Th e
Health Consequences
of Smoking

A Report of the Surgeon General: 1972

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE
            Public Health Service
   Health Services and Mental Health Administration

For de by the Superintendent of Documents, U.S. Government Printing Office
       Washington, D.C. 20402 - Price 70 cents.
            Stock Number 1723-0051


Honorable Carl Albert
Speaker of the House of Representatives
Washington, D.C. 20515

Dear Mr. Speaker:

Enclosed is the 1972 report on the health consequences of smoking,
as called for by Section 8 (a) of the Public Health Cigarette Smoking
Act of 1969. As you will see, it continues and strengthens the find-
ings of previous Public Health Service reports that cigarette
smoking is a hazard to the health of the American people.

Under this Act, I am also required to submit to you such recom-
mendations for legislation as I deem appropriate.

As you know, it has long been the position of this Department that
an adequate health warning should appear in cigarette advertise-
ments along with listings of "tar" and nicotine. We are in support
of the current efforts of the Federal Trade Commission to bring this
about through the exercise of its regulatory powers. Should these
efforts fail, however, we would return to our previous recommenda-
tions that this should be accomplished through legislative action.

With kindest regards,

Sincerely,

Elliot L. Richardson
  Secretary

iii


           Preface
v'
Six times since 1964, the Public Health Service has issued formal

reviews of the scientific evidence which links cigarette smoking to
disease and premature death. Each successive review, including
this one, has served to confirm and strengthen the conclusion of the
1964 Report, that cigarettes are a major cause of death and disease.

In the first three chapters of this report, the relationships be-
tween cigarette smoking and cancer, cardiovascular disease, and
non-neoplastic bronchopulmonary disease are reviewed and evi-
dence is presented which helps develop our understanding of the
mechanisms which are involved in these relationships. In the final
three chapters, information is presented on public exposure to air
pollution from tobacco, on the relationship between tobacco and
allergy, and on the harmful constituents which are found in ciga-
rette smoke.

In the past few years, millions of Americans have stopped smok-
ing because they have persuaded themselves that it is in their own
self-interest to do so; we must continue to encourage cessation as
the only certain way to protect both the individual and society from
the harmful effects of smoking. We must also, however, work to-
wards reducing the dangers of smoking for those who have not
quit by developing less hazardous cigarettes and encouraging less
hazardous ways of smoking. The chapter which discusses the
harmful constituents of smoke is a useful statement of our current
knowledge in this field; it should interest not only research scien-
tists but those who are concerned with public education and public
Policy.

Research in smoking and health continues, as this report shows,
both in this country and abroad and under both public and private
auspices ; furthermore, the range of this research is widening as the
significance of cigarette smoking as a public health problem becomes
more apparent. In establishing the present series of reports, first
under Public Law 89-92 and now under Public Law 91-222, the
Congress has given us a means of encouraging the research we need
and of building a better understanding of the problem.

JESSE L. STEINFELD, M.D.
      Swgeon Geneml


Table of Contents

Page

Letter of Transmittal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

."
111

PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . ..I      V

PREPARATION OF THE REPORT AND
ACKNOWLEDGMENTS . . . . . . . . . . . . . . . , . . . . . . . . . .    ix

Chapter 1. Introduction and Summary . . . . . . . . . . . . . . . . .     1

Chapter 2. Cardiovascular Diseases . . . . . . . . . . . . . . . . . . .    11
Chapter 3. Non-neoplastic Bronchopulmonary Diseases . . .    35
Chapter 4. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    57
Chapter 5. Pregnancy   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    81
Chapter 6. Gastrointestinal Disorders . . . . . . . . . . . . . . . . .    95
Chapter `7. Allergy   . . ,  . . . . . . . . . . . . . . . . . , . . . . . . . . . . .   101
Chapter 8. Public Exposure to Air Pollution from
        Tobacco Smoke  . . . . . . . . . . . . . . . . . . . . . . . . .   119
Chapter 9. Harmful Constituents of Cigarette Smoke . . . . .   139

Mex   . . . . . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . . . . . . . . . . . .   151

vii


Preparation of the Report and Acknowledgments

"Smoking and Health. Report of the Advisory Committee to the
Surgeon General of the Public Health Service"* was published in
1964. The following documents were subsequently published as re-
views of the medical literature as called for by Public Law 39-92.

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. The format
of publishing a supplement to a supplement became unwieldy, par-
ticularly in the light of the lack of availability of previous reviews
to the general public. Therefore, when P.L. 91-222 was signed into
law on April 1, 1970, calling for an B-month interval between the
previous report and the new report, the entire field was reviewed
with an emphasis on the most recent additions to the literature.
The product of this review was: "The Health Consequences of
Smoking, A Report of the Surgeon General : 1971."**

The present document, "The Health Consequences of Smoking, A
Report of the Surgeon General: 1972," includes a review of the
literature which has been published since the 1971 Report was
completed. It also includes an evaluation of the state of knowledge
in three areas which have not been previously reviewed in these
reports: allergy and tobacco, public exposure to air pollution from
tobacco smoke, and harmful constituents of cigarette smoke.

The National Clearinghouse for Smoking and Health has the
responsibility for the continuous monitoring and compilation of the
medical literature on the health consequences of smoking and for
the preparation of this document. This is accomplished through sev-
eral mechanisms :

o Referred to in this manuscript as the Surgeon General's Report.
** Referred to in this manuscript as "The Health Consequences of Smoking."

ix


1. An information science corporation is on contract to extract
articles on smoking and health from the medical literature of
the world. This organization provides a semi-monthly acces-
sions list with abstracts and copies of the various articles.
  Translations are called for as needed. Articles are classified
according to subject and filed 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 articles not identified by the
information science corporation are ordered.

3. Staff members review current medical literature and identify
pertinent articles.

Initial drafts of the present review were prepared by the staff
director, assistant staff director, and consulting editors. The first
drafts of the individual chapters were sent to experts for review,
criticism, and comment with respect to the articles reviewed, arti-
cles not included, and conclusions. The drafts were then revised
until they met with the general approval of the reviewers. The final
drafts were reviewed as a whole by the Director of the National
Clearinghouse for Smoking and Health, the Director of the National
Cancer Institute, the Director of the National Heart and Lung
Institute, the Director of the National Institute of Environmental
Health Sciences, and by six additional experts both within and out-
side of the Public Health Service.

Acknowledgments

The National Clearinghouse for Smoking and Health, Daniel
iHorn, Ph. D., Director, was responsible for the preparation of this
report. Staff Director for the report was John H. Holbrook, M.D.,
and Assistant Staff Director was Elvin E. Adams, M.D. Daniel P.
Asnes, M.D., and David G. Cook, M.D., were Consulting Editors.
The professional staff has had the assistance and advice of a num-
ber of experts in the scientific and technical fields, both in and out-
side of the Government. Their contributions are gratefully acknowl-
edged. Special thanks are due the following :

ANDERSON, WILLIAM H., M.D.-Chief, Pulmonary Section, School of Medicine,
University of Louisville, Louisville, Kentucky.
ANTHONISEN, NICHOLAS R., M.D., Ph. D.-Associate Professor, Department of
Experimental Medicine, McGill University, Montreal, Quebec, Canada.

x


AUERBACH, OSCAR, M.D.-Senior Medical Investigator, Veterans Administra-
tion Hospital, East Orange, New Jersey.
AYRES, STEPHEN M., M.D.-Director, Cardiopulmonary Laboratory, Saint Vin-
cent's Hospital and Medical Center of New York, New York, New York.
BAKER, CARL G., M.D.-Director, National Cancer Institute, National Institutes
of Health, Bethesda, Maryland.

BING, RICHARD J., M.D.-Professor of Medicine, University of Southern Cali-
fornia, Huntington Memorial Hospital, Pasadena, California.
BOCK, FRED G., Ph. D.-Director, Orchard Park Laboratories, Roswell Park
Memorial Institute, Orchard Park, New York.
BOREN, HOLLIS G., M.D.-Chief, Pulmonary Disease Section, The Medical Col-
lege of Wisconsin, Wood Veterans Administration Hospital, Milwaukee,
Wisconsin.

BOUTWELL, ROSWELL K., M.D.-Professor of Oncology, McArdle Laboratory for
Cancer Research, University of Wisconsin, Madison, Wisconsin.
COOPER, THEODORE, M.D.-Director, National Heart and Lung Institute, Na-
tional Institutes of Health, Bethesda, Maryland.
CORNFIELD, JEROME-Research Professor of Biostatistics, Graduate School of
Public Health, University of Pittsburgh, Biostatistics Project, Bethesda,
Maryland.
EPSTEIN, FREDERICK H., M.D.-Director and Professor of Epidemiology, School
of Public Health, University of Michigan, Ann Arbor, Michigan.
FALK, HANS L., Ph. D.-Associate Director for Program, National Institute of
Environmental Health Sciences, Research Triangle Park, North Carolina.
FARR, RICHARD, M.D.-Head, Department of Allergy and Clinical Immunology,
National Jewish Hospital and Research Center, Denver, Colorado.
FERRIS, BENJAMIN G., JR., M.D.-Professor of Environmental Health and
Safety, School of Public Health, Harvard University, Boston, Massachusetts.
FINKLEA, JOHN F., M.D.-Acting Director, Division of Effects Research, Na-
tional Environmental Research Center, Research Triangle Park, North
Carolina.

FITZPATRICK, MARK J., M.D.-Obstetrician, Perinatal Biology and Infant Mor-
tality Branch, National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, Maryland.
FRAZIER, TODD M.-Assistant Director, Harvard Center for Community Health
and Medical Care, School of Public Health, Harvard University, Boston,
Massachusetts.

FRESTON, JAMES, M.D.-Associate Professor of Medicine, Head, Division of
Gastroenterology, University of Utah Medical School, Salt Lake City, Utah.
GOLDSMITH, JOHN R., M.D.-Head, Environmental Epidemiology Unit, Bureau
of Occupational Health and Environmental Epidemiology, California State
Department of Public Health, Berkeley, California.
RAnN.4, MICHAEL G., JR., Ph. D.-Director, Immunology of Carcinogenesis
Program, Oak Ridge National Laboratory, Oak Ridge, Tennessee.
BARKAw, JOSEPH, M.D.-Clinical Professor of Medicine (Emeritus), The
Mount Sinai Medical School of the University of New York, New York, New
York.
"looINS, IAN T. T., M.D.-Professor of Epidemiology, School of Public Health,
university of Michigan, Ann Arbor, Michigan.
HorrM~~~, DIETRICH, Ph. D.-Chief, Division of Environmental Carcino-
genesis, American Health Foundation, New York, New York.
)iELLEa, ANDREW Z., D.M.D.-Chief, Research in Geographic Epidemiology,
Veterans Administration Central Office, Washington, D.C.

xi


KIRSNER, JOSEPH B., M.D., Ph. D.-Chief of Staff and Deputy Dean for Medical
Affairs, The Pritzker School of Medicine, University of Chicago Hospitals
and Clinics, Chicago, Illinois.

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.

KRUMHOLZ, RI~IIARD A., M.D.-Medical Director, Institute of Respiratory
Iliseases, Kettering Medical Center, Kettering, Ohio.
LENFANT, CI.AUDE J. M., M.D.-Associate Director for Lung Programs, Na-
tional Heart and I.ung Institute, National Institutes of Health, Bethesda,
Maryland.

LIEBOW, A~ERII.I. A., M.D-Professor and Chairman, Department of Pathology,
University of California (San Diego), La Jolla, California.
LILIENFELD, ABRAHAM, M.D.-Professor and Chairman, Department of Epide-
miology, School of Hygiene and Public Health, The Johns Hopkins University,
Baltimore, Maryland.

LOWELL, FRANCIS C., M.D.-Chief, Allergy Unit, Massachusetts General Hos-
pital, Boston, Massachusetts.

MCLEAN, ROSS, M.D.--Professor of Medicine, Bowman Gray School of Medi-
cine, Wake Forest Univei sity, Winston Salem, North Carolina.
MCMILLAN, GARDNER C., M.D.-Chief, Arteriosclerotic Disease Branch, Na-
tional Heart and Lung Institute, National Institutes of Health, Bethesda,
Maryland.

MACMAHON, BRIAX, M.D.-Professor of Epidemiology, School of Public Health,
Harvard University, Boston, Massachusetts.
MEYER, MARY B., MRS.-Assistant Professor of Epidemiology, The Johns
Hopkins University, Baltimore, Maryland.
MITCHELL, ROGER S., M.D.-Chief of Staff, Veterans Administration Hospital,
Denver, Colorado.

MURPHY, EDMOND A., M.D., SC. D.-Associate Professor of Medicine and Bio-
statistics, The Johns Hopkins Hospital, Baltimore, Maryland.
NEWILL, VAUN A., M.I).-Chief, Health Effects Branch, Environmental Pro-
tection Agency, Washington, D.C.

PAFF~NBARGER, RALPH S., JR., M.D-Chief, Epidemiology Section, Bureau of
Adult Health and Chi,onic Diseases, California State Department of Public
Health, Berkeley, California.

PARKER, CHARLES W., M.I,.-Professor of Internal Medicine, Division of Im-
munology, Washington University Medical School, St. Louis, Missouri.
PETERS, JOHN M., M.I).-Associate Professor of Occupational Medicine, School
of Public Health, Harvard University, Boston, Massachusetts.
PF,TERSOX, WIL.I IAM F., Xl).-Chairman, Department of Obstetrics and Gyne-
cology, Washington Hospital Center, Washington, D.C.
PETTY, THOMAS L., M.l).-Associate Professor of Medicine and Head, Division
of Pulmonary I )iseasrs, University of Colorado Medical Center, Denver,
Colorado.

RALI., DAvII) P., M.I).---Director, National Institute of Environmental Health
Sciences, Research Triangle Park, North Carolina.
RENZETTI, ATTILIO I)., JR., M.D.-Professor of Medicine, Pulmonary Disease
Division, University of Utah Medical Center, Salt Lake City, Utah.
ROBINS, MORTON-Chief of Study, Design, and Analysis Staff, Regional Medical
Programs Service, Health Services and Mental Health Administration,
Rockville, Maryland.

SAFFIOTTI, UMBERTO, M.D.-Associate Scientific Director for Carcinogenesis,
Etiology, National Cancer Institute, National Institutes of Health, Bethesda,
Maryland.

xii


SCHUMAN, LEONARD M., M.D.-Professor and Head, Division of Epidemiology,
School of Public Health, University of Minnesota, Minneapolis, Minnesota.
SHIMKIN, MICHAEL B., M.D.-Coordinator and Professor of Community Medi-
cine and Oncology, Regional Medical Program, University of California
(San Diego), La Jolla, California.

STAMLER, JEREMIAH, M.D.-Executive Director, Chicago Health Research
Foundation, Chicago, Illinois

VAN DUUREN, BENJAMIN L., M.D.-Professor of Environmental Medicine,
Institute of Environmental Medicine, New York University Medical Center,
New York, New York.

WYXDER, ERNEST L., M.D., President, American Health Foundation, New York,
New York.

The chapter on Harmful Constituents of Cigarette Smoke was
prepared somewhat differently from the rest of the report, being
the culmination of a one-day conference held in June 1970 to review
this area of knowledge and to discuss a draft report prepared in ad-
vance by staff of the National Institute of Environmental Health
Sciences and the National Clearinghouse for Smoking and Health.
Earlier in this section, some of these participants are acknowledged
as contributors to other parts of the report, namely, Dr. Daniel
Horn, who served as Chairman of the meeting, Drs. Daniel P. Asnes,
Fred G. Bock, Dietrich Hoffmann, Albert C. Kolbye, Gardner C.
McMillan, Umberto Saffiotti, Leonard Schuman, Benjamin L. Van
Duuren, and Ernest L. Wynder.

In addition, acknowledgments should be made to the following
who were also participants in the conference:

GORI, GIO BATTA, M.D.-Associate Scientific Director for Program, Etiology,
National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
GRIFFITH, ROBERT, Ph. D.-Director, Tobacco and Health Research Institute,
University of Kentucky, Lexington, Kentucky.
GUERIN, MICHAEL, Ph. D.-Senior Chemist, Oak Ridge National Laboratory,
Oak Ridge, Tennessee.

JARV~K, MURRAY, M.D.-Professor of Psychiatry and Pharmacology, Albert
Einstein College of Medicine of Yeshiva University, Bronx, New York.
KENSLER, CHARLES, M.D.-Senior Vice President, Life Sciences Division,
Arthur I). Little, Inc., Cambridge, Massachusetts.
KOTIN, PAUL, M.D.-Vice President for Health Sciences, Health Sciences Cen-
ter, Temple University, Philadelphia, Pennsylvania.
LIPTON, MORRIS, M.D., Ph. D.-Professor and Chairman, Ijepartment of Psy-
chiatry, University of North Carolina, Chapel Hill, North Carolina.
REMINGTON, RICHARD, M.D.-Associate Dean for Research, School of Public
Health, University of Texas, Houston, Texas.
SCHMELTZ, ERWIN, Ph. D.-Head, Lubricants Investigations, Eastern Utiliza-
tion Research and Development Division, U.S. Department of Agriculture,
Philadelphia, Pennsylvania.

STANTON, MEARL F., M.D.-Medical Officer, National Cancer Institute, Na-
tional Institutes of Health, Bethesda, Maryland.
TSO, TIEN C., M.D.-Plant Physiologist and Leader, Tobacco Quality Investi-
gations, Plant Science Research Division, ARS, U.S. Department of Agri-
culture, Beltsville, Maryland.

. . .
Xlll


The following professional staff of the National Clearinghouse for
Smoking and Health contributed to the preparation of this report :
Robert S. Hutchings, Emil Corwin, Elaine Bratic, Annabel W.
Hecht, Lillian Davis, Richard W. White, Richard H. Amacher,
Donald R. Shopland, Jennie M. Jennings, Dan Nemzer, Nancy S.
Johnston, and Gertrude Herrin.

Special thanks are due Theresa Klotz, Rosalie Levine, and Mildred
Ritchie.

xiv


CHAPTER 1


           Introduction and Summary


INTRODUCTION AND SUMMARY

Cigarette smoking continues to be a major health problem in the
United States today. It is still too early to tell whether the increas-
ing rate of giving up smoking by adults during the years 196'7,1968,
1969, and early 1970 and the plateauing of this effect during the
past year have had any measurable effect on the morbidity and
mortality associated with smoking. At the same time that the major
health professions, voluntary health agencies, and public service
agencies concerned have joined with government agencies to reduce
the magnitude of this problem through education, research efforts
devoted to understanding how cigarette smoking affects biological
function to produce disease continue at a high level.
This report is largely concerned with reviewing the research re-
ports which have become available in the past year. In this chapter,
brief summary statements are presented of the state of knowledge
in several areas. These are followed, where appropriate, by a "high-
light" statement of significant additions to knowledge made as a
result of the new research presented in greater detail in the body
of the report.
The state of knowledge in three areas, which have not been re-
riewed previously, is also presented in the report. These areas are :
Allergy, Public Exposure to Air Pollution from Tobacco Smoke,
and the Harmful Constituents of Cigarette Smoke.

SUMMARY: CORONARY HEART DISEASE

Cigarette smokers have higher death rates from coronary heart
disease (CHD) than nonsmokers. This relationship is stronger for
men than women. Cigarette smoking markedly increases an individ-
ual's susceptibility to earlier death from CHD. Cigarette smoking,
hypertension, and elevated serum cholesterol are major risk factors
contributing to the development of CHD; cigarette smoking acts
both independently and conjointly with these other factors to in-
Qeage the risk of developing CHD. Cigarette smoking may con-
tribute both to the development of CHD and to the exacerbation of
Preexistent CHD; both ni,cotine and carbon monoxide are thought
to contribute to these abnormal processes. Cigarette smoking is
associated with a significant increase in atherosclerosis of the aorta


and coronary arteries. Cessation of smoking is associated with a
decreased risk of death from CHD. The risk of CHD incurred by
pipe and cigar smokers is appreciably less than that incurred by
cigarette smokers.

Highlights of 1972 Report: Coronary Heart Disease

1. Recent epidemiological studies from several countries confinp!
that cigarette smoking is one of the major risk factors con.!
tributing to the development of CHD. Avoidance of cigaretb.
smoking is of importance in the primary prevention of CHD.'

2. Studies in man and animals have shown a greater myocardial
arteriole wall thickness in smokers than nonsmokers.

3. Experimental and epidemiological investigations implicate
the elevation of carboxyhemoglobin levels in smokers as a'
contributor to the development of CHD and arteriosclerotic
peripheral vascular disease.

4. Cigarette smoking is considered to be the major cause of pul.
monary heart disease (car pulmonale) in the United States in
that it is the most important cause of chronic non-neoplastic
bronchopulmonary diseases. Avoidance of cigarette smoking
is of importance in the primary prevention of pulmonary
  heart disease.

SUMMARY: CEREBROVASCULAR DISEASE

Cigarette smokers have higher death rates from cerebrovascular
disease than nonsmokers.

SUMMARY: NONSYPHILITIC AORTIC ANEURYSM*

Cigarette smokers have higher death rates from nonsyphilitic
aortic aneurysm than nonsmokers.

SUMMARY: PERIPHERAL VASCULAR DISEASE

Cigarette smoking is a likely risk factor in the development of
peripheral vascular disease. Cigarette smoking appears to aggravate
preexistent peripheral vascular disease.

o This summary statement is the same as that appearing in previous reports. because new
studies adding to the understanding of this area have not ????????? Conseqxntly. the literature
in this area is not reviewed and the statement is ?*o? included to complete this summary chapter.

2


SUMMARY: NON-NEOPLASTIC
BRONCHOPULMONARY DISEASES

Cigarette smoking is the most important cause of chronic obstruc-
tive bronchopulmonary disease (COPD) in the United States. Ciga-
rette smokers have higher death rates from pulmonary emphysema
and chronic bronchitis and more frequently have impaired pul-
monary function and pulmonary symptoms than nonsmokers. Ex-
cigarette smokers have lower death rates from COPD than do con-
tinuing smokers. Cessation of smoking is associated with improved
ventilatory function and decreased pulmonary symptom prevalence.
For most of the United States population, cigarette smoking is a
more important cause of COPD than air pollution or occupational
exposure; cigarette smoking may also act conjointly with occupa-
tional or environmental exposure to produce greater COPD mar.-
bidity and mortality. An infrequent genetic error, homozygous
alphal-antitrypsin deficiency, has been commonly associated with
the early development of severe, panacinar emphysema. Whether or
not cigarette smoking acts together with the J- `mozygous or hetero-
zygous deficiency states to increase the risk of developing either
panacinar emphysema or the more common forme of COPD has
not been adequately studied. Cigarette smoking exerts an adverse
effect on the pulmonary clearance mechanism. Respiratory infec-
tions are more prevalent and severe among cigarette smokers, par-
ticularly among heavy smokers, than among nonsmokers. The risk
of developing or dying from COPD among pipe or cigar smokers is
probably higher than that among nonsmokers but is clearly less
than that among cigarette smokers.

   Highlights of the 1972 Report:
Non-neoplastic Bronchopulmonary Diseases

1. Recent epidemiological and clinical studies from several
countries confirm that men and women cigarette smokers have
an increased prevalence of respiratory symptoms and have
diminished pulmonary function compared to nonsmokers.

2. Investigations of high school students have demonstrated that
abnormal pulmonary function and pulmonary symptoms are
more common in smokers than nonsmokers.

3. Recent occupational studies confirm that cigarette smoking is
an important cause of COPD, acting both independently and
in combination with occupational exposure.
4. Recent experimental studies confirm that cigarette smoking
exerts an adverse effect on pulmonary clearance and macro-
phage function.

3


5. Pulmonary macrophages obtained from cigarette smokers ex-
hibit characteristic morphologic differences when compared
  to those obtained from nonsmokers.

SUMMARY: CANCER

Cigarette smoking is the major cause of lung cancer in men and a
significant cause of lung cancer in women. The risk of developing
lung cancer in both men and women is directly related to an individ-
ual's exposure as measured by the number of cigarettes smoked,
duration of smoking, earlier initiation, depth of inhalation, and the
amount of "tar" produced by the cigarette. The risk of developing
lung cancer diminishes with cessation of smoking. Smokers of pipes
or cigars have a lower risk of developing lung cancer than cigarette
smokers. Certain occupations are associated with an increased risk
of developing lung cancer. In these occupational settings cigarette
smoking appears to exert an effect that produces much higher lung
cancer rates than those resulting either from the occupational ex-
posure alone or from smoking alone. Factors associated with urban
living result in an increase in the risk of developing lung cancer;
this effect, however, is minor compared to the overriding effect of
cigarette smoking.

The smoking of cigarettes, pipes, and cigars is a significant factor
in the d,evelopment of cancers of the larynx and oral cavity. Pipe
smoking is causally related to cancer of the lip. The significant asso-
ciation between smoking and the development of cancer of the
esophagus is somewhat stronger for cigarettes than for pipes or
cigars and the combined exposure to alcohol and cigarettes is asso-
ciated with especially high rates of cancer of the esophagus. Ciga-
rette smoking is associated with cancer of the urinary bladder in
men. There is also an association between cigarette smoking and
cancer of the pancreas.

Highlights of the 1972 Report: Cancer

1. Preliminary results from a major prospective epidemiological
study in Japan demonstrate a strong association between cig-
arette smoking and lung cancer. A dose-response relationship
was demonstrated for the number of cigarettes smoked. These
findings in an Asian population with distinct genetic and cul-
tural characteristics confirm the major importance of ciga-
rette smoking in the causation of lung cancer, a conclusion
which up to now has been based largely on studies of Cauca-
sian populations in the United States, Canada, and Europe.


2.

3.

4.

5.

6.

7.

Ex-smokers have significantly lower death rates for lung can-
cer than continuing smokers. The decline in risk following
cessation appears to be rapid both for those who have smoked
for long periods of time and for those with a shorter smoking
history, with the sharpest reductions taking place after the
first two years of cessation.

The risk of developing lung cancer appears to be higher for
smokers who have chronic bronchitis. Though both conditions
are directly related to the amount and duration of smoking,
an additional risk for lung cancer appears to exist for ciga-
rette smokers with chronic bronchitis which is independent of
age and number of cigarettes consumed.

Experimental studies on animals have demonstrated that the
particulate phase of tobacco smoke contains certain chemical
compounds which can act as complete carcinogens, tumor
initiators, or tumor promoters. Recently, other compounds
have been described that have no independent activity in two-
stage carcinogenesis but accelel ate the carcinogenic effects of
polynuclear aromatic hydrocarbons in the initiator-promoter
system.

Additional epidemiological evidence confirms a significant as-
sociation between the combined use of cigarettes and alcohol,
and cancer of the esophagus.

Epidemiological studies have demonstrated a significant asso-
ciation between cigarette smoking and cancer of the urinary
bladder in both men and women. These studies demonstrate
that the risk of developing bladder cancer increases with in-
halation and the number of cigarettes smoked.
Epidemiological evidence demonstrates a significant associa-
tion between cigarette smoking and cancer of the pancreas.

SUMMARY: PREGNANCY

Maternal smoking during pregnancy exerts a retarding influence
on fetal growth as manifested by decreased infant birth weight and
an increased incidence of prematurity, defined by weight. There is
increasing evidence to support the view that women who smoke
during pregnancy have a significantly greater risk of an unsuccess-
ful pregnancy than those who do not.

   SUMMARY: GASTROINTESTINAL DISORDERS
Cigarette smoking males have an increased prevalence of peptic
ulcer disease as compared to nonsmoking males and a greater peptic

5


ulcer mortality ratio. These relationships are stronger for gastric
ulcer than for duodenal ulcer. Smoking appears to reduce the effec-
tiveness of standard peptic ulcer treatment and to slow the rate of
ulcer healing.

Highlights of the 1972 Report: Gastrointestinal Disorders

1. A possible link between cigarette smoking and peptic ulcer
has been demonstrated in dogs in which nicotine was found to
inhibit pancreatic and hepatic bicarbonate secretion. This
could lead to peptic disease by depriving the duodenum of
sufficient alkaline secretion to neutralize gastric acidity.

2. An investigation in human volunteers has suggested that cig-
arette smoking decreases the effectiveness of the lower-
esophageal sphincter as a barrier against gastro-esophageal
  reflux.

SUMMARY: 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 the metabolism of the cyanide component of
tobacco smoke.

SUMMARY : NON-NEOPLASTIC ORAL DISEASE*

Ulceromembranous gingivitis, alveolar bone loss, and stomatitis
nicotina are more commonly found among smokers than among
nonsmokers. The influence of smoking on periodontal disease and
gingivitis probably operates in conjunction with poor oral hygiene.
In addition, there is evidence that smoking may be associated with
edentulism and delayed socket healing. While further experimental
and clinical studies are indicated, it would appear that nonsmokers
have an advantage over smokers in terms of their oral health.

TOP in.t'o?.ma.tion contained in the fob&g three summary state-
ru~nfs: A&q~y, P&lie Exposure to Air Pollution from Tobacco
Smoke. awl Harmfzl.1 Constitu.ents of Cigarette Smoke, is new and
uppears for the first time.

---

* This summary statement is the same as that appearing in previous reports, because new
sturliei adding t<, thez understanding of this area have not appeared. Consewentb. the literature
in this area is not reviewed and the statement is only included to complete this summa~`~ chapter.

b


SUMMARY OF THE 1972 REPORT: ALLERGY

1. Tobacco leaf, tobacco pollen, and tobacco smoke are antigenic
in man and animals.

2, (a) Skin sensitizing antibodies specific for tobacco antigens
   have been found frequently in smokers and nonsmokers.
   They appear to occur more often in allergic individuals.
   Precipitating antibodies specific for tobacco antigens
    have also been found in both smokers and nonsmokers.
(b) A delayed type of hypersensitivity to tobacco has been
    demonstrated in man.

(c) Tobacco may exert an adverse effect on protective mech-
  anisms of the immune system in man and animals.

3. (a) Tobacco smoke can contribute to the discomfort of many
   individuals. It exerts complex pharmacologic, irritative,
   and allergic effects, the clinical manifestations of which
   may be indistinguishable from one another.
(b) Exposure to tobacco smoke may produce exacerbation of
   allergic symptoms in nonsmokers who are suffering from
   allergies of diverse causes.

4. Little is known about the pathogenesis of tobacco allergy and
its possible relationship to other smoking-related diseases.

SI'JIMARY OF THE 1972 REPORT: PUBLIC EXPOSURE TO
    AIR POLLUTION FROM TOBACCO SMOKE

1. An atmosphere contaminated with tobacco smoke can con-
tribute to the discomfort of many individuals.

3 LI.

The level of carbon monoxide attained in experiments using
rooms filled with tobacco smoke has been shown to equal, and
at times to exceed, the legal limits for maximum air pollution
Permitted for ambient air quality in several localities and can
also exceed the occupational Threshold Limit Value for a nor-
mal work period presently in effect for the United States as a
Rhole. The presence of such levels indicates that the effect of
exposure to carbon monoxide may on occasion, depending
UPon the length of exposure, be sufficient to be harmful to the
health of an exposed person. This would be particularly sig-
nificant for people who are already suffering from chronic
hronchopulmonary disease and coronary heart disease.

". Other components of tobacco smoke, such as particulate mat-
ter and the oxides of nitrogen, have been shown in various

7


concentrations to affect adversely animal pulmonary and'
cardiac structure and function. The extent of the contribu.
tions of these substances to illness in humans exposed to the
concentrations present in an atmosphere contaminated with
tobacco smoke is not presently known.

SUMMARY OF THE 1972 REPORT:

HARMFUL CONSTITUENTS OF CIGARETTE SMOKE

A number of substances or classes of substances found in ciga.
rette smoke are identified as those which are judged to be con.
tributors to the health hazards of smoking. These constituents are
further divided into the most likely contributors to these health
hazards (carbon monoxide, nicotine, and tobacco "tar"), sub.
stances which are probable contributors, and those which are su.s.
pected contributors. The recom,mendations for control in this area
are to seek progressive reduction of all harmful constituents in
cigarette smoke with priority being given first to the most likely
contributors named and second to the probable contributors to the
health hazards of smoking. These judgments represent the consen.
sus of experts based on current knowledge and are subject to modi..
fication and further elaboration as more knowledge becomes
available.

8


CHAPTER 2


            Cardiovascular Diseases


Contents

                                     Page
Coronary Heart Disease
  Introduction                     13
  Epidemiological Studies               14
  Interaction of Smoking and Other Risk Factors         16
  Autopsy Studies                   19
  Experimental Studies                      21
    Nicotine and Cigarette Smoke              21
     Carbon Monoxide                   21
    Smoking and Thrombosis                  23
    Cholesterol Content of Tobacco and Tobacco Smoke    24
Cor Pulmonale (Pulmonary Heart Disease) . . . . . . . . . . . . .    24
Cerebrovascular Disease  . . . . . . . , . . . . . . . . . . . . . . . . . . . . .    24
Peripheral Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . .    25
Oral Contraceptives, Thrombophlebitis, and Smoking . . . . .    26
Highlights of Current Cardiovascular Information . . . . . . . .    27

References  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    27

LIST OF TABLES

Table L-Incidence (1963-1970) of heart infarct in relation
to tobacco consumption in "The Men Born in 1913,"
Goteborg, Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table 2.-Cigarette smoking at entry and subsequent 20-year
CHD incidence among Minnesota men . . . . . . . . . . . . . . . .
Table 3.-Human autopsy study. Comparison of the thick-
ness of myocardial arteriole walls in smokers and non-
smokers   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Table $.-Average values of carboxyhemoglobin and serum
cholesterol in Danish smokers and nonsmokers in control
group and group of patients with arteriosclerotic cardio-
vascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15


15




19






23

11


LIST OF FIGURES

Page

Figure l.-Canine autopsy study. Comparison of the thick-
ness of myocardial arteriole walls in 32 smoking dogs
killed after 875 days and 8 nonsmoking dogs . . . . . . . . . . .

20

12


INTRODUCTION

In the United States more people die from coronary heart disease
(CHD) than from any other disease; furthermore, CHD is the
single most important cause of excess death among cigarette
smokers (54, 57). The 1971 report, "The Health Consequences of
Smoking" (56)) outlined the growing magnitude of this problem
and summarized the relationship between smoking and coronary
heart disease as follows :

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 factors and can act jointly with certain of them to in-
crease 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 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
  catecholamines, 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.

13


b. Among individuals with coronary atherosclerosis, ciga.
rette smoking appears to create an imbalance between the
increased needs of the myocardium and an insufficient in-
crease in coronary blood flow and oxygenation.
c. Carboxyhemoglobin, formed from the inhaled carbon
monoxide, diminishes the availability of oxygen to the myo-
cardium 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 reduc.
ing the amount of oxygen available to the myocardium.
e. Cigarette smoking may cause an increase in platelet adhe.
siveness which might contribute to acute thrombus for-
  mation.

Recent epidemiological, pathological, and experimental studies
add to the understanding of the relationship between smoking and
CHD. These studies point to cigarette smoking as one of the major
risk factors leading to CHD and help clarify some of the biomech-
anisms through which this occurs.

EPIDEMIOLOGICAL STUDIES

A prospective study of 973 men born in 1913 in GGteborg,
Sweden, was undertaken in 1963 (51,52). The proportion of myo-
cardial infarctions among cigarette smokers was significantly
greater than among nonsmokers (P < .05), and the incidence of
myocardial infarction rose with increasing cigarette consumption
(table 1). Of the 35 individuals who experienced a myocardial in-
farction between 1963 and 1970, only two had been nonsmokers; in
the whole population of men born in 1913,56 percent were smokers.

Although angina pectoris was more common in smokers than
nonsmokers, the difference was smaller than for myocardial in-
farction and was not statistically significant (52).

Paffenbarger, et al. (42) reported on the health experience of
3,263 longshoremen studied over the past 18 years. During this in-
terval 1,098 were known to have died, 350 dying from CHD. Long-
shoremen who smoked more than 20 cigarettes a day faced a risk
of coronary death which was more than twice as great as that of
the group made up of both nonsmokers and smokers of less than 20
cigarettes a day (P < .Ol) .

Keys, et al. (30) analyzed the 20-year CHD incidence among 279
Minnesota men aged 47 through 57 years who were CHD free at
entry into the study. The relationship of cigarette smoking habits
at the start of the study to the subsequent incidence of CHD was
examined. The originally published table of results was incorrect

14


and the authors have supplied a corrected table which appeared
in a later issue of the same journal (table 2). The morbidity
ratio for "hard CHD" (CHD deaths plus myocardial infarctions not
resulting in death) among those smoking more than 10 cigarettes a

TABLE L-Incidence (1963-l 970) of heart infarct in relation to
tobacco consumption in "The Men Born in 1913," Giiteborg,
Sweden.

n = 855

Smoking                           Heart infarct
classification                       Number      Percent

Never smoked
n ti 207
Stopped smoking
n = 168
Cigarette smokers
1-14 cig/day
n = 234
15-24 cig/day
n= 138
225 cigiday
n = 33
Pipe/cigar
n = 75

( 2)        1.0


( 2)        1.0


(13)        6.0



( 9)        7.0


( 4)        12.0


( 5)         7.0

SOURCE: Tibblin, G.. Wilhelmsen. L. (51).

TABLE 2.-Cigarette smoking at entry and subsequent RO-year CHD
incidence among Minnesota men.'

   Number                       Smoking habit (cigarettes/day)
Age  of men     Item             NW`X  Stopped    <IO    10-19     >20

47948   53
49,50   51
51,52   69
x1,54   53
-55-57   51
J;-57  277
47-57  277
4:-w  277
47-57  277

47-57  277
~1-51  277
47-57  277

% with habit        23
% with habit        33
% with habit        33
% with habit        36
% with habit        24
Number of men     83
Hard CHD rate (%)    12.0
Hard CHD rate (SE) -t 3.6
Hard CHD Morbidity
Ratio            1.00
All CHD rate (%)   "21.7
All CHD rate (SE)   k 4.5
All CHD Morbidity
Ratio            1.00

19
20
26
30
33
71
15.5
+ 4.3

1.29     .83    1.43    1.77
221.1   516.7   k19.5   k26.9
k 4.8   ?I 6.8   2 6.2   r+ 6.1

.97     .77     .90    1.24

  9
14
14
  8
3:
10.0
* 5.5

19
10
14
13
18
41
17.1
2 5.9

30
23
13
13
i'z
21.2
+ 5.7

' Cigarette smoking habits, by age at start of the XI-year follow-up, ZO-year incidence rates
' per 100 men )  and standard ei-ram (SE) of the rates.
`"flrCt.q. .*A,+-                       "Hard cxD"--CHD death and myoeardial

~iohee.      angina peetoris and other CHD diagnoses. "Deaths"-from all ca"ses except
SoURCE: Modified from Keys, A., et al. (30).

15


day is similar to that reported from the large prospective studies.
However, with the small number of cases in each smoking category,
there are no statistically significant differences in the incidence of
CHD between the categories, either singly or combined.

Retrospective studies of CHD have recently been reported from
Czechoslovakia, Sweden, Norway, and India which corroborate
earlier studies linking cigarette smoking with excess CHD morbid-
ity and mortality.

The Prague study (19) included 443 men between the ages of 60
and 64 years. Significantly more (P < .05) individuals with a
"probable" myocardial infarction were found among cigarette
smokers than among nonsmokers or pipe and cigar smokers.

The smoking habits of 120 patients with myocardial infarction
who were hospitalized in Goteborg were compared with those of the
entire "men born in 1913" population sample (17, 62). A signif-
icantly (P < .Ol) greater number of smokers and heavy smokers
(more than 15 cigarettes a day) were found in the myocardial in-
farction group than in the population sample.

The Bergen, Norway, cross sectional study of 2,117 women and
2,472 men documented a relationship between smoking and CHD in
men, which was most marked in the 50 to 59 year old age group
(16). No effect of smoking on the prevalence of CHD in women was
demonstrable in this study, and the effect in men did not appear
to be related to the daily number of cigarettes smoked.

In New Delhi, 100 "well documented" cases of ischemic heart
disease were compared with an equal number of control cases (8).
In this study, significantly more (P < .Ol) of the case group smoked
cigarettes regularly than the control group (Morbidity Ratio = 2.1).
Mulcahy, et al. (40) recently found a positive association between
coronary heart disease mortality rate and calculated per capita cig-
arette consumption in 21 countries. He interpreted the results as
being consistent with the hypothesis that cigarette smoking is a
significant risk factor in CHD mortality.
Stamler, et al. (50) found that for both men and women the 1964
CHD mortality rates in 17 developed countries were related to aver-
age annual per capita cigarette consumption.

INTERACTION OF SMOKING AND OTHER RISK FACTORS

The Report of the Inter-Society Commission for Heart Disease
Resources summarized the evidence indicating that three risk fac-
tors (hypercholesterolemia, hypertension, and cigarette smoking)
are properly designated major risk factors for premature CHD
(28). Other possible risk factors including obesity, physical inac-
tivity, diabetes mellitus, elevated resting heart rate, electrocardio-

16


graphic abnormalities, a positive family history of premature CHD,
and psychologic and social factors have also been described (54,
55,56).
In the study of 973 men born in 1913 in Giiteborg, Sweden, sev-
eral coronary risk factors including elevated serum cholesterol, ele-
vated serum triglyceride, low physical activity at work, and smok-
ing were found to be related to an increased risk for the development
of coronary heart disease during the subsequent years of the study.
Failure to find a relationship between hypertension and an in-
creased risk of CHD may have been due to the fact that all patients
with hypertension in 1963 have been under treatment since that
time.

Tibblin and Wilhelmsen (52) found that as a patient accumulated
more risk factors his chance of developing CHD became substan-
tially greater. Werkij (61) reported from the same Gijteborg study
that patients who were smokers, had sedentary jobs, and had both
elevated cholesterol and triglycerides experienced a 4-year incidence
of new coronary events of about 20 percent; the 4-year incidence
among those who exhibited only one or two risk factors was much
lower, ranging from 0 to 3 percent. ECG changes and angina1 pain
were included in the definition of new coronary events.
Paffenbarger, et al. (42) evaluated coronary risk factors in the
study of 3,263 longshoremen. They found that, with the exception
of diagnosed heart disease, smoking was the most important factor
Predictive of high risk for coronary mortality.
Keys, et al. (30) in the study of 279 Minnesota men, concluded
that a positive cold pressor test, elevated serum cholesterol, and
elevated systolic blood pressure had major predictive power for
CHD death or infarction; in their analysis smoking seemed less
important.

Stamler (49) has analyzed the data on 13 deaths occurring dur-
ing the first years of the Chicago Coronary Prevention Evaluation
Program, which originally consisted of 519 coronary-prone male
volunteers aged 40 to 59 who were free from clinical CHD. Eleven
of the 13 decedents had three or more coronary risk factors at entry
into the program, and at least 8 were cigarette smokers at the time
of death. Forty-three men, who were cigarette smokers at entry
into the Coronary Prevention Evaluation Program, gave up smok-
ing and have remained active in the program. There have been no
deaths from cardiovascular causes in this group. Stamler (49)
commented : "Even though the number of decedents was small,
these data strongly suggest that continued cigarette smoking is as-
sociated with very high risk of premature death for very coronary-
Prone men, and that other preventive measures are by themselves
of limited value for them as long as they fail to give up cigarette
smoking."

17


As described in the 1971 report, "The Health Consequences of !
Smoking" (56), some studies have indicated that smokers show
increased levels of serum lipids while others have not. Such contra.
dictory results are also present in recent studies from Germany,
Poland, and Sweden (21, 39, 53).

After a patient suffers a myocardial infarction, he frequently
gives up smoking (17,26). Only fragmentary data are available on
what effect the cessation of cigarette smoking might have on the
likelihood of a recurrent myocardial infarction (9,34, 43). Ninety-
two survivors of a first myocardial infarction were studied over a
S-year period by Par&s Chavero, et al. (43). During this time, 37
pati,ents continued smoking, and 12 of them (32 percent) experi-
enced a second myocardial infarction. The 51 patients who did not
smoke during this 3-year period included 39 ex-smokers and 12 pa-
tients who had never smoked. Eight of the nonsmokers (16 percent)
experienced a second myocardial infarction. The smoking habits of
four of the patients were not known. Although the continuing
smokers experienced a greater rate of recurrent myocardial infarc.
tion than the nonsmokers, the difference was not statistically sig-
nificant (P = .07).

The role of genetic factors in the development of CHD and the
difficulties associated with the use of twin studies were discussed
in the 1971 report, "The Health Consequences of Smoking" (56).
Mailed questionnaires were used to establish the diagnosis of angina
pectoris in a study by Lundman, et al. of twin pairs discordant with
respect to smoking habits and in a study by Liljefors of twins with
CHD. Lundman, et al. (36) recently investigated 69 male twins with
the diagnosis of angina pectoris established by questionnaire. Only
22 percent of these diagnoses could be verified by clinical examina-
tion.

In a study of CHD, Liljefors (35) studied 91 pairs of twins from
the Swedish Twin Registry of 1967. The twins ranged in age from
42 to 67 years, and 51 pairs were monozygotic. Smoking habits were
not significantly different in pairs discordant for the probable
presence of CHD. However, Liljefors noted that ". . . in many pairs
the smoking habits were similar and that the material included few
pairs discordant with respect to smoking, so that it does not pro-
vide a suitable basis for conclusions as to the causal importance of
smoking for CHD." As observed in the 1971 report, "The Health
Consequences of Smoking" (56)) it would be surprising if genetic
factors did not play a role in heart disease; however, it is open to
question whether findings from twin studies can be used to dis-
tinguish between ". . . the hypothesis that genetic factors govern
the level of host susceptibility or resistance to the effects of an exo-
genous influence such as cigarette smoking and the hypothesis that
genetic factors `cause' both heart disease and smoking."

18


AUTOPSY STUDIES

In previously reported autopsy studies, Auerbach, et al. found
that aortic and coronary atherosclerosis in man were more common
and severe among smokers than among nonsmokers (5). They have
now extended their investigations to the myocardial arterioles of
men and beagle dogs (6). In a study of 1,184 men, they found that
the thickness of myocardial arteriole walls was greater, on the
average, in smokers than nonsmokers (table 3). The thickness in-
creased with the number of cigarettes smoked per day and with
age. The thickness was less, on the average, among cigar and pipe
smokers than among cigarette smokers, but it was greater than in
men who had never smoked regularly.

TABLE S.-Human autopsy study. Comparison of the thickness of
myocardial arteriole wa2Z.s in smokers and nonsmokers.'

Age
(Year)

Smoking

          Number of Me"         Percent of Men
       :Grade XGrade XGrade   SGrade $Grade :Grade
Total 0     1    2. 3    Total    0     1      2.3

< 45    None         22 2   19 1   100.0   9.1   85.4    4.5
    Cigar, pipe      4-    13   100.0    -  t25.0  y75.0
    Cig. 1-19      50 1   31 18   100.0   2.0   62.0   36.0
    Cig. 20-39     85 4   35 46   100.0   4.7   41.2   54.1
    Cig. 240      29 -   10 19   100.0    -   34.5   65.5

45-59   None         15 1   12    2   100.0   6.7   80.0   13.3
    Cigar, pipe     13 -    8    5   100.0    -   61.5   38.5
    Cig. 1-19      33 -   17   16   100.0    -   51.5   48.5
    Cig. 20-39     99 -   35   64   100.0    -   35.4   64.6
    Cig. 240      50 -   11   39   100.0    -   22.0   78.0

GO-69   None         56 4   36   16   100.0   7.1   64.3   28.6
    Cigar, pipe     35 -   22   13   100.0    -   62.9   37.1
    Cig. 1-19      92 -   44   48   100.0    -   47.8   52.2
    Cig. 20-39    193 -   58  135   100.0    -   30.1   69.9
    Cig. 240      87 -   21   66   100.0    -   24.1   75.9

2 70    None         32 2   18   12   100.0   6.3   56.2   37.5
    Cigar,pipe     40 -   19   21   100.0    -   47.5   52.5
    Cig. 1-19      30 -   12   18   100.0    -   40.0   60.0
    Cig. 20-39     46 -   12   34   100.0    -   26.1   73.9
    Cig. 240       g-    3    6   100.0    -  $33.3  t66.7

' 1" the right ventricular ~111 of 1.020 me" bu age and smoking habits.
' P=="tages based on less than ten cakes.
* Four Point Scale for the Thickness of bfyocardial Arteriole Walls:
  @-normsi thickness; l-slight thickness; 2-moderate thickness; 3-great thickness.
SoURCE: Auerbacb. 0.. et al. (6).

19


In one experiment, beagle dogs inhaled cigarette smoke daily
through tracheostomae. Twenty-eight dogs that died between days
57 and 875 formed one group; 32 dogs that were killed after 875
days formed another group. Eight control dogs were not exposed.
Beagle myocardial arteriole walls were found to be thicker in smok-
ing than nonsmoking dogs, in dogs smoking many cigarettes than
in dogs smoking fewer cigarettes, and in dogs smoking nonfilter cig-
arettes than in dogs smoking filter-tip cigarettes (figure 1). Also,
the thickness of arteriole walls increased with the duration of
smoking.

Group N
No smoking
8 Dogs

   .
   .
i

::
. . .

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

Group L
Nonfilter
Cigarettes
(% as many
cigarettes)
10 Doas

. . .
. . .

Group F                 . .
                      . .
Filter-Tip               :
Cigarettes                 .
10 Dogs
A----l-
Group H
Nonfilter

Cigarettes
12 Dogs I I

Grade of        0        1
Thickness

::
. .
.ii
:::


  :
::
:ii
. . .
. . .
..*
. . .
. . .
. . .
. . .
. . .
. . .
. . .
:::
. . .
. . .
. . .


2

Each dot represents one section. The three d.ots on a line represent the three
sections from a particular dog.

FIGURE L-Canine autopsy study. Comparison of the thickness of myocardial
arteriole walls in 32 smoking dogs killed after 875 days and 8 nonsmoking
dogs.

SOURCE: Auerbach, O., et al. (6).

20


EXPERIMENTAL STUDIES

NICOTINE AND CIGARETTE SMOKE

Schievelbein, et al. (47) investigated the effect of oral nicotine
administration over a 20-month period on lipid metabolism in 35
rabbits. Even though lipoprotein lipase levels and calcium content
of the aorta were significantly greater in the group given nicotine
than in the control group, the histological changes of arteriosclero-
sis were found with equal frequency in both groups. The authors
concluded that the epidemiological correlations between CHD and
cigarette smoking could not be explained by the pharmacologic ef-
fect of nicotine alone.

A study of the interaction of chronic nicotine administration and
acute hypoxia in 280 rats was performed by Wenzel and Richards
(60). Pretreatment of the rats with nicotine increased the mortality
during hypoxia, but the difference was not statistically significant.
Pretreatment with the nicotine also was associated with marked
variability of regression of hypoxic heart lesions. The interaction
of nicotine pretreatment and the hypoxic insult produced variable
effects on myocardial enzymes.

Aronow (1) recently studied the effect of cigarette smoking on
the A wave of the apexcardiogram in 20 men with CHD. The A wave
reflects the left ventricular filling wave associated with the impact
of blood upon the ventricular wall during left atria1 contraction.
He found that the mean maximum increase in A wave ratio after
smoking was 34 percent for high-nicotine cigarettes, 13 percent for
the low-nicotine cigarettes, and 6 percent for the non-nicotine ciga-
rettes. He ascribed these changes to increased myocardial ischemia
produced by cigarette smoking, which was reflected by a larger A
wave ratio in the apexcardiogram. While nicotine appears to have
produced most of these changes, the observation that a 6 percent
increase occurred in the absence of nicotine suggests the possibility
that carbon monoxide plays a role in this effect.

CARBON MONOXIDE

Because cigarette smoke contains from 2.7 to 6 percent carbon
monoxide (CO), significantly higher carboxyhemoglobin ( COHb)
levels are found in smokers than nonsmokers (j3,20,24,63). COHb
levels in nonsmokers are usually less than 1 percent, while those in
smokers average around 4 percent and may exceed 15 percent (4,
20, 56). Heavy smokers and those who inhale show the highest
carboxyhemogldbin levels (20).

Haebisch (24) found that a smoker with a daily consumption of
35 to 40 cigarettes easily attains and maintains for hours an alveolar

21


CO concentration of 50 p.p.m., which reaches or exceeds legally-
established ambient air quality standards (14,18, 23, 24).
Cohen, et al. (23) and Aronow, et al. (2) have shown that there
is no significant difference in mean expired air carbon monoxide
levels after patients have smoked tobacco or lettuce leaf cigarettes.
Although pipe and cigar smokers in the United States are reported
to have lower exposure to CO than cigarette smokers (20) , CO in-
toxication has been reported in cigar smokers (25).
CO exerts its adverse effects on the cardiovascular system of
smokers through one or more of the following mechanisms : (a) re-
duction of the amount of hemoglobin available for oxygen trans-
port ; (b) shift of the oxygen-hemoglobin dissociation curve to the
left with consequent interference in oxygen release at the tissue
level ; and (c) induction of arterial hypoxemia. CO may interfere
with the homeostatic mechanism by which 2,3-DPG controls the
affinity of hemoglobin for oxygen (56). CO has also been implicated
in experimental atherogenesis in animals (56).
Ayres, et al. (7) recently studied 41 patients during diagnostic
cardiac catheterization, at which time they inhaled either 5 percent
or .l percent CO. Arterial and mixed venous oxygen tensions were
decreased by administration of either concentration. In patients
with CHD, coronary artery 0, extraction decreased 7.9 percent after
inhalation of .1 percent CO and 30.5 percent after inhalation of 5
percent CO. Some of the patients with CHD experienced changes in
lactate and pyruvate metabolism indicative of inadequate myocar-
dial oxygenation. The higher level of CO inhalation in this experi-
ment is comparable to that experienced intermittently by cigarette
smokers.

Brewer and his colleagues (11) investigated cigarette smoking
as a cause of hypoxemia in residents of Leadville, Colorado, at an
altitude of 3,100 meters. The arterial p0, of 8 smokers was signif-
icantly lower (P < .05) than that of 12 nonsmokers, but this was
reversible upon cessation of smoking. They concluded that the ad-
verse effect of cigarette smoking on 0, transport may be especially
pronounced at high altitude and may restrict an individual's ability
to adapt to reduced 0, tensions (11,12).

Kjeldsen (31, 32) examined 993 industrial workers, about one-
half of whom were tobacco workers. Fifty-nine cases of arterio-
sclerosis were documented by such clinical symptoms as angina
pectoris and intermittent claudication or by a previous history of
myocardial infarction. While 20.9 percent of the 934 "control" in-
dividuals were nonsmokers, only 2 (3.4 percent) of the 59 patients
with arteriosclerosis were nonsmokers. A significantly higher per-
centage of diseased workers were heavy smokers and inhaled the
smoke.

22


The diseased smokers had significantly higher carboxyhemoglobin
and serum cholesterol levels than either smoking or nonsmoking
control patients. This was true after standardizing for differences
in levels of smoking between controls and diseased patients. As ex-
pected, there was a gradient in carboxyhemoglobin levels from
lower levels in light smokers to higher levels in heavy smokers
(table 4).

TABLE 4.-Average values of carboxyhemoglobin and serum choles-
terol in Danish smokers and nonsmokers in control group and
group of patients with arteriosclerotic cardiovascular disease.

Smoking
category

Carboxyhemoglobin             Serum cholesterol
(saturation percentage)           ba/lOO ml)

controls   patients   signifi-      controls   patients   signifi-
M?S.D.   M%S.D. canee       MIS.D.   MfS.D. cance

Smokers      4223.1 7.043.7 p<O.OOl   247244 290a33 p<O.OOl
         (738)'   (57)     k5.52    (738)    (57)     k4.89
Nonsmokers    0.4-c-0.9 0.520.7 n.s.      236e-49 284-e56 p<O.O2
         (1%)   (2)     tx0.16    (196)   (2)     k2.32
Light smokers   2.5k2.5 3.722.5 n.s.       245438 279k67 n.s.
         (121)    (3)     tz0.76    (121)    (3)     tz1.45
Moderate     4.ik3.0 7.3-c-3.6 p<O.OOl   246245 286250 p<O.OOl
smokers     (463)   (34)     k4.95    (463)   (34)     k4.52
Heavy smokers   5.7k3.0 7.Ok4.0 n.s.      253k45 298-c53 p<O.O5
         (154)   WV     tz1.45    (154)   cw     tz2.18

1, = Probability that difference is not due to chance.
t = Student's t calculation.
n.S. = not significant.

' The number of subjects in each category is enclosed in parentheses beneath the mean (M) and
Ytandard deviation (S.D.).
SOURCE: Kjeldsen, K. (31).

Kjeldsen also observed that the COHb levels of 8 to 19 percent
Seen in 40 percent of the patients with arteriosclerosis were of the
We magnitude as those provoking experimental atherosclerosis
and cardiac necrosis in animals.

SMOKING AND THROMBOSIS

Previous reports of the Surgeon General on smoking and health
have reviewed the effects of smoking on thrombus formation (54,
jgJ 56) The role of thrombosis in CHD remains an active area of
investigation Recent studies have not thus far yielded a unifying
@ncept of the effect of smoking on thrombosis (33, 41, 48).

23


CHOLESTEROL CONTENT OF TOBACCO AND TOBACCO SMOKE

Cholesterol glucoside has not previously been mported in tobacco i
or in any other plant (10). Bolt and Clarke (10) investigated t&i
sterolin and sterol fraction of flue-cured tobacco and found that;
cholesterol is one of the major components of the sterol fraction.
More recently, Grunwald, et al. (22) have confirmed that choles.
terol accounts for 10 percent of the total sterol in cigarette tobacco,
They also found that 8.6 percent of the total sterol content of ciga.
rette smoke condensate was cholesterol. Thirteen percent of the
cholesterol present in cigarette tobacco was transferred to the
condensate.

The biological significance of these findings remains to h
determined.

COR PULMONALE (PULMONARY HEART DISEASE)

The relationship between cigarette smoking and chronic obstruc.
tive bronchopulmonary disease (COPD) with car pulmonale was
discussed in the 1968 Supplement to "The Health Consequences of
Smoking" (55).

Although the extent of morbidity and mortality due to car
pulmonale and right heart failure is difficult to determine, COPD is
often complicated by these conditions (27).

The Pulmonary Heart Disease Study Group of the Inter-Society
Commission for Heart. Disease Resources recently summarized the
evidence linking cigarette smoking with COPD and concluded:
"Cigarette smoking is the major cause of pulmonary heart disease
in that it is the most important cause of the chronic non-neoplastic
bronchopulmonary diseases in the United States" (28).

CEREBROVASCULAR DISEASE

The 1971 report, "The Health Consequences of Smoking" (56),
summarized the data linking smoking to cerebrovascular disease as
follows :

1. Data from numerous prospective studies indicate that ciga-
rette smoking is associated with increased mortality from
cerebrovascular 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 con-
cerning CHD may also pertain to the relationship of smoking
and CVD, particularly cerebral infarction.

24


In the interim, additional reports have been published.
Dyken (15) performed a retrospective study on 285 patients with
cerebrovascular disease in Elkhart, Indiana. Even though low ciga-
rette consumption was noted in all groups, males who had cerebral
infarctions smoked significantly more than controls.
Paffenbarger, et al. (42) found that smokers of more than 20
cigarettes a day faced a slightly increased but not significantly
greater risk of dying from a stroke than those smoking lesser
amounts.

After 16 years follow-up, male cigarette smokers in the Framing-
ham study had more than three times the nonsmokers' risk of devel-
oping a cerebral infarction (29). However, Kannel commented : "It
is not clear that smoking actually affects the rate of cerebral athero-
genesis, and some other mechanism may be involved."

      PERIPHERAL VASCULAR DISEASE
The 1971 report, "The Health Consequences of Smoking" (56),
summarized the data relating smoking to peripheral vascular dis-
ease as follows :

1. Data from a number of retrospective studies have indicated
that cigarette smoking is a likely risk factor in the develop-
ment of peripheral vascular disease. Cigarette smoking also
appears to be a factor in the aggravation of peripheral vascu-
lar disease.

2. Cigarette smoking has been observed to alter peripheral blood
flow and peripheral vascular resistance.

Newly published studies add to our understanding of the effect of
nicotine or tobacco smoke on the peripheral circulation and of the
significance of smoking in peripheral vessel atherogenesis.

Martz, et al. (37) observed that some of the apparently con-
flicting data on the effects of nicotine upon the peripheral vascula-
ture may result from interpretations based upon indirect measure-
ments of microcirculatory variables. Hence, they studied vascular
changes in a bat wing under direct microscopic observation. They
noted a marked increase in the diameter of innervated, minute
arteries with intraperitoneal nicotine administration, but this effect
was abolished with sympathetic denervation.

Asano and Branemark (3) installed a direct, microscopic obser-
vation chamber in the connective tissue of two human volunteers.
One volunteer was a "healthy" 20-year-old male nonsmoker. The
other volunteer was a diabetic who had been a smoker for five years
and who ". . . had no apparent diabetic vasculopathy." The effects
of tobacco smoking on the microcirculation of these volunteers in-

25


eluded: I`. . . vasoconstriction, decrease in blood flow rate and fre-
quency of plasma spacing, blocking of blood flow in varying num-
bers of nutritive capillaries, shunting of blood from arterioles to
venules . . . . " These microcirculatory changes were said to result in
a decrease of nutritive blood flow in tissue.

As mentioned in the discussion of CHD, Kjeldsen ( 31, 32) stud-
ied several smoking patients with occlusive peripheral vascular
disease whose COHb levels were significantly higher than those of
control smokers. The levels of COHb in many of these patients were
comparable to those associated with experimental atherosclerosis
in animals. Astrup, et al. (4) have suggested that prospective stud-
ies should be performed to investigate the relationship between
COHb levels and the incidence of arterial disease.

In the Prague study (19) intermittent claudication was signif-
icantly (P < .Ol ) more common among cigarette smokers than non-
smokers. Twenty percent of the men in the age group of 60 to 64
who were heavy smokers (more than 25 cigarettes a day) had inter-
mittent claudication.

Riif (44) reported that all but 4 of the 98 patients admitted for
peripheral vascular surgery at the Karoline Hospital, Sweden, were
smokers.

Mathiesen, et al. (38) in Denmark followed the spontaneous
course of arterial insufficiency in 211 patients. Cessation of smoking
increased the number of patients displaying spontaneous improve-
ment.

ORAL CONTRACEPTIVES, THROMBOPHLEBITIS,
           AND SMOKING

In two studies from Great Britain and one from the United
States, it was reported that the use of oral contraceptives was asso-
ciated with a significantly increased risk of developing venous
thromboembolism (46, 58,59). The British investigators also noted
in their initial report that the affected patients were, on the average,
heavier smokers than controls (58). However, after an additional
year of study, a similar effect was not noted and they concluded
(59) : ". . . the earlier difference between the smoking habits of the
two groups can thus reasonably be attributed to chance (P = 0.08) ."
The American investigator (45) found ". . . no evidence that smok-
ing, acting either independently or in conjunction with oral contra-
ceptives, is a factor in idiopathic thromboembolism."

Cigarette smoking has not been clearly demonstrated to be a fac-
tor that contributes to the risk of idiopathic thromboembolism asso-
ciated with the use of oral contraceptives. Nevertheless, the
possibility that it may act to increase that risk has not yet been
completely ruled out.

26


HIGHLIGHTS OF CURRENT CARDIOVASCULAR
           INFORMATION

In addition to the comprehensive summary from the 1971 report,
"The Health Consequences of Smoking" (56), cited earlier in this
chapter, the following statements are made to emphasize the most
recent developments in the field :

1. Recent epidemiological studies from several countries con-
firm that cigarette smoking is one of the major risk factors
contributing to the development of CHD. Avoidance of ciga-
rette smoking is of importance in the primary prevention of
  CHD.

2. Studies in man and animals have shown a greater myocardial
arteriole wall thickness in smokers than nonsmokers.

3. Experimental and epidemiological investigations implicate
the elevation of carboxyhemoglobin levels in smokers as a
contributor to the development of CHD and arteriosclerotic
peripheral vascular disease.

4. Cigarette smoking is considered to be the major cause of
pulmonary heart disease (car pulmonale) in the United
States in that it is the most important cause of chronic non-
neoplastic bronchopulmonary diseases. Avoidance of ciga-
rette smoking is of importance in the primary prevention of
pulmonary heart disease.

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28


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29


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31


CHAPTER 3

Non-neoplastic Bronchopulmonary Diseases


Contents

                                     Paw
Introduction  .......................................    3'7
Epidemiological Studies  ..............................    38
COPD Mortality  ................................    38
COPD Morbidity  ................................    39
Cessation of Smoking  ...........................    41
Occupational Hazards  ............................    42
  Genetic Factors  .................................    44
Pathological Studies  .................................    45
Experimental Studies  ...............................    45
  Human Studies  .................................    45
  Animal Studies  ................................    46
  Overall Clearance  ...............................    47
Phagocytosis   ..................................    47
The Surfactant System  ..........................    48
Other Respiratory Disorders  .........................    48
Highlights of Current Bronchopulmonary Information  ....    48
References  .........................................    49

35


INTRODUCTION

Chronic bronchitis and emphysema are the chronic bronchopul-
monary diseases of greatest health importance in the United States
(71). The 1971 report, "The Health Consequences of Smoking"
(70), summarized the relationship between smoking and these dis-
eases as follows :

1. Cigarette smoking is the most important cause of chronic
obstructive bronchopulmonary disease in the United States.
Cigarette smoking increases the risk of dying from pulmo-
nary emphysema and chronic bronchitis. Cigarette smokers
show an increased prevalence of respiratory symptoms, in-
cluding cough, sputum production, and breathlessness, when
compared with nonsmokers. Ventilatory function is de-
creased 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 fre-
quency and severity of asthmatic attacks in patients al-
ready 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 smok-
ing 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
nonsmokers 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. However, exposure to excessive atmospheric pol-
lution or dusty occupational materials, and cigarette smoking
may act jointly to produce greater COPD morbidity and
mortality.

37


7. The results of experiments in both animals and humans have
demonstrated that the inhalation of cigarette smoke is asso-
ciated with acute and chronic changes in ventilatory func-
tion and pulmonary 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
characteristic 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.

Recent epidemiological, autopsy, and experimental studies con-
firm and extend the foregoing statements.

EPIDEMIOLOGICAL STUDIES

COPD MORTALITY

Over a period of 4 to 8 years, Burrows and Earle (20) studied 200
patients with symptomatic COPD whose mean FEV, was 1.0 !' 0.4
liter. Ninety-seven percent of these patients had a history of ciga-
rette smoking ; the average consumption for the entire group of 200
individuals was 23 cigarettes a day over a period of 41 years. Upon
entry into the study, 59 percent were still regular smokers and 38
percent had discontinued smoking. Eighty-nine percent of the group
were males and the mean age was 59.1 years.

A 47 percent 5-year mortality was observed in these 200 patients,
and most deaths were ". . . directly attributable to the underlying
lung disease or one of its complications." The relationship of con-
tinued smoking to the course of the disease was difficult to interpret.
Patients who stopped smoking prior to entry into the study had a
poorer survival than those who continued to use cigarettes. This was
related to a tendency for patients to give up smoking when their
illness was severe, and ". . . the apparent advantage of smokers was
eliminated when patients with similar FEV, levels were compared."
The authors reported no reduction of mortality in the group of pa-
tients who stopped smoking, even when smokers and ex-smokers
with similar FEV, levels were compared.

38


Reduction of cigarette smoking was associated with a history of
reduced expectoration, smaller measured sputum volume, and
I'. . . a favorable course of the vital capacity (P < .Ol) . . . ."
The 1971 report, "The Health Consequences of Smoking" (70))
included an analysis of the variety of ways in which smoking may
be related to disease. COPD was cited as an example in which smok-
ing probably initiates a disease process by producing progressive,
irreversible damage. The 200 patients reported by Burrows and
Earle (IO,11 ) may be representative of patients who have experi-
enced progressive and irreversible pulmonary damage after many
Years of exposure to cigarette smoke. In such cases, ". . . cessation
of smoking leaves impaired function which does not improve appre-
ciably but does not continue to deteriorate from continued exposure
to cigarette smoke. However, such function may deteriorate through
aging or through exposure to other harmful agents" (70).

COPD MORBIDITY

New reports of chronic bronchopulmonary disease prevalence
support the findings of earlier studies in which a greater prevalence
was found among smokers than nonsmokers.
A repeat study of a Berlin, New Hampshire, population sample,
Rhich included more than 1,500 individuals, was carried out in 1967
by Ferris, et al. (27). In both this survey and the earlier 1961 sur-
vey, a greater prevalence of chronic nonspecific respiratory disease
\Yas found in cigarette smokers than nonsmokers.
The 1967 Berlin study demonstrated that cigarette smokers who
inhaled deeply or moderately had generally higher prevalences of
chronic nonspecific respiratory disease than those who did not inhale
Or inhaled only slightly.
After standardization for age, sex, and smoking habits, the pre-
valence of chronic nonspecific respiratory disease in the 1967 survey
sample was slightly lower than in 1961. This may be accounted for
bY a decrease in air pollution.
ln a random sample of 609 residents of Glenwood Springs, Colo-
rado, a high prevalence of chronic bronchitis was found to be
Strongly related to smoking, particularly of cigarettes, and this rela-
tionship was independent of age, sex, or history of dust exposure at
Rork (5.2). Chronic airway obstruction was found to be predomi-
nantly a disease of elderly male smokers and increased in frequency
`ith increasing age after 49 years.
The Tecumseh study is a well-known continuing epidemiologic

inYestigation of the entire community of Tecumseh, Michigan. In
Ihis study the relationship of parental longevity to ventilatory
function and prevalence of chronic nonspecific respiratory disease

39


among sons was recently analyzed (17). Death before age 65 of
either parent was related to low values of l-second forced expiratoq
volume among the sons. Maternal death before age 65 was also asso.
ciated with increased prevalence of chronic bronchitis and emphy.
sema among sons. Some, but not all, of these relationships were
accounted for by differences in smoking habits of the sons. The
authors also concluded: "The evidence strongly suggests that con.
stitutional factors are involved" (17) .

A higher prevalence of chronic bronchitis was found among
smokers than nonsmokers (P < .Ol) in a study of 710 Yugoslavian
workers (43). There was a direct relationship between the lifetime
number of cigarettes smoked and the presence of chronic bronchitis,
Several papers have been published recently comparing respira.
tory symptoms such as cough and sputum production among
smokers and nonsmokers in different populations. Two of the neR
studies were prospective investigations (25, 38). In all instances,
symptoms were more common among cigarette smokers than non.
smokers (.2,6,&Z, 15,38,5.2, 63, 75):. In the three studies which re.
ported on pipe and cigar smokers, the frequency of respiratory
symptoms in this group was, in general, intermediate between those
of cigarette smokers and nonsmokers (6,15,5.2).
Results of studies of pulmonary function in representative sam-
ples of different populations (6, 17, 38, 63)) surveys of employees,
(15, 43, 57), and normal volunteers (75) indicate that cigarette
smokers have lower average pulmonary function than nonsmokers,
Pulmonary diffusing capacity was found by Van Ganse, et al,
(72) to decrease in men and women with aging and with an increase
in current or lifetime cigarette consumption.
In general, a dose-response relationship between cigarette con-
sumption and the development of respiratory symptoms and/or im-
paired pulmonary function was found in both men and women; as
cigarette consumption increased, these abnormalities were found
more frequently (6,38,52, 72, 75).

Woolf and Suero (75) studied the respiratory effects of cigarette
smoking in 298 normal women. The prevalence of cough, sputum
production, wheezing, and shortness of breath increased progres-
sively with increased cigarette smoking. The results of the follow-
ing tests of pulmonary function were significantly lower in smokers'
than in nonsmokers: forced vital capacity, forced expiratory vol.
ume in one second, maximal mid-expiratory flow, arterialized cap%
lary blood oxygen tension at rest, specific conductance, and pulm@
nary diffusing capacity and fractional uptake of carbon monoxide
during exercise.

Seely, et al. (63) examined 365 high school students in the Nev
Haven area. They found that students with 1 to 5 years' smoking ex.
perience had excessive cough, sputum production, and shortness of

40


breath. These young smokers also had lower flow rates at mid-vital
capacity and at lower lung volumes than nonsmoking students. The
authors have raised the question of whether smoking by high school
students may lead to developmental arrest of the lung. They feel
that follow-up pulmonary function studies in adolescents who stop
smoking will help clarify this question.

In a study of 556 high school students from Oklahoma City,
Adding-ton, et al. (1) reported that respiratory symptoms were sig-
nificantly more frequent in smokers than nonsmokers, but no signif-
icant differences were noted in the FEV, and the mean vital
capacity.

Snider, et al. (65) investigated 1,403 patients with documented
pulmonary tuberculosis for the presence of obstructive pulmonary
disease. Airway obstruction was found in 62 percent of white men,
3'7 percent of nonwhite men, 36 percent of white women, and 17
percent of nonwhite women. Sixty-eight percent of the patients
were current smokers and 15 percent were ex-smokers. Heavy
smoking had less effect on the presence of airway obstruction than
advanced tuberculosis or older age. These data were interpreted as
showing the predominant importance of tuberculosis as a factor
leading to airway obstruction in tuberculous patients. However, the
authors also concluded: "The present data suggest the possibility
of an additive effect of smoking with tuberculosis in producing air-
way obstruction."

CESSATION OF SMOKING

The salutary effect of stopping cigarette smoking on COPD mor-
tality and morbidity has been noted in previous reports of the
Surgeon General (69, 70).

A recent statement from the "Pulmonary Heart Disease Study
Group" of the Inter-Society Commission for Heart Disease Re-
sources (41) also emphasized this point : "The overwhelming cause
and effect relationship between smoking, bronchitis-emphysema and
Pulmonary heart disease is such that there is little doubt that a radi-
cal reduction or elimination of the cigarette habit would result in a
greatly lowered incidence of the chronic respiratory diseases and
ccr pulmonale."

In recent studies, a decrease in the prevalence of respiratory
symptoms among ex-cigarette smokers has been demonstrated (10,
15, 75). Higgins, et al. (38) interpreted data from 1957 and 1966
surveys of chronic respiratory disease in England as suggesting that
the benefits of giving up smoking on respiratory symptoms are less
in those who have smoked for many years than in those who have
smoked for shorter periods.
Raker, et al. (5) undertook a therapeutic program for previously

41


unrecognized mild to moderate cases of COPD. One hundred thirty-
four men were included in this study. Eighty-five percent of these
men were cigarette smokers, 11 percent were ex-smokers, and 4 per-
cent were nonsmokers. At the g-month follow-up, 61 subjects were
still in the treatment program. Patients were encouraged to stop
smoking, and at the 6-month follow-up 34 percent of the cigarette
smokers had stopped smoking, while 34 percent decreased their
cigarette consumption by at least half. At the follow-up evaluation,
approximately two-thirds of those who either gave up smoking or
decreased their cigarette consumption showed improvement in
symptoms. Thirty percent of those whose smoking habits did not
change showed improvement in symptoms. No significant differ-
ences were found in the pulmonary function studies at the follow-up
evaluation. Alteration of smoking habits was the single factor most
closely related to symptomatic improvement.

OCCUPATIONAL HAZARDS

As observed by Bouhuys and Peters (7), the relative contribu-
tions of cigarette smoking and industrial exposure to the loss of
lung function may at times be difficult to determine.

Recent studies in wool, textile, grain elevator, shipyard, pulp mill,
steel, and underground mining industries have documented a higher
prevalence of chronic bronchitis among cigarette smokers than non-
smokers (9, 13,19,.20,39, 42,47,50). Similar studies in steel, pulp
mill, machine shop, and welding industries indicate a greater fre-
quency of respiratory symptoms and/or diminished pulmonary
function in smokers than in nonsmokers (22,2S, 30,39).        '
Japanese investigators recently reported that former employees

of a poison gas factory had a high prevalence of chronic bronchitis
and expiratory slowing; a history of chronic bronchitis was ob-
tained from 67 percent of smoking men and 47 percent of nonsmok-
ing men who had manufactured mustard gas or lewisite (54).

In recent months several articles have been published on coal
workers' pneumoconiosis. Because coal miners are not allowed to
smoke at work, they must smoke their cigarettes during a shorter
period of time than non-miners; nevertheless, the average coal
miner smokes as many cigarettes a day as does the non-miner (51) .
Thus, his exposure tends to be more intense during the period in
which he is smoking. Also, the documented hazard of chronic expo-
suie to coal dust may be compounded by the deleterious effect of
smoking on ciliary function.

Ashford, et al. (4) studied approximately 30,000 working coal
miners in Great Britain. Their data suggest that smoking and pneu-
moconiosis act independently in the production of pulmonary symp-
toms.

42


A total of 801 working, anthracite coal miners from Pennsylvania
were investigated by Tokuhata, et al. (68). Twenty-four percent of
the smoking miners had pulmonary function impairment as com-
pared with 11 percent of miners who did not smoke. Because the
smokers developed their pulmonary function abnormalities after a
much shorter underground work exposure, the authors suggested
that smoking may significantly accelerate the development of
pneumoconiosis among coal miners.

Rasmussen and Nelson (61) studied 368 soft-coal miners from
the Southern Appalachian coal fields. All workers included in the
study had been involved in the coal industry for at least five years.
Miners with a smoking history of 30 pack-years or more showed a
significant (P < .Ol) reduction of FEV, when compared to non-
smoking miners. Impairment of oxygen transfer was greater in both
the 15 to 29.9 pack-year group and the 30 plus pack-year group than
among the lifelong nonsmokers (P < .Ol) .
One hundred sixty-two dyspneic soft-coal miners, who gave his-
tories of lifelong abstinence from cigarette smoking, were examined
by Rasmussen (60). Of these patients, 85.6 percent had some X-ray
evidence of pneumoconiosis. The group as a whole was ". . . not rep-
resentative of all coal miners, nor of all symptomatic coal miners."
Even though 56 percent of- these miners had "normal" ventilatory
capacities, i.e., an FEV, which was `75 percent or greater of the
predicted normal vital capacity, more than 90 percent had an
alveolar-arterial oxygen gradient during exercise which exceeded
19.9 mmHg. In more than 95 percent of the "normal" group, this
gradient was not associated with significant arterial oxygen desatu-
ration during exercise. The loss of pulmonary function in the entire
group of non-cigarette smokers was somewhat less than that found
in a group of miners composed of cigarette smokers and non-
smokers; nonetheless, these findings demonstrate that, in the ab-
sence of cigarette smoking, coal dust exposure may be associated
with abnormalities in oxygen transfer during exercise, despite the
Presence of a normal FEV,.
An autopsy study of 144 Appalachian coal miners was carried out
by Naeye, et al. (58). Several parameters of cardiac and pulmonary
structure were examined with regard to the effect of smoking. The
"olurne of pulmonary macules and nodules containing coal dust and
the concentration of silica crystals and collagen in these macules
and nodules were unrelated to smoking. Right ventricular hyper-
trophy, defined according to an index developed by Naeye, was pres-
ent in all groups of miners but was more severe in the bituminous
workers who smoked cigarettes. The emphysema index, which is a
meUurement of the percent of lung tissue comprised of abnormal
air space, was determined only in bituminous coal miners. It was

43


significantly greater in cigarette smokers than in nonsmokers.
Goblet cell hyperplasia, which appeared to be present in the entire
group, was somewhat greater in the bituminous coal miners who
smoked than in the nonsmokers, but the differences were not statis.
tically significant.

Several investigators have concluded that cigarette smoking by
itself is more important in the production of respiratory disease,
other than pneumoconiosis, among coal miners than is exposure t,e
coal dust (24, 34, 58, 68). Rasmussen questions this view (60).
There is no consensus in recent publications on what role cigarette
smoke may play in the development of coal workers' pneumoconio-
sis (24, 51, 53, 58, 68).

Weiss (73) examined 100 asbestos textile workers and found a
greater prevalence of pulmonary fibrosis among cigarette smokers
than nonsmokers. The prevalence increased with increasing amount
and duration of cigarette smoking and with increasing duration of
exposure to asbestos.

GENETIC FACTORS

An infrequent genetic error, homozygous alpha,-antitrypsin de-
ficiency, has been commonly associated with the premature develop
ment of severe, panacinar emphysema. It is postulated that alpha,.
antitrypsin is essential to protect the lung against the destructive
action of naturally occurring proteinases (36).

Related questions of current interest deal with the prevalence and
significance of the heterozygous deficiency state (intermediate
serum antitrypsin deficiency) and the interaction of smoking with
the severe and intermediate deficiency states. Mittman, et al. (49)
recently reviewed the limited data available on the smoking habits of
patients with alpha,-antitrypsin deficiency ; the cigarette smoke ex-
posure of patients with the intermediate deficiency appears to be
greater than that of patients with the severe deficiency.

Cigarette smoking has been reported to be a possible precipitating
factor in the development of COPD in the homozygous deficiency
state (40). Some studies (26, 44, 49, 67') have demonstrated an
association between the heterozygous deficiency state and the devel-
opment of COPD, while other studies have not (35,62). Mittman,
et al. (49) have suggested that the intermediate deficiency may
predispose to lung disease by accentuating an individual's suscepti-
bility to the harmful effects of external irritants. Whether or not
cigarette smoking acts together with the homozygous or hetero-
zygous deficiency states to increase the risk of developing either
panacinar emphysema or the more common forms of COPD has not
been adequately studied.

44


PATHOLOGICAL STUDIES

In previous investigations, a correlation has been found between
cigarette smoking and the histologic changes characteristic of
bronchitis and emphysema (70).

An autopsy study of 60 patients with COPD was performed by
Cullen, et al. (16). Although they did not find a correlation between
the smoking history, total emphysema score, type of emphysema, or
bronchial histologic features, the authors noted that only three pa-
tients were non-cigarette smokers. These three patients were pipe
or cigar smokers. Eight patients who had stopped smoking three
years before death had the same bronchial histologic abnormalities
as those who continued smoking until death. This suggests that the
bronchial abnormalities had become irreversible at the time of
smoking cessation.

Dunnill and Ryder (21) carried out a quantitative study of the
relationship between chronic bronchitis, emphysema, and smoking.
The lungs of 353 patients were examined at autopsy, and a smoking
history was available in 179 cases. A small but significant (P < .005)
difference was found between smokers and nonsmokers in the per-
centage volume of bronchial mucous glands. Emphysema, mainly
the centrilobular type, was found significantly (P < .OOl) more fre-
quently in men and women smokers than nonsmokers, and it oc-
curred at a much younger age in the smokers.

EXPERIMENTAL STUDIES

HUMAN STUDIES

Anderson (3) observed in a few patients with and without COPD
that cigarette smoking can produce V/Q (ventilation/perfusion)
changes resulting in a significant average drop in PaO, (partial
Pressure of oxygen in arterial blood).
Clarke, et al. (14) studied the bronchoconstrictor effect of plain
and filtered cigarettes in 16 men. Filtration of either the particulate
Or vapor phase of the smoke had a similar effect in reducing the
bronchoconstrictor response to cigarette smoke inhalation.
Using a reference cigarette developed by the University of
Kentucky, Diamond, et al. (28) measured pulmonary expiratory
resistance immediately after smoking. Heavy smokers, whose con-
trol resistance values were significantly higher than those of mod-
erate or nonsmokers, had a decrease in resistance, while nonsmok-
ers had an increase. Although selected ventilatory function tests did
not change significantly after smoking, the author noted that the
methods used in this study are probably not sensitive enough to
measure constriction in peripheral airways, where smoking is
thought to exert an adverse effect.

45


ANIMAL STUDIES

Frasca, et al. (32) made electron microscopic observations in
areas of fibrosis and emphysema of the lungs of dogs, which had
been subjected to experimental cigarette smoking as reported by
Hammond, et al. (37). Details of the smoking procedure were re-
viewed in the 1971 report, "The Health Consequences of Smoking"
(70). The major findings in the study of Frasca, et al. were : a com-
plete loss or marked reduction in the number of alveolar septal capil.
laries, a marked thickening of the alveolar septa due to increased
amounts of collagen, thickening of the pleural stroma due to large
amounts of collagen, and the presence of increased numbers of
macrophages in both the pleura and parenchyma. Many of these
macrophages were filled with pleomorphic cytoplasmic inclusions.
Crystalline-like structures were found in membrane-bound inclu-
sions and ferritin-like particles occurred both in large membrane-
bound aggregates and lying free in the cytoplasm.

Flint, et al. (29) reported a significant increase in the number of
polymorphonuclear leukocytes recoverable from the lungs of guinea
pigs following exposure of these animals to cigarette smoke. Re-
cause no changes in serum alpha,-antitrypsin levels were found in
this setting, the authors hypothesized that an imbalance may occur
between proteolytic enzymes released by polymorphonuclear
leukocytes and the inhibitors of these enzymes.
`The stress effects of forced mouth-breathing and inhalation of
cigarette smoke on lung mitochondrial phosphorylation were studied
in the guinea pig by Kyle and Riesen (45). Mouth-breathing alone
was associated with impaired efficiency of phosphorylation at two
mitochondrial loci, while mouth-breathing guinea pigs exposed to
cigarette smoke lost efficiency at only one of these sites.
Aviado and coworkers have studied the effects of hormones on
the pulmonary response to cigarette smoke inhalation and intra-
venous nicotine injection. Subcutaneous progesterone administra-
tion, prior to nicotine or smoke exposure, reduced the bronchocon-
strictor response in rats (64). A similar experiment involving
pretreatment of dogs with glucocorticoids resulted in variable bron-
choconstrictor responses after exposure to cigarette smoke (12).
Nitrogen dioxide (NO?), a gas found in cigarette smoke and some
industrially polluted air, can destroy cellular membranes and sub
cellular structures (25). Continuous administration of low concen-
trations of NO, in rats has produced an emphysema-like disease
(66). Falk has suggested that NO, may ". . . carry a major responsi-
bility for the high incidence of emphysema in cigarette smokers"
(25).
Stephens, et al. (66) examined ultrastructural changes in pulmo-
nary connective tissue of rats exposed to 2 to 20 p.p.m. of NO* for

46


varying periods of time. In the absence of significant cell destruc-
tion, striking alterations in both collagen fibrils and basement mem-
branes were found.

OVERALLCLEARANCE

Pavia, et al. (55,56) examined the effect of cigarette smoking on
the mucociliary mechanism of the human lung. A temporary slow-
ing of mucociliary clearance was found in a group of 22 elderly
smokers (56). Eight of these subjects had mild restrictive impair-
ment and two had airway obstruction. When percentage clearance
by elderly cigarette smokers and nonsmokers was compared, sig-
nificant differences were not demonstrable (55). In the latter study,
patients with functional evidence of lung disease were not included.
Deposition and clearance of inhaled 2~ particles of iron oxide la-
beled with lg8Au were studied in 19 young, normal subjects by
Lourenco, et al. (46). While tracheobronchial clearance began im-
mediately after inhalation in nonsmokers, it was delayed for periods
of 1 to 4 hours after inhalation in smokers.
Frances, et al. (3.2) studied the effect of cigarette smoke on par-
ticle transport on donkey nasociliary mucosa. This mucosa was
found to be much more resistant to the effects of cigarette smoke
than that in the donkey tracheobronchial tree. More recently, Albert,
et al. (2) published a report that in one of three donkeys tolerance
to cigarette smoke had developed in the tracheobronchial mucosa.
Weissbecker, et al. (74) examined in viva mucus flow rates in
cats exposed to cigarette smoke gas phase of varied composition.
Several compounds, e.g., isoprene and nitrogen dioxide, when added
in combination to the gas phase, were effective in reducing the
mucus flow, compared to the effect of the gas phase alone. Other
compounds, e.g., CO, diminished the mucostatic effect of the gas
phase. Compounds producing mucostasis were ineffective when
added to cigarette smoke. These experiments indicate that effects
observed from pure compounds cannot be used to predict the effect
of cigarette smoke on mucus transport.

PHAGOCYTOSIS

The recent literature concerning the effect of tobacco smoke on
macrophage function is reviewed in the chapter on allergy of this
report.

Pratt, et al. (59) have extended their studies on the ultrastruc-
ture of human alveolar macrophages. Macrophages obtained from
smokers tend to contain more heterogeneous inclusions than those
from nonsmokers. Angular and needle-like structures were observed

47


only in the inclusions of smokers. The authors concluded that these
structures ". . . may represent undigested smoke products. . . ."
In an investigation of early emphysema found in patients who

were autopsied, McLaughlin and Tueller (48) found brownish, pig-
mented alveolar macrophages in the intact parenchyma adjacent to
areas of emphysema. Such macrophages were not found in normal
lungs, but were found in sputum specimens of ". . . apparently
healthy cigarette smokers." In heavy smokers many of the macro-
phages also contained iron particles.

THESURFACTANTSYSTEM

Giammona, et al. (33) measured the surface tension of lung ex-
tracts and bronchial washings of dogs following exposure to ciga-
rette smoke. Elevated minimal surface tension values were found
in bronchial washings obtained from three dogs. The values re-
mained elevated for 48 hours after the cigarette smoke exposure;
the values obtained one week after the cigarette smoke exposure
were normal. The surface tension measurements of lung extracts
obtained from four autopsied dogs were normal.

OTHER RESPIRATORY DISORDERS

Finklea, et al. (28) studied acute, noninfluenzal respiratory dis-
ease in military cadets and found significantly higher incidence rates
for acute upper and lower respiratory illness among cigarette
smokers than nonsmokers. Intermediate rates were found for
lighter cigarette smokers, cigar, pipe, and ex-smokers.

HIGHLIGHTS OF CURRENT BRONCHOPULMONARY
            INFORMATION

In addition to the comprehensive summary from the 1971 report,
"The Health Consequences of Smoking" (70)) cited earlier in this
chapter, the following statements are made to emphasize the most
recent developments in the field:

1. Recent epidemiological and clinical studies from several
countries confirm that men and women cigarette smokers have
an increased prevalence of respiratory symptoms and have
diminished pulmonary function compared to nonsmokers.

2. Investigations of high school students have demonstrated that
abnormal pulmonary function and pulmonary symptoms are
more common in smokers than nonsmokers.

48


3.




4.




5.

Recent occupational studies confirm that cigarette smoking is
an important cause of COPD, acting both independently and
in combination with occupational exposure.
Recent experimental studies confirm that cigarette smoking
exerts an adverse effect on pulmonary clearance and macro-
phage function.

Pulmonary macrophages obtained from cigarette smokers ex-
hibit characteristic morphologic differences when compared
to those obtained from nonsmokers.

BRONCHOPULMONARYREFERENCES

(1) ADDINGTON, W. W., CARPENTER, R. L., MCCOY, J. F., DUNCAN, K. A.,
  MOGG, K. The association of cigarette smoking with respiratory symp-
  toms and pulmonary function in a group of high school students. Jour-
  nal of the Oklahoma State Medical Association 63(11) : 525-529,
   November 1970.

(2) ALBERT, R. E., ALESSAN~RO, D., LIPPMANN, M., BERCER, J. Long-term
  smoking in the donkey. Effect on tracheobronchial particle clearance.
   Archives of Environmental Health 22(l) : 12-19, January 1971.
(3) ANDERSON, W. H. Acute exposure to cigarette smoke as a cause of
  hypoxia. Chest 59,(5, Supplement) : 33S-34S, May 1971.
(4) ASHFORD, J. R., MORGAN, D. C., RAE, S., SOWDEN, R. R. Respiratory
  symptoms in British coal miners. American Review of Respiratory
   Disease 102(3) : 370-381, September 1970.
(5) BAKER, T. R., OSCHERWITZ, M., CORLIN, R., JARBOE, T., TEISCH, J.,
  NICHAMAN, M. Z. Screening and treatment program for mild chronic
  obstructive pulmonary disease. Journal of the American Medical As-
   sociation 214 (8) : 1448-1455, November 23,197O.
(6) BOUDIK, F., GOLDSMITH, J. R., TEICHMAN, V., KAUFMANN, P.-C. Epide-
  miology of chronic bronchitis in Prague. Bulletin of the World Health
   Organization 42 (5) : 711-722, 1970.

(7) BOUHUYS, A., PETERS, J. M. Control of environmental lung disease. New
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49


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50


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(46) LOURENCP, R. V., KLIMEK, M. F., BOROWSKI, C. J. Deposition and
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(48) MCLAUGHLIN, R. F., TUELLER, E. E. Anatomic and histologic changes
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   gas workers. American Review of Respiratory Disease 102(2) : 1'73-
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(55) PAVIA, D., SHORT, M. D., THOMSON, M. L. No demonstrable long term
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    1971.

(58) PENMAN, R. W. A summary of the conclusions from an international
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52


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(61) RASMUSSEN, D. L., NELSON, C. W. Respiratory function in Southern
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53


CHAPTER 4

Cancer


Contents

                                      Page
LungCancer  ......................................    59
Epidemiological Studies  ..........................    60
Experimental Aspects  ..........................    65
Other Cancers  ......................................    67
  Cancer of the Larynx  ...........................    68
  OralCancer  ...................................    68
Cancer of the Esophagus  .........................    `70
Cancer of the Urinary Bladder  ....................    72
  Cancer of the Pancreas  ..........................    74
Highlights of Current Cancer Information ...............    74
References  .........................................    75

LIST OF TABLES

Table l.-Some initiating agents in two-stage carcinogenesis    66

LIST OF FIGURES

Figure I.-Lung cancer mortality ratios of Japanese males
by amount smoked . . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . .
Figure 2.-Relative risk of lung cancer in ex-smokers of
cigarettes by length of cessation before diagnosis . . . . . . .
Figure 3.-Relative risk of lung cancer in ex-smokers of cig-
arettes by length of cessation and previous duration of
smoking   . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure 4.-Relative risk of cancer of theoral cavity, pharynx,
larynx, and esophagus associated with smoking and chew-
ing in various forms  ,..,,.,*,*..*...****...........
Fignre 5.-Death rates for cancer of the esophagus in Jap-
anese males by smoking and drinking characteristics . . . .
l%ure B.-Relative risk of urinary bladder cancer for males
by amount smoked . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Figure `I.-Relative risk of urinary bladder cancer for fe-
males by amount smoked . . . . . . . . . . . . . . . . . . . . . . . . . . .

61


63




64



70


71


72


73

57


LUNG CANCER

Cigarette smoking has been established as the major cause of
lung cancer. The 1971 report, "The Health Consequences of Smok-
ing" (39)) in summarizing this association, concluded :

1. Epidemiological evidence derived from a number of prospec-
tive and retrospective studies coupled with experimental and
pathological evidence confirms the conclusion that cigarette
smoking is the main cause of lung cancer in men. These stud-
ies 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 ces-
sation 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 signif-
icantly higher than for female nonsmokers, are lower than
for men who smoke. This difference may be at least partially
attributed to difference in exposure: the use of fewer ciga-
rettes per day, the use of filtered and low "tar" cigarettes, and
lower levels of inhalation. 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.

59


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 pollution in the etiology of lung cancer is presently incon.
elusive. Factors such as occupational and smoking habit dif-
ferences may also contribute to the urban-rural difference
observed. Detailed epidemiologic surveys have shown that the
urban factor exerts a small influence compared to the over-
riding effect of cigarette smoking in the development of lung
cancer.

7. Certain occupational exposures have been found to be assa-
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 ciga-
rette 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.

In the interim, additional epidemiological, pathological, and ex-
perimental studies have added to our understanding of these rela-
tionships.

EPIDEMIOLOGICAL STUDIES

The major prospective epidemiological studies to date, demon-
strating associations between cigarette smoking and specific dis-
eases, were conducted primarily in the United States, Canada, and
Great Britain in Caucasian populations. A large, prospective study
currently in progress in Japan adds to the weight of evidence sup
porting a causal relationship between cigarette smoking and lung
cancer. It is the first large-scale prospective study to be conducted in
a population characterized by genetic, dietary, behavioral, and cul-
tural influences distinctively different from those in previously ex-
amined Western populations. The 3-year preliminary prospective
data for lung cancer from this population of 265,118 adults in Japan
(20) demonstrate overall effects and dose-response relationships
similar to those observed in previous studies (figure 1).

60


The mortality ratio for male smokers of 1 to 9 cigarettes a day
was 2.7 and rose to 24.8 for smokers of more than 2 packs a day.
The mortality ratio was 6.9 for ex-smokers. Of the 122,261 men in
the study, 74.3 percent were daily smokers, 3.4 percent were ex-
smokers, and 19.1 percent nonsmokers. The percentage of males
who were daily smokers decreased with advancing age.

26

24 -

22 -

20 -

18 -

16 -
B
F14 -
z
5
1
r 12 -
s
10 -

a-

6-

                 9.





         5.7
d
2.7



    --- ----

--__

1

2.1

-

NOll      1-9      10-19     20-24     25-4

Number ofclgarettes smoked per day

1

FIGURE I.-Lung cancer mortality ratios of Japanese males by amount smoked.
~OWCE: Hirayama, T. (10).

In a prospective study of 12,322 Czechoslovakian males, Kubik,
et al. (19) analyzed various factors associated with the develop-
ment of lung cancer. During the 31/s-year follow-up period, 61 cases
of lung cancer were discovered. The incidence of lung cancer among
males aged 40 to 64 was 460/100,000 among heavy cigarette
smokers (more than 200,000 lifetime cigarettes), 90/100,000 for
light cigarette smokers (less than 200,000 lifetime cigarettes), and
10/100,000 for nonsmokers. There were no cases of lung cancer
song the 222 smokers of pipes and cigars.

61


In the past 50 years Poland has experienced a rise in cigarette
consumption and, more recently, a sharp rise in the incidence of and
mortality from lung cancer (16, 84). In the 5-year period between
1963 and 1967, the mortality rate from lung cancer for men rose
from 33.0 to 49.1 per 100,000. This increase was more pronounced
in urban areas. Lung cancer has been the leading cause of death
from malignant neoplasms in Polish men since 1959.

Additional studies conducted in Germany (26)) Lebanon (1))
Scotland (6), and Sweden (37) have demonstrated a strong asso-
ciation between cigarette smoking and lung cancer.

Rimington (28) examined the smoking habits and sputum pro-
duction of 21,579 British males aged 40 and older who were screened
for lung cancer by X-ray examination. During the follow-up period
of 36 to 56 months, 64 new cases of lung cancer were identified.
Because chronic bronchitis and lung cancer are both associated with
cigarette smoking, the data were standardized by cigarette con-
sumption categories. An increase in both lung cancer and chronic
bronchitis was demonstrated with increasing consumption, but for
each level of smoking there was a higher incidence of lung cancer
among the individuals with chronic bronchitis than among those
without this condition. Standardization with respect to age showed
that the differences in lung cancer incidence between those with
and without chronic bronchitis could not be accounted for by the
increase seen in these diseases with advancing age. It was concluded
that persons who smoke run a higher risk of chronic bronchitis than
nonsmokers and those smokers who develop chronic bronchitis run
a higher risk of developing lung cancer than smokers without
chronic bronchitis. The relationship between lung cancer and
chronic bronchitis was not demonstrated for pipe smokers.

Graham and Levin (7) examined the effect of cessation of ciga-
rette smoking on the risk of developing lung cancer in a retrospec-
tive study of 700 lung cancer patients. The risk of developing lung
cancer in ex-smokers declined sharply after cessation (figure 2).
The decline occurred both in those who smoked for less than 31
years and those who had smoked 31 years or more (figure 3). Those
who had smoked for less than 31 years had a lower risk of lung
cancer following cessation than those with the longer smoking his-
tory in each category of time following cessation. Although there
was an appearance of a somewhat more rapid rate of decline in risk
with time following cessation for those who smoked for the shorter
period, the difference was not statistically significant. The relative
risk for the development of lung cancer for pipe and cigar smokers
was 2.6. The reduction in risk following cessation of these forms of
smoking was not examined.

The relationship of smoking to lung cancer in women has recently
been examined by several authors. The smoking patterns of 142,857

62


Japanese women were described by Hirayama (10). Only 10.9 per-
cent were daily smokers of cigarettes. Women started smoking at
an older age than men and, in contrast to Western populations, there
was a higher percentage of smokers in the older age groups than
among younger women. The mortality rates were lower for women
than for men, but a dose-response relationship was demonstrated.
The lung cancer mortality ratio for women smokers of 1 to 9 ciga-
rettes a day was 2.65 and rose to 3.14 for smokers of 20 to 24 ciga-
rettes a day compared to nonsmokers.

50






40




Y 3o
.I
L
:
`L;
m
2 20







10

    1.00
. --n----

-I

23.30

Cii%          18       65       19       12       5        2

Controls       346        31       17       23       29       30

Months

Never
Smoked
(Smoked cigarettes only or with other forms and stopped all.)

O-6      7-12      13-36    37-120     >120

FIGURE Z.-Relative risk of lung cancer in ex-smokers of cigarettes by length
of cessation before diagnosis.
SOURCE: Graham, S., Levin, M. L. (7).

In two recent investigations (9, 13) , both similar in design, the
authors described higher rates of lung cancer among Jewish women
in Pittsburgh and Montreal than among Catholic and Protestant
controls. The proportion of epidermoid and anaplastic carcinomas
Was found to be lower for the 87 Jewish women with lung cancer in
these studies than for the non-Jewish women. A survey of smoking

63


habits in the two cities suggested that the increased incidence of
lung cancer in Jewish women could not be entirely attributed to
variations in smoking patterns. A low incidence of lung cancer was
found among Jewish males, and this was correlated with their low
cigarette consumption.

80 -

      74.4

70 -

60 -
;

I   Smoking duration before cessation

More than 31 years

1 Less than 31 years 1 1

    01                2-10

(Smoked clgarertes only or with other forms and stopped all.)

>lO

FIGURE 3.-Relative risk of lung cancer in ex-smokers of cigarettes by length of
cessation and previous duration of smoking.

SOURCE: Graham, S., Levin, M. L. (7).

The increased risk for the development of lung cancer among
uranium miners is well established. The 1971 report, "The Health
Consequences of Smoking" (39)) summarized the recent investiga-
tions in this area. The histologic types of 121 cases of lung cancer
in American uranium miners were studied by Saccomanno, et al.
(30) using the WHO classification of lung tumors. A marked in-
crease was noted in the small cell undifferentiated types with in-

64


creasing radiation exposure. The author examined the role of
tobacco in the etiology of these tumors stating, ". . . among uranium
miners, cigarette smoking is a potent co-carcinogen in the cause of
lung cancer, but exerts little, if any, influence on the cell type of
lung cancer. . . ."

EXPERIMENTAL ASPECTS

Chemicals present in the particulate phase of tobacco smoke have
been tested for their carcinogenic potential in experimental animals
and/or tissue and organ cultures and have been grouped according
to the type of activity observed. On mouse skin, certain chemicals
induce tumor formation and are called complete carcinogens; others
appear to act only in conjunction with additional treatment, and
are referred to as incomplete carcinogens. They include tumor initi-
ators and tumor promoters. Tumor initiators induce an irreversible
change in epidermal cells which causes them to respond to subse-
quent applications of tumor promoters with the development of skin
tumors. This two-stage mechanism of carcinogenesis, well known
for mouse skin, has not been demonstrated in other animal species or
tissues under comparable conditions.
Hoffmann and Wynder (11, 44) discussed the major initiators
and promoters found in cigarette smoke and described an additional
property of acceleration possessed by N-alkylated carbazoles,
N-alkylated indoles, and Trans-4, 4'-dichlorostribene (DCS) which
is a pyrolysis product of the insecticides DDT and DDD. These
compounds are inactive as complete carcinogens, initiators, or pro-
moters but accelerate the initiator-promoter activity of polynuclear
aromatic hydrocarbons (PAH) .
The initiating activity of polycyclic aromatic hydrocarbons in
two-stage carcinogenesis was investigated and reviewed by Van
Duuren, et al. (41). Several compounds previously thought to be of
little or no significance in tobacco carcinogenesis have been found
bY Van Duuren and other independent investigators to be tumor
initiators. Table 1 lists a number of these compounds. Tumor pro-
moting agents probably allow these weak carcinogens to express
their tumorigenic potential. Dibenz (a, c) anthracene which was re-
ported by Van Duuren, et al. (41) to be an initiating agent was
found by Lijinsky, et al. (22) to also act as a complete carcinogen in
mouse skin experiments.
In another investigation, Van Duuren, et al. (42) confirmed that
tobacco smoke condensate is primarily a tumor-promoting agent
With weak carcinogenic activity. They also found that benzo(a) -
PYrene, a carcinogen in cigarette "tar," acts as a tumor promoter
When applied to mouse skin in low doses over a long time period

65


TABLE L-Some initiating agents in two-stage curcinoge~.

Compound

-

t Dibenz (a,c) anthracene
t Chrysene
t Benz (a) anthracene
t 6-Methylanthanthrene
Chloromethyl methyl ether
Urethan
Triethylenemelamine
1,4-Dimethanesulfonoxy-2-butyne

--

-

t Those found in cigarette smoke.
SOURCE: Van Duuren, et al. (41).

after the application of an initiating agent. This supports the obser.
vation that the tumor-promoting activity of cigarette "tar" may
represent the summation of carcinogenic activities of the several
carcinogenic aromatic hydrocarbons present in ciggrette "tar."

In tobacco carcinogenesis research the choice of `bioassay is of
major importance. Mouse and rabbit skin models have been an im.
portant source of experimental data concerning tobacco carcino.
genesis (44). Several relatively rapid screening bioassays have b&n
recently suggested. Major (24) examined the effects of tumor pro.
moters and initiators on mouse skin, measuring cell numbers, cell
size, mitotic index, and epidermal thickness. Changes found during
the first five days were characteristic for different agents.

The effects of polycyclic aromatic hydrocarbons on the nonspecific
esterase activity in sebaceous glands of mice were examined br
Healey, et al. (8). The changes observed were not entirely specific
for carcinogenic activity and were probably related more to the
toxicity of the painted substances to the sebaceous gland cells. This
suggests that further improvement is needed in this system before
it can be a practical screening bioassay for potential carcinogenic
compounds.

Shabad (33) reviewed experimental studies from Russia and else.
where relating tobacco with tumor formation, and concluded, ". . . it
is indicated that cigarette smoke can actually induce lung cancer in
animals."

Leuchtenberger and Leuchtenberger (21) have described adeno-
mas and adenocarcinomas in the lungs of mice chronically exposed
to cigarette smoke.

Takayama (36) found that subcutaneous injections of cigarette
"tar" in newborn mice produced benign and malignant tumors of
the liver, lung, and lymphoid tissue.

66


The compound 7H-Dibenz (c,g) carbazole (7H-DBC) , a compo-
nent of cigarette smoke, was tested for its carcinogenic potential on
the respiratory tract of Syrian golden hamsters using 15 or 30 intra-
tracheal injections per week. Sellakumar and Shubik (32) found a
high percentage of squamous tumors of the trachea and bronchi in
the tested animals and observed that 7H-DBC appeared to be a
potent carcinogen for the respiratory system of hamsters.

Krasnyanskaya (18) has examined the effects of chronic expo-
sure to cigarette smoke on the respiratory tract of 95 rabbits. One
group was pretreated with an intratracheal injection of benz (a) -
pyrene. Although premalignant changes were found in treated ani-
mals, no malignancies were observed after four years of exposure.

OTHER CANCERS

The relationships between tobacco smoking in its various forms
and cancers of the oral cavity, larynx, esophagus, kidney, urinary
bladder, and pancreas were summarized in the 1971 report, "The
Health Consequences of Smoking" (39).

1. Cancer of the Larynx

a. Epidemiological, experimental, and pathological studies
support the conclusion that cigarette smoking is a signif-
icant factor in the causation of cancer of the larynx.
b. The risk of developing laryngeal cancer among cigarette
smokers as well as pipe and/or cigar smokers is signif-
cantly higher than among nonsmokers.
c. The magnitude of the risk for pipe and cigar smokers is
about the same order as that for cigarette smokers, or pos-
sibly slightly lower.

d. Experimental exposure to the passive inhalation of cig-
arette smoke has been observed to produce premalignant
and malignant changes in the larynx of hamsters.

2. Cancer of the Oral Cavity

  a. Epidemiological and experimental studies contribute to the
   conclusion that smoking is a significant factor in the devel-
   opment 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.
b. Experimental studies suggest that tobacco extracts and
   tobacco smoke contain initiators and promoters of cancer-
   ous changes in the oral cavity,

67


3. Cancer of the Esophagus

a. Epidemiological studies have demonstrated that cigarette
smoking is associated with the development of cancer of
the esophagus.

b. 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.
c. Epidemiological studies have also indicated an association
between esophageal cancer and alcohol consumption and
that alcohol consumption may interact with cigarette
smoking. This combination of exposures is associated with
especially high rates of cancer of the esophagus.

4. Cancer of the Urinary Bladder

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

c. Clinical and pathological studies have suggested that
tobacco smoking may be related to alterations in the me-
tabolism of tryptophan and may in this way contribute to
the development of urinary tract cancer.

5.  Cancer of the Pancreas
   Epidemiological studies have suggested an association be-
   tween cigarette smoking and cancer of the pancreas. The
   significance of the relationship is not clear at this time.

Additional relevant epidemiological, pathological, and experi-
mental data have been reported.

CANCER OF THE LARYNX

McNelis and Esparza (23) reported 14 cases of carcinoma in situ
of the larynx found among 387 vocal cord biopsies. Thirteen pa-
tients were men and with one exception all smoked cigarettes.

Lavelle (20) described 11 patients with carcinoma of the larynx
which occurred as a second primary cancer at least one year after
the successful treatment of an initial primary cancer of the
bronchus. "Although it was not possible to ascertain with certainty
the smoking habit of all these patients there were no definite non-
smokers among them."

68


ORAL CANCER

Leukoplakia of the oral mucosa represents a keratinization of
surfaces normally unkeratinized. Over a 23-year period, Sugar and
Banoczy (35) observed 535 patients with leukoplakia. Of the 324
patients examined in the latest survey, 96 (30 percent) had
leukoplakia for more than 10 years. Two hundred sixty-nine pa-
tients (83 percent) were smokers. Treatment was ineffective in
those patients who continued to smoke. Oral cancer eventually de-
veloped in 13 of 48 patients (27 percent) who had severe leukopla-
kia.

The initial changes in the mouth caused by smoking may not be
the hyperkeratotic lesions of leukoplakia. Meyer, Rubinstein, and
colleagues (25, 29) examined the effects of smoking on the surface
cytology of clinically normal oral mucosa and, in general, found
that smoking produced changes in cytoplasm characterized by less
mature cell configurations. These changes were most pronounced
on those surfaces most directly exposed to the stream of cigarette
smoke.

Etiological aspects of squamous cancers of the head and neck
were reviewed by Wynder (43). There was an increased likelihood
of a second primary tumor forming at the site of the first cancer if
a patient had been a heavy smoker, or if he continued to smoke,
after surgical removal of the first primary. From a preventive point
of view it was observed that squamous cell cancers of the head and
neck would be comparatively rare in the absence of tobacco and ex-
cessive alcohol consumption.

Jussawalla and Deshpande (1.5) examined various types of smok-
ing and chewing habits in a retrospective investigation of 2,005
patients in Bombay, India, who had histologically established can-
cers of the oral cavity, pharynx, larynx, and esophagus. Smokers
used either a manufactured cigarette or the Indian "bidi" which
contains a small quantity of shredded tobacco rolled in a dried leaf,
usually of the Temburni tree (Dtipyros MeZunoxyEon). Chewers
used "pan" made with betel leaf, lime, and spices. A small quantity
of tobacco was, on occasion, added to this mixture as an optional in-
gredient. Smoking and chewing both resulted in an increased risk of
cancer at each site examined with a striking increase in risk ob-
served in patients who had the combined habits of chewing and
smoking (figure 4). The independent contribution of tobacco to the
increased risk of cancer at each site could not be clearly isolated as
there was no control for chewing when smoking characteristics
were examined and vice versa.

Intra-oral smoking with the lighted end of a cigar or cigarette
inside the mouth is a custom found in parts of the Caribbean, South
America, India, and the Island of Sardinia. Morrow and Suarez

69


($3') examined 79 intra-oral smokers, most of whom had sought
medical attention for reasons other than symptoms associated with
smoking-related diseases. All but one patient demonstrated "nice.
tinic stomatitis" characterized by hyperplasia, acanthosis, hyper.
keratosis, and parakeratosis. Sixteen cases of squamous cell carci-
noma were found. These were located predominantly at the base of
the tongue, tonsillar fauces, and adjacent pharyngeal mucosa.

30

25

Old

CHEWING ONLY

I   SMOKING ONLY
El   CHEWING AND
      SMOKING

"X    Hypcmharynx      Larynx      Oesophagus

FIGWE 4.-Relative risk of cancer of the oral cavity, pharynx, larynx, and
esophagus associated with smoking and chewing in various forms.
SOURCE: Jussawalla, D. J., Deshpande, V. A. (15).

The oral mucosa of many experimental animals appears to be
resistant to the induction of cancers. Cohen, et al. (4) failed to pro-
duce any distinctive cancerous or precancerous changes in the
mucosal lining of surgically created buccal pouches of monkeys filled
with chewing tobacco for varying lengths of time. Homburger (1.2)
exposed the oral mucosa of Syrian golden hamsters to snuff and
7,12-Dimethylbenz (a) anthracene (DMBA) using a bit inserted-in
the mouth. Snuff alone failed to produce any changes that were not
also seen in the control animals who had a plain cotton plug inserted
in the mouth. Benzo (a) pyrene and DMBA caused a few carcinomas
of the oral mucosa, but they produced a much higher number of
cancers outside the mouth where the carcinogenic agents had spilled
onto the perioral skin. The authors observed that ". . . skin-painting
experiments are more sensitive indicators of carcinogenicity for the
oral mucosa than applications to the mucosa itself."

70


CANCER OF THE ESOPHAGUS

Cancer of the esophagus is associated with both tobacco and al-
cohol consumption.

In the prospective study from Japan, Hirayama (10) found no
significant association between the use of cigarettes or alcohol alone
and cancer of the esophagus, but there were high rates of esopha-
geal cancer among individuals using both cigarettes and alcohol
(figure 5).

30

0

Drinking
Daily

Smoking
Daily
Observed
Person-years

7.6
4

        5.1
4.2
Q-47
               0

- I-      +

22.5
-

-

+

27.9
-

+

1

,

-      +      ++       -      +      ++

66,080        59,062        48,799
     95,073        19,422        43,025

FWJRE S.-Death rates for cancer of the esophagus in Japanese males by smok-
ing and drinking characteristics.
SOURCE : Hirayama, T. (10).

Schoenberg, et al. (31) , using cohort analysis, examined mortal-
ity from esophageal cancer in the United States. Substantial ethnic,
geographic, and temporal variations were observed. On a state-by-
Jbte basis, mortality from esophageal cancer was correlated about
eWally with urbanization, per capita cigarette sales, and per capita

71


alcohol sales. The correlation with urbanization was partially ex.
plained by increased sales of tobacco and alcohol in urban areas.

CANCER OF THE URINARY BLADDER

In a retrospective study of 470 confirmed cases of transitional
cell or squamous cell cancers of the bladder, Cole, et al. (5) found a
consistent positive relationship between cigarette smoking and
bladder cancer. The relative risk and standard error for the devel.
opment of bladder cancer were 1.89 * 0.22 for male smokers and
2.00 t 0.33 for female smokers. A dose-response relationship was
demonstrated for both the number of cigarettes smoked per day
(figures 6 and 7) and various degrees of inhalation. Bladder cancer
has been shown to be associated with certain occupational categories
such as dye workers, certain textile workers, tailors, and nurses
(2, 14). Cole standardized the data with respect to occupation and
found that the risk demonstrated could not be explained by any in-
direct association with industrial exposure. Cole concluded : "Thh

     Observed

    Expected

Number of cigarettes
smoked per day

  70       36       140       85

109.5     54.6      109.1      61.4

Nonsmoker    1-9      1 o-29     30-49


        MALES

FIGURE 6.-Relative risk of urinary bladder cancer for males by amount smoked.
SOURCE: Cole, P., et al. (5).

72


           Observed

         Expected

Number of cigarettes smoked
    per day

50       13       30       12

68.2      11.7      20.8      4.3


Noosmelcer    x-l      1 o-29     30-49
       FEMALES

FIGURE `I.-Relative risk of urinary bladder cancer for females by amount
smoked.

SOURCE: Cole, P., et al. (5).

present findings indicate that about 35 percent of cases of cancer of
the lower urinary tract in the study population are associated with
cigarette smoking. If this association is accepted as causal, and if it
is generalized to the entire population of the United States, smoking
is associated with about 3,100 deaths per year from cancer of the
lower urinary tract." No significant association was found between
pipe or cigar smoking and bladder cancer.

Tyrrell, et al. (38) examined several factors including smoking
history and occupation in a group of 250 patients treated for uri-
nary bladder cancer in Ireland. No significant association between
occupation and bladder cancer was found. This may have been due
to the low concentration of high-risk industries for this cancer in
Ireland. A significant (P < 0.005) association was found in males
between cigarette smoking and cancer of the urinary bladder, but

73


no significant association was found for the 50 cases of bladder
cancer in females.

In an extensive review of cancer of the urinary tract, Clayson
and Cooper (3) included data that demonstrated an association be-
tween cigarette smoking and excessive mortality from bladder
cancer.

CANCER OF THE PANCREAS

Cancer of the pancreas was responsible for 9,696 deaths among
men and 7,190 deaths among women in the United States in 1967
(4Q). The United States age-adjusted mortality rate for carcinoma
of the pancreas has risen from 2.9 to 8.2 per 100,000 from 1920 to
1965 (27).

In the prospective Japanese study by Hirayama (IO), the pre-
liminary data showed a pancreatic cancer mortality ratio of 2.7
for male smokers and a mortality ratio of 3.0 for female smokers.
In an epidemiologic appraisal of cancer of the pancreas, Krain
(17') found that cigarette smoking and industrial exposure were
more strongly associated with this disease than either air pollution
or genetic factors.

HIGHLIGHTS OF CURRENT CANCER INFORMATION

In addition to the comprehensive summary from the 1971 report,
"The Health Consequences of Smoking" (39)) cited earlier in this
chapter, the following statements are made to emphasize the most
recent developments in the field :

1.

Preliminary results from a major prospective epidemiologi-
cal study in Japan demonstrate a strong association between
cigarette smoking and lung cancer. A dose-response relation-
ship was demonstrated for the number of cigarettes smoked.
These findings in an Asian population with distinct genetic
and cultural characteristics confirm the major importance of
cigarette smoking in the causation of lung cancer, a conclu-
sion which up to now has been based largely on studies of
Caucasian populations in the United States, Canada, and
Europe.

2. Ex-smokers have significantly lower death rates for lung can-
cer than continuing smokers. The decline in risk following
cessation appears to be rapid both for those who have smoked
for long periods of time and for those with a shorter smoking

74


3.

4.

5.

6.

7.

history, with the sharpest reductions taking place after the
first two years of cessation.

The risk of developing lung cancer appears to be higher for
smokers who have chronic bronchitis. Though both conditions
are directly related to the amount and duration of smoking, an
additional risk for lung cancer appears to exist for cigarette
smokers with chronic bronchitis which is independent of age
and number of cigarettes consumed.

Experimental studies on animals have demonstrated that the
particulate phase of tobacco smoke contains certain chemical
compounds which can act as complete carcinogens, tumor ini-
tiators, or tumor promoters. Recently, other compounds have
been described that have no independent activity in two-stage
carcinogenesis but accelerate the carcinogenic effects of poly-
nuclear aromatic hydrocarbons in the initiator-promoter
system.

Additional epidemiological evidence confirms a significant as-
sociation between the combined use of cigarettes and alcohol,
and cancer of the esophagus.

Epidemiological studies have demonstrated a significant asso-
ciation between cigarette smoking and cancer of the urinary
bladder in both men and women. These studies demonstrate
that the risk of developing bladder cancer increases with in-
halation and the number of cigarettes smoked.

Epidemiological evidence demonstrates a significant associa-
tion between cigarette smoking and cancer of the pancreas.

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   mice. Gann; Japanese Journal of Cancer Research 61(3) : 297-298,
    June 1970.

(37) TIBBLIN, G., WILHELMSEN, L. Rokningen som riskfaktor. (Smoking as
   a risk factor.) Lakartidningen 68(7) : 687-689, February 10, 1971.
(38) TYRRELL, A. B., MACAIRT, J. G., MCCAUGHEY, W. T. E. Occupational
   and non-occupational factors associated with vesical neoplasm in Ire-
   land. Journal of the Irish Medical Association 64(410) : 213-217,
   April 22, 1971.

(39) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking.
  A Report of the Surgeon General: 1971. Washington, U.S. Depart-
   ment of Health, Education, and Welfare, DHEW Publication No.
   (HSM) 71-7513, 1971. 458 pp.

(40) U.S. PUBLIC HEALTH SERVICE. NATIONAL CENTER FOR HEALTH STATIS-
   TICS. Vital Statistics of the United States-1967. Vol. II-Mortality,

77


   Part A. Washington, U.S. Department of Health, Education, and WeI.
   fare, Public Health Service Publication, 1969.
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   CHIONNE, S. Initiating activity of aromatic hydrocarbons in two-stage
   carcinogenesis. Journal of the National Cancer Institute 44 (5) : 1167-
   1173, May 1970.

(4.2) VAN DUUREN, B. L., SIVAK, A., KATZ, C., MELCHIONNE, S. Cigarette
   smoke carcinogenesis : Importance of tumor promoters. Journal of the
   National Cancer Institute 47 (1) : 235-240, July 1971.
(43) WYNDER, E. L. Etiological aspects of squamous cancers of the head
   and neck. Journal of the American Medical Association 215(3) : 452-
   453, January 18, 1971.

(44) WYNDER, E. L., HOFFMANN, D. The epidermis and the respiratory tract
   as bioassay systems in tobacco carcinogenesis. British Journal of
   Cancer 24 (3) : 574-587, September 1970.

78


CHAPTER 5


                   Pregnancy


Contents

Page

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    83

Effect on Birth Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    83

Effect on the Outcome of Pregnancy . . . . . . . . . . . . . . . . . . . .    83

Congenital Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . .    87

Cancer in Children Born to Smoking Mothers . . . . , . . , . . .    8'7
Long-Term Effects on Children Born to Smoking Mothers . .    88

Experimental Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    88
Summary  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    89

References  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    89

LIST OF TABLES

Table l.-Frequency of abortion and cigarette consumption    85

81


INTRODUCTION

The 1971 report, "The Health Consequences of Smoking" (23))
summarized the relationship between smoking and pregnancy as
follows :

Maternal smoking during pregnancy exerts a retarding in-
fluence on fetal growth as manifested by decreased infant
birth weight and an increased incidence of prematurity, de-
fined by weight alone. There is strong evidence to support the
view that smoking mothers have a significantly greater num-
ber of unsuccessful pregnancies due to stillbirth and neonatal
death as compared to nonsmoking mothers. There is insuf-
ficient evidence to support a comparable statement for abor-
tions. 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.

New epidemiological, experimental, and pathologic studies lend
support to the foregoing statements.

EFFECT ON BIRTH WEIGHT

Analysis of data from more than 100,000 births has shown that
infants of mothers who smoke during pregnancy have a mean birth
weight of 6.1 ounces (173 grams) less than infants born to non-
smoking mothers (29). Several recent studies confirm this relation-
ship (1,2,6, 7,10,13,15,18,25).

EFFECT ON THE OUTCOME OF PREGNANCY

New studies have been published concerning the effect of maternal
smoking on the outcome of pregnancy.
Kullander and Kallen (IS) performed a prospective study in
Sweden involving 6,363 pregnant women. These women completed
several questionnaires during the course of their pregnancy, and
in this manner specific information was obtained on smoking habits
for the entire pregnancy. Forty-four percent of the women smoked
cigarettes during pregnancy and 97 percent of these smoked during
the whole pregnancy.

83


Stillbirths, neonatal deaths, and deaths occurring before one year
of age were recorded to determine a "total death risk." This risk
was approximately 60 percent higher for children born to smoking
mothers as compared to those born to nonsmoking mothers.

Deaths occurring before one week of age and also deaths taking
place between the age of one week and one year were significantly
more frequent in children born to smoking mothers. Among children
dying before one week of age, significantly more cases of abruptio
placentae were found in smoking mothers than in nonsmoking
mothers. The higher level of neonatal mortality in children born to
smoking mothers was confined to those weighing more than 2,500
grams. Live-born infants weighing less than 2,500 grams had
equally high neonatal mortality rates whether they were born to
smoking or nonsmoking mothers. The stillbirth rate was greater in
smoking mothers than in nonsmoking mothers, but the difference
was not statistically significant.

An overall increased risk of spontaneous abortion among smoking
women was found, but this was primarily due to an association be
tween unwanted pregnancy and smoking. The authors found that
significantly (P < .OOl) more women with unwanted pregnancies
were smokers than women with wanted pregnancies; in addition,
spontaneous abortions were significantly (P < .OOl) more frequent
among women with unwanted pregnancies than among women with
wanted pregnancies. When correction was made for the mothers'
acceptance of pregnancy, the contribution of maternal smoking to
spontaneous abortion was of only borderline significance.

Also in the Kullander and Kallen study (13)) a decreased fre-
quency of preeclampsia among smoking mothers was noted. Mater-
nal smoking had no effect on the mean Apgar score of surviving,
non-malformed children.

A prospective study from Sweden of abortions in 4,312 pregnan-
cies was reported by Palmgren and Wallander (17). Only those
women who smoked throughout pregnancy were considered smokers.
The lowest abortion rate was found among nonsmokers, 7.8 percent,
while the highest rate was found among heavy smokers, 14.5 per-
cent (table 1). The difference is statistically significant (P < .OOl) .
Heavier smokers appeared to abort earlier in pregnancy. A history
of previous abortion was obtained twice as often in heavy smokers
as in nonsmokers.

Yerushalmy reported in 1964 on pregnancies occurring in women
participating in the Kaiser Health Plan of the San Francisco-Oak-
land area (24). The 1971 report, "The Health Consequences of
Smoking" (23), commented in detail on that report. Recently,
Yerushalmy published data on 13,083 pregnancies occurring in this
plan between 1960 and 1967, which included the 6,800 cases pre-
viously reported. (24, 25).

84


TABLE L-Frequency of abortion and cigarette consumption.

Result
of the
pregnancy

Nonsmokers     510 cigarettes    >lO cigarettes       Total

Abortion          177          148          60         385
               7.8%        9.1%       14.5%       8.9%
Delivery        2,087       1,486         354       3,927
             92.2%       90.9%       85.5%       91.1%

Total          2,264       1,634         414       4,312

SOURCE: Palmgren. B., Wallander. B. (17)

As in the 1964 study, he again found an increase in the incidence
of low birth weight infants (less than 2,500 grams) among smoking
mothers. These small infants had a significantly lower neonatal
mortality rate and fewer congenital anomalies than the small in-
fants born to nonsmoking mothers. The neonatal mortality rate for
single, live-born infants born to white, smoking mothers was
11.3/1000, while that for single, live-born infants born to white,
nonsmoking mothers was ll.O/lOOO; the difference is not signifi-
cant.

Taylor analyzed Yerushalmy's data for the probability of fetal
death and found no difference between smoking and nonsmoking
mothers (22).

Some of these findings are different from those reported in the
other recent, large-scale prospective studies (5, 13, 17, 19)) and
some of the differences may be a consequence of the definition of
"smoker" used. In the study of Kullander and KBllen (13), multiple
interviews were performed during pregnancy which allowed more
precise separation of the pregnant women into smokers and non-
smokers. In the study reported by Palmgren and Wallander (17))
only those women who smoked throughout pregnancy were con-
sidered smokers. The British Perinatal Mortality Study (5)) which
was discussed in the 1971 report, "The Health Consequences of
Smoking" (El), defined "smokers" as those women who smoked
regularly after the fourth month of pregnancy. The smoking history
was obtained shortly after delivery of the infant.

In contrast, Yerushalmy (25) defined "smokers" as women who
were smoking one or more cigarettes a day during the pregnancy,
and "nonsmokers" as women who never smoked and those who
stopped smoking either before or during the pregnancy. Because
the smoking history was obtained only once, usually early in preg-
nancy, some of the women who were classified as smokers could
have gone through a significant portion of their pregnancy as non-
smokers, and similarly some of the women who were classified as


nonsmokers could have gone through a significant portion of their
pregnancy as smokers. If smoking by pregnant women increases the
risk of an unsuccessful pregnancy, an imprecise separation of preg-
nant women into smokers and nonsmokers would tend to diminish
the magnitude of any differences found. One Swedish study (13)
and the British Perinatal Mortality Study (5) seemed to be at vari-
ance in statements about the frequency with which smoking habits
vary from one portion of the pregnancy to another. If this is a cul-
turally determined phenomenon, there is no way of estimating the
extent to which it applies to the patients participating in the Kaiser
Health Plan described by Yerushalmy.
MacMahon, et al. (14) commented on Yerushalmy's analysis of
mortality rates in low birth weight infants. They observed that
there are ". . . factors that affect birth weight without influencing
mortality ; for example, females have lower birth weights than
males but not the higher mortalities that might be predicted for
them on that account. If cigarette smoking is another such factor,
the explanation of the higher weight-specific mortalities for non-
smokers becomes immediately clear : it is an artifact of the analysis.
It is meaningful to compare category-specific rates only when the
specification of the category has the same implication for each of
the populations compared."
Perinatal mortality rates were similar in infants born to smoking
and nonsmoking mothers in a recent prospective investigation of
1,300 pregnancies from New Zealand (1) . Women were classified
as smokers or nonsmokers during their first `booking" at an ante-
natal clinic, and this was not later amended. This method of classi-
fication is similar to that used in the Yerushalmy study.
Comstock, et al. (6, 7) have reported in 1967 and 1971 on the
relationship of maternal smoking to the outcome of pregnancy. In
their studies, all perinatal deaths and samples of live births occur-
ring during a lo-year period among children whose mothers were
residents of Washington County, Maryland, were matched against
the records of a special census based on a household interview taken
in 1963. Maternal smokers were defined as women who were smok-
ing in 1963 and who had started to smoke prior to the pregnancy in
question; maternal nonsmokers were women who denied ever hav-
ing smoked. When this study is compared to previously cited studies
(5, 13, 17')) the data on the smoking status of the mothers during
pregnancy are imprecise, which limits their value.
In the 1967 study (6), maternal smoking was associated with an
increased risk of mortality for the child, both in the neonatal period
and for several years thereafter; however, this effect was thought
to be related to factors such as adequacy of prenatal or postnatal
environment and care, rather than a direct effect of maternal smok-
ing. Stillbirth rates were similar for smokers and nonsmokers.


The more recently published study (7) includes a 32 percent
sample of live-born, low birth weight infants and a 3 percent sam-
ple of live-born, larger infants born during the lo-year period pre-
ceding the census. The total births represented by these samples
were 4,641 to smokers and 7,646 to nonsmokers. The neonatal mor-
tality rate, when adjusted for environmental and socioeconomic
factors, was approximately one-third higher among infants born to
smoking mothers than among those born to nonsmoking mothers
(7). The categories of asphyxia, atelectasis, and immaturity ac-
counted for the greater neonatal mortality among infants born to
smoking mothers as compared to those born to nonsmoking mothers
(7) *

CONGENITAL MALFORMATIONS

As noted in the 1971 report, "The Health Consequences of Smok-
ing" (zS), the possible teratogenic effect of maternal smoking has
not been adequately evaluated. Additional studies have been pub-
lished in the interim, but rather than investigating congenital mal-
formations in both stillborn and live-born infants, most of the recent
studies have dealt only with live-born infants.
Fedrick, et al. (8) analyzed data from the large British Perinatal
Mortality Study for the incidence of congenital heart disease in still-
born and live-born infants of smoking and nonsmoking mothers. An
incidence of 7.3/1000 births was found in infants born to smoking
mothers as compared to 4.`7/1000 births for infants born to non-
smoking mothers, a statistically significant difference (P < .OOl ) .
Kullander and Killen (IS) noted no teratogenic effect of maternal
smoking in children dying before one year of age or in children
surviving one year of age. However, they observed that published
studies have been too small to exclude this possibility.
In a study of perinatal death occurring in infants weighing more
than 1,000 grams, Bailey (1) found that maternal smoking did not
lead to an increased incidence of congenital anomalies.
Yerushalmy (25) reported only on live-born infants weighing
less than 2,500 grams and found significantly fewer (P < .02)
anomalies among infants born to smoking mothers.
Comstock, et al. (7) found fewer than the expected number of
Congenital anomalies among live-born infants of smoking mothers.

CANCER IN CHILDREN BORN TO SMOKING MOTHERS

Neutel and Buck (16) studied the relationship between maternal
Smoking during pregnancy and the development of cancer in the off-
spring. The ba+se population was obtained from the British and
Ontario Perinatal Studies and consisted of 89,302 babies who sur-

87


vived at least seven days. There were 65 cancer deaths and 32 can.
cer survivors in the period from birth to a minimum of 7 and a
maximum of 10 years of age. For cancer of all sites, the children
of smokers had a relative risk of 1.3. The authors concluded: "Al.
though these results make it most unlikely that in utero exposure to
tobacco smoke has a broadly carcinogenic effect on the fetus, a re-
sponse confined to one tissue or expressed over a narrow age range
cannot be ruled out."

LONG-TERM EFFECTS ON CHILDREN BORN TO
        SMOKING MOTHERS

Goldstein (9) analyzed data from the British Perinatal Mortality
Study to determine factors influencing the height of 7-year-old
children. In the 1958 study, information was collected on 16,994
singleton births. In 1965, heights were measured "to the nearest
inch" on 13,127 of these children who could be followed up. The dab
were analyzed for the influence of parity, birth weight, length of
gestation, maternal age, maternal height, social class, number of
younger siblings, and maternal smoking habits during pregnancy.
Allowance was made for the sex and age of the child at the time of
measurement. The author's conclusions included the following:
"After allowing for the other variables, the children of mothers who
smoked 10 or more cigarettes a day after the 4th month of preg-
nancy, are on average about 1.0 cm shorter at age seven than the
children of mothers who did not smoke."

EXPERIMENTAL STUDIES

Becker and Martin (3) continued their experiments concerning
the effect of nicotine on pregnant rats. Offspring of rats given nico-
tine weighed significantly less at birth than saline-injected controls.
There were fewer live births among the nicotine-injected rats.

Kelly and Roy (12)) using cinephotomicrography, demonstrated
that nicotine crosses the mouse placental barrier in amounts ade-
quate to produce a measurable cardiovascular response.

Stalhandske, et al. (21) studied the in vitro metabolism of nico-
tine in livers of fetal, young, and adult mice. Cotinine was found to
be the major metabolite at all ages investigated.

Using radioactive compounds, Sieber and Fabro (20) identified a
variety of drugs in the preimplantation blastocyst and in uterine
secretions of pregnant rabbits. In animals receiving dose levels of
nicotine comparable to that encountered in man, significant amounts
of radioactivity were found in the preimplantation blastocyet. A
markedly higher concentration of radioactivity was observed in
uterine secretion than in maternal plasma.


Juchau (11) studied the levels of benzpyrene hydroxylase in the
placentas of smoking and nonsmoking women obtained both early in
pregnancy and at term. This enzyme hydroxylates benzo (a) pyrene,
a carcinogenic hydrocarbon found in tobacco smoke. Previous stud-
ies had shown that placentas, obtained at term from smoking
women, have a greater ability to hydroxylate benzo (a) pyrene than
the placentas from nonsmokers (23). Juchau corroborated this, but
also found very low levels in placental tissues obtained from healthy
smokers during first trimester dilatation and curettage or hystero-
tomy for therapeutic abortion. This lack of significant placental
drug metabolizing activity during the first trimester was in-
terpreted as a possible hazard to the fetus, particularly if the sub-
stance were active in the unmetabolized form. Enzyme levels were
undetectable in placental homogenates of nonsmokers at 8 to 16
weeks gestation.

The carcinogenic effect on the newborn of rats receiving benzo-
(a) pyrene during the latter half of pregnancy was studied by Bulay
and Wattenberg (4). An increased incidence of pulmonary adenoma
and skin papilloma was observed.

SUMMARY

Maternal smoking during pregnancy exerts a retarding influence
on fetal growth as manifested by decreased infant birth weight and
an increased incidence of prematurity, defined by weight. There is
increasing evidence to support the view that women who smoke
during pregnancy have a significantly greater risk of an unsuccess-
ful pregnancy than those who do not.

PREGNANCY REFERENCES

(1) BAILEY, R. R. The effect of maternal smoking on the infant birth
   weight. New Zealand Medical Journal 71(456) : 293-294, May 1970.
(2) BEAL, V. A. Nutritional studies during pregnancy. Journal of the Amer-
   ican Dietetic Association 58(4) : 321-326, April 1971.
(3) BECKER, R. F., MARTIN, J. C. Vital effects of chronic nicotine absorption
   and chronic hypoxic stress during pregnancy and the nursing period.
   American Journal of Obstetrics and Gynecology llO(4) : 522-533,
   June 15, 1971.

(4) BULAY, 0. M., WATTENBERC, L. W. Carcinogenic effects of subcutaneous
   administration of benzo(a)pyrene during pregnancy on the progeny.
   Proceedings of the Society for Experimental Biology and Medicine
  135(l) : 84-86, October 1970.

(5) BUTLER, N. R., ALBERMAN, E. D. (Editors). Perinatal Problems. The
   Second Report of the 1958 British Perinatal Mortality Survey. London,
   E. and S. Livingstone Limited, 1969. 395 pp.
(6) COMSTOCK, G. W., LUNDIN, F. E., JR. Parental smoking and perinatal
   mortality. American Journal of Obstetrics and Gynecology 98 (5) :
   708-718, July 1, 1967.

09


(7) COMSTOCK, G. W., SHAH, F. K., MEYER, M. B., ABBEY, H. Low birth
    weight and neonatal mortality rate related to maternal smoking and
   socioeconomic status. American Journal of Obstetrics and Gynecology
    111(l) : 53-59, September 1, 1971.
(8) FEDRICK, J., ALBERMAN, E. D., GOLDSTEIN, H. Possible teratogenic ef-
    fect of cigarette smoking. Nature 231: 529-530, June 25, 1971.
(9) GOLDSTEIN, H. Factors influencing the height of seven year old children
    -results from the National Child Development Study. Human Biol-
    ogy 43: 92-111, February 1971.
(10) GOUJARD, J., ETIENNE, C., EVRARD, F. Caracteristiques matemelles et
    poids de naissance. (Maternal characteristics and birth weight.)
    Revue du Praticien 19(28, Supplement) : 54, 59-62, 65, November 1,
     1969.
(11) JUCHAU, M. R. Human placental hydroxylation of 3,Pbenxpyrene duri
    ing early gestation and at term. Toxicology and Applied Pharmacology
    lS(3) : 665-675, March 1971.
(12) KELLY, M., ROY, F. H. Microcirculatory response of fetal mice to ma-
    ternal nicotine. (Abstract.) Clinical Research 19( 2) : 322, April 1971.
(13) KULLANDER, S., KLLLEN, B. A prospective study of smoking and preg-
    nancy. Acta Obstetricia et Gynecologica Scandinavica 50(l) : 8%94,
      1971.
(14) MACMAHON, B., ALPERT, M., SALBER, E. J. Infant weight and parental
    smoking habits. American Journal of Epidemiology 82(3) : 247-261,
      November 1965.
(15) MURPHY, J. F., MULCAHY, R. The effect of age, parity, and cigarette
    smoking on baby weight. American Journal of Obstetrics and Gyne-
    cology 111(l) : 22-25, September 1, 1971.
(16) NEUTEL, C. I., BUCK, C. Effect of smoking during pregnancy on the risk
    of cancer in children. Journal of the National Cancer Institute 47 (1) :
    59-63, July 1971.
(17) PALMGREN, B., WALLANDER, B. Cigarettriikning oeh abort. Konsekutiv
    prospektiv undersokning av 4312 graviditeter. (Cigarette smoking and
    abortion. Consecutive prospective study of 4312 pregnancies)
    Llkarrtidningen 60 (22) : 2611-2616,197l.
(18) PETTERSSON, F. Medicinska skadeverkningar av tikning. Rijkning och
    gynekologisk-obstetriska tillstand. (Harmful clinical effects of smok-
    ing. Smoking and gynecological-obstetrical condition.) Social-Medi-
    cinsk Tidskrift Z(Special No.) : 78-82, February 1971.
(19) RUSSELL, C. S., TAYLOR, R., LAW, C. E. Smoking in pregnancy, maternal
    blood pressure, pregnancy outcome, baby weight and growth, and
    other related factors. A prospective study. British Journal of Pre-
    ventive and Social Medicine 22(3) : 119-126, July 1968.
(20) SIEBFX, S. M., FABRO, S. Identification of drugs in the preimplantation
    blastocyst and in the plasma, uterine secretion and urine of the preg-
    nant rabbit. Journal of Pharmacology and Experimental Therapeutics
    176 (1) : 65-75,197l.
(2.2 ) STALHANDSKE, T., SL~~NINA, P., TJALVE, H., HANSSON, E., SCHMITERL~W,
    C. G. Metabolism in vitro of 14C-nicotine in livers of foetal, newborn
   and young mice. Acta Pharmacologica et Toxicologica 27(5) : 363-
     380,1969.
(22) TAYLOR, W. F. The probability of fetal death. IN: Fraser, F. C.,
    McKusick, V. A. (Editors). Congenital Malformations. Proceedings
    of the Third International Conference, The Hague, The Netherlands,
   September 7-13, 1969. New York, Excerpta Medica, August 1970.
    pp. 307-320.


90


(28) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking.
   A Report of the Surgeon General: 1971. Washington, U.S. Departr
   ment of Health, Education, and Welfare, DHEW Publication No.
   (HSM) 71-7513, 1971. 458 pp.

(Z4) YEBUSHALMY, J. Mothers' cigarette smoking and survival of infant.
   American Journal of Obstetrics and Gynecology 88 (4) : 505-518,
    February 15, 1964.

(25) YERUSRALMY, J. The relationship of parents' cigarette smoking to out-
   come of pregnancy-implications as to the problem of inferring causa-
   tion from observed associations. American Journal of Epidemiology
   93(6) : 443-456, June 1971.

91


CHAPTER 6


           Gastrointestinal Disorders


Contents

Page

Highlights of Current Gastrointestinal Information . . . . . . .    98
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    98

95


GASTROINTESTINAL DISORDERS

The 1971 report, "The Health Consequences of Smoking" (4),
summarized the relationship between smoking and peptic ulcer as
follows :

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.

Studies of the effect of smoking on gastric secretion in patients
with peptic ulcer and normal controls have produced conflicting re-
ports (4). Recently, Wilkinson and Johnston (5) reported a sig-
nificant inhibition of pentagastrin-stimulated gastric acid secretion
after cigarette smoking by normal volunteers, while Debas, et al.
(1) found no significant overall change. Wilkinson and Johnston also
studied patients with gastric and duodenal ulcers in whom a sig-
nificant inhibition of pentagastrin-stimulated gastric secretion was
observed after the patients smoked one or two cigarettes over a
Period of 10 to 15 minutes.
A study by Konturek, et al. (3) suggests that alterations in
pancreatic and biliary secretion may be responsible for the relation-
ship between smoking and peptic ulcer. Nicotine was infused in
mongrel dogs in doses corresponding to amounts absorbed from
smoking up to four cigarettes in one hour. In the pancreas, nicotine
inhibited the secretin-stimulated secretion of both fluid and bi-
carbonate, and the degree of inhibition was dose-related. Spontane-
OUs biliary secretion of bicarbonate was also depressed by the drug.
Nicotine had no effect on gastric secretion of acid, gastric mucosal
blood flow, or the mucosal barrier to hydrogen or sodium ions. This
inhibition of pancreatic and hepatic bicarbonate secretion may de-
prive the duodenum of sufficient alkaline secretion to neutralize gas-
tric acidity and may be one biomechanism linking cigarette smoking
and peptic ulcer.
Dennish and Caste11 (2) noted the clinical association between
cigarette smoking and heartburn. To investigate the biomechanism
of this relationship, lower-esophageal sphincter pressure determi-
nations were made before and after smoking in six normal male
volunteers. All of the volunteers were cigarette smokers. In each

97


subject after the onset of cigarette smoking, there was a rapid d+
crease in lower-esophageal sphincter pressure from the basal level.
This diminution in sphincter pressure persisted until smoking was
stopped, at which time the pressure returned rapidly toward nor.
mal. Mean basal pressure was 19.6 -C 2.1 (C 1 S.E.) mmHg. and
mean pressure during smoking was 11.4 2 2.2 mmHg. The differ.
ence between these pressures is statistically significant (P < .OOl),
No changes were noted when volunteers puffed on unlit cigarettes.
Variable responses were noted when volunteers smoked cigars and
pipes. The investigators concluded that cigarette smoking decrease
the effectiveness of the lower-esophageal sphincter as a barrier
against gastroesophageal reflux.

HIGHLIGHTS OF CURRENT GASTROINTESTINAL
           INFORMATION

In addition to the summary statement cited at the beginning of
this section, the following observations have been made:

1. A possible link between cigarette smoking and peptic ulcer has
been demonstrated in dogs in which nicotine was found to in-
hibit pancreatic and hepatic bicarbonate secretion. This
could lead to peptic disease by depriving the duodenum of suf-
ficient alkaline secretion to neutralize gastric acidity.

2. An investigation in human volunteers has suggested that
cigarette smoking decreases the effectiveness of the lower-
esophageal sphincter as a barrier against gastroesophageal
  reflux.

GASTROINTESTINAL DISORDERS REFERENCES

(1) DEBAS, H. T., COHEN, M. M., HOLUBITSKY, I. B., HARMKIN, R. C. Effect
   of cigarette smoking on human gastric secretory responses. Journal
   of the British Society of Gastroenterology 12: 93-96, 1971.
(2) DFNNISH, G. W., CASTELL, D. 0. Inhibitory effect of smoking on the
   lower esophagea! sphincter. New England Journal of Medicine
   284(20) : 1136-1137, May 20, 1971.

(9) KONTUREK, S. J., SOLOMON, T. E., MCCREICHT, W. G., JOHNSON, L. R.,
   JACOBSON, E. D. Effects of nicotine on gastrointestinal secretions.
   Gastroenterology 60 (6) : 1098-1105, June 1971.
(4) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking.
   A Report of the Surgeon General: 1971. Washington, U.S. Depart-
   ment of Health, Education, and Welfare, DHEW Publication No.
   (HSM) 71-7513, 1971. 458 pp.

(5) WILKINSON, A. R., JOHNSTON, D. Inhibitory effect of cigarette smoking
  on gastric secretion stimulated by pentagastrin in man. Lancet
  Z(`7725) : 628-632, September 18, 1971.

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CHAPTER 7

Allergy


Introduction  ........................................
Antigenic Properties  ................................
Skin Testing  .......................................
Additional Immunological Effects  .....................
Effect on the Immune Response   .......................
Irritant and Pharmacologic Effects  ....................
Clinical Allergy  ....................................
Summary  ..........................................
References  ......................  ..................

Page
103

104

105

107

108

109

110

111

112

101


INTRODUCTION

As early as 1886 reference was made to an entity called "tobacco
asthma" (64). Subsequently, controversy has arisen over whether
tobacco smoking causes clinical allergy (61) and whether such
tobacco allergy is associated with the major smoking-related dis-
eases (25, 69).

In 1957, Silvette, et al. (64) reviewed more than 100 papers con-
cerned with "the immunological aspects of tobacco and smoking."
They concluded that inadequate animal studies had been performed
in this area. Referring to clinical studies, they observed : ". . . virtu-
ally all reported clinical investigation has been limited to determi-
nations of cutaneous sensitivity to tobacco extracts; and it must be
regretfully admitted that much of this published work is equivocal,
uncritical, and inadequately controlled."
Such criticism is also applicable to many studies published since
then.

Epidemiologic studies designed to determine the prevalence of
tobacco allergy have not been carried out; hence, it is difficult to
evaluate the magnitude of the problem.
Allergy may be defined as a specific alteration in response medi-
ated by an antigen-antibody reaction. When a hereditary suscepti-
bility to allergic illness is present, the term atopy is used. For ex-
ample, hay fever and asthma are atopic diseases.
There is no single test or observation which can be used to de-
termine whether a substance may be responsible for allergic dis-
ease; however, fulfillment of the following criteria constitutes evi-
dence for such a relationship :

1. Demonstration that the substance is antigenic, i.e., capable of
stimulating the production of antibody and then reacting with
the antibody.

2. Demonstration that, upon exposure to the substance, signs and
symptoms simulating an allergic reaction are elicited which
disappear upon its removal.

3. Demonstration that the immunologic event is related to the
  clinical event.

Recent advances in the understanding of immunological reactions
as well as in the methodology of immunology are now being applied

103


to problems of clinical allergy. For example, Ishizaka (37)) using
radioimmunoelectrophoresis, recently reported that the so-called
"allergic antibody" (reagin, skin-sensitizing antibody (SSA),
atopic antibody) belongs to a new class of immunoglobulins, IgR,

Although the skin test remains a simple and definitive method of
demonstrating reagins in the allergic patient, there are many vari.
ables involved in this technique which must be carefully Weighed
when interpreting test results. In the area of tobacco skin testing,
such variables include: differences in antigenic content of the test
extract, differences in route of administration, and heterogeneity
of test groups.

ANTIGENIC PROPERTIES

Tobacco leaf contains a complex mixture of chemical components
including : celluloses, starches, proteins, sugars, alkaloids, pectic
substances, hydrocarbons, phenols, fatty acids, isoprenoids, sterols,
and inorganic minerals (69). Theoretically, relatively few of these
substances should be antigenic. Tobacco extracts of different compo
sition result from differences in tobacco types and species, process.
ing of tobacco, and preparation of the extract. Harkavy (26) has
shown in some patients a differential skin reactivity to extra&
from different types of tobacco. Coltoiu, et al. (9) reported that 13
different antigens capable of inducing precipitins in rabbits have
been isolated from tobacco pollen. Chu, et al. (7) prepared aqueous
extracts of five commercial tobacco products which stimulated anti-
body formation in rabbits. The antigens contained in the extracts
included both proteins and polysaccharides and had molecular
weights ranging from 20,000 to 60,000.

Silvette, et al. (64) reviewed several papers dealing with the
immunology of nicotine and concluded that nicotine was nonanti-
genie. Harkavy (25)) who performed some of the earliest studies
on the antigenicity of nicotine, could not exclude the possibility that
nicotine may act as a hapten. A hapten is a compound which, al-
though not antigenic by itself, reacts with antibody and conveys
antigenic specificity when combined with another compound.

With pyrolysis many of the tobacco constituents undergo reac-
tions involving oxidation, dehydrogenation, cracking, rearrange-
ment, and condensation (69). Many new compounds are formed.
Pipes (51) demonstrated, through exhaustion of passive transfer
reactivity in skin sites, that allergy to tobacco smoke in man is dis-
tinct from that of allergy to tobacco leaf. Tobacco smoke exhausted
reactivity in sites injected with tobacco smoke sensitized serum;
reactivity was reduced but not exhausted with tobacco extract. The
converse was true with passive transfer sites of tobacco-sensitized
serum; tobacco extracts abolished allergic reactivity whereas to-

104


bacco smoke extract produced a diminution but not total exhaustion.
He concluded that it would be useful to test human subjects for both
tobacco leaf and tobacco smoke sensitivity. Kreis, et al. (39) have
speculated that tobacco leaf antigenicity may be lost with pyrolysis.
Coltoiu, et al. (9) recently emphasized the importance of remov-
ing all irritants from test extracts. In a clinical setting, allergy to
tobacco additives such as menthol has also been suspected (47).

SKIN TESTING

Intracutaneous injection of test antigen is a widely used method
of skin testing. Patch tests have also been used in cases of suspected
contact dermatitis.

Rosen (54) has observed that skin testing does not accurately
duplicate the most common route of exposure to tobacco, i.e., tobacco
smoke inhalation. For those involved in the production of tobacco
products, inhalation of tobacco dust or direct contact with tobacco
may play important roles in sensitization (9).

The extensive literature on cutaneous sensitivity to tobacco ex-
tracts includes comparisons of the prevalence of positive skin reac-
tions in different groups, such as "normal" nonsmoking adults (17,
68) , "normal" smokers (17,33) , allergic patients (59,76), children
(41,50), tobacco workers (6,9), and patients with specific diseases,
e.g., thromboangiitis obliterans (28, 73). Harkavy reported on
tobacco skin reactions in several different groups of patients (30).
Many of the apparently discordant results in some of these reports
can be traced to failure to compare similar populations or to control
for differences in the test antigen or in the method of testing.

Sulzberger (66) studied the different types of skin reactions pro-
duced by intracutaneous injection of denicotinized tobacco extract.
Three types of positive skin responses were observed: eczematous
reactions ; immediate wheal-and-flare reactions ; and late reactions,
probably of the tuberculin type. The wheal-and-flare response has
been by far the predominant type (42).

   This immediate wheal-and-flare response is a specific immune re-
action (64) largely mediated by IgE. Patterson (48) recently pro-
posed a simplified model explaining the mechanism of action of the
skin sensitizing antibody (SSA) . "Subsequent to stimulation of the
animal by antigen, SSA are produced by cells of the lymphoid sys-
tem possibly located in the alimentary and respiratory tract. . . . The
SSA so produced are secreted in such a way that they reach the cir-

culation, where circulating cells, predominantly basophilic leuko-
cytes, are sensitized by attachment of the SSA to the cell surface.
In addition, the SSA also leave the vascular compartment and sen-
sitize mediator-releasing cells in tissues. The tissue cells are pri-
marily mast cells . . . The immediate-type allergic reaction occurs

105


when antigen is introduced into the individual sensitized by SSA,
either by transfer of antigenic molecules through the respiratory or
alimentary mucosal surf ace or by injection into the skin or vascular
system. The antigens reach the antibody on the surface of the mast
cells and initiate the intracellular events that result in mediator re-
lease from the cells." The actions of these mediators include smooth
muscle contraction, vasodilation, and increased capillary permeabil-'
ity which can produce such clinical pictures as hay fever, asthma,
and generalized anaphylaxis.

Until recently, direct skin testing and the passive transfer test
(Prausnitz-Ktistner reaction) were the only methods of studying
IgE mediated responses. In the passive transfer test, serum from
an allergic patient is injected into the skin of a normal subject.
After a suitable interval the antigen is injected into the prepared
site and adjacent normal skin. In a positive response, cutaneous
reactivity is transferred to the normal subject at the injection site.
The absence of a positive response in nearby normal skin excludes
nonspecific irritation as a cause of the response and shows that the
normal subject is not himself allergic to the antigen.
Harkavy and Witebsky (34) found and selectively absorbed
tobacco reagins in patients showing multiple sensitivities. This se-
lective absorption documented the immunologic mechanism of the
skin reaction. Passive transfer of the SSA was also reported by
Peshkin and Landay (50) and by Lima and Rocha (41). Lowell
(43) stated, "The individual possessing skin-sensitizing antibody
to the tobacco extract may be regarded as unequivocally allergic to
the extract. . . ." Despite the inability of Sulzberger and Feit (67)
to demonstrate tobacco reagins in their skin test positive patients,
several investigators have found them (.26, 50, 75).
Harkavy (23) biopsied urticarial wheals after intradermal injec-
tion of tobacco extract and found a local eosinophilia. He felt that
this helped confirm the allergic mechanism of the positive skin test.
He also biopsied the site of a delayed skin reaction to tobacco and
found an eczematous type of response.

The delayed type hypersensitivity reaction is manifested by in-
duration and erythema developing within 24 to 48 hours after injec-
tion of antigen. The absence of response in the first 6 to 8 hours
after exposure to antigen helps exclude an Arthus reaction, which is
also a slowly evolving allergic response. Serum antibodies are not
involved in the initiation of delayed type hypersensitivity; rather,
the initial step is thought to involve interaction of antigen and spec-
ialized lymphocytes (10, 11). Contact dermatitis is thought to be
very nearly a pure type, delayed hypersensitivity reaction (10,11) .

The foregoing discussion has highlighted the studies concerning
cutaneous sensitivity to tobacco extracts. Despite the complexities
and contradictions, numerous workers agree that tobacco extract

106


(leaf or smoke) is antigenic and can sensitize (2, 7, 9,18, .26,43, 50,
52, 64, 66, 76). Silvette, et al. (64) concluded, "It is, indeed, beyond
question that allergy to tobacco extracts, presumably atopic in na-
ture, is an established fact. . . ."

Lowell (43) observed that, in most instances, skin reactivity to
an extract of tobacco actually means the presence of allergy in some
degree to something in the extract. Armen and Cohen (2)) Harkavy
and Perlman (31), and Popescu, et al. (52) observed that tobacco
extract is weakly antigenic. Armen and Cohen (2) were able to
sensitize rabbits to tobacco proteins only after absorbing the pro-
tein to aluminum hydroxide, which served as an adjuvant.

Even though a positive skin test to tobacco extract may be due to
a specific allergic reaction, the interpretation of such a positive test
in a given patient or group of patients poses problems, since sen-
sitivity to a battery of antigens has been demonstrated in individ-
uals who are entirely free from allergic symptoms upon exposure
to the antigens. Rosen (54) stated that this lack of correlation be-
tween positive skin tests and clinical symptoms is greater for to-
bacco than for other antigens such as pollens, dusts, and feathers.
He and others have emphasized that the skin test has value only
when correlated with clinical evidence.

Analysis of skin test studies in nonsmokers (64) shows that ap-
proximately 15 percent of such "healthy" individuals give positive
reactions to tobacco extracts. Some studies of smokers reporting
a 30 percent or more prevalence of skin sensitivity to tobacco ex-
tract (33, 43) have considered patients with multiple sensitivities,
including that to tobacco. Atopic individuals have been noted to
have a greater prevalence of skin sensitivity to tobacco than non-
atopics (64) ; hence, in some studies an excess of atopic patients
may account for a substantial part of the elevated prevalence of
tobacco skin sensitivity reported for smokers.

Several workers have sought to use the skin test as a screening
device for indicating an unusual susceptibility to the adverse effects
of tobacco. DeCrinis, et al. (13), Fontana (l7), and Redisch (53)
have reported that patients with positive skin tests to tobacco ex-
tracts were more likely to have an adverse vascular response to
tobacco as indicated by a fall in peripheral skin temperature on
smoking. More recent studies have shown that a decrease in skin
temperature with smoking is a reproducible response to nicotine
found in "normal" individuals and does not appear to be confined
to a specific group of smokers (1,56, 70).

ADDITIONAL IMMUNOLOGICAL EFFECTS

Additional evidence is available to support the view that tobacco
induces immunologic changes in man and animals. Armen and

107


Cohen (2) , Chu, et al. (7)) Harkavy and Perlman (31)) and Zuss-
man (76) induced precipitin formation in animals sensitized to
tobacco extract. Kreis, et al. (39) studied precipitation reactions in
651 hospitalized patients, many of whom were suffering from tu-
berculosis or lung cancer. A precipitation reaction between the pa-
tients' sera and a commercial tobacco extract was found in 62.5 per-
cent of the patients. Chu, et al. (7)) using the same antigens as
those employed to stimulate precipitin formation in rabbits, found
serum antibodies in 40 percent of a group of smokers which precipi-
tated specificially with the tobacco antigens. Only 7 percent of a
group of nonsmokers demonstrated these antibodies.

Save1 (59) studied eight nonsmoking, allergic individuals who
developed immediate upper respiratory discomfort after being ex-
posed to cigarette smoke. As measured by the uptake of tritiated
thymidine, the lymphocytes of these individuals were stimulated by
cigarette smoke, while "normal" lymphocytes were depressed. The
author stated that the correlation of this test with specific forms of
clinical allergy remains uncertain.

Some investigators have observed abnormal laboratory test re-
sults in smokers as compared to nonsmokers, which may indicate
an allergic response in the former group. Schoen and Pizer (60) de-
scribed a smoking woman who demonstrated a striking blood eosino-
philia while smoking cigarettes. Upon cessation of smoking, the
eosinophil count returned promptly to normal levels. Resumption of
smoking was associated with a return of the eosinophilia. Heiskell,
et al. (36) found a significant increase in C-reactive protein and an
abnormal seroflocculant for ethyl choledienate in smokers as com-
pared to nonsmokers. Plasma histaminase levels were reported by
Kameswaran, et al. (38) to be elevated in smokers.

Experimental animal sensitization to tobacco was reported by
Friedlander, et al. (19) in male rats. Harkavy (29) confirmed these
results in male rats and also obtained positive Schultz-Dale reac-
tions in the sensitized animals ; however, female rats failed to dem-
onstrate this sensitization. Harkavy (24) reported cardiac histo-
logical abnormalities in three rabbits sensitized with denicotinized
tobacco extracts. The abnormalities found in the three rabbits, re-
spectively, included : intimal proliferation, focal fragmentation of
the internal elastic membrane, and loss of smooth muscle fibers in
the media of a branch of a coronary artery ; focal intimal prolifera-
tion and fibrinoid alterations in the media of a small coronary ves-
sel ; and a focus of myocardial fibrosis and necrosis.

      EFFECT ON THE IMMUNE RESPONSE

The effect of tobacco on the immune response has received some
attention. Early studies in rabbits suggested that tobacco smoke re-

108


tarded the production of agglutinins in rabbits immunized against
typhoid (14).

A variety of observations indicate that ingestion of antigenic
material by the macrophage may be an essential step in the immune
response (3). Bruni (5) found that cigarette smoke suppressed
phagocytosis in rabbits. Green and Carolin (20) performed in vitro
studies in rabbit alveolar macrophages and observed that cigarette
smoke inhibited the capacity of these cells to inactivate bacteria.
Harris, et al. (35) reported no differences in the phagocytic ability
of macrophages taken from human smokers and nonsmokers, but
he also concluded that his data neither contradicted nor supported
Green's work. Cohen and Cline (8), while noting that macrophages
from smokers had normal phagocytic capacity, demonstrated sub-
optimal macrophage function in an environment of low 0, tension,
a state found more frequently in smokers than nonsmokers. Max-
well, et al. (45)) using guinea pigs, found that smoke exerted no
effect on phagocytosis; nevertheless, smoke seemed to impair the
phagocytes' ability to inactivate bacteria. Nicotine has been shown
by Meyer, et al. (46) to exert a depressant effect on sheep pulmo-
nary alveolar macrophage respiration and ATPase activity. Re-
cently, Yeager (74) reported that water soluble constituents of
cigarette smoke depress protein-synthesis in rabbit, alveolar macro-
phages in vitro.

Lewis, et al. (40) found that cigarette smoking had a suppressive
action on secretory IgA production in normal subjects but not in
subjects with chronic respiratory disorders. Vos-Brat and Rumke
(71) recently reported that IgG serum concentrations and the rp-
sponse of lymphocytes to phytohemagglutinin were significant11
lower in smokers than nonsmokers.

A number of investigators have reported increased rates of res-
piratory illnesses among cigarette smokers (70). Finklea, ,et al.
(16) studied antibody response in 289 volunteers after the 1968
Hong Kong influenza epidemic. They reported a significant decrease
among cigarette smokers in the persistence of hemagglutination in-
hibition antibody after natural infection or vaccination with A,
antigens. They postulated that this antibody deficit among cigarette
smokers might be related to increased illness during influenza out-
breaks.

IRRITANT AND PHARMACOLOGIC EFFECTS

As Lowell (43) has emphasized, the pharmacologic. irritant, and
allergic effects of tobacco are difficult to distinguish. Acrolein and
acetaldehyde are potent irritants found in tobacco smoke, which, as
demonstrated in animal studies, are capable of releasing chemical
mediators such as histamine (58). Th,e inhalation of tobacco smoke

16


causes bronchial constriction, mucus hypersecretion, and ciliary
stasis (57) in man, all of which can contribute to a clinical picture
indistinguishable from an allergic reaction. Several authors (44,61,
63) share Sherman's (62) view that ". . . tobacco smoke is an im-
portant secondary factor in precipitating allergic symptoms
through its action as a nonspecific irritant."

Speer (65) recently compared the subjective responses of two
groups of nonsmokers to tobacco smoke exposure. One group of 191
patients suffered from documented allergies. In one-sixth of these
patients a positive skin test to tobacco extract was found, but only
a few patients were seen with objective symptoms which could be
traced to tobacco smoke. The other group of 250 patients had no
history of allergy and was studied by questionnaire only. Eye irrita-
tion, nasal symptoms, headache, and cough were common in both
groups. Speer concluded that these ,effects of tobacco smoke were
irritative rather than allergic in origin. The data presented in this
study demonstrate that tobacco smoke can contribute to the dis-
comfort of many individuals; they do not rule out a possible con-
tribution from allergic reactions.

Harkavy (30) cited experimental data distinguishing allergic
effects from pharmacologic effects of smoking such as increased
heart rate and decreased skin temperature.
Additional studies are needed to separate the pharmacologic, ir-
ritant, and allergic effects of tobacco smoke.

CLINICAL ALLERGY

It is important to understand what role tobacco and tobacco
smoke may play in clinical allergy because many individuals are
exposed to them in varying concentrations throughout the year.

A variety of conditions have been ascribed to allergic manifesta-
tions toward tobacco leaf or smoke including: asthma, rhinitis,
urticaria, angioneurotic edema (giant hives), contact dermatitis,
migraine headache, gastrointestinal symptoms, and various cardio-
vascular disturbances (64) ; however, some case reports are lacking
in documentation (4,49). A small group of patients having cutane-
ous sensitivity to tobacco and showing complete disappearance of
symptoms when free from exposure to tobacco were reported by
Rosen and Levy (55). Included in this group were cases of asthma
and urticaria.

Studies of atopic individuals have revealed a group of nonsmoking
patients with cutaneous sensitivity to tobacco who developed clinical
symptoms upon exposure to tobacco smoke (59, 76). In none of
these studies (54, 59, 76) have detailed immunologic investigations,
attempting to link clinical and immunologic events, been performed.
Lowell (43) reviewed case reports of contact dermatitis to to-

110


bacco among tobacco workers and noted that because of ". . . the small
proportion of exposed individuals who develop such lesions, and the
tendency for it to clear completely when contact with tobacco is
avoided and to return on reexposure, an allergic cause in certain
instances would appear to be highly probable." Recently, case re-
ports have appeared identifying tobacco smoke and tobacco smoke
residue as causes of contact dermatitis (6, 12, 7.2).

Harkavy's (28) early reports of a greater number of reactors to
tobacco extract among patients with thromboangiitis obliterans
(TAO) than among controls drew attention to the cardiovascular
system as a possible "susceptible" organ for allergic reactions (15).
Harkavy continues to be a strong proponent of the role of tobacco
allergy in a wide range of cardiovascular abnormalities, including
coronary artery disease (21, 22, 25, 27, 31, 32). This view on
tobacco allergy as one of the etiological factors in coronary heart
disease (CHD) has not received much attention.

Silvette, et al. (64) reviewed reports (28, 33, 66, 68, 73) on the
prevalence of skin sensitivity in patients with TAO as compared to
controls and cited possible reasons for a higher prevalence of posi-
tive skin tests to tobacco in these patients.
In general, the evidence relating TAO to tobacco allergy is incon-
clusive.

SUMMARY

1. Tobacco leaf, tobacco pollen, and tobacco smoke are antigenic
  in man and animals.

2. (a) Skin sensitizing antibodies specific for tobacco antigens
    have been found frequently in smokers and nonsmokers.
    They appear to occur more often in allergic individuals.
    Precipitating antibodies specific for tobacco antigens
    have also been found in both smokers and nonsmokers.
(b) A delayed type of hypersensitivity to tobacco has been
     demonstrated in man.
  (c) Tobacco may exert an adverse effect on protective mecha-
    nisms of the immune system in man and animals.
3.  (a) Tobacco smoke can contribute to the discomfort of many
    individuals. It exerts complex pharmacologic, irritative,
   and allergic effects, the clinical manifestations of which
   may be indistinguishable from one another.
(b) Exposure to tobacco smoke may produce exacerbation of
   allergic symptoms in nonsmokers who are suffering from
    allergies of diverse causes.

4. Little is known about the pathogenesis of tobacco allergy and
its possible relationship to other smoking-related diseases.

111


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116


CHAPTER 8

Public Exposure to Air Pollution
     From Tobacco Smoke


Contents

Page

The Extent to which the Components of Cigarette Smoke
Contaminate the Atmosphere and are Absorbed by the
Nonsmoker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . .   121
The Effects of Low Levels of Carbon Monoxide on Human
Health . . . . . . . . . . . . . . . . . . . .  . . . . . . . . . . . . . . . . . . . . . .   125
Allergic and Irritative Reactions to Cigarette Smoke Among
Nonsmokers  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . .   128
The Known Harmful Effects of the Passive Inhalation of
Cigarette Smoke in Animals . . . . . . . . . . . . . . . . .  . . . . . . .   129
summary  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . .   130

References  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   131

LIST OF TABLES

Table l.-Percent of COHb during and following exposure
to50p.p.m.of CO  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   124
Table 2.-Effects of carbon monoxide  . . . . . . . .  . . . . . . . . .   127

119


PUBLIC EXPOSURE TO AIR POLLUTION FROM
          TOBACCO SMOKE

The purpose of this chapter is to summarize the present state of
evidence concerning the effects of exposure to an atmosphere con-
taining either tobacco smoke or its constituents. Since the identifi-
cation of cigarette smoking as a serious health hazard to the smoker
was based on clinical and epider;iological observations that non-
smokers have much lower mortality and morbidity rates from a
number of conditions, it is obvious that cigarette smoking is nor-
mally a greater hazard to the smoker than is the typical level of ex-
posure to air pollutants produced by the smoking of cigarettes which
many nonsmokers experience. This would be consistent with the
voluminous data which show a dose-response relationship between
the level of exposure to smoke and the magnitude of its effect.
The research so far reported on the nature and effects of exposure
to smoke-pollutants in the atmosphere has not been as extensive and
well-controlled as that done on the health effects of smoking on the
smoker himself. Knowledge on this subject can be separated into
four major areas of concern :

1. The extent to which the components of cigarette smoke con-
taminate the atmosphere and are absorbed by the nonsmoker.

2.  The effects of low levels of carbon monoxide on human health.

3. Allergic, adverse, and irritative reactions to cigarette smoke
among nonsmokers.

4. The known harmful effects of the passive inhalation of ciga-
  rette smoke in animals.

  THEEXTENTTOWHICHTHE COMPONENTSOF
CIGARETTE SMOKE CONTAMINATE THE ATMOSPHERE
    AND ARE ABSORBED BY THE NONSMOKER

Theoretical models of this contamination have been constructed.
Owens and Rossano (44) have noted that most popular cigarettes
release into the atmosphere approximately 70 mg. of dry particulate
matter (about 60 mg. in the sidestream and slightly over 20 mg. in
the mainstream, about one-half of the latter being absorbed by the
smoker and one-half expelled into the ambient air) and 23 mg. car-

121


bon monoxide per cigarette. This material adds to the cleaning
problem of the air of any enclosed space and contributes to residual
odors. In a recent study of particulate matter filtration in domestic
premises (35), the authors observed that the smoking of one cigar
completely overcame the effect of an electrostatic filtration device
for one hour.

Atmospheric pollutants caused by smoking are derived from two
major sources : mainstream and sidestream smoke. Mainstream
smoke emerges from the tobacco product through the mouthpiece
during puffing, whereas sidestream smoke comes from the burning
cone and from the mouthpiece during puff intermissions (60). The
tobacco smoke released into the atmosphere consists of all the side-
stream smoke as well as that part of the mainstream smoke which
has been either held in the smoker's mouth or taken into his lungs
and then expelled. The actual amount of material to which individ-
uals are exposed in the presence of smokers depends upon the
amount of smoke produced, the depth of inhalation on the part of
the smoker, the ventilation available for the removal or dispersion
of the smoke, and the proximity of the individual to the smoker. The
length of time of exposure to those pollutants is extremely impor-
tant in determining how much is absorbed into the body. The pat-
tern of smoking influences the amount produced by altering the
content of the exhaled smoke. As shown by Dalhamn, et al. (10,
11) , mouth absorption removes approximately 60 percent of the
water-soluble volatile components (e.g., acetaldehyde) , 20 percent
of the nonwater-soluble volatile components (e.g., isoprene), 16
percent of the particulate matter, and only three percent of the car-
bon monoxide. Thus, the smoker who does not inhale "filters" a
portion of the smoke components in his mouth before expelling them
into the ambient air. On the other hand, the lungs retain from 86
to 99 percent of the volatile and particulate substances and approxi-
mately 54 percent of the carbon monoxide inhaled. Hence, the inhal-
ing smoker "filters" the mainstream smoke rather effectively before
expelling it into the ambient air. A factor which has apparently not
been investigated is the difference in the smokers' "filtration" of
mainstream smoke when the smoke is exhaled through the nose
instead of the mouth.

Thus, the nonsmoker breathes smoke-containing air composed of
sidestream smoke and mainstream smoke exhaled by smokers. The
inhaling smoker receives nearly the full amount of mainstream
smoke as well as a portion of sidestream smoke and smoke exhaled
by himself and other smokers. The smoker who does not inhale re-
ceives those compounds which are absorbed from the mainstream
smoke in his mouth, as well as absorbing the sidestream smoke and
the smoke exhaled by himself and other smokers contained in the
air he breathes.

122


Since pipe and cigar smokers inhale less commonly than do ciga-
rette smokers, their contribution to the substances in the air
breathed in exposure to smoke pollutants consists of a composite of
sidestream smoke and relatively unfiltered mainstream smoke
which has been held in the mouth and then expelled.

The actual effluents in the mainstream and sidestream cigarette
smoke have been considered by Pascasio, et al. (45) and Scassellati
Sforzolini and colleagues (50, 51) . These authors stated that "tar"
and nicotine levels in sidestream smoke may be significantly higher
than those of mainstream smoke and may be harmful to the non-
smoker. Actual volume measurements were not reported, however.

Actual measurements of the contamination due to cigarette smok-
ing have been carried out by a number of research groups. A recent,
well-controlled study by Harke (24) involved the smoking of 42
cigarettes in 16 to 18 minutes using German blend cigarettes of
85 mm. length, 18 mm. filter, and smoked to a 25 mm. butt length
in a room with a volume of 57 cubic meters (approximately the
equivalent of a room with a lo-foot ceiling and dimensipns of 12 by
14 feet). The author observed that in the absence of ventilation the
atmosphere contained up to 50 p.p.m. carbon monoxide and 57
mg./m.3 nicotine. With substantial ventilation, these levels fell sig-
nificantly (to approximately 10 p.p.m. carbon monoxide and JO
mg./m.3 nicotine). He also found that cigar smoke (9 cigars of Clear
Sumatra tobacco smoked in 30 to 35 minutes) produced similar
amounts of contamination while pipe smoke (3 grams of Navy type
medium cut tobacco smoked as eight pipefuls in 35 to 40 minutes)
produced much less. Other authors have made similar measure-
ments. Galuskinova (20) found that 3,kbenzpyrene levels in a
smoky restaurant were from 2.82 to 14.4 mg./lOO m." as compared
to outside atmospheric levels of 0.28 to 0.46 mg./lOO m.", although
burning of food particles may have contributed to the presence of
3,4benzpyrene in this setting. Kotin and Falk (33) have shown
that sidestream cigarette smoke condensate may contain more than
three times as much benzo(a)pyrene as mainstream smoke. Srch
(55) observed that the smoking of 10 cigarettes to a 5 mm. butt
length in an enclosed car of 2.09 m.3 volume produced carbon monox-
ide levels up to 90 p.p.m. Lawther and Commins (3.4)) working with
a ventilated chamber, found levels of up to 20 p.p.m. of carbon mo-
noxide after seven cigarettes were smoked in one hour; however,
peaks of up to 90 p.p.m. were recorded at the seat next to the smoker.
Coburn, et al. (9) recorded levels of 20 p.p.m. of carbon monoxide
in a small conference room after 10 cigarettes were "burned."
Harmsen and Effenberger (25) reported up to 80 p.p.m. of carbon
monoxide in an enclosed 98 m.3 room (approximately the equivalent
of a room with a lo-foot ceiling and dimensions of 18 by 20 feet) in
which 62 cigarettes had been smoked in two hours.

123


TABLE 1 .-Percent of COHb during and following exposure to 50
p.p.?n. of co.

Time during
exposure

Mean         Range

Number of
subjects

Preexposure                0.7        0.4-1.5        11
30 minutes                 1.3         1.3          3
  1 hour                   2.1        1.9-2.7        11
  3 hours                  3.8        3.6-4.2        10
  6 hours                  5.1        4.9-5.5         5
  8 hours                  5.9        5.4-6.2         5
12 hours                  7.0        6.5-7.9         3
15 `/z hours                   7.6        7.2-8.2         3
22 hours                 8.5        8.1-8.7         3
24 hours                 7.9        7.6-8.2         3

Time without exposure after
1 hour of exposure
    30 minutes
     1 hour
     2 hours
     5 hours

Time without exposure after
3 hours of exposure
    30 minutes
     1 hour
     2 hours

Time without exposure after
8 hours of exposure
    30 minutes
     1 hour
    1 i hours
    11 hours

Time without exposure after
24 hours of exposure
    30 minutes
     1 hour
     2 hours


SOURCE: stewart, et al. (56).

1.8         1.8          3
1.7        1.6-1.8         3
1.5        1.4-1.5         3
1.1        1.0-1.1         2





3.7        3.4-3.9         3
3.3        2.7-3.8         3
2.7        2.3-3.0         3





5.6        5.1-5.9         3
5.1        4.8-5.4         3
4.0           -          -
1.5        1.4-1.7        3





7.5        7.2-7.8         3
6.7        6.4-7.1         3
5.8        5.6-6.2         3

Another set of contaminants probably present in a tobacco smoke-
polluted atmosphere are the oxides of nitrogen. These, specificially
NO and NO,, have been shown to be present in tobacco smoke al-
though the type most likely to be present in the atmosphere is NO,.
No measurements have been reported of the amount of NO, in
smoke-filled rooms. The importance of obtaining and evaluating this
information is stressed by the results of Freeman and Haydon and

124


their colleagues (17, 18, 19, 27, 28) and of Blair, et al. (5) who ob-
served bronchial and pulmonary parenchymal lesions in rodents
continuously exposed to low levels of NO,.

Other experimenters have measured carboxyhemoglobin ( COHb)
levels in nonsmokers exposed to cigarette smoke pollutants. Srch
(55) observed that the COHb level in two nonsmokers rose from 2
to 5 percent (that of smokers from 5 to 10 percent) when seated in
the cigarette-smoke contaminated car mentioned above (exposure
to 90 p.p.m.) . Harke (2.4) reported that when seven nonsmokers
were exposed for approximately 90 minutes to a "smoked" room
containing 30 p.p.m. of CO there was a rise in COHb from a mean
of 0.9 percent to 2.0 percent. In 11 smokers subjected to the same
conditions, COHb rose from a mean of 3.3 percent to 7.5 percent.
With improved ventilation of the experimental room, the COHb
level decreased significantly.

The CO exposures and COHb levels reported above closely approx-
imate the results obtained following experimental chamber expo-
sure of humans to various levels of CO. The uptake of CO by the
person depends on, among other parameters: CO concentration,
previous COHb level, the level of activity, and the person's state of
health. Equilibrium between CO concentration in the lung and in
the blood requires over 12 hours exposure. However, as may be
noted in table 1, reproduced from Stewart, et al. (56) and derived
from measures of COHb in young sedentary males who were not
smoking, over half of the equilibrium COHb level is reached within
three to four hours of the onset of exposure. The equilibrium value
associated with 100 p.p.m. is approximately 14 to 15 percent COHb.
Exposure to 100 p.p.m. in the nonsmoker can lead to 3.0 percent of
COHb within 60 minutes and 6.0 percent in two hours (16). Of equal
significance is that COHb has a half-life of at least three to four
hours in the body. As shown in table 1, the COHb level fell only to
2.7 percent in the two hours following cessation of exposure to 50
p.p.m. from the end exposure level of 3.7 percent. This lengthy half-
life extends the period of effect of exposure to CO and provides for
a buildup of COHb concentration from fresh exposures.

  THE EFFECTS OF LOW LEVELS OF
CARBON MONOXIDE ON HUMAN HEALTH

The data on the effect of low levels of carbon monoxide on human
psychological and physiological function have been summarized in
two recent publications (8,58).

There is presently much discussion as to the physiologic and
Psychophysiologic effects of exposure to levels of CO approximating
50 to 100 p.p.m. Beard and Grandstaff (I) observed that exposure
to 50 p.p.m. of CO for from 2'7 to 90 minutes altered auditory dis-

125


crimination, visual acuity, and the ability to distinguish relative
brightness. McFarland (40) observed that COHb levels of 4 to 5
percent caused visual threshold impairment. Ray and Rockwell
(48), reporting on a study of the driving ability of three subjects
under varying CO exposure, observed that the presence of 10 per-
cent COHb was associated with increased response time for tail-
light discrimination and increased variance in distance estimation.
Schulte (52) observed that increased errors in cognitive and choice
discrimination tests were manifest at levels of COHb as low as 3
percent. Chevalier, et al. (7) have also observed that levels of 4
percent COHb in nonsmokers are associated with an increase in
oxygen debt formation with exercise similar to that seen in smokers.
On the other hand, other investigators utilizing complex
psychomotor tasks in men and monkeys have observed no decrement
in function upon exposures to CO at 50 to 250 p.p.m. (2, S, 23, 41,
56).

Animals exposed to low levels of CO ( 50 to 100 p.p.m.) continu-
ously for weeks have shown varying degrees of cardiac and cerebral
damage similar to that produced by hypoxia (21,47,57).
Finally, the possible effects of exposure to 50-100 p.p.m. CO on
patients with coronary heart disease (CHD) were investigated by
Ayres, et al. (1) who observed a decrease in arterial and mixed
venous oxygen tensions with COHb saturations of 5 percent. Certain
patients with CHD developed altered lactate and pyruvate metabo-
lism with COHb levels of 5 to 10 percent suggesting myocardial
hypoxia.

The evidence concerning the effect of low levels of carbon monox-
ide has recently been reviewed and evaluated by the National Air
Quality Criteria Committee of the National Air Pollution Control
Administration (58). The following is taken from the published
conclusions of the Advisory Committee (also see table 2) :

"Experimental exposure of nonsmokers to 58 mg/m3 (50
ppm) for 90 minutes has been associated with impairment in
time-interval discrimination. . . . This exposure will produce
an increase of about 2 percent COHb in the blood. This same
increase in blood COHb will occur with continuous exposure
to 12 to 17 mg/m3 (10 to 15 ppm) for 8 or more hours.. . .

"Experimental exposure to CO concentrations sufficient to
produce blood COHb levels of about 5 percent (a level pro-
ducible by exposure to about 35 mg/m3 for 8 or more hours)
has provided in some instances evidence of impaired perform-
ance on certain other psychomotor tests, and an impairment in
visual discrimination. . . .

"Experimental exposure to CO concentrations sufficient to
produce blood COHb levels above 5 percent (a level producible

126


TABLE 2.-Effects of carbon monoxide.

   E~Vi~OIlm.3Ital
     conditions               Effect                 Comment

58 mgJm.3 (50 p.p.m.)  Impairment of time-      Blood COHb levels not
for 90 minutes      interval discrimination    available, but antici-
               in non-smokers.        pated to be about 2.5
                                 percent.
                                Similar blood COHb levels
                           expected from exposure
                             to 10 to 17 mg./m.J (10
                           to 15 1l.p.m.) for 8 or
                                    more hours.

115 mg./m.3 (100
p.p.m.) intermit-
tently through a
facial mask

Impairment in perform-   Similar results may have
ante of some psycho-      been observed at lower
motor tests at a COHb    COHb levels, but blood
level of 5 percent.        measurements were not
                      accurate.

High concentrations
of CO were admin-
istered for 30 to 120
seconds, and then 10
minutes was allowed
for washout of
alveolar CO before
blood COHb was

Exposure sufficient to pro-  Data rely on COHb levels
duce blood COHb levels   produced rapidly after
above 5 percent has been   short exposure to high
shown to place a physio-   levels of CO; this is not
logic stress on patients    necessarily comparable
with heart disease.      to exposure over a longer

time period or under
equilibrium conditions.

measured.

SOURCE: Adapted from U.S. Public Health Service, Air Quality Criteria for Carbon Monoxide.
Washington, D.C., U.S. Department of Health, Education, and Welfare (58).

by exposure to 35 mg/m3 or more for 8 or more hours) has
provided evidence of physiologic stress in patients with heart
disease. . . ."

The levels of carbon monoxide found to be present in "smoked"
rooms (20 to 80 p.p.m.) are similar to the levels (30 to 50 p.p.m.)
which the Advisory Committee has concluded are associated with
adverse health effects :

"An exposure of 8 or more hours to a carbon monoxide con-
centration of 12 to 17 mg/m3 (10 to 15 ppm) will produce a
blood carboxyhemoglobin level of 2.0 to 2.5 percent in non-
smokers. This level of blood carboxyhemoglobin has been asso-
ciated with adverse health effects as manifested by impaired
time interval discrimination. Evidence also indicates that an
exposure of 8 or more hours to a CO concentration of 35 mg/m3
(30 ppm) will produce blood carboxyhemoglobin levels of
about 5 percent in nonsmokers. Adverse health effects as man-
ifested by impaired performance on certain other psychomotor

127


tests have been associated with this blood carboxyhemoglo-
bin level, and above this level there is evidence of physiologic
stress in patients with heart disease."

These levels of CO are also similar to that set as the time-
weighted occupational Threshold Limit Value of 50 p.p.m. for a
40-hour week (five f&hour days) which has been in effect in the
United States for the past several years (13). A further reduction
in this limit to 25 p.p.m. is now under consideration. These levels of
CO exceed those recently set by the Environmental Protection
Agency as the national primary and secondary ambient air quality
standards for CO (1.4). These standards are:

(a) 10 milligrams per cubic meter (9 p.p.m.) -maximum 8-
  hours concentration not to be exceeded more than once
  per year.

(b) 40 milligrams per cubic meter (35 p.p.m.) -maximum
  l-hour concentration not to be exceeded more than once
  per year.

ALLERGIC AND IRRITATIVE REACTIONS TO
CIGARETTE SMOKE AMONG NONSMOKERS

(A more detailed discussion of this subject is presented in the
Allergy chapter of this report.)

Several investigators have reported on the discomfort and symp-
toms experienced by both allergic and nonallergic individuals upon
exposure to tobacco smoke. Johansson and Ronge (S1,32) in 1965
and 1966 have observed that the acute irritation experienced by
nonsmokers in the presence of tobacco smoke is maximal in warm,
dry air and that nonsmokers experience more nasal irritation than
ocular irritation as compared with smokers exposed to similar
amounts of smoke in the atmosphere. Speer (5.4) studied the reac-
tions of 441 nonsmokers divided into two groups, one composed of
individuals with a history of allergic reactions and the other of in-
dividuals without such a history. The allergic group underwent skin
testing for the presence of sensitivity to tobacco extract while the
"nonallergic" group was determined solely by questionnaire con-
cerning subjective allergic responses. Approximately `70 percent of
both groups experienced eye irritation while other symptoms dif-
fered in their frequency from group to group (nasal symptoms:
allergic 67 percent, "nonallergic" 29 percent ; headache : allergic 46
percent, "nonallergic" 31 percent ; cough : allergic 46 percent, "non-
allergic" 25 percent ; and wheezing: allergic 22 percent, "nonaller-
gic" 4 percent). Thus, a significant proportion of nonsmoking in-
dividuals report discomfort and respiratory symptoms on exposure
to tobacco smoke.

128


Other authors have attempted to separate out those patients who
may have specific allergies to smoke. Zussman (61) found that in a
random series of 200 atopic patients 16 percent were clinically sen-
sitive to tobacco smoke, and that a majority of these were aided by
desensitization therapy. In an earlier study, Pipes (46) observed
that 13 percent of 229 patients with respiratory allergy showed posi-
tive skin tests to tobacco smoke. Save1 (49) has recently reported on
eight nonsmokers observed to be clinically hypersensitive to tobacco
smoke. After in vitro incubation of their lymphocytes with cigarette
smoke, increased incorporation of tritiated thymidine was recorded ;
similar exposure of the lymphocytes of those not sensitive resulted
in depression of tritiated thymidine uptake.

Luquette, et al. (39) have recently reported on the immediate ef-
fects of exposure to cigarette smoke in school-age children. They
observed that heart rate and blood pressure rose with such ex-
posure, although questions remain about the adequacy of their con-
trols .and the manner in which the experimental situation may have
excited the subjects, Finally, Cameron, et al. (6) observed that
acute respiratory illnesses were more frequent among children from
homes in which the parents smoked than among children of non-
smoking parents. The meaning of these results is uncertain since
smoking by the children was not considered and the level of ex-
posure to cigarette smoke in their homes was not measured. Shy, et
al. (53) in a study of second grade Chattanooga school children
failed to demonstrate a relationship between parental smoking
habits and the respiratory illness rates of their children.

THE KNOWN HARMFUL EFFECTS OF THE PASSIVE
INHALATION OF CIGARETTE SMOKE IN ANIMALS

A number of investigators have studied the effects of the passive
inhalation of high concentrations of cigarette smoke on the pulmo-
nary parenchyma and tracheobronchial tree of animals. The results
of these investigations are listed in detail in the recent report to
Congress, "The Health Consequences of Smoking," (59) in table 9
of the Bronchopulmonary chapter, and table 16 of the Cancer
chapter.

The pathologic changes observed in the respiratory tract of the
animals included parenchymal disruption, bronchitis, tracheobron-
chial epithelial dysplasia and metaplasia, and pulmonary adenoma-
tous tumor formation. Leuchtenberger, et al. (36) exposed 151
mice to the smoke of from 25 to 1,526 cigarettes over a period of 1
to 23 months and observed that 20 percent of the animals developed
severe bronchitis with atypism. Working with 30 control rabbits
exposed to up to 20 cigarettes per day for two to five years, Holland,
et al. (30) observed increased focal and generalized hyperplasia of

129


the bronchial epithelium and generalized emphysema in the ex-
posed rabbits. Hernandez, et al. (29) observed significantly more
pulmonary parenchymal disruption in adult greyhound dogs ex-
posed to cigarette smoke 10 times per week for approximately one
year than in nonexposed control animals.

Lorenz, et al. (38) observed no increase in respiratory tract tu-
mor formation above that seen in controls in 97 Strain A mice ex-
posed to cigarette smoke for up to 693 hours. Essenberg (15)) how-
ever, exposed Strain A mice to cigarette smoke for 12 hours a day
for up to one year and observed significantly more papillary adeno-
carcinomas in the exposed than in the control group. An increased
percentage of hybrid mice were found by Miihlbock (42) to have
alveolar carcinomas among the experimental group exposed to
smoke for two hours a day for up to 684 days when compared with
a nonexposed group. Similarly, Guerin (22) observed that 5.1 per-
cent of rats exposed to cigarette smoke for 45 minutes a day for
two to six months showed pulmonary tumors compared to 2.4 per-
cent of the control mice.

Leuchtenberger, et al. (37)) working with 400 female CF, mice,
observed only a slight increase in the presence of pulmonary adeno-
matous tumors among those exposed to cigarette smoke compared
with those in the control group. The authors commented that the
presence of tumors showed an age relationship independent of
smoking exposure. Otto (.43) found that 11 percent of a group of
albino mice exposed to 12 cigarettes a day for up to 24 months
showed pulmonary adenomas as compared with five percent of the
control non-exposed group. Dontenwill and Wiebecke (12) found
that increasing the exposure of golden hamsters to up to four ciga-
rettes a day for up to two years was associated with an increasing
percentage of animals showing desquamative metaplasia and bron-
chial papillary metaplasia. Harris and Negroni (26) exposed 200
C5'7BL mice to cigarette smoke for 20 minutes a day every other
day for life and found eight adenocarcinomas as compared to none
in the control group.

Because the damage observed in these experiments was seen after
prolonged exposure to high concentrations of cigarette smoke, and
because the comparability of animal exposure to smoke with that of
human exposure in smoke-filled rooms is unknown, it is presently
impossible to be certain from animal experimentation about the ex-
tent of the damage that may occur during long-term intermittent
exposure to lower concentrations.

SUMMARY

1. An atmosphere contaminated with tobacco smoke can con-
tribute to the discomfort of many individuals.

130


2. The level of carbon monoxide attained in experiments using
rooms filled with tobacco smoke has been shown to equal, and at
times to exceed, the legal limits for maximum air pollution per-
mitted for ambient air quality in several localities and can also ex-
ceed the occupational Threshold Limit Value for a normal work
period presently in effect for the United States as a whole. The pres-
ence of such levels indicates that the effect of exposure to carbon
monoxide may on occasion, depending upon the length of exposure,
be sufficient to be harmful to the health of an exposed person. This
would be particularly significant for people who are already suffer-
ing from chronic bronchopulmonary disease and coronary heart
disease.

3. Other components of tobacco smoke, such as particulate mat-
ter and the oxides of nitrogen, have been shown in various concen-
trations to adversely affect animal pulmonary and cardiac structure
and function. The extent of the contributions of these substances to
illness in humans exposed to the concentrations present in an atmo-
sphere contaminated with tobacco smoke is not presently known.

PUBLIC EXPOSURE TO AIR POLLUTION FROM TOBACCO
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135


CHAPTER 9

Harmful Constituents of Cigarette Smoke


Contents

Page

The Dose Relationship          141

References  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .   146

LIST OF TABLES

Table l.-Compounds in cigarette smoke judged most likely
to contribute to the health hazards of smoking , . . . . . . . . .   143
Table 2.-Compounds in cigarette smoke judged as probable
contributors to the health hazards of smoking . . . . . . . . . .   144
Table 3.-Compounds in cigarette smoke judged as suspected
contributors to the health hazards of smoking , . . . . . . . . .   145

139


HARMFUL CONSTITUENTS OF CIGARETTE SMOKE*

Cigarette smoke contains a large number and a wide variety of
compounds which may result in complex and multiple pathophysio-
logical effects on various tissues and organ systems. Although the
constituents of cigarette smoke are usually divided for convenience
into the two categories of particulate and gas phases,** many of
them exist in a distribution equilibrium, that is, they are present
partially in the gas phase and partially in the particulate phase.
This review concerns itself with judgments concerning the harmful
constituents of cigarette smoke whether these are found primarily
in the gas phase or in the particulate phase.

Constituents of cigarette smoke may enter the body by a variety
of routes. Theoretically, the route of entry and subsequent absorp-
tion could affect the degree to which various organs are subjected
to specific cigarette smoke constituents. Some constituents, par-
ticularly the water soluble components of the gas phase, may be
absorbed by the nasal and oropharyngeal mucous membranes, or
may be dissolved in the saliva and swallowed, thus allowing for pos-
sible gastric or intestinal absorption. Other constituents are ab-
sorbed along the tracheobronchial tree, and the distance which they
reach before being absorbed or deposited depends on such factors as
the depth of inhalation and the particle size. The absorption of gases
in the tracheobronchial tree appears to be in part dependent on the
adsorption of gases to particulate matter. Another factor affecting
the route and degree of absorption is the adequacy of pulmonary
clearance by which constituents deposited or dissolved in the mucous
sheath are delivered to the pharynx and then usually swallowed.

Of the hundreds of compounds identified in cigarette smoke, some
occur in the smoke in concentrations which may be considered suf-
ficient to present hazards to health. Other compounds appear in

o This report attempts to swnmarise the areas of general consensus reached in a special one-
day conference ?? experts in this field which met in June 19'70. This is not to imply that there
was unanimous agreement on all statements contained herein. A list of participants in the meet-
ing appears in the Acknowledgments.
o * It should be noted that there is. at present, no available instrumentation permitting the
separation and individual collection of the particulate and gas phases which duplicates the
precise physieochemical conditions prevailing in cigarette smoke as it is inhaled. A widely ae-
cepted arbitrary distinction between the two phases is as follows: If 50 percent or more of a
given constituent is retained on a Cambridge Alter (CM-l 13) during standardized machine smok-
ing of a cigarette, then the compound is considered to belong to the particulate phase: if on the
other hand more than 60 percent of the compound passes through the Cambridge filter under
these conditions, then the constituent is considered to belong to the gas phase.

141


borderline concentrations. Still others, although potentially harm-
ful, are probably not present in sufficient concentrations to con-
tribute to the hazard, and some may be hazardous only when they
interact with other substances in the smoke.
Substances and classes of substances in cigarette smoke which
have been judged to contribute to the hazard of cigarette smoking
have been classified into three priority groups. Those compounds
which are judged most likely to contribute to the health hazards of
smoking are listed in table 1. Additional substances which probably
contribute to the health hazards of smoking are listed in table 2.
Those compounds which are suspected contributors to the health
hazards of smoking in the concentrations in which they are present
in tobacco smoke are listed in table 3. Many other constituents of
tobacco smoke are considered to be toxic under some conditions but
probably do not present a health hazard in the concentrations in
which they are generally found in cigarette smoke; these are not
listed. This listing is not presented as final, and *may be subject to
modification as more information becomes available.*
In 1966, the Public Health Service prepared a technical report on
"tar" and nicotine (60). Tobacco "tar" is the name given to the ag-
gregate of particulate matter in cigarette smoke after subtracting
nicotine and moisture. In that report it was stated:

"It is clear that the overall risk associated with cigarette
smoking increases as the average number of cigarettes con-
sumed per day increases. In the studies which have reported
other measures of exposure such as pack-years, degree of in-
halation, and maximum level of cigarette consumption, the
same type of relationship holds."

Individuals may differ in their inherent susceptibility to diseases
in which cigarette smoking plays a role and differ in their exposure
to other factors which may increase the likelihood of these diseases.
Within these groups of varying risk, the degree of exposure to ciga-
rette smoke appears to be the most critical factor for the develop-
ment of smoking related disease. Therefore, the general statement
that the lower the dosage the lower the risk is the most useful guide
available. It was also stated that :

"It is possible for a cigarette to be altered in such a way
that its `tar' and nicotine content is reduced but certain other
harmful effects, for example the effect of the gaseous phase,
may be increased. Although this is a theoretical possibility,

o Subsequent to the conference on which this report was based. several studies were published
reporting the presence of N-nitrosamines in cigarette smoke. Since these substances are accepted
as carcinogens in experimental animals, they represent another portion of the "tar" which
probably contributes to the total health hazard (18, 24).

142


there is no evidence that this has occurred to any serious
degree."

The consensus is that there is inadequate evidence to support a
change in that view at the present time.

In addition, it was concluded that "the preponderance of scientific
evidence strongly suggests that the lower the `tar' and nicotine con-
tent of cigarette smoke, the less harmful would be the effect." Sev-
eral studies reported since that time have added strong support to
this position. The present review is an attempt to identify those
constituents of the "tar" as well as those constituents considered
part of the gas phase which are most likely to contribute to the
health hazards from cigarette smoking.

TABLE L-Compounds in cigarette smoke judged most likely to con-
tribute to the heaZth hazards of smoking.

Compound

Carbon Monoxide




Nicotine

I "Tar"

              Primary phase
Concentration in    classification
cigarette smoke    G-gas
micrograms/cigarette P-particulate       References

5,240-21,400      G     (1, 10, 23, 26, 29,
                   34, 35, 37, 42, 46,
                   49, 61, 63)
  200-2,400       P      (9)
3,000-33,000       P      (9)

1 "Tar" is defined as the total particulate matter collected by a Cambridge Alter (CM-113) after
subtracting moisture and nicotine and includes the class of compounds known as polycyclic
aromatic hydrocarbons (PAH) PAH are generally accepted as being responsible for a sub-
stantial portion of the carcinogenic activity of the total "tar." Although "tar" from different
cigarettes varies in its carcinogenic potential as measured by the bioassay methods in current
use. it remains the most practical single "indicator" of total carcinogenic potential. Special
mention should be made of Beta Naphthylamine which is a known human urinary bladder car-
cinogen for which there is no known safe level of exposure and which has been reported present
in tobacco smoke in very low concentrations (16. 28. 30) (0.022 &gm./cigarette).

It is recognized that the substances in cigarette smoke may inter-
act so that the combined pathological effects of several substances
may be quite different from the sum of their effects produced in
isolation. An example of this type of interaction might be the car-
cinogenic effects of tobacco "tar" as a result of the combined action
of cancer initiating, cancer promoting, and cancer accelerating
agents in producing the total effect. Such interactions theoretically
could take place among substances within the gas phase, or sub-
stances within the particulate phase, or between constituents of the
gas phase and constituents of the particulate phase. In the absence
of data which identify the interactions of cigarette smoke compo-
nents, judgments concerning the action or identification of harmful
substances in cigarette smoke have, of necessity, been made pri-

143


TABLE 2.-Compounds in cigarette smoke judged as probable con-
tributors to the health hazards of smoking.

Compound

              Primary phase
Concentration in    classification
cigarette smoke    G--gas
micrograms/cigarette P-particulate

References

Acrolein


Cresol (all isomers)

Hydrocyanic Acid


Nitric Oxide


Nitrogen Dioxide

Phenol

45-140        G     (12, 20, 21, 27, 36,
                43, 45)

68-97         P     (20,40)

100-400        G     (26, 38, 43,45,46,
                49,53)
O-600        G     (1, 3, 15, 40, 42,44,
                57)

O-10         G     (1, 40, 44, 57)

9-202         P     (7, 19, 20, 32, 50,
                 52)

marily on the basis of the action of the individual substances. Never-
theless, experimental evaluation of modified cigarette smoke should
be designed to take into account the possibility of such interaction.

Until there is a better understanding of the relative importance
of the interaction of the constituents of cigarette smoke in the de-
velopment of the diseases associated with cigarette smoking, it will
be difficult to assess the significance of the reduction or elimination
of one or several of the constituents named in this report. However,
it is reasonable to take the position that unless there is positive in-
formation to the contrary, cigarettes in which overall "tar" and
nicotine levels have been reduced present to the smoker lower con-
centrations of the harmful substances in the particulate phase. If,
at the same time, significant reductions are made in those gas phase
constituents which also contribute to the hazards of smoking, the
resulting product should be less hazardous to health.*

The consensus is that a progressive and simultaneous reduction
of all substances considered like19 to be involved in the health haz-
ards of smoking should be encouraged as the most promising step
available at the present time towards the development of a less haz-
ardous cigarette. Primary emphasis should be given to the reduc-
tion of the three substances or classes of substances named in the
first table, and as a second priority to the reduction of those sub-
stances or classes of substances in the second table before reducing

* An &a-native point of view held by some ia that smoking behavior is a response to the need
to reach II certain nicotine level and that lowering the amount of nicotine available from a
cigarette rnay result in an increase in the number of cigarettes smoked. the depth of inhalation.
or the number of puffs in order to maintain an accustomed level. Such an increase in smoking
might result in an increased inhalation of other hazardous substances in the smoke, thereby
potentially negating the effect of reducing the amount available in each cigarette.

144


TABLE 3.-Compounds in cigarette smoke judged as suspected con-
tributors to the health hazards of smoking.

Compound

              Primary phase
Concentration in    classification
cigarette smoke    o-gas
micrograms/cigarette P-particulate

References

Acetaldehyde         180-1,440

Acetone              88-650

Acetonitrile            140-200

Acrylonitrile            10-15

Ammonia              60-330

Benzene

12-100

2,3-Butadione           43-200
Butylamine               3

1 Carbon Dioxide      23,100-`78,300

Crotononitrile             4
Dimethylamine          10-11

DDT                 o-o.77

Endrin                 0.06
Ethylamine             10-11
Formaldehyde          20-41

Furfural              45-110
Hydrogen Sulphide       12-35
Hydroquinone            83

Methacrolein            9-11
Methyl Alcohol          go-300
Methylamine           20-22
Nickel compounds         O-O.58
Pyridine              25-218

G


G


G

G

G


G


G

P

G




G

P

P

P

G

G

P

G

P

G

G

G

P

P

(4, 21, 27, 36, 43,
45, 48, 49, 53, 59)
(12, 21, 27,36, 43,
45, 48, 49, 53)
(1243)

(12, 43)
(2, 22, 40, 41, 43,
64)

(11, 12, 25, 43, 45,
49, 53)

(43, 46, 49,53)
(31,40,41)
(1, 10, 15, 23, 26,
29,34,35,42,46,49,
63)
(43)

(31,40,41)
(17, 39, 54)
(14)

(22,31,40,41)
(4, 36, 43, 48, 53)
(4, 13,36)
(10,43,51,58)
(6,7)
(12,43)
(12, 21, 43, 46, 49)
(22,31,40,41)
(5, 8, 47, 65, 56)
(40,62)

' CO2 is included because of the hazard it may represent to those with CO, retention, such 8~
those with advanced COPD.

those named in the third table. In addition to the epidemiological
and pathological data gained from human studies, it is important to
develop better bioassay systems to evaluate cigarettes modified
by these general guidelines.

145


It should again be emphasized that, in addition to the variation in
chemical properties of the cigarette being smoked, procedures
within the control of the individual smoker such as how many ciga-
rettes he smokes, how far down he smokes the cigarette, and how
frequently and deeply he inhales are critical factors in determining
how much of the harmful substances which can be produced by the
burning cigarette is given the opportunity to injure him.

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(10)



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(12)

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150


INDEX

Abortion

effect of maternal smoking, 5,84,85
frequency, and cigarette consumption,
  85
Acetaldehyde
as suspected contributor to health haz-
ards of smoking, 145
Acetone

as suspected contributor to health
hazards of smoking, 145
Acetonitrile

as suspected contributor to health haz-
ards of smoking, 145
Acrolein

as irritant in tobacco smoke, 101
as probable contributor to health haz-
ards of smoking, 144
Acrylonitrile

as suspected contributor to health haz-
ards of smoking, 145
Adolescents

see Students, high school
Air pollution,

carbon monoxide from cigarette smoke,
7,121-123,125
effect on nonsmokers, 121-125
tobacco smoke as a factor, 7,121-124
Air quality
standards for carbon monoxide, 128
Alcohol consumption
effect on mortality rates from esopha-
geal neoplasms in Japanese males, 71
smoking and, in esophageal neoplasm
etiology, 4,68,70,71
Allergy
effect on cardiovascular abnormalities,
  111
tobacco and, 7,103-l 11
tobacco smoke irritants and, 110
Alphat -antitrypsin deficiency
in emphysema etiology, 44
smoking and, 44
Altitude,
effect on arterial oxygen tension, 22
Amblyopia, tobacco
cyanides and, 6
diet and, 6
smoking and, 6
Ammonia
as suspected contributor to health haz-
ards of smoking, 145

Angina pectoris
smoking and, in twin studies, 18
Antigen-antibody reaction
allergy and, 103-107
smokers vs. nonsmokers, 7,105,111
tobacco and, 7,104-107
Aortic aneurysm, nonsyphilitic
mortality rates. smokers vs. nonsmokers,
  2

Aromatic hydrocarbons, polycyclic
effect on tobacco carcinogenicity, 66
Arterial diseases
carboxyhemoglobin levels and, 26
smokers vs. nonsmokers, 26
smoking and, 25,26
Arteriosclerosis
autopsy studies and, 19,20
cigar smoking and, 19
experimentally induced in dogs, 19,20
pipe smoking and, 19
smokers vs. nonsmokers, 19,22,23,27
smoking classification and, 19
Asbestos

pulmonary fibrosis and, 44
Asthma

smoking and, 37
Atherosclerosis
see Arteriosclerosis
Autopsy studies
arteriosclerosis and, 19,20
coronary heart disease and, 19,20

Benz(a)anthracene
carcinogenicity, as component of ciga-
rette smoke, 66
Benzene

as suspected contributor to health haz-
ards of smoking, 145
Benzo(a)pyrene
as air pollutant from cigarette smoke,
123

carcinogenic effects during pregnancy in
rats, 89
cocarcinogenic effect on respiratory
tract in rabbits, 67
hydroxylation by the placenta, 89
in smoke streams, 123
Betel nut chewing
in Bombay, India, 69


in head and neck neoplasm etiology, 69
smoking and, 69
Birth weight
effect of maternal smoking, 5,83-87
Bladder neoplasms
relative risk in females by amount
smoked, 73

relative risk in males by amount smoked,
72,73
smoking and, 68,72-74
smoking characteristics in etiology of, 5
Body height
effect of maternal smoking, 88
Bronchial abnormalities
in smokers vs. nonsmokers, 45
Bronchial histological changes
smoking and, 45
Bronchitis

incidence in British males by cigarette
consumption, 62
occupational diseases and, 42
prevalence in smokers in Glenwood
Springs, Colorado, 39
prevalence in smokers vs. nonsmokers in
Yugoslavia, 40
smoking in etiology of, 37
Bronchopulmonary disease, chronic ob-
structive

alphat-antitrypsin deficiency and, 3.44
epidemiology in Tecumseh, Michigan,
39,40

morbidity, smokers vs. nonsmokers in
Berlin, New Hampshire, 39
mortality,  smokers vs. nonsmokers,
38,39
mortality rates for ex-smokers, and
smokers vs. nonsmokers, 3
mortality rates for pipe/cigar smokers vs.
cigarette smokers, 3
occupational hazards and, 4244
smoking in etiology of, 3,37
2,3-Butadione

as suspected contributor to health haz-
ards of smoking, 145
Butylamine
as suspected contributor to health haz-
ards of smoking, 145

Cancer

see Neoplasms and specific listings, e.g.,
Lung neoplasms
Carbon dioxide

as suspected contributor to health haz-
ards of smoking, 145

Carbon monoxide
as air pohutant from cigarette smoke,
7,121~123,125
e f fee t on blood carboxyhemoglobn,
levels, 21-23,127
effect on cardiovascular system, 22
effect on nonsmokers, 126
effect on psychomotor performance,
  126

effect on vision, 126
as most likely contributor to health
hazards of smoking, 8,143
psychological and physiological effects,
125128

Carboxyhemoglobin levels
blood cholesterol and, 23
during and following exposure to carbon
monoxide, 124,125
in nonsmokers exposed to cigarette
smoke, 125
occlusive peripheral vascular disease and,
  26

smokers vs. nonsmokers, 21-23
Carcinogenesis
experimental, 6567
initiating agents in cigarette smoke, 66
Carcinogens
effect on oral mucosa in laboratory ani-
mals, 70

Cerebrovascular disease
mortality rates, smokers vs. nonsmokers,

L

smoking and, 24,25
Cessation of smoking
effect on COPD morbidity and mortal-
ity, 41,42
effect on respiratory symptoms, 41,42
lung neoplasm development and, 62
myocardial infarct and, 17.18
as preventive measure in CHD, 17,18
as therapy in arterial diseases, 26
CHD
see Coronary heart disease
Children
effect of parental smoking, 129
passive smoking and, 129
respiratory illness and, 129
Cholesterol
in tobacco, 24
in tobacco smoke, 24
Chronic bronchitis
see Bronchitis
Chronic bronchopulmonary disease
see Bronchopulmonary disease, chronic
  obstructive

152


Chrysene

carcinogenicity, as component of ciga-
rette smoke, 66
Cigarette consumption
effect on mortality from lung cancer in
Poland, 61,62
Cigarettes
tar and nicotine content, 142,143
Cigarette smoking
see Smoking
Cigar smokers
carboxyhemoglobin levels in, 21-23
myocardial arteriole wall thickness in, 19
relative risk in esophageal neoplasm
development, 68
relative risk in laryngeal neoplasm de-
velopment, 67
Coal miners

pneumoconiosis and, 4244
Congenital malformations
maternal smoking and, 87
COPD

see Bronchopulmonary disease, chronic
obstructive

Coronary heart disease
autopsy studies, 19,20
carboxyhemoglobin levels and, 27
cross-sectional study in Bergen, Norway,
  16

epidemiological studies, 14-16
heredity as a factor, 18
incidence among Minnesota men by age
and smoking habit, 14-16
interaction of smoking and other risk
factors, 16-18

mortality rates and per capita cigarette
consumption in several countries, 16
mortality rates in longshoremen, 14
retrospective studies in Goteborg,
Sweden, 16

retrospective studies in Prague, Czecho-
slovakia, 16
smoking in etiology of, 1,2,13,14
twin studies, 18
Cor Puhnonale
see Pulmonary heart disease
cough

smokers vs. nonsmokers, 40
Cresol

as probable contributor to health haz-
ards of smoking, 144
Crotononitrile
as suspected contributor to health haz-
ards of smoking, 145

Cyanides
tobacco amblyopia and, 6

DDT

as suspected contributor to health haz-
ards of smoking, 65,145
Dermatitis

among tobacco workers, 111
Dibenz(a,c)anthracene
carcinogenicity, as component of ciga-
rette smoke, 66

7H-Dibenz(c,g)carbozole

carcinogenicity, as component of ciga-
rette smoke, 66,67
carcinogenic effect on respiratory tract
in hamsters, 66,67
Diet

tobacco amblyopia and, 6
Dimethylamine

as suspected contributor to health haz-
ards of smoking, 145
7,12-Dimethylbenz(a)anthracene
effect on oral mucosa in hamsters, 70

Edentulism
smoking and, 6
Emphysema

alphar -antitrypsin deficiency and, 44
experimentally induced in smoking dogs,
46

smoking in etiology of, 37
Endrin

as suspected contributor to health haz-
ards of smoking, 145
Epidemiological studies
bronchopulmonary diseases and smok-
ing, 3841
coronary disease and smoking, 14-16
esophageal neoplasms and smoking,
70,71
laryngeal neoplasms and smoking, 68
lung neoplasms and smoking, 60-65
maternal smoking and outcome of preg-
nancy, 83-87
oral neoplasms and smoking, 68-70
pancreatic neoplasms and smoking, 74
urinary bladder neoplasms and smoking,
72-74

Esophageal neoplasms
alcohol consumption and smoking in
etiology of, 4,5,71
mortality rates in Japanese males by
smoking and drinking characteristics,
71

153


smoking in etiology of, 4,70,71
Esophagus

effect of smoking, 98
Ethylamine

as suspected contributor to health haz-
ards of smoking, 145
Experimental studies
nicotine and cigarette smoke, 21
Ex-smokers

mortality rates from lung cancer, 5

Fetus

effect of maternal smoking, 5,83-89
Filtration

smoke, effect on bronchoconstrictor
response in smokers, 45
Formaldehyde
as suspected contributor to health haz-
ards of smoking, 145
Furfural

as suspected contributor to health haz-
ards of smoking, 145

Gas phase, cigarette smoke
effect on mucous flow rates in cats, 47
harmful constituents in, 143
Gastric secretions
effect of nicotine, 97
Gastrointestinal disorders
smoking and, 5,697,98
Genetic factors
in alphat+mtitrypsin deficiency, 44
smoking and, 44
Gingivitis

smoking and, 6

Heart disease

see Coronary heart disease
Heredity
alpha, -antitrypsin deficiency and, 44
coronary heart disease and, 18
smoking and, 18
Hydrocyanic acid
as probable contributor to health haz-
ards of smoking, 144
Hydrogen sulphide
as suspected contributor to health haz-
ards of smoking, 145
Hydroquinone
as suspected contributor to health haz-
ards of smoking, 145
Hypercholesterolemia
as a risk factor for coronary heart dis-
ease, 16 ,17

Hypertension
as a risk factor for coronary heart dis-
ease, 16,17
Hypoxemia

smoking and, 22
Hypoxia

effect of nicotine, 21
experimentally induced in rats, 21

Infant mortality
effect of maternal smoking, 83-87
low birth weight and, 86
Influenza

incidence from antibody deficit in rmok-
ers, 109

Intermittent claudication
smokers vs. nonsmokers, 22,26
Intraoral smoking
see Reverse smoking
Ischemic heart disease
morbidity ratio from, in New Delhi,
India, 16

Laryngeal neoplasms
epidemiological studies, 68
relative risk among cigarette, pipe and
cigar smokers, 67
smoking in etiology of, 4,67,68
Leukoplakia
oral neoplasm development in smokers
and, 68,69
smoking in etiology of, 68.69
Lip neoplasms

pipe smoking as cause of, 4
Lung cancer

see Lung neoplasms
Lung function

effect of smoking, 37.38
in smokers vs. nonsmokers, 40
Lung neoplasms
epidemiological studies, 6065
etiology and epidemiology, 59,60
incidence in British males by amount
smoked, 62
incidence in Czechoslovakian males by
amount smoked, 6 1
incidence in Jewish vs. non-Jewish
women, 63,64
incidence in uranium miners, 64,65
mortality ratios in Japanese males by
amount smoked, 6 1
mortality ratios in Japanese women, 63
prospective study in Japanese adults,
4,60,61

154


prospective study in Czechoslovakian
males, 6 1

relationship to chronic bronchitis and
smoking, 62
relative risk in exsmokers by length of
cessation and previous duration of
habit, 6264

smoking as cause, 4,5,59,60

Macrophages, alveolar
effect of tobacco smoke, 4748
in sputum specimens of smokers vs. non-
smokers, 48

Maternal-fetal exchange
effect of nicotine, 88

Maternal smoking

see Smoking, maternal
Methacrolein

as suspected contributor to health haz-
ards of smoking, 145
Methyl alcohol

as suspected contributor to health haz-
ards of smoking, 145
6-Methylanthranthrene
carcinogenicity, as component of ciga-
rette smoke, 66
Morbidity
from chronic bronchopulmonary disease,
3941
Mortality

from chronic bronchopuhnonary disease,
38,39
Mortality rates

esophageal neoplasms in Japanese males
by smoking and drinking character-
istics, 71
lung neoplasms in Japanese women, 63
pancreatic neoplasms in United States,
  74
Mortality ratios

lung neoplasms in Japanese males by
amount smoked, 61
Mouth neoplasms
see Oral neoplasrm
Myocardial arteriole walls
effect of filtered cigarettes in dogs, 20
thickness in smokers vs. nonsmokers,
2,19
thickness in smoking and nonsmoking
dogs, 2,20

Myocardial infarct
epidemiological study in Gomborg,
Sweden, 14.15
incidence among Minnesota men by age
and smoking habit, 14.15

incidence in men in Goteborg, Sweden,
by tobacco consumption, 15
incidence rates by smoking classifi-
cation, 15
smokers vs. nonsmokers in Goteborg,
Sweden, 16

Neonatal death
maternal smoking and, 83-87
Neoplasms
see aLsO Specific types of neoplasms,
e.g. lung neoplasms
smoking and, 4,5,59-75
Nickel compounds
as suspected contributors to health haz-
ards of smoking, 145
Nicotine

antigenic properties, 104
effect on apexcardiogram, 21
effect on birth weight in rats, 88
effect on bronchoconstrictor response
in laboratory animals, 46
effect on fetus in laboratory animals,
88

effect on gastric secretions, 97
effect on gastrointestinal secretions in
dogs, 6
effect on immune response in man, 109
effect on lipid metabolism in rabbits,
21

effect on peripheral circulatory system,
25,26
effects during pregnancy in laboratory
animals, 88
experimental studies, 21
hypoxia and, 21
as most likely contributor to health
hazards of smoking, 8,143
Nitric oxide

as probable contributor to health haz-
ards of smoking, 144
Nitrogen dioxide
effect on pulmonary tissue in rats,
46,47
in emphysema etiology, 46
as probable contributor to health haz-
ards of smoking, 144
Nitrogen oxides
as air pollutants in cigarette smoke,
124,125

Non-nicotine cigarettes
effect on apexcardiogram, 21
Nonsmokers
allergic and irritative reactions to ciga-
rette smoke, 128,129

155


allergic symptoms in, from tobacco
smoke exposure, 110,111
carboxyhemoglobin levels in, 125
passive smoking and, 121-125

Obesity
as a risk factor for coronary heart dis-
ease, 16

Occupational diseases
bronchitis, 42
chronic obstructive pulmonary disease,
3,4244

pneumoconiosis, 4244
pulmonary fibrosis, 44
smoking and, 3,4244
Occupational hazards
smoking and, 3,4,4244
Oral contraceptives
smoking and, 26
thrombophlebitis and, 26
Oral diseases, non-neoplastic
smoking and, 6
Oral hygiene

smoking and, 6
Oral mucosa

effect of carcinogens in laboratory ani-
mals, 70

effect of cigarette smoke, 6,69
effect of reverse smoking, 69
effect of tobacco/bidi smoking and
chewing, 69
Oral neoplasms

pipe smoking as cause, 67
relative risk in tobacco smokers and
chewers, 70

smoking in etiology of, 4,67-70
Oxygen tension
smokers vs. nonsmokers, 22

Pancreatic neoplasms
mortality rates in United States, 74
mortality ratios in Japanese male and
female smokers, 74
smoking and, 5,68,74
Particulate phase, cigarette smoke
carcinogenic accelerators in, 5,65
effect on pulmonary and cardiac struc-
ture and function, 7,s
harmful constituents in, 143
Passive smoking

effect on children, 129
effect on respiratory tract in laboratory
animals, 129,130
in neoplasm induction in laboratory
animals, 130

156

Perinatal studies
maternal smoking and, 83-88
Periodontal diseases
smoking and, 6
Peripheral vascular diseases
carboxyhemoglobin levels and, 26
smoking and, 2,25,26
Phagocytosis
effect of cigarette smoke in rabbits,
  109

effect of tobacco smoke, 47-48
Phenol

as probable contributor to health haz-
ards of smoking, 144
Physical inactivity
as risk factor in coronary heart disease,
16,17
Pipe smokers
carboxyhemogiobin levels in, 21
myocardial arteriole wall thickness in,
  19

oral neoplasms and, 67
relative risk in esophageal neoplasm
development 68
relative risk in laryngeal neoplasm
development, 67
Pneumoconiosis
prevalence in coal miners, 4244
smokers vs. nonsmokers, 4244
Post-operative pulmonary complications
smokers vs. nonsmokers, 38
Preeclampsia

smoking and, 84
Pregnancy

effect of maternal smoking, 5,83-87
Prematurity
effect of maternal smoking, 5,83-87
Pulmonary clearance
effect of smoking, 3,47
Pulmonary fibrosis
in asbestos textile workers, 44
smoking and, 44
Pulmonary heart disease
COPD and, 24
smoking as cause, 24.27
Pulmonary macrophages
effect of smoking, 3,4,4748
morphologic differences in smokers vs.
nonsmokers, 4.4748
Pyridine

as suspected contributor to health haz-
ards of smoking, 145

Radiation exposure
smoking and, in uranium miners, 64,65


Respiratory disorders, acute noninflu-
enzal

in smokers vs. nonsmokers, 48
Respiratory function tests
effect of smoking, 45
Respiratory infections
smoking and, 3,38
Respiratory symptoms
pipe/cigar smokers and cigarette
smokers vs. nonsmokers, 3,40
Reverse smoking
effect on oral mucosa, 6,69,70
nicotinic stomatitis and, 6,69,70
Risk factors

in coronary heart disease, 16-18

Skin

effect of tobacco extracts, 105-107
tobacco antigens and, 7,104,105
Skin testing
for reactions to tobacco, 105-107
Smoke, cigarette
carcinogenicity, 65,66
cocarcinogenic  effect on respiratory
tract in rabbits, 67
effect on apexcardiogram, 21
effect on breathing in guinea pigs, 46
effect on lung surface tension in dogs,
48

effect on nasociliary mucosa in don-
keys, 47
effect on phagocytosis in rabbits, 109
experimental studies in laboratory ani-
mals, 21
harmful constituents of, 8,141-146
Smoke, tobacco
as air pollutant, 7,121 ,122
allergic and irritative components,
effect on nonsmokers, 7,128,129
antigenic properties, 104
effect on macrophages, 47
irritants in, 109,110
Smokers vs. nonsmokers
arteriosclerosis and, 19
carboxyhemoglobin levels, 21-23
cerebrovascular diseases and, 25
oral diseases and, 6
respiratory symptoms, 40
thickness of myocardial arteriole walls,
19
Smoke streams
benzo(a)pyrene content, 123
effect on nonsmokers, 122,123
tar and nicotine content, 123

Smoking

bladder neoplasms and, 68,72-74
effect on cardiovascular system, 6,13,14
effect on esophageal sphincter, 97,98
effect on gastrointestinal secretions in
dogs, 6
effect on leukocytes in guinea pigs, 46
effect on lungs in dogs, 46
effect on mortality rates from esopha-
geal neoplasm in Japanese males, 71
effect on neoplasm recurrence at site of
primary, 69
effect on oxygen tension in arterial
blood, 45
effect on pentagastrin-stimulated gastric
secretion, 97
effect on peripheral circulatory system,
25,26
effect on pulmonary clearance, 47
heartburn and, 97,98
peptic ulcers and, 6,97,98
tobacco amblyopia and, 6
Smoking, bidi
in neoplasm etiology in Bombay, India,
69

Smoking, maternal
carcinogenic effects on fetus, 88
effect on abortions, 5,84,85
effect on birth weight, 5,83-87
effect on body height of children, 88
effect on fetal growth rate, 5,83-87
effect on neonatal mortality rates,
84-87

effect on neoplasm development in off-
spring, 87,88
effect on placental metabolizing activ-
ity, 89
effects during pregnancy, 5,83-87
teratogenic effects, 87
unwanted pregnancy and, 84
Smoking, parental
effect on children, 129
Snuff
effect on oral mucosa in hamsters, 70
Squamous cell carcinoma
smoking in etiology of, 69
Stomatitis nicotina
reverse smoking and, 6,69,70
Stroke
smoking and, 24,25
Students, high school
effect of smoking, 40,41
pulmonary function of smokers vs. non-
smokers, 3

157


respiratory symptoms in, 40,41
Surfactants

effect of tobacco smoke, 48

Tar content

as harmful component of cigarette
smoke, 142,143

Tars, tobacco

carcinogenicity, 65,66
definition, 143
Thromboangiitis obliterans
tobacco allergy and, 111
Thrombophlebitis
oral contraceptives and, 26
smoking and, 26
Thrombosis
effect of smoking, 23
Tobacco
cholesterol content, 24
effect on immune responses, 6,107-109
pharmacologic, irritative, and allergic ef-
fects, 7,109-l 11
Tobacco antigens
in smokers vs. nonsmokers, 107
Tobacco chewing
oral neoplasrm and, 69
Tobacco extracts
antigenic properties, 104,105
effect on skin, 105-107

irritants in, 184,105
thromboangiitis obliterans and, 111
Tobacco leaf
antigenic properties, 104,105
Tobacco pollen
antigenic properties, 104
Tuberculosis
smoking and, 41
Twins
smoking and coronary heart disease in,
  18

Ulcer, duodenal
smoking and, 6,97,98
Ulcer, peptic

increased prevalence in male smokers,
97

smoking and, 5,6,97,98
smoking as cause in dogs, 97,98
Urinary bladder neoplasms
see Bladder neoplasms

Vascular disease, peripheral
carboxyhemoglobin levels and, 26
nicotine and, 25
smokers vs. nonsmokers, 26
smoking as a risk factor, 2,25,26
Vision

effect of carbon monoxide, 126

158

*U.S. GOVERNMENT PRINTING OFFICE: 1972 O-445.191