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Related Documents:- 03685621-5775 Smoking & Health - Part 2 of 9
- 03685776-5930 Smoking & Health - Part 3 of 9
- 03685931-6085 Smoking & Health - Part 4 of 9
- 03686086-6240 Smoking & Health - Part 5 of 9
- 03686241-6395 Smoking & Health - Part 6 of 9
- 03686396-6550 Smoking & Health - Part 7 of 9
- 03686551-6705 Smoking & Health - Part 8 of 9
- 03686706-6854 Smoking & Health - Part 9 of 9
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Stock Number 01 7, OMIp021g..0
SMOKING
and
HEALTH
a report of the Surgeon General
0
The Health Consequences of Smoking.
p The Behavioral Aspects of Smoking
p Education and' Prevention
DHEW Publication No (PHS) i 79-50066'
U.S. DEPARTMENT OF HEALTH; EDUCATION, AND WELFARE
Public Health Service
Office, of the Assistant Secretary, for Health
Office on Smoking and Health
o3ssss38
THE SECRETARY'S FOREWORD
On January 11, 1964, the first Surgeon General''s Report on Smoking
and Health was published. It created' an instant-and jiustified-
worldwide reaction; For the reporta d'ocument of impeccable scientific
authority, established a frightening link between cigarette smoking
and several dlsabling or fatal diseases.
The report established that cigarette smoking is causally
related to lung cancer in men.
It revealed that cigarette smoking is directly related to il2ness
and death from heart disease and other ailments; thatt
cigarette smoking is the leading contributory cause of death
from chronic bronchitis and~ other lung disorders.
The report, in short, pronounced cigarette smoking a health
hazard of sufficient importance in the United States to:
warrant remedial'act'ion.
Today, 15 years after the original report, we publish a new Surgeon~
General's Report on Smoking and Health. This book is more than a
compendium of new data confirming the conclusions of the originall
report. For this document reveals, with dramatic clarity, that cigarette
smoking is even more dangerous-indeedy far more dangerous-than
was supposed in 1964.
The new report, for example, presents sobering information
about a subject not extensively treated in the 1964 report:
women and~ smoking. Among other things, the evidence
suggests that mothers who smoke during pregnancy face the
possibility of creating long-term, irreversible effects on their
babies: And as smoking levels among women go up, diseasee
and death rates go up also: lung cancer has inereased fivefold
among women since 1955. Women who smoke like men die like
men who smoke.
The report sheds new light on dramatically increased risks to
smokers exposed to certain occupational hazards. Workers in~
the asbestos, rubber, coal, textile, uranium, and chemical
industries, among others, face these risks.
And the new report, unlike its predecessor, takes up the
subject of smoking among children. The percentage of girls
aged' 12 to 14 who smoke, for example, has increased eightfold
since 1968. Among the age group 13 to 19, there are now 6
million regular smokers. One hundred~ thousand children
under 13 are regular smokers.
i
comprise a report on the health consequences of smoking, which the
Secretary of Health, Education, an6 Welfare is required~ by law to
submit to Congress each year. The remaining chapters deal with
behavioral aspects of smoking and with education and preventiom
This report is, in my judgment, a major contribution to knowledge
about smoking and health-and a major resource for physicians, public
health officials, educators and others who are concerned with
advancing the nation's health through a sound strategy of prevention:
Joseph A. Califano, Jr.
Secretary
Department of Health,
Education, and Welfare
January 11, 1979
v
Having established the clear danger of smoking and the legitimacy
of smoking as a public health issue, however, a final question remains:
How much can government usefully do to publicize the hazards of
cigarette smoking; to encourage citizens to stop smoking-or not to
start?
Cigarette smoking, after all, is not like most other environmental
hazards: It cannot be curbed simply through~massive public and privatee
expenditures, as in the case of water pollution abatement, on which
$265 billion will be spent in the next 10 years. Cigarette smoking is not
subject to the same kinds of government regulation and' control that
are now used, for example, to check the emission of toxic substances
into the environment. These hazards can be dealt with through
straightforward programs of abatement and st'rict regulation. When it
comes to smoking, there is, of course, a role to be played by regulation
and by economic and other incent'ives. But in a free society, research
and; education must be the major tools of any public-health program to
deal with smoking.
So the stepped-up smoking-and~health program launched by the
Department of Healths Education, and Welfare a year ago is primarily
one of research, education, and persuasion. I described; it last year, in
testimony before the House Subcommittee on Health and! the.
Environment, in these words:
'Make no mistake, our efforts are to reduce smoking. But they are
efforts grounded in persuasion and information that appeal to the
common sense of our citizens. They are not efforts based~ on~ coercion
and scare tactics. I have the greatest empathy for the millions of
Americans who: want to stop smoking, but who find it very, very
difficult to do so...
'...If our citizens...are given all the facts from government, or other
sources, and still d'o not wish to give up: a personal habit, however
hazardous, then, except for protecting the rights of non-smokers, I
think government can properliy d'o no more.'
How successful~ can such efforts be? Quite successful', to judge from
the record:
Today, more than 30 million Americans are ex-smokers. This does
not include the number of people who, after consid'ering the risks,
chose never to take up the habit; they must also number in the millions.
The number of cigarettes consumed per person in the United States
has declined from 4,345 in 1963 to 3,965 in 1978. In fact, per capita
cigarette consumption this past year is at its lowest level in 20 years.
Thesefact's, without a doubt,arein~ large part due to efforts by
public health agencies and voluntary groups to inform the public about
the risks of smoking.
iu
This document is significant for another reason It demolishes the
claims made by cigarette manufacturers and a few others fifteen years
ago and t'od'ay: that the scientific evidence was sketchy; that no link
between smoking and cancer was "proven." Those claims, empty then,
are utterly vacuous now. Fifteen years of additionall research
overwhelmingly ratify the original scientific indictment of smoking as
a contributor to disease and premature death. Ind'eed; even the
cigarette industry's own research from January 1964 throu& Decem-
ber 1973, at a cost of approximately $15 million, confirmed the lethal
dangers of cigarette smoking. Today there can be no doubt that
smoking is truly slow-motion suicide.
In truth, the attack uponi the scientific and' medical evidence about
smoking, is little more than an attack upon science itself: an attack
upon the epidemiological, clinical, and experimental research disci-
plines upon whichi these conclusions are: based. Like every attack upon
science by vested interests, fromi Aristotle's day to Galileo's to our own,
these attacks collapse of their own weight.
But why, the reader may nevertheless ask, should government
involve itself in an effort to broadcast these facts and to discourage
cigarette smoking?
Why, indeed? For one reason, because the consequences of smoking
are not simply personal and'privat'e. Those consequences, economic and
medical, affect not only the smoker, but every taxpayer.
When we consider two major nationall problems of health policy, we
find that cigarette smoking intensifies and complicates each one.
First among these problems is the spiraling cost of health care.
Health care costs nationwide now amount to $205 billion a; year-of
which the Federal Government pays $59 billion. Smoking accounts for
an estimated $5 to $8 billion in health care expenses; not to mention the
cost of lost productivity, wages, and absenteeism caused by smoking-
related illness; an annual cost estimated at $12 to $18 billion.
No person, given these staggering costs, can reasonably conclude
that smoking is simply a private concern; it is demonstrably a public
healthiproblem also.
A second major problem is that our health care system overempha-
sizes expensive medical technology and institutional care, while it
largely neglects preventive medicine and health promotion.
Certainly, if the government is to shift its health strategy toward
preventive rather than merely curative medicine, it cannot ignore
smoking. For snwking is the largest preventable cause of death in
America. When demographers look at death rates for diseases related
to cigarette smoking, they identify 84,000 deaths each year from lung
cancer, 22,000 deaths from other cancers, up to 225,000 deaths from
cardiovascular disease, and more than 19,000 deaths from chronic
pulmonary disease-every single one of them~ related to smoking. That
is why smoking is Public Health Enemy N'umber One in America.
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These efforts are not mere publicity;, the record suggests that every
timegovernment and voluntary agencies have intensified their efforts
to: spotlight the risks of smoking, more smokers have given up: the
habit and more have decided not to take it up.
Moreover, we know from surveys of public opinion and attitudes
that the great majority of smokers-90 percent-have either tried to
quit smoking or would probably quit, if only they could find an
effective way to do so.
These people need help.
So; too, do millions of children an& young people who must have the
facts if they are to make a truly informed choice whether to smoke.
Indeed, it is children who are the main focus of our efforts to inform
and' persuade: It is not'hing short of a national tragedy that so much
death and disease are wrought by a powerful habit often taken up by
unsuspecting children1'ured by seductive multimillion dollar cigarette-
advertising campaigns.
This new Report of the Surgeon Generali typifies the Department's
approach to the issue of smoking and healtK It is based on scientific
resear& Its purpose is to provide facts. Its persuasive power is in the
weight cf the scientific evidence.
We set out t'o publish it for three reasons: First, we wished to bring
together new information on smoking and health which has accumulat-
ed in the 1'5 years since SurgeonGeneral Luther Terry released the
epochall report of 1964.
Second; we wishedi to extend the area of inquiry into smoking and
healthi beyond medicine into the fields of education and behavioral
science. For many of the: remaining unanswered questions about
smoking and health are in these latter fields. We have some evidence
for example, that women smokers have more trouble giving up,
smoking than men-but why? Some observers believe.t'hat women are
more concerned than men about gaining weight wheni they stop
smoking. But in fact we do not know; the answers to that and other
question& about smoking must be pursued through future behaviorali
research.
Third and finally, we wished to provide a firm base of knowledge on
which health agencies throughout this nation-and the world-can
build their efforts to reduce cigarette-related death and disability. For
the problem of cigarette smoking is not just domestic; it is worldwide.
Smokers in the United States consume 615 billion cigarettes a year;;
worldwide, the consumption of cigarettes approaches three trillion
each year.
This, thens is the report: a compendium of 22 scientific papers on
smoking and health, commissioned by the Surgeon General of the
Public Health~ Service, compiled by 12 agencies of the Depart'ment of
Health, Educat'ion,, and Welfare, and reviewed by scientists who are
recognized experts in their fields of inquiry. Thirteen of the papers
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;u1d many other influences are encouraging young people to take up
<mukinl;,
Tlieconsideration of what is meant by "adequately informed" is a
Sciuntific and public health~policyproblem.
As this report shows, our knowledge of the relevant facts regarding
the health hazards of cigarette smoking'has increased manyfold since
19Ei'-3. And efforts at adequately informing the public have had' some
~uccess. According to survey data (Chapter 16), a: majority of smokers,
both adultsand teenagers, respond affirmatively to questions about
the health hazards of smoking andt'he desirability of quitting. Yet,
perhaps because nicotine is a powerful addictive drug, millions of
smokers seem~ unable to translate this information into personal action.
Further, we know so little about how to~ prevent smoking among
children and teenagers that the numbers of new smokers have
remainedl virtually constant.
Earlfier in this preface we not'e& changes that have taken~place in: the
composition of the smoking, population, in smoking behavior, im the
character of the: cigarette itself, and in~ smoking risks. We must take
these changes into account in our efforts to inform. If we can now
identify groups of people who are at high risk, what intervent'ions can
~ve design to reach them? Have previous educational efforts been too
broadly based? Do the changes in the nature of the cigarette argue for
a shift in emphasis, from less hazardous cigarettes to less hazardous
smoking? Are there specific instances where the weight of thee
scientific evid'ence an6 the magnitude of the health problem require
action by society, other than merely imparting information?
In addressing these questions, we must be sure we are active rather
than reactive in our approach. The hazards of cigarette smoking have
been established and the question has turned to what society's response
to~these hazards should be. If this report is successfuls it will encourage
the medical and public health communities to continue their search for
what the Advisory Committee: 15 years ago defined as "appropriate
remedial action."
Julius B. Richmond, M.D.
Assistant Secretary for Health
and Surgeon General
January 11, 1979
xv
I
cant relation between childt-ens" respiratory illhess and parental
smoking, (Chapter 11). Childrens' cigarette smoking habits are strongly
influenced by the smoking, habit's of family members and peers
(Chapters 17 and 18).
Minorities
The health consequences of cigarette smoking in minorities may be
particularly severe, yet little is knowni about these health consequences
at present. Survey data: indicate that the prevalence of cigarette
smoking among blacks exceeds that of whites (Appendix). Lung cancer
death rates among blacks exceed those of whites (Chapter 5). The
effects of maternal smoking on fetall development and infant healthi
may be especially significant among minority mothers with other risk
factors for complication of pregnancy (Chapter 8). Nonwhite workers
in industrial settings may be particularly susceptible to the combined
effects of cigarette smoking and occupational exposure to toxic agents
(Chapters 5 and'7).
Smoking and Occupational Exposure
In every race, sex, and age group;, blue-collar workers are especially
susceptible to the combined effect&of cigarette smoking and exposure
to toxic industrial agents (Chapter 7). Fumes from fluorocarbon
polymers are decomposed by the heat of burning cigarettes (Chapter
7); These and: other chemicals contaminate cigarettes, which are then
smoked (Chapter 7). Cigarette smoke contains many of the same
chemicals found to be workplace toxins, such as hydrogen cyanide and
carbon monoxide (Chapter 7). Exposure to coal dust, cotton dust,,
chlorine, and~ radiation combine additively with cigarette smoke to
produce lung damage (Chapters 6 and 7). Cigarette smoking acts
synergistically with exposure to asbestos to produce lung, cancer
(Chapters 5 and 7). Other documented examples of synergistic action
include rubber fumes; dust, and radiation from uranium mining
(Chapter 7). Studies have shown that cigarette smoking contributes t'oo
accidents in the workplace (Chapter 7).
Cigarette Smoking Behavior
The design of policy depends not only on our ability to identify high-
risk groups but also on our understanding of differences in the
cigarette-smoking behavior of these individuals. As numerous refer-
ences in Chapters 15-21 and the Appendix emphasize, there are serious
gaps in our understanding of the initiation of the smoking habit, the
nature of cigarette dependence and withdrawal, and the cessation of
smoking. Yet to designi and implement effective policies, we must
know how various target groups differ in each of these dimensions.
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numerous, as yet unid'ent'ified, dangerous substances remaining
(Chapter 14).
In addition to "tar" and nicotine, cigarette smoke contains a gaseous
phase with numerous components such as hydrogen cyanide, volatile
aromatic hydrocarbons, and carbon monoxide. Carbon monoxide, in
lparticular, has been identified throughout this report as a possible
crit~ical factor in coronary heart disease, atherosclerosis and sudden
death, occupationally related illness, chronic respiratory disease, fetal
gmowth retardationy and the noxious effect's of passive smoking
('Chapters 4, 6, 7, S; and 11). At present, we do not have standard,
reproducible measurements of the delivery of carbon monoxide in~ all
U.S. cigarettes. Yet, some published studies suggest that some
allegedly less harmfut cigarettes may have higher concentrations of
carbon monoxide. In Great Britain, the carbon monoxide delivery of
certain filter cigarettes exceeded that of other nonfilter cigarettes
(Chapter 14)'.
There is substantial experimental evidence, and some supporting
data from retrospective studies, that cigarettes with, reduced "tar" and
nicotine delivery should in principle have reduced risks of health
hazard (Chapters 2, 4 and 5). H'owever, there is only one single
controlled prospective study, quoted numerous times throughout this
report, of the effect of "tar" and nicotine content on mortality rates.
Such a study has not been repeated. The risks of overall mortality and
specific mortality from lung cancer and coronary heart disease were
lower in those smoking lower "tar" and nicotine cigarettes than in
those smoking higher "tar" and nicotine cigarettes. But the risks for
low "tar" and nicotine cigarette smokers were still significantly higher
than in nonsmokers. This study did not evaluate the risk of mortality
from other causes,,such as chronic obstructive lung disease. It does not
establish that low "tar" and nicotine cigarettes diminish the effect of
smoking on the unborn fetus or the developing child. Moreover, the
period of observation in this study was 1960 to 1972. Cigarettes
regarded as low in "tar" and nicotine during this time do not represent
current products. This study does not establish that currently available
low "tar" and nicotine cigarettes are necessarily less hazard'ous.
The "tar" and nicotine content of cigarettes is measured by
machines which smoke cigarettes according to a predetermined puff
rate, butt length, duration of puff, and volume of puff. An individual
smoker does not necessarily consume cigarettes in this standardized
manner. It is possible for a lbw "tar" and nicotine smoker to inhale in
one day much more of these constituents than ai smoker of cigarettes
with higher "tar" andl nicotine content. Some studies suggest that
individuals who smoke low "tar" and nicotine cigarettes may inhale
more deeply or smoke the cigarette further down to the butt to
compensate: fort'helowerconcentration of nicotine (Appendix). In
other experiments, individuals giiven low "tar" and nicotine cigarettes
xiu
Lung, and' Blood Institute, National Institutes of Health, Bethesda
Maryland.
Chapter 7.-Inte-raetion Between Smoking, and Occupational' Expo-
sures.
National Institute for Occupational Safety and' Health.
Jean G. Frenchy Dr. P.H., Health Scientist, National Institute for
Ocaupationall Safety and Health, Rockville, Maryland; Harvey P.
Stein, PhLD., Senior Chemist, National Institute for Occupational
Safety and Health, Rockville, Maryland; William J. McKay, M.D.,
Medical Officer, National Institute for Occupational Safety and
Health, Morgantowns West Virginia; Bruce E. Albright, M.D.,
Med'acali Officer, National Institute for Occupational Safety and
Health, Cincinnati, Ohio; George E. Casey, M.D., Medical Officer,
Nationall Institute for Occupational Safety and Health, R.ockville,.
Maryland; and C: Ilana Howarth, M.S., National Institute for
Occupational Safety and Health, Rockville, Maryland:
Chapter 8:-Pregnancyand Infant Health..
National Institute of Child Health and Human~Development.
Eileen G. Hasselmeyer, Ph.D., R.N., Chief, Pregnancy and Infancy
Branch, Center for Research for Mothers and Children, National
Institute of Child Health and Human Development, National
Institutes of Health, Bethesda, Maryland; Mary B. Meyer, M. Se.,
Associate Professor of Epidemiology, Johns Hopkins University
School~ of Hygiene and Public Health, Baltimore, Maryland;
Charlotte Catz, M.D., Pediatric Medical Officer, Pregnancy and
Infancy Branch, Center for Research for Mothers and Childten,
National Institute of Child Health and Human Development',.
National Institutes of H'ealthy Bethesda, Maryland; and Lawrence
D. Longo, M.D., Professor of Physiology and Obstetrics and
CivnFa~.tllnm~
increase the number of cigarettes they smoke. In this respect, there is
little epidemiological information concerning the: trade+off between
smoking a few higher "tar" cigarettes and smoking many lower "tar"
cigarettes, A few long-term follow-up studies suggest that many
smokers who voluntarily switch to low "tar" cigarettes may not
increase their frequency of cigarette consumption. The interpretation
the hazards associated with smoking is to quit.
no cigarettes at all, an6 that the single most effective way to reduce
hazards very much higher than would be encountered if they smoked
be cautioned that even the lowest yield of cigarettes presents health
more cigarettes or inhaling more deeply. And most of all, they should
monoxide. They should be warned'. that, in~ shift'ing to a less hazardous
cigarette, they may in fact increase their hazard if they begin smoking
available) levels of'other tobacco:smoke constituents, including carbon
levels of "tar" and nicotine but also (when the information becomes
caveats are in order: Consumers should! be advised to consider not only
however, that in presenting this information to the public three
Unti1 these scientific and behavioral issues are resolved, there can~be
no final assessment of the public healthi benefits of our present search
for less hazardous cigarettes. The preponderance of scientific evidence
continues, as ini 1966, to suggest that cigarettes with lower "tar" and
nicotine are less hazardous. It has become clear ini the years since,
undisclosed additives are themselves harmless.
proprietary matter. 1Wevertheless we do not know whether these
Finally, the successful marketing of these lbw "tar" and nicotine
cigarettes has require& the additioni of numerous flavor additives. The
nature and~ composition of these additives is to some extent a
habituated to cigarettes (Appendix).
has made it easier for our youth to experiment with and later become
the lowering of "tar" an& nicotine in cigarettes over the past 20 years
there is no conclusive evidence on this point, we need to know whether
cigarette consumption of potential new smokers (Appendix). Although
only to changes in the habits of current smokers, but also to the
The effect of a decrease in "tar" and nicotine content applies not
to a lower'"tar" cigarette.
of the motives and circumstances of an individual's decision to switch
of these studies is complicated, however, by our lack of understanding
Public Policy
The decision to smoke is a personal decision, but once this is said, it
remains unquestionably the responsibility of health officials to insure
that smokers and potential smokers are adequately informed of the
hazards. This is especially true in a society where hundreds of millions
of dollars are spent each year promoting cigarettes and where these
xiv
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sen
I
ACKNOWLEDGEMENTS
This report was prepared by agencies of the U.S. Department of
H'ealth, Education, and Welfare under the general editorship of the.
Office on Smoking and Health John M. Pinney, Director. These
agencies have asked that individual authors be listed, and this is
accomplished below.
Chapter 1.-i'ntradu,cti,on and Suman~aa-y:.
Office on Srnoking,and HealthL
Leonard M. Schuman, M.D., Professor and Director, Division~ of
Epidemiology, University of Minnesota, Minneapolis, Minnesota.
Chapter 2.-Mortality:
Center for Disease Control.
Elvin E. Adams, M.D.,, M.P.H., Practicing Internal Medicine, Fort
W orth, Texas.
Chapter 3.-Morbidit,y.
National Center forHealth~ Statistics.
Ronald W. Wilson, M.A., Chief, Health Status and Demographic
Analysis Branch, Division of Analysis, Nationall Center for Health
Statistics, Hyattsville, Maryland.
Chapter 4.-Cardiovascular Diseases.
N'ationall Heart, Lung, and Blood Institute.
G.C. McMillan, M.D., Ph.D:, Associate Director for Etiology of
Arteriosclerosis and Hypertension, Division of Vascular Diseases,
National Heart, Lung, and~ Blood Institute, National Institutes of
Health, BethesdaMaryland.
Chapter 5.-Cancer.
National Cancer Institute.
Chapter 6.-Non-Neoplastic Bronchapulmonary Diseases.
National HeartLung,,and Blood Institute.
Richard A. Bordow, M.D., Associate Research Physiologist, Universi-
ty of California at San Diego, San Diego, California; Claude J.M.
Lenfant, M.D., Director, Division of Lung Disease, National Heart,
Lung, and Blood Institute, National Institutes of Healthj Bethesda,
Maryland;, Sylvia Frank, Ph.D:, Consultant to Division of Lung
Disease, National Heart, Lung, and Blood Institute, National
Institutes of Health, Bethesda, Maryland; Malvina Schweizer, Ph.D.,
Assistant to the Director, Division of LungDisease National Heart,
Lung, and Blood Institute, National Institutes of Health, Bethesda,
Maryland; and Suzanne S: Hurd, Ph.D., Associate Director for
Planning and~ Evaluation, Divisiomof Lung Disease, Nationali Heart,.
Leonard S. Baker,, Expert, Office on Smoking and~ Health, RockvilUe,
Marylandi
Sandra: J. Brenman, Secretary, Office on Smoking and Health,
Rockville, Marylandl
Betty L. Budd, Secretary, Office on Smoking and Health, Rockville,
Maryland.
Harold E. Dahlgren, Editor, Informatics Incorporated, Rockville,
Maryland.
Lawrence Deyton, Public Health Anallyst, Office of the Assistant
Secretary for Health, Roekville, Maryland.
Ervin S. Duggan, Special Assistant to the Secretary, Office of the
Secretary, U.S. Department of Health, Education, and Welfare,
Washington, D:C:
Steve Fairbairn, Applications Manager, IPSD, Informatics Incorpo-
rated, Riverdale, Maryland.
Patricia B. Healy, Clerk, Office on Smoking, and Health, Rockville,
Maryland.
Jerry M. Hershovitz, Public Healthi Advisor, Environmental Health
Services Division, Bureau of State Services, Center for Disease
Control, Atlanta, Georgia.
Keith L. Hewitt, Editor, Informatics Incorporated, Rockville;
Maryland.
James W. Hicks, Chief, Technical Assistance Branch, Bureau of
Smallpox Eradication, Center for Disease Controi, Atlanta, Georgia.
Molly H'oary Data Entry Manager, IPSD, Informatics Incorporated,
Riverdale, Maryland.
Robert S. Hutchings, Associate Director for Health Information,
Office on Smoking and Health, Rockville, Maryland.
Bee B. Kafka, Administrative Officer, Office on Smoking and
Health, Rockville, Maryland.
Robert J. Kingon, Chief, Epidemiology and Program Studies
Section, Venereal' Disease Control Division, Bureau of State
Services, Center for Disease Control, At'lanta, Georgia.
Myra E. Kleinman, Clerk-Typist, Office on Smoking and Health,
Rockville, Maryland.
Elizabeth L. Lillie; Librarian, Iinformatics Incorporated's Rockville,
Maryland.
Ingrid B. Meyer, Manager, Biomedical Information, Informatics
Incorporated, Rockville, Maryland.
Franklin R. Miller, Public Health Advisor, Venereal Disease Control
Division, Bureau of State Services, Center for Disease Control,
AtlantaGeorgia..
Laura A. Miller, Special Assistant to the Secretary, Office of the.
Secretary, U.S. Department of Health, Education and Welfare,
Washington, D.C.
xxvil
1. INTRODUCTION AND SUMMARY.
Office on Srrnoking and Health
Ruth Behrens, Director, Center for Health Promotion, American
Hospital Association, Chicago, Illinois.
Richard A. Bordow, M.D., Associate Research Physiologist, Universi-
ty of California San Diego Medical Schools San Diego, California.
Lester Breslow, MLD., M.P.H., Dean, School of Public Health,
University of California at Los Angeles, Los Angeles, CaliforniaL
David M. Burns, M.D., Pulmonary Division,, University of California
at San Diego, San Diego, California.
Dee Burton, Ph.D., Director of Intervention, American H'ealth
Foundations New York, New York.
Thomas C. Chalmers, M.D., President and Dean, Mount Sinai
Medlcal'Center, New York, New York.
Paul Cleary, M.A., Research Associate, Department of Sociology,
University of Wisconsin, Madison, Wisconsin.
Sheldon Gl Cohen, M.D., Director, Immunology, Allergic and
Immunologic Diseases Program, National Institute of Allergy and
Infectious Disease, National Institutes of H'ealth4 Bethesd'a Mary-
land.
Theodore Cooper, M.D., Dean, Cornell University Medical College,
New York, New York.
Lester Curtiny Ph.D., Statistician National', Center for Health
Statistics, Hyattsville, Maryland.
Roy L. Davis, Director, Community Program Development Division,
Bureau of Health Education, Center For Disease Control~ Atlanta,
Georgia.
Robert M. Donaldson, Jr., M.D., Professor and Vice-Chairman,
Department of Internal Medicine, Yale University, New Haven;
Connecticut.
Joseph T. Doyle; M.D., Department of Medicine, The Albany Medicall
College of Union Universiity, Albany, New York.
Jeani G. French, Dr. P.H., Health Scientist, National Institute for
Occupational Safety and Health, Rockville, Maryland.
Gerald Ji. Gleich, M.D., Research Laboratory for Allergic Diseases,
Mayo Clinic, Rochester, Minnesota.
Robert S. Gordon, Jr., M.D., Special Assistant to the Director,
National Iinstitutes of Health, Bethesda, Maryland.
Vincent Garnell, PhLD., H'ealith Education Consultant Department
of Education, State of South Carolina, Columbia South, Carolina.
Dorothy E. Greeny Ph.D., Consulting Research Psychologist, Arling-
ton, Virginia.
Morton L. Grossman, M.D. Ph.D., Director, Center for Ulcer
Researchi and Education, Veterans Administration Wadsworth
Hospital Center, University° of California Los Angeles School of
Medicine, Los Angeles, California.
~
1S,. Psychosocial Influences on Cigarette Smoking.
National Iinst'itute on Drug Abuse
1!9. Modification of Smoking Behavior.
Nationall Institute on Drug, Abuse
PART I I I
EDUCATION AND PREVENTION
''4~ Youth Education.\ ational Institute of Education
21. Adult Education~
Office of Education
22. The Role of Health Care Provid'ers.
Center for Disease Control
M The Role of Educators.
Office of Education
Appendix: Cigarette Smoking in the United States, 1950-
1978.
Office on Smoking and Health
Index
On~ January 11, 1964, the Surgeon GeneralPs Advisory Committee on
Smoking and Health concluded: "Cigarette smoking is a health hazard
of sufficient importance in the United' States to warrant appropriate
remedialiaction."
Today, this report reinforces that major conclusion. It is backed up
by the weight of thousands of additional studies performed throughout
the world. Fifteen,years later, the scientific evidence on the health
hazards of cigarette smoking is overwhelhning.
The information in the health, consequences and! behaviorali parts of
this report has been brought together by 10 agencies of the United
States Public Health Scrvice: As will be seen, these agencies have
different research or regulatory missions but a common concern with
cigarette smoking as a contributor to illness, disability, and'death.
Since 1964, an estimated 30 million men and women have q;uit the
cigarette smoking habit. The prevalence of regular cigarette smoking
in the adult populationi has declined from approximately 42 percent to
33' percent (Appendix). Yet, in 1978, an estimated' 54 millioni men and
womeni smoked 615 billion cigarettes: Each year, the health damage
resulting from cigarette smoking costs this nation an estimated 27
billion dollars in medical care, absenteeism, decreased'work productivi-
ty, and accidents. A great fraction of these costs are borne by the
entire public-smokers and nonsmokers -through i health insurance,
disability pay.ments; and other private and taxpayer-supported! pro-
grams. In 1979, cigarette smoking is the single most important
preventable environmental factor contributing to illness, disability,
and death in the United'i States (Chapters 2 and 3).
This 1979 report describes our current knowledge of the health,
consequences of smoking;, the: behavioral aspects of smoking, and!
efforts in education and prevention. It presents strong conclusions
where they are warranted by the accumulated'i evidence. It provides
alternative working hypotheses when the available facts are not
sufficient to warrant conclusions. It suggests future lines of inquiry
where there are gaps in existing knowledge:
Adhering to this spirit of inquiry and recognizing the magnitude of
the public healthi problem, we must ask: What is our current
knowledge about "appropriate remedial action?" What scientific,
economic, and behaviorall facts are important for the design of public
policy toward cigarette smoking? What have we learned so far, and
where d'o we go from here?' To answ.er these questions, we must
confront three central facts: Individuals vary in their health riskss
associated with cigarette smoking. Individuals vary in their cigarette-
smoking behavior. The cigarette product itself i's changing.
vii
1':julL,tte N:. Murphy, Technical I'nformation Specialist, Bureau of
Iiualth Haducation, Center for Disease Control, Atlanta, Georgia.
Irnwnd K. Poole, Manager, Manuals and' Documentationy Infor-
matit,,; Incorporated, Rockville, Maryland.
'.t.:nrlall S. Pope, Public Health Advisor, Kidney Donor Activity
('hronic Dibeases Divisions Bureau of Epidemiology, Center for
V>; -, ~asc C'ontrol, Atlanta, Georgia.
("iiris Heisinger, Technical Director, IPSD, Informatics Incorporat-
~ d, l.iverdade, Maryland.
I)i)nalkl R. Shopland', Technical Information Officer, Office on
~mc~kini and Health, Rockville, Maryland.
I:arun~ M. Smith, Clerk-Stenographer, Office on Smoking and
Ile,tlthRockville, Maryland.
D.:rrry W. Sparks, Special Assistant to the Associate Director, Center
:~(ir Uisease Control, Washington Office,,Washington, D.C:
E;itellal M. Speaks, Clerk-Typist, Office on Smoking and Health,
I;'ockville, Maryland.
('arol M. Sussman` Technical, Science Editor, Office on Smoking, and,
Health, Rockuille, Maryland.
;elwN'n M. Waingrow, Public Health Analyst, Office on Smoking
and Health, Rockville, Maryland.
Ann, E: Wessel, Health Information Specialist, Office on Smoking
and Health, Rockville Maryland.
Paul Ji. Wiesner, M.D., Director, Venereal Disease Control Division,
Bureau of State Services, Center for Disease Control, Atlanta,
Georgia.
Molly A. Wolfe, Director, Clearinghouse Services Department,
I nformatics Incorporated, Rockville, Maryland.
xxvii
tal
>>y
,rs
3
Evidence is cited in this report that women may differ from men in
the initiation, maintenance, and cessation of smoking. It has been
suggested that the abstinence syndrome is more severe in women
(Chapter 15). Women are apparently more likely to fail in organized
cessation programs (Chapter 19). Survey data suggest an increase in
the prevalence of heavier smoking among younger females entering
the smoking population (Appendix).
In~ this respect, we need to study the effects of introducing filter
cigarettes in the 1950's and 1960's and the effects of the newer lower
"tar" cigarettes, in! t'he1970's upon the initiation ofsmoking;especiallyamong young women
(Appendix): We need to know whether advice is
effective in influencing, cigarette smoking, particularly among preg-
nant women during prenatal care.
Among children and teenagers, the experimental phase of cigarette
smoking (Chapter 17) may in fact be the critical point of intervention.
It is possible, and some investigators have suggested (Chapter 17); that
younger and older adolescents respond differently to different types of
antismoking intervention (Chapter 17). It also remains unclear
whether teenagers respond', more to contemporary peer pressure to
smoke or to adult smoking images (Chapter 17). Ifl adult family
members in fact have the most critical influence on t'eenage smoking
initiationthen the critical target population may be the adults and not
their children, (Chapter 17); Although the literature on the responsive-
ness of cigarette consumption to price is conflicting, some studies
suggest that the demand for cigarettes among teenagers may be more
price:sensitive (Chapter 18):
Survey data suggest t'hat individuals who attempt to quit cigarette
smoking have had considerably more success ini rapid and complete
cessation than in gradual reduction in the amount smoked (Chapter
15): Some studies in fact suggest that wiLhdrawal! symptoms are more
severe during gradual reduction (Chapter 15). Other studies suggest
that very few smokers can satisfy their addiction on less than 10 to 12
cigarettes daily (Chapter 16): On the other hand, there is some evidence
that lighter smokers are more successful at cessation (Chapter 18 and
Appendix): There is also inconclusive evidence that lower "tar" and
nicotine cigarettes can be a vehicle for cessation. These:results need to
be reviewed in light of the emergence of new personalized programs of
smoking cessation which have reported recent success (Chapter 16).
Finally, the available survey data indicate that the prevalence of
smoking is higher among minorities and blue-collar workers (Appen-
dix). Yet very little is known about motivations for initiation~ and
cessation of smoking among these individuals.
xi
CONTENTS
I1ntroductibn .............................................................. 5
,'~uznmary .................................................................10
Health Consequences of Smoking ...........................10
Mortality ..................................................... 10
Cause-Specific Mortality ............................. 12
Morbidity .................................................... 12
Cardiovascular Diseases ................................. 13
Cancer ........................................................ 15
Lung Cancer ............................................ 16
Cancer of the Larynx ................................ 16
Oral Cancer ............................................. 17
Cancer of the Esophagus ............................17
Cancer of the Urinary Bladder .................... 17
Cancer of the Kidney ................................ 17
Cancer of the Panereas.............................. 17
Experimental Studies ................................. 17
Non-Neoplastic Bronchopulmonary Diseases ....... 18
Interaction Between Smoking and
Occupational Exposures ............................... 19
Pregnancy and Infant Health ......................... 21
Birth Weight and Fetal Gtowth .................. 21
Perinatal Mortality .................................... 22
Lactation and Breast Feeding ..................... 22
Peptic Ulcer Disease ..................................... 23
Allergy and Itnmunity................................... 23
Involuntary Smoking ..................................... 24
Interactions of Smoking withi Drugs, Food
Constituents, and Responses
to Diagnostic Tests .................................... 25
Other Forms of Tobacco Use .......................... 27
Overalli Mortality ...................................... 27
Cancer ..................................................... 27
Tumorigenic Activity of Pipe and
Cigar Smoke Condensates........................ 28'
Cardiovascular Diseases .............................. 28'
Non-Neoplastic Bronchopulmonary Disease..... 28
Peptic Ulcer Disease .................................. 28
1-3
High Risk Populations
The adverse health effects of smoking vary considerably in their
nature and severity among individuals. They depend, for example, on
the duration and frequency of smoking, on the presence or absence of
concurrent illness or other environmental exposures, and on the
individual's, age and' sex. Some health~ effects are immediate, while
others may be delayed for years.
Most importantly, certaini individuals may be particularly prone to
these adverse health effects.
Women, youth, minorities, and' workers exposed to occupational
hazards in no way constitute an exhaustive list of. especially high risk
individuals. Every chapter in this report attempts to focus on
particular types of individuals of highest susceptibility. Cigarette
smoking acts synergistically with hypertension and elevated cholester-
ol to enhance the risk of developing coronary heart disease (Chapter 4):
Cigarette smoking may be a promoter or co-carcinogeni among those
individuals exposed to other cancer-causing agents (Chapter 5). It has
been suggested that there may be groups of smokers highly susceptible
to lung damage from cigarette smoke whose characteristics might be
detected by pulmonary function tests and histological studies or by the
presence of alpha-l-ant'itrypsin deficiency (Chapter 6). Those other risk
factors which may make maternal smoking more dangerous to the
fetus need' to be isolated, such as anemia, poor cardiac function,,
unfavorable age, and other socioeconomic factors (Chapter 8). Individ-
uals with rhinitis or asthma may in fact be more sensitive to the
nonspecific noxious effects of smoke (Chapter 10). Cigarette smoking
increases the risk of peripheral vascular disease in diabetics (Chapter
4).
Women and Smoking
The findings in the report have grave public health implications for
womem of all ages. Although the prevalence of cigarette smoking
among adult males has declined from approximately 53 percent in~ 1964
to 38 percent in 1978 (Appendix), the overall percentage of adult
female smokers remains virtually unchanged at about 30 percent
(Appendix). Cigarette smoking among younger women has increased,
particularly among teenage girls: The mortality rate from lung cancer
for women in 1978' was almost three times as high as in 1964, and the&
ratio of male to female mortality from lung cancer has decreased by
almost one-half (Chapter 5). Women who have smoking characteristics
similar to men experience overall mortality rates similar to men
(Chapter 2).
Cigarette smoking is a majior independent risk fact'or for fatal and
nonfatal heart attacks and' suddeni deathi in both men and women
(Chapter 4). The risk of heart attack is increased about tenfold in those
vut
t
I
of Allergy and Infectious Diseases, NationaP Institutes of Health,
Bethesda, Maryland; Robert A. Goldstein, 1VI.D.,, Ph.D., Chief,
Allergy and Clinical Immunology BranchImmunology, Allergic and
Immunolbgic Diseases Program, Nationall Institute of Allergy and
Infectious Diseases, National InstitutesofHealt'h Bethesda,
Nlaryland; and Sheldon G. Cohen, M.D., Director,, Immunology,
Allergic and Iimmunologic Diseases Program, National Institute of
Allergy and Infectious Diseases, National Institutes of Health,
Bethesda, Maryland.
Chapter 11.-InvoLuntarySmoking.
Center for Disease Control.
David Mi. Burns, M.D:, Pulmonary Division, University of California
at San Diego, San Diego, California.
Chapter 12.-Interactions of Smoking with Drugs, Food Constitu-
ents, and Responses to Diagnostic Tests.
Food and! Drug Administration.
Joseph H. Gainer, D.V.M., Acting Leader, Antibiotics in Animal
Feeds Staff, Bureau of Veterinary Medicine, Food and Drug
Administration, Rockville, Maryland; Charles M. Ise, Ph.D., Group
Leader, Division of Biopharmaceutics, Bureau of Drugs, Food and
Drug Administration, Rockville, Maryland; Phill H. Price, M.D.,
Medical Officer,, Division of Metabolism and Endocrine Drug
Products, Bureau of Drugs, Food and Drug Administration,
Rockville, Maryland; Robert Temple, M.D.,, Director, Division of
Cardio-Rena1 Drug Products, Bureau of Drugs, Food and Drug
Administration, Rockville, Maryland; Elizaheth M. Earley, Ph.D.,
Chief, Section of Cytogenetics, Division of Pathology, Bureau of
Biologics, Food and Drug,Administrations Bethesda, Maryland; John
E. Vanderveen, Ph.D., Acting Director, Division of Nutrition,
Bureau of Foods, Food and Drug Administrations Washington, D.
C.; Fred R. Shank, Ph.D., Assistant to the Director, Division of
Nutrition, Bureau of Food's, Food and Drug Administration,
Washington D. C.; S: I. Shibko, PhLD.,, Chief, Contaminants and
Naturali Toxicants Evaluation Branch, Division of Toxicology,
Bureau of Foods, Food~ and Drug Administration, Washington, D.
C.; Wiley W. Tolsons PhLD., Acting Direct'or,Bioresearch Monitoring
Staff, Bureau of Medical Devices, Food and Drug Administration,
Silver Spring, Maryland; and Joseph N. Gitlin, D.P.K, Assistant to
the Director for Clinical Radiology Systems, Bureau of Radiological
Health, Food and! Drug Administration, Rockville Maryland.
Chapter 13.-Other Forms of Tobacco Use.
Center for Disease Control.
David 1VI. Burns, M.D., Pulmonary Division, University of California
at Sani Diego, San Diego, California.
Chapter 14.-Constituents of Tobacco Smoke.
National Cancer Institute.
xix
women smokers who use estrogen-containing oral contraceptives
(Chapters 4 and 12).
The weight of evidence demonstrates that smoking during pregnan,
ey has,a significant adverse effect upon the well~being of the fetus and
the health~ of the newborn baby (Chapter 8).
There is abundant evidence that maternal smoking directly retards
the rate of fetal growth (Chapter 8) and increases the risk of
spontaneous abortion, of fetal d'eath,, and' of neonatal d'eath in
otherwise normall infants. More important, there is growing evidence
that children of smoking mothers may have rneasurable deficiencies in~
physical growth, intellectual development, and emotional development
that are independent of other known risk factors (Chapter 8). Children
of mothers who smoke during pregnancy do not cat& up with children
of nonsmoking mothers in various stages of development (Chapter 8).
Children and Teenagers
Smoking among teenage boys has remaine& virtually constant, and
among teenage girls it is actually increasing (Chapters 17, 18, and
Appendix). The average age of experimentation with cigarettes and
initiation of regular cigarette smoking has been decreasing (Chapter 17
and Appendix): Survey data suggest that teenage and early-youth
smoking habits are major determinants of lifelong cigarette consump-
tion. The mortality rates from all causes are significantly higher
among those who initiate smoking earlier in life (Chapter 2).
Evidence is accumulating that the health effects of smoking evolve
over a lifetime (Chapters 2, 3, 4, 5 and 6): Even when a morbid or fatat
consequence of smoking occurs in~ later life,, its antecedents may be
present even in childhood. For example, autopsy studies show that
cigarette smoking is associated with more severe and extensive
atherosclerosis of the aorta and coronary arteries (Chapter 4). Several
scientific questions have been raised about effects of smoking on the
severity of atherosclerosis in childhoodi and adolescence and the
premature development of adult forms of these lesions (Chapter 4).
Clinical, experimental, patholbgical, and epid'emiological studies in
humans and animals demonstrate that cigarette smoking produces
measurablie lung damage, even, in very young age groups (Chapter 6).
Young cigarette smokers, even those without respiratory symptoms,
have evidence of small airway dysfunction more frequently than
nonsmokers (Chapter 6). A number of recent studies have established a
higher prevalence of regular cough, phlegm production, wheezing, and
other respiratory symptoms in teenage and' young adult smokers ass
compared to nonsmokers (Chapter 6). The connection between~
pediatric respiratory illness and adult chronic respiratory disease has
been supported in prospective studies (Chapter 6).
Children and teenagers are susceptible in many ways to the effects
of others' smoking. Numerous research studies have found' a signifi+-
ix
I)orot}iy E. Green, Ph.D., Consulting Research Psychologist, Arling-
twn, Virginia.
Chapter 21.-Adutt Education.
Of fice of Education.
«'ialiam H. Creswell, Jr., Ed.D:, M.S., A.B., Professor and Head;
I>eptrrtment of Health and Safety Education, University of Illinois,
t'rhuna-Champaigns Illinois; Donald B. Stone, Ed.D., M.S., B.S.,
Professor of Health Education, Department of Health and Safety
b":ducation, University of Illinois, Urbana-Champaign, Illinois; and
Thomas W. O'Rourke, Ph.D., M.S., M.P.H., B.S., Associate Professor
of Health~ Education, U'niversityof Illinois, Urbana-Champaign,,
I ll i nois.
Chapter 22.-The Role of Health Care Providers;
Center for Disease Control.
Betty S: Segal,, Education Specialist, Bureau of Training, Center for
Disease Control,,Atlanta, Georgia.
Chapter 23,-The Role of Educators.
Office of Education.
Willfiam H. Creswell, Jh. Ed. D., M.S., A.B., Professor and Head,
Department of Health and; Safety Educationy University of Illinois,
Urbana-Champaign, Illinois; Donal6 B. Stone, Ed'.D., M.S., B.S.,
Professor of Health Education, Department of Health and Safety
Education, University of Illinois, Urbana-Champaign, Illinois; and
Thomas W. O'Rourke, Ph.D., M.S., M.P.H., B.S., Associate Professor
of Health Education4 University of Illinois, Urbana-Champaign,
Illinois.
Appendix.-Cigarette ~ Smoki-ng in the United States, 1950-197&
Office on Smoking and Health.
Jeffrey E. Harris M.D., Ph.D., Assistant Professor, Department of
Economics, Massachusetts Institute of Technology, Cambridge,
Massachusetts, Clinicat Associate, Medical Services, Massachusetts
Generat Hospital; Boston, Massachusetts:
The editors acknowledge with gratitude the many distinguished
scientists; physiciansand others who assisted in the preparation of this
report'by coordinating manuscript preparation, contributing critical
reviews of the manuscripts, or helping in other ways.
Josephine D. Arasteh, Ph.D., Health Scientist Administrator,
Human Learning and Behavior Branch, Conter for Research on
Mothers and Children; National' Institute of Child Health and
Human Devel'opment Nat'ional Institutes of Health, Bethesda,.
Maryland.
Roger W. Barnes, M.S., Staff Assistant to the Associate Commis-
sioner for Health Affairs, Food and Drug Administration, Rockville,
Niarylandl
xxi
The Changing Cigarette Product
The cigarette product itself has changed& considerably in the past 25
years. In 1954, when reports linking cigarettes to lung cancer first
appeared, less than 1 percent of cigarettesproduced were filter-tipped
(Appendix). The average "tar" delivery of cigarettes was approximate-
ly 36 mg. The average nicotine delivery was over 2 mg (Chapter 14 and
Appendix). In the years following this antismoking publicity, the
consumption of filter cigarettes rose rapidly, and the average "tar"
and nicotine deliveries of cigarettes decreased. By 1964, at the time of
the Surgeon General's first report, the market share of filter cigarettes
had reached 60 percent (Appendix): The average "tar" delivery of a
cigarette was about 23 mg. The average nicotine delivery was
approximately 1.3 mg (Chapter 14 and'Appendix):
Since thens the average "tar" and nicotine deliveries have continued
to decline. This was encouraged by a series of Government actions
beginning in 1966:In that year;thePublicHealth Service issued itsfinding, that "the preponderance of
scientific evidence strongly
suggeststhat the lower the'tar' and nicotine content of a cigarette, the
less harmful [will] be the effect." This was followed by the decision of
the Fod'eral! Trade Commission to begin measuring the "tar" and
nieotine yields of cigarettes and to permit manufacturers to begin
using this information in their advertising.
By 1977, the sales-weighted average "tar"' per cigarette approached~
17 mg; the sales-weighted average nicotine per cigarette approached'
11.1 mg (Chapter 14 and Appendix): This decline in "tar"' and nicotine ~
resulted from important changes in cigarette production technology-
the development of tobacco sheet reconstitution, improvements in
cigarette filtration and cigarette paper, the genetic manipulation of
tobacco strains; and increased use of plant stems and other tobacco
portions formerly regarded as waste. In the past 5 years, the market
share of cigarettes with "tar" delivery of 15 mg or less has increased'
dramatically and is now expected to exceed 30 percent. In 1977, nearly
one-half of the cigarette industry's $0:8' billion advertising and
promotional budget was devoted to these cigarettes.
How should we interpret these changes? What do these "tar" and
nicotine.measurements represent?
In one year, a typical one-pack-per-day smoker takes in 50,000 to
70,000 puffs through the burning column of a unique chemical factory
which contains over 2,000 known compounds (~Chapt'er 14). Many of
these compounds are established carcinogens (Chapter 14) and' appear
in the particulate phase or "tar" of the smoke. A nonspecific decrease
in "tar," however, does not necessarily imply a specific decrease in any
single dangerous substance. Moreover, there is as yet no unequivocal
evidence for the existence of "safe" levels of these carcinogenic
chemicals. Even if we could identify and selectively eliminate certai6
known carcinogenic chemicals from cigarette smoke, there may be:
xii
Snuff and Chewing Tobacco
and Oral Lesions . ................................... 29.
Constituents of Tobacco Smoke ....................... 29
Smoke Formation ...................................... 29
Toxic and Carcinogenic Agents .................. :. 30
Physiological Response to Cigarette Smoke.... 30
Reduction in Toxic Activity
of Cigarette Smoke ................................ 31
Behavioral Aspects of Smoking ..............................32
Education and Prevention ..................................... 33
References ............................................................... 35
1-4
8. Pregnancy and Infant Health.
National Institute of Child Health and Human Devel-
opment
9. Peptic Ulcer Disease.
National Institute of Arthritis, Metabolism and
Digestive Diseases
10. A1Nergy and Immunity.
National Institute of Allergy and Infectious Diseases
11. Involuntary Smoking.
Center for Disease Control
12. Interactions of Smoking with Drugs, Food Constituents,
and Responses to Diagnostic Tests.
Food' and Drug, Administration
13. Other Forms of Tobacco Use.
Center for Disease Control
14. Constituents of Tobacco Smoke.
National Cancer Institute
PART 11
BEHAVIORAL ASPECTS OF SMOKING
15. Biologicall Influences on Cigarette Smoking.
National Institute on Drug Abuse
16. Behavioral' Factors in the Establishment, Maintenance,
and Cessation of Smoking.
National Institute on Drug Abuse
17. Smoking ini Children and Adolescents: Psychosocial De-
terminants and Prevention Strategies:
National Institute of Child~ Health and~ Human Devel-
opment
xxx
1'J
.,
TABLE OF CONTENTS
I''w ;ccretary's Foreword
I''rcI acc
.1'ck nOwlcdgements
l. IntroGiuction and Summary.
Office on Smoking and Health
PART I
THE HEALTH CONSEQUENCES
OF SMOKING
2. Mortality.
Center for Disease Control
3. Morbidity.
National Center for Health Statistics
4. Cardfiovascular Diseases.
National Heart, Lung, and~ Blood Institute
5. Cancer.
National CancerInst'itute
6. Non-Neoplastic Bronchopulmonary Diseases.
National Heart, Lung, and Blood Institute
7. Interaction Between Smoking and Occupational Expo-
sures.
National Institute for Occupat'ional, Safety an& Health
to monitor the scientific literature on smoking and health. This
surveillance of world literature was performed by the National
Clearinghouse for Smoking and'Health (now succeeded by the Office on
Smoking and Healt!h). The updated report's were issued in 1967, 1968,
1969, 1971, 1972, ,1973, 1974, 1975, 1976, and 1978.
This current 15th anniversary volume on smoking and health is
offered as a detailed review and reappraisal of smoking and health
relationships. Its content's are the work of numerous scientists both
within~ and' outside the Department of Healt'h, Education, and~ Welfare.
All are acknowledged elsewhere.
On the following pages, this introductory chapter seeks to summa-
rize the principal findings and extensions of knowledge contributed by
the scientific community over these 15 years: An attempt has been
made to highlight particularly the earlier gaps in knowledge that have
been closed or shortened in the intervening period.
0
Summary
Health Consequences of Smoking
Mortality This 1979 appraisali strengthens earlier conclusions as to the relat'ion-
ship between smoking and mortality: Materials reviewed include the
seven original prospective studies and new data derived from long-
term follow-up of three: of these investigations: the British doctors'
study (20 years), the H'ammond study (12 years) and that initiated by
Dorn (16 years). Also reviewed are data from Japanese and Swedish
prospective studies. The overall findings yieU quantitative results over
time whi& are substantially identical with earlier conclusions. These
findings include:
1. The overall mortality ratio for all male current cigarette smokers,
irrespective of quantity, is about 1.7 (70 percent excess) compared to
nonsmokers.
2. Mortality ratios increase with amount smoked. The two-pack-a-
day male smoker has a mortality ratio of 2.0 compared to nonsmokers.
3. Overall' mortality ratios are directly proportional to the duration
of cigarette smoking. The longer one smokes, the greater the risk of
dyi ng.
4. Overall mortality ratios are higher for those who initiated their
cigarette smoking at younger ages compared' to those who began
smoking later. ,
5. Overall mortality ratios are higher among cigarette smokers who
inhale than among those who:d'o not.
6. Although mortality ratios for smokers are highest at the younger
ages and decline with increasing age, the actual number of excess
deaths attributable to cigarette smoking increases with age.
1-10
Introduction
In the 15 years which have elapsed since the Report of the Advisory
Committee on Smoking and Health to the Surgeon General of the U.S.
Public Health Service (15), there has been an increasing number of
scientific studies on the relationship between tobacco consumption an&
health. Where the 1964 Committee had access to some 6,000 articles in
the world literature on smoking and health; there are now, more than
30,000 such articles. In~ fact, no soun& epidemiologic study of chronic
disease today would omit frofn its design a history of tobacco use as a
significant factor. It is on this great'Uy expanded source of data that
this current review and re-evaluation of the evidence on the hazard of
smoking to human health is based.
For historical perspective, it should be remembered that concern
over the effect of tobacco on health did not begin with the Report to
the Surgeon~ General, although that evaluat'ion was the first American
review and judgmental analysis of the tobacco hazard for all aspects of
human mortality, morbidity, and specific diseases other than lung
cancer. Indeed, almost from the moment of its introductiom into
Europe im 1558; the Nicotiana tabaeum prompted serious concern over
the effects whi& uses of this leaf had on~human health. In less than 60
years, tobacco had become a staple agricultural commodity in Virginia
and its principal currency. The "tobacco culture" expanded rapidly
bothi societally and agronomically in America; in Europe,, in the 17th
Century, Simonis Paulli published his treatise "On the Abuse of
Tobacco" (6).
Although the growth of tobacco use has been extensively document,
ed, reliable data on its use within the total ULS, population did not
become available until 1880 (8). Since then, per capita tobacco
consumption has increased almost three-fold, with dramatic changes in
its forms of use. Prior to World War I, tobacco chewing was the
principal use in the United States, but the 1920's saw cigarette
consumption, particularly of prefabricated cigarettes, increase astro-
nomically as use of chewing and other smoking tobacco declined. A
cigarette consumption plateau im the 1930's was followed by a: sharp
increase during World War II, when widespread adoption of the
cigarette habit by women was added t'o large-scale consumption by
American troops. These changes in overall consumption and forms of
tobacco use had marked influences on mortality and disease patterns.
Concern over the effects of tobacco use on health increased over the
years, but it was not until the 20th century that systematic scientific
studies of the problem were launchedl Clinical impressions and
suspicions had been recorded and some had persisted for decades and
centuries before appropriate tools for scientific investigation were
developed. For example, the relationship between cancer of the lip and'
tobacco use was noted by Holland early in the 18th century (5) and
Soemmerring made the same observation in 1795 (13). Not until 1920,
1-5
19
Edward Lichtenstein, Ph.D, Professor of Psychology, College of Arts
and Sciences, University of Oregon, EugeneOregon.
William M. Marine, M.D.,, M.P.H., Professor and Chairman, Depart-
ment of Preventive Medicine, University of Colorado Medical
Center, Denver, Colorado.
James T. Massey, Ph.D., Mathematical Statistician, Office of Data
Systems, National Center for Health Statistics, Hyattsville, Mary-
land.
Joseph D. Matarazzo, Ph.D., Chairman, Department of Medical
Psychology, Health Sciences Center, University of Oregon, Portland,
Oregon.
Alfred! McAlister, Ph.D., Department of Health Services, School of
Public Health, Harvard University, Boston, Massachusetts.
William McGtaire, Ph.D., Professor, Department of Psychology, Yale
University, New Haven, Connecticut.
Simoni A. McNeely, Senior Program Coordinator, State and Local
EdUcationi Programs, Bureau of Elementary and Secondary Educa-
tion, U.S. Office of Education, Washington, D. C.
Harold A. Menkes, M.D., Associate Professor of Medicine Depart-
ment of Medicine, Johns Hopkins University, Baltimore, Maryland.
Ann M. Milne; Ph.D., Senior Associate, Natioaal Institute of
Education, Washington, D. C.
Kenneth Moser, M.D., Professor of Medicine and Director, Pulmo-
nary Division, University of California at San Diego, San Diego,
California.
Ian M. Newman, Ph.D., Professor and~ Chairman, Health Education,.
School of Health, University of Nebraska, Lincoln, Nebraska.
Albert Obermans M.D., Director, Division of Preventive Medicine,
School of Medicine, University of Alabama, Birmingham, Alabama.
Ralph S. Paffenbarger, Jr., M.D.,, Professor of Epidemiology,
Department of Health Services, California State Health Depart-
mentBerkeley, California.
Richard Peto, M.D:, Radcliff Clinic, Oxford University, Oxford,
England.
Malcolm C. Pike, Ph~D.,, Department of Community Medicine and
Public Health, University of Southern California School of Medicine,
Los AngelesCalifornia.
Umberto Saffiotti, M.D., Chief, Laboratory of Experimental
Pathology, Nationall Cancer Institute, Nationall Institutes of Healthy
Bethesda, Maryland.
John Salvaggio, M.D., Henderson Professor of Medicine, Depart-
ment of Medicine, TulaneUniversity; New Orleans, Louisiana.
Marvin A. Schneid'erman4 Ph.D., Acting Associate Director for
Science Policy, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland~
xxiv
the Advisory Committee to the Surgeon General of the Public Health
Service on Smoking and Health (15):
1. Cigarette-smoking males were found to have a 70 percent excess
risk of mortality over nonsmokers. Female smokers were found to have
an elevated risk of mortality, but less than that of males.
2. Cigarette smoking was judged to be causally related to lung
cancer in men, the magnitude of the effect of cigarette smoking far
outweighing all other factors. A similar trend was noted in females,
but studies then available presented insufficient grounds for a firm
jud'g-ment on causality (4). Included as evidence in the judgment of
causality were the several findings of a dose-response relationship: The
risk of death from lung cancer increased directly with duration of
smoking, number of cigarettes smoked per day inhalation, and,
indirectly, with age when smoking began; discontinuance of smoking
lowered the risk. For the combined group of pipe, cigar and pipe, and
cigar smokers, the risk of lung cancer was greater than for
nonsmokers, but was much less than for cigarette smokers.
3. Cigarette smoking was judged to be the most important of the
causes of chronic bronchitis in both men and women in the United
States and was found to increase the risk of dying from chronic
bronchitis and emphysema.
4. Male cigarette smokers were foun& to have significantly higher
death rates from~ coronary artery disease than nonsmoking males. The
data then available were borderline for a judgment of causality by the
rigid criteria employed'for all disease entities.
5. A causal relationship was not established' at the time for a number
of other cardiovascular diseases.
6. Significant associations between several other cancer sites and
tobacco use were judged! to be causal, including pipe smoking and lip
cancer, and cigarette smoking and laryngeal cancer.
7. Although the evidence revealed~associations between cancer of the
oral cavity and the several forms of tobacco use, between such tobacco
use and esophageal cancer, and' between cigarette smoking and urinary
bladder cancer, the data subjected to the judgment criteria did not at
that time support a judgment of causality.
A number of other diseases or conditions suggested to be associated
with smoking by clinical impressions or by showing excess mortalities
in the prospective studies were also scrutinized. They included: peptic
ulcer, tobacco amblyopia, cirrhosis of the liver, accidents, influenza and~
pneumonia, and low infant birth weight.
In the instance of peptic ulcer, epidemiologic studies indicated a
consistent excess risk of mortality from peptic ulcer, particularly
gastric ulcer, among cigarette smokers, but in 1964 a judgment of
causality could not be made.
Tobacco amblyopia had been clinically associated'with~pipe and'cigar
smoking, but the Committee could find'i no substantiation of this
1-8
7. Former cigarette smokers experience declining overall mortality
ratios as the years of discontinuance increase. After 15 years of
cessation, mortality ratios for former cigarette smokers are similar to
those who never smoked. Although mortality ratios for any given age
for former smokers are directly proportional to the amount smoked
before cessation and inversely related to the age of smoking initiation,
cc»ation~ of smoking does diminish such individuals' risk regardless of
these former factors, provide& they are not ill at time, of cessation.
(Actually, the mortality ratios among those who had discontinued
smoking loss than 1 year before enrollment in several of thee
prospective studies were higher than for current cigarette smokers.
This was also manifest in the total mortality rates for former cigar and
pipe smokers. Further analyses separating those who stopped smoking
because of illness from those ex-smokers who stopped for other reasons
revealed higher mortality rates among the former.).
8. Cigar smoking, is not without risk of increased mortality. The
overall mortality ratios for cigar smokers are somewhat higher than
for nonsmokers and are directly proportional to the number of cigars
smoke&per day.
9: Pipe smoking seems to have a slight effect in increasing overall
mortality, but individuals who combine their pipe smoking (or cigar
smoking)mith cigarette smoking experience a level of risk of mortality
intermediate between those who smoke only pipes or cigars and those
who smoke only cigarettes.
A number of new findings in the relationship between smoking and
overall mortality were found over the 15-year interval:
1. Calculations from prospective study data have indicated that life
expectancy at any given age is significantly shortene& by cigarette
smoking. For example, a 30- to 35-year-old, two-pack-a-day smoker has
a life expectancy 8' to 9 years shorter than a nonsmoker of the samee
age.
2. Overall mortality ratios increase with the "tar" and nicotinee
content of the cigarette. For smokers of low "tar" and~ nicotine,
cigarettes (less than~ 1.2 mg nicotine and less than 17.6 mg "tar"),,
overall mortality ratios are 50 percent greater than for nonsmokers
and 15 to:20 percent less than for all smokers of cigarettes.
3. For the 1964 report, data were inadequate for firm judgments on~
the mortality status of female cigarette smokers. Adequate follow-upp
in, the prospective studies during these past 15 years has reveale&
mortality ratios for female cigarette smokers somewhat less than those
for male smokers. This difference is deemed to be due to differences in~
exposure (later age of initiation, fewer cigarettes per day, and use of
cigarettes with lower "tar" and nicotine content). Female dose-
responses (quantity, age at initiation, duration of smoking, inhalationj
"tar" and nicotine content): are the sarne as for male cigarette smokers.
1-11
The 1964 Report did not address kidney or pancreatic cancer. While
retrospective studies were not examined, the seven prospective studies
indicated that the average mortality ratio for kidney cancer was 1.5.
Present knowledge about the relationship between smoking and the
various cancers is summarized below, excerpted from~ the conclusions
to be found in Chapter 5. As will be seen, the evidence is now
overwheltning.
Lung Cancer
1. Cigarette smoking is causally related to lung cancer in both men
and women.
2. The risk of develbping lung cancer is increased with increasingg
dosages of smoking as measured by: number of cigarettes smoked per
day, duration of smoking, age of initiation of smoking, degree of
inhalation, "tar" and nicotine content of cigarettes smoked, and
several other measurements.
3. Lung cancer mortality rates in women are increasing more rapidly
than in men and, if present trends continue, will be the leading cause
of cancer death in~women in the next decade.
4. Use of filter cigarettes and smoking of cigarettes with lower
amounts of "tar" and nicotine decrease lung cancer mortality rates
among smokers; however, these rates are significantly elevated
compared toxates for nonsmokers.
5. Ex-smokers experience decreasing lung cancer mortality rates
which approach the rates of nonsmokers after 10 to 15 years of
cessation. The residuat risk of developing, lung cancer in ex-smokers is
proportional to the overall dosage of lifetime cigarette-smoking
exposure, an&inversely related t'o the interval since cessation.
6. Pipe and cigar smokers have lung cancer mortality rates above
nonsmokers, but these rates are lower than those for cigarette
smokers:
7. Certain occupationall exposures can act synergistically with
smoking to significantly increase lung cancer mortality rates far above
those resulting from either exposure alone.
Cancer of the Larynx
8. Cigarette smoking is a significant causative factor in the
development of cancer of the larynx in men and women and is directly
related to several measures of dosage.
9. Pipe and cigar smokers experience approximately the same risk as
cigarette smokers for cancer of the larynx.
10. There appears to be a synergistic effect between smoking and
alcohol intake,, as well as between asbestos exposure and smoking, for
laryngeal cancer.
t
I
1-16
disease, smoking acts synergistically to increase the effective risk by
joining the risks attributable to hypertension and to smoking alone.
10. Cigarette smoking is a major risk factor for ischernic peripheral
vascular disease of arteriosclerotic type; cigarette smoking increases
appreciably the risk of peripheral vascular disease in diabetes mellitus.
11. Cessation of cigarette smoking improves the prognosis of
arteriosclerotic peripheral vascular disease and is advantageous to its
surgical treatment.
12. Cessation of smoking reducesthe risk of mortality from coronary
heart disease, and' after 10 years off cigarettes this risk approaches
that of the nonsmoker.
13. The relationship of smoking to the incidence of stroke is not
estakilished; however, an association with subarachnoid hemorrhage
has been reported in women.
In summary, for the purposes of preventive medicine, it can be
concluded that smoking is causally related to coronary heart disease
for both men and women~in the United States.
Cancer
The strongest evidence of a causal relationship: between tobacco use
and disease was delineated for lung cancer in the 1950's and 1960's and
subjected to the rigid criteria of appraisal in the 1964 Report. In the
intervening years, additional epidemiological, clinical, autopsy, and
experimentall studies have augmented and strengthened the earlier
conclusions, particularly with regard to women smokers, for whom
only preliminary data were then available.
New evidence has also accumulated since 1964 with respect to the
relationships between tobacco use and cancer of the larynx, oral cavity,
esophagus, urinary bladder, kidney, and pancreas:
In the case of laryngeal cancer, the accumulated evidence since 1964
has strengthened, but not materially changed, the conclusions of the
1964 Report.
In the case of cancer of the oral cavity, the 1964 Report had to base
its conclusions primarily on retrospective studies because of the
diversity of sites, their varying incidence of tobacco exposure, and the
relatively small numbers derivable in the early years of the prospective
studies. These studies, unfortunately, varied in approa& and either did
not separate the severall sites of the oral cavity or found the classes of
smoking too numerous for testing their significance: Thus, the only
firm judgment which could then be made was that a causal
relationship exists between pipe smoking and cancer of the lip.
The 1964 Report found' that an association existed betweeni tobacco
use and esophageal and urinary bladder cancer, but the Committee
could not determine from the available data whether there was a
causal relationship.
1-15
®
;,.,onar(i `,I. Schuman, M.D., Professor and Director, Division of
Universityof Minnesota, Minneapolis, Minnesota.
1. st:likoff, M.D., Professor, Mount Sinai, Medical Center,
~'<<rk, New Y"ork.
1;r n:u l 1.. 5himkin, M.D., Professor of Community Medicine and
r j;:,t,w~~,~V, 1)epartment of CommunityMedieine University of
~':,:if(jrni,uat San Diego, San Diego, California..
I.. Steinfeld; M.D., Dean, Medicat College of Virginia,
:i~,irnro,nrl %'inl,Yinia.
«~:Ili:rrnH'. Stewart, M.D., Professor, Department Preventive
',: i'ii ine and Public Health, Louisiana State University; New
r in!ian~, Louisiana.
%tidn(jn Tcrris, Mi.D., Professor and Chairman, Departrnentof
('~)rnmunity and Preventive Medicine, New York Medical College,
\(-w F<jrk, New York.
Luther Terry, M.D., President-Director, University Associates,
W;rhinVton, D.C:,
~icI,hen f3. Thacker, Mi.D., Chief, Consolidated Surveillance and
r~'~,mmunicaition Activity, Bureau of Epidemiology, Centerforf ('ontrol, Atlanta, Georgia.
T. (': T,~o; Ph.D., Chief, Tobacco Laboratory Plant Genetics and
Gcrmlrlirsm Institute, Unit'ed' States Department of Agriculture,
St:iznce and, Education Administration, Beltsville Agricultural
IC,- search Center, Beltsville, Maryland.
.%tary G'. Turner, Assistant Superintendent, Division of Adult and
(°ontinuing Education, Public Schools of the District of Columbia,.
«'ashinltUon, D. C,
John J. Witte, M.D:, Medical Director, Bureau of Health Education,
t'en~ter for Disease Controly Atlanta, Georgia.
Frit~z P. Witti, Editorial'Consultant, Alexandria, Virginia,
Ernst L. ti'ynd'er, M.D., President, American Health Foundation,
New York, New York.
Samueli S. C. Yen,, M.D., Professor and' Chairman, Department of
Reproductive Medicine, University of California at San Diego, San
Diego; C<ilfifornia.
Louis A. Zurcher, Ph:D., Provost and ' Dean, Graduate Schooli
Virt,=inia Polytechnic Institute and State University, Blacksburg,
1'irginia.
Finally,, the editors acknowledge the help of the following staff who
arnon~.r many others assisted in the preparation of the report.
Erica W. Adams, Editor, Informatics Incorporated, Rockville,
tilarviand.
William D. Adams, Management Consultant, Bureau of Laborato-
ries, Center for Disease Control; Atlanta, Georgia.
John L. Bagrosky, Program Analysis Officer, Office on Smoking,and
Health, Rockville, Maryland.
xxv
.-,
~
C.r
~
~;~
.
~J' ~
~i
CC
O
8
9
11. There is a substantial decrease in the risk of developing cancer of
the larynx with long-term use of filter cigarettes compared to the use
of nonfilter cigarettes; ex-smokers, after 10 years of cessation, have
mortality rates which approximate those of nonsmokers.
Oral Cancer
12. Epidemiolbgieal studies indicate that smoking is a significant
causal factor in the development of oral cancer. The risk increases with
the number of cigarettes smoked per day.
13. Pipe and cigar smokers experience almost the same high risk for
oral cancer as experienced by cigarette smokers.
14. A synergism exists between smoking and alcohol consumption for
oral cancer.
Cancer of the Esophagus
15. Cigarette smoking is a causal factor ine t'he development of cancer
of the esophagus, and the risk increases with~ the amount smoked.
16, The risk of esophogeal cancer for pipe and cigar smokers is about
the same.as that for cigarette smokers.
17. A synergism~ also exists for esophageal cancer and the marked
use of alcohol and cigarette smoking.
Cancer of the Urinary Bladder
18: Epidemiological studies have demonstrated a significant associa-
tion between cigarette smoking and bladder cancer in both men and
womem
19. Cigarette smoking acts independently and synergistically with
other factors, such as occupational exposures, to increase the risk of
developing cancer of the urinary bladder.
Cancer of the Kidhey
20. Cigarette smoking is associated with cancer of the kidney for
men. No data exist to substantiate a relationship for women.
Cancer of, the Pancreas
21. Cigarette smoking is related to cancer of pancreas, and several
epidemiological studies have demonstrated a: dose-response relation-
ship.
Experimental Studies
22. Ekperimentall studies on a variety of animal models have
confirmed the carcinogenic effects of tobacco smoke and its constitu-
ents oniseveral sites including lung, larynx, esophagus, and oral cavity.
1-17'
ltichaell R. Guerin, PND.,, Head of Bio-Organic Analysis Sectioni
AnalyticaliChemistry DivisionOak Ridge National Laborat'ory, Oak
iticdl;e, Tennesse.
Mariani Hamburg, Ph.D., Professor of Health Education, New York
</ niversity, New York, New York.
Jeffrey E. Harris, M.D., Ph.D., Assistant Professor Department of
Economics, Massachusetts Institute of Technology, Cambridge,
Niassachusetts; Clinical! Associate, Medicall Services, Massachusetts
Generall Hospital, Boston, Massachusetts.
Eillcen G. Hasselmeyer, Ph.D., R.N, Chief, Pregnancy and Infancy
Branch, National Inst'itute of Child Health and Human Develop-
ment, National Institutes of Health, Bethesda, Maryland.
Godfrey Hochbaum, Ph.D., Department of Health, Educations School
of Public Health, University of North Carolina, Chapel Hill, North
Carolina.
Dietrich Hoffmann, Ph.D., Chief, Divisioni of Environmental Carci-
nogenesis, Naylor Dana Institute for Disease Prevention, American
Health Fbundation, Valhalla, New York.
John H. Holbrook, M.D., Assistant Professor of Internal Medicine,
University of Utah Medfcall School, Salt Lake City, Utah.
Priscilla B. Holman, M.S. Ed., Writer-Editor, Bureaui of Health
Education, Center for Disease Control, Atlanta, Georgia.
Daniel Horn, Ph.D., Frenchtown, New Jersey.
Jerome H. Jaffe, M.D., Professor of Psychiatry, Department of
Psychiatry, College of Physicians and Surgeons of Columbia
University, New York, New York.
Robert B. Jaffe, M.D;, Professor and Chairman, Department of
Obstetrics, Gynecology, and Reproductive Sciences, University of
California at San Francisco, San Francisco, California.
Herschel Jick, M.D,,, Boston Collaborative Drug Surveillance
Program, Boston University Medicali Cent'er, Waltham, Massachu-
setts.
William, J. Jusko, Ph.D., Director, Clinical' Pharmacokinetics Labora-
tory, Millard! Fillmore Hospital, Buffalo, New York.
Harriet Page Kennedy, Technical Writer, Office of Cancer Commu-
nications, National Cancer Institute, Bethesda, Maryland.
Philip Kimbel; M.D., Head; Pulmonary Disease Sections Albert
Einstein Medical Center, Philadelphia, Pennsylvania.
Norman Allan Krasnegor, Ph.D., Deputy Chief, Clinical Behavior
Branch, Division of Research, National Institute on Drug Abuse,
Alcohol, Drug Abuse and! Mental Health Ad!ministration Rockville,
Maryland.
Elizabeth, A. Lee, Staff Specialist, American Hospital Association,
Chicago, Illinois:
Howard Leventhal, Ph.D., Professor of Psychology, Department of
Psychology, University of Wisconsin, Madison, Wisconsin.
xxiii
phages from smokers responding abnormally to migration inhibitory
factor (MIF) or antigen challenges, an& T lymphocytes in smokers
showing a diminished response to phytohemagghitinin (PHA), com-
pared to those of nonsmokers. However, the role of these alterations in
lung damage is unclear at this time.
11. Individuals with severe alpha,l-antitrypsin deficiency have an
excess risk for developing emphysema, and the onset of symptoms is
probably abbreviated in, these persons by smoking. It is unclear if
individuals with mild deficiency represent a group at special risk.
12. Other genetic factors may play a role in determining the risk for
COLD, but these are far outweighed by the effect of cigarette
smoking.
13. Certain occupations, primarily those exposing workers to dusty
occupational' environments, are related to COLD, and this relationship
is increased further by cigarette smoking. In none of these studies are
occupational effects as strong as smoking.
14. Although an increased risk of COLD due to air pollution probably
exists, it is small compared to that due to cigarette smoking under
conditions of air pollution, to which the average person is exposed.
15, Childhood respiratory disease appears to be a risk factor for
respiratory symptoms as an adUlt. However, cigarette smoking appears
to be a: more important factor in increasing the risk for developing
these symptoms.
Interaction Between Smokzng and Occupaticmal Exposures
An extensive review of the lit'erature on lung cancer in chromium an&
nickel workers and in uranium miners was prepared (12) for the 1964
Advisory Committee. Other studies had examined the relationships
among coali gas and asbestos workers as well as in exposures to arsenic,
hematite, isopropyl oil, beryllflums and copper. Significant excess lung
cancer mortality was noted for chromat;e, nickel, coal gas and asbestos
workers and for uranium miners; exposure to arsenic, hematite,
beryllium, and' copper remained suspect.
At the time of the 1964 report it was noted that "it must be
emphasized quite strongly that the population exposed to industrial
carcinogens is relatively small" (compared to the size of the smoking
populhtion), "and that these agents cannot account for the increasing
lung cancer risk in the general population." It was further noted: "Of
greater importance is the regrettable fact that in none of these
occupational hazard studies were smoking histories obtained'. Thus the
contribution which smoking, as a contributory or etiologic factor, may
have made to the lung cancer picture in these risk situations is
unknown"(15).
Despite increasing recognition that smoking and' occupational
exposures may each contribute to the development of certain disease
1-19
states, few investigators have addressed the ways in which these twc
factorsact together to produce disease.
This chapter has identified and illustrated six ways in which
smoking may act in combination with physical and chemical agents
found in the workplace to produce or increase a broad! spectrum~ of
adverse health:effects. The six modes of action listed below are not
mutually exclusive and several may prevail for any given agent. They
may be compounded'by occupational exposure to multiple chemical and
physical agents.
1. Tobacco products may serve as vectors by becoming contaminated
with toxic agents found in theworkplace, thus facilitating entry of the
agent into the body by inhalation, ingestion, and/or skin absorption:
2. Workplace chemicals may be transformed into more harmful
agents by smoking. Illustrative of this effect is the association between
polymer fume fever and smokers as a result of cigarette contamination~
in the workplace.
3. Certain toxic agents in tobacco products and/or smoke may also
occur in the workplace, thus increasing exposure to the agent. Carbon
monoxide levels in the occupational environment, for example, add to
already high blood carbon monoxide levels found in smokers. -
4. Smoking may contribute to an effect comparable to that which
can result from exposure to toxic agents found in the workplace, thus
causing an~ additive biological effect. For example, exposure to coali
dust may increase a smoker's risk of developing disease.
5. Smoking may act synergistically with toxic agents found in t'he
workplace to cause a much more profound effect thani t!hat anticipated
simply from the separate influence of the agent and smoking added
together. For example, cigarette smoking and exposure to asbestos
may int'eract synergistically to greatly increase the risk of lung cancer.
6. Smoking may contribut'eto accidents in the workplace.
Those who have the highest risk for occupationali exposures to toxic
agents in general also have the highest smoking rates. Surveys have
shown male blue-collar workers are much, more likely to smoke than
male white-eollar workers. From 1920 to 1966, tobacco consumption
increased as did, the introduction into the workplace of chemicals with
unstudied biological effects. During this same time period, the
mortality rates for certain disease states associated withi smoking and
occupational exposures continued to increase. Some of the effects
historically attributed to smoking may actually reflect interactions
between smoking and occupationaliexposures.
Curtailment of smoking in the workplace should be accompanied by
simultaneous control of occupational exposures to toxic physicali and
chemicat agents.
1-20
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8
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Perinatal Mortality
1. When adjustments are made for age-parity differences in
mothers, their socio-economic status, and previous pregnancy histories, '
the risk of perinatal mortality attributable to smoking is highly `
significant, independent of these factors, and is dose-related.
2. Maternal smoking increases the risk of fetal death through
maternal complications such as abruptio placenta, placenta previa,
antepartumi hemorrhage, and prolonged rupture of membranes.
3. Although maternal' smoking does not produce a lowering of mean
gestational age, preterm births are increased in frequency among
smokers, and a large proportion of the neonatal deaths occur among
these preterm births.
4. Smoking by pregnant women contributes to the risk of their
infants being victims of the "sudden infant death syndrome."
5. Maternal smoking can be a direct cause of fetal or neonataf death
in an otherwise normal' infant. The immediate cause of most smoking-
related fetal deaths is probably anoxiay which can be attributed to
placental' complications with antepartum bleeding in 30 percent or
more of the, cases. In other cases, the oxygen supply may simply fail
from reduced carrying capacity and reduced unloading pressures for
oxygen caused by the presence of carbon monoxide in maternal and
fetal blood. Neonatal deaths occur as a result of the increased~ risk of
early delivery among smokers, which may be secondarily related to
bleeding early in pregnancy and premature rupture of inembranes:
Considerable literature has appeared in the area of clinical and animal
experimental studies on the role of tobacco smoke, nicotine; and carbon~
monoxide, providing evidence for pathogenetic pathways accounting
for both lower birth weight and fetal death:
6. The accumulated evidence does, not support a''conclusion that
maternal smoking increases the incidence of congenital malformations.
Lactation and Breast Feeding
1. The epidemiologic studies on adequacy of lactation do not provide
data for a: conclusion on the effect of maternal smoking.
2. Although some animal studies reveall diminished milk production
(but no reduction in release) following nicotine administration, human
experimental studies have not t'hus far produced! evidence for a:
reduction ini lactation withi forced smoking of large numbers of
cigarettes over short periods of time.
3. There does exist a direct dose-response relationship, between thee
number of cigarettes smoke& and nicotine in breast milk.
4. Further detailed research in this area is imperative.
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5. Pipe.and cigar smokers have histological abnormalities of t'he lung,
at autopsy that are intermediate in degree between nonsmokers and~
cigarette smokers. Some categories of pathologic changes in cigar
smokers are similar to those seen in cigarette smokers.
6. The risk of pipe and cigar smokers developing lung cancer is
higher than~for nonsmokers, but is lower than for cigarette smokers. Imil
:
the updated prospective studies, the relative risks of lung cancer for '
cigar and pipe smoking ranged from 1.6 to 3.4 for cigars only an& fromi
.
1.8 to 8.5 for pipe only.
7. A dose-response gradient has been shown to be present in some
studies.
Tumorigenic Activity of Pipe and! Cigar Smoke Condensates
1. Pipe and cigar tobacco condensates have a carcinogenic potential
comparable to that of cigarette condensates.
2. The alkaline smoke from pipe and cigar tobacco is usually not
inhaled, and there appears to be a lower level of exposure of the
harmful components of smoke than is noted with the inhalation of
cigarette smoke.
Cardiovascular Diseases
1. Pipe and cigar smokers experience a small increase in coronary
heart disease mortality compared to nonsmokers.
2. Similarly, pipe and cigar smokers show slight excesses of
cerebrovascular death rates over nonsmokers.
Non-Neoplastic Bronchopulmonary Disease '
~
,
1. Pipe and~ cigar smokers experience mortality rates from chronic '
bronchitis and! emphysema that are intermediate between cigarette "f
smokers and nonsmokers. ~
2. Pipe and cigar smokers have significantly more respiratory
symptoms such as cough, sputum production, breathlessness,, and
wheezing than nonsmokers. A dose-response gradient is noted.
3. Little difference in~ pulmonary function was noted for pipe and
cigar smokers as compared to nonsmokers.
4. Pipe and cigar smokers had far less pulmonary pathology at
autopsy than did cigarette smokers.
Peptic Ulcer Disease
1. Cigar and pipe smokers experience higher death~ rates from peptic
ulcer than nonsmokers: these rates, based on prospective mortality
studies, indicated higher rates for gastric ulcer tham for duodenal ulcer.
2. Retrospective and cross-sectional studies failed to find an
association between pipe smoking and peptic ulcer.
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1. Sidestream smoke, which comes from the lighted tip of the
cigarette: between puffs, has higher concentrations of some of the
irritating and hazardous substances than does mainstream smoke (that
smoke inhaled by the smoker).
2. Children of parents who smoke are more likely to have bronchitis
andpneumonia during the first year of life; this effect is independent
of social class, birth-weight, and parentali cough and phlegm produc-
tion..
3. Simple extrapolation of d'ose-response relationships which are
traditionally used in, assessing the hazards of smoking to the smoker,
cannot be employed in assessing hazards in nonsmokers.
4. Cigarette smoking in enclosed spaces can produce carbon
monoxide (CO) levels well above the Ambient Air Quality Standard~ (9
ppm) even where ventilation is adequate.
5: Substantial proportions of the population experience irritation and~
annoyance when exposed to cigarette smoke. The eyes and nose are
most sensitive to irritation, and such irritation increases with
increasing levels of smoke contamination. Unrestricted smoking on
buses and planes annoys the majority of nonsmoking passengers even
under conditions of adequate ventilation.
6. Little or no physiological response to smoke was detected in
healthy nonsmokers exposed to cigarette smoke. Higher heart rates
detected may be due to psychological factors:
7. A slight reduction in maximum exercise capacity was noted in
older nonsmokers exposed to levels of CO occasionally found in
involuntary smoking situations.
8. Changes im psychomotor function, especially attentiveness and
cognitive function, at levels of CO found in involuntary smoking
conditions have been noted, but these effects are measurable only at
the threshold of stimuli perception.
9. Levels of COHb produced by involuntary smoking situations are
functionally insignificant im healthy individuals.
10. Levels of carbon monoxide which can be reached in cigarette
smoke-filledl environments have been shown to decrease the exercise
duration required to induce angina pectoris in pat'ients with coronary
artery disease. These levels of CO also have been shown to reduce the
exercise time until onset of dyspnea in patients with hypoxic chronicc
lung disease.
Interactions of Smoking with Drugs; Food Constitz.cents, and
Responses to Diagnostic Tests
The pervasiveness of tobacco use in our society and the frequency of
altered disposition and pharmacological'effects of many common drugs
on smokers make it apparent that cigarette smoking is one of the
primary causes of drug interactions in humans. An assessment of the
literature in this area provid'es the following,conclusions:
1-25
1. Most of the experimental work in humans, animals, and~ tissues w
involving enzyme systems indicates that the dominant effect of ~
smoking is enhanced drug disposition caused by induction of hepatic ~
microsomat enzymes. ~
2. Tobacco smoke, a complex mixture of noxious materials, contains, ~
among other compounds, enzyme inducers suchi as polycyclic aromat'ic ~
hydrocarbons, nicotine, cadmium and some pesticides, acrolein and~
~
hydrogeni cyanide. ;
3. The primary inducers are probably polynuclear aromatic hyd'rocar- ;
bons which are potent and persistent in tissues. While several of the `
hepatic microsomal drug-metabolizing enzymes are stimulated in '.'.
smokers, this enhancement is unpredictable, and the effects of f:
cigarette smoke on other potential rate-limiting disposition processes
for drugs are largely unexplored. '
4'. Cigarette smoking alters the pharmacologic effects of drugs or
their pharmacokinetics.
5. Tobacco smoke can induce the metabolismi in humans of
therapeutic agents, such as phenacetiny antipyrine, theophylline,
caffeine, imipramine, pentazocine, and vitamin C; examples of drugs
not affected by smoking include: diazepam meperidine, phenytoin,
nortriptyline, warfarin, and ethanol.
6. Tobacco smoke can modify the clinical! effects of drugs:
7. Marijuana smoking may produce reactions similar to tobacco
smoking since enzyme induction is also stimulated by the polycyclic
aromatic hydrocarbons in marijuana smoke.
& A woman who both smokes and uses oral contraceptives has a
greater risk for myocardial infarction.
9. There is a suggestion that smoking produces a more rapid decline
in influenza antibody titers after natural infection or vaccination with
influenza: virus.
10. Cigarette smoking appears to increase the serum carcinoem-
bryonic antigen level in otherwise healthy individuals:
11'. No information is available to indicate that the increase in~ body
burden of trace elements by smoking has toxic effects.
12. Since tobacco smoking does affect the values of a number of
clinicall laboratory tests in humans, the knowledge of an individual's
smoking, status is important for the interpretation of such tests.
Cigarette smoking increases the number of leukocytes, the red cell
mass, the levels of hemoglobin an& carboxyhemoglobin, the hemato-
crit, the mean corpuscular volume, platelet aggregation, plasma
viscosity, and tensile strength: of the clot; cigarette smoking decreases
the serum levels of creatinine, albumin, globulin (female smokers) and
uric acid (male smokers). These revert to normal' levels after cessation
of smoking.
1-26
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f'eptic Ulcer Disease
The 1964 Report appraised~ the evidence for a relationship between
tobacco use and peptic ulcer disease in five retrospective and the seven
prospective studies (mortality) an6 concluded that only an association
existed, particularly for gastric ulcers. The biological meaning of this
a.s.sociation was not clear, particularly since studies of the effects of
cigarette smoking on secretory activity and gastric motility were not
consistent.
For the current report, two of the prospective mortality studies have
hcen updated. Peptic ulcer disease mortality has continued to show
excesses among smokers of cigarettes.
A number of additional' studies of peptic ulcer disease and smoking
were also; ad'dressedl Five of these studies showed a higher proportion
of smokers among ulcer patients than among controls. Six studies
showed a greater prevalence among, male cigarette smokers than
nonsmokers, the median ratio being 1.7. The findings in women are
comparable. The majority of studies provided evidence of increased
frequency of peptic ulcer disease with increases in the amount smoked.
Experimental' an& clinical studies of gastric and pancreatic secretion
and pyloric reflkzx were extended in this period to resolve the
mechanism of action of smoking on occurrence of peptic ulcer disease.
On the:basis of the research data surveyed, it is concluded:
1. Epid'emiological' studies have found that cigarette smoking is
significantly associated withi the incidence of peptic ulcer disease and
increases the risk of dying from peptic ulcer disease. This risk is, on the
average, twice as high for smokers compared to nonsmokers, and
appears to be greater for gastric than for duodenal ulcer disease:
2. The risk of peptic ulcer disease is dose-responsive and exists for
both men and women.
3. While the pathogenetic mechanisms have not been clearly
etucidateds the association between smoking and peptic ulcer disease is
significant enough to suggest a causalirelationship:
4. Evidence that smoking retards healing of peptic ulcers is highly
suggestive:
5. Pipe smoking appears unrelated to peptic ulcer disease.
6. Experimental and! clinical studies on the effect of smoking on
pancreatic secretion and pyloric reflux suggest mechanisms by which
peptic ulcer disease may develop.
Allergy andImmunityAll'ergic manifestations to tobacco, its smoke, or its extracts were not
reviewed in the 1964 report. Various studies ini the late 1960's and
1970's probe& the relationship of smoking to immunologic mechanisms
and immune responses, not only in the acute infectious diseases, but
also in several of the chronic diseases such as pulmonary disease:
1-23
Figure 1.-Annual probability of dying, for ex-smokers
who quit smoking less than 5 years, current cigarette
smokers and nonsmokers, aged 55-64, U.S. veterans
1954 cohort, 16-year follow-up .................................. 31
Figure 2.-Annual probability of dying for ex-smokers who
quit smoking 5-9 years, current cigarette smokers and'
nonsmokers, aged 55-64, U.S, veterans 1954 cohort, 16-
year follow-up ....................................................... 32
Figure 3.-Annual probability of dying for ex-smokers who
quit 10-14 years, current cigarette smokers and
nonsmokers, aged 55-64, U.S. veterans 1954 cohort, 16-
year follow-up : ....................................................... 33
Figure 4.-Annuall probability of dying for ex-smokers who
quit 15+ years, current cigarette smokers and
nonsmokers, aged' 55-64, U.S: veterans 1954 cohort, 16-
year follow-up ....................................................... 34
LIST OF TABLES
Table 1.-Mortality ratios, differences in mortality
rates, and excess deaths by age; as derived
from two studies .................................................... 11
Table 2.-Estimated years of life expectancy (LE) for
males at various ages by amount smoked, as derived
from two st'udies .................................................... 12
Table 3;-Outline of prospective studies of smoking and
overall mortality .................................................... 13
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pressure, cardiac output, stroke volume, velocity of contraction,
myocardial contractile force, oxygen consumption, coronary blood flow
and arrythmias, increased mobilization and utilization of free fatty
acids, hyperglycemic effects, and~a decreased patellar reflex response.
3: Considerable evidence exists, although it is not uniformly
accepted, that smoking patterns of chronic smokers are to a large
degree dependent on the nicotine content of the cigarette and
dependent on what the nicotine delivery would be when measured' by
the standard methodology. Smoking patterns are depend'ent to
varying degrees, on the type of cigarette smoked, the number of
cigarettes smoked, the length of the cigarette burned, the number of
puffsand the depth and length~of inhalation,
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Reduction in Toxic Activity of Cigarette Smoke
1. At the present time, selective filtration of carbon monoxide has
not proven feasible.
Z Charcoal filtration has proven, successful in the removal' of certain
ciliatoxic substances from the gas phase of cigarette smoke.
3. Selected types of cellulose acetate filter tips selectively remove
volatile phenols.
4. Cigarette fillers low in wax-layer components deliver smoke
reduced in catechols, but there is a questioni as to whether selective
reduction in cathechols leads to a significant reduction of the
tumorigenic potentiall of cigarette smoke.
5. Lowering nitrate content of tobacco reduces volatile N-nitrosa-
mines in tobacco smoke, but it has not been shown that a reduction of
this compound will lead to a significant reduction in the tumorigenic
potential of the smoke..
6. Experimentally, a dose-response gradient is demonstrable for
"tar" application or smoke inhalation and tumor yield. A number of
technical approaches, including modification of the filler, has reduced
the "tar" content of smoke.
7. Similar technical approaches have reduced the nicotine.content of
tobacco smoke.
8. There is a possibility that nonvolatile N-nitrosamines can be
reduce& by addition~ of specific bacteria during the processing of
tobacco. Selective filtration is not feasible for their removal.
9: A number of methods have led to reduction of "tar" and of toxic
and tumorigenic agents in the smoke of cigarettes. Several approaches
have led to the reduction of the ciliotoxicity and to selective reduction
of the carcinogenicity and tumor-promoting activity of the smoke of
experimental cigarettes. Many of these methods have already been
incorporated in today's modified, blended U.S, cigarette.
1-31
19
Snuff and Chewing Tobacco and Oral Lesions
Snuff and chewing tobacco have not been found to increase mortality
(either overall or cause-specific) in the United States. Asian studies
have found~ an association between tobacco chewing and leukoplakia as
welli as oral cancer. These differences between the American and' Asian
studies can partially be explained by nutritional factors but are
confounded by other factors such as the use of other tobacco products
along with the use of snuff and chewing, tobacco in the United States.
Constituents of f Tobacco Smoke
Extensive research has advanced the cultivation of tobacco varieties
with commercially desirable characteristics. This research has also
been directed toward precursor-product relationships among specific
leaf tobacco components, agronomic characteristics, cigarette and
smoke constituents, and biological responses involving 151 variables.
Multivariate analysis has revealed that leaf characteristics serve as
markers to predict individual smoke components. Thus, there is
promise of modification for more desirable qualities and'use of tobacco.
Smoke Formation
1. The lighted cigarette generates about 2,000 compounds by a
variety of processes inclluding hydrogenation pyrolysis, oxidation,
decarboxylation, dehydrationy chemical condensation, distillation, and
sublimation.
2. Tobacco smoke has been separated into gas and particulate phases.
3: The gas phase components shown; to produce undesirable effects
include carbon monoxide, carbon dioxide, nitrogen oxides, ammonia,
volatile N-nitrosamines, hydrogen cyanide, volatile sulfur compounds,
nitriles and other nitrogen-containing compounds, volatile hydrocar-
bons, alcohols, aldehydes, and ketones.
4. The particulate phase consists generally of nicotine, water, and
"tar". "Tar," which is the total particulate matter after subtracting
moisture and nicotine, consists primarily of a wide variety of species of
polycyclic aromatic hydrocarbons (PAH) to which carcinogenicity is
attributed.
(a) These PAH include non-volatile N-nitrosamines, aromatic amines
(regarded as being the etiologic agents in bladder cancer),
isoprenoids, pyrenes, benzopyrenes, chrysenes, anthracenes, fluo-
ranthenes, carcinogenic aza-arenes such as the acridines and
carbazoles, and the mutagenic aza-arenes such as the quinolines
and phenanthridines.
(b) In addition, the "tar" contains simple and complex phenols,
cresols and naphthols, alkanes and alkenes, benzenes and
naphthalenes, carboxylic acids, and metallic ions, as well as
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1-29
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(a) Male current smokers of cigarettes reported a 33 percent excess,
and female current smokers a 45 percent excess, of work days lost
in comparisoni to persons who never smoked. Male former
smokers had an excess of 41 percent, and female former smokers
an excess of 43 percent, of work days lost. From the 1974 survey
data, this calculates to more than 81 million excess days of work
lost for the U,S: population in 1 year.
(b) Male current smokers had a 14 percent excess, and female
current smokers a 17 percent excess, of days of bed disability over
those who never smoke& Smokers in all age and sex groups,
except for women over age 65, reported more days in bed due to
illnesses than did persons who never smoked. From 1974 data,
this calleulates to more than~ 145 million excess days of bed
disability for the U.S. population in 1 year.
(c) The excesses of disability measures are dose-related.
(d) For most age and! sex groups, a higher proportion of current and
former smokers report longer limitation of activity due to chronic
diseases than do persons who never smokedl
5. A tendency was noted for higher proportions of former smokers
and those who never smoked, as compared to present smokers, to assess
their own health status as excellent.
6. Current smokers and former smokers reported more hospitaliza-
tions than nonsmokers in the year prior to interview. Data on~ the
reasons for these hospitalizations have not been analyzed!
While most studies show a reduction in the risk of mortality among
former smokers, data on disability and illness oft'en show continued
high~ risk among former smokers. This finding, should be: interpreted
more as an indication of the need for both additional data and further
analysis of existing data, rather than as an indication of the lack of a
beneficial impact on heaith status from smoking cessation.
These findings on morbidity are consistent with the vast amount of
evidence on the relationship between cigarette smoking and mortality:
Cardiovascular Diseases
The tremendous amount of research, on the relationship between
cardiovascular disease and smoking, undoubtedly stimulated by a lack
of adequate information in the areas of the nature of atherosclerosis,
the mechanisms of atherogenesis, and the pathogenetic pathways for
smoking,components, has provided a basis for firmer judgments on the
relationship than could be made in 1964. The present report on
cardiovascular disease and smoking draws heavily on the 1976
reference report on smoking and health (14)'and adds more recent
data:
Systematic observations on the association~ between smoking and
cardiovascular diseases have been made on considerably more than~ a
1-13
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clinical impression, since there had been no epidemiologic studies of
this now rare entity and experimental studies had not been adequately
controlled.
Cirrhosis of the liver had been found' to contribute to excess
mortality among cigarette smokers in the seven prospective studies.
However, because of the relationship of alcohol consumption (and
nutritional deficiencies) to cirrhosis, the correlation of heavy drinking
with heavy smoking, and lack of definitive studies on the compartmen-
talii:ation of these two factors at the time, there was inadequate
support of a causal association.
As for accidents, an obvious relationship between smoking and fires
in, the home was noted in 1964.
A moderate excess risk of mortality from influenza an& pneumonia
was noted in six of the seven prospective studies but, this association
had not been evaliuated by further studies. Other acute respiratory
illnesses had been studied in families and im college graduates and no
differences had beeni found between, cigarette smokers and nonsmok-
ers.
There had been some interest in the relationship between maternal
smoking during pregnancy and' pregnancy outcome. By 1964, five
retrospective and two prospective studies revealed ani association of
cigarette smoking during pregnancy with lower birth, weight and
premature deliveries. A relationship with fetal and/or neonatal death
was deemed equivocal at the time.
Finally, although smokers were found to differ from nonsmokers in
a number of ways; none of the studies appraised by the Advisory
Committee revealed any single variable discriminating significantly
between the two groups. The report emphasized'that "the overwhelm-
ing evidence points to the conclusion that smoking-its beginning,
habituation and occasional discontinuance-is to a large extent
psychologically and socially determined."
The Committee concluded: "Cigarette smoking is a health hazard of
sufficient importance in the United States to warrant appropriate
remedial' action."
The release of the Advisory Committee's Report to the Surgeon
General' stimulated many studies and reports, the data from~ which
augmented the earlier studies, strengthened~ the conclusions of the
Committee, provided information in areas for which data had not
existed, and~ shed light on the pathogenetic mechanisms of the
thousands of compounds in~ tobacco an& tobacco smoke. These studies
were epidemiologic clinical, experimental, and, in the area of smoking
control, psychologic andl sociologic as well..
The Federal Cigarette Labeling and Advertising Act of 1965 (P.L.
89-92) required the Secretary of Health, Education, and Welfare to
submit regular report's to Congress on t'he health consequences of
smoking, together with legislative recommendations. The purpose was
1-9
0
million individuals in the United States (the majority on men) and have
involvsd~ many millions of person-years of experience.
Sample sizes are now extensive in both retrospective and prospective
studies. Variables observed in retrospective studies have been~relative-
ly limited; in some prospective studies, they have been more numerous
and have allowed for complex analyses in which the independence of
smoking as a risk factor among other risk factors has been defined.
Autopsy and experimentall studies in animals have also been extended
and serve to clarify earlier issues.
The 1979 Report includes the following,conclusions:
1. The data collected from Western countries, particularly the
United States, but also the United Kingdom, Canada, and others, show
that smoking is one of three major independent risk factors for heart
attack manifested as fatal and nonfatal myocardial infarction and
sudden cardiac death in adult men and women. Moreover, the effect is
dose-related, synergistic with other risk factors for heart attack, and of
stronger association at younger ages.
2. Smoking cigarettes is a major risk factor for arteriosclerotic
peripheral vascular disease and is strongly associated with increased
morbidity from arteriosclerotic peripheral vascular disease and with
death from arteriosclerotic aneurysm of the aorta.
3. The data establish adequately that cigarette smoking is associated
with more severe and extensive atherosclerosis of the aorta and
coronary arteries than is found among nonsmokers. The effect is dose-
related.
4. Epidemiologic data on the association between cigarette smoking
and angina pectoris and cerebrovascular disease manifested as stroke
are not conclusive.
5. Smoking increases the possibility of a heart attack recurrence
among survivors of a myocardial infarction.
6. In acute experiments on arteriosclerotic patients withi angina
pectoris or with, intermittent claudication of peripheral vascular
disease, smoking or exposure to carbon monoxide reduces t'he patient's
established threshold for the precipitation of angina or claudication.
Both nicotine and carbon monoxide (CO) aggravate exercise-induced
angina.
7. Women who smoke and use oral contraceptives are at a
significantly elevated risk for fatal and nonfatal myocardial infarction.
A synergistic role of cigarette smoking and oral contraceptive use is
suggested for subarachnoid hemorrhage.
8. Smokers of low "tar" and nicotine cigarettes experience less risk
for coronary heart disease than smokers of high "tar" and nicotine
cigarettes, but their risk is considerably greater than that of
nonsmokers:
9. Cigarette smoking does not induce chronic hypertension. However,
in the presence of hypertension as a risk factor for coronary heart
1-14
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Subsets of females with smoking characteristics similar to those of
men experience mortalityrat'es similar to those of male smokers.
4. From~ the detailed data of two prospective studies (Hammond and
Dorn) the excess in mortality is noted to be greatest for the 45- to 54-
year age groups among men and women. Thus, smoking mortality is
premature mortality.
Cause-Specific Mortality
1. Although mortality rat'ios are particularly high among cigarette
smokers for such diseases as lung cancer, chronic obstructive lung
disease, and cancer of the larynx, coronary heart disease is the chief
contributor to the excess mortality among cigarette smokers.
2. Lung cancer and' chronic obstructive lung disease, in that order,
follow after coronary heart disease in accounting for the excess
mortality.
3. Pipe and cigar smoking are associated with elevated mortality
ratios for cancers of the upper respiratory tract, including cancer of
the oral cavity, the larynx, and the esophagus:
Morbidity
Following the 1964 Report to the Surgeon~ General, the National
Center for Health Statistics: began collecting information on smoking
as part of the National Health Interview Survey. On the basis of
probability samples of the population, estimates can be made for the
general population. These data have proven valuable in assessing the
relationships between tobacco use and illnesses, disability, and other
health indicators. The findings include:
1. In general, male and female current cigarette smokers tend to
report more chronic conditions, such as chronic bronchitis and/or
emphysema, chronic sinusitis, peptic ulcer disease, and arteriosclerotic
heart disease, than persons who never smoked.
2, A dose-response gradient was noted with the amount of cigarettes
smoked! per day for most of the chronic conditions. Particularly
impressive is the gradient for chronic bronchitis and/or emphysema,
with an increase in prevalence among male smokers of two packs or
more a day to four times that of those who have never smoked, and
among female smokers of two packs or more, to 10 times that' of those
who never smoked.
3. The age-adjusted incidence of acute conditions (e.g., influenza) for
males who had ever smoked was 14 percent higher, and'for females 21
percent higher, than for those who had never smoked cigarettes.
4. Indicators of morbidity which are not dependent upon physicians'
diagnoses include measures of disability su& as work-days lost, days in
bed, and days of limitation of activity resulting from chronic diseases:
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Tuberculosis Association urged'President Kennedy to establish a
commission to study the tobacco problem. On January 4, 1962,
representatives of these organizations met with Surgeon General
Luther L. Terry once more to urge action. A proposal from Terry to the
Secretary of Health; Education, and Welfare called for an expert
advisory committee to assess existing, knowledge and make appropri-
ate recommendations. In March, a resolution introduced by Senator
Maurine Neuberger (SJR174) called for the establishment of a
Presidentiall commission on tobacco and health, but it was never
brought to a vote.
On April 16, the Surgeon General presented a detailed proposal for
an advisory group to re-evaluate the 1959 position of the Service: He
cited' new studies on major adverse health effects, evidence that
medical opinion was now very strong against smoking, a: request from
the Federal Trade Commissionfor guidance on~ labeling and advertis-
ing of tobacco products, and a recent report of the Royat College of
Physicians of London which conclude& that "cigarette smoking is a
cause of lung cancer and bronchitis and probably contributes to the
development of coronary heart disease..." (10).
Consultations between the White House and~ Public Health Service
officials led to Surgeon General Terry's announcement on June 7, 1962,
of the planned formation of an expert committee to review all data on
smoking and health. Representatives of the American Cancer Society,
the American College of Chest Physicians, the American Heart
Association, the American Medical Association4 the Tobacco Institute,
Inc., the Food and Drug Administration, the Nationali Tuberculosis.
Association, the Federal Trade Commission, and the President's Office
of Science and Technology met with the Surgeon General on July 27 too
establish the work of the expert committee and to agree on a list of
some 150 scientists and physicians qualified to evaluate data on the
relationship between tobacco use and'health: Terry selected 10 from
the list and, thus, the Surgeon, General's Advisory Committee on
Smoking and Health was launched at its first meeting on November 9,
1962.
The members of the Committee were: Stanhope Bayne-Jones, M.D.,
L.L.D., Former Dean, Yale School of Medicine; Walter J. Burdette,
M.D., Ph.D., University of Utah; William G. Cochrane, 1VI.A.,, Harvard
University; Emmanuel Farber, M.D.,, Ph.D., University of Pittsburgh;
Louis F. Fieser, PhLD., Harvard University; Jacob Furth; M.D.,
Columbia: University; John B. Hickam, M.D., University of Indiana;
Charles LeMaistre, M.D., University of Texas; Leonard~ M. Schuman,
M.D., University of Minnesota; and Maurice H. Seevers, M.D., Ph:D.,.
University of Michigan.
The judgments of the Advisory Committee led to a series of
significant conclusions, released in 1964 in the now historic Report of
1-7
9
own
why
Ency;
I
~ the
rette
g. It
i'nce-
~ olda
ance
' and
~eat.
barch!
i
rette
may
The
als is
,i,only
iroxi
fe of
'st'em
o the
tand-
rmer
,tant,
g for
is its
total
rome
3rtial
,e of
;elfine
ience
ikely
ssful
it on
illion
~ated
ty of
those who do express an interest actually attend programs when
offered! It thus appears that available objective outcome data may be
based! on a small minority sample of smokers at large.
7. Objective data are lacking on most of the smokers who have been
willing, to attend formal programs. Public service clinics continue, but
lack of objective outcome data precludes the evaluation of their
efficacy. Similarly; proprietary programs remain virtually unmoni-
tored and unevaluated in an objective fashion. Controlled research has
yet to produce a clearly superior intervention strategy. However,
rapidly accumulating an& improving data now suggest that mult'i~-
component interventions offered by intervention teams with practical
knowledge regarding, the smoking problem are the most encouraging.
8. Too few carefully designed and implemented longitudinal studies
exist in~ the area of smoking in children and adolescents to allow for
true evaluatiom of the effectiveness of many past programs develbped
for them.
9. Inferences about the evolution of smoking suggest that by the end!
ofl the ninth grad'e very few adolescents are addictive smokers; the
critical level of the, onset of addictive smoking appears to be in high
school. Therefore, the true impact of any deterrence-of-smoking
program with adolescents may not even be measurable until after the
adolescent has entered high school. This problem is not unlike the
recidivism encountered in virtually all smoking cessation programs:
10: Too many programs for youth have focused on information about
smoking, or fear of serious disease due to smoking. Adolescents are
present-oriented and appear to: be less influenced by messages
concerning smoking that focus exclusively on long-term dangers.
11. A focus on research into prevention of the onset of addictive
smoking appears to be a: reasonable parallel course to follow along with
effort'sat'eontrol and~ cessation.
12. A promising new approach may be in the "inoculation" of
adolescents against various pressures to smoke which apparently
override their knowledge about the dangers of smoking, The approach
involves strategies to resist peer pressure, emphasis on understanding
of how advertising and mass media work to influence smoking, and
provision of information on ways to resist the models of parents,
siblings, and older students who smoke. Also included is a focus on the
immediate physiological effects of smoking rather tham on long-term
effects:
Education and Prevention
Resear& strongly indicates that educators and health~care providers
teach youth about smoking and health as much by example as through
formal instruction. But, despite a proliferation of a wide variety of
educational programs aimed at youth and adults, it is not known which
methods are most effective in preventing the start of smoking or in
1-33
Table 16.-Age-adjusted mortality rat'ios for male
cigarette-only smokers aged 55-64, by age began
smoking, and current number of cigarettes smoked per
day. Males in 25 Stat!es ...........................................21
I
Table 17.-Age-adjusted mortality ratios for males smoking
cigarettes only, by amount smoked and age began
smoking. U.S. veterans 1954 cohort ........................... 22
Table 18.-Percent distribution of male cigarette smokers,
by degree of inhalation of cigarette smoke and age.
Males in, 25 States .................................................23
Table 19.-Age-adjusted mortality ratios for male
cigarette+only smokers, by degree of inhalation of
cigarette smoke and' current number of cigarettes per
day. Subjects aged 45-54 at start of study. Males in 25
Stat'es .................................................... ....... ........ 23
Table 20:-Age-adjusted mortality ratios for male
cigarette-only smokers, by degree of inhalation of
cigarette smoke and age at start of study. Males in 25
States ................................................................... 23
"1
T
Table 21.-Age-adjusted mortality ratios for male
cigarette-only smokers, by degree of inhalationi of
cigarette smoke and age at start of study. Canadian
veterans . . . . . . . . . .. . . . . . . . . . 24'
Table 22.-Adjusted mortality ratios for males and
females, by tar and nicotine content of cigarettes usually
smoked! .. . . . . . .. . . . .. .. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . .. . . . ... 24
7
Table 23.-Adjusted mortality ratios for males and females
smoking low T/N cigarettes and subjects who never
smoked regularly .................................................... 24
7
Table 24.-Overalll mortality ratios of cigarette smokers
compared to nonsmokers, by sex and by tar and nicotine
content of cigarettes usually smoked ......................... 25
7
Table 25.-Age-adjusted mortality ratios of female
cigarette smokers, by number of cigarettes smoked'per
day and age. 25-State Study .................................... 26
I
CJ1
~
~
2-6. C!1
TABLE 4.-Mortality ratios for males currently smoking cigarettes only, by amount smoked
Doll Hammond Rogot Hirayama gest Hammond Weir Ccderlof
Numlxr of Horn Dunn
cigarettes (9) (17) (31,33) (25) (13) (20) (38) (2)
per day
British Males in U.S. Japanese Canadian Males in California
-
doctors 25 States veterans pensioners 9 States occupations SwLh
Nonsmokers 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
1-9 1.41(1-15) 1.45 1.25 1.41 1.34 1.44 1.20(1-7)
10-20 1.57(16-25) 1.75 1.51 1.56 1.70 1.79 1.40(8-15)
21 -39 2.16(>25) 1.90 1.69 1.&5(>20) 1.96 2.27 1.80(> 16)
40 ± 2.20 1.89 2.23 1.83
AII smokers 1.63 1.83 1.55 1.25 1.54 1.74 1.78 1.58
»
SO4q ~9 i 0
®
Gio Gori, Ph.D., Deputy Director, Division of Cancer Cause and
Prevention, National Cancer Institute, National Institutes of
Health, Bethesda, Maryland; Cornelius J. Lynch, Ph.D., Program
Manager, Smoking and Health~ Program, Enviro Control Incorporat-
ed, Rockville, Maryland; Thomas E. Nightingale, Ph.D., Physiologist,
Ehviro Control' Incorporated, Rockville, Maryland; Richard' L. Ellis,
Ph.D.,, Senior Chemist, Enviro Control Incorporated, Rockville,,
Maryland; and Dietrich Hoffmann, Ph.D., Chief, Division of
Environmental Carcinogenisis, Naylor Dana Institute for Disease
Prevention, American Health FoundationV'alhalla, New Irork.
Chapter 15.-Biological Influences on Cigarette Smoking.
National Institute on Drug Abuse.
Murray E. Jarvik, M.D., Ph.D., Professor of Psychiatry and
Pharmacology, University of California at Los Angeles, Chief of the
Psychopharmacology Unit, Veterans Administration Medical Cen-
ter Brentwood, Los Angeles, California, with the assistance of
Kevin Maxwell, Paula Pearlman, andJohn Fowler.
Chapter 16.-Behavioral Faetors in the Establishment, 1Vlainte-
nance, and Cessation of Smoking.
National Institute on Drug Abuse.
Ovide F. Pomerleau, Ph.D., Associate Professor of Psychiatry
Department of Psychiatry, University of Pennsylvania; Director of
the Center for BehavioraU Medicine at the Hospital of the University
of Pennsylvania, Philadelphia, Pennsylvania.
Chapter 17.-Smoking in, Children andAdolescents: Psychosocial
Determinants an.d Prevention Strategies.
National Institute of Child Health and Human Development.
Richard I. Evans, Ph.D., Professor of Psychology, Department of
Psychology, University of Houston; Allen Hendersons M.A., Peter
Hill, M.A., and Bet't'ye Raines, B.A., Predoctoral Research Fellows,
Department of Psychology, University of Houstons H'ouston, Texas.
Chapter 18:-Psychosocial Influ.ences on Cigarette Smoking.
National Institute on Drug Abuse. I
t
C.
t.
so
Lynn T. Kozlowski, Ph.D., Assistant' Professor of Psychology, r
Department of Psychology, Wesleyan University, Middletown, r
Connecticut.
Chapter 19.-Modif'acation of Smoking Behavior.
National Institute on Drug Abuse.
Terry F. Pechacek, Ph.D., Post-Doctoral Fellow, Laboratory of
Physiological Hygiene,, School of Public Health, University of
CJ
~
:11
Minnesota, Minneapolis, Minnesota.
~
Chapter 20:-FouthEdircation. ,~^+
National Institute of Education.
xx N
promoting cessation. Summarized below are some of the research '
findings, program~and experimentaliapproaches, and needs in the areas±
of smoking education and prevention discussed' in this part of the'
report.
~
1. Most educational programs are based on what seems reasonable
rather than on sound theoretical models. It is logical to assume, for
example, that young people who know about the harmful effects of '
cigarette.smoking on health will resist smoking. Thus, many programs `
are based on knowledge dissemination~ and a health threat. However,'
we know that 94 percent of teenagers say that smoking is harmful to
health and 90 percent of teenage smokers are aware of the health
threat.
2. The trend in adult education programs is toward emphasis on
personal responsibility for individual health and adoption of a health-
promoting lifestyle.
3. Researchers find that "significant adults"-physicians, nurses,
dentists, other health professionals, coaches, and parents-are power-
ful influences on teenage smoking. A nationwide survey of teenagers,
for example, indicated that 72 percent of the nonsmokers identified
physicians as the one group that could influence them not to start
smoking; 43 percent of the smokers felt that the physician's advice
would influence their decision to stop smoking..
4. Health professionals as a group have preceded the general public _
in improving their smoking habits; they have stopped smoking, moved
to less hazard'ous forms of tobacco, or reduced the amount smoked.
5. Several studies of inet'hodolbgies used in smoking education
reported mixed results, withi no method clearly predominating.
1-34
smokers of cigars only, by amount smoked. U.S. veterans
1954 cohort, 16-year follow-up .................................. 37
Table 37.-Age-adjusted mortality ratios of current
smokers of cigars only, by age began smoking. Ui.S.
veterans 1954 cohort, 16-year follow-up :..................... 37.
Table 38.-Age-adjusted mortality ratios of current
smokers of pipes only by amount smoked. U.S. veterans
1954 cohort, 16-year foldow-up. ..................................38
Table 39':-Age-adjusted mortality ratios of current
smokers of pipes only, by age began smoking. U.S.
veterans 1954 cohort, 16-year follow-up ...................... 38'
Table 40.-Age-adjusted mortali ty rat'ios of males smoking
cigarettes, pipes, and~ cigars in various combinations and
at various times. U.S: veterans 1954 cohort ................ 39
Table 41i.-Mortality ratios of current cigarette-only
smokers, by cause of death in eight prospective
epidemiological studies ............................................ 40
.
2-8
~ tissues
Efect of
hepatic
~ntains,
tomatic
~in and
I
drocar-
! of the
jted in
icts of
i
Xesses
,
I
iugs or
fns of
ylline,
drugs
lytOin,
f
,bacco
cyclic
has a
!cline
with
oem-
body
,r of
aal's
~st's.
cell
ato-
;ma
tses
tnd'
ion
piher Forms of' Tobacco Use
References have already been made to the relationships between other
forms of tobacco use and a number of specific diseases and cancer sites.
*-cial' at't'ention was given in the 1973 issue of The Health
Cun.RCyuences of Smoking to the role of pipes and cigars. This attention
waz particularly relevant inasmuch as the 1964 Report appeared~ to
have influenced a transient increase in consumption of cigars and pipe
tobacco due:to the prevailing belief that pipes and cigars were "safe."
For the present report, the summary conclusions presented here
refer to men only, since the:use:of pipes and cigars in the United States
is limited almost exclusively to them.
It can be conclude& that some risk exists from smoking cigars and
E)iE)es as they are currently used in the United States, but for most
diseases this is smallI compared to the risk of smoking cigarettes as they
are commonly used.
Overall Mortality
1. Overall mortality rates among pipe or cigar smokers are slightly
higher than for nonsmokers.
2. Mortality rates among smokers of pipes, cigars, or both in,
combination with cigarettes are intermediate between the high rates
of cigarette smokers and the lbwer rates of those who smoke only pipess
or cigars.
3. Mortality associated with, combinations of pipe and/or cigar and
cigarette smoking is dependent upon the level of consumption and
inhalation of each.
4. A dose-response relationship exists for the several forms of
tobacco: use and overall mortality in terms of amount smoked; degree
of inhalation, duration of smoking, and age at initiation of smoking.
Cancer
1. Prospective studies have shown that mortality rates from cancer
of the oral cavity, larynx, pharynx, and esophagus are approximately
equallin users of cigars; pipes, and cigarettes.
2. Although several factors appear to be involved'in cancer of the lip,
pipe smoking, alone or in combination with other forms of smoking is
causally relate& to lip cancer.
3. Heavy alcohol consumption in combination with heavy smoking of
Pipes and cigars is associated with higher rates of oral cancer than for
either alcohol' consumption or heavy smoking of pipes or cigars alone:
There is evidence that excessive alcohol consumption may increase the
pipe and! cigar smoker's risk for extrinsic laryngeal cancer. A distinct
synergism with heavy alcohol intake exists in esophageal cancer.
4. Cigar and' pipe smokers showed the same histological changes in
the larynx and esophagus at autopsy as did cigarette smokers.
1-27
ID
as
0
Table 26.-Age-adjusted mortality ratios of female
cigarette smokers, by number of cigarettes smoked per
(lay and degree of inhalation. Subjects aged 45-54 at
start of study. 25-State Study .................................. 27
Table 27.-Age-adjusted mortality ratios of female
cigarette smokers, by number of cigarettes smoked per
day and age began smoking. Subjects aged 45-54 at
start of study: 25-State Study .................................. 27
Table 28':-Age-adjusted mortality ratios of femalee
cigarette smokers, by number of cigarettes smoked
her day and degree of inhalation and age.
25-State Study ....................................................... 27
Table 29.-Age-adjusted mortality ratios for malles who are
ex-smokers of cigarettes, by former amount smoked per
day an& years since stopped smoking. Males in nine
States . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . . . . . . . . . . . . 28
Table 30.-Mortality ratios of ex-smokers of cigarettes only
who quit smoking on doctors' orders and for other
reasons, by certain dosage variables. U.S. veterans 1954
cohort, 16-year follow-up .........................................
........................................ 29
Table 31.-Mort'ality ratios of ex-smokers compared to
nonsmokers, by age an& number of years since stopping
smoking. Study of British doctors ............................. 35
Table 32.-Mortal[ty ratios for male smokers, by type of
tobacco used .......................................................... 35
Table 33.-Age-adjusted mortality ratios for male cigar
and~ pipe smokers, by amount smoked. Males in nine
States................................................................... ... 36
Table 34.-Age-adjusted mortality ratios for male cigar
and pipe smokers, by amount smoked. Canadian veterans
36
Table 35.-Age-adjusted~ mortality ratios for male
cigar and pipe smokers, by amount smoked. Males in
25 States .............................................................. 37
Table 36:-Age-adjusted mortality ratios of current
.
2-7
h
0
i v,
is
®
I
various ages by amount smoked, as derived from two
studies
TABLE 2.-Estimated years of life expectancy (LE) for males at'
Age
Cigarettes
30
40
50
60
smoked
per day
LE
Years
lost'
LE,
Years
lost
LE
Years
lost
LE
25 State Study
Nonsmokers
43.9
0
34.5
0
25,6
0
17.6
1-9 39:3 4.6 30.2' 4.3 21.8 3:8 14.5
10-19 38.4 5.5 29.3 5.2 21.0 4.6 14.1
20-39 37.8 6.1 28.7 5.8 20.5 5.1 13.7
40+ 35:8 8.1 26.9 7.6 19.3' 6.3 13.2
35 40, 50 60
U.S. Veterans Study
Nonsmokers
43.5
0
38.7
0
29.4
0
20.8
1-10 41.0 2.5 36.3 2.4' 27:5 1.9 19.0
10-20 38:7 4.8 34;1 4.6 25.2' 4.2 172
21-39 36.7 6.8' 32.0 6.7 23.4 6.0 15.8
40+ 34.8 8.7 29'9 8.8 21.6 7.8 14i4
SOURCE: Hammond, E.C. (17), Rogot, E.I (31).
Years
lost
0
3.1
3.5
3.9
4.4
0'
1.8.
3.6
5.0
6.4
The Major Prospective Epidemiological Studies
Below are brief outlines of the eight important prospective epidemio-
1'ogical studies and their results. Taken together, the eight studies
encompass more than 16 million person-years of experience an6 over
300,000 deaths. The data are presented in Table 3. Numbers in the
table have been rounded, for ease.of presentation.
The British Doctors Study (4)
In 1951, the British Medical Association forwarded to all Brit'ish~
doctors a questionnaire about their smoking habits. A total of 34,4000
men and 6,207 women responded. With few exceptions, a1ll men whoo
replied in 1951 have been followed for 20 years: Further inquiries about
changes in tobacco use and some additional demographic characteris-
tics of the men were made in 1957, 1966, and 1972. More than 10;000'
deaths have occurred in this population during the past 20 years.
The American Cancer Society 25-State Study (17)
In late 1959 and early 1960, the American Cancer Societ'y enrolled
1,078,894 men and women in a prospective study. Alll segments of thee
population were included except groups that coul6 not be traced easily.
A lengt'hy initial questionnaire was administered that contained
2-12
CONTENTS
l n trod uction .............................................................. 9
The Measures of Mortality .......................................10
The Major Prospective Epidemiological Studies .............. 12
The British Doctors Study .................................... 12
The American Cancer Society 25-State Study........... 12
The U.S. Veterans Study ...................................... 14
Japanese Study of 29 Health Districts .................... 14
The Canadian Veterans Study ............................... 14
The American Cancer Society 9-State Study ............ 15
California Men in Various Occupations :...................15
T he Swedish St'udy .............................................. 15
Mortality and Male Cigarette Smokers ......................... 15
Mortality and Amount Smoked .............................. 15
Mortality at Different Ages .................................. 17
Mortality by Duration of Smoking ......................... 17
Mortality by Age Began Smoking .......................... 19
Mortality by Inhalation of Cigarette Smoke .............20
Mortality by Tar and Nicotine
Content of Cigarettes ........................................22
Mortality and' Female Cigarette Smokers ...................... 25
Mortality and Ex-Smokers .......................................... 26
Mortality and Pipe and Cigar Smokers ......................... 30
Mortality by Cause of Death ...................................... 37
The Constitutional Hypothesis, Social,,
and Environmental Factors ...................................... 41
Summary of Overall Mortality Related to Smoking ........ 42
Summary of Smoking and Mortality
by Cause of Death ...........................................,.....44
2-3
Non-Neoplastie Bronchopulmonary Diseases
,
Of the non-neoplastic bronchopulmonary diseases, only chronic bron-
chitis was judged to be causally related to cigarette smoking in the
1964 Report. In fact, cigarette smoking was then deemed the most
important cause of chronic bronchitis in the U.S, and a cause of
increased risk of mortality from chronic bronchitis. A relationship to
pulmonary emphysema was deemed to exist, but a causal interpreta-
tion of this relationship could not then be ascribed. Cigarette smoking
was then judged to exceed atmospheric pollution and environmental
exposures as a cause of chronic obstructive lung disease (COLD). These
diseases rank second only to coronary artery disease as a cause of
Social Security-compensated disability.
In the 15 intervening years, the updating of several of the larger
prospective studies and numerous retrospective and cross-sectional
studies have strengthened'~ the conclusions of the 1964 Report.
1. Cigarette smokers have a higher prevalence of chronic bronchitis
and emphysema than~ nonsmokers and have an increased chance of
dying from these diseases compared to nonsmokers. These risks are
significant for both men and women who smoke, although higher rates
generally exist for men than women.
2. Cigarette smokers have an increased frequency of respiratory
symptoms, and at least two of them, cough and sputumi production, are
dose-related.
3. Pulmonary function abnormalities, as measured by various tests,
are greater among cigarette smokers than nonsmokers:
4. Impairment of pulmonary function can be detected among
smokers even in young age groups,, and respiratory symptoms can be
demonstrated in teenagers and adolescents who smoke.
5. Cigar and pipe smokers show higher mortality rates for chronic
bronchitis and emphysema than nonsmokers, but these rates are not as
great as those for cigarette smokers.
6. Cessation of smoking definitely improves pulmonary function and
decreases the prevalence of respiratory symptoms: Cessation reduces
the chance of premature death from chronic bronchitis and emphyse-
ma.
7. Although the majority of studies demonstrate a higher prevalence:
of pulmonary function abnormalities in smokers when compared to
nonsmokers, conflicting data make it difficult to substantiate racial
differences among smokers and nonsmokers.
8: Autopsy data have demonstrated more frequent abnormalities in
macroscopic and microscopic lung sections among smokers compared to
nonsmokers, and these effects were dose-related.
9. Several mechanisms have been suggested by which smoking might
induce lung damage, including an imbalance of protease-antiprotease.
10: A wide variety of alterations in the immune system have been
observed due to cigarette smoking. These alterations include macro-
e.
J
C
i
C
E
c
1-18
Behavioral Aspects of Smoking ,
Because of the research over the past 15 years, mu& is now known
5. Little is known about the millions of smokers who have quit on
their own. It has been estimated that 95 percent of the 29 millions smokers who have quit since
19+64 have done so on their own.
6. Survey data show that only one-third or less of smokers motivated
to quit are interested in formal programs, and only a smalll minority of
that this is at least partly responsible for lower rates of successful
cessation among, women.
syndrome is more severe in women than in men, and it seems likely
4. There is fragmentary evidence suggesting that the abstinence
rates of smoking.
withdrawal that typically leads to relapse and a return to baseline
abstinence. A partially-abstinent smoker is in a chronic state of
that subsides more quickly and is no worse than that seen in partial'
withdrawal from tobacco is associated with a withdrawal' syndrome
provocative role in relapse among abstinent smokers. Abrupt and totali
tobacco. The importance of the tobacco-withdrawal syndrome is its
symptom to appear following withdrawal from~ tobacco is craving for
3. By far the most common, and clinically the most important,
smokers to maintain abstinence.
opiate antagonists. This phenomenon has implications for understand-
ing the effect of nicotine on the body as well as in helping former
receptor sites for nicotine can be blocked' in a fashion analagous to the
2. Recent research suggests that specific central nervous system
nicotine in humansis approximately 20 to 30 minutes.
consume about 20 to 30 cigarettes during the smoking day (approxi-
mately one every 30 to 40 minutes) and that the biological half-life of
compatible with the observation that regular smokers commonly
be instrumental in the establishment of the smoking habit. The
proposition~ that heavy smokers adjust their plasma nicotine levels is
smoke, has been proposed as the primary incentive in smoking and may
1. Nicotine, the most powerful pharmacological agent in cigarette
presented in this section are the following:
Among the findings, tentative conclusions, and' areas for research
cessation of smoking can eliminate or greatly reduce the health threat.
is no exaggeration to say that smoking is the prototypical substance-
abuse dependency and! that improved knowledge of this process holds
great promise for prevention of risk. Establishment and maintenance
of the smoking habit are, obviously, prerequisite to the risk, and
smoking habit and the dependence process associated with smoking. It
This part of the report summarizes current understanding of the
biological, behavioral, and psychosocial aspects of the cigarette
little is known for certain, and questions far outnumber answers.
about the health dangers of smoking. But research into reasons why
the habit is so widespread and difficult to break is still in its infancy;
The Measures of Mortality
Overall mortality is a measure of the cumulative or total effect of a:
disease-causing agent on the health of a: population. Overall mortality
rat'es are particularly useful in determining the effect of agents that
influence multiple organ systems and result in increased death rates
from; several diseases. Overall mortality is the best way to measure the
sum of the risk due to cigarette smoking-related diseases: Smoking
directly exposes multiple sites in the respiratory tract to the chemical
constituents of tobacco smoke: This direct effect is most likely
responsible for the increased mortality smokers experience from
cancer of the lung, larynx, oral cavity, and esophagus, as well as the
chronic obstructive diseases of the lung, emphysema, and chronic
bronchitis. The more soluble compounds are absorbed into the blbod
stream where, unchanged or in some cases as toxic metabolites of
parent compounds, they act upon susceptible tissues not directly
exposed to cigarette smoke. This effect is most likely responsible for
the increased mortality smokers experience from ischemic heart
disease, aortic aneurysm, and cancers of the urinary bladder and
pancreas: Because of these complexities, only overalll mortality rates
can present an accurate statement of the impact of smoking on the
health of the population.
Although overall mortality is frequently used by epidemiologists and
statisticians, it has little immediate application to the practice of many
physicians, dentists, nurses, or other healtK professionals whose
orientation is primarily clinical and who deal more with specific
diseases and disease-specific mortality rates. Usually, when a: disease-
causing agent results in increased mortality for only one disease, there
may be a sharp increase in the death rate:for that specific disease, but
there will be very little change in the overall mortality rate for the
populatiom By contrast, cigarette smoking increases the death rates
for several diseases. As a result, overall mortality rates are increased
more than the disease-specific death rates for several' of the diseases
caused by cigarette smoking,
Overall mortality can be expressed in several ways. The most
commonly used terms are listed below with a brief discussion of their
significance.
1. Mortality Ratios: Obtained by dividing the death rate for a:
classification of smokers by the death rate of a comparable group of
nonsmokers. A mortality ratio has been consid'ered'to reflect the
degree to whi& a classification variable identifies or may account for
variations in death rates. As such, it is a measure of relative risk that
indicates the importance: of that variable relative to uncontrolded'
variables-an indicator of pot,enti.al biological significance:
2. Differences in Mortality Rates: Obtained by subtracting from the
death rate for smokers, the death rate of a; comparable group of
nonsmokers. This measure reflects the add& probability of death in a
2-10
0
r
0
r
to
h
n
P
~r-
~
P
d
t
e
E
i
Ri
c
led
ed':
ion
It
Introduction and Summary: References
(1) BRODERS, A.C: Sqpamous-celliepithelioma of the lip:,A study of'~ five hundred
and thirty-seven cases. Journal of the American Medical Association 74(10):
656-664, March 6~ 1920.
(2) BURNEY, L.E. Smoking and lung cancer-A statement of the Public Health
Service. Journal of the American Medical Association 171:, 1829-1837, 1959.
(3) CORNFIELD, J!, HAENSZEL, W., HAMMOND, E.C., LILIENFELD~, A.M.,
SHIMKIN, M.B., WYNDER, E.L. Smoking,and lung,cancer: Recent evidence
an&a discussiomof some questions. Journal of the National Cancer Institute
22: 173-203, 1959:
(4) HAMMOND, E.C. Smoking in relation,to the death rates of one million men and
women. In: Haenszel, W. (Editor). Epidemiological Approaches to the Study of
Cancer and Other Diseases. National Cancer Institute Monograph 19. U.S.
Department of Health~ Education and Welfare; Public Health Service,
National Cancerlnst6tute, January 1966, pp: 127-204.
(5) HOLLAND, J.J. Dissertatio inaugur. med. chir. sistens Carcinoma labii
inferiori's absque sectione persanatum. In: Wolff, J. Die Lehre von der
Krebskrankheit, Jena, 19114 Vo1. 2, pp. 52-78.
(6) JAMES, G, Treatise on tobacco, teacoffee and chocolate. (Translated from1 S:.
Paulli's Commentarius de abusu tabaci1 Americanorum veterii et herbae thee
Asiaticorium in Europa novo. 1665.),London, T. Osborn,11746.
(7)' LOMBARD, H.L., DOERING, C~R. Cancer studies in Massachusetts: Habits,
characteristics, and environment of individuals with and'without cancer. New
England Journal of Medicine 198: 481-487, 1928:
(8) MILMORE, B.K.,, CONOVER, A.G. Tobacco consumption in the United States,
1880 to 1955. Agricult'ural!Economic Research 8: 9-13, 1956.
(3) PEARL, R. Tobacco smoking,and longevity. Science 87: 216-217, 1938.
(10) ROYAL COLLEGE OF PHYSICIANS. Smoking and Health. Summary and
Report of the Royal College of Physicians of London on Smoking in Relation to
Cancer of the Lung and Other Diseases. New York, Pitman Publishing
Company;1962,70 pp.
(11) SCIENCE. Smoking and Health. Joint Report of the Study Group oni Smoking
and Health. Science 125(3258): 1129-1133, June 7,1957.
(12), SELTSER, R. Lung cancer and uranium mining. A critique. Archives of
Environmental Health 10(6): 923-936, June 1965:
(13) SOEMMERRING, S. Th. De Morbis Vasorum Absorbentium Corporis Humani!
Varrentrappii',Wennerii Traiectis ad Moenum, Publ.1795,105 pp.
(14) U.S: PUBLIC HEALTH SERVICE. A Reference Edition: 1976. U.S. Depart-
ment of Health, Education, and Welfare Public Health Service, Center for
Disease Control, HEW Publication No. (CDC) 78-8357; 1976, 657 pp.
(15) U.S. PUBLIC HEALTH SERVICE. Smoking, and Health. Report of the
Advisory Committee to the,Surgeon General of the Publio Health Service. U.S.
Dept. of' Health, Education, and Welfare, Public Health Service;, Center for
Disease Control, PHS Publication No. 1103,1964, 387 pp:
1-35
I
I
12
TABLE 11.-Age-adjusted mortality ratios for male cigarette-only
smokers, by age began smoking. U.S. veterans 1954
cohort
Age began
smoking
in years
Mortality
ratio
Nonsmokers 1100
25+ 1.32
20-24 1.51,
15-19 1.64
Under 15 1.86
SOURCE: Rogot, E. (31, 33);
TABLE 12.-Age-adjusted mortality ratios for male cigarette-only
smokers, by age began smoking. Japan
Age began
smoking
in years
Mortality
ratio
Nonsmokers 1.00 g
25+ 1.19'
20-24 1.19
Under 20 1g7 ~
SOURCE: Hirayama, T. (22).
TABLE 13.-Age-adjusted mortality ratios for Japanese male
cigarette smokers, by age began smoking and agee
at start of study
smoking
in years
Nonsmokers
35+
30-34
2fr29'
20-24
15-19
Uhder 15 '
SOURCE: Hirayema, T. (22).:
40-49 50-59 60-69
1.00 1.00 1.00
1.53 1.08 1.02
0.89 1.11 1.29
0:91~ 1.17 1.19
0:82 1.16 1.19
0:92 1.31 1.29
2:26 3.04 1.86
overalll mortality ratios increase the younger a person begins smoking
and the greater the number of cigarettes smoked per day.
Mortality by Inhalation of Cigarette Smoke
Inhalation~ of tobacco smoke is an important dosage variable. Most of
the excess mortality associated with cigarette smoking results from
diseases that require inhalation of smoke well into the lungs in order to
2-20
Age began Age at start of study
however, was the first systematic approach to that association made:
(1), In 1900, statisticians began to note increases in lung cancer. In
1928, Lombard and Doering presented initial suspicions of a relation-
ship between tobacco and disease when they noted~ that heavy smoking
was more common among cancer patients than among control groups
In the 1930's, trends in diseases such1 as lung cancer became evident,
promoting the start of intensive inquiries and animali experiments into
disease relationships and' into the chemical' composition and pathogen-
etic effects of tobacco and tobacco smoke. In 1938, Pearl found that
heavy smokers had a shorter life expectancy than nonsmokers (9), and
1939 saw the beginnings of large-scale epidemiologic studies of the
relationship between tobacco use and l ung, cancer. A large number of
clinical and pathological observations on effects of tobacco smoke on
man had accumulated by this time.
The end of the 1930's marked the beginning of almost 40 years of
retrospective (case-control) studies on selected diseases suspected of
association with tobacco use (primarily lung cancer, chronic bronchitis,
emphysema, and coronary artery disease) and prospective studies of
diseases and mortality among cohorts of smokers and nonsmokers. By
the early 1950's, there had been~ reports of many significant epidemio-
logic studies, and four of the seven prospective (cohort) mortality
studies had been launched. Tobacco was increasingly being identified
as a health hazard. In 1954, a group of tobacco manufacturers,
growers, and warehousemen establishe& the Tobacco Industry Re-
search Committee to Iaun& a research program on tobacco use and
health.
The accumulation of consistent results from a growing number of
studies on lung cancer led the then Surgeon General~ Dr. Leroy E.
Burney, to instigate the establishment by the National Cancer
Institute, the National Heart Institute, the American Cancer Society
and the American Heart Association of a scientific study group to
assess the problem. The group agreed that a causal relationship
between cigarette smoking and lung cancer existed (11); and on July
12, 1957 the Surgeon General placed the Service on record as saying
that the weight of evidence indicated a causative relationship between
excessive smoking and lung cancer. A brilliant analysis and defense: by
Cornfield, et al. of the evidence supporting this causali relationship by
appeared in 1959 (3): In that year, the U.S. Public Health Service
reiterate& its position and took one step further when~ Burney stated
that the principal factor in the increased incidence of lhng cancer was
smoking, part'icularlysmoking of cigarettes (2).
In the early 1960's, a trend toward policies of intervention was
hastened and encouraged by a number of events. On June 1, 1961 the
presidents~ of the American Cancer Society, the American~ Public
Health Association, the American Heart Association, and the National
TABLE 6.-Mortality ratios for male cigarette-only smokers, by
number of cigarettes smoked per day and age. Males
in 25 States
Number of Age
cigarettes
per day 35-44 45-14 55-64' 65-74 75-84
Nonsmokers 1.00 1:00 1.00' 1.00 1A0
1-9! 1.84 1.53 1.50 1.36
10-19 1.36 2.26 1.92' 1.65 1.55
20-39 1.91 2:41i 205 1.71 1.26
40+ 2.59 2.76 2.26 1.81
All smokers 1.82' 2:20 1.86 1.58' 1.35
SOURCE; Hammond, E.C. (17).~
TABLE 7.-Mortality ratios for male cigarette-only smokers, by
number of cigarettes smoked per day and age.
Canadian pensioners.
Number of Age
-
cigarettes
per dsy, 30-34 35~4' 45-54 55-64 65-74 75+
Nonsmokers 1100 1.00 1.00 1.00 1100 1100
1~_9 0.72 1.25 1.07 1.50 ll32 131
10-20 1i22 1.36 1.20 1.94 1:40 133
20+ 1101 1.35 1.27 2.15 1i45 1i42
All smokers 0.90 1.63 1.21 1.89 1i45 131
SOURCE: Doll, R. (9).
TABLE 8:-Mortality ratios for male cigarette-only smokers, by
number of cigarettes smoked per day and age. Males
in nine States
Number of Age
cigarettes
per day 50,54 55-59 60-64 65~'i9
Nbnsmokers 1.00 1.00 ~ 1.00 1.00
1-9 1.43' 1.15 1.46 1.37
10-20 1.72 1.65 1.83 1.59
21-39 2.11 1.83 2.20 1.65
40+ 2.30 2.84 1.56 1.84
All smokers 1.85 1.69 1.84 1.55
SOURCE: Hammond, E.C. (20).
of smoking, increase. Mortality ratios are as high as 1.66 for male'
cigarette'.smokers who have smoked for 35 or 40 years.
2-18
radioactive compounds such as potassium-40,,lea&210, polonium:
210 and radium-226.
(c) The particulate phase also contains agricultural chemicals an
additives as flavoring agents and humectants.
Toxic and Carcinogenic Agents
Compounds in cigarette smoke have been classified by an expert panel
int'o:
1. Those judged most likely to contribute to the health hazards of
smoking.
(a) 1 Carbon monoxide (gas phase).
(b):Nicotine and "tar" (particulate phase):
2. Those judged' as probable contributors to the health~ hazards o
smoking.
(a) Gas phase: acrolein, hydrocyanic acid, nitric oxide and nitrogen
dioxide.
(b) Particulate phase: cresols and phenol.
3. Those judged~ as suspected contributors to the health hazards of
smoking. ,
(a) Gas phase: acetaldehyde, acetone, acetonitrile, acrylonitrile
ammonia, benzene, 2-3 butadione, carbon dioxide, crotononitrile,
ethylamine, formaldehyde, hydrogen sulfide, methacrolein, meth-
yl aleohol, and methylamine.
(b) Particulate phase: butylamine, dimethylamine, DDT, endrin,
furfural, hydtoquinone, nickel compounds, pyridine.
These compounds have been so designated not only because of their
harmful actions but a15o because of their concentrations in tobacco
smoke. Although other constituents are considered toxic, they are not
present in concentrations deemed a health hazard.
A number of tumor initiators, co-carcinogens, and organ-specific
carcinogens have been isolated and identified. The majority of co-
carcinogens remain to be identified. The increased risk cigarette
smokers have for cancer of the esophagus, kidhey, and urinary bladder
suggests the possibility that cigarette smoke contains unidentified
organ-specific carcinogens besides the known trace amount's of
carcinogenic aromatic and N-nitrosamines.
PFhysiological Response to Cigarett'e Smoke
1. The smoking of a! cigarette seems to satisfy a smoker's
physiological and psychological needs, and it is generally accepted that
nicotine is the principal constituent responsible for cigarette smokers'
pharmacologic responses.
2. Nicotine causes the release of catecholamines, epinephrine and
norepinephrine. Several physiologic responses are attributed to
nicotine and/or catecholamines such as increased' heart rate and blood
information on age, sex, race, education, place of residence, family
history, past diseases, present physical complaints, occupational
exposures, and'various habits: Information on smoking includ'ed: type
of tobacco used, number of cigarettes smoked per day, inhalation, age
started smoking, and the brand of cigarettes used from whichi tar and
nicotine content of the cigarette could be calculated. Nearly 93'percent
of'the survivors were successfully followed for a 12-year period.
The U.S. Veterans Study (26)
This study followed the mortality experience of 250,000, U.S. veterans
who held Government li'fe insurance policies in, December of 195K
Almost all policy holders were white males. This group has been
followe& for 16' years. The most recent analysis was limited to overall
mortality, as death certificates were not obtained for those who died
during the last half of the study period. Smoking habits were
determined only once, at the onset of the study.
Japanese Study of 29 Health Districts (24)
In late 1965, a total of 265,118 men and women~in 29 health districts in
Japan were enrol9e& in a prospective study. This represented from 91
to 99 percent of the population aged 40 and older in these dfistricts: This
study provides a unique opportunity to examine the relationship of
cigarette smoking to death rates in a population with genetic, dietary;
and other culturall differences from previously examined Western
populations. At the time of the 8th year of follow-up, 11,858 deaths had
occurred and there were 1,269,382 person-years of observation. The
overall mortality rate for Japanese: males who began smoking at a
young age: was quite similar to that reported~ for U.S. males by
Hammond (17): Mortality ratios for most categories; however, are
consid'erably lower than those report& for the United States, Canada,
and Great BritainL This most likely reflects a lower average number of
cigarettes smoked per day, an~ older age at initiation of smoking, or
reduced inhalation of cigarette smoke among the Japanese.
In spite of these differences, the overall results of this study,
including the dose-response relationships for the various diseases
caused by smoking, are similar to the results of all the other major
epidemiological studies. The reliability and accuracy of the methods of
population selection used in other studies based'on limited samples of
the population are confirmed byy this study base(F on a total populationi
in a study area.
The Canadian Veterans Study (1)
Beginning in 1955, the Canadian Department of Nationall Health and
Welfare enrolled 784000 men and 14,000 women in a study of smoking-
related~ mortality. Information was obtained! on age, detailed smoking
2-14
.d
; !ii
'.10
~ec
11~
11c
an
iin~
I' U31,[;' 9.-Age-adjusted mortality ratios for male cigarette-only
smokers, by duration of smoking. Canadian veterans
Duration of
smoking
in years
Mortality
ratio
Under 5I 1.05
5-14 1.30
15-29 1.33
30-39 L53
40+ 1166
AIl smokera 1.52
-ni'f:CE: Best, E.W:R,.(7)
TABLE 10.-Age-adjusted mortality ratios for male cigarette
smokers who began smoking after the age of 20, by
duration of smoking. U.S. veterans
Duration i of
smoking
in years
Mortalityy
ratio
Under 15 110
15-24 L3Q
25--54 1.44
35 + 1.66
SOURCE: Kahn, HA. (28);
Mortality by Age Began Smoking
Overall mortality ratios exhibit an, inverse relationship with age of
initiation, of the smoking habit. Table 11 displays data from the U.S.
Veterans Study. Cigarette-only smokers who begani smoking after the
age of 25 have a mortality ratio of 1.32. For individuals who began
smoking under the age of 15, the mortality ratio is 1.86: Data from t!he
Japanese study are shown in Table 12. Again, a dose-response
relationship is demonstrated hut at a lower leveli than in t'he Uluted
States. When the Japanese data are broken down further "by age at
start of study"' and "age began smoking," as seen, in Table 13, it iss
d'emonstrated' that smokers who began smoking, under the age of 15
have mortality ratios that are very similar to those: in the United~
States data. Tables 14 and 15 show overall mortality ratios by "age
began smoking" and "age at beginning of study" for the Ui.S: veterans
and U.S. males in 25 States.
Overall mortality ratios by "age began smoking" and "number of
cigarettes smoked per day" for the ACS Study of 25 States and~ the
U'.S, Veterans Study are presented' in Tables 16 and 17. As expected,
2-19
TABLE 21.-Age-adjusted mortality ratios for male cigarette-only
smokers, by degree of inhalation of cigarette smoke
and age at start' of study. Canadian veterans
Degree
of Age at start' of study
inhalation 30-39 40-49 50-59 60-69
Nonsmokers 1.00 1.00 1.00 I:00
Do: not: ihh'ale 0:61 0.61 1.10 1178
Inhale smoke 1.29 1.12' 1.58 2:11i
SOU RCEi Best, E. W.R. (1).
TABLE 22.-Adjusted mortality ratios for males and females, by
tar and nicotine content of cigarettes usually
smoked
Mortality ratios
Sex
"'High"
T/N
"Medium"
T%N!
"Low"
TyN',
Males 1:00 0.94 0.85
Females 1.00 0.88 0.83
Total 1.00 0.91 0.84
SOURCE: Hammond; E.C. (J9).
TABLE 23.-Adjusted mortality ratios for males and females
smoking low T/N cigarettes and subjects who never
smoked regularly
Sex Mortality ratios
"Low"'T/NI Nonsmokers
Males 1.00, 0b1
Females 1.00 0.74
Total 1.00 0.66.
SOURCE: Hammond, E.C. (19).
was further reduced to 0;84 for the "low" T/N smokers. The mortality
ratios arelower for females than for males.
Iin a separate analysis, a comparison was also made between the
mortality ratios of "low" T/N smokers and nonsmokers: These data are
presented in Table 23. The mortality ratio of the "low" T/N group was
designated as 1.00. Nonsmokers have overall mortality ratios that are
about half those of "low" T/N smokers.
The combined' data from these two tables are shown in, Table 24.
Here, mortality ratios are calculated using nonsmokers as the
2-24
T
f
TABLE 5.-Mortality ratios for male cigarette-only smokers, by
number of cigarettes smoked per day and age. U.S.
veterans 1954 cohort, 16-year followup
Number of Age
cigarettes
per day 3044 3"'. 45-54 55-84 65-74
Nonsmokers 1.00 1.00 1.00 1.00 1.00
less,than 10 1.94 1.44 ll44 1.20 1.15
10 -20~ 1.27 1.79 1'.64 1.49 1.30
21-39' 1.76, 2:23 2.10 1.67 1.42'
40+ 2.33 2:72 2.13 1.86 1.65
All smokers 1.52 1.95 1.83 1.53', 1.32
SOURCE: Rogot, E.
significantmortaliityratio that varies from 1.25 to 1.45. Smokers of
more than two packs of cigarettes a day have an overall mortality ratio
that varies from 1.83 to 2.23.
Mortality at Different Ages
Overall mortality ratios by amount smoked at different , ages for
severall st'udies are presented in Tables 5 through 8. There is a decrease
in the mortality ratio with each increase in age for each smoking
category. Mortality ratios are consistently more than 2.00 for heavy
smokers between~ the ages of 30 to 50. These ratios decrease gradually
with age, but are still about 1.35 for meni over 75 years of age. This
decline does not iQnplya decrease in the effect of cigarette smoking on
health. Overall mortality rates increase dramatically with age in both
smokers and nonsmokers. If one uses another measure of mortality and
looksat the d'lfference in death rates between smokers an& nonsmokers
as illustrated in Table:1, it can be seen that the difference in, overall
mortality rates increases with age even though the: mortality ratio
decreases.
The decreasing mortality ratio with age is probably due to another
factor that should be consideredl The population of older males who
smoke two packs of cigarettes per day is probably quite different than
a younger group of two-pack-a-day smokers.
Mortality by Duration of Smoking
Overall mortality ratios increase with the duration of the smoking
habit. Mortality ratios by number of years smoked from two studies,
are presented in Tables.9 and 10. The mortality ratios remain quite
low, only slightly above the rates for nonsmokers for the first 5 to 15
years of the smoking habit, and then increase more rapidly as the years
2-17'
TABLE 17.-Age-adjusted mortality ratios for males smoking
cigarettes only, by amount smoked and age began
smoking. U.S. veterans 1954 cohort
Age began Current number of'cigarettes
smoking per day
in years Nonsmokers 1-20 21+
2p+, 1.00 1.36 1.59
Uhder 20 1.00 1.56: 1.82'
SOURCE'. Rogot, E.I (St, 59):..
on~ his own inhalation~ practices. Certainly, self-reporting of inhalation
is subject to~ considerable variation, but it may not be as inaccurate as
might be presumed. Available data show the expected dose-response
relationship between inhalation of cigarette: smoke and overall
mortality. Table 18' demonstrates that with advancing age the
percentage of moderate and deep inhalers d'rops and tthe percentage of
none-to-slight inhalers increases. This is consistent with increased
mortality for t'hose who inhale. It also makes the interesting,point that
a smoker who survives to old age:is different from the younger smoker.
It is likely that the lower mortality ratios experienced by older smokers
are partly a reflection of the fact that they smoke: in~ a less hazardous
fashion than do younger smokers. Older smokers are: less likely to
inhale than~ younger smokers. It is also likely that they take fewer
puffs per cigarette and smoke fewer cigarettes per day. If they havee
been faithful to their brand of cigarettes, they are likellyto.be smoking
an "older" brand. The brand is likely to be unfiltered and~ more typical
of the cigarettes sold 30 to 40 years ago which contained twice the tar
and nicotine of the average cigarettes soid today. Tables 19, 20, and 21
show age-adjusted mortality ratios by degree of inhalation and number
of'cigarettes smoked per day and age at start of study for three of the
large prospective studies. The overall mortality ratio is 2.W for the
moderate-to-deep inhaler who smokes 40 or more cigarettes per day.
The overall mortality ratio is 2.53 for 45- to 54-year-old men who inhale
deeply, but is 1.02 for noninhalers who are 75 to 84 years old. In the
Canadian~ study t!he highest mortality ratio was 2. 11 for those 60 to 69
years olff who reported inhaling, cigarette smoke. Hammond reported a
mortality ratio of 1.41 for noninhalers who are 45 to: 54 years old (15):
This suggests that cigarette smokers may underestimate the extent to
whichithey inhale cigarette smoke.
Mortality by Tar and Nicotine Content of Cigarettes
Overall mortality increases with the tar and nicotine content of
cigarette smoke. This relationship, was recently examined by Ham-
mond, et al. (19). In thi's study, tar and nicotine levels (T/N) were
defined as follows: "High" T/N, 25.845.7 mg tar and 2.0-2.7 mg
2-22
a
®
R
TABLE 18.-Percent distribution of male cigarette smokers by
degree of inhalation of cigarette smoke and age.
Males in 25 States
Degree
of Age
inhalation 40-49 50i59 60-69 70-79
nr 3.62 6.11 11.46' 19.74
1Q97 13_64 20;18 25.56
:;.lerate 57.94 56.31 51.10 40.82
'. Ic p 27.65 23.91 1725 13.88
:' ;al 100.00 100.00 ~ 100.00 100.00
SiIURCE: Hammond, E.C, (19).
:
TABLE 19.-Age-adjusted mortality ratios for male cigarette-only
smokers, by degree of inhalation of cigarette smoke
and current number of cigarettes per day. Subjects
aged 45-54 at start of study. Males in 25 States
Degree Nhmber of cigarettes per day
of
inhalation 1-9 10-19: 20-39 40+
None-sliRht 1.70 1.99 2.34 2.33
`doderate-deep 1.95 2.35 242 2.801
SOURCE: Hammond: E.C. (17).
TABLE' 20.-Age-adjusted mortality ratios for male cigarette-only
smokers, by degree of inhalation of cigarette smoke
and age at start of study. Males in 25 States.
Degree
of Age at start of study
inhalation 4`r54 554.4 65-74 75-54
None 1i41 1A3 1.32 1.02'
Slight 1.67 1.711 1.31 1.19:
Mnricrate 2.06 1.68 1.53 1-M
Deep 2.53 1.88 1.68~
SOURCE:Hammond, E.C. (¢ 7).
nicotine; "Medium" T/N, 17.6-25.7 mg tar and 1i.2-1L9 mg nicotine;
"Low"' T/N liess than 17.6 mg tar and less than 1.2 mg, nicotine: Table
22 shows the overall mortality ratios of male and female smokers by
these tar and nicotine levels. In this instance, the mortality ratio of the
"high" T/Ni smokers is represente& as 1.00 so as to iillzstrate the
reduction in overa'1l' mortality that occurs with lower T/N cigarettes.
There is a small but statistically significant (P. less than 0:0005)
reduction in the risk of dying withithe.use'of lower T/N cigarettes: The
mortality ratio was reduced to 0.91 for the "medium"'T/N smokers and
2-23
The following, is a summary of this research and our current
understanding'of this facet of human illlness in relation to tobacco use.
1. Tobacco and tobacco smoke extracts have been found to act as
antigens, including both precipitating and reaginic antibodies,, in
animals and man. These tobacco products can al§o sensitize lympho-
8. Because the ability to make a definitive diagnosis of tobacco
allergy is complicated by the difficulty in demonstrating a cause and!
and measurable degrees of physiologic impairment.
5. Alterations in assays of cell-mediated immunity are noted locally
and systemically in smokers.
6. Leukocytosis and reversible hypereosinophilia have been seen~ in
smokers.
7. Allergic individuals, particularly those with rhinitis or asthma,
may be more sensitive to the nonspecific effects of cigarette smoke
than healthy individ'uals.
(d) Alveolar macrophages from smokers have altered metabolism~
increased ~ compared to nonsmokers,
(c) Changes in the ultrastructure of macrophages are observed in
smokers.
(b) The number of macrophages isolated from smokers' lung fluid is
in the respiratory tract.
(a) Evidence indicates an adverse long-term effect on the mucocili-
ary transport mechanisms and mucus composition,
structures, and chronic smoking leads to consistent histologic changes
precisely define& role for tobacco in~ immune and allergic processes
cannot be delineated.
3. Several tobacco antigens have been isolated. However, epidemio-
logic studies on the frequency of true allergy to tobacco are
inconclusive.
4. Tobacco smoke exerts a variety of effects on respiratory tract
natural and derived components, additives, and contaminants that the
2. Tobacco and its combustion products present such ani array of
cytes participating imicell~mediated immune functions.
effect relationship between immunologic events and disease manifes-
tations, additionall evidence is required to establish a definitive role for
tobacco sensitization in causing allergic disease.
Involuntary Smoking -
The effects of involuntary smoking (passive or second-hand smoking)
on the nonsmoker were not examined or appraised in the 1964 report
but were initially discussed in the 1972 report, The Health Conse-
quences- of Smoking, and updated in the 1975 edition. The current
report's findings in this area are summarized below. It should be
understood that the literature is of recent vintage and~ onHy a limited
amount of systematic information regarding the health effects of
involuntary smoking on the nonsmoker is available.
ci
i r
x
s
d
a
e
['able. 4.-Mortality ratios for males currently smoking
ci~,rarettes only, by amount smoked ........................... 16
Table5:-Mortality ratios, for male cigarette-only smokers,
i)yy number of cigarettes smoked per day and' age. U.S.
vcterans 1954 cohort, 16-year follow-up :.....................17
Table 6.-Mortality ratios for male cigarette-only smokers,,
by number of cigarettes smoked per day and age. Males
in 25 States........................................................... 18
Table i.-Mort'ality, rratios for male cigarette-only smokers,
by number of cigarettes smoked per day and age:
Canadian pensioners ................................................ 18
Table 8.-Mortality ratios for male cigarette-only, smokers,,
by number of cigarettes smoked per d'ay and age. Males
in nine States ........................................................18.
Table 9.- Age-adjusted mortality ratios for male
cigarette-only smokers, by duration of smoking.
Canadian veterans .................................................. ,,,19
Table 10!-Age-adjusted mortality ratios for male cigarette
smokers who began smoking, after the age of 20, by
duration of smoking. U.S. veterans ...........................19'
Table 11.-Age-adjusted mortality ratios for male
cigarette-only smokers, by age began smoking. U.S.
veterans 1954 cohort ............................................... 20
Table 12.-Age-adjusted mortality ratios for male
cigarette-only smokers; by age began smoking. Japan.. 20
Table 13.-Age-adjusted mortality ratios for Japanese male
cigarette smokers; by age began smoki'ng and age at
start of study ........................................................ 20
Table! 14.-Age-adjusted~ mortality ratios for male
cigarette-only smokers, by age began smoking and age
at start of study. U. S. veterans 1954 cohort ............... 21
Table 15.-Age=adjpsted mortality ratios for male
cigarette-only smokers, by age began smoking and agee
at start of study. Males in 25 States ........................ 21
2-5
TABLE 30.-Mortality ratios of ex-smokers of cigarettes only
who quit smoking on doctors orders and for other
reasons, by certain dosage variables. U.S. veterans
1954 cohort, 16-year followup
Years since stopped smoking
Mortalityratios
Years, Quit for Quit on
since various doctors
stopped reasons orders
<5 1.23 1.55
5-9 L23 1.43
10-14 1.14 1.77
15-19 1.04 135
>19 1.06 1.16
Total 1.18' L52
Number of cigarettes per day
Mortality ratios
No: of Quit for Quit on
cigarettes various doctors
per day reasons orders
<10 1100 1.42'
10-20 1.17 1.48
21-39 1.W 1.53
>39 1.32 1.60
Total 1.18 152
Age started smoking
Mortality ratios
A
Age Quit for Quit on
began various doctors
(years) reasons orders
<15 1.36 1.59
15-19 120 1.55
20-24 1.12 1.49 :
>24 115 1.34:
Total 1.18' 1.52
SOURCE: Rogot, E. (93);
among smokers; compared to nonsmokers over the 16-year period. It
would be expected that the mortality experience of ex-smokers
initially would be similar to that of smokers, but with the passing of
time the mortality risk should move progressively closer to that of
nonsmokers. Figure 1 illustrates this. For ex-smokers who quit less
than 5 years prior to the beginning of the study, the mortality risk is at
2-29
qx
9.0
810
7.0 ',
6.0. ~
5.0 '
4.0
3.0
1.0~
0.9
0.8
0.7
0.6
:
p.--0 Never Smoked
p --G Ex-cigarette smokers
Stopped 5-9 years
Maximum amount smoked 21.39 cigarettes per day.
0.3
0----o Current cigarette smokers,
Smoking 21-39 cigarettes pecday.,
0.2
4
0!1
I 1 11 1 1 1 1 1, 1 1 1 1 1 1 11 1
1 2 3 4 5 6 7 8 9 10 111 12 13 14 15 16
YEARS OF FOLLOWUP
FIGURE 2.-Annual probability of dying for ex-smokers who quitt
smoking 5-9 years, current cigarette smokers and nonsmokers, aged
55-64, U.S. veterans 1954 cohort, 16-year follow-up
SOURCE: Rogot, E. (33).
2-32
036~~~,
"'8
8
J
qx
9.0
8.0
7.0
6.0
5.0
4.0
3.0
O---o Never Smoked -
P---ii Ex-cigarette smokers
Stopped 15 or more years ago
Maximum amount smoked 21-39 cigarettes per day.
0.3
0 ---0 Current cigarette smokers,
Smotdng 21-39 cigarettes per day.
02
1, 1~1 1 1 1 1 1' 1 I_ I _ I I t I i
1~ 2 3~~ 4 5 6 7 8~ '9'~ 10 11112 13~~ 14 15 16
YEARS OF FOLLONRJP
FIGURE 4.-Annual probability of dying for ex-smokers who quit.
15 + years, current' cigarette smokers and nonsmokers, aged 55-.64,
U.S. veterans 1954 cohort, 16-year follow-up
SOURCE: Rogot, E. (91),
2-34
Qx
9.0
8.0 ~
7.0
6.0
5.0
E
4.0 ~
3.0
8
J
0.3
0.2
O---O NevenSmoked
Q----0 Ex-cigarette smokers
StOpped: 10+14 years
Maximum amount smoked 21-39 oigarettes per day.
0----* Current cigarette smokers.
Smoking Q 1-39 cigarettes per, day.
I I 1 I I I I I I I I 1 I l 1 11
1 2 3 4 5 6 7 8 9' 10 11 12 13 14 15 16
YEARS OF FOLlOWUP
FIGURE' 3.-Annual probability of dying for ex-smokers who quit'
10-14 years, current cigarette smokers and nonsmokers, aged 55-64,
U.S. veterans 1954 cohort, 16-year follow-up
SOURCE: Roguti E. (dJ).
2-33
TABLE 33.-Age-adjusted mortality ratios for male cigar and
pipe smokers, by amount smoked. Males in nine
States
Type and
amount
smoked
Mortality
ratio
Nonsmokers 1.00
Cigar only
14 per day
1_03
4+ per day 124
All cigar smokers 1.09
Pipe onl y
1-10 pipefuls per day
1.05
10+ pipefuls per day 1119
All pipe smokers 1:09
SOURCE: Hammonda E.C. (20).
TABLE 34.-Age-adjusted mortality ratios for male cigar and
pipe smokers, by amount smoked. Canadian veterans
Type and
amount
smoked
Mortality
ratio
Nonsmokers 1.00
Cigar only
1-2 per day
1.14
3-10 per day 1.19
Pipe only
140 pipefuls per day
1.011
10+ pipefuls per day 1.00
SOURCE: Beati E.W.R. (1).
slightly below the mortality ratio of 1.55 of cigarette-only smokers who
have never smoked pipes or cigars.
The second, section of Table 40 shows that the mortality ratios of
current cigar smokers are: slightly decrease& among those also
currently smoking pipes and significantly increased among those also
currently smoking cigarettes. The third section shows that pipe
smokers with the : lowest mortality are those who have never smoked
cigarettes or cigars. Mortality ratios increase slightly with the addition
of current cigar smoking and jump moderately with the addition of
current cigarette smoking.
2-36
first nearly identical to that of smokers. Over the years, the risk
gradually falls to a position approximately halfway between that of
smokers and nonsmokers. Figures 2 and' 3 show that with longer
periods of cessation the mortality risk continues to approach that of
nonsmokers. In~ Figure 4, it can be seen that for ex-smokers who had
been off cigarettes for 15 or more years before the start of this study,
their mortality risk fluctuates about the mortality risk of nonsmokers
for the entire 16-year period.
The mortality experience of British doctors who were ex-smokers is
examined in Table 3L These data indicate that there are definite
benefits from quitting smoking no matter how long one has smoked.
Af ter 10 to 15 years, ex-smokers have a risk of dying that is similar to
that of those who have never smoked. The risk of dying from ischemic
heart disease decreases rapidly immediately after stopping smoking,
whereas the risk of dying from lung cancer decreases more slowly.
Overall mortality measures the net benefit of quitting, and, therefore,
drops more slowly than do d'eath rates for certain disease categories.
Mortality and Pipe and Cigar Smoking
Pipe and cigar smokers have mortality rates that are similar to those of
cigarette smokers for cancers of the oraU cavity, pharynx, larynx, and
esophagus. Pipe and cigar smokers have much lower death rates than
cigarette smokers for cancer of the lung; ischemic heart disease, and
chronic obstructive lung disease. Since these last three disease
categories account for the bulk of the excess mortality associated with
cigarette smoking, pipe and cigar smokers experience overall mortality
rates that are much lower than cigarette smokers. Inhalation~of smoke
is necessary to expose the heart and lungs to the harmful constituents
found in: tobacco smoke and pipe and cigar smokers report much less
inhalation of smoke than cigarette smokers. Pipe smoke and cigar
smoke contain nearly all the same chemical compounds found in
cigarette smoke, but pipe and cigar smoke tends to be alkaline in~ pH
rather than acid as is cigarette smoke. Alkaline smoke is irritating to
the respiratory tract. This is likely to be an important reason why pipe
and cigar smokers report a much lower level of smoke inhalation than
cigarette smokers.
Table 32 summarizes the mortality ratios for male smokers by thee
t'ype of tobacco used for the five studies that obtained data on~pipe and
cigar smoking. Cigar smokers have overall mortality ratios that are
from 6 to 25 percent higher than nonsmokers. Mixing cigarette
smoking with pipe or cigar smoking substantially increases the
mortality ratios, although they remain somewhat less than the
mortality ratios of cigarette-only smokers:
Dose-response relationships between overall mortality and thee
amount of tobacco smoked were examined in several studies. Data
2-30
TABLE 26.-Age-adjusted mortality ratios of female cigarette
smokers, by number of cigarettes smoked per day
and degree of inhalation. Subject's, aged 45-54 at'
start of study. 25-State Study
Number of
cigarettes Degree of inhalation of smoke
per day None-Slight Moderate-Deep
119 0.85 1.04
10 19 1.27 1.17
;t~-;;'9 1.41 1.581
161 + " 2.19
SOCRCE Hammond, E.C. (1Y):.,
TABLE 27.-Age-adjusted mortality ratios of female cigarettee
smokers, by number of cigarettes smok:,d per day
and age began smoking. Subjects aged 45-54 at
start' of study. 25-State Study
Number of Age began smoking
cigarettes
per day 25+ 1Fr29'
N,r,mokcrs 1100 1.00
0.95 0.88
ly 1.17 1,23
:i9 1.33 1i61
1'.85
`lTC'RCE: Hammond, E.C.,(17):
TABLE 28.-Age-adjusted mortality ratios of female cigarette
smokers; by number of cigarettes smoked per day
and degree of inhalation and age. 25--St'ate Study
Degree
of'' Age
inhalation 3.5--44 45-54 55-64 65-74 75-84
N,~nsmokem
\"ne 1.00
^ 1.00
1.01 1.00I
1.11 1.00
1.12 1.00
0.96
cht 1.22 1i21 1.28 1.26 1121
-furate 1.05 1.30 1.32 ll41 "
+'P 1.40 1.78 1.64
.~i~)C RCE: ~.H hmmond, E.C. (1 ,).
t'nited States. Smokers are now asking the question: "'W,i11 it help me
if I<<uit smoking?" Some of the first evidence concerning death rates
i~tl (,x-snlokersrequiredexplanation. The dat'a from the Hammond and
Elorn ,tuds of men in nine States are presented iniTabl'e29. It can be>kmn Uhat the
mortalit'yrat'ins of ex-smokers were liigheri~n the first
". caraCter quitting than for continuing smokers. After the first year,
2-27
TABLE 38.-Age-adjusted mortality ratios of current smokers of
pipes only, by amount smoked. U:S. veterans 1954
cohort, 16-year followup
No. of
pipefuls Mortality
ratio.
Nonsmokers 1.00
<5 0.93
5-9 1.12
10-19 1.08
> 19 1.21
Total 1.07
SOURCE: Ragot, E. (88).
TABLE' 39.-Age-adjusted mortality ratios of current smokers of
pipes only, by age began smoking. U.S. veterans
1954 cohort, 16-year followup
Age
began
years
Mortality
ratio
Nonsmokers 1.00
<15 1.0d
15-19 1.12
20-24 1.06
>24 1.06
Total i 1.07
SOURCE: Rogot, E: (ds).
in each of the eight prospective studies. These were classified
according to the International Statistical Classification of Diseases,
Injuries, and Causes of Death. The mortalityrat'ios of current cigarette
smokers by cause of death in the prospective epidemiological studies
are presented in Table 41. The causes of death have been grouped into
four categories: cancers, cardiovascular diseases, respiratory diseases,
and other conditions.
Mortality ratios for the "alll cancers" category are about twice as
high in smokers as in nonsmokers. Accordingly, cigarette smokers are
about twice as likely as nonsmokers to die of cancer. The highest
mortality ratio for malignancies is for lung cancer, followed'by cancer
of the larynx, oral cavity, esophagus, urinary bladder, and the
pancreas. Cigarette smoking, has been established as a major cause in
the development of these cancers. There are associations between
cigarette smoking, and cancer of the kidney and stomach, but further
research is needed to determine the exact nature of this association.
Cancer of the intestines and rectum do not appear to be related to
cigarette smoking.
2-38
TABLE 35.-Age-adjusted mortality ratios for male cigar and
pipe smokers, by amount smoked. Males in 25
States
Type and'
amount
smoked
Mortalityy
ratio.
No nsmokers , LOO
Cigar only
1-S per day
4 + per day
103
1.18'
All cigar smokers 1.09
Pipe only
1-9 pipefuls per day
1.08
9+ pipefuls per day 0.92
All,pipe smokers L04
SOCRCE: Hammond, E,C. (1n.
TABLE' 36.-Age-adjusted mortality ratios of current smokers of
cigars only, by amount smoked. US. veterans 1954
cohort, 16-year followup
No. of
cigars
per day
Mortality
ratio
Nonsmokers 1.0(1.
1-2 _ 1.11
3-4 1.13
5-8 1.22
9+ 129
Totgl! 1.16
SOURCE: Rogot, E. (sJ);
TABLE 37.-Age-adjusted mortality ratios of current smokers of
cigars only, by age began smoking. U.S. veterans
1954 cohort, 16-year followup
Age
began
(gears) Mortality
ratio
Nonsmokers 1.00
<15 1.22
15-19 123
20-24 1.16
>24 1.13
Total 1i16
SOl1RCE: Rogot. E. (39).
Mortafity by Cause of Death
The underlying cause of death was obtained from the death certificate
2-37
Intruduction
Cigarette smoking is the single most important environmental factor
contributing to premature mortality in the: United States. This
preventable, premature mortality is due to increased death rates
crmong cigarette smokers from several diseases, but primarily from
ischemic heart disease, cancersof the respiratory tract, and the chronic
nbstructive pulmonary diseases, emphysema, and chronic bronchitis.
The world's literature on smoking and! health at present consists of
more than 30;000' published articles from thousands of studies
(ronducted in every major country of the world. These data are housed
;n the fechnical Information Center of the Office: on Smoking and
liealt'h in the Department of Healths Education, and Welfare.
During the past 30 years, there have beeneight large prospective.
(,pidemiologicalstudiesconducted that were specifically designed to:
delineate the relationship between tobacco: smoking an& the develop-
ment of disease. Several of these studies were in progress at the time
') f the first report on smoking and health~ by the U.S. Government (37):
Within the past 2 years, reports on long-term follow-up have been
published from, four of these studies; which are still in progress (9; 19,
.11, .33): The longest follow-up comes from the study of British
physicians, from which, 20-year data have been published (9). The
largest study is the American Cancer Society study of men and women
in 25 States that enrolled more than one million subjects and is easily
one of the largest studies of all time. Twelve-year follow-up.d'ata from
t'hispopulation have been published (19). A representative population
study from Sweden includes data on men~and women (2).
The relationship between smoking and'overall mortality has been
reviewed by the Department of Healthy Education, and Welfare
severa[ times during the past 15 years. A report of the Advisory
Committee to the Surgeon General of the Public Health Service was
first published in 1964 (37). The subject was again reviewed in 1967,
1968, and1978 im The Health Consequences of Smoking(34, 35, 36):
The effect of cigarette smoking on overall mortality as reported in
the eight major prospective epidemiolbgica.l studies is summarized in
this chapter. Recently published data flrom these studies have resulted
in numerous refinements in our understanding of smoking and overall
mortality. The major conclusions drawn im 1964 still standbut they are
reinforced by the weight of evidence accumulated'from these and
other sources over the past 15 years. Conclusions regarding smoking
and overall mortality reported in previous reports willi not be presented
here. The summary appearing at the end of this chapter is a synthesis.
of all that is currently known about smoking and overall mortality. It
includes data: from previous reports as well as current conclusions
based on the most recently published data.
2-9
TABLE 1.-Mortality ratios, differences in mortality rates and
excess deaths by age as derived from two studies
Age
3,5-q4 45-,y11 5&-6t 65-74 75-84
Sl Velerans Study (Jnales)',
Total deaths 383' 366 13,840 17;$50 1,932'
Death rates: nonsmokers 127 264 1,056 2,411 6,214
D~ath rates: cigarett.esmokers 232 728 1,819 4,032 8,417'
:dortality ratio 1.83' 2.76 1.72' 1.67 1_36
Diff'erenoe in mortalit_v'
rates 105 464 763' 1~621 2,257'
Ezcess deaths as a
percentage of total 33 43 21 1T 8
Cr State StudV' (males)
Total deaths 631, 5,297 8,427' 8,1'L5 3,968
Death rates:,nonsmokers 210 406: 1j202 3,168 7,863
Death rates:,cigarette
smoker 397 925 2,202 4,788 9,674
Mortality ratim 1189 2.28' 1.83 1.51 1.23
Difference in mortality
rates 187 519 1,000 1,620 1,811
Excess deaths as a
percentage oftotal 33 38 25 13 4
SOURCE: Hammond, E.C. (t0); Kahn H;A. (26):,
1-year period for the smoker over that for the nonsmoker. As such, it is
a measure of personal healthsi~qn2ficance, a means for tiheindividual to
estimate'the added risk to which he or she is exposed.
3: Excess Deaths: Obtained by subtracting from the number of
d'eaths occurring in a group of smokers, the number of deat'hs that
wou1k3' have oceurr& if that group of smokers had experienced the
same mortality rates as a comparable group of nonsmokers. This
measure is an indicator of the public health significance' of the
differences; since it measures the number of people affected and,
thereflfore; the magnitude of the problem for society as a whole.
4. Life Expectancy: A concept that is easier to understand than to
calculate. At al given~ age, it represents the average number of years
one might be expected~ to live:
Table 1 illustrates the first three measures for five age groups of
men from the U.S. Veterans Study and the American Cancer Society
Study of Men in 25 States. Table 2' illustrates the effectof cigarette
smoking on life expectancy using data from~ the 25-State Study and the
U.S. Veterans Study. When~ compared to non-smokers, an average
young male smoker (30 to.40 years of age) who smokes more than 40
cigarettes per day lbses an estimated 8 years of life.
2-11
qx
9.0
6:0
7.0
6.0
5.0
4.0
3.0
O--0tA
.O'
fA"
0---0~ Never Smoked
Q-0 Ex-cigarette smokers
Stopped INss than 5 years ago
Maximum amount smoked, 21-39 cigarettes per day.
0.3
0.2
0.1
----* Current cigarette smokers,
Smoking 21-39 cigarettes per, day:,
1', 1 1 1 1 1 II I f 1 II 1 II 1 1 1
11 2 3' 4 5 6 7 8 9 10 11 12 13 14 15 16
YEARS OF FOLLOWUP
FIGURE 1.-Annual probability of dying for ex-smokers who quit
smoking less than 5 years, current cigarette smokers and nonsmokers,
aged 55-U, UIS. veterans 1954 cohort, 16-year follow-up
SOURCE: Rogot, E. (39).
2-31
8
TABLE 31.-Mortality ratios of ex-smokers compared to
nonsmokers, by age and number of years since
stopping smoking. Study of British doctors
Years since Mortality ratios
stopping
smoking . Ages
30-64 Ages
65+ All
ages
0(Current smokers) 2.0 1.6 L8
14 1.7 1.4 _ 1:5
5-9 1.6 1.4 1.5
10-14 1.4 1.2 L3'
15+ 1.1 1.1 1.1
Nonsmokers 10 1.0 1.0
SOURCE; Doll, R. (8).
TABLE 32.-Mortality ratios for male smokers, by type of
tobacco used
Study Non-
smoker Cigar
only Pipe
only Cigar
& pipe Cigarette
& C1gar
or pipe Cigarette
only
Men in 9 States(20)I 1.00 1.22' 1.12 1.10 1.43 1.68
British Doctors(4) 1.00 1!09 1.31 1.73
Canadian Veterans(1) 1.00 - 1.06 1.05 0.98 1.13 1.54
U:S. Veterans(26) L00' 1.16 1.07 1.08 1.51 1.55
Males in 25 States(1l) 1.00, 125 1i19 1.01 1.57 1.866
f rom the study of men in nine States, Canadian veterans, and the ACS
25-State Study are presented in Tables 33 through 35. There is a dose-
response relationship evident for cigar smoking that is small but found
consistently: There was no clear dose-response relationship for pipe
smoking. Data from the U.S. Veterans Study are presented' in Tables
36 through 39. Again, there appears to be a dose-response relationship
for cigar smoking, both for the number of cigars smoked per day and
for the age began smoking cigars. For pipe smokers, a dose-responsee
relationship was found for the number of pipefuls per day, but not for
the age began smoking.
The U.S. Veterans Study (31) contains the most detailed information
on pipe; cigar, an& cigarette smoking in various combinations and in
various sequences. These data on mortality ratios are shown~ in Table
40 and have been arranged by "increasing risk of mortality." The f irst
section shows the mortality experience of current cigarette smokers by
the present, past, or nonuse of pipes and cigars. Cigarette smokers who
have the lowest mortality ratio of 1.21 are those who also currently
smoke both pipes and cigars. Current cigarette smokers who formerly
smoked pipes and cigars have a mortality ratio of 1.48, which is only
2-35
CONTENTS
Introduction .............................................................. 5
Past Studies .............................................................. 5
Recent Studies .......................................................... 11
Conclusions ............................................................... 18
References ............................................................... 21
LIST OF TABLES
Table 1.-Age-specific ratios of prevalence rates of chronic
conditions for persons who had ever smoke& to persons
who had never smoked, by sex, age, and selected chronic
conditions: United States, Ju1y 1964 to June 1965 ........ 6
Table 2.-Ratios of age-adjusted prevalence rates of
chronic conditions for persons 17 years old and older
who have ever smoked, to persons who have never
smoked, by cigarette smoking status, number of
cigarettes smoked per day for present smokers-heaviest
amount, sex, and selected chronic conditions: United
States, July 1964 to June 1965 .................................. 7
Table 3.-Ratios of age-adjusted incidence of acute
conditions for persons 17 years old and older who havee
ever smoked, to persons who have never smoked, by
cigarette smoking status, number of cigarettes smoked
per day for present smokers-present amount, sex, and
selected acute conditions: United States July 1964 to
J u ne 1965 .............................................................. 9
Tablle 4.-Ratios of age-adjusted number of days of
disability per person 17 years old and older per year
3-3
analytic potential of the data to other researchers in the smoking area
through the use of NCHS's public-use data tape program.
TABLE 29.-Age-adjusted mortality ratios for males who are ex-
smokers: of cigarettes, by former amount smoked per
day and years since stopped smoking. Males in nine
States
Years since
stopped Cigarettes formerly
smoked per day
smoking 1-19 20+
0 (Smokers) 1.61, 202
Under 1 2.04 269
1-10! years 1.30 1.82
10+ years 1.08 1.50
however, death rates' for ex-smokers fell progressively so that after 10
years the former smokers of 1 to 19 cigarettes' had a: mortality ratio of
only 1.08.
The explanation for the.higher death rates in the 1styear after
quitting, is found in the fact that both healthy and sick individuals quit
smoking. The higher mortality ratio is experienced by those who quit
because of illness and not by those who quit for better health, In the.
study of U.S. veterans, a: differentiationi was made betweeni ex-
smokers who stopped smoking on the recommendation of a doctor and
those who quit for other reasons. About 10 percent of the smokers quit
on doctors' orders; this group had much higher mortality ratios than
those who stopped for other reasons.
These data are presented in Table 30; where the mortality ratios for
ex-smokers by "years sinee' stopping smoking," "maximum amount
smoked," "age began smoking," and "reason for quitting" are
examined. There'. is a direct relationship between mortality rates and
the maximum amount smoked, an inverse relationship between
mortality and "yearssince stopped smoking," and also an inverse
relztionship: bet'tiaeen mortality and "age began smoking."
A detailed analysis of the mortality experience of ex-smokers who
stopped for reasons other than doctors' orders is given in Figures 1
through 4. This information is on ex-smokers, aged! 55 to 64, from the
1954 cohort of the U!.S. Veterans Study, who formerly smoked from 21
to 39 cigarettes per day. "Years since stopping smoking" is consideredl
as a variable and the mortality rates are compare& with those of
current cigarette smokers and nonsrnokers: Annual probabilities of
dying are plotted on a logarithmic scale. This results in a fairly smoothi
and linear pattern for both smokers and nonsmokers. These lines also
appear to be parallel, or perhaps to diverge slightly. This indicates an
approximately constant or slightly increasing excess risk of dying
036`>5'700
9
'I' ABLE 14.-Age-adjusted mortality ratios for male cigarette-only
smokers, by age began smoking and age at start of
study. U.S. veterans 1954 cohort
Age began
kin Age at start ofl study
g
smo
in years
30-U
35--44'
4b.54
55-64
85-74'.
'nsmokers 1'.00 1.00 1;00 1.00 1.00:
48'
1 ll67 1
36 1.20:
~ 24 1.41 .
1.87' L72 .
1.56 , 1.39'
.9 1.44 2.00 2.17 1.70 1.45.
::ien 15 2.00 2.1s' 2.25 2.02' 1.42
SOURCE: Rogotj E. (9:, s9).
TABLE 15.-Age-adjusted mortality ratios for male cigarette-only
smokers, by age began smoking and age at start of
study. Males in 25 States
Age began
smokin Age at start of studyy
g
in~vears
45-.54
55-64
65-74:
75-84
.`~ nnsmokers 1.00 1.00 1.00 1.00
0+ 1.40 1.33 1.23 1.10
:S-P.9 1.81 1.75 1.25 '"
'11' ? 1 2.13 1:73 1.52 1.27.
:5.19 2.49 2.11 1.84 1.58
Under 15 3.01 2.26 2.00 1i59
SOURCE: Hammond, E.C. (17).
TABLE 16.-Age-adjusted mortality ratios for male cigarette-only
smokers aged 55-64, by age began smoking and
current number of cigarettes smoked per day. Maless
in 25 States
Age began
smokin Current number of cigarettes, per dayy
g
in years
Nonsmokers
1-9
10-19
20-39
40+
25+ 1.00 1.34 1.68 1.48' 1.77'
15-?A' 1.00 1.45 1.89 2.05 2.23'
Under 15 1.00 " 2.15 2.191 2.'58'
SOURCE: Hammnnd, E.C. (I7).i
expose target organs directly or through absorption of toxic substances
into the circulatory system. Ischemic heart disease, lung cancer, and
chronic obstructive disease are not as likely to develop~ in individuals
who do not inhale smoke. Techniques for quantitating inhalation have
been developed using carboxyhemoglobin as an index of smokee
inhalations but these methods have not beeni applied to studies of
overall mortality. Most studies asked the smoker to report subjectively
2-21
TABLE 25.-Age-adjusted mortality ratios of female cigarette
smokers, by number of cigarettes smoked per day
and age. 25-State Study
Number of'
cigarettes Age
per day 3.5 -44 45-54 55-64 65-74 7584
Nonsmokers 1.00 1.00 1.00 1.00 1.00
1-9 0.90 0.95 0.99 1.09 1.0T
10-19 0:97 1i22 1.31 1.1s 1.211
20-39 1.35 1i54 1.46 1.51 "
SOURCE: Hammond, E.C. (I7);1
outside the home match the smoking habits of men in various
occupations where men and women hold equal positions. Women with
the lowest rate of smoking are housewives who at present have few
mal'e counterparts with whom to identify.
Recent surveys have shown that women are also concerned about
weight gain that may accompany quitting smoking. Any significant
weight gain on quitting represents an increased intake of food, but if
one watches the diet on smoking cessation, weight gain can be avoided;
in fact, weight loss can be achieved!
In recent years, a few investigators have studied the relationships
between cigarette smoking and the development of lung cancer and
coronary heart disease in women. Death rates for these diseases are
similar in, women and men who have similar levels of exposure to
cigarette.smoke; the associations are outlined in later chapters dealing
with specific diseases. Overall mortality rates for women available at
present are from studies initiated 10 to 20 years ago, and thus reflect
the differences in accumulated exposure that were operative at that
time.
Overall mortality in women, varies in the same direction and in a
similar degree as men for the dosage variables commonly measuredl
Overall mortality for women increases with the number of cigarettes
smoked per day (Tables 25, 26, and 27): Table 26 shows that the overall
mortality ratio is 2.19 for females smoking more than: two packs a day
and inhaling moderately to deeply. Table 27 demonstrates that the
mortality ratio is 1.85 for females smoking more than two packs per
day who began smoking between the ages of 15 and 24. Mortality
ratios by "inhalation" and "age at start of study"' are shown ini Table
28. Noninhaling smokers have mortality ratios that are similar to
nonsmokers. Females withi an average age of 50 who inhale smoke
deeply have a mortality ratio of 1.78.
Mortality and Ex-Smokers
There is a: general recognition among smokers and nonsmokers alike
that cigarette smoking is a major cause of disease and deathi in the
2-26
Data from the United States and Swedish Twin Registries have beenI
examined to try to clarify the constitutional hypothesis. Cederlof, et al.~
(3) have published the most extensive data available on the interac-~
tions of smoking, environment, and heredity in the development of ,J
disease. Comparisons were made between smoking discordant monozy- ~
gotic (identical) pairs and smoking discordant dizygotic (fraternal) {
pairs, and between unmatched, twin pairs and matched twin pairs. j
When smoking and overall mortality are examined, treating all twins `,!
as "unrelated" individuals, a: strong correlation is found. The group ~
smoking more than 10 cigarettes per day has a: mortality ratio of about
°
2.0 compared to nonsmokers. This is true for both men and women in "~
all age groups.
When smokers and nonsmokers among the dizygotic pairs were ~J
compared, a mortality ratio of 1.45 for males and 1.21 for females was ~
observed. Corresponding mortality ratios for the monozygotic pairs ~
were 1.5 for males and 1.22 for females. Commenting on the
constitutional hypothesis and lung cancer, the authors observed that
"the constitutional hypothesis as advanced by Fisher and still
supported by a few has here been tested in twin studies. The results
from~ the Swedish monozygotic twin series speak strongly against this
constitutional hypothesis" (3):
Preston (27-30): has published several articles in which he examined
the excess mortality-above predicted values for men and women-
that has occurred in the United States and other countries. Genetic,
social, and environmental, factors were analyzed'n in ani attempt to
explain this phenomenom The genetic and social hypothesis received
some support from correlation analysis; however, the correlations were
weak and became trivial when cigarette smoking was taken into
consideratiom Prestoni observed: "Rather thani representing victimiza-
tion by nature or by hostile social forces, the current abnormal rates of
dying among older males appear to be largely self-imposed and
avoidable" (28),
Social, genetic, and environmental arguments are also weakened by
the observation that epidemiological studies of the effects of cigarette
smoking have been conducted in many countries on every major
continent and among peoples of diverse sociali and culturali back-
grounds who are exposed~ to a variety of environmental factors-all
with similar results. Cigarette smoking causes the same diseases, and
the same dose-response relationships are found wherever the effects of
cigarette smoking are studied.
Summary of Overall Mortality Related to Smoking
The following conclusions summarize the relationships that have been
established between smoking and overall mortality. Some conchisions
were drawn 15 years ago; others are based on data that have
2-42
(13) NATIONAL CLEARINGHOUSE FOR SMOKING' AND HEALTH. Smoking
and Illness. U.S. Department of Health, Education, and Welfare, Public
Health Service, Bureau of Disease Prevention and Environmental Control,
National Center for Chronic Disease Control;, National Clearinghouse for
Smoking and Health, PHS Publication Nb. 1662, July 1967,6 ppi
(1/,) WILSON R.W. Cigarette Smoking and Health~ Characteristics. United States,
July 1964-June 1965. U.S. Department'of Health, Education, and Welfare,
Public Health, Service, National Center for Health Statistics, Series 10, No. 34,
PHS Publication No. 1000May 1967,64 pp.
(15) WILSON R.W. Cigarette smoking, disability days and respiratory condition.
Journal of Occupational Medicine 15(3): 236-240, March 1971
(16) WILSON R.W. Testimony presented at Regional Forum sponsored by the
National Commission for Smoking and Public Policy. Philadelphia, June 16,
1977, 27 pP-
4
-,
3-22
TABLE 24.-Overall mortality ratios of cigarette smokers
compared to nonsmokers, by sex and by tar and
nicotine cont'ent of cigarettes usually smoked
,yY
le
Ls
-e
Sex Non-
smokers "Low"'
T/N "Medium"
T/N "High"
T/NI
S1aILs 1.00 1.66 1.85 1.96'
Fcmales 1U)0 1.37i 1.45 1.65.
Total 1.00 1.52 1.64 1.80
SOCRCE: Hammond, E'.C. (19):..
reference. Combining these data: from two separate analyses that are
not, exactly comparable result's in figures that are only approximate.
Hammond (19) also compared death rates of smokers of relatively
few (1-19) "high" T/N cigarettes with those of smokers who smoked
relatively large numbers (20-39) of "low" T/N cigarettes. The death
rates of these two groups were very similar and the differencee
between them was not statistically significant.
Mortality and Female Cigarette Smokers
It is important that attention be called~ specifically to the mortality
that females experience as a result of cigarette smoking. There has
been an increase in smoking among teenage girls over the past 10
years. At present, the percentages of teenage boys smoking and
teenage girls smoking are nearly identicall For some ages, there are
more teenage girl smokers than boy smokers. Over the past 10 years,
there has been~ a gradual: reduction in the percentage of the adult
populat'ion that, is smoking. Men have quit in greater numbers than
women. There has been~only a modest drop in~the percentage of'women
who are smoking, In~ Canada and several European countries,, smoking,
is decreasing among men but increasing among women. In the Unite&
States, physicians, dentists, and pharmacists have been the most
successful professional groups in giving up: smoking, but in the past
several years there has been~ an increase in smoking among nurses.
Severall suggestions have been made as to why women, do not quit
smoking. It may be that women do not generally perceive smoking as a
threat to their health. Lung cancer, heart attacks, and emphysema are
diseases that affect men more commonly than~ womem Women may
feel that they are in a low-risk group. Women took up smoking later
than men, generally smoked filter cigarettes, and smoked fewer
cigarettes per day than men. Lower overall death rates for women
smokers.are due to lower exposure.to~cigarett'e smoke.
Cigarette smoking for some women may be symbolic of equality
With men. It is known that the smoking habits of women employed'
2-25
nily
)nal
ype
age
and
,ent
,ans
)53.
een
rall
lied
ere
s im
91
'his
, of
try,
ern
1ad~
Cfiee
ta
by
are
.da,
of
or
dy,
ses
jor
of
of
on
nd
g-
ig
}iistory, residence, and occupation. During the 6 years of follow=up
there were 9,491 deaths of males and 1,794 deaths of females. Noo
recent follow-up has been reported.
The American Cancer Society 9-State Study (20)
I n this study, 187,783 white males were followed for an average of 44
months. The study began in early 1952. There were 11,870 deaths in
this population aged 50 to 70. The last significant report on this study
was published in 1958.
(California Men in Various Occupations (12)
1'his study examined the: mortality experience of 68,153 men, 35 to 64
years of age, over a period of 482,658 person-years of observation. A
total of 4,706 deaths occurred. These meni were in nine occupational
groups. The last published report from this st'udywas in 1970.
The Swedish Study (2)
A probability sample of 55,000 Swedish men and women was surveyed
i n 1963. A 10-year follow-up on smoking-related mortality was
published in 1975.
Mortality and Male Cigarette Smokers
Overall mortality rates for male cigarette smokers are significantly
higher than for nonsmoking males: The mortality ratios are as low as
1.25 for Japanese males and as high~ as 1.83 for the males in. the ACS
95-State Study. These results are shown in Table 4. Important evidence
for a causal relationship between smoking and overalll mortality is the
demonstration of dose-response relationships. In most epidemiological
studies, dosage has been measured by the number of cigarettes smoked
d'aily at the time of entry into the study. Other dose variables include
the maximum number of cigarettes smoked per day, age began
smoking, the depth of inhalations years of smoking, pack-years, tar and
nicotine levels of the brand of cigarettes used, the number of puffs per
cigarette, and the length of the unburned portion of the cigarette, as
well as combinations of these variables into various dosage scores: Alll
of these dosage variables have been shown in one study or another to
contribute to~ the degree of risk involved in smoking. Several of the
d'osage variablles as related to overall mortality are examined in this
section,
Mortality and Amount Stnoked
Mortality ratios for males currently smoking cigarettes only by
amount smoked are presented for the eight major prospective studies
in Table 4'. Even males smoking one to nine cigarettes a day have a
2-15
Table 2.-Coronary heart disease! mortality ratios
related to smoking-prospective studies ...................... 22
Table 3.-Coronary heart disease morbidity as related to
smoking ................................................................ 27
Table 4'.-The effect of the cessation of cigarette
smoking on the incidence of CHD ............................. 34
Table 5:-Annuall probability of death from coronary heart
disease, in current and discontinued smokers, by age,
maximum amount smoked, and age started smoking.... 35
Table 6.-Coronary heart disease morbidity as related to
smoking-.angina pectoris-prospect'ive studies ............. 47
Table 7.-Age-standardized death rates and mortality
ratios for cerebral vascular lesions for men and
women, by t'ype of smoking (~lifetime history) and age
at start of study .................................................... 51
4-5
TABLE 13.-Percent of persons 17 years old and older who have
been told by a doctor that they had heart trouble,
by cigarette smoking status, sex, and age: United
States, 1974
Sex and age
Total Present
smoker Former
smoker Never
smoked
Both sexes
17+ 9.0 7.8 12.9 9.4.
17+-44, 42 4.8 4':7 4.1
45-64 11.1 11.6 14!9 9.9
fi5 +
Male 22.9 17.9 28.5 23.3
17+ 8.9 8.2 13.8 8.4
17-44: 3.8 4.5 4.7 3.6
45-fi4' 12.0 13.0 15.2 10.0
65+
Female 24;5 18.6 28.5 26.5
17+ 9.0 7.4 11.4 9.9
17-44 4.6 5.1 4.9 4.4
45-64 10.3 10.0 14.3' 9,9
65+ 2L8 16.8 28.5 22.4
60URCE: Wilson, R.W: (I6):
Surgeon General's report was issued, largely as a result of data
collected from national probability surveys conducted by NCHS. These
data range from the standard health indicators, such as measures of
chronic and acute illness and measures of disability days, to less
commonly used~ indicators' of lifestyles. The results of analysis
performed~ on these' data vary from the more frequently reported
findings on, disability to data from the Index of General Psychological
Well-Being, first reported in this chapter.
The findings tend to be consistent with the large amount of evidence
on the relationship between cigarette smoking and mortality, i.e.,
people' who smoke cigarettes report more illness and disability than
people: who have: never smoked cigarettes. While many studies show a
reduction in the risk of mortality among former cigarette smokers,,
data on disability and illness often show continued high risk for former
smokers, indicating both a: lack of refinement in the current data to
distinguish between types of former smokers as well as the fact that
once certain diseases' occur they do not go away.
The most important aspect of these data collected by NCHS lies not
ini the substantive analysis prepared by the NCHS staff, but ini the
3-19
TABLE 4.-Ratios of age-adjustedl number of days of disability'
per person 17 years old and older per year who have
ever smoked, to persons who have never smoked, by ~`
number of cigarettes smoked per day for present ,,
smokers-heaviest amount, type of days of disability,,
smoking status, and sex: United States, July 1964 to
June 1965
Present smokers
Number of cigarettes
Type of disability
smoking status
days Total I smoked' per day-heaviest
,
,
smokers
amount
and sex
Under 21
0 41 and
11 ,
11-20
-4 over
Ratio1
Days of work
10883
Present smokers
Male ................. . .... 1.33 0.87 1.35 1i41 1.65
Female ...................
Former smokers 1.45 1.09 1:57 1183 274
Male ...................... 1i41 1.28 1.26 1.70 2.17
Female ...................
Days of bed
Disability
Present smokers L43 1.34 1.66 1.72
Male ...................... 1.14 0.98 1.20 1.16 1.49
Female...................
Former smokers 1.17 0.92 1.09 1.59 2.63
Male ........ .............. 1.31 1.27 124 1.45 1.65
Female ................... 1.39 1.09 1.61 1.49 4.57
t
t
'Adjusted by the indirect method to the age distributimnof the total civilian, noninstitutional
population of the
Uhited Statea -
2Daye of disability of given smoking category divided by days of diaabilityof "never emokers`
3Daya of work loas reported for currently.employed persona onl,¢. .
Figure: does not meet standards of reliability or precision.
SOURCE:: Wilson, R.W. (14).
The following year NCHS also collected data on smoking and
published' a report, Changes in Cigarette Snwking Habits Between 1955
and 1966 (1), which compared the 1966 data with similar data: collected
earlier as a part of the Current Population Survey conducted by the.
Bureau of the Census (4). The Census data, however, did not include
any health-related information. NCHS continued to monitor cigarette
smoking levels, but with no health data, in 1966, 1967, and 1968
3-10
036t 5'764
,
TABLE 9.-Percent of persons 17 years old and older, with one
or more hospital episodes in the year prior to
interview, by cigarette smoking status, sex, and age:
United States, 1974
~
Sex and age
Total Present
smoker Former
smoker Never
smoked
17+ Both sexes
13.1
18:5
14.4
12.7
17-44 12.3 13.8 lli7 12.0
45-64 12.9 12.3 15.1 12.1
65+ 16.5 16.5 19.7 15.3
17+ Male
10.2
10.5
12.8
8.3
17,44 7.0 8.6 8.0 5.3
45-64 13.1 12.4 14.5 12.5
65+ 17A 19:0 18.5 14.9
17+ Female
15.7
16.9
17:5
14.7
17-44 17.2 19.5 16.8 15.9
45-64 12.8 123 162 12.0
65+ 15.8 12.9 23.1 15.4
SOURCE: Wilson, R.W. (1B):
not only for increased public education, but also for increased
educational programs among health ~ professionals. About t'wo-thirds of
all present smokers had tried~ to stop smoking at some time (Table 12).
Since detailed smoking history information was not obtained it is
difficult with these data to determine the more precise relationships
between illness, physicians' advice to stop smoking, and' actual
attempts to stop. Some of the studies conducted in the past by the
National Clearinghouse for Smoking and Health and reported
elsewhere in this report have attempted to investigate these relation-
ships as well as some of the more attitudinal and psychological aspects
of smoking.
Respondents to the Health Interview Survey were asked if a: doctor
had ever told them they had heart trouble: Among persons under 65
years of age, a larger proportion of both, present smokers and former
smokers had been told that they had heart trouble compared with
persons who had never smoked (Table 13). For example, 15 percent of
the male former smokers aged 45 to 64 had beeni told they had heart
trouble compared to 10 percent of those who had never smoked. There
is some difficulty interpreting the data for persons over 65 years old,
where a higher proportion of those who had never smoked report heart
3-16
TABLE 7.-Percent of persons with chronic condition(s) causing ~ 7
limitations of activity, by cigarette smoking status,
sex, and age: United States, 1974
Sex and'age
Total Present
smoker Former
smoker Never
smoked
Both sexes
17+ 18.6 17.3' 22:4 18.9
17,44 8.8 9.8 9.4 8.0,
45-64' 23.7 26:2 24.7 22.3
65 k
Male 45.8 46.3 49.2 44.7
17+ 18.7 18.7 23.5 17.3
17-4 9,0 10.0 8.8 8.4
45-64 23.7 27.8 23.8 20.0.
65+
Female 51.0 52:5 50.9 514
17+ 18.4 15.8' 20:6 19.7
17-44 8.6 9.5 102 T8
45-'i4' z3.8' ?r1.4 .26.5 23.1
65+ 42.1 37.4 44.6 42.6
SOURGE: Wileon, R.W. (16):
interview surveys, there is a selectiom process by mortality thatt
removes a certain number of smokers and former smokers from the `i
data base. In addition, the group of former smokers is made up of two z~
very different kinds of people-those who quit smoking before there
was any noticeable deleterious impact on their health and those who
quit smoking because of poor health. There are some recent data from
the Health Interview Survey, althoug4 not yet fully analyzed, that
indicate whether the respondent quit smoking because of a specific
condition.
Respondents in the Health Interview Survey were asked whether
they perceived their health to be excellent, good, fair, or poor.
Although the differences are not large, there is a tendency for higher
proportions of former smokers and of those who have never smoked to
report their health status as excellent (Table 8). For example, among
males 17 to 44 years old, about 53 percent of the present cigarette
smokers said their health was excellent compared with~ about 60
percent for both the former smokers,and'those who had never smoked.
The data also indicate that smokers and former smokersare more
likely to: be hospitalized in the year prior to the interview than are.
persons who have never smoked (Table 9), However, the data have not
3-14
CONTENTS
Atherosclerosis ........................................................... 7
The Nature of Atherosclerosis in Man ..................... 7
The Effect of Smoking on Atherogenesis ................ 10
Experiments in Animals ....................................... 16
Research Needs ................................................... 18'
Conclusions ......................................................... 19
Myocardial Infarction ................................................. 19
The Nature of Myocardial Infarction...................... 19
Summary of Epidemiological Data ......................... 20
The Effect of Smoking on Myocardial
Infarction in Man ............................................. 38
The Effect of Smoking on Myocardial
Infarction in Animals ........................................ 40
Research Needs . .................................................. 40
Conclusions ......................................................... 41
Sudden Cardiac Death............................................... 41
The Nature of Sudden Cardiac Death in Man.......... 41
Sudden Cardiac Death in Animals .......................... 43
Summary of Epidemiological Data: ......................... 43
The Effect of Smoking on Sudden Cardiac
Death in Man .................................................. 44
The Effect of Smoking on Sudden Cardiac
Death in Animals ............................................. 45
Research N eeds ................................................... 45
Conclusions ......................................................... 45
Angina Pectoris ........................................................46
The Nature of Angina Pectoris in Humans .............46
Summary of Epidemiological Data ......................... 46
The Effect of Smoking on Angina Pectoris ............. 48
Research Needs ................................................... 48
Conclusions ......................................................... 49
Cerebrovascular Disease .............................................. 49
The Nature of Cerebrovascular Disease in Man........ 49 O
W
~
Summary of Epidemiological Data ......................... 50
The Effect of Smoking on~ Cerebrovascular Disease.. 50
C11
~
4-3 N
14. Ex-smokers who were ill when they quit smoking have higher
mortality rates thaniex-smokers who quit for other reasons..
15. Regardless of how long or how much an individual has smoked,
there is a decrease in overalli mortality when the person quits smoking,
provided the person is not ill at the time of quitting.
16. Overall mortality ratios for cigar-only smokers as a group are
somewhat higher than for nonsmokers.
17. Overall mortality ratios for cigar smokers increase with the
number of cigars smoked per day.
18. Overall mortality ratios for cigar smokers are inversely
proportional to the age at which the individual began smoking cigars.
19. Overall mortality ratios for pipe-only smokers as a group are only
slightly higher than for nonsmokers.
20. Overall mortality ratios of men who smoke cigarettes in
combination with pipes and~cigars are intermediate between those who
smoke pipes or cigars only and those who smoke only cigarettes.
Summary of Smoking and Mortality by Cause of Death
1. Mortality ratios are particularly high for a number of diseases
associated' with ~ smoking. These include:
a. Cancer of the lung
b. Chronic obstructive lung diseases, emphysema, an& chronic
bronchitis
c. Cancer of the larynx
d! Cancer of the oral cavity
e. Cancer of the esophagus
f. Ischemic heart disease
g. Cancer of the urinary bladder
h. Cancer of the pancreas
i. Aortic aneurysm (nonsyphilitic)
jL Ulcers of the stomach and duodenum
2. Coronary heart disease is the chief contributor to the excess
mortality associated with cigarette smoking.
3. Lung cancer is the second leading contributor to excess mortality
associated with cigarette smoking.
4. Chronic obstructive lung disease is the third leading contributor to
excess mortality associated with cigarette smoking,
5. Pipe smoking and cigar smoking are associated with elevated
mortality ratios for cancers of the upper respiratory tract, including
cancer of the oral cavity, thelarynx, and the esophagus.
0
2-44
TABLE 1.-Age-specific ratiosl of prevalence rates of chronic ~
conditions for persons who had ever smoked to ~
persons who had, never smoked, by sex, age, and
selected chronic conditions: United States, July 1964
to June 1965
Male Female
All Alli
Selected chronic conditions
ages,
17-44
45-64
65+
ages,
17-44
45-64
17+ years years years 17+ years years
years years
Ratio
All chronic conditions......... 1.09 1.272 1.17 1.09 0.90 1.26 1.02
Heart conditions (excluding
rheumatic heart': disease)~......
1.00
1.45
1.06
0.47
1.33
0.92
Arteriosclerotic heart
disease including
coronary disease ............. ..
ll50
t',
ll.80
1.22
0.75
t
1.63
H rtension without' h'eart
ype
involvement ......................
0.91
1125
0.86
0.95
0.57
117
0.75
Chronic bronchitis and/or
emphysema......................
2:30
2.67
2.38
3.43
2:86
Chronic sinusitis .................. 1.35 1.38 1.31' 1.34 1.25 1.34 1.19
Peptic ukber ....................... 2.00 2.38 1.88 1.59 1.56 1.82 1.52
Arthritis ........................... 0.95; 1.64 0.99 1A6 0.63 1.32 0.89
Hearing impairments............ 0.88! 1.31 1.06 0.97' 0.55 1.05 1.02
All other chronic
conditions ........................
1.07
1.19
1.15
1.08'
0.95
1.23'
1.03'
;{
65+
years
0.99
0.89 ;.;
'l
2.16
1.22
2.35
:
0.97 :
0.75 ,,
,
0.99
'Prevalence rate.of"ever smokers" divided b'y.prevalenoe rate of "never smokers."
y?
tExample: 1.27 - 829 65.4. i;
Figuredoes not meetstandArdsotreliabiliti.y or precision.
}Quantityy zero: -
30URCE: Wilson, R.W.(d;). .
percent more likely to report arteriosclerotic heart disease (Table 1).
Among the heaviest smokers the.relationships were even stronger. For
example, women who smoked between one and two packs a day
reported chronic bronchitis or emphysema almost five times more
frequently than did women who had never smoked (Table 2). In
addition, former smokers, particularly among the males, reported
higher rates of chronic illnesses than did the current smokers: Data
were not available to further analyze illness rates by the reason people
stopped smoking, i.e., the category of former smokers is composed of
both those who stopped because of poor health and those who stopped
to avoid poor health.
Data from~ this study also indicated that people who had ever smoked
cigarettes also had a: higher incidence of acute illnesses than di& people
who had never smoked. The age-adjusted incidence of acute conditions
3-6
for persons who had ever smoked was 14 percent higher among men --.
and~ 21 percent higher among women than among people who had
never smoked cigarettes (Table 3). As with chronic conditions, t'he,
former smokers reported higher rates of acute illness than did the "
present smokers.
However, just as t'he earlier studies were subject to criticism1 because
of their sample designs, this study was criticized because the disease'
information came from reporting in household interviews rather than '
from physician examination. Methodological studies on the accuracy of
the reporting of disease in which medical records are compared with `
household interview data have indicated a wide range of reporting :
completeness depending on the nature and the seriousness of the
specific disease (7).
Another indication of morbidity is the impact of illness on the _]
individual. Two of the indicators routinely collected in~ the Health ,
Interview Survey are the number of days lost from~work as a result of
illness or injury and the number of days which a person had to spend in
bed as a: result of illness or injury. These indicators are independent of
a physician's diagnosis and require only that a respondent attribute the
disability to an illness or injury, although the data: can also be analyzed
by specific disease categories. The data collection procedure requires
that respondents recall days spent in bed or days lost from work only
for the 2-week period prior to the week of the interview, thus reducing
memory loss. The data on work-loss days apply to currently employed
persons only and do not reflect long-term work loss from unemploy
ment or early retirement' as a result of illness or injury.
The age-adjusted'~ data from the 1965 Health Interview Survey
indicated that there were about 15 percent more bed-disability days
among current smokers than among people who had never smoked
cigarettes, and about a third more bed disability days among the
former smokers than among those who had never smoked (Table 4).
The levels of bed=disability days tended to increase as the number of ;
cigarettes smoked increased, as measured by the heaviest amount ]
smoked.
The number of work-loss days among both current an& former
cigarette smokers was markedly higher than among workers who had
never smoked. The age-adjusted rate of work loss was 33 percent
higher for male current smokers, 45 percent higher for female current
smokers, and 42 percent higher for both male and female former
smokers: As with disease and bed-day differentials, the heaviest'
smokers reported the highest rates of work loss. These data were used
by the Public Health Service in~its early national public ed'ucation~and ~
antismoking campaigns. The campaigns included television spots that 1
noted there were an estimate& 77 million "excess" work-loss days
associated with cigarette smoking; that is, if the sinokers had the same
rate of work loss as dU those workers who had never smoked, there
3-8
®
TABLE 3.-Ratios of age-adjust'edl incidence of acute conditions
for persons 17 years old and older who have ever
smoked, to persons who have never smoked, by
cigarette smoking status, number of cigarettes
smoked per day for present smokers-present
amount, sex, and selected acute conditions: United
States, July 1964 to June 1965
Cigarette smoking status Present smokers
Sex and selected
acute conditions
Persons
who Former Present
ever smokers smokers
smoked
Number of' cigarettes
smoked per day-present:
amount:
Under 11~-21) 21-40 , 41 and
11 over
Male R2tioz
AIl' acute conditions .......... 1.14 1.23 1.11 1.02 1.11 1.23 1.21
Infective and parasitic
diseases ....................... 1.21 1.36 1.16 1.24 1.59
Upper respiratoryy
conditions ..................... 1.03 1.22 0.96' 0.98 0.98 0.92 '
I nfluenza ................. ...... 1.25 1.36 1.22 122 1.19 1.28
Other respiratory
conditions ..................... 1.62: ' 1.54
Digestive system conditions:. 1.05 1.13 1.03' ' 0.90 1.41
Injuries ......................... 1.25 1.03 122 1.00 1.3.5 1,56
All other acute conditions ... 1.06 1.35 0.95 1.08 0.85 1.11
Female
All': acute conditions .......... 1.21 1.26 121 1:18 1.20 P:31
Infective and parasitic
diseases ....................... 1.35 1.62 129 ll26 1.04 2.29 t
Upper, respiratoryy
'
conditions ..................... 1.26 1.20 1.27 1i29 128 126
InflUenza ....................... 1.13 1.28 1.09' 1;23 1.03 0.99
Other respiratory,
conditions ..................... 1,68 ` 1.74
Digestive system conditions.. 1107 ' 1.04 0.78 1.05 ` '
lnjuries......................... 1i14 1.04: 1.17 0.89 1.40
All other acute conditions ... 1:22 1.31 1.19 1.29 1.15 1 113
'Adjusted by the indirect method to.the age distribution ~of the total civiiiannoninstitutional
population of the
United. StBtes.tIncidence rate for~ given smoking category dividtd by incidence rate for "never
smokers."
'FPgure does not meet standards otreliability or precision. ~
tQuantity zero..
SOURCE: W ilson, R. W. (14).
would have been 77 million fewer days lost from work (13). Thiss
represented 19 percent of all work-loss days from illness at that time.
More recent data are presented below.
3-9
Research Needs ................................................... 52
Conclusions ......................................................... 52
Peripheral Vascular Disease ........................................ 52
The Nature of Peripherall Vascular pisease in Man.. 52
Summary of Epidemiological Data ......................... 53
The Effect of Smoking on Peripheral
Vascular Disease .............................................. 53
Research Needs ................................................... 54
Conclusions ......................................................... 54
Aortic Aneurysm of Atherosclerotic Type ...................... 55
The Nature of Atherosclerotic Aortic Aneurysm ....... 55
Summary of Epidemiological Data ......................... 55
The Effect of Smoking on Aortic Aneurysm............ 56
Research Needs ................................................... 56
Conclhisions ......................................................... 56
High Blood Pressure .................................................. 56
The Nature of Hypertension ................................. 56
Summary of Epidemiological Data: ......................... 57
The Effect of Smoking on Blood~ Pressure .............. 58
Research Needs ................................................... 58
Conclusions ......................................................... 58
Other Conditions ....................................................... 58
Venous Thrombosis .............................................. 59.
Thromboangiitis Obliterans (Buerger's Disease)......... 66.
Oral Contraceptives, Smoking, Myocardial Infarction,
and' Subarachnoid Hemorrhage Among Women...... 60
The Effect of Smoking on Blood Lipids .................. 61
Other Constitutents of Smoke ...............................62
Discussion and Conclusions .......................................... 63
Table: L-Autopsy studies of atheroclerosis .................... 11
4-4
accumulated in the interval since publication of the first Surgeon
GeneralPs Report.
1. The overall mortality ratio: for all smokers of cigarettes is about
1.7 compare& to nonsmokers.
2. Life expectancy is significantly shortened by cigarette smoking. A
30-year-old, two-pack-a-day smoker has a life expectancy that is 8.1
years shorter than his nonsmoking counterpart.
3: Overall mortality ratios increase with the amount smoked. The
mortality ratio is 2.0 for the two-pack-a-day smoker as compared~ to
nonsmokers.
4. Overall mortality ratios for smokers are highest at younger ages
and decline somewhat with increasing age. This reflects a: relativee
decrease of the impact of smoking on health as death rates in general
increase with age. This is a relative effect. The actual number of excess
deaths attributable to cigarette smoking increases with age.
5. Overall mortality ratios are proportional to the duration of
cigarette smoking. The longer one smokes, the greater the risk of
dying.
6. Overall mortality ratios are higher for those who began smoking
at a young age as compared to those who began smoking later.
7. Overall mortality ratios are higher for those who report they
inhale smoke than for those who do not inhale.
8. Overall mortality ratios increase with the tar and nicotine content
of the cigarette: Overalli mortality ratios of low tar and nicotine (less
than 1.2 mg nicotine and less than 17.6 mg tar) cigarette smokers are
50 percent higher than for nonsmokers.
9. Overall mortality ratios for female smokers are somewhat less
than for male smokers: This probably reflects differences in, exposure
to cigarette smoke, such as starting smoking later, smoking cigarettes
with lower tar and nicotine content, and smoking fewer cigarettes per
day than men. r
10. Women demonstrate the same dose-response relationships with
cigarette smoking as men. An increase in mortality occurs with an
increase in the number of cigarettes smoked per day, an earlier age of
beginning cigarette smoking, a longer duration of smoking, inhalation
of cigarette smoke, and a higher tar and nicotine: content of the
cigarette. Women who have smoking characteristics similar to men
experience mortality rates similar to men.
11. Ex-smokers experience overall mortality ratios that decline as
the number of years off cigarettes increases. After 15 years, the
overall mortality ratios of ex-smokers are similar to those of
individuals who have never smoked.
12. Ex-smokers have overall mortality ratios that are directly
proportional to the number of cigarettes the person used to smoke.
13. Ex-smokers have overall mortality rat'ios that are inversely
related to the age at which the person began to smoke.
2-43
TABLE 8.-Percent of persons 17 years old and older, who
perceive their health to be "excellent," by cigarette
smoking status, sex, and age: United States, 1974
Sex and age
1bta1 Present
smoker Former
smoker Never
smoked
Both Sexes
17+ 42.T 41.5 43:0 42.8'
17-41 51.3 47.7' 55.4 53.1
45-64 34.0 32.6 36.7 32.0.
65+
Male 27.1i 24.7' 26.5 28.2
17+ 46.8 44.1 44.0 52.0:
17 -4S 56.7 52:9! 59.9 60.8
45-64 36.9 32:3' 38.0 40.9
65+
Female 25.5 19.2' 25.4 30.01
17 + 39.0 38.7 412 38.7
17-44 46.3 42.01 492 48.7
45-64 31.3 33.01 34.11 28.9
65+ 28.3 32.4 29.3 27:7
SOL'.RCE: Willon, R.W:(i6);
been analyzed to determine if this increased hospitalization is for
diseases usually associated with smoking.l
While smokers tended to report more hospitalizations than did
persons who had never smoked, there was no tendency for smokers to
report more frequent visits to physicians than those who had never
smoked; although former cigarette smokers reported the largest
proportion with five or more physician visits during the' past year
(Table 10).
Respondents in the 1974 Health Interview' Survey were also asked
whether they had ever tried to quit smoking, whether a doctor had
advised them to quit, an& whether they had been advised to quit
because of specific health conditions. Just under a quarter of all
persons w'ho had ever smoked reported that they had been advised~ by a
doctor at one time or another to stop smoking(Table 11). Surprisingly,
at least from; a public health point of view, at those ages at which the
effects of smoking often begin to manifest themselves, 45 to 64, less
than one-third of the smokers reported that they had been advised by
their physicians to stop smoking. This would appear to indicate a need
'There.are.manytypes.of analysesthat'~could'beperformed on these data that have not been done
becauseofdifferingpriorities and'lack of resources. For example, oneintereating area of
inveatigation thaV waabegunbut noTcomPlQted becausee of the apparent complexities of the issue, is
the relAtionahip betweean cigaretteamoking, health
v'ariableaand weight:.However. NCHS doeas make available.to researchers public-uae.data
tapeafrom,the variouaeurveya, so that they can eonducttheir ownanalysea (1Y),
3-15
1
t
9
a
r
e
u
r
0
ie
Y.
al
ic
)f
3.
,
(32) ROGOT, E. Smoking and life expectancy among U.S. veterans. American
Journal of Public Health 68(10): 1023-1025, October 1978.
(33) ROGOT, E. Smoking and mortality among U.S. veterans. Journali of Chronic
Diseases 27: 189-203; 1974.
(s4) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A
Public Health Service Review: 1967. U.S. Department' of Health, Educat'ion;
and Welfare, Public Health Service, Health~ Services and Mental Health
Administration. PHS Publication No. 1696, Revised, January 1968, 2`L'7 pp.
(35) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking,,1968
Supplement to the 1967 Public Health Service Review. U.S. Department of
Health, Education, and Welfare, Public Health Service, Health Services and
Mental Health Administration, DHEW' Publication No, 1696, 1968, 117 pp.
(86)~ U.S. PUBLIC HEALTH~ SERVICE. The Health Consequences of Smoking,
1977-1978. U~S, Department of Health+,Education, and Welfare, Public Health
Service, Health Services and Mental Health Administration. (In press)
(37), U:S. PUBLIC HEALTH SERVICE, Smoking and Health. Report of the.
Advisory Committee to the Surgeon General of the Public Health Service. U.S.
Department of Health, Education, andWelfare, Public Health Service, Center
for Disease Control, PHS Publication Alo. 1103, 1964, 387 pp:
(38) WEIR, J.M., DUNN, J.E.,, JR. Smoking and mortality: a prospective study.
Cuncer 25(1): 105-112, January 1970.
2-4 7
TABLE 3.-Outline of prospective studies of smokin~,~ and ovrrall inorlalitN
Doll
Dorn
Eic,;t r l'cLrl[
Authors Hill Hammond Kahn Hirayarna Jo,ie iLunmond
Iiorn I>unn
Linden Erilx~rg
Hrutee
Pet°
Pike Rogot Walker Breslow Lorich
(4-10) (14,16-19) (}1,26,31,:1~) (21,23-25) (1,13) (20) (12,yb) (2)
Males and Total population California Probability
British females S
U of Canadian White males males in sample of
Subjects
doctors in
25 .
.
veterans 29 health
districts in
pensioners in
nine States
vanous the
Swedish
States Japan occupations population
Population size 40,000 1,000,000 290,000 265,000 92,000 187,000 68,000 55,000
Females 6,000 562,671 <1% 142,857 14,000 27,700
Age range
ZO 85+
35-84
~~
40
and up
30-90 50-69 33-64 18-69
Year of 1951 1960 1954 1966 1955 1952 1954 1963
e nroll ment 1957
Years of
followup
20 years
12 years 13 years
8 years
6 years
4 years
ears
10 years
10 years y
reported
Number
of 10,072 150,000 87,000 21,000 11,000 12,000 4,700 4,500
deaths
Person n years
of 600,000 8,000,000 3,500,000 2,000,000 500,000 670,000 480,000 550,000
experience
z0 4,911-119C 0
we
f
Lnd
955
Led
;he
ide
tte
)68 .
0
I
through supplementaliquestions in the Current Population Survey. The
1970 Health Interview Survey contained many of the same smoking
and health questions as the 1965-1966 surveys, with the exception that
data: were not collected on all chronic diseases, but only on respiratory
disease. These data again showed increased reporting of selected
respiratory diseases and more work loss among smokers than among
those who had never smoked (15). In addition, the data continued to
document the decline in the proportion of cigarette smokers, particu-
larly among males, where the drop was from 51.0 percent in 1965 to
13.2 percent in 1970 (10). Smoking data were again collected in 1974 in
conjunction with a: special set of questions on hypertension (9).
Smoking questions were also asked on the 1976 and 1977 Health
Interview Surveys.
Most large scale studies on smoking an& health have tended to
investigate the role of smoking independently of other behavioral
variables, such as alcohol consumptiom and other life st'yle factors,
occupational and environmental hazards, and certain psychological
factors. These variables are known to be relate& to health status and
many are also related to smoking habits. Thus it may well' be that the
elimination of smoking without any changes in the other factors will
have only a partial impact on health status. The data collected on the
1977 survey were a part of a series of questions developed by Belloc
and Breslow for a study in Alameda County, California, on health
behavior, including such life-style factors as amount of sleep, eating
breakfast, eating between meals, physical activity, smoking and
drinking practices, and weight. It was found that persons with a
number of "good health habits" live considerably longer than those
with "poor health habits"'(2).
Recent Studies
Questions on cigarette smoking behavior which were added to the July-
December period of the 1978 Health Interview Survey will be
continued through December 1979. These questions for the first time
include information needed to determine tar and nicotine as well as
carbon monoxide (CO) levels. While national surveys on adult smoking
behavior conducted earlier by the National Clearinghouse on Smoking
and Health had inquired about brand names to determine tar and
nicotine levels, they did not include data on health characteristics.
NCHS has recently completed the first cycle of the Health and
Nutrition Examination Survey, im whi& a large national probability
sample of persons was brought to: mobile examination units for a very
extensive physical examination, including tests for cardiovascular and
pulmonary diseases (e.g., chest x-ray, EKG, spirometry and single
breath carbon monoxide diffusion) as well as a: number of biochemical
tests. Examinees were also asked about their smoking habits (8). While
3-11
S~slaSs9E0
who have ever smoked, to persons who have never
smoked, by number of cigarettes smoked per day for
present smokers-heaviest amount, type of days of
disability, smoking status, and~ sex: United States, July
1964 to June 11965 .................................................. 10
Table 5.-Days of bed disability per person 17 years old~
and old'er, by cigarette smoking status, sex, and age:
United States, 1974 ................................................ 12
Table 6.-Days lost from work per year due to illness and!
injury, per currently employed persons 17 years old and
older, by smoking status, sex, and age: United States,
1974 .....................................................................13
Table 7.-Percent of persons with chronic condition(s)
causing limitations of activity, by cigarette smoking
status, sex and~ age: United States, 1974 ................... 14
Table 8.-Percent of persons 17 years old and older, who
perceive their health to be "excellent," by cigarette
smoking status, sex, and age: United States, 1974.......15
Table 9.-Percent of persons 17 years old and older, with
one or more hospital episodes in the year prior to
interview, by cigarette smoking status, sex, and age:
Uni ted States, 1974 ................................................ 1fi
Table 10.-Percent of persons 17 years old and older, with~
five or more physician visits ini the year prior to
interview, by cigarette smoking status, sex, and age:
United States, 1974 ................................................ 17
Table 11.-Percent of persons 17 years old and older who
have ever smoked and who were ever advised by a
physician to stop smoking, by cigarette smoking status,
sex and age: United States, 1974 ............................. 18
Table 12.-Percent of present cigarette smokers 17 years '
old an& older who have tried! to stop smoking, by sex
and age: United States, 1974 ...................................18
Table 13.-Percent of persons 17 years old and older who:
have been told~ by a doctor that they had heart trouble,
by cigarette smoking status, sex, and age: United States,
1974 .....................................................................19
3-4
I
TABLE i.-Autopsy studies of atherosclerosis. (Figures in parentheses are number of individuals in
that smoking
category)1 [SM = smokers NS = nonsmokers]
Author, Autopsy
year, population
country
Wilens 989 consecutive
and Plair, male autopsies_
1962, at New York
U.S.A. City VA
hospitals.
G94+!-: s9co
11
Data
collection
Routine clinical
records of
previous and
present
admissions.
Cigarettes per day
Severity of aortic aclerosis
Above average Average Below average
9.9(161) 60.2- --- 29.8
19.1(152) 632 17.8
264(29g) 62.5 11.1
t25.1(199) 61.3 t13.6
Conclusions
The authon conclude that
in 60 percent of cases, the
degree of sclerosis at
autopsy was commen-
surate with age of patie_nt,
regardless of smoking
hab_ita In the remaining
40 percent there is evi-
dence that cigarette
smoking may he asso-
ciated with an above-
average de~.ee of aortic
' sclerosu. -
Comments
Smoking data unavailable
for 120 cesrs.
Each aorta specimen given
an "atherosclerotie age"
by comparison with a
standard. If "alhero-
sclerotic age" was found
to be 10 years more than
real age, the aorta was
said to show above-
average sclerosis.
tp<0.001 comparing 9.9
with 25.1 and 29.8 with
13.6.
(1)~ BESTE.W.R., JOSIE, G~H., WALKER, C:B: A Canadian study of mort'alityin
relation to smoking habits: A preliminary report. Canadian Journal of Public
Health 52: 99-106March 196L
(2) CEDERLOF, R.,,FRIBERGL., HRUBEC, Z., LORICH', U. The Relationship of
Smoking and Some Social Covariables to Mortality and Cancer Morbidity. A
Ten ~ Year Follow-up in ~ a Probability Sample of 55,000 : Swedish Subjects Age
18 to 69. Part'~ I and II. Stockholtn, Sweden, Karolinska Institute, Department
of Environmental Hygiene, 1975, 201, pp.
(3) CEDERLOF, R., FRIBERG, L, LUNDMAN, T. The interactions of smoking,
environment, and heredity and their implications for disease etiology. A report
of epidemiological studies on the Swedish Twin Registries. Acta Medica
Scandinavica, Supplement 612:7-128, September 1977.
(4) DOLL, R., HILL, A.B. Lung cancer and other causes of death in relation to
smoking. A second report on the mortality of British doctors. British Medical
Journal2: 1071-1081November 1, 1956.
(5) DOLL, R., HILL, A.B., Mortality of British doctors in relation to smoking:
Observations on coronary thrombosis. In: Haenszel, W. (Editor). Epidemiologi-
cal Approaches to the Study of Cancer and Other Chronic Diseases. National
Cancer Institute Monograph No. 19. U.S. Department of Health, Education,
and Welfare, Public Health Service, NationaliCancer Institute, January 1966,
pp, 205-26&
(6) DOLL, R., HILL, A.B. Mortality in relation to smoking: Ten years' observations
of British doctors. Part I British Medical Journal 1(5395): 1399-1410, May 30,
(7) DOLL, R., HILL, A.B: Mort'ality in relation to smoking: Ten years' observatiions.
of British doctors. Concluded. British Medical Journal 1(5396): 1460:1467, June.
6, 1964..
(8) DOLL, R., PETO, R. Mortality among, doctors in different' occupations. British
Medical!Journal 1(6074): 1433-1436;,June 4;1977.
(9) DOLL, R., PETO, R. Mortality in relation to smoking: 20 years' observations on
male British doctors. British MedicaliJournal 2(6051): 1525-1536, December 25,.
1976:
(10) DOLL, R., PIKE, M.C. Trends in mortality among British doctors in relation to
their smoking habits. Journal of the Royal College of Physicians 6(2): 216-222
January 1972.
(11) DORN; H.F: The mortality of' smokers and nonsmokers. Proceedings of the
Social Statistics Section of the American Statistical Association. Papers
presented at the Annual Meeting of the American Statistical Association,
Chicago, Illinois, December 27-30, 1958. Washington, D,C:,, American Statisti-
cal Association, 1959, pp. 34-71.
(12) DUNN, J.E., LINDEN, G., BRESL©W, L. Lung cancer mortality experience of
men in certain occupations in California. American Journal of Public Health
50(10): 1475-87, October 1960.
(13): EPIiDEMIOLOGY DIVISION, HEALTH SERVICES BRANCH, BIOSTATIS-
TICS DIVISION, RESEARCH AND STATISTICS' DIRECTORATE: A
Canadian Study of Smoking and Health. Department of National Health and
Welfare, Epidemiology Division, Health Services Branch, Biostatistics Divi-
~
~
sion, Research and Statistics Directorate,1966; 137 pp.
~
(14), HAMMOND, E.C. Evidence on the effects of giving up cigarette smoking.
American Journal of Public Health 55(5)'. 682-691, May 1965.
U1
(15) HAMMOND, E.C. Life expectancy of American men in relation to their smoking ~
habits. Journal of the National Cancer Institute 43(4): 951-962, October 1969.
.~
Atherosclerosis
Most studies of the pathology of atherosclerosis have been base6 on
autopsies of coroner's or hospital populations in whi& only a lfmite&
fraction of d'ecedents have been examined: They have been valuable
for an understanding of the pathogenesis and complications of
atherosclerosis. Such studies cannot be taken to represent the
prevalence of atherosclerosis in the general population. Studies which
attempt to minimize selection bias at autopsy by examining the great
majority of decedents in~a defined population~are rare (66, 114).
The most extensive and comprehensive autopsy study that has been
conducted is the International At'herosclerosis-Project, which collected
data from~ 15 cities in 14 countries and recorded more than 21,000
autopsies according to a standardized protocol and method of
evaluation (85). The study found a remarkably frequent occurrence of
atherosclerotic lesions in the United States; detailed international or
geographic differences in~ the severity of atherosclerosis; raised the
issue of whether childhood atherosclerosis evolves into adult forms of
atherosclerosis; and documented that, on the average, there are more
frequent and extensive coronary plaques in cases with coronary heart
disease than in comparison cases regardless of age, sex, geographic
location, or race. Approximately the same prevalence and extent of
advanced atherosclerosis were seen in coronary heart disease cases
regardless of age, sex, and with few exceptions of geographic
location. While individuals may show considerable variability in the
severity of atherosclerosis, the conclusion is that coronary atherosclero-
sis is of primary importance in the development of coronary heart
disease in a population (133). Another extensive study in five towns in
Europe has been~ reported by the World Health Organization (WHO)
(66).
The Nature of Atherosclerosis in Man
Information about atherosclerosis in man derives from pathological
studies and; from associations observed in clinical or epidemiological
studies.
The lesion~ or plaque is a cellular proliferation in the arterial intima.
It contains chiefly smooth~ muscle cells, but also fibrocytes and cells
typical of chronic inflammation. Lipid is commonly present along with
cellular products such as collagen, elastic tissue, glycosaminoglycans,
and cellular debris from necrosis. Elements of thrombus are common
both in and on the plaque. Focal calcificatiom is frequent. Thus, a
highly variable and complex range of lesions can be consid'ered'. under
the term, atherosclerosis.
The concept of the development of lesions is a synthetic one derived
from the observation of many lesions rather than from the actual
observation of a single lesion over time. At present, there is
4-7
TABLE 11.-Percent of persons 17 years old and older who have 0
ever smoked and who were ever advised by a
physician to stop smoking, by smoking status, sex,
and age: United States 1974
Smoking status
and sex All ages
17+
17-44'.
45-64
65+
Total ever smoked
Both sexes
23.9
19.6
292
30.1
Male 23.5 17.8 292 32.4
Female 24.4 21.8 292 25.3
Former smoker
Both sexes
21.3
142
26.3
282
Male 22:7 13.5 28.0 29:6
Female 18.9 15.0 22.6 24.2
Present smoker
Both sexes
25.2
21.5
31.1
32.6
Male 24.0 19.4 302 3Z0
Female 26.6' 23:9 32.1 26.2
SOURCE: Wilson, R.W. (16).
TABLE 12.-Percent of present cigarette smokers 17 years old
and older who have tried to stop smoking, by sex
and age: United States, 1974
Sex All ages
17
17-44
45-C4
65+
Both sexes 64:7 66.0 62:8' 61.1
Male 66.0 66.7 65.1 633
Female 632 65.3 602 57.9
SOURCE: Wil9on, R.W. (is):..
to have a slightly lower level of well-being than were nonsmokers:
Heavy smokers (more than 1 1/2 packs a day)' under 65 years of age
report the lowest levels of general well-being,and report mean levels of
general well-being at marginal levels or lower.
Conclusions
The available evidence in the relationship between cigarette smoking
and illness and disability has increased markedly since the first
3-18
M
lntroduction
For many years, researchers have beem accumulating evidence of the
relationship between cigarette smoking an& mortality, as well as data
on the relationship betweeni smoking and the prevalence of selected
chronic diseases. These findings are presented in detail elsewhere in
this report. It has been only recently that data have also become
available that indicate:a relationshipalt'hough a statistical relationship
and not an established causall relationship, between cigarette smoking
and disability and other health, indicators. This chapter of the report
will present some of these data based oni surveys conducted by the
National Center for Health Statistics (NCHS).
Past Studies
One of the few sources of national data on cigarette smoking and
health characteristics, and the only data set based on a large national
sample, is the National Health Interview Survey. This is a continuous
survey conducted by NCHS' each year since 1957. Interviews are
conducted in a national probability sample of approximately 40,000
households, with a new sample selected each year. Information is
obtained on a wide range of health characteristics, including incidence
of acute illnesses and injuries, prevalence of selected chronic diseases,
short- and long-term~ disability associated with illness and injuries,
utilization~ of health services, and related healthh~ topics such as health
insurance coverage, usual sources of medical care, and use of
prescription medicine. One of the topics on which data have beem
periodically collected is cigarette smoking behavior. Some data on cigar
and pipe smoking have also been collected.
Shortly after the Surgeon General's first report, Smokiny and
Health,, was published in 1964, NCHS began collecting informatiom on
smoking as a part of the Health Interview Survey. The result of this
effort was a report, Cigarette Smoking and Health Characteristics (14),
which was the first such study based on a national probability sample.
While several! significant studies had been~ conducted earlier, such as
those by Hammond and Horn (5, 6), they were, for the most part, not
based on scientifically designed sampl es; and were therefore subject to
the criticism that the findings could not be generalized to the total
population. NCHS's first report om smoking,, based on the fiscal year
1965 survey, presented data on the relationships between' cigarette
smoking, the incidence of selrected acute ill~nessesand the prevalence of
selected chronic diseases, as well as information on~ the relationship
between smoking and measures of disability, su&as restricted activity
days, bed days, and work-loss d'ays.
The data showed, for example, that male cigarette smokers were
almost 2 1/2 times more likely to report chronic bronchitis or
emphysema than, were those who had never smoked, and almost 60
3-5
E
Morbidity: References
(1) AHMED, P.I., GLEESON, G.A. Changes in Cigarette Smoking Habits Between
1955 and' 1966. U.S, Department of Healthj Education, and Welfare, Public
Health Service,, Health Services and Mental Health Administration, National
Center for Health Statistics, Series 10, No. 59, PHS Publication No. 1000, Apri1
1970, 33 pp:
(2): BELLOC, N:B. Relationship of health practices and mortlality: Preventive
Medicine 2: 67-81, 1973:,
(3) FAZIO;,A.F. A Concurrent Validational Study of the NCHS General Well-Being,
Schedule. U.S. Department of Health, Educationj and Welfare, Public Health~
Service, Health Resources Administration, National Center for Health
Statistics, Series 2j No. 73, DHEW PublicationiNo. (HRA) 78-1347, September
1977, 53'pp.
(4) HAENSZEL, W., SHIMKIM, M.B., MILLER, H.P. Tobacco Smoking, Patterns
in the United States. Public Health Monograph, No. 45. U.S. Department of
Health, Education, and Welfare, Public Health Service, PHS' Publication No.
463, 1956 111! pp.
(5) HAMMOND; E1C. Smoking in relation to death rates of one million men and
women. In: Haenszel, W. (Editor). Epidemiological Approaches to the Study of
Cancer and Other Chronic Diseases. National Cancer Institute Monograph No.
19. U.S. Department of Health, Education+ and Welfare, Public Health
Serviee;,National Cancer Institute, January 1966, pp. 127-204:
(6), HAMMONDE.C:, HORN, D. Smoking and death rates - Report on 44 months of
follow-up: of 187,783 men. Journal of the American Medical Association
166(10); 1159-1172,1958.
(7) MADOW, W:G. Net Differences in Interview Data on Chronic Conditions and
Information Derived' From Medical Records. U.S. Department of Health,
Education; and Welfare, Public Health Service, Health Services and Mental
Health Administration, National'~Center for Health~Statistics, Series 2, No. 57,
DHEW Publication No. (HSM),73-1331, June 1973,58 pp.
(8), MILLERH.W. Plan and Operation of the Health and Nutrition Examination
Survey: United States, 1971,1973: U.S. Department'~ of Health,,Education; and
Welfare, Public Health Service, Health Resources Administration,, National
Center for Health Statistics, Series 1,, Nos. 10a, 10b, DHEW Publicatiow No.
(HSM),73-1310, February 1973, 123 pp.
(9) MOSS, A.J., SCOTT,, G. Characteristics of Persons with Hypertension: Unite&
States, 1974! U.S. Department of Health{, Education, and Welfare, Public
Health Service, National Center for Health Statistics, Series 10, No. 121,
DHEW Publication No. (PHS) 79-1549, 1979. (In press)
(10) NATIONAL CENTER FOR HEALTH! STATISTICS. Cigarette smoking:
United States, 1970. U.S: Department of Health, Education, and Welfare,
Public Health Service, Health Services and Mental Health Administration,
National Center for Health Statistics. Monthly Vital Statistics Report
21(3)(Supplement), June 2, 1972, 8 pp.
(11) NATIONAL CENTER FOR HEALTH STATISTICS. Health~ United States,
1976-1977. U.S. Department of HealthEducation, and Welfare, Public Health
Service; Health Resources Administrationj National Center for Health
Statistics, National Center for Health Services Research, DHEW Publication
No. (HRA) 77-1232, 1977; 441 pp.
~
(12) NATIONAL CENTER FOR HEALTH~ STATISTICS. Standardized~ Micro-Data
~
Tape Transcripts: U.S. Department of Health, Education, and Welfare, Public
Health Servioe;,Natlonal Center for Health Statistics, DHEW Publication No.
~J1
(PHS) 78-1213, June 1978; 36 pp. ~
~
3-21
TABLE 5.-Days of bed disability per person 17 years old and
older, by cigarette smoking status, sex, and age:
United States, 1974
l
Sex and age Total
Male
Present Former Never
smoker smoker smoked
Days per person per year
17+
17-U
45-64
65+
17+
17-44
45--64
65+ 6:1
4.2
6.5
13.9
Female
8:7
6.6
9.6
13.9 6.7'
5.3'
8.0 ~
12.9
7.9
6.9
92
10.3 6.1
316
5.1'
13.2
9.3
6.8
9.4'
18.4 5.1
2:9
1 6.5
12:4
8.6
6.1
9.1
13.6
Note:, Actual number of bed-disaaidity days - 1,076,131',000
Expected number of, bed-disability days .'~
if all persons had'same rate as persons
who never smoked
-
930,237,000
Excess bed-disability days s 145,894,000
SOURCE: Wilson, R.W. (16);
the smoking data have not yet been fully analyzed, this study will
provide a valuable source of information on smoking and~ health:
A second cycle of t!he'. Health and Nutrition Examination Survey is
currently in~ the field (1976-1980) and also includes questions on
smoking habits as well' as data on carboxyhemoglobin, an indicat'or of
CO in the blood. These data will be helpful in assessing the accuracy of
self-reported' cigarette smoking levels.
Disability data from the 1974 Health Interview Survey provide
results very'similar to those found'a decade earlier. They indica.te't'hat
smokers in all age and sex groups; except for women over age 65,,
report more days in bed due to illness than do persons who have never
smoked (Table 5): If the number of excess bed! days is calculated, as it
was, for the earlier antismoking campaigns, it is estimated that there
were almost 150 million (145,894,000) excess bed days among smokers
and former smokers: This type of calculation assumes that smokers and'
former smokers, would experience the same rate of bed disability if
they did! not smoke as did those who had never smoked cigarettes:
Currently employed smokers al~o report more days lost from work as
a result of illness and injurythanido employed persons who have never
smoked (Table 6). If "excess" work-loss days are calculated for
'
3-12
Conclusions
Cigarette smoking has been shown to enhance the prevalence and
extent of atherosclerosis of the aorta and coronary arteries in men.
Experiments on the effects of nicotine or carbon monoxide on
experimental atherogenesis in animals have produced conflicting
result's and~ are inconclusive. Chronic inhalation of whole smoke is
associated with the development of hyaline thickening of myocardial
arterioles in dogs. In man, cigarette smoking is associated with fibrotic
and hyaline changes in small arteries and arterioles in the myocardium.
t
i
Myocardiai Infarction
The Nature of Myocardial Infarction
Heart attack as generally understood can comprise nonfatal or fatal
myocardial infarction, cardiac arrest or asystole, and cardiac standstill
or ventricular fibrillation. Asystole and fibrillation result in sudden~
cardiac death. These conditions are: generally the result of cardiac
ischemia which, in turn, is generally attributable to coronary athero-
sclerosis, although other conditions may uncommonly precipitate heart
attack.
Myocardial infarction is that condition in which a volume of heart
muscle fibers in~ a discrete part of the heart dies because of inadequate
circulation. It is generally larger than 5mm in diameter and may be
several centimeters in major diameter. It may vary from a small
subendocardiaU portion of the heart to the full thickness of the
myocardiali wall. It may, particularly when subendocardial in location,
impinge on the conducting system of the heart an& be conducive to
disturbances in conduction. The infarction may affect primarily the
pumping capacity of the muscle an& lead to acute or chronic circulatory
failure. The most common location of infarction involves the left
ventricle, but involvement of the right ventricle and atria is common.
If the myocardial infarction does not prove to be fatal, it may be
subject to local extension during the acute episode of illness. Healing is
by scar formatiom The patient is at high risk of a second attack.
The association~ between atherosclerosis of the coronary arteries and
myoca.rdial infarction is close. Most cases examined at autopsy show an
involvement of about 70 percent or more of the surface of the major
vessels, an& more than 50 percent stenosis of the lumen with or
withoutt recent thrombosis. However, a small minority of cases show
less extensive lesions and narrowing, and it has been speculated that
these infarctions may have arisen because of vascular spasm, or
because of transient vascular occlusion by thrombi that have dissolved
after obstructing the coronary circulation.
Ischemia of a local mass of heart muscle initiates a complex chain of
biochemical, functional, and structural events at the level of the heart
muscle: cell that continues to be a subject for intensive research. A
4-19
TABLE 6.-Days lost from work per year due to illness and
injury, per currently employed person 17 years old
and older, by smoking status, sex, and age: United
States, 1974
ey is
s on
)r of
:y of
vide
that
' 65.,
ever
as it
here
kers
and
y if
,tes.
kas
wer
for
Figure does not meet standards ofl reliability or precision,
Note:: Actual number of work-loss days =
379,389,000
Expected number of work-loss d9ys
if all workers had' the same rate
as workers who never smoked =
298,021j00
Ekcess work-loss days = 81,368,000 1
Sex and age
Total PresenG Former
smoker smoker Never
smoked
lalald Days per person per year
17+ 4.5 5.1 5.0 3.4
1744 4.2 5.5 4.2 3.0
15-o-S 5.0 4.5 5.5 4.4
65+ 3J8 0.3 7:9
17+ Female
4i8
5,6
4.5
17-d4 4.6 5:3 4.3
45-64 5.6; 6.5 5.4
65+ 0.9: . .
SOURC& Wilson, R.'W: (16).
employed persons under 65 years of age, there would have been an
estimated 81,368,000 "excess" work-loss days among smokers and
former smokers, accounting for over 21 percent of alli work-loss days.
This is about the same proportioni as a decade ago.
Another measure of the impact of illness is whether a person is
limited in major activity, such as work or keeping house, or limited in
other activities such as social or recreational activities as a result of
chronic illness. This is a measure of long-term chronic disability as
opposed to the bed-days and work-loss indicators that can result from
both short-term acute illness or injury and chronic disease. For most
age and sex groups, a higher proportion of current smokers and former
smokers report they have a limitation of activity than do persons who
have never smoked, although the differences are not always striking
(Table 7)i One factor that may attenuate these differences is the
higher mortality rate for persons who have smoked' cigarettes. One of
the major causes of mortality that has been shown to be related to
cigarette smoking, heart disease, is also one of the major causes of
limitation of activity. Since the above findfngs were obtained~ from
3-13
particularly cigarettes. The trend in such data is that a history of
cigarette smoking is associated in a dose-related manner with thee
severity or extent of aortie or coronary atherosclerosis. In somee
etudies, the differences in atherosclerosis between smokers and
nonsmokers are statistically significant. In others, the trend! is
coagrruent but not statistically significant. These autopsy studies
d'ocumenb'ing smoking behavior have generally not permitted' analysis
for risk factors other than smoking that might affect the severity of
atherosclerosis, and have: not permitted multivariate analysis common
in the large prospective.population studies dealing with the morbidity
and mortaiityof heart attack.
A recent report (132) has provided additional information by
analyzing its data in~ two categories according, to the presence or
at,sence of diseases associated with smoking on the one hand
(emphysema, lung cancer) and~ coronary heart disease on the other
(myocardial infarctionhypertension, diabetes, stroke). Atherosclerotic
in%,olvement of both the coronary arteries and aorta was greatest in
heavy smokers and least in nonsmokers in the total sample of 1,320
men, and in each of the two categories of disease noted above. This
study of inem aged 25 to 64 years represents the examination at
autopsy of residents of the Greater New Orleans area who died in
Orleans parish from any cause: Smoking history information, general-
1V, was obtained retrospectively from a respondent with a close
knowledge of the decedent (88). The WHO study of five towns
reported' on the association between smoking and atherosclerosis only
from Yalta (79). The study has less relevance than the New Orleans
study for the United States population. It reported a positive:
association between raised plaques in the aorta and smoking. It failed
to find' a clear association between coronary artery narrowing or
infarction of the heart and smoking. Calcification of plaques in the
aort'a: and coronary arteries was related to coexisting alcohol consump-
tion:
While data from most aut!opsyseries are inadequate for multivariate
analysis, several prospective population studies now have sufficient
standard risk factor data together with autopsy findings to present
preliminary analyses ('131). A prospective study of cardiovascular risk
factors among 8,000 Japanese-Americans living on the island of Oahu
has recently published more extensive systematic pathological findings
on the vessels in 137 autopsies from the cohort in associatiom with prior
risk factor observations. Cigarettes smoked' per day were positively
and independently associated with the extent of atherosclerosis
affecting both the aorta and coronary arteries: The aortic regression
coefficient was statistically significant at the 0.05 level and the
coronary coefficient at the 0.01 level (112).
A recent study of autopsies from a Veterans' Administration
hospital (:15) reported that advanced coronary artery atherosclerosis
4-15
TABLE 3.-Coronary heart disease morbidity as related to smoking. (Risk ratios-actual number of CHD
manifestations shown in parentheses)' [SM = Smokers NS = Nonsmokers EX = Ex-smokers]-
_ _ _
Continued
PROSPE(TIVE STUDIES
Author, Numher and Data Follow- Number of
year, type of collection up incidente Cigareltes%day Pipes, cigara Age variation Comments
country population years
Epntein, 6,565 male Initial 4 96 male, Males Malen Reexamination
1967. a.it femak medical 92 female 4059 60 and over 40-59 of patienta
D.S_.A. reaidenta esamina- CHD in- NS .................. 1.00(I) LOq7) SM ............ 1A0(2) wap
spread
of Tecumaeh, tiun and eluding EX .................. 6.53(10) 1.27(l1) 60 and over over I 1i2dyear
Mirh. repeat deaths, Cigarettes ........... 5211(36) 1.96(Zi) SM ............ OB6(6) period, but
follow-up angi.na, and Females data arc re-
examina- myocardial NS ................. 1.00(21) 100(47) ported in
lions. infaretiona. EX .................. 0.89(3) . 1.31(5) terms of
Cigarettea ........... 1.02l14) 0.42(2) 4-year inci-
denre rates.
Actual number
of CHD inci-
dents derived
from data on
. incidence and
total in smok-
ing clasv.
:;9 C0
controversy over whether the fatty streaks 'seen in~ childhood~ are the
precursors of the more fibrous, raised, and complex adult lesions, or
whether some or many adult lesions arise independently of fatty
streaks (which also occur in adult life) (89): The usual prevalence of
atherosclerotic lesions in~ adult life is such that the aorta and carotid
arteries are affected about'a decade before the coronary arteries and
cerebral arteries, and the latter are affected a decade in advance of the
arteries of the leg. However, such relationships are not constant;
individual variations are: commoni and, indeed specific clinical syn-
dromes of localized atherosclerosis are recognized.
Atherosclerotic plaques distort and narrow the calibre of the
affected arteries. This reduces the flow of blood through them and
creates the condition called ischemia. When ischemia becomes severe,
the organs and tissues deprived of blood no longer function properly
and clinical'disease occurs in the form~of coronary heart disease, stroke,,
or peripherat vascular disease. The occurrence of severe ischemia: may
arise because of the enlargement of plaques, or it may be precipitated
by the development of thrombosis (clot) on plaques, or by other
complications that can affect them. The various diseases resulting
from ischemia: are considered subsequently in this chapter.
Conditions that predispose to the onset of disease in the future,
increasing the: risk of its occurrence, are spoken of as "risk factors".
The concept of risk factors arose from clinical experience with
cardiovascular disease, particularNycoronaryheart diseaserather than
with atherosclerosis itself. Prospective population studies such as those
considered in the Pooling Project (107) further developed the
predictive value of selected factors such as cigarette smoking and
levels ofblood pressure and cholesterol.
Risk factor associations for atherosclerosis as distinct from coronary
heart disease are limited in their documentation. The International
Atherosclerosis Project (85), dealing with~ autopsy data, concluded that
the severity of atherosclerosis is closely associated' with the proportion
of total calories derived from saturated fat in~ the diet of the
population, with~ the serum cholesterol levels measured in the
population and with hypertension. The association with smoking was
not examined. The WHO (66) study documented the association of a
number of disease states and conditions with the extent and severity of
atherosclerosis. A recent report has described't'he associations between
several variables measured during life and the extent of atherosclero-
sis of the aorta and coronary arteries seen at autopsy in Japanese-
Americans participating in a prospective cardiovascular risk factor
study (112). Statistically independent associations were found by
multivariate analysis between aortic atherosclerosis and age at death,
cigarettes smoked per day, serum cholesterol concentration, and blood
pressure levell Coronary atherosclerosis was related to relative body
TABLE 2.-Coro>rtary heart disease mortality ratios related to smoking-prospective studies. (Actual
number of
deaths shown in parentheses)1 [SM = Smokers NS = Nonsmokers]-Continued
Author, Number and Follow- Number
year, type of Data up of Cigaretten/day Cigsrs, pip. Age varietion Commenta
muntry population mlleetinn (yeara) deaUm ---
Weir and 68,163 Calif. Qumtion 5~ 1,718 NS ........ 1.00 3SJ4 /.551 55-U 6569 NS includee
Dune, forni. m.le naire .nd AII smokers 160 NS ......... 100 100 1,00 1.00 pp. and
1970, workera tollow.up 210 ....... 139 210........ 472 2.05 141 1.17 cigarn.
U.S.A. 36u yean of death 220 ....... 1.67 !20 ........ 6.14 3.17 164 1.26 SM includes
of age at certifiatc >30 ....... 1.74 ±30 ........ &57 3.33 1,66 1.36 e:amuken.
entry. >40 ........ 793 3.15 1.42 1.42
All ......... 6.24 295 1.56 124
A
Pooling 7,427 white Medinl ez- 10 29 NS ........ 1.00 (27) 1.00 (2T)
PrnJeet, nulea amination <LO ....... 1.65 (34) 1.20 (24)
American 30.59 yeux and 20 ......,., 1.70 (66)
Heart ol age at follow-up. >20 ....... 3.00 (68)
Aaocu-
tion,
1970, entry.
U.S.A.
'Unieee othervri.e epaeified, diqparltiee between the total number of deathe and the .um of the
individual emoking eategoeen are due to the exclueion of either ueueional, mieeellnneorra, mixed, or
ex-
..
.moken.
a"p" values apecified only for thoee provided by.uthon.
SOURCE: U.S. Public Health Service (138).
V_ItIS;y9C0
©
TABLE 3.-Coronary heart disease morbidity as related to smoking. (Risk ratios-actual number of CHD
manifestations shown in parentheses)1 [SM = Smokers NS = Nonsmokers EX = Ex-smokers]-
Continued
PROSPELTIVE STUDIES
Author,
year,
country Number and
type of
population Data
collection Follow-
up
yean Number of
ineidenta
Cignrettea/day
---
Pipea, cigara Age varfation
Comments
Taylor, 2,571 male Interviewa 5 46 deatha. NS and EX ......... L00(62) All CHD
et al. railroad and rcgu- 33 myonr- All eunent ......... 1.77(150)
- including EKG
1970
U.S.A.
empbyen
40-59
lar folbw-
up eaamina-
dial-io-
farcLa- diagnosen.
ycan of tion. 78 angina
age at - peetont
entry. 55other
CND.
212 total.
Dayton 422 male U.S Interviews up to 8 27 audden <10 ................. 1.00(25) No data on
et al., veterane par- and routine deaths , 10-20 ............... 1.04(22) NS ae a
1970, ticipet3ng y follow-up 4/ definite >20 ................. L17(18) aeparate
U.SA. conlrolp in a exgminn- myonrdial g.oup,
cliniwl trial of tiona infarctiona
a diet high in
unaalu-
nted faL
6 Y~S ,9~0
and cholesterol. The amount of sterol externalized metabolically by
the present time, data to settle the validity of these interpretations are
roticplaques, and'might cause the primary cellular changes facilitating
other conventional risk factors or agents to produce lesions in man. At
from tobacco, could be fundamental to the pathogenesis of atheroscle-
capable of inducing, somatic cell mutation, including mutagens derived
smooth muscle cell neoplasia. In this view, environmental agents
vascular cells leading to a local proliferation analogous to benign
consider whether this represents a mutation or transformation of
correct interpretation is that plaques are monoclonal~ it is necessary to
monotypic character as it has developed (21, 22, 104, 105, 135). If the
proliferate to form plaques. It has been found that the cells that
constitute individual fibrous atherosclerotic plaques in adults are
homogenous for an isoenzyme marker. That is, each plaque must either
be monoclonal or initially polyclonal with the development of a
designates a prior abnormality of the smooth muscle cells that
not necessarily contradict the concepts stated above, but which
A novel theory of atherogenesis has been proposed recently that does
the nature of atherosclerosis in humans.
barrier function. It should be noted that the foregoing views are
derived from animal experimentation but appear to be congruent with
by thrombosis. Thrombosis, necrosis, calcification, hemorrhage, and
ulceration may further complicate the lesion, A large number of agents
are suspected to be capable of injuring endothelium and altering its
through a continuation or cyclical repetitions of the same processes or
promptly, and appearances suggestive of a migration of smooth muscle
cells to the lesion are seen: Local cellular production of glycosaminogly-
ca.ns, collagens, and elastin follows. Progression of the lesions can be
metabolic overload, failed homeostasis, cellular proliferation, and
necrosis. In addition, the stigmata of mild chronic inflammation occur
subendothelial exposure to plasma and to plateletsfollowed by cellular
hypothesis is endothelial' injury, impaired barrier function, and
structural lipids spill into the extracellular compartment of the intima
where they contribute to the lipid burden. The sequence in this
such cells may exceed the local capacity of HDL to accept and
transport it away. Cellular necrosis occurs and both intracellular and
not available.
cases, smokers with nonsmokers and different levels of smoking,
These investigations compare, within their particular group of study
below as Table 1.
investigations into this aspect of smoking. This table is reproduce&
report, The Health Consequences of Smoking (138), lists severali
common. Table 19 (pp. 49-51) of the 1976 reference edition of the
Autopsy studies in which smoking, behavior has been recorded are not
The Effect of Smoking on Atherogenesis
TABLE 3.-Coronary heart disease morbidity as related to smoking. (Risk ratios-actual number of CHD
manifestations shown in parentheses)' [SM = Smokers NS = Nonsmokers EX = Ex-smokers]-
Contir.ued
Author,
year,
country Numhcr end
type of
population Data
collection Follow-
up
yean Number of
incidenla
Jenkine, 3,182 malea Initial 4 1/2 104 myo-
et el., 39-59 yean nrdical cardW
1968, of age at e.emina- infareliona
U.S.A. entry. tion and
follow-up
by repeat
e.amina-
- tione.
Kanncl, 5,127 males Medical 12 228 mya
et al., and females eaxmination ardial
1968, 30.59 yean and follow- infare-
U.S.A. of age. up, tiuna.
380 CHD.
PROSPECTIVE STUDIES
Cigarettes/day Pipea, cigara Age vuiation Cotnmenta
-- --
NS .................. 1.00(2l) (Includea non-
EX .................. 247(15) (p<0.(p1) 39-49 SOS9 amoken and
Current ............. 278(68) NS ........... 1.00(4) 1.00(6) ex-amuken.
0-15,'day ........... 11.39(45) (P<0.OD1) Current ....... 423(35) 2.26(33) NS includea
>16 ................. 3.06(59) (comparing ~ former pipe
0-15 and 16. ) and cigar
emaken
Risk of CHD (ovenll)
Myocacdial Infarction .
Male~ Femalea
NS .................. 1.00(21) LOlq31)
All SM .............. 1.51(153) I.71(23)
He_ary SM .......... I.SSf59)
Malea Femalee
>20 ................. 2,41(76) 0.93f3)
NS .................. 1.00(61) 100(89)
1-l0 ....... .......... 1:34(25) 086(18)
I120 ............... ].80(9o) L23(l8)
9F. 0
Auerbach and associates have reported on the effect of the chro
inhalation of whole smoke through a tracheostomy apparatus in be
dogs. A hyaline thickening of myocardiat arterioles was found in the
the degree of change being related to the duration and amount smok
(16).
At the present time, animal experiments on atherogenesis and
have provided conflicting data and must be regarded as unsatisfacto
Experiments have variously employed continuous: and intermit'ten
exposure, have estimated lesions biochemically and morphologicall
and have used' diverse short- or long-term dietary loads so tha~
comparisons of results are difficult. Animal experiments remain to
done in which CO or nicotine are varied in a setting of whole smoke
administered by inhalation without aversive stress and in a suitable
atherogenic context.
Research Needs
While current autopsy data on humans leave no reasonable doubt tha
smoking promotes atherosclerosis of the aorta and coronary arteries ii
4
men, equivalent data do not exist for women or for other major
arterial beds. Within practicaL limits of study, it would be informative
for pathogenetic concepts to have better information on multiple-ris
factors, including oral contraceptives in conjunction with smoking and
with smoking cigarettes of different potential hazard, in autopsy;
studies. In particular, it would' be of great interest to know the
influence of smoking on the development of the common fatty streaks
and occasional fibrous plaques found at autopsy in adolescents and
young adults.
The mechanisms by which smoking enhances atherogenesis require`
elucidation. Such information might assist in the fabrication of a
cigarette less hazardous in terms of atherogenesis and its conse'-
quences. Conceptual frameworks and biological systems exist within
which to study the mechanisms by which smoking enhances atherogen-
esis: They include effects on the arterial endothelium, which may alter
its permeability to macromolecules; effects on end'othelial-platelet
interactions which influence thrombogenesis or affect the proliferation
of intimal, cells; effects on the metabolism of the vessel' wall; and
systemic and local effects on lipoprotein or sterol metabolism. With~
respect to the monoclonal hypothesis, research to identify mutagens or
promoting agents at the level of the vessel'wall is feasible.
A necessary step in such research will be the use of animal models
and biological systems that have a high level of analogy with man and
that are credible both in terms of experimentalL atherogenesis and in
their exposure to cigarette smoke.
4-18
ab
I TABLE 1.-Auto studies of atherosclerosis. F5 res in
~ psy ( gu parentheses are number of individuals in that smoking
category)1 [SM = smokers NS = nonsmokers]-Continued
®
Author, Autopsy Data
year, population collection Cigarettes per day
country
Auerbach, 1,372 autopsies Interview with
et al., of male next of kin.
1965, patients in -
U.S.A. Orange, New
Jersey, VA .
hoepital for
whom smoking
habit data were
available and
who did not
have overt CHD
at death.
Degree_ of coronary artery atheroscleroefe (overall age-
adjusted results)
No athero-
sclerosis Slight Moderate Advanced
NS .............. 5.6(69) 57.3 21.8 15.3
Current
cigarette
<20 .......... 26(139) 30.9 37.3 29.2
20-99 ......... 0.8(299) 19.7 42.1 37.4
>40 .......... 0.6(144) 18.1 35.4 45.9
Avtandilov,
1965, 259 male and Not specified,
141 female but there were: Comparative size of mean area of atherosclerotic legions
in inner coat of coronary arteries.
Russia autopsies. 180 SM and Right coronary artery Left coronary artery
- 220 NS. SM NS SM NS
. ....... T15.5(30) 1.3(32) T8.3 22
40-49 .:..... t236(34) 11.5(27) Y15.8 4.4
50-59 ....... t36.3(39) 14.8(39) }27.9 9.9
. . 6Ub9 ....... . f31.9(32) 23.8(36) f26.5 225
70-79 ....... 41.9(18) 31.7(36) - 26.1 35.8
a'u
Conclusions . Comments
The authors eonclude that
the percentage of men
with an advanced degree of
coronary atherosclerosis
was higher among ciga-
rette smokera than among
nonsmokers and that the
percentage increased
with amount of cigarette
smoking. This relation-
ship persisted even
when cases were matched
for age and cause of
death.
The author concludes that Causes of death 96-athero-
the worst changes were sclerotic, 102-accidental,
the
found in the left and. 2(YGvariuus diseases.
right coronary arteries }T-tesl for significance
with less severe changes of difference between
in circumflex artery means is significant
and aorta. at p<0.05 level.
41.,4,SS?9E0
~ TABLE 1.-Autopsy studies of atherosclerosis. (Figures in parentheses are number of individuals in
that smoking
~ category)' [SM = smokers NS = nonsmokers] -Continued
_Author, Autopsy Data
year, population collection Cigarettea per day Conclusions Comments
country - --
1
Viel 1,150 males Interview with The results concerning intemal fibrous streaks and fatty The authors
conclude that:
et al., and 290 relatives. plaques in the left anterior deacending coronary artery "No relationship
be-
1968 females who are reported in graphic form only. An examination of tween atherosclerotic
Chile died violently this data indicates that the moderate and heavy smokers lesions and the use of
in 1961-1964. appeared to show consistently higher percentages of tobacco was discernible_."
Smoking infor- diseased areas than the nonsmokers. But the statement
mation avail- of the authors implies that these differenas were not
able only on statistically significant when subjected to an analysis
566 males. of variance.
Strong 747 males 31- Interview with
et al., 64 years of next of kin
1969 age autopsied within 8 weeks
U.S.A. , between 1963- of death.
1966 at Charity
Hospital in
New Orleans.
Basal Group (excluding diseases related to smuking or The authors conclude that: This report
concerns only
CHD). Mean percentage of c_oronary artery internal "Atherasclerotie in- ages 25-64. -
surface involvcsi with raised lesions (number of cases). volvemenl of aorta and No data on
statistical
White coronary arteries is significance provided.
Es-34 35-44 " 55-64 greatest in heavy
NS .................................. Z(5) 19(14) 2l1(6) 30(11) smokers and least in
1-?A cigarettes/day ................. 9(14) 17(10) 26(16) 39(7) nonsmokers."
>25 cigarettes/day ................. 12(9) 31(14) 26(25_) 39(ZO)
Negro .
NS .................................. 4(14) 3(8) 16111) 17(14) ~
1-24 cigarettes/day ................. 3(39) 11(31) 14(30) 28(22)
>?.5 cigarettes/day ................. 17(10) 14(17) 29(12) 16(11)
'Ualeee otherwise specified, disparities between the total number of individuals and the sum of the
individual amoking catsgoriee are due to the exclusion of either ocaasional, miscellaneous, mixed,
or ex- .
._._ _. ._ ~.
smokera eA .rK~ ... v
~ ~ .., . ..
. .. , . ... '
SOURCE: U.S. Public Health Service (tsa).
ZM~ I.-/~,i;rJto
reduction in arterial blood flow such that cellular oxygen~ demand is
not met by oxygen supply causes myocardial cells to shift their
metabolism to anaerobic glycolysis and to accumulate lactate and other
acidic metabolites: Such acidosis depresses cellular contractility. For
reasons that remain to be clarified, cell membranes are damaged by
ischemia. Moreover, the mitochondfia are sensitive to ischemia and
rapidly lose their ability to synthesize adenosine triphosphate, and are
unable to maintain the energy requirements of the cell to live and
function. Cell death ensues (65, 137). The organized contraction of the
heart is integrated by the sequential spread of an electrical stimulus.
Ischemia, with or without overt infarction, can disrupt this integration
and alter rhythmic stimulation, causing bradycardia or asystole or,.
more commonly, aberrant foci of electrical activity and fibrillation.
Hypoxia is not identical with ischemia since hypoxia can occur while
the circulation maintains the local concentrations of other ions and
substrates. However, the lack of adequate cellular oxygen is so
important a part of the events summarized above that the addition of
hypoxia to a marginally tolerated ischemia may initiate critical
changes.
Since the major risk factors can be shown to enhance atherogenesis,
it is usually implied that their association with heart attack is through
the ischemia resulting from coronary atherosclerosis. However, direct
effects upon cardiac function may also play a role. Hypertension
increases the work and mass of the heart and creates a larger
nutritional demand and relative ischemia. Nicotine releases catechol-
amines and transiently increases cardiac rate and! work. Carbon
monoxide decreases oxygen availability to the heart.
Animal models of acute myocardial infarction include embolism of
the coronary arteries, slow or rapid constriction of arteries; intimal
sclerosis and narrowing by various techniques and, by dietary
cholesterol, atherosclerosis leading to acute or subacute myocardial
ischemia and infarctionL These different models can serve different
experimental purposes. Each has limited analogy to myocardial
infarction in man because infarction in man is itself a pathologically
variable phenomenon and~ because of anatomical differences in size and
circulation between animal and human hearts. Perhaps the model
creating events most like those in man is the nonhuman primatee
(particularly M. fascicularis) with advanced dietary atherosclerosis. It
is however, a variable one (58).
Summary of Epidemiological Data
The epidemiological concept of risk factors for myocardial infarction~is
based' on data: gathered prospectively or retrospectively about myocar-
dial infarction rather than about atherosclerosis per se. As noted in the
section~ on atherosclerosis, the data that associate risk factors with
humani atherosclerosis seen at post mortem are limited. On the other
TABLE 3.-Coronary heart disease morbidity as related to smoking. (Risk ratios-actual number of CHI)
manifestations shown in parentheses)' [SM = Smokers NS = Nonsmokers EX = Ex-smokers]-
Continued
Author, Number and Duta
year, type of collection
eountry population
PROSPECTIVE STUDIES
Follow- Number of
up incidentv Cigarettes/day hpes, cigan A
ge
varialion Comment
a
years _ _
_ _
-
Shapiro 1I0,000 male Raseline med- 3 Total Males Females Males only Males Females Total myo-
e( al., and female ical inter- -unspeci- NS .................. 1.00 1.00 NS ......... 1.00 35-"
45-54 55-6/ 35-44 45.5{ 55-64 cardial in-
1969, enrollees view and fied. All current........... 2.14 2.00 SM ......... 1.82 1.00 1.00 1,00
1.00 1.o0 1.00 farctiun in-
U.S.A, of Health eMamination cigarettes.......... (p<O.OI) (p>d01) (p<0.01) 2.47 3.06 1.69 225 287
1.80 includes those
Insunncp and regular <20 ................. 1.50 0.52 215 132 1.25 231 165 dead within
Plan of fullow-up. >20 ................. 2.33 1.77 3.01 329 1.81 ---48 hours
Greater >40 ................. 6.36 10.09 7.69 5.30 20.25 11.79 4.07
5.92
NS include
35=64 yean ex-_smoke_rs.
of age.
New York (HIP)
Keys 9,186 malen Intcrvicws 5 65 dealhe. NS, EX
1970 in 5 roun- and regu- 80 myocar- (SM <20) ........ 1.00(306)
Yugo- tries 40.5_9 lar follow- dial in- All current
alavia years of up ecamina- fanrtions. (>20) ............. 1.31(108)
Finland age at entry. . lion by 128 angina Italy larsl pectoris. Nethe_r- phypjcians. 15_5 other ~
lands
Greece i428 total.
9,_1 L q ;9C 0
fncludes all
CHD incid_ence
including EKG_
diagnases.
Coven all
muntriea in-
veatigated
except U.S.A.
tDifferenae between total
CHD and the
sum of smnking
gtoups u due
to difference_
in figures
presented by
aulhors.
TABLE 1.-Autopxy ntudicM of atherorrrlerads. (F1Rurrw In parrnthewrs are number of Indl.idnal. {n
thwt swol.lag
catego ry)' ISM m smokers NS - nonsmokera+]-C'ontinued
~
t--~
W
Author, Autopsy Dnta
year, population collection Cigarettes per day C_unc_lu_s_io_ns Cummenty
country
Sackett, 893 total, Patient The resulta ooncerning aortic atherv_sclerosis are given in
et al., including 433 interview on form of figure_ presentation of ridit-analysis.
1968, male and 450 admission. U.S.A. female (white)
patients autop-
sied at Roswell
Park Memorial
Hospital. '
Represents all
deaths 1956-1964 ,
exclusive of 81
male pipe and
cigar smokers
and 55 incom-
plete files.
t~:.4.sS9C0
The authors condude that
among males, ". . , a
large increase in the
severity of aortic athero-
sclerosis occurred in the
. groups using either ciga-
relte® only or both ciga-
rettes and alcohol as
compared with the group
using neither cigarettes
nor alcohol . . , lhere
was only a small and
statistically insignificant
difference between the
group using cigarettes
. alone and the group using
both cigarettes and alcohol,
. . ." The severity of
aortic alherosclerosis
increased with increasing
use of cigarettes, when
measured-both by in-
tensity and by duration
of smoking.
TABLE 5.-Annual probability of death from coronary heart
disease, in current and discontinued smokers; by age,
maximum amount smoked, and age started smoking
.
A
Age started smoking
15-19 20-24:
Maximum daily
Age number of ci
a Discontinued Di
ti
d
g
-
Current
Current
scon
nue
rettes smoked
smokers
for five or
smokers
for five or
more years more years
(Probability x 105)
55-64 ............................ 0
10-20
214-39 501
798
969 -
568
766 501
811
872 -
551
&98'
66-741 ........................... 0 1,015 - 1;015 -
10-20 1,501 1~169 1,478 1,213'.
21-39 1,710 1m 1,573 1,098'
'For age group 6fr74, probabilities for discontinued smokers are for 10 or more years of
diseontinuancemnoe data
for the 6-9.year discontinuance group sre not given.. _
SOURCE: Ul S. Public Health Service (1s8):
amount smoked' and to the age at which~ smoking began, in a study of a
small subset of the population.
In industrial societies which share about the same generali nutrition-
al and metabolic circumstances as the United States, it has been shown
repeatedly that cigarette smoking is associated with a considerable
increase in risk of myocardial infarctionland death following infarction
when compared to the risk among, nonsmokers. The effect is dose-
related in terms of years of smoking, number of cigarettes smoked~ per
day, and the habit of inhaling. The association is generally consistent,
reproducible, and predictive. It is independent in the sense that its
effect is found when other risk factors for heart disease are controlled
in statistical analysis. The effect is seen chiefly in cigarette smokers.
Pipe and~ cigar smokers are apparently at only minor increased risk.
The effect is greatest in young middle life and~ decreases with age to
become a minor risk beyond age 65. Cessation~ of smoking reduces, over
time, the increased risk attributable to smoking toward the risk of
nonsmokers. While most of the data have been~ gathered on men, there
are sufficient data to provide similar general conclhsions that cigarette
smoking is also a: risk factor for myocardial infarction in women. The
studies of Hammond and Garfinkle, listed in Table 2, and of Shapiroo
and colleagues, in Table 3, record positive associations between
smoking and mortality and~ morbidity from CHD in large populationss
of women. It has been observed that women who use oral contraceptive
pills are at higher risk of infarction if they also smoke (102). Recently,
a case-control study has reported that, among 55 women who had
suffered myocardial infarction below the age of 50 years, the
proportion of smokers was 89 percent compared to 55 percent among
4-35
correlates significantly with the occurrence of new myocardial
infarction among, men who have had a prior attack. Mulcahy and
colleagues (97) have reported that over a 5-year period, subsequent
smoking after an infarction did not affect morbidity, but there was an
increased mortality among those who continued to smoke. In the
British civil servant study (:115), it was found that among those with
existing evidence of ischemic heart disease, the mortality rates over 5
years were 4.7 and 4.0' percent among those who smoked relative to
nonsmokers. Again, in a Swedish study (154), those who ceased to
smoke after a heart attack had only half the rate of nonfatal
recurrences, and half the rate of ca.rdiovascular mortality of those who
continued'to smoke over a 2-year follow-up period.
There is persuasive evidence from population studiAs in the United
States and in the United' Kingdom (35) that ex-smokers adopt a lesser
risk after ceasing to smoke, which in~ time is little different from the
nonsmoker who never smoked. The 1976 reference report on~ The
Health Consequences of Smoking (138) tabulated several important
studies in~ Tables 15 and 16 on page 42 (reproduced' above as Tables 4
and 5): The Framingham Heart Study (50) also reports a beneficial
effect below the age of 65. Men who stopped smoking had coronary
attack rates only one-half those who continue to smoke 10 or more
cigarettes per day. In~ a paper that may be germane, although it relates
to differences in exposure rather than cessation, Hammond and
associates (53) find' that smokers of low tar and' nicotine delivery
cigarettes had lower death rates from coronary heart' disease than
those who smoked the same number of high tar-nicotine cigarettes.
Bothl groups of smokers, however, had higher rates than~ nonsmokers.
It is of interest in discussing other risk factors that physical activity
markedly shortens the half life of carboxyhemoglobin in the blood and
that active people attain lower equilibrium levels than sedentary ones
when smoking (27, 56, 1l,.5). Physical' activit'y, particularly when heavy,
has been shown in several studies to reduce the incidence of heart
attack, and it can be speculated that at least some of this effect may
arise from a reduced burden of COHb among physically active smokers
(145). Morris and colleagues obtained evidence in a study of British
civil servants that, among men who did not exercise vigorously during
their leisure time, smokers had 2.5 times the risk of nonsmokers.
Among the physically active group, however, the relative risk of
smokers was 1.5. The amount of tobacco used daily was the same:in the
two groups (95).
The Effect of Smoking on Myocardial Infarction in Man
The epidemiological, data that associate cigarette smoking and
myocardial infarction are summarized in the preceeding section. The
effect is major and adverse for the incidence of first events; it is
4-38
weight, cigarettes smoke& per day, and serum cholesterol concentra-
tion.
Models of experimental atherosclerosis in species as different as
bi'rds, rodents, dogs, swine, and nonhuman primates have been
developed. The majority of these models have been induced by feeding
saturated fat or cholesterol leading to fat-rich plaques that resemble
the fatty streaks of childhood or the very fat-laden plaques occasional-
ly seen in adult life. Other experimental'techniques of inducing lesions
are: the use of physical'injury; to arteries leading,to acute proliferative
plaque development with little or no lipid accumulation; the induction
of intimal thrombi with their tissue organization~ yielding fibro-fatty
plaques; immunologic vascular injury with lipid or cholesterol feeding;
and; recently (in chickens), viral infection. Among different species of
nonhuman primates, the same dietary regimen will produce character-
istically a somewhat different distribution of plaques in the arterial
tree. Different experimental diets will produce lesions that are
characteristically more fatty or more fibrous. Spontaneous fibrous or
fibro-fatty plaques occur in~ many species including birds, rabbits,
swine, and nonhuman primates: The enhancement of spontaneous
atherogenesis in chickens by polycyclic hydrocarbons has been reported
(1); A strong genetic control exists in pigeons both for the expression
of experimental atherosclerosis and for its localization predominantly
either in the aorta or in~ the coronary arteries. Thus, there is a wide
variety of experimentali and spontaneous animal models available with
which to study atherogenesis.
A huge body of literature deals with the pathogenesis of human and
experimental atherosclerosis. Several recent reviews provide a detailed
and critica.l: considerationi of current concepts (3,21,22,84,89,
117,119,126,155,156). The various interrelationships of different patho-
genetic processes suchas cellular proliferation, lipid accumulationand
thrombotic phenomena are not fully understood. Nevertheless, it is
possible to synthesize available data into a frequently explbred major
working hypothesis, of the initial stages of atherogenesis based on
extensive experimental data (see particularly 117,155,156) that support
the pathogenetic concept that the arterial endothelium functions
normally to separate the intima and media: from the blood. The
hypothesis holds that locaU injury results in failure of this barrier
function or in loss of endothelial cells an& exposure of the subendothe-
lium to whole plasma and to blood platelets. Platelets and plasma
contain growth factors capable of inducing smooth muscle cells in the
intima and adjacent media to multiply. This loss of barrier functioni
also allows macromolecules such, as fibrinogeni and very low density
(VLDL), intermedlate,, low density (LDL); and high density (HDL)
lipoproteins freer access to the vesseli wall. More lipid is internalized by
intimal smooth muscle cells and macrophages than their lysosomal
digestive systems can catabolize, and they become overloaded withi fat
4-9
significantly increased incidence rate for smokers among men who
were current users of cigarettes. Among femalies, the trend was
positive but not significant. A study of the incidence over 5 years of
angina among 10,000 Israeli men found that there was a higher
incidence rate among men who smoked over 20 cigarettes a day than in~
those who smoked less, but the difference did not reach the 0:01 level
of significance (91). In addition, a questionnaire survey (45) of about
70,000 persons has foun& that more smokers than nonsmokers admit'te&
to chest pain. Some nine different kinds of angina-like and nonanginal
pains were included as chest pain. Reid and associates have reported a
significant association between angina and current cigarette smoking
among British civil servants (110).
The Effect' of Smoking on Angina Pectoris
As noted above, the predictive risk factor association of smoking wit4
the incidence of angina pectoris is not clear. However, there is evidence
among persons with angin& that smoking lessens the threshold of
exercise for the onset of paim Aronow (7, 8, 9, 10, 12) has reporte&
clinical studies in which smoking cigarettes with highy low, or no
nicotine content aggravated angina. In these studies, high nicotine
cigarettes aggravated exercise-induced angina more than~ l'ow nicotine
cigarettes, and low nicotine cigarettes more than~ cigarettes without
nicotine. He has also reported in patients with angina pectoris an&
coronary artery stenosis documented by angiography that when 50
parts per million of CO were inhaled until the mean COHb level of
venous blood was raised to 2.68 percent, it was accompanied by a
significant decrease in exercise time before anginal pain. There was
also a decrease in~ the amount of cardiac work represented by the
product of systolic blood pressure and heart rate needed before the
onset of angina compared to when~ air was breathed. S-T segment
depression of 1.0 mm or greater in the electrocardiogram occurred
earlier, after less exercise and at lower cardiac work levels among,
these patient's when they breathed CO rather than air. Although it is
uncommon; there are patients in whom the act of smoking a cigarette
will itself precipitate an attack of angina (26, 1.1,3).
An interpretation of such data is that, in the patient with a
compromised regional myocardial blood supply who can provide little
or no compensatory increase in circulation to meet an increased cardiac
demandy smoking enhances both hypoxia and cardiac demand,,
resul ting in a more severe ischemia and an earlier onset of angina.
Research Needs
Epidemiological data with respect to the predictive or risk factor
association of smoking and angina pectoris tend to show an~ inconsis-
tent positive associatiom Despite this unsatisfactory state of affairs,
4-48
0
w
~
cx~
cJ
N
W
I
~
TABLE 2.-Coronary heart disease mortality ratios related to smoking-prospective studies. (Actual
number of
deaths shown in parentheses)1 [SM = Smokers NS = Nonsmokers]-Continued
Author, Numler and Follow- NumG:r
year,- tgpe of Data up of Cil;areltes!day Cigsrs, pip. Age vadation C mmenU
eountry pnpulation rnllection (yean) deaths -
Hinyama, 265,118 . Tnined in- 1 91 NS ...... _ 1.00 (17) Prelimin-
1%7, Japanese terviewen 124 ....... 113 (69) . ery report.
J.p.n adults over and follow- - >25 ....... I W_ (5_1
. age 100 up of death
certifirate.
Kannel 5,127 males :Nediral ex- 12 52 NS _...... 1.00 (27)
et al., and femalee _ Inatinn SM >20 ... 220125)
19NL aRc 30.59. and G.S.A. follow-up.
(p<9,o5)
Hammond 358,534 Qutstinn- 6 1019 Males Fumalts Males tH asal on
and malee rrgimand NS 100, 190 4039 5"9 6_0-89 7079 59deaths.
Carfinkel, 445,875 follow-up 19 ........ 1.27 084 NS .....,... 1.00 1.00 1,00 L00 1969. lemnlea of
dealh 10 19 .,.... 160 1.72 1 9 ....._.. 160 1.59 1.48 1.14
C.S.A. aC,r40-79 rerti0catr. 20-30...... 173 1.52 1a19.__.. 259 213 1.52 1,41
at entry. >40 .,..... 177 0.61 31-'i0 ....... 3.76 2.40 1.91 149
>40 ,...,... 5.51 2.79 1.79
147
Femalea
IAO 1.00 1.00 100
1-9 ......... 131 1.15 1.04 0.76
10-19....... 20R 2.37 ~ 1.79 098
'LQ.30....... 8.62 2.6R 2.08 127
>40........ t3.31 3.73 t2.02
zs~c-s9ca
,
,
of cases occur in individuals with no prior clinicaL evidence of CHD.
The standard CHD risk factors have been confirmed also to be
predictors of sudden cardiac death in both a case control study (44) and
in a prospective cohort investigation~ (38). Whether death from CHD is
sudden does not appear to depend' upon~ the mix of risk factors, and no
combination of standard' risk factors (including smoking) appears to
designate those destined to die suddenly in contrast with those who
will experience a more protracted~ death. The proportion of sudden
cardiac deaths to more protracted deaths is about the same whether or
not prior overt CHD has been recognized (38, 71). Evidence has been
accumulated in several studies that, in the presence of recognizable
heart disease, ventricular premature beats are associated with an
excess liability to sudden ca.rdiac death (142). A recent study by
Ruberman~ and associates (118) followed 1,739 men in the New York
City area who had a myocardial infarction at least 3 months before
entering the study. They were examined' for ventricula.r premature
beats by means of a continuous 1-hour record of the electrocardiogram.
The follow-up period was from 6 months to 4 years, averaging 24.4
months. During this perio6 there were 208 deaths, ofl which 85 were
classified as sudden cardiac deaths (defined here as occurring within
minutes and in the absence of signs or symptoms suggesting acute
myocardial infarction). Much higher mortality was experienced in
those subjects manifesting complex beats (runs, early beats, bigeminal,
and multiform beats) than in those without. The authors report that by
the 3-year observation point the risk of sudden cardiac death, adjusted
for age, was four times above the comparison experience, and the risk
of death~ from any cause was 2.6 times greater than expected.
Moreover, although su& complex beats were often associated in this
study with other findings that relate to severe heart damage, they
were shown to be independent risk factors.
Autopsy studies on persons dying sudden cardiac deaths have
produced somewhat variable findings. In general there is a close
association with extensive and severe coronary atherosclerosis, and an
appreciable number of patients show evidence: of old or recent
myocardial infarction. Reichenbach and coauthors (109) have tabulated
data from several studies. Their own experience in the Seattle,
Washington area was that 97 percent of deced'ents had & prior history
of heart disease (much higher than other studies); 55 percent had!
pathological evidence of old myocardial infarction; 8 percent had less
than 75 percent luminal stenosis in any major coronary artery with the
remainder showing 75 percent or greater stenosis in one or more
vessels; and 57 percent had occlusion, of one or more vessels. Recently
formed thrombi were found~ in 10 percent of hearts, which was,
generally, appreciably less than other studies; acute myocardial
infarction was found in only 5 percent of hearts, which also was,
generally, appreciably less than in other studies. Other reports that
4-42
genetic strain of stroke-prone, spontaneously-hypertensive rats has
been developed.
Summary of Epidemiological Data
The epidemiological data on cerebrovascular disease (stroke) and
smoking were summarized in the 1976 reference edition of the report
on The Health Consequences of Smoking (138), Table 137 (pp: 64-66).
Kannel' reviewed the subject for the Third World Conference on
Smoking and Health~(68):
The results of various studies have not been congruent and no
conclusion can be stated with confidence. Kannel has noted that the
prospectively collected data have been difficult to interpret because of
deficiencies, such as small sample numbers, failure to consider
separately cerebrali hemorrhage and ischemic infarction, failure to
consider separately men and women, and inadequate classification by
age.
The 1976 report on The Health Consequences of Smoking (138))
comments (on page 152 and in light of its data in Table 7 on page 153
reproduced below as Table 7) on the:possible role of age dependency in
the various studies, noting that cigarette smoking may be a risk factor
for stroke at all' ages, but that other causes of stroke may be
proportionately so important in older ages that the smoking risk is
masked by strokes due to other causes in studies that do not involve
very large populations: Although two very large studies, involving
about 250,000 and 1,000,000 respondents, found relative risks of about
1.52 and 1.41 for cigarette smokers (41), no certain conclusion can be
offered at the present time because of apparently conflicting data. A
recent study of a large cohort of women has reported that the risk of
subarachnoid hemorrhage is significantly associated both with ciga-
rette smoking and with the use of oral contraceptives. The risk to
cigarette smokers was 5.7 times that of nonsmokers while it was
increased 6.5 times for users of oral contraceptives. The risk was
increased 22 times among women who both smoked and used oral
contraceptives compared~ to nonsmokers and nonusers (106).
The Effect of Smoking on Cerebrovascular Disease
It has been noted that risk factor data are inconclusive on the relation
of smoking to the incidence of stroke. Carbon dioxide causes
cerebrovascular dilatation. Both nicotine and CO increase cerebral
blood flow (123): Unlike the case of cardiac metabolism, there is no
evidence that nicotine affects cerebral oxidative metabolism in a dose
equivalent to smoking. It is uncertain that these effects relate in any
way to stroke: It may be speculated that pathogenetic mechanisms
could' operate through effects oni blood platelets, oxygen transfer,
emboli from the heart, or through vessel wall toxicity and enhanced
atherogenesis of large and small'vessels to the brain. There are no data
4-50
the case controls (p < 0:001). A dose relationship was present.
Compared to nonsmokers, heavy smokers using 35 or more cigarettes a
day had an infarction rate estimated to be increased' 20 times. The
women did not use oral contraceptives (124)'.
The final report of the Pooling Project considers data from the
Albany civil servant study, the Chicago Peoples, Gas Co. study, the
Chicago Western Electric Co. study, the Framingham community
heart' study, and the Tecumseh community study. It presents typical
findings from prospective studies and ones that are particularly
important for the United States because the data are derived from
several locations in the country: In this report (107); fatal and nonfatal,
myocardial infarction and sudden coronary heart disease death have
been designated as major coronary events.
Cholesterol values, blood pressure readings, and smoking history
observed just once in men at the beginning of a 10-year follow-up
period showed a high predictibility of risk of CHD. Multiple logistic
analysis showed these three characteristics to be independent.
Combinations, of these risks were not additive but compounded. The
highest combined quintile of risk characteristics compared to the
lowest quintile had a relative risk of CHD events of about 6 to 1. About
40 percent of cases emerged from the 20 percent at highest risk, while
86 percent emerged from the upper 60 percent of risk traits, and 96
percent derived from the upper 80 percent. Not only is risk of CHD
events associated with the more deviant levels of these traits, but
appreciable risk may attach to combinations of mild deviations of risk
factors.
Stnoking habit was classified as, more than a pack of cigarettes a
day, about a pack a day, about half a pack a day, less than half a pack,
cigar and pipe only, never smoked and past smokers. For most
analyses, the report groups past smokers, never smoked, and smokers
of less than half a pack a: day into a single group labeled nonsmokers,
noting, that the majority of the less than a half pack per day smokers
were only occasional users: This group of nonsmokers was then
compared with those who smoked more. It was found that men who
smoked a pack or more a day had a standardized incidence or risk ratiol
of a first major coronary event 2:5 times that of the nonsmoker
(confidence interva12.1 to 3'.1). Those who reported smoking more than
a pack a day were found to have 3.2 times the risk of nonsmokers in
terms of standardized' incidence ratio (confidence limits 2.6 to 4.2). The
risk of pipe and cigar smokers was intermediate between that of the
nonsmokers ~ and the half a pack a day smokers, but was not
statistically different from either group in this study. Risk was found
'This cald;ulation removes that portion of any, difference attributable to age differentials. The
average rate for the
total group iaassigned the value.of100: The rates far.subgroupa are.proportional to.the average for
the entiree group
after removing the effects of age.
4-36
n
consider a history of smoking in relation to autopsy examinations and
sudden death are those of Spain and coworkers (127, 128) and
Friedman and~ associates (44).
Two major mechanisms for sudden cardiac death may be postulated.
One is asystole or arrest, generally arising in response to severe
ischemia and impending or spreading acute myocardial infarction. The
other is ventricular fibrillation arising from regionaL myocardial
ischemia and ventricular ectopy and modulated by a number of
circumstances that may contribute to electrical instability of the heart.
Sudden Cardiac Death in Animals
Sudden death has been reported in nonhuman primates that were fed
cholesterol to induce atherosclerosis (58), and it has been induced in
many experiments by acute coronary ligation or obstruction. The latter
experiments have produced a large body of data on the ability of
regional ischemia to initiate ventricular fibrillation and sudden cardiac
death, and' have helped to elucidate local' tissue metabolism, electrical
behavior, and the relation of neural and pharmacologic agents to the
precipitation or control, of arrythmias and fibrillation..
Summary of Epidemiological Data
Sudden cardiac death is the first manifestation of coronary heart
disease (CHD) in about 20 percent of CHD deaths. Of all CHD deaths
about 50 to 60 percent are sudden (71).
The 1976 reference report on smoking, and health (138) noted in
Table 3(p. 26) data oni sudden cardiac death from the Pooling Project
that found an increased mortality ratio of 1.9 for men who smoked
either 10=or-less or 20 cigarettes a day, and a ratio of 3.36 for those
smoking more than 20 a day, in comparison with nonsmokers (1.00). A
more recent report combines data from, Framingham and the Albany
Civil Servant Study (38, 71). These data relate to men only, and are
derived from 1,838 subjects from Albany, New York, and 2,282 from
Framingham, Massachusetts, aged 45 to 74, and were collected
prospectively over 16 years: Sudden death was defined as demise
within one hour of onset. Deaths within 30 days of a known heart
attack were excluded as were those of subjects found dead in bed. Data
are presented on the associations between sudden cardiac death and a
number of factors such as age, a prior history of CHD, blood pressure,
serum cholesterol, and other items. Smoking was found to be a risk
factor, with smokers having a threefold higher rate than nonsmokers.
In a multivariate analysis of systolic blood pressure, electrocardio-
graphic evidence of left ventricular cardiac hypertrophy, relative body
weight, cigarettes smoked per day, and serum cholesterol as contribu-
tors to risk among men ages 45 to 54 an6 55 to 64 at their biennial
examination antecedent to deathy it was judged that, of these factors,
the use of cigarettes was the most' potent contributor to sudden death:
4-43
TABLE 2.-Coronary heart disease mortality ratios related to smoking-prospective studies. (Actual
number of
deaths shown in parentheses)' [SM = Smokers NS = Nonsmokers] -Continued
Authur, tiumlxr zn,t E'~~Ikrv:- Numt-
ycnr, tylx~ nf [)aln up of CIgaretlestday Cigan, pilry Age vxriation Commrnl
muntpIxgrulation callrrtion (yean) Jeaths
StrolxI
and GxII
1965
Swit.r-_
IanA 3,749 malc
Suixv phy-
>iciani- Quivtlnn-
naire and
follaw-uy
of death
n~rtificutc. 9 162 NS ........
120 .......
>_20 .....,. 1.00
1.48
1.76 NS
SM 1.00
1.45
Be+t, Appro.i- Qmslinn- 6 2,0110 NS ........ 100 Cip,urs
1966
('anada mal<ly
78,(q0 nain~ and
follow-up All smoken
G10 1.60 (13N0)
1.55 (207) NS _
SM . 100
0.98
(16)
male Cana_- of dcath 10-20 1.5A (766) Fipa
dien
vetcrane. mrtificate. >20 ....,.. 178 ('277) NS ..
SM . 190
0.96
(95)
Hahn 0.5. mplc Quextion- 8 I(2 10.990 NS ,.,.... . 100 12997) Cigan
1966 vcleran. neim and All smokers 174 14160) NS .. E 00
l:.S.A. 2,265,674 fallow-up 19 ..... 1.39(4J9) SM . 1.04 (623)
~ I.rum of Aenth 10-20 ...... 1.78/2102) Npen
yean. cecliGeate.. 21 39 1.64 (1212) NS .. 100
>39 .....,. 200 (266) SM . 1.08 (366)
t~; t.+!: :~9C 0
30J9 fAl-69 70 and over
NS ....,._. 1110 Idp 100
<10 0.97 (18) 1.56 (221)) 171 (99)
10-20 1.45111.5) 1.67(W) 1.29 (941
>20 ......., 185 5 (6,5) 1.76 (1134) 1.73 (28)
. . .
I.M
TABLE .2.-Coronary heart disease mortality ratios related to smoking-prospective studies. (Actual
number of
deaths shown in parentheses)1 [SM - Smokers NS = Nonsmokers]-Continued
Awhoq ?iumlar and Fnllnu. Vuml.r
_.. , tp{. of Ilata up of fiqamt0.s day CiRan, pqxr Ag, rariation Commenls
muntry Ixtpulation mllcctinn (r.an) dtatha
Paffenhzr50,OOll male B. line 17 51 1,146 15 ........ 1.011 30-04 ~t5-54 Sa-69
~tvand former ten~iew: (PGOFlII
matched SM _.__ I.i0/~l NS 100 LOO l.W
K'in4 etudenL, xnd exam. eith (PF6611 1969 ination aml 2292 SM 190 (A4) 1.60 (161) 1.20 (134)
L'S.A folInw-aP mntrok
6c Acath
nrlificate. -
Pe[tentwr- 3,268 male Imtixl multi- 16 291 1:S and <2U 1A0(1871 (1 <601)
Qcr ct el., Innphqrq- pha.ric SM >20 ... 2(1H f1541 -
1970, men 35 64 +tteaning ~- GS.A vvan of aml follow-
agc. up of dcath
crrtifieata.
Taylnr 2,571 male Inti-iewa 5 46 M1S ........ IAO (4) Uata apply
et al., railn>ad and ngula_r <20 .. .. 1.9i (Y()) . only tu
1970 emPloyeen fnllo-p >20 --360 (7l1 t4oie free
L.S.A. 40 59 )ean crim- - of CHD
.
uf age at ination. . . at entry
entry.
C~_IllSs9£0
cases will emerge (68). Wald, et al. (146) have reported a closer
association between blood COHb ia smokers and myocardial infarction,
angina, or intermittent claudication (considered together) than with
smoking history in a survey of Copenhagen workers.
An acute effect of CO on intermittent claudication has beennoted by
Aronow, et al. (11). They have reported that patients manifesting
intermittent claudication of the calf or thigh~ muscles, and angiograph-
ic evidence of iliofemoral arteriosclerosis, who breathed CO to increase
mean venous COHb levels from 1.08 to 2.77 percent, experienced a
decreased exercise threshold to produce leg paim
Table A30 (pp. 129-13% of the 1976 report on The Health
Consequences of Smoking (138) lists a number of experiments in man in
which the effect of smoking or of nicotine was assessed on some aspectt
of the peripheral circulation of the arm or leg. The data are not
consistent, although the: tabulated data in normal individuals tend to
show a decrease in skin temperature and a decrease in blood flow. In
another study, calf-blood flow was measured plethysmographically in~
51 men, aged 59, who were heavy smokers, but who ceased to smoke
for about 2 months. They showed an increase in blood flow during
reactive hyperemia (62) after the cessation period. No experiments on
animal models of chronic peripheral vascular disease and smoking have
been found.
Research Needs
In general, epidemiological data are adequate. It is likely that current
epidemiological research will provide additional data to furnish more
exact figures than are currently available. New studies appear to be
unnecessary except to establish levels of risk for different "less
hazardous" cigarettes. The possible association~ of postmenopausal
estrogen treatment, smoking, and' PVD in older women may warrant
attention.
However, it is not clear what roles atherogenesis, nicotine, CO, and
perhaps t'obacco allergy may play in the development and expression of
PVD in smokers or in its responsiveness to smoking withdrawal.
Studies of the mechanisms responsible for these aspects of smoking
and PVD are warranted' and may also have interest for the study of
the pathogenesis of atherosclerosis in general.
Animal studies involving chronic or acute smoking, hypertension,
atherogenesis, and~ PVD are possible, particularly in nonhuman
primates conditioned t'o smoke. These may offer a direct, if difficult,
experimental approach to understanding the circulatory effects of
smoking and smoke components on PVD.
Conclusions
Cigarette smoking is a major risk factor for ischemic peripheral
vascular disease of arteriosclerotic type. It increases appreciably the
4-54
there would seem, relatively little reason to attempt to study the issue
further at this time.
Conclusions
Studies of the possible role of smoking as a risk factor for the incidence
of angina pectoris suggest a positive association, but the findings are
inconsistent.
In patients with angina pectoris, smoking lowers the threshold for
the onset of angina. Both nicotine and CO aggravate exercise-induced
angina.
Cerebrovascular Disease
The Nature of Cerebrovascular Disease in Man
The underlying circumstances of stroke are varied. They include
tumors and bleeding dyscrasias leading to intracerebrat hemorrhage or
infarction, unusual diseases of blood vessels in the brain, aneurysms of
intracranial vessels embolism, thrombosis, vascular rupture, and
atherosclerosis of the vessels of the neck and their distributing vessels
in the brain.
The great majority of strokes, perhaps more than 90 percent, may be
classified either as intracerebral hemorrhage associated primarily with
hypertension, or ischemic cerebral infarction associated with athero-
thrombotic disease of the vessels of the neck and their main
distributing, branches in, the brain. Infarction is more common than
hemorrhage. The clinical diagnostic subclassification or separation of
hemorrhagic stroke and ischemic stroke contains an appreciable
margin for misclassification. It is these conditions that are under
consideration here, rather than the rare disorders.
The risk factor data for stroke have been considered recently by twoo
panels, (31, 40). They are less clearly defined than those for coronary,
heart disease. The strongest gradients of risk are associated with age,
blood pressure, preexisting, cardiovascular disease, and diabetes
mellitus. Prospective studies have not found a clear and direct
relationship with serum~ cholesterol concentration. It has been of
interest that a Japanese study has recently reported that among a
population with a high incidence of stroke but low levels of blood
cholesteroll by Western standards, there was no evidence that
hypercholesterolemia defined as levels above 200 mgm/100 ml
inereased~ the incidence of stroke. Cerebral infarct developed in 11
percent of those with hypertension~ and hypercholesterolemia and 21
percent of those with hypertension alone (r01);
Models of cerebrovascular disease in animals have largely been
limited to acute occlusive manipulations. Only recently have experi,
mentaL dietary and hypertensive sclerosis of cerebral vessels with
cerebral hemorrhage (58) been reported in nonhuman primates. A
4-49
(16), HAMMOND, E.C. Smoking habits and air pollution in relation to lung cancer.
In: Lee, D.H.K. (Editor). Environmental Factors in Respiratory Disease.
Fogarty International Center Proceedings No. 11, New York, Academic Press,
1972. pp. ,177-198:
(n) HAMMOND, E.C. Smokinginxelation to the death rates of one million men and
women. In: HaenszelW'. (Editor). Epidemiological Approaches to the Study of
Cancer and Other Chronic Diseases, NationaliCancer Institute Monograph 19.
U!S. Department of Health, Education, and Welfare, UIS. Public Health
Service, National Cancer Institute, January 1966, pp. 127-204.
(18) HAMMOND, E.C, GARFINKELa L. Coronary heart disease, stroke, and~aortic
aneurysm. Factors in the etiology. Archives of Environmental Health~ 19(2):
167-182, August 1969.
(19) HAMMOND, E.C., GARFINKEL, L., SEIDMAN, H., LEW E.A. "Tar" and
nicotine content of cigarette smoke in relation to death rates. Environmental'
Research 12(3)1263-274, December 1976.
(20) HAMMOND, E.C:, HORN; D. Smoking and death rates-Report on forty-four
months of follow-up on 187,783 men. I. Total' mortality: Journal of the
American Medical Association 166(10): 1159-1172, March 8, 1958.
(21) HIRAYAMA, T. Operational aspects of cancer public education in Japan. In:
Summary Proceedings of the International Conference on Public Education
About Cancer. UICC TechnicallReport Series, Volume 18, Geneva, 1975, pp. 85-
90!
(22) HIRAYAMA, T. Prospective studies om cancer epidemiology based on census
population in Japan. In: Bucalossi, P., Veronesi, U., Cascinelli, N. (Editors)j
Cancer Epidemiology, Environmental Factors. Volume 3. Proc.eedings of the
11th International l Cancer Congress, Florence, 1974, Excerpta Medica, pp. 26-
35.
(23) HIRAYAMA, T. Smoking and drinking-Is there a connection? Smoke Signals
16(7): 1-8, July 1970:
(24) HIRAYAMA, T. Smoking in relation to the death rates of 265,118 men, and
women in Japan. Tokyo, National Cancer Center, Research Institute,
Epidemiology Division, September 1967; 14.pp:
(25) HIRAYAMA, T. Smoking in relation to the death rates: of 265;118 men~ and
women in Japan. A report on 5 years of follow-up. Presented'at the American
Cancer Society's 14th Science Writers' Seminar, Clearwater Beach, Florida,
March 24-29; 1972,15 pp.
(26) KAHN, H.A. The Dorn study of smoking and mortality among U.S. veterans:
report on 8 1/2 years of observation. In: Haenszel, W: (Editor). Epidemiologi-
cal Approaches to the Study of Cancer and Other Chronic Diseases. National
Cancer Institute Monograph 19. U:S. Department of Health, Education{ and
Welfare, Public,Health, Service, National Cancer Institute, January 1966. pp.
-1-125~
(27) PRESTON, S.H. The age-incidence of death from smoking. Journali of the
American Statistical Association 65(331): 1125-1130, September 1970.
(28) PRESTON, S.H. An international comparison of excessive adult'~ mortality.
Population Studies 24(1); 5-20, March 1970.
(29) PRESTON, S.H. Mortality differentials by social class and smoking habit. Social
Biology 16(4): 280-289, December 1969.
(30) PRESTON, S:H. Older male mortality and' cigarette smoking. A demographic
analysis. Institute of International Studies, Berkeley, California, University of
California,,1970,150 pp.
(81) ROGOT;, E. Smoking and General Mortality Among U.S. Veterans, 1954-1969.
U,S. Department'~ of Health, Education, and: Welfare, Public Health Service,
National Institutes of Health, NationaliHeart and Lung Institute, Epidemiolo-
gy Branch, DHEW Publication No. (NIH) 74-544,1974, 65 pp.
2-46
TABLE 3.-Coronary heart disease morbidi ty as related to smoking. (Risk ratios-actual number of CHD
manifestations shown in parentheses)1 [SM = Smokers NS = Nonsmokers EX = Ex-smokers]-
Continued
Author, Number and
year, type of
euuntry population
Paul et al., 1,9m Weatern
1963, Electnc Co.
U.S.A. male worken
participeting
in a proapec'
Live aludy
for 4 1/2 ycan
PROSPECTIVE STUI)IES
Data Follow- Number of
collectiun up incidents
y ~y
Cigalettee%de
y --- -
Rpea, cigan Age variation
CommenU
Scncening Nuncoronary fi9 developed
examination Coronary rontrule clinieal
and
~ mven (6_7)
... (1,766) ouronary
hislury, VS .................. 23 33 diseave,
1-7 ................. 2 7 . 47 angina .
9-12 9 11 pertoris,
13-17 ............... 6 12 28 myocardial
18-22 ............... 47 30 infarction,
.
23-27 _... ....... ............
3
2
13 deethe CHD.
>28 ................ 9 6
- - (p<0.006)
- -
'Unleea otherwiee epecitied, dieparitiee between the total oumbe_r ot maniteatatione and the eum of
the individual smoking categories sre due to the exclueion of either oacaeional, miaoelleneoue,
mixed, or
e:bmokere. -------Source: U.S. Public Health Service (1J8).
TG L 5:~,9C 0
that indicate that an exacerbation of regional ischemia may promote
electrical instability of the heart, fibrillation, or asystole. Further
researchwill' be required if these mechanisms are to be well understood
and if they are to be shown to be : actual mechanisms in man in relation
to smoking and suddendeath.
Angina Pectoris
The Nature of Angina Pectoris in Humans
Pain in the thorax may have several different origins and can create a
difficult problemi of differential diagnosis. Angina pectoris arises
typically in, the face of exercise and! increased demand for work and
oxygen on the part of the heart which cannot be met immediately in
the presence of ischemia imposed~ by coronary atheroscleosis. The
origin of the pain is thought to be the ischemic myocardium. It can
occur in individuals with or free from preexisting myocardial
infarction. Since the common use of angiographic diagnostic methods,
it has become apparent that angina: al§o occurs occasionally in persons
with little or no evidence.of coronary arteriosclerosis.
Angina pectoris is associated with an increased death rate from
heart attack. Women survive better than men. Among the risk factors
associated with~ a poorer prognosis are hypertension, cardiac hypertro-
phy, congestive heart failure, and electrocardiographic abnormalities
(149). Recent studies employing angiography have shown a close
relationship between the extent of coronary arteriosclerosis and
prognosis in angina pectoris. Reeves and associates (108) have
summarized these reports to indicate that if only one of the three
major coronary artery branches is significantly stenosed, an annual
mortality rate of about 2 percent results; if two major branches are
stenosed', the resulting annual mortality rate is about 7 percent a year;
with three-vessel disease, it is about 11percent a year.
Summary of Epidemiological Data
The major studies on smoking in relation to the incidence of angina
pectoris in the United States are not consistent in their conclusions.
The 1976 report on smoking and health (138) has tabulated four major
reports in Table 5 on page 33. (Table 5 is reproduced below as Table 6.).
Doyle an& colleagues (38) report no association in al 10-year follow-up
of men from the Albany civil servant study, together with men fromi
the Framingham Heart Study. Jenkins, et al. (63) reported a slight
positive association, but not a statistically significant one. Similarly,
Kannel and Castelli (70) reported on both, men and women fromi the
Framingham Heart Study and found a positive risk association among
men and a negative one among women. In a large study of 110,000 men
and women enrolled in a: health insurance medical care plan in New
York City and followed for 3 years, Shapiro, et al. (122): reported a:
4-46
dealing directly with experimental cerebrovascular disease in animals
and smoking that examine such pathogenetic hypotheses.
Research Needs
Clarification of the existing conflicting epidemiological data may be
sought. It has been suggested by Kannel (68) that a retrospective study
of brain infarctions under the age of 55 years might help to resolve
some uncertainties.
Chronic experimental cerebrovascular disease of hypertensive or
atherosclerotic types in animals has received little attention. Such
disease has recently been produced in nonhuman primates (58), While
its characterization is incomplete, it may possibly offer an opportunity
to study the effects of smoking or of smoke constituents. The effect of
smoke constituents on the stroke-prone rat is also an area for study:
Conclusions
The relationship of smoking to the incidence of stroke is not
established. An association with subarachnoid hemorrhage has been
reported in women.
Peripheral Vascular Disease
The Nature of Peripheral Vascular Disease in Man
Atherosclerotic peripheral vascular disease (PVD): is primarily a
stenosing or occlusive disorder of the arteries of the legs. Other
branches of' the aorta such as the subclavian, celiac, or renal arteries
may be diseased similarly, but use applies the term to the arteries that
supply the leg unless noted otherwise. Atherosclerotic involvement
resembles that of the coronary arteries or aorta, but the plaques are
more fibrous and cellular and contain less fat. Involvement includes
not only the large iliac and femoral arteries, but extends to branches in
the anastomotic connections around the knee and to the lesser
branches of the lower leg and foot. Thrombosis is common, and
embolism from ulcerated plaques in the aorta or iliac arteries occurs.
The effect is to create distal circulatory ischemia of a chronic nature
that can be complicated by acute occlusive events. The circulation to
the leg may become inadequate to the needs of the muscles during
exercise. Pain in the calf or thigh is precipitated by exercise, relieved
by rest, and is designated intermittent claudication. It resembles
angina pectoris in these respects and it is often a changeable and
unstable symptom. Severe ischemia will result over time, in some
individuals, in tissue atrophy and necrosis or ischemic gangrene.
The risk factors for atherosclerotic peripheral vascular disease are
generally similar to those for coronary heart disease, but an elevated
blood pressure may be only a minor contributor to risk of PVD (68).
4-52
di,
on
03685837
Peripheral vascular disease has been reported in experimental'
dietary atherosclerosis in the nonhuman primate, but the subject has
only recently received systematic study (144).
Summary of Epidemiological Data
Kannel has recently reviewed the data pertaining to occlusive
peripheral vascular disease (68). Severali clinical reports find that about
90 percent of individuals with arteriosclerotic obstructive peripheral
vascular disease (PVD) are cigarette smokers. This is a marked excess
of smokers compared to the general or age- and sex-matched
population. Moreover, clinical experience finds that continuation of
smoking worsens prognosis after surgical therapy (157). In one clinical
study of 187 consecutive patients who underwent surgical vascular
grafting with synthetic grafts for arterial occlusive disease of the
lower abdominal aorta and iliac arteries, the patients who continued to
smoke more than a pack a day had three times the graft occlusion rate
of nonsmokers, both in absolute terms and in month-patency time
(113). Koch (75) has reported that cessation of smoking will lead' to a
reversion of risk to that of nonsmokers over 5 years. Diabetes is a
strong risk factor for PVD; it acts synergistically with smoking. A
diabetic who smokes is reported to have a 50 percent greater risk of
PVD than one who does not (151). Lawton has reported from a small
series examined by angiography that smoking is associated with
atherosclerotic distortion of the distal aorta and common iliac arteries
in a dose-dependent manner, but not with lesions in the external iliac
or femoral arteries,(77).
Epidemiological studies have also demonstrated an association of
PVD with smoking. In, one, it was concluded that cigarette smoking
was more common than expected! for both sexes among those with
PVD, that it was an independent risk factor, and that 70 percent of
nondiabetic PVD was related to smoking (152). The prospective
Framingham Heart Study reports a strong association between
smoking and obstructive peripheral vascular disease including inter-
mittent claudication (68): At all ages and in both sexes a higher
incidence of claudication was found in smokers. Heavy smokers had.a
three times greater incidence and the risk tended; to relate directly to
the number of cigarettes smoked. The effect was independent by
multivariate analiysis. At any levet of other risk factors the smoker is
at greater risk than the nonsmoker. Smoking was found to contribute
as strongly to PVD in women as in~ men. Data for pipe and' cigar
smoking do not appear to be available.
The Effect' of Smoking on Peripheral Vascular Disease
The epidemiologicali and clinical evidence for smoking as a risk factor
has been, noted above. The Framingham data on multiple risk factors
allow the identification of a top decile of risk from which 40 percent of
4-53
A case control study based on the Kaiser-Permanente health insurance,
.,
system in California (44) has reported on 197 sudden cardiac deaths `
among men. The case to control findings with reference to percentage'-e
of smokers among 40- to 54-year-old decedents were 67.9 and 39.3. It ~.
was found that smoking had a somewhat stronger relationship to `.~
deaths occurring 1 hour after onset of symptoms than to instantaneous
deaths or those within 1 hour. Talbott, et al. (134) have reported on
sudden death among white women and find an excess use of tobacco
and alcoholl among those dying suddenly.
The relationship of smoking to sudden death among those with
existing recognized CHD has had little attentioni In a prospective
study, Graham and associates (51) found no association bet'ween ;.
smoking and mode of death in patients known to have had a prior"
infarction. Oberman and co-workers found no relationship between the '
major risk factors including smoking and~ sudden death in patients''
evaluated earlier for ischemic heart disease (100). It was found that the'
best five variable models to predict sudden death in this group of '
patients included the number of coronary arteries obstructed 70
percent or more, the use of digitalis or diuretics, premature beats and
ventricular conduction~ defects. The Coronary Drug Project (29), which
was also a prospective study, reported a 5-year age and~ race adjusted
sudden death-rate ratio of smokers to nonsmokers of 1.28 (t value 1.98)
in the placebo or customary therapy group.
The Effect of Smoking on Sudden Cardiac Death in Man
The epidemiological associations have been noted above. The act of
cigarette smoking does not appear to be immediately related in time to :
sudden death. In relation to second heart attacks, Moss and' colleagues :..
(96) report a prospective follow-up study of patients discharged from ;.
hospital after myocardial infarction. They reported on~ 42 deaths '
(sudden and nonsudden) of cardiac nature in the following 6 months.
Information on smoking prior to death was available on 28 patients; of A
only5 were said to have smoked in the week before d'eath
these
.
;
The mechanisms postulated to explain the association of sudden :
cardiac death with smoking have been described under atherogenesis':
and under myocardial infarction as possible mechanisms for effects of ~
smoke, nieotine; and CO. They include accelerated atherogenesis, .~
enhancement of ischemia through~ inotropic effects, increased platelet ~
adhesiveness obstructing coronary flow, or, through increased cardiac
work caused by nicotine, and simultaneously reduced oxygen delivery
to the heart due to CO. Any of these mechanisms can be evoked as
possible initiators of critical ischemia and of sudden death due to
asystole or to ventricular fibrillation. The smoking and health report of
1976 (138) tabulates in Table A21 (pp. 109-114) the effects of smokingg
and nicotine on the cardiovascular system in man. While these data
4-444
The Effect of Smoking on Aortic Aneurysm
Aside from the strong risk factor association noted above, nothing
more is known about smoking and~ aneurysm formation in man. It may
be speculated that CO exposure enhances the circumstances that .
promote plaque growth and medial hypoxia, which leads to attenuation
and necrosis of the aorta. It may also be speculated that smoking may
lead to excessive thrombosis, whichi leads to excessive plaque develop- ,
ment and aneurysm formation. However, there are no data ini men
with aneurysm formation that allow comment on these speculations:
Spontaneous medial calcific arterioslcerosis occurs ini the rabbit,
particularly along the thoracic aorta, leading to mild' localized
aneurysmal dilatations (55). It has generally not been specifically
reported in relation to smoking' or smoke products, although it may
possibly have been observed incidentally in various experiments.
Wanstrup and associates (14r1 reported the enhancement of such
change with CO exposure. Schievelbein (120) studied the chronic effect
of nicotine in animals (rabbits) liable to develop spontaneous arterio-
sclerosis in the absence of an atherogenic diet. There was no
enhancement of morphological arteriosclerosis by nicotine, but the
aortas of the experimentally treated' group contained more calcium,
more free fatty acids, and more lipoprotein lipase. Aneurysmal
differences were not noted.
Research Needs
Atherosclerotic aneurysms of the aorta are uncommon. Study of their
pathogenesis is not likely to be promising in the absence of convenient
animal model analogues. A study of experimental poststenotic
dilatation might illuminate atherogenic processes in relation to
smoking. Research initiatives in this area show little promise at
present.
Conclusions
Cigarette smoking is a strong risk factor for atherosclerotic aortic
aneurysm. The association provides a mortality ratio of about eight
among males who smoke more than about 40 cigarettes a day and a
dose relationship is evident.
High Blood Pressure
The Nature of Hypertension
Many fact'ors are known to be involved in and affect the control of
arterial blood pressure: It is directly dependent on cardiac output and
total peripheral resistance. Some of the factors influencing pressure
include the renin-angiotensin system, aldosterone, catecholamines,
central and peripheral nervous activity, plasma volume, changes in
4-56
hand, there is a very large body of data, suitable for treatment by
sophisticated analytical methods, that associates risk factors with
myocardial infarction. Usually, the data are treated in terms of fatal
infarcts including both sudden and nonsudden (acute)Aeath. However,
analyses have dealt with sudden death alone, morbidity, and congestive
heart failure in individuals free of detectible heart disease on initial
study, individuals with some evidence of disease when first seen, and
those experiencing second' heart attacks.
Prospective studies of risk factor associations with myocardial
infarction or coronary heart disease (CHD) have identified~a number of
clinical descriptors strongly associated with liability to future infarc-
tion. These descriptors include age, male sex relative to female sex
before age 65, blood cholesterol level, arterial blood pressure, and
cigarette smoking. Other associations have also been documented,
including, the "Type A personality," diabetes mellitus, obesity, blood
uric acid, the use of oral contraceptives, hematocrit reading, evidence
of coronary heart disease : or other atherosclerotic disease, vital'
capacity, family history, and physical inactivity: Recently high density
lipoprotein (HDL): has been shown to be apparently protective against
myocardial' infarction (49, 92).
Reports dealing with risk factors, particularly smoking, but in many
studies with other risk factors as well, have been extensively tabulated
in the 1976 reference edition of The Health Consequences of Smoking.
(138) (Tables 1-4, pp. 19-31, Tables 9-14, pp. 38-41; Table A6, pp. 89-93;
Tables A17-A18; pp. 101-102). The tables of the prospective studies of
CHD mortality (Table 2, pp. 22-25) and morbidity (Table 4, pp. 26-31)
are reproduced' below as Tablles 2 and 3. The major risk factors of blood
cholesterol level, blood pressure,, and cigarette smoking, are indepen-
dent and strong predictors of susceptibility to CHD. Each is dose-
relate& to the liability to CHD, and each of about the same importance
when considered independently. Cessation of smoking and reduction: of
high blood pressure will reduce the risks of cardiovascular disease. As
summarized in Tables 15 and 16 on page 42 of the 1976 report (138)
(and reproduced below as Tables 4 and 5); it has been found that ex-
smokers suffer fewer myocaridal infarctions than continuing smokers.
With reduced blood pressure it has been shown that less cerebrovascu-
lar disease: and congestive heart failure occur. The effect of reducingg
blood cholesterol on liability to CHD remains under study.
Identified' risk factors account for a major part but not all of the
variance in CHD among a population. Cigarette smoking is an
important risk factor, but it is not essential, nor is it, in those parts of
the world~ in which people have levels of cholesterol in the range of
about 160 mg percent, as strong a risk factor as in the United States: It
has been reported from a follow-up study of about 265,000 adults over
40 years old in Japani (99) that smokers compared with nonsmokers
have a relative mortality ratio of 1.22 for death from all causes and
4-21
A small number of experiments involving, the effect of CO on
atherogenesis have been~ reported. Initial reports found an enhance-
ment of atherogenesis in the aorta of cholesterol-fed rabbits (13, 14)
and in the coronary arteries, but not the aorta, of squirrel monkeys
(148): However, subsequent experiments (130) on cholesterol-fed
rabbits from the same laboratory, which had earlier concluded that
there was a: positive effect of CO on atherogenesis, have led' to the
conclusion that there is no direct enhancement of cholesterol accumula-
tion im the aorta. These more recent short-term experiments controlled
dietary hypercholesterolemia by pair feeding and also studied the
uptake of radioactive tracer cholesteroli from the blood by the aorta.
i+do macroscopically visible atherosclerotic lesions were seen in any
animals, although the aortic free cholesterol of the animals fed
cholesterol was increased in comparison with the animals receiving no
cholesterol. The free cholesterol,! content of the aortic arch was
increased significantly in the animals exposed'to CObut there were no
significant differences for the thoracic aorta or for the combined
segments. The aortic uptake of labeled cholesterol from the blood was
not affected by CO exposure in either hypercholesterolemic or normal
animals. The authors suggest that their earlier result may have been
due to a relative excess of hypercholesterolemia: in CO-exposed animals
that had not been pair fed to maintain equal levels of plasma
cholesterol. Possible effects of CO diminishing VLDL secretion and
chylomicron~ catabolism~ have been discussed by Topping (136). Other
recent studies by Davies and colleagues (32) failed to find that
exposure of cholesterol-fed rabbits to CO for 4 hours per day yielding
carboxyhemoglobin (COHb) levels of 20 percent produced any differ-
ences in the aortic content of lipids including cholesterol. The
morphological extent of coronary atherosclerosis was greater in the
animals exposed to CO. Malinow and associates (80) failed to find an
enhancing effect of CO in sodium chloride and cholesterol-fed
cynomolgus monkeys. In experiments (2) with White Carneau pigeons
(which develop fibro-fatty spontaneous as welL as dietary atherosclero-
sis), no enhancement of spontaneous aortic atherogenesis was found'
after exposure to CO. Enhancement of coronary atherogenesis was
seen in cholesterolLfed birds exposed to CO and killed after one year of
exposure, but not in those sacrificed after about a year and a half.
Exposure also enhanced hypercholiesteremia. It has been reported that
spontaneous arteriosclerotic disease in rabbits is aggravated~ by
exposure to CO (147):
It has been reported that, in rabbits, hypoxia increases cholesteroI
atherogenesis and hyperoxia diminishes it (72, 74). Hyperoxia has also
been reported to enhance the regression of plaques in rabbits (139).
Hypoxia and CO have been reported to cause subendothelial edema in
rabbits (1'3,73) and smoke inhalation (46) to lead acutely to desquama-
tion of aortic endothelial cells and adhesion of platelets in rabbits.
4-17
a
(156) WOLINSKY, Hl A new look at atherosclerosis: Cardiovascular Medicine: 41-54,
September 1976:.
(157) WRAY, R., DEPALMA, R.G., HUBAY, C.H, Late occlusion of aortofemoral
bypass grafts: Influence of cigarette smoking: Surgery 7Q(6): 969-973,
December 1971.
tive studies have now collected sufficient standard risk factor data,
including smoking information and autopsy findings, to report
preliminary multivariate analyses. While more data might be desirable
in order to establish better the dimensions of effect as seen at autopsy,
and more data are needed to extend multivariate analyses, there is no
reasonable doubt that cigarette smoking, enhances atherogenesis. This
knowledge establishes a fundamental rationale.for the findings on the
incidence of heart attack, including sudden cardiac death, aortic
aneurysm, and peripheral vascular disease in relation to smoking. It is
somewhat uncertain, but likely, that smoking has an adverse effect on
the recurrence of heart attack among survivors of a prior myocardial
infarction.
On the other hand, epidemiologic data on the association between
cigarette smoking and angina pectoris and cerebrovascular disease
manifested as stroke are not conclusive. There are major and
unresolved inconsistencies between existing reports. While certain
reports on~these diseases may have more technical strength than others
an& thus provide more credible conclusions, a basis for drawing final
conclusions is not established in these two conditions: It is of interest
that, in acute experiments on atherosclerotic patients with angina
pectoris or with the intermittent claudication of peripheral vascular
disease, smoking or exposure to carbon monoxide reduces the patients'
established threshold for the precipitation of angina or claudication.
There is no apparent relationship between smoking and the
incidence of hypertension. Available evidence indicates a neutral or
slight hypotensive effect. Nevertheless, in the presence of hyperten,
sion, smoking joins with~ hypertension to affect the patient with the
cardiovascular burdeniof both risk factors.
There are opportunities for further epidemiological research into
smoking as a risk factor for cardiovascular disease; these have been
detailed in each of the foregoing sections. The need! and priority of such
research should be debated in~specific cases. It ca.n be argued that little
public health or medical therapeutic advantage would arise from a
clarification of the relationship of smoking to angina or cerebrovascu-
lar disease in the face of the existing conclusive evidence of its adverse
effect on the incidence of heart attack and lung diseases and the
benefits of smoking avoidance or cessation. On~ the other hand, it could
be of some medical value to learn~more accurately what the association
may be for second heart attacks. It would be of great interest for
preventive medicine to know whether smoking affects the severity of
atherosclerosis of the aorta and coronary arteries in childhood and
adolescence and~ the premature development of adult forms of lesions
in youth. It would also be of great interest to learn whether present-
day cigarettes modified to deliver less tar and nicotine are less
hazardous for cardiovascular health: Earlier data, which no longer
represent current products, found that low tar and nicotine cigarettes
4-64
Data from several epidemiological studies indicate that, when
hypertension is present, its combination with another risk factor, such
as elevated~ blood lipids or smoking, is synergistic.
The Effect of Smoking on Blood Pressure
The chronic epidemiological effects of cigarette smoke on the incidence
and level of hypertension and in conjunction with hypertension as an
additional risk factor for cardiovascular disease have been noted above:.
The acute and transient effect of smoking in man~is to increase heart
rate and blood~pressure to a minor degree. These effects are thought to
be due : primarily to the action of nicotine releasing cathecholamines. In
the 1976 report on The Health Consequences of Smoking (138), Table.
A20 (pp. 103-108) and Table A21 (pp. 109-114) summarize a series of
acute effects of smoking, and nicotine on the blood pressure of animals
and' humans. Table A22 (p. 115), notes the effects on catecholamines in
humans and' animals. Beaumont and colleagues (17) have recently
reported: on a paroxysmal arterial hypertension as a reaction to
cigarette smoking in~ which, under clinical diagnostic testing,, a single
high nicotine cigarette induced a rise in blood pressure of about 50 mm
Hg systolic and 20 mm Hg diastolic over about 20 minutes. The
reaction was accompanied by headache, palpatations, and: sweating.
The reaction was elicited' ini 13 of 178 persons tested, all of whom were
moderate to heavy smokers.
Research Needs
It would be of some interest for an understanding of chronic
hypertension to elucidate the pathogenesis of what appears to be a
very mild hypotensive chronic effect of smoking. Since genetic and
induced animal models of hypertension and hypertensive vasculopathy
exist, including stroke-prone : spontaneously hypertensive rats, it may
be informative to assess the acute and chronic effects of smoke and
smoke constituents in them.
Conclusions
Cigarette smoking does not induce chronic hypertension. Indeed,
present evidence indicates that it is associated with~ a mild chronic
hypotensive effect. However, in the presence of hypertension as a; risk
factor for coronary heart disease, smoking acts synergistically to
increase the effective risk by joining the risks attributable to
hypertension and to smoking, alone.
Other Conditions
Among other conditions of interest are arterial and venous thrombosis,
the synergism of smoking with oral contraceptives in relation to
4-58
i 0
TABLE 3.-Coronary heart disease morbidity as related to smoking. (Risk ratios-actual number of CHD
manifestations shown in parentheses)1 [SM = Smokers NS = Nonsmokers EX = Ex-smokers]-
Continued
PROSPECTIVE STUDIES
Aulhor, Number and Data Follow- Number of
year, type of trollection up incidenta Cigarettes/day
country populalion yeare
Dunn 13,148 male Data only up to 14 Total un-
et al, patienla in on new epcciCied.
1970 periodic health incidenta
U.S.A. eaeminetion e:tracted
clinio from
clinic
recorda
Pipea, cigan Age variation
Pooling 7,427 white Medical 10 53g
Project, malea 3059 examination Includea Never smoked ...... 1.00(53) I.OD(53)
American yeara of andfoIlow- fatal and <10 ............... 1.65(72) 125(54)
Heart age at entry. up. nonfatal 20 ................. 208(205)
Aeaoeiation myorardial >20 ................ 3.72(151)
1970, infarction
U,S.A. and sudden
death.
O()w~ )CO
~5
30-39 40-49 So-59 flncludea
Naw NS, EX, and
SM l.01)(25) 1.01)(125) 1.M157) <20 cigarettea!
jHigh day.
SM 217(10) 0.90(31) l41(53) 1 )20 ciga-
nttte9/day.
Includes all
CHD but
exclude
death.
No data avail-
able comparing
emoYen and
nonemokere.
44
ml
TABLE 7.-Age-atandardized death rates and mortality ratios for cerebral -ascular lesions for men and
women,
by type of smoking (lifetime history) and age at start of study
Type of smoking
Age groupe
55-U4 6574
CVL death rates per 100,OBB petaon-yeam
Men
Nerer smoked regularly 28 92 349 1.356
Pipe, cigv 25 100 369 1,371
Cigarette and other $8 129 361 990
Cigarette only - 42 190 477 1,168
Total 85 116 391 1=
Women
Never smoker regularly 18 57 228 1.082
Cigarette 38 66 315 1,277
Total 26 61 238 1,091
Men
CVL mortality ratios
Neve+ smoked regularly 1.00 1.00 1.00 1.00
Qipe' eigar 0.89 1.09 L06 1.01
Cigarette and other 1.00 1.40 1.08 0.73
Cigarette only 1.50 1.41 1.37 0.86
Women
Never nnolced regularly 1.00 1.00 1.00 1.00
Ciguette . 211 1.54 1.38 1.18
NOTE. - CYL - Cerebral ra.eulv lauona
Sol1RCE: U. S. PoESc Hea1tA Savice (/ldF
608Sf 9E0
®
t
TABLE 2.-Coronary heart disease mortality ratios related to smoking-prospective studies. (Actual
number of
deaths shown in parentheses)i [SM = Smokers NS = Nonsmokers]
Author. Numlwr and Follow. Numler
praq ~ tylw of Uxta up of
euunlry. ho{rulalion colkMion (yean) deatha
Nummom{ I%7'F3 Quv9tion- 31/2 5,297 NS ......
end white malp
naire aml All smoken
Horn, in 9 rtate~s follow-up <10
I958, 50 69 yean of dcath 10 20
C.S.AA uf ag,, . artltlcate 20 40 ......
>40 .......
Bnyle 2,7R2 mal., 17clall d 10 93
et ul..
1964, Fram-
ingham, midical
raamina-
C.S A. 30 62 years
of age.
1,913 mal e, lim and
follow-up.
R
Alhany,
39 .55 yean
Cip,aretta/day Ctqan, plan Age variation
1.01/(709) Ciparg
WI)
<O
'( 5U-54 5559 6064 6569
L7U (376q .
p
NS
..
LW NS LW
(90)
1.00
Q42)
LW (2U1)
LW (Z73)
129 (192) SM . 129 _ (4_20) All snaken 1.93 (765) 1.N5 (962) 1.E6 (921) 1.41 (713)
189 (i1fi1) pipa <10 .... _.. 1.3% (35) 1.38 (50) 1.17 (49) 127 (5H)
220 (60!) NS .. 1.00 10 20 ....... 2W (213) 204 (24S) 1.91 IZl5) 15f1 (15N)
241 (118) SM . 1.03 (312) >d1 ........ 2.51 (Aii) 2.47 (199) 1.92(18) 1.56 (73)
1.00 (?))
2q0 (73)
2W (17)
1.70 (201
3.50 (361
of aRe:
Doll and Approxi- Qu.tion- 10 1,376 NS ........ 100 3544 4Sbf 65A1
Hill, makdy nalm und All amoken )85 NS ......... 1911 1.00 1.W
196/, 41,000 follow-up 1 14 ....... 129 114 ........ 3.73 1.40 1.71
Gmat malc Bntlah of death 15-'L4 ...... 127 15-24 ....... 445 1.73 I.Zf
Britam physi<ixn,. , certificate. >29 1.43 >25 ........ 136 192 158
0344~~;9co
G~mmnLp
Data aPPly
only to malen
aRr.d 40 49
and fm
of t'HD at
entry. NS
inelude pipc,
cigar and
u -nkem
to rise rapidly above half a pack a day and to be almost twice as high in
the pack a day group of cigarette smokers.
Among additionali recent papers, the Framingham Heart Study
reports that smoking 20 cigarettes a day is associated with an annual
incidence of coronary events per 1,000 ini the fifth, sixth, and seventh
decades of life of 11.9; 19.3, and 19 per 1000 of population. The
corresponding rates for nonsmokers were 3.6, 5.7, and 15.3 (~69). The
Western Collaborative Group Study (116) in California: has detailed a
dose relationship of relative risk analysed for the fifth and sixth
decades of life among meni smoking either less than a pack per day, a
pack, and more than a pack in comparison with nonsmokers. Thee
reported relative risks were 1.05, 1.53, and 1.93' in the fifth decade, and
0.098, 1.63, and 2.32 in the sixth. Reid and colleagues (110) have
reported on more than 18,000 male civil servants in, Great Britain
between, the ages of 40 and 64 who were followed over 5 years of
prospective study. The risk of death from coronary' heart disease was
lowest among nonsmokers or ex-smokers. Current smokers had a
significantly higher risk of death from CHD. Moreover, when classified
by inhalation habit, inhalers were found to have higher risk of CHD
death than those who do not inhale. In yet another study from Great
Britain, more thanZ4,000 physicians have been followed for 20 years. It
is reported' that annual death rates (per 100,000, standardized for age)
among light, mediumi and heavy smokers for ischemic heart disease
are 501, 598, and 677 respectively (35):
There have been inconsistent reports on the effect of smoking on the
occurrence of' a second or subsequent heart attack. Studies in New
York (150) fail& to find a relationship between smoking and second
heart attacks; while the Newcastle and Scottish studies (;43, 111) did
find an adverse trend. A recent contribution to this issue has been the
findings of the Coronary Drug Project Resear& Group (29) who
reported' on 2,789 male survivors of myocardial infarction in the New
York Heart Association cardiac functional' classes I or II. These men
had been~ randomized to placebo treatment and usual care. They were
followed for 5 years and provide a natural history study under usual
current therapy conditions. Smokers at the time of entry into the study'
were at somewhat higher risk than nonsmokers. The relative risk of
smoking after myocardial infarction was appreciable, but less than for
men withi no prior history of heart' attack as, for example, those
documented in the Pooling Project (~107). The absolute risk of death is
mu& higher for men who have already experienced a myocardial
infarction, however, so that the difference in mortality rates for them
between smokers and nonsmokers becomes correspondingly important.
In this study, the hospitalization rate was 36 percent higher for
cardiovascular events among smokers than nonsmokers.
Other recent papers include the Western Collaborative Group Study
(64), which has reported that the number of cigarettes smoked daily
4-37
TABLE 4.-The effect of the cessation of cigarette smoking on
the incidence of CHD. (Incidence ratios-actual
number of cases or events are shown in parentheses)
Author
i
A
year, Results Comments
eountry
All myocardial
All CHD' events infarction.
Jenkins, Never smoked....................... 1.00(30) 1:00(21.)',
et a1.,
1968' Current
cigarette smokers ................ 2.36(84)
2.78(68)
U.S.A. Former
cigarette smkers :............... 2.15(19)
2.47(15)
Death from CHD
Smoked 1-19 cigarettes/day
Smoked >20
cigarettes/day
Hammond
and Garfinkel, Never
smokedl regularly ............... 1.00(1;841)
1.00(1,841),
Male data only
1969, Current
U.S.A. cigarette smokers :.............. 1.90(1,063) 255(2,822)
Siopped'~ <1 year ..................1i62(29) 1.61(62)
14 ............................... 1.22(57) 1.51(154)1
5-9 ............................... 1.26(55), 1i16(135)
10-19 .............................. 0.96(52)' 1.25(133)
>20 ............................... 1.08(70) , 1.05(80)
All ex-cigarette smokers ......... 1.16(253) 126(564)
Total definite myocardial'infarction
Shapiro, Never smoked .................................................... 1.00
et aG, Current cigarette smokers ...................................... 1:87
1969, Stopped' <5 years ................................................ 0.76
U:S.A.
First major
All CHD deaths coronary event
Pooling Project, Never smoked ...................... 1.00(27) 1.00(53),
American Heart' >Vz packlday ....................... 1.65(34) 1.65(72)
Association 1 pack/day ........................ 1.70(86)', 2.08(205)
1970, >1 packldag ........................ 3.00(68)~ 3.28(151)
U:S:A. Ex-smokers .......................... 0.80(19)! 1.25(51)
SOURCE: U. S. Public Health Service (138).
1.16 for all cardiovascular diseases in males. The reported ratios were
1.64 among men and 1.57 among women for ischemic heart disease.
This effect on ischemic heart disease was related directly to the
4-34
0
TABLE 2.-Ratios of age-adjustedl prevalence rates of chronicc
conditions for persons 17 years old and older who
have ever smoked, to persons who have never
smoked, by cigarette smoking status, number of
cigarettes smoked per day for present' smokers-
heaviest amount, sex, and selected chronic conditions:
United States, July 1964 to June 1965
Cigarette smoking status Present smokers
Sex and selected
chronic conditions
Persons
who Former Present
ever smokers, smokers
smoked
Number of cigarettes
smoked per day-heaviest'
amount
Under 11-20 21-40 41 and
11 over
Male Ratio;
All chronic conditions...... 1.17 126 1.18 0.92 1.04 1.30 1.54
Heart conditions (excluding,
rheumatfirheart disease):... 1.22 1.44 1.12' 0.93 1.07 1i29 1.71
Arteriosclerotic heart
disease, including, coronary disease ............ 1.67 2:22 1.56 L44 2.11 '
Hypertension without
heart involvement ........... 1.02 1.07 1.00 0.93 0.88 1.20 1.27
Chronic bronchitis and/or
emphysema ................... 240 2.50 2:40 2.30 3.10 4.10
Chronic sinusitis ............... 134 1.40 1.30 0.93 122 1S7 1.78
Peptic ulcer .................... 1;92 1.75 1i96 1.25 1.92 2.17 2.75
Arthritis :....................... 1.07 1.24 0.99 0.97 0.87 1.16 1.16
Hearing impairments ......... 1.06 1.14 104 0.98 0.94 1.14' 1.34
All other chronic
conditions ..................... 1.13 1.23 1!09 0.90 1.01 125 L50
Female
All chronic conditions...... 1.12 1.23 1.09 0.88' 1!05 1.39! 2.00
Hearti conditions (excluding
rheumatic heart disease).... 0.91 126 0.81 0.65 0.81 1.05
Arteriosclerotic heart
disease, including
coronary disease ............ 129' 0.86
Hypertension without
heart involvement ........... 0.86 0.98 0.83' 0.86 0.76 0.90
Chronic bronchitis and7or
emphysema ................... 283 217 3.17 133 3.33 4.92 9.67
Chronic sinusitis ............... 1.26 1.32 1.24 0.97 1.26 1.56 114
Peptic ulcer .................... 1.63 1.63 1.56 1.25 1.56 2.13
Arthriti......................... . 0.99 1.12 0.98 0.86 0.97 1.11, 1168
Hearing,impairments......... 0.93 0.97 0.90 0.72 0.91 1.14
All other chronic
conditions ...................... 112 1.25 1.09 0.89 1.04 1.41 208
'Adjusted bythey indirect method to the age distribution of the total civilian,,
noninstitutionallpopulationofthe
United States.
'Prevalence rate for given smoking categorydivided b'yy prevalence rate for "never smokers." Ratios
of 1.00 '- sameas"never smoked."
'Even though the asterisks in this column replace figures with large sampling errors, each of the
six of the replaced
ratioe were larger than the ratios for the lower smoking amounts.
'Figuredoes not meet standardA of reliabilityor precision...
SOURCE: Wilson, R.W. (1;):
3-7
Intr
LLui
Th
tha
bec
sm
19E'
for
fro
subarachnoid hemorrhage about six times and that the additional, usee
of cigarettes increases the risk to about 20 times (106).
The mechanisms that may underlie these phenomena: in women are
considered elsewhere, but estrogen and estrogen analogue administra-
tion to men with cancer of the prostate or with preexisting myocardial
infarction have been shown to increase the risk of heart, attack (30,
141), These reports did' not contain information on smoking, however.
While the associations between smoking, orat contraceptive use, and
enhanced risk of cardiovascular disease are not in, doubt, research
opportunities exist in seeking explanations for the effect.
The Effect of Smoking on Blood Lipids
The report, The: Health Consequences of Smoking of 1976 (138), dealt
with~ the question of a possible effect of smoking on blood or serum
cholesterol. Acute effects in man~and animals were tabulate& in Tables
A25 and A25a (pp. 119-124). Case control and population studies are
listed in Table A7 (pp. 94-98). The data are not very uniform, but there
is a preponderance of results in man in which smokers have a
somewhat higher blood cholesterol level than nonsmokers. Paul (103)
has recently presented additional data with this same finding. Dawber
has analyzed the Framingham Heart Study data in~ terms of pipe,
cigar, and cigarette smoking (33). Since these forms of smoking deliver
different amounts of tar, nicotine, and CO to the smoker, such an
analysis might reflect specific responses on the part of the serum lipids.
No major differences were found. Pipesmokers had! average cholesterol
levels, of about 216.25 mg, cigar smokers of 220.95 mg, and cigarette
smokers of 224.34 mg (nonsmokers 223.83 mg). These differences are
too small' to account for the observed differences in risk associated
with type of smoking habit. There may indeed be a minor tendency for
cigarette smokers to have slightly elevated blood cholesterol levels for
whatever reason, but smoking and cholesterol are clearly established
independent risk factors.
Experimental data based on acute manipulation of smoke exposure
or nicotine appear to show a consistent elevation of free fatty acids in
the blood. Animals exposed to CO and high cholesterol diets have been
reported to develop more hypercholesterolemia than expected, but
confirmation has not been established with whole smoke (14,136).
Other recent reports have foun6 HDL levels to be a strong and
independent risk factor for coronary heart disease that has an inverse
relationship (4:9, 92, 94); high levels are protective and low levels are
associated' with increased risk. Both in a subset of the Tromso study
(94) and~ in the Framingham study (49), almost identical HDL
cholesterol, levels among smokers and nonsmokers were found; there
was no significant association~ between them.
Observations on 10,000 males in Israel'show that alpha: cholesterol is
depressed among smokers of cigarettes compared' to nonsmokers and
4-61
ex-smokers, with the trend persisting in different age groups. The
concentration of alpha cholesteroli decreased according to increased
amounts smoked daily when the smokers were grouped as never
having smoked, and having smoked O to 10; 11 to 20, and more than 20
cigarettes smoked per day. Tot'al serum cholesterol~ and hence beta
cholesterol, were increased in direct relationship: to the amount smoked
(48). HDL cholesterol has also been measured among approximately
4,000 men and women who are the adult offspring of the original
Framingham Heart Study cohort. After controli for reported alcohol
consumption, subscapular skinfold thickness, and age in~ multiple
regression analysis, cigarette smoking was found to be associated with
significantly lower HDL levels in both men~ and women. There was no
evidence of lower HDL cholesterol among former cigarette smokers
(47): In an examination of 447 women and 471 men aged 40 or 41 in~
Holland, it has been found! that HDL cholesterol is (as expected) higher
in women than in men. Cigarette smoking was associated with a
reduced serum HDL-cholesterol in both men and women. Among the
women there was also a strong, negative association with the use of
oral contraceptives that was independent of smoking (4):
Hulley and colleagues (59) have recently reported in a multiple-risk-
factor intervention trial group that over a period of a year the change
in serum thiocyanate ('a.n indirect measure of smoking activity) showed
a univariate regression coefficient, with an HDL cholesterol of -.12
that was significant at less than the 0.05 level. The multivariate
regression coefficient was -.15 and significant at less than~ 0.01. While
more data should be gathered to ascertain the effect of smoking on
HDL levels, present indications are t'hat, when other factors that also
affect HDL levels are controlled in statistical analysis, cigarette
smoking displays an independent inverse relationship with HDL level§.
Moreover, since total cholesterol levels appear to be slightly elevated
among smokers, lipoprotein cholesterol that is positively atherogenic
will also be increased, Consequent'ly, it can be hypothesized that the
effect of smoking on CHD morbidity and mortality may be to somee
degree a reflection of altered~lipoprotein metabolism..
Other Constituents of Smoke
Smoke is a: remarkably complex mixture of chemica.l, substances and
physical chemical st'ates: Our understanding of the relationships of
nicotine and CO and of whole smoke to cardiovascular disease have
been noted above: Other substances have attracted some investigation
also. Those of possible cardiovascular interest include cadmium, zinc,
chromium, carbon disulphide, carbon dioxide, hydrogen cyanide, oxides
of nitrogen, and polonium-210. McMillan (90) concluded that, while
these substances provide interesting grounds for speculation as to their
possible role in cardiovascular disease, only nicotine and~ CO offer both
data and rational concepts for a role in smoking and cardiovascular
4-62
although, as noted above, it has been shown that there is a rising
gradient of risk of cardiovascular death for smokers of the same
number of low, medium, and high tar and nicotine cigarettes (53): If
such studies are feasible, they could provide for the public and for
cigarette production~ important information about the risks to be
attributed to different smoke deliveries of tar, nicotine, CO, and
perhaps other substances:
A major need is to underst'and' better the mechanisms by which
smoking can induce or affect the evolution of myocardical infarction.
Animal experiments using several different models of myocardial
ischemia or infarction in conjunction with exposure to smoke
constituents alone, and in~ combination, should provide some clarifica-
tiom They could be conducted under precise if somewhat artificial
circumstances. Nonhuman primates susceptible to experimental ath-
erosclerosis have been trained to smoke in a humanlike manner
without overt stress or aversion (86), and studies of whole smoke of
different characteristics in a; more natural setting of acute and chronic
inhalation exposure can be done.
Conclusions
Cigarette smoking is a major independent risk factor for thee
development of fatal and nonfatal myocardial infarction in men and
women in the United States: It also appears to be a risk factor for
second heart attacks among those who have experienced one, an&
diminishes survival after a heart attack among those who continue to
smoke. It acts synergistically with high~ blood pressure and elevated
blood cholesterol. The effect is directly related to the amount smoked.
Ceasing, to smoke reduces the risk towards that of nonsmokers.
Smokers of low tar and nicotine cigarettes have a higher risk than
nonsmokers, but they have a lesser risk than those who smoke high t'ar
and nicotine cigarettes.
Sudden Cardiac Death
The Nature of Sudden Cardiac Death in Man
A recent symposium (28) on sudden cardiac death has delineated the
nature of the problem and the many definitions that are used to
classify it. The data gained from hospital practice and from coroner's
experience differ quantitatively from the findings of prospective
epidemiological studies, but the nature of the disorder is probably the
same in all the samples. Coronary heart disease (CHD) accounts for 90
percent of examples of sudden cardiac death, but t'here are other
cardiac causes for suddendeath (28).
In a prospective epidemiological study, Kannel and associates (71)
reported that individuals with overt CHD are four times as liable to
sudden death as those without CHD. They report that about 55 percent.
4-41
®
LIST OF FIGURES
Figure 1.-Relative risk of lung cancer for males, by
number of cigarettes smoked per day and long-term use
of filter (F) and nonfilter (NF) cigarettes .................. 18
Figure 2.-Relative risk of lung cancer for females, by
number of cigarettes smoked per day and long-term usee
of filter (F) and nonfilter (NF) cigaret'tes .................. 19
Figure 3.-Lung cancer mortality in continuing cigarettee
smokers and nonsmokers as a percentage of the rate
among ex-cigarette smokers at the time they stopped
smoking . . .. . . . . . . . . . .. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . ..
. . . . . . . . . . . . . . . . 26
Figure 4.-Relative risk of develbping larynx cancer for
males, by number of cigarettes smoked per day and use
of filter and nonfilter cigarettes ............................... 35
Figure 5.-Reld.tive risk of developing larynx cancer for
females, by number of cigarettes smoked per day and
use of filter and; nonfilter cigarettes ......................... 36
Figure 6.-Relative risk of developing larynx cancer for
male ex-smokers, by years of smoking cessation.......... 37
Figure 7.-Relative risk of developing larynx cancer for
female ex-smokers, by years of smoking cessation ....... 38.
Figure 8.-Relative risk of pancreatic cancer in~ males, by
number of cigarettes smok& ................................... 52
LIST OF TABLES
Table L.-Lung cancer mortality ratios-prospective
studies . . . . . . . . . .. . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . .
. . . . . . . . . . . . . . . . . .12
5-5
M
I
0
I
0
S0'"~~`y9 c 0
TAHLf: G-(_ononary heart diNeaae morbidity as releted to NmokinR - an{fina pectoriN - proxptrtive
NtudieN
(Risk ritioN-ac_tual number of CHD manifestations shown in parentheaes).' [SM = Smokers NS =
NonxmokerN]
AuW, Numbv..ed
Y- !~ ^l
<uuoVY papW.uo.
Ihu
tollecUne
mxh t>Se m.l~. r>tialru
19l~, p6 Ysn ..mio.4o.
U.3A of yc. W.........
1yn m.ls, fdb.up
AIOUY,
1f066 ls .
m~
l.aklr, 1.1AI ..N 1.iY.1
a N., PA ! Y rdiel
IYEl, .1 ae41. uuei.aYw
U.S.A .ee fnoo.-
wM
~
s Ns._........._ ..................LOqY)
AH .....~..nt
eiryeUS ............ ..........tMnE)
>16 ...............................LlN1q
(~(.n
.0~ Ppa
LeW, 6.In sls aemeN u 109 Wb
a a. ud r.m./. <vaaie.Ya. Na ................................ ulU(la)
U.S.A Y~n d Y~ uA /db.- Hr, 9a. >m . .
IONI np. igiwtr ......................tAMrn
... . r.m.i.
NS ............................. ...ILq63)
fFSuaN SM ....................0.iY16/
~apho, I10p00..k B.Wis i
x Y., .nd fea.N sedral
nm, enNMS d v
U.S.A. Ne. YaA .eA
G1tY
HIP aS-N 1m ud
Yw a R.W
.!~
fdb.-up
N3 ..........................IAO
GLnea yvKls......... L6E
.._........S.m
~+o .................._....-
~ Vel~ aiAs~i. R.d11.4 ~P^'b En.w Je tnW wsEs d.uufe.rHor ud Ih wm d Ile itli.ibW .moYiej ah~~.n due
to Ne aatlu.on of a1bQ e~..l. mi.plOma.. su.4 v
n..Waa .. ... . . - .. .. .
.. S9UHGC: U. S. PoNk HsN\ 3..b (11q.
rdb..~p Numbe+
a
~~ iecJent.
ae...tw!d.Y
10 61 NB ................................1 OOnO)
................. LOMSI)
<al .............................. .1.11(IS)
7f1 ............................... 09Nn)
B >al ...............................L1611r)
To1J Wls Pewls YJ.
Un.pee NB ......................1.0U 1.00 NS-.......1.00 61/
ifd G.rea SY........11.'n N3 .......................... 1.00
tlwells............11n lA e l uprtla......... p,0
<40 ..................... 111 120 <tl ........................ YM
)YL ....................136 ._ . NO . ... ... .. 10.n
................... . ..
Concl usions . ........................................................ 36
Oral Cancer ...........................................,................, 39
Epidemiological Studies ........................................39
Other Forms of Tobacco .............................,.........40
Other Risk Factors .............................................. 40
Leukoplakia ........................................................ 41
Animal Studies ...................................................41
Concl usions ......................................................... 42
Cancer of the Esophagus ............................................42
Epidemiological Studies ........................................42
Other Forms of Tobacco Use ................................43
Other Risk Factors .............................................. 43
Autopsy Studies .................................................. 44
Animat Studies ......................,................,...........44
Conclusions ......................................................... 44
Cancer of the Urinary Bladder and Kidney ..............,....45
Bladder Cancer ................................................... 45
Epidemiological Studies .................................. 45
Other Risk Factors ....................................... 47
Animali Studies :.................. .................. ........ 47
Kidney Cancer .................................................... 47
Epidemiological Data ..................................... 47
Conclusions ......................................................... 49
Cancer of the Pancreas ..............................................50
Epidemiological Studies ........................................50
Other Risk Factors .............................................. 51
Animal Studies ...................................................51
Conclusions ......................................................... 53
Mechanisms of Carcinogenesis ..................................... 53
Smoke Composition .............................................. 53
Experimental Models ............................................ 53
Concepts of Carcinogenesis . ................................... 54
Aryl Hydrocarbon Hydroxylase .............................. 57
Multi-Stage Model of Carcinogenesis ....................... 58
References ............................................................... 59
5-4
CONTENTS
Introduction .............................................................. 9
Lung Cancer ............................................................. 9
Trends in Lung Cancer Mortality ........................... 10
Epid'emiological Studies ........................................ 11
Dose-Response Relationships .................................. 12
Number of Cigarettes Smoked Per Day ...........12
Age at Which Smoking Began ........................ 13
Inhalation of Cigarette Smoke ........................ 14
Tar and Nicotine Content of Cigarettes ........... 15
Lung Cancer in Women ....................................... 16
Trends in Cigarette Consumption
among Females .........................................16
Epidemiological Studies :................................. 20
Dose-Response Relationships ........................... 21
Patterns of Cigarette Use .............................. 21
Twins...............: ................................................. 23
Lung Cancer and the Use of Other Forms
of Tobacco ...................................................... 23
Histology of Lung Cancer ..................................... 23
Cessation of Smoking ........................................... 24
Lung Cancer and, Air Pollution .............................. 25
Lung Cancer and Occupational Factors .................,.. 27
Asbestos...................................................... . . . . . 28
Uranium Mining ........................................... 28
Nickel ......................................................... 28
Chlbromethyl Ethers ..................................... 29
Animal Studies ................................................... 29
Skin Painting and Subcutaneous Injections ....... 29
Tracheobronchial Implantation and Instillation... 29
Inhalation Carcinogenesis ............................... 30
Nitrosamines................................................ 30
Phagocytosis .........., ...................................... 31
Conclusions ......................................................... 31,
Cancer of the Larynx ................................................ 32
Epidemiological Studies ........................................ 33
Asbestos ........: ....................................................34
Animal Studies ...................................................34
5-3'
heart attack by clinical criteria is not possible. A considerable number
of infarcts are clinically unrecognized. It is also possible that the
initiation of ischemia or of platelet aggregation begun at one time
might culminate in heart attack only hours later. At present, it is not
possible to clarify these temporal uncertainties.
The Effect of Smoking on Myocardial Infarction in Animals
There are: limited data on the effect of smoke constituents on
experimental myocardial infarction in animals. Table A20 (pp. 103-108))
of the 1976' reference edition of The Health Consequen.ces of Smoking
(137) lists 18' separate publications involving the effect of smoke and
nicotine on cardiovascular function. Three studies used animals with
coronary artery narrowing or ligation. In one there was an increase in
the frequency of nicotine-induced arrhythmias. This was less evident
as the time interval (up to 45 days) increased between artery ligation
and nicotine challenge. In another study,, nicotine increased coronary
blood flow less in the presence of coronary narrowing than in, normal
animals. One paper reported that animals with damaged myocardium
due to isoproterenol lesions or ligation of the coronary artery
responded to a nicotine challenge with an increased expression of
arrhythmias: It was found that it required more nicotine to increase
coronary flow and heart rate in rabbits with dietary-induced athero-
sclerosis than in normal animals. It was also reported that in dogs with
acute coronary occlusion that nicotine caused coronary vasodilation in
the normal heart, but in ischemic myocardium, flow increased only
proportional, to aortic pressure. Dogs with coronary oeclusion manifest
excessive left atrial pressure and ventricular arrhythmias on exposure
to nicotine (36).
The effect of CO inhalation on monkeys with experimental'
myocardial infarction produced electrocardiographic evidence of
greater myocardial ischemia and increased liability to induced-ventric-
ular fibrillation (34).
Research Needs
The epidemiological data relating smoking to myocardial infarction
leave no doubt that smoking is a major risk factor for both, fatal and
nonfatal CHD. Data in certain situations need strengthening or
verification. There is much less information concerning women than
men. Data are few on the effect of smoking on myocardial infarction in
old age. The published reports on the adverse effect of smoking on the
incidence of second heart attacks are probably adequate, but are
inconsistent and not well-defined. Studies to investigate the separate
relationships of nicotine and CO in whole smoke to the incidence of
myocardial infarction would be particularly useful. Detailed data on
the effect of "less hazardous" cigarettes compared with, ordinary
cigarettes in relation to myocardial infarction are not available,
a
.4
4-40
was 4.4 times as high in those smoking two packs or niore per day as
those who never smoked. This study also examined the coron
arteries microscopically and found that fibrous thickening of t
coronary arteries and intramyocardial small arteries was mo
frequent in smokers: The most marked difference between smokee
and nonsmokers was found in the arterioles of the myocardiu
Advanced hyaline thickening of arterioles was found in 90:7 percent' o
those smoking two or more packs per day, in 48.4 percent of th
smoking less than one pack per day, and in none of those who nevsmoked regularly. The study reported
on a selected series of 1,
autopsies from which coronary arterial disease deaths, diabetes, ari
those with~ hearts weighing more than 500 g were excluded. A receri
report (98) reaffirms the occurrence of intramyocardial small-arte
sclerosis in smokers. A decrease in arteriolar muscle wall thickness i'
the myocardium; especially in smokers, was found that was attribu
to a lower blood perfusion pressure distal to the small artery lesio
noted above.
Overall, there does not appear to be substantial reason to doubt tha
male cigarette smokers examined at autopsy manifest more coron
and aortic atherosclerosis than nonsmokers. The effect is dose-rela '
Hyaline thickening of arterioles in the heart apparently is strongl
associated with smoking. Specific morphologicall features of plaqu
that would be characteristic of smoking have not been: delineated.
Experiments in Animals
Table A23 (pp. 116-118) of the 1976 report, The Health Consequences.o7A
Smoking (138), lists seven experiments in which nicotine had incons'
tent effects on both spontaneous and diet-induced atherosclerotio
lesions in rabbits. In an additional paper, Schievelbein (120) ha3
reported no induction of spontaneous arteriosclerotic lesions b
nicotine in rabbits, although the aortic content of free fatty acids an.
of calcium was reported increased in this long-term experimen ,
Fisher, et al. (42) reported no increase in atherogenic effect with small
doses of nicotine in animals that were also hypertensive and fed
eholesterolL
These experiments have involved the injectionior oral administration
of nicotine rather than inhalation and generally have employed
unusually large doses of nicotine. Fyuivalent experiments in species
such as swine or nonhuman primates that might be preferable to
rabbits have apparently not been performed, nor have experiments
that simultaneously involve whole smoke or carbon monoxide (CO)
administration. The overall impression from available data is that
nicotine does not affect atherogenesis in; animals. Specific experimen-
tal data, however, are unavailable to permit a conclusion about a
possible effect on experimental atherogenesis of nicotine inhaled in~
smoke in doses experienced chronically by smokers.
I
4-16
(3S) DAWBER, T.R. The interrelationship of tobacco smoke components to
hyperlipidemia and other risk factors. In: Wynder,,E.L., Hoffmann, D., Gori,
G.B., (Editors): Proceedings of the Third World Conference on Smoking and
Health, New York, June 2-5, 1975. Volume I. Modifying the Risk for the
Smoker. U.S. Department of Health, Education, and Welfare, Public Health
Service, National Institutes of Health, National Cancer Institute, DHEW
Publication No. (NIH) 76-1221,1976pp. 285-292.
(34) DEBIAS, D.A., BANERJEE, C.M., BIRKHEAD, N.C., GREENE, C.H., SCOTT;
S.D., HARRER, W.V. Effects of carbon monoxide inhaiathon on ventricular
fibrillation. Archives of Environmental Health 31(1): 42-46, January-February
1976..
(35) DOLL, R., PETO, R. Mortality in relation to smoking: 20 years' observations on
male British doctors. British Medical'Journal2(6051): 1525-1536, December 25j
.
1976.
(36) DOWNEY, H.F., BASHOUR, C.A., BOUTROS, I.S., BASHOUR, F.A., PAR-
KER, P.E. Regional myocardial blood flow during nicotine infusion: Effects of
beta adrenergic blockade and acute coronary artery, occlusion. Journal of
Pharmacology and Experimental Therapeutics 202(1); 55-68, July 1977.
(3~) DOYLE; J.T., DAWBER, T.R., KANNEL, W.B., KINCH, S.H., KAHN, H.A.
The relationship of cigarette smoking, to coronary heart disease. The second
report of the combined experience of the Albany, New York,,and Framing-
ham, Massachusetts, studies. Journal of the American Medical Association
190(10): 886-890, December 7;1964.
(88) DOYLE,, J!T., KANNEL, W.B.,, MCNAMARA, P.M.,, QUICKENTON, P.,
GORDON, T. Factors related to suddenness of death from coronary disease:
combined Albany-Framingham st'udies. American Journal of Cardiology 37(6):
1073-1078, June 1976.
(39) EMERSON, P.A., MARKS, P. Preventing thromboembolism after myocardial
infarction: Effect of low-dose heparin or smoking. British Medical Journal
1(6052): 18-20, January 1, 1977.
(40) THE EPIDEMIOLOGY STUDY GROUP. Epidemiology for stroke facilities
planning: Report of'the Joint' Committee for Stroke Facilities. Stroke 3: 360-
371MayJune 1972.
(41) FEINLEIiB, M., WILLIAMS, R.R. Relative risks of myocardial infarction;
cardiovascular disease and peripheral vascular disease by type of smoking. In:
Wynder, E.C., Hoffmann, D., Gori, G.B., (Editors). Procecdings of the Thir&
World Conference on Smoking and Health, New YorkJune 2 5, 1975. Volume
I. Modifying the Risk for the Smoker. U.S. Department of Health, Educat'ion;,
and Welfare, Public Health Service, National Institutes of Health; National
Cancer Institute, DHEW Publication No. (NIH) 76-1221, 1976, pp. 243-256.
(42) FISHER, E.R., ROTHSTEIN, R., WHOLEY, M.H., NELSON, R. Influence of
nicotine on experimental atherosclerosis and its determinants. Archives of
Pathology 96: 298-304; November 1973.
(43)FIVE-YEAR STUDY BY A GROUP OF PHYSICIANS OF THE NEWCAS.
TLE UPON! TYNE REGION. Trial of clofibrate in the treatment of ischaemic
heart disease. British Medical Journal4: 767-776, December 25, 1971.
(Yf4) FRIEDMAN, G.D:,,KLATSKY, A.L., SIEGELAUB, A.B. Predictors of sudden
cardiac death. Circulation (Supplement III to Volumes 51 and 52): III-164!
III-169;,December 1975.
(45), . FRIEDMAN, G:D., SIEGELAUB, A.B., DALES, L.G. Cigarette smoking and
chest pain. Annals of InternaliMedicine 83(1): 1-7; July 1975.
4-69
0
I
disease that command serious attention~ atthe present time. As noted
very briefly above in the section on thromboangiitis and considered in a
separate chapter, hypersensitivity to tobacco protein does offer
reasonable concepts in relation to the pathogenesis of arteriosclerosis,
thrombosis, and angiitis. Its investigation will require more systematic
study and the use of immunolbgic methods superior to those employed'
in the past.
Discussion and Conclusions
The present report on cardiovascular disease and smoking is able to
summarize andl to comment on, far more extensive and detailed data
than were available 15 years ago. It draws heavily on the 1976
reference report on smoking and health, (138) and adds recent
references.
Systematic observations on the associations between smoking and
cardiovascular diseases have been made on considerably more than a
million individuals in the United States alone and have involved many
millions of person-years of experience. The majority of these have been
gathered on men.
Sample sizes are now extensive in both retrospective and prospective
studies. The variables observed in retrospective studies have been
relatively limited; in some prospective studies, they have been more
numerous and have allowed for complex analyses in which t'he
independence of smoking as a risk factor among other risk factors has
been defined:
The data: collected from western countries, particularly the United
States, but also the United Kingdom, Canada, and' others, show that
smoking is one of three major independent risk factors for heart attack
manifest as fatal an& nonfatal' myocardial infarction and sudden
cardiac death in adult men~ and women. Moreover, the effect is dose
related, synergistic with other risk factors for heart attack and of
stronger association at younger ages. Based on smaller but still
extensive samples, smoking cigarettes is strongly associated with
increased morbidity from arteriosclerotic peripheral' vascular diseasee
and with death from arteriosclerotic aneurysm of the aorta.
There is no reasonable doubt that cigarette smoking as a risk factor
for these cardiovascular diseases has been proven. Its dimensions as a
risk factor for them have been established for the American public.
Atherosclerosis, the basic lesion of ischemic disease: studied at
autopsy, has been observed in restricted samples and limited numbers
of cases. Nevertheless, the data establish adequately that cigarettee
smoking is associated with more severe and extensive atherosclerosis
of the aortaa and coronary arteries than is found among nonsmokers.
The effect is related to the amount smoked. Existing autopsy data
have not allowed adequate multivariate analysis, but several prospec-
4-63
~r
e
7ae
~4
ial
re
d
ry
an
'rs
ity
nd
ies
f.
~ay
ers
;ish
ing
of
the
md
'he
apparently also adverse for second attacks, but this is not yet well
defined.
The mechanism of effect is usually attributed to an enhancement of
coronary atherosclerosis in smokers and the consequent occurrence of
cardiac ischemia and ischemic necrosis of heart muscle. Other
phenomena have been offered as supplementary mechanisms. Aronow
has recently discussed these in the context of relative ischemia and
cardiac effects (5, 6). In patients with exercise-inducible angina,,
smoking various nicotine or non-nicotine-containing cigarettes was,
found to aggravate angina and in a manner related to the nicotinee
content. Nicotine-containing cigarettes increase heart rate and blood
pressure transiently, non-nicotine cigarettes do not. The nicotine effect
is mediated through catecholamine discharge. Both nicotine and non-
nicotine cigarettes increase blood CO. There is a decreased availability
of oxygen for the heart. Aronow reports a rise in left ventricular end-
diastolic pressure an& a decrease in stroke volume due to a negative
inotropic effect of CO on the myocardium. Jain and associates (60)
have found that, in normal subjects, smoking decreases the preejec-
tion/left ventricular ejection time ratio and external isovolumetric
contraction time, whereas in patients with coronary heart disease these
measurements increased on smoking. They concluded that left-ventric-
ular performance isdiminished after cigarette smoking in the presence
of significant coronary artery disease.
In the individual with ischemic heart disease, it is hypothesized that
nicotine: may aggravate ischemia: by increasing cardiac oxygen
demand but not supply; by increasing platelet adhesiveness (78) and
causing, circulatory obstructioni at the microvascular or macrovascular
level;, by lowering the cardiac threshold to ventricular fibrillation (20);
and by depressing conduction and' enhancing automaticity (52)
favoring the development of arrhythmias. CO might aggravate
ischemia: by exaggerating hypoxia, producing a negative inotropic
effect, reducing the fibrillation threshold (6), or increasing platelet
adhesiveness (25). Regardless of which of these several mechanisms
might operate in individual cases, it can be hypothesized~ that patients
on the border of myocardial ischemia may be pushed into impending or
actual infarction by the effects of nicotine and CO. Moreover, it may be
speeulated thatin the:presence of coronary atherosclerosis of a degree
insufficient to cause ischemia, the actions of smoking on platelet
pathophysiology may precipitate occlusive thrombosis and infarction.
These possiblle mechanisms for the conversion of marginal ischemia
into overt infarction may be thought to require that the attack follow
immediately in time or coincide with the act of smoking. In fact,
experience with myocardial infarction or sudden death does not seem
to support the: idea that the majority of habitual smokers suffer
myocardial infarction or sudden death in such close temporat relation-
ship to the act of smoking. However, the exact timing of the onset of
4-39
1000
Incidence as
per cent,of,
rate at.tirne
ofistoph ny.
(logscale)
1:00
10
m
Non-smokers
10 15 20
Years since stopping
FIGURE 3.-Lung cancer mortality in continuing cigarette smok-
ers and nonsmokers as a percentage of the rate among ex-cigarettee
smokers at the time they stopped smoking
SOURCE: UICC Technical Reports (PI,.B)
difficult to: estimate how much of the excess urban mortality can be.
5-26
BRONCHIAL CARCINOMA
Continuing
Cigarette
smoking
/
.X Ex-cigarette
~
I smokers
A
Given the characteristics of its associations with heart attack (such
as strength, graded relationship, independence, consistency, antece-
dence, loss of relationship on withdrawal, predictive capability, and a
degree of coherence), it can be concluded that smoking is causally
related to coronary heart disease, in the common sense of that idea and
for the purposes of preventive: medicine. It may be argued that the
characteristics of the associations noted above would occur if people
who were constitutionally liable to heart attack were also constitution,
ally liable to smoke; that is, that smoking activity and susceptibility to
atherosclerotic heart disease were both due to some underlying
constitutional condition of the individual. An attempt has been made to
study this point' by observing large numbers of monozygotic and
dizygotic twins. The result has been inconclusive. A discussion of
references will be found in the 1976 report on The Health Consequences
of Sm,oking (p. 44ff.) (138). It should be noted, however, that the fact
that risk in smokers reverts to normal or nonsmokers' levels after they
cease to smoke is contrary to the constitutional concept as expressed
above, unless further complex assumptions are made and'it is assumed
that large numbers of individuals underwent a change in their
underlying constitutional factor in midlife, acquired low risk, and
ceased to smoke because of that new constitution. This is not to say
that genetic susceptibility or resistance may not also be a risk factor
that plays a role in the individuall expression of or resistance to disease
along with other risk factors, or that people who stop smoking may not
also adopt additional' health-oriented behaviors when they stop; but the
constitutional hypothesis as expressed above does not provide a
credible basis to doubt that cigarette smoking is a cause of coronary
heart disease.
From the point of view of cardiovascular disease, research on the
mechanisms whereby smoking, causes its adverse effects and a more
precise quantification of certain risk factors through epidemiological
studies are significant topics of inedical science. The major goal in
smoking and cardiovascular disease research is, however, the develop-
ment of long-term effective methods of smoking avoidance and
cessation.
4-66
0
myocardial infarction, thromboangiitis obliterans, the effect of
smoking on blood lipids and lipoproteins, and tobacco constituents
other than CO and nicotine.
Venous Thrombosis
Pathological studies in human autopsies that address the question of a
difference in the presence of venous thrombi in relation to smoking
habits have not been reported. On the other hand, epidemiological
studies have clearly shown that conditions such as myocardial
infarction or peripheral vascular disease that are commonly induced or
accompanied pathogenet'icalNy by arterial thrombosis are more common
in smokers than nonsmokers. Vessey an& Doll (140) reporte& in a case
controli study among 84 women with venous thromboembolism (deep
vein thrombosis or pulmonary embolism) that there were no apprecia-
ble differences in smoking habits of subjects with or withoutt venous
thromboembolism. In the same paper, the authors mention a mortality
study conducted among British doctors and report that among 31 male
d'eaths from venous thromboembolism over 15 years of observation, the
age-standardized mortality rates per 100,000 were 96 among nonsmok-
ers, 57 among cigarette smokers, and 71 among pipe and cigar smokers.
Lawson and coworkers (76) report the absence of an effect of smoking
on venous thromboembolism among premenopausal women who were
users of oral contraceptives. It has been reported that smokers suffer
less thrombosis of'the deep veins of the leg after myocardial infarction
(39, 83). The failure to confirm such a finding has also been published
(5T): There have been a number of studies of various aspects of blood
coagulation and platelet pathophysiology in relation to smoking. In
general, these have been acute experimental investigations. Table A27
(pp. 126-1138) of the 1976 report on smoking and health (138) recorded
a number of such studies, including a review by Murphy. The data tend
in the direction of phenomena that might be expected to promote
thrombosis. However, confounding variables are uncertain and' the
meaning of in vitro tests for in vivo phenomena of thrombosis is not
established.
From the limited data available, smoking does not appear to enhance
venous thrombotic disease:
The interest in venous thrombosis and smoking lies not only in the
question of the presence or absence of an association but in its possible
meaning for arterial thrombosis. Arterial thrombosis is involved to an
important degree in atherogenesis, and in the precipitation and
complication of heart attack, ischemic stroke, and peripheral vascular
dlsease. There are research opportunities to learn more about
thrombosis in general and, in particular, in relation to possible
pathogenetic associations with smoking.
4-59
r.
al
vessel elasticity, red cell mass and blood viscosity, sodium metabolism,
obesity, an& genetic predisposition. The manner or means by which
most cases of hypertension-essential hypertension-develop is not
understood. The effect, however, is to enhance atherogenesis and
atherosclerotic diseases, particularly heart disease and stroke, and to
shorten life.
Experimentali models of hypertension im animals are available for
research. There are both, genetic models and those induced by
hormonal and surgicall procedures. However, smoke or smoke constitu-
ents have not been assessed in such models.
Summary of Epidemiological Data
Arterial hypertension is a very common disorder constituting a risk
factor for atherogenesis, stroke, heart attack, heart failure, renal
failure, and retinal damage. Hypertension is a continuous variable and
an independent risk factor.
Althou& smoking can raise blood 'pressure acutely, there is no
evidence that smoking induces hypertension. On the contrary, smokers
appear to have, on the average, a slightly lower blood pressure than
nonsmokers. Table A8 (pp: 99-100) of the 1976 report on smoking and'
health (138) tabulates several studies; recent reports repeat such data
trends or show little relationship (23;129).
An exception to these data is the finding of Kahn and'associates (67)
in: their study of 10,000 Israeli male civil servants. In a period of 5
years, they found that the incidence of hypertension adjusted for age
was about two times greater in smokers than nonsmokers. However,
the conclusion can be considered in additional ways. Since weight gain
is associated with an increase in blood pressure and weight loss is
associated with a decrease in blood pressure and; moreover, since
smokers tend not to gain as much weight as nonsmokers, this complex
relationship has attracted; attention. Seltzer (121) has offered data in
which~men who stopped smoking gained about 8 pounds and showed an
increase of about 4 mm Hg in systolic blood pressure. In examining the
data for weight change, it was found that continuing smokers who lost
weight had a: decrease in systolic blood pressure of about 3 mm Hg,
while.quitters who also lost weight had an increase in blood pressure of
about 2 mm~ Hg. The gradient between these two groups was about 5
mm Hg in systolic blood pressure. The reference report of 1976 on The
Health Consequences of Snwking (138) comments critically on this
report (p. 138ff.); and notes a marginal sample size.
Available data indicate that smoking is not a major risk factor for
hypertension, and in practice, the association is slightly negative. In
this sense, it should be balanced against the other strong positive risk
factor associations of smoking for various expressions of heart attack,
for PVD, aortic aneurysm, lung disease, and cancers.
~ , `~ 4-57
accounted for by cigarette smoking alone. It is possible that there is an
interaction between the carcinogens in cigarette smoke and other
compounds in the ambient atmosphere.
Epidemiologic investigations thus far indicate that the most
important cause of lung cancer is cigarette smoking and that urban
factors such as air pollution have very little independent effect on the
diwPlnnmpn}_nf T.« }',L:~ .a,~_--. __~
-- °---- .
1
l
3
- ------------------
'.
45
35
N:
CASES
9
54
CONTROLS 1/0 61
8
112
15
8
2955
5
593
15
264
NON F NF F NF
SMOKER 1-20 21+
FIGURE 5.-Relative risk of developing larynx cancer for females,,
by number of cigarettes smoked per day and use of filter (F) and
nonfilter (NF) cigarettes
SOURCE: Wynder~ E.G (253)
Conclusions
1. Epidemiological; experimental, and autopsy studies indicate thatt
cigarette smokibg is a significant causative factor in the develbpment
of cancer of the larynx.
2. The risk of developing cancer of the larynx in pipe and cigar
smokers is similar to that for cigarette smokers:
5-36
NF
1+
ber of
lfilter
),000) iat of
It be
!s in
NON'
SMOKER'
F NF
1-10
F NF
11-20
F NF
21-30
F NF
31+
FIGURE 2.-Relative risk of lung cancer for females, by number of
cigarettes smoked per day and long-term use of filter (F) and
nonfilter (NF) cigarettes
SOURCE: Wynder, E:L. (f3J)
The epidemic of lung cancer in women has lagged behind~ that in
meny primarily because:of differences in patterns of cigarette smoking.
There are fewer women smoking than men, but the gap is narrowing.
Among teenagers in several age: categories, girls are smoking more
than boys (155). Table 8 shows the percentage of the U.S. adult
population who are currently smoking cigarettes for selected years. In
1975, approximately 29' percent of adult females were smoking,,
whereas 39 percent of adult males were smoking (155). It should also
be note& that, over the past decade, there has been a 2.6 percent
5-19
rance
eaths
ntage
.3. It
ipt'o
neous
~ed on
jbacco
~
with
ctive
ween
prior
n the
tients
t the
up of
ed 70
and
~hich
lusted
~ 1.98).
I
~t of
I eto
~rgues
from
leaths
nths.
~ts; of
,
idden
mesis
cts of
nesis,
3telet
Lrdiac
ivery
ed as
.ze to
)rt of
)king
data
suggest hypotheses for mechanisms of sudden death in man, they do
notof course, deal directly with cases of sudden death. .
The Effect of Smoking on Sudden Cardiac Death in Animals.
The smoking and health report of 1976 (138) has tabulated in Table
A20'(pp. 103-108) papers concerned with the effect of smoke or nicotine
on the cardiovascular system of animals. In the presence of myoca.rdiall
ischemia, exposure to tobacco smoke or nicotine may precipitate
conditions of increased cardiac demand, relative ischemia, and, in one
experiment, arrhythmias. Bellet and colleagues (20) found that the
ventricular fibrillation threshoU was reduced in dogs exposed by
intubation to cigarette smoke both in the presence and in the absencee
of acute myocardial infarction.
Malinow and colleagues failed to induce infarction or sudden death
in cholesterol-fed cynomolgus monkeys by chronic exposure to CO(80).
There are, however, no animal experiments in which animals have been
brought chronically to a state of incipient myocardial' ischemia by
atherogenesis and then exposed to whole smoke by inhalation in a
nonstressful setting.
Research Needs
There are fewer data on sudden cardiac death than on myocardial
infarction in general. Smoking is clearly a strong risk factor for sudden
death, but present indications are that it is not unique among, the mix
of risk factors for coronary heart disease and that it is not highly
predictive: However, there are theoretical reasons to speculate that
smoking might have a relationship to sudden death, not only through
its effects on the circulation, but also through a myocardial' one. It
should be considered whether present epidemiological and clinical
research data are adequate to exclude in smokers a myocardial element
in sudden cardiac death, in relation to either first or multiple heart
attacks, or whether additional research is warranted.
The mechanisms of sudden cardiac death, its precursor states, and
preventive therapy require further elucidation. These should be
clarified where possible: in man and in experimental animal models
with close analogy to man. The study of smoking or of smoke
constituents as variables in such studies may be informative both about
sudden death and the role of smoking in its occurrence.
Conclusions
Smoking is a powerful risk factor for sudden cardiac death. It is,
however, only one of the general group of risk factors that contribute
to coronary heart disease and sudden death. The mechanisms by which
smoking might induce sudden death, in addition to am exacerbation of
coronary artery arteriosclerosis, can be hypothesized f rom~ experiments
4-45
C
.
U11
~
`.T
~JZ
C
W
Tablie 2.-Lung cancer mortality ratios for males, by
current number of cigarettes smoked per day, from
selected prospective studies ......................................13
Table 3.-Lung cancer mortality ratios for males, by age
began smoking, from selected prospective studies ........ 14
Table 4.-Lung cancer mortality ratios for males, by
degree of inhalation, from, selected prospective
studies ..................................................................15
Table 5.-Age-adjusted lung cancer mortality ratios for
males and females, by tar and nicotine in cigarettes
smoked . .. . .. .... . ...... .. .. .. . . .. .. . . . ..... .. . ... . .. . ... .. . .... . .. ..
.. .16
Table 6.-Age-adjusted lung cancer mortality ratios for
males and females, comparing those who smoked' a few
high T/N cigarettes with those who smoked many low
T/N cigarettes ....................................................... 17
Table 7.-Mortality rates for lung cancer and cancer of
the respiratory tract for white females in the United
States per 100,000 population, for selected years: 1940 to
1976 ................................................,.................... 20
U'nited' States ........................................................ 20
Table 8.-Percent of adult population who were current
cigarette smokers in selected years in the
Table 9.-Percent of teenagers who were current cigarette
smokers in, selected years in the United States ........... 21
Table 10.-Lung cancer mortality ratios for women-
prospective st'udies .................................................. 21
Table 11.-Lung cancer mortality ratios for females, by
number of cigarettes smoked per day: A.C.S. 25-State
Study . . . . ... .. . . . .. . . . ... . . . . . . . . . . .. .. .. . . . ..... . . .. .... ... ..
... .. . . . .. 22
Table 12.-Lung cancer mortality ratios for femalos, by
number of cigarettes smoked per day: H'aenszel' and
Taeuber .................................... ............................ 22
Table 13.-Lung cancer mortality ratios for females, by
duration of smoking: Swedish Study ......................... 22
5-6
Introduction
Cancer has been~ the second leading cause of death in the United' States
since 1937. There were an estimated 390,000 deaths from cancer in 1978
(4); The association between tobacco smoking and the development of
lung cancer was first suggested in the 1920's and early 1930's (159;
206). In the early 1950's, more thani a dozen retrospective studies were
published which first generally alerted the medical and scientific
community to the health hazards associated! with cigarette smoking.
The public was informed of the results of these studies, and as a
consequence there was a significant, but brief dip in, the per capita
consumption of cigarettes. The next decade brought an intensive
worldwide investigation into: the various diseases associated' with
cigarette smoking. The first official statement on smoking and health
by the U.S. Government was contained in the Report of the Advisory
Committee to the Surgeon General of the U.S. Public Health Service,
which was released 15 years ago. The evidence available at that time
warranted the conclusion that "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. The risk of developing lung
cancer increases with the durationi of smoking, and the number of
cigarettes smoked per day, and is diminished by discontinuing
smoking" (217). In the 15 years since the 1964 Surgeon General's
Report was published, these conclusions have been confirmed by
numerous investigat'ions in many countries. Cigarette smoking has also
been implicated as a significant cause of cancer of the larynx, oral
cavity, esophagus, urinary bladder, kidney, and pancreas. As data
concerning the relationship of smoking to the development of cancer at
various sites became available;, they were summarized and published in
the annual issues of the: Health Consequences of Smoking (209, 210,
211, 212, 212a, 213, ,214215; 216).
This chapter reviews the epidemiological and experimental data for
each of the cancer sites associated with cigarette smoking. Discussions
of the specific cancers are presented sequentially, based on the
strength of the association with~cigarette smoking: cancer of the lung,
larynx, oral ca.vity, esophagus, urinary bladder, kidney, and pancreas.
Lung Cancer
This year more people in the United States willl die from lung cancer
than from any other malignant disease. In 1950, when the nation first
became generally aware that there was an association between
smoking and lung cancer, there were 18,313 lung cancer deaths. In
1964, there were 45,838 deaths froml lung cancer. The National Center
for Health Statistics reported that in 1976 there were 86,267 deaths
from lung cancer in the United States (150). It is estimated that there
5-9
I
I
I
t
I,
11
(62), JANZON, L. Smoking, cessation and peripheral circulation. A population study
in 59-year-old men with plethysmography and segmental measurements, of
systolic blood pressure. VASA 4(3): 282-287,1975.
(68), JENKINS, C.D., ROSENMAN, R.H., ZYZANSKI, S.J. Cigarette smoking. Its
relationship to coronary heart disease and related risk factors in the Western
Collaborati ve Group Study. Circulation 38(6): 1140-1155, December 1968.
(64) JENKINS,, C.D., ZYZANSKI, S.J.,, ROSENMAN, RH. Risk of new myocardial
infarction in middle-aged men with manifest coronary heart disease..
Circulation 53(2): 342-347, February 1976:.
(65) JENNINGS, RB. Relationship of acute ischemia to functional defects and
irreversibility. Circulation 53(3, Supplement 1): 1-26-1-29, March 1976.
(66), KAGAN, A.R., STERNBY, N.H., UEMURA, K., VANECEK, R., VIHERT,
A.M., LIFSIC, A.M., MATOVA, E.E., ZAHOR, Z.,,ZDANOV, V:S. Atheroscle-
rosis of the aorta and coronary arteries in, five towns. Bulletin of the World
Health; Organization 53(5-6): 485-645, 1976:
(67) KAHN, H.A.,,MEDALIE, J.H., NEUFELD, H.N:, RISS, E., GOLDBOURT; U.
The incidence of hypertension and associated factors: The Israeliischemic heart
disease study. Americal Heart Journa184(2): 171-182, August 1972.
(68) KANNEL, W.B. Epidemiologic studies on smoking in cerebral and: peripheral
vascular disease. In: Wynder, E.'L., Hoffmann, D:, Gori, G.B., (Editors):
Proceedings of the Third World Conference on Smoking and Health, New
York, June 2-5, 1975. Volume I. Modifying the Risk for the Smoker. U.S.
Department of Health, Education, and Welfare, Public Health Service,
Nationali Institutes of Health, National Cancer Institute, DHEW Publication
No. (NIH)16-1221, 1976, ppj 257-274.
(69), KANNEL, W.B. Some lessons in cardiovascular epidemiology from Framing-
ham. American Journal of Cardiolbgy 37: 269-282, February 1976.
(70) KANNEL, W:B., CASTELLI, W.P. Significance of nicotine, carbon monoxide
and other smoke components in the development of cardiovascular disease.
U.S. Public, Health Service, DHEW Publicatiom No. (NIH)', 76-1221, 1976, pp.
369-381.
(71) KANNEL, W.B. DOYLE, J.T., MCNAMARA, P.M, QUICKENTON, P:,.
GORDON; T. Precursors of sudden coronary death. Factors related to the
incidence of sudden death. Circulation 51!: 60fi-613, April 1975.
(72) KJELDSEN, K., ASTRUP,,P., WANSTRUP,,J. Reversallof rabbit atheromato-
sis by hyperoxia.. Journal of Atherosclerosis Research 10: 173-178,1969.
(78) KJELDSEN; K., THOMSEN, H.K. The effect of hypoxia on the fine structure
of the aortic intima in rabbits: Laboratory Investigation 33(5):' S33-543, 1975.
(7k)~ KJELDSEN, K., WANSTRUP, J., ASTRUP, P. Enhancing influence of arterial
hypoxia on the development of atheromatosis in cholesterol-fed rabbits.
Journal of Atherosclerosis Research 8: 83.5-84.5,1968.
(75)' KOCH, A. Smoking and peripheral arterial'disease. In: Wynder, E.L. Hoffmann,
D., Gori, G;B. (Editors). Proceedings of the Third World Conference on
Smoking and~Health~,New York, June 2-5, 1975. Volume 1. Modifying the Risk
for the Smoker. U.S. Department of Health, Education, and Welfare, Public
Health Service, National Institutes of Health, National Cancer Institute,
DHEW Publication No. (NIH) 76-1221, 1976, pp. 281-283.
(76) LAWSOND.H., DAVIDSON, J.F., JICK, H. Oral contraceptive use and'venous
thromboembolism: Absence of an effect of smoking. British Medical Journal 2:
729-730, September 17,1977.
(77) LAWTON, G. Cigarette consumption an& atherosclerosis. Their relationship in
the aortic and iliac and femoral arteries. British Journal of Surgery 60(11):
873-876,,November 1973.
4-71
0
TABLE 4.-Lung cancer mortality ratios for males, by degree of
inhalation, from selected prospective studies
1
a
Degree
of'
inhalation
Mortality
ratio
A.C.S. 25-
State Study(6+u)
Nonsmoker
1.00
None 8.00
Slight 8.92
Moderate 13.08
Deep 17.00
Swedish
males(32)
Nonsmoker
1.00
None 3.70
Light inhalation 7.80
Deep inhalation 9.20
Tar and Nicotine Content of Cigarettes
The major constituents of cigarette smoke that cause lung cancer are
among the more than 2,000 different compounds found in cigarette
smoke: Cigarette filters, first introduced during the mid=1950's, havee
the effect of trapping tar. Data presented by Maxwell (136) show that,
in 1976, more than 600 billion cigaret'tes were smoked and that 88:4
percent of these were filtered. It has been known that the risk of
developing lung cancer increased with the tar and nicotine content of
cigarettes. Until recently, however, there has not been a great deal of
evidence that individuals who switch to lower tar and nicotine
cigarettes experience less lung cancer mortality (27). It has been
argued that, if the tar an& nicotine content of tobacco were reduced,
individuals might increase the number of cigarettes smoked per day
and thereby abolish any benefit that might be gained. Alternatively,
those who switch to low tar and nicotine cigarettes might inhale the
smoke more deeply than smokers of high~ tar and nicotine cigarettes,
and thereby exposure to tar and nicotine might not be reduced. In a
ldrge prospective study by Hammond, et al. (67);, these tar an& nicotine
relationships were examined with respect to lung cancer. The 897,825
men~ and women in 23 States were divided into 3 tar and nicotine
categories. The high tar and~ nicotine (T/N) category was defined as 2.0
to 2.7 mg, of nicotine and' 25.8 to 35.7 mg of tar. The' medium TXNN
category was defined as 1.2 to 1.9 mg of nicotine and 17.6 to 25.7 mg of
tar. The low T/N category included~ cigarettes containing less than 1.2
mg of nicotine and less~than, 17.6 mg of tar. A matched-group analysis,,
similar to age standardization, was utilized: Individuals in each group:
were alike with respect to age, race, number of cigarettes smoked per
day, age when they began to smoke cigarettes, place of residence,
5-15
(94) MJOS, O.D., THELLE, D.S., FORDE, O.Ht, VIK-MO, H! Family study of high
density lipoprotein cholesterol and! the relation to age and sex. Acta Medica
Scandinavica 201(4): 323: 329,1977.
(95) MORRIS, J.N., CHAVE, S.P.W., ADAM, C., SIREY, C., EPSTEIN, L.,
SHEEHAN, D.J. Vigorous exercise in leisure-time and the incidence of
coronary heart-disease. Lancet 11: 333-339, February 17,1973.
(96) MOSS, A.J., DECAMILLA, J.,,DAVIS, H. Cardiac Death in the first 6 months
after myocardial infarction: Potential for mortality reduction in the early
posthospital period; American Journal of Cardiology 39(6): 816-820, May 26,
1977.
(97) MULCAHY, R., HICKEY, N., GRAHAM, I.M., MACAIRT, J. Factors affecting
the 5-year survival' rate of men following acute coronary heart disease.
American HearGJournal 93(5): 556-559, May 1977.
(98), NAEYE, R.L., TRUONGL.D. Effects of cigarette smoking on intramyocardial
arteries and arterioles in man. American Jburnal of Clinicali Pathology 68(4):
493-498;,October 1977.
(99), NAKAYAMA, Y. Epidemiologicaliresearch in, Japan on smoking and cardiovas-
cular diseases. In: Schettler, G., Goto, Y., Hata, Y., Klose, G. (Editors).
Atherosclerosis IV. Proceedings of the, Fourth International Symposium,
Tokyo, 1976. Berlin, Springer-Verlag, 1977, pp. 149-153.
(100), OBERMAN, A., RAY, M., TURNER, M.E., BARNESG., GROOMS;,C. Sudden
death in patients evaluated for ischemic heart disease. Circulation 51/52
(Supplement III); 170-172, December 1975.
(101) OMAE, T:,,TAKESHITA, M., HIROTA, Y. The Hisayama study and joint study
on cerebrovascular diseases in Japan, In: Scheinberg, P. (Editor). Cerebrovas-
cular Diseases. Proceedings of~ the Tenth, Princeton Conference, New Jersey,
1976. New York, Raven Press, 1976, pp. 255-265.
(102)1 ORYH.W. Association between oral contraceptives and myocardial infarction.
A review. Journal of the American. Medical Association 237(24): 2619-2622,
June 13,1977.
(103), PAUL, 0. Discussion on Dr. Dawber's Paper (The interrelationship of tobacco
smoke components to hyperlipidemia and other risk factors). In: Wynder, E.L.,
Hoffmann, D., Gori, G:B.,, (Editors). Proceedings of the Third World
Conference on Smoking and Health, New York, June 2-5, 1975. Volume I.
Modifying the Risk for the Smoker. U!S, Department of Health, Education,
and Welfare, Public Health Service, National Institutes of Health, National
Cancer Institute, DHEW' Publication No. (NIH) 76-1221, 1976, pp. 293-295.
(104) PEARSON, T.A., DILLMAN, J.M., SOLEZ, K., HEPTINSTALL, R.H. Clonal
markers in~ the study of the origin and growth of human atherosclerotic
lesions. Circulation Research 43(1): 10-18, July 1978.
(105) PEARSON, T.A., WANG, A., SOLEZ, K., HEPTINSTALL, R.H. Clonal
characteristics of fibrous plaques and fatty, streaks from human aortas.
American Journal iof Pathology 81(2): 379-387, November 1975.
(106) PETITTI, D.B., WINGERD, J. Use of oral contraceptives, cigarette smoking,
and risk ofisubarachnoidihaemorrhage. Lancet 2: 234-236, July 29, 1978.
(107) THE POOLING PROJECT RESEARCH GROUP. Relationship of blood
pressure, serum cholesterol, smoking habit, relative weight! and ECG
abnormalities to incidence of major coronary events: Final report of the
Pooling Project. Journal of Chronic Diseases 31(4): 201306, Aprili1978.
(108) REEVES, T.J., OBERMAN, A., JONES, W.B., SHEFFIELD, L.T. Natural
history of angina pectoris. American Journal of Cardiology 33: 423-43U; March,
1974.
(109) REICHENBACH, D.D., MOSS, N:S,, MEYER, E. Pathology of the heart in
sudden cardiac death. The American Journal of Cardiology 39(6): 865-872, May
26,1977:.
4-73
0
(110) REID, D.D., HAMILTON, PJ.S., MCCARTNEY, P., ROSE, G., JARRETT, RJ.,
KEEN, H. Smoking and other risk factors for coronary heart-disease in British
civil servants. Lancet 2(7993): 979-984, November 6, 1976.
(111)' RESEARCH COMMITTEE OF THE SCOTTISH SOCIETY OF'PHYSICIANS.
Ischaemic heart disease. A secondary prevention trial using clofibrate. Report
by a Research Committee of the Scottish Societyof Physicians. British Medical'
Journal 4: 775-784; December 25,1971.
(112) RHOADS, G.G.,,BLACKWELDER, W.C., STEMMERMAN, G.N., HAYASHI,
T., KAGAN, A. Coronary risk factors and autopsy findings in Japanese-
American men. Laboratory Investigation 38(3): 304 311,1978.
(113) ROBICSEK, F., DAUGHERTY, H.K., MULLEN, D.C: MASTERS, T.N:,
NARBAY, D., SANGER, P.W., COOK,,J.W. The effect'~of continued~ cigaret'te
smoking on~ the patency of synthetic vascular grafts in Leriche syndrome.
Collected Works on Cardio-Pulmonary Disease 20: 62-70, December 1975.
(114) ROCK, W., OALMANN, M., STRONG, J. Community pathology of myocardial
lesions in men 25 to 44 years of age. Laboratory Investigation 32(3):' 433,
March 1975. (Abstract)
(115). ROSE, G., REID, D.D.,, HAMILTON, P.J.S., MCCARTNEY, P., KEEN, H.,.
JARRETT; R.J. Myocardial ischaemia, risk factors and death from~eoronary
heart-disease. Lancet 1(8003): 105-109, January 15, 1977.
(116) ROSENMAN, R.H,, BRAND, R.J., SHOLTZ, R.I.,,FRIEDMAN, M. Multivariate
prediction of coronary heart' disease during 8.5 year follow-up in the Western
Collaborative Group Study. American~ Journal of Cardiology 37(5): 903-910,
May 1976.
(117), ROSS,,R., GLOMSET, J.A. The pathogenesis of atherosclerosis (Parts One an&
Two). New England Journal of Medicine 295(7): 369-377, August 12, 1976 and
295(8): 420-425, August 190 1976.
(118) RUBERMAN, W., WEINBLATT, E., GOLDBERG, J.D., FRANK, C.W.,
SHAPIRO, S. Ventricular premature beats and' mortality after myocardial
infarction. The New England Journal of Medicine 297(14): 750-757, October 6,
1977:
(119) ST. CLAIR, R.W. Metabolism of the arterial wall and atherosclerosis. In:
Paoletti, R., Gotto, A.M. Jr. (Editors), Atherosclerosis Reviews, Volume 1. New
YorkRaven Ptess,1976,pp: 61-117.
(120) SCHIEVELBEIN, H. The evidence for nicotine as an etiological factor in
cardiovascular disease. In: Wynder, E.L., Hoffmann, D.,, Gori, G.B. (Editors).
Proceedings of the Third' World Conference on Smoking and Health, New
York, June 2-5, 1976. Volume I. Modifying the Risk for the Smoker. U.S.
Department of' Health, Education, and! Welfare, Public Health Service,.
National Institutes of Health, National Cancer Institute, DHEW Publication
No.(NIH) 76-1221; 1976, pp. 297-307:
(121) SELTZERC.C. Effect of smoking on~blood pressure. American Heart Journal
87(5): 558-564, May 1974.
(1.22) SHAPIRO, S., WEINBLATT, E., FRANK, C.W., SAGER, R.V. Incidence of
coronary heart disease in a population~ insured for medical' care (HIP).
Myocardial infaretion, angina pectoris, and possible myocardial infarction.
American Journal iof Public Health 59 (Supplement 6): 1-101, June 1969.
(123) SKINHOJ, E., OLESEN, J., PAULSONO.B: Influence of smoking and nicotine
on cerebral blood flow and metabolic rate of oxygen in man. Journal of
Applied Physiology 35(6): 820-822, 1973.
(124) SLONE, D., SHAPIRO, S:, ROSENBERG, L., KAUFMAN, D.W., HARTZ, S.C.,
ROSSI, A.C., STOLLEY, P.D., MIETTINEN, O.S. Relation of cigarette
smoking to myocardial infarction in young womem New England Journal of
Medicine 298(23): 1273-1276, June 8,1978.
Table 14.-Lung cancer mortality ratios for females, by
degree of inhalation: A.C.S. 25-State St'udy ................ 22
Table 15.-Lung cancer mortality ratios in ex-cigarette
smokers, by number of years stopped smoking............ 25
Table 16.-Mortality ratios for cancer of the larynx-
prospective studies .................................................. 33
Table 17.-Mortality ratios for cancer of the oral cavit'y-
prospect'iwe studies .................................................. 40.
Table 1&-Mortallty ratios for cancer of the esophagus-
prospective studies .................................................. 43
Table 19:-Bladder cancer mortality ratios-prospective
studies . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ... . . . . . .
. . . . . . . . . . . . .. . . . . 46
Table 20:-Kidney cancer mortality, ratios and relative
risks: selecte6 prospective and retrospective studies ..... 48
Table 21.-Kidney cancer mortality ratios, by amount
smoked: Us S. Veterans Studiy ..................................49.
Table 22.-Pancreatic cancer mortality ratios-prospective
studies ............................... ................................... 51
Table 23.-Mortality ratios for cancer of the pancreas
among Swedish subjects, aged 18-69, by sex and
amou nt smoked ...................................................... 52
Table 24.-Carcinogenic, promoting, and ciliatoxic agents
in the gas phase of tobacco smoke ............................ 55
Table 25.-Carcinogenic agents in the particulate phase
of tobacco smoke ................................................... 56
Table 26.-Tumor promoters and co-carcinogens in the
particulate phase of tobacco smoke ........................... 57
5-7.
TABLE 7.-Mortality rates for lung cancer and cancer of the
respiratory tract for white females in the United
States per 100,000 population for selected years, 1940
to 1976
U
Year Lung and Bronchus Respiratory System
1940 - 3.6
1945 - 4:6
1950 4.7 5.4
1955 5.1 5.7,
1960 5.91 6.4'
1965 8.0 8.6
1970, 12:3 13.1
1975 17.8 18.8
1976 19.5 20.5
SOURCE: National Center for HealthStatistics (150)
TABLE S.-Percent of adult population who, were current cigarette
smokers in selected years in the United States
Year Percent smokers
Females Males
1964' 31.5 52:9'
1966 33.7 51.9
1970 30.5 42.2
1975 28.9 39.3
Percent reduction
since 1964
2:6
13.6
SOURCE: National Clearinghouse for Smoking and Health (d55))
reduction in the number of adult females who smoke cigarettes,
whereas there has been a 13.6 percent reduction in the number of'
adult males smoking. Trends in the percentage of teenagers who are
regular cigarette smokers are presented in TAble 9. Cigarette smoking
among girls has increased steadily, so that at the present time equal,
numbers of boys and girls are smoking cigarettes and many of the
differences which existed in the past between male and female
smokers have disappeared.
Epidemiologicat Studies
Three of the large prospective epidemiological studies contain informa-
tion on lung cancer in women. Data from,these studies are summarized
in Table 10. A number of retrospective studies have examined the
5-20
TABLE 6.-Age-adjusted lung cancer mortality ratios* for males
and females, comparing those who smoked a few
high T/N' cigarettes with those who smoked many
low T/N cigarettes
1-19 high' T/N 20-39 low TLN
cigarettes/day cigarettes/day'
Males 1.00 1i6
Females 19D 2.1
'The mortality ratio for the . categoryy with ~ lowest risk was made.l.Wso 4h'e increase in risk
with smoking morecigarettes/d®ywuld be illustrated.
SOURCE: Hammond, E. C1(67)
"the data for women though less extensive, point in the: same
direction" (217); Today, 15 years' later, the lung cancer epidemic among
women is well established. Several investigators had predicted~ sharp
increases in lhng,cancer mortality among,women. In 1966, Linden (118)
examined lung cancer mortality in California women and predicted:
"One can expect to see further increase in the number of lung cancer
deaths and the death rates as the increasingproport'ions of women who
smoke cigarettes reach the age when lung cancer is most likely to
occur."
In 1964, lung cancer was the fifth leading cause of death from cancer
in women. It became the fourth ~ leading cause in 1967'and'moved to the
third leading cause of death from cancer in 1969, passing cancer of the
uterus. Projections for 1979 indicate that lung cancer is approaching
cancer of the colon and rectum as the second leading cause of death
from cancer in women. If present trends are not reversed, during the
next decade lung cancer willi become the.leading cause of death from
cancer in womenexceeding deaths from~cancer of the breast.
In 1955, there were only 4,100 deaths from lung cancer in women. In
1976, the National Center for Health Statistics reported there were
20,455 deaths from lung cancer among females in the United States
(150); the American Cancer Society estimated that in 1978 this
increased to 21,900 deaths (4).
These increases are not due to increases in the population. Death
rates for lung cancer have been steadily rising in women, especially in
the past decade. The lung cancer mortality rate for white females in
1950 was 4.7 per 100,000; by 11976 this had risen to 19.5 per 100,000. This
is more than a fourfold increase (Table 7).
The Surveillance, Epidemiology and End Results (SEER) Program
of the National Cancer Institute recently reported that the lung cancer
death rate for black females exceeded that of white females (16.8
blacks, 15.0 whites)(15.1f). Data from this survey are collected from 10
geographic areas in the United States and therefore do not represent
5-17
(125) SMALL, D.M. Cellular mechanisms for lipid deposition in atherosclerosis (Parts
One and'. Two), The New England Journal of Medicine 297(16): 873-877,
October 20+ 1977 and 297(17): 924-929, October 27,,1977:
(I26) SMITH, E.B., SMITH, R.H. Early changes in aortic intima. In: Paoletti, R,
Gotto, A.M., Jr. (Editors): Atherosclerosis Reviews, Volume 1. New York,
Raven Press,1976pp. 119-136.
(127) SPAIN', D.M., BRADESS, V.A. Sudden death from coronary heart disease:.
Survival time, frequency of thrombi, and cigarette smoking. Chest 58(2): 107-
110, August 1970:
(128) SPAIND.M., SIEGEL, H.,,BRADESS, V.A. Women smokers and~sudden death.
The relationship of cigarette smoking to coronary disease. Jburnal of the
American Medical Association 224(7): 1005-1007,,May14; 1973.
(129) STAMLER, J., RHOMBERG, P., SCHOENBERGER, J.A., SHEKELLE, RB.,
DYER, A., SHEKELLES., STAMLER, R, WANNAMAKER, J. Multivariate
analysis of the relationship of seven variables to blood pressure: Findings of
the Chicago Heart Association, Detection Project in Industry, 1967,1972.
Journal of Chronic Diseases 28(10): 527-548, November 1975.
(d30) STENDER, S.,,ASTRUP. P., KJELDSEN, K. The effect of carbon monoxide on
cholesterol in the aort'ic wall of rabbits. Atherosclerosis 28(4): 357-367,
December1977.
(131) STRONG, J.P., OMAE, P. (CHAIRMEN). Workshop 3. Epidemiology of
atherosclerosis and! geographic differences in risk factors. In: Schettler, G.,
Goto, Y., Hgta, Y.,,K1ose; G. (Editors). Atherosclerosis IV. Proceedings of the
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pp. 92-120.
(132) STRONG, J.P., RICHARDS;, M.L. Cigarette smoking and atherosclerosis in
autopsied men. Atherosclerosis 23(3): 451-476, May/June 1976.
('188) STRONG, J.P., SOLBERG, L.A., RESTREPO, C. Atherosclerosis in persons with
coronary heart disease. Laboratory Investigation 18(5): 527-W7, May 196&
(134) TALBOTT, E., KULLER, L.H.,, DETRE, K., PERPER, J. Biologic and
psychosocial risk factors of sudden death from coronary disease in white
women. The American Journal of Cardiology 39(6): 858-864, May 26, 1977.
(135) THOMAS, W.A., FLORENTIN, R.A., REINER,, J.M., LEE, W.M., LEE, K.T.
Alterations in population dynamics of arterial smooth muscle cells during,
atherogenesis. IV. Evidence for a polyclbnal origin of hypercholesterolemic
diet-indueed atherosclerotic lesions in young swine. Ekperimental and
Molecular Pathology 24: 244-260, 1976.
(136) TOPPING, D.L~ Metabolic effects of carbon monoxide in relation to atherogene-
sis. Atherosclerosis 26(2): 129-137, February 1977.
(137) TRUMP, B.F:, MERGNER, W:J., KAHNG, M.W., SALADINO, A.J. Studies on
the subcellular pathophysiology of ischemia. Circulation 53(3) Supplement 1: I-
17-1-26, March 1976.
(188) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking, A
Reference Edition: 1976. U.S. Department of HealthEducation, and Welfare,
Public Health Service, Center for Disease Control, HEW Publication No.
(CDC) 78-8357, 1976; 657 pp.
(139) VESSELINOVITCHD., WISSLER, R.W., FISHER-DZOGA, K., HUGHES, R.,
DUBIEN, L. Regression of atherosclerosis in rabbits. Part' 1. Treatment'~ with
low-fat diet, hyperoxia, and hypolipidemic agents. Atherosclerosis 19: 259-275,
1974.
(140) VESSEY, M.P., DOLL, R. Investigation of relation between use of oral'
contraceptives and thromboembolic disease. A further report. British Medical
Journal 2(5658): 651-657, June 14,1969.
4-75
16
154
1220
19
139
12
Y
2
W
~ 12
4 $ 167
W I
cc
CASES
N:,
CONTROLS
5
166
5 6
443 585
PRESENT 1-3 4 6 7-10 11+ NON
SMOKER SMOKER
FIGURE 6.-Relative risk of developing larynx cancer for male ex-
smokers, by years of smoking cessation ~
SOURCE: Wynder, E.L. (YSJ).
3. There are positive dose-response relationships for the development
of laryngeal cancer with the number of cigarettes smoked per day and
the-duration of cigarette smoking.
4. There is a synergistic effect with t'he use of cigarettes and alcohol.
The risk of developing cancer of the larynx is much greater for heavy
smokers who also drink heavily, compared with individuals who only
have exposure to either substance.
5-37
M
H
were 92;400'deaths from lung cancer in 1978 (4). For every preventable
death from highway accidents, there were approximately two deaths
from lung cancer which could have been prevented~ if the individual'
had not smoked cigarettes. There are about 280 deaths from lung
cancer each day in the United~ States.
This epidemic increase in lung cancer is reflected in rapidly changing
mortality rates in~ both, men and women. The mortality rate for men in
1950 was 19.9/100,000/year. This rose to 41.4 in 1964, and to 63.0 in
1976. The comparable figures for white females were 4.7 in 1950 and
8:0 in 1965, and climbing rapidly to 19:5 in 1976 (Table 7).
According to results from the National Cancer Institute's Surveil~
lance, Epidemiology,, and Etid Results (SEER)' Program, the mortality
rates for black males and females are higher than for whites, In 1976,
the lung cancer mortality rate for black males was 93.0, for black
females it was 17:4 (154). Due to recent increases in death rates among
females, the ratio of male to female mortality for lung cancer has
dropped1rom 7:1 to less than 4:1.
While recent years have seen dramatic increases ini relative survival
rates for acute leukemias in children, Hodgkin's disease, multiple
myeloma, and certain other malignancies, there has been little increase
in survival rates for lung cancer. The 5-year survival rate for lung
cancer in all states is 8 percent for males and 12 percent for females.
(151): The difference in survivali rates between males and females can
be explained by sex-specific differences in histology or stage of the
disease.
Trends in Lung Cancer Mortality
In the United States there has been in the past few years a significant
reduction in the percent of males and females who smoke cigarettes.
As yet, there has not been a decline in the age-adjusted total mortality
rates for lung cancer. When the lung cancer mortality rates by age are
examined from~ 1950 through 1975, there is a continuining increase in
older age groups for both males and females: This is probably due to
the elevated, risk experienced by older persons who use nonfiltered,
high tar and nicotine cigarettes and who have d'one so for the majority
of their lives. However, for female cohorts born in 1950-54 and male
cohorts born in 1935-39 and 1940-44, the age-specific lung cancer
mortality rates are below those of previous cohorts. This probably
results from the reductions in cigarette consumption which have
occurredin these groups.
There has been a change in the epidemic of lung cancer in England
and Wales, as summarized by the International Union Against Cancer
(UICC) workshop on the biology of cancer (243):
In England' and Wales, lung cancer mortality stopped increasing in
men under the age of 50 years during the 1950's and more recently
has fallen in men under the age of 60 years. The death rate from
5-10
TABLE 15.-Lung cancer mortality ratios in ex-cigarette
smokers, by number of years stopped smoking
Yearss
stopped
smoking
Mortalityy
ratio
Still Smoking 15.8
1-4 16.0
5-9 5.9
10-14 52
15+ 2:0
Nonsmokers 1.0
SOURCEa DoII;,R. (47a)
The magnitude of the residual risk which ex-smokers experience is
determined by the cumulative exposure to cigarette smoke which the
individual experienced before he quit smoking. The risk at any point in
time would be determined by the maximum amount the individual
smoked, the years since stopping smoking, the age when smoking
began, degree of inhalation, and reasons for quitting smoking. The
lung cancer mortality experience : of ex-smokers is graphically present-
ed in Figure 3. The risk of developing lung cancer increases with age,
for bothi smokers and nonsmokers. The incidence in cigarette smokers
is much higher than in, nonsmokers. It can be seen that the lung cancer
mortality of ex-smokers is initially similar to that of smokers, but, with
the passage of time, the mortality risk moves progressively closer to
that of nonsmokers. It is interesting to note that',,exeept for the first 2
years after stopping smoking, there is a: continued increase in the risk
of develbping lung cancer among ex-smokers, although it is less thanthat of those who continue to
smoke. The slope of this line is less than~
that for nonsmokers, and so there is a convergence of these two curves.
Lung Cancer and Air Pollution
A number of studies have been conducted in which the relative
influence of cigarette smoking, urban residence, and air pollution in
the etiology of lung cancer is examined. Eight of the earlier studies
were reviewed in the 1971, Report of the Surgeon General (212). More
recent publications include: "Epidemiolbgical review ofl lung cancer in
man" by Higginson and Jenseni (75) and a report of a task group, "Air
Pollutioni and Cancer," edited by Cederlof, et al. (31). There have also
been studies by Doll (43), Weiss (229); Carnow (30)j and Kotin and Falk
(109).
Lung cancer is consistently more, common in urban than in rural
areas. There is only a small urban-rural lung cancer gradient for
nonsmokers. There is a much larger urban-rurall gradient.for smokers.
Cigarette consumptioni is generally greater ini urban areas, but it is
5-25
Y
N
cc
W
~
W
18
36
728
14 ~- 0 3
I 72
CASES
N:
CONTROLS
1
52
2
203'
4
1350
PRESENT 1-3: 4-6 7+ NON
SMOKER SMOKER'
FIGURE 7.-Relative risk of developing larynx cancer for female
ex-smokers, by years of smoking cessation
SOURCEd Wynder, E.L. (25s): ' 5. There is a substantial decrease in the, risk of d'eveloping cancer
of
the larynx with the long-term use of filter cigarettes (10 years or
more); compared', to t'he use of nonfilter cigarettes.
6. There is a gradual reduction in the risk of developing laryngeal
cancer after cessation of smoking. After approximately 10 years, the
risk of developing cancer of the larynx is similar to that of nonsmokers.
7. It has been reported that exposure to both asbestos and cigarette
smoking synergistically increases the likelihood of an individual
developing cancer of the larnyx.
5-38
(141) VETERANS' ADMINISTRATION COOPERATIVE UROLOGICAL RE
SEARCH GROUP. Treatment and survival of patients with cancer of the
prostate. Surgery, Gynecology and Obstetrics 124(5): 1011-1017, May 1967.
(142) VISMARA, L.A., VERA, Z~, FOERSTER, J.M., AMSTERDAM, E.A., MASON,
D.T. Identification of sudden death risk factors in acute and chronic coronary
artery disease. American Journal of Cardiology 39(6): 821-828, May 26, 1977.
(1/,3) VON AHIJ, B. Tobacco smoking the electrocardiogram, and angina pectoris.
Annals of the New York Academyof Sciences 90(1): 190-198, September, 1960.
(144) WAGNER, W.D., ST. CLAIR, R.W., CLARKSON, T.B. Angiochemical and
tissue cholesterol changes of Macaca fascicularis fed~ an atherogenic diet' for 3
years. Experimentalland'MolecularPathology 28(2): 140-153, April 1978.
(1I,5), WALD, N.J: Carbon monoxide as an aetiological agent, in arterial' disease-
Some human evidence. In: Wynder, E.L., Hoffmann, D.,,Gori, G:B. (Editors).
Proceedings of the Third World Conference on, Smoking and Health, New
York, June 2-5, 1975. Volume I. Modifying the Risk for the Smoker. U.S.
Department of Health, Education, and Welfare, Public Health Service,
National Institutes of HealthNational Cancer Institute, DHEW Publication
Nb.(NIH) 176-1221,1976, pp. 349-361.
(146) WALD, N.,, HOWARD, SJ, SMITH, P.G;, KJELDSEN; K. Association between
atherosclerotic diseases and carboxyhaemoglobin levels in tobacco smokers.
British Medical Journal 1: 761-765, March 31,1973.
:
(147) WANSTRUP, J., KJELDSEN, K., ASTRUP, P. Acceleration of spontaneous
intimal-subintimal changes in rabbit aorta by a prolonged, moderate carbon
monoxide exposure. Acta Pathologica et Microbiologica Scandinavica 75(3):
553-362,1969:
(148) WEBSTER, W.S., CLARKSON, T.B., LOFLAND, H'.B: Carbon monoxide-
aggravated atherosclerosis in the squirrel monkey. Experimental and Molecu,
lar Pathology 13: 36-50, 1970,
(149) WEINBLATT, E., FRANK, C.W:, SHAPIRO, S., SAGER, R.V. Prognostic
Scandinavia and some other Western European countries. In: Steinfeld, J.,.
Griffiths;,W., Ball, K., TaylorR.M. (Editors). Proceedings of the Third World
Conference on Smoking and Health, New York, June 2-5, 197& Volume II.
Health ~ Consequences, Education, Cessation i Activities and Social 1 Action. U.S.
Department of Health, Education, and Welfare, Public Health Service,
National, Institutes of Health, National Cancer Institute; DHEW Publicat'ion~
No. (NIH) 77-1413, 1977, pp. 171-177:
(155) WISSLER, R.W., VESSELINOVITCH, D., GETZ, G.S. Abnormalities of the
arterial wall and its metabolism, in atherogenesis. Progress in Cardiovascular
Diseases 18(5): 341-369 ,,March/Apri1 1976.
factors in angina pectoris-A prospective study. Journal of Chronic Diseases
21: 231-245; July1968.
(150), WEINBLATT, E., SHAPIRO, S., FRANK, C.W., SAGER, R.V. Prognosis of
men after first myocardial infarction: Mortality and first recurrence in
relation to selected parameters. American Journal of Public Health 58(8);'
1329-1347, August 1968,
(151) WEINROTH, L.A., HERZSTEIN, J. Relation of tobacco smoking to arterioscle-
rosis obliterans in, diabetes' mellitus. Journal of the American Medical
Association 131(3); 205-209, May 1946.
(152) WEISS, N.S: Cigarette smoking and arteriosclerosis obliterans: An epidemiolog-
ic approach. American Journal of Epidemiology 95(l): 17-25; 1972.
(15,Y) WESSLER, S., MING;, S.-C., GUREWICH, V., FREIMAN, D.G. A critical
evaluation of thromboangiitis obliterans. The case against Buerger's disease.
New England Journal of Medicine 262(23): 1150-1160, June 9,1960.
(154) WILHELMSEN, L. Recent studies on smoking and CVD epidemiology:
4-76
Thromboangiitis Obliterans (Buerger's Disease)
Buerger's disease is a relatively rare vascular disease that severely
affects the legs and sometimes affects the arms and other vessels. It is
usually present as a painful ischemic disease of progressive and
subacute type in young male adults. Pathologically, there is a focal
subacute inflammatory phase involving the artery, nerve, and vein
coursing in the limb. The vascular inflammation is accompanied by
arterial and venous thrombosis and' local obstruction to the circulation.
A migrating thrombophlebitis is often prominent. Lesions may heal
with vascular sclerosis and new lesions may appear at other sites. The
ultiinate : outcome is ischemic loss of the limb(s) and when the lesion
extends to other vessels, loss of life: While the disease has been
regarded as a fulminant form of atherosclerosis (153), the more
common view with stronger evidence is that it is a separate disease (87)
and a vasculitis. An infectious etiology (24) has been proposed, as has a
hypersensitivity cause (54). Risk factors such as hypercholesterolemia
or diabetes are not present and coronary heart disease occurs only very
late in the course of the disease.
Smoking has been noted clinically to be strongly associated with
Buerger's disease (68). Retrospective studies indicate that its occur-
rence among nonsmokers must be very rare. The lesions are compatible
with an angiitis of hypersensitive or immunologic pathogenesis.
Therefore, it has been speculated that hypersensitivity to tobacco
components may be the basis of thromboangiitis obliterans (54). The
evidence for this theory is suggestive but inadequate at present.
Adequate investigations will probably require the use of much purer
tobacco antigens than have been available in the past (19). There is
conceptual interest for the pathogenesis of atherosclerosis in such
investigations that extends beyond thromboangiitis itself since athero-
sclerotic lesions commonly show evidence of a slight inflammatory
component and since a form of coronary atherosclerosis bearing a
remarkable resemblance to advanced plaques in man has been
produced in~ fat-fed rabbits by immunologic means (93), and also
because a glycoprotein~ isolated from tobacco leaves has been shown to
activate Factor XII in samples of human plasma, resulting in the
generation of clotting activity, fibrinolytic activity, and kinin activity
(18).
Oral Contraceptives, Smoking, Myocardial Infarction, and
Subarachnoid Hemorrhage Among Women
Extensive population studies have determined that the risk of non-
fatal myocardial infarction among women during, child bearing ages is
increased by a factor of about two times by the use of estrogen-
containing oral contraceptives, and that it is increased to about 10
times the expected value when users also smoke (61, 81, 82, 102). A
recent study reports that oral contraceptive use increases the risk of
4-60
was started, and durationi of smoking. Whether the risk based' on the
previous smoking profile is high or low, there is a fairly rapid initial
decline!in risk following cessation of smoking which occurs over a 2- to
3- year period. It takes from 10 to 15 years, however, untili the risk of
developing lung cancer approaches the risk of nonsmokers.
7: Pipe and cigar smokers have lung cancer mortality rates which are
higher than those of nonsmokers but which are considerable lower
than those of cigarette smokers (see conclusions ini the Chapter on
Other Forms of Tobacco U5e for further refinements and qualifica-
tions concerning pipe and cigar smoking).
8. Air pollution may be associated with the development of lung
cancer; however, detailed epidemiological surveys indicate that the
influence of air pollution on the development of lung cancer is small
compared, to the overriding effect of cigarette smoking. It is probable
that there is a synergistic effect betweeni cigarette smoking and air
pollution in causing lung cancer. Air pollution does not appreciably
influence lung cancer mortality rates in nonsmokers.
9. Certain occupational exposures, particularly uranium mining and
working, with asbestos, act synergistically with cigarette smoking,
resulting in lung cancer mortalityrat'es which exceed by several times
the lung cancer mortality rates of unexposed cigarette smokers. Lung
cancer mortality in these situations can be attributed to both cigarette
smoking and the occupational exposure.
10. In the past few years,, progress has been made in the
development of animal models in which to study lung cancer. At the
present time!it is possible to reproduce in animals the major categories
of respiratory tumors observed in man using tobacco smoke, subfrac-
tions of tobacco tar or specific compounds found in cigarette smoke.
Cancer of the Larynx
Approximately 1 percent of alll deaths from cancer are from cancer of
the larynx. It is estimated that in 1978 there were 3,350 deaths from
cancer of the larynx, with 2,900 occurring in males and 4501occurring in
females. The National Center for Health Statistics reported 3,351
deaths from cancer of the larynx in~ 1976. There were 2,808 deaths in
males and 543 deaths in females (150). The most common histological
lesion is squamous, cell carcinoma~ Approximately 70 percent are
located in the glottis and 25 percent in the supraglottic region (132).
Laryngeal cancer is predominantly a disease of males, although the
incidence for females has increased somewhat over the past 20 years
(181, 238): A typical patient with cancer of the larynx would be a 60=
year-old male who was a heavy cigarette smoker and' also a moderate-
to-heavy alcohol drinker (132). The: 5-year survival rate is improving,
and is presently at approximately 60 percent for all stages in both
males and females.
5-32
0
Chloromethyl' Ethers
Epidemiological and experimental studies (59, 114) have identified
chlbromethyl ethers as potent carcinogens for the human and animal
respiratory tract. Investigations are in progress to more fully
characterize these relationships, but the closing of the plants producing
these substances makes it unlikely that the relative contribution of
cigarette smoking to this t'ype of occupational lung,cancer will ever be
known.
Animal Studies
Experimental animal' mod'els have been develope& in which to study
tobacco-induced~ carcinogenesis. Over the past 30 years, this field has
acquired considerable sophistication and has enhanced our understand-
ing of carcinogenesis in humans.
Experimental careinogenesis has advanced to the point where it iss
now possible to reproduce in animals the major categories of
respiratory tumors observed in humans and to link the induction of
certain types of respiratory tumors to definite categories of exposure
(176). By intratracheal administration of polynuclear hydrocarbons in
rats and hamsters, bronchogenic squamous cell carcinoma is induced.
Certain systemic carcinogens, particularly diethylnitrosamine in
hamsters, give rise to adenomatous tumors of bronchial and bronchiolar-
alveolar origin, as well as to papillary tumors in the trachea. Of the
main types of respiratory tumors seen in human pathology, only one,
the oat celt carcinoma, has not yet been found to be reproducible in
experimental animals (176).
Skin Painting and Subcutaneous Injecticrns
The earliest animal models for studying tobacco carcinogenesis
involved the.single or repeated painting of shaved or unshaved animal
skin with solutions containing whole tobacco tar, various tobacco
condensate subfractions, or single chemical compounds known to be
present in tobacco smoke (161). Subcutaneous injections of various
substances or fractions found in tobacco were also used as experimen-
tal models. Considerable criticism was directed towards these: early
studies, but they effectively demonstrated that a variety of carcino-
genic compounds were found in tobacco smoke and that tobacco tar
was a potent carcinogenic substance. Early experiments of these types
have been reviewed by Wynder and Hoffmann (245).
Tracheobronchial' Implantation and Instillation
More complex experiments have been performed using, direct implan*
tation, instillation, or fixation of suspected mat'erials in the trachea-
bronchial tree of animals. Several authors have reviewed these studies
(1'15 143, 175, 176, 245).
.
5-29
Phagocytosis
Another factor which may be important is phagocytosis by macro-
phages, Some macrophages with engulfed' particles remain in the lung
for an extended period of time. A recent study by Palmer, et al. (162))
showed that macrophages metabolized the potent carcinogen ?',12-
dfinethylbenz(a)anthracene (DMBA) and released the majority of the
resultant derivatives into the surrounding medium. Unlike macro-
phages, cells from lung and! tracheal tissues tended to retain the
DMBA metabolites that they produced. This and related work by
Harris, et al. (69a) showe& that the human pulmonary macrophages
under some conditions in vitro may permit the accumulation of
metabolic products of carcinogens.
Conclusions
11. Cigarette smoking is the major cause of lung cancer in both men
and! women. This fact has been supported by prospective and
retrospective epidemiological studies, clinical studies, autopsy studies,
and experimental studies in animals. This conclusion is based on a
weight of evidence which exceeds by several times the evidence
available when this same conclusion was first reached in 1964.
2. The past 15 years have brought little significant progress in the
earlier diagnosis or treatment of lung cancer. Taken as a whole, 30
percent of lung cancer patients live 1 year, and only 10 percent live 5
years after diagnosis. Fbrtunat'ely, lung cancer is largely a: preventable
disease. Significant reductions in the number of deaths from lung
cancer can be achieved if a significant portion of the smoking
population can be persuaded to stop smoking and if a reduction can be
brought about in~ the number of young people who take up smoking.
3. Lung, cancer mortality is increasing in women and is increasing
more rapidly than any other cause of death. If present trends continue,
lung cancer will be the leading cause of cancer death among women in
the next decade.
4. There are dose-response relationships for developing lung cancer
with the number of cigarettes smoked'! per day, the duration of
smoking, the: age of starting, to smoke, degree: of inhalation, tar and
nicotine content of cigarettes, and several other measures of dosage:.
5: The long-term use (10 years or more) of filter cigarettes is
associated with lower death rates from lung cancer than those
experienced by persons who smoke an equal' number of nonfilter
cigarettes..
6. Ek-cigarette smokers experience decreasing lung cancer mortality
rates, relative to continuing cigarette smokers. The risk of developing,
lung cancer for ex-smokers depends on the type of smoker he or she
used to be. The risk is proportional to the number of cigarettes
previously smoked per day, degree of inhalation, the age when smoking
5-31
TABLE 11.-Lung cancer mortality ratios for females, by number
of cigarettes smoked per day: A.C.S. 25-State Study
Cigarettes
smoked1
per day
SOLPRCE: Hammond, E.C. (65)
Mortality
ratios
TABLE 12.-Lung cancer mortality ratios for females, by number
of cigarettes smoked per day: Haenszel and Taeuber
Cigarettes
smoked
per day
SOURCE: Hsenszel W: (64).
Mortality
ratios
TABLE 13.-Lung cancer mortality ratios for females, by
duration of smoking: Swedish Study
Duration of
smoking in
years
SOURCE: Cederlof, R. (9Y)
Mortality ratios
TABLE 14.-Lung cancer mortality ratios for females, by degree
of inhalation: A.C.S. 25-State Study
Degree
of
inhalation
Mortali ty ratios
Nonsmokers 11(!0
None to slight 1.78
Moderate to deep 3.70
the
ial
~I to
of
i
ue
rer
on
",a-
TABLE 16.-Mortality ratios for cancer of the larynx-
prospectiive studies
Number Mortality ratio
Study Population size of
deaths Nonsmokers Smokers
A.G.5..9-
State Study(68), 188,000 males 24 -
British
doctors(47a)
34,000 males
38
1A0
13J00
U1S. veterans(90): 239,000 males 54 1.00 9.95'
A.C.S. 25- 440;000 males 57' 1.00! 6.09-males,
State Study(65), 8.99-males,
California males
in 9 occupations
68,000 males
11
-
-
(228)
Japanese
study(77a,80)',
122;2Q0 males
38
1.00
11.83
142,800, females 6 1_0Q, 9.00
Comments
Allllarynx
cancer deaths
occurred in
smokers
Includes
cancer of
larynx and
other upper
respiratory
sitea.
ages 45-64
ages 65-79
All larynx
cancer deaths
occurred l in
smokers
Epiderniological Studies
Many epidemiological studies have investigated' the relationship
between smoking habits an& cancer of the larynx. The major
prospective studies are outlined in Tabl e 16. In these studies, cigarette
smokers had a mortality ratio which was 6 to 13 times greater than
that of nonsmokers. In three of the prospective studies, mortality
ratios could not be calculated because all of the deaths from cancer of
the larynx occurred in cigarette smokers.
Recent retrospective studies confirm prior evidence of a strong
positive association between cancer of the larynx and cigarette
smoking (56, 238; 252; 258). Wynder, et al. (238) found that thelarge,
.
sex difference has diminished somewhat over the past 20 years. This is
most likely due to the increase in femalc cigarette smokers in age
groups for which laryngeal cancer rates are high. The relative risk for
developing laryngeall cancer for male cigarette smokers was 15.8; for
female cigarette smokers it was 9.0. There was also a strong dose+
response relationship in the relative risk of laryngeal cancer with both
5-33
40
35
30
25
20
15
10
5
NON
F
SMOKER 1-10
F NF
11-20
F NF
21-30
F NF
31-40
F NF
41+
FIGURE 4.-Relative risk of developing larynx cancer for males, by
number of cigarettes smoked per day and use of filter (F) and
nonfilter (NF) cigarettes
SOURCE: Wynder, E.ll. (253)
in cigarette smoke. This is accomplished by the intratracheal instilla-
tion of benzo(a)pyrene in combination with particulate dusts into
hamster lungs. In this animal model, laryngeal tumors, as well as
tumors in other parts of the respiratory tract, are induced (1/3, 176,
177):
however, by the direct application of carcinogens known to be present
5-35
15 years there has been little change in the incidence of large-cell,
bronchiolo-alveolar, and mixed and undifferentiated carcinomas. There
has been an increase in adenocarcinoma and a decrease in squamous
cell carcinomas.
In 1962, Kreyberg (111a) categorized epidermoid, small-cell, and
large-cell carcinoma of the lung as Group I and adenocarcinoma and
bronchiolo-alveolar carcinoma as Group II. He noted that the risk for
smokers was substantially greater for Group I than for Group II
year period. They found, that well-differenbiated squamous cell'
221). Other investigators have disputed this classification (9, 14, 15, 100,
230; 254).
Weiss, et al. (230) foll'owed the experience of 6,136 men over a 10-
tumors. This view has been supported by some investigators (40, 47,
men~ who had had lung cancer. In this study all cell types seemed to be
related to smoking to about the same degree.
Most recently, Vincent, et al. (221) reviewed the histopathology of
lung cancer in patients seen over a 13-year period at the Roswell, Park
Memorial Institute. Their data indicated that adenocarcinoma is
becoming progressively more prevalent, compared to other forms of
lung cancer. They were unable to disassociate smoking as a causative
factor in any of the presently defined pathological categories of lung
cancer.
carcinoma, small~-ce11 carcinoma, and adenocarcinoma displayed a dose-
response relationship to smoking, but poor-differentiated squamous
cell carcinoma did not.
More recently, Auerbach, et al. (10) examined histologic types of
lung cancer associated with smoking habits from autopsy data on 662
Cessation of Smoking
There is a: decrease in the risk of developing lung cancer after cessation
of smoking, This decrease in risk occurs over a period of several years.
After 10 to 15 years, the risk of dying of lung cancer for ex-smokers
has decreased to point where it is only slightly above the risk for
nonsmokers. All of the major studies show this reduction in risk. The
most recent data from the British Doctor's Study are presented here
for illustration (Table 15). The mortality ratios for ex-smokers w6re
higher in the first year after quitting than~ they were for continuing
smokers. The explanation for this is that both healthy and sick
individuals quit smoking. Higher mortality is experienced by those who
quit because of illness: Lower mortality is experienced~ by those who
quit while experiencing apparently good health. In the U.S. Veterans
Study, a differentiation is made between ex-smokers who stopped
smoking on the recommendation of a doctor and those who quit for
other reasons. About 10 percent of the smokers quit because of doctors'
orders and were presumabl{y ill. This group had much higher death
rates from lung cancer than those who stoppe6 for other reasons.
5-24
e
i
ar
nt
Ci
TABLE 3.-Lung cancer mortality ratios for males, by age began
smoking, from selected prospective studies
Age began
smo king
in years
Mortality
ratio
A.C.S. 25-
State Study(65)
Nonsmoker
1100
25+ 4':O8
20-24 10.08
15-19 19:69
under 15 16:77
Japanese
study(78)
Nonsmoker
1.00'
25+ 287
Z(-24 3.85
under 20 4.44
U.S. Nonsmoker 1100
veterans(90) 25+ 5.20
2D-21'. 9:50
15-19 14.40
under 15 18:700
after the age of 25 have mortality ratios which are only 4 to 5 times
greater than those of nonsmokers.
Inhalation of Cigarette Smoke
Inhalation of tobacco smoke is an important dosage variable. Inhala-
tion of smoke well into the lungs is the major mechanism whereby lung
tissue is exposed to the carcinogens which ultimately produce' lung
cancer. Techniqques for quantitating the degree of tobacco smoke
inhalation have been developed using carboxyhemoglobin levels or end
expiratory carbon monoxide levels as' an index of smoke inhalation.
These objective methods of measuring inhalation have not been
applied to studies of lung cancer mortality. In most investigations, the
smoker was asked to report subjectively on his own inhalation
practices. This is subject to considerable variation but is not as
inaccurate as might be presumed. Available data show a strong dose-
response relationship between self-reported inhalation of cigarettee
smoke and lung cancer mortality. Representative figures from selected
prospective studies are presented in Table 4. These data suggest that
cigarette smokers may underestimate the degree to which they inhale
cigarette smoke. Those who report that they do not inhale cigarette
smoke experience lung cancer mortality ratios which are 4 to 8 times
greater than for nonsmokers. Deep inhalation results in mortality
ratios which are as high as' 17 times greater than for nonsmokers.
5-14
TJ
a.i
~u
Sv
m;
TABLE 1.-Lung cancer mortality ratios-prospective studies
Population Size Number
of deaths Nonsmokers Cigarette
smokers
British
doctors(47a)
34;000 males
441
1.00
14.0
Swedish 27;000 malP.s 55 1.00 82
study(32) 28,000 females 8 1100 4.5
Japanese 122,000 males 590 1.00 3.76
study(77a;78) 143,000 females 148' 1.00 2.03
A.C.S. 25- 440,000 males 1,159' 1.00 9.20
State Study(65) 562,000' females 183 1.00' 220
U.S. veterans(90) 239;0001 males 1,256 1.00 12:14'
Canadian
veterans(20),
78,000 males
331
1100
14.2
A.C.:S. 9=
State Study(68),
188,000 males
448'
1.00
10.73
California males
in 9 occupa-
tions(228)
68,Q00 males
368
1.00
7:61
Dose-Response Relationships
An important factor ini the causal relationship between smoking and
lung cancer is the demonstrationi of dose-response relationships. In
most epidemiological~st'udies, dosage has been measured by the number
of cigarettes smoked per day at the time of entry into t'he study. Other
dose variables which have beeni examined include the maximum
number of cigarettes smoked per day, the age an individual began
smoking, the degree of inhalation of tobacco smoke, the total number
of years an individual has smoked, the 'totali lifetime number of
cigarettes smoked, tar and nicotine levels of the brand of cigarettes's
used, the number of puffs per cigarette, the length of the unburned
portion of the cigarette and combinations of these variables into
"dosage" scores. All of these variablres have been shown in one study or
another to contribute to the risk of developing lung cancer. Only a few
representative! samples of dosage variables as related to hing, cancer
mortality are examined in this section.
Number of Cigarettes Sm.oked Per Day
The risk of developing lung cancer increases with the' number of
cigarettes smoked per day. In~t'he U.S. and British populEations, the risk
of developing lung cancer for individuals smoking more than~two packs
5-12
©
:f.
TABLE 2.-Lung cancer mortality ratios for males, by current
V
number of cigarettes smoked per day, from selected
prospective studies 0
Cigarettes
smoked
per day,
Mortality
ratio
A:C.S. 25-
state study(65)
Nonsmoker
1.00
1-9 4.62
10-19 8,82
20-39 14.69
40 + 18.77
British
doctoss(/,7a)
Nonsmoker
P.00
1-14 7.80
15-24 12.70.
25 + 25.10
Swedish males(3.2) Nonsmoker 1.00
1-7 230 ,
8-18 8.80
16+ 18.90
Japanese males(78)', Nonsmoker 1.00
1-9 1.90,
10 -1+1 3.52
15-24 4:11,
25-49 4:57
50+ 5.78
a day is approximately 20 times that of nonsmokers (47a, 65, 68, 80,
228): Data for Swedish males are of the same magnitude (32). Japanese
males who smoke 50 or more:cigarettes a day experience a risk which is
5,8 times greater than for nonsmokers. Hirayama noted that the slope
of the dose-response curve for lung cancer was less in Japan than in
the United States and that this was probably due to the lower
percentage of regular deep inhalers, a lower level of environmental
promoting conditions, and also a higher percentage of adenocarcinoma
in, Japan than in the United States (78). Table 2 presents lung cancer
mortality ratios from selected prospective studies for males by the
current number of cigarettes smoked per day.
Age at which Smoking Began
Lung cancer mortality ratios exhibit an inverse relationship-with the
age of initiation of the smoking habit. Lung cancer mortality ratios for
males by age at whi& they began smoking are presented in Table 3.
Most cigarette smokers began the habit while in high school and' are at
the greatest risk of developing lung cancer. Those who began smoking
5-13
III
R
0
TABLE 21.-Kidney cancer mortality ratios, by amount smoked:
U.S. Veterans Study ~
Cigarettes
smoked
per day
Mortality
ratios
Number of
deaths
Nonsmokers 1.00 39 ,
1-9 0.97 4
10-19 1.34 21
2i> 38 1.68 16
40+ 275 5
All cigarette smokers 1.45 46
SOURCE: Kahn,,H.A~. (90):
Earlier retrospective reports of the associatiom of renal adenocar6-
noma with smoking reported a relative risk ratio of about 5.0 for
cigarette smokers compared to nonsmokers (16, 17). They did'find a
positive association between cigarette smoking and cancer of the renal
pelvis, as had Schmauz and Cole (180). Wynder, et al. (248) reported a
moderate but significant association between cigarette smoking and
renal ad'enocarcinoma for both males and females: There were positive
dose-response relationships with the number of cigarettes smoked' per
day. The results of these studies are: summarized in~ Table 20. A dose-
response relationship with the number of cigarettes smoked per day
was also found in the study of UIS, veterans (Table 21).
Conclusions.
1. Epidemiological studies demonstrate a significant association
between cigarette smoking an& cancer of the urinary bladder im both
men and women. Supporting evidence from other disciplines supports
the conclusion that cigarette smoking is one of the causes of cancer of
the urinary bladder.
2. Epidemiologic studies show a positive dose-response relationship
for developing bladder cancer with increases in the number of
cigarettes smoked per day.
3. Cigarette smoking acts independently as a cause of bladder cancer
and'probably acts synergistically with other risk factors for bladder
cancer, such as occupational exposure.to certain aromatic amines:
4. Epidemiological studies have demonstrated an association of
cigarette smoking, with~cancer of the kidney among men. There is some!
evidence of a dose-response relationship with the number of cigarettes
smoked per day in the.development of kidney cancer.
5-49
C
C~
T
~
Ul ~
CD
N
O
ts
F,
md in
~ and
unted
:o and
same
iret'te
.er on
poor
l and
ction
I
between alcohol and tobacco in the development of oral cancer are the
studies of Rothman and Keller (170); Feldmany et al. (58), Graham, et
al. (6.2); Browne, et al': (28) and' the Third National Cancer Survey
(233). In the latter survey, cancer of the oral cavity was associate&
significantly with both cigarettes and alcoholi The relative strength of
each exposure aft'er controlling for the other was evaluated by
multiple regression~ analysis. For cancer of the pharynx, the standard-
ized regression slope (based on standard deviation units) in males, after
controlling for age, race, education, and~cigarettes or alcohol, was 0.104
for alcohol and 0:084 for cigarettes. For cancer of the oral cavity and
gums, the values were: alcoho10.081 and cigarettes 0:018: For cancer of
the lip and tongue, the values were: alcohol 0.057 and cigarettes 0.043.
Hence, in this survey, oral cancer in males was somewhat more related
to drinking than to smoking.
Rothman and Keller (170) also reported a strong synergy between
the two exposures. They attributed 76 percent of oral cancer in males
to the interaction of tobacco and alcohol. Feldman, et al. (58) found
that nonsmoking alcohol' users had only a slightly increased risk for
head and' neck cancer, whereas smokers who did not use alcohol still
had two to four times the risk of abstainers from alcohol and tobacco.
The risk for the heavy drinker who smokes; however, was from 6 to 15
times greater than for the individ'ual who did! not use tobacco or
alcohol. In the study of Graham, et al. (~62), the relative risk for heavy
smoking alone was only 1.54; for heavy drinking alone it was 1.70:.
Heavy smoking and heavy drinking resulted in a relative risk of 2.49..
When this was combined with~ inadequate dentition, the risk rose to
7.68. Browne, et al. (28): reported that alcohol and tobacco use wass
particularly prevalent among patients with oral squamous cell
carcinoma.
Leukoplakia
Leukoplakia of the orall mucosa represents an abnormal thickening and
keratinization of the oral mucosa. Leukoplakia is generally recognized
as & precursor of malignancy in the oral' cavity and is associate6 with
tobacco use in various forms. The largest survey of leukoplakia in a
Western population has been conducted by Banoczy and associates (13,
168, 199). Leukoplakia is quite common in India where tobacco and
betel~nut chewing occurs and where bidis are smoked. The prevalence
and incidence of leukoplakia has been reviewed in several large studies
(21, 130;,137; 192).
Animal Studies
An ideal animal model in which to study oral carcinogenesis has not
been found. Cigarette smoke.and cigarette-smoke condensates general-
ly fail! to produce malignancies when applied' to the oral cavity of mice,,
rabbits, or hamst'ers. Mechanicali factors, such as secretion, of saliva,
5-41
interfere with the retention of carcinogenic agents. The only positive
results with carcinogens have been obtained with benza(a)pyrene, 20-
methyl-cholanthrene, and 9,10-dimetyl-1,2 benzanthracene applied to
oral mucosa. These studies have been reviewed in previous reports of
the Ui.S, Public Health Service (212, 217).
salivary gland, and its structure and function differ from those of the
the cheek pouch of hamsters. The cheek pouch, however, lacks the
resulting from~the use of either substance alone.
and tobacco results in a higher risk of developing cancer than that
and the development of cancer of the oral cavity: The use of alcohol
3. There is a synergism between cigarette smoking and alcohol usee
the development of cancer of the orali cavity. The risk of using these
forms is of the same general magnitude as that of using cigarettes.
2. The use of pipes, cigars, and chewing tobacco is associated with
have been described.
response relationships with the number of cigarettes smoked per day
causal factor in the development of cancer of the oral cavity. Dose-
1. Epidemiological studies indicate that smoking is a significant
Conclusions
months after diagnosis (152).
the esophagus (3). The prognosis is extremely poor with a 5-year
survival rate of only 3 percent; the median survival time is less than 6
for whites (39): Epidermoid carcinoma is the most common cancer of
mortality in the United States are substantially higher for blacks than
esophagus in 1978 (4). In addition, esophageal cancer incidence and
The National Center for Health Statistics reported that there were
7,224 deaths from cancer of the esophagus in 1976. There were 5,343
deaths in males and 1,881 deaths in females (150), It has been
estimated that these figures rose to 7,100 deaths from cancer of the
Cancer of the Esophagus
studies range from 1.3 to 11.1, compared to nonsmoking controls (24:,
A number of retrospective studies have been published concerning
smoking and esophageal cancer. Risk ratios for smokers in these
smoked per day is shown. Available evidence indicates a similar
relationship for men~and women.
positive dose-response relationship for the number of cigarettes
These relationships are shown in Table 18. In several of these studies a
mortality ratios for male cigarette smokers range from 1.82 to 8,'75.
a significant relationship between smoking and esophageal cancer. The
Data; from the major prospective epidemiological studies demonstrate
Epidemiological Studies
105, 133, 174, 178, 186, 194 204; 235, 24'6):
5-42
Multi-Stage Model of Carcinogenesis
One unifying hypothesis is the multi-stage model of carcinogenesis.
This model has been proposed in various forms by several scientist's and
has recently been given attention by Armitage (6), Doll (42), and Peto
(165). In the multi-stage model, carcinogenesis is considered a diseasee
of interact'ions.
The transformation of a: normal cell to a malignant one would
require two or more separate stages, each with a characteristicc
probability of occurrence determined by one or more of the carcinogens
present. The initiation~ and~ development of cancer would thus be a
multi-stage, multi-causal process, in which both externall and internal
factors act in a sequence of several steps before the cancer would
appear clinically. The multi-stage conceptt of carcinogenesis offers a
plausible explanation for some of the peculiarities of the induction of
lung cancer (such as the multiplicative effect of asbestos on cigarette
smokers and the changing risks of ex-smokers). It is likely that
development of cancer in each organ or tissue requires a different set
of factors to induce malignant changes. It should not be surprising that
cigarette smoking can induce malignant changes in as many organ
systems as it does: Evidently, among the 2,000 chemical compounds
found in cigarette smoke, there are sufficient careinogens; tumor
initiators, co-careinogens; and tumor promoters to induce cancer in
multiple-organ systems. Certainly, over the long time period in~ which
the smoker is exposed to the products of tobacco combustion, there is
sufficient time to satisfy the most complex multi-phased or multi-
causall process. Given this model, it is not surprising that tobacco
carcinogenesis is additionally influenced by a number of environmental
factors (76): This would explain the synergism for lung cancer observed
in cigarette smokers in various occupations, such as asbestos workers
and uranium miners.
5-58
8
Case
PJ=
COntf01
Y Con
1.
[r
~
31
gat
~.
m
11; e 611
smc
~ 2a 2
1141
% resl
reh
gre
%
Me
_ll Sm
1 1-20 21-40 41+ Cig
Ciyarettes per Day
int,thr
cor
FIGURE 8.-Relative risk of pancreatic cancer in males, by number 2,0
of cigarettes smoked wh
SOURCE: Wynd~r, E.L. (248)',
col
cal
cor
TABLE 23.-Mortality ratios for cancer of the pancreas among
col
Swedish subjects
by sex and amount
aged 18-69
,
,
mE
smoked
a
p
Number of
sm
cigarettes Males Females
per day Sn
Nonsmokers 1.0 1.0 W
1-7 1.6 2.4
4 2:5
8-15 3
.
Ea
1b+ 5.9 10
All cigarette Cil
1 25
smkers 3
.
va
co
sti O
R: W
ments is not found in tobacco smoke, a number of other nitrosamine ch ~
compounds, such as dimethyll nitrosamine and methyliethylnitrosamine,. ic C11
~
Cancer of the Pancreas
The National Center for Health Statistics reported that there were
19;738 deaths from cancer of the pancreas among men and women in
the United States in 1976 (150). Deaths from cancer of the pancreas
were expected to exceed 20,000 in the United States during 1978 (4).
The incidence of cancer of the pancreas has increased threefold since
1930 (100, 111), and it now ranks fourth in frequency among fatal
neoplastic diseases (187):
The most common form of pancreatic cancer in humans is
adenocarcinoma, which originates from the epithelial duct cells of the
pancreas. Acinar and islet cell tumors are relatively rare. Because of an
extensive venous and lymphatic drainage system, metastases can occur
relatively early in the course of the disease, contributing to the poor 3-
year survival rate of 2 percent (152). Morgan and Wormsley (149) have
reported that most studies have shown a: mean survival time after
diagnosis of less than 6 months.
Pancreatic cancer is more common among men than women in the.
United States, but the male-to-female ratio has been decreasing
steadily from 1.6:1 during the period of 1940 to 1949 to 1.3:1 observed
from 1965 to 1969 (152).
Epidemiological Studies
Several prospective epid'emiologic investigations (20, 32, 65, 79, 80, 90,
228) have reported mortality ratios for cigarette smokers of approxi-
mately 2.0compared to nonsmokers. These data are presented in Table
22. Not all of these investigations demonstrate a dose -response
relationship with the number of cigarettes smoked per day; this is
probably due to the small number of deaths in each smoking category.
In~a retrospective case control study with 81 cases of cancer of the
pancreas, Wynder, et all (248) showed a definite dose-response
relationship with a relative risk of 5.0 for males smoking more than
two packs of cigarettes a: day. These data are presented in Figure 8.
The dose-response data from the Swedish study are presented in Table
23.
Pancreatic cancer mortality in the United States was examined by
cohort analysis for the period 1939 to 1969 by Bernarde and Weiss (16):
White men were found to be at greater risk of developing pancreatic
cancer than white women, and the same relationship existed for
nonwhites. With the passage of time, there was a shift of the cohort
mortality rate curve by age toward younger groups: These data appear
to be compatible with an hypothesis which relates environmental
factors to the: et!iology of pancreatic cancer. Air and water pollut'ion
ionizing radiation, and improved diagnosis are unlikely to explain the
observed differences; because these factors would be expected: to
influence both race and sexes more or less equally. Cigarette smoking,
T:k
r(
t'he number of cigarettes smoked per day and the duration of smoking.
A distinct synergism with combined alcohol and tobacco use was also
described', with a relative risk of 22,1 for the smoker of more than 35
cigarettes a day who was also a heavy drinker. This study also
examined the relative risks experienced by long-term filter cigarette
smokers. At every level of consumption, both males and' females who
smoked filter cigarettes had a lower risk than did nonfilter smokers.
Among men, the reduction, in risk ranged fromi 25 to 49 percent for
cancer of the larynx, and a substantial lowering of risk was also found
for women. For ex-smokers, the risk of developing, laryngeal cancer
diminished gradually with time in a curve that paralleled that for
cancer of the lung. The most rapid reduction in risk occurre& during
the first 5 years after cessation of smoking. After approximately 10:
years, the risk approached that of nonsmokers. Severall of these:
relationships are demonstrated in Figures 4 through 7.
Williams and Horm (233), using data from the Third National
Cancer Survey, reported a strong dose-response relationship for the
number of cigarettes smoked per d'ay and the risk of developing cancer
of the larynx. The relative risks for males, controlling for age and race,
were 2.9 for level-one smokers, 3.3 for level-two smokers, and 17.7 for
levelAhree smokers (the levels for cigarette-smoke exposure were
established by using both the amount and the duration of cigarette
use). Considering tobacco use at eaeh level of alcohol consumption, the
risk of developing cancer of the larynx increased as tobacco exposure
increased'. There was a positive association for the intake of alcoholic
beverages and the development of cancer of the larynx. In previous
reports of the U.S. Public Healt4 Service (212, 217); most of the older
retrospective epidemiological studies have been reviewed (22, 56, 172,
174, 184, 185, 193, 196,, 203; 205, 218, 237, 24'6, 250): ~
Asbestos
Severali authors have found an association between asbestos exposure
and cigarette smoking with development of laryngeal carcinoma (28,
121;148, 190, 197).
Animal Studies
The Syrian golden hamster has been found to be a suitable species for
the investigation~of cancer of the larynx. The distribution of malignant
lesions in the upper airway of the hamster is not due to an unusual
susceptibility of the larynx for tumor induction~but rather reflects thee
distribution of smoke aerosol precipitation within the upper respira-
tory tract. The most recent experimental studiesare those of Bernfeid,,
et a1. (18), Dontenwill, et al. (49, 50), Homburger (:86), and Karbe and
Koster (93); Cigarette smoke inhalation has not been found to induce
laryngeal tumors in other rodents. Such tumors have been induced,
5-34
(J,6) FROST, H. Investigations into the pathogenesis of arteriosclerosis: drug'
prophylaxis. In: Shimamoto, T., Numano, F., Addison, G.M., (Editors); l
Atherogenesis, Volume II. Proceedings of the Second International S ~
YmPo-' :
sium on Atherogenesis, Thrombogenesis an& Pyridinolcarbamate Treatment,"
Tokyo, May 18-20,1972: Amsterdam,,Excerpta Medica,1973, pp. 32-50. .~
(I,7)GARRISONR:J., KANNEL, W.B., FEINLEIB, M., CASTELLIW.P., MCNA-'',
MARA, P.M., PADGETT, S.J. Cigarette smoking and HDL cholesterol. The
Framingham Offspring8tudy. Atherosclerosis 30: 17-25,1978. ~
(48) GOLDBOURT, U., MEDALIE, J.H. Characteristics of smokers;,nonsmokers and
ex-smokers among 10,000 adult males in Israel. II. Physiologic, biochemical
and genetic characteristics. American Journal' of Epidemiology 105(1); 75-86,
1977.
(49) GORDON, T., CASTELLI, W.P., HJORTLAND, M.C., KANNEL, W.B:,
DAWBER, T.R. High density lipoprotein as a protective factor against
coronary heart disease. The Framingham study. American Jburnal of Medicine
62: 707-714, May 1977.
(50) GORDON, T., KANNEL, W.B., MCGEE; D.,, DAWBER, T.R. Death and
coronary attacks in memafter giving up cigarette smoking. A report from the
Framingham study. Lancet' 2: 1345-1348, December 7;1974'. +
(51) GRAHAM, I., MULCAHY, R.,, HICKEY, N'., SYNNOTT, M. Mode of death
related to smoking in patients with coronary heart disease. Journal of the Irish
Medical Association 70(7): 234-235, May 14,1977.
(54') GREENSPAN, K., EDMANDS, R.E., KNOEBEL, S.B., FISCH, C. Some effects
of nicotine on cardiac automaticity, conduction, and inotrophy. Archives of
Internal Medicine 123(6): 707-712, June 1969.
(53) HAMMOND, E.C., GARFINKEL, L., SEIDMAN, H., LEW, E.A. "Tar" and
nicotine content of cigarette smoke in relation to death rates. Environmental
Research 12(3): 263-274, December 1976.
(54) HARKAVY, J. Tobacco allergy in~cardiovascular disease: A review. Annals of,
Allergy 26(8): 447459, August 1968:
(55) HAUST, M.D.,, MORE, R.H. Spontaneous lesions of the aorta in the rabbit. In:
Roberts, J.C., Jr., Straus, R. (Editors): Comparative Atherosclerosis. The
Morphology of Spontaneous and Induced Atherosclerotic Lesions in Animals
and'Its Relation to Human Disease. New York, Harper and Row, 1965pp: 255-
275.
(56), HAWKINS;,L.H. Blood carbon monoxide levels as a function of daily cigarette
consumption and physical activity. British Journali of Industrial Medicine
33(2): 123-125, May 1976.
(57) HAYES, M.J., MORRIS, G.K., HAMPTON, J.R. Lack of effect of bed rest and
cigarette smoking on development of deep venous thrombosis after myocardial
infarction. British Heart'Journa138(9) 981-983, September 1976.
(58) HOLLANDER, W., PRUSTY, S., KIRKPATRICK, B., PADDOCK, J. NAGRAJ,
S. Role of hypertension in ischemic heart disease and cerebralivascular disease
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(59) HULLEY, S.B.,,COHEN, R.,,WIDDOWSON, G. Plasma high-density lipoprotein,
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function after cigarette smoking by chronic smokers: Comparison of normal
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October 1, 1976.
,
4-70
0
and females smoke cigarettes: A recent survey (155) of cigarette
smoking behavior shows that women do not smoke as far down on~ the
cigarette where proportionally more nicotine and tar are inhaled. More
than 91 percent of females use filter cigarettes, compared with 80
percent of males. Females report that they do not inhale cigarette
smoke as d'eeply into their lungs as males do. Women also smoke fewer
cigarettes per day and select brands of cigarettes with lower tar and
nicotine yields, compared to men. In 1975, 76.7 percent of current
female smokers smoked a pack or less per day, whereas this was true
for only 63.6 percent of males (155). In the past, women began smoking
later than men, but at the present time this is no longer true. The
available evidence suggests that women who smoke cigarettes in the
same amount and with~ equal depth of inhalation as men are likely to
experience death rates similar to those found in men.
Twins
The best way to control genetic factors as a potentially complicating
variable in studies of lung cancer and cigarette smoking is to conduct
the investigation in a population of twins who are discordant as to
smoking habits (one smokes, the other does not): Cederlof, et al. ('33)
published new data on smoking and lung cancer from the Swedish
Twin~ Registries in 1977. Although~ the number of deaths from lung
cancer among the monozygotic twins is quite low, the trend is clear.
The authors state, "The well-documented evidence of a causal
association between smoking and lung cancer found in other studies
has been further supported."'
Lung Cancer and the Use of Other Forms of Tobacco
Pipe and cigar smokers in the United States have experienced lung
cancer mortality rates that are somewhat higher than those of
nonsmokers but substantially lower than those of cigarette smokers
(1). Most pipe and cigar smokers report that they do not inhale the
smoke, and as a consequenee the total~ exposure is relatively low. There
is little evidence that lung cancer is associated with the use of chewing
tobacco or snuff. These relationships are explored in detail in the
Chapter on Other Forms of Tobacco Use (specifically in Tables 15, 16,
17 and 22 of that chapt'er):
Histology of Lung Cancer
There are several different histolbgic types of lung malignancies in~
humans. These include: squamous cell carcinoma, adenocarcinoma,
small cell carcinoma, large cell carcinoma, bronchiolo-alveolar, and
mixed and undifferentiated carcinomas of the lung. The predominent
type of carcinoma in males is squamous cell carcinoma, whereas the
most common~ lung cancer in females is adenocarcinoma. Over the past
5-23
I
p
I
TABLE 22.-Pancreatic cancer mortality ratios-
prospective st'udies.
Study'
population Size of
population
Nonsmokers All ~ cigarette
smokers
Canadian
veterans,
78,000
(10), males 1.00 1.96
A.C.S. 25-
State
Study
440;000'
(65)i males 1.00 2.69.
U.S.
veterans
239
000
(00) ,
.
males
1.00:
1.84
Japanese 122,000
study males 1.00 1.41 males
(17a,80) , 143,000
females 1.00 1.94 females
California
occupations
63,000
(228) males 100 2.43
Swedish, 55,000
study males and 1.00 3.1' males
(s3) females 1.00 2:5 females,
high risk occupations, and dietary practices are more likely to explain
these differences: Cigarette smoking is an exposure which is closely
related to cohort and sex difference.
Other Risk Factors
There is epidemiologic evid'ence which~ links pancreatic cancer with
increased dietary fat and protein intake (80, 228). An increased
incidence of pancreatic cancer has been observed in chemists and
indhstrial workers exposed' to beta naphthylamine (131). A survey of
d'eath certificates of member chemists of the American Chemical
Society indicates an increased relative frequency of pancreatic cancer
('1;24). However, specific chemical exposures could not be traced.
Animal Studies
There: are relatively limited numbers of experimental laboratory
studies concerning cigarette smoking and cancer of the pancreas. Pour,
et ali (!112, 166), using a nitrosamine compound, induced pancreatic
neoplasms in hamsters which were histologically similar to those in
humans. Although the particular nitrosamine used in these experi,
5-51
(78) LEVINE,' P.H. An acute effect of cigarette smoking on~ platelet function. A
possible link between smoking and arterialithrombosis. Circulation 48: 619-623o
September 1973.
(79) LIFSIC, A.M. Atherosclerosis in smokers. Bulletin of the World Health
Organization 53(5-6): 631-638,1976:
(80) MALINOW, M.R, MCLAUGHLIN, P., DHINDSA, D.S., METCALFE, J.,
OCHSNER, A.J., IIIHILL, J., MCNULTY, W.P. Failure of carbon monoxide
to induce myocardial infarction in cholesterol-fed cynomolgus monkeys
(Macaca fascicularis). Cardiovascular Reasearch 10: 101-108,1976.
(81) MANN, J.I., INMAN, W.H! W., THOROGOOD, M: Oral contraceptive use in
older women and fatal myocardial infarction. British Medical Journal 2: 445-
447, August 21',1976.
(82) MANN, J.I., VESSEY M.P., THOROGOOD, M., DOLL, R. Myocardial
infarction in young women with special reference to oral contraceptive
practice. British Medical 'Journal 2: 241-245; May 3, 1975.
(83) MARKS, P., EMERSON, P.A. Increased: incidence of'deep vein thrombosis after
myocardial infarction in nonsmokers. British Medical Journal 3(5925): 232-234,
July 27,1974.
(84) MCGILL, H.C., JR. Atherosclerosis: Problems in pathogenesis. In: Paoletti, R
Gotto A.M., Jr. (Editors). Atherosclerosis Reviews, Volume 2 New York,
Raven Press, 1977, pp. Z7-65
(85) MCGILL, H.C., JR., (Editor): General findings of~ the International Atheroscle-
rosis Project. Laboratory Investigation 18(5): 498-502, May 1968.
(86) MCGILL, H.C., JRROGERS, W:R:, WILBUR, R.L., JOHNSON, D.E. Cigarette
smoking baboon model: Demonstration, of feasibility (40119)j Proceedings of
the Society for Experimental Biology and Medicine 157: 672-676,1978.
(8z) MCKUSICK, J.A., HARRIS, W.S., OTTESEN, O.E., GOODMAN, RM.,
SHELLEY, W.M., BLOODWELL, R.D. Buerger's disease: A distinct clinical
and: pathologic entity. Journal'of the American Medical~Association 181(1): r
12, July 7, 1962.
(88)! MCMAHAN, C.A., RICHARDS, M.L., STRONG, J.P. Individual cigarette usage:
Self-reported data as a function of respondent-reported data. Atherosclerosis
23(3): 477-488, May/June 1976.
(89) MCMILLAN, G.C., Development of Arterioscleroais.The American Journal of
Cardiology 31: 542-546, May 1973.
(90) MCMILLAN, G.C. Evidence for components other than carbon monoxide an&
nicotine as etiological factors in cardiovascular disease. In: Wynder, E.L.,
Hoffmann, D., Gori+ G.B. (Editors): Proceedings of the Third Worl& Confer-
ence on Smoking and Health;,New York, June 2 5, 1975. Volume I. Modifying
the Risk for the Smoker. U.S: Department of Health, Education, and Welfare,
Public Health Service, National Institutes of Health, National Cancer
Institute, DHEW Publication No. (NIH) 76-1221, 1976, pp. 363-367.
(91) MEDALIEJ.H.,,SNYDER, M., GROEN, J.J., NEUFELD, H.N:, GOLDBOURT,
U., RISS, E. Angina pectoris among 10,000 men. 5 year incidence and
univariate analysis. American Journal of Medicine 55: 583-594, November
1973.
(92), MILLER, N:E., FORDE, O.H., THELLE, D.S., MJOS,,O.D. The Tromso Heart
Study. High-density lipoprotein and coronary heart disease: A prospective
case-control study. Lancet 1(8019): 965-968, May 7, 1977:
(98)MINICK, C.R., MURPHY, G.E. Experimental induction of atheroarteriosclero-
sis by the synergy of allergic injury to arteries and~lipid-rich diet. II. Effect of
a repeatedly injected foreign protein in rabbits fed a lipid-rich, cholesterol-
poor diet. American Journal of Pathology 73(2): 265-300, November 1973.
4-72
I
2. The risk of developing esophageal cancer with the use of other
forms of tobacco, such as pipe and cigar smoking, is about the same
order of magnitude as that for cigarette smokers.
3: Epidemiologica.l' studies also indicate a synergistic relationship
between the use of alcohol and tobacco and the development of cancer
of the esophagus:
4. Experimental studies show that chemical compounds found! in
cigarette smoke are capable of inducing carcinoma of the esophagus in
experimental animals. In some experimental models, esophageal
carcinogenesis is enhanced if the carcinogen is dissolved in a dilute
alcohol solution.
Cancer of the Urinary Bladder and Kidney
Bladder Cancer
Most cancers of the urinary bladder are transitional or squamous cell
carcinomas which appear either alone or in~ combination. Unless these
produce hematuria or obstruct the bladder outlet, they remain
undiagnosed until quite: late, making a cure unlikely. For patients
diagnosed with~ bladder cancer from 1960 to 1973, the 5-year survival
rate was approximately 60 percent for whites and 30 percent for
nonwhites (240): The average annual incidence for males is about three
times that for females, but this ratio may change as the larger
proportioni of women who are now smoking reach the age where
bladder cancer rates are high, (38):
The Nationali Center for Health Statistics reported that there were.
9,673 deaths fromi bladder cancer in, the United States in 1976. There:
were 6,759 deaths among males, and 2,914 deaths among females (150).
It is estimated that 9,900 people died of bladder cancer in 1978 (4).
Epidemiological Studies
Epidemiological data on the relationship between smoking and cancer
of the urinary bladder have been accumulating for well' over 20~ years.
Bladder cancer mortality ratios from the larger prospective epidemio-
logical studies are summarized in Table 19. On the average, cigarette
smokers are about twice as likely to die from cancer of the bladder as
nonsmokers.
There have been numerous retrospective studies of the effect of
smoking on cancer of the bladder (5, 36, 38;, 41, 55, 101, 102, 124, 125,
147, 186, 195, 207, ;240;, 251 253, 255). Several of these studies show a
positive dose-response relationship between the number of cigarettes
smoked per day, the duration of cigarette smoking or the lifetime
number of cigarettes smoked, and an increased risk of developing
bladder cancer.
5-45
I
I
0
0
TABLE' 5.-Age-adjusted lung cancer mortality ratios* for males
and females, by tar and nicotine in cigarettes's
smoked
Males Females
High ~ TIN 1.00 1.00
Medium T7N 0.95 0.79
Low T7N' 0,81, 0.60
The mortalityratio?or the category with highest risk was made1.W so.that:.the relative.reductions
in risk with
the use of lower T/N cigarettes could tievisualized.
SOURC& Hammond, E.C: (67)
occupational' exposure to dust fumes, chemicals, etc., education~ prior
history of lung cancer, and prior history of heart disease. Results of
this analysis are presented ini Table 5. The mortality ratio for the
category with the highest risk was made 1.0 so that the relative
reduction, in risk with the use of lower T/N cigarettes could be
visualized. For males smoking the same number of cigarettes per day,
there appears to be a 20 percent reduction in risk of developing lung
cancer with the use of low TXN cigarettes. For females, there was a 40
percent reduction in the risk of developing lung, cancer with the use of
low T/N' cigarettes, keeping the number of cigarettes smoked per day
constant. The amount of G'ar and nicotine taken into the body per day
depends on the number of cigarettes smoked, as well as on the'tar and
nicotine content of each cigarette. Hammond conduct'ed' a second
matched-group analysis comparing subjects who smoked 1 to 19' high
T/N cigarettes per day and those who smoked 20 to 39! low T/N
cigarettes per day'. These results are presented in Table 6. The number
of cigarettes smoked per day was a relatively more important variable
than the tar and nicotine content of cigarettes: The mortality ratio was
1.6 for males and 2.1 for females who smoked 20 to 39 low T/N
cigarettes a day, compared to individuals who smoked only 1 to 19 high~
T/N' cigarettes per day.
Wynder and St'ellinan (253) conducted a large retrospective study of
1,034 white! males and females with histolbgieally proved cancer of the
lung and larynx. Relative: risks were consistently lower among long-
term smokers of filter cigarettes, compared to smokers of nonfilter
cigarettes: These groups were standardized for number of cigarettess
smokeds duration of smoking, inhalation, and' cigarette butt length.
These dose-response relationships are presented in Figures 1 and 2.
Lung Cancer in Women
Trends in Cigarette Consumption Among Females
In 1964, the Adt%isory Committee to the Surgeon General concluded
that cigarette smoking was causally related to cancer in men, and'that
ch
~e-
~a
ly
W
6
>Ie
B_
I
Cardiovascular Diseases: References
(1) ALBERT, R.E:,,VANDERLAAN, M., BURNS, F.J., NISHIZUMI, M. Effect of
carcinogens on chicken atherosclerosis. Cancer Research 37(7): 2232-2235, July
1977:
(2): ARMITAGE, A.K., DAVIES R.F., TURNER D.M. The effects of carbon
monoxide on the development of atherosclerosis in the White Carneau pigeon.
Atherosclerosis 23(2); 333-344, MarchlApri1197fi.
(3) ARMSTRONG, M.L. Regression of Atherosclerosis. In: Paoletti, R., GottoA.M.
Jr. (Editors). Atherosclerosis Reviews;, Volume 1, New York, Raven Press,
1976, pp. 137-182.
(4) ARNTZENIUS; A.C.,, VAN GENT, C.M.,, VAN DER' VOORT, H., STEGER-
HOEKC.I.,,STYBLO, K. Reduced high-density lipoprotein in women aged 40-
41 using oral contraceptives: Consultation Bureau Heart ProjectL Lancet: 1221-
1223, June 10,,1978.
(5) ARONOW, W.S. Carbon monoxide and cardiovascular disease: In: Wynder, E:L.,
Hoffmann; D., Gori, G.B. (Editors): Proceedings of the Third World Confer-
ence on Smoking and Health, New York, June 2-5, 1975. Volume I. Modifying
the Risk for the Smoker. U.S. Department of Health, Education, and Welfare;.
Public Health Service, National Institutes of Health, National Cancer
Institute; DHEW Publication No. (NIH) 76-1221,1976, pp. 321-328.
(6) ARONOW, W.S. Introduction to smoking and cardiovascular disease. In:
Wynder, E.L., Hoffmann, D.,, Gori, G.B. (Editors). Proceedings of the Thir&
World Conference on Stnoking and Health, New YorkJune 2-51975. Volume
I. Modifying the Risk for the Smoker. U.S. Department' of Health, Education,
and Welfare, Public Health Service, National Institutes of Health, National
Cancer Institute, DHEW Publication No. (NIH) 76-1221, 1976, pp. 231-236.
(7) ARONOW, W.S., CASSIDY, J., VANGROW, J.S. MARCH, H,, KERN, J.C.,
GOLDSMITH, J.R., KHEMKA, M., PAGANO, J.,, VAWTER, M. Effect of
cigarette smoking and breathing carbon monoxide on cardiovascular hemody-
namics in anginal patients. Circulation 50(2): 340347; August 1974.
(8) ARONOW, W.S., ISBELL, M.W. Carbon monoxide effect on exercise-induced
angina pectoris. Annals of Internal Medicine 79(3); 392-395, September 1973.
(9) ARONOW, W.S:, KAPLAN, M.A., JACOB, D. Tobacco: A precipitating factor in
angina pectoris. Annals of Internal Medicine 69(3); 529-536, September 1968.
(10) ARONOW, W.S.,, ROKAW, S.N. Carboxyhemoglobin caused by smoking non-
nicotine cigarettes. Effects in angina pectoris. Circulation 44: 782-788,,
November 1971.
(11) ARONOW, W.S., STEMMER, E.A., ISBELL, M.W. Effect of carbon monoxide
exposure on intermittent claudication. Circulation 49: 415-417, March 1974..
(12) ARONOW, W.S., SWANSON, A.J. The effect of low-nicotine cigarettes on~
angina pectoris. Annals of Internal Medicine 71(3): 599-601, September 1969.
(13) ASTRUP, P. Some physiological and patholbgical effects of moderate carbon
monoxide, exposure. British Medical Journal 4(5838): 447-452, November 25,
1972.
('14 ASTRUP, P., KJELDSEN, K., WANSTRUP, J. Enhancing influence of carbon
monoxide on the development of atheromatosis in cholesterol-fed rabbits.
Journal of Atherosclerosis Research 7: :343-&54 1967.
(15)i AUERBACH, 0., CARTER, H.W., GARFINKEL, L., HAMMOND, EIC.
Cigarette smoking and coronary artery disease: A macroscopic and~ microscopic
study. Chest 70(6): 697-705, December, 1976.
(16)' AUERBACH, 0., HAMMOND, E.C:, GARFINKELi La, KIRMAN, D: Thickness
of walls of myocardial arterioles in relation to smoking and' age: Findings in
men and dogs. Archives of Environmental Health 22: 20-27, January 1971.
4-67
have been found in cigarette smoke (81). This points to a class of
compounds which should be investigated for their carcinogenic
potentialt in cancer of the pancreas.
Konturek, et al. (108) has reporte6 that nicotine inhibits pancreatic
bicarbonate secretion in the dog by direct action on the organ. This hass
le& to speculation that inhibition of dtict cell secretion~ of bicarbonate
could lead to intracellular pH changes and subsequently play a role in
careinogenesis:
Conclusions
1. Epidemiological data from prospective and retrospective investi-
gations have demonstrated a significant association between cigarette
smoking and cancer of the pancreas.
2. Several epidemiological studies contain evidence of a dose-
response relationship for the number of cigarettes smoked per day. The
relative risk of developing cancer of the pancreas is about five times
greater for a two-pack-a-day smoker than for a nonsmoker.
Mechanisms of Carcinogenesis
Smoke Composition
Cigarette smoke for use in experimental studies is usually separated
into a gas phase and a: particulate phase by passing whole smoke
through an appropriate filter. The compounds retained' by the filter
constitute the particulate phase and are referred to as "tar." More than
2,000 compounds have been identified in cigarette tar. The gas phase,
which makes up more than, 90 percent of the volume of whole smoke,
contains a much smaller number of compounds. The particulate phase
can be subdivided into categories based on the solubility of the
compounds in acid, neutral, or basic solvents. Most of the chemical
compounds which participate in the induction and maintenance of thee
malignant process are contained in the neutral portion of the
particulate phase. A detailed analysis of the components of cigarette
smoke is presented in the Chapter on the Constituents of Tobacco
Smoke. This subject has also been reviewed in~ detail by H'offmann and
Wynder (83).
Experimental Models
Cigarette smoke, whole tobacco tars; the gas phase of cigarette smoke,
various tobacco condensate subfractions, and single or multiple
compounds known to be present in tobacco smoke have been used inn
studying the mechanisms of carcinogenesis in experimental animals:
Rats, mice, hamsters; guinea pigs rabbits; dogs, monkeys, donkeys,
chickens, and other animals have been used in studying the carcinogen-
ic properties of tobacco smoke.
5-53
I
1
12
TABLE 17:-Mortality ratios for cancer of the oral cavity-
prospective studies
Study
Number Cigarette
Population size of Nonsmokers
deaths smokers
Comments
A.C:S. 9= Only 3
State Study(68) 188,000: males 55 1.00 18.00 deaths
among
nonsmokers
British Includes
doctors(47a.) 34;000 males 38 1.00 13.00 lip, tongue,
mouth,
pharynx,
larynx, and
trachea
U!S: veterans(90) 239,000 males 61, 1.00 4.09
A.C.S: 25- 440,000 males 95 1.00 9.90 Ages
State Study(65) 45--64
California mal@s
in 9 occupations 68,000 males 19 1.00 - 2.76
(228),
Japanese 122,200 males 43 1.00 2.88 males
study(77a;80) 142,800 females 11 1.00 1.22 females
Swedish 55,000 Swedish 5 deaths
study(42) males and females 15 Mortality ratios not in non-
published smoking
males.
10 deaths in
smoking
males.
Other Forms of Tobacco
All forms of tobacco use expose the oral cavity to compounds found in
raw tobacco or tobacco smoke. In most of the prospective and
retrospective studies where other forms of tobacco use were accounted
for, significant correlations were'found between1he useof tobacco and
the development of oral cancer. These relationships are of the same
general magnitude or slightly greater than those found with cigarette
smoking. These relationships are examined in detail in the Chapter on
Other Forms of Tobacco Use.
Other Risk Factors
Other than tobacco use, alcohol consumption and possibly poor
dentition appear to be risk factors for the development of oral and
pharyngeal cancers. The most recent investigations of the interaction
be
stt
al.
(z'
sig
eai
mt
1ZE
col
fol
gu
th(
He
to
th4
to
th;
he.
ha
Th
tin
alt
Snl
HE
W
7.E
pa
cai
Ar
Ar
be,
ly
ral
sections at autopsy of male former cigarette smokers,
standardized for age ............................................... 27
Table 10:-Expected and observed prevalence rates of
"cough" among smoking partners to co-twins who either
had or had not the symptom "cough" ....................... 35
Table 11.-Age-adjusted prevalence of chronic bronchitis
score by occupation and smoking habits in, men 25 to 64
years of age, Tecumseh, 1962-1965 .............................39
Table 12.-Prevalence for cough day or night in both
sexes in winter by cigarette smoking and by chest
illness before age 2 ................................................ 39
f
6-5
0
I
0
Q
(17) BEAUMONT, J: L.,, BUXTORF, J.-C:, JACOTOT, B., JAN, F. L'es accidents
hypertensifs paroxystiques observes chez lea fumeurs (Incidence of paroxys-
mal hypertension in smokers). Concours Medical'98(17): 2611-2612, 2615-2617,
April124, 1976;
(18)' BECKER, C.G., DUBIN, T. Activation of factor XII by tobacco glycoprotein.
Journal of Experimental Medicine 146r457-467;1977.
(19) BECKER, C.G., DUBIN, T., WIEDEMANN, H.P. Hypersensitivity to tobacco
antigen. Proceedings of the National Academy of Sciences of the U:S:A. 73(5):
1712-1716, May 1976.
(20) BELLET, S., DEGUZMAN, N.T., KOSTIS, J.B., ROMAN; L., FLEISCHMANN;
D. The effect of inhalation of cigarette smoke on ventricular fibrillation
threshold in normal, dogs and dogs with,acute myocatdial'infaretion. American
Heart Journal 83(1)i 67-76, January 1972.
(21) BENDITT, E.P. The monoclonal hypothesis, which holds that the proliferating
cells of an atherosclerotic plaque all stem from one mutated cell, suggests new
lines of' research on, the causes of coronary disease. Scientific American: 74-85
February, 1977.
(22) BENDITT, E.P., BENDITT, J.M. Evidence for a monoclonal origin of human
atherosclerotic plaques. Proceedings of the National Academy of Sciences of
the U.S:A 70(6): 1753-1R56, June 1973.
(23) BERGLUND, G., WILHELMSEN, L. Factors related to blood pressure in a
general population sample of Swedish men. Aeta Medica Scandinavica 198(4):
291-298, October 1975.
(24) BERNARD;, J.G., MOREL, E. Peripheral arteritis-infectious aetiology. In:
Shimamoto, T., Numano, F:, Addison, G.M. (Editors). Atherogenesis, Volume
II: Proceedings of the Second International' Symposium on Atherogenesis,.
Thrombogenesis and Pyridinolcarbamate Treatment, Tokyo, May 18-20, 1972
Amsterdam, Excerpta Medica, 1973, pp. 325-329:
(25) BIRNSTINGL, M.A., BRINSON, K., CHAKRABARTI, B.K. The effect of
short-term ~ exposure to carbon monoxide on platelet stickiness, British Journal
of Surgery 58(11): 837-839, November 1971.
(26) BRITISH MEDICAL JOURNAL. Cigarette smoking and chest pain. British
Medical Journali4(5993): 368, November 15,1975. / (27)' CASTLEDEN, C.M., COLE,, P.V.
Carboxyhaemoglobin level9 of smokers and
nonsmokers working in the : City of London. British Journal of Industrial
Medicine 32: 115-118, 1975.
(28) CORDAY, E., DODGE, H.T., (Guest Editors)~ Symposium on Identification and
Management of the Candidate for Sudden. Cardiac Death. The American
Journal of Cardiology39(8): 813-815, May 26, 1977.
(29) THE CORONARY DRUG PROJECT RESEARCH GROUP. Cigarette smoking
as a risk factor in men with a prior history of myocardialiinfarction. Journaliof
Chronic Diseases, 15 pp. (to be published).
(30) THE CORONARY DRUG PROJECT RESEARCH GROUP. The Coronary Drug
Project: Initiali findings leading to modifications of its research protocol.
Journal' of the American Medical Assocation 214(7): 1303-1313, November 16,
1970:
(S1) COUNCIL ON CEREBROVASCULAR DISEASE. Risk factors in stroke due to
cerebral infarction. A statement for physicians prepared by a subcommittee
and approved by the executive committee of the Council on Cerebrovascular
Diseases of the American Heart Association. Stroke 2(5): 423-428, September-
October 1971.
(32) DAVIES, R.F., TOPPING, D.L., TURNER, D.M. The effeet' of intermittent
carbon monoxide exposure on experimental atherosclerosis in the rabbit:
Atherosclerosis 24: 527-536, September 1976.
4-68
0
harmfull occupational interactions by eliminating cigarette smoking
from their lifestyle. This would'probabliyeliminate the vast majority of
the 11u ng cancers which are occupationally related.
Short of giving up smoking entirely, it might be impossible for the
worker to avoid many of the risks of develbping cancer which may be
related to his employment. Smoking at home but not on the job will not
avoid this interaction, because the tars which are trapped in the
airways will still be there when the individual goes to work.
Asbestos
In 1935, Lynch and Smith (127) in the Uhited~States an&Gloyne (61) in
in the United Kingdom reported' an association between asbestos and
lung cancer. In 1968, Selikoff, et al. (188, 189) first took into account
the interaction between cigarette smoking and asbestos exposure in
the development of lung cancer. They estimated that asbestos workers
who smoked cigarettes had eight' times the lung cancer risk of smokers
without this occupational exposure: This was estimated'to be 92 times
the risk of nonsmokers who did not work with asbestos. This study has
been continued' and is supported by other investigations which
consistently show a potent synergism between the carcinogens of
tobacco smoke and asbestos (19, 69). There is evidence that exposure to
asbestos carries some real risk to nonsmokers; however, this is of a low
order of magnitude compared' to the risks experienced by cigarette
smokers (135, 157).
Uranium Mining
Lung cancer is an occupational risk associated withi uranium mining.
The causative agents in the atmosphere of mines are alpha particles
resulting from the decay of short-lived radon daughters (12, 48).
Several investigators (7, 126, 173, 224, 225, 226) have extensively
studied'underground uranium miners: in the United States. The
combined effect of tobacco smoke an& radon daughter exposure results
in high death rates from lung cancer among uranium miners. The risk
for cigarette-smoking uranium: miners is at least four times greater
t'hanfor cigarette smokers who do not work in the mines:
Nickel'
Epidemiolbgical studies by Morgan (146) and Doll' (44) and experimen-
tal studies by Hueper (89) and Sunderman, et al. (200, 201202):suggest
that exposure to nickel or nickel carbonyl'is a potent carcinogen for t'he
respiratory tract in humans and animals: The interaction of cigarette
smoking on the risk of respiratory cancer in nickel workers will
probably never be adeq;uateliy studied, since the Mond process for
refining nickel is rarely used and conditions in nickel refining factories
have improved.
5-28
7
N
t,
b
(]
TABLE 25.-Carcinogenic agents in the particulate phase of
tobacco smokel
Smoke compounds
Tumor Ihitiators2 Bioli Aot.2
Amount in
smoke of one cigarette
Benzo(a)pyrene (i+ + +) 16-5ong
5-Methylchry5ene (+ + +) 0.6ng
Dilienz(a,h)anthracene (+ +) 40ng
Benzo(b)fluoranthene (+ + ), 30ng
Benzo(j)fluoranthene 60ng
Dibenzo(a,h)pyrene (+ +); present
Dibenzo(a,i)pyrene (+ +) present
Dibenz(a,j)acridine (+ +) 3-lOng
Indeno(1,2,3-cd)pyrene ( + ) 4ng
Benz(a)anthracene (:+) 40-70ng
Chrysene (+) 44-64ng
Methylchrysenes ( + ) 18ng
Methylfluoranthenes (+) 50ng,
Dibenz(a,o)anthracene (+) present
Dibenz(a,h)acridine ( +' ) Oang
Dibenzo(c,g)earbazole (+) 0:7ng
Bonzo(c)pbenanthrene (+) present
Organ specific carcinogens3
A. Esophagus
N'-Nitrosonornicotine 140ng
Nitrosopiperidine 0-9ng
Nitrosopyrrolldine 1-140ng
Unknown Nitrosamines ?'
B. Lung
Polonium-210 0.03-1.3pCi4
Nickel , compounds a600ng
Cadmium compounds 9-70ng
Unknowns ?
C. Pancreas
Nitrosamines ?
Unknowns ?
D. Kidney and Bladder
P-Naphthylamine 22ng
x-Aminofluorene present
x-Aminostilbene present
o-Toluidine present
Unknown Aromatic Amines ?
o-Nitrotoluene 21µg
Unknown Nit'ro compounds °.
Di-n-butylnitrosamine 0.3ng,
Unknown ~ nitrosamines ?
'So far with certainty identified.,
=Biol. Act..- Relativeearciieogenic.a¢tivityonmouseskin. + + + highly.active; + + moderately
active; + weaklyactive.
'These carcinogens also mayact;on other target organs
pCi i- picoCurie., lo-1zCurie.
SOURCE: Wynder, E.L. (P43)
5-56
Lung tumors which closely r6semble lesions found in human
cigarette smokers can be induced in hamsters by intratracheal
instillation of benzo(a)pyrene ('BaP). BaP' induces a low incidence of
bronchogenic tumors in hamsters when adtninistered in saline; but
when it is adsorbed into <1i µ ferric oxide carrier particles, its
carcinogenicity is increased. When administered in the absence of BaP,
ferric oxide particles alone do not induce tumors (176). The: rate of
elimination of BaP from the lung influences its.tumorigenicity (71, 72).
When BaP is administered alone or in simple mixtures with particles,
95 percent is eliminated within 24 hours. However, BaP adsorbed to
particles is retained within the lung for several days (71, 72): Thus, the
duration of the exposure to the carcinogen may be important to tumor
induction by polycyclic aromatic hydrocarbons (PAH). These studies
suggest that the particulate carrier increases the retention of PAH in
the lung with~ a consequent increase in the exposure of respiratory
tissue to the carcinogen.
In the hamster system, intratracheally-instilled BaP ferric oxide
particles and' subcutaneously-administered diethylnit'rosamine (1.4.2,,
143) were synergistic. inhaled' ferric oxide particles have also been
found to enhance carcinogenicity of subcutaneously adtninist'ered
diethylnit'rosamine(158) in the peripheralilung,
Inhalation Carcinogenesis
Various species, including mice, rats, hamsters, and dogs have been
exposed to cigarette smoke or to aerosols of its chemical constituents.
Most of these substances have been administered to the experimental
animallin a passive fashion. Active inhalation experiments more closely
simulating human smoking behavior have been conducted by Rockey
and Speer (169) and Auerbach, et al. (11,, 66). Ini these experiments,,
animals were trained to inhale voluntarily through openings in thee
trachea.
Nitrosamines
A number of nitrosamines present in tobacco products or smoke have
been found to produce respiratory tract tumors in animals. Various 1W-
nitroso compounds of a: nicotine metabolite, which are present in cured
tobacco and chewing, tobacco,, can induce respiratory tract tumors in
mice and hamsters (70, 77). Diethylnitrosamine, a volatile component
of cigarette smoke, is a potent inducer of lung tumors in hamsters
(141). Other nitrosamines present in tobacco products or smoke which
have been shown to produce lung,or tracheal tumors in animals includee
nitrosopiperidine (99) and N-nitrosodiethanolamine (81). This last
compound is thought to be derived during curing from the maleic
hydrazide triethanolamine salt which is sprayed on growing tobacco
plants to reduce sucker formation.
5-30
C
a
rl.
a
v
a
r.
1
t
.
1~
s
r
LIST OF FIGURES
Figure 1.-Comparison of increasing small airways disease
to smoking and pulmonary function .......................... 19
LIST OF TABLES
Table 1.-COLD mortality ratios in six prospective
studies.................................................................. .. 10
Table 2.-Smoking habits when last asked~ and death
from chronic bronchitis and emphysema .....................10.
Table 3.-Mortality in ex-cigarette smokers from chronic
bronchitis, emphysema, and pulmonary heart disease
compared with mortality in lifelong nonsmokers.......... 11
Table 4.-Prevallence of abnormalities in tests of small .
airway function in smokers...................................... 14
Table 5.-Degree of emphysema in current smokers and in
nonsmokers according to age groups ..........................25
Table 6.-Age-standardized percentage distribution of male
subjects in each of four smoking categories according to
degree of emphysema ............................................. 26
Table 7.-Means of the numerical values given lung
sections at autopsy of male current smokers and
nonsmokers, standardized for age......................... ~...26
Table 8.-Means of the numerical values given~ lung
sections at autopsy of female current smokers and
nonsmokers, standardized for age.............................. 27
Table 9-Means of the numerical values given lung
6-4
M
TABLE 24.-Carcinogenic, promoting, and ciliatoxic agents in the
gas phase of tobacco smoke*
I. Carcinogenst
Stnoke compuunds.
Amount in
smoke of one cigarette
H3C____ N - NO Dimethyihitcosamme 5-180ng'
H3 C---
R
1-1 N - NO Dialkylnitrosamines 2-80ng
R',"' (4 compounds)
Nittosopyrrolidine 1-110ng
NO
Nitrosopiperidine 0=9ng "
NO'
H2N-NH2
HzC-CHCI
II., Tumor promoters
HCHO
IIH. Ciliatoxic agents
HCN
HCHO
HzC-CH~-CH0
HaC-CHO
Hydrazine 24-4ng
Vinyl chloride 6-16ng
Formaldehyde 20-90µg
Hydrogen cyanide 100-70qNg
Formaldehyde Z4'-90pg
Acrolein 4fr140jig
Acetaldehyde 18-1,440Fg
*List is based only on publications with unambiguous.identirications of tumorigenicamoke compound9:.
tTobacco smoke.issuspectedlof also containing 1Lv?.s.(arsine); Ni(CO).(niekel carbonyl) and possibly
other volatile
chlorinated alefins than virtylchloride and nitro+olefins.
"ng ~ 10-"g
...Pg.- lp-eg
SOURCE: Wynder, E.Ill (243)
the second part contains a list of organ-specific carcinogens. The tumor
promoters and co-carcinogens found in the particulate phase of tobacco
smoke are listed in Table 26.
Many chemical carcinogens or initiators must be partially metabo-
lized before they can exert their carcinogenic effects. Of the chemical
carcinogens present in cigarette smoke, the metabolism of the
polyaromatic hydrocarbons (PAH); in particular benzo(a)pyrene, has
been most widely st'udied'. The enzyme, aryl hydrocarbon hydroxylase
(AH'H), is responsible for the conversion' of PAH into a number of
hydroxylated derivatives (60, 91, 191).
5-55
TABLE' 19.-Bladder cancer mortality ratios- prospective
studies
Population
Study
size
Non-
smokers All
cigarette Comments
smokers
ACS 187,783 Smokers of 1fl`20 cigarettes
Males in White Includes all urinary,
9-State Study(68) Males 1.00 2.00 tract cancers.
Includes Prostate..
British
doctors(47a)' 34;0000
Male
Doctors 1.00 2.11
Canadian 78,000 Genitburinary,cancecs
Veterans(.40) Males 1.00: 1.40 considered as a group
ACS 1,Q00,000
25 State Study(65) Males and 1.00 2:00 (Males 45-64)
Femalhs 1.00 2.96 (Females 65-79)
U.S. Veterans(90); 2,265,000
Person-
Years 100 2:15
California 68,153
Males in 9
occupations(228) Males 1.00 289
Japanese 265,118
study(77a,80), Males and 1.00 1.36 (Males)
Females 1.00 2:711 (Females-P: 0.05).
Swedis}i 55,000!
Study(82) Males and 1100 1i8© (Males)', Bladder +
Females 11O(/ 1.60 (Females) other urinary
organs
Wynder and Goldsmith (240) reported that the risk of developing
bladder cancer decreased among ex-smokers and! approached that of
nonsmokers about 7'years after quitting smoking.
Several authors have calculated the percentage of bladder cancers
which can conservatively be attributed to the cigarette smoking habit.
Wynder and Goldsmith (240)~estimated''t'hat 40 percent of male bladder
cancers and 31 percent of female bladder cancers may be attributed to
smoking cigarettes. This is in agreement with the estimates by Cole, et
a]. (38) of 39 percent in males and 29 percent in~females.
In a cohort analysis of men and women in the United States,
Denmark, England, and Wales, Hoover and Cole (87) examined the
strength~ of the association between cigarette smoking, the develop-
ment of bladder cancer, and successive birth cohorts. Increasing rates
of bladder cancer were observed in populations characterized by an~
5-46
solvent for carcinogenic hydrocarbons in tobacco smoke or alter
microsomal enzymes in the mucosal cells of the esophagus (234). This
hypothesis has received support from experimental observations by
Kuratsune, et al. (113): The picture is complicated by the fact that
alcoholism may be accompanied by severe nutritional deficiencies
which may also predispose an individual to certain diseases.
Autopsy Studies
Histologic changes in the esophagus in relationship to smoking of
tobacco in various forms were investigated by Auerbach, et al. (11). A
total of 12;598 sections were made from esophageal tissue obtained
from 1,268 subjects. It was found that tobacco smoking, in any form
resulted in the formation of atypical nuclei, disintegrating nuclei,,
hyperplasia, an& hyperactive esophageal glands. Each of these
parameters was significantly more abnormal in smokers than in
nonsmokers; however, these changes were more frequently seen and
more severe in~cigarette smokers (11).
Animal Studies
There is experimental evidence that benzo(a)pyrene is able to
penetrate the cell membranes of the esophageal'' epithelium, producing
papillomas and squamous cell carcinomas. This process can be
accelerated and better penetration achieved if the carcinogen is
dissolved in an aqueous ethanol solution. This effect was reported by
Kuratsune, Horie, and Kohchi (88;,113). Nitrosamine-induced esopha-
geall cancer in experimental animals has also been reported by a
number of investigators (34, 52, 53, 5h; 179). These observations are
significant because a variety of nitrosamine compounds have been
identified in cigarette smoke.
Schmaehl (179) administered methyl-phenyl-nitrosamine orally or
subcutaneously to Sprague-Dawlley rats. Carcinomas of the esophagus
were found in 46 to 87 percent of the anihnals: Simultaneous
application of 25 percent ethyli alcohol did not affect the tumor
incidence.
Mirvishi (140) has reported that 3H-thymidine incorporation in rat
esophageal epithelium cani be inhibited in the presence of nitrosamine
in vivo and in vit'ro; lending further support to the role of these
compounds in esophageal carcinogenic mechanisms.
Conclusions
1. Epidemiological' studies demonstrate: that cigarette smoking is a
significant causal factor in the development of cancer of the
esophagus. The risk of developing esophageal cancer increases with the
amount smoked.
5-44
f
C
k
c
TABLE' 20.-Kidney cancer mortality, ratios and relative risks:
selected prospective and retrospective studies
MortalitY ' ratio or
...._l.- ,.1
Stud slze kitlne
'oiatna -e .-.,.r,m
Population
~-- ~ Comments
d
type cancer
an
deaths
ACS' 440,558 males.
25 State Prospective 104 1.00 1.42 Age 45-84
Study(65) study 1.57 Age 65-79
IJ.S. 2,285,000
Veterans(90) person years. 141 1.00, 1.45
Prospective
study
California 68;153' males.
Males in Prospective 271 1100 2.46
9Occupatians(228)study
Japanese 122,2611
study(77a) males: 30 1.00 1.20
Prospectivee
study,
Bennington, Retrospective Risk ratio for
1lavbscher(16a,1:"), study of 100 1.00 5.1 Pipe - 10.3
renal adCnocarcinoma. Cigar - 12:9'
100~cases
190 controls
Schmauz Retrospective For smokers of
Cole(180) study. 18 1100 10.0 more than 2'1V2
43 cases of renal pks/day,
pelvis or ureter.
451 controls
Armstrong(8) Retrospective
study, 106' 1.00 1.06
106 adenocarcinoma
of kidney:
30 carcinoma of 30 1.00 1.80i
renal pelvis:
139 controls.
Wynder Retrospective study,
et aIJ(21,8a) 202' adenocarcinoma 1.00 200 (Males)
of kidney. '
394 controls. 1100 1.50 (FAmales),
cancer of the kidney. The mortality ratios for all, cigarette smokers
varied from 1.42 to 2.46, compared to nonsmokers. The results of these
studies are summarized in Table 20.
TABLE 18.-Mortality ratios for cancer of the esophagus-
prospective studies
Study Population ~ size Number of Nonsmokers Cigarette Comments
deaths smokers
A.C.S: 9-
1 nonsmoker Esophagus
and other
State Study(68): 188,000 males 33 smokers 1.00 - respiratory
British sites
Esophagus
doctors (47a) 34,000 males 65 1.00, 8.75 and other
U.S, veterans(90)
293;00(11
11L
1.00
6.17 respiratory
sites
A.C.S. 25-
State Study(65)
440,000 males
46
1.00
4.17
California males
in 9 ocoupations
86,000,
32
1.00
1.82'
(228)
Japanese
Study(Y7a)
122,200 males
215
1.00
2.35
Swedish
Study(32)I
55,000 Swedish
males and females
.1 nonsmoker
12 smokers
1.00
Other Forms of Tobacco Use
In most of the prospective and retrospective epidemiolbgical investiga-
tions, the: association of esophagus cancer with the use of tobacco in
other forms was examined. These relationships are discussed in~ somee
detail in the Chapter on Other Forms of Tobacco Use. The mortality
ratios for cancer of the esophagus are approximately equali in' users of
cigars, pipes, and cigarettes.
Other Risk Factors
Numerous investigations have been made into the synergistic relation-
ships between the use of tobacco in various forms, alcohol consumption,
and the development of cancer of the esophagus (78, 92, 105, 18,2;,183;.
,20l,1 208, 233, 235, 249). Some investigators report that tobacco is a
more important carcinogen than alcohol in the development of cancer
of the esophagus, but others report that the reverse is' true. Most of
these studies support a~ synergism with the combined use of tobacco
and alcohol, resulting in higher rates of cancer of the esophagus
compared to those resulting from the use of either substance alone.
The mechanism of the association is not known. Alcohol may act as a
I
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0
9
ff
0
I
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0
I
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(243) WYNDER, &L., HECHT, S. (Editors). Lung Cancer. A Series of W6rkshops on
the Biology of Human ~ Cancer. Report No. 3: UICC Technical Report Series-
Volume 25. GenevaInternationaliUnion Against~Cancer,1976,170 pp.
(244) WYNDER, E.L., HOFFMANN, D. The epidermis and the respiratory, tract'~ as
bioassay systems in, tobacco carcinogenesis. British Journal of Cancer 24(3):
574-587, September 1970.
(245) WYN'DER:, E.La, HOFFMANN, D. Tobacco and Tobacco Smoke. Studies in
Experimental Carcinogenesis. New York, Academic Press,1967; 730 pp:
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(21r7)1 WYNDER,,E.L., MABUCHI, K., BEATTIE, E.J.,,JR. The epidemiology of lung
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(2/,8)! WYNDERE.L., MABUCHI, K., MARUCHI, N., FORTNERJ.G. A case control
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5-74
TABLE 4.-Prevalence of abnormalities in tests of small airway function in smokers-Continued
Author
Year
Country
Reference
Number and type
of population Sub-groups
McCarthy, D.J. 131 volunteers from
1976 a smoking cessation
Winnipeg clinic - varying smoking
(106) historyb
L
13
% smokers with abnormal test
CV% CC`7o LNz VisoV V,,,..z V,,,.so FEVi.o FEV%
9
Armstrong, J.G. 101 asymptomatic smokers light smokers 10 28
1976 and ZO nonsmoking heavy smokers 30 34
Australia controls aged 18-39
(7)
Fairshter, RD. 18 asymptomatic mild none 55.6
1977 smokers aged 29.8t5.4
USA yrs. 24 volunteer non-
(50) smoking controls
Knudson, R.J. 1900 white randomly se-
1977 lected subjects aged 25-
USA 54 (426 smokers)
(85)
Cherniack, R.M. 1456 randomly selected
1977 subjects from 3 cities
USA, Canadg (40% smokers) aged 25-
(31) 54.
'6zssg9Eo
symptomatic smokers
(n=150)
asymptomatic smokers
(n=276) 9.1
6.0 12.9
8.7 30.4
15.4
Montreal (na275)
Men
15
28
14
10
Women 14 17 19 14
Portland (n-208)
men
15
22
17
3
women 36 30 47 15
I
Introduction
The chronic non-neoplastic bronchopulmonary diseases pose a major
worldwide health challenge. The chronic obstructive lung diseases
(COLD), chronic bronchitis, and emphysema comprise the majority of
these illnesses and rank second only to coronary artery disease as a
cause of Social Security-compensated disability (73). Previous reports
on the health consequences of smoking (141-1.¢9), have reviewed the
relationship betweeni smoking and these disorders. They are summa-
rized below.
Cigarette smoking is the most important cause of COLD. Cigarettee
smokers have higher mortality rates from chronic bronchitis and
emphysema, an increased prevalence of respiratory symptoms, and
diminished performance on pulmonary function testing compared to
nonsmokers. These differences become more marked as the number of
cigarettes smoked increases. Cigarette smokers without respiratory
symptoms have evidence of small airway dysfunction more frequently
than do nonsmokers. The relationship between cigarette srnoking and
COLD has been demonstrated ini many different national groups and is
more striking in men than in women. Pipe and cigar smokers have
higher morbidity and mortality rates from COLD than do nonsmokers
but are at lower risk for COLD than are cigarette smokers.
Certain occupational exposures are associated with an increased
incidence of COLD, but the relationship is not as strong as for
cigarette smoking. The combination of these occupational hazards and
cigarette smoking has been~ observed ini many studies to result in,
additive effects on morbidity from, COLD. Exposures to cotton fiber,
asbestos,, an& coal dust in particular appear to act in concert with
cigarette smoking in promoting the development of pulmonary disease.
The impact of cigarette smoking in the development of coal workers'
pneumoconiosis is unclear. Although air pollution may contribute to
the prevalence of symptoms of respiratory disease, cigarette smoking
is far more important in producing respiratory disease. Cigarette
smoking and air pollutiom may interact to produce higher rates of
pulmonary disease than are seen~ with either factor alone.
Cigarette smokers experience an increased risk for respiratory
problems other than COLD. They experience more frequent respira-
tory tract infections. In response to mild viral respiratory illness
cigarette smokers develop abnormal but reversible changes in certain
pulmonary function tests. Cigarette: smokers have nyore protracted
respiratory symptoms following mild viral illness and are at greater
risk for developing postoperative respiratory complications and
possibly spontaneous pneumothorax as compared~ to nonsmokers.
Cigarette smokers who die from diseases other than COLD have
anatomic evidence of COLD more frequently than do nonsmokers.
Autopsy studies have shown a dose-response relationship between
cigarette smoking and the microscopic changes of COLD. Histologic
6-7'
I
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I
3
(210) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking, 1968:
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(218) VALKO; P. Koureni, a vyskyt zhoubnych novotvaru hrtanu (Smoking and
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(219) VAN DUUREN,B:L: Tumor-promoting and co-carcinogenic agents in chemical
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5-72
M
Bronchitis: A non-neoplastic disorder of structure or function of the
bronchi resulting from infectious or noninfectious irritation: The
term bronchitis should be modified by appropriate words or phrases
to indicate its etiology, its chronicity, the presence of associated
airways dysfunction, or type of anatomic change. The term chronic
bronchitis, when unqualified, refers to a condition associated with
prolonged exposure to nonspecific bronchial irritants and accompa-
nied by mucous hypersecretion and' certain structural alterations in
the bronchiL Anatomic changes may include hypertrophy of the
mucous secreting apparatus an& epithelial metaplasia, as well as
more classic evidence of inflammation. In epidemiologic studies, the
presence of cough or sputum production on most days for at least
three months of the year has sometimes been accepted' as a criterion
for the diagnosis.
Pulmonary Emphysema: An abnormal enlargement of the air spaces
distal to the terminal nonrespiratory bronchiole,, accompanied by
destructive changes of the alveolar walls. The term emphysema may
be modified by words or phrases to indicate its etiology, its anatomic
subtype, or any associated airways dysfunction.
COLD: This term refers to diseases of uncertain etiology character-
ized by persistent slowing of airflow during forced expiration. It is
recommende6 that a more specific term, such as chronic obstructive
bronchitis or chronic obstructive emphysema, be used whenever
possible.
It shoul& be noted that these definitions may have serious
inadequacies (138); particularly when applied to longitudinal studies
assessing the natural history of COLD (56). In the following discussion,
cognizance is taken~of these Iimitat'ions:
Smoking and Respiratory Mortaiity
Numerous retrospective and prospective studies have shown a greatly
increased mortality from COLD among smokers as compared to
nonsmokers. Results from the major prospective studies relating
smoking to mortaiity from COLD are presented in the Chapter on
Mortality and reproduced; in Table 1. These studies represent over 13
million patient years of observation and approximately 270,000 deaths
from all causes. The number of deaths related to COM is probably
underestimated since some of the deaths attributed to pneumonia or
myocardial disease may have been due to complications of COLD. In
addition, these mortality figures do not include a sizeable number of
individuals for whom COLD may have been a major contributory cause
of death. For example, it is not uncommon for individuals to have
COLD and lung cancer simultaneously.
6-9
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9
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0
0
Q
In
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Atlantic City,,New Jersey, November 14, 1972, 10 pp.
(118) LINDENNG. The increasing rate of lung cancer mortality in California women.
California School Health: 12=16, January 1966.
(119) LEVIN, M.L., GOLDSTEIN, H., GERHARDT; P.R. Cancer and tobacco
smoking. A preliminary report. Journal of the American Medical Association
143(4); 336-338, May 27,,1950.
(120) LI, F.P., FRAUlOIENI,J,F., JR., MANTEL, N., MILLER, R.W. Cancer mortality
among chemists. Journali of the Nationall Cancer Institute 43(5): 1159-1164,
November 1969:
(121) LIBSHITZ, H.I., WERSHBA, M.S., ATKINSON, G.W., SOUTHARD, M.E.
Asbestosis and carcinoma of the larynx. A possible association. Journal of the
American Medical Association1228(12): 1571-1572, June 17, 1974.
(122) LICKI'NT, F. Der tabakrauch als ursache des lungenkrebses (Tobacco smoke as
causes ofl lung cancer): In: Atiologie und Prophylaxe des Lungenkrebses. 2.
Statistische Voraussetzungen zur Klaerung der Tabakrauchaetiologie des
Lungenkrebses. Dresden, Theodor Steinkopff, 1953, pp. 76-102.
(123) LIEBERMAN, J. Aryl hydrocarbon hydroxylase in bronchogenic carcinoma.
New England Journal ofl Medicine 298(12): 686-687,,March 23, 1978.
(124) LILIENFELD, A.M., LEVIN, M.L.,,MOORE, G:E. The association of smoking
with~caneer of the urinary bladder in humans: American Medical Association
Archives of Internal Medicine 98: 129-135, 1956.
(125) LOCKWOOD; K. On the etiology of bladder tumors in Kobenhavn-Frederiks-
berg, An inquiry of' 369 patients and 369 controls. Acta Pathologica et
Microbiologica Scandinavica 51 (Supplementum 145): 1-1611961.
(126) LUNDIN; F.E., JR., LLOYD, J.W., SMITH, E.M., ARCHER, V.E., HOLADAY,
D.A. Mortality of uranium miners in relation to radiation exposure, hard-rock
mining and cigarette smoking-1950 through September 1967. Health Physics
16(5); 571-578, 19691
(127)' LYNCH, K.M,, SMITH, W.A. Pulmonary asbestosis III: Carcinoma of the lung
in asbesto-silicosis. American ~Journal of Cancer 24(1): 56-64, May 1935.
(128)~ MCCONNELL, R.B., GORDON, K.C:T., JONES, T. Occupational and personal
factors in the aetiolbgy of carcinoma of the lung. Lancet 2(6736); 651-656,
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(129) MCLEMORE, T.L.,,WARR, G:A., MARTIN, R.R. Induction of aryl hydtocarbon
hydroxylase in human pulmonary alveolar macrophages and peripheral
lymphocytes by cigarette tars. Cancer Letters 2: 161-167; 1977.
C
5-66
hypersecretion~ and airflow obstruction. They suggested that there is a
susceptible population of smokers who develop a more rapid decline in
forced expiratory volume, eventuating in severe obstructive lung
disease.
Pathological evidence of the effects of smoking on small airway
histology was presented' by Niewoehner, et al. (112) in~ an autopsy study
of 39' men (20 nonsmokers, 19 smokers) who died suddenliy from
nonrespiratory causes. They observed a respiratory bronchiolitis in the
lungs of smokers but rarely observed these changes in nonsmokers
(p<0.002): They postulated that these changes were precursors of
emphysema and responsible for the subtle function abnormalities
observed in young smokers. In a second autopsy study of 168' male
victims of sudden death~ age6 16 to 65,, Kleinerman and Rice (83)1 age-
matched 18 nonsmokers and 18 smokers. They observed significantly
more chronic bronchiolitis, emphysemaand parenchymallpigmentation
in lung tissue in smokers versus nonsmokers.
Prospective pathological evidence that abnormalities in tests of
smalll airway function reflect structural alterations in small airways
has recently been presented by Cosio, et al. (37). They examined! thee
relationship between preoperative pulmonary function tests and
graded! pathologic lesions in the small airways (Group I-IV) in 36
patients (30 smokers, 4 ex-smokers, 2 nonsmokers) who went to
surgery for an open lung biopsy (localized disease). These data are
presented in Figure 1. Subjectis with the lowest pathological score
(Group I) were younger, had smoked fewer cigarettes, and had a
normal FEVI percent. Subjects with minimal pathologic changes,.
Group II, could be separated from Group I (least pathological changes)~
by severad tests of small airway function (closing capacity, volume of
isoflow comparing air and helium on the flow volume curve, and slope
of the alveolar plateau). The mean cigarette consumption~ in Group II
was more than twice that of Group I. Group II-IV subjects
demonstrated progressivelyabnormal function tests but only Group IV
demonstrated a substantial amount of emphysema. The authors
concluded that structural abnormalities in the small airways can be
detected in living patients with normal FEV,,percent by tests of small
airway function. However, as noted by Thurlbeck (140), the maximum
mid-expiratory flow rates also showed changes that were close to
significant in Group I and II diseases.
These findings lend' support to the postulated natural history of
smoking induced lung changes advanced by Dosman, et al. (44, 45).
They suggest that the effects of smoking on the lung are sequential,
beginning with changes in the peripheral airways and progressing
through stages of alterations in~ the mechanical properties of alveolar
walls and loss of elastic recoil, and finally leading to the overt
developmentt of chronic bronchitis and emphysema with a reduction of
((
F:
st
CONTENTS
Introduction .............................................................. 7
Definitions ................................................................ 8
Smoking and Respiratory Mortality ............................... 9
Smoking and the Natural History of COLD .................. 10
Youthful. Smoking and Respiratory Morbidity .......... 11
Early Stages of Respiratory Dysfunction ................. 12
Respiratory Morbidity in the Adult ........................ 19
Ventilatory Function ............................................ 21
Cessation and Reversibility of Functional Changes .... 22
Lung Pathology .................................................. 23
Smoking and the Pathogenesis of Lung Damage............ 25
Proteolytic Lung Damage ..................................... 26
Interference with Immune Mechanisms ................... 30
Effect on~ Clearance Mechanisms ............................32
Interaction of Smoking with Other Risk Factors
for COLD ............................................................. 33.
Alpha-1-antitrypsim Deficiency ............................... 33
Other Genetic Factors .......................................... 34
Occupational Exposures ........................................ 36
Air Pollution ...................................................... 36
Socioeconomic St'atus ............................................ 38
Childhood Respiratory Illness and Adult Respiratory
Disease ........................................................... 38
Summary ........................................................ ........ 39
Research Recommendations ......................................... 41
References ............................................................... 43
6-3
0
I
U
increase: in cigarette smoking among successive birth cohorts. The
association~ was consistent in both men and women and was also found
for different nationalities and for urban and rural groups. These:
findings are consistent with a causal role for cigarette smoking in the
development of bladder cancer. It is interesting that the cohort
analysis for bladder cancer is similar to and parallels that of cancer of
the pancreas.
Other Risk Factars
Certain occupational'exposures are associated with an increased risk of'
developing bladder cancer. Those who work with dyestuffs, rubber,
leather, print, paint, petroleum, and other organic chemicals are
particularly at risk. The common denominator appears to be aromatic
amines. A number of specific carcinogens for the human bladder have
been identified, including aminobiphenyl, 2-naphthylamine, benzidine,
1-naphthylamine, and 4-nitrobiphenyl (35). Some of these compounds
are found in cigarette smoke. The relationship between cigarette
smoking and occupational exposure is complex. It is likely that
cigarette smoking can act as a sole agent in the development of
bladder cancer; however, there may also be synergistic interactions
between cigarette smoking,and~ occupational exposures.
Animal Studies
Numerous experiments have been undertaken~to examine the relation-
ship: of tobacco smoking to bladder carcinogenesis. The areas of major
concern have centered upon aromatic amines, nitrosaminestryptophan
metabolism ('107) and's more recently, non-nutritive sweetness, as in
saccharin and cyclamates. The effect of these classes of compounds on
the etiology of bladder cancer in experimental' animals has been
extensively reviewed im the literature.
Kidney Cancer
For 1978, the estimated incidence of kidney and other urinary cancers,
exclusive of cancer of the bladder, was 9,400 for males and 5,700 for
females. The estimated number of deaths for these same cancers was
4,600 in males and 2,800 in females (4). The 5-year survival rate
following the diagnosis of kidney cancer is 40 to 50 percent (',151).
Epidemiological Data
In most of the prospective studies, cancer of the kidney refers to
tumors arising from the renal parenchyma as well as tumors in the
renal pelvis and ureter. In some of the retrospective investigations,
tumors at these various sites are considered separately in relationship
to cigaret'te smoking. In several of the large prospective epidemiologi-
cal studies, an association was found between cigarette smoking and
5-47
0
It has not been possible to duplicate the same conditions of smoke
inhalation in experimental animals as are found in humans. Many
animals are obligate nose breathers, and under these circumstances
turbulent precipitation of smoke particles in the nasal' passages
prevents most of the active compounds from reaching the lungs. A
variety of alternate approaches have been used. The painting,of shaved
mouse skin with whole tobacco tar and various chemical constituents
has been widely used. Other investigators have used subcutaneous
injection, intratracheal instillation, implantation, and feeding. Tissue
and organ cultures have also been used to study carcinogenesis.
Chapter 14 cont'ainsa more complete discussion of this subject.
Concept's of Carcinogenesis
Carcinogenesis is a complex process involving multiple steps and
various compounds operating at different points in the sequence.
Chemicali compounds have been classified as to the respective roles
they play in the process of carcinogenesis. Cigarette smoke and tobacco
tar act as complete carcinogens, since: no additional compounds or steps
are necessary to induce malignant changes in a variety of animal
systems. When, individual chemical compounds and subfractions are
examined, however, the process of carcinogenesis becomes increasingly
complex. Chemicals which can induce the first steps of malignant
transformation, are known as carcinogens or tumor initiators. Tumor
promoters are: compounds which continue the process of tumor
formation when they are applied to tissue following initial treatment
with a chemical carcinogen (23). Compounds known as co-carcinogens
exert their effects when administered~ simultaneously with carcinogens
or tumor init'iators: Compounds which act as co-carcinogens do not
necessarily have tumor-promoting properties. Mouse skin is frequently
used for identifying co-carcinogens as well as promoters (85). Catechol
is a potent co-carcinogen but is inactive as a tumor promoter. On~ the
other hand, phenol, a tumor promoter, has no known~ co-carcinogenic
activity (219). Data: such as these support the idea that tumor
promotion and co-carcinogenesis are independent phenomena with
distinct mechanisms of action; Bothi promoters and co-carcinogens play
an~important role in tumor induction by tobacco products (161):
Additionally, Hoffmann and Wynder (82, 244) have described the
property of tumor acceleration possessed by N-alkylat'ed carbazoles
and certain other compounds. These compounds are inactive as
complete carcinogens, initiators, or promoters but accelerate the
initiator-promoter activity of polynuclear aromatic hydrocarbons.
The carcinogens, tumor promoters, and ciliatoxic agents which have
beenidentified in the gas phase of tobacco smoke are listed in Table 24..
The major carcinogenic agents which have been identified in the
particulate phase of tobacco smoke are listed in Table 25. The first part
of Table 25 lists the 17 agents which are identified as tumor initiators;
ti
5-54
(224) WAGONER, J.K., ARCHER, V.E., CARROLL, B.E., HOLADAY, D.A.,
LAWRENCE, P.A. Cancer mortality patterns among U.S. uranium miners and
millers, 1950 through 1962. Journal of the National Cancer Institute 32(4): 787-
801, April 1964.
(225) WAGONER, J.K.,, ARCHER, V.E., LUNDIN, F.E:,, JR., HOLADAY, D.A.,
LLOYD, J.W. Radiation~ as the cause of lting cancer among, uranium miners.
New EnglandJournal of Medicine273(4); 181-188, July 22, 1965:
(226) WAGONER, J.K., MILLER, R.W., LUNDIN, F.E., JR., FRAUMENI, J.F., JR.,
HAIJ, M.E: Unusual cancer mortality among a group of underground metal
miners. New England Journal of Medicine 269(6): 284-289: August 8, 1963.
(227) WATSONW.L., CONTE, A.J. Smoking and lung cancer. Cancer 7(2): 245-249,
March 1954:
(228) WEIR, J.M., DUNN, J.E:,, JR. Smoking and mortality: A prospective study.
Cancer 25(1); 105-112, January 1970.
(229): WEISS, W. Lung cancer mortality and urbaniair pollution. American Journal of
Public Health,68(8): 773-775, August 1978.
(230) WEISS, W:, BOUCOT, K.R:, SEIDMAN, H., CARNAHAN, W:JI Risk of lung
cancer according to histologic, type and cigarette dosage. Journali ofi the
American Medical Association 222(7)t 799-801, November 13,1972.
(231) WELCH, R.Ms, LOH, A., CONNEY; A.H. Cigarette smoke: Stimulatory effect
on metabolism of 3, 4-benzpyrene by enzymes in rat lung. Life Science 10(Part
I): 215-221, 1971.
(232) WICKEN, A.J! Environmental and personal factors ini lung cancer and
bronchitis mortality in Northern Ireland, 1960-62. London, Tobacco Research
Council, Research Paper No. 9, 1966, 84 pp.
(233) WILLIAMS, R.R., HORM, J.W. Association of cancer sites with tobacco and
alcohol consumption and socioeconomic status of patients: Interview, study
from the Third National Cancer Survey. Journal of the National Cancer
Institute 58(3): 525-547, March 1977.
(234) WYNDER, E.L. The epidemiology of cancers of the upper alimentary and upper
respiratory tracts. Laryngoscope 88(1, Part 2): 50-51, January 1978.
(235) WYNDER, E.L., BROSS, I.J. A study of etiological factors im cancer of the
esophagus. Cancer 14(2): 389-413; March-April 1961.
(236) WYNDER, E.L., BROSS, I.J., CORNFIELD, J., O'DONNELL, W.E. Lung
cancer in women. A study of environmental factors. New England Journal of
Medicine 255(24): 1111-1121, December 13, 1956.
(237) WYNDER, E.L., BROSS, I.J., DAY, E. A study of environmental factors, in
cancer of the larynx. Cancer 9(1): 86-110, January-February 1956.
(238): WYNDER, E.L., COVEY, L.S, MABUCHI, K., MUSHINSKI, M. Environmen.
tal factors in cancer of! the larynx. A second look. Cancer 38(4): 1591-1601,
October 1976.
(239) WYNDER, E,L., BROSS;, LJI, FELDMAN, R.M. A study of the etiological
factors in cancer of the mouth. Cancer 10(6): 1300-1323;,November-December
1957:
(24n) WYNDER, E.L., GOLDSMITH, R. The epidemiology of bladder cancer. A
second look. Cancer 40(3): 1246-1268, September 1977:
(241) WYNDER; E.L., GORI, G.B. Contribution of the environnfent to cancer
incidence: An epidemiologicaU exercise. Journal of the National Cancer
Institute 58(4): 825-832, April 1977.
(242) WYNDER, E.L., GRAHAM, E.A. Tobacco smoking as a possible etiologic factor
im bronchiogenic carcinoma. A study of six hundred and eighty-four proved
cases. Journal of the American Medical Association 143(4): 329-336, May 27,
1950.
I
8
I
5-73
~
TABLE 4.-Footnotes
FEV - Forced expiratory volume
FEVi.a - FEV in 1 second
VC -- vital capacity
FVC - forced vital capacity
FEV% - FEVto/FVC x 100
V,,, - maximum flow
Vm.. 50 - maximum flow at 50% of vita) capacity
V,,,,, 25 - maximum flow at 25% of vital capacity
CV - closing volume
RV - residual volume
TLC - total lung capacity
CV% - CV/VC x 100
CC% - (RV + CV)/TLC x 100
,~NZ/L - slope of the alveolar plateau
ViBoV - volume of isoflow
abbreviatione and definitions of pulmonary function teate
^eatimated from bar graph -
°obtained from apirometry
aobtained from plethysmography
szssR9Eo
closing volume is the lung volume at which the depend'ent lung zones
stop contributing to the expired air flow and when expressed as a
percent of total lung, capacity is called closing capacity. The slope of
the alveolar plateau is usually measured as the change in nitrogen~
concentration per liter. The precise physiologic event that this test
measures is unclear, but it is thought to reflect the degree of
homogeneity of ventilation and; when abnormal, to be a sensitive
indicator of small airways dysfunct'ion.
Maximum expiratory flow rates at 25 and~ 50 percent of vitali
capacity (59); measure:flow at lung volumes where the resistance of the
small airways comprises a: larger proportion, of the total resistance.
Such measurements appear to be of particular value in assessing small
airway function when performed' before and after inhalation, of an 800
percent helium and 20 percent oxygen mixture (72): Changes in both
maximat flow rates and changes in the lung volume at which the same
flow is achieved (volume of isoflow) indicate smalL airways dysfunc-
tion.
Severali reports have demonstrated a higher prevalenee.of abnormal-
ities in these tests of smalli airways function in smokers as compared to
nonsmokers. However, as can be seen in Table 4, studies show wide
variability in the percent of smokers demonstrating an abnormal test.
Such variability mostlikely reflects testing of different populations
(rand'om vs. selected), the use of different standards of normalcy, and
the application of different techniques for the same test. As can be
seen from Table 4, a dose-response relationship often exists between
the intensity of smoking and the percent of smokers with abnormal
tests.
In a recent study, Dosman, et al'. (43) examined~ the relationship
between respiratory symptoms and tests of small airway function in
clinically healthy cigarette smokers. They found that the presence of
individual symptoms (cough, sputum, wheezing, and shortness of
breath) correlated poorly or not at all with measured values for
dynamic lung compliance, closing volume, closing capacity, slope of the
alveolar plateau, and helium-oxygen flow curves. Moreover, 53 percent
of their smoking population conformed to the American Thoracic
Society criteria for a diagnosis of chronic bronchitis although all had a
forced expiratory volume FEVi> 70 percent. They suggested that
s3mptoms could not be used to detect smokers who have abnormalities
of small airway function.
The insensitivity of certain respiratory symptoms in the adult as a
predictor of future development of COLD has been emphasized by
Fletcher, et al. (57) in a prospective study of 792 men, aged 30 to 59,
who were followed for 8 years. They found that smoking was strongly
related to the presence of symptoms (mucous hypersecretion) and to
the develbpmentof airflow obstruction (loss of forced expiratory
volume); but they could find no relationship between mucous
6-13
0
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I
r.
to (96) KELLERMANN, G., SHAW, C.R., LUYTEN-KELLERMANN, M. Aryl hydro-
ic carbon hydroxylase inducibility and bronchogenic carcinoma. New England
Journal of Medicine 289(18): 934-937, November 11973.
(97) KELLERMANN, G., LUYTEN-KELLERMANN, M., SHAW, C.R. Genetic
variation of aryl hydrocarbon hydroxylase in human lymphocytes. American
Journal of Hhman Genetics 25: 327-331, 1973.
(98) KELLEY, T.F. Polonium-210 content of mainstream cigarette smoke. Science
149(3683): 537,538, July30, 1965.
(99) KENDRICK, J., NETTESHEIM, P:,, HAMMONS, A.S. Tumor induction in
tracheal grafts: A new experimentat model for respiratory carcinogenesis
st'udies. Journal of'the NationaliCancer Institute 52(4)::1317-1320, April 1974.
(100) KENNEDY, A. Relationship between cigarette smoking and histological type of
lungcancer in women. Thorax 28(2): 204-208, March 1973.
(101) KERRW.K., BARKIN, M,, LEVERS, P:E.,,WOO, S.K: C., MENCZYK, Z. Thee
effect of cigarette smoking on, bladder carcinogens in mam Canadian Medical
Association Journa193(1): 1,7; July 3, 1965.
(102), KIDA, H., OMOTO, T., SAKAMOTO, K., MOMOSE,' S. Fukuoka ken hokubu ni
okeru boko shuyo no ekigaku to tokei (Statistical and epidemiological studies
on tumor of the urinary bladder in the northern parts of Fukuoka Prefecture).
Hifu to Hinyo 30(5) 1883-889, October 1968.
(103) KILIBARDA, M., PETROVIC., D., PANOV, D., DJURIC, D. Contamination
with polonium210, uranium and radium-226 due to smoking. Health Physics
12(11): 1808, November 1966. (Abstract)
(104) KIRYU, S:, KURATSUNE, M. Polycyclic aromatic hydrocarbons in the
cigarette tar produced by human smoking. Gann 57: 317-322, August 1966.
('105) KISSIN, B., KALEY, M. M., SUi W. H., LERNER, R. Head'.and neck cancer in
alcoholics. The relationship to drinking, smokingand dietary patterns: Journal
of the American Medical Association 224(8): 1174-1175, May 21, 1973.
(106) KNUDTSON, K.P. The pathologic effects of smoking tobacco on the trachea
and bronchial mucosa. American Journal of Clinical Pathology 33(4): 310-,317;.
April 1960.
(10Y) KOCHEN, W., HOCHBERG, K. Utersuchungen ueber dem tryptophan-stoff-
wechsel beim blasen-carcinom (Studies about the tryptophan metabolism in
carcinoma of' the bladder). Zeitschrift fuer Krebsforschung 72(3): 251-264,
January 29, 1970.
(108): KONTUREK, S.J., DALE, J., JACOBSON, E.D., JOHNSON, L.R. Mechanisms
of nicotine-induced inhibition of panereaticsecretion of bicarbonate inthe dog,
Gastroenterology 62(3): 425-429, March 1972.
(109) KOTIN, P., FALK, H'.L. Polluted urban air and related enviromental factors in
the pathogenesis of pulmonary cancer. Diseases of the Chest 45(3): 236-246,
March 1964.
(110) KRAIN, L.S. Ctossing of the mortality curves for stomach and pancreatic
carcinoma: International!Surgery57(4); 307-310, April 1972:
(111) ~ KRAIN, L.S. The rising incidence of carcinoma of the pancreas. An epidemiolog-
ic appraisall American Journal of Gastronenterology 54(5): 500-507, November
1970.
(111a) KREYBERG, L. Hist'ological lung cancer types; A morphological and biological
correlation. Acta Pathologica et Microbiolbgica Scandinavica (Supplement)
152, 1962, 92 pp.
(112) KRUEGER, F.W., POUR, P., ALTHOFF, J. Ihd'uction of pancreas tumours by
Di-Isopropanolnitrosamine: Naturwissenschaften 61(7): 328, July 1974. (Ab.
stract)
(113) KURATSUNE' 'M., KOHCHI, S., HORIEA. Carcinogenesis in the esophagus. I.
Penetration of'benzo(a)pyrene and other hydrocarbons into the esophageali
mucosa. Gann 56(2) : 177-187, April 1965.
5-65
M
ing. In a re-survey (122) done a: year later of a: segment of this
population (2,749 white students), he found a similar rate of smoking
for both girls and boys (30.2 and 32.4 percent, respectively). Cessation
of smoking, resulted in only partial reversibility of respiratory
symptoms within this time interval.
Kiernan, et al. (80): surveyed the respiratory symptoms and smoking
habits of a British population of 25-year-olds followed since birth and
previously examined at age 20. Current smokers had a 6.8 percent
crude prevalence rate of cough, day or night, as compared to a 3.1
percent rate: for those who had never smoked. Individuals who were
smokers at age.20 and 25 had an 11.6 percent prevalence of symptoms,
and individuals who had smoked at.20: but were ex-smokers at 25 had a
3.9 percent prevalence of symptoms.
In summary, these clinicali data suggest that cigarette smoking even
in these young age groups produces pulmonary symptoms. Cessation of
smoking leads to at least partial resolution of symptoms. Pulmonary
function (127) and histologic (:112) abnormalities also have been
observed in young smokers, confirming clinica.t suspicions of lung
injury in this group.
Early Stages of Respiratory Dysfunction
In an effort to identify individuals at highi risk for developing COLD, a
number of investigators have examined the relationship of smoking to
physiological changes not detectable by standard spirometry. Individu-
als with functional abnormalities in tests of small airway function may
be such, a high risk group. Anthonisen, et al. (5) observed abnormalfltiess
of regional gas exchange, as determined by inhaling 133Xe, in a group
of individuals with mild chronic bronchitis and well preserved lung
function as measured spirometrically. The authors attributed these
abnormalities to peripheral airway disease and suggested that the
functionally important lesions in chronic bronchitis might be in the
peripheral airways: Other investigators showed that airways less than
2 mm contributed little: to the totaD pulmonary resistance in patients
with normal lungs but were: the main site of airflbw obstructions in
patients with chronic bronchitis and emphysema (19, 69, 97). These
earlier reports le& to the development of tests believed to measure
small airway function.
A decrease in the ratio of dynamic to static compliance with
increases in respiratory frequency was demonstrated by Woolcock, et
al. (160) in a group of bronchitics with normal standard' spirometry.
This "frequency dependence of compliance" test appears to be a
sensitive indicator of small airway dysfunction but it is cumbersome to
perform and~ available in few laboratories.
The measurement of closing volume and of the slope of the alveolar
plateau on, a single breath nitrogen washout (6) are technically easier
to record and have been widely appl'aed~ in epidemiological surveys. The
6-12
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.r
closing
stop C(
percen
the al,
concen
measul
homog
indicat
:Vlax
capaci
small'
Such 1
airwa'
pereet
maxir
flow i
tion.
Sev
iUies i
nonsn
varial
Such
(rand
the a
seen
the ii
tests.
In
bet'w.
clinic
indiv
breal
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allvec
of tl
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TABLE 3.-Mortality from chronic bronchitis , emphysema, and 0
pulmonary heart disease in ex-cig arette smokerss
compared with mortality in lifelo ng nonsmokers. I
®
No. of deaths divided by number expected in lifelong No. of deaths in lifelong
nonsmokers. Years,since stopped smoking nonsmokers
I
0+ 5 5-9 10--14 >15
35.6 34.2 47.7 7.3 8.1 2
E
Current,smokers are d&ecribed as having stopped 0 years ago. .
SOURCE: Doll, R. (42)
Clinical data are more readily obtained than pathological or
physiologicali data. However, the relationship of early respiratory
symptoms to subsequent development of COLD is unclear. Physiologi-
cal data can be'quite specific (disease versus no disease), but, until
recently, functional tests were unable to detect the early effects of
smoking on lung function. Tests of smalli airway function may identify
su& a stage, i,e:, airways abnormality prior to symptoms and before
airflow reduction can be measured by conventional spirometry.
However, longitudinal studies demonstrating that individuals with
abnormal'tests of small airway function are at greater risk for COLD
are unavailable. Pathological data are the most specific and sensitive
parameters relating smoking to lung changes but generally are
inaccessible during life. A few studies are now available relating lung
pathology to smoking in young individuals.
Youthful Smoking and Respiratory Morbidity
A number of recent studies have established a higher prevalence of
respiratory symptoms in adolescent, teenage, and young adult smokers
as compared to nonsmokers. Bewley and Bland (13) examined; the
relationships between smoking and the prevalence of respiratory
symptoms in 14,033 children aged 10: to 12-1/2 in two separate areas of
the Unitett Kingdom. In this questionnaire survey, 4.7 percent
ackttowledged smoking at least one cigarette per week ("smoker") and
about 1 percent of the boys smoked more than one cigarette per day.
Male smokers, who outnumbered female smokers threefold, reported'
more morning cough (17:4 to 6.4 percent)s cough during the day or
night (41.4 to 20.5 percent), and' cough of 3 months duratiqn (14.5 to 4.8
percent) than, their nonsmoking classmates. These relationships were
similar to those in females although based on smaller numbers of
smokers.
Rush (1,23); in a survey of 12,595 high school students in Rochester,.
New York, found that reported respiratory symptoms (regular cough,
phlegm production, and/or wheezing)- strongly correlated with smok-
II
8
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(192) SMITH, L. W., BHARGAVA, K., MANI, N. J.,, MALAOWALLA, A.M,
SI'LVERMANS., JR. Oral cancer and precancerous lesions in 57,518 industrial
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(193), STASZEWSKI, J. Palenie a rak wargi, jamy ustneji migdalkow i' krtani
(Tobacco smoking and! its relation to cancer of the mouth tonsils and larynx).
Nowotwory 10(2): 121-132, 1960:
(194) STASZEWSKI,, J. Palenie tytoniu a rak przelyku i~ zoladka oraz choroba
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1961.
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5-71
®
a
I
I
N
TABLE 4.-Prevalence of abnormalities in tests of small airway function in smokers
Author
Year
Country
Reference
% smokers with abnormal test
Number and type CV% CC% AN2 VisoV V,,.xzs V,,.,so FEVIO FEV%
of population Sub-groups -
L
Buist, A.S. 524 cigarette smokers all smokers 35 44 47 11
1973 attending an emphysema <20 pack years 28 31
USA screening center 20-40 pack years 33 45
(20,21) >40 pack years 49 64
Benson, M.K. 214 heavy male smokers, young 12 6
1974 aged 2"5; 75 non- (20-30)
Great Britain smoking controls middle aged 34 21
(12) (40-55) -
Dirksen, H. 58 randomly selected
1974 smokers, aged 59;
Sweden 38 nonsmoking controls
(41)
Hutcheon, M. 17 mild smokers selec- 23.5 4&-67d 12
1974 ted from hospital
Canada r, personnel, aged 27.6
(72) ± 3.2 years; 18 age-
matched controlse
Marco, M. 71 volunteer smokers Smokers 18.5 20.3 0
1976 with normal spiro- Ex-smokera 11.7 11.9 0
Belgium metric testing All smokers 23.9 25 0
(103)
Ezss~39EO
TABLE 5.-Degree of emphysema in current smokers and in
nonsmokers according to age groups
Age
group
Degree of
emphysema Subjects
who never
smoked
regularly Current.
pipe or
cigar
smokers
Current cigarette
smokers#
<'/2t l/i-1>f 1-2t 2+ t
0-0.75 53 18 12 3 2 -
1-1.75 2 11 4 9 24 5
2-2.75 - 1 2 17i 130 56
<60' 3-3.75 - L 5 12 50 38
4-4.75 - - - 4 8 7
5-&.75 - - - - 4 5 1
7-9.00 - - - - 3 1
Total9 55 31 23 45 221 112
Mean 0.10 0.83 1.29 2.37 2.56 2.86
SD 0.04 013 0.26 0.16 0.07 0.10
0-0.75 35 17 4 - - -
1-1.75 1 8 1 - 4 1
2-2.75 2 3 4 5 37 23
64-69 3-3.75 2 2 2 9 42 24
4-4.75 - - 1 8' 11 9
5-6.75 - - - 1 8' 1
7-9:00 - - - 1 5 4
Totals 40 30 12' 19 107 62'
Mean 0.39 0.95 1.90 3.59 3.39 3.37
SD .0.13 0.16 0.34 0.35 0.15 0.2(1
0-0.75 68' 21 2 - - -
1-1.75 4 28 10: 8 2 2
2-2.75 5 22 13 23 40- 9
70 or 3-3<75 4 8 5 10 38 18
older 4-4.75 - 2 1 7 11, 7
5-6.75 - 1 - 2 9 3
7-9.00 - - - 1 12 5
Totals 81 82' 31 51 112' 44
Mean 0.50 1i66 Z15 2.98 3.68 3.91
SD 0.39 0.11 0.17 0.20: 0.17 0.27
Subjecta who smoked regularly up to time oftiterminal iillness.
tPackages/day.
60CRCE: Auerbach, 0. (10)
;
L
Smoking and the Pathogenesis of Lung Damage
In recent years, numerous investigators have examined the mecha-
nisms by which' smoking might induce lung damage. Three major
pathogenetic possibilities by which' smoking may damage the Iungs'
6-25
m
ur
a
9
I
evidence of bronchiolitis may be more common in cigarette smokers
than~in nonsmokers.
Increased susceptibility to and premature development of emphyse-
ma occurs in individuals with severe genetically determined' deficien-
cies of an antiprotease, alpha-l-antitrypsin. There is some evidence
that smoking hastens the development of COLD in such individuals but
it is unknown whether smoking places subjects with less severe types
of deficiency at a greater risk for developing emphysema.
Experimental animal and human data have demonstrated that
inhalation of cigarette smoke impairs pulmonary clearance, ciliary
funct!ion and alveolar macrophage activity. Pathological changes of
emphysema and fibrosis have been note& in dogs trained to inhale
cigarette smoke through a tracheostoma; these changes follow a dose-
response relationship.
Many recent studies confirm and extend these observations. In
addition~ there have been considerable advances in our understanding
of the relat'ionship of smoking to the natural history and pathogenesis
of these disorders. In the following discussion, these relationships will
be examined in subjects of all ages as well as in animal models.
Evidence will be presented documenting the effects of smoking on the
integrity of the bronehopulhnonarysystem, and the proposed pathogen-
etic mechanisms will be reviewed. Finally, a number of other risk
factors whi& may interact with smoking in producing lung damage
will be scrutinized.
Definitions
The terms chronic bronchitis and emphysema have been used
diagnostically for many years, but the criteria on which each diagnosis
rests have only recently been stated clearly (54). Physicians often use
these terms interchangeably to describe a patient with chronic airflbw
obstruction. The confusion between chronic bronchitis and emphysema
has been compounded further by the manner in which they have been
defined by various scientific societies in different studies, and in
different nations (55).
Clinically pure forms of chronic bronchitis and emphysema are the
exceptions rather than the rule. They are often difficult to distinguish
from each other in patients with~ chronic airflow obstruction because
(1) some degree of each may coexist in the same patient; (2) both
disorders are usually characterized by expiratory flbw obstruction;, and
(3) patients with either disorder frequent'1y present the same symptom:
dyspnea on exertion. Consequently the clinician oft'eni lubels the
patients with chronic expiratory flow obstruction as having COLD.
The most widely accepted definitions ini the United' States are those
of a joint committee of the American College of Chest Physicians and
the American Thoracic Society (4):
6-8
Buist, et al, (22) followed a group of 75 smokers attending a smoking
cessation clinic and observed significant improvementt in closing
volume; closing capacity, and the slope of the alveolar plateau at 6 and
12 months in subjects who stopped smoking. McCarthy, et al. (105)
found similar improvement in 131 subjects who stopped smoking;
resumption of smoking led to subsequent development of abnormali-
ties in the slope of the alveolar plateau and closing capacity. These
findings are especially pertinent in view of the suggestion~ by Cosio, et
al. (37) that some of the pathologic changes present when tests of small
airway functions are abnormal can be reversed.
As a group, ex-smokers usually perform better on conventional
pulmonary function testing than smokers, but they do not perform as
welll as nonsmokers (67), Several studies have confirmed that there is
improvement in performance on standard spirometric function tests
following cessation of smoking in small numbers of patients (85, 115,
159), but there is stilli debate as to whether the normal decline in
ventilatory function (i.e., FEV) is accelerated in ex-smokers as
compared to nonsmokers. In the Framingham study, Ashley, et al. (8)
observed that men and women who continued to smoke had a greater
decline in forced vital capacity (FVC) than those who stopped;
however, they could not demonstrate consistent changes in the FEV,
following smoking cessation. They attributed this to the impreciseness
and insensitivity of the FEVrmeasurement. In women ex-smokersthe
decline in FVC was similar to that of female nonsmokers; in male ex-
smokers, the decline in FVC was slightly greater than that of male
nonsmokers. Fletcher, et al. (57) observed that cessation of smoking
halved the rate of loss of FEV and returned; the rate of decline in FEV
to normal in "susceptible" smokers. However, the lost FEV was not
recovered. Smoking cessatiom had' no effect on the normal rate of
decline in "unsusceptible"' individuals. Similarly, in a two-year
followup of 118 continuing, ex-smokers, aged 27 to 56, Manfreda, et al.
(100) noted that subjects who continued to refrain from smoking had a
smaller decline in FEV,.a/FVC ratio than did smokers; in the male ex-
smokers the decline in ventilatory function fell at about the same ratee
as that for nonsmokers.
In summary, it is clear that smoking cessation leads to: improve&
performance on standard pulmonary function tests. However there is
still debate as t'o whether the normal decline in ventilatory' function is
accelerated in ex-smokers as compared to nonsmokers.
Lung Pathology
Auerbach, et al. (10) studied the relationship between age, smoking
habits,, and emphysematous changes in whole lung sections obtained' at
autopsy frorn 1,443 males and 388 females. A total of 7,324 sections 1
I
II
0
I
0
II
0
I
6-23
TABLE 6.-Age-standardized percentage distribution of malee
subjects in each of four smoking categories according
to degree of emphysema
Degree of
emphysema Subjects
who never
smoked
regularly
M Current!
pipe or
cigar
smokers
M
Current
cigarette
smokers (%)
<1' 11+
0-0.75 (none) 90.0 46.5 13.1 0.3
1-1.75 (minimal) 3.8 33.0 16.4 5.2
2-2.75 (slight); 3.3 13.01 33.7 42.6
3-3.75 (moderate) 2:9 6.3 25.11 32.7
4=9.00(advanced to far advanced) 0 1.2 11.7 192.
Totals 100.0 100.0 100:0 100.0'.
Packages6day,
SOURC& Auerbach, 0. (10)
TABLE 7.-Means of the numerical values given lung sections at
autopsy of male current smokers and nonsmokers,
standardized for age
Subjects who Current pipe
never smoked or cigar Current cigarette smokers,
regularly smokers
<.5
Pk. .5-1'
Pk. 1-2
Pk. >2
Pk.
Number of subjects 175 141 66 115 440 216
Emphysema 0.09 0.90 1.43 1.92 2:17 227
Fibrosis
Thickening, of 0.40 1.88 2.78 3.73 4.06 4.28:
arterioles
Thickening of 0.10, 1.11 L35 1.66 1.82 1.89.
arteries 0.02 0.23 0.42' 0.68' 0.83 0.90
NOTE: Numerical valueswere determined I by rating each lung section on seslAS ~ of, 04 for
emphysemaa and'
thickening of arterioles, 0-7 for fibrosis, and Oa3!for thickening of!arteries: .
SOURCE: Auerbach, 0. (9)
have been scrutinized. They are: (1) altering, protease-antiprotease
balance in the lungs, (2) compromising immune mechanisms, and (3)
interfering with pulmonarycDearance mechanisms.
Proteolytic Lung Damage
Emphysema is characterized by irreversible destruction of alveolar
septal tissue. If severe, this dlsruption may result in loss of elastic
(14y) MORGAN, R.W:,,JAIN, M.G. Bladder cancer: Smoking, beverages an&artificial
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Re-Examination and Update of Information on the Health Effects of
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mouse. Nature New Biology 236(65): 107-109, March 29,1972:
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(156) NEBERT, D.W., GOUJON, F.M., GIELENJ.E. Aryl hydrocarbon hydroxylase
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(155a) NATIONAL CLEARINGHOUSE FOR' SMOKING AND HEALTH. Patterns
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(155) NATIONAL CLEARINGHOUSE~ FOR SMOKING AND HEALTH. Adult Use
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Research, and Statistics, National Center for Health, Statistics. (To be
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(154c) NATIONAL CENTER FOR HEALTH' STATISTICS. Vital Statistics of the
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Health, Education, and Welfare, Public Health Service, Office of Health
(151,b) NATIONAL CENTER FOR HEALTH STATISTICS. Vital Statistics of the
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(154n.)' NATIONAL CENTER FOR HEALTH STATISTICS. Vital Rates of the United
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National Cancer Institute. DHEW Publication No. (NIH) 78-1837, 1978, 67 pp.
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MENTAL HEALTH SCIENCES. NATIONAL INSTITUTE FOR OCCUPA-
TIONAL SAFETY AND HEALTH. Estimates of the fraction of cancer in the
(153) NATIONAL CANCER INSTITUTE. NATIONAL INSTITUTE OF ENVIRON-
No. (NIH) 73-272; 1972,pp: 43-46, 81-84.
National Institutes of Health, National Cancer Institute. DHEW Publication
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(152) NATIONAL CANCER INSTITUTE. End results in~cancer. Report No. 4. U. S.
No. (NIH) 77-922,1976, pp. 1145.
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(151) NATIONAL CANCER INSTITUTE. Cancer patient survival. Report No. 5: U.S.
Department of Health, Education, and Welfare; Public Health Service,
National Institutes of Health, National Cancer Institute, DHEW Publication
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(1.¢9) MORGAN, R.G.H., WORMSLEY, K.G. Progress report. Cancer of the pancreas.
271: 308-310, 1976.
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(148) MORGAN; R:W., SHETTIGARA, P.T. Occupational asbestos exposure, smok-
16,1974.
sweeteners. Canadian Medical Association Journal III: 1067-1070, November
5-68
population, and for emphysema it was 9:8'per 1,000 population. In 1970,
persons with chronic bronchitis lost, on the average 1.4 workdays per
year, whilre those with emphysema lost more than 5 workdays per year
due to disability from these diseases.
The relationship between smoking and an increased prevalence of
respiratory symptoms in~ the adul t has been well establfishe& in~ studiess
of hospital and clinic patients, working groups, total communities, and
representative samples of the community (141, 145). Such symptoms,
particularly cough and sputum production, increase with increasing,
dosage of cigarettes smoked. The association of smoking with~
wheezing is similar, though less marked, to that seen with cough and'sputum. Chest illness during
the past 3 years, cough lasting 2 weeks or
more, and breathlessness are usually more prevalent in smokers than
in nonsmokers, but evidence for a dose-response is inconsistent. This
may be related to a decision by the smoker to reduce cigarette
consumption upon recognition of such symptoms (67).
COLD is more common~ in men thani in women; however, these
differences must be corrected for differences in the smoking habit,
since there are more male than female smokers. A number of earlier
studies found conflicting data regarding the prevalonce of symptoms
in women with smoking habits equivalent to those in men (139).
Lebowitz and Burrows (90), ini a recent study of 2,857' randomly
selected subjects aged 14 to 96, found no significant differences in the
telephone. The presence of infection was evaluated by krological' tests
for several viruses, Mycoplasma pneumoniae, and Hemophilus influen.
zae performed three times during the year. Among bronchitics,
infections (as measured by serological tests) were more frequent in
smokers than in nonsmokers; however clinical respiratory illness was
greater in nonsmokers. The authors suggest that this disparity may be
due to different perception of mild symptoms as disease in, the two
groups:
prevalence of symptoms in younger men and women with equivalent
smoking habits. However, male symptom rates were consistently
higher above the age of 60 and in ex-smokers with a greater than 23
pack-year smoking history.
In a survey of 500 working women, aged 25 to 54, Woolf (161) noted
a strong correlation between the number of cigarettes smoked and the
prevalence of respiratory symptoms (cough, sputum production`
wheezing, and shortness of breath). In comparing these results to
published data on men, Woolf concluded that smoking had similar
adverse effects on the respiratory system in women and men.
The relationship between smoking and acute respiratory infection
was examined by Monto, et al. (110) in individuals with COLD and in
two similar groups (comparable in age, sex, number of family
members) with no history of flow obstruction or chronic bronchitis: The
presence of respiratory illness was ascertained weekly, usually by
In
resp:
least
a gr
como
won
prev
e
of
h,
e
h,
se
fic
l4.
:h,
se
he
?M
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5-69
19 smokers and 36 nonsmokers. They could find no difference in IgA
levels; however, IgG levels,were twice as high in~smokers.
In summary, a variety of alterations in the specific immune system
have been observed that are presumably due to cigarette smoking.
Macrophages from smokers respond abnormally to MIF or antigen
challenges. T' lymphocytes obtained by bronchopulmonary lavage in
smokers showed a: diminished response to PHA compared to those of
nonsmokers. Cigarette smoke suppresses production of immunoglobu-
lin by B lymphocytes in lymphoid celll culture. However the role of
these abnormalit'ies in the pathogenesis of lung damage is unclear.
Effect on Clearance Mechanisms
The mucociliary transport system protects the lung against inhaled
particulate matter. Its two major components are the respiratory
mucus blanket (secreted by submucosal and goblet cells) and the
ciliated columnar epithelial cells lining the larger airways: Denudation
of epithelium, an increased number of goblet cells, and squamous
metaplasia have been demonstrated by Auerbach, et al. (11) in, dogs
exposed to cigarette smoke via a tracheostoma, and! by Leuchtenber-
ger, et al. (91) and Rylander (!124)', in mice and guinea pigs exposed to
cigarette smoke via their upper airway passages. Similar morphologic
abnormalities have been observed in human cigarette smokers (58). _
A number of investigators have examined! the effects of cigarette
smoke on mucociliary function, employing a wide variety of experi-
mental techniques. These studies have scrutinized the effects of gas
and particulate elements of cigarette smoke in both acute and chronic
situations.
Short-term exposure to cigarette smoke causes ciliostasis and
decreased mucociliary transport in most animals (152). The ciliotoxic
effects of cigarette smoke are not peculiar to tobacco cigarettes; they
have been observed in protozoans following exposure to smoke from
lettuce an& grass cigarettes (60). The data relating these effects to
specific particulate or gas phase elements of cigarette smoke are
conflicting (38): Moreovertherelevance to human conditions of animall
models demonstrating altered! mucociliary function in "smoking"
(tracheostomized) animals has been questioned, since,, in humans,
cigarette smoke passes the upper airways which might alter its
ciliotoxic capacity for the lower airways (152). Pata regarding the
effects of acute cigarette exposure on mucociliary clearance in man
also are conflict'ing,(152).
Long-term exposure to cigarette smoke has been examined in
animals and in man. Tracheal' mucous velocity has been shown to bee
decreased in purebred beagle dogs (153) exposed to 100 cigarettes per
week for 13.5 months. In donkeys (2), low level exposure to wholee
cigarette smoke accelerated tracheobronchial clearance; at intermedi-
m
6-32
TABI
~
mm thick were graded on a: scale of 0 to 9 according to the severity of
emphysema. No distinction was made between centrilobular and
panlobular emphysema. The men were classified by age, type of
smoking (pipe cigar or cigarette), and amount of cigarette smoking M Ag
,,.
Smoking habits were ascertained by interviews with relatives. Within
each of the six smoking categories, the mean degree of emphysemaa
increased with age. Adjusting the data for age revealed~ that the mean
degree of emphysema was lowest among men who never smoked, was
higher in pipe or cigar smokers, and highest among regular cigarettee
smokers. A dose-response relationship was found for the number of -2 ` <f
cigarettes smoked per day and! the severity of emphysema. These data
are presented in Tables 5 and 6.
In a subsequent histologic st'udy of tissue from 1,582 men and 368
womeny Auerbach, et al. (9) were able to show that rupture of alveolar
septa (emphysema) and fibrosis and thickening of the small arteriess
and! arterioles were far greater in smokers than in nonsmokers and
increased with increasing amount smoked (Tables 7 and 8).
When these researchers examined former cigarette smokers, they
found that those who had stopped more than 10 years prior to death
'= %
th
h
lb
ic
h
th
h
d
t
d l
h
d l
k
d
th
ose w
o
g
c
anges
an
o
a
s
oppe
ess
a
ess mar
e
pa
than 10 years before death. But even in~ those who had stopped for
more than 10 years, there was a greater degree of pathological change
in those who had been smoking more than one pack per day than in
those who had been smoking less than one pack per day (Table 9).
In a clinicopathologic study of 196 men and 46 women, Mitchell, et
al. (107) found that the totali exposure to cigarettes was related to
clinicali symptoms of chronic airway obstruction and to both alveolar
and airway pathologic features. The severity of patholbgic change was
related to the amount of smoking. ~~ 70
Several recent studies have shown evidence of small airway 01
abnormalities in young smokers. Cosio, et al. (37) found squamous
metaplasia of the airway epithelium as well as chronic inflammatory
infiltrate and a slight increase in the connective tissue in the walls of
the small airways. Kleinerman and Rice (83) found significantly more
emphysema, parenchymal pigment, and chronic bronchiolitis in the
lungs of smokers as compared to age-matched nonsmokers (median age
27.5 years). , 191 sU
In summary, cigarette smokers demonstrate more frequent abnor- ~ ~ Sol
malities in macroscopic and microscopic lung sections at autopsy than
do nonsmokers. Furthermore, there is a dose-response relationship A
4' Smt
between these chanaes and the intensity of smokina. Hist'olozic
~I in '
th
l
i
i
tt
ll
i
id
f
ogy was more common
gare
rways pa
o
n c
e
ev
sma
a
ence o
of 1& I nisn
-matched nonsmokens in an auto
s
stud
k
th
in
p
y
y
age
smo
ers
an
sudden-death victims. "3( patl
6-24
Cancer: References
(1): ABELIN, T., GSELL, O:R: Relative risk of pulmonary cancer in~cigar and pipe
smokers. Cancer 20 (8): 1288-1296, August 1967.
(2) ABRAMSON, RK., HUTTON, J.J. Effects of cigarette smoking on aryl
hydrocarbon hydroxylase activity in lungs and tissues of inbred mice. Cancer
Research 35: 23-29, January 1975.
(3) ACKERMAN, L~V., REGATO, J.A. Cancer diagnosis, treatment and prognosis.
St. Louis, C.V. Mosby Company, 1970, p.,412.
(4) AMERICAN CANCER' SOCIETY. 1978 Cancer Facts and Figures. American
Cancer Society, Inc:, New York,1977, p. 12.
(5) ANTHONY,,H.M., THOMAS, G.M. Bladder tumours and smoking. International
Journal of Cancer 5(2)r266-272, March~15, 1970.
(6) ARMITAGE, P., DOLL, R. Stochastic models for carcinogenesis.,In: Proceedings
of the Fourth Berkeley Symposium on Mathematical Statistics and Probabili-
ty. Biology and Problems of Health, Volume 4. Berkeley, University of
California Press,1961'.
(7) ARCHER, V.E., WAGONER, J.K., LUNDIN, F.E., JR. Uranium mining and
cigarette smoking effects on man. Journaliof OccupationaliMedicine 15(3)r204-
211, March 1973.
(8) ARMSTRONG, B., GARROD, A., DOLL, R. A retrospective study of renal
cancer with special reference to coffee and animal protein consumption.
British Journal of Cancer 33: 127-136,,1976,
(9) ASHLEY, D.J.B., DAVIES, H.D. Lung cancer in women. Thorax 24: 446-450,
1969.
('10)i AUERBACH, 0., GARFINKEL, L., PARKS, V.R. Histologic type of lung
cancer in relation to smoking habits, year of diagnosis and'sites of metastases.
Chest 67 (4):382-387; April 1975.
(11) AUERBACH, 0., HAMMOND, E.C., KIRMAN, D., GARFINKEL, L. Effects of
cigarette smoking on dogs. II. Pulmonary neoplasms. Archives of Environmen-
tal Health 21(6)i 754768; December 1970.
(T1a): AUERBACH0., STOUT, A.P., HAMMOND, &C., GARFINKEL, L. Histologic
changes in esophagus in relation to missing smoking habits. Archives of
Environmental Health 11(1): 4-15, July 1965:
(12) BAIR, W.J. Inhalation of radionuclides and carcinogenesis. In: Hanna, M,G., Jr,
Nettesheim, P., Gilbert, J.R. (Editors): Inhalation Carcinogenesis. Proceedings
of a Biology Division, Oak Ridge National Laboratory Conference, Gatlinburg,
Tennessee, October 8-11, 1969. U.S. Atomic Energy Commission, Division of
Technical Information, AEC Symposium Series No. 18, April 1970, pp. 77-101L
(13) BANOCZY, J., SUGAR, L. Progressive and regressive changes in Hungarian
oral leukoplakias in the course of longitudinal studies. Community Dentistry
and Oral Epidemiology 3: 194-197, August 1975.
(14) BEAMIS, J.F., STEIN, A., ANDREWS, J.L., JR. Changing epidemiology of lung
cancer. Medical Clinics of North America 59(2); 315-325, March 1975.
(15), BELCHER, J.R Adenocareinoma and smoking; Communications to the Editor.
Chest 67(5): 622-623, May 1975.
(16) BENARDE, M.A., WEISS, W.,A cohort analysis of pancreatic cancer, 1939-1969.
Cancer 39(3)i 1260-1263, March 1977.
(16a) BENNINGTON, J.L., FERGUSON, B.R., CAMPBELL, P.B. Epidemiologic
studies of carcinoma of the kidney. IL Association of renal! adenoma with
smoking. Cancer 22(4): 821-823, October 1968.
(17) BENNINGTON, J.L., LAUBSCHERF.A. Epidemiologic studies on carcinoma
of the kidney. I. Association of~ renal adcnocarcinoma with smoking. Cancer
21(6): :1069-1071, June 1968.
I
5-59
®
®
played by both macrophages and lymphocytes has been offered by
several investigators.
The alveolar macrophage system, plays an important role in the
overall immune response as an antigenic "processor." Warr and Martin
(154) studied alveolar macrophages lavaged from four healthy smokers
and four healthy nonsmokers. Only two members of each group were
reactive to skin~ tests with Candida albicans. The migration of
macrophages from nonsmokers was inhibited by migration inhibitory
factor (MIF) whereas macrophages from smokers did, not respond, to
MIF. The cells from smokers were noted to migrate three times faster
than those from nonsmokers. When Candida antigen was added to the
medium cells from the nonreactive subjects (both smokers and
nonsmokers) were not inhibited. The cells from the reactive nonsmok-
ers were inhibited, but not those from reactive smokers. Thus,
macrophages from smokers did not respond normally either to MIF or
antigenic challenge.
The B and T' lymphocytes participate in humoral and' cell-mediate&
immune mechanisms, respectively. Warr, et al. (155) noted that a
greater number of T cells and B cells were recovered by human
bronehopulmonary lavage from smokers than from nonsmokers.
Daniele, et al. (39)~ examinedt'heT and B cell populationsins peripheral'
blood of smokers versus nonsmokers and found no difference in either
the absolute number of cells or the lymphocyte response to phytohema.
glhztinin (PHA) or concanavalin A. In a lavage study of five smokers
the lymphocyte subpopulation did; not differ from~ that in nonsmoking
subjects,(h=8), but cells from smokers showed a diminished response
to PHA and concanavalin A. They concTud'ed that cigarette smoking
may impair cellular immune defenses.
In contrast, Silverman, et al. (131) found that young smokers had an
increased number of T lymphocytes in peripheral blood and an
enhanced response to PHA. No differences were found in the response
of older smokers or those with a history of heavier cigarette
consumption as compared to controls. A number of other studies havee
examined the relationship of smoking to T-celli function; these are
reviewed in the Chapter on Allergy and Immunity.
Roszman and Rogers (121) noted that both the nicotine and the
water-soluble fraction of whole cigarette smoke suppressed the
immunoglobulin response of lymphoid cell cultures to antigen chal-
lenge. When concentrations of over 200 micrograms per milliliter of
nicotine of the water-soluble fraction were added, they were able to
suppress completely the immunoglobulin response; this suppression~
also occurred in cells exposed 2 hours prior to the antigenic challenge.
In, a subsequent experiment, they found suppression of mitogen-
induced blastogenesis by cigarette smoke (120). Warr, et al: (156)
examined immunoglobulin levels in bronchopulmonary lavage fluid in
mm
I
0
®
I
6-31
TABLE 26.-Tumor promoters and co-carcinogens in the
particulate phase of tobacco smokel
Smoke compounds Amount in
smoke of one cigarette
Tumor promoters
Volatile phenols
1501500µg
tinknown~ weakly, acidic compounds
L'nknowm neutral compounds v
~
Cb-carcinogens
Pyrene
5Q200ng
Methylpyrenes 304OOng
Fhjoranthene 100-260ng
Methylfluoranthenes 18(Ing
Benzo(ghi)perylene 60ng
Benzo(e)pyrene 30ng
Other PAH ?
Napthalcnes 0.3-&.3µg
1-Methylindoles 083Ag
9-liethyloarbazoles 0'14W
4,4'-Dichlorostilbene 1.5µgz
Other neutral compounds ?
Catechol 2OO- 6WNg
4-Alkylcatecholl l0µg
Other acidic compounds ?
'So far with certainty identified.
2Values ace decreasing because.of lesser use of DDT and DDD for tobacco eultivation..
SOURCE: Wynder, E.L. (P4.f)
Aryl Hydrocarbon Hydroxylase
AHH activity is present in most tissue of the body. It is indklced by
treatment in vivo or in vitro with a variety of PAH or related
chemicals. Tobacco smoke inhalation elevates AHH activity in
respiratory tissues of laboratory animals (2, 51, 231) and in human
peripheral lymphocytes and puhnonary alveolar macrophages(29, 129).
Inducible levels of the enzyme vary both with the tissue and with the
i¢ldiwid'ual (60; 97, 156).
Kellermann, et al. (25, 96) reported that the percentage of lung and
laryngeal: cancer patients with highly inducible AHH levels was much
greater than in the normal population. On the other hand, there have
been reports in which the inducibility of AHH in lung cancer patients
either did not differ signiflicantly from~ controlled populations (123) or
was lower than in controls (17). Further research is necessary to clarify
the relationship between cigarette smoking, AHH inducibility and~ the
development of cancer.
5-57
N
0
I
0
®
In another study from the same laboratory,, Blue and Janoff (16)
demonstrated that cigarette smoke condensates elicited the release of
elastase from human PMNs. When human PMNs were incubated in
artt'ro with cigarette smoke condensate, three enzymes were released:
beta-glucuronidase, acid phosphatase, and elastase. The elastase was
active in digesting elastin, even in the continuing presence of cigarette
smoke condensate. When mixtures of human PMNs and cigarette
smoke condensate were instilled into rat lung in vitro, elastase was
released and could be: traced to connective tissue targets using
immunohistochemical and enzyme-histochemical techniques: This
study appears to be particularly relevant in view of previous studies
demonstrating that cigarette smoke recruits leukocytes into the lung
airways (81,124'), immobilizes them (46), and, inhibits their chemotaxiss
in vitro (17).
The role of the pulmonary macrophage in proteolytic lung damage
has been evaluati& by severali investigators. Alveolar macrophages are
normally important in, cleansing the lower airways by phagocytising
and digesting foreign particulate matter. Bronchopulmonary lavage
studies have documented increased total numbers of macrophages in
lavage fluid~ of smokers as compared to nonsmokers (65, 1,56). Keast
and Holt (79) exposed mice to smoke via a special~ apparatus and found
sustained elevations in bronchopulmonary macrophage populations.
Changes in the ultrastructure of macrophages have been reported in
smokers. Pratt, et al. (116) observed pigmented cytoplasmic inclusions
in macrophages from cigarette smokers. Brody and Craighead (18)
observed that the pigmentation appeared~ to be due, at least in part, to
an increased number of lysosomes and phagolysosomes: In addition,
distinctive "smoker's" inclusions were observed within these cyto-
plasmic organelles which appeared plate-like and' cryst'allographically
consistent with kaolinite. The authors presented some preliminary
evidence that these particles are derived from, inhaled tobacco smoke.
Kaolinite is a common clay mineral found in the soil in many t,obacco
growing regions and is sometimes used as a tobacco additive in the
production of cigarettes for the purpose of reducing tar content. A few
studies have shown that when macrophages engulf kaolinite they
release beta-gulcuronidase and lactic acid dehydrogenase, lysosomal
enzymes believed to play a role in cell!death and fibrogenesis in vivo (3,
66, 157). In a recent study, Matulionis and Traurig (10.4) exposed
pulmonary macrophages of mice in situ to cigarette smoke tLnd found:
(1): an increase in number, variety, and size of lysosome-like bodies, in
the macrophage; (2) the appearance of multinucleation; and (3) an
increased size of the macrophages. After cessation, of smoke exposure,
macrophage morphology and population size returned toward normal.
A considerable increase in elastase-like esterase and protease
activity was demonstrated by Harris,, et al. (64) in human alveolar
macrophages in smokers as compared' to nonsmokers. In a subsequent-
6-29
M
M
a
I
I
I
8
I
study, Rodriguez, et al. (119) demonstrated that human alveolar
macrophages from smokers released elastase into serum-free culture
mediums unlike those from nonsmokers. Elastase was not detectable in
cell homogenates from either smokers.or nonsmokers, implying that
this enzyme is not stored. The authors suggested that cigarette
smokers have the potentiall for a 20-fold increase in elastase released in
the lungs when the increased number of macrophages in lungs of
smokers also is considered.
Potentially important effects of cigarette smoke`also have been
demonstrated on alveolar macrophage pinocytosis (164)1 cell adhesion
(61), cell migration (154); and protein synthesis (94', 95, 163): The data
relating the effect of cigarette smoke to alveolar macrophage
phagoocytosis and bacteriocidal activity are conflicting (61, 130, 135,
137) but generally have shown cigarette smoke to have a suppressant
effect. At least some of the toxic effects of the gas phase of cigarette
smoke on macrophage activity may be due to the oxidant, acrolein (74):
In summary, a number of recent investigations have suggeste& that
a destruction of the: elastic framework of the lungs seen in COLD may
result from a protease-antiprotease imbalance. Although definitive
evidence is lacking, it appears that alveolar macrophages and PMNs
are the most important sources for the proteases: Cigarette smoke
appears to increase the rate of synthesis and release of elastase in vitro
from human alveolar macrophages and increases their numbers.
Antiproteases are inhibited' from counteracting protease activity in~ the
presence of cigarette smoke in vitro. Possible deleterious effects of
cigarette smoke also have been demonstrated on a variety of functions
of the human alveolar macrophage:
Interference with Immune Mechanisms
The lungs have a highly developed lymphatic system and the capacity
to effect local immune responses. Inhalation of tobacco smoke produces
significant changes in cellular and humoral immunity in both animal
and man. H'owever, the role of such changes in the pathogenesis of
lung disease remains speculative. Waldman, et al. (151) reported that
cigarette smokers of more than 1/2 pack per day had! an increased risk
of influenza-like illnesses although the length of illness was no
different than for nonsmokers.
Finklea, et al. (52) noted that smokers had more frequent subclinical
influenza: than nonsmokers; subsequently he observed that thee
serological response (hemagl'utination antibody titers) to either
vaccination or natural infection with A-2 antigens was similar to that
in nonsmokers but not as long lasting (51).
Cigarette smoke appears to adversely affect the nonspecific
(phagocytosis) defense mechanisms provided by the: alveolar macro-
phage. Evidence for an effect on the specific (immune) defense roles
6-30
pla,
sev4
T
ove
(15,
anc
rea
ma
fac
MI
the
me
nol
ers
me
ani
I
The proteases are a group of enzymes which probably serve a wide
range of functions in the normal host. Proteases with particular
elastolytic capability (elastases) are synthesized and released by
alveolar macrophages which are found in increased numbers in
bronchopulmonary lavage fluid of smokers. They are also present in
significant concentrations in polymorphonuclear leukocytes (PMNs).
The antiproteases, of which alpha-l-antitrypsin is the most abun-
dant, are found primarily in blood although alveolar macrophages and
bronchial secretions are additional sources of antiproteases. An excess
of protease within the lung may arise from any circumstances in whi&
there is increased release of protease which is not matched by
availability of antiprotease activity at the site of such release. Various
types of experimental support for the proteolytically mediated
hypothesis of lung damage have been presented in recent years (15, 75,
77)132).
Crude leukocyte extracts can digest lung tissue (76, 92); and
homogenates of leukocytes can prodtzce emphysema (101, 103) when
instilled into the lungs of animals: The degree of damage depends on
the proteolytic activity of the instillate (82). Recently, Senior, et al.
(129) instilled purified human loukocyte elastase into the tracheas of
hamsters. At two months the lungs of the animals showed mild, patchy
emphysema. In a related study, Schuyler, et al. (126) administered
elastase to hamsters intravenously and demonstrated significant loss
of elastic recoil at low lung volumes when their lung histology was
normal. The authors suggested that submicroscopic lesions may
antedate obvious morphologic evidence of emphysema.
The mechanisms by which cigarette smoking may alter the protease-
antiprotease balance have been the subject of several recent investiga-
tions. Janoff and Carp (74a) demonstrated that unfractionated
cigarette smoke condensate suppressed antiprotease activity in vitro.
Elastin-agarose gels were impregnated with cigarette smoke conden-
sate. Elastases were then allbwed to diffuse through the gels toward a
counter-diffusing sample of antiproteases. The effectiveness of the
antiproteases in blbcking the enzyme was determined by the extent of
elastin destruction in the plates. Elastins, proteases, and antiproteases
from different sources, in6iding, purified human leukocyte elastase
and human alpha-l-antitrypsin, were tested. In all situations, the
cigarette smoke condensate suppressed the inhibitory activity of the
antiprotease. In a followup study, Carp and Janoff (26) demonstrated
that fresh cigarette smoke also suppressed elastase-inhibitory activity
of human serum. In addition, treatment of serum with model oxidantss
caused a similar suppression of elastase inhibition. These in vitro
observations suggested to the researchers that emphysema in cigarette
smokers might be due in part to the suppression of antiprotease
activity by oxidizing agents present in cigarette smoke:
6-28
11
Ir
dem
elas
vitr'
bete
acti
smo
smo
rele
imn
stuc
den
airv
i& v
T'
has
nor
and
stu(
lav:
and
sus
C
smc
in
obs
an
dis
pla
cor
evi
Ka
grc
prc
stu
rel
en.
66,
pu:
(1)
thc
inc
mZ
ac1
mc
~;
7. INTERACTION BETWEEN SMOKING
AND OCCUPATIONAL EXPOSURES.
0
9
I
9
I
National Institute for Occupational Safety and Health
(53) DRUCKREY, H., PREUSSMANN; R., BLUM, G., IVANKOVIC, S., AFKHAM,
J. Erzeugung von karzinomen der spelseroehre dur& unsymmetrisehe
nitrosamine (Esophageal carcinomas induced by asymmetric nitrosamines),
Naturwissenschaften 50(3): 100:101,1963!
(54) DRUCKREY, H.,, PREUSSMANN, R., IVANKOV'IC;, S., SCHMAEHL, D.
Organotrope carcinogene wirkungen bei 65 verschiedenen N-nitroso-verbin-
dungen an BD-ratten (Organotropic carcinogenic effects of 65 different'~ N-
nitroso- compounds on BD-rats), Zeitschrift fuer Krebsforschung 69(2): 103-
201, March 22, 1967.
(55); DUNHAM, L.J., RABSON, A.S., STEWART, H.L., FRANK, A,S: YOUNG, J.L.,
JR. Rates, interview, and pathology study of cancer of the urinary bladder in
New Orleans, Louisiana. Journal of the National Cancer Institute 41(3): 683.
709, September 1968.
(56) DUTTA-CHOUDHURI, R., ROY H.,, SEN GUPTA B.K. Cancer of the larynx
(68
(65
(69c
and hypopharynx. A clinicopathological study with~ special reference to
aetiology. Journal of the Indian Medical Association 32 (9): 352-362, May 1,
1959.
(57) EBENIUS, B. Cancer of the lip. A clinical study of 778 cases with particular
regard' to predisposing factors and radium therapy. Acta Radiologica 24
(Supplement 48): L-232, 1943. (7
(58) FELDMAN, J.G.,,HAZAN; M., NAGARAJAN, M.,,KISSIN, B. A case-control
(59) investigation of alcohol, tobacco, and diet in head and neck cancer. Preventive
Medicine 4(4): 444-463, December 1975,
FIGUEROA,, W:G:,, RASZKOWSKI, R.,, WEISS, W. Lung cancer in chlorome-
thyl methyl ether workers. New England Journall of Medicine 288(21): 109fr
1097, May 24, 1973.
(60)~ GIELEN, J.E., GOUJON, F.M., NEBERT, D.W. Genetic regulation of aryl
hyd'rocarbon hydroxylase induction, II. Simple Mendelian expression in mouse
tissues in vivo. Journal of Biological Chemistry 247(4): 1125-11f37, February 25,
1972.
(61) GLOYNE, S.R. Two cases of squamous carcinoma: of the lung occurring in
asbestosis. Tubercle 17: 5-10, October 1935.
(62) GRAHAMS., DAYAL, H.,,ROHRER, T.,,SWANSON; M., SULTZ, H.,,SHEDD,
D., FISCHMAN, S. Dentition, diet,,tobacco, and alcohol in the epidemiology of
oral cancer. Journal of the National Cancer Institute 59(6): 1611-1618,.
December 1977.
(63) HAENSZEL, W., SHIMKIN; M.B., MANTEL, N. A retrospective study of lung
cancer in women. Journal of the National Cancer Institute 21(5): 825-842,.
November 1958.
(64) HAENSZEL, W:, TAEUBER, K.E. Lung-cancer mortality as related to
residence and smoking histories. II. White females. Journal of~ the Ngtional'
Cancer Institute 32(4); 803-838, April 1964.
(65) HAMMOND, E.C. Smoking inirelation to the death rates of one million men and
women. In: Haenszel; W. (Editor). Epidemiological Approaches to the Study of
Cancer and Other Chronic Diseases. National Cancer Institute Monograph No.
19. U.S. Department of Health; Education, and Welfare, Public Health
Service;,National Cancer Institute, January 1966, pp. 127-204:
(66) HAMMOND, E.C., AUERBACH, 0., KIRMAN, D., GARFINKEL, L. Effects of
cigarette smoking,on dogs. I. Design of experiment, mortality, and findings in
lung parenchyma. Archives of Environmental Health 21(6): 740-753, December
1970.
(67) HAMMOND, E.C., GARFINKEL,,L., SEIDMAN, H., LEW, E.A. Some recent
findings concerning cigarette smoking. In: Hiatt, H.H., Watson, J.D;, Winst'en,.
J.A. (Editors). Origins of Human Cancer. Book A: Incidence of Cancer in
Humans. New York, Cold Spring Harbor Laboratory, 1977, pp. 101-112.
5-62
G
,
(7
i
Examples Where Action Between Smoking and
Occupational Exposure Has Been Suggested or Only
Hypothesized .................................................... 15
Cadmium ..................................................... 15
Chloromethyl Ether ....................................... 15
Beta-Naphthylamine and Other Aromatic
Amines .................................................... 16
Trends in Smoking Habits and in Morbidity and Mortality
Rates for Various Occupational Groups ...................... 17
Summary and Recommendations .................................. 18
Recommendations for Research .............................. 19
References ............................................................... 20
LIST OF FIGURES
Figure 1. -Respiratory cancer rates among uranium
miners by cigarette usage and~ radiation exposure
compared with rates among nonminers ...................... 14
7-4
TABLE 1.-COLD mortality ratios in six prospective studies
British Men in 25 States U;S., Canadian MenJn California ~~
Doctors 45-64 65-79 Veterans Veterans 9 States Occupations ~
Emphysema and/or
bronchitis 2,4.7
10.08
-
230
4.3
Emphysema with-
out bronchitis -
6.55
11.41
14.17
7.7
Bronchitis - - - 4.49 11.3 - -
SOURCE: See Table 41 of Chapter 2. Mortality.
TABLE' 2.-Smoking habit when last asked and death from
chronic bronchitis and emphysema
Annual death.rate per 100,000 men, standardized for age X2
N
f Current'
N
E
t
k
C Current smokers
b Nonsmokers Trend
o: o
deaths on-
x-
°n ex smoker
smokers urren
smo
ers
any tobacco any to
aeco.
(g/day)
vs
(dose
N
smoker other response)
1-14 15-24 25
254 3 48 44 50: 38 50 88 25.58' 47.73
p<0.o01
SOURCE: DolIJ R. (4P)
Doll and Peto (42) have recent'ly reported their 20-year followup of
34,440 British male physicians. The data, presented in Table 2,
demonstrate an increased mortality ratio in all current smokers and a
dose-response relationship to the number of cigarettes smoked. They
also found a: 1.5-fold higher deathi rate in smokers who inhaled as
compared to smokers who did not inhale. The mortality in individuals
who quit smoking increased during the fifth to ninth year but
thereafter fell sharply (Table 3). The authors suggest that the men
who died during this period from lung disease stopped smoking
because they had irreversible disabling disease such that a few more
years of normal functional decline resulted in their death.
Smoking and the Natural History of COLD
The adverse effects on the lungs of smoking have been demonstrated
in very young, working, age, and elderly populations. Altihough there is
a clear relationship between the presence of COLD and a: prior history
of smoking, only a small proportion of smokers are severely disabled
and die from COLD. Therefore, many investigators have scrutinized
the natural history of smoking-related lung changes in~ an attempt to
identify smokers at increased risk of developing COLD. Three methods
have been employed: clinical~ physiological, and patholbgical.
TA
P,
Y
A
rf
a
rE
sl
t]
r
P
6-10
(36) COBB, B.G., ANSELL, J.S. Cigarette smoking and cancer of the bladder.
Journal of the American Medical Association 193(5)i 329-332, August 2, 1965.
(37) COLE, P. Cancer and oecupation: Status and needs of epidemiologic research.
Cancer 39(4): 1788-1791i, April 1977.
(38) COLE, P., MONSON, R.R., HANING; H., FRIEDELL, G.H. Smoking and
cancer of the lower urinary tract. New Englandi Journal of Medicine 284(3)c
129-134, January 21, 1971.
(39) DAY, N.E. Some aspects of the epidemiology of esophageal cancer. Cancer
Research 35(2): 3304-3307November 1975:
(40) DEANER, R.M., TRUMMER, M.J. Carcinoma of the lung,in women. Journal of
Thoracic and Cardiovascular Surgery 59(4): 551-554, April 1970.
(/,Z) DEELEY, T.J.,, COHEN, S.L. The relationship between cancer of the bladder
and smoking.. In: Bladder Cancer. Proceedings of the 5th Inter-American
Conference on Toxicology and Occupationali Medicine. Coral Gables; Florida,
University of Miami, School of Medicine, 1966pp. 163-169.
(42), DOLL, R. The age distribution of cancer: Implications for statistical models of
carcinogenesis. Journal of the Royal Statistical Society 134(Part 2): 133-166,
1971.
(!,3) DOLL, R. Atmospheric Pollution andl Lung Cancer. Environmental Health
Perspectives 22: 23-31, February 1978.
(44) DOLL, R. Cancer of the lung and nose in nickel workers. British Jburnal of
Industrial Medicine 15(4): 217-223, October 195K
(45) DOLL, R. Strategy for detection of cancer hazards to man. Nature 265(5595):
589-596, February 17, 1977.
(46) DOLL, R., HILL, A.B. A study of! the aetiology of carcinoma of the lung. British
Medical Journali2: 1271-1286, December 12, 1952.
(47) DOLL, R., HILL, A.B., KREYBERG, L. The significance of cell type inirelation
to the aetiology of lung cancer. British Journal of Cancer II: 43-48,1957:
(47a) DOLL, R.,,PETO, R: Mortalityin, relation to smoking: 20 years' observations on
male British doctors. British Medical Journal 2(6051); 1525-1536, December 25,
1976.
(48): DONALDSON, A.W. The epidemiology of lung cancer among,uranium miners.
HealthiPhysics 16: 563-569, 1969.
(.49) DONTENWILL, W., CHEVALIER, H..J., HARKE, H.-P., LAFRENZ, U.,
RECKZEH, G., SCHNEIDER, B. Investigations on the effects of chronic
cigarette-smoke inhalation in Syrian golden hamsters. Journal of the National
Cancer Institute 51(6): 1781-1806, December 1973.
(50) DONTENWILL, W., CHEVALIER, H.-J!, HARKE, H.-P., KLIMISCH, H.J.,.
KUHNIGK, C:, RECKZEH', G., SCHNEIDER, B. Untersuchungen ueber den
effekt der chronischen zigare menrauchinhalation beim Syrischen goldhamster
und ueber die bedentung des Vitamin A auf die bei~ berauchung gefundenen
organveraenderungen (Studies on the effect' of chronic cigarette, smoke
inhalation in Syrian golden hamsters and'& the importance of Vitamin A on
morphological alterations after smoke exposure): Zeitschrift fuer Krebsfor-
schung und Klinische Onkologie 89(2): 153-180, 197Q:
(51) DRATH, D.B.,,HARPER, A., GHARIBIAN, J., KARNOVSKY, M.L., HUBER,
G.L. The, effect of tobacco smoke on the metabolism~ an& function of rat
alveolar macrophages. Journal of Cellular Physiology 95: 105-1131978.
(52) DRUCKREY, H., LANDSCHUETZ, C., PREUSSMANN, R. Oesophagus-carci-
nome na& inhalation von methyl-butyl-nitrosamin (MBNA) am ratten
(Carcinomas of' the oesophagus, induced by inhalation of inethyl-but'yl-
nitrosamine (MBNA) in rats). Zeitschrift fuer Krebsforschung 71(2):,135-139,
July 1968.
©
0
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5-61
1000
800
600
400
200
200
180
W
v 160
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~ 140
K
120
100
SMOKING INDEX F~,EV.I/EVC~
cry/v~r .. 1.0.,
.
120
MMF RV'
%Wa
7t/0r
% Pr.d
J 0.9 100 } j
~ 0.8~I 80.
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0.7 7,111 -TT 60
0.8 40
1 -- ~
1 t0O
~ -- ~ ~
T I
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CC VISpVLNZ/L oVmo.60,
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~1
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300
200
100
1
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1J
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400
300
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PAT:HOLOGV GROUPS~.
1; MEAWS.E..,-- F<0.05.nE--<P0r011
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170
100
80
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I
FIGURE 1.-Comparison of increasing small airways disease
(Group I-IV) to smoking and pulmonary function
SOURCE: Cbsio, M. (J7)
FEVI percent. However, the mechanisms responsible and the demon-
stration of such a sequenee remain to be demonstrated.
In summary, a variety of function abnormalities believed to
represent small airway dysfunction occur in smokers. Many such
individuals demonstrate normal expiratory flow' rates as measured by
conventional spirometry. In one prospective study abnormalities in
tests of small airway function appeared to correlate well with
pathologic abnormalities of the peripheral airways. It has been
suggested that such changes may be precursors of further a~normality
if smoking were continued'; however, prospective studies relating small
airway physiological and/or pathological! abnormalities to the subse-
quent development of COLD are lacking.
Respiratory Morbidity in the Adult.
In 1970, in the United States, the combined prevalence of chronic
bronchitis for members of both sexes over age 17 was 29.5 per 1,000
6-19
0
TABLE 4.-Prevalence of abnormalities in tests of small airway function in smokers-Continued
Author % smokers with abnormal test
Year Number and type
Country of population Sub-groups CV% CC& AN2
- VisoV V.m V,,bo FEVi.o FEV6
-
Reference L
Cherniack, 12.M.
1977 1456 randomly selected
subjects from 3 cities Winnipeg (n-112)
men
14
28
12
USA, Canada (40% smokers) aged 25- women 20 26 20
(31) (Cont'd) 54.
combined 17 25 23
Oxhoj, H.
1977 502 randomly selected
50 and 60 year old male 50-year-old men
ex-smokers
13
18
32
2
5
10
Sweden smokers - 129 nonsmoking moderate smokers 9 15 41 3 5 18
(114) controlsb heavy smokers 12 20 58 7 10 37
60-year-old men
ex-smokers
10
17
18
2
4
15
moderate smokers 19 24 38 2 17 22
heavy smokers 23 22 45 1 18 22
Manfreda, J.
1977 534 randomly selected
smokers and ex-smokers Men (n-301)
Canada aged 2455 Smokers 21.1 28.7 45.4 24.1 19.8 13.4
(98,100) ex-amokers 14.2 17.0 25.5 22.8 21.9 11.4
Women (n-233)
smokers
6.7
6.7
45.3
24.7
323
25.9
ex-smokers 4.4 5.9 19.1 12.0 20 189
szssgsEo
23
26
10
7
22
10
18
22
12.8
7.9
82
6.7
®
Although definitive evidence is lacking, it appears that PMNs and
alveolar macrophages are. the most important sources for the
proteases. Cigarette smoke appears to increase the rate of synthesis
and release of elastase in vitro by human alveolar macrophages.
Antiproteases are inhibited in the presence of cigarette smoke in vitro.
Cigarette smoke also has been demonstrated to impair a variety of
functions of the human alveolar macrophage.
Inhalation of tobacco smoke produces detectable changes in compo-
nents of the cellular and humoral immune systems in~ bothanimal and
man. Macrophages obtained' by lung lavage from smokers respond
abnormally to MIF or antigen challenge. T lymphocytes obtained from
bronchopulmonary lavage show a diminished response to PHA in
smokers. Cigarette smoke suppresses production of immunoglobulin by
B lymphocytes in lymphoid cell' culture. However, the role of these
abnormalities in the pathogenesis,of lung damage is unclear.
Individuals with severe alpha-l-antitrypsin deficiency have an
excessive risk for developing COLD; the onset of symptomatic COLD
is probably accelerated by smoking. The natural history of individuals
with mild or moderate alpha-l-antitrypsin deficiencies is unclear, as is
the effect of smoking on such individuals.
Genetic factors other than alpha-l-antitrypsin deficiency appear to
play a role in determining the risk for COLD. Common lung diseases
may be due to a: combination of risk factors varying from one
individual to another. The risk may be modulated by different genes in
combination and by different environmental factors (e.g., smoking).
A recent study examined the relationship of smoking to socioeco-
nomic status and, chronic respiratory disease. The prevalence of chronic
bronchitis was higher in cigarette smokers than in nonsmokers, higher
in blue-collar workers than white-collar workers, and least among men
with the: most educa.tion, However, most of the differences in the
prevalence of chronic bronchitis in subjects of differing occupational,
educational, or income classes was attributable to differences in
smoking habits: Compared with smoking, poor occupations, educational
background, and economic circumstances have only a weak deleterious
effect.
Childhood respiratory disease appears to be a' risk factor for
respiratory symptoms as an adult. However, cigarette smoking appears
to be a more important factor in increasing risk for developing these
symptoms.
Research Recommendations
The extensive studies already performed have identified several areas
that merit particular investigational attention because of their promisee
in elucidating the effects of smoking and other risk factors upon the
development of COLD:
I
0
n
a
I
0
6-41
(1) Current data suggest that early detection of pulmonary
Investigations documenting the relationships between tests for small
functional and histolbgic changes in asymptomatic smokers may
identify populations which are particularly susceptible to: COLD.
ties to the development of COLD.
the impact of smoking cessation upon these early abnormalities, and;
most important, to (b) define the relationship of these early abnormali-
extended. In addition, longitudinal studies are needed to (a) document
airways dysfunction, pulmonary histology, and symptoms should be
(2) Similar longitudinal studies in patients with well-defined COLD
should be carried out to define the effects of smoking cessation on
clinical, physiologic, and anatomic parameters.
genesis of pulmonary elastic tissue injury has received substantial
(3) The protease antiprotease imbalance hypothesis for the patho-
support from investigations reported to date. Observations are
available which suggest mechanisms by which cigarette smoke might
promote an injury-inducing imbalance in man. Appropriate extensionss
of both in vitro and in vivo investigations which bear upon~ this
man.
among investigators pursuing resear& in vitro, in animals, and in
program also should provide for effective interchange of information
vivo investigations (in animal model's and in man). Such a balanced
support should' seek a balanced program providing, for in vitro and in
impacts upon these mechanisms to promote COLD. Thus, research
the development of COLD in man and the manner in which smoking
to the primary goal, i.e., elucidation of the mechanisms responsible for
smoking and the mucociliary ("clearance") ~ apparatus are warranted.
In all of the above areas, research planning should include attention
(6) Further investigations of the relationship between cigarette
immune system interactions should be encouraged.
of relevant in vitro and in vivo investigations dealing, with smoking-
(5) There are in vitro effects of smoking and cigarette smoke on both~
the humoral and cellular components of the immune system. Extension
be encouraged.
longitudinal, of subjects with severe and mild-moderate deficiencies
should be undertaken. Multi-center studies with pooling of data should
of cigarette smoking and other risk factors, and the mechanisms
responsible for COLD. Carefully designed studies, cross-sectional and
deficiencies of alpha-l-antitrypsin appear to be a particularly promisr
ing, population in which to study the natural history of COLD, the role
(4) Subjects with genetically-determined severe and mild-moderate
research.
the biologic importance of the expanding body of promising in vitro
important to assure that in vivo research be carried out to determine
relationship should be performed. It woul& appear particularly
(2)
(k)
(5)
(6)
(7)
(8)
®
(175) SAFFIOTTI, U. Experimentali respiratory tract carcinogenesis. Progress in
Experimental Tumor Research 11: 302-333, 1969.
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to inhalation exposures. In: Hanna, M.G., Jr., Nettesheim, P., Gilbert, J.R.
(Editors): Inhalation Carcinogenesis. Proceedings of a Biology Division, Oak
Ridge National Laboratory Conference, Gatlinburg, Tennessee, October 8-11,
1969. Atomic Energy Commission, Division of Technical Information, AEC
Symposium Series No. 18; April 1970, pp. 27-54.
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induction of bronchogenic carcinoma. Cancer Research 28: 104-124, January
1968.
(178) SANGHVI, L.D., RAO, K.C.M.,, KHANOLKAR, V.R Smoking and chewing of
tobacco in relation to cancer of the upper alimentary tract. British Medical
Journal 1(4922): 11i1i1-1114, May 7, 1955.
(179) SCHMAEHL, D. Investigations on esophageal carcinogenicity by methyl-
phenyl-nitrosamine and ethyl~ alcohol ini rats. Cancer Letters 1(4);: 215-218,
1976. ,
(180) SCHMAUZR., COLE, P. Epidemiology of cancer of the renal pelvis and ureter.
Journal of the National Cancer Institute 52(5): 1431-1434, May 1974.
(181) SCHNEIDERMAN, M.A. Time trends: United States 1953-1973. Laryngoscope
88(1Supplement~8): 6, 44-49,1978.
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mortality patterns of esophageal cancer in the United States, 1930-67. Journal
of the National Cancer Institute 46(1): 63-73, January 1971.
(183) SCHOTTENFELD, D., GANTT, R.C., WYNDER, E.L. The role of alcohol and
tobacco in multiple primary cancers of the upper'digestive system, larynx, and
lung: A prospective study. Preventive Medicine 3(2): 277-293, June 1974.
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as an~ etiologic factor in disease. I. Cancer. Cancer Research, 10(1); 49-58,
January 1950.
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cancer associees aux facteurs tabac et alcool chez 1'homme (Research on: the
localizations of cancer associates with tobacco and alcoholic factors in man).
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1957.
(186) SCHWARTZ, D., FLAMANT, R., LELLOUCH, J., DENOIX, P: F: Results of a
French survey on the role of tobacco, particularly inhalation, in different
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1961.
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comparison of white and black populations. CA-A Cancer Journal for
Clinicians 26(1)`. 2-13, January/February 1976:.
(188) SELIKOFF, I. J., BADER,,, R. A.,, BADER, M. E., CHURG, J., HAMMOND, E.
C. Asbestosis and neoplasia. American JournaL of Medicine 42(4): 487-496,
April 1967. *
(189) SELIKOFF, I. J., HAMMOND, E. C., CHURG, J. Asbesto*s s.s exposure, smoking,
an& neoplasia: Journal' of the American Medical Association 204(2): 104-110,
April 8; 1968.
(190) SHETTIGARA, P. T., MORGAN, R. W. Asbestos,, smoking, and laryngeal
carcinoma. Archives of Environmental Health 30(10); 517-519, October 1975.
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activation of benzo(a)pyrene proceeds by a diol-epoxide. Nature 252: 326-328,
November 1974.
5-70
(18), BERNFELD, P.,, HOMBURGER; F., RUSSFIELD;, A.B: Strain differences in
the response of inbred Syrian hamsters to cigarette smoke inhalation. Journal
of tbe National Cancer Institute 53(4): 1141-1157, October 1974.
(19) BERRY, G., NEWHOUSE;, M.L.,, TUROK, M. Combined effecU of! asbestos
exposure and smoking on mortality from lung cancer in factory workers.
Lancet 2(7775): 476-479, September 2, 1972.
(20) BESTE.W.R. A CanadiamStudy of Smoking and Health. Ottawa, Department
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LAOWALLA, A.M.,, BILIMORIA, K.F. A followup study of oral cancer an&
precancerous lesions in 57,518 industriaU workers of Gujarat,, India. Indian,
Journal of Cancer 12(2): 124-129, June 1975.
(22) BLUEMLEIN, H., Zur kausalen pathogenese des larynxkarzinoms unter
beruecksichtigung des tabakrauchens (Causal pathogenesis of laryngeal
carcinoma with respect to tobacco smoking). Archiv fuer Hygiene und
Bakteriolbgie 139(5): 349-404; 1955.
(23) BOCK, F.G. Tumor promoters in tobaeco and cigarette-smoke condensate.
Journal of the National Cancer Institute 48(6): ~ 1849-1853, June 1972.
(24) BRADSHAW, E., SCHONLAND;, M. Oesophageal and lung cancers in Natal
African males in relation ta certain socio-economic factors. An: analysis of 484
interviews. British Journaliof Cancer 23(2): 275-284, June 1969.
(25) BRANDENBURG, 1H., KELLERMANN, G. Aryl hydrocarbon hydroxylase
inducibility in laryngeal carcinoma. Archives of Otolaryngology 104: 151-152,
March 1978.
(26), BRODERS, A.C. Squamous-cell epithelioma of the lip. A study of five hundred
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656-664, March 6, 1920:
(27), BROSS, I.D.J., GIBSON, R. Risks of lung cancer in smokers who switch to filter
cigarettes. American Journaliof! Public Health 58(8): 1396-1403, August 1968.
(28)! BROWNE, R.M., CAMSEY, M.C., WATERHOUSE, J.A.H., MANNING, G.L.
Etiological factors in oral squamous cell carcinoma. Community Dentistry and
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(30) CARNOW, B.W: The "urban~factor" and']ung cancer: Cigarette smoking or air
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V. (Editors). Air pollution and cancer: Risk assessment'~ methodology an&
epidemiological evidence. Report of a task group. Environmental Health~
Perspectives 22: 1-12, February 1978.
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Smoking and Some Social I Covariables to 1 Mortality and Cancer Morbidity. A
Ten Year Follow-Up in a Probability Sample of 55,p00 Swedish Subjects, Age
18-69, Part 1 and' Part 2. Stockholm, The Karolinska Institute;,1975, pp. 1-91.
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mice. Journal of the Nat'ional Cancer Institute 39(5): 903-912, November 1967.
(85) CLAYSON, D.B. Occupational Bladder Cancer. Preventive Medicine 5(2): 228-
244, June 1976.,(Abstract),
{.
(:.
(4:
(.
('.
(l
suggested that common lung, diseases may be due to a combination of
risk factors, varying from one individual to another, and that this risk
may be modulated by different genes in combination and by different
environmental factors (e.g., smoking). Long-term prospective studies
are necessary to answer these questions.
Occupational Exposures
Exposure to certain occupationall environments has been shown to be
associated with several forms of non-neoplastic bronchopulhnonary
disease. An increased prevalence of COLD is found with exposures to
coal and granite dust and cotton fiber. This risk is increased further by
cigarette smoking: However, in none of these studies is the relationship
of COLD to occupation as strong as that tasmoking.
A discussion on the proposed modes by which smoking interacts with~
occupational exposures is presented in the Chapter on the Interaction
Between Smoking and Occupational'i Exposures.
Air Pollution
The relationships among air pollution, smoking, and COLD remain
controversial. Reasons for this controversy include difficulties in
controlling such variables as socioeconomic class, degree of crowding,
ethnic differences, and age distribution, as well as in determining the
exact type and amount of individual pollution exposure. Measuring
individual pollution exposure, even within~ a small area, is difficult
since both amount and type can vary dramatically from street to street
(e.g., proximity of a st'reet to a heavily traveled expressway).
In an effort to control as many of these variables as possible, two
basic approaches in study design have been~ utilized. The first approach
has been to find areas where different pollution levels have been well-
measured and then to select populations that are as similar as possible
in these areas. Thus, a population in a low-pollution area can be
compared with a similar population in a high-pollution area. The
secon& approa& has been to select a population that is as uniform as
possible (for example, twins), and then measure individual responses to
different pollution exposures.
Using the first approach, the Community Health an& Environmental
Surveillance System evaluat'ed the excess COLD (i.e., rate of COLD
experienced above that of nonsmokers) in subjects in two communities
of differing air pollution: Salt Lake City (high), and' Oe Rocky
Mountain Area (low). Finklea, et al. (53) commenting on the data,
noted that smoking was the most important risk factor in developing
abnormal pulmonary function but that smoking and exposure to air
pollution had a synergistic effect.
The relationship among smoking, air pollution, and COLD were
analyzed in an autopsy study of tissue samples from St. Louis, Missouri
(high pollution) and Winnipeg, Canada (low pollution) (16e). Three
6-36
hundre(
emphys ~
residen ~
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In summary, these data suggest that adult cigarette smokers have
respiratory symptoms more frequently than do nonsmokers and that at
least some sympt'oms (i.e., cough~ and sputum production) increase with
a greater dosage of cigarettes. While it is clear that COLD is more
common in men than in women, it is uncertain whether men and
women with equivalent smoking,histories have a similar increase in the
prevalence of respiratory symptoms and COLD.
Ventilatory Function
Subt'le, functional abnormalities (i.e., in tests of small airway function)
have been recognized in smokers in whom standard spirometric
measures are normal. These studies were reviewed'in a previous
section. It is generally recognized that the standard pulmonary
function~ tests only become abnormall late in the pathological process,
perhaps after some irreversible structural changes have occurred.
The majority of epidemiologicall surveys investigating the preva-
lrence of functional abnormalities in smokers have employed measure-
ments of ventilatory capacity, usually FEV. Measurements of airways
resistance, diffusing capacity, lung volumes, and nitrogen~ mixing have
been used much less frequently.
These studies, which were recently reviewed by Higgins (67), have
confirmed that lung function is consistently worse in smokers than~ in
nonsmokers. One major exception to this finding was a report on a
study from the Kaiser Permanente multiphasic health check clinic
(128) in which 65,086 white, black, and oriental smokers and
nonsmokers, aged 20 to 79, answered a: self-administered questionnaire
about smoking habits and'underwent pulmonary function testing.
Significant differences were observed between white male and female
smokers and nonsmokers with respect to their performance on
pulmonary function tests. However, differences were not observed
between black and oriental smokers and~ nonsmokers. An explanation
was not readily apparent.
In a survey of New York City postal and transit workers, Densen, et
al. (:40) found the lowest values for FEV, among cigarette smokers.
Stebbings (133), in a further analysis of Densen's d'ata,, noted
significantly less decline in FEV, among black smokers when~compared
to white smokers. This difference persisted even when corrections weree
made for differences in amount smoked, age at which smoking began,
inhalation patterns, and smaller initial lung volumes in~ blacks. Black
and white nonsmokers did not differ in~ the rate of decline in FEW By
age 60, blacks who smoked one pack per day had a .34 liter smaller
cumulative decrease in FEVi than whites who smoked the samee
amount.
In a study of male-female differences in pulmonary function of
young smokers with similar smoking history, Enjeti, et al. (47) found
abnormalities in tests of small airway function in males, but not in
M
0
®
M
im
6-21
F
(130) MALAOWALLA, A.M., SILVERMAN, S., JR., MANI, N.J., BILIMORIA, K.F.,
SMITH, L.W. Oral cancer in 57,518 industrial workers of Gujarat, India. A
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LACE, K.M. Management of cancer of the larynx. Journal of~ the South
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(13.4) MARTINEZ, I. Retrospective an& prospective study of carcinoma of the
esophagus, mouth, and pharynx in Puerto Rico. Boletin de lk Asociacion
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bronchogenic carcinoma. British Medical Journal 1(6063): 746-749, March 19,
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(136) MAXWELL, J.C., JR. The 1976 Maxwell report on cigarettes. Tobacco Reporter
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(140) MIRVISH, S.S. N-nitroso compounds: Their chemical land !in vivo formation and
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(141) MONTESANO, R:, SAFFIOTTI, U. Carcinogenic response of the respiratory
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5-64
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(7
CONTENTS
Introduction .............................................................. 5
Ilhistrative Examplles of Different Modes of Action
Between Smoking and Occupational Exposures ............. 5
Tobacco Products May Serve as Vectors by Becoming
Contaminated with~ Toxic Agents Found in the
Workplace, Thus Facilitating Entry of the Agent by
Inhalation, Ingestion, and/or Skin Absorption~ ........ 5
Workplace Chemicals May Be Transformed Into More
Harmful Agents by Smoking ............................... 5
Certain Toxic Agents in Tobacco Products and/or
Smoke May Also Occur in the Workplace, Thus
Increasing Exposure to the Agent ........................ 7'
Hydrogen Cyanide ......................................... 7
Carbon Monoxid'e ........................................... 8
Methylene Chloride ........................................ 8
Other Chemical Agents ................................... 9
Smoking May Contribute to an Effect Comparable to
That Which Can Result From Exposure to Toxic
Agents Found in the Workplace, Thus Causing an
Additive Biological Effect ................................... 9
Coal Dust ..................................................... 9
Cotton Dust .................................................. 9
Beta-Radiation .............................................. 10
Chlorine .......................................................10.
Exposure Among, Fire Fighters ....................... 10
Smoking May Act Synergistically with Toxic Agents
Found in the Workplace to Cause a Much More
Profound Effect Than That Anticipated Simply
From the Separate Influences of the Agent and
Smoking Added Together ................................... 11
Asbestos ...................................................... 11
Exposures in the Rubber Indust'ry ................... 13
'
Radon Daught'ers .......................................... 14!
Exposure in GoU Mining ...............................15
Smoking May Contribute to Accidents in the
Workplace ....................................................... 15
7-3
M
a
U
a
I
female smokers: They suggested that men respond differently to
habitual! cigarette smoking at an earlier stage than d'o women.
Few reports have shown a consistent dose-response relationshipp
between cigarette smoking and functional abnormality. In a recent
study, Burrows, et al. (23) demonstrated an inverse relationship
between ventilatory function and pack-years, even in subjects who
denied! cough and sputum.
The long-term effects of cigarette smoking on lung function have
been examined in several prospective studies. These have usually
shown that the rate:of decline of FEV in smokers is greater than in the
nonsmoker (67). This was again suggested in the 10-year followup of
the Framingham cohort (8).
In a large prospective study of Londoni working men, Fletcher, et al.
(57) recognized a"suscept'ible" group of smokers whose rate of decline
in FEV was steeper than that for nonsmokers. However, there was
another group of smokers who lost FEV almost as slowly as did
nonsmokers. The authors suggest that the.effect of smoking on FEV in
"susceptible" individuals may be underestimated by focusing on the
mean FEV of all smokers, as is usually done in prevalence surveys. As
noted earlier, they found no relationship between the rate of decline in
FEV and' productive cough when~ smoking habits were taken into
account. This is in conflict with Gregg's data (62), in which only
smokers with bronchial hypersecretion were likely to develop function-
al decline.
In summary, the majority of epidemiological surveys have found a
higher prevalence of functionali abnormalities ini smokers as compared
to nonsmokers. There are conflicting data as to the effect of smoking
on pulmonary function in different racial groups and whether men and
women with equivalent smoking habits have similar reductions in
pulmonary function. It is clear that cigarette smoking produces a: more
rapid decline in FEV and~ a higher prevalence of productive cough.
However, it is unclear whether the presence of productive cough by
itself predicts the risk for a more rapid decline in~ FEV independent of
that increased risk associated with cigarette smoking. It has been
suggested that there may be a "susceptible" group of smokers whose
rate of decline in FEV is much greater than that in both~ "unsuscepti-
ble" smokers and nonsmokers and that "unsusceptible" smokers and
nonsmokers have similar rates of decline in FEV. Therefore, preva-
lence surveys of functional abnormallties in all smokers may underesti-
mate the impact of cigarette smoking in the "susceptible"' population.
Cessation and Reversibility of Functional Changes
Smoking, cessation results in a reduced prevalence of symptoms in~ all
age: groups and in reduce& mortality rates. The effects of smoking
cessation on pulmonary function have been~ considered at various
stages of functional abnormality.
6-22
Buif
cessat
volum
12 mc
found
resurr.
ties ir
f indin
aL (37
airwa!
As
pulmc
welli -,
impr(
follov
159),
venti
comp
obser
declit
howe
fo11oS
and i
decli,
smok
nons°
halvf
to nc
recoi
decli
follo
(1'oa;
smali
smol
as tY
In,
perf
still
acce
Lun
Aue
hab;
aut(
unassociated with a history of preceding bronchitis (63, 136, 158).
Radiographic studies of alpha-l-antitrypsin deficient patients have
revealed decreased vascularization of the lower lobes (134).
Several retrospective studies in patients with severe deficiency have
demonstrated an~ association between smoking and the age at which
emphysema becomes manifest. However, control nonsmoking subjects
with a similar phenotype have not been included. Black and Kueppers
(14) evaluated 18 patients with alpha-l-antitrypsin deficiency who had
never smoked' and had little or no exposure to occupational or urban air
pollution and' compared~ them to 36 individuals with similar phenotype
(PiZZ) who were (or had been) smokers. A larger percentage of
individuals who smoked had impaired lung function early in life.
However, there was considerable variability as to clinical course,
degree of pulmonary function abnormality, and appearance of the
roentgenogram among, the nonsmokers. The authors recognized that
their study was biased in favor of individuals with symptomatic
disease; however, they noted that the rarity of the PiZZ phenotype and
the need to identify nonsmokers with no other exposure to respiratory
irritants would have required an enormous screening program.
Prospective studies scrutinizing these relationships are lacking.
The nat'urali history of the states with less severe deficiencies of
alpha-l-antitrypsin is unclear (86). Cross-sectional studies have found
such a deficiency more frequently in patients with COLD thani would
be expected by chance alone (87, 93). However, several other reports
obtained fromi population studies have suggested that mild forms of
antit'rypsin, deficiency are not important risk factors for emphysema
(30, 34, 111): Mittmani (108) recently reviewed the controversy as to
whether the MZ phenotype is a significant risk factor for COLD but
could not resolve the issue based on current evidence. Longitudinal
studies in suchi individuals have not been reported. Because the natural
history of the mild deficiency state is unclear, the effect of smoking on
such individuals remains unsettled.
In summary, individuals with severe alpha-l-antitrypsin deficiency
have an excessive risk for developing COLD; the onset of symptomatic
COLD is probably abbreviated by smoking. The natural history of
individuals with mild deficiency states for alpha-l-antitrypsin is
unclear, as is the question~of whether they represent a group at special
risk from cigarette smoking.
Other Genetic Factors 4
Continued interest has been shown in the possible contribution of
genetic factors (other than alpha-l-antitrypsin deficiency) to the
pathogenesis of COLD. In earlier studies (71, 88, 89), the existence of
kindreds with a high incidence of COLD had been noted, but the
relative importance of genetic factors an6 smoking, habits was unclear.
6-34
TABLE 11.-The age-adjusted* prevalence (percent) of chronic
bronchitis score by occupation and smoking habits
in men 25 to 64 years of age, Tccumseh, 1962-65
Chronic bronchitis
Occupation No.
examined
All Non-
smokers Cigarette
smokers
Professional and
managerial
421
12.3
4.9
26:7
Farmers 411 16.2' - -
Clerical and~ sales 114 16.1 5.4 32,01
Craftsmen and
operatives
782'
18.2
5.3
31.5
Service 33' 28:1 - -
Laborers' 35 30.0 - -
White-collar 535 12.9 t9 27:1
Blue-collar 850 18.9 5.4' 31.6
Agricultural 48 19.4 - -
*Adjusted to the age distribution of men and women in TecumeYeh 255 to 64 years of age. Includes 7
farm laborers.:
SOURCE: Higgins, M. W. (68)
TABLE' 12.-Prevalence (%) for cough day or night in both sexes
in winter by cigarette smoking and by chest illness
before age 2* (Figures in parenthesis aree
population)
Chest illness under 2:yrs: of age Cigarette smoking
Never Present
No chest illness 5.2 (1361) 13.7 (1141)
One or more chest illness 9.1 (397) 16.5 (423)
Excludes 577 persons-exsmokers:andthaee where history of cigarette smoking and ofiahest illness
before age2and history of cough day and.nigh't are unknown. SOURCE: Coldey, J.R.T. (35)
In a followup study of the same cohort (80), the association of cough
prevalence with current smoking habits and with childhood respiratory
tract illhess was confirmed and strengthened.
Summary
Cigarette smoking, even in young age groups, prodltces lung damage.
Cessation~ of smoking leads to at least partial resolution of symptoms.
Pulmonary function and histologic abnormalities have been observed'
in young smokers, confirming clinical' suspicions of lung damage in this
group.
6-39
®
0
TABLE 10.-Expected and observed prevalence rate (percent) of
"cough" among smoking partners to co-twins who
either had or had not the symptom "cough"
Monozygotic pairs
"Coughing" status in
non-smoking, partner No, at risk Prevalence rate for "coughing" among
smoking co-twins, percent
Expected ©hserved:
No "cougNl' 497 4 12
"Cough" 41, ?4 37
SOURCE: Cederlof, R. (29)
Cohen, et aL (32,, 33); in a family study in Baltimore, Maryland, found
an, increased prevalence of pulmonary function abnormalit'ies in, first-
degree relatives of COLD cases as compared to first-degree relatives of
nonpulmonary cases, eveni when Pi variant relatives were excludedL In
all groups, smokers demonstrated a higher frequency of function
abnormalities. The authors suggested that there is some interaction of
familial factors with smoking. In al similar study in rural areas outside
Rochester, Minnesota, Miller, et al. (106) found a twofold increased
prevalence of functional abnormalities in family members of subjectss
with COLD as compared to families of controls matched for age, sex,
occupation, and smoking, exposure.
Cederlof, et al. (27, 28) examined the relationship of smoking to
symptom prevalence among monozygotic and dizygotic twins who
were both discordant and concordant for smoking habits. They
observed that the hypermorbidity for COLD symptoms relat'ed' to
smoking persisted even after controlling for zygosity; they concluded
that a causal relationship of smoking, and COLD symptoms was
supported. However, genetic factors had ~ an ~ appreciable influence.
In a more recent analysis of their twin data, Ced'erlof, et al. (29)
examined the prevalence of cough among monozygotic pairs discordant
for smoking. The results are presented' in Table 10. They assumed that
the nonsmoking symptomatic co-twin had a predisposition to cough.
The smoking co-twin had a threefold increase in prevalence of cough
compared to his asymptomatic nonsmoking co-twin-a 1-1/2 times
increase compared to the symptomatic nonsmoking co-twin. The
prevalence rates were higher in the smoking group4 than in non-
smoking groups but highest in the "predisposed" smoker. The authors
suggested that hereditary factors were equally as important as
smoking for the development of cough in the: smaller "predisposed"
group:
These findings lend support to earlier suspicions that genetic factors
may play a role in determining the risk for COLD. Kazazian (78) has
6-35
N
A
CO N'
Introduc.
Bior
Hist
Smoking
Birt
Plac
Gesi
Fet,
Lon,
RolE
Evic
ar
Su7r
Cigarett
Ove
Spor
Peri
Cau.
Corr.
Prec
Pret
Prej
G
Sud.
Sun
Lactatio
Intr
Epic
Exp
Physiolo
Stuc
A variety of pulmonary functional abnormalities believed to
represent small airway dysfunctiom occurs in smokers. Many such
individuals demonstrate normal expiratory flow as measured by
conventional spirometry. In one prospective study, abnormalities in
tests of small airway function appeared to correlate well with
pathologic abnormalities of the peripheral airways. It has been
suggested that such changes may be precursors of more extensive
anatomic-functionall abnormalities if smoking were continued. How-
ever, prospective studies relating small airway physiological and/or
pathological abnormalities to the development of COLD are lacking.
Adult cigarette smokers have respiratory symptoms more frequently
than do nonsmokers; some symptoms (i.e., cough and sputum
production) increase with & greater dosage of cigarettes. While it is
clear that COLD is more common in men than in women, it is uncertain~
whether men and women~ with equivalent smoking histories have a
similar increase in the prevalence of respiratory symptoms and' COLD.
In the majority of epidemiological surveys, a higher prevalence of
functional abnormalities has been found in smokers as compared to
nonsmokers. There are conflicting data as to the effect of smoking on
pulmonary function in different racial groups and whether men and
women with equivalent smoking habits have similar reductions in~
pulmonary function. It is clear that cigarette smoking produces a more
rapid decline in FEV and a higher prevalence of productive cough.
However, it is unclear whether the presence of productive cough by
itself predicts the risk for a more rapid decline in. FEV independent of
that increased risk associated with cigarette smoking. It has been
suggested that there may be a "susceptible" group of smokers whose
rate of decline in FEV is much greater than that in both "unsuscepti-
ble" smokers and nonsmokers and' that "unsusceptible" smokers and
nonsmokers have similar rates of decline in FEV. Therefore, preva-
lence surveys of functional abnormalities in all smokers may underesti-
mate the impact of cigarette smoking in the "susceptible" population.
Several studies have confirmed that there is improvement in
standard spirometric function tests following cessation of smoking, but
there is still debate as to whether the normal decline in ventilatory
function is accelerated in ex-smokers as compared to nonsmokers.
Cigarette smokers demonstrate more frequent abnormalities in
macroscopic and microscopic lung sections at autopsy than d'o
nonsmokers. Furthermore, there is a dose-response relationship
between these changes and the intensity of smoking. Histologic
evidence of small airways pathology is more: common in cigarette
smokers than in age-matched nonsmokers in one autopsy study of
sudden death victims.
A number of recent investigations have suggested that destructive
lung changes seen in the emphysematous form of COLD may result
from excess liberation of, or failure to inhibit, proteases in~ the lung.
6-40
1
I
8. PREGNANCY AND INFANT HEALTH.
National Institute of Child Health, and Human
Development
a
0
a
0
0
I
(19) BROWN; R., WOOLCOCK, A.J., VINCENT, N:J., MACKLEM, P.T. Phyaiologi-
cal!effects of experimental airway obstruction with beads. Journallof Applied
Physiology 27: 328=335, 1969:
(20) BUIST, A.S., FLEET, L.V., ROSS, B.B. A comparison of conventional
spirometric tests and the test'~ of closing volume in an emphysema screening
center. American Review of Respiratory Disease 107: 73.5-743,1973.
(21) BUIST, A.S.,, ROSS, B.B. Quantitative analysis of the alveolar plateau in the
diagnosis of early airway obstructiom Americam Review of Respiratory
Disease 108: 1078-1087, 1973.
(22): BUIST, A.S:, SEXTEN; G:J., NAGY, J.M., ROSS, B.B. The effect of smoking
cessation and modification on lung functions: American Review of Respiratory
Disease 114: 115-122, 1976.
(28) BURROWS;,B., KNUDSON, R.J., CLINEM.G:, LEBOWITZ, M.D. Quantativee
relationships betwf:en~ cigarette smoking, and ventilatory function. American
Review of Respiratory Disease 115: 195-204'; 1977.
(24) BURROWS;, B:, LEBOWITZ, M.D., KNUDSON, R.J. Epidemiologic evidence
that childhood problems predispose to airways disease in the adult (An
association between adult and pediatric respiratory disorders), Pediatric
Research 11(3):218-220,1977.
(25) CAMNER, P., PHILIPSON, K., ARVIDSSON, T. Withdrawal of cigarettee
smoking. Archiivesof Environmental'Health 26: 90-92,1973.
(26) CARP, H~, JANOFF, A. Possible mechanisms of emphysema in smokers in vitro
suppression of~ serumielastase-inhibitory, capacity by fresh cigarette smoke and
prevention.by antioxidants. American Review of Respiratory Disease 118: 617-
621, 1978.
(27) CEDERLOF, R., FRIBERG, L., HRUBEC, Z. Cardiovascular and respiratory
symptoms in relation to tobacco smoking. Archives of Environmental Health,
18(6): 934-940, June 1969.
(28) CEDERLOF, R., FRIBERGL., JONSSON, E., KAIJ,,L. Respiratory symptoms
and 'angina pectoris' in twins with, reference to smoking habit's. An
epidemiological study with mailed~ questionnaire. Archi ves of~ Environmental'
Health,13(6): 726-737, December 1966.
(29) CEDERLOF; R., FRIBERG; L~ LUNDMAN, T. The interactions of smoking,
environment, and heredity, and their implications for disease etiology. Acta
Medica Seandinovica 612(Supplement); 1-128, 1977.
(30) CHAN-YEUNG, M., ASHLEY, M.J., COREY, P., MALEDY, H. Pi Phenotypes
and the prevalence of chest symptoms and lung function abnormalities in
workers employed in dusty industries. American Review of Respiratory
Disease 117(2): 239-2A5,1978:
(31) CHERNIACK, R.M. Smoking an&chronic airways obstruction. National Heart,
Lung and Blood Institute, Division of Lung Diseases. National Technical
Information Service PB 272 154Sept'ember 1, 1977, pp. 1-41.
(32) COHEN, B.H., BALL, W:C., JR., BIAS, W.B., BRASHEARS, S., CHASE, GA.,
DIAMOND, E.L.,, HSU, S.H.,, KREISS, P., LEVY, D.A., MENKES, H.A.,
PERMUTT, S., TOCKMAN, M.S. A genetic epidemiologic study of chronic
obstructive pulmonary disease I. Study design and' preliminary observations.
Johns Hopkins Medical Journali137c 95-104,1975.
(33) COHEN, B.H., BALL~ W:C., JR., BRASHEARS, S:, DIAMOND, E.L., KREISS,
P.,,LEVY, D.A., MENKESH.A., PERMUTT, S., TOCKMAN, M.S. American
Journal of Epidemiology 105(3): 223-2314 1977.
(34) COLE; R.B., NEVIN, N.C:,, BLUNDELL, G., MERRETT, J.D. MCDONALD,
JLR., JOHNSTON, W.P. Relation of alpha-l-antit'aypsini phenotype to the
performance of pulmonary function tests and to the prevalence of! respiratory
illness in a working,population. Thorax 31: 149-157;,1976.
(35) COLI
adu
air
197
(36) COM
J.A
27(;
(s7); CoS:
DO
in
Me
(38) DAL
of.
(39) DAr
BE
coi l
toI
(.G0), DEP
re:
VE
191
(41) DIR
ce:
an
85
(42) DO'.
(43) D0;
re
he
2Y.
(44) DO
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M
(45) DO
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(46) EI(
le
1'
(47) EN
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(48) ER
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(49) EF
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(50) FA
v
F
(51) FI
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(52) FI
f
Recommendations for Research
1. Studies on the health effects of smoking should take occupational
exposures into consideration and vice versa. Whenever possible, studies
should include data on nonsmoking workers as well as unexposed
smoking and nonsmoking controls.
2. The increasing rates of lung cancer in nonwhite males compared to
white males should be investigated further with respect to occupation-
al exposures and smoking habits:
3. The change in smoking habits of blue-collar workers over the last
decade provides an opportunity to assess more critically the contribu-
tion of smoking versus occupational exposure to certain~ disease states.
Cohorts should be identified and followed prospectively for this
purpose.
4. W'orkplace agents which interact with the smoking of tobacco to
produce adverse health effects should be identified.
5. Investigation of the mechanisms of synergism~ between smoking
and occupational exposures is needed.
6. The impact of the combination~ of smoking and workplace
exposures upon reproductive experience merits further study.
7. The impact of smoking in the workplace upon accidents meritss
further study.
8. The lack of information on the effect of sidestream smoke in the
development of occupationaU disease in nonsmoking workers merits
attention.
9. The effects of cessation of smoking upon lung cancer risk among
those occupationally exposed to: toxic workplace agents requires
investigation.
,
~ 7-19.
0
a
M
1
I
I
0
M]
0
consumption in the towns where the subjects lived. This method of
estimating air pollution is subject to the same limitations cited for the
previous two studies, i.e., limited sensitivity to small risks due to air
pollution.
In summary if an increased risk of COLD due to air pollution exists,
it is small compare& to that due to cigarette smoking under conditions
of air pollution to which the average person is exposed. The possibility
remains that the two kinds of exposure may interact to increase the
total effect beyond that contributed by each exposure separately:
Socioeconomic Status
In a morbidity survey (117) of the non-institutionalized population of
the United States (1964), socioeconomic status appeared to be an
important risk factor in determining rates of reporting chronic
bronchitis, asthma, and emphysema. Rates were higher among those in
lower socioeconomic classes. This relationship had been previously
recognized in the United Kingdom (118).
In a recent study, the relationship of smoking, to socioeconomic
status and chronic respiratory diseases was examined in 9,226 residents
of Tecumsehs Michigan, observed from 1962 to 1965 (68). The
prevalence of chronic bronchitis was higher in cigarette smokers than
in nonsmokers, higher in blue-collar workers than in~ white-collar
workers, and! least among men with the most education (Table 111).
There was no significant association between the prevalence of asthmaa
and smoking, habits, occupation, education, or income. Most of the
differences in the prevalence of chronic bronchitis in subjects of
differing occupational, educational', or income classes were attributable
to differences in smoking habits. Compared with smoking, poor
occupations, educationaU background, and economic circumstances
have only a weak deleterious effect.
Childhood Respiratory Illness and Adult Respiratory Disease
A connection between pediatric respiratory illness and adult respira-
tory disease has long been suspected on clinical grounds. Burrows, et
al. (24) recently reported that physician-confirmed chronic bronchitiss
and/or emphysema and abnormalities in measures of expiratory flow
are more common~ in older subjects with su& history. They suggested
that childhood'respiratory illness leads to an increased susceptibility to
the effects of bronchial irritants and respiratory infections.
In a prospective study of 10-year-olds followed since age 2 (n A 3899),,
Colley, et al. (35) found that subjects with a history of respiratory tract
illness before age 2 had an increased likelihood of developing,
respiratory symptoms by age 20. However, cigarette smoking appeare&
to be an even~ more important factor in increasing risk for developing
these symptoms (Table 12).
TAB
Occapa
Profes: -
man:
F2rme
Clerica
Crafts:
oper
&rvia
LaHori
White
Blue-c
Agr'scc
Ad
soi
TAI
No cl
one ,
E
and h
sc
I
pre
tra
Su~
Cif
Ce;
Pu
in ;
gr(
,
Workers who continue to smoke may experience continuing reexposure
and recurrent symptoms. Although complete recovery has been
reported to occur usually within 12 to 48 hours after exposure is
terminated, an autopsy report has attributed permanent lung damage
to repeated episodes of polymer fume fever (89). Pulmonary edema
following exposure to heated polytetrafluoroethylene has also been
reported(26, 73). Polymer fume fever was first recorded in 1951 (33) as
a result of two workers being exposed to the fluorocarbon polymer,
polytetrafluoroethylene, heated to 450-500° C. The particular decompo-
sition produet(s)'responsible for polymer fume fever have not yet been
identified, but temperatures in excess of 315°'C have been sufficient to
cause symptoms. The temperature.of the combustion zone of cigarettes
is approximately 875° C (82):
Numerous outbreaks of pol1ymer fume fever among smokers have
been attribut& to the decomposition of workplace polytetrafluoroe-
thylene by lit cigarettes and inhalation of the harmful decomposition
products with cigarette smoke. One report (18) describes aviation
employees whose work involved contact with door seals that had~ been
sprayed with an unspecified fluorocarbon polymer. In one case, a
worker smoking during, a break realized by the: taste of his cigarette
that it had become contaminated. Although the worker extinguished
the cigarette, he experienced! shivering and~ chills, which lasted
approximately 6 hours, beginning 1/2 hour after this incident. Another
illustrative report (12) describes outbreaks of polymer fume fever
among workers who smoked when their hands were contaminated with
polytetrafluoroethylene used as a mold release agent. There was no
recurrence of symptoms after smoking at the plant was prohibited. An
outbreak of polymer fume fever among workers using,liquid fluorocar-
bon polymer in the production of imitation crushed velvet was likewise
attributed to decomposition of fluorocarbon polymer by lit cigarettes
(85). Processing temperatures at this plant were too low tapyrolyze the
polymer. The seven affecte& workers were all cigarette smokers,,
whereas most of the workers without symptoms were nonsmokers.
After work practices were changed to prohibit smoking in the work
area and to require hand washing before smoking, no further
symptoms at this facility were reported. Other outbreaks of polymer
fume fever attributed to cigarette smoking have,also been reported (1,
11144, 76 90).
The effects of smoking, cigarettes contaminated with known
amounts of tetrafluoroethylene polymer have been studied with the
assistance of human volunteers. (22). Nine out of ten subjects were
reported to exhibit typical polymer fume fever symptoms after each
had smoked just one cigarette contaminated with 0.40'mg tetrafluoro-
ethylene polymer. Onset of symptoms ranged' from~ 1 to 3.5 hours after
smoking; recovery time averaged 9 hours.
I
1
1
7-6
TABLE' 8:-Means of the numerical values given lung sections at
autopsy of female current smokers and nonsmokers;
standardized for age
<11 Pk: >11 Pk.
Number of subjects 252 33'.
Emphysema 0.05 ll37
Fibrosis 0.371 2.89
Thickening of arterioles 0.06 126
Thickening of arteries 0.01 0.40
NOTE: Numerical values were determinedby ratio<g: each lung sectionn on sealesof 0-4 for emphysema
and
thickening ofthe arterioles, 0.7 for £ih'rosis, and i0-3 fon thickeningof the arteries.
SOURCE: Auerbach,,0: (9)
TABLE 9.-Means of the numerical values given lung sections at
autopsy of male former cigarette smokers;,
standardized for age
Formerdy Stnoked Stopped > 10 yr. Stopped < 10 yr.
Number of subjects 35 66 51
Emphysema 0.24 0.70 1.08
Fibrosis 1i14 1.74 2.44
Thickening of arterioles 0.57 0.93 1.25
Thickening of arteries 0.04 0.16, 0.36
<1 Pk. Pk. <1 Pk. Pk..
1i70
3.46
1.57
0.64
131
1169
3.30
1.59
0.61
NOTE: Numerical values for each finding were determined b'yy rating each lung section onecales.of
0-4 for
emphysema and thickening of the arterioles, 0-7for.fibrosis, and 0. 3 for thickening of the
arteries.
SOURCE: Auerbach, 0.: (9)
recoil, enhanced~ collapsibility of the airways, and airflow obstruction.
The elastic properties of the' lung are attributed~ to the appropriate
distribution of elastin in its connective tissue framework. Recent data
suggest that the lung damage observed in emphysema may be due to
injury of this elastic framework by proteolytic enzymes released (and
not inhibited) in the lung. Formulation of this hypothesis was'cak,alyze&
by the discovery that emphysema is extremely common in individuals
who are severely deficient in alpha-l-antitrypsin (48), a glycoprotein
that inhibits several proteases. Subsequently, it was postulated that
conditions interfering with the normal balance between protease and
antiprotease activity could give rise to an excess of free protease (i.e.,,
elastase) in the lung and initiate lung' destruction~(1Q9).
Subjects who Current cigarette
never smoked smokers
regularly
6-27
0
0
0
6
0
no
(69) HOGG, J.C., MACKLEM, P.T., THURLBECK, W.M. Site and nature of airway
obstruction in chronic obstructive lung disease. New England Journal of
Medicine 278(25):,1355-1360; 1968.
(70) HRUBEC, Z., CEDERLOF, R., FRIBERG, L., HORTON, R., OZOLINS, G.
Respiratory symptoms in~twins. Archives of Environmental Health 27(3): 189-
195, September 1973.
(71) HURST, A. Familial emphysema. American Review of Respiratory Disease
80(1): 179-180;,1959.
(72) HUTCHEONM., GRIFFIN, P., LEVISON, H., ZAMEL, N. Volume of isoflow.
A new test in detection of mild abnormalities of lung mechanics. American
Review of Respiratory Disease 110(4): 458-465, October 1974.
(73) IMBODEN, C.A., Jr. Rising mortality from chronic respiratory disease.
American Journal of Public Health 58: 221~222, 1968. (Letter)
(74) JAKAB, G.J. Adverse effect of a cigarette smoke component, aerolein, on
pulmonary antibacterial defenses and on viral-bacterial interactions in the
lung. American Review of Respiratory Disease 115: 33-38;,1977:
(74a) JANOFF, A.,, CARP, H. Possible mechanisms of emphysema in smokers.
Cigarette smoke condensate suppresses protease inhibition in vitro. American
Review of Respiratory Disease 116: 65-72,1977.
(75) JANOFF, A., ROSENBERG, R., GALDSTON, M. Elastase-like, esteroprotease
activity in human and rabbit alveolar macrophage granules. Proceedings of
the Society, for Experimental Biology and Medicine 136(3): 1054-1058, 1971.
(76) JANOFF, A., SANDHAUS, R.A., HOSPELHORN, V.D., ROSENBERG, R.
Digestion of lung proteins by human leukocyte granules in vitro. Proceedings
of the Society for Experimental Biology and Medicine 140: 516-519, 1972.
(77) KAPLAN, P.D., KUHN, C., PIERCE, J.A. The induction of emphysema with
elastase. I. The evolution of the lesion and the influence of serum. Journal of
Laboratory and Clinical iMedicine,82(3): 349-356, 1973.
(78) KAZAZIAN, H.H. A geneticist's view of lung disease. American Review of,
Respiratory Disease 113: 26L-266, 1976.
('79) KEAST, D., HOLT,, P. Smoking and immune response. New Scientist 61: 8(i6-
807March 28, 1974.
(80) KIERNANK.E., COLLEY, J.R.T., DOUGLAS,,J.W:B., REID, D. Chronic cough
in young adults in relation to smoking habits, childhood environment, and
chest illness. Respiration 33: 236-244', 1976.
(81) KILBURN, K.H., MCKENZIE, W. Leukocyte recruitment to airways by
cigarette smoke and particle phase in contrast to cytotoxicity of vapor. Science
189: 634637,1975.
(82)1 KIMBEL, P., WEINBAUM,, G. Role of leucoproteases in the genesis of
emphysema. In: Junod, A., De Haller, R(Editors). Lung Metabolism. New
York, Academic Press,,1975, pp. 25-41.
(83) KLEINERMAN, J., RICE, D.B. Evidence for preclinical' lesions in lungs of
young smokers: A postmortem epidemiologic-pathologic correlative study. In:
Steinfeld{ J., Griffith, W., Ball, K., Taylor, R.M. (Editors). Proceedings of the
Third World Conference on Smoking and Health, New York, June 2-5, 1975.
Volume IL Health Consequences, Education, Cessation Activities, and Social
Action. U.S. Departtnent of Health, Education, and Welfare, Public Health
Service, National Institutes of Health, National Cancer Institute, DHEW
Publication No. (NIH) 77-1413, 1977;pp: 161-169..
(84) KNUDSON, R.J'., LEBOWITZ, M,D., BURTON, A.P., KNUDSON, D.E: The
closing volume test: Evaluation of nitrogen and bolus methods in a random
population, American Review of Respiratory Disease 115(3): 423-434, 1977.
(85) KRUMHOLZ, R.A., CHEVALIER, R.B.,, ROSS, J.C. Changes in cardiopulmo-
nary functions related to abstinence from smoking. Annals of Internal
Medicine 62(2): 19'7-207, 1965.
Introduction ,
Despite increasing, recognition~ that both smoking and occupational
exposures contribute independently to the development of certain
disease states, few investigators have addressed the ways in which
these two factors act together to produce disease: Some of the effects
historically attributed to smoking may actually reflect an interaction
between smoking and occupational exposure. This cannot always be
quantified at the present time, but at least six different ways have
been identified in which smoking may act with physical and chemical
agents found in the workplace. These actions are not mutually
exclusive and~several may prevail for any given agent.
Six ways in which smoking may act with physical and chemical
agents to produce or increase adverse health effects are:
1. Tobacco products may serve as vectors by becoming contaminated'
with toxic agents found in the workplace, t'hus facilitating entry of the
agent by inhalation, ingestion, and/or skin absorption.
2. Workplace chemicals may be transformed into more harmful
agents by smoking.
3. Certain toxic agents in tobacco products and/or smoke may also
occur in the workplace, thus increasing exposure to the agent.
4. Smoking may contribute to an effect comparable to that which
can result from exposure to toxic agents found in the workplace, thus
causing an additive biological effect.
5. Smoking may act synergistically with toxic agents found; in the
workplace to cause a much~more profound effect'than that anticipated
simply from the separate influences of the agent and smoking added
together.
6. Smoking may contribute to accidents in the workplace.
Exposure to multiple physical and chemical agents in the workplace
can compound these various types of actions.
Illustrative Examples of Different Modes of Action Between
Smoking and Occupational Exposures
Tobacco products may serve as vectors by becoming contaminated
with toxic agents found in the workplace, thus facilitating entry
of the agent by inhalation, ingestion, and/or skin absorption.
Workplace chemicals may be transformed into more harmful
agents by smoking. r
Investigations of outbreaks of polymer fume fever provide clear
illustrations of both of these modes of action. Polymer fume fever is a
disease with influenza-like symptoms caused by inhalation~ of fumes
from heated polytetrafluoroethylene, e.g., Teflon® (59), Typical
symptoms inclktde chest discomfort, fever, leukocytosis, headache,
chills; muscular aches, and weakness. Since the symptoms are so
similar to influenza, polymer fume fever may be difficult to diagnose.
7-5
the population. A literature review on pancreatic cancer was conducted
by Krain to help identify real causes or associations for pancreatic
cancer. His report indicated that only the data oni industrial carcinogen
exposure and cigarette smoking show both the trend and the statistical
magnitude of association to consider them as real causes or associations
(48).
Since 1966 the consu mption of " tobacco products has decreased in
blue-collar workers while the number of ind'ustrial, exposures has
continued to increase (17, 56). The increasingly higher rates of lung
cancer in nonwhite malies, independent of smoking habits, may reflect
the late entry of nonwhites into industrial settings and the fact that
they have jobs with higher risk for occupationall exposure to toxic
agents.
Summary and Recommendations
Although precise relationships between smoking and occupational
exposures cannot always be: quantified; the necessary data aree
beginning to accumulate.
From 1920 to 1966 tobacco consumption increased as did the
introduction into the workplace of chemicals with unstudied biologic
effects. Workers with the greatest risk of exposure t'o industrial agents
in' many cases had the highest smoking rates. Since 1966 the
consumption~ of tobacco products has decreased in male blue-collar
workers while the introduction of new chemicals into the workplace
has continued to increase.
At least six different ways have been illustrated~ by whi& smoking
may act with physical and chemical agents in the workplace to produce
or increase.adverse health effects. These actions need not be mutually
exclusive, and exposure to multiple physical and chemical agents in the
workplace can compound these various typesof actions.
The examples of the interactions between~ the smoking of tobacco
products and industrial exposures cited in this report indicate that a
curtailment of smoking in certain occupational settings would
contribute to the reduction of specific disease processes: The Nationat
Institute for Occupational Safety and Health has therefore recom-
mended in certain circumstances that workers exposed to particular
agents refrain from smoking, However, it is important to note that in
some situations (for example, radon daughters and chloromethyl ether)
the contribution of occupational exposures to adverse health effectss
was greater than the contribution of cigarette smoking. Therefore, the
curtailment of smoking in the workplace should be accompanied by
simultaneous control of occupational exposures to toxic physical and
chemical agents. Both are needed!
7=18 :~
Table 11L-Perinatal mortality and selected pregnancy
complications by maternal smoking levels................... 40
Table 12.-Fetali and neonatal deaths by maternal smoking
and other coded condit'ions .......................................41
Table 13.-Preterm births by maternal! smoking habit,
relative and attributable risks, derived from published
studies ..............,.................................................... 44
Table 14.-The relation of the concent'rations of fetal to
maternal carboxyhemoglobin in mothers who smoke
during pregnancy ................................................... 72
8-7
M
®
0
I
I
0
0
I
degree of exposure to chloromethyl ether and an exposure index was
calculated for each man by cumulating the total exposure.
Chronic cough and expectoration~ showed a dose-response relation-
ship to chemical exposure: Chronic cough was also related to smoking,
but for each smoking category chronic cough was more common for
exposed than for unexposed men.
The 10-year incidence of lung cancer was dose-related to chemical
exposure but not to cigarette smoking. All cancers were small cell
carcinomas, occurred in men younger than 55, an& had an induction-
latent period of 10 to 24 years. The 10-year mortality rate in this group
of workers was 2.7 times that expected, and lung, cancer accounted for
the excess number of deaths.
Bronchogenic carcinomas linked to cigarette smoking are most oftien~
squamous cell in type with long induction-latent periods and, in the
absence of occupational agents, tend to occur after the age of 60. The
cancers which ten& to occur in workers exposed to chloromethyll ether
are small cell in type, have short induction4atent periods, and tend to
appear before the age: of 55. The absence of a relationship between
cigarette smoking and' lung, cancer in this study may be due to the
competing effect of chloromethyl ether which results in lung cancer in
exposed workers before the long-term carcinogenic effect of cigarette
smoking could be demonstrated. However, cough related to cigarette
smoking appears earlier in exposed workers, thus demonstrating the
action of cigarette smoking with exposure to chloromethyl ether in the
development of chronic cough symptoms. This case study a15o:points up
the complex issues involved~ in understanding the actions between
smoking and occupational exposures.
Beta-Naphthylamine and Other Aromatic Amines
Doll, et al. found an excess risk of bladder cancer in a series of studies
(24, 25) of inen, employed in coal gas production in England and Wales.
Most of the gas workers were smokers. Chemical studies showed that
inside the retort houses gas workers inhale& beta-naphthylamine and
other aromatic amines (known bladder carcinogens). Since aromaticc
amines are, also found in cigarette smoke (83), the gas workers who
smoked received exposure to bladder carcinogens from~ two sources.
This evidence is difficult to interpret at the present time. There are
reports of associations between cigarette smoking and bladd'er cancer
(30; 92); however, occupat'ional~exposures were generally not controlled
in these studies. There is a need to assess further the action between
smoking and exposure to aromatic amines.
M
7-16 "
(86) KUEPPERS, F.,, BLACK, L. Alpha-l-antitrypsin and its deficiency. American
Review of Respiratory Disease 110: 176-194, 1974.
(87) KUEPPERS, F.,, FALLAT, R., LARSON, R.K. Obstructive lung disease and
alpha-l-antitrypsin ~ deficiency gene heterozygosity. Science 165: 899-900, 1969.
proteases in purulpnt sputum: Digestion of human lung and inhibition of
alpha-l-antitrypsin Journal of Laboratory and Clinical Medicine 77(4): 713-
727, 1971.
(98) LIEBERMAN', J., MITTMAN, C., SCHNEIDER, A.S. Screening for homozy-
gous and heterozygous alpha-l-antitrypsin deficiency: Journal of the American
Medical Association 210: 2055-2060, 1969:
(94), IAW; R.B. Effect of a phagocytic load on macrophage protein and nucleic acid
biosynthesis. Journal of Cell'Biology67: 248a, 1975. (Abstract)
(92) LIEBERMAN, J., GAWAD, M.A. Inhibitors and activators of loukocytic
1958:
(88) LARSON, R.K., BARMAN, M.L: The familialioccurrence of chronic obstructive
pulmonary disease. Annals of Internal Medicine 63(6): 1001-1008, December
1965.
(89) LARSON, R.K., BARMAN, M.L. KUEPPERS, F., FUDENBERG, HIH. Genetic
and environmentali determinants of chronic obstructive pulmonary disease.
Annals of Internal Medicine 72(5): 627-632, May 1970.
(90) LEBOWITZ, M.D., BURROWS, B. Quantitative relationships betKveenicigaretten smoking and chronic
productive cough. International Journal of Epidemiology
6(2): 107-113;,1977.
(91) LEUCHTENBERGER, C., LEUCHTENBERGER, R., DOOLIN, R. A correlated
histological, cytological and cytochemical study of the tracheobronchial tree
and lungs of mice exposed to cigarette smoke. 1. Bronchitis with atypical
epitheliali changes in mice exposed! to cigarette smoke. Cancer 11': 490-506,
(95) LOW, R.B. Proteim biosynthesis by the pulmonary alveolar macrophage:
Comparison of suspended and adhered cells. American Review of Respiratory
Disease 109(4): 741, 1974: (Abst'ract).
(96)1 LOW, R.B., BULMAN, C.A. Substrate transport by the pulmonary alveolar
macrophage. Effects ofl cigarette smoke. American Review of Respiratory
Disease 116: 423-431',1977.
(97) MACKLEM, P.T., MEAD, J. Resistance of central and peripheral airways
measured by a retrograde catheter. Journal of Applied Physiology 22(1); 395-
401,1967.
(98) MANFREDA, J.,, NELSON, N., CHERNIACK, R.M. Prevalence of~ respiratory
abnormalities in a rural and an urban community. U,S. Department of Health,
Education, and Welfare, Public Health Service, National Institutes of Health,
National Heart, Lung, and Blood Institute, Division of Lung,Disease. National
Technical Information Service, PB 272154; September 1,1977, pp. 42<80:
(99) MANFREDA, J., NELSON, N., CHERNIACK, R:M. Prevalence of respiratory
abnormalities in~ a rural an& an urban community. American Review of
Respiratory Disease 117: 215-226, 1978.
(100) MANFREDA J., NELSON, N., CHERNIACK, R.M. Two year followup: The
general population of Charleswood'and Portage La Prairie. U.S. Department
of Health, Education, and Wel4are, Public Health Service, National Institutes
of Health, National Heart, Lung, and Blood Institute, Division of Lung
Diseases. National Technical Information Service, PB 272 154, September 1,
1977, pp: 97-105.
(101): MARCO, V., MASS, B., MERANZE;, D.R., WEINBAUM, G., KIMBEL, P.
Induction of experimental emphysema in dogs using leukocyte homogenates.
AmericanReview of Respiratory Disease 104: 595-598, 1971.
6-48
(10;
(i0~
(116
~
C~7
~
(118' ~Aj
83.7
4
1
m`
70
S
0
4.4.
Urandum W"IIa Man Uranl1m Whita Mila. Uranf.m MInM, Wlilla MM
MImaN, Na11r. MI',narl Ciqaratta 1l00WLMOrWhOSmOkaC
Nlv4r STOWE WIrO Mava 5rnbkarl MOrt, SrnOkarf 2 Or MOra
SmOkaG CiNwt4l. 6mCk.0 M1O NOnSmOkarf G%Ckf(CraY
FIGURE' 1.-Respiratory cancer rates among uranium miners by
cigarette usage and radiation exposure compared with rates among
nonminers
SOURCE: Archer, V.E ($)_
Radon Daughters
A substantial excess of lung cancer, reduced pulmonary function, and''
emphysema has been reported among uranium miners (48): The excess
has been attributed primarily to irradiation of the tracheobronchiali
epithelium by alpha particles emitted during the decay of radon (Rn)
and its daughter products. In a study of uranium miners, Archeret al.
(4): found that respiratory cancer rates among, smoking and non-
smoking uranium miners were six to nine times greater than among
nonminers with similar smoking habits. The lung cancer rate for
nonsmoking uranium miners was 7.1 per 10,000 person years compared
to 1.1 for nonminers who did not smoke. The lung cancer rate for
uranium miners who smoked! was 42.2 per 10,000 person years
compared to 4.4 for nonminers who smoked two or more packs of
cigarettes a day (Figure 1). There was also a definite association
between the prevalence of emphysema and the cumulative amount of
cigarettes smoked, as well as with accumulative radiation exposure.
J
J
1
f
c
7-14
Tobacco Smoke ............................................. 52
Nicotine ...................................................... 53
Carbon Monoxide .......................................... 57
Carbon Monoxide Uptake and Elimination..... 58
Effects on Feta1 Growth and~ Development ... 60
Carbon Monoxide Effects on Tissue.
Oxygenation .......................................... 61
Effects on Newborn Animals ...................... 65
Polycyclic Hydrocarbons ................................. 65
Studies in~ Humans .............................................. 67
Tobacco Smoke ............................................. 67
Carbon Monoxide .......................................... 70
Vitamin Bi2 and Cyanide Detoxification............ 73
Vitamin C ................................................... 74
Research Issues ......................................................... 74
Fetal Death ........................................................ 75
Neonatal Death ................................................... 76
Spontaneous Abortion ........................................... 77
Preeclampsia ....................................................... 77
Sudden Infant Death Syndrome ............................. 77
Long-Term Follow-Up .......................................... 77
Birth Weight and Placenta ................................... 78
Experimental Studies ........................................... 78
Lactation and Breast Feeding ............................... 78
Tobacco Smoke ................................................... 79
,
Nicotine ............................................................. 79
Carbon Monoxide ................................................. 80
Polycyclic Hydrocarbons ........................................ 81
References ............................................................... 82
LIST OF FIGURES
Figure 1.-Percentage distribution by birth~ weight of
infants of mothers who did not smoke during pregnancy
and of those who smoke& one pack or more of cigarettes
per day ..... ...........................................................17
Figure! 2.-Ratio of placental weight to birth weight by
length of gestation and maternal smoking category..... 18'
w
8-4
Adverse effects from cyanide may occur from sublethal doses.
Hydrogen cyanid'e and cyanide salts inhibit cytochrome oxidase.
Cyanide can form complexes with heavy metali ions. Formations of
these complexes in the body can rapidliy cause disturbances in enzymee
systems in which heavy metals act as co-factors either alone or as part
of organic molecules (2, 15, 27). Thiocyanate itself has toxic effects,
especially inhibition of uptake of inorganic iodide into the thyroi&
gland for incorporation into thyroxin (91). The National Institute for
Occupational Safety and Health~ has estimate& that over 20,000
workers in 75 different occupationall groups have potential occupation-
al exposure to cyanide (62):
Carbon Monoxirle
Cigarette smoking causes increased exposure to carbon monoxide (CO).
A CO concentration of 4 percent (40,000 ppm) in cigarette smoke leads
to an alveolar CO concentration of 0.04 to 0.05 percent (400 to 500
ppm); which produces a carboxyhemoglobin (COHb) concentration of 3
to 10 percent (21, 40, 68). Goldsmith, et al. (29) estimated that the
cigarette smoker is exposed to 475 ppm CO for approximately 6
minutes per cigarette.
In~ a: study of COHb levels in British steelworkers, Jones and Walters
(39) found a 4.9 percent end of shift COHb saturation~ in nonsmoking
blast furnace workers compared to 1.5 percent saturation in non-
smoking unexposed controls. For heavy cigarette smokers, the levels
were 7.4 percent for blast furnace workers and 4.0 percent for smoking
unexposed controls. The COHb levels of blast furnace workers who
smoked were in a critical range. Studies by Aronow (5-9), Anderson (3),,
and Horvat (36) and their associates have shown that levels of COHb in
excess of 5 percent can cause cardiovascular alterations which are
dangerous for persons with cardiovascular disease.
Potential oecupationall exposure to CO is common (37). Since a
significant number of workers have coronary heart disease and many
smoke, additionaL occupational exposure to CO may increase cardiovas-
cular morbidity and mortality.
Methyl'ene ChI,trride.
Methylene chloride is metabolized to CO in the body (28). COHb levels
in bloo& increase with increasing environmental concentrations of
methylene chlbride as well as with increasing physical activity at thee
time of exposure (10,, 80). Maximum COHb levels occur 3 to 4 hours
after exposure is discontinued.
Mean methylene chloride concentrations of 778 ppm over a 3-hour
exposure period produced a maximum COHb level of 9.1 percent 4
hours after exposure was discontinued. Twenty hours after this
7-8
exposure -
percent pr
Based o
chloride fr
worker wl
CO from n
Other Ch,(
Other chE
tobacco pr
acetone, a
gen sulfic
phenol, an
Smoking
can resull
thus caus
CoalDtisi
Coal dust
produce c
plays a si
significan
smoking
exposure
miners w
decreased
smoking
Cotton D
Many inv
smokers ;
nonsmoki
produces
cough, ai
formerly
on the fir
be accom
The acut
dust gra
eventuall
In the
diminutic
and~ the
dysfuncti
(153) WANNER, A., HIRSCHJ.A., GREENELTER, D.E., SWENSONE.W:, FORE, '
T. Tracheal mucous velocity in beagles after chronic exposure to cigarettee
smoke. Archives of Environmental Health 27:370-371,1973, "
(154)~ WARR, G.A.,, MARTIN, R.R. Im vitro migration of human alveolar macro-`
phages: Effects of cigarette smoking. Infection and Immunity 8(2): 222-227,,
1973.
(155) WARR, G.A., MARTIN, R.R.,, HOLLEMAN, C.L., CRISWELL, B:S. Classifiica-
tion, of bronchial lymphocytes from nonsmokers and: smokers. American
Review of Respiratory Disease 113: 96-100 1976.
(156) WARR, G:A., MARTIN; R,R., SHARP, P.M., ROSSEN, R.D: Normali human
bronchial immunoglobulins and proteins. American Review, of Respiratory
Disease 116: 25-30;,1977:
(157) WEISSMANN, G. The role of lysosomes in inflammation and disease. Annual
Review of Medicine 18: 97-112,1967.
(158) WELCH, M.H!, REINECKE, M.E. HAMMERSTEN, J.F., GUENTER, C.A.
Antotrypsim defaciencyin pulmonary disease: The significance of' intermediate
levels. Annals of Internal Medicine 71(3): 553-542, September 1969.
(159) WILHELMSEN, L. Effects on bronchopulmonary symptoms, ventilation, and
lung mechanics of abstinence from tobaeco smoking. Scandanavian Journal of
Respiratory Disease 48: 407-414, 1967:
(160) WOOLCOCK, A.J., VINCENT, N.J., MACKLEM, P.T. Frequency dependence of
compliance as a test for obstruction of the small airways. Journal of Clinical
Investigation 48: 1097-1105, 1969:
(161) WOOLF, C.R. Clinical findings, sputum examinations, and pulmonary function
tests related to the smoking habit of 500 women. Chest 66: 652-659, 1974.
(162) WYATT, J.P. Environmental factors in chronic lung disease. In: Lee, D.H.K..
(Editor). Environmental Factors on Respiratory Disease. Fogarty Internation-
al Center Proceedings No. 11, New York, Academic Press, 1972, pp. 119-137.
(Abstract)
(163) YEAGER, H. Alveolar cells: Depressant effect of cigarette smoke on protein
synthesis. Proceedings of the Society of Experimental Biology and Medicine.
31(I): 247-250; 1969.
(164) YEAGER, H., ZIMMET, S.M., SCHWARTZ, S.L. Pinocytosis by human alveolar
macrophages: Comparison of smokers and nonsmokers. Journal of Clinical
Investigation 54(2): 247-251, 1974.
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With respect to tobacco products serving as vectors, the National
Institute for Occupational Safety and Health (NIOSH) has thus far
ident'ified the following agents as potential occupational contaminants
of tobacco and tobacco products:
Agent Major Health Effects
Formaldehyde (61) Respiratory irritant, dermatitis
Boron Trifluoride (57) Respiratory irritant, joint dis=
ease
Organotin (66) Respiratory irritant
Methyli Parathion (65) Reduced erythrocyte cholinester-
ase activity
Dinitro-ortho-Creosol (60) Kidney damage, peripheral neu-
, ritis; CNS disturbances.
CarbaryU (58) Inhibition of acetylcholinesterase
Inorganic Fluorides (63) Fluorid'e osteosclerosis
Inorganic Mercury (64) CNS' disturbances, kidney dam
age, peripheral neuritis
Lead (81 94) Nervous system toxin, renal
toxin, changes in hematopoiet-
ic system
Additional research is clearly warranted to identify other workplace
chemicals which are transformed into more toxic agents by tobacco
smoking.
Certain toxic agents in tobacco products and/or smoke may also
occur in the workplace, thus increasing exposure to the agent.
Hydrogen Cyanide
Hydrogen cyanide has been found in cigarette smoke at concentrations
as high~ as 1,600 ppm (83). In 1973 Pettigrew and Fell (69) found the
plasma thiocyanate (a metabolite of cyanide) levels of smokers
significantly elevated as compared to those in nonsmokers: In 1973
Radojicic (71) reported a study of 43 workers in the electroplating
division of an electronics firm in Nes, Yugoslavia. He found that the
majority of workers exposed to cyanide complained of fatigue,
headache, asthenia, tremors of the hands and feet, and pain and
nausea. The urinary thiocyanate concentrations of the exposed group
of workers were higher at- the end of the work shift than before
exposure at work. Urinary thiocyanate concentrations were signifi-
cantly higher among exposed smokers than unexposed smoking,
controls, significantly higher among exposed nonsmokers than unex-
posed nonsmokers, and significantly higher among exposed smokers
than among, exposed nonsmokers. These findings demonstrate that
smoking and occupational exposure can each contribute to a worker's
total exposure to and intake of cyanide.
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found no significant excess deaths from lung cancer in either smoking
or nonsmoking groups at low to moderate exposures. However, a
highly significant increase in~ lung cancer deaths was seen~ in the
severely exposed~ who also smoked.
The above: mentioned! studies and other similar studies have shown~
that cigarette smoking and asbestos exposure together are associated
with extremely high rates of lung cancer. But what role does each play
in this process? Two general hypotheses have been proposed to answer
this question (14): The additive hypothesis suggests that asbestos
exposure and cigarette smoking act independ'ent'Uy to produce lung
cancer and that the excess risk seen when both are experienced
together is due to the sum of their risks. The multiplicative
(synergistic) hypothesis contends that each of the involved risk factors
has a certain value for its risk an& that the product of these two risks
(asbestos exposure x cigaret'te smoking) describes how they work
together to bring about a certain result (lung cancer). Selikoff's data
suggest a synergistic effect. However, in the study by Berry, et all (14),
the male data: do not fit either hypothesis while the female data easily
support the multiplicative hypothesis. A more recent study by
Martischnig, et all (50) of 201 men with confirmed bronchial carcinoma
was much less consistent with the multiplicative hypothesis and
pointed more closely to the additive hypothesis. However, the smoking
histories were obt'ained! retrospectively, smoking-specific estimates
were not available, and the, data are difficult to interpret. Regardless
of whether the action is additive or synergistic, a substantial risk faces
smokers who are exposed to asbestos. The extraordinary increase in
lung cancer resulting fromi the interaction of cigarette smoking and
asbestos exposure: has le& the Johns-Manville Corporation to ban
smoking,in its asbestos plants (38):
Other neoplasms have been associated with exposure to asbestos but
appear to be: independent of smoking habits: Eighty-five to ninety
percent of mesothelioma has been attributed' to exposure to asbestos
(84). The relationship of pleural and peritoneal mesothelloma to
smoking and asbestos exposure was investigated by Hammond and
Selikoff (31). Calculations from their studies reveal 0.38' deaths from
pleural mesothelioma per 1,000 man years of observation among
asbestos-exposed cigarette smokers and 0.39 for exposed nonsmokers.
Rates for peritoneal mesothelioma were 0.73 for smokers and 0.83 for
nonsmokers (74). On the other hand, esophageal cancer rates were
significantly increased, but only among smokers. Rates for stoma&
and colon cancer showed no such restriction (31, 75).
In 1971 Weiss (87) explored the relationship of asbestosista cigarette
smoking. He examined 100 asbestos textile workers by chest X-ray and
questionnaire. Pulmonary fibrosis was found in 40 percent of' 75
workers who smoked and 24 percent of 25 nonsmokers. Weiss
determined that age, sex, and duration of exposure to asbestos were
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pressure and concentration (parts per million) in inspired
air ....................................................................... 71
Figure 15.-The degree of compensation necessary to
offset the effects of elevated fetali carboxyhemoglobin
concentrations ........................................................ 73
LIST OF TABLES
Table 1.-Birth weight under 2,500 grarns by maternal
smoking, habit, relative and attributable risks derived
from published studies ...................................:........13
Table 2.-Mean birth weight of infants of smoking and
nonsmoking mothers, by other biologic and socioeconomic
factors .................................................................. 15
Table 3.-Birth weight under 2,500 grams by maternal
smoking, and other factors ....................................... 16
Table 4.-Spontaneous abortions by maternal smoking,
habit and desideration of pregnancy .......................... 32
Table 5.-Perinatal mortality rates per 1,000 live: births to
smoking and nonsmoking mothers, and relative risks for
infants of smokers by maternal age, parity, and years of
school . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
. . . . . . . . . .. . . . . . . . . . 33
Table 6.-Examples of perinatal mortality by maternal
smoking status related to other subgroup
characteristics ..............................................:......... 34
Table 7.-Cause of stillbirth related to smoking habit..... 36
Table 8.-Cause of neonatal death related to smoking
habit ........................................................... 1........ 37
Table 9.-Stillbirths according to cause in relation to
maternal smoking during pregnancy .......................... 37
Table 10.-Fetal and neonatal deaths by coded cause and
maternal smoking habit ........................................... 38
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ate and hi& levels whole cigarette smoke had twice the effect of
filtered smoke in decreasing clearance:
The long-term, effects of cigarette smoking on mucociliary function
in man are unclear. Most of the, evidence indica.tes that long-term
smoking reduces mucociliary transport (152). Animal and human
studies have suggested that cessation of smoking may allow partial
recovery of mucociliary function (1, 25).
Interaction of Smoking with Other Risk Factors for COLD
Alpha-l-antitrypsin Deficiency
It would be usefut to identify the populations at special risk of
d'eveloping, COLD from smoking so that such populations might be
made aware of the risk. Persons with significant deficiencies of alpha-
1-antitrypsin may be such a population.
Eriksson (48) was the first investigator to observe a relationship
between the presence of markedly decreased serum-trypsin inhibitory
capacity and panlobular emphysema. Since Eriksson's paper, much
research has been published'concerning, this intriguing observation.
Severe alpha~l-antitrypsin deficiency is due to a rare genetic trait
which occurs in approximately 1 in 2,000 people (.¢;9); Less severe
reductions are found' in approximately 2 to 10 percent of thee
population. Alpha-l-antitrypsin inheritance patterns indicate multiple
codominant alleles at one gene locus. Some alleles (notably Z, S, and
"nulP') are associat'ed with substantially reduced serum levels of alpha-
1-antitrypsin. The autosomal cod'ominant inheritance allows multiple
combinations of alleles associat'ed~ with low or normal serum levels of
the antiprotease. For example, extremely low levels are associated
with the ZZ homozygous state, intermediate levels with the MZ
heterozygous state, and normal levels with the MM state. Thus, a wid'ee
range of serum levels may be encountered which depend upon the
particular alleles involved. The particular phenotype of a given patient
can be identified by antigen~antibody crossed gell electrophoresis but
not by measurement of serum levels alone, because alpha-l-antit'rypsin
is an acute phase reactant. The pathophysiologic implications of a
reduction in antiprotease activity have been discussed in previous
sections: Severe deficiency of alpha-l-antitrypsin has been associated with a
particular type of pulmonary emphysema. While the majority of lungs
of emphysematous patients reveal bullous or centrilobular deformities,
particularly of the upper lobes, this hereditary disorder reveals a
panacinar change, most severe in the lower lobes (63, 136, 158).
Populations with this genetically relat'ed- form of emphysema have a
greater percentage of females than is usually observed' in the general
emphysema population. Their disease begins earlier, is more severe, is
characterized by dyspnea rather than cough, and frequently is.
6-33
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TABLE 1.-Birth weight under 2,500 grams by maternal smoking habit, relative and attributable risks
derived
from published studies
Smokers Births <2,500 gm(%) Relative Attributr
Nonsmokers - - risk able
Study Propor- Non-
(No.) No. Smoker smoker: risk'
tion smoker
nonsmoker (%)
Cardiff 7,176 6,238 .465 4.1 8.1 1.98 31
US Collaborative
White 8,466 9,781 .536 4.3 9.5 2.21 39
Black 11,252 7,777 .409 10.7 17.5 1.64 21
-
California, Kaiser
Permanente
White 3,189 2,145 .402 3.5 6.4 1.83 25
Black 934 479 .338 6.4 13.4 2.09 27
Montreal 3,954 3,004 .432 5.2 11.4 2.19 34
Ontario 27,316 21,062 .435 4.5 9.1 2.02 31
Percentage of total birth weights <2,500 gm attributable to maternal smoking. Attributable risk in
population - b(r-1) divided by b(r-1) +1 where b - proportion of mothers who smoke and r-
._..
relative risk of low birth-weight - smoker rate/nonsmoker rate
SOURCE: Meyerq M.B. (115).
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Trends In Smoking Habits and in Morbidity and Mortality Rates
for Various Occupational Groups
Surveys (56) have shown that male blue-collar workers are much more
likely to smoke cigarettes than white-collar workers. While in 1970
only 37 percent of white-collar workers were reported to be current
smokers, 51 percent of those in blue-collar occupations smoked. Also,
more ex-smokers are found among white-collar workers than among
blkze-collar workers (35 percent and 28 percent respectively). Smoking
among white-collar workers dropped from 48' to 37 percent between
1966 and 1970; during the same : time period smoking among, blue-collar
workers dropped from 62 percent to 51 percent.
The pattern among female employees is quite different (56): There
was little difference in smoking rates between white- and blue-collar
female workers, 36 and 38' percent respectively, in 1970. In addition,
the smoking rates for 1966 were the same as those for 1970 in both
groups of female workers. During the: period studied, the increased
cessation of smoking among, female workers was offset by the
increased initiation of smoking in~ the same group.
In a study by Boucot, et al. (16); 121: new lung cancers developed
among 6,136 men aged 45 and older who volunteered to report
semiannually for chest X-rays and answer questionnaires about
symptoms, smoking habits, and so forth, over a 10ryear period
beginning in 19511. The risk of developing lung cancer increased with
increasing age, was higher in nonwhites than in~ whites, and bore a
dose-response relationship to cigarette smoking. The highest lung
cancer risk was among asbestos workers, 42.9/1000 man-years (crude
rate), The risk was 2.2/1000 man-years (crude rate) for men in
occupationali categories not thought to be associate& with an increased
risk of lhng cancer. Wlteni adjust'ed for age, race, an6 smoking, these
rates were respectively 23.0/1000 and 1.4/1000'man-years. Occupation-
al categories showing somewhat increased risk were metal workers,
cooks, and automobile drivers. A higher percentage of nonwhites (22.6
percent) i than whites (13.5 percent) worked in occupations thought to
be at increased lung cancer risk. The excess lung cancer rate in
nonwhite males could not be attributed to smoking.
The smoking habits in various occupational groups demonstrate
ample opportunity for interaction between cigarette smoking and
physical and chemical agents in the workplace. In general~ those who
have the highest smoking rates also have the highest risk for industriali
exposures. Both the consumption of tobacco products an& exposure to
industrial agents increased steadily from 1920 to 1960. This is reflected
in certain mortality trends. For example, the United States age-
adj usted mortality rate from carcinoma of the pancreas has been
reported to have risen~from~2.9 to 8.2 per 1'00;000~population from 1920
to 1965, an increment of 283 percent. The rise was found to be real and
threefold in magnitude when adjustments were made for the aging of
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Figure 3.-Mean birth weight for week of gestation
according to maternal smoking habit: control week
singletons .............................................................. 19
Figure 4.-Percentage of birth weights under 2,500 grams
by maternal smoking leveli for early, average, and late-
term births ........................................................... 20
Figure 5.-Theoretieal cumulative mortality risk according
to smoking habit, in mothers of different age, parity,
and social class groups ........................................:... 31
Figure 6.-Percentage distribution by weeks of gestation
of births to nonsmokers, smokers of less than one pack
per day, and smokers of one pack per day or more..... 43
Figure 7.-Probability of perinatal, death for smoking and
nonsmoking mothers, by periodi of gestational age....... 45
Figure 8.-Risks of selected pregnancy complications for
smoking and nonsmoking, mothers, by perioA of
gestational age at delivery....................................... 46
Figure 9.-Time course of carbon monoxide uptake in
maternal and fetal sheep exposed to varying, carbon
monoxide concentrations .......................................... 59
Figure 10.-Iduman maternal' and fetal! oxyhemoglobin
saturation curves showing carbon monoxide effect....... 62
Figure 11.-The partial pressure at which the
oxyhemoglobin saturation is 50 percent, P50, for human
maternal and fetal blbod as a function of blood
carboxyhemoglobin concentration ............................... 63
Figure 12.-Fetal values of oxygen partial pressure as a
function of carboxyhernoglobin concentrations during
quasi-steady-state cond[tions ., ........ ..................,.......... 64
Figure 13.-Thermogram from a near-term~ pregnant
patient before and after smoking ..................,...........68
Figure 14.-Percent carboxyhemoglobin in maternal and
fetal blood as a function of carbon monoxide partial
8-5
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not responsible for the difference noted. Seventy-three.of the above
cigarette smokers were then questioned concerning amount and
duration of smoking. The prevalence of fibrosis was 23 percent of 13
workers who smoked less than one pack per day and 43 percent of 60
who smoked one or more packs per day. Of 18 workers who smoked a:
pack or more per day for less than 20 years and had less than 20 years
of asbestos exposure, 28 percent had' fibrosis. Of 19 workers who
smoked more than 20 years and with more than 20 years of exposure to
asbestos, 74 percent had fibrosis. This study suggested' that the
prevalence of pulmonary fibrosis increases with an increasing amount
and duration of cigarette smoking as well as with an increasing
duration of exposure to asbestos: Due to the small size of the observed;
group, Weiss was unable to determine whether cigarette smoking and
asbestos exposure were working in an additive or multiplicative
manner. A study recent'liy published by Weiss and Theodos indicatess
that type of asbestos as well as smoking habits are factors in the
development of pleuropulmonary disease in asbestos workers (88).
In summary, workers exposed to tobacco smoke and asbestos
experience far greater levels of lung cancer than would be expected
from the contribution of either tobacco smoke or asbestos alone:
However, other adverse health effects of occupational exposure to
asbestos (for example, mesothelioma); appear to be independent of
smoking habits. Thus; smoking varies in its contribution to the
development of different adverse health effects resulting from
occupational exposure to a particular occupational agent.
Exposures in the Rubber Industry
In a study of rubber workers, Lednar, et al. (47) reported that smokers
exposed to fumes and dust, particularly talc and' carbon black, had a
significantly higher risk of developing a pul'monary disability than did
nonsmokers. The combination of smoking and occupationali exposure
significantly elevated the probability of developing an early pulmonary
disability. The authors reported that a rubber worker exposed to dust
and smoking was associated with 10 to 12 times the risk of pulmonary
disability retirement compared to the risk of a nonsmoking, nonoccupa-
tionally-exposed rubber worker. This elevated risk was found where
there were exposures to respirable particulates and/or solvents. Thiss
study suggests that smoking and occupational exposures in the rubber
industry are synergistic since the authors report that a rubber worker
who smoked and was exposed to talc had an excess relative risk of 3.40,
whereas an excess relative risk of 1.77 would be expected if the effects
of smoking and work exposure were additive. The mechanism of this
interaction is not yet understood.
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CONTENTS
Introduction .............................................................. 9
Biomedical Aspects of Smoking .............................. 9
Historical Considerations ........................................ 9
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11
and Fetal Growth
Birth Wei
ht
Smokin
....................
g
g,
,
Birth Weight ...................................................... 1'1
Placental Ratios .................................................. 14
Gestation ........................................................... 17
Fe tal' Growt'h ....................................................... 19
Long-Term Growth and Development ..................... 21
Role of Maternal Weight Gain .............................. 24
Evid'ence for Indirect Associations Between Smoking
0
and! Birth~ Weight .............................................26 A
Summary ........................................................... 27
Cigarette Smoking and Fetal and Infant Mortalit'y......... 28
Overview ........................................................... 28
Spontaneous Abortion ........................................... 30
Perinatal Mortality .............................................. 32
Cause of Death ................................................... 36
Complications of Pregnancy and Labor ................... 39
Preeclampsia .. . . . . . .. . ... . .. . .. . .. .. . . . . . ... . . . . .... . . ... .. .. .. .
... 41
Preterm Delivery................................................. 42
Pregnancy Complications and Perinatal Mortality by
Gest'ation ......................................................... 43
Sudden Infant Death Syndrome ............................. 44
Summary ........................................................... 46
Lactation and Breast Feeding ..................................... 4Introduction
........................................................ 48
Epidemiological Studies ........................................ 48
Experimental Studies ........................................... 49
Studies in Animals ........................................ 49
Nicotine ...................................................... 49
Studies in Humans ....................................... 50.
N' t' d T b S k 50
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Physiologic-Experimental Studf es ................................. 52
Studies in Animals ............................................... 52
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Introduction
Biomedical Aspects of Smoking
Data accumulating in the scientific literature during the past decade
strongly corroborate findings reported in the 1960's that cigarette
smoking during pregnancy has a significant and adverse effect upon
the well-being of the fetus, the health of the newborn baby, and the
future development of the infant and child. Adverse: effects on
pregnancy range from increase& risk for reproductive loss, fetal
mortality, preterm birth, and neonatal death to retardation in~ fetal
growth as reflected in birth measurements of lower mean body weight,
shortened body length, and smaller head circumference, as well as to a
number of problems of adaptation in the neonatall period. In addition,
there is suggestive evidence of long-term impairments in physical
growth, diminished intelliectual function, and deficiencies inbehavioral
development for those babies who survive the first 4 weeks of life. It
appears that children of smoking mothers do not catch up with~ the
offspring of nonsmoking mothers in various phases of development.
The present chapter highlights previously reported and recent
studies on the relationships between cigarette smoking and pregnancy
outcome,, including sections on~ historical considerations, birth weight
and fetal growth, fetal and infant mortality, lactation and breast
feeding, and physiologic-experimental' studies. The concluding section
of this chapter, entitled R.esearch Issuesidentifies questions and areas
of concern that need clarification and further investigation.
Historical Considerations.
In 1957, Sidnpson~ (172) reported that infants born to women who
smoked during their pregnancies were of significantly lower birth
weight relative to babies borni to nonsmokers: During the intervening
20 years, there has been, increasing concern, coupled with the conduct
of a large number of related studies, about the effect of smoking
d'uring pregnancy upon the well-being of the developing fetus and
infant.
Concern about the effects of exposure to tobacco and' cigarette
smoking during pregnancy upon reproductive loss, maternal health,
pregnancy outcome, and infant welb-being dates back a century. In
1902,, Ballantyne (9) quest'ioned' what might be the effect of tobacco
poisoning upon antenatal life. While he did not specifically mention
maternal smoking during pregnancy, he summarized the opinions of a
number of authors writing during the latter part of the 19th century
about the risks of spontaneous abortion for women who worked in
tobacco factories. He referred specifically to an 1879~paper by Decaisne
from France and to an 1868 report by Kostial from Austria about
female tobacco workers. Ballantyne wrote that both of these authors
"were quite convinced that abortion was very frequent in women
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(51) MATERNE; D., LAUWERYS, R., BUCHET, J.P.,,ROELS, H., BROUWERS, J.,,
STANESCU~ D. Investigations sur les risques resultant de 1'exposition au
cadmium dans deux entreprises de production et deux entreprises d'utilisation
du cadmium (Investigations on the risk resulting from exposure to cadmium in
two production plants and two plants using cadmium). Cahiers de Medecine du
Travail 12(1 and 2): 5-76, March-June 1975.
(52) MERCHANT;, J!A., HALPRIN, G.M., HUDSON, A.R., KILBURN, K.H.,
MCKENZIE, W.N.,,JR., HURST, D.J., BERMAZOHN, P. Responses to cotton
dust. Archives of Ehvironmentral Health~30(5): 222-229, May 1975.
(53) MERCHANT, J.A., KILBURN, K.H., O'FALLON, W.M., HAMILTON, J.D.,
LUMSDEN, J.C. Byssinosis and chronic bronchitis among cotton textile
workers. Annals of Internal Medicine 76(3): 423-433i March 1972.
(54) MERCHANT, J.A., LUMSDEN, J.C., KILBURN, K.H.,, O'FALLON W.M.,
UJDA, J.R, GERMINO, V.H., JR., HAMILTON, J.D. Dose response studies in
cotton textile workers. Journal of Occupational Medicine 15(3): 222-230, March
1973.
(55) MERCHANT, J.A., LUMSDEN, J.C., KILBURN, K.H., O'FALLON, W.M.,
UJDA, J.R.,, GERMINO, V.H., JR, HAMILTON, J.D. An industriali study of
the biological effects of cotton dust and cigarette smoke exposure. Journal of
Occupational Medicine 15(3): 212-221, March 1973.
(56), NATIONAL CLEARINGHOUSE FOR SMOKING' AND HEALTH. Adult Use
of Tobacco, 1970. U.S. Department of Health, Education, and Welfare, Public
Health Service, June 1973;,137 pp.
(57) NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH.
Criteria for a Recommended Standard....Occupational Exposure to Boron
Trifluoride. U.S. Department of Health, Education, and Welfare, Public
Health Service, Center for Disease Control, National Institute for Occupation-
ali Safety and Health, DHEW (NIOSH)' Publication No. 77-122, December
1976,83 pp.
(58) NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH.
Criteria for a Recommended Standard....Occupational Exposure to Carbaryl.
U.S. Department of Health, Education and Welfare, Public Health Service;
Center for Disease Control, National Institute for Occupational Safety and
Health, DHEW (NIOSH) Publication No. 77-107;,September 1976,192 pp.
(59) NATIONAL INSTITUTE' FOR OCCUPATIONAL SAFETY AND HEALTH.
Criteria for a Recommended Standard....Occupational Exposure to Decomposi-
tion Products of Fluorocarbon Polymers: U.S. Department of Health,
Education, and Welfare, Public Health Service, Center for Disease Control,
National Institute for Occupational Safety and Health, DHEW (NIOSH)
Publication No. 77-193, September 1976, 112 pp.
(60) NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH.
Criteria for a Recommended Standard.... Occupational Exposure to Dinitro-
Ortho-Cresol! U.S. Department of Health, Education, and' Welfare, Public
Health Service, Center for Disease ControlNational Institute for Occupation-
al Safety an& HealthDHEW (NIOSH), Publication No. 78-131, February 1978,
147 pp.
(61) NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH.
Criteria for a Recommended St'andard.... Occupational I Exposure to Formalde-
hyde. U.S: Department of Health, Education, and Welfare, Public Health
Service, Center for Disease: Control, National Institute for Occupational
Safety and HealthDHEW (NIOSH) Publication No. 77,126,,December 1976,.
165 pp.
7-23
(34) HARRIS, T.R, MERCHANT, J.A., KILBURN, K.H., HAMILTON, J.D.
Byssinosis and' respiratory diseases of cotton mill workers. Journal of
Occupational Medicine 14(3): 199-206, March 1972.
(35)' HENDRY, N.W. The geology, occurrences, and major uses of asbestos. Annals
of The New York Academy of Sciences;132(1): 12-22, December 31,1965.
(36) HORVAT, M., YOSHIDA, S., PRAKASH, R., MARCUS, H:S.,, SWAN, H.J.C.,
GANZi W. Effect of oxygen breathing on pacing-induced angina pectoris and
other manifestations of coronary insufficiency. Circulation 45(4): 837,844,
April 1972.
(39) HOSEY, A.D. Priorities in developing criteria for "breathing air" standards.
Journal of Occupational Medicine 12(2): 43-46, February 1970.
(38), JOHNS.MANVIL'LE. President's Bulletin No. 640-1. Denver, Johns-Manville
Corporation, January 1, 1978, 20 pp.
(39)' JONES, J.G., WALTERS, D.H. A study of carboxyhaemoglobin levels in
employees at an integrated steelworks. Annals of Occupational Hygiene 5:
221-230,' 1962.
(40), JUDD, H.J. Levels of carbon monoxide recorded on aircraft flight'~ decks.
Aerospace Medicine 42(3): 344-348, March 1971.
(41) KIBELSTIS, J.A.,, MORGAN, E.J., REGER, R., LAPP, N.L., SEATON, A.,
MORGAN', W.K.C. Prevalence of bronchitis and airway obstruction in
American~ bituminous coal miners. American Review of Respiratory Disease
108(4): 886-893;1973.
(l,2) KJELLSTROM T., EVRIN, P.-E., RAHNSTER, B. Dose-response analysis of
cadmium-induced tubular proteinuria. A study of urinary #rmicroglobulin
excretion among workers ima battery fact'ory. Environmental Research 13(2):
303-317; April i 1977:
(43) KRAIN, L.S: The rising incidence of carcinoma of the pancreas-Real or
apparent? Journal of Surgical Oncolbgy 2(2) i 115-124,1970.
(44): KUNTZ, W.D.,, MCCORD, C.P. Polymer-fume fever. Journal of Occupational
Medicine 16(7):'480-482, July 1974.
(;45) LAUWERYS, R. BUCHET, J.P.,, ROELS, H. Une etude de la fonction
pulmonaire et renalb de travailleurs exposes au cad'mium (A study of
pulmonary and renal function in workers' exposed to cadmium). The 18th
International Congress on Occupational Health, Brighton, England, Septem-
ber 14-19, 1975pp. 279-280. (Abstract)
(46) LAUWERYS, R.R., BUCHET, J.P.,,ROELS; H.A., BROUWERS, J., STANES-
CU, D: Epidemiological survey of workers exposed to cadmium. Effect'~ on
lung, kidney, and severalibiological indices: Archives of Environmental Health
28(3): 145-148~ March 1974.
(47) LEDNAR, W:M., TYROLER,, H.A., MCMICHAEL, A.J., SITY C:M. The
occupational determinants of chronic disabling pulmonary disease in rubber
workers. Journal of Occupational Medicine 19(4):263-268; April 1977.
(48)~ LUNDIN, F.E., JR., WAGONER, J.K., ARCHER, V.E. Radon Daughter
Exposure and Respiratory Cancer. Quantitative and Temporal Aspects. U.S.
Department of Health, Education, and Welfare, Public Health Service,
Nationali Institute for Occupational Safety and Health, National Institute of
Environmental Health Science. Joint Monograph No. 1, June 1971, 175 pp.
(49) LYNCH, K.M., SMITH, W.A. Pulmonary asbestosis III: Carcinoma of lung ini
asbesto-silicosis. American Journaliof Cancer 24(1): 56-64, May 1935.
(50) MARTISCHNIG, K.M., NEWELL, D.J., BARNSLEY, W.C., COWAN, W.K.,,
FEINMANN, E.L.,, OLIVER, E. Unsuspected exposure to asbestos and
bronchogenic carcinoma. British Medical Journal 1(6063): 746-749, March, 19,
1977.
7-22
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workers in tobacco [factories]...." Ballantyne concluded by stating,
"While there is much doubt, therefore, regarding the evil effect of
nicotism in~cutting short antenatal lifethere seems to be no shadow of
doubt that there is a very large infantile mortality in postnatal life
among the offspring of women workers in tobacco. Possibly this may
be due in part to the influence of the milkbut it is more probable that
it is on account of congenital debility."
Discussioni of the problem of smoking during pregnancy at the turn
of the century appears to have been~ base& on empiricali evidence and
anecdotal reports. Until the end of the 1920's; there was a sparsity of
reports on this topic in the scientific literature. Thereafter, several
articles were published reporting the results of animal studies and
clinical investigations pertinent to t'he effects of nicotine and smoking
during pregnancy upon~ reproductive loss, maternal healt'h, and
pregnancy outcome:
In 1935, Sontag and Wallace (175) investigated the effects of
cigarette smoking during pregnancy upon fetal heart rate. Their
observations were made during, the last 2 months of pregnancy on
eight mothers and their fetuses. Their data: revealed that the smoking
of one cigarette by the pregnant woman generally produced an
increase in the rate of the fetal heart beat, and sometimes a decrease.
They concluded that there was "a definite an& real" increase in the
fetal heart rate after the mother began to smoke a cigarette and that
this was probably due to transplacental transfer of nicotine into the
fetal circulation.
In 1935 and again in 1936, Campbelll (23, 24) reported that heavy
cigarette smoking was prejudicial to efficient childbearing as a: result
of chronic nicotine poisoning. Campbell warned that excessive smoking
in certain cases was detrimental to maternal health. He noted that, in
generaly a woman who smoked during pregnancy was likely to have
more difficulty during the course of pregnancy, parturition, and
lactation~ t'han a woman who did not smoke.
In 1940, Essenberg and associates (4'6), in a well-designed study,
investigated the effects of nicotine and cigarette smoke on pregnant.
female albino rats an6 their offspring. The three groups of subjects
include& a group of animals that received intraperitoneali or subcuta-
neous injections of solutions of chemically pure nicotine, a: second
group of animals that were exposed to tobacco smoke that approximat-
ed human smoking of one pack of cigarettes a day, and a third group of
animals that were untreated.
The immediate effects on the animals in the two treate& groups
were similar, although more severe in the injected group. It was
reported that:
1. Two-thirds of all the young of treated mothers were underweight;
the young from nicotine-injected mothers were more underweightt
than those fromi mothers exposed to tobacco smoke.
(77'), SIDOR R., PETERS, J.M. Prevalence rates of chronic non-specific respiratory
disease in fire fighters. American ~ Review of Respiratory Disease 109(2): 255-
2fi1, February 1974.
(78) SLUIS-CREMER, G:K., WALTERS, L.G., SICHEL, H~S. Chronic bronchitis in
miners and non-miners: An epidemiological survey of a community in the gold-
mining area in the Transvaal. British Journal of Industrial Mediaine 24(1): 1-
12, January 1967.
(79) STELL, P.M., MCGILL, T. Exposure to asbestos an& laryngeali carcinoma
Journal of Larynogology and Otology 89(5): 513-517, May 1975.
(80) STEWART RD., HAKE, C.L. Faint-remover hazard: Journal of the American
Medical Association 235(4): 398-401, January 26, 1976.
(81) TOLA, S., NORDMAN, C.H. Smoking and bloo& load concentrations in lead-
exposed workers and' an unexposed population. Environmental Research~ 13:
250-255,1977.
(82) TOUEY, G.P., MUMPOWER, R.C., II. Measurement of the combustion-zone
temperature of cigarettes. Tobacco 144(8): 18-22, February 22,1957.
(88) U.S. PUBLIC~ HEALTH SERVICE. Smoking and Health. Report of the.
Advisory Committee to the Surgeon General of~ the Public Health Service. U.S.
Department of Health, Education, andWelfare, Public Health Service, Center
for Disease Control, PHS Publication No. 1103,,1964, 387 pp:
(84): WAGNER;, J.C., GILSON, J.C:, BERRY, G., TIMBRELL, V. Epidemiology of
asbestos cancers. British Medical Bulletin 27(1):: 71-76, 1971.
(85) WEGMAN, D,H., PETERS, J.M. Polymer fume fever and cigarette smoking.
Annals of Internal Medicine 81(1): 55-57, July 1974.
(86) WEISS, W. Chloromethyl ethers, cigarettes, cough and cancer. Journal of
Occupational Medicine 18(3)r 194-199, March 1976.
(87) WEISS, W. Cigarette smoking, asbestos, and pulmonary fibrosis. American
Review of Respiratory Disease 104(2): 223-227{ August 1971:
(88) WEISS, W., THEODOS, P.A. Pleuropulmonary disease among asbestos workers
in relation to smoking and type of exposure. Journal of Occupational Medicine
20(5): 341-345; May 1978.
(89) WILLIAMS, N., ATKINSON, G,W., PATCHEFSKY, A.S. Polymer-fume fever:
Not so benign. Journal of OecupationaliMedicine 16(8): 519-522, August 1974.
(90), WILLIAMS, N., SMITH, F.K., Polymer-fume fever. An elusive diagnosis.
Journal of the American Medical Association, 219(12): 1587-1589, March 20,
1972.
(91) WOOD, 1L. Biochemistry: In: Wood, J.L. (Editor). Chemistry and Biochemistry
of Thiocyanio Acid and its Derivatives: New York, Academic Press Ine.,,1975,
pp. 156-221.
(92) WYNDER, E.L., GOLDSMITH, R. The epidemiology, of bladder cancer. A
second look. Cancer 40(3): 1246-1268, September 1977.
(93), YUSTE; P.C., DE GUEVARA, M.L. Influencia del fumar en los accidentes
laborales. Encuesta estadistica (The influence ofi smoking on industrial
accidents. A statistical study). Medicina y Seguridad deliTrabajo 21(84): 38-46,
October/December 1973. `
(94) ZIELHUIS, R:L., STUIK, E.J., HERBERR:F.M.,,SALLE, H.J.A.,,VERBERK,.
M,M:, POSMA, F.D:, JAGER, J.H. Smoking habits and levels of lead and
cadmium in blood in urban women. International Archives of'Occupational and'
Ehvironmental i Health 39: 53-58, 1977.
7-25
I
®
exposure the COHb level' remained elevated (4.4 percent versus Q:88
percent prior to exposure) (80):
Based on this time lag, prohibiting a worker exposed to methylene
chloride from smoking on the job would not be sufficient to protect the
worker who smokes after he leaves work from the additive burdens of
CO from methylene chloride and tobacco smoke.
Other Ch;emieal Agents
Other chemical agents found' in tobacco, or in the combustion of
tobacco products, and~ also potentially found! in the workplace include:
acetone, acrolein, aldehydes, arsenic, cadmiumi formaldehyde, hydro-
gen sulfide, ketones, lead, methyl nitrite, nicotine, nitrogen dioxide,
phenol~ and~ polycyclic compounds (83).
Smoking may contribute to an effect' comparable to that which
can result from exposure to toxic agents found in the workplace,
thus causing an additive biological effect.
Coal Dust
Coal dust and cigarette smoking appear to act in an additive fashion to
produce obstructive airway disease. Althoughi dust exposure albne
plays a significant role in the development of this disease, there: is a
significantly higher prevalence of obstructive airway disease in
smoking miners than in nonsmoking miners with the same dust
exposure (41). Flow volume curve data suggest that nonsmoking
miners with dust-indUced chronic obstructive airway disease havee
decreased flow rates primarily at higher lung volumes, whereas
smoking miners have decreased flow rates at all lung volumes (32).
Cotton Dust
Many investigators have noted that among cotton workers, cigarette
smokers show increased prevalence of byssinosis when compared to
nonsmoking cotton workers (13;, 53, 54, 55). Cotton dust inhalation
produces an acute clinical syndrome consisting of chest tightness,
cough, and; shortness of breath in cotton workers (34). This was
formerly known as "Monday morning fever" since symptoms develop
on the first day of work after an absence. The clinica.li syndrome may
be accompanied' by significant reduction in pulmonary function, (52).
The acute clinicall and functional abnormalities produced by cotton
dust gradually become more frequent as the disease progresses,
eventually resulting in chronic obstructive airways disease (34).
In the acute phase of the illness there is a: significantly greater
diminution in pulmonary function in smokers than in nonsmokers (55),
an& the relationship of cotton dust and smoking, to pulmonary
dysfunction appears to be additive.
7-9
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TABLE' 3.-Birth weight under 2,500 grams by maternal smoking
and other factors (Ontario data)
Smoker:
Births under 2
500 grams
, nonsmoker
Factor and class (per hundred total births)
Relative risk
Maternal smoking: packs per day
Packs per day
01 <1 1+ <1 1
Hospital status
Private
4.4
7.11
10.6
1.6
PtSblic 5.8 10.3 16.5 1.8
Mother's height '
< 62!inches 5.9 10.8 15.1 1.8'
62-64 inches 4.7 7.9 12.8' 1.7
65-67 inches 3.9 6.2 10.1 ll6
68+ inches 2.7 6.0 9.3' 2.2
Ptepregnant weight
< 120 pounds
6.1
10.2
15.8
1.7
120-134 pounds 42 6.3 9.5 1.5
135+ pounds 3.3' 5.1 8.7 1.5
Sex of child
Male
4.2
7:3
11.5
1.7
Female 5.2 8.3 12.7 1.6
SOURCE: Meyer, M.B. (115).
1+
2.4
a8
2.6
2.7'
2.6
3.5
26
2.2'
26
2:7
2.4
California ('203)'. At an interview early in pregnancy, information was
obtained about numerous factors related to the: pregnancy, including,
the woman's smoking habits. Placentas were weighed by specially
trained personnel after the cord and attached membranes had been
trimmed off according to Benirschke's protocol, an extremely impor-
tant procedure to reduce variability of measurement. The study was
confined to black or white women who delivere6 single, live infants
without severe anomalies between 37 and 43 weeks' gestation and for
whom at least one hemoglobin value during gestation had been
reported. Because placental ratios change with gestational age, it is
important to compare values specific for weeks of gestation at the time
of delivery. Results of this study are shown in Figure 2. At each
gestational age', from 37 through 43 weeks, the more the mother
smoked during pregnancy the higher is the placental ratio. Comparison
of the observed mean weights by smoking level showed that, as
expected, birth weights decreased as smoking level increasedi Further-
more, mean placentali weight's were the same:or slightly lower for light
smokers and slightly higher for heavy smokers (over 20' cigarettes per
day) than for nonsmokers. Ratios were higher for black than for whitee
women and tended to increase as maternal'hemoglobin level decreased.
This trend was most marked in black women who smoked (203).
D
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8-16
(58) FINKLEA, J.F.,, SHY, C.M., LOVE, C.J., HAYES, C.G:,, NELSON, RS.,
HOUSE, D.E. Health consequences of sulfur oxides: Summary and conclusions
based upon CHESS studies of 1970-1971. In: Health Consequences of Sulfur
Oxides: A Report from~ CH'ESS, 1970-1971. UIS. Etivironment'al Protection
Agency Publication No. EPA-650/1-74-004,1974.
(5l,), FLETCHER, C.M. (Fditor): Terminology, definitions, classification of chronic
pulmonary emphysema and related conditions. A report of the conclusions of a'
Ciba. Guest Symposium. Thorax 14: 286-299,1959.
(55)~ FLETCHER, CX, JONES, N.L., BURROWS, B, NIDEN, A.H.. American
emphysema and' British bronchitis. A standardized comparative study.
American Review of Respiratory Disease 90; 1-13,1964.
(56) FLETCHER, C.:, PETO, R. The natural' history of chronic airflow obstruction.
British Medical Journal~1: 1645-1648, 1977.
(57) FLETCHER, C., PETO, R., TINKER, C., SPEIZER, F.E. The Natural History
of Chronic Bronchitis and~ Emphysema: An Eight-Year Study of Early Chronic
Obstructive Lung Disease in Working Men in London, Oxford, Oxford
University Press, 1976, 272 pp.
(58) FRASCA, J,M., AUERBACH, 0., PARKS, V.R., JAMIESON, J.D. Alveolar cell
hyperplasia in~ the lungs of smoking dogs. Experimental and Molecular
Pathology 211: 300-312, 1974.
(59) GELB, A.F., GOLD, W.M., WRIGHT, R.R., BRUCH~ H.R., NADEL, J.A.
Physiologic diagnosis of subclinical emphysema. American,Review of Respira-
tory Disease 107(1): 50-631973.
(60) GRAY, J.P., KENNEDY, J! R. Ultrastruct'ure and physiological effects of
nontobacco cigarettes on tetrahymena. Archives of Environmental Health 28:
283-291, 1974.
(61) GREENG.M., CAROLIN,,D. The depressant effect of cigarette smoke on the in
vitro antibacterial activity of alveolar macrophages. New England Journal of
Medicine 276(8): 421-427, 1967.
(62) GREGG, I. A study of the causes of progressive airways obstruction in chronic
bronchitis. In: Current Research i in Chronic Respiratory Disease, 11th Aspen
Emphysema Conference,, UiS, Public Health Service, Publication No. 10721,
1968, pp. 235-248.
(63)~ HAMMARSTEN, J:F., WELCH, M., RICHARDSON, R.H., PATTERSON, C0.,,
GUENTER, C.A. Familial alpha-l-antitrypsin deficiency and pulmonary
emphysema. Transactions of the American Clinical and Climatological
Association 80(1): 7-14, 1969.
(64) HARRIS, J.O., OLSEN, G.N.,,CASTLE; J.R., MALONEY, A.S. Comparison of
proteolytic enzyme activity in pulmonary alveolar macrophages and blood
leukocytes in smokers and nonsmokers: American Review of Respiratory
D isease 111: 579-586, ,1975.
(65), HARRIS, J,O., SWENSON, E.W.,, JOHNSON, J!E., III: Human alveolar
macrophages: Comparison~ of phagocytic ability, glucose utilization, and
ultrastructure in smokers and nonsmokers. Journal of Clinical Investigation
49(11): 2086-2096, November 1970.
(66), HEPPLESTON, A.G., STYLES, J.A. Pathology: Activity of a macrophage
factor in, collagen formation, by silica. Nature 214:: 521-522, April 29, 1967.
(67), HIGGINS, I.T.T. Epidemiology of chronic respiratory disease: A literature
review. U.S. Environmental Protection Agency, Office of Research and
Development, 1974, pp. 1-129.
(68) HIGGINS, M.W.,, KELLER, J.B., METZNER, H.L~ Smoking, socioeconomic
status, and chronic respiratory disease. American Review of Respiratory
Disease 116: 403-410,,1977.
6-46
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(71) HL
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(72) HL
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(73) IM
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(74): JA
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(75) JA
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(76) JA
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(82) K.
(83): K
(84) K
(85) K
(62) NATIONAL INSTITUTE' FOR OCCUPATIONAL SAFETY AND HEALTH.
Criteria for a Recommended St'andard....Occupational Exposure to Hydrogen'
Cyanide and Cyanide Salts (NzCN, KCN, and Ca(CN}2). U.S. Department of
Health, Education, and Welfare, Public Health Service, Center for Disease
Control,, National Institute for Occupational Safety and Health, DHEW
(NIOSH) Publication No. 77-108, October 1976,191 pp.
(63) NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH.
Criteria for a Recommended Standard.... Occupational Exposure to Inorganic.
Fluorides. U & Department of Health, Education, and Welfare, Public Health
Service, Center for Disease Control, National Institute for Occupational
Safety and Health, HEW Publication No: (NIOSH) 76-103,1975,191 pp.
(64)' NATIONAL INSTITUTE FOR' OCCUPATIONAL SAFETY AND HEALTH.
Criteria for a Recommended St'andard.... Occupational , Exposure to Inorganic
Mercury. U.S. Department of Health, Education, and Welfare, Public Health
Service,, National Institute for Occupational Safety and Health, HSM 73-
11024, 1973, 129 pp.
(65) NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH.
Criteria for a Recommended' Standard.... Occupationall Exposure to Methyl
Parathion. U.S. Department of Health, Education, and Welfare,,Public Health
Service, Center for Disease Control, National Institute for Occupational
Safety and Health, DHEW (NIOSH) Publication No. 77-106, September 1976,
177 pp.
(66) NATIONAL INSTITUTE FOR OCCUPATIONAL SAFETY AND HEALTH.
Criteria for a Recommended Standard.... OccupationaliExposure to Organotin
Compounds. U.S: Department of Health, Education, and' Welfare, Public
Health Service, Center for Disease Control, National Institute for Occupation-
al Safety and Health, DHEW (NIOSH) Publication No. 77-115, November
1976, 187 pp.
(67) NAUS, A., ENGLER, V., HETYCHOVA, M.,,VAVRECKO'VA, 0. Work injuries
and'smoking. Industrial Medicine and Surgery 35(10): 880-881, October 1966.
(68) OSBORNE, J.S., ADAMEKS., HOBBS, M.E. Some components of gas phase of
cigarette smoke. Analytical Chemist'ry, 28(2):211-215February 1956.
(69) PETTIGREW, A.R., FELL, G.S: Simplified colorimetric determination of
thiocyanate in biological fluids, and its application to investigation of the toxic
amblyopias. Clinical Chemistry, 18(9): 996-1000, September 1972.
(70) PISCATOR, M., ADAMSON, E., ELINDER, C G:, PETTERSSON, B., STENL
INGER P. Studies on cadmium exposed women. Eighteenth International
Congress on Occupational Health, Brighton{ England, September 14-19, 1975,
pp. 281-282. (Abstract)
(71) RADOJICIC, B. Odredivanje rodanida u mokraci u radnika izlozenih cijanidima
(Determination of thiocyanates in urine of workers occupationally exposed to
cyanides). Arhiv za Higijenu Rada i Toksikologiju 24: 227-232, 1973.
(72) RENTCHNICK, P. (Fditor): Recent results in cancer research 3. In: Hueper,
W:C. Occupational and Environmental Cancers of the Respiratory System.
Berlin, Springer-Verlap, 1966, pp. 38-56, 166-170.
(73) ROBBINS, 1J., WARE, R.L. Pulmonary edema from teflon fumes. Report of a
case. New Ehgland Journal of Medicine 271(7): 360,361August13,,1964.
(74) SELIKOFF, I.J. Cancer risk of asbestos exposure. In: Hiatt, H.H~, Watson, J.D.,
Winston, J.A. (Editors). Origins of Human Cancer. New, York, Cold Spring
Harbor Laboratory, 1977, pp. 1765-1783.
(75) SELIKOFF, I.J., HAMMOND; E.C:,, CHURG, J. Asbestos exposure, smoking,
and neoplksia. Journal of the American Medical Association 204(2): 106-112,
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(76) SHERWOOD, R.J. The hazards of fluon. Transactions of the Association of
Industrial Medical Officers 5: 10-12 1955.
4
(78) ~
(80)
(86)
(90)
(92
(93
(94
7-24
Non-Neoplastic Bronchopulmonary Diseases: References
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(4 AMERICAN COLLEGE OF CHEST PHYSICIANS. AMERICAN THORACIC
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(14) BLACK, L.F., KUEPPERS, F. Alpha-l-antitrypsin~ deficiency in nonsmokers.
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(15) BLACKWOOD, C.F., HOSANNAH', Y., PERMAN, E., KELLER, S:, MANDL, I.
Experimental emphysema in rats: Elastolytic titer of inducting enzyme as
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(16) BLUE, M.L., JANOFF, A. Possible mechanism of emphysema in a cigarette
smokers. Release of elastase from human polymorphonuclear leukocytes by
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(17) BRIDGES, R.B.,KRAALa J.H.,HUANG, L.J.T., CHANCELLOR, M.B. Effects
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1975.
5
0
I
®
Ji
6-43
r
125
Non-smokers
85
,Cl Smokers
.
3650
3400
-42400
75{ 1 1 11 1 11 1 1 2150
35 37 38 39 40 41 42 43+
Gestatan n completed weeks
FIGURE 3.-Mean birth weight for week of gestation according to
maternal smoking habit: control week singletons
SOURCE: Bbtltr, N.R. (20).
were compared within units of gestationaL age. Butler and Alberman,
in an analysis of data from the British, Perinatal Mort2lity Study of
17,000 births in Great Britain in, March, 1958, found lower mean birth,
weights for smokers' than for nonsmokers' babies at each week of
gestation from 36 through 43, as shown in Figure 3('20). Evidence of
the same birth weight relationship is presented in Figure 4(113) taken
from Meyer's analysis of data from the Ontario Perinatal Mortality
Study (142, 143). This Figure shows that, as one would expect, the
proportion of births under 2,500 grams decreases as gestation
increases. It also shows, within each gestational age group, the effect
of maternal smoking on birth weight, as the frequency of lbw-weight
births increases directly with smoking level for term births of early,
average, and late time of d'elivery.
Fetal Growth
As the low birth weight associated with maternal smoking is
independent of gestational age and is not due to a significant reduction
in mean gestation, it must therefore be due to a reduction in the rate of
fetal growth. In several studies the relationship between maternal
smoking and other body measurements besides birth weight has been
examined. Kullander and Kaellen, in a prospective study of 6;376 births
in Malmo, Sweden, found that, as the level of maternal smoking,
increased, the body length, head circumference, and shoulder circum-
ference decreased consistently for both male and female babies (89).
8-19
,I
Q
8
I
;i.
9
who was a light or nonsmoker had more than a threefold higher rate of
chronic nonspecific respiratory disease than the new fire fighter in the
same smoking category.
Smoking may act synergestically with toxic agents found in the
workplace to cause a much more profound effect than that
anticipated simply from the separate influences of the agent and
smoking added together.
Asbestos
Asbestos provides one of the most dramatic examples of adverse health
effects resulting from interaction betweem the smoking of tobacco
products and an agent used' in the workplace. Asbestos, the generic
term used to describe chain-silicates, was first used in Finland' to
strengthen clay pottery about 2500 B.C. (79). Modern indkzstriali use of
asbestos is relatively more recent, dating from 1880 when~ it was used
to make heat- and, acid-resistant fabrics (35, 72). From that beginning
its usefulness has grown immensely, outputhaving increased over one
thousandfold+in the past 60~years (79):
With, increasing industrial importance has come an increasing
awareness of the adverse health consequences incurred by working
with asbestos: Asbestosis was first reported' early in the twentieth~
century, an& subsequent individual observations and epidemiological
studies have well defined the association of this nonmalignant
t
respiratory disease with asbestos exposure. In 1935 Lynch and Smith
reported a suspected association between asbestosis and lung cancer
(49): Succeeding epidemiolbgical studies have given significant support
to these early reports.
In 1968 a prospective study of insulation workers by Selikoff, et al.
(75); defined cigarette smoking as an additional hazard to the health of
workers exposed to asbest'os. In a study of 370 asbestos insulation
workers, 1963-1967, Selikoff found that of 87 men with no history of
cigarette smoking none died of bronchogenic carcinoma, while 24 of
283 cigarette smokers did die of that disease. This study suggested that
asbestos workers who smoke have 8 times the lung cancer risk of all
other smokers and 92 times the risk of nonsmokers not exposed to
asbestos. This same group of insulation workers was restudied 5 years
later (31). At that time 41 of the 283 smolters had died of bronchogenic
cancer. In a larger prospective study involving 11,656 insulation
workers, in the United States and Canada, 134 deaths due to lung
cancer were found among 9,591 men with a history of regular cigarettee
smoking (31). Of the 2,066 noncigarette smokers followed' over the
same 5-year period, only two deaths were due to lung cancer.
Over a 10-year period, Berry, et al. (14) studied' 1,300 male and 480
female asbestos factory workers in, whom a smoking history was
known. The male and female groups were then evaluated on whether
they had low to moderate or high asbestos exposure. The researchers
m
I
11
7-11
These studies suggest unfavorable effects of maternal smoking
during pregnancy on the child's long-term growth, intellectuat
development, and behavioral characteristics. Although~ these changes
are difficult to study because of the vast complexity of possible
antecedent' and confounding variableshigh priority should be given to
obt'aining conclusive answers about the role of fetal exposure to
maternal smoking in these conditions. The fact that the direction of
observed differences in a variety of different studies is the same adds
to the urgency of this questionL
Role of Maternal Weight Gain
In the search for mechanisms through which maternal smoking
reduces birth weight, the question has been asked whether it might be
an indirect result of reduced appetite, less intake of food, and lower
maternal weight gain. Severali early studies reported no differences
between~ smoking and nonsmoking women in intake of food or in
weight gain and concluded that the effect of maternal smoking on
birth weight was not mediat!ed in this way (8, 54, 76, 101, 141,, 212):.
Recently the question has been raised agai6 by Rush in a study of
births to 160 women~ of whom~ 41 smoked throughout pregnancy. His
evidence showed'~ that the mean weekly weight gain was reflected in
the infant's weight at birth~(162): In a subsequent study, Davies; et al.
examined the interrelationships of cigarette smoking, in pregnancy,
maternal weight gain, and fetal growth. By analysis of covariance of
480 mother-infant pairs from the total of 1,159 included in the study,
these authors statedc "Correction of birth weights within smoking,
groups to a common meani maternal weight gain appears to remove
most of the differences between infants of nonsmokers and heavy
smokers, although technically these corrected means are still statisti-
cally heterogeneous." That is, the effect of smoking on birth weight
was still observed although diminished by these procedures. Fromi this
the authors concluded that "a large part of the effect of maternal
smoking is mediated' through maternal weight gain withi only a very
small additional direct effect on the fetus. This suggests that
increasing weight gain in smoking mothers might prevent some of the
harmful effects of smoking on fetal growth." However, the alternative
explanation that lower maternal weight gain and' fetal growth
retardation are both independently related to cigarette smoking in
pregnancy is also mentioned (34).
Other studies have not corroborated these findings. '1VIau reports
results of the German prospective study in which 6,200 pregnant
women were examined every month from the first trimester to
delivery and the children followed~ for up to three years. Smoking was
classified'as none, 1 to 5, 6 to 10, or more than 10 cigarettes per day. No
significant association was found between~ smoking habit and weight
gain. Oni the other hand, there was a close correlation between the
il
8-24
0
(19) CAPODAGLIO, E., PEZZAGNO, G., BOBBIO, G.C., CAZZOLI, F. Indagine
sulla funzionalita' respiratoria di lavoratori addetti a produzione elettrolitica
di cloro e soda (A study of the respiratory function in workers engaged in the
electrolytic production of chlorine and soda). Medicina del Lavoro 60(3)i 192-
202, 1969.
(20) CHESTER, E.H., GILLESPIE, D:G:, KRAUSE, F.D. The prevalence of chronic
obstructive pulmonary disease in chlorine gas workers. American Review of
Respiratory Disease 99(3): 365-373, 1969.
(21) CHEVALIER, R.B:, KRUMHOLZ, R:A., ROSS, J.C. Reaction of nonsmokers to
carbon monoxide inhalation. Cardiopulmonary responses at rest and duringg
exercise. Journal of the American Medicali Association 198(10);: 1061-1064,
December 5,1966:
(22) CLAYTON, J.W., JR. Fluorocarbon toxicity and biological action. Fluorine
Chemistry Reviews 1(2): 197-252, 1967.
(28) COWDRY, E.V., CRONINGER, A., SOLARIC, S., SUNTZEFF, V. Combined
action of cigarette tar and beta radiation ori mice. Cancer 19(2)i 344-352,
March/April 1961.
(24 DOLL, R, FISHER, RE.W., GAMMON, E.J., GUNN, W.,, HUGHES, G.O.,
TYRER, F.H.,,WILSON, W. Mortalityof gasworkers with special reference to
cancers of the lung and bladder, chronic bronchiti's,, and pneumoconiosis.
British Journal of Industrial Medicine 22(1): 1-12,1965.
(25) DOLL, R., VESSEY, M.P., BEASLEY, R.W.R, BUCKLEY, A.R., FEAR, E.C.,
FISHER, R.E.W., GAMMON, E.J., GUNN, W., HUGHES, G:O:, LEE, K.,.
NORMAN-SMITH, B. Mortality of gasworkers-final report of a prospective
study. British Journal of Industrial Medicine 29(4): 394-406, 1972.
(26) EVANS, E:A. Pulmonary edema after inhalation of fumes from polytetrafluoro-
ethylene (PTFE). Journal' of Occupational Medicine 15(7): 599-601, July 1973.
(27) FASSETT, D:W: Cyanides and nitriles. In: Patty, F.A. (Editor). Industrial
Hygiene and Toxicology, Second Revised Editiona Volume II. New YorkJohn
Wiley and Sons, Inc., 1963, pp. 1991-2036.
(28); FODOR, G:G., PRAJSNAR, D, SCHLIPKOETER, H.-W. Endogene CO-Bildung
durch inkorporierte Halogenkohlenwasserstoffe der Methanreihe (Endogenous
CO formation by encorporated halogenated hydrocarbons of the methane
series). Staub Reinhaltung der Luft, 33(6): 258-259, June 1973.
(29) GOLDSMITH, J.R., TERZAGHIJ., HACKNEY, J.D. Evaluation of fluctuating
carbon. monoxide exposures. Theoretical approach1 and a preliminary test of
methods for st'udying effects on human populations of! fluctuating,exposures
from multiple sources. Archives of Environmental Health 7(6) 647-663;
December 1961
(30) HAMMOND, E.C. Smoking,in relation to the death rates of one million men and
women. In: Haenzel; W. Epidemiological Approaches to the Study of Cancer
and Other Chronic Diseases. National Cancer Institute Monograph No. 19. U.S.
Department of Health, Education, and Welfare, Public Health Service,
National Cancer Institute, January 1966, pp. 127-204.
(31) HAMMOND, E.C., SELIKOFF, I.J. Relation of cigarette smoking to risk of~
death of asbestos-associated disease among insulation workers in the United
Stgtes: In: Bogovski, P., Gilson, J.C:,, Timbrell, V., Wagner, J.C:, Davis, W.
(Editors):, Biologicali Effects of Asbestos. International Agency for Research
on Cancer, Scientific Publication No. 8, Lyon, France, International Agency
for Research on Cancer, 1973, pp: 312-317.
(32) HANKINSON, J.L., REGER, R.B.,, MORGAN, W.K.C~ Maximal expiratory
flows in coal miners. American Review of Respiratory Disease 116(2); 175-180,
1977.
(33)~ HARRIS,,D.K. Polymer-fume fever. Lancet 261(6692): 1008-1011, December 1,
1951. v
7-21
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11
Exposure in Gold 1lfining
An epidemiological study of a gold mining community in South Africa
suggests that a synergistic interplay between smoking and exposures
in the gold mine is responsible for the excess prevalence of chronicc
bronchitis among, smoking miners (78). A significantly higher preva-
lence of chronic bronchitis was observed among smoking miners (50.5
percent) than among smoking nonminers (28.0 percent), nonsmoking
miners (8.2 percent), or nonsmoking nonminers (6.7 percent). In
addition, evaluation of the data for smokers by age as well as by the
amount of tobacco smoked per day showed'that chronic bronchitis was
significantly more common in, miners than, in nonminers for every age
and smoking category. The gold miners in this study were exposed, to
relatively low dust levels with high free silica content (50 to 70 percent)
in contrast to the high dust levels with low silica content in coal miners.
Stnoking may contribute to accidents in the workplace.
In a 9-month study of job accidents, the total, accident rate was moree
t'han~ twice as high among smokers as among nonsmokers (93). Other
authors have suggested that injuries attributable to smoking were
caused' by loss of attention, preoccupation of the hand for smoking,
irritation of the eyes, and cough (67)..
Smoking can, also contribute to fire and explosions in occupational
settings where inflammable and explosive chemical agents are used. In
many of these areas smoking is prohibited'. For example, smoking is
not permitte&in coal mines and miners are personally fined if found in
violation of this provision.
Examples where action between smoking and occupational
exposure has been suggested or only hypothesized
Cadmium,
Several studies of the effects of occupational exposure to ca.dmium on
smokers and nonsmokers have been conducted (42, 45, 46, 51, 70).
Pulmonary function~ is poorer in smokers than in nonsmokers exposed
to cadmium, and smokers also had a higher incidence of proteinuria
than did nonsmokers in a cadmium-exposed population in, a Swedish
battery factory. An additive rather than a potentiating effect seems
more likely from the limited data.
Ciloromet'hylRh.er i
A group of 129 men in a chemical plant where chloromethyli ether was
used were screened by 70 mm chest photofluorograms and questionr
naires regarding age, smoking habits, and respiratory symptoms at
intervals averaging 8.5 months for 5 years and follow-up for an
additional 5 years (86). Each job classification was ranked according to
7-15.
i
I
I
M
a
I
W.
INFANT WEIGHT AND PARENTAL SMOKING HABITS
10
8
c
6
4
2
0
4 5 6 7 8 9 t0~ t 1
BIRTH WEIGHT (SCALE IN POUNDS: INTERVALS OF 4 OZ.)
FIGURE' 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 of cigarettes per day
30URCE: MacMahon, B. (103).
As described in another section of this chapter, the carbon monoxide
present in cigarette smoke combines with maternal and fetal
hemoglbbin and results in a reduced carrying capacity of the blbod for
oxygen and also a reduction~ of the pressure at which oxygen is
delivered to the fetal tissues: Somewhat similar reductions of oxygen
availability for the fetus occur at high altitude and in cases of
maternal anemia. Under these conditions, increases in placental ratios
have also been observed that are in proportion to the elevation or to
the degree of anemia (14, 88; 108). The possibility that these changes
may represent physiologicali responses to relative fetal hypoxia, with
increased oxygen delivery by a larger placenta and decreased oxygen
demand by a smaller fetus, has been considered (14, 88, 108, 202, 203).
If this is the case, it is important to know whether a mechanism that
might increase the possibility of survival at a lower birth weight is
accompanie& by any long-term costs in later growth and development.
Gestation
The consistent finding that mean birth weights were lower and the
frequency, of low-weight babies higher for women who smoked during
pregnancy than for similar nonsmokers raised the obvious question of
0
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a
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8
®
8-17
~
(102) MARCO, M., MINETTE, A. Lung function changes in smokers with normal
conventional spirometry. American Review of Respiratory Disease 114` 723-
738, 1976.
(103) MASS, B., IKEDA, T., MERANZE, D.R.,, WEINBAUM, G., KIMBEL, P.
Induction of experimental emphysema: Cetlular and species specificity.
American Review of Respiratory Disease 106: 384-391, 1972. C
IN
(104) MATULIONIS, D.H., TRAURIG; H:H. In, situ response of lung- macrophages
and hydrolase activities in cigarette smoke. Laboratory Investigation 37(3):
314-326,1977:
(105) MCCARTHYD.S., CRAIG, D.B., CHERNIACK, R.M. Effect of modifncation of
the smoking habit on1ung function. American Review of Respiratory Disease
114:i103-113; 1976.
(106) MILLER, R:, KUEPPERS; S:F:, HEPPER, N.G: A comprehensive study of hostt
factors for chronic obstructive pulmonary disease in~ a North American rural
community: Genetic characteristics. Bulletin of the International Union
Against Tuberculosis 51(1, Tome 2): 629;,1976.
(107) MITCHELL, R.S., STANFORD, RE., JOHNSON, J.M., SILVERS, G.W.,
DART, G., GEORGE, M.S. The morphologic features of the bronchi,
bronchioles and aliveoli in, chronic airway obstruction:; A clinicopathologic
study. American Review of Respiratory Disease 114(1): 137-145, July 1976.
(108) MITTMAN, C. The PiMZ phenotype: Is it a significant risk factor for the
development of chronic obstructive lung disease? Americam Review of
Respiratory Disease 118: 649-652, 1978:
(109) MITTMAN, C. (Editor): Pultnonary emphysema and proteolysis. New York,
Academic Press, 1972,562 pp,.
(110) MONTO, A.S., HIGGINS, M.W:, ROSS, H.W. The Tecumseh Study of
respiratory illness. VIII. Acute infection in chronic respiratory disease and
comparison groups. American Review of Respiratory Disease 111(1)c 2736,
January 1975.
(111) MORSE~ J.O., LEBOWITZ, M.D., KNUDSON, R.J., BURROWS, B. Relation of
protease inhibitor phenotypes to obstructive lung diseases in a community.
New England Journal of Medicine 296(21)r1190-1194, 1977;
(112) NIEWOEHNER, D.E., KLEINERMAN, J.,, RICE, D.B. Patholbgic changes in
the peripheral' airways of young cigarette smokers. New England Journal of
Medicine 291: 755-758,,1974:
(113) OSHIMA, H., IMAI, M., KAWAGISHI, T. A study on air pollution effects on the
respiratory symptoms in the city of Yokkaichi, Central Japan. Mie Igaku 16(1):
25-29; June 1972.
(114) OXHOJ, H., BAKE, B!, WILHELMSEN, L. Ability, of spirometry, low-volumee
curvesand the nitrogen ~ closing volume test to detect smokers. Scandinavian
Journal of Respiratory Disease 58: 80-96, 1977:
(115) PETERSON, D.L, LONERGAN, L:H., HARDINGE, M.G. Smoking and
pulmonary function. Archives of Environmental Health 16: 215-218, 1968.
(116) PRATT, S.A., FINLEY, T.N., SMITH, M.H., LADMAN, A.J. A comparison of
alveolar macrophages and pulmonary surfactant (?) obtained from the lungs of
human smokers and nonsmokers by endobronchial lavage. Anatomical Record
163(4): 497-508;1969.
(117) Prevalence of selected chronic respiratory conditions, United States-1970.
DHEW Publication No. (HRA) 74-1511, 1973, Series 10; No. 84.
(118) The Registrar General's Decennial Supplement, England and Wales, Oceupa-
tionaliMortality: 1931, Her Majesty's Statqonery Office, London,,1951.
(119) RODRIGUEZ, R.J.,, WHITE, R.R., SENIOR, R.M., LEVINE, E.A. Elastase
release from human al veolar macrophages: Comparison between smokers and
nonsmokers: Science 198(4314); 313.314, 1977.
6-49
9
V
(35) COLLEY, J.R.T., DOUGLAS, J.W.B., REID, D.D. Respiratory disease in young
adults: Influence of early childhood lower respiratory tract illness, social class,,
air pollution, and smoking. British Medical Journal 3(5873): 195-198, July 28,
1973.
(36) COMSTOCK, G.W., STONE, R.W., SAKAI, Y., MATSUYA, T., TONASCIA,
J.A. Respiratory findings and urban living. Archives of Environmental Health
27(3)::143-150, September 1973.
(:Yy) COSIO;, M., GHEZZO, R.H., HOGG, J.C., CORBIN, R,, LOVELAND, M.,
DOSMAN', J.,,MACKLEM, P.T. The relationships between structural'changes
in small~ airways and pulmonary function tests. New England Jburnai of
Medicine 298: 1277-1281, 1978.
(38) DALHAMN, T. Effect of cigarette smoke on ciliary activity. American Review
of Respiratory Disease 93(3xSupplement): 108-114,1966.
(39) DANIELE, R.P., DAUBER, J.H., ALTOSE, M.D., ROWLANDS, D.T., GOREN-
BERG, D.J. Lymphocyte studies in asymptomatic cigarette smokers. A
comparison between lung and peripheral blood: American Review of Respira-
tory Disease 116: 997-1105,1977.
(d0) DENSEN, P.M., JONES, E. W., BASS, H.E, BREUER, J:, REED, E, A survey of
respiratory disease among New York City postal and transit, workers. 2.
Ventilatory function tests results: Environmental Research 2(4): 277-296, July
1961
(.G1) DIRKSEN, H., JANZON, L., LINDELL, S.E. Influence of smoking and
ED
I
qlt
8
cessation~ of smoking in lung function. A population study of closing volume
and nitrogen wash-out. Scandinavian Journal of Respiratory Disease
85(Supplement): 266-274; 1974.
(42) DOLL, R., PETO, R. Mortality in relation to smoking: 20 years', observations on
male British doctors. British Medical Journal'2: 1525-1536,1976..
(4,3) DOSMAN; J., BODE, F., GHEZZO, R.H., MARTIN, R., MACKLEM, P.T. The
relationship between symptoms and functional abnormalities in clinically
healthy cigarette smokers. American Review of Respiratory Disease 114(2):
(.Gk) 297=304, August 1976.
DOSMAN, J.A., GHEZZO, R.H., BODE, F., MARTIN, R.R., MACKLEM, P.T. I
Tests of, early diagnosis of airway obstruction: A perspective. Revue Francais
Maladies Respiratoires 5: 377389,1977.
(I5) DOSMAN, J., MACKLEMP.T. Diseases of small airways. Advances in Internal
Medicine 22: 355376, 1977:
(46) EICHEL, B:, SHAHRIK, H.A. Tobacco smoke toxicity: Loss of humam oral
leukocyte function and fluid-oell metabolism. Science 166(3911): 1424-1428,
1969.
(47) ENJETI, S., HAZELWOOD, B.,, PERMUTT, S., MENKES, H., TERRY, P.
Pulmonary function in young, smokers. Male-female differences. American
Review of Respiratory Disease 118: 667-675,1978:
(48) ERIKSSONS. Pultnonary emphysema and alpha-l-antitrypsin deficiency. Aeta
Medica Scandinavica 175: 197=205a,19641
~
(;49) ERIKSSON; S. Studies in a,-antitrypsin deficiency. Acta Medica Scandinavica
(50) 177(Supplement 432): 1-85, 1965.
FAIRSHTER, R.D., WILSON, A.F. Volume of isoflow: Effect of distribution of,
ventilation. Journal of Applied Physiology: Respiratory, Environmental~ and
Exercise Physiology 43(5): 807-811,1977.
(51) FINKLEA, J.F., HASSELBLAD, V., RIGGAN, W.B., NELSON, W.C., HAM-
MER, D.I., NEWILL, V.A. Cigarette smoking hemagglutination inhibition C
response to influenza after natural disease and immunization. American ~
Review of Respiratory Disease 104(3): 368-376;,September 1971. ~
(f1
(52) FINKLEA, J.F., SANDIFER, S.H.,, SMITH, D.D. Cigarette smoking and CO
epidemic influenza. American Journal of Epidemiolbgy 90: 390-399, 1969.
~
~
6-45
factors could bias data. For example, as reported in the data from the
Collaborative Perinatal Study of the NINCDS (1959-1966);, U.S.
mortality rates were higher for black than for white babies, while
white women were more often smokers and smoked more cigarettes
than black women (137): Selection of births on the basis of smoking
alone would tend to include more nonsmokers who were black and at
high risk and more smokers who were white and at basically low risk,
thereby minimizing the apparent effects of maternal smoking on
perinatal loss. In~ three reported studies in which adjustment for other
factors was carried out, a significant independent association between
cigarette smoking, and infant mortality persisted (20, 22) 30, 169). Of
the studies that revealed no significant increase in mortality risks for
smokers' infants, one (207) controlled for race alone. "Hence, at least
part of the discrepancy in results between the two groups of studies
may be explained by a lack of control of variables other than smoking"
(192);
The second important point presented in the 1973 report was the
suggestion that cigarette smoking might be more harmful to the
fetuses of certain women than of others. Analysis of data by
socioeconomic status (2, 22, 29), race (137, 163, 188, 206, 207); previous
obstetrical experience (22, 151, 169), and maternal age (20) indicated
that the increased~ perinatal mortality risk associated with maternal
smoking varied considerably with these other factors (192). ~
Spontaneous Abortion
The results of severat past studies have demonstrated a statistically
significant association between maternal cigarette smoking and
spontaneous abortion (74, 89, 141,, 147, 188, 212). Data from some of
these studies have documented a strong dose-response relationship
between the number of cigarettes smoked and the incidence of
spontaneous abortion (147, 188, 212). Spontaneous abortions are
difficult to study because of problems in ascertainment. The most
complete ascertainment is possible when the mother's history of past
spontaneous abortions is used, despite problems of recall. Differences
in rates between smokers and nonsmokers are largest when this
method is used (141, 212). In prospective studies, many early
spontaneous abortions will, be missed,,and bias will occur if one group
tends to register earlier than the other. Nevertheless, higher rates of
spontaneous abortion are also reported among smoking mothers in
prospective studies (89). The study by Kulland'er and, Kaellen counted
spontaneous abortions through the eighth month of gestation and
noted that the largest increase was among smoking women whose
pregnancies were unwanted. Although this was a prospective study,
with smoking data collected repeatedly during prenatal care, the
method of analysis was retrospective: Rearrangement of their table to
8-30
TABLE7.-Cause of stillbirth related to smoking habit
Cause of stillbirth Percentage incidence
Nonsmokers Smokers
Maternal disease 0:01i -
Maternal I hypertension 0.19 0.17
Difficult labour 0:09 0.05
Antepartum hemorrhage 0:11 0.39
Congenital malformation 0.'32 0.27
Haemolytic disease - 0.13
Infection 0.01 -
Anoxia (without obvious cause) 0,24 0.23
Other cause stillbirth - 0.02
Macerated stillbirth (without obvious cause) 0.29 0.23
Total stillbirths 1.30 1.54
SOURCE: Andrews, J. (2).
Cause of Death
The weight of evidence presented in this chapter clearly indicates that
maternal smoking does increase the risk of spontaneous abortion, early
and late fetal death, and early neonatali death. This being, so, it is
appropriate to attempt to identify mechanisms of action and interme-
diate pathways between the cigarette smoke and the fatal event. Clues
to these mechanisms' might be found if certain causes of death showed
an excess among the infants of smoking mothers. Several authors have
reported cause-specific mortality rates for the infants of smokers and
nonsmokers. Andrews ~ and McGarry (2) reported stillbirth rates of 1.30
per 100 births for nonsmokers and 1.54 per 100 for smokers, among
which 0.11 an& 0.39 were due to antepartum hemorrhage for
nonsmokers and smokers respectively. For neonatal deaths, causes
showing excess rates for infants of smoking mothers were "immaturi-
ty (no other cause)," "respiratory distress syndrome," and "pneumo-
nia," with overall rates of 1.10 and 1.40 for nonsmokers, and smokers,
respectively (Tables 7 and 8). Comstock, et al. (30) compared observed
neonatal deaths of smokers' babies with numbers of deaths expected at
nonsmoker rates. Out of 100~ total observed deaths, smokers' infants
had excesses of 17 due to immaturity, 15 due to asphyxia and
atelectasis, and 7 due to birth injuries, with deficiencies of--7 due to
congenital' defects and -4 due to "other," leaving a net excess of +28.
Ini the prospective study of 9,169 pregnancies carried out by Goujard,
et al. (63), causes of stillbirth that increased significantly with
maternal smoking were "abruptio placentae" (p =.005) and "unknown
cause" (p=0:0005). Overalli differences in stillbirth rates showed an
excess for smokers.at a significance levell of p=0:0001(Table 9).
8-36
TABLE 2.-Mean birth weight of infants of smoking and
nonsmoking mothers, by other biologic and
socioeconomic factors
Prepregnancy factors Mean birth
weight (gm) Mean difference
Nonsmokers-Smokers(gm)
Grav'rda's age <V years
Smokers
3
219
, 193
Nonsmokers 3,412
Parity > 4 previous pregnancies
Smokers
287
3
, 286
Nonsmokers . 3,573
Previous birth ~ <2,500 grams
Smokers
912
2
, 208'.
Nonsmokers 3;120
Gravida's height <60 inches
Smokers
3,058'
201
Nonsmokers 3,259:
Gravida's prepregnancy weight <100 lbs.
Smokers
2
918
, 246
Nonsmokers 3,164
Gravida's education: less than high school'graduate
Stnokers
196
3
, 253
Nonsmokers 3,446
Husband's education: less than high school graduate
Smokers
196
3
, 256.
Nonsmokers 3,452
Husband's occupation: unskilled laborer, service
worker
Smokers
3
224
, 217
Nonsmokers 3,471
SOURCE: van den Berg, B.JI (193).
Kullander and! Kaellen reported placental ratios of 0:171, 0175, 0.178;
and 0.188, respectively, for nonsmokers, smokers of less than 10
cigarettes a day, those smoking 10~to 20 a day, and those smoking more
than 20 cigarettes per day, based on a prospective study of 6,376
pregnancies in Malmo, Sweden (89), Wilson compared the ratios of
untrimmed, fresh placenta weights to birth weights for 1,895 deliveries
in Sheffield, England'y finding a significantly higher ratio for babies
born to smokers than to nonsmokers. He suggested that the increase
might signify a response by the placenta to chronic hypoxia in the
fetus (202):
Wingerd, et al. have now published a definitive study of this
relationship, using dat'a: from a prospective study of 7,000 pregnancies
among members of the Kaiser Foundation Health Plan in Oakland,
R
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TABLE 5:-Perinatal mortality rates per 1,000 live births to
smoking and nonsmoking mothers, and relative risks
for infants of smokers by maternal age, parity, and
years of school (10 % random sample of medical
certificates of births in Quebec in 1970-71)
Maternal Total births Perinatal deaths per
characteristics 1,000 live births
Nonsmokers Smokers
Age
Smoker:
nonsmoker
Relative risk
< 25 3,143; 12.1 16.1 1.33
25-34 3,717 12.6 13.2 1.05
35+ 757 23.0 41.7 1.81
Parity
0 1
2,798
14.2
18.7
1.32
1-3 3,959 11.2 11.2 1.00 :
4+ 860: 21:8' 36.1 1.66
Years of school
< 8
1,600'
14.5
18.8
1.30
9-11 3;043' 12.8 19.7 1.54
12+ 1,170, 13.5 ('8.9) (0.66)
Ezcludesbirths weighingdess than,1j00t grams..
Rates in p,arenthesesbased on fewer than 10 deaths.
SOURCE: Fabia,J. (47):
perinatal mortality rates by maternal smoking, are shown within
categories of other relevant factors. These studies show that perinatal
mortality rates vary with maternal smoking level and~ also with~ t'he:
other factors shown. The general statement can be made that the :
detrimental effect of maternal smoking oni fetal survival is greater in
groups of women who already have a higher risk of perinatal loss for
other reasons: Women, characterized by low social class, low level ofl
education, less than optimum maternal age, or being black have higher
risks of perinatali mortality than their counterparts, and! their relative
increase in risk due t'o maternal smoking is enhanced. Studies in which
the population, by' design or by chance, includes mainly or only women
without other reproductive risk factors show the smallest differences
between the risks of smokers and nonsmokers (22, 30, 47, 137, 155, 163,
206). L
A series of articles by Meyer, et al: reports analyses of data fromi the
Ontario Perinatal Mortality Study of all single births in 10 Ontarioo
teaching hospitals in 1960-61, including 51,490 births, 701 fetal deaths,,
and 655 neonatal deaths (115, 116,, 117): For the Ontario study,
sponsored and support'ed! by the Maternal and Child Health Branch of
the Ontario Department of Health (142, 143); detailed data: were
8-33'
I
Q
I
0
I
0
0
0
8
N
8
I
L
0
mothers included questions on the maximum amount smoked during
pregnancy, expressed as packages per d'ay (142, 143). The large size of
this study and the richness of its available: information provided a
valuable resource for sorting out complex interrelationships between
maternal smoking,, other factors, and perinatal loss. In the first article
of the series, the differential risk of smoking based on maternal
characteristics was demonstrated' by extensive cross-tabulation of
perinatal mortality rates for 3 levels of smoking (none, less than a
pack, 1 pack or more per day) within 52 subgroups of other maternal
variables. Risk ratios for light smokers compared with nonsmokers
showed excess death risks of less than 10 percent for women of youngg
age, low parity, and normal hemoglobim At the other extreme,
mothers of high~parity, public hospitalistatus, with, previous premature
infants, or withi hemoglobin under 11 grams and who were heavy
smokers (one pack or more per day) had increased perinatal mortality
risks of 70 to 100 percent. Risks for light smokers who had other
antecedent risk factors and for heavy smokers with otherwise good
prognosis fell between these extremes when compared with nonsmok-
ers. These relationships show how selection of a study population from
one end or the other of this spectrum of smoking-associated risk levels
would influence the relative risk found for smoking when no
adjustment is made for these other factors (I17). Other studies in
which similar cross-tabulations have been made between maternal
smoking level and socioeconomic level, maternal age, parity, .previous
pregnancy history, and other such factors have corroborated these
findings (2, 22, 29, 47,102, 169).
Because of possible interactions between maternal smoking and thee
other independent variables, Meyer, et al. undertook further analysis
of the Ontario data to define and measure the independent effect of
maternal smoking on the risk of perinatal mortality. For this a
multiple regression analysis was used to compare the relative
importance of smoking and other factors in their influence on perinatali
mortality and on the frequency of low birthweight, of preterm
delivery, and of placental complications (115). When the rates of
perinatal mortality by smoking were adjusted for the effects of alt
other factors, perinatal mortality rates per thousand births were 23.5
for nonsmokers, 28.2 for smokers of less than a pack per day, and 31.8
for smokers of a pack or more per day. In other words, light smoking
increased the risk by 20 percent and heavy smoking increased it by 35
percent. This is a highly significant, dose-related, independent effect,
but it is less strong than the relationship to perinatal mortality of
hospital pay status (a 55 percent increase for public status mothers),
age-parity differences, or a history of previous pregnancy loss (190
percent greater risk if there is a previous loss compared with
primiparity or with a previous pregnancy with no fetal or neonatal
loss) (115):
8-35
I
I
3
0
a
0
®
E o E
cn z cn
O O O O
a C0 N i ~
d
FIGURE 5.-Theoretical cumulative mortality risk according to
smoking habit, in mothers of different age, parity, and social class
groups
SOURCE: Butler, N.R. (eo).
obtain incidence rates of spontaneous abortion for subgroups of
smokers and nonsmokers gives rates and relative risks of spontaneous
abortion~ by desid'eration of pregnancy (Table 4), More of the smokers'
than nonsmokers' pregnancies were unwanted! (19 percent versus 13
8-31
N
I
weight as well as on the other factors listed also showed fewer,
smokers' children with normal neurological status and lower scores for .
smokers' children on 6 out of 8 tests of intellectual functiom The fact~ .
that few of these differences reached "statistical significance" does not'
rule out the possibility that harmful long-term~ effects may exist (38,
`
43). st; ,
In the California study by Wingerd and Schoen (:204), the net effect I
of various factors on length at birth an& height at 5 years was ~
determined in 3,707 single-born, white, California children. Children of ~
smoking mothers were found to be shorter (p<0.001) at birth and at 5_;
years than children of nonsmoking mothers. (Intellectual development
was not measure& in this study.)
In a prospective study of children~ of low birth weight, Dunn and ~
coworkers analyzed! growth with respect to maternal smoking habits of ;
81 who were "small-for-dates," 99 "truly premature," and~ 146 controls '1
of full birth~ weight. At 61/2 years of age, the children of nonsmoking 4~
mothers had a slightly greater mean height and weight in all three l
categories. The mean social class of the smoking mothers was lower ;:
than that of the nonsmokers, but within the two lowest social classes, ~
IV and V (77 percent of all subjects), the nonsmokers' children had a.~
greater mean height and weight than their counterparts whose ~
mothers smoked. Statistically significant differences in favor of ~
nonsmokers' children were demonstrable with regard to weight gain `.
and growth in length/weight at'1 to 4 years and with regard to actual ,
height at 4 and 61/2 years and weight at 61/2 years in the full birth
weight controls (.l,3). There was no evidence that the children of
smoking womeri "caught up" in growth with~the nonsmokers' children,,"
a concept postulate& by Russell, et al. (164) but not corroborated by a
other studies.
Dunn also evaluated the neurological, intellectual, and behavioral .;
status of these children at age 7 and analyzed the results according to ~'
the mothers' smoking habits during pregnancy. Neurological abnor- ;z
malities, including minimal cerebral dysfunction and abnormal or °~
borderline encephalograms, were slightly more common among
children of smoking, women, although this difference was not quite ~
statistically significant. In a battery of psychological tests, the mean
scores of' children~ of nonsmoking mothers were better than those of
smokers' children in 45 out of 48' correlations, and the difference was
significant in 14 of these. Factorial analysis of variance suggested that
these differences could be only partially attributed to the slightly
lower social status of smokers' children. Some significant differences in
favor of nonsmokers"children were also demonstrated with respect to
behavior ratings and! school placement (44). These results are very
similar to those of Hardy and Mellits in that the direction of the
differences is almost always in favor of the nonsmokers' child. Perhaps
more attention should be paid't'o these patterns and less to the question
8-22
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9
TABLE 10.-Fetal and neonatal deaths by coded cause and }.'
maternal smoking habit (English speaking mothers
Observed
Expected observed~
P
Coded cause Nonsmoker Smoker smoker' expected ~ valuet
Fetal deaths
Unknown
75
125
81.4
43.6
0.003
Malformations 32' 24 34.7 -10.7 N.S.
Hemolytic disease 11 15 1119 ' 3.1 N.S.
Anoxia 16 29 17:4 11:6 N.S.
Maternal, cause 31 45 33.7 11.3 N.S.
All others 8 13 8:7 4.3 N.S.
Total 173' 251 187.9 63.1 0.003
Neonatal deaths
Unknown
52'
51
56.5
-5.5
N.S:
Malformations 22 24 23.9' 0.1 N.S.
Hemolytic disease 7 8 7:6 0.4 N.S.
Respiratory difficulty 46 63 50.0 13:0 N.S.
Prematurity alone 33 65 35.8 292 0.005
Maternal' cause 2 6 2.2 3.8 N.S.
All others 16 16 17.4 -1:4 N.S.
Total 178 233 193.3 39.6 0.06
Total' births 15,240 16,549
n
3
N.S. - Not significant.
Based on nonsmoker rate... tP value derived from ch'i squarebasedone aa null hypothesis of no
difference between smokeesandnonamokers
SOURCE: Meyer, M.B. (116):
For fetal deaths, the largest category of coded cause was "un-
known," and by far the largest and most significant smoking-related
difference fell in this category (p=0.003). Smokers also showed more
than expected fetal deaths due to anoxia an& maternal causes and
fewer'deaths than expected due to malformations. In other categories
only minor mortality rate differences were found between the two
groups. For neonatal deaths' the largest cause of death category was
"unknown," but here there was no excess for smokers' infants. Most of
the smoking-related excess of neonatal deaths was among those
attributable to prematurity alone (p = 0.005), with additional numbers
in the related category of "respiratory difficulty." Differences
between observed and expected deaths in other categories were
negligible.
The tentative conclusion to be: drawn from these findings is that
many of the excess fetal deaths associated with maternal smoking do
not have any recognizable pathology but occur from otherwise
unknown causes. A significant excess also occurs as a result of
antepartum hemorrhage or abruptio placentae. The excess neonatal
deaths among the : infants of smokers appeared' to be due to
prematurity and to related respiratory problems. In other words, these
8-38
0
(120) ROSZMAN; T.L., ELLIOTT; L.H., ROGERS, A.S. Suppression of lymphocyte
Respiratory Disease 111(4): 453-457,1975,
function by products derived from cigarette smoke. American Review of
(121) ROSZMAN; T.L., ROGERS, A.S. The immunosuppressive potential of products
derived from cigarette smoke. American Review of Respiratory Disease 108:
1158-1163, 1973.
population: The results of! two linked surveys separated by one year.
(122) RUSH, D. Changes in~ respiratory symptoms related to smoking in a teenage
International Journal of Epidemiology 5(2): 173-178, 1976:,
(12S) RUSH, D. Respiratory symptoms in a group of American secondary school
Journal of Epidemiology 3(2): 153-165, 1974.
students: The overwhelming association with cigarette smoking. International
(124) RYLANDER, R. Pultnonary cell'responses to inhaled cigarette smoke. Archives
of Environmental Health 29: 329-333, 1974.
(125) SAWICKI, F. Air pollution and prevalence of chronic nonspecific respiratory
diseases. In: Brzezinski, Z., Kopczynski~ J., Sawicki, F. (Editors). Ecology of
Chronic Nonspecific Respiratory Diseases. International Symposium, Septem-
ber 7-8, 1971, Warsaw, Poland, Panstwowy Zaklad Wydawnictw Lekarskich,
1972, pp. 3-13..
(126)', SCHUYLER, M.R:, RYNBRANDT, D:J.,, KLEINERMAN, J. Physiologic and
morphologic observations of the effects of intravenous elastase on the lung.
American Review of Respiratory Disease 117: 97=102; 1978.
(12Y) SEELY, J.E., ZUSKIN, E., BOUHUYS, A. Cigarette smoking: Objective
evidence for lung damage in teen-agers. Science 172: 741-743,1971.
(128)~ SELTZER, C.C., SIEGELAUB, A.B., FRIEDMAN; G.D., COLLEN, M.F.
Differences in pulmonary function related to smoking habits and race.
American Review of Respiratory Disease 110(5); 598-608, November19741
Clinical and Experimental Immunity 22(2); 285-292, November 1975.
In vitro lymphocyte reactivity and T-cell levels in chronic cigarette smokers.
(129) SENIOR, R.M., TEGNER, H., KUHN, C.,, OHLSSON, K., STARCH'ER, B.G.,
PIERCE, J.A. The induction of pulmonary emphysema with human leukocyte
elastase. American Review of Respiratory Disease 116: 469-475,1977.
(130) SHEA, J.W., HUBER, G.L., HOLMES, L., NOMANS;, S.A. The effect of
experimental tobacco smoke inhalation on inn vitro alveolar macrophage
bactericidal function. Journal of Laboratory and ClinicaliMedicine 92(2): 270-
282, 1978.
(131) SILVERMAN, N.A., POTVIN, C., ALEXANDER, J!C., JR.,,CHRETIEN, P.B.
(132) SNIDER, G:L HAYES, J.A., FRANZBLAU, C., KAGAN, H.M., STONE, P.S:,
NORTHY, A.L. Relationship between elastolytic activity and experimental
emphysema-inducing properties or papain preparations. Americam Review of
Respiratory Disease 110: 254-262, 1974.
(13S) STEBBINGS, J.H., JR. A survey of respiratory disease among New York City
postal and transit workers. IV. Racial differences in the FEVi. Environmental
Research 6: 147-158,1973:
(134) STERLING, G.M. Mechanism of bronchoconstriction caused by cigarette
smoking. British Medical Journal 3: 275-277; July 29, 1967.
(135) STUART;, R.S., HIGGINS, W.H., BROWN, P.W. In, vitro toxicity of tobacco
smoke solutions to rabbit alveolar macrophages. Archives of Environmental
Health 33: 135-140, 1978:
(1.46): TALAMO;, R.C., ALLEN, J.D., KAHAN, M.G.,, AUSTEN, K.F. Hereditary
alpha-1-antitrypsin deficiency. New England Journal of Medicine 278(7); 34fr
351, February 15, 1968.
(1gy): THOMAS, W.R., HOLT, P.G., KEAST; D. Cigarette smoke: an& phagocyte
function: Effect! of chronic exposure in vivo and acute exposure in vitro.
Infection andiImmunity 20(2): 468-475, 1978.
(140);
(141)
(142)
('143)'
(144).
(144
(146)
('14r
(148
(149
(15C
(15:
NONSMOpcERS SMO/iERS TOTAL BIRTHS 27,1202NE5TOTAL DEATHS 694. 624PROBABICITY OF OEATH 023 .029
"w,.~oc.r~
~~.~
crbu[bt kS ~.
I' = 95% Cl
24 26'. 32 36 40 42 t
GESTATIOM. WEEKS
FIGURE 7.-Probability of perinatal death for smoking and
nonsmoking mothers, by period of gestational age. Bars show 95
percent confidence intervals
SOURCE: MeyerM.R. (118).
cases and 27 percent of the controls smoked less than a pack per day; 24
percent of the cases and 10 percent of the controls smoked' a pack per
day or more: The habits of the remaining 1 to 2 percent of mothers
were unknown (180): Bergmam and Wiesner noted the effects of
exposure to cigarette smoke (passive smoking) on infants, including
the increased frequency of respiratory infections in the infants of
smoking mothers, and~ stated their impression that the amount of
smoking seemed unusually heavy at meetings of parents who had lost
children to SIDS. The authors.studied! 56 families who lost babies to the
sudden infant death syndrome and 86 control families: They reported
that a higher proportioni of SIDS mothers smoked during pregnancy
than controls (61 percent versus 42 percent), more smoked after
pregnancy (59 percent versus 42 percent), and SIDS mothers smoked a
significantly greater number of cigarettes than controls. These authors
indicate that exposure to cigarette smoke (passive smoking) appears to
enhance the risk for SIDS for reasons not yet known (15). Ilowever,
whether prenatal' or postnatal exposure is more important cannot be
determined. Naeye, et al., in their analysis of 125 SIDS victims from
the population, of the Collaborative Perimatall Project of the NINCDS,,
st'ated: "The gestations that produced the SIDS victims were
characterized! by a greater frequency of mothers who smoked
cigarettes and~ had anemia" than was true for the whole population of
53,721 infants or for a set of 375 controls matched on important factors
8-45
(:a) Lack of comparability between smokers and' nonsmokers with
respect to other important variables that influence perinatal
mortality, such as race, socioeconomic stat'us, age, parity, and
others.
(b) Interaction between the effects of maternal smoking and these
other variables, which makes maternali smoking more dangerous
for the fetus in some pregnancies than in others.
4. Studies failing to take account of these other variables may show
unusually high or unusually low risk ratios.
5. In one large study, the perinatal mortality risk increased by 20
percent for the infants of smokers of less than~a pack per day and by 35
percent for smokers of a pack per day or more, compared with
nonsmokers, after simultaneous adjustment to balance the effects of
variables other than smoking. These increases are similar to: those of
other large studies with appropriate control of other variables.
6. Excess deaths of smokers' infants are found mainly in the coded
cause categories of "unknown"' and "anoxia" for fetal deaths, and in~
the categories of "prematurity alone" and "respiratory difficulty" for
neonatal deaths. This finding indicates that the excess deaths result
not from abnormalities of the fetus or neonate, but from problems
related to the pregnancy:
7. Increasing levels of maternal smoking result in a highly
significant increase in~ the risks of placental abruptions, placenta:
previa, bleeding early or late in pregnancy, premature and prolonged
rupture of membranes, and preterm delivery-all of which carry high
risks of perinata] loss.
8. Although there is little effect of maternal smoking on mean
gestation, the proportion of fetal deaths and live births that occur
before term increases directly with maternal smoking level. Up to 14
percent of all' preterm deliveries in~ the United States may be
attributable to maternalismoking..
9. According to the results of one large study, the most significant
difference between smokers' and nonsmokers' risk of perinatal
mortality and! pregnancy complications occurs at the gestational ages
from, 20 weeks to 32 or 36 weeks.
10. These findings lead to the conclusion that maternal smoking can
be a direct cause: of fetal'or neonatal death ini an otherwise normal
infant. The immediate cause of most smoking-related fetal deaths is
probably anoxiay which can be: attributed to placental complications
with antepartum bleeding in 30 percent or more of the cases. In other
cases, the oxygen, supply may simply fail from reduced carrying
capacity an& reduced unloading pressures for oxygen caused by the
presence of carbon monoxide in, maternal and fetal blood. Neonatal
deaths occur as a result of the increased risk of early delivery among
smokers, which may be secondarily relate6 to bleeding early in
pregnancy and premature rupture of membranes.
8-47
I
(1n) THURLBECK, W.M. Aspects of chronic airflow obstruction. Chest' 72: 341-349,
1977.
(139): THURLBECK, W.M. Chronic airflow obstruction in lung disease. V. Major
problems in pathology. Philadelphia, W.B. Saunders Co., 1976, pp. 235-287.
(140) THURLBECK, W.M. Small airways: Physiology meets pathology, New England
Journal of Medicine 298: 1310-1311,1978.
(1.41); U.S. PUBLIC HEALTH SERVICE. Smoking and Health. Report' of the s
142) AdvisoryCommitt'ee to the Surgeon General,of the Public Health Service. U.S.
Department of Health, Education, and Welfare, Public Health Service, Center
for Disease Control. PHS Publication No. 1103, 1964,387 pp.
U:S, PUBLIC HEALTH' SERVICE. The Health Consequences of Smoking. A
Public Health Service Review: 1967. U.S. Department of Health, Education, 6
(143) and Welfare, Public Health Service,, Health Services and Mental' Health
Adininistration, DHEW Publication Nb. 1696, Revised, January 1968, 227 pp.
UIS. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking, 1968.
1:W) Supplement to the 1967 Public Health Service Review. U.S. Department of
Health, Education, and Welfare, Public Health Service, Health Services and
Mental Health Administration. DHEW Publication No. 1696, 1968, 117 pp.
U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking,1969:.
Supplement to the 1967 Public Health Service Review. U.S. Department of
Health, Education,, and Welfare, Public Health Service, Health Services and
Mental Health Administration. DHEW Publication No. 1969-2, 1969, 98 pp.
9
(145) U.S. PUBLIC' HEALTH SERVICE. The Health Consequences of Stnoking. A
Report of the Surgeon General: 1971. U.S. Department of Health, Education,
and' Welfare, Health Services and Mental Health Administration. DHEW
0
(14G) Publication No. (HSM) 71-7513, 1971458 pp.
UIS. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A M
Report of the Surgeon General: 1972. U.S. Department of Health, Education,
and Welfare, Public Health Service, Health Services and Mental Health
0
1974. U.S. Department'of Health, Education, and Welfare, Public Health
Service, Health Services and Mental Health Administration. DHEW Publica-
M
tion No. (CDC) 74-8704, 1974124pp,
(149) U.S. PUBLIC HEALTH SERVIC& The Health Consequences of Smoking:
1975. U.S. Department of Health, Education, and Welfare Public Health
Service, Health~ Services and' Mental Health Administration: DHEW' Publica-
tion No. (CDC) 76-.8704, 1975{,235 pp. 0
(150) VAN DER LENDE; R:, DE KROON, J.P.M., TAMMELING; G.J:, VISSER,
B.F., DE VRIES;, K., WEVER-HESS, J., ORIE, NiG.M. Prevalence of chronic
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151) Netherlands: In: Brzezinski Z., KopezynskiJ., Sawicki, F. (Editors)., Ecology
of Chronic Nonspecific Respiratory Diseases. International Symposium,
September 7-8, 19714 Warsaw, Poland, Panstwowy Zaklad Wydawnictw
Lekarskich, 1972, pp. 27r33:
WALDMAN, RH.,, BOND, J.O., LEVITT; L.P. HARTWIG, E.C., PRATHER, 0
R.L., BARATTA-NEILL, J.S., SMALL, P.A., JR. An evaluation of influenza
Administration, DHEW Publication No. (HSM) 72-7516, 1972,158 pp.
(147) U.S. PUBLIC HEALTH SERVICE: The Health Consequences of Smoking:
1973. U.S. Department of Health, Education, and Welfare, Public Health
Service, Health Services and Mental Health Administration. DHEW Publica-
tion No. (HSM) 73-8704, 1973, 249 pp,
(148) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking:
immunization. Influence of route of administration and, vaccine strain.
Bulletin ofi the World~Health Organization 4L 543.548; 1969.
(152) WANNER, A. State of the art. Clinical aspects of mucociliary transport.
American Review of Respiratory Disease 116: 73-1J25, 1977.
6-51 In
Lactation and Breast Feeding 1
Introduction
In 1902, Ballantyne (9) suggest& the possibility of detrimental effects
of breast feeding on babies whose mothers worked in tobacco factories.
In the intervening years, questions have been raised concerning the:
interactiorn between cigarette smoking and lactation, as well as the
relationship of cigarette smoking to the quantity of milk produced, to
the presence of constituents of cigarette smoke within the milk, and to
effects upon the nursing infant mediated through changes in either the
quantity of milk availablie or the substances within the milk. ,
Epidemiological Studies
Underwood, et al. (188)', in a study of 2,000 women from various social
and economic strata, observed a trend, though statistically insignifi-
cant, toward more frequent inadequacy of breast milk production
among those smoking mothers who attempted to nurse, as compared to
nonsmokers. They concluded that smoking does not interfere with
breast feeding to any significant degree. H'owever, this study, based on
interviews of puerperal womeny was not designed to analyze the effect
of smoking on breast feeding and presents only percentile results. No
data are provided to permit a reanalysis to determine the validity of
their conclusions.
Perlmans et al. (1.49) also present anecdotali data. They found that in,
their postpart'um, population practically all smoking women started to
consume cigarettes within two days after delivery. Although they
collected' milk between the fourth and ninth postpartum days to
determine nicotine content, they do not report and compare actual
amounts of milk secreted'by both smokers and nonsmokers. They noted
that of the 55 smoking, lactating mothers, 11 failed to have enough
breast milk for the needs of their babies. No comparative study was
done in a nonsmoking but otherwise equivalent population.
Mills (120) studied the nursing patterns of 520 women giving birth to
their first live-born infant. Among the mothers nursing their babies
for a minimum of 2 months and beyond, the mean nursing period was
significantly shorter for smokers than for nonsmokers. Moreover,
among the 24 mothers who: had given~ up~ smoking during at least the
final 3 months of their pregnancies, the average length of nursing was
identicali to that of the nonsmokers: There ` was no significant
difference between smokers and nonsmokers with regard to complete
inability to nurse their offspring. This study is difficult to interpret
because the author did not determine the reason(s) for the discontinua-
tion of nursing among the women.
Surveys of larger populations of women, smokers and nonsmokers,
are needed to~ determine accurately the effect of smoking on milk
8-48
3. The ratio of placenta weight to birth weight increases with
increasing levels of maternal smoking. This increase may signify a
response to reduced oxygen availability due to ca.rbon~ monoxide and
may have some survival value for the fetus,
4. There is no overall reduction in the duration of gestation with
maternal smoking, indicating that the lower birth weight of smokers'
infant's is due to retardation of fetal growth.
5. The pattern of fetal growth retardation that occurs with maternali
smoking is a decrease in all dimensions: body length, chest circumfer-
ence, and head circumference are smaller if the mother smokes.
Smokers' babies are short for dates as well as light and do not exhibit
reduction iniponderal index.
6. Studies of long-term growth and development give evidence that
smoking during pregnancy may affect physical growth,, mental
development, and behaviorali characteristics of children at least up to
the age of 11.
7. Overwhelming evidence indicates that maternal smoking during
pregnancy affects fetali growth rate directly, that fetall growth rate is
not due to characteristics of the smoker rather than to the smoking nor
mediated by reduced maternal appetite, eating, and weight gain.
Cigarette Smoking and Fetal and Infant Mortality
Overview
In contrast with the strong, consistent relationship of maternali
smoking to reduced birth weight, the relationship of maternal smoking
to perinatal mortality has been marked by variation in the level of
increased risk for women who smoke. This has led to controversy as t'o
whether there truly are lethal effects for the fetus or neonate caused
by maternal smoking.
Earlier epidemiological studies of the association between maternal'l
cigarette smoking and perinatal mortality (fetal deaths, neonatali
deaths, or perinatali deaths) were reviewed in the 1971, 1972, an& 1973
reports on The Health Consequ.ences of Smoking (190-192). The 1971
report gave details of 12 studies of maternal smoking and the incidence
of spontaneous abortion, stillbirth, and neonatal death ('20; 41, 54, 87,
101, 1,41, 151, 164', 166, 188, 206, 212). The increased risk of loss among
smokers varied from study to study. Inconsistencies between studies
were described, and it was noted that both smoking habits and'
perinatal loss were influenced by such factors as social class, maternal'
age, and parity. Rush and Kass reviewed the English language
literature in 1972 and found reports of 12,388 perinatal deaths an&
abortions with a mean excess perinatat loss for smokers of 34.4 percent.
Where reported, excess loss was higher among the poor and among
blacks. Their study of black and white women in~ Boston showed excess
.
8-28
TABLE' 12.-Fetal and neonatal deaths by maternal smoking and
other coded conditions (Ontario Perinatal Mortality
Study data. Canadian-born, Ehglish-speaking women,
N= 31,789 births, 411 perinatal deaths)
Deaths of smokers' babies
Coded condition Observed-expected differences'
Fetal P) Neonatal
Admission status.
Ttue labor 15.3' N.S. 26.3 N:S:
Toxemia -0.9' N.S. 0.7 N:S:
Abruptio placentae 48.5 0.001 2.5 N:S:
Ellective cesarean section -2.3 N.S. -5.9 N!S:
Induction ~ 11.9 N.S. 4!8 N'S:
Rupture of membranes only 0.4 N.S. 13.9 0.04'
Other obstetric abnormality 16.8 0.06 6.0 0.01
Duration of': rupture ofl membranes
< 24' hours 32.2 N.S. 13:7 N.S.
2t--0S hours 2.3 N.S. 33 N.S:
48+ hours 14.3 N.S. 19:4 0.01
In caul 8.5 0.02 1.7 N.S:
Unknown 5.8 N.S. 1.7 N.S.
Bleeding during pregnancy
None 2.6 N.S. -5.4 N.S.
Before 20 weeks 23.'7 0.01 41.3 0.0001,
After 20: weeks 32.2 0.0005, 3.3 N.S.
Complications of labor
None 19.2 N.S. 22.2 N.S.
PI'acenta previa 7.6 N.S. 6.6 N.S.
Ab'ruuptio placentae 32.3 0.002 6.2 N.S.
Abnormal uterine action 0.7 N.S. 4.9 N.S.
Cephalopelvic disproportion, q
dystbcia -2.4'. N:S: 1.8 N.S.
Tumultuous labor 8.4'. NS: 7.1 N.S.
Postpartum hemorrhage -4.6' N:S: -8.0 0.06
N.S. - Not significant. 'Rased on nonsmoker rath.
tP value derivedfromcfii square.b'ased'on a null~hypothesis of no difference between smokers and
nonsmokers.
SOURCE: Derived from Meyer, M:B: (116).
The conclusion may be drawn that maternal! smoking increases the
risk of fetali and neonatal death at least partly by increasing the
incidence of these complications. The mechanisms of action of various
components of cigarette smoke in bringing about these events are
discussed'in another section of this chapter.
Preeclampsia
It has been a consistent finding in almost all published studies that the
incidence' of preeclampsia and toxemia, however defined, is negatively
associated with maternal smoking (2, 10, 31, 42, 74, 89, 101; 146, 164,
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summarized in the chapter on smoking and pregnancy in The Health'
Consequences of Smoking A Report of the Surgeon Generat: 1971, whichI
concluded: "Maternali smoking during pregnancy exerts a: retarding;
influence on fetal growth as manifested by decreased infant birth;
weight and an increased' incid'ence of prematurity, defined~ by weighe 4
alone" (190). The same conclusion has been drawn from subsequent
studies. : ~
In the chapter on pregnancy in The Health Consequences of Smoking
in 1973, a detailed, critical review is given of studies published to thatt
date. The chapter summary of the evidence that the association
between maternal smoking and reduced birth weight is one of cause
and effect includes the following (192):
t:
1. Results are consistent in all studies, retrospective and prospective;
from many different countries, races, cultures, and'geographic settings
(2,7,20,22,30;31,41147;54,62,72,81,86,89,109,115,118,119,125-,
127,137,141-143,1'47,151,152,157,161,163,164166,169,172,185,189,
192, 193, 206, 212). ~
2. The relationship between smoking and reduced birth weight is
independent of all other factors that influence birth weight, such as'
race,, parity, maternal size, socioeconomic status, sex of child, and other
factors that have been studied (1, 2, 7, 20, 22,, 31, 47; 54, 71, 101, 102,
115, 118, 119, 142,, 143, 152, 157, 164; 169, 192, 193): It is also
independent of gestational age (2, 19, 20; 22, 54, 72, 115, 141 157, 163,
166; 169, 192, 206). ="
3. The more the woman smokes during pregnancy, the greater the
reduction in birth weight;, this is a dose-response relationship (2, 22, 31,
47, 54, 89,,101 102, 103, 115, 118, 119, 137, 142, 143, 169;,189,,192, 193;
206). x~
4. If a woman gives up smoking during pregnancy, her risk of
delivering a: low-birth-weight baby is similar to that of a nonsmoker
(22, 54, 101, 103, 206). `~
To illustrate typical results of studies showing, the association
between maternal smoking and an increased proportion of low-birth-
weight infants, five published studies with an aggregated totall of
almost 113,000 births in Wales, the United States, and Canada are
summarize& in Table 1. In these populations, 34 to 54 percent of the
mothers smoked during pregnancy and on the average had twice as
many low-birth-weight babies as the nonsmokers. Under these
conditions, from 21 to 39 percent of the low-birth-weight incidence in
the total population could be attribute& to maternal smoking (2, 20, 47,
115, 13y, 142, 143).
An outstanding, feature of the relationship between maternal
smoking and birth weight is its dependence on the level of maternal
smoking and its independence of the large variety of other factors that
influence birth weight, such as mat'ernai size, maternal weight gain,
age, parity, socioeconomic status, and sex of chil& (1, 2, 20, 22, 31, 47,
8-12
deaths occurred in babies who were born preterm, but were without
other pathology. There is no convincing evidence that maternal
smoking increases the incidence of congenitaP malformations: Results
of published studies, reviewed in the 1973 report, show relative risks
for smokers versus nonsmokers ranging from 0.31 to 1.55 (192):
0
Complications of Pregnancy and Labor
Observations from the Ontario study and other data showed that
women who smoked during, pregnancy had excess fetal deaths either
unexplained or attributed~ to anoxia and excess neonatal deaths due to
premature delivery. These findings suggested that maternal smoking
might increase the risk of certain pregnancy complications that were
related, in turn, to these causes of perinatal loss. A direct relationship
between maternal' smoking level and the incidenee of placenta previa,
abruptio placentae, bleeding during pregnancy, and premature rupture
of membranes had been reported previously (2, 31, 63, 115, 189).
Underwood, et al., found higher rates for smokers than for nonsmokers
of bleeding, abruptio placentae, and placenta previa combined, and of
premature: rupture of membranes in three groups of women with
different socioeconomic and racial backgrounds (188). In a large st'udy
of births to U.S. Navy wives, the same complications increased with
maternal smoking. In the latter study, the incidence of premature
rupture of membranes increased within four levels of maternal
smoking from none to 311+ cigarettes per day (189). Kullander and
Kaellen found a significant increase in the frequency of abruptio
placentae among children, dying before the age of 1 week (89).
Andrews and McGarry found increased incidence of abruptio placentae
and other forms of accidental antepartum hemorrhage to be associated
with maternal smoking. They stated that this was thought to be the
cause of premature delivery in 1.2 percent of smokers compared with
only 0:5 percent of nonsmokers. The incidence of accidental hemor-
rhage specific for parity was higher for smokers than for nonsmokers
at all, parities, rising to 3.16 percent of smokers who were para 4 or
more (2)~ Similarly, Russell, et aL found an increase in vaginal' bleeding
during early pregnancy among women who smoked (165). In the study
by Goujard, et al., as previously noted, a: large proportion of the
increase in stillbirths among smokers was caused by abruptio placentae
(63). Naeye reviewed the clinical and postmortem material from the
3,897 fetal and infant deaths in the Collaborative Perinatal Project of
the NI'NCDS (137) and reported an association between perinatal
mortality rates caused by abruptio placentae and number of cigarettes
smoked by the mother (131): Abruptio placentae was the underlying
cause identified in 11 percent of all the deaths in this large study (129).
The Ontario data corroborated these findings, as shown in~ TabUe 11.
Increasing levels of smoking resulted in a highly significant increase in
the risks ofl placental abruptions, placenta previa, bleeding, an&
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second pregnancy of the pair, but not the first. Comparison of the
mean birth weights for the first infants in each pair showed that
future smokers had babies who weighed less than those of women who
did not take up smoking and more than~ those of women who were
already smokers and continued to smoke. Silverman concluded: "These
findings neither confirm nor deny the hypothesis that the smoker
rather than the smoking per se causes a reduction in birthweight"
(171);
Evidence for a direct effect of maternal smoking on fetal growth as
presented in this chapter is extremely strong. Furthermore, the
biological effects of carbon monoxide, nicotine, and other known
components of cigarette smoke are compatible with the findings from
epidemiologic studies. Therefore, there seems little value in arguing
that this direct effect does not exist. On the other hand, smokers are to
some extent self-selected, and comparisons of "smokers" and "non-
smokers" in a population reveal differences between them. These may
be related to calendar time trends, peer group influence, cultural and
ethnic background, social class, or personality type. Because the
relationship between~ maternal smoking and birth weight is so strong,
these differences do not obscure it. More problems arise from lack of
adjustment for differences between smokers and nonsmokers in the
distribution of such factors as age, parity, socioeconomic status, and
race when~the relationship of maternal smoking to perinatal mortality
is under study; these issues are discussed in detail in another section of
this chapter. In addition, attention should be paid to the possibility that
psychological makeup and strength of addiction to cigarette smoking
may have an independent influence on some of the outcomes being
studied. Future studies should! not only adjiust for independent factors
that influence whether or not a woman~ becomes a smoker and smokes
during pregnancy but should also distinguish between the effects of a
personality type that adopts smoking and the physical effects of the
smoke on mother, placentay and fetus.
Summary
1. Babies born to women who smoke during pregnancy are on the
average 200 grams lighter than babies born to comparable women who
do not smoke. The whole distribution of birth weights of smokers'
babies is shifted downnvard; and twice as many of these babies weigh
less than 2,500 grams compared with babies of nonsmokers: There is
abundant evidence that maternalt smoking is a direct cause of the
reduction in birth weight.
2. Birth~ weight is affected by maternal smoking independently and
to a uniform extent, regardless of other determinants of birth weight.
The more.the mother smokes, the greater the reduction in birth weight
of the baby.
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Evidence for Indirect Associations Bet'ween Smoking and Birth
Weight'
Yerushalmy has suggested that smoking is an index to a particular
type of reproductive outcome and does not play a causal role in~ t'hee
production of small-for-dates infants (206-208). The line of reasoning
and evidence presentedi by Yerushalirny and the responses to it aree
discussed in detaili in the 1973 report on The Health Comequences of
Smoking (192). The problems inherent in Yerushalnay's study, in which
he found a higher percentage of lbw birth weights among 210
nonsmokers who later became smokers than among nonsmokers who
did not take it up, have been described. The most serious of these
problems is t'he bias introduced by the study design resulting in
significantly younger ages for the "future smoker" group (mean age
19.70±0.15) than for his nonsmokers (22.10±0.04); the doubly retro-
spective nature of the information gathered (women being asked about
smoking habits at the time of previous pregnancies); and! lack of
control for other important factors influencing birth weight, such as
primiparity and sex of child.
Silverman addressed the question of whether the smoker rather than
the smoking, was responsible for increased frequency of low birth
weight by comparing pairs of births to the same woman, using data:
from the 1963 private census of the population of Washington County,
Maryland (28): In this census all members of the household were liste&
with birth dates, and all members were asked whether and how muchi
they smoked and when~ they had started! Using, these data, Silverman~
constructed a population of pairs of births that occurred during the 17=
year period prior to the census date of July 15, 1963. Assuming that the
mothers did not stop smoking during pregnancy and that the age of
starting was accurately reported, she was able to compare birth
weights in first and second births of 143 women~ who smoked~ during
the second pregnancy, but not during the first, with corresponding
birth weights from 382 women who smoked during neither pregnancy
and 491 women who smok& during both pregnancies. The many
problems inherent in this study were faced, and' adjustments were
made insofar as possible. For example, as in Yerushalmy's study,
significantly more of the future smokers (44.8 percent) were under 20
years of age at the time of the first study births compared with 24.5
percent of the continuing nonsmokers. Young, primiparous mothers
are known to have lighter babies than older mothers with higher
parity. When weights were compared specific for maternal age and sex
of child, the mean birth~ weight for the first member of the birth pair
was lower in four out of six comparisons and higher in two. With
simultaneous adjustment for the effects of infant sex, maternal age,
and birth order, there, were no significant differences in mean birth
weight difference among pairs in which the mother smoked during
both pregnancies and pairs in which the mother smoked during the
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their age, but had a shorter crown*rump length, a smaller transverse '
head diameter, less ossification of forelimb bones, shorter vibrassae,
and shorter claw length in~ relation to fetali age. Nishimura and Nakai
(136) reported numerous malformat'ions; particularly of the skeletal
system of fetal mice ('st'rain~ S) whose mothers received injections of
nicotine. These developmental anomalies included delayed osteogenesiss
and malformation of major joints, polydactyly, syndactyly, spinal
curvature, etc. The critical period for producing these abnormalities
was longer than for many other drugs tested, extending from the 6th
through the 14th day of gestation. In a subsequent study, Geller (57))
showed that doses of nicotine, about 15 percent of that used by
Nishimura and Nakai, resulted in no fetal abnormalities. Landauer (91)
a1Go noted multiple congenital abnormalities in white leghorn chicks in
which the eggs were injected with~ varying concentrations of nicotine
sulfate at several stages of incubatiom The predominant lesion noted
was shortening and twisting of the neck, secondary to abnormal
development of the cervical spine.
Several groups have shown that nicotine administration~t'o pregnant
rats resulted in prolonged gestation (11, 13, 75, 79). For instance, in~
Sprague-Dawley rats receiving daily inj ections of 3 mg of nicotine per
kg of body weight throughout the 21 days of gestation, the onset of
labor was delayed 1 day in 40~ percent, d'elayed~ 2 days in another 40
percent, and the remainder delivered on the third day, (13), Maternal
weight gain in nicotine-treated rats is also significantly less (12, 78, 79).
Damage to the placental capillaries of nicotine-treated dogs was
reported by Fischer (52).
That nicotine definitely crosses the placenta into the fetus has been
d'emonstrated~ by a number of workers (66, 187). Nicotine and its
metabolic product, cotinine, are also found in amniotic fluid (194): The
question of the rate at which nicotine and~ its metabolites cross the
placenta is of some interest. Tjalve et al (187) showed that, following
maternal injection of C'1-labeled nicotine, radioactivity appeared
rather quickly in the placenta and fetal tissuesreaching a peak in both
in about 30 minutes. In studies of rhesus monkeys with catheters in
maternal and fetal blood vessels and amniotic fluid, Suzuki, et al. (182)
measured nicotine levels following a single injection of 0.5 to 1.0 mg
3H-nicotine into the maternal circulation. The decrease in maternal
nicotine concentration was a double exponential process. Initially there
was a rapid decrease as nicotine became distributie& in various
maternal body compartments. Then there was a slow decrease due to
the metabolism of nicotine and its crossing the placenta. Fetali nicotine
concentration increased rapidly; then a plateau developed, followed by
a slow decrease as nicotine was metabolized and re-entered the
maternal circulationL It was noted~ that the fetall adrenal glands, heart,
and kidneys tended to accumulate the nicotine.
i
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TABLE' 4.-Spontaneous abortions by maternal smoking habit
and desideration of pregnancy
Spontaneous abortions
per 100 pregnancies Smoker:
nonsmoker
Relative risk
Smokers Nonsmokers
Total spontaneous abortions 9.4' 72 1.31
Pregnancy wanted 7.8 6.5 1.20:
Pregnancy unwanted 16.0 11.9 1.34
SOURCE: Kullander, S. (89).
percent), but the increased risk of spontaneous abortion was seen
among smokers whether or not the pregnancy was wanted (89).
The method for studying spontaneous abortions that may be t'he
least subject to error if carefully done is the traditional, retrospective,,
case-control approach, used recently by Kline and coworkers (87). In
their study a log-linear analysis was used to test the hypothesis that
maternal smoking is associated with spontaneous abortion, controlling,
for confounding variables such as age, number of previous spontaneous
abortions, induced abortions, and live births. Of the cases of spontane-
ous abortion, 41 percent were smokers compared with 28 percent of the
controls, giving an odds ratio of 1.8. This leads to the conclusion that
smoking during pregnancy is a risk factor for spontaneous abortion.
Perinatal Mortality
Most of the epidemiological studies about which questions of causality
have arisen have used perinatal death (late fetal and early neonatal);
neonatal death, or combinations of these as their outcome variable.
Ascertainment and recordkeeping may start at 20 weeks, at 28' weeks,
or at the time of registration. These differences in definition and
design affect the study results but are not fundamental' to the basic
questions raised in the 1973 report and by other authors.
Progress toward~ resolving these questions has been made since the
1973 report