, sex, and the nature of the smoking habit in terms of
amount and duration of smoking. Pertinent findings are presented
below from the studies of veterans in the United States (62) and
Canada (24) and the extensive data reported by Hammond (47), Doll
and Hill (25, 26, 27), and Borhani (17).

The relative excess mortality associated with cigarette smoking is
generally expressed in terms of a mortality ratio. This statistic is
defined as the ratio of the number of observed deaths among smokers,
to the expected deaths among smokers, if the age-specific mortality
rates observed among non-smokers had prevailed (62). The process
of computing the expected number of deaths among smokers takes
into account and adjusts for any differences in the age distribution
of the smokers and the nonsmokers under observation. Generally
smokers are defined as persons currently smoking cigarettes, and non-
smokers as those who never smoked or who never smoked regularly.

Table 2 shows the mortality ratios for coronary heart disease deaths
among current cigarette smokers according to the amount smoked
daily in U.S. and Canadian male veterans.

TaBLE 2.—Coronary heart disease mortality ratios, age-adjusted among
current cigarette smokers by amount smoked daily

 

 

 

Cigarettes smoked daily
Under | 10-20 | 21-39 | More | 404-
10 than 20
U.S. male veterans. .....______.-____--_- 13 1.7 1.8 |..--_- 2.0
Canadian male veterans__._.______....--- 1.6 1.6 |------ 1.8 |. ...

 

 

 

 

 

 

Source: U.S. veterans study (52) and Canadian pensioners study (1/4).

In both studies (24, 52) the mortality ratios were similar and in-
creased with increasing intensity of cigarette smoking. Slightly higher
ratios are reported in the U.S. veterans study for current smokers of
cigarettes only.

The U.S. veterans study also permitted the comparison of age-
specific coronary heart disease mortality rates for ex-smokers and
current cigarette smokers (table 2A). From these data, it appears
that cessation of cigarette smoking is followed by a reduction in risk
of coronary heart disease mortality as compared to those who continue
to smoke cigarettes.
TapLE 2A.—Annual death rate per 100,000 from coronary heart disease
by age, cigarette-smoking status and number of cigarettes smoked per
day, U.S. veterans study

 

 

 

45-54 55-04 65-74
Number smoked per day * Current Ex- .{ Current Ex- Current Ex-
cigarette | smokers? | cigarette | smokers‘ | cigarette | smokers *
smokers smokers smokers
| to 9.-------------- 195 125 594 432 | 1,374 1, 105
10 to 20._----------- 297 133 830 557 | 1,577 1, 260
21 to 39_------------ 390 57 912 743 1, 701 1, 366
40+ ____------------ §02 |_------- 1, 101 646 1, 955 1, 482

 

 

 

 

 

 

 

1 This is the current rate of smoking for current cigarette smokers and the maximum rate attained for ex-

i tte smokers. .
oe smokers who stopped for reasons other than doctor’s orders.

Source: U.S. veterans study (62).
The Hammond study findings summarized in table 3 are based on
coronary heart disease deaths reported over a 4-year period among
approximately 1 million persons (441,000 men and 563,000 women).

TaBLE 3.—Coronary heart disease mortality ratios among current
cigarette smokers only, by amount smoked daily

 

 

 

Cigarettes smoked daily
Age and sex Non-
smokers
Under 10 10-19 20-39 40+

Men:

45 to §4.__.._------------- 1.0 2.4 31 Bl 3. 4

55 to 64.._--.------------ 1,0 1.5 1.9 2.0 2.1

65 to 74__..-..----------- 1.0 13 1.6 1.6 (4)

75 to 84..___.-----.------ 1.0 1.2 1,4 Li [--------
Women:

45 to 54.._._-.------------ 1.0 a9 2.0 2.7 |.-------

55 to 64.__-------.------- 1.0 1.3 1.6 2.0 |_-------

65 to 74____---------.---- 10 1.1 14 19 |---_----

75 to 84...-.-..---------- 1.0 |_..-----j---..---]..------]--------

 

 

 

 

 

 

1 Expected deaths were less than 10.
Sourcz: Hammond, E. C. (47).

Tables 3 and 4 show that both men and women who smoke cigarettes
have relatively higher death rates from coronary heart disease than
nonsmokers, although men have higher rates than women. For each
sex and for each age group, the mortality ratios for coronary heart
disease generally increase with increased intensity of cigarette smok-
ing (table 3). The highest mortality ratios for both men and women
are observed in the 45-54 year age-group; the coronary heart disease

49
death rates among heavy smokers in this age group are three times the
death rates for nonsmokers for both sexes. The mortality ratios for
both men and women decrease with advancing age in each intensity
category. This trend may reflect the effects of selective survival of
smokers who have survived the elevated risks at younger ages of cor.
onary heart disease and other diseases associated with cigarette
smoking.

Another explanation of the decrease in mortality ratios with agi
is that the effect of smoking, while substantial in increasing death
rates, cannot be expected to be proportionate to all other causes of
coronary heart disease as age advances. Considering the advanced de-
gree of atherosclerosis generally found among nonsmokers over
65, the deleterious effect of smoking is more appropriately represented
by the excess in death rates among smokers. Table 4 below shows
the observed death rates from coronary heart disease among persons
studied by Hammond and classified by age, sex, and smoking status,
Although the mortality ratios decreased with age, differences in death
tates, which reflect the numbers of persons who die in each age group,
increase. This could be interpreted to mean that, although relative to
other factors, the role of cigarette smoking tends to diminish with ad-
vancing age, the number of excess deaths per 100,000 smokers continues
to rise with advancing age.

Taste 4.—Age-specific death rates Jrom coronary heart disease per
100,000 persons by age, sex, and smoking status

 

 

 

 

 

 

 

 

Smokers of Excess rate Mortality
Age and sex cigarettes Nonsmokers | smokers/non- ratio
only smokers !
Males:
45 to §4__._-22 422 150 272 2.8
55 to 64_-__2 996 542 454 1.8
65 to 74___.2 2-2. eeeee 2, 025 1, 400 625 15
75 to 84__ le 3, 871 3, 132 739 1.2
Females:
45 to 54__2 2022 66 33 33 2.0
55 to 64__2222- 2-2 275 163 112 1.7
65 to 74___ 2 941 653 288 14
75+ 2-2-2 2, 349 1, 973 376 1.2
1 Calculated from the data.

Sourcr: Hammond, E. C. [(47), p. 145.]

The relative decrease in death rates from coronary heart disease
associated with the cessation of cigarette smoking is illustrated by
table 4A.

50
Taste 4A.—Coronary heart disease (men). Age-standardized death
rates for ex-cigarette smokers with history of cigarette smoking only,
by former number of cigarettes smoked per day and years since last
cigarette smoking. Death rates for current cigarette smokers with history
of cigarette smoking only and men who never smoked regularly are
shown for comparison. Men aged 50-69

 

 

 

 

Smoked 1-19 cigarettes a day Smoked 20+ cigarettes a day
Ex-cigarette smokers (years
since last cigarette smoking) | | Number | Death | Number | Number | Death
of men of deaths rate ofmen of deaths rate
Under 1 year... ------ 746 27 | 11,005 2, 244 77; 11,070
1 to 4 years..-------- 1, 844 51 718 5, 435 195 1, 003
5 to 9 years. --------- 1,770 48 725 5, 803 152 732
10+ years_---------- 4, 209 84 498 8, 142 206 679
Total ex-
smokers - - - -- 8, 569 210 635 | 21, 624 630 813
Current cigarette
smokers-.--------- 22, 808 781 947 | 56, 886 1, 895 1, 029
Never smoked regu-
larly .-.----------- 55,728 | 1,114 502 | 55, 728 1,114 502

 

 

 

 

 

 

 

1 Four or more but less than 10 deaths expected in some of the component 5-year age groups.
Source: Hammond, E. C. {(47), p. 148}.

Dolt and Hill

In a prospective study by Doll and Hill (27) of mortality among
British physicians whose smoking habits had been previously recorded,
there were 1,369 deaths in the course of 10 years in which the underly-
ing cause was coronary heart disease (27, table 1). The physician popu-
lation under observation totaled 320,185 person-years. The CHD
deaths were classified into three major subcategories: Group 1, com-
prising 35 CHD deaths in which an associated condition related to
smoking, e.g., lung cancer, was recorded on the death certificate; Group
2, comprising 721 CHD deaths in which no other significant contribu-
tory cause of death was recorded on the death certificate; and Group 3,
comprising 613 CHD deaths which were associated with some other
contributory cause, including conditions known to predispose to coro-
nary heart disease, e.g., hypertension, diabetes, and obesity. The CHD
death rates for smokers and nonsmokers based only on Group 1 deaths,
while subject to large variation, show the largest differentials (data not
shown). Among smokers of 25 or more cigarettes daily, the age-ad-
justed CHD death rate was nearly eight times that in nonsmokers.

Based on Group 2 coronary heart disease deaths, presumably uncom-
plicated by any other significant disease, the mortality ratio of age-
adjusted death rates among continuing cigarette smokers to non-
smokers is found to be 1.6, and for heavy smokers to nonsmokers the

51
ratio is 2.0. However, as shown in table 5, the mortality: differentials
between smokers and nonsmokers are much larger at the younger ages.

TABLE 5.—Mortality ratios for different types of coronary heart disease
by smoking habits

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Group 21 CHD Group 3 CHD
ining c ng cigarette
Age group a sm —a ontinaing cit
Non- Non-
smokers smokers
Al 25 or more All 25 or more
amounts | per day amounts ;| per day
35 to44__. 0 1.0 4.7 9.7] ( () ()
45 to 54... 1.0 3.8 3.5 1.0 L1 1.7
55 to 64... 1.0 1.4 1.6 1.0 1.4 1.9
65 to 74_______ 1.0 1.4 1.8 1.0 1.4 8
75 to84__00 1.0 1.1 2.0 1.0 -8& 2
85 plus.__...-8 1.0 1.0 () 1.0 14 (*)
Age adjusted— All ages_ 1.0 1.6 2.0 1.0 1.1 9
' See text for definitions.

4 Not calculable; no rate for nonsmokers because of so few deaths.
? Very few men in this category.

Source: Data in above table based on values from Study of British Physicians. Table 3 (27).

The mortality ratios shown for Group 3 deaths, i.e, CHD deaths
accompanied by some other complicating disease, Suggest that, for
all age groups combined, smokers do not have any special risk to
this type of coronary death. However, smokers below the age of 65
appear to be at a somewhat greater risl-, while no consistent differen.

In summary, the study substantiates other mortality studies’ find-
ings that CHD mortality ratios (current cigarette smokers vs. non-
smokers) increase with the number of cigarettes smoked daily, that
the ratios are highest in the age group 45-54, and that they decrease
48 age advances. Moreover, smoking apparently is associated with
deaths from coronary heart disease among persons free of other
Serious disease states,

In a prospective study of California longshoremen, Borhani (17)
reported on the mortality experience of more than 3,700 men observed
for 10 years. Table 6, derived from his data, provides some additional
insights on both the independent and the interaction effects of ciga-
rette smoking.

Men 45-64 years of age who were heavy smokers experienced higher
death rates from coronary heart disease than did nonsmokers independ-
ent of whether they were hypertensive or nonhypertensive.

52
TaBLE 6.—Mortality ratio from coronary heart disease among male
hypertensives and nonhypertensives by smoking history and age

 

Blood pressure status ! Non- Hea
Age group p smokers 3 smokes 2

 

45 to 54...---------- Nonhypertensive---_-.--------- L0 2.2
Hypertensive___-_-.----------- 2.5 9. 6
55 to 64...---------- Nonhypertensive--_.---------- 10 5.8
Hypertensive. ---.-..--------- 5.9 9. 4

 

 

 

 

1 ertensives are defined as those having systolic blood pressure of 160 mm. Hg. or over or diastolic
plod aressure of95mm. Hg. or over. Nonhypertensives have systolic blood pressure less than 160 mm. Hg
or diastolic blood pressure less than 95mm. e

3 Nonsmokers in this particular study are defined as those not smoking any cigarettes or less than 20
cigarettes per day. Smokers are those who smoke 20 or more per day.

Source: Borhani, N. O., et al, (17).

An analysis was made by Schor (86) of 181 adult males who died
from coronary heart disease generally less than 2 years after receiving
a periodic health examination. The results of this study and those of
Doll and Hill suggest that sudden death from previously undetected
coronary heart disease frequently occurs among cigarette smokers. If
this is true, it may, in part, account for the small differentials in the
prevalence of coronary heart disease between smokers and nonsmokers
observed in some morbidity prevalence surveys. As will be described
in the following section, longitudinal, prospective morbidity studies
also show that smokers are more likely to die from sudden attacks of
coronary heart disease.

Coronary Hearr Disease Morsiprry*

In chapter 11 of the 1964 Surgeon General’s Report, several prospec-
tive studies on the incidence of coronary heart disease (24, 31, 78, 88)
established that smokers were subject to higher rates than nonsmokers.
The relationship was reported to be more marked under 50 years of
age than among older persons and appeared to be associated with
myocardial infarction but not with angina pectoris. Since the 1964
report, recent findings from large-scale, on-going prospective studies
have been reported, providing additional insight on the interaction
between smoking and other important coronary heart disease risk fac-
tors. Current findings are summarized in the following pages includ-
ing tables 7 to 13. Whenever possible, data are shown separately for
findings related to angina pectoris and those pertaining to myocardial
infarction, including sudden death attributed to coronary heart dis-
ease. Higgins (60) has drawn attention to the fact that “many factors
may influence or be affected by smoking habits, and obscure those
differences between smokers and nonsmokers which are directly re-
lated to the use of tobacco.” In her review of the literature, Higgins
identified differences between smokers and nonsmokers in genetically

*Also may include mortality data in this presentation.

58
determined qualities (23), in physique (77, 93), in personality (37,

47, 48, 65, 68, 69), and in social, cultural, religious, and economic
characteristics (46, 49, 68,84).

Age :
The effect of age on the incidence of coronary heart disease with

regard to cigarette smoking is shown in table 7 based on recent data
from the Framingham Study as yet unpublished.

TABLE 7.—Incidence rates and morbidity ratios Jor coronary heart
disease by age and smoking status of men 12-year experience, Fra-
mingham, Mass.

 

 

 

 

 

Incidence rates per 1,000 Excess rates Morbidity ratio
per 1,000
Age
Smokers
Non- Smokers minus Non- Smokers
smokers non- smokers

smokers
35 to 44.008 1.4 4.1 2.7 1.0 2.9
45 to 54.-0 22 4.6 11,1 6.5 1.0 2.4
55 to 64.-02- 16.2 25. 4 9.2 1.0 1.6

 

 

 

 

 

 

Source: U.S. Public Health Service, Framingham Study (06). (Updated 1967)

When the incidence rate of coronary heart disease among male non-
smokers between 35-44 years of age is compared with that among older
nonsmokers, the rate is seen to triple every 10 years. This marked
increase in incidence among nonsmokers reflects the effect of other
important risk factors and perhaps accounts for the decrease in mor-
bidity ratio as age advances. The independent effect of smoking on
the incidence of coronary heart disease is believed to be more appro-
priately represented by the excess morbidity rates, which increase
from 2.7 per 1,000 smokers in the age group 35-44 to 9.2 per 1,000
smokers 55-64 years of age.

High Blood Pressure

Although the inhalation of cigarette smoke is frequently accom-
panied by acute transient elevations in blood pressure, habitual smok-
ers tend to have lower blood pressures than do nonsmokers (48). But,
given the presence of high blood pressure in an individual, smoking
acts as an additional risk factor for the development of coronary heart
disease (17, 28, 29, 50, 53, 55, 95, 96). Both the independent and the
combined effect, of cigarette smoking is clearly shown in table 8 de-
rived from the experience of the Framingham and Albany studies
(30).
TaBLE 8.—Age-adjusted morbidity ratios for coronary heart disease
among smokers and nonsmokers according to level of systolic blood
pressure

 

 

Systolic blood pressure Nonsmokers of Cigarette

cigarettes smokers
Under 130 mm. Hg- ---------------------------- 1.0 2.1
130 mm. Hg and over. ------------------------- 1.8 3.8

 

 

 

Source: 10-year Framingham and 8-year Albany experience ($0).

High Serum Cholesterot

It ig not now conclusively known if cigarette smoking by itself can
cause increases in serum cholesterol. Dietary influences as well as en-
dogenous production and elimination of cholesterol must be evaluated
in greater detail with simultaneous analysis of the roles of other
risk factors, including smoking. One study of a small population of
twins in Sweden, as reported by Lundman (67), suggests that smoking
monozygotic twins tend to have lower cholesterol levels than their
nonsmoking control twins, although the differences are not statistically
significant. Other studies suggest that smokers generally have higher
serum cholesterol than nonsmokers (13, 67, 88). However, given the
presence of high serum cholesterol, smoking increases the risk of cor-
onary heart disease (95,96).

The independent any synergistic effect of cigarette smoking is dem-
onstrated by the data in table 9 derived from the combined experience
of the Framingham and Albany studies (30).

Taste 9.—Age-adjusted morbidity ratios for coronary heart disease
among smokers and nonsmokers according to level of serum cholesterol

 

 

Serum cholesterol level Nonsmokers of Cigarette

cigarettes smokers
Low !_____.------~------------ ee ne ne eee 10 1.8
High!____...---------------------------------- 2. 0 45

 

 

 

! “Low” is below median. “high” is above median value of serum chloesterol.
SouRcE: 10-year Framingham and 8-year Albany experience ($0).

Pulmonary Fumetion

The acute effects of cigarette smoking upon pulmonary function are
expressed mainly through increase in airway resistance. The dif-
ferences in pulmonary function between smokers and nonsmokers ap-
pear to be greater than can be accounted for by acute effects from a
recently smoked cigarette (50, 91). The relationship of coronary heart
disease to lowered pulmonary function as reflected by low vital capacity
and cigarette smoking is observed in the data published by the Na-

271-894 O—67 ——5 55
una LUSCILULES OF Health based on the 12-year experience in Framing-
ham (96). Morbidity ratios derived from this publication are shown in
table 10.

TaBiE 10.—Age-adjusted morbidity ratios for coronary heart disease
among smokers and nonsmokers according to level of vital capacity

 

 

Vi i No e Cigarette

Nal capacity “cigarettes” | Cigarette
Under 3 liters.__--- 22-2 1.0 1.7
3 liters or more_..-__- ete 17 2.4

 

 

 

Source: The Framingham heart study. (98).

Here again, the independent and combined effects of cigarette smok-
ing are observed.
Physical Inactivity

A physically inactive or sedentary individuel seems to run a higher
risk of developing coronary heart disease (89, 40, 41, 76). Spain (88)
reported that, in his prospective study of 3,000 men “* * * the rela-
tionship of occupational physical activity to smoking habits revealed
that one of six sedentary workers were heavy smokers and one of five
strenuous workers were heavy smokers.” Weinblatt, in reporting the
experience of the Health Insurance Plan of Greater New York (100)
also found that a higher proportion (41.9 versus 36.0 percent) of cig-
arette smokers were classified in the “most active” physical activity
category.

The independent and the combined effects between cigarette smok-
ing and physical activity are shown in table 11. The morbidity ratios
for myocardial infarctions are derived from published data.

TaBLE 11.—Age-adjusted morbidity ratios for myocardial infarctions
among smokers and nonsmokers according to physical activity level

 

 

 

 

Physical activit: N kk f Cigarett

sical activity omamokers o Cigarette
Most active _-.-- 2 1.0 2. 6
Least active... 22 eee Seee ell 2.4 3.4

 

 

SOURCE: Weinbiatt, E. (100).
Socioenvironmental Stress

Since 1955, research on socioenvironmental stress in relation to cor-
onary heart disease has increased greatly (83, 92). Among the factors
studied that indicate a strong association with coronary heart disease
incidence and prevalence is sociocultural mobility, that is, moving
from one social setting to another. The interaction of this factor and

56
cigarette smoking has been reported by Syme (90, 91) in both an ur-
ban and rural setting. Apparently in both areas cigarette smokers
were more culturally mobile than nonsmokers. The independent effect
of cigarette smoking on the incidence of coronary heart disease is
shown in the morbidity ratios in table 12 derived from the North
Dakota study (97).

TABLE 12.—Age-adjusted morbidity ratios for coronary heart disease
among smokers and nonsmokers according to sociocultural mobility
status

 

 

Never smoked Current and
Sociocultural status cigarettes former cigarette
smokers
Stable. __-.--------------------------+-------- 1.0 1.5.
Highly mobile... .-.----------------------------- 2.3 3.2

 

 

 

Source: North Dakota study. (8!)

Personality Type

Various investigators have long suspected a possible pathogenetic
role of the central nervous system in coronary heart disease (35). In
a series of reports, Rosenman (8/, 82) and Jenkins (57) have described
a personality pattern or overt emotional complex which, while asso-
ciated with other known risk factors, appears to predict coronary heart
disease more effectively than do other risk factors. This emotional com-
plex, “which they have termed Behavior Pattern Type A, is composed
of an enhanced competitiveness, drive, aggressiveness and hostility,
and an excessive sense of time urgency.” Recent unpublished data based
upon prospective observation of more than 3,000 men for a 44-year
period (52) discloses that smokers have a higher percentage (54 versus
47 percent) of type A persons among them. Moreover, the incidence of
coronary heart disease is shown to be related independently to both
smoking status and personality type. Morbidity ratios, derived from
the incidence data, are shown in table 13 which clearly demonstrates
the independent effects of cigarette smoking and its interaction with
personality characteristics.

TasLe 13.—Morbidity ratios of cigarette smokers as compared to non-

 

 

smokers by personality type
Personality type Nonsmokers of Cigarette
cigarettes smokers
Behavior type B._.....--.---------------------- LO 2. 0
Behavior type A__.-..__-.---------------------- 2.5 4,4

 

 

 

Source: Unpublished data from Western Collaborative Group Study, San Francisco, Cali. (8%).

5T
Multiple-Risk Factors

The method of analysis traditionally employed by epidemiologists,
that of the comparison of rates for multiple cross-classifications of
the data, generally requires a large study population at relatively high
incidence of significant events. Since coronary heart disease incidence
rates are low and study populations are necessarily small because of
practical and practicable limitations, definitive analysis of the inde-
pendence and interaction between risk factors have generally been re-
stricted to two factors at a time. Truett (95) applied a multiple logistic
function proposed by Cornfield to investigate the independent effect
on the incidence of coronary heart disease of seven risk factors: Age,
serum cholesterol, systolic blood pressure, relative weight, hemoglobin,
cigarettes per day, and ECG abnormalities. The method was used in the
analysis of data compiled in the Framingham study during a 12-year
period. A discriminant function coefficient was computed for each risk
factor. These coefficients represent the relative importance of each fac-
tor with respect, to the other six factors in the development of coronary
heart disease. While theoretical considerations underlying the logistic
risk function are not fully satisfied by the actual data, the approxima-
tion given by the function to observed rates is very good.

Consequently, Truett and Cornfield believe that the present compu-
tations permit the conclusion that “the most important risk factors,
aside from age itself, are cholesterol, cigarette smoking, ECG abnor-
mality, and blood pressure” (95 ).

MANIFESTATION oF Coronary Heart Disease

Coronary heart disease is essentially comprised of three major mani-
festations or subcategories :

1. Fatal myocardial infarctions, including sudden deaths attrib-
uted to coronary heart disease;

2. Nonfatal myocardial infarction; and

3. Angina pectoris.

Generally, investigators in their analysis of the relationship of risk
factors to the incidence of coronary heart disease have not subdivided
the observed coronary events into the three major subcategories pri-
marily because the paucity of events in each category did not permit
definitive conclusions on any differences observed. However, the pool-
ing of data from some of the larger prospective studies holds promise
of a more complete analysis of the independent and synergistic effects
of each risk factor on each of the subcategories of coronary disease.
Findings from these analyses might provide some insights into the
underlying pathophysiological mechanisms through which a risk factor
operates. The pooled data from the Albany and Framingham studies
and data from the HIP study include the observed associations of

58
cigarette smoking with each of the three major manifestations. Mor-
bidity ratios have been derived from these studies and are presented
in table 14.

TABLE 14.—Age-adjusted morbidity ratios for subcategories of coronary
heart disease among smokers and nonsmokers

 

 

 

Framingham-Albany Health insurance plan
Disease category
Non- Cigarette Non-

smokers of smokers smokers of Cigarette

cigarettes cigarettes smokers
Fatal myocardial infarction. ..__--_ 1.0 2.4 1.0 2.1
Non-fatal myocardial infarction. - - -- 1.0 2.3 LO 18
Angina pectoris___.._.....--------- 1.0 11 1.0 1.7

 

 

 

 

 

Source: Second Report of the Combined Experience from Albany and Framingham Studies (90). Un-
published Data from Health Insurance Plan Study (100).

The association of cigarette smoking to angina pectoris is not a con-
sistent one. A clear-cut association was found in the Health Insurance
Plan Study (ratio of 1.7); a similar association is also found in un-
published data from Framingham considered separately. However, no
association between cigarette smoking and the incidence of angina
pectoris was found in the Albany experience. Cederlof (19), in his .
analysis of prevalence data on angina pectoris obtained by question-
naire, found no statistically significant difference in prevalence rates
between 453 monozygotic twin pairs with dissimilar smoking habits.
In a larger study of about 9,000 persons from the twin register where
genetic factors were uncontrolled, Cederlof (79, 20) did find a sig-
nificantly higher prevalence of angina pectoris among smokers than
nonsmokers, particularly in men (ratio of 1.6) (67).

Friedman (42) and Epstein (36) have clearly described the in-
herent biases in prevalence studies which may lead to findings of risk
gradients that are different from those obtained in prospective inci-
dence studies. One of these limitations is that fatal cases are under-
represented in a prevalence survey. Thus, since it appears that cigar-
ette smoking is more closely related to the incidence of fatal myocar-
dial infarctions than to other forms of coronary heart disease, it is ex-
pected that morbidity ratios derived from prevalence surveys would be
lower than those computed from incidence data. With these restrictions
in mind, Russek (83) in a survey of 12,000 men in 14 occupational
groups found that the morbidity ratio of coronary heart disease preva-
lence among cigarette smokers was as high as 1.8. In contrast, in a study
of 77 identical and 89 fraternal twins in Sweden, comparing smokers
with their respective nonsmoking twins, Lundman (67) reported no
excess prevalence of overt or silent coronary heart disease. However,

59
the prevalence of these conditions, as Lundman concluded, “was too
low to permit of definitive conclusions.”

CarpIovascULaR REsPonsE To SMOKING AND/oR NICOTINE

As noted in the Surgeon General’s 1964 Report, nicotine has definite
physiologic effects on the cardiovascular system of experimental ani-
mals and of man. These include increases in heart rate, systemic arte-
rial pressure, cardiac output, stroke volume, and velocity of myocardial
contraction, all resulting in an increased myocardial tissue oxygen
demand (16). Coronary blood flow studies will be reported in the next
section under a separate subheading. These effects parallel those ob-
served with catecholamines (epinephrine and norepinephrine). The
effects can be blocked by the injection of tetraethylammonium chloride
and markedly reduced by adrenalectomy (22). Nicotine has been re-
peatedly shown to release endogenous catecholamines (57, 58, 59, 60,
102). However, the mechanism by which nicotine affects the cardio.
vascular system is more complex than the release of catecholamines
from the adrenal medulla. Direct and indirect (via the carotid body
and other chemoreceptors) stimulation of the vasomotor center, stimu-
lation of sympathetic ganglia, release of norepinephrine from local
stores, and release of antidiuretic hormone are included among other
postulated mechanisms of action involved in nicotine’s effect on the
cardiovascular system (16, 63, 86).

Coronary Blood Flow in Normal Subjects

The action of smoking and/or nicotine on the coronary blood flow
of normal human subjects has not yet: been definitively established, but
apparently normal subjects can increase their coronary blood flows
sufficiently to maintain a compensatory blood supply to the myocar-
dium despite the increased myocardial tissue demand for oxygen
caused by cigarette smoking. Earlier findings of increased coronary
blood flow in normal men, in response to cigarette smoking (11), were
not reproduced in a more recent study (6). In this latter study, al-
though a trend towards a slight increase in coronary blood flow was
observed in the particular normal persons studied, it was not
significant.

Direct injection of nicotine into the left coronary artery of dogs un-
der conditions of constant flow rate resulted in increased coronary vas-
cular resistance (38, 64). This response could be reduced by vagal nerve
stimulation or prior adminstration of acetylcholine; an immediate in-
crease in cardiac contractile force was also observed that could be
similarly reduced. It was concluded that these responses to nicotine
resulted from sympathetic nervous system activity or from the release
of catecholamines by myocardial chromaffin tissue (64).

Blood from the smoke-exposed lung tissue of dogs, directly perfused

60
into the coronary artery, failed to increase coronary resistance (38).
This effect was thought to be secondary to that of histamine, known
to act as a coronary vasodilator, which apparently is released from the
lung tissue of dogs during their exposure to smoke (8).

When blood from the smoke-exposed lung was perfused through
the systemic circulation of dogs while the coronaries were being
perfused with non-smoke-exposed blood, the typical release of cate-
cholamines occurred with many of the usual effects on cardiovascular
parameters except that the coronary vascular resistance increased
under these experimental conditions, apparently due to the increased
activity of the sympathetic nervous system (38).

Since it is well known that exposing dogs to cigarette smoke without
isolating and separately perfusing the coronary circulation normally
results in an increase of the coronary blood flow (38), the manipulation
of experimental conditions as described suggests that there is a
masking effect by the catecholamines on nicotine’s direct action on
the coronary circulation (38).

These studies may relate, by analogy, to humans and indicate that
smoking, in “normal” individuals, may produce at least two actions
that can affect coronary blood flow: (1) a decrease in coronary blood
flow by a possible direct action of nicotine on the coronary circulation
(demonstrated in dogs), and (2) an increase in coronary blood flow
as the usual resultant of varying responses to the intermediating
action of catecholamines and other physiologic processes (demonstrated
in both animals and humans).

Coronary Blood Flow in Subjects with Coronary Heart Disease

The effect of cigarette smoking on coronary blood flow was studied
in patients with coronary heart. disease (79). As was seen in normal
subjects, significant increases in heart rate, arterial pressure, and
cardiac output were noted. In contrast to the normal individuals
studied, patients with coronary heart disease distinctly showed a
much less significant compensatory increase in their coronary blood
flows. These results were confirmed by a later study (16), using the
Rubidium 84 method to estimate coronary blood flow. This study also
showed that in the coronary patients studied, there was no adequate
compensatory increase in coronary blood flow to meet the increased
myocardial tissue demand for oxygen. Coronary blood flow appar-
ently decreased as a result of cigarette smoking, in this particular
study group of coronary patients. Although the decreases noted were
not marked, they were statistically significant, and indicated that a
difference existed between these coronary patients as compared to the
normal subjects studied.

A difference in the coronary blood flow response to nitroglycerine
has also been demonstrated in normal subjects compared to subjects
with coronary heart disease. This was shown in studies using the

61
nitrous oxide (18, 44) and the Rubidium 84 (15) methods to measure
coronary blood flow. In response to nitroglycerine the normal indi-
viduals generally increased their coronary blood flow significantly,
but the coronary patients generally did not.

Animal studies have also demonstrated the decreased ability of
atherosclerotic coronary arteries to increase coronary blood flow, as
compared to the coronary arteries in normal animals (94). Dogs with
experimentally produced coronary artery insufficiency also show this
decreased ability (22). Similar differences between animals with nor-
mal coronary arteries as compared to atherosclerotic coronary arteries
have been demonstrated in response to ergonovine (80).

The above studies indicate that the effect of nicotine upon the car-
diovascular system, mediated in part by the action of released catechol-
amines, is generally to increase heart rate and cardiac output, and to
raise systemic arterial pressure temporarily. Findings concerning the
effect of nicotine on coronary blood flow are presently thought to be
largely due to the indirect effects of nicotine upon the cardiovascular
system. Other animal studies indicate that there may be a direct action
of nicotine on the coronary vasculature to increase coronary vascular
resistance, thus tending to reduce coronary blood flow. There are no
human studies on the direct action of nicotine by itself on the coronary
vasculature; such studies, involving the direct injection of nicotine
into diseased human coronary arteries, might be dangerous. Normal
individuals apparently can increase their coronary blood flows to com-
pensate for the increased myocardial tissue oxygen demand, but ap-
parently some patients with coronary heart disease cannot, as shown
by their response to smoking.

Thus some patients with coronary heart disease may be at a par-
ticular disadvantage when smoking and under other stresses since
their coronary arteries apparently cannot dilate to supply blood flow
adequate to meet the increased oxygen demand associated with nico-
tine-induced catecholamine release. The interaction of the above ef-
fect with recent findings concerning carbon monoxide, described in
the next section, may be especially important in those individuals with
coronary heart disease. The present studies indicate that the effect of
cigarette smoking on coronary blood flow, in the presence of pre-
existing coronary heart disease, may, in part, contribute to the in-
creased incidence of acute myocardial infarctions that have been
observed to be associated with cigarette smoking. No relationship be-
tween the smoking effect on coronary blood flow and the pathogenesis
of coronary atherosclerosis per se is presently suggested. Additional
research is needed.

Carbon Monoxide Effect

The gaseous phase of cigarette smoke contains about 4 percent car-
bon monoxide. This quantity can increase the levels of carboxyhemo-

62
globin saturation of cigarette smokers from 2 percent to 10 percent
(21). The average nonsmoker, depending on environmental exposure,
usually has less than 2 percent earboxyhemoglobin saturation (10).
Since smokers of one pack or more a day may have chronically elevated
carboxyhemoglobin levels of more than 4 percent (9), there may be
appreciable differences in the carboxyhemoglobin levels between some
heavy cigarette smokers and nonsmokers. _

In addition to displacing oxyhemoglobin, carbon monoxide effects a
shift in the oxygen-hemoglobin dissociation curve (2, 3, 4 6, 6). This
may result in a decreased release of oxygen at the tissue level. A series
of studies (62, 62) has been performed on young adults to analyze
the effect of cigarette smoking on carboxyhemoglobin levels, and the
consequent effect on some parameters of cardiopulmonary function.
An increased post exercise oxygen debt was observed after cigarette
smoking as compared to controls. This, in part, may reflect not only
ventilatory disturbances but also a decreased supply of oxygen in
the blood due to the carbon monoxide effect, resulting in less available
oxygen to meet the increased tissue demand. Similar post-exercise
oxygen debts have been noted after inhalation of enough carbon
monoxide to produce comparable blood levels of carboxyhemoglobin

21).

The consequence of the smoking/carbon monoxide effect appears to
be especially important in the myocardium where relatively more
oxygen is normally extracted from the coronary circulation as com-
pared to other organ systems. (Coronary venous ‘blood usually has
an oxygen saturation of less than 25 percent, whereas blood leaving
some other organs is about 75 percent saturated with oxygen (4).)

Dogs were exposed to carbon monoxide to elevate their carboxy-
hemoglobin saturation levels (9). In response to inhalation of carbon
monoxide there was an increase in coronary blood flow but a decrease
in coronary arterial-venous oxygen differences. Patients with coronary
heart disease were also studied following inhalation of enough carbon
monoxide to elevate their carboxyhemoglobin saturation levels to the
range of 5 to 12 percent (9). In response to carbon monoxide there was
generally an increase in the cardiac output and the coronary blood
flow in most of the patients. While the systemic arterial-venous oxygen
differences varied, either increasing or decreasing, the coronary ar-
terial-venous oxygen differences decreased, indicating a decreased
oxygen extraction by the myocardial tissue despite the myocardium’s
increased demand for oxygen. These decreases in myocardial oxygen
extraction are related to increases in the carboxyhemoglobin satura-
tion levels. It was observed that some patients evidently could com-
pensate by increasing their coronary blood flows adequately to supply
the myocardial tissue with sufficient oxygen, as indicated by a rise in
myocardial oxygen uptake in these individuals. However, the other

63
patients with coronary heart disease, evidently more severe, could not
increase their coronary blood flow rate enough to compensate for the
decreased oxygen carried by the blood. This latter group of patients,
even though they had increased cardiac output, had less significant
increases of coronary blood flow than those noted in the first group
of patients. The coronary arterial-venous oxygen differences and the
myocardial tissue oxygen uptakes both decreased, indicating that the
myocardial tissue oxygen demand was not being met. entirely.

The reduction in the amount of oxygen available to the myocardial
tissue caused by the absorption of carbon monoxide from tobacco
smoke may be especially critical in persons with pre-existing coronary
heart disease, especially when they cannot significantly increase coro-
nary blood flow to compensate for increased myocardial tissue oxygen
demand. The carbon monoxide effect may, in part, contribute to the
increased incidence of myocardial infarctions that occur in cigarette
smokers. Additional research is needed.

Studies on In Vitro Thrombus Formation

Recent studies have indicated that cigarette smoking may accelerate
thrombus formation of human blood in vitro. Platelet adhesiveness,
as measured by in vitro tests, also appears to be increased by cigarette
smoking (1, 43, 71, 87). Other studies, comparing smokers with non-
smokers, indicate that the platelet survival time of the smokers is
shortened (73) and the platelet turnover rate is increased (72). Studies
of animals show there is also an increased tendency for the platelets
to adhere to the vascular endothelium.

Platelet adhesiveness is reported to be increased in in vitro studies
using the Chandler rotating loop (32, 33, 34) ; these studies generally
show a consistent acceleration of the rate of thrombus formation.
Other in vitro tests show changes in thrombus formation and some
parameters of coagulation as a result of smoking (56, 66, 87). How-
ever, problems in experimental design and the multiplicity of tests
used, measuring either the same or overlapping portions of the com-
plicated coagulation process with varying results, cause difficulty in
evaluating these results (72).

The mechanism of changes in characteristics of the platelets in
smokers is being investigated, but there are indications that the release
of catecholamines, especially epinephrine, caused by the absorption
of nicotine during smoking may be intimately involved (71, 72). In
small doses, epinephrine has been shown to promote thrombus forma-
tion and coagulation, but in large doses it inhibits these processes.
Changes in the electrical charge of the platelet membrane have also
been implicated in increasing platelet adhesiveness (101), increasing
adherence to the vascular endothelium, and accelerating thrombus
formation as measured by the Chandler loop method. Some of the
alterations in thrombus formation may be mediated by an interaction

64
with serum-free fatty acids and cholesterol (70) but current evidence
suggests that inhalation of cigarette smoke acts primarily through
other independent factors (101). Thus, cigarette smoking may cause
an acceleration of the in vitro thrombus formation of human blood. It
is reasonable to suspect that cigarette smoking, in part by affecting
the thrombus-forming process in human blood, may account for some
of the excess coronary heart disease deaths that occur in cigarette
smokers, especially some of the deaths certified as “acute coronary
thrombosis.” Further research is necessary before any definite con-
clusion can be made.
Autopsy STUDIES

The two most significant pathological studies of the relationship of
smoking history to atherosclerotic changes in human coronary arteries
have been reported by Auerbach and Strong. Auerbach (7) studied
1,372 males for whom a smoking history was available and who had
died of causes other than coronary heart disease. He found that the
percentage of men with an advanced degree of coronary atherosclerosis
was higher among cigarette smokers than among nonsmokers, and that
the percentage increased with amount of cigarette smoking. Both
among smokers and nonsmokers the percentage of men with advanced
coronary atherosclerosis also increased with age. This relationship
held up even when the following were excluded: men with a history
of diabetes, men who had died of any type of heart disease, and men
whose hearts weighed 400 gm. or more. A matched set analysis was
also carried out (reincluding some diabetics and heart disease deaths)
and again the percentage of men with advanced coronary athero-
sclerosis was less among nonsmokers than among men who had been
current cigarette smokers, and this percentage increased with the
amount smoked.

Strong (89) in a study of coronary arteries from 645 autopsied
males, 20 to 64 years of age, excluded patients with diseases he
thought to be associated with smoking (emphysema, lung cancer,
etc.), or with coronary heart disease (myocardial infarction, hyper-
tension, diabetes, stroke, etc.). He found that the mean percent of
coronary intimal surface occupied by raised atherosclerotic lesions
was approximately twice as great in heavy smokers (25+ cigarettes/
day), and about one-third greater in light.smokers (less than 25/day),
than in nonsmokers. Calcified lesions and mean coronary wall thickness
measured radiographically were on the average highest in heavy
smokers and lowest in nonsmokers. Differences among these smoking
categories were generally greatest at younger ages.

These autopsy studies suggest that smoking, in addition to the
acute immediate effect associated with the act of smoking, has a
chronic effect leading to advanced degrees of atherogenesis. However,
these findings may, in part, reflect the differences noted between

65
smokers (7,89), particularly heavy smokers, and nonsmokers in regard
to greater obesity, higher dietary fat intake, and higher serum choles.
terol levels. Further analyses of autopsy series are needed to.determine
the independent effects of cigarette smoking on atherogenesis.

SMOKING AND CEREBROVASCULAR DISEASE

An increasing amount of evidence has accumulated in the past few
years relating the development of clinical cerebrovascular disease to
cigarette smoking. Most of this information has come from the pros-
pective mortality studies.

Hammond has reported the following data from his large prospec-
tive study (47), noted in table 15.

TABLE 15.—Cerebral vascular lesions. Age-standardized death rates, by
type of smoking (lifetime history) and age at start of study

 

 

 

 

 

 

 

 

 

 

 

Age
45-54 55-64 65-74 78-84
CVL death rates per 100,000
person-years
MEN
Never smoked regularly_._____.________ 28 92 349 1, 358
Pipe, cigar__---..-...-.--------_-__8 25 100 369 1, 371
Cigarette and other_._..___-.._..__..__. 28 129 361 990
Cigarette only_.__.___--_--_-_-- 42 1380 477 1, 168
Total___-_--_ ee 35 116 391 1, 272
WOMEN
Never smoked regularly.______..______. 18 57 228 1, 082
Cigarette___..-_-._-2 ee 38 88 315 1, 277
Total__-_-.. 2-2 25 64 238 1, 091
CVL mortality ratios
MEN
Never smoked regularly__________._____ 1. 00 1. 00 1. 00 1. 00
Pipe, cigar_.......--...--..-----_-___. . 89 1. 09 1. 06 1.01
Cigarette and other_.__._..-.._..______. 1. 00 1. 40 1. 03 73
Cigarette only..-....._..2.2-22-_22 oo. 1. 50 1. 41 1. 37 . 86
WOMEN
Never smoked regularly____...-..-_.___ 1. 00 1. 00 1. 00 1. 00
Cigarette. _._......---.-----.----_---- 2.11 1. 54 1. 38 1,18

 

 

 

 

 

Source: E. C. Hammond (47).

66
Between the ages of 45 and 74 the death rates from stroke for male
smokers were 37 to'‘50 percent higher than those for male nonsmokers of
comparable age. In female smokers the death rates from stroke were
38 to 111 percent greater than those for nonsmokers. Above the age of
~4 the differences between the two groups were much less.

The data in Table 16 concerning smoking and death rates from stroke
are derived from the U.S. veterans study (62).

Tape 16.—Mortality ratios and death rates for stroke as underlying
cause among current smokers of cigarettes only

 

 

 

Quantity of cigarettes smoked per day
0 19 10-20 21-39 40+
Mortality ratio (all ages). ------ 1. 00 1. 51 1. 42 1. 70 1. 59
Death rates:
Age 55 to 64..._---------- 59 92 112 125 130
Age 65 to 7A__.---.------- 280 323 312 382 502

 

 

 

 

 

 

SouRcE: U.S. veterans study (62).

When stroke was certified as the principal cause of death, the death
rates for smokers were higher than for nonsmokers; however, no pro-
nounced increase was noted in the mortality ratios as the degree of
smoking increased. The death rates from stroke for all ages was 59
percent higher in heavy smokers (40 or more cigarettes) than in
nonsmokers.

TaBLe 17.—Mortality ratios and death rates for stroke as the underlying
or contributory diagnosis among current smokers of cigarettes only

 

 

 

 

 

Quantity of cigarettes smoked per day
0 | 1-9 | 10-20 21-39 40+
Mortality ratio (all ages) ------- 1.00 1. 45 1. 45 1.75 1.€3
Death rates:
Age 55 to 64.-..---------- 101 152 174 195 26
Age 65 to 74_.-.---------- 424 14 520 616 724

 

 

Source: U.S, veterans study (52).

Stroke, listed as either the underlying or contributory cause of death
on the death certificate, was also associated with progressively increas-
ing mortality ratios and death rates as the extent of smoking in-
creased. Heavy smokers here had an 83 percent greater mortality from
stroke than nonsmokers.

Mortality data by underlying cause of death may often be mislead-
ing, particularly when stroke is concerned. Many stroke patients have

67
concomitant coronary heart disease, or may develop pneumonia and
other complications that may hasten death. The death certificate Thay
carry stroke as the underlying cause or as the contributory cause of
death, depending upon the interpretation of the physician at the time,
The important addition of these data is that smoking is associated
with a higher mortality from stroke, whether the stroke is recorded as
either the underlying cause or as the contributory cause of death.

These two studies indicate that smoking may be associated with a
higher mortality from stroke in the relatively younger age groups
(under age 74). More than one-half the strokes that occur each year
are in the group above age 75 and in this group there is no evidence
relating. smoking to cerebrovascular disease.

Another large study has been conducted analyzing the mortality of
50,000 former students who entered Harvard University or the Univer-
sity of Pennsylvania during the years 1916-50 (74, 76, 76). From this
population 171 deaths from cerebrovascular accidents have been identi-
fied. A review of the medical records from their college years has been
carried out, and selected factors were correlated with the later occur-
rence of stroke. Seven precursive “risk factors” present at the time
of college attendance have been defined : Cigarette smoking, high blood
pressure, excess body weight, short stature, a history of early parental
death, a history of nonparticipation in college sports, and a history
of “heart consciousness” (also shown to be correlated with coronary
heart disease). Cigarette smoking and a history of early parental death
were more strongly correlated with thrombotic stroke than with hem-
orrhagic stroke. Students who smoked more than 10 cigarettes daily
were at twice the risk of having a fatal stroke than were those who
smoked less or not at all.

In 1965 the Framingham study (64) reported that while an excess
development of thrombotic brain infarction appeared to be associated
with cigarette smoking, statistically significant differences could not
be demonstrated with the small number of cases available at that time.
More recent data from Framingham indicates that cigarette smoking
increases the risk of stroke in males. The relatively small number of
women smokers had too few strokes for adequate analysis.

The new epidemiological evidence, then, indicates that cigarette
smoking may be more closely associated with cerebrovascular disease
in the population between the ages of 45 and 74 years than was previ-
ously indicated. If cerebrovascular thrombosis (thrombotic brain in-
farction) accounts for this association, it is possible that some of the
considerations of how cigarette smoking may produce coronary throm-
bosis also apply to the pathogenesis of cerebrovascular disease. Further
research is essential to understand the relationships that exist between
cigarette smoking and cerebrovascular disease.

68
SMOKING AND AORTIC ANEURYSM

Additional information on mortality data concerning aortic aneu-
rysm has been provided by the U.S. veterans study (62) and the Ham-
mond (47) studies, as noted in tables 18 and 19, respectively.

TaBLE 18.—Mortality ratios and age-standardized death rates for aortic
aneurysm in U.S. veterans, current smokers of cigarettes only

 

 

 

Number of cigarettes smoked per day
0 1-9 10-20 21-39 40+
Mortality ratio__.....--------- 1. 00 2. 12 5. 53 5. 95 7. 26
DEATH RATES
Age:
55 to 64___.-------------- 6 13 27 43 44
65 to 74__...------------- 25 57 123 157 221

 

 

 

 

 

 

Source: U.S. veterans study (52).

TABLE 19.—Mortality ratios and age-standardized death rates for aortic
aneurysm

 

Age 45-4 years Age 65-79 years

 

Females {' Males Females Males

 

Mortality ratio.._.-.-.---------------- 3. 89 2. 62 3. 33 4, 92
Deathrates.....--.------------------- 14(1) 18(7) | 43(78) | 118(24)

 

 

 

 

 

t Numbers in parentheses indicate death rates of those who never smoked regularly.
Source: Hammond, E. C. (47).

It is apparent that there is a close association between cigarette
smoking and death caused by aortic aneurysms.

Thus, the additional evidence confirms the previously observed asso-
ciation between cigarette smoking and death due to nonsyphilitic
aortic aneurysm.

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85
CHAPTER 2

 

Smoking and Chronic Bronchopulmonary
Diseases (Non-neoplastic)

CONTENTS
Page
Introduction__._---------------------------------------- 89
Chronic Bronchopulmonary Disease Mortality ---__-_.------ 90
Chronic Bronchopulmonary Disease Morbidity - .-_...------ 96
Studies Relating Smoking to Respiratory Symptoms-__.- 96
Studies Relating Smoking to Pulmonary Function_--- --_- 99
Relation of Smoking to Heredity or to Constitutional Factors._. 101
Pathology Studies--------------------------------------- T04
Animal Experiments------------------------------------- 106
Ciliatoxic Effects of Cigarette Smoke-_.__-___-__---------- 107
Other Factors Associated with Chronic Bronchitis or Em-
physema or Both_--.-_---.------------------------------ 108
Additional Considerations Regarding Smoking and Em-
physema_-___------------------------------------- 110
Cited References......_.__------------------------------- 111
Sapplemental References-_--_------------------------------ 117

271-304 O—67——7 87
INTRODUCTION

Purpose or THs Rerort

This report reviews additional pertinent data relative to smoking
and chronic bronchopulmonary diseases—specifically chronic bron-
chitis and pulmonary emphysema.

The reader is referred to the Surgeon General’s 1964 Report (68)
and recent textbooks for background information on the chemistry of
tobacco smoke, the metabolism and toxicity of specific components
of tobacco smoke, the physics of its retention in the air passages and
the lungs, and the mechanics of pulmonary function.

DEFINITIONS

The scope of this chapter will be limited to emphysema and chronic
bronchitis and it may be useful to present definitions of both terms.
There have been many definitions of chronic bronchitis and emphy-
sema. Those used in the Surgeon General’s 1964 Report had been pro-
posed by the American Thoracic Society in 1962 (37). With the in-
creasing public health interest in chronic bronchopulmonary disease,
attempts have been made to develop precise definitions to categorize
these diseases and to isolate them satisfactorily from other pulmonary
conditions. A task force sponsored by the Chronic Respiratory Dis-
eases Control Program of the Public Health Service and the National
Tuberculosis Association deliberated this together with related prob-
lems for a week in October 1966. They adopted the following
definitions (72) :

“Chronic bronchitis is a clinical disorder characterized by excessive
mucous secretion in the bronchial tree. It is manifested by chronic or
recurrent productive cough. The diagnosis of chronic bronchitis can
be made only if other bronchopulmonary or cardiac disorders are ex-
cluded as the cause for these symptoms. The predominant pathologic
change is hypertrophy and hyperplasia of the mucous secreting glands
in the trachea and bronchi.

Pulmonary emphysema is an anatomic alteration of the lung
characterized by destruction of alveolar walls accompanied by abnor-
mal enlargement of the air spaces distal to the terminal, nonrespira-
tory bronchiole.”

These definitions will be used to describe chronic bronchitis and
emphysema as understood in the present report. They are being used

89
to emphasize the lack of progress in defining the two conditions for
purposes of differentiating them from other diseases of the lung. Ref.
erence may be made to the Surgeon General’s 1964 Report where near-
ly identical definitions will be found.

Inability to distinguish between chronic bronchitis and emphysema
has hampered medical research and exchange of information. The
P.H.S.—-N.T.A. task force report states further :

“Although patients having only chronic bronchitis tend to have
more cough and sputum than do those having only pulmonary emphy-
sema, the array of symptoms, physical findings, and pulmonary
physiologic abnormalities are similar in both diseases.

“Chronic bronchitis and emphysema coexist in many patients * * *”

This statement may help to explain some of the difficulties encoun-
tered by research workers in studying these diseases and why the re-
searchers are limited to describing symptoms and signs observed in the
populations under investigation. It may also explain why it is diffi-
cult to distinguish these conditions in the present report which seeks
to record the research findings related to smoking and chronic respira-
tory disease published since the Surgeon General’s 1964 Report. Re-
search findings on both diseases are not considered separately in this
report but are grouped in population studies, pathology studies, and
animal experiments. Additional considerations pertinent to pul-
monary emphysema are then provided.

CHRONIC BRONCHOPULMONARY DISEASE
MORTALITY ?

Mortality from chronic bronchopulmonary diseases has continued
the upward trend well established at the time of publication of the
conclusions cited in the Surgeon General’s 1964 Report. Deaths in the
United States from emphysema or chronic bronchitis or both have
risen steadily from about 3,000 in 1950 to more than 20,000 in 1964,
as can be seen in table 1.

TaBLE 1.—Mortality from emphysema and/or chronic bronchitis (ISC
codes 601, 602, 527.1) ,

 

 

Year Number Year Number Year Number

of deaths of deaths of deaths
1964_____-... 20, 208 || 1959___.____. 10, 433 |} 1954.--_--__- 4, 877
1963_---_.--. 19, 443 |} 1958_...__._- 9, 328 || 1953...------ 4, 657
1962__-._-.-. 15, 915 || 1957_._-___._- 8, 186 || 1952._------- 3, 846
1961_._-__---.- 13, 302 |} 1956..-..___- 6, 535 |) 1951..---__.- 3, 660
1960__-_._._. 12,426 || 1955_..._____ 5, 616 || 1950_..-.-_-. 3, 157

 

 

 

 

 

 

 

 

Source: Vital Statistics of the United States, 1950-1964 (70).

* All death rates throughout this chapter are per 100,000 population, unless
otherwise indicated.

90
The increase and aging of the population during the same period
does not account for this rise. Age-adjusted mortality rates for emphy-
sema without mention of chronic bronchitis increased about ten times
for men, from 1.3 per 100,000 in 1950 to 12.6 in 1964. A similar, al-
though perhaps somewhat less dramatic, increase occurred among
women, from 0.2 per 100,000 in 1950 to 1.6 in 1964, Death rates from
chronic bronchitis rose less precipitously, doubling during the same
period (69, 70). How much of this increase is the result of improved
diagnosis of these diseases and how much the result of a true change
in mortality patterns cannot be determined at the present time. Asso-
ciations have been demonstrated between these conditions and
smoking.

PorvunaTion STUDIES

Included in this broad category are investigations that collected
‘nformation from a group or groups of persons either by a series of
questions, by some form of physical examination, or by a review of
recorded data such as hospital records and death certificates.

Prospective STUDIES

In the Surgeon General’s 1964 Report, findings from seven prospec-
tive studies were presented, Additional data have been reported from
four of these investigations in the past 3 years. Information relevant
to smoking and chronic respiratory disease will be summarized here.

The study of mortality among policyholders of U.S. Government
Life Insurance policies available to persons who served in the Armed
Forces between 1917 and 1940 was initiated in 1952. Almost all the
293,658 policyholders were white males. Recently Kahn (44) pub-
lished a report that included all deaths from July 1954 through De-
cember 1962, a period of 814 years.

The relation of cigarette smoking to death from bronchitis and
emphysema is presented by mortality ratios in table 2 and by specific
risk of mortality in table 2A. Given the definitions previously cited,
these tables also illustrate the difficulties in separating these diseases.
The first row of table 2 gives combined mortality ratios and the next
two rows give the same data in an attempt to delineate the specific dis-
eases, Mortality ratios are given by the number of cigarettes smoked
per day at the time the men were enrolled in the study. Mortality
from these diseases is much higher among cigarette smokers than
among those who never smoked and rises with the number of ciga-
rettes smoked daily. The ratios are much higher for emphysema alone
than for chronic bronchitis with or without mention of emphysema.

A similar study of veterans was begun in Canada in 1955. Answered
questionnaires were returned by nearly 78,000 men whose subsequent
mortality for a period of 6 years was recently analyzed by Best and

91
his associates (12). Deaths from chronic bronchitis and emphysema
have been summarized in table 3 which gives mortality ratios by
the number of cigarettes smoked each day. Here, again, the mortality
is much higher among smokers and is directly related to the number
of cigarettes smoked. The mortality ratios reported for both diseases
combined are similar to those reported for the U.S. Veterans study,

TABLE 2.— Age-adjusted mortality ratios Jor current smokers of cigarettes
only, by number of cigarettes smoked daily

Cigarettes smoked per day at entrance to study

Cause of death Occasion

never 19 10-20 21-30 +
smoked

 

 

 

Bronchitis or emphysema or both (500-502,

527.1)_..------- 2, 1.0 4.6; 10.0 | 11.8 18,2
Bronchitis with or without emphysema

(500-502). 1.0 3.6 4.5 4.6 8.3
Emphysema (527.1).-___.-.__.____.._. 1.0; 5.3) 14.0] 17.0] 25.3

 

 

 

 

 

 

Sounce: U.S. Veterans study (44).

TaBLe 2A.—Age-specific annual probabilities of death per 100,000
person-years, for current smokers of cigarettes only

 

 

 

Cigarettes smoked per day at entrance to study
Occasional ” 0 All
eld] 19 10-20 21 + | quantities
Chronic bronchitis and/or
emphysema:
Age 55 to 64_____________ 2 12 32 30 39 29
Age 65 to 74..___________ 10 66 100 141 322 113
Chronic bronchitis:
Age 55 to 64... 2-228. 1 5 5 5 5 4
Age 65 to 74... _____ 5 15 22 30 46 23 .
Emphysema without
bronchitis:
Age 55 to 64__-___________ 1 7 27 26 34 25
Age 65 to 74_.__________e 5 52 78 111 276 90

 

 

 

 

 

 

 

1 Annual probabilities of death at each single year of age were combined into 10-year age groups by using
weights proportional to the distribution of the U.8. male Population in 1960. Not shown if less than 50
berson-years of observation at any single year of age in the 10-year interval.

Source: U.S. Veterans study (44).

When the two diseases are separated, the ratios for emphysema in the
Canadian study are similar to those for chronic bronchitis in the
U.S. study, and the ratios for chronic bronchitis are similar to those
attributed to emphysema in the United States. This illustrates the

92
problems of definition and one of the difficulties of direct comparison
between studies, especially when different countries are involved.

TaBLE 3.—Age-adjusted mortality ratios for smokers of cigarettes only
by number of cigarettes smoked daily

 

Cigarettes smoked per day at entrance to
study
Cause of death

 

 

 

Non | 19 10-20 | 21+
smokers
Bronchitis or emphysema or both. ------------- 1.0; 6.1! 410.0! | 10.4!
Bronchitis with or without emphysema (500-502) _ 1.0} 7.0 |13.7 14.6
Emphysema (527.1)_._--.-------------------- 1.0| 4.8 6.1 6.9

 

 

 

 

1 Calculated from (12).
Source: Canadian Pensioners study (/2).

A study among British physicians, the first of the large prospective
studies, was started in 1951 with the sending of a short questionnaire
to the 59,600 registered physicians then resident in the United King-
dom. Usable replies were received from 34,455 men and 6,192 women.
Ten years of observation of mortality in relation to smoking was
recently reported for this population by Doll and Hill (29, 30). Their
findings on mortality from chronic bronchitis as related to smoking
included emphysema and are given in table 4. Only the standardized
death rates were presented in the report but the mortality ratios have
been calculated from them to offer an easier comparison with the
other two studies. Again, it is clear that mortality from these combined
diseases (no attempt was made to differentiate them in the published
report) is strongly and directly related to the amount of cigarette
smoking.

TaBLE 4.—Standardized death rates, per 100,000 population, for
bronchitis and emphysema for male smokers of cigarettes only, by
number of cigarettes smoked daily

 

 

 

 

Cigarettes smoked per day at entrance to study
Cause of death
Never 1-14 15-24 25+
smoked
Bronchitis (including emphysema—502,
527.1)... ie e----------- 5 34 64 106
Mortality ratios_......._.....---..----- 1.0 6.8 12.8 21.2

 

 

 

 

 

SOURCE: Study of British Physicians (29, 30).

93
The fourth of the prospective studies is the largest. More than 1
million men and women living in 25 States were enrolled in this
investigation in late 1959 and early 1960. A report of the first 4 years
of observation was published recently by Hammond (36) and mor.
tality from emphysema and chronic bronchitis as related to smoking
is given in table 5. A slight departure from the usual assignment of
cause of death should be mentioned. When the cause of death was listed
as chronic bronchitis with emphysema, it was combined with emphy.-
sema alone. For this reason, the cause of death in table 5 is not quite
the same as any of the causes listed in the other tables. Again, it is
clear that mortality from these entities is related to smoking for both
men and women. This was the only one of the four studies wit enough
women enrolled to provide meaningful data.

TABLE 5.—Mortality ratios for deaths due to emphysema and bronchitis
with emphysema for cigarette smokers—men and women in 2 age
groupst

 

Men (age in years) Women (age in years)

 

 

Cause of death
45-64 65-79 45-04 65-79
Emphysema and bronchitis with emphy-
sema (502, 527.1)_....- 2-08 6.5 11.4 4.9 7.61

 

 

 

 

 

t Mortality ratios of nonsmokers in the above categories are 1.00 by definition.
' Calculated from (36). :

Source: Hammond, E. C. ($6).

Before summarizing the data presented from these four investiga-
tions, two further points should be made. Excessive mortality was
largely confined to cigarette smokers. The mortality ratio for chronic
bronchitis and emphysema, for pipe and cigar smokers combined, in
the U.S. veterans study, was only 0.99; in the Canadian study it was
about 1.6 (based on only nine deaths) ; in the study of men from 25
States it was 1.37; and among British doctors the standardized death
rate was 15 (compared with five among nonsmokers). Whatever may
be the relationship of pipe and cigar smoking to chronic bronchitis
and emphysema, it is clear that it is substantially less important than
the relationship of cigarette smoking.

In two of these studies, stopping cigarette smoking is seen to have
an effect on subsequent mortality from chronic bronchitis and emphy-
sema. In the course of the followup of the British physicians
(29, 30) it was possible to estimate the number of years a man con-
tinued smoking after he had answered the initial questionnaire. For
chronic bronchitis the mortality rates at first increased after cessation
of smoking and later fell well below the rate for men who continued
to smoke. The death rate from chronic bronchitis, per 100,000

94.
ex-smokers of 5 years or more was 37 compared with a rate of 59 for
all other smokers. Similarly, in the study of U.S. veterans, the mor-
tality ratio for chronic bronchitis and emphysema was 10.1 for all
male current cigarette smokers but only 7.6 for men who had stopped
smoking for reasons other than “Doctor’s orders.”

RerrosPective STUDIES

Wicken (75) made a study of lung cancer and bronchitis mortality
in Northern Ireland. During the 3 years, 1960-62, a total of 1,262 men
and 630 women, aged 35 years or more, were certified as having died
of bronchitis. For each of these persons a control was selected—the
next person in the Register of the same sex and 5-year age group who
last resided in the same area and who died of a nonrespiratory illness.
Personal interviews with relatives of the decedents were carried out
for about 94 percent of the subjects and controls to determine the
decedents’ smoking habits. In addition, a random sample of about
1,500 households in Northern Ireland was selected and one member of
each household was interviewed to obtain details of the age, sex, smok-
ing habits, and other information on all adult members. This informa-
tion on all adult members was used to define the adult population of
Northern Ireland in order to calculate death rates.

Bronchitis mortality for both men and women was associated with
smoking and directly related to the number of cigarettes smoked daily,
as seen in table 6. ‘

TABLE 6.—Age-standardized death rates per 100,000 population from
bronchitis for adults 35 years old and over as related to smoking habits

 

 

 

Number of cigarettes smoked daily Smoker of-—
Nonsmoker Cigarettes, Pipes or
1-10 11-22 B+ Pp or cigars
cigars
Men__.-| (124)! 64 |(245) 189 |(300) 220 |(168) 284 (62) 99 | (289) 118
Women._| (490) 58 | (57) 77 | (20) 118 | (15) 201 |.--------- (2) 165

 

 

 

 

 

 

1 Figures in parentheses show the number of deaths upon which the rates are based.
Sovgce: Wicken study (76).

Using these data, Wicken applied the bronchitis death rates observed
among male non-smokers to all the male population of Northern Ire-
land and estimated that had these rates prevailed, only 45 percent of
the male deaths from bronchitis would have occurred.

RésumME

_ Recent data from the four prospective studies and the one retrospec-
tive study all reveal, for men, an association between cigarette smok-

95
ing and mortality from bronchitis and emphysema. All report an
increasing gradient of mortality with an increasing amount smoked,
This was also true among women although only one prospective study
and the retrospective study included enough women to permit calcula-
tion of death rates. Mortality was consistently higher among cigarette
smokers than among men who smoked pipes or cigars. These are
consistent associations that might be expected if there were a causal
relation between cigarette smoking and these diseases. In addition, if
such a relationship exists, cessation of smoking should be followed by
a reduction in mortality. This did occur in the two studies that in-
cluded information on changes in smoking habits.

These data, then, strongly support the conclusion that cigarette
smoking is at least one of the causes of chronic bronchitis and
emphysema.

CHRONIC BRONCHOPULMONARY DISEASE MORBIDITY
Srupres Retatinc Smoxine To Respmatory SyMPToMs

Most surveys of chronic respiratory disease are confined to the fre-
quency of signs or symptoms of disease. The National Center for
Health Statistics, however, in interviews from J uly 1964 to June 1965,
asked about certain chronic conditions including chronic bronchitis
and emphysema (72). This was asked in a national sample of 42,000
households containing about 134,000 persons. After answering ques-
tions about health for himself and other members of the household, the
respondent was asked questions about their smoking habits. A strong
relationship was found between smoking habits and the presence
of chronic bronchitis or emphysema or both. This is presented in
table 7.

TaBLE 7.—Age-adjusted prevalence rates of chronic bronchitis and/or
emphysema per 100 persons 17 years and over, by sex, and smoking
status—number of cigarettes per day (heaviest amount)

 

 

 

Present smokers
Never Former
smoked smokers
1-10 11-20 21+
Men._......_-._- 22-2 eee. 1.0 2.5 1.1 2.3 3.3
Women._._._.._---._-..._____- 1.2 2.6 1.6 4.0 6.5

 

 

 

 

 

 

Source: National Center for Health Statistics (72, Fig. 5).

96
In another study of the epidemiology of persistent cough, Wynder
(80) and his associates evaluated the smoking habits, occupation, and
residence (urban or rural) in a male population comprised of 315
hospital patients in New York, and 315 in California, and of 239
Seventh-Day Adventists living in California who were not hospital
patients. Persistent cough was reported from 23 percent of the Ad-
ventists (who do not smoke), 45 percent of the New York patients,
and 53 percent of the California patients. Coughing was more fre-
quently reported by cigarette smokers than by those who smoked pipes
or cigars, as shown in table 8. Inhalers also had a higher rate of
persistent cough and the rate of cough increased with smoking in each
age group. Wynder found no correlation between urban or rural resi-
dence and persistent cough. Analysis of the California group showed
a higher rate of persistent cough that was independent of the number
of cigarettes smoked.

Tapie 8.—Percent of men with persistent cough as related to smoking

 

 

 

 

 

 

habits
Ch
Non- | Pipes/ igarettes only Mixed
smoker | cigars smoker
1-10 | 11-20 | 20+
New York patients_---.---------- 14 33 45 46 67 51
California patients--..------------ 22 30 45 74 74 66
Seventh-Day Adventists_---------- 93 |.__--_|------|.-----|------]------

 

 

 

 

Source: Wynder, E. L. et al. (80).

Deane and her associates (28) studied symptoms in relation to smok-
ing in a group of about 500 outside telephone workers over age 40
working in the San Francisco and Los Angeles areas. Symptoms were
reported on a modified version of the British Medical Research Council
questionnaire. Regardless of the definition of the respiratory symp-
tom—persistent cough and phlegm, persistent cough, phlegm, and
shortness of breath—it was consistently experienced by a greater pro-
portion of those who currently smoked cigarettes than those who did
not.

Coates and his coworkers (20) also found among 1,584 postal work-
ers aged 40 or more (all employees of the Detroit Main Post Office),
that for every symptom—cough and phlegm, chronic phlegm alone,
wheezing, shortness of breath—the prevalence was two to three times
greater among moderate (15-24 cigarettes per day) and heavy (25 or
more) smokers than among those who did not smoke. These differences
in symptom prevalence were observed for both men and women but
“chronic bronchitis” was reported more often by men, which Coates
ascribes to their being heavier smokers. The prevalence of chronic

97
cough and phlegm among ex-smokers was no greater than in
nonsmokers.

Very few studies have been carried out to estimate the association of
morbidity and smoking in young people. Peters and Ferris (60) retro.
spectively tallied the number of visits to the clinic at the University
of Health Services for 1,623 Harvard students and 404 Radcliffe sty-
dents. Smoking information had been gathered on these students in
their freshman and senior years. Smokers made significantly more
visits to the clinic in total and for respiratory diseases in particular,
There was a positive correlation between years smoked and the num-
ber of respiratory disease visits.

In contrast to most studies which select population groups, Huhti
(43) studied virtually the entire population, age 40-64, in a commune
in western Finland. Although it was a mostly rural population, some
industrial workers were included. More than 95 percent of the men
and women invited responded to the survey. Questionnaires (based on
that of the British Medical Research Council) and medical examina-
tions were completed for 730 men and 890 women. Only 18.7 percent
of the men were nonsmokers and 21.6 percent ex-smokers, compared
with 86.1 percent nonsmokers and 3.6 percent ex-smokers among
women. Prevalence of both cough and phlegm production was signifi-
cantly higher among smokers than nonsmokers as seen in table 9.

TABLE 9.—Percent of men and women with cough (3 months in the year)
and with phlegm (3 months in the year), related to smoking habits

 

 

 

 

 

 

 

 

 

Cigarettes smoked per day
Non- Ex-
smokers | smokers
1-14 15-24 25+
Cough
Men__.__..---2-2--__ 31.5 40.8 42.4 4.1 8.5
Women-____.._.- 22 oe 10.4 | (8 of 7 women 4.5 13.3
smoking 15+
cigarettes/day)
Phiegm
Men_......__-. ee 38.0 42.9 42.4 10.7 17.7
Women_._.._-..__.-____. 10.4 | (4 0f 7 women 5.9 13.3
smoking 15+
cigarettes/day)
Source: Huhti, E. (48).
RéEsuME

In all the prevalence studies that have been identified and reviewed,
significantly more cigarette smokers consistently reported having
symptoms related to chronic respiratory disease. This was true for
cough, production of phlegm, wheezing, and shortness of breath. It

98
was also true when the respondents were asked not about symptoms
but about disease, that is, chronic bronchitis and emphysema, and in
one instance was reflected in the number of clinic visits for respiratory
diseases. Prevalence of these symptoms increased with the amount of
cigarettes smoked. It was less among pipe and cigar smokers, and ex-
cigarette smokers among whom the prevalence, in some reports, ap-
proached that of nonsmokers.

Srupres RELATING SMoKING To Putmonary Funcrion

Many of the surveys outlined in the previous section on respiratory
symptoms also included lung function tests as part of the examination.
Huhti (43), for example, in his Finnish study took chest. X-rays and
collected information on vital capacity, 1-second forced expiratory
volume (FEV;..) and peak expiratory flow (PEF) as shown in table
10.

Tapie 10!.—Mean values of lung function tests among men and women

 

 

 

by smoking hahits
Cigarettes smoked per day Non- Ex
smokers smokers
1-14 15-24 25+
FEV} (liters):
Men__-__.__-------------- 3.17 3. 30 3. 08 3. 46 3. 39
Women. -..--.--- jew e eee eee 2, 74 (?) ?) 2. 42 2. 32
FVC (liters):
Men.___..---.---.------- 4, 40 4.51 4, 26 4, 40 4,51
Women_-_-_.-------------- 3. 53 () @ 3. 18 3. 19
PEF (c.c./sec.):
Men_____..-------------- 518 537 517 569 551
Women. ...-.--..-------- 431 () (?) 410 403

 

 

 

 

 

 

1 Although this table presents data for all ages combined, the same differences were apparent in each
5-year age grouping.

2 Only 7 women smoked 15 or more cigarettes per day.

Sovxrce: Huhti, E. (43).

Among men the FEV, , value was lower for smokers than nonsmok-
ers. The PEF value was slightly lower, but the vital capacity was un-
related to smoking. In this study none of the values seemed to be clear-
ly related to the number of cigarettes smoked. Among the relatively
small number of female smokers in this study, most of whom smoked
between one and 14 cigarettes per day, almost all the lung function
values were better than in the female nonsmokers. Female smokers
were slightly taller in height and slightly lighter in weight than fe-
male nonsmokers, which may account for this finding. However, fe-
male ex-smokers had slightly reduced FEV. and PEF when compared

99
with female nonsmokers, similar to the relationship noted between
male ex-smokers and male nonsmokers.

Coates (20) observed no relation between smoking habits and vital
capacity or FEV... He did find, however, that the ratio of FEV,,/
VC was significantly lower among heavy smokers (25 or more ciga-
rettes per day) than nonsmokers. This was found for all but the old-
est group of workers, but here the number of subjects was small.

Peters and Ferris (69) asked 133 Harvard College seniors to com-
plete a questionnaire on respiratory symptoms and to perform some
sample tests of pulmonary functions. Of these, 124 responded. When
classified by smoking history, the smokers were found to record more
frequent cough, phlegm production, breathlessness, and wheezing with
or apart from colds. There was no difference in vital capacity be-
tween smokers and nonsmokers. Although the forced expiratory vol-
ume in 1 second (FEV;,.) was less for heavy smokers than nonsmok-
ers, this was not significant by itself. As a ratio of vital capacity this
did show a significant decrease. The air flow rate using the Wright
peak-flow meter and other flow rates determined from tracings of the
Stead-Wells spirometer (FRis%, FRso%, FRes%, FR.%) did show
statistically significant reductions in heavy smokers as compared to
nonsmokers, These data show that relatively young cigarette smokers
have some impairments of ventilatory function, in turn suggesting
the possibility of a rather immediate effect of cigarette smoking on
respiratory symptoms and ventilatory function.

A series of experiments has been done by Krumholz and his asso-
ciates (49, 50, 61) to evaluate cardiopulmonary function in young
apparently healthy persons. The first experiment (49) involved 18
house staff physicians ranging in age from 24 to 37 years. Nine had
smoked at least one pack of cigarettes a day for the preceding 5 years
and nine had not smoked for at least the same time period. Extensive
pulmonary function studies were done at rest and after exercise. The
smokers were found to have a greater oxygen debt after exercise, de-
creased diffusing capacity at rest and with exercise, and decreased
total lung capacity and vital capacity.

In the second Krumholz experiment (50) 10 young staff physicians,
all of whom had smoked at least one pack a day for 5 years, were given
pulmonary function tests immediately after and again 3 weeks after
abstinence from smoking. Six physicians refrained from smoking for
6 weeks and were tested again. After 6 weeks of no smoking, expira-
tory peak flow and pulmonary diffusing capacity were significantly
increased. Heart rate and oxygen debt after exercise were decreased.
After 6 weeks functional residual capacity was decreased and inspira-
tory reserve volume and maximal voluntary ventilation were
increased.

100
The final study (67) again used 20 young medical persons divided
among 10 smokers and 10 nonsmokers. The mean pulmonary com-
pliance was significantly greater for the nonsmokers than for the
smokers.

Since cigarette smokers have a chronically elevated carboxy-
hemoglobin level, usually greater than 2 percent and occasionally
exceeding 10 percent, a study (79) was performed having nonsmokers
‘nhale enough carbon monoxide to raise their carboxyhemoglobin
levels to the range seen in a control group of cigarette smokers. This
maneuver caused the development, in the study group of nonsmokers,
of an increased oxygen debt with exercise and a reduced pulmonary
diffusing capacity at rest. These changes after carbon monoxide in-
halation were similar to those found without carbon monoxide in-
halation when comparing cigarette smokers to nonsmokers. (Further
data concerning smoking and carbon monoxide is presented and dis-
cussed in the chapter on cardiovascular diseases in this report.)

Résumé

Findings from various studies relating smoking to pulmonary func-
tion are less consistent for certain criteria of measurement than from
those relating smoking to respiratory symptoms. They are, however,
consistent in that they all report some form of diminished pulmonary
function among cigarette smokers, even when relatively young smokers
were studied. This is true of the studies outlined here as well as others
that have not been included (28, 40, 56, 58, 81). The usual measure-
ment found to be lower among smokers is the 1-second forced expira-
tory volume (FEV 10) either alone or as a ratio of the vital capacity
(FEV,,./VC). Vital capacity alone was generally not found to be
associated with smoking but diminished flow rates, such as FR:s, FR;
and the peak expiratory flow (PEF), were often observed. In these
studies, distinct quantitative relationships were not observed between
impairment of pulmonary function and the number of cigarettes
smoked daily.

RELATION OF SMOKING TO HEREDITY OR TO CON-
STITUTIONAL FACTORS

Although various surveys and studies consistently show an associa-
tion between smoking and respiratory symptoms and mortality from
respiratory disease, there have been objections to interpreting this
relation as causal. Arguments have been made that smokers and non-
smokers may differ in some respects, perhaps biological, that are
relevant to the occurrence of disease. Others have suggested that pre-

101
dispositions to smoking and respiratory disease may have a common
genetic basis,

One method of trying to estimate the importance of heredity and
constitutional factors is to study the effect of tobacco smoking among
pairs of twins, particularly identical (monozygotic) twins. If, when
one twin in each pair of monozygotic and dizygotic twins is a smoker
and the other is not, an excess morbidity does not appear among the
smoking twins, it would seem that the exposure to tobacco smoke was
insufficient to result in greater morbidity. Cederlof and his associates
(76, 17) in Sweden studied smoking in relation to morbidity from
various causes among 12,889 pairs of twins. Replies to a mailed ques-
tionnaire dealing with smoking habits and residential history were
received from 10,947 pairs (85 percent). Replies to a second question-
naire with medical questions were received from both members of
9,319 pairs—another response of about 85 percent.

A subject who answered “Yes” to the question, “Do you regularly
have a cough?” was regarded as having “cough.” If, when asked, “For
how many consecutive months a year do you have a cough?,” the
subject checked more than 3 months, he was regarded as having
“bronchitis.”

If the group comprising only one of each twin pair (the first twin
on the twin registry) is considered as a random population, the as-
sociation observed between smoking and respiratory symptoms is given
in table 11.

TaBLe 11.—Prevalence of ‘cough?’ and “bronchitis” among smokers and
nonsmokers by sex and age

 

 

 

Cough Bronchitis
Sex and birth year
Smoker Nonsmoker Smoker Nonamoker

Men:

1886-95... ie 17.7 17.8 7.4 5.5

1896-1905__--2.2 2-2 8. 15.5 6.6 6.7 2.5

1906-15_ 22-2 15.0 5.5 6.3 1.6

1916-25... 22 13.8 3.5 4.9 1.2
Women:

1886-95____.- ee 25.0 8.7 8.3 2.7

1896-1905___.__--________ 18.0 7.0 8.0 2.4

1906-15_-_-2-2 2 14.2 5.5 4.8 1.4

1916-25_____-___.__ 11 3.8 2.9 .6

 

 

 

 

 

Source: Cederlof, R., et al. (17).

These findings are similar to those previously reported for various
populations. These respiratory symptoms were then analyzed among
twin pairs with discordant smoking habits, that is, one twin of the

102
pair never smoked and the other either had smoked or still smoked at
the time of the survey. The findings are presented in table 12.

TaBLE 12.—Prevalence of “cough” and “bronchitis” among smokers and
nonsmokers in smoking-discordant twin pairs

 

. Cough . Bronchitis
Twins Number of
pairs

Smoker Nonsmoker Smoker Nonsmoker

 

 

Monozygotic:
Men..--------------- 14.6 7.7 6.6 11 274
Women-.------------- 13. 6 7.6 3.0 2.3 264

Dizygotic:

Men..--------------- 12.3 5.5 4.5 1.8 733
Women-------------- 14.5 5.7 5.5 1.8 653

 

 

 

 

 

 

Source: Cederlof, R., et al. (/7).

This table shows that the prevalence of respiratory symptoms was
much higher among the smokers in twin pairs than the nonsmokers.
The authors concluded that this hypermorbidity “speaks in favor of
a causal interpretation.”

Ina further analysis of the data from monozygotic twin pairs with
discordant smoking habits, Cederlof and his coworkers (15) divided
the series into a “low risk group” in which the nonsmoking twin
did not have “cough,” and a “high risk group” in which the non-
smoking twin had “cough.” The two groups of smoking co-twins
corresponding to the two nonsmoking risk groups had higher than ex-
pected prevalence rates. The observed value for smokers in the low
risk group, however, was only half that expected for nonsmokers in
the high risk group. This suggests that for some individuals the
genetic influence may be more important than smoking in the devel-
opment of cough. But, because any high risk group is only a small part
of the population, the total genetic effect will be much smaller than the
effect of tobacco.

Lundman (63) made a detailed study of twin pairs in Sweden. Of
247 twin pairs asked to participate, 196 pairs were examined (80
percent), of which 92 were monozygotic and 104 dizygotic. All par-
ticipants were interviewed and examined without knowledge of their
smoking habits. All twin pairs were concordant with respect to urban/
rural residence and discordant in smoking habits. After estimation
of lifetime exposure to smoking, 30 pairs were considered concordant,
thus limiting analysis to 77 monozygotic and 89 dizygotic pairs. The
smokers in both groups of twins had significantly higher frequencies
of some respiratory symptoms, such as persistent cough and morning
phlegm, but not of other symptoms such as dyspnea, “day cough”, and
“day phlegm”. Smokers also had “an increase in the unevenness of

271-394 O—67——8 103
ventilation measured by nitrogen washout, and an increase in airway
resistance as measured by dynamic spirometry.”

REsuME

Two recent studies (17, 53) of populations of identical and fraternal
twins show that for some individuals in the populations studied
a genetic element appears to be of some importance for the development
of cough. However, the effect of smoking was clearly shown to be
much more important for most of the individuals in the total popula-
tions studied. One study (53) also clearly showed that smoking twins
more often had reduced ventilatory function tests as compared to
their respective nonsmoking twins.

These data provide strong confirmatory evidence that cigarette
smoking can cause chronic bronchitis; however, no inferences with
respect to pulmonary emphysema can be based on these data. Studies
such as these, when specifically designed to provide additional in-
formation about pulmonary function, may be helpful in evaluating the
relationship between cigarette smoking and pulmonary emphysema.

PATHOLOGY STUDIES

Very few papers relating the gross and microscopic appearance of
the trachea, bronchi, and lung parenchyma to tobacco smoking have
appeared in the last 3 years. Auerbach and his coworkers have con-
tinued their analysis of bronchial tissues taken frdm 758 subjects (7)
and lung parenchymal tissue taken from 1,340 men (8). They pub-
lished a report (9) correlating findings in the bronchial tree with
findings in the lung parenchyma of 267 men who were included in
both previous studies. They reported a high correlation between
fibrosis in the lung parenchyma and different abnormalities of the
bronchial epithelium, such as hyperactive glands, increased number of
cell rows in the ciliated epithelium, and increased frequency of cells
with atypical nuclei. As reported previously by and summarized in the
Surgeon General’s 1964 Report, more frequent and more severe ab-
normalities were observed among cigarette smokers. Sections of the
bronchial tree among ex-smokers were more like those of nonsmokers
while fibrotic changes in the lung parenchyma were more like those
observed among smokers.

Changes in the bronchial tree similar to those described by Auer-
bach and his coworkers were reported in a series of 100 random adult
autopsies by Hernandez and Anderson and their associates (38). They
reported a higher frequency of abnormal epithelial hyperplasia, goblet
cell hyperplasia, round cell infiltration, congestion, and edema in

104
bronchi from smokers than nonsmokers. There was, however, no evi-
dence of more bronchial gland hyperplasia.

These same workers also studied macroscopic sections of single lungs
from 211 routine autopsies on adults (/, 2). Analysis was limited to
165 of these cases on whom smoking histories were obtained, usually
from relatives. Without knowing the identity of the subject or his
smoking history, each lung section was classified on a scale from 0 to 6
by severity of emphysematous changes. The type of emphysema was
also described as panlobular (changes throughout the secondary pul-
monary lobules), centrilobular (changes located around the centers
of the secondary lobules), or mixed. The severity of emphysematous
changes was about the same for men and women, but for each sex,
changes were more severe among smokers than nonsmokers, as seen
in table 13.

TaBLE 13.—Mean severity of emphysema classified by macrosections by

 

 

 

 

 

 

sex and smoking history
Mean de- Mean de-
Number] gree of em- Number] gree of em-
physema physema
Men: Women:
Smokers...----- 96 2.3 Smokers_------- 18 21
Nonsmokers- - - - 11 11 Nonsmokers- - -- 40 .8

 

 

 

Source: Anderson, A. E., Jr., et al. (#).

Perhaps more important was the observation that the type of pa-
thology seemed strongly related to smoking (2). Of 48 subjects whose
lung macrosections were classified as having mainly centrilobular
emphysema, 45 persons had been smokers. In contrast, the 62 subjects
judged to have panlobular emphysema were divided in the expected
proportions, 38 smokers and 24 nonsmokers.

Petty and his associates (61) also studied postmortem findings in
the lungs of a series of 253 men over age 40, unselected for smoking,
who died in two Denver hospitals during a 6-year period from 1959 to
1965. The presence and severity of emphysema was estimated and
graded in four categories, from 0 to 3+. During the last 3 years of
the study bronchi of 179 men were examined for mucous gland hyper-
plasia. Independent of the morphological studies, smoking histories
were obtained for each person, apparently by questioning relatives,
although this is not clearly stated. Men were grouped according to the
amount of cigarettes smoked during their lifetimes by calculating
pack-years of smoking. (One pack-year is the number of cigarettes
smoked if a person smoked one pack per day for a year. A pack-year
could also mean smoking two packs a day for 6 months, one-half pack
a day for 2 years, or any equivalent amount.)

105
Of the group of 179 individuals, 54 had mucous gland hyperplasia,
Of the 54 persons involved, 51 had smoked more than 20 pack-years,
and the remaining three were essentially nonsmokers. In contrast,
approximately one-third of the 125 men in whom mucous gland hyper-
plasia was not found were essentially nonsmokers. When the total
group of 253 men was studied for evidence of pulmonary emphysema,
114 were found to have moderate or severe pulmonary emphysema. Of
the 114, 98 had smoked more than 20 pack-years. The other six, who
essentially were nonsmokers, had either asthma, previous tuberculosis,
deep-seated lung infections or other demonstrable relationships with
previous pulmonary disease. In contrast, approximately one-third of
the remaining 1389 men, who had either very mild or no emphysema,
were essentially nonsmokers.

Only one study has been found in which the frequency of abnormal
bronchial epithelial cells in living persons is compared with smoking
history. Robbins (63) studied a group of 103 college students between
the ages of 17 and 24. Of the 45 who had never smoked, atypical
epithelial cells were found in six (18 percent). This compares to 26
(45 percent) of the 58 students who had been smoking 10 or more
cigarettes daily for 1 to 8 years. Cytological examination was done
without knowledge of whether the specimen came from a smoker or
nonsmoker.

ANIMAL EXPERIMENTS

Results of two experimental studies relating smoke inhalation to
lung parenchymal changes in dogs have been published in the last
3 years. Hernandez and his coworkers (39) used 23 healthy greyhounds
retired from racing. Eight served as controls and 15 were exposed to
high concentrations of cigarette smoke for 30-45 minutes twice daily
in wooden inhalation chambers. Seven animals were exposed for ap-
proximately 5 months and the remaining eight were sacrificed after
almost 15 months of smoke inhalation. Disruption of the lung paren-
chyma was assessed macroscopically by comparison with preselected
standards graded in severity from 0 to 3. Assessment was made without
knowledge of the source of the lung specimen. Lung damage among
dogs that were exposed longer showed significantly greater disruption
of the lung parenchyma.

Auerbach and his associates (5, 6) tracheostomized 10 adult beagles
and, in an attempt to approximate human smoking more closely,
exposed them to cigarette smoke through the tracheostomy tube.
Five dogs died during this experiment and the remaining five were
sacrificed after approximately 14 months of exposure. Other beagles

106
were kept as controls; two had tracheostomy openings. These control
dogs were sacrificed at the time the last five smoking dogs were sacri-
ficed. Lungs of the dogs exposed to cigarette smoke showed microscop-
‘cally the presence of dilated air spaces, especially beneath the pleural
surface. Here the alveolar septa showed a fibrous thickening of the
walls with areas of rupture and dilated air sacs. Padlike attachments
to alveolar septa were found. These zones of connective tissue sur-
rounding dilated air sacs were also visible macroscopically as white
areas on the lung surface. There was no thickening of the walls of
small arteries and arterioles within the lung. The lungs of the control
dogs were normal in appearance with none of these changes. These
abnormalities approximate but are not fully concordant with some
of the typical pathological findings in human emphysema. This ex-
periment does indicate that inhaled cigarette smoke apparently can
damage the pulmonary parenchyma of dogs. Other findings (6) as
yet unpublished, indicate that abnormalities of the bronchial epi-
thelium resulted that approximate many of the histopathologic find-
ings of human chronic bronchitis.

Rockey et al. (64) have noted that cigarette smoke produces bron-
chial and parenchymal changes in dogs that approximate some of the
histopathologic findings found in human smokers who have chronic
bronchitis and/or pulmonary emphysema. Mouzakis (57) has noted
similar changes in rabbits, and in dogs exposed to cigarette smoke
through tracheostomies.

Résumé

Researchers carrying out pathological studies have consistently re-
ported epithelial hyperplasia of the bronchial tree associated with
smoking. They have also reported that fibrosis and emphysematous
changes in the lung parenchyma, although observed among non-
smokers, occur much more frequently among men and women who have
histories of smoking. Changes in the lung parenchyma, approximating
some of the changes noted in human emphysema, have also been pro-
duced experimentally in dogs by exposure to cigarette smoke.

CILIATOXIC EFFECTS OF CIGARETTE SMOKE

The toxic effect of tobacco smoke on the ciliary defense mechanism
of the respiratory system has been confirmed by additional experi-
mental studies (9, 10, 13, 23, 24, 26, 27, 45, 47, 77, 78) which seek
to determine more exactly the mode of action of the ciliatoxic agents
contained in tobacco smoke. As yet, hydrogen cyanide and acrolein
appear to have the greatest ciliatoxic effects of the agents that have
been identified in the gaseous phase of tobacco smoke, although for-

107
maldehyde, crotonaldehyde, formic acid, acetic acid, proprionic acid,
and some phenols are also ciliatoxic (25, 46, 48, 73, 77, 79). Further
information may be obtained from a special symposium on ciliary
activity held in 1965 (48). A recent study (22) suggests that oxidative
enzymes such as adenosine triphosphatase, apparently important to
ciliary activity, may be adversely affected by cigarette smoke. Addi-
tional research is necessary before precise conclusions can be stated
concerning which, if any, of the identified ciliatoxic agents contained
in tobacco smoke are most damaging to the human respiratory system.

OTHER FACTORS ASSOCIATED WITH CHRONIC BRON-
CHITIS OR EMPHYSEMA OR BOTH

It is not the purpose of this report to discuss all the factors that
may play a role in the development of chronic bronchitis and em-
physema. It is important, however, to recognize that these condi-
tions do exist among people who do not smoke and that many smokers
apparently escape all signs of affliction. It is also important to recog-
nize that other factors have been associated with the development of
chronic respiratory disease, or chronic bronchitis and emphysema,
as we have defined chronic respiratory disease. We must be concerned
with the multiple etiology of biological processes. One factor already
cited is the role of hereditary or constitutional factors in the develop-
ment of respiratory symptoms, either operating alone or in conjunc-
tion with other factors such as smoking.

Aside from the personal pulmonary pollution inherent in smok-
ing, occupational exposures (a wider form of pollution) and exposure
to various pollutants in the atmosphere have both been shown to influ-
ence the prevalence of respiratory signs and symptoms. Studies made
in some specific industries—for example, pulp mill workers in New
England (32), coal miners in West Virginia (31), and gold miners
in South Africa (66, 67)—have shown an increased frequency of
respiratory symptoms or of diminished pulmonary function among
men exposed to certain dusts and fumes.

These studies indicate that cigarette smoking is generally more
important than the occupational exposures in producing respiratory
disease in the workers. These studies also suggest that cigarette smok-
ing may interact’ with some occupational exposures to produce even
greater deleterious effects. Cigarette smokers outnumber by far the
workers subjected to unusual environmental exposures. Also, there has
been a general improvement in many occupational environments, in the
continuing effort to remove or reduce the exposure to specific indus-
trial air pollutants.

108
Climatic and meteorologic variations involved with differences in
quantity and quality of specific air pollutants make investigations of
atmospheric pollution very complex. There have been many studies,
however, attempting to examine the association of air pollution with
chronic respiratory disease. Often comparisons of mortality and mor-
bidity are made between urban and rural areas, assuming a difference
in air pollution but not measuring it directly. Wicken (75) in his
retrospective study of mortality from chronic bronchitis in Northern
Ireland found higher mortality rates with greater degrees of urbaniza-
tion. Air pollution was suggested as a factor.

Holland and Reid (42) compared the prevalence of respiratory
symptoms, sputum production, and lung function in London and in
three county towns. The London men had more and severer symptoms,
produced more sputum and had poorer lung function test results.
Smoking habits were shown to be closely related to respiratory dis-
turbance but urban-rural differences in these habits could not explain
the greater frequency of respiratory symptoms in London.

A Canadian study reported by Bates et al. (11) indicates that among
four cities studied, the city with the lowest amount of industrial dust-
fall and sulfur dioxide levels had the study group with the lowest
prevalence of chronic bronchitis. Preliminary results also indicate
that this group had the lowest decline of pulmonary function. The
groups of males in each city were approximately concordant for
other factors, including the influence of cigarette smoking.

Ferris and associates (3, 4, 9%) studied air pollution and its effect
on respiratory symptoms and functions in two separate towns—Chilli-
wack, British Columbia, and Berlin, N.H. After standardizing the
data for age and cigarette smoking, they observed a correlation be-
tween symptoms of chronic bronchitis and the level of air pollution
as measured by the mean sulfation rate. They also found pulmonary
function tests to be better in Chilliwack when controlled for smoking
habits and age. This may be associated with the lower level of air pol-
lution in Chilliwack.

Studies of populations of twins are especially valuable in assessing
the influences of constitutional factors and environmental considera-
tions, such as cigarette smoking and air pollution. Cederlof (14), using
interview techniques on a large population of twins in Sweden, found
that compared with smoking, air pollution was of secondary im-
portance in causing respiratory symptoms indicative of chronic bron-
chitis and/or emphysema. In both the monozygotic and dizygotic
twins, again using the co-twin control method, individual variations
suggested that the propensity to develop cough from smoking also
may well be pertinent with regard to air pollution but that, when
considering the total population, individual variations appear to be
of minor influence (15).

109
Other studies (55, 76) have suggested a relation between air pollu-
tion and symptoms or mortality from chronic respiratory disease,
although they were not controlled for differences in cigarette smoking.

The contributions of air pollution, industrial pollution, and personal
pollution have been summarized recently by Higgins (40). He con-
cluded, as we must from the available evidence, that all “* * * three
types of pollution are associated with increased amounts of respiratory
disease and respiratory disability.” All the recent evidence, however,
does not alter the conclusion in the Surgeon General’s 1964 Report that
“the dominant association in the United States is between cigarette
smoking and chronic respiratory disease.”

ADDITIONAL CONSIDERATIONS REGARDIN: @ SMOKING AND EMPHYSEMA

This crucial question must be answered affirmatively before an infer-
ence can be made that smoking directly causes pulmonary emphysema:
Does inhaled tobacco smoke have a direct toxic effect on the alveolar
tissue in the lung parenchyma which is important in the pathogenesis
of pulmonary emphysema? At present, it cannot be answered.

If future evidence supports such a finding of a direct toxic effect,
we will have the missing link to the present chain of evidence showing
a strong association between cigarette smoking and many cases of
pulmonary emphysema and an inference of causation may validly be
made. The available evidence that follows has only indirect pertinence
to the question.

The experiments of the Auerbach, Hernandez, and Rockey groups
support the thesis that there is a direct toxic effect of cigarette smoke
on the pulmonary tissue. Possibly this direct toxic effect, if proven to
exist, contributes to the rupture and fibrosis of the alveolar tissue.
However, in these animal studies there were also some differences from
the typical anatomic findings of human pulmonary emphysema.

Surfactant, a fluid substance lining the alveolar cell walls, appar-
ently is important for maintaining tissue surface tension and thus the
spatial configuration of the alveolar walls (65). Zn vitro abnormalities
have been noted in surfactant as a result of cigarette smoke (21, 74).
Alveolar macrophages (specialized cells that incorporate and remove
foreign material from the affected lung area) are reportedly damaged
in vitro by cigarette smoke (35). Abnormalities of the alveolar macro-
phages and lipophages with inhalation of cigarette smoke are also
reported (64) in cytological studies of human bronchial washings,
apparently reflecting damage in vivo.

Studies (49, 50, 51,62) of the pulmonary function of relatively young
smokers and nonsmokers also indicate that abnormalities of pulmonary
diffusion noted in cigarette smokers, may, in part, be related to a
direct toxic effect of cigarette smoke. However, some of these abnormal-
ities are related to the unevenness of pulmonary ventilation associated

110
with airway abnormalities. Damage to the pulmonary arterial capil-
Jaries has frequently been noted on autopsy examination of smokers.
This damage may be a direct effect?of smoke inhalation and, function-
ally, may impair the vascular perfusion of the alveolar tissue, thus
jeading to further deficiencies in alveolar tissue function.

The possibility must also be considered that the accelerated in vitro
thrombus formation (discussed in the cardiovascular chapter of this
report), associated with cigarette smoking, may be the basis for mul-
tiple small thromboses in the pulmonary arterial capillaries.

‘Additional research is also needed to answer questions concerning
other factors that may account for the apparent increased suscepti-
bility of some individuals to cigarette smoke, such that they have a
marked excess mortality from this disease. Genetic and constitutional
factors may be important to some individuals’ development of pulmo-
nary emphysema, just as these factors appear to be important in the
development of cough in smokers, as reported by Cederlof and his
associates (14, 15, 16, 17). An increased susceptibility of some indi-
viduals to the emphysema associated with cigarette smoking has been
suggested, but not proved, by the occasional reports of “familial”
emphysema (41, 52).

Other probable causes of pulmonary emphysema, such as allergic or
infectious disease processes, also should be investigated for interactions
with and without smoking. Other apparent causes of pulmonary
emphysema, such as possibly atmospheric air pollution, may be inter-
acting with cigarette smoking to produce effects even more deleterious
to human health.

The observation that other probable causes of pulmonary emphy-
sema may exist should not detract from the strong relationship that
has been shown to exist between cigarette smoking and pulmonary
emphysema. Further investigations of the mechanisms of injury to the
cellular and subcellular structures of the lung tissue are recommended
(34). Also, clarification of diagnostic nomenclature and criteria would
be helpful, as indicated in the earlier discussion of definitions in this
chapter.

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CHAPTER 3

 

Smoking and Cancer

CONTENTS

Page

General Chemical and Experimental Data on Carcinogenesis
and Tobacco Smoke- ---------------------------------- 127
In Vitro Cellular Changes by Tobacco Smoke- ---------- 129
In Vivo Tumor Formation by Tobacco Smoke- -- - - ----- 129
Tumor-Promoting Agents in Tobacco Products---------- 130
Lung Cancer-------------------------------00000rr-00- 131
Mortality Data_-_-_---------------------------------- 131
Histopathology of Lung Tumors. --------------------- 140
Experimental Pulmonary Carcinogenesis---- ----------- 144

Additional Evidence Concerning Experimental Carcino-
genesis__._-----------------------------7-- 77777 144

Cancer of the Buccal Cavity and Pharynx (Lip, Mouth,
Throat)._.._.----------------------- 0-0 cert 145
Cancer of the Larynx------------------------------------ 148
Cancer of the Esophagus- - - ------------------------------ 149
Cancer of the Urinary Bladder---------------------------- 153
Cancer of the Stomach. -__.------------------------------- 157
Cancer of the Pancreas. _-_.__---------------------------- 158
Cited References____--.--------------------------------- 161
Supplemental References. -------------------------------- 167

125
GENERAL CHEMICAL AND EXPERIMENTAL DATA ON
CARCINOGENESIS AND TOBACCO SMOKE

Polynuclear Aromatic Hydrocarbons

Ascriteria for the presence of polynuclear aromatic hydrocarbons in
tobacco smoke, the list of J. W. Cook (20) has been widely accepted
by tobacco chemists.

The Surgeon General’s 1964 Report and Cook’s paper are in agree-
ment with respect to the presence of benzo(a)pyrene (3: 4-benzopy-
rene), dibenz(a,h)-anthracene (1,2: 5,6-dibenzanthracene),’ benzo(c)
phenanthrene (3: 4-benzophenanthrene), and dibenzo(a,i)pyrene
(3,4: 9,10-dibenzopyrene), all having carcinogenic activity.

Cook considers, furthermore, as identified : Benz(a) anthracene (1,2-
benzanthracene) marginal carcinogenic activity; chrysene, benzo(e)
pyrene (1,2-benzopyrene), questionable carcinogenic activity; benzo
(g,h,i)-perylene (1,12-benzoperylene) , benzo(b)fluoranthene (3,4-
benzofluoranthene) carcinogenic (59, 106), and benzo(j) fluoranthene
(10,11-benzofluoranthene) carcinogenic (106).

Indeno (1.2.3-cd) pyrene (2,3-phenylenepyrene) has since been iso-
lated from tobacco smoke (45). This polynuclear aromatic hydrocar-
bon was found to be carcinogenic (44, 59). The following carcinogens,
or questionable carcinogens, were isolated by Kiryu and Kuratsune
(55) in the smoke of cigarettes smoked by human volunteers: benz
(a)anthracene, chrysene, benzo(a)pyrene, benzo(e) pyrene, benzo(b)
fluoranthene and benzo(k)fluoranthene. The carcinogenic polynuclear
aromatic hydrocarbons are regarded as the major initiating car-
cinogens in tobacco smoke.

N-Heterocyclic Aromatic Hydrocarbons

The Surgeon General’s 1964 Report lists as carcinogenic compounds
three N-heterocyclics, dibenz(a,j) acridine, dibenz(a,h) acridine and 7
H-dibenzo-(c,g)carbazole. An independent investigation has con-
firmed the presence of the first named compound in cigarette smoke
(107).

N-Nitrosamines

_N-nitrosamines are among the most powerful known animal car-
cinogens. Since tobacco smoke contains secondary amines (57, 71)

*Dibenzo (a,h)anthracene in the Surgeon General's 1964 Report should be
replaced by dibenz(a,h) anthracene (24).

2 Benzo(g,h,i)perylene was not tested for carcinogenicity until 1966 and then
was found to be inactive (44).

127

 
and most tobaccos, certainly Burley and Maryland varieties, contain
nitrates (64), tobacco smoke can be considered as a potential environ-
ment for the formation of N-nitrosamines. The major nitrates in
tobacco are alkaline nitrates.

Neurath, et al., isolated three aliphatic N-nitrosamines from the
smoke of a cigarette rich in volatile basic components and high in
nitrate content. One of them tentatively has been identified as methy-
n-butyl-nitrosamine (72).

When the particulate matter, “tar,” was collected from cigarettes
not enriched with basic components or when the smoke particulate
matter was collected without aging and not in cold traps, N-nitros-
amines could not be isolated from cigarette smoke (72). Since the
only other publication concerned with the isolation of nitrosamines
in cigarette smoke was based on cold trap collection of “tar,” the
positive finding of three N-nitrosamines appears questionable (86).

In summary, tobacco smoke can be regarded as a potential environ-
ment for the formation of N-nitrosamines. However, additional infor-
mation is needed to substantiate their presence in tobacco smoke.

Polonium 210

_ Several investigators (33, 35, 50, 76, 92, 93, 112) have found trace
amounts of Po”! in tobacco leaf and cigarette smoke. The concentra-
tion of Po*** in lung tissue is relatively high (33, 67) as compared to
other body tissues and is higher in smokers than in nonsmokers (33,
43,65, 66). ;

Lung tumors have been induced experimentally by intratracheal
implantation of various radioactive substances. These radioactive sub-
stances must, however, be present in the respiratory environment above
a certain threshold level and must be in contact with the target organ
long enough to be effective (68, 77, 88, 107). Because Po?” emits alpha
particles, it has been implicated as a lung cancer initiator (48, 68, 76,
77). More research is needed before definitive conclusions can be made.
Until such time, however, Po?!° should be considered as a potential
tumor initiator in tobacco smoke.

Selenium

Selenium has been mentioned as possibly being important in the
pathogenesis of human lung cancer (100). Preliminary reports suggest
that selenium may be present in some cigarette papers. Because earlier
reports (17, 34, 97) indicated the ingestion of selenium caused cancer
of the liver in mice, a recent investigation (101) by the National Can-
cer Institute was conducted, with negative results. So far the earlier
reports of the carcinogenicity of selenium have not been substantiated.
Additional information is needed on the possible carcinogenicity of
selenium and its presence in cigarette smoke before selenium can be
indicted as an agent in human cancer.

128
Phenols

Tobacco smoke contains a large number of phenols (107). Several
of them are known to be tumor promoting agents when applied in
high concentrations to mouse skin previously treated with a tumor
initiator (24).

In Vrrro CeLtuLar CHances By Topacco SMOKE

Lasnitzki (60) extended her studies with tobacco smoke condensate
on cultured human fetal lung tissue to include a “highly purified
fraction of hydrocarbons” isolated from cigarette smoke condensate.
In 33 out of 50 treated lung tissue explants, the epithelium of the
bronchi was hyperplastic and sometimes showed squamous changes.
These changes were not observed with the untreated controls.
Although a hydrocarbon-free fraction was weakly active by producing
some squamous metaplasia in these explants, these tissue culture tests
point strongly to carcinogenic hydrocarbons as the active group in
the smoke. The findings with purified carcinogenic hydrocarbons in
organ culture (22) support the finding that polynuclear aromatic
hydrocarbons are one group of active smoke constituents. Carcinogenic
hydrocarbons are also the only group of chemical components that
have been demonstrated in vitro to induce malignant conversion of
single cells (7, 13).

In summary, tobacco smoke has been demonstrated in vitro to induce
pathological changes in tissue explants. Although such changes may
be induced by different smoke constituents, as yet the carcinogenic
hydrocarbons are the only agents identified in tobacco smoke which
have been shown to induce malignant changes in’ tissue cultures.

In Vivo Tumor Formation sy Topacco SMOKE

Passive inhalation experiments with tobacco smoke have not yet
led to fully established squamous carcinoma in mice (109). This
method of application has resulted only in papillomatous growth in
the tracheobronchial mucosa of a few hamsters. None of the tumors,
however, was found to be invasive (30, 111). It appears that passive
inhalation may not lead to the induction of squamous cell bronchogenic
cancer in experimental animals. This conclusion can also be applied
to passive inhalation studies in which the animals are infected by a
virus before long-term smoke exposure (62, 210). The pathological
changes seen in the mice were reversible whether or not the animals
were previously infected with a virus. The hyperplasia and metaplasia
seen in mice and rats after passive inhalation appears, at least in part,
to be secondary to viral or bacterial infection that is enhanced by
exposure to tobacco smoke. The relatively negative findings with pas-

129
sive inhalation experiments probably relate to the relatively smal]
amounts of smoke aerosols that bypass the nasal passages. The defen-
sive nature of the upper respiratory tract against airborne irritants
has to be fully appreciated in the evaluation of any passive inhalation
study.

Active inhalation studies with tracheostomized dogs, as carried out
by Rockey, (79, 80) and Auerbach (2), suggest that this approach
may lead to the induction of bronchogenic carcinoma. The change in
the bronchial epithelium after 1 year of active smoking indicates
early pathological changes that may, upon continued smoke exposure
lead to tumors in the bronchi.

So far, neither passive nor active inhalation studies have contributed
to our knowledge about the nature of the tobacco smoke carcinogens.
Studies with the particulate matter, tar, of cigarette, pipe, and cigar
_ smoke, however, have clearly demonstrated that at the site of applica-
tion tumors can be induced. Tumors have been induced on the skin
of mice and rabbits, the ears of rabbits, the subcutaneous tissue and
hilum of rats and the cervices of mice (9, 11, 22, 31, 32, 46, 48, 61, 74,
82, 83, 8h 107, 108).

Only relatively few investigators have been concerned with the
nature of chemical carcinogens in tobacco smoke (47, 84, 107). Al-
though the acidic and nicotine-free basic portions of tobacco tar had
been found to have weak tumorigenic activity, the only fraction shown
to have induced significant numbers of tumors is fraction B of the
neutral portion (2 percent of the whole condensate) (107). This B
fraction was further fractionated into three subfractions from which
only B, was shown to have tumorigenic activity (47). The B, frac-
tion equals 0.6 percent of the tar and combines all aromatic hydro-
carbons with three to seven rings including the carcinogenic ones.
This can be considered as evidence that in in vivo studies, the poly-
nuclear aromatic hydrocarbons are the major carcinogens in tobacco
smoke. Although these compounds alone can account for only a small
portion of the tumorigenic activity of tobacco tar, they are, neverthe-
less, the only identified carcinogens and tumor initiators in tobacco
smoke shown by experimentation to be biologically active. Their
tumorigenic effect is enhanced by the presence of tumor-promoting
agents in the smoke.

Tumor -Promoting AcENTs In Tospacco Propucts

In the experimental setting, the tumorigenicity of tobacco smoke
condensate cannot be solely explained by the presence of known car-
cinogens. In assays on mouse skin and rat subcutaneous tissue, the
known carcinogens must be enhanced by other components such as
tumor-promoting agents. In fact, it has been demonstrated that to-

130
bacco extract and tobacco smoke condensate can act as promoters to
mouse skin previously treated with tumor-initiating carcinogenic
polycyclic aromatic hydrocarbons (10, 12, 96, 107). Although some
tumor-promoting activity of tobacco “tar” can be explained by some
phenols and carboxylic acids, additional tumor promoters in tobacco
products remain to be isolated and identified.

It is important, however, that a significant decrease of the poly-
nuclear aromatic hydrocarbons in tobacco “tar” leads to a significant
decrease of the overall activity of the “tar” on mouse skin (9, 46, 108,
109).

m summary, experimental studies have demonstrated that the par-
ticulate matter of tobacco smoke, “tar,” is tumorigenic. Some poly-
nuclear aromatic hydrocarbon-carcinogens have been identified as con-
tributing significantly to the overall tumorigenic activity of tobacco

smoke condensates in the experimental setting.

LUNG CANCER
Morrauiry Data*

The annual number of deaths in the United States from cancer of
the lung (International Classification of Diseases, Codes 162, 163) rose
from 18,313 deaths in 1950 to 45,838 in 1964 (94). In this 15-year
period, deaths from lung cancer totaled 467,442. During this same time
period the death rate for cancer of the lung almost doubled, a rise
from 12.2 deaths per 100,000 population in 1950 to 24 deaths per
100,000 population in 1964. (The corresponding age-adjusted rate has
also nearly doubled, therefore the increase in the death rate cannot be
attributed to the changing age composition of the population.) The
lung cancer mortality in the male population increased from 19.9
deaths per 100,000 population in 1950 to 41.4 in 1964, while in the
female population the deaths increased from 4.5 to 7.1 per 100,000
population over the same time period.

The mortality experience of the individual male cohorts during
1949-64 (fig. 1) shows that at any given age the risk of dying from
lung cancer was almost always higher for the more recently born
cohort. Within each cohort, the death rate for lung cancer increased
steadily to the end of the life span.

Figure 2 shows the death rate for women by cohort groups and age
at death. One can see the increasing death rate slope for each more
recently-born cohort, starting with cohort F—those women who were
26-30 years old in 1930. This corresponds to the time when smoking
became increasingly popular among women.

1 AN death rates throughout this chapter are per 100,000 population unless
otherwise indicated.

131
SST

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4000

2000 >—

 

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I

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a
o

NUMBER OF DEATHS PER 100,000 POPULATION
»
a

 

    

AOS -1079
-Betore 1875

   

 

 

 

I | J | ! I ! I I |

 

 

  

40 “4 so 58 60 8 To ws 80 aSene
AGE IN YEARS

4000

60.0

200

109
eo

60

40

20

oe
oe

oe
Os

 

Fieurg 1.—Cancer of the lung among men, by birth cohort and age at death;
1949, 1954, 1959, and 1964.

 
eT

aainog

.

(76) BIASHBIP DBI JOJ J9}UVH [BUONEN

 

 

NUMBER OF DEATHS PER 100,000 POPULATION

 

 

 

    

 

  
 
 
  
  
 
 
 

 

 

   

  

 

 

1000 1000
800 }— 800
600 600
409 400
200 —200
100 109
sok COWORT OF PERIOD OF leo
FEMALES BIRTH
of |
6 oI 925=182B 60
1920-1924
4or- 1915-1919 —40
1910-1914
1908-1909
20 .. 1900-1904 20
1895-1899
onuenee es 1BBO= 1894
10 1885-1889 10
oe fh a rn 1aao- 1884 oa
ost . 1875-1879 tos
De ceeceesenecs reteset - Before 1075
on os
az oz
ou l 1 | | l l ! | | Ol
20 45 30 38 60 6s 70 75 80

 

AGE IN YEARS

@5 ond
over

 

Fucure 2.—Cancer of the lung among women, by birth cohort and age at death:

1949, 1954, 1959, and 1964.

 
In the female population the greatest percentage increase (116 per-
cent) over the 15-year period, 1949-64, occurred in the 35-44 year age
group. The next highest percentage increase was noted in the age
group 45-54 years. The death rate from lung cancer among women,
25 years and over, rose steadily with advance in age for each year
during 1950-64, and the cohort experience shows that these death rates
continued to increase for each cohort to the end of the life span.

Hammond’s (40) prospective study provides extensive information
about the lung cancer mortality experience of both men and women in
relation to cigarette-smoking history as presented by mortality ratio?
and by death rates per 100,000 person-years. (Table 1).

TasLe 1.—Lung cancer mortality ratios and death rates * of smokers by
sex and specific age groups

 

 

 

45-64 years 65-79 years
Females Males Females Males
Mortality ratios____........__- 2.17 7. 84 11. 76 11. 59
Death rates_.._.-..---- 22-2 e 2(7)15 | 2 (11)87 | 2(17)30] 2 (23)262

 

 

 

 

 

1 Computed from app. table 19.
2 Numbers in parentheses indicate death rate for nonsmokers.

Sourcr: Hammond, E. C. (tables 24 and 26, app. table 19 (40).

Tables 2 and 3 below show the relationships of number of cigarettes
smoked per day, degree of inhalation, and age smoking began, to
lung cancer mortality ratios and death rates for males and females,
respectively. Generally, mortality ratios and death rates increase with
increasing amount of cigarettes smoked and degree of inhalation, and
with a longer lifetime history of smoking. Table 3 shows the relatively
lower lung cancer mortality among women as contrasted to men, but
reveals, for the most part, the same relationship to amount smoked,
degree of inhalation, and age when smoking began.

Table 4 illustrates the fact that cessation of cigarette smoking is
associated with a decline in lung cancer death rates.

* The mortality ratio is the ratio of the death rate of smokers to that of non-
smokers—the mortality ratio of nonsmokers always being one, by definition.

134
TABLE 2.

—Lung cancer (men). Number of deaths, and age-standardized

death rates and mortality ratios, by current number of cigarettes

smoked per day, degree of inhalation, and age began smoking, by
age at start of study *

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Age 35-54 Age 55-60 Age 70-84 All ages, 35-84
Number of cigarettes a day, degree
of inhalation, and age began
smoking Num- | Death | Num- | Death | Num- | Death | Num- Death
ber of | rate | berof| rate | berof] rate { ber of | rate
deaths deaths deaths deaths
Current number of cigarettes a day:
9 38 12 ci] 5 134 26 56
15 4 &7 168 10 23 82 90
138 88 216 204 27 446 381 159
26 47 50 334 6 754 82 201
Degree of jnhalation:
None or slight... -----.----------- 19 2 87 203 4 193 120 102
114 52 17 224 20 401 311 138
Deop-..------------0-------2---- 55 55 3 206 13 63s wi 178
Age began cigarette smoking:
25 or older. 5 7 12 65 3 85 20 30
20 to 24... 31 36 72 212 7 306 110 118
15 to 19.-.- 112 4 176 250 2 490 318 155
Less than 15. 35 n 87 302 9 424 101 183
Never smoked regularly. i 6 a 10 u 25 49 12
Lung cancer mortality ratios (men)
Current number of cigarettes a day:
1 tO 9.-- 2 nnn n ee een ne nen nne en nee eee 6.17 |.....--- 3. 53 5.32 4.60
10 to 19. - -- 3.90 -| 8.77 9. 62 7.48
20 to 30._...---.-------- +--+ --- | ---- => 9.37 -| 13.82 -| 17.62 13.14
40 plus ....---.------------------]----2 2° 7.67 |_.---.-- 17.47 }..------ 20.84 |..----.. 16. 61
Degree of inhalation:
None or slight. 4.75 |.------- 10, 60 }..------ 7.65 |-------- 8,42
Moderate_....--- 8.48 -| 11.72 15.88 11.45
Deep.....----------------------- 9.00 13.93 25.26 j_.----- 14.31
Age began cigarette smoking:
25 or older. 2.77 3.39 j-.------ 3.38 |-------- 3.21
20 to 4... 11.11 ~} 12,11 J-_.----- 9.72
15 to 19._--..--..------ 13. 06 19.37 -| 12.81
Less than 15...---.------------ 15.81 {--..---- 16.76 |..-.-.-- 15.10
1 Mortality ratios are based on death rates carried out to 1 more significant figure than shown.
Source: Hammond, E. C. {table 20 (40)].
271-394 O—67——10 185
TABLE 3.—Lung cancer (women). Number of deaths, age-standardized
death rates, and mortality ratios, by type of smoking (lifetime history),
current number of cigarettes smoked per day, degree of inhalation, and
age began smoking, by age at start of study }

 

 

 

 

 

Age 40-54 Age 55-74 All ages, 40-74
Type of smoking (lifetime history)
Number | Death | Number| Death | Number/ Death
of rate of rate ot rate
deaths deaths deaths
25 4 77 12 102 7
48 u 3 23 81 16
Current regular cigarette smoking

15 8 5 7 20 8

2B 7 2 50 50 35

16 13 9 18 2 13

7 i 18 48 45 2

7 6 16 21 23 2

35 14 i 43 46 7

 

 

Lung cancer mortality ratios (women)

 

 

 

 

 

Never smoked regularly... 1.00 |-......... 1.00 [.......--. 1.00
History of cigarette smokin: 2.82 jee. 1.08 [.......... 2.20
Current regular cigarette smoking
2.08 [-....----. 0.62 |.---...... 1.06
4.43 |. 2222. 4.91 |..-..-.-.. 4%
3.33 1.12 178
2.90 4.04 3.70
1.55 1% 1.70
3.78 3.60 3.65

   

 

 

 

 

 

 

 

1 Mortality ratios are based on death rates carried out to 1 more significant figure than shown.
Source: Hammond, E. C. [table 23 (40)].

186
TABLE 4.

tality ratios for ex-cig
only, by former numb
last cigarette smoking. Death
a history of cigarette smoking only. Men

are shown for comparison. Men aged 50-69.

—Lwung cancer (men). Age-standardized death rates and mor-
arette smokers with a history of cigarette smoking
er of cigarettes smoked per day, and years since
rates for current cigarette smokers with
who never smoked regularly

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Smoked 1-19 cigarettes aday | Smoked 20+ cigarettesaday Mortality ratio,
cigarette smokers (years
eee last cigarette smoking)
Number | Number| Death | Number | Number Death | 1-19 2+
of men | ofdeaths} rate | of men | of deaths rate
7468 3 108 2, 244 3 487 |_.--.---|--------
1,844 5 cc") 5, 435 33 190 |......--|--------
1,770 1 15 5, 803 22 108 |__..-.--|--------
4,209 1 6 8, 142 5 16 j.---.---|--------
Total ex-smokers. -..-- 8, 569 10 30 21, 624 8 119 12.0 7.9
Current cigarette smokers...) 22, 808 80 97 56, 886 351 205 6.5 13.7
Never smoked regularly--..- 55, 728 32 15 55, 728 32 15 }..------|--------
1 Computed from source.

Source: Hammond, E. C. [table 21 (40).

The Dorn study (49) of U.S. veterans provides additional informa-
tion on the relationship of dosage to mortality ratios and death rates
for males who smoked cigarettes only (table 5).

TABLE 5.—Lung cancer mortality ratios and death rates for U.S. veterans
by age, type, and amount of smoking

 

 

 

 

 
 

 

 

 

 

Number of cigarettes/day
0 19 10-20 21-39 40+-
pr'| mri |pR| MR |DR| MR |DR/} MR | DR; MR
Current cigarette smokers
only:
Age 45 to $4_....---..----|------|--------|---2--| eee eee 24 52 72 |._.-----
Age 55 to @4.___....-----. 10 1.00 70 7.00} 123 | 12.30! 206) 20.501 338 33.80
Age 65 to 74.._.--...----- 30 1.00} 135 4,50 | 265 8.83] 432 | 14.40] 696 23.20
Age 75 plus. 1.00 |-...--
Total. ---....-----.---- 1.00 j.--.-. 5.49 9.91 17,41 23.93
Ex-cigarette smokers only...-|.-----|--------]------ 95 248 9.33 |_..... 8. 24

 

 

 

 

 

 

 

 

 

 

 

 

1 DR, Death rate; MR, Mortality ratio.
Source: U.S. veterans study [app. table A (49)].

187
The mortality ratios of the Dorn (49) study can be compared with
those of the Canadian veterans study, in table 6:

TaBLe 6.—Lung cancer mortality ratios for Canadian veterans by age,
type, and amount of smoking

 

 

 

 

 

Number of cigarettes/day
0 | 1-9 10-20 214
Current cigarette smokers only:
Age 30 to 49... 22-2 1. 00 2. 47 4.15 4. 08
Age 50 to 69__._--_----- ee 1. 00 10. 71 26. 92 26. 83
Age 70 plus____-_.__---...----.-_- 100] 12.15 9. 43 24, 53
Total__..---2 ee 1 00 10. 00 16. 41 17. 31
Ex-cigarette smokers only total_.____.__- 6. 06

 

 

Source: Canadian Pensioners study [(8), Table 8.1 and 8.2].

From the data shown in table 2 mortality ratios of 17.47 and 29.84
may be noted for smokers of 40+ cigarettes per day, age 55-69 and
70-84, respectively. The Dorn (49) study (see table 5) similarly shows
mortality ratios of 33.80 and 23.20 for smokers of 40+ cigarettes per
day, age 55-64 and 65-74, respectively. The Canadian study (see table
6) shows mortality ratios of 26.83 and 24.53 for smokers 50-69 and 70
years of age and older respectively who smoked over 20 cigarettes per
day. There is rather close agreement among the three large prospec-
tive studies for the general range of mortality ratios observed in heavy
smokers. From the data supplied by the Doll and Hill survey of
British physicians (28, 29) a mortality ratio of 31.86 can be calcu-
lated for all smokers of more than 25 cigarettes per day, as com-
pared to a mortality ratio of approximately 8, for smokers of 1-14
cigarettes per day (see table 8).

There is relatively little risk of lung cancer associated with pipe or
cigar smoking, probably because smoke from these sources is rarely
inhaled. “Mixed smokers,” i.e., smokers of cigarettes, pipes, and/or
cigars, have less risk than do smokers of cigarettes only, also suggest-
ing that they may smoke fewer cigarettes or inhale less tobacco smoke
than do smokers of cigarettes only (see tables 7 and 8).

138
TABLE 7.—Lung cancer mortality ratios by type and amount smoked

 

 

 

Current smokers of cigarettes only
pipe andjor Exemokers of
Allamounts 1-9 10-20 21-39 40+ nipe and{o ¥
per day
12. 14 5, 49 9. 91 17, 41 23, 93 1 67 5. 00

 

 

 

 

 

 

 

Source: U.S. veterans study (app. table A (49)].

TABLE 8.—Lung cancer death rates by type of smoker and amount smoked

 

 

 

Cigarette smokers
An —| Given up | Mima | Pipe or
Nonsmokers | SMoKets |, mounts| 1-14 | 15-24 | 25+ | smoking
per day :
7 71 120 57 129 223 24 52 43

 

 

 

 

 

 

 

 

 

Source: Study of British physicians [tables 23 and 24 (28)).

Taste 9.—Lung cancer death rates for ex-smokers of cigarettes by

 

 

 

length of time stopped smoking
Continuing Ex-amokers
cigarette Nonsmokers
smokers
Less than 5 years 5-9 years 10-19 years 20-+- years
128 67 49 18 19 7

 

 

 

 

 

 

SouRcE: Study of British Physicians {table 25 (28)}.

The preceding studies show appreciably lower mortality ratios and
death rates from lung cancer with the cessation of cigarette smoking
(see tables 4, 5, 6, 7, 8, 9). This lower risk is evident irrespective of the
quantity of cigarettes formerly smoked.

The Doll and Hill study (28) of British physicians is of particular
interest in respect to ex-smokers. Over the 10-year period of the study
(1951-61) 29 percent of the smokers of cigarettes only, had signifi-
cantly decreased (one-half pack cigarettes or more) their smoking (in-
cluding those who stopped) and 5 percent had switched to pipes
and/or cigars.

While the overall lung cancer mortality of men over age 25 in
England and Wales had increased 22 percent over this 10-year period,
that for the physician group decreased 7 percent. Since the total
physician group is involved in these figures, we can compare this
population group to the entire population of England and Wales
where there was no general decrease in amount of smoking. This can
be thought of as a controlled cessation experiment and the beneficial

139
effects of stopping or decreasing the amount of smoking become quite
evident.

Wicken (102), in a retrospective study of lung cancer mortality in
Northern Ireland during the period 1960-62, reported the following
results (Table 10) : .

TaBLE 10.—Lung cancer mortality ratios and death rates, by sex, age 36
and over, by type and amount of smoking, Northern Ireland, 1960-62

 

 

 

Cigarette smokers
Non- amount per day Cigarettes | Pipe and
smokers and pipe | cigar only
and cigar
1-10 11-22 | 238+
Male:
Mortality ratios_.______ 1,00 | 483 | 9.33 | 21.2 5, 22 2.27
Death rates_._._.__.___ 18 87; 168) 383 94 41
Female:
Mortality ratios. _._____ 1.00 | 2.27) 6 72) 19.0 ].-_-.._}L
Death rates..___-_______ 11 25 74 | 210 |... ote

 

 

 

 

 

 

SouxcE: Wicken, A. J. ((108), Table 17).

Wicken also analyzed the proportion of lung cancer deaths which
would have occurred if the lung cancer mortality rates of the least
susceptible groups had been applied to the whole population of North-
ern Ireland, and found that. males would have had only 18 percent of
the lung cancer mortality if none smoked and that if they lived in
truly rural areas they would have only 10 percent of the mortality.
Thus, the difference—8 percent—may be attributable to the urban or
suburban residence factor, possibly air pollution. If no females
smoked, they would have had only 65 percent of the total female lung
cancer mortality, and 53 percent if they lived in truly rural areas.
Thus, for females, the difference of 12 percentage points might be
attributed to the urban environment. The magnitude of these differ-
ences depends on the prevalence of lung cancer in the various sub-
groups of the particular population studied.

Hisroparuoiocy or Lune Tumors

Classification of lung cancer by histologic type was discussed in the
Surgeon General’s 1964 Report with the conclusion that the squamous,
undifferentiated, and oat-cell carcinomas were far more frequently
found in smokers than in nonsmokers, while adenocarcinoma was rela-
tively more frequent in nonsmokers, especially women. Changes in the
bronchial mucosa resulting from the inhalation of cigarette smoke in-
cluded loss of cilia, basal cell hyperplasia, and the appearance of
atypical cells with irregular hyperchromatic nuclei. These changes, it
was concluded, were related to the premalignant process of the de-

140
velopment of invasive carcinoma. Auerbach (6) has more recently
reported on a study of the pathology of the tracheobronchial trees of
339 men who died from causes other than lung cancer and of 63 men
who died from lung cancer. Up to 55 cross-sections of the tracheo-
bronchial tissue were studied in each case. The 389 non-lung cancer
cases included 65 men who had never smoked cigarettes and 274 men
who had smoked in various amount. Figure 3 shows that only 1.38
percent of the slides from those who never smoked regularly have
60 percent or more atypical cells, whereas 76 percent of the slides of
those smoking more than two packs a day had 60 percent or more
atypical cells. (See figs. 3 and 4).

 

PERCENT OF SLIDES WITH LESIONS
SHOWING 60% OR MORE ATYPICAL CELLS

92.1

 

 

 

 

 

 

 

 

76.8
34.9
3.4 4.7
3 cCm71 1
Never Smoked  <I/2Pock (/2-1Pock !-2 Packs 2+ Packs Luag
Regularty A Day A Doy A Doy A Dey Cancer

 

 

 

Ficure 3.—Percent of slides with lesions showing 60 percent or more atypical
celis

Source: Auerbach, O., et al. [Table 1(5), updated 1967]

Auerbach (4) has also studied the bronchopulmonary autopsy ma-
terial from 255 men and three women who died of lung carcinoma of
varying histological types, ranging in the spectrum of the WHO
classification (103) from the highly differentiated to the undiffer-
entiated squamous cell carcinoma, with others being oat cell, polygonal
cell, acinar, and adenocarcinoma. A search for double primaries was
made, and by using strict criteria, multiple primary invasive carci-
noma was found in 3.5 percent of the autopsies studied. When less

141
 

PERCENT OF SLIDES WITH
CARCINOMA-IN-S/ITU

 

 

 

 

{5.0
1.4
4.3
0.8
0.0 nian __
Never Smoked <I/2 Pack (/2-1Pack I-2Pocks 2+ Packs Lung
Requlerly A Day A Day A Day A ODay Cancer

 

 

 

Fieure 4.—Percent of slides with carcinoma in situ.
Source: Auerbach, O., et al. [Table 2(5), updated 1967].

strict criteria were used, but very doubtful cases excluded, up to 12.5
percent double primaries were found. This study suggests that multi-
ple primary bronchial carcinomas in the same patient may be more
frequent than previously suspected. Further studies are necessary in
this area, since therapeutic implications are also involved.

The differentiation of tumor types as related to smoking habits in
various groups with clinically diagnosed lung cancer has again been
investigated in several recent studies, In one study (19), of 417 cases
of histologically proven lung cancer, 87 percent were smokers. Among
the squamous cell cancer cases 89 percent were smokers; among the
undifferentiated cell cancer cases 90 percent were smokers, and among
those with adenocarcinomas, 60 percent were smokers. A study (99)
dealing specifically with alveolar cell cancer of the lung reports that
91 percent of the 180 males in whom this tumor type was diagnosed
were smokers and, similarly, that 65 percent of the 85 females with
this type tumor were smokers. Another study (704) was made of lung
cancer cases in nonsmokers, defined as persons smoking not more than
one cigarette a day for 10 years. This study group included eight males
and 26 females. Of this group, only four patients had epidermoid
carcinoma (two males and two females), Both males had a history of
occupational exposure to respiratory irritants. Of the two women,
one had an unusual history of carcinoma, including multiple basal cell
skin cancers and in sifu carcinoma of the cervix.

A study (1) was made of 666 histologically proven cases of lung
cancer. A smoking history was recorded on 442 of the men in this

142
series. The chart below takes into account smoking histories as re-
lated to three histologic groups: undifferentiated, squamous, and
adenocarcinoma, (see table 11).

TABLE 11.—Distribution of lung cancer deaths by cellular type and

 

 

type of smoking
Cellular type Nonsmoker | Pipe smoker Cigarette
smoker
Undifferentiated _.---.------------------- 4 14 124
Squamous-------------------------0--27> 6 24 211
Adenocarcinoma. ..---------------------- 2 1 56

 

 

 

 

source: Ashley, D. J. B., et al. [(/) Table 4.]

Insufficient information is provided in this study to specify in detail
the past smoking histories, but the data suggest that cigarette smoking
may be related to adenocarcinoma in some instances. .

The preceding studies indicate that squamous, undifferentiated, and
oat-cell carcinoma rarely occur in nonsmokers. However, it appears
that cigarette smoking may also be associated with alveolar cell car-
cinoma and glandular carcinoma of the bronchi. This relationship has
been previously suspected. In fact as early as 1950 Wynder and Gra-
ham (105) demonstrated this relationship. This was also shown in the
study by Haenszel (39). Greater standardization and precision of diag-
noses are needed to establish how few cases of undifferentiated or squa-
mous carcinoma occur in nonsmokers who have been established to have
never smoked appreciable amounts during their lifetimes. If 100 per-
cent accurate smoking histories were obtainable on every case of lung
cancer, it is suspected that very few cases of undifferentiated or squa-
mous cancer would be found in persons who had never smoked.

A report (98) on lung cancer in uranium miners noted a frequency
of lung cancer, occurring almost entirely in the cigarette-smoking
miners, greater than the frequency to be expected in a similar sized
cigarette-smoking nonuranium mining population. A recent report
(85) on bronchogenic carcinoma in asbestos workers also noted an in-
creased frequency of lung cancer, occurring entirely in the cigarette
smoking asbestos workers. This frequency was greater than the fre-
quency to be expected for a similar population of cigarette smokers
who were not asbestos workers. These reports suggest that cigarette
smoking may interact with certain other environmental exposures to
increase the frequency of lung cancer occurrence still further.

Analysis of occupation and other environmental exposures must be
performed simultaneously to detect which interactions with smoking
seem to be especially dangerous.

148
EXPERIMENTAL PutmMonary CARCINOGENESIS

Experimental attempts to produce lung cancer involve the admin-
istration of tobacco smoke condensates and of carcinogens known to be
present in tobacco smoke, either in vitro to preparations of cells or
im vivo in experimental animals. Difficulties are encountered with the
viability of tissue cultures and experimental animals when subjected
to these various substances. Studies of human tissue from lung cancer
patients indicate that abnormalities of the tracheobronchial mucosa,
such as loss of cilia, basal cell hyperplasia, squamous metaplasia, and
cellular atypism are important in the pathogenesis of human lung
cancer caused by smoking. These changes have been experimentally
produced in dogs exposed to cigarette smoke through a tracheostomy
(2, 79, 80). A large number of dogs is now being studied to determine if
lung cancer can be experimentally produced by this technique; if the
dogs continue to smoke for a longer time, malignant changes may ap-
pear subsequent to the already noted premalignant changes. The squa-
mous metaplasia involved in the premalignant changes may explain
why cigarette smoke condensate most readily produces cancer in the
squamous epithelium of the skin of laboratory animals.

AppitionaL Evipence ConcerNING EXPERIMENTAL CARCINOGENESIS

The inhalation of tobacco smoke by mice was reported to increase
the frequency of glandular tumors (37, 41, 63, 70). Syrian hamsters
exposed to cigarette smoke developed a small number of tumors in the
tracheobronchial epithelium (30, 1/0). Cigarette smoke condensate
has been studied in tissue culture preparations (38), and implantation
of cigarette smoke condensate exposed lung tissue subcutaneously has
been reported to cause malignant growths (26). Cigarette smoke con-
densate also causes skin tumors when applied topically (9, 11, 46, 48, 61,
74, 82, 107, 108). This was confirmed by a large-scale study with about
8,000 mice by the Tobacco Industry Research Council of England (22).
Repeated injections of cigarette smoke condensate in rats produced
sarcomas (32, 82, 83, 84). Since 1963 two studies have reported nega- —
tive results when cigarette smoke condensate was administered intra-
tracheally to rats and Syrian hamsters (25, 42) , respectively.

Bronchoscopic painting of cigarette smoke condensate rapidly causes
squamous metaplasia in dogs and may accelerate carcinogenesis (91).
Carcinogens, known to be present in tobacco smoke, have been applied
to cells in tissue culture with the observation of malignant changes (7)
and other effects (22), such as differential growth inhibition of normal
but not malignant cells (2%). Inhalation (53, 78, 90), intratracheal
administration (25, 36, 42, 54, 81), subcutaneous, intraperitoneal and
intravenous injection, oral administration, and skin painting of car-
cinogens have all induced pulmonary tumors (87).

144
The search continues for an experimental animal system in which
the inhalation of tobacco smoke will produce malignant
tissue changes closely approximating those observed in human
pulmonary cancer. When dealing with passive inhalation of tobacco
smoke, however, a problem of the defensive barrier of the nasal passage
is introduced. So far, dogs inhaling cigarette smoke through tra-
cheostomies seem to be the most promising system, but there are
problems in keeping the experiments going for the length of time nec-
essary for lung cancer to develop. Additional research is needed. using
cultured lung tissue together with autograft and homograft studies to
determine in vivo results. Additional insight may thus be gained into
in vivo systems. It should be noted, however, that it may not be possible
ever to achieve histologic identity in pulmonary cancer production, not
only because of difficulties in duplication of man’s smoking action for
reasons of anatomic and physiologic differences, but also because of
inherent species’ differences in cellular response.

CANCER OF THE BUCCAL CAVITY AND PHARYNX (LIP,
MOUTH, THROAT)

The Surgeon General’s 1964 Report concluded that the causal re-
lationship of pipe smoking to the development of cancer of the lip
appeared to be established. Although there were suggestions of a
relationship between cancer of other specific sites of the oral cavity and
the several forms of tobacco use, their causal implications could not be
stated at that time.

The National Center for Health Statistics (94) reports that during
1964, 28 female and 157 male deaths occurred from cancer of the lip.
During the period 1950-64, male mortality from this disease declined
about 67 percent. This was partially due to changes in the diagnostic
classification but was mainly due to increased early diagnosis and
therapy. During the period 1958-64 when the seventh revision of the
International Classification of Diseases was in use, total mortality
from cancer of the lip remained about the same, but when analyzed
by age, substantial decreases occurred in this death rate for each 10-
year age group from 55-84 years.

As for cancer of the oral cavity, other than the lip, the total death
rate showed no marked variation from 1950-64 (3.1 and 3.3 deaths per
100,000 population, respectively). In 1964, the death rate for cancer
of these sites in the male population was about three times the cor-
responding rate in the female population (5.1 and 1.6 deaths per
100,000 population, respectively).

145
Morratrry Data From tae Larce Prosrecrive Sruprs

Hammond (40) has reported data for males having cancer of the
buccal cavity or pharynx, as the underlying cause of death, by mor-
tality ratio and age-standardized death rates (table 12).

TABLE 12.—Buccal cavity and pharyngeal cancer mortality ratios and
death rates for male smokers, by type and specified age groups

 

 

 

Cigarettes Pipe and/or
Males Males Males
45-04 years 65-79 years 55-84 years
Mortality ratio. _-__...--.--_____. . 9. 90 2. 93 4,94
Death rates____.-....22-- 222 +e 1(1) 8 '(7) 20 1(3) 15

 

 

 

 

' Numbers in parentheses indicate death rates of persons who had never smoked cigarettes regularly.
Source: Hammond, E. C. (40).

The Dorn study (49) also has provided information with relation to
amount and type of smoking on males dying from cancer of the buccal
cavity and pharynx (table 13) :

TaBLEe 13.—Buccal cavity and pharyngeal cancer mortality ratios and
death rates for U.S. veterans, by age, type, and amount of smoking

 

Current smokers of cigarettes only

 

 

 

 

 

 

 

Pi Cigars Pipe
Number of cigarettes per day and/or| only | only
cigars
0 1-9 10-20 | 21-39 | 40+
Buccal Cavity:
Mortality ratio....-......--.-.-. 10 0.86 2.93 7. 34 5.73 3. 89 4.11 3.12
Death rates:
Age 45 to 54__ - 2B 97
Age 55 to 64__. 222 2 3 6 12 9 5 3 2
Age 65 to 74. _. 222-22 2-8. 4 fee 10 19 9 15 18 u
Age 75 plus. -- 12 <n
Pharynx:
Mortality ratio._...-....-....--- 1.00 7.11 | 12.81] 14.59] 19.34 3.06 f...-... 1
Death rates:
Age 55 to 64_. 2-22-22 9 8 & 2
Age 68 to 74_.-_, 22-2. 1 12 22 10 39 Cn rn 4

 

 

 

 

 

 

 

 

 

SouRkce: U.S. veterans study [app. table A (49)].

The Canadian pensioners study (8) has not reported separately on
deaths from cancer of the buccal cavity and pharynx.

The Doll and Hill studies (28, 29) of British physicians have re-
ported on cancer of the mouth and pharynx, including cancer of the
nose (table 14).

146
TaBLE 14.—Death rates from cancer of upper respiratory tract and
digestive system by site and type of smoker

 

 

Non All Cigarette Mixed Pipe or
Bite smokers smokers smokers smokers clear
smokers
ee
Mouth, pharynx, or nose_------ 0 6 5 10 4
Larynx or trachea.------------ 0 6 5 3 10
Esophagus-------------------- 4 10 6 19 8

 

 

 

 

 

 

Source: Study of British physicians, [table 12 (88)).

Data on the relationship between amount of cigarettes smoked and
the death rates were also provided (see table 15).

TaBLE 15.—Death rates from cancer of upper respiratory tract and
digestive system by site and amount smoked

 

 

 

 

Amount of tobacco smoked daily (g.) !
Site
Non- All 1-14 15-24 26+ Cessa-
smoking | amounts| tion
Mouth, pharynx, or nose_--.----- 0 7 4 1 21 6
Larynx or trachea..-.----------- 0 6 2 2 15 5
Esophagus--------------------- 4 12 8 14 20 2

 

 

 

 

 

 

1(g.) = 1gm.=1 cigarette per day=1{ oz. tobacco per week.
Source: Study of British physicians (table 13 (25)}.

Additional significant information comes from a study (69) of 102
cigarette smokers, all of whom were “cured” of a primary mouth or
throat cancer and remained asymptomatic for at least 3 years. Of these
patients, 37 stopped smoking while 65 continued. Of the 37 who stopped
smoking, only two had a second primary cancer develop in a different
site in the buccal-pharyngeal area, whereas 14 of those who continued
to smoke developed a second cancer in a different site in the buccal-

pharyngeal area.
Exprrtmentar STUDIES

In one study (56), pipe smoke condensate was dissolved in sputum
and applied behind the ear of mice. Although no ear lesions were ob-
served, two animals developed scirrhous and planocellular cancer, re-
spectively, of the lower jaw, perhaps as a consequence of licking the
ears of other mice. In another experiment (37), rats were placed in
chambers and exposed to cigarette smoke. Five of 68 surviving rats
developed tumors of the buccal mucosa, three of these animals had
malignant invasive lesions.

147
In another setting (27), in which the oral area of mice was painted
with cigarette smoke condensate for 15 months, no lesions were noted
in the oral cavity. However, a significant increase in lung tumors,
lymphosarcoma, leukemia, and reticulosarcoma was observed.

Résumé

The Surgeon General’s 1964 Report established the causal relation-
ship of pipe smoking with lip cancer, but did not find sufficient evidence
for a causal relationship of specific forms of smoking with cancers
of other sites in the oral cavity and pharynx. Current information
strengthens the association between the various forms of smoking and
the general category of cancers of the buccal-pharyngeal area but
present information remains inadequate for a judgment of causality,
Knowledge of the interaction of smoking and other factors known or
suspected as causative agents, when available, could assist in such a
judgment.

CANCER OF THE LARYNX

The Surgeon General’s 1964 Report concluded : “Evaluation of the
evidence leads to the judgment that cigarette smoking is a significant
factor in the causation of laryngeal cancer in the male.”

The National Center for. Health Statistics reports (94) that 2,494
deaths attributed to cancer of the larynx occurred in 1964, as com-
pared with 1,852 deaths in 1950, a 34 percent increase. Almost all these
deaths occurred in the male population, with a male-to-female ratio of
about 8 to 1. The total death rate in 1964 was 1.3 deaths per 100,000
population, which represented only a slight increase over the death
rate of 1.2 noted in 1950. The mortality impact of this disease occurs
primarily after middle age, there being a five-fold increase in the death
rate for males over 75 years as compared to males under 55 years of
age.

The Hammond study (40) reports the following information for
laryngeal cancer deaths of males with a history of regular cigarette
smoking, in terms of mortality ratios and death rates:

TaBie 16.—Laryngeal cancer mortality ratios and death rates for male
cigarette smokers, by specified age groups

 

Cigarette smokers

 

 

Age 45-64 Age 65-79
Mortality ratios.......-.-.------2-22 2 eee. 6. 09 8 99
Death rates_..._-...-------------- eee eee 1(1) 4 1(2) 14

 

 

 

1 Numbers in parentheses indicate death rates of persons who had never smoked cigarettes regularly.
Source: Hammond, E. C. [table 24 (49)].

148
The Dorn study (49) of U:S. veterans reports the following laryn-
geal cancer mortality ratios related to amount of cigarettes smoked,
and smoking of pipes and cigars, or cigars only.

TaBLE 17.—Laryngeal cancer mortality ratios and death rates for U.S.
veterans, by age, type, and amount of smoking

 

 

 

Number of cigarettes per day
ee | Sisy
and iy
0 1-9 10-20 21-39 40+ cigar
Mortality ratio_..------ 1 | 3.27 | 8.45 13. 62 18.85 | 7.28 | 10.33
Death rates:
Age 55 to 64._.-.-.- a 4 5 20 4 3
Age 65 to 74__._.-_|------ 7 13 | a 12 20
Age 75 to 84..__.-- 13 |_..--_-}------}- eee -]------

 

 

 

 

 

 

 

 

gourceE: U.S. Veterans study [app. table A (49)].

The Doll and Hill study reported their data in terms of cancer of
the larynx or trachea (see tables 14 and 15) for relationships with
type and amounts of tobacco smoking.

The Canadian study did not provide separate data on cancer of
the larynx. No additional information has become available, since the
Surgeon General’s 1964 Report, relating the several forms of smok-
ing, ie., cigarettes, cigars, and/or pipes, to specific laryngeal cancer
sites (intrinsic versus extrinsic larynx).

The study previously referred to (69) which analyzed the develop-
ment of second sites of cancer after cure of a primary oral cancer,
reports that of 37 smokers who stopped smoking, none developed
cancer of the larynx but that four of 65 continuing smokers developed
cancer of the larynx. Although small numbers are involved, beneficial
aspects of smoking cessation are suggested.

Résumé
Additional epidemiological evidence supports the previous con-

clusion that cigarette smoking is a significant factor in the causation
of cancer of the larynx.

CANCER OF THE ESOPHAGUS

The Surgeon General’s 1964 Report concluded: “The evidence on
the tobacco-esophageal cancer relationship supports the belief that
an association exists.” However, the Committee at that time noted
that there was not adequate data on which to base a decision as to
whether the relationship was causal.

The National Center for Health Statistics (94) reports that from

149
1950 to 1964 the mortality from cancer of the esophagus rose about
8 percent in the male population and 9 percent in the female popula-
tion. In 1964, males had a death rate for esophageal cancer that was
3.7 times higher than the female rate. The greatest relative increases
were in the age groups under 65 years, especially the age group
35-44 years.

Mortairy Data From THe Large Prosrecrive Stupies: The Ham-
mond (40) study reports the following death rates and mortality
ratios for males in the age groups 45-64 and 65-79 who have a history
of smoking regularly:

TABLE 18.—Esophageal cancer mortality ratios and death rates Jor male
cigarette smokers, by specific age groups

 

 

Age 45-14 Age 65-79
Mortality ratios_.__._.......-.----.-_~..------- 4.17 1.74
Death rates....._.__....--...0 2-4. ....------- 1(1) 4 1(4)7

 

 

 

1 Numbers in parentheses indicate death rates of persons who have never smoked regularly.
Source: Hammond, E. C. [table 24 (40)].
The Dorn study (49) reports the following mortality ratios and
death rates in relation to number of cigarettes smoked per day plus
other forms of smoking: -

TaBLE 19.—Esophageal cancer mortality ratios and death rates for
U.S. veterans, by age, type, and amount of smoking

 

 

 

Number of cigarettes per day Pipe Cig
only
0 1-9 10-20 21-39 40+
Mortality ratios__-| 1.00] 1.76 | 4 71 11.50 | 7.65 | 4.05 | 5.33 1. 99
Death rates:

Age 55 to 64___ 1 2 5 14 9 5 8 |------
Age 65 to 74___ 3 j------ 16 25 10 20 23 18
Age 75 to 84_._ 45 |. --2--}-2. || eee 41 |__-__- 72

 

 

 

 

 

 

 

 

Source: U.S. Veterans study [app. table A (49)}.

The Canadian veterans study did not give separate information
about deaths from esophageal cancer.

Autopsy studies of smokers as compared with nonsmokers, spe-
cifically observing the pathological changes in esophageal tissue, have
been performed by Auerbach (3). A microscopic study was made of
12,598 sections of esophageal autopsy tissue from 1,268 men, who died
from causes other than esophageal cancer. The smoking histories were
recorded but not known to the person examining the slides. The find-
ings were strikingly similar to the abnormalities generally accepted as

150
yepresenting premalignant tissue changes in the respiratory tract
epithelium. Esophageal epithelial cells with atypical nuclei were found
far more frequently in cigarette smokers than in nonsmokers. The term
“atypical nuclei” describes nuclei with an irregular distribution of
chromatin. Other abnormal changes including giant nuclei may also be
present. Basal cell hyperplasia and hyperactive glands also were found
more frequently in cigarette smokers than in nonsmokers. An in-
crease in frequency with amount of cigarette smoking was noted for
both epithelial cells with atypical nuclei and basal cell hyperplasia.
Atypical nuclei in epithelial cells were also more frequently found
in ex-cigarette smokers as compared to nonsmokers. Tables 20 and 21
illustrate the frequency of these findings:

TABLE 20.—Atypical nuclet in basal cells of epithelium of esophagus of
males, by smoking habits and age

 

 

 

Never Current
smoked cigarette Ex-cigarette | Pipe, cigar Other
regularly
Atypical nuclei
Num-| Per- |Num-| Per- |Num-| Per- |Num-| Per- | Num-j Per-
ber | cent | ber | cent | ber | cent | ber | cent | ber | cent
A. ALL MEN
Number men-...-.---------- O1 j.-.-.-- 779 |.-.---- 181 |_..---- 80 j_------ 62 |...----
Total sections !. -..-.--.----- 787 | 100.0 | 6,752 | 100.0 | 1,686 | 100.0] 766} 100.0] 522) 100.0
No atypical nuclel...-.------ 733 | 93.1 167 2.5 770 | 48.5 53 6.9 198 37.4
Some but <60 percent
atypical......--.----------- 52 6.6 | 6,389 | 79.8 765 | 48.3 68s | 89.8 317 60.7
60 percent or more atypical... 2 0.3 | 1,196 | 17.7 51 3.2 2 3.3 10 1.9

B. MEN UNDER AGE 50

 

 

Number men. --.------------ 26 |--.---- 236 - 2B I, 9 : 7
Total sections !. -..- 223 | 100.0 | 2,069 | 100.0 258 | 100.0 77 | 100.0 53) 100.0
No atypical nuclei. 190} 85.2 7m 34 56! 21.7 1 1.3 4 7.8
Some but <60 percent

atypical.......------------- 33 | 14.8] 1,853} 900 105 | 75.6 74) 96.1 46 86.8
60 percent or more atypical---|...----|...---- 185 6.6 7 2.7 2 2.6 3 5.7

G. MEN AGED 50-69

Number men. --...----.---.-- 44 |e 445 |_.----- 100 |...---- 38 |...---- 31 |.------
Total sections !.......---..-- 370 | 100.0 | 3,853 | 100.0} 953 | 100.0 310 | 100.0 256 | 100.0
No atypical nuclel.......--.-| 373 | 98.4 83 2.2 461 | 48.4 37) 11.9 74 23.9
Some but <60 percent

atypical_____.....---------- 4 1.1 | 2,915 | 75.6 452 | 47.4 21) 84.2 178 60.5
60 percent or more atypical... 2 0.5 855 | 22.2 40 4.2 12 3.9 4 1.6

D. MEN AGED 70 OR OLDER

Number men--......----..-- 21 |_....-- a 4 |__...-- 42 |._...-- % |...-.--
Total sections ! 185 | 100.0 840 | 100.0 375 | 100.0 379 | 100.0 213 | 100.0

  

No atypical nuclei.......-.--| 170] 91.9 13 1.5 253 | 67.4 15 4.0 117 54.9
Some but <60 percent

atypical..............-.---- 15| 8.1] G21) 74.0) 118) 31.5) 353] 93.1 93 | 43.7
0 percent or more atypical-..|....---|------- 206 | 24.5 4] ui n| 29 3 1.4

 

 

 

 

 

 

 

 

 

 

 

1 Sections with some epithelium present.
Source: Auerbach, O., et al. [table 2($)}.

271-394 0-67-11 151
TABLE 21.—Atypical nuclei in basal cells of epithelium of esophagus of
males, by amount of smoking and age

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Never smoked Current cigarette smokers
Cells with atypical nuclei y <1 Pack 1-2 Packs 2+ Packs
Num-| Per- | Num-| Per- | Num-| Per- | Num- |- Per-
ber cont ber cont ber cent ber cent

A. All ages. .....-------------------- ol 170 418 187 .

Total sections !__........-..----- 787 | 100.0} 1,544! 100.0] 3,620! 100.0] 1,870 100.0

No atypical nuclel____.-.. ..-.-. 733 93.1 80 5.8 a 11 30 28

Some but <60 percent atypical _. 82 66) 1,841) 868] 2,957) 81.5 | 1,001 0.2

60 percent or more atypical....... 2 08 14 7.4, 633 17.4 449 23.4
B. Men under age 50:

Number men____---_.-.--------- 2 49 132 55 |...

Total sections '._........-..-..-- 223 | 100.0 433 100.0; 1,169] 1000 457 1020

No atypical nuclef_.__..---.....- 190] 85.2 48 11.1 2 1.8 2 O44

Some but <60 percent atypical.. 33 14.8 382 88.2] 1,089 93.2 382 83.6

60 percent or more atypical. 3 07 a 5.0 2 140
C. Men aged 50-69:

Number men....--...----------- “4 92 240 113

Total sections !__ 379 | 100.0 7e9 | 100.0! 2,116; 1000 948 100.0

No atypical nucl 373 98.4 30 a8 8 ao 35 37

Some but <60 percent atypical... 4 1.1 04 | «=87.9} 1,607 75.9 614 648

60 percent or more atypical__._.- 2 -O5 65 &3 491 4.2 2 31.5
D. Men aged 70 or older:

Number men_.._.-...----_.-...- 21 3 4! 19

Total sections !__..-_-_.-..------ 185 | 100.0 100.0 a4; 100.0 174 100.0

No atypical nuclei_......-.._--.- 170 01.9 i 3.4 2 Lt

Some but <60 percent atypical_. 15 8&1 25) 82.3 261 75.9 05 64.7

60 percent or more atypical . 46 14.3 83 24.1 71 4.2

 

 

 

 

 

 

 

 

 

 

' Sections with some epithelium present.
Sovugrce: Auerbach, O., et al. [table 3(9)].

EXxperRIMENTAL Srupres

Because of the association noted between esophageal cancer and
aleohol consumption reported in the Surgeon General’s 1964 Report,
a study (58) was undertaken to consider the possibility that the car-
cinogens known to be present in tobacco smoke could penetrate esopha-
geal tissue more readily, if dissolved in aqueous solutions of ethanol.
Mice were exposed to several compounds by intraesophageal tubation.
Tissues were then removed and studied by fluorescence microscopy.
Deeper penetration and a different distribution were found when
benzo(a)pyrene was dissolved in aqueous solution of ethanol as com-
pared to benzo(a)pyrene dissolved in olive oil. It was also found that
benz (a) anthracene and fluoranthene dissolved in ethanol solution or
aqueous caffeine solution could penetrate the epithelium of the
esophagus.

Résumé

The present evidence strengthens the conclusion that a four-fold to

five-fold increased risk of dying from esophageal cancer is associated

152
with tobacco smoking. Autopsy evidence indicates that smokers have a
greater frequency of pathologic changes of the esophageal tissue, some
of which are generally considered to be premalignant. It has been .
demonstrated that known carcinogens such as benzo(a)pyrene and
others can penetrate the esophageal tissue when dissolved in aqueous
ethanol or caffeine solutions. The present evidence suggests that smok-
ing may be a causal factor in the development of esophageal cancers,
but is still insufficient for a firm judgment of causality. More informa-
tion on alcohol as a confounding variable and/or interactant is vitally
needed.

The data on women for the preceding categories of buccal, pharyn-
geal, laryngeal, and esophageal cancers have not been reported due to
the relatively too few cases involved. However, Hammond has pooled
these data into one group. Table 22 shows an increased mortality ratio
in this overall combined category but the number of deaths is still too
small for significant conclusions to be drawn.

TABLE 22.—Mortality ratios and age-standardized death rates for cancer
in women aged 46-64 by site and amount smoked

 

Never Cigarette smoking Heavier cigarette
a smoked smoking !

 

Death Death Mortality Death Mortality
rate rate ratio rate ratio

 

Buccal cavity, pharynx, larynx,

 

 

 

 

 

 

and esophagus--..........-- 2 3 1.79 6 3.17
Lung ?.._----2- 22 eee q 15 2.17 25 3. 63
Pancreas._.__.---..---------- 6 11 1.81 16 2. 58

1 Smoked 20 d ttes
ds men or ati ten a day y roger ans of , pogan § smoking or smoked 10 or more cigare' a

Source: Hammond, E. C, [table 26 (40)].

Table 22 also shows the dosage effect of smoking on women, for dif-
ferent cancer sites—an increased amount of smoking being reflected
in an increased mortality ratio.

CANCER OF THE URINARY BLADDER

The Surgeon General’s 1964 Report concluded: “Available data
Suggest an association between cigarette smoking and urinary blad-
der cancer in the male but are not sufficient to support judgment on the
causal significance of this association.”

The National Center for Health Statistics (94) reports that there
has been no change in the death rate from cancer of the bladder and
other urinary organs during the period 1950-64. For 1964, the male

153
death rate from this cause was 5.8 deaths per 100,000 population, and
the female death rate was 2.6 deaths per 100,000 population.

The mortality data from the large prospective studies are presented
below. The Hammond study reports the following mortality ratios and
death rates for cancer of the bladder and other urinary tract sites, for
males, by history of regular smoking :

TABLE 23.—Bladder cancer mortality ratios and age-standardized
death rates for male cigarette smokers, by specified age groups

 

 

Cigarette smokers
Age 45-64 ; Age 65-70
Mortality ratios___.._..-------..----222-2 2-8 2. 00 2.98
Death rates. __..___. 22-22 1(4)7 (17)50

 

 

 

‘1 Numbers in parentheses indicate death rates for persons who have never smoked regularly.
Source: Hammond, E. C. [table 24 (40)].

The Canadian Pensioners study (8) included bladder cancer in
the general category of genitourinary cancer.

TABLE 24.—Genitourinary cancer mortality ratios for Canadian veterans
by age and amount smoked

 

 

 

Ni
M ty ratios famber of cigarettes smoked per day
14 10-20 | 21+
All ages..__-.-..--.---- 222 --eeee 1. 33 L 44 1. 43
Age 70+_._--..---------- eee L 10 2, 24 2. 43

 

 

 

Source: Canadian pensioners studv [table 8.2 (8)}.
The Dorn study of U.S. veterans (49) reports the following mor-

tality ratios and death rates for males by quantity of cigarettes
smoked per day and by pipe and/or cigar smoking:

TABLE 25.—Bladder and other urinary tract cancer mortality ratios and
death rates for U.S. veterans, by age, type and amount smoked

Number of cigarettes smoked per day rire
an

 

Cigars | Pipe

 

0 19 10-20 21-39 | 40+

 

Mortality ratios_| 1. 00 110] 1L93]} 320] 2.52] 1.09] 094] 1.20
Death rates:

Age 45-54___}.______]_._____ 13 WW {tel} fee jee ee
Age 55-64___| 8 2 12 14 20 14 18 14
Age 65-74___| 22 25 28 96 45 20 9 28
Age 75-84...1 89 9 {_____ lJ ----f

 

 

 

 

 

 

 

 

Source: U.S. veterans study {app. table A (49)].
154
The Doll and Hill survey of British physicians (28) reports the
following standardized death rates for cancer of the urinary bladder:

TABLE 26.—Death rates for cancer of urinary bladder by type of smoking

 

Type of smoking

Nonsmokers

 

All smokers Cigarette smokers Mixed smokers {Pipe or cigar smokers

 

7 11 13 12 7

 

 

 

 

 

Source: Study of British physicians {table 14 (28)].

TABLE 27.—Death rates for cancer of urinary bladder by amount smoked

 

Amount of tobacco smoked daily (g.)!

 

1-14 15-24 25+ All amounts Ceesation

 

10 ll 13 12 8

 

 

 

 

 

11 g.=1 cigarette/day = Koz. tobacco/week.
Source: Study of British physicians (table 15 (#8)].

The Hammond and the Dorn studies report mortality ratios of
more than 2.00 in smokers of more than 20 cigarettes per day. The
Canadian study reports the same for men over 70 years, who smoke
more than 10 cigarettes per day. The Doll and Hill survey is incon-
sistent with those previously mentioned in that it shows no association
between type of smoking or amount smoked and bladder cancer.
However, this survey consists of but 38 deaths due to bladder cancer.

Two controlled retrospective studies of bladder cancer patients
have been reported since the Surgeon General’s 1964 Report. In both
studies these patients had a significantly greater percentage of smok-
ers, the majority of whom were cigarette smokers, as compared with
controls. The first study (18) reported 94 percent smokers in the
patient group and 74 percent in the control group. When analyzed
by the amount smoked, the patient group had 80 percent heavy smokers
(greater than one pack per day for 30 years) as compared to only 45
percent heavy smokers in the control group. The second study (89)
reported 93 percent smokers in the patient group and 84 percent in
the control group. However, when compared by the amount smoked,
there was a much larger difference between the two groups; there being
86 percent of the patient group with a high “smoking index” (amount
smoked X duration of smoking) as cémpared to only 66 percent in
the control group. The latter study also reported a greater frequency
of inhalation and “cigarette only” smoking in the patient versus
controls groups.

155
Autopsy Srupres

There have been no reported studies analyzing changes in the
bladder tissue of smokers compared with nonsmokers. Studies of this
type would be helpful to determine if smoking is associated with
pathologic changes commonly thought to be premalignant in other
' types of tissue.

EXPERIMENTAL CARCINOGENESIS

Cigarette smoke condensate as well as several tobacco smoke con-
stituents were implanted with cholesterol directly into the bladder
of mice (16). Only hydroquinone produced a significant number of
bladder tumors.

Merazotic Strupies or ENDOGENOUS CARCINOGENIC SUBSTANCES IN Man

Certain ortho-aminophenols and ary] hydroxylamines are known
to be carcinogenic (16). Three normal intermediate metabolites of
tryptophan are ortho-aminophenols (3-hydroxyanthranilic acid, 3-
hydroxy-2-amino-acetophenone, 3-hydroxykynurenine) and are known
to induce cancer when placed in the bladder of mice (15).

Kerr, et al. (51, 52), performed metabolic studies on six men, three
smokers and three nonsmokers. He found that the three nonsmokers
had substantially increased urinary excretion values of 3-hydroxyan-
thranilic acid and 3-hydroxykynurenine, after having smoked for 5
weeks, with a concomitant decrease in the excretion of N’-methylnico-
tinamide, a normal end product of tryptophan metabolism. After hav-
ing stopped smoking for 5 weeks, the three smokers showed decreased
urinary excretion of these same intermediate metabolites and an in-
crease in N’-methylnicotinamide excretion.

The carcinogenic metabolites increased an average of 50 percent
while the normal end metabolite decreased an average of 34 percent
in response to cigarette smoking. A reversal was noted after the men
stopped smoking. These studies suggest that cigarette smoking changes
the normal metabolic pattern of tryptophan, leading to the accumula-
tion of carcinogenic metabolites in the urine. Further studies are
needed to confirm these findings.

Another study, designed to detect abnormalities of tryptophan (6)
in patients with various neoplastic or nonneoplastic conditions of the
urinary tract, showed that 29 of 201 bladder cancer patients had both -
kynurenine and 3-hydroxykynurenine, in contrast to eight of 167 pa-
tients with other urinary tract diseases, neoplastic and nonneoplastic.
However, more renal cancer patients had 3-hydroxyanthranilic acid
than bladder cancer patients. This study did not include data concern-
ing current smoking habits of the patients studied.

156
Resume

The additional epidemiological, clinical, and experimental data
strengthen the association between cigarette smoking and cancer of
the urinary bladder, but are stil] insufficient to infer that the relation-
ship is causal.

CANCER OF THE STOMACH

The Surgeon General’s 1964 Report stated that no relationship has
been established between tobacco use and stomach cancer. No new
evidence refutes this statement.

Epidemiological evidence does not show a significant relationship
between smoking and stomach cancer. The overall mortality ratios,
although greater than for nonsmokers, are smaller than for any other
disease related to smoking. There is also no gradient with the amount
of tobacco smoked.

TasLE 28.—Male mortality ratios and death rates for cancer of stomach
by specified age groups

 

 

Age 45-64 Age 65-79
Mortality ratios..........---.------------------ 1.42 1. 26
Death rates.....-.----------------------------- 1(11) 16 (57) 72

 

 

 

! Numbers in parentheses indicate death rates of persons who had never smoked cigarettes regularly.
Source: Hammond, E. C. [table 24 (40)}.

TABLE 29.—Mortality ratios and death rates for cancer of stomach
by age, type, and amount smoked, in U.S. veterans

 

 

 

Cigarettes/day Pi
an Cigar Pipe
0 19 10-20 21-39 40+ =
Mortality ratio
(total) _....-.----- 1.00 | 2.17 | 1.61 | 1.35 | 1.87 | 1.21 | 1.20 1, 40
Death rate:
Age 45 to 54____ 10 j------ 7 jj. uuu]. ---|----}ee ee -ede e
Age 55 to 64____ 13 27 21 24 53 15 9 21
Age 65 to 74__.. 28 68 48 58 46 40 46 57
Age 75 to 84.... 87 j__-___|..----]-----.]------ 114 212 |_.----

 

 

 

 

 

 

 

 

 

Source: U.S. Veterans study [app. table A (49)].

157
TaBLe 30.—Death rates for cancer of stomach by type and amount
smoked, in British physicians

 

 

 

Amount of tobacco daly (g.) ! .
Non- All Cigarette Given up Pipe or
amokers {smokers} smokers smoking | Mixed
1-14 15-4 25-+ All
amounts
27 25 30 28 28 26 28 18 14 30

 

 

 

 

 

 

 

 

 

 

‘1 g.=-1 cigarette per day={ oz. tobacco per week.
Source: Study of British physicians [tables 14 and 15 (#8)}.

Résumé
Although cigarette smokers appear to have slightly higher death

rates from cancer of the stomach, the differences are small and do
not bear any consistent relationship with amount smoked.

CANCER OF THE PANCREAS

The Surgeon General’s 1964 Report did not report on cancer of
the pancreas.
The more recent epidemiologic evidence shows an increase in the

death rates and mortality ratios for creatic cancer among male
cigarette smokers (40, 49). Comparably elevated ratios are noted for

females but not to the extent noted for males (40) (see tables 22, 31,
32, 33). Both the U.S. veterans study (49) and the Canadian pensioners
study (8) reveal a gradient of mortality risk increasing with the

amount of cigarettes smoked. Data are insufficient to draw any con-
clusions for pipe and/or cigar smokers.

TABLE 31.—Mortality ratios and death rates for cancer of pancreas
by sex and specific age groups in cigarette smokers

 

 

 

Age 45-64 Age 65-79
Female Male Female Male
Mortality ratio....._______.___ 1,81 2. 69 14,41 2.17
Death rate..____.-..__-._ 2(6) 11 *(7) 19 | 2 (32) 45 7(31) 66

 

 

 

 

 

1 Computed from app. table 19.
3 Numbers in paren eses indicate death rates of persons who had never smoked cigarettes regularly.

Source: Hammond, E. C. [tables 24, 26, and app. table 19 GO}.

158
TaBLE 32.—Mortality ratios and death rates for cancer of pancreas
by age, type, and amount smoked, an U.S. veterans

 

 

 

Cigarettes/day Pt
and/or | Cigar Pipe
0 1-9 10-20 | 21-39 | 40+ ogee
Mortality ratio
(total)_. ---------- 1.00| .87| 193] 2.18) 1.87 | 1.13) 152 74
Death rate:
Age 45 to 54_..-|------|------ 9 21 |------ 26 |__.---|------
Age 55 to 64_.-- 13 15 24 26 21 19 21 22
Age 65 to 74..-- 29 29 50 56 27 38 58 19
Age 75 to 84_.--| 109 }------|------|------|------ 32 33 68

 

 

 

 

 

 

 

 

 

Source: U.S. veterans study fapp. table A (49)].

TABLE 33.—Male mortality ratios for cancer of pancreas of current
cigarette smokers by amount smoked

 

 

 

Cigarettes/day
0 1-9 10-20 21+
Mortality ratio_....----------- 1. 00 1. 40 1, 96 2. 37

 

 

 

 

 

Source: Canadian pensioners study [table 8.2 (8)).
Résumé
An association between cigarette smoking and pancreatic cancer
is implied, but in the absence of data on other possible causal factors,

confounding variables and interactants, the significance of this asso-
ciation is not clear.

159
(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

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177
CHAPTER 4

 

Other Conditions and Areas of Research

CONTENTS

Page
Smoking and Peptic Uleer_.__--.------------------------- 181
Smoking and Disturbances of Vision--_--_------------------ 183
Smoking and Cirrhosis of the Liver _.___------------------- 184
Effects of Smoking During Pregnancy-.------.-------------- 185
Smoking and Accidents_--_-_..---------------------------- 187
Psychosocial Aspects of Smoking -------------------------- 188
References.__..__.------------------------------------- 193

179
SMOKING AND PEPTIC ULCER

Since the publication of the Surgeon General’s 1964 Report, three of
the continuing prospective mortality * studies (2, 3,6,7) have provided
additional information which confirms the association between ciga-
rette smoking and mortality from peptic ulcer, especially gastric ulcer.
The mortality ratios increase with increases in amounts smoked. The
tables presented below illustrate the relationships involved. Although
Hammond’s (6) study contained a large number of females, insufficient
deaths from peptic ulcer have occurred in cigarette smoking females
to provide statistically reliable data. A trend is observable among cigar
and/or pipe smokers with regard to increased mortality from gastric
ulcer, but the number of deaths is too small for significant conclusions
to be drawn.

TaBLE 1.—Death rates and mortality ratios for gastric and duodenal
ulcers by specific age groups of male cigarette smokers

 

 

 

Age 45-64 Age 65-70
Site Death rate Mortality Death rate Mortality
ratios ratios
Gastric ulcer___..-.-.-...----. 1(2) 7 2.95 (7) 26 4.06
Duodenal ulcer_.__.-.-....2--- (3) 7 2. 86 (21) 31 1. 50

 

 

 

 

 

1 Number in parentheses indicates death rate for persons who never smoked regularly.
Source: Hammond, E. C. [table 24(6)).

TABLE 2.—Male death rates and mortality ratios for gastric and duodenal
ulcers by specific age groups for current and ex-smokers of cigarettes
only

 

 

 

 

Current cigarette smokers only Ex-cigarette

smokers only

Site Death rate Mortali Mortali

m malo” catio”
(total) (total)
55-64 65-74 75-84

Gastric ulcer... _____- 1(2) 7 (5) 17 (—)26 4.13 2.74
Duodenal ulcer_.__--.._- (4) 8 (10) 29 | (37) 122 2. 98 2.13

 

 

 

 

 

 

' Number in parentheses indicates death rate for persons who have never smoked.
Source: U.S. veterans study [app. table A (7)].

* All death rates throughout this chapter are per 100,000 population, unless otherwise indicated.

181
TABLE 3.—Peptic ulcer death rates by type and amount smoked, in males }

 

 

 

 

Cigarette smokers
Given up Mixed Pipe or
Nonsmokers | All smokers cigarette smokers cigar
All 1-14 | 15-24 25+ smoking
amounts
0 | 13 13 2 18 19 12 12 10

 

 

 

 

 

 

 

‘ Includes gastric and/or duodenal ulcers.
BovEce: Study of British physicians [tables 23 and 24 (#)}.

A recent survey (13), based on a national sample of 42,000 house-
hold interviews, shows that the prevalence of peptic ulcer is almost 100
percent greater in male cigarette smokers and over 50 percent higher
in females who smoke cigarettes as compared to those males and females
who had never smoked. Hammond’s data (5) shows twice the number
of cigarette smokers reporting the occurrence of peptic ulcer over a
2-year follow-up period as contrasted to nonsmokers. This also in-
creases with increases in the amount smoked.

Several small retrospective clinical studies (4, 8, 12) have shown
significantly more smokers and less nonsmokers in their peptic ulcer
patients as compared to control groups. Doll (1) reviewed various pro-
spective studies on gastric ulcer therapy regimes, such as: diet—bland,
normal, high and low fat; milk drips with alkali; drugs; and advice
to stop smoking. The best results were obtained in patients who stop-
ped or cut down on their smoking habits. The Surgeon General’s 1964
Report (14) points out the conflicting literature concerning the effects
of smoking on gastric secretion and motility. Lee (10), in a small
series of peptic ulcer patients and controls, showed that after smoking,
74 percent of patients and 58 percent of controls had a significant rise
in free gastric acidity. Those subjects with initially normal or hyper-
acidity had the greatest response, whereas, of those with initial hypo-
acidity only 28 percent had an increase in gastric acidity. Five of nine
controls, smoking a non-nicotine cigarette preparation, also had a rise
in gastric acidity, perhaps due to factors in smoke other than nicotine
or to oral stimulation.

Résumé

Cigarette smoking is shown to be associated with peptic ulcer.
This relationship is greater for gastric than duodenal ulcer and is
proportional to the amount smoked. The etiology of the peptic ulcer
diathesis is still unknown. Smoking is a definite risk factor in peptic
ulcer mortality. It may also be a factor in the delay in healing of a
gastric ulcer. More research is needed on the physiological effect of
smoking on the gastrointestinal tract.

182
SMOKING AND DISTURBANCES OF VISION

Tosacco AMBLYOPIA

Recent evidence points to the tobacco and/or alcohol amblyopias as
being manifestations of nutritional amblyopia (4, 7, 8, 17, 26, 26).
Various deficiencies in factors of the vitamin B complex have been
implicated (4, 6,7, 10, 17,26, 26).

A new theory that chronic low vitamin B,, levels potentiate the
toxic effects of cyanide in tobacco has recently been expounded
(8, 10, 22, 23).

The anatomical lesion in amblyopia seems to be a demyelinization
of the optic pathways, particularly in the papillomacular bundle
(10, 17,25).

In view of the fact that cyanide is neurotoxic, more research is needed

.

+n this area to further elucidate its association with this disease entity.

Oruer Diseases

Several studies have hypothesized that Leber’s optic atrophy, which
also is attributed to a demyelinization process in optic pathways, may
be associated with a defect in cyanide detoxification, which is aggra-
vated by the cyanide in tobacco smoke (1, 27).

VisuaL AcuITy

The Surgeon General’s 1964 Report, and others, cite evidence of
increased levels of carboxyhemoglobin in smokers (20, 24), due to the
carbon monoxide content in tobacco smoke. It has been suggested that
a decrease in nighttime visual discrimination in smokers is related to
this increase in carboxyhemoglobin levels (9, 15, 16, 19). It may also
possibly be due to the relative anoxia produced by the carbon monoxide
inhalation from tobacco smoke. A value of only 5 percent carboxyhemo-
globin saturation, not uncommon in smokers, creates a physiological
state of anoxia equivalent to being at an elevation of 8,000 feet, with an
arterial O, saturation of only 91 percent (15, 16).

Resume

It is suggested that tobacco amblyopia is but a manifestation of
nutritional amblyopia, which is aggravated by tobacco smoking. More
research is needed on the toxicity of tobacco smoke, with special con-
cern for the cyanide component. Experiments have shown a visual
discrimination deficit, possibly related to the carbon monoxide content
of tobacco smoke. Further work is needed in this area in order to

ascertain any clinical consequences.

271-394 O - 67 ~ 13

188
SMOKING AND CIRRHOSIS OF THE LIVER

Increased mortality of smokers from cirrhosis of the liver is found
in the prospective studies. This has generally been thought to be largely
secondary to an association between smoking and heavy alcohol con-
sumption. Published data are inadequate to test this interpretation.

The three prospective studies (7, 2, 3, 4) all show increased death
rates and mortality ratios from cirrhosis of the liver in cigarette
smokers.

TaBLe 1.—Mortality ratios and death rates for liver cirrhosis by sex
and specific age groups

 

 

 

45-64 65-70
Female Male Female Male
Mortality ratio...._....___.__- 2. 16 2. 06 11.40 1,97
Death rate..-_...---..--2 3(5)10 2(9)19 (10)14 (16)31

 

 

 

 

 

! Calculated from app. table 19 ($).
? Numbers in parentheses indicate death rates for persons who have never smoked regularly.

Source: Hammond, E. C. [tables 24, 26, and app. table 19 (3)].

TaBLE 2.—Male mortality ratios and death rates for liver cirrhosis by
age and amount smoked, in U.S. veterans

 

 

 

 

Current smokers of cigarettes only
0 19 10-20 | 21-39 40+

Mortality ratio (total) .._._.__- 1.00 2.72 3.15 3. 61 5. 50
Death rate:

Age 45 to 54.___..____.__. 9 [---L Lee 7 7 162

Age 55 to 64..__.____ __- 15 12 35 44 46

Age 65 to 74... 16 74 57 57 87

Age 75 to 84.__..._._.____. 53 [------ |---| eee]

 

 

 

SouRce: U.S. veterans study [app. table A (4)].
Doll and Hill present their data with respect to cirrhosis of the
liver and alcoholism combined. See table 3.

TABLE 3.—Male death rates for liver cirrhosis by type and amount
smoked, in British physicians

 

 

 

Number of cigarettes
Non- All Ciga- Given | Mixed | Pipe
smokers | smokers| rette up smok-/ smokers| or
smokers | 1-14 | 15-24/ 25+ All ing elgar
amounts
Cirrhosis of liver and
alcoholism -._...... 0 it 12 5 8 43 15 3 ll 5

 

 

 

 

 

 

 

 

 

 

Source: Study of British physicians, [tables 21 and 22 (1).

184
The Surgeon General’s 1964 Report points out the association be-
tween heavy smoking and excessive alcohol intake. In view of the
fact that “The increased death rate from cirrhosis among smokers
may reflect the consumption of alcohol and associated nutritional
deficiencies rather than the effect of cigarette smoking” (6), further
research is needed to elucidate the association between smoking and —
cirrhosis of the liver.

EFFECTS OF SMOKING DURING PREGNANCY

The current new literature on pregnancy and smoking supports the
Surgeon General’s findings that there are a greater number of “low
birth weight” babies and premature babies as defined by weight alone
(2,500 g.) in those women who smoke during their pregnancy (6, 9,
18, 20, 21, 24-26, 28, 30-32, 36). Furthermore, this decreased weight
has been shown to be consistent in each trimester (28, 31, 32, 34, 36)
and is proportional to the amount smoked during pregnancy (5, 24-
26, 30-32, 34, 36) .

There are many factors which affect the outcome of pregnancy.
These include constitutional, pathobiological and psychological fac-
tors. Multiple-regression analyses of these various factors have shown
smoking to be a significant negative independent variable with respect
to birth weight (2, 5,27). .

Smoking has been linked to increased incidence of abortions and/or
stillbirths (6, 25, 26, 28, 30, 36), premature rupture of membrances
(30-32) and decreased male/female birth ratios (1/, 25, 26) ; however,
other studies do not support these findings (7, 9, 24, 30-32).

The significance of low birth weight and prematurity in regard to
increased fetal and infant mortality, has not been clearly demon-
strated. Most studies show no increased mortality (9, 31, 32). How-
ever, Yerushalmy (34) and Underwood (32), point out that although
the overall mortality is the same between infants of smoking versus
nonsmoking mothers, premature babies (as defined by birth weight of
less than 2,500 g.) of smoking mothers have decreased mortality.
Other studies show a slight but significant increase in fetal mortality
for mothers who smoke (6, 8). MacMahon (19) shows that rather
than increasing the proportion of low birth weight babies, smoking
actually causes a shift to the left in the entire weight distribution
(fig. 1).

Jansson (15) in his study states: “Thus, in the absence of other com-
plications, smoking mothers seem to make a proportionally greater
contribution to infants in the weight group just below 2,500 g. where
the prognosis is better.”

185
 

   

—— Non-smokers
~“=—= Smokers

 

 

 

tT
4 5 6 7 8 9 10 11

Ficure 1.—Percentage distribution by birth weight! of infants of mothers who
did not smoke during pregnancy and of those who smoked one pack or more
per day.

Source : MacMahon, B., et al. (fig. 1 (19) ].

Steele (29) suggests that smoking is associated with sudden unex-
pected deaths in infancy. The relationship of smoking in mothers to
increased fetal morbidity, either perinatally or after long-term follow-
up, has not been adequately probed and is a major area for future
research.

Some studies show a relationship between smoking and decreased
gestational age (6, 8, 32); others do not (1, 27).

Gestational age probably is a better indicator of fetal prematurity
than birth weight. Therefore, it may better reflect perinatal risk. Yet
even in the studies showing a correlation to smoking, this relationship
is less marked than that to birth weight (6, 8, 24, 32). This may be
due to the relative difficulty in determining the last menstrual period
accurately and therefore the true gestational age.

The mechanisms by which smoking affects pregnancy have not been
elucidated. Events influencing decreased fetal birth weight have been
attributed to several factors:

1. Placental vasoconstriction due to nicotine. No direct evidence of
this exists at the present time. The effects of smoking on uterine blood
flow are being conducted in animal experimentation (2).

* Birth weight (scale in pounds ; intervals of 4 ozs.)

186
2. Increased carbon monoxide in cord blood (72).

3. Decreased carbonic anhydrase activity due to increase in cord
carbon monoxide (20).

4. A postulated direct effect on the fetus of some toxic agent in
cigarette smoke.

5. Decreased caloric intake due to decrease in appetite of smokers
(10). Several studies have shown that there is no difference in weight
gain during pregnancy between smokers and nonsmokers (28, 30, 36).
Since smoking in general, does decrease appetite, it-might be well to
consider a difference in the type and/or distribution of caloric intake
between smokers and nonsmokers.

Kumar (17) has shown an increase in human uterine activity after
smoking, both in frequency and magnitude of contractions. However,
these findings were not observable in every patient. There was no
significant effect. of nicotine on myometrial strips in vitro from preg-
nant human uteri.

King and Becker (4, 16) have done experimental work with nico-
tine on pregnant rats. High concentrations of nicotine had greater
toxic effects on pregnant rats than controls. The offspring were lighter
in weight and survived less well than controls.

Resume

Clearly, more research is needed to elucidate the significance of the
relationship of smoking in pregnancy and low birth weight. Addi-
tional long-range morbidity studies are needed, as well as studies on
the effect of smoking on uterine activity and placental blood flow.

Smoking does have an effect on the outcome of pregnancy. How-
ever, it is not known whether this effect is deleterious or not.

Until such evidence is presented so as to clearly define the role of
smoking in pregnancy, it is more prudent at this time to advise
pregnant women to stop or decrease their cigarette-smoking practices.

SMOKING AND ACCIDENTS

The most obvious contribution of smoking to accidents is as a cause
of fires. Estimates of the proportion of fire loss due to “smoking and
matches” (includes fires attributed to careless smoking and the care-
less use of matches and lighters by smokers; does not include misuse
of matches by children) vary from 19 percent to 25 percent. The

187
National Fire Protection Association gives “smoking and matches” ag |
a reported cause of fire in various buildings for 1965 as follows (3):

 

 

 

 

 

 

 

 

Percent
Apartments 26
Boarding and rooming houses . 30
Dormitories, etc 24
Dwellings (1- and 2-family) 19
Hospitals 21
Hotels, seasonal 24
Hotels, year round 35
Motels. 20
Nursing 25

 

In 1965 there were 163,900 fires linked to smoking or the matches
used in smoking with a concomitant property loss of $80,400,000—in
1964, there were 159,400 fires and a property loss of $79,500,000 (6).
The statistics on the number of deaths attributed to those fires are
not available, but it is estimated that 1,800 people per year will die due
to fires caused by smoking and matches (7).

Smoking has been shown to cause decreased visual discrimination
especially under conditions of low illumination (4). This could have
serious implications with respect to night-time driving.

Several studies (7, 2, 6) have indicated an association between
smoking and traffic and industrial accidents, but the evidence is insuffi-
cient at this time to draw any significant conclusions. More research
is needed in this area. .

PSYCHOSOCIAL ASPECTS OF SMOKING

There has been a sharp increase in the attention devoted to behav-
ioral research since the Surgeon General’s 1964 Report. A number of
new concepts have been developed and more sophisticated multi-
variate approaches are being used. However, because of the recency
of these studies, very little in the way of findings has been published
on which firm conclusions may be based.

One of the byproducts of the Surgeon General’s 1964 Report has
been its stimulation of more research in all areas of smoking, includ-
ing the psychosocial. Much research will soon be completed but has
not yet been reported in the literature.

Three behavioral science conferences have been held since the Sur-
geon General’s 1964 Report. The content of these conferences are either
in print (9) or will shortly be published (11, 2/). These conferences
dealt with many different studies and research findings, theories,
methodological criticisms, and discussions on a number of important
issues. Among the primary purposes was the development and speed-
ing up of communications among those doing work in the field, pre-

188
venting duplication and wasted effort, developing better measuring
instruments, and providing assistance in conceptualizing new theo-
retical models or further developing approaches already proposed.

Much prior research in the psychosocial aspects related to smoking,
while yielding valuable data and suggestive theory, has been concerned
largely with discrete variables or attributes and has looked for gross
differences between smokers and nonsmokers. Since it is unlikely that
such research will discover that either group possesses an attribute
that is unique to it other than the behavior of smoking, the ability
of any single attribute to differentiate between these two populations
is bound to be limited. It is because of this that a number of investi-
gators have turned toward trying to distinguish subgroups of smokers,
as well as toward developing more unifying concepts. These efforts
are part of the attempt to obtain greater insight into the dynamics of
smoking and develop more powerful predictive instruments.

One area that shows conceptual and methodological maturation is
that of the study of smoking and personality. Much prior research
studied smoking in relation to such concepts as extroversion, intro-
version, neuroticism, emotional stability, orality, femininity, mascu-
linity, hypochondriasis, psychosomatic symptoms, risk taking and
chance orientation, psychopathic tendencies, achievement needs, social
approval, relationships to authority, independence, aggression, and
the like.

At the 1966 behavior research conference, it was pointed out that .
a better understanding of the total personality structure must be
achieved in order to increase understanding of some of the psycho-
logical correlates of smoking. Factor and hierarchical models have
much to contribute to this approach (7). At the 1967 conference this
and other points pertinent to personality research related to smoking
were discussed, and a reminder of the utility of multivariate tech-
niques was repeated (20). Toward this end these investigators are now
studying university students, seeking factors in the realm of person-
ality integration such as experience of control, scope of awareness,
reality contact, self-insight, temporal perspective, independence, anxi-
ety, and the like. After these factors have been identified they can be
used as independent variables in testing hypotheses suggested by other
developments, such as the recently developed typology of smokers,
illustrating the potential yield from a cross-fertilization of unifying
concepts.

Theories which emphasize the role of anxiety in the development of
personality and in the understanding of personality dynamics (7) pro-
vide a unifying frame of reference which, when combined with an
understanding of the gratifications derived from smoking, may lead to
useful explanations and investigations into smoking behavior. They
may also provide some cohesiveness to research on such concepts as

189
guilt, self-punishment, need to fail, and risk-taking behavior as they
relate to the initiation, continuation, or inability to discontinue smok-
ing. Concepts from depth psychology, and ego psychology in par-
ticular may additionally illuminate the source and function of some
of the apparent inconsistencies among attitudes, beliefs, and behavior
noted by various investigators beyond that provided by dissonance
theory (2).

Another area showing some growth is represented by attempt to dis-
tinguish between the different levels of dosage to which smokers expose
themselves beyond that indicated by the average number of cigarettes
smoked daily. More sophisticated dosage measurements (18) obviously
have application in epidemiological research. They may also prove use-
ful in psychosocial research. There is the possibility that an interplay
exists between the degree and kind of exposure, physiological and
psychological processes, and the dynamics, mechanisms, or degree of
difficulty involved in achieving long-term cessation of smoking.

Another conceptual development was contained in the proposal, re-
ported at the first of the national behavioral conferences (16) and later
refined (15), of a new way to define smokers—in terms of the smoker’s
use of cigarettes to help manage affect, i.e., emotions. From the types
of smoking identified (habitual smoking, smoking to increase positive
affect, to reduce negative affect, and psychologically addictive smok-
ing) and from a theoretical discussion of the dynamics involved in
their formation, possibilities exist for the development, testing, and
application of theories and techniques for producing cessation either
in a clinic or a natural setting. By identifying differences between
smokers in the psychological use of cigarettes, the typology makes it
possible to develop theories and techniques to reinforce behavior
change and to expand knowledge of the dynamics of smoking behavior.

These concepts are undergoing empirical identification and verifica-
tion at both the national level and in a variety of clinical settings
studying behavior change.

In one study (73), for example, which compared three methods of
aid to people who were trying to give up smoking, efforts were made to
assess the subjects’ progress, the nature of the change process, and the
social-psychological factors which influence the ability to give up
smoking and resist resuming. The investigators are analyzing their
data from the conceptual base of smoking types as well as from other
points of view in an examination of cessation processes.

The smoking typology is also being applied in an analysis of a survey
of adults’ and adolescents’ smoking habits and attitudes in the United
Kingdom (10). At the recent 1967 behavioral conference results were
presented showing the relation between these smoker types and nervous
irritation and relaxation smoking scales, wishing and trying to give up
smoking, and addiction indicators for both adolescents and adults.

190
There were other kinds of analyses described in this research which
provide the stimulus for further development and testing of theory.

In this country, a parallel set of surveys has been going on which
utilized many questions from the above-mentioned survey just as that
survey also borrowed from it. Cross-cultural comparisons are thus
possible.

The national surveys of adult smoking behavior, beliefs, and at-
titudes in this country stimulated, and were also based upon, an
organizing framework which discussed some dimensions of a model
for behavior change (6). This framework incorporated the concepts
related to the typology of smokers previously mentioned and also
leaned heavily on a behavior model developed originally to provide
a theoretical base underlying participation in a mass K-ray screening
program (3, 4, 12). Four dimensions of the framework are discussed
and postulated as being essential in considering whether smoking be-
havior change will or will not take place. They are: The motivations
for change (e.g., the exemplar role, economics, esthetics, mastery, and
others beside the health threat) ; the perception of the threat (e.g., the
awareness of the threat, the acceptance of the importance of the threat,
the personal relevance of the threat, and beliefs about the susceptibility
of the threat to intervention) ; the reasons for smoking in terms of
affect management, and the potential development and use of alterna-
tive psychological mechanisms; and factors supporting or inhibiting
continuing reinforcement (e.g., the role of social forces, interpersonal
influences, the mass media, the behavior and attitudes of certain key
groups, and the general level of acceptability of the behavior).

Backed by the longitudinal data at the national level and subject
to multivariate analysis, this conceptual framework can potentially
be developed to the point whereby the parts may be related quan-
titatively and qualitatively to each other and thus afford a more
dynamic interpretation of the behavior change under consideration.
The possibility also exists for the development of an instrument for
the prediction of change, as well as an opportunity for the verification
of some prospective findings reported earlier (14). These constructs
have also since been extended to considerations of the process of either
taking up smoking or remaining a nonsmoker (5).

In another area of investigation, one project (79) is concerned not so
much with individual differences but with cultural differences in val-
ues, attitudes, and behavior related to smoking among various ethnic
groups in the Southwest and has as its main assumption the probable
existence of a common core of psychosocial factors operating to pro-
duce different motivation patterns among young people socialized in
a particular cultural environment.

Another kind of research—that of the controlled experiment
manipulating one variable at a time with a number of small samples—

271-394 0 - 67-14 . 191
has advantages which were discussed at the 1967 behavior research
conference (8). The use of such laboratory methods and controls has
been shown to be particularly useful in communications research,
including the study of factors that affect a person’s acceptance and use
of health information. More systematic efforts are needed which will
relate the content of the message, the form of the message, the kind of
medium used, and the characteristics of the communicator to changes
in smoking behavior which are also related to the psychosocial nature
of the target audience. In particular, emotion-provoking communica-
tions need to be studied in relation to various factors that are known
to maintain actions, such as public commitment and conformity to
group norms.

As in the case with epidemiological investigations, however, it is
probable that more prospective research studies combining social-
psychological, sociological, and anthropological concepts must be car-
ried out before a better understanding of smoking behavior initiation
(or non-initiation), continuation, or change can be achieved.

192 |
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