Th e
Health Consequences
of Smoking

A Report of the Surgeon General: 1971

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
             Public Health Service


For sale by the Superintendent of Documents, U.S. Government Printing OI%x
          Washington, D.C. 2040'2 - Price $1.75


This report is a comprehensive review of more than 20 years
of research into the problem of smoking and health. This re-
search has been carried on under the sponsorship of many groups
in this country and abroad, including governments, universities,
private research institutions, voluntary health agencies, and the
tobacco industry.

Seven years ago, an advisory committee to the Surgeon General
concluded that cigarette smoking is a serious hazard to health and
is related to illness and death from lung cancer, chronic broncho-
pulmonary disease, cardiovascular disease and other diseases. In
the intervening years, a great deal of new research has been com-
pleted.  This has resulted in a growing understanding of the bio-
mechanisms whereby cigarette smoking adversely affects the hu-
`man organism and contributes to the development of serious
illness.

It is encouraging that cigarette consumption in this country is
declining.  If this decline can be maintained, it will result in better
health for our population and in fewer deaths among those of our
@tizens who are in their most productive years of life.

JESSE L. STEINFELD, M.D.,
       Surgeon General.


Acknowledgments

The National Clearinghouse for Smoking and Health, Daniel
Horn, Ph.D., Director, was responsible for the preparation of this
report. Daniel P. Asnes, M.D., was consulting editor.  Staff direc-
tor for the report was David G. Cook, M.D.
The professional staff has had the assistance and advice of a
number of experts in the scientific and technical fields, both in
and outside of the government.  Their contributions are gratefully
acknowledged.  Special thanks are due the following:

ANDERSON, WILLIAM H., M.D.-Chief, Pulmonary Disease Section, University
of Louisville School of Medicine, Louisville, Ky.
AKTHONISEN, NICHOLAS, R., M.D.-Ph. D.--Associate Professor, Department
of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
AUERBXH, OSCAR, M.D.-Senior Medical Investigator, VA Hospital, East
Orange, N.J.

AYRES, STEPHEN M., M.D.-Director, Saint Vincent's Hospital and Medical
Center of New York, Cardiopulmonary Laboratory, New York, N.Y.
BAKER, CARL, M.l).-Director, National Cancer Institute, National Institutes
of Health, Bethesda, Md.

BELLET, SAMUEL, M.D.-Director, Division of Cardiology, Philadelphia General
Hospital, Philadelphia, Pa.

BI~`G, RICHARD J., M.D.-Professor, of Medicine, California Institute of Tech-
nology, Pasadena, Calif.

BOCK, FRED G., Ph. D.-Ijirector, Orchard Park Laboratories, Roswell Park
Memorial Institute, Orchard Park, N.Y.
BOREN, HOLLIS, M.D.-Professor of Medicine, Marquette School of Medicine,
Wood VA Hospital, Milwaukee, Wis.

BOUTWELL, ROSWELL Ii., M.D.-Professor of Oncology, McArdle Laboratory
for Cancer Research, University of Wisconsin, Madison, Wis.
COOPER, THEODORE, MD-1 iirector, National Heart Institute, National In-
stitutes of Health, Bethesda, Md.

CORNFIELD, JEROME-Research Professor of Biostatistics, University of Pitts-
burgh Graduate School of Public Health, Riostatistics Project, Bethesda, Md.
EARL, CHRISTOPHER J., M.L).-National Hospital, London, England.
EPSTEIX, FREDERICK H., M.D-Professor of Epidemiology, University of
Michigan, School of Public Health, Ann Arbor, Mich.
FALK, HANS L., Ph. I).--.Associate Ijirector for Laboratory Research, National
Institute of Environmental Health Sciences, Research Triangle Park, N. C.
FERRIS, BENJAMIN G., JR.. M.I).-Professor, Department of Physiology, Har-
vard School of Public Health, Boston, Mass.


FITZPATRICK, MARK J., M.D., M.P.H.-Obstetrician, Perinatal Biology and In-
fant Mortality, National Institute of Child Health and Human Development,
National Institute of Child Health and Human Development, National In-
stitutes of Health, Bethesda, Md.

FRAZIER, TODD M.-Assistant Director, Harvard Center for Community Health
and Medical Care, Harvard &ho01 of Public Health, Boston, Mass.
GOLDSMITH, JOHN R., M.D.-Head, Environmental Epidemiology Unit, Cali-
fornia State Department of Public Health, Berkeley, Calif.
HANNA, MICHAEL G., JR., Ph. D.-Biology Division, Oak Ridge National Lab-
oratory, Oak Ridge, Tenn.

HIGGINS, IAN T. T., M.D., M.R.C.P.-Professor, Department of Epidemiology,
University of Michigan Schclol of Public Health, Ann Arbor, Mich.
HOFFMANN, DIETRICH, Ph. D.-Division of Environmental Toxicology, Ameri-
can Health Foundation, New York, N.Y.
ISRAEL, ROBERT A.-Director, Division of Vital Statistics, National Center for
Health Statistics, U.S.P.H.S., U.S. Department. of Health, Education and
Welfare, Rockville, Md.

KELLER, ANDREW Z., D.M.D., M.P.H.-Chief, Research in Geographic Epide-
miology, Veterans Administration Central Office, Washington, D.C.
KIRSNER, JOSEPH, M.D.-Professor of Medicine, University of Chicago School
of Medicine, Chicago, Ill.

KNOX, DAVID L., M.D.-Associate Professor, The Wilmer Ophthalmological
Institute, The Johns Hopkins University School of Medicine, Baltimore, Md.
KOLBYE, ALBERT C., JR., M.D., J.D.-Deputy Director, Bureau of Foods, Food
and Drug Administration, U.S. Department of Health, Education and Wel-
fare, Washington D.C.

KOTIN, PAUL, M.D.-Director, National Institute of Environmental Health
Sciences, Research Triangle Park, North Carolina.
KRUMHOLZ, RICHARD A., M.D.--Director, Institute of Respiratory Diseases,
Kettering Medical Center, Kettering, Ohio.
LIEBOW, AVERILL A., M.D.-Professor and Chairman, Department of Path-
ology, University of California at San Diego, La Jolla, Calif.
LILIENFELD, ABRAHAM, M.D.--Professor and Chairman, Department of
Chronic Diseases, Johns Hopkins School of Hygiene and Public Health,
Baltimore, Md.

MACMAHON, BRIAN, M.D.-Professor of Epidemiology, Harvard University
School of Public Health, Boston, Mass.
MCLEAN, Ross, M.D.-Medical Consultant, Regional Medical Program of
Texas, Austin, Tex.

MCMILLAN, GARDNER C., M.I).--Chief, Arteriosclerotic Disease Branch, Na-
tional Heart and Lung Institute, National Institutes of Health, Bethesda, Md.
MITCHELL, ROGER S., M.I).-Director, University of Colorado Medical Center,
Webb-Waring Institute for Medical Research, Denver, Colo.
MURPHY, EDMOND A., M.D., SC. D.-Associate Professor of Medicine and Bio-
statistics, The Johns Hopkins Hospital, Baltimore, Md.
PAFFENBARGER, RALPH S., JR., M.D.-Chief, Bureau of Adult Health and
Chronic Diseases, California State Department of Public Health, Berkeley,
Calif.

PETERS, JOHN M., M.D.-Associate Professor of Occupational Medicine, Har-
vard University School of Public Health, Boston, Mass .
PETERSON, WILLIAM F., M.D.--Chairman, Department of Obstetrics and
Gynecology, Washington Hospital Center, Washington, D.C.
PETTY, THOMAS L., M.D-Associate Professor of Medicine, University of
Colorado Medical Center, Denver, Colo.

vi


SAFFIOTTI, UMBERTO, M.D.--Associate Scientific Director for Carcinogenesis
Etiology, National Cancer Institute, National Institutes of Health, Beth-
esda, Md.

SCHUMAN, LEONARD M., M.D.-Professor and Head, Division of Epidemiology,
University of Minnesota School of Public Health, Minneapolis, Minn.
SHIIMKIK, MICHAEL B., M.D.-Coordinator, Regional Medical Program, Uni-
versity of California at San Diego, La Jolla, Calif.
STAMLER, JEREMIAH, M.D.-Executive Director, Chicago Board of Health,
Health Research Foundation, Chicago, 111.
UNDERWOOD, PAUL B., JR., M.D.--Associate Professor, Department of Ob-
stetrics and Gynecology, University of South Carolina Medical School,
Charleston, S.C.

VAN DUUREN, BENJAMIN L., M.D.-Professor of Environmental Medicine, In-
stitute of Environmental Medicine, New York University Medical Center,
New York, N.Y.

VICTOR, MAURICE, M.D.-Professor of Neurology, Department of Neurology,
Case Western Reserve, Cleveland, Ohio.
WYNDER, ERNEST L., M.D-President and Medical Director, American Health
Foundation, New York, N.Y.

The following professional staff of the National Clearinghouse
for Smoking and Health contributed to the preparation of this re-
port: John H. Holbrook, M.D., Richard W. White, Robert S. Hutch-
ings, Elaine Bratic, Annabel W. Hecht, Richard H. Amacher,
Donald R. Shopland and Jennie M. Jennings.
Special thanks are due Nancy S. Johnston, Kathryn Carlysle,
Mary E. Dement, and Mildred H. Ritchie.

vii


           Contents

                                       Page
PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .     ...
                                                        111

ACKNOWLEDGMENTS   . . . . . . . . . . . . . . . . . . . . . . . . . . . .      v
Chapter 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . .     1
Chapter 2. Cardiovascular Diseases . . . . . . . . . . . . . . . . . . .    15
Chapter 3. Chronic Obstructive Bronchopulmonary
       Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   135
Chapter 4. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   231
Chapter 5. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   385
Chapter 6. Peptic Ulcer . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   419
Chapter 7. Tobacco Amblyopia . . . . . . . . . . . . . . . . . . . . . . .   431


CHAPTER 1

       General Considerations,
Preparation of the Present Document,
     and Summary of the Report


GENERAL CONSIDERATIONS

The first major development in the modern history of the effects
of smoking on health occurred in 1950 with the publication of four
retrospective studies on smoking habits among lung cancer pa-
tients and among controls (1, 4, 6, 7). At that time, the question
was, "Are smokers more likely to get lung cancer than nonsmok-
ers?" Although some epidemiologists were satisfied that the an-
swer was in the affirmative, others turned for confirmation to
prospective studies in which the smoking habits of large popula-
tions were recorded and the populations followed to identify sub-
sequent mortality. The first report of Hammond and Horn in 1954
(Z), showed significantly elevated overall death rates for smokers
as compared to nonsmokers. This elevation in death rates, almost
entirely confined to those who smoked cigarettes, together with the
evidence for a gradient according to the amount smoked, changed
the question from one concerning only lung cancer to one concern-
ing overall death rates and from one concerning smoking to one
primarily concerned with cigarette smoking. In effect, the question
became, "Do cigarette smokers have higher overall death rates
than nonsmokers and smokers of pipes and cigars?"

With the publication of the later reports of the major prospec-
tive studies in the late 1950's and early 1960's, it became clear that
cigarette smokers had higher overall death rates than nonsmokers,
as well as higher death rates from a number of individual causes
of death. The question then became, "Why?"

When the Advisory Committee on Smoking and Health to the
Surgeon General was established in 1962, it undertook the evalua-
tion of the scientific evidence up to that time. The conclusion of the
Committee in its 1964 Report was that: "Cigarette smoking is a
health hazard of sufficient importance in the United States to war-
rant appropriate remedial action." Not only did the Committee
conclude that the evidence clearly showed that male cigarette
smokers do in fact have higher death rates than nonsmokers but
that the convergence of epidemiological, experimental, and path-
ological evidence also clearly indicated a cause-and-effect relation-
ship for several of the implicated diseases, particularly cancer of
the lung and chronic bronchitis. In several other important dis-
eases, the evidence on biomechanisms to explain epidemiological

3


associations was felt to be inadequate at that time to draw firm
conclusions about a cause-and-effect relationship.

Three and one-half years later, when The Health Consequences
of Smoking: A Public Health Service Review, 1967 was published,
the conclusions of the 1964 review were taken as a starting point,
and the nature of the task of interpreting the scientific evidence
was restated as follows :

1. How much mortality and excess disability are associated with
smoking?

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

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

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

That and subsequent reviews in 1968 and 1969 have provided
some answers to these questions, particularly in summarizing the
evidence for various theories as to how cigarette smoking affects
the human organism to produce elevated disease and death rates.

At least five different processes have been suggested whereby
cigarette smokers experience higher mortality or morbidity rates
than do nonsmokers.

1. Cigarette smoking initiates a disease process by producing
progressive irreversible damage. In this case, the total effect would
be approximately proportional to the total accumulated dosage
experienced over the years. Cessation of smoking leaves impaired
function which does not improve appreciably but does not continue
to deteriorate from continued exposure to cigarette smoke. How-
ever, such function may deteriorate through aging or through
exposure to other harmful agents. It appears that such a relation-
ship probably exists for chronic obstructive lung disease and pos-
sibly for the development of atherosclerotic heart disease.

2. Cigarette smoking initiates a disease process with continual
repair and recovery until some critical point is reached at which
the process is no longer reversible. The total effect would therefore
be affected to some extent by accumulated exposure but would be
affected also by the level of contemporary smoking. Cessation of
smoking would result in a rapid reduction of risk provided the
critical level initiating an irreversible process has not been
reached. The evidence supports this kind of mechanism accounting
both for the high dose-response relationship in lung cancer and for
the reduction in risk from lung cancer among ex-smokers.

3. Cigarette smoking promotes a disease process either by
providing positive support to the development of a pathological
condition or by interfering with and diminishing the normal capa-

4


bility of the organism to cope with and defend against a disease
process. This may take place by promoting the development of a
subclinical disease to a clinically recognizable one, by promoting a
mild disease state t.o a more severe form, or by increasing fatality
rates of severe disease states. This type of mechanism could ac-
count for modestly increased mortality rates for a number of se-
vere diseases for which there is no evidence that cigarette smoking
itself has a role in initiating the disease. Some of the excess mor-
tality from infectious respiratory disease and from coronary heart
disease might take place through this kind of mechanism.

4. Cigarette smoking produces a set of temporary conditions
which increase the probability that a critical event will occur with
attendant disability and possibly fatal consequences. For example,
there is evidence to support the theory that each cigarette can pro-
duce a set of conditions which increase the probability of myocar-
dial damage through increased demand for oxygen at a time when
the suppy is diminished. Presumably, once the supply/demand im-
balance is alleviated, the probability of myocardial damage would
revert to its normal level. Cessation of smoking should have an
almost immediate effect of reducing the risk sharply for morbidity
or mortality produced through this mechanism.

5. Cigarette smoking may be artificially related to excess dis-
ability or death by way of a close association with some other con-
dition or exposure which is found at a high level in smokers, but
not in nonsmokers, and is itself responsible for the disease. The one
cause of death for which cigarette smokers have elevated death
rates that is generally interpreted in this way is cirrhosis of the
liver. Since most heavy consumers of alcoholic beverages are smok-
ers, and since alcohol consumption is an important part of the
process that produces cirrhosis of the liver, the high rate of cirrho-
sis among cigarette smokers is discounted as resulting from this
kind of artificial relationship. Some authors have proposed that
there may be genetic factors that link smoking and certain diseases
in this fashion. Obviously, the cessation of smoking would have no
effect on morbidity or mortality from diseases which are artificially
related to smoking.

These different ways in which cigarette smoking can be related
to elevated morbidity and mortality rates are important considera-
tions in attempting to estimate the potential public health benefits
of giving up smoking, For some types of relationship, there would
be no benefits ; for some, rather small benefits ; for some, substan-
tial benefits, taking place over a long period of time; and for
others, substantial benefits taking place rather rapidly.

During the past few years, a sharp reduction has taken place
in the cigarette smoking habits of the U.S. population. The Na-

5


tional Center for Health Statistics has recently published a com-
parison of smoking habits in the US. in 1955 and 1966 based on
two large scale household surveys (5). These showed a drop in
cigarette consumption in men under 55 years of age but no appre-
ciable change among those 55 or over. Among women, every age
group showed an increase in the eleven year period. A recent sur-
vey conducted for the National Clearinghouse for Smoking and
Health, based on a much smaller sample (approximately 5,000
interviews), was conducted in the Spring of 1970 (3) (table 1).
Even with the smaller number of cases, it is clear that a much
larger drop took place in the four years from 1966 to 1970 than
in the eleven years from 1955 to 1966. The drop extended to the
age group 55-64 among men, again with no appreciable drop
among men over age 65. For the first time, the increase in smok-
ing among women leveled off, or even dropped slightly among
women under 55. The increase among women over 55 was of a
lesser magnitude than previously observed.

TABLE I.-Percentage of Current Smokers of Cigarettes (regu-
larly or occasionally) by sex and age. U.S. Surveys: 1955 and
1966 (CPS-Current Population Surveys) and 1970 (NCSH-
Survey conducted for National Clearinghouse for Smoking &
Health) .I

                      Male                      Female
              CPS      CPS      NCSH       CPS      CPS     NCSH
ALW           1955      1966      1'970        1956      1966      1910

18-24 --__------ 53.0     48.3    247.0       33.3     34.7     231.1
25-34 ---------- 63.6     58.9     46.8       39.2     43.2     40.3
35-44 _---_-__-- 62.1     57.0     48.6       35.4     41.1     39.0
45-54 _-_-___--- 58.0     53.1     43.1       25.7     37.3     36.0
55-64 --~_---~-~ 45.8     46.2     37.4       13.4     23.0     24.3
65+ ----__-_-- 25.8     24.6     23.7       4.7      8.1     11.8
11955 survey based on approximately 46,000 persons; 1966 survey based on approximately
35,000 persons; 1970 survey based on approximately 5,000 persons.
2 Estimated.

With the massive changes in smoking behavior which have
taken place among adults in the past few years, largely as an
expression of the desire to protect health, changes should be ex-
pected in mortality rates among those groups which have experi-
enced the greatest reduction both in accumulated dosage and in
concurrent dosage. An analysis of U.S. mortality rates for 1970
and the years to follow will provide a very valuable addition to the
knowledge concerning the effects of smoking on death rates.

  PREPARATION OF THE PRESENT DOCUMENT
Following the publication of Smoking and Health-Report of
the Advisory Committee to the Surgeon General-in 1964, the fol-

6


lowing documents were published as reviews of the medical litera-
ture concerning the health consequences of smoking, as called for
by Public Law 89-92 :

1. The Health Consequences of Smoking, A Public Health Serv-
ice Review: 1967.

2. The Health Consequences of Smoking, 1968 Supplement to
the 1967 PHS Review.

3. The Health Consequences of Smoking, 1969 Supplement to
the 1967 PHS Review.

These documents reviewed the medical literature which had
been published since the original Surgeon General's Report. This
format of publishing a supplement to a supplement has become
unwieldy, particularly in the light of the lack of availability of the
previous reviews to the general public. Therefore, when Public
Law 91-222 was signed into law on April 1, 1970 calling for an
eighteen month interval between the last report and the new re-
port, the decision was made to review the entire field with em-
phasis on the most recent additions to the literature.

The National Clearinghouse for Smoking and Health has the
responsibility for continuous monitoring and compilation of the
medical literature on the health consequences of smoking. This is
accomplished through several mechanisms :

1. A scientific review corporation is on contract to extract arti-
cles on smoking and health from the medical and scientific litera-
ture of the world. This organization provides a semi-weekly acces-
sions list with abstracts and copies of the various articles. Trans-
lations are called for as needed. Articles of pertinence are identi-
fied by a series of code words and phrases.

2. The National Library of Medicine, through the Medlars sys-
tem, sends the National Clearinghouse for Smoking and Health a
monthly listing of articles in the smoking and health area. These
are reviewed, and pertinent articles are ordered.

3. Staff members keep up with the current contents of medical
and scientific literature and identify articles of pertinence.

Initial drafts of the present review were prepared by Clearing-
house staff and consultants who reviewed the previous reports and
identified those articles which have been important in the develop-
ment of knowledge in this field. These were abstracted and placed
into tabular form, and a draft text of the report was prepared.
The first drafts of the individual chapters were sent to experts
for review, criticism, and comment with respect to the articles re-
viewed, those articles not included, and conclusions. The drafts
were then revised on the basis of these comments and rewritten
until they met with general approval of the reviewers. The final

7


drafts were reviewed as a whole by the Director of the National
Clearinghouse for Smoking and Health, the Director of the Na-
tional Cancer Institute, the Director of the National Heart and
Lung Institute, the Director of the National Institute of Environ-
mental Health Sciences, and by six additional experts both within
and outside of the Public Health Service.

SUMMARY OF THE REPORT

CARDIOVASCULAR DISEASES

Comnary Heart Disease

1. Data from numerous prospective and retrospective studies
confirm the judgment that cigarette smoking is a significant risk
factor contributing to the development of coronary heart disease,
including fatal CHD and its most severe expression, sudden and
unexpected death. The risk of CHD incurred by smoking of pipes
and cigars is appreciably less than that incurred by cigarette
smokers.

2. Analysis of other factors associated with CHD (high serum
cholesterol, high blood pressure, and physical inactivity) show
that cigarette smoking operates independently of these other fac-
tors and can act jointly with certain of them to increase the risk
of CHD appreciably.

3. There is evidence that cigarette smoking may accelerate the
pathophysiological changes of pre-existing coronary heart disease
and therefore contributes to sudden death from CHD.
4. Autopsy studies suggest that cigarette smoking is associated
with a significant increase in atherosclerosis of the aorta and
coronary arteries.

5. The cessation of smoking is associated with the decreased
risk of death from CHD.

6. Experimental studies in animals and humans suggest that
cigarette smoking may contribute to the development of CHD and/
or its manifestations by one or more of the following mechanisms :

a. Cigarette smoking, by contributing to the release of catecho-
lamines, causes increased myocardial wall tension, contraction
velocity, and heart rate, and thereby increases the work of the
heart and the myocardial demand for oxygen and other
  nutrients.

b. Among individuals with coronary atherosclerosis, cigarette
smoking appears to create an imbalance between the increased
needs of the myocardium and an insufficient increase in cor-
onary blood flow and oxygenation.

c. Carboxyhemoglobin, formed from the inhaled carbon mon-


oxide, diminishes the availability of oxygen to the myocardium
and may also contribute to the development of atherosclerosis.
d. The impairment of pulmonary function caused by cigarette
smoking may contribute to arterial hypoxemia, thus reducing
the amount of oxygen available to the myocardium.
e. Cigarette smoking may cause an increase in platelet adhesive-
ness which might contribute to acute thrombus formation.

Summary Statement of Recent Additions to Knowledge Relating
Smoking and Coronary Heart Disease.-A number of epidemi-
ologic studies have provided additional evidence concerning ciga-
rette smoking as a significant risk factor in the development of
CHD. Experimental studies on animals have suggested that ciga-
rette smoking, particularly the absorbed nicotine and carbon mon-
oxide, contributes to the development of atherosclerosis.

Cerebrovascular Disease

1. Data from numerous prospective studies indicate that ciga-
rette smoking is associated with increased mortality from cere-
brovascular disease.

2. Experimental evidence concerning the relationship of smok-
ing and cerebrovascular disease is at present insufficient to allow
for conclusions concerning pathogenesis. However, some of the
pathophysiological considerations discussed concerning CHD may
also pertain to the relationship of smoking and CVD, particularly
cerebral infarction.

Nonsyphilitic Aortic Aneurys,m

Cigarette smoking has been observed to increase the risk of
dying from nonsyphilitic aortic aneurysm.

Peripheral Vascular Disease

1. Data from a number of retrospective studies have indicated
that cigarette smoking is a likely risk factor in the development
of peripheral vascular disease. Cigarette smoking also appears to
be a factor in the aggravation of peripheral vascular disease.
2. Cigarette smoking has been observed to alter peripheral blood
flow and peripheral vascular resistance.

CHRONIC OBSTRUCTIVE BRONCHOPULMONARY DISEASE

1. Cigarette smoking is the most important cause of chronic
obstructive bronchopulmonary disease in the United States. Ciga-
rette smoking increases the risk of dying from pulmonary emphy-
sema and chronic bronchitis. Cigarette smokers show an increased
prevalence of respiratory symptoms, including cough, sputum pro-

9


duction, and breathlessness, when compared with nonsmokers.
Ventilatory function is decreased in smokers when compared with
nonsmokers.

2. Cigarette smoking does not appear to be related to death
from bronchial asthma, although it may increase the frequency
and severity of asthmatic attacks in patients already suffering
from this disease.

3. The risk of developing or dying from COPD among pipe and/
or cigar smokers is probably higher than that among nonsmokers,
while clearly less than that among cigarette smokers.

4. Ex-cigarette smokers have lower death rates from COPD
than do continuing smokers. The cessation of cigarette smoking is
associated with improvement in ventilatory function and with a
decrease in pulmonary symptom prevalence.

5. Young, relatively asymptomatic, cigarette smokers show
measurably altered ventilatory function when compared with non-
smokers of the same age.

6. For the bulk of the population of the United States, the im-
portance of cigarette smoking as a cause of COPD is much greater
than that of atmospheric pollution or occupational exposure. How-
ever, exposure to excessive atmospheric pollution or dusty occu-
pational materials and cigarette smoking may act jointly to pro-
duce greater COPD morbidity and mortality.

7. The results of experiments in both animals and humans have
demonstrated that the inhalation of cigarette smoke is associated
with acute and chronic changes in ventilatory function and pul-
monary histology. Cigarette smoking has been shown to alter the
mechanism of pulmonary clearance and adversely affect ciliary
function.

8. Pathological studies have shown that cigarette smokers who
die of diseases other than COPD have histologic changes charac-
teristic of COPD in the bronchial tree and pulmonary parenchyma
more frequently than do nonsmokers.

9. Respiratory infections are more prevalent and severe among
cigarette smokers, particularly heavy smokers, than among
nonsmokers.

10. Cigarette smokers appear to develop postoperative pul-
monary complications more frequently than nonsmokers.
Sunzmal'y Statement of Recent Additions of Knowledge Relat-
kg to Chronic Obstructive n,,onchopul??zonar!! Disease.-Studies
have demonstrated that cigarette smokers show increased symp-
toms and pulmonary dysfunction as well as mortality from COPD
when compared to nonsmokers. Investigations of alpha,-antitryp-
sin deficiency in relationship to pulmonary emphysema have sug-

10


gested that cigarette smoking may act jointly with hereditary fac-
tors in the pathogenesis of pulmonary emphysema. A pathological
study on animals has shown that long-term inhalation of cigarette
smoke produces lesions characteristic of pulmonary emphysema.

Lung Cancer.

CANCER

1. Epidemiological evidence derived from a number of prospec-
tive and retrospective studies, coupled with experimental and
pathological evidence, confirms the conclusion that cigarette smok-
ing is the main cause of lung cancer in men. These studies reveal
that the risk of developing lung cancer increases with the number
of cigarettes smoked per day, the duration of smoking, and earlier
initiation, and diminishes with cessation of smoking.

2. Cigarette smoking is a cause of lung cancer in women but
accounts for a smaller proportion of the cases than in men. The
mortality rates for women who smoke, although significantly
higher than for female nonsmokers, are lower than for men who
smoke. This difference may be at least partially attributable to
differences in exposures : the use of fewer cigarettes per day, the
use of filtered and low "tar" cigarettes, and lower levels of inhala-
tion. Nevertheless, even when women are compared with men who
apparently have similar levels of exposure to cigarette smoke, the
mortality ratios appear to be lower in women.

3. The risk of developing lung cancer among pipe and/or cigar
smokers is higher than for nonsmokers but significantly lower
than for cigarette smokers.

4. The risk of developing lung cancer appears to be higher
among smokers who smoke high "tar" cigarettes, or smoke in such
a manner as to produce higher levels of "tar" in the inhaled
smoke.

5. Ex-cigarette smokers have significantly lower death rates for
lung cancer than continuing smokers. ,There is evidence to support
the view that cessation of smoking by large numbers of cigarette
smokers would be followed by lower lung cancer death rates.

6. Increased death rates from lung cancer have been observed
among urban populations when compared with populations from
rural environments. The evidence concerning the role of air pollu-
tion in the etiology of lung cancer is presently inconclusive. Fac-
tors such as occupational and smoking habit differences may also
contribute to the urban-rural difference observed. Detailed epi-
demiologic surveys have shown that the urban factor exerts a
small influence compared to the overriding effect of cigarette smok-
ing in the development of lung cancer.

11


`7. Certain occupational exposures have been found to be asso-
ciated with an increased risk of dying from lung cancer. Cigarette
smoking interacts with these exposures in the pathogenesis of lung
cancer so as to produce very much higher lung cancer death rates
in those cigarette smokers who are also exposed to such substances.

8. Experimental studies on animals utilizing skin painting,
tracheal instillation or implantation, and inhalation of cigarette
smoke or its component compounds, have confirmed the presence of
complete carcinogens as well as tumor initiators and promoters in
tobacco smoke. Lung cancer has been found in dogs exposed to the
inhalation of cigarette smoke over a period of more than 2 years.

Cancer of the Laqmx

1. Epidemiological, experimental, and pathological studies
support the conclusion that cigarette smoking is a significant fac-
tor in the causation of cancer of the larynx. The risk of develop-
ing laryngeal cancer among cigarette smokers as well as pipe and/
or cigar smokers is significantly higher than among nonsmokers.
The magnitude of the risk for pipe and cigar smokers is about the
same order as that for cigarette smokers, or possibly slightly
lower.

2. Experimental exposure to the passive inhalation of cigarette
smoke has been observed to produce premalignant and malignant
changes in the larynx of hamsters.

Oral Cancer

1. Epidemiological and experimental studies contribute to the
conclusion that smoking is a significant factor in the development
of cancer of the oral cavity and that pipe smoking, alone or in
conjunction with other forms of tobacco use, is causally related to
cancer of the lip.

2. Experimental studies suggest that tobacco extracts and to-
bacco smoke contain initiators and promoters of cancerous changes
in the oral cavity.

Cancer- of the Esophagus

1. Epidemiological studies have demonstrated that cigarette
smoking is associated with the development of cancer of the esoph-
agus. The risk of developing esophageal cancer among pipe and/
or cigar smokers is greater than for nonsmokers and of about the
same order of magnitude as for cigarette smokers, or perhaps
slightly lower.

2. Epidemiological studies have also indicated an association
between esophageal cancer and alcohol consumption and that alco-
hol consumption may interact with cigarette smoking. This com-

12


bination of exposures is associated with especially high rates of
cancer of the esophagus.
Cancer of the Urinary Bladd,er and. Kidney

1. Epidemiological studies have demonstrated an association of
cigarette smoking with cancer of the urinary bladder among men.
The association of tobacco usage and cancer of the kidney is less
clear-cut.

2. Clinical and pathological studies have suggested that tobacco
smoking may be related to alterations in the metabolism of tryp-
tophan and may in this way contribute thereby to the development
of urinary tract cancer.

Cancer of the Pancreas

Epidemiological studies have suggested an association between
cigarette smoking and cancer of the pancreas. The significance of
the relationship is not clear at this time.

Summary Statement of Recent Additions of Knowledge Relating
Smoking and Cancer.-Epidemiological studies have confirmed that
cigarette smokers incur an increased risk of dying from lung can-
cer and that those smokers who switched to filter cigarettes incur
a lesser risk. Pathological studies have shown that cancer of the
lung and cancer of the larynx have been found in animals exposed
to the long-term inhalation of cigarette smoke.

SMOKING AND PREGNANCY

Maternal smoking during pregnancy exerts a retarding influence
on fetal growth as manifested by decreased infant birthweight and
an increased incidence of prematurity, defined by weight alone.
There is strong evidence to support the view that smoking mothers
have a significantly greater number of unsuccessful pregnancies
due to stillbirth and neonatal death as compared to nonsmoking
mothers. There is insufficient evidence to support a comparable
statement for abortions. The recently published Second Report of
the 1958 British Perinatal Mortality Survey, a carefully designed
and controlled prospective study involving large numbers of
Patients, adds further support to the conclusions.

PEPTICULCER

Cigarette smoking males have an increased prevalence of peptic
ulcer disease and a greater peptic ulcer mortality ratio. These
relationships are stronger for gastric ulcer than for duodenal
ulcer. Smoking appears to reduce the effectiveness of standard
Peptic ulcer treatment and to slow the rate of ulcer healing.

13


TOBACCO AMBLYOPIA

Tobacco amblyopia is presently a rare disorder in the United
States. The evidence suggests that this disorder is related to nutri-
tional or idiopathic deficiencies in certain detoxification mecha-
nisms, particularly in handling the cyanide component of tobacco
smoke.

INTRODUCTION REFERENCES

(I ) DOLL, R., HILL, A. B., Smoking and carcinoma of the lung. Preliminary
  report. British Medical Journal 2: `739-748, September 23, 1950.
(2) HAMMOND, E. C., HORN, D. The relationship between human smoking
   habits and death rates. Journal of the American Medical Association
   155: 1316-1328, August 7, 1954.

(3) HORN, D. Address given at National Conference on Smoking and Health,
   San Diego, Calif., September 9-11, 1970. 13 pp.
(4) LEVIN, M. L., GOLDSTEIN, H., GERHARDT, P. R. Cancer and tobacco smok-
   ing.  A preliminary report. Journal of the American Medical Asso-
   ciation 143(4) : 336-338, May 27, 1950.
(5) NATIONAL CENTER FOR HEALTH STATISTICS. Changes in cigarette smoking
  habits between 1955 and 1966. U.S. Department of Health, Education,
   and Welfare, April 1970. 33 pp.

(6) SCHREK, R., BAKER, L. A., BALLARD, G. P., DOLGOFF, S. Tobacco smoking
   as an etiologic factor in disease.  I. Cancer.  Cancer Research 10:
   49-58, 1950.

(7) WYNDER, E. L., GRAHAM, E. A. Tobacco smoking as a possible etiologic
  factor in 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.

14


CHAPTER 2

           Cardiovascular Diseases


Page
21
38
38
39
40

Introduction  ........................................
Epidemiological Studies. ..............................
  Coronary Heart Disease Mortality  .................
  Coronary Heart Disease Morbidity  .................
  Retrospective Studies. ............................
  The Interaction of Cigarette Smoking and Other CHD
    Risk Factors  ..................................
    Smoking and Serum Lipids  ...................
    Smoking and Hypertension. ...................
    Smoking and Physical Inactivity  ...............
    Smoking and Obesity  .........................
    Smoking and Electrocardiographic Abnormalities.
    Smoking and Heart Rate  .....................
The Effect of Cessation of Cigarette Smoking on Coronary
Heart Disease .....................................
The Constitutional Hypothesis  ........................
Autopsy Studies Relating Smoking, Atherosclerosis, and
SuddenCHDDeath  ................................
Experimental Studies Concerning the Relationship of
Coronary Heart Disease and Smoking  ................
  Cardiovascular Effects of Cigarette Smoke and
   Nicotine.. ....................................
  Coronary Blood Flow  ............................
  Cardiovascular Effects of Carbon Monoxide  .........
  Effects of Smoking on the Formation of Atherosclerotic
   Lesions .......................................
  The Effect of Smoking on Serum Lipid Levels  ........
  The Effect of Smoking on Thrombosis  ..............
  Other Areas of Investigation. .....................
Cerebrovascular Disease  .............................
Nonsyphilitic Aortic Aneurysm  ........................
Peripheral Arteriosclerosis  ...........................
  Experimental Evidence. ..........................
Thromboangiitis Obliterans ...........................
Summary and Conclusions  ............................

40
41
41
41
43
47
47

47
48

52

56

56
58
59

63
65
66
66
66
67
72
73
73
74

17


  Coronary Heart Disease  ..........................
  Cerebrovascular Disease  ..........................
  Nonsyphilitic Aortic Aneurysm  ....................
  Peripheral Vascular Disease  ......................
References ..........................................

FIGURES

1. National Cooperative Pooling Project, Inter-Society Com-
  mission for Heart Disease Resources . . . . . . . . . . . . . . .
2. Risk of coronary heart disease (12 years) according to
  cigarette smoking habit and presence of "predisposing
   factors" (men 30-59 at entry). Framingham Heart
  Study..........................................
3. Estimated coronary heart disease death ratios in a 17-51
  year follow-up, and frequencies of paired combinations
  of six high-risk characteristics in college, for all ages
   at death  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4. Relationship between smoking status and serum choles-
  terol level at initial examination, and incidence of clin-
  ical coronary heart disease in men originally age 40-59
  free of definite CHD. Peoples Gas Light and Coke
  Company Study,1958-1962.......................
5. Average annual incidence of first myocardial infarction
  among men in relation to overall physical activity,
  class, and smoking habits (age-adjusted rates per
  1,000) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

LIST OF TABLES

(A indicates tables located in Appendix at end of Chapter)

1. Sudden death and acute mortality with first major
   coronary episodes . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Coronary heart disease mortality ratios related to
   smoking-prospective studies . . . . . . , . . . . . . . . . . .
3. Sudden death from coronary heart disease related to
   smoking.....................................
4. Coronary heart disease morbidity as related to
   smoking.....................................
5. Coronary heart disease morbidity as related to smok-
   ing-angina pectoris-prospective studies . . . . . . .
A 6. Coronary heart disease morbidity and mortality-
   retrospective studies . . . . . . . . . . . . . . . . . . . . . . . .
A 7. Differences in serum lipids between smokers and non-
    smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Page
74
75
75
75
75

23

24

25

43

44

23


26


30


32


37


93


98

18


LIST OF TABLES (CONT.)

(A indicates tables located in Appendix at end of Chapter)

A 8. Blood pressure differences between smokers and non-
    smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9. Death rates from coronary heart disease, by systolic
   blood pressure: ILWU mortality study, 1951-1961
10. Death rates from coronary heart disease, by diastolic
   blood pressure: ILWU mortality study, 1951-1961
11. Death rates from coronary heart disease, among hy-
   pertensives and nonhypertensives : ILWU mortality
    study, 1951-1961.............................
12. Death rates from coronary heart disease among men
   without abnormalities related to cardiopulmonary
    diseases by weight classification in 1951: ILWU
   mortality study, 1951-1961 . . . . . . . . . . . . . . . . . .
13. Death rates from coronary heart disease, by electro-
   cardiographic findings in 1951: ILWU mortality
    study, 1951-1961.............................
14. 1958 status with respect to heart rate, blood pressure,
    cigarette smoking, and ten-year mortality rates, by
    cause (1,329 men originally age 40-59 and free of
   definite coronary heart disease) Peoples Gas Com-
    pany Study,1958-1968.......................
15. The effect of the cessation of cigarette smoking on the
    incidence of CHD . . . . . . . . . . . . . . . . _...........
16. Annual probability of death from coronary heart dis-
    ease, in current and discontinued smokers, by age,
    maximum amount smoked, and age started smoking
A 17. Incidence of new coronary heart disease by smoking
    category and behavior type for men 39-49 years
    of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A 18. Incidence of new coronary heart disease by smoking
    category and behavior type for men 50-59 years
   of age . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
19. Autopsy studies of atherosclerosis . . . . . . . . . . . . . . . .
A 20. Experiments concerning the effects of smoking and
    nicotine on animal cardiovascular function . . . . . .
A 21. Experiments concerning the effects of smoking and
    nicotine on the cardiovascular system of humans. .
-422. Experiments concerning the effect of nicotine or
    smoking on catecholamine levels . . . . . . . . . . . . . . .
x 23. Experiments concerning the atherogenic effect of
    nicotine administration, . . . . . . . . . . . . . . . . . . . . .

Page

103


42


42

42

45

45

45

46

46

105

106
53


107


113


119


120



19


LIST OF TABLES (CONT.)

(A indicates tales located in Appendix at end of Chapter)

24. Experiments concerning the atherogenic effect of
    carbon monoxide exposure and hypoxia . . . . . . . . .
A 25. Experiments concerning the effect of smoking and
    nicotine upon blood lipids (Human Studies) . . . . . .
A 25a. Experiments concerning the effect of smoking and
    nicotine upon blood lipids (Animal Studies) . . . . . .
A 26. Experiments concerning the effect of carbon mon-
    oxide exposure upon blood lipids . . . . . . _ . . . . . . . .
A 27. Smoking and thrombosis . . . . . . . . . . . . . . . . . . . . . . . .
28. Deaths from cerebrovascular disease related to
    smoking.....................................
29. Deaths from nonsyphilitic aortic aneurysm related to
    smoking-prospective studies . . . . . . . . . . . . . . . . . .
A 30. Experiments concerning the effect of nicotine and
   smoking upon the peripheral vascular system . . . .

Page

64

123

127

129
130

68

71

133

20


INTRODUCTION

Coronary Heart Disease (CHD) cuts short the lives of many
men in the Western World in their prime productive years. More
Americans die from heart disease than from any other disease. In
196'7, in this country, a total of 345,154 men and 227,999 women
were classified as dying of arteriosclerotic heart disease (ASHD)
(196)) a category which consists largely of what is commonly
called CHD. During the years from 1950 to 1967, the age-adjusted
death rate from ASHD increased 15.1 percent (196, 197).

Besides the many deaths attributed to CHD, much morbidity
results from this disease. The National Health Examination Sur-
vey of 1960-1962 estimated that 3.1 million American adults, ages
18 to 79, had definite CHD and 2.4 million had suspect CHD,
togethes representing about 5 percent of the population. It was
further estimated that of Americans under age 65, almost 1.8 mil-
lion had definite CHD and 1.6 million had suspect CHD (195).

`There are several manifestations of CHD, all related in part to
the basic process of severe atherosclerosis, a disease of arteries in
which fatty materials (lipids) accumulate in the form of plaques
in the walls of medium and large arteries. This process, as it occurs
in the coronary arteries, leads to stiffening of the wall and narrow-
ing of the lumen which, when severe, result in a diminution in the
blood supply to the cardiac muscle. Angina pectoris, a major mani-
festation of CHD, results from diminution in blood supply relative
to the needs of the myocardium. If the blood supply to a portion
of the myocardium is completely obstructed, due for example to the
formation of a thrombus at the site of atherosclerotic narrowing,
necrosis or death of a portion of heart muscle may occur. This
occurrence is known as a myocardial infarction. In many cases, a
disturbance of cardiac rhythm occurs at the time of thrombosis,
and the patient may die immediately. It is estimated that approxi-
mately 25 percent of patients suffering coronary artery occlusion
die within the first three hours following the occlusion (table 1)
(88). Not infrequently, sudden death occurs in patients with severe
coronary atherosclerosis but without a demonstrable arterial occlu-
sion. In these cases, it is thought that the meager blood flow to a
Portion of the myocardium becomes so diminished with respect to
cardiac needs as to lead to a fatal arrhythmia, as well as to, per-
haps, a myocardial infarction.

21


CIGARIEITE SMOKING(S) AT ENTRY-WITH CONTROL OF SERUM CHOLESTEROL (C) AND DIASTOLIC BLOOD PRESSURE (W-AND TEN YEAR INCIDENCE
AND MORTALITY RATES. 7,594 WHITE MALES AGE 30-59 AT ENTRY, POOLING PROJECT

RATE
PER 1.000
150-

FIRST MAJOR
CORONARY EVENT

RATE
PER 1,000
150-

ALL CHD DEATHS

82

loo-

92

loo-

            7 I    ,,_(_
                               1 ju
50-         45                                   50-
W-I                         ).
                      .i' (,
     20                                 '*a,,'
                                      (_
                                      '.1.
                                       /"
o-

RISK     NONE     S    C OR H S+C OR
FACTORS   OF 3    ONLY    ONLY   SSH

NUMBER 28      97      74     167
OF EVENTS

C+H   C+H           NONE     S
     +s            OF 3    ONLY

31      82             17      50

384     595           1,249    2,018    1,302    1,794     384     595

NUMBER   1,249    2,018    1,302   1.794
OF MEN

National Cooperative Pooling Project; smoking status at entry and IO-year age-adjusted rates per 1,000 men for first major coronary event (incling nonfatal MI.
fatal MI. and sudden death due to CHD) and any coronary death. U.S. white males age 30-59 at entry. Al! rates age.adjusted b
white male population 1960. Graphs present rates for noncigarette VS. cigarette smokers at entry wdh srmultaneous control o { IO-year age groups to the U.S.
                                                                  blood pressure and serum cho-

lesterol level. For this latter analysis, the following cutting points were used:
     (a) Cigarette smoking   S -any use at entry
     (b) Serum cholesterol C -   250 mg./dl.
     (c) Diastolic blood pressure H -   90 mm. Hg.
SOURCE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88).

C OR H S+C    C+H    C+H
ONLY OR S-j-H         +s

41      90      12      42


FIGURE l-National Cooperative Pooling Project; smoking status at entry and IO-year age-adjusted rates per 1,000 men for
first major coronary event (includes nonfatal MI, fatal MI, and sudden death due to CHD) and any coronary death. U.S.
  white males age 30-59 at entry. All rates age-adjusted by 10 year age groups to the U.S. white male population 1960.
Graphs present rates for noncigarette vs. cigarette smokers at entry with simultaneous control of blood pressure and serum
cholesterol level. For this latter analysis, the following cutting points were used:
    (a) Cigarette smoking-S-any use at entry
    (b) Serum cholesterol-C-2250 mg./dl.
    (c) Diastolic blood pressure-H-290 mm. Hg.

SOURCE: Inter-Society Commission for Heart Disease Resources. National Cooperative Pooling Project Data (88).

TABLE l.-Szcldden death and acute mortality with first major coronary episodes

Author. year.   Number and
country,      type of
reference    population

Data
collection

Event

Number
of
events

Proportion per
1,000 events
(as calculated on
the basis of age-
adjusted rates)

Comment

Pooling
Project.
American
Heart
Association,
1970.
U.S.A.
(88).

7,594 males    Medical exam-  All first major coronary
males 30-59    ination and   episodes, nonfatal and fatal.     501        l,ooo.o
yem-s of age   follow-up.   Sudden death (death
at entry.               within 3 hours of onset
Ten-year               of acute illness).           123         245.5
experience.             All acute deaths with
                   first episodes.             166         329.3

Data from the Pooling Project, Council on
Epidemiology. American Heart Association.
a national cooperative project for pooling
data from the Albany civil servant. Chicago
Peoples Gas Co., Chicago Western Electric
Co., Framingham Community, Los Angela
civil servant, Minneapolis-St. Paul business
men,  and other prospective epidemiologic
studies of adult cardiovascular disease in the
United States.

SOURCE: Inter-Society Commission for Heart Disease Resources (88).
Representative references include: (54. 9L, 14.9. 177) and others listed as
6a-6k in Inter-Society Commission for Heart Disease Resources report.


,-









I -







I

CIGARETTE SMOKING:

0 NONE

>l PKG./DAY               196'

123

NONE             ANY ONE

12
9.7

PREDISPOSING FACTORS (CHOLESTEROL 3250, HYPERTENSION, DIABETES)
`SIGNIFICANTLY DIFFERENT FROM "NONSMOKER" P<.O5

FIGURE 2-Risk of coronary heart disease (12 years) according to cigarette
smoking habit and presence of "predisposing factors" (men 30-59 at entry).
Framingham Heart Study.

SOURCE: Kannel, W. B., et al. (94).

Numerous epidemiological studies have indicated that cigarette
smokers have increased mortality ratios for CHD ; that is, cigarette
smokers show significantly increased death rates compared with
nonsmokers (table 2). The risk incurred by cigarette smoking in-
creases with increasing dosage and, as measured by mortality
ratios, is more marked for men in the younger age groups, under
age 60, although the absolute increment in death rates experienced
by smokers over that of nonsmokers continues to increase with
increasing age. Table 2 lists the mortality ratios found in the major
studies. Certain of these studies, including those at Framingham,
Massachusetts, the He&h Insurance Plan of New York City
(HIP), and at Tecumseh, Michigan, have analyzed morbidity as
well as mortality from CHD and have indicated that the risk of
developing fatal and nonfatal CHD is greater among cigarette
smokers than among nonsmokers (tables 3 and 4). Conflicting
evidence has been published concerning the relationship of ciga-
rette smoking and the incidence of angina pectoris. While some

24


I







I


)



I


,



I



0







2


1



0

Cl#lrcttcr -A
No SC-M -6

    1.0   1.2   354
1.0           5Zk
mL
66    31   483

175 85   1112

Clsarttbr -A
M./JK<12.9 -6

20

    15       96
       1.3   122
10   279
fld
       153
391   469   289
978

Cigarettes -A
$3. BP 130+ -B

Cigarettes -A
Height <66 -B

1.5

2.4
i5i
140

2.0
9s
124

Cigarettes -A

Parent dead -9

1.6

No sport -A
Ht.,  %<lt.9 -B

No sport-A
$3. BP 130+ -B

No sport -A
Hctght<BB -B

No sport -A

Parent dead -6

Sp. BP 130+ -B

A- A+ A- Ai    A- A+ A- At
B- B- B+ 9+    B- B- B+ Bt

Ht.l'%<l2.9 -A
Height <68 --B

Ht./w<l2.9 -A
Pwcnt dead -Et

Sp. BP 130+ -A

Height<68 -B        3

Sys. BP 130+ -A

Parent dead -B

       2.5
     73
        69
1.4

3

3

Height<68 -A

Parent dead --B

1.6

A- A+ A- A+

B- E- S+ B+

      PRESENCE (+) OR ABSENCE (-) OF CHARACTERISTICS (1 w B)
Top numberr in ban me CHD decedents wth paired cambinatlonr of charactsrirtlcr: bottom numben,
control subjects with comblnrtiont.
`1.8= 354 x 175
   66   524

FIGURE S-Estimated coronary heart disease death ratios in a 17-51 year
follow-up, and frequencies of paired combinations of six high-risk charac-
teristics in college, for all ages at death.
SOURCE: Paffenbarger, R. S., et al. (1.46).

25


TABLE Z.-Coronary heart disease morta&

                 (Actual number of deaths

                       [SM = Smokers

Author,
Year,
countrY, NutymFo;nd     Data
reference  oooulation    collection

Hammond  187,783     Question-      3%    5,297  NS .l.OO  (709)
and      white males   naire and        All smokers .1.`70 (3361) 2(p<o'oo1)
Horn,     in 9 states    follow-up              <lO .1.29  (192)
1958,      50-69 years   of death                lo-20 .1.89 (864)
U.S.A.    of Bge.      certificate.               W-40 .2.20  (604)
(77. 78).                               >40 .2.41  (118)

Follow- Number
(Yeuaprs,   of
     deaths

Cigarettes/day

Doyle     2,282 males.   Detailed      10       93  NS .l.OO   (20)
et al.,     FLW"-      medical               All smoken .2.40   (73)
1964.     ingham. examina-              <20 . . .2.00   (17)
U.S.A.     30-62 years   tio" and                20 .1.70   (20)
(54).     of age.     follow-up.     8         >20 .3.50   (36)
       1,913 males.
         Albany,
         39-55 years
         of age.

Doll and    Approxi-    Question-     10     1.376  NS  _. .l.OO
Hill.      "lately      "sire and              All smokers .1.35
1964,      41.000      follow-up                1-14 .1.29
Great     male British  of death                 15-24 ,127
Britain    physicians.   certificate.              >25 .1.43
(50).

Strobe1    3,749 male   Question-      s      162  NS  . . .l.OO
and Gsell   Swiss phy-   naire and
1965      sicians.     follow-UP               l-20  .1.48
Switzer-            of death               >20 . .1.16
land               certificate.
(180).

Best,      Approxi-    Question-      6     2.000  NS  _. .l.OO
1966      mately     naire and              All smokers .1.60 (1380)
Canada    78.000      follow-up           -  <lO . .1.55  (337)
(24).     male Cana-   of death               lo-20 .1.58  (766)
         dian       certificate.              >20 .1.78  (277)
         veterans.

Kahn
1966
U.S.A.
(98).

U.S. male
veterans
2,265,674
person
y-2al.S.

Hirayama. 265,118
1967.      Japanese
Japan     adults over
(84).     age 40.

Question-
naire and
follow-up
of death
certificate.

        -
Trained in-
terviewers
and follow-
up of death
certificate.

s/r,   10,890  NS  .l.OO (2997)
         Allsmokers .1.74 (4150)
         l-9  1.39  (439)
         10-20  .I.78 (2102)
         21-39  . 1.84 (1292)
         >39 2.00  (266)

1      91   NS .l.OO  (17)
         l-24 __ ., .1.13  (69)
         >25  .l.OO   (5)

Kannel    5,127 males   Medical ex-    12       52  NS _. .l.OO (27)
et al..     and females   amination             SM>20 ,220 125) 3 (P<O.O5)

1968,      age 30-5s.    and
U.S.A.             follow-up.
(94).

1 Unless otherwise specified, disparities between the total number of deaths
and the sum of the individual smoking categories are due to the exclusion
of either occasional, miscellaneous, mixed, or ex-smokers.

26


ratios related to smoking-prospective studies

shown in parentheses ) 1

NS = Nonsmokers]

Cigars, pipes

Age variation               Commenta

Cigars               so-54    55-59    60-64    65-89
NS. .l.OO       NS . 1.00  (90)  1.00 (142)  1.00 (204) 1.00 (273)
SM. .1.28 (420)    Allsmokers  .I.93 (765)  1.85 (962)  1.66 (921)  1.41 (713)
Pipes        :I0 . ..1.38  (35)  1.38  (50)  1.17  (49)  1.27  (58)
NS. .l.OO       lo-20 .2.00 (213) 2.04 (258)  1.91 (235)  1.68 (158)
SM. .1.03 (312)    >20 . ..2.51 (203) 2.47 (199)  1.92 (129)  1.56  (73)

Data apply
only to males
aged 40-4s
and free
of CHD at
entry. NS
include pipe.
cigar and
ex-smokers.

       35-44    45-64    65-84
NS     .l.OO     1.00     1.00
1-14      .3.73     1.40     1.71
16-24      .4.45     1.73     1.27
225      .1.36     1.92     1.68

NS. .l.OO
SM. .1.45

Cigars               30-49    50-69    70 and over
NS. .I.OO       NS  .l.OO     1.00     1.00
SM. .0.98  (16)   <lO  ..__. . ..0.97  (18) 1.56 (220)  1.71 (99)
Pipes        lo-20   .1.45 (115)  1.67 (567)  1.29 (94)
NS. .l.oo       >20  ,. _. __ .1.85  (65)  1.76 (184)  1.73 (28)
SM. .0.96  (95)

cigar.4
NS. .l.oo
34. .1.04 (628)
Pipes
NS. .l.oo
SM. .1.08 (386)

Prefimin-
arY report.

' "P" values specified only for those provided by authors.

27


TABLE 2.-Coronary heart disease mortality ratios

(Actual number of deaths
    [SM = Smokers

Author,
Year.    Number and
country,    b-P.2 of
reference   population

       Follow- Number
Data           of           Cigarettes/day
collection  (Y%)  deaths

Hammond   358,534
and      male!3
Gartinkel,   445,875
1969,      females
U.S.A.     age 40-7s
(76).     at entry.

Question-
naire and
follow-up
of death
certificate.

                              -
6    14.819          Make Females
         NS  .l.OO   1.00
         1-9  .1.27   0.84
         lo-19  .1.60   1.22
         20-30  .1.73   1.52
         >40  .1.77   0.61

Paffenbar-  50,000 male   Baseline     17-51    1,146   NS  . . . . .l.OO
ger and    former     interview        matched  3M  .1.50 (385) (p<o.ol)
Wing     students.    and ~XBIII-         with
1969               ination and        2,292
U.S.A.             follow-up        controls
(146)              by death
                  certificate.

Paffenbar-  3,263 male   Initial multi- 16     201   NSand<ZO 1.00 (137)
ger et al.,   longshore-   phssie          SM >20 .2.08 (154) (p<o'ol'
1970,     men 35-64    screening
U.S.A.     years of     and follow-
(144).     age.       up of death
                  certificate.

Taylor     2,571 male    Interviews      5      46   NS  .l.OO   (4)
et al..     railroad     and regulxr             :20 .1.97   (20)
1970,      employees    follow-up               >20 .3.60   (22)
U.S.A.     40-59 years exam-
(183).    of age at    ination.
         entry.

Weir and   68,153 Csli-   Question-     5-8     1,718  NS .l.OO
Dunn.     fornia male   mire and              All smokers .1.60
1970,      workers     follow-up              210 .1.39
U.S.A.     35-64 years   of death               520  1.67
(205).     of age at    certificate,              >30 ,, .I.74
         entry.

Pooling    7,427 white   Medical ex-    10      239  NS .l.OO  (27)
Project,    nK+les      amination              <lO . ..1.66  (34)
American   30-59 years   and                   20 .l.lO  (86)
Heart     of age at    follow-up.              >20 ._.. .3.00 (68)
Associa-    entry.
GO".
1970,
U.S.A.
(88).

1 Unless otherwise specified, disparities between the total number of deaths
and the sum of the individual smoking categories are due to the exclusion
of either occasional. miscellaneous, mixed. or a-smokers.

28


wleted to snloliing-l)rospective stztdies (cont.)

shown in parentheses) '

NS = Nonsmokers]

Cigars, pipes                   Age variation                Comments

        41/-&Y
NS  .1.00
1-u .l.fiO
IO-19 ,.  .2.69
?ll-30  3.76
>40 5.51

NS   1.00
l-9 .1.31
10-19 .2.08
20-30 .3.62
>40 .t3.31

   Ml&d
51,-59    60-CY
1.00     1.00
1.59     1.48
2.13     1.X2
2.40     1.91
2.79     1.79
  FtVTll7lCS
1.00     1.00
1.15     1.04
2.37     1.79
2.68     2.08
3.73     t2.02

70-79
1.00
1.14
1.41
1.49
1.47

tBased on
5-S deaths.

1.00
0.76
0.9R
1.27

        JO-44    45-5:    55-69
NS .l.OO     1.00     1.00
        (P<O.Ol )

SM 1.80 (88) 1.60 (163) 1.20 (134)

Data apply
only to
those free
of CHD
at entrY.

       35-44
NS  ....... .l.OO
ZlO  ....... .4.22
k20  ....... .6.14
530  ....... .8.57
>40  ....... .7.93
All  ........ .6.24

45-54    55-64    65-69
1.00     1.00     1.00
2.05     1.41     1.17
3.17     1.64     1.26
3.33     1.66     1.36
3.15     1.42     1.42
2.95     1.56     1.24

NS includes
pipes and
cigars.
SM includes
ex-smokem

1.00 (27)
1.20 (24)

29


TABLE 3.-Sztdden death frow coronary
        (Mortality ratios--actual number

Author
year,
country,
reference

Numbw and
type of
population

Data       Follow-up
collection       years

   -

Number
of
deaths

Pooling
Project,
American Heart
Association,
1970. U.S.A.
(b-8).

7,427 white
males 30-5s
years of age
at entry.

Medical
examination
and
follow-up.

10        145

TABLE 4.-Coronary heart disease

             (Risk ratios--actual number of CHD

              [SM = Smokers   NS = Nonsmokers


PRCISPECTIVE STUDIES

Author,
Year.    Number and     Data     Follow-   Number of
country.     type of      collection     UP     incidents
reference   population              years

Cigarettes/day

Detailed       10   243muo-    NS .l.OO (52)

medical
examina-
tion and
follow-u*.

cardial    All smokers ._ .2.36(191)
infarc-     <20  _. _. .1.98 (44)
tions and   20 . . . . . . . . . . ...2.05 (64)
CHD      >20  3.04 (83)
deaths.

Doyle     2.282 males
et al.,    Framingham,
1964,     3C-62years
U.S.A.    of age.
(5.4).   1,913 males
        Albany,
        39-55years
        of sge.

stam1er   1,329 CHD-
et al.,    free male
1966,     employees of
U.S.A.    Peoples Gas
(177).    CompanY
        4b-59 years
        of age.

Epstein,   6,565 male
1967,     and female
U.S.A.    residents
(61).    of Tecumseh.
        Mich.

Interview       4   46 CHD     NS ._ ._ .l.oo (27
and exarnin-
ation with          <lO cigarettes. 2,S2 (6)
                       < 5 cigars.... I
clinic                     < 5 pipes.....
follow-up.                  10-19 cigarettes.3.67 (8)

>20 cigarettes. 3,83 (2S)
> 5 cigars. ._ I
> 5 pipes.....

-

Initial
medical
examinit-
tion and
repeat
follow-up
examinlr-
tions.

4    96 male.                M&8
     92 fern&              40-59
     CHD in-    NS .__... . ..l.OO  (1)
     &ding    EX ._. ._..... 6.53 (10)
     deaths,    Cigarettes  .5.!20 (36)
     angina, and            Females
     myocardial  NS _. .l.OO (21)
     infarctions. EX .0.89  (3)
             Cigarettes  .1.02 (14)

`Unless otherwise specified. disparities between the total number of mani-
festations and the sum of the individual smoking categories are due to the
exclusion of either occasional, miscellaneous. mixed, or ex-smokers.

30


/,! r11.f rlisease related to smoking

,,f deaths shown in parentheses)

Cigarettes/day         Cigars, pipes          Comment

St.v.cr smoked  ........... 1.00 (15)    1.00 (15)   See table 1 for description of
10  .................. .1.90 (23)    1.36 (13)     Pooling Project.
20  ................... .1.90 (50)
>2"   ................ ..3.3 6 (44)

,uorbidity as related to smoking

manifestations shown in parentheses) 1

EX = Exsmokersl

PROSPECTIVE STUDIES-Continued

Pipes, cigars          Age variation           CO"l"X"ts

Data include
CHD deaths,
only on males
40-49 years of
age and free of
CHD on entry.
NS includes
pipes, cigars.
and ex-smokers.

NS includes
a-smokers.
Includez all
CHD.

Males-Continued
  60 and over
   1.00 (7)     SM
   1.27(11)
  1.96 (23)     SM
FCmales-Continued
  1.00(47)
   1.31 (5)
   0.42 (2)

M&8
  40-59
.1.80(Z)
60 and Gwer
. ...0.86(6)

Reexamination
of patients
was spread
over l$$-byear
period, but
data are re-
ported in
terms of
4-year inci-
dence rates.
Actual number
of CHD inei-
dents derived
from data on
incidence and
total in smok-
ing class.

31


TABLE 4.-Coronary heart disease
   (Risk ratios--actual number of CHD
  [SM I Smokers   NS = Nonsmokers

PROljPECTIVE STUDIES

Author,
year.
country,

Number and
type of

reference   population

Jenkins,   3,182 males
et al.,     39-59 years
1968,     of age at
U.S.A.    entry.
(90).

Data
collectioll

Initial
medical
examina..
tion and
follow-up
by repeat
examina-
tions.

Follow-
UP
Years

4:;

Number of
incidents

Cigarettes/day

104 myo-     NS . . . . . . . . . . ..I.00 (21)

eardial     EX  ........... .2.47 (15)
infarctions. Current  ...... .2.78 (68)
        O-15:day  ..... .t1.39 (45)
        >I6 .......... ..3.0 6 (59)

K@.ollel,   5,127 males
et al.,     and females
1968.     30-59 YQB1`S
U.S.A.    of age.
(9.5).

Medical       12
examina,.ion
and follow-
UP.

Shapiro   110,000 male    Baseline med-    3
et al.,     and female     ical inter-
1969.     eor0llee5      view and
U.S.A.    of Health      examination
(172).    Insurance     and regular
        Plan of       follow-up.
        Greater
        New York
        (HIP)
        35-64 y-ears
       of age.

228 myo-       Myocardial Infarction
cardial                M&8
infarc-    NS ._ .l.OO (21)
tions.     All SM 1.51(153)
380CHD.   Heavy SM .I.85 (59)
           Risk of CHD (mwrall)
                    M&8

NS ._ .l.OO (61)
l-10 .1.34 (25)
11-20 .1.80 (90)
>20  .2.41 (76)

                       -
Total                 Moles
unspeci-    NS  .l.OO
fied.      All current .2.14
          cigarettes ( p<O.Ol)
         <20 .1.50{
         >20 . . . . . . . . ...2.33/
         >40  . . . . ...6.36

Keys
1970
Yugo-
slavia
Finland
Italy
Nether-
lands
GrWCe
(Ill).

9,186 males     Interviewr.     5      65 deaths.   NS, EX
in 5 coun-      and rcgu-          80 lnYocar-    (SM <20) .1.00(305)
tries 40-59     lar follow-           dial in-   All current
gears of       up examina-          farctions.   020)  .1.31(103)
age at entry.    tion by           128 angina
            local              pectoris.
           physicians.         155 other

t428 total.

`Unless otherwise specified, disparities between the total number of mani-
festations and the sum of the individual smoking categories are due to the
exclusion of either occasional, miscellaneous, mixed. or es-smokers.

32


morbidity as related to smoking (cont.)
manifestations shown in parentheses)'
EX = Ex-smokersl

PROSPECTIVE STUDIES-Continued

Pipes, cigars

Age variation           Comments

~P<O.OOl)

(P<O.OOl)
(comparing
CA5 and 16+)

      99-49    so-59
NS. .l.OO (4)  1.00 (6)
Current 4X3(35) 2.26(33)

tIneludes non-
smokers and
ex-smokers.
NS includes
former pipe
and cigar
smokers.

Myocardial infarction-Continued
FeWlde8
1.00(31)
1.71(23)

Risk of CHD (overall)-Continued
FWl&*
1.00(89)
0.86(U)
1.29(x3)
0.93 (3)

Females        Males onlg
  1.00         NS .l.OO
  2.00         SM .1.82
(Y>O.Ol)          (P<O.Ol)

1.77

5.92

   Ml&8         F&?WW&3    Total myo-
ss-44 1.541 55-64  35-44  45-54 55-64  cardial in-
1.00  1.00  1.00    1.00   1.00  1.00   far&ion in-
2.47  3.06  1.69    2.25   2.67  1.80   eludes those
0.52  2.15  1.32~
3.04  3.29  1.81j   1.25   2.31  1.66   dead within
                         48 hours.
10.09  7.69  5.30   20.25  11.79  4.07
                        NS include
                         a-smokers.

Includes all
CHD incidence
including EKG
diagnoses.
Covers all
countries in-
vestigated
except U.S.A.
t Difference
between total
CHD and the
sum of smoking
group8 is due
to difference
in figures
presented by
authors.

33


TABLE 4.-Coronary heart disease

              (Risk ratios--actual "umber of CHD
             [SM = Smokers   NS = Nonsmokers

PROSPECTIVE STUDIES

Author,
Yea=,
country.
reference

Taylor.
et al.
1970
U.S.A.
(183).

N"t;m yo;"d
population

2.571 male
railroad
employees
40-59
years of
age at
entry.

Data     Follow-
collection     UP
        Y.X3*S

Interviews     5
and regu-
lar follow-
up examina-
tion.

Number of
incidents

Cigarettes/day

46 deaths.   NS and EX .l.OO (62)
33 myocar-  All current .1.77(150)
dial-in-
farctions.

78 angina
pectoris.
55 other
  CHD.

212 total.

Dayton   422 ma1eU.S.    Interviews    "p to 8 27 sudden    <lO  .l.OO (25)
et al.,    veterans par-   and routine         deaths.    IO-20 . . . . . . . ...1.04 (22)
1970,    tieipating as    follow-up         44 definite   >20 . . . . . . . . ...1.17 (13)
U.S.A.    controls in s    examina-          myoeardial
(4% 49).  clinical trial of   tions.            infarctions.
       a diet high in
        unsatu-
        rated fat.

DU""    13,148 male     Data only    up to 14 Total un-
et al..    patients in     on new           specified.
1970     periodic health   incidents
U.S.A.    examination    extracted
(55).    clinics.       from
                   clinic
                   records.

Pooling   7.427 white     Medical       10      538
Project,    males 30-59     examinai ion        Includes     Never smoked .l.OO (53)
American   years of       and follow-         fatal and   <lO  .1.65 (72)
Heart     age at entry.    UP.              nonfatal     20  . . . . . . . . . ..2.08(205)
Association                           myoeardial  >20 ,328 (154)
1910.                                infarction
U.S.A.                               and sudden
(88).                               death.

Paul et al.. 1,989 western   Screening
1963.     Electric Co. exami"a:ion                         COTOWQ/
U.S.A.    male workers   and                               cases (87)
(148).    participating    history.                   NS   23
        in a prospec-                           l-7    2
        tive study                             8-12      9
       for 455 years.                          13-17      6
                                          18-22   41
                                         23-27      3
                                          >28    9

`Unless otherwise specified, disparities between the total number of mani-
festations and the sum of the individtial smoking categories are due to the
exclusion of either occasional, miscellaneous, mixed, or ex-smokers.

34


morbidity as ,related to smoking (cont.)
manifestations shown in parentheses)!
EX = Ex-smokersl

PROSPECTIVE STUDIES-Continued

Pipes, cigars          Age variation           Comments

All CHD
including EKG
diagnoses.

No data on
NSasa
separate
group.

     30-39    40-49    50-59   t Includes
tLow                       NS, EX, and
SM 1.00(25) 1.00(125) 1.00(157)   <20 cigarettes/
%High                       day.
SM 2.17(10) 0.90 (31) 1.41 (53) $>2OCiga-
                       rettes/day.
                        Includes all
                         CHD but
                         ezcludes
                         death.
                        No data avail-
                       able comparing
                         smokers and
                         nonsmokers.

1.00(53)
1.25(64)

GmmmaTy
  controls
  (1,786)
    33
    7
    11
    12
    30
    2
    6
(P<O.O05)

88 developed
clinical

coronary
disease,
47 angina
pectoris,
28 myocardial
infarction,
13 deaths CHD.

35


studies have shown an increased risk of this manifestation among
smokers, others have not (see table 5).

From these longitudinal st.udies, it has become increasingly clear
that cigarette smoking is one of several risk factors for CHD and
that it exerts both an independent effect and an efiect in conjunc-
tion with the other risk factors. The basic concept may be ex-
pressed as follows: The more risk factors a given individual has,
the greater the chance of his developing CHD. The importance of
the constellation of coronary risk factors which include cigarette
smoking, high blood pressure, and high serum cholesterol in pre-
dicting the risk for CHD is illustrated in figures 1 through 3. Other
risk factors are included in certain of these figures and are dis-
cussed below.

Knowledge of the effects of cigarette smoke on the cardiovascu-
lar system has developed concurrently with the knowledge derived
from the epidemiological studies. Nicotine, as well as cigarette
smoke, has been shown to increase heart rate, stroke volume, and
blood pressure, all most probably secondary to the promotion of
catecholamine release from t.he adrenal gland and other chromaffin
tissue. This release of catecholamines is also considered to be the
cause of the rise in serum free fatty acids observed upon the in-
halation of cigarette smoke. Studies concerning the effect of nico-
tine on cardiac rhythm have also suggested that smoking might
contribute to sudden death from ventricular fibrillation.
In addition, research efforts have also been directed toward the
effects of smoking on blood clotting and thrombosis; since many
cases of sudden death and myocardial infarction are associated
with thrombosis in a diseased coronary artery branch. Cigarette
smoking may be associated with increased platelet aggregation in
vitro and thus might play a role in the development of such throm-
bi or platelet plugs in viva.

Other mechanisms have been investigated. Because cigarette
smoking has been shown in some studies to be related to the prev-
alence of angina pectoris as well as to the incidence of myocardial
infarction, it has been suggested that smoking enhances the de-
velopment of atherosclerotic lesions. Autopsy and experimental
studies have shown that cigarette smoking plays a role in athero-
genesis. The administration of nicotine has been observed to in-
crease the severity of cholesterol-induced atherosclerotic lesions in
experimental animals. Attention is presently being given to carbon
monoxide, which is present in cigarette smoke in such concentra-
tions as to cause carboxyhemoglobin concentrations in the blood
of smokers as high as 10 percent. Based on research in animals,
it is reasonable to conclude that the atherosclerotic process may be
enhanced, in part, by the relative arterial hypoxemia in cigarette

36


A "LIIV, ,
year,
country.

Number and
type of

Data    Follow-up Number
collection year8     of

Cigarettes/day

Cip*l3
and PiPcs

Age variation

comments

reference   Population                   incidents
DOYk    2,282 males.     Detailed      10      Rl    NS  ._ ,_ _. .__. .1.00(30)                                    NS include ex-
et al..    Framingham,    medical                 All  . . .1.09(61)                                      smokers and
1964,    30-62 years     examination             <20 .1.17(16)                                     Pipe and
U.S.A.   of age.        and                    20 .0.99(18)                                      cigal
(54).   1.913 males,      follow-up.     x          >20 . . .1.15(18)                                      smokers.
       Albany.
       39-55 years
       of age,

Jenkins  3,182 males     Initial medical   4%     29    NS  ..l.OO (9)                                     NS include
et al.,    wed 39-69     examination              All current                                                former pipe
1968,    at entru.      and follow-                cigarettes  . ..1.44(16)                                      and ciaal
U.S.A.              up by repeat              >16  ,. ,, ._ ..1.63(14)                                      smokers.
(90).               examina-
                  tion.

KanlWl   5,127 males     Medical       12     107
et al..    and females    examination              NS  
U.S.A.   years of age     and follow-              Heavy SM. .ZO
(94).    30-59         "P.                    cigarette3 . .

NS  
Cigarette SM

  M&8
 1.00 (16)

.2.04(17)
FWLflkl
.1.00(68)
.0.65(16)

   Shapiro  110.000 male    Baseline       3      Total          Males Females    M&8                     M&8      t CP<O.Ol)
    et al..    and female     medical           Unspee- NS  .l.OO    1.00    NS. .l.OO               35-44 45-54 55-64 T(p<0.05)
    1969,    enrollees of     interview           ified  current               SM. .$1.71    NS  .._...... ..l.OO   1 .oo   1.00  NS include
    U.S.A.   New York City   and examina.              cigarettes t1.91    1.20            Current cigawttes .3.40   1.57   2.06    ex-smokers.
    (172).   HIP 35-64      tion and                :40  .1.51]                 <40 ,,,...,,,. ..2.35   1.40   1.54
           years of age.    regular                 >40 . . . . . . ..4.85$   1.20             >40  ., .10.15   2.m   6.15
                      follow-up.                                                           FlWUdC8
                                                                      NS  .l.OO   1.00   1.00
                                                                     Current cigarettes .1.56   1.67   0.97
                                                                      <40  .1,67   1.63   1.04
":                                                                      >40  -   4.12 -

    t Unless otherwise specified, disparities between the total number of     to the exclusion of either occasional, miscellaneous. mixed, or ex-smokers.
   manifestations and the sum of the individual smoking categories are due


smokers caused by the increased carboxyhemoglobin level.

With respect to the acute event of myocardial infarction, atten-
tion has been focused on the role of nicotine. Nicotine stimulates
the myocardium, increasing its oxygen demand. Other experiments
have demonstrated that in the face of diminished coronary flow
(due to partial occlusion from severe atherosclerosis in man or to
partial mechanical obstruction in the animal), nicotine does not
lead to an increase in coronary blood flow as seen in the normal
individual. These effects exaggerate the oxygen deficit when the
supply of oxygen has already been decreased by the presence of
carboxyhemoglobin. Thus, a marked imbalance between oxygen
demand (which has been increased) and oxygen supply (which
has been decreased) is created by the inhalation of CO and nico-
tine. This imbalance may contribute to acute coronary insufficiency
and myocardial infarction.

EPIDEMIO.LOGICAL STUDIES

Numerous epidemiological studies, both retrospective. and pros-
pective, have been carried out in various countries in order to iden-
tify the risk factors associated with the development of coronary
heart disease (CHD) . Many of these studies have included smok-
ing as one of the variables investigated. Tables 2 to 4 present the
major findings.

CORONARY HEART DISEASE MORTALITY

Table 2 lists the various prospective studies concerning the rela-
tion of CHD mortality and smoking. These studies demonstrate the
dose-related effect of cigarette smoking on the risk of developing
CHD. For example, the Dorn Study of U.S. Veterans as reported
by Kahn (93) reveals progressively increasing mortality ratios,
from 1.39 for those smoking 1 to 9 cigarettes per day to 2.00 for
those smoking more than 39 cigarettes per day, Although the data
are not detailed in the accompanying tables, several of these stud-
ies have also shown that increased rates of CHD mortality are
associated with increased cigarette dosage, as measured by the
degree of inhalation and the age at which smoking began. Although
not as striking, the data for females reveal the same trends.

In most studies, the smokers' increased risk of dying from CHD
appears to be limited mainly' to those who smoke cigarettes. Some
studies that have investigated other forms of smoking have shown
much smaller increases in risk for pipe and cigar smokers when
compared to nonsmokers. However, the recent study by Shapiro,
et al. (172) of a large population enrolled in the Health Insurance
Plan (HIP) of New York City showed a significantly increased

38


risk for the development of myocardial infarction and rapidly fatal
myocardial infarction for a group consisting of both pipe and cigar
smokers.

Table 3 details the findings of the American Heart Association
Pooling Project on sudden death. The Pooling Project, a national
cooperative project of the AHA Council on Epidemiology, is de-
scribed in table 1 (88). Cigarette smokers in the 30 to 59 year age
group incurred a risk of sudden death from CHD substantially
greater than that of nonsmokers. Pipe and cigar smokers were
observed to show a risk slightly greater than that of nonsmokers
(table 3).

The relative risk of CHD mortality is greatest among cigarette
smokers (as well as among those with other risk factors) in the
younger age groups and decreases among the elderly. In table 2,
Hammond and Horn found that for those smoking more than one
pack per day, the risk is 2.51 in the 50 to 54 year age group and
1.56 in the 65 to 69 year age group. Although the relative risk for
CHD among smokers decreases in the older age groups, the actual
number of excess deaths among smokers continues to climb
since the differences in death rates between smokers and nonsmok-
ers continue to rise.

CORONARY HEART DISEASE MORBIDITY

Tables 4 and 5 list the prospective studies carried on in a num-
ber of countries to identify the risk of CHD morbidity incurred
by smoking. Here, CHD morbidity includes myocardial infarction
as well as angina pectoris. Certain studies, notably those of Doyle,
et al. (54)) Keys, et al. (111) , and Taylor, et al. (183) include a
number of CHD deaths in their data that could not be separated
out using the information provided in their respective reports.
As noted in the discussion on CHD mortality, the CHD risk ratio
increases significantly as the number of cigarettes smoked per day
increases. Similarly, the HIP data of Shapiro, et al. (I?`?) show
that the elevated morbidity ratios declined with increasing age as
has been shown for mortality ratios.

A recent monograph edited by Keys (111) dealt with the 5-year
CHD incidence in males age 40 to 59 from seven countries. As
summarized in table 4, cigarette smoking was found to be associ-
ated with an increased incidence of CHD in the U.S. railroad
worker population, 2,571 individuals (183). None of the differences
in ratio between smokers and nonsmokers was statistically signifi-
cant for the 13 other population samples which varied in size from
505 to 982 individuals, from the five other countries. (Smoking was
not considered in the two Japanese populations.) When more cases

39


become available to provide greater statistical stability to the rates,
this. intercultural comparison should prove illuminating.

The results of those studies which have separated out angina
pectoris as a manifestation of CHD are presented in table 5. Doyle,
et al. (54) found no relationship between this manifestation of
CHD and cigarette smoking. Both Jenkins, et al. (90) and Kannel,
et al. (94) observed increased risk ratios among male cigarette
smokers although these differences were not statistically signifi-
cant. More recently, Shapiro, et al. (172) found a significantly
increased risk for angina among their male cigarette smokers as
well as increasing risk ratios with increasing dosage among both
males and females, particularly in the younger age groups. A
variety of hypothetical explanations have been advanced to account
for this seeming contradiction. Among these are the relatively
small number of cases, the difficulties associated with the definitive
diagnosis of the syndrome, and differences in the methods of clas-
sifying those cases of angina pectoris which are followed by myo-
cardial infarction.

RETROSPECTIVE STUDIES

Table A 6 presents data from the various retrospective studies
of CHD prevalence. Most of these are case-control studies and show
an increased percentage of smokers among those with clinical CHD
when compared with a selected control population, usually without
apparent CHD. Two of these studies include data on mortality.

THE INTERACTION OF CIGARETTE SMOKING AND
     OTHER CHD RISK FACTORS

The preceding section has reviewed the epidemiologic evidence
which supports the judgment that cigarette smoking is a signifi-
cant risk factor in the development of CHD. Many of the studies
discussed above have identified a number of biochemical, physio-
logical, and environmental factors, other than cigarette smoking,
which also increase the risk of developing CHD. These risk factors
include elevated serum lipids (particularly serum cholesterol) and
hypertension, which, with cigarette smoking, are considered to be
of greatest importance. Other factors are obesity, physical inac-
tivity, elevated resting heart rate, diabetes (as well as asympto-
matic hyperglycemia), electrocardiographic abnormalities, and a
positive family history of premature CHD (88).

A number of these studies have also found that these factors,
when present in the same individual, exert a combined effect on
the risk of developing CHD. Figures 1 through 3 depict this inter-
action of risk factors. As may be noted in Figures 1 and 2, the

40


additional factor of smoking greatly increases the risk of develop-
ing CHD among those people already at high risk because of other
factors.

Furthermore, these studies have shown that the effect of smok-
ing on the risk of developing CHD is statistically independent of
the other risk factors. That is, when the effect of the other factors
is statistically controlled, smoking continues to exert a significant
effect on increasing the risk of developing and dying from CHD.

Smoking and. Serum Lipids

The interaction of smoking and serum lipid levels in the develop-
ment of CHD should be considered in the light of information con-
cerning the relationship of smoking to serum lipid levels. Table A7
presents studies which deal with the association between smoking
and lipids, notably cholesterol, triglycerides, and lipoproteins (con-
cerned with lipid transport). While some of the studies have indi-
cated that smokers show increased serum levels of these lipid con-
stituents, others have not. The populations investigated and the
methods of the various studies show significant variation. This lack
of comparability makes interpretation of the findings difficult.

It is clear, however, that in the presence of high serum choles-
terol, cigarette smoking increases the risk of CHD. Figure 4 de-
picts the data from the Chicago Peoples Gas, Light and Coke Com-
pany study which show that smoking greatly increases the risk of
CHD in each of the cholesterol groups.

Smoking and Hypertension

Some epidemiological studies have indicated that smokers tend
to have lower mean systolic and/or diastolic blood pressures than
nonsmokers, while other studies have not found this to be the case
(table A8). Reid, et al. (155)) in a study of 1,300 British and
American postal workers, found that the blood pressure difference
between the smoking and nonsmoking groups was eliminated after
controlling for body weight.

Tables 9 through 11, derived from the study by Borhani, et al.
(27)) demonstrate the following associations : That for both smok-
ers and nonsmokers, the risk of dying from CHD increases with
increasing diastolic or systolic pressure, and that the risk of mor-
tality from CHD is higher among smokers than among nonsmokers
in each blood pressure group. Cigarette smoking, therefore, has
been shown to elevate CHD mortality independently both of its
effect on blood pressure and of the effect of hypertension on CHD.

Smoking and Physical Inactivity
The recent study by Shapiro, et al. (272) of more than 110,000

41


TABLE 9.-Death rates from coronary heart disease, by systolic blood pressure:
           ILWU mortality study 1951-61

(Coronary heart disease rts classified under IX Code 420)

Smokers

Nonsmokers

              Systolic blood   Person-years    Death    Person-years   Death
   Age group      pleSSure in 1961  of observation    rate'    of observation   rate'

45-54  (130 1,877        27       2.413        8
                 139-149 2,066        34       2,912        l?
                  150-169 740        95       1,177        26
                  >170 369       109        672        45
55-64 . . <130 1,067        84       1.560        26
                  13&-149 1,380        94       2,401       525
                  150-169 647        93       1,558        46
                   >170 524       210       1,117       126

1 Rate per 10,000 person-years of observation.
2 p<O.O25.
3 p<O.Ol
SOURCE: Borhani, N. 0.. et al. (27).

TABLE lO.-Death rates from coronary heart disease, by diastolic
    blood pressure: ILWU mortality study, 1951-61
     (Coronary heart disease as classified under IX Code 420)

Smokers           Nonsmokers

Age group

Diastolic blood  Person-years
pressure in 1951 of observation

Death
rate'

Person-years
of observation

Death
rate'

45-54

55-64

     <@I
    80- 89
    go- 99
    >lOO

     <SO
    80- 89
    9cb 99
    >lOO

1,527        26       1,700        6
2,115        47       2,947        17
961        52       1,507        33
448        89       1.020        20
1.059       104       1.447       221
1,521        59       2,704        15
669       194       1,521       346
369       163        954       147

1 Rate per 10,000 person-years of observation.
2 p<o.o5.
3 P<O.Ol.
SOURCE: Borhani. N. 0.. et al. (27).

TABLE Il.-Death rates from coronary heart disease, among hypertensives and
      nonhypertensires: ILWU mortality study, 1951-61
           (Coronary heart disease as classified under ISC Code 420)

Smokers

Nonsmokers

            Blood pressure      Person-years    Death    Person-years    Death
   Age group      StatUS 1        of observation    rate 2   of observation    rate 2

45-54 _.  Hypertensives    883       125       1.871       "32
          Nonhypertensives   4,169        29       5,303        13
55-64 _.  Hypertensives    931       150       2.219        95
          Nonhypertensives   2,637        93       4.407       3 16

1 According to the WHO recommendation, the following cut-off points are recommended for the
definition of hypertension:

(1) Normotension-below 140190 mm. Hg.
(2) Hypertension-systolic blood pressure 160 mm. Hg. or over, or diastolic 95 mm. Hg. or
over, or both.

(3) Borderline-the residual category. In this analysis. Normotensives and Borderlines were
combined and the population ~8s gr<,npcd into `Nonhypertensives' (1 and 3) and `Hypertensive?
(2).

1 Rate per 10,000 person-years of observation.
3 P<O.Ol.
SOURCE: Borhani, N. O., et al. (7).

42


INCIDENCE
PER 1,000 MEN

80

80-                                          -

70-                                           -

     ALL       NON     NON     NON    SMOKERS   SMOKERS   SMOKERS
            SMOKERS SMOKCRS SMOKERS
            <225    225-274    275 +    <2?5    225-274   275+

CHD     46'         1       5       2       9       16       12
N     1329'       187      235      71      336      317      151
AGE     49         49      50       51      50      49       50

SYSTOLIC
PRESSURE   134

133      136      139      131      133      135

1.19     1.21      1.18     1.12     1.15      1.17

FIGURE 4-Relationship between smoking status and serum cholesterol level
at initial examination, and incidence of clinical coronary heart disease in
men originally age 40-59, free of definite CHD, and followed subsequently
without systematic intervention, Peoples Gas Light and Coke Company
study, 1958-1962.  *For 34 men, no information on smoking status was
available; one of these men had a coronary episode.
SOURCE: Stamler, J., et al. (177).

persons participating in the Health Insurance Plan of New York
City has further identified and elaborated upon the interaction of
the various risk factors. Physical inactivity, both in employment
and during leisure time, was found to be a potent risk factor for
the development of CHD, particularly for rapidly fatal myocardial
infarction.

Figure 5 depicts the effect which smoking exerts on CHD in
combination with physical inactivity. Of note, also, is the observa-
tion that within each activity grouping, smoking greatly increases
the risk of myocardial infarction, thus exerting an independent
effect.

Smoking and Obesity

The analysis by Truett, et al. (190) of the risk factor data from
the Framingham study revealed that weight, while a significant
risk factor, had a considerably smaller effect on CHD incidence
than serum cholesterol, cigarette smoking, or elevated blood pres-
sure. The results concerning the interaction of smoking and obesity
from the San Francisco longshoremen study are shown in table 12.

43


11.0

10.0

9.0

  8.0
%
5  7.0
x
b
s  6.0
E
;  5.0
;
P
g  4.0
K

3.0



2.0



1.0

  Not
dead
within
48 hrs.

Dead
within
48 hrs.

10.89

5.72
(57)

5.18
(46)

Least
active

5.78

4.48
(166)

1.30
(41)

More
active

NONCIGARETTE SMOKERS
  6.33

3.76
(47)

3.03

Least
active

r

MOE
active

Note: Both for cigarette smokers and noncigarette smokers differences between rates among the least
and more active men are statistically sign,ficant for total MI and rapldly fatal MIS at the 0.99 confidence
level. For other MIS the difference is statistically significant only for the nonsmokers (confidence level 0.95).

FIGURE 5-Average annual incidence of first myocardial infarction among men
in relation to overall physical activity class and smoking habits (age-ad-
justed rates per 1,000)
(Actual number of deaths or myocardial infarctions are represented by
figures in parentheses)
SOURCE: Shapiro, S., et al. (-172).

This table shows that cigarette smokers in the 55 to 64 year age
group were observed to have higher CHD death rates than non-
smokers in all weight categories. Similar findings, although not in
all weight groups, were observed for the 45 to 54 year age group.
Cigarette smoking is thus shown to he a CHD risk factor indepen-
dent of body weight.

44


TABLE 12.-Death rates from coronary heart disease avlong men without
abnormalities related to cardiopulmonary diseases by weight classification
        in 1951: ILWU mortality study, 1951-61
        (Coronary heart disease as classified under ISC Code 420)

Age group

Weight
classification 1

       Smokers

Person-years    Death
of observation    rate z

     Nonsmokers

Person-years    Death
of observation    rate ?

45-54  Not overweight , .    388        21        219        I
         Slightly overweight    962        2R       1,096        0
          Moderately overweight   1,383        28       1.574        28
          Markedly overweight    1,055        22       1,197        0
55-64  Not overweight    222        43        247        0
         Slightly overweight    536        15        605        36
          Moderately overweight    855       109       1,320       311
       Markedly overweigh<    735        X8       1,653       312

`The four classes are defined in the text.
2 Rate per 10,000 person-years of observation
3 P<O.Ol.
SOURCE: Borhani, N. O., et al. (271.

TABLE 13.-Death rates from coronary heart disease, by electrocardiographic
      findings in 1951: ILWU mortality study, 1951-61
         (Coronary heart disease as classified under ISC Code 420)

Smokers

Nonsmokers

Age group

Electrocardiographic
findings in 1951

          Death               Death
Person-years          Person-years
of observation   rate 1   of observation    rate 1

46-54 .........  Abnormal ..............    586       102       1,020        39
          Normal  ...............   4,454        38       6.134        15
55-64 .........  Abnormal  .............    583       2.23       1,149        96
          Normal  ...............   3,031        86       6,479       231

1 Rate per 10,000 person-years of observation.
2 P<O.O05.
~O~RCS: Borhani. N. 0.. et al. (87).

TABLE 14.-1958 status with respect to heart rate, blood pressure, cigarette
smoking, and lo-year mortality rates, by cause (1,829 men originally age
     40-59 and free of definite coronary heart disease)
         Peoples Gas Co. Study, 1958-68

1953 risk factor status

Heart
rate

NH
Ii
NH
H
NH
Ii
NH
Ii

All

Cigarette
smoking

  NH
  NH
  NH
  NH
   H
   H
   H
   H

-
     NUl"bCY
     of men

NH        378
NH         45
H        107
H         30
NH        491
NH        127
H        103
H         44

Ten-year mortality. 1968-68

  All causes        CHD
Number   Rate   Number Rate

?1,325

20    '48.3      5    ' 12.0
6    114.9      3    70.3
14    118.3      6    51.8
8    221.6      3    62.0
57    116.8     19    38.9
22    171.1      8    62.3
22    190.4      6    66.0
13    266.4      6    94.9

162    113.2     55     39.4

' Rate per thousand. All =ates are age-adjusted by 5-year age groups to U.S. male population,
1960. High (H) : Heart rate 280; 210 cigarettes per day; diastolic blood pressure 290 mm. Hg.
NH is not high, i.e., below specified cutting points.
`No smoking data available on 4 of the 1,329 me".
~UWE: Berkson. D. M., et al. (43).

45


TABLE 15.-The effect of the cessation of cigarette smoking
         on the incidence of CHD

(Incidence ratios--actual number of cases or events are shown in parentheses)

Author.
Yea=.
count.rY,                   Kesults                      COltllll~ntS
reference

Jenkins

                                           -
                         Ail myocardial
       All CHD events           infarction
Neversmoked  . ..t. 1.00(30)      l.OO(Zl)

et al.,
1968
U.S.A.
(90).

current
cigarette smokers . 2.36(84)
Former
cigarette smokers .2.15 (19 1

            Death from CHD

2.78(68)

2.47(15)

Hammond

    Smoked I-i9 cigarettes/day      Smoked >20
                         cigarettes/day
NWer

and Garfinkel,
1969.
U.S.A.
(76).

smoked regularly . . ,_ .1.00(1,841)
current
cigarette smokers 1.90(1,063)
stopped <l year .1.62  (29)
l-4  .1.22  (57)
5-9  . ,126   (55)
l&19  .0.96   (52)
>20  1. .1.08   (70)
AI1 ex-cigarette smokers .1.16 (263)

l.OO(1.841)   Male data only

2.55 (2.822)
1.61 (62)
1.51 (154)
1.16 (135)
1.25 (133)
1.06  (80)
1.28 (564)

Shapiro
et al..
1969.
U.S.A.
(17s).

Pooling Project,
American Heart
Association
1970.
U.S.A.
(88).

  Total definite myocardial infarction
Never smoked  .................................... .l.OO
Current cigarette smokers  ........................ .1.87
Stopped 25 years ................................. .0.76

        AU CHD deaths
Never smoked ., .1.00(2'7)
>`h pack/day  .1.65(34)
1 pack/day ._ ,... _. .1.70(86)
>l pack/day  .3.00(68)
Ex-smokers  .0.80(19)

First major
coronary event
1.00 (53)   See table 4
1.65 (72)    for description
2.08(205)    of Pooling
3.28(X4)    Project.
1.25 (51)

TABLE 16.-Annual probability of death from coronary heart disease,
in current and discontinued smokers, by age, maximum amount smoked,
            and age started smoking

   Age started smoking
15-W                20-24

Maximum daiLv
number of &a-
r&es smoked

Current
smokers

Discontinued           Discontinued
for five or     Current    for five or
more years    smokers   more years
(Probability X10 s,

56-64   . . ,_.   . .  0           601                 501       -
             lo-20           798        568        811        551
             21-39           969        766        872        698

65-74 1 . .   0          1.015                1.015

lc-20      1;501       1,169     11478       1,213
21-39          1,710       1,334       1,573       1,098

1 For age group 65-14. probabilities for discontinued smokers are for 10 or more years of dis-
continuance since data for the 5-9 year discontinuance group we not given.
SOURCE: Cornfield. J., Mitchell. S. (4.5).
Based on data derived from Kahn, H. A. (93).

46


Smoking and Electrocardiographic Abnormalities

Electrocardiographic (ECG) abnormalities such as T-wave and
ST-segment changes as well as a number of arrhythmias are use-
ful indicators of CHD and may, therefore, be predictive of the
development of clinically overt CHD manifestations. The results
summarized in table IS, from the prospective study by Borhani,
et al. (27), reflect the joint predictive value of smoking and ECG
abnormalities on the death rate from CHD.

Smoking and Heart Rate

Recent analysis by Berkson, et al. (23) of the data derived from
the Chicago Peoples Gas, Light and Coke Company study of
middle-aged men revealed that resting heart rates of 80 or greater
were associated with an increase in the risk of death from CHD.
These authors found that this association was independent of the
other major coronary risk factors.

Table 14 presents i`ne interaction between smoking, blood pres-
sure, and elevated heart rate in increasing the risk of CHD mor-
tality. This study shows that cigarette smoking increases CHD risk
in the presence of elevated heart rate as well as in its absence.

THE EFFECT OF CESSATION OF CIGARETTE
SMOKING ON CORONARY HEART DISEASE

A number of epidemiological studies have been concerned with
the CHD incidence and mortality among ex-cigarette smokers as
Compared with current smokers (51, 76, 88, 90, 93, 172). These
studies are listed in table 15. Table 16 presents the data derived by
Cornfield and Mitchell (45) from the Dorn Study of U.S. Veterans
(93).

Ex-cigarette smokers show a reduced risk of both myocardial
infarction and death from CHD relative to that of continuing ciga-
rette smokers. The Pooling Project (88) and the Western Collab-
orative Study Group (192) which adjusted for the other risk fac-
tors of elevated serum cholesterol and blood pressure observed this
relationship. Hammond and Garfinkel (76) noted that cessation of
smoking is accompanied by a relative decrease in risk of death
from CHD within 1 year after stopping.

This decreased risk of CHD among ex-smokers further strength-
ens the relationship between smoking and CHD. It must be noted,
however, that the group of ex-smokers is composed of individuals
who have stopped smoking for a variety of reasons. Those who
stop because of ,ill health and the presence of symptoms are gen-
erally at high risk and can bias the group results in one direction;

47


those healthy persons who stop as part of a general concern about
their health and may adopt a number of self-protective health prac-
tices are generally at low risk and can bias the group results in the
other direction. Therefore, ex-smokers as a group are not fully
representative of the entire population of smokers and may have
limited value in predicting what would happen if large numbers of
cigarette smokers stopped smoking purely for self-protection. Cer-
tain incidence studies, such as the Pooling Project (88)) were initi-
ated with only clinically healthy individuals. The data from such
studies, as well as those from the British physicians study, contain
ex-smoker data less influenced by these biases.

Fletcher and Horn (63) have recently presented data derived
from the British physicians study of Doll and Hill. Over the past
lo-15 years, cigarette smoking rates among British physicians
have declined significantly in comparison with those of the general
British population. The information presented by these authors
concerning all cardiovascular diseases showed that for individuals
between the ages of 35 and 64, the age-adjusted death rate for CHD
declined by 6 percent among physicians and rose by 10 percent
among the male population of England and Wales during the
period from 1953-57 to 1961-65.

THE CONSTITUTIONAL HYPOTHESIS

The effect of smoking on the incidence of CHD has been found
to be independent of the influence of the other CHD risk factors.
When such risk factors as high serum cholesterol (177)) increased
blood pressure (27)) elevated resting heart rate (23)) physical in-
activity (2 72), obesity (27)) and electrocardiographic abnormali-
ties (27) have been controlled, cigarette smokers still show higher
rates of CHD than nonsmokers.

It has been suggested by some (39, 170) that the relationship
between cigarette smoking and CHD has a constitutional basis.
That is people with certain constitutional make-ups are more likely
to develop CHD, and the same people are more likely to smoke
cigarettes. This hypothesis maintains that the relationship between
cigarette smoking and CHD is thus largely fortuitous and that the
significant relationships are between the genetic make-up of the
individual and CHD and between the genetic make-up of the indi-
vidual and his becoming a cigarette smoker. Two sets of epidemio-
logic data bear on this hypothesis.

It has been maintained that people with a certain temperament
are more likely to smoke and also more likely to develop CHD.
These characteristics have been demonstrated for those with the

48


of 1.6, while those in the second group were found to have one of
approximately 1.1. The authors concluded that this difference be-
tween the two groups provides better support for the importance
of constitutional factors as against the importance of cigarette
smoking in the development of angina pectoris.

A similar study was done using the responses of 4,379 U.S. Vet-
eran twin pairs (approximately 60 percent of estimated available
total) who completed the mailed questionnaires (38). Cederlof, et
al. found a significantly increased prevalence of chest pain and
"angina pectoris" among smokers when Group A was analyzed.
Analysis of the smoking-discordant matched twin pairs (Group B)
revealed no association between smoking and cardiovascular symp-
toms among the monozygotic pairs. The dizygotic pair data did
show a slight association. The authors concluded that this lack of
association among the monozygotes and its presence among the
dizygotes and unmatched pairs strengthens the case for a constitu.
tional hypothesis.

A major problem in ,these studies is the small number of cases
available and, therefore, the statistical instability of the results,
In the Swedish study, among the 274 monozygotes, only 19 smokers
and 16 nonsmokers were classified as having angina pectoris while
among the 733 dizygotes, 25 smokers and 25 nonsmokers were so
classified. In neither group was the difference between the prev-
alence ratios found in the Group A analysis and that in the Group
B analysis of statistical significance. Analysis of the data on women
shows a similar lack of significance.

Similar criticisms may be made of the study which utilized the
U.S. Veteran Twin Registry. In that study, the authors observed
that the difference in the prevalence of angina pectoris between
the low-cigarette-exposure and high-cigarette-exposure dizygotic
groups was not present among the monozygotes. The authors ques-
tioned whether the excess morbidity associated with cigarette
smoking found in the dizygotic group was causal as it was not pos-
sible to reproduce the association when studying monozygotic
smoking-discordant twin pairs. As noted above, the numbers in this
study are also small so that the differences in rates do not approach
statistical significance.

Tibblin (288) has questioned the value of a mailed questionnaire
to diagnose heart disease. The questionnaire as originally con-
structed was used and validated by interview technique alone (157,
158). Cederlof, et al. (~$0) conducted a study to determine the
validity of this questionnaire as a mailed instrument by personally
interviewing and examining 170 of the twin pairs who had replied.
Of the eight males who were diagnosed as having "angina pectoris"
by the questionnaire. four were found to be free of symptoms on

50


clinical examination, while among 204 responding negatively, two
were found to have angina by clinical criteria. None of the 11
women who were diagnosed as positive by questionnaire was found
to be clinically affected, and of the 136 reporting as negative, three
had symptoms of angina pectoris.

Other major difficulties associated with these studies include the
problems of using prevalence data in the investigation of a disease
(CHD) from which a significant number of those affected die
shortly after the onset of symptoms, the inclusion of ex-smokers
in the smoking population, and the low numbers of heavy cigarette
smokers in the Swedish population.

In general, the problems of using twin registries to study the
etiology of cardiovascular disease with mortality and morbidity
ratios in the neighborhood of 2 to 1 are much more difficult than
in studying the etiology of bronchopulmonary disease in which the
relationships are of the order of magnitude of 4 to 1.

More recently, Friberg, et al. (69) reported on mortality data
from the Swedish Twin Registry. The authors suggested that part
of the increased mortality observed among smokers when com-
pared with nonsmokers was not due to smoking per se but to fac-
tors associated with smoking. The very small numbers of total
deaths presently available (47 deaths among 706 dizygotic pairs
and 13 deaths among 246 monozygotic pairs) do not provide a sta-
tistically stable base for deriving any conclusions at the present
time.

Hauge, et al. (81) have recently reported on the influence of
smoking on the morbidity and mortality observed in the Danish
Twin Register. Among 762 monozygotic and same-sexed dizygotic
twin pairs, angina pectoris was found to be significantly more fre-
quent in those cotwins with a higher consumption of tobacco than
in those with a lower or no consumption. A similar tendency was
observed for myocardial infarctions but was not of statistical
significance.

Seltzer, who has been a proponent of the constitutional hypothe-
sis, in a recent review of some of the experimental, clinical, and
pathological data relating smoking and CHD, concluded that the
evidence from these areas has not "reasonably substantiated" the
"hypothesis" of the acute effect of cigarette smoking on the coro-
nary circulation, nor has the chronic effect of cigarette smoking on
the cardiovascular system been shown to be a "clear" and con-
sistent one (170). His views are contrary to those of most re-
searchers in this field,

Although the data from the twin studies are inconclusive with
regard to a role for genetic factors in heart disease, it would be
surprising if genetic factors did not play such a role. It is open to

51


question whether findings from twin studies can be used to distin-
guish between the hypothesis that genetic factors govern the level
of host susceptibility or resistance to the effects of an exogenous
influence such as cigarette smoking and the hypothesis that genetic
factors "cause" both heart disease and smoking.

AUTOPSY STUDIES RELATING SMOKING,

ATHEROSCLEROSIS, AND SUDDEN CHD DEATH

A number of researchers have investigated the cigarette smoking
habits and the cardiovascular pathology of those individuals dying
suddenly from CHD and of large populations of individuals with
and without histories of overt CHD.

Spain and Bradess (175) recently analyzed the smoking habits
of 189 individuals who died suddenly and unexpectedly, apparently
from the first acute clinical episodes of CHD. The authors noted a
close correlation of a history of cigarette smoking with this type
of sudden death and also with shorter survival times following the
acute episode. This association was strongest in those persons
under 50 years of age.

The authors also observed that those surviving very short pe-
riods of time showed a notable lack of intracoronary artery throm-
bi at autopsy and that the frequency of thrombi present increased
with increasing survival time. They suggested that thrombi found
at autopsy may be the result rather than the cause of certain
instances of myocardial infarction, particularly of lesions showing
subendocardial necrosis. This finding is of significance in the study
of the effect of smoking on myocardial metabolism and oxygen
supply and demand rather than on thrombus or platelet plug
formation.

While the autopsy study of Spain and Bradess (175) concerned
sudden death among smokers, other autopsy studies from various
countries have been directed towards the relationship of cigarette
smoking to the presence of atherosclerotic disease in the aorta and
coronary arteries. These are concerned with the long-term effects
which smoking has on the cardiovascular system and are sum-
marized in table 19. The studies of Auerbach, et al. (12)) Avtan-
dilov, et al. (13)) Sackett, et al. (165)) and Strong; et al. (182)
found that aortic and coronary atherosclerosis were more common
and more severe among smokers than among nonsmokers. Auerbach,
et al. (12) noted that this relationship persisted when the cases
were matched for both age and cause of death or when the follow-
ing cases were excluded; men with a history of diabetes; men who
had died of any type of heart disease; and men whose hearts
weighed 400 grams or more. Sackett, et al. (165) found that the

52


(Figures in parentheses are number ut individuals in that smoking category)'
             [SM = smokers    NS = nonsmokers]

Author.
Year.
countru,
reference

Autopsy
population

Data
collection

Cigarettes per dny

Conclusions            Comments

Wilens

989 consecutive

Routine clinical

Severity of am-tic sclerosis

The authors conclude that  Smoking data unavailable

and Plair,  male autopsies    records of             Above average    Average  Below average  in 60 percent of cases. the   for 120 cases.
1962,     at New York     previous and NS  . . .  9.9(161)       60.2       29.8    degree of sclerosis at    Each aorta specimen given
U.S.A.    City VA        present      <20  . 19.1(162)       63.2       17.8     autopsy was e"mme"-     an "atherosclerotic age"
(214).     hospitals.       admissions.   20-30 .,,,..... 26.4(288)       62.5       11.1     surate with age of patient.  by comparison with a
                             >30  .t25.1(199)       61.3      t13.6     regardless of smoking     standard. If "athero-
                                                              habits. In the remaining   sclerotic age" was found
                                                              40 percent there is evi-    to be 10 years more than
                                                                dence that cigarette     real age. the aorta was
                                                              smoking may be ass"-     said to show above-
                                                                  ciated with an above-     average sclerosis.
                                                             average degree of aortic   tp<O.OOl comparing 9.9
                                                                  sclerosis.             with 25.1 nnd 29.8 with
                                                                           13.fi.

Auerbach.  1,372 autopsies    Interview with  Degree of coronary artem utherosclerosie (overaU age- The authors conclude that
et al.,     of male        next of kin.     adjusted reavlta)                        the percentage of men
1965,     patients in                       No athero-                     with an advanced degree of
U.S.A.    Orange, New                       *clero8is    Slight   Moderate Advanced coronary atherosclerosis
(12).     Jersey. VA                NS  . . . . . . . . 5.6 (69)     67.3     21.8     15.3    was higher among ciga-
        hospital for                current                                rette smokers than among
        whom smoking              cigarette                              nonsmokers and that the
        habit data were             <20 .2.6(139)     30.9     31.3     29.2    percentage increased
        available and                20-39  .0.8(299)     19.7     42.1     31.4    with amount of cigarette
        who did not               >40 . . . . ..0.6(144)     18.1     36.4     45.9    smoking. This relation-
        have overt CHD                                               ship persisted even
        at death.                                                      when cases were matched
                                                               for age and cause of
                                                                   death.

     1 unless otherwise specified, disparities between the total number of in-
    dividuals and the sum of the individual smoking categories are due to the
cn
w    exclusion of either occasional. miscellaneous, mixed, or ex-smokers.


TABLE 19.-Autopsy studies of atherosclerosis (cont.)

                   (figures in parentheses are number of individuals in that smoking category)'
                                       [SM = smokers    NS = nonsmokers]

!E    Author,
     year,      Autopsy         Data
    cou"trY.     population      collection              Cigarettes per day                  Conclusions            CO"l"l.3h
    reference
   Avtandilov. 269 male and     Not specified,   Comparative size of mean area of alhe+osclerotic ~&WUI The author concludes that  Causes of death 96-athero-
    1966,     141 female      hut there were:   in inner coat of eosmkwu a+teriea.              the worst changes were    sclerotic, lO%accidental.
     RUSB~IS    autopsies.       130 SM and         Right ~o?`onaw artery     Left cosona~~ artery  found in the left and      POP-various diseases.
     (16).                 220 NS.             SM        NS        SM     NS    right coronary arteries   tT-test for sjgnificance
                                30-3s Q5.5(30)     1.3(32)      t6.3     2.2    with less severe changes    of difference between
                                40-4s t23.6 (34)    11.6(27)     t1e.e     4.4    in circumflex artery       means is significant
                                60-59 ..t36.3(39)     14.8(39)      127.9     9.9    and aorta.            at P<O.O6 level.
                                 60-69 . . t31.9(32)    23.8 (36)      t26.6    22.5
                                  7&79 41.9(13)     31.7(36)       26.1    36.8

   Sack&t.   393 total,       Patient     The results concerning aortic atherosclerosis are given in The authors conclude that
                        interview on    form of figure presentation of ridit-analysis.        *"mng males, ". . . *

et al..     including 433
1968,     male and 450
U.S.A.    female (white)
(165).    patients autop-
       sied at Roswell
       Park Memorial
       Hospital.
      Represents all
       deaths 1956-1964
       exclusive of 81
       male pipe and
       cigar smokers
       and 66 incom-
       plete files.

admission.

large increase in the
severity of an-tic athero-
sclerosis occurred in the
groups using either ciga-
rettes only or both ciga-
rettes and alcohol as
compared with the grouD
using neither cigarettes
nor alcohol. there
was only a small and
statistically insignificant
difference between the
group using cigarettes
alone and the group using
both cigarettes and alcohol,

. . . " The severity of
sortie atherosclerosis
increased with increasing
use of cigarettes, when
measured both by jn-
tensity and by duration
of smoking.

`Unless otherwise SDmjfied, disparities between the total number of in-
dividumk and the aum oi the individual smokinp categories are due to the
crrlll-ion or r`thcr -c..ionr,. m,.r-ueneous. m,x`.d. Or rx-amokera.


TABLE lD.-Autopsy studies of atherosclerosis (cont.)

(Figures in parentheses are number of individuals in that smoking category)'
            [SM = smokers    NS = "o"B",OkerB]

Author.
ye*=,
cou"trY.

Autopsy
population

Data
collection

Cigarettes per day

Comme"tB

reference

Vie1

et al..
1968
Chile
(100).

1,150 males
and 290
females who
died violentIy
in 1961-1964.
Smoking infor-
mation avail-
able only on
666 "W&IeB.

Interview with   The results concerning internal fibrous streaks and fatty The authors conclude that:

relatives.

plaques in the left anterior descending coronary artery  "No relationship he-
are reported in graphic form only. An examination of tween atherosclerotic
this data indicates that the moderate and heavy smokers  lesions and the "se of
appeared to show consistently higher percentages of tobacco was discernible."
diseased areas than the nonsmokers. But the statement
of the authors implies that these differences were not
statistically significant when subjected to an analysis
of variance.

strong    741 males 2&     Interview with   tlasal group (ezcluding diseases related to smoking DT
et al..     64 years of      next of kin     CHD). Mean percentage of eo+ona+y artery internal
1969     age autopsied     within 8 weeks   surface involved with raised lesions (number of cases).
U.S.A.    betwen 1963-     of death.                            White
(182).    1966 at Charity                             25-84   85-14   4544   55-61
        Hospital in                NS  . . . . . . . . 2 (5)  lS(14)  20 (6)  30(11)
        New Orleans.              l-24 cigarettes/day _.._ S(14) 17(10) 26(16) 39 (7)
                             >25 cigarettes/day .12 (9) 31(14) 26(25) 39(20)

The authors conclude that:  This report concerns o"Iy
"Atherosclerotic in-      ages 26-64.
volvement of aorta and    No data on statistical
coronary arteries is       significance provided.
greatest in heavy
smokers and least in
nonsmokers."

NS  .

      Negro
4(14)   3 (3) 16(11) 17(14)

l-24 cigarettes/day 3(39) ll(31) 14(30) 28(22)
>25 cigarettes/day .17(10) 14(17) 29(12) 16(11)

`Unless Otherwise specified, disparities between the total number of in-
dividuals and the sum of the individual smoking categories are due to the
exclusion of either occasional. miscellaneous, mixed, or a-smokers.


severity of aortic atherosclerosis, as measured both by intensity
and duration, increased with increasing use of cigarettes and that
this dose-relationship persisted when the patients were matched
for the consumption of alcohol. On the other hand, Viel, et al.
(ZOO) concluded from their study of accidental deaths in Chile
that "no relationship between atherosclerotic lesions and the use
of tobacco was discernible." Examination of the data (provided in
graph form only) indicates that heavy smokers showed consistently
higher percentages of diseased areas than nonsmokers, but appar-
ently these differences were not statistically significant when sub-
jected to an analysis of variance.

Thus, in addition to the acute effects which smoking exerts on
cardiovascular physiology, cigarette smoking is associated with a
significant increase in atherosclerosis.

EXPERIMENTAL STUDIES CONCERNING THE
RELATIONSHIP OF CORONARY HEART DISEASE
            AND SMOKING

Several areas of interest in cardiovascular pathophysiology have
been investigated in the search for the mechanisms by which ciga-
rette smoking contributes to cardiovascular disease, particularly
coronary artery disease. Previous Public Health Service Reviews
(191, 192, 193, 198) have described in detail and commented on
the results of experiments by many teams of researchers.

Central to the discussion which follows is a concept of cardiac
physiology which provides a framework for analysis and under-
standing of the varied research. That concept concerns the dynamic
balance between myocardial oxygen need and supply.

CARDIOVASCULAR EFFECTS OF CIGARETTE SMOKE AND NICOTINE

The inhalation of tobacco smoke or the parenteral administra-
tion of nicotine has been found by many researchers to be asso-
ciated with a number of specific acute cardiovascular responses.
These responses have been observed in human as well as animal
subjects, including increased heart rate, blood pressure, cardiac
output, stroke volume, velocity of contraction, myocardial contrac-
tile force, myocardial oxygen consumption, arrhythmia formation,
and electrocardiographic or ballistocardiographic changes (tables
A20 to A22). The effect of these responses on coronary blood flow
will be discussed in a following section.

That the acute effects observed following the inhalation of ciga-
rette smoke are due primarily to the nicotine present in the smoke
may be seen in the results of a number of experiments. In humans,
Irving and Yamamota (89) and Von Ahn (202) duplicated the

56


effects of cigarette smoking by the administration of nicotine intra-
venously. Similar results in animals were noted by Kien and
Sherrod (112).

The mechanism by which cigarette smoke and hence nicotine in-
duces these changes has been of interest to numerous investigators.
Nicotine has long been known as a stimulator of both sympathetic
and parasympathetic ganglia. Research has centered, therefore, on
the function of catecholamines, mainly epinephrine and norepi-
nephrine, as mediators, of these responses. Using isolated rabbit
atria1 myocardium, Burn and Rand (35) noted that the prior ad-
ministration of reserpine to the perfusate blocked the increased
rate and amplitude of contraction seen following the administra-
tion of nicotine. West, et al. (208) showed that the in vivo cardiac
stimulating effect of nicotine was blocked by tetraethylammonium
chloride. Leaders and Long (12.5)) Romero and Talesnik (156),
and, more recently, Ross and Blesa (160) have all demonstrated
this blockade in animals using agents such as pentolinium, hexa-
methonium, guanethidine, and reserpine.

More direct evidence of the catecholamine-releasing effect of
nicotine has been found by Watts (203) and Westfall, et al. (209,
210, ,211) (table A22). Among animal subjects, nicotine adminis-
tration and the inhalation of the smoke of standard cigarettes
caused significant increases in peripheral arterial epinephrine lev-
els, while cornsilk cigarette smoke inhalation evoked no such
change. In humans, cigarette smoking was found to be associated
with a significant increase in urinary epinephrine excretion.

The source of these nicotine-released catecholamines, particu-
larly those which mediate the immediate and local cardiac re-
sponses to intracoronary injections of nicotine, is felt to be the
myocardial chromaffin tissue (35, 160). The more widespread
effects are most probably mediated by hormones released from the
adrenal gland.

According to recent research of Saphir and Rapaport, catechol-
amine release may not be the sole mediator of these responses
(166). These investigators reported that intra-arterial injections
of nicotine into the mesenteric circulation of cats were followed
within 1 to 2 seconds by enhanced myocardial performance, in-
creased left ventricular systolic pressure, and increased systemic
resistance. Sectioning of the mesenteric afferent nerves led to a
diminished response. The authors concluded that the cardiovascu-
lar response to nicotine may also be neurogenic in nature. Nadeau
and James (112) injected nicotine directly into the sinus node
artery of dogs and noted an initial bradycardia, due probably to
direct vagal stimulation, followed by tachycardia, due probably to
catecholamine release.

57


That the presence of nicotine may predispose the myocardium,
particularly a hypoxic or previously damaged myocardium, to ar-
rhythmia formation is suggested by the research of Balazs, et al.
(16), Bellet, et al. (21)) and Greenspan, et al. (74). Balazs pro-
duced myocardial lesions in dogs either by pretreatment with iso-
proterenol or ligation of the anterior descending coronary artery.
It was found that while normal animals did not develop arrhy-
thmias upon challenge with small doses of intravenous nicotine,
the animals with damaged myocardiums responded with increased
arrhythmia formation shortly after their spontaneous arrhythmias
had ceased. More recently, Bellet, et al. (20) studied the effect of
cigarette smoke inhalation on the ventricular fibrillation threshold
in anesthetized dogs. They observed a statistically significant de-
crease in the threshold following smoke inhalation. Greenspan, et
al. (74), using isolated dog right ventricular myocardium, ob-
served that nicotine perfusion increased the automaticity of the
Purkinje fibers system and decreased the conduction velocity. The
authors consider that these two nicotine-induced effects probably
predispose the myocardium to the initiation of arrhythmias.

CORONARY BLOODFLOW

Studies in animals and humans (tables A20, A21) have noted
alterations in coronary blood flow (CBF) following the inhalation
of cigarette smoke or the administration of nicotine. Generally,
exposure of the normal subject to these agents results in an in-
crease in flow. Kien and Sherrod (112)) Leb, et al. (126)) Ross
and Blesa (160)) Travell, et al. (189)) and West et al. (208))
working with normal animals, and Bargeron, et al. (27)) working
with normal humans, have demonstrated this response. As with
the other cardiac responses to the administration of nicotine, it has
been found that the augmentation in CBF is most probably due to
the release of catecholamines. Using instantaneous coronary arte-
rial flow measurement in dogs, Ross and Blesa (160) were able to
reproduce the effects of intracoronary nicotine with the adminis-
tration of epinephrine and were able to block the response to nico-
tine by pretreatment with pentolinium.

The direct action of catecholamines on the coronary arteries
may not, however, be solely responsible for the increase in CBF
seen with cigarette smoking and intravenous nicotine administra-
tion. It appears that the catecholamine-induced increase in myo-
cardial work and therefore in myocardial oxygen requirement is a
prerequisite for the increase in CBF. Kien and Sherrod (112))
using tracheostomized dogs, found that without blood pressure and
cardiac output changes CBF did not increase following either the
inhalation of cigarette smoke or the administration of nicotine

58


intravenously, although CBF did increase following such changes.
Recent work by Leb, et al. (126) has utilized Rb@ as a radioactive
marker in order to distinguish capillary flow from overall total
CBF. The authors consider that this capillary flow represents that
portion of CBF which is effectively involved in nutrient and
oxygen exchange. The researchers observed that the increase in
effective coronary flow was almost proportional to the nicotine-
induced increase in myocardial oxygen consumption. However, the
increase in total coronary flow which may be due to increased
myocardial shunting was far in excess. Thus, the increased work
evoked by the effect of nicotine on the myocardium may induce
local hormonal release in the myocardium and coronary vessels
leading to coronary vasodilatation and increased CBF.

This homeostatic response to increased work appears to be fully
effective only in the subjects with normal coronary arteries. Bellet,
et al. (22)) working with normal dogs and dogs that had ,under-
gone either coronary artery ligation or artificially-induced coro-
nary artery narrowing, noted that the increase in CBF following
the intravenous administration of nicotine was significantly less
among the animals with coronary insufficiency. Work with humans
discussed above has revealed a similar increase in CBF with smok-
ing in normals. Regan, et al. (154) studied seven men with EKG-
proven myocardial infarction and observed that cigarette smoke
evoked slight increases in myocardial oxygen consumption in only
three patients and caused no overall rise in CBF. A number of
other investigators have noted that patients with overt CHD do
not respond to the stimulus of cigarette smoke as readily as do
normals (67, 149, 164).

Thus, patients with compromised coronary circulation may not
he capable of increasing their coronary flow in the face of the in-
creased demands of a myocardium stimulated by nicotine or ciga-
rette smoke. In the normal state, the heart responds to increased
oxygen demands by increasing coronary flow because even at rest
oxygen extraction is almost at a maximal level. Any further in-
crease in extraction may produce coronary sinus PO, values incom-
patible with proper tissue oxygenation.

CARDIOVASCULAR EFFECTS OF CARBON MONOXIDE

Carbon monoxide (CO) is a colorless and odorless gas, 10~
levels of which have significant effects on human and animal physi-
ology which are just now beginning to be understood. According
to Wynder and Hoffmann (215)) it is present in cigarette smoke
in concentrations of approximately 2.9 to 5.1 percent. The concen-
tration of CO in smoke is subject to many factors, among them

59


the type of tobacco and the porosity of cigarette paper. The con.
centration of CO in smoke has been found to increase significantly
toward the last puffs of the cigarette.

According to Chevalier, et al. (41), a concentration of approxi.
mately 4 percent CO in cigarette smoke will produce alveolar levels
of around 0.04 percent which, equilibrated with hemoglobin, result
in carboxyhemoglobin (COHb) concentrations of from 3 to 10 per.
cent. A number of investigators have compared COHb levels in
smokers and nonsmokers. Goldsmith and Landaw (73) reported
the analysis of expired air samples obtained from 3,311 longshore.
men. Using a regression analysis, they calculated the concentra.
tion of COHb and found that nonsmokers showed levels of 1.2 per.
cent while those smoking over 2 packs per day had levels of 6.8
percent and that smokers of lesser amounts had intermediak
levels. Occupational exposure accounted for the mean nonsmokers'
level being over 1.0 percent, an unusual finding in comparison with
other studies. Kjeldsen (113) interviewed and obtained blood
samples from 934 CHD-free smokers and nonsmokers. The mean
COHb level for 196 nonsmokers was 0.4 percent while all inhaling
smokers had a mean level of 7.3 percent. All 416 cigarette smokers,
regardless of inhalation or amount smoked, showed a mean level
of 4.0 percent.

Carbon monoxide has many varied and significant effects on
human physiology. An overall review of these effects may be found
in a discussion by Lilienthal (127) or more recently in an exten-
sive review by the United States Public Health `Service National
Air Pollution Control Administration (194). Apart from its effects
on respiratory and circulatory function, CO has been found to
affect certain central nervous system functions adversely. These
effects are probably due to interference by CO with the proper
oxygenation and oxidative metabolism of the tissue in question.

CO interferes with oxygen transport in a variety of ways. First,
the affinity of hemoglobin for CO is approximately 200 times
greater than its affinity for oxygen, and thus CO can easily dis-
place oxygen from hemoglobin. Second, CO shifts the oxyhemo-
globin dissociation curve. By increasing the avidity with which
oxygen is bound by hemoglobin, CO interferes with 0, release at
the tissue level. This is of greatest importance at the tissue level
where the oxygen content of the capillary blood has been reduced
to approximately 40 percent saturation. Here the shift can sub-
stantially decrease the oxygen tension supplying the tissues.

Third, and of more recent note, is the possible interference by
CO with the homeostatic mechanism by which 2, S-diphosphogly-
cerate (2, 3-DPG) controls the affinity of hemoglobin for oxygen.
Bunn and Jandl (3$) have recently reviewed the various experi-

60


ments concerning this glycolytic intermediate. The question of
whether the low levels of CO present in the blood of smokers can
affect this homeostasis is presently under investigation (29, 143),
and firm conclusions cannot be drawn at this time.

Apart from its effect on hemoglobin affinity, CO appears to
induce arterial hypoxemia, and this may act as an additional cause
of tissue hypoxia. Ayres, et al. (1 4,15) observed unexpectedly that
exposure of individuals to CO sufficient to raise their levels of
COHb to between 5 and 10 percent was associated with a signifi-
cant fall in arterial PO,. Greater fall in venous p0, was noted,
but this was considered secondary to increased tissue extraction.
In a recent article, Brody and Coburn (30) suggested that this
COHb-induced arterial hypoxemia was due to the interaction of a
number of factors. These authors noted that in the presence of
veno-arterial shunts or of an imbalance in the ventilation-perfu-
sion ratio, the shift in the oxyhemoglobin dissociation curve in-
creased the alveolar-arterial OZ gradient and resulted in arterial
hypoxemia. The presence of shunts as small as 2 percent of cardiac
output as well as of approximately 10 percent COHb was found
to cause an increase in the gradient. Such ventilation-perfusion
(V/Q) abnormalities have recently been noted even in asymp-
tomatic smokers (see Chapter on Chronic Obstructive Broncho-
pulmonary Disease). The increased levels of COHb found in the
blood of smokers may interact with these V/Q abnormalities to
further decrease available oxygen.

In normal individuals, coronary flow can increase to meet the
increased oxygen demands of a stressed myocardium (as that
under nicotine stimulation), while in individuals with severe CHD
coronary flow cannot respond as readily. In such cases, myocardial
oxygen extraction must be increased above the almost maximal
extraction found at rest. Any interference with arterial oxygen
levels or hemoglobin affinity could very well decrease available
oxygen supplies below the level required for proper tissue func-
tion. That this occurs is suggested by the experiments discussed
below.

Chevalier, et al. (41) exposed 10 young nonsmokers to CO con-
centrations sufficient to induce COHb levels of approximately 4
Percent. Taking measurements from blood specimens obtained at
cardiac catheterization under resting and exercise conditions, the
authors noted that the ratio of oxygen debt to oxygen uptake in-
creased significantly under conditions of increased COHb. Accord-
ing to the investigators this implied that the same work was being
done at a greater metabolic cost. These same authors (221, 1.22)
had previously noted similar findings among smokers and observed

61


that cessation of smoking was associated with a significant im-
provement in oxygen debt accumulation.

More recent work by Ayres, et al. (15) has focused on the dif-
ference in response to CO exposure between 7 normals and 4 pa-
tients suffering from CHD (proven arteriographically) . The induc-
tion of a COHb concentration of approximately 9 percent in the
normals was followed by an increase in coronary blood flow, a
decrease in hemoglobin-oxygen percent extraction and no change
in myocardial oxygen consumption, coronary sinus oxygen tension,
and lactate and pyruvate extraction ratios. The induction of simi-
lar COHb levels in the CHD patients was followed by no change
in coronary blood flow, a decrease in the hemoglobin-oxygen ex-
traction ratio, and no change in myocardial oxygen consumption.
However, these patients did manifest a decrease in coronary sinus
p0, as well as a decrease in lactate and pyruvate extraction. The
latter measures indicate that the myocardium was functioning
under hypoxic conditions. Because the coronary flow could not in-
crease and because the myocardium could not extract O? from
HbO, which was under the influence of CO, coronary sinus oxygen
tension decreased to a point which could inactivate certain oxida-
tive enzyme processes. Thus, the myocardial function of persons
with CHD may be unable to compensate for the stresses induced
by smoking.

Although COHb levels resulting from the CO present in the
atmosphere during periods of high air pollution are much lower
than those due to the inhalation of cigarette smoke, these concen-
trations of COHb might contribute to the manifestations of CHD.
Cohen, et al. (44) studied the case fatality rates for patients ad-
mitted to 35 Los Angeles area hospitals with myocardial infarction
in relation to atmospheric CO pollution. The authors observed an
increased MI case fatality rate in areas of increased pollution, and
then only during periods of relatively increased CO pollution.

An area of interest which has been discussed in previous reports
concerns the presence of hydrogen cyanide in tobacco smoke.
According to Wynder and Hoffmann (215), the amount present
ranges from 11 to 32 micrograms HCN per puff. It is known that
a significant amount of this material is d.etoxified to thiocyanate
and excreted as such in the urine or saliva. However, cyanide is a
potent inhibitor of oxidative metabolism. Such inhibition of myo-
cardial oxidative metabolism may be of importance when combined
with the other factors mentioned above which tend to decrease the
oxygen supply available and increase the need for oxygen on the
part of the myocardium.

62


EFFECTS OF SMOKING ON THE FORMATION OF
     ATHEROSCLEROTIC LESIONS

A number of autopsy studies have demonstrated a significant
association between cigarette smoking and the presence of aortic
and coronary artery atherosclerosis, even in men without a his-
tory of clinical CHD. The possible pathophysiologic mechanisms
for the atherogenic influence of cigarette smoking are discussed
in this section.

A number of investigators have studied the effect of nicotine
administration, either subcutaneously or intravenously, upon athe-
rosclerotic changes in the aorta and coronary arteries of animals
(table A23). When administered alone, nicotine induces certain
necrotic changes in the arterial wall. However, in combination
with the administration of increased amounts of cholesterol in the
diet, nicotine aggravates either subendothelial fibrosis (75) or
definite atheromatous lesions (46, 75, 80, 130, 178). Studies by
Choi (42) and by Wenzel, et al. (207) did not demonstrate this
synergism between cholesterol and nicotine.

The other major cigarette smoke component under discussion
m this chapter, carbon monoxide, has also been recently implicated
in atherogenesis. Table 24 presents the studies which have related
exposure to CO in combination with increased dietary cholesterol
to both macroscopic and microscopic aortic and coronary athero-
matosis. Astrup, et al. (IO) exposed cholesterol-fed rabbits to CO
continually over a period of up to 10 weeks. The experimental
group showed increased aortic atheromatosis over that shown by
the control group, also cholesterol-fed. Kjeldsen, et al. (114)
observed that exposure of rabbits to increased oxygen concentra-
tions significantly reduced the amount of cholesterol-induced
atheromatosis in rabbits. Most recently, Webster, et al. (204) have
extended this research to primates. These investigators found that
cholesterol-fed squirrel monkeys developed significantly more
coronary artery atherosclerosis when exposed intermittently to CO
Over a `I-month period than when exposed only to room air.

Recent discussion has centered on the mechanisms whereby CO
can induce these changes (9, 212). Astrup (9)) referring to pre-
vious experiments in humans which had shown increased vascular
Permeability for albumin upon chronic exposure to CO (II), con-
siders it likely that this increase in permeability allows for in-
creased filtration of lipoproteins into arterial walls. This, he con-
siders, is a primary cause of intimal and medial lipid accumulation
and, therefore, of atherosclerosis.

Another point of view has been stressed by Whereat (212)) who
considers the filtration theory to be an inadequate hypothesis for

63


TABLE 24.-Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia

Author.
ye*=.
country,
reference

Number and
type of animal

Procedure                                  Results

Astrup    24 female       Regular diet plus 2 percent         The experimental group exposed to carbon monoxide showed increased macro- and
et al.,     albino rabbits.    cholesterol:                    microscopic aortic atheromatosis over that show" by control animals. Micro-
1967                    I. (12) control.               scopic examination revealed intimal lipoid deposition limited in penetration by
Denmark                II. (12) continual exposure to        the internal elastic membrane. Coronary vessels were found to show similar
(f0).                      carbon monoxide:           changes. Carboryhemoglobin. (COHb) levels averaged 16-19 percent during the
                          0.017 percent for 8 weeks.      first 8 weeks and 33 percent during the final 2 weeks.
                          0.035 percent for 2 weeks.
-
Kjeldsen   24 castrated male   Regular diet plus 2 percent           The experimental group exposed to hypoxia showed increased macroscopic aortic
et al.,     albino rabbits.     cholesterol:                    atheromatosis over that shown by control animals. Microscopic examination re-
1968,                   I. (12) control.               waled more intimal and subintimal lipid deposition in the aortas of the exposed
Denmark                II, (12) continual exposure.         rabbits than in those of the nonexposed. The total amount of cholesterol de-
(117).                     to hypoxia:              posited in the aortas of the experimental group was three times higher than in
                   10 percent-O2 for 6 weeks.      those of the control group.
                    9 percent O2 for 2 weeks.

Kjeldsen   24 castrated male   Regular diet plus 2 percent          Macroscopically, the experimental group showed significantly fewer atheromatous
et al.,     albino rabbits.     cholesterol:                  changes. Microscopically, the experimental group showed significantly less aortic
1969.                   I. (12) control.               intimal lipid deposition.
Denmark                II. (12) exposure to 28 percent
(114).               0% for 10 weeks.

Webster   22 female squirrel   Diet containing 0.5 percent          The experunental group exposed to carbon monoxide showed a greater mea" per-
et al.,     monkeys.       cholesterol and 25 percent fat:        centage of coronary arteries with atherosclerotic lesions and more lumen occlu-
1970.                   I. (10) control.                sion among the affected arteries.  There were significantly more CO-treated
U.S.A.                IL (12) experimentaUyexposed to     monkeys than control monkeys having 35 percent or more apparent atbero-
(204).                    200-300 p.p.m. carbon monoxide   sclerotic stenosis among the affected arteries. Aortic atherosclerosis was appar-
                         for 20 hours per week for 7      ently not aggravated by exposure to CO. COHb levels at the end of each exposure
                         months.                period averaged 16-26 percent during the flnal 24 weeks of the experiment.


mural lipid accumulation. The author notes that when the oxida-
tion of the pyridine nucleotide, nicotinamideadenine dinucleotide
(NAD) , is impaired, the reduced form of this nucleotide (NADH)
provides an essential factor for fatty acid synthesis. Fatty acid
synthesis in the aorta and heart is carried out by mitochondrial
enzymes whose hydrogen donor is NADH. Substances which slow
or impair the reoxidation of this compound tend to increase mito-
chondrial fatty acid synthesis (and decrease fatty acid utilization)
in the arterial wall. Carbon monoxide prevents this oxidation proc-
ess both directly and indirectly. Indirectly, it decreases the oxygen
available for diffusion into the tissue. Directly, carbon monoxide
can stall the process of NADH oxidation by combining with cyto-
chrome oxidase. Further research is required into this problem,
particularly in view of the fact that cyanide is also a respiratory
chain inhibitor and thus may also adversely affect arterial wall fat
metabolism.

THE EFFECT OF SMOKING ON SERUM LIPID LEVELS

In the discussion concerning the epidemiological aspects of CHD,
it was noted that increased serum cholesterol was a significant
risk factor for the development of overt CHD. Serum triglycerides
have also been related to CHD incidence. Of concern also is the
immediate effect which cigarette smoking has upon blood lipid
levels.

The studies concerning this immediate effect are presented in
tables A25 and A25a. The table is divided into a section concern-
ing studies on humans (table A25) and one concerning studies
utilizing animals or in vitro systems (table A 25a). Although no
consistent response was noted for serum cholesterol, serum free
fatty acids were found consistently to rise following smoking. AS
with other cardiovascular reactions to nicotine and smoking, it
appears that the fatty acid response is also mediated by catechol-
amine release. This relationship has been observed in a number
of experiments by Kershbaum, et al. (105,106,108,109,110) and
Klensch (118). That nicotine is primarily responsible for this rise
may be seen by reference to the study by Kershbaum, et al. (105)
in which lettuce-leaf cigarettes of minimal nicotine content had a
negligible effect upon serum free fatty acids in comparison with
that of regular cigarettes.

While attention has been centered upon nicotine as the agent
inducing the immediate increase in serum lipids, recent studies
have been concerned with the effect of chronic exposure to carbon
monoxide on serum lipid metabolism. These studies are listed in
table A26. Among rabbits fed increased amounts of cholesterol,

65


the authors observed significant increases in cholesterol and tri.
glyceride concentrations in those exposed to CO versus those
maintained in a normal atmosphere.

THE EFFECT OF SMOKING ON THROMBOSIS

In the study of CHD, a number of investigators have turned
their attention to thrombosis because myocardial infarction and
sudden coronary death frequently result from thrombotic events,
A thrombus may be of either gross or microscopic dimensions, and
a minute thrombus at a strategic site may precipitate a fatal ar-
rhythmia. However, thrombotic and prethrombotic states are dif.
ficult to detect except when gross, and the emphasis has been pri-
marily on factors which can be studied conveniently. Coagulation
is now thought to have a secondary role in the consolidation of an
arterial thrombus and little if any in initiating the process. The
prime mechanism in thrombogenesis appears to be the reaction of
the platelet. Several papers have been written about platelet re.
activity in vitro but few about the effect of smoking on platelet
behavior in vivo. The assay of fibrinolysis, which may also be im-
portant, has received scanty treatment. The relevant studies are
listed in table A27. Many of these are discussed in the 1968 sup-
plement (192) and by Murphy (140). Corroborative data are still
inconclusive as to whether smoking shortens platelet survival.

OTHER AREAS OF INVESTIGATION

Certain other aspects of cardiovascular pathophysiology may be
of importance in the relationship of smoking to CHD. Glucose me-
tabolism and insulin response, when altered, may alter myocardial
response. This topic has been covered in detail in the 1968 Supple-
ment to the Health Consequences of Smoking (192). Also, varia-
tions in blood hemoglobin and hematocrit may adversely affect
coronary blood flow. A number of studies showing a possible rela-
tionship of smoking to hemoconcentration have been reviewed pre-
viously (192,192), and the reader is referred to those discussions.

CEREBROVASCULAR DISEASE

The term cerebrovascular disease (CVD) refers to a number of
different types of vascular lesions affecting the central nervous
system : subarachnoid hemorrhage, cerebral hemorrhage, cerebral
embolism, and thrombosis (ICD Codes 330 to 334). In 1967 in the
United States, a total of 93,071 males and 109,113 females were
listed as dying from CVD as the underlying cause (196).
Epidemiological studies indicate that cigarette smoking is asso-

66


ciated with increased mortality from cerebrovascular disease,
whether CVD is listed as the underlying or as a contributory cause
of death. Table 28 presents the results of the seven major epidemi-
ological studies. The smoking of pipes and cigars does not appear
to increase significantly the risk of dying from CVD. The impor-
tance of high blood pressure and diabetes as risk factors for mor-
tality from CVD has recently been noted by Hammond and Gar-
tinkel (76). The data from their study, as presented in table 28,
also indicate that the mortality ratio for cigarette smokers is
greater for persons under 75 years of age than for older
individuals.

Many of the pathophysiological considerations discussed in the
sections concerning CHD may also pertain to the relationship of
smoking and CVD, particularly cerebral infarction.

In a study reported by Kuhn (123)) 20 habitual smokers re-
frained from smoking for one-half day, and base line retrograde
brachiocerebral angiograms were taken; they then smoked one
cigarette, inhaling deeply, and had repeat angiograms. Those over
60 years of age failed to have significant acceleration of flow as
demonstrated in carbon dioxide inhalation experiments.

More recently, Miyazaki (132) studied the effect of smoking
on the cerebral circulation of 12 moderate/heavy cigarette smokers
as measured indirectly using an ultrasonic D,oppler technique to
record internal carotid artery flow. Measurements were made be-
fore and after ordinary smoking and showed an increase in cere-
bral blood flow and a decrease in cerebral vascular resistance in
all subjects. No significant difference in response was observed
between the 4 younger and 8 older (over 60 years of age) subjects.
More research is needed to clarify the role of cigarette smoking
in the acute pathogenesis of CVD manifestations. However, the
chronic effect of smoking upon the cerebral circulation (particu-
larly its extracranial portion) is likely to be similar to the effect
Of smoking upon the aortic and coronary atherosclerosis.

NON-SYPHILITIC AORTIC ANEURYSM

Aortic aneurysm is an uncommon but not rare cause of death.
In 1967 in the United States, a total of 8,448 men and 3,173 women
were listed as dying from aortic aneurysm as the underlying cause
(196). Cigarette smoking appears to inc.rease the risk of dying
from this disease, perhaps by promoting the atherosclerotic proc-
ess which underlies this type of aneurysm. As illustrated in table
29, the mortality ratios for cigarette smokers are high relative to
other cardiovascular diseases in which smoking increases the risk,
and the risk increases in proportion to the amount smoked.

67


TABLE B.-Deaths from eerebrovascular disease Telated to smoking
(Mortality ratios--actual number of deaths shown in parentheses)'
            [SM = smokers    NS = nonsmokers]

PROSPECTIVE STUDIES

                              Number of
Author,                      Follow- deaths due
Ye*=*    Number and     Data      UP   to CVD as
                        years underlying   Cigarettes per day    PJt;
country,     type of     collection                                 cigars
reference   population                  CB"W

Age variation            Comments

Hsmmond  137.783 white Questionnaire   355     1,050   NS .l.OO  (164)                                   t (P<O.Ol)
and Horn,  males in 9     and follow-             Cigarettes
1958,     states 50-69   up of death               SM  .t1.30 (656)
U.S.A.    Years of age.   certificate.             Other SM 1.26 (330)
(77, 78).                                Cigarettes only
                                     <lO . . 1.24  (41)
                                  10-20 . .I.44 (140)
                                  >ZO 1.46  (83)

Doll and
Hill,
1964,
Great
Britain
(50).

Approximately  Questionnaire
41,000 male    and follow-
British      up of death
physicians.    certificate.

KlXlIlCl
et al..
1965
U.S.A.
(96).

5,127 males    Medical
and females   examination
30-59 year?,    and follow-
of age.       UP.

605   NS  . ..l.OO
   All SM ..I.06
   All
    cigarette  1.12
    1-14 . . . ..l.lO
   15-24 . .I.09
   >25  . 1.26

13   NS  .I.00   (6)                                   Data apply only
   Heavy SM                                                to males 3&59
    (>20)  .3.23   (8)                                       ye*rs Of me
                                                        at entry.
                                                      Data apply only
                                                        to cerebral
                                                        infarction.

1 Unless otherwise specified, disparities between the total number of deaths
and the sum of the individual smoking categories arc due to the exclusion of
either occasional, miscellaneous, mixed. or ex-smokers.


TABLE 28.-Deaths fmm cerebrovascular disease wzltcted to srrrokiag (cont.)
       (Mortality ratios-actual number of deaths shown in parentheses)
               [ SM = smokers    NS = nonsmokers]


                   PROSPECTIVE STUDIES

                               Number of
Author.                           deaths due                    Pipes
Year.    Number and     Data     Follow- underlying   Cigarettes per day       and               Age variation            Comments
country,    type of     collection   UP years to CVD as                    cigars
reference   population                   Ca"Be

Kahn.     U.S. male     Questionnaire
1966.     veterans     and follow-
U.S.A.    2,266.674     ~1, of death
(93).     person       certificate.
        year*.

Hammond  358,534 males   Questionnaire
and      445,875      and follow-
Garfinkel.   females 40-79  UP of death

Sly!     2.008   NS _.. .l.OO (614)
          All               SM
           current .1.30(1.394) NS
          current

          cigarettes .1.52 (692) NS
           1-9  1.51  (98) SM
          lo-20  1.42 (326)
          21-39  . . . .1.70 (216)
          >39  . 1.59   (37)

6      4,099

Pipes
.1.06 (82)
.1.00(614)
Cigare
.1.00(614)
. .1.08(136)

Current                   tBased on onlg
regular         M&8          6-9 deaths.
riaarettc JO-49 50-59  60-69  70-79

1969,   years of age   certificate.                                          NCTer
U.S.A.    at entry.                                                      smoked  1.00
(76).                                                               l-9  .2.79
                                                                10-19 .I.14
                                                                20 39 .2.21
                                                                >40  .1.64


                                                                Never
                                                                 smoked   1.00
                                                                 l-9  .1.50
                                                                lo-19 .2.60

1.00   1.00
1.95   1.30
1.48   t1.44
2.03   1.62'
2.40   1.72
FC7lllllC8

1.00   1.00
1.26   1.26
2.70   2.16

1.00
0.95
0.92
1.22
0.68

1.00
0.83
0.57

20-39 .2.90   2.67   1.83   1.28
>4n .t5.70 t3.52    -    -

      * Unless otherwise specified, disparities between the total number of deaths
     and the aurn of the individual smoking categories are due to the exclusion of
%     either occasional. misceIIaneous. mixed, or ex-smokers.


TABLE %.-Deaths from ccrc4wvrcsczclnr disease related to smoking (cont.)
   (Mortality ratios--actual number of deaths shown in parentheses)'
           SM = Smokers.     NS = Nonsmokers.

PROSPECTIVE STUDIES

Paffen-    3,263 male     Initial multi-    16       67 NSand
barger.    longshoremen  phasic                <20 __. 1.00  (42)
et al.     35-64 years    screening               >20 _. ._ .1.15  (26)
1970      of age in     and follow-
U.S.A.     1951.       UI, of death
(144).               crrtificnte.

RETROSPECTIVE STUDY

Prlff`Z"-    >50,000 male   Initial college
bsrger    University    entrance
and      students      medics1 CY-
Williams   followed up    nminations
1967      to 50 ye*rs.    with follow-
U.S.A.              up of death
(145).              certificate.
                  Controls-
                  surviving
                  classmates
                  age-matched.

                    Death Rates
              Cases (1.58)   Controls (615)
SM  45.0      31.3(P<O.O1)
Cigarette SM >10 per day 20.9      11.2 (p<O.Ol)

The 63 deaths from
occlusive stroke
contributed to the
statistical sig-
nificance.
The 95 deaths from
hemorrhagic
stroke showed
no statistical
significance as
* single group.

' Unless otherwise specified, disparities between the total number of deaths
and the sum of the individual smoking categories are due to the exclusion of
either occasional, miscellaneous, mixed, or ex-smokers.


TABLE .29.---Deaths from nonsyphilitic aortic aneurysm related to smoking-proslwctive stltdies
         (Mortality ratios--actual "umber of deaths show" in parentheses)'
                    [SM = Smokers    NS = Nonsmokers]
                                                    -~

Author,
Ye*=.
country.

Number and      Data
  type of     collection

Follow-up  Number
yems     of      Cigarettes per day          Pipes       Cigars         comments

reference    population                      deaths

Hammond 187,783 white   Questionnaire      3%     68   NS . .1.00(25) (expected)
and Horn.  males in 9      and follow-up               SM  ., ..2.`72(68) (~<0.005)
1958.     states 50-69     of death
U.S.A.    years of age.    certificate.
(77,78).

Kahn,     U.S. male      Questionnaire      8 y:     491  NS __.,.......,,,.._. 1.00 (68) NS ..1.00(68) NS ..1.00(68)
1966,     veterens      and follow-up               Current cigarettes  I,,. 5.24(234) SM ..1.13 (8) SM ..2.06(24)
U.S.A.    2.265.614      of death                 l-9 cigarettes/day .2.12 (13)
(9.9).     person yenrs.    certificate.                 10-20 ,...., ,. .5.53(124)
                                          21-39  .5.95 (76)
                                   >39 ,.,............. 7.26 (17)

Hammond  358,534 males
and     445,875 females
Garfinkel.  40-79 years of
1969,     nge at entry.
U.S.A.
(76).

Weir and   68,153 California
DU"".     male workers
1970,      35-64 years of
U.S.A.    age at entry.
(20.5).

Questionnaire
and follow-up
of death
certificate.

Questionnaire
and follow-up
uf death
certificate.

6      337   NS  ........... .l.OO
          l-9  .2.62
          10-19  ......... ,335
         20-39  ......... ,454
         >40  ........... .R.OO

5-8     51 NS   ,. _. ,. ,. .l.OO                             SM include
         All  _. .2.64                            a-smokers.
         k-10  _. _. .2.44                           NS include pipe
         -c20  __ __ .2.88                              and cigar
         230  _. ,. . .2.64                              smokers.

Data apply only
to males 50-69
years of age.

1 Unless otherwise specified, disparities between the total number of
deaths and the sum of the individual categories are due to the exclusion
of either occasional, miscellaneous. mixed. or ex-smokers.


PERIPHERAL ARTERIOSCLEROSIS

Peripheral arteriosclerosis represents the effects on the vascu-
lature of the extremities of the pathophysiologic processes which
produce coronary and aortic atherosclerosis. A number of studies
have been concerned with smoking as a risk factor in the develop-
ment of this disease. Kannel, et al. (95) observed, in the Framing.
ham study, that diabetes mellitus and elevated serum cholesterol,
as well as cigarette smoking, were also risk factors in the develop.
ment of peripheral vascular disease.

Juergens, et al. (92) reviewed the records of and contacted 478
male patients with arteriosclerosis obliterans (a severe form of
peripheral arteriosclerosis), who had been patients at the Mayo
Clinic between 1939 and 1948. The diagnosis of this condition was
based upon certain clinical criteria: the presence of intermittent
claudication, the marked diminution or absence of lower extremity
arterial pulsations, and objective trophic manifestations of per-
ipheral limb ischemia. Smoking information was available on 401
patients. These patients were compared with a control group of
350 Mayo Clinic patients of similar age who showed no clinical
evidence of vascular disease. It was found, for males under the
age of 60, that 2.5 percent of the cases and 25 percent of the con-
trols were nonsmokers. However, no difference was noted between
the percentages of heavy smokers in each group. The authors also
implicated high blood pressure and elevated serum cholesterol as
risk factors in the occurrence of this disease.

Begg (19) noted similar findings in a study of 294 male patients
with intermittent claudication who were patients at the Western
Infirmary in Glasgow, Scotland. ,In comparing the smoking his-
tories of 100 patients with this complaint with those of 116 healthy
male controls, the author found that 1 percent of the patients and
21 percent of the controls had never smoked. A total of 42 percent
of the patients smoked more than 20 cigarettes per day while only
24 percent of the controls had a similar history of heavy smoking.
The author concluded that smoking, while not a prime cause of
peripheral arterial disease, is a significant cofactor in its develop-
ment in almost all cases. The author also noted obesity, high blood
pressure, and elevated serum cholesterol as risk factors.

Schwartz, et al. (168) compared the prevalence of risk factors
in four groups of subjects : 141 cases with arteriosclerotic disease
of the lower limbs, 551 cases with coronary arteriosclerosis, 58
cases with both conditions, and finally an indefinite number of
control individuals who had been hospitalized for injuries. The in-
vestigators reported that certain risk factors, including hyper-
cholesterolemia, hypertension, and cigarette smoking, were signifi-

72


cant in both coronary and lower limb arteriosclerosis. The authors
noted that the inhalation of cigarette smoke appeared to be an
important risk factor for coronary arteriosclerosis up to age 55
while in arteriosclerosis of the lower extremities, inhalation ap-
peared to increase the risk even in the older age groups.

Widmer, et al. (213) compared 277 male patients with arterial
occlusion of the limbs as demonstrated by aortography or oscillog-
raphy with 2,082 men demonstrated by oscillography to be free of
arterial disease. The authors found that cigarette smoking, parti-
cularly heavy smoking, was significantly more frequent among the
cases with arterial occlusion than among the controls. Increased
beta-lipoproteins and systolic hypertension were also found to be
more common among the cases.

EXPERIMENTALEVIDENCE

A number of experimenters have investigated the acute effects
of smoking or nicotine upon the peripheral circulatory system.
These investigators, as listed in table A30, have measured effects
in terms of alterations in skin temperature and blood flow as meas-
ured by plethysmography, radioactive iodinated albumin clear-
ance, or radiosodium clearance from the skin. The majority of
these studies have shown significant decreases in peripheral blood
flow and skin temperature upon smoking, particularly in persons
without manifest peripheral vascular disease. The study of Freund
and Ward (68) demonstrates the difference in peripheral vascular
reactivity found between normals and patients with arterioscle-
rotic changes in the vessels of their extremities. The work of
Stromblad (181) on blockade of this response with automatic sys-
tem blockers indicates that the reactivity of these vessels is sec-
ondary to the local release of catecholamines. Most probably, the
degenerative changes associated with this disease create a stiffen-
ing of the vessel wall and prevent rapid alteration, particularly
dilatation, in response to the catecholamines liberated by smoking
or nicotine.

THROMBOANGIITIS OBLITERANS

Thromboangiitis obliterans (Buerger's Disease) (TAO) is an
uncommon obstructive vasculitis primarily involving the arteries
and veins of the extremities. Severely affected patients may even
lose their limbs secondary to ischemic changes. Much discussion
has centered upon the question as to whether this disease is a clin-
ical and pathological entity separate from peripheral arterioscle-
rosis. McKusick, et al. (128) consider it to be a distinct entity

73


while Eisen (57) concludes that TAO is the acute inflammatory
phase of severe arteriosclerosis.

Clinically, it has been shown that smoking aggravates this dis.
ease and cessation of smoking frequently aids in complete or par.
tial remission. Razdan, et al. (153) and Brown, et al. (32) found
very few nonsmokers in groups of patients diagnosed as having
typical TAO. A recent study from Israel (16) involved a case-
control comparison of 46 patients with TAO and 32 matched con-
trols. Although the controls were found to smoke less per day than
the patients, this difference was not found to be statistically sig-
nificant. However, 100 percent of the smoking patients and only
72 percent of the smoking controls were inhalers, a difference sig-
nificant at the 0.02 level.

CARDIOVASCULAR DISEASES

SUMMARY AND CONCLUSIONS

CORONARY HEART DISEASE

1. Data from numerous prospective and retrospective studies
confirm the judgment that cigarette smoking is a significant risk
factor contributing to the development of coronary heart disease
including fatal CHD and its most severe expression, sudden and
unexpected death. The risk of CHD incurred by smokers of pipes
and cigars is appreciably less than that by cigarette smokers.
2. Analysis of other factors associated with CHD (high serum
cholesterol, high blood pressure, and physical inactivity) shows
that cigarette smoking operates independently of these other fac-
tors and can act jointly with certain of them to increase the risk
of CHD appreciably.

3. There is evidence that cigarette smoking may accelerate the
pathophysiological changes of pre-existing coronary heart disease
and therefore contributes to sudden death from CHD.
4. Autopsy studies suggest that cigarette smoking is associated
with a significant increase in atherosclerosis of the aorta and coro-
nary arteries.

5. The cessation of smoking is associated with a decreased risk
of death from CHD.

6. Experimental studies in animals and humans suggest that
cigarette smoking may contribute to the development of CHD and/
or its manifestations by one or more of the following mechanisms :

a. Cigarette smoking, by contributing to the release of catechol-
amines, causes increased myocardial wall tension, contraction

74


velocity, and heart rate, and thereby increases the work of the
heart and the myocardial demand for oxygen and other
nutrients.

b. Among individuals with coronary atherosclerosis, cigarette
smoking appears to create an imbalance between the increased
needs of the myocardium and an insufficient increase in coro-
nary blood flow and oxygenation,

c. Carboxyhemoglobin, formed from the inhaled carbon mon-
oxide, diminishes the availability of oxygen to the myocardium
and may also contribute to the development of atherosclerosis.
d. The impairment of pulmonary function caused by cigarette
smoking may contribute to arterial hypoxemia, thus reducing
the amount of oxygen available to the myocardium.
e. Cigarette smoking may cause an increase in platelet adhesive-
ness which might contribute to acute thrombus formation.

CEREBROVASCULAR DISEASE

1. Data from numerous prospective studies indicate that ciga-
rette smoking is associated with increased mortality from cerebro-
vascular disease.

2. Experimental evidence concerning the relationship of smok-
ing and cerebrovascular disease is at present insufficient to allow
for conclusions concerning pathogenesis. However, some of the
pathophysiological considerations discussed concerning CHD may
also pertain to the relationship of smoking and CVD, particularly
cerebral infarction,

        NON-SYPHILITIC AORTIC ANEURYSM
Cigarette smoking has been observed to increase the risk of
dying from nonsyphilitic aortic aneurysm.

PERIPHERAL VASCULAR DISEASE

1. Data from a number of retrospective studies have indicated
that cigarette smoking is a likely risk factor in the development
of peripheral vascular disease. Cigarette smoking also appears to
be a factor in the aggravation of peripheral vascular disease.
2. Cigarette smoking has been observed to alter peripheral
blood flow and peripheral vascular resistance.

CARDIOVASCULAR REFERENCES

(1) ACHESON, I?. M., JESSOP, W. J. E. Tobacco smoking and serum lipids in
   old men. British Medical Journal 2: llOS-1111, October 28, 1961.
(2) ADLER, I., HESSEI, 0. Intl,avenous injections of nicotine and their ef-
  fects uljon the aorta of rabbits. Joul,nal of Medical Research 15:
   229-Xl, 1906.

75


(3) ALLISON, R. L)., ROTH, G. M. Central and peripheral vascular effects
  during cigarette smoking. Archives of Environmental Health 19(2) :
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89


CARDIOVASCULAR




APPENDIX TABLES


TABLE AG.-Coronary heart disease morbidity and mu?-tality--rctrospcctivc studies

Author,
Y--P
country,
reference

                   (Actual number of cases shown in parentheses)'
                [SM z Smokers       NS r Nonsmokers      EX = Ex-smokers]


Numix F and       Data
tyr ? ,!f       collrction                Cases (percent)                 Controls (llercent)
l.rij,uiatlon
    ._____ -.....

Comments

English
et al.,
1940.
U.S.A.
(60).

Mills and
Porter.
1957,
U.S.A.
(281).

1.000 r ,,le: .>ith
m:rl:if+' HI),
40 >   3 ,rf age.
Con!: L: i.000
mslr r.on-CHD
patients.

474 white male
coronary deaths.
Controls: 606
white males.

1 I,,'      Pcrccrrt Smokers                        Pcrce?d Smolxss
.Id /!b  79.7(1X?)                  61.9(302) (p<O.OOl)
JO 59 ,,., ,,. .71.7(3X2)                  73.9(371) (not signilicant)
Iill II,`O\CL` 63.8(431)                  61.8(327) (not significant)
All RYES  .69.t;                       FG.3    (P<O.O5)

UndrBned.

              40-4!/
              (56)
NS  .7.14
All cigawttes   83.93
Pipes. cigars  8.93

so-50   SO-F9  70 or ouc7  40-4"   5"-69   00-89  70 or over
(135)   (153)   (130)    (21'3)   (lxx)   (114)   (88)
6.Fti   18.30   33.84    19.91   24.4i   35.09   54.12
82.23   49.02   18.44    70.X3   59.94   43.86   lF.47
11.11   32.68   47.70    9.26   16.47   21.05   29.41

Ruechley   Males reporting     Question-     NS  ._ _. ._ .20.4 (23)                   NS  ., ._ .42.1(51)
et al.,     CHD to California    naire and   520  . . . ..61.1 (69)                   520 I.. .46.3(56)
1956,     Health Survev      interview.   >"a  .1x.5 (21)                   120  11.6(14)
U.S.A.     with matched
(33).     controls frwn
         Same S"WfY
         (included those
         surviving first
         myocardial
         infarction)


f             TABLE A&-Coronary heart disease morbidity and mortality---retrospective studies (cont.)
                                    (Actual number of casa shown in parentheses)*
                               [SM = Smokers       NS = Nonsmokers      EX = Ex-smokers]

     Author,
     Year.       Number and       Data
    country,       type of       collection                Cases (percent)                 Co"trols (percent)         Comments
    reference      population

       ~-.                ._
Russek and  97 male nnd 3       Interviews           Tobacco usagc>~o cigarettes/day                              Patients

Zohman.   female coronary     by        50 1,ercent.                              35 percent.                included 89
195%     patients. Controls:    authors.                                                              with classical
U.S.A.    100 healthy controls                                                                     myocardial
(16s).     of similar age,                                                                        in'farction
       sex. occupation.                                                                       and 11 with
       and ethnic origin.                                                                     angina pectoris.

Spain and  269 males identified   3,000 males   NS  
Nathan,    as having CHD by    in New    <40/day
1961.     physical examination  York City   >40./day
U.S.A.    and history. Controls:  inter-     EX
(176).     2,637/3.000 males     viewed and  Cigar, pipe
        identified 8s       examined       Total
        not having CHD     by medical
                      group.

.30.0 (81)                   29.0 (772)
.29.0 (78)                   33.0 (870)
13.0 (33)                    9.0 (234) (p<O.O5)
14.0 (39)                   14.0 (361)
.14.0 (38)                  15.0 (400)
.100.0(269)                   100.0(2.637)

Mulcahy and 400 mr.' : less than    Interview.                 M&8                     M&8                 Control smoking
Hickey.    GO )`I' I'\ of age with           NS  _.... . . 4.50 (18)                   18.2(110)                 data obtained
1967      classical (`HD. Dntn           Shl  .t. ._ .90.75(363)                    70.6(427)                 from estimated
Ireland    compnre~~ with male           ES ,, ._ .., 4.75 (19)                   11.2 (68)                 smoking habits
(295. lS6). populnti,,n co"-              Total  _. .100.00(400)                   100.0(605)                 of Irish
        sumplion figures.                                                                     population of
                                                                           same age group.

Schwartz   612 male 1~x1 ients
et al..     with anplna or
1966.     myocardial
France    infarction.
(169).     612 age-matched
         CO"tl"lS.
~~_____

Interview,    Average amount
laboratory,    per day as
and        rigarettes  .18.6
clinical ex-  All SM  .86.0
aminstions. Inhalers _. .59.0

15.5 (p<0.0001)
X6.0



45.0(p<0.00001)

Data apply only to
those under 55
years of age.


       (l%cL.ual nuIII"el' 01 CLlC.5 .l."W,, 11, yarrriLtk%rs, -
[SM = Smokers       NS = Nonsmokers       EX = Ex-smokers]

Author,
Y-r,
country.
reference

Number and
type of
population

Data
collection

Villiger and
Heyden-
Stucky,
1966.
Swit-
zer-
land
(201).

100 cases with      Hospital
recent myocardial    history or
infarctions.        interview.
72 males, 28 females,
100 age-matched
controls (72 male
industrial
employees and 28
females in hospital
for other diagnoses).

Cases (percent)

cor1tro1s (percent)

Comments

                MaZcs(72) FemaZes(28) Mok!s( 72) Fcmaz~(z8)
NS  ............................ 6.94       71.4     t25.0     82.1
Cigarettes  ....................... 66.7       28.6      45.x      14.3
l-19 cigarettes/day  ............. .lE.l       10.7      23.6      10.7
>20  ........................... .48.6       17.9     t22.2      3.6
Cigar, pipe  ..................... .44.4       ...      27.x       ..
EX  ............................. 4.2        ...      t15.3      3.6

These are not p"re
smoking classes.
t (P<O.Ol)

DGrken,    205 males UP to 44
1967.     years of age with
Cei-lllS.lly   myocardial infarc-
(52).     tion or sudden
        death (139 deceased,
        66 living). Controls
        ---Hamburg age-
        matched citizens
        selected randomly.

Death cer-    NS  . . 1.0  (2)
tificate re-   Cigar&4 Units
view. In-    1-5  1.5  (3)
terview of   10-15  . . ,322 (62)
patient    20-30  ., .43.6 (84)
or kin.     >35  ._ ._ _. .21.8 (42)
                    100.0(193')

(only 28 were mixed
or cigar smokers)

18.4 (76)

10.4 (4X)
46.5(192)
22.5 (93)
2.2 (9)
100.0(413)
(62 were mixed or
cigar smokers)

Ex-smokers listed
under nonsmokers.
Smoking information
available only on
193/205. These
cigarette categories
include mixed or cigar
smokers recalculated
as to number uf ciga-
rettes. No patients
or controls smoked
pilIes exclusively.

   Darken.    33 females "D to     Death cer-    Cigarettes per day
    1967,     44 years of age      tificates.    0 ,. ,. .,._. 6.1  (2)                   CR.!? (X4) (1~<0.001)
    CC~allY   with myocardial     inter-      l-5                           17.3(23)
     (5.3).     infarction or sudden   views.      6-15  .4x.5 (16)                    16.5(22)
            death. Controls-133          20-30 ._ ._ .__. .39.4 (13)                    3.0 (4)
            females 27-44 years           >35   G.l (2)                    
           of age from clinic
           without CVD or lung
            caneer.
2


t

TABLE A6.-Coronary heart disease morbidity and mortality-retrospective studies (cont.)
                (Actual number of cases .&own in parentheses)'
          [SM = Smokers       NS z Nonsmokers       EX = Ex-smokers]

Author.
Ye==.
cou"tly,
reference

Number and
type of
population

Data
collection

Hyams
et al..
1967,
.J=pa"
(87).

79 males surviving    Interviews
myoeardial infarc-    by trained
tion. 157 age-       personnel.
matched controls
hospitalized for non-
CVD but include
hypertensive disease.

Cases (percent)

-NS  . .10.1  (8)
l-9 cigarettes

    Co"trols (percent)


21.0 (33)

per day __. 7.0  (6)                  10.5 (13)
lo-15  . . 25.4 (18)                    33.9 (42)
16 20  . . ..35.2 (25)                   25.X (32)
21-34  ., ,._. .22.5 (16)                    17.7 (22)
>35  9.9  (7)                    12.1 (15)
All SM  .lOO.O (71)                   100.0(124)

Comments

Mulcahy
et 81..
1967,
Ireland
(237).

100 female patients   Hospital     SM  ,. ._ __ .63.0 (63)
less than 60 years     interviews.  NS  .33.0 (33)
uf age admitted to            EX ., ,, t., 4.0  (4)
hospital with CHD.               Total  lOO.O( 100)

Stejta.
1967.
Poland
(179).

70 male and
female patients
with recent onset
exertional angina
pectoris. 54 controls
of same age.

Direct               Pre~nlcnce of siak factors
interviews.   .A rtuinn patient8
            60.0

45.6(261)
45.3(259)
9.1 (52)
100.0(572)

Smoking on controls
obtained from
statistics of
smoking in
Irish Republic.
Sudden death
not included.

Control grollp


48.l(P>O.l)

Authors then followed
the 70 patients for
3 years and noted
that smoking signifi-
cantly intluenced
the incidence of
coronary occlusion.

Schimmler 603 males with

Hospital

NS  9.0 (44)                    26.0(1X7) (n<O.OOl)

                                                                        . .
et al..     healed myocnrdial    interviews.  EX  _. ,. .1!2.0 (59)            20.0;142) (p<O.OOl)
196R,     infarctions. 114 male          Cigar, pipe _. .12.0 (62)                    11.0 (77)
C.WlUl"Y   co"trols of same age           <l'.l cigarettes .26.0(129)                   14.0(101) (P<O.OOl)
(167).    without detectable            >20  ,. .42.0(209)                    29.0(207) (P<O.OOl,
       heart disease.                  Total  .1""."(503,                   100.0(714)
                                                     __-                       ~___--


-
Author,
  ye*=,
country.
reference

   I'ABLE A~.-~~`O?`OWW!/ l/(YLl.t ~1Sl'fISc' ~lll~`hti!t!J (L?ld li101 tdliU--,`c(r./)SJ)c &I LY Stltdlcs (CorLt.)
                    (Actual number of cases shown in parentheses) '
                [SM = Smokers       NS = Nonsmokers       EX 7 Es-smokrrs]


Number and       Data
type of       collection
population                          Cases (percrnt)                 Controls (percent)

Comments

                                                                           --____
Hood et al..  230 males surviving   Interview                   12301                      (X5.5,

1969.
SWdlZ"
(X5).

Jouve
et al.,
1969.
France
(91).

early first myocardial  and exam-   Never smoked _. .1.75
infarction. Contruls:   ination.    EX before
855 randomly selected           infarction  .I.75
males 50 years of             EX after
*I?`?.                     infarction  . . . ..!29.1
                      <15 cigarettes .28.3
                      >I5 cigarettes .22.6
                       All  ., ._ .80.0
                      Pipe  .16.5

1,229 CHD patients:   Interview.                43.0
802 males, 427
females. Controls:
743 individuals of
both sexes: age.
sex, and social
class matched.

24.2

I!l.i


27.4
20.0
47.4
X.X

13.0(r1<0.0001)

Knstl,     275 mnle railway     Interview    NS  __ ., ., .20.0 (65)                   29.x (X2)
1969.     employees up to 65    and ex-    Z-20 cigarettes or
C`Z"l*"Y   yc*rs of age sur-     amina-     UP to 6 cigars. .32.0 (88)                    63.X (X2)
(9X).     viving myocardial    tion.      >20 cigarettes or
        infarction. 276 con-           >6 cigars.  ..48.0(132)                    R.!) (19)
        trol employees with
        minor circulatory
         disturbances.

1 Unless otherwise specified. disparities between the total number of eases
and the sum of the individual smoking categories are due to the exclusion of

s   either occasional, miscellaneous. mixed. or ex-smokers.


Author, year.
country,
reference

TABLE A'i.-Differences in serum lipids between smokers and nonsmokers

Number and
type of
population

(Actual number of individuals shown in parentheses)'
    [SM = Smokers    NS = Nonsmokers]


                Results

Comments

Gofman
et al,.
1955.
U.S.A.,
(72).

401 male
e"lplWW?S
20-59 years
of zlge.

Lipid:
tsf c-12
Sf 12-20
Sf 20-100
Sf 100-400
Cholesterol

           Difference between SM and NS         tSf refers to Svedberg
   Ages 20-29       Ages 80-.79        Ages40-59     flotation units of
  (NS 56, SM 37)    (NS 56, SM 67)     (NS 17, SM 44)   centrifuged lipoproteins
I. +59.9 P<O.OOl     f19.9 p<o.o5     + 3.9 p<o.o5
+ 9.4 p<O.OOl     + 5.4 p<o.os     - 3.5 p<o.o5
. +20.0 p<O.O25     + 9.1 P<O.OS     + 8.5 p<o.o5
flir.8 p<O.O25     +12.1 p<o.o5     - 4.5 p<o.o5
+21.2 p<o.o5      + 9.0 p<o.o5     - 4.8 p<o.o5

Thomas,
1958,
U.S.A.
(185).

621 medical
students.

                        Serum cllolrst&sol mg. percent
                           NS (264)       SM (2.57)
                       Obscrved/Ezpected Obsemed/Ezpccted
<250  .,  170/157        149/161.6
>250     87/99.6       115/102.4
Chi Square Value = 5.2 p<O.O25

Dawhcr        2,253 males                                   Serum cholesterol mg. percent   The authors conclude that
ct RI..         participating                                     29-44          45-59     there is evidence of a
1959,         in the Framingham   NS . . ..t....................  216.1(149)       228.3(131)   gradient of cholesterol with

U.S.A.
(47).

study 29 59
YCRI`S of Rge.

KWWllPIl
et al.,
1959.
Finland
(97).

   ___-
525 males in
various
occupntions
20-59 ycal's
of zwe.

All cigarettes  ..............................  224.8(874)     229.5(589;
<lO  ......................................   217.4 (75)       229.1 (76)
lo-19  .....................................  221.1(134)       230.1 (96)
Zlt-39  .....................................  225.8(551)       227.8(350)
>40  .....................................  229.0(114)       238.5 (68)
Piprand cigar  .............................  214.9(128)       227.1(166)

                         Serum cholesterol mg. percent
                       Wcet Finland East Finlatid   Helsinki
NS  .................................  208.0(64)   226.6 (39)   235.1 (62)
SM  ................................  228.7(91)   249.7(103)   257.8 (166)

T
Increasing amount of cigarette
smoking in younger men.

The authors state that no
trend WBS noted associating
increasing amount smoked with
increasing serum cholesterol,
although smokers and nonsmokers
did have different overall
kVC,S.


TABLE A'?.-Differences in senm lipids between smokers and nonsmokers (cont.)
            (Actual number of individuals shown in parentheses)'
                 [SM = Smokers     NS = Nonsmokers]

Author, year,       Number and
country,          type of
reference         population

22 1 rnnd0mly                              Mean strum cholesterol   Mean l3etnlAlpha
rh"sen pensioners                              mg. percent      lipoprotein ratio
G-X5 yf%L's "f      NS  _. .._ ._  214(38)           2.0(36)
age.            5 cigarettes/day    .X01(12)           2.1(11)
              10     213(34)           1.8(33)
              20    201(33)           1.9(35)
               >30  .._._ ._.......... 206 CR)           1.8 (R)

Api~rvximately                   Cholesterol my. percent      RctnlAlphn lipoprotein. ratio  No data given "n numbers in
GOIJ healthy                    25-Y!,        40-55        254!)        40-55     each gr"uI).
malrs 2s55                  tA SE      A    E      A    E       A E    tAPAfrIcan.
YERI`S of REC.       NS 179   197     222   246     2,x9   3.34     3.75   4.59   %E~~~Euvopenn.
               "Heavy" SM    1X6   223     204   236     3.82   4.40     4.07   5.40

Results                               Conments

314 mnlr military                              Serum cholcstcrol Serum phospholipids  No serum lipid differences
recruits 14-25                                 my. perrcat      mg. pc rcent      f<,und am"ng the rsrinus
years of we.       NS ,, ,, ,. ,. ,, ,, ,._ ., ., ,(145). ,. __ _. .,  203.8          21R.0        smoking groups.
              (Cigarettes per day) l-10 (53).  206.8          222.3
              11-19 ,., ., ,, ,, _.. (54). _. ,. _.  213.1          224.7
             >ZO . . . . . . . . . . . . . . . . . . . ..(62).............  202.3          210.6

7F monozygotic       I. Mimozygotcs discordant for smoking: Smokers showed slightly lower levels  The a"th"rs conclude from the
twin pairs and         of cholesterol, triglycerides, and phospholipids than nonsmokers.        differing MZ and DZ results
Xi rlizygotir       II. Dizygotes discordant for smoking:  Smokers showed significantly higher   that constitutional factors
twin pairs obtained      levelv of phospholipids. No differences for cholesterol and triglycerides.     are probably m"re importnnt
from Swedish Twin                                                     than smoking in determining
Registry.                                                            lipid levels.


8

TABLE A7.--Diferences in serum lipids between smokers and nonsmokers (cont.)

                           (Actual "umber of individuals shown in parentheses)1
                                    [SM = Smokers    NS = Nonsmokcrsl

  Author, year,       Number and
   country,          type of                            Results                                CO"ll"e"t.8
   reference        population

Fidanza        111 male prisoners                             Serum cholesterol mg. percent      No statistically significant
et al.,         34-69 years of                          Agce <39   40-49    SO-59     60-69    differences found between
I!)GG.          ape.            NS           195(E)   189(10)   176 (7)   SM nnd NS.
Italy                      <20 cigarettes/day    209 (5)   201(16)   202(13)   196(10)
(FL).                       >20 cigarettes/day    197(6)   175 (7)   171 (7)    . .
                                               Serum triglyceride8 mg. percent
                          NS           x4.7      71.9     86.0
                          <20 cigarettes/day     84.6     99.4     101.9     89.8
                          >20 cigarettes/day  .   91.0     86.0      66.7 .

Kedm and       200 clinically                     Serum cholcaterol   Phospholipids     Total lipids    Serum cholesterol also noted
Dm<,wski,       healthy malrs                     nag. percent      mg. pe+cent      n&g. percent     tn increase with increasing
l!lM,          2B-50 years of     NS(100)  . . . . .   170.2                    1,234.8         intensity and duration of
Poland                                 268.11
             uge.           SM 100)     224.9
(99).              3  P<O.Ol   257.6 I  p>o.os   1.362.1
                                                 Beta-lzpoproteina   1  P<O.Ol   smoking.

Total fatty acids   percellt of total.
ng. percent      lipoproteine

NS(100)  ..__   797.8          43.1
SM 100)                p<O.Ol        p<O.Ol
      .._   869.9          49.9

Hark%"
et al.,
1967.
U.S.A.
179).

G67 former nltvnl
aviation cadets
4x years of age
(average).

--__
   Sencm cholesterol
  Found to be related
   to cigarette smoking
   p<o.o5.

S13~rn triglyceridca      Lipoproteins
Found not to be related   Sf c-12 related. p<o.o5
to cigarette smoking.   Sf 20-100 unrelated.
               Sf 100-400 unrelated.

Heyden-
Stuck,. and
Schibler-
Reich, 1967,
Switzerland
(82).

500 plant workers
30-60 years of
age.

                   Serum cholesterol Serum t~iglycwides No statistically significant
                           mg. percent      ?ng.percent     difference found between
<lOcigaretteslday  _. _, _.  210.0(334)         110.0       SM and NS.
>I0 cigarettes/day  _. __ __ __ __ __  260.0(166)         180.0


TABLE A7.-Differences in serum liln'ds between smokers and nonsmokers (cont.)
            (Actual "umber of individunls show" in parentheses)'
                [SM = Smokers    NS = Nonsmokers]

Author, year,
country,
reference

Number and
type of
population

Rl?Slllts                                comments

Higgins
and Kjelsberg,
1967.
1J.S.A.
(83).

Pinrherly
nnd Wright,
l!l67.
E"gl*"d
(1,50).

5,030 male and
female residents
of Tecumseh.
Michigan, 16-79
years of age.

2,000 men
participating in
executive health
examinations
2%70 years of
age.

                             M&8          Fe??llZh
NS __ __ _. _. _.  209.9  (360)       210.1f1,439)
Cigarette      212.5( 1,426)       212.4 (910)

                                  Percentage with .wrunz  The authors noted that smokers
                       Serum cholesterol   choleatcroZ>170     showed significantly higher
                         mg. percent      mg. percsnt      ( p<O.OOl) serum cholesterol
NS(677)    236.2           19.0         levels than nonsmokers.
Ex-smoker(388) ._...._....._._._..  246.0           2R.O
1-19 cigarettes/day(424)    239.2           24.0
>20 cigarettes/dny(Sll)    249.4           30.0

Van Buchem,
1967,
Nethevlands
(181)).

918 randomly chose"                              Semm cholesterol              The Ruthors found no
meles 4c-59 yearn                 O-209 mg. pement  210-?4!i mg. Percent >eso nw. Percent   correlation between smoking
of age for entry     NS . . . . .  12.4 (32)       14.0 (44)       14.2 (41)      and serum cholesterol levels.
into prospective     Cigarette SM    71.6 ( 184)       67.8(213)       68.2(197)
study.          Other ,_....______.._. 16.0 (41)       18.2 (57)       17.6 (51)

Hwle et al.,
1968,
1J.S.A.
(28).

1.104 male factory
employees 20-64
yrars nf age.

                     Serum cholcsted   Scram Beta-lipoprotein  Beta-lipoproteins were found
                       mg. percant         my. percent      to increase with nge. but
NS ,. ._ ._ __ __ _. __ __ _. ._ __
SM           243(519) 1 ,,<O,OOs    0.325 i           smokers hnd higher levels
   .  251(576) j        0.351 f p<:0.001     than nonsmokers at all ages.

Caganova       49 males living                            Se7-urn cholcatcrol   Strum Beta-lipoprotein
et al..         in youth hostel.                             "lg. percrnt        mg. pcrrcnt
196X,          21.6 average we.     NS(34)
Czechoslovakia                  SM (1.5) ._. .,. . . _,._,___ 1X8.20] r,<o,025     359.x0]
                     214.205        498.4OJ p<o.o01

(36).                                                      Beta/alpha lipoyrotein ratio
                         NS(34)  . . . . . . . . . . . . . . .  1.16
                          SM(15)  _. . _. _. _. t.. .  1.55  D<0.o25


Author, year,
country,
reference

  TABLE AT.--Differences in serum lipids between smokers and nonsmokers (cont.)
                (Actual number of individuals show" in parentheses)'
                    [ SM = Smokers    NS = Nonsmokers1

Number and
type of                            Results
population

Comme"ts

Modzelewski
and Malec,
1969.
Poland
(133).

140 males 20-68
gears of *ge.

Scram-cholesteml     Serum Beta-lipoproteins
NS (20) p<O.Ol      NS p<O.Ol
Heavy smokers       Heavy smokers

Strum free fatty arida
NS p<O.Ol
Heavy smokers

Kjeldse",
1969,
Denmark
(113).

334 employees of
"*rioUS firms
in Copenhagen.

                              Smum cholesterol mg. percent
NS (196) ..,..._...,_...._..__.__._..__._.._.....__... 2361 p<o,ol
SM (738) ._............_.._........................... 247j

Pozner        64 male and                    Serum cholesterol  Serum triglycerides  Total phospholipids  Significant figures refer to
and Billimoria,    female healthy                   mg. percent       mg. prrcent      mg. percent     heavy smokers as compared
1970,          volunteers 19-30     NS(20)  . . .  176.3          68.6           193.4         with nonsmokers.
England        ye*rS of age.       Light SM (17)    172.1          68.4           188.9
(152).                        (Over 7.3
                          cigarettes/day)
                          Heavy SM ( 27 )    200.0 P<O.OS      87.6 p>O.O5       215.0 P<O.OOl
                            (Over 22.5
                           cigarettes/day)

1 Unless otherwise specified, disparities between the total number of eases
and the 8um of the individual smoking categories are due to the exclusion
of either occasional. miscellaneous. mixed, or ex-smokera.


TABLE A&-Blood pressure differences between smokers and nonsmokers
     (Actua! number of individuals shown in parentheses)'
          [SM = Smokers     NS = Nonsmokers]

Author, year.
countlY,
reference

Number and type
of population

Results                               Comme"ts

Dawber et al.,   1,253 male
1959. U.S.A.    and female
(47).        residents         NS(149)  ,.. _._ ._. .._ .._ .._.
            of Framingham.     Cigarettes ( 374 )  .
                         <10(75)  . . . .I . .
                        IO-19(134)  
                       zo-39(551)  
                         >40(114)  . . . . . .,
                        Pipe and cigar(128)  

.........
.........
.........
.........



           Systolic blood preaaure No association found
          Ages 29-44      45-59 between systolic blood
...................  138.8       143.0  pressure and smoking.
...................  132.5       140.3
...................  134.7       144.0
...................  129.4       141.6
...................  132.2       138.9
...................  136.1       141.5
...................  136.0       141.9

Edwards et al.,   1,737 male                     Proportion of n&err with "Hypmtmion" (~200~100 mm. Hg.)
1959, England   patients of        NS  _. , . . . . . . . . . .  2'7.2 percent (151)
(56).        general prac-       Cigarettes  _. . . . . . . . . . . .  20.5 percent (730)
            titioners over      Pipe _. _. 25.9 percent (341)
            60 yeTarS of age.

Karvonen et al.,  526 males in                                      Systolic blood pm.wuw         No data on pipe and
1959. Finland    various regions                             West Fixland    East Finlund      Hebim ki   cigar smokers. No
(97).        of Finland        NS  ., ._. ,. . 139.2(64)      142.6 (39)     132.8 (62)  statistical significance
            2s s9 years of      SM  _. 133.2(91)      135.4 (103)     129.8 (166) noted.
            BBC.                                           Diastolic blood pmssure
                          NS  . _,  84.7         86.8          89.6
                          SM  . .  81.9         84.1          86.8

Clark et al.,     1,859 male civil                                  Mean systolic         Mean diastolic Nonsmoker and smoker
1967. U.S.A.    servants.                                    blood-prcsuwe        blood-pressarc  groups were of similar

(43).

NS(728)  .,...,.,..,..... .,.. . . . . . .  137.0  (p~O.05)    83.gl (pZO.05)   average a???.
SM (407)    133.6           R2.5 (


          TABLE AS.-Blood pressure differences between smokers and nonsmokers (cont.)
                          (Actual number of individuals show" in parentheses)'
                                 [SM = Smokers    NS = Nonsmokers]


            Number and type                          Results
  l-ef.Se"Ce       of population                                                            Comments


Higgins and    5.030male and                   Age adjweted                Age adjusted
Kjelsburg.     female residents             mean systolic blood ~msuuw       mean diastolic blood pressure
1967. U.S.A.    of Tecumseh, Michigan,           M&8      F#?l&lJ        M&s      Females
(8s).        16-79 years of age.    NS  t, .137.9 (360)   84.5 (1439)      136.6 (360)  82J(1439) 1 (p<o 001)
                         Cigarette .136.4(1426)   81.4 (910)      131.6 (1426)  79.0 (91O)J '

Reid et al.,     676 male British               Mean systolic blood p~edmwe                         The author did note
1967. England   and 625 male              (adjusted for difference in weight)   Mean diastolic blood pressure    SM-NS blood pressure dif-
(1.55).        American postal              UK           U.S.A.            UK       U.S.A.    ferences prior to
            workers 4&59      NS . . . . ...128.2 (45)         124.8 (89)           79.3        81.0    controlling for weight,
            years of age.       l-14 grams 130.2 (27)         133.0 (60)           79.4        82.1    but not after such control.
                        16-24 grams 128.5 (232)         127.7(169)           78.5        77.3
                        >25grams 127.9 (70)         128.1(218)           77.6        77.1
                        All amounts 129.1(519)         128.6(447)           78.7        773

Tibblin, 1967.    895 males in                                                       -
                                    Blood pressrcre
Sweden                                           1 l&145/     150-170/            Numbers in parentheses
          GGtehorg, Sweden,              ~110/~70(89)
(187).                                             75-95(468)
            born in 1913.                                  loo-110(220) >175/>lI5(75)  represent total in blood
                          NS  . . . _. . . 18.0        23.0        25.5        34.7      Pressure group.
                        l-14 cigarettes  . .29.2        29.2        25.6        18.7      The author noted
                        >I5 cigarettes  . 28.1        20.9        15.5        17.3      a stepwise decrease with
                      Pipe and cigar  . .11.2        8.6        10.0         4.0     level of blood pressure
                                                                        as smoking increased.
`Unless otherwise specified, disparities between the total "umber of i"-
dividuals and the sum of the individual smoking categories nre due to the
exclusion of either occasional, miscellaneous. mixed, or ex-sm"kem.


  TABLE A17.-Zmidence of new coronaq heart disease by smoking category and behavior type for men 39-49 years of age
                        (Numbers in parentheses are number of CHD cases in each subgroup)

                                                         Smoking group

                              FlXlIl.?T       Current and                 Cigarettes
Behavior             NeVer    cigaf;cete      former pipe
  type              smoked                  and cigar only       1-15         16-25        26 and over        Total

A  .._ ., . .  `5.3(5)        13.3 (7)        1.3(l)          1.6(l)        15.X(15)         14.9 (16)         9.3(45)
B  . . . . . . . .  1.3(Z)         5.1 (3)        2.2(Z)          7.3(4)        3.1 (3)         4.9 (4)         3.3(18)
   Total    2.9 (7)         9.1(10)        1.8(3)          4.9 (5)        9.3(1X)         10.4(20)         6.2(63)

                                                             Analysis of variance table

  SOUITC                                    Sum of squares        d.f.        Mean square         F            P

Within cells _. _. . . _.    59.471          2,245          0.026                      . .
Regression on age . _. _. _. _. . . . .     0.458            1          0.45R          17.296          0.001
Retwsen smoking groups 2 _. _. . _.     0.504            5          0.101          3.81          0.002
Between behavior types 2     0.329            1          0.329          12.43          0.001
Interaction    .     0.396            5          0.079          2.99          0.011

1 Rates are age-adjusted nnnual incidence per 1,000 men.              effect but ignoring interaction. thus yielding an estimate of each main ef-
`Mean squares for "between smoking grwps" and "between behavior     fsct unconfounded by other significant main effects.
types" are each computed eliminating the general mean and the other main      SOURCE: Jenkins. C. D. rt al. (90).


TABLE Al8.--Zncidence of new coronary heart disease by smoking category and behavior type for men 50-59 years of age
                        (Numbers in parentheses are number of CHD cases in each subgroup,)

Smoking group

Behavior           NNCT
iYPf            snmkcd

Former
cigarette
smokers

Current and
former pipe
and cigar only

1-15

Cigarettes

  16-25

26 and over

Total

A  _... `12.4(5)
B .._... .._  10.0(4)
   Total    11.1(g)
-.

  Sourre

1X.6(8)
5.1 II)
14.2(9)

21.8 (8)
8.4 (3)
14.9(11)



Sum of S4"BTes

16.4(5)        21.5 (9)        30.0(14)        20.4(49)
4.?(l)        21.1 (7)         19.1 (5)        12.0(21)
11.5(6)        21.3(16)        26.0(19)        16X(70)
     Analysis of variance table -          ..__


   d.f.        Mean S4"BlY         F        T-

Within cells .............................................    63.527
Rwression on axe ......................  ., ....................     0.171
Uetween smoking groups - ...................................     0.522
Between behavior types 1 .....................................     0.296
lnternction  ....................................................     0.129

1 Rates are age-r.djusted annual incidence ner 1,000 men.
: Mean squares for "between smoking groups" and "between behavior
types" are each computed eliminating the acnersl mean and the other main

       911          0.070                      
         1          0.171          2.54          0.111
         5          0.104          1.496          0.188
         1          0.296          4.24          0.040
         5          0.026          0.37          0.870

effect but ignoring interaction, thus yielding an estimate of each main ef-
fect unconfounded by other significant main effects.
SOURCE: Jenkins, C. D. et al. (90).


TABLE A20.-Experiments concernixg the cfects of smoking and nicotine OYI unimnl cc~~dio~~asc~~la~ function.

Author.
  Ye**.      Number and       Smoking      Heart     Blood    Cardiac     Coronary
country,      type of        procedure      rate     pressure    output      blood                 Comments
reference     population                                          flow

Bell&     39 experiments     Inhalation      Definite    Definite                     Coronary artery ligation increased the frwuency
et al.,     on dogs which      of tobacco      increase. increase.                      of nicotine-induced severe arrhythmias; these
1941.     had undergone     smoke in                                       hecame less evident with increasing time since
U.S.A.    P"ron**y         chamber.                                        ligation.
(21).     artery liga-      Nicotine       Definite    Definite
        tion up to        intravenous increase.   increase.
        45 days before.     0.2-1.2
                     mg./kg.

     Burn and   10 rabbits,        Experimental                                   Isolated "trial specimen showed increased rate and
      Rand.     5 rxperimental,     animals pre-                                    incrensed amplitude of contractions with admin-
       1958,     6 control,        treated with                                      istrati"" of nicotine proportional to pretreat-
      England   isolated atria.      intraperitoneal                                     mat. These reactions were blocked by reserpine,
       (35).                  nicotine and                                      and the authors consider nicotine effects to be
                           the atria of                                      mediated by catecholamine release from chro-
                          both groups                                       maffin store in myocardium.
                           excised and
                           perfused with
                           nlrotine.
              ___~
     West et al., 33 normal        C0*0ll*lY      Definite                             1. Myocardial contractility increased 40-90 per-
       l%R,     ndult mongrel      intra-        increase                               cent in 15/15 animals tested accompanied by
      U.S.A.    dogs.           arterial      (systolic).                              ST segment depression and T-wave inversion
       (?OSi,                 nicotine:                                         and blacked by tetraethylnmmonium chloride.
                          I. 0.2~2.2                                       II. Coronary blood flow increased 19 percent upon
                           !a./ka.                                          left circumflex artery injection: coronary blood
                          II. 0.04-l                                           flow showed no change upon left anterior de-
                           wz.lks.                                        scending artery injection, 64 observations on
                                                                          10 dogs.
                                                                       (Tetmethylammonium chloride blocked CBF in-
                                                                        crc*sc. )
                                                                     The authors found no evidence of coronary vase-
                                                                        constriction in these healthy animals.
s


TABLE A20.-- -Experiments concerning the efects of smoking and nicotine on nnimd cardiovascular function (cont.)

Author,
ye**.
country,
reference

Number and
type of
population

Forte     27 observa-
et al.,     tions on 6
1960.     dogs.
U.S.A.
(65).

Smoking      Heart
procedure      rate

Blood
PRSS"lT

Cardiac
output

c"E3,"                comments

fl"W

Intravenous
nicotine up
to 21.5 mg.
given 8s 5-15
ag./kg /
minute.

Definite
initial
increase
then
decrease.

No change.

No significant change in either left ventricular
work or myocardial oxygen extraction.

Kicn and   21 ndult doss      Cigarette              Definite    Definite    Increase       Effects of cigarette smoke were duplicated by in-
Sherrod,                smoke under            increase.   increase.   following      travenoua nicotine and epinephrine.
1960,                  positive                              increase      During cigarette smoke inhalation. it wns noted
U.S.A.                 pressure via                           in blood       that without blood pressure or output changes.
(112).                 tracheostomy.                          pressure       coronary blood flow did not increase and that
                    Nicotine 20                             and cardiac     while adverse EKG changes were noted they eor-
                    wg.lkg. intra-                          output.       related morn closely with decreased cardiac oxy-
                     venously.                                       gen utilization than with actual cardiac work.
                   Epinephrine 5
                     eg./ka. intra-
                     VenouslY.

Travel1    14 normal        Intravenous                           Definite       Nicotine-induced coronary blood flow and heart
et al.,     rnbbits and       nicotine                              increase       rate increase in the atherosclerotic animals re-
1960,     16 rabbits        0.01-0.1 mg.                           in normals.     wired 10 times and 2 times. respectively, the
U.S.A.    with severe                                                    amounts required in the normal animals.
(189).    cholesterol-
        induced athero-
        sclerosis.


TABLE AZO.-Experiments concerning the eflects of smoking and nicoline on animal cardiovascular function (cont.)

Author.
yea=,
eoutry,
reference

Number and
type of
population

Smoking
p*0Wdll*e

comments

Bell&     I. 10 normal dogs   Intravenous                            I. 125 percent   The authors noted that:
et al..    II. 9 dogs at       nicotine,                               increase     1. The response of coronary blood flow to nico-
19G2.        varying in-     20 ag./kg.l                           II. 82.5 percent      tine resembled that of anoxemia in the pres-
U.S.A.       terva1s fol-     minute for                              increase        ence of coronary insufficiency.
(22).       lowing coro-    15-20 minutes.                         III. 83.3 percent    2. The greater the induced coronary impairment
           nary artery                                        increase        the smaller the increment in coronary blood
           ligation.                                                      flow.
       III. 7 dogs with
           varying
           grades of
           artilicially-
           induced coro-
           nary artery
           narrowing.

Leaders    15 adult         Left anterior                                     Nicotine and norepinephrine both increased coro-
and      mongrel         descending                                      nary vascular resistance and myocnrdial contrac-
Long.     dogs.           intracoronary                                     tile force (the former measured by B constant-
19G2.                  injection of                                      volume variable-pressure system) The action of
U.S.A.                  nicotine or                                       nicotine was blocked by pretreatment with hex-
(125).                 norepinephrine.                                  amethonium. pentolinium, resetpine. or gusme-
                                                                  thidine.

Larson    13 adult         Intravenous            Definite    Definite               Systrmic vnscular resistance and pulmonary artery
et al..     mongrel         nicotine.              incrense. increase.              and left atria1 pressures showed biphasic re-
l9G5.     dogs.           0.02 mg./kg./                                      sponses of increase followed by decrease.
U.S.A.                 minute for
(194).                  lo-12 minutes.


TABLE ABO.-Experiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.)

i;       Author,
        year.         Number and                Smoking
       c0untl-Y.         type of                  procedure                             comments
       reference        population

     Folle     7 dogs of 30 investigated      I. Cigarette smoke inhalation       I. No change in coronary vascular resistance.
       et al.,     (Remainder experienced       to isolated left lower lobe       II. 5/6 showed increase in coronary vascular resistance due, according to
       1966,     catheterization failures).       nnd then blood perfused coronnry      the author. to general sympathetic nervous system stimulation.
       U.S.A.                         arteries.                III. 4/5 showed increase in coronary vascular resistance. The authors con-
       (84).                       Il. Cigarette smoke to rest of           elude that the cardiac effects of tobacco arise almost entirely from
                                  lung and then blood passed to       the extracardiac actions of smoking instead of the direct response
                                   general circulation.              of the heart.
                               III. Kieotine perfused directly
                                   into left coronary artery.

Nadeau and
James.
1967.
U.S.A.
(14P).

26 dogs

Nicotine 0.01-10.0 pg. into
sinus node artery.

Heart rate showed initial slowing (due probably to vagal stimulation) fol-
lowed by acceleration (due probably to vagal paralysis and catecholamine
release). No systemic blood pressure changes noted.

Romero and
Talesnik,
1967.
U.S.A.
(156).

16 experiments
on isolated
cat heart.

Nicotine in varying doses in
perfusatr of coronary arteries.

Over 5 pg. of nicotine was found to produce an initial bradycardia asso-
ciated with increased coronary flow, followed by prolonged tachycardia
with an initial decrease in coronary blood flow followed by a prolonged
increase. Pretreatment with heramethonium or reserpine prevented both
the myocardisl stimulation and the increase in coronary blood flow. The
authors consider the action of nicotine to be a combination of a direct
vasoconstrictive effect and an indirect catecholamine-releasing vasodilating
effect.

Put-i
et al..
1968.
U.S.A.
(252).

22 mongrel dogs

I. (14) Intravenous nicotine         I. Nicotine produced a definite increase in the force and velocity of left
   SO &g./kg./minute fur 3-4          ventricular contraction.
   minutes                II. Pretreatment with propranolol produced (relative to results of Group I) :
Il. (8) Propranolol pretreat-            (a) A further increase in left ventricular systolic pressure.
   ment, then 50 pg.lkg./minute        (bl A decrease iv velocity of Jhortening.
   nicotine for 3-4 minutes           (c) A significant increase in left ventricular end-diastolic pressure.
                       The authors conclude that ~mp,rsnolol probably impairs the norepinephrine-
                       like effects of nicotine on the myocardium while enhancing its peripheral
                         "*80pre880* e*ects.    -


TABLE AZO.-Experiments concerning the effects oj smoking ad wicotixt OH u)lit)ld co?.dio(.~~scz~l~~~ fwctiox (cont.)

Author.
  year.         Number and                Smoking
country,         type of                  pr"Ced"r.5                             Comments
reference        population           ___-. -
BalWZs    Beagle dogs with lesions     I. Normals (3 ~G per experiment) :    I. (a) No evidence of nrrhythmins: (b) A single or B few ectopic beats
et al.,     induced in myocardium by      (a) 4 Pg./kg. intravenous          in 2/3 normal dogs.
1969.     either: (1) Isoproterenol       nicotine, (b) 40/1g./kg.        II. Extrasystoles noted in 2/3 animals during the first day after cessation
U.S.A.    pretreatment, or (2)          intravenous nicotine.           of the arrhythmia induced by the lesion alone. but not thereafter.
(16).     ligation of the anterior    11. Experimental (3). 4 pg./kg.         These sod nicotine-induced arrhythmias were of n short duration.
        descending coronary artery.      intravenous nicotine

Creensoan  Cardiac muscle isolated from   Nicotine 2-100 ug.,`cc. in           Nicotine perfusion produced:

et al.,
1969,
U.S.A.
(74).

the right ventricle of 10
adult dogs.

Tyrode's solution perfusate.

(1) A" increaw in myocardial contractile force apparently independent
   of adrcnergic innervation.
(2) An increased nutomaticity of the Purkinje fiber system apparently
  due to release of catech"lamin& from rhromaffin tissue stores.
(3) A decrease in conduction velocity.

The authors conclude that the latter two effects probably predispose to ar-
rhythmia formation.

Saphir and
Rapaport,
1969.
U.S.A.
(166).

SR mongrel cats

Nicotine 5-12 Kg. kg. injected
intraarterially to mesenteric
circulation.

I. Mescnteric injection "I nicotine was followed with l-2 seconds by:
   (a) Increased left ventricular systolic pressure (LVSP).
   (b) Increased systemic resistance.
   (c) Enhanced myoeardial performance.
II. Left ventricular injection of nicotine was followed by.
   (a) Increased LVSP.
   (b) Bradycardia.
   (c) Enhanced myocardial performance greater than that seen in
      mesenteric-injected group.

III. Pretreatment with phenoxybenznmine diminished the increase in LVSP
   while proprnnolol pretreatment diminished the enhancement of my-
   "cardial performance while LVSP still showed a significaut increase.
IV. Mesenteric sympathetic nerve section led to a diminished response.
The authors conclude that the cnrdiovascular responses to nicotine msy be
neurogenic in nature with receptors distributed in certain abdominal
arteries.


   TABLE AZO.-Experiments concerning the effects of smoking and nicotine on animal cardiovascular function (cont.)
-

Author,
year.
country,
reference

Leb et al.,
1970,
U.S.A.
(126).

Smoking
procedure

Comments

  p&&ion

12 mongrel dogs and

Nicotine 100 eg.lkg. for      Effective Coronary Flow (ECF) is that part of the total coronary flow

CBF measured with use of
Rb3' and digital counter.

2 minute intravenously.

(TCF) which is "effectively ' involved in nutrient exchange.
Nicotine injection was followed by:
(1) 96.6 percent increase in TCF.
(2) 51.1 percent increase in ECF.
(3) 73.1 percent increase in myocardial oxygen consumption and analysis
     revealed that capillary flow increased almost proportionately to my-
    ocardial oxygen consumption whereas the increase in TCF was far
     in excess.

(4) Definite increases in cardiac output, heart rate. left ventricular work,
   and aortic pressure.

Ross and
Bless.
1970.
U.S.A.
(160).

  10 dogs undergoing
instantaneous coronary
arterial flow measurement.

Nicotine 10-100 fig. intra-
  coronary injection.

Nicotine injection ~8s followed by:
( 1) Increased contractile force.
(2) Decreased myocardial contraction time.
(3) Decreased time necess8ry to reach peak tension.
(4) Decreased total stroke systolic CBF.
(5) Increased total stroke diastolic CBF.
(61 Increased total stroke CBF.
(7) Changes similar to intraarterial ppinephrine.
(8 1 Changes blocked by pentolinium pretreatment.
(9) No change in heart rate or blood pressure.
The authors conclude that catecholamines released from the ventricular
myocsrdium mediated these responses to nicotine.


TABLE A21.-Experiments concerning the effects of smoking. and nicotine on the cardzovascular sy.stcw~ of lm~~tans

Author,
ye*=*
countrY,
reference

Number and
type of
population

Smoking       Heart
PlYlCCdUrC       rate

Blood   Electrocardiogram    Stroke     Cardiac
PW2*SUW  ballistocardiogram    volume     output  CC&0;d"=Y       Comments
                                     flow

Russek
et al.,
1955,
U.S.A.
(164).









nargeron
et al..
1957,
U.S.A.
(17).

I. 28 healthy     1 standard and 1     I. Increase. Increase.    EKG:                               Denicotinized cigs-
   male smokers   denicotinized                       I. 16/2R showed                           rettcs evoked changes
   21-60 years    cigarette.                           significant                           of a lesser degree
   of age (aver-                                   changes.                             in normals and CHD
   age42).                                 II. No sig-                              subjects. but in the
II. 37 male patients              II. Increase. Increase.       nificant                             latter group there
   with overt                                     changes.                            was no significant
   clinical CHD                                 BCG :                                 difference between
   42-70 yearsof                                I.                                 these changes.
   age (*"erage                                II. 18/37 showed
   64j.6 were                                     significant
   nonsmokers.                                    change.                  -
14 of 30 healthy    1 cigarette       Insignificant Increase.                                Definite   Corunary vascular
adult male vol-    inhaled at        increase.                                         increase.  resistance fell
unteer smokers    intervals of                                                          signifirnntly.
and nonsmokers   20 seconds.                                           Myocardial O2
who underwent                                                                     "Saxl? untler\vent no
successful                                                                        significant change.
catheterization                                                                    Pyruvat< rstraction
l&53 years                                                                       fell slightly.
of age.                                                                          Authors consider
                                                                           lark of increase in
                                                                           heart rate as due to
                                                                           hawlinc nvprehensive
                                                                           tnrhycnrdia.
                                                                           _____


TABLE AZL-h'rperiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.)

Author.
Ye*=,
countrY,
reference

Nut;;z;f""d
population

Smoking
procedure

Heart
rstc

Blood   Electrocardiogram    Stroke     Cardiac
masure  ballistocardiogram    volume     output  C-&W       Comments
                                     flow

2 standard

cigarettes in
25 minutes
inhaled at
minute
intervals.

Definite

increase.

Definite

increase.

                           -
Increase.   No signi- Myocardial 0, COI~SUIIIP-

flcant   tion rose ol?ghtly in
change.   3 out of 7.
     The author considers
      that the EKG changes
      noted on smoking are
      probably due less to
      decreased coronary
      blood flow than to
      increased workload
      (oxygen need) where
      uxyuen supply does
      not increase.
     Noted no evidence of
      myocardial ischemia
      during smoking.

Regan
et al..
1960,
U.S.A.
(1.54).

`I males with
history of
EKG-pr~~en
myocardial
infsrctiun
undergoing
cardiac ca-
theterization.

Thomas and  113 clinically
Murphy.    healthy young
1060,       males.
U.S.A.
(186).

One standard
cigarette
smoked at
own pace.

Definite
incresse.

Definite                Definite
increase.               increase.

Definite
increase.

Pulse pressure showed
a decrease.
Smokers responded
slightly hut signi-
ficantly more
actively than non-
smokers.
BCG changes were
increasingly common
with increasing age.
weight, and serum
cholesterol.


TABLE A21.--Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.)

Author.
Year.
country,
reference

Number and
type of
PoPulation

Smoking       Heart
Procedure       rate

Blood   Electrocardiogram    Stroke     Cardiac   COr0"ZM-Y
pressure  ballistocardiogram    volume     output    blood        Comments
                                    flow

Van Ah",
1960.
Sweden
(202).

The author
reviews a
series of
experiments
performed
between
1944-1954.

Cigarette
smoking.

I"CTe*StL

EKG: Slight ST
segment
depression
and T-wave
flattening.

EKC changes more
prominent in young,
clinically healthy
subjects than in
older, habitual
smokers. Intra-
venous nicotine and
smoking showed
identical cardio-
vascular effects.
Smohing elicited
angina pectoris in
a number of CHD
patients.

Irving and   5 normal males,   (a) Shamsmoking. (a) No     No change.             (a) No change. No change.        Cardiac output
Yamamoto,   15 patients with                  change.                                             measured by dye
1963,       diseases not de-   (h) Non-inhalation (b) No    No change.             (b) No change. No change.         dilution technique.
England    fined, 19-M years     smoking.        change.
(X0).      of age, all mod-  (c) 2 standard     (c) Definite Widened               (c) Definite   Definite
         crate-heavy        cigarettes in      increase.  PUL?.                   increase. increase.
         cigarette smokers.     10 minutes.             pressure.
                    (d) Nicotine 0.6    (d) Definite Definite               (d) Definite   Definite
                        mg. intra-       increase.  increase.                  increase.   change.
                        V~llOUSlY.

m


`JIAIXE A21.-E.rllc,~i,)lents concerning the effects of smoking and nicotine on the cardiovascular q&em of humans (cont.)

Number and
type of
population

Smoking       Heart
procedure       rate

Blood   Electrocardiogram    Stroke           Coro"ary
P)`ESs"re  ballistocardiogrsm    volume             blood        Comments
                                    Row

I. 14 volLl"trers   Single cigarette

  with clinical
  CHD, Is/14
  smokers,
  riverap2 axe
   x0.5.
II. 5 patients
   with nngina
   pectoris, all
   smokers, sve-
   rage *x6! 43.4.
III. 14 patients
  with history of
   definite myo-
   cnrdinl infarc-
   tion, all smok-
   ers averaxe
   age 54.1.

smoked at own
rate in G-7
minutes.

-

5 mnlc nnd 3     ? standard
female patients    cigarettes in
with heslrd      10 minutes at
myocardinl infarc-   rest and under
tion 48-69 years   graded exercise.
of nge Z/B non-
smokers.

Definite     Definite
increase increase
in all      in all
groups.     groups.

I. 10      27 percent
  percent   increase.
  increase.

II. Inter-    I"tmme-
   mediate   diste
   change.   change.

III. 8 per-    1 percent
   cent     increase.
   decrease.

Definite
increase
at rest
and at
exercise.

No signifi-    No signifi-         The author contrasts
cant changes   cant            this response with
at rest or     changes          that see" among
during      at rest or         healthy young
exercise.     during           individuals.
          exercise.


.4uthr.
Ye" r,      Numlrr nnd       Smoking       Heart      IJlood   Electrocerdioarnm    Stroke     Cardiac
country.       tyne of        procedure        ret"2      P~PSB"~`?  ballistocnrdiogram    "olume     OUtPUt  C"b,x-&T       COTLItleIltS
reference     nopulatiorr                                                                flow

Sen Gupta   6 healthy male    1 untipped        Increase    Increase    No change.
and Ghosh,   nonsmokers.     cigarette in       in all      in all
196'7,     8 healthy male     5-7 minutes.       KroIII)s.     KP3"I)S.    6/8 showed ST
India      smokers.                                      rhanges.
(171).    6 patients with                                  All showed ST
         CHD, nonsmokers                                 and T-wave
        3 patients with                                    changes.
         CHD. smokers.                                 All showed ST
        36-64 years of age.                                 and T-wave
                                                   changes.

AIXllUW
rt al.,
lY68.
U.S.A.
(5).

10 male patients   1 rtandard high     Definite     Definite                                        Product of systolic
with classical     nicotine cigs-      increase.    increase.                                       blood pressure and
angina pertoris.   rctte in 5                                                             hart rate showed a
32%5Y wars of age  minutes.                                                             significant increase
                                                                           on smoking while left
                                                                           ventricular ejection
                                                                           time vnlurs did not.
                                                                           All patients developed
                                                                           angina more rapidly
                                                                           under a constant
                                                                           exercise load if they
                                                                           had smoked before
                                                                           exercising.

   Kerrivan    24 male and 1     2 filtered ciga-     Delinite     Delinite                         Cardiac           The increase in
    et al.,      female healthy    rettes in 15       increase    incrensc                         index.           cardiac index. heart
    lY68,      smokers. average   minutes with      under      under rest                        Definite          rate. and blood
    U.S.A.      age, 45.        measures taken     rest and     and exercise                       increase          pressure during
    (lfJ2).    H male and 2       at rest and during   exercise     conditions.                        under rest         exercise with smoking
             female healthy exercise.         conditions.                                and             was the sum of such
             nonsmokers,                                                         exercise          increases seen with
             average age 33.                                                       conditions.        smoking or exercise
                                                                           separately.
                                                                           Neither group showed
                                                                           increases in peri-
Y                                                                           pheral vascular
                                                                           resistance.


TABLE APL-Experiments concerning the effects of smoking and nicotine on the cardiovasculw system of humans (cont.)

Author,
yea=.
COU"bY.
reference

Number and
type of
population

Smoking       Heart
procedure       rate

Blood   Electrocardiogram    Stroke     Cardiac
pressure  ballistocardiogram    volume     output  Cr,;;;=Y       Comments
                                     flow

Allison     30 healthy male    2 standard ciga-    Definite     Increase.                         Increase fol-        Definite decrease in
and Roth,    subjects.        rettes smoked      increase.                               lowed by          pulmonary blood
1969,     19-59 years of      in 12-16 minute                                          decrease          .volume as indicated
U.S A.      age.          period.                                                within 20         by impedance methods
(3).                                                                      minutes.          of thoracic pulse
                                                                           volume.

Aronow and  10 male patients   1 low nicotine      Definite     Definite                                       All patients developed
Swanson.    with classical     cigarette in       increase. increase.                                      angina sooner if
1969,      angina pectoris.   5 minutes.                                                            they smoked before
U.S.A.      32-59 years of                                                                    exercising.
(7).       age.

Aronow and  10 male patients   1 non-nicotine     No change.   No change.                                      No difference noted
SWZHISO",    with classical     cigarette in                                                           in time or onset
1969,      angina pectoris.   5 minutes.                                                            of exercise-induced
U.S.A.    32-59 years of                                                                       angina between
(6).       age.                                                                          smoking and "on-
                                                                           smoking procedures.

Marshall
et al..
1969,
U.S.A.
(229).

42 normotensive
healthy male
prisoners
18-50 years of
age.
13 nonsmokers.
16 moderate
smokers.
13 heavy smokers.

3/4 of one standard  Insignificant Insignificant                                    Blood pressure response
cigarette.        increase. increase.                                       to cold pressor test
                                                                 noted to he greater in
                                                                 heavy smokers.
                                                               Presyneopal reactions
                                                                to 40 degree head-up
                                                                  tilt more frequent
                                                                  in smokers.


TABLE A22.-Experiments concerning the effect of nicotine or smoking on catecholamine levels

Author, year.
  country,   Nu$royd          Procedure                                 Results
  reference        subject                                                         -.
Watts,       11 dogs          0.02-0.60 mg/kg.          Nicotine administration was associated with significant increases in peripheral arterial
1960,                      nicotine intravenously.      epinephrine levels. Ganglionic blocking agents prevented this effect.
U.S.A.
(am).

Westfall
and Watts,
1963.
U.S.A.
(210).

22 mongrel dogs

Cigarette smoking via
tracheal cannula;
1 cigarette/8 minutes
for 35 minutes.

Regular cigarette smoke evoked a statistically significant increase in adrenal vein,
vena CBYB, and femoral artery levels of epinephrine. Cornsilk cigarette smoke evoked
no change.

W.&fall      21 male vol""teers   3 cigarettes smoked in       Smoking at rate noted for 2% hours evoked a significant increase in urinary rpine-
and Watts,     approximately 25    30 minutes.            phrine. but not norepinephrine levels.
1964,        ye*4 of age:
U.S.A.       11 nonsmokers.
WI).        10 smokers.

Westfall et al..   Mongrrel dogs      Standard cigarette smoke     Smoke inhalation evoked a rise in cardiac output, stroke volume, blood pressure. and
1966.                     exposure via endotracheal     plasma cstecholamine levels. Pretreatment with propranolol diminished the cardiac
U.S.A.                     tube. Smoke inhalation      output and stroke volume responses hut increased the blood pressure response-the
(209).                    every third inspiration for    latter effect due to the release of alpha-receptor activity by beta-blockade.
                         3 minutes.


d             TDLE A23.--Experiments concerning the atherogenic effect of nicotine administration

Author, year,
  country,     Number and type            Procedure                                 Results
  reference       of animal                                                            -___- _____
Adler et al..     Rabbits         Nicotine 1.5 mg. intravenously in 5 percent    The authors noted an artcrionecrosis of the aorta, affecting mainly the
1906,                     solution C of 7 days per week for more than    inner muscular layers. Macroscopically, early changes consisted of
U.S.A.                     4 months.                      small areas of caleareous ridging and aneurysmal dilatation without
(2).                                               notable fatty degeneration or intimal discontinuity. Microscopically.
                                                early changes appear& in the muscle cells of the media, and "chalky"
                                                    deposits were noted between the elastic fibers.

HuePer,
1943,
U.S.A.
(86).

I. 6 mongrel dogs.  Nicotine subcutaneously. Increasing dosage up   1. 4/6 animals died of infection and showal marked edema and focal
             up to 2.5 cc. of 3 percent solution for 1         hyalinization of the media of the aorta and large elastic arteries.
              month,                           2/6 animals were sacrificed and showed thickening and hyalinizs-
                                          tion nf the walls of the coronary arteries and edema of the media
                                            as well as endothelial proliferation of other arteries.
II. 60 rats.       Increasing doses up lo 1 cc. of 1 percent       II. Much less nortic involvement than that found in the dogs; infre-
              solution for 1 month.                   quent arteriolar changes consisting of fibrosis and thickening of
                                             the media.

Maslova,
1956,
USSR
(180).

Czochra-
Lysanowicz
et al.,
1969,
U.S.A.
(46).

Rabbits

1. (10) Nicotine subcutaneously 1 percent
  solution 0.2 cc. daily for 115 days.

II. (14) Nicotine plus 0.2 grams cholesterol
   per day.

III. (10) Cholesterol only

Rnbhits

I, (10) 1.0 g. cholesterol/day for 100
  days.

11. (10) Cholesterol plus 0.0015 g. nicotine/
   day intravenously.
IIJ. (4) Nicotineonly.

I. Aortic wall---acute swelling of elastic fibers with focal fragmenta-
   tion and partial disintegration- no intimal fat deposits seen.
   Coronary vessels--thickening of the vessel wall-no fat deposits.
II. Aorta--"massive" deposits of "cholesterol" in the intima and vasa
   vasorum with "loosening" of the sortie wall. Coronary vessels-
   the larger vessels showed moderate fat deposition and the smaller
   vessels showed swelling of the elastica.
III. Aorta-isolated lipid deposition in the arch and ascending portions
   only. Coronary vessels---no fat deposition.

Index of aortic lesion density (cholesterol infiltration) :
I. 2.5.
II. 3.4.

III. No aortic lesions noted.


Author, year,
cnuntry.
reference

Number and type
  of animal

Procedure

Rrsults

Wenzel et al.,
1959,
U.S.A.
( 127).

Rabbits

Thienes
1960,
lJ.S.A.
(1X4).

Newborn rats and
mice.

Grosgogeat
et al.,
1965.
Frnnce
(75).

Male rabbits

I. (12) Cuntrol untreated.
II. (12) Control diet plus 1 percent
   cholesterr,l nnd 5 percent cottonseed
   oil added.
111. (12) Control diet plus oral
   nicotine 2.28 mg./kg./day.
Iv. (12) ncaimen II DIu!; ~711 nicotine
   2.28 m~./kg./day.
V. (12) Regimen II plus oral nicotine
   1.42 mg./kg./day.
VI. (12) Regimen II ~,los oral nicotine
   0.57 mg./kg./day.

Nicotine subcutaneously up to 5 mg./kg.
twice daily by the end of 1 month.
Animals nntrrpsied at I year.

I. ( 10) Nicotine subrutaneoujly 0.15
   m,E./day.
   (10) Controls-saline injected.
   Sacrificed at from 20-120 days.
II. (27) Same as Group I
   (27) Controls--saline injected.
   Sacrificed at 90 days.

Significant diffrrrnws in a<,rtic subendothclinl fibrosis betwwn control
and exw~imental yrwps noted w11y in II and IV. In group IV, the
nicotine-treated grcn~~) showed mow srwre change

III. (66) Nicotine subcutaneously
   0.:3&1.5 mg./dny.
   Sacrificed at 30 days.
IV. (24) Nicotine subcutaneously 0.75
   ma./day.
   (24) Controls--saline injected.
   One-half of each group ate cholesterol-
   enriched diet (0.5.-1.0 percent choles-
   terol added).

Sacrificed at 60 days.


TABLE A23.-Experiments concerning the atherogenic effect of nicotine administration (cont.)

Author. year,
countrY,
reference

Number and type
  of animal

Procedure

ReSUlt.3

Hass et al..
1966,
U.S.A.
(80).

Male rabbits

1.
II.
III.
IV.
V.
VI.

  Nicotine   Diet     Vitamin D
(8) Control   Control   Control     I. Infrequent medial calcific disease without lipid locnlization.
(7) Control    Cholesterol Control    II. No medial caleific disease but frequent intimal atheroma formation.
14) Nicotine   Control   Control    III. Rare cnlcific medial degeneration; no intimal atheromatous disrase.
15) Nicotine   Cholesterol Control    IV. The largest number of atheromatous lesions.
(9 1 Control    Cholesterol Vitamin D   V. No medial calcific disease.
14) Nicotine   Cholesterol Vitamin D   VI. Consistent medial caleific disease.
(Sacrificed at various times)

Control-no treatment.
Nicotine-subcutaneous injections in oil-
increasing amounts 2 times per week.
Vitamin D--subcutaneous injections UP to
6-8x 1oJ IU.

Cholesterol-250-500 mg. cholesterol added

Choi.
1967,

Albino rabbits

per 100 g. diet.
I. Nicotine l-5 mg./kg./day intraperi-
  toneally.

I. Increasing nicotine dosages were associated with decreased atheroma
  formation (findings not statistically significant).

Korea
(42).

   Cholesterol 1 g.lday (in varying      II. Nicotine alone produced no atheroma formation but was associated
   combinations with controls)         with the presence of aortic medial calcification and endothelial
II. Nicotine alone.                     hyaerplasia.
III. Cholesterol alone. (Sacrificed at 60 days)   III. Cholesterol alone was associated with a definite increase in atheroma
                                formation.

Stefanovich     Female albino,

I. (10) Diet supple-

Percent of am-tic  In both stock and cholesterol-fed animals, nicotine was also noted to

et al..        rabbits.            mented with 2.0
1969,                        percent choles-
U.S.A.                       terol. Nicotine in-
(178).                       tramuscularly
                         2.78 mg./kg./day.
                         5/7 days.
                      11. (10) Cholesterol
                           only.
                       III. (10) Nicotine only.
                       IV. (1") Contrul.
__ ~- -___- __~

surface involuad
with
athwoscleTosia
  I. 9.4
II. 5.7
III. 0.1
TV.

increase aortic triglyceride content and to decrease aortic free cho-
lesterol content.


TABLE A25.-Experiments concerning the effect of smoking and nicotine upon blood lipids
                           (Human Studies)

Author.
ye**,
country,
reference

Number and
type of
population

Smoking       Plasma free
procedure       fatty acids

Serum      Serum
cholesterol   triglycerides       Other             Comments

Page
et "I.,
1959,
U.S.A.
(147).

13 male and
I female
laboratory
workers
17-51years
of *ge.

2 nonfiltered
cigarettes
in 10 minutes
and blood
1Wels
measured
over30-
minute
period.

No change.

Serum lipoproteins
No change (10 subjects).

Kershbaum 31 male
et al.,     patients or
1961.      staff 16-72
U.S.A.    years of age,
(104).    I normals,
        1 CHD.
        17 other
        medical
        diagnoses.

I. 17 subjects
   smoked 2
   "on-filter
   cigarettes
   in 10
   minutes.
II. 9 controls.
III. 5 subjects
   smoked 6
   cigarettes
   in 40
   minutes.

Mean rise       No change.   No change.                  The authors consider the in-
I, 351 fiEq./L.                                   crease among controls to be
II. 9.X pEq./L.                                     due to fasting.
III. 27%2,304
   /LEq./L.

Kershbaum   I. 17 male    I., II., III.,        Mean rise                                       No difference found between re-
rt al..        patients    2 non-filter       I. 858 fiEq./L.                                 suits following inhalation or
1962,        with healed  cigarettes in      II. 320 &E&L.                                     noninhalation.
U.S.A.       myocardial   10 minutes.      III. 292 /.lEq./L.                                 Statistically significant difference
(10.9).      infarctions. IV. No smoking.    IV. 20 /IEq./L.                                    found between increases in
        II. 16 non-CHD                                                         Groups II and III and
           patients.                                                              Group I.
       III. 10 normals.

2             IV. 13 normals.


TABLE R25.-~;:.cl)cl'iltl(,?ll.s conwwi?lg the effect of srt/ok;ing and nicolim Icpon blood lipids (cont.)

Author.
yen*.
country,

Number and      Smoking
type of        prorrdurr

      (Human Studies)
1 SM - Smokers    NS = Nonsmokers]

Plasma free
fatty acids

Serum      Serum
cholesterol   triglycerides       Other             Comments

Definite irlcreasp
at start of
smoking peri~xl.

                         -.        -
3 patients with trimc-   Both free and total urinary
thaphan camphor-     catecholamines increased with
sulfanate (Arfonad)    smoking and the author
pretreatment and 8     considers them as mediators
formerly sdrenalecto-   of the FFA increase.
mizcd patients showed
either minimal or no
elevation.

-           ~-___
NS-dcfinitc     No change   NS- -definite

incveasc at
6 hours.
SM--definite
increase at
6 hours.

in either increasr
$?roup.      at 2 hours.
       SMslight
        increase
        at 2 hours.


Author.
year,
c'ountrg.
reference.

Number and
type of
population

Serum      Serum
cholesterol   t.riglycerides       Other             Comments

Frank1    5 male and 1    2 stnndnrd        No rhanpe.                                       Subjects werr in nonfasting,
et al.,     female        riaarettes                                                     nonbnsnl state.
1966,      healthy       inhaled in
U.S.A.     smokers       10 minutes.
(66).     24- 2!l
        scars rrf age.

Kcrshbnum 43 norm"1 male    I. Terminal
et al.,     heavy cigarette     segment of
l!W,      or cifial         cigar in 20
l1.S.A.     smokers.         minutes~- 15
(I,,,;)     21 4G years       subjects.
         of ape.       II. :i riparettes
                      in 20 minutes
                      15 subjects
                      (includintz ti
                     from group I).
                  III. Cipnwttr
                      inhalation or
                      nuninhalation
                      G subjects.

I. Indefinite
   increase.
II. Dcfinitc
   inrwesc.
III. I"urcaw with
   inhnlatio"
   zrcatcr thnn
   with "on-
   inhalation
   in every
   suhjeci.

Cip:u. smoking in 11 subjects
hhuwed a" intermediate in-
creaw in the excretion of
"rin:lry catecholamines as .
compalctl to thnt with +a-
rvtte smoking.

Klensch,    56 observations   1 standard        l)eli"itc                                         Ir~<lvfinitc increase in venous
1966,      on student     cigarrttt-         increase.                                        t*l)int.phri"r levels.
(krmany   smokers 20-24   in 4 minutes.
(118).    yeal of age.   FFA measured at
                   lG-25 minutes.


h

TABLE A25.-E.rperiments concerning the effect of smoking and nicotine upon blood lipids (cont.)
                             (Human Studies)

Author,
war.
country.
reference

Murchison
and
Fyfe.
1966.
Scotland
(139).

Numm;rz';"d
  population
-~
R male and 4
female mod-
erate smokers
with various
diseases 37-
67 years of
age.

Smoking       Plasma free
procedure       fatty acids

2 cigarettes
in 15 minutes.
I. I.it-riga-
   rettes.
II. Unlit-ciga-
   rettes.

I. Definite     No change.   No change.                 Both regular and sham smokers
   increase.                                     showed significant increases
II. No change.   No change.   No change.                   in concentration of serum
                                             P!Pif xid 2nd significznt
                                             decreases in concentration of
                                            serum palmitic acid.

Serum      Serum
cholesterol  triglycerides       0tIxi             comments

Kershbaum 6 normal

Various types

et al..
1967,
U.S.A.
(105).

heavy
cigarette
smokers
28-45 years
of age.

of cigarettes
of known
nicotine
content.

Regular cigarettes,
filter cigarettes.
charcoal-filte,
cigarettes. pipe
tobacco plus
cigarettes all
showed similar
increase in FFA.
Lettuce leaf
cigarettes had
negligible effect.

Ruth catecholaminc and
nicotine excretion rates showed
wsponses to the various ciga-
rettes similar to that of the
FFA response.


TABLE A25a.-Experiments concerning the effect of smoking and nicotine u/Ion blood lipids
                            (Animal Studies 1

ANIMAL AND Ih' VITRO STUDIES

Author.
ye==,
countrv.

Plasma free
fatty acids

SelUll     Serum
cholesterol triglycerides

Other           Comme"ts

reference  poG&tion

Wenael and 49 male     I. Untreated co"tro&                                     Group II and IV   The authors consider a" el-
Beckloff,   N.3V        12 subjecta.                                            showed an im-   evated cholesterol/ p&s-
1958.     Zealand   II. Regular diet plus                                          mediate in-      pholipid ratio to be a
U.S.A.    white       0.1 percent cboleaterol-                                     crease in plasma   notable indication of
ml6).     rabbits.       12 subjects.                                        cholestero) and    atherogenic susceptibility.
             III. Regular diet plus 2.28                                     phospholipids    The concomitant increase
                 mg./kg./day nicotine                                      with a level-     in phospholipids with the
                 in water-12 subjects.                                      with B leveling    cholesterol may negate
              IV. Diet plus-                                             of respon*e      the ilnportance of nico-
                 (a) 0.1 percent cholesterol                                   at 4 weeks.      tine-induced hypercho-
                (b) 2.28 mg./kg./day                                  Group IV showed    lrsterolemis as an
                      nicotine in water-                                    n further in-     atherogenic stimuius.
                  12 subjects.                                            crease at R-12
                                                                wrek period.

Kershbaum 6 monarel   Intravenous infusion of 20       Definite increase in
et al.,     dogs.     mg./kg. nicotine             lS,/l5 observations.
l!)Rl,             in 20 minutes.
1' S.A.
t ,34).

Kc,, ilbaum 20 adult     I. 9 received IM nicotine        I. Sirrnilirant inrrease         No change
c d..     mongrel      daily for 6 weeks:            in U/9 doas.              in "ny
otj      dogs.        up to 1 ma./ka.          II. No rhange.                BrOUP.
`-.S.A.           II. 5 placebo injection.        III. NI\ change.
(1071.           III. 6 control.


5

TABLE A25a.-Experiments concerning the eflect of smoking and nicotine upon blood lipids (cont.)
                              (Animal Studies)

         ANIMAL AND IN VITRO STUDIES
-

Author.   NWIlber
yeer,      and
country.    tYPe of
reference  population

Smoking
Procedure

Serum       Plasma frer   SeIWll
triglycerides     fatty acids  cholesterol      Other

Cnmments

Kershbaum 2X adult    Intravenous infusion of nicotine.                   No change.
et al.,     mongrel
1DGG.     doa%
U.S.A.
(Inn).

                                                      -.
Kersbbsw,, Spraaw-   Nicotine perfusion.
et al.,     Dawlev
1867.     rat
1J.S.A.     fat-pad
(110).    tissue.

The authors report on the
results of the use of ne-
thnlide (a Beta-ndrener-
gic blockrr), phenoxy-
benzamine, and chlor-
promazine to block the
FFA response to nicotine.
Only nethnlide rna~ suc-
rc.`cuC1,1 1,11{ !i:i:: c<,r.y!i-
tutes an indication that
nicotinr stimulatfzs Beta-
adrcnergie receptors to
release rntecholamines
which. in turn, stimulnte
the release of FFA.

4lthough nicotine perfusion
WBS not associated with
FI:A wlense from fat tis-
sue. epinephrine did
producr a significant in-
rwaw in FFA release.
The authors conclude
that the sympathetic
TLFI`YOUS system mediates
the FFA response to
nicotine in the intact
animal.


K jf2ldsrn
and
DRmanard
l!ltiX,
Denmark
(11.5).

K jeldsen,
1060,
Denmnrk
, 1 ,:,1

K it~ldsm,
l!lG!l.
I)r,nmnrk
(J1.1).

Number and
type of
population

4 male students zs-27
y<`<al's of age.

-

I. 12 control and 12 exposed
  togradunlly increasing CO
  c,mcentrations (0.015-0.40
  peri.x,t) over n 4-week
  period.

II. 12 control nnd 12 exposed to
   0.020 pwccnt co for 35 days.
III. 12 control and 12 cxposcd to
   to 0.020 perrent co for
   7 wwkq. then 0.036
   tte'rernt CO for 3 weeks.

serum I,h&ster,,l nnd triplyccride conwntrations rose to significantly higher
lr~r]~ during :l of tht. s wwks. No rhnngcs noted in serum phospholipida.


                          TABLE A27.Smoking and thrombosis
     - ___~~   -___~                                                                     -
4:      Author.
       year,   Number and   Experi-  tit2           Partial Recalcified
                                      PI-O-   thrombo-   plasma   Platelet   Platelet   Platelet   Platelet
      country.    type of     mental    clotting   tbrombin  plasti"   clotting  adhesive-   count   survival  turnover    Other      COHlllle"tS
      reference  poPulati0"   conditions '    time     time     time     time "ess
     ~___~         .~___
     Black-    16 adult     12 individuals                                                         Pl4Z.Wla

burn     schizo-      smoked 2
et al..    phrenic     high-
196!l.    patients, 8    nicotine
U.S.A.   university    stananra
(25)    studrnts, all   brand
       smokers.     cigarettes.
  -~ ~~-_- ___
MUhtmi   7 white males Comparctl
ana     with either   after
Murphy.  CVD 0,     periods of
t!ml.    COPI). "11    abstincncr
U.S.A.   hravy      or continua-
iljl).    smc,kr~m 3%   tion of
        72 YPB1'6 of   smoking.
        8BC.
--~~ __-~   ___~
Ambrrls   20 healthy    Drrp inhala-
and     malt? nc,n-    tic," <lf one
Mink.    sm<,kinp     nonfiltcred
l!l64.    mrdiral     rigarettt-.
U.S.A.   stdrnl~ <::30
(4).     yeal's of PPE.

hshby    27 male     13 wntrots
et al..    medical     measured at
1 9 6 5 (    students and   2 separate
Iwland   hxwl,ital     times 14
(8).     staff       subjects
        memtrers.    measured
                 before and
                 afte,
                sm(,ki"a 2
                 cigarettes
                 in 20
                 minutes.

(-)









(-)

(-)

(-)









(-)

     --




       (-)





  __.



(6)      (+-)
     increase


         .-






       (i-l
     incremr

                    stupvan
                     time
                     (6)



              Platelet ___--
                  clumping
                     time
(-)    (f)    (+)       (t)
     Avv-0RFP incrmre




                  --- ~~-. ____ __-
                3'hromhoplastin 2 students
                   r,c 2,~ r-rrtion    became ill.
(-)                   tip,,,      Results
                     `- 1      reflect
                            data on 1x.


                           Increase of
                            subjects
                            greater
                            than that
                            of controls
                            at p<O.Ol.


Author.                     Whole          Pnrtial  ltecalcified
Year,   Number arrd   Experi-     blood    Pro-   thrombo-   plasma   Platelet   Platelet   Platelet   rkitdet
country,    type of     mental    clotting  tbrombin   plastin   clotting  ndhesive-   count   survival  turnover    Other     commc"ts
referrnce  populntion   conditions 1    time     time     time     time     "es?3
Sogani   I1 obsrrvations Smoked 2 cis-                                                       Fihrinolvsi.?  fjiri-- ~
and     on "Isle     arettes or                                                          (f)      tobacco
Joshi.    >mokers all   :! biris or                                                          CllXLY%3~    wrapped in
1965,     regular      rhrwrrl 1     (-)     (6)           I --I      (f)                                 l~,bZiCW
India    tobacco      hetcl nut                              Inrreasc                                leaf.
(174). IlhPI`S.      rluid in 20

                minutes,
Engel-                                        .- ~-___
      40 male and   2 cigarettes

berg,    20 female    in 20
1 !I 6 5,    huspital pa-   minutes
U.S.A.   ticnts. all
(5.Y).    smokers IT-
      6X years of
      ;ige.

sc,n      4 fernalp     in 15
""d     patients     minutes.
Fyfr,    with       lit UT unlit                               (t)
lOfiR, various      cigawttrs.
Scotland  diseases, all
(MD,.    heavy
      smokers 37-
      67 years
      <>f age.

ChlWldlCT
(in ritm)
thrombosis
time
  +
decrease

Throw&
time
(*)
decrease

(f)
increase

t Smoking both
lit and unlit
cigarettes
caused a rise
in platelet
adhesiveness
which the
authors
correlated
with rise in
plasma non-
esterified
fatty acids.


TABLE A27.-Smoking and thrombosis (cont.)

z       Author,                     Whole          Partial Recalcified
       Year.   Number and   Experi-     blood    Pro-   thrombo-  plasma   Platelet   Platelet   Platelet   Platelet
      country,    type of     mental    clotting  thrombin  plastin   clotting  adhesive-   count   survival  turnover    Other      Comments
      reference  population   conditions 1    time    time     time     time ness

     C.lynn    21) male and   :i cigarettes                                                          Platelet   Smokers found
       et al.,    li fcmalc    in 30                                                             scrotinin    to have a
       19GG.    smokers and   minutes.                               (-)                          (6)      greater
       C*"*d*   9 male and                                                                   Plutclet     t~ndcncy for
       (71).    21 frmale                                                                   adcxosinc    platelet
             nvnsmukcrs                                                                 nucleotidc    aggregation
             Ii-i6 jears                                                                   (6)      than non-
             of age.                                                                           smokers.

Engelbrr~ 9.1 male and   1 cinarette
and     53 female    in 5 minutes
Futter-   patients and
man.    mcdicnl
l!lGi,    h<,uw ~ltatf.
U.S.A.
(5s).

Thmmbuu   No relation
jormu tion    found with
time      increase in
(+)      free Patty
decrease     acids.

                            Platclct
                           ndhwxncc to
(i)     (2)     C-t)            sYlsclLlnr
increase  increase  decrease          Lndothclircm
                            (+)
                            increase
                          Fibrinolusis
                             (5)
                            decrease
                           Thrombus
                           jormntiom
                             timt
                             (+)
                            decreasr


TABLE A30.-Experiments concerning the effect oj nicotine ant1 smoking xpon
           the peripheral vascular system

Author, year
country. reference

Moyer and Maddock,   20 subjects (including heavy smokers) were studied for the effects of
1940. U.S.A. (I%,).    the following procedures on skin temperature: the inhalation of a
             lit cigarette, inhalation through an empty paper tube. or the ad-
             ministration of 1 mg. nicotine intravenously. All subjects rrsponded
               with decreased cutaneous temperature following the smoking and
              nicotine procedures. No changes were noted following sham smoking.

Mulinos and Shulman,   A number of experimental groups, each consisting of 6-17 persons,
1940, U.S.A. (198).    were studied for the effects of deep breathing and cigarette smoking
              on skin temperature and digit or limb plethysmography. The au-
              thors concluded that deep breathing alone could account for the
             changes in temperature snd blood flow noted upon smoking and
               noted that denicotinized cigarettes evoked the same or greater
              vasoconstriction as that noted following the smoking of a standard
                cigarette.

Shepherd, 1951,
Ireland (179).

50 young male smokers were studied with plethysmography before
and after the normal and rapid inhalation of a standard cigarette.
The author noted that rapid inhalation was associated with a pro-
longed decrease in extremity blood flow while a more natural rate
of inhalation was followed by a momentary deerease in flow. The
author considered the former reaction to represent the pharmacolo-
gic effect of the smoke and the latter tu represent the physiologic
response to deep breathing, as the natural inhalation of r.n unlit
cigarette produced the fame transient decrease in flow as did the
natural inhalation of the lit cigarette.

Friedell. 1953.
U.S.A. (70).

52 male and 48 female young smokers and nonsmokers were studied
for the effects of smoking on hand blood volume as measured by
the use of radioactive iodinated albumin. The inhalation of un-
filtered cigarettes was associated with an average decrease in hand
blood volume of 19 percent in men and 33 percent in women; while
filtered cigarettes showed respective decreases of I1 percent and
21 percent.

StrBmhlad. 1959,
Sweden (18f ).

11 male and female subjects (smokers and nonsmokers) were studied
for the effect of the intra-arterial administration of nicotine (bra-
chial artery) on blood flow to the hand as measured by venous
occlusion plethysmogrsphy. Increasing doses of nicotine were asso-
ciated with increasing numbers of individuals manifesting vase-
constriction. The vasoconstrictive effects of nicotine were abolished
by the prior administration of either hexamethonium or pentolinium.

Bamett and Boake     9 male patients with intermittent claudication (7 were heavy smokers)
1960 Australia (~8)    were studied for the effect of smoking on blood flow to the leg BS
               measured hy venous occlusion plethysmography. Smoking an un-
               filtered cigarette was found not to produce any consistent changes
                in blood flow to the calf or foot of the affected leg,

Freud and Ward,
1960. U.S.A. (68)

15 mde prison inmates  (1 ess than 35 years of age) and 14 male
patients with peripheral vascular disease (approximately 65 years
of age) were studied for the effect of smoking on digital circulation
as measured by skin temperature, plethysmography, and radiosodium
clrarance from the skin. Smoking was found to adversely affect
the first and third measurej in a significant manner (while plethys-
mographic values were variable)  only in the healthy prisoners
and not at all in the parient group.

R&h and Schick,      100 normal individuals underwent 425 experimental procedures con-
1960,U.S.A. (161).     cerning the effect of smoking on the peripheral circulation. Smok-
               ing was found to be associated with a decrease in extremity skin
                temperature.

133


TABLE A30.-Esperiments conwrning the effect of nicotine and smoking upOn
         the peripkeral vascular system (cont.)

Author, year,
country. reference

Rottenstein et al..     8 males (18~1 yeam of age) were studied for the effect of intm.
1960, U.S.A. (162).   venous .nicotine on extremity temperature and bled flow. Intra.
             venous nicotine was found to evoke a decrease in skin temperature
            while increasing muscle blood flow. The former effect began swner
                and lasted kmger than the latter.

Allison and Roth,
1969. U.S.A. (4).

30 healthy indzviduals (19-59 years of age) were studied for the effect
of smoking two cigarettes on eXtreIdY Puke vohm?s and ski,,
temDerature. Smoking was found to be associated with a 2-6 per.
cent deereast, in skin temperature and ZI 45-50 percent decrease in
blood pulse volumes to segments of the finger. calf. and toe.

134


CHAPTER 3

Chronic Obstructive Bronchopulmonary Disease


Contents

Introduction .........................................
Epidemiological Studies ..............................
  COPD Mortality. ................................
  COPD Morbidity. ...............................
  Ventilatory Function. ............................
  Genetic Factors. ................................
    Alpha,-antitrypsin ...........................
  Air Pollution ....................................
  Occupational Hazards. ...........................
     Cadmium ...................................

Pathological Studies  .................................

Experimental Studies  ................................
  Animal Studies  .................................
   Studies in Humans  ..............................
  Studies Concerning Pulmonary Clearance  ..........
     Overall Clearance  ...........................
     Ciliary Function  ............................
     Phagocytosis ................................
  Studies Concerning the Surfactant System  .........

Other Respiratory Disorders  ..........................
  Infectious Respiratory Diseases ....................
  Postoperative Complications  ......................

Summary and Conclusions  ...........................

References  .........................................

FIGURES

1. Percent of lung sections with Grade IV or V fibrosis . . .   161
2. Percent of lung sections with Grade II or III emphysema   162

LIST OF TABLES

(A indicates tables located in appendix at end of chapter)
1. Chronic obstructive bronchopulmonary disease mor-
  tality ratios. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Page
139

141
141
145
146
148
150
152
153
154

154

158
158
163
164
164
164
165
172

172
172
174

175

1'76

142

137


   LIST OF TABLES (Continued)
(A indicates tablets located in appendix at end of chapter)

A2. Smoking and chronic obstructive pulmonary disease
    symptoms-percent prevalence. . . . . . . . . . . . . . . . .
A3. Smoking and ventilatory function . . . . . . . . . . . . , . . .
A4. Glossary of terms used in tables and text on smoking
    and ventilatory function. . . . . . . . . . . . . . . . . .
5. Cessation of smoking and human pulmonary function
A6. Epidemiological studies concerning the relationship
    of air pollution, social class, and smoking to chronic
    obstructive bronchopulmonary disease (COPD) . .
A7. Epidemiological studies concerning the relationship
    of occupational exposure and smoking to chronic
    obstructive bronchopulmonary disease. . . . . . . . . . .
8. Studies concerning the relation of human pulmonary
    histology and smoking . . . . . . . . . . . . . . . . . . . . .
9. Experiments concerning the effect of the inhalation of
   cigarette smoke upon the tracheobronchial tree and
   pulmonary parenchyma of animals . . . . . . . . . . . . . .
AlO. Experiments concerning the effect of the chronic in-
    halation of NO:> upon the tracheobronchial tree and
   pulmonary parenchy-ma of animals . . . . . . . . . . . . .
11. Experiments concerning the acute effect of cigarette
    smoke inhalation on human pulmonary function. .
12. Experiments concerning the effect of cigarette smoke
    on human and animal pulmonary clearance. . . . . . .
A13. Experiments concerning the effect of cigarette smoke
    or its constituents upon ciliary function . . . . . . . .
A14. Experiments concerning the effect of cigarette smoke
    on pulmonary surfactant and surface tension . . . .
A15. Studies concerning the relationship of smoking to in-
    fectious respiratory disease in humans . . . . . . . . .
A16. Complications developing in the postoperative period
    in patients undergoing abdominal operations . .
A17. Arterial oxygen saturation before and after operation

Pafie

195
206

215
l-19

216

218

155

I.59

220


166


170


221


`LP;,


226


230
"30

130


              INTRODUCTION

Chronic obstructive bronchopulmonary disease (COPD) is char-
acterized by chronic obstruction to airflow within the lungs. The
term COPD refers to three common respiratory ailments; namely,
chronic bronchitis, pulmonary emphysema, and reversible obstruc-
tive lung disease (bronchial asthma) ,*
Chronic bronchitis has been defined as the chronic or recurrent
excessive mucus secretion of the bronchial tree. It is characterized
by cough with the production of sputum on most days for at least
three months in the year during at least two consecutive years
(217).
Pulmonary emphysema is that anatomically defined condition of
the iung characterized by an abnormal, permanent increase in the
size of the distal air spaces (beyond the terminal bronchiole) ac-
companied by destructive changes (217).
Patients can suffer from both of these conditions simultaneously.
The symptoms as well as the abnormalities in pulmonary function
observed in the presence of the two ailments may be quite similar.
Patients with chronic bronchitis suffer from productive cough with
or without dyspnea (breathlessness both at rest or on exertion)
while pulmonary emphysema is characterized mainly by dyspnea.
COPD comprises a spectrum of clinical manifestations; thus, it is
frequently difficult to determine whether a particular patient is
suffering from one of the two specified diseases alone or which one
predominates when both are thought to be present.
COPD is responsible for significant mortality in the United
States. In 1967, a total of 21,507 men and 3,88.5 women were re-
corded as dying from chronic bronchitis and emphysema (221).
This figure does not include a sizable number of individuals for
whom COPD was a contributory cause of death.
During the past two decades, a major increase has taken place
in the mortality from COPD in the United States. In 1949. the
death rate from COPD was 2.1 per lO!J,OOO resident population,
while in 1960 it was 6.0 (zz~), and in 1967, 12.9 (221). Although

* Because mortality from bronchial asthma does not appear to be related to Cigarette smoking.
the term COPD will be used henceforth to refer only to chronic bronchitis and Dulmonam
emphysema. Exacerbation of preexisting bronchial asthma has been observed among Cigarette
smokers, Further elaboration ,,f this question may be found in a pretiow l'ublic Health Service
Review CZ.M).


                                                        139


much of this rise is probab y due to changes in certification and
recording methods as well as to an increased interest on the part
of the medical community, an appreciable proportion is also gene
erally accepted as reflecting a real increase in disease. Similar in-
creases over the past `LO to N years have also been observed in
Canada (7) and in Israel (54). The lack of a similar increase in
Great Britain, a country with an extremely high rate of COPD,
may be the result of a number of factors including improved
therapy and decreased air pollution. Moreover, it is also likely that
the diagnosis of COPD has been made more commonly and ac-
curately in Great Britain for a longer time than in the United
States, or elsewhere. Furthermore, the British definitions of hron-
chitis and emphysema have differed in the past from those used in
the United States.

The mortality from and prevalence of COPD is probably under-
estimated. In a study of death certificates, Moriyama, et al. (170)
reported that COPD is often omitted as a contributing cause of
death. In a study of more than 350 autopsies, Mitchell, et al. (169)
noted that the disease often goes unreported and that emphysema
was occasionally found unassociated with severe clinical airway
obstruction. Hepper, et al. (I 10) observed that ventilatory test re-
sults were abnormal in 10 percent of 714 patients in whom no
symptoms, signs, or past history of pulmonary disease were noted.
They concluded that severe degrees of ventilatory impairment may
be undetected by history and physical examination alone. Boushy,
et al. (10) evaluated clinical symptoms, physiologic measurements
of airway obstruction, and morphologic bronchial and parenchymal
changes in 90 males with bronchogenic carcinoma. The authors
found that when either clinical, physiologic, or pathologic evidence
of COPD was used alone, one-third to one-fourth of the patients
were considered normal, but when all three criteria were used to-
gether, only one patient wa:; free of COPD. The importance of
COPD as a contributing cause of mortality is now beginning to be
more fully recognized.

Clinicians have long observed that the majority of their patients
suffering from COPD lvere cigarette smokers (2, 150). Epidemio-
logical studies have validated this impression by indicating that
cigarette smokers are at a much greater risk of developing or dying
from this disease and that the risk increases with increased dosage
of cigarette smoke, reaching in the smoker of two packs or more a
day a level as high as 18 times that of the nonsmokers (132). The
salutary effect of giving up smoking has also been borne out by
clinical obsel-vation and epidemiological studies.

In a number of studies, smokers were found to suffer more fre-
quently than nonsmokers from pulmonary symptoms including

140


cough, cough with production of phlegm, and dyspnea. By a variety
of pulmonary function tests, smokers were shown to have dimin-
ished function as compared to nonsmokers and also to have a
steeper slope of the expected decline of function with age. Tests of
ventilation/perfusion relationships in the lung have revealed ab-
normal function in smokers. Autopsy studies have indicated that
smokers dying of causes other than COPD have significantly more
changes characteristic of emphysema than nqnsmokers.

Several recent studies have validated the clinical impression that
among patients who undergo surgery, cigarette smokers run a
greater risk of developing complications in the post-operative
period than nonsmokers.

Abundant experimental evidence of the role of smoking in
bronchopulmonary disease has been obtained from experiments
employing animals and tissue and cell cultures. Recent work has
demonstrated, in dogs trained to inhale cigarette smoke through a
tracheostoma, that emphysema, pulmonary fibrosis, and other path-
ologic changes in the pulmonary parenchyma and bronchi develop
and that these changes are proportional to the total dosage of cig-
arette smoke inhaled. In vivo and in v&-o studies have shown that
whole cigarette smoke, or certain fractions thereof, inhibit ciliary
activity of the bronchial epithelium, adversely affect the mucous
sheath, and inhibit the phagocytic activity of the pulmonary
alveolar macrophage. These abnormalities lead to retarded clear-
ance of inhaled foreign matter including infectious agents from
the lungs, thus predisposing the individual to respiratory infec-
tions. Evidence also exists that pulmonary surfactant may be ad-
versely affected by cigarette smoke.

The convergence of these lines of evidence, which will be de-
scribed in more detail in the body of this chapter, leads to the
judgment that cigarette smoking is the most important cause of
COPD in man.

EPIDEMIOLOGICAL STUDIES

    COPD MORTALITY

Numerous epidemiological studies, based on a variety of POP-
ulations and carried on in a number of countries, have investi-
gated the association between cigarette smoking and COPD. They
have shown a greatly increased mortality and morbidity from
COPD among smokers as compared to nonsmokers. Results from
the major prospective studies relating smoking and COPD mortal-
ity are presented in table 1. The majority of the studies separate

141


TABLD L-Chronic obstructive bronchopulmonary disease mortality ratios
           (Actual number of deaths shown in parentheses)'
               SM = Smokers.     NS = Nonsmokers

PROSPECTIVE STUDIES

Author,
year,  Nummyd      Data     Follow-up    Number      Cigarettes/day        Chronic
country,              collection     Y=WS     of deaths      pipes. cigars        bronchitis        Emphysema       Other
reference    population

Hammond
and
Horn,
1958.
U.S.A.
(1oK).

-

Doll and
Hill
1964
Great
Britain
(70).

187,783 white Questionnaire
males in 9    and follow-up
states 50-69   of death
year8 of age.   certificate.

3%

Approximately Questionnaire
41,000 male   and follow-up
British      of death
physicians.    certificate.

10

      338     Cigarettes
SM ,308  NS . . . .I.00 (30)
NS . 30  <lO . .1.67 (10)
         IO-20 .3.00 (67)
         >20 . .3.64 (40)
         All . .2.85(231)
             Pipes
         NS  .l.OO (30)
         SM  . .1.77 (23)
              Cigars
         NS  .I.00 (30)
          SM  . . . . 1.29 (18)

      292                    Cigarette8
  Chronic                  NS  . .l.OO
bsonchitia                 1-14  .6.80
      111                 16-24 .12.80
  Other                  >25 .21.20
      181                 All  . . .11x0
                        Pipes and
                          Cigars
                        SM  _. .3.00

Cigarettes
NS _. .l.OO
1-14 .0.66
15-24 .1.08
>26 .0.63
AU  .0.81
Pipes and
  Cigars
SM . . ...0.78


TABLE l.-Chronic obstvuctive broncl~opulvvlov~f~~~ disease mortality ratios (cont.)

Author,
Year,
country,
reference

NutTmyoyd
population

Data
collection

    (Actual number of deaths shown in parentheses)'
        SM = Smokers.    NS = Nonsmokers


Follow-UP    Number      Cigarettes/day        Chronic
Years     of deaths      pipes, cignrs        bronchitis


           PROSPECTIVE STUDIES

Emphysema       Other

Best,     Approximately Questionnaire     6           124                  Cigarettes        Cigarcttcs
1966.     78,000 male   and follow-up                                 NS  . ..l.OO      NS  .l.OO
Canada    Canadian     of death                                    <lO  . . . ..7.02(17)   <lo  .4.81 (9)
(JO).     veterans.     certificate.                                   lo-20 .13.65(49)   lo-20  .6.12(21)
                                                         >20 t. .14.63(12)   >20  ..t. 6.93 (7)
                                                          All  .11.42(78)   All .._.. 5.X5(37)
                                                             Pipe8            Pipe8
                                                          SM  ,,..,, 2.11 (5)   SM .._._. 0.75 (2)
                                                             Cigars            Cignra
                                                          SM  .3.57 (1)   SM . ..3.33 (1)

Hammond,  440,658 males  Interviews by     4
1966,     662,671      ACS volun-
U.S.A.    females      teers.
(103).    35-84 years
        of age in
        25 states.

Kahn.    U.S. male     Questionnaire     8 `h
1966,     veterans     and
1J.S.A.    2.265,674     follow-up
(132).    person years.   of death
                  certificate.

      389
SM . . . ...369
NS . . . ...20

     nfnks
NS  .l.OO (20)
SM (age
45-64) .6.55(194)
SM (age
65-79) .11.41(175)

Bronchitis   NS  .l.OO (31)
SM .,...., 64 AllSM . ..6.49(348)
NS .13  Current cigs-
Emphgsema    retk  .10.08(229)
SM . . . ...284       Pipes
NS ..,,.. 18 SM .2.36 (9)
              Cigars
         SM _. .0.79 (5)

  Cursrllt ciga-       Current ciga-
   rcttcn o,dy        rrttl27 onlg
NS  .1.00(13)   NS  .l.OO (18)
l-9  . ..3.63 (5)   l-9  .5.33 (10)
lo-20 .4.61(22)   10-20 .14.04 (93)
21-39  .4.67(12)   21-39 _. .17.04 (62)
>39 . . ...8.31 (4)   >39  .25.34 (17)
All  . ..4.49(43)   All  .14.17(186)


f

TABLE l.-Chwnic obstructive bronchopdmonary disease mortality ratios (cont.)
             (Actual number of deaths shown in parentheses)'
                 SM = Smokers.     NS = Nonsmokers

Author.
Year,
country.
reference

Num;ebb"f"d
population

Data     FOllOWUP
collection     Years

Number
of deaths

Cigarettes/ day
pipes, cigars

Chronic
bronchitis

Emphysema

Other

PROSPECTIVE STUDY

Weir and  68,163 males   Questionnaire    S-8            58                                 Cigarettes
Dunn. in various     and                                                     NS  ._ `1.00
1970,     occuPstions   follow-up                                                 &lO  . .8.18
U.S.A.    in California.  of death                                                  220 . . ...11.80
.._.
I.zZ.2,.              certlticate.                                               ,>30  .20.86
                                                                        Ail  .12.33

RETROSPECTIVE STUDY --

Wicken,   1,189 males.   Personal inter-         1,188 obtained                 Cigarettes
1966,               view with            retrospec-                    odu
NOtih-              relatives of           tively.                    NS  . ..1.00(124)
em                individuals          SM . . .1,064                I-10  .2.95(246)
Ireland             listed on            NS  ,124                11-22  . . .3.43(300)
017).              death                                     >23  . .4.44(168)
                 register.                                        Mixed
                                                          SM  . . ,156 (62)
                                                     Pipes 07 cigars
                                                          SM  . . . . ..1.84(289)

1 Unless otherwise specified, disparities between the total number of deaths
and the sum of the individual smoking categories are due to the exclusion

of either occasional, miscellaneous, mixed, or ex-smokers.
? NS includes pipe and cigar smokers; SM includes e-x-smokers.


the findings for chronic bronchitis and emphysema. Such specific
grouping of the mortality data should be viewed with some reser-
vations in the light of the difficulties mentioned above in dis-
tinguishing the two diseases clinically.

The dose relationship of increased mortality ratios with increased
consumption of cigarettes is indicated by the results of all the
studies which present rates for different levels of smoking. Kahn
(132)) for instance, noted that those smoking only 1 to 9 cigarettes
per day incurred an emphysema mortality ratio of .5.33 while those
smoking over 39 per day incurred one of 2.5.34. Pipe and cigar
smokers were found in some studies to have slightly elevated mor-
tality ratios in comparison with nonsmokers although other studies
did not show this. The risk of dying from COPD among cigar and
pipe smokers appears to be much less than that incurred by
cigarette smokers but may be somewhat greater than that among
nonsmokers (table 1) .

The effect of stopping smoking on COPD mortality is reflected in
t.he results of Doll and Hill (70, 71) in their study of British physi-
cians. They found that during the years immediately following
cessation of smoking, mortality ratios remained elevated and did
not begin to decline below the level of continuing smokers until
nearly a decade later. This delay in response is probably due to two
factors: the presence in the ex-smokers' group of many who quit
for reasons of ill health and the long-term effects of cigarette
smoke on the respiratory tree, some of which are irreversible.
Kahn (1.32) aIso noted that the age-specific mortality ratios for
ex-smokers were lower than those for continuing smokers of cor-
responding amounts of cigarettes.

A better estimate of the potential effect of stopping smoking on
COPD mortality can be gained by studying the death rates in a
population in which a high proportion of smokers have stopped
smoking to protect their hea1t.h rather than as a response to ill
health. Among doctors age 35-64 in England and Wales, many of
whom have stopped smoking cigarettes, there was a 2~1 percent
reduction in bronchitis mortality between 1953-.57 and 1961-65,
as compared with a reduction of only 4 percent in all men of t.he
same age in England and Wales, among whom there was no reduc-
tion of cigarette smoking. (85).

COPD MORBIDITY

Many investigators have studied the prevalence of bronchopul-
monary symptoms (including those of chronic nonspecific respira-
tory disease) amon, rr smokers and nonsmokers. These studies are
outlined in table AZ. Their results indicate that the cigarette

145


smoker is much more 1ikel.v to suffer from respiratory symptoms
such as cough, sputum prc'duction, and dyspnea than is the non-
smoker. Such symptoms, particularly cough and sputum produc-
tion, increase with increasing dosage of cigarette smoke. Table A2
also shows that pipe and cig.lr smokers experience COPD symptoms
more frequently than nonsmokers although not to the degree found
in cigarette smokers. These morbidity findings are similar to the
mortality findings presented above.

Similarly, cessation of cigarette smoking has been shown to be
associated with a decrease in symptom prevalence. Mitchell, et al,
(168) studied 60 patients who succeeded in stopping smoking and
84 continuing smokers. Among the ex-smokers, more than 70 per-
cent reported improvement in their cough while less than 5 percent
of the continuing smokers did so. Wynder, et al. (237) followed
224 ex-smokers of cigarettes and noted that `7'7 percent reported
cessation of persistent cough and an additional 17 percent reported
definite improvement. Hammond (102) reported similar results
concerning cough and shortness of breath in a study of a large
group of ex-smokers.

VENTILATORY FUNCTION

Another type of quantification of the effects of smoking on the
bronchopulmonary system has been obtained by those groups of
investigators who have studied pulmonary function in various
groups. Results are presented in table A3, and a glossary of the
terms used in the various tests is presented in table A4. The pa-
rameters investigated have included maximal breathing capacity
(maximal voluntary ventila.tion) , expiratory flow rates, forced
expiratory volume, and vital capacity. Although certain of these
parameters appear to be more sensitive measures of pulmonary
dysfunction than others, the overwhelming majority of these stud-
ies have shown diminished function among smokers. An increase in
the expected age-diminution rate in smokers has been observed in
those studies which employed either repeated examinations or
examinations at many different age levels. Higgins, et al. (117)
conducted a nine-year follow-up examination of 385 male residents
of a British industrial town who were age 55-64 at the beginning
of the study. Among the survivors who were tested initially and
nine years later, the average decline in FEV,,,;, was smallest in non-
smokers, slightly greater in ex-smokers, and greatest in smokers.
As with COPD mortality and symptom prevalence, the impairment
of pulmonary function shows a dose-relationship with increasing
amounts of cigarettes smoked.

146


The data contained in table A3 provide two different kinds of
information. The majority of the studies were conducted on un-
selected populations, which probably include a number of individ-
uals with clinically manifest COPD. Therefore, these studies re-
flect the prevalence of COPD-related dysfunction (as determined
by pulmonary function tests) in relation to smoking. However,
some studies of younger individuals have revealed that pulmonary
function tests are abnormal in clinically asymptomatic smokers.

Krumholz, et al. (140) and Rankin, et al. (189) have shown that
pulmonary diffusing capacity is impaired in young asymptomatic
smokers when compared with age-matched nonsmokers. Similar
impairment in other pulmonary function tests was noted by Peters
and Ferris (182, 183) in an asymptomatic college-age group and
by Zwi, et al. (241) and Krumholz, et al. (140, 142) in groups of
young asymptomatic physicians and medical students.

Several investigators have employed tests which measure the
relationship of ventilation and perfusion (V/Q relationships) in
the various pulmonary segments. These tests are predicated on
observations that some segments of the lung may be relatively
under or overperfused and that, likewise, segments may be under
or overventilated. Anthonisen, et al. (IO) investigated pulmonary
function in 10 male smokers with clinically mild chronic bronchitis,
all of whom had smoked cigarettes for at least 20 years. Regional
pulmonary function was studied using radioactive xenon. Despite
the fact that overall pulmonary function was nearly normal in sev-
eral patients, all had depressed V/Q ratios in some lung regions
with the basal areas being those most commonly affected. The au-
thors suggested that significant disease in the peripheral airways
may exist in patients whose chronic bronchitis is clinically mild
and who show no present impairment of ventilatory capacity. The
radioactive xenon test may reveal severe compromise of local gas
exchange when usual studies of ventilatory capacity do not reveal
any impairment. Similar results concerning peripheral airway ob-
struction in bronchitic patients with normal, or only minimally in-
creased pulmonary resistance, have been observed by Woolcock,
et al. (234). These authors also noted that their patients demon-
strated frequency-dependent compliance which was unaffected by
the administration of bronchodilator aerosols.

Strieder, et al. (214) have recently investigated the mechanism
of postural hypoxemia in 24 asymptomatic smokers and non-
smokers. They found that standard ventilatory tests and lung vol.-
umes were normal in both the smoking and nonsmoking groups.
However, the arterial ~0' measured in the supine position was
significantly lower among the smokers and alveolar-arterial oxygen
gradients, while breathing room air, were larger in smokers than in

147


nonsmokers (more so in the sllpine than in the erect position). The
increase in alveolar-arterial O2 gradients was greater for heavy
than for light smokers. The authors concluded that maldistribution
of ventilation and perfusion accounted for the observed hypoxemia.
They also felt that this mild diffuse airway disease among asympto..
matic smokers is physiologically significant mainly because of in-
volvement of small bronchi, as expressed by maldistribution unac-
companied by gross airway obstruction. A similar ventilatory
distribution abnormality among smokers has also been observed
by Ross, et al. (198) with the more severe alterations found in the
long-term smokers.

Although of concern in the consideration of COPD, such dis-
turbances of the V/Q relationship may also have adverse effects
upon cardiac function depending upon the level of hypoxemia (219).
The discussion in the section on Coronary Heart Disease noted that
carbon monoxide has adverse effects on both oxygen transport and
alveolar-arterial exchange as well as on oxygen debt developed with
exercise (50). Further research is needed on the joint effect of these
pulmonary and carbon monoxide induced hypoxemic influences,

A number of other studies have provided further evidence con-
cerning the adverse effect of smoking on ventilatory function,
Table 5 presents those experjments which deal with the effect of
cessation of smoking on pulmonary function. Among the param-
eters which have been noted to improve after stopping smoking
are : diffusing capacity, compliance, resistance, maximal breathing
capacity, and forced expiratory volumes. These parameters showed
improvement within 3 to 4 weeks after cessation of smoking.

GENE'TIC FACTORS

Recent interest has been shown in the possible contribution of
genetic factors to the pathogenesis of COPD. Earlier studies (127,
147') had noted the existence of kindreds with high incidences of
chronic bronchitis, emphysema, or both diseases. In addition to the
presence of genetic susceptibility, Larson, et al. (1.47') also observed
that all but one of the 11 symptomatic individuals in their two
kindreds were smokers. They postulated that the susceptibility of
some smokers to develop emphysema may be, at least partially,
genetically detemined.

More recently, Larson, et al. (148) studied 156 relatives of COPD
patients and 86 control individuals. The subjects underwent pul-
monary function testing, including forced expiratory volume and
residual volume total lung capacity measurements. The authors
observed that pulmonary function abnormalities were most prev-
alent among the relatives who smoked and least prevalent among

148


TABLE 5.-Cessation of smoh-ing and hman pulmonary function'

Author,
Ye=-.
country,
reference

Krumholz
et al.,
1965,
U.S.A.
(141).

10 physicians
25-33 years
of age.

Wilhelmsen,  16 smokers.
1967,       (43.7 mean
U.S.A.      e-t`).
(130).

  Following 3 weeks abstinence     RoUowing 0 wrcks abstincncc (6 subjects only)t t All subjects were >5 pack
Lung volumes--no significant change.   Lung volumes:                        per year smokers.
Peak expiratow flow rate-increase    Inspiratow reserve volume-increase (g<O.O6).
(P<O.Ol)                  Functional residual capacity-increase (p<O.O5).
                      Maximal breathing capacity-increase (p<O.O2).
Mean diffusing capacity:           Mean diffusing capacity-no change.
Resting-increase (p<O.SZ)
Exercise-no change.
Compliance-increased in 6/8 tested.   Compliance-continued to show increase.

Vrrluc prior to ccasatim           Vnlue after cessation      Significanec      Mean duration of the non-
Vital capacity .4.50               4.57          Not significant.      smoking period was 40
FEvl.cl  ..,, .3.38               3.52          p<o.o5.           days.
FEV&FVC  .75.0               76.8           Not significant.
PEFN  .F.97               7.45          Not significant.
MEFR 50%  ., ,, . ..3.81               3.93          Not significant.
MEFR 25%  .1.31               1.50          p<o.o5.
Inspiratory resistance .2.07               1.43          p<o.o25.
Expiratory resistance .2.80               2.04          p<n.o2.
Compliance  No change          ~. .~                            .-
Alter 1 month ccsaatim         After 18 months cessatim
?KDC increase (p<O.OOl).          Increase (P<O.Ol).
FEV l.D increase (piO.01).          Increase.

Petrrson
et al.,
1968,
U.S.A.
(184).

12 smokers
studied at
m&us
intervals and
compared with
12 continuing
smokers.

1 Abbreviations are explained in the glossary of bronrhnpulmonnry table A4.


the nonsmoking controls. No relationship of this increased preva-
lence could be demonstrated to alpha,-antitrypsin deficiency (see
below). In addition, nonsmoking relatives and smoking controls
were observed to show approximately the same prevalence of ab-
normalities. However, due to t.he large proportion of females in the
nonsmoking relative group and to the clustering of two-thirds of
the affected relatives in 10 families, firm conclusions cannot at
present be drawn from this study concerning the relative contribu-
tions of smoking and of heredity to the pathogenesis of COPD.

In order to determine the relative significance of smoking and
heredity in the pathogenesis of COPD, Cederlof, et al. (45,16) have
used the twin-study methods on registries in both Sweden and the
USA. The specific details of this method are described in the set-
tion on Coronary Heart Disease. As may be noted from a summary
of their work at the end of table A2, the authors compared the
symptom prevalence among monozygotic and dizygotic twins who
were both discordant and concordant for smoking habits. They
observed that the hypermorbidity for COPD symptoms related to
smoking persisted even after controlling for zygosity and concluded
that a causal relationship of smoking and COPD symptoms was sup-
ported. However, genetic factors were still found to have an appre-
ciable influence. Lundmann (15.9) has applied this method to the
study of pulmonary function. He studied 37 monozygotic and 6:!
dizygotic twin pairs, measuring forced expiratory volumes and
nitrogen washout gradients, and matched the various pairs for
smoking discordancy. He observed that both of these parameters
were adversely affected in twin,; who smoked and that these changes
were correlated with cigarette consumption. The results are out-
lined at the end of table A3.

AZpha,-cmtit~~~psin (A,AT) --Of more recent note and discus-
sion has been the discovery of an association between a hereditary
predisposition to COPD and t;he relative or absolute absence of
alpha,-antitrypsin, a serum glycoprotein enzyme. Eriksson (78)
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 added
research has been published concerning many facets of this intrigu-
ing area.

It appears that A,AT deficency is inherited as an autosomal
recessive trait (78, 216) although Kueppers (12.:) considers the
transmission to be by an autosomal codominant allele. It has been
estimated that up to .5 percent of the general population may be
heterozygous for this gene (l,TJ) although full cross-sectional
studies of the population remain to be done.
Homozygous or severe deficiency of this enzyme has been asso-

150


ciated 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 (101, 215, 226). Patients with emphysema who are
found to have the homozygous deficiency have been observed to
include a greater percentage of female patients than is usually ob-
served in the general emphysema population. Their disease begins
earlier, is more severe, is characterized by dyspnea rather than
cough, and frequently is unassociated with a history of preceding
bronchitis (101,215, 226). Radiographic studies of A,AT-deficient
patients have revealed decreased vascularization of the lower lobes
and increased vascularization of the upper lobes (101, 21.1). It is
estimated that between 1 and 2 percent of patients with COPD have
this homozygous deficiency (7'8, 216). In family studies, it has been
found that almost all the homozygous individuals are symptomatic
by the age of 40 and that those who are not usually show alterations
in pulmonary function studies. Guenter, et al. (!18) studied `7 per-
sons with homozygous deficiency. Of the five symptomatic individ-
uals, 4 smoked and all had abnormal timed vital capacity. Neither
of the two asymptomatic individuals smoked or had this change in
vital capacity. All 7, however, were noted to be hypoxemic at rest
and to have decreased pulmonary diffusing capacity.

It has been suggested (15:) that the lack of this proteinase in-
hibitor in the serum of homozygous patients predisposes them to
emphysema in the following manner: Leukocytes present in the
blood contain significant amounts of proteinase enzymes as part of
the overall defense mechanism against infection ; the breakdown of
these cells during acute infection releases proteinases into the pul-
monary tissues and these, without the presence of a normal inhib-
itor, may contribute to the breakdown of the structural proteins of
lung tissue.

Heterozygous individuals have been defined as those who show
levels of A,AT intermediate between those of normals and those
with homozygous deficiency. At the present time, there is much
debate about whether or not heterozygotes for A,AT are at a
greater risk of developing COPD than are A,AT normals. A major
difficulty is the lack of a precise definition of heterozygosity. At
present, the best method for the determination of the level of A,AT
appears to be that of crossed serum immunoelectrophoresis be-
cause levels of trypsin inhibitory capacity (TIC) have been shown
to rise acutely with infections.

Welch, et al. (126) feel that heterozygotes do not show an in-
creased susceptibility to COPD. The hetelozygotes which they
studied showed symptoms of bronchitis and did not present the

151


lower lobe perfusion defects frequently noted in homozygotes. They
also found no difference in the number of COPD patients among the
heterozygotic and the general population. Other investigators, no-
tably Lieberman, et al. (IS.;, 15S), Kueppers, et al. (244), and
Larson, et al. (118) found significantly increased percentages of
COPD patients among those with heterozygous deficiency as corn--
pared with the general population. Lieberman, et al. (155) ob-
served that the percentage of heterozygotes among a group of
healthy industrial workers was 4.7 percent while that among a
group of patients with emphysema was 18.1 percent. In a recent
review, Falk and Briscoe (7.9) considered that the available evi-
dence points to an increased prevalence of COPD among hetero-
zygotes.

Of more central interest to this discussion, however, is the pos-
sible relationship of smoking to the predisposition of disease among
the heterozygote population. Kueppers, et al. (144) studied three
populations: younger controls, older controls, and a group of
COPD patients. They observed that of the 25 heterozygotes with
COPD, only 2 were over 70 years of age, both were female and non-
smokers. The remaining 23 were cigarette smokers. Nevertheless,
studies which adequately sort out the factors of genetic susceptibil-
ity and cigarette smoke exposure have yet to be reported.

An important question is to what extent the relationship between
smoking and COPD is influenced by identifiable genetic factors. At
present, it is possible to identify what appears to be only a very
small group of susceptibles for whom genetic factors may be para-
mount in the pathogenesis of their ailment. Of greater public health
import is whether lesser degrees of genetically identifiable suscep-
tibility interact with cigarette smoking to account for a significant
proportion of the problem.

AIR POLLUTION

Numerous epidemiological studies have been conducted in order
to examine the effect of air pollution on human nonneoplastic res-
piratory disease. Three major types of studies have been utilized:
observation of the mortality and morbidity due to an acute episode
of increased air pollution, observation of the day-to-day variation
in mortality and its relation to air pollution levels, and geographica!
comparisons. The majority of studies fall into the third category,
and these are detailed in table A6.

A number of studies did not show an association among air pol-
lution, respiratory symptoms, and pulmonary dysfunction (81,20.4).
More recent studies which evaluated the factors of smoking, social
class, and air pollution separately noted a greater prevalence of

152


COPD symptoms, pulmonary dysfunction, and COPD mortality
in areas of high pollution (12, I-71, ISG, 1.1.:). Lambert and Reid
(146) observed that in the absence of cigarette smoking the corre-
lation between COPD symptoms and air pollution was slight and
suggested that the two factors may interact to produce higher rates
of disease.

The evidence which has accumulated in the past 7 years gives
further support to the conclusion of the Surgeon General's Xd-
visory Committee on Smoking and Health as stated in its 1964 Re-
port that: "For the bulk of the population of the United States, the
relative importance of cigarette smoking as a cause of chronic
bronchopulmonary disease is much greater than atmospheric pol-
lution or occupational exposures."

OCCUPATIONAL HAZARDS

Exposure to various dusty occupational environments has been
shown in many studies to be associated with the development of
various forms of nonneoplastic lung disease. Lowe (1.78)) in a re-
view of the relationship of occupational exposure and chronic
bronchitis, noted that among workers exposed to dust significant
increases in COPD mortality \vere observed. These occupations
included coal mining, tinning, galvanizing, riveting, and caulking.
Commenting on a previously unreported study of more than 20,000
steel workers, he observed that the relationship between mean dust
exposure levels and COPD prevalence wxs much stronger among
smokers than among nonsmokers.

More recently, Bouhuys and Peters (37) reviewed those specific
industrial exposures related to lung disease. COPD was found to be
associated with exposure to coal dust, asbestos, bagasse dust, iso-
cyanates, various irritant gases, and textile dusts (cotton, flax, or
hemp).

Studies which have investigated the interrelationship between
smoking, industrial exposure, and COPD are listed in table A?`. Ad-
ditional compounds, not listed in the table, but which also appear to
be related to COPD, are chlorine (49) and washing powder dust
(97). Cigarette smoking and harmful dust exposures appear to act
in a combined manner in the production of COPD.

Although an increased prevalence of COPD is found with cer-
tain occupational exposures, in none is the relationship as strong
as that between COPD and cigarette smoking. To demonstrate an
increased occupational risk, careful analysis of smoking habits is
required. The relative importance of cigarette smoking appears to
be much greater than occupational exposure as an etiologic factor
in COPD.

153


CadlTzium--Chronic industrial exposure to cadmium in man has
been found to induce pulmonary emphysema without significant
accompanying chronic bronchitis (34, 35, 210).

Nandi, et al. (177) recently investigated the contribution of the
cadmium in cigarette smoke to the pathogenesis of emphysema.
Analyzing whole cigarettes, ash, and fibers, they found that an
average of 69 percent of the cadmium present in the cigarette (ap-
proximately 16 micrograms/20 cigarettes) is inhaled in the smoke,
In a related study (Z&3), these investigators showed that the level
of cadmium in water-soluble liver protein on autopsy was three
times greater in those patients with a history of chronic bronchitis,
emphysema than that found in those without such a history. Un-
fortunately, no smoking histories were available.

PATHOLOGICAL STUDIES

The relationship between smoking habits and pathological
changes in the bronchial tree and pulmonary parenchyma has been
investigated by several groups of workers. Metaplastic changes,
although found in nonsmokers, are much more common in smokers
(table 10, Cancer Chapter), and a dose-relationship of increasing
metaplasia with increased smoking has been evident in many of the
studies.

Pathological studies which deal primarily with pulmonary
parenchymal and non-metaplastic bronchial changes are presented
in table 8. Goblet cell distention, alveolar septal rupture, thickened
bronchial epithelium, and mucous gland hypertrophy have been
found to be more frequent in smokers than in nonsmokers. Auer-
bath, et al. (17) noted a dose-response relationship between the
amount of smoking and the degree of septal rupture.

Anderson, et al. (4, 5) studied the difference in the type of
emphysema shown by smokers and nonsmokers. In their study,
listed in table 8, they noted that the group of patients with panlobu-
lar emphysema was comprised of equal numbers of smokers and
nonsmokers while of patients with centrilobular emphysema, 98
percent were smokers. More recently, the same authors studied
lung macrosections from 80 nonsmokers. While most were normal,
24 demonstrated parenchymal dilatation and disruption consistent
with panlobular emphysema. Thurlbeck, et al. (217) have also ob-
served that centrilobular emphysema rarely occurs in nonsmokers.

154


TABLE 8.-Stltdies concerning the relation of human pulmonary histology and smoking'
                 (Actual number of deaths shown in parentheses)
                    SM = Smokers.    NS = Nonsmokers

Author.
  Year,
country,  Nwnne",pd                              Results
reference     population

Chang,    62 males and 43     Distentia of goblet rrlls (hy percent of smoking group)
1957,     females autopsied                                  w of
U.S.A.,    within 5 hours of        NOW       Ft?W     `h of surfarc    RWjIICC
Korea     death (no data  NS(22) 13.6        22.7        31.8        22.7
(47).     available on case SM(49) 12.2        10.2        10.2        1x.4
        selection)

comments

Most of
surface
  9.1
26.5

        The auth6rs also noted
         that smokers' lungs
Whole mL7face  showed shorter cilia
         and thicker epithelium
  22.5      (20 percent nonsmokers
         and 36 percent smokers
         had respiratory disease.)

Ide et al..   93 males autopsied                Mean thickness of tracheal and      Meax cilinry height in tmchca   No cigar or pipe
1959,     within 6 hours of               bronchial epithclium (a) in         and bronchus on cigarette      smokers were included.
U.S.A.    death. No cases                cigarette smokers and nonsmokers       .smolcw~ and nonsmokers
(129).    of pneumonia                    Trachea     IIronchas              TTlXhCa     nronchlu
        or lung disease  NS(23)    52.x        47.7        (23)      6.39        5.95
        included.      Light(31)    62.0        57.5        (29)      5.62        5.49
                  HeavY(l0)     66.2        61.9        (10)      4.89        4.66

Auerbach   654 males over                         Age-standardizrd pcrcentnge distribution of subject8     The authors also noted s
et al.,     60 years of r&w?                        acrordiwg to dcwrcr of 71LptuTv of the alvcolur septum8      dose-reponse relation-
1963.     nutopnied at    Dcyrcc oj TUptlCrC          o-0.25   0.5-0.75   1.0-1.25   1.5-1.75   2.0-2.25   "7.5-3.00  ship between smoking
U.S.A.    East Orange    Never smoked    19.4     50.5     24.9      3.6      1.6           and degree of rupture.
(17).     VA Hospital.   Current cigarette            .4      5.1     16.2      39.2   39:; tN one had ever smoked
                   tc urrent cigar         24.6     45.4     26.2      3.8           cigar&n regularly.
                  tc .
                    urrent pipe     5.4     23.0     53.5     15.9      2.2       
                  Current pipe, cigar    4x      1.6     46.5     33.6      7.5       
                                          .~


TABLE L-Studies conceming the dation of humun pulmonary histology and smoking (cont.)

                          (Actual number of deaths shown in parentheses)
                                    SM z Smokers.     NS = Nonsmokers
-                     ___-                                                          -__.
Author,
  yenr,     Number and
cou"trY.      type of                                Results                                  Comments
reference     pop"lntion
_.~ __ ~ .-- _- _~~__ -.__-         -~-                                        -._-
Anderson   39 malts and                     Swcrity of emphysema (mean deg+ee)                 The a"thors also noted that:
et al.,     32 fe1nales                            M&8                     Ft.W&8         Every person showing se-
1964,     (Caucasians)    NS(4) .._....._.,.............._ 1.5 3 (not sip"ifiea"t)        (20) 1.0
                                   (12) 1.9 tp<oOo5)
                       3           vere disease was R smoker.
U.S.A.    ll"dCQWi"g     SM (35)  __ .  2.3                               Among those with panlobu-
(5).     routine autopsy                                                           ISI. emphysema, there WZLT
        (40-97 years                                                            an equal distribution of
        of age.)                                                                   smokers and nonsmokers
                                                                        while nmong those with
                                                                           centrilohular emphysema
                                                                           98 percent were smokers
                                                                        and only 2 percent were
                                                                           nonsmokers.

                      -
Anderson   107 males and         Percentage didtribwtim of       Mean severity of cmphyeema
et al..     5R females         tobacco ~8~8 in 105 necropsiw                       MeWI   Statistical
1966.     autopsied for      bg degree of cnwhvsma severity       CategoN        Sevetitu Sign&mace
U.S.A.    whom smoking     None  . . . 36 (12/33)    SM(114)  . . . . . . . . . . . . .  2.3
(6).      data was        Mild . . . . . . . , 69 (68/84)    NS(51) ._.. .., . . .._..__.....  0.9 (p<o'ool)

        available.        Moderate  . . . 91 (30/33)    Male(107)  . . . . . . .  2.2
                     Severe . . . 93 (14/15)   Fernale  . . . . .
                                              Never smoked   I
                                       1.2 (P<O.OOl)
                                                        . . .  0.9
                                           <20 cigarettes/day  . . . . . . .  1.9
                                           20-40 cigarettes/day  . . . . . .  2.4
                                           >40 cigarettes/day  . . . . . . . . .  2.3

Megahed   60 male patients                         Mucous okmad hypertrophy
et al.,     with chronic                                     Percent
1967.     bronchitis under-               NS  . . . . . .  29   (2/7)
Egypt     going bronchial                SY  . . . . . .  77   (33/43)  (P<O.O2)

(163).    biopsy and
         lavsge.


TABLE 8.-Studies concerning the relation of human pulmonary histology and smoking (cont.)
                  (Actual number of deaths shown in parenth=cs)
                        SM - Smokers.    NS z Nonsmokers

Author,
  war.     Number and
country,      type of
reference    population

Auerhach   5c2 malts au-

Results                                  comments

Dcgrcc of trachral and brwnchial artcrinlar thickming

et al.,     topsict1 nt Enst                                   (bv percentngc of smokrss)
lW8,     Or:,ncc vn                               0.0&0./r    0.5.-0.9    1.0-1.4    1.5-1.9
U.S.A.    Hospital.      Never smoked (122)   _.  46.1      38.3      13.3      1.3
(14).              <20 eigarcttcs/day (120)              Il.7      22.0      33.5      28.4
                                  
                20-40 cigarettes/day (254)    5.0      8.G      37.4      40.!,
                >10 cigarettes/day (66)  _,  1.3       1.4      31.5      45.3

I Nume~~~us eh caeriments. detailing rhangcs iu bronchial epithelium are dctnilcd t~bul~~rl~ in tha C:~ncr~~ ohnrltvr

2.0s

4.4
X.1
20.5        __-


EXPERIMENTAL STUDIES

ANIMAL STUDIES

A number of investigators have studied the effect of the inha]a-
tion of cigarette smoke on the macroscopic and microscopic strut-
ture of the tracheobronchial tree and pulmonary parenchyma of
animals. Studies dealing with metaplasia and cellular atypism of
the trachea and bronchi are listed in table Al6 of the cancer chap-
ter. Studies more directly concerned with the pathology of COpD
are listed in table 9. They show that cigarette smoke exposure is
associated with changes similar to those found in humans with
COPD, i.e., bronchitis, parenchymal disruption, alveolar septal
rupture, alveolar space dilatation, and the loss of cilia and ciliated
cells in the bronchial mucosa.

The investigations of Auerbach and his coworkers (15, 16, 88)
have demonstrated by the use of both light and electron microscopy
that dogs who inhale cigarette smoke through tracheostomas de-
velop progressively more severe lesions of the bronchi and paren-
chyma with increased exposure to cigarette smoke. In electron
microscopic studies of specimens taken from the lungs of dogs thus
exposed to cigarette smoke, the following changes were observed:
In 5 dogs sacrificed after only 44 days of smoking exposure, there
was a proliferation of goblet cells as well as a partial loss of cilia
in the lining cells, and in 5 dogs sacrificed after 420 days or more of
exposure, the number of cell layers in the bronchial epithelium was
found to be twice that of the nonsmoking dogs. Goblet cells and
ciliated columnar cells were no longer present ; instead, the surface
was lined with columnar and cuboidal cells with stubby projections
in place of cilia. Mitotic figures were frequently observed in the
basal cells. These findings may be relevant to carcinogenesis as
well as to the development of COPD.

In a long-term experiment, carried out by the same group, dogs
were exposed to varying doses of cigarette smoke. Details of the
experimental procedure have been outlined in the section on Pul-
monary Carcinogenesis. The animals were separated into non-
smoker, filter-tip cigarette, nonfilter-light, and nonfilter-heavy ex-
posure groups. The dogs were "smoked" for 8'75 days, or approxi-
mately 29 months. The animals which died during the experiment
and the animals sacrificed after day 875 were examined for pul-
monary parenchymal changes as well as for bronchial epithelial
alterations. As seen in figures 1 and 2, dose-related pathological
changes, including fibrosis and emphysema, were found in the lung
parenchyma of the exposed dogs. These changes were similar to
those seen in the lungs of humans with COPD.

158


TARLE 9.-Experiments concerning the effect of the inhalation of cigarette smoke ?Lpon the tmchco-bronchial tree and pulmonary
                          parenchyma of animals'
                                (Actual number of animals shown in parentheses)

Author,               A. Type of
  Yes=.
country,   A::Y        exposure
                    B. Duration                                    Results
reference     strain       C. Material

Leuchten~  603 CF1      A. Inhalation.
berger,    female mice.  B. Up to 8 ciga-               Number

et al.,
1960,
U.S.A.
(1.w).

r&es/day for
"Pto2yeaI-s.
C. Cigarette smoke.

Number of mica showing specified chnngca
   Number

Months
c?zposu+e
  0
l-3
4-R
9-23
l-23

  Of           of          NO         Mild
cigarettes         mice        ehangr      bronchitis
  0            150         146          2
10&200           36          20          9
260-600           36          19         10
600-1600          34          19          7
25-1526          151          xx         33

Severe bronchitis
with atyptin
2 (no atypism)
7

7

8
30

Holland
et al..
1963,
(121).

60 rabbits.

A. Inhalation.
R. Up to 20 ciga-
  rettes/day for
  2-5.
C. "Normal ciga-
  rette smoke".

N0tTld
Controls  
Exposed  




          Cytology of tmchcobrouchial murosa

                      Focal hypcrplnaia
  (30)21/30         6/30
  (30) 7/30         10130

Gcnerdired
hyyerplaaia
  3/30
  I)/30

Hernander Adult Grey-   A. Inhalation.
et al..     hound      B. Twice daily/
I!lf,f,      doas.         5 per week.
U.S.A.             C. Cigarette
(111).                smoke.

                Number of
                  sections
I. Controls    (8)112
II. All exposed  (15) 205
III. Exposed <l year    (7) 98
IV. Exposed >l year  CR)107

Mm )s
number of
mo,zths
   
10.50
  4.60
14.74

  Mmn
pnrrnchymal    Groups
disruption/dog   W?IlpilTHl       P-U&O
  O.il.50        I-111       insignificnnt
  0.!)58:1        II-I        insignificant
  0.6421       III-IV       P <0.05
  I.2350       IV-I        P <0.02


TABLE 9.--Experiments concerning the effect of the inhalation of ciga,rctte smoke U~O?L tltc tmcheo-l~roncl~ial twc and pulmonary
                        parcncll,z/ttia of animals' (cont.)

(Actual number of nnimnls shown in parentheses)

huerbach
et al..
1967,
U.S.A.
(f&16).

Results

                 ~-
Beagle dogs.   A. Active inhalation  Controls (lo)-No evidence of pulmonnrv fibrosis or s&al rupture.
           via tracheostomy. Exposed (lo)-Early (sacrificed) :
         B. Up to 12 cigRrcttes                1. Alveolar space dilatarion.
            per day for up                 2. I'ad-like attachments to alveolar septa.
            to 423 days.                Medium czpo.wm: Septal wall thickening.
         C. Cigarette smoke.              Latest crposarc:
                                    1. Focal subpleuriil pulmonary fibrosis.
                                     2. Ruptured alveolar septa.
                                     3. Granrtlomata.

FrWX&
et al..
1968.
U.S.A.
(88).

Beagle dogs.

A, Active inhalation Electron microscopic results:
  via tracheostomy. After 44 days -   Increased number of goblet cells.
B. Up to 12 ciaarettes             Decreased number of cilia on surface lining cells.
  per dny for "P   After 420 dsys-   Increased number of epithelial cell layers.
  to 423 days.                Loss of ciliated columnnr cells.
C. Cigarette smoke.              Frequent interruptions in basement membrane.

lNumerous experiments detailing changes in bronchial epithelium aredetailed tabularly in the Cancer Chapter


80 -

20

                                12.9

                    5.7        '.

0
     GROUP N:      GROUP F:      GROUP L:      GROUP Ii:
    NONSMOKING    FILTER-TIP     NO FILTER     NO FILTER
                      (% as many cigmttes)
                             as Group H

FIGURE l.-Percent of lung sections with grade IV or V fibrosis.

SOURCES: Hammond, et al. (104).

Several investigative groups have exposed rodents to various
ambient concentrations of nitrogen dioxide over prolonged periods
of time. This gas is found in cigarette smoke and in some indus-
trially polluted air. The results of these studies are outlined in
table AlO. It is clear that chronic exposure to low levels of NO, is
capable of inducing lesions in the bronchial tree although the rela-
tionship between these changes, cigarette smoking, and the devel-
opment of COPD remains to be determined.

Rosenkrantz, et al. (196, 1.97) have recently undertaken experi-
ments dealing with pulmonary cellular metabolism. They exposed
Swiss albino mice to cigarette smoke or its vapor phase for varying
lengths of time. On autopsy, animals exposed to cigarette smoke
showed elevations in the levels of lung DNA, lactate, and glycogen
which the authors conclude reflect hyperplasia and macrophage
infiltration. Similarly, a dose-related increase in lung hydi*oxypro-
line was observed. This was considered to be due to increased fi-
broblastic collagen synthesis.

161


98.6

80 -

60 -

24.3

GROUP N:
NONSMOKING

GROUP F:      GROUP L:      GROUP H:
FILTER-TIP      NO FILTER     NO FILTER
        (% ss msny cigarettes)
           ss Group H

FIGURE 2.-Percent of lung sections with grade II or III emphysema.
SOURCES Hammond, et al. (10.4).

Aviado and coworkers have performed a series of experiments
on live animals and in heart-lung preparations to study the effect
of cigarette smoke on pulmonary physiology and structure (18,1g,
20,21,22,179,180,199, 200,201,202). The authors observed that
cigarette smoke causes acute bronchoconstriction both by the re-
lease of histamine and the stimulation of parasympathetic nerve
pathways in the lung. Bronchial arterial injections of nicotine were
found to cause reactions similar to those observed after cigarette
smoke inhalation. The bronchoconstriction was usually followed by
bronchodilatation which the authors attributed to sympathetic
stimulation. As mentioned in the Chapter on Cardiovascular Dis-
eases, nicotine has been shown to induce the release of catechola-
mines.

Experiments by Aviado and coworkers as well as other authors
(66, 99) using guinea pigs showed that exposure to cigarette
smoke was associated with increased bronchopulmonary resistance
and decreased pulmonary compliance. The authors related these
changes to the bronchoconstriction of terminal ventilatory units.

162


Similar experiments in dogs showed that the increase in resistance
following either cigarette smoke exposure or intravenous nicotine
could be blocked by pretreatment with atropine. As a parasympa-
thetic blocker, atropine would decrease the acute bronchoconstric-
tive phase.

Most recently, Aviado and his colleagues (20, 130) have at-
tempted to induce physiologic and anatomic changes similar to
those found in the lungs of patients with emphysema. They ex-
posed male rats to cigarette smoke, the introduction of the enzyme
papain, as well as to partial tracheal ligation. In 10 rats exposed
to cigarette smoke twice daily for 30 minutes over a period of 10
weeks, no changes in pulmonary compliance or resistance were
noted. Also, no abnormal histological changes were observed in the
group exposed only to cigarette smoke. However, animals who
underwent tracheal ligation as well as smoke exposure showed in-
creased numbers of enlarged air spaces and increased pulmonary
resistance when compared with animals who underwent only
tracheal ligation.

STUDIES IN HUMANS

The acute effects of cigarette smoke inhalation on bronchopul-
monary function in man have been investigated by a number of
workers. The results of these studies are presented in table 11. The
majority of studies, particularly the more recent ones, found that
the inhalation of cigarette smoke is associated with an acute in-
crease in pulmonary resistance and a decrease in pulmonary com-
pliance. Chapman (48) also observed decreases in pulmonary dif-
fusing capacity and arterial O? tension. Chiang and Wang (51)
noted changes in nitrogen washout time and alveolar dilution fac-
tor, alterations which reflect impaired alveolar ventilation and gas
mixing.

James (1.~1) examined the effect of prior smoking on the mul-
tiple breath nitrogen washout test in 41 pneumoconiotic miners and
5 normal young males. Prior smoking of a cigarette in the subject's
normal manner was found to adversely affect the indices of dis-
tribution in 20 percent of the miners and in all of the 5 normals
who smoked within one hour of testing. The author suggests that
smoking be prohibited prior to any series of pulmonary function
studies.

Anderson and Williams (9) studied the acute effect of cigarette
smoke inhaIation upon the ventilation-perfusion (V/Q) measure-
ments in the lung in normals and in patients with COPD. Cigarette
smoking was observed to cause acute changes in the V/Q measure-
ments, and the COPD patients were found to be particularly liable
to these changes.

163


Finally, Robertson, et al. (194) studied the effect of unfiltered
and filtered cigarette smoke and cigar smoke upon bronchial re-
activity in 19 of the most reactive persons in a group of 91 heavy
smokers. They observed that bronchial reactivity was significantly
reduced by increasing he retention efficiency of the filter and that
reactivity to inhaled cigar tobacco was no less than that to cigarette
smoke. They concluded that differences in inhalation account for
the difference in COPD prevalence observed between cigarette and
cigar smokers.

STUDIES CONCERNING PULMONARY CLEARANCE

Overa. Clecirance

The ability of the lung to rid itself of inhaled particles that can-
not be easily exhaled is dependent upon a number of physiologic
mechanisms including ciliary activity, the mucous sheath, and the
pulmonary alveolar macrophage. Studies concerning the effect of
human cigarette smoking and the exposure of animals to cigarette
smoke on this clearance system are presented in table A13. LaBelle,
et al. (115) and Bair and Dilley (23) observed no change in clear-
ance following the exposure of rats, rabbits, or dogs to cigarette
smoke. The latter authors noted, however, that normal clearance
rates obtained prior to smoking were too low to reflect any sig-
nificant change except complete cessation.

Albert, et al. (3) exposed donkeys to cigarette smoke via nasal
catheter and observed impairment of clearance times. Holma (125)
obtained similar results in rabbits.

In a relat.ed study, Albert, et al. (2) studied the bronchial clear-
ance times of 9 nonsmokers and 13 cigarette smokers in a total pop-
ulation of 36 subjects. The rates of bronchial clearance were slower
on the average in the cigarette smokers when compared with the
nonsmokers, although a wide variation was present in each group.
In relation to their study mentioned above, they also noted that the
shape of the whole lung clearance curves seen in smokers (with
markedly prolonged 50 percent clearance times) was similar to that
developed in the donkey following acute exposures to sulfur dioxide
or cigarette smoke.             .
                             . .

Numerous experiments have shown that cigarette smoke or cer-
tain constit.uents of cigarette smoke adversely affect and can even
bring about a cessation of ciliary activity in respiratory epithelium
it/ ~`i?*o and it) ~it,,o in cultures of ciliated microorganisms. The re-
sults of a number of these experiments are presented in table 12.

164


Ciliary activity has been shown to be affected by particulate matte1
as well as by the gas phase components of cigarette smoke. The rel-
ative importance of these two large classes of components of smoke
in producing ciliastasis is presently a matter of some discussion.
Dalhamn and Rylander (63, 61) consider the particulate phase to
be of greater importance while Battista and Kensler (28, 29) con-
clude that gas phase components are more important in the induc-
tion of ciliastasis.

Studies investigating the effect of cigarette smoke on the
morphology of the tracheobronchial tree in animals have noted a
decrease or absence in the number of cilia in smoke-exposed ani-
mals. Recently, Kennedy and Elliot (131) studied the effect of the
direct exposure of cigarette smoke upon the electron microscopic
structure of protozoan mitochondria. After 42 minutes of exposure
to mainstream smoke, they noted destruction of the internal mem-
brane structure of the mitochondria.

Thus, cigarette smoke has been shown to be toxic to ciliary func-
tion by pathological (including electron microscopic) and physio-
logical methods.

Phugocytosis

The effect of cigarette smoke upon pulmonary alveolar phago-
cytosis, one part of the clearance mechanism, has been studied by
several authors. Masin and Masin (162) observed increased varia-
tion in the size of lipid inclusions in sputum macrophages obtained
from smokers as compared to those obtained from nonsmokers.
They attributed these differences to a combined effect of irritation
of the alveolar lining, increased turnover of alveolar cells., and in-
creased injury to the macrophages. Green and Carolin (96) noted
that cigarette smoke inhibited the ability of rabbit alveolar macro-
phages to clear cultures of S. a?ATeus. This effect was noticeably
reduced by filtration. Similarly, Yeager (239) exposed rabbit
alveolar macrophages which had been induced by M. bovis to cigar-
ette smoke and observed a dose-dependent decrease in protein syn-
thesis. This alteration occurred at smoke solution concentrations
that did not affect cell viability. The alteration was only partly re-
versible and was due mainly to gas phase components. Myrvik and
Evans (175) observed similar protein synthesis alterations in
macrophages exposed to NO,.

Roque and Pickren (195) obtained alveolar macrophages at
thoracotomy from 17 smokers and 4 nonsmokers, They found a
decrease in the activity of oxidoreductases and hydrolases in the
macrophages of smokers. The reduction in the enzymatic activity
was directly proportional to the amount of stored fluorescent ma-
terial present in the macrophages. This material was thought t.o

165


TABLE Il.-Experiments concerning the acute effect of cigarette smoke inhalation on human pulmonary function

Author,
Y-u-,
country.
reference

Bickerman
and
Barach,
1954,
U.S.A.
(31).

Number and
type of

A. Method =
B. Material 1
C. Duration of

RemIta

   population

I. 66 male and
   25 female
   patients
   with chronic
   nontuberculous
   respiratory
   disenws
   ( swrage age
   50).
II. 20 male and
   7 female
   normal suh-
   jects (average
   age20).

      smoking

A. Pulmonary
   function.
B. 3 cigarettes.
C. 30 minutes.

   Vital capacity ( VC)
I. lo/91 decrease.
II. No significant change.

Ma&nd breathing capacity  B/91 patients showed
IO/91 deerease.         VC incresse due to
No significant change.     clearance of secre-
                  tions. All mild or
                   moderate smokers.

Eich,
et al..
1957.
U.S.A.
(76).

I. 31 patients with
   obstructive
   PUb~OIWY
   emphysema.
II. 14 normal
   subjects.
III. 6 patients with
   respiratory
   complaints.
   All habitual
   smokers.

A. Esophageal balloon
   technique to
   mecL9ure pulmonary
   compliance and
   resistance.
B. 1 cigarette.
C. Undefined.

  Mean airway resistance
I. Statiaticslly significant
   increase.
II. No change.
III. No change.

Mean aimmu compIiance
   No change.

   No change.
   No change.


TABLE Il.-Experiments concerning the acute effect of cigarette smoke inhalation on human pulnaonam function (cont.)

Author,
Ye*=,
cou"trY,
reference

Attinger
et al.,
1958,
U.S.A.
(19).

Number and
type of
population

I. 20 normal
   subjects
   (10 Sm.
   10NS).
II. 34 patients with
   various diseases;
   9 rheumatic heart
   diseases, 8 pul-
   mOn*rY mlPhY-
   sema, 7 asthma,
   5 pulmo"aly
   fibrosis,
   5 undefined.

    A. Method 1
   B. Material 1
   C. Duration of
      smoking

A. Esophagal balloon

I. No change.

Ftesulta                     CO"l"E"ts


      No change.

  technique to meas"re
  pulmonsry compliance
   and resistance.
B. l-4 cigarettes.       II. Expiratory resistance rose        No change.
C. 10 minute interval         signiticantly only among
   between              patients with
   cigarettes.             emphysema.

Motley and  125 males and         A. Pulmonary           41 smokers             Pulmomrg~ compliance     Various groups of
KUZ"l*",   16 females             function.           (8 "ornlals,                                normals and cardio-
1968.     (24-70 years of       I%. 2 cigarettes.          33 patients           Significant decrease after     pulmonary patients
U.S.A.    age-"ormals        C Undefined.            with cardio-             smoking.              showed little or no
(f74).    and patients).                           pUl"lO"*lY                              change in arterial
                                          disease).                       p02 during exercise
                                                                           and at rest follow-
                                                                          ing cigarette smoke
                                                                           inhalation.
                                                                      .-.
Nadel and   I. 22 patients with     A. Body plethy-             Airwev cmdvctance/thoracic gas vdumC        Nicotine hitsrtrate
CO"VO&      cardiopulmonary      smography.       I. 18/22 significant decrease (inhibited by pretreatment       aerosol evoked no
1961,        disease--all       B. 15puffs.             with isoproterenol aerosol).                     change.
U.S.A.       smokers.        C. 5 minutes.       II. 31/36 significant decrease (inhibited by pretreatment with
(176).   II. 36 normals (21                        isopmtercnol aerosol).
           smokers, 16
           nonsmokers).


Author,
war,
countlY,
reference

Number and
type of
population

A. Method 1
B. Material '
C D;a&a$";gof

   -                          -..


Results                     Comments

Sim""ss"",
1962,
Sweden.
(207).

Zll"ld
et al.,
1963.
England,
(240).

I. 9 male and 7
   female normals
   (most smokers).
II. 15 male nnd 1
   female pulmonary
   disease patients
   (most smokers).
~
I. 6 male and G
   female nonsmokers.
II. 6 male and 6
   female smokers
   (18-32 years
   of age.)

A. Pulmonary
   function.
B. l-2 cigarettes.
C 5-6 minutes
   PCP cigarette.

   MmnFEVl o
  (immediately ejtcr)
I. Significant decrease.
II. Significant decrease.

   McanFEVl o
   (45 minutes letcr)
No significant decrease.
Significant decrcnse.

No siunifirnnt changes
ohserved in FEV/FVC.

A. Body plethy-
   smography.
B. 1 cigarette.
C. Undefined.

Airway resistance
I. Significant increase.
II. Significant increase.

1965.
Ireland
(48).

__-
McDermott
and
Collins,
1965,
Wales
(160).

I. 12 normal
   v"lu"teers
   (all smokem).
11. G patients with
   chronic "on-
   specific lung
   disease.

I. 32 normals.
II. 2X with chronic
   bronchitis
   (All ciga-
   rette smokers
   35-GO years
   of age.)

A. Pulmonary function
   Arterial blood
   studies.
B. 1 cigarette.
C. Undetined.

I. All showed a decrease in diffusing capacity.
II. 4/6-significant decrease in arterial O2 tension.
   No change in vital capacity or FEV.

A. Body plethy-
   smography.
B. Cigarette.
C. Undefined.

Mean airway resiatancc              Light smokers showed
I. Significant increase.               greater changes than
II. Significant increase.               heavy smokers.


Miller and   10 normal
SProule,    cigarette
1966,     smokers
U.S.A.     (40 years
(1GG).    ofage).

A. Esophaeeal ballwn
   technique.
B. 1 cigarette.
C. One inhalation
   Pc3-Y ao-FO
   seconds.

FEvo.5
No significant
change

Dynamic
compliance
Significant
decrease.

Inspiretory and
erp,iratory rceistmca
   Significant
    increase

Sterling.   11 normal adults
1967.     (E smnkers,
England   3 nonsmokers)
(219).

Chiang and 7 male normal
W*nEC.    nonsmokers
1970.      (L-43 years
Formosa   of age).
(51).

A. Body plethy-
   smography.
B. 15 inhalations.
C. 5 minutes.

  Airway rcsiatancc
Significant increase (Return
to normal in 30 minutes).

A. Pulmonary function    Nitrogetr roaskcwt      L1my clcnrancc      Aleeolar dilution All luna volumes,

   Nitrogen washout.
B. 2 cigarettes.
C. Undefined.

tima
Significant
increase.

A. Body plethy-
   smography.
B. 1 cigarette.
C. Undefined.

Guvatt    110 subjects;
et al..     50X smoked
1970.     between meas-
England   ures 202
(lml).    did not fimoke.

-

  ' All the experiments listed concern studies of sulmonary function be-
fore and after smoking the epecified number of cigarettes (unless other-
wise specified).

illll,.L!
Significnnt
increase.

factor     excrpt for residual
Significant    \-olumr showed no
decrense.    significant change.
        No significant
         change in any of
         the flow rates.

    Brunckoconstrictio?~       On the avernge. non-
Significant increase with smoking.    smokers and es-smokers
                       sh<,wed tnonchodilation
                       and nm<,kers showed
                       I,~~rnch~~constriction.
                       Thr authors postulate
                       that the result among
                       nonsmokers is due to
                       the> rclcnsc of ndrenal
                       hoymonrs in these sub-
                       pxts.
        ~-_- __


TABLE 12.--Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance

Author,
Yea=.
countru,
reference

Subjects         Method

RBUkS                           Comments

Laurenzi   Swiss-Webster     Mice exposed to    Significant increase in S. aureu8 retention in mice expceed to:
et al..     male mice.        aerosol of s. au7euuB   (a) hypoxia-retention ratio 2.5 (10 percent Oa).
1963,                  and sacrificed at      (b) cigarette smoke-retention ratio 4.5.
U.S.A.                 intervals following
(149).                 exposure to various
                      stimuli.

LaBelle
et al..
1966,
U.S.A.
(145).

Albino female
rabbits.

Silver iodide or
colloidal gold
intratrachesllu.

17-30 hours of exposure to cigarette smoke caused no change in pulmonary
clearance as compared with controls breathing room air.

Bair and   Sprague-Dawley    Radioactive aerosol. Acute exposure to cigarette smoke had no gross effect on clearance. Chronic
Dilley,    female rats.                 exposure to cigarette smoke (up to 18-20 cigarettes/? hour day/5 day week
1967.     male beagle dogs.   Radioactive aerosol.   for UP to 420 days) had no observable effects. The authors noted, however,
U.S.A.                         that normal clearance rates were too low to reflect anything but complete
(2.9).                               cessation.

Albert
et al.,
1969.
U.S.A.
(9).





--

36 subjects
undergoing 117
experiments.

                                              so perct?nt   90 percent t Approximate values.
                                              clearance    clearance  None of 9 nonsmokers
Radioactive tagged                   Number of   Average    time       time    had 60 percent times
FeOZ particles                      eubjects     age    (minutes)   (minutes )  over 200 minutes or
measured with    Nonsmokers  .   9       28        88        367    90 percent times over
Scintillation      All smokers  . . . . . .  14       33       172       t496    600 minutes while
counter.       20-29 cigarettes/day . . . .   7       29       191       ts19    6/14 smokers exceeded
            30-40 cigarettes/day   I       36       163       t414    both these limits.
             Uranium miners . .   3       62       310        580
           Cigar and pipe smokers   4       46        81        316
            Emphysema patiats .   2       66       330        676


TABLE 12.-Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance (cont.)

Author,

year.
country,
reference

Subjects

Method

Results

Commenta

Albert
et al.,
1969,
U.S.A.
(8).

Holma,
1969,
U.S.A.
(125).

Donkeys exposed
to cigarette
smoke by nasal
cstheter.

Rsdiosetive tagged    Average                                Trachael transit  Those donkeys exposed
Fe02 particles      number                                   time      to the greatest
measured with    cigarettes in    Perrent clearance   Halftime clearance                amount of smoke
Scintillation     .%hour period   Control  Cigarsttc Control  Cigarette  Control  Cigarette showed residual
counter.          1X-24       58      69     1.2      1.9      0.6      1.2    impairment of
               36         58      64     1.0      3.4      0.4      6.8    clearance for et least
                                                             2 months after acute
                                                              exposure.

Rabbits
(anesthetized).

C+* monodisperse   Exposure to fresh cigarette smoke (1.5 cc. puffs, 40 nuffs/X minutes) caused
polystyrene      a "significant" increase in lung retention 10 minutes following cessation of
aerosol.         exposure.


originate in tobacco smoke. The authors suggested that the tobacco
smoke may have induced abnormalities in the mitochondria of the
macrophage. In a study of pulmonary macrophages harvested by
endobronchial lavage from smokers and nonsmokers, Pratt, et al.
(187) observed that the macrophages of smokers contained an ab-
normal pigment.

These studies indicate that the function of pulmonary clearance
carried on by the macrophage and ciliary systems is adversely af-
fected by cigarette smoke.

STUDIES CONCERNING THE SURFACTANT SYSTEM

The surfactant system of the lung consists of various biologically
active compounds such as phospholipids and mucopolysaccharides
which are present in the alveolar lining. Normal pulmonary func-
tion is influenced and partly determined by the integrity of this
system (203). The purpose of the surfactant system is to main-
tain the proper amount of surface tension in the alveoli so that the
expansion and contraction of the alveoli are facilitated.

Studies concerning the effect of cigarette smoke upon the sur-
factant system and the surface tension of the pulmonary alveoli
are presented in table A14. Exposure of rat and dog lung extracts
to cigarette smoke has been found to induce a notable decrease in
the maximal surface tension demonstrated by the extracts (94,
165, 2.24). Cook and Webb (57) observed that surfactant activity
was diminished in smokers and in patients with pulmonary disease
when compared with healthy nonsmokers.

Scarpelli (203) in a recent review, concluded that the lowering
of maximal surface tension by cigarette smoke has been demon-
strated reasonably well. The relationship of these findings to the
pathogenesis of emphysema is unclear at this time.

OTHER RESPIRATORY DISORDERS

INFECTIOUS RESPIRATORY DISEASES

Several studies have examined the question of whether ciga-
rette smokers are at an increased risk of developing infectious res-
piratory and bronchopulmonar~ disease. Table Al.5 presents a
summary of these studies. Lowe (1.57) observed an excess of
smokers among `i0.5 tuberculosis patients, but Brown and Campbell
(43) in a similar study found that the difference was not present
lvhen the cases and controls were matched for alcohol intake. More
recent studies have been concerned with the frequency of upper
respiratory infections among groups of smokers and nonsmokers.
A number of investigators (lOS,181, 183) have reported increased

172


-ates of respiratory illnesses among smokers. Finklea, et al. (83)
studied a male college population (prospectively) during the
1968-69 influenza epidemic. They found that smokers of all amounts
experienced more clinical illness than did nonsmokers and that this
relation was dose-dependent. Similarly, smokers required more bed
rest than nonsmokers.

A survey conducted by the National Center for Health Statistics
(220), involving approximately 134,000 persons, showed that male
cigarette smokers reported 54 percent more cases of acute bron-
chitis than males who had never smoked cigarettes, while female
smokers reported 74 percent more acute bronchitis than did females
who had never smoked. Male cigarette smokers reported 22 percent
more cases of influenza than did males who had never smoked cigar-
ettes, while the female smokers reported an excess of 9 percent.

Experimental evidence in support of this relationship has been
noted by Spurgash, et al. (211). Mice were challenged with
Klebsiellu pneumoniae or Diplococcus pneumoniae before or after
a single exposure to cigarette smoke. They observed that those ani-
mals exposed to smoke exhibited a decrease in resistance to respira-
tory infection, as shown by an increase in mortality and a decrease
in survival time. Preexposure to cigarette smoke was found to have
no significant effect on resistance of mice to influenza infection
initiated by aerosol exposure. However, exposure of infected mice
to smoke resulted in significantly higher mortality, thus suggest-
ing that cigarette smoke can aggravate an existing respiratory
viral infection.

In the light of the experimental evidence presented above con-
cerning the effect of cigarette smoke on pulmonary clearance,
phagocytosis, and ciliary function, it seems reasonable to conclude
that such changes in tracheobronchial physiologic function would
predispose a person to respiratory infections or aggravate already
existing ones.

Further evidence is derived from the work of Henry, et al. (109)
and Ehrlich, et al. (7'5). These investigators exposed squirrel
monkeys to atmospheres containing 10 and 5 p.p.m. of nitrogen
dioxide. They observed that this exposure increased the suscepti-
bility of the animals to airborne Klebsiella pneumoniae as demon-
strated by increased mortality and reduced lung clearance of viable
bacteria. Infectious challenge with influenza virus 24 hours before
exposure to 10 p.p.m. was fatal to all monkeys within three days.
Infected controls showed symptoms of viral infection but did not
succumb to the infection. The extent to which the various oxides of
nitrogen present in cigarette smoke contribute to the increased SUS-
ceptibility to respiratory disease noted in smokers is presently
undefined.

173


POSTOPERATIVE COMPLICATIONS

Several studies have been published which examine the questions
of whether smokers run an increased risk of developing postopera,
tive pulmonary complications over nonsmokers undergoing similar
operations.

Morton (173) reported on a study of more than 1,100 patients
undergoing abdominal operations in which he found that cigarette
and mixed smokers were significantly more likely to develop bran.
chitis, bronchopneumonia, or atelectasis during the postoperative
period than nonsmokers (table A16).

Wiklander and Norlin (229) examined the incidence of post-
operative complications in 200 patients undergoing laparotomy in
the winter months when it was expected that pulmonary compli-
cations would be at their maximum. These authors found no sig.
nificant differences between the frequency of complications in
smokers and nonsmokers. No information about the definition of
a smoker and no data on dosage of tobacco smoke were reported.

Piper (186) observed the prevalence of postoperative pulmonary
complications in 150 patients undergoing laparotomy. Of the total
sample, 66.7 percent developed pulmonary complications during
the first postoperative week. All patients considered in the statis-
tical analysis as having pulmonary complications had radiographic
evidence of disease. Of the cigarette smokers, 73.5 percent had
complications as compared to 55.5 percent of the nonsmokers.
When the smokers were divided according to dosage, heavy smok-
ers being those consuming more than 10 cigarettes per day for the
previous six months, 55 percent of light smokers and 88 percent
of heavy smokers were considered to have postoperative compli-
cations. Piper also reported that stopping smoking for up to four
days preoperatively had no apparent effect on the incidence of
complications.

Wightman (228) reported on the incidence of postoperative pul-
monary complications in 455 patients undergoing abdominal oper-
ations and in 330 patients undergoing other operations. Of the
cigarette smokers, 14.8 percent developed complications as com-
pared to 6.3 percent of the nonsmokers. The substantial difference
between these figures and those of Piper (186) is due to the latter's
use of radiographic criteria alone. Wightman utilized only clinical
criteria.

Morton (178) has recently reported a study of postoperative
hypoxemia in 10 patients, 5 of whom were cigarette smokers. Four
of the smokers had chronic bronchitis. He found that the smokers
had a more pronounced decrease in arterial oxygen saturation, Per-
sisting into the second postoperative day (table A17).

174


In summary, the majority of studies so far reported indicate
that cigarette smokers run a higher risk of developing postopera-
tive pulmonary complications than do nonsmokers, corroborating
a long-held clinical impression. The risk of developing such com-
plications appears to increase with increasing dosage of cigarette
smoke.

SUMMARY AND CONCLUSIONS

1. Cigarette smoking is the most important cause of chronic ob-
structive bronchopulmonary disease in the United States. Ciga-
rette smoking increases the risk of dying from pulmonary emphy-
sema and chronic bronchitis. Cigarette smokers show an increased
prevalence of respiratory symptoms, including cough, sputum pro-
duction, and breathlessness, when compared with nonsmokers.
Ventilatory function is decreased in smokers when compared with
nonsmokers.

2. Cigarette smoking does not appear to be related to death from
bronchial asthma although it may increase the frequency and se-
verity of asthmatic attacks in patients already suffering from this
disease.

3. The risk of developing or dying from COPD among pipe and/
or cigar smokers is probably higher than that among nonsmokers
while clearly less than that among cigarette smokers.
4. Ex-cigarette smokers have lower death rates from COPD
than do continuing smokers. The cessation of cigarette smoking
is associated with improvement in ventilatory function and with
a decrease in pulmonary symptom prevalence.
5. Young, relatively asymptomatic, cigarette smokers show
measurably altered ventilatory function when compared with non-
smokers of the same age.

6. For the bulk of the population of the United States, the im-
portance of cigarette smoking as a cause of COPD is much greater
than that of atmospheric pollution or occupational exposure. HOW-
ever, exposure to excessive atmospheric pollution or dusty occupa-
tional materials, and cigarette smoking may act jointly to produce
greater COPD morbidity and mortality.

7. The results of experiments in both animals and humans have
demonstrated that the inhalation of cigarette smoke is associated
with acute and chronic changes in ventilatory function and pul-
monary histology. Cigarette smoking has been shown to alter the
mechanism of pulmonary clearance and adversely affect ciliary
function.

8. Pathological studies have shown that cigarette smokers who
die of diseases other than COPD have histologic changes charac-

175


teristic of COPD in the bronchial tree and pulmonary parenchyma
more frequently than do nonsmokers.
9. Respiratory infections are more prevalent and severe among
cigarette smokers, particularly heavy smokers, than among
nonsmokers.

10. Cigarette smokers appear to develop postoperative pulmo-
nary complications more frequently than nonsmokers.

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191



TABLE AZ.-Smoking and chronic obstructive pulmonary disease symptoms'--percent prevalence
      (Numbers in parentheses represent total number of individuals in particular smoking group)
               SM z Smokers.      NS = Nonsmokers.      EX = Ex-smokers.

Author,
Yea*,
country,
reference

Cough         Sputum production

Breathlessness
or dyspnea

Chest illnesses

Other

comments

Short     2,031 male and     NS t. 1.6  (496)                               NS .lO.Q
et al..     female insurance  SM 6.4 (1,293)                               SM ..18.0
1939,     policy holders.
U.S.A.
(206).

Oswald    3,602 male and
and      2,242 female
Medvei,    clerical
1956,     workers 40-66
England   years of *ge.
(178).

  Chronic Bronchitis
      M&.4
NS ..lK.B  (474)
SM .18.4 (1,940)
     F.?TW&?8

NS . . . ol2.1  (619)
SM 18.8  (679)

Chest illnesses
as repre-
sented by
frequent
colds.

Chronic
bronchitis
defined by
habitual
cough and
sputum
production.

Phillips    1.274 male        NS . . . . 2.0  (461)
et al..     factory workers   SM . . ..61.0  (823)
1966.     without overt
U.S.A.    pulmonary
(185).    disease or
        heart failure.

Higgins    301 male and                     Cough and sputum                               Chronic Bronchitis
1957,     280 female                          Males           M&8          MlLI.3            M&S
England   rural dwellers                   NS .._. `7.1  (28)   NS . . 7.1  NS t. ,, 3.6  NS  3.6
(112).    26-74 years of                  SM .63.9  (222)   SM . . .19.x  SM .ll.l  SM  . . 9.9
        we.                             Females          FtTlVLldtT8         FE?Jdt?8           Females
                                  NS ._ 4.6  (176)   NS .21.6  NS . 9.7  NS . . . . 3.4
                                  SM __ ._ .17.2   (93)   SM . . 9.7  SM _. ._ .16.1  SM 8.6


(Numbers in parentheses represent total number of individuals in particular smoking group)
        SM = Smokers.      NS = Nonsmokers.      EX = Ex-smokers.         ___~ ~~~~-.__ -

Author.
Ye**.

Number and

country.      type of
reference     population

Higgins    94 mnles and
and      92 femalf?s
Cochran,   randomly chose"
1958,      (members of an
England   asriculturnl
(114).     rumrnunity.)

Cough         Sputum production

nrcnthless"ess
or dyspnea

Chest illnesses

    FWLlLlC8          M&X          Mdet?
Cmgh and sputum    NS ._ _. __ _. .33.3 NS  0.0
NS     (6)  SM. ._.___. 29.3 SM 16.0
SM ..24.0  (75)     Femalea         Females
NS ,.... ,._. 3.1  (64)  NS, ,,,. . ..45.3 NS 10.9
SM 3.0  (20)  SM .,.. 20.0 SM 10.0

Edwards   1,737 male out-
et al.,     patirnts on
lQ59.     lists of
England   general PPRC-
(74).     titioners >60
        ytzars of age.

Other

NS Il.0
SM ._ _. 6.1
     FCVfdCS
NS  . . . 0.0
SM ._ 6.0

  Chronic bronchitis
NS _. 16.6  (151)
Cigarettes 29.7  (719)
l- 9 23.4  (235)
lo-19 ._ 31.2  (369)
>20  33.7   (175)
Pipe  18.5   (340)

_______..
Flirk     222 mnle        NS .lO.O  (61)  NS ..25.0  (49)               NS 30.0 (4'7)
and      patients not     SM u55.0 (167)  SM ..65.0 (156)               SM __ 60.0(138)
Pato".    suffering from
1969,     overt cardio-
U.S.A.     pulmonary
(86).     discnse, 2&QO
        years of age.

Higgins    716 males in                     Cough and sputum                                Chronic bronchitiv
et al.,     various                      SM __ 7.1  (86)  NS 9.4 NS . 7.1     SM 14.3
1969,     occupations                    NS .36.8  (676)  SM .24.9 SM 20.2     NS ._ 3.5
England   `26-64 years
(126).    of age.


-

TABLE A2.-Smoking and chronic obstructive pulmonary disease sy,,zptonzs'-perce,at prccalence (cont.)
        (Numbers in parentheses represent total number of individuals in particular smoking group)
                 SM = Smokers.      NS = Nonsmokers.      EX = Ex-smokers.

Author.
Year,
country,
reference

Number and
type of
population

Cough

Sputum production

Breathlessness
or dyspnea

Chest illnesses

Higgins,   393 males in
1959,     various
England   occupations
(113).    56-64 years
        of age.

           -_
LiebeschuetzJ47 male
1959,     soldiers
England   20-30 years
(156).    of age.

Other

COlIllWSt3

Cough and suutam                               Chronic bronchitis    Chronic
NS . . . 6.1   (33)   NS _. 18.2  NS _. 3.0  NS 0.0        bronchitis
1-14 g/day 9.7 (173)   1-14 g./day   30.1 l-14 g/day   23.7 1-14 kc/day 13.9        defined as
>15  . . . . .42.3  (142)   >15. ,. ., ,, ,. 33.8  >I5 .,2x.0  >16 . . . . 17.6        persistent
                                                          sputum and
                                                          at least I
                                                          chest illness
                                                          in past 3
                                                          years.
                                                         Tobacco gram
                                                          equivalents
                                                          ELlY:
                                                          1 cigarette
                                                          = 1 g1'Flm,
                                                          1 cigar =
                                                          2-5 grams,
                                                          1 pipe =
                                                          lb-25 grams.

NS .......  0.0  (52)
SM ....... 13.0  (83)

   Asbford    4,014 male                                                            Rcspiratorg nymntoma  Respiratory
    et al.,     coal workers.                                                            NS . . . . 10.3  (6'77)   symptoms-
    1961,                                                                         EX 19.5  (123)   "bronchitis
    England                                                                     Cigarettes 21.1 (1,504)   and/or
    (11).                                                                    Pipeonly 36.1 (202)    asthma". No
                                                                           Cigarettes            dose rcln-
                                                                           and pipe 37.1   (90)    tionship
:                                                                           All SM  21.7 (3.214)   found.


TABLE AZ.-Smoking and chronic obstructive pulmonary disease syw~ptoms'---percent prevalence (Cont.)

                 (Numbers in parentheses represent total number of individuals in particular smoking group)
                             SM = Smokers.      NS = Nonsmokers.      EX = Ex-smokers.

  Author.
   war.     Number and                                   Breathlessness
  cou"trY,      type of         Cough         Sputum production      or dyspnes      Chest illnesses         Other         CO"l"lk?"tS
reference    population

Bower,    96 male and      NS ._ 4.1  (49)   NS . .20.4                  NS . . . f34.7                     Chest illneas-
1961,     77 female      SM .27.6  (76)   SM . . . .34.2                  SM .38.2                      chest colds
U.S.A.    hank employees Pipe, cigar     (13)   Pipe, cigar 16.4                  Pipe, cigar                       during each
(41).     40-70 years                                                       63.9                      of last 2
        of age.                                                                           winters.

Fletcher and 363 male London   NS     (30)   NS . . . . . 8.7    NS     NS . . . 4.3
Tinker,    transport      I-14 B./day 16.6 (166)   1-14 g/day .29.9    l-14 g/day 8.2   1-14 g/day
1961,     employees     >16 . . .27.3 (116)   >16  . .36.9    >16  . . 8.6         8.2
England   40-60 years                                                 >16  . 10.7
(35).     of lige.

Read     170 male and
and      132 female     NS
Selby.     individuals     SM
1961,     interviewed     EX
Australia   in an ou&
(291).    patient       NS
        clinic (not     SM
        all patients).

Male.9

  4.4
. . ...23.1
.21.2
  Ft?Wl&8

  4.9
_. 18.6

BEJChWn   1,461 male       NS .10.2  (263)
et al.,     light        SM .23.3(1.198)
1962,     industry      <l paek-
U.S.A.    employees in     year .ll.O  (267)
(24).     California.      l- 9 . . . .17.0 (263)
                  10-19 . .26.0 (303)
                   20-29 .21.0 (236)
                  3&39 . .28.0 (144)
                   40-49 . . . .39.0  (92)
                   60-59 . . ..34.0  (29)
                   >60  . . . . .60.0  (24)

NS .......... 11.0
SM .......... 30.4
<l pack-
year  ..... .12.0
l- 9 ....... .18.0
lo-19 ....... .32.0
20-29 ....... .34.0
30-39 ....... .40.0
40-49 ....... .37.0
50-59 ....... .46.0
>60  ....... .62.0

NS .......... 9.8
SM ......... .14.6
<l paok-year .lO.O
l- 9 ....... .12.0
l&19 ....... .ll.O
20-29 ....... .1&O
30-39 ....... .21.0
40-49 ....... .13.0
60-69 ....... .3&O
>fiO  ....... .29.0

-


`I'ABLE AZ.--Smoking and chronic obstructive pulmonary disease synlptol)ls'--pPrcent prevalence (cont.)
       (Numbers in parentheses represent total number of individuals in particular smoking group)
                  SBl = Smokers.      NS = Nonsmokers.      EX = Ex-smokers.

Author,
Year,
country,

Number and
type of

Cough

Sputum production

Breathlessness
or dyspnea

Chest illnesses         Other

reference    population

Boucot    6,137 males      NS . . . . 13.0  (806)
et al., 1962,  enrolling      SM .31.6(6,951)
U.S.A.    in pulmonary
(36).     neoplasm project.

Ferris     90 male and                                                               Chrmic Nonspecific
et al.,     71 female                                                          Respiratory Diwaee
1962,     flax mill-                                                                    M&8   Ft??S&8
U.S.A.     workers.                                                       NS .lS.O(ZO) 10.0(60)
(82).                                                                     EX 12.6(16)
                                                                        l-20 .27.3(22) .
                                                                  >20 .53.1(32) 60.0 (4)

   Ferris     642 male and                                                                Chronic bronchitis   Age-specific
    and      625 female                                                                    M&8        rE&?s.
    Anderson,  residents of                                                             NS . . 13.8  (126)
    1962.     New Hampshire                                                           EX  Il.9   (71)
    U.S.A.    town chosen                                                         Cigarettes 40.3 (340)
    (81).     by random                                                               l-10 ..29.8
            sampling of                                                             11-20 . .34.2
            -XllS"S.                                                                21-30 . .42.3
                                                                           31-40 ..61.1
                                                                           >41  . .7&S
                                                                           FeWde8
                                                                           NS .I..... 9.4  (378)
                                                                           EX  . . ulO.8   ($7)
                                                                        Cigarettes 19.8 (208)
                                                                           l-10 .13.1
                                                                           11-20 .22.2
                                                                           21-30 .
                                                                           31-40 . . .27.3
                                                                           >41 . . . .  
:


H

TABLE A2.-b'~~~ol;i~~g and chronic obstructive pulmonar?y disease s?l,,lplottls'-pe~cerLt ~~w~~c~lencc (cont.)
         (Numbers in parentheses represent total number of irldividuals in particular smoking group)
                  SM = Smokers.      NS = Nonsmokers.      EX = Ex-smokers.

Author,
ye*=,
country,
reference

Number and
type of
population

Cough

Sputum production

Breathlessness
or dyspnea

Chest illnesses

Other

Comme"ts

Goldsmith   3,381 active                                                                 Revpiratory
et al.,     or retired                                                                   conditions
1962,      longshoremen.                                                            NS __ 31.4  (744)
U.S.A.                                                                        Moderate/ heavy
(95).                                                                     smokers 43.0 (1.238)

coates    1.342 mole and                                                         Cough and chronic phlegm Current
et al..     242 female                   NS ..11.2 (747)       NS 14.7                  NS ,. 4.0        smoking
1965.     Detroit post                 1-14 .12.7 (266) (not aig.) 1-14 28.2(~<0.001)           l-14 5.3 (not sig.)   data.
U.S.A.    offirc                     15-24 .2'7.6 (402) (p<O.O01)15-24 .30.`7(9<0.001)           15-24 17.2(p<0.001)
(59).     e"lPloyces.                  >25 . 36.4 (170) (p<O.O01)>25 . .34.1(~<0.001)           >25 ._ _. 25.3(p<O.O01)

Deane
et al.,
1965.
U.S.A.
(67).

508 te1e-
phone
c"mp*"y
workers.

  Pcrsistcnt cough.    NS includes
  phlegm, d2/spnca     ex-smokers,
NS 4.5   (200)   pipe, and
Current cigarette       cigar
smokers 15.9   (308)   smokers.

Huhti,     653 male and
1965,     823 fern&
Finland    residents of
(226).    a Finnish
        CO"ll"U"*l
        region,
        40-64 years
        of age.

M&S

NS _. _. 4.1 (122)







                NS 5.9
                NS __ __ ._ 10.1
EX ,.... 8.5 (141)







                EX
                EX _. _. .17.7







                   . . . .._ 13.3
1-14 . . ...31.6 (108)    1-14 _. .38.0
15-24. ._ .40.8 (191)






                 1-14
                16-24 .42.9






                    .10.4
>25 __ .42.4  (85)   >26  .42.4
     Fern&s          FCT7L&#

NS ._ .__ 4.6 (709)
EX .13.3  (30)
1;:: .::I.:,":: (:67:
>25  .     (1)

15-24
b-25   . . .57.0

Males

NS _. __ 16.6







NS 29.2
EX ._ .24.8
1-14






EX  .26.0
15-24




   . . . . .33.3
    .26.2
>25




1-14 . .31.8
   Females



    . .14.3

16-24
>25  . ..14.0

Chronic bronchitis
   Males

NS 5.7
EX _. 16.3
l-14 _. 38.0
15-24  . 41.4
>26  .40.0
     FW%&8

NS 4.6
EX 13.3
1-14 10.4
15-251
`25 / .....57.0

Es-smokers
represent
those who
have
stopped
smoking
for "lore
than 1
month.
Dyspnea
Grade II
only.


TABLE A2.-Smoking and chronic obstructive pzclmonary disense s?/,,rpto,t,s'-percent p~c~~vzlenw (cont.)
        (Numbers ia pnrentheses represent total number of individuals in particular smoking group)
                 SM = Smokers.      NS = Nonsmokers.      EX z Ex-smokers.

Author,
war,
countiT,
reference

Number and
type of
population

Cough         Sputum production

Breathlessness
or dyspnea

Chest illnesses

Other

Comments

Wynder    315 male          New York Citg
et al.,     patients in     NS .14.0  (44)
1965      New York City  Pipe, cigar 33.0  (64)
U.S.A.    and 315 male    Cigarettes:
(298).    patients in       l-10 ..45.0 (44)
        California.      10-20 .46.0 (38)
                    >20 . .67.0  (86)
                     California
                   NS  . . ..22.0  (69)
                 Pipe. cigar 30.0 (32)
                   Cigarettes:
                     l-10 ..45.0 (64)
                  IO-20 . ..74.0 (91)
                    >20 .14.0 (69)

Fre0llr    1,055 randomly                                                           Cli~iical signs of
et al.,     chosen males in                                                              bronchitis and
1966      Bordeaux 3s-70                                                             rcspiratorU
Fi-ZUlC.?    years of age.                                                               insrcficienry
(92).                                                                        NS 25.4   (46)
                                                                           SM ._ 54.4   (4781

   Haynes,    179 male                                                                 Aacmgr number of   Hea\
    et al..     preparatory                                                           *cwrr rrugiratory     StIlOkel-
    1966      school                                                                    illrfcsscs per 10      mure than
    U.S.A.    students                                                             studcllts (adjuatcd     10 cign-
    (108).     14.-19 yeam                                                                  for flw)        rettes
            of nge.                                                                NS  0.36       per day.
                                                                           All smokers 2.30
                                                                           Heavy SM  3.34
:


TABLE A2.-Smoking and chronic obstructive pulmonary disease symptoms'-percent prevalence (cont.)
          (Numbers in parentheses represent total number of individuals in particular smoking group)
                 SM = Smokers.      NS = Nonsmokers.      EX = Ex-smokers.

Author,
Y-S-.
country,
reference

N,y;F$nd
population

Cough        Sputum production

Breathlessness
or dyspnea

Chest illnesses         Other         Comments

Dellsen    6.313 male            Post&           Poetal             Postal                                  Dyspnea
et al..     and 7,291      NS  . . . 7.0 (903)       13.1              19.8                                    represented
1967,     female postal   Pipe. cigar 12.4 (628)       17.4              24.8                                    by Grade II
U.S.A.    and transit     Cigarettes                                                                    Only.
(68).     workers.       only . .27.0(2,687)       28.9              31.7
                        Transit          Transit            Transit
                 NS . .,... 6.4(1,012)       9.6              11.7
                 Pipe, cigar 10.6 (`766)       14.1              14.2
                  Cigarettes
                   only . . ..23.6(3.'746)       23.7              21.9

Higgins    926 white       NS . . . . ...16.4 (162)   NS........... 31.1   NS . . . . . . . 6.0
et al.,     male resi-     SM . . . . ...47.2 (613)   SM _. . . 46.2   SM . . . .10.7
1968,     dents of      EX .19.3 (144)   EX ,285   EX . . . . . . . . ...16.8
U.S.A.    Marion
(128).    County, West
        Virginia,
        26-69 years
        of age.

Holland    9,786 male            M&8             F`DJZ&?~      Males   Ft3lWlt%
and      and female     NS  . . . . . . 3.8(1,900)      3.2t3.137)       2.4     2.1
Elliott.    school        SM  . . . . 6.3(1,098)       6.3 (664)       6.1     8.3
1968.     children.       EX  . . . . . 2.9(1,782)       4.3(1,161)       39     4.2
England              <l cigarette/day  . . . . . . . . . . . . . ..6.8(876)           6.8
(121).               l-2  . . . . . . . . . . . . . . . . . . . . . . . . . . ..6.6(417)           a.4
                   3-4  . . . . . . . . . . . . . . . . . . . . . . . . . . ..6.6(124)           8.1
                   >6 . . . . . . . . . . . . . . . . . . . . . . . . . . . ..9.9(142)           18.8


TAULE A2 .-Smoking and chronic obstmutive pulmonary disease sZ/,)lpto,,rs'-percent pw~vzlence (cont.)
         (Numbera in parentheses represent total number of individuals in particular smoking group)
                  SM = Smokers.      NS = Nonsmokers.      EX = Ex-smokers.

Author,
  year,     Number and                                     Breathlessness
country,      type of         Cough          Sputum production       or dyspnea     Chest illnesses        Other         comments
reference    pORUlS2tiOZl
Gandevia   762 male and          M&8                                                                 Productive

1969      1,304 female    NS  . . .10.3 (234)                                                      cough upon
Australia   patients      SM .61.3 (628)                                                            reuueat.
(93).     from 13 general      Fslnd`S9
       practices      NS . . .10.6 (867)
       in all parts of   SM . .31.4 (447)
       Australia.

Rimington 41,729 male
1969     and 22,295
England   female persons
(199).    participating
        in mass
        miniature
        radiography
        screening.









Wilhelmsen 313 males
et al.,     6&64 years
1969,     of age randomly
Sweden    S~lllDkd fro",
(251).    population
        of Gateborg.

  Age-adjusted total   Cigarette
   prevalence of      dosage
  chronic bronchitis     gradient
     M&8        significant
NS 5.1 (9.066)   to P<O.OOl.
EX . ., 9.8 (6.610)
Pipe . .  9.0 (2,921)
Cigarettes   (23.243)
l- 9 . . ., 9.1
10-19 . . 16.0
>20  .20.6
    Ft2?Mks
NS _. 3.4(12.361)
EX ., 3.8  (969)
Pipe ._ 0.0
Cigarettes    (8,986)
1.. 9 6.1
lo-19  10.6
>20  . .18.6
Chkric bronchitis
NS ._ 1.0   (88)
EX _. 3.0   (61)
1-14 grams/
day 6.0   (94)
>16 . . ...17.0   (64)


Author,
Year,
CountrY,
reference

Number and
type of
population

Sputum production

Breathlessness
          Chest illnesses
or dyspnea
      .___-

Lnmhert 9,975 malt           I'( rxiatcjlt cough nnd phlegm
and       and female                 Alnlrs
Reid,       reslKmdrrs          <I.f/`~      A!U     AW
i9iO.      to a postal          .I5 45     45-55    55-65
England    -"YV`Zy     NS 7(227)    6(200)   ll(171)
(14F).      (4.688 males  ES _. 7 (303)   ll(3.5R)   15(335)
         and 5,287    (20 .15(521)   22(488)   30(490)
          frmr1lcs     20  . . . . ..2R(191)   ZR(204)   32(149)
         35 69 years   120 .97(14X)   2X(136)   42(121)
         of age).                  FCnlRlC8
                 NS 3(500)    4(637)    5(925)
                  EX ,,.,. 3(127)    8(128)    7 (94)
                  <20 9(602)   13(472)   16(306)
                  20 . . . . ..16(12X)   27(122)   31 (77)
                  i20  .23 (22)   26 (39)   43 (7)
             ~~___ .___-
Lefcoe     310 malt
and       physicians
wonnacott.   in London
1970.      and Ontario.
Canada     25-74 years
(151).     nf a!zc.

Aw
65-69
7 (61)
lS(148)
37(139)
38 (37)
26 (12)

6 (21)
7 (41)
11 (65)
14 (7)

  (1)

  Age-standardized rates   Excluded from
  of chronic rcapiratory    ex-smokers
       disease         are those
NS  . . 1.0   (88)   cigarette
EX __ ,. 5.0   (61)   smokers who
SM . . . .34.0  (101)   now smoke
Pipe, cigar  .12.0   (33)   pipes or cigars.

-~   __I_~ .~
' Data collectrd lw &her direct interview, questionnaire. review of medical records and/or medical examination.


TABLE ABa.--Stroking and chronic obstructivt pulmonary dise~~sc s~~,lpto)t/s'-percent prevnlence

(Numbers in parentheses represent total number of individuals in particuar smoking group)
         SM z Smokers.     NS = Nonsmokers.     EX = Ex-smokers.

Author.
Year,    Number and
c0untl-Y.     type of
reference   popuation

Cederlof 9,319 twin
et al..    pairs

Cou.yuh                    Bronchitis                               comments
                                        .- -~~.
Observed/             Obscrued           Explanation of analyses for      All ex-smokers included
expected  Hypermorbidity  expected Hypemwzbidity  respiratory symptom          with smokers.

1966.    registered    Group A :      eases       ratio       case.9      ratio
Sweden   in Sweden     Mnlcs  .393/151.9      2.6      157/50.8    3.1
(46).    of 12.889      FC"l"lf?S  .136/ 49.4      2.8       43D1.2    3.8
      availnble.     Group n SM/NS:
                 MZ Males  14.tV7.7      1.9      6.6/ 1.1    6.0 (2'74)
                   Females   13.6/?.6      1.8      3.0/ 2.3    1.33(264)
                 DZ Males  12.3D.5      2.26      4.5/ 1.8    2.54(733)
                   Females   14.5/5.7      2.57      5.5/ 1.8    3.0 (653)

prevalence:

Croup A analysis-using each
firstborn twin as one group
in a" unmatched relationship
to each secondborn twin.
Group B analysis-using each
twin set as matched pair.
All comparisons in Groups A
and B are between smoking-
discordant pairs.

MZ-monozygotir
pairs:
DZ-dizygotic pairs
Author concludes that
since hypermorbidity
for smoking persists
in smoking-discordant
MZ population. a
cnsunl relationship of
smoking and bwncho-
pulmonary symptoms
iy supported.

Cederlof 4,3'7!l twin               Pr~~~~~lcnce of rrapiratory eymptoms
et al . .    pairs (all    Group A:
1969,    U.S. veterans)   NS  ................ 4.3     4.3              1.6
U.S.A.   in I'.S.        I-10  ................ G.4     6.4              2.7
(45).    National      11-30  ............... .15.3     15.3              8.0
       Academy of    >Rl  ............... 27.7     27.7             16.8
       Sriences Twin  Pipe, ci!z?ar  ............. 1.1     7.1              2.7

No ex-smoken included
in C.mur, B analysis.
The authors conclude
that the data indicate
R strong probability
of a causal connection
with smoking. Even

Rwistty (of   Group R:                 NS SM        NS SM                        these symptoms.
9,oni) nvial-     MZ   .,, ., ., _. .._ 2.4    5.4        1.8    4.8                        however, seem to be
nhlr)        nz .,  2.0    9.8        1.6    9.1                        influenced by genetic
                                                                           factors.

' Data collected by either dirert interview, questionnaire, review of medical records and/or medical examination.


      TABLE A3.-Smoking and ventilatory function
(Numbers in parcntheses represent total number of individuals in particular smoking group)
        NS = Nonsmokers.    SM = Smokers.    EX = Ex-smokers.

Author,
ye==.
country.
reference

Chivers,
1959,
Enaland
(52).

Number and
type of
population

MBC             EFR               FEV              vc        Miscellaneous     COllllll~llt6

463 malr                             Height-in-inches                                  iMean EFR
employees   Cigarettes/day:         64"       66"        68"       70"                           in liters
of alkaline    o-5  .  t97(28)     91 (35)     108 (31)    lOl(21)                          per minute.
industry     6-20  . . .._ 89(50)     xx (75)     101 (112)    109 (76)                          Regression
plant.       >20  ..t .._... 63 (6)     88.5 (9)     92.5 (9)    113(12)                          analysis of
                                                                           data revealed
                                                                           a significant re-
                                                                           lationship between
                                                                           smoking and de-
                                                                           creasing function.

Higgins    773 males        25-94   55-a                                                                  expressed
et al.,     in various NS 145 (66) 101 (29)                                         FEVO 75
                                                                 as &an indirect
1959,     occupations EX 143 (31) 89 (62)                                                            MBC.
Enaland    (25-34 and 1-14 gr*nls
(116).     65-64 years   .140(193) R7(167)
        of age).   >lS mxms
                 ,133 (89) 80(136)
___-
Wilson    28 male                                                                    RV/TLC
et al.,     residents of                                             NS 6.69 (14)NS . . . . . . 21.1
1960     Dallns,                                                SM a4.44 (14)SM  . . . . . 227.01
U.S.A.    TtZX*?,,
(232).    former
        rural
        dwellers;
        matched
        for hody
        surface. a$?.?,
        and height.


                TABLE A3.-Smoking an,d ventilatorp function (cont.)
              (Numbers in parentheses represent total number of individusls in particular smoking group)
                              NS = Nonsmokers.    SM = Smokers.    EX = Ex-smokers.

Author.
Ye*=,    Number and
country,                MBC
reference    type of                       EFR               FEV
       oooulation                                                        vc        Miscellaneous      CO~llXtllts

Ashford   4,014 male
et al.,                      gEsv* .o                            Data represent
        coal workers                              Age:             SM                            results after
1961,     at 3 Scottish                           <21-30 4.09(103) 3.96(280)                          correction for
Scotland   collieries.                             21-30 .3.86(182) 3.77(665)
(11).                                                                           sitting height.
                                        31-40 .3.44(138) 3.88(777)                      SM includes pipe
                                               41-50  . 3.04 (110)  2.96 (756)                          smoker.
                                               51-60  .2.71(102) 2.66(610)                         Data on ex-smoker
                                       >60 . ..2.38 (42) 2.21(237)                          not included.
                                                              FEVl o found
                                                               &&cant; lower
                                                                           for SM than NS.

Fletcher   363 msle                    Mean mak EFR
and      London                  NS . . __.  670 (30)
Tinker,    transport                 1-14 grams   637(166)
1961,     employees.                 >I6 grams   6!28(116)
England                          EX . . . . .  666 (61)
(85).

Franklin   213 male                                                                           Hesvv smoker
and      factory               J-vi .o "",o.;; y.;g
Lowell.    workers                          HWNY 2,670  3,611
                                    Light `2,489     2,716 Light . . 3,703 (69)             represents *n

1961,     40-60 years                                    *2.666  `2.284 Heavy .`3,678(104)             *mount equal
                                                                           to or more
U.S.A.    of age.                                                                         than 30 pack
(87).                                                                           ye*lY.


     TABLE A3.-Smoking and wentilator~ function (cont.)
(Numbers in parentheses represent total number of individuals in particular smoking group)
        NS = Nonsmokers.    SM = Smokers.    EX = Ex-smokers.

Author.
Yew.    Number and
country,    type of        MBC
reference   population

EFR               FEV             vc         Miscellaneous       Comments

Balchum   1.451 male                      MMEFR
et al..     employees                NS 16.6 (38)
1962,     in                     Pack/year:
U.S.A.    California                <l 16.0 (267)
(24).     light indus-                 l-9 10.0 (263)
        try.                     10-19 10.0 (303)
                             20-29 19.0 (236)
                             30-39 33.0 (144)
                             40-49 . 38.0 (92)
                            5s59 . . 55.0 (29)
                              >60 71.0 (24)

7.8(19)

8.0
6.0
12.0
24.0
26.0
40.0
45.0
62.0

Data for: MMEFR
given as percent
of individrmls
with a value of
<500 L/M;
FEVl.O
given as percent
of individuals
with value of
<70 percent
of expected.

Goldsmith  3,311 active
et al.,     or retired
1962,     longshow-
U.S.A. men.
(95).

    MEFR
NS  . . . . . . ..313.63(260)
Pipe, cigar 299.26 (126)
EX . . 295.23(102)
Cigarettes/day:
crzo..... 309.73(144)
20-40 . 303.44(346)
240..... 307.63 (67)

2.80
2.84

2.89
2.91
2.90

Authors concluded
that cigarette
smoke WBS found
to have B slight
effect on
pulmonary
function.

Martt.     73 healthy
1962.     medic"1 per-                                         DLCO      Smokers defined


U.S.A.    sonnel with-                                                           NS  . . . . . 33.10(30)  asthosesmoki"g

(162).    out signifi-                                     SM <S years .?28.40 (8) >20cigarettes'

        cant age                                                       6-10 yesrs .328.20(10)  day for varyi"a

        difference                                       >lO years .624.90(25) periods.

        between
        smokers and
        nonsmokers.


     TABLE A3.-Smoking at&d uetitikLtOv:J function (cont.)
(Numbers in parcntheses represent total number of individuals in particular smoking group)
        NS = Nonsmokers.    SM = Smokers.     EX = Ex-smokers.

              .-
Author.
  Ye=-,    Number and
c0untl-Y.    type of       MBC             EFR               FEV            vc          Miscellaneous       Comme"ts
reference   population
Revotskie   1,130 male                             FEV*.o                              Data presented
et al..     and 1,813                                      M&8    FETMlt!S                            in terms of

1962,
U.S.A.
(192).

Krumholz
et al.,
1964,
U.S.A
(140).

female
residents in
Framing-
ham par-
ticipating
in the pro-
spcctive
study.
~.
18 physicians
24-37 years
of age.

NS . . .0.98 (65)
Cigarettes/day:
l-10  .0.9? (SO)
IO-29  .0.91(163)
>30 .0.90 (81)

                    -
MEFR

NS  ........  680  (9)
SM  ........ `690 (9)

0.98(255)

0.99 (92)
0.93(157)
0.91 (22)

ratio of
observed to
predicted
values.

-          .-___           ~__
          Mean DL
               NS SM
       Rest  . . . . . . ...36   231
       Exercise:
        2 minutes .SO   341
        4 minutes .60   '43

Zwi      20 medical                      MMEFR

3 minutes
  Dost exercise 39   '35
Authors found

et al.,
1964,
U.S.A.
(241).

studentsor NS _.. 187  (10)
graduate   SM. .`193 (10)
physicians.

4.34
`6.09

6.77
15.53

a sipnifirant difference
betwrcn SM and
NS for RV `TLC,
complianre. and non-
elastic resistance.

Coates     1,342 male
et al.,     and 242

Age:

FEV1.0        Timed VC'    FEVl.O/VC
NS   >SS &/day NS >.25/day     NS   >25/ahl

1965,     female post                               40-44  `2.99(186)  2.85 (69)  3.89   3.85     30.77     0.74
U.S.A.    office                                   46-49  52.95(170)  2.64 (42)  3.92   3.83     30.74     0.70
(53).     employees                                60-64  '2.75(116)  2.62 (22)  3.71   3.74     '0.74     0.70
       >40years                                66-69  '2.64 (64)  2.44 (18)  3.54   3.61     so.74    0.68
       of sge.                                  60-64  '2.35 (53)  2.30  (8)   3.30   3.33     '0.72     0.70          .-


qQ?o!
  z3
   . -.
   : .
   .
gii









:cB p-
`d oi
2',0
: *.
. .
: :
: :
: :
.
. .
I
"F%
Zm


    TABLE A3.-Smoking ad vmtilatory function (cont.)
(Numbers in parentheses represent total number of individuals in particular smoking group)
        NS = Nonsmokers.    SM = Smokers.    EX = Ex-smokers.

Author,
Ye=-,    Number and
country,    type of         MBC
reference   population

Edelman
et al..
1966,
U.S.A.
(79).

410 male
community NS  . . . .  164 ( 162 )
dwellers   current
ar- 103      cigarette
years of    smokers. . 6 161(118)
*ge.     EX . . . . . . . ., 167 (98,
       Pipe, cigar . 167 (47)

EFR             FEV            vc          Miscellaneous        COllllll~!ltS

1.89



7.86
8.09
8.20

yp.0



12.64
2.80
2.91

vitai capacity
   4.93



   * 4.14
   4.17
   6.08

Ex-smokers of
cigarettes only.
Difference signifi-
cant between NS
and current
cigarette smokers
fit p<O.Ol.

Peters     124 male                        MEFR
and      college *ge               NS . . ..*10.28 (41)       FEVl.0                            Heavy smoker refers
                                                      4.68                                to greater than
Ferris.    students.                 Moderate 10.06 (64)          4.69                       86.3        or equal to 1
1961,                           Heavy . . . .  9.64 (29)          4.43                       83.9        pack years.
U.S.A.                           EX . .  9.48 (10)          4.14                       83.2       Moderate smoker
(282).                                                                           includes pipe and
                                                                           cigar smokers.
                                                                           Difference between
                                                                           NS and heavy
                                                                           smoker is
                                                                           significant.

Higgins    926 white
et al..                                   FEV1.0
        l?l~le                                   NS  . . 3.64(160)
1968,     residents                                EX  . 3.26(143)
U.S.A.    of Marion                              Cigarette SM 3.48(611)
(128).    county,                                  1-14  Lt.61 (88)
        west                                   16-24  . ., 3.67(273)
        Virginia,                                >26 .  8.30(160)
        20-69 years
        of age.


TABLE A3.-Smoking and wentilator~/ function (cont.)

Author.

(Numbers in parerltheses represent total number of individuals in particular smoking group)
       NS = Nonsmokers.    SM = Smokers.     EX = Ex-smokers.

year,   Number and
country.    type of
reference   pornllation
Sluis-    53Fwhite
Cremrr    malr
and      filrtory
Sichel,     workers
106X.     over 35
South     years of
Africa    REV.
(208).

MBC          EFR               FEV              vc          Miscellaneous

                  J-44      45-54      >55
       NY  553(106)    627(101)           FEVf .o
                               444(27)    ss-44 45-54 >a5
      Crams/day:                              3.70   3.22   2.76
       l-14 557 (26)    619 (17)    410 (7)    3.64   3.31   2.24
       15-24  532 (94)    446 (35)    401(13)    3.66   2.94   2.28
      >?,S t52R (66)   t494 (31)   t380(10)    3.64   3.05 t2.12

Commrnts

1 cigarette:

1 gram.
1 ounce tobacco =
26 granls.
1 cigar = 2 to 5
grams.
t Derived slopes
found signifi-
cantly different
from 0.

stanescu   a7 malt bus                                        F'EV.                 Nitrogen gradient

et al..     drivers;                                         ~ 1."                  _..
                                               Yow1gcr     Older   YoNnger Older   Younger   Older
1963,     27 aged                           NS 4,470(14)   3,310(40)   6,125   4,290     1.63    2.49
Rumania   20-25, 60                          SM 4,500(13)   `3,200(20)   `5.285   `4.290    11.47    5 3.77
(919).    wed 40-60,
        all without
        respiratory
        symptoms.
___-                         -
Dense"    5,287 male                                 Fj:V. _--                           FEV expressed as

et al.,
1969,
U.S.A.
(89).

postal and
7,213 mnle
transit
workers in
New York
City.

NS  
All cigarette  
<25 grams/day  
225 awns/day   

Pos:~~
Wh itr.
3.29 (685)
3.11(2,340)
3.14 (1,292)
3.06 (1.038)
Transit
White
3.39 (620)
3.11(2.941)
3.15(1.929)
3.02(1,011)

NS  ....................................
All cigarette  ............................
<26 grams/dsy  .........................
225 grams/day ...........................
-

Non-zuhitc
3.05  (204)
2.94  (768)
2.96  (693)
2.93  (161)

Now-white
3.08  (298)
2.99(1.041)
3.00  (891)
2.96  (149)

standardized for
specilied postal
and transit
workers at age
45 and at sitting
height of 35
inches.
Includes mixed
smokers.


    TABLE A3.--Smoking md ventilatoq function (cont.)
(Numbers in parentheses represent total number of individuals in particular smoking group)
       NS = Nonsmokers.     SM = Smokers.    EX = Ex-smokers.        --

Author,
war.
count.lY.  Nutn$r;nd     MRC          EFR               FEV              vc          Miscellaneous        COltllll~llts
reference   Dopulation
       _

         FEvl.O                              FEV expressed as
NS  _. .`97.6 (12)                              percent of
SM  _. 78.4 (58)                              predicted value
                                                for age, sex,
                                               and height.

Rankin    60 male
et al.,     and 10
1969,     female
Australia   patients
(190).     with chronic
        alcoholism
        26-66 years
        of age.

Wilhelmsen 313 male
et al..     residents
1969,     of Giiteburg
Sweden    50-54 years
(231).     of age.
__~
Lefcoe    310 male
and      physicians
w<1nna-    of London.
rott,      Ontario.
1970,
Canada
(151).

                      PEFR                VC                  1963 values only
NS  ...........................  525(M)                4.83
EX  ...........................  539(67)       3.69       4.71
1-14 grams/day ................  521(94)       3.62       4.33
>15 grams/day ................  492 (64)       3.39       4.56

     MMFR
NS . .  4.09 (88)
Cigarette
smokers.   3.64(101)
EX  3.99 (61)
Pipe, cigar   4.17 (33)

MMFR has been
standardized for
age and height.


TABLE A3.-Smoking and ventilatorp function (cont.)

Author,
Year,
country,
reference

(Numbers in parentheses represent total number of individuals in particular smoking group)
         NS = Nonsmokers.    SM = Smokers.    EX = Ex-smokers.



        FEV              Miscellaneous                    Comments

Lundman,
1966.
SWNkll
(159).

31 MZ and
62 DZ twin
pairs selected
from Swedish
Twin-Pair
Registry.

FE"1.0

Significant diflerences
between smoking discordant
twin pairs found for:
  1. Group A MZ males
     and females.

N2 washout gradient
Significant differences
between smoking dis-
cordant twin pairs
found for:
  Group B DZ males.

MZ = monozygotic.
DZ = dizygotie.

The author concludes that the degree of ventilation as measured by Nz
washout was correlated with cigarette consumption. The FEVleO
was significantly lower for smokers and there was a correlation
with cigarette consumption.

Explanation of analyses for respiratory symptom prevalence:
  Group A analysis-using each firstborn twin aa one group in an
   unmatched relationship to each secondhorn twin.
  Group B analysis-using each twin set as matched pair. All
   comparisons in Group A and B are between smoking-discor-
   dant pairs.

2. Group B DZ males.
3. Group A DZ males.

1 Not significant (difference or trend)
2 p<o.o5
3 P<O.Ol

4 p<o.o05
6 P<O.OOl


TABLE Ad-Glossary of terms used in tables and text on smoking and ventilatory function

Symbol

Term              Volume or rate                           Definition

MBC.. _. Maximal breathing
         capacity.

Liters. . . . .  The maximal volumt of gas that can be breathed in one minute.

MVV. .Maximal voluntary
          ventilation.

EFR. Expiratory flow rate. . . . . . . . .Liters/minute. . . . .  Rate of flow for a specified portion of a forced expiration (MMEFR-rate
PEFR. Peak expiratory flow rate.                           of flow measured for middle half of FVC).
MEFR. .Maximal expiratory flow rate.
MMEFR. .Maximal midexpirstory

flow rate.

FEVt Forced expiratory
          volume.

Liters. .  Volume expired within a specified time interval. (FEV1~O-v~lume expired
                     in first second of expiration.)

VC. ......... .Vital capacity ................ ..Liters. .........................  Maximal volume of a gas that can be expelled from the lungs by forceful
FVC. ........ Forced vital capacity.                             effort following a maximal expiration.

FEVt/VC. . Forced expiratory
         volume/vital capacity.

Percent. . . . .  Volume of forced expiration (in time specified) related to vital capacity.

D,,. _. Pulmonary diffusing        ml/min/mmHg            The ability of a chosen gas to pass from the alveolus to within the pulmonary
          caparity.                                   capillary.
                     .-                            -
N2 washout.. Nil.rogen washout          Exponential              The stepwise pulmonary alveolar clearance of a gas. (Slope of curve depends
          gradient.               Curve.                 upon the uniformity and adequacy of ventilation of all parts of the lung,)
                                              It may be done as a singlt-or multiple-breath procedure.

        Compliance. . . . Litcrs/CMHZO.. . . _, _.  Volume change of the lung produced by a unit pres~~ure change.
__---                                                           ~-
RV. _. Residual volume. . . . .Liters. .  Volume of gas remaining in the lungs at the end of a maximal expiration.

TLC. . Total lung capacity. . . ~. .Litrrs.  Volume of gas contained in the lungs at the end of a maximal inspiration.

FRC.  .Funrtional residual         Liters. . .  Volume of gas remainina in the lungs at the resting expiratory level.
         capacity.

Aleveolar volume. . . Litrrs. .  Volume of gas contained in pulmonary alveoli.

SOURCE: Co!"roe, J. et al. (56)


TABLE A&-Epidemiological studies concerning the relationship of ai,,.
  pollution, sociul class, awl smoking fo chronic obstructive
       blonchopulmonary disease (COPP)

Author,
Ye*=.
countrY,
reference

Number and type
of PoP"latio"

Higgins,
1957,
England
(122).

301 males and
280 females
living in 2
SeDX'ate
districts.
(45-64 years
of age. t

college of
General
Practi-
tioners,
1961,
England
(55).

Ferris and   1,219 males and
Anderson,   females living
1962,       in 3 different
U.S.A.     areas of a New
(b-1).      Hampshire town.

MO&,
1962,
U.S.A.
(171).

339 male trapsport
employees from
London and
Norway.

iXS males and
iX2 females
45-64 years of
age from
medical doctors'
case lists.

-

Male data only (170) :                 w_
(*) The frequency of recurrent chest illnesses was high-
  er in the more polluted region but the prevalence of
  other respiratory symptoms and mea" values were
    similar.

(b) Significant difference observed in COPD mortalit,
  rate.

(a) Male urban inhabitants manifested almost twice the
prevalence of chronic bronchitis as rural males; this
difference could not be explained On the basis of
  smoking habits.

(b) NO significant urban/rural differences noted for
  PEFR.'

(c) No significant urbanirural differences noted for
   COPD SS-n,pton,s among females

Following adjustment for differences in smoking habitj, n.
significant differences in chronic bronchitis were observed
among the 3 pollution areas.

The excess prevalence uf serious respiratory symptoms (dy.
spnea, \vheezing) and PEFR dysfunction among London
Transport employees was only partly eliminated after
standardization for smoking, and the author suggests
that this ia due to differences in air pollution levels.

Sehoettlin,   2,622 males
1962,       45-i5 years
U.S.A.     of age.
(204).

(a) No positive correlation found between chronic respira-
tory illness and city size.
(b 1 A positive correlation was found between chronic res.
piratory illness and cigarette smoking (particularly du-
ration).

Anderson
et al..
1965,
Canada
(0.

Holland
and
Reid,
1965,
England
(124).

i78 residents of
Berlin, N.H., and
918 residenti of
Chilliaack,
Canada.

6i6 male transport
employets in
London and rural
England.

Berlin. New Hampshire, has higher SO, and particulate air
pollution levels and the higher respiratory disease preva-
lence rates among its residents were not accounted for
by age differences, but were accounted for after stan-
rlardization for smoking habits (except that PEFR and
FEV, 9 dysfunction was more prevalent in New Hamp-
shire, `and the authors suggest that this difference w
fleets ai], pollution differences).

,a) I.~,don emplo,-e?s manifested a greater prevalence of
COPD symptoms and PEFR dysfunction than did the
rural employees.

(b 1 Smoking habit differences alone were not sufficient to
csplain this difference in COPD manifestations.
(CI Both groups manifested pulmonary dysfunction car-
related with tobacco consumption.

Bates
et al.,
1966,
Canada
(27).

216 hospitalized    Winnipeg (cleanest of all areas in SO2 and industrial
veterans fwm      du~tfnlli  rrsidents manifeqted decreased prevalence of
v*rit)us areas of    che,t illnesses, less se\cre grades of dyspnea. and less
Canada (all      slnlturn volume prorl;lred when compared to residents of
standardized for    all ,,ther areas.
age, tobacco
consumption, and
occupation).                    _-

216


TABLE AG.-Epidemiological studies concerning tile relationship of air
  pollutions, social clus,s, uxtl smoking to ch?,ovic obstmctive
      bronchopulmonary disease (COPD) (cont.)

AUthOr.
Yea=,
countrY.
reference

Number and
type of
uowlation

Results

                                         ~.
Ashley,     Standardized      Positive correlations:
1969,      mortality       (a) Smoke concentration and bronchitis mortality.
England    ratios for      Ibl so2  and smohv c~rnoentration and bronchitis mor-
(12).      males (1958-63)     tality and social class.
         for 53 boroughs     (CJ Pollution and social class.
         with air pollution
         indexes.

Holland     10,971 children     Factors affecting pwvalmce of respiratory symptoms:
et al..      over 11 years of     (a) Smr~kingPhighly significant association.
1969.       age in 4 areas.     (b) Area of r?aidencr (pollution) --significant association
England               except for periods of cough and phlegm lasting more
(1,"2).                    than 3 weeks.

(cl Social class. age. sex-n" association noted.

Winkelstein  842 females
and       ""El. 25 years of
Kantor,     age in various
186'J.       regions of
U.S.A.     BUffal".
(233).

(a 1 The incrc:~~<~~l ~1 v\alencr uf w-l~irat~vr>- ,)mptoms could
  not be explained by social class differences.
(b) No overail association noted betwpen productive cough
  and air pollution.

Coolev and
Reid,
1970.
England
(58).

Lambert
and
Reid,
1970,
England
(146).

10.X87 children
G-10 years of
ape from eon-
trasting urban
and rural areas.

Illnesses considered included chronic cough, past bronchitis,
blocked nose.

(a) Every geographic area showed a clear gradient of in-
creasing illness prevalence with decreasing social class.
,b) Social classes I, II, and III showed no urban:rural
gradient while IV and V showed a clear excess in fre-
quency of chest illnesses among urban residents over
rural residents.

8,975 males and    (a 1 The trend of increasing prevalence of bronchitic sump-
females        tams from rural to urban respondents was not negated
responding      by adjustment for smoking differencff.
to questionnaire   ib) After adJuetme"t for age and smoking habits. male
S"I`VCY.        respondents manifested a clear correlation of persistent
            cough and phlegm prevalence with increasing air pollu-
             tion. Correlation was not BS striking in females.
           (c) Although the proportionate rise in symptom preva-
           lence increased with air pollution similarly in each smok-
           ing group, the absolute differences in morbidity risk in-
            creased with increased cigarette consumption, suggffting
           synergistic influences of cigarette smoking and air pollu-
              tion.

(d) In the absence of cigarette smoking, the correlation
between the prevalence of persistent cough and phlegm
and air pollution was slight.

' See GIossary of Terms: Bronrhopulmonary table A4.

217


TABLE A~.--E'l,idr?lriological st1idie.S ConCW?Ling the rehtionship of OCCUpatiOnal
ezposwrc and smoking to chronic obstructive bonchopul~~~onary disease

Author,
Ye=-,
c0u"tl-Y.
reference

Number and
type of
population

Results

Higgins     135 males        Miners showed increased symptom prevalence (breathless-
et al.      (84nonminers.     ness, cough, sputum).
1956,       101 miners)     Miners showed increased prevalence of chronic bronchitis.
England    without pneumo-   Miners showed decreased MBC.'
(119). eoniosis.       Differences in smoking between the two groups did not a~-
                       count for above differences.

Phillips     1.274 males     None of the-industrial environments were associated wiz
et al..      factory emplowes   an increased prevalence of chronic cough.
1956,       (coke and      Cigarette smoking and age were directly correlated with
U.S.A.     electrolytic       increased prevalence of chronic cough.
(18.5).      process 1.

Higgins     325 males 25-34     Miners as compared to workers in non-dusty occupations:
et al.,      years of age and    25-34 years of age-significantly increased prevalence of
1959,       401 males 55-64      chronic bronchitis and MBC abnormalities.
England    years of age in     X-64 years of age-less significantly increased prevalence
(116).      various "ccupa-      of chronic bronchitis and MBC abnormalities than in
          tions.            25-34 years of age group.
                      No smoking information available.

Chivers,
1959,
England
(5%).

463 males in      No significant differences in PEFR' between dusty and
non-dusty and      non-dusty Pl`""PS.
dusty occupations  Cigarette smoking (especially in those >40 years of age)
(lime and soda     was associated with decreased PEFR values.
ash exposure).

Higgins     300 male miners    Miners showed increased prevalence of symptoms and de-
and       and 300 male      creased MBC values which remained even after standard.
Cochrane,    nonminers 35-64    ization for smoking habits.
1961,       yeal of age.     Total dust exposure was not directly correlated with these
England                 findings.
(115).                 Wives of miners showed similar symptom and test change.
                      as compared with wives of nonminers.

Brinkman
and
Coates.
1962,
U.S.A.
(42).

1.31'7 males 40-65
years of age
with various
silica exposure
histories.

Increased silica exposure was associated with an increased
prevalence of chmnic bronchitis.
Highest prevalence of chronic bronchitis was noted in the
non-exposed group; and this group was noted to have
the highest number of smokers and highest consumption.

Hyatt
et al.,
1964.
U.S.A.
(1.28).

261 male miners
and ex-miners
4s55years
of age.

Increased history of underground work was associated with
an increased broncbopulmonarv symptom prevalence and
decreased pulmonary function values.
The impairment of pulmonary function associated with
underground work was separate from effect of smoking;
but smoking and underground work did show additive
effects.

ElW""d
et al.,
1965.
Ireland
(77).

2,525 male and
female flax
workers over 35
years of age.

Preparing room workers who manifested byssinosis symp-
tams also showed an increased prevalence of chronic
bronchitis independent of age or smoking when compared
with non-preparing room workers.
Female workers manifested a significant association be-
tween byssinosis symptoms and smoking while msle work-
ers did not.

Sluis-Cremer 827 miners and
et al.,      nonminers over
1967.       35 years of age.
South Africa
(ZO9).

Those smokers exposed to gold mine dust manifested more
symptoms of CQPD 1 than did non-dust exposed smokers.
while prevalence of symptoms, among nonsmokers. was
similar for the two groups.

218


TABLE A7.-Epidemiological studies concerning the relationship of occupational
exposure and smoking to chronic obstructive bronchopulmonary disease (cont.)

Author,
Ye==.
countlY,
reference

Number and
tYDe Of
population

Results

Sluis-Cramer X27 miners and     The dose relationship of cigarettes and COPD 1 symptoms
et al., 1967,   nonminers over    wss much more noticeable among those exposed to dust.
South Africa  35 years of age.   Thr authors stressed the synergistic actions of cigarette
(2OY). (cont.)              smoking and dust exposure.

Bouhuys
et al.,
1969,
U.S.A.
(39).

455 male cotton     Those exposed to dust manifested a significantly greater
textile workers    prevalence of byssinosis symptoms than nonexposed.
(214 exposed to   Smokers manifested a significantly greater prevalence of
dust in carding     byssinosis symptoms than nonsmokers.
and spinning     No significant differences in Monday morning FEV' values
rooms, 241 not     were observed between smokers and nonsmokers.
exposed)       Prevalence of byssinosis symptoms did not show any re-
             lationship to length of employment.

Bouhuys
et al,.
1969,
U.S.A.
(38).

216 male hemp     Hemp workers (especially the older ones) were noted to
workers and 247    have different smoking habits from control group--fewer
workers in other    heavy smokers. more light smokers, more ex-smokers due
industries in      to doctor's orders.
ssme region,    Aged 20-49 - a. No difference in FEV1.9' values. between
20-69 year?,                controls and hemp workers in any smok-
of sge.                    ing category.
               b. No difference in FEV1.o values between
                       men in different smoking categories.
            Aged 59-69 - 3. Hemp workers manifested decreased
                 FEV1.9 values in all smoking groups
                        except for heaviest smokers. Ex-smok-
                  ers had lowest FEVI.o values.
               h. Those smoking most had lower FEVI.9
                       values as compared with light and non-
                        smokers.
             The authors conclude that:

There appears to be no synergism between smoking and
hemp exposure as to effect on FEV,.o although the
selection process whereby those with symptoms have o
greater tendency to stop smoking may obscure such a
relationship.

Chester
et al.,
1969.
U.S.A.
(49).

139 male chlorine   Chlorine-exposed group manifested no difference in symp-
plant workers     toms and a decreased MBC value when compared with
(55 with history    non-exposed group.
ofsevereex-     Smokers in chlorine-exposed group had significantly de-
posure).         creased MBC and FEV values as compared with non-
             smokers in non-exposed group.

Greenberg    121 workers in
et al.,      washing powder  Sensitized group manifested lower FEV1.o/FVC' values
                      as compared with nonsensitized group even after smok-
1970.      factory (48 found   ing habits w'ere controlled for.
England     to be sensitized
(97).      to product,
          73notj.

Tokuhat"
et al.,
1910,
U.S.A.
(218).

801 male miners

Increased mine exposure was associated with residual vol-
"me and FEV abnormalities even after adjustments for
age and smoking.
A systematic exposure-impairment relationship wss noted
only among smokers while relatively few nonsmokers
showed COPD impairment,

Smoking miners manifffted more X-ray alterations and
COPD symptoms than nonsmokers. regardless of num-
ber of years of underground exposure.

r See Glossary of Terms in Bronchopulmonary table A4.

219


Author.
sea=,
countrY.
reference

Animal                     Results

Freeman
and
Haydon.
1964
U.S.A.
(90).

Spi-agUe-DaWleY
rats.

23 p.g.m.:
(a, after 37-41 days-moderate hypertrophy and hyper-
   plasitl uf bronchial anil bmnchiolar egithelium.
(b) after 146-157 days-[ 1) Advanced hypertrophy and
                  hyperplasia of bronchial and
                 bronchi&x epithelium.
                (2) Increased lung volume.
               (3) Proliferation of Connective
                   tissue.

HlWd@ll
et al..
1965
U.S.A.
(107).

Haydon
et al..
1967
U.S.A.
(106).

Sprague-Dawley
rats.

12.~ p.p.m. to death:
!a) Mrpertrophy and occasional metaplasia of bronchial
    and hronchiolar epithelium.
(b) Increase in number of actively secreting goblet cells.

       --        ___lll
Albino rabbits.     g-12 p.p.m. for 4 months:
            ia) Abnormal dilatation of peripheral air spaces.
             (b) Decreased density of alveolar walls.
           (c) Hrpertrophy and hyperDlasia of bronchial epithelium
                 (especially terminal bronchiolar)
             (d) Increase in size of alveolar ducts.
              le) Increased elastic tissue staining.
             (f ) Increased alveolar size.

Freeman
et al..
1968.
U.S.A.
(91).

Sprague-Dawley
rats.

0.8 p.p.m.-2 p.pm. for entire lifespan:
(a) Alveolar distention.
(b) Reduction in number of cilia.
(c) Epithelial inactivity ("dormancy").

Freeman
et al.,
1968.
U.S.A.
(89).

Spra!qx-Dawley
rats.

18 p.p.m.
(a.1 5 days-terminal bronchiolar rpithelial hypertrophy.
(b) 4 weeks- ( 1) Widespread bronchiolar epithelial hy-
            pertrophy.
         (2) Non-necrotizing emphysema.

Blair
et al.,
1969,
U.S.A.
(32).

Female Swiss
Albino mice.

Kleinerman,  Male Syrian Golden
1970.       hamsters.
U.S.A.
(136).

0.5 p.p.m.:

la) 6 hours'dav for 3 months-pneumonitis.
(b)  24 hours/day for 3 months- (1) Respiratory bronchi-
                       alar obstruction.
                   (2) Alveolar expansion
                       and brnnchiolar
                       inflammation con-
                      sistent with early
                       focal emphysema.

100 p.p.m. for 5'2 hours:
(a) thymidine autoradiography-intense burst of prolif.
    eration of epithelium returning to normal in 4 days
    (more persistent distally).
(b) electron microscope-( 1) Decreased number of se-
                   cretory cells + secretory
                    granules.

(2) Increased number of lyso-
    somal structures.
(3 ) No change in number of
    ciliated cells.

220


TARLE AlS.---Experimrxts concerning the effect of cigarette smoke or its
        constituents upon ciliary function

Author,
ye==,
countrr,
reference

System

Method '

Results

Mendenhall In vitro:     Cigarette smoke   ControlsPciliary  activity depressed spproxi-
and      Calf trachea.   by direct appli-   mateI\. 4 percent.
Shreeve.             cation or in    Experimental&ciliary activity depressed a~-
1937,               solution.        proximately 40 percent.
U.S.A.
(164).

Rakieten   In vitro:      I. Nicotine in    I. Ciliary activity depressed only upon ea-
et al..     (a) rabbit     Locke-Ringers    posui-e to 100 mg. percent solution.
1942,       and rat      solution.     II. Ciliary activity dwressed after 15-20 min-
U.S.A.      trachael   II. Cigarette smoke   utes exposure depending on concentration
(188).      rings.       in solution.      of smoke in solution.
        (b) human
          nasal
          Ill"C"llS
          membrane

Kordik    III vitro:

Nicotine in Locke's Nicotine at 1O--5 g,:cc had no effect on CiliarY

et al.,     Rabbit       solution.
1952,       trachea
England
(137).

Hilding,    In vitro:     Cigarette smoke
1956.     Cow trachea    (direct
U.S.A.              exposure).
(120).

Krueger
and
Smith,
1958,
U.S.A.
(139).

In viuo:
Rabbit
  trachea

Cig.arette smoke.

Dalhamn,   111 uiz.0:      Cigarette smoke.
1959,     I. Rat
Sweden     trachea
(59).    In t&-o:
        II. Rabbit
          trachea
       III. Humafi
          ciliated
          lll"~"SZl
&lk      In vitro:     Cigarette smoke.
et al..     Rat and rabbit
1959       tracheal
U.S.A.     epithelium.
(80).

Railenger,  In i.itro:      Cigarette smoke
1960,     H11mall      in solution.
U.S.A.      bronchial
(25).      and tracheal
         epithelium
          obtained
         during
          anesthesia.

activity.

All tracheas showed depressed or absent ciliary
activity.

Cigarette smoke decreased ciliary activity by
approximately 200 beats/minute.

I. T/10 showed cessation of ciliaw activity
after one exposure.

II. 6:lO showed cessation of ciliary activity
  after one exposure.

III. fi/T showed cessation of ciliary activity
  after one cigarette exposure.

Decreased ciliary activity noted on exposure to
cigarette smoke:
(a) Repetitive exposure was associated with
  persistence of response over longer periods
  of time.

(b f "Tar"-rich cigarette was more inhibitory
than "tar'`-poor.
(P) Filtered smoke was less inhibitory than
unfiltered.

Ciliary activity was fully inhibited within 5-28
minutes of exposure depending upon concen-
tration <,I smoke in solution.

221


TABLE A13.-Eeperiments concerning the effect of cagarette smoke or its
       constituents upon diary function (cont.)

Author,
year.
country,
reference

system

Method 1

Results

Wynder
et al.,
1963,
U.S.A.
(236).

In viva:      Cigarette smoke;  Unfiltered cigarette smoke--eiliastaais by 2ud-
Fresh water   and its fractions   5th puff.
  ItlUSSd     in solution.    Acid (phenolic) fraction solution-immediate
  ciliated                 ciliastasis.
  epithelium.            Whole extract fraction solution-no cilia&&
                     Neutral fraction solution-no ciliastasis.
                 1 percent phenol solution-immediate ciliast+
                       sis.

Dalhamn   In viva:      Cigarette smoke.   Unfiltered cigarettes-ciliastasis in 3/S cati
and      Cat trachea.               after 5 cigarettes.
Rylander.                   Filtered cigarettes-no ciliastasis after 8 cig+
1964,                          rettes (5 cats).
Sweden                      Controls-no ciliastasis (5 eats).
(61).

Ballenger   In vitro:     Nicotine in solution. Initial stimulation of activity followed by de-
et al.,     Human                 cline and complete ciliastasis after 12-24
1965,       ciliated                hours of exposure.
U.S.A.      tracheal
(26).      epithelium
          obtained
          during.
          anesthesia.

Dslhamn   In viva:      Cigarette smoke.  The longer the time interval between expo-
and      cat tracklea.               sures, the more puffs were required to cause
Rylander,                         ciliastasis.
1965,
Sweden
(62).

Wynder    In vim:     Various compounds Formic, acetic, propionic, benzoic acids all
et al.,     Fresh water   in solution.      more ciliatoxic than phenol.
1965,       mussel               Oxalic acid lass ciliatoxic than phenol.
U.S.A.      ciliated              Formaldehyde, acrolein more ciliatoxic than
(235).      epithelium               phenol.

C!XSO"    In viva:      Cigarette smoke.      Percent decrease in ciliamy activity
et al..     Cat trachea.              Control . . . .   0
1966,                          Unfiltered smoke . . .  53
U.S.A.                         cell"lose acetate filter . .  46
(44).                         Carbon cellulose acetate filter . .  30

Dalhamn.   h viva:      Cigarette smoke.    Mean number of puffs required to produce
1966,     Cat trachea.                          ciIiastiai8
Sweden                         No filter ................................  91
(60).                          Charcoal filter  .......................... 170
                             Commercial cellulose acetate filter ........ 194
                             Charcoal and acetate filter .............. 512
                             Cambridge filter ........................ 600

Kensler    In vioo:      Cigarette smoke   Rabbit trachea-Total smoke condensate of 3
and      Rabbit       and components   cigarettes. gas phase condensate of 7 ciga-
Battista,     trachea,     in Tyrode's      rettes caused similar ciliastasis.
1966.      cat trachea,  solution.      Other species--All found sensitive to ciliastatic
U.S.A.     dog trachea,             components of cigarette smoke. Bulk of ac-
(lS5).      monkey                tivity noted in gas phase (HCH. formalde-
          trachea.                hyde, acrolein)
          rat trachea.

222


TABLE A13.-Experiments concerning the effect of cigarette smoke or its
       constituents upon diary function (cont.)

Author,
Y-r,
countrY.
reference

system

Method 1

Dalhamn   In viva:      Cellulose aeetate-
and      Cat trachea.   filter cigarettes
Rylander,            with varying
1967.               amounts of
Sweden              "tar" but simi-
C-55).              lar gas phases.

D*lh*"ln   In viva:
and      Cat trachea.
Rylander,
1968,
Sweden
(64).

Unfiltered and
Cambridge-filter
cigarettes.

Resu1t.s

Increased amounts of tar were associated with
decreased number of puffs required to inhibit
eiliary sctivity.

Whole smoke found to be markedly more toxic
to ciliary activity than volatile (gas) phase
at lower dosages (puff volume). This differ-
ence diminishes with increasing puff volume.

Kaminski   In viva:     Whole and filtered Wet chamber adsorption significantly reduced
et al..     Cat trachea.   cigarette smoke   the ciliastatic activity of whole smoke, but
1968,              exposed or unex-   did not affect the ciliastatic activity of smoke
U.S.A.              posed to "wet    previously filtered by Cambridge or charcoal
(183).              chamber" made    filters.
                  to stimulate
                  oral mueosa
                  and saliva.

Krahl     In viva:     Cigarette smoke   Significant ciliastasis. reversible.
and      Common     dissolved in
Buhnash.    molluek     sea water.
1969.       ciliated
U.S.A.     epithelium.
(188).

Battista   In vitro:     Cigarette smoke   The authors observed that:
and       Chicken     or HCN in      (1) The more diluted smoke required more
Kensler,     tracheal     TYrode'e        puffs to cause ciliastasis.
1970,      epithelium.   solution.       (2) Activated charcoal filtered smoke was
U.S.A.                          less ciliastatic than cellulose acetate filtered
(2.3).                          smoke and also contained less HCN and
                                acrolein.

(3) HCN alone was ciliastatic but recovery
was more rapid than after cigarette smoke
alone.

They conclude that the gas phase components
are more related to ciliastasis (as particulate
matter is not significantly decreased by char-
coal filtration while HCN and acrolein are).

Battista    In viva:      Cigarette smoke.   The authors observed that:
and      Hen trachea.             (1) Whole smoke acutely depressed ciliarv
Kensler,                         activity in 4-6 puffs.
1970.                       (2) Gas phase was only slightly less depres-
U.S.A.                            sant than whole smoke.
(99).                          (3) Chronic exposure (1 cigarette/day for
                            32 days) to smoke resulted in no apparent
                       permanent defect in ciliary activity (al-
                          though mucous production was signifi-
                              cantly increased).

223


TABLE Al.?.-Ezperi~uexts comerning the effect of cigarette smoke or its
        consLitzcents upon ciliary function (cont.)

__-
Author.
  year.
country,
reference

system        Method 1

Results

Dalhamn   In viva:     Unfiltered cigarette Average mmzber of pufis required to arve.qt
and      Cat trachea.   and cigar smoke.           ciliatu activity
Rylander,
1970,                Cigarette smoke 13) (p<:o,ol)
                                Cigar smoke . .114J
Sweden                       The authors note that cigar smoke is of a
(65).                          different pH and that it contains more iso-
                             prene, acetone, toluene. and acetonitrile.

Kennedy   In viva:      Mainstream      Electron microscopic observations:
and      Protozoan    cigarette smoke.   (1) After 7 minutes exposure-alteration of
Elliott,      (ciliated)                 mitochondrial structure.
1970.                         (2) After 42 minutes exposure-destruction
U.S.A.                           of internal mitochondrial membrane atrw-
(134).                            ture.
                             (3) Gas phase alone, while ciliatoxic, did
                             cause mitoehondrial swelling but no dis-
                               ruption of membrane structure.

`Unless otherwise stated, method entailed the direct observation of ciliarv activity using
markers.

224


TABLE A14.-Experiments concerning the effect of cigarette smoke on pzclmonavy surfactmt aml swfacc tcnsiot?

  Author,
   year,
  country.         system           Method                                Results
  refwence                                                               __~
Miller and    Rat lung extracts      Cigarette smoke:   (1) Exposure to cigarette smoke was associated with decreased surface tension in lung extract.
Bondurant,                   (1) Applied to   (2) Surface tinsion of rats (lung extracts) exposed to'cigarette smoke was decreased
1962,                           extract.         as compared with those not exposed.
U.S.A.                      (2) Exposure
(165)                          of rats.

Cook       40 subjects undergoing                        Surface tension
and Webb     hronchoscopy:                           VdUfS of lrurfactnnt
1966,        14 normal                                      20     100     Stability in&z (reflectn   t Values significantly
U.S.A.       1 nonsmokers with                               percent   pcrccnt     sxrfactnnt activity)     different from
(57)         pulmonary disease                               area ama                       values of normals
           19 smokers with and                 Normal  . .     6.6    GO.0           1.61          at p<o.o2 level.
            without pulmonary                Pulmonary
            disease.                        patients   . . .   t17.0    t50.0           1.00
                                       Chronic smokers    15.7    51.0           1.04
                                                                .~
-
Giammona    In vitro:           Exposed to       In vitro:
1967,        Surfactant material     cigarette       Exposure to cigarette smoke was associated with a significant decrease in maximal surface
U.S.A.       induced from dogs      smoke for          tension.
($4)        and rats.           3 hours/day      In viva:
         In viva:              for up to       Dogs and cats (exposed for 1 week)-no significant change.
          Dogs, cats, and        3 weeks.        Guinea pigs (exposed for 3 weeks)-significant decrease in maximal surface tension.
           guinea pigs.

Webb.
et al.
1967,
U.S.A.
(224)

Bronchial
washing.
from
dog lunss.

Direct
exposure to
cigarettr smoke.

            S!Lrface tension valtcrs of .%LTf~Ct~,lt
                    20 pcrce1zt       100 PCTCCTII
             Number     nrcn           arca          Stability index
contra1       11             60.1)              1.60
Smoke  .     10   ,;I; (P<O.O02
        3      45.85 (P<O.O02)        0 x4


    TABLE AIS.--Studies concerning the relationship of smoking to infectious respiratory disease in hunms
                             (Actual "umber of cases shown in parentheses)
                                    SM = Smokers     NS = Nonsmokers

  Author,
  Ye*=.       Number and        Data
  country,       type of        collection                         Results                            Comments
reference     population

Mills,      118 male and      Hospital                                         Cases    Controls     The author stated that
1960.      female patients     Interview.         Mean age . . . . . . . .     49.6      49.6       there was a
U.S.A.     with pneumonia                   NS  . . . . . .  .     16.26     25.21      significant difference
(167).     and 472 healthy                  Cigarettes only . . . .     63.66     62.33       in tobacco "sage
          individuals fmm                   Mixed  . . . . . . . . . . . . . . . . . . . . . . ..*..     21.19     22.46       between the
         "random" sample.                                                                two gro"ps.

LOW&      620 male and      Interview by                            Males               Ft??WltX    Cigarette smokers
1966,       135 female        trained                           CCUlt%   Controls        Cams   chtrols  include pipe smokers.
England    tuberculceis       social        NS  . . . . . . . . . . . . . . .     2.6     8.1           37.3     61.4   The author noted a
(157).     patients and 419    worker.      Cigarettes/day: l-9 . . . .     9.2    12.9           20.6    25.7   significant deficiency
          male and 249                   10-19  . . . . . . . . . .     38.1     35.6           30.8    20.5   oi'non- and light
          female control                   20-29 ,,.............     29.4    21.4                      smokers and a"
         outpatienti.                    30-39 .,.............     11.3     9.3           11.4     2.4   excess of heavy
                                   >ro  . . .     9.4     6.7                      smokers e.mo"g
                                                                           the cases
                                                                           ~~
Dowling.    Individuals       Interview and                    Ezposed to placebo    &posed to infeetima agent No statisticnlly
et al..      exposed to        medical                              Percent               Percent
1967.                                                                           significant
          "infectious       examination.                        developing             developing   differences
U.S.A.     cold agent"                                  Number    "Cow'        Number    "cold"    noted.
(76).      and placebo.                 NS . ..t............     111      10           323      34
                                 SM .,.....,.........     `I'8      14           249      36


TABLE A15.-Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.)
                         (Actual number of cases shown in parentheses)
                             SM = Smokera    NS = Nonsmokers

Author.
ye*=,
countrY,
reference

Number and
type of
population

Data
collection                         Results                            Comments

Boake,
1958.
U.S.A.
(9.7).

Parents of
59 families.

Interview

NS  . . . . . . . . . . . . . . . . . . . . . . . ..(24)
Cigarettes/day: l-10  (19)
  11-20  . . . . . . . . . . . . . . . . . ..(25)
>20  (19)
Pipe. cigar  . . . , ,. (14)

      Number of          No statistically
Pl38lXt-   reepiratory  r11nesse.d    significant
years    iam?sees  person-year*   differences
120      624      6.2      noted.
99      629      6.3
108      486      4.6
99      424      4.3
12      304      4.2

Shah
et al..
1959,
India
(205).

Tuberculosis       Survey, X-ray,
institute         and
emploYee8.        interview.

                     Tuberculous          Normal or     t Numbers in
                     bu X-ray          nontuberculous     parentheses
NS .,......................    t10 (19.7)          178 (168.3)      represent figures
SM _...,,,............_....     36 (26.3)         215 (224.7)      "expected" by use of
                                                 2 x 2 contingency
                                                 table.
                                                Tuberculoua
                                                 employees were
                                                 found to have
                                              significantly fewer
                                                 nonsmokers and
                                                 more smokers.


TABLE A15.-Studies concerning the relationship of smoking to infectious respiratory disease in humans (cont.)
                          (Actual number of cases shown in parentheses)
                             SM = Smokers    NS = Nonsmokers

Author. year,    Number and
countl;y;       type of
reference     vooulation

Data
collection                          Results                          Comments

Brown

306 male and

et al..
1961,
Australia
(4).

female
tuberculosis
clinic
pntients,
221 male and
female
outpatients.

Interview

         Smoking habits prior to diagno&
                      Tuberczdous patients
                         (percent)
NS  . .._................ ..__...       9.1
Cigarettes/day: l-9      10.5
  IO-19  ,,........,....      34.3
  20-29          26.3
  30-39  . . . . . . . .       7.2
>ro  . . . . . . . ..~~.......      6.2
  Pipes ,,..._._. ,..,,_,.....,_..       5.9

Controls
(percent)
19.9
15.4
19.5
25.8
6.4
9.1
4.6

Data presented only
on Queensland
S8nlplC.
The authors noted
rhat the
significant difference
between the
patients and
controls WBS not
present when the
groups were
matched for
alcohol intake.

Havnes
et *I.,
1966.
U.S.A.
(108).

191 male
prep school
students.

Interview

       Average number of respiratory illnesses/l0 students
                 (adjusted for age)
                                     All 8cucre lower
                      All      All smere    or combined
                   respiratory   respiratory    respiratory
                    episodes     episodes     episodes
NS (99)        11.1        1.6        0.36
SM (92)   . . . .     20.2        6.7        3.34

P*rIlell
et al.,
1966
Canada
(181).

47 smoking-       Interview                    Median number of illnesses/student               The authors noted
nonsmoker pairs    and health                                     All      All          that these
of student nurses    service                                    respiratory   other         differences were
matched for age    records.                                    disaasest   illnesses         stntistically
und parents                       NS (47)  . . . . .      2.08      2.99          significant.
occupational                       SM (4'7)  . . . . . . .      2.64      5.00        t Particularly
C&.5.                                                                   tracheitis,
                                                                           bronchitis,
                                                                           and pneumonia.


        TABLE AX.-Studies concerning the relationship of smoking to infectious ,respiratory disease in hmans (conf.)
                                    (Actual number of cases shown in parentheses)
                                          SM = Smokers    NS = Nonsmokers

       Author,
        year,       Number and        Data
       country.       type of        collection                         Results                            Comments
       reference     population

     Peters      1,496 Harvard     Medical his~tory,     Number of visita to etudent health unit for rcwimtmy illness/student    t p<O.OOl.
      et al.,      and           chart review,           (ccrmmon colds. pharyngitis, b+onchitis. largngitis.
       1967,       370 Radcliffe      and                     pneumonia--not allergic rhinitis)
       U.S.A.     students.        questionnaire.                             HllTVlVd      Radcliffe
       (185).                                   NS  . . . . . . .      1.44 (771)      1.44 (193)
                                            SM ,,,,..._._...,... .     t2.27 (725)      2.27 (177)
                                         <z years smoked .      2.00
                                            3-4  ., .      2.30
                                            >5  .,.,................      2.60

     Finklea     1,811 male        Questionnaire        Heavy smokers-21 percent more clinical illnesses than nonsmokers:     The authors also
      et al.,      colll=ae         prior to                   20 percent more requiring bed rest than nonsmokers      noted that:
      1969       students.      A2/HK/63       Liph't smokers-10 percent more clinical illnesses than nonsmokers;      (a) Smokers
      U.S.A.                  epidemic and               7 percent more requiring bed rest than nonsmokers.         exhibited
       (83).                   follow-up on                                                        serologic
                            morbidity.                                                          evidence of
                                                                           increased
                                                                           subclinical
                                                                A2/HK/C8
                                                                           infection.
                                                                           (b) Therewasno
                                                                           difference in the
                                                                           vaccination
                                                                           status
                                                                           between
                                                                           smokers and
                                                                           nonsmokers.

.I


TABLE AlG.-Complications developing in the postoperative period
     in patients undergoing abdominal operations

Men over 20

                                           Percent
                           Percent
Group                CCWZS                      broncho-
                            chest                      Percent
                                    Percent  pneumonia    t&al
                            Ck&W     bronchitis    and    complicntia"
                                          ateleetasis     rate

Smokera    300       41.7       63.0       6.3       68.3
Light Smokers .  180       68.4       27.7       3.9       31.6
Nonsmokers  . .   66       92.6        6.0       1.6        7.6

Women over 20

Smokers  . . . .   23       39.1       43.6       11.4       60.9
Light Smokers   62       77.6       20.9        1.6       22.6
Nonsmokers .  518       88.8        8.1        3.1       11.2

SOURCE: Morton. H. J. V. (f7s)

TABLE A17.-Arterial oxygen saturation before and after operation

Arterial oxygen saturation (percentage)

Group

CCL%    Before
number   operation    Day 1     Day 2     Day 3

                         1       94       93       94
                         2       94       93       94        .
Nonsmokers             .       3       96       93       34
                         4       95       90       84       . .
                         6       94       90       33       . .

                         6       95       91       89       91
                         7       92       89       81       89
Smokers                 . .    8       91       89       86       89
                         9       93       91       88       92
                         10       90       87       88       92

SOURCE: Morton. A. (171).

230


CHAPTER 4

Cancer


Introduction  ........................................

Lung Cancer  .......................................
  Epidemiological Studies  ..........................
    Prospective Studies  ..........................
    Retrospective Studies  ........................
  Lung Cancer Trends in Other Countries  ............
  Histology of Lung Tumors  ........................
  Lung Cancer Relationships in Women  ..............
  Lung Cancer, the Urban Factor, and Air Pollution. ...
  Lung Cancer and Occupational Hazards  ............
     Uranium Mining  ............................
    Other Occupations ............................
     Nickel ......................................
      Asbestos ....................................
      Arsenic .....................................
     Chromium ...................................
  Pathological Studies. .............................
  Pulmonary Carcinogenesis  ........................
    General Aspects of Carcinogenesis  .............
      Polynuclear Aromatic Hydrocarbons  .......
       Nitrosamine Compounds. ..................
       Pesticides and Fungicides. ................
       Radioactive Isotopes  .....................
       Inhibitors of Ciliary Movement  ...........
    Experimental Studies  ......................
      Skin Painting and Subcutaneous Injection. ..
       Tissue and Organ Culture  ................
       Tracheobronchial Implantation
          and Instillation  ......................
         Inhalation   .............................
       Reduction in Tumorigenicity  ..............
  Summary and Conclusions  ........................

Cancer of the Larynx  ....................
  Epidemiological Studies  ..............
  Pathological Study  ..................
  Experimental Study  .................
  Summary and Conclusions  ............

Oral Cancer  ............................
  Epidemiological Studies  ..............
  Experimental Studies  ................
  Summary and Conclusions  ............

...........

...........

...........

...........

...........

............

...........

Page
237

239
240
240
240
244
246
251
252
256
256
256
256
257
257
257
258
258
258
264
264
266
266
267
267
267
267

268
268
275
276

277
277
280
281
281

284
285
288
289

233


Cancer of the Esophagus  .............................
  Epidemiological Studies  ..........................
  Pathological Study  ..............................
  Experimental Studies  ............................
  Summary and.Conclusions  ........................
Cancer of the Urinary Bladder and Kidney ..............
  Epidemiological Studies (Bladder)  .................
  Epidemiological Studies (Kidney)  .................
  Experimental Studies  ............................
  Summary and Conclusions  ........................
Cancer of the Pancreas  ...............................
  Summary and Conclusions  ........................
References  .........................................

FIGURES

1. Lung cancer, Finland and Norway . . . . . . . . . . . . . . . . . . .
2. Percent of smoking dogs with tumors . . . . . . . . . . . . . . . .
3. Percent of lung lobes with tumors in smoking dogs . . . . .
4. Effects of chronic cigarette smoke inhalation on the

245
274
274

hamster larynx . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   284

1.
2.

A3.

A4.

5.

6.

A7.
8.

9.

10.

LIST OF TABLES

Lung cancer mortality ratios . . . . . . . . . . . . . . . . . . . .
Lung cancer mortality ratios for males by duration of
cigarette smoking . . . . . . . . . . . . . . . . . . . . . . . . . . .
Outline of methods used in retrospective studies of
smoking in relation to lung cancer . . . . . . . . . . . . .
Group characteristics in retrospective studies on lung
cancer and tobacco use . . . . . . . . . . . . . . . . . . . . . . .
Annual means of total lung cancer mortality and sex
ratios for selected periods in Finland and Norway
Epidemiologic and pathologic investigations concern-
ing smoking and histology of lung cancer . . . . . . .
Grouping of pulmonary carcinomas . . . . . . . . . . . . . .
Tumor prevalence among males and females 35-69
years of age, by t.ype of tumor and smoking
category  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Epidemiologic investigations concerning the relation-
ship of lung cancer to smoking, air pollution, and
urban or rural residence . . . . . . . . . . . . . . . . . . . . . .
Pathologic and cytologic findings in the tracheo-
bronchial tree of smokers and nonsmokers . . . . . .

P age
289
289
292
292
293
293
293
296
296
299
299
299
299

241


244


323

329

246

247
334

250

253

259

234


    LIST OF TABLES (Continued)
(A indicates tables located in appendix at end of chapter)

11. Identified or suspected tumorigenetic agents in
    cigarette smoke . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
A12. Autopsy studies concerning the presence of radio-
    activity in the lungs of smokers . : . . . . . . . . . . . . .
A13.  Experiments concerning the effects of the skin paint-
    ing or subcutaneous injection of cigarette smoke
    condensate or its constituents upon animals . . . . .
A14.  Experiments concerning the effect of cigarette smoke
    or its constituents on tissue and organ cultures . .
A15.  Experiments concerning the effect of the instillation
    or implantation of cigarette smoke or its constitu-
     ents into the tracheobronchial tree of animals . . . .
A16. Experiments concerning the effect of the inhalation
    of cigarette smoke or its constituents upon the
    respiratory tract of animals . . . . . . . . . . . . . . . . . .
1'7.  Data on pedigreed male beagle dogs of groups F, L,
    H,hand N . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
18. Summary of principal cause of death (days No. 57
    through No. 875) in dogs of groups F, L, H, h and N
19. Data on dogs with lung tumors indicating type of
     tumor and lobe in which the tumor was found . . . .
20. Laryngeal cancer mortality ratios - prospective
     studies   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ml. Outline of retrospective studies of tobacco use and
    cancer of the larynx . . . . . . . . . . . . . . . . . . . . . . . . .
~422. Summary of results of retrospective studies of tobacco
    use and cancer of the larynx . . . . . . . . . . . . . . . . . . .
A23. Number and percent distribution by relative fre-
    quency of atypical nuclei among true vocal cord
    cells, of men classified by smoking category . . . . ,
A24 Number and percent distribution, by highest num-
    ber of cell rows in the basal layer of the true vocal
    cord, of men classified by smoking category . . . .
25.  Deposition of I%-labeled smoke particles in particu-
   lar regions of the respiratory tract . . . . . . . . . . . .
26.  Classification of the five registered stages of epithe-
    ha1 changes at the larynx . . . . . . . . . . . . .  . . . . .
27. Oral cancer mortality ratios-prospective studies. .
A%. Outline of retrospective studies of tobacco use and
    cancer of the oral cavity . . . . . . . . . . . . . . . . . . . . .
A%a. Summary of results of retrospective studies of smok-
    ing by type and oral cancer of the detailed sites. .

Page


265


335

337


343

346

349


270


271


272


278


354


358

359

360


282

283
286


361


368

235


429.

30.

A31.

A::la.

A32.

A33.

33.


A3.5.

A35a.

::6.

    LIST OF TABLES (Continued)
(A Indicate5 tables located in appendix at end of chapter)

Experimental  studies concerning  oral carcino-
genesis   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Esophageal cancer mortality ratios-prospective
studies   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary of methods used in retrospective studies
of tobacco use and cancer of the esophagus . . . . .
Summary of results of retrospective studies of to-
bacco use and cancer of the esophagus . . . . . . . . .
Atypical nuclei in basal cells of epithelium of esoph-
agus of males, by smoking habits and age . . . . . .
Atypical nuclei in basal cells of epithelium of esoph-
agus of males, by amount of smoking and age . . . .
Kidney and urinary bladder cancer-prospective
studies   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Summary of methods used in l,etrospective studies of
smoking and cancer of the bladder . . . . . . . . . . . .
Summary of results of retrospective studies of smok-
ing and cancer of the bladder . . . . . . . _ . . . . . . .
Pancreatic cancer mortality ratios-prospective
studies   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Pngr


371


290


375


378


379


3%


294


381


383


29e

236


INTRODUCTION

During the early years of this century, a number* of pathologists
and clinicians reported a dramatic increase in the incidence of lung
cancer. Autopsy studies and studies of lung cancer death rates re-
vealed a significant increase beginning prior to World War I and
continuing during the ensuing years. This epidemic of lung cancel
continues to the present day, with nearly 60,000 deaths expected
from this disease in the United States during 1970.

Beginning in the 1920's, a number of reports appeared which
suggested a relationship between lung cancer and tobacco smoking
(4, 20.3, 278). Since that time, many clinical and epidemiological
studies have been published which confirm this relationship. The
1964 Report (291) contains a thorough review and analysis of the
data available at that time as well as an excellent discussion of the
considerations necessary for their evaluation.

Major epidemiological studies have demonstrated that smokers
have greatly increased risks of dying from lung cancer compared
to nonsmokers. An increased risk of lung cancer has been found
for every type of smoking habit investigated, but two character-
istics of the risk are particularly evident : The risk is much greater
for cigarette smokers than for smokers of pipes and cigars, and
among cigarette smokers a dose relationship exists. That is, the
more one smokes, as measured by total pack-years of smoking,
present level of smoking, degree of inhalation, or age at start of
smoking, the greater is the Csk. It has also been shown that the
risk of lung cancer among ex-smokers decreases with time almost
to the level of nonsmokers; the time required is dependent on the
degree of exposure prior to cessation.

Pathologists have found that the squamous cell or epidermoid
form of lung cancer is the most prevalent one in cigarette smoking
populations and that this form accounts for a major portion of
the rise in lung cancer deaths (2.5:). Such studies have also indi-
cated a lower prevalence among smokers for oat-cell and adeno-
carcinomas of the lung than for the squamous form, but in most
studies a higher frequency of these tumors is found among smokers
than among nonsmokers.

Smoking has been implicated in the development of other types
of cancer in humans. Among These is cancer of the larynx. A num-

237


ber of epidemiological studies have demonstrated incseased mar-
tality rates for laryngeal cancer in smokers, particularly cigarette
smokers, compared with nonsmokers. Autopsy studies have re-
vealed that a clear dose-relationship exists between smoking and
the development of cellular changes in the larynx, including carci-
noma in situ.

Cancers of the mouth and oropharynx have been found to be
more common among users of all types of tobacco than among
abstainers. Although smoking is a definite risk factor in the de-
velopment of malignant lesions of the oral cavity and pharynx, its
relative contribution in conjunction with other factors such as poor
nutrition and alcohol consumption has not been fully clarified.

Similarly, although smokers are more likely to develop carci-
noma of the esophagus than nonsmokers, the relative additional
contribution of smoking in conjunction with nutritional factors
and alcohol consumption requires clarification.

Smokers have been found to be more at risk for the development
of cancer of the urinary bladder than are nonsmokers, and there
is evidence to suggest that some smoking-induced abnormal meta-
bolic product or abnormal concentration of a metabolic product
may be responsible for this increased risk. In addition, cancer of
the kidney is apparently more common in smokers than in non-
smokers, but the epidemiologic evidence for this relationship is
not as definite as for bladder cancer.

Epidemiological studies have indicated an association between
smoking and cancer of the pancreas. The significance of this rela-
tionship is unclear at this time.

Experimental studies have demonstrated the carcinogenicity of
the condensate of tobacco smoke, or "tar." This material, when
painted on the skin of animals, leads td the development of squam-
ous cell tumors of the skin. Researchers have shown that this
condensate contains substances known as carcinogens, capable of
inducing cancers. Among these carcinogens are several chemicals
which have been identified as tumor initiators, that is, compounds
which initiate changes in target cells and also tumor promoters,
or compounds which promote the neoplastic development of initi-
ated cells. Other, as yet unidentified, factors are presumably also
involved because the sum of the carcinogenic effects of the known
agents does not equal that of cigarette smoke condensate.

Numerous experiments have been performed in which whole
cigarette smoke, filtered smoke, or certain constituents of smoke,
such as the "tar," are administered by varying methods to animals
or to tissue and cell cultures in order to investigate the neoplastic-
inducing properties of cigarette smoke. Particular difficulty has
been encountered in experiments which have attempted to deliver

238


whole cigarette smoke to the larynx and into the lungs of experi-
mental animals. This has resulted in the use of other methods such
as the implanting of pellets containing suspected carcinogens and
the instilling into the trachea of suspected carcinogens as such, or
adsorbed onto fine inert particulate matter as a carrier. The dif-
ficulty with the inhalation studies has been twofold. First, the
animals, particularly the smaller species such as the rat, frequently
die from the acute toxic effects of the nicotine and carbon monoxide
in the tobacco smoke. Second, the upper respiratory tract of experi-
mental animals, particularly the nose, is much different from anal-
ogous human structures, resulting in a more efficient filtration of
smoke in the upper respiratory tract. Nevertheless, in rodents and
canines, progressive changes apparently indicative of ultimate neo-
plastic transformation have been identified in the respiratory tract.

Recently, two studies in different species and in different target
organs have been reported concerning the development of early in-
vasive cancer following the prolonged inhalation of cigarette smoke.
Auerbach and his coworkers (II) trained dogs to inhale cigarette
smoke through a tracheostoma. After approximately 29 months of
daily exposure, these investigators found a number of cancers of
the lung.

Dontenwill (7'6) in the second of these two studies, exposed ham-
sters to the passive inhalation of cigarette smoke over varying and
prolonged periods of time. He observed the development of pre-
malignant changes and, ultimately, invasive squamous cell cancer
of the larynx.

LUNG CANCER

Cancer of the lung in the United States accounted for 45,383
deaths among males and 9,024 deaths among females in 1967 (289).
It is presently estimated that approximately 60,000 people will die
of lung cancer during 1970.

The alarming epidemic of lung cancer is a relatively recent
phenomenon. Death rates for lung cancer (ICD Codes 162, 163)
rose from 5.6 (per 100,000 resident population per year) in 1939
to 27.5 in 1967 (289, 290). This rapid increase followed the in-
creased use of cigarettes among the United States population. The
increase has occurred principally among males, although more re-
cently females have shown a similar rising pattern.

The converging evidence for the conclusion that cigarette smok-
ing is the major cause of lung cancer is derived from varied types
Of research including epidemiological, pathological, and laboratory
investigations.

239


EPIDEMIOLOGICAL STUDIES

Numerous epidemiological studies, both retrospective and pros-
pective, have been carried out in different parts of the world to
investigate the relationship between smoking and cancer of the
lung. These studies are outlined in tables 1, 2, A3, and A4.

Prospective Studies

The major prospective studies concerning the relationship of
smoking and lung cancer are presented in table 1. In all, these
investigations have studied more than a million persons from a
number of different populations for up to 10 years. These studies
show increased lung cancer mortality ratios for cigarette smokers
of all amounts ranging from 7.61 to 14.20 among male smokers as
compared to nonsmoking males. The one major prospective study
of female cigarette smokers reveaIs an overall mortality ratio of
2.20 (118).

Also uniformly present in these studies is a dose-related increase
in the mortality from lung cancer with increasing amounts of cigar-
ettes smoked per day. Other measures of exposure show similar
trends. Hammond (118) reported increased mortality ratios asso-
ciated with increased inhalation (table 1) as well as with increased
duration of smoking (table 2).

Ex-smokers show significantly lower lung cancer death rates
than continuing smokers. In their study of more than 40,000 British
physicians, Doll and Hill (74, 75) noted a decrease in lung cancer
mortality rates with increasing time since smoking stopped (table
1). During the past 20 years, half of all the physicians in Britain
who used to smoke cigarettes have stopped smoking. While the
death rates from lung cancer rose by `7 percent among all men from
England and Wales during the period from 1953-57 through 1961-
65, the rates for male doctors of the same ages fell by 38 percent
(96).

Pipe and cigar smokers have been shown in the prospective stud-
ies to have lung cancer mortality rates higher than those of non-
smokers, although these are generally substantially lower than
those of cigarette smokers (table 1).

Retrospective Studies

More than 30 retrospective (case-control) studies have been re-
ported concerning the relationship of smoking and lung cancer.
These studies are outlined in tables A3 and A4. Table A4 presents
the percent of nonsmokers and of heavy smokers among both cases
and controls as well as the relative risk ratios for all smokers.

240


TABLE I.-Lung cancer wwrtality mtios
(Actual number of deaths shown in parentheses)'
  SM = Smokers.    NS = Nonsmokers.

        Prospective studies

Author,   Number
ye*=.   and type
COUntrY,    of   col$;don Follow-   Number   Regular cigarette      Pipe
                       UP      of      smoking only       cigar        Inhalation
reference pooulation          years    deaths    (cigarettes/daY)

Exsmokers

CODUll@Xd.9

       _                                    -
-_-
Hammond 187.783    Qucstion-    31/&       448                   Pipe      No data            Bso7xhogcnic       341/448
and     white     naire and       SM 443 NS ,.., 1.00 (15) NS 1.00 (15)             (1Szcluding adenocarcinma)    deaths with
Horn,    males     interview.       NS  16 <IO 8.00 (24) SM 2.57 (18)             Never smoked 1.00     microscopic
1958,    in 9                        10-20 .10.50 (84)      Cigar                 Prchmsly <! pack/day     woof. In-
U.S.A.   states                    >20 . ..23.40(117) NS 1.00 (15)             Continuing  .16.94     eludes those
(120).   ages                         All  . . .t10.73(397) SM . 1.00 (7)             Duration
       60-69.                                                              of i  <1 year .16.50     regular
                                                                         l-10 years (10.44     cigarette
                                                                       cessation  >lO years 1.51     smokers who
                                                                   Previously >I pack/day     also smoked
                                                                       Continuing  .46.21      pipes and
                                                Durntion] <l year .58.23     cigars.
                                                                        of J l-10 yesrs .22.82    t With or
                                                                       cessation  >lO years .17.79      without
                                                                           microscopic
                                                                           proof.

Doll and  Approxi-   Question-    10         212 NS ..I.. 1.00 (3)   Pipe and Cigar   No data            Cigarette smokers
Hill,     matelv    mire and      SM 209 1-14 . . . 8.14 (22) NS 1.00 (3)             NS ._ ,t ._... . . . 1.00  (3)
1964,    41,000     followup        NS   8 15-24 .19.86 (63)   Gmmsldw               Continuing  _. .18.29(124)
Great    Illale     of death             >25 ,, .32.43 (57) l-14.. 6.00 (12)             Duration  <fi ye*rs 9.57 (6)
Britain   British    certificate.                        15-24.. 6.43 (6)               of    5--o years 7.00 (7)
(74).    physicians                               >25 .13.71 (3)     I
                                                             cessation lo-20yean 2.57 (3)
                                                                   >zoyears 2.71 (2)

   Best,    Approxi-   Question-    6        331 NS . . . . 1.00 (7)      Pips      No data                           t Refers
    1966.    mately    naire and     tSM 324 <10 . . . 10.00 (67) NS . . . 1.00 (7)             NS ,. _, 1.00  (7)  toeur-
    1966,    78,000     followuP        NS .   7 lo-20 .16.41(204) SM .4.36 (18)             Ex-smokers of              rent
    Canada   male     of death             >20 .17.31 (63)      cigar               cigarettes only _. . 6.06 (18)  cigarette
    (21).    Canadian   certificate.             All . .14.20(246) NS .l.OO  (7)                                   smokers
!z           V&3C%C3.                                SM . ..2.94 (2)                                   only.
                                                                           --


TABLE l.-Lung cancer mortality ratios (cont.)

(Actual number of deaths shown in parentheses)~
  SM = Smokers.    NS = Nonsmokers.

Prospective studies

Author.   Nlllllber
Ye*=,  and,4'"     Data   Follow-   Number
              collection              Regular cigarette      Pipe
country,                   UP   d2hs     smoking only       cigar          Inhal&i0n
reference population                                                                  Exsmokers       Comme"ts
                      Ye*!3          (cigarettes/day )

Kahn    U.S. male Question-    8%      1,266                  Pipe
(Do=").  veterans   mire and      SM .1,178 NS . . . 1.00 (78) NS . .l.OO (73) Nodata
1966,    2.266.674   followup        NS. 78 l-9 . . . . 6.49 (45) SM . . . .1.34 (17)                 NS . . . . . . . . 1.00 (78)
U.S.A.   person    of death               10-20 . . 9.91(303)     Ciga+                   Number of eigarettcs/dau:
(189).   ye**s.     certificate.            21-39 . . .17.41(315) NS . , .l.OO (73)                  l-9 . . . . . . 0.96  (4)
                             >39 . . .23.93 (82) SM . . ..1.69 (6)                 10-20  . . . . . . . 3.43 (39)
                                  All . . .12.14(749)   Pipe and cigar                  21-39  . . . . . . . 9.33 (67)
                                                NS . . . .l.OO (78)               >39 . . . . . . . . 3.24 (19)
                                                SM . . . .1.66 (20)

Hammond.440.563    Interviews 4      Males    Current cigarettes      Pipe           Males                        ICD code
1966,    III&e     by ACS            1.169      OdU     NS .l.OO (49) NS  . . . . 1.00 (49)                  162 only.
U.S.A.   662,671    volunteers.      srd .l,llO      Males     SM . . .2.24 (21) Slight . . 8.42(120)
(118).   females                NS  49 NS . . . 1.00 (49)     Cigar     Moderate .11.46(311)
       35-84                  FtWtaL%   l-9 . . . . 4.60 (26) NS . .l.OO (49) Deep . . .14.31(141)
       years of                 183 10-19 7.48 (32) SM . . ..1.86 (22)       FOUL%
       age in 25               SM .  81 20-39 . .13.14(381)   Pipe and cigar   NS  . . . . . 1.00(102)
       states.                 NS .  102 >40 . .16.61 (82) NS . .l.OO (49) Slight . . . . . 1.78 (251

-All                                  .~.,
   . . . . . 9.20(719) SM . ..0.90 (11;
   F.Z?iWh~                        3.70 (46)

NS . . . . . l.OO(l02,                   J

1-19 . . . 1.06 (20)
>20 . . 4.76 (60)
All . , 2.20 (81)


TABLE I.-Lung cancer mortality ratios (cont.)

(Actual number of deaths shown in parentheses)'
  SM = Smoker%.    NS = Nonsmokers.

Prospective studies

Author,   Number          Follow-
year,  andow     Dats     "P    Number
count.lY.          Eollection              Regular cigarette      Pipe

reference population          years  de%    smoking only       cigar          Inhalation           Exsmokers
                                 (cigarettes/day)                                                COllUlWlt5

Bllell    69,866
et al.,  American `l?$ind 3
1967,    Legion-   followup
U.S.A. naires     of death
(49).    36-76     certificate.
       years of
       age and
       older.

804 NS , . . . 1.00
   <20 . . . . 2.90
    20 . . . 3.60
   >20 4.90

Hirayama. 266,118    Trained     1?4       43 NS . . . . . 1.90 (3)                                           Preliminnry
1967,    male and   PIIS         SM 40 l-24 . 2.69 (29)                                               report.
JC3p8n   female nurse              >26 . . . 6.68 (6)
(1.25).   adults     interview
       40 years   and fol-
      of age and  lowup of
       older.     death
               certificate.

Weir and 68,163    Question- 6-S        368 NS . . . . 1.00
DUIIII,    males in   naire and              5~10 . 3.12
1970,    various    followup               *20 . . . 9.06
U.S.A.   OCC"PB-    of death              >30 . . . 9.66
(SO6).   tions in    certificate.              All . . . . . 7.61
       California.

1 Un1ee.a otherwise specified, diaparitiea between the total number of deaths
and the hum of the individual smoking categories are due to the exclusion

NS include
pipe and
cigar
smokers
SN include
ex-smokers.

E  of either occasional. miscellaneous, mixed, or exemokem.


TABLE Z.-Lung cancer mortality ratios for males
   by duration of cigarette smoking

(Actual number of deaths are shown in parentheses)

Age began cigarette smoking   35-54

25 or older     2.Ti (5)
20-24       5.83 (31)
15-19        8.71(112)
<15      12.80 (35)

SOURCE: Hammond.E. C. (118,.

55-69         70-84         35-84

3.39 (12)       3.38 (3)      3.21 (20)
11.11 (72)     12.11 (7)      9.72(110)
13.06 (176)      19.37 (27)      12.81(315)
15.81 (57)      16.76 (9)     15.10(101)

These smoker-nonsmoker risk ratios range from 1.2 to 36.0 for
males and from 0.2 to 5.3 for females.

Although not presented in tabular form, the data concerning lung
cancer and pipe or cigar smoking are similar to those found by the
prospective studies mentioned above. However, a study by Abelin
and Gsell (1) conducted on a rural Swiss population noted that an
increased risk of lung cancer was present among heavy cigar and
pipe smokers (as well as cigarette smokers) to a greater degree
than previously reported. The authors suggest that their findings
might be due to differences in either the amount smoked or the car-
cinogenicity of Swiss and German cigars. The difference might also
be explained by the greater use and more frequent inhalation of
small cigars in Switzerland as compared to other countries where
large cigars are more commonly smoked but rarely inhaled.
Kreyberg (15.$), in a review of 887 cases of lung cancer in Norway,
noted that pipe smokers showed an increased risk of lung cancer,
although this risk was substantially lower than that for cigarette
smokers.

LUNG CANCER TRENDS IN OTHER COUNTRIES

Several studies of particular interest are those in which the
changing mortality from lung cancer has been investigated in
countries in which cigarette smoking has become popular and wide-
spread only in recent years. In those countries where accurate
statistics for lung cancer mortality are available for both t.he pre-
smoking and post-smoking periods, long-term trends can be studied
in some detail,

Two such studies have dealt with lung cancer mortality trends
in Iceland. Dungal (83) noted in 1950 that lung cancer was a rare
disease in Iceland and felt that this rarity could be explained by
the relatively late onset of heavy tobacco smoking in the Icelandic
population when compared to that of Great Britain and Finland.
He observed that the annual per capita consumption of tobacco did
not reach one pound in Iceland until 1945, while Great Britain and
Finland passed that amount before 1920. In 1967, Thorarinsson, et
al. (276) noted a sharp rise in the incidence of lung cancer in Ice-

244


60-

50-

40-

30-

4-



3-





2-

-Finland

I I -Norway

I I
1934-36   1939-41   1944-46   1949-51   1954-56   1959-61  1963-64

Calendar Years

FIGURE I.-Lung cancer, Finland and Norway.
SOURCE: Kreyberg, L. (154).

land after 1950 and found a correlation between that increase and
the increasing sale of cigarettes in that country.

Kreyberg (154) analyzed the lung cancer death rates of both
Norway and Finland in relation to the use of tobacco in those two
countries over the past 100 years. Figure 1 shows the substantial
difference in lung cancer mortality between the two countries.
Kreyberg observed that cigarettes came into use in Norway in 1886
Mile the Finnish population (more closely allied to Russia socio-
economically) was consuming more than 100 million cigarettes per
Year during the decade of the 1880's. Cigarettes remained scarce in
Norway until after World War I, and this 30-year lag in consump-

245


TABLE EL-Annual means of total lung cancer mortality and sex ratios
      for selected periods in Finland and Norway

Year

1936-38  ...................      192        33            34        30
Sex ratio  ................          6.8 : 1                   1.1 : 1
1963-66  ...................     1,319        121            366        79
Sex ratio .................         10.9 : 1                   4.6 : 1

SOURCE: Kreuberg. L. (154)

tion behind that of Finland is reflected in a similar lag in total lung
cancer mortality and sex ratios (table 5).

HISTOLOGY OF LUNGTUMORS

A number of investigators have focused their interest upon the
relationship of cigarette smoking to the varied histology of lung
tumors. The major histological types of lung cancer include squa-
mous cell (epidermoid) carcinoma, small and large cell anaplastic
carcinomas, adenocarcinoma (including bronchiolar and alveolar
types), and undifferentiated carcinoma (153). A review of these
studies (table 6) indicates a closer relationship between cigarette
smoking and epidermoid carcinoma than between cigarette smok-
ing and adenocarcinoma (42, 22 3).

The work of Kreyberg (153) in Norway, over the past 20 years,
provides evidence of a specific histologic relationship. This inves-
tigator noted that a clearer association is obtained if the various
types of pulmonary carcinomas are grouped. Table A7 presents his
groupings of the specific histologic types. Using this classification
as a basis for analysis of lung cancer sex-ratios in Norway,
Kreyberg has observed that Group I carcinomas are significantly
more frequent among males while Group II carcinomas show an
approximately equal distribution among males and females. The
author considers the recent rise in lung cancer in Norway to be a
reflection of the increased prevalence of Group I carcinomas. Table
8 presents a summary of Kreyberg's investigation concerning 793
male and female cases of lung cancer. Among both males and fe-
males, the risk ratio among smokers is substantially higher for
Group I types than for those of Group II. However, adenocarcinoma
among males shows a risk ratio of 2.9, signifying a relationship
with smoking. Kreyberg attributes the lower rates noted among
females to their significantly lower consumption of tobacco in all
forms.

246


    TABLE B.-Epidemiologic and pathologic investigations concerning smoking and the histology of lung ca.nce+
                              (Actual number of cases shown in parentheses)

Author,      Number of
  yea=,       persons and
country.     case selection                            ReaUlt.3                                   Comments
reference       method

Wynder    644 autopsies on                 Percent ca8es by histologic type and smoking history              The percentage of chain
and      males with                            AU lung cance+8 other than                    smokers in the general
Graham,   confirmed                                 adenocorcinoma (605)      Adenocarcinoma ( 39 )   population (7.6) was
1950,     lung cancer.       Nonsmokers .._.._............t......        1.3               10.3         significantly less than
U.S.A.                Light cigarette smokers .        2.3                7.7        among the patients with
(316).                  Moderate ,.._,........................       10.1               16.4         adenocarcinoma. The
                      Heavy  ,,___.,_........................       36.2               38.6         authors refrained from
                      Excessive          30.9               10.3         making any definite
                      Chain  ,,...._.._____._................       20.3               18.7         conclusions due to the
                                                                           insufficient number
                                                                           of ease-s.

DO11      916 male and 79        Percent patients with lung can.ce~ by average amount smoked daily ower 10 ~a~8      No statistically
and      female cases                                          Male.4                    significant difference
Hill.      with histologically                                     Oat-cell 07                    was found between
1952,     confirmed                       Epidennoid ( 475 )     anaplastie (303)   Admocarcinoma (33)   the amounts smoked by
England   lung cancer.       Nonsmokers         0.2 (1)          0.7 (2)          6.1 (2)       the patients in the
(Y3).                  Smokers:                                                      different histological
                     <5 cigarettes/day       2.9 (14)          3.9 (12)          6.1 (2)       groups. Number of
                       6-14        35.6 (169)          36.3(110)         21.2 (7)      proven adenocarcinomas
                       15-25  . . . . .      36.8(175)          34.7(105)          48.5(16)       too small for
                       >25        24.4(116)          24.4 (74)          18.2 (6)       conclusions.

                                                        Ft3tWl.e8
                                                       Oat-cell 07
                                   Epidermoid ( 18 )      wuzplastic (38)   Adenocarcinoma (10) Males-105 unclassified
                      Nonsmokers        61.1 (11)         31.6(12)         50.0 (6)       tumors.
                      Smokers :                                                     Females -13 unclassified
                     <5 cigarettes/day       5.6 (1)          16.8 (6)         20.0 (2)       tumors.
                       5-14        22.2 (4)          23.7 (9)         10.0 (1)
                       16-25        6.6 (1)         18.4 (7)          .
                       >25  . . . . . . . . . .       6.6 (1)         10.6 (4)         20.0 (2)


   TABLE 6. Epidemiologic and pathologic investigations concerning smoking and the histology of lung cancer' (cont.)
                               (Actual number of cases shown in parentheses)
-~-. --.            -~~.
Author,      Number of
  Y`ZU,       pcrsn': :klld
country,     case :;e*c c,ion                            Results                                   Comments
reference       mc:h~.d

Brrslow    493 male and 25     Pcrccnt of patients with specific lung cancers by tobacco umgc during the 20 ye~m prior to study Nonsmokers include pipe
et nl.,     female cabe~                                                                end cigar smokers only.
I!#64     with histnloyically                         All lung cancers other tharl                     The authors conclude
U.S.A.    proven lung                                adcnocarcinoma Adenocarcinoma     Controls   that cigarette smoking
(43). cancer.                                    (472)        (46)          (518)    appears to affect the
         51x age and       Nonsmokers         6.9          13.0         24.4     development of
         sex-matched       Cigarette smokers _.  . .      94.1          87.0          75.6     withelial carcinoma
         COlll~OlS.                                                                    more than that of
                                                                           adenocarcinoma.
                      ~--___
SChWElrtZ   430 male and               Pexewt of amokers by hi8tdoQic tupe and 8'TllOki?LQ historv
et nl.,     female cases
1957,     with histologically                   Epidermoid    Anaplastic     Unknown type   Cylindrical + Difference
FlYLnCe    confirmed lung     Cases        96.0          97.0          96.0          100.0     significant
(247).     cancer. 4 matched   Controls         79.ot         83.01        79.0t          96.0     et PZO.05 level.
         control gL'o",,s.
       -..         __.
Hal?Il%Xl   158 female                  Relative risk for specified tumors (smokers/n~?~~mokers)             134 cases with final
et al.,     CaYPS of                                                                histological
1958,     lung cancer.                                 Group I (Kreybwg)     Adenocarcinoma    determination.
U.S.A.                Adjusted for ege and occuyation.        3.0t            1.19

(ff3).                                                                       t Difference from
                                                                           unity significant at
                                                                           p~O.01.

Hae"s7.Cl   2,191 male                           Standardized mortality ratios                     Cases obtained from a
and      casm of
Shimkin.                                                                          10 rwcent saml&s of
        lung cancel                                  Epidcrmoid and mdiffemntiated           lung ceneer deaths in
1962,     with aderwatc                                          carcinomas     Adenocarcinoma   U.S.A. doring 1958.
U.S.A.    histologic data.     White males total  _, . . . .        100            100       The authors noted an
(II?).                  Never smoked  . . . . .._._..          6             18
                      Ex-smokers                                                  absence of important
                              ..I....................         34             46      differentials by
                    (1 pack/day _. _,        123            116      histologic type.
                    >l I,aek/day _.  .._.....,I...._.....___......_        499            467
                   -__ ___--


:       ' Dtlta obtained from patient. interview and other sourscs.

_---.---.-.----- ~-~~~-


TABLE K-Tumor prevalence among males and females 35-69 years of age, by type of tumor and smoking category
                        (Smokers constituted 85 percent of populations studied)

Sex and type of tumor

Total

Smoking category

  Smoking
  all methods

NO"-
smokers

Risk
ratio
among
smokers

Males
Epidermoid  carcinoma  ............................................    434          431           3          17.0          26.4
Small cell anaplastic carcinoma  ..................................    117          116           1           6.7          20.4
Adenocarcinoma  ..................................................     88           83           6          28.3           2.9
B~~,nchiolol-nlvrola~. carcinoma ......................................................
Carcinoid  ......  ..................................................     46           39           7          39.7           1.0
Bronchial gland tumor ......................................  ....    ...................

Total  . . .    685          669          16          90.7           7.4

Females
Epidennoid carcinoma  ............................................
Small cell anaplastic carcinoma  ...................................
Adenocarcinoma  ..................................................
Rronchiolol-alveolar carcinoma  ...................................
Carcinoid  .........................................................
Bronchial gland tumor ............................................

12           9           3           .75          12.0
8           6           3           ,785          6.6
66           14          42          to.5           1.3
.                                . . . .          .
32           I          25           6.3           1.1
.  .           .                     .          . . . .

   Total  . . . . . . . . . . . . .    108           35          73          18.3           1.9

`Number that would be expected if incidence rate among smokers were      SOURCE: Kreyberg, L. (154)
equal to that of nonsmokers.


LUNG CANCER RELATIONSHIPS IN WOMEN

Lung cancer death rates for women are presently much lower
than the corresponding rates for men. In addition, it has been ob-
served that among certain strains of mice exposed to carcinogenic
agents, the male animals show a greater tendency to develop lung
tumors than do the females (200, XV) although there are strains
for which this is apparently not so. The extent of the influence of
endocrine factors in the sex variation in the incidence of lung
tumors is unknown.

As of 1967 in the United States, women accounted for only about
one-sixth of the total deaths from lung cancer (289). However, the
lung cancer death rate in women has risen by over 400 percent in
the past 40 years. From 1950 to 1967 alone, the rate per 100,000
population doubled, increasing from 4.5 to 8.9 (289,290).

A number of retrospective studies concerning lung cancer and
cigarette smoking among women have found that the difference in
the prevalence of lung cancer between males and females is ac-
counted for principally by those tumors classified as Kreyberg's
Group I (154,311) . These, as was noted above, are the tumors, par-
ticularly in males, which show the closest relationship with smok-
ing. Haenszel, et al. (123), in a study of 158 women with lung
cancer, observed that the sex differential for lung cancer death
rates diminishes, but does not fully disappear when only non-
smokers are considered,

Hammond (118) found that the death rate for lung cancer in
nonsmoking males was somewhat higher than for nonsmoking fe-
males. However, the difference in male-female rates was much
greater when smokers were compared. It appears that a substantial
part of the difference in death rates between male smokers and fe-
male smokers can be explained mainly by differences in their smok-
ing habits.

These differences in smoking habits between males and females
are of two types. First, overall consumption among females is still
significantly lower than that among males. In 1966 (,%?I), 30 per-
cent of males reported that they had never smoked while for fe-
males the corresponding figure was 59 percent. This study also
noted that nearly three times as many males as females reported
consuming more than 20 cigarettes per day. Second, it has been
shown that women smoke differently than men (303) : They begin
smoking later than men (114) and do not smoke cigarettes as close
to the end, where proportionally more nicotine and "tar" are in-
haled. Women smoke more filter-tip and "low tar and nicotine"
cigarettes than men. Furthermore, cigarette smoking still tends to
be heavily concentrated among women under the age at which lung
cancer is most likely to occur.

251


Finally, analysis of the ratio of male and female lung cancer
death rates (283, 284, 285, 286, 287, 288, 289, 2.90) reveals that
since 1960 this ratio has shown a steady decline, reflecting the
greater relative rise in mortality from lung cancer in the female
population.

LUNG CANCER, THE URBAN FACTOR, AND AIR POLLUTION

A number of studies have been concerned with the relative influ-
ences of smoking, urban residence, and air pollution in the etiology
of lung cancer. Table 9 lists studies performed in the United States,
Great Britain, and Japan which have dealt with this question. Kotin
and Falk (149, 250) and more recently the Royal College of Physi-
cians (228) have reviewed the literature concerning the influence
of atmospheric and environmental factors in the pathogenesis of
lung cancer.

The studies listed in table 9 show a number of important trends.
Lung cancer death rates are found to be higher among urban popu-
lations than among rural populations. It is not known to what ex-
tent this urban factor in the etiology of lung cancer is due to
differences in the levels of air pollution. Other factors associated
with urban residence which may influence the etiology of lung
cancer are : differences in smoking habits between the two popula-
tions, occupational differences, and possible differences in the re-
porting of lung cancer deaths (228).

The studies also uniformly show that within each urban/rural
grouping, lung cancer death rates increase with increased smoking.
Whether air pollution acts with cigarette smoking to influence lung
cancer death rates in a combined manner is presently unclear (112,
126, 261, 265), and the evidence concerning a separate role of air
pollution in the etiology of lung cancer is still inconclusive (228).

The recent report of the Royal College of Physicians on air pollu-
tion and health (228) concluded that "the study of time trends in
the death rates of lung cancer in urban areas demonstrates the
overwhelming effect of cigarette smoking on the distribution of the
disease. Indeed, only the detailed surveys that have taken individual
smoking histories into account have succeeded in separating the
relatively very small influence of the `urban factor' on the over-
riding effect of cigarette smoking in the development of cancer of
the lung."

252


          TABLE 9.-Epidemiologic investigations conwxing the wlationsl,ip of hng cancer to
                   smoking, air polhtion, and urban or rural residence
                               (Actual "umber of deaths shown in parentheses)

  Author,      Population
  Ye*=.       studied and
country.      method of                               Results
reference     data collection                                                                  Comme"ts


Doll,       Estimated death rates                Lung canecr mortality (1950) per 1,000                  Authors noted that
1953,       from lung cllncer                    M&.9                 FC?Tl&S        Nonsmokers   estimates are based on
England     in English                London Other urban Rural    Londo?~ Other urban Rum4   All area8   very few deaths.
(70).       population and    Age:
          among nonsmokers   25-44  0.126    0.095    0.070      0.028    0.028    0.012    0.020
          obtained from      45-64  1.672     1.264    0.861      0.194    0.162    0.120    0 090
          general register.     65-74 3.124    2.00G    1.164      0.440    0.32F    0.288     `219

Stocks and   Death rates in                         Male lung cancer death rates 195161 (prr 100.000) ngctl 51-74  The authors noted the
Campbell,    England and                                                                upward gradient among
1955,       Northern Wales.                                  Rural (68)   Mixed (118)   Urban (5.79)   nonsmokers. pipe
England     Review of patient  Nonsmokers __.............._.......,......_      14                 131
(8.55).                                                                            smokers and light
          chart or interview  Pipe    .._.........__...      41        25        143      c.igerette smokers and the
          with kin or      Cigarettes: Light      87        153        297      lack of a similar
          physicians.       Moderate ,,.,,........._....._,.......,...     183        132        287      gradient among
                       Heavy ._....................,..........     363        303        394      moderate and heavy
                                                                           cigarette smokers.

Hammond    187,783 white males                Age etandardized death rates dve to bronchogcnic carcinoma (males) -
                                                                           Data excluded
and Horn,    in 9 states.                                                                  adcnocarcinoma. when
1958.       Questionnaire                                  Suburb       City of      City of       standardized for age and
U.S.A.      and interview.                       Rural        or town     10,300-50,000
(120).                                                                   >SO.OOO      smoking, rural rate was
                      Nonsmokers  .            4.7 (2)      9.3 (3)      14.7 (4)      still noted to be 26
                      Cigarette smokers  66.2 (62)      71.7 (67)      70.9(69)      85.2(83)      percent less than urban.
                                                            .~


        TABLE g.-Epidemiologic investigations concerning the relationship of lung Cancer to
             smoking, air pollution, and wban or rural residence (cont.)
                           (Actual number of deaths shown in parentheses)

  Author,      Population
   Ye-.       studied snd
  country.       method of                               Results                                comments
reference     data collection

HW"SZ.4     10 percent of all           Age- md emoking-standardized lung cancer mOrt&tU rsaQtii%           Standardized Mortality

et al..      white male lung              (epidermoid and undifferentiated carcinontas mh)             Ratio = IOO for U.S.
1962,       canwr deaths in
U.S.A.                                                          white males age 35 and
           U.S.A. for 1958           Metropolitan counties            Nonmetropolitan counties
(11.3).                                                        over in 1958. The authors
          for whom next of         >50,000  ,119             2.600-50.000  . .QO
         kin or physicians                                              *ISO noted ". . joint
                          lO,OOO-50.000  .I61             Rural nonfarm .74         eff'Xt.s Of residence and
         supplied smoking        2.600-10.000  . .99             Farm  . . . . . . . . . ...57         smoking histories in the
          data. 2.191 cases                                               @chedule of hng-cancer
         with adequate                                                 =ateS far greater than
          information.                                                      those expected on the
                                                               a.%umption of additivity
                                                                           of the separate
                                                                           effects. . :'

DOU       41,000 male British                     Standardized death rates for lung cancer          The authors noted that
and Hill,     physicians.
1964.       Questionnaire and                                                       rural mortality data

England                         Conurbation(49) Large Towns (34) Small Towns (ad)
         follow-up of death                                                 Rural (IS)
                       Nonsmokers       0.03                                      were affected by a

(74).                                                 0.00         0.11          0.12
          certificate.      Cigarette smokers:                                            significant number of

                        1-14  . . . . . . . . . . . . . .._     0.48                                    city residents
                                                    0.32          0.87          0.52
                        16-24 .._..........     1.31                                  retiring to the country.
                                                    1.66          1.06          1.16
                        >25  . . . . .._.........     1.90          4.43         2.20          1.17

Wicken,     1,908 male and
1966.                          Lung tamer death rate pe+ lOO,OOO--age- and smoking-standardized
         femalelu"gcs"eer                                                           Total number of deaths

Northern     deathsover 35                 Inner      outer     Belfast   urtmn                    noted under method of
                                                                    STlUdl
Ireland                                                                        data collection include
          Years of *ge from              Belfaet     Belfast    Environs   AT.X8      TOWM
(308).                                                                        RUTal
          register. Personal                                                             964 contTob3.
                      Males     X7(241)    139(167)    136(46)    118(185)    137(26)    47(149)
          interviews with    Females     22 (38)     17 (24)    12 (6)     23 (35)
          kin or physicians.                                               22 (6)    12 (43)


TABLE 9.-Epidemiologic in.vestigations concerning the relationship of lung cancer to
     smoking, air pollution, and urban or rural residence (con&)
              (Actual number of deaths shown in parentheses)

Author.      Population

Yea=,       studied and
COUIltrV.       method of

Results

referenee

Buell
et al..
1967.
U.S.A.
(49).








Hitosugi,
1968,
Japan
(126).

  data collection

304 lung cancer           Age-adjusted lung cancer death rates per 100.000 man years and mottalitg ratios  The authors noted the lack
deaths among                                                                of death-rate difference
American                                         San Francisco/      AU other     between Los Angeles and
Legionnaires                           Los Angeles      San Diego     California countiee   San Francisco regions
aged 25 and over.                         Rate    Ratio    Rate    Ratio    Rate   Ratio   and concluded that
Questionnaires to   Nonsmokers  _,.,..._.__.....    28.1     2.6     43.9     3.9     11.2     1.0   photochemical smog ia
next of kin.      Smokers :                                                      not related to
             <I pack/day  .,,...........    63.6     6.7     11.1     6.9     61.02     6.4   lung cancer.
              k-1  . . . .   126.0    11.3    134.6    12.0    124.9     11.2
             >l  . .   241.3    21.6    226.0    20.2    137.6     12.3

185 male and                                     Lung caacer death rate per 100,000    The authors postulated a
female lung cancer                                                       slight synergistic
deaths and 4,191                                          PoUution region         effect between smoking
matched controls   Males                                LOW      Intermediate     High  and air pollution.
aged 36-14. Data   Nonsmokers  .._.......,.,...,........... . . . . .     11.6         3.8         4.9
from          Smokers :
questionnaires      1-14 cigarettes/day  _. . .     10.6        14.2        23.6
and interviews.     >16 ,,,,,....................................    21.3        18.6        31.4
             Fern&a
             Nonsmokers  ,,.,...__.._._._..._...............     4.6         6.9         3.8
             Smokers:
              1-14 cigarettes/day .     19.7        16.6        16.3
              >16  . . . . . .     12.4        20.6        17.1
                                     Age- and smoking-adjusted lung cancer
                                               death rate per 100,000

E

Males . . ..___._.................................
Females  . . . . . . . . . . . . . . . . . _.._.._...............

LOW      Intermediate     High
16.1        22.4        28.4
7.6        11.6         8.1


LUNG CANCER AND OCCUPATIONAL HAZARDS

Uranium Mining

The excess risk for the development of lung cancer among uran-
ium and fluorspar miners has been known for more than 30 years.
In a recent review, Bair (17) noted that radon and radon-decay
products are the only inhaled radionuclides to be epidemiologically
related to lung cancer. Lundin, et al. (178), in a continuation of
the work initiated by Wagoner, et al. (299, 300, 301)) have re-
cently reported on a l7-year follow-up of 3,414 white underground
uranium miners. The authors estimated that smoking uranium
miners experienced an excess of lung cancer ten times greater than
did nonsmoking miners.

Saccomanno (231)) in recent testimony, analyzed the data of the
United States Public Health Service (USPHS) Study Group as
presented by Lundin, et al. (178) above. He reported that cigar-
ette smoking uranium miners incurred lung cancer rates four times
greater than those of other cigarette smokers.

Of the 62 lung cancer deaths in this population, 60 occurred in
smokers. He also observed that among 100,000 uranium miners
700 lung cancer deaths per year would be expected to occur among
cigarette smokers compared with only 4 among nonsmokers.

Other Occupations

Nelson (199) has recently reviewed certain environmental and
occupational hazards as they relate to inhalation carcinogenesis.
He observed that cancer of the respiratory tract has been linked
epidemiologically and, in some cases, experimentally with occupa-
tional exposure to the following materials: chromium, nickel,
arsenic, and asbestos. Doll (72) and Goldblatt (100)) in earlier
reviews, also noted an association with coal, natural gas, and
graphite exposures.

Nickel

Morgan (194) noted that much of the nasal and lung cancer at-
tributed to nickel exposure may have been due to arsenical impuri-
ties found in processed nickel prior to 1925. Doll (69) found that
the number of excess deaths among nickel workers under 50 years
of age had declined following the change in nickel manufacturing
processes. The experiments of Hueper (1.~1) and Sunderman, et al.
( 267,268,26.9) have shown that both guinea pigs and rats develop
lung cancer following chronic exposure to nickel carbonyl or nickel
dust. Sunderman and Sunderman (270) also reported that ciga-
rette smoke contains nickel and that this concentration of nickel

256


may be capable of inhibiting the induction of lung aryl hydroxylase,
an enzyme which is able to detoxify aromatic hydrocarbons includ-
ing known carcinogens such as benzo[a]pyrene.

Asbestos

In 1955, Doll (71) found that lung cancer was a definite hazard
among asbestos workers, In a more recent study, Selikoff, et al.
(Zl,ZnZ) examined the relationship of smoking and asbestos ex-
posure to lung cancer. These authors followed 370 people who had
been asbestos workers during the years 1942-1962. Over a 5-year
follow-up period, 94 deaths occurred in this group, of which 24 were
due to bronchogenic carcinoma. The authors noted that according
to data obtained from Hammond (118), only 3.16 deaths from lung
cancer would have been expected among smokers, and calculated a
7.6 to 1.00 mortality ratio due to asbestos exposure. None of the 87
nonsmokers or pipe and cigar smokers died of lung cancer. When
the expected number of nonsmoker deaths (0.26) is compared with
the actual number (~4) which occurred among the smoking asbes-
tos workers, an extremely high mortality ratio of 92 to 1 is obtained,
thus reflecting the possible interaction of asbestos exposure and
cigarette smoking.

Exposure of mice (179) and rats (106) to asbestos dust or the
intratracheal injection of chrysotile asbestos dust has resulted in
the production of significant numbers of primary pulmonary car-
cinomas. Miller, et al, (181) exposed hamsters to intractracheal
injections of benzo[a]pyrene. These authors observed that the addi-
tion of the chrysotile variety of asbestos to the injections appeared
to promote benzo[a]pyrene carcinogenesis in the respiratory tract,
as determined by the time of appearance and yields of papillomas
and carcinomas.

Auenic

A recent epidemiologic study by Lee and Fraumeni (16.3) has
indicated an excess of lung cancer deaths among smelter workers
exposed to arsenic for more than one year. Cigarette smoking was
not taken into account in their computations. Experimental work
on the induction of cancer in animals using arsenic has yielded
either negative or inconclusive results (133,135).

Chromium

Exposure to industrial bichromate compounds has been associ-
ated with an excess of lung cancer deaths (22,25cJ). Laskin, et al.
(159) have recently reported that intrabronchial pellet implanta-

257


tion of various chromium compounds in rats is associated with the
development of squamous cell carcinomas and adenocarcinomas.
However, Nettesheim, et al. (ZOO) exposed mice to chromium oxide
dust and observed that it had no discernible effect on lung tumor
incidence.

PATHOLOGICALSTUDIES

Investigators who have conducted detailed autopsy studies on
patients who died of lung cancer have reported the increased pres-
ence, when compared to noncancer patients, of bronchial epithelial
changes which they considered to be precursors of bronchogenic
carcinoma (7, 8, 23, 51,. 101, 208, 220, 279, 309). Such changes
include squamous metaplasia, atypical squamous metaplasia (with
acanthosis, dyskeratosis, and numerous mitotic figures), and car-
cinoma in situ. Carnes (51) noted that carcinoma in situ was pres-
ent in 119 cases of lung cancer but not in any of the 119 controls
who were matched for age, sex, and race.

Autopsy studies comparing the frequency of these cancer-
related changes in the lungs of smokers and nonsmokers are pre-
sented in table 10. Virtually all the studies noted an increased
prevalence of these epithelial alterations among smokers as com-
pared with nonsmokers. Definite dosage-dependent relationships
were evident in the results of many of the reports. Also, Auerbach,
et al. (14) observed that the number of cells with atypical nuclei
decreases progressively in the bronchial mucosa of ex-cigarette
smokers, depending upon the number of years between cessation of
smoking and death, although it usually remains above that found in
nonsmokers.

The cytologic studies included in this table (182, 198, 222) all
noted an increased percentage of sputum specimens showing meta-
plasia among smokers as compared with nonsmokers.

PULMONARYCARCINOGENESIS

General Aspects of Carcinogenesis

Agents found in cigarette smoke which have been identified as,
or are suspected of being carcinogenic, are listed in table 11. The
list includes certain compounds which most probably contribute to
the pathogenesis of the various cancers discussed in the other sec-
tions of this chapter. Many other agents have been identified in
tobacco and tobacco smoke. At the present time, they do not appear
to bear a direct relationship to carcinogenesis. Stedman (262) and
Wynder and Hoffmann (319) provide detailed listings and discus-
sions concerning these materials.

258


TABLE lO.-Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokers
                    (Actual number of cases show" in parentheses)

Author.
Y==,
countrY,
reference

NuIu""`,";f
method of
selection

R.?sllIts                                   Comments

Chang.
1967,
U.S.A.
and
K0rell
(55).

105 males and
females 40-86
years of age.

          Percent of cases with brmachid basal cell hyperactivity
Nonsmokers  . . . . . . . . . . , . . .    23.6 (34)
smokers  . . . . . . . . . . . . .     43.7 (71)
Heavy smokers . . . . . . . . . . . . . . . , . . . . . . . . .    t61.3 (31)

Smokers included
pipe snd cigar
smokers.
t psO.01 in com-
parison with
nonsmokers.

Hamilton
et al..
1957.
U.S.A.
(117).

Selected
autopsy
material.

                Number     Age range
Smokers  . . . . . . . . . . . . . . . .  16         39-71
Nonsmokers    20         26-83

Percent of cues with:
Bad cell     SQuamoua
hyperplasia    metaplaaia
  86.6        20.0
  40.0        15.0

Tsmaitional
metaplaaia
  40.0
  36.0

No lung cancer
patienta included.

     Sanderud,   100 males                   Percent of case6 with bronchial ag~arno~n epithelial netaplaia         Nonsmokers in-
       1956.      autopsied at           Nonsmokers  . . . . . . . . . . . . . . . . .    64.0 (39)          elude those
      Norway    Gade Institute         Pipe . . . . . . . . . . . . . . . . . . . . . . . . .._.........._..................    80.6 (20)          smoking less
       (240).     on whom             All cigarette  . . . . . . . . . . . , . . . . . . . . .    79.0 (38)          than or equal to
              smoking data          Cigarettes per day:                                              6 grams per day.
               was available.            E&14  . . . , . . .     70.0 (23)
                                 16-26  . . . . . . . . . . , . . . . .    90.0 (10)
                                 >ZS . . . . . . . . . . . . . . . . , . . . . , . . . . . . , . . .    100.0 (6)

     Knudtaon,   100 persons                               Percent of cases with:               Atupical    Age, occupation,
       1960,      23-86 years                  No. of        NO       Basal cell     SQWtnOU8     proliferative    and site of
      U.S.A.     of age                       P+%WWd      change     hgperplasia    metapIa.&     ?"dWAlsia     residence were
       (1.47).     autopsied at  Nonsmokers . . . . . .  (21)         41.6         23.6        14.3         9.6       found to have no
               Seattle     Cigarettes/day:                                                          appreciable
               Veterans      1-9   . . , . . . . . . .   (9)        17.8         11.1        11.1         . .        effect.
               Hospital on    10-16  . . . . . . . . . . . . . . . . .  (11)         18.2         18.2        64.6         9.1
               whom       16-20 . . .._........._.. (44)        20.4         29.6        29.6        29.6
              smoking     >21  . . . . . . . . . , .   (9)        11.1         33.3        44.4        11.1

it               data was    Pipe or cigar  , . , . , .   (6)          . .        100.0         . .          
               available.
rg


TABLE lO.-Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokevs (cont.)
                         (Actual "umber of cases shown in parentheses)

Author.
year,
country,
refrrenee

Results                                  COlllllle"tS

Auerbach   339 persons
et al..     22-m years
1961,      of age
U.S.A.     autopsied at
(f2).     East Orange
         Veterans
        Hospital
         (excludes
         lung
         Wl"C.X)

Nonsmokers:
<40 years of age
40-59  .
60-69  .
>70  . . . .
Smokers <l pack/day:
<40 years of age
40-59  
60-49  .
>70  . .
Smokers >l pack/day:
<40 years of age
4rk69  
6lL69  . . . . . .
>70  



.

........
........
........
........

........
........
........
........

. .   8
  11
  28
  18

  14
. . .  24
  36
  22

  17
._.. 63
. . . .  84
. . . .  15

Number of
sections
of bronchial
epithelium

333
560
1,463
918

727
1,240
1.772
1,101

880
3,027
4,136
756

Percent sectimla Percent sections
with cilia absent   with bone
and sntirel~   atypical cells
atypical cell8   and cilia absent

              0.3
               
              0.1
              0.6

   0.1          4.7
   1.0          16.9
   0.5          10.8
   0.6          9.4

   1.5          12.5
   4.5          17.4
   6.9         20.5
   9.8         23.7

The suthors noted a
dose-response re-
lation of smoking
to:
  a. loss of cilia,
  b. increase in
     number of
    atypical
     cells,
  c. carcinoma
     in situ.
Average "umber of
sections per case
equaled 62.3.

Cross
et al..
1961,
U.S.A.
(64).

140 persons                    Percent aectiom showing changes in bronchial epithcltum (number of sectiona) t The authors noted
autopsied at                                      Squamow   Atypicd   Carcinoma          that the differ-
Iowa City                      NW??tld   Hyperplmia   metapimia   ?fWtUplLISG    in situ   Carcinoma  ence between
Veterans    Nonsmokers (31) . . 61(562)     36(137)     8 (33)     t15 (68)             . . . .   smokers and "on-
Hospital    Smokers ( 109 ) . . . . . . . . . . . . . 44(570)     43(662)     16(197)     20(263)     l(12)     2.6(34)    smokers was
on whom                                                                       statistically
smoking                                                                       significant.
data was
available.


TABLE lO.-Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (cont.)
                         (Actual "umber of cases show" in parentheses)

Author.
ye.8=,
c0u*t.rY,
reference

%:k;oaf
method of
selection

Results                                  comments

Auerbach
et al.,
1962.
U.S.A.
(14).

72 autopsied
former ciga-
rette smokers
who had been
smoking for
210 yc*lg
and had
ceased
25 years ago.

                        Number of     Percent sections Percent s&ions Percent sectiona Each a-smoker
                       sectimu of     with cilia absent with mmc atypi- with 50 percent   matched with a
                         brachial      and entirely    cd celk and   atypical eel&   current smoker
             Number       epithelium      atypical cells    cilia absent  and cilia preeent  plus "ever-smoker
Nonsmokers   72          3,166           0.0         0.1          0.6      for age. OCC"PB-
Rx-smokers .   12          3,436           0.2         0.9          2.5      tion. and resi-
Current smokers .   72          3,537           8.0        19.0         80.8      dence. There was
                                                                  an average of
                                                                  50.3 sections per
                                                                  subject and none
                                                                   had less than 18
                                                                   sections.


TABLE IO.--Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (cont.)
                        (Actual number of cases shown in parentheses)

Author,    Number of
  Year,      cases and
country,    method of                                  ResU1t.S                                  COllUIl.Xlts
reference     selection

Auerbach   456 male and                                       Percent *ec-   Percent sec-   Percent *ec-    Major findings
et al..      302 female                           Number of      tima with     timw with    tiom with 50    noted:
1962.      smokers and                          wctiona of     cilia absent   wme atypi- percmt atypical    Urban nonsmokers
U.S.A.     nonsmokers                             bronchial     and entirely   cd cells and    ceUs and       showed more
(13).     autopsied and                 Number     epithelium    atypical cell.9   cilia absent   cilia present     lesion than rural.
         matched for   Males :                                                               Both lesions and
         rage. oceu-     Nonsmokers . . . . .  41         2,346                   0.1         0.7       atypical nuclei
        pation. and    Cigarette smokers  . . . . . .  75         3,393      6.9        21.2        78.6       were much less
         residence.    Females: . .                                                           frequent in non-
                   Nonsmokers . . . . . . . .  47         2,379          . .         0.1         0.5       smokers and less
                  Cigarette smokers .  76         3,607         2.5        13.3        62.6       frequent in pipe
                  Males :                                                               and cigar smokers
                   Nonsmokers . . .  36         1.106      0.3         0.2         0.6       than in cigarette
                   Cigar smokers  . . . . . . .  36         1,733                   10.0        10.7       smokers.
                   Cigarette smokers . . . . . .  35         1.626         12.8        27.3        83.1      57.1% of cases bad
                                                                           60-55 sections
                                                                           31.5% of eases had
                                                                           40-49 sections
                                                                           7.3% of cases had
                                                                           30-b9 sections
                                                                           4.6% of cases had
                                                                           16-29 sections

Robbins,
1966,
U.S.A.
(2.22).

103 students                          Percent in each cytologic clads                        Smokers defined as
17-24 years                                  Slight&     Moderat&       strmg1y      those having eon-
of age who                           Normal       atypicd      &p&l       atypical      sumd 210 ciga-
underwent   Nonsmokers (45)  . . . . . . . .  86.7          4.4          8.9           .         rettes a day for
WXOSOl     Smokers (58)  . . . . .  55.2         32.8         10.3          1.7         21 year.
sputum
induction.


TARI E lO.---Pathologic md cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (cont.)
                          (Actual number of crises shown in parentheses)

Author.     Number of
year.      cases and
country,     method of
reference     selection

Results

Maltoni    1,000 healthy                                             Number    Percent ahowinp mctaplasia
et al.,      males who   Nonsmokers  . .      294            41.16
1968,      underwent   Smokers:
Italy      sputum       l-10 cigarettes/day _. . ".   189            47.09
(182).     induction.     11-20  .     385            51.43
                   21-30 . .      93            61.29
                   >30 . .    39            69.23            -~~- __
Nasiell,    50 nonsmoking                           Sputum crtologic changes              Percent with    t Regarded by
1968.      outpatients,                               Percent              Percent with    utupical       author 89 "real
SWdCn    39X smokers                   Number        M&S      Mean age   metaplasia    metap1naiat      premalignant
(198).        
         wrtmpatmg Nonsmokers    50           42         57.1        18           4        change."
         in general    Smokers  _. 393           73         46.6        62          27
         health exam-
         ination who
         underwent
         SPUtUm
         induction.

Spain
et nl.,
1970,
U.S.A.
(258).

15'7 males and
TX females
nutopsied fol-
lowing sudden
or accidentnl
death fol
whom smok-
ina data were
available (ex-
smokers ex-
cluded from
female data).

Males :

Nonsmokers .
Ex-smokers
<l pack
>l pack
Females:




Nonsmokers  
<l pack . .  
>l pack  

-









.........
.........

.........
.........
.........






........
.......


.



.


,...


........
........
........





Number

    36
.    21
    32
    6.8

    34
.    18
.    26

Percent with metaplasia  The authors found
                no evidence af
     50.0         carcinomn in situ
     67.7         or pwneoplastic
     62.5         atypicnl changes.
     73.5

34.1
33.3
46.1


In order to facilitate understanding of the relationships of the
various compounds to one another, the third column presents the
presently underst.ood relative importance of each of the various
groups of compounds. These compounds have been tested only in
animals or tissue cultures, and it should be stressed that the rela-
tive importance of one compound may not be the same in man as
it is in animals.

Table 11 is divided into two major sections. The first section
details those compounds which are considered to be or are suspected
of being cancer initiators. These are compounds which induce
irreversible changes in responsive cells. In the second section are
listed those compounds which are considered to be or are suspected
of being tumor promoters. These compounds promote the malrg-
nant reproduction of cells in which neoplastic changes have been
initiated. A number of these initiators may also act as complete
carcinogens in their own right. The evidence concerning the two
stage initiation-promotion mechanism is still rather limited for
respiratory tract carcinogenesis.

The pol~nuclear aromatic hydrocarbons (PAH) listed are pres-
ently considered to play a very significant role in pulmonary car-
cinogenesis due to tobacco smoking. These compounds act as tumor
initiators or complete carcinogens. The particular role of these
agents in environmental and occupational carcinogenesis has been
reviewed by Falk, et al. (93). That such hydrocarbons are pro-
duced from tobacco during human smoking has been shown by
Kiryu and Kuratsune (2-N). These authors reported the presence
of benz[ a] anthracene, chrysene, benzo[ alpyrene, and benzo-
[blfluoranthene in the "tar" produced by normal smoking and
measured in either filters or stubs.

Two hydrocarbons which have frequently appeared in the litera-
ture on experimental tobacco carcinogenesis may not actually be
present in tobacco smoke. They have been used as representatives
of carcinogenic PAH, a class which includes many constituents that
have been ident.ified in cigarette smoke condensate. They are
`Y,?C!-dimethy!benz[a]anthracene  and 3-methylcholanthrene and
have been frequently used as tumor initiators or complete carcino-
gens, particularly in skin painting and tracheal implantation
experiments.

The nitrosumine compounds listed are potent carcinogens affect-
ing many organ systems, including the respiratory tract (188,
199). Nagee and Barnes (181) have presented a detailed account
of experiments in this area. Xitrosamines have been identified in
trace amounts in tobacco "tar" and the conditions required for their
formation (the presence of secondary amines and nitric oxide) are

264


TABLE Il.-Identified or suspected tumorigenic agents in cigurette smoke'

Estimated
concentrs-
tion in 100
cigarettes
(85 mm.
"onfilter)

Presently understood relative
importance in experimental
  tobacco carcinogen&s

I. Complete carcinogens and tumor initiators:
Polynuclear aromatic hydrocarbons  ........
   1. Benzo (a) pyrene  ..................
  2. Dibe"z(a,hlanthracene   ..........
   3. Be"zo(b)fluora"thene  .............
  4,Benzo(j)fluoranthene  ..............
  6. Dibenzo(a,iJ pyrene  ...............
   6. Benz(a)anthracene  ..............
  7. Cbrysene  ..........................
  8. Indeno(l,2,3-cd),,yrene  ...........
  9. Be"zo(ciphenanthrene'  .............
  10. MethyIbenzo(a)pyre"es  ..........
  11. Methylchrysenes  ....................

N-heterocyclic hydrocarbons  ..........    l-2
1. Dibenz(a,h)acridine  ............    0.01
2,Dibenz(a,j)acridine  ................    1.0
3. `IH-dibenzo (c&z) carbazole  ...........    0.07

N-nitrosamines"                     l-10

1. Dimethylnitrosamine  .............    0.4
2. Diethyinitrosamine  ...............   TKXe
3. Methyl-n-butylnitrosamine  ..........   TlYWe
4. Nitrosopyrrolidine  ..................    0.4
5. Nitrosopiperidine  ..................   TP3C-Z

Epoxides, peroxy compounds. and la&ones:
1. Epoxides  ...........................
2. Peroxides  ...................
3. LarAones  ...........................
   a. a-Leva"re"olide  ................
  b. a-Levantenolide  ................

No data
PRSe"t


20.0
2.0

N-alkyl-heterocyclics:
1. I-methylindoie  .....................

Pesticides and fungicides :<
1. TDE  .............................
2.o,l;-DDD  .......................
3. DDT  ......................
4. Maleic hydrazide  .................

10-100
10.?OO
IO-IOF
10-100


2-3





1.5"

Beta-naphthyiamine  ..,.,,,,..

Polonium 210  

10-30 "I3
3.9
0.4
0.3
0.6
TlYSe
0.3
2.0
0.5
TCDX
0.1
2.0

Tumor initiators

Tumor initiators.

suspected carcinogens of possible
importance (presence in fresh
smoke possible).

Certain of these compounds 8~
know" carcinogens; presence in
smoke condensate not established.

Possib!e initiator.

No essentiai contribution suspected.

Suspected b!adder carcinogen:
of doubtf"i significance at
reported ievels.

Of some importance on!y in the

-;irocuries   case of relatively high conten-
       tration. but not important at
       reported levels.

Nickelcompounds  .  Present  Suspected carcinogens of some
                                 importance.

265


TABLE Il.-Identified or suspected tumorigenic agents in cigarette smoke'
                  (cont.)

Estimated
concentra-
tion in 100
cigarettes
(85 mm.
nonfilter)

Presently understood relative
importance in experimental
tobacco carcinogenesis

II. Tumor promoting agents:
Neutral promoters (polymers)
   (unknown structures.)

No data  Of possible importance.

Volatile phenols    20-30 mg.  Of possible importance.
  1. Phenol
2. Cresol

Nonvolatile fatty acids    20.100 mg. Of minor importance.
  1. Stearic acid
2. Oleic acid

N-alkyl heterocyelics:                      Of possible importance.
1. I)-methylcarbazole  . . . . . . . . . . .  Present

1 Modified and expanded from (319. 320) with reference to (52, 60, 89. Ill. 149. 402. 261.
299,494.295).
2 Has not been tested as an initiator, but is a known complete carcinogen.
3 See Neurath. (9X),
`See (112,128).

found in tobacco smoke (38). However, nitrosamines may be arti-
facts dependent on the method of smoke collection (201).

Neurath (202) considers the nitrosamines listed in table 11 as
being present in fresh cigarette smoke (253, 254). However, con-
clusive confirmation of their presence in fresh smoke is not available
(38,138,15.5,319).

Certain of the pesticides and fungicides presently in use on
tobacco have been found to be carcinogenic (91,273,280). A num-
ber of these, such as DDT, are now being phased out of regular
domestic use. The compounds listed have been shown to be present
in trace amounts in mainstream tobacco smoke (I 11,128). A recent,
extensive review by Guthrie (2 12 ) provides more detailed informa-
tion concerning these agents.

Radioactive isotopes can be found in tobacco and tobacco smoke
(105). Potassium-40, while present in tobacco leaf, is not trans-
mitted in any substantial amount to mainstream smoke (230).
Polonium-210 (PO,,,,), however, is transmitted into the mainstream
smoke (94, 123, 142, 145, 215, 217). A number of autopsy studies
(table A12) have shown that the bronchial epithelium of smokers
contains significantly more Po~,~ than that of nonsmokers. LitBe,
et al. (172, 173, 17s) have also noted that the concentration of
polonium was markedly higher at sites of bronchial bifurcation.
These authors stress the importance of this finding for pulmonary
carcinogenesis by noting that bronchogenic carcinomas are fre-

266


quently located at bifurcations and that the polonium levels which
they found in those regions probably have biologic significance
(~16). Other investigators (11.1, 217') have not observed this
excess at bifurcations, and in a recent discussion Wynder and Hoff-
mann (8.20) concluded that it appears unlikely that PO?,,, in the
amounts present in cigarette smoke plays a role in tobacco car-
cinogenesis.

Although not listed as a separate group, there are a number of
agents in cigarette smoke which are potent inhibitors of ciliary
movement. Their importance in cnrcinogenesis derives from the
increased amount of time which they afford the kno1v-n carcinogens
to be present on the surface of the bronchial epithelium. These
inhibitors include volatile aldehydes, hydrogen cyanide, nitrogen
oxides, volatile phenols, and certain volatile acids such as formic
and acetic (1.29).

In some respects, the animal and tissue culture studies detailed
below apply to neoplastic transformations, not only in the lung but
in ot,her tissues in which tobacco smoke, particularly cigarette
smoke, is believed to play a role. These general experiments will be
presented here, however, with the experiments which bear on lung
tissue directly.

Skin Painting a,nd Shxtaneous Injection

Numerous animal studies on rats, mice, and rabbits, have been
performed utilizing known carcinogens, whole tobacco "tar," and
various tobacco condensate subfractions, or compounds known to
be present in tobacco smoke. These experiments involve the single
or repeated painting of shaved or unshaved animal skin. A selected
number of these studies js presented in table A13. Numerous other
studies, performed prior to and following 19.5:3, are reviewed by
lvynder and Hoffmann (319).

The skin painting method is still considered to be a valid pro-
cedure for the identification of agents suspected of participating in
Pulmonary carcinogenesis, as well as for the quantification of the
reduction in tumorgenicity of specific agents,

The exposure of tissue and organ cultures to cigarette smoke, its
condensates, or its conhtituent compounds has been shown to sig-
nificantly alter patterns of cell growth and reproduction. Table A14
Presents an outline of these experiments. Once again, less severe
effects have been noted lvhen filtered smoke was used (165).

267


Tracheobronchial Implantation and Instillation.

More complex experiments concerning the carcinogenicity of
cigarette and tobacco smoke are represented by those which involve
the direct implantation, instillation, or fixation of suspected ma-
terials into the tracheobronchial tree of animals. Certain of these
experiments are outlined in table AX. Recent reviews by Saffiotti
(233,234) Laskin, et al. (159)) and Montesano, et al. (189) as well
as that by Wynder and Hoffmann (319) provide more detailed and
extensive accounts of these experiments.

Of note among the results outlined in this table are the following :
The enhanced carcinogenicity found when benzo[a]pyrene (B[a]P)
is combined with a carrier such as hematite dust (235)) and the
definite increase in bronchial epithelial preneoplastic and neo-
plastic changes among dogs treated with smoke condensate as com-
pared with those undergoing only physical bronchial stimulation
(224).

Inhalation

Various species, including mice, rats, hamsters, and dogs, have
been exposed to cigarette smoke or aerosols of its constituents.
These inhalation experiments are outlined in table A16. It must be
noted that the majority of the studies listed involve the passive
inhalation of the material presented usually in a chamber. Active
inhalation experiments, exemplified by the work of Rockey and
Speer (223) and Auerbach and his colleagues (11, 129) involved
animals which were trained to inhale voluntarily, thus more closely
simulating human smoking.

Results of note among these experiments include the following:
Miihlbock (195) observed that cigarette smoke inhalation en-
hances the already substantial rate of spontaneous alveolar cell
carcinoma format.ion in hybrid mice, and various investigators in-
duced adenomas in experimental animals (108, 168, 206). Harris
and Negroni (I 21) found that exposure to cigarette smoke achieved
some enhancement of adenocarcinoma formation in mice but did
not observe proven squamous cell carcinoma. Some of their mice
had also been exposed to Swine influenza virus aerosol. In a related
study, Boren (32) exposed hamsters to cigarette smoke at set inter-
vals over a 4%hour period. The author observed alterations in pul-
monary cell kinetics (the pattern of DNA synthesis) as demon-
strated by H"-thymidine autoradiography. The pattern of the label-
ing response to cigarette smoke was significantly different from
that of the response to high oxygen concentrations.

Auerbach, et al. (22) have reported the development of early

268


invasive squamous cell bronchogenic carcinoma in dogs following
a period of direct inhalation of cigarette smoke. These investiga-
tors trained beagle dogs to inhale cigarette smoke through a
tracheostoma (50) and divided the animals into groups according
to dosage as detailed in table 17. A number of dogs died during the
course of the experiment which ran for 875 days, or approximately
29 months. The causes of death are listed in table 18. All of the
remaining dogs, with the exception of group "h" (high exposure,
heavy weight), were sacrificed shortly after day 875 ; the survivors
among the heavier dogs are continuing to smoke.

Examination of the respiratory tree of the animals revealed a
number of tumors (table 19). Most of these were similar to the type
of tumor which in man is referred to as bronchiole-alveolar. This
tumor arises in the bronchiolar and alveolar epithelium and tends
to be multicentric. Two striking characteristics of these bronchiolo-
alveolar tumors were the existence of a histologic spectrum (from
a tumor resembling the benign condition of adenosis to frankly
malignant tumors with invasion of the pleura and surrounding
parenchyma) and the marked tendency to squamous change. Inva-
sive bronchiole-alveolar tumors were found in 12 dogs in the group
which had been exposed to the largest dosage of cigarette smoke.
Several had tumors of more than one category. Ten of these dogs
had invasive bronchiole-alveolar tumors which did not extend into
the pleura, one dog had an invasive bronchiole-alveolar tumor
which extended to the pleura, and four had invasive bronchiolo-
alveolar tumors extending into the pleura beyond the pleural-
pulmonary junctions. In addition, two bronchogenic squamous cell
carcinomas were found in this group (table 19). The dosage de-
pendence of tumor formation is shown in figures 2 and 3.

Major findings of the study were twofold. First, that smoking
filter-tip cigarettes was less harmful, both in terms of pulmonary
parenchymal damage and lung tumors, than smoking identical
cigarettes without filters. This supports the generally held view
that total particulate matter is a meaningful indicator of the car-
cinogenic potential of a cigarette, Second, lung cancer of two types
found in man was produced by the inhalation of cigarette smoke.
TWO of the dogs were found to have early invasive squamous cell
carcinoma of the bronchus, and both belonged to the high-dosage
group. These carcinomas were indistinguishable from early invasive
squamous cell carcinomas found in the bronchial tubes of human
beings who smoke cigarettes. The majority of tumors found in the
dogs were of a bronchiole-alveolar type, which although not as
common as squamous cell cancer in man, is not rare in humans.
This type is often included in the category of adenocarcinoma. A
number of studies have shown an excess of these tumors among

269


TABLE IT.-Datu on pedigreed m& beagle dogs of groups F, L, H, h, and N
         (Some of the figures apply only to dogs surviving 8'76 days or longer)

Filter
**O"p
F

NO
filter
gri?p

NO
filter
grour,
H

fE*       Nonsmokers
group         grO"P
h           N

Number of doss on day No. 67'
Weight at start (day No. 1) mean weight (pounds)
Cigar&e s per dog II, 875 days _. t..
Mcarr numlwr of c~ynrettes per day _. _.
Eauivalertt number of cigarettes per day for 150 pound man
Type of cigarettes:'

                                              ___-
12             12            24            38           R

25.0            26.1           26.0           31.9          30.7
6,143           3,103          6,129           6.129          none
  7.02            3.64            7.0            7.0         -
42.1            21.2            42.0           32.9

Milligrams of tar per cigarette .
Milligrams of nicotine per cigarette
Total dosage in 875 days:
Grams of tar per dog _.  
Grams of niecrtinp per dog  
Dosage in Xi5 days relative to starting weight:
Grams tar/pounds weight  
Grams nicotine/pounds weight _. _,

17.8
1.17


109.3
7.19

4.31            4.12            8.31
0.29            0.22            0.44

34.8            34.8           34.8         -
1.85            1.85           1.85

103.5           207.8
6.56           11.12

207.8         -
11.12         -


6.61         -
0.35         -

-_I          ____
' The smoking dogs were divided into CLOUDS F. L. H. and h on dav No. 67.
? Dogs of groups L, H. and h smoked filter-tip cigarettes during a training period at the start of ,the experiment, but smoked nonfilter cigarettes thereafter.
SOI'H~~~S: Adapted from Hammond, E. C. et al. (119).


TABLE I%-Swmnary of principal cause of death (days No. 57 through No. 875) in dogs of groups F, L, H, h, atztl N
        (Each death classified according to most severe condition-some dogs <liwl of n n>mbinnti<m <,f rauses list&

NO
filter

          Principal cause of death                         Group
                                                   IA                               _.
                                                              ~~~___
Pulmonary emphysema and fibrosis _,                           2                     -           2
Cc~r r)ulmonnle (pulmonnry emphysema and fibrosis with
right heart enlargement)                             3           5                      8
Pulmonary infarction  .      1           1           2           *5                      9
Bronchopneumonia       -                      3           I          -           4
Aspiration of food . . . . . . . . . . . . . . . . . . . . . . . . . .      1           1                                -           2
Uncertain _._.,..._,,,.,.,._.,.,,..,,,,........,....,.                           2           1                      3
Number of deaths __,.,.,........._..__.,.,,,,..__.___,      2           2          12          12          -          28
Number surviving 876 days . . . . .     10          10          12          2 R           8          66
Total number of dogs . . . . .     12          12          24          :3X           8          94

  SOURCE: Hammond, E. C. et al. (119).


TABLE lg.-lhtcc on dogs with lung tunlors indicating type of tumor and lobe in w'hich the tumor was found
                NTfber      Age at                              Early ssxuunous
Group           ",%if                 death     Lobes with bronchido-alveolar tumors     cd bronchial
                                 cigarettes     (Years)     Non-invasive        Invasive        carcinoma

Group N (nonsmokers)  . . . . . . . . . . . . . . N      904a
                         N      904b

Group F (filter-tip)  . F
                          F
                          F
                          F

878a        6,161
879a        6.170
885~s        6,224
X90a        6,269

Group L (no filter)  . . . . . . . . . . . . . L
                          L
                          L
                          L
                          L
                          L
                          L

347         1,055
812         2,847
87th        3,103
87'7a        3,107
xnza        3.127
896a        3,183
899a        3,195

Group H (no filter)   H
                         H
                         ii
                         H
                         H
                          H
                          H
                         H
                         H
                         H
                         H
                         H
                         H
                         H
                         H
                         H
                         H
                         H
                         H

135          518        2.5
259         1,343        3.3
563         3.404        4.1
716         4,689        5.0
753         5,030        3.x
760         5,088        4.2
868         5,970        5.3
R'ifia        6,129        4.9
R77a        6,138        5.4
R'78n        6,147        5.3
xa2a        6.183        6.4
883a        6,192        4.7
8858        6.210        5.0
889a        6,246        5.0
890a        6,255        4.9
892a        6,213        6.1
8!lZb        6,213        5.3
897a        6.318        5.2
X!)7b        6.318        4.5

5.1        LA
4.9        RA

6.1        LA
4.7        LA
5.2        LA
5.4        LA

3.x        LA, LC
5.1        RA
5.1        LA, RA
5.2        LA, LC
5.2        LA. LD
5.3        LA, RD
5.4        LA

RC
LA, RA, RD
LD. RA


RI
LA
LA



. .
RA
LA
RA. RD. RI

LA
LC, RA
RA
LC

1.A
LA, RA, RD

-
LA, LD. RA
LA
LA

LA
LA, RA
LA

-

-
LA, RA
-
LA

-

-
-

-

-

-

-

-
-
-
-

-

-
LABB
-
-
-
LMB
-
-

-
-
-


TABLE lg.-Data on. dogs with lung tumors indicating type of tumor and lobe in which the tumor was found (cont.)

Day of
death

Number
  of
cigarettes

Age at
death
(years )

                       Early squamous
I.ohrs with bronchiolo-alveolar tumors    cell bronchial
Non-invasive        Invasive       carcinoma

Group h (no filter)  .,,..,........... . . h      606         3.760        4.6        LA
                          h      626         3,928        4.4                      I,A, RI
                          h      649         4,143        5.0        RI             T.A. RA
                          h      794         5.400        5.1        LA, HA

LA, left apical lobe; LC, left cardiac; LD left disphragmatic: RA. right
apical; RC, right cardiac; RI, right intermediate; RD. right diaphragmatic;
LABB, left apical branch bronchus; LMB. left main bronchus.

start of smoking. The letter "a" or "b" follows the day of death of dogs
sacrificed after day 3875.

For smoking dogs, the day of death indicates the number of days since      Sorinc~: Auerbach. 0. et al. (II ).


80

58.3

TUMORS
DOGS

NONSMOKING

FILTER-TIP      NO FILTER
       (% as many cigarettes)
           as Group H

GROUP H:
NO FILTER

2            4            7           19
s        i?        -ii       24

FIGURE 2.-Percent of smoking dogs with tumors.
SOURCE: Adapted from Auerbach, O., et al. (11).

20.8

0
     GROUP N:      GROUP F:       GROUP L:     GRLu. 8,
    NONSMOKERS    FILTER-TIP      NO FILTER     NO FILTEI

4.8

TUMORS       2            4            12          35
LOBES     56       xi        s4      158

FIGURE S.-Percent of lung lobes with tumors in smoking dogs.
SOURCE: Adapted from Auerbach, O., et al. (11).

274


cigarette smokers (C, .i;?, II,`), but the magnitude of this relation-
ship is not as great as that with squamous cell cancer in man.

Reduction in Tumorigenicity

The importance of reducing total particulate matter in cigarette
smoke is reflected in the dose-dependent results of the Auerbach-
Hammond study. A major objective of experimenta tobacco car-
cinogenesis must be the reduction in the tumorigenicity of cigarette
smoke and other tobacco products. In a recent article (320),
Wynder and Hoffmann have reviewed the various methods applied
to achieve this goal. Among therje methods are the modification of
the tobacco itself, the modification of the conditions of tobacco
pyrolysis, the use of additives, and the use of filters. The use of
filters should produce a reduction of particulate matter as well as
of gas phase components.

Bross (44) studied 974 cases of lung cancer at Roswell Park
Memorial Institute and concluded that smokers who switched to
filter cigarettes showed a decreased risk of developing lung cancer.
However, even after switching, heavy smokers were still found to
have a mortality risk five times that, of nonsmokers.

More recently, Wynder, et al. (3.24) reported on an interview
study of 350 patients with histologically confirmed lung cancer and
552 age and sex-matched controls. They found that subjects who
had switched from nonfilter to filter cigarettes ten or more years
prior to the study incurred a lower relative risk of lung cancer at
all consumption levels than that incurred by those who continued to
smoke nonfilter cigarettes. The authors suggest that this difference
in relative risk may be due to the lower "tar" content in filter
cigarette smoke. Prospective studies concerning the effects of filter
cigarette smoking are presently being conducted.

Apart from variations in "tar" exposure due to filtration, it
appears that different patterns of smoking result in the inhalation
of varied amounts of "tar." Graham, et al. (103) simulated dif-
ferent inhalation patterns with the use of an analytic smoking ma-
chine. He found that smoking a given number of puffs over a long
period of time results in greater "tar" retrieval than smoking them
over a short period. Also, he observed that taking most of the puffs
at the end of the cigarette results in the highest retrieval while
taking most at the beginning results in the smallest retrieval.
Complementing these observations is the same author's case/con-
trol study (102) of 183 men with lung cancer and 161 men with
diseases not related to tobacco smoking. He found that the lung
cancer patients had significantly greater high "tar" yield cigarette
smoking patterns than the controls. The risk of lung cancer was
found to increase with the increase in mean number of puffs per

275


cigarette, the average length of time taken to smoke a cigarette
(except in the highest number of puffs category), and the taking
of more puffs at the end of the cigarette.
These findings, and those of the study of Auerbach, et al. (11),
add further support to the dose-response relationship between lung
cancer and total cigarette smoke condensate exposure.

SUMMARY AND CONCLUSIONS

1. Epidemiological evidence derived from a number of prospec-
tive and retrospective studies coupled with experimental and path-
ological evidence confirm the conclusion that cigarette smoking is
the main cause of lung cancer in men. These studies reveal that the
risk of developing lung cancer increases with the number of cigar-
ettes smoked per day, the duration of smoking, and earlier initia-
tion, and diminishes with cessation of smoking.

2. Cigarette smoking is a cause of lung cancer in women but
accounts for a smaller proportion of cases than in men. The mor-
tality rates for women who smoke, although significantly higher
than for female nonsmokers, are lower than for men who smoke.
This difference may be at least partially attributed to difference in
exposure; such as, the use of fewer cigarettes per day, the use of
filtered and low "tar" cigarettes, and lower levels of inhalation.
Nevertheless, even when women are compared with men who ap-
parently have similar levels of exposure to cigarette smoke, the
mortality ratios appear to be lower in women.

3. The risk of developing lung cancer among pipe and/or cigar
smokers is higher than for nonsmokers but significantly lower than
for cigarette smokers.

4. The risk of developing lung cancer appears to be higher among
smokers who smoke high "tar" cigarettes or smoke in such a man-
ner as to produce higher levels of "tar" in the inhaled smoke.

5. Ex-cigarette smokers have significantly lower death rates for
lung cancer than continuing smokers. There is evidence to support
the view that cessation of smoking by large numbers of cigarette
smokers would be followed by lower lung cancer death rates.

6. Increased death rates from lung cancer have been observed
among urban populations when compared with populations from
rural environments. The evidence concerning the role of air pollu-
tion in the etiology of lung cancer is presently inconclusive. Factors
such as occupational and smoking habit differences may also con-
tribute to the urban-rural difference observed. Detailed epidemio-
logic surveys have shown that the urban factor exerts a small
influence compared to the overriding effect of cigarette smoking in
the development of lung cancer.

276


7. Certain occupational exposures have been found to be asso-
ciated with an increased risk of dying from lung cancer. Cigarette
smoking interacts with these exposures in the pathogenesis of lung
cancer so as to produce very much higher lung cancer death rates
in those cigarette smokers who are also exposed to such substances.

8. Experimental studies on animals utilizing skin painting,
tracheal instillation or implantation, and inhalation of cigarette
smoke or its component compounds, have confirmed the presence of
complete carcinogens as well as tumor initiators and promoters in
tobacco smoke. Lung cancer has been found in dogs exposed to the
inhalation of cigarette smoke over a period of more than two years.

CANCEROFTHELARYNX

Cancer of the larynx is a disease which predominantly affects
males in the 55 to 70 year age group. In 1967, a total of 2,468 males
and 329 females died of laryngeal cancer in the TJnited States. With
the development and application of more effective therapy during
the past 30 years, the death rate for cancer of the larynx appears
to be dropping slightly (282, 289) ; however, the incidence con-
tinues to rise. Figures from the Connecticut Cancer Registry (88)
show that the age-adjusted incidence per 100,000 population of
cancer of the larynx for males rose from 3.0 in 1950 to 5.6 in 1961.

EPIDEMIOLOGIC`AL STUDIES

A number of epidemiological studies have investigated the rela-
tionship between smoking habits and the development of cancer
of the larynx. The major prospective studies, as outlined in table
20, show that smokers of cigarettes run an approximately six-to-
tenfold risk of dying from this form of cancer as compared to non-
smokers. Smokers of pipes and cigars incur a three-to-sevenfold
risk. The retrospective studies listed in table A21 uniformly show
fewer nonsmokers and more smokers among eases wit.h cancer of
the larynx than among matched controls. Table A22 summarizes
the relative risk ratios derived from the retrospective studies. The
wide variation is due to a number of factors, including type of popu-
lation and interview technique. But, in general, the magnitude of
most of these ratios is of the same order as in the prospective
studies.

Wynder, et al. (312) have distinguished between cancer of the
intrinsic and extrinsic larynx. Tumors arising on the vocal cords
are classified as intrinsic and constitute approximately 70 percent
of the lesions. The extrinsic larynx is composed of those sections of
the larynx excluding the vocal cords and may also be referred to as

277


TABLn Xl-Laryngeal cancer mortality ratios
(Actual number of deaths shown in parentheses)'
    SM = Smokers.    NS = Nonsmokers.
            -___.
          Prospective studies

Number

Author,
year,
cou"tly.
reference

Number and
type of
population

Data      FOllOW-
collection      UP
         years

Hammond
and
HOI.",
1958,
U.S.A.
(fZ0).

187.783 white
males 5c-69
years of age
in 9 states.

Questionnaire
and follow-
up of death
certificate.

Doll and
Hill,
1964,
Great
Britain
(74).

Approximately   Questionnaire     10
41,000 male     and follow-
British       up of death
physicians.     certificate.

Kahn      U.S. male      Questionnaire
(Darn).     veterans.      and follow-
1966,      2.265.674       up of death
U.S.A.      person years.    certificate.
(139).

                        ____
Hammond,   440,558 males    Interviews
1966,      562,671 fc     by ACS
U.S.A.     males 35-84     vo1u"teers.
(118).     years of age
          in 25 states.

  of
laryngeal
CanCer
deaths

Cigarettes/day

Pipes, cigars

COlIlIll~"t3

24    Cigarette smokers W/24.         Cigar    Data referring to mortality

SM . .24
NS 0

3/24
Mired
4124

l`atio included cancer of
esophagus and mouth.

   16
SM ..16
NS 0

  All smoke+8 by amount
      in gsame
NS . _. .   
1-14  1.00
15-24  __ __ __ ._ __. 1.00
>25 _. ._ _. _. ,, 7.60

Pipe and cigart  t Includes data on ex-
NS . 1.00    smokers of pipes and cigars.
SM 5.00    No NS died of laryngeo-
           tracheal cancer. therefore
            l-14 gram SM set as 1.00
            standard.
          Data combine laryngeal
            and tracheal carcinoma.

R IL

54

NS ..__.....__. 1.00 (3)

Pipe

Refers to current cigarette

I_
     SM .51    l-9 ..__._._..... 3.27 (1)   NS 1.00 (3)  smokers only.
     NS 3    l&20  8.45(10)   SM .10.33 (6)
             21-39  .13.62(11)    Pipe and cigar
             >39 ,............ 18.85 (3)   NS 1.00 (3)
              All  ,. 9.95(25)   SM .._. 7.28(11)

4         57    NS ._..__._... 1.00 (3)    Pipe and cigar  Male data only.
     SM ..54    SM (age 45-64)  6.09(32)   NS  1.00 (3) Pipe and cigar data refer to
     NS 3    SM (age 65-79)  8.99(18)   SM 3.37 (4)  males 55-84 years of age.


TABLE ZO.-Loyi~~gcnl cmccr 7nwtalitjj ratios (cont.)
    (Actual number of deaths shown in parentheses)'
       SM - Smokes.     NS = Nonsmokers.

              I'rosyective studies

Author,
year,
country,
reference

Number and
type of
population

Data
collection

Number
  of
lawngeal
caneel
deaths

Cigawttrslday         Pipes, cigars          C""l"lZ?"tS

Wrir and
Dunn,
1970,
U.S.A.
(906).

68,153 males     Questionnaire      5-8        11    NS            -
                                                             No nonsmokers died of
in various      and follow-            SM ..ll    *lo  1.00                  Inryn~.eal carcinoma,
occupations     up of death            NS 0    220  ., . 5.00                  therefore -cl0 smoker set
in California.    certificnt~.                    >30  5.84                  as 1.00 standard.
                                                                   NS includes pipe and cigar
                                                                      smokers.
                                                                     SM includes ex-smokers.

' Unless otherwise specified, disparities between the total number of deaths
and the sum of the individual smoking categories are due to the exclusion
of either occasional, miscellaneous, mixed, 01' ex-smokers.


t.he hypopharynx. These authors noted that the percentage of heavy
smokers among the patients with cancer of both the extrinsic and
intrinsic larynx was significantly greater than that among controls.
However, it is of interest that the excess risk of laryngeal cancer
among cigar and pipe smokers in this study could be attributed to
the extrinsic laryngeal group.

As in studies of oral cancer, it appears that alcohol consumption
should also be taken into account in studies of laryngeal cancer.
Wynder, et al. (872) reported a significantly increased risk of
extrinsic cancer among those with alcohol intake above 7 ounces of
whiskey per day. With less than this amount, no increased risk wa,s
evident. Schwartz, et al. (&8), noted no effect in relation to alcohol
intake. Further research into the interaction of these two variables
is necessary.

Auerbach, et al. (9) studied histological changes in the larynges
of 942 men, age 21 to 95, who were autopsied at a single hospital
between 1964 and 1967. Cases of primary cancer of the larynx were
excluded from the study. Smoking histories for all cases were
obtained from family members of the deceased by trained inter-
viewers. The randomized histological sections were graded by one
observer. Tables A23 and A21 summarize the findings in the true
vocal cord. Of the men who never smoked, 7.5 percent had no cells
with atypical nuclei, only -1.3 percent had sections with areas con-
taining 60 to 69 percent of cells lvith atypical nuclei, and none had
a higher percentage. The 116 ex-smokers had laryngeal histology
similar to that of the nonsmokers, as far as atypical nuclei were
concerned. HoLvever, disintegrating nuclei \vere found in JO.5 per-
cent of the ex-cigarette smokers and in only ()..I percent of the
remaining cases. Only one of the 9 1 cigar and or pipe smokers had
no atypical cells. Three had carcinoma irl sitrc, and one case had a
section showing early invasive primary carcinoma.

The highest percentage of atypical cells IVWS found among the
cigarette smokers. The proportion of cases with a high degree of
cellular change increased with increased daily smoking. None of
the pack-or-more-a-day smokers n-as free of atypical nuclei in the
laryngeal epithelium. Of those ivho smoked t\vo or more packs per
day, 85 percent had 1eGons xvith 60 percent or more atypical cells
as compared to -1 percent of the nonsmokers. Between 10 and 18
percent of the cigarette smokers had areas of carcinoma irz sitl(,
and .I of the 64-I cases showed early microscopic invasion. The
thickness of the basal level of the true vocal cord was also directl!
related to the amount smoked.

280


EXPERIMESTAL STUDY

Dontenwill (76) has recently reported the development of an
effective and practicable method 1)~ n-hi& small rodents (ham-
sters. rats? mice) can be exposed to long-term passive inhalation of
cigarette smoke in a mannel' nhich circumvents the fatal effects of
acute toxicity. which ruincc! earlie:, attempts but allows for a dosage
of smoke great enough to induce the development of chronic patho-
logical changes. The SJ.rian Golden hamster was found to be the
most suitable species for such inhalation experiments for several
reasons : its resistance to pulmonar!- infections, its resistance to the
effects of nicotine a.5 compared to that of rats or certain strains of
mice, and, especially, its susceptibility to develop tracheobronchial
cancers after treatment nith carcinogens, in contrast to its almost
total freedom from the spontaneous development of these tumors.

Dontenwill demonstl*atecl that the concentration of deposited
cigarette smoke uas greatest in the hamster's larynx as compared
to the other portions of the exposed respiratory tract (table 25))
and that the lar\-ngeal epithelium was the tissue which underwent
the greatest smoke-induced histological changes.

In studying the changes in the larynx, the author differentiated
five stages of epithelial change, using as his reference the Atlas of
Tumor Pathology of the Armed Forces Institute of Pathology (5).
Table 26, quoted by Dontenwill, describes the five types of change.
They range from benign. such as epithelial hyperplasia, to pre-
malignant. exemplified by pseudoepitheliomatous leukoplakia.

The results of the inhalation experiment are presented in figure
-1 in which a dosage-related increase in the severity of the epithelial
changes is represented in graphic form. The author also reported,
and depicted with photomicrographs, the finding of an early inva-
sive squamous cell carcinoma. This form of cancer is the predomi-
nant type involving the human larynx.

SUMMARY AND CONCLUSIONS

1. Epidemiological, experimental, and pathological studies sup-
port the conclusion that cigarette smoking is a significant factor in
the causation of cancer of the larynx. The risk of developing
laryngeal cancer among cigarette smokers as well as pipe and/or
cigar smokers is significantly higher than among nonsmokers. The
magnitude of the risk for pipe and cigar smokers is about the same
ol.cler as that for cigarette smokers, or possibly slightly lower.

2. Experimental exposure to the passive inhalation of cigarette
smoke has been observed to produce premalignant and malignant
changes in the larynx of hamsters.

281


TABLE 25.~Deposition of `"C-lubeled smoke pwticies
  in particular regions of the respimtoq tract'

Organ

Traced
radio-
activity   01-g?in
CnCi)

Head and palate 6.11  Head. palate

Tongue

0.41  Oral cavity
     in total.

Larynx      (r 39
Trachea     0.26
Lungs       6.35 1
   Total     14.12

Eitimated    Deposition
radio-       of
activity     particles
(nCi)       ( % 1

         Traced
Proportional depwsition
area of the  in relatirm
respiratory    to the
tract   ProPortional

j-3

1.6

          0.1-0.3   X561-187
1   ,Zl.i       0.6      X62.3
           1000     Xl

  1~11).0

282


TABLE 26.-Classification of the five registeredstages of epithelial charzgcs at the lwynx'.'

stage

-.-__~  --__~  __--   ~- ~.-. . ~~      - ..--. .~
                                        Drskerntosis (we-
                                           mature atypical
Acanthosis (thickm-    H, ,,erkr,xt<&     Pnrakeratosis (in-      cornification
  ing of stratum       increased      complete cornifica-     changes in the    Mitosis
  spinosum multi-      cornificntion      tion of nuclei in     nucleus prolifern-
  cellular layer)     (stratum corneum)   the stratum corneum)    tion of the basal

1. t'nchvdwmia (epithelial hywrplasia)        +             +              t              t         t

2. Leuroplakin          +             +-              1              r         t

4. t'apillrnnntou~ kwruplakia          +             t              t             +it        f


                                               TOTAL  146

  34    35    8    6    10    7    11    4    5    17    4    5
                   .    .    . . . .  .    . .    .    . . . . .
5

                     .    . . . . . .
  4

                 . .        . .             . . . .
  3

2            . . . . .    . . . . .    . .    .
52
c
"  ,I                      I             I   I

2    4    6    8    10 12 14 16    18 20   22-28
            SMOKE EXPOSURE, months

      . ZONE ANIMAL    &=ANIMAL LIVING     O=LARYNX CANNIBALIZED

FIGURE 4.-Effects of chronic cigarette smoke inhalation on the hamster larynx.
Review of the results of the inhalation experiments: number of smoke-ex-
posed animals with and without changes in the larynx, duration of smoke
exposure, and number of animals still alive.
SOURCE: Dontenwill, W. (7G).

ORAL CANCER

The cancers included in this category are those of the lips, tongue,
floor of the mouth, hard and soft palate, gingiva, alveolar mucosa,
buccal mucosa, and oropharyns. It is estimated that 15,000 of these
cancers will be diagnosed in the United States in 1970, accounting
for about 2.5 percent of the estimated 600,000 malignant neo-
plasms reported (289). A variety of histological types of malig-
nant neoplasms can affect these tissues, but squamous cell car-
cinoma is by far the predominant type, accounting for about 90
percent of the cancers.

The incidence of and mortality from oral cancers has remained
steady over the past 20 to 30 years. The Connecticut Cancer Reg-
istry (88)) which is a fairly reliable index of incidence, noted that
the incidence among males remained between 15.8 and 16.3 per
100,000 population during the years from 1950-1961. Examination
of mortality rates over the past 20 to 30 years (882, 289) reveals
a similar constancy.

The apparent lack of change in mortality from oral cancer in

284


contrast to the sharp increase that took place in lung cancer rates
in those years is probably due to serreral of the following factors.
First, pipe and cigar smoking are both significantly related to can-
cer of the oral cavity, and the increase in cigarette smoking among
men, noted between 193r and 1955, has been, to a large degree,
accompanied by corresponding l,eduetions in the use of pipe.; and
cigars. Second, aside from the V:CYiOUS changes which the Interna-
tional Classification of Diseases (ICD) had undergone during t.hat
period, the diseases discussed above are recorded in ICD Codes
140-148 which include some neoplwms not found to he related to
the use of tobacco. The various sites of cancer themselves do not
contribute equally to the o\~e~all 1,atc and are subject to nidely dif-
ferent cure rates, so that their contl.i1)ution. to the total incidence
rate is different from their colltri~Jiltil~ll to the c~vt>rall mortality
rate from oral cancer. Although more than 31,000 cancers of the
oral cavit)- were estimated ;1~ nelvl:- di:cyno.& ill 1967, the total
number of individual5 rcco~~ierl ;is tlJ,ing front oral wncer during
that year was only 6,71 x (~8:)).

Oral cancer occurs predominantly in people of the middle and
older age groups. More than 90 percent of all oral cancers occur in
persons over age -15, with the average age at time of diagnosis
approximating 60. Although the majority of oral cancers occur in
men, there is recent evidence that the ratio of males affected to
females affected is decreasing (2.57).

~EPII,E?~~IOI,~)GIC.L\L STUDIES

The use of tobacco in various forms has been associated with the
development of cancer of the oral cavity and pharynx. The studies
in this area of concer1, at-t' ?rul~- international, many having been
carried out in Asian :" :ll~ns as well as in the M'est.
The major pr(J~im,: ; t' u!~i:lumic~logic~~l htudies have found in-
creased rates of fhcw .`::I "`.:rs for cigarette smokers as well as for
pipe and cigar sni:)kei~:: (see table 27). Pipe smoking, per se, has
long been recognizt:cl :~s a cause (Jf lip cancer (?!I1 ) . The methodol-
ogy and results of the numerous retrospective studies are sum-
marized in tal,lti:.i X28 ar:d AZ&. These studies almost uniformly
show significant relalionships between the various forms of tobacco
use and )`.' `::"-c'-: 1,; -1 P c:`.:: ;:t\-ity and pharynx.

Studir5 !I; .`$-. :!: ,t' 1;~: h:~~e examined the prevalence or inci-
dence of pl'enliijJ~J:,.!.. :i~n& , ,G;lrch as oral lettkoplakia, as well as
that of cancer of the oral cavitp. In many of thwe studies, forms of
tobacco use not prevalent in lyestern countries have been investi-
gated, including reverse smoking (in which the lighted end of t.he
cigarette is kept in the mouth close to the palate) and the chewing

285


TABLE 27.-Oral cancer mortality ratios-prospective studies

Author
year.
country,
reference

Number and
type of
population

Data
collection

   (Actual number of deaths shown in parentheses)
     SM= Smokers.    NS = Nonsmokers.


FOllOW-   Number
UP Years     of           Cigarettes
       deaths

Pipes, cigars

Comments

Hammond  187.783 white    Questionnaire      3 $6                   20/56         Pipe    MiXCd   Data referring to mortality
and      males in 9      and follow-up                                      5/M     21/56    ratio do not include cancer of
HOlYI,     states 50-69     of death             NS ..3                          Cigar        larynx and esophagus.
195R,      years of aEe.    certificate.                                           6/66       t Excludes two occasional
U.S.A.                                                                           only smokers.
(110).

Doll nnd    Approximately   Questionnaire      10         19     All smokera by amount      Pipe and cigar    No NS died of oral CBIICCI',
Hill,      41,000 male     and follow-up          SM   .19         in gram.9        NS  ....... 1.00      therefore 1-14 gram
1964.      British        of death             NS  .. .   NS            -
                                               ..............        SM  ....... 1.00      smoker set as 1.00
Great     physicians.     certificate.                    1-4  ............. 1.00                    standard.
Britain                                        15-24  ............ 0.25
(74).                                         >25  ............. 5.25
                                       - .... ..-- .
Kahn     U.S. male      Questionnaire      Xl/,        61   NS  .............. l.OO(ll)       Pipe       Data do not include pharynx.
(Darn),    wternns.      and follow-up          SM   .50   tCias/day 1-9  .... 0.86 (1) NS  ....... l.OO(ll)  t Refers to current cigarette
1966,      2.265.674      of death             NS   .ll   lo-20  ............ 2.93(13) SM  ....... 3.12 (4)   smokers only.
U.S.A.     ,:cI`:ioll YCBTS.    cel~tifirnte.                   21-39  ............ 7.34(20)       Cigar
(139).                                        >39  ............. 5.73 (3) NS  ....... l.OO(ll)
                                            All  .............. 4.09(37) SM  ........ 4.11 (9)

H~~IllOlld.  410,65;: males    Interviews by      4         95   NS  .............. 1.00 (`7)  t Pipeand/or      t Male data only. Pipe and
1966,      T,C2,1;71 females   ACS volunteers         SM   .33  SM (age 45-64)  ... 9.90(63)   cigar.            cigar data refer to males
U.S.A.     :ii-' I ycnrs "f                     NS  .. .  SM (sge65-`79)  .. 2.!33(25) NS  ....... 1.00 (7)   55-84 years of age.
(118).     apt ill 25 states.                                              SM  ....... 4.94(15)

Weir and   FR,lS:i lN.ales    Questionnaire      5-R        19   NS  .............. 1.00                   SM includes ex-smokers.
Dunn,     in vat ious      and follow-up                 -10  ............. 3.69                    NS includes pipe and
1970,      occupations     of death                     -t20  ............. 1.17                    cigar smokers.
U.S.A.     in California.    certificate.                   >3n  ............. 6.62
(.W(i).                                        All  .............. 2.76


of "pan" or "Nass," which are mixtures of tobacco with either betel
nut or lime ash, and other ingredients (241, 2.55, 256). Snuff
dipping, a habit in which snuff is placed in the gum and ret.ained
there for prolonged periods, has also been associated with the
development of oral cancer (1118, 210)) as has the chewing of
tobacco (124, 193,211,298).

The risk of developing a second primary mouth or throat cancer,
after the recognition of the first primary cancer, has been found
to be greater in continuing smokers than in those who quit smok-
ing. All of the patients studied by Moore (190) were asymptomatic
for at least three years following the treatment of the first cancer.
Of the 117 patients with adequate smoking histories, only 4 of 33
(9 percent) who quit smoking developed a new primary cancer.
On the other hand, 27 of 74 (36 percent) who continued to smoke
developed a second primary cancer.

However, a study by Castigliano (53) of patients treated fol
oral cancer did not show a greater risk of a second primary among
continuing smokers. In this study, 5 of 26 (19 percent) of those
patients who did not quit smoking developed a second primary
cancer as compared to 9 of 51 (18 percent) of those who did quit.
The rate of quitting smoking in the two studies is markedly dif-
ferent (36 percent in the Moore study and 62 percent in the Casti-
gliano study). From the data presented in the two papers, it is not
possible to evaluate the other significant ways in which the pop-
ulations may have differed.

Keller (1~0) studied 408 males with histologically confirmed
squamous cell cancer of the mouth or pharynx. This author dealt
with the question of recurrent tumors in a somewhat different
manner. The patients were observed for the development of a sec-
ond or third primary cancer at an anatomically discrete site of
the mouth and pharynx within a median period of three years after
the first cancer. He found that a second or third cancer (termed a
coexisting cancer) developed in 28 of the 408 cases. Among these
23 cases with 32 coexisting neoplasms, 21.7 percent were heavy
smokers, but among their matched controls, there were no heavy
smokers. Coexisting cancers were most commonly found on the soft
Palate, an anatomical site that is in direct contact with the main-
stream of tobacco smoke.

More recently, Wynder, et al. (S1S) studied 62 male and 23
female patients with multiple primary cancers of the mouth and
pharynx. They observed that heavy smoking prior to the develop-
ment of the oral cancer was associated with a greater likelihood
of developing a second primary. Also, continued smoking after t.he
fil'st primary was found to have a significant association with the
occurrence of a second primary.

287


With or without smoking, use of alcohol appears to contribute
to the development of oral cancer (124, lJ0, 183, 2.97, 322). In a
study of male veterans, Keller (110) found that heavy smoking
and heavy drinking were associated with cancer of the mouth and
pharynx. X:0 studies are presently available which determine the
relative contributions and possible interactions of heavy smoking,
heavy drinking, and concurrent nutritional deficiencies in the etiol-
ogy of these cancers.

EXPERIMENTAL STUDIES

In 1964, the Advisory Committee to the Surgeon General on
Smoking and Health (291) reported that cigarette smoke and ciga-
rette smoke condensates had failed to produce cancer when applied
to the oral cavity of mice and rabbits or to the palate of hamsters
and t.hat the oral mucosa appears to be resistant in general to can-
cer induction even when highly active carcinogens such as benzo-
[alpyrene are applied. Some of the difficulties in experimental de-
sign were attributed to the fact that mechanical factors, such as
secretion of saliva, interfere with the retention of applied carcino-
genic agents on the tissues of the oral cavity and pharynx. Positive
results with certain carcinogens have, however, been obtained in
the hamster cheek pouch, but it has also been pointed out that the
cheek pouch lacks salivary glands and that its structure and func-
tion differ from those of the oral mucosa. The majority of these
studies are outlined in table AZ9.

Although cigarette smoke condensate acts as a complete carcino-
gen on mouse skin, the work of several authors (319) supports the
concept that cigarette smoke contains cancer promoters that may
be of special importance, particularly in oral carcinogenesis. Elzay
(90) has reported that whole cigarette smoke is a promoting agent
for the hamster cheek pouch. More importantly, regarding the
chewing of tobacco, Bock, et al. (27. .30), Van Duuren, et al. (.Z!1$),
and Wynder and Hoffmann ($21) have shown that unburned to-
bacco products contain tumor promoters that might contribute to
the promoting activity of the smoke.

Roth, et al. (d?li , ~27) have shown that the dye-binding capacity
of the DNA of oral epithelial cells is significantly enhanced in
cigarette smokers in contrast to nonsmokers, probably reflecting
an increase in the DXA content of oral epithelial cells in smokers.
Smokers had values of dye-binding capacity intermediate between
nonsmokers and "1 patients with proven oral cancer. Those smok-
ers who refrained from smoking for up to six months showed a
significant decrease toward more normal values.


SUMMARYANDCONCLUSIONS

1. Epidemiological and experimental studies contribute to the
conclusion that smoking is a significant factor in the development
of cancer of the oral cavity and that pipe smoking, alone or in
conjunction with other forms of tobacco use, is causally related to
cancer of the lip.

2. Experimental studies suggest that tobacco extracts and
tobacco smoke contain initiators and promoters of cancerous
changes in the oral cavity.

CANCER OF THE ESOPHAGUS

Esophageal cancer accounted for 4,306 deaths among American
males in 1967 and 1,321 deaths among females. The death rate
from esophageal cancer has remained relatively constant since
1939.

EPIDEMIOLOGICAL STUDIES

The major prospective epidemiological studies (table 30) have
indicated a significant relationship between smoking and esopha-
gea! cancer. Overall mortality ratios for male cigarette smokers
range from 1.74 to 6.17. There are insufficient data concerning
females for establishing firm conclusions.

A number of retrospective studies concerning the relationship
of smoking and esophageal cancer are outlined in table A31 and
&la. Smokers incur risk ratios ranging from 1.3 to 6.6 when
compared with nonsmokers.

As in studies of oral cancer, the effect of alcohol consumption
must be taken into account in studies of esophageal cancer. Because
a relationship between alcohol consumption and tobacco use is
kno1v-n to exist, Wynder and Bross (310) analyzed the association
between tobacco consumption and esophageal cancer after adjust-
ing for alcohol intake. They found that in the absence of alcohol
consumption, there was no association between the use of tobacco
and esophageal cancer but that in the presence of alcohol consump-
tion, an increasing relative risk with increasing number of ciga-
rettes smoked was apparent, as well as an association between
cigar and pipe smoking and esophageal cancer.

More recently, Takano, et al. (Z'6), in a retrospective study of
`?(I0 patients with esophageal carcinoma, found an increased risk
mith smoking which was magnified by increased alcohol consump-
tion. Martinez ( 183) analyzed the association of tobacco usage
and esophageal cancer after controlling fol. age, sex, and alcohol
consumption. Increasing relative risks with increasing tobacco use

209


TABLE 30.-Esophageal cancer mortu& ratios-prospective studies

(Actual number of deaths shown in parentheses)'
   SM = Smokers.     NS = Nonsmokers.

Author,
year,
countrY,
reference

Number and
type of
population

Data       Follow-
collection     up years

Number of
esophageal
cancer
deaths

Cigarettes/day

pipes, cigars        Commmts

Hammond
and
HOlTl,
1958.
U.S.A.
(120).

1X7.783 white
males in 9
states EDIM!,
yenrs of age.

Questionnaire
and follow-up
of death
certificate.

3%

     34    Cigarette smokers        Pipe    Mticd      Data referring to
NS ___ 1     15/33.             2/33    cigarette      mortality ratios
SM . ..33                    Cigar   smokers       included cancer
                           2/3.1    13/33        of mouth
                                            and larynx.

Doll and

Approximately

Questionnaire

10

29

All smokers bu amount

tl'ipe and cigar

t Includes ex-

Hill,       41,000 mnlc       and follow-up                        in grama        NS 1.00         smokers of pipe
1964,       British          of death                         NS  , ._ 1.00        SM 2.00         and cigars.
Great      physicians.       certificate.                        1-14 2.00
Britain                                               15-24 3.60
(74).                                                >25 5.00
                                                    All  3.00
-____-      __
Katm      U.S. male        Questionnaire      8 `A          111    NS  l.OO(tl)         Pipe         t Refers to
(Darn),     veterans         and follow-up            NS 11   t1-9 1.76 (2)         1.99 (3)         cigarette
1966.       2,265,674        of death               SM . ..lOO    10-19 4.71(18)          Cigar          smoking
U.S.A.      person years.      certificate.                     20-39 .11.50(24)         5.33(12)         OdY.
(139).                                                >25  7.65 (3)
                                                    All  6.17(47)

Hammond,   440.sj5X malrs      Interviews by       4            46    NS  1.00 (6)       Pipe and Cigar
1966.       562,671 females   ACS volunteers.            NS . 6    SM (age             NS 1.00
U.S.A.     35 a4 years of                         SM 40     45-64) 4.1'7(32)      SM 3.97(14)
(118).      age in 25 States.                                 SM (age
                                                  65-79) 1.74 (8)


(Actual number of deaths shown in parentheses)
  SM= Smokers.     NS = Nonsmokers.
              .

Author
year.
country.
reference

Number and
type of
population

Data       Follow-
collection     up years

HirElYalIla,   265,118 male      Trained PHS       II/&     SM . ..21    NS  l.OO(p<O.Ol)
1867,       and female       nurse inter-                       SM  2.47(21)
Japan      adults 40         view and
(125).      years of age      follow-up
          and older.        of death
                       certificate.

Weir and    6X,153 males      Questionnaire       S-R           32    NS ._ _. 1.00
DUllll,      in various       and follow-up                      *lo 1.27
1970.      occupations       of death                         -czo 1.69
U.S.A.      in California.      ccrtilicate.                        >30 l.f?2
(SUB).                                                All  1.82

' Unless otherwise specified,  disparities between the total number of
deaths and the sum of the individual smoking categories are due to the
exclusion of either occasional, miscellnncous, mixed, or ex-smokers.

Comments

Refers to all
forms of
smoking.

NS includes pipe
and cigar
smokers.


were noted. The consumption of very hot beverages was also found
to be related to the development of esophageal cancer.

PATHOLOGICALSTUDY

Autopsy studies of smokers as compared with nonsmokers, spe-
cifically observing the pathological changes in esophageal tissue,
have been performed by Auerbach, et al. (15). A microscopic study
was made of 12,598 sections of esophageal autopsy tissue from
1,268 men who died from causes other than esophageal cancer. The
findings were strikingly similar to the abnormalities generally ac-
cepted as representing premalignant tissue changes in the respira-
tory tract epithelium. Esophageal epithelial cells with atypical
nuclei (having an irregular distribution of chromatin) were found
far more frequently in cigarette smokers than in nonsmokers. Basal
cell hyperplasia and hyperactive glands were also found more fre-
quently in cigarette smokers than in nonsmokers. An increase in
frequency with amount of cigarette smoking was noted for both
epithelial cells with atypical nuclei and basal cell hyperplasia.
Tables A32 and A33 summarize these findings.

EXPERIMENTALSTUDIES

Kuratsune, et al. (156) investigated the possibility that the car-
cinogens known to be present in tobacco smoke could penetrate the
esophageal epithelium more readily if dissolved in aqueous ethanol.
Mice were exposed to several compounds by esophageal intubation.
Tissues were then removed and studied by fluorescence microscopy.
Deeper penetration and a different distribution were found when
B[a]P was dissolved in aqueous ethanol as compared to B[a]P in
olive oil. It was also found that benzo[a]anthracene and fluoran-
thene dissolved in ethanol solution or aqueous caffeine solution
could penetrate the epithelium of the esophagus.

Horie, et al. (132) reported on the development of 10 papillomas
and one squamous cell carcinoma of the esophagus in a group of
63 mice periodically forced to drink a solution of benzo[a]pyrene
dissolved in diluted ethanol. Twenty-six papillomas and one squam-
ous cell carcinoma also developed in a group of 63 mice to which
4nitroquinoline l-oxide was administered in the same way. None
of the 67 control animals given only diluted ethanol developed
neoplasms.

Several other authors have reported nitrosamine-induced esopha-
geal cancer in experimental animals (56, 79, 80, 81) . As noted
above, the presence of nitrosamines in cigarette smoke is still a
subject of debate.

292


SUMMARY AND CONCLUSIONS

1. Epidemiological studies have demonstrated that cigarette
smoking is associated with the development of cancer of the esopha-
gus. The risk of developing esophageal cancer among pipe and/or
cigar smokers is greater than that for nonsmokers and of about
the same order of magnitude as for cigarette smokers, or perhaps
slightly lower.

2. Epidemiological studies have also indicated an association be-
tween esophageal cancer and alcohol consumption and tthat alcohol
consumption may interact with cigarette smoking. This combina-
tion of exposures is associated with especially high rates of cancer
of the esophagus.

CANCER OF THE URINARY BLADDER AND KIDNEY

EPIDEMIOLOGICAL STUDIES (BLADDER)

Cancer of the urinary bladder accounted for 6,019 deaths among
American males and 2,743 deaths among American females in 1967
(289). Incidence rates have increased from 1949 to 1962 (88)) but
the death rates from bladder cancer have remained relatively
stable during that period. Improvements in early diagnosis and
therapy may have masked the increasing incidence of this disease.

A number of epidemiological studies have indicated that smokers
have an increased risk of contracting or of dying from bladder
cancer (see tables 34 and A35). Certain of these studies include
kidney cancer mortality in the results. The major prospective stud-
ies, with the exception of that of British physicians, have shown
bladder cancer mortality ratios among cigarette smokers ranging
from 1.40 to 2.89. Smokers of more than 1 pack per day were shown
to incur ratios of 3.42 to 5.41. The study by Doll and Hill (74, 7'5)
of British physicians, on the other hand, reports death rates for
smokers to be lower than those of nonsmokers based on 38 bladder
cancer deaths. The mortality ratios for pipe or cigar smokers are
substantially lower than those among cigarette smokers. Pipe
smokers were shown by both Hammond and Horn (120) and Kahn
(139) to incur ratios approximating 1.20.
Retrospective studies (table A35a) have also shown an increased
proportion of smokers among bladder cancer patients when com-
pared with matched controls. Relative risk ratios for bladder can-
cer among smokers range from 1.0 to 7.3 among all smokers and
up to 10.3 among heavy smokers of all types.

293


TABLE 34.-Kidney and urinary bladder cancer--prospective studies-Mortality ratios
               (Actual number of deaths shown in parentheses)'
                   SM = Smokers.     NS = Nonsmokers.

Author,
  yen=.    Number ar.d     Data     Follow-   Number
country,     type of     collection   up years     of      Cigarette/day                Kidney     Bladder         Comments
reference   population                    deaths                Pipe. cigar


Hammond  187,783 white   Questionnaire    3 I/(?

and
Horn,
1958.
U.S.A.
(120).

males in 9     and
states.       intrrview.

   287 NS 1.00(383      Pipe
       <lO 2.00(14) NS ..1.00(38)
SM .249  lo-20 X00(42) SM t, .1.17(21)
NS 38  >20 3.42(41)      Cigar
                   NS .1.00(38)
                   SM .1.06(19)

Data include patients
dying of prostatic
carcinoma.
Data refer to
microscopically
PlW"Wl
carcinomas.

Doll and   Approximately Questionnaire 10
Hill,      41,000 male    and follow-
1964,      British      UP of death
Cl-eat     physicians.    certificate.
Britain
(74).

Best,     Approximately Questionnaire 10
1966,      78,000 male    and follow-
Canada    Canadian     UP of death
(21).     veterans.     certificnte.

Hammond,  440,66X males   Interviews by    4
1966.     562.671       ACS
U.S.A.     females      volunteers.
(11X).     35-84 years
        of age in 25
         states.

38

NS ..l.OO
SM ..0.41

  All SM bg
amount in grams
NS . ..l.OO
l-14 .0.59
15-24 .0.65
>25 .0.76
All .0.`71

114   NS 1.00        Pipe                        Refers to
   <lO 1.33(29) NS .l.OO                        genitourinarv
   lo-20 1.44(67) SM .0.56(10)                      cancers as a
   >20 1.43(16)      Cigar                        group.
   All 1.40(10) NS ..I.00
               SM .1.16 (3)

Bladder
    138
SM ,115
NS 23
Kidney
   104
SM 82
NS 22

     Cigarettes         Cigarettes   Male data onl2/.
NS  .1.00(22)       1.00(23) Bladderincludes
SM (age 45-64)  .1.42(64)       2.00(59)   other urinary
SM (we 65-79)  .1.57(28)       2.96(S)   tract cancers.


  `I'ABLE 34.-KicOlc7!y und wimry hladdcr cancer-prospective studies--Mortality ratios (cont.)
                    (Actual number of deaths shown in parentheses)'
                           SM = Smokers.     NS = Nonsmokers.


Number and     Data     Follow-   Number
type of     collection
pom&ition            "I) Years  de:ftha    Cigarette/day    Pipe, cigar       Kidney     Bladder

comments

Kahn     U.S. malt     Questionnaire

(Darn),    vetcrnns     and folluw-
13FF,      2,265,G74     up of death
U.S.A.     person       certificate.
(138).     years.

Hirayama,  265,118 male   Trained PHS
1067,     ana female    nurse inter-
Japan     adults 40      view and
(125).    yea,? of age    follow-up
        and older.     of death
                  certificate.

Weir and   FR,lRR males   Questionnaire
DlIIlll.     in various     pnd follnw-
1070,     occupations    up of death
1J.S.A.    in California.   certificate.
(sns).

-.- .___
S'/,    Bladder               NS  _... .1.00(38)       1.00(52) Bladder includes
         224               Pipe  .1.32 (6)       1.20 (8)   other urinary
     SM ,112               Cigar  .O.W (6)       0.94 (10)   tract calleers.
     NS . 52              Ciaarettes/day:
     Kidwey                  l-9  .a.97 (4)       1.10 (6)
         141                10-19  .1.34(21)       1.93(U)
     SM ,102                20-38  l&8(16)       3.20(34)
    NS 39               >39 .2.76 (5)       2.62 (6)
                         All  . .1.45(46)      2.15(82)
                         _.--.                                -___
l',$ SM    6  NS 1.00                               Bladder cancer only.
           SM . . ..lO.OO (6)                                Refers to all
                                                    forms of smoking.

6-8

Bladder
   27
Kidney
   27

NS
a10
?20
>30
All

1.0"     NS . ..l.OO     SM include ex-

.0.&i
.3.30
.2.57
.2.46

?lO   .1.52      smokers.
520   .2.81     NS include pipe
>30   .5.41      and cigar
A11   .2.89      smokers.

' Unless otherwise specified,  disparities between the total number of
deaths and thr sum nf the individual smoking categories are due to the
exclusion of either wcasional. miscellaneous, mixed, or w-smokers.


EPIDEMIOLOGICAL STUDIES (KIDNEY)

A total of 5,894 Americans died of cancer of the kidney during
1967. A relationship between smoking and this type of cancer has
been suggested by several epidemiological studies. The three major
studies which separately examine the relationship of kidney cancer
to smoking (table 34), namely those of Hammond (II 8)) Kahn
(139), and Weir and Dunn (306)) have shown mortality ratios for
all cigarette smokers to range from 1.42 to 2.46. Retrospective
studies by Bennington, et al. (18, 19) have indicated a significant
association between all forms of smoking and renal adenoma and
adenocarcinoma.

EXPERIMENTAL STUDIES

Numerous experiments have been undertaken by many investi-
gators to elucidate the relationship of tobacco smoking to bladder
carcinogenesis. The two areas of major concern have centered upon
the presence of a known bladder carcinogen, beta naphthylamine,
in cigarette smoke and the presence of abnormal tryptophan me-
tabolism in patients with bladder cancer.

By virtue of data gathered concerning industrial exposure of
workers, beta naphthylamine has long been known as a bladder
carcinogen. Complementing such data was the work of Hueper, et
al. (136) who subjected mongrel dogs to daily subcutaneous injec-
tions and oral administration of commercial beta naphthylamine.
Thirteen of the 16 animals developed bladder papillomas and car-
cinomas of the bladder. Saffiotti, et al. (236) fed hamsters a diet
containing up to 1.0 percent beta naphthylamine and observed that
18 of 39 animals developed bladder tumors, almost all typical tran-
sitional cell carcinomas. More recently, Conzelman, et al. (5.9) ad-
ministered beta naphthylamine to 24 rhesus monkeys for more
than 30 months. Transitional cell carcinomas of the urinary blad-
der were induced in 9 of the animals, and a dose-response relation-
ship was apparent.

Pailer, et al. (207') and Miller and Stedman (185) failed to find
this amine in cigarette smoke. However, more recently, Hoffmann,
et al. (127) identified it in cigarette smoke. The authors, noting
the minute quantity present in each cigarette (2.2 x l&`g), hesi-
tated to attach a biological significance to the finding.

Of more recent interest have been the metabolites of tryptophan
present in certain patients with bladder cancer. A number of nor-
mal and abnormal metabolites of tryptophan have been found to
be carcinogenic when tested by implantation in the bladders of mice.
These include 3hydroxykynurenine (OHKy), 3-hydroxyanthranilic

196


acid (OHA), 3-hydroxy-2-amino-acetophenone (all orthoamino-
phenols), the g-methyl ether of xanthurenic acid (CHXa) , xanthu-
renic acid (Xa) , L-kynurenine (KY), quinaldic acid, and 3-meth-
oxyanthranilic acid (3CHOA) (2, 36, 37, 39, 47, $8). OHKy and
OHA are frequently present in human urine, as is kynurenic acid
(WA).
Certain investigators have concentrated their attention on the
presence of abnormal tryptophan metabolites and increased
amounts of normal tryptophan metabolites in the urine of patients
with bladder cancer as compared with selected controls (1, 10, $6,
97, 148, 211, 2;3, 32.9). These authors have observed the increased
excretion of Ky, KyA, OHKy, anthranilic acid, OHA, and acetylky-
nurenine in such patients. Yoshida, et al. (Jz!?), in a recent study
concerning the relationship between tryptophan metabolism and
heterotopic recurrences of human urinary bladder tumors, reported
that those patients with recurrences showed abnormal metabolfte
excretion more often than those without recurrences.

The relationship of smoking to these biochemical findings is
presently uncertain. Kerr, et al. (123)) in 30 experiments on 3
smokers and 3 nonsmokers who were given large doses of trypto-
phan, found that smoking increased the urinary excretion of OHKy
and OHA and decreased that of N'methylnicotinamide (an end
product of tryptophan metabolism). Kerr concluded that smoking
interferes with the normal metabolism of tryptophan. Recently,
Brown, et al. (is) studied 15 adults under smoking and abstinence
conditions and found that except for the basal excretion of acetylky-
nurenine, tryptophan metabolite excretion did not change with
smoking or cessation. The authors also compared 13 nonsmokers
and 17 regular cigarette smokers under basal and tryptophan-
loaded conditions. No differences were observed in the excretion of
the measured tryptophan metabolites. However, due to its instabil-
ity, OHA was not measured. The authors concluded that the rela-
tionship of smoking to urinary bladder cancer was probably not via
its effect on the kynurenine pathway of tryptophan metabolism.

Another experimental approach to the relationship of smoking
and urinary bladder cancer is reflected in the work of Schlegel, et
al. (241, 215). The authors observed an elevated concentration of
certain ortho-aminophenols in the urine of bladder cancer patients
and cigarette smokers, when compared with nonsmokers (241).
More recently (215) , the same group compared the chemilumines-
cence of the urines of smokers, nonsmokers, and bladder tumor
patients. They noted that nonsmokers showed the lowest level of
luminescence (which they relate to the presence of aromatic hydro-
carbons) and the bladder tumor patients the highest level. The
normal cigarette smokers' level was found to be intermediate.

297


TABLE 36.-Pancreatic cancer mortality ratiosqrospective studies
       (Actual number of deaths shown in parentheses)'

                                    S.M x Smokers.    NS = Nonsmokers.
       .____-
  Author.
  year,    Number and       Data      I+llOW-UP    Number                                      Comments
  country,      type of       collection      years     of deaths         Cigarettes        Pipes, cigars
reference     population
___~
Best.       Appro\imntelp  Queutionnni;~      F     SM 35    Currntt ~cigarcttes OnLY)       Pipes            --

7x.000 male
Canadian
vrternns.

and folk,w-up
of death
crrtiiicate.

NS 1.00           NS .l.OO
<lO ., 1.40 (5)       SM ..2.60 (6)
to-20 1.96 (16)           Cigars
>20 .,.. 2.37 (7)        NS .l.OO
                   SM .2.63 (1)

           -~ ~-___                                             -:
Hammond    140,55X male5    Intcrvicms b,      4           262  NS~.. 1.00 (29)                  Male data only.

19GG       St;L'.liil fcmnies   ACS                SM . ..a233   SM (age
U.S.A.      .15-x4 )Iw,w     v~,ln"tre~.s.            NS 29    45-64 )  Z.G9(158)
(IIY).      of nge in 25                              SM (age
        stntrs.                                    65-79)  2.17 (75)

Kahn
(Darn )
10 c G

          __
    344 NS 1.00 (88)         Pipes ~~~
                                     t Refers to current smokers
tSM . ..256   1-9 0x7 (8)       NS .1.00(88)    of all types.
NS X8  lo-20 1.93 (65)        SM ..0.74 (8)

1J.S.A.      per`s,," yr?ll'b.    certifiratc.                     21-39 2.18 (43)           Cigar8
( I.79 ,                                           >39 1.87 (7)       NS .l.OO(SS)
                                           All 1.84(125)        SM .1.52(27)
                                                                     Both
                                                                  NS .l.OU(RUt

                                      SM .0.93;13;
Hirasrima,   265.11~ malr     Trained PHS      111     SM 14  NS t. 1.00                                      -

l!lCi,       and femnle     nurse inter-                  1 (P<O.Ol)
                               SM . . ...15.56 (14)J

          and <,lder.      deathcertificate.
  ~-__  -~___        .~
Weir and    G'.153 maleh     Questionnaire      5-u    SM . ..-`I1  NS -1.00                      SM includes cx-smokers.

D11"",
l!liO,
U.S.A.
(.:06).

and fulloa-up
of death
cc1-tificatc.

t10 2.04
f20 2.45
>a0 1.44
All   2.43

NS includes pipe and cigar
smokers.


At present, no definite conclusions can IX: rlra\vn concerning the
interrelationships of bladder cancer, abnormal tryptophan metab-
olism, and tobacco smoking. Further study is required in this and
the other areas of bladder cancer pathophysiology.

SUMMARY AND CONCLUSIONS

1. Epidemiological studies have demonstrated an association of
cigarette smoking with cancer of the urinary bladder among men.
The association of tobacco usage and cancel' of the kidney is less
clear-cut.

2. Clinical and pathological studies have suggested that tobacco
smoking may be related to alterations in the metabolism of trypto-
phan and may in this way contribute to the development of urinary
tract cancer.

CANCER OF THE PANCREAS

Several prospective epidemiologic studies have suggested a rela-
tionship between cigarette smoking and cancer of the pancreas
(table 36). A retrospective study of 465 cases of pancreatic cancer
by Ishii, et al. (137) has shown a dose-related increased risk of
pancreatic cancer in association with smoking. Analysis of dietary
data revealed that the relative risk for pancreatic cancer from
smoking was considerably greater than from dietary factors.

No experimental studies relating to this question have been
reported.

SUMMARY AND CONCLUSIONS

Epidemiological studies have suggested an association between
cigarette smoking and cancer of the pancreas. The significance of
the relationship is not clear at this time.

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320


    CAKCER




APPENDIX TABLES


TABLE A3.-Outline of methods used in retrospective studies of smoking in relation to lung cancer

Author,
yesr,
cou"trY,
reference

Sex of
cases

Number of persons and method of selection

C8StZS                        Controls

Collection of data

Miiller 1939,    M      RF lung cancer decedents       A6 healthy men of the same age          Cases: Questionnaire sent to relatives of de-
Germany                                                                ceased.
(196).                                                               Cqntrols: Not stated.

Schairer and
Schi%iger,
1943,
Germany
(242).

93 cancer decedents autopsied   2iO men aged 53 and 54               Cases: Questionnaire sent to next of kin.
( *ver*ge age 53.9).                                   Controls: Questionnaire sent to 700.

Potter and
Tully,
1945,
U.S.A.
(911).

M      43 male patients wer 40 years of   1,847 patients of same grwp with diagnoses   Cases and controls interviewed in clinics.
       nge.                    other than cancer.

Wassink.
1948,
Nether-
lands
(304).

x      134 male clinic patients with   100 normal men of same age groups *s cases.   Cases: Interviewed in clinic.
       lung cancer.                                            Contrds: Not stated.

Schrek et al.,
1950.
U.S.A.
(24G).

M      82 male lung c*ncer c*ses among   527 I  miscellaneous tumors other than lung,   Smoking habits recorded during routine hos-
      5,003 patients recorded, 1941-    lnrynx, pharynx, or lip.               pita1 interview.
       48.

Mills and
Porter,
1950,
U.S.A.
(186).

M      444 respiratory cancer decedents.   430 sample of residents matched by age in   Cnses: Relatives queried by mail question-
                         Columbus, Ohio, from census tracts strati-    "aire or personal visit.
                            tied by degree of air pollution.           Contruls: House-to-hoose interviews.


TABLE AL--OutZinc of methods tmd in ?`etyospective stndies of smoking in relation to hng CCL~CEI` (cmt.)
                                                                          ~__-~__

Author.
  year.
cou"trv.
reference

Levi* et al.,
1950.
U.S.A.
(169).

Wynder and

M






hl--F

Number of persons and method of selection
                   ____I_

Collection of data

        Cases                        Controls                                      -
236 c~nrer hospitsl patients with   481 patients in same hospital with nonma-   Cases and Controls: Routine clinical history
diagnosed lung cancer.         lignant diagnoses.                  taken before diagnosis.


                                                          1
                                __-.
605 hospital and private lung   780 patients of several hospitals with diag-  Nearly all data by persona1 interview; 8 few

Graham,
1950,
U.S.A.
(SIG).

cancer patients in many cities.    noses other than lung c8"cer.

cases by questionnaire: a few from inti-
mate acquaintances. Some interviews with
knowledge or presumption of diagnosis,
some with none. 595 diagnosed by tissue
examination, nine by sputum, and one bu
pleural fluid examinntjon.

McConnell
et al., 1052,
England,
(J80).

Doll and
Hill,
1952,
Great
Britain
(73).

M.~F






M-F

100 lung cancer patients, un-   200 inpatients of same hospitals, matched by   Personal interviews by the authors of hoth
selected, in 3 hospitals in Liv-    "ge snd sex. without cancer.             cases and controls.
erpool area.                                                              ~-
1,465 patients with lung cancer   1.465 patients in same hospitals, matched by   Personal interviews of cases and controls by
in hospitals of several cities.    sex and age group; some with cancer of    *ll"0*WS.
                     other sites, some without cancer.

Sadowsky
et al.,
1953,
U.S.A.
(232).

M     477 patients with lung cancer   616 patients in smne hospitals with illnesses  Personal questioning by trained interviewers.
       in hospitals in 4 states.        other than cancer.




                                   -


TABLE AZ.-Outline of methods used in I'etrospective studies of smoking in wlatiox to llcng cancer (cont.)

Author,
Ye8r.
countly.
reference

sex of
casea

Number of persons and method of selection     .--____
Cases                                                 Collection of data
                          Controls

Wynder and
Cornfield,
1963,
U.S.A.
(914).

                                                                  __~      ____
M     63 physicians reported in AMA   133 physicians of same group dying of can-   Mail questionnaire to estates of decedents.
      Journal 8s dying of cancer of    ES of certain other sites.
       the lung.

Koulumies,
1953,
Finland
(151).

M--F

                                           _____
812 lung cancer patients diag-   300 male outpatients of samr hospital over  Cases nnd controls questioned about smoking
nosed at one hospital.         40 yerlrs of age.                  habits when taking case histories. 351 di-
                                             w"os~s confirmed histologically; 494 diag-
                                               noses confirmed by clinical. X-ray. and
                                                    o"erative data.

Lickint,
1953.
Gt2l-l"2l"Y
(170).

M-F

                                                 .-__             .___ __~
246 lung cancer patients in a   2,002 sample of persons without cancer liv-   Personal interviews by staff members of co-
number of hospitals and clinics.    ina in the same area and of the swne sex    o~~crating hospitals and clinics.
                     and age range BS cases.

Breslow
et al.,
1964,
U.S.A.
(49).

M-F

                                      ._I -___ ___~            -____
518 lung cancer patients in 11   518 patients admitted to same hospitals about   Crises and controls questioned by trained
California hospitals.         the same time, for conditions other than    interviewers,  enrh matched pair by the
                    cancer or chest disease. matched for raw.    same prrsun.
                     sex. and age grovp.

     -
     Watson and     M-F    301 patients at Memorial Hospi-   468 patients of SIJ~C clinic during smne   The 769 consecutive patients of case and
      conte.             tal with lung csneer.        period with diagnoses other than lung    rontwl proups wrre questioned by the
      1964,                                     cancer.                       anme trained interviewer. Control group
      U.S.A.                                                         includes patients with oral nnd esophageal
       (SOS).                                                                  cilncer and bronchitis.
      -.                                         -.              -__ .___ __-~ ~.
     Gsell,        M     135 men with diagnosis of bron-  135 similar hospital patients with diagnoses   I'wwnnl interviews, all by the same person.
       1954,               chial carcinoma.           other than lung c~"cer, and of the same
       Switzerland                                 age.

E       (107).
      -                                            .______-
VI


TABI E AX.-Outline of ttretllods used in ?etrospcctivc studies of sl)loki)/g in ?-elation to lung cancc)` (cont.)

Author,
Year,
country,
reference

Sex of
enscs

Number of persons and method of selcctinn

C*SeS                        Controls

Collection of detn

Randig.
1054,
Germany
(2f8).

M-F

44X lung cancer patients in a   512 pntients with other diagnoses, matched   Controls were interviewed at about the ssme
"ulnber of West Berlin haspi-    for XK:p.                        time as the crtses, each case-control pair
ta1s.                                               by the same physician.

Wynder et al.,
1956.
U.S.A.
(311).

Segi et al..
1957.
Japan
(f.50).

Mills and
Porter,
1057.
U.S.A.
(187).

F      105 patients with lung cancer in
       several New York City hospi-
       tals.

M-F    207 patients with lung wncer in
       33 hospitals in nil parts of
       the country.

M--F

578 residents of defined areas
dying of respiratom cancer.

1,304 patients at Memorial Center with tu-   Cases: Personal interview or questionnaire
mors of sites other tha" respiratory or    mailed to close relatives or friends.
upper alimentary.                  Controls: Personal interview.

~.(i:~li patients free of cancer in 420 local   Case- and controls by personal interview
health centers,  selected to approximate    using long questionnnirc on occupational
the sex and age distributions of cases.       and medical history nnd living habits.

3.310 rwpuletion sample approximately pro-
portionnl to cases as regards areas of resi-
dence. and 10 years or more in the area.

Cases: From death certificates. hospital rec-
ords, and close relatives or friends.
Controls: Personal home visits or telephone
CZlll.9,  usually interviewing housewife.

Stocks.       M-F
1957,
England
(263).

Schwartz and M
Denoix,
1957.
Fra"Ce
(247).

                         .-
2,356 patients suffering from or   0.362 unselected patients of the same area   Cases: Histories taken at the hospital from
dying with lung cancer within    admitted for conditions other than cancer.    relatives by health visitors.
certain areas.                                        Controls: Personal interview in hospital.

                                                       -
602 patients with bronchopul-   1,204 patients (3 groups) in same hospitals   Personal interviews in t,he hospital; eases
monary cancer in hospitals.      with other c~"cer, with nonmalignant ill-    and controls at about the some time by
                     ness. and accident cases, matched by 888    the same interviewer.
                       gr"Up.


TABLE AX-Outline of methods wed in retrospective studies of smoking in relation to lung cnnccr (cont.)

Author,
yCir.
rountry,
referenre

Sex of
c*ses -

Number of persons and method of selection

CS.SlS.                      Controls

Collection "f data

Haenszel and
Shimkin,
lY58.
U.S.A.
(113).

F      153 lung cancer patients avail-   33Y patients in same hospital and service at   Personal interviews by resident, medical so-
       able ior interview in 29 hos-    same time, next older and next younger    cial worker, or clinic secretary.
       pit&.                   than each case.

Lombard and M
Snegireff,
1959,
U.S.A.
(176).

500 men dying of lung cancer.   4,23X controls in 7 groups including volun-   Personal interviews by trained workers.
microscopically confirmed.      teers, hospital and clinic patients, random
                     population sample, and house-to-house sur-
                      vey samples.

Pernu,
1960,
Finland
(211).
-~
Haenszel
et al.,
1962,
U.S.A.
(112).

MF    1,606 respiratory cancer patients   1,773 cancer-free persons recruited by Parish   Cases: From ease histories or mailed ques-
       in 4 hospitals and from cancer    Sisters of 2 institutes in all parts of the    tionnaires.
       registry.                  rountry.                      Controls: Questionnaires distributed by Par-
                                                           ish Sisters.
                                          -                               ___- -
M      2,191 sample of 10 percent of   31,516 random sample from Current I'OPU-   Cases: Uy mail from certifying physicians
      white male lung cancer deaths    lation Survey.                      and family informants.
       in the U.S.A. in 195X.                                   Clmtrols: Personal interview by census enu-
                                                           mer:,t,,rs.

__
Lancaster.
1962,
Australia
(158).

M      238 hospital patients with lung   476 in 2 groups, 1 with other cancer, 1 with   Personal interviews of both cnws and con-
       cancer.                  some other disease, matched by sex and    trrlle in hospitals.
                             age.

Haenszel and F
Taeuber,
1964.
U.S.A.
(115,.

                                          .-___-~                    .___
749 sample of 10 percent of   RIJXY random sample from Current Popula-   Casts: RY mail from certifying physicians
white female lung cmxer deaths    tion Survey used to estimate population    and family informants.
in the U.S.A. in 1968 and    hnse.                         Controls: Personal interview by CC~SUS enu-
1959.                                                  merntors.



Author,
w?*r,
reference

TABLE A4.-Group characteristics in retrospective studies on lung cancer and tobacco use
                       SM = Smokers.    NS = Nonsmokers.

            Males                                      Females

Cases               Controls                     Cases               Controls
                                                       __
Percent Percent         Percent Percent Re%Y-                                 .__ Relative Comments
                                          Percent  Percent         Percent  Percent   risk

       no"-   heavy          non-          ratio          IlO"-                 non-         ratio
Number                           heavy                     heavy
      smokers smokers' Number                                                   heavy
                       smokers smokers' SM:NS? Number smokers smokers' Number smokers smokers' SM:NS'

                                                                         ____
Miiller,        X6     3.6    66.1      86    16.3    36.0     "5.4     (4)     (1)     (4)      (`)     (`1     1')     . .
1939 (196).

Schairer and
Scbiiniger,
1943 (242).

93

3.2

31.2

270

15.9

9.3

"5.7

(4)

(4)

(4)

(4)

(4)

(4)

. . .  16female
    case* not
    analyzed.

Potter and      43     7.0    30.2    2.804     26.0    23.0     34.1     (4)     (`)     (`)      (4)     (4)     (4)
Tully,
1945 (218).

-__              _______
Wassink.      134     4.3    54.x      100     19.2    19.2     4.7     (0     (`)     (4)      (4)     (4)     (`1     . . .  Percentages
1948 (304).                                                                           estimated
                                                                           from chart.

Schrek et al.,     x2     14.6    18.3     522     23.9     9.2     1.8     (4)     (4)     (4)      (4)     (4)     (`)     . . .
1950 (24G).

                                                             _____
Mills and      444     7.2     _..      430    30.6     . . .     6.7     (4)     (4)     (4)      (4)     (4)     (4)     . . .
Porter,
1950 (186).

Levin et al.,     236     15.8           481     21.7          1.5     (4)     (4)     (4)      (4)     (4)     (4)     . Quantity
1950 (171).                                                                           smoked not
                                                                           considered.

  Wynder and    605     1.3    51.2     780     14.6    19.1    13.0      40    57.5    25.0     552    79.6     1.2    2.9
   Graham.
   1950 (316).
ii
Q


TABLE AL-Group ckamctev?stics in retrospective stzc,dics on lung cancel and tobacco use (cont.)

0                                          SM = Smokers.    NS - Nonsmokers.
  ~-         __~
                              MZllCS                                      FC"lRleS

    Author.           C*.x%               Controls                     Cases               Controls
     Year.                                        - Relative                                       Relative  Comments
   refrrencr         1'cHYnt rrl?cnt         rcrcent  Percent   risk         Percent  PrlTent         Percent Percent   risk
                   ,,c>n-    heavy           non-   heavy    ratio          IlO"-    heavy           Iloll-   heavy   ratio
           N umlwr  srnllhcl,b smokers' Number,  smokers smokers'  SM:NS" Number smokers smokrrs' Number  smokers smokers' SM:NS?
  ~_____      ~... -                           -             -
  nirchnell      93     5.4     3X.5     IRF     6.5    23.2 1.2      7     57.1           14     7X.6     . . .     2.8
   et al.,
   1!,6'2 (180),

25.1

1,357

4.5

13.4 9.4

10X

37.0

11.1

10X

54.6

0.9

2.1  Percentage
    "heavy"
    smokers
    understated.

__--~~   ~__ ___-.        __.
Sndowsky      477     :3.X           615     13.2     .,. 3.9     (1)     (1)     (1)      (1)     (1)     (`1       Gradient
et ill.,                                                                           with amount
1953 (IOS,).                                                                           smoked.
                                                                           _____ ~~~
Wyndrr and     (i :3     4.1     67.6      133    20.6    29.3 36.1     (`)     (9   -(a)      (`)     v )     (4)     
COlVlfit?kl,
,053 (314).

Watson and     265     1.9     71.7     287     9.7     61.6     35.6      36     58.3     2.x      181     32.0     1.1    3.3
Conte,
1954 (305).
-~
(;stdl,        135     0.7     6X.1     135     16.9    14.0    326.8     t')   (1).     (`)      (`1     (1)     (0    
1954 (107).


TABLE A4.-Group characteristics in retrospective stzcrlies on lung cancer and tobacco use (cont.)
                       SM z Smokers.     NS = Nonsmokers.

           Md.3                                     Females

Author.          CCiSC?S               Controls                    Cases               Controls
Year.                    R%ve                                   - Relative   Comments
reference        Percent Percent     Percent pc;t             Percent  Percent         Percent Percent   risk
   2 non-   heavy          non-          ratio   Num- non-    heavy           non-         ratio
            smokers smokers' Number smokers smokers' SM:NF                                 heavy
                                                   ber   smokers smokers' Number  smokers smokers' SM:NS?

Randig,      415     1.2     34.2     381     6.8     17.9     35.1     33    51.5     3.0     131     70.3      0    2.2
1954 (218).

Wynder et al.,  (`)     (4)     (`)      (4)     (4)     (`)      . . .    105    56.2     16.2     1,304     66.0     3.4     1.4
1956 (911).

Segi et al.,    166     .~I     . . .    2,124     .     . . .     ,. .                                      Quantities
1957 (?50).                                                                           smoked stated
                                                                           as averages
                                                                           only. Differences
                                                                           are statistically
                                                                           significant.

Mills and
PlTter,
1957
(187).

434     x.4

26.0

1,588

27.6

5.3

4.2

94

83.0

4.3

1,722

73.3

0.5

0.6  Percent "heavy"
    smokers under-
    stated. Only
    50:; S"1`YLIJ
    response among
    female cLlscs.

Stocks,      2.101     1.9     28.2    6.960     8.7    22.3     4.9    255    57.6     17.2    3,402     68.6     10.7     1.6
1957 (268).

Schwartz and   602     1.0     53.2     1,204     9.6     36.2     10.4    (`1     (4)     (4)      (`)     (1)     (4)
Denoix,
1957 (147).

Haenszel and   (*)     (`)     (6)      (`)     (4)     (4)           15x    51.9     14.6     339     694     8.2     2.6
Shimkin,

E   1968 (113).
d


         TARLE A4.--Group characteristics in mtyospective sfrc.tlics OPL lung camcr and tobacco MC (cont.)
                                       SM = Smokers.     NS = Nonsmokers.

                           M&S                                     FelI%-&S

  Author,          CFXSCS               Controls                    CCiSf3               Controls
   war,                     R&W
reference         Percent Percent         Percent  Percent                                            Relative   Commrnts
                                                         Percent
         Num- non-    heavy                                       Percent
                                       heavy                                 Percent  Percent   risk
                                  non-
          ber                                   ratio               heavy
              smokers smokers'                                 "all-
                           Number                                              non-   heavy   ratio
                               smokers smokers' SM:NS? Number smokers smokers'  Number  smokers smokers' SM:NS'

Lombard and   500     1.6          4,238     11.0          7.9    (4)     (4)     (1)      (J)     (1)
Snegireff,                                                                           (`1     Authors'

1959 (176).                                                                           calculations for
                                                                           heavy smoking
                                                                           based on lifetime
                                                                           number of packs
                                                                           of cigarettes.

PLWlU,      1,477     6.6    34.5     713     37.2    20.8     8.4    129    85.3   26.4-   1,060    91.6 ;    0.7
1960 (211).                                                                           1.9 Quantities
                                                                           given only in
                                                                           grams per day.

Hal?llSZel    2,191     3.4    41.9      (4)     16.2     12.0     6.2 (4)     (1)   (1) - (1)     (4)     (`)     . . Population
et al.,
1962 (212).                                                                           sample of
                                                                           R1.516 used as
                                                                           base. Not a case-
                                                                           control study.

Lancaster,    23x     2.5    86.1     476    20.1     11.2     9.8  (`)T (`1     (4)      (4)     (4)
1962 (158).                                                                           (4)     .


Haenszel and (`)     (4)     (4)      (4)     (4)     (4)      . . .    749    60.9     11.5      (&I     67.3
Taeuber.                                                                           2.5    1.3 Population

1964 (11.5).                                                                           sample of
                                                                           34.33S used
                                                                           88 base. Not
                                                                           a case-control
                                                                           study.


          TAHLE Al.-Grout cltaructeristics in retrospective studies on lung cancw nnd tobacco usr (cwt.)
                                     SM = Smokers.     NS = Nonsmokers.

                         M&S                                     Females

Author.          Cases               controls                    Cases               Co"trols
Ye==,                    *fitiF                                      Relative   Comments
reference        Percent Percent     Percent ?erc;t             Percent  Percent         Percent  percent   risk
   %?- "On-   heavy          non-          ratio         non-    heavy          non-
            smokers smokers' Number smokers smokenl SM:NS Number smokers smokers' Number         heavy   ratio
                                                                        smokers smokers' SM:NS?

Wicken,      803     4.0    40.0     803     14.0    22.0     8.9    151     58.0    29.0     151    80.0     17.0    2.9 Heavy smokers-
1966 (308).                                                                           greater than
                                                                           23 a day.

Gelfand et al.,   32     6.3     . .      32    63.0     . . .    `26.3    (4)     (`)     (`)      (4)     (4)     (1)     .
1968 (98).

                                                              --
Hitosugi.     124     6.6    67.8    1,839     13.2    66.0     2.6     61     54.1     6.6    2,352    80.5     2.9    2.3  Air pollution
1968 (225).                                                                           fou"d to have
                                                                           no effect on
                                                                           lU"Y Cancel
                                                                           rates of non-
                                                                           smokers. Heavy
                                                                           amokers-great-
                                                                           er than 15 a day.

Bradshaw and   45     0.0           341     31.7          . .    (4)     (`1     (`1      (`1     (4)     (4)     . .
Schonland.
1969 (41).

Or"los et al.,    94     7.5    58.5    1,811     42.9     58.9     9.3     24    95.R     0.0    1,278    Xl.7     9.7    0.2  Heavy smokers-
1969 (204).                                                                           greater than
                                                                           15 R day.

Wynder et al..  210     1.4    67.5     420    21.0    40.9    320.8     30     16.7     44.0     132     57.6     23.3    6.18 Heavy
1970 (334).                                                                           sm<,kers-
                                                                           grenter than
                                                                           20 II day.

   ' For this table, heavy smokers are defined BS those smoking 20 or more      3 Based upon fewer than 5 case nonsmokers
ii  cigarettes per day, unless otherwise stated.                         4 Does not apply.
w   `Computed according to method of Cornfield. J. (61).


TABLE A?`.-Grouping of pulmonary carcinomas

Group I:

A. Epidermoid carcinoma.
B. Small cell anaplastic carcinoma ("oat-cell" carcinoma).

Group II:

A. Adenocarcinoma.
B. Bronchiole-alveolar cell carcinoma.
C. Carcinoid tumor.
D. Mucous gland tumor.

Extra (not included in I and II):
  A. Large cell undifferentiated exrcinoma.
  B. Combined epidermoid and adenocarcinoma.

Unsuitable for diagnosis.

SOURCE: Kreyberg, L. (15.3).

334


    TABLE AlB.-Autopsy studies concerning the presence of radioactivity in the lungs of smokers
                                NS = Nonsmokers.    SM = Smokers.

AlIthOt+,
Year.            Number
country.             of                               Results                            Comments
reference            cases

Little et al..
1964,
U.S.A. (175).

NS . . . . . . 5
SM  _. . . . . . . .1!2

       Port0 level.3 in vavioue tisauelr (pclg tissue)            Vertebral bodies, renal
Peribronchia!                              Bronchial      cortex. spleen, and
lymph nodes         Lung (average)           epithelium      urinary bladder showed
  0.011               0.001-2               negligible      no differences.
  0.011               0.008                0.028-1.25

Hill, 1965,
U.S.A. (1%`).

                   Mcaw Pd'o levels in variown tiswrss (pc/kg tissue)            The authors found no
                 Brmchial tree   AlVLdZC    Total lung      Liver      Kidneu      excessive concentrations
NS . . . . . . 6        3.1         3.4        3.2        14.8        15.0       at bronchial bifurca-
SM  . . . . . . . . . . . . 4        7.3         9.9        8.6        20.0        20.5       tions.

Little et al..
1966,
U.S.A. (274).

NS . . . . . . . . 8
SM  . . . . . . .26

P&O levela in variou.4 epithelial tiusw regions of lung (pc/g)t
Site:
Mainstem bronchus  . <O.Z- 1.1
Lobar bronchus  . _, _. t.. . _. <0.2- 1.0
Basal segmental bronchus _. t.. . <O.Z- 2.6
Upper segmental bifurcation  <0.5- 1.8
Lower segmental bifurcation  . . <0.5-13.9

The authors noted con-
sidernble interpersonal
variation but did find a
trend relationship be-
tween increased daily
consumption and in-
creased Pc?O levels in
lung parenchyma. No
such relationship was
noted for age of indi-
vidual at death or for
total pack-years.

t Smokers only.


   TABLE Ale.-Autopsy studies concerning the presence of radioactivity in the lungs of smokers (cont.)
                                NS = Nonsmokers.     SM = Smokers.

Author,
yea=.
country,      N"omPcr                             Results                            Comments
reference            CBSes

Ferri and
Barntta.
1966.
U.S.A. (95).

Rajewsky and
Stahlhofen.
1966.
Germanv (217)

                      Mran Porlo levels in various tissuea (pc/Q wet tissue)
                    LU?lQ               Liver             Kidney
NS  _. . . . . . 10        0.031               0.103               0.080
SM  . . . . . .I4        0.065               0.125               0.070
                                                    ~~ ._~___

NS . . t
SM  . . . . . .I2

     Mean P&o levels in various ttisucs (pc/g)
Lung parenchyma       Bronchial tree     Bronchial bifurcatim
   0.0025             0.0020             0.0012
   0.0078             0.0017             0.0047

t Data not given. Smokers
were considered those
using more than 1 pack
a day.

The authors noted that
their figures were con-
siderably smaller than
those of Little et al.
(173, 174) and also
disagreed with their
data on bifurcation.

Little and
Radford.
1967.
U.S.A. (17~).

SM  . .26


Pipe  . . . . . . . 2
Ex-cigarette  . . . . . . 1
Never  . . . . . . . 8

  Mean Po*`o levels in variozls cpithelial tissues (pclg wet tisare)
Bronchial wnll and suhmucosa . . . . 0.004
Bronchial epithelium:
Trachea  _. . . . . . . . . . . 0.120
Lobar bronchi _. . _. _. . . . . . . . . . 0.190
Segmental bifurcation  _. . . . , . . . . . . . 4.600


   TABLE A13.-Experiments concerning the effects of the skin painting or
subcutaneous injection of cigarette smoke condensate or its constituents upon animals

Author.
Year.
country,
reference

Animal
and
strain

A. Method,
B. Frequency and/
   or duration,
C. Material

Results                            Comments

Wynder
et al.,
1963.
U.S.A.
(317).

CAFl mice  A. Painting shaved skin.                       Pcrccnt animals with:                 t Number in paren-
       B. 3/week for 2 years.     Treatment:                        Papillonast      cancert   thesis represents
        C. Whole cigarette smoke     "Tar" alone   _.     59.0(81)       44.0 (81)   total in that
           condensate in acetone.   "Tar" and croton oil     42.0(31)        9.7 (31)   experimental group.
           Croton oil once/week.    Acetone alone . _. . . .        (30)        (30) Skin-painting
                          Acetone and croton oil       (14)         (14)   experiments prior
                                                                           to 1953 are fully
                                                                           detailed in tab-
                                                                           ular form in this
                                                                           article.

Passer      5 different   A. Painting unshaven     No malignant tumore noted in either grou".

et al.,
1956,
England
(200).

l"O"Se
strains
(101).

   skin.
B. B/week for 9
   months.
C. Whole "tar" or
   neutral fraction.

Papilloma noted on one animal (in whole "tar" group) which later regressed.

Orr et al.,
1955,
England
(205).

Mice of 2                                    -~
        A. Painting skin.                                     Nwmber animals with:
strsins.   B. 1 or P/week for        Treatment:             I'ajJillo?rl"s
           1X months.        Benzpyrene l/week followed 4/50 at 18 months (separate group received only
       C. 20 percent cigarette       by "tar" Z/week.        benz~yrrnr and showed no tumors).
           "tar" in acetone.       "Tar" alone _, _. _. .  O/50 at 1X months.
           0.3 percent
           henzpyrenc.


     TABLE A13.-Experiments concerning the effects of the skin painting OT
subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.)

Author.
war.
country,
reference

Animal
and
strain

A. Method,
B. Frequency and/
   or duration.
C. Material

Results                            C0lllIlleIlt8

Wynder
et al.,
1966,
U.S.A.
(818).

Mice of 4    A. Painting shaved skin.       Strain                       P~pilZOVW8    Ca&nomaa      No tumors noted with
separate   B. B/week for 80 days.        C5lBL . . . .    lo/89        Z/89         acetone alone.
strains.   C. Whole condensate         Swiss . . .    22/86        12/86        stresses
           in acetone.                                                              differences in
                                                                          susceptibility of
                                                                           strain.

Hamer and   Outbred     A Pninting unqhnved               Treatment:               PCZpillomil4
Woodhouse,   albino        skin.                  "Tar" B/week     l/60
1956,       strain    B. Varied for 18 months.         "Tar" and eroton oil l/week. .     z/30
U.S.A.      mice.     C. Whole "tar"/acetone,         B(a) P 3 times then "tar" P/week     4/30
(116).                benzpyrene [B(a)Pl.        B(a)P 3 times .._..._.............     o/30
                    croton oil.

Sugiura,     Rockland    A. Painting unshaved                  Papillomas    Carcinoma8
1956.       Swiss        skin.                            16/44        12/44    (onb 44/60
U.S.A.      albino    B. 3/week for 2 yeare.                                     lived from
(166).      mice (60).  C. Whole "tar".                                      365-696 days).

Graham
et al.,
1957,
U.S.A.
(201).

Albino New  A. Painting shaved skin.       Treatment:                     PapiUomas    Carcinoma*      The authors review
Zealand   B. S/week for 6 years.         Condensate    41/41        5/41         previous experiments
rabbits.   C. Whole condensate.          Condensate and eroton oil l/week.      lO/lO        z/10         with rabbits in
                              Croton oil and acetone l/week.         o/3        O/3          tabular form.
                             Acetone l/week .     O/7         O/7

Guerin and
Cuzin,
1957,
U.S.A.
(109).

Mice     A. Painting Aeck skin.     Original number            Survivoss      Papi&mae      Sarcomas t Control group.
(Pasteur  B. Z/week for >l year.      tc. 112      51          O/61          O/61    f Experimental group.
strain.)   C. Whole condensate.       SE. 672  . . .   220          10/220         6/220


                TABLE AIS.-Experiments concerning the efects of the skin painting or
          subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cont.)

     Author,  A%Y'   A. Method,
      year.           B. Frequency and/
     country,     strain       or duration.                               Results                            Comments
     reference           C. Material

   Wynder     Swiss mice   A. Painting skin.                                          Percent      Percent
    et al..              B. Varied for 12         Treatment:                 Number      papillomw    carcinomas
    1967,                 months.            S/week  ..,................     60          12.0          8.0
    U.S.A.             C. Whole condensate       B/week  . . . . . .     50          38.0          16.0
     (828).                in acetone.          Z/week  . . . . . . . .     40          10.0          3.0
                                        l/week  . .     40          6.0          .

   Wynder and  CAFl or    A. Painting shaved skin.                                      Percent      Percent   Swiss mice noted
    Wright,     Swiss    B. S/week for lifespan.   Treatment CAFI:             Number      papillomaa    carcino7naa   to be more smt-
    1951,       mice.     C. Whole "tar" or nicotine    Whole "tar"  . . . . . . .     30          53.0         27.0     ceptible.
    U.S.A.                free "tar" derived      Nicotine free "tar" .     40          13.0         26.0   Majority of carcino-
    (S28).               from pipe and        Cigarette "tar"  .     30          30.0          30.0    gem noted to be
                      cigarette tobacco.        Pipe "tar"  .__.._.........     30          60.0         20.0     in neutral fraction
                                      Treatment Swiss:                                           of condensate.
                                        Whole "tar"       30          53.0          10.0
                                        Nicotine free "tar" .     40          43.0         20.0
                                    Cigarette "tar"  .     30         63.0         33.0
                                     Pipe "tar"  . .     30          63.0         60.0

   Gellhorn,     Paris R III  A. Painting shaved skin.        Treatment:                    Popillumalr   Carcinomas
    1958,       mice     B. Varied for l-2 years.         Benzpyrene (twice only)    20/529        6/629
    U.S.A.            C. "Tar" in acetone.          Croton oil (5/6 week)     4/26        O/26
    (99).                 benzpyrene.             "Tar" (5/6 week)  .     3/659        Z/559
                        eroton oil.             Acetone (E/6 week)       o/30        o/30
                                       "Tar" and croton oil (5/6 week)    10/175        O/176

   Bock and     Swiss      A. Painting skin.                                                 Percent
    Moore,      female    B. S/week for lifespan.    Group:              Number living at 6 mo?tths  Skin tumors at 64 weeks
    1959.       mice     C. Whole condensate       Painted  . . .       49               13.0
    U.S.A.                irradiation.         Painted and irradiated         65               44.0
    (28).                                 Irradiated  . . . . . . .       36               . . .
3


             TABLE A13.-Erpwimnts concerning the effects of the skin painting or
        subcutaneous injection of cigarette smoke condensate or its comtituents u~)ot~ nni),lrrls (uIw~.)

  Author,     Animal    A. Method.
  Year.      and    a. Frequency and/
  country.     strain       or duration,                               Results
reference           C. Material                                                                  Comments


Druekrey,    Rats       A. Subcutaneous              G70up:
1961,                                                                Sarcowm.3              t Control group.
                     inlectiu".                tc  . . . . . . . . .     l/75
GW"l?2"Y            13. l/week for 60 weeks.                                                    i Expeumental group.
                                     $E ..._........_..._............,,,    15/75
(7.9).              C. Smoke condensate in
                     trirauwli" nnd
                     alcohol.

Bock et al.,   ICR Swiss   A. PRintins shaved skin.                                                            -
                                                        Sllr?~iz~illg      Pcrcc n t      Z'urcnt Sl;iu
1962,       mice     R. IO/week for 1 year.     Trcutment:                nt 1x WCT/,~S     Skin Cnnccr
U.S.A.                                                                          neoplasia
                 (`. Ciwrette "tar".        Standard ciaarette      24/30
(Sl).                                                                   25.0          54.0
                                   Standard cigsrette     21i30          5.0          57.0
                                   Stnndard cigercttc      18130          33.0          44.0
                                  Standnrd cigarette      13'30          23.0          62.0
                                  Filter cigarette     30/30          7.0          27.0
                                   Filter cigarette     30130          3.0          23.0
                                    Acetcme only       fin/fit?          
                                    Control                               . . .
                                                          65/65                    

Roe,       Albino mice  A. Painting shaved skin.    Trer.tment:
1962.                                                         Sur~iwws       Pcrccnt skin twnors
                 H. S/week for 84 weeks.                                                        Author concluded
                                "Tar"a"d0.025mg.B~o~P .._.      26
1J.S.A.                                                                         12.0
                 C. Whole smoke "tar"                                                         that cigarette
                                "Tar"and0.06mg.B(a)P        15
(225).                                                                         27.0         smoke contains
                     with added B(a)P     "Tar" and 0.25 mg. B(a)P        15               13.0         cocarcinogens.
                     in acetone.         "Tar" and 1.25 mg. B(a) P        14               64.0
                                B(a)P 1.25 mg. ,. _.      14               

Druekrey and Rats       A. Subcutaneous              Treatment (BP mg.:wecli):
Schildbach.                                                              Snrconln.9
                    injection.                  30  
1963.                                                                   s/30
                Il. l/week for 700 days.             10  
Ger"L_"Y                                                                 14140
                C. Benzpyrene in
(82).                                         3         X/60
                    trirapwlin.                 - (solvent)  ,. ,, ,. ,,     Z/75


Author,
yeal-9
country,
reference

      TABLE Al3.-Ezperinwnts concerning th effects of the skin painting OT
  subcutaneous injectiorr of cigarette smoke condensate or its constitzen,ts upon, animals (co~f.)
                                        ~___ ..__~~

Animal   A. Method,

ana    13. Frenuency and/
strain       or duration,
       C. Material                                  Results

Comments

                                     __-
Hornburger  CAFl mice  A. Painting shaved skin.                           CO"l,h2Ll~      Percent
et al.,             B. Z-3/week for 2 years.    Condensate:                autopaiea      Papillomaa
1963.              C. Various tobacco        Pipe tobacco       77          35.0

U.S.A.
(131).

cOndensates in
acetone.

Cigar tobacco     x4
Cigarette tobncco     x2
Benzpyrene       54
Acetone only _.     62

27.5
27.0
10.0

Bock et al.,
1965,
U.S.A.
(29).

Swiss ICR   A. Painting clipped skin.
mice     B. lo/week for 11 weeks.
        C. Various smoke
           condensates in
           acetone.

Percent concentration of ta,
  (type cigsrette) :
8.2 (standard)    
8.3 (standard)  
7.9 (English standnrd)
8.7 (king)  
4.0 (filter)  ,..
4.4 (filter)  
2.5 (filter)  
Acetone control  
untreated cOntlol  

Z'wrcnt
szcr7,ivitz.u
1 I zrr~cka
!)(i.O
!)3.0
90.0
100.0
9X.0
100.0
97.0
94.0
100.0

. .

Pcrwnt
CLl?LC-<`?
30.0
27.0
24.0
28.0
9.0
10.0
4.0

          ____
Pwccnt
Carcinomas
  15.0
  16.0
   15.0
  20.0

Prrcent
cancer ana
papillama
  67.0
  67.0
  58.0
  69.0
  36.0
  41.0
  16.0

                           .___                      ____.___
   Van Duuren   Swiss ICR/                                                                           ___.
                   A. Painting shaved ski".
    et al..                                                    Cumulative ?~wnbcr of mice: roith  t 7.12-dimethyl-
             Ha mice   B. Initiating agent once-   Initiator Promotor                     Par~illoma.9    Carcinomas
    1966.                                                                           benz ( B ) anthraccne.
                        Promoter 3/week for   DMBA .Ether tobacc,) leaf ,`strnet     4120
    U.S.A.                                                                           o/20
                        12-14 months.      0 . .Ether tobncco leaf wtrxt  _.     o/20
     (296).                                                                           O/20
                   C. DMBAt. tobacco       DMBA  .Choloroform tubacro leaf extract     l/20        O/20
                      extracts riga-      0 . .Choloroform tobnrw lenf extract _     o/20        o/20
                        rette "bd'.        DMBA Cigarette "tar"         11120        4/20
                                0 . .Ciunrctte "tnr"     O/20        o/20
                                      0 . . .Awtone  
E                                                               o/20        o/20
   ~ ~~~~___      .I__.__~~       ~-~. __- ~~                ~___~~ _-__


     TABLE AlS.-Experiments concerning the effects of the skin painting or
subcutaucous injection of cigarette smoke condensate or its constituents upon animals (cont.)

Author,
yeal'.
country.
reference

Animal
and
strain

A. Method
l3. Frequency and/
   or duration.
C. Material

Results                             C0ltlllleTlts

Munoz et al . .  Swiss ICR/  A. Painting shaved skin.    Dark tobacco "tat"
1968.       48 mire   B. Varied.             4.0 percent  .................
U.S.A.             C. "Tar" from dark        8.0 percent  .................
and                  (Colombian ) and     Light tobacco tar:
Colombia              light (U.S.A.)        4.0 percent  .................
(197).                tobaccos.           8.0 percent  .................
                                  Acetone  ..................... I

At risk        TUWUJKi
81           SO
71           46


95          26
98           64
91           0

Carcinomas The authors noted
   17     a shortened latent
   16     period for dark
         tobacc".
    6
   20
    0

Davies and
Day.
1969.
Great
Britain
(65).

Albino
mice

A. Painting shaved skin.
IS. Varied regimen.
C. Cigarette and
   cigar condensate.

       Percent of carcinoma-bearing animals at 116 weeks           The authors concluded
    Tmatmcnt:           (actual number of animnln in parentheses)      that the lack of
                  300 mg.     1.50 n&g.      75 mg.    37.5 mg.   difference in re-
Standard cigarette . . . 20.1(29)     13.2(19)     0.7 (1)           sulta from the first
Cigar           27.1(39)     11.1(16)     2.1(3)    and third groups
Cigar tobacco cigarette           13.9(10)        .      under treatment
                                                  suggests that the
                                                   increased tumori-
                                                  g&city of cigar
                                                   tobacco is due to
                                                physical processing
                                                   tsctors.


TABLE A14.-Experiments concerning the effect of cigarette smoke or its constituents on tissue and organ cultures

Author,
Ye*=,
country,
reference

Tissue or
org*n culture

Material/delivery                           Results

Bouchard
and May.
1960,
France (35).

Mouse lung.

Tobacco smoke condensate
perfusion for 24 hours
and subsequent
grafting under renal
capsule of mice.

Increased number of mitotic abnormalities in the treated cultures: particularly in
the first 5-10 days after grafting.

Awa et al..
1961,
Japan (16).

Human fetal lung.

Direct exposure to

smoke from:
a. Whole cigarettes.
b. Tobacco alone.
c. Paper alone.

Paper smoke induced the most severe changes, consisting of cytoplasmic vacu-
olization and nuclear pyknosis. Also noted were a decrease in the mitotic index
and an increase in abnormal divisions, more so with paper smoke than with
the other two.

Thayer and
Ke"Sler,
1964,
U.S.A. (275).

KR mammalian
tumor cells.

Cigarette smoke
condensate applica-
tion; filtered and
unfiltered
cigareftes.

Significant growth inhibition was shown in unfiltered smoke. Cytotoxic compo-
nents were noted in hoth the gas and particulate phases.

Berwald and
Sachs,
1965.
Israel ( 1" )

SWR mice and
golden hamster
embryos.

Direct application of
benzo(a)pyrene
IB(a)PI.

Benzo(a) pyrene caused increased cell transformation as manifested by:
a. Hereditary random growth pattern.
b. Progressive growth as tumors after subcutaneous injection into adults.
c. Ability to grow continuously in culture.

Cracker et al.,
1965,
U.S.A. (63).

Diamond.
1965.
U.S.A. (68).

Suckling rat
trachea in
orgnn culture.

Variuus con-
tinuous cell
strains
(mammalian).

Application of
B(a) P in acetone.



Application of
II (a) P in either
dimethylsulfoxide
(DMSOI or paraffin.

Treated cultures revealed cellular metaplasia.  basal cell hyperplasia. increased
mitotic rate, and increased H"-thymidine incorporation proportional to the con-
centration of material and duration of application.

Inhibition of cell growth.


TABLE A14.--Ercprri)tlents concerning the effect of cigarette smoke OT its constituents on tissue and organ cultures (cont.)

Author,
year.
CXJ""tl-Y,
refercnw

Material/delivery                           Results

Il,,renfreund et al.,   Hamster lung       Application of        a. increased appearance of new small chromosomes and telocentric chromosomes.
1%x,           tissue.           B(a) I' in either       b. Increased ability to grow in hamster cheek pouch and there become spindle-
U.S.A. (89).                     DMSO or dimethyl-          cell sarcomas.
                            fc~rmamide.

Chickerl embryo

~.
Application of

                               .-.~__
Increased mitotic activity and increased incidence of anomalous mitoses.

1:1(x.           muxular          tobar?,, extract.
F'wlnre (110).      explants.

Lxhnitzki.        Mice nronatnl      Application of a hy-      a. Increased basal cell hyperplasia and pleomorphism of newly formed cells.
l!KX.           t, achra.          drocarbun-enriched      b. Increased epithelial mitosis.
EnKland (160).                   fraction of whole
                            smoke cundensate.

I,us"itzki,        Human fetal lung     Application of a hy-     a. Cellular enlargement and promotion of growth of new bronchi.
196x,           in organ culture.     dmcarbon-enriched     b. Increased mitoses, bronchial epithelial hyperplasia. and 8c1uamous metaplasia.
E"gla"d (161)                   fraction of whole       c. Inhibition of stromal growth.
                            smoke condensate.                                                         -
                 -
Char, et al.,       Muuse lung        Application of          a. Cellular disorganization.
I!l6!l.           burl embryonic      B(nlP in DMSO.      b. Cellular pyknosis: nuclear shape and size irregularities.
U.S.A. (54).      cultures.                    c. Increased epithelial mitotic rate and decreased mesenchymal mitotic rate in
                                  those cultures exposed to B(a) P versus those exposed to pyrene or DMSO.

Leurhter,bergel     Mouse lung        Exposure to fresh smoke:
and            and kidney         a. Unfiltered.        a. Decreased RNA production, pyknosis, and death of cells.
Leuchtenberger,    tissue and         b. Activated         b. Similar results, hut changes were of minimal severity.
l!f68.           t3I'&?an cultures.         charcoal filter.
Switzerland (165).                c. Cigarette or        c. Similar effects as group a., but less swerc.
                              cigar tobacco.
__-


TABLE Al4.--Ezf,c,rit,crt/ts cowcerning the effect of cigarette ,ytttol<(' 01' its constit/(ents 0~1 tissue and organ cf(ltures (cont.)
                   __~         ~~..____               ~_____~__-~~~
    Author,                                                                          ______-

     YCBI`,          Tissue OP
    country.        urgan culture        Mntcrial/delivery
   reference                                                             Hr5ults
~-__~
Cracker,        Various organ                                  ~__~  __~ --
                           Ayplirntion of                                     ___~ -__
                             Squamous metnplasia: frwuent pleumuuphic cells: dedifferentiation of epithelium
1910.           cultures:          I%(n)P in scrutn.        (inhibited by Vitamin A).
U.S.A. C/X?),       a. Wholr suck-
                 lina hamster
                 tracheas.
              1). Whole brvn-
                 rhinl tubes
                 from late
                fetal doas
                and monkeys.
                           ~__~         ~--__~ ~ ---~ ~._~~~    ~ ..--~ ~.         -~__


L
v.

Author.
  war,
countlY.
reference
-__
Blacklock.
1051.
GlY*t
Britain
124).

-

Della Porta
et al..
195X,
U.S.A.
(67).

TABLE A15.--Ezpm-iments concerning the effect of the instillation or implantation of
cigarcttc> smoke or its constituents into the tracheobronchial tree of animals

   Animal
    and
   strain

CR white
rats.

A. Method
B. Frequency and/
   or duration                                Results
C. Material                                                              .-
A. Injection into      4.46bcnzpyrene:                     Number with tumors/number czposed
   lung parenchyms    a. 3 mg. in olive oil                   5/6 **rconl*.
   by thol.ncotomy.     b. :: mg. in olive oil with dead Tb bacilli      Z/4 sarcoma. 4/8 squamous cell carcinoma.
I{. once.           c. 5.75 mg. in cholesterol pellet           l/R squamous cell carcinoma.
(`. 3.4~ber,zp.vrene     Cigarette "tar":
   in olive oil,        a. In olive oil                      O/10.
   with dead Tb      b. In olive oil with dead Tb bacilli          l/X sarroma. l/R squamous cell carcinoma.
   bacilli or in      Controls:
   cholesterol.        a. 0.15 cc. olive oil                   o/4.
   cipnrette "tar".     b  0.15 cc. olive oil with dead Tb bacilli        n/4
                c. Cholesterol pellets                  o/4.
                      -

Syrian golden
hamsters.

A. Direct tracheal
   instilllation.
B. Weekly up to
   45 weeks.
C. 1 percent 7,12-dime-
   thylbenz(a)anthra-
   cene (DMBA).
   cigarette "tar"
   roncmtrate.

Mate&l:
a. DMBA 50 pg./week
b. "Tar" 200 pg./week  
c. DMBA 50 ,*g./week  
   then "tar" 200.

WFEka
45
32
12

  ,& week
d. DMBA 100 fig./week
e. DMBA 100 pg.lweek   1
  and "t.al." 500     \
pg./week )

30
17

20

Survivors at 20
twskslosiginal
number exposed
    10/20
    11/21
    9/20

l/20

9/20

Number of
hamsters with
tracheobrmwhial
carcinomas
  at death
     2

4

3

Rigdon.
1060.
U.S.A.
(221).

White Pekin    A. Intrntrarheal     No neoplastic changes noted in either the experimental or control groups.
ducks.          injection.
Controls: 99    B. Daily for 721 days.
Experimental    C. Tobncro condensate
group: 52       in liquid p&r&turn.


TABLE A15.-Experiments concerning the effect of the instillation or implantation of
cigarette smoke or its constituents into the tracheobronchial tree of animals (cont.)

  Author,              A. Method
  Year.              B. Frequency and/
country,   A:iIT'       or duration                                Results
reference      strain     C. Material                             ___.
Blacklock.   CB white rats.   A. Inoculation at                                       Number         Percent with
1961,                   thoracotomy.                                     of rats       malignant tumo+e
Great                B. Once and sacrificed   C""tr"ls  . . . . ~. . . . . . ~.        276     1.5 (1 carcinoma, 3 sarcomas)
Britain                  at 1 week-2 years.  Cigarette condensate _. _. .        72    11.1 (6 carcinomas. 2 sarcomas).
(15).                C. Cigarette tobacco    Eucerin alone  _. _,        44     2.3 (1 sarcoma).
                       smoke condensate
                       rn eucerin.

Herrold and  Syrian golden    A. Intratracheal                       Number of      Number with        Number of tracheo-
Dunham,    hamsters.        inoculation.      Material:             hameters       tumors           bronchial tumors
1962,                B. 0.5 ct./week for      B(a) in TweenGO        6           3         5 (3 pspillomas, 2 carcinomas).
U.S.A.                   5/6 months.       B(a)P in TweenFO'         6           3         9 (4 pspillomas, 5 carcinomas).
(121,.               c. Benz0 (a) pyrene      Tween60         6           0
                       I" Tween60       B(a) P in olive oil          6           0
                       or olive oil.        Olive oil  _.        6           0

Rockw et al.. Doas.

1962,
U.S.A.
(azr).

A. Bronchial inoculation
   0~' stimulation.
B. 3-5 times/week
   for rr* to 5
   years.
c. Cigarette smoke
   condensate.

Sqlcamous

                                       P7C-      metapluaia
           Number     Invasive    Carcinoma- enneeroua   with atypical   lnflam-
Procedure:      of dog.9 carcinoma     ii1 sit76     changes     changea     mation
Controls   27                                    6         24
Manipulation of
  bronchus     25        -        -                  7         26
Smoke condensate 130         1         3        25        98        128

            ____. ______ __-
     Tipton and   Mongrel dogs.    A. Bronchial
      Crockw,   Control proup and    inoculation.
       1964,      experimental   B. Daily for 8 days.
      U.S.A.     Kl`OllP--19.    C. Cigarette smoke
       (177).                   condensate.
iz     _____ ._I_ .-____-

Y

Rapid induction of swamous metaplasia in condensate-exposed animals. No tabular
data is presented.


TABLE A15.-Experiments concerning the eflect of the instillation or implantation of
cigarette smoke or its constituents into the tracl~eobronchial tree of animals (cont.)

Author,
year,
country,
reference

Animal
and
strain

A. Method
B. Frequency and/
   or duration
C. Material

Results

Saffiotti et al., Syrian golden
1966,       hamsters.
1J.S.A.
(237).

A. Intratracheal
   inoculation.
B. Weekly for 15 weeks.
C. B(a)P (3mg.j
   attarhed to fine
   hematite dust.

Number autopsied:

Male 23
Female _. _.  17

          Percent tumor-
Nwmber of     bearing of
tmnor-bearing   auruivors at
  animal8      15 zoecks
   15          100.0
   11          100.0

Total     Total number
nscmbcr    of rcspiratorv
of turnore   tract ca?wPT*
24          18
17          16

Kuschner,
1968.
U.S.A.
(1.57).

Hamsters

A. Wire mesh pellet
   implantation
   into bronchus.
B. Lifetime.
c. B(a)P.
   methylrholan-
   thwnr (MCA).

                           Number of
                            surrivors/original
Implant:                        number in group
Wire mesh only _. __ __ _. _. _. _.      34135
MCA        RR/91
D(a)P         x9/91

Number of
animals with
lung canecr
  --
  43
  57

Saffiotti et al., Syrian golden
196X.       hamsters.
U.S.A.
(235).






Borisyuk,    Wistnr rats.
1969,
Russia
(J4).

A. Intratracheal
   inoculation.
B. Weekly for 15
   weeks.
C. B(a) I' attached
   to a fine
   hrmatite dust.

A. Intratrarheal
   intubation.
B. Monthly up to
   IO months.
C. Cigarette "tar".

                                              Number of
                                              hamster8 with
                           Number alctopaied         respiratory
Inoculate:                                          tract tumor.3
Control          176
B(a)P in hematite          55             36
Hematite only  _. _. _.        41

                           Number final/         Dumtiou of
                                initial            inocz&tion
Inoculate:                                          (months)
Controls          11/20      12
Unfractionated "tar"        24/200     10
Denicotinized "tar"        9/45      R (l/9 metaplasia)
Neutral "tar" fraction        14/100     8 (Z/14 carcinomas,
                                           l/14 papillary adenoma).


             TABLE Al&-ll'xperiments concerning the eflect of the inhalntion of cigarette smoke
                  or its constituents upon the respiratory tract of animals
                        (Figures in parentheses represent total number survivors in specific group)
          -                                       -~-~__~~
   Author,
    war.     At%='     A. Type of exposure
   c0untl-Y.                B. Duration                           Hesults
  reference        strain     C. Material                                                       Comments


Lorenz et al..    Strain A mice:    A. Chamber.                                                         -~

1943,                                    E. No increase in tumor formation over that noted in controls.This strain of mice does
            tc. 97.       R. Up to 693 hours.
U.S.A. (177).                                                                        have a hereditnw
            IE. 97.       C. Cigarette smoke.                                              tendency t<, tumol
                                                                           formntion.
                                                                           tc'. C<rntr~~I.
                                                                           jE. Espwimcntnl.
___~~ .__~~.
Essenbera.      Strain A mice:    A. Chamber.         Percent of lmg tremors                           No epidevmoid cnnrer
1952.         c. 32.        B. 12 hours per day     c. 59.4(29)                                   noted. papillsry
U.S.A. (!!a).     E. 36.           for 1 yerir.        E. 91.3(15)                                   ndenorarcinomn wxs
                      C. Cigarette smoke.                                              most common.
                                                                           i'crcentage diffcwnw
                                                                           is sirnificant at
                                                                           II 0.01 h4.

Miihlbock,      Hybrid (020 x     A. Chamber.         Pemcut with nlz~colrlr mrcirlomnn
1955,                                                                           No other type of
            DBA) mice:    B. 2 hours per day for    c. 31.0                                     lung tum<>rs were
Netherlands     c. 32.           up to 684 days.     E. 79.0                                     found.
(295).        E. 29.        C. Cigarette smoke.
-
Leuchtenberaer  CF, albino mice:   A. Chamber.         23 of tkc espr~imcntnl mice showrd:
et rd.,         C. snd E. 275.   B. To 8 cinarettes        15 basal cell hyperplasin.
1958.                       per day from        14 atypical bnsnl cell byperplasiu.
U.S.A. (166).                 11-201 days.         7 dynplnsia.
                       C. Cigarette smoke.       2 squamous cell metnplasia.
                             .~
Cuerin,                                                          .__
           IC and Wistar     A. Chamber.          Pmwutrrgc of rats with t~trlmo~rr~rti tamom
1969.          strain rats.    B. 45 minlltes         C. 2.4 percent of :(!I survivors.
Frence (loa).    c. 40.           per day from      E. 5.1 yercent of 68 survivors.
            Ix. 100.          Z-6 months.
                       C. Cigarette smoke.               ~. -___.__ -~~ -~


TABLE AlG.-Experiments concerning the eflect of the inhalation of cigarette smoke
    or its constituents upon the respiratory tract of animals (cont.)
       (Figures in parentheses represent total number survivors in specific group)

Author,
Year.
country,
reference

Animal     A. Type of exposure
and      B. Duration
strain     C. Material

Results                        Comments

Leuchtenberger  Female CFI mice:  A. Chamber.
et. al..        c. 243.       B. 54-G cigarettes
1960.         E. 360.          per day for 1
U.S.A. (167).                  month to 2 years.    Namber
                      C. Cigarette smoke.      of mice
                                        151  
                                        150  
                                         36 __....
                                         36  . . .
                                         34 ,.....
                                         51  . . .
                                         63 __....

Number of
cigaseltes
25-1.626
     0
loo- 200
25& 500
600-1.600
loo- 400
IO& 400

Ezposwc
length
(months )
  1-23
    0
  l- 3
  4- 8
  9-23
  3- 6
  3- 6

Number with
wvcfe bronchitis;
pcribronchilis;
atypical &the-
lial prolifcrntion
    30
     2
     7
     7
     8
     4
    17

Leuehtenberger  Female CFI mice:  A. Chamber.          Number                     Pcrcsnt of mice     Presence of tumors
et al..        c. 166.       B. l/+3 cigarettes       of mice            Ezpomre    with pulmom+y      showed an age.
1960,         E. 231.          per day for        examined            ( daua I    adenomatous tumom     relationship
U.S.A. (168).                  17-600 days.        81        0        66          independent of
                       C. Cigarette smoke.       39     17- 99        41          smoking exposure.
                                        35  ,  100-199        37
                                        61  _. _. . . ,  20&600        66

Otto. 1963,
Ger"la"Y
(206).

Albino mice.
C. 60.
E. 169.

A. Chamber.
B. Approximately
   12 cigarettes per
  day for varying
   intervals.
C. Ciaarette smoke.

Number
of mice
examined
C. 60
E. 189

Ew~osrre       Number with
NO"&         lung tulnorr
Varying    3 pulmonary adenomas.
upto   21 pulmonary adenomas.
months.    2 epithelisl carcinomas.


TABLE A16.-Experiments concerning the effect of the inhalation of cigarette smoke
    or its constituents upon the respiratory tract of animals (cont.)
      (Figures in parentheses represent total number survivors in specific group)

Author,
war.
country,
reference

Animal     A. Type of exposure
and      B. Duration
strain     C. Material

Results

Dontenwill and   Golden hamsters.   A. Chamber.         Number of          D&l
Wiebecke,      c. -        B. Up to 4 cigarettes     animals            average
1966.         E. 320           per day for up      dead at           ezpomre
Germany                     to 2 years.        640 dags          (cigaretlea)
(77).                   C. Cigarette smoke.        40  . . . . . . . . . . . . . .      1
                                          40  . . . . . . . . . . . . . .      2
                                          80  . .    l-2

143  . . . . . . . . . . .._ .    l-4

Comments

              MET des = desquams-
    Histologic      tive metaplasia.
    findings in     MET branch = bron-
    dead animals     chial papillary
8/ 40 MET des       metaplasia.
S/ 40 MET des       PAP tracb = tracheal
44/ RO MET des (3 MET   papillomat* or
branch. 2 PAP trseh)    intense tracheal
67/143 MET des (13 MET  metaplasia.
branch. 8 PAP trach)

Leuchtenberger  CF, mice.       A. Chamber.
and                    B. Up to 1,000 hours.
Leuchten-                C. Cigarette smoke,              Marked sguanous
berger 1966,                   exposure to in-              cell metaplasia
Switzerland                   fluenza virus                  (percent)
(1.54).                      (PRR).         Controls (100) :
                                         Male
                                         Female

Smoke exposed (59) :
  Male
  Female
Virus exposed (59) :
  Malt   11.0
  Female    -
Smoke and
virus exposed (88) :
  Male    9.0
  Female   29.0

Marked
dgsplaaia
(percent f

6.0

21.0
-

43.0
54.0

Marked
tmnsgression
of lung
parolchyma
(percent)

3.0

13.0
5.0

t1tJ.o
t33.0

tEpithelia1 tissues
of these animals
showed an increased
frequency of cellular
atypism. The
authors concluded
that PRB influenza
virus may act as a
cofactor in malig-
nant transformation.


  TARLE A16.--Ezpo`iments concerning the effect of t//t, inldntion of cigarette smoke
       0~ its constituents upon the respiratory fvxct of animals (cont.)
         (Figures in parentheses represent total number survivors in srxcific group)
-~___~~

Animal     A. Type of exposure
and      13. I)ur*tion                           Results                        Comments

   Author,
    war.
   countrv.
  reference       strain

Kockey and     Mongrel dogs:
SPCW,        c. 11.
1966.         E. l!l.
U.S.A. (CBY).









~-~-----~
Aucrbnch      Heagle dogs:

C. Material

.\. Trnrhral fenestra-                          Sqlcamous             tCarcinom* in situ
   tisl" (IO).                     Hyprrplnsin metapln-              noted in 5 seppnrate
  N<l\tril inhal;)-                       with    &a with   PT&    Cnrci-  sites in this
   lion (9).                  Inpam- atyliical   atypical cancerous nLJma   animal.
II. Tracheal fenestra-               mation fcntarcs   features   chnn.wn   in aita
   tion-2R4 trrat-     C"nLro!s (II) 9      1       1      0      0
   ment days.        Tracheal
Nostril inhnlation-     fencstra-
   1x0 treatment       tion (JO) 10      5      6      1      t1
   days.           Nostril in-
<`. Cigwette smok?.       halntion (9) 6      0      0      0      0

A. `I',~arhe<,stomn.     ControlG. experimental:                                           -.

et al..
196'7,
U.S.A. (10).

C. 10 (2 with    II. up trr 12           No histoklgir change in bronchial epithelium:
tracher,stomn).     cixxrettes per        n. 1 animal died at 24 days and no histologic change noted.
E. 10.           dw for up          b. 5 animals sacrificed at 421 days and nuclear atypism
              to 421 IIRYS.        noted in all.
          C. Cigarette smoke.        r. 2 animals died st 229 and 278 days and nuclear atypism
                            was noted but of lesser severity than in those sacrificed at
                            421 days.

Hnrris and     GIRL mice:     A. Chamber.                                     Number of      This strain of mice
Negroni,       c. 200.       14. Smoke-12 ciga-         Treatment         Nwnber   lung carcinomas      is noted for its
1967,         E. 1,437.          rettes per 20       Controls .   200         0           lack of spontaneous
England                     mire for 12       Influenza aerosol *lone     6X2        16          lung tumor formation.
(111).                      minutes every      Benzpyrene aerosol                             Animals exposed to
                          other dny for        (4 erPos"res)     200         2           cigarette smoke
                          lifetime.         Smoking     200         8 (all sdeno-    showed no hyper-
                      C'. Cigarette smoke,                                     carcinomas)  plastic epithelial
                          influenza virus     Influenzn and benzpyrene   200         3           changes such as
                          acr~>soI. henz-      Influenzn and smoking     165         3           those noted by
                          pyrene aerosol.                                             Leuchtenberger.
       -~                               ~___


          TABLE AlG.-Ezpeviments concerning the effect of the inhalation of cigarette smoke
               or its constituents upon the respiratory tract of cmhals (font.)
                     (Figures in parentheses represent total number survivors in specific group)
_____-            .___~                                ___~                ._____

Author.
year,
country,
reference

Animal     A. Type of ~XPOSUFP
and      B. Duration
strain     C. Material

- ___~ ~__~~                     --
Wynder et al..    Male C57BL6     A. Chamber.
1%X,          mice:       1~. Up to 315
rJ.S.A. (3~7).    c. and E.-        cinarettes.
             more than 40.  C. Cigarette smoke,
                         nitrogen dioxide,
                          volatile acids
                         and aldehydes
                          fuund in ciza-
                          rette smoke,
                          swine influenza
                          virus.

Results                        comments

                                                   -___
Cnnclusions: t                               tResults not provided
No squamous cell respiratory cancer noted. This is attributed  in tabular form.
  to the limitation of inhalation time (CO and nicotine acute
  effects) and to the anatomically and physiologically intricate
  nasal passn~e defense system.

Expusurr to cigarette smoke, NOZ, or wlatile wide and alde-
hrdes leads to reactive hypewlasia and metaplasia, both of
which wcw nrjted to be reversible.
Swine influenza virus esposurc  produced hyperplastic and
metaplastic effects which could not be enhanced by subse-
quent cx~osu~e to cigarette smoke.

Laskin et al..    Rats:          A. Chamber.                                  Squamous cell
1070,         c. 45.        B. 1 hour per day       ISL?)msir,e              Number    carcinoma8
U.S.A. (1%).    E. 3.            for up to        Atmospherr controls  . .     3        o/ 3
                          680 days.        Atmnrphcrc plus benzo(n)-
                       c. Benz0 (a) pyrene       pyrcnc exp0sure      21        2121
                   aerosol, so,     so, rontlols     3        o./ 3
                         atmosphere     SO, plus benzo(a)-
                          (3.5 P.P.rn.).       pyrene exp,E"rr      21        5121
____-.                                    -._____
Hammond      Heagle dogs.      See text             See tex1.
et al.,
1970,
U.S.A. (II!?).


TABLE A21.-Outline of retrospective studies of tobacco use and cancer of the larynx

Author,
ye==.
country,
reference

               CiWZS                              Controls
        -                                                               Collection of data
St?X  Number          Method of selection        Number         Method of selection

Schrek et al..
1950.
U.S.A. (246).

M.

73

Referrals from V.A. hospitals in "entire
midwest" to V.A. Cancer Center, Hines.
Illinois, during 1942-44; patients with
larynx-pharynx tumors clinically or his-
tologically diagnosed:
                     Percent
  Nonsmokers  . 13.7
  Cigarettes  79.6
  Cigars  _.  3.7
  Pipes _. _.  6.8

522

From same set of referrals. patients  Random sample of 6.003
with tumors other than lip, lung, lar-    admissions; question-
ynx-pharynx:                   naires from Hines re-
                           ferrals for 1942-44;
                            records included
                    Percent    smoking history.
  Nonsmokers  _. _. 23.9
  Cigarettes  . . . 63.2
  Cigars  . . . . 10.0
  Pipes  __. ,_, . . . . . 11.6

Valko,         M-F   226   Clinic patients with cancer of the larynx:    108   Clinic patients of same age group with   Medical history and pues-
1962.                                                    other diagnoses:                  tionnaire in clinic.
Czechoslovakia                                 Percent                            Percent
(Pi%?).                    Nonsmokers  . .  7.6           N onsmokera  . 22.2
                       Cigarettes  _. . . . . . . . . . 83.2
                       Cigars  . . . .  4.4
                        Pipes  _. . . . . . . . 10.6

Sadowsky et al.,
1963,
U.S.A. (P9B).

M.    273

White male admissions to hospitals in
New York City, Missouri. New Orleans,
Chicago; patients with diagnosed laryn-
geal tumors. 1938-43:
                    Percent
  Nonsmokers  _. _. .  4.0
  Cigarettes only  . . 60.1
  Cigars only  .  2.2
  Pipe only  . .  4.8
  Some combination  . . . . . 28.9

616

From same set of admissions, patients   Sample of 2.605 out of
with illnesses other than cancer:       2,347 interviews (in-
                           cluding smoking his-
                           tory ) by trained lay
                    Percent    interviewers.
  Nonsmokers  13.2
  Cigarettes only  . . 63.3
  Cigars oniy  . . .  3.4
  Pipe only . . . . .  7.0
  Some combination  . 23.1


           TABLE A21.-Outline of retrospective studies of tobacco we and cancer of the larynx (cont.)

         Author.
          year.                     C*XS
         countrY,                                                     Controls

         reference    S&X  Number          Method of selection        Number                               Collection of data
                                                                    Method of selection

     Bliimlein,        M.    241   Clinic patients with cancer of larynx:     200   Patients with no laryngeal disease:    Personal history taken in
       1956.                                       Percent
       GY"8llY                                                                     Percent    clinic. Patients and
                              Nonsmokera  . _.  0.8           Nonsmokers  _. _. 18.0     controls -aver 40 years
       (26).                    Heavy smokers   79.3           Heavy smokers    4.3     of age.
                              Inhalers  95.0           Inhalers _. 17.0

     Wynder et al..     M.    209   White male inpatients Memorial Cancer   209   Patients with other than epidermoid   Trained lay interviewers.
       1956,                 Research Center during 1962 to 1954.         ClNlCW,
      U.S.A. ($12).                                               individually matched controls
                        with benign or malignant epidermoid          in same institutions:
                            tumors of larynx:
                                                Percent                            Pwcent
                              Nonsmokers  _.  0.5           Nonsmokers  10.5
                            Cigarettes  X6.0           Cigarettes  _. 13.7
                            Cigars    7.5           Cigars  10.1
                             Pipes  _.  5.0           Pipes  _.  3.8
                          Cigars/pipes . _. _. __ _,  1.0          Cigars/pipes _. ._ /.  1.9

     Wynder et al..     M.    132   Laryngeal cancer patients at Tata Mem-                                 -.
                                                        132   Controls individually matched as for  Interviews for smoking
       1956,                  orial Hospital, 1962-54:                   U.S.A. data above:
       India (.sfZ).                                                                          and medical histories.
                                                Percent                            Percent
                             Nonsmokers  . 13.6           Nonsmokers  _. _. 30.3
                              Bidis  _, _. `78.8           Bidis  62.1
                            Cigarettes  _, _. .  5.3           Cigarettes __  4.6
                              Hookah  _.  1.6           Hookah  _.  0.8
                              Chilum  . .  0.8           Chilum    2.3

     Schwartz et al..    M.    121   Patients hospitalized from 1954 through   242
       1957,                                                Same time and sources; patients hospital-   Cases and controls indi-
                         1956 with laryngeal cancer. in Paris         ized for non-cancerous conditions or
       France (248).                                                                     vidually matched within
                           and other large cities:                   trauma:                      institutions; each mem-
                                                Percent                            Percent    ber of a set questioned
                              Smokers    96           Smokers (p<O.Oti)  _.  84     by the same trained lay
                              Inhalers    68           Inhalers (p<O.O5)    47     interviewer.
                           Roll their own cigarettes  44
z                                                          Roll their own cigarettes .  31
CJl


TABLE AZl.--Oxtlirw of ?et?ospcctive shcdies of tobacco use and came?` of the la?Unx (cont.)

Author,
Year.
country,
reference

               ChSi?S                              Controls
                              -~__                                     Collection of data
Sex  Number          Method of selection        Number         Method of selection

Wynder et al.,
1957.
Sweden (szr").

M.    60

Wynder et al..
1958.
Cuba (9251.

M.    142
F.     ;32

Patients at Radiumhemmet with squam-   271   Patients from same source and time,   By trained lay inter-
"us-cell cancer of larunx, from 1952         with cancer other than squamous-cell   viewers in hospital.
through 1955:                         of larynx:
                    Percent                            Percent
  Nonsmokers     5           Nonsmokers  .  24
  Cigarettes    47           Cigarettes _. _. _. .  36
  Cignrs .   17           Cigars   9
  Pipes       15           Pipes  _.  16
  Mixed  . . .  1'7           Mixed _. __ __  13

Clinic patients in Havana during 1956-57.   220   Same source and time: apparently pa-   Interview of patients
with histologically diagnosed epider-   214    tients with cancers other than larynx.    in clinic.
moid cancer of larynx.                   lung, or oral cavity. matched for age:
                   Percent                            Percent
                 Male Female                        Mnle Fenale
  Nonsmokers   1     13           Nonsmokers  . .  16     66
  Cigarettes    62    72           Cigarettes  .  45    27
  Cigars  20     6           Cigars    22     6
  Pipes    1     . .            Pipes . . .   1     .
  Mixed  _.  16     9           Mixed _. 16     

Dutta-Choudhuri
et al.,
1959,
India (86).

M-F   5R2

Patients in Calcutta cancer hospital dur-
ing 1950-54, with laryngeal tumor diag-
nosed and confirmed by biopsy or smear:
                     Percent
  Nonusers  14.1
  Cigarettes or bidi `77.8
  Chew _.. _. .t... ..__. _._.  3.1
  Both  . ._  5.0

288   Not specified

Tobacco histories oh-

                   tained during 1951-54.
                         apparently by inter-
                  Percent viewer.
Nonusers  _. 41.7
Cigarettes or bidi  52.1
Chew  _.  3.8
Both  _,  2.4


TABLE AZl.-Outline of ?etrospectiue stzcdies of tobacco use and cancw of tht la~.qnv (coot.)

   Author,
    Year*
   country,
   reference

Staszewski,
1960,
Poland (259).

               CilS~                              Controls

Sex  Number                                                                Collection of data
                 Method of selection        Number         Method of selection                      -
M.    207   Patients admitted to chronic disease hos-   912   Pntients admitted during 1957 and 1958  Author interviewed pa-
F.     13    pita1 during 1957 and 1958 with histo-  1.813    to chronic disease center for cancer-    tients suspected of lung
         logically confirmed squamous-cell car-        ous and noncancerous conditions pre-    cancer for smoking
          cinema of the larynx:                  sumably not related to tobacco con-    histow and background.
                                          sumption:
                              Percent                            Percmt
            Nonsmokers    0.5           Nonsmokers  _. 17.3
            Cigarettes only  . . . 87.9           Cigarettes only  . 60.5
          Pipes and/or cigars . .  1.9           Pipes and/or cigars  11.1
           "Heavy smokers" 88.4           "Heavy smokers"  49.0
            Inhalers  96.1           Inhalers _. _. 66.8
            Female smokers . 30.8           Female smokers  _,  8.4
                                                .__I_~~

Rozenbilds.
1967.
Australia
c??29).




Terracol et al..
1967.
France
(P74).

M.
F.







M.

191   Patients admitted to 3 major hospitals
21    with cancer of larynx and hypopharynx:
                         Percent
       Nonsmokers  _. _. . .  8
       Smokers  _,  92
       Heavy smokers  30
                            __-
961   Private service and clinic patients of ENT
     hospital:               Percent
       Nonsmokers  12.1
       Smokers  , _, 87.9

Svoboda,
1968,
Czechoslovakia
(272).

M.
F.

205
10

Patients admitted to a regional hospital
over 8 period of 6 wars all confirmed
histologically:
                     Percent
  Nonsmokers  2.93
  Cigarettes  . . , . , . . 94.63
  Pipes . _.  2.44

No controls.                     Patient interviews.

No rc,ntrols.                     Patient interviews.

Male controls                  Cases: patient interviews.
                            Controls: not stated.
                    rerccnt
  Nopsmokers  _. _. 22.0
  Cigarette (approximately) 71.0
  Pipes (approximately) 7.0


TABLE A22.-Summary of results of retrospective studies of
       tobacco use and cancer of the larynx
(Figures in parentheses represent ratios based on less than 5 case nonsmokers.)

Investigator reference

Relative risk ratio 1 ali
smokers to nonsmokers

Schrek et al., U.S.A. (246)  .........................................
Valko, Czechoslav'akia (292)  .........................................
Sadowsky et al., U.S.A. (132)  .......................................
Bliimlein. Germany (26)  .............................................
Wynderet al., U.S.A. (31P)  .....................................
Wynder et al., India (312)  ...........................................
Schwartz et al .. France ( 24.4)  ......................................
Wynder et al., Sweden (SE?)  .......................................
Wynder et al., Cuba (325)  ...........................................
Dutta-Choudhuri et al., India (86)  .................................
Stazewski. Poland (2jg)  ...........................................
Svoboda, Czeehoslavakia (271)  ......................................

2.0
3.6
3.1
27.6
23.6
3.1
4.6
6.0
( 18.9) (males only)
4.3
(40.0) (males only)
8.3

1 Computed according to method of Cornfield. J. (61)

358


    TABLE A23.-Number and percent distribution by relative frequency of atypical nuclei
          among true vocal cord cells, of men classified by smoking category
                       (100 percent atypical cells defined as carcinoma)
-                                                             Current cigarette smokers

NUTC  PPT-     NIL?%   Pt?T-     NW7l-   Pt?T-     N,1t?l-   Per-      NUT?%-   Per-      NWll-  PSr-
be?   cent       be?    cent      ber   cent      ber   cent       her   cent      ber   cent

Total  _. _. _.   XX   100.0      116   100.0      94   100.0      125   100.0      329   100.0      190   100.0

None  . .
Less than 50  _. _.
50-59  . . . . . . . . . . . . . . . . . .._.........
60-69 . . . . .._..._._................
70-79  
RO-x9  ,
go-99  . . . . . . . . . . . . . .
100:

Carcinoma in situ _. _.
Invasive carcinoma  _. .


Source: Auerbach, 0. et al. (9).

68    76.0
R    9.1
10    11.4
4     4.5
0
0
0

0
0

X6    74.1
14    12.1
13    11.2
1     .S
2     1.7
0
0

0 -
0     .-

1     1.1
4    4.3
50    53.0
23    24.5
9    9.6
2    2.1
1     1.1

3    3.2
1     1.1

1     .R        0     -        0     -
25    20.0        4     1.2        0     -
54    43.2       x7    26.4       29    16.3
21    16.8       116    35.3       76    39.4
9     7.2       44    13.4       38    20.0
2     1.6       19     5.8       11     6.8
0             5     1.5        0     -

13    lfl.4       52    15.8       36    18.4
0     -        2     .6        2     1.1


TABLE AZ&--Number and percent distribution, by highest number of cell rows in the
   basal layer of the true vocal cord, of men classified by smoking category

Current cizarette smokers

Number of
cell rows

Neversmoked       Ex-cigarette
regularly         smokers

N,,m-   Per-     NUWL-   Per-
her   cent       her   cent

Less than 1       l-2 packs        2 or more
pack a day        a day         packs a day

NW%   Per-      NU?W   PW-      NU7tb  PB7-
ber   cent       ber   cent      her   cent

Total  _. .   XX   100.0      116   100.0      94   100.0      125   100.0      329   100.0      190   100.0

Less than 5 cell rows .............   30    34.1        I    6.0       4    4.3       3    2.4        1     0.3        0    ...
5cellrows  ........................   23    33.0       27    23.3      20    21.3       21    21.6       38    11.6       20    10.5
6cellrown .........................   R    9.1       15    12.9      15    6.0       26    20.0       51    15.4       24    12.6
7 cell POWS .........................   6    6.8       12    10.3      16    19.1       12    9.6       36    11.6       19    10.0
8 cell rows .........................   3    9.1       14    12.1       9    9.6       13    10.4       30    9.1       23    12.1
9 cell rows .........................   1     1.1        7    6.0       1    1.4       6    4.8       26     7.9       14    7.4
10 or more cell TclWS  ...............   6     6.8       34    29.4      21    22.3       39    31.2      146    44.1       90    47.4

Source: Auerbach. 0. et al. (9).


TABLE A%.-Outline of retrospective studies of tobacco USC and cancer of the oral cavity
          (Data obtained fmm patient interview and other sources)

   Author,
    Year.
   cuuntly,
   reference
___.

               CIISCS                              Clmtrols

Sex  Number          Method of selection        Number         Method of selection              Comments

Hwdcrs.
1920,
U.S.A. (43).









Ebenius,
1943.
Sweden (87).

526   Series of clinic patients with epithelioma
11   of the lip:               Percent
       Tobacco users  80.5
       Smokers  _. 75.1
       Cigarettes  .  0.9
       Chewers  24.0
       Pipes  69.0
       Cigars  . 38.5

439   Clinic patients with cancer of the lip:
33                      Percent
                     MdlC Female

-

Tobacco users _. . . 79.7    -
Tobacco users

-~
Levin et al..
1950,

            (all pipes)  -   57.6
          Pipes ,, __ 61.8    -
           Chew or use snuff 47.4    -
          Cigars and cigarettes 12.9    -
                            ~___
M.    143   Cancer Institute patients with cancer of
          the lin:

500   Series of clinic patients without epithe-
     lioma of the lip:
                        Percent
       Tobacco users  78.6
       Smokers  _. 75.2
      Cigarettes  44.4
      Chewers _. 13.4
      Pipes  _. . 28.6
      Cigars  _. _, 44.0     ,
300   Not defined.                 t Estimate of prevalence
                                of use.
                       Percent
                     Malr Female
      Tobacco users  fill.7
      Tobacco users    - t1-2
      Pipes 22.9    -
      Chew or use snuff 60.7    -
      Cigars and cigarettes 32.5    -

                       __~
51   Cancer Institute patients with non-can-

1J.S.A. t 169).

                  Percent
Smokers  I.. ,. . 34.5
Cigarettes  _. 45.3
Pipes  . 48.1
^.

                             cer diseases of same site:
                                                  Percent
                                Smokers  74.0
                              Cigarettes  43.0
                              Pipes  30.7
Ugars  _. t.. 26.5           CiKar.9  34.9


E            TABLE A28.-Outline of retrospective studies of 101mcc0 use und cancer of the oral cavity (cont.)

Author,
year,
country,
reference Sex

Mills nnd Porter,
1950,
U.S.A. (186).

-__-~ ~.
Moore et al..
1953.
U.S.A (183).

Sadowsky et al..
1953.
U.S.A. (232).

__-----
Sanghvi et al..
1955,
Indin (241).

M.









M.

M.

(Databbtalned from patient interview and other sources)

Number

CEW?S

Method of selection

Number

Controls

Method of selection

comments

124   Deaths from cancer of oral cavity in Cin-
     cinnati and Detroit, 1940-45 and 194%
      46 respectively:
                         Percent
       Cigarettes only  35.5
       Pipes, cigars. or
           

combmatlons 54.8

112   Patients over 50 years old since 1951 with
      cnneer of oral cavity:

                  Percent
Chewers  68.0
Pipes  ._ 42.0
Cigars and cigarettes  . 38.4

1x5   Sample of population of Columbus, Ohio,
     in same proportion of color, sex. and
     age as in cases:
                        PeTCCXt
      Cigarettes only  32.4
      Pipes. cigars, or
           .
        combmatlons  29.7

3R

Patients of same age groups with be-
nign oral lesions or benign surgical
conditions:
                    Percent

Chewers . 31.6
Pipes  _. _. 47.4
Cigars and cigarettes  _. . 52.6

1.1:36   Hospital patients with lip, oral, and phar-   615   Patients with illness other than cancer:
      yngeal cancer, 1938-43:                                      Percent
                          Percent          Cigarettes only  ............. 53.3
       Cigarettes only  .............. 42.3           Cigars only  .................  3.4
       Cigars only  .................  4.0           Pipes only  ..................  7.0
        Pipes only  .................. 17.8           Mixed  ...................... 23.1
        Mixed  ...................... 28.2

657   Hospital patients with cancer of oral cavi-   28X   Hospital patients with diseases other   Smoking is of bidis among
Xl   ty and pharynx:                   112    than cancer:                    both cases and controls.
                       Percent                              Perrcnt
                     Male Female                         Male Female

Smoke andchew 38.8    3.7           Smokeend chew _. 24.0    -
Smoke only  . 46.7 6.2           Smoke only   60.0   6.3
Chew only  . . 11.7   64.2           Chew only  8.7   23.2
Neither ._ __ _.  2.7   26.9           Neither  17.3   70.5


TABLE A28.-Outline of retrospectiur studies of idmx-o USC rend mnccr of the oral c'clvity (cont.)
                 (Data obtained from patient interview and other sources)

Author,

s=**,
country.
reference

               CJS`3                              Controls
   -~-~
Ses  Number          Method of selection        Number         Method of selection

Comments

     --..
Ledermann,      M.    240   Patients with cancer of oral cavity snd    62   Patients with c~nccr of skin, bone, and   Differences between cases
1955.                    phannx:                           muscle:                       and controls for both
France (162)                                  Percent                            Percent    high nnd low alcohol in-
                        Nonsmokers  4.6           Nonsmokers 17.2     take are ihsignificnnt
                        >20 cigarettes per day  23.4           >20 cigarettes per day  . , 18.6     when smoking is con-
                                                                           trolled.
-~ _____~
Wynder et al.,     M.    543   Patients with cancer of oral cavity:      207   Patients with cancer of other sites and
1957,         F.    116                               232    benign diseases:
U.S.A. (SIS).                                Percent                              Perce?l t
                                       Male Female                         Mals Fcmnlr
                        Nonsmokers   3    47           Nonsmokers  10    70
                        Cigars _. .  20    -           Cigars _. _.   13    -
                        Pipes . . .  11    -           Pipes    6    -
                        Mixed _.   R    -           Mixed   8    -
                        Chew _.   17    -           Chew   H    -
                        Cigarettes  57    53           Cigarettes  63    30
                        >35 cigarettes                        >35 rivarettes
                         per day  29    -             per day                -~
                                                                   17
                       >I6 cigarettes                        >16 cigarettes
                        per day _.  -    34             per day         11
- ~~~..._~
Schwnrtz et al.,    M.    332   Hospital patients with cancer of oral CBV-   60X   Hospitnl patients with non-czmcer ill-
1957.                   ity and pharynx:                     ness and accident CISCS. matched by
France (248).                                               *ge:
                                          Percent                            Perccn t
                        Nonsmokers  16.4           Nonsmokers    23.4
                       Cigarettes only  62.7           Cigarettes only  58.2
                       Pipes only  . . . . . .  3.3           Pipes only  3.0
         __-                                                                       ~-~


w
L         TARLE A28.-Ozctlinc, of retrospcctirlc studies of iol~ctccr~ I(SP red cunccr of the oral cnvitg (conf.)
                                 (Data obtained from patient interview and other sources)

Author,
Yt?ZW,
country,
reference

               Cases                              Controls
   ___ .-~                                    __._____~ -~
Srs  NUl?lb?l          Method of selection        Number         Method of selection

COl""lC"tS

Wynder et al.,
1951,
Cuba (8.25).

                                                                           -__
M. ,
    Ii':   Hospital rlinic Datients with cancer of   220   Patients in same clinics with non-malig-
F.     :34   I,L.RI cavity and pharynx:              214    nnnt conditions, matched by sex and
                                          age:
                            PCTCtXlt                            Percent
                          Male F~malc                         Male Female
           Nonsmokers   4    24           Nonsmokers   16    66
           Cigarettes                           Cigarettes
             jtreduminantly    45    62            predominantly . .  45    21
          Cigars predominantly 33    12           Cigars predominantly 22    6

Wynder et al.,     M.    115   Male patients with cancer of oral cavity   115   Male patients in same hospital with can-   Alcohol data significant
1957,                    and pharynx:                       cer of sites other than oral, pharynx,    only for hypopharynx.
Sweden ( 822 )                                           larynx. lung, esophagus, breast:
                                          PeTcent                            Pdrcent
                        Cigarettes   36.6           Cigarettes    36
                        Cigars  _. . 13.0           Cigars  .   9
                       Pipes  . . 12.2           Pipes  . . . .  16
                       Mixed  _. _. . . . 15.7           Mixed  _.   13

Peacock et al..
1960,
U.S.A. (210).

M.
F.

25   Hospital r>atients with oral cancer:       14   Patients in same hospital without oral
20                                72    cancer and 111 male and 100 female
                                    out-patients. randomly selected.
                        Percent        32.6 percent of first group, and 43.3 per-
      Chewed or used snuff over 20              cent of second group chewed or used
       years (all patients)  . 56.6          snuff over 20 years.

Staszewski,
1960,
Poland (259).

M.

3R3

Male patients with oral cancer:
                     Percent
  Nonsmokers  . _. _.  5.7
  "Heavy" smoking index  72.8
  Cigarettes only  . 72.3
  Pipes and/or cigars  . 12.8

912   Male patients with other cancerous and
     non-cancerous conditions:
                        Percent
      Nonsmokers  . . . 17.3
      "Heavy" smoking index  . . . 49.0
      Cigarettes only  60.5
      Pipes and/or cigars   11.1


TABLE A28.-Outline of retrospective studies of tobacco MSE and cnmw of tlic ora1 cnvit!! (coTat.)

(Data obtained from patient interview and other sources)

   Author,
    year,
   country,
   reference

Vogler et al..
1962.
U.S.A. (698).

               Cases                              Controls                     Comments
S-X%  Number          Method of selection        Number         Method of selection                    .__
M.    188   Clinic patients with cancer of lip and oral   521   Patients of same clinic with other can-   t Due to varying tabular
E'.     92   cavity:                        1,064    cer or non-malignant conditions:       treatment of data, per-
                            Percent                                  centages of tobacco
                          Male Fsmale                                   users are not all based
           Chewers _. $32.9    -                             Percent    on the same number of
           Excessivechewers 22.9    -                          Male Fern& eases.
           Snuff dippers         -
                     .      72.0           Snuff dippers     t6.1
            Excessive snuff

dippers   -   41.3
Tobacco users  . 90.0   90.0           Tobacco users  56.0   56.0

Vincent and
March&s.
1963,
U.S.A. (997).

M.
F.

66   Successive patients with lesions of buccal
16   cavity and oropharynx:
                      Percent
                     Od   OTO-
    Males :            Cavity pharynz
      Nonsmokers  3.0    -

      <20 cigarettes
       per day  t. 1X.3   15.1
      >20 cigarettes
       per day  78.1   84.9
    Females:
      Nonsmokers  55.5   26.6
      <20 cigarettes
       per day  -    --~

      >20 riaarettes
       per day  . . ._ 44.5   71.4

100   Successive patients attending gastroin-   Male patients used con-
50    lestinnl clinic, age-matched:          siderably more alcohol
                               than male controls.
                              Data refers to all forms
        Pcrccnt                   of smoking expressed
         27.0                   as cigarette equivalents.
                             t`icawttt. equivalents:
         24.0                     1 cigar r= 5 cigarettes
                              1 Pipe = 2 cigarettes
         4!l.O                    t BN-Betel nut.

R2.0

8.0

10.0
    __---- -


H

TABLE A28.-Outline of retrospective studies of tobacco use and cancer of the oral cavitsf (Cont.)

(Data obtained from patient interview and other sources)

   Author,
    Year.                     Cases                              controls
   c0untl-Y.                                                                           Comments
   reference    Sex Number         Method of selection        Number         Yethod of SelEetion

Sbantr and       M.    662   Patients with oral and phawngeal eaneer   300              Controls residing in
Krishnamurthi, F.    206   (unsure of confirmation) :             100               same area matched
1964,                                                     Percent       for we. sex, and
India (I&?).                                     BlLCCd   Anterior   P0&rio+       ehas:
                     Males:             Lip mueomz    tongue    tongue   Phownz   males
                      No tobacco habit   -       2.0      7.2      2.0      6.3      89.1
                        Smokers    50.0      46.7      66.6      76.0      72.8      62.7
                     Number of eases . (12)     (293)     (69)     (48)    (130)     (800)
                     Females:                                               Fanal@
                      No tobacco habit . . .  14.3      11.0      33.3       -      40.0      88.8
                       Smokers . . . . .   -       4.7              -      8.8       -
                        Number of cases  (7)    (162)  (Iif      (4)     (26)     (100)

Wahi et al..      M.    589   Patients with oral and pharyngeal car-   689   Patients matched for age, sex. religion,
1966.         F.    232   cinema:                        232    and social class.
India (sOa).                                   Percent           Pwcent
                        Nonsmokers  . . . . . . , .  9.62             66.6
                        Smokers  . . . . . . 17.06             21.2
                      Chewers (Betel nut)  . . . . 86.44              6.9
                        Both . . . . . 37.88              6.4

Hirayama.       M.    369   Patients with oral and pharyngeal card-   277   Patients with other (unspecified) dis-  Found only a suggestive
1966,         F.    176   IUXllP.:                         I63 eaws:                        association between
Central and                                 Percent                Pemmt               alcohol-drinking and
South East                                Male Female            Male Female                oral cancer in non-
Asia ( 1 24)                 Nonusers  .  1.6   2.6              17.0   33.0                chewers only.
                        Smokers  . _. . 17.1    2.6              23.3    1.2                t BN-Betel nut.
                      Smokers. tBN and
                         tobacco chewers 46.7    6.6              24.9    1.8


TABLE A28.-Outline of retrospective studies of tobacco use and cancer of the oral cavity (cont.)

(Data obtained from patient interview and other sources)

   Author,
    year.
   country,
   reference
-
Keller,
1967,
U.S.A. (140).

                CSS.3                              Controb

Sex Number          Method of selection                                              Commenta
                                    Number         Method of selection

M.    408   Patients with waumnow cell cw&uxna of   406   Next male patient admitted to same hos-   Excessive alcohol con-
         oral cavity and oropharynx confirmed        pita1 within 5 year we range.         aumption noted for
         histologically. Three New York City VA                               c*spJ involving floor,
         Hospitals 196368:                                              meaophwynx. and
                              Percent                 Percent               tongue.
           Nonusers  , . . . . . . . . . . . . .  6.1                   14.2              Findings indicate tbe
           Cigarettee  . . . . . . . . . . . . . 68.6                  66.4 (p<O.OOOl)         association of heavy
          Pipe only  . . . . . . . . . . . . .  4.0                   2.9                drinking with cancer
           Cigar only  . . . . . . . . . .  6.9                   6.1               independent of the
                                                                    amount of tobacco wed.

Martinez,
1969,
Puerto Rico
(18s).

M.
F.

38

Patients with epidermoid carcinoma of
oral cavity and pharynx:



                    Percent
  Nonsmokers  . . . . . . . . . . . . . . lS.7
  Heevy tobacco usera  . . . . . 24.8

345
114

116 mmle snd 38 female hospital or clinic   Csscs found to conwme
patients without cancer: 330 male and    more alcoholic bever-
76 femde resident of ~arne region.    aoes than controb.
age and lex matched.
        Percent
         19.2
         12.2 (p<0.0001)

Keller,
1970,
U.S.A. (141).





__--

M.

304

Patients with primary basal or u~uwnous
cell carclnoms of lip:
                    Percant
  Nonsmokera  . . . . . . . _ . . . . .  7.8
  Cigarettea only  . . . . . . . . . . . 60.2
  Pipe only  . . . . . . . . . . . . . . . . . . .  6.0
  Pipe, other  . . . . . . . . . . . , . . . .  6.8

304

Patients from same hospital matched for
ape and race.
        Percmat
        16.6 (D<O.~l)
         62.8
          3.4
         0.4 (p<O.Ol)


f

TABLE h28a.-Swwnnry of results of retrospective studies of smoking hy type and oral cancw of detailed sites

Author
reference

Cigarettes
and cigars

Bidis

Pipes     Pipes and     Cigars      Tobacco     Betel nut
0"lY     other forms     0"lY      chewing     chewing

Miscellaneous

Broders (4.?). .... ..Li p (6) ................................ .I,ip (+) ................... ..Li p (-). ...... Lip (+). ....................

Ebenius (87). ........  .......... .I.ip (6).                                            .....................
                            ............... Lip (+). ................................... Lip (-)

Levi" et "I. (169). ..Lir I (-). ............................... .Lip (+), .................... Lip (I). .....................................

Mills and
Porter (18G)

Oral (I). . . .._.__._.._....... . . . ,..,.._.__.................. . . . . . . . . . . . . .  . .Pipes and cigars
                                                                          combined-oral
                                                                         (+).

Moore et al. (193). _. Lip,       . Lip,         . . . . . Lip,        Snuff-lip,
                        mouth C-j.         mouth (-)                    mouth (+)            mouth (+).

Sadowsky
et *I. (231)


Sanghvi et al.
(241)

Lip, tongue,      Lip, tongue,    . Tongue,     . .
other oral.                     other oral (+)           other
pharynx (-).....                                    oral (8)......

  ,.. Oral (+) ..,. .., ,,... . . . . . . . . . ,...,. ,....... Oral (f). . . . . If smokers and
                                                                          chewers-base
                                                                   of tongue,
                                                                   hypopharynx
                                                                         (+).

Lederma" (102). Oral (+) _. _. . . . . . . . . . . . . . .

Wynder et al.
(313)

Floor of       . . . . . Each site      . . . . . Each site (f) Gingiva,     
mouth                       except                        lip (*).....
Male (`)                    tongue t+j....
Female (+)

Schwartz et al.
(248)

. . Pharynx (+) . .Oral (-) . ._. . .,. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .


  TABLE A~~~.-SUVLMCW~ of results of retrospective studies of smoking by type and orr~l cnncc~ of dr:/r~iled sitczs (cont.)
                                       ___-             ____.
   Author
  reference               Cigarettes
            Cigarettes                      Pipes      Pipes and              Tobacco     Betel nut
                      and cigars    Bidis       only     other forms  C?"Zg      chewing     chewing     Miscellaneous
- ._____
Wynder et al.     Oral and      . . _. . . . ..Oral and     . . . . _,.  
( ,385 )         Ph*rynx.                                    pharynx,
            Male (6)                                      Male (+).
           Female (f)                                    Female (+)
__-I_~ __~            -____                                                      ______
Wrnder et al.    Pharynx (+) ,   . Tongue,     .Pipes and cigars
(31.9)         other sites (-)                                    gingiva,                        eombined-
                                                    pharynx (+).                    tongue ($).
                                        ~-
Peacock et al.         .  _. . Oral (f)`. .Snuff-oral (f)'
(1'10)

-~____ ~____       .~                     .____
Staszewski (~`59). Lip, oral           Pipes and cigars
           cavity Gt)..,..                                                               combined-lip.
                                                                           oral cavity (*).

__ __~ __                                                          .__I_-
Voaler et RI.     _.    _, ,, . . . . .  _,  . . , . . . ..A11 forms com-
f PBS)                                                                           bined (+),
                                                                           Female (+)
                                                                           Snuff-lip and
                                                                           bucesl cavity in
                                                                           hoth cases.

______~~                                            .___ _I_~        .____.
Vinrcnt and           _.    . .    All forms
Marrhetta                                                                           combined-
(1!)7)                                                                           oral (i-j.
                                                                           pharynx (+).

                                                ___~ ~.        --~                _I_~~ ~--
      Shanta nnd      . .         . . . . . . . . . . . ..Lip.        All smoking types
       Kti\hnamurthi                                                                   huccal      -pharynx (+).
       (25G                                                                        mur<,sa (+).  post tongue
                                                                           (+).
                                                                           All forms com-
                                                                           bined-lip, oral
                                                                           cavity, pharynx
c-2
%                                                                           t-t).
                                              ~~~  ~__ ____  ___-                 ~--__


   TABLE AZBa.-Summary of results of retrospective studies of smoking by type and oral cancer of detailed sites (cont.)

   4uthor                 Cigarettes             Pipes     Pipes and             Tobacco     Betel nut
   reference      Cigarettes     and cigars    Bidis       only     other forms  Ch;      chewing     chewing     Miscellaneous

WRhi zt nl.      Anterior         . . . Anterior     All forms com-
( SOI ,          tonyue and                                                          tongue and    bined--all
             bUCCa1                                                             buccal       sites (+).
             "l"C"tXl,                                                            "l"C"SB.
            Males (f)                                                         *MaleJ (+)
   -~
Hiraynmn (124). __  _. _,  .A11 sites (-) _. . All sites (-) Allsites (-) _. _. Ill forms com-
                                                                           bined-base of
                                                                           ton&we (f),
                                                                           oropharynx (+I.
                                                                           Smoking only
                                                                           combined
                                                                           -bueeal
                                                                           rn"C"SB (+).

Krller (140) _. All sites (f)  .All sites (-). .A11 sites (--) . . .A11 types smoking
                                                                           combined, heavy
                                                                           -floor of
                                                                           mouth and
                                                                           tongue (+).

LMarlincz (283). _. .Oral cavity.     ,.._,_,._.,_............ . . . . . . . . . . . . . . . .._......_...... . . . . . . . . . . . . . . . . . . . . . . ..__ All types of
            pharynx (+)                                                              smoking. heavy.
                                                                           combined-oral
                                                                           cavity c-t).
                                                                           pharynx (+).

Keller ( 141). ._ Lip t-j..  . . . I,iP (+). .Lip (-) _. . . . .  _. _. All types of

smoking com-
bined-lip (+).

I Only in individuuls of low economic status and over 60 YWIIT old.
  Symb~,ls: (+) = sivificant association.
        (--) 7 associntio" absent or not significant.
        ( o ) : z+ssociiltio" of doubtful significance.


TABLE A29.-Experimental studies concerning oral carcinogenesis

  Author.
   ye*=,
  cou"tly.
  reference

Kreshover,
1952.
U.S.A.
(152).

    Animal
     and
    strain

78 Swiss and
C57 mice.

A. Method.
B. Frequency and/
or duration.                                   Results
C. Material.

A. Painting of lower    No macroscopic or microscopic changes in controls or experimental animals.
   lip mucocutaneous
   region.
B. 10 times in 76 days.
C. Cigarette smoke
   "co"ce"trate".

Sallcy.
1954,
1l.S.A.
(238).




FIl,lsti and
Ermala,
1955,
Finland
(130).

Noore and
Miller.
1!)5X.
U.S.A.
,192).

36 Syrian        A. Painting of cheek                            Number of      Number with     `Number with
hamsters.          pouch.          Treatment:                   survivors      benion tumors      carcinoma
           B. 3 per week for 16       Acetone solvent      5             1             2
                weeks.            Benzene solvent      4                         -
             C. Benz(a)pyrene in
                acetone or benzene.                                             
60 Albino mice     A. Painting of lips     No oral 0~ labial changes seen in controls or experimental animals.
(40 co"tr"ls).       and oral cavity.
             B. 140 times in 12
                months.
             C. Tobacco "tar".

80 Syrian        A. Material soaked onto                                                 Inpammatiun
Golden hamsters.      wad and secured                          Original    Surviving    Number   and basal cell
               in cheek pouch.     Treatment :                  number    ouer 1 YeaT    tumo?8    hyperpbmia
             B. Wads replaced 8        C""trols   30        23                 4
                times in 2 years.       Smoke condensate   80        55                32
             C. Smoke condensate       Benz (a) pyrene   20        16                 9
                Benz(a) purene.

Guerin.
1959,
France
(108).

Strain IC and
strain W rat.

A. Chamber inhalation                Original                          Rued
   of tobacco smoke.                  number        Survivors            tumote
B. Daily (?).         Controls    40            39              o/39
C. Up to 6lh months.    Experimental   100            68              5/68 (3/6 detlnite
                                                                epithelioma)


TABLE A29.-~sl,c~i),lelltnl studies concwning oral carcinogenflsis (cont.)

      _.__. -
  Author.
   year,
  conntrY,    *,:YY
  reference        strain

Peacock et RI.,   124 Syrian

A. Method.
I(. Frequency nndi
0~ d"rntion.
C Material.

A. Packing of cheek

                          Krsults


No tumors noted in any of the 42 animals surviving over 1 year.

1960,
U.S.A
(210).

Dunham and
HWKJld.
1962.
U.S.A.
(84).

Moore nnd
Christo-
phewm.
1962,
U.S.A.
(191).

Salley.
1963.
U.S.A.
(139).

Coldcn hamsters.      pwrrh.
           n. I year.
           C. Snuff, Tobacco,
               Bland material.

SyI,ian (L,ldrn
hamsters.

A. I'acking of cheek
   pouch.                             Original
13. Normal lifespan or    Treatment:              uun2 her        Survivors
   5X30 months.      Betel Quid     375      nw; over I yea,
(`. lletrl rluid ingredients  DMHA and MCA   71      .iGlil over 5-30 months
i 12 dimethylbenz(a)-
nnthrncene (DMBA),
Mcthylcholnnthwzne
(MCA) in beeswax
lwllets.

A. I'ainting oral mucosa.                                           itnimnls with
II. 3 per week for 683     Treatment:                                lesions (tinlc)
   days.           Controls  . . .   0 1x (at :392 dR).).
C. Cigarrttc smoke      Smoke condensate       O:`LO (at 33i dws) (10 showed hyprr-
   condensate.                                         keratosis).
   DMBA in 0.5';;     DMBA  . _. . . .   14/21 microscopic cancers (nt 90 days)
   petlwlatum.                                     (invasive squamous cancer originating
                                             in the skin at the edge of the pouch).

CAFl strain
mice.

A. Ultraviolet light
   ~x,,osure to and
   painting of lips.
I<. :3 ,lrr week for 9X
   weeks.
C`. 13 (a) P in acetone
   Cigarette smoke
   `(1X' light.

                                        ~___
Treatment:                   A'umhcr         Duration        TUWlOT8
Ultraviolet light and                           wwks
cigarette smoke     40            94            --
B(alP and UV light ,. _. ._. ._.   40            4x
I:V light _.   40            !I4            -
B(alP . . . .._....   40            45            -


TABLE AZ9.-Experimental studies concerning oral earcinogerwsis (cont.)
                 ._____                ____~

Author.
year*
countrY.
reference

A:i'
strain

A. Method.
B. Freauency and/
or duration.
C. Material.

Hamsters

A. Application to
   cheek pouch.
B. See laults.
c. See results.

Bock et al.,
1964,
U.S.A.
(SO).

ICR Swiss
mice.

A. Fainting mouw
   skin.
B. See results 36 weeks.
C. Various extracts of
   unburned tobacco
   DMBA.

Results

Treatment:

Orininal
Nwnber

Surviaovs    Duration    Lcsiona

Ciaarettes 5 per week  
DMBA once . .
Croton oil 3 per week  _.
DMBA once and cigarettes
5perweek .._.....,...,._..

DMBA once then croton oil
5 per week  

-

Treatment:

  7 hyperplasia
  6 dyskeratosis
   3 carcinoma
__-- ~_
Number tumors/
number mice
with tumors
(amall yapillomae)

DMBA once then:
Acetone benzene extract
Concentrated Bn(OH12 extract
Diluted Ba(OHj2 extract _.
DMBA only  
Acetone benzene extract _.
Coneentracted Brr(OHlz extrnct
Diluted Ba (OH) 2 extract



,.






      2.5
..,.      0.5
.      0.5

      2.5
      0.5
,...      0.5

16/7
18/B
6/i?
-

-

-

-

None       .T                                         -
    ........  ....................  .............

70
13
10

30

28

55        fi4
6        128
10        30

28        81

27        RI

-
2 hyperplasia
-

12 hyperplasia
4 dyskeratosis
1 carcinoma


3

TABLE A29.-Experimental studies concerning oral careinogenesia (cont.)

Author.
Y=*=.
cou"tlY.
reference

Animal
and
strain

A. Method.
B. Frequency and/
or duration.
c. Mcctertal.

Results

Pretzel et al.,   Swiss Webster mice  A. Swabbing of labi                           Original         Percent at 13 months with
1964,       with some having     "l"EOS&                                  number       Papilloma8        CCWlCIW
U.S.A.      liver damage in-   B. Up to 13 months.                    . . . . . . . .   40            74            46
(213).      duced either by              Alcohol and Ccl, treated
                      C. B(a) P in acetone.    Alcohol treated . . . . . . . _. . . . .   40            34            60
          CC14 or ethyl              cc14 treated  . . . . . . . . . . . . .   40            90            40
           alcohol.                        No toxin . . . . _. ._. . . . . . . . . . . . . .   40            42            16

Reddy and
Anguli.
196'7.
India
(219).

.___.~
EhY.
19fi9.
U.S.A.
(90).

Swiss female
mice.

A. Intravsginal
   instillation.
B. Daily for 324-380
   days.
C. "Pan" mixture of
   *ree* nuts, lime,
   and chewing
   tobacco.

Original
number
  60

suwivors
  40

    Lesiona
3/40 raised papillomatow,
   malignant growths
4/40 poesible carcinoma-
    in situ.

Syrian Golden
hamsters.

A. Application to
   cheek pouch.
B. Daily for 200 days.
c. see results.

Treatment:
DMBA   Alcohol
DMBA   Alcohol
DYBA   . . .
DMBA   . . . . . .
   Alcohol

     Original
      number
Smoke    29
. . . . . .    29
Smoke    29
.,....    29
Smoke    29
Smoke    29

Mo+talit~   Number
sate     animab
41.0       17
66.0       10
42.0       14
48.0       16
42.0       14
42.0       14

Percent     Percent
with      with
tumors     cancer
100.0       60.0
60.0       40.0
100.0       70.0
100.0       88.0
  -        -
  -        -


TABLE A31.-Summary of methods used in retrospectvie studies of tobacco use and cancer of the esophagus

Author,
war.
countw,
reference

               Cases                              Controls

Sex  Number         Method of selection        Number         Method of selection            Collection of data

Sadawsky et al.,
1953.
U.S.A. (231).

M.

104   White patients admitted during 1938-43 to   615   White patients with illneesea other than   Obtained by 4 specially
     selected hospitals in New York City,        e~ncer admitted to .wnne group of hos-    trained lay interviewera.
     Missouri. New Orleans. and Chicago.         pitals during same period.           242 records out of B total
                                                             of 2,841 excluded be-
                                                                cause of incomplete or
                                                          questionable smoking
                                                                 histories.

Sanghvi et al.,
1955.
India (a(f).

M.

73

Consecutive clinic admissions to Tata me-
morial Hospital, Bombay.

283

101

Consecutive clinic admissions of patients   BY means of "detailed
without cancer.                  questionaw." No other
Consecutive admissions of patients with    details given.
eaneers other than intraoral or eso-
pbagus.

Wynder et al..
1957,
Sweden (JB?).

M.
F.

39
35

Patients admitted to Radiumhemmet,   116   Patients admitted to s&me hospital with
Stockholm, during 1962-66.           156    cancer of akin, head and neck region
                               other than squamous cell cancer. leu-
                                 kemia. colon.  and other sites. No
                               matching.

Staszeweki.
1960,
Poland (460).

M.    24

Patients admitted to Oncological Institute   912   Other patients sent to Institute with   No detrih given on
during 1957-59.                     symptoms probably not etioloeicalb    method of d&x collec-
                                 connected either with amokine or with    tion. No age adjust-
                               diseases of esophagus. stomach or du-    ment or matchine. Av-
                                 odenum.                     wage *ee of cancer
                                                      patients, 60.6: eontrob,
                                                             63.


TABLE A31.--Summary of methods use,d in retrospective studies of tobacco use and cancer of the esophagus (cont.)

Author,
Year.
country.
reference

sex

Schwartz et al..
1961,
France (249)

M.

C*SeS                              Controls

Number

362

Method of selection        Number         Method of selection           Collection of data

Admissions to hospitals in Paris and a
few large provincial cities since 1964.

362

Healthy individuals admitted to same hos-   Interviewed by team of
pita1 because of work or traffic acci-    specially trained inter-

Wynder and
Br0ss.
1961,
U.S.A. (SZO)

M.






F.

160






37

Wynder nnd
Brass,
1961.
India (810).

Takano et al.,
1968,
Japan (272)

dents-matched by 5 war age group
and time of admission.

Cancer patients seen in Memorial Hospi-   150   Patients seen in same hospitals during
tal, New York City, and Kingsbridge        same time period with other tumors.
and Brooklyn VA Hospitals during        64%malignant tumor: 3@;&benign con-
1950-59 (86% white).                 ditions. Matched by sge with cancer
                                  patients.
Same hospitals and ssme time period BS    37   Same ss with regard to male controls.
male patients (86% white).             43% had malignant and 57~)$ benign
                                  tumors.

viewers who interviewed
the largest proportion
possible of all cancer
patients. Cases and
matched controls inter-
viewed by ssme person

Data collected by trained
interviewers.

M.
F.

67   Admitted to Tata Memorial Hospital Bom-   134   Patients with other forms of cancer ex-  Interviewed by one per-
27    bay.                          cept for oral cavity and lungs: &s well    son.
                                   as various benign diseases.         10% of male and 4% of
                                                               female cancer eases
                                                       histologically confirmed.

M.
F.

167
33

Patients with esophageal cancer.

lfi?
33

Patients with cancerous and non-can-   Interviews at various
cerous diseases of non-digestive organs.    hospitals. Cases and
                          controls age-matched.


   ~~ _..__~~               ~____~~                         ~~__---~
Bradshaw and     ,M    9x   Patients with esophagrnl cancer.         34,   I'atirnts with non-malitmant disease.     Hospital interviews by

Schonland,
1969,
South Africa
(41).

trained African social
workers.

MCilTi"CZ,
19F9.
Puerto Rico
(133)

                                                     -~ ~__.__~. -
M.    120   Patients with confirmed epidermoid eso-   :x0   120 mnlr. S!l female patients in same hos-   interviews by trained
E`.     5 9     phageal canrer diagnosed in 1966.       177     pital with non-cancerous diagnoses.     Personnel.
                                        240 mnl~, 11X female members from SSIE
                                           rommurrity.                      _____-


ki           TABLE A3la.-Summrg of results of retrospective studies of tobacco use and cancer of the esophagus

      Author.
       Yl?:,r,
      rountw.
     reference

Sadowsky et al.. 1953.
U.S.A. (231).

Percent nonsmokers
Cases     Controls


3.x       13.2

Percent heavy smokers

Cases   Controls
       
         -

Percent inhalers
among smokers

Caxa   Controls

-     -.

Relative risk ratio.
All smokers to
  nonsmokers
All    Heavy
smokers smokers

4.0     -

Sangvhi et al.
1955.
India (1041).

Wynder et al.,
1957,
Sweden (322).

M --
F

     6.5       17.3




    13.0       24.0
(about)RS.O (about)92.0

Awmzgc ~tumbcr of                       3.6     -
hidia smnlicd
15.3     14.1



                                 2.1     -
                                 2.0     -

Staszewki.
i960
Poland (260).

18.0         95.x    59.0        x7.5    80.0         -     -

Schwartz et al..

3.0       11.0      Total amount smoked      39.0    38.0        6.6

1961.                                               daily (cigarettes)
France C-`/9).                                               16.X     16.0

Wyndrr and Brass.
1961. U.S.A. and
India (SIO).



Takanu et al..
ISCH,
Japan (271).

American males           5.0       15.0         48.0    33.0                        3.4     4.4
America" females          41.0       78.0         27.0     16.0                        6.1     3.2
India" males             13.0       28.0                                         2.6
Indian females           18.0       94.0                                         4.5

                   17.0       23.0                                         1.3

Bradshaw and Schonland,                       16.3       31.7         31.6     5.9         -     -        2.6    11.1

1969,
South Africa (41).

Martinez. 1969.                             14.0       23.5         11.9     8.6                        1.8     3.5
Puerto Rico (183).


TABLE A32.-Atypical nuclei in basal cells of epithelium of esophagus of males, by smoking habits and age

Atnical nuclei

Never smoked          current
tWUbHlY          Cigarettes

Ex-cigarettes         Pipe, cigar          Other

NW&    Pet-       NWE-    Per-       NUlTl-    PW-      NU?iT.    PCS--      NUT%   Pe+-
her     cent        ber     cent        ber     rent       bcr     cent       ber    cent

A. Allmen:
  Number men  . . . _.   91
  Total sections'  .  737
  No atypical nuclei  _. .  733
  Some but <60 percent atypical  f....   62
  60 percent or more atypical . .   2

B. Men under age 50:
  Number men   26
  Total sections  . .  223
  No atypical nuclei  . _.  190
  Some but <60 percent atypical     33
  60 percent or more atypical _. _.   -

C. Men aged 50 -69:
  Number men  .   44
  Total sections  . _. _.  379
  No atypicnl nuclei  .  373
  Some but <60 percent atypical .   4
  60 percent or more atypical  .   2

D. Men aged 70 or older:
  Number men . . . . ~. .   21
  Total sections  . . . . . . . . . . . . . . .._..._  186
  No atypical nuclei  _.  170
  Some, but <60 percent atypical     15
  60 percent or more atypical .   -
                        -____

1 Sections with some epithelium present.
Source: Auerbach, 0. et al. (15).

3

-        779      -        131      -        89      -        62      -
100.0       6.762     100.0       1.586     luo.o       766     100.0       622     100.0
93.1        167      2.5        770     48.5        53      6.9       195     37.4
6.6      6.389     793        765     48.3       68R     X9.8       317     60.7
0.3       1,196     17.7         51      3.2        25      3.3        10      1.9

-        236
100.0       2,069     100.0
85.2        71      3.4
14.8      1,853     90.0
-        136      6.6

-        445               109
100.0      3,853     100.0        963
98.4        83      2.2        461
1.1       2,915     75.6        452
0.5        856     22.2         40

-        98               44
100.0        840     100.0        375
91.9        13      1.5        253
8.1        621     74.0        11R
-        206     24.5         4

2x
25R
56
195

luu.o
21.7
75.6
2.7

100.0

48.4
47.4
4.2

luu.o
67.4
31.5
1.1

9
77
1
74
2

3x
310
37
261
12

42
379
15
353
11

-
100.0
1.3
96.1
2.6

100.0
11.9
X4.2
3.9

100.0
4.0
93.1
2.9

7      -
53     100.0
4      7.6
46     86.8
3      6.7

31      -
256     100.0
74     28.9
178     69.6
4      1.6

24      -
213     100.0
117     64.9
93     43.7
3      1.4


i\. ,411 ages  ................   III
  Tt,t:tl section-; I  ...............   7x7
  NC, atypirnl nuclei  ..............   733
  Some but *<fill percent ntsuical  .....   52
  60 percent or more atypical  ........    2

8. Men under ax-c 50:
  Number me,,  .................   26
  Total srrti<,nr '  ...............   221
  No ntypirnl nurlei  ...............   190
  S,,",? bill <:c;u p,`l'rcrlt atYJlicnl  .....   33
  611 perrrnt or mc,rc atypical  ...........

(' Mm agml 6O-G!1:
  Numbc, men  .................   44
  Total sections '  .................   379
  NC, atypical nuclei  ................   373
  S,,mc but <GO pcrccnt atypical  .....    4
  GO lw~`rent 0~ mow atypical  ........    2

D. MWl a$RYl in ,)1` Clldc~r:
  N,,mkr~ rncn  ............    21
  Total secti<,ns '  ...................   lR5
  No atypical nuclei  ...............   170
  Some but `:Gn peK!ent atypical  ....   15
  GO pr,`cent 01 m,rl'e atynicnl  .........

' Sections with some epithelium present.
Source: Auerbnch, 0. et al. (15)

          1 i!)
100.0        1,544
!13.1          x9
6.6        1,341
0.3         114

           !)
100.0         433
85.2          4x
14.x         3x2
. . .           3

           !12                  240                   113        -

100.0         789       100.(1         2.116       lou.u          148      lUU.0
9x.4          30        3.X           1X        O.!)           35        :3.i
1.1         694       R7.0         1.6Oi       75.!1          F14       64.S
0.5          65        8.3          491       23.2          299       31.5

          :3:,
100.0         322
!)I.!)          11
3.1         2G5
           46

            41R        -          137        -
100.0         3.rY20      100.0         1,57!)      100.0
5.x           :i!l        I.1          ,3!l        2.5
X6.X         2,957       Xl.5         1,091       69.1
7.4          6 :3,3       17.4          44!1       2X.4

100.0
11.1
RX.2
0.7

132                   55
l.lti!)      1 lJ(l.0          457
21        1.X           2
I .OX!l       !I3 ."          3h"
50        5.0           73

            41        -           19
1011.0          :14-l      100.0          174
3.4                   _           2
R2.3          "61       iT,.!I           95
14.3           x:5       `24.1           77

100.0
0.4
83.6
16.0

-
100.0
1.1
54.7
44.2


   TABLE AIL-Summaq of methods used in retrospective studirs of sntoking nnd ca~ccr of the i&&k~~
                                          ____
Author.
year,                    CZWZS                                     Contwls
countrY.                   ____.                                   ___~               ___ .-
reference       Sex    Number           Method of selection             Numbrl            Method of selection
                                             _______  ___~              ____I_

Lilienfeld et al.,
1956,
U.S.A. (171).

M.

  F.



M.




M.
F.







--
M.
F.




M.
F.

M.

321

llfi

Admissions to Roswell Park Memorinl Institute.
1945-55 over 45 years of age.
Same as males

Schwartz et al.,
1961.
France (e@)

214

Admissions to hospitals in Paris and a few
large provincial cities since 1954.

337

109
317

214

No disease patients.

Benign bladder conditions.
No disease patients.
      _I-       ~~-
Healthy indi\Gduals admitted to same hospital
because of work or trnffic accident, matched
by 5 year age group.

Lockwood.
1961,
Denmark (175).

-

-

2R2
R7

All bladder tumors reported to Danish Cancer
Register during 1942-56 and living at time
of interview in Copenhagen and Fredericks-
burg. (Includes bladder papillomas).

28'2
x7

A. Fwm election wlls matched with cases ac-
curding to xx, age, marital status. occupa-
tion, and residence.

H. Another control group obtained from sam-
pit, <jf Danish Morbidity Survey (1952. 1953.
.and 1954) compared with respect to smok-
ing historica.

Wynder,
1963,
U.S.A. (326)

200
50




100
20

First phase:
  Admission to several hospitals in New
   York City during January 1957-Decem-
   ber 1960.
Second phase:
  Admission to same hospitals during 1!161.

Admissi(m to same hospitals (excluded cancel
of w'ipiratow system, upper alimentary tract,
myornrdinl infarction) matched by sex and
age.
Snrnc ns above.

Cobb and Ansell,
1965.
U.S.A. (57)
_I~__

136

Patients admitted to VA Hospital in Seattle
1951-61.

120 patient; with cancer of sigmoid colon, 222
pntirnts with non-neoplnstic pulmonary dis-
c':ise.


     TABLE AXi.-Summary of methods used in retrospective stltdies of s~tloking and carwe)' of the bladder (cont.)

    Author,
     war.                    Cases                                     COllt~OlS
    country.
    reference       Sex    Numhe:           Method of selection             N umbw            Method of selection
-
Staszewski.          M.     159    Patients with histologically confirmed bladder     750     Undefined srnnw age-matched.
1966.                          carcinoma.
Poland (201).

D~elry nnd Cohen.                                                     -
                M.     127    Patients with histologically confirmed bladder                                 -___
                                                             127      Patients in same hospital with non-cancerous
1966,                          carcinoma.                              or pulmonary disease matebed ior age.
England (66).

Yoshida et al.,         M.     163     Patients with bladder cancer.                163   "Compa&on cases."
196X,             F.      29                                      59
Japan (390).
-__~
Kidn et al..           M.      88    Admissions to 15 hospitals in North Fukuoka      xx
1968,                                                          Selected from patients hospitalized in fame re-
                E`.      26      prefecture.                          26     &ion for non-urinary ailments and we-
Japan (144).                                                            matched

Dunham et al.,      -if.     334    Admissions to New Orleans hospitals with his-     350     Admissions tu same hospitals with non-ncoplas-
1968.             E'.      150    tologic diagnosis of bladder carcinoma.          177
U.S.A. (85).                                                         tic diseases and diseases unrelated to peni-
                                                                   tourinary tract.

Anthony and Thomas.    M.     ax1    Patients with papilloma and esncer of bladder     275     Surgical patients without ~aneer previously in-
1970.                          at Leeds betweeen 1958-67.
England (9).                                                         ten&wed for lung cancer study.


     TABLE A35a.Summary of results of retrospective stzldies of smoking and cancer of the bladder
-... __        -                                                            -~ ._

Author,           Percent nonsmokers
veal-.           ___~

Percent heavy smokers

Percent cigarettes    Relative risk ratio:
  smoked     All smokers to nonsmokers
           ~.____~

  cointr;.
  reference      sex

Lilienfeld et al., M.
1956. F.
U.S.A. (171).

                                           All
ClW?S   Controls      CCW3   Controls     C*SeS              Heavy Cigarette          Comments
                                   Controls smokers smokers smokers
                                        -__I_                      ___-
15.0     29.0       .            61.0    44.0       2.3    . .   .2.7     Cigarette and other.
37.0     83.0             . .                     1.4          

                                                       ~~__                       -______
Schwartz et al., M.      11.0     20.0                    x3.0    70.0       2          2.2     Cigarette only.
1961,
Fr*nce (249).

Lockwood. M.
19G1. F.
Denmark (175).

9:o
66.0

13.4
66.0

30.0
4.0

15.0
4.0

--__  ~- - --__  ---~~~  ~___
30.0     1.5.0       1.6     8.0    3.0     Cigarettes main mode of
            1.5     1.2          smoking.

wynder et al.. M.
19GR. F.
U.S.A. (326).

7.0     18.0
61.0     86.0

47.0    23.0
6.0     ._.

85.0


     ~___- ___-- ~~ ~--__ ____~. ___
63.0       2.9     5.2    3.3     Phases A and B eom-
       3.9    .           bined.

    -                                                                           _____
Cohb and Ansell. M.      4.6     25.8       79.4    43.3       .            7.3    10.3    
llfl.5.
U.S.A. (57).

Stnsruwski, M.
1%X.
Poland (261).

                                       .~~~__~~_
6.7     16.0       86.7    65.7       X7.1    72.2       2.7     3.1     2.9     CiKWettC4 0,-h'.

De&y and Cohen, M.
1966.
Enalnnd ( 66 ) .

                                         ~~_I_ ._
2.4      7.1        .     . . .        . .            3.1         . .


     TABLE A3Sa.-Summaw~ of results of retrospective studies of smoking and cancer of the bladder (cont.)


   Author.                     Percentnt~rettes    Relative risk ratio:
                  I'crrmt nonsmokers    Percent heavy smokers               All smokers to nonsmokers
   YCBI',                  ~~                               ___ .-
  country.                                                       All   Heavy Cigarette          Comments
  rrfermce     SC\    Casrs   contrkJs      Cases   controls     Cases   Controls smokers smokers smokers
                                                     .-
Yn-hirln et al      M       R.O     22.7     43.4 - 33.0        _~     -       3.4     3.7 -
19GS.         2,`      62.1     8G.4        -     -              -
Japan (.?.%I).
_--
Kida et al.,                                             .-
            M.      11.0     11.0     32.0    29.0        -             1.0          -
1968,         F.      16.0     21.0              -                      1.4 -
Japan (144).                                                                           .-~
Dunham et RI..     iv.      X.6     14.5        -     -       49.4    45.4       1.R          1.8     Cigarettes onb.
19GR,         F.      62.2     61.5              -       32.0    2R.2       1.0 -    1.1
U.S.A. (85).
__~
Anthony and      F.      fi.3    6.3 - -     -       36.6   29.1 --  1.0 -    1.3     Cigarettes only.
Thomas,                                                                          More than 16 a day.
1870,
England (3)


CHAPTER 5

                  Pregnancy


Contents

Introduction   .......................................
Effect on birthweight  ................................
Effect on outcome of pregnancy  ........................
Experimental studies  ................................
Summary  ..........................................

References  .........................................

LIST OF TABLES

1. Summary of methods used in study of smoking and human
pregnancy  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2. Maternal smoking and infant weight . . . . . . . , . . . . . .
3. Maternal smoking and prematurity . . . . . . . . . . . . . . , . . ,
3. Comparison of abortion, stillbirth, and neonatal death in
smoking and nonsmoking mothers . . . . . . . . . . . . . . . . . . .
5. Human experimental data on smoking and pregnancy , .
6. Animal experimental data on the effect of smoking and
nicotine on pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I'flp?
389

389

390

407

415

415

391
397
400

405
408

411

387


INTRODUCTION

In recent years, there has been increased research on environ-
mental factors which may adversely affect the unborn child. The
potential effect of maternal smoking on the fetus has been of par-
ticular interest because of the large number of pregnant women
who smoke and because smoking is an environmental influence
which could be controlled. Based on 1970 surveys of smoking
habits in representative samples of the U.S. population, it is
estimated that one-third of American women in the child-bearing
age group of 15 to 44 years are cigarette smokers. What propor-
tion of these give up smoking or cut down substantially on their
smoking during pregnancy is not known.

EFFECT ON BIRTHWEIGHT

Epidemiological and experimental studies have supported the
view that maternal smoking during pregnancy exerts a retarding
influence on fetal growth (tables 2, 6). Analysis of over 100,000
births shows that the infants of mothers who smoke during preg-
nancy have a mean birthweight of 6.1 ounces less than the infants
born to nonsmoking mothers (table 2). Several studies have docu-
mented that this effect is independent of other factors known to
exert a negative influence on infant birthweight, such as elevated
maternal blood pressure and small maternal size (1, 36, 39). The
reduction in infant birthweight is greater among heavy smoking
mothers than light smoking mothers (12,21,,03,30,~1,50,58), and
has been found in pregnancies terminating in each trimester (12,
16,23,40,51,54). In a study of more than 48,000 women, Under-
wood, et al. (51) demonstrated that infants born to women who
smoked during part of their pregnancy were significantly smaller
than infants born to nonsmokers, and that infants born to women
who smoked throughout their pregnancy were significantly smaller
than the infants born to women who smoked during part of their
pregnancy. Russell, et al. (39) have presented evidence that al-
though infants born to smoking mothers weighed less than those
of nonsmoking mothers, they grew more rapidly during the first
six months of life. At one year of age, children born to smoking
mothers weighed nearly the same as those born to nonsmoking
mothers. They concluded that smoking exerts a retarding influence

389


on fetal growth and that after delivery this is largely compensated
for by a period of more rapid growth.

As documented in more than 15 prospective and retrospective
studies, smoking mothers have significantly more infants who are
premature, as delined l)y wlzight alone (<2,500) grams, than do non-
smoking mothers (table 3). Buncher (4) studied the mean dura-
tion of pregnancy in smokers and nonsmokers in a survey which
included 49,897 live births. He found that women smoking 20
cigarettes a day had a mean length of gestation which was approxi-
mately one day shorter tha.n that of nonsmoking women. He calcu-
lated that this shortening of gestation is enough to account for only
10 percent of the known reduction in birthweight that is associated
with maternal smoking.

EFFECT ON OUTCOME OF PREGNANCY

Some controversy has surrounded the question of whether ma-
ternal smoking during pregnancy is associated with an increased
risk of spontaneous aborti'on, stillbirth, and neonatal death. Table
4 summarizes the studies which have dealt with this question. Some
of the studies did not dem.onstrate such an increased risk (7, 34,
*SO, 51)) while others did (1.2, 23, 33, 58). Many of these reports
(7, 23, 33, ,34, i 7, 3.9, 58) .were based on retrospective studies and
included women delivering their infants in hospitals and infants
whose names appeared on listings of newborn children (table 1).
As Russell, et al. (3.9) ha1.e pointed out, such studies may be sub-
ject to selective bias since they tend to underrepresent women who
have aborted. These retrospective studies also did not systemat-
ically control for maternal social class, parity, and maternal age,
all of which are related to the outcome of pregnancy and also are
related to smoking in some populations. In a prospective study of
more than 2,000 pregnant women, Russell, et al. (39) have demon-
strated a significantly higher percentage of unsuccessful pregnan-
cies (that is, abortion, stillbirth, or neonatal death) among women
who smoked during their pregnancy than among those who did
not. He interpreted his findings to mean that 20 percent of ". . . un-
successful pregnancies in women who smoke regularly would have
been successful if the mother had not been a regular smoker" (38).

The Second Report of the 1958 British Perinatal Mortality Sur-
vey published in 1969 is one of the largest prospective studies to
deal with this question (.5) . It included 98 percent of the total births
registered during one welzk in March 1958 throughout England,
Scotland, and Wales. In this study, a large amount of obstetric and
sociobiologic information was obtained on 17,000 singleton births.
This study reported that "the mortality in babies of smokers was
significantly higher than in those of nonsmokers." The increase in

390


TABLE l.-Summary of methods used in study of smoking and hzman pregnancy

-                                                   ______
Author.
  Year,    Retrospective
country,      or    N"zber          Data collection                  Case selection
reference   orosrxctive "ersons

Simpson,
1957.
U.S.A. (44).

R.

7,499

Questionnaire was filled out 48 hours
after delivery for all patients at
San Bernardino County Hospital
for 3 wars. Same form used for
2 years at St. Bernardines Hos-
pital and Loma Linda Hospital.

Multiple births excluded.

LOW,
1959,
England (29).

It.

2,042

Questionnaire was filled out for every
woman delivering at one of six
Rirmingham hospitals over a 5-
month period.

Non-Europeans and women  with    Social workers performed
twin births were rxcluded.          interviews.

Frazier et al.,      F.       2,736     (al Interview.                 All Neur<r women seen at Raltimwe
1961,                       (bl Prenatal clinic history.           Maternity Interviewing Service in
U.S.A. (12).                   (c) Birth and stillbirth certificates.       1!16!1 who WCL`C scheduled fop de-
                                                livery at HaItimore City Hosl,ital
                                              and who received prenatal care in
                                                  clinic "f Baltinwre City Health
                                                    Ikrlartme"t.
___~
Herriot et al..      K       2,745    Questionnaire filled out for Aber-
1962.                       deen city residents who were de-
Scotland (16).                   livered in Aberdeen City Hospital
                           over a l-year period.

Nonsxwkers include occasional
smokers.

Save1 and
Roth,
1962.
U.S.A. (41).

K.

I.416

1.500 consecutive patients admitted
to Newark Beth Israel Hospital
were interviewed.

Comments

The county hospital population
was different. with 50.6 per-
cent of the births being
"Mexican".


TABLE L-Summary of methods used in study of smoking and human pregnancy (cont.)

Author.
  war,    Retrospective   NU"lblS-
CountrY.      or        of            Data collection                  Case selection                 C""l"W"tS
reference   prospective    PCI'S""E

Yerushalmy,      P.        9X2     Form questionnaire.             Pregnancies terminating in abortion
1962,                                                  WPR excluded.
U.S.A. (53).

Murdoch.
1963.
U.S.A. (SO).

O'Lane,
iYb&,
U.S.A. (33).

1~.




R.

500




1.031

Personal interview by sothov.




Standard U.S. Naval Obstetrical Code
Sheet was used with supplemental
questions. Additional information
was obtained from prenatal his-
tory.

All mothers delivering at Nebraska
Methodist Hospital from Septem-
her 1962 to January 1963.

1,031 Caucasian women who had
single pregnancies delivered WI-
ginally over n B-month period.

"Smokers" defined as those
smoking regularly each day.

Zabriskie.
1963.
U.S.A. (58).

R.

2.000

History was obtained during the
postpartum period from 2,000 con-
secutive births  over a B-month
period.

Twin deliveries were omitted.

Yeruuhalmy,
1964.
U.S.A. (51).

P.

6,X00

Personal interview.

All women were members of Kaiser
Foundation Health Plan. Only
pregnancies terminating in single,
live births included. All races ex-
cept whites and Negroes were ex-
cluded.

5,3X1 whites 1,419 Negroes.

MacMahon et al.,
1965.
U.S.A. (24).

R.      12,192     Mnil questionnaire.

Mothers of single. white, legitimate
live births. Mothers were residents
of Massachusetts and delivered in
May or June of 1963.

Birthweight based on birth
certificate.


TABLE L-Summary of methods used in study of smoking and human pregnancy (cont.)

Author,
ye*=.    Retrospective   Number
country,      or        of            Data collection                  Case selection                 C"mme"ts
reference   prospective    persons

McDonald and
Lanford.
1965.
U.S.A. (96).

I'        177     Interview

White, unmarried primigravidas re-
ceiving obstetric care over a 2-
year period.

Peterson et al.,
1965,
U.S.A. (34).

R.

7,740

Cooperative study involving 17 hos-
pit& in 13 states, using U.S. Air
Force obstetrical code.

Includes only those multiparss whose
prior  infants  weighed >2.500
grams (Caucasians). All preg-
nancies  with  B"Y  complicntion
were excluded. Ceserean sections
and induced delivery were ex-
cluded.

Robinson,
1965.
Burma (37).

P.       1,614     Interview.

Regular attendees at prenatal clinic.

46.X percent of women smoked
cheroots.

Underwood et al.,
1965,
U.S.A. (50)

R.       4,440

interview by obstetrical resident.
Data was obtained on 16.158 preg-
nancies from the 4,440 women.

Puerperal wonw" from Roper Hos-
pital and Medical College Hospi-
tal. Only infants weighing >I,000
rrams WEI`P included.

Women from Roper Hospital
were of above average eco-
nnmic status. Women from
Medical College Hospital in-
cluded Negro and white
patients.

Downing and
Chapman.
1966.
U.S.A. (7).

R.

5,659

Review of clinic records from 1952
to 1958.

Six-year tot"1 of obstetrical patients
at clinic.


TAULE l.-Szcmmar~/ of ~trclhock used tn study of smoking and huwlan pregnancy (cont.)

Number
of
*erson':

2.02:1

      Data collection


Epidemiologic questionnaire. Much
data collected uver telephone. Ad-
ditional datn obtained from birth
certificates.

Rcinkr nnrl
Hrndrrso"
14fX.
U.S.A. (SG).

Ii.

3.151;    Registration data of prenatal clinic.

       Case selection


Study population was identified by
the listing of newborn infants in
ii Seattle newspaper during May.
June.  and July of 1964. Twins
were excluded.

      Comme"ts


95.4 percent of mothers were
white.

Negru women who delivered single,
live infant- from 1962-64.

Patients receiving care at "concep-
cion palncias" in Caracas.

Underwood et al..
Illfii.
U.S.A. (51).

I'

4X.605

Code sheets submitted from 44 world-
wide  navel  installations. Code
sheets were completed by the at-
tending physician upon the mo-
ther's admission to the labor room.

Women with single pregnancies de-
livered of infants weighing more
than 500 grams between July 1,
1963, and June 30, 1965.

Duffw and
MacCillivray,
I'JFX.
Scotland, (8).

Mulcahy and
Knaugs,
1YliP.
Ireland (28).   .-

II

2,543

Antenatalclinic records.

All "booked" marriezl city primi-
gravidae attending the antenatal
clinics during 1960. 1964. and
1965.

The number of cigarettes
smoked was not considered.

3.6X1

Mothers admitted to the Coombe
Hospital from April 1963 to Oc-
tober 1964.


Author.

TABLE I.-Summary of methods used in study of smoking and human pregnancy (cont.)

  year,   Retrospective   Number
country.      Or        of            Datn collection
reference                                                     Case selectio"                 Comments
        prospective    persons
-

Russell et al.,      P
1968,
England (89).

Tokuhata,
1968,
U.S.A. (49).

R.

Ihmcher,
1969,
U.S.A. (4).

R.

Butler and       1'
Alberman,
1969.
Great Britain (5).

      ~~~-__
Terris and       R.
Gold,
1969.
U.S.A. (47).

2.110

2.016

49.R97

17.000

197

-









-

Data collected by Senior resesrch
midwives over  a 4- to fi-year
period.

Women attending the two main ma-
ternity units in Sheffield, who
"comprised n reasonably repre-
sentative sample." Multiple preg-
nancies were omitted.

Personal interview or mail question-
naire of surviving family members.

Women selected from Memphis and
Shelby County death registry who
died of cnncer of genitalia or
breast since 1950 and who had
been married.

Included some threatened abor-
tions and some with "bad"
obstetrical histories.

Control group taken from same
registry. They died of causes
other then cancer and were
matched for rnce, age at
death, and year of death.

Data obtained from U.S. Naw ob-
stetrical study from 1963 to 1965.
Smoking dats obtained by physician
at the time of mother's admission
to labor room.

Women with single pregnancies de-
livered of infants weighing more
than 500 grams between July 1.
1963, and June 30, 1965.

Includes cases reported by
Underwood et al. (47) in
1967.

The British Perinetal Mortality Sur-
vey of 1958 when n large amount
of obstetric and sociobiologic in-
formation wns obtained from birth
sttendants, records, and nt inter-
view with the mothers.
        --

Public Health Nurse interviewed each
mother on first or second post-
partum day.

98 percent of the total births reg-
istered during 1 week in Msrch
1958 throughout England, Scot-
land, and Wales.

Another 7,000 perinatal deaths
were surveyed by identical
methods over a &month
period.

Premature   Negro   ward   births
(<`&SO0 grams) with no known
cause of prematurity. Controls
were matched by sex, birth order
of infant, nge, and marital status
of the mother.


         TABLE I.-~Summary of methods used in study of smoking and Izunlan pregnancy (cont.)

Author.
  year,    Retrospective   Nlllllber
coontry,               ;f            Data <o::ei:i"i,                  Case seiection
            3r
refewnce   prospective    T)PI`SO"S                                                             Lommcnts
                       ~___
Mulcahy et al.,     I'        100     lntcwiew by physician.
1970,                                                 100 mothers of term infants who

Ireland (28).                                            wew free from all sianifirent medi-
                                                  ical and obstetrical complications.
                                                  All were between 20 and 30 years
                                                    of age and were Para III or less.
                                                     All had normal deliveries. Half
                                                  were smokers of 10 or more ciga-
                                                     rettes per day.


    TABLE 2.-Maternal smoking and infant weight
(Numbers in parentheses indicate absolute number of infants in respective groups)

Author,
reference

Nonsmoker

Infant weight                    Difference in mea" weight
                             of infant of smoker             Comme"ts
          Smoker                versus nonsmokrr

Lowe (29)                       <lO cigarettes       >I0 cigarettes                 Effect on infant weight WBS independent
                               per day            Per day                     of maternal sge, parity, or complica-
        Male . . . . . 7.43 lbs.   (607)   7.1x (187)          7.05 (165)                      tions of pregnancy.
        Female  7.23 Ibs.   (539)   6.74 (163)          6.67 (147)
        Total  7.33 lbs.  (1,146)   6.38 (350)          6.87 (312)   170 g.   (6 oz.)

Frazier              3,osog. (1.717)               2,924 g. (1.019) 156 8. (5.5 OZ.)         Nonsmokers include occasional smokers.
et al..
(12).

Herriot     No data  (1,473)               No data (1.272) 160 g. (6.6 oz.)        Effect on infant weight was independ-
et al..                                                               ent of maternal age, parity. height,
(16).                                                                     or social class.

Save1 and    White  . 3,374 g.   (383)                3,141 g.   (428) 233g. (8.2 oz.)         Ciy*Tc.ttC#
Roth     Negro .._... 3,173g.   (364)                3.031g.   (240) 142 g. (5.002.)          per day        Infant weight
(41).                                                                    White smokers:
                                                                         l-10 3,ZlOg.  (161)
                                                                          11-20  ._ 3,198g.  (184)
                                                                          >zo  . . 3,OlOg.  (83)
                                                                      Negro smokers:
                                                                      l-10 3,042g.  (169)
                                                                          11 20  3.012g.   (57)
                                                                           >ZO  ._ _. _. _. 2,968 g.  (14)

Murdoch            7 Ibs. 7.5 oz.   (243)              6 Ibs. 15 oz.   (258)       8.5 oz.          Cigasrttce
(30).                                                                    PCT duy        Infant weight
                                                                           l-10  t.. 7 lbs. 2 oz.
                                                                          11-20  _. 6 lbs. 11 oz.
                                                                      >20 .._........ 6lbs.lOoz.
                                                                           >40  . . . 61bs. $02.

     O'Lane               2.9'78 g.   (666)               2,938 g.   (465)  40 g. (1.4 OZ.)
li:       C-w).
-4


TABLE 2.-Maternal smoking and infant weight (cont.)

(Numbers in parentheses indicate absolute number of infants in respective groups)

                           Infant weight                   Difference in mea" weight
Author,                                                    of infant of smoker             Comments
reference         Nonsmoker                 Smoker                versus nonsmoker

Zabriskie             3,320 g. (1,043)                3,091 g.   (967) 229 8. (8.1 OZ.)         Cigarettes
(58).                                                                  per day        Infant weight
                                                                           <lo  . 3.205g.  (260)
                                                                          10-20 3,090g.  (396)
                                                                     20-30 ._ ._ __ __ __ 2.9'7Og. (264)
                                                                         >30  3,190s.  (38)

MacMahon   Male  124.00~. (3,063)               116.3 oz. (3,173)       7.1 oz.         Cigarettes      Infant weig%t
et al.,     Female  . . . 119.9 oz. (2.906)               111.9 oz. (3,011)       8.0 oz.          ,WT day         ( oumx?s )
(24).                                                                           Male      Fe"l&
                                                                           /In
                                                                           1."  Y21.2 ($59) ??C,.E (595)
                                                                          lo-20 115.2 (1.262)   112.2 (1.259)
                                                                        20-40 114.6( 1,166)   108.9 (1,088)
                                                                          >40 113.2 (66)   111.7  (49)

McDonald

Light smoker

Heavy emoker

No significant difference be-

and
Lanford
(26).

111.68 oz.   (81)    110.83 oz.(42)   109.38 oz.(48)     tween mea" birthweights.

Underwood
et al.,     Group:
(50).        I 3,622g. (2,406)

Cigarettes
pe+ day
  <lO
10-20
  >20
  <lO
l&20
  >20
  <lO
10-20
  >20

           Fm >20 cigarettes per day
 3,349 g.       353 g. (12.5 oz.) (p<O.OOl)
 3,236 g. t (1.720)
 3.169 g.
. 3.171 g.       212 g. (7.5 oz.) (p<O.OOl)
 3.146 g.  t (660)
 3,092 g.
 2,936 g.      115 8. (4.1 oz.) (p<o.ool)
 2,965 s. t (3,040)
 3,011 g.

II  . 3,304 g.   (661)

III ___ __ 3,126g. (7,776)






.

Patients were divided into 3 grows:
   I. .Private patients of above av-
       erage economic status.

II. .White patients of average
    economic .status.

  III. .Negro patients of low eco-
       nomic status.
t Total for all smokers in each grwp.

Ravenholt   Male . . `7.80 lbs.   (171)              7.21 lbs. t(167) 59 lbs. (9.4 oz.)         t Smoked >4.000 cigarettes during preg-
et al..     Female  . 7.60 lbs.   (160)              7.05 lbs. t(171) .46 lbs. (7.2 oz.)          "*"W.
(35).


   TABLE 2.-Maternal smoking and infant weight (cozt.)
(Numbers in parentheses indicate absolute number of infants in respective groups)

                           Infant weight                   Difference in mea" weight
Author,                                                    of infant of smoker             Comme"ts
reference         Nonsmoker                 Smoker                versus nonsmoker
Reinke and            3.135 g. (1,542)               2.987 8. (1.614) 14R g. (5.2 oz.) (p<O.OOl)
Henderson
($6).
~-                                                                     ~___             -
Kizer (19).   Data not svailable           Deta not available               97 g. (3.4 oz.)        Total number of patients-2,095.

Underwood                        Cigarettes
et al..                           per day
(51).              3.396 g. (24,665)    l-10 . . . . . 3.286g. (7,609) 109g. (3.80~)
                                11-30  . 3,196 g. (14.450)  199 8. (7.Ooz.)
                                >30  3,182g. (1,570) 213 g. (7.502.)                           .___
Mulcahy              113.3 oz.        Cigalettee
and                            per day
Knaggs                           l- 4  111.4oz.            1.9 oz.
(28).                             5- 9  102.30%.           11.0 oz.
                                10-14  . 102.0 oz.           11.3 oz.
                                16-19  I.. 102.9 oz.           10.4 oz.
                                >20  . 102.40%           10.9 or..

Russell      BP                                         The effect of ma&al smoking on fetal
et al.,    <140/ 90 117.2 2 .7 oz.   (9R4)            107.2 !I 1.0 oz.   (496)      10.0 oz.          weight ~8s independent of maternal
(39).      140/ 90 114.2 3- 1.2 oz.   (340)            103.9 & 2.4 oz.   (117)       5.3 oz.          parity. age. height, educational level,
        >150/100 99.3 -c 2.6 oz.   (138)             90.8 15.3 oz.    (35)       8.5 07..          attitude to pregnancy or work during
                                                                  pregnancy, father's social class, con-
                                                                  sort's social class. and sex of the child
                                                                       or premature delivery.

Butler and
Alberman
(5).

3,375 g. (11,146)           3,205 g. (4.660) 170 g. (6;~)

fieductio" of mean birthweight of babies
born to smokers WBS independent of
unduly high proportion of babies born
preterm, and maternal factors includ-
ing social class and maternal height.

     Mulcahy              3.83 kg.   (50)                3.43 kg.    (50) 396 g. (14 oz.)
2      et *I.,
       (29).
9


TABLE 3.-Maternal smoking and prematurity (cont.)
(Figures in parentheses are the absolute number of premature births)

Author.
reference


Simpson
(44).









Lowe
(43).

   Premature by                Percent of premature infants         Mean duration of pregnancy
       Duration of ~ ~----        Comments
Weight    gestation                Nonsmokers   Smokers             Nonsmokers    Smokers

<2.600 B.          Name of hospital:                                             Number and percent of
                 County 7.77  (144)  11.48   (96)                             premature infants:
                 Loma Linda  6.16   (86) 12.13   (49)                              Nonsmokers 6.39 (328)
                 St. Bernnrdines 5.21   (98) 10.50 (119)                              Cigarettes per day:
                                                                           l-5 . . 7.06 (47)
                                                                           6-10 .11.18 (89)
                                                                         11-15 .11.36 (31)
                                                                           lfi-20  .13.6
                                 21-m ._ ._ .25.0 I::;
                                                                           >30 .33.3   (9)
                                            ___-
      <260 days                 6.4   (57) 10.6   (58)           279.9 days    278.5, days   At each week of gestation, the
                                                                        mean birthweight was lower
                                                                          in babies of smokers.

Frazier
et al..
(12).

<2,500 8.

11.2   (175) 18.6   (179)            38.7 weeks   3X.4 weeks Infants of smokers weighed less
                                             than infants of nonsmokers
                                             for a wide range of preg-
                                             nancy duration.

Herriot    No data    No data    Social class:                                                   2,745 patients in the study.
et al ..                      I and II  ......... 4.0        4.8                                At each week of gestation, the
(16).                      III  .............. 3.5        6.8                                  mean birthweight was lower
                         IV andV  ........ 6.3       12.6                                   in babies of smokers.

Save1 and          36 weeks   White  ............... 2.6    (10)   4.9   (21)       White .39.8       39.4
Roth                   Near,,  .............. .13.7    (50) 11.3   (27)      Negro .38.X       38.8
(41).
       t<zsoo g.          White  ............... 1.8    (7)   3.7  (16)-                           t Premature by weight but ma-
                      Negro  ............... 3.6   (13)   8.3   (20)                            ture by date (>37 weeks).


TABLE 3.-Maternal smoking and prematurity

(Figures in parentheses are the absolutr number of premature birth?)

Author.
reference

   Premature by

       Duration of -
Weight    gestation

Percent of premature infants

Nonsmokers   Smokers

  Mean duration of pregnancy
___~ -
    Nonsmokers    Smokers

Yerushalmy <5',C. lbs.
(54).

5.9   (36)   8.1    (30)

Murdoch
(30).

<2.500 g.                        3.3    (R) 13.6   (35)

O'L&ine     <2,500 B.                        5.1    (29) 11.x   (55)
(83).

Zabriskie    <2,500 g.                        3.83   (40)   9.93   (95)                            Ciparette.s
(58).                                                                           per day:       Prematurity
                                                                           <lO 6.54 (260)
                                                                           10-20  9.11 (396)
                                                                           20-30  .14.39 (264)
                                                                           >30 .10.53  (38)
                                 ___ ~~   -~~~___
Yerushalmy  <5 Ibs. 8 oz.        White  3.5   (112)   6.4   (138) (p<O.Ol)                      Infants of smoking mothers
(54).                   A'.egro  4.9    (46) 13.4   (64)                            weighed less then infants of
                                                                           nonsmoking mothers in each
                                                                           gestational age.

               <37 weeks  White .t5.9   (188)   6.5   (140)                            t DilPerence betwwn smokers and
                       Negro .13.4   (125) 16.7   (X0)                             nonsmokers not significant.
            -
MrDonald ,
        <2 500 I?.                      Cigarettes per day
and                           4.6   (4)     <lo     4.8   (2)
Lanfurd                                  >lO     8.3   (4)
(LO).

   Pctersnn    <2,600 g.                     Cigarettes pm day                                  Overall incidence of prematurity
    rt al.,                          2.5 (111)     I-10     3.0   (35)                              in smokers vs. nonsmokers
    (54).                                    11-20     4.x   (80)                             significant at p<O.OOl.
g --                                     >20     3.4   (16)                                     .-


TABLE 3.-Maternal smoking and prematutity (cont.)
(Figures in parentheses are the absolute number of premature births)

Author,
reference

  Premature by

       Duration of ~
Weiaht    gestation

Percent of premature infants         Mean duration of pregnancy

Nonsmokers   Smokers             Nonsmokers   Smokera

Comme"ts

Peterson
et al.,
(contd.)
t.14 )

<37 weeks

      Cigarettes ncr day
1.3   (58)     l--l0     1.4   (16)
          11-20     2.3   (36)
          >20     2.4   (11)

Robinson    <2.500s.
(37).

Underwood <2,500 g.
et al..
(50).

Group:
   I

II

III

Downing   No data    No data

and
Chapman
(7).

16.5 (152)           31.0 (181)

Cigarettes per day

4.5 (108)     <IO     4.2
          10-20   5.9
         <20     7.2
7.5 (42)     <lO    12.6
          10-20   12.5
        >20    16.9
9.9 (770)     <IO     14.1
          lo-20   14.8
         >20    10.2

Percentages and absolute num-
ber of premature births 8re
based on 16.158 pregnancies
recorded in 4,440 women.
Group I. Smokers vs. "on-
smokers p<O.O26.
Group II., III. Smokers vs.
nonsmokers p<O.OOl.

2.2   (66)            3.3   (88)

Reinke and  <2,500 g.                10.6  (163)           16.7  (2'70)            37.7  weeks   37.67 weeks  p<O.OOl
Henderson        <35 weeks       20.3 (313)           22.8 (368)                            p>o.o5
(3-C).


TABLE 3.-Maternal smoking and prematurity (cont.)
(Figures in parentheses are the absolute number of premature births)

           Premature by
Author, ~
reference           Duration of __
        Weight    gestation

Percent of premature infants

Nonsmokers   Smokers

Mean duration of pregnancy

Nonsmokers    Smokers

Underwood  <2,500 K.
et al..                          5.7
(51).

<36 weeks         5.R

Iluncher
(4).

   Cigarette8 .wec day
1,417)     l-10     7.6 (671)
       1 l-30     9.4 (1,358)
        >30     11.2  (176)
1,442)     l-10     6.9 (525)
       11-30     7.5 (1,084)
       >30     7.5  (118)

Prematurity by birth weight ro8e
directly to B significant degree
(p<O.Ol) with each smoking
category.

Data suggested that smoking in
any trimester decreased birth
weight.

                           _________
Birth                 t Smokes 20 cigarettes per day.
Male   39.55 weeks t 39.35 weeks
Female 39.69 weeks t 39.51 weeks

Rutler and   <2,600 g.                6.4 (602)            9.3 (433)
Alberman
(5).

Terris
and
Gold
(47).

A significant (p<O.Ol) difference
was found between percent of
mothers who smoked and
those who had premature
deliveries and the control
group.


mortality rate was found for both stillbirths and neonatal deaths,
and was somewhat greater for stillbirths but not significantly so
(see Butler, table 4). The authors state that ". . . the differences
between mortality rates in babies of smokers and nonsmokers pray-
tically disappear when they are compared within groups of similar
birthweights . . . It therefore seems reasonable to conclude that the
increased mortality found in babies of mothers who smoke is ac-
counted for by the overall excess of low birthweight babies in this
group. . . " with their attendant high risks.
In 1964, Yerushalmy (Si) reported on a group of 6,800 women

whose pregnancies terminated in single, live births, excluding still-
births and abortions. The study was prospective and was controlled
for maternal age and parity. He noted that neonatal mortality in
infants born to smoking mothers and weighing less than 2,500
grams was significantly less than that of small infants born to
nonsmoking mothers. He referred to these small infants of smoking
mothers as being "apparently healthier" than those infants weigh-
ing less than 2,500 grams who were born to nonsmoking mothers.

As this report showed, whe-n compared to infants weighing more
than 2,500 grams, a small (<:2,500 grams) infant faces a greatly
increased risk of neonatal mortality, whether it is born to a smok-
ing mother or to a nonsmoking mother (54). The neonatal death
rate for the small infants of srnoking mothers was less than that for
small infants of nonsmoking mothers, but neither group can be
considered "healthy," having sharply elevated death rates. The
overall neonatal mortality for babies born to white smoking
mothers was 12 percent higher than that for babies born to non-
smoking mothers. This is not significantly greater than the neo-
natal mortality of infants born to nonsmoking mothers. On the
other hand it is also not signilicantly different from the 31 percent
excess mortality reported by Butler, et al. (5)) which is statistically
significant.

Interpretation of the neonatal mortality among the infants
weighing less than 2,500 grams in the Yerushalmy study is dif-
ficult. By considering only live births, the series may have included
a higher proportion of infants whose smaller birthweight was pri-
marily due to a modest growth retarding influence of maternal
smoking and not to other more serious congenital defects and intra-
uterine influences. Butler, et. al. (5) have shown that smoking
mothers have significantly more stillbirths than nonsmoking
mothers, and Russell, et al. (39) have found this to be true for both
stillbirths and abortions.

For reasons which aren't clear, smoking mothers have been
found to have a reduced incidence of preeclamptic toxemia as com-
pared to nonsmoking mothers (51) . However, given the presence of

404


TABLE I.-Comparison. of abortion, stillbirth, and neonatal death in smoking and nonsmoking mothers

                                     NS = Nonsmokers   SM = Smokers
-                       Numbers                          kares/l.""" torai births
         _____--_                 .____  -___ .____  -__  ___~~

  Author,      Total births     Abortions    Stillbirths  NdY:2'                            Neonatal
                                                   Abortions                                Comments

reference     NS                                                  Stillbirths
                 SM     NS SM    NS SM                                     deaths
                                          NS SM    NS SM      NS SM     NS SM
-
LlJXVe        1,l.M     66X               t47               i23.0 t30.0             t Includes first-day
(28).                                                                 deaths.
                                 --                 ~___                          ____
Frazier       1.717    1,010              t11   t16 40   2x                t6.4 t15.5     23.3   27.5   t "Fetal death".
et al.,
(12).

Save1
and
Roth
(41).

O'Lane
(33).

White
  3x3
Negro
  364

  1.027

        -                                          ____-

42s               2 3     4 2                5.2    7.0     10.4    4.7

240               8    4     6 3                22.0   16.7     13.7 12.5
                   -..                   -___~-
X87     91   112                       8R.6   12fi.3

Zabriskie      2.x50    2.769    250   348                       87.7 125.7
(58).

                                     -.                           ~-___~         -~____
Yerushalmy  White
(54).       3.218    2,163                       40   30                           12.4   13.9
        Negro
           939     480                       22   11                           23.4   22.9
           -                                      ___--~         .____-
Peterson      4.455    3,285                                            0.6    1.2      4.0    0.9
et al..
(S4).


TABLE 4.-Comparison of abortion, stillbirth, and neonatal death in smoking and nonsmoking mothers (cont.)
                             NS = Nonsmokers   SM = Smokers

                Numbers                         Rates/l,000 total births

Author.
reference

Total births
NS    SM

Abortions
NS SM

Stillbirths
NS SM

Neonatal
deaths
NS SM

Abortions
NS SM

Stillbirths
NS SM

Neonatal
deaths
NS SM

Comments

Downing
and
Chapman
(7).

3.029    2,630

                                         --
126   107     t32   t29             41.6   40.7    $10.6   tll.0              t Stillbirth plus
                                                             neonatal death.

ITnrlrrwnorl    "J,YQ1:    73.fiE                                            8.4    8.7 +,,1 r,n* In...,..,
                                                                         ,.l.Y ,A,,,1   , YnCI""ra ikrkata:
et al..                                                                           deaths in premature
(52).                                                                           infants (p>0.05).

Russell     iBI':                                                                    t Includes abortion.
et al.,      <14Oi90 984 496             t27 t32                         t27    t65              stillbirth, and
(39).      =140/90 340 117              t14   ts                               63               neonatal death.
         >140/90 133 35              tzo   t11      { 41
                                                              145 1 314             t Blood pressure.

Tokutata    White                                                                        Data based on use of
(49).       2.555     743            t246 tll2                        t96   t151               cigarettes only.
        Nonwhite                                                                    t Includes stillbirths
          1,236     350            t174 t64                        t141   t1s3               and miscarriages.

Rutler       11,145    4,660              215   129    146   80                19.3   27.6     13.1   17.2
and
Alberman
(5).

Source: Modified and expanded from Butler and Alberman (5).


preeclampsia, smoking appears to increase the risk to the fetus be-
cause of low birthweight and increased perinatal mortality (8).

In a case-control study of sudden, unexpected death in infancy,
Steele, et al. (46) observed that the percentage of smokers among
mothers of cases of sudden, unexpected death, 61.2 percent, was
significantly greater than the percentage among mothers of con-
trols, 39.5 percent.

The possible teratogenic effect of maternal smoking has not been
adequately evaluated. Although it does not appear to be a major
factor, there have been too few studies to determine whether ma-
ternal smoking is a significant teratogenic risk (5, 23, 28, 50).

Concern has been expressed about the possible long-term effects
on the children of women who smoke during pregnancy. Butler (6)
recently reported the results of a follow-up at age seven of the
babies studied in the British Perinatal study of 1958. He found that
the children of the mothers who were "heavy" smokers during
pregnancy showed significantly decreased height, retardation of
reading ability, and lower ratings on "social adjustment" than the
children of nonsmoking mothers. The differences were independent
of such factors as social class, age of mother, and parity.

EXPERIMENTAL STUDIES

In the past decade, research on the effect of smoking on pregnancy
has increased. Summaries of human and animal experimental data
in this area of study are found in tables 5 and 6. Elevated carbon
monoxide levels have been found in maternal and fetal blood in
women who smoke. Carbon monoxide is an inhibitor of carbonic
anhydrase and as might be expected the activity of this enzyme is
decreased in the cord blood of infants whose mothers smoke. The
significance of elevated fetal carbon monoxide is not clear; how-
ever, in an extensive monograph on this subject, Longo, (22) has
concluded that ". . . the decreased availability of oxygen resulting
from elevated (fetal) carboxyhemoglobin levels is probably in-
jurious to fetal tissues." Other changes noted in the infants of
smoking mothers have included a mild metabolic acidosis and a
higher mean hematocrit (56). Two studies (9,52) have shown that
placentas of women who smoke have a significantly greater ability
to hydroxylate benzo[a]pyrene than the placentas from nonsmok-
ers. Such findings suggest the possibility of fetal exposure to car-
cinogens; however, the significance of these findings is presently
speculative.

Early animal studies (10, 42) showed that rats and rabbits ex-
posed to nicotine or cigarette smoke have smaller offspring and
more unsuccessful pregnancies than control animals. Recent radio-

407


%
m

TABLE 5.--Human experimental data on smoking and pregnancy

Author.
ear.
country,
reference

Design of study                            Results                      comments

Sontag and
Wallace.
1935.
U.S.A. (45).

Fetal heart rate beforr and after smoking was   Average fetal heart rate before smoking ~8s 144.0.
studied Ii1 times in 5 patients.              The average fetal heart rate for the eighth to the
                                  twelfth minute after starting to smoke was 149.0.

Hlrddon et al.,
1961.
U.S.A. (14).

Carbon monoxide levels were measured in 50   (,I, Carbon  monoxide levels  were significantly
smokers and nonsmokers in a prenatal clinic.    (p<O.Ol ) higher in smokers than in nonsmokers.
Twenty-six paired maternal and umbilical vein   (b) Carbon monoxide concentrations in paired cord
blood specimens  wwr obtained at parturition    and maternal blood specimens were approximately
and tested for co levrls.                  equal.
                        ~-1 Oi rnrrying rapnrity  in rnrrl ?I$ m.aterz*!
                                 blood was reduced in smokers compared to non-
                                  smokers.

Heron. 1962,
New Zealand
(15).

58 pregnant smoking women were studied during
labor to determinr the effect which smoking
might have on the "grading" of the infant at
birth. CO levels were measured in both mother
and fetus.

-~~ -
Kumar and
ZOWkiS.
1963,
U.S.A. (?O).

The in rlir*o eftects of riaarette smoking on uterine
actively were studied in 1'7 pregnant gravidas
near term and not in labor. The in vitro effect
of nicotine on human pregnant and nonpreg-
nant myomrtriel strips was studied.

(a) CO levels in maternal and fetal blood were
higher in patients who smoked.
(b) Hespirntions in infants of mothers who smoked
took longer to be established and peripheral ey-
anosis w*s more common.

A control group who
had never smoked
was compared with
the survey group.

(a) In more than half (10/171. a definite increment
in uterine activity was noticed during cigarette
smoking.

(b) No oxrtoric effect of nicotine on myometrial
strips was noted.

Young and
Pugh
1963,
England (55).

Blood CO levels were studied in 19 full-term par-   CO content of umbilical vein blood at normal deliv-     Blood CO levels were
turient women. 16 of whom had normal deliv-    eries was .S2 and .36 volumes percent in infants      also studied in non-
e&s. Six of these smoked 10 to 20 cigarettes a    of mothers who smoked and mothers who did not      smoking male lake-
day. Mnternal blood was analyzed 15 to 30    smoke. as  compared with .33 and 28 volumes      ratcry workers in
minutes prior to delivery. Fetal blood was taken    percent,  rapeetively, in  the maternal venous      London and in
from the placental end of the umbilical vein.     blood.                                 males in Antarctica.


              TABLE 5.-Human experimental data on smoking and pregnancy (cont.)

   Author,
    Year.
   country.                 Design of study                            Results
   reference                                                                           Comments


Mantell,          Cord bloods from 50 smokers and 50 nonsmokers   A decrease in carbonic anhydrase activity in the     Carbon monoxide is
1964,            were analyzed for carbonic anhydrase activity.    cord bloods of infants whose mothers smoked was
New Zealand                                                                           an inhibitor of
                                                noted.
(25).                                                                           carbonic anhydrase.



Seoppetta,         CO concentrations were measured in the venous   CO levels were higher in smokers than in non-
1968,            blood of 46 pregnant women, including smokers    smokers. CO concentrations were approximately
Italy (65).        and nonsmokers. Funicular venous blood was    the same in maternal and funicular venous blood.
               analyzed at the time of delivery.
       -
Younoszai et al.,    32 women with normal pregn+ncies were studied   (a) Mean CO saturation of Hb in the venous blood
1968,           of whom 16 smoked >20 cigarettes a day. Both
Canada (56).                                     of the cigarette smoking mothers at the time of
               groups of women had normal deliveries and    delivery was 8.3 percent and in the nonsmoking
               healthy infants. Biochemical changes in the first    mothers 1.2 percent. The corrffponding mean um-
               48 hours of life were studied in the infants.      hilical vein blood levels were 1.3 percent and .I
                                                percent.
                                 (b) The blood Ph. pCOz and bicarbonate and lac-
                                             tate values in both groups of infants were within
                                                normal limits.
                                            (c) The infants of smoking mothers showed a
                                               higher mean hematocrit and mild metabolic acid-
                                                osis.
__
Engel et al.,        37 experiments were performed on placental blood   Human placental blood has a lower relative affinity
1969,            samples obtained from 15 pregnancies to detcr-    for CO than adult hiowl. It was calculated that the
U.S.A. (9).        mint relative affinity of human fetal Hb for CO    affinity constant of fetal Hb was approximately
           and Oz.                            20 percent less than that of Hb A.


TABLE 5.-Human experimental data on smoking and pregnancy (cont.)

Author,
Year,
country.
reference

Nebert et al..
1969,
U.S.A. (92).

Welch et al.,
1969,
U.S.A. (51).

Design of study                           Results                      Comment.8

Aryl hydrocarbon hydroxylase activity was de-   Significantly higher (p<O.OOl) levels of aryl hydro-
termined in the placentas obtained from 97    carbon hydroxylase were found in women with
women at the time of childbirth: 46 of the    a history of cigarette smoking.
women smoked between 20 and 40 cigarettes per
day during pregnancy and 51 women were non-
smokers.

Benzpyrene hydroxylase and aminoazo dye:     Enzymes were found in the placentas from all 17
N-demethylase activity was measured in 17 hu-    smokers. No detectable activity was observed in
man placentas obtained after childbirth from    the placentas of nonsmokers.
smokers and in 11 human placentas obtained
from nonsmokers.


TABLE 6.-Animal experimental data on the effect of smoking and nicotine on pregnanq

Author,
yea=.
CalmtrY,
reference

Animal             Design of study

Results                  comments

Essenberg et al
1940,
U.S.A. (IO).

Schoeneck,
1941,
U.S.A. (0).

Nishimura and
Nakai,
1958,
Japan (SZ).

Albino rat.

393 "young" from pregnant rats exposed to   The young of treated mothers were under-
tobacco smoke and 113 Young from preg-    weight; the young from nicotine injected
nant rats which received parenteral nico-    mothers were more underweight than those
tine were studied.                   from smoked mothers. Increased fetal wast-
                              age and neonatal deaths were observed in
                              treated animals as compared to controls.

Rabbit.









M0US.L

Smoke from one cigarette was blown into   (a) Offspring from "smoked" female rabbits
the nostril of healthy does by means of a    were smaller at birth than controls (17
catheter earh day. The does were "smoked"    percent).
daily throughout pregnancy and lactation.   (b) The stillbirth rate was 10 times as great
170 young from 28 litters of 7 "smoked"    in the "smoked" group.
does were studied. The offspring were not   (c) The mortality rate was greater in the
subjected to smoking at any time.         offspring of the "smoked" does.

230 pregnant mice were injected, parenter-   Nicotine had R lethal effect upon mice em-
ally, with nicotine. Animals were sacrificed    bryos and also had a tcrntogenic effect on
at term and mid-pregnancy to investigate    their skeletal systems.
the state of the pregnancy and the develop-
ment of the offspring.

113 "young" served as
controls.

Litters from the pre-
vious generation
served as controls.

22.5 full-term fetuses
removed from 29
untreated mice were
used as controls.

Gatling.
1984,
U.S.A. (ZJ).

Chick embryo.

Chicken embryos were treated with doses of   Nicotine induced cephalic hematoma forma-
nicotine varying from 12 I.rg. to 1,000 $.    tion and central nervous system depression.
The effects of phenothiazinea. corticoste-
raids. and catecholamines were also studied.


      TABLE 6.-Animal experimental #data on the effect of smoking and nicotine on pregnancy (cont.)

   Author.
    Ye*=,
   countru,       Animal              Design of study                        Results                  comments
   reference

Becker and      Ret.         100 primipara pregnant rats received a sin-
King,                                               (a) Mortality was greater among pregnant   100 nonpregnant rats
                     gle heavy subcutaneous injection of nico-
1966,                                                  rats than among controls.               served as controls.
                      tine on the 21st day of pregnancy. one
U.S.A. (2).                                        (6) Pregnant rats showed more marked hy-
                      day prior to expected term delivery. Fetal    perventilation and less body temperature
                         wastage.  weight of newborns. neonatal    depression than controls.
                         deaths.  and pregnant animals' responses   (c) Delivery was delayed 2 to 4 days.
                         were noted.                    (d) The young weighed less than normal and
                                                 survived "poorly" during the first 48 hours
                                                       of life

King and       Rat.         Pregnant and nonpregnant rats were in-  Osborne-Made] rats LDSO:
Becker,                                                                      mg./kg.
                      jetted subcutaneously with heavy doses of
1966,                                                    Pregnant adults  27.4
                       a 2 percent solution of pure nicotine for
U.S.A. (17).                                               Nonpregnant females  _. 33.6
                the purpose of determining the LD60 for     Neonates  14.56
                     females of this strain (Osborne-Mendel).
                 The LDSO for neonates of this strain was   Pregnant rats tended to die significantly later
                        also determined within 6 to 24 hours of    than nonpregnant rats, hut their tolerance
                         normal birth.                      for nicotine WBS less.
-
Mosier and      Rat.         Alternate pregnant rats received oral nico-
Armstrong,                                          (a) On higher nicotine intake. there was
                     tine in the dosage of either .05 mg./g. or
1967,                                                  lowering of food intake.
                    .lO mg./g. of food. On the 20th day, the
U.S.A. 07).                                         (b) There was no change in fetal weight or
                      rats were killed and the fetuses were re-    length on either concentration.
                         moved.                       (c) There appeared to be no effect on the
                                                 number of live and "absorbing" fetuses.


TABLE 6.-Animal experimental #data on the effect of smoking and nicotine on pregnanq (cont.)

Author,
ye*=.
cour.trY,
reference

Animal              Design of study

Results                  C0mments

Becker et al..
196%
U.S.A. (8).









Tjiilve et al..
1968,
Sweden (48).

Rat.










MO"%?.

Controlled populations of pregnant rats were   (a) With the lower dosage of nicotine, the   Control rats were in-
injected twice daily with doses of nicotine    birthweights, survival, and developmental    jetted with saline.
varying from .5 mg./kg. to 5 mg./kg. Ef-    status did not differ from controls.
fects on pregnant rats and newborn were   (b) With thhe higher dosage, pregnant rats
studied.                      consumed less food and gained less weight
                             than control mothers. Delivery dates were
                          prolonged 2 to 4 days or more. Young
                           were underweight and fetal in ap~)ea~ance.
                          There were no abortions and no premature
                              Young.

The passage of "C-nicotine and its metabo-   (a) Nicotine and its metabolites accumulated
lites from the mother into the fetuses was    in the placenta and passed into the fetus.
studied.                      (b) The metabolites present in the fetus
                             originated from the mother.

(c) The passage of nicotine into the fetus
was the same during the last four days of
pregnancy.

Fabro and
Sieber,
1969,
U.S.A. (II).

Rabbit.

( l-methyl-"C) -caffeine and G-(3H) -nicotine   (a) One hour after ("HJ-nicotine treatment,   Radioactivity in
were given to 6-day pregnant rabbits. The    a high level of radioactivity compared with    uterine secretion
dose for nicotine was 50 Pg./kg.. intra-    that in maternal plasma was found in    was not found in
venous, producing plasma levels similar to    uterine secretion (ratio: 103).          nonpregnant curl-
those attained in man by cigarette smok-   (b) Unchanged radioactive nicotine and some    tro1s.
ing (.06-.09 pz/ml.).              of its metabolites were present in the pre-
                         implantation blastoeyst (blastocyst/plasma
                             ratio z 3)

e
w


f
P

Author,
year.
co"ntrY.
reference

TABLE B.-Animal experimental ,data on the effect of smoking and nicotine on pregnancy (cont.)



  Animal              Design of study                        Results

comments

Welch et al.,
1660,
U.S.A. (52).

Rat.

Rats which were pregnant for 18 days were
given 40 ma/kg. of 3.4 -benzpyrene: 1,2-
benzanthracene; 1.2.5.6 -dihenzanthracene;
chrysene: 3,4 -benzofluorene: anthracene;
pyrene: fluoranthene; perylene; or phen-
anthrene orally,  and BP-hydroxylase sc-
tivity in the placenta was measured 24
hours later.

All compounds tested stimulated:          Placenta from control
BP-hydroxylase activity in the placenta.    rats possessed very
1,2-benzanthracene wss the most active in-    low BP-hydroxylase
ducer of BP-hydroxylsse.               activity.

Younossai
et al.,
:3ca,
Canads
(57).

Canada (52).
Kirschbaum
et al.,
1970,
U.S.A. (18).

Rat.

Pregnant rsts were exposed to smoke from
regular tobacco cigarettes. non-nicotine cig-
erettes mede with Iettnw leaves nnd non-
nicotine cigarettes (lettuce leaves) to which
15 mg. of nicotine was added. The rats
were forced to inhale cigarette smoke by
placing their cages in a smoking chamber.
CO levels were maintained between 2 and
X percent by exposing the animals to smoke
5 times s day st Z-hour intervals. Other
groups of rats were fed restricted diets,
receiving from 65 to 80 percent of the
food consumed by control rats.

Sheep.

Intravenous injection of fresh solutions of
nicotine, and simulated smoking of eiga-
ret&,  were carried out upon pregnant
ewes. Cardiovascular functions, including
gaseous exchange and blood flow of both
the ewes and their fetuses were studied
for acute effects.

(a) Fetuses of all smoked rats were growth   Control rats were
retarded compared to control animals, those    handled in the ssme
exuosed to tobacco smoke (cigarette) being    wny except that
most severely affected.                they were not ex-
(b) The amount of food consumed by rats    posed to cigarette
exposed to cigarette smoke wss reduced.     smoke.
(e) There wss B significant direct relation
between fetal body weight and the average
amount of food eaten during pregnancy.
(d) Fetal weight was reduced in prpportion
to the decrease in maternal food intake in
the two groups of rats exposed to the let-
tuce leaf cigarette smoke. In rats exposed
to tobacco cigarettes, fetal weight was re-
duced more than expected from the de-
crease in maternal food intake.

-

No significant changes were observed as a   Eath experiment in-
result of either nicotine administration or    eluded s control
smoke inhalation.                  period during which
                              attainment of a
                              steady state was
                              the aim.


isotope studies in mice (18) have indicated that nicotine and its
metabolites accumulate in the placenta and are passed into the
fetus.

Many of the experimental studies were designed to determine the
pathophysiology of the effect of maternal smoking on the fetus.
The experimental conditions in the several studies varied greatly as
did the results. No unified concept of the effect of maternal smoking
on fetal growth or on the outcome of pregnancy can be derived from
the presently available research.

SUMMARY

Maternal smoking during pregnancy exerts a retarding influence
on fetal growth as manifested by decreased infant birthweight and
an increased incidence of prematurity, defined by weight alone.
There is strong evidence to support the view that smoking mothers
have a significantly greater number of unsuccessful pregnancies
due to stillbirth and neonatal death as compared to nonsmoking
mothers. There is insufficient evidence to support a comparable
statement for abortions. The recently published Second Report of
the 1958 British Perinatal Mortality Survey, a carefully designed
and controlled prospective study involving large numbers of pa-
tients, adds further support to these conclusions.

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418


CHAPTER 6

Peptic Ulcer


                                     Page
Summary  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   423

References  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   429

LIST OF TABLES

1. Smoking and peptic ulcer disease morta1it.y . . . . . . . . . . .   424
2. Summary of results of retrospective and cross sectional
studies of peptic ulcer and smoking . . . . . . . . . . . . . . . . . .   425
3. Methods used in retrospective and cross sectional studies
of peptic ulcer and smoking . . . . . . . . . . . . . . . . . . . . . . . .   427

421


PEPTIC ULCER

It has been estimated that 10 to 12 percent of all people will suf-
fer from peptic ulcer disease at some time in their lives (17). In
the U.S.A. in 1967, there were 5,323 deaths from gastric ulcer and
4,502 deaths from duodenal ulcer (22). Several studies have docu-
mented an association between smoking and peptic ulcer disease,
which is stronger for gastric ulcer than for duodenal ulcer.

Prospective studies indicate that male cigarette smokers have
increased peptic ulcer mortality ratios (see table 1). Although a
trend toward increased mortality from gastric ulcer is seen in cigar
and/or pipe smokers, the data do not allow significant conclusions
to be drawn. Similarly, no firm conclusions can be drawn about
female smokers.

Retrospective studies have consistently shown smaller numbers
of nonsmokers in the peptic ulcer groups than in matched control
populations (tables 2 and 3).

Cigarette smoking has been shown to reduce the efficacy of
antacid therapy in documented peptic disease (3) and to slow peptic
ulcer healing (7). One study indicated that smokers who had
undergone surgical treatment for their peptic disease had more
major complications, including recurrence of peptic disease, than
nonsmokers (14 ) .

Numerous studies in both animals and man have been performed
to investigate the effect of smoking or the administration of nico-
tine on the gastrointestinal tract. Studies of gastric secretion and
motility in normal controls and in patients with peptic ulcer dis-
ease as well as in experimental animals have produced conflicting
results (4,16,18,19,20).

SUMMARY

Cigarette smoking males have an increased prevalence of peptic
ulcer disease and a greater peptic ulcer mortality ratio. These rela-
tionships are stronger for gastric ulcer than for duodenal ulcer.
Smoking appears to reduce the effectiveness of standard peptic
ulcer treatment and to slow the rate of ulcer healing.

423


TABLE L-Smoking and peptic ulcer disease mortality
(Numbers in parentheses represent actual number of deaths)
SM L Smokers   NS = Nonsmokers   G = Gastric   D = Duodenal

Author,
ye*=,
country.
reference

Number and
type of
population

Doll and   41,000 male
Hill,      British
1964,     physicians.
Great
Britain
(5.6).

    Data
  collection


Questionnaire
and follow-up
of death
certificate.

                              Mortality ratios
Actual
deaths                Cigarettes/day       Pipe         Cigar         comments
SM     NS             Gastric Duodenal Gastric Duodenal Gastric Duodenal

  54                   tPeptic             Pipe/cigar         t Tots1 number of
         NS              1.00                 4.00             deaths were too
         All cigarette        7.00                               small to allow
         l-14 gs. per day     2.33                              separate examin-
         15-24           10.33                               ations.
         >25             7.33

Hammond, 440.658      Interviews by   G-83 11 NS 1.00 (11) 1.00 (22)
,966.      males 35-     ACS volunteers D-93 .22 SM (aae 45-64) 2.95)  -.. 2.861 ^I.
U.S.A.    84 years of             SM (age65-79) 4.061 ""' 1.50]`=
(11).     age in 26
        states.

Kahn,     U.S. male     Questionnaire   678  . ,. .12 NS . 1.00(12) l.OO(26) l.OO(12) 1.00(26) l.OO(12) 1.00(26)
1966,     veterans      and follow-up  D-119 . . ...26 SM                    2.84 (4) 1.59 (5) 2.90 (7) 1.58 (8)
U.S.A.    2.265.674     of death               Allcigarette 4.13(39) 2.98(57)
(Id).     person years.   certificate.               l-9  __._. 3.96 (6) 2.30 (6)
                                    lo-20 __________ 2.77(13) 2.74(26)
                                      21-39  . :. 6.46(X) 3.98(22)
                                      >39  . . . . . . . ..11.6? (6) 2.89 (3)

Weir and   68,163 males   Questionnaire       44      NS  .    1.00                            No deaths from
Dunn. in various     and follow-up            All cigarette      0.53                             gastric ulcer oc-
1970.     occupations    of death               210  1.00    0.40                             curred in "on-
U.S.A.    in California.   certificate.              -c20  . 1.67    0.69                             smokers and risk
(IS).                                 230 _. 2.38    0.32                            of those smoking
                                                                           z?lO/day wss set
                                                                           at 1.00. NS in-
                                                                           cluded pipe.
                                                                           cigar, and
                                                                           .x-smokers.


Author,
Year,
e"u"trY,
reference

SW   Number

CZWes
  Method of selection

Numhrr

              

C"ntr"ls                     C"mme"ts
Method of selection

Barn&t,       M      66 Gastric.    Patients admitted between 1913 and    500   Selected at random from the gen-   1. Retrospective review
1927.             178 Duodenal    1926. Only cases with complete          eral admissions-males. 20-60 years    records at Peter Bent
U.S.A. (2).                    smoking history selected.               of age.                   Brigham Hospital.
                                                                           2. Ulcer diagnosis prob-
                                                                           ably well established.

Trowell,
1934,
England
(31).

M      50 Duodenal   Not stated

Allibone and
Flint,
195%
England
(I).

MandF 107

Consecutive admissions to hospital
of patients with gastric and du-
odenal hemorrhage or perforation.

Doll et al.,
1958,
England
(7).

M and F  327 Gastric.    Ulcer patients in Doll and Hill Lung
      33X Duodenal.    Cancer Study plus additional pa-
                tients in Central Middlesex Hospi-
                 tal.

Edwards et al.,   M      1,137        Men aged 60 and over on 11 General
1959,                         Practioners' lists were examined
England                       and interviewed by these practi-
(8).                        tioners. Represents about 84 per-
                            cent of all such me" on these
                            lists.

(9 percent "on-response due to death
and/or untraced.)

400   Selected at random from wards of   1. Interviewed by inves-
     a general hospital.             tigator.
                          2. Ulcer diagnosis con-
                           firmed by X-ray and/or
                             S"Tgery.

107   Matched by we, sex. and time of   Patients and controls in-
     admission from acute general sur-    twviewed by same
     pical emergency admissions.       observer.

                     -~-.___~ ~~
1.143   Patients with non-ulcer diseases.   1. Same interviewers and
      Each case matched with 2 co"-    questionnaire in cases
      trol patients of same sex, B-year    and controls.
      am ProuP,  and 5llr"c type of   2. Ulcer diagnosis proh-
      place of residence. Male patients    ably well established.
      matched by social class.

Of 143 considered to have
a peptic ulcer. 53 were
confirmed by X-ray.


TABLE 2. Methods used in retrospective and cross sectionat studies of peptic ulcer and smoking (cont.)

Author,
Year.
country.
reference

Sex   Number

Method of selection

Number

Contlnls

Method of selection

Comme"ts

Kasanen and M
ForsstrSm.
1966.
Finland
(18).

43 Gastric.    Successive male admissions with pep-    100   Successive men treated at medical  A special questionnaire
67 Duodenal.    tic ulcer treated at medical clinic          clinic who had no gastrointestinal    wes used for the
         or outpatient department of Uni-          symptoms or signs of CHD.       interview.
         versity Hospital. Only patients
          under 66 years of age or those
         who had been working were in-
          cluded.

Gillies and
Skyring.
1968,
196R.
Australia
(9).

M and F  100 Gastric.    Patients with peptic ulcer were se-    150   Matched by age and sex from the  Diagnosis well established
      60 Duodenal.    lected from hospital admissions in          seme ward at the same time and    with X-ray, gastros-
                 1967.                           with absence of signs or symp-    copy. or surgery.
                                            toms or past history of upper
                                              gastrointestinal disease.

Gillies and     M and F   10 Gastric.    1,405 workers from a broadcasting    100   Two control groups:           All information obtained
Skyring.            48 Duodenal.    company, a manufacturing corn-           1. 100 peptic ulcer patients we-    by question card. All
1969,              1R Uncertain    peny, and a bus company were            viously reported by authors.    ulcers were proved by
Australia             location.     interviewed for a history of pep-   1,329      2. 1.329 workers without ulcer.    X-ray or surgery.
(IO).                         tic ulcer.

Monson.       M and F   62 Gastric.   643 physicians fmm Massachusetts    625   Controls were physicians without   Diagnosis established by
1970.              462 Duodenal.    who responded a5irmatively to I)          ulcer disease who were matched    X-ray or SUrgelY except
U.S.A. (15).         139 Not       questionnaire sent to them in 1967         to ulcer patients by year of birth.    for 46 "clinical" cases.
                   specified.    asking how many had had LL pep-
                            tic ueer.


TABLE 3.-Summary of results of retrospective and cross sectional studies of peptic ulcer and smoking

Author,
  ye*c
co""trY.
reference

Barnett,
1927,
U.S.A.
(2).

    Percent nonsmoker

         ChS.33   controls

Total . . 18.0     26.0
Gastric  . . . . 16.0
Duodenal  . . . 20.0

Amount of tobacco used

C*WS          Co"trols

Trowel&
1934.
England
(91).

Duodenal  8.0     17.0                            Average number:
                                                 Cigarettes  12.0 per day. .ll.l per day
                                                 Pipe    1.6 ounces per week. 2.16 ounces per week

Allibone and
Flint,
1958.
England
(1).

38.0     64.0

Doll et sl.,
1968.
Englend
(7).

Gastric:
  Males . 1.3
  Females . 61.1
Duodenal:
  Males 2.1
  Females 53.7

4.7
66.8

5.8
62.0

Gastric:   Percent emoking >25 cigarette8 per day
  Males . . 10.6            11.3
  Females 1.1             1.1
Duodenal:
  Males ._ ._ 10.2            12.1
  Females 1.9            1.9

     Edwards                               Percent of peptic ulcer bu
      et al..                                  smoking category
      1959,                              Never smoked . . . . . . .  6.0
      England                           Formerly smoked  . . . . . . . . . . *..*  6.7
       (8).                              Cigarettes:
                                          l-9 per day  _. _. .  9.4
                                        lo-19 per day  _. . . . . . .  9.3
                                      >?Operday  . . . 12.0
                                        Pipe  . . . . . . . . . . . . . . . . . . . . .  6.6
e                                       Pipe end cigarettes  . . . . . . .  8.5
v


TABLE 3.-Summary of results of retrospective and cross sectional studies of peptic ulcer and smoking (cont.)

Author,
year,           Percent nonsmoker
eountrY. ~
reference               Cases   Co"trols

         "Peptic"  . . 10.0     40.0

Kasanen
end
ForsstrSm.
1966,
Finland
(IS).

           Amount of tobarco used ~-.
           Cases          Co"trols

Cigarettes per dsy:

<lO . 10.0            7.0
10-20 . 19.0            11.0
20  . 42.0            26.0
>20  . 19.0            10.0

Gillies end
Skyring,
1968.
Australia
(9).

Gastric  18.0     44.0
Duodenal 62.0     71.0

Mean number cigarettes per day:
  Gastric . 23.3
  Duodenal 23.2
Duration of smoking (years) :
  Gastric 30.2
  Duodenal 24.2

17.1
23.0

28.0
28.2

Gillies end
Skyring,
1969.
Australia
(10).

Gastric  ........ 17.9     55.6
Duodenal  ...... 36.6

Monson.
1910.
U.S.A.
(15).

Duodenal  ...... 32.1
Gastric  ........ 19.2
Not Specified . 43.2

46.7

Percent smoking >20
cigarettes per day
Age:      Gastric   DUOlhWl
  20  ......... 38.8     21.3     30.1
  30  ......... 45,.7     43.0     41.1
  45  ......... 60.2     49.6     46.3
  60  ......... 64.1     40.4     44.0


REFERENCES

(1) ALLIBONE, A., FLINT, F. J. Bronchitis, aspirin, smoking, and other fac-
  tors in the aetiology of peptic ulcer. Lancet 2: 179-182, July 26, 1958.
(2) BARNETT, C. W. Tobacco smoking as a factor in the production of peptic
   ulcer and gastric neurosis. Boston Medical and Surgical Journal
   197(12) : 457459, September 22, 1927.
(3) BATTERMAN, R. C , EHRENFELD, I., The influence of smoking upon the
  management of the peptic ulcer patient. Gastroenterology 12 (4) : 575-
   585, April 1949.

(4) COOPER, P., KNIGHT, J. B., JR. Effect of cigarette smoking on gastric
   secretions of patients with duodenal ulcer. New England Journal of
   Medicine 255(l) : 17-21, July 5, 1956.
(5) DOLL, R., HILL, A. B. Mortality in relation to smoking: 10 years' obser-
  vations of British doctors. Part I. British Medical Journal l(5395) :
   1399-1410, May 30, 1964.

(6) DOLL, R., HILL, A. B. Mortality in relation to smoking: 10 years' obser-
   vations of British doctors (concluded). British Medical Journal
  l(5396) : 1460-1467, June-G, 1964.

(7) DOLL, R., JONES, F. A., PYGOTT, F. Effect of smoking on the production
   and maintenance of gastric and duodenal ulcers. Lancet 1: 657-662,
   March 29,1958.

(8) EDWARDS, F., MCKEOWN, T., WHITFIELD, A. G. W. Association between
   smoking and disease in men over sixty. Lancet 1: 196-201, January
    24, 1959.

(9) GILLIES, M., SKYRING, A. Gastric ulcer, duodenal ulcer and gastric car-
   cinoma: A case-control study of certain social and environmental fac-
   tors. Medical Journal of Australia 2(25) : 1132-1136, December 21,
   1968.

(10) GILLIES, M. A., SKYRING, A. Gastric and duodenal ulcer. The association
   between aspirin ingestion, smoking and family history of ulcer. Medi-
   cal Journal of Australia 2(6) : 280-285, August 9, 1969.
(11) HAMMOND, E. C. Smoking in relation to the death rates of 1 million men
   and women. IN : Haenszel, W. (Editor). Epidemiological Approaches
   to the Study of Cancer and Other Chronic Diseases. Bethesda, U.S.
   Public Health Service, National Cancer Institute Monograph No. 19,
   January 1966. pp. 12'7-204.

(12) KAHN, H. A. The Dorn study of smoking and mortality among U.S.
   veterans: Report on 8% years of observation. IN: Haenszel, W. (Edi-
   tor). Epidemiological Approaches to the Study of Cancer and Other
   Chronic Diseases. Bethesda, U.S. Public Health Service, National
   Cancer Institute Monograph No. 19, January 1966. pp. 1-125.
(IS) KASANEN, A., FORSSTROM, J. Social stress and living habits in the etiology
   of peptic ulcer. Annales Medicinae Internal Fenniae 55(l) : 13-22,
    1966.

(14) MITTY, W. F., JR., ROUSSELOT, L. M., DELANY, G. J. Smoking and its
    relation to nutritional status of patients following gastrectomy; a
   five-year follow-up survey of 171 patients. Annals of Surgery 150 (1) :
   76-84, July 1959.
(15) MONSON, R. R. Cigarette smoking and body form in peptic ulcer. Gastro-
   enterology 58 (3) : 337-344, March 1970.

429


(16) PACKARD, R. S. Smoking and the alimentary tract: A review. Gut 1:
    171-174, 1960.

(17) PALMER, W. L. Peptic ulcer. Chapter 32. IN: Paulson, M. (Editor).
   Gastroenterologic Medicine. Philadelphia, Lea & Febiger, 1969, pp.
     710-757.

(16) SCHNEDORF, J. G., Iw, A. C. The effect of tobacco smoking on the
   alimentary tract. An experimental study of man and animals. Journal
   of the American Medical Association 112(10) : 898-904, March 11,
    1939.

(19) STEIGMANN, F., DOLEHIDE, R. H., KAMINSKI, L. Effects of tobacco smok-
    ing on gastric acidity and motility of hospital controls and patients
    with peptic ulcer. American Journal of Gastroenterology 22 : 399-409,
     1954.

(20) THOMPSON, J. H. Effects of nicotine and tobacco smoke on gastric secre-
    tion in rats with gastric fistulas. American Journal of Digestive
    Diseases 15(3) : 209-217, March 1970.

(21) TROUTELL, 0. A. The relation of tobacco smoking to the incidence of
    chronic duodenal ulcer. Lancet 1: 808-809, April 14,1934.
(12) U.S. PUBLIC HEALTH SERVICE. NATIONAL CENTER FOR HEALTH STATIS-
    TICS. Vital Statistics of the United States-1967. Vol. II-Mortality,
    Part A. Washington, U.S. Department of Health, Education and Wel-
    fare, Public Health Service Publication, 1969.
(28) WEIR, J. M., DUNN, J. E., JR. Smoking and mortality: A prospective
    study. Cancer 25( 1) : 105-112, January 1970.

430


CHAPTER 7

Tobacco Amblyopia


Contents

Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . .   436

References  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   436

433


TOBACCO AMBLYOPIA

Tobacco amblyopia (tobacco-alcohol amblyopia) is that syn-
drome of visual failure occurring in association with the use of
tobacco, with or without the concurrent use of alcohol, and with or
without concurrent nutritional deficits. The disease has a subacute
onset, leading to a loss of visual acuity and color perception (12).
It is characterized by centrocecal scotomas which are bilateral but
not necessarily symmetrical and which have sloping diffuse edges
and by the presence of nuclei of denser visual loss within the large
scotomas (22,23). Such visual impairment is not unique to tobacco
amblyopia, as it is also seen in neurodegenerative disorders, such
as Leber's hereditary optic atrophy (7,25).

Clinical information on tobacco amblyopia has appeared in nu-
merous articles throughout the past century. This information has
been reviewed by Silvette, et al. (17) and, more recently, by
Dunphy (5). Pure tobacco amblyopia (TA) , that is amblyopia
unassociated with excessive alcohol intake or the exposure to other
toxins, is rarely seen in the United States today (12). Walsh, et al.
(23) have observed that when TA is found it is usually present in
association with nutritional or idiopathic vitamin deficiencies.
Victor (22) recently observed that the type of visual defect seen in
tobacco amblyopia may be found in clinical circumstances in which
tobacco is clearly not a causative factor. He questions whether TA
is distinguishable from other forms of amblyopia.

The prevalence of this disorder has been variously estimated in
the past at from 0.5 to 1.5 percent of all eye clinic patients (20,23).
However, currently in the United States, it appears to be a rare
condition. Silvette, et al. (17) have observed that the incidence of
tobacco amblyopia appears to have decreased substantially during
the past decades. Other authors (3, 15) have also commented on
this trend. Although reference has been made to the increased fre-
quency of certain types of tobacco usage in patients with this dis-
order, adequate population studies with proper controls have yet to
be performed. The association of this disorder with the use of
tobacco is strengthened by the frequent clinical observations of
improvement following the cessation of smoking although improve-
ment has been noted by some to occur without cessation.

Research into the pathogenesis of tobacco amblyopia has cen-

435


tered upon the interrelationships of cyanide metabolism, vitamin
B,,, and other vitamin deficiencies. Three reviews of this material
have recently appeared (1, 12, 2.2). Numerous studies reviewed in
these articles suggest that tobacco amblyopia may result from the
incomplete detoxification of the cyanide present in tobacco smoke.
This failure of detoxification may stem from or be intensified by
inadequate dietary intake of necessary nutritional factors. This
may be the reason for the association of this disorder with exces-
sive alcohol intake and with its related nutritional deficits (2, 4, 6,
8,9,10,11,13,14,16,18, 19,21,24,26,27,28).

SUMMARY AND CONCLUSIONS

Tobacco amblyopia is presently a rare disorder in the United
States. The evidence suggests that this disorder is related to nutri-
tional or idiopathic deficiencies in certain detoxification mechan-
isms, particularly in handling the cyanide component of tobacco
smoke.

REFERENCES

(1) CANADIAN MEDICAL ASSOCIATION JOURNAL. Tobacco amblyopia. (Edi-
  torial) Canadian Medical Association Journal 102(4) : 420, February
   28, 1970.

(2) CHISHOLM, I. A., BRONTE-STEWART, J., FOULDS, W. S. Hydroxocobalamin
   versus cyanocobalamin in the treatment of tobacco amblyopia. Lancet
   2(7513) : 450-451, August 26, 1967.

(5) DARBY, P. W., WILSON, J. Cyanide, smoking, and tobacco amblyopia.
   Observations on the cyanide content of tobacco smoke. British Journal
   of Ophthalmology 51(5) : 336-338, May 1967.
(4) DREYFUS, P. M. Blood transketolase levels in tobacco-alcohol amblyopia
   Archives of Ophthalmology `74(5) : 617-620, November 1965.
(5) DUNPHY, E. B. Alcohol and tobacco amblyopia: A historical survey.
   American Journal of Ophthalmology 68(4) : 569-578, October 1969.
(6) FOULDS, W. S., BRONTE-STEWART, J. M., CHISHOLM, I. A. Serum thio-
   cyanate concentrations in tobacco amblyopia. Nature 218 (5141) : 586,
   May 11, 1968.

(7) FOULDS, W. S., CANT, J. S., CHISHOLM, I. A., BRONTE-STEWART, J.,
   WILSON, J. Hydroxocobalamin in the treatment of Leber's hereditary
   optic atrophy. Lancet l(7548) : 896-897, April 27, 1968.
(8) FOULDS, W. S., CHISHOLM, I. A., BRONTE-STEWART, J., WILSON, T. M.
  Vitamin B,, absorption in tobacco amblyopia. British Journal of
   Ophthalmology 53 (6) : 393-397, June 1969.
(9) FOULDS, W. S., CHISHOLM, I. A., BRONTE-STEWART, J., WILSON, T. M.
   The optic neuropathy of pernicious anemia. Archives of Ophthalmol-
   ogy 82(4) : 427-432, October 1969.

(10) FREEMAN, A. G., HEATON, J. M. The aetiology of retrobulbar neuritis in
   Addisonian pernicious anaemia. Lancet l(7183) : 908-911, April 29,
    1961.

436


(11) HEATON, J. M., MCCORMICK, A. J. A., FREEMAN, A. G. Tobacco amblyo-
   pia : A clinical manifestation of vitamin-B,, deficiency. Lancet
   2(7041) : 286-290, August 9, 1958.

(12) KNOX, D. L. Neuro-ophthalmology. Archives of Ophthalmology 83(l) :
    103-127, January 1970.

(13) LINDSTRAND, K., WILSON, J., MATTHEWS, D. M. Chromatography and
   microbiological assay of vitamin B1? in smokers. British Medical
    Journal 2 (5520) : 988-990, October 22, 1966.
(14) LINNELL, J. C., SMITH, A. D. M., SMITH, C. L., WILSON, J., MATTHEWS,
    D. M. Effects of smoking on metabolism and excretion of vitamin B,,.
    British Medical Journal 2(5599) : 215-216, April 27, 1968.
(15) SCHEPENS, C. L. Is tobacco amblyopia a deficiency disease- Transactions
   of the Ophthalmological Society of the United Kingdom 66: 309-331,
     1946.

(16) SCHIEVELBEIN, H., WERLE, E., SCHULZ, E. K., BAUMEISTER, R. The influ-
    ence of tobacco smoke and nicotine on thiocyanate metabolism.
    Naunyn-Schmiedebergs Archiv fiir Pharmakologie und Experimentelle
    Pathologie 262(3) : 358-365, February 5, 1969.
(17) SILVETTE, H., HAAG, H. B., LARSON, P. S. Tobacco amblyopia. The evolu-
    tion and natural history of a "tobaccogenic" disease. American Journal
    of Ophthalmology 50( 1) : 71-100, January 1960.
(18) SMITH, A. D. M. Retrobulbar neuritis in Addisonian pernicious anae-
    mia. (Letter) Lancet l(7184) : 1001-1002, May 6, 1961.
(19) SMITH, A. D. M., DUCKETT, S. Cyanide, vitamine B,,, experimental
    demyelination and tobacco amblyopia. British Journal of Experimen-
    tal Pathology 46(6) : 615-622, December 1965.
(20) TRAQUAIR, H. M. Toxic amblyopia, including retrobulbar neuritis. Trans-
    actions of the Ophthalmological Society of the United Kingdom 50:
    351385, 1930.

(21) VICTOR, M. Tobacco-alcohol amblyopia. A critique of current concepts of
   this disorder, with special reference to the role of nutritional deficiency
   in its causation. Archives of Ophthalmology 70(3) : 313-318, Septem-
    ber 1963.

(22) VICTOR, M. Tobacco amblyopia, cyanide poisoning and vitamin B,, de-
   ficiency. A critique of current concepts. Chapter 3. IN: Smith, J. L.
   (Editor) Neuro-Ophthlamology. Symposium of the University of
   Miami and the Bascom Palmer Eye Institute. Hallandale, Florida,
   Huffman Publishing Co., 1970. pp. 3348.
(2s) WALSH, F. B., HOYT, W. F. (Editors) Neurotoxic substances affecting
   the visual and ocular motor systems. Chapter 15: IN: Clinical Neuro-
   Ophthalmology, Volume 3, 3rd Edition. Baltimore, The Williams &
   Wilkins Company, 1969. pp. 2613-2616.
(24) WATSON-WILLIAMS, E. J., BOTTOMLEY, A. C., AINLEY, R. G., PHILLIPS,
   C. I. Absorption of vitamin B12 in tobacco amblyopia. British Journal
   of Ophthalmology 53 (8) : 549-552, August 1969.
(85) WILSON, J. Leber's hereditary optic atrophy: A possible defect of cya-
   nide metabolism. Clinical Science 29(3) : 505-515, December 1965.
(26) WILSON, J., MATTHEWS, D. M. Metabolic inter-relationships between
   cyanide, thiocyanate and vitamin B,, in smokers and nonsmokers.
    Clinical Science 31(l) : l-7, January 1966.

437


(27) WOKES, F., PICARD, C. W. The role of vitamin B,, in human nutrition.
    Clinical Nutrition 3 (5) : 383-390, September-October 1955.
(28) WYNDER, E. L., HOFFMANN, I). Certain constituents of tobacco products.
    Chapter 8. K. Vapor phase of tobacco smoke. IN: Wynder, E. L.,
    Hoffmann, I). (b:ditors). Tobacco and Tobacco Smoke. Studies in Ex-
    perimental Carcinogenesis. New York, Academic Press, 1967. pp.
     451-453.

43.3


Index

Abortions

smoking effects on, 13
Abortions, spontaneous
comparison of stillbirth and neonatal
death with, in smoking and nonsmok-
ing mothers, 390,405406
Acidosis
metabolic, smoking mother effects on in-
fant, 407

Adenocarcinoma
prevalence in male and female smokers
and nonsmokers, 250
relationship of cigarette smoking to,
246-249,296
Adenoma
papillary, induction in rats by exposure
to cigarette tars, 348
pulmonary, induction in mice by ciga-
rette smoke inhalation, 349
renal, relationship of smoking to, 296
Adrenal gland
catecholamine release from, nicotine
  effects on. 36

Advelvt;y Committee on Smoking and
establishment and conclusions of study
by, 3
report on cigarette smoke and conden-
sates effects on oral cavity of animals,
288

Age

atypical nuclei in esophageal epithehum
arranged by smoking and, 379-31

current cigarette smokers by sex and, 6
effects on CHD, 27.39

AHA

see American Heart Association
Air pollution
as cause of COPD, 152,216-217
effect on COPD development, 175
relationship of lung neoplasms, smoking
and place of residence, 252-255
role in etiology of lung cancer, 11, 276
Alcohol
effect of consumption on esophageal
neoplasms in smokers, 289,293
effect of consumption on laryngeal neo-
plasms among tobacco users, 280
effect of consumption on tobacco am-
blyopia 435436
effect of heavy consumption and heavy
smoking on oral neoplasms, 288
ethanol, penetrability of dissolved
benzo(o)pyrene in mice esophageal epi-
thelium,, 293

relationship of smoking and, in human
tuberculosis, 172
Alcoholism
patients with, smoking and ventilatory
function in, 213

Amblyopia
characterization of, 435
development from cyanide component
of tobacco smoke, 14
incidence of, 435
American Heart Association
pooling project on CHD, 23, 28, 30, 39
Aminoazo dyes

activity in placenta of smoking mothers,
410

Angina pectoris
cause bf, 21

incidence with cigarette smoking, 24,37
in Danish twins. smokers vs. nonsmok-
ers,.51
in twms, constitutional factors, 50-51
prospective studies of, CHD morbidity
relation to smoking 37,39
Animals
see ulso specific animals e.g., cats, dogs,
rabbits, etc.
atherosclerotic lesion development in,
smoking enhancement, 36
carcinoma induction in, from arsenic,
  257

cigarette smoke effect on pulmonary
physiology and structure in, 162
development of lesions from cigarette
smoke inhalation, 11
effects of nicotine on cardiovascular
system of, 57, 107-112
esophageal neoplasms in, induction by
nitrosamines, 292
respiratory tract of, neoplastic changes
following cigarette smoke inhalation,
238-239
ski of, carcinogenicity of tobacco tars,
238.267
tests of, -4th smoke carcinogens, 12
ventilatory function change from smok-
ing, 10

Anti-trypsin, alphat
COPD predisposition from genetic ab-
sence of, 150
determination using immunoelectro-
phoresis, 151
relationship in pulmonary emphysema,
  10-l 1
Anthranihc acid, 3hydroxy-
urinary excretron of, smoking effects on,
  296

Aorta

aneurysms of, cigarette smoking effect
on.9.61.71.15
atherosclerosis' in, long term smoking
effects, 52-56

Areca nut
see Betel nut
Aromatic compounds
carcinogenic properties in cigarette

439


smoke from, 264,265
detection in urine using chemilumi-
nescence technique, 297
stimulation of placental BP-hydroxylase
activity in pregnant rats by, 414
Arrhythmia
formation in nicotine stimulated dam-
aged myocardium, 58
Arsenic
lung neoplasm mortality in smelter
workers exposed to, 257
respiratory tract carcinoma in workers
exposed to, 256,257

Arteries

aneurysm in aortic, cigarette smoking ef-
fects on. 9.67,71,75
atherosclerotic, increased by cigarette
smoking, 8,63
flow of carotid, cigarette smoking effects
on, 67
hypoxemia, development from cigarette

smoking, 9

occlusions of, cigarette smoking effects

on, 73

walls of, mechanism of lipoprotein infii-
tration, 63
walls of nicotine-induced necrosis, 63
Arteriosclerosis
see also Thromboangiitis obliterans
in aorta and coronary arteries, cigarette
smoking effects on, 45.52-56
cigarette smoking effects on, 8
development by increased carboxyhemo-
globin formation, 9
development of, carbon monoxide ef-
fects on, 63
de$opment of, effects of nicotine on,
lece;tde3v;lopment in, smoking enhance-
periphdral, cigarette smoking effects on,
  72-73

Arteriosclerotic heart disease (ASHD)
see Coronary disease
Asbestos workers

see Occupations
ASHD
see Coronary disease

Asia

see also specific countries of Asia
Central and Southeast. relationship of
tobacco use and neoplasms of oraicav-
ity, 366
Asthma
bronchial, cigarette smoking effects on,
10,175

Atherosclerosis
see Arteriosclerosis
Atropine

effects on bronchoconstriction in dogs,
  163
Australia

COPD morbidity in smokers in, 203
laryngeal neoplasms in, relationship to
tobacco use, 357

lung neoplasm in, retrospective studies
of,.327

peptic ulcer in, methods for retrospec-
tive and cross-section studies of
smoking and, 426,428

Bacteria

effect of cigarette smoke on acuon ,,f
macrophages on, 165
pneumonia, mice resistance fogowrng
cigarette mhalatron, 173

Bank employees
see Occupations
Benz(e)acephenanthrylene

carcrnogenic properties in cigarette
smoke from. 264.265

Benz(o)anthrackne
alcoholic sohrtion of, penetrabihry of
mice esophageal epithelium, 292
Benz(u)anthracene, 7,12dimethyl
carcinoma induction in hamsters follow.
ing instillation of, 346
skin painting with, Papihoma and talc,.
noma induction m mice by, 341
Benzo(b)fluoranthene
see Benz(e)acephenanthrylene
Benzo(i)fluoroanthene
carcinogenic properties in cigarette
  smoke from. 265
Benzo(c)phenanthrene
carcinogenic properties in Cigarette
smoke from, 265
Benzo(rsr)pentaphene
carcinogenic properties in cigarette
  smoke from. 265

3,4-Benzopyrene
see Benzo(u)pyrene
Benzo(a)pyrene

ability of smoking mothers to hydroxy).
ate, 407
alcoholic solution of, penetration of
mice esophageal epithelium, 292
carcinogenicity of, in relation to asbestos
in hamsters,, 257

carcinogenrc properties in CQarette
smoke from, 264,265
detoxification by lung aryl hydroxyiase,
  257
effects of instillation or implantation in
animal tracheobronchial tree, 346-347
effects on animal tissue and organ cul-
tures in? 343-345
effects wtth influenza virus on cigarette
inhalation by mice, 352
sarcoma induction in rats following in-
stillation of, 346
skin painting with, papilloma induction
in mice by, 337-338
Benzo(a)pyrene, l-methyl-
carcinogenic properties in cigarette
smoke from, 265
Betel nut
chewers of, relationship with oral cavity
neoplasms, 366,369-370
Birth weight
see Neonate

Blacks

maternal smoking and infant weight, 397
m;;;fqnga: smoking and prematurity,
Bladder neoplasms
frequency in smokers vs. nonsmokers,
238. 293-295
methods of retrospective studies of
smoking and, 293,381-384
presence of tryptophan metabolites in

440


urine of patients with, 296-297
relationship of cigarette smoking to, 299
urinary, cigarette smoking relationship,
13

U.S. mortality in 1967, 294
Blood

see also specific components of blood,
e.g., cholesterol, lipids, platelets
carboxyhemoglobin formation in, from
smoking, 60,75
clotting, cigarette smoking effects on, 9,
36

Blood circulation. coronarv

alteration foUo&ing cigarette smoke in-
halation, 58
effect of variations in hemoglobin and
hematocrit, 66
Blood pressure
diastolic, cigarette smoking effects, 8, 23
diastolic, in smokers with CHD, 21-22,
24,42

high, risk factor in arteriosclerosis ob-
literans. 72
hiah. risk.in mortalitv from CVD. 67
hypertensive vs. nori-hyperten&ey mor-
talitv rates of CHD in 42
nicotine effects on, 36
relationship of smoking and CHD, 43,47
smokers vs. nonsmokers. 41.42. 103-104

- . - _ _

systolic, mortality from elevated, with
CHD. 42

BP-hydroxylase
see under Enzymes

Bradycardia

development in dogs given nicotine, 57
British Perinatal Mortality Survey
results of, 390

Bronchitis. chronic

cigarette'smoking cause and effect rela-
tionship, 3,9
definition, 139
mortality in cigarette smokers, 175
mortality rates in 1967.139
smokers-vs. nonsmokers, 195-205
Bronchogenic carcinoma
see Carcinoma, bronchogenic
Bronchopneumonia
development in dogs following cigarette
smoke inhalation, 271
Bronchopulmonary disease, chronic ob-
structive

see also Asthma, bronchitis, emphysema,
respiratory diseases
ai;16p;ll17ution relationship in, 152,
characterization of, 139
cigarette smoking effects on develop-
ment, 4,9-l 1: 175
effect of smokma cessation on develou-

increased prevalence of heterozygotes in,
ment, 10 -
genetic factors in pathogenesis of, 148,


151-152
150-152.205

mortality in pipe, cigar, and cigarette
smokers, 175

mortality rates from, 139-145
smoking effects on ventilation-perfusion

measurements in, 163

Buerger's disease
see Thromboangiitis obliterans
Burma

methods used in smoking study and
human pregnancy, 393 -
Butylamine. N-methyl-nitroso
suspected ~carcinogknic properties in ciga-
rette smoke from, 265

Cadmium

in cigarette smoke, relation to emphy-
sema pathogenesis, 154
Calves
see Cattle
Canada
COPD morbidity of smokers in, 204
human experimental data on smoking
and pregnancy, 409
infectious resuiratorv disease in. relation-
ship to smoking, 228
kidney and bladder neoplasms in smok-
  ers in. 294
mortality rates from COPD, 139-141, 145
mortality ratios from COPD, 143
mortality ratios in smokers and non-
smokers from pancreatic neoplasms,
  298
thrombosis in, smoking relationship, 132
veterans of, lung neoplasm mortality
ratios in smokers and nonsmokers, 24 1
Carbazole, 9-methyl-
possible importance in tobacco carcino-
genesis, 266
Carbon-14
labeled smoke particulate deposition in
hamster respiratory tract, 281-282
Carbonic anhydrase
see Enzymes
Carbon monoxide
in cigarette smoke, formation of car-
boxyhemoglobin, 8-9
effects on cholesterol-fed rabbits, 6566
effects on human physiology, 6062
levels in ciaarette smoke. 59
levels in fe'tal blood of smoking mothers,
  407410

Carboxyhemoglobin
effects of elevated, on fetal tissues, 407
formation in blood of smokers, 60, 75
formation from CO in cigarette smoke,
8-9
Carcinogens
action on oral cavity, effect of saliva,
  288
listing of, in cigarette smoke, 265-266
in smoke, effect on oral cavity, 12

Carcinoid

prevalence in male and female smokers
and nonsmokers. 250

Carcinoma
formation following animal skin painting
induction in rats exposed to cigarette
with smoke condensates. 337-342

tars, 348

undifferential, relationship to cigarette
smoking, 248-249
Carcinoma, alveolar
induction in mice by cigarette smoke in-
halation, 349

441


Carcinoma, anaplastic
prevalence in male and female smokers
and nonsmokers, 250
Carcinoma, bronchogenic
development in dogs following cigarette
smoke inhalation, 269,272-273
mortality from, relationships to smok-
ing, air pollutton and residence, 253
mortality in smokers vs. nonsmokers as-
bestos workers, 257
Carcinoma, epidermoid
mortality from, relationship to smoking,
air pollution and residence, 254
prevalence in male and female smokers
and nonsmokers, 250
relationship of cigarette smoking to,
_ 246-249

Carcinoma, epithelial
induction in mice by cigarette smoke in-
halation, 350

Carcinoma, oat cell
relationship of cigarette smoking to, 247
Carcinoma, squamous cell
development in mice drinking alcoholic
benzo(u)pyrene, 292
in oral cavity, relationship to tobacco
use, 366-367

Carcinoma, tracheobronchial
induction in hamsters by cigarette smoke
instillation, 346-347
Cardiovascular diseases
see also Coronary disease
atherosclerotic, cigarette smoking rela-
tionship, 4

Cardiovascular system
nicotine and cigarette smoke effects on,
56-58, 107-l 18
Catecholamines

adrenal gland release, effect of nicotine

on, 36

effect on blood flow in coronary arte-
ries, 58
release by cigarette smoking, 8
release in animals by nicotine, 57, 119
Cats
cardiovascular function in, smoking and
nicotine effects on, 110, 111
ciliary function in, effect of cigarette
smoke on, 222-224
lungs of, ngarette smoke effect on sur-
factant activity, 225
Cattle
ciharv function in. effect of ciearette
smoke on, 221   '

CRF

---

see Blood circulation coronary
Central nervous system
effects of carbon monoxide in smoke on,
  60

Cerebrovascular disease
definition of, 66
mortality from, effects of cigarette
smoking on, 9
mortality rates from, smokers vs. non-
smokers, 66-70

Cessation of smoking
effect on COPD development in British
physicians, 142
effect on COPD morbidity in smokers vs.
nonsmokers, 146
effect on development of COPD, 140

442

effect on mortality from COPD from,
175

improvements in respiratory system,
148,149

relation to incidence and mortality from
CHD, 32,4648,106
CHD

see Coronary disease
Chemiluminescence
see Luminescence
Chewing

see Betel nut and tobacco
Chickens

ciliary function in, effect of Cigarette
smoke on, 223
embryos of, effect of cigarette smoke
on, 344
embryo of, nicotine effects on CNS, 411
Chile

atherosclerosis autopsy studies in, 55
atherosclerosis in, no smoking effect
found, 56
Cholesterol
rabbits fed, carbon monoxide effects on,
  65-66
secrufnh' 8cigarette smoking relationship

serum, control in coronary disease,
21-22
serum, relationship of cigarette smoking
to levels of, 41,43
serum, relationship of elevated with ciga-
rette smoking in peripheral vascular
disease, 72

serum, m smokers vs. nonsmokers, 41,
  98-102
serum, in smokers with CHD, 23-24, 43
synergistic relationship of carbon mon-
oxide in coronary atheromatosis, 63
Chromium
respiratory tract carcinoma in workers
exposed to, 256

Chromium compounds
lung neoplasm mortality from, 257-258
Chronic obstructive pulmonary disease
see Bronchopulmonary disease, chronic
  obstructive
Chrysene
carcinogenic properties in cigarette
smoke from, 265

Chrysene, lmethyl-
carcinogenic properties in cigarette
smoke from, 265
Cigarette filters

ad;6ytag;; m reduction of particulates,
reduciion of lung neoplasms from, 13
Cigarette smoke

alteration of coronary blood flow, 58
bronchogenic carcinoma induction in
dogs inhaling, 269,270
cadmium levels in, 154
carbon monoxide levels in, 59
carcinogenicity of components to ani-
mals, 12,277

cause of death in dogs from inhalation,
271
ciliary movement inhibition, 267
efF4;tS;;5tissue and organ cultures, 267,


effect of nickel on induction of lung aryl
hydroxylase, 256-257
high tar, risks in, 11
inhalation by dogs, lung neoplasm devel-
opment, 268-269,212-214
inhalation effects on animal respiratory
tract,, 268-269, 349-353
inhafatron effects on hamster larynx,
281,284
listing of identified or suspected tumori-
genie agents, 264261
2-naphthylamine identified in. 265
neoplastic changes in animals inhaling,
238-239

tobacco amblyopia relationship to cyan-
ide metabolism in, 435436
Cigarette smoke condensates
carcinogenic effect on animal oral cav-
ities, 288
carcinogenic properties on animal skin,
  331-342

effects of instillation or implantation in
animal tracheobronchial tree, 346-348
effects on tissue and organ cultures,
343-344

painting skin of animals with, 331-342
Cigarette smokers
arterial occlusions in, 73
atherosclerosis in aortic and coronary ar
teries, 52-56
atypical nuclei in male esophageal epi-
thelium, 379-380
bladder neoplasms in, 293-295
cell rows and atypical cells in vocal cords
of, 280, 359-360
cessation effects on COPD morbidity,
146,197,199,203-204
cessation lowers lung neoplasm rate in,
  11

changes in vent&tory function and pul-
monarv histologv. 115
CHD mAHA po%ng project, 28, 30, 39
CHD risk by, 23-25
comparative risk for lung neoplasms, 237
decline in British physicians, 48
development of altered ventilatory func-

tion H young, 10

de;;l;$ynt of esophageal neoplasms,
development of laryngeal neoplasms, 12
development of oral neoplasms, 12
development of second primary oral neo-
plasms in continuing, 287
effect of filters on emphysema develop-
ment, 162
effects of inhalation on bronchial reacti-

vity, 164

effect on cardiovascular system, 56-58,
107-118

effects on uterine activity in gravidic
women, 408

esophageal neoplasm mortality ratios in,
290-29 1

etiological cause of lung neoplasms? 239
histology and smoking relationshrp of
lung neoplasms in 246-249
infant birth weight, 397-399
inhalation effects on human pulmonary
function, 163,166-169
kidney neoplasms in, 294-296

laryngeal neoplasm induction in,
354-351
lu2n4~-2nrplasm mortality in, 240,
mortality from cerebrovascular disease,
61-70

mortality rates affected by sex, 3
mortality ratios from COPD, 142-144
mortality ratios from pancreatic neo-
plasms in, 298
mortality ratios from peptic ulcers in,
424
peptic ulcer in, smoke effects on antacid
therapy, 423

percentage of women of child-bearing
age, 389
possible processes for increased mortal-
ity in, 4-5

postoperative pulmonary complications
in, 174,230
pulmonary surfactant activity in, 172,
225

relationship of asbestos in lung neoplasm
mortality, 257
relationship in coronary and lower limb
arteriosclerosis, 72
relationship of former to lung neoplasm
development, 276
relationship to infectious respiratory dis-
ease, 172,226-229
relationship to laryngeal neoplasm devel-
opment in, 28 1
relationship to lip or oral cavity neo-
plasms, 36 l-370

relationship to lung neoplasms, 275
relationship with bladder neoplasms in
men, 299
relationship with dust on COPD develop..
ment. 153

with peptic ulcer, 427
risk in CHD, 8
risk of COPD in, 140
survey by age and sex, 6
survey of U.S.. 6

Cigarettes
development of esophageal neoplasms ~
bv. 12.293

tar levels of, relationship to lung neo-
plasm development, 276
Cigar smokers
atypical nuclei in male esophageal epi-
thelium, 319
bladders neoplasms in, 293-294
cell rows and atypical cells in vocal cords
of, 280, 359-360
COPD morbidity in, 146, 197-198,
201.202,204-205
effects of smoke on bronchial reactivity,
164

esophageal neoplasm mortality ratios in,
290
kidney neoplasms in, 294-295
lack of risk in CVD, 67
laryngeal neoplasm induction in, 12,
354-357
lung neoplasm incidence in rural Switzer-
land. 244
lung neoplasm mortality in, 11,240-243
mortality ratios from COPD in, 142-143,
145

443


myocardial infarction in, 32, 38-39
relationship to infectious respiratory dis-
ease, 227
relationship of laryngeal neoplasms de-
velopment in, 281
relationship of neoplasms of oral cavity
with,, 12, 361-365.367-371
mortahty ratios from pancreatic neo-
plasms in, 298
mortality ratios from peptic ulcer in,
424
risk of CHD, 8
risk of COPD, 10
risk of lung neoplasm development, 276
Ciliary activity

see Respiratory system
Circulation

see Blood circulation
Cirrhoses
see Liver
Civil servants

see Government employees under Occu-
pations
Coal miners

see Occupations
Congressional legislation
see Laws

Connecticut Cancer Registry
figures on age-adjusted larynx neoplasm
incidence,.277

fifm~ on mcidence of oral neoplasms,
Constitutional hypothesis
relationship to CHD and smoking, 4849,
  105-106
COPD
see Bronchopulmonary disease, chronic
  obstructive
Cornsilk
smoking, tack of arterial epinephrine
level increase, 57

Coronary blood flow
see Blood circulation, coronary
Coronary disease
see also Angina pectoris
age- adjusted rates in smokers, 23
arFLriosclerotic, mortality rates in U.S.,
atherosclerosis in, effects of smoking on,
4,63
bl;r;d4y;me of smokers vs. nonsmok-
carbon dioxide effects on oxygen uptake
in, 62
cigarette smoking relationship, 5
death ratios of paired combinations of
high risk, 25
fist, mortality rates in smokers vs. non-
smokers, 24, 26-29
incidence and mortahty rates in former
smokers, 46.4748
infarction in NYC pipe and cigar smok-
ers, 32.38-39

infarction relationship to physical activ-
ity, smokers vs. nonsmokers, 44
in smokers with predisposing factors, 24
morbidity relationship of smoking to,
32-35,37,39,93-91
mortality and morbidity retrospective
studies, 40,93-97

444

mortality from, relationship to electre
cardiographic findings, 42
mortality in obese vs. non-obese, 45
mortality rates in, hypertensives vs. non-
hypertensives, 42
mortality rates in, smokers vs. non-
smokers, 21-22
mortality rates in, with increased carbon
monoxide, 62
mortality rates of paired combinations
of high risk, 25
mortality rates of cigarette smokers
from? AHA pooling project, 28,30,3V
mortahty rates of U.S. veterans, 26, 38
myocardial infarction in Danish twins,
51

ni;;tin; effect on coronary blood flow
relaiion of triglycerides to, 65
relationship of blood presure and smok-
ing, 45,41

relattonship of heart rate and smoking,
45,.47

relatronship of physical activity and
smoking41,43,44
relationship to constitutional makeup
and smoking, 4849, 105-106
relationship to ECG abnormalities and
smoking, 45,47
relationship to obesity and smoking,
4345
risk factors, 23-24,4041
smokers age effects on development, 27,
39

smoking risk factor, 8
sudden mortality in, smoking effects on,
52

Coronary heart disease
See Coronary disease
cows
see Cattle
Cresol

suspected carcinogenic agent of cigarette
smoke, 266
Cuba
laryngeal neoplasms in, relationship to
tobacco use, 356
relationship of tobacco use and neo-
plasms of oral cavity, 364
CVD

see Cerebrovascular disease
Cyanides

metabolism of, pathogenesis of tobacco
amblyopia relationship to, 435436
in tobacco amblyopia etiology, 14
Czechoslovakia
laryngeal neoplasms in, relationship to
tobacco use, 354,357
serum lipid difference in smokers vs.
nonsmokers in. 101

Death rates

see Mortality rates
Denmark

atherogenic effect of carbon monoxide
and hypoxia, 64

bladder neoplasms in, methods and re-
sults in retrospective studies of smok-
ing and, 381,383

carbon monoxide effects on human
blood lipids in, 129


carbon monoxide effects on rabbit blood
lipids in, 129
serum lipid differences in smokers vs.
nonsmokers in, 102
twins in, angina pectoris in smokers vs.
nonsmokers,.51

Deoxyribonucleic acid
content increase in smokers oral epi-
thelial cells, 288
levels in mice lung exposed to cigarette
smoke, 161
Diabetes

effect on CHD in smokers, 24
risk in mortality from CVD, 67
Diabetes mellitus

relationship with cigarette smoking in
peripheral vascular disease, 72
Dibenz(a,h)acridine
carcinogenic properties in cigarette
smoke from,.265

Dibenz(aj)acridme
carcinogenic properties in cigarette
smoke from, 265

7H-Dibenzo(c,g)carbazole
carcinogenic properties in cigarette
smoke from, 265

Dibenzo(a,i)pyrene
see Benzo(rst)pentaphene
Diethylnitrosamine
suspected carcinogenic properties in ciga-
rette smoke from, 265
7,12-Dimethylbenz(a)anthracene
see Benz(a)anthracene, 7,12dimethyl-
Dimethylnitrosamine
suspected carcinogenic properties in ciga-
rette smoke from, 265
2,3-Diphosphoglycerate
effects of carbon monoxide on, 6061
DNA

see Deoxyribonucleic acid
DO&E

atherogenic effects of nicotine in, 120
bt&d;; rrrplasms in, fed 2-naphthyl-
brady&dia and tachycardia in, follow-
ing nicotine injection, 57-58
bronchogenic carcinoma induction in,
from cigarette smoke inhalation, 269,
210

cigarette smoke instillation or implanta-
tion effects on tracheobronchial tree
of. 268,347
death in, causes from cigarette smoke m-
halation, 271
effect of cigarette smoke on pulmonary
clearance in, 164, 170
fetal bronchial tubes of, effect of ciga-
rette smoke on, 345
lungs of, cigarette smoke effects on sur-
factant activity, 112, 225
lung neoplasms following cigarette
smoke inhalation, 239,277
lung neoplasms in, types and lobes where
found. 269.272-273
myocardium of, nicotine effects on, 58
neoplasm development in smoking, per-
centages of, 274

activity of, effect of smoking, 165
aryl hydrocarbon hydroxyiase activity in
placentas at childbirth, 410
aryl hydroxylase, effect of nickel in ciga-
rette smoke on induction of, 257
benzo(a)pyrene hydroxylase, activity in
placentas of smoking mothers, 410
carbonic anhydrase, carbon monoxide
inhibition in fetal cord blood of smok-
ing mothers, 407
carbonic anhydrase, decrease in activity
in fetal cord blood in smoking
mothers. 409

pulmonary histological changes in ciga-   Epidermoid carcinoma
rette smoke inhaling, 158, 159160      see Carcinoma, epidermoid

respiratory tract of, cigarette smoke in-
halation effects on, 268,352, 353
smoke induced bronchoconstriction in,
atropine effects, 163
smoking and nicotine effects on blood
lipids in, 127-128
smoking and nicotine effects on cardio-
vascular function in, 101-l 12
smoking and nicotine effects on cate-
cholamine levels in, 119
Donkeys
effect of cigarette smoke on pulmonary
clearance in, 164, 111
Ducks

cigarette smoke instillation or implanta-
tion effects on tracheobronchial tree
of, 346

Duodenal ulcer
see Peptic ulcer
Dusts

COPD development from, 153, 218

Egypt

relation of human pulmonary histology

and smoking, 163 -
Electrocardiograph

-.

findings on, CHD mortality relationship
to,.42
readmg abnormalities, relationship to
smoking and CHD, 45.47

Electroph&esis

use in determining serum levelof alphar-
antitrypsin, 151
Emphysema
alphar-antitrypsin absence type genetic
factors, 150
cigarette smoking effects on, 9
development in dogs following cigarette
smoke inhalation, 27 1
development of, relation of cadmium in
smoke to, 154
grade II or III, smokers vs. nonsmokers,
  162
mechanism inalphar-antitrypsin absence

type of, 151

mortality from, effect of cigarette smok-
ing on, 175
mortality rates from, in 1967, 139
pulmonary, definition, 139

Employment

see Occupations
England

see United Kingdom
Enzymes
see also Papain

445


Epinephrine

levels in arteries, cigarette smoking ef-
fects on, 51
Epitheliomas
tip, relationship of tobacco use with, 361
Epoxides
suspected carcinogenic agents in ciga-
rette smoke, 265
Esophageal neoplasms
frequency in smokers vs. nonsmokers,
12,238

induction in animals by nitrosamine, 292
methods and results of retrospective
studies of tobacco use, 289, 375-378
mortality rates in U.S. for 1967, 289
relationship to smoking, 293
Esophagus
basal cells of epithelium of, atypical
nuclei in male smokers 292, 379-380
Ethanol
see Alcohol
Ex-smokers

see Smokers (former)

Factory workers
see plant workers under Occupations
Fatty acids
blood, effect of smoking on levels of, 65
levels in smokers vs. nonsmokers, 102
rise in blood serum after smoking, 36
suspected carcinogenic agents of ciga-
rette smoke, 266
Fetus

heart beats in, increase in smoking
mothers, 408
tissues of, effects of elevated carboxy-
hemoglobin on, 407
Fibrosis

in lung, smokers vs. nonsmokers, 161
Fibrillation

ventricular, death from, 36
Filters

see Cigarette fitters
Finland

blood pressure differences in smokers vs.
nonsmokers in, 103
COPD morbidity in smokers of,, 200
lung neoplasms in, restrospectrve smok-
ing study of methods in, 325,327
lung neoplasm mortality in, relationship
to tobacco use, 245-246
peptic ulcer in, methods and results for
retrospective and cross section studies
of smoking and, 426,428
serum lipid differences in smokers vs.
nonsmokers of, 98.99
smoking and nicotine effects on human
blood lipids in, 124
Fluoranthene

alcoholic solution of, penetrability of
esophageal epithelium, 292
Flax mill workers
see Occupations
Former smokers
see Smokers (former)
Formosa

acute effect of cigarette smoke on
human pulmonary function in, 169
France
bladder neoplasms in, methods and re-

suits in retrospective studies of smok-
ing and, 381-383
CHD mortality and morbidity in, 94,97
COPD mortality of smokers in, 201
cigarette smoke effects on animal lung
tissue in, 343
cigarette smoke effects on chicken em-
bryos in, 344
cigarette smoke inhalation effects on rat
respiratory tract, 349
esophageal neoplasms in, retrospective
studies of tobacco use with, 378
laryngeal neoplasms in, relationship to
tobacco use, 355,357

lung neoplasms in, retrospective smoking
study of methods in, 326
relationship of tobacco use and neo-
plasms of oral cavity, 363
Framingham Heart Study
morbidity ratios in CHD, 24

Fungicides

concentration in cigarette smoke, 265,
266

Gastric ulcer
see Pentic ulcer

Genetics

factors of. cigarette smoking relation-

ship, S '

factors of, in COPD pathogenesis, 148,
150-152,205

twin-studies, effects of smoking, 49-52,
99

Germany

CHD morbidity and mortality in, 95-96,

97

cigarette smoke inhalation effects on ani-
mal respiratory tract in, 350
laryngeal neoplasms in, relationship to
         ^--

tobacco use, 355

lung neoplasms in, retrospective smoking
study of methods in, 323,325,326

polonium-210 levels in lungs of smokers

in, 336

smoking and nicotine effects on human
blood lipids, 125
Glossary
of terms used in smoking and ventilatory
function, 215
Glucose

metabolism and insulin response, altera-
tion effects on myocardial response, 66
Glycogen
levels in mice lung exposed to cigarette
smoke, 161

Government employees

see Occupations
Graphite

respiratory tract carcinoma in workers
exposed to, 256
Great Britain
see United Kingdom
Guanethidine
blockage of nicotine cardiac stimulation
by, 57

Guinea pigs

lung neoplasm development following
chronic nickel carbonyl or dust inhala-
tion, 256

446


bv s-l

lungs of, cigarette smoke effects on sur-
factant activity, 225
respiratory changes in, exposed to ciga-
rette smoke, 162

Hamsters

benzo(a)pyrene inhalation by, effect of
asbestos dust on carcinoma induction,
  257
bt$; ;;plasms in, fed 2-naphthyl-
cigarettd smoke instillation or implanta-
tion effects on tracheobronchial tree
of, 268, 346-348
laryngeal malignancies in, following
smoke inhalation, 12
laryngeal neoplasms following cigarette
smoke inhalation, 239
larynx `of, effect of cigarette smoke in-
halation on, 28 1, 284
lung and embryos, effects of cigarette
smoke tars on, 343-344
pulmonary changes from chronic nitro-
gen dioxide inhalation, 220
respiratory tract of, C-14 labeled particu-
lates deposition in, 281-282
respiratory tract of, cigarette smoke in-
halation effects on, 268,35 1
Health Insurance Plan (NYC)
myocardial infarction in  ipe and cigar
smokers under, 32.38-3 4)

Heart

see also Arrhythmia. brachycardia, myo-

cardium and tachy&rdia
cardiac rhythm of, effect of nicotine on,
36
fetal, increased rate by maternal smok-
ing, 408
myocardium of, nicotine effects on oxy-
gen demand, 38
myocardium of, cigarette smoking effect

on, 5,8

rate, relationship to smoking and CHD,
45.47
Heart disease
see Cardiovascular diseases and coronary
disease

Heights
decreased, in children of smoking

mothers, 407
Hematite dust

respiratory tract neoplasms in hamsters
exposed to, 348
Hematocrit
infant, smoking mother effects on, 407,
  409
variations in, effect on coronary blood
flow, 66
Hemoglobin
see also Carboxyhemoglobin
affinity for oxygen, CO effects on 2,3di-
phosphoglycerate control of, 6061
varia$~sg in, effect on coronary blood
Hens '
see Chickens
Heterocyclc compounds
carcinogenic properties in cigarette
smoke, 264,265
Hexamethonium
blockage of nicotine cardiac stimulation

-.r>-.

HIP of NYC
see Health Insurance Plan (NYC)

Hookahs

smokers of, laryngeal neoplasm induc-
tion in, 355
Hungary
retrospective smoking study of methods
for lung neoplasms in, 328
Hydrocarbons
see Aromatic compounds heterocyclic
compounds
Hydrogen cyanide
in cigarette smoke, effects on body oxi-
dative metabolism, 62
3-Hydroxyanthranilic acid
see Anthranilic acid, 3-hydroxy-
3-Hydroxykynurenine
excretion of, smoking effects on, 296
Hydroxyproline
level in mice lung exposed to cigarette
smoke,. 161
Hypertension
see Blood pressure
Hypoxemia
arterial, carbon dioxide effects on, 61,'
  15
Hypoxia
aortic atheromatosis development in
rabbits exposed to, 64
postoperative, development in smokers,
174,230

postural, mechanism in asymptomatic
smokers vs. nonsmokers, 147

Iceland
lung neoplasms in, relationship to tobac-
co smoking, 244
Indeno( 1,2,3 ,-cd)pyrene
carcinogenic properties in cigarette
smoke from, 265

lndia

esophageal neoplasms in, retrospective
studies of tobacco use with, 378
laryngeal neoplasms in, relationship to
tobacco use, 355,356
relationship of smoking to tuberculosis
in, 227
relationship of tobacco use and neo-
plasms of oral cavity in, 362,366
smoking and nicotine effects on human
cardiovascular system, 117
smoking relationship to thrombosis in,
131

Indole, l-methyl-
possible initiator in tobacco carcinogene-
sis, 265

Industrial workers
see plant workers under Occupations
Industrial hazards
effect of dust on COPD development,
  17s

- .-

effects on COPD development in smok-
ers, 153-154, 218-219
Infant
see also Neonate
sudden death in, relation of smoking and
nonsmoking mothers, 407
Influenza virus
effect on dogs inhaling cigarette smoke,
  351
                      447


resistance of mice following cigarette
smoke inhalation, 173
Inhalation studies

see under Cigarette smoke
Ireland

acute effect of cigarette smoke on
human pulmonary function, 168
CHD mortality and morbidity in smok-
ers and nonsmokers in, 94
CHD mortality and morbidity in, 96
lung neoplasms in, retrospective smoking
study of methods in, 328
maternal smoking and infant weight, 399
methods used in smoking study and
human pregnancy, 394,396
northern, mortality rates from COPD,
144

occupational exposure and smoking rela-
tionships to COPD in, 218
relationship of lung neoplasms to smok-
ing, air pollution and residence in, 254
serum lipid differences in smokers vs.
nonsmokers in, 99
smoking and nicotine effects on human
peripheral vascular system, 133
smoking relationship to thrombosis in,
  130
Israel

cigarette smoke effects on animal em-
bryos in, 343
mortality rates from COPD in, increase,
  140
Italy
human experimental data on smoking
and pregnancy, 409
serum lipid differences in smokers vs.
nonsmokers in, 100
tracheobronchial tree changes in smokers
and nonsmokers in, 263

Japan

bladder neoplasms in, methods and re-
suits in retrospective studies of smok-
ing and, 382,384
CHD mortality and morbidity in, 96
cigarette smoke effects on human fetal
lung tissue in, 343
esophageal neoplasms in retrospective
studies of tobacco use in, 378
kidney and bladder neoplasms of smok-
ers in, 295
lung neoplasms in, retrospective smoking
study of methods in, 326,328
lung neoplasm mortahty of smokers and
nonsmokers in, 243
mortality ratios from esophageal neo-
plasms in, 291
mortality ratios from pancreatic neo-
plasms in cigarette smokers in, 298
relationships of lung neoptasms to smok-
ing, air pollution, and residence in, 255

Kidney neoptasms
mortality rates in U.S. for 1967,296
relationship of tobacco use, 13, 299
in29;;;cers and nonsmokers, 238,
Korea
relation of human pulmonary histology
and smoking in, 255

tracheobronchial tree changes in smokers
and nonsmokers of, 259

Lactones

suspected carcinogenic agents in ciga-
rette smoke, 265

Laparotomy

postoperative pulmonary complications
following, in smokers vs. nonsmokers,
174

Laryngeal neoplasms
development in hamsters following ciga-
rette smoke inhalation, 239
development in smokers, 12,281
mortality in smokers vs. nonsmokers,
237-238
mortality ratios from, 277-279
relationship to tobacco use and develop-
ment of,, 354-357
relative risk ratios from tobacco use,
277,358

U.S. mortality in 1967,277

Larynx

epithelial changes in, classification of:
281,283
hamster, C-14 labeled particulate deposi-
tion in, 281-282
Laws
PL 89-92, requirements for smoking haz-
ards literature review, 7
PL 91-222, requirements for smoking

hazards review, 7
Lip neoplasms

relationship of tobacco use, 361, 362,
365,367
relationship to pipe smoking, 289
Lipids
blood effect of smoking on levels of,
65-66,123-128
serum, differences in smokers vs. non-
smokers, 4 1,98-102
Lipoproteins
infiltration in arterial walls, carbon mon-
oxide effects on, 63
in smokers vs. nonsmokers, 99-102
Liver
cirrhosis   of, rates among cigarette
smokers, 5
Longshoremen

see Occupations
Luminescence

techniques of, use in determining aro-
matic hydrocarbon in urine, 297
Lung diseases
see Bronchopulmonary diseases, adeno-
carcinoma, carcinoma, tuberculosis
Lungs
tibroses in, smokers vs. nonsmokers, 16 1
hamster, C-14 labeled particulates depo-
sition in, 281-282
human, effects of cigarette smoke on tis-
sue from, 343-345
Lung neoplasms,
air polhrtion role in etiology of, 11
cause and effect relationship of smoking,
  276

cigarette smoking risks, 11
development in dogs following cigarette
smoke inhalation, 239
effect of sex on development, 11

448


environmental and atmospheric factors
of, 252-255
groupings, 246-334
group characteristics of tobacco use in
smokers and nonsmokers, 240, 244,
329-333

h;;,9';;; and smoking relationships,
mortality expected in U.S. in 1970,237,
219

---

mortality from chromium compounds,
257-258

mortality in cigarette smokers by dura-
tion, 240,244
mortality in smelter workers exposed to
arsenic. 257
mortality in smokers and nonsmokers,
240-243
mortality, in smokers in Norway and
Finland, 245-246
occupational exposure effects on patho-
genesis of, 12
prevalence in males and females by
tumor type, 246,250
reduction in number using filter-type
cigarettes, 275
relationship of asbestos and smoking to,
257

relationship of female smoking, 246,251
relationship of smoking to, 237
retrospective study methods for smoking
relationships, 240,323-328
smoking cause and effect relationship, 3
smoking habit study of patients with, 3
types implicated in smoking, 237
U.S. mortality rates for 1939 vs. 1967,
239

Macrophages
effect of cigarette smoke of action on
staphylococcus, 165
Mammals
see also specific mammals
cells of, effect of cigarette smoke tars
on, 343
Medical students
see Occupations
Methylbenzo(a)pyrene
see Benzo(a)pyrene, l-methyl-
9-Methyl carbazole
see Carbazole, 9-methyl-
Methylchrysenes
see Chrysene, 1 methyl-
Methyl-indole
see Indole, lmethyl-
Methyl-n-butymitrosamine
Fe Butylamine, nmethyl-nitroso-
N -Methylnicotinamide
see Pyridinium compounds, 3carba-
moyl-l-methyl-
Mice
bladder neoplasms in, induction by
tryptophan metabohtes, 296
embryo, lethal effects of nicotine on,
411
esophageal epithelium of, alcoholic
benzo(a)pyrene penetrability of, 292
esophageal epithelium of, oil desolved
benzo(a)pyrene penetrability of, 292

lungs of, effects of cigarette smoke on,
343.344

lung neoplasm incidence in, from chrom-
ium oxide dust exposure, 258
pulmonary carcinoma induction in,
following asbestos dust inhalation, 257
pulmonary changes from chronic nitro-
gen oxide inhalation, 16 1,220
pulmonary changes in cigarette smoke
inhaling, 159
pulmonary clearance in, cigarette smoke
effects on, 170
resistance to pneumonia bacteria follow-
ing cigarette inhalation, 173
respiratory tract of, cigarette smoke in-
halation effect on, 268-269, 349-353
skin painting of, smoke condensates ef-
fects on, 267, 337-342
Miscarriages

see Abortion, spontaneous
Mollusks

ciliary function in, effect of cigarette
smoke on, 223
Monkeys
atherogenic effects of carbon monoxide
and hypoxia, 64
ciliary function in, effect of cigarette
smoke on, 222
fetal bronchial tubes of, effects of ciga-
rette smoke on, 345
Rhesus, development of bladder neo-
plasms from 2-naphthylamine, 296
squirrel, nitrogen oxide effects on resis-
tance to pneumococcus, 173
Morbidity ratio
Cyoys in4smokers with predisposing fac-
CHD `in smokers vs. nonsmokers, 21-22,
24,30-35
CHD, relation to smoking, 32-35,37, 39
CHD, retrospective studies, 40,93-97
in Danish twins, smoking effects on,
  49-s 1

development of COPD in smokers vs.
nonsmokers, 145, 195-205
Mortalitv rates

from bladder neoplasms in U.S. for
1967,293

from bronchopulmonary disease,
141-145

cerebrovascular disease, smokers vs. non-
smokers, 66-67,68-70
CHD, paired combinations of high risk
characteristics in, 25
CHD, retrospective studies, 40,93-97
CHD in smokers vs. nonsmokers, 24,
26-29
CHD in U.S., 21
in Danish twins, smoking effects on, 51
fr;y67es;f;ghageal neoplasms in U.S. in
from &dney neoplasms in U.S. for 1967,
296
from lung neoplasms for 1939 vs. 1967
in U.S., 239
from lung neoplasms expected in 1970,
237,239
from lung neoplasms in smelter workers
exposed to arsenic, 251
from oral neoplasms in 1967,285

449


from peptic ulcer in U.S. in 1967,423
in former smokers, relation to CHD, 46,
4748

in Swedish twins, smokers vs. non-
smokers, 5 1
smokers vs. nonsmokers, 3
U.S. male veterans from CHD, 26,38
Mortality ratios
CHD with high risk characteristics, esti-
mated, 25
from esophageal neoplasms, prospective
and retrospective studies, 289-291
from laryngeal neoplasm, 277-279
from lung neoplasms in smokers in Nor-
way and Finland, 246
from lung neoplasms,, in males by ciga-
rette smoking duratton, 240,244
from pancreatic neoplasms in smokers
and nonsmokers, 298-299
from peptic ulcer in smokers and non-
smokers, 424
smokers vs. nonsmokers, from lung neo-
plasms, 240-243
Mouth neoplasms
frequency in smokers and nonsmokers,
238 .

smoking induced, 12
Mucopolysaccharides
function as surfactants in lung tissue,
  172
Mussels

ciliary function in, effects of cigarette
smoke on, 221,222
Myocardium
effects of hydrogen cyanide in smoke
  on. 62

oxygen consumption in nicotine stimu-
lated, 59
oxygen requirements for, nicotine ef-
fects, 58

2-Naphthylamine

development of bladder carcinomas and
papillomas in dogs, hamsters and mon-
keys given, 296
suspected bladder carcinogen in tobacco

smoke, 265

National Center for Health Statistics
survey of U.S. smoking habits by. 56
survey on relationship of smoking and
incidence of respiratory disease,. 173
National Clearinghouse for Smoktng and
Health

responsibilities, 7
1970 survey of smoking, 6
National Cooperative Pooling Project
mortality statistics from coronary dis-
ease, 21-22

National Library of Medicine
assistance in literature review on smok-
a, 7
llatudE=

rwatory tract carcinoma in workers
exposed to, 256
NW-
St-ZlZhCkS
Neonate
see also Fetus. pregnancy, prematurity
birth weight, effect of maternal smoking
on, 389, 397-399

450

death, comparison of stillbirth and abor-
tions in smoking and nonsmoking
mothers, 395,405406
death, differences of birth weight and, in
smoking and nonsmoking mothers, 404
death, smoking mothers effects on 415
rats, LDso nicotine determination, 412
Neoplasms
see also specific neoplasms, adenocarci-
noma, carcinoma, lung neoplasms, etc.
adenomatous, induction in mice by ciga-
rette smoke inhalation, 350
bladder, in smokers and nonsmokers,
293-295,381-384
bladder, methods of retrospective studies
of smoking and, 293,381-384
bl;$I;;9 relationship of tobacco usage
bladder. relation&u to ciaarette smok-
ing, 13,299 - -
bladder. U.S. mortalitv in 1967.293
development in smoking dogs, percent-
ages of, 274
esophageal, frequency in smokers and
nonsmokers, 12, 238
esophageal, methods and results of retro-
spective studies of tobacco use in, 289,
375-378
esophageal, mortality ratios, 289-291
esophageal, mortality rates for U.S. in
1967,289

esophageal, relationship to smoking, 293
kidney, mortality rates in U.S. for 1967,
296

kidney, relationship to tobacco use, 13,
299
kidney, in smokers and nonsmokers,
238,294-295
laryngeal, 12,237-239,281
laryngeal, relationship of tobacco use
and development of, 354-357
laryngeal, relative risk ratios from tobac-
co use, 277,358
laryngeal, U.S. mortality in 1967, 277
ho. relationshin to smokine. 289
lip; relationship to tobaico use, 361,
362,365,367
mammalian, cigarette smoke effect on,
343

oral cavity, relationship of tobacco use,
285,36 l-367
oral cavity, relationship to smoking, 289
pancreas,  relationship to smoking,
298-299

Netherlands

cigarette smoke inhalation effects on
mice respiratory tract in, 349
lung neoplasms in, retrospective smoking
study of methods for, 323
serum lipid difference. in smokers vs.
nonsmokers of, 101
New York City
myocardial infarctions in cigar and pipe
smokers in, 32,38-39
New Zealand
human experimental data on smoking
and pregnancy, 408409
Nickel compounds
suspected carcinogenic agents in ciga-
rette smoke, 265


Nickel workers
see Occupations
Nicotine

atherogenic effects of 120-122
effect on blood lipids, 123-l 28
effect on blood pressure, 36
effects on cardiac rhythm of heart, 36
effects on cardiovascular system, 56-58,
  107-118
effects on catecholamine release from
adrenals, 36,119
effects on heart rate., 36
effects on myocardmm oxygen demand,
  38
effects on myometrial strips in gravidic
women, 408
effects on peripheral vascular system, 72,
75.133-134
effects on pregnancy, 411414
induction of necrosis in arterial walls, 63
neurogenic effects of, 57
Nitrogen dioxide
pulmonary changes in rodents chron-
ically inhaling, 161,220
Nitrogen oxide
effects on resistance of squirrel monkeys
to pneumococcus, 173
4-Nitroquinohne l-oxide
alcoholic solution of, development of
papillomas in mice drinking, 292
N-Nibosamines
carcinogenicity in cigarettes smoke,
  264-266
esophageal neoplasms induced in animals
by. 292

Nitrdsopiperidine
see Piperidine, nitroso-
Nitrosopyrrolidine
see Pyrrolidine, nitroso-
N'methyhticotinamide
urinary excretion of, smoking effects on,
  297
Nonsmokers
see also Smokers vs. nonsmokers
carboxyhemoglobin effects on oxygen
uptake, 61
Norway
lung neoplasms in, for pipe smokers, 244
lung neoplasm mortality in, relationship
to tobacco use, 245-246
tracheobronchial tree changes in smokers
and nonsmokers of, 259

Oat cell carcinoma
see Carcinoma, oat cell
Obesity

relationship to CHD mortality, 43
relationship to smoking and CHD,4345
relationship with smoking in peripheral
arteriosclerosis, 72
Occupations
see also Industrial hazards
asbestos workers, respiratory tract carci-
noma, 256
asbestos workers, lung neoplasm mortal-
ity in smoking, 257
bank employees, smoking and COPD,
  198
coal miners, impaired pulmonary func-
tion in smoking, 163

coal miners, respiratory tract carcinoma,
256

coal miners, smoking and COPD, 153,
197,218-219
coal miners, smoking and ventilatory
function, 207
flax mill workers, smoking and COPD,
199

government employees, blood pressure
differences in smokers vs. nonsmokers,
99

longshoremen, mortality from smoking-
related cerebrovascular disease, 70
longshoremen, mortality rates from CHD
in, 28
longshoremen, smoking and COPD, 200
longshoremen, smoking and ventilatory
function, 208
medical students, serum lipid differences
in smokers vs. nonsmokers, 98
medical students, smoking and nicotine
effects on blood lipid levels, 124
medical students, smoking and thrombo-
sis relationships, 130
medical students, smoking and ventila-
tory function, 209-210
nickel workers, lung neoplasms in, 256
physicians, bladder and kidney neo-
plasms in smoking, 293,294
physicians, cessation of smoking effect
on COPD, 142
physicians, COPD mortality rates, 149
plt;t;"4;s, decline in cigarette smoking
physi&s, mortality from srnoking-
related cerebrovascular disease, 68
physicians, mortality rates from CHD,
26
physicians, mortality ratios from esopha-
geal neoplasms, 290
physicians, mortality ratios from peptic
ulcer in smoking and nonsmoking, 424
physicians, pulmonary function follow-
ing cessation of smoking, 149
physicians, smoking and ventilatory
function. 209-210. 213
plant workers, occupational exposure
and smoking relationships to COPD,
153,218,219
plant workers, smoking and COPD, 198
plant workers, smoking and ventilatory
function, 206-208
post office workers, blood pressure dif-
ferences in smokers vs. nonsmokers,
104

post office workers, smokers and ventila-
tory function, 209
post office workers, smoking and COPD,
200,202
prisoners, serum lipid differences in
smokers vs. nonsmokers, 100
prisoners, smoking and nicotine effects
on peripheral vascular system, 133
railroad employees, coronary heart dis-
ease, morbidity in smoking, 34
railroad employees, mortality and mor-
bidity from CHD, 97
railroad employees, mortality rates from
CHD, 28
smelter workers, lung neoplasm mortal-

451


ity from arsenic exposure, 257
soldiers, smoking and COPD. 197
steel workers, COPD development from
dust exposure, 153
students,, carbon monoxide effects on
blood hpids, 129
students, infectious respiratory disease in
smokers vs. nonsmokers, 228-229
students, mortality from smoking-related
cerebrovascular disease, 68
students, mortality rates from CHD, 28
students, smoking and COPD, 201
students, smoking and nicotine effects
on blood lipid level, 125
students, smoking and thrombosis rela-
tionships, 130

students, smoking and ventilatory func-
tion, 211
telephone company employees smoking
and COPD, 200
textile workers, occupational exposure
and smoking relationship to COPD,
218-219
transportation employees, smoking and
COPD, 198.202
transportation workers, air pollution re-
lationship to COPD, 216
transportation workers, smoking and
vent&tory function, 207,212
utility company employees, CHD mor-
bidity in smoking, 30
uranium miners, lung neoplasms in
smokers and nonsmokers, 256
veterans, bladder and kidney neoplasms
in smoking, 294-295
veterans, COPD mortality rates, 143
veterans, CHD morbidity in smoking, 32
veterans, effects of smoking on twin, 50
veterans, lung neoplasm mortality in
smoker and nonsmoker, 24 l-243
veterans, mortality rates from CHD, 26,
  38
veterans, mortality from smoking-related
cerebrovascular disease, 69
veterans, mortality ratios from esopha-
geal neoplasms, 290
veterans, mortality ratios from peptic
ulcer in smokers vs. nonsmokers, 424
Oleic acid
suspected carcinogenic agent in cigarette
smoke, 266
Olive oil
penetrabihty of benzo(a)pyrene in mice
esophageal epithelium, 292
Oral cavity neoplasms
estimated incidence in U.S. for 1970,
  284
mortality from in 1967,285
relationship of tobacco use. 285, 289,
  361-367
Organs
cultures of, cigarette smoke effects on
cell growth and reproduction, 267,
  343-345

Oropharynx neoplasms
frequency in smokers and nonsmokers,
  238
Oxygen
see also Hypoxemia
myocardial consumption of, following

nicotine stimulation, 58,75
transport in body, carbon monoxide
effects,, 60,75

uptake m nonsmokers with specific car-
boxyhemoglobin levels, 6 I,75

Palate

hamster, C-14 labeled smoke particulates
deposition in, 281-282
Pancreatic neoplasms
relationship to smoking, 13,238
relationship of smokmg to mortality
from, 298-299

Papain

pulmonary effects on rats exposed to
ciarette smoke with. 163

Papiliimas

development in mice drinking alcoholic
benzopyrene, 292
formation following skin painting with
smoke tars, 337-339,341
induction in hamsters exposed to ben-
zo(a)pyrene, 346-347
Pentolinium

blockage of nicotine cardiac stimulation
by, 57

Peoples Gas Light and Coke Co.
study of CHD, serum cholesterol and
smoking relatronships, 43
Peptic ulcer
antacid efficacy and healing of, effects
of cigarette smoking on, 423
development in smokers, 13
mortality from, in U.S. m 1967,423
mortality ratios from, in smokers and
nonsmokers, 424
retrospective and cross section study
methods for smoking relationship to,
425427

Peroxides

suspected carcinogenic agent in cigarette
smoke, 265

Personality characteristics
re~$u$ip to CHD and smoking, 4849,
Pesticides

content in cigarette smoke, 265, 266
Phagocytosis
pulmonary alveolar, in smokers vs. non-
smokers, 165

Pharyngeal neoplasms
fr;y8ency in smokers vs. nonsmokers,
relaltnship to tobacco use, 362-364,
Phenol

suspected carcinogenic agent of cigarette
smoke, 266
Phosphohpids
function as surfactants in lung tissue,
  172

smokers vs. nonsmokers, 99-100, 102
Physical activity
relationship to CHD and smoking, 41,
43!44

relattonship to myocardial infarction,
smokers vs. nonsmokers, 44
Physicians
see Occupations
Piperidine, nitroso-

452


suspected carcinogenic properties in ciga-
rette smoke from, 265
Pioe smokers
atypical nuclei in male esophageal epi-
thelium, 379
bladder neoplasms in. 293-294
cell rows and atypical cells in vocal cords
of, 280,359-360
COPD morbidity in, 146, 197-198,
201-205
development of chronic bronchopulmo-
nary disease, 10
development of esophageal neoplasms,
13,293

development of lung cancer, 11
development of oral neoplasms, 12
esophageal neoplasm mortahty  ratios,
290
kidney neoplasms in, 294-295
lack of risk in CVD, 67
laryngeal neoplasms induction, 12,
354-357
lung neoplasm incidence in Norway, 244
lung neoplasm incidence in rural Switzer-
land, 244
lung neoplasm mortality in, 324-327
m;$Gty rates from COPD, 142-143,
mortality ratios from pancreatic neo-
plasms, 298
mortality ratios from peptic ulcer, 424
myocardial infarction in, 32, 38-39
peptic ulcer in, 427
relationship to infectious respiratory dis-
ease, 227
relationship to laryngeal neoplasm devel-
opment, 281
relationship to lip neoplasms, 289
relationship to oral cavity neoplasms,
361-364,367
risk of CHD, 8
risks on lung neoplasm development,
276

Placenta

ability to hydroxylate benzo(a)pyrene in
smoking mothers, 407

Platelets

adhesiveness of increased, from cigarette
smoking, 9
aggregation of, cigarette smoking effects
on, 36
blood, effect of smoking, 66,75
Poland
bladder neoplasms in, methods and re-
sults in retrospective studies of smok-
ing and, 382,383
CHD mortality and morbidity in, 96
esophageal neoplasms in, retrospective
studies of tobacco use with, 378
laryngeal neoplasms in, relationship to
tobacco use, 357
relationship of tobacco use and neo-
plasms of oral cavity in, 364
serum lipid differences in smokers vs.
nonsmokers in, 100,102
smoking and nicotine effects on human
blood levels in, 124
yo3pg relattonships to thrombosis in,
Pollution
see Air pollution

Polonium-2 10

suspected carcinogenic agent in cigarette
smoke, 265-267, 335-336
Post office workers
see Occupations
Postoperative pulmonary complications
see Respiratory system
Potassrum40

present in tobacco leaf, 266
Pregnancy

see also Abortion (spontaneous), pla-
centa, stillbirth, neonate
human, methods used in smoking study
of, 391-396
maternal smoking during, effect on fetal
growth and weight, 389,397-399
maternal smoking during, effects on fetal
growth, 13,415
nicotine effects on myometrial strips in,
  408
unsuccessful, smoking effects on, 13
Prematurity
maternal smoking and, 390,400403
Prisoners

see Occupations
Proteins

see Lipoproteins
Pro tozoae

ciliary function in, effect of cigarette
smoke on, 165,224
Public Health Service
review of medical literature on smoking
hazards, 7
1967 study of, starting point for new
studies, 4
Public laws
see Laws
Puerto Rico

esophageal neoplasms in, retrospective
studies of tobacco use with, 378
relationship of tobacco use and neo-
plasms of oral cavity in, 367
Pulmonary system
see Respiratory system
Pyrrolidine, nitroso-
suspected carcinogenic properties in ciga-
rette smoke from. 265

Rabbits

atherogenic effects of carbon monoxide
and hypoxia, 64
atherogenic effects of nicotine, 120-122
blood lipids in, smoking and nicotine
effects on 127

cardiovascular function in, smoking and
nicotine effects,, 108, 109
ciliary function m, cigarette smoke ef-
fect on, 221-222
cholesterol fed, carbon monoxide effects
on, 65-66
offspring of, nicotine and smoke effects
on birth weight, 407
offspring, smoking effects on stillbirth
and mortality, 411
pregnant, tritium-labeled nicotine effects
in, 413
p;\nnary changes in cigarette smoking,
pulmonary clearance in, cigarette smoke
effect on, 164, 170. 171
                      453


skin painting, smoke condensate effects
on, 267,338
Railroad employees
see Occupations
Rats

atherogenic effects of nicotine in, 120,
121

blood liuids in. nicotine and smoke ef-
fects, i28
ciliary function in, cigarette smoke on,
221,222
LDso. nicotine determination in female,
412

lung neoplasms, from intrabronchial im-
planting of chromium compounds, 258
lung neoplasms, from nickel carbonyl
and dust inhalation, 256
lungs, cigarette smoke effects on surfac-
tant activity, 172,225
offspring, nicotine and smoke effects on
birth weight, 407
pregnant, aromatic compound stimula-
tion of placental BPhydroxylase activ-
ity, 414
pregnant, fetal wastage and neonate
death in nicotine and smoking, 411
pulmonary carcinoma induction follow-
ing asbestos dust inhalation, 257
pulmonary changes from chronic nitro-
gen dioxide inhalation, 161,220
respiratory tract of, cigarette smoke in-
halation effects, 268,349,353
sk227py4y, smoke condensates effects,
trachia of, cigarette smoke effects, 343
tracheal ligation of, cigarette smoke and
papain effects on, 163
tracheobronchial tree of, cigarette smoke
effects on, 268.346-349
Reading ability
in children of smoking mothers, 407
Reserpine
nicotine cardiac stimulation blockage by,
57
Respiratory system
see also Bronchopulmonary disease,
larynx, lungs, trachea
acute effect of cigarette smoke on
human pulmonary function, 163,
  166-169

animal, cigarette smoke instillation or
implantation effects on, 268,346-348
animal, effect of cigarette smoke inhala-
tion on, 268-269,349-353
effect of cigarette and cigar smoke on
bronchial reactivity, 164
effect of cigarette smoke on human cili-
ary function, 165,221-224
effect of cigarette smoke on human pul-
monary clearance, 164,170
glossary of terms used in testing, 215
histological changes in smokers, 154-157
improvements in function following
smoking cessation, 148,149
pathological changes in cigarette
smokers,.1 75
postoperatrve complication in, of smok-
ers vs. nonsmokers, 174-176.230
pulmonary alveolar phagocytosis in
smokers vs. nonsmokers, 165

pulmonary infarction in dogs inhaling
cigarette smoke, 271
surface tension of, effect of cigarette
smoke on, 172,225
surfactant activity of, in smokers vs.
nonsmokers, 172,225
surfactants in, definition, 172
tests of function of, in smokers,
146-147,206-214

Respiratory tract diseases
see also Asthma. bronchitis. broncho-

pulmonary disease, emphysema, pneu-
monia, tuberculosis
infectious,
226-229  smoking effects on, 172,
infections, prevalency among smokers,
10.176

pathological and cytological changes in,
of smokers vs. nonsmokers, 258-263
ventilatory function in, smokers vs. non-
smokers, 175
Rhodesia

retrospective smoking study of methods
for lung neoplasms in, 328
Rubidium-84
tracing capillary flow in coronary blood
flow, 59

Rural populationsr
lung neoplasms 111, suspected etiology of
increased, 276

Rural residences
lung neoplasm incidence in, in Switzer-
land, 244
relationships of lung neoplasm to smok-
ing, ah pollution, and, 252-255
Russia
atherogenic effects of nicotine on rabbits
in, 120
atherosclerosis autopsy studies in, 54
cigarette tar effects on rat tracheobron-
chial tree in, 348

Saccharides
see Mucopolysaccharides
Saliva

interference in action of carcinogens on
oral cavity, 288
sarcoma
formation following animal skin painting
with smoke condensates, 338,340
induction in rats by cigarette smoke in-
jection, 346-347
Scotland

see United Kingdom
Sex

ages of cigarette smokers by, 6
effect of, in alphaantitrypsm deficiency
emphysema, 151
effect of, on laryngeal neoplasm inci-
dence development, 277
effect of, in mortality in cigarette
smokers,.276

effect of, m lung neoplasms and tobacco
use, 244,329-333
lung cancer mortality by, 252
lung neoplasm development by, 11
mortality rates of cigarette smokers by,
3
ratios of, in lung neoplasm mortality in
Norway and Finland, 245-246

454


Sheep

pregnant, nicotine injection and smoke
inhalation effects on, 414
Smelter workers
see Occupations
Smokers (former)
see nlso Cessation of smoking
atypical nuclei in male esophageal epi-
thelium in? 379-380
CHD mortahty probability in, 46
incidence of CHD and mortality in,
  4648
lung neoplasm mortality ratios in,
  241-242
lung neopksms in, lowered rates, 11
mortality rates from COPD, 175
mortality rates from lung neoplasms,
  276

Smokers vs. nonsmokers
see also Nonsmokers
bladder neoplasxns in, 293-295, 381-384
cell rows and atypical cells in vocal cord
of, 280, 359-360
CHD mortality in, 21-22
comparison of abortions, stillbirth and
neonatal deatli in, 390.405406
development of COPD in, 141, 145,
195-205
differences in emphysema types in, 154,
  156
effect of cigarette smoke on post-opera-
tive pulmonary complications, 175
effect of sex on mortality from CHD,
  28-31
esophageal e
nuclei in, 2 % ithelial cells with atypical
         2
esophageal neoplasm mortality ratios in,
290-29 1
excretion of tryptophan metabolites in,
  297
frequency of esophageal neoplasms in,
  238
frequency of kidney neoplasms in, 238
frequency of mouth and pharyngeal neo-
plasms in, 238
fr;r;;;y of urinary bladder neoplasms
grodp characteristics in lung neoplasms
and smoking in, 240,244,329-333
laryngeal neoplasms in, relationship to
tobacco use, 354-357
lung fibrosis development F, 161
1u2n4~-2~30plasm mortahty ratios in,
lung neoplasm mortality in uranium
miners, 256
morbidity ratios from CHD. 24
mortality from cerebrovascular disease,

67-70

mortality from CHD, 24, 26-29
mortality from CHD in Swedish twins.

51 -

mortality from laryngeal neoplasms in,
237-238
mortality rates, 3
mortality ratios of COPD in, 142-144
mortality ratio from laryngeal neo-
plasms, 278-279
mortality ratios from pancreatic neo-
plasms in, 298

myocardial infarction relationships to
physical activity, 44
pathological and cytological changes in
respiratory tract of, 258-263
peptic ulcer in, correlated amounts of
tobacco use, 427428
postoperative hypoxemia in, 174,230
postural hypoxemia mechanism in
asymptomatic, 147
postoperative pulmonary complications
in, 174-175,230
pulmonary alveolar phagocytosis in, 165
relation between CHD and serum choles-
terol level, 43
relationship to infectious respiratory dis-
ease, 172,226-229
serum lipids in, 41,98-102
surfactant activity in lungs of, 172, 225
type of lung neoplasms in male and fe-
male. 250

Snuff

dippers of, relationship to neoplasms of
oral cavitv. 287.361.364-365

Social adjustments '    '

in children of smoking mothers, 407
Socioeconomic relationships
in COPD, 152-153,216-217
Soldiers

see Occupations
South Africa

esophageal neoplasms in, retrospective
studies of tobacco use. 378
occupational exposure &d.smoking rela-
tionship to COPD in, 219
retrospective study of methods for lung
neoplasms in, 328
Serum lipid differences in smokers vs.
nonsmokers in, 99
Spontaneous abortions
see Abortions, spontaneous
Squamous cell carcinoma
see Carcinoma, epidermoid
Steel workers

see Occupations
Stearic acid

suspected carcinogenic agent of cigarette
smoke, 266
Stillbirths
abortions and neonatal death and, in
smoking and nonsmoking mothers,
390,405 406
effects of maternal smoking, 41.5
Students

see Occupations

Sugars
see Glucose. mucopolwaccharides

Surface tens&n a -
see Respiratory system
Surfactants

see Respiratory system
Sweden

acute effects of cigarette smoke on
human pulmonary function, 168
blood pressure differences in smokers vs.
nonsmokers in, 104

CHD mortality and morbidity in, 97
COPD morbidity in smokers in, 203,205
effect of cigarette smoke on animals cili-

ary function in, 221-224
esophageal neoplasms in, retrospective

455


studies of tobacco use with, 378
genetic studies of twins in, smoking ef-
fects on, 50.99
laryngeal neoplasms inJe1ationship to
tobacco use, 356
relationship of tobacco use and lip neo-
plasms in, 361
relationship of tobacco use and neo-
plasms of oral cavity, 364
serum lipid differences in smokers vs.
nonsmokers of, 99
smoking and nicotine effects on human
cardiovascular system, 115
smoking and nicotine effects on human
peripheral vascular system, 133
tracheobronchial tree changes in smokers
and nonsmokers in, 263
Switzerland
CHD morbidity and mortality in,
smokers vs. nonsmokers, 95
cigarette smoke effects on mice lung and
kidney tissue in, 344
cigarette smoke inhalation effects on
mice respiratory tract, 351
lung neoplasm incidence in cigar and
pipe smokers of rural, 244
retrospective smoking study of methods
for lung neoplasms in, 325
serum lipid differences in smokers vs.
nonsmokers of, 100

Tachycardia

development in dogs induced by nico-
tine, 57
TAO
see Thromboangiitis obliterans
Tars, tobacco

carcinogenicity on animal skin, 238
carcinogenic properties from cigarette
smoke, 1 l! 264,265
content m cigarettes, relationship to lung
neoplasm development, 275,276
sarcoma induction in rats following in-
stillation,, 346

skin paintmg with, carcinoma induction
from, 337-342

Telephone company employees
see Occupations

Teratogenesis

maternal smoking implications in, 407
m mice embryos, nicotine effects on,

411

Tetraethylammonium chloride
bl;;k;g7e of nicotine cardiac stimulation
Textile workers
see Occupations
Thromboangiitis obliterans
definition, 73
remission of. cessation of smoking ef-
fects. 74
Thrombosis

smoking effects on, 66, 130-l 32

Tissues

cultures of, cigarette smoke effects on
ceie-g;;wth and reproduction. 267,
hypoxia of, carbon monoxide effects on,
  61
Tobacco

see also all forms, e.g. Cigarettes, etc.
456

chewing of, relationship to lip and oral
cavity neoplasms, 361-363,365366
leaves, presence of potassium40 in, 266
Tobacco amblyopia
see Amblyopia
Tobacco tars
see Tars, tobacco

Tongue

hamster, C-14 labeled particulate depo.
sition in, 281-282

Toxemia

preeclamptic, incidence in smoking and
nonsmoking mothers, 404,407
Trachea

hamster, C-14 labeled particulate depo-
sition in, 281-282

Transportation employees
see Occupations
Triglycerides

CHD incidence relationship to, 65
smokers vs. nonsmokers, 99-100, 102
Trypsin
see Anti-trypsin, alpha,
Tryptophan metabolism
alterations by smoking, 297
alteration in UriIWy tract neoplasms by
smoking, 13
carcinogenicity in mice bladders, 2"'
relation of excretion in smoke rs and
nonsmokers. 297

Tuberculosis

relationship of smokers vs. nonsmokers
to, 172,226-228

Tumorigenic agents
see Carcinogens
Twins

angina pectoris development in, smoking
effects on, 50-5 1
genetic studies of smoking effects on,
49-52

smoking effects on mortality and mor-
bidity in, 5 1

Ulcers
see Peptic ulcers
United Kingdom

bladder neoplasms in, methods in retro-
spective studies of smoking and.
382-384

blood pressure differences in smokers vs.
nonsmokers in, 103. 104
British Perinatal Mortality Survey of.
390,395,404,415

cigarette smoke effects on human fetal
lung and mice trachea, 344
cigarette smoke effects on human pul-
monary function, 168, 169
cigarette smoke effects on mice respira-
tory tract. 352

cigarette smoke implantation effects on
rat tracheobronchial tree in, 346-347
comparison of abortions, stillbirths and
neonatal deaths in smoking and non-
smoking mothers, 406

"3,`,9 tnoqrbidity in smokers in, 195-197.
effect. of cigarette smoke on animal cili-
acv function in. 221
human experimental data on smoking
and pregnancy, 408

kidney and bladder neoplasms in


smokers in, 294

lung cancer mortality in males in Eng-
land and Wales, 240
maternal smoking and infant weight in,
397,399
methods used in smoking study and
human pregnancy, 391,394-395
mortality from cerebrovascular disease
related to smoking in, 68
mortality rates from COPD in, lack of
increase, 140
mortality ratios from esophageal neo-
plasms in, 290
mortality ratios from laryngeal neo-
plasms in, 278
mortality ratios from peptic ulcer in
smokers and nonsmokers in, 424
occupational exposure and smoking rela-
tionships to COPD in 218-219
peptic ulcer in, methods and results of
retrospective and cross section studies
of smoking and, 425428
physicians in, decline in cigarette smok-
ing rates, 48
physicians in, mortality from lung neo-
plasms in smokers and nonsmokers,
241

pulmonary function in, cigarette smoke
effects on, 168
relationships of lung neoplasms to smok-
k, air pollution, and residence in,
253-254

relationship of smoking tuberculosis in,
226

retrospective smoking study of methods
for lung neoplasms in, 324,326
serum lipid differences in smokers vs.
nonsmokersin, 101, 102
smoking and nicotine effects on animal
cardiovascular function in, 107
smoking and nicotine effects on human
blood lipids in, 126
smoking and nicotine effects on human
cardiovascular system in, 115
smoking relationships to thrombosis in,
  131
United States

acute effect of cigarette smoke on
human pulmonary function in,
166-167,169
atherosclerosis autopsy studies in, 53-
55

bladder neoplasms in, methods and re-
sults in retrospective studies of smok-
ing and, 381-384
blood pressure differences in smokers vs.
nonsmokers in, 103-104
CHD mortality and morbidity in
smokers vs. nonsmokers in, 30-35, 37,
93-94

comparison of abortions, stillbirth and
neonatal death in smoking and non-
smoking mothers, 405406
cigarette smoke effects on animal tissues
in, 343-345
cigarette smoke effects pulmonary sur-
factants and surface tension, 172, 225
cigarette smoke implantation effects on
animals tracheobronchial tree, 346-348
cigarette smoke inhalation effects on ani-

mal respiratory tracts, 349-350, 352,
354
Co&D morbidity in smokers in, 195,
196,198-200,201-202,205
effects of cigarette smoke on animal cili-
ary function in, 221-224
esophageal neoplasms in, retrospective
studies of tobacco use, 378
esophageal neoplasm mortality in, in
1967, 289

human experimental data on smoking
and pregnancy in, 4084 10
human pulmonary function following
cessation of smoking in, 149
kidney and bladder neoplasms in
smokers in, 293-295
laryngeal neoplasm incidence in 1967,
277

laryngeal neoplasm in, relationships to
tobacco use, 278-279,354-355
lung neoplasm mortality in smokers and
nonsmokers in, 240-243
maternal smoking and infant weight,
397-399

methods used in smoking study and
human pregnancy, 391-395
mortality from aortic aneurysm related
to smoking in, 7 I
mortality from cerebrovascular disease
related to smoking, 68-70
mortality from lung neoplasms expected
in 1970,237,239
mortality rates for bladder neoplasms in
1967,293

mortahty rates for COPD, increase of
139-140

mortality rates for kidney neoplasms in
1967,296

mortahty rates for lung neoplasms in
1939 vs. 1967,239

mortality ratios for COPD, 142-145
mortality ratios for esophageal neo-
plasms in, 290-294
mortality ratios for laryngeal neoplasms,
278-279

mortality ratios for pancreatic neoplasms
in smokers and nonsmokers in, 298
mortality ratios for peptic ulcer in
smokers and nonsmokers in, 424
occupational exposure and smoking rela-
tionships to COPD in, 218-219
oral neoplasm incidence in, estimated for
1970,284

peptic ulcer mortality in 1967 in, 423
peptic ulcer in, methods and results for
retrospective and cross section studies
of smoking and, 425.426428
polonium-210 levels in lungs of smokers
in, 335-336
populations of, COPD development in,
10

relationship of human pulmonary histol-
ogy and smoking in, 155-157
relationship of tobacco use and lip neo-
plasms, 361-365,367
relationship of tobacco use and neo-
plasms of oral cavity, 36 l-365, 367
relationship of lung neoplasm to smok-
ing, air pollution, and residence in,
253-254

457


relationship of smoking to infectious res-
piratory disease in, 227-229
retrospective smoking study methods for
luna neoolasms in. 323-328
serum l&d differences in smokers vs.

nonsmokers in, 98,100,101
smoking relationship to thrombosis in,
130,131
smoking and nicotine effects on animal
cardiovascular function in, 107-112
smoking and nicotine effects on human
blood lipids, 123-l 26
smokinn or nicotine effects on human
cate&olamine levels, 119
smoking and nicotine effects on human
cardiovascular system, 113-l 14, 116,
117-119
smoking and nicotine effects on human
peripheral vascular system, 133-134
surveys of cigarette smoking in,, 6
tracheobroncbial tree changes m smokers
and nonsmokers in, 259-263
Uranium miners
see Occupations
Urban environment
contribution to lung cancer mortality,
  11
relationship of lung neoplasms, smoking,
air pollution to, 252-255

Urban populations
lung neoplasms in, suspected etiology of
increased, 276
Urinary bladder
see Bladder

Uterus

cigarette smoking effects on gravidic,
408

Utility Company employees
see Occupations

Vascular system
see also Blood circulation, cardiovascular
system, cerebrovascular system, throm-
boangiitis obliterans
peripheral, smoking and nicotine effect
on, 9,72-73,75, 133-134
Venezuela
maternal smoking and infant weight in,
450
methods used in smoking study and
human pregnancy, 445
Ventricular fibrillation
death from, nicotine effects on, 36
Ventilatory function tests
see Respiratory system
Veterans

see Occupations
virus

influenza, cigarette smoke effects on re-
sistance of mice with, 173
influenza, nitrogen oxide effects on
squirrel monkey resistance to, 173
Vitamin deficiency
relationship to tobacco amblyopia

Xenon
radioactive, regional pulmonary function
using, 147

458

z!z U. 5. GOVERNMENT PRINTING OFFICE: 1971 O-420-719