A Reference Edition

Selected Chapters From 1971 Through 1975 Reports
  With Cumulative Index For All Reports
            19641975

U.S. Department of Health, Education, and Welfare
         Public Health Service
         cmltar for Dii Control
          Athnta, Gewpia 30333


THE HEALTH CONSEQUENCES OF SMOKING

          A Reference Edition

Selected Chapters From 1971 Through 1975 Reports
   With Cumulative Index For All Reports
             1964-1975

U.S. Department of Health, Education, and Welfare
           Public Health Service
           Center far Diia50 Controi
          Atlanta, Georgia 30333

1976

HEW Publication Nd. (CDC) 78-8357


October    1977

Honorable Thomas P. O'Nelll
Speaker of the House of Representatives
Kashfngton, D.C.  20515

Dear ?fr. Speaker:

As required by Section 8(a) of the Public Health Cigarette Smokfng Act of
1969 (Public Law 91-222). enclosed is the 1976 Report to Congress on the
Health Consequences of Smoking.

This year's report includes the "Bibliography on Smoking and Health -
1975," the official abstract bulletin of the National Clearinghouse for
Smoking and Health. Bureau of Health Education. Center for Disease Control.
Public Health Service.  It presents the scientific information published
since last year's report to Congress.  Also part of this year's report is
'The Health Consequences of Smoking. a Reference Edition." a compilation
of selected chapters from previous reports to Congress.  This reference
edition was prepared to emphasize the fact that the major health risks
from smoking are know" and that recent scientific information refines
the understanding of these relatlonshlps.  Without doubt. cigarette smoking
is a cause of cardiovascular disease. various types of cancer, and respira-
tory disease.  Its toll lo illness and premature death 1s needless and
preventable.

Because of ny strong commitment in reducing the morbidity and mortality
which result from smoking. the Department 1s conducting a major review of
its prograrrm 1" this field in order to introduce administrative and
legislative proposals to combat this problem.

Sincerely.

Joseph A. Cslifano. Jr.

Eoclosure


PREFACE

?e health consequences of cigarette smoking are well established.
ad have bee; clearly understood for several years. The causal re-
k ionships between cigarette smoking and an excess risk of devel-
Fing cardiovascular disease, respiratory tract cancers, and chronic
1 structive lung disease, as well as the risk to the fetus, are well
cumented and accepted by the scientific and health communities.

r the past several years, new additions to the literature have
bstantiated
i'      these risks and further explained the mechanisms
which smoking produces disease, disability, and death; however,
search has identified no new major health risks. Therefore, it
ems appropriate at this time to prepare a reference document
viewing the full range of health hazards due to smoking.

is reference report consists of selected chapters from previous
ports to the U.S. Congress which present summations of the
i own health hazards from smoking. Because the 1971 report was
review of all information on smoking and health at that time,
chapters were included from reports prior to that time. This
`ference, coupled from the annual Bibliography on Smoking and
le
E alth, represents a complete description of major smoking and
alth information.

e scientific evidence is clear and unavoidable, and the important
k now is to convert this knowledge into programs for reducing
d eliminating the preventable death and disability related to the
oking habit.

Theodore Cooper, M.D.
Assistant Secretary for Health


TABLE OF CONTENTS

Page

PREFACE ~.._...___.___._..__________..._.......... ...
                                                         111

TABLEOFCONTENTS . . . __. . _. _ _ _. _ _. . . . . . . . . . . _. . . . .   v

PREVIOUS PUBLIC HEALTH SERVICE REPORTS

ON SMOKING AND HEALTH _ _ . _ _ _ _ _ . . . _ . . . . . . . . . . . . . . .  vii

ACKNOWLEDGEMENTS . . . . _ _ . _ . _ . . . . . _ . . . _ _ _ _ _ . . . . . . . .   ix

CHAPTER 1

CHAPTER 2

CHAPIER 3

CHAPTER 4

CHAPTER 5
CHAPTER 6
CHAPTER 7

CHAPTER 8

CHAPTER 9

Overview (197.5 Report) _ . . . . . _ . . . . _ . _ _ . . _ . _ . . .   1

Cardiovascular Disease _ . . _ . . . . _ . . . . _ _ _ . . _ _ _ _ . . .   9
Part 1 (1971 Report, Chapter 2) _ _ . . . . . . _ . . . _ . _ . _ .   11
Part 2 (1975 Report, Chapter 1) . . _ . . . . . . . . . _ . . . . _ 131
Chronic Obstructive Bronchopulmonary Disease

(1971 Report, Chapter 3) . . . . . . . _ . . . _ _ . . _ . . . . . . 161
Cancer (1971 Report, Chapter 4)  . . . . _ _ _ . . . . . . . . . _ 257
Pregnancy (1973 Report, Chapter 4) . . . . . _ . _ . . . _ . . _ 411
Peptic Ulcer Disease (1973 Report, Chapter 5) . . . . . _ _ _ . 465
Involuntary Smoking (1975 Report, Chapter 4) . . . . . . . . 479
Allergy (1972 Report, Chapter 7) . _ . _ _ . . . . . . _ . . . . . 509
Tobacco Amblyopia (197 1 Report, Chapter 7)  . . . . . . . 527

CI-IAPIER 10 Pipes and Cigars (1973 Report, Chapter 6)  _ . . . . . . . . _ _ 535
CHAPTER 11 Exercise Performance (1973 Report, Chapter 7) . . . _ . _ . _ 607
CHAPTER 12 Harmful Constituents of Cigarette Smoke

      (1972 Report, Chapter 9)  . _ . . . . . _ . _ . _ _ . . _ . . _ _ _ . 621

INDEX    This Report . . . _ . . _ _ . . . . _ _ _ . . . _ . . . . _ . . _ _ . . . _ 635
CUMULATIVE INDEX (1964 - 1975) _ . . . . . . _ _ . _ . . . . . . . _ . . . . . 000


Previous Public Health Service Reports
   on Smoking and Health

Reviews of the scentitic evidence linking smoking to health effects began
in 1964 with Smoking and Health, Report of the Advisory Committee to the
Surgeon General of the Public Health Service or as subsequently referred to
"the Surgeon General's Report." After this report, Public Law 89-92 was
passed requiring supplemental reports to Congress on this subject. In
compliance, three reports were submitted:

1. The Health Consequences of Smoking, A Public Health Service 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.

In April 1970, Public Law 91-222 amended the previous law and called for
an updated report on the health effects of smoking no later than January 1,
197 1, with annual reports thereafter. The Health Consequences of Smoking,
A Report of the Surgeon General: 1971, a comprehensive review of all the
scientific literature available to the National Clearinghouse for Smoking and
Health and with emphasis on the most recent additions to the literature was
that updated report. Since then, the following annual reports on the health
consequences of smoking have been submitted:

1. The Health Consequences of Smoking, A Report of the Surgeon

General, 1972.

2. The Health Consequences of Smoking, 1973.
3. The Health Consequences of Smoking, 1974.
4. The Health Consequences of Smoking, 1975.

Each report since the original "Surgeon General's Report" has reviewed
the scientific literature relevant to the association between smoking and

Vii


cardiovascular diseases, non-neoplastic bronchopulmonary diseases. and
cancer. Smoking as related to the following diseases and condiiions has been
reviewed periodically in the reports:

Pregnancy(1967.1969, 1971,1972,1973)
Peptic Ulcer Disease (1967,197 1,1972,1973)
Public Exposure to Air Pollution from Tobacco Smoke (1972,197s)
Noncancerous Oral Disease (1969)
Tobacco Amblyopia (197 1)
Allergy (1972)
Harmful Constituents of Cigarette Smoke (1972)
Exercise Performance (1973)
Pipe and Cigar Smoking (1973)
Overview: The Health Consequences of Smoking (1975)

. . .
vlu


ACKNOWLEDGMENTS

Preparation of this reference edition, The Health Consequences of Smoking,
was the responsibility of the National Clearinghouse for Smoking and Health;
Charles A. Althafer, Acting Director; David M. Burns, Medical Staff Director;
Priscilla B. Holman, Technical Editor; Donald R. Shopland, Technical In-
formation Officer.

Individual chapters comprisin, 0 this reference volume are from reports which
were prepared under the direction of Daniel Horn, Ph.D., Director of the
Clearinghouse,-currently on assignment to the World Health Organization.

The following persons served as medical staff directors or consultants for the
preparation of the reports whose chapters are included in this reference edi-
tion: Elvin E. Adams, M.D.; Daniel P. Asnes, M.D.: David M. Burns, M.D.;
David G. Cook, M.D.; John H. Holbrook, M.D.; Paul Schneiderman, M.D.;
and H. Stephen Williams, M.D.

The following persons provided assistance and advice for the preparation of
reports whose chapters are included in this reference edition.

Reviewers'

AncJerson,`William H., M.D. - Chief, Pulmonary Disease Section, University
of Louisville, School of Medicine, Louisville. KY.
Anthonisen, Nicholas, I?., M.D., Ph.D. - Director, Respiratory Division for
the Health Sciences Center, Winnipeg General Hospital, Winnipeg, Canada.
Auerbach, Oscar, M.D. - Senior Medical Investigator, Veterans Hospital, East
Orange, NJ.

Ayres, Stephen M., M.D. - Professor and Chairman, Department of Internal
Medicine, St. Louis University Medical School, St. Louis, MO.
Baker, Carl, M.D. - Director, Program Policy Staff, Health Resources Ad-
ministration, U.S. Department of Health, Education, and Welfare, Wash-
ington, D.C.
tBellet, Samuel, M.D. - Director, Division of Cardiology, Philadelphia
                                                    -_
General Hospital, Philadelphia, PA.
Bing, Richard .I, M.D. - Visiting Assoctie in Biomedical Engineering,
California Institute of Technology, Pasadena, CA.
Bock, Fred G., Ph.D. - Director, Orchard Park Laboratories, Roswell Park
Memorial Institute, Orchard Park, NY.
Boren, Hollis, M.D. - Professor of Medicine, University of South Florida
Medical Center, Tampa, FL.

Boutwell, Roswell K., M.D. - Professor of Oncology, McArdle Laboratory
for Cancer Research, University of Wisconsin, Madison, WI.
Brass, Irwin, M.D. - Director of Biostatistics, Roswell Park Memorial
Institute, Buffalo, NY.

`Current addresses.
`Deceased.

ix


Cooper, Theodore, M.D. - Assistant Secretary for Health, U.S. Department
of Health, Education and Welfare, Washington, DC.
Cornfield, Jerome - Research Professor of Biostatisticr, University of
Pittsburgh Graduate School of Public Health, Biostatistics Project,
Bethesda. MD.

Earl, Christopher J., M.D. - National Hospital, London, England.
Epstein, Frederick H., M.D. - University of Zurich, Zurich, Switzerland.
Falk, Hans L., Ph.D. -`Associate Director for Program, National institute of
Environmental Health Sciences, National Institutes of Health, Research
Triangle Park, NC.

Farr, Richard, M.D. - Director, Department of Medicine, Section of Allergy
and Clinical Immunology, National Jewish Hospital and Research Center,
Denver, CO.

Ferris, Benjamin G., Jr., M.D. - Professor, Department of Physiology,
Harvard School of Public Health, Boston, MA.
Finklea, John F., M.D. - Director, National Institute for Occupational Safety
and Health, Center for Disease Control, Public Health Service, U.S.
Department of Health, Education and Welfare, Rockville, MD.
Fitzpatrick, Mark J., M.D., M.P.H. - Fairhaven Medical Associates, Inc.,
Fairhaven. MA.

Frazier, Todd M. - Assistant Director. Harvard Center for Community Health
and Medical Care. Harvard School of Public Health, Boston, MA.
Freston, James, M.D. - Associate Professor of Medicine; Chairman, Divisions
of Gastr.oenterology and Clinical Pharmacology, University of Utah
Medical School. Salt Lake City, UT.
Goldsmith, John R., M.D. - Medical Epidemiologist, Epidemiological Studies
Laboratory, California State Department of Health, Berkeley, CA.
Gori, Gio B., Ph.D. - Deputy Director,  Division of Cancer Cause and
Prevention, National Cancer Institute, National Institutes of Health,
Bethesda, MD.

Hanna, Michael G., Jr., Ph.D. - Director of Basic Research, Frederick Cancer
Research Center, Frederick, MD.
Harkavy, Joseph, M.D. - Clinical Professor of Medicine(Emeritus1, the Mount
Sinai Medical School of the University of New York, New York, NY.
Harke, H. -P., Ph.D. - Forschunginstitut der Cigarettenindustrie, e.V.,
Hamburg, Germany.

Higgins, fan T. T.. M.D., F.R.C.P. - Professor, Department of Epidemiology,
University of Michigan School of Public Health, Ann Arbor, Ml.
Hoffmann, Dietrich, Ph.D. - Member, and Chief, Division of Environmental
Carcinogenesis, Naylor Dana Institute for Disease Prevention, American
Health Foundation, Valhalla, NY.
Israel, Robert A. - Acting Deputy Director, National Center for Health
Statistics, Public Health Service. U.S. Department of Health, Education,
and Welfare. Rockville, MD.

`Current addresses.
`Deceased.

X


Jennings, Michael, M.D. - Epidemic Intelligence Service, Center for Disease
Control located at Ohio Department of Health, Columbus. OH.
Keller, Andrew Z., D.M.D., M.P.H. - Chief, Research in Geographic
Epidemiology. Medical Research Service. Veterans Administration Central
Office, Washington, DC.

Kirsner, Joseph, M.D. - Professor of Medicine, University of Chicago School
of Medicine, Chicago, IL.

Knox. David L., M.D. - Associate Professor, The Wilmer Opthalmological
Institute, The Johns Hopkins University School of Medicine, Baltimore.
MD. -

Kolbye, Albert C., Jr., M.D., J.D. - Director, Office of Sciences, Bureau of
Foods, Food and Drug Administration, U.S. Department of Health,
Education and Welfare, Washington, DC.
Kotin, Paul, M.D. - Senior Vice President of Health, Safety, and Environ-
ment Division, Johns-Manville Company, Denver, CO.
Krumholz, Richard A.. M.D. - Medical Director, Institute of Respiratory
Diseases, Kettering Medical Center, Kettering, OH.

Lenfant, Claude, J. M., M.D., - Director, Division of Lung Diseases, National
Heart and Lung Institute, National Institutes of Health, Bethesda, MD.
Liebow, Averill A., M.D. - Professor and Chairman, Department of
Pathology, University of California at San Diego, LaJolla, CA.
Lilienfeld, Abraham, M.D. - University Distinguished Service Professor of
Epidemiology, Johns Hopkins School of Hygiene and Public Health,
Baltimore, MD.

Lowell, Francis C., M.D. - Chief, Allergy Unit, Massachusetts General
Hospital, Boston, MA.

MacMahon, Brian, M.D. - Professor, Department of Epidemiology, Harvard
School of Public Health, Harvard University, Boston, MA.
McLean, Ross, M.D. - Professor of Medicine and Chief of Pulmonary
Services, Bowman Gray School of Medicine, Wake Forest University,
Winston-Salem, NC.

McMillan, Gardner C., M.D. - Assistant Director for the Etiology of
Arteriosclerosis and Hypertension, National Heart and Lung Institute,
National Institutes of Health, Bethesda, MD.               -_
                                                 - _
Manning, Kathleen M., R.N. - Department of Staff Development, Boston
City Hospital, Boston, MA.

Meyer, Mary 8.. Mrs. - Assistant Professor of Epidemiology, The Johns
Hopkins University, Baltimore, MD.
Mitchell, Roger S., M.D. - Chief of Staff, Veterans Administration Hospital.
Denver, CO.

Murphy, Edmond A., M.D. - Professor of Medicine and Biostatistics. The
Johns Hopkins University, Baltimore, MD.
Nettesheim, Paul, M.D. - Group Leader, Respiratory Cnrcinogenesis Group.
Biology Division, Oak Ridge National Laboratory, Oak Ridge, TN.

' C~mnc addresses.
`Deceased.

xi


Newill, Vaun A., M.D. - Executive Office of the President, Office of Science
and Technology, Washington, DC.

Paffenbarger, Ralph S., Jr., M.D. - Epidemiologist, California State Depart-
ment of Health, Berkeley, CA.

Parker, Charles W.. M.D. - Professor of internal Medicine, Division of
Immunology. Washington University Medical School, St. Louis, MO.
Peters, John M., M.D. - Associate Professor of Occupational Medicine,
Harvard University School of Public Health, Boston, MA.
Peterson, William F., M.D. - Chairman, Department of Obstetrics and
Gynecology, Washington Hospital Center, Washington, DC.
Petty, Thomas L., M.D. - Professor of Medicine; Head, Director of
Pulmonary Medicine, University of Colorado Medical Center, Denver, CO.
Rall, David P., M.D. - Director, National institute of Environmental Health
Sciences, National Institutes of Health, Research Triangle Park, NC.
Rauscher, Frank J., M.D. - Director, National Cancer Program, National
Cancer Institute, National Institutes of Health, Bethesda. MD.
Reinke, William A., Ph.D. - Professor, Department of International Health,
The Johns Hopkins University, 8altimore. MD.
Renzetti, Attilio D. Jr., M.D. - Professor of Medicine, and Head, Pulmonary
Disease Division, The University of Utah Medical Center, Salt Lake City,
UT.

Ringler, Robert L., Ph.D. - Deputy Director. National Heart and Lung
Institute, National institutes of Health. Bethesda, MD.
Robins, Morton, M.D. Health Consultant, Westat, Inc., Rockville, MD.
Saffiotti, Umberto. M.D. - Associate Director, Carcinogenesis Program.
Division of Cancer Cause and Prevention, National Cancer Institute,
National Institutes of Health, Bethesda, MD.
Schuman, Leonard M., M.D. - Professor and Head, Division of Epidemiology,
University of Minnesota School of Public Health, Minneapolis, MN.
Shimkin, Michael B., M.D. - Professor of Community Medicine and
Oncology, School of Medicine, University of California at San Diego,
LaJolla, CA.

Stamler, Jeremiah, M.D. - Professor and Chairman, Community Health and
Preventive Medicine and Dingman Professor of Cardiology, Northwestern
University Medical School, Chicago, IL.
Underwood, Paul B., Jr., M.D. - Professor, Department of Obstetrics and
Gynecology, and Director of Gynecologic.Oncology, University of South
Carolina Medical School. Charleston, SC.
Van Duuren, Benjamin L., M.D. - Professor of Environmental Medicine,
institute of Environmental Medicine, New York University Medical
Center, New York, NY.

Victor, Maurice, M.D. - Professor, Department Head, Neurology, Case
Western Reserve, Cleveland, OH.
Wynder, Ernest L., M.D. - President and Medical Director. American Health
Foundation, New York, NY.

xii


The following staff persons at the National Clearinghouse for Smoking and
Health or at the Center for Disease Control contributed to the preparation of
one or more reports whose chapters are included in this report:

Richard H. Arnacher, Elaine Bratic, Marjorie L. Brighman, Kathryn Carlysle.
Emil Corwin, Winthrop N. Davey. M.D., Lillian Davis. Mary E. Dement. Julia
M. Puller, Sandy Harris, Annabel W. Hecht, Gertrude Herrin. Priscilla B.
Holman, Robert S. Hutchins, Theresa Klotz, Jennie M. Jennings. Nancy S.
Johnston, Sanda Lager, Seth N. Leibler, Ed. D., Rosalie Levine. Mary
Mitchell, Dan Nemzer, Mildred Ritchie. James A. Robertson. Donald R.
Shopland, Kathleen H. Smith, Elsie Van Valkenburg, and Richard W. White.

. . .
Xl11


Chapter 1

Oveniew - The Health Consequences of Smoking

Source:

1975 Report, Overwew - The Health Consequences of Smoktng.
              pages 1 8.

1


OVERVIEW - HEALTH CONSEQUENCES OF SMOKING

  The statement, "Warning: 77re Surgeon General Has Determined
That Cigarette Smoking Is Dangerous to Your Health," has been
required by law on cigarette packaging since 1970 as a part of the
Public Health Cigarette Smoking Act of 1969. This Act was a
response by the U.S. Congress to the scientific information on the
health consequences of cigarette smoking summarized in reports then
avaiIabIe (the Surgeon General's Report of 1964 and the subsequent
1967, 1968, and 1969 PHS Health Consequences of Smoking). This
Act was passed because a series of important questions concerning
cigarette smoking and health had been answered.

  The following discussion summarizes the basic questions, the
methodology used to determine the answers, and the answers
themselves.

  The initial question to be answered concerning the health
consequences of smoking was "`Are there any harmflt/heaIth effects
of smoking cigarettes?" The answer to this question was provided in
two ways. First, it was demonstrated that some diseases occurred
more frequently in smokers than in nonsmokers. Second, a causal
relationship was established between smoking and these diseases.

  Concern about the possible health effects of smoking started
when scientists began looking for an explanation to account for the
rapidly increasing death rate from lung cancer. The early retrospec-
tive studies showed a link between lung cancer and smoking. The
first prospective studies, however, found that only oneeighth_of.the
excess overall mortality found among smokers could be accounted
for by lung cancer; the rest was 1argeIy due to coronary heart disease,
chronic respiratory disease, and other forms of cancer. They also
found that the effect on overall mortality was largely confined to
cigarette smokers rather than the users of other forms of tobacco.

  However, demonstrating an association by statistical probability
is not enough to establish the causal nature of a relationship.
Deterpining that the association between smoking and excess death
rates is cause and effect was a judgment made after a number of
criteria had been met, no one of which by itself is sufficient to make
this judgment. These criteria as listed in the Surge0;: General's

3


Advisory Committee Report (1964) were the consistency, strength,
specificity, temporal relationship, and coherence of the association.

  In addition, con.vincing theories about the mechanisms whereby
smoking contributes lo the various diseases responsible for the excess
mortality among cigarette smokers were developed from the evidence
on the biochemical, cytologic, pathologic, and pathophysiologic
effects of cigarette smoking, thereby providing the necessary support
for the decision that the relationship was causal.

   The most important specific health consequence of cigarette
smoking in terms of the number of people affected is the
development of premature coronary heart disease (CHD). Boih
prospective and retrospective studies clearly established that cigarette
smokers have a greater risk of death due to CHD and have a higher
prevalence of CHD than nonsmokers. Long-term followup of healthy
populations has confirmed that a cigarette smoker is more likely to
have a myocardial infarction and to die from CHD than a
nonsmoker. Cigarette smoking has been shown to be one of the
major independent CHD risk factors and to act in combination with
other major alterable CHD risk factors (high blood pressure and
elevated serum cholesterol). Autopsy studies have shown that
persons who smoked cigarettes have more severe coronary athero-
sclerosis than persons who did not smoke. Physiologic studies and
animal experiments have indicated several mechanisms whereby these
effects can take place.

  A second major health consequence of smoking is the develop-
ment of cancer in smokers. Cigarette smoking was firmly established
as the major risk factor in lung cancer. The risk of developing lung
cancer was found to be 10 times greater for cigarette smokers than
for nonsmokers. The risk of developing lung cancer increases with
the number of cigarettes smoked per day and is greater in cigarette
smokers who report inhaling, who started smoking at an early age, or
who have smoked for a greater number of years. Smokers of filter
cigarettes have been shown to have a lower risk of developing lung
cancer than smokers of nonfiiter cigarettes, but the risk remains well
above that for nonsmokers. The risk of developing cancer of the
larynx, pharynx, oral cavity, esophagus, pancreas, and urinary
bladder.was also found to be significantly higher in cigarette smokers
than in nonsmokers. Pipe and cigar smokers were found to have
elevated risks for the development of cancer of the oral cavity,
pharynx, larynx, and esophagus when compared to nonsmokers.
Fewer pipe and cigar smokers than cigarette smokers report that they
inhale. As a result lungs of pipe and cigar smokers receive much less

4


exposure to smoke than the lungs of cigarette smokers. This is
probably the primary reason for the lower incidence of cancer of the
lung for pipe and cigar smokers compared to cigarette smokers.

  Women have had far lower rates of lung cancer than men. This
has been attributed to the fact that fewer women than men smoke
and the fact that women smokers generally select filter and low tar
and nicotine cigarettes. However, the percentage of women smokers
in the United States has increased steadily in the last 30 years, and
since 1955 the death rates from lung cancer in women have increased
proportionately more rapidly than the rates for men, reflecting this
increased proportion of women smokers.

  The tar from cigarette smoke has been found to induce
malignant changes in the skin and respiratory tract of experimental
animals, and a number of specific chemical compounds contained in
cigarette smoke were established as potent carcinogens or cocarcino-
gens. Malignant changes including carcinoma in situ were found in
the larynx and in the sputum exfoliative cytology. of experimental
animals exposed to cigarette smoke.

  Nonmalignant respiratory disease is a third area of smoking-
induced morbidity and mortality. Cigarette smokers have been
shown to have more frequent minor respiratory infections, miss more
days from work due to respiratory illness, and report symptoms of
cough and sputum production more frequently than nonsmokers.
Retrospective and prospective studies with long-term followup have
found that cigarette smoking is the primary factor in the develop-
ment of chronic bronchitis and emphysema in the United States.
Cigarette smokers have also been found to be more likely to have
abnormalities of pulmonary function and have higher death rates
from respiratory diseases than nonsmokers. Data from autopsy
studies have shown that cigarette smokers were more likely to have
the macroscopic changes of emphysema, and that these changes are
closely related to the number of cigarettes smoked per day. MUCOUS
cell hyperplasia has been found more often in cigarette smokers.
Cigarette smoke aIso inhibits the ciliary motion responsible for
cleansing the respiratory tract.

  An additional area of health concern has been the effect of
cigarette smoking during pregnancy. Mothers who smoke cigarettes
during the last two trimesters of their pregnancy have been found to
have babies with a lower average birth weight than nonsmoking
mothers In addition cigarette smoking mothers had a higher risk of
having a stillborn child, and their infants had higher late fetal and

5


neonatal death rates. There are some data to show that these risks
due to cigarette smoking are even greater in women who have a high
risk pregnancy for other reasons. These effects may occur because
carbon monoxide passes freely across the placenta and is readily
bound by fetal hemoglobin, thereby decreasing the oxygen carrying
capacity of fetal blood.

  Having established that cigarette smoking is a significant causal
factor in a number of serious disease processes, two additional
questions became important. They are "Can the health consequences
to the individual be averted by stopping smoking or by changing the
cigarette. " and "What are the overall public health consequences of
cessation and of the changes made in cigarettes?"

  The first question is the simpler of the two to answer. In the
individual, cessation of cigarette smoking results in a rapid decline of
the carbon monoxide level in the blood over the frrst 12 hours.
Symptoms of cough, sputum production, and shortness of breath
usually improve over the next few weeks. A woman who stops
smoking by the fourth month of her pregnancy has no increased risk
of stillbirth or perinatal death in her infant related to smoking. The
deterioration in pulmonary function tests that occurs in some
smokers becomes less rapid than that of continuing smokers. The
death rates from ischemic heart disease, chronic bronchitis, and
emphysema also become less than those of the continuing smoker.
The risk of developing cancer of the lung, larynx, and oral cavity
declines relative to the continuing smoker in the first few years after
cessation and IO to 15 years after stopping smoking approximates
that of nonsmokers. A smoker who switches to filter cigarettes and
has smoked them for IO years or longer has a lower risk of
developing lung cancer than a smoker who continues to smoke
nonfilter cigarettes. The risk to a filter cigarette smoker, however,
still remains well above that of a nonsmoker.

  The public health benefits of cessation are more difficult to
determine than the effects of cessation on the individual. Just as
cause-specific death rates have reflected the effect of cigarette
smoking on certain diseases, they should also reflect any substantial
benefits to be gained by cessation or reduction in cigarette smoking.
Several factors combined to produce a reduction in per capita dosage
of tobacco exposure in the United States for the years 1966-1970.
First, per capita consumption of cigarettes declined from 4,287
cigarettes per person in 1966 to 3,985 in 1970. Second, during this
period there was a slow but significant decrease in the average tar and
nicotine content of cigarettes as well as a decrease in the amount of

6


tobacco contained in the average cigarette. The decline in per cnplfa
consumption during those years occurred in the face of a substantial

, increase in the proportion of young women becoming smokers as
cornpared to women of previous generations and SO reflected

t predominantly a decrease in cigarette consumption by men.

   Since 1970, although the per capita consumption of cigarettes
has increased. the average levels of tar and nicotine have continued to
decline, making it more difficult to predict what has happened to per
capita dosage.

  Examination of cause-specific death rates for the period of this
declining per capita consumption reveals that there was a downturn
in the male death rate from ischemic heart disease beginning in 1966
which reversed the upward trend that had occurred over the previous
two decades. This decline in the death rate from ischemic heart
disease has not occurred in women.

   The male death rate from chronic bronchitis has also been
declining since 1967, and the male death rate for emphysema has
declined since 1968 when it was first recorded as a separate category.
Female death rates for these two diseases have not shown these
trends.

  Despite the impressive coincidences of the decline in death rates
among males occurring at the same time that there was a decline in
per capita cigarette consumption, it is impossible to be certain of the
exact cause of the decline in the death rates. These diseases are
influenced by a variety of factors in addition to cigarette smoking
such as blood pressure and air pollution. Some of these factors have
also been subject to major control efforts which may have
contributed to the decline in the death rates. In addition, there have
been therapeutic advances in the treatment of these problems which
may also have helped lower the death rates.

  A decline in male death rates from lung cancer should also
follow the decline in per capita consumption. This rate would not be
influenced as much by changes in other etiologic factors or changes in
therapy because cigarette smoking causes from 85 to 90 percent of
all lung cancer and there have been no major improvments in survival
due to changes in therapy. With lung cancer, however, two
additional considerations must be kept in mind. A decline in death
rates from lung cancer would be expected to lag several years behind
a decline in per capita consumption. In addition, the decline in
consumption and switch to low tar and nicotine cigarettes occurred

7


predominantly in the younger age groups where death rates from
Lung cancer are low. For these reasons, it is necessary to look at lung
cancer death rates by age group rather than total lung cancer death
rates. The lung cancer rates by age groups for 1971 suggest a decline
in the lung cancer rates for the younger males (under 4S), but the
confidence limits on these trends at present remain wide enough
that it is impossible to say whether this is a real decline or merely
a leveling off. The national health statistics broken down by 5-year
age groups are currently available only through 1971. The data by
age group from a few more years will be necessary to determine
whether the changes in smoking behavior which have taken place
have reversed the trend of the preceding 4.0 years of continually
increasing lung cancer rates in men. In 1971, the last year for
which detailed mortality statistics are available, the accumulated
exposure to cigarettes reached its peak among men born between
19 I5 and 1919, a group then in their early 50's. Cumulative
exposure has continued to decline with each successive S-year birth
cohort born since then. The trends of the last few years offer some
hope that the peak of the "lung cancer epidemic," as some have
termed this phenomenon, may have been reached with this group
and that future years will show a slow but consistent decline.

8


Chapter 2
       cardidar~s

Pan I - 1971 Rspori, Chapter 2, 15 - 174.
                     paQa
Pan I1 - 1975 Remrt, Chapter 1. 9 - 38.
                     paws


Chapter 2

Cardiovascular Diseases

Part I


Contents

Introduction

Paga

   Smoking and Obesity . _ . : i - . . . . . . . . _`. . . . . . ii-; `. `. : :!; 39
   Smoking and Electrocardiographic Abnormalities. I.--I; 43
    Smoking and Heart Rate . : .`;-:t.`: ;:i;..' i,   .;-  .I ..,>
                                         _, .`_*.*._`. . . . .  43
The Effect of Cessation of Cigarette Smoking on Coronary i
Heart Disease.. . .";. ; ::; ::`;f: _ 1';. e5'.:1'l      
                          . , . .". `: i 1` ; 5' . . :' . . . ,-.y'T. 43
The Constitutiona] Hypothesis ;: .;~J:-~-~,~: ;:!;:Y,< ,`t.: ;:,I )y.F.>  44
Autopsy Studies Relating Smoking, ~Atheros~lerosis, and ~' "- ti
Sudden CHDDeath . . . . .`;:..`; .!..`~...`.~.~.;:`....~~`~.I':i'~')::  48
Experimenta Studies Concerning `the `Relationship of '
Coronary Heart Disease and Smoking . . `. .: : : : : . ; : . `. .`." `.'  52
Cardiovascular Effects of Cigarette Smoke and
  Nicotine . * - , _ , -`.":" ." I  `;I,'   a;;:,
                       . . .._.............._........   52
  Coronary Blood Flow _ . . . . _ .
                  `. .I,o.y'L'; P .:t &j.`;;:!:`! *1! !&j `<>*<..a.irTJr; ;`-
                             . . . . . . . . . . . ..-....... ) :54
Cardiovascular Effects of Carbon Monoxide . ;i .`i; I. 5 ::f. 1 .`i'.55
Effects of Smoking on the Formation of Atherosclerotic  _,`.
   Lesions       -- .-..- I-, II--     . .I `i
            . . . . . . . . . . . .._. . . ...`::. . . . . . ..-.. .:;r'.. .
The Effect of Smoking on Serum Lipid Levels . . J:~!:~ ;; ?:s- 59
                                  .f 61
The Effect of Smoking on Thrombosis . i; ;:;J.:. :Y,:.,`~~~~l~`~~~ 62
Other Areas of Investigation               - _L.
                                       ._
                      . , : ., . . ., . . . . ., . . - - .-. :. 2 - , .

               . . , -* , ?Z I. . Iit. i . . . . . . ,:;-, '..,,' *- . :; 62
Nonsyphilitic Aortic Aneurysm . . y.;. . `. . . .:. ;`I-. . .,;r:t:!.r.~r.- .'  63
Peripheral Arteriosclerosis . ;`.`. .: ; . .-::`;:!u. ;. ;. . . .: ::1?-:3!;.$68
                -`.,:r--`:;i~ ,`) -, .,? := i ,*,-' ,r`
`. Experimental Evidence.`:".~~.;.",~,~!,I^;.!;.-f!~,.: ~~~;, ,:,r-:  I- .69
Thromboan.itis ObIiteran;Y :`~:x-~iif*:i?~~. f;:F:nfi- ./-:s;f :+.3 `,;Q-j
                        . . . . . . . . . ..`................
Summary and Conclusions . . . . . . -. .- `eiIj,ure -, `!::,y-;.p::2,
                          . . . ...* :..- . . . . . s..: . . . . -.
              _ _...,, W..`.`. I-.--.

13


  -Coronary Heart Disease . . . . _ . _ . _ . _ . .
  Coronary Heart Disease . . . . _ . _ . _ . _ . .           Pap
                                    Pap
                                      ..-..-....a..
                                      ..-..-....a..    70
                                          70
  Cerebrovascular Disease . . . . _ . . _ . _ . . . .
  Cerebrovascular Disease . . . . _ . . _ . _ . . . . . . . ..-......
                                       . . . ..-......
  Nonsyphilitic Aortic Aneurysm . _ . . . . . .
  Nonsyphilitic Aortic Aneurysm . _ . . . . . .            71
                                         71
                                       . . . . . . ..---.
                                       . . . . . . ..---.
  Peripheral Vascular Disease _ . _ . . . ; -. . .
  Peripheral Vascular Disease _ . _ . . . ; -. . .            71
                                         71
                                       . . . . . ..-....
                                       . . . . . ..-....    71
                                           71
References.. _ _ . : :... . . . _ ; :;.;+;ii;;T F
References.. _ _ . : :... . . . _ ; :;.;+;ii;;~ F            .' .'
                   `,............~`."""
                   `,............~`."""   71
                                         71
                           ,..
                           ,..
                 FIGURES
                 FIGURES

`11 National Cooperative Pooling Project, Inter-Society Com-

3  ~ssion for Heart Disease Resources, :;. `!,: .+ ..; I, ,,., i c r . .
               .2-i.-. ,"`+."...j_.~ 1g
p Risk of coronary heart diseas;?"(l2 years) according to   .--
..&; . . cigarette smoking habit and-presence of "p&&&ing
j';. factors" .(men 30-59 at entry). Framingham Heart
$!. cl -\- `Study. .`:`---.`:.`:`.`::"-"`:`::.-"` "
                     a.. . . . . :. :. . . . . . .
               . -s- : I . - .;,;.-.;-;,'
               ratio: "i'ca 17-51   2.
3. Estimated coronary heart disease'death
  year follow-up, and frequencies of paired combinations
  of six high-risk characteristics in college, for all ages
   at death _ . . .                    .I     ", `_
                . . . . . . . . . . . . . . . . . . . . . . . ;..ii- ,-..... . .   21
4. Relationship between smoking status and serum choles-
  terol level at initial examination, and incidence of chn-
  ical coronary heart disease in men originally age 40-59
  free of definite CHD. Peoples Gas Light and Coke
  Company Study, 1958-1962.. . . . -1.. . . . . . . . . .,. :. . . . . . ~. -39

6. Average annual incidence of first myocardial infarction
  among men in relation to overall physical activity,
  class, and smoking habits ,,(age-adjusted rates per
1,000) . . . . ..'.~.........; . . . . . . . . . . . . ..1..~.....-.'40
       . :.: 1i- 1 _,a   , . . ::._a , _ .;. _-<.  .; :...I
                  _, :-.
       aLIST OF kABiESs'   -, . . ; . J. ~..~~j'~'.-~~~;jsij~
                                           -: , : .
(A indicates tables located in Appendix at end of Chatte;? ::, ji;L2,.
           .._ .._ . . . L . . . .   ._. ,. I
1. Sudden death and acute mortality with first major.-:
    coronary episodes . 1 . ; :`; . ! :.I:. .e.:. :. ; ;r:`.`.-. . . r-y::  19

2. Coronary heart disease mortality ratios related to
   smoking-prospective studies. _ -mci-J; ;IJedz:i.>< ..`;`.`.=~:rc-, ,.22
3. Sudden death from coronary heart disease related to :`. - '
   smoking _ ..; -. ;r - - .-; . . . . :< ;`.-; . -`. ..-i;! _ ;`: /. `$i*;;. .`.:r!-!f; 26
4. Coronary heart disease morbidity as .-related .to .<%TL?-~
  smoking. _ .; :. . . . .:. . . . . . .;. . . . . . . . -; 1 :.;-:-:,:.- ;,;~&;_?~~
5. Coronary heart disease morbidity as related to smO~~,R~~.~ &d
  ing-angina pectoris-prospective studies Y.`: i -.-. .rX2 33
A 6. Coronary heart disease- morbidity and modid+-

r  retrospective studies `. . .-. . . . .`. . .' .`.- ; y'. ;-.       ::w,
                    ~.>,:Ai.:-,.L:~t8g
                                        . . . . . : . . -
A 7. Differences in serum lipids between smokers and non- r"c!l'%.
  smokers.                            .1---- --.
              . . . . . . . . . . . . *.......-......   . :. . .  -.94

EI
~_ - --
14


usr 0~ TABLES (CONT.)

  [A indicates tables located in Appendix at end of CII~~~~,
    ^                                  Page
A 8. Blood pressure differences between smokers and non-   i
   smokers . . . .-;.: 7:. m-i,;`.-,r-            :-
                   .I.. -:..;; . . . . :.:.-.r`.-.::~):.`,,  99'
9. Death rates from coronary heart disease, by systolic - +J
k -L - blood pressure: ILWU mortality study, 1951-1961   38
10. Death rates from coronary heart disease, by diastolic : !:J::'
-,
% ..L  blood pressure : ILWU mortality study, 1951-1961   38
.-II. Death rates from coronary heart disease, among hy- ..?- ;;bl:
   pertensives and nonhypertensives : ILWU mortality ' 1 t-j ;
   study, 1951-1961_. ;:..:F:': ;`I. ;;;~;;.f~.i ;+ j: F?;< :i.yi-i.>{rg ,38
,12. Death rates from coronary heart disease among men. ,a;
   without abnormabties related to cardiopulmonary
   `diseases by weight classification in 1951: ILWU
   morfa1if.y study, 1951-1961. : ;":`;`!?":?~~`:?;!:?;~-I:;`-.::`;:!   41
13. Death rates from coronary heart disease, by electro- :

    cardiographic findings in 1951: ILWU mortality
    study, 1951-1961.............................
14. 1958 status with respect to heart rate, blood pressure,
    cigarette smoking, and ten-year mortality rates, by
    cause (1,329 men originally age 40-59 and free of
    definite coronary heart disease) Peoples Gas Com-
    pany Study,1958-1968.......................
15. The effect of the cessation of cigarette smoking on the
     incidenceof CHD . . . . . . .._.._......._........
16. Annual probability of death from coronary heart dis-
    ease, in current and discontinued smokers, by age,
    maximum amount smoked, and age started smoking
A 17. Incidence of new coronary heart disease by smoking
   category and behavior type for men 39-49 years
   of age --.........................-.~........
A 18. Incidence of new coronary heart disease by smoking
                                        -- --

101

    category and behavior type for men 60-59 years
   of age . . . . . _ . . .`. . _ . .3 . . _`. . . .: .-T. .`1 .: . . . ..-. _ . .  302
19. Autopsy studies of atherosclerosis _ . . _ . . . . . . . . . . . .  49
A 20. Experiments concerning the effects of smoking and
    nicotine on animal cardiovascular function . . . . ; . 103
A 21. Experiments concerning the effects of smoking and
    nicotine on the cardiovascular system of humans. .   109
A22. Experiments concerning the effect of nicotine or    

   smoking on catecholamine levels          - 115
                                   e.......,.......
A 23. Experiments concerning the atherogenic effect of
    nicotine administration                  - .- 116
                           . . . ..-..................

41

41


42

42


     LIST OF TABLES (CONT.)
(A indicates tales located in Appendix at end of Chapter)

Page

24. Experiments concerning the atherogenic effect of
   carbon monoxide exposure and hypoxia _           60
425. Experiments concerning the effect of smoking and
   nicotine upon blood lipids (Human Studies) *' rx.-.--rclf-
                                            .----s   119
C125a.Experiments concerning the effect of smoking and.<f`16! .
   nicotine upon blood lipids (Animal Studies) -f--C z-.`,! 123

A 26.

4.27.
28.


29.


A 30.


         ~INTRODUCTION
Coronary Heart Disease (CHD) cuts short the lives of m&y
men in the Western World in their prime productive years. More
Americans die from heart disease than from any other d&ease- In
1967, in,this country,-a'tota-of 345,154 men and 227,999 women
were classified as dying `of arteriosclerotic heart disease (ASHD)
(196), a category which consists largely of what is commonly
called CHD. During the years,from 1950 to 1967, the age-gdjusted
death rate from ASHD increased 15.1 percent (196, 197).
: Besides the many deathsattributed to CHD, much morbidity
results from this disease. The National Health Examination Sur-
vey of 1960-1962 estimated that 3.1 million American adults, ages
18 to 79, had definite CHD and 2.4 million had suspect CHD,
together representing about 5 percent of the population. It was
further estimated that of Americans under age 65, almostl.8 mil-
lion had definite CHD and 1.6 million had suspect CHD (195).
There are several manifestations of CHD, all related in part to
the basic process of severe atherosclerosis, a disease of arteries in
which fatty materials (lipids) accumulate in the form of plaques
in the walls of medium and large arteries. This process, as it occurs
in the coronary arteries, leads to stiffening of the wall and narrow-
ing of the lumen which, when severe, result in a diminution in the:
blood Supply to the cardiac muscle. Angina pectoris, a major mani-
festation of CHD, results from diminution in blood supply relative
to the needs of the myocardium. If the blood supply to a portion
of the myocardium is completely obstructed, due for example to the
formation of a thrombus at the site of atherosclerotic narrowing,
necrosis or death of a portion of heart m.uscle. may occur.2his
occurrence is known as a myocardial infarction. In many cases, a
disturbance of cardiac rhythm occurs at the time of thrombosis,
and the patient may die imkediately. It is estimated that approxi-
mately 25 percent of patients suffering coronary artery occlusion
die within the first three hours following the occlusion (table 1)
(88). Not infrequently, sudden death occurs in patients with severe
coronary atherosclerosis but without a demonstrable arterial OCC~U-
sion. In these cases, it is thought that the meager blood flow to a
portion of the myocardium becomes so diminished with respect ,tO
cardiac needs as to lead to a fatal arrhythmia, as well as to, per-
haps, a myocardial infarction.


                                                                 _I  . .        I .
CIMRiTTS! IWOKINO !a AT emTRY-WITM CDrnL Df !ERUY CHOUrrrROL (
AND MORTALITY MT   7,594 WHITE UMES APE SO-49 AT ENTRY, POOLINO P  JECT
                        %o AND &~,DLJC';LDDD ,,i&I&-AND YKN YEAR INCIDENCE
                                                                 
                                         171                :i b, ;; :;   ;;
                                                           ;.". _*,


,,,
;
   2 FIOVFJZ l-National Cooperative Pooling Project; smoking status at entry and M-year ag&adjus;ed rates per 1,000 men for
:.
..I, : /- -
5 ,,-  first mqjor coronary event (includes nonfatal MI, fatal MI, and sudden death due to CHD) and any coronary death. U.S.
    r, :
.l',    white males age 30-69 at entry. All rates age-adjusted by 10 year age groups to the U.S. white male population 1960,
; -' \`I. ,I .? c; Graphs present rates for noncigarette vs. cigarette smokers at entry with simultaneous control of blood pressure and serum
 ,,`.`,. - :J cholesterol level. For this latter analysis, the following cutting points were used: _
`. ".$, ;
I'.'  ." -; i.:
..,:.       (a) Cigarette smoking-S-any use at entry
.,", `,`W .&                                                                           
        (b) Serum cholesterol-C-~260 mg./dl.
,j : ;.,, ;*< :;, :.' `, (c) Diastolic blood pressure-H-290 mm, Hg.    _I                                          .
    ,- ..d'.
::, `,: ey ,
: :T' s~ `:. k-q ~OUECE: Inter-Society Commisiion for Heart Disease Resources,
I d.1. L) . v


I-









I -

                     `.; ,
m >lmPKG./DAY  `1,' .  1 ' `.' 196'
            .s ,  .  ,: .z..A:,, ___;

37

-










12
x7
-

NONE             ANY ONE    . 7'.    P
               

PREDISPOSING FACTORS (CHOLESTEROL > 250. HYPERTENSION. DIABETES)
*SIGNIFICANTLY DIFFERENf FROM "NONSMOKER" P<.D5   ,. .$. ._   =
                       
                       <.        ,         7 ,: :;
                                       : _ + 3 _-
                       . .                   .= `.-

E~CURE Z-Risk of coronary heart disease (12 years) according to cigarette
smoking habit and presence of "predisposing factors" (men 30-59 at entry).
Framingham Heart Study.        . .:
SOURCE: Kannel, W. B., et al. (9.4). _ $-,         f    `.: ; .I< 1..
                                                 --      _-
                                        :,;: _,
                                          :.  ;.     ,_* :: : : _
     <                         .          .     ;;..    1, .F
     :                                    -`. I    *    ,`<
             : : ;' r.. -- ., _ :                   ; 1   s-j ^I __ .;,` -i
                 I             .
                              _-            I   +.    .Y
Numerous epidemiological studies have indicated that cigarette
smokers have increased mortality ratios for CHD ; that is, cigarette
smokers show significantly increased death rates compared with
nonsmokers (table 2). The risk incurred by cigarette smoking in-
creases with increasing dosage and, as measured by mortality
ratios, is more marked for men in the younger age groups, under
age 60, although the absolute increment in death rates experienced-
by smokers over that of nonsmokers continues to increase with
increasing age. Table 2 lists the mortality ratios found in the major-'
studies. Certain of these studies, including those at Framingham,
Massachusetts, the Health Insurance Plan of Neti York City
(HIP), and at Tecumseh, Michigan, have analyzed morbidity as
well as mortality from CHD and have indicated that the risk of
developing fatal and nonfatal CHD is greater among -cigarette
smokers than among nonsmokers (tables 3 and 4). Conflicting
etidence has been published concerning the relationship of ciga-
rette smoking and the incidence of angina pectoris. While some

20


   CI**nttn --I
3   SF. BP 130+ --B
              2.4
         .    131
2              140
      1.4   1.4
  LO   238   201
1   324   442   373
clI!Il
  644
O-  I

  CI~."ttsl `-A
3   H,ilhl <69 -B

            2.0
2
  ---.. 1.5       96
          I.3   124
  1.0   Z??
1 Lllllh
          199
  346 468   394
  875
0

no rpxt-A
SP. BP no+ -6
. _- :`:.

I

O-

i

    C' ! .  k. .1.
2              1.1               1.9
                        ).
              7b           1.3   124
             102    1.0   1.1  -  149
1                          232
                         4`2

        ,-
sp. BP 130+ _A

hnnl dud --II :
. . ;         2.5

  3



  2


' 1


10



  3

.._ 2


  I


-0



3



_ 2


  I



-0


3


2


1



-0



3

/- A+ A- A+


TABIF. 2.-Cormry heart disease mortality

                 (Ati number of dathm

  [SM = SmoLcn

    AMhOG                .* __.
    ,a=,
   amnh. Nmbcr,d .~. --. `: ;
      pOD&tiOn " Data
   rcfermm           cdkctIon

  Hunmoad  187.7BS   QucaLIm-  ;"I a% 6.297 NS . . . . . ..!!l.OO (709)
   md     rhItcmrkm   nab.? md   __-.___  -.----.-Msmokcn .1.70 (assl)
- Horn.     fne.t.ba
- 1968. '   c&-69 ,e*n
   V.SA    oflpr    - mate.
-\   (,,, ,I).   _, _. , :

:
t
  `.


`(v<O.M)l)

Doll and    Avvmri-    QrreLdion-     10     1.S76 NS  . . . . ..-. 1.00          .
Ea.      matd      n&c and              All amokera .l.SS
1964.     41.000     : fouoa-~p   --.      f !      1-14  _ . . .129    .i.` .,
Grut     rmk British  ofdatb j   `?t .- . 16-24 . . . .137   , _ I 1 :
Bri~b    Vh~kh~~.  -&l*. . .---I `;: . :.i. - -`:>26 . . . . . . ..*.43
(50).                          :                 : ,, ,- I
                        .-      ,,     . . ,(;:,
                                                    7

stmbel    a.743 male   Question-      e      162  NS  . . . . . . ..LOO

md Gc.eU  eSti phy-  enrim and       :..                   i _
                                               -;:,..>-.c     -2
1966      skiam.     fOUOW-Up      I.__ _,    l-20  . . . . ...1.48
swit.mr-         of death
hnd . -7                 ' ">20 ________ 1.76   (`c: 1,

                crrti6ute.                                  

(150).                    .--         i ~~

Bat.     Appmri-    Quatioa-      6
    mat.& `. , naircmd L :-7 j _ 2.000 NS  . . . . .._. 1.00
1966                           Allsmoker, .I.60 (1380)
Ctnadn    78,cmo      fOlhLWD   c- ; ,tt,;j .-is
                    ;, `Z I;,..  ;:_- <lO ..____.f 1.66 (937)
@I)-  ___ mdecana-   of death               lo-20 . . . ...1.68
    . dhn _. I `ertifiutc ..L,.,:iT_;`t-             (766)
                         >20 ..:..::1.78 (277) --,:
     returns. `- r.      a:  ; _L;;,~ -2                 ,I
                                                ,kF .,

lrdm
1966
U.S.A.
. (88).

us. In&    Qoestion-      8%   10,890 NS ________ 1.00 (2997)
  vctcrula    nrire and           Allsmokcrs .1.74 (4160) :
  2.266.674   fouoov-up :, -.. :" 1-3 ..-.__-. 1.39 (43SP ; :`..`.
   Del-m   ~I. of dalb  _ry t :- ..`I   IO-20 _.._. .1.78 (2102)  1'   : :
i Jan.
I '           ecrticlute. '           PI-39
          . I      ; I               ___.._ 1.84 (1292)   ;
. .
1         fl .,y.-, : ;   : : 7-q ;-`,l,. c 2
                         . . --?>39...... . .-.f.OO (266)   i.

Hhw. 266,118     Rmincd in-   * 1     91  NS ____ ____ 1.00 fl7)    .

nmks LIcdiulu-    l2      62 NS ..__ .-..l.OO (27))


ratios related to smoking-prospective studies
dlcmn b parentheses)'

NS = Nonamokenl

                          -

_.-

                           . .                              
  .~           __-_
    Cigars      I. ,...
NS..l.OO .- `- : NS ..`.   so-Sb   6649    6-I    6548
                   . . . . . 1.00 190) 1.00 (142) 1.00 (204) 1.00 (273) . rI.C : b,.?zmG
SM..1.28 (420) ..AUsmokcrs .193 (765) 1.85 (962) 1.66 (921) 1.41 (718) .<., .,,,:,!;,.;
    Pipu           . . . . . . ..I.38 (36) 1.98 (60, 1.17 (49) 127 (68)
   NS..l.W -  -""l<bp20 .:. ..2.00 (213) 2.04 (268) 1.91 (236) 1.68 (168) :;   -.A;;

   fZd..l.OS (312)                    `_ ' &.;r
      >20 . . . . i::.Z.Kl (203) 2.47 (199) 1.92 (129) 1.66 (78) .t z -s:. :;.$> ).
                                                 ,, '

                                               Data WDIJ
                  : . . 7.
                        . . .
                : : ~. ._                        or& to maks
                 . .                             4red40-49
                                 -.                  md irea
                                        CucED~t
                                       entw.NS
                                              Include Dive,

               .___ ~. ~----. ._.-._. ---  __. _.._ -..-  _. -. --._-. .
~~~___~ _ -- .- ..---                                  eksrmd
          :        .-I    : I     a:;-. I,    . ..-f..  er-amoken.

                  Sd-bb   bsmb    85-64 : .          
          NS  . . . . . . . ..l.OO   1.00     1.00                   :t.: .
           I-14  . . . . . .x73   : 1.40     1.71 !             ? _ : 
          lb24  . _. . .4.46     1.79     1.27    . . :              i.%.
          >26  . . . . . ...1.36     1.92     1.68 --.
                                    -..-.-   _ _.   _ _
            _. .~ _ .- _- -   _- - -

                                                      
NS. .I.@,
sy..1.46          .I                        :
                   -                               
                                 ;.:-.. ._,      : :


Tllsu 2.-Coronaty heart disease mwtdity ratios
                      (A&ml number of dacha

                           (SM = Smokrn

5mond

:c4*!`1L- :,                       C..,`.".
ti-.:t !N-z           _'
                 ., ;-:-- -._ :
                             . . . .
`2 t:.!iJ` .               :     : . . I; ,.. :..,  :.
c i:..Z!.-           :.   . . . ._
                                  ::


Paffcnbu- 60.000 m&   BUClIlIIT     17-61    1.146 NS  . . . . . . . . 1.00
zcr md ._ former    intervIew   -..--r-mddxd  24 . . . . . ...1.60  (886)  (D<o.ol t
Wing     studenta.    and cx.m-     `h-,d& . . ,(
198D              indon and     gl: * .&2  . . . :2-c
                                      
U.8.A.          follow-up     ".control. : -. L. :
(Ill)              br death       -`.L    -..L _. .   :-;.
                ccrtiflute.      `-.i .    ;:.; .,    .~        

Pa!Yeobm- 6.263 male   lnltlsl muIt& 16     tel   NSmd<20 1.00 (137)
*er et II.   Jonpaborc-   DbMiC              SM >20  . . ..z.os
1970.     men 8664   screeninp
U.8&    Jean of     and follow-
(zra).    m.       09 of dcnth
                 CcrtIflc~Cs.

Tad.x   _,K71 m.l*   lntcrvlew.    6 ,_ 46   NS  . . . . . .._ 1.00   (4) ,* .,
  o ? ?o??     railroad    md rmulqr            . <20 . . . . . . . .I.97   (20) I < i.
  1970..     -Db?m   foollaw-up
- USA    4&69 ye=n ULPL-     -.: :c,  (-:, ;I! >2@ . . . . . . . .S.60   (22) c:

  (18s).    of aamat   Ln.t,on. ! : `.Z. :, 1 !I,i;; <.`.I .   `:-, <       , .:`.

Pooh    T.427 white   XedIcrI a-    10      239 NS ._._
me m&s                              . . . . .I.00 (27)
                 unIaatlm
Amdan                     :.,_ `. :-   <lO I . . . . . . .1.65  (84)  ,`,.- .I.,,.
        m-69 rearm   and
Hurt                  ;, .,
            fdow-up.          20 . . . . . . . . .I.70  (86)        .i-
        of are at
Aualc eat+.                  `=.  >20 . . . . `. . . . S.00  (68) -:,,L.
              ___ .-  _ .--w------y--_           .:     -, <-;
tJ=b                 -_.
                  :.           _ `) -               ,,.. :-., I/
                                                     
1970.                     ., ...                     * ,,,
US&                              :..

(Jr).   - : _.! , _`., + I .).
    `- .; ,.         _.'  - r. , ,:I-; ,._ .. _-. .,
                                                            
                                                       _,

24


related to smoking-prospective ntudies (cont.)

.hom in 9.~theses)I .,s'?     '
NS = Nona.a~cn] ^ A'..- --.+-.. --. .-

: T, `.
  :

   - I r - - ---~ --- -,o-"  as--51   ,s-4* , .`-.. ----- - ------ - ..
    NS . ..`...... 1.90     1.00   1.00                ,:i, `I',3 '
        .;.; (D<o.ol)                :, !L ..:mr.i'-    ,,C`^i~
                                      / , " .._     . .:: . _* -
      8X __._.__.. 160 (88) 1.60 (1613 1.20 (124)    ,.,- `>A.: :. .>t,.
                                   - __. __    ._.
.            .:vl_.,: "I _ 7:..:..-?,1      ,r; -:;    ;ic :I
    -,;.'z     ,l?:.z:. : .'    L-c,:-..- .?I- I(: ..`i -5    . ,,' ~.
               . . .

_~   ~. ~.   -. _  SC-II    b6-6b    65-d&   .86-m  . ..NSincluda __ `.
`5 .:         us _ ,....... 1.00     1.00     1.00   .`: 1.00   -, i; ?: DfDa mad   :
I-.. 2        &IO  . . . . . ...4.22     2.06     1.41   1.17  .I>l!~.`dpsm. `:   ,I .- i-
                                                          l. -,
r: `.(T ___    520  . . . . . ...6.14     a.17     1.64 .i  1.26   '!I!&:&. ml inchlda    ^
,..
   7.'  -_-. *Jo  . . . . . . ..I357     ldl   1.66  .,r 1.86 ..rrf?,eramoktn.- '
         e.2 .ro . . . . . . ..i.sa     a.16     1.42 :-I  1.42 <>,I! .- . :- 7
. r-'       AU  . . . . . . ...6.24     2.96   l-66 i  1.24            ..' _


TMLE 3.Pudden death from coronary

Project.
Amcriua aart
hwciation.
1970. U.SA.
(88).

TABLE 4.-Coro7uzry heart disease

   (Risk rstlos-actus1 number of CHD

  [S?d = Smokers   NS = Nonsmokcn

Dorh    2.282 nula     Dctdkd       10   24a mro-    NS  . . . . . . . . . . . . 1.00 (62)
cc al..    F~minghlm.   mcdkd           CSKdM    AU smokers . _. .2.36(191)
1964.     3W2 yean usminn-          infrrc-     <20  . . . . . . . . . .I.98 (44)
. USA.    of Lge.       tian snd           tions and   20  . . . . . . ..__.._ 2.06 (64)
(84).   1,913 m&s      folka-up.          CHD     >20  . . . . . .._.. 3.04 (83)
        An=w.                     dathx.
        X9-66 ran
        of sgc.

8Lunlcr   1.329 CHD-     Int.e?vicv       4   46 CHD     NS  . . . . . . . . . . . . 1.00  (2)
ct&    free mrk     mnd uamio-
1666.     anDlo7rn of    stion 4th       =`; ;ig;;t.ty: 2.92 (6)
                  4
USA.    PcoulQ Gas    clinic                    < 6 vbca.....
(177) _    COUlD=V      folbr-up.                l&19 cigarette.3.67 (8)
        40-59 ,an
        of *se.                              > 6 PIPCS.....

4    96 mak.                Male*
     92 femak              40-58
     CED in-   NS  . . . . . . . . . . ..l.OO  (1)
     duding    EX  . . . . . -. . . ...6.63 (10)
     deaths,    Clg.rrttea  . . . . .6.20 (36)
     msirm. and            Femakm
     ,nyocudIII  NS  . . . _. . . . . . . . 1.0 (21)
     idsrctlon..  EX  . . . . . . . ._ . . , 0.80 (1)
            Cfp.RtrcS  . . ...1.02 (X0

26


heart disease related to smoking

of death shorn fn Darentbesca)

Ci~rcttesldru         Clean, Dive          Comment

Never smoke3  ........... 1.00 (16)   1.00 (16)   See t&k 1 for der.crlDthn of
210  ............... z.. .. .t.90 (23)   1.86 (13)    Pooling Project.
20  . .:.: ...... . ....... .x.90 (60)
z-20  .................... 5.36 (40

morbidity US related to smoking

msoifstrtions shown in psrcothesea)'

EX = Exxsmokcnl

PROSPECTIVE STUDIES-Continued

Pipes, clears

Age variation           cornmenb

Dats include
CHD deaths.
only on m&s
4049 remn of
we md f rrr of
CHD on entry.
NS includa,
PIPeE. c&w%
and cx-smoken.

NS include
cr-smokera.
Includn all
CHD.

Mole&ntinued     M.Zk.                            Recxrmination
  80 and WdT         N-59                            Of pdenb
   1.00 (7)    SM . . ..l.SO(Z)                          WOJ spread
   l.z?(ll)         60 and over                        cwer 1y,.a-yar
   1.96(23)    SY . ...0.86(6)
Femah-contlnued                                    period. but
                                               dsta are re-
   1.00(47)                                        DOdZd in
   1.11 (6)                                        tcrma of
   0.42 (2)                                        4-year in&
                                               dence r.tes.
                                               Actual number
                                               of CHD inci-
                                               dents derived
                                               from dsta on
                                               incidmce and
                                               tot4 In smok-
                                    ha CLsl.

27


TABLE 4.-Coronary heart disease

              (Rhk rrtIm--sctrul number of CHD
              (SM = Smokcn   NS = Nonamatcm

PROSPECTIVE STUDIES

eAUthOr.
*-.    Number knd     Lkt,    Polkm-   Number ot
camtrr.     t7De Of      eolkctlcm     UP     incidenti         Clgl3rtttM/&T
rdcrarcc   pOpllhti0n             la-

Jenkins.   3,lfJZ mda     Initid       4%   104 m,o-     NS __ . . . . ..- . ..I.00 (21)
et 8L.     19-69 ,cIn     m&cl1           UldLl    EX ._.___ . . . . . . 1.47 (16)
1968.     of sge at      usmin8-        hhrrtbnm. Cumnt _ ., ._. .2.78 (68)
U.S.A.    mtl7.        uon rnd                  o-lS/daT ._-._. t1.as (46)
(901.               fol!er-up                  >I6 _ -.*-.. . . . . . WI6 (69)
                  br -t
                  aunlnr-
                  uon8-

Kmoel.   6.127 mslea     Y&d       l2   226 myc-       kr,c,a rnforc:ifm
et al..    and females    crur.fnstbn        UIdW                M&8
1968.     to-59 yt*ra     end follow-         Snflrc-    NS . . .,* . . . . . . . 1.00 (21)
U.S.A.    of *pz.       UP-              tiorl~.     AU slid . . . . . . . . 1.61(16a)
(94).                              a80 CHD.   aesvy SM . . ..I.86 (69)
                                        Ri.k of CHD (owrdI)
                                                     Mdu
                                     NS .._____ _ . .._ 1.00 (61)
                                         l-10  . . . . . . . . . . . I.24 (25)
                                         II-20 . . . . . . ..__ 1.80 (90)
                                         >20  . . . . .._..._ 2.41 (76)

Shapiro   110.000 male    Bwelioc mcd-    a   Tot&l                Mok.
et IL.    sod femak     kd ioter-          un*pecl-    NS  . . . _. . . . __ .I.OO
1969.     cnr0lk3      ricr md          tied.      At1 cul~cnt . . . .2.14
U.S.A.    of Ecmhh      rxamin*ticm                 cigsrettea (p<O.Ol)
(171).    In~ur~ncc     md rcsnhr                 <20  . . . . ..__... 1.r.o
        Phn of       follow-up.                 >20  . . , . . . . . . .2.33
        Greater               I
                                         >40  . . . . . . . . . ..B.JC
        New York
        (HIP)
        a-4 le.=
        of .gc.

K,.     9,186 m&s     Iotervie~     5     65 dcatha.   NS. EX
1970     In 6 coun-     and r--          80 nwocIIr-
Ytlp+                                    (SM <20) I. .1.00(306)
        tria lo-59     Isr foibw-           dial in-   AU current
ah&    Icall of      np examins-          f.rction%
PinLnd                                      (>20)  . . . . . ..1.31(103)
        .*e at entrY.    lion br           128 8ngir-m
ItAb               Lxrl
NdhU-                              DCCti?iU.
                  Dhysici*nr        156 other
lands                             -

C-
(III).

t428 totaL

28


mwbidity as related to smoking (cont.)
mmnifahtioos show in p~renthmcs)'
EX = Ex-emokersl

PROSPECTIVE STUDIES--Continued

(~<O.OOl)

(D<O.OOl)
(comDsrinr
O-16 and 16+)

      SS-I#    m-so
NB .._... 1.00 (41  1.00 (6)
Current 4.2S(36) 2.26(83)

MVocwdi.4 inf~rclion-G.mtinued
FC?Mh
X.00(81)
1.71(23)

Risk of CHD (ovrrlI)-Continued
FC?IWXlU
1.00(89)
0.86(18)
1.29(18)
0.93 (3)

Fcmolu        hf.&s onllr
  1 .oo        NS _. . . .l.OO
  2.00        SY _.... .I.82
(D>o.ol)          fD<o.ol)

  1.77

6.92

   Afar.9         FE3Wk4    Total myo-
ss-44 bS-Sb 66-41  36-44 4554 6-4  cardial in-
1.00  1.00  1.00   1.00   1.00  1.00   farctlon in-
2.47  3.06  1.69   256   2.87  1.80  eludes t&ma

a.62 2.16  1.a2               dead wiitbin
3.04  329  1.81    116  2.81  1.66   48 hours.

10.09 7.63 6.80'  20.26 11.79 4.07
                      NY include
                        a-smokers.

29


TABLE 4.-4honaa( heart disease

               (Risk r~tiow-~~tn.I number of CED
              [SM = Smokers   NS = Noosmokem

PROSPECTIVE STUDIES

T*ylor.   2.571 mdc     Interviewa
et *I.     railroad       and r--
l370     empbvcc3     I& follow-
U.S.A.    4069        up eramins-
(189).    ,an or       Lion.
        ?? o ?
        ?*????

Ihrton   422 mdc U.S.   Inkrvicws
et d.    rcterrns p.r-   and rouline
1970.     ticipatiog *I   fo~iow-up
U.S.A.    cootrol3 in I    examina-
trs. 19).  clinics1 trial of   lions.
        a diet high in
        Wltd"-
        rated fat.

6     46 destha.   NS .nd EX . . . .l.OO (62)
     33 myoc.r-  AU current . . . .1.77 (160)
      dlrl-ia-
      frrctiona.
     78 rnpin8
      pdoria.
     66 other
       CUD.

212 total.

up to 8  27 sudden    <lo __.__._.... 1.00 (26)
      deaths.    l&20  . . . . . . . . . . 1.04 (22)
    44 definile    >20  . . . . . . . . . . . 1.17 (13)
      myocardial
     infarctions.

DtUIZl    13,145 male     Dsta only    up to 14 Total un-
et rl.,    p*tienb in     on *cur           ape&&d.
1970     periodic health   incidents
U.S.A.    examination    extracted
(55).    clinics.       from
                  clinic
                  recorda.

POOtiIlp   7.427 while     Medical       10      638
Prujtct.    mrla 30-59    examination       Includea     Never Fmokcd .l.OO (63)
American   ,can of      xnd follow-         fatal and   <IO  _ _ _. . _. . _ .1.65 (72)
Hart     yc *t entrY.    UP.             oanfatrl     20  __. . . __ . . . . 2.08(206)
Asrocktion                           myocardial  >20  . . . . . . . . . ..3.28(164)
1970.                               infarction
USA.                              nnd audden
car).                              death.

Pmxl CL IL. 1.939 Wntcrn   Screening
lP63,    Ekctric co.    crsmination                         COTOMW
TJmsa    rmk workera   and                              CaBCS 167)
(li.4).   prticipatinp   history.                  NS .__ .__.... .   23
        In. prmpcc-                          l- 7  _ . . . . . . .    2
        tire atw3Y                            8-12  . . . . . . . . _    9
       for 4% ,C.rn.                         la-17  . . . . . . . . -    6
                                        18-22     .----- 41
                                            .._..... -
                                        23-27  , . . . . . . .    a
                                        >28  ___ . . . . . . .    9

30


       ,/. ,,... y.   -I .`J. ~- ,J ., -1 . . , : . . . ,, , ,, -.. :'  ,. .  ._  .:,, .-;
                    _
    , :s. !  ,`.' .'        ; 1. i, :i:;.-,        . .
                     :* ;-,2          . I,,.i: ,  ,.Z' `: ,_ ,>' f `., ; -'
                       ' .;              .,. , :

           ,I ..- ` tios   JO-19 .( ; bo-bf    60-59   t Includea    ;
              SM 1.00(26) 1.00(126) 1.00(167,   NS. EX. and
."          

        _._ I,.    tHlgb                      <20 cigarettes/
                           . --:     . ,   day.

      .I           SM 2.17(10) 0.90 (31) 1.41 (63) :>ZOei`~a-
        . . .     .`.d ..I  )*,-J.. .iz- ._,               ; ,
                                           r&es/dry.

               ,' I  :.:.* ;`..     ,_I.' -:
                               ,`., :     Include. all '
                  .                     CHD blrt
__   I .._. . .
.,_. _.. :.I  :: :,:-*   I ;-car. ,., -; `.. : - . . r  `-
                                       .' czcludr.

._. 1.26(60 '       =   . i . . -.. 1. . . -* . . . ..1..---
              :. . .-, `. 1; ,.,., -; , =...; ,. I   :
                                ,,, +i   : 1;. -*.
                                            __ .:.

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

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

Knowledge of the effects of cigarette smoke on the cardiovascu-
lar system has developed concurrently with the knowledge derived
from the epidemiological studies. Nicotine, as well as cigarette
smoke, has been shown to increase heart rate, stroke volume, and
blood pressure, all most probably secondary to the promotion of
catecholamine reIease from the adrenal gland and other chromaffin
tissue. This release of cateeholamines is also considered to be the
cause of the rise in serum free fatty acids observed upon the in-
halation of cigarette smoke. Studies concerning the effect of nico-
tine on cardiac rhythm have also suggested that smoking might
contribute to sudden death from ventricular fibrillation.

  In addition, research efforts have also been directed toward the
effects of smoking on blood clotting and thrombosis; since many
_ cases of sudden death and myocardial infarction are associated
with thrombosis in a diseased coronary artery branch. Cigarette
smoking may be associated with increased plateIet aggregation in
Vitro and thus might play a role in the development of such throm-
bi or platelet plugs in viva.                ,
Other mechanisms have been investigated. Because cigarette

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

32


;f .'   ,;p, - -.
$,,:" : 1(' -: :  TABLE S.-Coronary heart disease morbidity aa related to smoking -angina pectoris+woapective atudiee .+, .
                      (Rl#k +.l~-utu~l number of CHD mrnlfntatlon# shown In parenthesn)~                 `,,.  ;,
                                                                           ,;, -.
                                                                           !
                                        [SY = Smokera    NS z Nonsmokers]

                                                             Cll?#M       -.
                                            Clmrcttedday      wd DiDC.                   :.-, :
                                                   .I `., : AgevarIatIon ,. `t `.I " Commcntr
                                                                           ?`. . .

                                                                           NS Include ez-

Malu Fmalsc    M&b                  Male*      t (PCO.01)

                                                                 >4o  ..*,..a . . . . . . .  -  4.12 -
   ' Unb c4h-d~ ~e~ltlcd. dlwultla between the total number of
,A  , -ntf-Ulom *ad the bum OK the lndlrldurl wnoklns caegx,ries .re due    to the acluslon of citbw aculonal, mLcelLne0ur. mlred. or ex-rmokrtn.


smokers caused by the increased carboxyhemoglobin level.

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

EPIDEMIOLOGICAL STUDIES

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

CORONARY HEART DISEASE MORTALITY

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

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

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

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

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

CORONARY HEART DISEASE MORBLLIITY

Tables 4 and 5 list the prospective studies carried on in a num-
ber of countries to identify the risk of CHD morbidity incurred
by smoking. Here, CHD morbidity includes myocardial infarction
as well as angina pectoris. Certain studies, notably those of Doyle,
et al. (541, Keys, et al. (III), and Taylor, et al. (185) include a
number of CHD deaths in their data that could not be separated
out .using the information provided in their respective reports.
As noted in the discussion on CHD mortality, the CHD risk ratio
increases significantly as the number of cigarettes smoked perday
increases. Similarly, the HIP data of Shapiro, et al. (17.2) sha$
that the elevated morbidity ratios declined with increasing age as
has been shown for mortality ratios.

A recent monograph edited by Keys (111) dealt with the &year
CHD incidence in males age 40 to 59 from seven countries. As
summarized in table 4, cigarette smoking &as found to be associ-
ated with an increased incidence of CHD in the U.S. railroad
worker population, 2,571 individuals (183). None of the differences
in ratio between smokers and nonsmokers was statistically sjmifi-
e-ant for the 13 other population samples which varied in size from
505 m 962 individuals, from the five other countries. (Smoking was
not considered in the two Japanese populations.) men more cases
                         .   .

35

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

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

RETROSPECTIVE STUDIES

Table A6 presents data from the various retrospective studies
of CHD prevalence. Most of these are case-control studies and show
an increased percentage of smokers among those with clinical CHD
when compared with a selected control population, usually without
apparent CHD. Two of these studies include data on mortality.

THE INTERACTION OF CIGARETTE SMOKING AND
     OTHER CHD RISK FACTORS

The preceding section has reviewed the epidemiologic evidence
which supports the judgment that' cigarette smoking is a signifi-
cant risk factor in the development of CHD. Many of the studies
discussed above have identified a number of biochemical, physio-
logical, and environmental factors; other than cigarette smoking,
which also increase the risk of developing CHD. These risk factors
include elevated serum lipids (particularly serum cholesterol) and
hypertension, which, with cigarette smoking, are considered to be
of greatest importance. .Other facto&-are obesity, physical inac-
tivity, elevated resting heart rate, diabetes (as we11 as asympto-
matic hyperglycemia), electrocardiographi~~abnormalities, and a
positive family history of premature CHD (88).

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

36


additional factor of smoking greatly increases the risk of develop-
ing CHD among those people already at high risk because of other
factors.
Furthermore, these studies have shown that the effect of smok-
ing on the risk of deveIoping CHD is statistically independent of
the other risk factors. That is, when the effect of the other factors
is statistically controlled, smoking continues to exert a significant
effect on increasing the risk of developing and dying from CHD.

Smoking and Serum Lipids
The interaction of smoking and serum lipid Ievels in the develop-
ment of CHD should be considered in the light of information con-
cerning the relationship of smoking to serum lipid levels. Table A7
presents studies which deal, with the association between smoking
and lipids, notably cholesterol, triglycerides, and lipoproteins (con-
cerned with lipid transport) _ While some of the studies have indi-
&,ed that smokers show increased serum IeveIs of these lipid con-
stituents, others have not. The populations investigated and the
methods of the various studies show significant variation. This lack
of comparability makes interpretation of the tidings diflicult
It is clear, however, that in the presence of high serum choles-
terol, cigarette smoking increases the risk of. CHD. Figure 4 de-
picts the data from the Chicago Peoples Gas, Light and Coke Com-
pany study which show that smoking greatly `&eases the risk of
CHD in each of the cholesterol groups.

Smoking and Hypwtemion
Some epidemiological studies have indicated that smokers tend
to have lower mean systolic and/or diastolic blood pressures than
nonsmokers, while other studies have not found this to be the case
(table A 8). Reid, *et al. (155)) in a study of 1,300 British and
American postal workers, found that the blood pressure difference
between the smoking and nonsmoking groups was eliminated after
controlling for body weight.
Tables 9 through 11, derived from the study by Borhani, et aL
(27) , demonstrate the following associations : That for both amok-
ers and nonsmokers, the risk of dying from CHD increases with
increasing diastolic or systolic pressure, and that the risk of mor-
tality from CHD is higher among smokers than among nonsmokers
in each blood pressure group. Cigarette smoking, therefore, ham
been shown to elevate CHD mortality independently botb'of its
effect on blood pressure and of the effect of hypertension on CL-ID.

Smoking and Phyticul inactivity
The recent study by Shapiro, et al. (172) of more fhan 110,00fr


TABLE Q.-Dsath rate6 from coronas hem9 dineuse, b sy&& b&d $wuMc:

4664 . . . . . . . . . . . . . . . . `.:. -   <so   .J 1,627 * A 26      1.100 :... 6

38


MCIDEKCE
PER 1.000 MEN                                            80
   80--                         -1 y
                                                    _
                                                  , _.
   70-

   ta-

   50-

   40- 35

      ALL       NON     NON     NON   SMOKERS   SMOKERS   SMOKERS
             SMOKERS SMOKERS SMOKERS
               <225    225-274    275+    <225    225-274 275-f-

CHD 46.        1       5       2       9       16 12
  n 1329'       187     235      71      336      317 151
AGE 49        49      50      51      50      49 SO
SYSTOLIC
PRESSURE   13        133      136      139     131      133 13s

WElGHl 1.16       1.19     I.21     I.JE     1.12     1.15 1.17
RATIO

FIGURE 4-Relationship between smoking status and serum cholesterol level
at initial examination, and incidence of clinical coronary heart disease in
men originally age 40-59, free of definite CHD, and followed subsequently
without systematic intervention, Peoples Gas Light and Coke Company
study, 195&1962.  *For 34 men, no information on smoking status was
available; one of these men had a coronary episode.
SOURCE: Stamler, J., et al. (177).

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

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

Smoking and Obesity

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

39


1f.O



10.0



  91)



  a.0
I
1  71)



Y  6.0
Q
;&o
h
i  41)



  1.0



  2.0



  1.0



  0.0

r

DWd
wlthln
45 hrs.

IO.89

5.72
WI

5.75

NONCIPhRmE SMOUERS
6.33

r

3.76
147)

2.57
(31)

(Actual numbat of dcathr or myocardlel InfarctIons are represented by
tlgurer in psrantharar)
sov*ca: Bhapko, 8., at al. (171).

Thfr table showe that cigarette smokers in the 66 to 64 year age
group were observed to have higher CHD death rate8 than non-
#m&are In all weight categories. Similar Andings, although not in
all weight groups, were observed for the 46 to 64 year age group.
CInaretta amoking la thus ahown to be a CHD risk factor indepen-
dent of body weight.

40


TABLE 12.-Death rates from coronary heart disease among men without
abnornuzlities related to cardiopulmonary diseases by weight classification
         in I95I: ILWU mwtalily stufiy, 1951-61
         (Coronary heart dixrse as classified under ISC Code 4201

                                Smoke"            Nonsmokvrs

                 W&ht      PCIXXVJC~~   DeaLtI    P.Zl?X?~-~~~    Death
  Age &Troup       etaaihcation 1   of o!acrvslion    rati =    of ob,erv,tion    r*tc =

45-54 . . _. ._ _.  Not ovcrrcizht          388       21        279        `I
          Slightly overweight        962       28       1.096        a
          Moderately orcrwrinht     1.383       28       1.674       28
          btarkedh orcrweipht     1.035       22       1.197        0
55-6`  _. __ __ __  Not overwcisht          222       43        247        0
          Slightly ovenvcipht       536       76        -606       S6
          Yoderrtch ovcrwcight     855       la9       1.320       111
        Markedly ovcrwcigh<      735       88       1.663       `12

`The four clr~~se sre defined in the text.
z Rate per 10.000 ~)t~on-~eal~ of observ.tion.
' p<O.Ol.
Source: Borhani. N. 0, et =I. 07).

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

Smokers            Nonamokm

4L-64 . _ _. _  Abnorm.l . _ . ._ __ . . . . .    686       102       1,020       99
          Normal  _ . _ __ . . ._ _ . . .  ..4.454       3n       6,134        16
SZ-64 . _. ._ ._ _.  Abnormal  . . . . . __ . . . .    683       :23       I.149       96
          Normal  _ . . _ _ . _ . . _ .   3.a3i        86       6.479       `31

1 Rate per IO.OOO person-yw.rs of obsenrstion.
* D<0.005.
Sov~ce: Borhani, N. 0.. et rl. (X7) _

TABLE 14.-1958 status with respect to heart rate, blood pressure, cigarette
smoking. and IO-year m0rtaZity rates. by cause (I.329 men originatly age
      do-59 and free of dejinite coronary heart disease)
          Peoples Gas Co. Study, 1958-68

19K8 risk fmtor status

Ten-year mortality. 196868

Reart
T).t.z

NH

Cipardte
smokinp

  NH

  AU C*Uses     CHD-
Number   Rate   Number Rats

20    = 48.3      6    `l2.0

H        NE       NE         46         6    114.9      a    70.1
NH        NH         H        107        14    118.3      6    61.8
H        NH         a         a0         8    221.6      a    62.0
NH         H        NH        491        67    116.8     19    a.%9
a         H        NE        127        22    171.1      8    62.X
NH         n         a        103        22    180.4      6    66.0
H         H         El         44        IS    266.4      6    919

All                           1.325       162    118.2     66    so.4

1 Rak per thousand. AII r.ta mre o prrdjluted by brew WC erouga to U.S. mnle popnktkm.
1360.. Hkh (H B : Heart r11c z80: ZlO tlpwcttu txr dw: dlutolic blaod snr.surc 30 mm. Es.
NH is mot binb. Lc.. hbr spccilcd cuttins polnb.
`No mreking datr rv~ilabk OP 4 of the l,fZP p1a.
Sovvx: Betron. D. H.. ct d. (Ml.

41

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

       AK CHD mett.
Never smoked . . . . . . . . . . . . . .1.00(10)
CllrrCd
cloarttt ~mokrrn . _. . . . . .2.36(U)
Former
dmrctlc smoken . :. . . . .2.16(19)

           Death f ,-mm CHD

?? ?????????o
infarction
  l.OO(Zl)

2.78 (66)

2.47(16)

Hunmood
and Gmrtlnkd.
19sB.
USA
(76).

   Smoked l-10 cigarctLu/&y      Smoked >lO
Never                     cig.rruc./day

smoked r~~ulrb _ ._ . . .1.00l1.841)    l.OO(1.841)   Yale da. only
CUlTCUt
clemrettc amaken . _. . _ ._ l.DO(1.063)    2.66 (2.822 )
stoD,Xd <I YclC . . . . . . . . .1.62  (29)     1.61 (62)
1-4  . . . . . . . . . . . . . . . . . . . 1.22  (6-r)    1.61 (164)
LB  . . . . . . .._ . . . . . . . . . . 126  (66)    1.16 (136)
IO-19  .._ . . . . . . . . . . .._.. 0.96  (62)    1.26 (1383
>20  . . . . . . . . . ..-....... 1.08  (70)     1.06  (80)
AU cx-dnardte smokers . -1.16 (263)    1.28 (6641

N  Total &finite myacardial infarction
ever smoked .._...._._... _ . . . . . . .._...... . . . . . . ..I.00
Current cigarcite smokers  ......................... 1.87
StDPM S6 Yeara ................................. .0.78

        AR CHD &aLhs
Never smoked . . . ._. . . . . . . .1.00(27)
>`j4 wck/dsy  _ _.._.___. ._ .1.66(34)
1 wck/dq  . . . _ . . . .._. . ..1.70(.66)
>1 Drck/dry  . . . . . . . . . .._.. 3.00(68)
Exsmokcrx . . _ . . . . . . . . . . . . 0.80(19)

Pirmf major
CormION event
1.00 (63)  See table 4
1.66 (72)    for description
2.08(205)    of Pmlinp
3.28 (154)    PrOiKt.
1.25 (61)

TAEKE 16.-Annual probability of death front coronary heart da%ease,
in current and discontinued enwkers, by age, maximum amount smoked,
            and age started Bmoking

.-e-v._ _ ..___. 0          601       -        601       -
        lo-20          198        608        811        661
        7.149          S60        766        612        698

&`I(' -.__ . . . . . . .._   0         1.016       -       1.016       -

             lo-20         1.601       1.169       1.478       1.21t
             21-M         l.710       l.ur       1.ma       1.0911

* For - group 66-74, ~r.,b.blUUa for dkeantlnrrsd -ken o R for 10 Or mOrr - d dh--
adinn.~cc dacc d.t. for the 64 ,err dk.zantLntunu craw .R not riven.
Sxmcx: thmtldd, J, Yft&c~I. 8. (44).
Bud cm da@ derived Irma IhIm. 1. A. (#I).

42


Smoking and Electrocardiographic Abnormalltzes

Electrocardiographic (ECG) abnormalities such as T-wave and
ST-segment changes as well as a number of arrhythmias are use-
ful indicators of CHD and may, therefore, be predictive of the
development of clinically overt CHD manifestations. The results
summarized`in table 13, from the prospective study by Borhani,
et al. (279, reflect the joint predictive value of smoking and ECG
abnormalities on the death rate from CHD.

Smokzng and Heart Rate

Recent analysis by Berkson, et al. (25) of the data derived from
the Chicago Peoples Gas, Light `and Coke Company study of
middle-aged men revealed that resting heart rates of 80 or greater
were associated with an increase in the risk of death from CHD.
These authors found that this association was independent of the
other major coronary risk factors.

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

THE EFFECT OF CESSATION OF CIGARETTE
SMOKING ON CORONARY HEART DISEASE

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

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

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

43

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

Fletcher and Horn (63) have recently presented data derived
from the British physicians study of Doll and Hill. Over the past
lo-16 years, cigarette smoking rates among British physicians
have declined significantly in comparison with those of the general
British population. The information presented by these authors
concerning all cardiovascular diseases showed that for individuals
between the ages of 36 and 64, the age-adjusted death rate for CHD
declined by 6 percent among physicians and rose by 10 percent
among the male population of England and Wales during the
period from 1953-57 to 1961-65.

THE CONSTITUTIONAL HYPOTHESIS

The effect of smoking on the incidence of CHD has been found
to be independent of the influence of the other CHD risk factors.
When such risk factors as high serum cholesterol (1771, increased
blood pressure (27)) elevated resting heart rate (251, physical in-
activity (172), obesity (27), and electrocardiographic abnormali-
ties (27) have been controlled, cigarette smokers still show higher
rates of CHD than nonsmokers.

It haa been suggested by some (39, f7U) that the relationship
between cigarette smoking and CHD has a constitutional basis.
That is peopIe with certain constitutional make-ups are more likely
to develop CHD, and the same people are more likely to smoke
cigarettes. This hypothesis maintains that the relationship between
cigarette smoking and CHD is thus largely fortuitous and that the
significant relationships are between the genetic make-up of the
individual and CHD and between the genetic make-up of the indi-
vidual and his becoming a cigarette smoker. Two sets of epidemic
logic data bear on this hypotheeis.

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

44


Type A behavior pattern of Rosenmann, et al. (159) which is
characterized by competitiveness, excessive drive, and an enhanced
sense of time urgency. The prospective study organized by the
western Collaborative Group indicates that individuals who ex-
hibit this type of personality are more likely to have or develop
CHD than those without it (Type B), whether or not they smoke.
When the incidence rates of CHD are analyzed with respect to
smoking and personality types (tables A 17, A 18)) it is noted that
in both Type A and Type B individuals the incidence of CUD is
greater among cigarette smokers than among nonsmokers. This
research indicates that both personality type, as measured in these
studies, and cigarette smoking contribute independently as risk
factors to the development of CHD. To what extent such behavior
patterns are determined constitutionally or represent acquired
characteristics is still open to question.
The other type of research designed to study the genetic hypoth-
esis has made use of data from registries of twins. Cederlof,
et al. (37, 38, 39, 40) have utilized the Twin Registries of Sweden
and the Veterans Follow-Up Agency of the U.S. National Academy
of Sciences-National Research Council to investigate the relative
contributions of heredity and smoking to cardiovascular and bron-
chopulmonary symptom prevalence. Data obtained by mailed ques-
tionnaires were analyzed for the following characteristics: zy-
gosity of the same-sex twin pair, urban-rural residence differences,
smoking concordance, and history of various symptoms. Compari-
sons were made between smoking discordant monozygotic (iden-
tical) pairs and smoking discordant dizygotic (fraternal) pairs,
and between unmatched twin pairs and matched twin pairs. Smok-
ing discordance has been defined somewhat differently in various
reports but, in general, describes twin pairs in which the smoking
habits differ between the two members of the same twin pai:
Analyzing the data obtained from 9,319 Swedish twin pairs
(`72.3 percent of the possible respondents), Cederlof, et al. (39)
found that respiratory symptoms were more common among smok-
era in both the unmatched and matched smoking discordant twin
pair groups. The authors analyzed the data in two distinct man-
ners. Group A analysis, which did not control for genetic factors
ntihzed two groups; the first composed of all the firstborn, and the
second of those listed second on the birth certificates. Group B
analysis utilized MZ and DZ t&n pairs which were discordant for
smoking, thereby controlling genetic factors. "Angina pedoris," a8
defined by a certain pattern of responses to the questionnaire, was
found to be more prevalent among smokers in Group A, but this
difference was not present when the data from Group B were an-
alyzed. Males in the first group exhibited a "hypermorbidityratio"

45

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

A similar study was done using the responses of 4,379 U.S. Vet-
eran twin pairs (approximately 60 percent of estimated available
total) who completed the mailed questionnaires (38). Cederlof, et
al. found a significantly increased prevalence of chest pain and
"angina pectoris" among smokers when Group A. ~8s analyzed.
Analysis of the smoking-discordant matched twin pairs (Group B)
revealed no association between smoking and cardiovascular symp-
tams among the monozygotic pairs. The dizygotic pair data did
show a slight association. The authors concIuded that this Iack of
association among the monozygotes and its presence among the
dizygotes and unmatched pairs strengthens the case for a constitu-
tional hypothesis.

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

Similar criticisms may be made of the study which utiliyed the
U.S. Veteran Twin Registry. In that study, the authors observed
that the difference in the prevalence of angina pectoris Mween
the low-cigarette-exposure and high-cigarette-exposure dizygotic
groups was not present among the monozygotes. The authors ques-
tioned whether the excess morbidity associated with cigarette
smoking found in the dizygotic group was causal as it was not pos-
sible to reproduce the association when studying monozygotic
smoking-discordant twin pairs. As noted above, the numbers in this
study are also small so that the differences in rates do not approach
statistical significance.
~ Tibblin (188) has questioned the value of a mailed questionnaire
to diagnose heart disease. The questionnaire as originalIy con-
structed was used and validated by interview technique alone (157,
158). Cederlof, et al. (40) conducted a study to determine the
validity of this questionnaire as a mailed instrument by personally
interviewing and examining 170 of the twin pairs who had replied.
Of the eight males who were diagnosed as having "angina pectoris"
by the questionnaire. four were found to be free of symptoms on

46

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

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

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

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

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

Seltzer, who has been a proponent of the constitutional hypothe-
sis, in a recent review of some of the experimental, clinical, and
PothO~Ogica~ data relating smoking and CJID, concluded that the
evidence from these areas has not "reasonably substantiated" the
"hypothesis" of the acute effect of cigarette smoking on the coro-
narY circulation, nor has the chronic effect of cigarette smoking on
ihe cardiovascular system been shown to be a "clear" and eon-
gist& one (170). His views are contrary to those of most re-
achers in this fieid.

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

47

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

AUTOPSY STUDIES RELATING SMOKING,

ATHEROSCLEROSIS, AND SUDDEN CHD DEATH

A number of researchers have investigated the ci&rette smoking
habits and the cardiovascular pathology of th,ose.individuaIs dying
suddenly from CHD and of large populations of individuals with
and without histories of overt CHD.

Spain and Bradess (175) recently analyzed the smoking habits
of X89 individuals who died suddenly and unexpectedly, apparently
from the first acute clinical episodes of CHD. The authors nofed a
close correlation of a history of cigarette smoking with this type
of sudden death and also with shorter survival times following the
acute episode. This association was strongest in those persons
under 50 years of age.

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

While the autipsy study of Spain and Bradess (175) concerned
sudden death among smokers, other autopsy studies from various
countries have been directed towards the relationship of cigarette
amoking to the presence of atherosclerotic disease in the aorta-and
.coronary arteries. These are concerned with the long-term effects
.which smoking has on the cardiovascular system and are `sum-
marized in table 19. The studies of Auerbach, et al. (IZ), Avtan-
dilov, 8 al. (IS), Sackett, et al. (165), and Strong, et al. (~82)
round that aortic and coronary atherosclerosis were more common
and more severe among smokers than amongnonsmokers. Auerbach,
et al. (12) .Gted that this relationship persisted when the cases
were matched for both age and cause of death or when the follow-
ing cases were excluded ; men.with a history of diab&; men who
had died of any type of heart disease ;. and men whose hearts
weighed 400 grams, or more. Sackett. et al. (165) found that the

40


    TAEILE lO~Autopet( studiea o/ athsroaclaroaia
(Flguta la pwmthnn an number of Indivldualc In that amoklnc ertrn0r7)~
           [SM = anoken    NS = nonmokcrs]

AdhOt,
7*rr,      Aubpr7        D&tA
COUl-li~.     DODUktlOC,      collcctlon

Comment4

odjwkd rrrulk)
       No othcro-
        NkTO6b   Slight
NS .;.., ,.,. 6.6 (69) --.`-. 67.8
Cumnt
elgarctte
<20 *.,.*1 l.6(139)     30.9
20-39 .,.,0.8(299l     lg.7
>49 ,,.`.;.0.6(144)     18.1

            the percentage of men
            with .?I o dv*need deorn of
M0hub. Advonccd coronary d,herolckm~k
21.8     16.8    wu hlpbcr .mong elsn- -
            rette rmokcn thnn among
             nonrmokem and that the
873     29.2 '   pcrecntagc hcreued
42.1     87.4    with amount of elgrretts
96.4     46.9 I  8moklng. This relation-
            lblp DM'dlted CvCIl
             nhm cad" were mhtehed
            for age and UUI~ of
             death.


TABIX 19.-Autopsy studies oj athumsch'osia (cm:.)

                     (?`I- In DuSrrthC.4. w number of IndlrlduLL in that fimOkiU ukmr7)'
                                       [9X = mmken    NB = noo~mekenl
Ln    Anthor,
0     Y-t      AntaDtoprl        Dab
     OoOMtn,     DODUbtk"3 '      wnudm              Ckamtta DCr dw                 conctuliona           cornlnmta
    rdmu
    Avtandlh, 219 mab and     Nat BDrChdd,   fh,SDWdW #(I# of maan a,~ of athbtcrobrutb b&BU The rutbar eoncluda that  Cawa of dath 9l-&mro-
     1966,     141 f*mmb      but there rarer   in inn47 mat of covmary a.rkriar.              the wont ehanga rm    Acrotle, lOZ-wcldrntA,
     Flunrlr    ~~~D~l~.       180 9X uid         Rlpht COTOMY ortsru    h/1 mrona.ry orby found In the left and      202varloru dlrcua.
     (Ia).                220 NS.            srd       Nf       mf     NS    rlsklt ??????? o ??????   tT-tent for +~.lltuncr
                             a049 ,*.tla.s(ao,     Lscaz)      ma     2.2   nlth h mvcra changer    of hlffcrenca klwcen
                             40-49 . , tzs.ecao    11.6(27)     tu.a 4.4   hi clreu.m.8a artery      means II llgnldunt
                              so-t.9 ..tae.a(so,    14.8(89)     t27.9 9.9    &rid wti.          at P<O.oe luvel.
                                  (IO-40 . .ta1.9 (32)
                     70-78 ,. 41.9il8i    25.8(86)      128.5
                                               al.7(86)    `26.1    22.6
                                                                ati.8
  `thckrrt.   aoa tot4       P&tlmt      The raulta eorrccrnl~~ wrtle ~theroaelerc& .re ~&VU in The tiutbon conclude that


   TABLE lg.-Autopsy studies of atheroacletoei.9 (cont.)
(Fhm In prrcnthesn o re number of lndlvldurla In that #moklng e&tcp~t~)'
           [SM = nnoken    NS = nonbmokeml

WC1      1,160 m*ka      IntervIew rlth   The resulti concemlng lnternrl Abrow &e&s and frttlThe authors conclude tbnt:
et IL,     and 290        rclrtlrn.      plaques In the left anterior descending coronmy artery  "No relatlonahlp be-
1868     femrln who             art reported fn uraphic form only, An txsmin%tion of twcln ~thtmsclrmtlc
Chile     died vlolcntly             this data Indlcater that the modernlc and heavy umoken  Mona and the use of
000)     In 1961-1964.              nppcared to ahow consistently hlpher Dcr0enUen of tobacco WM divxmlbls."
        Smoklne Infor-              dlwrsed uenr than the nonsmokcn. But the statement
        mrtlon awlI-              of the authors implies that thcac dlfcrmca were not
        rble only on              rtatlstieally aixniflesnt when rubjreted to in borlyrle
        666 mmln.                 of vsrlwlce.

fbmr    141 mrln 20-     IntervIew rltb   Ilwal Croup (czcludinu dirmwc +rh:rd Lo rmokinp CT The authors conclude tbat: TbL wor( concetpn 0114
et aI,     64 yearn of      next of kin    CHD). Mron percmhps of ~070~~ w!cw inJumuI "Atberoselrmtlc lo-      agea Lb-64.
1969     we ~utoprled     WIthIn 8 WeekJ   rurfecs involved with rairrd JAonr (number of earcr). valvemmf of aotirad    No &tr on atdstld
UQA.    bctrm 196b     of death.                           Whitd          COvJII.lY wierles ll      8lyollkmce Dmrlded.
(J66)     1866 st Chwltl                            ts-34   SK-44   G-K4   K&s4   z`reatmt In bavy
        IkUDltd h               NS I,- . . . . ..I............ 2 (6) 19(14) 20 (6) SO(l1) unokcnmdle~th
        New Orleans.             l-24 cl,nrettn/dw . , , , 9(14) 17(10) 26(16) 29 (7) nonunokm."
                           126 ciewctlcs/day . ...12 (9) Sl(14) 26(26) 89(20)
                                                NWV
                             NS  . . . . . . ..a.......... 4(14)  a 18) 16(11) 17(14)
                          1-24 elrxrettcs/day :.:. s(39) ii ir(a0) 28(22)
                          >26 clmrettes/day  . . ..17(10) 14117) 29(12) 16(111

                                                     .-.
`~IGJW dm-wlre ~~eclAed, dlsparitlcs bctwen the total number of ln-

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

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

EXPERIMENTAL STUDIES CONCERNING THE
RELATIONSHIP OF CORONARY HEART DISEASE
            AND SMOKING

Several areas of interest in cardiovascular pathophysiology have
been investigated in the search for the mechanisms by which ciga-
rette smoking contributes to cardiovascular disease, particularly
coronary artery disease. Previous Public Health Service Reviews
(191, 19.2, 193, 198) have described in detail and commented on
the results of experiments by many teams of researchers.

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

CARDIOVASCULAR EFFECTS OF CIGARETTE SMOKE AND NICOTINE

The inhalation of tobacco smoke or the parenteral administra-
tion of nicotine has been found by many researchers to be asso-
ciated with a number of specific acute cardiovascular responses.
These responses have been observed in human as well as animal
subjects; including increased heart rate, blood pressure, cardiac
output, stroke volume, velocity of contraction, myocardial contrac-
tile force, myocardia1 oxygen consumption, arrhythmia formation,
and electrocardiographic or ballistocardiographic changes (tables
A20 to A22). The effect of these responses on coronary blood flow
will be discussed in a following section.

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

52

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

The mechanism by which cigarette smoke and hence nicotine in-
duces these changes has been of interest to numerous investigators.
Nicotine has long been known as a stimulator of both sympathetic
and parasympathetic ganglia. Research has centered, therefore, on
the function of catecholamines, mainly epinephrine and norepi-
nephrine, as mediators, of these responses. Using isolated rabbit
atria1 myocardium, Bum and Rand (55) noted that the prior ad-
ministration of reserpine to the perfusate blocked the increased
rate and amplitude of contraction seen following the administra-
tion of nicotine. West, et al. (208) showed that the in vivo cardiac
stimulating effect of nicotine was blocked by tetraethylammonium
chloride. Leaders and Long (125). Romero and Talesnik (156),
and, more recently, Ross and Blesa (160) have all demonstrated
this blockade in animals using agents such as pentolinium, hexa-
methonium, guanethidine, and reserpine.
More direct evidence of the catecholamine-releasing effect of
nicotine has been found by Watts (203) and Westfall, et al. (209,
210, 221) (table A22). Among animal subjects, nicotine adminis-
tration and the inhalation of the smoke of standard cigarettes
caused significant increases in peripheral arterial epinephrine lev-
els, while cornsi!k cigarette smoke inhalation evoked no such
change. In humans, cigarette smoking was found to be associated
with a significant increase in urinary epinephrine excretion.
The source of these nicotine-released catecholamines, particu-
larly those which mediate the immediate and local cardiac re-
sponses to intracoronary injections of nicotine, is felt to be the
myocardial chromaffin tissue (35, 160). The more widespread
effects are most probably mediated by hormones released from the
adrenal gland.

According to recent research of Saphir and Rapaport, catechol-
amine release may not be the sole mediator of these responses
(166). These investigators reported that intra-arterial injections
of nicotine into the mesenteric circulation of cats were followed
within 1 to 2 seconds by enhanced myocardial performance, in-
creased left ventricular systolic pressure, and increased systemic
resistance. Sectioning of the mesenteric afferent nerves led to a
diminished response. The authors concluded that the cardiovascu-
lar response to nicotine may also be neurogenic in nature. Nadeau
and James (14.2) injected `nicotine directly into the sinus node
artery of dogs and noted an initial bradycardia, due probably to
direct vagal stimulation, followed by tachycardia, due probably tb
catecholamine release.

53

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

CORONARY Bmn FLOW

Studies in animals and humans (tables A20, A21) have noted
alterations in coronary blood flow (CBF) following the inhalation
of cigarette smoke or the administration of nicotine. Generally,
exposure of the normal subject to these agents results in an in-
crease in flow. Kien and Sherrod (112), Leb, et al. (126), Ross
and Bless (160), Travel], et al. (189), and West et al. (208))
working with normal animaIs, and Bargeron, et al. (179, working
with normal humans, have demonstrated this response. As with
the other cardiac responses to the administration of nicotine, it has
been found that the augmentation in CBF is most probably due to
the release of catecholamines. Using instantaneous coronary arte-
rial flow measurement in dogs, Ross and Blesa (160) were able to
reproduce the effects of intracoronary nicotine with the adminis-
tration of epinephrine and were able to bIock the response to nico-
tine by pretreatment with pentobnium.
The direct action of catecholamines on the coronary arteries
may not, however, be solely responsible for the increase in CRF
seen with cigarette smoking and intravenous nicotine administra-
tion. It appears that the catecholamine-induced increase in myo-
cardial work and therefore in myocardial oxygen requirement is a
prerequisite for the increase in CBF. Kien and Sherrod (112),
using tracbeostomized dogs, found that without blood pressure and
cardiac output changes CRF did not increase following either the
inhalation of cigarette smoke or the administration of nicotine

54


intravenously, although CBF did increase folIowing such changes.
Recent work by Leb, et al. (126) has utilized Rb8' as a radioactive
marker in order to distinguish capillary flow from overall totai
CBF. The authors consider that this capillary flow represents that
portion of CBF which is effectively involved in nutrient and
oxygen exchange. The researchers observed that the increase in
effective coronary flow was almost proportional to the nicotine-
induced increase in myocardial oxygen consumption. However, the
increase in total coronary flow which may be due to increased
myocardial shunting was far in excess. Thus, the increased work
evoked by the effect of nicotine on the myocardium may induce
local hormonal release in the myocardium and coronary vessels
leading to coronary vasodilatation and increased CBF.

This homeostatic response to increased work appears to be fully
effective only in the subjects with normal coronary arteries. Bellet,
et al. (22), working with normal dogs and dogs that had under-
gone either coronary artery ligation or artificially-induced coro-
nary artery narrowing, noted that the increase in CBF following
the intravenous administration of nicotine was significantly less
among the animals with coronary insufficiency. Work with humans
discussed above has revealed a similar increase in CBF with smok-
ing in normaIs. Regan, et al. (1.54) studied seven men with EKG-
proven myocardial infarction and observed that cigarette smoke
evoked slight increases in myocardial oxygen consumption in only
three patients and caused no overall rise in CBF. A number of
other investigators have noted that patients with overt CHD do
not respond to the stimulus of cigarette smoke as readily as do
normals (67,149,164).

Thus, patients with compromised coronary circulation may not
be capable of increasing their coronary flow in the face of the in-
creased demands of a myocardium stimulated by nicotine or ciga-
r&e smoke. In the normal state, the heart responds to increased
oxygen demands by increasing coronary flow because even at rest
oxygen extraction is almost at a maximal level. Any further in-
crease in extraction may produce coronary sinus p0, values incom-
Nible with proper tissue oxygenation.

CARDIOVASCULAB EPFECTS OF CARBON MONOXIDE

Carbon monoxide (CO) is a colorless and odorless gas, low
levels of which have significant effects on human and animal physi-
ok%?y which are just now beginning to be understood. According
to WCjynder and Hoffmann (21.5). it is present in cigarette smoke
in concentrations of approximately 2.9 to 5.1 percent. The concen-
tration of CO in smoke is subject to many factors, among them

55

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

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

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

CO interferes with oxygen transport in a variety of ways. First,
the affinity of hemoglobin for CO is approximately 200 times
lz'reater than its afiinity for oxygen, and thus CO can easily dis-
PlsCe oxygen from hemoglobin. Second, CO shifts the oxyhemo-
globin dissociation curve. By increasing the avidity with which
oxygen ia bound by hemoglobin, CO interferes with 0, release at
the tissue level. This is of greatest importance at the tissue level
where the oxygen content of the capillary blood has been reduced
b Proximately 40 percent saturation: Here the shift can sub-
tintially dec&e the oxygen tension supplying the tissues.

Third, and of more recent note, is the possible interference by
0 with the homeostatic mechanism by which 2, 3-diphosphogly-
-rate (2, 3-DPG) controls the affinity of hemoglobin for oxygen.
BUM and Jandl (54) have recently reviewed the various experi-

36


merits concerning this glycolytic intermediate. The question of
whether the low levels of CO present in the blood of smokers can
affect this homeostasis is presently under investigation (29, l&?),
and firm conclusions cannot be drawn at this time.
Apart from its effect on hemoglobin affinity, CO appears to
induce arterial hypoxemia, and this may act as an additional cause
of tissue hypoxia. Ayres, et al. (14,15) observed unexpectedly that
exposure of individuals to'C0 sufficient to raise their levels of
COHb to between 5 and 10 percent was associated with a signifi-
cant fall in arterial p0 Greater fall in venous pOi was noted,
but this was considered secondary to increased tissue extraction.
In a recent article, Brady and Coburn (30) suggested that this
COHb-induced arterial hypoxemia was due to the interaction of a
number of factors. These authors noted that in the presence of
veno-arterial shunts or of an imbalance in the ventilation-perfu-
sion ratio, the shift in the oxyhemoglobin dissociation curve in-
creased the alveolar-arterial O? gradient and resulted in arterial
hypoxemia. The presence of shunts as small as 2 percent of cardiac
output as well as of approximately 10 percent COHb was found
to cause an increase in the gradient. Such ventilation-perfusion
(V/Q) abnormalities have recently been noted even in asymp-
fomatic smokers (see Chapter on Chronic Obstructive Broncho-
pulmonary Disease). The increased levels of COHb found in the
blood of smokers may interact with these V/Q abnormalities to
further decrease available oxygen.

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

Chevalier, et al. (41) exposed 10 young nonsmokers to CO con-
centrations sufficient to induce COHb levels of approximately 4
percent. Taking measurements from blood specimens obtained at
cardiac catheterization under resting and exercise conditions, the
authors noted that the ratio of oxygen debt to oxygen uptake in-
creased significantly under conditions of increased COW. Accord-
ing to the investigators this implied that the same work was being
done at a greater metabolic cost. These same authors, (121,162)
had previously noted similar findings among smokers and observed

57


that cessation of smoking was associated with a significant im-
provemeat in oxygen debt accumulation.
More recent work by Ayres, et al. (15) has focused on the dif-
ference in response to CO exposure between 7 normals and pi pa-
tients suffering from CHD (proven arteriographically). The induG
tion of a COHb concentration of approximately 9 percent in the
normals was followed by an increase in coronary blood flow, a
decrease in hemoglobin-oxygen percent extraction and no change
in myocardial oxygen consumption, coronary sinus.oxygen tension,
.&id lactate and pyruvate extraction ratios. The induction of simi-
Iar COW levels in the CHD patients was followed by no change
in coronary blood flow, a decrease in the hemoglobin-oxygen ex-
traction ratio, and no change in myocardial oxygen consumption.
However, these patients did manifest a decrease in coronary sinus
p0, as well as a decrease in lactate and pyruvate extraction. The
latter measures indicate that the myocardium was functioning
under hypoxic conditions. Because the coronary flow could not in-
crease and because the myocardium couId not extract 0, from
IGO, which was under the influence of CO, coronary sinus oxygen
tension decreased to a point which could inactivate certain oxida-
five enzyme processes. Thus, the myocardial function of persons
with CHD may be unable to compensate for the stresses induced
by smoking.

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

An area of interest which has been discussed in previous reports
concerns the presence of hydrogen cyanide in tobacco smoke.
According to Wynder and Hoffmann (225), the amount present
ranges from 11 to 32 micrograms HCN per puff. It is known that
a significant amount of this material is detoxified to thiocyanate
and excreted as such in the urine or saliva. However, cyanide is a
potent inhibitor of oxidative metabolism. Such inhibition of myo-
cardial oxidative metabolism may be of importance when combined
with f&e other factors mentioned above- which tend to decrease the
oxygen supply available and increase the need for oxygen on the
part of the myocardium.

58


EFFECTS OF SMOKING ON THE FORMATION OF

          ATHEXOSCLER~T Ic LESIONS
A number of autopsy studies have demonstrated a significant

association between cigarette smoking ar.d the presence of aortic
and coronary artery atherosclerosis, even in men without a his-
tory of clinical CHD. The possible pathophysiologic mechanisms
for the atherogenic influence of cigarette smoking are discussed
in this section.

A number of investigators have studied the effect. of nicotine
administration, either subcutaneously or intravenously, upon athe-
rosclerotic changes in the aorta and coronary arteries of animals
(table A23). When administered alone, nicotine induces Cedin
necrotic changes in the arterial wall. However, in combination
with the administration of increased amounts of cholesterol in the
diet, nicotine aggravates either subendothelial fibrosis (7.5) or
definite atheromatous lesions (46, 75, 80, 130, 178). Studies by
Choi (AZ) and by Wenzel, et al. (207) did not demonstrate this
synergism between cholesterol and nicotine.

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

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

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

59


TABUS !U.-Expdmnta evncedng the athemgmic efect of carbon monde ezpoeure and hyporia

Ucldrcn   X4 cutrated mde  hdat dlct p!U8 X WKent         Tbr uDer~mcntd1 D,V"D cxpored to hYDoxl4 lboaed kaCP?6sed ttW~OD!O UHtlS
et al,    rlblno rabblta.    cboleateml:                  atberomatod# over that ahown by eontml o nim& bfkroacoDk uamtnathxI rc
ID68.                  I. (12) control.              w&d mom Intlmal and sublatin lipid dcposltlon In the o ortu of the cr~mod
Dcnmrrt               II. (12) continub, qry~~~m.        rabbit-s than In those of the noncxwaed. The total amount of ebcltiterol dt-
(117).                   to hypoxia:            Posited In tbs sort&n of the experiment&l Om"D wan tbrn tha t&her thw h
                 10 DWCe"t.$ for 6 weeks.     chow of tbe cootrol sroup.
                  8 DetCWIt Ox for 2 weeks.

uetdrcn   x4 ca1lrrtAd male  h~ulat dlst DlUS 2 percent         bhOtWODkdY, the exDerhe"tll WOUD ahowed &diCl"tb feWt StbWoUMbUI
et aL.     albino rrbbltr.    cholcsteml:                changn. Micro~coDlc~ll~, tie uperlmrntal PKIUD ~hoaed ~ignlflcant~ krr rortlo
1060.                  I. (12) conttc1.              Intimrl liDId deposItIon.
Dmmwk               11. (12) CXDOIUM t0 28 DtrCmt
(JJ4).              O2 for 10 weeks.
Webster   x2 femrb lpulrrel  Diet eontalnlng 0.1 percent         The uprr~mtntal proup cxpoml to trrbon moaoxldr rhowad 8 prertrt maan Wr-
e &I..     moakeya.       chol~~ttrol rnd 26 DUCC"t fat:       eentalpe of comnar~ rrtcrlar rlth rtheruclemtlc lcalon~ rnd more lumen occlu-
1970,                  I. (IO) control.
U.S.A.                                   don among the &ccted arteries Them wm ~lmifluntb mom CO-treat4
                 11. (12) eIDdme"trk!Y UpO8d t0     monkeys than control monkcn having 11 per-ant or more o ????*? athem-
(W).                   200400 P.P.~. errbon monoxide   AerotIc rtenorlt among the wTected arterlcr. Aorttlc atbcmrclcroaL wu &PP*~-
                      for 20 hOWa DW week for 7     cntlv not agemwkl by exposure to CO. COHb IevcL at the md of each ewaun
                         montha.               perlad averaged 18-28 percent durlw the flnrl 24 wrnkr of tbhs apsrlment

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

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

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

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

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

TEE EFFECT OF SMOKING ON THROMBOSIS

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

OTHER AREAS OF IFNEXT~GATION

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

CEREBROVAXKJLAR DISEASE

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

62


ciated with increased mortality from cerebrovascular disease,
whether CVD is listed as the underlying or as a contributory cause
of death. Table 28 presents the results of the seven major epidemi-
ological studies. The smoking of pipes and cigars does not appear
to increase significantly the risk of ,dying from CVD. The impor-
tance of high blood pressure and diabetes as risk factors for mor-
tality from CVD has recently been noted by Hammond and Gar-
finkel (76). The data from their study, as presented in table 23,
also indicate that the mortality ratio for cigarette smokers is
greater for persons under 75 years of age than for older
individuals.

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

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

More recently, Miyazaki (15.2) studied the effect of smoking
on the cerebral circulation of 12 moderate/heavy cigarette smokers
88 measured indirectly using an ultrasonic Doppler technique to
record internal carotid artery flow. Measurements were made be-
fore and after ordinary smoking and showed an increase in cere-
bral blood flow and a decrease in cerebral vascular resistance in
all subjects. No significant difference in response was observed
between the 4 younger and 8 older (over 66 years of age) subjects.
More research is needed to clarify the role of cigarette smoking
in the acute pathogenesis of CVD manifestations. However, the
chronic effect of smoking upon the cerebral circulation (particu-
h]JT its extracranial portion) is Iikely to be similar to the effect
Of smoking upon the aortic and coronary atherosclerosis.

NON-SYPHILITIC AORTIC ANEURYSM

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

63


TABW PL-Deaths jrma cerebruva.mdar disease related to making
(Xcutdity ratIoa--actual number of death8 ahown In ~nrmthesca)~
            [SM = lmokcn    NS = non~mdrsnl

PROSPECTIVE STUDIES

Age r1rhtIon

commcntr

1.060   NS . . . . . . ..l.OO  (lE4)                                 t(Pco.01).
   Ckarcttn
     SM  . . . . ..tl.aO  (666)
    Other SM  . .1.26 (HO)
      Ciuarstter only
    <IO  ..,,,,,. 1.24 (41)
    x-20  ..,., ..1.44 (140)
    >20  . . . . . . . 1.46  (83)

Doll and   ADDR~u~~Y Questlonnalrs 10      606 NS  . ..,...,. 1.00
RIU     41,ObO mole   md fqlIow-              All SM ,,.,., 1.06
1064,     Brltlsh     up of death              All
CRlt    phyrlelan~.    certine*te.              clgrrctta 1.12
B?ibLn                                 l-14  . . . . ..l.lO
(lob.                                  16-24 . ...,. 1.W
                                   >26  .,,,,... 1.26

Kmnsl    6,127 males    MedICal       12      1s  NS  . . . .L.OO   161                                     Data o o~lu onlv


TABLE `&I.-Deaths from cerebrovaamlar diseaee related to making (cont.)
      (Mortality ntlw-actual number of dwthr ahown In partnthnel)'
              [SM = mokcn    NS = nonamokersl

PROSPECTIVE STUDIES

Irhn.     U.S. mab    Queatloonalra 6%    2,008 NS  . . . . . . . . 1.00  (614)     PIPU
1060.     Vetm-uIl     and follor-              AU              shl  . .1.06 (82)
U.S.A.    2966.674     up of death             current . . . .1.60(1,894) NS . .1.00(614)
(011.     pmon      MrufiUk              Chtl-tnt             CXQLW
        Y-                         dgetla . 51.62 (682) NS  . .1.00(614)
                                      1-v  . . . . . , . 1.61 (88) 8M ..1.06(186)
                                    lo-20 . . ...1.42 (826)
                                   21-89 . . . ..l.?O (216)
                                    >se  .# ..*.* 1.69 (87)

Elmmond 868.d64 make Quatlonn~lm 6
md      446,876      and follow-
Cuflnkd, fcrmla 40-79 UP of death
196O.     ,eara of we   CertlIlC~tc.
U.S.A.    at entry.
(78).

4.09D

CUW#UC
rcoukw
duortfle 40-u
Never
rmoktd 1.00
l-9  . . . ...2.79
lo-18  . . ...1.14
2049 . . ...2.21
,>40  . . . ...1.64

NeVW
amoked  1.00
l-9 . . . ...1.60
IO-19  . . ...2.60
20-39 . . ...2.90
>tO  . . . ..t6.70

  Maksr
so-se  004

1.00   1.00
1.96   1.to
1.48  tl.44
LOS   1.62'
2.40   1.72
Fcnrclkr

1.00   1.00
1.26   1.26
2.70   2.16
2.67   1.88
t6.62    -

   trlued on only
     69 death.
TO-78

1.00
0.86
0.92
1.22
to.68

1.00
0.83
to.67
1.26


T)~BLE 28.-Deaths from cerebromscular dieease veluted to smoking (cont.)
  (Mortrllty ratios-actual number of dtrtha ehoan In parentheses)l
           SY = Smoken.    NS = Nonsmokers.

PROSPECTIVE STUDIES

Pbf?ra.    8.268 m&b    IraM multi- 16      67 NSand
buglt,   bnoabaremhn pbdc             -30, . . . . . . . ..l.OO  (42)
rtd.     s-e4 Yea"    lC~e+nltlg              x0 . . . . . . . al.16  (26)
1970     of .* In     and follow-
U.&A.    1961.       UD of death
(144).              ceruncrte.

                               RETROSPECTIVE STUDY

>SO,OOO male  Inltlal eolleps                                 Death Rater                       The 69 deaths from

barper    Unlvcnlty    entrsnce                          Corer (fad,   Catrok (ala)                    occlualvc stroke
u.d      ,tudrnt.,     medld cx-              SM  ,,..,.,,...,,...,..,. 46.0     81.8 (p<o.oi)                    contributtd to the
wluluu   folloned up    UnInbtlonI            Clgnrette SM >tO per day . 20.9     11.2(P<O.O1)                   atatlatlcd slg-
1067     to 60 Ye.".    with follow-                                                               nlHcanee.
U.S.A.             UD of death                                                               The 96 deaths from
(146).              cetiincatc.                                                               hemurrhs&
                 ConkoIl-                                                                arrokeabowed
                sumlving                                                                 no statlatlc~l
                 claasmstes                                                            slgnIflcancc"
                an+-makhcd.                                                              8 single group.

  ' Unlm othcr-wkc ~~eclRed, dlap4tl.x between the total number of deaths
md the aum of tbs ladivldual smoking qtwries are due to the cxcluion of
dtbcr ~~~lond, mbeellanmua, mhd, or ex-mmokcn.


TABLE 29.-Deatha from nonsyphilitic aortic aneurysm related to umoking-prospective studiee

(Mortdlty rallar-nctual number af death ahown In parentheses)'
       [SM = Smokera    NS = Noasmokenl

Author,
Ye-.
countl7,
rdermcs

FoUoa-up Number
Ye*"     of
       deaths

Clgarcttes per day

Hammond 187,783 white   Questionnaire      3%     68 NS . . . . . .,. .1.00(26) (cxwcted)
and Horn.  males In 9     and follow-up               SM  . . I..,,. 2.72(68) (P<O.o06)

1968.
U.S.A.

ststes 60-69
year0 of age.

(77, 78).

Kdm.

U.S. m&e     QuestIonnalre

8%    491 NS  .,,,,,,,..,...,.. s1.00 (68) NS ..1.00(68) NS ..1.00(68)

1386.
U.S.A.
IUS).

                       .-
veteranl      and f0bV.U~         Current cIgarettea . ,. .6.24(2343 SM ,.1.1a csi SM . .2.06(24j
2.266,674      of death                 l-9 cigarettes/day . .2.12 (13)
Derlon yean.    ecrtincatc.                lo-20  .,,,.,,....,, ,..6.63(124)
                                21-39  ..a,,,.. (.a ..,.. 6.96 (76)
                                >39  . . . . . . . . . . . . . . . . . 7.26 (17)

Hammond 368.634 males    Queationn~irc      6      337 NS  . . . . . . . . . . . . 1.00                            Data r~uly onlv

and      446.816 femrles   and follow-up               1-9  . . . . . . . . . ..2.62                             toms1ec SO-69
GarRnkcl.  40-79 ye,* Of   of death                  10-19 .:.....,..8.86                             yt.m of Lge.
1369,     age at entry.    certificate.                20-3s  . . . . . a.... 4.64
V.S;A*                                    >40
(76).                               , . . . . .._.I . ..8.00

Web ind  68,163 Callfomla Queatlannalre      S-8     61 NS  . . . ..,.,...* 1.00
DlInIl,    tide workera   and fOl!OW-Up               All  . . . ,. . . . . . . . .2.64
1970.     E-64 ye.n ot   al death                  Cl0  I.. ..a,. a .,.2.44
U.S.A.    age at entry.    crrtificste.                 520  ,... * . . . . . . . 2.88
(IDS).                                ZSO . . . . . . . . . ...2.64

' Unlnr ofJwrwlse 1~4fled, dl#parltlh between the total number of
dsrthl and the sum of the Indlvldual cskgorlw .re due to the urclulon

Sk! Include
cr-amoken.
NS include plge
and clg~r
amoken.

m    of elthcr oeculonrl, mlscell~neou~, mlxed, or rxamokcn.


PERIPHERAL ARTERIOSCLEROSIS

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

Juergens, et al. (9.2) reviewed the records of and contacted 478
maIe patients with arteriosclerosis obIiterans (a severe form of
peripheral arteriosclerosis), who had been patients at the Mayo
Clinic between 1939 and 1948. The diagnosis of this condition was
based upon certain clinical criteria: the presence of intermittent
claudication, the marked diminution or absence of lower extremity
arterial pulsations, and objective trophic manifestations of per-
ipheral limb ischemia. Smoking information was available on 401
patients. These patients were compared with a control group of
350 Mayo Clinic patients of similar age who showed no clinical
evidence of vascular disease. It was found, for males under the
age of 60, that 2.5 percent of the cases and 25 percent of the con-
trols were nonsmokers. However, no difference was noted between
the percentages of heavy smokers in each group. The authors also
impIicated high blood pressure and elevated serum cholesterol as
risk factors in the occurrence of this disease.

Begg (19) noted similar findings in a study of 294 male patients
with intermittent claudication who were patients at the Western
Infirmary in Glasgow, Scotland. .In comparing the smoking his-
tories of 100 patients with this complaint with those of 116 healthy
male controls, the author found that 1 percent of the patients and
21 percent of the controls had never smoked. A total of 42 percent
of the patients smoked more than 20 cigarettes per day while only
24 percent of the controls had a similar history of heavy smoking.
The author concluded that smoking, while not a prime cause of
peripheral arterial disease, is a significant cofactor in its develop-
ment in almost ali cases. The author also noted obesity, high blood
Pressure, and elevated serum choIestero1 as risk factors.

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

68

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

Widmer, et al. (215) compared 277 male patients with arteriaI
occlusion of the limbs as demonstrated by aortography or oscilIog-
raphy with 2,082 men demonstrated by oscillography to be free of
arterial disease. The authors found that cigarette smoking, parti-
cularly heavy smoking, was significantly more frequent among the
cases with arterial occlusion than'among the controls. Increased
beta-lipoproteins and systolic hypertension were also found to be
more common among the cases.

EXPERIMENTAL EVIDENCE

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

THROMBOANGIITIS OBLITERANS

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

69

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

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

CARDIOVASCULAR DISEASES

SUMMARY AND CONCLUSIONS

CORONARY HEART DISEASE

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

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

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

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

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

70


velocity, and heart rate, and thereby increases the lvork of the
heart and the myocardial demand for os'gen and other
nutrients.

b. -among individuals \vith coronar> atherosclerosis, cigarette
smoking appears to create an imbalance betlveen the increased
needs of the mvocardium and an insufficient increase in coro-
nary blood flow and oxygenation.

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

CEREBROVASCULXR DISEASE

1. Data from numerous prospective studies indicate that ciga-
rerte smoking is associated with increased mortalit>- from cerebro-
vzscnlar disease.

`3. Experimental evidence concerning the relationship of smok-
ing and cerebrovascular disease is at present insufficient to allow
for conc!usions concerning pathogenesis. However, some of the
pathophgsiological considerations discussed concerning CHD may
also pertain to the relationship of smoking and 0-D, particularly
cerebral infarction.

NON-SYPHILITIC XORTIC ANEURYSM

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

PERIPHERAL VASCULAR DISEASE

1. Data from a number of retrospective studies have indicated
that cigarette smoking is a likely risk factor in the development
of peripheral vascuiar disease. Cigarette smoking also appears to
be a factor in the aggravation of peripheral vascular disease.
2. Cigarette smoking hB's been observed to alter peripheral
b!ood f?ow and peripheral vascular resistance.

C'ARDIOVASCULAR REFERESCES

(1) ACHESON. R. M., JESSOP, W. J. E. Tobacco smoking and serum lipids in
   old men. British Jledical Journal 2: 110~1111, October 28, 1961.
(2) ADLER, I., HESSEL. 0. Intl-avenous injections of nicotine and their ef-
   fects upon the. aorta of rabbits. Journal & Medical Research 15:
   229-239, 1906.

71


(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)



(11)

(1')



(1s)

(14)



(15)

(16)

(17)

(18)

(19)

ALLIsoN, R. D., Row, G. 51. Central and peripheral vascular effects
durir.g cigarette smoking. Archives of Envik-onmental Health 19(2) :
189-198, August 1969.

A~I~,Rus, J. I,., MINK, I. R. Effect of cigawtte smoking on b!ood coay-
lation. Clinical Pharmacology and Therapeutics 5(4) : 428431, 1964.
~~o~ow, W. S., KAPLAN. M. A., JACOB, D. Tobacco: A precipitating
factor in angina pectoris. Annals of Internal Medicine 69(3): 529-
536, September 1968.

ARONOW, W'. S., SWANSON, A. J. Non-nicotiniwd cigarettes and angina
pectoris. Annals of Internal Medicine 70(6) : 1227, June 1969.
~ONOW, W. S., SWANSON, A. J. The effect of low-nicotine cigarettes
on angina pectoris. Annals of Internal Medicine 71(3) : 599-601,
September 1969.

ASHEY, P., DALBY, A. M., MILLAR. J. H. D. Smoking and platelet sticki-
ness. Lancet 2: 158-159, July 24, 1965.
ASTRUP, P. Effects of hypoxia and of carbon monoxide exposures on
experimental atherosclerosis. Bnnals of Internal Medicine 71(Z) :
426427, August 1969.

XSTRUP, P., KJELDSEN. K., WANSTRUP, J. Enhancing influence of carbon
monoxide on the development of atheromatosis in cholesterol-fed
rabbits. Journal of Atherosclerosis Research 7: 343-354, 1967.
ASTRIJP, P., PAULI, H. G. (Editors). A Comparison of Prolonged Ex-
posure to Carbon hlonoxide and Hypoxia in Man. Reports of a Joint
Danish-Swiss Study. Scandinavian Journal of Clinical and Labora-
tory Investigation 22 (Supplement 103) : 1368. 71 pp.
AUERBACH, O., HAMMOND, E. C., GARFINKEL, L. Smoking in relation
to atherosclerosis of the coronary arteries. New England Journal of
Medicine 273(15) : 775-779, October 7, 1965.
AVTANDILOV, G. G., KOLENOVA, V. I., PONOMACNKO, 0. V. Kureniye
tabaka i stepen'  ateroskleroticheskogo porazheniya koronarnykh
arteriy serdtsa i aorty. (Tobacco smoking and the degree of athero-
sclerotic lesions of coronary arteries of the heart and aorta.) Kar-
diologiya 5 (1) : 30-34, January-February 1965.
AYRES, S. M., G~ANNELLI, S., JR., ARMSTRONG, R. G. Carboxyhemoglo-
bin: Hemodynamic and respiratory responses to small concentrations.
Science 149: 193-194, July 9, 1965.

AYRES, S. M., hIwELLER, H. S., GREGORY, J. J., GIANNELLI, S., JR,
PENNY, J. L. Systemic and myocardial hemodynamic responses to
relatively small concentrations of carboxyhemoglobin (COHB) i-Ar-
chives of Environmental Health 18(4) : 699-709, April 1969.
BUAZS, T., OHTAKE, S., Cuhfrmrics, J. R., NOBLE, J. F. Ventricular
extrasystoles induced by epinephrine, nicotine, ethanol, and vaso-
pressin in dogs with myocardial lesions. Toxicology and Applied
Pharmacology 15 (1) : 189-205, July 1969.
BARGERON, L. hr., JR., EHMKE, D., GONLUBOL, F., CASTELLANOS, A.,
SIEGEL, A., BING, R. J. Effect of cigarette smoking on coronary blood
flow and myocardial metabolism. Circulation 15: 251-257, February
1957.

BmNm, A. J., BOAKE, W. C. Cigarette smoking and occlusive arterial
disease of the legs. Medical Journal of Australia 1: 240-242, Feb-
ruary 13, 1960.

Bm, T. B. Characteristics of .men with intermittent claudicatjon.
Practitioner 194 (2) : 202207, February 1965.

72


(20) BELLET, S., FLEISCHMANN. D., Ro~~AN, L., DEGUZMAN, N. The effect
    of cigarette smoke inhalation on the ventricular fibrillation threshold.
    Circulation (Supplement 3) 4`2(4) : 135, October 1970.
(21) BELLFT, S., KERSHBAUM. A., MEXDE. R. H., JR, SCHWARTZ, L. The ef-
    fect of tobacco smoke and nicotine on the normal heart and in the
    presence of myocardial damage produced by coronar)- ligation. Amer-
    ican Journal of the hIedical Sciences 201(l) : 40-51, January 1941.
(22) BELL=. S.. WEST, J. W., MULLER. 0. F:, MAXZOLI, U. C. Effect of
   nicotine on the coronary blood flow and related circulatory parame-
   ters. Correlative study in normal dogs and dogs with coronary in-
   sufficiency. Circulation Research 10(l) : 27-34, January 1962.
(23) BERKSON, D. hl., STAMLER. J. LINDBERG. H. A., MILLER. W. A., STEVENS,
    E. L., SOYUCENIC. R., TOKICH, T. J., STAhlLER, R. HEART rate: An
   important risk factor for coronary mortality-ten-year experience
   of the Peoples Gas Co. Epidemiologic study (1958-68) _ IN: Jones,
   R. J. (Editor). Atherosclerosis. Proceedings of the Second Interna-
   tional Symposium. New York, Springer-Verlag, 1970. pp. 382389.
(24) BEST, E. W. R. A Canadian Study of Slnoking and Health. Ottawa,
    Department of National Health and Welfare, 1966. 133 pp.
(-05) BLACKDURN, H., JK., ORhln. E., HARTEL G., PUNSAR, S. Tobacco smoking
   and blood coagulation: Acute effect on plasma Stypven time. Ameri-
    can Journal of the Medical Sciences 238: 448451, October 1959,
(26) BLOMGTRAND, R., LUND~~AN, T. Serum lipids, smoking and heredity.
   Acta Medica Scandinavica 180(Supplement 455) : 51-60, 1966.
(27) BORHANI. N. O., HECHTER, H. H., BRESLOW, L. Report of a lo-year
   followup study of the San Francisco longshoremen. Mortality from
   coronary heart disease and from all causes. Journal of Chronic
    Diseases 16: 1251-1266, 1963.

(28) BOYLE, E.. Jru., MORALES, I. R., NICHAM~N. M. Z., T,UBERT, C. R., JR,
   WATKINS, R. S. Serum beta lipoproteins and cholesterol in adult
   men. Relationships to smoking, age, and body weight. Geriatrics
    23( 12) : 102-111, December 1968.

(29) BREWER, G. J., EATON, J. W., WEIL, J. V., GROVER, R. F. Studies of red
   cell glycolysis and interactions with carbon monoxide, smoking, and
   altitude. Advances in Experimental Medicine and Biology 6: 95-114,
     1970.

(JO) BRODY, J. S., COBURN, R. F. Carbon monoxide-induced arterial hypoxe-
   mia. Science 164(3885) : 1297-1298, June 13, 1969.
(Sf) BRONTE-STEWART, B. Cigarette smoking and ischaemic heart disease.
   British Medical Journal I: 379-384, February 11, 1961.
(12) BROWN, H., SELLWOOD, R. A., HARRISON, C. V., MARTIN, P. Throm-
   boangiitis obliterans. British Journal of Surgery 66 (1): 59-63,
   January 1969.

(39) BUECHLEY, R. W., DRAKE, R. hf., BRESLO~, L. Relationship of amount
   of cigarette smoking to cornary heart disease mortality rates in men.
   Circulation 18 (6) I 1085-1090, December 1958.
(34) BUNN, H. F., JANDL, J. H. Control of hemoglobin function within the
   red cell. New England Journal of Medicine 282(25) : 1414-1421,
    June 18, 1970.

(35) BURN, J. H., RAND, M. J. Action of nicotine on the heart. British Medi-
   cal Journal 1: 137-139, January 18, 1958.
(36) CAGANOVA, A., CACAN. S., SIMKO, V. Lipijy krvneho sera u nefajcia-
   ray a fajciarov. (Blood serum lipids in nonsmokers and smokers.)
   Bratislavske Lekarske Listy 60(3) : 38'7392, September 3,1968.

73


(37) CEDERLOF, R. The T\\-in Method in Epidemiological Studies on Chronic
   Disease. Institute of H>-giene of the Karolinska Institute, Department
   of Environmental Hygiene of the Sational Institute of Public Health,
    Department of Sociology. University of Stockholm, Stockholm, 1966.
    71 PP-

(38) CEDERLOF, R., FRIBERC, L., HRU~EC, 2. Cardiovascular and respiratory
    symptoms in relation to tobacco smoking. A study on American
    twins. Archives of Environmental Health 18(6) : 934-940. June 1969.
(39) CEDERLOF, R., FRIBERC, L., JOXSSOX, E., Karl. L. Respiratory symptoms
    and "angina pectoris" in twins with reference to smoking habits.
   An epidemiological study with mailed questionnaire. Archives of
    Environment31 Health 13 (6) : 726-737, December 1966.
(40) CEDERLOF, R., JONSSON, E.. LUNDMAN, T. On the validity of mailed
    questionnaires in diagnosing "angina pectoris" and "bronchitis".
    Archives of Environmental Health 13(6) : 738-742, December 1966.
(41) CHEVALIER, R. B., KRIJXHOLZ, R. A., Ross, J. C. Reaction of non-
   smokers to carbon monoxide inhalation. Cardiopulmonary responses
    at rest and during exercise. Journal of the American hledical Asso-
    ciation 198(10) : 1061-1064, December 5, 1966.
(42) CHOI, Y. Y. Effect of nicotine upon cholesterol-induced atherosclerosis
    in rabbits. New Xedical Journal lO(7) : 685-693, 1967.
(48) CLARK, V. A., CHAPMAN, J. M., COULSOS, A. H. Effects of various fac-
    tors on systolic and diastolic blood pressure in the Los Angeles
    Heart Study. Journal of Chronic Diseases 20: 571-581, 1967.
(44) COHEN, S. I., DEANE, hl., GOLDWITH, J. R. Carbon monoxide and sur-
    vival from myocardial infarction. Archives of Environmental Health
    19(10) : 510-517, October 1969.

(45) CO&WELD, J., MITCHELL, S. Selected risk factors in coronary disease.
    Possible intervention effects. Archives of Environmental Health
    19(3) : 382-394, September 1969.

(4s) CZOCHRA-LYSAXOWICZ, Z., GORSKI. hi., KEDRA, M. Wplyw nikotyny i
   kofeiny na rozwoj miazdzycy u krolikow. (The effect of nicotine and
   caffeine on the development of arteriosclerosis in rabbits.) Annales
   Universitatis Mariae Curie-Sklodowska; Section D: Medicina 14(20) :
    181-206, 1959.

(47) DAWRER. T. R.. FUNNEL, W. B., REYOTSKIE, N., STOKES, J., KAG~N, A.,
   GORDON, T. Some factors associated with the development of coronary
   heart disease. Six years' followup experience in the Framingham
  study. American Journal of Public Health and the Nation's Health
   49 (10) : 1349-1356. October 1959.

(48) DAYTON, S., PEARCE, XI. L. Diet and atherosclerosis. Lancet l(7644):
   473-474. February 28, 1970.

(49) DAYTON, S.. PEARCE, M. L., HASHIMOTO, S., DIXON, W. J., TOMNAXJ, U.
   A Controlled Clinical Trial of a Diet High in Unsaturated Fat in
   Preventing Complications of Atherosclerosis. Circulation 40 (1 Sup-
   plement ll), July 1969. 63 pp.

(50) DOLL, R., HILL, A. B. Mortality in relation to smoking: 10 years' ob-
   servations of British doctors. (Yart I) British Medical Journal
    1(5395) : 1399-1410, hlay 30, 1964.

(51) DOLL, R., HILL. A. B. Mortality in relation to smoking: 10 years' ob-
   servations of British doctors. (Concluded) British Medical Journal
   l(5396) : 1460-1467, June 6, 1964.

74


(52) D&KEN, Ii. Die Rauchgexohnheitenbej jdngeren Herzinfarkt-patien-
   ten. (Smoking habits of plunger patients with m)~ocsrdial infax-
   tion.) Miinchener medizinische Wochenschrift 109(J) ; 187-192
   January 27, 1967.

(53) DORKEN, H. Die Rauchgewohnheiten bei jiingeren Frauen mit Herzin-
   farkt. (The smoking habits of younger females with my-ocardial in-
   farction.) Mtinchener medizinische Wochenschrift 109(41) ; 2129
    2134, October 13, 1967.

(54) I)OYLE. J. T.. I)AWRER, T. R., I<ANP;EL. w. B.. KISCH. s. H. KAHN, H.
   A. The relationship of cigarette smoking to coronary heart disease.
   The second report of the combined cvprrience of the Albany, N.Y..
   and Framingham, blass.. studies. Journal of the American Medical
    Association 190( 10) : 886890, I)crcmber 7, 1964.
(55) DUNN, J. P., IPSEN, J., ELSOM, K. O., OHTANI, &I. Risk factors in coro-
   nary artery disease, hypertension and diabetes. American Journal
   of the Medical Sciences 259(S) : 309-322, May 1970.
(5~) EDWARDS. F.. McKu)wx, T., W~~ITFIELD, A. G. \\I. Association between
   smoking and disease in men over sixty. Lancet 1: 19&-200, January
    24, 1959.

(57) EISES, hI. E. Coexistence of thromboangiitis obliterans and arterio-
   sclerosis: Relationship to smoking. Journal of the American Geria-
    trics Society 14 (8) : 816-858, August 1966.
(58) ENGFLDERC, H. Cigarette smoking and the in nitro thrombosis of hu-
   man blood. Journal of the American Medical Association 193(12) :
    1033-1035, September 20, 1965.

(59) ENGELBERG, H., FUTTERMAN, M. Cigarette smoking and thrombotic co-
   agulation of human blood. Archives of Environmental Health 14 (2) :
   266-2'70, February 1967.

(GO) EKCIXH, J. P., WILLIUS, F. A., RERKSON, J. Tobacco and coronary
   disease. Journal of the American Medical Association 115(16) :
    1327-1329, October 19, 1940.

(61) EPSTEIN, F. H. Some uses of prospective observations in the Tecumseh
   Community Health Study. Proceedings of the Royal Society of Medi-
   cine 60( 1) : 4-8, January 1967.

(62) FIDASZA, F., IhIBIMBO, B., DI BENEDETTA, C. Indagine epidemiologica
   delle cardiopatie ischemiche nei reclusi de1 penitenziario di S. Stefano
   di Ventotene. (Epidemiological investigation of ischemic heart di-
   sease in prisoners of S. Stefano di Ventotene prison.) Gironale dell'
    Arteriosclerosi 4: 255-267 1966.

(63) FLETCHER, C. &I., HORN, D. Smoking and health. WHO Chronicle 24(8) :
   345-370, August 1970.

(64) FoLW L. E.. SAMANEK, M., Avrmo, D. M. Cardiopulmonary effects
   of tobacco and related substances. II. Coronary vascular effects of
   cigarette smoke and nicotine. Archives of Environmental Health
   12(6): 712-716, June 1966.

(65) FORTE. I. E. WILLIAMS, A. J. POTGIETER, L., SC~IMITTHESNER, J. F.,
   EIAFKENsCHtEL, J. H., RIEGEL, C. Coronary blood floi\- and cardiac
   oxygen metabolism during nicotine-induced increases in left ventricu-
   lar work. Annals of the New York Academy of Sciences 90(l) :
   174-183, September 2'i, 1960.

(66) FUNKL, W. S., FRIEDMAN, R.. SOLOFF, U. A. Cardiac output, blood
   Pressure and free fatty acid responses to smoking in the nonbasal
  state. American Journal of the Medical Sciences 252(I) : 39-44,
   July 1966.

75


(67) FRANKL, W. S., WINTERS. W. L.. SOLOFF. L. A. The effects of smoking
   vn the cardiac output at rest and during exercise in patients with
   healed myocardial infarction. Circulation 31 (I) : 42-44, January 1965.
(68) FREUND. J., WARD, C. The acute effect of cigarette smoking on the
   digital circulation in health and disease. Annals of the New York
   Academy of Sciences 90(l) : 85-101, September 27, 1960.
(69) FRIBERG, L., CEDERLOF, R., LUNDMAN, T., OLSSON, H. Mortality in
   smoking discordant monozygotic and dizygotic twins. A study on the
   Swedish Twin Registry. Archives of Environmental Health 21(4) :
    508-513, October 1970.

(70) FRIEDELL, M. T. Effect of cigarette smoke on the peripheral vascular
   system. Radioactive iodinated albumin used as indicator of volu-
   metric change. Journal of the American hfedical Association 152(10) :
   897-900, July 4, 1953.

(71) GLYNN, M. F., hfusTARn, J. F., BUCHANAN, M. R., MURPHY, E. A.
   Cigarette smoking and platelet aggregation. Canadian Medical Asso-
   ciation Journal 95(11) : 549-553, September 10, 1966.
(72) GOFMAN. J. W., LINDCREN. F. T., STRISOWER, B.. DELALLA, 0.. GLAZIER,

(75)


(74)



(75)







(76)



(77)




(78)

F. TAX~PI.IN, A. Cigarette smoking, serum lipoproteins, and coronary
heart disease. Geriatrics lO(8) ; 349-354, August 1955.
GOLDSMITH, J. R., LANDAW, S. A. Carbon monoxide and human health.
Science 162(3860) : 1352-1359, December 20, 1968.
GREENSPAN, K., EDMANDS, R. E., KNOEBEL, S. B., FKCH, C. Some
effects of nicotine on cardiac automaticity, conduction, and inotropy.
Archives of Internal Medicine 123(6): 707-712, June 1969.
GROSCOCEAT, Y., ANGUERA, G., LELLOUCH. J., JACOTOT, B., BFXUMONT,
J.-L., PATOIS, E., i%ANIER, E. L'intoxication chronique par la nico-
tine chez le lapin nourri au cholesterol. Effets sur la paroi aortique
et sur la lipidernie. (Chronic nicotine poisoning in the rabbit on a
cholesterol diet. Effects on the wall of the aorta and on lipidemia.)
Journal of Ather-osclerosis Research 5(3) : 291-301, 1965,
HAMMOND, E. C., GMXFINKEL, L. Coronary heart disease, stroke, and
aortic aneunsm. Factors in the etiology. Archives of Environmental
Health 19(2) : 167-182, August 1969.
HAMMOND, E. C., HORN, D. Smoking and death rates-rrport on forty-
four months of follow-up of 187,783 men, I. Total mortality. Journal
of the American Medical Association 166 (10) : 1159-1172, March 8,
1958.

HAMMOND, E. C., HORN, D. Smoking and death rates--report on forty-
four months of follow-up of 187,783 men. II. Death rates by C&UC.
Journal of the American Medical Association 166(11) : 1294-1308,
March 15, 1958.

(79) HARLAN, W. R., OBERMAN, A., &IITCHELL. R. E., GRAYAIEL, A. Con-
   stitutional and environmental factors related to serum lipid and
  lipoprotein levels. Annals of Internal Medicine 66(3) : 540-555,
    March 1967.

(80) HASS, G. M., LANDERHOI.M. W., HEMMENS, A. Production of calcific
  athero-arteriosclerosis and thromboarteritis with nicotine, vitamin
  D, and dietary cholesterol. American Journal of Pathology 49(4) :
   739-771, October 1966.

(81) HAuGE, M., HAKVALD, B., REID, D. D. A twin study of the influence
   of smoking on morbidity and mortality. Acta Geneticae Medicae et
   Gemellologiae 19 : 335-336, 1970.

76


(82) HEYDEN-STUCKY, S.. SCHIBLER-REICH, S. Kardiologische Risikofaktoren
    bei Schweizer Mannern. (Cardiological risk factors in Swiss men.)
    Schweirerische Rledizinische Wochenschrift 97(l) : 20-25, January
     7, 1967.
(53) HIG~~XS. hr. lV., KJELSBERC, al. Characteristics of smokers and non-
    smokers in Tecumseh, Michigan. II. The distribution of selected physi-
    cal measurements and physiologic variables and the prevalence of
     certain diseases in smokers and nonsmokers. American Journal of
    Epidemiology 86(l) : 60-77, July 1967.
(a&) HI~~YAJIA, T. Smoking in relation to the death rates of 265,118 men
    and women in Japan. National Cancer Center, Research Institute.
    Tokyo, September 1967. 14 pp.
(85) HOOD, B., TIEBLIN, G., WEI.IN, G., ORNDAHL. G., KORSAX-BCNGTSEN, K.
    Myocardial infarction in early age. III. Coronary risk factors and
    their deficient control. Acta hledica Scandinavica 185(4) : 241-251,
    April 1969.
(86) HL'EPER, W. C. Experimental studies in cardiovascular pathology. VII.
    Chronic nicotine poisoning in rats and in dogs. A.M.A. Archives of
    Pathology 35: 846-856, 1943.
(87) HYAII-IS, L., SECI. M., .ARCIIER, M. Myocardial infarction in the Japan-
    ese. A retrospective study. American Journal of Cardiology 20(4) :
    549-554, October 1967.
(68) IXTER-SOCIETY CohihiIss1or-i ~`OR HEART DISEASE RESOURCES. Athero-
    sclerosis Study Group and Epidemiology Study Group. Primary pre-
    vention of the atherosclerotic diseases. Circulation 42(6) : X-S&A-95,
     December 1970.
(89) IKYING, D. W., YAJIA~IOTO. T. Cigarette smoking and cardiac output.
    British Heart Journal 25: 126135, 1963.
(90) JENKINS, C. D., ROSENhlAN, R. H., Z~zaxslcr, S. J. Cigarette smoking.
    Its relationship to coi-onary heart disease and related risk factors in
    the Western Collaborative Group Study. Circulation 38(6): 114O-
    1155, December 1968.
(91) JOUVE, A., ROCHU, P., AVRIL, P. Enquetes epidemiologiques sur l'athero-
   sclerose dans la region Provencale. (Epidemiological investigations of
   atherosclerosis in the Provence region.) Union Medicale du Canada
    98 (5) : 761-766, May 1969.
(9-O) JUERGENS, J. L., BARKER, N. W., HINES, E. A., JR. Arteriosclerosis ob
   literans: Review of 520 cases with special reference to pathogenic
   and prognostic factors. Circulation Zl(2) : 188-195, February 1960.
(9.1) KAHN, H. A. The Darn study of smoking and mortality among U.S.
   x'eterans: report on 8% years of observation. IN: Haenszel, N. (Edi-
   tor). Epidemiological Approaches to the Study of Cancer and Other
   Chronic Diseases. Bethesda, U.S. Public Health Service, National
   Cancer Institute hlonograph No. 19, January 1966. pp- l-125.
(94) KANNEL, IV. B., CASTEI.LI, W. P.. hlcNAhrAR4, P. M. Cigarette smoking
   and risk of coronary heart disease. Epidemiologic clues to patho-
   genesis. The Framingham study. IN: Wynder, E. L., Hoffmann, D.,
   (Editors). Toward a Less Harmful Cigarette. Bethesda, U.S. Depart-
   ment of Health, Education, and Welfare, Public Health Service, Na-
   tional Cancer Institute hIonograph No. 28. June E9#. pp. 9-20.
(95) ~(ANNEL, JV. B., DAWDER, T. R., SKINNER, J. J., JR., McNaazAR.4, M,
   Sr~unr~~r~. D. Epidemiological aspects of intermittent claudication:
   The Framingham Study. Circulation (Supplement II to Vols. 31 and
   32) : 121-122, October 1965.

                                       77


(96) LSh.EL, 15'. B., I)AWBER, T. R., COHEN, >I. E., McNauti~, P. >I. Vas.
   cular disease of the brain--epidemiologic aspects. The Framingham
   stud\-. American Joui-nai of Public Health and the Sation's Health
   .55(g) : 1355-1366, September 1965.

(97) KAK\.O.\`EN. 11.. OR>rA. E., KEYS. A., FIDAszA, F. RROSEK. J. Cigarette
   smoking, serum-cholesterol, bloodpt-essure, and body fatness. Obser-
   vations in Finland. Lancet 1: 492-494, March 7, 1969.
(98) I(ASTL. 0. Berufliche und Umweltanalyse infarktkranker Eisenbahn-
   hediensteter. (Occuliationnl and envirnnmental analysis of infarct
   patients in railway service.) hledizinischc Klinik 6-L (42) : I9II-1917,
    October 17, 1969.

(99) KEDRA, >I.. I)hIOW'SKI, G. The influence of tobacco smoking on the devel-
   opment of atherosclerosis and on the composition of blood lipids.
    Polish Medical Journal 5( 1) : 37-43, 1966.
(100) KEDRA, M., KOROLKO, A. Tobacco smoking and blood clotting. Bulletin
    of Polish >Iedical Science and History 8: 145-148, October 1965.
(101) KEDR~, IX, POLESZAX, J., PITERA, A. Wplyx palenia tytoniu na poziom
    tluszczowcow krwi. (Influence of tobacco smoking on the blood lipid
    levels.) Polski Tpgodnik Lekarski 20(D) : 1452-1454, September 27,
      1965.

(102) GXRIGAN, H., Jarx, A. C., I)OYLE, J. 7'. The circulatory response to
    cigarette smoking at rest and after exercise. American Journal of
     the .\Iedrcal Sciences ",iS(") ; 11%I I!). I.`vl,~-u:li-y IX%.
(103) KmsHBr\uhl, A., BELLET, S., CAPLAN, R. F.. I+XNBERC. L. J. Effect of
    cigarette smoking on free fatty acids in patients with healed myo-
    cardial infarction. American Journal of Cardiology lO(2) : 204-208,
    August 1962.

(104) FERSHBAUJI. A., RELLET, S., I)ICKSTEIN, I'. I(., FEINBERG, L. J. Effect of
   cigarette smoking and nicotine on serum free fatty acids. Based on a
    study in the human subject and the experimental animal. Circulation
    Research 9 (3) : 631-638, May 1961.

(105) KERSSIB~UM, A., BELLET, S., HIRABAYASHI, hl., FEINBERC, L. J. Regular
    filter-tip, and modified cigarettes. Nicotine excretion, free fatty acid
    mobilization and catecholamine excretion. Journal of the American
     Medical Association ZOl(7) : 545-546, August 14, 1967.
(106) I<ERSHRAUhl. A., PELLET. S.,.JlhqENEZ, J.,FEIMERc,L.J. Differences in
   effects of cigar and cigarette smoking on free fatty acid mobilization
    and catecholamine excretion. Journal of the American Medical Asso-
    ciation 195( 1.7) : 1095-1098, March 28, 1966.
(107) KERSHBAUM, A., BE~.IET, S., KHORSANDIAN, R. Elevation of serum cho-
    lesterol after administration of nicotine. American Heart Jw-ml
    69(2) : 206210, February 1965.

(108) KERSHBAUM, A., JIhlENEZ,J., BELLET. s., ZANUlTIXI, 11. Modification of
   nicotine-induced hyperlipidemia by anti-adrenergic agents. Journal
    of Atherosclerosis Research 6: 524-530, 1966.
(log) KERSHBAUM. A.. KNOR~ANDIAN, R., CAPLAN. R. F.. BELLErr. S.. FErN-
    BERG, L. J. The role of catecholamines in the free fatty acid response
    of cigarette smoking. Circulation 28 (I) : 52-57. July 1963.
(110) E;ERSHBAUM, A.. OSADA, H., SCRIABINE:, A., RELLET, S., PAPPAJOHN,
    I). J. Influence of nicotine on the mobiiization of free fatty acids from
   rat adipose tissue in vitro and in the i:,olated perfused dog limb. Cir-
    culation 36(4. Supplement 2) : 20. October 196'7.
(111) KEYS. A. (Editor-). Coronary Heart Disease in Svvc-n CountI-ies. CirCU-
    lation 41(4, Supplement 1) : 1970. 211 pp.

78


(112) KEN, G A., SHERROD. T. R. .Action of nrcotine and smoking on coronary
   circulation and m)-ocardial oxygen utilization. Annals of the ?iex
    York academy of Sciences 90(l) : 161-173. September 27. 1960.
(~1s) KJELDSEN, K. Smoking and Xtherosclerosis. Investigations on the sig-
    nificance of the carbon monoxide content in tobacco smoke in athero-
    genesis. Copenhagen, slunksgaard, 1969. Il.5 pp.
(114) KJELDSEN, K., ASTRC'P, P., WANSTRUP, J. Rex,ersal of rabbit atheroma-
   tosis by hyperoxia. Journal of Atherosclerosis Research lO(2) : 173-
    178, September-October 1369.

(115) KJELDSEN, K., DA~IGMKD, F. Influence of prolonged carbon monoxide
    exposure and altitude hypoxia on serum lipids in man. Scandina\-ian
   Journal of Clinical and Laboratory Investigation 22 (Supplementurn
    103) : 16-19,1968.

(116) KJELDSEN, K., MOZES, M. Buerger's disease in Israel. Investigations on
    carboxyhemoglobin and serum cholesterol levels after smoking. Acta
    Chirurgica Scandinavica 135( 6) : 495-498, 1969.
(117) XJRDSEN, K., WANSTRUP, J., ASTRUP, P. Enhancing influence of arte-
   rial hypoxia on the development of atheromatosis in cholesterol-fed
    rabbits. Journal of Atherosclerosis Research 8(5) : 835-845, 1968.
(118) KLENSCH, H. Blut-Katecholamine und -Fetts%uren beim Stress durch
    Rauchen und durch kijrperliche Arbeit. (Blood catecholamines and
    fatty acids under stress induced by smoke and exercise.) Zeitschriir
    fiir Kreislaufforschung 55(10) : 103%1044, October 1966.
(119) KO~.~INEN, A. Cigarette smoking and serum lipids in young men. Brit-
    ish Medical Journal 1: 1115-1116. -April 21. 1962.
(120) KONTTINEN, A., RAJASALMI, &I. Eifect of heavy cigarette smoking on
    post-prandial triglycerides, free fatty acids, and cholesterol. British
   Medical Journal 1(5334) : 850-852, Jlarch 30, 1963.
(121) ~UMHOLZ, R. A., CHEVALIER, R. B., Ross, J. C. Cardiopulmonary func-
   tion in young smokers. A comparison of pulmonary function measure-
    ments and some Cal-diopulmonary responses to exercise betxveen a
   group of young smokers and a comparable group of nonsmokers.
   Annals of Internal Medicine 60(4) : 603-610, April 1964.
(122) KNMHOLZ, R. A., CHEVXIER, R. B., Ross, J. 6. Changes in cardiopul-
   monary functions related to abstinence from smoking. Studies in
    young cigarette smokers at rest and exercise at 3 and 6 xeeks of
   abstinence. Annals of Internal JIedicine 62(2) : 197-207, February
      1965.

(123) KUHN, R. A. Mode of action of tobacco smoke inhalation upon the cere-
   bral circulation. Annals of the New York Academy of Sciences 142
    (Article 1) : 67-71, March 15, 1967.

(124) LARSON, R. K., FUKUDA, P., MURRAY~, J. F. Systemic and pulmonary
   vascular effects of nicotine in anesthetized dogs. American Review of
   Respiratory Diseases 91(4) : 556.561, April 1965.
(12.5) LWERS, F. E., LONG, J. P. Action of nicotine on coronary vascular re-
   sistance in dogs. American Journal of Physiology 203(4) : 621-625,
     October 1962.

(126) LEE, G., DERNTL. F., ROBIN, E., BIXG, R. J. The effect of nicotine on
   effective and total coronary blood flow in the anesthetized closed-chest
   dog. Journal of Pharmacology and Experimental Therapeutics 173
    (1) : 138-144, May 1970.

(127) LILIENTHAi, 3. L., JR. CaI.bon monoxide. Pharmacological Review 2:
    324-354, 1950.

79


(128) hlCIiusicK, V. A.. HAKKrs, \V. S., OMESEN, 0. E., GOODVAS, R. >I.,
   SHELLEY, \V. >I., BLOODWELL, R. D. Ruergcr's disease: A distinct clin-
    ica) and pathologic entity. Journal of the American ,\Iedical .Xssocin-
    tion 181(l) : 5-12, July `7, 1962.

(129) MARSHALL, W. J., JR.. STAXLEY, E. L., KEZDI, P. Cardiovascular effects
    of cold pressor tests, 40" head-up tilt. and smoking on smokers and
    nonsmokers. Diseases of the Chest 56(4) : 290-296. October l'J63.
(130) MASLOVA, K. K. The influence of nicotine on experimental atherosclero-
    sis. Bulletin of Experimental Biology and Medicine 41: 20-23. 1956.
(1~1) MILLS, C. A., PORTER, M. hf. Tobacco smoking and automobile-driving
    stress in relation to deaths from cardiac and vascular causes. .4meri-
    can Journal of the Medical Sciences 234(l) : 35-43, July 1957.
(132) hflYAZAK1, M. Circulatory effect of cigarette smoking, with special ref-
    erence to the effect on cerebral hemodynamics. Japanese Circulation
    Journal 33(9) : 907-912, September 1369.
(133) MODZELEWSKI, A., hIALEC, A. Zachowanie sie niektorych Lipidow we
    krwi u palaczy. (Patterns of certain blood lipids in smokers.) If'iado-
    mosci Lekarskie 22 (3) : 229-233, February 1.1969.
(134) MOWR, C. A., MAnnOCK, W. G. Peripheral vasospasm from tobacco.
    A.M.A. Archives of Surgery 49(2) : 277285. February 1940.
(135) MULCAHY, R., HICKEY, N. J. Cigarette smoking habits of patients with
    coronary heart disease. British Heart Journal 28: 404-408, 1966.
(136) MULCAHY, R., HICKEY, N. J. The role of cigarette smoking in the cau-
    sation of atheroscierosis. Geriatrics 22(2) : 165-174, February 1967.
(137) MULCAHY, R., HICKEY, N. J., MAIJRER, B. J. Coronary heart disease in
    women. Study of risk factors in 100 patients less than 60 years of
    age. Circulation 36 (4) : 5'775SF, October 1967.
(138) MULINOS, M. G., SHULMAN, I. The effects of cigarette smoking and deep
    breathing on the peripheral vascular system. Studied by five methods.
    American Journal of the Medical Sciences lW(5): 708-720, May 19-111.
(139) MUKCHISON, L. E., FYFE, T. Effects of cigarette smoking on serum-
    lipids, blood-glucose, and platelet adhesiveness. Lancet Z(7456) : 182-
    184, July 23, 1966.

(140) MURPHY, E. A. Thrombozyten, Thrombose und Gerinnung, (Thrombo-
    CY~ZS, thrombosis and clotting.) IN : Schievelbein, H. (Editor). Niko-
    tin: Pharmakologie und Toxikologie des Tabakrauches. Stuttgart
    (West Germany), Georg Thieme Verlag, 1968. pp. 178-192.
(141) MUSTARD, J. F., MURPHY, E. A. Effect of smoking on blood coagulation
    and platelet survival in man. British Medical Journal l(5334) : 846-
    849, LMarch 30, 1963.

(142) NADEXI, R. A., JAMES, T. N. Effects of nicotine on heart rate studied
   by direct perfusion of sinus node. American Journal of Physiology
    212(4) : 911-916, April 1967.

(143) OSKI, F. A., GOITLIEB, A. J., MILLER, W. W., DELWORIA-PAPADO~OULOS,
   M. The effects of deoxygenation of adult and fetal hemoglobin on the
    synthesis of red cell 2,3-diphosphoglycerate and its in vim conse-
    quences. Journal of Clinical Investigation 49 (2) : 400-407, February
     1970.

(14.4) P=FENBARCER, R. S., JR., LAUGHLZN, M. E., GIMA, A. S., BLACK, R. A.
   Work activity of longshoremen as related to death from coronary
   heart disease and stroke. New England Journal of Medicine 282(20) :
    1109-1114, May -14, 1970.

80


(145) PAFFENURGER, R. S., JR., ~'ILLIAMS, J. L. Chronic disease in former
   college students. V. Early precursors of fatal str-oke. -American Jour-
   nal of Public Health and the Nation's Health j?(8): 129&1299.
   August 1967.

(146) PAFFENRARCER, R. S.. JR., WIXC, X. L. Chronic disease in former college
    students. I[. The effects of single and multiple characteristics on risk
    of fatal coronary heart disease. American Journal of Epidemiology
    90 (6) : 527-535, December 1969.

(147) PACE, I. H., LEWIS, L. A., \fOINUDDIN, hi. Effect of cigarette smoking
    on serum cholesterol and lipoprotein concentrations. Journal of the
    American hfedical Association 171(11) : 1500-1502, November 14,
      1959.

(148) PAUL, O., LEPPER, 31. H., P~~ELAN, W. H., DIJPEKTUIS, G. W., MACML-
    LAN, A., hICKEAr;, H., PARK, H. A longitudinal study of coronary
    heart disease. Circulation 28( 1) : 20-31, July 1963.
(149) PENTECOST. B., SHII LIKCFORD, J. The acute effects of smoking on myo-
    cardial performance in patients with coronary arterial disease. Brit-
    ish Heart Journal 26: 4221129,1964.

(150) PINCHERLE, G., WRIGHT, H. B. Screening in the early diagnosis and
    prevention of cardiovascular disease. Journal of the College of Gen-
    eral Practitioners 13: 280-289, 1967.

(15I) POZNER, H., BILLIMORIA, J. D. Effect of smoking on blood-clotting and
    lipid and lipoprotein levels. Lancet 1(7&O) : 1318-1321, June 20,
     1970.

(152) PURI, P. S.. ALAMY, D., BING, R. J. Effect of nicotine on contractility
    of the intact heart. Journal of Clinical Pharmacology 8(5) : 295-301,
    September-October 1968.

(1.53) R,UDAN, A. N., SIKGH. R. P., SRIVASTAYA, V. K. Thromboangiitis obli-
    terans. A clinical study of 125 cases. International Surgery; Bulletin
    4'7 (2) : 122-125, February 1967.

(154) RECAN, T. J., HELLEHS, H. I(., BIP;C, R. J. Effect of cigarette smoking
    on coronary circulation and cardiac work in patients with arterio-
    sclerotic coronary disease. Annals of the Xev.7 York Academy of Sci-
    ences 90(l) : 186-189, September 27, 1960.
(155) REID, D. D., HOLLAND, W. IV., ROSE, G. A. An Anglo-American cardio-
    vascular comparison. Lancet 2( 7531) : 1375-13'78, December 30, 1967.
(156) Ronturo, T., TALESSIK, J. Influence of nicotine on the coronary circula-
    tion of the isolated heart of the cat. Journal of Pharmacy and Phar-
    macology 19 (5) : 322-328, 1967.

(157) ROSE, G. A. The diagnosis of ischaemic heart pain and intermittent
    claudication in field surveys. Bulletin of the World Health Organi=-
    tion Z'(6) : 645458, 1962.

(158) ROSE, G. A. Chest pain questionnaire. Milbank Memorial Fund Quar-
    terly 43(2, part 2) : 3239. April 1965.

(159) ROSENMAN. R. H., FRIEDMAx,M.,STRAUS, R., wUR%f, ~KOSITCHEK, R.,
    HAHN. XV., WERPHESSEN, N. T. A predictive study of coronary heart
    disease. The Western Collaborative Group Study. Journal of the
   American Xedical Association 189 (1) : 15-22, July 6, 1964.
(IGO) Ross, G., BLESA, hf. I. The effect of nicotine on the coronary circu1ation
    of dogs. American Heart Journal `79(l) : 96102, January 1970.
(161) ROTH, G. >I., SCHICK. R. 31. The effects of smoking on the peripheral
    circulation. Diseases of the Chest 37(Z) I 203-210, February 1960.

81


(162) ROTTENSTEIN. H., PEIRCE, G.. Russ, E.. FELDER, D., ~IONTCOMERY, H.
    Influence of nicotine on the blood tlow of resting skeletal muscle and
    of the digits in normal subjects. Annals of the New York Academy
    of Sciences 90(l) : 105113, September 27, 1960.
(169) RUSSEK, H. I., %HMAS, B. 1,. Relative significance of heredity, diet and
    occupational stress in coronary heart disease of young adults. Based
    on an analysis of 100 patients between the ages of 25 and 40 years
    and a similar group of 100 normal control subjects. American Journal
    of the Medical Sciences 235(3) : 266277, March 1958.
(164) RUSSEK, H. I.. ZOHMAN, B. L., DORSET, V. J. Effects of tobacco and
    whiskey on the cardiovascular system. Journal of the American Me&
    ical Association 157( 7) : 563-568, February 12, 1955.
(16.5) SACKETT, D. L., GIBSON, R. W., BROSS, I. D. J., PICKEN. J. W. Relation
    between aortic atherosclerosis and the use of cigarette and alcohol.
    An autopsy study. New England Journal of Medicine 279(26) : 1413-
    1420, December 26, 1968.

(166) SAPHIR, R., RAPAPORT, E. Cardiovascular responses of the cat to mesen-
    teric intra-arterial administration of nicotine, cyanide and venous
    blood. Circulation Research 25(6) : 713-724, December 1969.
(167) SCI~IM%ILER, W., NEFF, C., SCHI~IERT, G. Risikofaktoren und Herzin-
    farkt. Eine retrospektive studie. (Risk factors and myocardial in-
    farct. A retrosliective study.) Munchener Medizinische Wochenschrift
    llO(27) : 1585-1594, July 5. 1968.

(168) SCHWARTZ, D., LELLOUCH, J., ANCUERA, G., RICHARD, J. L., BEAUMONT,
    J. 1,. Etiologie comparee de l'arteriopathie obliterante des membres
    inferieurs et de I'arteriopathie coronarienne. (Comparative etiology
    of lower limb obliterative arteriopathy and of coronary arteriopathy.)
    Archives des hlaladies du Coeur 58: Supplement No. 3, 2&32, 1965.
(169) SCHWARTZ, D.. LELLOUCH, J., ANGUFXA, G., BEAUMONT, J. L., LENECRE,
    J. Tobacco and other factors in the etiology of ischemic heart disease
    in man: Results of a retrospective survey. Journal of Chronic Dis-
    eases 19 (1) : 35-55, January 1966.

(170) SELTZER, C. C. The effect of cigarette smoking on coronary heart dis-
     ease7 Where do we stand now? Archives of Environmental Health
    20(3) : 418423, March 1970.

(171) SEN GIJETA, A. N., GHOSH, B. P. Observations on some cardiovascular
    and biochemical effects of tobacco smoking in health and in ischaemic
     cardiacs. Bulletin of the Institute of Post-Graduate Medical Educa-
    tion and Research 9(Z) : 45-57, April 1967.
(172) SFXAPIRO, S., WEINBLATT, E., FRANK, C. W., SAGEX, R. V. Incidenc~?~
    Coronary Heart Disease in a Population Insured for Medical Care
    (HIP). Myocardial infarction, angina pectoris. and possible myocar-
    dial infarction. American Journal of Public Health and the Nation's
    Health 59(6) : Supplement to June 1969. 101 pp.
(173) SHEPHERD, J. T. Lffect of cigarette-smoking on blood flow through the
    hand. British hledical Journal 2: 1007-1010, October 27, 1951.
(174) SOCANI, R. K.. JOSHI, K. C. Effect of cigarette and biri smoking and
   tobacco chewing on blood coagulation and fibrinolytic activity. Indian
    Heart Journal 17: 238-242, July 1965.

(175) SPAIN, D. hl., BRADESS, V. A. Sudden death from coronary heart dis-
    ease. Survival time, frequency of thrombi, and cigarette smoking.
    Chest 58(Z) : 107-110. August 1970.

82


(176) SPAIN, D. M., SATHAN, D. J. Smoking habits and coronary atheroscIe-
    rotic heart disease. Journal of the American Medical Association 177
    (10) : 683-688. September 9. 1961.

(177) sT,OfLER, J.. BEMSOS, D. x, LETISsOs;. Jr.. LISDBEXC, H. A., .?IoJ~N-
    mm, L., MILLER, W. A., HALL, Y., XSDELMAN. S. L. Coronary artery
    disease. Status of preventive efforts. Archives of Environmental
    Health 13 (3) : 322-335, September 1966.
(278) STEFASOMCH, V., GORE, I., KAJIYAMA, G.. IWANAGA, Y. The effect of
    nicotine on dietary atherogenesis in rabbits. Experimental and Molec-
    ular Pathology 11(l) : 71-81, August 1969.
(179) STEJFA, M., JR. Predictive significance of risk factors in exertional an-
    gina pectoris. Cardiologia 51(6) : 336-339, 1967.
(ISO) STROBEL, .?I., GSELL. 0. Mortalitat in Beziehung zum Tabakrauchen:
    9 Jahre Beobachtungen bei .I\rzten in der Schaeiz. (Mortality in rela-
    tion to tobacco smoking. Sine years of observation in Swiss doctors.)
    Helvetica JIedica Act3 32(6) : 347-592. December 1965.
(181) STROMBLAD, B. C. R. Effect of intra-arterially administered nicotine on
    the blood flow in the hand. British Xedicai Journal 1: 484-485,
    February 21, 1959.
(182) STRONG, J. P., Rrclr~~os. hf. I,., NCGILL, H. C., JR., EGCEN, D. A.,
    ?IIC!hIURMY, 31. T. On the association of cigarette smoking with coro-
    nary and aortic atherosclerosis. Journal of Atherosclerosis Research
    10(Z) : 303-317, Sovember-December 1969.
(183) TAYLOR, II. L., I~L,NX-Z~RN, H., Kcrs, A., PARLIS, R. `iv., VASQUEZ, C.,
    PUCHXER, T. Five-year follow-up of employees of selected U.S. rail-
    road companies. IN: Keys, A. (Editor). Coronary Heart Disease in
    Seven Countries. American Heart Association ;LIonograph No. 29,
    1970. pp. 20-39.

(IUS) THIENES, C. H. Chronic nicotine poisoning. Annals of the New York
    Academy of Sciences 90 (1) : 239-248. September 27, 1960.
(185) THOMAS, C. B. Familial and epidemiologic aspects of coronary disease
    and hypertension. Journal of Chronic Diseases 7(3) : 198-208, March
     1958.

(186) THOMAS. C. B., MURPHY, E. A. Circulatory responses to smoking in
   healthy young men. Annals of the Xew York Academy of Sciences
    90(l) : 266-276, September 27, 1960.
(187) TIBBLIN, G. High blcad pressure in men aged 50. A population study of
   men born in 1913. Acta Medica Scandinavica (Supplementum 470) :
    l-84, 1967.

(188) TJBBLIN, G. Kommentar till en svensk tvillingundersb;kning. (Comment
   on research on twins in Sweden.) Lakartidningen 65 (47) : 46544655,
    November 20, 1968.

(189) Tax& J., RINZLER, S. H., KXKP, 1). Cardiac effects of nicotine in the
    rabbit with experimental coronary atherosclerosis. Annals of the New
   York Academy of Sciences 90(l) : 290-301, September 27, 1960.
(190) TRUW, J., CORSFIELI), J., KANSEL. W. A multivariate analysis of the
   risk of coronary heart disease in Framingham. Journal of Chronic
    Diseases 20: 511-521, 1967.

(191) U.S. PUBLIC HEM.TH SERVICE. The Health Consequences of Smoking. A
   Public Health Service Review: 1967. lrashington, r.S. Department of
   Health, Education, and 1Velfare. Public Health Service Publication
    No. 1696, 1967. 199 pp.

83


[lgz) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking.
   1968 Supplement to the 1967 Public Health Service Review. Washing-
    ton, U.S. Department of Health, Education, and Welfare, Public
    Health Service Publication No. 1696. 1968. 117 pp.
(193) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking.
    1969 Supplement to the 1967 Public Health Service Review. Washing-
    ton, U.S. Department of Health, Education, and Welfare, Public
    Health Service Publication NO. 1696-2, 1969. 98 pp.
(194) `U.S. PUBLIC HEALTH SERVICE. NATIONAL AIR POLLUTION CON-
    TROL ADMINISTR.4TION. Air Quality Criteria for Carbon alon-
    oxide. Washington, U.S. Department of Health, Education and Wel-
    fare, National Air Pollution Control Administration Publication NO.
    AP-62, March 1970. 158 pp.

(195) U.S. PUSL~C HE,UTH SERVICE. NATIONAL CENTER FOR HEALTH
    ST-XTISTICS. Vital and Health Statistics. Data from the National
    Health Survey. Coronary Heart Disease in Adults-United States
   1960-1962. Washington, U.S. Department of Health, Education and
    Welfare, National Center for Health Statistics Series 11, NO. 10,
    September 1965. 46 pp.

(196) U.S. PUBLJC HEALTH SERVICE. NATIONAL CENTER FOR HEALTH
    STXTISTICS. Vital Statistics of the UnIted States-1967. Vol. II.-
    Mortality, Part A. Washington, U.S. Department of Health, Educa-
    tion and \Velfnre, Public Health Service Publication, 1969.
(197) U.S. PUBLIC HEALT~I SERVICE. NATIONAL CENTER FOR HEALTH
    STATISTICS. Vital Statistics Rates in the United States 1940-1960.
    Washington, U.S. Department of Health, Education and Welfare,
    Public Health Service Publication No. 1677, 1968. 881 pp.
(198) U.S. PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Ad-
    visory Committee to the Surgeon General of the Public Health Serv-
   ice. Washington, U.S. Department of Health, Education, and Welfare,
    Public Health Service Publication No. 1103, 1964. 387 pp.
(199) VAN RUCHEM, F. S. P. Serum lipids, nutrition and atherosclerotic cotn-
   plications in man. Acta Medica Scandinavica 181(4) : 403-416, April
     1967.

(200) VJEL, B., DONOSO, S., SALCEDO, D: Coronary atherosclerosis in per'sons
   dying violently. Archives of Internal Medicine 122(2) : 97-103, Au-
     gust 1968.

(201) VJLJcER, U., HEYDEN-STUCKY, S. Das Infarktprofil. Unterschiede zwi-
   schen infarktpatienten und Kontrollpersonen in der Ostschweiz. (The
   infarct profile. Differences between infarct patients and controls in
    East Switzerland.)  Schweizerische Medizinische Wochenschrift
    96(23) : 748-758, June 11, 1966.

(202) VON AHN, B. Tobacco smoking, the electrocardiogranland angina pec-
   toris. Annals of the New York Academy of Sciences 90(l) : 190-198,
    September 27, 1960.

(ZOJ) WA=% D. T. The effect of nicotine and smoking on the secretion of epi-
   nephrine. Annals of the New York Academy of Sciences 90(l) : 74-
    80, September 27, 1960.

te04) WEBSTER, W. S., CJ-ARKSON, T. El., LOFLAND, H. B. Carbon monoxide-
   agflava~~ atherosclerosis in the squirrel monkey. Experimental and
   Molecular Pathology 13 (1) : 3650, 1370.
(205) WEE, J- hf., DUNN, J. E., JR Smoking and mortality: A prospective
   study. Cancer 25(l) : 105-112, January 1970.

84


(206) WENZEL, D. G. BECKLOFF. G. L. The etfect of nicotine on experimental
    hypercholesterolemia in the rabbit. Journal of the American Phar-
    maceutical Association; Scientific Edition 47(5) : 338-343, hIay 1958.
(1707) \VENZEL. D. G., TURSER, J. .I., KISSIL, D. Effect of nicotine on choles-
    terol-induced atherosclerosis in the rabbit. Circulation Research 7:
    25fS-261. March 1959.

(208) WEST, J. W., GUZMAN, S. V., BELLET, S. Cardiac effects of intracoro-
    nary arterial injections of nicotine. Circulation Research 6: 389-395,
     May 1958.

(209) WESTFALL, T. C., CIPOLLOSI, P. B., EDMUN~O~ICZ, A. C. Influence of
   propranolol on hemodynamic changes and plasma catecholamine levels
    following cigarette smoking and nicotine. Proceedings of the Society
    for Experimental Biology and Medicine 123: 174-179, 1966.
(210) WESTFALL. T. C., WATTS. D. T. Effect of cigarette smoke on epinephrine
    secretion in the dog. Proceedings of the Society for Experimental Bi-
    ology and Medicine 112(4) : 843-847, April 1963.
(211) IVVESTFALL, T. C.. WATTS, D. T. Catecholamine excretion in smokers and
    nonsmokers. Journal of Applied Physiology 19(l): 40-42, January
      1964.

(212) WHEREAT. A. F. Is atherosclerosis a disorder of intramitochondrial
    respiration? Annals of Internal Medicine 73(l) : 125-127, July 1970.
(31~) WIDMER, L. I(., HAKTMANN, G., DUCHOS~~. F., PLECHL, S.-C. Risk fac-
    tors in arterial occlusion of the limbs. German hledical Monthly 14
    (10) : 476-479, October 1969.

(214) WILENS, S. L.. PLAIR, C. bl. Cigarette smoking and arteriosclerosis.
    Science 138: 975-977, November 30, 1962.
(215) WYNDER, E. I,., HOFFhlAPiN, D. Tobacco and Tobacco Smoke. Studies in
    Experimental Carcinogenesis. New York, Academic Press, 1967.
    730 pp.

85


CARDIOVASCULAR

APPENDIX TABLES

87


Mlllr and   414 white male      Undcflned.                 10-19   SO-59
Purlpr,                                                 GO-69 70 or over 10-49   SO-59   oo-co 70 or *"cl
        coronary deaths.                           (5(i)   (135)   (153)
19Kl.                                                        (130)   (216)   (188)   (114)   (MX)
        Controlr: 606               NS  ., ., . ,I,14    G.GG   lb.30   33.84    19.91   24.41
U.S.A.                                                                       35.09   64.12
        white males.               All cixPrettc8  . ..11. . ..83.93   82.23   49.02   18.44    10.83   69.94   43.86   16.41
(l3ll.                          Pipes, cigars  ,. _. 8.83   11.11   32.68   4l.SO    9.26   16.47   21.05   29.41

Bucchley   Malrs rcvoriin~     Question-    NS  . . . . . . . . . . . . . .?0.4 (23)
et r.1..     CIID to California                                              NS  . . . . . . . . . . .42.1(61)
                      naire snd   520  . . . . . . . Cl.1 (69)
1058.                                                         S?O ., ,. I.. .46.3(S)
        IIrnlth Survey      interview.   >20  . ,, .* *. *.. ,18.6 (21)
U.S.A.                                                           >20  . . . . .11.6(10
        with mntched
(33).     contm3ls from
        slmr I"rvCY
         (included there
        surviving Arot
         myocardi~l
         infarction).


\D
0

                             rctrospectiuc studies (cont.)
TAULE AG.-Coronaq hnrt discusc morbidity and worlulity-
                (Actual number OC casca ahown in pnrcnthesn)'
          [ SM = Smokers       NS = Nonsmokers       EX = Ex-smokers1

Author.
year.
COUntrY,
rcrrrence

Number nnd
type of
Donulntiu"

Dstn
collcctian

Cnscs (percent)

Controls (percent)         Comments

Rusrsk and 97 mule and 3       Interviews           Tobacco ~<anyc>jU cigurctkalday                             Psticnts
Zohmrn.   lcmalc coronary     bs       70 percent.                             35 percent.                included 83
199.     pntientl. Controls:    authors.                                                           with chwical
U.S.A.    100 healthy control3                                                                  mkucnrdiut
(165).    of similar "g-2.                                                                     iliiairliu"
        sex. occupation.                                                                    nnd II WlLh
        and ethnic origin.                                                                   sngtna pcctorin.

SDai" and  269 males identified   3,000 mr1es   NS .,....., .30.0 (81)                   29.0 (772)
Nnthe",   8s hnving CHID by    in New    <lo/day ,,.. 29.0 (7.8)                   33.0 (870)
1961,     physical cxunlinntio"  York City   >40/day ,. .13.0 (33)                   9.0 (234) (D<o.ob)
U.S.A.    nnd history. Controla: Inter.     EX ,..,....,, . ..14.0 (301                   14.0 (361)
1176).    2,63?/3,000 male3     viewed and  Cigar. P~DC .ll.O (38)                   16.0 (400)
        iilcnrifirrl LLI       cxnmined       Tlltnl  ,100,0(2601                  100.0(2.637)
        "<lt hsvinv CHD     by medical
                      UW"P.

NS ..,,.,,.,.,.. rsa (is)
Shl  ,. ,., ,. .00.75l3CB)
EX ..,I ,.. ,. 4.15 (10)
Total  ..,....,,, 100.00~400)

Schwartz   612 male pntient3    Interview,    Average amount
et RI.,     with angina or     laboratory,    per day 89
1966.     myocardiel        and       cigarettes  .18.6
France    infarction.        clinlcel FX-  All SM  , . . .86.0
(169).    612 cue-matched     amindona.  Inhalers .59.0
         contrals.

15.5 (p<0.0001)
X6.0

Data snply O"IY lo
those under 55
ycurs or auc.

45.0(D<O.O0001)


TABLE A&-Coronary hart discnsc morbidity awl mortnlify- rcfrospecfiuc studies (cont.)

      (Actud number of canes shown In p8rc"thnc.a)'
ISM = Smoken       NS = Nonamokcrs       EX = Ex-smokers]

Number nnd
type or
DOpUlUtiWl

lhta
collection                Caacs (Percent)                 Controla (percent)         Comnrrnta

DBrkcn,   205 mah up to 44    Dcsthcer-    NS ,. . ,. 1.0 (2)                   18.4 (76)              Ex.smokrrr 11stcd
1967.     years of nge with    tlfmte re-   Cigorefti L'"ifr                                               undrl. nunsmukcr~.
Germany   mvocnrdial infsrc-    view. In-    1-6 ,,,...,.,.... 1.6 (3)                   10.4 (43)                Smokiua it!luln~nlii,"
(59).     tin" or sudden      tcrview of   IO-16  ,. . . . .32.2 (621                   46.5(192)                nvnilnblc o"ly on
        death (139 deceased,   patient    20-30  . . . . . . . . . ...43.6 (84)                   22.5 (83)                1?3/205. Thrsc
        6G living). Co"trols   or kin.     >36  . . . . . . . . . . ...21.8 (42)                    2.2 (9)               ciK(olrPLtc CnLcKOrir8
        -Hnmburp ngr-                       100.0~193)                 ~ 100.0(413)               i"rllldP n~ihr,Ll 01 cisnr
        matchcvl citizens '               (only 28 were mixed                     (G2 wcrc mixed nr           sm<,krrn ri~,ils.ulntrd
        selected randomly.               or cigar smokers)                      cigar smokers1            as LLI nutnhcr cbt CLKLL.
                                                                           I.P~~LY No vntir,ntr
                                                                           or controls brnilkcd
                                                                           "ii'rn cxcIu5i\rly.

    Dbrken,    33 females up to     Death cer-    Cioaretlcs prr dau
     1967.     44 yrnrsofngc      tificotcs,    0  . . . . . . . . . . ,.... 6.1  (2)                   63.?(841 (P<O.OOl)
     CettlWly   with myocsrdial     in tcr-      1-S                           1X3(23)
     (55).     infnrction or sudden   view.      6-15 ~~ .,......, 43.5 (ICI                   16.5(22)
             dcnth. Controls-133          ?O-30 . ..I....... 10.4 (13)                    3.0 14)
             fcmnlcn 27-44 YCR~R           >36  . . . . ..~.. c.1  (2)                   
             of time frcam clinic
           without CVD or lung
Lc7            CLi"CFt.
P                                                                           _--


TABLE A&-Coronary heasl disease morbidily and mortalily--7etro~ective studies (cont.)
               (Aeturl number of cum shown In ~nrenthesn)~
         [Shl = Smokers       NS = Nonsmokers       EX = Ex.smokeral

Cl3CO (pcrccnt)

Cummcntl

refcrcncc      population

Hybms    79 maln Iurvivino.    Interviews NS  . *... . . . . . . . 10.1  (S)                   21.0 (33)
et al,     myocsrdial infnrc-    by trained   l-9 eiearettes
1967,     lion. 167 age.       DW3Otltl.d.    perday 1.0  (6)                   10.5 (13)
Jkpnn    matched controls            lo-15 .._..., ,,,., 26.4 (18)                   33.9 (42)
(87).     hospilalired for nan-           16-20 ,..,..., ,. .35.2 (25)                   26.8 (37.)
        CVD but include             21-34  . . . 22.6 (1G)                   17.7 (22)
        hypcrtenaive diaeare.          >36  . 9.Y  (7)                   12.1 (15)
                              AllSbl  . . . . . . . . . . 100.0 (71)                  100.0(1!40
                                                -
Mulcahy    100 fet"ak DSthltS   Hospital     sm . . . . . . . I .I., 63.0 (63)                   45.6(261)               Smoking on controlr
et al.,     less than GO yesrs    interviews. NS  .,.....,,..,,, 33.0 (33)                   45.3(2511)                obtsinrd from
1967,     of age admitted t0            EX . . . . . . . . . . . . . 4.0  (4)                    0.1 (52)                stulisticn of
Ireland    hospital with CHD.               Total  . . . ..100.0(100)                  100.0(572)                smoking in
(IJIb.                                                                           Irish I~rpulrl~c.
                                                                           Sudclrn dvn\h
                                                                           ""1 IrlCIIIIICII.

Stejfa,    70 maleand        Direct               Plcvolcncc Of risk factora                              Authurs then fullowcd
19G7.     female patient3      interview.   Angina patient.,                         Control DIOllD             lhr 70 pnlirnts for
Poland    with recent onrct                60.0                                                  3 yrnr, and rrutcd
(179,.    exertional angina                                               48,1(p>O.l)              Lhnl amgaktng sinnifi.
        Deftotis. 54 control3                                                                  canlly inilurnr*,<l
        of same age.                                                                      the incidrncc ~1
                                                                           rormary ocrlurion.

Schimmler 603 males with      Hospital     NS ..,.....,,.,. 9.0 (40                   Z&0(187) (p<O.OOl)
et al..     healed myocsrdisl    interviewa.  EX  . .12.0 (59)
1968.                                                          2o.otl42) (p<o.oo1l
        infnrctiona. 714 mr~lc          Cisar, pipe ,. .12.0 (62)                   11.0 (711
Ccrmany   controll of same age           <IO cignrettel ,. .25,0(129)                   14 O(lOl) (n<O.OOl)
(IG7).    without dctcctable            >20  ..I. .42 0(2(13)                   29.or2oiI (P<O.OOl)
        hc.rt discaac.                  Total   100.0(503)                  100.0(714)
                         ,


Hood et al., 230 mnlel ru~viving   InlCrViCW                  (230)                      (8651
IOGP,     enrIy first myocsrdinl  snd exam-   Never smoked  .I.75                      24.2
SWdWl    infnrclion. Controls:   ination.    EX before
(8s).     855 raniiomly aelccted           Infarction ._ .I.75                      19.7
        mnlex 50 year3 of             EX nftcr
        B&-C.                     infarction  .2I1.1                       
                             <16 cignrottea .28.3                       27.4
                             >I6 cigarettes .22.6                       20.0
                              All ,, ,,. ., .EO.O                       47.4
                              Pipe   16.5                       8.8

JOUVC     1.229 CIID patients:   Interview.               43.0                      13.0~P<0.0001)
et al.,     802 malcs.427
1961.     fcmsics. Controls:
FranCe    743 individuals of
(91).     both BCXCJ: age.
        sex. and socinl
        class matcbedd.

Icrst1.     275 mrde railway     Interview    NS  . . . . . . . . . I... .ZO.O 1.55)                   29.8 (82)
1969.     FmploycPr UP to 65    and ex-    Z-20 cigarettes or
Germany   years of e.gc sur-     amina-      UD to 6 cigars.. .32.O (88)                   63.3 (82)
(98).     viving myocnrdial    tion.      >20 CigaretleS or
        infarction. 215 con-           >S cigars.  . . . . . ..48.0(132)                    6.9 119)
        trol employees with
        minor circulstory
        diaturbanccs.

    ' Unless otherwise specified. disparities pween the total number of case9
    and the sum of the individual smoking categories are due to the exclusion of
u    tither occuionrl, miacellaneoua. mixed, or ex-smokera.
w

-


TABLE A?`.-Differences in sertcm lipids betlceen sl,iokers and nonsmokers
         (Aciusl number of ind\vlduslo shown in parrnthm)'
             [Sat = Smukcn    NS = Nonsmokers]

Author. year.       Number and
countrv.          type of

Results

Comments

                      Diflermcc bctu,ern S,!l and NS          tSf relrrs to S~edbere
              ngca 90-19       Ages JO-S9        Apt-a4049     flotation unit8 of
Lipid:           f NS 55. SM 37)    (NS 66. SM 67)     (NS 17. Shl 44)   centrlfugcd lil,iaproteins.
tsr  o-12 . . . . ,. +59.9 lJ<O.OOI     +19.9 p<o.o5     + 3.9 P<O.OS
sr 12-20 .., .t.. + 9.4 p<o.o01     + 6.4 p<o.os     - 3.5 p<o.o5
Sl 20-100  +20.0 D<O.O25     f 9.1 D<o.o6     + 8.5 P<O.O5
Sf 100-400  ., ,. +1s.s P<O.O26     +12.1 p<o.os     - 4.5 D<o.os
Cholesterol t21.2 P<O.OS      f 9.0 p<a.o5     - 4.8 P<O.O5


TABLE A7.--l~i~crc~cccs in scrttn~ li?Jids between s7tlokeTs nntl 71ons7nokcrs (cont.)
           (Actual numbrr of Individuals shown in pnrtnthnrr)'
                I SM = Smuhe1.r    NS = Nonamokerrl

Ul~im~trnn~i      7C mlinrizyxutic       I. Mmozyrzutes discordnnt fur smoking: Smokers showed slightly lower levels  The auLhur> concludu from the
antl I.unrlmnn,    tbvin ~:LIIS nnd        of cholesterol. triRlyccridcs, and pho~pholiyid~ than nonsmokers.        di!Trring 512 and DZ rc~ult~
I !I 1: G ,         k7 <IIzygulic       II. Dizygatcs discordant fur Ymoking:  Smokers showed aignificsntly higher   that ronstituti~mal fnclore
S~t~llrn        twin nuir$ obtained      levels of phoupholipids. No diflcrencPs for cholnterol and triglycerldee.    are probnbly mum imporlnnt
(2'7).         from Swedish Twin                                                     than amuking in dctrnnlning
            Registry.                                                         lipid lcvcia.


200 clinicdly
hcnlthy males
20-50 years of
UKB.

             Strum cholcatcrol   Phorpholipidr     Total lipid8    Serum cholNLerol alao noted
               mg. percent      mp. pcmcnt      mg. pcrccnt     to increwe with increnrinv
NS(100)  . . .   110.2   P<O.Ol   26R.l          1.234.8        intensity and duration uf
Shl 100)  ,.,..*.....   224.0 I        257.6   p>o.o5   1.362.1 I  p<o.o1   amuking.
         j
                       11, lo-lapoprotc~iu
            Totnl fully acidr   ;Jcrccrlt 01 tot01
               mL7. vcrcrut      I~~~oirrotciu~

NS(100)  . . . . . . . . . . .  707.i
Shl 100)  . . . .   BG0.3 \  D<o.ol    43.1
                           4D.O   p10.01


           TABLE A7.-Diffcrcnccs in scmn~ lipids 6elwccn smokers and nonsmokers (cont.)
                            (Actual number of individuals shown in parcnthmcs)'
                                  [SM = Snrokers    NS = NonJmok<,rsl
                                               -
Author, year.
   country.    Nut;;:`o;nd                         Rnulls                               Commenls
  rcfcrcnce        papulatiun

llirgina        5,03U mnk und                                   Mnlcr          Fcmafer
and Kjrlrberp.    lcmolc reridcntd     NS I.... ,.,e. . . ,, . ,, ..t.,. .I...  209.0  (360)       210.1~1.439)
lVJ7.         uf Trcumsoh.      Clgnrette  . ,.a . I. * 3 I. I. . I,.  212.6(1,426)       212.4 (110)
U.S.A.         blichiann. 16-79
(al).         Yrnrs 01 BKC,

Pincherly
and Wright,
,967.
Ennisnd
(150).

2.000 ml.?"
participating in
executive benlth
examinations
28-10 years of
iwe.

                                Percentage with 8-m  The authors noted that amokcrs
                      Serum cholcslrrol   chofeaterol>270     ahownl significantly biphcr
                        tng. petcni1      mg.pcrcmlt       (p<O.OOl) .erum ChulLnlcrol
NS(G71)  . . . . .  ?36.2           19.0         levels than nonsmokers.
Ex-smoker(388)  _. . . . . _. ., ._ _, .,  24C.0           28.0
1-19 cigaretteslday(424)  . . .  239.2           24.0
>20 cigarettes/duy(Sll)    249.4           30.0

Van Buchem.
1967,
Netherlands
(19Pl.

--
Quvlr ct al..
19BM. .
U.S.A.
i la ) .

918 randomly chowen                            Strum clLolcafcrol              The nuthon found no
maks 40-SY yearn                O-209 mg. portent PIO-249 mg. percent >250 mg. percent   correlution bctwwn smokbnu
of age for entry     NS .,t...,.....,..... 12.4 (32)       14.0 (40       14.2 (41)      and serum chokntrrol Icvela.
Into prospective     Ciparettc SM    `lt.6(184)       67.8(213)       68.2(197)
study.          Other  . . . .  16.0 (41)       18.2 (61)       17.6 (61)

1.10% male lnctory                         Snum chorcslcrd   Strum Bclo-liyoprotcin Dcta-lipoprotrins were found
rmaloyem 20.64                           mg, pcrccllt         mp. pcrccnt      to increase with age. but
Y*nrl Of age.       NS . . . . . . . . . . . . . . . . .  243(519)                         smokers had hivhcr lcvcl~
              SM                   251(576)  p<o.oos
                 . ,                               than nonsmoker at nil 86~~.

    Ceganova       49 mf1k8 living                           Sunlm cliolcslcrol   Strum Beta-lipoprotein
     ct al..         in youth hostel,                           mg. percc,,l        mo, pcrccnt
     1968.         21.6 BYerage aye.     NS(34)  . . . . . . . . .I. .
     Czechoslovakia                           188.20)        359.80 (
                            SM (15) . . . . . . . . . . . . . . . . ., 214.2oj "<".025    498.4Oj P<O.OOl
      (36).                                                   Drla.ldyhn lipoprotein ratio
                              NS(34)  .l.....I...........................,..,I..II.I.  1.16
                              SM(16)                                   D<".026
                                    . . . . . . . . . ,... .,.... . ...,..., ,,..  1.66
a
-4


TABLE A'l.-Differcnccs in serum lip'ds between smokers and nonsmokers (cont.)
           (Actunl number al Individual3 shown In pnrcnlhwcs)l
                IShl = Smukcrv    NS = Nonsmokcrsl


T~BLC A&--Blood pressure differences between smoker8 and nonsmokers
    (Actual number of indlviduab ahown in parenthneaa)'
         [Shf c Smokers    NS = Nonsmokera]

Karvonen et d.,  625 malea in                                     Svrfolir blood preuurc        No dutn on P~PC nnd
19.50. Finland   various regions                            Weal Fiulnrtd    Earl Finland     Hclrirlki   cigar amokcra. No
(97).        of Finland        NS  ,,. . . .t ..I .  139.2(64)      142.6 (39)      132.8 (62)  statistical rigniticnncc
           2&59 ye*rs of      Shf ..,,.,.....,.,.,................ 133.2(91)      135.4 (103)     129.8(166)  noted.
           age.                                        Diastolic blood prcarure
                         NS  , . . . . . . . . . .  84.7         6G.B         89.6
                         Shf  . ,I. . . . ,. I,. ..a . ., . .  81.9         84.1         86.8

Clark et al..    1.859 male civil                                 hlcan ayatolic         Afean diurtolic Nonsmoker and smoker
1967. IJ S.A.    wrvarits.                                    blood-preanrrc        bloo&~rcsa~~re  groups wercof similar


TABLE AL-Blood pressure difemnces between smokers and nommohre (cont.)
           (Actual number of individusla shown In aarentheeea)1
                [SM = Smokers    NS = Nonsmokers1

HIpgins and    6.030 male and                   Age c.dituted                Age adjusted
KjcLburo.     female r&dent@             mean wrtdic blood PICMUW        mran diwlolic blood r)rcdru~e
1967, U.S.A.   b! Tecumseh, MLrhlpan.           M&8      Femokr        Maka     Ft?V&#
(JJI.        lb-79 P?aII al .&!e.   NS  . . . . . . . .137.8 (960)   84.6(14391     136.6 (WI)
                        Clparetk , ..196.4(1426)   81.4 (010)      131.6(1426)

Reid et ti..     676 mak Brlthh

1967. Enoland   and O?G male
(JS6),       American POSW
          worken (D-69
          YCnrl of age.

        (djualcd/or diflnencc in wcigld)
         UK Ncan watolic blood yr-rd

                     U.S.A.
NS . . . . .128.2 (46)        124.8 (80)
I-14~ramc 130.2 (27)        133.0 (60)
16-24 trama 128.6(232)        127.7(169)
>26 PT~UIB 127.9 (`JO)        128.1(218)
All amounta 129.1(619)        128.6 (447 I

The author did notz

MUX diadtoldic b&d yrcrrvrc    Shf-NS blood "rcaeurr dlf-
    UK       Lf.5.A.    lcrmcm prior to
    70.9        81.0     rnntrolling fur wciuht.
    19.4        62.1     but nut sltcr such cuntrol.
    78.6        71.3
    71.6        17.1
    78.7        77.8
             -
JS'O-J70/            Numbers in parcnthcwa
Ioo-Iro(zro~ >J7sl>IJs(rs,  reurewnt tatnl in blood
   25.5        34.7      yrcllure group.
   26.6        18.7      The nulhor noted
   15.6        17.3     a stcpwiue dwrcue with
   10.0         4.0      ICI,@1 01 blood pwsJ"re

Tibblin. 1967.   896 m&3 In
SW&tl      GGtebn?, SW&J&
(Jar).       born in 1913.

           L?locd prcrr,rre    J JS-145/
          ~110/~70(a9)    7*95 (468)
NS  . . . . . . . . . . . .t. . . . . IP:O        23.0
l-14 clgaretta,  *....,..... 29.2        21.2
>I6 cigar&k-a  . . . . . . . . . . . 28.1        20.9
Pipe and cigar  , . ,, 11.2         8.6

ditiduala and the aum cl tbc individual smoking categories are due to the
excluioa of either oeeuional, mlrel+oua, mhd, or ex-smokera.


TABLE A17 .-Incidence of new coronary heart disease by smoking category and behavior type for men 59-49 years of age
                   (Numb-m in pnrentheses are number oC CHD cases in each aubnroup)

Smoking group

NW.3
smoked

Currot and
former pipe
and ciynr only

I-16

Cigarcttez

  16-25

2C rnd over        TOtAl

1.6(l)       15 8(15)        14.9(16)         9.3(461
1.3(J)        3.1 (3)         4,9 (0         3.3(18)
4.3(5)        9.3(18)        10.4(20)         6.2(63)
                                   ---
                                    --
     Analysis of variance Iable

Source

Sum of sauark-0

d.C.

`Eater nre sue-adjusted nnnual incidence per 1,000 men.
*Mean SQUH~TI for "betwccm smoking groups" and "between behavior
Iypea" are each computed eliminating the general mean and the other main

effect but ignoring interaction. thus yicldine m eatimak al each main o f-
feet unconfounded by other significant main ef?~ta.
SOUKCS: Jcnkino. C. D. et al. (90).


TABLE AlS.-Incidence of new coronary heart disease by smoking category and behavior type for men 50-59 years of age
                    (Numbera in psrcntheaes are number of CHD cylea in cacb nubgroup)

                             Former      Current and                 Cigarettes
  BehaVlOr           Never        cigarette     fOiTlCl' DiDC
    tYDC            amokcd        amoken     and cigar only        1-16         16-25        26 and over        TOlal

A . ** . . . .~. .., . . . . . .,..  `12.4(K)        18.6(B)       21.8 (8)        16,4(6)        21.5 (9)        30.0(14)     20.4 (43;
B .*....... . . . . . . . . . . ...,.,  10.0(4)        6.1(I)        6.4 (3)         4.7(l)       21.1 (I)        19.1 (51        12.0(21)
   Total  . ., . . . . , .,  11.1(g)        14.2(9)       14.9(!1)        11.6(6)       21.3116)        Z&0(19)        16.8(70)
                                                                           -

Analysis of variance table

Wltbin eclb . . . . . ., ,#I......,.. ,....,. ,.. . . . . . . . . . . ..,.    63.627          911         0.070                      
Regreuion on age . . . . . . . . ..*..*.*..* ,..... ..,.,... . . . . . . . . .     0.117           1         0.171          2.64          0.111
Dctwctn smoking groupa: . . . ,.. . . . . . . . . . ., . . . .., , ~, . . . ,     0.522           6         0.104          1.496         0.188
Between behavior typea 2 ..,...~.....,., . . . . . . . ,.,... .,..,,......     0.296           1         0.296          4.24          0.040
hkr.ction . . . . . . . . . . . . . . . . . . . . . . . . . ..I . . . . . . I ,....,,.,..,.,,     0.129           6.         0.026          0.37          0.870

IFLaLpl are age-hdjuattd annual incidence per 1.000 men.            cflect buL ignoring interaction, lhur yielding an catimate of each mnln rf-
`Yew ~puarea for "between smoking groups" and "between behavior    feet uncanloundL4 by other significant rn~~in ellectr.
trpn" are each computed eliminating the general meon and the other msin      SOURCE: Jenkins. C. D. et nl. (901.


TAULE .420.-Expcrinrents concwning the cffccts of swoking ant1 nicotine on animal cardiovascttlar function

West cl nl.. 33 norm01
1958,     ndult rn0ngrcl
U.S.A.    rlous.
(:`OS)

COIOn&I-Y
intro-
ortcrinl
nicotine:
1. 0.2-2.2
uz./ka.
II. 0.04-i
)ig./ks.

Dttli"iW
incrensc
(ey3lolic).

(Tctrnuthylammonium chloride b!ockcd CUF In-
crcnsc.)

The authors found no evidence of coronary YLBD.
mnalriction In tbeuc healthy rnimala.

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

Author,
  YCIT.      Number and       Smoking     Heart     Blcmd    Cardiac     CCTO"tIW
EO""tcJ,      type of        DKXCd"~C      rate    DXW"R    OUtPUt      blood                Commenld
rdcrence     DoDulnlio"                                         flow

Forte     27 obscrvn-       intravenous            Definite           No cbanw.    No signlflcant change I" either left ventricular
et nl.,     tiono on 8        nicotine up            initial                    work or myocardlal oxygen extraction.
1060,     dogs.          I3 21.6 "lg.            increase
U.S.A.                 given 83 6-16           then
165).                 !.w./kg./              dccroase.
                     minute.

-
Kicn and   21 adult doas      Ciasrette             Definite    Definite    Increase      ERccts of cigarette smoke were duplicated by In-

Shrrrod,
1960.
U.S.A.
IlIP).

smoke under
positive
pressure via
tracheostomy.
Nicotine 20
pg./kg. intrs-
ve"ou8Jy.
Epinrphrine 6
w./kg. intra-
ve"ausly.

increaae.   i"crea8e.   followi"g      trnvenous nicotine and eDi"eDbrl"C.
              incrcnse     During cigarette smoke Inhalation. it WBI noted
              in blood      that without blood pressure or output chanp+a,
              prC*s"rC      coronary blood Row did not Incrrnse and tbnt
              and cardiac     while adverse EKG changea were noted they COP
              0"tD"t.       related Marc claaeiv with decreued cardinc OXY-
                        gel, utilization than with actual cardiac wGrk.

TraVCll    14 norm"1        intravenous                           DCli"itC       Nicotinc.induced coronary blood flow and heart
CL RI.,     rabbits nnd       nicotine                             increase       rate increase in the atheroeclulotic nnlmals re-
IICO.     1C rabbits        0.01-0.1 mg.                          in normals.     auirrd 10 times and 2 timn. ~IIB~C~LIVCI~. thr
U.S.A.    with severe                                                 emwnta rwuircd in the norms1 animula.
flS9).    cholratwxzl-
        induced ather-
        sclerosis.


TADLD A20.--6zpcrimcnts concerning the cflccts of smoki,tg nud nicofinc on animal cardiovnecular function (cont.)

Numbrr and
type oc
raopulntion

Smoking
proccdurc

Comments

Dellet     I. 10 narmol dose   l"trevcnaus                           1.126 percent   The nuthors noted that:
et al..    11. 9 dous at       nicotine.                              increase    1, The rCBPO"Se of coron.ry blood flow to "ica-
1962,       varying in-     20 ug./kg./                        II. 82.6 percent     line resembled that of anoxtmia I" t(c Drrs-
U.S.A.       tervnls Iol-     minute for                             l"CV?WX        cnce of eoronsry i"3ufllciency.
(22).       lowing core-    15-20 mi"ute3.                     111, 83.3 DE'K'Znt    2. The grater the induced coronary imwlrment
           nary artery                                       increase       the smaller the increment in coronary blood
           ligation.                                                    Row.
       III. 7 dogs with
           varying
           grndcn of
           srtificinlly-
           induced corcw
           nary artery
          narrowing.

Leaders   16 adult         Left anterior                                 Nicotine and norcyinrphrine both ir\crcnacd corc-
and      mongrel         descending                                  nary vascular rcsiotance and myucnrdinl contrsc-
Long.     dogs.          i"tracoro"nrY                                  tile force (the formor mcanurcd by e. conalant-
196?,                  injection of                                   volume variable~prcssurc rystem). The action of
U.S.A.                 niwtinc or                                  nicotine was blocked by prrtrcatment wilh hcx-
(125).                 norepincphrine.                                 amethonium, pmtolinium. rcsrrpinc. or I(U&~C
                                                                tbidinc.

Lk?-Wll    13 rdult         Intravenous            Definite   Definite             Systemic vnscular rrsiatnnce ond pulmonnrr nrten
et al..     mongrel         nicotine,              incrcasc. incraw.             and left atria1 ~rr~surca show4 biphnaic rr
1965.     duga.          0.02 mg.lke.1                                  ?~ponoen of increase followed by drcrcsac.
U.S.A.                 minute for
(JZJ).                 IO-12 minutes.


P      TABLD A20.-&p&??~nt8 concerning t/te eflecls of smoki~tg wd nicotine ox anirrla~ cafdiovQscU~ar flt?Iction (cont.)
0
m       Author.
        yr.r.         Number and                Smukina
       cuuntry,         type of                 ptOC`%lUtC                            C"mlne"tl
       refrrencc       population

FOIL?     7 dog-a of 30 inveatleated
et al..     (Rcmoinder expcrirnced
1966,     cntbcterizntion fnilurra).
U.S.A.
(64).

h'adcau and
J&mm.
1961.
U.S.A.
(144).

26 dogs

1. Cigarette smoke inhnlntian
  to isolated left lower lobe
  and then blood perfused coronary
  srtcries.

11. Cunrctte smoke to rest of
   lunu and then blood pnascd to
   gcnrral cireullltion.
III. Nicotine perfuocd directly
   into left coronary nrtery.

Nicotine 0.01-10.0 pg. into
sinus node artery.

I. No change in cor~n&ry vw~lnr resistance.
II. S/G show~~i increase in c~r~ne.ry va~ulor tesiatance due, actordine to
  the author. to gcncral aympathetlc nervou~l ayatem stimulation.
IIt. 415 showed ~nrrcn~e in corunnry vascular rnisldnce. The authors eon-
   cldc that the cnrdiac eflcct~ of tobacco arise nlmotlt entlrcly from
   thr extracnl.rlinc actiona of smoking instend of the direct reaponae
   of the 111.nrt.

HeurL rate showed initial slowing (due probably to vnaal stimulation) fol-
lowed by r.ccelcrntiun (due probably to vagnl pnrnlyais and cntecholamine
reluse~. No systrrnic blood pressure changes nuted~

22 monurel dopa      I. (IO Intrnvcnour nicotine

cnrct.

I. Nlcotinr pruduccd B dclinitc incrcnre In the force and vt~l~~city of left

   50 irr./kg.lminutc fur 3-4          \L.~IIIC~II;II. c\jnt~actiun.
   minutes              II. Prrtrcntmcnt with proprsnolol produced (r&live to rP3u1IP Of Group 1):
II. (8) Prcpranolol pretreat-           (a) A further increase in left vrntriculsr ayatolic prrsnlrr.
   ment, then 50 hK./kg./minute       (b) A dccrensc in velocity of shortening.
   nicotine fur 3-d minutes          (c) A aignificxnt incrtnae in lrft vrntrirular cnd.diwtolic prc*rurc.
                    The authors CO~CIUIIO thnl proprnnolol probably lmpnira the no,rcpinrpbrirl~
                      like cfIccts of nicotine on the myocardium while cnhrnclng ita wriphrral
                        ve.*oprcssor enecta.


TASLD AZO.-Ezpetiments concerning Llle eflccts of smoking a,td nicotine on atiirttnl cardiovascdar function (cont.)

Author,
  YC`T.        Number end                Smoklna
cuuntry.         type of                 ptOCCdUre                            Comments
l-dcrcncc       populntlon

D1Iaza    Bcaule dona with lesions     1. Normsb (3-6 per exveriment):     I. (a) No evidence of arrhythmias; (b) A ainele or ~1 few ectopic brats
Cl al..     Induced in myocardium by       (a) 4 PK./kg. intravenous         in Z/3 normal dogs.
1969.     either: (1) IaavroierenOl       nicotine. lb1 40 ,%/kg.       II. Extrnsystoles noted in 2/3 animals during the firat dny nftcr cesantlon
U.S.A.    vrctrcatmcnt. or (2)         intravenous nicotine.            of the arrhythmia induced by the lesion alone. but not thcrenfter,
(Id).     ligation of the anterior    II. Experimentnl (3), 4 )iK./kg.          These and nicotine-induced arrhythmias wcrc of II abort clurution.
       descending ecmnar~ artery.     intruvenoua nicotine

Greensvan Cardiac muaeleisalated from   Nicotine Z-100 ~~p./cc. in          Nicotine perfusion produced:
Cl 81..     the right vcntriele of 10     Tyrode'n solution verfuunte.        (I) An increase In myocnrdlnl contractile force avusrently indrvcndrnt
1969.     adult dogs.                                       of adrcnergic innervation.
U.S.A.                                            (2) An increased automuticity of the Purkinje Aber ~ystcm ~lvpe.rently
(74).                                       due to release 01 catecholamin& from chromnmn tissue ~turn.
                                                 (3) A dccresse in conduction velocity.

The authors conclude that the latter two eirectn vrobnbly predispose to nr.
rhythmia formation.

Swhlr and
RaPSPOrt.
1969.
U.S.A.
(166).

88 mongrel cats

Nicotine 6-12 pg./kg. injcctrd
lntrnarterially to mesenterie
circulatio".

I. hlesenteric injection of nicotine WLI followed with 1-2 secunda by:
   (a) Increased left ventricular ayatalic prcasure (LVSP).
   (b) Increased systemic resistance.
   (c) Enhanced myocvrdial performance.
II. Left ventricular injection of nicotine WBB followed by:
   (a) Increased LVSP.
   (b) L1radycardia.
   (c) Enhanced myocardisl pcr!ormnnce grcnter than that wxn in
      mcrenterir-injected group.

111. Prctrcntmcnt with phcnoxybcnznmine diminished the incrcnlc in LVSP
   while pr~~pl`nnoli~l prctrrutmcnt diminiJhcd the tnhnncrmcnt of my-
   ocardial perfurmnncc while LVSP still showed D. niKnif~cnnt IIIC~PU~~.
1V. MNrntvrie sympsthctic ncrvc section led to a diminished rc*i,on~u.
The nuthurs ctmeludc thnt the cnrdiovnsculnr IC'IPO~BCB to nlcntinc m&y be
ncurogenic in nature with receptors distributed in ccrtnin abdominal
srterica.


TABLD A20.-Ezpsriments concerning the etfects of smoking and nicotine on animal cardiovascular function (cont.)

Smoking
procedure

Comments

Lrb ct al.,     12 mon~rcl dov and         Nicotine 100 u#.lkt. for     Effecelive Corunary Flow (ECF) 11 that part of the totnl COTU"*T) IloW
1910.     CBF measured with UIC of        2 mln!lLC Intravenously.       (TCF) which il "ellcctivelr ' involved In nutria1 exchonec.
U.S.A.     Rb" and digital counter.                         Nicotine injection WM followed by:
(J,6).                                           (11 96.6 gcrccnt increase in TCF.
                                                (2) 61.1 percent lncrense in ECF.

(3) 73.1 percent increase In mwcardial oxysen ccnaumption and annl~aia
   revealed that capillav flow increased almost ptovortimatcly to my-
   wardial oxygen consumption whereas the increase in TCF W~LI f&r
   In CXCCJ8.

(4) Definite increases In cardiac output, hesrt rate. left ventricular work,
   and oorlic pressure.

Ross rnd
BIna.
1970,
U.S.A.
(160).

  10 does undergoIng
inatrntulcwJs COlO"r.ry
arrerinl flow meuurement.

Nicotine lC-100 BB. lntra-
  coronary injection.

Nicotine injection was followed by:
(11 Increurcd tontractilc force.
(2) Decreawl myocardial cuntrnction time.
(3) Dccrensed time RCCCJI~~Y to reach peak tension.
(4, Dccreucd total stroke ustolic CBF.
(5) Incrcwcd total stroke dirutolic CBF.
(6 I Increased total stroke CBF.
(7) Changes similar to intraarterial rDin&rine.
(8) Changes blocked by pentolinium pretreatment.
(9) No change in heart rate or blood ~r~rure.
The authors conclude that eatecholamines released from the ventricular
mywardium mediated thrae I~~FIOIIIFI to nicotine.


     TABLE A21.- Experiments concerning the efects of smoking. and nicotixc on the cardiovascular system of humana

Author,
  Year.   Nypy;;nd      Smoking       Heart      Blood   Electrocardiogram    Stroke     Cnrdiac  %%"
eounlry,                 procedun       rate      PttBY"te  ballistocard~ugrsm    volume     OutDUt              Commenta
referrnee     DODUhth,                                                              Row

Rusaek      I. 28 healthy    1 standard and 1     I. Incresae. Incrcaee.    EKG:                               Denicotinircd cign-
et al.,        male amokera   denicotlnired                      I. 16/29 showed                         rettes evoked changes
1955.        21-60 yearn    cigsrettc.                           significnnt                           of R lesser dcgrcc
U.S.A.       of age (aver-                                  chnnaex.                            in normnle and CliD
(ISi).       ape 42).                                  II. No sis-                             subjoeU, but in the
        II. 37 male patients              II. Increeae. 1ncre.s.w.       nineant                       latter group thcr'e
           with overt                                    chansce.                           wc,s no aiguiflcnnt
           clinical CHD                                BCC :                                dilTcrcnce between
            42-10 yeara of                               I.                                these change+..
           .-ge (bvenge                               II. 18/37 showed
           64) ( 6 were                                   aiKnificnnt
           nonsmokers.                                   chnnue.

DIrgeron    14 of 30 healthy   1 cigarette       Insinnilicsnt Increase.                               Dcnnite   Coronary vrl8cIIIflr
et al..      adult mnle vol-    inhaled at        increase.                                        increase.  re3i3tBncc fill
1967.      untccr smokera    intervals of                                                        si!pificelrtly.
U.S.A.     and nonrmokers   20 aeconda.                                          Myacerdinl O3
  fJ71.      who underwent                                                                   usage unllcrwc"l no
          BUCCeSSfUl                                                                    aienlfirsnt chnnac.
          catheterization                                                                  Pyruvnte extrnction
          18-63 years                                                                     fell slightly.
          of age.                                                                        Authora conaldrr
                                                                           lack of incrcnw in
                                                                           heart rate u due to
                                                                           bascllne nl>prrhcnsive
                                                                           tschyrardia.


F
0     TABLE A21.- Expriments concerning the eflects of smoking and nicotine on the cardiovascular s@?T?t of humans (cont.)

      Author,
       Y-r.
      cou"trY.   NUt~pbc"o;"d      Smoking       Heart      Dlood   Elcctrocardiopram    Stroke     Cardiac
                          prowlure       rate      pre49urc  b@lliatocardloprrm    volume     output  cYl"Y
      reference     potNlstio"                                     nOow        Comment4

Repm
et al..
1860,
U.S.A.
(IS4).

7 mnlca with     2 standard       DCA"lte     Dcnnite                         Incrcaac.  No aipnl- Myocsrdlal 0, conaump-
bintory of       cirarettn In      Increase. increcae.                                licnnt    tlon row sliuhtl,`in
EKC.DWWl     26 minutes                                                  change.   3outof7.
myocsrdial      inhaled at                                                         The author considcra
Inf~rctlo"      minute                                                            that the EKG chsnrca
undergoing      Intervals.                                                           notrd on amokinw are
cardiac ~a-                                                              probably due ICYS to
theteriration.                                                         decreased coronor~,
                                                                           blood Row than to
                                                                           incrcawd worklond
                                                                       (oxygen "red) where
                                                                    oxygen supply dwcs
                                                                           not incrcwe.
                                                                           Noted no cvidrnce of
                                                                          myocardirl irchcmla
                                                                          during anwkinp.

Thomas and  113 clinlcallu     One rtandard      Definite     Definite               Definite      Definite         Pulse yrcsaurc ahowed
MUWhY,    healthy young    cigarette        increase. increase.               incrcaae.     increase.         a decrease.
1960,      males.         smoked at                                                        Smokers rrr~mnded
U.S.A.                 own pace.                                                    slightly but sisnl-
(166).                                                                           Acantly more
                                                                           actively lhan "on-
                                                                           smokrra.
                                                                           BCC change were
                                                                           incrcnninfly common
                                                                           with incrraaing ale.
                                                                           wright, and serum
                                                                           ehulcaterol.


TADLE AZl.--Experin~ents concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.)

Author.
YCBT,
country.
retcrencc

Number nnd
type of
Dopulnlion

Smoking       Heart
procedure       rate

Blood   Electrocardiosram    Stroke     Cardiac
lltC33"t.?  bnllirtocardioyrnm    v0lume     output  cti:o":w       timmcntd
                                   now

Von Ah",    The author      Cigarette        Increase.            EKG: Slight ST                         EKG changes more
1960.      reviews *       smoking.                         HCg"lC"t                              prominent in younr,
SWCd?"     arries of                                     denreeaion                            clinicnlly healthy
(POZ).     expcrimenta                                   nnd T-wnve                           aubjccla than /II
         performed                                   nattc"i"c.                             older. hltbitunl
         IJCLWCC"                                                                       amokcrs. Intro-
         1944-1954.                                                                      venou nicutinc end
                                                                           smuki"K ahuwr<l
                                                                           ldcnticnl cardie
                                                                           YLLICUllll rllrcts.
                                                                           Smoking clicitcd
                                                                           angina pectoria in
                                                                           a number of CllD
                                                                           patlerts.

lrvinp end   3 normal males,    (8) Shsmamoking. (a) No    No change.             (a) No change. No change.        Csrdiac output
Y nmnmoto.   15 patients with                  change.                                             mesyurcd by dye
1963.      di>enses not de.  (b) Non-inhalation lb) No    No change.             (IJ) No cbrnge. No change.         dilutwn tvchniwc.
Ennlnnd    fined. 19-66 yesra     smoking.       change.
(89).      ol nw. all mod-   (c) 2 standard     (c) Definite Widened               (c) DefiniLe   DeAnire
         ernte-heavy        cigarettes in      increase.  vulse,                   increaaae.   increase.
        cisaretti smokers.     10 minutes.             pressure.
                    (d) NicotineO.6    (d) Definite Definite               (d) Dcfinlt-e   Dellnit-
                       mg. intra-       increase.  increase.                 i"CV3.W.   change.
                       Ye"ousIy.


TAOLE A21.--6ccpcri~~~ents concerning the efects of smoking and nicotine on the cardiovascular system of humans (cont.)

Author.
  Year.
country.
rclercnce

Prntrcost

Nut$r;nd      Smoking       Heart      Blood   Eleclrocardiosrnm    Stroke     Cardiac
             DhXFSi!J~~       rate      PRSl"W  ballistocnrdloeram    volume     OUtDUt  C"d;o,n;lY       Comment.8
pODUt`,tiO"                                                              How

I. 14 volunteers   Single ciKarette    Definite     Definite                I. 10      21 DerCe,,t

;b"J         with clinical
Shelling-      CIID, 13/14
l~,ril,       smokers,
11164.        averape *pe
U S.A.       39.6.
(149).     II. 6 patients
          with angina
          pCCtAri.3. &it1
          smokers, ave.
          rage age 43.4.
       111. 14 Datk"tS
          with history ol
          definite myo.
          cnrdinl infsrc-
          tlon, all smok.
          em *"eraBe
          age 64.1.

smoked at own     increase    increase                 geW"t   incrcaw.
rate in 6-l       in all      in all                   increase,
minutes.         ITOUDI.     !JrO"DS,

II. Inter-    Interme-
  medipte   dlnte
   change.   change.

III. a DCP    1 D~rG?r,t
   cent     incresac.
   decreaae.

Frulikl     6 male and 3     2 rtandsrd       Definite                       No signih-    No signifi-        The author contrnnta
P! HI.,      female Datients    cigarettes in      incrense                       cant changes   cant           this rnponse with
lcKJ5,      u*ith healed      10 minute3 at      al rest                        at rest or     chnngL-3          that LI~C" amo,,p
U.S.A.    myocardisl inlarc-   rest and under     and at                        during      at rest or         hcnlthy you"&!
(ti?).      tion 48-69 years   graded exercise. exercise.                       exercise.     during           individuals.
         01 age Z/8 non-                                                     exercise.
         smokers.



TABLE A21.- Experiments concerning the e&Tech of smoking atld nicotine on the cardiovascular system of hman8 (cont.)

AUlbW,
year.      Number and      Smoking       lienrt      Blood   Electrocardiocrnm    Stroke     Csrdinc
CO"IltlY,      1ype of        procedure       rate      pWSs"rC  bnllistocnrdiogram    volume      cK,"d"v
                                                           output ^          C4mmentc

reference     populntion                                                              1lLlW

Allison     30 healthy male   2 standard ciga-    Definite     Increase.                        Increase fol-       Definite drercnac in
and Roth,    aubjectr.       retta smoked      Increase.                                lowed by         pulmonary blwd
1969.     1949 years of      In 12-16 minute                                         decrease         wulume 83 indicated

U.S.A.
(3):

nge.         period.

within 20
minutes.

by impwloncc mc\boda
of thorocic PUIX
volume.

Aronow and  10 male patienta   1 low nicotine      Definite    Definite                                     All patients dcvclopcd
SWltOOD.    with classical     cigarette in       increase. increase.                                   angina moner if
1969.      fingina pectoris.   6 minutes.                                                         they amoked bclore
U.S.A.     32-59 yeara of                                                                   exercising.
(7).       aye.

Aronow and  10 male patients   1 non-nleotlne     No chanw.   No chance.                                    No dlfiercncr natcd
Swanson.    with claraical     cigarette in                                                         In time or onset
1969.      anpina pectaria.   6 minutea.                                                         of excrcistcinduced
U.S.A.    32-69 yeara of                                                                  *ngir,0 bctwe,n
(6).       ape.                                                                        anwkina and non-
                                                                           rmoklng prucrdurca.

Mershsll
et III.,
1969.
U.S.A.
(129).

42 normotenslvc   314 of one standard  Insignificant lnsignificnnt                                   Blood prr-srurc rrB"onle
healthy male     cigarette.        increase.    increanc.                                     to cold prwsor teat
prisoner8                                                                     noled to Lw grcntrr in
13-50 yean of                                                                  heavy amokcra.
a!ze.                                                                       Prc5~n~opnl rcnctiona
13 nonsmokera.                                                                  to 40 dcgrre bced-up
16 moderate                                                                     till moi-c Irruucn1
smokers.                                                                     in smokers.
13 heavy smokers.


TABLE A22.-.?hpeti?ncnts concerning the cgcct of nicotine or smoking on cutcchoht~inc lcuch

WMlfril      22 mongrel doga     Clgnrette smoking via       Ile~uler ciunrette smoke evoked a atatlatically aignlflcent incrcndc In nilrrnnl vein.
md Watta,                 trneheal cnnnula:          vena cave. and femoral artery levels of eDinepbrine. CornsIlk cigarcttc amukr woked
1063,                     1 cigarette/8 minutea       no chnnse.
U.S.A.                    for 36 minutes.
(ZIO).

Wes1fall     21 male volunteers   3 ciunrettcs smoked in       Smoking nt rnte noted for 2',4 hours evoked B signlficnnt Incrcn8c In urinnry cplnc-
and Wntta.     ap~roximnlely 26    SO minulca.             phrinc. but not norcpincphrlne Irvels.
1ec4,        yenre of n*e;
U.S.A.       11 nonsmokers,
(II!).       10 amokem.

wmtfsll et al.,   MOnkTVZl dOK8      Standard cigarette amokc     Smoke inhalntian cvoknl R r/Be In cardloc output. atrokc volume. blood nrrw\!rc, nnd
1966,                     cxwsure vin cndotrnchcnl     plarmn catccholnminc levels. Prctrcntmcnt with prvprnnolol diminial~cd the cnrdinc
U.S.A.                    tube. Smoke lnhnlntion      output and ntrokc volume reeponsn but increased the blood prcsaure rrsponsc-the
(209,.                   every third inspiration for    latter cflect llue to the release of alpha-receptor activity by betn.bloekade.
                        3 minutes.


E            TABLE A23.-Experiments concerning the atherogenic eflect of nicotine administrution
m       Author. ye.,,
         couotn.     Number and tyDe            Procedure                               Results

  rercrciee      cl mlmal~

Adler et al..    Rabblb         Nlcotlne 1.6 mg. IntravenouaLv in 6 oercent    The authors noted an artcrionecrosir of the aorta. anectins mainly the

1906,
U.S.A.
(2).

mlutlo" 6 O! 7 dnya per week for more than
4 munthr.

inner muscular 18ycrs. hlocrorcopicslly. early changa consisted Of
,mall nrens of calcnrcuus ridging nnd aneur~smsl dilatation without
notable fatty degeneration or intimnl discontinuity. hlicroucopicnlly.
rarly changes appeared in the muscle cells of the media. and "chalky"
depositi wcrc noted between the elastic Rbcn.

HUWW.
1943.
U.S.A.
(SS).

I. 6 moni~el donr.  Nicotine subcutaneously. lncreaaing dosage up   I. O/G ~njmn1s died of infection nnd showed marked cdcmo. n!ld f0Cnl
             UP to 2.6 cc. 013 percent solution fur 1        hynlinizntion of the mcdin of the e.ojin and lnrgc clustic nrtvriL*.
             month.                       216 nn,mnls wcrc sncrificed and show4 thickcninn and hynlinizo-
                                     tion of the WSH~ of the mronory artcries nnd cdcmn uf the mcllin
                                       BP well as ondothclial prulifelntion of other aIzc.ricB,
II. 60 rati.      Increaalne doses UP to 1 cc. of 1 percent      II. Much It-15 *ortic involvement than that found in thr doga: inlrc-
             solution for 1 month.               quent r,rteriolnr changes consisting of Rbrosia and thickcninu of
                                           the media.

MS6lOVa,      Rabbi&          I. (10) Nicotine aubeutaneously 1 percent    I. Aorlic wall---acute swelling of claxtic fibem with loco1 frognlenta-
1966,                       solution 0.2 cc. daily for 116 days.        lion and partial disintegration-no intimal lot deposits SCC~.
USSR                                           Coronary vessels-thickening 01 thr vessel wall-no fat deposits.
(130).                  II. (14) Nicotine ~1~s 0.2 grams cholesterol   II. Aorta-"massive" deposits of "cholesterol" in the intlma nnd YLLSIL
                          per day.                       vniorum with "lcmsening" of the aotiic wall. Cotonnry VMSVII-
                                              the larger vcsscl~ showed mticrntc fnt depositlou nnd the ~mllllcr
                                                  ve~scls showed swelling of the cliuLicn.
                     III. (IO) Cholesterol only.            III. Aorta--i.olatd lipid deyusition in the arch snd a.vccndinv. portiune
                                                  only. Coronary vessels-no fat dcpusitiun.            --
Czochra-      Rnbbita          I. (10) 1.0 g. cholesterol/day for 100      ln~irx uf nul-tic lnion density (cholesterol inr~ltrstion):
Lysanowicr                   dnye.                      I. 2.5.
et al.,                  Il. (10) Cholesterol plus 0.0015 g. nicotine/    II. 3.4.
1969.                       day intrnvenourly.
U.S.A.                  111. (4) Nicotine only.               III. Nu nurtic lcsiono noted.
(46).


Author, year,
  CO""lrY.     Number and type            I'rllcrilurc                                RcvultJ
  rcfcrrncc       of nnimnl
--
Wcnzrl Pl al..    Rabbits          I. (12) C,~ntwl untlcntod.            Gcncrni Rn~l!n~`s: Mnrkul .sorlic nntholonic involvrmrnt w'ns noted in nil

1050.                    II.  fl
U.S.A.
(frn7).                   III.

                      IV.

                      V.

12) Cs~ntrul ,licl plu3 I percent
cholcstcrl,l nnd 5 ,icrccnt cuttanseed
oil nddcd
12) Cnnlrol diet plus oral
nicotine 2.2H mp./kC./dny.
12) Rraimen 11 plus oral nicotine
2.2R ma./ha./day.
12) Regimen 11 plus oral n&line
I.42 mu./ks /~lny.

Thicncs
1960,
U.S.A.

            VI. (12) IleKimcn II plus oral nicotine
                0.57 mg /ka./dey.
Newborn rata nnd   Nicotine subcutnncousiv un to 5 mg./kg.      No nnrrini pathology noted. hledinl dwrnwntion wcn more Irn~unltiv

mice.

twice daily by the end of 1 month.
Animals autonsied at 1 year.

hlale rabbits       I. (10) Nicotine subculnncounlv 0.16

Sicnilicont diflcrcncn in aorlic subrndothrilnl fibrail brtwwn control

Sncrificcd at GO days.


i=           TABLE AZ?,.--Eccperimenls concerning the QtherOgeniC cfCct of nicotine administration (Cont.)
OJ      Author. year,
        countw,     Number and type            Procedure                                Reaulb
        rcfewnce       of animrl

     Hua cl al.,     Male rabbits            Nicolinc   Diet     Vilomin D
       1966,                     I. (8) Conlrol   CO"ltOl   Control     I. Infrwucnt medial calcific disease without llpid localization.
      U.S.A.                    11. 17) Control   Cholrsterol Cuntrol     II. No medial calcific disease but Ireguent intimal atherurna formation.
       (80).                    III. (14) Nicotine   CU"ttOl   CO"ttUl    III. Rare cnlcilic medinl degeneration; no intimal athcro"bntous dlscost.
                            IV. (15) Nicotine   Cholcslerol Control    IV, The Iaw=t number of ntheromataus lesions.
                             V.  (91 Control    Cholesterol Vitamin D   V. No medial calcific diseaae.
                            VI. (14) Nicotine   Cholesterol Vitamin D   VI. Conslrtent medial calcific disease.
                             (Sacrificed at various times)
                             Control-no treatment.
                            Nicotine-subcutaneous injectiona in oil-
                          increasing amounts 2 times per week.
                           Vitamin D--subcutanwus injections up Lo
                              6-8 x 1w III.
                           Cholesterol--260-500 mg. cholesterol sdded
                              per 100 g. diet.
      Choi.        Albino rabbita      I. Nicotine l-5 mg./kg.lday intraperi.      I. Increasing nicotine dosages were aswciatcd with dccrcnscd athcroma
       1961.                        t0"MllY.                     formation (findings not statistically significant).
       Korea                      Cholesterol 1 g.1dr.y (in varying       II. Nlcotinc ulone prcduccd no nthcruma formation bul WBJ usur,ciat<xl
       (42).                      combinations with controls).           with the prewncc of sortic mcdinl cnlcificalio" und endulholial
                              II. Nicotine alone.                   hyperplsais.
                       111. Cholesterol alone. (Sacrificed at 60 days)   III. Cholesterul alone we.3 xssociated with a definite incrcnsp in nthcromn
                                                             formntio".
      Stcfsnovich     Female albino      I. (10) Diet supple-    Pcreent Of aortic   In both stuck and cholcslcrol-fed animals. nicotine was also nolrd to
       et al.,        rabbits.           mentrd with 2.0    sur/ncc i"tfolued    increase aortic triglyceride content and to decrease nortic free cho-
        1969.                        uercent choler.    wilh           lestcrol content.
        U.S.A.                       terol. Nicotine in-   ollicrwclcrolid
        (178).                      tramuscu\~rly       1. 9.4
                                 '2.18 mK./kK./dny.     II. 5.7
                                 5/l days.         III. 0.1
                Ii   II. (10) Cholesterol      IV.
                                 only.
                           III. (10) Nicotine only.
                              IV. (IO) Contml.




     Klsnsch.   SG obscrvntionr   1 standard       Definite
      1066.                                                                      Inclrfinito incrcn~c in ~cn(ins
              on student     ciunrettr        incwue.
      Cetmany                                                                     cpirwphrinc IVVPI$
              smokers Z&24   in 4 minutes.
       IIJS).    ye8.n of *go.   FFA measured at
                        16-25 minuter.
t;;
r


Author,
ycnr.     Number nnd      Smoking       Plnsma rrcc     Swum     Scmm
CoLInIrY,     LYPC <>I       prOCCd"rC       fatty ncidr     cholrstclol   triglyccridcs       ottlcr             Comments
rerrrcnce    wpulotiou

hlurchiron  0 melt and 4    2 cigarettes        I. Dclinitc     Nu rhngc.   Nu chan~c.               Uoth regular nnd sham amokers
and      fcmnle mod-    in 15 minutes.        incwose.                                   shawcd significant incrcn.4cs
FYIIZ,     mate smokers   I. Lit-cign-      II. No change.   No ClLmKe.   No chnnw,                  in conccntrntion of IcNm
I'JGC.     with various       rc1tes.                                                 oieic acid nnd SLgnlfirnnt
Scotland   discnses 31-    11. Unlit-cign-                                                dccrcnars in conuvlltrl~tion of
(139).    67 ycnrs of        rettcs.                                                 ~crum Pnllnitic acid.
        age.

Kerrhbaum 6 normal
et .I.,     heavy
106i,     cipnrette
U.S.A.     amukcrs
(105).     20-15 years
        of nE!e.

Vnrlous types
of cigarettes
of known
nicotine
content.

llrsulai. cigarcttrr.
filtrr ciKnrrttes.
chmcllnl-filtP,
ciunlcttcs. pipe
tobnccn PI\B
cignreltes nil
showed similnr
increiw in FFA.
Lcltuce Ical
cimrettes hnd
negligible eRect.


ANIMAL AND IN VITRO STUIlIES

Kerrhbaum 20 adult     I. 0 reccivcd I?4 nicotine

et al.,
1 II c 5 ,
U.S.A.
(107).




                    TABLE AZ?.Smoking and thrombosis
        --
Author.                    wlmle          Partial Rexaleif~ed
YtiT.   Numbrr and   Expcrl.     blood     Pro-   thrombc-   Dlrrsma   Plotrlet   Platelet   PlaL?let   Platelet
ctiuntt-y.    type of     mental    clotting          pInstin   clotting  adhrsive-   count   SUlViVal  turnover    Other     Comments
rcrcrcnte  populntion   conditions '    lime  ":Ein   tlme    time "~88
-_-___- -
Blnck-    16 dUlL     12 individuals                                                       PloU"U

burn     achizo-      rmokcd 2                                                     llypvtn
et al.,    phlwnic     hlph.                                                           time
1053.    pnticntn. 8    nicotine                                                          (-)
U.S.A.   university    atsndard
(25).    atud,,ntr. nil   trR,id

ii"!1     with cithcr   IlflCr                                                      clumping
Murphy.  CVDur     periods of                                                         time
l%i3.    COI'O. Dli    nbstinence    (-)     c--j    (-)           (-)     (-)    (+)    (4-l       (2)
U.S.A.   hrn\y      or cuntinua-                                        dacrenae increase
(Ill,.   smokers 35-   Lion of
      72 YPBi-5 of   smoking.

       aYe
Ambrus  20 hoolthy    Deep inhala-                                                Thromboplaslir~ 2 studrnts

and     mule nr,n-    tl"n of one                                                     yc,lmltlon    I~~~plmc ill,
Ml"k.    smukinv     nonfiltered    1-j          (-)     f--j     (`c)     C-J                   1imr      R<YUllS
1964.    mcdiclil     cigarette.                            increase                        c--j      rcllcct
U.S.A.   9tutlents <30                                                                       dstn 0" IY


-
blurchi.  R m&s nnd   2 cigswttcs                                                               t Smvkinv bu\h


                      TARLE A27.-Svtoking and thrombosis (co?rl.)
Ll


Sfo,-er and Maddock.    10 subject3 (including heavy smokers) were studied for the eKectr of
1940. U.S.A. (IS,).    the following procedurea on skin temperature: the inhalation of a
               lit cigarette. inhalation through an empty paper tube. or the ad-
               ministration of 1 mg. nicotine intravenously. All subjects responded
               with dcc,enscd cutaneous temperature following the smoking and
              nicotine procedures. No changer were noted fallowing sham smoking.

SIul,nos and Shulman.   A number of experimental groups. each consisting of 6-17 persons.
1910. u.s A. (138).    were studied for the et?ectJ of deep breathing and cigarette smoking
               on skin temperature and dtgit or limb plethysmography. The BU-
              ?hors concluded that deep breathing alone could account for the
               changes in temperature and blood Row noted won smoking and
               noted that denicotinized cigarettes evoked the same or greater
               rawconstriction 8s that noted following the smoking of a standard
                ClKarelle.

50 young male smoker. were studied with plethysmcgraphy before
sod afrrl- the normal and rapid inhalntlon of .a standard ciearettr.
The author noted that rapid inhalation was associated with n pro-
longed drclrase in extremity blood flow while a more natural rate
of Inhalation was follo\red by a momentary decrease in flow. The
author considered the former reaction to represent the pharmacolo-
TIC rKect of the smoke and the latter to re1)rc9ent the physiologic
rcspon~e to dceep breathlox. ns the natural inhalation of an unht
cigarette produced the same t~-an~wnt decrease in flow as did the
netural inhalatzon of the lit cigarette.

52 male and IS female young smoker; and nonsmokers were studied
for the effectc of smoking on hand blood volume aa measured by
the use of radioactive wdinated albumin. The inhalation of un-
Altercd c~garettcs xvzs associated with an average decrease in hand
blood volume of 13 percent in men and 33 percent in >vomen: while
filtered cxgarettrs showed respective decreesa of 11 nerwnt and
2, percrnt.

Stromb!ad. 1959.
Saedcn , Ii, ,.

11 mnie and femnle subjects (smokrrs and nonsmokers) were studicd
for the eilect of the intra-arterial administration of nicotine (bra-
chial artery) on blood flow to the hand as measured by veno~~l
occlusion plpthysmozraphy. Increasing doses of nicotine were asso-
ciated with increasing nombers of individuals manifesting vase-
constriction. The vasoconStTxtive eKec!s of nicotine were abolished
by the prior administration of either hexamethonium or Dentolinium.

Bmnetr and Boake     9 male patients with intermittent clsodication (`I were heavy smokers)
1960X"srnlia 118,.    were studied ior the cKect of smoking on blood flow to the leg a5
              measured h,- vc11ous occlusion plethgsmogr-aphy. Smoking an un-
               filtered cigarette was found not to p:-educe aray consistent changes
               in blood Row to the caLf or foot of the affected leg.

Freund and Ward.
1960. U.S.A. (68).

15 male prkon inmates (less then 35 years of age) and 14 male
patients with peripheral vascular disease la~~roximatcly 65 years
of ape, were studied ior the effect u: smoking on digital circulation
as rwasurrd by skin temtxrsture. plc:hysmoglsphy, and radiosodium
CIPP~R~CC from the skin. Smokina WRS iound to adversely affect
the fib;: and third ~FISUIP~ in a stp~iricant manner (while plethva-
montaphic valurs weac rsr-isb!r)  only in the healthy prisoners
and not at a,, in the Sargent group.

Roth and Schick.      100 normal tndividuals undrruent 425 cxperlmcntal procedures con-
1960. U.S..4 (161).     cerntng the eflrrt 01 srnok~~~ on the petipheznl circulation. Smak-
              ing II-Z, found to be as.oclsted with a drrrrxe in extremity skin
                tP"De**t"*C.

129


130


Chapter 2
Cardiovascular Diseases

Part II

131


CONTENTS

                                    Page
Coronary Heart Disease (CHD)  .............................. 135
    Introduction  .....................................
  Cigarette Smoking as 3 Major Risk Factor for               -135

      Coronary Heart Disease  .......................... .136
  Cigarette Smoking in Relation to Other Risk
     Factors for Coronary Heart Disease  .................. .137
        Hypertension ............................. .137
       Cofflee Drmking _ _ _ . _ _ _ _ . , _ _ . . _ . ,141
         Ventriculx Premature Beats ................... .142
   Carbon hlonoxide .................................. ,142
      Introduction  ................................. -142
     Sources of Carbon hlonoxide Esposu re and
        Human Absorption  ......................... .143
     Effects on Healthy Individuals  ..................... .148
      Effects on Persons With Atherosclerotic
          Cardiovascular Disease ....................... .I49
     Studies on the Pathogenesis of Cardiovascular
          Disease ................................. .150
   Nicotine ....................................... ..15 1
   Acrolein ....................................... ..15 1

Cerebrovascular Disease ................................ .,.151

Effects of Smoking on the Coagulation System  .................. .154

Summary of Recent Cardiovascular Findings  .... , ... , ........... .155

Bibliography  .............. _ .......................... .156

133


List of Tables

Table I. - Age-standardized blood pressure changes (mm tlg)
  at followup for continuing cigarette smokers and
  quitters according to weight clrsnges _ . . . _ _ 139

Table 2. - Number of subjects who had developed hypertension
  at followup for continuing cigarette smokers and
  quitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...140

Table 3. - Mean percent of carboxyhemoglobin saturation in
  smokers and nonsmokers by sex and race . _ . . _ _ . _ _ . . _ . _ _ 144

Table 4. - Alean percent of carbosybemoglobin saturation in
  smokers and nonsmokers by employment status _ . . _ . 14.5

Table 5. - Median percent carbo~yl~enloglobln (COHb) saturation
  and 90 percent range for smokers and nonsmokers by
  location _ . . . . . . . . . _ . _ .  146

Table 6. - Alean percent carboxyhemoglobin (COHb) saturation
  in cigarette smokers I hour after last cigarette . . . .  147

Table 7. - Age-standardired death rates and mortality ratios
  for cerebral vascular lesions for men and women by type
  of smoking (lifetime history) and age at start of
  study . . . . . . . . . . .._...____...._____._______.____ 153

134


COROXARY HEART DISE,\SE (CHD)

itirrodlrcliorl

  Coronary Heart Disease (CHD) is the most frequent C`XUSS of
death in the United States and is the most important single c3use of
excess mortality among cigarette smokers. The evidence relatins
smoking to CHD has been reviewed in previous reports on the health
consequences of smoking (61. 62. 63. 64. 65. 66. 67. 6Sj. The
following is a brief summary of the relationships between smoking
and CHD presented in these reports.

  Cigarette smoking, hypertension, and elevated serum cholesterol
are the major alterable risk factors for myocardial infarction and
death from CHD. Cigarette smoking acts both independently as a risk
factor and synergistically with the other CHID risk factors. The
magmtude of the risk increases directly wi'th the amount smoked.
The excess risk of CHD amon? smokers has been demonstrated in
some Asian, Black, and Caucasian populations and is proportionately
greater for younger men, especially those below age 80. Cessation of
cigarette smoking results in a reduced mortality rate from CHD
compared with the mortality rate for those who continue to smoke.

  Pipe and cigar smokers have a slightly higher risk of death from
CHD than nonsmokers. but they incur a much lower risk than ciga-
rette smokers. This has been attributed to the lower levels of inhala-
tion that characterize most pipe and cigar smoking.

  Data from autopsy studies have shown coronary atherosclerosis
to be more frequent and more extensive in cigarette smokers than in
nonsmokers, and experimental work in humans and animals has
suggested several mechanisms by which smoking may influence the-
development of atherosclerosis and CHD. The formation of carboxy-
hemoglobin, release of catecholamines, creation of an imbalance
between myocardial oxygen supply and demand, and increased
platelet .adhesiveness leading to thrombus formation have all been
demonstrated in smokers and proposed as explanations for the excess
CHD mortality and morbidity among smokers.

135


Cigarette Stnot?ittg as a .Ilajor Risk Facror
   for Corottary Heart Dherrse

  The evidence establishing smoking as a major risk factor in CI1D
has been reviewed in previous reports (lil. 62. 63. 64. 62. 66. 67.
6s). During the last year new epidemiologic data have been published
on the relationship between coronary artery disease and smoking.

  Bengtsson (9. 10) studied the smoking habits of women with
myocardial infarction (hiI) in Goteborg, Sweden. He found that
smoking w3.s significantly more common in a group of 46 women (80
percent smokers), ages 50-54, who had a myocardial infarction than
in ;1 control group of 578 herllthy nonhospitalized women (37.2
percent smokers).

  Other investigators examined the effect of cigarette smoking on
sunrival of people with acute myocardial infarction. In a study of
400 patients with documented myocardial infarction who survived to
he admitted to a coronary care unit, Helmers (26, 27, 2s) found no
significant difference between the percentages of smokers and
nonsmokers among survivors studied after ihe first 24 hours. from 2
days until discharge, and from discharge to 3 years. Reynertson and
Tzagournis (53). in a 5-year prospective study of 137 patients with
documented CHD at age 50 or less, were also unable to find sny
relationship between CHD mortality rates and smoking habits.
Smoking habits after entrance into the study were also considered
and again rio difference in mortality rates was found.

  The Coronary Drug Project (17) found an effect of cigarette
smoking on mortality after myocardial infarction. This group studied
2,789 men ages 30-64 years for 3 years after myocardial infarction
and found a statistically significant correlation between cigarette
smoking determined 3 months after a myocardial infarction and
mortality (t-value of 2.94). None of these studies (Z 7, 26, 27, 28, 52)
were able to examine the smoking habits of the group of people who
die suddenly as a first manifestation of CHD, and therefore may have
excluded that group in which there is the highest excess mortality
due to cigarette smoking (31).

  Additional data from the Swedish twin study of Friberg, et al.
(23) have been reported. They found an excess CHD mortality
among smokers in dizygotic twins with different degrees of smoking,
but no similar excess in monozygotic twins. Although the numbers
\vcrc too lrnal1 to be significant, the authors suggest that this tends to
>uppc>rt the theory that both smoking and CHD are constitutionally

136


determined. These data must be viewed with caution. however, since
the difference was demonstrable only in the older age group (born
1901 - 1910). \J'hen the younger age group (born 191 1 - 19?5) ~3s
considered, no excess CHD mortality was seen in the dizygotic group
but a small excess was noted in the monozygotic group (three CHD
deaths in the high smoking group and one in the low smoking group).
Also the difference in cigarette consumption between the t!igh and
low smoking groups was rslativeiy small (seven cigarettes per day).
Consequently, data from this study are not sufficient to warrant the
conclusion that both smoking and excess CHD mortality are
constitutionally determined rather than smoking being a cause-of the
excess CHD mortality.

Cigarette Smoking in Relation to Other Risk Factors
      for Coronary Heart Dbease

  Cigarette smoking, elevated serum cholesterol, and elevated
blood pressure are generally accepted as the three major modifiable
risk factors for CHD. However, there is less agreement concerning
other CHD risk factors - obesity, physical inactivity, diabetes
mellitus. elevated resting heart rate, psycholopic type A behavior,
etc. The following studies present recent evidence on the relation-
ships between smoking and hypertension, coffee drinking, and
ventricular premature beats.

  Results from several studies have shown that smokers on the
average have slightly lower blood pressure than nonsmokers. Some
investigators have attributed this finding to the fact that smokers on
the average weigh slightly less than nonsmokers. Three current
studies (24, 36. 55) discuss this relationship. Gyntelberg and Meyer
(-74), based on their evaluation of 5,249 men ages 40-59, were of the
opinion that lower blood pressure in smokers could not be accounted
for by differences in weight. age, or physical fitness. Kesteloot and
Van Houte (36), in a study of 42.804 men, performed a multiple
regression analysis on age, weight, and height and found that
cigarette smokers had lower blood pressure than nonsmokers;
however,  When they included serum  cholesterol values in the
analysis, the difference in blood pressure was reduced to approxi-
mately I mm Hg. Although tllis difference was statistically signifi-
cant based on the large population. the actual difference in blood
pressure was too small to be of clinical importance.

137


  Seltzer (55) studied 794 men selected for their initial good
health and normal blood pressure (below 140 systolic and 90
diastolic) and followed them for changes in cigarette smoking habits,
weight. and blood pressure. During the S-year period of the study
104 men gave up smoking. For every age group except those over 55.
there was a significantly greater weight gain (8 lb) among the
"quitters"  than among the continuing smokers (3.5 lb). Blood
pressure increased 4 mm Hg systolic and 2.5 mm Hg diastolic in the
quitters with no change in systolic and a slight reduction in diastolic
(-1.1 mm Hg) in persons who continued to smoke. in order to
examine blood pressure changes in relation to weight change, both
continuing smokers and quitters were grouped according to their
weight changes during the period of study (Table 1). The most
significant finding was an increase in the systolic blood pressure
(+ 1 .77 mm Hg) among the quitters even in that group with significant
weight loss. In contrast, the continuing smokers with significant
wei$t loss had a decline in systolic blood pressure (-3.28 mm Hg).
Diastolic blood pressure in quitters showed an increase with weight
gain and no change with weight loss, while continuing smokeys
showed a decrease in diastolic pressure with weight loss and no
change with weight gain. The data on subjects whose blood pressure
had increased to hypertensive levels (systolic > 1.50 and diastolic >
9.5) were evaluated, and it was found that quitters had a much higher
frequency of becoming hypertensive than continuing smokers (Table
2).

  Seltzer, in interpreting these data, suggested that cigarette
smoking tends to inhibit blood pressure increases, with only minimal
pressure rises occurring even in instances of substantial weight gain.
When this inhibiting effect of cigarette smoking is removed as in the
case of the quitters, sharp rises in blood pressure become evident. He
cautioned, however, that the development of hypertension in some
quitters may have been responsible for decisions to lose weight and
that his data do not allow an evaluation of the degree of blood
pressure changes according to how recently cigarettes were given up.

  The results of the ischemic fleart disease study by Kahn, et al.
(34) raise additional questions about Seltzer's data. Kahn followed
10,000 Jsraeli male civil service employees for 5 years to determine
what factors were associated with an increased incidence of
hypertension. He presented no data concerning persons who stopped
smoking, but he did show that the incidence of hypertension
increased with age and that the age-adjusted incidence of hyper-
tension in smokers was over twice that of nonsmokers (76.9/ 1000
for smokers versus 35.4/1000 for nonsmokers). Seltzer reported no

138


TABLE 1. - Age-standardized blood pressure changes (mm IIg)l at followup for
continuing cigarette sn~nkers and quitters according to weight chofrges

                                Weight Change (LB)
                 Significant      No Significant         Modcrate
   Smoking Clas           wt LOS       Wt Cl13ngc          WI Gain

                            II)              lb              lb
                    NO.    -25 to -5    No.    -4 lo +4    No.     +5 IO +12

Mean systolic BP changes;
Continuing smokers       32     -4.00     84     -1.52     71      2.85
Quitters               13      1.77      27      2.22     27       4.04

Mean diastolic BP changes:
Continuing smokers       32     -3.28     84     -2.04     71       0.13
Quitters               13     -0.31     27     -1.96     27       4.30

`Standardized on basis of age distribution of current cigarette smokers.
Source: Seltzer, C.C. (j-5).

  Significanl
    WI c;ain
     II) -
No.    +I3 IO +30



24        I .sll
32        3 69




24       -0.04
32       3.94


        TABLE 2. - Number of subjects who hod developed hyperrensiorl at
            followup for contirruhg cigorettc smokers and quirters

   Blood preaure           Continuing cigarette snnokers               Quitters
      levels                 Number          Percent          Number           Pcrccnt

Systolic blood pressure lSO+             6             2.8             9             x.7
Systolic blood pressure 160+              2             0.9              5              4.8

Diastolic blood pressure 9S+              3              1.4             5             4.8

Source: Seltzer, C.C. (55).


data on the incidence of hypertension in nonsmokers, and the age
distribution for his group of smokers (the original source of the
quitters) is heavily weighted toward younger age groups .(with only
33 of 214 men age 50 years or over). According to Kahn's data, this
age group would be expected to have a lower incidence of
hypertension, and, in fact, Seltzer found only small numbers of men
who developed hypertension (eight with diastolic hypertension)
(Table 2). Making interpretations based on such small numbers is
hazardous; for example, the difference between current smokers and
quitters in the incidence of diastolic hypertension could have been
produced by only three men quitting smoking because they
developed hypertension.

Coffee Drinking

  The Boston Collaborative Drug Study (12) recently reported a
correlation between coffee drinking (> 6 cups per day) and
myocardial infarction that persisted after controlling for the effect of
cigarette smoking. This was a retrospective study of 276 patients
with a hospital discharge diagnosis of myocardial infarction and
1,103 age, sex, and hospital-matched controls discharged with other
diagnoses. In addition to the usual limitations of retrospective
studies, this study has several characteristics that make interpretation
difficult. In controlling for the effect of cigarette smoking, the
investigators divided the smokers into those who smoked one pack or
less per day and those who smoked more than one pack per day.
Because cigarette consumption is highly correlated with coffee
consumption (29, 39), it can be expected that within such broad
smoking categories those who were heavy coffee drinkers tended to
be heavier smokers than those who consumed smaller amounts of
coffee. It is also possible that the hospitalized controls represented
persons who drank less coffee than the general population because of
serious chronic illnesses. These characteristics of the study design do
not allow firm conclusions to be made concerning the extent to
which the relationship between coffee drinking and myocardial
infarction is independent of the relationship of both variables to
cigarette smoking.

  The question of the independent nature of this relationship is
also dealt with in a prospective study by Klatsky, et al. (39) of 464
patients with myocardial infarction who previously had had multi-
phasic health checkups. Both ordinary controls and CHD risk
factor-matched controls were drawn from 250,000 people who had
undergone the same multiphasic health checkups. The investigators
did not find an independent correlation between coffee drinking and
myocardial infarction when risk-matched controls were used.

141


  The Framingham Study (I$) recently published data on coffee
drinking based on a I?--year followup of 5,209 mrn and women ages
30-67. An incrensed risk cfdeath from all causes was demonstrated in
coffee drinkers, but this relationship was accounted for by the associ-
ation between coffee consumption and cigarette smol;i,g. No
association between coffee drinking and myocardial infarction or
between coffee drinking and the development of CHD, stroke, or
intermittent clsudication was demonstrated. Heyden, et al. (29) also
found no relationship between excessive coffee consumption (> 5
cups per day) and atherosclerotic vascular disease.

Vettrrictrlar Prmratrtre Beats

  Ventricular premature beats have been shown to be a risk factor
for sudden death from CHD. Vedin, et al. (69). in a study of 793
men 111 Goteborg, Sweden, examined the frequency of rhythm and
COl~dUc~iOJ~ disturbances at rest and during exercise. They found no
statistically significant correlation between cigarette smoking habits
and the presence of supraventricular or ventricular premature beats
at rsst or during exercise.

CARBON MONOXIDE

Itrtrodrictiott

  Carbon monoxide has long been recognized as a dangerous gas,
but until recently concentrations which produced carboxyhemo-
globin levels below 15 to 20 percent were thought to have little
effect on humans. Currently there is considerable interest in
determining the effect of chronic exposure to low levels of carbon
monoside (65. 66, 67, 68).

  Carbon monoxide is present in concentrations of 1 to 5 pelcent
of the gaseous phase of cigarette smoke (II, 45). The concentr%tion
varies with temperature of combustion as well as with factors which
control the oxygen supply such as the porosity of the paper and
packing of the tobacco. The amount of carbon monoxide produced
increases as the cigarette burns down. Carboxyhemoglobin levels in
smokers vary from 2 to IS percent depending on the amount
smoked, degree of inhalation, and the time elapsed since smoking the
lrtst cigarette.

Carbon monoxide, which has 230 times the affinity of oxygen
for hemoglobin, impairs oxygen transportation in at lcast Iwo ways:

142


First, it competes with oxygen for hemoglobin binding sites. Second.
it increases the affinity of the remaining hemo@obin for osyfen.
thereby requiring a larger gradient in Paz between the blood and
tissue to dsliver a given amount of oxygen; this increased gradient is
usually produced by a lowering of the tissue Po2.

  Carbon monoxide also binds to other heme-containing pig
ments, most notably myoglobin, for which it has e\`en a greater
affinity than for hemoglobin under conditions of low Paz. The
significance of this binding is unclear, but may be important in
tissues, such as the heart muscle, which have both high oxygen
requirements and large amounts of myoglobin.

Sources of Carbon hlonoxide Exposure and flumarl A bsorpriorl

  Several researchers (13, 32, 35. 57. 60. 70) have estimated the
relative contribution of cigarette smoking and air pollution to the
human carbon monoxide burden as measured by carboxyhemoglobin
levels (COHb). Kahn, et al. (35), in a study of 16,649 blood donors.
determined that smoking was the most important contributing
factor, followed by industrial work exposure. Nonsmoking industrial
workers had COHb levels of 1.38 percent, and nonsmokers without
industrial exposure had levels of .7S percent. Cigarette smokers. on
the other hand, had very high levels. Smokers with industrial
exposure had levels of 5.01 percent, while smokers without industriai
exposure had levels of 4.44 percent (Tables 3 and 4). Stewart, et al.
(57) found similar results in a nationwide survey of blood donors and
noted marked variation in mean COHb levels in residents of different
cities measured at different times of the year (Table 5). However. in
all areas, smokers still had COHb levels two to three times higher
than nonsmokers and had increasing COHb levels with increasing
level of cigarette consumption (Table 6). Similar findings were
reported by Torbati, et al (60) in a study of 500 male Israeli blood
donors.

  Nonsmoking workers exposed to atitomobile exhaust - London
taxi drivers (32) and garage and service station operators (13) ~ have
higher baseline levels of carboxyhemoglobin than nonsmokers of the
general population. But even in these high exposure occupations
smokers have markedly higher COHb levels (8.1 and 10.8 percent)
than nonsmokers (6.3 and 5.5 percent). An extreme is represented
by New York City tunnel workers who are exposed to an average of
63 ppm CO with peak exposure levels as high as 217 ppm CO:
cigarette smokers still maintained much higher COHb levels (5.01
percent) than nonsmokers (2.93 percent) (8).

143


TABLE 3. -Mean percent of carbo.~yhemoglobit1 saturation in smokers and
           notwnokers by sex alId race

  Total Sample        1       Nonsmokers           Smokers1

No.     jz+s,-         NO.     x+q        No.     2 +s,

Total Sample      16,649      2.30 t 0.02      10,157      0.85 2 0.01     6,492      4.58 t 0.03
hlalc         10,542       2.66 + 0.03      5,888       1.00 + 0.01      4>654      4.76 + 0 04
Female        6,107      1.68 + 0.03      4,269      0.64 + 0.01      1.838      4.10 + 0.06

White          15,167      2.28 to.02      9.474      0.85 f. 0.01     5.693      4 66 + 0.04
htale         9,669      2.65 f 0.03      5,508      1.00 * o.o\      4,161       4 tl3 * 0.04
Female        5,498       1.63 f. 0.03      3,966       0.64 * 0.01      1,532       4 19 + 0.06

  Black          1,429      2.59 5 0.06        641
    Male            829      2.91 *0.10        347
    Female          600      2.15 c 0.09        294

`Smokers are defined as those who smoked on the day of giving blood.
NOTE. - % = mean percent: ST= standard error of mean percent.
Source: Kahn, A., et al. (35).

0.86 t 0.03       788      4.00 f 0.08
1.07 2 0.05       482      4.24 + O.lC
0.62 + 0.04       306       3.63 f 0 12


TABLE 4. - hfearz percerzt of carbo.~.~llzt~rnoglobin saturation in smokers
       arzt! Izutzwzokers by euzployrnerzt statzis

I           Nonsmokers               Smokrrs'

xiss;

I     No.

I.38 t 0.04  I    1,738

5.01 t O.OG

G.955         0.7M f 0.0 1   I    4,224          4.44 f u.u`l

   Persons not employed          1,678         0.6 3 +_ 0.02          531         4 24 f 0. I I

`Industrial workers are employed in either durably or ~mndur,~bls good> manufacturing (craflsmen. operalives. or I~borrrs). Smokers
are defined iis those who smoked on lhe day UC giving I~lood.
NOTE. - i = mean percent; S, = stnnd.lrd error of mean percent.
Source: Kahn, A., et al. (35).


TABLE 5. - Median percent carbo~yylrerrloglobin (COHb) saturation and 90 percetrt
       range for smokers and wmtnokers by location

Location

Anchorage
Chicago
Denver
Dciroit
rlonolulu
Houston
Los Angeles
hliami
Milwaukee
New Orleans
NW York
PhOWlX
St. Louis
S.111 Lake City
Slin IFruncisco
SeJttle
Vermont.
NW Ilampshire
Washington, DC

Cigarette Smokers                      Nonsmokers  .

Median          Range


4.1             0.9 - 9.5
5.8            2.0 - 9.9
5.5             2.0 - 9.8
5.6             1.6 - IO.4
4.9             1.6 - 9.0
3.2             1.0 - 7.8
6.2            2.0 - 10.3
S.0             1.2 - 9.1
4.2            1.0 - 8.9
5.5             2.0 - 9.6
4.8            1.2 - 9.1
4.1            09 - 8.7
5.1            1.7 - 9.2
5.1            1 5 - 9.5
5.4            1.6 - 9.8
5.7            1.7 - 9.6


4.8             1.4 - 9.0
4.9             1.2 - 8.4

hlcdian          K3llge


1.5           0 6 .- 3.2
I .7            I.0 - 3 2
2.0            o.!, - 3.7
1.6            0.7 - 2.7
I.4            0.7 - 2.5
1.2            06-35
1.u            I.0 - 3.0
1.2            0 4 - 3.0
1.2            0.5 - 2.5
1.6            I.0 - 3 u
1.2            0.6 .- 2 5
1.2            0.5 2 5
1.4            0.9 - !.I
I.?            0 G 2,s
1.5            0 h 2.1
1.5            0.M - 2 7

   I.2            0 K - ?..I
s   1.2            0.6 2.5

l--

Source: Stewurt, K.D., et III. (57).


TABLE 6. - Mean percent carhoxyl~emoglobirr (COiIb) saturation in cigarette
        smokers I hour after bst cigarette

Location            Nonsmoker

       Packs of Cigucttcs Smoked Per day

CK        %-I         I        1 5i        2

hlilwukuc
Now Htimp\hirc,
Vermont
New York City
Washington, DC
LOS Angclcs
Chicago

1.3          3.0        4.2        5.3        6.2        4,7


1.4          3.3        4.4        5.1        67        5.3
1.4           3.1        4.3        4.1        5.x        63
1.4          3.8        4.6       5.2        5.x        6 6
2.0          4.0        5.2        6.0        1.4        7.5
2.0          4.x        5.4        6.3        7. I        1.1

Source: Slewart, R.D.. et al. (57)


  Studies on the CO burden of each cigrette have determined the
body burden of CO per cigarette to be 7.10-S.66 ml (40). and the
increase in COHb level produced by smoking one ci_rar?tte to he .94
to I .6 percenr after I:! hours of abstinence (40. 33). The hali-life for
the washout of CO in healthy college smokers (40) was catculated to
be from 3 to 5 hours.

  Several studies have been published on the effects of carbon
monoxide on healthy individuals. Small doses of CO (COZb levels
2.4-5.4 percent) were found to have no effect on heart rate (56).
Raven, et al. (5f), in a study of young men exposed during exercise
on a treadmill to 50 ppm CO (COlIb levels 2.5 percent in
nonsmokers and 4.1 in smokers), found no decrease in maximum
aerobic capacity when the subjects were tested at 25" C. In a similar
experiment conducted at 35" C by the same researchers (20). there
was a decrease in maximum aerobic capacity in nonsmokers exposed
to SO ppm CO, but not in smokers despite an increase in the
carboxyhemoglobin levels of I.5 percent in both groups. They
postulated a possible physiologic adaptation of smokers to carbon
monoxide. Ekblom and Huot (22) studied five young men who
inhaled CO to reach given COHb levels. They reported that as COHb
levels increased, there was a decrease in maximal oxygen uptake and
lower heart rates at maximal treadmill exercise.

  Sagone, et al. (54), in a study of 9 cigarette smokers and I8
nonsmokers ages 20-32, showed significantly higher values for COHb,
red cell mass, hemoglobin, and hematocrit in the smokers. Levels of
2,3 DPG were unaltered while oxyhemoglobin affinity I'50 and A'fP
levels were significantly lower in the smokers. The three smokers
with highest red cell mass had normal arterial blood gases and one
smoker had very high values of red cell mass which returned to
normal after he stopped smokin,. 0 The authors interpret these data-as
evidence of tissue hypoxia.

  Millar and Gregory (43), in a study of both fresh heparinized
blood and ACD-stored blood from a bIood bank, showed a reduction
in the oxygen carrying capacity of up to 10 percent in the blood of
cigarette smokers; this reduction persisted for the full 21-day storage
life of blood bank blood.

Cole, et al. (16), in a study of pregnant women, found COHb
levels in the fetus to be 1.8 times a~ great as those in the

148


simu!taneou,ly measured bloat! ot t!1t` m0tI1rr. Fct31 l~100d \v3s
exposed to carbon monoxide in vitro. and Iztd! h~mo~!ol~in \vas
found to 113~2 a shift of the osyh~mo~obin disassociation curve to
the left as occurs \vit!l adult !lemo_clobin. The !li$ler fetal CO!!b
levels were attributed to tile lower fetal Po2 and a resultant decrease
in the ability of oxygen to compete for t!X fetal I~emoglobin. It was
felt by the authors that the hi& COHb levels may be responsible for
the lower birth wei$t of infants born to mothers who smoke.

   Effecis ofi Persons wirll
A rheroscleroric Carrliovascdar Disease

  Aronow and Isbe!! (5) and Anderson, et a!. (I) have shown a
decrease in the mean duration of exercise before the onset of pain in
patients with angina pectoris exposed to low levels of carbon
monoxide (50 and 100 ppm). Carboxyhemoglobin levels were
significantly elevated (2.9 percent after 50 ppm; 4.5 percent after
100 ppm) and the systolic blood pressure, heart rate, and product of
s>.stolic blood pressure times heart rate (a measure of cardiac work)
were a!! significantly lower at onset of angina pectoris.

  In a continuation of this work. Aronow, et al. (2. 3) studied
eight patients durin: two separate cardiac catheterizations, one
during which each patient smoked three cigarettes and one during
Lvhich each patient inhaled carbon monoxide until the maximal
coronary sinus COHb level equalled that produced by smoking
during the first catheterization.  All eight had angiographically
demonstrated CHD (> 75 percent obstruction of at least one
coronary artery). Smoking increased the systolic and diastolic blood
pressure, heart rate. left ventricular end-diastolic pressure (LVEDP),
and coronary sinus. arterial, and venous CO levels. No changes were
noted in left ventricular contractility (dp/dt), aortic systolic ejection
period. or cardiac index, and decreases were found in stroke index
and coronary sinus. arterial, and venous Pq When carbon monoxide
was inhaled. increased LVEDP and coronary sinus, arterial, and
venous CO levels were noted; there were no changes in systolic and
diastolic blood pressure, heart rate, or systolic ejection period; and
decreases in left ventricular dp/dt, stroke index, cardiac index and
coronary sinus. arterial, and venous Paz were found. .These data
suzoest that carbon monoxide has a negative inotropic effect OR
m;&ardia! tissue resulting in the decrease in contractility (dp/dt)
and stroke index. \I'hen the positive effect of nicotine on contrac-
tility and heart rate is added by cigarette smoking, the net effect is
increased cardiac work for the same cardiac output. in the heart with

149


coronary artery disease there is a greatly restricted capacity to
increase blood flow in response to this increase in cardiac work. The
result is early cardiac decompensation manifested by elevation in
LVEDP and angina pectoris.

  Aronow, et al. have also shown decreased exercise time prior to
onset of angina pectoris in persons exercised after riding for 90
minutes on the Los Angeles Freeway (4). In a related study, they
demonstrated a decrease in exercise time before claudication in a
group of patients with intermittent claudication who were exposed
to 50 ppm CO (6).

Studies otr the Putlrogertesis of Curdiovascniur Disease

  In a review of some of their work on carbon monoxide, Astrup
and Kjeldsen (7) noted that in cholesterol-fed rabbits exposed to I70
ppm carbon monoxide for 7 weeks (COHb 16 percent) and then to
310 ppm for 2 weeks, the cholesterol content of the aorta was 2.5
times higher than that of cholesterol-fed, air breathing controls.
Groups of cholesterol-fed rabbits intermittently exposed to carbon
monoxide for 13 or 4 hours per day produced three- to fivefold
increases in the cholesterol content of their aortas. Cholesterol-fed
rabbits made hypoxic at IO and 16 percent oxygen had 3 to 3.5
times tlie aortic cholesterol content, while those exposed to 26 and
28 percent oxygen had a considerable decrease in cholesterol
aciumulation.

  Theodore, et al. (5s) studied the aortas of monkeys, baboons,
dogs. rats, and mice fed a normal diet but exposed to very high levels
of CO (COHb levels 33 percent) and found no atheromatous changes
in their aortas.

  Further work by Astrup and Kieldsen (38) revealed that in rab-
bits fed normal diets but exposed to 180 ppm carbon monoxide for 2
weeks, there were local areas in their hearts of partial or total necro%
of myofihrils; in the arteries there was endothelial swelling, formation
of subendothelial edema, and degeneration of the myocytes. When
the aortas of these rabbits were examined (37), the Iuminal coats
showed pronounced changes characterized by sevcrc edematous
reaction with extensive swellin, 0 and formation of srrbendothelial
blisters and plaques. The authors postulate that carbon monoxide
increases endothelial permeability to albumin which results in
formation of edema leading to changes indijtirl~Ir;il,,lt~l~ from early
atherosclerosis.

150


  Evidenc2 that this mecllJnism rnsy occur in Ilunlans is provided
by the findings of Panins (50) \vho showed an increased trans-
capillary escape rat2 for 13 1 I- labzlrd albumin in humans exposed to
.-I3 percent CO (COHh 20 p2rcent) for 3 to 5 hot115. hut not in thoss
mad2 hypoxic to an altituti? of -I300 mrters (I~emoglobin 75 percent
saturat2d).

  By exposing rabbits to different conccntmtions of carbon
monoxide (SO. 100, and 180 ppm) for varying periods (.S, 2. 4, 8,
24. and 48 hours), Thornsen and Kjeldsen (59) were able to show a
threshold of 100 ppm of CO for myocardial damage. The demonstra-
tion of damage at this level of CO (COHb 8-10 percent) is possibly
explained by the ratio of carboxyrnyodobin to carboxyt~erno_elobin
which is about 3 to 1 in myocardium at ambirnt POT. Thus, a
COHb level of 10 percent would be accompanied by a cnrboxymyo-
globin level of 30 percent in heart muscle. This ratio is even greater
under hypoxic condltlons with a ratio of 6 to I when the arterial Paz
is below 40 mm Hg (15).

Nicotine

  In a study of the effects of smoking cigarettes with low and
hi* nicotine content, Hill and Wynder (30) noted increasing serum
epin2phrine levels with increasing nicotine content of the smoke. but
serum nor2pinephrine levels were unchanged. However. increasing
serum epinephrine levels with increasing number of low nicotine
content cigarettes smoked were also noted.

Acrolein

  Egle and Hudgins (21) did inhalation studies with acrolein on
rats. Inhalation of this aldehyde at concentrations below those
encountered in cigarette smoke resulted in a significanj increase in
blood pressure and heart rate in rats.

CEREBROVASCULAR DISEASE

  There has been conflicting evidence on whether there is an
increased risk of cerebrovascular disease due to smoking (61, 62, 63,
64. 65. 66. 67, 65). A prospective study by Paffenbarger, et al. (4s)
of 3,991 lon&oremen followed for I8 years showed no correlation
between fatal strokes and smoking. However, both the Dot-n study of

151


U.S. veterans (3-i) and Hammond's study of one million men and
women (175) showed a small but slgniticsnt increase in tile death rates
from cerebrovascular disease among cigarette smokers. The Framing-
ham i&year followup of men ages 45 to 54 (32) and PafTenbar~er`s
study of men who entered IIarvard between 1916 and 1940 (49) also
showed an excess risk of cerebrovsscular disease associated wit11
cigarette smoking.

  TWO recent studies provided more data on this topic. Ostfctld. et
al. (46, 47), in a study of 2,748 people ages 65-74 receiving old age
assistance in Cook County, Illinois, were unable to find any relation
between cigarette smoking habits at the start of the study and
incidence of new strokes or prevalence of transient ischemic attacks.
Nomura, et al. (44), in a study of the population of Washington
County, Maryland, ages 25 and older, were unable to find any
relation between cigarette smoking and either mortality or morbidity
from stroke. Nomura noted that  "in atherosclerotic strokes the
Framingham study and Paffenbarger's investigation of former college
students included a great percentage of stroke cases under the age of
55. Because these two studies found an association between cigarette
smoking and atherosclerotic strokes and the present study did not, it
may be that the association is age-dependent."

  Hammond (25) provides some data which may clarify this
relationship. Analysis of his data shows that the difference between
cerebrovascular death rates in cigarette smokers and nonsmokers
increases as persons get older except in males ages 75-84 (Table 7),
indicating that the excess death rates associated with cigarette
smoking increase with advancing age. The ratio of the death rates for
smokers and nonsmokers (mortality ratio), however, decreases with
3ge. reflecting the fact that cerebrovascular disease death rates
attributable to other causes increase with age more rapidly than
death rates attributable to smoking. Cigarette smoking may well be a
risk factor for stroke at all ages, but other causes of strokes become
proportionally so important in older age groups that in studies not
based on very large populations the risk due to cigarette smoking%'
masked by the large total number of strokes due to other causes.

152


CVL Death Rates per 100,000 Person-Years

hlen

Never woked regulxly
Pipe. cigx
Clgtirctlc and other
Clgarettc only

28         92        349
25        100       369
2x       129        36 I
42        130        477

Total                                           35        116

Never smoked regularly
Clg;lrcllc

Tot;11

18
38

25

57
X8

64

391

22x
315

238

1,3sti
1,371
9'10
l,lbY

I.272

I .0X!
I.277

I ,09 I

CVL hfortalitv Ratios

Never smoked regularly                                I 00        1.00       1.00       I .oo
Pipe, cigx                                        0.119        I 09        I .06        I .o I
Clgarelle dnd other                                  I .oo       1.40       1.03        0.72
CigJrclle anl!                                      1.50       I.41        1.37       0.X6

                    Women

Never smoked regulxrly
CIprectc

NOTE. - (`VL = Crruhrdl vtiscul~r Ies~ons.

I .oo       1.00        1.00        I 00
2.1 I        I.54        I.!X        I Iii


EFFECTS OF S.\lOKISG ON THE CO.AGULATION SYSTEM

  Several studies have contributed to an understandinq of the role
of smoking in thrombogenesis. Lri,inr l-J/), in a controllc`d double
blind study, showed that smoking a sin~Je cigarette increased the
platelet's response to a standnrd a:_crqatin g stimulus (ADP). This
phenomenon did not occur when lettuce lca11` cigarettes were smoked
and was independent of a rise in free fatty acids in the plasma. The
author postulates that this may be due to increasing epinephrine
Jcvelr.

  These data may have relevancrt for two other studies. In the
clinical trial of the possible prevention of heart attack by
hyperlipidemic drugs in Newcastle, En~lnnd, (19) it was found that
cigarette smokers were at increased risk of sudden death. This
increased risk was not present in smokers treated with clotibrate.
Llowrver, the researchers were unclble to relate this reduction in risk
to any effect of clofibrate on st`m~n lipids. Kscfntly Carvaiho, et at.
(13) evaluated 79 patients with familial i~yp~rbetslipoproteintlniia
and noted that their platelets had an increased sensitivity to
aggregating stimuli (ADP). Treatment with clofibrate returned the
ADP sensitivity to normal without significantly altering serum lipids.
This demonstrated effect of clofibrate may provide some insight into
the Newcastle study. The reduction in the escess risk of sudden
death could be due to a clofibratr induced reversal of increased
sensitivity to aggr-egating stimuli produced by smoking.

154


SUJIhlARY OF RECEST C:\RDlO\`,ASCL'LAR FINDISCS

  1. Data from one recent incidcncr: study suggest that ciCarc't;-?
smokers are more likely to develop hypertension than 3ri
nonsmokers. There is some evidence that suggests that stoppir.:
smoking may be accompanied by a rise in blood pressure.

  2. Cigarette smoking has been shown to be the major sourc< of
elevated carbosyhemoglobin levels, with occupational esposnrs and
air pollution being far less important in most circumstances.
Carboxyhemoglobin levels in cigarette smokers are two to three
times the levels in nonsmokers and increase with the amounts
smoked.

  3. Elevated carboxyhemoglobin levels have been shown to
decrease maximal oxygen uptake in healthy people as weft 3s to
decrease the exercise tolerance of persons with angina pectoris and
intermittent claudication. The carboxyhemoglobin levels at which
these effects take place 3re well within the range productld b!:
cigarette smoking.

  4. Carbon monoxide at levels of exposure commonly reachi`d
by cigarette smokers has been shown to decrease cardiac contractlfitb,
in persons with coronary heart disease.

  5. Carbon monoxide has been shown to produce changes Iik?
those of early atherosclerosis in the aortas of rabbits.

155


BlBLIOGKAPHY

ANDERSON. E. W., ANDEL5IAN.  K J.. S7 R..ICCkl. J. .\j.. I.ORTUIN. N J.,
  KNELSON. 1. H. Effect of low level carbon mono\lde rxpowre on onwt snd
  duratron of' an@na pectons. A %tudy of Icn p311en1s with ischcmic hext dtiwJre.
  Annals of Inlern~l hjrdicine 79(1):46-50, July 1973.

ARONOW. w. s.. c~ssl~y, J.. VANGROW. J. s.. hIARCH, ~1.. KERN. J. C..
  GOLDShtITH. J. R.. KHEMKA. bl.. PACANO. 1.. VAWTER. ht. tffecc of
  cigarette smoking and breathing carbon monoxide on cardlovnvul~r hemo-
  dynamics in anginal patients. Clrculalion 50(?).340-347. August 1974.

ARONOW. W. S.. COLDShI t-I-H. J. R.. KERN. J. C., JOHNSON. L. L. Effect of
  smoking ciguettes on cardiovasculx hemodynamlcs. Archives of Environmental
  Health 28(6): 33@332, June 1974.

ARONOW, W. S.. HARRIS, C. N.. ISBELL. 11. W.. ROKAW. S. N., I?.lPARATO. B.
  Effect of freeway travel on angna pectotis. Annals of Internal hledlclne 77(S):
  669-616. November 1972.

ARONOW, W. S.. ISBELL, bl. W. Carbon monoxide effect on exercise-induced Jngina
  pectoris. Annals of lnrernsl hlcdicinr 79(3): 392.395. September 1973.

ARONOW. \V. S.. STEslhlER. E. A.. ISBELL. M. W. Effect of carbon monoxide
  exposure on intermlttenr claudicatlon. Circul3rion 49(3): 4154 17. March 1974.

ASTRUP, P.. KJELDSEN. Kc. Carbon monoude. smoking. and atherosclerosis. hledlcal
  Clinics of North Amtxca SS(2): 323.350. Alsrch 1974.

AYERS. S. ht.. EVANS, R.. LIGHT. D., CRIESB:\CH, J., RElhlOLD. F., FERRAND.
  t. I-., CRISCITIELLO, A. Hetith effects of rhposure to i\lgh ConcentraIlons of
  automotIve emissions. Studies in hrldge and tunnel workers m New York City.
  Archwes of Environmental HeJth 27(3): 168-178, September 1973.

BENGTSSON. C. Smoking habits in 3 popul;ltion sample of women and m women with
  iccharmlc heart direxe. Ac13 Mrdica Scandmwica (Supplementurn 549): 6064.
   1973.

BENGTSSON. C. Prevalence of multiple "risk factors" for ischaemlc heart disease in
   H omen  wth  and without known ischaemlc heart disease. Acta Medica
  Sczmdinavica (Supplementurn 549): 97-105. 1973.

BOPHOVEN. C.. NIESSEN, H. 1. Amounts of oxides of nitrogen ;Ind carbon
  monoxide in cigxette smoke, wkth and without inhalation. Nature 19214801):
  458-459. November 4, 1961.

BOSTON COLLABORATIVE DRUG SURVEILLANCE PROGRAM. Coffee drinking
  and xute myocardul infarctIon. Lancec 2(7790): 1278-1281. December 16,
   1972.

BUCHWALD. H. Exposure of garage and service starion operalives IO c;lrbon
  monotide: A survey based on carbo\yhemodobin levels. American lndust+d
  Hyp~ene Association Journal 30(6): 570-575. November-December 1969.

CARVALHO. A. C. A.. COLAfAN. R. W.. LEES. R. S. Clofibrate reverssl of pl3lelet
  hypersenslwtty ,n  hyperbet3lipoproleinem~3. Circulation SO(3): 570-574.
  September 1974.

COBURN. R. t-. The cubon monowde body sfores. Annals of the New York Academy
  of sc,ences 174: I l-22. October 5. 1970.

1

2

3

4

9





IO





II





12

13





14





IS


16

17

18

19

20

21

22

23

24





2s

26

27

28

29

30

COLE, P. V.. HAWKINS. L. K. KOBE.RTS. D. Smo!.mg dunn_e pregnmcy and 11s
  eff~rs 03 the Iems. journal of Ob\trtrlcs and Cynxcology of the British
  Commonuralth 79(9): 782-787. S?ptcmh<r IY72.

CORONARY DRUG PROJECT KEStARCll GROUP. Fxtors lntlucncing long-term
  prognosis after recovery from myocardul Infarctron- Three-year findlnes of the
  coronuy drug prcqect. Journal of Chron~ Dwdces 17(6): 267-285, August 1974.

DAWBER. 1. R.. KXNNEL. W. B.. GORDON. T. Coffee and car&ovascular dware.
  Obscnations from the Frarnm_pham Study. New England Journal of Medlclne
  291(17): 871-874.0ctober 24. 1973.

DEWAH, H. A. Trial of clofibrate in the treatment of jrchaemic bear1 diseaw. crve-year
  study by a group of physicrans of the Newcastle upon Tyne Regron. Britrth
  htedlcal Journal 4 (5790): 767-775, December 25. 1971.

DRINKWATER. B. L.. RAVEN. P. B.. HORVATH. S. hl..CLINER. J. A.. RUHLlNG.
  R. 0.. BOLDUXN. N. W.. TAGUCHl. S. Air pollution, e\erc,se. and heat stress.
  Archivesoi Environmental Health 28(4): 177-181. April 1974.

EGLE. J. L.. Jr.. HUDGINS. P. Al. Dose-dependent sympathomimt`tlc and cardio-
  inhthitory rffsctr of acrolrm and formddrhyde rn the anesthctued 131.
  To\icology and Applied Phxmacology 28: 358-366, 1974.

EKBl.011. B., HUOT, R. Respone to subma\lmal and ma\lrnal exrrctse at dlfferrnl
  levels oi carbo\yhemoglobin. Acta Physiologica Scandlnavrca 86(4): 474-482.
   December 1972

FRIBERG. L., CEDARLOF. R.. LORICH. U., LUND\tAN. T.. DEFAIRE. U.
  Morr.Ait) ,n t\nn> in wlation IO vnokm~ h.ib,ts and alcohol problems. Archwes of
  Environmental ifr.dth 27(S). 294-304. November 1973.

GYNTELBERG. E. \IEYER. J. Relationship between blood pressure and phywal
  fitness. wnokmg and alcofiol consumptmn in Coprnhrlzsn males aged 40-59. Acta
  hledlca S~and,navlca 195(5): 375-380, hfay 1974.

HASI1IOND. E. C. Smoking in relation to the death rates of' one million men and
  women. lrrr Hacnwel, W. (Editor). Epidemiologxzal Approaches to the Study of
  Cancer and Other Chronic Dwases. Bethesda, hld.. U.S. Public Health Service,
  National Cancer lnstltute Monograph No. 19. January 1966. pp. 127-204.

HELLIERS. C. Proposls for the first day after admission. Acta Medica Scandmavica
  (Supplrmentum 555): 14-26, 1974.

lIEL>lERS, C. Pro+xis for the hospital period from the second day after admis5lon.
  Acta Slcdica Scandinavica (Supplementurn 555): 31-41. 1974.

HELMERS. C. I.on_e-t?rm prognosis. Arta hledrca Scandinawca (Supplementurn 555):
  54-65.1974.

HEYDEN. S.. BARTEL. A.. CASSEL. J.C. HA.\fES. C.C. TYROlER. H. A.
  hltItR. R. F;~lf<ekonwn~ <;riatserkr.~nkungen und Ri>ikot;rktoren I" der
  Evan~County/G~or~a-sludle. (Cofte e concumpt~on. vascular dixJ\es, and rixk
  (actors m the Ev;lnc County. Georgia. study.) Zeittchrlft fur Ernahrungswwens-
  chdft (Supplement 14): ILIO. 1972.

157


31  ISTERSOCIETY CO\lMISSION FOR HEART DISE:\St KESOURCES ~thcrorclero-
    ski Study Group .Ind Eptdrmlology Study Group. Prlmxy pre\entron of the
    atheroxl?rotlc di\cJsrs. C~rcularmn 42(6): A-54-A-95, Dcccmber 1370.

32  JOXES. R. D.. COSt>lINS. B. T.. CtRNIK. A. A. Blood Icad and cxrboyyhemo$obm
    levels in London tn\r drivers. Lancet 7(7772): 302.303. August 12, 1972.

33  KAHN. H. A. The Darn ctudy of smoking and mortahty among U.S. veterans: Report
    on 8% years of ob\erwtmn. In: Haensrel.  W. (Edttor). Ep~dsmiolo+al
    Approaches 10 the Study of Cancer and Other Chronic Diseases. Bethesda. Md..
    U.S. Public He.llth Setwce, National Cancer Institute Monograph No. 19. January
     1966, pp. l-125.

34  K;XtlN. H. A.. MED<\LIE. J. H.. NEUI-ELD, tf. N., RISS. E.. GOLDUOURT. U. The
    Incidence oi hypertcnuon 2nd assocufed factors: The Iw.xt tschemrc he.ut drwa\e
    study. Amcr~can tlurt Journ;ll 84(2): 171-162. Ausust 1972.

35  );,tlIN. A.. RUTLEDGE. R. B., DAVIS. C. L.. ALTES. J. A., CANTNER. C. E..
    TIIORNTON. C. A.. WALLACE. N. D. Carbo\yhrmogobin sourcec m the
    \letropolr~an St. Lows population. Archwcr 01 Enwronrnrntal tlcalth 29(3):
     I.!?-1 35. Scptemhcr 1974.

36  Kt.Sl LLOOT. H.. VAN HOUTE. 0. An cpidcmioloeic wwcy ofartcrial blood presture
    ,n a l~rce m.& popul~rion group. American Joum~I of IIpidemlolo,g 99(l):
     14-29. Jx~uary 1974.

37  I;JLLDSLN, R., ASTRUI', P., \V>\NSTRUP, J. Ultr~\tructural Intmul changes I" the
    rabbit aorta after a modcrate carbon monoxide cyposure. Alherosclero~~s 16( 1):
    67-82, July-August 1972.

38 KJELDSEN. E.. THOMSEN. H. K., ASTRUP, Y. Eit&ts of carbon monoxide on
    myocardiurn. Ultrastructural chsnrrs m rabblls sfter moderate. chronic e\powre.
    Clrculstion RL`search 34(3): 339.348. March 1974.

39  KLATSKY. A. L, t RILDXIAN, C. D., SIECELAUE. A. B. Coffee drinking prmr to
    acute myocardlal mfxction. Journ~J of the American hledrcal Association 226(S):
     540-543. October 29. 1973.

40  LANDAW. S. A. The effects of cigarette smoking on total body burden and excretion
    r3tes of carbon monoxrde. Journal of Occupatmnal Medicine 15(3): 231.235,
      5lxch i 973.

41  LE\;INE, P. H. An acute effect of cigarette smoking on platelet function. A possible
    hnk between smoking and arterial thrombosis. Circulation 48(3): 619-623;.
     September 1973.

42  \l&EE. D. Section 28. The probability of developing certain cardiovascular diseases in
    eight years at specified values of some characterrstics. In: Kannsl, W. B., Gordon,
    T. (Editors). The FramIngham Study: An cpidemiolorrcal investigation Of
    cardiovascul.u disease. U.S. Departmt-nt of Health. Education. and Welfare. Public
    Health Service. Natmnal Instrtutes of Health. Publication No. (NIH) 74-618, May
     1973. 152 pp.

43 MILLAK, R. A.. GRI-,(;ORY. I. C. Reduced oxygen content in eqwhhrated fresh
    hrp,rrinrzed and ACD-stored blood from cigarrttc smokcrc. Bntlsh Journal of
    Anarsthecta44( 10): 1015.1019, October 1972.

44  NO\lURA. A.. CO\fSTOCK, G. W., KULLEK. L. TDS.\SCIA. 1. A. Qurettr making
    and strokes. Stroke 5(4):4X3486. July-August 1974.

158


46 OSTFELD. A. hf., SHEK;EI.LE. R. B.. K;1..\\1',\SS. H L. Tr~nwnt icchrrnlc .~llxk\
    and risk of stroke m an elderly poor popul.~lion. Stroke 4(h): 9809Yh.
     November-December 1973.

47  OSTFELD. A. M., SHEKELLE, R. B.. KLAWANS. H , 1 U10, H. hl. Epidemloloey of
    stroke in an elderly welfare population. American Journal ol` Puhllc tlealth 63(S):
     4SO--l58. May 1974.

48 PAFFENBARCER, R. S., Jr. Faclors predisposing to Patal stroke m long>horcmen.
     Preventive Medicine i(4): 522-525. December 1972.

49  PAFFENBARGER, R. S., Jr.. WING. A. L. Chronic disease in former college students,
    XI. Early precursors of nonfaral stroke. American Journal of Epldemlology 9-t(6):
     524-530, Drcember 197 I.

50  PARVING. H. -H. The effect of hypoxia and carbon monouldr exposure on plasma
    volume and capillary prrmcabdity to albumin. Scandinavian Journal of Clmical
    and Laboratory investigation 3U( 1): 49-56. September 1972.

51  RAVEN. P. B.. DRINKWATER. B. L., RUHLING. R. 0.. BOLDUAN. N..TAGUCtll.
    S.. CLINER. J., HORVATH. S. ht. Effect of carbon monoxide and peroxyxetyl
    nitrate on man's maxmmt aerobic capacity. Journal of Applied Physiology 36(3):
     288-293, hlarch 1973.

52 REYNERXON, R. H., TZACOURNIS. hl. Clinical and metabolic characterislics.
    Effects on mortality in coronary disease. Archives oi 1ntern.d hlediclne 132(5).
     649653, November 1973.

53 RUSSELL, hl. A. H. Blood carhoxghaernoglobin changes during: tobacco \moklng.
    Postgraduate Medical Journal 49(576)' 684.687, October 1973.

54  SAGONE. A. L., Jr., LAWRENCE, T., BALCERZAK, S. P. Effect of smoking on tissue
    oxygen supply. Blood 4 l(6): 845.85 1. June 1973.

55  SELTZER. C. C. Effect of smoking on blood pressure. American lfrart Journ.rl 87(S):
    558-564, May 1974.

56  SHEPHARD, R. J. The influence of small doses of carbon monoxide upon heart rate.
    Respiration 29(5/6): 516-521. 1972.

57 STEWART, R. D., BARETTA, E. D., PLATTE, L. R., STEWAKT, E. B..
    KALBFLEISCH, J. H., VAN YSERLOO, B.. RIXlM. A. A. Csrboxyhemogobm
     levels in American blood donors. Journal. of the American hledlcal Association
    229(9): 1187-l 195, August 26. 1974.

58  THEODORE, J., O'DONNELL, R. D., BACK, K. C. Toxicological evaluation of carbon
    monotlde in humans and other mammalian species. Journal of Occupstlonal
    hiedicine 13(S): 242-255. hfay 1971.

59 THOMSEN. H. I<., KJELDSEN. K. Threshold limit for carbon monoxide-Induced
    myocudlal damage. An electron muoscopic study in rabbits. ArchIves oi
    Environmental Health 29(2): 73-78. August 1974.

60 TORBATI. I.D.; HAR-KEDAR. I.. BEN-DAVID. A. Carbo\yhcmoglobin Icvelr in
    blood donors in relation to c~garel!e smoking And to orcupstlonal expowre to
    carbon monoxtde. Israel Journal ot blcdwal Sc~encrs lO(3): 241-244, hIarch
      1974.

159


61 US. PUBLIC HtAI.TH SERVICE. %nokin~ ..d Ilralth. Kcport ot the ~d\,wry
    Committee to the Surgeon General of the Public tlralth Service. Wsshinpton. U.S.
    Department oi Health. Education, and Welfare. Pubhc IlcJlth Setvice Pubhcatwn
    No. 1103. 1964. 387 pp.

62  U.S. PURLIC HEALTH SERVICE. The Health Conwquences of Smoking. A Public

63 US

64 U.S

Health Sew~ce Rcwew: 1967. U.S. Dcpartrncnt of Health. Education. And
Welfare. Washington. Public Health Serwce Pubhcatlon No. 1696. Revised
January 1968. 227 pp.

PUBLIC HEALTH SERVICE. Ihe Health Consequences of Smoking 1968.
Supplement IO the 1967 Public Health Scrwce R&ew. U.S. Dcpartmcnt of
Health. Education. and Welfare. Washington, Public Health Service Publwation
1696, 1968. II7 pp.

PUBLIC HEALTH SERVICE. The Health Consequences of Smoking 1969.
Supplement to the 1967 Public Health Sew~ce Review. U.S. Department of
Health, Education. and Welfare. Warhington. Public Hrslth Servrce Publtcafion
1696-Z. 1969. 98 pp.

65  U.S. PUBLIC HEAL.rH SERVICE. The Health Consequrnces of Smokmg. A Report of
    lhe Surgeon General: 1971. U.S. Drputment ol Health. Educatmn. and Welfare.
    Washington, DHEW Publication No. (fiShi) 7 I-75 13, 1971, 458 pp.

66  U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smokmg. A Report of
    the Surgeon General: 1972. U.S. Department of Health. Education. and Welfare.
    Washingron, DHEW Publication No. (HSM) 72-6516, 1972. IS8 pp.

67  U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking: 1973. U.S.
    Department of Health, Education. and Welfare. Washington. DHEW Publication
    No. (HSM) 73-8704. 1973. 249 pp.

68  U.S. PUBLIC HEALTH SERVICE: The Health Consequences of Smoking: 1974. U.S.
    Department of Health, Education. and Welfare. Washington. DHEW Publication
    No. (CDC) 74-8704. 1974. 124 pp.

69 VEDIN, J. A., WILHELMSSON, C. E.. WILHELhtSEN. L.. BJURE, J.. EKSTROhl-
    JODAL. B. Relation of restmg and exercise-induced eclopc beats IO other
    ischemic manifestations and to coronsry risk factors. Men born in 1913.
    American Journal of Cardiology 30(l): 25-3 I, July I I. 1972.

70 WALLACE, N. D., DAVIS, G. L., RUTLEDGE, R. B.. KAHN, A. Smoking and
   carboxyhemoglobin in the St. Louis Metropolitan population. Theoretical and
   empIrica considerations. Archives of Environmental Health 29(3): 136-142,
    September 1974.

160


Chapter 3
     Chronic Obstructive Bronchopulmonq Disease

source:

1971 Report, Chapter 3, pages 135 - 230.

161


Contenfs

Introduction .........................................

Epidemiological Studies ..............................
  COPD Mortality .................................
  COPD Morbidity .......................... .._...
  Ventilatory Function. ............................
   Genetic Factors .................................
    Alpha,-antitrypsin ...........................
   Air Pollution ....................................
  Occupational Hazards ............................
      Cadmium. ..................................

Pathological Studies  .................................

Experimental Studies  ................................
   Animal Studies  .................................
   Studies in Humans  ..............................
  Studies Concerning Pulmonary Clearance  ..........
      Overall Clearance  ...........................
     Ciliary Function  ............................
     Phagocytosis ................................
  Studies Concerning the Surfactant System  .........

Other Respiratory Disorders  ..........................
  Infectious Respiratory Diseases ....................
  Postoperative Complications  ......................

Summary and Conclusions  ...........................

References ..........................................

FIGURES

1. Percent of lung sections with Grade IV or V fibrosis . . .     187
2. Percent of lung sections with Grade II or III emphysema     188

LIST OF TABLES

(A indicates tables located in appendix at end of chapter)
1. Chronic obstructive bronchopulmonary disease mor-
  tality ratios.. . . _. . _. . . . . . . _. . . . . . _ . . _ . . . . . . . .

Page
165

.167
167

171
172
174
176
178
179
180

180

184
184
189
190
190
190
191
198

198
198
200

201

202

168

163


   LIST OF TABLES (Continued)
(A indicates tsbics locstetl ~n :~ppendix at end of chapter)

A2. Smoking and chronic obstructive pulmonary disease
    symptoms-percent prevalence. _ _ _ , . _ . . . . . . . _ _ .
A3. Smoking and ventilatory function . . . . . . . _ _. _ _ . . _
AJ. GIossary of terms used in tables and text on smoking
    and ventilatory function.. _ . _ _ _ . . . . . . . . . . . . . . . _
5. Cessation of smoking and human pulmonary function
AG. Epidemiological studies concerning the relationship
   of air pollution, social class, and smoking to chronic
   obstructive bronchopulmonary disease (COPD) . .
A7. Epidemiological studies concerning the relationship
   of occupational exposure and smoking to chronic
    obstructive bronchopulmonary disease. . . _ . . . _ . .
8. Studies concerning the relation of human pulmonary
   histology and smoking . . . . . . . . . . . . . . . . . . . . . . .
9. Experiments concerning the effect of the inhalation of
   cigarette smoke upon the tt,acheob~.o2lc)lial tree and
   pulmonary parenchymn of animals . . . . . . . _ _ . . . . .
AlO. Experiments concerning the effect of the chronic in-
   halation of I\`O? upon the trncheobronchial tree and
   pulmonary parench>-ma of animals _ . _ . . :. . . . . . .
11. Experiments concerning the acute effect of cigarette
   smoke inhalation on hutnnn pulmonary function. .
12. Experiments concerning the effect of cigarette smoke
   on human and animal pulmonary clearance. . . . . . .
A13. Experiments concerning the effect of cigarette smoke
   or its constituents upon ciliary function . . . . . . . . .
Al4. Experiments concerning the effect of cigarette smoke
   on pulmonary surfactant and surface tension . . .
ATS. Studies concerning the relationship of smoking to in-
   fectious respiratory disease in humans . . . . . . . . . .
A16. Complications developing in the postoperative period
  in patients undergoing abdominal operations - .-. .
A17. Arterial oxygen saturation before and after operation

Paw


221
232


241
175

242

244


181

185

246

192


196


247


251


252


256
256


ISTI?ODLCTIOS

Chronic obstructive bronchopulmonary disease (COPD) is char-
acterized by chronic obstruction to airflow within the lungs. The
term COPD refers to three common I-espiratory ailments: namely,
chronic bronchitis, pulmonary emphysema, and reversible obstruc-
tive lung disease (bronchial asthma) .*

Chronic bronchitis has been defined as the chronic or recurrent
excessive mucus secretion of the bronchial tree. It is characterized
by cough with the production of sputum on most days for at least
three months in the year during at least two consecutive years
(217).

Pulmonary emphysema is that anatomically defined condition of
the iung characterized by an abnormal, permanent increase in the
size of the distal air spaces (beyond the terminal bronchiole) ac-
companied by destructive changes (217).

Patients can suffer from both of these conditions simultaneously.
The symptoms as well as the abnormalities in pulmonary function
observed in the presence of the t1v-o ailments may be quite similar.
Patients with chronic bronchitis suffer from productive cough with
or without dyspnea (breathlessness both at rest or on exertion)
while pulmonary emphysema is characterized mainly by dyspnea.
COPD comprises a spectrum of clinical manifestations; thus, it is
frequently diffleult to determine nhether a particular patient is
suffering from one of the two specified diseases alone or which one
predominates when both are thought to be present.

COPD is responsible for significant mortality in the United
States. In 1967, a total of 21,507 men and 3,885 women were re-
corded as dying from chronic bronchitis and emphysema (221).
This figure does not include a sizable number of individuals fol
whom COPD was a contributory cause of death.

During the past two decades, a major increase has taken place
in the mortality from COPD in the United States. In 1949, the
death rate from COPD was 2.1 per lOp,OOO resident population,
Tvhile in 1960 it was 6.0 (zz?), and in 1967, 12.9 (2'1). Although

165


much of this rise is probably due to changes in certification and
recording methods as well as to an increased interest on the part
of the medical community, an appreciable proportion is also gen-
erally accepted as reflecting a real increase in disease. Similar in-
creases over the past 20 to SO years have also been observed in
Canada (7) and in Israel (3L). The lack of a similar increase in
Great Britain, a country with an extremely high rate of COPD,
may be the result of a number of factors including improved
therapy and decreased air pollution. Moreover, it is also likely that
the diagnosis of COPD has been made more commonly and ac-
curately in Great Britain for a longer time than in the United
States, or elsewhere. Furthermore, the British definitions of bron-
chitis and emphysema have differed in the past from those used in
the United States.

The mortality from and prevalence of COPD is probably under-
estimated. In a study of death certificates, Rloriyama, et al. (170)
reported that COPD is often omitted as a contributing cause of
death. In a study of more than 350 autopsies, hlitchell, et al. (169)
noted that the disease often goes unreported and that emphysema
was occasionally found unassociated with severe cIinica1 airway
obstruction. Hepper, et al. (110) observed that ventilatory test re-
sults were abnormal in 10 percent of 714 patients in whom no
symptoms, signs, or past history of pulmonary disease were noted.
They concluded that severe degrees of ventilatory impairment may
be undetected by history and physical examination alone. Boushy,
et al. (40) evaluated clinical symptoms, physiologic measurements
of airway obstruction, and morphologic bronchial and parenchymal
changes in 90 males with bronchogenic carcinoma. The authors
found that when either clinical, physiologic, or pathologic evidence
of COPD was used alone, one-third to one-fourth of the patients
were considered normal, but when all three criteria were used to-
gether, only one patient was free of COPD. The importance of
COPD as a contributing cause of mortality is now beginning to be
more fully recognized.

Clinicians have long observed that the `majority of their patients
suffering from COPD were cigarette smokers (1, 150). Epidemio-
logical studies have validated this impression by indicating that
cigarette smokers are at a much greater risk of developing or dying
from this disease and that the risk increases with increased dosage
of cigarette smoke, reaching in the smoker of two packs or more a
day a level as high as 18 times that of the nonsmokers (132). The
salutary effect of giving up smoking has also been borne out by
clinical observation and epidemiological studies.

In a number of studies, smokers were found to suffer more fre-
quently than nonsmokers from pulmonary symptoms including

166


cough, cough with production of phlegm, and dyspnea. By a variety
of PUhIIOnar?- function tests, .cmokers were sho\\-Il to ltave dimin-
ished function as compared to nonsmokers :ind also to have 3
steeper slope of the espected decline of function lvith age. Tests of
ventilation./perfusion relationships in the lung have revealed ab-
normal function in smokers. Autopsy studies have indicated that
smokers dying of causes other than COPD have significnntl3~ more
changes characteristic of emphysema than nonsmokers.
Several recent studies have validated the clinical impression that
among patients who undergo surgery, cigarette smokers run a
greater risk of developing complications in the post-operative
period than nonsmokers.

Abundant experimental evidence of the role of smoking in
bronchopulmonary disease has been obtained from experiments
employing animals and tissue and cell cultures. Recent work has
demonstrated, in dogs trained to inhale cigarette smoke through a
tracheostoma, that emphysema, pulmonary fibrosis, and other path-
ologic changes in the pulmonary parenchyma and bronchi develop
and that these changes are proportional to the total dosage of cig-
arette smoke inhaled. In vice and in vitro studies have sho\vn that
whole cigarette smoke, or certain fractions thereof, inhibit ciliar)
activity of the bronchial epithelium, adversely affect the mucous
sheath, and inhibit the phagocytic activity of the pulmonary
alveolar macrophage. These abnormalities lead to retarded clear-
ance of inhaled foreign matter including infectious agents from
the lungs, thus predisposing the individual to respiratory infec-
tions. Evidence also exists that pulmonary surfactant may be ad-
versely affected by cigarette smoke.

The convergence of these lines of evidence, which will be de-
scribed in more detail in the body of this chapter, leads to the
judgment that cigarette smoking is the most important Cause of
COPD in man.

EPIDE31IOLOGICXL STUDIES

    COPD MORTALITY

Numerous epidemiological studies, based on a variety of pop-
ulations and carried on in a number of countries, have investi-
gated the association between cigarette smoking and COPD. They
have shown a greatly increased mortality and morbidity from
COPD among smokers as compared to nonsmokers. Results from
the major prospective studies relating smoking and CQPD mortal-
ity are presented in table 1. The majority of the studies separate

167


           TA~LD l.-Chronic obstructive broncltopulmonary disease mortality ratios
                          (Actual number of deaths shown in pnrcntbewa)'
                                  SM = Smukcrs.    NS = Nonsmokers

                                      PKOSFECTIVE STUDlF;S

Author.
yc.r.    Number and     Date     Follow.up    Number      CiRnrcttcs/dry        Cbr0tlk
countly.     type of      collection     Yeal.8     of deaths      PlucJ. cignn        bmnchitir        Empbyaema       Other
rdcrence   po9ulntion
Hammond 187.783 white Queatiannaire     31/j          33s     Ciporcltrr
bnd      maim in 3    and follow-up        ShI ., ,308  NS ,. .I. .l.OO (30)
Horn.    e.te.te3 50-69   of death            NS ., ,, 30  <lo .,I . ..I.67 (10)
lII.58.     ye*r3 01 sgr.   certificate.
U.S.A.                                      lo-20 ..,, .3.00 (671

(105).                                      >?O . . . . -3.64 (40)
                                          Ail ,.. . .2.151231)
                                              Pipw
                                           h's  ., .I.00 (90)
                                           sn  ...I..1.77 (23)
                                            Cigar,
                                           NS  ,., . ..I.00 (30)
                                           Shl  . ..I 1.23 08)

Doll and   Approximately Qucationnnire    10                                                          ___..-..
                                       292
Hill                                                         Ciporctfca
        41.000 male                                                                       Ciiinrt.llvY
                and follow-up           Chronir
1964                                                     NS  , .I.00                    N .s
        Llritish                                                                           . . . ..I.00
                  of death             bronchilit                 l-14  .6.80
Great                                                                           1 I4 . . ..O.GS
        phssicians.    certificate.                111
Drilnin                                                    15-24 ,12.80                    15-24 ,l.OH
                                    Other                  >zs  .21.20                    >ZG .ucn
(70).                                    181                All . . ...11.60                    All  . . . ..U.til
                                                       I'ilwr art11                      I'ijt,,a ct PIII
                                                           Cif7orr                        (`i!,o ra
                                                         sat  .3.00                    S>I  ,....UiH
                                          --.---__----              _-_- --..


Author.
)`cnr,  Nu,m$;nd     DlIln     Follow-up    NUttlbCt      Cip.nrrttcs/doy        Chronic
country,              eollcction     YPtlTS     of denths      pipes, cignrs        bronchitis        Emphysema       Other
rdcrcnee   909ulntion

                                     PROSPECTIVE STUDIES

net.    Approximntelr Qucstionnairc     6
IOGG.     78,000 mole   nncl follow-up
Conndn   Cnnndian     of dcnth
(JO).     vctcrnns.     certificate.

Hammond. 440.568 males  IntPrriews by     4
IIGG.     5li?.GiI      ACS volun-
U.S.A.    icmnlcs      twrs.
(103).    35-M years
        of ape in
        25 3taLes.

124                   Cionrcttea
                NS  , ,I.00
                <IO  . . . ..7.02(17)
                 IO-20 ., .13.65(49)
                >20 . . ..I4.G3fIZ)
                 Al,  11.42(781
                     Pill0

Shl ,, ,. .2.11 (5)
    CipClr8
Shl  3.57 (1)

   Ciporcltra
NS ,..... 1.00
<IO  . . . ...481 (91
10-20  . . . ..6.1?(21)
>?O  .G.03 (7)
All .5,Y5(3?1
     Pijlc.4
Shl  ,,..,.. 0.75 (2)
     C10flta
Shl .,...,, 3.33 (1)

      380                                   nloicr
Sbl . . . ...369                              NS  ., .l.OO (20)
NS  . . . . ..?a                              SM (nge
                                      45-60  , .6.65(114)
                                    S!l! (age
                                     65-79) .11.41(175)

     Kuhn.    U.S. male    Questionnaire     S?l,     Hronciiitis   NS
       1966.                                           . . . ..I.oo (31)    Cunc7lt cign-       Currmt cigo.
              veterans     snd              Shl 64
       U.S.A.                                    AIlShI . ..6.49(348)
             2,265.674                                            rtttcr odv        rcltea ml/v
                     fOUOW-Up           NS . ..I3  Current ciga.
       (1J:l.                                                 NS .,..,. l.OO(l3)   NS 1.00 (18)
              person years.   of death            Emphvacmo    rette .10.08 (229)  1-O  . . . . . 3.63 (5)   l-9  ,.,.,.. 5.33 (10)
                       certificate.          ShI  . . . ...284      Pipe8       IO-20  .4.61(22)   10-20 .14.04 (93)
                             NS .,...., 18 Shl ~.2.36 (9) 21-39 .,,. 4.5i(12)   21-39 . ,. .17.04 (62)
                                                 Cipora      >a9  . . ...8.31 (4)   >39 ,. .26.34 (171
                                        Shl . ...,. 0.70 (6) All .I.... 4.49(43)   Ail ..:...14.17(186)
w
m


r,
0

Wickcn.   1,189 moles.   Personal inter-         1,188 obtoincd
1066.               view with            rctrosncc.
North-             relntives of           tiveiy.
err1               individuals          Shl .1,064
lrelsnd             listed on           NS  . . . ..I24
(227).              death
                register.

`Unless otherwise specified, disparities between the total number of deaths
and the mourn of the individual smoking cntcgoriea are due to the exclusion

         Ciyarcltcs
            odu
       NS ,...., LOO(124)
       I-10  ,,, .2.95(245)
       II-??  . . ..3.43(300)
       >?3  . . . ..4.44(168)
           hlirrd
       Shl . . . ..I.55 (62)
        I'ipca or ciynrr
       Shl ., . . .1.84(ZB9)                       -
of either occasional, miscellnnwus. mixed, or ex.smokcrs.
2 NS includus aijic and cigur smokwr: SXl includes rx-rmokcra.


the findings for chronic bronchitis and emphysema. Such specific
VJUPing Of the mortality data should be viejved with some reser-
vations in the light of the difhculties mentioned above in dis-
tinguishing the two diseases clinically.
The dose relationship of increased mortality ratios with increased
Consumption of cigarettes is indicated by the results of all the
studies which present rates for different Ievels of smoking. Kahn
(13-3), for instance, noted that those smoking only 1 to 9 cigarettes
per day incurred an emphysema mortality ratio of 5.33 while those
smoking over 39 per day incurred one of 25.34. Pipe and cigar
smokers were found in some studies to have slightly elevated mor-
tality ratios in comparison with nonsmokers although other studies
did not show this. The risk of dying from COPD among cigar and
pipe smokers appears to be much less than that incurred by
cigarette smokers but may be somewhat greater than that among
nonsmokers (table 1) .

The effect of stopping smoking on COPD mortality is reflected in
the results of Doll and Hill (70, 71) in their study of British physi-
cians. They found that during the years immediately following
cessation of smoking, mortality ratios remained elevated and did
not begin to decline below the level of continuing smokers until
nearly a decade later. This delay in response is probably due to two
factors: the presence in the ex-smokers' group of many who quit
for reasons of ill health and the long-term effects of cigarette
smoke on the respiratory tree, some of which are irreversible.
Kahn (131') also noted that the age-specific mortality ratios for
es-smokers were lower than those for continuing smokers of cor-
responding amounts of cigarettes.

A better estimate of the potential effect of stopping smoking on
COPD mortality can be gained by studying the death rates in a
population in which a high proportion of smokers have stopped
smoking to protect their health rather than as a response to ill
health. Among doctors age 35-64 in England and Wales, many of
whom have stopped smoking cigarettes, there was a 24 Percent-
reduction in bronchitis mortality between 1953-57 and 1961-65,
as compared with a reduction of only 4 percent in all men of the
same age in England and Wales, among whom there was no reduc-
tion of cigarette smoking. (84).

COPD MORBIDITY

Many investigators have studied the prevalence of bronchopul-
monary symptoms (including those of chronic nonspecific respira-
tory disease) among smokers and nonsmokers. These studies are
outlined in table AZ. Their results indicate that the cigarette

171


smoker is much more likely to suffer from respiratory symptoms
such as cough, sputum production, and dyspnea than is the non-
smoker. Such symptoms, particularly cough and sputum produc-
tion, increase with increasing dosage of cigarette smoke. Table A2
also sholvs that pipe and cigar smokers experience COPD symptoms
more frequently than nonsmokers although not to the degree found
in cigarette smokers. These morbidity findings are similar to the
mortality findings presented above.

Similarly, cessation of cigarette smoking has been shown to be
associated with a decrease in symptom prevalence. Nitchell, et al.
(168) studied 60 patients who succeeded in stopping smoking and
84 continuing smokers. Among the ex-smokers, more than 70 per-
cent reported improvement in their cough while less than 3 percent
of the continuing smokers did so. Wynder, et al. (2.37) followed
224 ex-smokers of cigarettes and noted that 77 percent reported
cessation of persistent cough and an additional 17 percent reported
definite improvement. Hammond (102) reported similar results
concerning cough and shortness of breath in a study of a large
group of ex-smokers.

VENTILATOKY FUXCTION

Another type of quantification of the effects of smoking on the
bronchopulmonary system has been obtained by those groups of
investigators who have studied pulmonary function in various
gIWUpS. Results are presented in table A3, and a glossary of the
terms used in the various tests is presented in table A4. The pa-
rameters investigated have included maximal breathing capacity
(maximal voluntary ventilation), expiratory flow rates, forced
expiratory volume, and vital capacity. Although certain of these
parameters appear to be more sensitive measures of pulmonary
dysfunction than others, the overwhelming majority of these stud-
ies have shown diminished function among smokers. An increase in
the expected age-diminution rate in smokers has been observed in
those studies which employed either repeated examinations or
examinations at many different age levels. Higgins, et al. (117)
conducted a nine-year follow-up examination of 385 male residents
of a British industrial town who were age 55-64 at the beginning
of the study. Among the survivors who were tested initially and
nine years later, the average decline in FEV,.;, was smallest in non-
smokers, slightly greater in ex-smokers, and greatest in smokers.
As with COPD mortality and symptom prevalence, the impairment
of pulmonary function shows a dose-reIationship with increasing
amounts of cigarettes smoked.


The data contained in table XX provide two di;?erent kinds of
information. The majority of the studies \vere conducted on un-
selected populations, which probably include a number of individ-
uals with clinically manifest COPD. Therefore, these studies re-
flect the prevalence of COPD-related dysfunction (as determined
by pulmonary function tests) in relation to smoking. However,
some studies of younger individuals have revealed that pulmonary
function tests are abnormal in clinically asymptomatic smokers.

Krumholz, et al. (140) and Rankin, et al. (189) have sho\vnthat
pulmonary diffusing capacity is impaired in young asymptomatic
smokers when compared with age-matched nonsmokers. Similar
impairment in other pulmonary function tests was noted by Peters
and Ferris (182, 183) in an asymptomatic college-age group and
by Zwi, et al. (241) and Krumholz. et al. (lS0, 142) in groups of
young asymptomatic physicians and medical students.

Several investigators have employed tests which measure the
relationship of ventilation and perfusion (V/Q relationships) in
the various pulmonary segments. These tests are predicated on
observations that some segments of the lung may he relatively
under or overperfused and that, likewise, segments may be under
or over-ventilated. Anthonisen, et al. (IO) investigated pulmonary
function in 10 male smokers with clinically mild chronic bronchitis,
all of whom had smoked cigarettes for at least 30 years. Regional
pulmonary function was studied using radioactive xenon. Despite
the fact that overall pulmonary function was nearly normal in sev-
eral patients, all had depressed V/Q ratios in some lung regions
with the basal areas being those most commonly affected. The au-
thors suggested that significant disease in the peripheral airways
may exist in patients whose chronic bronchitis is clinically mild
and who show no present impairment of ventilatory capacity. The
radioactive xenon test may reveal severe compromise of local gas
exchange when usual studies of ventilatory capacity do not reveal
any impairment. Similar results concerning peripheral airway ob
struction in bronchitic patients with normal, or only minimally in-
creased pulmonary resistance, have been observed by Woolcock,
et al. (234). These authors also noted that their patients demon-
strated frequency-dependent compliance lvhich was unaffected by
the administration of bronchodilator aerosols.

Strieder, et al. (214) have recently investigated the mechanism
of postural hypoxemia in 2.1 asymptomatic smokers and non- .
smokers. They found that standard ventilatory tests and lung vol.-
umes were normal in both the smoking and nonsmoking groups.
However, the arterial ~0' measured in the supine position was
significantly lower among the smokers and alveolar-arterial oxygen
gradients, while breathing room air, were larger in smokers than in

173


nonsmokers (more so in the supine than in the erect position) _ The
increase in alveolar-arterial 0: gradients I\-as rrenter for heaq
than for light smokers. The authors concluded that mnltlistribution
of ventilation and perfusion accounted for the observed hyposemin.
They also felt that this mild diffu5.e air\\-a>- disease among asympto-
matic smokers is physiologically significant mainly because of in-
volvement of small bronchi, as expressed by maldistribution unac-
companied by gross airway obstruction. X similar ventilatory
distribution abnormality among smokers has also been observed
by Ross, et al. (198) with the mere severe alterations found in the
long-term smokers.

Although of concern in the consideration of COPD, such dis-
turbances of the V/Q relationship may also have adverse effects
upon cardiac function depending upon the level of hppoxemia (213).
The discussion in the section on Coronary Heart Disease noted that
carbon monoxide has adverse effects on both oxygen transport and
alveolar-arterial exchange as well as on osygtn debt developed with
exercise (50). Further research is needed on the joint effect of these
pulmonary and carbon monoxide induced h>-poxemic influences.

A number of other studies have provided further evidence con-
cerning the adverse effect of smoking on ventilatory function.
Table 5 presents those experiments which deal with the effect of
cessation of smoking on pulmonary function. Among the param-
eters which have been noted to improve after stopping smoking
are: diffusing capacity, compliance, resistance, maximal breathing
capacity, and forced expiratory volumes. These parameters shelved
improvement within 3 to -1 weeks after cessation of smoking.

GENETIC FACTORS

Recent interest has been shown in the possible contribution of
genetic factors to the pathogtnesis of COPD. Earlier studies (127.
147) had noted the existence of kindreds with high incidenres of
chronic bronchitis, emphysema, or both diseases. In addition to the
presence of genetic susceptibility, Larson, et al. (1:7) also observed
that all but one of the 11 symptomatic individuals in their two
kindreds were smokers. They postulated that the susceptibility of
some smokers to develop emphysema may be, at least partially,
genetically detemined.

More recently, Larson, et al. (1;8) studied 156 relatives of COPD
patients and 86 control individuals. The subjects underwent pul-
monary function testing, including forced espiratory volume and
residual volume./total lung capacity measurements. The authors
observed that pulmonary function abnormalities were most prev-
alent among the relatives who smoked and least prevalent among

174


Krumhulz    10 physicians         F&lowing J wecka abslincnce     FoUowinp c weeks obalincxcc (6 tubjocts mily)t ! All subjcets were >E Dock
eL al.,      25-33 ycara      Lung volumes--no significant ehnnae.   Lung volumes:                     per ycnr smokcra
1965.      or hKC.         Pcnk e&pirntory flow rntl-incrensc     Insplrntury rcscrvc volumcinerease (p<O.O6).
U.S.A.                   (I~<O.Ol),                  Functiorlul rcsidlini CnDncity-incrcnse (p<O.O6).
(141).                                         Xll~xirnnlbrcnt)~inn rupncitu-incrclrse (p<O.OZ).
                     Meon dillusing CaDacity:          hlc,nn dlllusing cngor~ty-nochunw.
                      ncslinK-incrcn.w (p<O.32)
                       Exercise-no change.
                     Compliance-increased in Gi8 tcsted.   tim~lisncccon~inued to show inercluc.                      -
Wilhelmacn,  16 smokers.        Value prior to ccesation           V&c after ccswtion      Siyniliconcc      hlcon durntion of the non
1961,       (43.7 menn      Vital capacity . .4.60              4.67          Not significant.      smoking prriti WOB 40
U.S.A.     sw).          FEV    . ...,, .3.33
          FE":*;,,v,                       3.52          D<o.o6.          days.
(030).                          ,, . ..76.0              iC.8          Not sirnificnnt.
                  I'EFIi  . .C.97              1.45          Nut sipnlficnnt.
                    MEFR 50%  ..,.,.... .3.81               3.93          Nut 3ignificnnt.
                    hlEFR 25p:a  . . . . . .I.31               1.50          ,`<O.OB.
                      Inrpirntorr resistance .2.07               1.43          P<O.v25.
                     Expiratorv rnistnnce .2.80               2.04         p<O.O?.
                      Complinnce  ~, No chnnge

Peterson
et al.,
1968.
U.S.A.
(JSL).

12 smokers
studied nt
various
intervnls and
compared with
12 continuing
smokers.


the nonsmoking controls. So relationship of this increased preya-
lence could be demonstrated to ;LIr)hfl,-antitr?-psin defcienc>- (.we
below). In addition, nonsmoking reIati\.es and -;nroking controls
were observed to sho\v approsimntely the same pre\.:llence of :tb-
normalities. However. due to the large proportion of females in the
nonsmoking relative group and to the clustering of tuo-thirds of
the affected relatives in 10 families, firm conclusions cannot nt
present be dralvn from this study concerning the relative contribu-
tions of smoking and of heredity to the pathogenesis of COPD.
In order to determine the relative significance of smoking and
heredity in the pathogenesis of COPD, Cederlof, et al. (;;s, ;c) have
used the twin-study methods on registries in both Sweden and the
USA. The specific details of this method are described in the sec-
tion on Coronary Heart Disease. As may be noted from a summary
of their work at the end of table A 2, the authors compared the
symptom prevalence among monozygotic and dizygotic twins who
were both discordant and concordant for smoking habits. The\
observed that the h~~permorbidit~ for COPD symptoms related to
smoking persisted even after controlling for zygosity and concluded
that a causal relationship of smoking and COPD symptoms iv-as sup-
ported. HoLvever, genetic factors were still found to have an appre-
ciable influence. Lundmann (1.59) has applied this method to the
study of pulmonary function. He studied 37 monozygotic and 62
dizygotic tlvin pairs, measuring forced expiratory voiumes and
nitrogen washout gradients, and matched the various pairs for
smoking discordancy. He observed that both of these parameters
were adverseI>. affected in txvins ivho smoked and that these changes
were correlated \vith cigarette consumption. The results are out-
lined at the end of table X3.

AZr,I~a-,-a,~ti~~.~~sin (X,XT) -Of more recent note and discus-
sion has been the discovery of an association between a hereditary
predisposition to COPD and the relative or absolute absence of
alpha,-antitrypsin, a serum glycoprotein enzyme. Eriksson (78)
was the first investigator to observe a relationship between the
presence of markedly decreased serum trypsin inhibitory capacity
and panlobular emph!-sema. Since Eriksson's paper, much added
research has been published concerning many facets of this intrigu-
ing area.

It appears that X,-XT deficiency is inherited as an autosomal
recessive trait (~8, 2IG) although Kueppers (IL') considers the
transmission to be by an autosomal codominant allele. It hlis been
estimated that up to 5 percent of the general population may be
heterozygous for this gene (1.51) although full cross-sectional
studies of the population remain to be done.
Homozygous or severe deficiency of this enzyme has been asso-

176


ciated with a particular type of pulmonary emphysema. \Vhile the
majority of lungs of cmphysematous patients reveal ~UIIOLIS or
centrilobular deformities, particularly of the upper lobes, this
hereditary disorder reveals a panncinar change, most severe in the
lower lobes (101, 215. 226). Patients with emphysema who are
found to have the homozygous deficiency have been observed to
include a greater percentage of female patients than is usually ob-
served in the general emphy-sema population. Their disease begins
earlier, is more severe, is characterized by dyspnea rather than
cough, and frequently is unassociated with a history of preceding
bronchitis (101 , "~5, ~6) _ Radiographic studies of A,AT-deficient
patients have revealed decreased vascularization of the lower lobes
and increased vascularization of the upper lobes (101, 21.1). It is
estimated that between 1 and 2 percent of patients with COPD have
this homozygous deficiency (78 , 216). In family studies, it has been
found that almost all the homozygous individuals are symptomatic
by the age of -10 and that those ivho are not usually show alterations
in pulmonary function studies. Guenter, et al. (38) studied 7 per-
sons with homozygous deficiency. Of the five symptomatic individ-
uals, .I smoked and all had abnormal timed vital capacity. Neither
of the two asymptomatic individuals smoked or had this change in
vital capacity. All 7, however, were noted to be hypoxemic at rest
and to have decreased pulmonary diffusing capacity.
It has been suggested (I.?;) that the lack of this proteinase in-
hibitor in the serum of homozygous patients predisposes them t.o
emphysema in the following manner: Leukocytes present in the
blood contain significant amounts of proteinase enzymes as part of
the overall defense mechanism against infection ; the breakdown of
these cells during acute infection releases proteinases into the pul-
monary tissues and these, \vithout the presence of a normal inhib-
itor, may contribute to the breakdown of the structural proteins of
lung tissue.

Heterozygous individuals have been defined as those who show
levels of X,AT intermediate between those of normals and those
with homozygous deficiency. At the present time, there is much
debate about whether or not heterozygotes for A,AT are at a
greater risk of developing COPD than are A,AT normals. A major
dificultv is the lack of a precise definition of heterozygosity. At
Present, the best method for the determination of the level of A,AT
appears to be that of crossed serum immunoelectrophoresis he-
cause levels of trypsin inhibitory capacity (TIC) have been shown
to rise acutely with infections.

Welch, et al. (26) feel that heterozygotes do not show an in-
creased susceptibility to COPD. The heterozygotes tvhich they
studied showed symptoms of bronchitis and did not present the

177


lolver lobe perfusion defects frequentI>- noted in homozygotes. The>-
also fo~~nd no difference in the number of COPD patients among the
heterozygotic and the gtner:\l population. Other inve~iiigators, no-
tably Lieberman, et al. (I.,;, I.;.;), Rueppers, et al. ( IAL), and
L;irson, et al. (I.;$) found significantly increased percentaF;es of
COPD patients among those lvith heterozpgous deficiency as com-
pared with the general population. Lieberman, et al. (~55) ob-
served that the percentage of heterozygdtes among a group of
healthy industrial xvorkers was 1.7 percent while that among a
group of patients with emphysema was 18.1 percent. In a recent
re\,iew, Falk and Briscoe (79) considered that the available evi-
dence points to an increased prevalence of COPD among hetero-
zygotes.

Of more central interest to this discussion, however, is the pos-
sible relationship of smoking to the predisposition of disease among
the heterozygote population. Kueppers, et al. (IL-$) studied three
populations: younger controls, older controls, and a group of
COPD patients. They observed that of the 25 heterozygotes with
COPD, only 2 \vere over 70 years of age, both were female and non-
smokers. The remaining 23 were cigarette smokers. Nevertheless,
studies which adequately sort out the factors of genetic susceptibil-
ity and cigarette smoke exposure have yet to be reported.

An important question is to \vh.at extent the relationship between
smoking and COPD is influenced by identifiable genetic factors. At
present, it is possible to identify what appears to be only a very
small group of susceptibles for whom genetic factors may be para-
mount in the pathogenesis of their ailment. Of greater public health
import is whether lesser degrees of genetically identifiable suscep-
tibility interact with cigarette smoking m account for a significant
proportion of the problem.

AIR POLLUTION

Numerous epidemiological studies have been conducted in order
to examine the effect of air pollution on human nonneoplastic res-
piratory disease. Three major types of studies have been utilized :
observation of the mortality and morbidity due to an acute episode
of increased air pollution, observation of the day-to-day variation
in mortality and its relation to air pollution levels, and geographical
comparisons- The majority of studies fall into the third category,
and these are detailed in table A&

A number of studies did not show an association among air pol-
lution, respiratory symptoms, and pulmonary dysfunction (81,205).
More recent studies which evaluated the factors of smoking, social
class, and air pollution separately noted a greater prevalence of

178


COPD symptoms, pulmonary ds,sfunction, and COPD mortality
in areas of high pollution (21, 122, l;li, 2,;s). Lambert and Reid
(146) observed that in the absence of cigarette smoking the corre-
lation bet\\-een COPD symptoms and air pollution was slight and
suggested that the two factors may interact to produce higher rates
of disease.

The evidence which has accumulated in the past 7 years gives
further support to the conclusion of the Surgeon General's Ad-
visory Committee on Smoking and Wealth as stated in its 1964 Re-
port that: "For the bulk of the population of the United States, the
relative importance of cigarette smoking as a cause of chronic
bronchopulmonary disease is much greater than atmospheric pol-
lution or occupational exposures."

Exposure to various dusty occupational environments has been
shown in many studies to be associated with the development of
various forms of nonneopiastic lung disease. Lowe (158)) in a re-
view of the relationship of occupational exposure and chronic
bronchitis, noted that among workers exposed to dust significant
increases in COPD mortality were observed. These occupations
included coal mining, tinning, galvanizing, riveting, and caulking.
Commenting on a previously unreported study of more than 20,000
steel Jvorkers, he observed that the relationship betrveen mean dust
exposure levels and COPD prevalence was much stronger among
smokers than among nonsmokers.

Alore recently, Bouhuys and Peters (37) reviewed those specific
industrial exposures related to lung disease. COPD was found to be
associated with exposure to coal dust, asbestos, bagasse dust, iso-
cyanates, various irritant gases, and textile dusts (cotton, flax, or
hemp).

Studies which have investigated the interrelationship between
smoking, industrial exposure, and COPD are listed in table A?. Act;
ditional compounds, not listed in the table, but which also appear to
be related to COPD, are chlorine ($9) and washing powder dust
(!?7), Cigarette smoking and harmful dust exposures appear to act
in a combined manner in the production of COPD.

Although an increased prevalence of COPD is found with cer-
tain occupational exposures, in none is the relationship as strong
as that between COPD and cigarette smoking. To demonstrate an
increased occupational risk, careful analysis of smoking habits is
required. The relative importance of cigarette smoking appears to
be much greater than occupational exposure as an etioIogic factor
in COPD.

179


Cad,,zilc,)r-CC:hl.onic industrial esposure to cadmium in man has
been found to induce pulmonary emphysema without significant
accompanying chronic bronchitis (32, 35, 210)

Nandi, et al. (177) recently investigated the contribution of the
cadmium in cigarette smoke to the pathogenesis of emphysema.
Analyzing \I-hole cigarettes, ash. and filters, the>- found that an
average of 69 percent of the cadmium present in the cigarette (ap-
proximately 16 microgram5 20 cigarettes) is inhaled in the smoke.
In a related study (2.53). these investigators showed that the level
of cadmium in water-soluble liver protein on autopsy was three
times greater in those patients with a history of chronic bronchitis;
emphysema than that found in those without such a history. Un-
fortunately, no smoking histories were available.

PXTHOI~OGIC~I~ STUDIES

The relationship betn-een smoking habits and pathological
changes in the bronchial tree and pulmonary parenchpma has been
investigated by se\-era1 groups of lvorkers. Xetaplastic changes,
although found in nonsmokers, are much more common in smokers
(table 10, Cancer Chapter), and a dose-relationship of increasing
metaplasia with increased smoking has been evident in many of the
studies.

Pathological studies which deal primarily with pulmonary
parenchgmal and non-metaplastic bronchial changes are presented
in table 8. Goblet cell distention, alveolar septal rupture, thickened
bronchial epithelium, and mucous gland hypertrophy have been
found to be more frequent in smokers than in nonsmokers. Auer-
bath, et al. (17) noted a dose-response relationship between the
amount of smoking and the degree of septal rupture.

Anderson, et al. (;, 5) studied the difference in the type of
emphysema shown by smokers and nonsmokers. In their study,
listed in table 8, they noted that the group of patients with panlobu-
lar emphysema was comprised of equal numbers of smokers and
nonsmokers while of patients with centrilohular emphysema, 98
percent \vere smokers. Xore recently, the same authors studied
lung macrosections from 80 nonsmokers. While most were normal,
24 demonstrated parenchymal dilatation and disruption consistent
with panlobular emphysema. Thurlbeck, et aL> (217) have also ob-
served that centrilobular emphysema rarely occurs in nonsmokers.

180



hlcgnhed   50 male patients                          Mucous eland hupcrlrophu
et II..     with chronic                                    Pcrcm&
1967.     bronchitis under-               NS  . . . . . . . . . . . ..~........  PO
Egypt                                                 (2/7)
        goinK bronchial                ShI  . ,. ,, .I., ., I  77   (33/431  (P<O.O2)
(163).    biupsy and
         IRVngL-.


(Actual number of dcnths shown in percnthcser)
  SM = Smokers.    NS = Nonsmokers

Author.
  YCBl.8
country,  Nutr$y;nd                             RLYUll3                                 Conimcnti
reference    populnlion

Auerbach   662 mnles au-                       Deproc 01 tmchcal and brachid arlct-iofw thickcniw
et al.     top&d at Esrt                               .( bv pcroccntq~e of amokcral
1968.     Orange VA                              0.044    as-0.D    1.0-11    1.6-1.9    r.o+
U.S.A.    Hospitnl.     Never smoked (122)  .,,.,I,.,........  46.1      31.3      13.3      1.3      
(IO.              <20 cignretto/dny (120)  , ~.  11.7      22.0      33.6      28.4      4.4
                 20-40 cigarettes/day (284)  . . . . ..~........  6.0      R.6      37.4      40.9      8.1
                >40 cigarcltn/day (66)  . .  1.3      1.4      31.6      45.3      20.6

' Numerourr experiments dttailing changes in bronchial epithelium ore dctoilcd tnbulnrly in the Cnnccr chapter.


ESPERI.\IESTXL STCDIES

Xsrsrx~ STUDIES

A number of investigators have studied the effect of the inhala-
tion of cigarette smoke on the macroscopic and microscopic str-uc-
ture of the tracheobronchial tree and Pulmonary parench>.ma of
animals. Studies dealing with metaplasia and cellular atypism of
the trachea and bronchi are listed in table Xl6 of the cancer chap-
ter. Studies more directly concerned with the pathology of COPD
are listed in table 9. They show that cigarette smoke exposure is
associated with changes similar to those found in humans vvith
COPD, i.e., bronchitis, parenchymai disruption, alveolar septal
rupture, alveolar space dilatation, and the loss of cilia and ciliated
celIs in the bronchial mucosa.

The investigations of Auerbach and his coworkers (15, 16, 88)
have demonstrated by the use of both light and electron microscopy
that dogs \vho inhale cigarette smoke through tracheostomas de-
velop progressively more severe lesions of the bronchi and paren-
chyma lvith increased exposure to cigarette smoke. In electron
microscopic studies of specimens taken from the lungs of dogs thus
exposed to cigarette smoke, the following changes were observed :
In 5 dogs sacrificed after only 44 days of smoking exposure, there
was a proliferation of goblet cells as well as a partial loss of cilia
in the lining cells, and in 5 dogs sacrificed after 120 days or more of
esposure, the num'ber of cell layers in the bronchial epithelium was
found to be twice that of the nonsmoking dogs. Goblet cells and
ciliated columnar cells were no longer present; instead, the surface
was lined with columnar and cuboidal cells with stubby projections
in place of cilia. 3Iitotic figures were frequently observed in the
basal cells. These findings may be relevant to carcinogenesis as
well as to the development of COPD.

In a long-term experiment, carried out by the same group, dogs
were exposed to varying doses of cigarette smoke. Details of the
experimental procedure have been outlined in the section on Pul-
monary Carcinogenesis. The animals were separated into non-
smoker, filter-tip cigarette, nonfilter-light, and nonfilter-heavy ex-
posure groups. The dogs were "smoked" for 87.5 days, or approxi-
mately 29 months. The animals which died during the experiment
and the animals sacrificed after day 875 \vere examined for Pul-
monar3' psrenchymal changes as well as for bronchial epithelial
alterations. As seen in figures 1 and 2, dose-related pathological
changes, including fibrosis and emphysema, were found in the lung
parenchyma of the exposed dogs. These changes were similar to
those seen in the lungs of humans with COPD.

184




IOO-            --__-


                                          91.7

a0 -

20 -

                               17.9
                              I.-
                    57

0        00
     GROUP N:      GROUP f:      GROUP L:     GROlJP H:
    NONSMOKING    FILTER-TIP     NO FILTER     NO FILTER
                         (% 25 many clpretter)
                            as Gro"D H

Several investigative groups have exposed rodents to various
ambient concentrations of nitrogen dioxide over prolonged periods
of time. This gas is found in cigarette smoke and in some indus-
trially polluted air. The results of these studies are outlined in
table A10. It is clear that chronic exposure to low levels of NO? is
capable of inducing lesions in the bronchial tree although the rela-
tionship between these changes, cigarette smoking, and the devel-
opment of COPD remains to be determined.
Rosenkrantz, et al. (196, 197) have recently undertaken experi-
ments dealing with pulmonary cellular metabolism. They exposed
Swiss albino mice to cigarette smoke or its vapor phase for varying
lengths of time. On autopsy, animals exposed to cigarette smoke
showed elevations in the levels of lung DNA, lactate, and glycogen
which the authors conclude reflect hyperplnsia and macrophage
infiltration. Similarly, a dose-related increase in lung hydroxypro-
line was observed. This was considered to be due to increased fi-
broblastic collagen synthesis.

187


GROUP N:
NONSMOKING

GROUP F:      GROUP L:     GROUP H:
FILTER-TIP      NO FILTER     NO FILTER
        (`A as many cigaretb)
            a* Group H

FIGURE Z.-Percent of lur:g sections with grade II or III emphysema.
SOURCES Hammond, et al. (104).

Aviado and coworkers have performed a series of experiments
on live animals and in heart-lung preparations to study the effect
of cigarette smoke on pulmonary physiology and structure (18, 19,
20,21, 22, 179, 180, 199, 200,201, 202). The authors observed that
cigarette smoke causes acute bronchoconstriction both by the re-
lease of histamine and the stimulation of parasympathetic nerve
pathways in the lung. Bronchial arterial injections of nicotine were
found to cause reactions similar t,o those observed after cigarette
smoke inhalation. The hronchoconstriction was usually followed by
bronchodilatation which the authors attributed to sympathetic
stimulation. As mentioned in the Chapter on Cardiovascular Dis-
eases, nicotine has been shown to induce the release of catechola-
mines.

Experiments by Aviado and coworkers as well as other authors
(66, 99) using guinea pigs showed that exposure to cigarette
smoke was associated with increased bronchopulmonary resistance
and decreased pulmonary compliance. The authors related these
changes to the bronchoconstriction of terminal ventilatory `units.

188


Similar experiments in dogs shelved that the increase in resistance
following either cigarette smoke exposure or intravenous nicotine
could be blocked by pretreatment ivith atropine. Xs a parasympa-
thetic blocker, atropine would decrease the acute bronchoconstric-
tive phase.

Nest recently, Xviado and his colleagues (00, 130) have at-
tempted to induce physiologic and anatomic changes similar to
those found in the lungs of patients with emphysema. They ex-
posed male rats to cigarette smoke, the introduction of the enzyme
papain, as we11 as to partial tracheal ligation. In 10 rats exposed
to cigarette smoke tlvice daily for 30 minutes over a period of 10
weeks, no changes in pulmonary compliance or resistance were
noted. Also, no abnormal histological changes were observed in the
group exposed only to cigarette smoke. However, animals who
underwent tracheal ligation as well as smoke exposure showed in-
creased numbers of enlarged air spaces and increased pulmonary
resistance when c\ompared with animals who underwent only
tracheal ligation.

STUDIES IN I-TUhIhNS

The acute effects of cigarette smoke inhalation on bronchopul-
monary function in man have been investigated by a number of
workers. The results of these studies are presented in table 11. The
majority of studies, particularly the more recent ones, found that
the inhalation of cigarette smoke is associated with an acute in-
crease in pulmonary resistance and a decrease in pulmonary com-
pliance. Chapman (&8) also observed decreases in pulmonary dif-
fusing capacity and arterial 0, tension. Chiang and Wang (51)
noted changes in nitrogen washout time and alveolar dilution fac-
tor, alterations which reflect impaired alveolar ventilation and gas
mixing.

James (131) examined the effect of prior smoking on the mul-
tiple breath nitrogen washout test in 41 pneumoconiotic miners and
5 normal young males. Prior smoking of a cigarette in the subject's
normal manner was found to adversely affect the indices of dis-
tribution in 20 percent of the miners and in all of the 5 normals
who smoked within one hour of testing. The author suggests that
smoking be prohibited prior to any series of pulmonary function
studies.

Anderson and 1ViIliams (9) studied the acute effect of cigarette
smoke inhalation upon the ventilation-perfusion (V/Q) measure-
ments in the lung in normals and in patients with COPD. Cigarette
smoking was observed to cause acute changes in the V/Q measure-
ments, and the COPD patients were found to be particularly liable
to these changes.

189


Finally, Robertson, et a1. (194) studied the effect of unfiltered
and filtered cigarette smoke and cigar smoke upon bronchial re-
activity in 19 of the most reactive persons in a group of 91 heavy
smokers. They observed that bronchial reactivity was significantly
reduced by increasing the retention efficiency of the filter and that
reactivity to inhaled cigar tobacco was no less than that to cigarette
smoke. They concluded that differences in inhalation account for
the difference in COPD prevalence observed between cigarette and
cigar smokers.

STUDIES CONCEKNING PULMONARY CLWRANCE

Owercdl Gkarance

The ability of the lqng to rid itself of inhaled particles that can-
not be easily exhaled is dependent upon a number of physiologic
mechanisms including ciliary activity, the mucous sheath, and the
pulmonary alveolar macrophage. Studies concerning the effect of
human cigarette smoking and the exposure of animals to cigarette
smoke on this clearance system are presented in tabIe A13. LaBelle,
et al. (145) and Bair and Dilley (23) observed no change in clear-
ance following the exposure of rats, rabbits, or dogs to cigarette
smoke. The latter authors noted, however, that normal clearance
rates obtained prior to smoking were too low to reflect any sig-
nificant change except complete cessation.

Albert, et al. (3) exposed donkeys to cigarette smoke via nasal
catheter and observed impairment of clearance times. Holma (185)
obtained similar results in rabbits.

In a related study, Albert, et al. (2) studied the bronchial ciear-
ante times of 9 nonsmokers and 14 cigarette smokers in a total pop-
ulation of 36 subjects. The rates of bronchial clearance were slower
on the average in the cigarette smokers when compared with the
nonsmokers, although a wide variation was present in each group.
In relation to their study mentioned above, they also noted that the
shape of the whole lung clearance curves seen in smokers (with
markedly prolonged 50 percent clearance times) was similar to that
developed in the donkey following acute exposures to suIfur dioxide
or cigarette smoke.

Numerous experiments have shown that cigarette smoke or cer-
tain constituents of cigarette smoke adversely affect and can even
bring about a cessation of ciliary activity in respiratory epithelium
in vivo and in vitro in cultures of ciliated microorganisms. The re-
sults of a number of these experiments are presented in table 12.

190


CiliarY acti\`it?: has been shown to be affected bp particulate matter
as me]] a.~ by the gas phase components of cigarette smoke. The re]-
ative importance of these tno large classes of components of smoke
in producing ciliastasis is presently a matter of some discussion.
Dalhamn and Rylander (63, 6J) consider the particulate phase to
be of greater importance while Battista and Kensler (~8, 29) con-
clude that gas phase components are more important in the induc-
tion of ciliastasis.
Studies investigating the effect of cigarette smoke on the
morphology of the tracheobronchial tree in animals have noted a
decrease or absence in the number of cilia in smoke-exposed ani-
mals. Recently, Kennedy and Elliot (1.31) studied the effect of the
direct exposure of cigarette sinoke upon the electron microscopic
structure of protozoan mitochondria. After 42 minutes of exposure
to mainstream smoke, they noted destruction of the internal mem-
brane structure of the mitochondria.
Thus, cigarette smoke has been shown to be tosic to ciliary func-
tion by pathological (including electron microscopic) and physio-
logical methods.

Phayocytosis
The effect of cigarette smoke upon pulmonary alveolar phago-
cytosis, one part of the clearance mechanism, has been studied by
several authors. Masin and hlasin (162) observed increased varia-
tion in the size of lipid inclusions in sputum macrophages obtained
from smokers as compared to those obtained from nonsmokers.
They attributed these differences to a combined effect of irritation
of the alveolar lining, increased turnover of alveolar cells, and in-
creased injury to the macrophages. Green and Carolin (96) noted
that cigarette smoke inhibited the ability of rabbit a]veo]ar macro-
phages to clear cultures of S. au?-eels. This effect was noticeably
reduced by filtration. Similarly, Yeager (239) exposed rabbit
alveolar macrophages which had been induced by M. botiis to cigar-
ette smoke and observed a dose-dependent decrease in protein syn-
thesis. This alteration occurred at smoke solution concentrations
that did not affect cell viability. The alteration was only partly rc-
versible and was due mainly to gas phase components. LMyrvik and
Evans (175) observed similar protein synthesis alterations in
macrophages exposed to NO,.
Roque and Pickren (19.5) obtained alveolar macrophages at
thoracotomy from 17 smokers and 4 nonsmokers. They found a
decrease in the activity of oxidoreductases and hydrolases in the
macrophages of smokers. The reduction in the enzymatic activit?
was directly proportional to the amount of stored fluorescent ma-
terial present in the macrophages. This material was thought to


                                         191


rcfcrrn-ci      pop;lallon            smoking

Blckerman   I. 66 mslc and       A. Pulmonary
and         26 Icmale           function.

Reaultd

Commentd

  Vi&d ctlmcib (VC)
I. lo/91 dccrcaae.

Maximal brcafhing capacity  9/91 patient8 showed
lo/e1 dccreaae.         VC LIICTPLWC due to

BBnzh,      paLlent        B. 3 cigarettes.        II. No aignlficant change.       No aign(flcnnt change.     ClebrlnCC of apcrc-
1954.        with chronic      C. 30 minutes.                                              liona. All mild cr
U.S.A.       nontubcrculous                                                             mdcratr enwkcra.
(11).        rCSpira\OV
          di3eam
          (avernge ego
          601.
       II. 20 male snd
          7 female
          normsl aub-
          jecta (average
          age20).

Elcb.      I. 31 patients with     A. Esophrgwl bslloon        Mc4.n uiru,ay rcriatawc     Mean airwov compliancs
ct al..        obxtrucllvc         twhnisuc to         1. Stntiatlcolly ai~nincant          No chsngc.
1917,        Pllllnlmnry         m~1p~s11rc Dulmonnry        InCrNL?IP.
U.S.A.       eml'hyncma.         com~~llnt~rc nnd       II. No chnnuc.                No change.
(76).    ll. 14 normul           rusiatnncc.        III. No chsngr.                No change.
           subjwtd.        8. 1 cigarrttc.
       III. 6 patients with      C. Undcfind.
           respiratory
           cumplainls.
           All habitual
           smokcn.                                                                        --



Chupmon,   I. 12 normal        A. Pulmonarv function    1. All showed P dccrcnse In diRtwing ca~acily.
lDGS,        volunteer.          Artcriul blood     II. 4/b--aiynlficont dccrrnac in artcrinl O1 tcl~sl00.
Ireland       (nil smokera).        atudiea.            No change in vilnl cnpacily or FEV.
(48,.    11. 6 pnticnla with     B. I ciulrctre.
           chronic non-      C. Undelirrcd.
           apccilic lung
           dieeaae.

McDermott   I. 32 normnle.        A. Body Dlcthy.                   Afcon oirwav rcairtatwc             Light amokcra ahowcd

nnd     II. 28 with chronic        smosrnl,hy.                   I. Siu~iflcnnt incrcnac.              prrnter chnrlu~n 1hnn
COlliM.      bronchitis       B. Cigercttc.                     II. Sigoificnnt lncresse.              hc.vy amokrrd.
1966.        (All ciyn-       C. Undefined.
WDler       rctte smokera
(160).       3560 years
         of ace.)


Author.                      A. hlcthod '
  year.       Number and         ,3. Mnlcrinl J
country.        type or           C. Durnliun of                        Result-4                    COlll~Clila
rcIcrmu!       Dopulation            emuking

Miller and  10 normal           A. Eaovhsuenl bnllwn                   DUWl77tic        Inapimtory at-d
Suroule,   cignrcttt             tcchniaue.        FEVo 6        compliance      cxyiratorv rcaiatanec
1966.     smokcn           l3. 1 cigarette.       No signiicant       Significant         Significant
U.S.A.    (40 yeara          C. One inhnlntion        chnnge          dccrcnae.           increuse
(166).    al age).              evcrY 30-60
                          seconds.

Sterling,   11 "ormal adulta       A. Body plethy-                        Airway rceidtance
1067,      (8 smokers,            smouaphy.                        Significant increase (Return
England   3 nonsmokers).       B. 16 inhalationa.                         to nom-al in 30 minutes).
(113).                   C. 6 minutes.

Cbiang and 7 male normal
WanK.    nonsmokers
1970,     (c-48 yeat
FWlTl03a   of rae).
(61).

A. Pulmonary function    Nitrogetr wnahout
   Nitrogen washout.        time
B. 2 cigarettes.          Significant
c. Undefined.            iricrease.

Guyatt    710 nubjecb:         A. Ilodr plethy-
et al.,     608 smoked            amograDhu.
1910.    betwe?" mens-     B. 1 cigarette.
Englnnd   urm 202           `2, Undefined.
(100).    did not smoke.

w     `All the exucriments listed concern studies of pulmonnry function b+
z    iore and after smoking the epecifled number of cigarettee (unless otber-
     wise soeeifLd).


Author.
YCLI.
cuunlry,
rclcrcnee

Subjccta

Method

LaUrCnXl   Swiss-Webster     Xlicc exposed to    Significnnt incrcjbsc in S. ourcu8 rctcntion in mice cxp+8c%l to:
CL nl.,     male mice.       nermul of s. DurcuI   (n) hyrruxin-retention ratio 2.5 (IO prrccnt 02).
196%                  and ancrificcd at      (b) cignrcttc smuhc-rctintion riilio 4.5.
U.S.A.                 Intcrvnla following
(149).                 CXwrure 10 vilrious
                     stimuli.

LSDCIIC    Albino female     Silver idideor     17-30 hours uf cx~~wrc to cirrnrvttc amukc caused no change In pulmunnr/
et al..     mbbib.         colloidnl gold     elenrnnce ns cumjlnrcyl with controlr breathing room air.
1966.                  intrntrachellly.
U.S.A.
(1151.

Bair and   SpraaudJhwlw   Radioactive aer&.  Acute cxposurc to cignrctte smoke hnd no proo, oflect on clenrance. Chronic
Dillcy.    frmale rata,                  erl>orurc tu ciplrrctte rmukc cut) to l&20 cigarettes/7 hour day/6 dnu wwk
L967.     mule beogle dep.  Radioactive aerwol.   for "1, to 420 doye) hod no ubscrvnblc rllcctr. The authors noted, however,
U.S.A.                          thnt normnl clrnrance rntcx were too low to rcflcct anything but complete
(05).                              cerse.tion.

                                                               so pcrcmt   90 pcrcrnt t ADproximntc villuc3.
                                                                clcaronce    CICOIUIICe   None of `I nonamokcrs
Albert    3G subjecta       Radlonctive tagged                   Number oj   "lvcraoc    time      time    hnd GO pc~ccnl time-a
et al..     undergoing 117   FeOZ particles                      subjcctr     aoe    (minulcr)   (mixuterI  over 200 minu(cY or
1969.     uperimcnts.      mensured with    Nonsmekerr  .   0       28       88       367    90 p~,rcmL limes over
U.S.A.                 Scintillation     All smokers  ,. ,. . , , .  14       33       172       1406    600 ntinuta while
(2).                  counter.       `X+20 cigarettcs/dny  ..,,,...   7       23       191       t519    6/14 am,>kws cxcwlcd
                                30-40 cisorettes/day  ,.._,.,..   7       36       163       1474    both thcsc limits.
                                Uranium miners ,.   3       62       310       b80
                                Cigar nnd ~ipc smokrra  ,.....   4       46       07       3'76
                                Emphywmu patients . .   2       66       330       G7G


TAEZLE le.--E'zperinamts concerning the effect of cigarette smoke on human and animal pulmona~ clearance (cont.)

Author.
Y-r,
CO""tl-7,
rcfcrence

Subjects         MOtbOd                          nesuita                          COnlml?ntn

Albert    Donkey8 exwsed    Radioactive tagged    AVWQ7C                               Tmchoel franail  Thmc donkeys CxDoacd
et al.,     to CiKF,Rtte     FcOz particles      number                                  lime       to the KrCnl`-Bt
1969.     smoke by nasnl     measured wilb    cigarcllca in    Percent clcara?lcc   Ilaltlime clmrance               emount of smukc
U.S.A.    catheter.        Scintillation     z-hour period   COnlrOl  CiQ~rclle Cotllrol  Cioarclle  Conlrd  Cigartile showed rczidunl
(3).                  CO"nter.          1n-24       5.3      GO     1.2      1.9     0.G      I.?    Impnirmrnt of
                                  3c        5R      64     1.0      3.4      04      6.8    clrsrnnrc fur nt h.nt
                                                                           2 month3 afkr ucuk
                                                                           CXpW"rC.

Helms.   Rabbits '       CP' monodisperse   Ihmsurc tu Irrsh ciaurct~c smoke (1.6 cc. nulTr, 40 puiTsl8 minxten) caured
1069,     (nncsthctlrcd).     PolYstYrcne       n "sianificnnt" increnrc in lung retention 10 minutes followinK cessation of
U.S.A.                 aer0301.         eX,lOS"rC.
(IIS).


originate in tobacco smoke. The authors suggested that the tobacco
smoke may have induced abnormalities in the mitochondria of the
macrophage. In a study of pulmonary macrophages harvested by
endobronchial lavage from smokers and nonsmokers, Pratt, et al.
(187) observed that the mncrophages of smokers contained an ab-
normal pigment.

These studies indicate that the function of pulmonary clearance
carried on by the macrophage and ciliary systems is adversely af-
fected by cigarette smoke.

STUDIES CONCERNING THE SURFACTANT SYSTEM

The surfactant system of the lung consists of various biologically
active compounds such as phosphoiipids and mucopolysaccharides
which are present in the alveolar lining. Normal pulmonary func-
tion is influenced and partly determined by the integrity of this
system (103). The purpose of the surfactant system is to main-
tain the proper amount of surface tension in the alveoli so that the
expansion and contraction of the alveoli are facilitated.

Studies concerning the effect of cigarette smoke upon the sur-
factant system and the surface tension of the pulmonary alveoli
are presented in table Al4. Exposure of rat and dog Iung extracts
to cigarette smoke has been found to induce a notable decrease in
the maximal surface tension demonstrated by the extracts (94,
165, 224). Cook and Webb (57) observed that surfactant activity
was diminished in smokers and in patients with pulmonary disease
when compared with healthy nonsmokers.

Scarpelli (203) in a recent review, concluded that the lowering
of maximal surface tension by cigarette smoke has been demon-
strated reasonably well. The relationship of these findings to the
pathogenesis of emphysema is unclear at this time.

OTNER RESPIRATORY DISORDERS

INFECTIOUS RESPIRATORY DISEASES

Several studies have examined the question of whether ciga-
rette smokers are at an increased risk of developing infectious res-
piratory and bronchopulmonary disease. Table A15 presents a
summary of these studies. Lowe (157) observed an excess of
smokers among 705 tuberculosis patients, but Brown and Campbell
(4s) in a similar study found that the difference was not present
when the cases and controls were matched for alcohol intake. More
recent studies have been concerned with the frequency of upper
respiratory infections among groups of smokers and nonsmokers.
A number of investigators (1U8,181,183) have reported increased

198


rates of respiratory illnesses among smokers. Finklea, et al. (8~)
studied a male college population (prospectively) during the
1!XS-F9 influenza epidemic. They found that smokers of ail amounts
experienced more clinical illness than did nonsmokers and that this
r&tion was dose-dependent. Similarly, smokers required more bed
rest than nonsmokers.
A survey conducted by the National Center for Health Statistics
(290)) involving approximately 134,000 persons, showed that male
cigarette smokers reported 54 percent more cases of acute bron-
chitis than males who had never smoked cigarettes, while female
smokers reported 74 percent more acute bronchitis than did females
who had never smoked. MaIe cigarette smokers reported 22 percent
more cases of influenza than did males who had never smoked cigar-
ettes, while the female smokers reported an excess of 9 percent.
Experimental evidence in support of this relationship has been
noted by Spurgash, et al. (211) _ Mice were tihallenged with
h'lcbsiclla pneumoniae or Di$ococcw pneumoniae before or after
a single exposure to cigarette smoke. They observed that those ani-
mals exposed to smoke eshibited a decrease in resistance to respira-
tory infection, as shown by an increase in mortality and a decrease
in survival time. Preexposure to cigarette smoke was found to have
no significant effect on resistance of mice to influenza infection
initiated by aerosol exposure. However, exposure of infected mice
to smoke resulted in significantly higher mortaiity, thus suggest-
ing that cigarette smoke can aggravate an existing respiratory
viral infection.
In the light of the experimental evidence presented above con-
cerning the effect of cigarette smoke on pulmonary clearance,
phagocytosis, and ciliary function, it seems reasonable to conclude
that such changes in tracheobronchial physiologic function would
predispose a person to respiratory infections or aggravate already
existing ones.
Further evidence is derived from the work of Henry, et al. (109)
and Ehrlich, et al. (75). These investigators exposed sWirr&
monkeys to atmospheres containing 10 and 5 p.p.m. of nitrogen
dioxide. They observed that this exposure increased the suscepti-
bility of the animals to airborne Klcbsiellu pneumoniae as demon-
strated by increased mortality and reduced lung clearance of viable
bacteria. Infectious challenge with influenza virus 24 hours before
exposure to 10 p.p.m. was fatal to all monkeys within three days.
Infected controls shoxved symptoms of viral infection but did not
succumb to the infection. The extent to which the various oxides of
nitrogen present in cigarette smoke contribute to the increased sus-
ceptibiljty to respiratory disease noted in smokers is presently
undefined.

                                     199


POSTOPERATIVE COMPLICATIONS

Several studies have been published which examine the questions
of whether smokers run an increased risk of developing postopera-
tive PUhonarY complications over nonsmokers undergoing similar
operations.

Morton (173) reported on a study of more than 1,100 patients
undergoing abdominal operations in which he found that cigarette
and mixed smokers were significantly more likely to develop hron-
chitis, bronchopneumonia, or atelectasis during the postoperative
period than nonsmokers (table A16).
Wiklander and Norlin (229) examined the incidence of post-
operative complications in 200 patients undergoing laparotomy in
the winter months when it was expected that pulmonary compli-
cations would be at their maximum. These authors found no sig-
nificant differences between the frequency of complications in
smokers and nonsmokers. No information about the definition of
a smoker and no data on dosage of tobacco smoke were reported.
Piper (186) observed the prevalence of postoperative pulmonary
complications in 150 patients undergoing laparotomy. Of the total
sample, 66.7 percent developed pulmonary complications during
the first postoperative week. All patients considered in the statis-
tical analysis as having pulmonary complications had radiographic
evidence of disease. Of the cigarette smokers, 73.5 percent had
complications as compared to 55.5 percent of the nonsmokers.
When the smokers were divided according to dosage, heavy smok-
ers being those consuming more than 10 cigarettes per day for the
previous six months, 55 percent of light smokers and 88 percent
of heavy smokers were considered to have postoperative compli-
cations. Piper also reported that stopping smoking for Up to four
days preoperatively had no apparent effect on the incidence of
complications.

Wightman (228) reported on the incidence of postoperative pul-
monary complications in 455 patients undergoing abdominal oper-
ations and in 330 patients undergoing other operations. Of the
cigarette smokers, 14.8 percent developed complications as com-
pared to 6.3 percent of the nonsmokers. The substantial difference
between these figures and those of Piper (186) is due to the latter's
use of radiographic criteria alone. Wightman utilized only clinical
criteria.

Morton (172) has recently reported a study of postoperative
hypoxemia in 10 patients, 5 of whom were cigarette smokers. Four
of the smokers had chronic bronchitis. He found that the smokers
had a more pronounced decrease in arterial oxygen saturation, Per-
sisting into the second postoperative day CtabIe A17) -.

200


In summary, the majority of studies so far reported indicate
that cigarette smokers run a higher risk of developing postopera-
tive pulmonary complications than do nonsmokers, corroborating
a long-held clinical impression. The risk of developing such com-
plications appears to increase with increasing dosage of cigarette
smoke.

SUNNARY AND CONCLUSIONS

1. Cigarette smoking is the most important cause of chronic ob-
structive bronchopulmonary disease in the United States. Ciga-
rette smoking increases the risk of dying from pulmonary emphy-
sema and chronic bronchitis. Cigarette smokers show an increased
prevalence of respiratory symptoms, including cough, sputum pro-
duction, and breathlessness, when compared with nonsmokers.
Ventilatory function is decreased in smokers when compared with
nonsmokers.

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

2. The risk of developing or dying from COPD among pipe and/
or cigar smokers is probably higher than that among nonsmokers
while clearly less than that among cigarette smokers.
4. Ex-cigarette smokers have lower death rates from COPD
than do continuing smokers. The cessation of cigarette smoking
is associated with improvement in ventilatory function and with
a decrease in pulmonary symptom prevalence.
5. Young, relatively asymptomatic, cigarette smokers show
measurably altered ventilatory function when compared with non-
smokers of the same age.

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

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

8. Pathological studies have shown that cigarette smokers who
die of diseases other than COPD have histologic changes charac-


teristic of COPD in the bronchial tree and pulmonary parenchyma
more frequently than do nonsmokers.
9. Respiratory infections are more prevalent and severe among
cigarette smokers, particularly heavy smokers,  than among
nonsmokers.

10. Cigarette smokers appear to develop postoperative pulmo-
nary complications more frequently than nonsmokers.

CHRONIC OBSTRUCTIVE BRONCHOPULXONARY

DISEASE REFERENCES

(I) ABBOTT, 0. A., HOPKINS, W. A., VAN FLEIT, W. E., ROEINSON, J. S.
   A new approach to pulmonary emphysema. Thorax 8: 116-132, 1953.
(2) ALBEKT, R. E., LwPhfANN, M., BRISCOE, W. The characteristics of bron-
   chial clearance in humans and the effects of cigarette smoking.
   Archives of Environmental Health 18(5) : 738-755, May 1969.
(S) ALBERT, R. E., SPIEGELMAN, J. R., SHATSKY, S., LIPPMANN, M. The effect
   of acute exposure to cigarette smoke on bronchial clearance in the
   miniature donkey. Archives of Environmental Health 18 (1) : 30-41,
   January 1969.

(4) ANDERSON, A. E., JR., FIJRLANFXO, J. A.. FORAKER, A. G. Bronchopul-
   monary derangements in nonsmokers. American Review of Respira-
   tory Diseases lOl(4) : 518-527, April 1970.
(5) ANDERSON, A. E., JR., HERNANDEZ, J. A., ECKERT, P., FOFMKER, A. G.
   Emphysema in lung macrosections correlated with smoking habits.
   Science 144 (3621) : 1025-1026, May 22, 1964.
(6) ANDERSON, -4. E., JR., HERNANDEZ, J. A., HOLMES, W. L., FORAKER, A. G.
   Pulmonary emphysema. Prevalence, severity, and anatomical patterns
   in macrosections, with respect to smoking habits. Archives of Environ-
   mental Health 12(5) : 569-57'7, May 1966.
(7) ANDERSON, D. 0. Observations on the classification and distribution of
   pulmonary emphysema in Canada.  Canadian Medical Association
   Journal 89: 709-716, October 5, 1963.

(8) ANDERSON, D. O., FERRIS, B. G., JR., ZIcKhfANTEL, R. The Chilliwack
   Respiratory Survey, 1963. Part IV. The effect of tobacco smoking on
   the prevalence of respiratory disease. Canadian Medical Association
   Journal 92(20) : 1066-1076, May 15, 1965.

(9) ANDERSON, W. H., WrLLrArxs, J. B. Effects of cigarette smoke on dis-
   tribution of pulmonary perfusion. In: Current Research in Chronic
   Respiratory Diseases. Proceedings of the 11th Aspen Emphysema
   Conference, Aspen, Colo. U.S. Department of Health, Education, and
   Welfare, Public Health Service Publication No. 1879, 1969. pp. 75-79.
(10) ANTHONISEN, N. R., BASS, H., ORIOL, A., PLACE, R. E. G., BATES, D. V.
   Regional lung function in patients with chronic bronchitis. Clinical
   Science 35: 495-511, December 1968.

(11) ASHFORD, J. R., BROWN, S., DUFFIELD, D. P., SMITH, C. S., FAY, J. W. J.
   The relation between smoking habits and physique, respiratory symp-
   toms, ventiIatory function, and radioIogical pneumoconiosis amongst
    coal workers at three Scottish collieries. British Journal of Preventive
   and Social Medicine 15 : 106-11'7, 1961.

202


(12) ASscLEY, D. J. B. Environmental factors in the aetiology of lung cancer
    and bronchitis. British Journal of Preventive and Social ,\Iedicine
    23 (4) : 258-262, November 1969.
(13) ATTINCER, E. O., GOLDSTEIN, ,\I. >I., SEG,U, \I. S. Effects of smoking
    upon the mechanics of breathing. I. In normal subjects. American
    Review of Tuberculosis and Pulmonary Diseases 77(l) : l-16,
    January 1958.
(14) AUERBACH.' O., HaAlMOXD, E. C., GARFINXEL. L., Thickening of walls of
    arterioles and small arteries in relation to age and smoking habits.
    New England Journal of Xedicine 278( 18) : 980-984, Xay 2, 1968.
(15) AUERUACH, 0.. ~IAhlMOND, E. C., KIRBIAN, D., GARFINKEL, L. Emphysema
    produced in dogs by cigarette smoking. Journal of the American
    RIedical Association 199(4) : 241-246, January 23, 1967.
(16) AUERBACH,~., IIAM~~OND,E.C.,KIR~~AN,D.,GAPSXNKEL,L. Emphysema
    produced in dogs by cigarette smoking. In: Hanna, hf. G., Jr.,
    Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis.
    Proceedings of a Biology Division, Oak Ridge National Laboratory
    Conference, Gatlinburg. Tennessee, October 8-11, 1969. U.S. Atomic
    Energy Commission Symposium Series 18, April 1970. pp. 375-387.
(17) i%UERBACH, O., STOUT, A. P., HAsrhlOr;D, E. C., GARFINKEL, L. Smoking
    habits and age in relation to pulmonary changes. Rupture of alveolar
   septums, fibrosis and thickening of walls of small arteries and
    arterioles. New England Journal of Medicine 269 (20) : 1045-1054,
    November 14, 1963.
(13) AVIADO, D. >I., CARRILLO, L. R. Hormones and pulmonary effects of
    tobacco. I. Corticosteroids and their antiasthmatic action. Archives of
    Environmental Health 18(6) : 925-933, June 1969.
(19) A\'rAoo, D. >I., PALECEK, F. Pulmonary effects of tobacco and related
    substances. I. Pulmonary compliance and resistance in the anesthetized
   dog. Archives of Environmental Health 15(2) : 187-193, August 1967.
(XI) AVIADO, D. >I., SADAVONGVIVAD, C.,~ARRILLO, L. R. Cigarette smoke and
   pulmonary emphysema. Influence of bronchodilators and biogenic
   amines in experimental induction in rats. Archives of Environmental
   Health 20 (4) : 483-487, April 1970.
(21) AYIADO, D. >I., SAMANEK, M. Bronchopulmonary effects of tobacco and
   related substances. I. Bronchoconstriction and bronchodilatation: In-
   fluence of lung denervation. Archives of Environmental Health 11(Z) :
    141-151, August 1965.
(22) A~IALIO, D. >I., SAMANEK, M., FOLLE, L. E. Cardiopulmonary effects of
    tobacco and related substances. I. The release of histamine during
   inhalation of cigarette smoke and anoxemia in the heart-lung and
   intact dog preparation. Archives of Environmental Health 12(6) :
    70>724, June 1966.
(23) BAIK, W. J., DILLEX, J. V. Pulmonary clearance of "9FEz.0, and "`CR,O,
   in rats and dogs exposed to cigarette smoke. In: Davres, C. N. (Edi-
   tor). Inhaled Particles and Vapors. II. Proceedings of an International
   Symposium. Cambridge, September 28 to October 1, 1965, Oxford,
   Pergamon Press, 1967. pp. 251-271.
(24) ?&XHUhl, 0. J., FELTON, J. S., JAhfISON, .I. N., GAINES, R. % CLARKE,
   D.R.,OwAx,D., TEE INDUSTRIAL HEALTH COIlhfITTEE,TlIE 'X'UBEXKU-
   LOSIS AND HEALTH ASSOCIATION OF Los ANGELES COUNTY. A SurveY
   for chronic respiratory disease in an industrial city. PreIiminary re-
   sults. American P&view of Respiratory Diseases 86(5) 1675-685,
    November 1962.

                                      203


C-05) RALLEXCER, J. J. Experimental effect of cigarette smoke on human
   respilztory cilia. Sew England Journal of Medicine 263 (17) : 832-835,
    October 27, 1960.

(26) BALLESGER, J. J., DAWON, F. W., DERUYTEK, 31. G., H,ARDING, H. 13.
   Eifects of nicotine on ciliary activity itz Titro. ;1nnals of Otologg,
   Rhinology and Lary-r;gology 74(2) : 303-311, June 1965.
(27) BANS, D. V.. GORDON, C. A., PAUL, G. I., PLACE, R. E. G., SNIDAL, D. P.,
   WOOLF, C. R. Chronic bronchitis. Report on the third and fourth stages
   of the coordinated study of chronic bronchitis in the Department of
   Veterans Affairs, Canada. sledical Services Journal, Canada 22(l):
    l-59, January 1966.
(28) BAT~IST~, S. P.. KEKSLER, C. J. Use of the nonimmersed in vitro chicken
   tracheal preparation for the study of ciliary transport activity.
   Cigarette smoke and related components. Archives of Environmental
    Health 20 (3) : 318-325, March 1970.

(29) BATTISW, S. P., KENSL~, C. J. Mucus production and ciliary transport
   activity. In ~ivo studies using the chicken. Archives of Environmental
    Health 20 (3) : 32&338, hlarch 1970.

(20) BEST, E. W. R. A Canadian Study of Smoking and Health. Ottawa,
   Department of National Health and Welfare, 1966. 137 pp.
(31) BICKERXAX, H. A., BARACII, A. L. The effect of cigarette smoking on
   ventilatory function in patients with bronchial asthma and obstructive
   pulmonary emphysema. Journal of Laboratory and Clinical Medicine
   43 (3) : 455-462, March 1954.

(32) BLAIR, IV. H., HENRY, 31. C., EHRLICII, R. Chronic toxicity of nitrogen
   dioxide. II. Effect on histopathology of lung tissue. Archives of En-
   vironmentzl Health 18(2) : 186-192, February 1969.
(33) BOAKE, \v. C. A Study of illness in a group of Cleveland families. XVIII.
   Tobacco smoking and respiratory infections. New England Journal of
    hfedicine 259(26) : 1245-1249, December 25, 1958.
(34) BONNELL, J. A. Emphysema and proteinuria in men casting copper-
   cadmium alloys. British Journal of Industrial hIedicine 12: 181-195,
   July 1955.

(35) BOXNELL, J. A., KAZASTZIS. G.,KING, E. A follow-up study of men ex-
   posed to cadmium oxide fume. Bsitish Journal of Industrial Medicine
   16: 135-147, 1959.

(36) BOWCOT, K. R., COOPER, D. A., WEISS, W. Smoking and the health of
   older men. 1. Smoking and chronic cotigh. Archives of Environmental
   Health 4(l) : 69-72, January 1962.

(87) BOUHUYS, A. PETERS, J. hf. Control of environmental lung disease. New
   England Journal of Medicine 283(11) : 5'73-582, September 10, 1970.
(38) BOUHKJ~S, A., SCHILLINC, R. S. F., VAN DE WOESTIJSE. K. P. Cigarette
   smoking, occupational dust exposure, and ventilatory capacity. Ar-
   chives of Environmental Health 19(6) : 793-797, December 1969.
(89) BOUHUYS, A., WOLFSON, R. L., HORNEX, D. W., BRMN, J. D., ZUSKIN, E.
   Byssinosis in cotton textile workers. Respiratory survey of a mill with
   rapid labor turnover. Annals of Internal Medicine 71(Z) : 257-269,
   August 1969.

(40) BOUS~Y, S. F., HELGASON, A. IT., BILLIC, D. M., GYORKY, F. G. Clinical
   physiologic, and morphologic examination of the lung in patients with
   bronchogenic carcinoma and the relation of the findings to postopera-
   tive deaths. American Review of Respiratory Diseases lOl(5) : 685-
   695, May 1970.

204


(41) BOWER, G. Respiratory symptoms and wntllatory function in 172 adults
  employed in 3 bank. American Review of Respiratorp Discuses 83:
    6&l-689, 1961.
($2) BR[h'lih~~?.i, G. L., COATS, E. 0.. JR. The prevalence of chronic bronchitis
   in an industrial population. American Review of Respiratory Diseases
    86: 47-54, 1962.

(4s) BROWN, K. E., CahxFBELL, A. II. Tobacco, alcohol and tuberculosis.
   British Journal of Diseases of the Chest 55 (3) : 150-158. 1961.
(44) CARSON, s., GDLDHAhlER, R., CARPENTm, R. ReSponSeS of ciliated
   epithelium to irritants. Mucus transport in the respiratory tract.
   American Review of Respiratory Diseases 93 (3, Part 2) : 8692,
     March 1966.

(45) CEDERLOF, R. FRIBEXG, L., ITRUB%, 2. Cardiovascular and respiratory
   symptoms in relation to tobacco smoking. Archives of Environmental
   Health 18 (6) : 931940, June 1969.

(46) CEDERLOF, R., FRIRERC, L., JONSSON, E., KAIJ, I,. Respiratory symptoms
   and "angina pectoris" in twins with reference to smoking habits. AA
   epidemiological study with mailed questionnaire. Archives of Environ-
   mental Health 13 (6) : `726-737, December 1966.
(47) CHAXG, S. C. Microscopic properties of whole mounts and sections of
   human bronchial epithelium of smokers and nonsmokers. Cancer 10
    (6) : 12461262, November-December 1957.
(48) CHMhIAN, T. T. The acute effect of cigarette smoking on pulmonary
    function. Journal of the Irish Medical Association 56(333) : 72-74,
     alarch 1965.

(49) CHESTER, E. H., GILLESPIE, D. G., KIZAUSE, F. D. The prevalence of
   chronic obstructive pulmonary disease in chlorine gas workers. Amer-
   ican Review of Respiratory Diseases 99 (3) : 365-3'73, March 1969.
(50) CHEVALIER, R. B., K~UJMHOLZ, R. A., Ross, J. C. Reaction of nonsmokers
    to carbon monoxide inhalation. Cardiopulmonary responses at rest
   and during exercise. Journal of the -4merican Medical Association
    198(10) : 1061-1064, December 5, 1966.
(51) CHIANG, S. T., WANG., B. C. Acute effects of cigarette smoking on pul-
   monary function. American Review of Respiratory Diseases lOl(6) :
    860-868, June 1970.

(52) C~IIVERS, C. P. Respiratory function and disease among workers in alka-
   line dusts. British Journal of Industrial Medicine 16: 51-60, 1959.
(53) CoATES, E. O., JP, BOWER, G. C., REINSTEIN, N. Chronic respiratory
   disease in postal employees. Epidemiologic survey of a group em-
   ployed in one building. Journaf of the American Medical Association
   191(3) : 161-166, January 18, 1965.

(54) COHCU, J. Chronic bronchitis and emphysema. Observations on trends
   and distribution according to death certificate data, Israel 1960 to
   1964. Israel Journal of Medical Sciences 3(6) : 885-889, November-
    December 1967.

(55) COLLEGE OF GENERAL PRACTITIONERS. Chronic bronchitis in Great Brit-
   ain. A national survey carried out by the respiratory diseases study
   group of the College of General Practitioners. British Medical. Journal
   2: 973-979, October 14, 1961.

(56) COMME, J. H., JR., FORSTEX. R. E., II, DIJBOIS, A. B., BRISCOE, W. A.,
   CAmSEN, E. The Lung. Clinical Physiology and Pulmonary Function
   Tests. Chicago, Year Book Medical Publishers, Inc., 1963. 390 pp.
(57) COOK, W. A.,. WEBB, W. R. Surfactant in chronic smokers. Annals of
   Thoracic Surgery 2 (3) : 327333, h1ay 1966.

205


(58) COOLEY, J. R. T., REP, D. D. Urban and social origins of childhood bron-
   chitis in England and iTales. British Medical Journal 2(5303) : L'13-
   217 April 25. 1970.

(jg) Dtinxar~, T. The effect of cigarette smoke on cilinry activity in the
   upper respiratory tract. .\..\I..~. Archives of Otolar)-ngology 70: 16G
    168, 1959.

(~0) DuHAhrN, T. Effect of cigarette smoke on diary activity. American
   Review of Respiratory Diseases 93 (3) : 108-114, Ilarch 1966.
(61) DALHAMN, T., RYLANDER, R. Ciliastatic action of smoke from filter-
   tipped and non-tipped cigarettes. Nature 201(4317) : 401--101, Janu-
   ary 25, 1964.
(6:) DALHAMN, T., RYLANDER. R. Ciliastatic action of cigarette smoke. Vary-
   ing exposure times. Archives of Otolaryngology 81(4) : 379-382, April
     1965.

(63) D,%H,xhm', T., RYLAXDER, R. Tar content and ciliotoxicity of cigarette
   smoke. Acta Pharmacolog~cs et Toxicologica 25(3) : 369-3'72, 19G7.
(64) DALHXMN, T., RYI.AxDER, R. Ciliotoxicity of cigarette smoke and its
   volatile components. American Review of Respiratory Diseases 98(3) :
   509-511, September 1968.

(GA) DALHAMX, T., RYLXNDLR, R. Ciliotosicity of cigar and cigarette smoke.
    Archives of Environmental Health 20(2) : 252-253, February 1970.
(66) DAMS, T. R. A., BXTTISTA, S. P., KI?%SLER, C. J. AIechanism of respirn-
   tory effects during exposure of guinea pigs to irritants. Archives of
    Environmental Health 15(4) : 412-419, October 1967.
(67) DEANE, M., GOLDSNIT~, J. R., TUJU, D. Respiratory conditions in out-
   side workers. Report on outside plant telepflone workers in San Fran-
   cisco and Los Angeles. Archives of Environmental Health lO(2) :
    323-331, February 1965.
(68) DENSEN, P. M., JOKES, E. W., Bass, H. E., BREUER, 3. A survey of respi-
   ratory disease among Xew York City postal and transit workers.
   1. Prevalence of symptoms. Environmental Research 1: 262-286, 196'7.
(69) DENSEN, P. M., JOSES, E. W.. Bass, H. E., BREW%, J., REED, E. A survey
   of respiratory disease among New York City postal and transit work-
   ers. 2. Ventilatory function test results. Environmental Research
   Z(4) : 277-296, July 1969.

(70) DOLL, R., HILL, A. 13. Mortality in relation to smoking: Ten years'
   observations of British doctors. (Part I) British Medical Journal
   l(5395) : 1399-1410, May 30, 1964.
(72) DOLL, R., HILL, A. B. hlortality in relation to smoking: Ten years'
   observations of British doctors. (Concluded) British Medical Journal
    115396) : 1460-1467, June 6, 1964.                        - .
(7-O) DOWING, H. F., JACKSON, G. G., INOWE T. Transmission of the expeti-
    mental common cold in volunteers. II. The effect of certain host factors
   upon susceptibility. Journal of Laboratory and Clinical Medicine
   50 (4) : 516525, October 1957.

(73) EDELSfAN, N. H.. MITThfm, C., NoRrzrs, A: H., COHEN, B. II., SHOCK,
   N. W. The effects of cigarette smoking upon spirometric performance
   of community dwelling men. American Review of Respiratory Diseases
   94 (3) : 421-429, September 1966.

(7-1) EDWARDS, F., MCKEO~N, T., WHITFXLD, A. G. W. Association between
   smoking and disease in men over sixty. Lancet 1: 196-200, January
    24, 1959.

(75) EAmICH, R.. HENRY, M. C., FENTERS, J. Influence of nitrogen dioxide on
   resistance to respiratory infections. In: Hanna, &I. G., Jr., Nette-

206


    sheim, P.. Gilbert, J. R. (Editors). Inhalation Carcinogenesis. Pro-
    ceedings of a Biology Division, Oak Ridge Sational Laboratory Con-
    ference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomic
    Energy Commission S>mposium Series 18, April 1970. pp. 243-257.
(76) EICH, R. H., GIL~E~~T, R., AUCHINCLCSS, J. II.. JR. The acute effects of
    smoking on the mechanics of respiration in chronic obstructive pul-
    monary emphysema. American Review of Tuberculosis 76: 22-32,
      1957.
(77) ELWOOD, P. C., PEh%%ro~, J., MERRITT, J. D., CARLY, G. c. R.,
    bfcAULAY, I. R. Byssinosis and other respiratory symptoms in flax
    workers in Northern Ireland. British Journal of Industrial aiedicine
    22 :2'7-37, 1965.
(78) ERIKSSON, S. Studies in Alpha,-antitrypsin Deficiency. Acta hledica
    Scandinavica 1'77 (Supplementum 432) : 1965. 85 pp-
(79) FALK, G. A., BR~SCOE, W. A. Chronic obstructive pulmonary disease and
   heterozygous alpha,-antitrypsin deficiency. Annals of Internal Medi-
    cine 72(4) : 595-596, April 19'70.
(80) FALK, H. L., TRE~IER, H. M., KOTIN, P. Effect of cigarette smoke and its
    constituents on ciliated mucus-secreting epithelium. Journal of the
    National Cancer Institute 23 (5) : 999-1012, November 1959.
(81) FERRIS, B. G., JR., ANDERSON, D. 0. The prevalence of chronic respiratory
   disease in a New Hampshire town. American Review of Respiratory
    Diseases 86(Z) : 165-177, August 1962.
($2) F~lsrus. B. G., JR, ANDERSON, D. O., BURGESS, W. A. Prevalence of
   respiratory disease in a flax mill in the United States. British Journal
    of Industrial Medicine 19: 180-185, 1962.
(83) FINKL~, J. F., SANDIIXX, S. H., SWTH, D. D. Cigarette smoking and
   epidemic influenza. American Journal of Epidemiology 90(5) : 390-
    399, November 1969.
(84) FLETCHER, C. &I., HORN, D. Smoking and health. WHO Chronicle 24(B) :
    34&3'iO, August 1970.
(~5) FLEXCHER, C. Bf., TINKER, C. M. Chronic bronchitis. A further study of
   simple diagnostic methods in a working population. British Medical
    Journal 1: 1491-1498. May 27, 1961.
(86) FLICK, A. I,., PATON, R. R. Obstructive emphysema in cigarette smokers.
   A.M.A. Archives of Internal Medicine 104: 518-526, 1959.
(87) FRANKLIN, W., LOWELL, F. C. Unrecognized airway obstruction associ-
   ated with smoking. A probable forerunner of obstructive pulmonary
   emphysema. Annals of Internal Medicine 54 (3) :379-386, March 1961.
(88) FRASCA, J. M., AUERBACB, 0.. PARKS, V. R., JAMIESON, J. D. Electron
   microscopic observations of the bronchial epithelium of dogs. 11. Smok-
                                                     -
   ing dogs. Experimental and filoleculat Pathology 9(3) : 380-399.
    December 1968.
(gg) F-MAN, G., CRASE, S. C. STEPHENS, R. J., FIJRIOSI, N. J. Pathogenesis
  of the nitrogen dioxide-induced lesion in the rat lung: A review and
  presentation of new observations. American Review of Respiratory
   Diseases 98(3) : 429-443, September 196%
(go) FREE;~~AN, G., HAYDON, G. B. Emphysema after low-level exposure to
  NO,. Archives of Environmental Health S(1) : 125-128, January 1964.
(91) F~E>~AN, G., STEPHENS, R. J., CRANE, S. C., FUnIOSI, N. J. Lesion of the
  lung in rats continuously exposed to two parts per million of nitrogen
   dioxide, Archives of Environmental Health 17(Z) : 181-192, August
    1968.

                                       207


(92) FREOUR, P., COI:DRAY. P.. Rousst-L, A., SERISE. -\. Les bronchites.chi,oni-
    ques et l'insuffissnce I-espiratorie dans l'agglomeration de Bordeaux.
     (Chronic bronchitis and respiratory insufficiency  in Bordeaux).
    Journal de LIedecine de Bordenus 113 (2) : 1865-1873, December 1~66.
(99) GAKDESU, B. A productive cough upon request as an index of chronic
    bronchitis: The effec!s of age, sex, smoking habit, and environment
    upon prevalence in Australian general practice. Y!Iedical Journal of
     Australia l(1) : 16-20, January 4, 1969.
(9.6) GLAhlhIONA, S. T. Effects of cigarette smoke and plant smoke on pulmo-
    nary surfactant. American Review of Respiratory Diseases 96(3) :
     539-541, September 1967.
(95) GOrDshUTrr, 3. R., HECHTEX, H. H., PERKIKS, N. M. RORHANI, N. 0.
    Pulmonary function and respiratory findings among longshoremen.
    American Review of Respiratory Diseases 86(6) ;867-874, December
       1962.
(96) GREEN, G. M., CAROLIN, D. The depressant effect of cigarette smoke on
    the in ~?ifro antibacterial activity of alveolar macrophages. New Eng-
    land Journal of Medicine 276(8) : 421-427, February 23, 1967'.
(97) GREENBERG, X., MILNE, J. F., WATT, A. Survey of workers exposed to
    dusts containing derivatives of Bacillus subtilis. British Xedical
     Journal 2: 629-633, June 13.1970.
(98) GUENTER, C. A., WELCH, 31. H., RUSSELL, T. R., HYDE, R. M., Hnarxr~n-
    STEN, J. F. The pattern of lung disease associated with alpha-l anti-
    trypsin deficiency. Archives of Internal nfedicine 122 (3) : 254-257,
     September 1968.
(99) GUILLERM, R., SAIXDELLE, A., FALOT, P., HEE, J. Action de la fumee de
    cigarette et de qutlquesuns de ses constituants sur les resistances
    ventilatoires chez le cobage. (Action of cigarette smoke and some of
    its constituents on ventilatory resistance in the guinea pig.) Archives
    Internationales de Pharmacodynamie et de Therapie 167 (1) : 101-
     114, May 1967.
(100) GUYATT, A. R., BERRY, G., ALPEKS, J. EL, BRAMLEY, -4. C., FLETCHER,
   C. M. Relationship of airway conductance and its immediate change on
   smoking to smoking habits and symptoms of chronic bronchitis. Amer-
   ican Review of Respiratory Diseases 101(l) : 44-54, January 1970.
(ror) HAMMARSTEN, J. F., WELCH, M. H., RICHARDSON, R. H., PATTERSON,
   C. D., GUENTER, C. A. Familial alahai-antitrypsin deficiency and pul-
   monary emphysema. Transactions of the American Clinical and Clima-
    tological Association SO(l) : 7-14, 1968.
(102) HAMMOND, E. C. Evidence on the effects of giving up cigarette smoking.
    American Journal of Public Health and the Nation's Health 55-p):
    682491, May 1965.
(10.7) HAnfhfoND, E. C. Smoking in relation to the death rates of 1 million men
   and women. In : Haenszel, W. (Editor). Epidemiological Approaches
   to the Study of Cancer and Other Chronic Diseases. Bethesda, U.S.
   Public Health Service, National Cancer Institute Monograph No. 19,
    January 1966. pp. 127-204.
(104) HAMhfoPr'D, E. C., AUERBACH, o., KIRMAN, D., GAZLF'NKEL, L. Effects of
   cigarette smoking on dogs. I. Design of experiment, mortality, and
   findings jn lung parenchyma. Archives of Environmental Health
    21(6) : 740-753, December 1970.
(105) HAMMOND, E. C., HORN, D. Smoking and death rates-report on forty-
   four months of follow-up of 187,783 men. II. Death rates by cause.

208


    Journal of the American Xedical Association 166(1I): 1294-1368,
     March 15, 1958.
(IUG) HAYWN, G. B.. DA~IDSOX;, J. T., LILLINCTON, G. A.. WASSERMAS, K.
    Nitrogen dioxide-induced emphysema in rabbits. American Review of
    Respiratory Diseases 95 (5) : 7977805, hlay 1367.
(JOT) HAYM)N, G. B., FREEMAN, G., FKJKIOSI, N. J. Covert pathogenesis of
   NOZ induced emphysema in the rat. Archives of Environmental Health
    11(6) : 776-783. December 1965.

(108) HAYXES, W. F., JR., KRS~ULO~IC. V. J.. BELL, A. L. L.. JK. Smoking h<bit
    and incidence of respiratory tract infections in a group of adolescent
    males. American Review of Respiratory Diseases 93(5) : 730-735,
    May 1966.

(109) HENRY, >I. C., FIXDLAY, J., SPANCLER, J., EHRLICII, R. Chronic toxicity
   of NO, in squirrel monkeys. III. EtIect on resistance to bacterial and
    viral infection. Archives of Environmental Health 20(5) : 566570,
    I\Iay 1970.

(110) HEPPER, X. G., HYATT, R. E., FOULER, W. S. Detection of chronic
    obstructive lung disease. An evaluation of the medical history and
    physical examination. Archives of Environmental Health 19 (6) : 806
    S13, December 1969.
(III) HERXANDEZ, J. A., ANDERSON, A. E.. JR., HOLMES, W. L., FORAKER, A. G.
    Pulmonary psrrnchymal defects in dogs following prolonged cigarette
    smoke exposure. American Review of Respiratory Diseases 93( 1) : 78-
    83, January 1966.

(11-0) HIGGIXS, I. T. T. Respiratory symptoms, bronchitis and ventilatory
    capacity in random sample of an agricultural population. British
    1Iedical Journal 2: 1198-1203, November 23, 1957.
(113) HICCI~;S, I. T. T. Tobacco smoking, respiratory symptoms, and ventiIa-
    tory capacity. Studies in random samples of the population. British
    Medical Journal 1: 325-329, February 7,1959.
(114) HIGGISS, I. T. T., COCURAN, J. B. Respiratory symptoms, bronchitis and
    disability in a random sample of an agricultural community in
    Dumfriesshire. Tubercle 39: 296301, 1958.
(115) HIGGIXS, I. T. T., COCHRANE, A. I,. Chronic respiratory disease in a
    random sampie of men and women in the Rhondda Fach in 1958.
    British Journal of Industrial Medicine 18: 93-102, 1961.
(116) HIGGIXS, I. T. T.. COCHR~NE, A. L., GILSON, J. C., WOOD, C. H. Popula-
    tion studies of chronic respiratory disease. A comparison of miners,
    foundry\vorkers, and others in Staveley, Derbyshire. British Journal
    of Industrial Medicine 16: 255-268, 1959,
(117) HIGGIXS, 1. T. T., GILSON, J. C.. FERRIS, B. G., JR., WATZRS, >I. E.,
    CAhlPBELL, H., HIGGINS, M. W. Chronic respiratory disease in an
    industrial totvn: A nine-year follow-up study. Preliminary report.
    American Journal of Public Health and the Nation's Health 58(9) :
    1667-1676, September 1968.

(118) HIGGI~s.I.T.T.,HI~~I~s, M.W.,LOCKSEIIN, M. D.,CAXALE, N.Chronic
    respiratory disease in mining communities in Marion County, West
    Virginia. British Journal of Industrial hledicine 25 (3) : 165-175,
    July 1968.

(119) HIGGINS. I. T. T., OLDHAM, P. D., COCHRANE, A. L., GILSON, J. C. Res-
    piratory symptoms and pulmonary disability in an industrial town.
    Survey of a random sample of the population. British JIedicaI
    Journal 2: 904-909, October 20, 1956.

209


(fix,?) HILDIXG, A. C. On cigarette smoking, bronchial cai-cinema and ciIiary
     action. II. Experimental study on the filtering action of cow's lungs.
     the deposition oi tar in the bronchial tree and removal by cilinry
     action. lu'ew England Journal of Medicine 254(25) : 1135-1160. June
     22, 1956.
(121) HOLLAND, W. W., Errram-, A. Cigarette smoking, respiratory symptoms
    and anti-smoking propaganda. An experiment. Lancet l(7532) I 41-43,
     January 6, 1968.
(I%?) HOLLAND. W. W., HUIL, T.. BENNETT, A. E., ELLIOTT, A. Indications
     for measures to be taken in childhood to prevent chronic respiratory
     disease. Milhank, Memorial Fund Quarterly 47 (3, part 2) : 215-227,
     July 1969.
(12s) HOLLAND, R. II., KOZLOWSKI, E. J., BOOKER, L. The effect of cigarette
     smoke on the respiratory system of the rabbit. A final report. Cancer
     16(S): 612-615, Xay 1963.
(I%$) HOLLAND, Vi. W., REID, D. D. The urban factor in chronic bronchitis.
     Lancet l(7383) : 4451148, February 27, 1965.
(12.5) IIOLMA, B. The acute effect of cigarette smoke on the initial course of
    lung clearance in rabbits. Archives of Environmental Health 18(2) :
     1'71-173, February 1969.
(126) HUHTI, E. Prevalence of Respiratory Symptoms, Chronic Bronchitis and
    Pulmonary Emphysema in a Finnish Rural Population. Field survey
    of age group 40-64 in the Harjavalta area. Acta Tubercuiosea et
    Pneumologica Scandinavica (Supplementurn 61) : 1965. 111 pp.
(107) HURST, A. Familial emphysema. American Review of Respiratory Dis-
     eases 80: 179-180, 1959.
(1%) HYATT, R. E., KISTIN, A. D., MAIL~N, T. K. Respiratory disease in
    Southern West Virginia coal miners. American Review of Respiratory
     Diseases 89 (3) : 387-401, March 1964.
(129) IDE, G., SUNTZEF-F, V., COW'DRY, E. V. A comparison of the histopathology
    of tracheal and bronchial epithelium of smokers and nonsmokers.
     Cancer 12(3) : 473-484, May-June, 1959.
(130) ITO, H., AVJILDO, D. XI. Pulmonary emphysema and cigarette smoke.
    Experimental induction and use of bronchodilators in rats. Archives of
     Environmenta Health 16(6) : 865-870, June 1968.
(131) JAMES, R. H. Prior smoking as a determinant of the distribution of
    pulmonary ventilation. American Review of Respiratory Diseases
     101(l) : 105-107, January 1970.
(132) KAHN, H. A. The Dorn study of smoking and mortality among U.S
    veterans: Report on 8'h years of observation. In : Haenzel, W. (Edi-
    tor). Epidemiological Approaches to the Study of Cancer and Other
    Chronic Diseases. Bethesda, U.S. Public Health Service, National
    Cancer Institute Monograph No. 19, January 1966, pp. 1-125.
(133) KAMINSKI, E. J., FANC~IER, 0. E., CALANDRA, J. C. In viva studies of the
    ciliastatic effects of tobacco smoke. Absorption of ciliastatic compo-
    nents by wet surfaces. Archives of Environmental Health 16(Z) : 18%
     193, February 1968.
(134) tJENNEDY, J. R., ELLIOTT, A. h1. Cigarette smoke: The effect of residue
    on mitochondrial structure. Science 168(3935) : 1097-1098, May 29,
      1970.
(135) KENSLER, C. J., BATTISTA, S. P. Chemical and physical factors affecting
    mammalian ciliaty activity. American Review of Respiratory Diseases
     93(3, Part 2) : 93-102, March 1966.

210


(136) ~LEISET.!.:S. J. E;iects of X02 in hamret-5: AutoradiographIc ano.
    e!ec:rsr. microscopic aspects. In: Hanna, !,I. G., Jr., Settesheim, P.,
    Gi:%r:. J. I?. (Editors). Inhalation Csrcinogenesls. Proceedings of a
    B!l!oz- Di:-ision, 0ak Ridge Sationai Laboratory Conference, Gntlin-
    burg. `iiwessee, October 8-11, 1963. U.S. .ktomic Energy Comniss!on
    S:.x!xsium Series 15, r\pril 1970, pp. 271-281.
(137) IiORDIE. P., BULERJSG. E., BURY, J. H. Ciliary movement and acetyl-
    choline. British Journal of Pharmacology and Chemotherapy 7: 67-
     79. 1953.

(123) KRAIZL. 1.. E., BL-LXGH, .\I. H. Studies on Ii\-ing ciliated epithelium.
    Xxericln Review of Pespiratory Diseases 99(5) : 711-718, Nay 1969.
(129) KRCGER, -1. P., s?dlTIi, R. F. Eifects of gaseous ions on tracheal ciliary
    rate. Proceedings of the Society for Experimental Biology and hfedi-
    tine 5s: 41"-114, 1958.

(140) &!U\lHOLZ, R. .A., CHEVALIEq R. B., ROSS, J. C. Cardiopulmonary func-
    tier. in young smokers. A comparison of pulmonary function measure-
    menrs and some cardiopulmonary responses to exercise between a
   &~oup of young smokers and a comparable group of nonsmokers.
    .Xnnals of Internal Medicine 60 (4) : 603-610, April 1964.
(222) KTUYEOLZ. R. A., CHEVALIER, R. B., ROSS. J. C. Changes in cnrdiopul-
    mor.ar&- functions related to abstinence from smoking. Studies in
    xocrg ci;aretre smokers at rest and exercise at 3 and 6 weeks of ab-
    srirxence. =\nnals of Internal Medicine 61(Z) :197-207, February 1965.
(14-1) Ii~.vxaorr. R. .A., CHEVALIEX, R. B., ROS, J. C. A comparison of pul-
    mortar>- co.mpiimce in )-oung smokers and nonsmokers. American
    Rex-:ew oi Respirsrory Diseases 9?(l) : 102-107, July 1965.
(1:s) KLIIPTEE~. r'. fdentificsrion of the heterozl-gous state for the afpha,-anti-
    trx~zsin C?ticienc>- gene in man. Biochemical Genetics 3(3) :X3-288,
       -
      ISFCI-

(I;;) ~CIEPPTPX F.. FALLAT, R., LARSOS, R. K. Obstructive lung disease and
    aluta.-aztitmpsln deficiency gene heterozvgosity. Science 165(38963 :
   S9%9il. August 29, 1969.

(145) ~BELLE, C. ii-`., BEWLACQUA, 3. M., RRIEGER, H. The influence of ciga-
    rette -make on lung clearance. An experimental approach. Archives
    oE Enxir.xxmental Health l`Z(5) : 58%596, Nay 1966.
(1:6) L~NRZFZT, P. U., REID, D. D. Smoking, air pollution, and bronchitis in
    Bri-ain. Lancet l(7652) : 853-857, April 25.1970.
(fL7) I-xKios. R. I;.. Ba~~rax. al. L. The familial occurrence of chronic ob-
    structive pulmonary disease. Annals of Internal Medicine 63(6) :
    lOOl-lops, December 1965.

(148) LARSOS, I?. 6., BARXAN, hf. L., KIJEPPERS, F., FUDENBERC, H. H. Genetic
    and en\-konmental determinants of chronic obstructive pulmonary
    dise,e. .\nnals of Internal Medicine 72(5) : 627-632, May 1970.
(149) L~~`PAI-zI, G. -4.. G~;,~xEKI, J. J., E~RIGA, R. B., CAREY, J. P. Clear-
    ance of hacreria by the lower respiratory tract. Science 142: X72-
     1573. Den'oer 20 1963.

(150) LEEX. W. L. B. z& investigation into bronchitis. Lancet 2: 762-765,
    Octo.ber 13, 1956.
(151) LEXOE. S. \I., WONSACOTT, T. H. The prevalence of chronic respiratory
   disease in rhe male physicians of London, Ontario. Canadian Medical
    ;\ssociation Journal 102(g) : 381-385. February 28. 19'70.
(152) LEUCEXE~CERGER.C., LELXHTENBEXGER, R.. ZEDRUN. W.,%AFFER, P. A
    correlzred histological, cl-tological, and cytochemical study of the
    tracheobronchial tree and lungs of mice exposed to cigarette smoke.

211


11. Varying reslwnses of major bronchi to cigaiettr smoke, absence of
bronchogenic carcinoma after prolonged ezpojore, and disappearance
of bronchial lesions after cessation of exposure. Cancer 13(-t) : 721-
732, July-August 1960.

(153) LEIvjS, G. P.. LYLE. H., ~lILI.ER, S. Association hrtwcen elevated hepatic
    Xvater-soluble protein-bound cadmium levels and chronic bronchitis
    and/or emphysema. Lancet Z(`i631) : 1330-1333, December 29, 1969.
(154) LIEBERMAN, J. Heterozygous and homozygous alpha,-antitrypsjn den-
   CienCy in patients with pulmonary emphysema. Sew England Journal
    of Medicine 281(F) : 279-284, August 7, 1969.
(15.5) LIEBERMAN, J., nhTThIAN, C.. SCHNEIDER, A. S. Screening for home-
   zygous and heterozygous alpha,-antitrypsin deficiency. Protein eiec-
    trophoresis on cellulose acetate membranes. Journal of the Imerjcan
    Medical Association ZlO(11) : 20X-2060, December 15, 1969.
(156) LIEBESCHUETZ, H. J. Respiratory signs and symptoms in young soldiers
    and their relationship to smoking. Journal of the Royal Xrmy Medical
    Corps 105: 76-81, 1959.

(157) LOWE, C. R. An association between smoking and respiratory tubercu-
    losis. British Xiedical Journal 2: 1081-lOS6, November 10, 1956.
(158) LOGE, C. R. Chronic bronchitis and occupation, Joint meeting f;o. 1.
    Section of Occupational Medicine with Section of Epidemiology and
    Preventive Medicine. Proceedings of the Royal Society of Medicine
    61(l) : 98-102, January 19F8.

(159) LUK~MAN, T. Smoking in Relation to Coronary Heart Disease and Lung
    Function in Tlvins. A Co-twin Study. Acta Medica Scandinavica 180
    (Supplement 455) : 1966.75 pp.

(160) M~DERXOTT, M., COLLIXS, M. hl. Acute effects of smoking on lung air-
    ways resistance in normal and bronchitic subjects. Thorax 20: 562-
    569, 1965.

(161) XARTT, J. >I. Pulmonary diffusing capacity in cigarette smokers. An-
    nals of Internal Medicine 56(l) : 39-45, January 1962.
(162) bfaslN, F., i%~ASIN, hI. Frequencies of alveolar cells in concentrated
    sputum specimens related to cytologic classes. Acta Cytologica lO(5) :
    362-367, September-October 1966.

(~6s) MEGAHED.G.E.,SENNA,G. &EISSA, M. H., SALEH, S.Z., EISSA,H. A.
    Smoking versus infection as the aetiology of bronchial mucous gland
   hyperttophy in chronic bronchitis. Thorax 22 (3) : 2'71-278, May 1967.
(16.4) NENDENHALL, W. L., SIIREEVX, K. E. The effect of cigarette smoke on
   the tracheal cilia. (Abstract) 28th Annual Meeting, April 21-24, 1937,
    hiemphis, Tennessee. The Scientific Proceedjngs of the American%-
   ciety for Pharmacology and Experimental Therapeutics, Inc. Journal
   of Pharmacology and Experimental Therapeutics 60: 111-112, 1937.
(165) XILLER, D., BOXDURANT, S. Effects of cigarette smoke on the surface
    characteristics of lung extracts. American Review of Respiratory
    Diseases 85(5) : 692-696, May 1962.

(166) &fILLm, .7. AI., SPROULE, B. J. Acute effects of inhalation of cigarette
   smoke on mechanical properties of the lungs. American Review Of
   Respiratory Diseases 94 (5) : 721-726, November 1966.
(167) ~IELS, C. A. Tobacco smoking: Some hints of its biologic hazards. Ohio
    State Medjcal Journal 46(12) : 1165-1170, December 1359.
(168) MITCHELL, R. S., WEBB. N. C., FILLEY, G. F. Chronic obstructive bron-
   chopulmonary disease. III. Factors influencing prognosis. American
   Revjew of Respiratory Diseases 89(6) : 87%896, June 1964.

212


(169)

(170)

(171)



(172)

(173)

(174)



(175)



(176)



(177)

(178)

(179)

fl80)

(I8I)

(182)

(18J)

(184)

(185)

I\IITCHELL, R. S., SILX-ERS, C. W., DART. G. .I.. I'ETTY, 'JZ. I,.. \'ISCENT,
T. N., RYAN, S. F., FILLEY, C. F. Clinical 2nd morphologic m-r&-
tions in chronic ainvay obstruct:on. .\merican Review Of Respiratory
Diseases 97(l) : 54-61, January 1368.
h~ORIYA&,, I. >I., D~wsm, T. R., K.as~ifL, IV. B. Evaluation of diag-
nostic information supporting medical certification of deaths from
cardiovascular disease. In: Haenszel, W. (Editor). Epidemioiogicai
Approaches to the Study of Cancer and Other Chronic Diseases.
Bethesda, U.S. Public Health Service, h'ational Cancer Institute >IOn-
ograph No. 19, January 1966. pp. 405-419.
~IOP.K, T. A Comparative Study of Respiratory Disease in England and
Wales and Norway. Acta Medica Scsndinavica 172 (Supphmentum
384), 1962. 100 pp.
~IoKros, X. Postoperative hyporaemia. Medical Journal of Australia
Z(7) : 341-342, August 16, 1969.
MORTON, H. J. V. Tobacco smoking and pulmonary complications after
operation. Lancet 1: 368-3'70, &larch 18.1944.
MOTL~, H. L., KUZMAN, 1%`. J. Cigarette smoke. Its effect on pulmonary
function measurements. California Medicine 88 (3) : 211-220, March
1958.

MYRVIK, Q. N., Ev~ss, D. G. lrretabolic and immunologic activities of
alveolar macrophages. Archives of Environmental Health l-1 (1) : 92-
96, January 1967.

NALIEL, J. A., COXROE, J. H., JR. Acute erTects of inhalation of cigarette
smoke on airway conductance. Journal of Applied Physiology 16: `i13-
716, 1961.

XANDI, hf., JICK. H., SLOXE, D., SHAPIRO, S., LEWIS, G. P. Cadmium con-
tent of cigarettes. Lancet Z(7634) : 1329-1330, December 20, 1369.
OSWALD, N. C., NEDIEL, V. C. Chronic bronchitis; the effect of cigarette-
smoking. Lancet 2: 843-844. October 22, 1955.
PALECEK, F., AVIADO, D. XI. Pulmonary effects of tobacco and related sub-
stances. II. Comparative eliects of cigarette smoke, nicotine, and his-
tamine on the anesthetized cat. Archives of Environmental Health
15 (2) : 194-203, August 1967.

PaEcKK, F., OSKOUI, RI., AVIADO, D. 11. Pulmonary effects of tobacco
and related substances. III. Inhibition of synthesis of histamine in
various species. Archives of Environmental Health 15(2) : 2044213,
August 1967.

PARNELL, J. L., ANDERSON, D. 0.. KINNIS. C. Cigarette smoking and
respiratory infections in a class of student nurses. New England
Journal of Medicine 274 (8) : 979-984, May 5, 1966.
Pmms, J. XI.. FERRIS, B. G., JR. Smoking, pulmonary functions and
respiratory symptoms in a college-age group. American Review of
Respiratory Diseases 95 (5) : 774-782, May 1967.
mm, J. .\I., FERRIS, B. G., JR. Smoking and morbidity in a college-age
group. American Review of Respiratory Diseases 95(5) : `783-789,
Ilay 1967.

mK-WN,`D. I., LONERCAN, L. H., HAKDIKCE, M. G. Smoking and pul-
monary function. Archives of Environmental Health 16(2) : 215-218,
February 1968.
PHILLIPS, A. &I., PHILLIPS, R. \I'., TKOMPSON, J. L. Chronic cough.
Analysis of etiologic factors in a survey of 1.274 men. Annals of in-
ternal hledicine 45(2) : 216231, August 1956.

213


(1~6) PIPER, D. W. Respiratory complications in the postoperative period.
    Scottish 3Ie;lical Journal 3(5) : 193-198, Jlay 1938.
(187) PRAIT, S. ;\., FISI.EY, T. h'., SMITK, >I. If., LADXAN. -4. J. X comparison
   of alveolar macrophngcs and pulmonary surfactant (?) obtained from
   the lungs of human ~mokcrs and nonsmokers by endobronchial lava@-
    Anatomical Record 163(4) : 497-508, April 1969.
(18s) RAKIEXEN, N., RXKIETEN, ,?I. L., FELDMAN, D., BOYKIN, &I. J., JR. Mam-
   malian ciliated respiratory epithelium. Studies with particular refer-
    ence to effects of menthol, nicotine, and smoke of mentholated and
    nonmentholated cigarettes. A.hI.A. Archives of Otolarpngology 56:
    494-503, 1942.

(189) RANKIN, J., GEE., J. B., CHOSY, L. W. The influence of age and smoking
   on pulmonary diffusing capacity in healthy subjects. &Iedicina Thora-
    cnlis 22(3) : 366374, 1965.

(190) RANKIN, J. G., HALE, G. S., WILKINSON, P., O'Dxy, D. 31.. SANTAMARIA,
   J. N., BAI~ARCZY, G. Relationship between smoking and pulmonary dis-
    ease in alcoholism. Medical Journal Jf Australia l(14) : 730-733,
    April 5, 1969.

(191) READ, J., SELEY. T. Tobacco smoking and ventilatory function of the
    lungs. British $IedicaI Journal 2: 1104-1108, October 28, 1961.
(192) RE~OTSKIE, N.. CANNEL, W., GOLDSMITH, J. R., DATER. T. R. Pul-
    monary function in a community sample. American Review of Respi-
    ratory Diseases 86(G) : 907-911. December 1962.
(193) RIXIKCTON, J. Chronic bronchitis, smoking and social class. A study
    among working people in the towns of Mid and East Cheshire. British
    Journal of Diseases of the Chest 63 (4) : 193-205, 1969.
(134) ROBERTSON, D. G., WARRELL, D. A., NEWTON-HOwEs, J. S., FLETCHER,
    C. M. Bronchial reactivity to cigarette and cigar smoke. British &red-
    ical Journal 3(X&5) : 269-271, August 2,1969.
(195) ROQ~E, A. L., PICKREN, J. W. Enzymatic changes in fluorescent alveolar
    macrophages of the lungs of cigarette smokers. Acta Cytologica 12
    (6) : 420-429. November-December 1968.
(196) ROSENKRANTZ, H., ESSEX, H. J., SPRAGUE, R. Lung hydroxyproline lev-
    els in mice exposed to cigarette smoke. Life Sciences 8(11, Part 1) :
    571-576, June 1, 1969.

(197) ROSENKRANTZ, H., SPRAGUE, R. Biochemical screen to investigate whole
    smoke and vapor phase effects in mice. Archives of Environmental
    Health lS(6) : 917-924, June 1969.

(198) ROSS, J. C., LEY, G. D., KRUMHOLZ, R. A., RAHBARI, H. A technique for
    evaluation of gas mixing in the lung: Studies in cigarette smokers
    and nonsmokers. American Review of Respiratory Diseases 95@):
    447-453, March 196'7.

(199) SAMIASEK, hl., AVIADO, D. M. Bronehopulmonary effects of tobacco and
    related substances. II. Bronchial art&al injections of nicotine and
    histamine. Archives of Environmental Health ll(2) : 152-159, Au-
    gust 1965.

(200) SAMANEK, M., A~IADO, D. M. Bronchopulmonary effects of tobacco and
    related substances. IV. Bronchial vascular and bronchomotor re-
    sponses; their suggested defense function. Archives of Environmental
    Health 11(Z) : 167-176, August 1965.
(201) SAMAXEK, M., AVIADO, D. RI. Cardiopulmonary effects of tobacco and
    related substances. III. Pulmonary vascular effects of cigarette smoke
    and nicotine. Archives of Environmental Health 12(6) : 71'7-724, June
      1966.

214


(20) SA~IANEK, M., X~IAD~, D. >I., PESKIS. G. W. B~OIK~O~U~IIIOII~~~ cff~ts
     of tobacco and related substances. III. Axon reflexes elicited from the
    visceral pleura. Archives of En\-ironmental Health 11(2) : 160-166,
     August 1965.
(203) SCARPELLI, E. JI. The Surfactant System of the Lung. Philadelphia, Lea
    & Febiger, 196% 269 pp.
(004) SCIIOETTLIX, C. E. The health effect of air pollution on elderly males.
    American Review of Respiratory Diseases 86(6) : S78-897, December
      1962.
(205) .%a~, J. R., ~YI\IIAWADEKM, 51. S., DEsHh~uKH, P. A., PIILJTAXE, P. N.
    Institutional survey of pulmonary tuberculosis with special reference
    to smoking habits. Indian Journal of Medical Sciences 13(5) : 381-
     392, nxay 1959.
(PO6) SHORT, J. J., JOHNSON, H. J., LEY, H. A., JR. The effects of tobacco
    smoking on health. A study of 2,031 medical records. Journal of
    Laboratory and Clinical Xedicine 24: 586-589, 1939.
(207) SIMONSSON, B. Effect of cigarette smoking on the forced expiratory flow
    rate. American Review of Respiratory Diseases 85: 534-539, 1962,
(208) SLUIS-CREMER, G. K., SICHEL, H. S. Ventilatory functions in males in n
    Wit-watersrand town. Comparison between smokers and nonsmokers.
    American Review of Respiratory Diseases 98(2) : 229-239, August
      1968.
(209) SLUIS-CREMER. G. K., ~VALTEHS, L. G., SICHEL, H. S. Chronic bronchitis
    in miners and nonminers: An epidemiological survey of a community
   in the gold-mining area in the Transvaal. British Journal of Indus-
    rial Medicine 24(l) : l-12, January 1967.
(~10) SLIITII, J. P., SXIITH, J. C., ~ICCAIL, A. J. Chronic poisoning from cad-
    mium fume. Journal of Pathology and Bacteriology SO: 287-296, 1960.
(211) SPURCASA, A., EHRLICH, R., PETZOLD, R. Effect of cigarette smoke on
   resistance to respiratory infection. Archives of Environmental Health
    16(3) : 385-391, March 1968.
(212) S~,X?;EXU. D. C.. TECULESCU, D. B., PACU~URU, R., GAVKILESCU, N.
   Chronic effect of smoking upon pulmonary distribution of ventilation
   in healthy males. Respiration 25 (6) : 497-504, 1968.
(219) STERLIXC, G. 11. >Iechanism of bronchoconstriction caused by cigarette
   smoking. British Medical Journal 3: 275-277, July 29, 1967.
(~14) STRIEDER, D. J., MIJRPIIY, R., KAZEMI, H. Mechanism of postural hy-
   poxemia in asymptomatic smokers. American Review of Respiratory
    Diseases 99(5) : 760-766, BIsy 1969.
(215) TALAMO, R. C., ALLEN, J. I)., KAHAN, >I. G., AUSTEN, K. F. Hereditary
   alpha,.antitrypsin deficiency. New England Journal of Medicine 278
    (7) : 345-351, February 15, 1968.
(216) TARKOFF, hl. P., KUEFPEXS, F., hIILLER, W. F. Pulmonary emphysema
   and alpha,.antitrypsin deficiency. American Journal of Medicine 45
    (2) : 220-228, August 1968.
(217) TIIURLBECK, W. XI.. HENDERSON. J. A., FRASER, R. G., BATES, D. V
   Chronic obstructive lung disease. A comparison between clinical roent-
   genotogic, functional and morphologic criteria in chronic bronchitis,
   emphysema, asthma and bronchiectasis. Medicine 49(Z) : 81-145.
     March 1970.
(zfe) TOKIJHATA, G. K., DESSAUER. P.. PENDERGRASS, E. P., HART&TAN, T.,
   DIGON, E., ;~IILLER, W. Pneumoconiosis among anthracite coal miners
   jr, Pennsylvania. American Journal of Public Health and the Nation's
   Health 60(3) : 441-451, March 1970.

                                        215


(219) U.S. PUnLtc HEALTS~ SERVICE. The Health Consequences of Smoking.
    1968 Supplement to the 1367 Public Health Re\-iew. \Vashington. U.S.
    Department of Health, Edl;cntion. and Welfare. Public Health Service
    Publication So. 1696. 1968. lli pp.

(220) U.S. PUBLIC HEALTH SEI~~ICE.~'~TIO-;,~LCESTER FOR HEXLT~I STATISTICS.
    Cigarette smoking and health characteristics, United States, July
    1964June 1965. Washington, U.S. Department of Health, Education,
    and Welfare, Vital and Health Statistics Series 10, No. 34, Public
    Health Service Publication No. 1000, >Iay 1967. 61 pp.
(221) U.S.PUBLIC HEALTH SERVICE.NAT:ONALCESTEKFOR HEALTH STATISTICS.
    Vital Statistics of the United States-1967. 1'01. II-Xortality-, Part
    A. Washington, U.S. Department of Health, Education, and Welfare,
    Public Health Service Publication, 1969.
(22) U.S. PC`BLIC HEALTH SERVICE.NATIONALCESTERF~RHEALTH STATISTICS.
    Vital Statistics Rates in the United States 1940-1960. Washington,
    U.S. Department of Health, Education and IVelfare, Public Health
    Service Publication No. 16'77, 1368. 881 pp.
(223) U.S. PUBLIC HEALTH SERVICE. Smoking and Health. Report of the Ad-
    visory Committee to the Surgeon General of the Public Health Serv-
    ice. Washington, U.S. Department of Health, Education, and Welfare,
    Public Health Service Publication No. 1103, 196-l. 387 pp.
(2,O:) WEBB, W. R., COOK, W. A., LANIUS, J. W., SHAIT, R. R. Cigarette smoke
    and surfactant. American Review of Respiratory Diseases 95(Z) :
    244-247, February 196'7.

(225) WEIR, J. BI., DUNN, J. E., JR. Smoking and mortality: A prospective
    study. Cancer 25(l) : 105-112, January 1970.
(226) WELCH, 31. H., REINECKE, M. E., HAhfAlAxsTEN, J. F., GUENTER, C. A.
    Antitrq-psin deficiency in pulmonary disease: The significance of in-
    termediate levels. Annals of Internal Medicine 71(3) : 533-542, Sep-
     tember 1969.

(397) WICKEN, A. J. Environmental and personal factors in lung cancer and
    bronchitis mortality in Northern Ireland, 1960-62. Tobacco Research
    Coucil, Research Paper No. 9, 1966. 84 pp.
(128) WIGIITMAN, J. A, K. A prospective survey of the incidence of postopera-
    tive pulmonary complications. British Journal of Surgery 55 (2) : 85-
    91, February 1968.

(229) WIKLANDER, O., NORLIN, U. Effect of physiotherapy on post-operative
   pulmonary complications: A clinical and roentgenographic study of
    200 cases. Acta Chirurgica Scandinavica 112: 246-254, 1957.
(290) WILHELMSEN, L. Effects on bronchopulmonary symptoms, ventilation,
   lung mechanics of abstinence from tobacco smoking. Scandinavian
    Journal of Respiratory Diseases 48(3/4) : 407414, 1967.
(231) WILHELM~EN, L., OH&%, I., TIBBLIN, G. Decrease in ventilatiry capacity
   between ages of 59 and 54 in representative sample of Swedish men.
    British Medical Journal 3 (5670) : 553-556, September 6, 1969.
(232) WILSON, R. H., MEADOR. R. S., JAY, B. E., HIGGINS. E. The pulmonary
   pathologic physiology of persons who smoke cigarettes. New England
    Journal of Medicine 262(19) : 956961, hIaY 12. 1960.
(2s~) WINKELSTEIN, W., KANTOR, S. Respiratory symptoms and air PolIution
   in an urban population of Northeastern United States. Archives of
    Environmental Health 18(5) : 76&777, bfay 1969.
(234) WOOLCOCK, A.J.. VINCENT, N. J., MACKLEM, P. T. Frequency depend-
   ence of compliance as a test for obstruction in the small airways.
   Journal of Clinical Investigation 48: 1097-1105, 1969.

216


2.75) WYNDER, E. L., GOODVAS, I). A., HOFFMAN.S, D. Cllintoxic components
   in cigarette smoke. Ii. Carboxy!;c acids znd nldehydes. Cancer 18(4) :
    505-509, April 1965.

:L'36) WYNDER, E. L., KAISER. II. E., GOODMAN, II. A., HOFFIIXNP;, D. A method
    for determining cili,st,tic components in cigarette smoke. Cancer 16
    (9) : 122-1225. September 1963.

(257) WYNDER, E. L., KAUFMAN, P. L., LESSER, R. L. A short-term follow-up
    study on ex-cigarette smokers. With special emphasis on persistent
    cough and weight gain. American Review of Resp~ratury Diseases
    `S(4) : 645-655, October 1967.

(5s) WYNDER, E. I,., LEMON. F. R., MAKTEL, N. Epidemiology of persistent
   cough. American Review of Respiratory Diseases 91(5) : 679-700,
    hlay 1365.

(~39) YEAGEK, H.. JR. Alveolar ~~11s: Depressant effect of cigarette smoke on
   protein synthesis. Proceedings of the Society for Experimental Bi-
    ology and Medicine 131(l) : 247-250, May 1969.
(-040) &MEL, N., YOUSSEF, H. H., hIhE, F. J. Airway resistance and peak
   expiratory flow-rate in smokers and nonsmokers. Lancet 1: 1237-1238.
    June 8, 1963.

(z$z) Zwr, S., GOLDMAX, H. I., LEVIN, A. Cigarette smoking 2nd pulmonary
  function in healthy young adults. American Review of Respiratory Dis-
    eases 89(l) : 73-81, January 1964.

217


RRONCHOPTJLMONARY

APPENDIX TABLES

219


TABLE AZ.-,Smoliing and c/Lronic obslrrrctiua pttlwonar~ discase su'ttptonls'-percolt prevalence
     (Numbcn in garcnthcwe rcprcscnt tolnl number of individusl in yatiiculnr smoking group)
               Shl = Smokera.      NS = Nanamokcra.     EX ; Ex-amokere.

Author,
  ycllr,
countl-Y,  Nutt$rO;nd                                  Drcnlhl~~snns
                       Cowh        Sputum production      or dyspnea       Chest illncssses        Other         Commenle
rcfcrcnce     DoPUhtiOn                                                                           ____
Short     2,031 male and     NS I... 1.6 (496)                              NS ,, .ID.O                 C.hril illnrssra

Oswnld    3,602 male nnd                                                            Chronic Bronchilir   Chronic
and      2.2*12 femnle                                                                 nfh        br<lncllltlJ
Mcdvei,    clerical                                                              NS , ., 16.8  (470   J~fi$,rLl IlY
1956.     workers (k-65                                                    sm ., ..16.4 (1.940)    halrilul\l
England   YCRt3 of age.                                                                FClTdCl       cuuuh nnd
(178).                                                                      NS  ,.,.,. 12.1 (610)   Rpill"",
                                                                     sm .,,... la.8 (618)   ,>rducLllln.

PhilliDe    1.274 mnle       NS `2.0  (461)
et al.,     fnctor~ workcn   sm . ..Gl.O  (823)
1966.     wiLhout overt
U.S.A.    pulmonary
(185).    dircnsc or
        hcnrt failure.

   Higgins    301 male nnd                    Ccmoh and spufum                               Chronic Bronchilia
    1957,     280 ffmnle                         hfolcs           Malea          `41&l            Malts
    Enslnnd   i-oral dwellers                  NS . ,,  7.1   (28)   NS..........7.1 NS . . . ..I... a.6 NS I,,.... 3.6
   (II?).    26-74 yeDrS of                  SM . ,. ,. 63.9  (222)   531 ..I. . . . ...19.8  Shl . . . . . . . . . 17.1  Sbf  , ., I.. 9.9
            we.                            FtWU21.24         Ft??7l~fGJ         FO7I&#           FL-?Mlt-,
                                   NS ., ,, 4.6 (176)   NS .,I. . . . ...21.6  NS . 9.7  NS . ,, . ., 3.4
                                     sm ,... 17.2   (93)   sm . , . 9.1  Shf .a . . ..16.1  Shl . . . . 8.6
k
r


T,\nr.~ A2.-Smokhg and chronic obstructive pulmonary, disease sl/jliptotlis +m+xnt pcvalence (coral.)
       (Numbers in pnrcnthcvrs rcyrescnt tatnl number of individunl~ in vnrticular smoking nroUV)
                 Sbl = Smokers.      NS = Nunsmokers.      EX = Ex.amokrra.

and      92 frmnlcs
Cochran.   randomly chosen
1958.      (members of an
England   agricullurel
(114).     commur*itu.)

Edwards   1,131 male out-
et al..     ImticntY on
1959.     lists of
Ennlnod   lmlcral prnc-
(74).     titionera >60
        YCPci of DBF.

Cammrnta

Couoh and sputum    NS .,... . . . . ...33.3 NS I..,. 0.0           hlalca
NS     (6)  S!d . . . . . . . . . ...29.3 SH 16.0     NS . . . . . . . 0.0
Sbf ., ..24.0  (151     FtWIalW        Femdcs      SM  . . . 6.7
NS ., ,, 3.1   (G4)  NS . . . . . ...46.3 NS . 10.9          FCrntllC#
Shl .I ,I 3.0  (20)  SH ..,.., .20.0 Shf ..I 10.0     NS  . ,,,, .` 0.0
                                        S.M  ,,....I 6.0

                                          Chronic bronchilir
                                        NS  .,, ,, 1C.6   (151)
                                        Cigarette8 29.1   (778)
                                        l-9 . ...23.4  (236)
                                        lo-19 . ...31.2  (361)
                                       >20  . . . . . 33.7 (176)
                                       Pipe  . . . 18.6  (340)

-

Flick     222 mnle        NS . . . . . . . 10.0  (61) NS ..,,,.... 26.0  (49)               NS . . 30.0 (47)
and      pntitnts not     sm ,. ,. ..66.0 (167) Sbl ,, ..66.0 (1.66)               SM . . . 60.0(138)
Pnton,    auffvrina from
1359.     avert rnnlio-
U.S.A.    D\lllilOnF.~y
(86).     dincnac. ZO..OO
        r*rnofopc.

Hiuuina    716 maln In                    Couoh and c~ulutn                               Chronic bronchitis
et al.,     VR?/OUI                      SM ,. ., ., ,. 7.1  (86)  NS . ,. . . . . .a.., 0.4 NS s I. . . 7.1     SM  , ,,.., 14.3
106D.     OCCUD~UO~~                   NS ,. ., ,. 36.0  (1176)  SM ,, ,, ,, ,. ,, .24.9 SM .a .a 20.2     NS . . . . . . 3.b
England   26-64 yc(~rc,
(IIS).    of age.


--

Liebnchuetr,l47 male        NS ,. ,, ,. 0.0  (621

   lC59,     soldiers       Shi ,. ., ,. 13.0  (83)
   Elsland   20-30 years
    tl.76).    of ogc.
  - --
  Ashford    4.014 male
   Et al.,                                                                  Rcnpiraloru ayrn~,lomr Rwpirntov
           coal workers.                                                          NS . . . . . . 103  (677)   symplumn-
   lQC\.                                                                     EX  . ,. ,. 19.6
   ,England                                                                           (123)   "bronchitis
                                                                           and/or
    (11).                                                                 Cignrcttes 21 1 (1,604)
                                                                           Pipe only 36.1  (202)   uthmn". Nu
                                                                           Cizarcttn           duua 1.<,1>,-
3                                                                           and DIDC 37.1   (90)   tionslaip
                                                                           AIlShI 21.7 (3,210   f"Ul-ld.


t4             TAllI E A2.- .Ytt~okin~~ 117rtf chrouic obstricclilrc prtlt~lcr?rcrrl~ tliucccw .ul/~Jr/J~o~~lY'--
td                                         ],c:rcclll /murlfcm: (CWll.)

IP               (N\,,,,~,Q~ ,n ,,nrcnthws rrprcucnt t,,tuI n,,n\l~cr of l,~dlvldunl~ in ~nrtlcufnr amokinv k!:ro'JD)
                                 SM z= Slnok~rr.      NS ~1 Nunanwkvra.      1,:~ := Ex.smokurs.

      Author,
       YPUi-.     NumLcrnnd                                 Urcnthlc~sncas
      country.      type uf        Cough        Sputum prduction     01 dyapnea      Chest illnesses        Other         Comment.9
     rrfcrrncc    nnpulntion
    -______- --
    Dnwcr.    06 malt nnd      NS . . . . . . . . 4.1  (49)   NS .,. . . ...20.4                  NS . . . .31.7                    Cheat lllnws-
     1861.     11 lcmulc      Shl .#. .27.0  (76)   Shl  . . . . . ...34.2                  Sht ,,.,.I 88.2                     clllY!t COllll
     U S.A.    bnuk om~~loycoa l'lvc, clunr 1.   (19)   l'inc. clgor lG.4                 I'il~c.cluar                       duringcach
     01).     40.10ycnrs                                                     63.0                     01 Ilint z
             of I,YV.                                                                           Wlr~tPIR.
              -
    Flrtchvr nnd 3G3 mnlc I.w~don                                                                           --
                       NS . ,  8 ,   (80) NS  ..,..,.a., 8.7    NS . . . . . . . . .  .I   NS . . .a. 4.S
     Tlukcr,    trQnalwrt     t-14 g./dny 16.6 (1GC)   I-14 a./dny ..ZI.U    1..14 n./dny *. 8.2   1-14 n./doy
     lOGI,     Cm[ll"Yl'L*     >lS . . . ...27.0 (110)   >lG  . . . . . . . ..aO.D    >lG . . ...*.. 8.0         8.2
     Ynulnnd   40 GoYchrI                                         >lS . ...10.7
      185).     01 DPB.

    Read     170 malcand           M&a
      and      132 Iernnlc     NS ..,..s.. 4.4
      SCIIJY.     indlvldunla     SM . . . . . ...23.1
      1961.     lntervicwed     EX . . . . . ...21.2
      Auatdlr   inanoub           FHlt.llC~
      (191).    Datient       NS , 4.9
             clinic (not     SM . . . . . ...18.6
             all paticntsl,

     BIlebum   1.461rnale      NS . . . . ...10.2  (263)   NS..........ll.O NS.......... 9.8
      et al..     llaht        SM . . . . . . ..23.3(1.108)   SM ., . . . . ...30.4    SM . . . . . . . ...14.6
      IDVZ.     Industry      <I wck.           <I wck-
      U.S.A.                                           <1 rx~ck-year .lO.O
             cmvloym in     YCar . . . ..ll.O  (267)
      (PO.                                year . . . ...12.0     I- u . . . . . ...12.0
             C~lifomla.     l- 9 . . . ..I?.0 (2Ed)    l- 9 . . . . . . ..u.o    lb-10 . . . . . . ..ll.O
                      10-19 . . ...26.0 (aos)   lib-19 . . . . . ...32.0    20-29 . . . . ...18.0
                        20.29  . . ...21.0 (236)   20-2'3 . . . . . . . . 34.0    30-39 . . . . . ...21.0
                        30-31  . . ...28.0 (144)   30-39 . . . . . ...40.0    40-49 . . . . . ...13.0
                        ra-49  . . . ..ae.o  (12)   40-49 . . . . . . . . 37.0    m-59 * ,. .* . . .9&O
                        60-69  . . ...84.0  (28)   So-60 . . . . . ...46.0    >60  .,. . . ,, .29.0
                        PO  . . . ..GO.O  (24)   X0  *..II... 62.0


?`,\uLE AZ.-Slnoking and chronic obstwclil~e pulmomr~ discasc' .S~III~~O~II.S `-.-pcrcoil prcunleuce (co?it.)
       (Numbers In ~nrentbrsw re~resrnt tutnl number ol individunls in ~nrticular smoking aroun)
                 SM = Smokcra.     NS = Nonsrnoken.     EX = Ex-smokers.

Author,
  YCPT,     Number snd                                  nrenthlcssnns
countrY,      type of         Cough        Sputum Drduction     or dyspnea      Chest illness-        Other        Commcnte
refrrencc   population
           -
Boucot    6,137 mslcs      NS . . 13.0  (806)
et Ill.. 1862.  cnroliina      SM .31,6(6.331)
U.S.A.    in pulmonary
(36).     neoplasm project.

Ftrria    90 male and                                                            Chraic Nonrpccific
CL &I,.     71 female                                                            Reepiralory Dbcosc
llC2.     Rnx mill-                                                                 n1a1ca   Frtlld<I
U.S.A.    workers.                                                             NS  ..lG,O(?O) lO.O(GO)
(Rf).                                                                      ES  , 12.6(16)
                                                                         I-20 .27.3(X22) , ,
                                                                    >20 .63.1(32) GO.0 (4)

   Fenis    642 male and                                                             Chronic Irorkchilir   hgc-,prcifir
    and      6?5 frmnle                                                                 ?lrnlCI        r*tm.
    AlldCrWn.  wnidcnts of                                                           NS  . . . . . . 13.8  (126)
    1962.     New Iinmpshire                                                        EX . ,, ,, ..lI.O   (77)
    U S.A.    town chosen                                                          Cianrcttcs 40.3  (340)
    IElI.     by randurn                                                            l-10 . ...218
           rumpling of                                                           11-20 . .34.2
           CC"S"S.                                                              21-30 . 4?.3
                                                                           31-40 G1.1
                                                                           >:I  ., .SG.3
                                                                           F'cnlol~,
                                                                           NS . 0.4  (97Lo
                                                                           El . 10.8   (37)
                                                                           Cignrcttn 19.8  (208)
                                                                           I-10 .13.1
                                                                           II-20 ..I. 22.2
                                                                           21-30
                                                                           31-40 .27.3
F=:                                                                           >41  .`
u                                                                           --


(Jf6).    e. Finnish      1-14 .,.., 31.6 (108)
       commun*l     15-24, . . . ..4O.S (191)
      region,       >25  .,.... 42.4  (86)
      40-64 yearn          Femah
       of age.       NS . . . . . ..I 4.6 (709)
                 EX . . . ..13.3  (30)
               1-14 . . ...10.4 (77)
                 16-24 .*,.,. 43.0   (6)
                 >26  .,....# *.   (1)

      TABLE AP.--Smoking and chronic obstructive pulmonary disease s~?~ipto?t~s `-percEnt prevalence (cont.)
             (Numben I" Qarcntbu.~ reQreaent total number of individuals in ~articulnr smokinn p.rOUD)
                            SM = Smokers.     NS = Nonsmokers.     EX z Er-amokera.

Author,
  y-2.r.   Numm:ri"d                                    Brcnthlrss"ess
CO""W.                  Cough         SQUh" prcductic.n       or dyepnes     Cheat Illnessw       Other         Commcntd
refcrcnce     QoQularloa

Goldsmith   3,381 wtive                                                           Respiretory
et al.,     or retired                                                                cotiditiona
1862,     longahoremcn.                                                         NS
U.S.A.                            hI"d6;;;;;h$:y (74"
(9s'.                                                                  smokcn 43.0 (1,298)

Co&lea    1,342 male and                                                  Covgh and chronic phlcotn Current
et al.,     242 female                 NS . . . ..ll.Z (747)       NS 14.7                 NS . . . . 4.0        smoking
1966,     Detroit poet               l-14 , ..12.7 (266) (not LiK.) 1-14 .28.2(Q<O.OOI)            l-14 . . . .  S.t("at alp.)  dntll.
U.S.A.    omce                  16-24 . ..2'7.6 (402) (p<O.W1)16-24 .30.7(~<0.001)           16-24 . . . . 17.2(Q<O.001)
(63).     employees.                   >26  . . . 36.4 (170) (P<o.oOI)>25 . .a4.i(D<O.o01)           >26  . . . . . 26.8(Q<o,~o~~

Deane     608 tele-                                                            Pcrairfcnf cough,    NS includrs
s?t al..     DhO"e                                                          phfcpm. dwvnca     cx-arnokera,
1966,     CO"lQII"Y                                                            NS . . 4.6  (ZOO)   pigc. and
U.S.A.     workers.                                                         Current CIgBreIle       ckar
(671.                                                                       smokere 16.9  (308)   amukcn.

Huhtl,    653 mrlc and           Ml&#           Malt.            Malt,                  Chronic bronchifir   Ex-smiakrra
1966.     823 female     NS . ..I.... 4.1 (122)
Finland    reeidentP of     EX . . . . 6.6  (141)

NS . ,. 10.7
EX , . . ., ,. ,. 17.7
1-14  . . . .38.0
16-24  .,. . .42.9
>26  . . . . . .42.4
   FC7WJlC8

NS . . 4. .:-.. . 16.6
`ix . .24.8
l-14 . . . . ,* .2G.O
IS-24  ,,,..... 26.2
>25  . ., .31.8
   FOdC8

NS .  6.9      NS ., ,, . . 29.2
EX **.... . ..13.3      EX  . . >. .33.3
l-14  . . . . . .10.4      1-14  * ,,..... 14.3

     Molcl
NS  . . . . 6.7
EX  . *. . . 16.3
1-14 , . . I 38.0
16-24  ,...41.4
>26  ,,... 40.0
    FCTdU

NS . . . 4.6
EX  .,, . . 13.3
x-14 . 10.4

16-24
>?6 I . . .67.0

lb-26
>=   . . ...67.0


Author,
  YCBT.     Number and                                     BreathlnsnpJs
count-Y,      type of         Cough         Sputum production       or dyopneu     Chest illnesses,        Other        Conlmvntd
reference     populntion

Wynder   316 male         New York Cily
et al..     patirntr in     NS I.., .14.0  (44)
19G6      Nrw York City   Pipe. cigar 33.0  (64)
U S.A.    and 316 male    Cigrrcttcs:
(PSB).    patient3 in       l-10 . ..46.0 (44)
        California.      10-2.0 . .46.0  (88)
                  >20 . ...67.0 (86)
                    Catifornia
                   NS  .~ . . . . 22.0  (69)
                 Pipe, cigar 30.0 (32)
                   Cigarettes:
                     l-10 .46.0  (64)
                    lo-20 . ..74.0 (91)
             >20 . . ..`?4.0 (69;                                                            --.-
FIPOID    1.066 randomlv                                                            Clinical aipna ot


TABLE A2.-.%tokinn and chronic obstructive pulmonary disease syltlpto,t~s'-percent prevalence (cont.)

(Numbcra in parentheses represent t&l number of individuals in particulbr smoking group)
      SM = Smokera.      NS = Nonemokem.      EX = Ex-amokera.

Cough        Sputum production

Dreatblwsness
or dyapnea

Chest Illne4ace

0ti-M         Commenti

DCllWlI    6,ais IIW&            POI(rrl           PCWld            Poltd                                 Dyepnca
a &I.,     and 7.29 1      NS ..a ,. ,. 7.0 (908)       13.1              IQ.8                                  rcurcscntcd
1967.     fernah POStAl   Pipe, clgsr 12.4 (628)       11.4              24.8                                   by Grade 11
U.S.A.    snd ban&It     Clgarettrs                                                                  OIIIY.
(88).     worken.       only . a. .27.0(2.687)       28.9              31.7
                        Transit          Transit            Tromit
                   NS  . . . 6.4(1,012)       9.6              11.7
                 Pipe, cigar 10.6 (766)       14.1              14.2
                   cigucttea
                    onlr  , . . .23.6(8,`746)       23.7              21.9

Efggins    926 white       NS  .I,,... 16.4  (162)   NS . . . . . . . . . . . 31.1   NS , . . , , ,. 6.0
et al.,    de A-     l-f  ..a . . ..47.2 (61s)   SM , ,a ., ., .4&Z   snl . ., ,* . ,* ..10.7
1968.     dents of       EX s.,,.,. 19.9 (144)   EX . . ,... 28.6   EX . . . . . . . ..16.8
U.S.A.    hlatlon
(116).    county, West
        Virginia.
        26-69 ycsn
        of age.

Holland    8,788 mrlc            Nolcr             Fcmolcs      N&I   FVdC#
snd      and female     NS  . ,, . . , 8.8(1,000)      9.2(3,137)       2.4     2.1
Elliott,    lChOOl        SM  . . . . . . . 6.3(1.038)       6.9 (664)       6.1     8.3
1968.     ebildrcn.       EX  . , . . . . . 2.9 (1,782)       4.3(1.161)       3.9     4.2
England             <l cignrette/dny ..,.,...,.... 6.8(876)           6.8
(112).               l-2  . . . . . . . ~ . . . . ..s.....,,.... 6.6(417)           8.4
                   3-4  .,.,,,.......,..,........... 6.6(120           8.1
              >5 *.,./ . . . . . . . . . . . . ..# . . . . ..9.`3(142)           18.3


Commenls

        Austrnlin.
niminnton 41,723 mnic

   prcvnlrncc 01      di,WgC
  chronic bronchilia     RlO<ll,`lil
     ,Ilulcr        ai~rliflcnrll
NS . . ..e. 6.1 (9,056)   to ~<O.OOl.
EX ,, 9.8 (6.610)
Pipe .,.. 9.0 (2.9211
cigsrcttrr    (23.243)
I- 9 ,,,.. 9.1
10-19 16.0
>20 , 20.6
    FC,lltll~#
NS .,.... 3.4(12,361)
EX ,..... 38 (D69)
PiDc . . 00
Cigarcttcs     (8.986)
1- 9 ,.. 6.1
lo-19 . 10.6
>20 * I. 18 6
  Chronic bronchilir

rt al.,     G&54 yesra                                                            NS . . . 1.0   (88)
1IEl.     of nac rnndomly                                                         EX , . . . * 3.0   (67)
Swcdcn    snmplcd irom                                                           l-14 grnms/
(231).    Pu~~uIc.tloI\                                                             day ., 6.0   (04)
       uf Guhborg.                                                           >16 ,.,., 17.0   (GO
        -.


TAULE AZ.--Smoki?lg and chronic obstructive p~tlnmm~ discasc sutttptol,ls'-pcrcolt preuahce (co7lt.J

(Numben in parentheses represent total number of individual* in wrticular amokinn `?rouP)
       SM = Smokers.      NS = NonsmLkcrs.      EX = Ex-smokers.

Author,
YCBT,     Number and                                   Drcnthlcssneas
countw,     type of         Cough         Sputum production      or dyspnca    Chest illnesses        00.X?           Commcnta
rctrrcnce    DoPulation

      Pcrnistent couph otldphlcgm
              Mnlcr
       nclc      rtuc     Aoc      Age
      ss-IS     is-55    65-05     M-48
NS It... 7(?27)    G("OU1   ll(171l    1 (01)
ES  . . . . . I(3031   11(3GBl   16(33G)   18(14Y)
<!!u  ,.. .lG(G"I)   22(488)   30(4101   37(13'))
20  . . . . ..23(lUl)   ZH(200   32(140)   98 (31)
>20  . . ..27(1481   26(1X)   42(121)   26 (12)
             Fcmalcr

NS .I.,. 31600)    4(G37)    K(O26)    6 (211
EX     311271    al1281    1 (041    1 1411

           <20 . . . o;mz;  13(472)  16(3OC)  11 (CGi
                  20  . . . . ..lC(1281   27(122)   31 (711   14 (7)
                  izo  . ...23 (22)   26 (301   43 (7)   . . (11

LCfCW     310 male                                                     Agc.rlondardizcd roka   Excluded from
rnd       Phuriciens                                                of chronic rer~~irot~rv    examokcra
Wonnacott.   in London                                                             dircaae        nt~' thvac
1970.      and Ontario,                                                      NS  . . ...**. t. 1.0   (881   clgurctk
Cnrda     26-74 yerAT                                                      EX  ..*,,. .*.. 6.0   (61)   amokcn who
(151).      of am.                                                         SM  .,,....,.. 34.0 (101)   now Bmoke
                                                                 Plpr, clgsr , .12.0   (aa)   pipn or clnrn.

' Data collected by either dlrcct lnteylw, puntionnnirs. rcvicw of medical records and/or medical cxamlnation.


          TABLE A23 .-S9rloltirlg and chro~~ic f~bslr~rlcliuc lI~tltilu7ictrU tlisvclsc s~~tl~~Lo~~is'-~l~l'cc,lt prmlcncc
               LNumbcra In parrnthcszu rcprrscnt tutol n~~rnbcr of individunb in pal-ticunr smoking group)
                            Shl = Smnkcra.    NS = Nurlsnwkrw    EX = Ex-emokcrs.

Author,
YCLLT.
countty.  Nutm$:,;nd            Cough                   Bronchitis                              Commcnta
rcfcrcnce   popuation
Ccdcrlol 9.319 twin               Obacrved/            Obscrvcd          Explnnotion of nnsl~nes for      All ex.snrokcrs ir~cludcd
et .I.,    paira                 czjectcd  IIupcrmorbidilu  cxllcclcd Ilyyermorhidity  rc3pirotory eymplorn          with smnkcrn.
136G,    rcairtcrcd    Croup A:      C(IICII       ratio      COlCd      ralio     VNV8lCliCC:              MZ--monorYKotlc
Swcdcn   in Swcdcn     hlnlcr . . . . ...393/151.9      2.c      157/60,8    3.1         Croup A analyale-using each    pPlr8
(46).    01 12,RRB      FC?YIL?les  . . . ..lW 49.4      2.8      a/11.2    3.8         flr~tbom twin an one proup   DZ-dizynolic ueira
       availuble.    Grau~ II Shl/NS:                                  In sn unmntchcd relat!onshlp Author concludes thnt
               hlZ Males , , 14.6/1.1      1.9      G.C/ 1.1    6.0 (274)      to each urcondborn twin.     ~llnee hypcrmorbldltv
                  Females . . l&6/7.6     1.8      3.0/ 2.3    1.33(264)     Group I.3 annlysis-uuiop each    for amsklnr pcraista
                DZ Mnlcs , . . 12.3/6.6      2.26      4.6/ 1.8    2.5,1(733)      twin set BJ matched pair.     in bmukinil-ill~rur,lrlnl
                  Females , , . 14.6/6.?      2.67     LB/ 1.6    3.0 (663)     AU compnrisons in Groups A    hlZ popuIe:ion. o
                                                             and B circ bctwwn smoking    CBIURI rcIntio~~~tI/~ ot
                                                             discordnnt pain.          smokmn nnd brnnrho-
                                                                           DuhOt,lltY B,"lDt"",l
                                                                           IS luyD"rtLYl.

Cederlol 4,379 twin              Prevalence of reapiralceu symptoms                                No cx.amukcrs lnciuilcd
et al..    pairs (all    Group A:                                                        in Croup II an0ly~11-1.
1969.    U.S. veterarls)   NS  . . ., ,, ,. 4.3     4.3             1.G      Group A--as above.            The nutliurr conclude
U.S.A.   in U.S.        l-10  . . . . . . . . 6.4     6.4             2.7      Grouv B--n3 above.            that the dntn indiente
145).    National      11-30 . . . . . . . . . . . . . . 16.3    18.3             8.0                           *strong probability
       Academy of    >31  . . . . . . . .27.1    27.1             16.6                            of rh cnu~al connection
       Sciences Twin  Pipe, cigar . . 7.1     7.1             2.1                            with amokinK. Even
      RegistrV (of   Group B:                NS    sn1        NS    snr                       thcsc a)`m,~t,rm~.
       9,000 avial.     hlZ  . . . . . . . . . . . . . . . . . . . . 2.6    6.4        1.6    4.6
       able),                                                                  howcvcr. acem to be
               DZ . . . . . . . . . . ..., .,., ,..,, ,., 2.0    9.8        1.6    9.1                      influvrrccd by gcnctic
                                                                           factors.

    ' Dab collccted'b~ either direct interview. questionnaire, review of medical records and/or mcdicnl examination.
N


(Numbers in parcnthcscs rrprcuunt total number of individuals in ynrticulrr amokinx R~QUD)
       NS = Nonsmokers.    Shl = Smokers.    EX = Ex-amokere.

EFR               FEV

vc        bliaccllancour     Commcnb

rorcrcncc   pop"lution
-_.. -
Chivcl-s.   463 m.lc                            Ilcight-in-inchca                                tblrn" EFII
1069.     rmlhyrcs   Cigcuettes/dny:         64"       66"        680'       70"                          I" lltcm
Ennland   of olknline    &rJ  . . . . . . . . . . . . *. t97(28)     91 (35)     108 (91)    lOl(21)                        par minute.
(51).     industry     6-20 ..~....,.......... R9(60)    RR (75)     101 (112)     1w (76)                         RCgrl3Ul""
        plnnt.      >7.0  ,..... ,.. .,, ,,, 63 (6)     RR.6 (9)     92.6 (9)    llS(lZ)                         annl,als of
                                                                           dn~n rcvralvd
                                                                           L 8iPiiincsnr r*
                                                                           h,tionahiv bclwc-z"
                                                                           smuking and dc
                                                                           crceviny function.

Hlgglnl   773 male3       26-64   65-64                                                               cxprcsanl
Et al.,    Invarious NS 146 (66) 101 (29)                                         FE"o.75

                                                                           DEB n>c~n indlrcct
1969,     occupstionl EX 143 (31) 89 (62)                                                          MUC.
England   (25-34 and 1-14 grnms
(116).    66-64 YeFall   .140(193) 87(167)
        of age).   >I6 Drnml
                ,183 (89) m(ia6)                                                                  -
WilSO"    28 male                                                                  RV/TLC
et al.,     residenta of                                               NS . . . . 6.69 (14, NS . . . ,. . . 21.1
1960     nnllsa,                                                   Sbf ,..,I `4.44 (IO SM  . . . . . . . `27.01
U.S.A.    TCXBS.
1?32).    former
        rural
        dwL4en;
        mntched
        for body
        aurrare. all.?.
        and height.


TOLD A3.--Smoking and vmlilatcq function (cont.)

(Numberr In parentheeca reprcscnt total number of individunls In gnrticulnr omoking group)
       NS :: Nonsmokers.    Shl = Smokas.    EX = Ex-enwkera.

EFR

FEV

vc        blleceunneoua      Comment.4

Ashford   4.014 mnle
et LI.,     coal workera                            Age:   FNESVl .o   snr
lD61.     at 3 Scottish                            <n-a0 4.09(103) a.06~280)
Scotl.nd   collieries.                                21-x .3.66(m) x.77(666)
(11).                                         31-40 a.44fla8) 9.88(m)
                                            41-60  .3.04(110) 2.06(766)
                                           61-60 .2.71(102) Z.KC(CIO)
                                           >co . ..2.88 (42) 2.21(297)

Dnta rcprcjent
reaulb nfter
correction fur
dtti"E hCiKht.
SM lncludcs ylpc
smoker.
Datr on cx.amokcr
not Included.
FEV,,O found
r,ipnlllcs"t: lower
for Shl tbsn NS.

Fletcher   a63 male                    Mean peak EFR
and      London                  NS . . . . . ,..  670 (SO)
Tinker.    CT!l"PPti                 l-14 prune   637(166)
1961,     employees.                >I6 grams   628(116)
Ensland                      EX ,....,.. 666 (61)
(85).

Franklin   213 male                                                                          llcavy smoker
and      factow               FEV1.0 FEVo".;: y.;;
LOWdl.    workcra                            FIenVY 2.670  3,dll  2.71; Light . . 3.703 (69)             rcyrcecnta 8"

                                     ListIt `2.489                                    amount wusl
lOGI.     40-60 ycrlrs                                      `2,666  `2.284 mnvy .~3,678(100             to or "lure
U.S.A.    of nw.                                                                      thsn 30 pack
(87).                                                                           YEIIII.


                          240 . , I 307.63 (67)         2.90

blsrlt.    73 healthy
1962.     medical per-                                        DLC#      Smukcn ,luRnrrl

U.S.A.    aanne with.                                                        NS  . , . . ., , . a3.10(30)  a* `hurt y'n"kinc

(IS!).    out signifi.                                              SLI <6 yce.n .`28.40 (8)  >zo ciKurcllcu/

        eant we                                                   6-lOyears . ..JZB.ZO(lO)  dny for varying

        diflcrence                                                         >I0 YEB,S  .`24.00(26)  pcriuds.

between
smokers and
nonmoken.


TABLE A3.-Smoking and vmtilatory /unction (cont.)

            (Numberr In DatentheSer tepre~enl total number of individuals in particular smoking group)
                           NS = Nonrmokrre.    SM = Smokers,    EX = Ex-smokers.

AilthOr.
  YC@.i-.
C0"thll-Y.               MBC
,efCtenCe   PWUltItiOtl                     EFR               FEV           vc         Mfacelkneou8      Comment4

Revotakle   1,130 male
et al.,     and 1.813                           FE"I.O                           Data prcacntrd
                                                  M&l    Fmah
1862,     female                                                                           in tcrma of
                                           NS
U.S.A.    relidtnti In                         . . ...0.98 (66) 0X18(255)                           ratio of

(IPI).                                   Cigsrettes/dny:
        Framinp-                                                                           obaervcd to

       ham par-                         l-10 .0.97 (90) 0.99 (92)                           9rcdlcted
                                            10-29
       ticipating                                .0.91(163) O.OS(167)                           valuca.
                                            >30
        in the pro-                               ..0.90 (81) 0.01 (22)

        spective
        study.

KrumboL  18 physicians                    MEFR
et al..     24-37 yee.ra              NS . en . . . .  660 (9)                       hftan DL
lB64.     or *ge.
U.S.A.                   Shl ..,.., ,. `690 (9)                                      NS SN
                                                                       Rat  . . . . . . . . . 36   `81

(ILO).                                                                    Excrclre:
                                                                         2mlnuta ..60   `41
                                                                         4 minutes ..60   148
                                                                        8 mlnuks

zwi      20 medical                                                             port exrrclae 39   `86

*t PI..                              MNEFR
     ntudcnbor NS . . . 187 (lo)                                            Authors found

1964.     graduate                         4.84       6.17
             Sbl aa.1193 (10)                                           a signitlcont diRercncc

U.S.A.    uhysicisns.                       `6.09       `6.63                         bctwecn Shf and

(P&l).                                                              NS for RV/TLC.
                                                                  complinnce. nnd non-

CO&b,    1.342 male
et al..     and 242
1966.     female 9oat
U.S.A.    oNice
(5-J).     emDloYecs

                              elastic realslance.
      FEV,.O       Timed VC'
Age:     NS   >25 o'oldau NS >tS/dau   FEVI,/VC
                                NS   >fS/daU
ID-44  `2.08(186)  2.86 (60)  3.89   3.86     `0.17    0.14
46-49  `2.96(170)  2x4 (42)  3.92   3.83     2 0.74    0.70
60-64  `2.X(116)  2.62 (22)  9.71   3.74     `0.74    0.70
            2.44 (18)  3.64   8.61     `0.14    0.68

h)            >roueste
            Of *gc.                                65-59 `2.64 (64)
k.i                                     G&64 l2.36 (63) 2.30 (8)   3.30   3.33     `0.12    0.70


    TADLD A3.Stnokitlg and vmlilator~ funcliotr (cont.)
(Numben In percnthcacn rcprcacnr total number of lndividu8ls In patilcul~r lmDkln# E~OUPI
       NS = Nonsmokcre.    SM = Smokcra.    EX = Ex-amokera.

Author,
YCU,
LO"lltlT.  NuttAi-;nd       MLIC            EFR             FEV           vc          Ml,cell*nmu        Commrnta

Xrumholr   20 mrls                                           Pulmonwy cmnpftime'a Mean body surfnce
et d.,     medlcd                                                           NS  , ., ,,,, ,, .0.241(10)  .rca for 2 ~1'0uUfl
1961,     ltuden(a or                                                        SM  , ,.., . . .~0.177(10)  ~08 not hnifl-
U.S.A.    graduate                                                    Compliancr/FRC    eanlly d,Rcrrnt.
(14:).    Dhyalclms.                                                        NS  ,,,...,.,. 0.064     Smokcls arc those
                                                                      SM  . ,* ,. .*. .`0.042     wit11 rc~unl to or
                                                                           g,ratr,' Ihhn 5
                                                                           pack ycor history.

RankIn    126 malea   NS ,., 118.1 (68)
et al..    nlthout a SM , ..`111.7 (67)                  FEV1.0             DL  DL/ NS Includea pipe
                                             NS .,..,,.,. . ..106.6               NS  . . ..Sl.l  d"eo,ar .",I CiYLII. arnl)krrs
  1066,     P-t                                  SM . #, *. . . *. * .`102.7               SM . .`26.9   volume  snd ox-smoke~a ot
  U.S.A.    hlatarq                                                                      ~l'<lh,Cl' thn" I
  (Iao).                                                                           8.22
         of reaplrr-                                                                   `4.96   puck ycor.
         tory                                                               0. VLIUCB have


                  TABLE AB.--Stt~oking and wmtilalory function (cont.)
                  (Numbsra In parenthcxs represent totnl number of individunh In pnrticulrr Bmoklng group)
                                 NS = Nonsmokers.    Shl = Smokers.    ES = Ex-smokera.

     Author,
      Ye-.  Nunniw;nd
     countlY,                NUC            EFR
     rdCre"Ct   DoDulntion                                   FEV           vc         MliCClhlRXl~        Comment8


    Edclmno   410 male                             FEVI.0
     et al..                                                  Vital ctlpocifv
           community NS                                                                     Ex.amokcra of
                      . ...*...  164(162)          7.89
     1066.                                                 2.83          4.98
            dwellers   ClllYent                                                                  CigDrettcS only.

     U.S.A.    ao-10s     dgarettte                                                                DifTerence aipnlll-

     (73).                                                                           cnnt bctwcen NS
            yean of    smokera. , `161(118)          7.36            `2.64          `4.14
            P.P.3.      EX  ,.,...... 167 (98)          8.09                                               end current
                                                         2.80          4.77
                 Pipe. clear 167 (47)          8.20                                               ciclrrette amokers
                                                         2.01          6.08                     at p<O.Ol.

    Petem     124 male                        MEFIZ              FEV
     End                                                Fh'V,,dVC
            college aPe                NS                                                   Heavy smoker refers
                                 *,,..... `10.28 (41)            1.0

     Femla.                                                4.68                      `87.6        to prc.ter than
            Btudenb.               Maderate . 10.06 (64)
     1967,                                                 4.69                       ES.8
                               H`=vY                                                  or cgual to I
                                      . . . . .  9.64 (29)
     U.S.A.                                                4.43                       83.9        pack yc.m.
                            EX . ..*... 9.48 (IO)
     (1st).                                                 4.74                       81.2       IxIodcratc nmokcr
                                                                           includcn ulac and
                                                                           cigar anickera.
                                                                           D~Rcrrncc brtween
                                                                           NS and hcnvy
                                                                           smoker la
                                                                           eiy"lRcA"t.

    RiopIns   926 white
     et d.,     msle                             FEVl.0

     1968,                                         NS
            resIdenta                                  . . . . . . . .  8.64060)

     U.S.A.                                        EX  . . . . . . . . &26(lta)
            of Narian
     (Ifa).    County,                          Cinarcttr SM 8.48 (611)

            west                                  l-14  . ...,.. B.67 (88)

           Virginia.                               16-24  . . . . . ., a.67 (273)
                                                >26
            20-69 years                              . . . . . . . . a.ao(m)

            of .p?.
w"
w


rrfrrcnec  pOpil&Nl
Sluia-     633 white                         35-44      G-54     >SS      Fh"J.O                   1 cignrrtlc z
CRWWr    mnlc                NS        S63(106)    627(101)    444(H)    ss-44 45-54 >Gs                 1 gin",.
                             . . . . . . . .
and      fflctorv             Grams/day:                             3.70  3.22  2.76                1 D""PC lobocco =
Sichcl.    workers              l-14 . . . . . . 657 (2C)    619 (17)    410 (7)    3.c4   3.31   2.24                 2c grrtms.
19&P.     over 36               15-24  . .  632 (94)    446 (36)    401(13)    3.66  2.94   2.28                1 cigar = 2 10 6
South    ycrsrs of              >?5    t52a (66)   t494 (31)   t380(10)    3.54  3.05 12.12                 grnms.
AirkCl    .ge.                                                                          t Derivnl BIUIIPI
(tw).                                                                           found sunifi-
                                                                           ranlly dillcrcnt
                                                                           frurn 0.

SlBlM_CU   87 male bus                          FE"1.o               Nifrogcn gradient
et 81..     drivers:                                  Younper     OIdcr   YouQ?er Old&-7   Younger   Older
1968.     27 anrd                            NS  ,.I.. 4.470(14)   3.310(40)   6,126   4,?90     1.63    2.49
Rumania   20-26. 60                           Shl  . . . ..`4.5OOl131   `3,200(20)   '6.285   '4,290    Il.47    83.77

        BYIll"lQmB.
DenWl    6.281 male                                       FEV, n                         FEV exprcaacd 111

et &I.,
1969,
U.S.A.
(69).

postal and
7,213 mole
transit
workers in
New York
City.

    A."
  POSlOl
1Slritc
3.29 (666)
3.11t2.340)
3.14 (1.292)
3.06 (1.038)
Tronait
ll'hitc
3.39 (620)
3.11(2,941)
3.16(1,929)

Non-white
3.05  (2041
2.04  (768)
2.96  (699)
2.93  (161)

Na-vhilc
3.08  (298)
2.99(1.041)
3.00  (691)

226 gramaldey ,. ,. . . , . . . .  3.0?(1,011)      2.96 (149)


(Numbers in parentheses rcprcscnt totul number of individunh in Dnrticular smoking group)
       NS = Nunsmukrrs.    Shl = Smukcrr.    EX - Ex-smokcru.

EFR               FEV

vc

Miscellanwu        Commcntr

                     PEFR               vc                  1963 vnlum only.
NS  . . . . . . . . . . . . . . . . . . . . . . . 1.  626(88)    FEVl,O
                               3.17       4.83
EX  . , . .  631tb7)       3.69       4.77
1-14 grams/day .,., . . ..,  621(90       3.62       4.83
>I6 grams/day ., ,I. .., ,.  492(GO       3.31       4.66                     --
     NBIFR                                                  NblFR hua Lccn
NS  , . .  4.09 (88)      ;;;I.0                              ~lnnllnrdlrcd for
Cignrrtte                                                      ogc nnd hciuht.
amokers.   3.64(101)             3.11
EX ,  3.99 (61)             3.38
Pipe, cigar   4.17 (33)             3.17


TAELE AS.--Smoking and vent&tory function (cont.)

(Numbs-8 In psrenthcaea rcprcacnt total number of lndivldurb In pw-tlcular amoklnr WJuD)
        NS = Nonsmokers.    Shl = Smokers.    EX = En.smokem.

AUbX,
Year,
countl-y,                     FEV             Miacellsneoua                   Commcnta
rtfcrcncs

Lundmnn.   87 hlZ and         FEV, n            N. wanhout nndicnt   hlZ = monorygotle.

62 DZ twin
prim aelectcd
from Swedlrh
Twln.Pair
Rerl1tty.

Slgnlftcant dlffercnccs
between smoklnp discordant
twin DltIl found for:
  1. G~OUD A MZ males
     and fern&e.

2. Group n DZ malea,
8. Gmuu ADZ nudes.

Slgnlficant diFferencea
between smoking dls-
cordant twin pain
found far:
  Grouu B DZ malee.

DZ = dirygotlc.

The author concludea that the danwe of ventllrtlon II mcssured by N,
w&shout was correlated with cigarette conaumptlon. Tbr FEY,,,
WBI aignlficrntly lower for amokera and tbcre wns a ecrrelstiuti
with clgsrette consumutlon.

Explan&tlon of rnalysea for rnplratow wnptam prevalencr:
  Grouu A nnrlvsls-u~lnn each Aratborn twin " ona PIO"P In .n
   unmatched relstlcnshlp to each wcondborn twin.

Group B w~alyala-wing ekfb twin set u mstcb*d unlr. All
comp~rlson~ In Grour, A rnd B are bctwetn nnoklw-dlscor
dant DllrI.

' Not lignlflcnnt Cdlflerence OI trend),
: D<O.OK
2 KO.01

' P<O.O011
' KO.001


TABLE Al.-Glossaq/ o/ terms rcscd in tables and tezt on smoking and venlilatory ~unclion

Symbol            Term              Volume or rate                         Dl2R"illO"

MDC., , ,, , . Muxlmal brenthine
         CLlDlCilY.
nlvv. . . . . . Mnxlmal voluntary
         vc"tllP.tlo".

EFR.. . . Explratory Row rate.. , . . . . . . , .Llters/mlnute. , . . ,`. . , . . . .  Rntc of flow for a speciflcd portio" of II forced expiration IhfMEFR-rate
PEFR., . ., , Peak expiratorr flow rate.                       of flow menauwd for middle hnlf of FVC).
XIEFR.. , . ,, , .Maximal expiratory flow rate.
hlMEFR., . . .Maximal midcxpirntory
         Row rate.

FEVt.. . . . Forced `ZDhtOW         Liters., ., . ., . , ,. , , ,. , ,. Volume expired within 8 speciRed time Interval. (FEVt.,,-volume explmd
         volume.                                in tlrst second of expiration.)

VC.. _. . . . .Vital capscity. . . . . , . . , , ..Llters. _. . I. , . . . . . . , Maximal volume of a paa that can be expelled from the lung8 by fOtCrful
FVC......... Forced vital capacity.                         effort fallowi"g a maximal expiration.
FEV,/VC.. Forced explratory         Percent.. . . . . . , . . . volume of forced explratio" (In time specified) related to vital CLP~C~~Y.
         vulume/vital capacity.

D `, , . ,, .,. Pulmonary ditTusinz
         capacity.
N2 washout.. Nitrogen washout
         gradient.

ml/min/mmHg


Exponential
CUrYE.

The ability of 8 chose" gns to peas from the alvmlua Lo wlthl" tbc pulma"srY
capillary.
The stepwIse pulmonary alveolar clearance of 8 gala. (Slope of e"rvc dcpcnda
upon the uni!ormity and adequacy of ventilation of sll parta of the lung,)
It may be done e.s II nlnglc--or multipl+-brcuth procedure.

     Compliance. . . . . , . , . . .Liters/CMH20. ,, . . . . ,. ,, , , ,, ,, ,  Volume change of the lung produced by 6 unit prrsaure change.

RV.. . . . . .Residual volume. . . . . . . . .Liters. . . . . , . , , I,I ,. , Volume of gno remaining In the lungs at the end ol a maximal eXplrnti0".

TLC. . . . .Total lung capacity.. . . . . . ..Litcrs., . . . . . , , . , ,, , Volume of gas tontnined in the lung3 at the end al a mnximal l"BDlrBtiD".

FRC. . . . ~,.,. Functional residual        Liters., *. , . . , , , . , , . , . , . . Volume of gns remaining in the lungs at the relting expiratory ICVCI.
         capncity.

             Alcveolnr volume. . ., . . ., . . ,. ., Liters., . . . . . . .  Volume of gas contained in pulmonwy slvcoll.
E                         I

P       SOURCE: Cmroc, J. et al. (56)


TABLE A&-Epidemiological studies concerning the relationskip of air
   pollution, social class. and smoking to chronic obstructive
        bronchopulmonary disease (COPD)

Hipnina.    3111 m&!+ and     Male drt. onlv (170):
19.57.      280f.x11a!-~       (a) The frequency of recurrent chest illneua PU bioh-
Erwllod    Iivinz in 2          cr in thr more pollukd region but the prcvslencc of
(IlL).     JeDarak           other repiratory symptoms and mc~o values were
         districts.           similar.
         (4&54 Pea"      (b) Significant difference observed In COPD mortality
         of age.)            rate.

CoUNnc of   787 m.le .nd       (I) bl& urban inhabitanb manifested almat twice the
Gemcml     782 femdea          prevalence of chronic bronchitis 8s rurrl m*les: this
Prncti-     43-64 Year-3 01        diKerence could not he explained on the b&s of
tiO"elT..     WC from           amoking habits.
1961.      medical docton'    (b) No sipificant urban/rural ditlarences noted for
England    caz.c lied.           PEFR.'
(55).                  (c) No significant urban/rural diflerenca noted for
                         COPD symptom% mow fernala.

E-err,, and   1.219 mal.x and
Anderson.   fernala living
1962.      in 3 different
U.S.A.     a- of L New
(81).      HamDxhir? town.

Mork,
1962.
U.S.A.
(171,.

339 male traPsDort
employees from
London and
N0YWaY.

SchoettLin.
1962.
U.S.A.
(fQ4).

Followina adjustment far ditTerences in smoking habie. no
significant differences in chronic bronchitis were observed
mnong the 3 pollution -I-.

Tbc excess ~rev~lencc of serious reapiratow symptom?l (dy-
spnea. wh-ing) snd PEFR dysfunction among London
Trsnsport employees was only partly eliminated after
standardization for xnokinu. and the author su~ge4ti
that this is due to differences in air pollution levels.

-.

(a) No positive correlation found between chronic reaDira-
tory illness and city size.

(b) A positive correlation was found between chronic re9-
piratory illncsrr and cigarette smoking (psrticdarl~ du-
ration)

Andenwo
ct al..
1965.
Csnada
(8).

718 residents of    Berlin. New Hampshire. has higher SO2 and particulate air
Berlin, N.H.. and   pollution levels and the higher respiratory disease preva-
918 resident, of     knee rates among its residenu were not accounted for
Cbilliwack.       by age differences. but were sccounted for after stan-
Can-da.         dardization for smoking habits (except that PEFR and
          FEV*.O dysfunction was more prevnkant in New Hamp-
            shire. and tic authors suzgest that this difference re-
             fleets sir pollution differences).

EolLnd     676 male tranapxt   (a) London employees manifested a greater prevalence of
and       cmD~oyees in     COPD symptoms and PEFR dysfunction than dihthe
Reid,      London .nd run,   T"Td emplorees.
1966.      EIIl7Lnd       (b) Smoking habit differences lloae were not sufficient to
Engknd                 explain this difference in COPD manif~trtiona.
(110.                (c) Both groups manifested pulmonary dvfuoction car-
                     related with tobacco consumption.

B.&Z
et mL,
1966.
CMd.
(27).

216 hospitalized   Winnipeg (clesnest of all areas in SO, and industrial
vcter*ns f tom     dustfall) residenls nmnife+& decreased prevalence of
vmiow areas 01    chest ilbewea. less sercrc grade of dysunea. and less
Candr (*U      sputum voImc produced when compared to resideota of
ntandwdlz.4 for    Ill other areall.
WC. tnbscco
conwmptioa. and
occupation)

242


__-
  AU*hO!-.
  year.       Number and
  CO""tm.       type of                     RC3Ult.T
refermcc      population
___-__
Ashley.     Standardized      Positive correlations:
1969.      mortality         (a) Smoke concentration and bronchitis mortality
Ensland    ratios for       (b) SO?  and smoke concentration and bronchitis mor-
(12).      males (1958-63)      tahty and socml class.
         for 53 boroughs     fcl Pollution and WCIBI class.
         with air pollution
         indexe..

Winkelstein  842 females       (a, The incrrssed ,,revalence ol rc~pirntory symptoms could
and       over 25 yeal of      not be explained by social class differences.
Kantor.     86e in vanou3     (b) No overall association noted between productive cough
,069.       regions of         and air pollution.
U.S.A.     BlZT=lo.
(233).

COOICY and   10.X87 children     Illnrzses considered included chronic cough. past bronchitis.
Reid.      6-10 Year3 of      blocked nose.
1910.      age from coo-    (n) Every geographic area showed a clear gradient of in-
England    trsstlng urban     creasing zllness prevslrnce with decreasing social class.
(58).      and rural area*.   (b) Social classes 1, II. and 111 showed no urban/rural
                      sradirnt while IV and V showed a clcnr excess in fre-
                      quency of chest illnesse, among urban residents over
                      rural residents.

                                                      -
Lamhrrr    9.975 males and     (a) The trend of increasing prevalence of bronchitic symp-
and       frmaleJ         turns from rural to urban resnondents was not nwated
Reid.      responding       by adjustment for smoking difference.
1970.      to questionnaire   (b) After adjustment for age and smoking habits. male
England    ,"TYW.         respondents manifested a clear correlation of persistent
(146).                 cough and phlegm prevalence with increasing air pollu-
                      tion. Correlation was not as striking in females.
                   (c) Although the proportionate riw in symptom preva-
                      lence increased with air pollution similarly in each smok-
                    ing group, the absolute ditTerenc= in morbidity risk in-
                      creased with increased cigarette consumPtion. sWP?stiW
                    ayncrgistic influenceJ of cigarette smoking and air POIIU-
                      tion.

(d) 1" the absence of cigarette smoking, the correlat%n
between the prevalence of persistent couah and phlegm
and air pollution was slight.

`See Ghsary of terms: Bronchopulmonnrv table A4.

243


TABLE AT.-E~~idemiological stwlirs concerning the relationship of occllljationat
  erpo~~re and slnoktng to clrronic obstructive broncltopulr~~onar~~ disease

   Ant&It-.
   P-.       Number and
  e0anu-Y.       type Of                     R.ZSUlti
  refct-cnc.2      D"p"ktlOIl

HiPEl3J     185 m.k,        Miner* sborved incrc,cd sympc`ml ~rcvrkncc (bm*tbleu-
  et IL       (84 nonminers.     "c-s. cough. sputum,.
  1956.       101 mincnb      Mincn xbowd increased prevllcnce al chronic bronchitis.
  Enntid    without poeurn+   Miners showed dccrcwed MELC.'
  (119). mniaaia.       Differences in smoking betwren the two groupn did not u-
                       rount for shove differcnccx.

PhiLLip.     1.274 mrln       None of the-industrial cnvironmenw wsere assoclrced with
  ct IL.      f.ct0I-Y cmLlloycs   an incrcrscd prcvaknce of chronic cough.
  1956.       (coke and      Cigmrcrte smoking and age were directly corrcl~ted with
  U.S.A.     ektrolytic       incresxd prcv~knce of cbmnic cou&.
  (185).      PI-X-).

Higrins     325 m&x 2s34     Mince m compared to workcn in non-.Lusty occuptiiona:
et .I..      re.n of ape md    2534 YCIIX of mg-icpificsntly increased prcvmlmce of
  1959.       401 m&3 L&b4      chronic bronchitis and MBC rbn"rm.litiezx
EnnLnd    years of *ge in     6564 Yeam of am--lnx signiticmntly increased prcvrlence
  (1161.      "*rious occup.-      of chronic bmncbitis mod MBC ~boorm~titia than in
          tiona.            25-34 9c.n of age group.
                      No amokin~ informrtion available.

Chivcn.     4.53 m*ka in       No significant diffcrenee in PEFR' between dusty and
1959.      *?*?????? o d     non-dustr m-o"iF.
Ennhnd    duatr occw.tiona  Ciramttc smoking (apccirllv in those >tO ye~n of age)
(59).      (lime md xxi-     sxs ruociated with decrcued PEFR v~lua.
          Mb uposum~.

Fiireins     300 mak miner.    Miners showed incrra~ed prevalence of symptoms and de
and       and 300 mak      creased MBC value which remained even after standard-
c"cbrwne.   nonminer 3-4    iration for smoking habits.
1961.      yea13 of .KF.     Torrl dust cxmure wm not dirvcthr correlated with these
Engbnd                 hndiwx.
(115).                 Wiva of miners showed similsr symr)tom nod tert changes
                       u compmrd with -iv- of nonminen.

Brinkmm    1.317 mxlt_ 4-s   Incrcucd ailicl exposure wu lssociati with r+n increased
md       ye.?5 of LKe      prcv&nce of chrnnic broacbith.
cata.     ritb v.rious     Higbrrt prcrsknce of chronic bronchitis -xx noted in the
1962.      ailiu tXpon"rC     non-expowd -up: and this group wsx noti to have
U.S.A.     hhtorier.        tie hirhea number of smoken and bisbest consumption.
OX).

Hyatt      267 male min,m    Increued history of undewround work xvxs a%.oci~Led Witi
cl d..      md tx-minen     o n incrtued bmnchopulmonrv s~~tom prevd~~ce and
1964.      45-55 yc.n       decreu& p"lmonSry function rahwx
USA.     of .OC.       The impairment of pubn"n8r~ function Luociated with
(**a,.                undergground work wss se~rr~(c from effect of smokimx:
                    but rmokinp md under-und work did show *dditioF
                      &ecu.

ElW"Od     2.628 mde and    Preparing room worken who umoifested hmiami -P-
CL *I..      fern& flu       tarns *kc. .h"aed an incrPrwd prevnknce of chronic
1965.      worken ""CT 35    bronchitis inderxndent of ape "I- smoking When ComP*d
IrcLod     Jean of .pe.      with non-prepm-ing mom workers.
(77).                 Fern... worken manifested s signib`cant wi=ti"" b
                    tarrn byuiaosia wm~tozzu and amoking while mrk work-
                      m did not.

Sluis-Cmmcr a27 minet-3 md     Those smokcn cxpoad to nold mine duJt mnnifatcd more
ct al..      nonminen over    s~mptomr of COPD ' Thea did noa-durt exp~cd smoken.
1961.      3s yarJ of .OC.    rbik prcvmknce of swptoms. uooog nonsmoker% VU
Suth .\fric.               *imil*r for the two k7rouLm.
1 WY).


TABLE A7.-Epidemiological studies concerning the relationship of occupational
exposure and smokzng to chronic obstructive bronchop?cl,nonary dzsease (cont.)

  *=I=.      Number and
country.       t-e of                     Result5
reference      pCJIXJla50ll               -__
Sluis-Cremer 827 miners and    The dose rclationxhiv of c~g~rettp. and COPD' JY~P~O~U

et *I.. 1967.   nonminers over    we.3 much more noticeable among those cxpoaed to dulL
South Africa  35 years of *gc.   Thr authors strnxed the syn-istIc rctiana of cisarrtte
(?09). (cont.)              smoking and dust exvo~urc.

BOUhUYS
et J..
1969.
U.S.A.
(99).

455 male cotton    Those exposed to dust manifested a significantly greater
textile workers    prevslence of byssinosilr sym~tom'~ than nonexvcsed.
(214 exposed to   Smoker, msntie?ted a significantly greater vrevrlmce of
dust in carding    byssinosia symptoms than nnnamoken.
and spinnina    No aignificsnt dlffcrencn in Monday morning FEV' vnlues
rooms. 241 not     were observed between smoker, and nonsmoken.
expo3ed~.       Prevalence of bysxinosis symptoms did not show any re-
              lstionxhip to length of employment.

Bouhuys
et al..
1969.
U.S.A.
(38).

Chester
et al..
1969.
U.S.A.
(49).

216 male hemp
workers and 247
workers in other
industries in
same region.
2069 years
of age.

139 male chlorine   Chlorine-exposed group manifested no difference in symp-

plant workers
(55 with history
of severe ex-
pasure,.

Hemp workers (especially the older ona) were noted to
have different smoking hnbitn from control group-fewer
heavy smokers. more light smokers. more ex-smokers due
to doctor`, orders.

Aged 20-49 -a. No difference in FEV, 0' values between
        controls and hemp &kern in cay smok-
           ing catel3ory.

      b. No di!Terence in FEV,., valum between
           men in different smokmg catpgorier.
Ap-ed SC+69 -3. Hemp workers manifested decreased
        FEV,.O values in .II smoking gmuvs
           except for heaviest smokers. Ex-smok-
        ers had lowest FEVIsO values.
     b. Those smoking moot had lower FEV, o
           values 1c1 compared with Light and non-
           smokers.
The authors conclude that:
There appesn to be no synersism between smoking and
hemv exposure as to effect on FEV, o although the
selection D~OCCSS whereby those with sy'mptoms have L
  zreater tendency to stop smoking may obscure such a
  relationship.

tams and D decreased MBC value when compared with
non-exposed IJroup.

Smoken in ehlorine-exvowd group had significantly de-
creased MBC and FEY values at) compared with non-
smokers in non-exposed group.

Greenberg    121 workers in
et al..      washing powder  Ser.sitized group manifested lower FEV,.dFVC' valua
                      IS comvnred with nonsensitized group even after smok-
1910.       factory (48 found   inp habits were controlled for.
England     to be sensitized
(911.      to $Iraduct.
          73 "CA).           __-
Tokuhat.    801 male miners    Incrensed mine cx~)osurc WRS associated with residual vol-
et al..                 umr and FEV abnormalities even after adjustments for
1970.                   .sge and smoking.
U.S.A.              A systematic ervosurc-impairment relationship ~a9 noted
(218).               only -"ml: smokers while relatively few nonxmoken
                    showed COPD impairment.

Smokrnn minen manifested more X-ray mIteration and
COPD JymDtoms than nonxmakers. regardle=., of n~m-
be= of Ye*- of underground exposure.

245


TaLE AIQ.-Ezpe~~ltn~ concerning the egect of the chronic inhdation of x0x
upon ihe irachcobronchial tree and pulmonary parenchma of animals

freeman    SpragucD~sl~Y    25 D.p.m.;
and       rnt%        (n, after 37-41 drya-moderate brDcrtrODhY md byper-
Hsydon.                plrsrr of bmnchisl and bronchiolar rpirhelium.
1964              (h) dter 146-157 &P-(I) Advanced ~YDC~~WD~Y md
U.S.A.                              hyperphaim of broochis and
(90).                                    bronchiolrr epltbeIium.
                                   (2) Increucd lunp vohlmr.
                               (3) Proliferation of coonectlve
                                        tlrsue.

Rwdon
et .I..
1965
U.S.A.
(107).

12.5 p.p.m. to d.z.th:
(a) Hypct-tmphy and occasion=1 metapluls of bmnchial
   and hronchiolsr epithelium.
(b) Incrtuc in number of sctivcly aecrrtlnrr roblct CCUX.

Haydon
et rl..
1967
U.S.A.
(106).

Albino rabbita.

Fr*Ul*ll    SprarucDawlcr    0.8 mp.m.-2 p.p.m. for entire lifespan:
et .I.,      rats.           (a) Alveolar distention.
1968.                (b) Reduction in number of da.
U.5.k                 (cl Epithelial inactivity ("dormancy").
(91).

FWCUIan
et *l..
1968.
U.S.A.
(89).

Bhir
et .I..
1969.
U.S.A.
(3X).

SvagucDawleu
rata.





Female Swiss
Albino mice.

18 D.P.m.
(a) 5 days-terminal bronchiolar epithclial bm?lertrophy.
(b) 4 weeks-(l) Widcapread bmnchiolar epitbelial by-
            vs-trophr.
         (2) Non-necratizing emphysema.

0.5 P.D."L:
(PI 6 hours/day for 3 months--pneumonitis.
(b)  24 boun/day for 3 months-(l) &3Diratiw hmnchi-
                        okr obstruction.
                    (2) Alveolar expmsion
                        and bronchi&r
                        infiammstion con-
                        sistent with early
                        focal emphywna.

Klcincrmm.  Male Smi.n Golden  100 D.p.I'n. for 5% houra:
1970.      hamsten.      (a) thymidinc autoradiography-intense burst of pmlii-
U.S.A.                  eration of cpithelium retUrninE to normal in 4 days
(IJO).                     (more lxraistent distdy).
                   (h) electron micro,copt( 1) Decrcsaed number of ICJ-
                                        CrdmY cella + mcrrto~
                                         granules.

(2) Increased number of brso-
    aomd structures.
(3) No chmge in number of
    ciliated cella.

246


AUthOr.
year.
country.   system
reference

and
Shreeve,
1937.
U.S.A.
(160.

Rakictcn
et al..
1942.
1J.S.A.
(188).

Calf trachea.

In ritro:
(al rabbit
  and rat
  tmcharl
  rings.
(b) human
  naJal
  lllUCO"S
  membrane

Method 1

I. Nicotine in    1. Caliary sctivlty dcpreued only upon er-
Locke-Ringers    pmurc to 100 mg. percent mlution.
solution.     11. Ciliaw activity depressed after 15-20 min-
II. Cisarette smoke   ute exweure depending on concentration
In ecdution.      of smoke in soiution.

Kordik    In oitro:     X&tine in Locke's Nicotine at ID--J g./cc had no eflecct on ciliary
CL .I..     Rabbit      solution.       activity.
1952.      trachea
England
(137).

Hilding.   In vitro:     Cigarette smoke   All tracbes, showed depressed or absent riliary
1956.     Cow trachea    (direct        mtivity.
U.S.A.            exposure,.
(120).

Krueger    In viva:      Cisarertc smoke.   Cigarette smoke decreased ciliarv activity by
and      Rabbit                  approximately 200 beata,minute.
Smith.      trachea
1958,
U.S.A.
,199,.

Dalhamn.   1~ vim:      Cigarette smoke.   1: `I/IO ahowed retsstion of ciliaw activity
1959.     I. Rat                    after one explmure.
Sweden     trachea               II. 6/10 showed cessation of ciliary activitg
(59).    In vitro:                    after one expol"r.5
        II. Rabbit               III. 6/7 ahowed cation of ciliary activity
         trachea                 after one cigarme exposure.
       III. Humsn
         ciliated
         Dl"CO3a

Fslk      In vitro:     Cigarette smoke.   Decreased ciliam activiW noted on expaaure to
et al..     Rat and rabbit              cigarette smoke:
1959       tracheal               (a) Repetitive exp~nure -ELU associated with
U.S.A.     epithelium.               persistence of response user longer periods
(80).                           of time.
                           (b) "Tar"-rich clgarette WZY more inhibitory
                              than "tar"-poor.

cc) Filtered smoke was I- inhibitory than
Wlfillcred.

BIllleWCr.  In vitro:     Cigarette unoke   Ciliary activity =su fully inhibited within 628
1960.     Human      in solutioa.      minum of erpmure depending upon concen-
U.S.A.     bronchial               tration of smoke in solution.
(15).      .nd tracheal
         epitbclium
         obtained
         durinr
         r*e.tbnla.

247


TABLE X13.-Ezp~rimmts concerning the effect of czgnrette smoke UT its
        co~stitzlenfs upon diary function (cont.)

Krnder
et rL.
1963.
U.S.A.
(896,.

In riror      Cinarrttc smoke:   Unfiltered ci~~rctte smokwili~tasia bp Znd-
Frab a.ter   and ita fractions   5th poty
  mussel     in solution.     Acid fpbenolic) fraction solution-immedialc
  diata-3                 ciliastlrrh.
  epitbelium             I%%& extr*ct fraction solution--oo cililataris.
                     Neutral fraction solution-no ciliaatasia.
                    1 percent phenol solutica+-immediate ciliuta-
                      sin.

D~lhunn   In &-or      Cig.rrtte smoke.   Unfiltered eigarctte?r--ciliasstsala in 3/6 csta
and      cst trscbc8.               after 5 cigarettes.
Rylandcr.                      Filtered cigarettes--no ci1ieata.G after 8 ciga-
1964.                           rett`?_ (6 cata).
SWed?fJ                        Controls-no cili.utasis (6 cab).
(61).

Balleoacr   In rib-o:     Nicotine in solution. Initlsl stimulation of activitT fallowed by de-
ct *I..     axl3.a                 cline mnd complete ciliuWi8 sfter 12-24
1965.       uij.ted                 hours of erwnure.
U.S.A.      mched
(26).      e>it0rhm
          obtazned
         d-ring.
         .2atbesiL

Dalhamn   In tirar      Cigarette smoke.   The longer the time interval between expo-
and      Cst trxter               sure-s, the more puffs were required (0 ca~ae
Rylandcr.                        ciliastasis.
1965.
swwde?3
(61,.

Wvnder    In rim:     Various compounds Formic. acetic. proDionic. benzaic acids alI
et sL.     FrcGl rua:R`   in soluhxL      more ciliatoxic than phenol.
1965,       masel                Oxalic acid Ins ciliatoxic than phenol.
U.SA.      cihted               Formrldebvde.  acrolein more ciliatoxic than
(35).      cpitbelium               phenol.

CBTSOIJ    In R'COT      Cigareltr smoke.      Perccv2 dccnruc in ciiiary activity
et .L..    c*r traclla              Control . . . . . . . . . . . . . . . . . . . . . . .   0
1966.                         Unfiltered smoke . . . __ __ _... . . . . . . . . .  63
U.S.A.                        C4lulose aceLate filter . . _. . ._ . . . . . . .  46
(44).                         C.rbon cellulose ncetste filLcr . . . . . . . -. . .  so

D&was.   In rite:      Cigrrette smoke.    Mean number of puffs requirrd to v&uca
                                                     --
1966.     Cat rrubcl.                         CiIiadLG
Swdm                        No filter . . . . . . _. . . . . . . . :. . . .  91
(60).                         Chnrcoal filter ._ __ _ _. _. . . . . . . . . . . . 170
                         Commcrrial cellulose acetate tilLer . . . . . 194
                        Chsrcoal and acet.tc filter . . . . . . . . . . . . 612
                            Cambridpc filter . . . . . . . . . . boo

Ken&r    III G-9:      Cianrettc smoke   Rabbit trachea-Total smoke condemw& of 2
and      Rabbit      mnd componenta   cigareiten, gas phase condensate of 7 ci&%-
B.ttisu.    trdlcs.    in Tyrode's      rctte caused similar ciliastasis.
1966.      cat t.chea.  Yolution.     Other sDeeiar--All found scnaitive to ciliaatrtic
U.S.A.     don trde.,            components of cigarette smoke. Bulk of a~-
(135).     monkc7              tivitg noted in gal phase (HCH. fommkk-
         tncba                bud=-. rcrokia).
         I-St machcr

248


TABLE A13.--Erpen'msnts concerning the rdcct oj kgarette smoke or its
        comtitucnts upon diary junction (cont.)

Author.
ye-r.
CD"3h-S.    SIStem        Methcd '                IkS"lb
reference

Kaminski   In virlo:      Whole md filtered Wet chamber adsrotion aignificantlrr reduced
et II..     c*t trP.chea.   cigarette smoke   tbc cilirstaric activity of whole smoke. but
1968.               er$cm?d or uler-   did not affect the ciliastatic activity of smoke
U.S.A.              posed to "Wet     previously filtered by Cambridge or cbuwal
(ISJ).              chamber" made   filters.
                  to stimulate
                  oral mucoma
                  and saliva

Klrhl     In viw:      CiRarette amokc   SimiBcant ciliastasis. reveaible.
md      ConmOD     dissolved in
BulmMb*    mollusk     sea water.
1968.    ciiirtcd
U.S.A.      cpithclinm.
(IN).

B.ttiata
and
Ken&r,
1970,
U.S.A.
(ra).

Bdtlsta
md
ILenskr.
1970.
U.S.A.
(19).

In vitro:     Cigrrette smoke   The autban observed that:
  Chicken    or HCN in      (1) The more diluted smoke required more
  trxhed    TYrode's         puRa to cau3c ciliastasis.
  cpitbelium.  solution. .    (2) Activated rbarcoal filtered smoke wu
                       less eiiia3tatic than ceilulose acetnte filtered
                       smoke and ~LYO contained less HCN and
                       acmkio.

(3) HCN alone Wm ciliastatic but recovery
WLS mare rapid than after cigarette smoke
alone.

They conclude that the ~a, phase components
are more related to ciliastaeis (as particnlste
matter is not aignificantb decrearred by char-
coal filtration while HCN and acmlein nre).

In o&m:      Ciearette smoke.   The authors ab,crved th.t:
Hen tracha.              (1) Whole smoke acuteb depressed ciliuy
                       activity in 44 puffs.

249


Dalhamn   In vim:     Unfilteredcigarette Acrmor number of puda required to arrest
and      Cat trachea.   and c,ge.r smoke.           diary nctivity
Rylander.                Cigsrette smoke . ._. __. 73 (p<o,ol,
1970.                           Cigar smoke . _. _. _. __ ,114 I
Sweden                     The authors note that cisar smoke ti of a
(65).                         different pH and that it contains more iso-
                         prenc. acetone. tolucne. and acetomtrilc.

Kennedy   In viva:      hlainstream      Electron microscopic observations:
and      Protozoan    cigarette smoke.  (1) After 7 minute exp*ur&-*lte"tion of
Elliott.     (ciliated J                mitochondrial Btructure.
1970.                        (2) After 02 minute exposure-destruction
U.S.A.                           of internal mitochondrial membrane atruc-
(IJ4).                           ture.
                            (3) Gas phase lone. while ciliatoxic. did
                           c&use nGtochondria1 swelling but no di+
                               mptian al membrane structure.

`Uoleaa otherwise atnted, method entailed the direct observation of ciliarv activity using
markers.

250


TABLE A14.--Espcrinrents concerning the eflect o/ cigarette smoke on pulmonary surfactarlt and sttrface tension

Author,

U.S.A.
(tzb)

do&r lungs.

Control  .     11                   cc.7              I 60
Smoke      10            ,5,a (P/,0.002)
            I             0 a4

E                          /                                                                I----

l-


TAULD A16.4tudies concerning the relationship of smoking to infectioue rewiratory dieeaee in humans
                     (ACLU&I number of CB.I~ shown in parenthmcs)
                           Shl -` Smokerl    NS = Nonamokcra

AUhX,
Ye&r,
eountrY.

Number wd
tY9e of

Data
couectlo"~                        xteauh                           Commcntd

rerrrPnei     DOpUhtiO"

MU,      118 mnlc mnd      HOLJplbl                                       C.WC#    Controls     The suthor st~lcd that
1960,      fcmde patienb     Intel-dew.         hlcan cue ,,,................ I........%.    49.6      49.6       thcru xl~y n
U.S.A.     with pneumanlm                  NS  . . . . . . . . . . . . . . . . . . . . . . . . . . . . .  . . . . .    16.26     26.21      algnificnnt diflcrnce
(1.57).     and 412 hwlthy                Cigarette3 only .,.... . ,........ , . . . . . . . .     63.66     62 33       in toboer usage
         lndlvidurla from                  Mixed ..,,. I . . . . . . . . . . . . . . . . , . . . . ,.h.    21.19     22.46       between the
        "random" SU,-&.                                                             two groupl.

LOW,      620 male and      Interview by                           Nolc*               FC%lalC8   Clgnrettc smokers
1966,      186 frmsle       trained                          C,lJCC   COnttd#        COCI   control4  Include pipe amokrrs.
England    tubercdds       social        NS  ,,,,,.....,.........,     2.6     8.1           31.3    61.4   The author noted a
(157).     patIenti and 419    worker.       Cwarettes/day: 1-S . .     8.2    12.9          20.6    21.7   .igniAcnnt drncirncy
         male and 249                   10-19  . . . . . . . . . . ...*     38.1    35.6          30.8    20.6   of non- and light
         female control                  20-29  . . . . . . . . ..I....    29.4    27.4                     smokers and an
         outpstienh.                   30-39 .,.............     11.3     9.3          11.4     2.4   excr,, of hruvy
                                 >4o  I.,.,.....I.,.....     0.4     6.7 I                    amokcrr among
                                                                           the C,,~PI

Dowllng,    Indlvidurrb
et al.,      UDOd t.0
1967,      "Infectious
U.S.A.     cold agent"
(751.      and plncebo.

Interview and
medical
cxaminatlon.

              Expored to placebo    Ezporcd to infrcliour lioenl No stitlaticnllY
                      Pcrcmt               Pcrccnt   aigniftcnnt
                    dewloping             drurloping   dilTrrrnccs
               A'umbcr   "cold"        Numbnr   "cold"    noted.
NS  . . * . . . .     111      10          928      34
Shl  . . , * .     78      14          248      36


TABLE AlS.-stt(die8 conceming the rck~tionsltip of smoking to in/eclio~ts respiratory disease in hwllan8 (Cont.)
                         (Actunl numbrr of ~OIICJ ~huwn in wrrnthraca)
                            SM = Smokers    NS = Nonamokcra

AUt.hX,
  yc*r.      Number and        Dnts
country.       type cl        collection                        ncaults                           Comments
rclcrcncc      gopulation

Bcakc.     Parc"tT3 of       Interview                                   Number of          No statidtlcslly
1068,      69 famillm                                           Prrr'm-  rcrpirotofy IUrutrcr/    aipnificont
U.S.A.                                                       lltL%r,    iuncsctc  gtrrm.yrarr   diflerenccu
($5).                             NS . ..I.. . . . . . . . ,.. (24)      120      624      6.2      natcd.
                                Ciraretti/day: I-10 . ,...... (19)       BB      629      6.8
                                   11-20  . . . . . . . . . . . . . . . . . (26)      108      486      4.6
                                 >20  . . . . . . . ..~............ (IQ)       89      424      4.8
                                Pipe, clnnr  . . ..* .,.. (II)       72      804      4.2

Shah
ct al.,
19G9,
Indla
(loa).

Tuberculosla      Survey, X.ray,
Institute        and
emlhyea.       Interview.


Author, ye&r,    Number nnd
colllltiy,       type of         Dntn
rcfcrmce     DOPUhtiOn       collection                         Ilrrulls                         Commrnta

Drown     306 mnle und                                                                           -
                    Interview                   Smoking habile prior lo diagnorid               Data nrrscntcd only
et al.,      irmnlc                                         Tubcwrlour yolicnlc Controlr    on Queenrlnnd
1061,      tuberculosis                                               (pcrccnl)     (percent)    aample.
Aurtrnlia    clinic                        NS ,...,,....._..,..,,,._..,..,.,..      9.1        18.0     The authors noted
(4).       pnticnts.                     Cignrcttcs/dny: 1-Q .      10.6        16.4      that the
         221 male and                      10-11        34.3        19.6      aignihrnnt diRcrencc
         fcrnslc                          20-29  . . ..I..      26.3        26 a      bctwecn the
         outpatienta.                       30-39  . . . .      1.2         6.4      potienta and
                                     >10 ..,,...........,.........,.,.      6.2         9.1      mntrols ~09 not
                                      Pipc5  . . . . . . . . . . . . . .._........      6.9         4.6      present when the
                                                                           gro"", were
                                                                           matched for
                                                                           alcohol intake.

Haynes     191 male        Interview              Average number of rcapiratory iUncnrerli0 students
et al..      prep school                                 (adjurlcd Ior age)
1866.      studcntd.                                                       AU .OYCIC her
U.S.A.                                                  All
(Joal.                                                         AU SCYC~C    or combined
                                                   rrapiratory   rrapirotory    rcapirotory
                                                    cpiaodcr     EpiaOde4     cpiaoder
                                NS (99)   ..,........,....,,     11.1        1.6        0.36
                                Sbl (92) ., ,.......,...,,,,    20.2        6.1        3.34

Pm-rlcll     41 smoking-       Intcrvlew
et al..                                         Median number o/ illnca~cclttudcnt              The uthors noted
         nonsmoker palm    and health
1966                                                            AU      All          that these
         Of atudtnt numes    service
Cfintldn                                                     rcspirntory   other         dillercnces were
         mnLchcd for WC    rccorda.
(J~J).                                                      dirrarcrt   illncsrra        statistically
         and parrn~3'                      NS (47)  . . . . .      2.08      2.99          rlgnlfitsnt.
         xcupntional                     Shl (47)  .,.................      2.64      6.00        t Particularly
         CILIIS.                                                                 tracbcitia,
                                                                           bronchitls.
                                                                           and pncumonl~.


      Author,
       yI'.r,      Number nnd        Dntn
      C"U"lry.       WPC of        collcctio"                        Rcvulte
      rrfercnrc                                                                           Commcnle
               DOPUlntiOn

    rrtrrs     1.496 H~tvard     Medical history.     Number of viails to rtudcnt health unit for rrspirahy Plneao/atudent    t e<0.001.
     et al..      nnd           chart review.           (comnic-n colda, pharyngitis. bronchitis. larynoitld,
     1967.      310 Radclifle      and                    pt~cumonia-not allrruic rhinilir)
     U.S.A.     atudenta.        questionnaire.                            Harvard      Radclife
      IISY).                                 NS  . . . . . . . . . . . . . . . . . . .      1.44 (771)      1.44 (193)
                                         Sbl  . . . . . . . . . . . . . . . . . . . .     tz.27 (726)      2.27 (177)
                                         <2 YCRTS amoknl .,,....,      2.00
                                         3-4 .,...,..........,,,.      2.30
                                         >G  . . . . . . . . . . . . . . . . . . .      2.60

    Finklea     1,811 mule       Questio""slrc       Iicnw rmokcn-21 pcrccnt more clinicnl IIIIINL)R than nonsmokera:     The authors .Iso
      Cl nl.,      CUllVgC          prior to                   20 percent mom twuirinz bed rest than nonsmokers      nolcd that:
      19c9       dudents.      h,lliK/68       Light smokers-10 pcrccnt more clinical Illnc3ma than nonsmokers:
      U.S.A.                                                                           (n) Smokrra
                          epidemic ond               7 wrccnt more squiring bed rcat than nonamokcrn
      (BY).                                                                           rrhlbltml
                           follow.uu on                                                      BcroIwIc
                           morbidity.                                                       cvlllPllcc of
                                                                           Incr,,nwd
                                                                           subrlitlicnl
                                                               A2111KIG8
                                                                           infcclion.
                                                                           (b) Thcrc wn& no
                                                                           diflcrcncc in tI<c
                                                                           vnccinotion
                                                                           slnh;s
                                                                           brlwcrn
                                                                           smokers und
                                                                           nonainr>kcra.
N
?l


TABLE A16.-Complications developing in the postoperative period
     in patients undergoing abdominal operations

GtWUD               CZLBeS



Smoken ______.___.......... 300
Linbt Smok m-8 . . . . . .  180
Nmamokcm ._.._.._........ 66

Percent
chest
clear


41.1
68.4
92.3

       PerWIlt
       brancho-    PKCKlt
PCk-Cmt p"eaunmdOnir    tot*,
bronchitis         complication
      atelcctasis     rllte

63.0       3.3       58.3
27.1       3.9       31.6
6.0       1.3       7.6

Smokcra  _. _. __. . .   23
Light Sm 0 k em . . . . . . . . . . .   62
Nonsmokers . _.. . ._. . . .  518

Souscz: Morton. H. J. V. (172)

                         60.9
39.1       43.5       17.4
77.5       202       1.6       22.5
88.8       8.1       3.1       112

TABLE A17.--Arterial ozygen saturation before and after operation

Arterial oxygen saturation (percentage)

                        1       94       93       94       . .
                        2       94       93       94       . .
N onsmokers                                        94       . .
              . .   .   .    3       96       93
                        4       93       90       04       . .
                        6       94       90       93       . .

6       95       91       89       91

I       92       89       81       89

S mokem                                                 89
       .  _ . . . . .    . . . . . .    8       91       83       86
                        9       93       91       88       92
                        10       90       87       88       92

SOURCE: Morton. A. (17P).

256


Chapter 4

        Cancer

Source: 1971 Amcart, Chapter 4, pages 231 - 384.

257


Contents

Introduction  ......................................

Lung Cancer  .......................................
  Epidemiological Studies  ..........................
     Prospective Studies  ..........................
    Retrospective Studies  ........................
  Lung Cancer Trends in Other Countries  ............
  Histology of Lung Tumors  ........................
  Lung Cancer Relationships in Women  ..............
  Lung Cancer, the Urban Factor, and Air Pollution. . _ .
  Lung Cancer and Occupational Hazards  ........ _ ...
     Uranium blining  ............................
    Other Occupations ..... _ ... ;. .................
      Nickel ......................................
     Asbestos ....................................
     Arsenic .....................................
     Chromium............-...........~......-.~.
  Pathological Studies. .............................
  Pulmonary Carcinogenesis .. _ .....................
    General Aspects of Carcinogenesis . . _ . _ _ . _ . _ _ _ .
      Polynuclear Aromatic Hydrocarbons . _ . _ _ _
       Kitrosamine Compounds. ..................
       Pesticides and Fungicides .................
       Radioactive Isotopes  .....................
       Inhibitors of Ciliary Novement _ . . _ . . _ . _ . _
    Experimentai Studies  ......................
      Skin Painting and Subcutaneous Injection. ..
       Tissue and Organ Culture  ............. _ ..
       Tracheobronchial Implantation
          and Instillation  ......................
        Inhalation   .................... _ ........
       Reduction in Tumorigenicity ..............
  Summary and Conclusions  ........................

Cancer of the Larynx  ................................
  Epidemiological Studies  ..........................
  Pathological Study  .... :. ........................
  Experimental Study  .............................
  Summary and Conclusions  .............. _ .........

Oral Cancer _............__..._ .....................
  Epidemiological Studies  ..........................
  Experimental Studies  ............................
  Summary and Conclusions  ........................

Page
263

265
266
266
266
270
272
277
278
282
282
282
282
283
283
283
284
284
284
290
290
292
292
293
293
293
293

294
294
301
302

303
303
304
307
307

310
311
x4
315

259


Cancer of the Esophagus  .............................
  Epidemiological Studies  ..........................
  Pathological Study  ..............................
  Experimental Studies  ............................
  Summary and.Conclusions  ........................
Cancer of the Urinary Bladder and Kidney ..............
  Epidemiological Studies (Bladder)  . _ ...............
  Epidemiological Studies (Kidney)  .................
  Experimental Studies  ....... _ ........ _ ...........
  Summary and Conclusions  ... _ ....................
Cancer of the Pancreas ...............................
  Summary and Conclusions  ........................
References  ................. . .......................

FIGURES

1. Lung cancer, Finland and Norway . . . . . . . . . . . . . . _ _ . . .
2. Percent of smoking dogs with tumors . . . . . . . . . . . _ . . . .
3. Percent of lung lobes with tumors in smoking dogs . . . . _
4. Effects of chronic cigarette smoke inhalation on the

271
300
300

haaster larynx . . . . . _ _ . . . . . . . . . . . . . . . . . . . . . . . . . .    310

1.
2.

A3.

A4.

5.

6.

A7.
8.

9.

Lung cancer mortality ratios . . _ _ _ . . . . . . . . . . . . . . _
Lung cancer mortality ratios for males by duration of
cigarette smoking . . _ . . . _ . . . . . . . . . . _ . _ . . . . . . .
Outline of methods used in retrospective studies of
smoking in relation to lung cancer . . . . . . . . . . . . .
Group characteristics in retrospective studies on lung
cancer and tobacco use _ . . . . . . _ . . . . . . . . . . . . . . .
Annual means of total lung cancer mortality and sex
ratios for selected periods in Finland and Norway
Epidemiologic and pathologic investigations concern-
ing smoking and histology of lung cancer . . . . . . .
Grouping of pulmonary carcinomas _ . _ . . . . . . . . . . .
Tumor prevalence among males and females 35-69
years of age, by type of tumor and smoking
category ._......__...._....................
Epidemiologic investigations concerning the relation-
ship of lung cancer to smoking, air pollution, and
urban or rural residence . . . . . . . . . . . . . . . . . . . . . .
Pathologic and cytoIogic findings in the tracheo-
bronchial tree of smokers and nonsmokers _ . . . , _

10.

LIST OF TABLES

Page
315
315
318
318
319
319
319
322
322
325
325
325
325

267

270

349

355

272

273
360

276

279

285

260


    LIST OF TXELES (Continued)
(A indicates tcibles located in appendix at end of chapter)

11.  Identified or suspected tumorigenetic agents in
    cigarette smoke _ . . . . _ . _ . . . . . _ . _ . _ . _ _ . . . . . . . .
X12. Autopsy studies concerning the presence of radio-
    activity in the lungs of smokers . : . . . . . . . . . . . . .
A13.  Experiments concerning the effects of the skin paint-
    ing or subcutaneous injection of cigarette smoke
    condensate or its constituents upon animals . . . . .
A14.  Experiments concerning the effect of cigarette smoke
    or its constituents on tissue and organ cultures . .
A15.  Experiments concerning the effect of the instillation
    or implantation of cigarette smoke or its constitu-
     ents into the tracheobronchial tree of animals _ . . .
X16. Experiments concerning the effect of the inhalation
    of cigarette smoke or its constituents upon the
    respiratory tract of animals . . . . . . . . . . . . . . _ _ . .
17.  Data on pedigreed male beagle dogs of groups F, L,
    H,hand N . . . . . . . . . . . . .._.__...............
18.  Summary of principal cause of death (days No. 57
    through No. 875) in dogs of groups F, L, H, hand N
19. Data on dogs with lung tumors indicating type of
    tumor and lobe in which the tumor was found . . . _
20. Laryngeal cancer mortality ratios - prospective
     studies   . . . . . . .._...._.._..............-..._
A21. Outline of retrospective studies of tobacco use and
    cancer of the larynx . . . _ . _ . . _ . . . . . . _ . . . . _. . . _
X22. Summary of results of retrospective studies of tobacco
    use and cancer of the larynx _ . . . . . . . . . . . . . . . . . .
A23. Number and percent distribution by relative fre-
    quency of atypical nuclei among true vocal cord
    cells, of men classified by smoking category . . . . .
A24. Number and percent distribution, by highest num-
    ber of cell rows in the basal layer of the true vocal
    cord, of men classified by smoking category . . . .
25.  Deposition of lGlabeled smoke particles in particu-
    lar regions of the respiratory tract . . . . _ . _ . . . . .
26.  Classification of the five registered stages of epithe-
    lial changes at the larynx . . _ _ . . . . . _ . . . . . . . .
27. Oral cancer mortality ratios-prospective studies. .
A28. Outline of retrospective studies of tobacco use and
    cancer of the oral cavity _ . . . . . . . . _ . . . . _ . . . . . .
A28a. Summary of results of retrospective studies of smok-
    ing by type and oral cancer of the detailed sites..

PCaa


291


361

363

369

372

375


296


297


298


304


380

384

385

386


308

309
312


387


394


261


30.

X31.

:31.

36.

    LIST OF TXBLES (Continued)
(=\ indicates tables located in appendix at end of chapter)

Experimental studies concerning oral cnrcino-
genesis __..__._..._.__......._........_....
Esophageal cancer mortality ratios-prospective
studies   _ . , . . _ _ _ _ . . . . _ . . . . . . . . _ _ . . . . . . . . . . . .
Summary of methods used in retrospective studies
of tobacco use and cancer of the esophagus . . . . . .
Summary of results of retrospective studies of to-
bacco use and cancer of the esophagus . _ _ . . . . . .
At:-pical nuclei in basal cells of epithelium of esoph-
agus of males, by smoking habits and age . . . . . .
At)-pica1 nuclei in basal cells of epithelium of esoph-
agus of males, by amount of smoking and age . . . .
Kidney and urinary bladder cancer-prospective
studies   _ . . _ . . _ . . _ . _ _ _ _ . . _ _ . . . . . . . . . . . . . . . .
Summar)- of methods used in retrospective studies of
smoking and cancer of the bladder _ . . . . . . . . . .
Summary of results of retrospective studies of smok-
ing and cancer of the bladder . . . . _ _ . . . _ _ _ . _ _
Pancreatic cancer mortality ratios-prospective
studies   . . . . . _ . _ . . _ _ _ _ . . . . _ . _ . . . _ . _ . . . . . . _ . .

Pwgc


397

316


401


404

405


406


320


407


409


324

262


INTRODUCTION

During the early years of this century, a number of pathologists
and clinicians reported a dramatic increase in the incidence of lung
cancer. Autopsy studies and studies of lung cancer death rates re-
vealed a significant increase beginning prior to World War I and
continuing during the ensuing years. This epidemic of lung cancer
continues to the present day, with nearly GO,000 deaths expected
from this disease in the United States during 1970.
Beginning in the 1920's, a number of reports appeared which
suggested a relationship between lung cancer and tobacco smoking
(2, 30.3 , 278). Since that time, many clinical and epidemiological
studies have been published which confirm this relationship. The
19G-l Report (-391) contains a thorough review and analysis of the
data available at that time as well as an excellent discussion of the
considerations necessary for their evaluation.
Xajor epidemiological studies have demonstrated that smokers
have greatly increased risks of dying from lung cancer compared
to nonsmokers. An increased risk of lung cancer has been found
for every type of smoking habit investigated, but two character-
istics of the risk are particularly evident: The risk is much greater
for cigarette smokers than for smokers of pipes and cigars, and
among cigarette smokers a dose relationship exists. That is, the
more one smokes, as. measured by total pack-years of smoking,
present level of smoking, degree of inhalation, or age at start of
smoking, the greater is the risk. It has also been shown that the
risk of lung cancer among ex-smokers decreases with time almost
to the Ievel of nonsmokers; the time required is dependent on the
degree of exposure prior to cessation.
Pathologists have found that the squamous cell or epidermoid
form of Iung cancer is the most prevalent one in cigarette smoking
populations and that this form accounts for a major portion of
the rise in lung cancer deaths (15~). Such studies have also indi-
cated 3 lower prevalence among smokers for oat-cell and adeno-
carcinomas of the lung than for the squamous form, but in most
studies a higher frequency of these tumors is found among smokers
than among nonsmokers.

Smoking has been implicated in the deveropment of other types
of cancer in humans. Among these is cancer of the larynx. A num-

263


her of epidemiological studies have demonstrated increased mar-
talitY rates for laryngeal cancer in smokers, particularly cigarette
smokers, compared with nonsmokers. Autopsy studies have re-
vealed that a clear dose-relationship exists between smoking and
the development of cellular changes in the larynx, including carci-
noma in situ.
  Cancers of the mouth and oropharynx have been found to be
more common among users of all types of tobacco than among
abstainers. Although smoking is a definite risk factor in the de-
velopment of malignant lesions of the oral cavity and pharynx, its
relative contribution in conjunction with other factors such as poor
nutrition and alcohol consumption has not been fully clarified.
  Similarly, although smokers are more likely to develop carci.
noma of the esophagus than nonsmokers, the relative additional
contribution of smoking in conjunction with nutritional factors
and alcohol consumption requires clarification.
Smokers have been found to be more at risk for the development
of cancer of the urinary bladder than are nonsmokers, and there
is evidence to suggest that some smoking-induced abnormal meta-
bolic product or abnormal concentration of a metabolic product
may be responsible for this increased risk. In addition, cancer of
the kidney is apparently more common in smokers than in non-
smokers, but the epidemiologic evidence for this relationship is
not as definite as for bladder cancer.
Epidemiological studies have indicated an association between
smoking and cancer of the pancreas. The significance of this rela-
tionship is unclear at this time.
Experimental studies have demonstrated the carcinogenicity of
the condensate of tobacco smoke, or "tar." This material, when
painted on the skin of animals, leads to the development of squam-
ous cell tumors of the skin. Researchers have shown that this
condensate contains substances known as carcinogens, capable of
inducing cancers. Among these carcinogens are several chemicals
which have been identified as tumor initiators, that is, compounds
which initiate changes in target cells and also tumor promoters,
or compounds which promote the neoplastic development of initi-
ated cells. Other, as yet unidentified, factors are presumably also
involved because the sum of the carcinogenic effects of the known
agents does not equal that of cigarette smoke condensate.
Numerous experiments have been performed in which whole
cigarette smoke, filtered smoke, or certain constituents of smoke,
such as the "tar," are administered by varying methods to animals
or to tissue and cell cultures in order to investigate the neoplastic-
inducing properties of cigarette smoke. Particular difficulty has
been encountered in experiments which have attempted to deliver


whole cigarette smoke to the larynx and into the lungs of experi-
mental animals, This has resulted in the use of other methods such
as the implanting of pellets containing suspected carcinogens and
the instilling into the trachea of suspected carcinogens as such, or
adsorbed onto tine inert particulate matter as a carrier. The dif-
ficulty with the inhalation studies has been twofold. First, the
animals, particularly the smaller species such as the rat, frequently
die from the acute toxic effects of the nicotine and carbon monoxide
in the tobacco smoke. Second, the upper respiratory tract of experi-
mental animals, particularly the nose, is much different from anal-
ogous human structures, resulting in a more efficient filtration of
smoke in the upper respiratory tract. Nevertheless, in rodents and
canines, progressive changes apparently indicative of ultimate neo-
plastic transformation have been identified in the respiratory tract.

Recently, two studies in different species and in different target
organs have been reported concerning the development of early in-
vasive cancer following the prolonged inhalation of cigarette smoke;
Auerbach and his coworkers (11) trained dogs to inhale cigarette`.
smoke through a tracheostoma. After approximately 29 months of
daily exposure, these investigators found a number of cancers of
the lung.

Dontenwill (76) in the second of these two studies, exposed ham-
sters to the passive inhalation of cigarette smoke over varying and
prolonged periods of time. He observed the deveIopment of pre-
malignant changes and, ultimately, invasive squamous cell cancer
of the larynx.

LUNG CANCER

Cancer of the lung in the United States accounted for 45,383
deaths among males and 9,023 deaths among females in 1967 (289).
It is presently estimated that approximately 60,000 people will die
of lung cancer during 1970.

The alarming epidemic of lung cancer is a relatively recent
phenomenon. Death rates for lung cancer (ICD Codes 162, 163)
rose from 5.6 (per 100,000 resident population per year) in 1939
to 27.5 in 1967 (289, 290). This rapid increase followed the in-
creased use of cigarettes among the United States population. The
increase has occurred principally among males, although more re-
cently females have shown a similar rising pattern.

The converging evidence for the conclusion that cigarette smok-
ing is the major cause of lung cancer is derived from varied types
of research including epidemiological, pathological, and laboratory
investigations.

265


EPIDEMIOLOGICAL STUDIES

Numerous epidemiological studies, both retrospective and pros-
pective, have been carried out in different parts of the world to
investigate the relationship between smoking and cancer of the
lung. These studies are outlined in tables 1, 2, A3, and A4.

Prospective Studies

The major prospective studies concerning the relationship of
smoking and lung cancer are presented in table .l. In all, these
investigations have studied more than a million persons from a
number of different populations for up to 10 years. These studies
show increased lung cancer mortality ratios for cigarette smokers
of all amounts ranging from 7.61 to 14.20 among male smokers as
compared to nonsmoking males. The one major prospective study
of female cigarette smokers reveals an overall mortality ratio of
2.20 (118).

Also uniformly present in these studies is a dose-related increase
in the mortality from lung cancer with increasing amounts of cigar-
ettes smoked per day. Other measures of exposure show similar
trends. Hammond (118) reported increased mortality ratios asso-
ciated with increased inhalation (table I) as well as with increased
duration of smoking (table 2).

Ex-smokers show significantly lower lung cancer death_- .rates
than continuing smokers. In their study of more than 40,000 B$tish
physicians, Doll and Hill (74, 75) noted a decrease in lung carricer
mortality rates with increasing time since smoking stopped (table
1). During the past 20 years, half of all the physicians in Britaig
who used to smoke cigarettes have stopped smoking. While the
death rates from lung cancer rose by 7 percent among all men from
England and Wales during the period from 1953-57 through 1961-
65, the rates for male doctors of the same ages fell by 38 percent
(96).

Pipe and cigar smokers have been shown in the prospective stud-
ies to have lung cancer mortality rates higher than those of Bon-
smokers, although these are generally substantially lower than
those of cigarette smokers (table 1).

Retrospective Studies

More than 30 retrospective (case-control) studies have been re-
ported conc&ning the relationship of smoking and lung cancer.
These studies are outlined in tables A3 and A4. Table A4 presents
the percent of nonsmokers and of heavy smokers among both cases
and controls as well as the relative risk ratios for all smokers.

26.6


(Actual number of deaths shown in porenthcsn)'
  Shl= Smokcrn.    NS = Nonsmukcra.

Author,   Number
yenr.  wdo'qw  co'zP  Follow-   NUmbCr   Regular cigarette      I'irw
EO"rlLl-Y.                  UP   dcaok    smoking only       cigar       Inbalntion           Exsmokcrs         CDmlliCnt3
reference popuL5tion          YcBrl          (ciBarctter/day)

Hammond 187.783    Queation-    3 `h       448                  Pills      No dotn             fIro,lchoocnic       341l.448

and     white     nnirc and       SN 443 NS ..I.. 1.00 (16) NS .,. ;.OO (16)             (Errludinp adcnocnrcinoma)    drnth? with
IIorn.    msles     interview.       NS ,  16 <lO I... 8.00 (24) Shl . . 2.67 (18)             Ncvcr smoked . 1.00     mirrn~copic
19GB.    in 9                       10-20 . ..lO.GO (84)     Cigar                 Prcuioualu <I pack/don     Dr""!. 1,~.
U.S.A.   SCaleS                       >20  . . . . 23.40(\17) NS .,. 1.00 (1G)            Continuing  . ,,. ,, .16.94     ClUllc-3 t1w,e
(110).   LDCB                     All . ..t10.73(397) SII ,,. 1.00 (7)            Duration
       60-69.               1  <I year I, 16.60     rcyul1,r
                                                                      of    I-10 year9 .10.44     cirnrcttc
                                                                    CtSBOtioll  >I0 yenrs , ( 1.61     amokcrs who
                                                                   PrcviourlV >I pack/day     ntv~ amokd
                                                                  Continuing  , . .46.21     ply<* und
                                                                    Duretion
                                                                      uf
                                                                    cesrstion 1  <l ycsr . .68.23     riguru.
                                                                         l-10 years .22.82    t wtltl "I
                                                                          >lO year* .17.79     w\lh""t
                                                                           micrwcopic
                                                                           vrwf.   -
Doll and  ApprOXi-   QucsCion- 10        212 NS ...I 1.00 (3)   Pipe and Cigar   No data            Cigeretlc rmokcrr
Hill,    mstely    naire and       SM ,  209 l-14 ,.,. 8.14 (22) NS ., . . 1.00 (3)            NS . ..I. .,.. .,..... ~. 1.00  (3)
1964,    41,OdO    fOllOWUP        NS .   8 16-24 ,. .19.86 (63)   Groma/dav              Continuing  t . . . . . . . . . . 18.21(124)
Grest    male     of dcatb             >25 . . . . 32.43 (67)  l-14.. 6.00 (12)            Durnlion  <6yettra 9.61 (b)
Britnin   UriLirb    certificate.                          15-24 ., 6.43 (G)              of    6-9 years 7.00 (7)
(70.    physiciana                                  >26 .13.71  (3)    I
                                                             c~ssi,tiun lo-20 ycara 2.67 (3)
                                                                      x0 ycrrs 2.11 (2)

Beat.    APDroxi-   Queetion-    6        331 NS  . . . . . 1.00  (7)      Pipe      No dnts                           1 II, fcra
1966.    mntcly    nairc nnd       tSM  324 <lO  . . .lO.OO (67) NS . ..I.00 (7)            NS . . ,. 1.00
lBC6,                                                                           (`I)  to ciir-
       78.000    fObVUD        NS ,                                        Examokrra of              r, nt
Canada                        `l lo-20 . ..16.41(204) Shl ,I,. 4.36 (18)
       male     of donth
(II).                            >no .I?.31 (63)     Cigar
       Canadian                                                    cixorctl~~ only 6.06 (18)  cixnrs tic
               certificate.             All  .14.?O(ZdG) NS ..I.00  (I)                                  an,ilkLr!d
       YewranD.                                SM . ..2.94 (2)                                  only.
                                                                           __~- -. .-


TABLE l.--Lung cuttce~ mwtulity rattie (cont.)

(Actud number of dcrtha rhown In DWeQthW=)'
  SM = Smoktn.    NS = Nonsmokem.

       Prodpectlve studies

8%      1,266
   sbi .1,118
    NS . 7.6

Reguh eiwctte
smoklnn only
(clparettra/day)

PIPS
cl&x

Inhalhtion           Exsmokcn

Cammcr

NS ,*... 1.00 (78)
1-B *,.. 5.49 (46)
lo-20 . , . 9.91 (am)

21-39 . . .17.41(816,
>S9 . .a a23.93 (8'2)
AU  , ,.. .12.14(749)

   Pip
NS  . . ..l.OO (78) Nodata
sbl *.. .1.84 (17)
   Cigar
NS . . ..l.OO (78)
SM . . ..I.69 (6)
Pip. and cigar
NS . . ..l.OO (78)
SM . ...1.66 (20)

NS . . . . . . ,....a 1.00 (78)
Number of ciparsttoldav:
l-9 .,,,. *.*...  0.96 (4)
lo-20  . . . . ..I..  l.48 (89)
21-89  .,......* 9.88 (17)
>a@  . . . . ...****  8.24 (19)

IU
-

Hum.nond.440.668    InterviewB   4     Mdu
1966,    mbles     by ACS           1,169
U.S.A.   662.671    voluntetn.      SM .l.llO
(Jl6).   fer4er                NS . 40
       w-a4                 FOlWh
       ,e.n of                   188
       .gt In 26               SM. 81
       statea.                NS 6 102

Cuncnt ei0aret1cc      Pips
    oh      NS  . . ..l.oa (49)
    hfda     SM . ...2.24 (21)
NS a.... 1.00 (49)     Cigar
1-S .*.. 4.60 (26) NS . . ..l.OO (49)
lo-19 . . . 7.48 (82) Sbl . . ..1.86 (22)
20-39 . ..13.14(981)   Pipe and cioar
>40 ,,.. 16.61 (82) NS a... 1.00 (49)
AU a.... 9.20(719) SM . ...0.90 (11)
   Fcmdu

NS .,... 1.00(102)
l-19 , ., , 1.06 (20)
>20 . . . a 4.76 (60)
All . . . . . 2.20 (81)

     Mdecr
NS . . . ..s.. 1.00 (43)
Slight . . . . . . 8.42(120)
Moderate ,a .11.46(811)
DWD . . . . . ..14.81(141)
    FCiVlOL~

ICD cD11c
162 only.

NS ,....... 1.00(102)
Slkbt ..a... 1.78 (26)

8.70 (46)


TABLE I.-Lung cancer mortality ratios (cont.)

(Aetusl number of deaths &own in Darcnthpsea)l
  SM = Smokers.    NS = Nonsmokers.

Prospective studies

Author,   Number          FOUOW-
Year.  andoyw    Data     UP           Regular cizzarette      Pipe
~0"l-ltl-Y.          collection   years  N"zber    smoking only       cigar         InhalPtlon           Exsmokcrs       Comment.9
nferenee poPulatlcn                deaths    (cigarettes/day)

nucu    69.868     Question.    3        a04 NS 1.00
et al.,    Americm   naire and              <20  ,.,. 2.30
1967.    LcpiOW    fOllOWUP                20  ,.. 3.50
U.S.A.   nsirea     of death               >20 . . . . 4.90
(AD).    36-76     certificate.
       ye&l-a of
       out and
       older.

Hlrw~m~.265.116    TUiW?d     1%        4s NS . . . . . 1.00 (a)                                           rrcllmlnnrr
1067.    mnlcand   PIIS          SM .  40 l-24 . . 2.69 (29)                                              report.
Jbpan   femnle nurse               >26 . . . . 6.68 (6)
(lfb).   adulb     IntervIew
       40 ye."   and fol-
       of we and  lowuu of
       older.     death
              ccrtlflcate.

   ??o? o nd 68.169     Qumtlon- 68        BE8 NS ..a. 1.00                                                NY Include
    Dunn.   mah In   nnlre and              510 ., . 8.12                                              pipo nnd
    1970,    V~rloub    fOllOWUP               220 , , , 8.06                                                 cigar
    U.S.A.   OCCUP..    of derth               >a0  ,. , 9.66                                                 amoken
    (roa) *   tiona in   certith(c.              AU a.. 7.61                                                YJI include
           C~llfOn\lll.                                                                           cx-amoker~.

   L Unlm, otbcrai~e mpecifled, disparltlcs between the total number of death8
   and the bum of the Indlvldtml amoklng cbtewxies w-e due to the cxclu~l~n
r-4  of clthtr ocrralonrl. mlacell~neous, mlxed, or exsmokcra.
z


TABLE 2,Lung cancer mortality ratios for tit%
  by duration of cigarette smoking
(,4ctusl number of death arc sboan in parenthesa)

age began cigareYe smokine   35-64

25 or older _...........     2.77 (6)
*Is24 ________.........     6.83 (31)
15-19   .___............     8.71(112)
<I6  ..____._.__.......    12.80 (36)

SOURCE: H.mmond.E. C. (118).

66-69        7&84         36-84

3.39 (12)      3.38 (3)       321 (20)
11.11 (712)      12.11 (7)      9.72(110)
           19.37(27)      12.81l315)
13.06(176)
16.81 (67)      16.76 (9)      16.10(101)

These smoker-nonsmoker risk ratios range from 1.2 to 36.0 for
males and from 0.2 to 5.3 for females.

Although not presented in tabular form, the data concerning lung
cancer and pipe or cigar smoking are similar to those found by the
prospective studies mentioned above. However, a study by Abelin
and Gsell (1) conducted on a rural Swiss population noted that an
increased risk of lung cancer was present among heavy cigar and
pipe smokers (as well as cigarette smokers) to a greater degree
than previously reported. The authors suggest that their findings
might be due to differences in either the amount smoked or the car-
cinogenicity of Swiss and German cigars. The difference might also
be explained by the greater use and more frequent inhalation of
small cigars in Switzerland as compared to other countries where
large cigars are more commonly smoked but rarely inhaled.
Kreyberg (154)) in a review of 887 cases of lung cancer in Norway,
noted that pipe smokers showed an increased risk of lung cancer,
although this risk was substantially lower than that for cigarette
smokers.

LUNG CANCER TRENDS IN OTHER COUNTRIES

Several studies of particular interest are those in which the
changing mortality from Iung cancer has been investigated in
countries in which cigarette smoking has become popular and wide-
spread only in recent years. In those countries where accurate
statistics for lung cancer mortality are available for both the pre-
smoking and post-smoking periods, long-term trends can be @@ied
in some detail.

Two such studies have dealt with lung cancer mortality trends
in Iceland. Dungal (83) noted in 1950 that lung cancer was a rare
disease in Iceland and felt that this rarity could be explained bY
the relatively late onset of heavy tobacco smoking in the Icelandic
population when compared to that of Great Britain and Finland.
He observed that the annual per capita consumption of tobacco did
not reach one pound in Iceland until 1945, while Great Britain and
Finland passed that amount before 1920. In 1967, Thorarinsson, et
al. (276) noted a sharp rise in the incidence of lung cancer in Ice-


60-

50-

40-

30-

1934-36   1939-41

194446   1949-51   1954-56

     Calendar Years

1959-61  1963-64

FIGURE I.-Lung cancer, Finland and Norway.
SOURCE : Kreyberg, L. (154) _

land after 1950 and found a correlation between that increase and
the increasing sale of cigarettes in that country.

Kreyberg (154) analyzed the lung cancer death rates of both
Norway and Finland in relation to the use of tobacco in those two
countries over the past 100 years. Figure 1 shows the substantial
difference in lung cancer mortality between the two countries.
Kreyberg observed that cigarettes came into use in Norway in 1886
while the Finnish population (more closely allied to Russia socio-
economically) was consuming more than 100 million cigarettes per
year during the decade of the 1880's. Cigarettes remained scarce in
Norway until after World War I, and this 30-year lag in consump-

271


TABLE 5.-An7nd mesons of totd lung cmter mcwtality and sez ratios
     fur sekcted periods in Finland and Norway

      Year


193G3.8 .__.._._.._._.._...
Sex rrtio  . . _ _ . . . .
1S6a-66 __...__....._......
Sex ratio . . .._ _. _ _. _ . . . . .

   Fidnnd                  NOTtCLZlf

Make     FnnoIU         M&a      Fmdrr

192        ss            34        30
    6.8 : 1                   1.1 : 1
i.al9       121           366        7s
   10.9 : 1                  4.6 : 1

tion behind that of Finland is reflected in a similar lag in total lung
cancer mortality and sex ratios (table 5).

HISTOLOGY OF LUNG TUMOFCS

A number of investigators have focused their interest upon the
relationship of cigarette smoking to the varied histology of lung
tumors. The major histological types of lung cancer include squa-
mous cell (epidermoid) carcinoma, small and large cell anaplastic
carcinomas, adenocarcinoma (including bronchiolar and alveolar
types), and undifferentiated carcinoma (1.53). A review of these
studies (table 6) indicates a closer relationship between cigarette
smoking and epidermoid carcinoma than between cigarette smok-
ing and adenocarcinoma (42,113).

The work of Kreyberg (153) in Norway, over the past 20 years,
provides evidence of a specific histologic relationship. This inves-
tigator noted that a cIearer association is obtained if the various
types of pulmonary carcinomas are grouped. TabIe A7 presents his
groupings of the specific histologic types. Using this classification
as a basis for analysis of lung cancer sex-ratios in Norway,
Kreyberg has observed that Group I carcinomas are significantly
more frequent among males while Group II carcinomas show an
approximately equal distribution among males and females. The
author considers the recent rise in lung cancer in Norway to be a
reflection of the increased prevalence of Group I carcinomas. Table
8 presents a summary of Kreyberg's investigation concerning 793
male and female cases of lung cancer. Among both males and fe-
males, the risk ratio among smokers is substantially higher for
Group I types than for those of Group II. However, adenocarcinoma
among males shows a risk ratio of 2.9, signifying a relationship
with smoking. Kreyberg attributes the lower rates noted among
females to their significantly lower consumption of tobacco in all
forms.

272


Number ol
vcrauns and
C.lO sclccllon
mctbod

nt4+..4                                 Comment8

Nonsmokers  . . .
Smokera:
<6 eiKarettes/day
6-14  . , .
16-26  .., , , ,
>25  ,... . .

Epidrmloid (475)
  0.2 (1)

  Nalt-l
oat-ccl1 BI
annplaatia (101)
  0.1 (2)

2.9 (IO          a.9 (12)
36.6~1c9)         ZC.3~11OJ
3C.8 (176)         34.7(10GJ
24 4(lIG)         24.4 (70

Epidcrmoid (18)
61.1 (11)

6.6 (1)
22.2 (4)
6.6 (I)
6.6 (1)

FCTllo(C#
oat.ccu or
an.aphtic (19)
31.6(12)

16.8 (6)
23.7 (0)
18.4 (7)
10.6 (4)

Admocarcimmo (IO) blolc~-10G unclaui!X
   GO.0 (6)      t"~O~.
             Fcmslw-13 unclwifiul
   20.0 (2)      tumors.
   10.0 (1)

.,.
20.0 (2)

ti                                                          --                           __.-_-_.-..


z     TABLE 6. Epidemiologic and pathologic investigations concerning emokhg and the histology of hg came? (cont.)
e                                 (Actual number of can ahown In parenlbcam)

      Author.      Number of

et al..
1967,
FWlC-2
(%ll).

female cases
with hl~tologlcaUy                  Epidcrtnoid    ATUlPhlic     Udwwn tvps   Cvlindrkd + Difference
confirmed Jung    crsea  . . . . ~ . . . .      96.0         81.0         86.0         100.0     siyniRcant
cancer. 4 matched   Controls  . .      79.0t         83.0t        79.0t         06.0     *t p~O.06 Icvel.

        control IlwUDLI.

Hwn,zel   168 female                  Relative risk for apccified tumorr (rmokn*/wnrmokera)             134 man with nnnl
st .I..     case9 or                                                                bialoloaicnl
1968,     lung cnrlccr.                                  Grmp I (Xrwbcrg)    Admocarciwma    determinulion.
U.S.A.                Adjusted for age and occupation. ,,..,.....I..        3.0t           1.19      t Diffcrcnce from
(ii%).                                                                        unity aigniRcrsnt8L
                                                                       ll~O.Ol.

Haen32el   2.181 mnlc                           Stnutnrdircd martdilv roliar                    Cuts obtslncd from t.


rrrrrcncc       mr, h,Nl

Cohen     411 malt and
.nd      Icmalc CUBY Of
Hossain.   lung cancer with
1966,     histolugic
U.S.A.    dingnosia 1939-63   Nonsmokera  . . .
(56).     at one husvital.     Smokers  .

and      frmule EOHCB of
DUVle&    hialoloyirslly                        Unili~crcmlti~tcrl
IDGI.     dlngnurcd        Nonsmokera        2.8 (4)
Enulnnd   lunn cancer.      Pipe  .      9.9 (14)
(6).                  Cigarette  . . . . . . . . . . . .      87.3(124)
                   <lo/day  .,.,,.......,...      14.1 (20)
                   l&20 . . . ,. . . . . ~. . . . . . . .      33.6 (48)
                   21-30  .      12.0 (17)
                   31-40  . . . . . . . . . . . . . . . . . . .      14.1 (20)
                   >ro  , *. . . I..      7.1 (IO)

Souvnww
2.6  (G)
9.9 (20
87.6(211)
22.4  (64)
41.6(100)
21.6  (62)
12.9 (31)
6.2  (16)

           clylllctlc s"wkl,iy
Adcnocarcinom    P,,,IParl to bc `il
3.4 (2)      llronyly rclutcd to
  1.7 (1)      adcnocsrcillomn 113 lo
94.9(663      (he olhcr 2 tywa.
22.0(13)      A~blcy'r data on `.ootul
33.9(20)       number of civurcltc
16.9(10)      smukrrs BTL'
  8.6 (6)       inconuistvnl with
  6.1 (9)      hi3 brcnkduwn ol


TADLE 8.-Tumor prevalence among males and females 85-69 uears of age, by type of tumor and smoking catvory
                     (Smoken conatltutcd 86 percent of popul&tlons rtudled)

Sex and type of tumor

TOtd

Smoking category

  Smoking
all mcthoda

Non-
smokera

nisk
rntio
aml>ng
smokers

Total . ..a. . . ..I... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    108          3s          13          18.3          1.9

1 Number that would be exueeted II Incidence rate among smokers were
eauI to that of nonsmokers.

SOURCE: Kreyberg, L. (154)


       LUNC CANCER RELATIONSHIPS IN \VOXEN
Lung cancer death rates for lvomen are presently much lourer
than the corresponding rates for men. In addition, it has been ob-
served that among certain strains of mice exposed to carcinogenic
agents, the male animals show a greater tendency to develop lung
tumors than do the females (200, .?07) although there are strains
for which this is apparently not so. The extent of the influence of
endocrine factors in the sex variation in the incidence of lung
tumors is unknown.

AS of 1967 in the United States, women accounted for only about
one-sixth of the footal deaths from lung cancer (289). However, the
lung cancer death rate in women has risen by over 400 percent in
the past 40 years. From 1950 to 1967 alone, the rate per 100,000
population doubled, increasing from 4.5 to 8.9 (289, ~0).
A number of retrospective studies concerning lung cancer and
cigarette smoking among women have found that the difference in
the prevalence of lung cancer between males and females is ac-
counted for principally by those tumors classified as Kreyberg's
Group I (~54,311). These, as was noted above, are the tumors, par-
ticularly in males, which show the closest relationship with smok-
ing. Haenszel, et al. (113). in a study of 158 women with lung
cancer, observed that the sex differential for lung cancer death
rates diminishes, but does not fully disappear when only non-
smokers are considered.

Hammond (118) found that the death rate for lung cancer in
nonsmoking males was somewhat higher than for nonsmoking fe-
males. However, the difference in male-female rates was much
greater when smokers were compared. It appears that a substantial
part of the difference in death rates between male smokers and fe-
male smokers can be explained mainly by differences in their smok-
ing habits.

These differences in smoking habits between males and females
are of two types. First, overah consumption among females is still
significantly lower than that among males. In 1966 (281), 30 per-
cent of males reported that they had never smoked while for fe-
males the corresponding figure was 59 percent. This study also
noted that nearly three times as many males as females reported
consuming more than 20 cigarettes per day. Second, it ,has been
shown that women smoke differently than men (303) : They begin
smoking later than men (114) and do not smoke cigarettes as close
to the end, where proportionaIIy more nicotine and "tar" are in-
haled. Women smoke more filter-tip and "low tar and nicotine"
cigar&es than men. Furthermore, cigarette smoking stiII tends to
be heavily concentrated among women under the age at which lung
cancer is most likely to occur.

277


Finally, analysis of the ratio of male and female lung cancer
death rates (283, 284, 285, 286, 287, 288, 289, 290) reveals that
since 1960 this ratio has shown a steady decline, reflecting the
greater relative rise in mortality from lung cancer in the female
population.

LUNG CANCER, THE URBAN FACTOR, AND AIR POLLUTION

A number of studies have been concerned with the relative influ-
ences of smoking, urban residence, and air pollution in the etiology
of lung cancer. Table 9 lists studies performed in the United States,
Great Britain, and Japan which have dealt with this question. Kotin
and Falk (149,150) and more recently the Royal College of Physi-
cians (228) have reviewed the literature concerning the influence
of atmospheric and environmental factors in the pathogenesis of
lung cancer.

The studies listed.in table 9 show a number of important trends.
Lung cancer death rates are found to be higher among urban popu-
lations than among rural populations. It is not known to what ex-
tent this urban factor in the etiology of lung cancer is due to
differences in the levels of air pollution. Other factors associated
with urban residence which may influence the etiology of lung
cancer are: differences in smoking habits between the two popula-
tions, occupational differences, and possible differences in the re-
porting of lung cancer deaths (228).

The studies also uniformly show that within each urban/rural
grouping, Iung cancer death rates increase with increased smoking.
Whether air pollution acts with cigarette smoking to influence lung
cancer death rates in a combined manner is presently unclear (112,
126, 264, 26.5), and the evidence concerning a separate role of air
pollution in the etiology of Iung cancer is still inconclusive (228).
The recent report of the Royal College of Physicians on air pollu-
tion and heaIth (228) concIuded that "the study of time trends in
the death rates of lung cancer in urban areas demonstrates the
overwhelming effect of cigarette smoking on the distribution o? the
disease. Indeed, only the detailed surveys that have taken individual
smoking histories into account have succeeded in separating the
relatively very small influence of the `urban factor' on the over-
riding effect of cigarette smoking in the development of cancer of
the lung."

278


Author.      POQUhtiOn
  Y`,!ll-,       atudird and
c0untl-Y.      moth& at                              Results                               Commmla
re1crcnce     data collection

Doll.       Estimated death r&ten                Lung canccv morlalily (1950) PET 1,000                 Authors noted that
1163,       from lung c*nwr                   Nnlcs                 Fcmalcr        Ncmtnokcra   ce.~I:n~tL~ arc boscd on
Ennlnnd     in English                London Olhcr urban Rural    Lordott Ofhcr urbarl Rural   AI1 arcad   "cry few dcutha.
(70).       DoQulsllon and    Age:
         ~rnons nonsmokers   26-44 ..I.,,  0.126    0.096    0.070      0.028    0.028    0.012    0.020
         obtained fram      46-64  . , . ,  1.612    1.264    0.861      0.194    O.lG2    0.120    0.000
          general register.    65-74 .,. 3.124    2.006    1.1G4      0.440    0.326    0.288     I.219

Stocka and   Death ratn in                        Nda lung catictr dcalh ratea 19S2-61 (PC? 100,000) (~Pc, 54-71  The authors noted the
CampbeU.    England and
1966,       Northern Wales.                                Rurd (66)  Mind (116)   Urban (559)   upward nrsdicnt amonr
                                                                           nonsmokers, yiyc
Ewlnnd     Review of Datient  Nonsmokers ,~......,........,.,.,,,,,,..,..      14        , ,        131      smokers and light
(266).      chart or Interview  Pipe  . , , , . . . . . , . .      41        26        143     dgsrctt~ smokcra and the
          with kin or      Cigarettes: Light ,. . _.      87       163        291      lack of a simllnr
         vhyaicisns.       hloderate .~...........,,,.,,.......,,..,..     183       132        287     gradient LrnO"Y
                      Heavy  . . ..I..I...._............,,,.,......     363       303        304      mdcrnlc and hrsvy
                                                                           cigarette amokerr.

Hammond   187.783 white m&s                 Age alandardircd dcalh rafcb due Lo bronchoonric carcinoma (mdcs)  Data excluded
and Horn.    in 9 s!nlea.                                                              adcnocnrcinomn. when
1968,      Questionnafrc                                Suburb       Cily ol      Cifv of      standardized for BIL' and
U.S.A.      and interview.                      Rural       0, to*n     10,00040.000    >50.000      smoking. rural rate WLI
(IN).                 Nonsmokers  . . , , .   ,         4.7 (2)      9.8 (3)      14.7 (4)      aHll noted to bc 26
                     Cigarette smokers . , .  66.2(62)      11.1(61)      70.8(58)     86.2(63)      porccnt lcua than urban.


Author,      POlHJl~ti0n
  YCli-.       studied and
COUhY,       method OC                              Results                               Comments
refcrcnec     data collection

Hlrn3lcl     10 percent ol all          ~0~. and rmokinprt.andordizcd lung conce~ rno?tiitU %%tb           Standcrdircd Mortality

et al.,       white mnle Lund           (cpidermoid and undiferentiated carcinomua &VI              Ratio = 100 for U.S.
1962,       cancer depths in                                                    whlte males age 36 and
U.S.A.      U.S.A. for 19G8           Nctrovolitan countier           Nonmslropditan counti         Over In 1968. The authora
(JJ~).      for whom next of         >50.000  ,,......,....119            2,EOc-50,000  , .QO         rho noted I', joint
          kin or physiciana         10.000-60.000  . . ,151            Rural nonfarm .I4          ef?ch, cl rcaldence snd
          supplied smoking         Z&00-10.000  ,,......... 99            Farm  . .I. I.. .67          Bmokine histories in the
          data. 2,191 cnsee                                                  schedule of iuny-csncer
          with adeguate                                                         r~l-?_ far *re*ter lh"
          Incormatlon.                                                            those expected on the
                                                                         taumption of ~dliitlvity
                                                                           of the ser~nrutc
                                                                           ellectd . ."

DOU
and Hill,
1964.
Enuland
(70.

41,000 male British                       Slandardircd death rater for lunp CLIRCCY          The authors noted that
physiciana.                                                             rural marte.llty dub
Questionnaire and              Conurbatian(49) Large Towtu (34) Small Towtu (3P)  Rurd (Jab   were aKrcl*.d hy L
follow-UP of death  Nonamokero  . .    0.03         0.00         0.11     0.12    slgnlncsnt number uf
certihcate.      Clearetle smokers:                                             city reiidenla
             l-14 .~.,..,...,...,.    0.48         0.32         0.87         0.62     retiring to the cuulitry.
             16-24  . . . . . . . . . . . . . . .    1.31         1.88         1.06         1.16
           .  >26  . . . . . . . . *    1.90         4.43         2.20         1.17

Wleken.     1.908 male and               Lung cancw dcafh rate per IOO.OOO-age. and rmohirlo.rtand6rdizrd    total number uf drIllha
1966,       female luw ctincc-i-                                                         noted under mcthlid uf
Northern     deaths over 36                fnnn      OUlC7     Ucllaa t   Urban      Small          dat. cullcction lncludc
Ireland      years of L(lC from             Dcl~d     Dcllaat    Environs   Arta      TOWl-4     Rural   964 conhols.
(soa, *      rc~i9t.m. Personal  Malea  . . , . .   lG7(241)    139(167)    135(46)    llB(185)    137 (26)    47(149)
          interviews with    Femalea  , t,   22 (38)    17 (24)    12 (6)    23 (36)    22 (6)    12 (43)
         kin or physicians.


          TABLE g,-Epidemiologic inue8ligalions concerning the relationeilip o/ lung cancer to
                mking, air pollution, and urban or rural reeidence (confi.)
                                 (Acted number ol death shown In prrmtbesm)

        Author.      PODUhtlO"
        Year,       atudlcd wd
       CouncrY.      method of                              Results                               Commtnta
       relerence     data collectlon

      BUell       804 IWO ernecr          Apaadju~trd Lund cancer dsa;h ratra per IW.OOO man yrarr and moriolity ratior  The authors noted the lack
       et d..      deaths .mong                                                             of dcath.rate dlllcrencu
       1961,       Amerlcm                                       San Froncircol      AU other     bctwecn Loa Anaels, and
       U.S.A.      Leglonnrlrcs                           Lor Anoslu     Son Disoo    Colifomio counlisc  San Frw~claco rryiona
       449).      o ged26andovn.                        Ratr    i2atio    Rots    Ratio    RDId   Ratio   and concludrd thrt
                Quc~tlcnnalrem to   Nonsmokers  , . . . , , . . . . . . .    26.1     2.6     49.0     3.9     11.2     1.0   photochemlcal 8mw Ia
                next of kin.      Smokers:                                                    not relstnl to
                            <1 prcklday  .b.*I.III,..I.    C3.6     6.7     77.1     6.0     61.02    6.4   lung c.nccr.
                                . . . . . . . . . . . . . . . . . . . ..a.   126.0    11.8    134.6    12.0    124.9    11.2
            $:  . . . . . . . . . . . . . . . . . . . . . . .   241.3    21.6    22G.0    20.2    131.6    12.8

     Rltwugl,     186 male and                               Lung entlcer dsolh rats PET 100.000    The &uthOn DOBtUhtd L
       1DbB.       ternale lung e*ncer                                                    &llpht syner,zlatlc
      Japm      deatha rnd 4,191                                      POuutim rsOion
       (11.4).                                                                          et?rct betwan amoklog
                mrtcbcd controla   Male*                              LOW      Intsrmtdiati     Hioh  rnd .lr DOllUtlUn.
               aged 36-74. Dot&   Nonamokcrr  . . . . . . ..s.. ..,...........,....,,..,    11.6         8.8         4.9
                from          Smokers:
               aucstlonnrlrea     l-14 clearettes/day  . . . . . . . . . . . . . . . . . . . . . . . . . . .    10.6        14.2        28.6
                and Inkrvlavs.'     >I6  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    21.3        18.6        81.4
                           F4Vlnle#
                          Nonsmokera . I,., II......I....,.......,....I...     4.6         6.9         a.0
                           Smokera:
                           1-14 clearetteslday ..,.. . . . . . . . . . . . . . . . . . . .    19.7        16.6        16.9
                          >16 .a,..a.a..nas....a ,,...,,................    12.4        20.6        11.1
                                                Ape and cmokinp.ndjustcd lung cotlcs?
                                                           death rots pn 100,000

                                                            LOW      Intsrmrdiok     lliph
                           MRlCl  III~II~..I.....I..o...~.o..,...,.,,II,.,    16.1        22.4        28.4
E                           Fomaln  . . . . . . . . . . . . . . . . . . . . . ..l.......I....I..     7.6        11.6         8.7
w                                                                           __


LUNG CANCER AND OCCUPATIONAL HAZARDS

C'ranium Mining

The excess risk for the development of lung cancer among uran-
ium and fluorspar miners has been known for more than 30 years.
In a recent review, Bair (17) noted that radon and ridon-decay
products are the only inhaled radionuclides to be epidemiologically
related to lung cancer. Lundin, et al. (178), in a continuation of
the work initiated by Wagoner, et al. (299, 300, 301)) have re-
cently reported on a 1'7-year follow-up of 3,414 white underground
uranium miners. The authors estimated that smoking uranium
miners experienced an excess of lung cancer ten times greater than
did nonsmoking miners.

Saccomanno (2.3~ ), in recent testimony, analyzed the data of the
United States Public Health Service (USPHS) Study Group a.!
presented by Lundin, et al. (178) above. He reported that cigar-
ette smoking uranium miners incurred lung cancer rates four times
greater than those of other cigarette smokers.

Of the 62 lung cancer deaths in this population, 60 occurred in
smokers. He also observed that among 100,000 uranium miners
700 lung cancer deaths per year would be expected to occur among
cigarette smokers compared with only 4 among nonsmokers.

Other Occupations

Nelson (199) has recently reviewed certain environmental and
occupational hazards as they relate to inhalation carcinogenesis.
He observed that cancer of the respiratory tract has been linked
epidemiologically and, in some cases, experimentally with occupa-
tional exposure to the following materials: chromium, nickel,
arsenic, and asbestos. Doll (72) and Goldblatt (IOU), in earlier
reviews, also noted an association with coal, natural gas, and
graphite exposures.

Nickel

Morgan (194) noted that much of the nasal and lung cancer at-
tributed to nickel exposure may have been due to arsenical impuri-
ties found in processed nickel prior to 1925. Doll (69) found that
the number of excess deaths among nickel workers under 50 years
of age had declined following the change in nickel manufacturing
processes. The experiments of Hueper (134) and Sunderman, et al.
( 267,268,269) have shown that both guinea pigs and rats develop
lung cancer following chronic exposure to nickel carbonyl or nickel
dust. Sunderman and Sunderman (270) also reported that ciga-
rette smoke contains nickel and that this concentration of nickel

282


may be capable of inhibiting the induction of lung aryl hydroxylase,
an enzyme lvhich is able to detoxify aromatic hydrocarbons includ-
ing known carcinogens such as benzo[a]pyrene.

Asbestos

In 1955. Do11 (71) found that lung cancer was a definite hazard
among asbestos vvorkers. In a more recent study, Selikoff, et al.
(251, 252) examined the relationship of smoking and asbestos ex-
posure to lung cancer. These authors followed 370 people who had
been asbestos workers during the years 1942-1962. Over a 5-year
follow-up period, 94 deaths occurred in this group, of which 24 were
due to bronchogenic carcinoma. The authors noted that according
to data obtained from Hammond (118)) only 3.16 deaths from lung
cancer would have been expected among smokers, and calculated a
7.6 to 1.00 mortality ratio due to asbestos exposure. None of the 87
nonsmokers or pipe and cigar smokers died of lung cancer. When
the expected number of nonsmoker deaths (0.26) is compared with
the actual number (24) which occurred among the smoking asbes-
tos workers, an extremely high mortality ratio of 92 to 1 is obtained,
thus reflecting the possible interaction of asbestos exposure and
cigarette smoking.

Exposure of mice (179) and rats (106) to asbestos dust or the
intratracheal injection of chrysotile asbestos dust has resulted in
the production of significant numbers of primary pulmonary car-
cinomas. AIiller, et al, (184) exposed hamsters to intractracheal
injections of benzo[a]pyrene. These authors observed that the addi-
tion of the chrysotile variety of asbestos to the injections appeared
to promote benzo[a]pyrene carcinogenesis in the respiratory tract,
as determined by the time of appearance and yields of papillomas
and carcinomas.

Arsenic

A recent epidemiologic study by Lee and Fraumeni (163) Ffai
indicated an excess of lung cancer deaths among smelter workers
exposed to arsenic for more than one year. Cigarette smoking was
not taken into account in their computations. Experimental work
on the induction of cancer in animals using arsenic has yielded
either negative or inconclusive results (133, 135).

Chromium

Exposure to industrial bichromate compounds has been associ-
ated \vith an excess of lung cancer deaths (22,P55). Laskin, et al.
(159) have recently reported that intrabronchial pellet implanta-

283


tion of various chromium compounds in rats is associated with the
development of squamous cell carcinomas and adenocarcinomas.
However, Nettesheim, et al. (ZOO) exposed mice to chromium oxide
dust and observed that it had no discernible effect on lung tumor
incidence.

PATHOLOGICALSTUDIES

Investigators who have conducted detailed autopsy studies on
patients who died of lung cancer have reported the increased pres-
ence, when compared to noncancer patients, of bronchial epithelial
changes which they considered to be precursors of bronchogenic
carcinoma (7, 8, 23, 51,. 104, 208, 220, 279, 309). Such changes
include squamous metaplasia, atypical squamous metaplasia (with
acanthosis, dyskeratosis, and numerous mitotic figures), and car-
cinoma in situ. Cames (52) noted that carcinoma in situ was pres-
ent in 119 cases or^ lung cancer but not in any of the 119 controls
who were matched for age, sex, and race.
Autopsy studies comparing the frequency of these cancer-
related changes in the lungs of smokers and nonsmokers are pre-
sented in table 10. Virtually al] the studies noted an increased
prevalence of these epithelial alterations among smokers as com-
pared with nonsmokers. Definite dosage-dependent relationships
were evident in the results of many of the reports. Also, Auerbach,
et al. (14) observed that the number of cells with atypical nuclei
decreases progressively in the bronchial mucosa of ex-cigarette
smokers, depending upon the number of years between cessation of
smoking and death, although it usually remains above that found in
nonsmokers.

The cytologic studies included in this table (182, 198, 222) ali
noted an increased percentage of sputum specimens showing meta-
plasia among smokers as compared with nonsmokers.

PULMONARYCAFLCINOGENESIS

General Aspects of Carcinogenesis

Agents found in cigarette smoke which have been identified as,
or are suspected of being carcinogenic, are listed in table 11. The
list includes certain compounds which most probably contribute to
the pathogenesis of the various cancers discussed in the other sec-
tions of this chapter. Many other agents have been identified in
tobacco and tobacco smoke. At the present time, they do not appear
to bear a direct relationship to carcinogenesis. Stedman (262) and
Wynder and Hoffmann (S19) provide detailed listings and discus-
sions concerning these materials.

284


1068,      &uLopslcd mt           Nonsmokom . . . :, , . , . , , . . , , . . . , , . . .-. . . . ,y. ,:. , .
Norwn~                                      84.0. (89)          cludo tbas
        Cnde Institute         Pl9e  . . * , . , *, , , * . . . . * , , , , . . . . . . . , , . . . . , , , . . , . , . , , , , ,    80.6 (20)          amoklng Inn
trio).     on whom            All cigarette  . . sg . . . . . . . . . . an..., . . . . . . . . . . . . . ..t...... . . . .    78.0 (88)          than or equal Lo
        smoking data         Clgsrdtps per day:                                             6 gram. per dry.
         was available.           6-14  . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .    70.0 (23)
                          ) 16-26  ..1...............III.....,I.....I........,....I....1.    90.0 (10)
                          X6 ,.....,,,.,,.............,.,,,I..,,...,........,..,,..,.    100.0 (6)

Knudtson,   100 D,ci-eOna
1960.                                       Pncmt 01 colu with:              AlVgLXl    Age. occuuntlon.
        23-86 yesrd                   No. of        NO
U.S.A.                                                Baaal cell    Squomour     g+olilc+aliuo    and site or
        of age                      PCWXl4
(147).                                    change     hvrm&da    WWt&WiG     mct4ula8ia     rcaldencs were
        autwsied at  Nonsmokers . . , , , . . . . . ,, .  (21)        47.6         26.6        14.8         9.6
        senwc     Clgarettea/drr:                                                         found to hevr DO

         Veterans                                                                 rDprccl&lls
                   l-9   . . . , . * * . . . . , . . , . ,   (9)        77.0         11.1        11.1
        Hospital on    lo-16                                                              eflcct.
                     .*.*..*,......... (11)                                      . .
                                            18.2         18.2        64.6         9.1
         whom       16-20 .*.*..*,,..,,.,,.  (44)        20.4         29.6        28.6        20.6
        amoklng      >21  , . . . *. . . . ,. ,. ., ,. ,   (9)        11.1         88.8
         data WLI                                                   44.4        11.1
               Pipe or clgw  I....I`.,,,.   (6)         . .        100.0
         ~Vllll~!Jl`Z.                                                    . .         . .


TABLE IO.-Pathologic and cytologic findings in the traclreo-bronchial tree of smokers and nonsmokers (cont.)
                      (Actual number of cues ahown in psrenthna)

Author,
  Y-r.   NE%f
countrY,    method of                                 RcauPd                                 C0mfTlentd
rofernee     aelretion

Auerbach   339 pcreons                                 Number oj    Percent rectionr Pcrcmt secfiow    The authora noted.
et al..     22-88 ye.m                         Numbrr      rcctimu     with cilia ablent   with some       dcdcrrsvonse lx-

1961,
U.S.A.
(If).

of age
mJtopalcd nt
Enst Orange
Veterans
HOSDitAl
(excludes
lung
CUtCW),

Nonamokcn:

ot
perswu

01 bronchial     and entirclu
cpithelium     atypical cell4

atypical cella
and cilia absent

<40 yean of .ge . .*. . . . . . . . . . .   a
4&69  ,.. ., ., ., . . .I .., . . ., , . . ,.  11
6049  . . . , .a . . . ,. . . . , , ., .  28
>70  .,..........,.,..,,*.,,...... 18
Smokera <l pack/day:
<ro years of age ..,,,....,,...... 14
40-69  . . ., . . . . . , . . , , , , . . . .  24
bC-GB ,.,,..,..,,.,.,.,....,..,o. 36
>70  . . . , . . . . . . . , . . . , , .,  22
Smokers >l pack/day:
<ro Yeara of llpe . . . . . . . . . . . ` .,...  17
40-69  . . . . . . . ,, , ,, . ,. ,. . . . . .  63
SO-68  . . . . . . . . . . . . . . . . . . . . . . . . . . . .  84
>70 .,..,.,`.........,. ,,.,, ,,.., 16

383
660
1,463
918

.

0.3

0.1
0.6

121         0.1          4.1
1,240         1.0         16.9
1,772         0.6         10.8
1,101         0.6          9.4

lath of smoking
Lo:
  a, lose al clllr.,
  b. lncrearc In
    number of
    atypical
    ceh.
  c. carcinoma
    in ailu.
Averbgc number of
aectiona per oil0
e~uald 62.3.

am         1.6         12.6
3.027         4.6         11.4
4.186         6.3         20.6
766         9.8         23.7

CKW      140 personr                 Pcrcnlt rectiou showing chunpta in bronchi& rpilhclium (number 01 mcctionr) t The nuthOr8 noted
et al..     autopeicd at                                   S.Jl`flt?lOW   AlVpicd   Carcinoma          that thr diflcra
lP61,      Iowa City                      Normal   Ilyvcrp,liuia   mct,lvla4ia  rnCt4Vhlia    in aitv   Crrrcitwmo  ence bclxccn
U.S.A.     VpterU!I~    Nonamoken (al)  ..II,..I.. Gl(GC2)    X(131)     a (33)    tl6(68)     . . . .      .a..   smokers and non.
(64).     iioaplt.1    Smokera (109) .,,,......... 44(670)     43(662)     16(197)     20(263)    l(12)    2.6(34)    amokera W~I
         on whom                                                                     ,t~llC,liC~lllY
         smohinr                                                                      algnlncsl~t.
         data WBI
         available.


    TADLE 10.~Pntlrologic and cytologic findings in the traclreo-bronchial tree of smokers and nomnokcrs (cmt.)
                             (Aclual nurnbcr uf cose4 ahown in vnrcnttwn)

Author.    Numbrr of
  Year,     CQ~ES nnd
c""ntlY.    method of                                ncsulta                                 Commcnls
reference    selcclion

AUCrbaCh   72 sulopsicd                           Nurnbcr of     Pcrccnt scctim~ Pnccnt scclims Percent rrctiow Each cx-smoker
et al.,     former ciga-                        acctiona Of     with cilia obacnt tuitJ~ smncalvpi- with 60 gerccnt   matched with a
1962.      rette smokers                          brmtcAia1      and cnlircly
U.S.A.                                                          cd ecu4 and   atypical cell4   CUI~C~L smoker
         who had been              Number       epill~clium      alvpical cella
(II).                                                           cilia abrent  and ciiia grerrnt  vlua never-smoker
         smoking for  Nonsmokers . , , , . . ,   72          3,156          0.0         0.1          0.6      for ape, oceuvn-
        210 years   EIxx-amokerr . , , .   12          3.436          0.2         0.9         2.6      tion. and rcsl-
         and had     Current amoken . . .   72          3,537          8.0        18.0         80.8      dcnce. There wu
         ceased                                                                      *n llb'ernge of
        26 yetll-8 .*o.                                                                  GO.3 e.CCtlDna vcr
                                                                           subject nnd none
                                                                           had leas than 18
                                                                           sections.


   TABLE lo.-Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (cant,)
                              (Acluul number ol CLI(CB ahown In pnrenthraca)

AUthW.    Number of
  Year.     CLSCB and
CO"l-htCJ.    mcthnd of                                Ihulta                                 Cummcnld
rctcrcnce    sclrclian

Auerbrch   466 male and                                      Prreed #cc-   Percc?d ,CC.   Percent ICC.    Major llndlnrs
ct al..     302 fcmnle                         Number of     tionr utith     tion.4 with   lion4 wit.4 50    lW1d:
1962,      amokera rnd                          rccliotu 01     cilia abacnt
U.S.A.                                                80md afypi- prtccd alylricnl    Urbun nonamokcrn
         nonsmoken                           brachial     and nltircly   cd cell1 and
(13).                                                                    cdl, and      ghowrd more
         ~u~opaled nnd                 Number     epithetturn    ulvpicol cell8   cilia abrmt   cilia prrrmt     lesion than rure.l.
         mntched for   blslea:                                                            Both lmlona and
         we. OCC".    Nonemokcrs 1. ,. . ,,`.. .  41         2,346                   0.1         0.1       ._LY9iCII nuclei
         DatiOn, and    Cigarette amokera . . . , . 1  76         3.303      62        21.2        78.6       were much lrw
         residence.    Females: ,,                                                         2reQucnt In nan-
                   Nonamokcn  . . . . . . , . . . .  41         2.919          .         0.1         0.6       nmokem and lcae
                  Cisarettc smokera , , , . ,  76         3,607         2.6        13.8        62.6       Ireclucnt In plvc
                  Mlll~:                                                             snd cigar amokera
                  Nonsmokers . .s,, , , . . . .  36         1,106          . .         0.2         0.5       thnn In clgareltc
                  Cimr smokers  , , , . , ,. , .  86         1,133         0.8        10.0        10.7       smokera.
                  Clsaretteamokera . . . . . .  36         1,62t        12.6        27.8        89.1      K'I.I$`O of e.ara h&d
                                                                           6b66 sectiona
                                                                   al.ayfo of cuea had
                                                                           40-40 arclions
                                                                      7.370 01 CBBNI had
                                                                           30-s asctiona
                                                                         4.6% of cn~rtl hrd
                                                                           16-20 scctlwls

Robbina,    103 students                                                                       -^_
                                      Percent in rwh evtolollio ctddr                       Smokora drilncd LLI
  1ICC.      11-24 years
  U.S.A.                                             Slightly     Modrratclv       Strongly      those hnvlnu con-
         of aze who                          NOWWl
  (PPO.                                           afvpicd     l7!YPiCOl        4tupical      #urned 210 ciye-
         underwent   Nonamokera (46)  . . . . * .*,.. ~ ..,....  86.1         4.4         a.9
         aerosol     Smokers (68)                                                         rsttn n dw for
                           I. *.* . . *.,,.......,,,  66.2         32.8         10.8          1.7        21 Ye*?.
         sputum
          induction.     I


Aulhar.    Number of
year.      COHPI~ nnd
cowltrY.     method of
rcfcrcnce     srlrctlon

Results                                 Commcnla

Number    Pcrcmt rhmuinn mrlolrla#ia
234            41.16

189            41.09
886           61.43
  93            6 I .29
  38            CO.29

Nasiell.    60 nanamoklng                           Sputum cvlologic ehanpca             Pcrcrnt ruilh    t RlKilrdiYl by
19G8.      wtpnlicnt~.                             l'crcL71t             Percent with    alvpicd      author a8 "rcrl
Sweden    398 smukera                  Number        nra1c1      Airan aye   mclnphrio    mclapluriat     vrcmnliununt
(ISA).     parMpr.ting Nonsmokers . , . . . ,  60          42         67.1        18          4       chsnyc."
         In wneral   Smokers  . . . , , . . , . . 398          73       kG.6        62          27
        health exam-
        lnation who
        underwent
        suutum
        induction.

Spnin     167 males and                                           Number    Prrccnt with mc(apkuia  The authors found
et PI.,     78 femsles    AldeB:                                                             no evidcnrc of
1970.     autopsied foL   Nonamokera  . ., . . . . . . . . . . . . . . . . . . . . . ., a.. , . ., ,    36            60.0         carcinoma in rilu
U.S.A.    lowing sudden   Ex-smokers  . . . . . . . . . . (. . . . . . . . . . . ,. . . , . . . . . . . . , , (. . . ,. . . .    2~            67.7         Or DrenCOVh8lk
(258).    or accidental    <1 wck .I. . . . . . . ..t I... . . . . . . . . . . . . . . . . . ,, . . . . . . . . . . . . .    32            62.6         &LYpicnl ctinngca.
        dcnth for     >I pack . . . . . . . . . . . . . . . . . . . . ,.....I... . . . . ,..,..,,..,,,..,,, ,    68            13.6
        whom smok-   Females:
        ing data were   Nonsmokera  . . . . . . . . . . . . , . . . . . . . . . +. . , , , , , .    34            34.1
        available (ex.   <I v,sck ..*a* . . . . . . . . . . . . . . . . . . . . . ...I . . . . . . .,,,, . .,...,.,,,                83.3
        smokers ex-    >l pndc  . . , ,, ,. . , . . . . ., . . . ., ..~. . . . . . . . . ..,                46.1
        eluded from
        female data).


In order to facilitate understanding of the relationships of the
various compounds to one another, the third column presents the
presently understood relative importance of each of the various
groups of compounds. These compounds have been tested only in
animals or tissue cultures, and it should be stressed that the rela-
tive importance of one compound may not be the same in man as
it is in animals.

Table 11 is divided into two major sections. The first section
details those compounds which are considered to be or are suspected
of being cancer initiators. These are compounds which induce
irreversible changes in responsive cells. In the second section are
listed those compounds which are considered to be or are suspected
of being tumor promoters. These compounds promote the maI%-
nant reproduction of cells in which neoplastic changes have been
initiated. A number of these initiators may also act as complete
carcinogens in their own right. The evidence concerning the two
stage initiation-promotion mechanism is still rather limited for
respiratory tract carcinogenesis.

The polynuclear aromatic hydrocarbons (PAH) listed are pres-
ently considered to pIay a very significant role in pulmonary car-
cinogenesis due to tobacco smoking. These compounds act as tumor
initiators or complete carcinogens. The particular role of these
agents in environmental and occupational carcinogenesis has been
reviewed by Falk, et al. (93). That such hydrocarbons are pro-
duced from tobacco during human smoking has been shown by
Kiryu and Kuratsune (146). These authors reported the presence
of benz[a]anthracene, chrysene, benzo[a]pyrene, and benzo-
[blfluoranthene in the "tar" produced by normal smoking and
measured in either filters or stubs.

Two hydrocarbons which have frequently appeared in the litera-
ture on experimental tobacco carcinogenesis may not actually be
present in tobacco smoke. They have been used as representatives
of carcinogenic PAH, a class which includes many constituents that
have been identified in cigarette smoke condensate. They-ai-e
7,12-dimethylbenz[a]anthracene and 3-methylcholanthrene and
have been frequently used as tumor initiators or complete carcino-
gens, parCcuIarly in skin painting and tracheal impIantation
experiments.

The nitrosamine compounds listed are potent carcinogens affect-
ing many organ systems, including the respiratory tract (188,
189). hlagee and Barnes (181) have presented a detailed account
of experiments in this area. Nitrosamines have been identified in
trace amounts in tobacco "tar" and the conditions required for their
formation (the presence of secondary amines and nitric oxide) are

290


TABLE IL-Identified or suspected tumorigenic agents in cigarette smoke'

I. Complete urcioantna and tumor initiators:
I'olynuclar mromatic hydrocarbons  ........
   1. Bcnw(~)p9rene  ....................
   2. Dibcnrlr.h)snthmcene  ..............
   3. Bcnu,(b)fluaranthene  ...............
   4. Bcnw( j)fluoranthenc  ...............
   S.Dibenzo(a.i)pyrene  .................
   6. Benz(a)anthracene  .................
   7. Chrvsene  ...........................
   8. Indena(l.2.3.cd)pyrene ..............
   9. Ben7.o(c)pheoanthrcne~  .............
  10. ~cthylbenra(.)pyrc"es  .............
  11. MethylcblTsenea  ....................

X0-30 UP
3.3
0.4
0.3
0.6
Trace
0.3
2.0
0.6
TTllCC
0.1
2.0

N-heterocyclic hydrocarbons  ..............
1. Dibenrls.h)acridine  ................
Z.Dibenr(a.j)ncridine  .................
3.7Hdlb~zo(c.z)carbarole  ...........


N-nitrossmio~a  .........................

1-2
0.01
1.0
0.07

l-10

1. Dimetb~lnitrosnmine  ................    0.4
2. Diethylnicroae.mine  .................   TlTLC-2
3. ~lethpl-n-butylnitro.aminc  ...........   TWlCTZ
4. Nitraopyrrolidine  ..................    0.4
5. Nitrosopipcridine  ...................   T0TC.Z

Epoxidea. perory compound% and lactones:
1. Eporides  ...........................
2. Peroxides  ..........................
3.Lkctones  ...........................
   L. ,-Levantenolide  ................
  b. p-Levantenolide  ................

No data
Present
.
20.0
2.0

N-alkyl-hcterocyclics:
  1. I-methylindole  ......................


Paticidn and fungicides:'
l.TDE  ...............................
Z-c,.;-DDD  ...........................
3.DDT  ...............................
4. Malcic bydrrzide  ....................


BeLwnsphthylamine  ......................

Present  Possible initiator.

    No essential contribution sus9eetcd.
10-100
10.100
10-100
10-100

2-3

Tumor initiators.

Tumor initial-am.

~uspcrted carcinonens of possible
im~artance (presence in fresh
smoke possible).

Certain of these compounds are
known carcinogens; presence in
smoke condensate not established.

Suspected bladder carcinosen:
of doubtful significance at
reported Iev&.

Polonium 210  _. . . _. . . . . . . ..--    1.60   Of .90me importance only in the
                           gicocuriea   caz.e of relatively high conix~n-
                          trslion. but not impo&nt at
                                reported levch.


TABLE Il.-Zdentified or suspcctcd tumorigenic agents in cigorettc smoke'
                    (cont.)

II. Tumor promotinp nnenta:
Neutral pmmotur (polmera)
   (unboan ,tructuren.)

No data  Of pwsible importance.

VoLtilc pbm&  . . . . . . . . . . . . . . . . . . . . . . . . .  20.30 my.  Of porGble immxtance.
  1. Phenol
2. cresc.1

Nonvolatile fatty s&da  . _. . _. . . _. . . .  20-100 mu. Of minor importance.
  1. St.sric acid
2. Oleic acid

N-dkyl heterocfdics:                      Of possible imwrtancc.
1. S-mstbylcrrbarole  . . . . . . . . . . . . . . . .  Present

found in tobacco smoke (38). However, nitrosamines may be arti-
facts dependent on the method of smoke collection (201).

Neurath (202) considers the `nitrosamines listed in table 11 as
being present in fresh cigarette smoke (253, 254). However, con-
clusive confirmation of their presence in fresh smoke is not available
(38,138,155,319).

Certain of the pesticides and fungicides presently in use on
tobacco have been found to be carcinogenic (91,273,280). A num-
ber of these, such as DDT, are now being phased out of regular
domestic use. The compounds listed have been shown to be present
in trace amounts in mainstream tobacco smoke (1 II, 128). A recent,
extensive review by Guthrie (111) provides more detailed informa-
tion concerning these agents.
Radioactive isotopes can be found in tobacco and tobacco smoke
(205). Potassium-40, while present in tobacco leaf, is not trans-
mitted in any substantial amount to mainstream smoke (230).
Polonium-210 ( PoZID) , however, is transmitted into the mainstream
smoke (94, 123, 142,145, 215,217). A number of autopsy studies
(table AI2) have shown that the bronchial epithelium of smokers
contains significantly more Po~,~ than that of nonsmokers. Littie,
et al. (172, 173, 174) have also noted that the concentration of
polonium was markedly higher at sites of bronchial bifurcation.
These authors stress the importance of this finding for pulmonary
carcinogenesis by noting that bronchogenic carcinomas are fre-

292


quently located at bifurcations and that the polonium levels which
they found in those regions probably have biologic significance
(216). Other investigators (12.3, 217) have not observed this
excess at bifurcations, and in a recent discussion Wynder and Hoff-
mann (320) concluded that it appears unlikely that Poz10 in the
amounts present in cigarette smoke plays a role in tobacco car-
cinogenesis.

Although not listed as a separate group, there are a number of
agents in cigarette smoke which are potent inhibitors of ciliary
movement. Their importance in carcinogenesis derives from the
increased amount of time which they afford the known carcinogens
to be present on the surface of the bronchial epithelium. These
inhibitors include volatiIe aldehydes, hydrogen cyanide, nitrogen
oxides, volatile phenols, and certain volatile acids such as formic
and acetic (129).

Expen`mental Studies

In some respects, the animal and tissue culture studies detailed
below apply to neoplastic transformations, not only in the lung but
in other tissues in which tobacco smoke, particularly cigarette
smoke, is believed to play a role. These general experiments will be
presented here, however, with the experiments which bear on lung
tissue directly.

Skin Painting and Subcutaneous In.jection

Numerous animal studies on rats, mice, and rabbits, have been
performed utilizing known carcinogens, whole tobacco "tar," and
various tobacco condensate subfractions, or compounds known to
be present in tobacco smoke. These experiments involve the single
or repeated painting of shaved or unshaved animal skin. A seIected
number of these studies is presented in table A13. Numerous other
studies, performed prior to and following 1953, are reviewed by
Wnder and Hoffmann (319).                            -.
  The skin painting method is still considered to be a valid pro-

cedure for the identification of agents suspected of participating in
pulmonary carcinogenesis, as well as for the quantification of the
reduction in tumorgenicity of specific agents.

Tiss-ue and Organ Culture

The exposure of tissue and organ cultures to cigarette smoke, its
condensates, or its constituent compounds has been shown to sig-
nificantly alter patterns of cell growth and reproduction. Table Al4
presents an outline of these experiments. Once again, less severe
effects have been noted when filtered smoke was used (165).

293


Tracheobronchial Implantation and instillation

More complex experiments concerning the carcinogenicity of
cigarette and tobacco smoke are represented by those which involve
the direct implantation, instillation, or fixation of suspected ma-
terials into the tracheobronchial tree of animals. Certain of these
experiments are outlined in table A15. Recent reviews by Saffiotti
(233,2.3:) Laskin, et al. (159). and hiontesano, et al. (189) as well
as that by Wynder and Hoffmann (319) provide more detailed and
extensive accounts of these experiments.

Of note among the results outlined in this table are the following:
The enhanced carcinogenicity found when benzo[a]pyrene (B[a]P)
is combined with a carrier such as hematite dust (235), and the
definite increase in bronchial epithelial preneoplastic and neo-
plastic changes among dogs treated with smoke condensate as com-
pared with those undergoing only physical bronchial stimulation
(2%).

Inhalation

Various species, including mice, rats, hamsters, and dogs, have
been exposed to cigarette smoke or aerosols of its constituents.
These inhalation experiments are outlined in table Al& It must be
noted that the majority of the studies listed involve the passive
inhalation of the material presented usually in a chamber. Active
inhalation experiments, exemplified by the work of Rockey and
Speer (223) and Auerbach and his colleagues (II, ff9) involved
animals which were trained to inhale voluntarily, thus more closely
simulating human smoking.

Results of note among these experiments include the following:
Miihlbock (195) observed that cigarette smoke inhalation en-
hances the already substantial rate of spontaneous alveolar cell
carcinoma formation in hybrid mice, and various investigators in-
duced adenomas in experimental animals (108, 168, 206). Harris
and Negroni (121) found that exposure to cigarette smoke achieved
some enhancement of adenocarcinoma formation in mice but did
not observe proven squamous cell carcinoma. Some of their mice
had also been exposed to Swine influenza virus aerosol. In a related
study, Boren (32) exposed hamsters to cigarette smoke at set inter-
vals over a 48-hour period. The author observed alterations in pul-
monary cell kinetics (the pattern of DNA synthesis) as demon-
strated by H3-thymidine autoradiography. The pattern of the label-
ing response to cigarette smoke was significantly different from
that of the response to high oxygen concentrations.

Auerbach, et al. (11) have reported the development of early

294


invasive squamous cell bronchogenic carcinoma in dogs following
a period of direct inhalation of cigarette smoke. These investiga-
tors trained beagle dogs to inhale cigarette smoke through a
tracheostoma (50) and divided the anima!s into groups according
to dosage as detailed in table 17. A number of dogs died during the
course of the experiment which ran for 875 days, or approximately
29 months. The causes of death are listed in table 18. All of the
remaining dogs, with the exception of group "h" (high exposure,
heavy weight), were sacrificed shortly after day 875; the survivors
among the heavier dogs are continuing to smoke.
Examination of the respiratory tree of the animals revealed a
number of tumors (table 19). Most of these were similar to the type
of tumor which in man is referred to as bronchiole-alveolar. This
tumor arises in the bronchiolar and alveolar epithelium and tends
to be multicentric. Two striking characteristics of these bronchiolo-
alveolar tumors were the existence of a histologic spectrum (from
a tumor resembling the benign condition of adenosis to frankly
malignant tumors with invasion of the pleura and surrounding
parenchyma) and the marked tendency to squamous change. Inva-
sive bronchiole-alveolar tumors were found in 12 dogs in the group
which had been exposed to the largest dosage of cigarette smoke.
Several had tumors of more than one category. Ten of these dogs
had invasivee bronchiole-alveolar tumors which did not extend into
the pleura, one dog had an invasive bronchiole-alveolar tumor
which extended to the pleura, and four had invasive bronchiolo-
alveolar tumors extending into the pieura beyond the pleural-
pulmonary junctions. In addition, two bronchogenic squamous cell
carcinomas \r-ere found in this group (table 19). The dosage de-
pendence of tumor formation is shown in figures 2 and 3.
Major findings of the study were twofold. First, that smoking
filter-tip cigarettes was less harmful, both in terms of pulmonary
parenchymal damage and lung tumors, than smoking identical
cigarettes without filters. This supports the generally held view
that total particulate matter is a meaningful indicator of the car-
cinogenic potential of a cigarette. Second, lung cancer of two types
found in man was produced by the inhalation of cigarette smoke.
Two of the dogs were found to have early invasive squamous cell
carcinoma of the bronchus, and both belonged to the high-dosage
group. These carcinomas were indistinguishable from early invasive
squamous cell carcinomas found in the bronchial tubes of human
beings who smoke cigarettes. The majority of tumors found in the
dogs lvere of a bronchiole-alveolar type, which although not as
common as squamous cell cancer in man, is not rare in humans.
This type is often included in the category of adenocarcinoma. A
number of studies have shown an excess of these tumors among

295


TILE 17.-Data on pcdigrecd male beagle dogs of groups F, L, H, h, and N
          (Some of the figures (rnuly only lo doga surviving 876 dwa or longer)

Filter      I-E,
group          oroup
F            L

12            12
26.0           26.1
6,143           3,103
  7.02           3.64
42.1           21.2

17.8           34.8
  1.11           1.86

109.3          103.6
  1.19           6.66

  4.31           4.12
  0.29           0.22

NO
nikr
grO"p
II

2b
26.0
6.1'28
  7.0
42.0

34.8
  1.85

207.8
11.12

  0.91
  0.44

fEr       Nonsmokera
           ETOUP
YP         N

a0           0
al.9         SO.7
E.129          no,is
  7.0         -
a2.9         -


84.8         -
  1.86        -


207.8         -
11.12        -


  6.61        -
  o.aa        -

' The smoking doga wetc divided Into grwDe F, L. H, and h on day No. 67.
' Dogs of gwunl L. ii, snd h amok& hltcr.tiD clgarcttcs during B training period nt the start of tbc uporlment. but amoktd nonfilter clU&retttl tbcrcaf'er.
SUUHCE: Adardrd from lIammond, E. C. et hl. (110).


  TABLIZ l&-Summary of principal cause of death (&us No. 57 through No. 875) in dogs of groups F, L, H, h, and N
           (Each death clwained according to m&st scvcre condition--eome doas diad ol a combinstion uf ce,uses listed)

                                    Filter          NO         No
                                    tip          filter        nltcr    n%
         Principal C.USC of death                        N~~~y;;cra
                                 Croup        c TO" p    C;oiuD       Cr"UD                  Total
                                     F           I,                    h          N

Pulmonwy emphysema nnd fibrosis . . . . . . . . . . . . . . . . . . . . .     -                     2
Cur pulmunale (pulmonary emphysema and fibrosis with                                    -          -          2

right heart enlargement)  . . . . . . . . . . . . . . . . . . . .     -                     3
Pulmonary infarction  . . . . . . . . . . , . . . . .,.               -                    6                     8
                                      1           1          2
Broncho~neumonla ..,.,...,..,........,......,,..,....                                    6          -          9
                                      -                     3
Aauir&tion of food . . . . . . . . ., . . . . . . . . . . . . . . . . . ,... , . .               -                    1          -          4
                                      1           1
VnCWtsi"                                                     -          -                     2
       . . . . . . . . . . ..1...............................                          2
Number of deatha . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .               -                     1          -          a
                                      2          2          12
Number surviving 876 dam                                                      12                    20
                . . . . . . . . . . . . . . . . . . . . . . . . . . . . .     10          10
Total number of dogs                                              12          26          0          66
             . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .     12          12          24          38          8          84

SOURCE: Hammond, E. C. et al. (111).


TABLETS.- Data on dogs with lung tumors indicating type of tumor and lobe in which tile tltmor wae found


CIOUD          %xf   N%bcr      &c at                             Early n~u~lnou
                                          dCBlb   Lubcn wiLh bmnchialo-rlv~~~~i~mo~    ccl1 bmnchlnl
                               cignrcttcs     (Years)     Non-invnoive                   CnKIrIUma

9048
904b

-

6.1
4.0

LA
IU

8788        6,161        6.1
879a        6.170        4.1
8868        G.224        6.2
890a        6.269        5.4

LA
LA
LA
LA

347         1.055        3.8        LA. LC
812         2,847        6.1        I1A
876n        3,103        6.1        LA,RA
8778        3,107        6.2        LA.LC
8R2a        3.127        1.2        LA, LD
Aclria        3.lh3        6.3        I.h, l(D
8lJliu        3,I'JG        6.4        l.h

6IH        2.L
l.:i4:I        3..1
3.404        47
4.6nv        6.0
s.o:io        3n
G.lJKH        4.2
6.970        13
G.l'LY        I.9
G. I :I"        6.1
C,l47        6.3
6,1X3        6.4
6,192        4.7
C,?IO        6.0
6.246        6.0
6.255        I.9
6.?73        6.7
6.273        6.3
G.3lX        6.2
G.3lR        4.6

IIC:
I.h. RA, 1tn
1.11. IlA

I(1
1.A
L A

.
LA
LC.RA

ItA
LC

-

-

-

-
-

-

-

-
LA
1.h. Ilh, IlD
-_

-
LA. 1.1). IlA
LA
LA
-
LA
LA, KA
LA
-

-
LA, 11A
-
LA

-
-

-
-
-
-

-
-

-
-
-



-

-.
-
.-
-.
-
-
LAUII
-
-
--
L51U
--
-
-.
-

-


TABLE l&-Data on dogs with lung tumors indicating type of tumor and lobe in which the tumor was found (cont.)

Number
  of
cigarettes

hKC at
death
(Years)

CrOUD h (no filter)  . . ...* . . . . . . . . . . a..... h      606         3,761        4.6        LA                         -
                         h      626         3,928        4.4                     LA, RI          -
                         h      649         4.143        5.0     iI             LA, RA         -
                         h      794         5,400        5.1        LA, RA          -            -

LA. left apical lobe; LC, left cardiac: LD left diaphrsgmatic; RA, risht
spicnl: RC. ripbt cardiac; RI, right intermediate; RD, right dinpbragmatic;
LAUD. left nuical branch bronchus; LMB. left main bronchus.

start of smoking. The letter "a" or "b" follows the day of dcutb of doga
sacrilicetl after day #876.

For smoking dopa, the day of death indicates the number of days since      SOURCE: Auerbach. 0. et al. (I!),


  58.3
-- - -..---

GROUP N:
NONSMOKING

GROUP F:      GROUP L:      GROUP H:
FILTER-TIP      NO FILTER     NO FILTER
        (I/Z a* many ciparrtlcs)
            .s Group H

i
i
;:i

TUMORS        2           4            7           19
DOGS       -ii        12        i;i       Fi

FIGURE 2.-Percent of smoking dogs with tumors.
SOURCE: Adapted from Auerbach. O., et al. (11).

60

s
4   40
b
s
Y                                           20.8 _
s
&   20

0
     GROUP N:      GROUP F:       GROUP L:     GROUP H:
    NONSMOKERS    FILTER-TIP     NO FILTER     NO FILTER
                        (`A as many cigIrstta)
                             II Grout H

TUMORS       2           4            12          35

LOBES     M       SC        sr       1-z
FIGURE J.-percent of lung lobes with tumors in smoking dogs.
SOURCE: Adapted from Auerbach, 0.. et al. (11).

300


cigarette smokers (6, ~2, 11.2). but the magnitude of this reiation-
ship is not as great as that with squamous cell cancer in man.

Reduction in Tumorigenicity

The importance of reducing total particulate matter in cigarette
smoke is reflected in the dose-dependent results of the Auerbach-
Hammond study. A major objective of experimental tobacco car-
cinogenesis must be the reduction in the tumorigenicity of cigarette
smoke and other tobacco products. In a recent article (320).
Wynder and Hoffmann have reviewed the various methods applied
to achieve this goal. Among these methods are the modification of
the tobacco itself, the modification of the conditions of tobacco
pyrolysis, the use of additives, and the use of fiIters. The use of
filters shouId produce a reduction of particulate matter as well as
of gas phase components.

Brass (14) studied 974 cases of lung cancer at Roswell Park
Nemorial Institute and concluded that smokers who switched to
filter cigarettes showed a decreased risk of developing lung cancer.
However, even after switching, heavy smokers were still found to
have a mortality risk five times that of nonsmokers.

More recently, Wynder, et al. (324) reported on an interview
study of 350 patients with histologically confirmed lung cancer and
552 age and sex-matched controls. They found that subjects who
had switched from nonfilter to filter cigarettes ten or more years
prior to the study incurred a lower relative risk of lung cancer at
all consumption levels than that incurred by those who continued to
smoke nonfilter cigarettes. The authors suggest that this difference
in relative risk may be due to the lower "tar" content in filter
cigarette smoke. Prospective studies concerning the effects of filter
cigarette smoking are presently being conducted.

Apart from variations in "tar" exposure due to filtration, it
appears that different patterns of smoking result in the inhalation
of varied amounts of "tar." Graham, et al. (103) simulated dif-
ferent inhalation patterns with the use of an analytic smoking ma--
chine. He found that smoking a given number of puffs over a long
period of time results in greater "tar" retrieval than smoking them
over a short period. Also, he observed that taking most of the puffs
at the end of the cigarette results in the highest retrieval while
taking most at the beginning results in the smallest retrieval.
Complementing these observations is the same author's case/con-
trol study (102) of 183 men with lung cancer and 161 men with
diseases not related to tobacco smoking. He found that the lung
cancer patients had significantly greater high "tar" yield cigar&e
smoking patterns than the controls. The risk of lung cancer was
found to increase with the increase in mean number of puffs per

301


cigarette, the average length of time taken to sm.k,-t :a cign~tZc
(except in the highest number of puffs category), ti:ti, ;be rAki,%
of more puffs at the end of the cigarette.
These findings, and those of the study of Xuerbrrhh .I: :>, !, ~.i,j,
add further support to the dose-response relationsti:, i~et~c?en- Cung,
cancer and total cigarette smoke condensate expo~.rr~~.r:.

SUXSIARY AND CONCLUSIONS

1. Epidemiological evidence derived from a numo::?-.C nrc:~+n~:-
tive and retrospective studies coupled with experimm<X .hxd' pat'h+
ological evidence confirm the conclusion that cigar&z& smnk-itid; is>
the main cause of lung cancer in men. These stud& yz'i-,<&~-a~ -;he
risk of developing lung cancer increases with the mFizr,of. cigar:
ettes smoked per day, the duration of smoking, an!:e:nCier iniaia-
tion, and diminishes with cessation of smoking.

2. Cigarette smoking is a cause of lung cancel 5 xmm @rrt
accounts for a smaller proportion of cases than in LF:Z, Y%: ZXX-
tality rates for women who smoke, although sigti:it:zr;Jp h&iier
than for female nonsmokers, are lower than for r?xtn ~dcssmok;l
This difference may be at least partialIy attributed :`D ~.Lf%r~nt?r ia
exposure; such as, the use of fewer cigarettes per rtiy ~ t&e :rse `3s
filtered and low "tar" cigarettes, and lower level3 #& irr%a!a:ion.
Nevertheless, even when women are compared w&F men v&o a?-
parently have similar levels of exposure to cigar&z smoke, the
mortality ratios appear to be lower in women.

3. The risk of developing lung cancer among p$e aridG>or ciwr
smokers is higher than for nonsmokers but signifi~l~~:~~~~~;\re~~ &-ran
for cigarette smokers.

4. The risk of developing lung cancer appears to5ehighur amor.g
smokers who smoke high "tar" cigarettes or smokt in- ~~uh~a.rna~~ti
ner as to produce higher levels of "tar" in the inhaM smoke..

5. Ex-cigarette smokers have significantly lower &aUr -rates-for
lung cancer than continuing smokers. There is evi&nc~~%u support
the view that cessation of smoking by Iarge nurnbz=, s.f &`garette
smokers would be followed by lower lung cancer &a~&: CYL%&

6. Increased death rates from lung cancer ham: 4ezz ;Itlssrved
among urban populations when compared with pq~~~$~~ns~ from
rural environments. The evidence concerning the rzitt $2 :tir poi'iu-
tion in the etiology of lung cancer is presently incolc,r&si~~ FBctitrs
such as occupational and smoking habit difference may- z&o. cm-
tribute to the urban-rural difference observed. D&;+d. epjdcmio-
logic surveys have shown that the urban factor ~xexi;s a smalI
influence compared to the overriding effect of cig~.~~:e~ ~mok;hg in
the development of lung cancer.

302

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

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

CANCEROFTHELARYNX

Cancer of the larynx is a disease which predominantly affects
males in the 55 to 70 year age group. In 1967, a total of 2,468 males
and 329 females died of laryngeal cancer in the United States. With
the development and application of more effective therapy during
the past 30 years, the death rate for cancer of the larynx appears
to he dropping slightly (288, 289) ; however, the incidence con-
tinues to rise. Figures from the Connecticut Cancer Registry (88)
show that the age-adjusted incidence per 100,000 population of
cancer of the larynx for males rose from 3.0 in 1950 to 5.6 in 1961.

EPIDEMIOLOGICALSTUDIES

A number of epidemiological studies have investigated the rela-
tionship between smoking habits and the development of cancer
of the larynx. The major prospective studies, as outlined in table
20, show that smokers of cigarettes run an approximately six-to-
tenfold risk of dying from this form of cancer as compared to non-
smokers. Smokers of pipes and cigars incur a three-to-sevenfoId
risk. The retrospective studies listed in table A21 uniformly show
fewer nonsmokers and more smokers among cases with cancer of
the larynx than among matched controls. Table A22 summarizes-
the relative risk ratios derived from the retrospective studies. The
wide variation is due to a number of factors, including type of pop-
lation and interview technique. But, in general, the magnitude of
most of these ratios is of the same order as in the prospective
studies.

Wynder, et al. (31.2) have distinguished between cancer of the
intrinsic and extrinsic larynx. Tumors arising on the vocal cords
are classified as intrinsic and constitute approximately 70 percent
of the lesions. The extrinsic larynx is composed of those sections of
the larynx excluding the vocal cords and may also be referred to as

303


w
0
4.                      TABLE 20.--Laryngeal cancer vtortalit2/ ratios

(Actual number of drnths shown in pnrenthc-ses)'
   Shf = Smukcrs.    NS = Nonsmukcra.

         Prospective etudica

Author.
Y-2&*.
country,

Number and      Data
type of      collcctlon

FOUOW-
U"

Cizarcttes/dny

Plpea, cleara

Comments

rcfrrr"cc    DOPUlUllO"            y&w     dr1rtha

Hammond   187.763 whlta   Qucntlo""nlrs     n'/JJ        24    Clgnrcttc smokers 11124.         Cigar    Dntn rcfsrring to mortality
and       males 60-68     and follow-     `.      s,v .24                           3/24      rntlo i"Cl~~dCd ennccr of
Hot",      ycal-8 of age     UP of Jcnth           NS 0                          Mizcd     csophagua nnd mouth.
1966,      In 9 statea.     certificate.                                          4124
U.S.A.
(IrnOl.

Doll and    Appr0ximatd.y   Qutstlonnaire     10         16    All rmokcra by amount                t Includea data on BX-
Hill,                                                       Pipe and cigart
         41,000 male     and follow-           SM ..16         in gramr        NS .,.. 1.00    smokem of pipes and clunra.
1964,      British       "P of death           NS 0    NS . . . . . . . . . . a..  . .     SM . 6.00
Crut                                                                  No NS died of lnr~n.geo-
         Dhysicinna.     certificate.                    l-14  . . . . . . . . . . . . 1.00
BriWn                                                                     tracheal esnccr, therefore
                                            16-24
( 71) .                                            . . . . . . . . . . 1.00                 l-14 pram SbI set 08 1.00
                                            >?G . . . . . . ,. 4. . . . 7.60                 rtrndsrd.
                                                                        Data combinc leryn~csl
                                                                           md tracheal carcinoma.

Kahn      U.S. male      PucBtlonnorre     8%        64    NS
(Darn),                                         . . . . . . . . 1.00 (8)       Pipe     Refers to cu~`rc"t cipurcttc
         veterana,      and follow-           Shf .61    l-9
1866,                                            . . . . . . ..a.... 3.27 (1)   NS . . . . 1.00 (3) amokera only.
         2.266.674      UP of deeth           NS 3
U.S.A.                                        la-20  , ., ., ,, ** *. * 8.46(10)   SM . ...10.33 (6)
         Pwm" yean.    ccrtlflcate.                   21-39
(ISO).                                            . . . . . . . . . . . 19.62(11)    Pipe 4nd cigar
                                            >39  . ., .I ., .,, . .16.85 (3)   NS .a. 1.00 (3)
                                            All  . . . . . . . . . . . . . . fI.D5(26)   SM .,. 7.28(11)

Iinmmond.   440,658 mnln    Interviewa       4         G7
1966,                                         NS                            Male data only.
         662.671 fe                                 . . ..I. ,... . . 1.00 (3)    Pipe and cigar
                    by ACS
U.S.A.                                SM .64
         males 35-84                          SM (aw46-60 . . 6.09(923 NS .a.. 1.00 (8) Pipe and clpar d8ts refer to
                    volunteera.
(118).     YeQrl of age                  NS..3 SM (ngc65-79) . . 8.99(18)   Sbl . ,, , 8.87 (4)  m&lea KG-84 ye*" of aIC.

          I" 26 atatea.


TABLE ZO.--LarUngcal cancer mortality ratios (cont.)

(Actual number of drnth3 shown I" psrcnthcses)l
  Shl = Smokars.    NS = Nunamokcrs.

Author,
Y-2.-T,
eou"trY,
rrfurcnce

Number and
type of
DoPulation

Data
collection

Cigarettcs/daY        Plpca, cigars         Commcnta

Weir and
DU"",
1870,
U.S.A.
(sob).

68,163 mnle.    Qucc.rlonnaire     6-8        11    NS  . . . ., ,. ., ,  -                No ncnsmoken died of
In various      snd follow-           SM ..ll    ?I10  . .I ,.. . . . . 1.00                 hryn~rbl carcinuma.
occupatio"s     "D of death           NS . o    220  . ,. ., . . . 6.99                 tlivrcfitrc 210 ami,Lc,r set
in California.    certificate.                   >a0  a . . . ., 6.84                ~1s 1.00 standard.
                                                                NY inch\dca ulve snd clxar
                                                                   amukcra.
                                                                 Shl includes rx.smohcja.

' Unless otherwise apecifwd. disparities between the total number of dcatha
xnd the aum of the Lndivldual smokins categories arc due to the exclusion
of either occasional. miscellaneous. mixed, or ex-smokers

W
s


the hypopharyns. These authors noted that the percentage of hea\->
smokers among the patients \vith cancer of both the extrinsic and
intrinsic larynx was significantI>- greater than that among controls.
However, it is of interest that the excess risk of laryngeal cancer
among cigar and pipe smokers in this study could be attributed to
the extrinsic laryngeal group.

As in studies of oral cancer, it appears that alcohol consumption
should also be taken into account in studies of laryngeal cancer.
Wynder, et al. (315) reported a significantly increased risk of
extrinsic cancer among those with alcohol intake above 7 ounces of
whiskey per day. With less than this amount, no increased risk was
evident. Schwartz, et al. (%8), noted no effect in relation to alcohol
intake. Further research into the interaction of these two variables
is necessary.

PATHOLOGICALSTUDY

Auerbach, et al. (9) studied histological changes in the larynges
of 942 men, age 21 to 95, who were autopsied at a single hospital
between 1961 and 1967. Cases of primary cancer of the larynx \vere
excluded from the study. Smoking histories for all cases were
obtained from family members of the deceased by trained inter-
viewers. The randomized histological sections were graded by one
observer. Tables A23 and A?? summarize the findings in the true
vocal cord. Of the men who never smoked, 75 percent had no cells
with atypical nuclei, only 4.5 percent had sections with areas con-
taining 60 to 69 percent of cells with atypical nuclei, and none had
a higher percentage. The 116 ex-smokers had laryngeal histology
similar to that of the nonsmokers, as far as atypical nuclei were
concerned. However, disintegrating nuclei were found in 40.5 per-
cent of the ex-cigarette smokers and in only 0.4 percent of the
remaining cases. Only one of the 91 cigar and/or pipe smokers had
no atypical cells. Three had carcinoma in situ, and one case had a
section showing early invasive primary carcinoma.

The highest percentage of atypical cells was found among the
cigarette smokers. The proportion of cases with a high degree of
cellular change increased with increased daily smoking. None of
the pack-or-more-a-day smokers was free of atypical nuclei in the
laryngeal epithelium. Of those who smoked two or more packs per
day, 85 percent had lesions with 60 percent or more atypical cells
as compared to 3 percent of the nonsmokers. Retween 10 and 18
Percent of the' cigarette smokers had areas of carcinoma in site,
and 4 of the 644 cases showed early microscopic invasion. The
thickness of the basal level of the true vocal cord was also directly
related to the amount smoked.

306


Dmtenwill (76) has recently reported the development of an
effective and practicable method by lvhich small rodents (ham-
sters, rats, mice) can be exposed to long-term passive inhalation of
cigarette smoke in a manner which circumvents the fatal effects of
acute toxicity which ruined earlier attempts but allow-s for a dosage
of smoke great enough to inpuce the development of chronic patho-
logical changes. The Syrian Golden hamster was found to be the
most suitable species for such inhalation experiments for several
reasons : its resistance to pulmonary infections, its resistance to the
effects of nicotine as compared to that of rats or certain strains of
mice, and, especially, its susceptibility to develop tracheobronchial
cancers after treatment with carcinogens, in contrast to its almost
total freedom from the spontaneous development of these tumors.
Dontenwifl demonstrated that the concentration of deposited
cigarette smoke was greatest in the hamster's larynx as compared
to the other portions of the exposed respiratory tract (table 25),
and that the laryngeal epithelium was the tissue which underwent
the greatest smoke-induced histological changes.
In studying the changes in the larynx, the author differentiated
five stages of epithelial change, using as his reference the Atlas of
Tumor Pathology of the Armed Forces Institute of Pathology (5).
Table 36, quoted by Dontenwill, describes the five types of change.
They range from benign, such as epithefial hyperplasia, to pre-
malignant, exemplified by pseudoepitheliomatous leukoplakia.
The results of the inhalation experiment are presented in figure
4 in which a dosage-related increase in the severity of the epithelial
changes is represented in graphic form. The author also reported,
and depicted with photomicrographs, the finding of an early inva-
sive squamous cell carcinoma. This form of cancer is the predomi-
nant type involving the human larynx.

SUMMARY AND CONCLUSlOSS

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

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

307


TABLE X.-Deposition of "C-labeled smoke particles
  in particular regions of the respiratoqj tract'

He.d and pslate _. 6.11  Head. palate

TODEUC ___ _. ._... . 0.41  Oral cavity
                 in total.

Larynx  _. . . . 0.39
Trachea  __ __ __ __ OX
Luns,  . . . . 695 I
   Total  . . . . . .14.12

EStitlll3ted   Deposition
radio-       of
activity     particles
(nCi)       (70)

5.6        37.4

1.6        10.9

7.6 (traced1   51.7

`14.1        100.0

0.1-0.3   X561-187
0.6     X62.3
1000    Xl


TABLE 26.-Classification of the five registered stages of epithcliaI changes at the laru?ix','

                                      Dyskeratosia (nre.
                                         mnture e..(yplcril
Acnnthasls (thicken-   Hyperkwntosis     Parakeratosls (in.      cornification
ing of strntum       increased      complete corniRcn-     changes In the    hlito3i3
spinosum multi-      cornification      tion 0Cnuelel in     nucleus Drolifcrn.
cellulnr kwert     (rtroturu comeum)  the stratum corneum)  lion yf)j;,bnxaI

1. Pachydermia (cpithelirrl hywrDlania)  . . . . , . . .       t             t             t              t         t

6. Pseudoe~ith.liomatous leucoptakia . . ,. . . . . .       t            -t            t           tt+       t

f Symbols: t = negative: $ = mlnimnl; f = weak; ++ = medium; i-4-f = BtronE.
1 From Atlas of Tumor Pathology of the Arm& Forces Institute al Pathology.
SOURCE: Adapted from Dontenwlll, W. (76).


TOTAL 146

2    4    ii    a    IO    12    14 16 18 20   22-s-3
            SMOKE WPOSURE. months

. ZONE ANIMAL    Q=AN~MAL LIVING     O=lARYNX CANNIBALIZED

FIGURE do--Effects of chronic cigarette smoke inhalation on the hamster larpx.
Review of the results of the inhalation experiments: number of smoke-ex-
posed animals with and without changes in the larynx, duration of smoke
exposure, and number of animals still alive.
SOURCE: Dontenwill, `8. (76).

ORAL CANCER

The cancers included in this category are those of the lips, tongue,
floor of the mouth, hard and soft palate, gingiva, alveolar mucosa,
buccal mucosa, and oropharyns. It is estimated that 15,000 of these
cancers will be diagnosed in the United States in 1970, accounting
for about 2.5 percent of the estimated 600,000 malignant neo-
plasms reported (289). A variety of histological types of malig-
nant neoplasms can affect these tissues, but squamous cell car-
cinoma is by far the predominant type, accounting for about 90
percent of the cancers.

The incidence of and mortality from oral cancers has remained
steady over the past 20 to 30 years. The Connecticut Cancer Res-
istry (88). which is a fairly reliable index of incidence, noted that
the incidence among males remained between 15.8 and 16.3 per
100,000 population during the years from 1950-1961. Examination
of mortality rates over the past 20 to 30 years (P&Z, 289) reveals
a similar constancy.

The apparent lack of change in mortality from oral cancer in

310


contrast to the sharp increase that took place in lung cancer rates
in those years is probably due to several of the following factors.
First, pipe and cigar smohing are both significantly related to can-
cer of the oral cavity, and the increase in cigarette smoking among
men, noted between $$O and 1955, has been, to a large degree,
accompanied by corresponding reductions in the use of pipes and
cigars. Second, aside from the various changes ivhich the Interna-
tional Classification of Diseases (ICD) had undergone during that
period, the diseases discussed above are recorded in ICD Codes
140-148 which include some neoplasms not found to be related to
the use of tobacco. The various sites of cancer themselves do not
contribute equally to the overall rate and are subject to widely dif-
ferent cure rates, so that their contributions to the total incidence
rate is different from their contribution to the overall mortality
rate from oral cancer. Although more than 20,000 cancers of the
oral cavity were estimated as newly diagnosed in 1967, the totai
number of individuals recorded as dying from oral cancer during
that year was only 6,718 (ZQO).

Oral cancer occurs predominantly in people of the middle and
older age groups. More than 90 percent of all oral cancers occur in
persons over age 45, with the average age at time of diagnosis
approximating GO. Although the majority of oral cancers occur in
men, there is recent evidence that the ratio of males affected to
females affected is decreasing (9.57).

The use of tobacco in various forms has been associated with the
development of cancer of the oral cavity and pharynx. The studies
in this area of concern are truly international, many having been
carried out in Asian nations as well as in the West.

The major pro.specti\~e epidemiological studies have found in-
creased rates of these cancers for cigarette smokers as well as for
pipe and cigar smokers (see table 27). Pipe smoking, per se, has-
                                                       -
long been recognized as a cause of lip cancer (~91) _ The methodol-
ogy and results of the numerous retrospective studies are sum-
marized in tables A28 and A28a. These studies almost uniformly
show significant relationships between the various forms of tobacco
use and c-nsr:rs of the oral cavity and pharynx.

Studies in Asi:ln I~`* +iqns have examined the prevalence or inci-
dence of premalignatit ch:inge, such as oral leukoplakia, as well as
that of cancer of the oral cavity. In many of these studies, forms of
tobacco use not prevalent in IVestern countries have been investi-
gated, including reverse smoking (in which the lighted end of the
cigarette is kept in the mouth close to the palate) and the chewing

311


Number and
tyne of
population

Data
collection

FOIIOW-
up yea14  N"omIber         Cipnrettea         Pipea. cIgara         Comment8
       deaths

Hemmond  187.783 white    Qucntionnaire      3 1%       66
and      mnlcs in 9      and follow-up         tSN   .61
Horn,     stntc. 3a-Go    of dcnth            NS ..3
1068,     ycllra of nKe.    ccrtincnt.zo.
U.S.A.
(14'0).

Doll and    Ap~`rurlmntrly   Quratlunrrnlre     10         10
llill,      41,000 mslc     nnd follow-UP         Shl  . ,I9
1964.     llrltirh       of drbth            NS ..a
Crrnt     physicinns.     ccrtificntc.
Dritain
(71).

Kahn     U.S. msle      Questionnaire     B!/r       61   NS  ._.... l.OO(ll)       Pipe      Data do not Include pharynx.
(Darn),    veterans.      and follow-up         Shl  .60  tCigs/dsy 1-9 . . . , 0.8C (1) NS  ..*.*.. l.OO(ll) t Refera to current clgarctte
10G6,     2.265.614      of dcnth            NS  . .I1   lo-20 ..,,,......, 2.93(13) Shl ..,.... 2.12 (4)   smoken only.
U.S.A.    r)utsol! yesrs.    certinca1c,                  21-39  . . . ., ,, 3. . . . 7.34(20)       Cipar
IIJY).                                      >N  . ,. . . . 6.73 (3) NS  *...... l.OO(ll)
                                          All  . . . . . . . . . . . . . . 4.@3(37) Shl  .,..,,,. 4.11 (0)

Hammond.  440,LGE malra    Intcrvlcws by      4
I')CG.      bG%.G71 Ivmnlea   ACS vuluntccm
V.S,A.     .15-X4 yt:arn of
(JIJ).     rwc in X.5 Ststca.
           _.
Wclr end   68.1G3 males    Questionnaire      6-8
Dunn,     In vnlious     and follow-up
1070.      occupstiona     of death
U.S.A.     in California.    certlflcnte.
(SOF).


of "pan" or "Xass," which are mixtures of tobacco with either betel
nut or lime ash, and other ingredients (2L1, 255, ,056). Snuff
dipping, a habit in which snuif is placed in the gum and retained
there for prolonged periods, has also been associated with the
development of oral cancer (193, 210), as has the chewing of
tobacco (124,193,241,998).

-The risk of developing a second primary mouth or throat cancer,
after the recognition of the first primary cancer, has been found
to be greater in continuing smokers than in those who quit smok-
ing. All of the patients studied by Moore (190) were asymptomatic
for at least three years following the treatment of the first cancer.
Of the 117 patients with adequate smoking histories, only 4 of 43
(9 percent) who quit smoking developed a new primary cancer.
On the other hand, 27 of 74 (36 percent) who continued to smoke
developed a second primary cancer.

However, a study by Castigliano (53) of patients treated for
oral cancer did not show a greater risk of a second primary among
continuing smokers. In this study, 5 of 26 (19 percent) of those
patients who did not quit smoking developed a second primary
cancer as compared to 9 of 51 (IS percent) of those who did quit.
The rate of quitting smoking in the two studies is markedly dif-
ferent (36 percent in the Moore study and 62 percent in the Casti-
gliano study) _ From the data presented in the two papers, it is not
possible to evaluate the other significant ways in which the pop-
ulations may have differed.

Keller (140) studied 408 males with histologically confirmed
squamous cell cancer of the mouth or pharynx. This author dealt
with the question of recurrent tumors in a somewhat different
manner. The patients were observed for the development of a sec-
ond or third primary cancer at an anatomically discrete site of
the mouth and pharynx within a median period of three years after
the first cancer. He found that a second or third cancer (termed a
coexisting cancer) developed in 28 of the 408 cases. Among these
28 cases with 33 coexisting neoplasms, 21.7 percent were heavy: --
smokers, but among their matched controls, there were no heavy
smokers. Coexisting cancers were most commonly found on the soft
Palate, an anatomical site that is in direct contact with the main-
stream of tobacco smoke.
More recently, Wynder, et al. (315) studied 63 male and 23

female patients with multiple primary cancers of the mouth and
pharynx. They observed that heavy smoking prior to the develop-
ment of the oral cancer was associated with a greater likelihood
of developing a.second primary. Also, continued smoking after the
first primary was found to have a significant association with the
occurrence of a second primary.

313


IJ'ith or without smoking, use of alcohol appears to contribute
to the development of oral cancer (1_7:, 120, 15'9, 297. 32). In a
study of male ve6%ans, Keller (ILO) found that heavy smoking
and heavy drinking were associated with cancer of the mouth and
phan-nx. No studies are presently available which determine the
relative contributions and possible interactions of heavy smoking,
heavy drinking, and concurrent nutritional deficiencies in the etiol-
ogy of these cancers.

EXPERIJIENTAL STUDIES

In 196-1, the Advisory Committee to the Surgeon General on
Smoking and Health (291) reported that cigarette smoke and ciga-
rette smoke condensates had failed to produce cancer when applied
to the oral cavity of mice and rabbits or to the palate of hamsters
and that the oral mucosa appears to be resistant in general to can-
cer induction even when highly active carcinogens such as benzo-
[alpyrene are applied. Some of the difficulties in experimental de-
sign were attributed to the fact that mechanjcal factors, such as
secretion of saliva, interfere with the retention of applied carcino-
genic agents on the tissues of the oral cavity and pharynx. Positive
results with certain carcinogens have, however, been obtained in
the hamster cheek pouch. but it has also been pointed out that the
cheek pouch lacks salivary glands and that its structure and func-
tion differ from those of the oral mucosa. The majority of these
studies are outlined in table A29.

Although cigarette smoke condensate acts as a complete carcino-
gen on mouse skin, the work of several authors (319) supports the
concept that cigarette smoke contains cancer promoters that may
be of special importance, particularly in orai carcinogenesis. Elzay
(90) has reported that whole cigarette smoke is a promoting agent
for the hamster cheek pouch. More importantly, regarding the
chewing of tobacco, Bock, et al. (27,30), Van Duuren, et al. (29:),
and Wynder and Hoffmann (321) have shown that unburned to-
bacco products contain tumor promoters that might contribute to
the promoting activity of the smoke.

Roth, et al. (226, ,R.H') have shown that the dye-binding capacity
of the DNA of oral epithelial cells is significantly enhanced in
cigarette smokers in contrast to nonsmokers, probably reflecting
an increase in the DNA content of oral epithelial cells in smokers.
Smokers had values of dye-binding capacity intermediate between
nonsmokers and 21 patients with proven oral cancer. Those smok-
ers who refrained from smoking for up to six months showed a
significant decrease toward more normal values.

314


I. Epidemiological and experimental studies contribu:e to the
conclusion that smoking is a significant factor in the development
of cancer of the oral cavity and that pipe smoking, alone or in
conjunction with other forms of tobacco use, is causali>- related to
cancer of the lip.

2. Experimental studies suggest that tobacco estracts and
tobacco smoke contain initiators and promoters of cancerous
changes in the oral cavity.

CANCER OF THE ESOPHAGUS

Esophageal cancer accounted for 4,306 deaths among -American
males in 1967 and 1,321 deaths among females. The death rate
from esophageal cancer has remained relatively constant since
1949.

EPIDEMIOLOGICALSTUDIES

The major prospective epidemiological studies (table 30) have
indicated a significant relationship between smoking and esopha-
geal cancer. Overall mortality ratios for male cigarette smokers
range from 1.73 to 6.17. There are insufficient data concerning
females for establishing firm conclusions.

A number of retrospective studies concerning the relationship
of smoking and esophageal cancer are outlined in table A31 and
A31a. Smokers incur risk ratios ranging from 1.3 to 6.6 when
compared with nonsmokers.

As in studies of oral cancer, the effect of alcohol consumption
must be taken into account in studies of esophageal cancer. Because
a relationship between alcohol consumption and tobacco use is
known to exist, \Vynder and Eross (810) analyzed the association
between tobacco consumption and esophageal cancer after adjust-
ing for alcohol intake. They found that in the absence of alcohd
consumption, there was no association between the use of tobacco
and esophageal cancer but that in the presence of alcohol consump-
tion, an increasing relative risk with increasing number of ciga-
rettes smoked \vas apparent, as well as an association bet\\-een
cigar and pipe smoking and esophageal cancer.

More recently, Takano, et al. (wz?), in a retrospective study of
3-00 patients with esophageal carcinoma, found an increased risk
with smoking which was magnified by increased alcohol consump-
tion. Martinez (28.7) analyzed the association of tobacco usage
and esophageal cancer after controliing for age, sex, and alcohol
consumptioir. Increasing relative risks with increasing tobacco use

315


               TABLE 30.-Esophageal cancer mortdity ratios--prospective studies
                             (Actual number of deaths shown in puenthnn)'
                                  SM = Smokera.    NS = Nonsmokcn.

Author,                                    Number of
  ye.70   Nu,rn;:r;nd       Data       FOllOW.    esophnae&\
countlY.                  collection     UP yenn     cllnccr       Cigarette3/dny        Pip-, CigIrl        Commcntd
rtfcrenee     DoQulntlon                         deaths

Hammond   187,783 white      Quutionnairc      3 %          34    Cigarette amokcra       Pipe    hftied      De.tn rcfcrring to
and       malts in 3        and follow.up           NS 1     16133.             z/33    cigarette      mortality ratios
Horn,      State K&69      of death               sar , 33                   Cigar   amokera      Included cancer
lOS8.      ye*n of age.      ccrtiflcate.                                        2133    13/K!        al mouth
U.S.A.                                                                           and larynx.
(190).

Doll and    Approximately    Questionnaire      10           29     ~11 amokera bu amount    tPipe and ciuar      t Includes ex-
Hill,       41.000 mnlc       and follaw.u~                        in yramr       NS . . * 1.00         amaker, of pipe
1964,      British         of death                        NS . ,. 1,. 1.00        Shf . 2.00         and cigara,
Great      physicians.       certificate.                       l-14  . . . . 2.00
Britrln                                              IS-24  ,.., 3.60
(74).                                             >25 . . 6.00
                                                  All  . ., . 3.00

  Kahn      U.S. male        Questionnaire      E?`r          111   NS  . . . . . l.OO(ll)         Pipe         t Rcfrra to
   (Ihrll).     Yt-tel'B"9        and follow-up            NS . ..I1   t1-9 . . 1.76 (2)        1.99 (3)         cigarette
   1966,      2.265.674        of death               SM  . ..lOO   lo-19  . . . . 4.71(18)         Cigar          smokinl
   U.S.A.     person yearn.      certlflcate.                       20-39  ., .11.60(24)        6.33(12)         only.
    (139).                                             >25  . . 7.65 (3)
                                                    All  . . . 6.17(47)

Hammond,   440.55R male8     Interview by       4           46   NS .., . 1.00 (6)       Pipe und CiQa.r
    1966.       662.671 females   ACS volunteers.           NS ,.. 6    Shl (iire            NS .._. 1.00
    U.S.A.     35-84 YCBT9 or                        Shf  40                    St4 I... 3.97(14)
                                                      45-60 4.17(32)
    (IIS).     we in 26 States.                              Shl (age
                                                      65-79) 1.74 (81


TABLE SO.--Esophageal cancc?' Ino,`talitu rafios-p,`ospcctiuo studies (cont.)
           (Actual number of dcnthr shown in w.rcnthcs<%)
               Shl= Smokers,    NS = Nonamokrrs.

  Author
  YCDT.
country,   Nuttny;nd       Datn       FQllOW-
                       collection     "II YCQl-3                                             Comments
relercncc     populntiun

Hirnynms.   265,118 male      Trained PIiS       l',`r     Slil _, 21   NS . . .., 1.U,O(D<o.o1)                  RClClS to nll
IiiCl.      and female       nurse inter-                      Shl I.. . . . 2.47(21)                      forms of

Jrvnn
(JPJ).

view nnd
~OllOWUD
of dcnth
certificate.

smoking.

Weir and    68.163 males      Quertionnnirc       6-8          32    NS ,, . 1.00                     NS inClUdc'8 PiDC
Dunn,      in vnriou3       and follow-up                     -`-IO . . 1.21                        and ciunr
1070.      occupntians       of death                        *20 . . . . 1.69                        smoben.
U.S.A.     in Cnliforniu.      ccrtlncatc.                      >30 . . ., 1.82
(306).                                              All ,. . 1.82

1 Unlcso otherwise epcciflcd. disparities between the totnl number of
drolhs and the rum of the individual smoking cntegoriee are due to the
exclwion of either occnsional, misceUnneoue. mixed, or ex-amokcrs.


were noted. The consumption of very hot beverages was also found
to be related to the development of esophageal cancer.

PATHOLOGGIL STUDY

Autopsy studies of smokers as compared with nonsmokers, spe-
cifically observing the pathological changes in esophageal tissue,
have been performed by Anerbach, et al. (15). A microscopic study
was made of 12,598 sections of esophageal autopsy tissue from
1,268 men who died from causes other than esophageal cancer. The
findings were strikingly similar to the abnormalities generally ac-
cepted as representing premalignant tissue changes in the respira-
tory tract epithelium. Esophageal epithelial cells with atypical
nuclei (having an irregular distribution of chromatin) were found
far more frequent.ly in cigarette smokers than in nonsmokers. Basal
cell hyperplasia and hyperactive glands were also found more fre-
quently in cigarette smokers than in nonsmokers. An increase in
frequency with amount of cigarette smoking was noted for both
epithelial cells with atypical nuclei and basal cell hyperplasia.
Tables A32 and A33 summarize these findings.

EXPERIMENTALSTUDIES

Kuratsune, et al. (156) investigated the possibility that the car-
cinogens known to be present in tobacco smoke could penetrate the
esophageal epithelium more readily if dissolved in aqueous ethanol.
Mice were exposed to several compounds by esophageal intubation.
Tissues were then removed and studied by fluorescence microscopy.
Deeper penetration and a different distribution were found when
B[a]P was dissolved in aqueous ethanol as compared to B[a]P in
olive oil. It was also found that benzo[a] anthracene and fluoran-
thene dissolved in ethanol solution or aqueous caffeine solution
could penetrate the epithelium of the esophagus.

Horie, et al. (132) reported on the development of 10 papillomas
and one squamous cell carcinoma of the esophagus in a group of
63 mice periodically forced to drink a solution of benzo[a]pyrene
dissolved in diluted ethanol. Twenty-six papillomas and one squam-
ous cell carcinoma also developed in a group of 63 mice to which
4-nitroquinoline l-oxide was administered in the same way. None
of the 6'7 control animals given only diluted ethanol developed
neoplasms.

Several other authors have reported nitrosamine-induced esopha-
geal cancer in experimental animals (56, 79, 80, 81). As noted
above, the presence of nitrosamines in cigarette smoke is still a
subject of debate.

318


1. Epidemiological studies ha\-e demonstrated that cigarette
smoking is associated rvith the development of cancer of the esopha-
gus. The risk of developing esophageal cancer among pipe and;or
cigar smokers is greater than that for nonsmokers and of about
the same order of magnitude as for cigarette smokers, or perhaps
slightly lower.

2. Epidemiological studies have also indicated an association be-
tlveen esophageal cancer and alcohol consumption and tthat alcohol
consumption may interact with cigarette smoking. This combina-
tion of exposures is associated with especially high rates of cancer
of the esophagus.

CANCER OF THE URISXRY BLADDER AND KIDNEY

EPIDEMIOLOGICALSTUDIES (BLADDER)

Cancer of the urinary bladder accounted for 6,019 deaths among
American males and 2,743 deaths among American females in 1967
(289). Incidence rates have increased from 1949 to 1962 (88), but
the death rates from bladder cancer have remained relatively
stable during that period. Improvements in early diagnosis and
therapy may have masked the increasing incidence of this disease.
A number of epidemiological studies have indicated that smokers
have an increased risk of contracting or of dying from bladder
cancer (see tables 31 and A3.5). Certain of these studies include
kidney cancer mortality in the results. The major prospective stud-
ies, with the exception of that of British physicians, have shown
bladder cancer mortality ratios among cigarette smokers ranging
from 1.40 to 2.89. Smokers of more than 1 pack per day were shown
to incur ratios of 3.12 to 5.41. The study by Doll and Hill (74, 75)
of British physicians, on the other hand, reports death rates for
smokers to be lower than those of nonsmokers based on 38 bladder
cancer deaths. The mortality ratios for pipe or cigar smokers are
substantially loxver than those among cigarette smokers. Pipe
smokers were shown by both Hammond and Horn (120) and Kahn
(13.9) to incur ratios approximating 1.50.
Retrospective studies (table A35a) have also shown an increased
proportion of smokers among bladder cancer patients when com-
pared with matched controls. Relative risk ratios for bladder can-
cer among smokers range from 1.0 to 7.3 among a11 smokers and
up to 10.3 among heavy smokers of all types.

319


u
N
0

TABLE 34.-Kidncu ami urinnru blatldcr cancer-prospective studies--Mortalit2/ ratios
              (~ctunl numlcr uf dcutha shown in ~~nrcnthescs)'
                  Shl = Smokers.    NS = Nonsmukcis.

Author,
)`car.    Number and     Data     FCIIIOW.   Number
CO"lllTY,     type Of     collection   "I, years     of     Cignretle/day    Pipe. cigar      Kidney     Blnddcr        Commcnta
refcrcnce   wl,ulation                   denlhs

Hnmmund  187,183 white   Questionnaire    3%       287 NS ,. 1.00(B)      Pipe
snd      malen in 9     and                    <IO 2.00(14) NS ..1.00138)
Ilurn.     SLUlCS.      interview.         SM ,241 IO-20 2.00(42) Shl . ..1.17(21)
I!ltH.                             NS 38 >20 ,.. 3.42((l)     Cipar
U.S.A.                                               NS ..l.O0(3R)
(100).                                               Shl , ..l.OG(I'i)

Doll snd    AnDroximatelv Questionnaire 10         38              NS . ..I.00

       
llill.      41,000 mule    and follow.                           Sht ,O.dl
11c4.     Llritish      ua of death
Crest     Dhyeicinns.    certificate.
nritain
(fb).

  All Sdf bv
amount in ~rcarnn
NS ..I.00
1-14 .0.69
16-24 . .o.c5
>25 .0.76
All I. .O.?l

BCSl,     Apuroximntelr Questionnaire 10        114  NS . 1.00        Pipe                       Rcfcrr to
1966.     18.000 mall?    nnd follow-               <lo ,, 1.33(29) NS ..l.OO                      pcnitourinnry
Canad&    Canadian     UP of death               lo-20 ,, 1.44167) SM . ..O.SG(lO)                     CRrlCCIB 89 D
(91).     veterans.     certificate.                >30 .,. 1.43(16)      Cigar                       gruu*.
                                       All ,. 1.40(10) NS . ..I.00
                                                  SM . ..1.16 (3)

Hsmmond,  440,568 mules   Interviews by    4     Bladder                    Cioarcllrc        CiQCl'ClfCl    hfnlc dn1n OlllY.
1966,     6GZ.G7 I      ACS                13R              NS  ,I . . .I .* .1.00(22)      1.00(23) Blwhlcr IncluilM
U.S.A.    females      volun1eere.         SM  ,116              SM (age 45-64)  . ..1.42(64)      Z.OO(GCJ)   olher urinary
(II(i).    35-R4 years                  NS . 23              SFll (nse 65-78)  . ..1.5'7(?8)      2.96(66)   tract COnLECrI.
        of ace in 25                   Ridmu
        SLllbX.                        104
                                Shl 82
                                NS 22


AUtllUr.
yc)Lr.  Nyne'yd     Dnta     Follow-   Number
roun1ry,             c011cct10n   "V yenre
rcfcrcncc   population          de%    Ciuarette/day

Knhn     U.S. nlRlc     Questionnaire    a',/.    B!addcr
(Darn),    vcte:ana     nnd follow.            224
196C,     2.266,674     "P of denth         Shl  172
U.S.A.    person      certificate.         NS . 62
(139).    years.                     Kld,lcy
                                   141
                               Shl ,102
                               NS 93

Pipe, CiBfit      Kidney     Bladder        Comnlcnta
                                     -

NS ,, ,, ,,, ,,,. .1.00(39)
I'irle _. ., ,, ,. .1.32 (6)
Cignr .,.. ,. .,.,. ..0.77 (6)
CiKarettes/duy:
  l-9 ..I ,,,.... 0.97 (4)
IO-19  ,...,.,.... 1.34121)
20-30 . . . . . . . .l.GB(lG)
>39 .,,. ,,, ,. . ..2.76 (6)
All ,.,.,... l.IG(IC)

1.00(62)  Dladder includca
1.20 (8)   other urinnry
0.94(10)   tract CLIIICCIY.

1.10 (6)
1.93(37)
9.20(u)
2.52 (6)
2.1G(B?)

-

Hlraunmn.  2GG.110 mnlc   Trnincd PIIS    1 `ii   SM    C  NS 1.00                                 rllnddcr cn>>ccr only.
lOG7.     nnd fcmnle    nurse intcr-               Shl .lO.OO (6)                              ncrcm to ali
Japnn     adults 40     view and                                                          inrmr of swokinu.
(IPJ).    YCLlM of nge   foilow-up
        nnd older.     of dcnth
                 ccrlificnte.

Weir and   68.163 males   Qucstionnalre    6-8    Biaddcr                      NS .x.1.00    NS . ..l.OO     ShI include. ex-
Dunn. in vnrious     and follow-             27                      ?lO ..0.6G    210 , . .1.82      smokcra.
1970,     occupations    UP of dcnth         Kidmu                      -c20 .3.30    -e20 . .2.81     NS include ~ipc
U.S.A.    In California.   ccrtilicnte.             27                     >30 . .2.67    >30 . .6.41      snd clgor
(306).                                                       All . .2.40    All . .2.89      amakcra.

`Unless othrrwivc spccificd. dirpnrities between the total number of
drnths nnd the sum of the individual smoking categories are due to the
exclusion of rithcr occnsianal, miscelloneoua. mixed. or ex-smokers.

W
h,
Y


EPIDEMIOLOGICALSTUDIES (KIDYEY)

A total of 5,53-1 Americans died of cancer of the kidney durir.::
1967. A relationship between smoking and this type of cancer has
been suggested by several epidemiological studies. The three major
studies which separately examine the relationship of kidney cancer
to smoking (table 34), namely those of Hammond (I I&), Kahn
(139), and Weir and Dunn (~`06)~ have shown mortalit>- ratios for
all cigarette smokers to range from 1.43 to L-16. Retrospective
studies by Bennington, et al. (18, 13) have indicated a signilicant
association between all forms of smoking and renal adenoma and
adenocarcinoma.

Numerous experiments have been undertaken by many invtsti-
gators to elucidate the relationship of tobacco smoking to bladder
carcinogenesis. The two areas of major concern have centered upon
the presence of a known bladder carcinogen, beta naphth>-lam:ne.
in cigarette smoke and the presence of abnormal tryptophan me-
tabolism in patients with bladder cancer.

By virtue of data gathered concerning industrial exposure of
workers, beta naphthylamine has long been kno\vn as a bladder
carcinogen. Complementing such data was the work of Hueper, et
al. (136) who subjected mongrel dogs to daily subcutaneous injec-
tions and oral administration of commercial beta naphthylamine.
Thirteen of the 16 animals developed bladder papillomas and c21--
cinemas of the bladder. Saffiotti, et al. (236) fed hamsters a diet
containing up to 1.0 percent beta naphthylamine and observed that
18 of 39 animals developed bladder tumors, almost all typical tran-
sitional cell carcinomas. More recently, Conzelman, et al. (59) ad-
ministered beta naphthylamine to 24 rhesus monkeys for more
than 30 months. Transitional ceil carcinomas of the urinary biad-
der were induced in 9 of the animals, and a dose-response relation-
ship was apparent.

Pailer, et al. (207) and Miller and Stedman (183) failed to End
this amine in cigarette smoke. However, more recently, Hoffmann,
et al. (127) identified it in cigarette smoke. The authors, noting
the minute quantity present in each cigarette (2.2 x 10--g), hesi-
tated to attach a biological significance to the finding.

Of more recent interest have been the metabolites of tr>-ptophan
present in certain patients with bladder cancer. A number of nor-
mal and abnormal metabolites of tryptophan have been found to
be carcinogenic when tested by implantation in the bladders of mice.
These include 3-hydroxykynurenine (OHKy), 3-hy-droxyanthranilic

322


acid (OHA), 3-hydroxy-%-amino-acetophenone (all orthoamino-
phenols), the S-methyl ether of santhurenic acid (CHSa), santhu-
renic acid (,Ya), I>-kynurenine (KY), quinnldic acid, and Zmeth-
oxyanthranilic acid (3CHO.1) (2, 36, 37, 39, $7, $8). OHKy and
OHX are frequently present in human urine, as is kynurenic acid
(KYA).

Certain investigators have concentrated their attention on the
presence of abnormal tryptophan metabolites and increased
amounts of normal tryptophan metabolites in the urine of patients
with bladder cancer as compared with selected controls (1, 40, $6,
97, 118, 214,243, 329). These authors have observed the increased
excretion of Ky, KyA, OHKy, anthranilic acid, OHA, and acetylky-
nurenine in such patients. Yoshida, et al. (329), in a recent study
concerning the relationship between tryptophan metabolism and
heterotopic recurrences of human urinary bladder tumors, reported
that those patients with recurrences showed abnormal metabolite
excretion more often than those without recurrences.
The relationship of smoking to these biochemical findings is
presently uncertain. Kerr, et al. (1$3), in 30 experiments on 3
smokers and 3 nonsmokers who were given large doses of trypto-
phan, found that smoking increased the urinary excretion of OHKy
and OHA and decreased that of N'methylnicotinamide (an end
product of tryptophan metabolism). Kerr concluded that smoking
interferes with the normal metabolism of tryptophan. Recently,
Brown, et al. (45) studied 15 adults under smoking and abstinence
conditions and found that except for the basal escretion of acetylky-
nurenine, tryptophan metabolite excretion did not change with
smoking or cessation. The authors also compared 13 nonsmokers
and 17 regular cigarette smokers under basal and tryptophan-
loaded conditions. No differences were observed in the excretion of
the measured tryptophan metabolites. However, due to its instabil-
ity, OHA was not measured. The authors concluded that the rela-
tionship of smoking to urinary bladder cancer was probably not vk
                                                       - -
its effect on the kynurenine pathxvay of tryptophan metabolism.
Another experimental approach to the relationship of smoking
and urinary bladder cancer is reflected in the work of Schlegel, et
al. (2: :, 2:~). The authors observed an elevated concentration of
certain ortho-amincphenols in the urine of bladder cancer patients
and cigarette smokers, when compared with nonsmokers (245).
More recently (?$5), the same group compared the chemilumines-
cence of the urines of smokers, nonsmokers, and bladder tumor
patients. They noted that nonsmokers showed the lowest level of
luminescence (\vhich they relate to the presence of aromatic hydi-o-
carbons) and the bladder tumor patients the highest level. The
normal cigarette smokers' level was found to be intermediate.

323


Hnmmond   440.55n nl?.lPJ    Inlcrvicws by
1OGG       `56?.671 Irmnh   ACS
U S.A.      JG-WI ycn1'3     volunteers
(Ira).     of nge in 26

Kahn
(Don)
1966
U.S.A.
(139).

4          262
     S&l . ..233
     NS .., 20

8:;         344
     tshl 1 ,ZSG
     NS 68

_.~.
NS . ...% 1.00 (29)

Shl (WC
4644)  2.63 ( 168)
Shl (RBC

hlnlc dsln only.

65-79)  2.17 (76)
NS ,.,.. 1.00 (88)

1-I 0.87 (81
LO-20 1.93 (65)
21-31 2.18 (43)
>no ..I 1.87 (7)
All ..I 184(125)

Piwa

       t ~lrferr to current amok=
NS ..1.00(88)    or .II (YDCJ.
Shl ..0.74 (8)
  Cipar8
NS .1.00(88)
Shl a .1.5?(27)
   rIotI,
NS .l 00(H)

Shl .0.93(13)

Iiirnrnmn.   2G5,llX InrllC    Tmincd PllS      1 `,`1     Shl  ,, I4   NS ,, 1.00   I (P<O.Ol)
1967.      11111l rcmilic     nuwc inlcr-               SM . . . ..lG.SG c14rt

(SOGI.                                          All 2.43                                    -
1 Unlras otberwisc snccifwd.  disnor,itics bctwcen the total number of


At present, no definite conclusions can be tlr:~xvn concerning the
interrelationships of bladder cancer, abnormal trJ.ptophan metab-
olism, and tobacco smoking. Further study is required in this and
the other areas of bladder cancer pathophysiology.

Suhrhijtrw ANDCONCLUSIONS

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

3. Clinical and pathological studies have suggested that tobacco
smoking may be related to alterations in the metabolism of trypto-
phan and may in this way contribute to the development of urinary
tract cancer.

CANCER OF THE PANCREAS

Several prospective epidemiologic studies have suggested a rela-
tionship between cigarette smoking and cancer of the pancreas
(table 36). A retrospective study of 465 cases of pancreatic cancer
by Ishii, et al. (1~`) has shown a dose-related increased risk of
pancreatic cancer in association with smoking. Analysis of dietary
data revealed that the relative risk for pancreatic cancer from
smoking was considerably greater than from dietary factors.

No experimental studies relating to this question have been
reported.

SUhlMARYANDCONCLUSIONS

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

REFERENCES

(I) ABELIS, T., GSELI., 0. T. Relative risk of pulmonary cancer in cigar and
   pipe smokers. Cancer 20(8) : 1288-1296, August 196'7.
(-") ALrFnso, A., PAPA, S., TANCKEDI, F.,+E~rcro, RI. A., QUA LIAIUELLO, E.
   Tryptophan-nicotinic acid metabolism in patients with tumours of the
   bladder and kidney. British Journal of Cancer 18: 386-389, 1964.
(3) ANTKO.~~Y, H. >I., THOMAS, G. M. Bladder tumours and smoking. Interna-
   tional Journal of Cancer 5(Z) : 266272, March 15, 1970.
(C) ARlilS, A.. WAGNER, D. H. Primary carcinoma of the lung. A diagnostic
   study of one hundred and thirty-five cases in 4 years. Journal of the
   American Medical Association 106(8) : 587-591, February 22, 1936.

325


(5) ASH, J. E., BECK, JI. R.. WILKES, J. D. Tumors of the upper respiratory
   tract and ear. IN: Atlas of Tumor Pathology. Section IV-Fascicles
   12 and 13. Washington, Armed Forces Institute of Pathology, 19G4.
(6) ASHLEY, D. J. B., DAYIES. H. D. Cancer of the lung. Histology and bio-
   logical behavior. Cancer 20(2) : 165-174. February 1967.
(7) AUERBACH. 0. The pathology of carcinoma of the bronchus. New York
   State Journal of ;\Iedicine 49: 900-907, April 15, 1949.
(8) AUERBACH, O., GERE, J. B., PAIVLOWSKI, J. M., hIuEHsAB1, G. E.. SMOLIN,
   H. J., STOUT. A. P. Carcinoma-in-situ and early invasive carcinoma
   occurring in the tracheobronchial trees in cases of bronchial carci-
   noma. Journal of Thoracic Surgery 34(3) : 298-309, September 1957.
(9) AUERBACH, O., HAUMOND, E. C., GARFINKEL, L. Histologic changes in
   the larynx in relation to smoking habits. Cancer 25(l): 92-104,
   January 1970.

(IO) AUERBACH. O., EiAhlhlosD, E. C., KIRMAN, D.. GARFINKEL, L., STOUT.
   A. P. Histologic changes in bronchial tubes of cigarette-smoking dogs.
   Cancer 20 (12) : 2055-2066, December 1967.
(II) AUERBACH, O., HAMMOND, E. C., KIRMAN, D., GARFINKEL, L. Effects of
   cigarette smoking on dogs. 11. Pulmonary neoplasms. Archives of En-
   vironmental Health 21 (F) : `754-768, December 1970.
(1-7) AUERBACH, O., STO~~T, A. P., HAMXOND, E. C., GAKFINKEL, L. Changes in
   bronchial epitheljum in relation to cigarette smoking and in relation to
   lung cancer. New England Journal of hledicine 265(6) : 253-267,
    August 10, 1361.

(13) AUERBACII, O., STOUT, A. P., HAM,MOND, E. C., GARFINKEL, L. Changes in
   bronchial epithelium in relation to sex, age, residence, smoking and
   pneumonia, New England Journal of hfedicine X7(3) : 111-119, July
    19, 1962.

(14) AUEREAW, O., STOUT, A. P., H.-\hlhIOSD, E. C., GARFINKEL, L. Bronchial
   epithelium in former smokers. New England Journal of Medicine
    267 (3) : 119-125, July 19, 1962.

(2.5) AUEXIMCH, 0.. STOUT, A. P., HAMMOND. E. C., GARFINKEL, L. Histologic
   changes in esophagus in relation to smoking habits. Archives of En-
   vironmental Health 11(l) : 4-15, July 1965.
(16) XWA, A., OHNUKI, Y., PONERAT, C. >I. Some comparative effects of
   smoked paper, tobacco and cigarettes on chromosomes in &TO. Texas
   Reports on Biology and BIedicine 19: 518-528, 1961.
(17) BMR, W. J. Inhalation of radionucIides and carcinogenesis. IN: Hanna,
   M. G., JR., Nettesheim, P.. Gilbert, J.R. (Editors) _ Inhalation Carcin-
   ogenesis. Proceedings of a Biology Division, Oak Ridge National
   Laboratory Conference, Gatlinburg, Tennessee, October &ll, 1969.
   U.S. Atomic Energy Commission Symposium Series 18, April 1970,
   pp. 77-101.

(18) BENNINGTON, J. L., FERGUSON, B. R., CAMPBELL, P. B. Epidemiologic
   studies of carcinoma of the kidney. II. Association of renal adenoma
   with smoking. Cancer 22(4) : 821-823, October 1968.
(19) BENNINGTON, J. L., LAUBSCHER, F. A. Epidemiologic studies on car-
   cinoma of the kidney. I. Association of renal adenocarcinoma with
   smoking. Cancer 21(6) : 1069-1071, June 1968.
(20) BmwVALD, Y., SACHS, L. Iu vitro transformation of normal cells to tumor
   cells by carcinogenic hydrocarbons. Journal of the National Cancer
   Institute 34 (4) : 641-658, October 1965.
("1) BEST. E. W. R. A Canadian Study of Smoking and Health. Ottawa, De-
   partment of National Health and Welfare, 1966, 137 pp.

326


("2) BIDsrRL'p, P. I,.. CASE, R. A. 31. Carcinoma of the lung in workmen in the
    bichromates-producing industry in Great Britain. British Jourr131 of
    Industrial 3ledicine 13: 260-264, 1956.
(23) BLACK. H., ACKER~IAS, L. V. The importance of epidermoid carcinoma
   in situ in the histogenesis of carcinoma of the lung. Annals of Surgery
    136( 1) : 44-55. July 1932.
(24) BLACKLOCK, J. W. S. The production of lung tumours in rats by 3:4
   benzpyrene, methylcholanthrene and the condensate from cigarette
    smoke. British Journal of Cancer ll(2) : 161-191, 1957.
(105) BLACKLOCK, J. W. S. An experimental study of the pathological effects
    of cigarette condensate in the lungs with special reference to carcino-
    genesis. British Journal of Cancer 15(j): `i45-762, December 1961.
(1'6) BLIJMLEIN. II. Zur kausalen Pathogenese des Larynxkarzinoms unter
    Beriicksichtiyng des Tahakrauchens. (Causal pathogenesis of
    laryngeal carcinonia with respect to tobacco smoking.) Xrchrv fur
    Hygiene und Rakteriologie Miinchen 139: 349-404, 1955.
(27) BOCK. F. G. The nature of tumor-promoting agents in tobacco products.
    Cancer Research 28 (I 1) : 2363-2:?68, November 1968.
(28) BOCK, F. G., XOORE. G. E. Carcinogenic activity of cigarette-smoke
    condensate. I. Effect of trauma and remote X irradiation. Journal of
    the Kational Cancer Institute 22(2) : 401-111, February 1953.
(-09) BOCK, F. G., XOORE, G. E., CLUK, P. C. Carcinogenic activity of cigar-
   ette smoke condensates. III. Biological activity of refined tar from
   several types of cigarettes. Journa) of the National Cancer Institute
    34(J) : 481493, April 1965.
(30) BOCK, F. G., XOOR& G. E., CROUCH, S. K. Tumor-producing activity of
   extracts of unburned tobacco. Science 145(3684) : 831-833, August 21,
     1964.
(31) BOCK, F. G., ~~OOKE, G. E., DO~VD, J. E., CLARK, P. C. Carcinogenic activ-
   ity of cigarette smoke condensate. Biological activity of refined tar
   from certain brands of cigarettes. Journal of the American bledical
    Association I81 (8) : 668-673, August 25, 1962.
(3-O) BOREX, H. G. Pulmonary cell kinetics after exposure to cigarette smoke.
   IN: Hanna, ,\I. G., JR., Nettesheim, P., Gilbert, J. R. (Editors). InhaIa-
   ation Carcinogenesis. Proceedings of a Biology Division, Oak Ridge
   Sational Laboratory Conference, Gatlinburg, Tennessee, October 8-11,
   1969. U.S. .%tomic Energy Commission Symposium Series 18, April
    1970. pp. 229-241.
(33) BORESFREUSD, E., KRIM, hf., SANDERS, F. K., STERNBERG, S. S., BENun%
   A. XaIignant conversion of cells in vitro by carcinogens and viruses.
   Proceedings of the National Academy of Sciences of the United States
    of America 56: 672-679, 1966.
(.?A) BORISYUK, Y. P. Rak Iegkikh u krys, vyzvannyy intratrakheal'nym
  vvedeniyem prodoktov kureniya. (Cancer of the lung in rats induced by
   intratrachea) jntubation of tobacco smoke products.)  Voprosy
   Onkologii 13 (6) : 49-53, June 1969.
(35) BOCCHARD, J., MAY, R.. 31. L'effet des goudrons de tabac sur Ies greff*s
  sours-capsuiaires de poumon chez la souris. (The effect of tobacco tars
  on sub-capsular implants of the lung in mice.) Archives d'kaatomie
  &Iicroscopique et de Morphologic Experimentale 49 (3) : 307-332, 1966.

                                      327


   (36) BOllAND. E. The Biochemistry of Bladder Cancer. Sl>ringfield, Ill.,
       C. C. Thomas, 1963. 95 pp.
   (37) BOYLAND, E., BUSBY, E. R., DUKES, C. E., GRO&-IX, P. L., MANSON, D.
      Further experiments on implantation of materials into the urinary
      bladder of mice. British Journal of Cancer 18(3) : 575-581, September
           1964.
   (36) BonAND, E.. ROE, F. J. C. Carcinogenic nitrosamines which may be
       present in cigarette smoke. IN: Severi, L. (Editor). Lung Tumors in
      Animals. Perugia. Division of Cancer Research, University of Perugja,
       June 1966. pp. 667-676.
   (39) BOYLAND, E., WATSON, G. 3-hydroxyanthranilic acid, a carcinogen pro
       duced by endogenous metabolism. Nature 177(4514) : 837-838, May
         5, 1956.
   (40) BOYLAND, E., ~ILLIABIS, D. C. The metabolism of tryptophan. 2. The
       metabolism of tryptophan in patients suffering from the cancer of the
       bladder. Biochemical Journal 64: 578-582, 1956.
   (41) BRADSHAW, E., SCHONLAND, M. Oesophageal and lung cancer in Natal
         African males in relation to certain socio-economic factors. An anal-
        ysis of 484 interviews. British Journal of Cancer 23(Z) : 275-284,
         June 1969.
   (42) BIKESLOW, L., HOAGLIN, L., RASMUSSEN, G., ABRAM& H. K. Occupations
       and cigarette smoking as factors in lung cancer. American Journal of
       Public Health and the Nation's Health 44 (2): 171-181. February 1954.
   (49) BRODERS, A. C. Squamous-cell epithelioma of the lip. A study of five
       hundred and thii.ty-seven cases. Journal of the American Medical
       Association 74 (10) : 656-664, March 6, 1920.
   (44) BROSS, I. D. J. Effect of filter cigarettes on the I-isk of lung cancer. IN:
       Wynder, E. L., Hoffmann, D. (Editors). Toward a Less Harmful
       Cigarette. Bethesda, Md., U.S. Public Health Service, National Cancer
       Institute Monograph No. 28, June 1968. pp. 35-10.
   (45) BROWN, R. R., PRICE, J. M., BURNEY, S. W., FRIEDELL, G. H. Lack of
      effect of smoking on the excretion of tryptophan metabolites by man.
      Cancer Research 30(3) : 611-6i4, hlarch 1970.
    (4s) BROWN, R.R., PRICE, J. hi., SATTER, E. J., WEAR, J. B. The metabolism of
      tryptophan in patients with bladder cancer. Acta Unio Internationalis
       Contra Cancrum 16: 299303, 1960.
   (47) BRYAN, G.,T. Role of tryptophan metabolites in urinary bladder cancer.
      American Industrial Hygiene Association Journal 30(l) : 2734,
       January-February 1969.                            -.

   (48) BRYAN, G. T., BROWN, R. R., PRICE, J. M. Mouse bladder carcinogenicity
      of certain tryptophan metabolites and other aromatic nitrogen com-
     pounds suspended in cholesterol. Cancer Research 24(4) : 596-602,
       May 1964.
  (49) BUELL, P. E., DUNN, J. E., BRESLOW, L. Cancer of the lung and Los
     Angeles-type air pollution. Prospective study. Cancer 20(12) : 2139-
       2147, December 1967.
  (50) CAHAN, W. G., Kmhfm, D. An effective system and procedure for
     cigarette smoking by dogs. Journal of Surgical Research 8(12) : 567-
       575, December 1968.
  (51) CARS& W. H. The respiratory epithelium of patients with lung cancer.
      IN: The Morphological Precursors of Cancer. Proceedings of an
      Intzernational Conference held at the University of Perugia, June 1961.

328


A publication of the Division of Cancer Research, University of
Perugia, Italy. pp. 625-634.

(5~) CARUC~~O, N., Rossr, S. Evaluation of polynuclesr hydrocarbons in
   cigarette smoke by gloss cap111ary columns. Journal of Gas Chroma-
   tography S(2) : 103-106, February 1967.
(53) CASTIGLIAXO, S. G. Influence of continued smoking on the incidence of
   second primary cancers involving mouth, pharynx, and 12~~. Journal
   of the American Dental Association `U(3) : 580-585, September 1968.
(5~) CHAN, P. C., SAKDERS, F. K., WYNDER, E. L. Effect of 3,4-benzo(a)
   pyrene on mouse lung primordia in vitro. Nature 228 (5208) : 847-818,
    August 23, 1969.

(55) CHANG, S. C. Microscopic properties of whole mounts and sections of
   human bronchial epithelium of smokers and non-smokers. Cancer
   10 (6) : 12361261, December 1957.

(56) CLAPP, N. K., C~u\rc, A. W. Carcinogenic effects of diethylnitrosamine
   in RF mice. Journal of the National Cancer Institute 39 (5) : 903-916,
    November 1967.

(57) COBB, B. G., ANFXLI, J. S. Cigarette smoking and cancer of the bladder.
   Journal of the American Xedical i\ssociation 193(5) : 329332,
    August 2,1965.

(58) COHEN, S., Hossars, S. Primary carcinoma of the lung. A review of 417
   histologically proved cases. Diseases of the Chest 49(l) : 67-74,
    January 1966

(59) CONZELAIAN, G. &I., JR., MOULTON, J. E., FLANDERS, L. E., III, SPRING%
   K.. CROL'T. D. XV. Induction of transitional cell carcinomas of the uri-
   nary bladder in monkeys fed 2-naphthylamine. Journal of the Nationitf
   Cancer Institute 42 (3) : 825-836, hIay 1969.
(60) COOK, J. W. Tobacco Smoke and Lung Cancer. London, The Royal Insti-
   tute of Chemistry. Lecture Series No. 5, 1961. 18 pp.
(61) CORXFIELD, J. A method of estimating comparative rates from clinical
   data. Applications to cancer of the lung, breast, and cervix. Journal of
   the National Cancer Institute 11: 1269-1275, 1951.
(62) CROCKER, T. T. Effect of benzo(a)pyrene on hamster, rat, dog, and
   monkey respiratory epithelia in organ culture. IN: Hanna, RI. G., JR.,
   Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Carcinogenesis.
   Proceedings of a Biology Division, Oak Ridge National Laboratory
   Conference, Gatlinburg, Tennessee, October 8-11, 1969. U.S. Atomic
   Energy Commission Symposium Series 18, April 1970. pp. 433-443.
(63) CROCKS, T. T., NIELSEN, B. I., LASNITZKI, I. Carcinogenic hydrocar- _
   bans. Effects on suckling rat trachea ih organ culture. Archives of
   Environmental Health 10 (2) : 240-250, February 1965.
(64) CPQss. K. R., WALZ, D. V., PALBIER, G. K., WARNER, E. D. A study of the
   tracheobronchial epithelium and changes related to smoking. Journal
   of the Iowa Zfedical Society Sl(3) : 13'7-140, March 1961.
(65) DAVIES, R. F., DAY, T. D. A study of the comparative carcinogcnicity of
   cigarette and cigar smoke condensate on mouse skin. British Journal
   of Cancer 23(Z) : 363-368, June 1969.

(66) DEELEY, T. J., COHEN, S. L. The relationship between cancer of the
   bladder and smoking. IN : Bladder Cancer. Chapter 13, Proceedings of
   the 5th Inter-American Conference on Toxicology and occupational
   medicine, the University of Uiami, School of hfedicine, Coral Gables,
   Fla.. 1966. pp. 163-169.

329


(67)

(68)

(69)

(ro)

(71)

(72)

(73)

(71)

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

DELLA PORTA, G., KOI.B, L., SHUBIK. P. Induction of tracheobtonchial
carcinomas in the Sj-rian golden hamster. Cancer Research 18: 592-
597, June 1958.

DIAhzoND, L. The effect of carcinogenic hydrocarbons on rodent and pri-
mate cells in vitro. Journal of Cellular and Comparative Physiology
66: 183-195,1965.

DOLL, R. Cancer of the lung and nose in nickel workers. British Journal
of Industrial hledicine 15 (4) : 217-223, October 1958.
DOLL, R. Mortality from lung cancer among nonsmokers. British Journal
of Cancer 7 : 303-312, 1953.

DOLL, R. Mortality from lung cancer in asbestos workers. British Jout-
nal of Industrial Medicine 12 (1) : 81-86, January 1955.
DOLL, R. Occupational lung cancer: A review. British Journal of Jndus-
trial Medicine 16: 181-190. 1959.
DOLL, R., HILL, A. B. A study of the aetiology of carcinoma of the lung.
British Medical Journal 2: 1271-1286, December 13, 1952.
DOLL, R., HII.L, A. B. Mortality in relation to smoking: Ten years' obser-
vations of British doctors. (Part 1) British Medical Journal l(5395) :
1399-1410, May 30,1964.

DOLL, R., HILL, -4. B. Mortality in relation to smoking: Ten years' obser-
vations of British doctors.  (Conciuded) British Medical Journal
l(5396) : 1460-1467, June 6, 1964.

DONTENWILL, W. Experimental investigations on the effect of cigarette
smoke inhalation on small laboratory animals. IN: Hanna, M. G., Jr.,
Nettesheim, I'., Gilbert, J. R. (Editors) _ Inhalation Carcinogenesis.
Proceedings of a Biology Division, Oak Ridge National Laboratory
Conference, Gatlinburg, Tennessee, October 811, 1969. U.S. Atomic
Energy Commission Symposium Series 18, April 1970. pp. 389-412.
DONTENWILL, W., WIEBECKE, B. Tracheal and pulmonary alterations
following the inhalation of cigarette smoke by the golden hamster. IN:
Severi, L. (Editor). Lung Tumors in Animals. Perugia, Italy, Divi-
sion of Cancer Research, University of Perugia, June 1966. pp. 519-
526.

DRUCKREY, H. Experimental investigations on the possible carcinogenic
effects of tobacco smoking. Acta Medica Scandinavica 1'70, (Supple-
ment 369) : 24-42,1961.

DRUCKREX,H.,LANDSCHUTZ,C.,PREUSSMANN. R.Oesophagus-carcinome
nach Inhalation von Methyl-butyl-nitrosamin (MBNA) an Ratten.
(Carcinomas of the oesophagus, induced by inhalation of methyl-but&
nitrosamine (MBNA) in rats.) Zeitschrift fur Krebsforschung 71(2) :
135-139, July 1968.

DRUCKREY,H., PXEUSSMANN, R., BLUM,G., rVANKOVIC, S., AFKHAM,J.
Erzeugung von Karzinomen der Spelserahre durch unsymmetrische
Nitrosamine. (Esophageal carcinomas induced by asymmetric nitro-
samines.) Naturwissenschaften 50 (3) : 100-101, 1963.
DRUCKREY, H., PREUSSMANN, R., IVANKOVIC, S.. SCHMML, D. Organo-
trope carcinogene Wirkungen bei 65 verschiedenen N-nitroso-Verbin-
dugen an BD-Rattan. (Organotropic carcinogenic effects of 65 different
N-nitroso compounds of BD-rats). Zeitschrift fiir Krebsforschung
69(Z) :103-201, March 22, 1967.
DRUCKREY,. H., SCHILDBACH,  A. Quantitative Untersuchungen zur
Bedeutung des Benzpyrens fur die carcinogene Wirkung van Taba-
krauch. (Quantitative studies on the significance of behzopyrene for

330


the carcinogenzeffect of tobacco smoke.) Zrxitschrift ftir Krebsfor-
schung 65: 165470, 1963.

(89) DUSCAL. N. Lung carcinoma in Iceland. Lancet 2(66X) : 21%247,
    Xugust 14, 1950.

(84) DCXIia31. L. J., HERROLD, K. 31. Failure to produce tumors in the ham-
   ster cheek pouch by exposure to ingredients of betel-quid; hisiopatho-
   logic changes in the pouch and other organs by exposure to known
    carcinogens. Journal of the National Cancer Institute 29(6) : 10.17-
    1067, December 1962.

(85) DCSHASI. L. J., RAESOS, A. S., S'I'EWART, H. L., FRMK, A. S., YOUNG,
   J. L., JR. Rates, interview, and pathology study of cancer of the uri-
    nary bladder in New Orleans. Louisiana. Journal of the National
   Cancer Institute 31(3) : 683-709, September 1965.
(86) DUTTA-CZIOUDHUKI, R., ROY, H., S&N GUFTA, B. K. Cancer of the larynx
    and hypopharynx. A clinicopathological study with special reference
    to aetiology. Jouxnal of the Indian Medical Association 32(Y) : 35%
    362. May 1, 1939.

(87) EBESIUS, B. Cancer of the lip. A clinical study of 778 cases with particu-
    lar I-egard to predisposing factors and radium therapy. Acta Radio-
    logic3 (Suljplement 48) : 1-lUl,
                         `Pq`7 1913.
(~8)  EI~E?;XRG H. CAMPEELL, P. C., FLANKERY. J. T. Cancer in Connecticut.
           9 I
    Incidence characteristics 1935-1962. Hartford, Connecticut State De-
    partment of Health, 1967. 97 pp.

(89) ELMESHORBT, H., RECKZEW, G. Xromatjsche Kohlenwasserstofie jm
   Tabakrauch. (-Aromatic hydrocarbons in tobacco smoke.) Beitrage zur
    Tabskforschung Z(5) : 160-20-1, Alay 1964.
(901 ELZAY. R. P. Edect of alcohol and cigarette smoke as promoting agents
    in hamster pouch carcinogenesjs. Journal of Dental Research 48(6,
    Part 2) I 1200-1205, November-December 1969.
(92) EPDEIS, S. S., XNDWA, J., JAFF-EE, H., JOSH!, S., Fans, H., MANTEL, N.
   Carcinogenicity of the herbicide ma~e~c hL/dl.azide. Xature 215(5108) :
    13Sg-1390, September 23, 1967.

(g-7) ESSESBERG, J. &I. Cigarette smoke and the incidence of primary neo-
   plasm of the lung in the albino mouse. Science 116: 561-562, November
    21, 1952.

(9s) FXK, H. L., KOTIN, P., JIEHLER, A. Polycyclic hydrocarbons as carcin;
   ogens in man. Archives of Environmental Health 8 (5) : 721-730, May
     1964.

(94) FEP?RI. E. S., B~RATTA, E. J. Polonium-210 in tobacco, cigarette smoke
   and selected human organs. Public Health Reports 81(2) : 121-127,
   February 1966.

(95) FEXRI, E. S., RARATTA, E. .J. Poionium-210 in tobacco products and hu-
   man tissues. Radiological Health Data and Reports 7(9) : 485-488,
    September 1966.

(96) FLFTCHER, C. >I., HORS, D. Smoking and health. WHO Chronicle 24 (8) :
    315-3;0, August 1970.

(97) FMEDELL, G. H., BLXSEY, S. W., BELL, J. R., SOTO, E. Pathology as re-
   lated to tr!-ptophan metabolite excretion, occupational history, and
   smoking habits in patients with bladder cancer. Journal of the Na-
    tional Cancer Institute 43(l) : 303-306, July 1969.
(98) GELFAX;, 31.. GRAHAM, 1. J. P., LICHTMAN, S. Carcinoma of bronchus
   and the smoking habit in Rhodesian -Africans. British Medical Journal
   3 (5616) : 468-469, August 24,196~

331


(99) `SELLHoRN, A. The cocarcinogenic activity of cigarette tobacco tar. Can-
    cer Research 18(G): 510-517, June 1958.
(100) GoLnaUTT, M. W. Occupational carcinogenesis. British Medical Bulletin
    14 (2) : 136140, 1958.

(101) GRAHAM. E. A., CRONIE;CER. A. B., W'Y~.DER, E. L. Experimental produc-
    tion of carcinoma with cigarette tar. IV. Successful experiments with
    rabbits. Cancer Research 17(11) : 1058-1066, December 1957.
(102) G~HAW S. Cancer of lung related to smoking behavior. Cancer 21(3)
    523-530, March 1968.

(103) GRAIIAhg. S., CROUCII. S.. LEYIN, M. L., BOCK. F. G. Variations in
    amounts of tobacco t;tr retrieved from selected models of smoking be-
    havior simulated by smoking machine. Cancer Research 23(7): 1025
    1030, August 1963.

(104) GRAY. S. H., CORDONNIER, .I. Early carcinoma of the lung. A. M. A.
    Archives of Surgery 19: 1618-1626, 1929.
(105) GRECORY. L. P. Polonium-210 in leaf tobacco from four countries. Science
    150: `74-76, October 1, 1965.

(106) GROSS, P., DE TREVILLE, T. P., TOLKER, E. B., KASCHAK, M., BABYAK,
    M. A. Experimental asbestosis. The development of lung cancer in rats
    with pulmonary deposits of chrysotile asbestos dust. Archives of En-
    vironmental Health 15 (3) : 343-355, September 1967.
107) GSELL, 0. Carcinome bronchique et tabac. (Bronchial carcinoma and
    tobacco.) Medecine et Hygeine 12(279) : 429-431, Ilecernber 1, 1954.
(109) GUERLN, M. Tumeurs pulmonaires et cancer buccal chez le rat soumis a
    l'inhalation de fumee de sigarette. (Pulmonary tumors and oral can-
    cers in rats subjected to inhalation of cigarette smoke.) Bulletin de
    I'Association Francaise pour 1'Etude du Cancer 46(Z) : 295-309.1959.
(101)) GUEXIH. M. CUZIH. J.-L. Action cnrcinogene du goudron de fumee de
    cigarette sur la peau de souris.  (C aicrno enic action of tar from
                          . g
    cigarette smoke on mouse skin.) Bulletin de I'Association Francaise
    pour I'Etude du Cancer 44(3) : 387-408. 1957.
(110) GuIhlARD, J. Alterations cellulaires provoquees in vitro, sur des tibro-
    blastes quiescents et en mitose. par des goudrons entiers de tabac.
    (Cellular changes induced in vitro in quiescent fibroblasts and those
    in mitosis by nonfractional tobacco tar.) Archives des Sciences
    Physiologiques 20(2) : 153-167. lY66.

(111) GIJTHRIE, F. E. The nature and significance of pesticide residues on
    tobacco and in tobacco smoke, Beitrage zur Tabakforschung 4 (6) :
    229-246, November 1968.
(112) H~NSZEI., W., LOVELAND, D. B., SIRKEN, M. G. Lung-cancer mortality as
    related to residence and smoking histories. I. White males. Journal-of
    the National Cancer Institute 28(4) : 947-1691, April 1962.
(11s) HAENSZEL, W., SHIMKIN, Xi. B. A retrospective study of lung cancer in
    women. Journal of the National Cancer Institute 21(5) : 825-842,
     November 1958.

(114) H~NSZEL, W., SHMKIN, Bf. I?., MILLER, H. P. Tobacco smoking Patterns
   in the United States. Public Health Monograph NO. 45, May 1956.
    111 pp.

(115) HAENSZEL, \V., TAEUBEX, K. E.. Lung-cancer mortality as related to
   residence and smoking histories. II. White females. Journal of the
    NatIonal Cancer Institute 32(4) : 803-838, April 1964.
(116) Harm, D., WOODHOUSE, D. L. Biological tests for carcinogenic action of
   tar from cigarette smoke. British Journal of Cancer 10: 49-53, 1956.

332


(117) HAhIILTON, J. D., SEPP, A., BHOWS, T. `2, >IACDONAl.D. F. `iv. nlorpho-
   logical changes in smokers' lungs. Csnatlisn 3Icdical Association
    Journal 77(3) : 177-182, August 1, 1957.
(118) HASIMOXD, E. C. Smoking in relation to the death rates of 1 million men
    and women. IN: Haensael, W. (Editor). Epidemioiogical Approaches
    to the Study of Cancer and Other Chronic Diseases. Bethesda, Md.,
    U.S. Public Health Service, National Cancer Institute Monograph,
    No. 19, January 1966. pp. 127-204.

(119) HAhIhlOND,E. C., AUERUACH, 0.. KI,RMAN, D., CARFINXEL, L. Effects of
   cigarette smoking on dogs. I. Design of experiment, mortality and
   findings in lung parenchyma. Archives of Environmental Health
   21(6) : 740-753, December 1970.

(120) HAMMOND, E. C., HORN, D: Smoking and death rates-report on forty-
    four months of follow-up of 187.783 men. II. Death rates by cause.
    Journal of the American Medical Association 166( 11) : 129441308,
    hlarch 15, 1958.

(121) HARRIS, R. J. C., NEGRONI. G. Production of lung carcinomas in C57BL
   mice exposed to a cigarette smoke and air mixture. British Medical
    Journal 4( 5580) : 637-641, December 16, 1967.
(12) HERROLD, K. hI., DUNI~AM, I,. J. Induction of carcinoma and papilloma
    of the tracheobronchial mucosa of the Syrian hamster by intratracheal
    instillation of benzo (a) pyrene. Journal of the National Cancer Insti-
    tute 28(2) : 467-491, February 1962.

(103) HILL, C. R. Polonium-210 in man. Nature ZOS(5009) : 423-428, October
     30, 1965.

(124) HIRAYAMA, T. An epidemiological study of oral and pharyngeal cancer
    in Central and Southeast Asia. Bulletin of the World Health Orgnn-
    ization 34 (1) : 41-69, 1966.

(fZ.5) HIRAYAhIA, T. Smoking in relation to the death raes of 265,118 men and
    women in Japan. Tokyo, National Cancer Center, Research Institute,
    Epidemiology Division, September 1967. f4 pp.
(126) HITOSUGI, M. Epidemiological study of lung cancer with special refer-
    ence to the effect of air pollution and smoking habit. Bulletin of the
    Institute of Public Health 17 (3) : 237-256, September 1968.
(127) HOFFMANN, D., MASUDA, Y., WYNDER, E. L. Alpha-naphthylamine and
    beta naphthylamine in cigarette smoke. Nature 221(5177) : 254-256,
    January 181969.

(128) HOFFMANN, D., RATHKAMP, G. Chemical studies on tobacco smoke. Y.
    Quantitative determination of chlorinated hydrocarbon insecticides in
    cigarette tobacco and its smoke. Beitrage zur Tabakforschung 4 (5) :
    201-214, July 1968.

(129) HOFFMANN, D., WYNDER, E. 1~. Chamber development and aerosol dis-
    persion. IN: Hanna, hf. G., Jr., Nettesheim, P., Gilbert, J. R. (Editors).
    Inhalation Carcinogenesis. Proceedings of a Biology Division, Oak
    Ridge National Laboratory Conference, Gatlinburg, Tennessee, Octo-
    ber S-11.1969. U.S. Atomic Energy Commission Symposium Series 18,
    April 1970. pp- 173-191.

(130) HOISTI, L. R., ERMALA, P. Papillary carcinoma of the bladder in mice,
    obtained after peroral administration of tobacco tar. Cancer 8(4) :
    679-682, July-August 1955.

(131) IIOMBURGER, F., TREGER. A., BAKER, J. R. hIouse-skin painting with
    smoke condensates from cigarettes made of pipe, cigar, and cigarette

333


tobaccos. Journal of the National Cancer Institute 31/G) : 1145-1459,
December 1963.

(1.~) HORE,A., Komrrr, S., KURATS~E, ,?I. Csrcinogenesis in the esophagus.
   II. Experimental production of esophageal cancer b\- administration
    of ethanolic solution of carcinogens. Gann 56(5) : X9--1:1, October
      1965.

(153) HUEPER, W. C. Experimental studies in metal csncerigenesis. VI. Tissue
    reactions in rats and rabhits after parenteral introduction of suspen-
    sions of arsenic, beryllium, or asbestos in lanolin. Journal of the
    National Cancer Institute 15(l): 113-129, August 1954.
(1.~4) HUEPER, W. C. Experimental studies in metal cancerigenesis. IX. Pul-
   monary lesions in guinea pigs and rats exposed to prolonged inhala-
    tion of powdered metallic nickel. A.M.A. Archives of Pathology 65:
     600-607. June 1958.

(1.~5) HUEPER, XV. C., PAYXE, W. W. Experimental studies in metal carcino-
   genesis. Chromium, nickel, iron, arsenic. Archives of Environmental
    Health 5 (5) : 445-462, November 1962.
(136) HUEPER, W. C.. WILEY, F. H., WOLFE, H. D., RASTA, K. E., LEWSC, M.
   F., BLOOD, F. R. Experimental production of bladder tumors in dogs
    by administration of beta-naphthylamine. Journal of Industrial Hy-
    giene and Toxicology 20(l) : 46-84, January 1938.
(137) ISHII, K., NAKAXU& K., OZAKI, H., YAhYAm, 9.. TAXWHI, T. Suizo-
   gan no ekigaku ni okeru mondaiten. (Some aspects of the epidemiology
   of cancer of the pancreas.) Nippon Rinsko 26 (8) : 1839-1842. August
      1968.

(188) JOHXSOS, D. E., MILLAR, J. D.. RHOADES, J. W. Nitrosamines in tobacco
    smoke. IN: Wynder, E. L., Hoffmann, D. (Editors). Toward a Less
    Harmful Cigarette. Bethesda, hid., U.S. Department of Health, Edu-
    cation, and Welfare, Public Health Service, Sational Cancer Institute
    Monograph 28, June 1968. pp. 181-189.
(239) KAHN, H. A. The Dorn study of smoking and mortality among U.S. vet-
    erans: Report on 8?& years of observation. IN : Haenszel. WV. (Editor) _
    Epidemiological Approaches to the Study of Cancer and Other Chronic
    Diseases. Bethesda, Md., U.S. Public Health Service, Sationai Cancer
    Institute Monograph No. 19, January 1966. pp. l-125.
(140) KELLER, A. 2. Cirrhosis of the liver, alcoholism and hea\T smoking asso-
    ciated with cancer of the mouth and phar-ynx. Cancer `70(6) : 101%
    1022, June 1967.

(l-&f) KELLER, A. 2. Cellular types, survival, race, nativity, occupations, habits
    and associated diseases in the pathogenesis of lip cancers. American
    Journal of Epidemiology 91(5) : 486499, May 1970.
(l/2) KELLEN, T. F. Polonium-210 content of mainstream cigarette smoke.
    Science 149(3683) : 537-538, July 30, 1965.
(l-53) -9, W. K(., BARKIN, M., LEXRS, P. E., Woo, S. K-C., XESCZYK, Z. The
    effect of cigarette smoking on bladder carcinogens in man. Canadian
    Medical Association Journal 93(l) : l-7, July 3, 1965.
(144) KJDA, H., Oafcrro, T., SAKAMOTO, K., hloaross, S. Fukuoka ken hokubu ni
   okeru boko shuyo no ekigaku to tokei. (Statistics and epidemiology
   of urinary bladder tumors in northern Fukuoka, Japan.) Hifu to
    Hinyo 30(5) : 883-889, October 1968.

(145) KILIB~A. >I., PEI'ROVIC, D., PANOV, D., D~LTRIC, D. Contamination with
   polonium-21% uranium and radium-226 due to smoking- Health Phy-
    sics 12: 1808, December 1966.

334


(146) KIRYU, S., KURATSUSE, ,\I. P~l~--c);di~ aromatic h)-drocarbons jn the ciga-
    rette tar produced by human smoking. Gann 57: 317-3'72, ..\ugust 1966.
(127) KNUnrSOS, K. P. The pathologic effects of smoking tobacco on the tra-
   chea and bronchial IIIUCOS~. American Journal of Clinical Pathology
    33(4) : 310-317, April 1960.

(148) KOCHEN, Iv., IIOCHBERG, I;. Untersuchugen uber den Trypthophan-Stoff-
    wechsel beim Blasen-Carcinom. (Studies about the trypmphan metab-
   olism in the carcinoma of bladder.) Zeitschrift fur Krebsforschung
    73(3) : 251-264, January 29, 1970.

(1A9) KOTIN, P.. FALK, H. L. Atmospheric factors in pathogenesis of lung can-
    cer. Advances in Cancer Research 7: 475-514, 1963.
(150) KOTIN, P.. FAI.K, H. L. Polluted urban air and related environmental
    factors in the pathogenesis of pulmonary cnncer. Diseases of the Chest
    45(3) : 236-246, March 1964.

(151) KOULUhlIES, &I. Smoking and pulmonary carcinoma. Acts Radiologica
    39: 255-260, 1953.

(1.52) KRESHOVER, S. 3. The effect of tobxcco on epitheljal tissues of mice.
    Journal of the American Dental Association 45 (6) : 528-540, Novem-
     ber 1952.
(1.5;) KREYRERG, L. Histological Lung Cancer Types. A hIorphologica1 and Bio-
   logical Correlation. Acta Pathologica et Microbiologica Scandinavica
    (Supplementurn 157) : 1962. 92 pp.

(154) KREYBERG, L. Aetiology of Lung Cancer. A Morphological Epidemiologi-
    cal and Experimental Analysis. Oslo, Universitetsforlaget, 1969. 99 pp.
(15.5) KUIIN, II. Tobacco alkaloids and their pyrolysis products in the smoke.
    IN : Van Euler, U.S. (Editor). Tobacco Alkaloids and Related Com-
    pounds. New York, Macmillan, 1965. pp. 37-51.
(15~) KURATSUE;E, >I., KOHCIII, S., HOME, A. Carcinogenesis in the esophagus.
    I. Penetration of benzo(n)pyrene and other hydrocarbons into the
   esophageal mucosa. Gann 56(2) : 177-187. 1965.
(157) K:L'SCHP;ER, M. The J. Burns Amberson Lecture. The causes of lung can-
   cer. American Review of Respiratory Diseases 98(4) : 573-590, Otto-
     ber 1968.

(158) L~XC~STER, H. 0. Cancer statistics in Australia. Part II. Respiratory
   system. Medical Journal of Austrjlia 1: 1006-1011, June 30, 1962.
(159) LASKIN, S., KUSXNFZR, M., DREW, R. T. Studies in pulmonary carcino-
   genesis. IN: Hanna, 3'1. G., Jr., Nettesheim, P., Gilbert, J. R. (Editors).
   Inhalation Carcinogenesis. Proceedings of a Biology Division, Oak
   Ridge Iiational Laboratory Conference, Gatlinhurg, Tennessee, Octo-
   ber g-11,1968. U.S. Atomic Energy Commission Symposium Series 18,
    April 1970. lip. 321-351.

(260) L~SNITZKI, I. The effect of a hydrocarbonenriched fraction from ciga- 1
   rette smoke on mouse tracheas grown in vitro. British Journal of
    Cancer 22( 1) : 105.-109, March 1968.

(161) LASNITZKI, I. The effect of a hydrocarbon-enriched fraction of cigarette
   smoke condensate on human fetal lung grown in u&o. Cancer Research
    28(3) :5X6-513. Xawh 1968.
(162) LEDERMANN, S. Cancers, tabac, vin et afcool. (Cancers, tobacco, wine
   and alcohol.) Concours Medical 1 i 1107, 1109-1111, III3-1114, 19%.
(f&j) LEE, A. ill., FRAUMENI, J. F., JR. Arsenic and respiratory cancer in man:
   An occupational study. Journal of the National Cancer Institute 42
    (6) : 1045-1052, June 1969.

(16~) LELJC~~TENBERCER, C., LEUCHTENBLRGER, R. The role of influenza virus in
   the development of malignant transformation in vitro and in the res-

335


   piratory ti-act of mice, with and without exposure to cigarette smoke.
    Rivista di Biologia 59: 445463, 1966.
(165) LECCSITENBERCER, C., LEUCHTESBERCER. R. Cytologic and cytochemical
   effects on primary mouse kidney tissue and !ung organ cultures after
    eXPOSUrt' to tvhole. fresh smoke and its gas phase from unfiltered, char-
   coal-filtered, and cigar tobacco cigarettes. Cancer Research ?9(4) :
    862-872, April 1969.

(166) LEUCKTESBCRGER, C., LEUCfiTfXBERCE& R., DOOUN, P. F. A correlated
   histological, cytological. and cytochemical study of the tracheobron-
    chial tree and lungs of mice exposed to cigarette smoke. I. Bronchitis
    with atypical epithelial changes in mice exposed to cigarette smoke.
    Cancer 2(3) : 490-506, May-June 1958.
(167) LEWRTESBERCER, C.. LEWXTENBERCER, R., ZEBRUN, W., S~~AF~ER, P.
    A correlated histological, cytological, and cytochemical study of the
    tracheobronchial tree and lungs of mice exposed to cigarette smoke. II.
    Varying wsponses of major bronchi to cigarette smoke. absence of
   bronchogenic carcinoma after prolonged exposure, and disappearance
    of bronchial lesions after cessation of exposure. Cancer 13(4) : 721-
    732, July-August 1960.

(163) LLUCWTESRERGER, R., LEUCHTENBERCER, C., ZEBRUS, W., SHAFEXR, P. A
    correlated histological, cytological, and cytochemical study of. the
    tracheobronchial tree and lungs of mice exposed to cigarette smoke.
    III. Unaltered incidence of grossly yisible sdenomatous lung tumors
    in female CF, mice after prolonged exposure to cigarette smoke. Can-
    cer 13(5) : 956-958, September-October 1960.
(169) LEWIS, >I. I,., GOLDSTEIN, H., GERIMRDT, P. R. Cancer and tobacco smok-
   ing. .I preliminary report. Journal of the American Medical Associa-
    tion lJY(4) : 33G-338, May 27, 1950.

(1;~) LICKIST. F. Jjer Tabakrauch 31s Ursache des Lungenkrebses. Spezieller
   Teil IV. iitiologie und Prophylaxe des Lungenkrebses. (Tobacco smoke
   as cause of lung cancer. Special Section IV. IN: Etiology and
   Prophylaxis of Lung Cancer.) Dresden, Theodor Steinkopff, 1953.
    pp. 66-141.

(171) LILIESFELD, A. M., LEVIN, BI. I,., MOORE, G. E. The association of smok-
   ing with cancer of the urinary bladder in`humans. A.M.A. Archives of
    Internal Medicine 98: 123-135, 1956.
(170) LITTLE, J. B., RA~FORD, E. P., JR. Polonium-210 in bronchial epithelium
   of cigarette smokers. Science 155(3762) : 606-607, February 3, 1967.
(173) LITTLE, J. B., RADFORD, E. P., JR., MCCOMBS, H. I.., HUNT, V. R. Polo-
   nium-210 in lungs and soft tissues of cigarette smokers. Radiation
    Research 22: 209. 1964.

(175) LII-KLE, J. B., RADFORD, E. P., JH., mcOMBS. H. L., HUNT, V. R. Distribu-
   tion of Polonium-210 in pulmonary tissues of cigarette smokers. New
   England Journal of Medicine 273 (25) : 1343-1351, December 16,196s.
(175) LOCKWOOD, K. On the etiology of bladder tumors in Kobenhavn-
   Frederiksberg. An inquiry of 369 patients and 369 controls. Acta
   Pathologica et Microbiologica Scandinavica 51 (Supplementurn 145) :
    1961. 166 pp.

(176) LOXIBARD, H. L., SXECIREFF, L. S. An epidemiological study of lung
    cancer. Cancer 12(z) : 406-413. March-April 1959.
(177) LOREZZ, E., STEWART, H. L., DANIEL, J. II., NELSON, C. V. The effects of
   breathing tobacco smoke on strain A mice. Cancer Research 3: 123,
     1933.

336


(178) LVSDIS, F. E., JR., LLO~D,J. W., Sw~ri, E. M., ARCIIER, V. E., HOLADAY.
    D. A. hlortatity of uranium miners in relation to radiation exposure.
   hard-rock mining and cigarette smoking-1950 through September
    1967. Health Physics 16( 5) : 571-578, May 1969.
(1;s) LYSCII, K. >I., ~TCIVFX, F. A., CAIN. J. R. Pulmonary tumors in mice
   exposed to asbestos dust. A.AI.A. Archives of Industrial Health 15:
    207-214, hlarch 1957.

(180) hlcCor?NELL, R. B., GORDON, K. C. T., JONES, T. Occupational and Per-
    sonal factors in the aetioloby of carcinoma of the lung. Land 2:
    651-636. October 4, 1952.

(181) XIACEE, P. N., BARNES, J. M. Carcinogenic nitroso compounds. Advances
    in Cancer Research 10: 163-246, 1967.
(1810) MALTONI, C., CARR~I, D., CANEPARI, C., GHEX-~I, G. Incidenza della
   metsplasia squamosa dell'epitelio respiratorio in rapport0 al fumo di
   sigaretta. Studio citologico su 1000 individui di sesso maschile ap-
    parentemente sani. (Incidence of squamous metaplasia of the respira-
   tory epithelium in relation to cigarette smoking. Cytological study on
    1000 apparently healthy male individuals.) Cancro 21 (4) : 349-356,
      1968.

(183) MARTIXEZ, I. Factors associated with cancer of the esophagus, mouth,
   and pharynx in Puerto Rico. Journal of the National Cancer Institute
    42(6) : 1069-1094, June 1969.

(284) hIILLER, L., SMITH, W. E., BERLIPI'ER, S. W. Tests for effect of asbestos
   on benzo(a)pyrene carcinogenesis in the respiratory tract. Annals of
    the New York Academy of Sciences 132( Article 1) : 489-500, Decem-
    ber 31, 1965.

(285) hIILLER, R. L., STEDMAN, R. L. Essential absence of beta-naphthylamine
    in cigarette smoke condensate. Tobacco 165(B) : 32, t\ugust 25, 1367.
(186) hIILLs, C. A., PORTF~, M. hI. .Tobacco smoking habits and cancer of the
   mouth and respiratory system. Cancer Research 10: 539-542, 1950.
(187) MILLS, C. A., PORTER, hf. hl. Tobacco smoking, motor exhaust fumes, and
   general air pollution in relation to lung cancer incidence. Cancer Re-
    search 17: 981-990, 1957.

(188) hIONTESAN0, R., SAFWOTTI, U. Carcinogenic response of the hamster
    respiratory tract to single subcutaneous administrations of diethyl-
    nitrosamine at birth. Journal of the National Cancer Institute 44 (2) :
    413-417, February 19'70.

(189) MONTESANO, R., SAFFIOTTI, U., SHUBIK, P. The role of topical and sys-
    temic factors in experimental respiratory carcinogenesis. IN: Hanna,
    M. G.. Jr.. Nettesheim, P., Gilbert, J. R. (Editors). Inhalation Car-
   cinogenesis. Proceedings of a Biology Division, Oak Ridge National
    Laboratory Conference, Gatlinburg, Tennessee, October S-11, 1969.
    U.S. Atomic Energy Commission Symposium Series 18, April 1970,
    pp. 353-371.

(190) hfOORE, C. hlultiple mouth-throat cancer. American Journal of Surgery
    llO(3) : 534-536, October 1965.

(291) MOORE, C., CHRISTOPHERSON, 1%`. M. The effect of cigarette-smoke con-
    densate on hamster tissues. Exteriorized oral pouch and skin. A.M.A.
    Archives of Surgery 84 (4) : 425-431, April 1962.
(192) MOORE, C., hIILLER, A. J. Effect of cigarette tar on the hamster pouch.
    A.M.A. Archives of Surgery 76 (5) : `786-793, May 1958.
(193) MOORE, G. E., ~ISSENGER, L. I,.. PROEHL, E. C. Intraoral cancer and the
   use of chewing tobacco. Journal of the American Geriatrics Society 1:
    49'7-506, 1953.

337


(194) MORGAN, J. G. Some observations on the incidence of re-piratory cancer
    in nickel workers. British Journal of Industrial Medicine 15: 224-234,
      1958.

(195) MUHLBOCK, 0. Carcinogene Wet-king van Sigarettenrook bij Muizen.
    (Carcinogenic action of cigarette smoke in mice).  Sederlands
    Tijdschrift voor Ceneeskunde 39(31) : 227T~22'iS. July 30. 1955.
(196) XIULLER, F. H. Tabakmissbrauch und Lungencarcinom. (Tobacco misuse
    and lung carcinoma). Zcitschrift fiir Krebsforschung 49 (1) : 57-85,
     1939.

(197) fiful;oz, N., CORREA. P., BOCK, F. G. Comparative carcinogenic effect of
   two types of tobacco. Cancer 21(3) : 376-389, March 1968.
(198) NASIELL, &I. The Epithelial Picture in the Bronchial Mucosa in Chronic
    Inflammatory and Neoplastic Lung Disease and its Relation to Smok-
    ing. A comparative histologic and sputum-cytologic study. Stockholm,
   Cytology Laboratory, Department of Pathology at Sabbatsberg Hos-
    pital, Karolinska Institotet, 1368. 72 pp.

(189) NELSON, N. Inhalation carcinogenesis in man: Environmental and occu-
    pational hazards. IN: Hanna, bI. G., Jr., Nettesheim, P., Gilbert, J. R.
    (Editors). Inhalation Carcinogenesis. Proceedings of a Biology Divi-
    sion, Oak Ridge Nntional Laboratory Conference, Gatlinburg,
    Tennessee, October 8-11, 1969. U. S. Atomic Energy Commission
    Symposium Series 18, April 1970. pp. 3-12.
(zoo) NETTESHEIM, P., HAHN& X. G., JR., DOHERTY, D. G., XEK-ELL, R. F.,
    HELLMAN, A. Effects of chronic exposure to artificial smog and chrom-
    ium oxide dust on the incidence of lung tumors in mice. IS: Hanna.
    M. G., Jr., Kertesheim, P., Gilbert, J. R. (Editors). Inhalation Carcin-
    ogenesis. Proceedings of a Biology Division, Oak Ridge National
    Labratory Conference, Gatlinburg, Tennessee, October 8-11, 1969.
    U.S. Atomic Energy Commission Symposium Series So. 18, April 1970.
    pp. 305320.

(201) NEURATII, G. Zur Frage des Vorkommens van N-Sitroso-Verbindungen
    im Tabakrauch. (Occurrence of n-Nitroso compounds in tobacco
    smoke.) Experientia 23 (5) : 400-404, 1967.
(202) NEURATH, G. Stickstoffverbindungen des Tabakrauches. (Nitrogen com-
   pounds in tobacco smoke.) Arzneimittel-Forschung 19 (i) : 1093-1106,
    Jury 1969.

(203) OCHSNER, A., DE BAKEY, M. Primary pulmonary malignancy. Treatment
    by total pneumonectomy. Analysis of 79 collected cases and presenta-
    tion of 7 personal cases. Surgery, Gynecology and Obstetrics 68: 435-
    461, 1939.

(PO4) ORMOS, J., KARACSONYI, G., BILICZKI, F., SZONYI, F. Lung cancer in the
    Hungarian plain. Neoplasma 16(fi) : 66'7-675, 1969.
(205) ORR, J. W., WOODHOUSE, D. L., HAMER, D., MAYCHANT, J., HOW-L., J. S.
    Cigarette tobacco tars. British Empire Cancer Campaign Annual Re-
    port 33: 238-239, 1955.

(206) 0~70, H. Experimentelle Untersuchungen an Miiusen mit passive1
    Zigarettenrauchbeatmung. (Experimental investigations on mice
   through passive inhalation of cigarette smoke.) Frankfurter Zeitsch-
    rift fiir Pathologic 73: 10-23. 1963.

(207) PAILER, IX, HIJBSCH, W. J., KUHN, H. Untersuchung der aliphatischen
    und aromatischen primiiren und sekundaren Amine dcs Zigaretten-
    rauches mit Hilfe der Gaschromatographip und Massenspektrometric.
    (Study of the aliphatic and aromatic primary and secondary amines
   of cigarette smoke by gas chromatography and mass spectrometry.)

338


    Fachliche Jlittcilungen der Oestert-eichischen Tabakregie Xo. 7: 10%
     118. April 1367.
(208) P~PANICOL~OC, G. N., KOPROWSKA. I. Carcinoma-in-silx of the right
    lower bronchus: A case report. Cancer d(I) : 111-146, January 1951.
(,"`Jg) PasSEu, R. D., ROE, E. 11. F.. .\IIDDLEYTOS. F. C., BERGEL, F., E\TERET.~,
    J. L.. LzlvLs, G. E.. MARTIN. J. B., Rol-rxso, E., SIMS, P. Cigarette
    smoking and cancer. British Empire Cancer Campaign Annual Report
     32: 60-62, 1954.
(210) PEACOCK, E. E., JR., GREENBERG, B. G., BPA~LEY, B. iv. The e&A of
    snuff and tobacco on the production of oral carcinoma: An esperimen-
    tal and epidemiological study. Annals of Surgery 151(4): 542-550,
     April 1960.
(211) PERNU, J. An epidemiological study on cancer of the digestive organs
    and respiratory system. A study based on 7,078 cases. Annaled
    hledicinae Internae Fenniae 49 (Supplement 33) : 1960. 117 pp.
(212) POTTER, E. A.. TULLY. 31. 1~. The statistical approach to the cancer prob-
     lem in Massachusetts. American Journal of Public Health and the
     Nation's Health 35: 485-490, May 1945.
(213) PROTZEL. M., GIARDISA, A. C., ALLIANO, E. H. The effect of liver imbal-
    ance on the development of oral tumors in mice following the applica-
    tion of benzpyrene or tobacco tar. Oral Surgery, Oral Medicine and
    Oral Pathology lS(5) : 622-635, November 1961.
(214) QUACLIARIELLO, E.,TASCREDI, F., FEDELE, L..S~ccox~.C. Tryptophan-
    nicotinic acid metabolism in patients nith tumours of the bladder.
    Changes in the excretory products after treatment with nicotinsmide
    and vitamin B,. British Journal of Cancer 15: 367-372, 1961.
(215) RADFORD, E. P., JR., HUNT, V. R. Polonium-210: A volatile radio-element
    in cigarettes. Science 143(3603) : 247-249, January 17, 1964.
(SIG) RUMFORD, E. P., HUNT, V. R., LITTLE, J. B. Carcinogenicity of tobacco-
    smoke constituents. Science 165(3890) : 312. July 18, 1969.
(217) RAJEWSKY, B., STAHLHOFEN, W. Polonium-210 activity- in the lungs of
    cigarette smokers. Nature 209(5030) : 1312-1313, March 26, 1966.
(218) RAXDIG, K. Untersuchungen zur iitiologie des BronchialkaL-zinoms.
    (Investigations on the etiology of bronchial carcinoma.) Offentliche
    Gesundeheitsdienst 16(9) : 305-313, December 1954.
(219) REDDY, D. G., AXNGULI, V. C. Experimental production of cancer with
    betel nut, tobacco aLid slaked lime mixture. Journal of the Indian
    hledical Association 49 (7) : 315-318, October 1, 1967.
(r'0) REISGOI.D, I. >I.. OTTOMAS, R. E.. KOSWALER. B. E. Bronchogenic car-
   cinoma: A study of 60 necropsies. American Journal of Clinical Path-
    ology 20: 515-525, 1350.
(721) RICDOS. R. Il. Effect of tobacco condensate on respiratory tract of whit&
    Pekin ducks. -1.AI.A. ,\rr!Lives of Pathology 69(l) : 55-63, January
      1960.
(X??) ROBRIICS, \V. 7`. Bronchial epithelium in smoking and nonsmoking c01-
   lege students. Journal of the American College Health Association
    11(.4) : 265-266. April 1966.
(~2;) ROCKC\`, E. E., SPCER, F. !). The ill effects of cigarette smoking in dogs-
   Intel national Surgery 46(6) :. 5?1-530, December 1966.
(oz$) ROCKEY, E. E., SPEER, F. D.. THONPSOX, S. A., Airs, K. J.. HIROSE, T.
   Exl,crimental study on effect of cigarette smokc.condensate on bron-
   chial niucoca. Joumnl of the American >Icdical Association 182 (11) :
    109&1Oi)8, December 15. 1962.

                                         339


(-025) ROE, F. J. C. RI+ of :Ll-t)L~nzop~l WI,- ,n rnrcInOfct~~ris t+ ~~~~~~~~~ .r:nokc
    condensate. ti:iturc l!tlili;:l:~) : lll3*~-llll)~l, June Ifi> ]YGL'.
(Z?6) ROTH, D.. T.`KEDRICKSoS. 0. T., OPPESI~EI~I. .A., ~.orDos, M. nio:ls.ny of
    the effects of smoking on 1rS.4 cont<nt of human tesliir~rot-y epi-
    thelium. Cancer 21 16) : ll::Z-I 1::6. June 1968.
(~`27) Rorfr. Lt., OPPENIIEISI, I-\.. i%~DlUCr;SDs. 1). T. t)S&,l,yrr,,lrnt ciy,.
    binding by oral epithelium. Its relation to smoking habits. .Archives of
    Environmental Hcnlth 17( 1) : 59-61, July l'JG8.
(225) ROYAL COLLEGE OF Pt<~stcr~~s. .~ir p~llutioll and Iic:,lth. S~,,i,,,ary am)
    Report on Air Pollution and Its Effect on Ifealth. Ry the Comnl;ttce of
    the Royal College of Physicians of l.ondon on Smoking rind Atmos-
    phcric Pollut&l. Pitman Mctlical and Scientific Publishing Co., I.trl.,
    London, 1370. SO pp.

(229) ROZEh-WLDS, J. G. Carcinoma of the larynx anil hypopharynr in South
    Australia 1352-1966. bledical Journal of Australia 2((i) : t'-)4-?:9,
    August 5, 1367.

(230) RUNECKLES, V. C. Natural radioactivity in tobacco and tobacco smoke.
    Nature X91(1786) : 322-:125, July 12. 1961.
(231) SACCOMAN~GO, G. Radiation exposure of utnnium miners. U.S. Cotigress.
    Radiation Standards for Ui-anium Mining. Hearings before the Sub-
    committee on Rcsea~ch, Development, and Radiation of the Joint
    Committee On Atomic Energy, Congress of the Unitcil Stntcs. 91st
    Congress, 1st Session, March 17. arId 18. 1969. pp. ~01-315.
(_OYZ) SADOWSKY, D. A., GILLIAM. A. G., CORSFIELD, J. The statistical assaci:t-
    tion between smoking and carcinoma of the lung. Journal of the Sa-
     tional Cancer Institute 13: 1237-1~58. 1953.
(233) SAFFIOTTI, U. Esperimental respiratory tract carcinogenesis. Progress
    in Experinlental Tumor Reseal-ch 11: 303-333, 1969.
(254) SAFFIOTTI, U. Experimental rcsliiratory tract carcinogcnwis and its
    relation to inhalation exposures. IS : Hanna. >I. G., Jr., Srtte<heim.
   P., Gilbert, J. R. (Ilditors) Inhalation Cal cinogenesis. Proceedings of
   a Biology I)ivision, Oak Ridge Sational Laboratoi-y Confewnce,
   Gatlinburg, Tennessee, October 8-11, 1963. U.S. Atomic E~rergy Com-
    mission Symposium Series 18, April 1970. pp. 27-54.
(235) SAFFIOTTI, U., CEFIS, F., Ko~n, L. H. A method for the esperimental
   induction of bronchogenic carcinoma. Cancer Research 28 (1) : 101-
    124, January 1968.

(236) SAFFIOTTI, U., CEFIS, F., MONTESANO, It., SELLAKUMAR, A. R. Induction
    of bladder cancer in hamsters fed aromatic amines. Chapter 10. Ih':
   DEICHMANN, W. B., LAMPE, K. L. (Editors) _ Rladder Cancer. Proceed-
   ings of the 5th Inter-American Conference on Toxicology and OCCUPY-
   tional hledicine. Coral Gables, University of .\Iismi, School of .1Iedi-
    tine, 1967. pp. 129-135.

(237) SAFFIOTTI, U., CEFIS, F., SHU~IK. P. Histopathology and histogenesis of
   lung cancer induced in hamsters by- carcinogens carried by dust par-
   ticles. In: Severi. L. (Editor). Lung Tumors in Animals. Peru&,
    Ui\rision of Cancer Research, University of Perugia, June 1966. pp.
     537-546.

(~$8) SALLEY, J. J. Experimental carcinogenesis in the cheek pouch of the
   Syrian hamster. Journal of Ilental Research Z(2): 253-262, April
      1954.

(239) SALLEY, J. J. Smoking and oral cancer. Journal of Dental Research 42
    (Supplement to NO. 1) : X8-339, 1963.

340


(240) SAXDERUD, K. Squamous metaplasia of the respiratory tract epithelium:
    A" autopsy study of 21-l cases. 2. Relation to tobacco smoking, OCCUPY-
    tion, and residence. Acta Pathologica et Jlicrobiologics Scsndinavica
     43(l): 47-61, 1358.

(,oI+z) S,~NGIIVI, I.. D.. RAO. K. C. >I.. KHAXOLKAR, V. I?. Smoking and chewing
    of tobacco in relation to cancer of the upper alimentary tract. British
    Medics1 Joul-nal 1: 1111-1114. May 7, 1955.
(24-o) SCHARIRE, E.. SCHOSICFB. E. Lungenkrebs und Tabnkverbrsuch. (Lung
    cancer and smoking.) Zeitschrift fiir Krebsforschung 54: X1-269,
      1943.

(z~.?) SWLECEL, J. U., PIPKIN, G., B,\SOWSKY, L. Urine composition in the
    etiology of bladder tumor formation. Journal of Urology 9'7(3) : 4'79-
     481, March 1967.

(244) SCHLECEL, J. U., PIPKIN, G. E., NrsrirhluRA. R.. DUKE, G. A. Studies in
    the etiology and prevention of bladder carcinoma. Journal of Urology
    101(3) : 317-324, March 1969.

(245) SCHLEGEI., J. U., PIPKIN, G. E., SHULTZ, G. N. The aetiology of bladder
    turnout-s. British Journal of Urology 41(F) : 718-723, December 1969.
(S~G)SCHREK, R.,BAKER,L.X., BALLARD,G. P., DOLGOFF, S. Tobacco smoking
    as an etiologic factor in disease. I. Cancer. Cancer Research 10: 49-58,
     1950.

(947) SCHWARTZ, D., DENOIX, P.-F. L'enquette francaise sur I'Gtiologie du can-
    cer broncho-pulmonaire. Role du tabac. (French investigation on the
    etiology of bronchopulmonnry cancer. Role of tobacco.) Semaine des
    Hopitaux de Paris 33 (62/7) : 3630-3643, October 30, 1957.
(248) SCHWARTZ, D. I)EXOIX, P.-F., AMXJERA, G. Recherche des localisations
    du cancer associees aus facteurs tabac et alcool chez l'homme. (Rc-
     search on the localizations of cancer associates with tobacco and alco-
    holic factors in man.) Bulletin de I'Xssociation Francaise pour I'Etude
    du Cancer 44: 336361, 1957.

(24.9) SCHWARTZ, D., FLAMAST, R., LELI.OIJCM, J., DENOIX, P.-F. Results of a
    French survey on the role of tobacco, particularly inhalation, in dif-
    ferent cancer sites. Journal of the National Cancer Institute 26 (5) :
    fO8.S1108, hlay 1961.

(2.50) SEC:, hf., FUKUSXXIMA, I., FLJJIS~KU, S., KURIHARA, hI., SAITO, S., ASANO,
    K., KAXIOI, XI. An epidemiological study on cancer in Japan. The
    report of the Committee for Epidemiological study on Cancer, Spon-
    sored by the Ministry of Welfare and Public Health. Gann 48 (Sup-
    plement) : April 1957. 63 pp.

(251) SELIKoFF, I. J. BmDER, R. A., BADER, M. E., CHURG, J., HAMMOND, E. C.
    Asbestosis and neoplasia. American Journal of hledicine 42(4) : 487-
    496, April 1967.

(252) SELIKOFF, I. J., NaMMOXD, E. C., CHURC, J. Asbestos exposure, smoking,
    and neoplasia. Journal of the American hledical Association 204(2) :
    106112, April 8, 1968.

(252) SERFOXTEIN, W. J., HURTER, P. Nitrosamines as environmental carcino-
    gens. 11. Evidence for the presence of nitrosamines in tobacco smoke
   condensate. Cancer Research 26(4, Part 1) : 575-579, April 1966.
(254) SERFOHTEIN, W. J., SitfIT, J. H. Evidence for the occurrence of N-nitros-
   amines in tobacco. Xature 214(5084) : 169-170, April 8, 1967.
(255) SHANTA, V.. KRISHNAMURTHI, S. Further studies in aetiology of ear-
    Cinemas Of the upper- alimentary tract. British Journal of Cancer
    17(l) : 8-23, March 1963.

341


(256)

(57)

(258)

(259)

(260)

(261)

(262)

(263)

(264) STOCKS, P. Recent epidemiological studies of lung cancer mortality,
    cigarette smoking and air pollution, with discussion of a new hypothe-
    sis of causation. British Journal of Cancer 20(4) : 595-623, December
     1966.

SHASTA, I'., I;RISIlSAIICRTtll. S. Fult'ncr studies in etiology of car-
cinomas of the upprr alimentary tlact. Acta; Unio Internz.tionalis
contra Cancrum `LO: 586-534. 1964.

SIL\~ERMAN. S., JH., G,ILASTE. 51. Oral Cancer. University of California,
San Francisco .\Irdical Center, January 1370. 56 pp.
SPAIN, D. M., BRADESS, V. A., TARTER. R., MATERO. A. Metaplasia of
bronchial e[)ithclium. Effect of age, sex, and smoking. Journal of the
American Medical Association 311(8) : 133X-1331, Fcbwary 23, 1970.
ST,CZZE\VSKI, J. Palenie a rak wargi, jamy ustnej, migdalkow i krtsni.
(Tobacco smoking and its relation to cancer of the mouth. tonsils and
larynx.) Nowotwory lO(2) : 121-132. 1360.
STASZEWSKI, J. Palenie tytoniu a rzik l)rzelyku i zoladka oraz choroba
wrzodowa. (Smoking and its relation to carcinoma of the upper diges-
tive tract (esophagus and stomach) and to peptic ulcer.) Polski
Tygodnik Lekarski 16( 16) : 287-292, May 4, 1960.
STASZEWSKI, J. Smoking and cancer of the urinary bladder in males in
Poland. British Journal of Cancer 20( 1) : 32-35, March 1966.
STEDMAN. R. L. The chemical composition of tobacco and tobacco smoke.
Chemical Reviews 68 (2) : 153-207, April 1968.
STOCKS, P. Cancer incidence in Xorth Wales and Liverpool region in
relation to habits and environment. British Empire Cancer Campaign
Annual Report 35 (Supplement to Part 2) : 66-35, 1957.

(265) STOCKS, P., CABIPBFLL, J. M. Lung cancer death rates among non-
    smokers and pipe and cigarette smokers. British Medical Journal 2:
    923-929, October 15. 1955.

(266) SUGIURA, Ii. Experimental production of carcinoma in mice with cigar-
    ette smoke tar. Gann 47(2) : 243-244, June 1956.
(267) SUNDER%fIAN, F. IV., DONNELLY, A. J. Studies of nickel carcinogenesis
    metastasizing pulmonary tumors in rats induced by the inhalation of
    nickel carbonyl. American Journal of Pathology 46(6) : 1027-1041,
     June 1965.

(268) SUXDERMAN, F. W., DONNELLY, A. J., WEST, B., KINCAID, J. F. Nickel
    poisoning. IX. Carcinogenesis in rats exposed to. nickel carbonyl.
    A.M.A. Archives of Industrial Health 20(l) : 36-41, July 1959.
(269) SUNDmhuN, F. W., KINCAID, J. F., DONNELLY, A. J., WEST, B. Nickel
    poisonjng. IV. Chronic exposure of rats to nickel carbonyl. A report
    after one year of observation. A.M.A. Archives of Industrial Health
    16(6) : 480-485, December 1957.

(270) SUNDEX~~AN, F. W., SUNDERMAN, F. W., JR. Nickel poisoning. XI. Impli-
    cation of nickel as a pulmonary carcinogen in tobacco smoke. American
    Journal of Clinical Pathology 35(3) : 203-209, March 1961.
(271) SVOBODA, V. An analysis of some possible epidemiological factors in-
    volved in carcinoma of the larynx. Neoplasma 15 (6) : 677-684, 1968.
(272) TXANO, K.. OSOCOSHI, K., KAhIIhlURA, N., K~NDA, K., KANE, K.,
   KAMIYAMA, R., SAKAhroro, K., SATO, H., SHIRAI, Y., SEI, RI., TANABE,
    T., HORINO, BI., MmAhlI, Y., MOTOJI, H., MORITA, H., OKIHATA, H.,
    HIKAYAMA, T. Shokudogan no ekigaku, toku ni atsui inshokubutsu,
   inshu, kitsuen narabi ni eiyo ketsuho ni tsuite. (Epidemiology of can-
    cer of the esophagus.  with particular reference to the effect of hot

342


(275) T~IAI-CR, P. S., KESSLER. C. J. Cigarette smoke: Charcoal filters reduce
    compownts that inhibit o *Tl.o\vth of cultured humnn cells. Science 1.16
     f3i-l-l) : G-I?-641, October .?I), 1364.

(_7;6) TIIORARISSSON, H., H.XLLGRIJISSOX, d., BJAKS,~SO~, O., PETERSEN, G.
    Carcinomn of the lung in Iccl~~nd. Disesscs of the Chest 52(6) : `is&
    759, Ikcemher 19GS.

(~77) TI~TOS, 0. L., CKOCKER, T. T. Duration of bronchial squamous meta-
     Ill;1ii:l I)rodurwl 111 cl<~.ci hy riz;lt ctte smoke rontlcn~~tc. JOUI-nnl of the
    S:ltional Cancer Institute X1(?.) : 487-495, September 1964.
(1'73) TYLETOTE, F. E. Cz~ncer of the lung-. Lancet 2: `X6-2J$, July 30, 1927.
(27~~ U~IIKER, IV., STO~GX. C. Bronchn:enic c3~cinonla-in-sillc. Report of n
    cnsc \vith ilositix-e hiopiy, cytoloyqical e\aminntion, 2nd fobectomy.
     Cancer S(P) : :X-:74, Jlarch 1352.

(-!a~) K.S. I)EFIRTMWT of HXALTH. EDUCATION. ASD ~VELFAIIE. Report of the
     Secrctzry's Comrnis~icn  on Pejticidps` and Their Relationship lo
    En\-ironmental Health. [Vnshington, U.S. Dcpal-tment of Health, Edu-
     cation. 2nd 15'elfnrc. L)ecemher 1969. 677 pp.
(-751) U.S. P~BI.I~ HEALTH SERVICE. SATIOS \I CCSTFX FOR HCALTII ST-\TIS-
     TICS. Changes in cigarette smoking habits betivecn 193; and 1966.
     \t'a;hingon, U.S. Ircpn~ tn!cnt of Ht~3lth, Eductltion, and Welfare.
     Vital nnri Ht~alth St:ctiitici Series IO. Numiw~ .,9, Pul,lic Health Serv-
     iv. Publ:catlon So. lW0, XpI,il 1970. 33 p)I.
I?S_7) KS. P~.CLIC H~ALTI~ Scrtxrw. SITIOSAL CESTI:R FUR HEALTII STATIS-
    TIC.5 IIor-tnfity from :listcl;es aP:ocintctl with :tnokiflg: C'llitetl States,
     I!).;cI-(;~. IV;l:hinxtnn, L.S. Jk!l:trtntent of Health, Education, and
    Welfare, \`itnl and Health Statistics Series 20, Ko. 4, Public Health
    &l-vice Publication So. 1000, October IWiG. 45 pp.
(283) U.S. PI~RLIC HEALTIf SERVICE. NATIOXAL CEXTER FOR HEALTH STATE-
     TICS. \`ital St~ti~tlcs of the united Stzttes--1961. Vol. II-AIortality,
    Part A. IVashington, U.S. Ikpartment of Health, Education, and Wvcl-
    fax, Public Healrh Service Publication, 1964.
(28:) U.S. Pr-ULIC HEALTI~ :F:RVICE. NATIOXAL CENTER FOR HEALTI~ STATIS-
    TICS. \-ilsl Stnti-tics of the L'nitecl States--1962. Vol. II--3Iortality.
    Pnrt A. \Vashln$on, U.S. Ueprtrtment of Health, Education, and Wel-
    fare, Public Hraith Selyice Publication, 1964.
(253) U.S. P~ELIC HEALTH SERVICE. NATIONAL CESTER FOR HEALTH STATIS-
    TICS. 1.ital Stati,ticj of the UnIted States-1963. Vol. II--,\IOrtalltY,
   Part .A. ~Voshin;ton, II.S. Ikpnrtment of Health, Education, and Mel-
    fare, Public IIeal:h Service Publication, 1965.
(z&s) U.S. Pt-BLIC HEXLTII CUWCE. K.~TIOSAL CENTER FOR HEALT~I STATIS-
    TICS. Vita] Statistics of the United States--1964. Vol. II->Iortalits,
   part .A. ivashrngton. C.S. Iwpnrtnmt of lldth, Etlucstion, and Wel-
    fale, Public Health Se-r\-ice Publication. 1366.
(~8;) U.S. PUBLIC HEALTF~ :ERWX. SATIONAL CESTER FOX HEALTII STATIS-
    TICS, Vital Statistics of the United States-1965. Vol. II--JlortalitY,

343


     Pzrt -1. Washington, U.S. Department of Health, Education, and Wel-
      fare, Public Eiealth Service Publication. 1967.
(289) U.S. PUBLIC HEALTH SERVICE. NATIONAL. CESTER FOR HEUTI[ STATIS-
     TICS. Vital Statistics of the United States-t966 1'01. II--.\fortatity,
     Part -1. Washintwn, U.S. Department of Health, Education, anti \Vel-
      fate, Public Health Service Publication, 1068.
(989) U.S. PVBLIC HEALTU SERVICE. NATIONAL CESTER FOR HEALTU STATIS-
     TICS. Vital Statistics of the United States--1967. Vol. II-Mortality,
     Part X. Washington. U.S. Department of Health, Education, and IVcl-
      fare. Public Health Service Publication, 1969.
(290) U.S. PI+%LIC HEN.TH SERVICE. NATIOXAL CENTER FOR HEXLT~? STATIS-
      TICS. Vital Stattstics Rates in the United States 1940-1960. Wash-
     ington, U.S. Department of Health, Education. and \Velfare, Public
     Health Service Publication No. 1677, 19G8. 881 pp.
(-091) U.S. PLXLIC HEALTH SERVICE. Smoking and Health. Report of the Ad-
     visory Committee to the Surgeon General of the Public Health Service.
     W'ashington, U.S. Department of Health, Education, and Welfare,
     Public Health Service Publication No. 1103, 1364. 387 pp.
(232) VALKO. P. Koureni a vyskyt zhoubnych novotvntu hrtanu. (Smoking and
     occurrence of malignant tumors of the lar);rrx.) Ccskoslovenska
     Otolaryngologie 1: 102-105, 1952.
(293) VAS DCfREN, B. L. Tobacco carcinogcnesis. Cancer Research 28(11) :
      9757-236Z, Sorember 1368.
        -3
(295) V;.as L)L'CREx, B. L., SIVA~;, A., LANGSETH, L.. GOLDSCHXIDT, 8. M.,
     SEC~L, A. Inltintors and promoters in tobacco carcinogenesis. IN;
     IVynder. E. L., Hoffmann, D. (Editors). Toward a Less Harmful
     Cigarette. Bethesda, U.S. Public Health Service, National Cancer In-
     stitute JIonogrnph So. 23, June 1366; pp. 173-180.
(295) V;\r DUUREN, B. L., SIVAK, A., GOLDSCH~IIDT, B. &I., KATZ C.,
     ~IELCHIONNE, S. Initiating activity of aromatic hydrocarbons in two-
     stage carcinogenesis. Journal of the National Cancer Institute 44(5) :
      1167-1173. May 1370.
(296) V.as DGUREN, R. L.. SIVAK, A., SEGA~A., ORRIS, L., LANCSETH, L. The?
    tumor-promoting agents of tobacco leaf and tobacco smoke condensate.
     Journal of the National Cancer Institute 37(4): 513-526. October 1966.
(297) VJS~EXS, R. G., M~RCIWTTA, F. The relationship of the use of tobacco
     and alcohol to cancer of the oral cavity, pharynx or larynx. American
     Journal of Surgery 106(3) : 501-505. September 1963 .
(298) \-OCLER, W. R., LLOW, J. W., MILMORE, B. K. A retrospective study of
    etiological factors in cancer of the mouth, pharynx, and larynx. Can-
                                                      -.
     cer 15(Z) : 246-258. March-April 1962.
(299) WAGOSER, J. K., ARCKER, V. E., CARROLL, B. E., HOLADAY, D. A., LAW-
    RESCE, P. A. Cancer mortality patterns among U.S. uranium miners
    and millers, 1950 through 1962. Journal of the National Cancer fnsti-
    tute 3'1(4) : `787-801, April 1964.
(300) !VAGOSFX. J. I<., ARCHER. V. E., LUSDIN, F. E., JR., HOLADAY, D. A.,
    LLOYD, J. W. Radiation as the cause of lung cancer among uranium
    miners. New England Journal of hfedicine 273(4) : 181-188, July 22,
      1965.
(JOI) WACOSER, J. K., MILLER, R. W., LUNDIN, F. E.. JR.. FRAUMENI, J.`F., JR.,
    HA~J, 31. E. Unusual cancer mortality among a group of Ut&TgrOUll(~
    metat miners. New EngLand Journal of, Medicine 269(G) : 361-289,
     August 8, 1963.

344


(SOP) W~HI, P. N., KEH.UI, Cr., LAS~IRI, B. Factois influencing oral and oro-
    pharyngeal mncers in India. British Journsl of Cancer 19(4) : GAL'-
    660, December 1965.
(303) ~AINCHOW, S. ;\I., Hans. D., IKARD, F. F. Dosap? p!ttcrns of ci&nrettc
    smoking in American adults. American Journal of Public Health and
    the Nation's Health 58(l) : 54-70, January 196s.
(304) WASS~NK, W. F. Ontstaansvoor\~aar-den voor 1ongkanl;er. (Conditions
    for the origin of lung cancer.) Nederlands Tijdschrift voor Genees-
    kunde 92 (46) : 3732-3747, November 13, 13-18.
(305) WATSON;, W. L., CONTE, A. J. Smoking and lung cancer. Cancer `i(2) :
    245-249, March 1954.
($06) ~VEIR, J. AI.. DUNN, J. E., JR. Smoking and mortality: A prospective
    study. Cancer 25 (1) : 105-112, January 1970.
(307) WEISBURGER, J. H., WEISBURCER, E. K. Tests for chemical carcinogens.
    IN: Busch, H. (Edito:-). hlethods in Cancer Research. New York,
    Academic Press, 1967. pp. 307-398.
(306) WICKEN, A. J. Environmental and Personal Factors in Lung Cancer and
    Bronchitis Mortality in Northern Ireland, 19GO-62. London, Tobacco
    Research Council, Research Paper No. 9, 1966. 84 pp.
($09) WILLIAMS, >I. J. Extensive carcinoma-in-silu in the bronchial mucosa
    associated with two invasive bronchogenic carcinomas. Report of case.
    Cancer 5(J) : `740-747, July 1952.
(310) WYNDER, E. L., BROSS, I. J. A study of etiological factors in cancer of
    the esophagus. Cancer 14 (2) : 389413, March-April 1961.
(311) WYKDER. E. L., BROSS, I. J., CORPI'FIELD, J., O'DONNELL, W. E. Lung can-
    cer in women. A study of environmental factors. New England Jour-
    nal of Medicine 255(2-f) : 1111-1121, December 13, 1356.
(312) WYNDER, E. I,., BROSS, I. .I., DAY, E. A study of environmenta factors in
    cancer of the Iai-ynr. Cancer 9(l) :86-110, January-February 1956.
(313) WYNDER, E. L., BROSS, I. J. FELDXA~;, 1~. IhI. A study of the etiologiral
    factors in cancer of the mouth. Cancer 10 (6) : 1300-1323, November-
     December 195'7.
(314) WYXDER. E. L., CORNFIELD, 3. Cancer of the lung in physicians. New
    England Journal of Medicine 248 (11) : 441444, RIarch 12, 1953.
fJf5) WYNDER, E. L., Dow, H., B~ocrr, D. A., GAXTT, R. C., MOORE, 0. S.
    Epidemiologic investigation of multiple primary cancer of the upper
    alimentary and respiratory tracts. Cancer 24 (4) : 730-739, October
     1969.
(316) WYNDER, E. L., GRAHAM, E. A. Tobacco smoking as a possible etiologic
    factor in bronchiogenic carcinoma. A study of six hundred and eighty-
    four proved cases. Journal of the American Medical Association 143
    (4) : 329-336, May 27, 1950.
($17) WYNDER, E. L., CRAHASI, E. A., CRONINCER, A. B. Experimental produc-
    tion of carcinoma with cigarette tar. Cancer Research 13: 855-864,
     1953.
(118) WYNDER, E. L., GRMIAM, E. A., CROXINCER, A. B. Experimental produc-
    tion of carcinoma with cigarette tar. II. Test with different mouse
    strains. Cancer Research 15: 445-448, 1955.
(319) WYNDEZR, E. L., HOFFMANN, D. Tobacco and Tobacco Smoke. Studies in
    Experimental Carcinogenesis. New York, Academic Press, 1967. 7.X
      PP-
(320) WYNDER, E. L., HOFFMANN, I). Experimental tobacco carcinogenesis.
    Science 162(3856) : 862-871, November 22, 1968.

                                       345


(~21) WY~ER, E. L., HOFFXAX~, D. A study of tobacco carcinogenesis. K.
    Tumor promoting activity. Cancer 21(Z) : 2S9-.X1. -August 1365.
(3%) \VYNDER, E. L., IIL'LTBERC, S., Jacosssos. F.. BROS:. 1. J. En\-ironmental
    factors in cancer of the upper alimentary tract. ;\ Sxvedish study with
    special reference to Plummer-Vinson (Paterson-Kelly) syndrome.
    Cancer lO(3) : 17@487, May-June 1957.
(.%?3) WYKDER, E. L., KOPF, P., Z~LER, H. A study of tobacco carcinogenesis.
    II. Dose-response studies. Cancer lO(6) : 1193-1200, Sovembcr-De-
     cember 1957.

($24) WYSDER, E. L., Mavsucu, K., BEATTIE, E. J., JR The epidemiology of
    lung cancer. Recent trends. Journal of the Xmerican Medical Associa-
    tion 213 (13) : 2221-2228. September 28, 1970.
(S25) WYXDEB, E. L., NA\-AMETE, A., AROSTEGUI, G. E., LLAJIBES, J. L. Study
    of environmental factors in cancer of the respiratory tract in Cuba.
    Journal of the National Cancer Institute 20(4) : OS-6i3, April 19jS.
(328) WYNDER, E. L., OXDERDOSK. J., MANTEL, N. -Xn epidemiological investi-
   gation of cancer of the bladder. Cancer lfi(11) : 1388-1407, Xovcmber
     1963.

($27) WYNDER, E. L., Tncrrcnr, K. T., BADEN, V., HOFFXCS. D. Tobacco car-
    cinogenesis. IS. Efect of cigarette smoke on respiratory tract of mice
    after passive inhalation. Cancer 21(l) : 131-153, January 1968.
(3%) WYXDER, E. L., WRIGHT. G. X study of tobacco carcinogenesis. I. The
    primary fractions. Cancer 10(Z) : 25j-271, Xarch-.Aliril 1957.
(Yap) YOSHIDA, O., BROWN, R. R., BRYAN, G. T. Relationship bet\\-een trypto-
    phan metabolism and heterotopic recurrences of human urinary blad-
    der tumors. Cancer 23(4) : 773-760, April 19;6.
(830) YOSHIDA, O., hIIY&AwA, >I., HMMDA, T., OI(~A, K. Bokogan no ekigaku
    ni okeru mondaiten. (Some aspects of the epidemiology of urinary
    bladder cancer.) Nippon Rinsho 26(8) : 1850-1854, August 1968,

346


347



TALILE A3.- Oullinc o/ ttletilods wed in retrospective slItdies of s7ttokitig i7i wlntion LO Ilorg C(I7ICL'I' (COtll.)

Doll and
Hill,
1952.
Greet
Britain
(73).

M-F

1,466 psticnta with lung ce.new   I.465 patients in VJTIC hospitals, matched by   ~ersunnl interviews of cases and controla by
in hospitals of 1cvcr~1 cities.    sex arid age group: some wilh cancer of    almonen.
                     other sitcs. some without c~nccr.

Sadowaky
et al.,
1963.
U.S.A.
(ZSP).

M     411 patients with lung cnncer   616 patients in ~arne hospitnb with illnesses  ~orsonal questioning by trained intcrviwcrn.
      in hospitals in 4 states.        other than cancer.


Wyndcr and
Cllr"llCld,
1053.
U.S.A.
(314).

M

G3 physicinn reported in AMA   133 vhysicinns of same group dying of can-   Mail qucationnnire to eutntca of dccnlcnta.
Journal *a dYlnR or CDnCcr of    ECT uf certain other sites.
the lung.

Lickint,
1163.
Grrmany
(170).

hl-F




W
ul


                          hlnlcs                                     Fcmnlcs

Author.          CO\C3               Controls                    CilYC3              Cunlrols
  ycnr.                                        Rclntive                                     Rcliitivc Cumrncnta
rrrcrc"rc         I'r,rcrnt  rrrccnt         rcrccnt Percent   ritlk                           rcrccnr Pcrccnt   risk
               I,,`".   hrnvy          non-   hcitw    ratio    Pr1crnt 1y;t
                                                         "Cl". /             ll"n-   hcaw   wtiu
        Number  snrukvrs rmx,kcrs' Number  smokers smokers1 Sht:NS Number smokrrs smokers' Number  emokcn, smokers' SM:NS'

miiih,        RG     3.5    G5.1      86    1c.3    36.0     `5.4     (`)     (1)     (1)     (`I     (`I     (`I    .
1939 (196).

Schnircr nnd    OR     S.?    31.2     270    16.0     9.3     lG.7     (`)     (1)     (`1     (`)     (`)     (`)    I6 fcrn,~lc
Schunlccr.                                                                           CDII(LY nr4t
1943 I?IP).                                                                           Rllnl) LL.II

Potter and      43     7.0    30.2    2.RO4    26.0    23.0     14.1     (1)     (`)     I')      (1)     (`1     (`I     .
Tully.
1945 (?I.").

Milla end      444     7.2          430    30.L .I.     6.7     I')     i')     I'1     I')     I')     I')
r'urlrr.
1950 (186).

Wrndcr nnd    605     1.3    51.2     7HO    14.G    19.1    13.0     40    57.5    25.0     552    71.6     1.2    2.!,
Crnhnm.
1350 (JJ6).


hl<C"llllCil      03     5.4    38.G     18G     G.5    23.2     1.2      7    Gl.l           14    78.G     2.h
r,1 nl.,
I!,52 (IBO).

                                                                           _._.. -..-_
Sndowky      477     3.x     ,I,     GIG    13."     ,,,     3.1     (`1     (1)     (`)      (`1     (1)     (`) ,. I;li\ili,~n,
,`I III,,                                                                           \, /!I, ,,III"II,>,
I*J5R ("3:).                                                                           rr!,wh,~il.
                                                                           ---- _-_.--._
WYntlcr and     GR     I.1    C7.G     133    20.G    23.3     `C.l     (1)     (`1     (`1     (`1     (`)     (`I ,..
Curlblirld.
1:15:1 ,314).

~-
Kuulumtcs     HI2     0.0    GR.`)     300    18.0    25.0    3c.o     ,                (`)     (`I   (`) ,~,-------
1053 (121,.

LickinL                                                                           - _-.
          2'2 4     1.8    36.X    1,000    lC.0     4.n    `10.1      22    G 1.0     66    1,002    00.4     0.1    5.3
IV53 (170).


Ilnndic.      415     1.2    34.2     381     6.8    17.9     35.1     33    51 G     3.0     131    70.3      0    2.2
l'J54 (.'IS).



Cellond cl ul..   32     G.3           32    c3.0         `26.3    (`I     (1)     (0     (1)     (1)     (1)    
1065 19x1.

-
\Vyncicr ct al.,  210     1.4    67.5     420    21.0    40.`)    220.8    30    lG.7    14.0     13?    57.6    23.3    6.78  li~ni~


TABLE A?`-Grouping of pulmonary carcinomas

Group I:

A. Epidermoid carcinoma.
B. Small cell nnaplastic carcinomn ("oat-cell" carcinoma).

Group II:

A. Adenacarcinoms.
B. Bronchi&-alveolar cell carcinoma.
C. Carcinoid tumor.
D. hlucous gland tumor.

Extra (not included in I and II):
  A. Large cell undifferentiated carcinoma.
  B. Combined epidermoid and sdenocsrcinama.

Un.uitab!e for diagnosis.

360


Little et al.,                               Po"' 1rrcLt in vorioue liaaucr (PC/g tissue)             Vcrlcbral budicY. rcnul
1961.                            Pcribronchia!                             Bronrhinl      eorlcx. spleen and
U.S.A. (173).                       lymph mdcr         Lung (nvcrogc)           rpilhclzutn      ur,n,iry Lloilllcr stliiwcd
              NS ,. . . . 6       0.011              0.001-Z              nrglisiblc
              SM                                                               no dificrencrs.
                 . . . . . . . . . . . ..12       0.011              0.00s               0.028-I .2G


TABLE AlZ.-Autopsy studies concerning the presence of radioactivity in the lunga of smoker8 (cant,)
                         NS = Nonsmokers.    SM = Smokers.

Ferrl end                             Nran Pa"@ htlr in various ttbs~ca (PC/~ wet hue)
Bnratta,                             LUW              Liver             Kidney
1866,           NS  , ,. ,,,,.... . ..lO        0.031              0.103              0.080
U.S.A. (98).       SM  . . . . . . . * . . * . * .14        0.066              0.126              0.070

Rajewasky and
StAhlhOfWl.
1966,
Canmy (927).

                        hfoan PdlO levela in various ltiruo (PC/g)            tData not given. Smokcrn
               Lung narrnchyma       Uronchid trrrr     Bronchial bijurcution      were connldcrcd those
NS . . . . . . . . . . . . . . . t         0.0026             0.0020            0.0012          using more than 1 pack
SM  .*. . . . . ,, ., . ..I2         0.0078             0.0017             0.0047          P dnu.
                                                             The authora noted tbht
                                                               thclr tln~rcs were con-
                                                              nldcrablu nm.sller tbhn
                                                                thoak! of LItlIe et al.
                                                            (27~. 171) and alao
                                                              dianereed with tbel?
                                                                data on bilurcatlon.

Rsdford,
1967,
U.S.A. (17)).

SM  ............. .zs

Plpe  ............. 2
Ex-ekarttte  .. , ... 1
Never  ............ 8

Bronchial wall snd aubmucoaa         .: ..;.
                  ..................    .......... 0.004
Bronchial epithelium:
Trachea  .................................................... 0.120
Lobar bronchi ............................................... 0.190
Segmental bifurcalion  ....................................... 4.soo


Wynder    CAFt mice  A. Painting shaved skin.
ct .I,             II. Jiwcck fur 2 years.
1963.             C. Whole cigarette smoke
U.S.A.                condensate in acetone.
(317).                Croton oil oncc/wcek.

PBlSCY      5 different   A. Painting unshaven
CL al..      rnO"IC       akin.
1955.       Strains    IJ. Z/week for 9
England     (101).       months.
(109).             C. Whole "tar" or
                    neutral fraction.

w
Q\
w


     TABLE A13.-Expetimenta concerning the ejects of the skin painting or
subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cmt.)

Author.
year.
country.
rcfcrcme

Anlmrl
and
strain

Commcn*a

Wynder
et A,
1966.
U.S.A.
(316).

Author.    Anlmrl    A. Method.
                A. Method.
  year.      and    B. Frequency and/
               B. Frequency and/
country.     strain       or dur~tio".
                    or dur~tio".                              Resultd
                                                        Resultd                           Commcn*a
rcfcrcme           C. Material
                 C. Material

Wynder     Mice of 4
        Mice of 4    A. Painting shaved skin.
                A. Painting shaved skin.       Sfrain
                                     Sfrain                     PopiUoma4
                                                          PopiUoma4    Corc~a
                                                                        Corc~a     No tumor8 noted with
                                                                           No turrrora noted with
et A,       acparste
          acparste   ll. Z./week for 80 days.
                ll. Z./week for 80 days.        C57BL . . . , . . . . . .
                                    C57BL . . . , . . . . . .    lo/89
                                                                10/89        2/89
                                                                          2/89         aectune alone.
                                                                           aectune alone.
1966.       straina.
          straina.   C. Whole condensate
                C. Whole condensate         Swiss
                                    Swiss . . . . . .
                                        . . . . . .    22/86
                                                               22/86       12/86
                                                                         12/86       strwsea
                                                                           strwsea
U.S.A.                I" ~EClO"C.
                    I" ~EClO"C.                                                            diRcrcncc8 in
                                                                           diRcrcncc8 in
(316).                                                                           susceptibility of
                                                                           susceptibility of
                                                                           strain.
                                                                           strain.

Hamar and   Outbrrd    A. Plintlng unshaved
WOOdhOUW,   albino       skin.
1966.       8trfiin    B. Varied for 18 months.
U.S.A. mice. C. Whole "tar"/scetone.
(IJU).               IJenrLJyrene [D(a)Pl,
                    crotun oil.

   Trcalmmt:              P4piUomor
"Tar" P/week . .     l/60
"Tar" and etoton oil l/week. . . .    2130
B(a) P 3 times then "tar" `2/wwk    4130
ll(n)l' 3 time . . . . . . . . . . . . . . . . .     o/30


  Author,  A22"'    A. Method,
  yrnr.           Il. Frn,,wncy and/
  country,     atrrin       or durntion,                              Rcnulb                           Commcntd
rcfcrc"ca           C. hlntrrinl

Wyndcr     Swh mice   A. Pnintina skin.                                         Percrnt      PCKClll
ct ul,,             B. Vsricd for 12         TRblmCnt:                Nnmbcr      pap~llomar carrinmnor
1957,                 months.           S/week  ..,.....,...,,,, ,,,,.     so         12.0          8.0
U.S.A.             C. Whole condensate       Jiweek       50         38.0         16.0
(3?J).                in acetone.          Z/week       40         10.0          30
                                   l/week  ..I     40          ti.0          

Wynder and  CAF, or    A. Painting shaved skin.                                     Percent      PL-rCClll   Swiss mlcc nolcd
Wright,     Swiss    Ll. J/week far lifespan.   Trcalmcnt CAF,:             Xirmbcr      poplllomad carcinomor   ,o br l\lOi-e I",.
1957.       mice.     c. whole "tar" 07 nicotine    Whole "tar"  I.,,     30         53.0         27 .o     rrptiblr.
U.S.A.                free "tar" derived      Nicotine free "tar" , ,, .,     40         73.0         26.0   hlnlorlty of carcino-
(J?Bl.                from pipe and        CiKarelte "tar" .,     30         30.0         30.0     grns noted to br
                  cigarette tobacco.        ripe -tRT'*         30         60.0         20.0     in nciitral fraction
                                  Trcalmc~~t Swiar:                                         of condenrntc.
                                   Whole "tar" ,, ,, ,,     30         63.0         10.0
                                   Nicotine fret "tar" I, ,.     40         43.0         20 0
                                Cignrette "tar" ,,     30         63.0         33.0
                                  Pipe "tar" .,... ,, ,.. .,,     30         63.0         60.0

Celihorn,     Pnris R III  A. Pointing shaved skin.        Trcnlmcnt:                   Fapilfomas    Carcinoma0
1358,       mice     B. Vnricd for l-2 years.         Benrpyrcnc (twice only) _, ,,    20/529       5/%5:9
U.S.A.            C. "Tnr" in acetone.           Cru:on oil (516 wcrk)  .., ._, ,,     4126        O/26
(991.                bcnzpyrene,            "Tnr" 1516 rveck)       3/551       2/5G9
                    croton oil.              Acetone (5,`G \vcck) ,, ._ .,     o/30        O/30

Bock and    Swiss

A. Painting skin.

"Tar" and croton oil (5iG week)    101175       o/175

                                 PCWCtll

     bloore.      female    B. S/week rol. lifespan.     Group:              Number liuirly ot G montha  Skin tumor8 at C4 wcrl;s
     1959.       mice     C. Whole condensate       Painted         4'3
     U.S.A.                                                                      13.0
                        irradiation.         Painted and irradiated         c5              44.0
     (29).                               Irrndiated  I.       36               
w
2


Bock et al..    ICR Swiaa   A. I'alntlna ahtved akin.
19t2.       mice     B. IO/week for 1 year.     Trcritmcnt:
U.S.A.             C. Cigarette "tnr".        Stnndnrd cigarette
(JI).                               Standard cigolvtte
                                  Stnndnrd ciRarcLtc
                               Standnrd ciKnrctte





.



.

Pcrrcnt Skin
neopla0ia
  64.0
  51.0
  44.0
  62.0
  27.0
  23.0

I..

IDGZ.
U.S.A.
(225).




Druckrey and Rnte
Schildbsch.
1063,
Germany
(82).

B. J/week for 84 wcrka.
C. Whole smoke "tar"
   withaddadB(n)P
   in acetone.


A. Subcutaneous
   injection.
B. l/week for 700 dsya.
C. B~IIZDYEYI~ in
   tries rylin.


Homhurscr  CAFi mice   A. Pointing shaved skin.                         (`O,"l,lClC      Pcrccnt       I'CICC7Il
EL al..             11. Z-3/week for 2 years.    Condcnaalc:               Uiit"pSiCS     Pa,"ii"mol    Corcirioirtna
1963.              C. Various tobacco        Pipe tobnccu ,.       77
U.S.A.                                                               35.0         15.0
                   condenantea I"       CiEnr tobacco     Ml         21.5
(IS!,.                                                                          16.0
                    tlCeto"e.          Cianrette tohncco     H2         27.0         lG.O
                                  Uc"zpyrc"c       54         10.0         20.0
                                  Acetone only . . ..I......     G2                    

Bock ct &I.,   Swiw ICR   A. Painting clipped akin.                                                                -
                                                       I'( TCC,IL                  I'crrcnt
1965.       mice     II IO/week for 11 wwks.   Percent conccntrntion of tRr
U.S.A.                                                  aurb,ii,irlg       Pcrrsnt      C"IICCI und
                C. Various smoke          (WPC ciporcttc) :          I I werka
(IO).                                                               c0llrt-I       ~~~:pillomo
                    conaensatee in       9.2 (.3tnndlhrd)              !iLO
                                                             30.0         Gi.0
                    neetone.           8.3 (stnndntd)  ,,..,,,... ..,..    33.0         ?7.0         61.0
                               7.9 (English stsndnrd)  .I,..,..    90.0         24.0         KS.0
                                  8.7 (king)  ,,    100.0         2M.O         CU.0
                                   4.0 (Rltcr)      `IX.0          0.0         36 0
                                   4.4 1 liiter)  ,    100.0         10.0         41.0
                                   2.5 (filler)      07.0          4.0         16.0
                                   Acetone control  . .    94.0          
                                   Untrcstcd cmltrvl  .                          ..I
                                                        100.0                    

Van Duurcn   Swiss ICR/  A. Painting shaved akin.                               Cumulntil'c number 01 mire with  t l.ll-dimclhyl-
et al.,      Ho mice   B. Initinting agent once--   Itrilinlor P'romolcr
  1966,                                                             I'a],iilolriaa    Corcirio,nM   livlir(ll,u"ll~r,lcr"c.
                    Promoter J/week for   DXIUA ,.Ether t(ihaccn lent cxtlnct  ,, ,, ., ,,
U.S.A.                                                              4/20        o/20
                    12-14 months.
  (006).                             0 . . 5. .Ethcr tobacco IrnI exttnct      o/20        O/20
                C. DhlBAt. tobacco      DhlBA . ,Chulorufurm tobacco lcof extract .    l/20        O/?O
                    extrncts cige,.       0 . , . Chuiurolorm tvbncco Ical cxtrnct . , , ,    O/20        o/20
                    rette "tar"        DhlBA ,.Cimrcllc "t,ir"  .~~,,.,...~....,... ..,,    11/:0        4120
                            0 . . . . .CiEnrette "tnr" .., .., ,, ,. ., ,,, .,     o/20        o/20


     TABLE A13.-Ezpcri~r1rnls conccnring the eflccts of tltc skin painting or
subcutuncous injcctiott o/ ciga7.cttc smoke condensate or ifs cans~it~tenls upon animals (cont.)

Author,           A. Method
yrnr,     Animal    u. Frcqucncy and/
CO""LlY,     snd
relersncc              or duration.                             Results                            Commrnla
        slrnin    C. Material

Munaz tt al..  Swiss ICW  A. Painting shaved akin.   Dark tobacco "for"            At risk       TUmOrI     Carcinoma, The aulhura noled
1868,       40. mice   IS. Vnrid.            4.0 percent  ,, ,.     81          50          17     & JtiurlrntYl Intent
U.S.A.             C. "Tar" from dark      8.0 percent  I.. . . .     71          46          1G    gcnud for dark
and                 (Colombian) and     Liohl tobacco for:                                         tutJncev.
Colombia              light (U.S.A.)       4.0 percent  . . , , . . , , ,. . . . ,     95          26           6
(197).                Lobaccoa.          8.0 percent  . . . .     18          64          20
                                 Acetone  , . . . . . a . . , 8.. .     91           0          0
                                                   ._
Davlea and   Albino     A. Pslntlngahaved akin.            Percent of cnrcinama-bearing attimala a( 116 wcckr           Tbe suthurs concluded
DlY,       mice     Il. Varied rcRimrn.           T*CatTtlcl,l:                                        th.t thr lnrk of
1868.                                                (acfual number of animala in porcnthracn)
                C. Cinnrette and                           SOL) mu,     150 mo.      78 mp.    87.3 mu.   diflrrrncc In rc-
Crcrt                cimr condensate.
Uritrln                            Stnndrrd ci~arctte . t , a . . 20.1(20l     13.2(10)     0.7 (1)     . .      tiulta Ircbm the Ant
                                  Ciwr          27.1(31)
(86).                                                                 lI.l(lG)     2.1(3)    and thlrll YFIIODI
                                  Cigar lubacco ciunrcttc           13.9(10)      .       .      u,,dcr trrutmrnt
                                                                           rdvvrata that Ibc
                                                                           lncrrallcd turnuri-
                                                                           weniclly ol cluLr
                                                                           tobrco is duel0
                                                                           physical ~race~lne
                                                                           Iretars.


TILE Al&-Erperimenta concerning the effect of cigarette smoke or itu constituents On tiSSUe and T?an mltU?`Cs

    Author.
    yea*.
    countly,
   rclercncc

Boucbard
and Mw,
1960,
Frmcs (95).

    Tiaaus or
   0rg.n culrurr


Mouse lung.

    Materlal/deUvev


Tobacco amokc condensate
perfusion for 24 hours
and aubseauent
praftinx under renal
capsule of mice.

                     Re_"ltd

Increased number of mitotic abnormalitin In the treated CUhUres; vntiicula*b in
the nrat 6-10 dsra after prafting.

AWS et 81..
1961.
J&pan (la).

Direct exposure to
smoke from:
a. Whole cIgareLLen.
b. Tobacco alone.
e. Paper alone.

Paper smoke Induced the moat scvcre chanpet. conslstin'iz of CYtODlnlmiC VnrJ-
olization and nuclear pyknoais. Alao noted were & decrease in the mitollc index
and an incrcaac in abnormal divirionn, more L)O with paper amoke tbnn With
the other two.

Tharcr and
Kcnaler,
196d.
U.S.A. (276).

KB mammslian
tumor cells.

Cisarctlc smoke
condensate applica-
tion: filtered mnd
untiltercd
cigarettes.

SipniRcanr prowth inhibition was shown In unfiltered smoke. C~tot~xlc COmDD-
nentr were noted in both the pls e.nd particulate phases.

Berwald and
Sscha.
19CB.
Israel (PO).

Cracker ct al..
1965.
U.S.A. (6-J).

SWR mice and
golden hamrter
embryos.


Suckling mt
traches in
oretin culture.

Direct application of
bcnro(n)pyrene
[B(a)Pl.


Application of
U(a)P in acetone.

~rnro(a)pyrcnc caused lncrcastd cell trnnsformatlon M manlfrr!nl by:
a. Ilcrcditary random growth pattern.
h. Prusrnaivc p.rovth 81 tumor8 after rulruLrnevur injection Into adulld.
C, Ability to Bruw continuously in culture.                  ---
Treeled culture, revrolcd cellular mcteplnsia. baanl cell hypcrplaaia, izicwaoryl
mitotic rate, and incrstiard HI-thumidinc incorporntiun pro@ortiun*l to t.bc con*
centration of material and durstinn of spplicatiun.

Dirmond.        Vnriuus con-

Avolication of

-

                                
      196G.           tinuoue cell        II(n) P in either
      U.S.A. (68).      Itrain*          dimcthylsulfoxide
                  (mammalian).      (DMSOI or pnrnffin.
K
\o


TADLE Al4.--Ezpcrimente concerning the cfect of cigarette smoke or ile consliluct~te on lireue and organ cttIL~rc8 (co?I~.)

Aulhor,
yr*r.
CD"",tY.
rcfvrcnce

Burcnfrc""d et LI.,   Hamster luhr      Application of         e... lncreawd ~ppc~~rnnce of new rmrll chromoaomts and tclocrntrle ehromosomca.
1966,          t1BIue.           B(a)Pineither       b. Incre~rcd ability tu grow in hnmsler cheek pouch and there become Bpindle-
U.S.A. (33).                   DMSO or dimetbyl-         cell s~rColn*~.
                           Iormamldc.

Cuimard.   Chlcken embryo     Application 01         lncrc~ecd mitotic activity and incrrlaed incidence 01 snomalou# mltoacs.
1966,           muscular         robaccu extract.
France (110).     eXphtl.

Lasnitrkl.        Mice nmnatal      Appllcatlun of II hy.      u. Incrcnscd buanl cell hypcrplarla and pleomorphlam of newly lormrd cclla.
IPGR.           trachea.          droclrbon-enriched      b. Increa~rd cyllhclial mi:oair.
England (160).                  fraction of whole
                           smoka condensate.

Larnitzkl,        Human fetal lung     Application of a hy-      a.. Cellular enlargement and promotion of growth of new bronchi.
1868,           In orpsn culture.     drocarbon-enriched      b. Increased mitoae,, bronchial epithelial hyperplssia. and a~u~rnou~ mctaplnsln.
England (161).                  fraction of whole        c. Inhibition of stromal growth.
                           smoke condensnte.

Ghan et al..       hlouae lung
1969.           bud embryonic
U.S.A. (S4).      cuIturcs,

Application of
D(a)P in DMSO.

a. Cellular disorganization.
b. Ccllul~r pyknosis: nuclear ahape and size Irrepularlties.
c. lncrcaac-d cllithclinl milotic rntc and decrcrsed mcacnchymol mltotic rnlc in
thorc cul~urw exposed to D(a)P ver~ua those cxpnrd to pyrcnc or DMSO.

Lcuchtcnbcrger     MouYe lung       Exposure to fresh smoke:
and           and kidney        a. Unfiltered.         a. Decreared RNA production, pyknoslr. and death of cella.
Leuehtenberger.    tissue and         b. Activated          b. Similar rcsulh. but chanpts were of minlmal severity.
1969.           orlcsn culture3.        charcoal Rker.
Switzerland (16s).                c. Cigarette or         c. Similar elects as group a., but Ins severe.
                             cigar tobacco.


    Author.
    Y<~llT.          Tirnuc or
   rountry.        oryon culture        hlntrriolldrlivcry                          llrrults
   tef,,tCr,CB

Cruckcr.         Various organ      Apvlicntion uf         Squnmoug mrtaylusls: frcqucnt plcomor~~bic CPIIO: dnliflrrcntlutlon ol cpllbrllum
                                                                           _-.-


1970.           cult"rca:          Il(u)l'in8er"m.         (inhl!~ited by L'itlimin A).
U.S.A. 162).      n. Whole suck-
                ling hamster
                trncheer.
              b. Whole bron-
                chin1 tubes
                from late
                fetal dogn
                and monkws.


TADLE A15.-Erperiments concerning the cflecl of the insti[[ation 01 implantation of
  cigarette smoke or its constituents into the tracheobronchial tree of animals

Author,
YCI r.
COUntPI,

Animal
and

A. Method
B. Fre~uencu and/
   or duration

Rnults

reference      atrain     c. nlntcrial

nlacklock.   CD white      A. Injection into      3.4-brnrpyrcne:                     Number wilh lumorr/numbcr erporcd
1967.      ,a,,.          Lund parrnchyma    .5. 3 mg. in olive oil                  K/6 Barcornll.
crrht                  by tharacotomy.     b :I mu. in ulive oil with dead Tb bacilli      Z/4 sarcoma, 4/B sguamou~ cell carcinomr.
Uritain               B. Once.            c. 5.15 rn~. in cholrstcml pellet            l/8 ~qui1rnou8 ccl1 tarcinoms.
IPO.                C. 3.4-benrpyrrne     Cignrctlr "tnr":
                      in olive oil,        II. In olive oil                     o/10.
                      with ~lcad Tb      b. In ulivc oil with dad Tb bncllll          I/8 aureoma, l/8 ~pue.mou~ cell crrcinomm.
                      bncilli or in      ClllltVUlY:
                      cholesterol,       8. U 15 cc. olive oil                   O/4.
                      cigarette "tar".     b. 0.15 EC. ulive oil with dead Tb bacilli       O/I.
                                  c. Cholntcrol pcllcts                 O/4.

Della Port&   Syrisn golden    A. Direct tracheal
et al..      hamstera.        instilllstlon.
1968,              B. Weekly'up to
U.S.A.                  46 weeks.
(67).               C. 1 percent 7,12-dime-
                      thylbenz(a)nnlhra-
                      cent (DMUA).
                      cigarette "La,"
                      concentrate.

hlnterial:                 lYetk4
n. DMBA 50 ,,c./wek , . . ., ,      46
b. "Tar" 200 /,,g./wrk        32
c. DMBA hO,,c./wcek  .      12
   then "tar" 200.
   ,,a./ NWk I.,..,......      30
d. DhlDA 100 ug./week . .       17
e. DMDA 100 irK./wffk   1
   and "tar" 500             20
  ,&week ...I..*II.**I

Suruivorr at t0
vwke/orioinal
number erportd
    10/20
    11/21
    9/20

-
T/20

9/20

-

-

Ripdon.     White Pekin

A. Intratracheal

No nronlastic chanacl noted in either the exocrimentrl or control PTOUDB.

                                                                _
ducks.          injecti,,rr.
Control3: 99    B. Dsily for 721 days.
Experimental   C. Tobacco cundensate
group: 62     1 In liauid petrolntum.


   thorncutumy.
B. Once and auriflced
   at I week-2 YEBTB.
C. Cigarette tubscco
   smoke condensnte
   In eucerin.

     Rockry et nl., Dupy.        A. llrunchial inoeulntion                                               SQllonlo",
      19GZ.                   or 3:imulntion.                                          PTC-     ~~lUpl,l,lU
      U.S.A.               B. 3-5 times/week                NU"LbCr    IItuosruc    Carcinoma-   Canccro"`   W\lli al",`i<al   Infhm-
      (ZPO.                  far up to 5      Procedure:      oj dooa carcirloma     in tilu     CllonQcs     rhanpca     rrlollorl
                           ysara.          Controls I.. I,,   21                -        -         6         24
                        C. Cigarette smoke      Manipulation of
                           condensate.        bronchw     25        -        -        -         7         26
                                        Smoke condrnsnte 130         1         3        25        98        128

     Tiuton and   hlongrel dons.   A. Bronchml       Rspid induction of squamous mrtnplasis in condenautr-exposed animals. No tabular
      Cracker,   Control crou" and    inoculation.       data is prrsentcd.
      1964.      experimrntal  B. Daily for 8 days.
      U.S.A.     Broup-Ii).    C. Cignrette smoke
      (nil).                  condensate.
w
2:


z             TABLE AlS.-Experiments concerlting the e#ect of the inslillation or i~nplantation of
a              cigarette smoke or its covstitfce7lts itlto tlic tracheobrodiinl tree of animzts (cont.)

       Aulhor,             A. Method
        yes*,       Animal    B. Frcaucney snd/
       W""l*Y,       and        or duration                               Ilcsulta
       rcfcrcnce      etraln     C. Matrrinl

     S~fflottl et nl., Syrian golden    A. lntrntracheal                                     Percent tumm-
      1066,      hrmstcrl.        Inoculation.
      1l.S.A.                                                  Number 01     bmrinu 01       TO101    Told number
                     B. Weekly for 16 weeks. Number autopsicd:
       (1S7).                                               tumor.bcarinp   *"r"t"OT, at      number   oj ropirnlory
                       C. D(a)P (3 ma.)                            animolr      IS wceka      of tumor8   tracl Cil"CITl
                           attnrhcd to fine     Male I, *. 23         15         1OJ.O         24         18
                           ham&tile dust.     Female , . .  17         II         100.0         17         16

     Kuxhnrr,    IIsmstcra.      A. Wire mesh pellet                               Number of
      1OGtl.                                                                          Number of
                           implantation                                 rurvimra/oripinaf
      U.S.A.                                                                          .nimnl~ It Ill,
                           into bronchus.    Il"VlP."t:
      (lS7).                                                        number in proup         lunp cllnccr
                        B. LiCetime.         Wire mesh only , ,,, ,. ..,, ,, . ,. .,, ,,      34135
                      C. B(a)P,                                                         -
                                        BICA  . , . , .      es/91             43
                           methylcholan-      U(fl)P  ,.......,.,.,....... ..,...., . . . . . . .      89/91             67
                          threne (MCA).

     Satllntti et PI., Syrian solden    A. lntratracheal
      1068.      hamsters.                                                                Number 01
                           inoculation.
      U.S.A.                                                                          hamrlcr, w1111
                        A. Weekly for 16                               Number oufopricd
       (235).                                                                           rC*,,IrIIfor"
                           weeks.         I"OCUlate:                                        frarl furnorl
                        C. B(s)P nttsched      Control  . I.. ,, ., . . ,. ,, ,. ,, ., ,        176
                           to B fine                                                       -
                                        B(a) P in hcmRtite  , , , .        65            35
                           hematite dust.     Hemntite only  , . ., ,        41            -

     Borisyuk.    Wigtar rata.    A. Intratrscheel
      1960.                                                       Number final/         Durul,or~ 01
                           intubation.
      Russia                                                            inifinl
                     B. Monthly up to                                                   ~norulflli0x
                                       I"OCUhte:
       (Sib.                                                                           ("Wllllll)
                           10 months.       Controls  . . . . .      Ill20     12
                        c. Cigarette "tar".      Unfrnctionsted "tnr" . ., ,. ,, . .,, . .      24/?00     10
                                      Dcnicotinixd "tar" , . .      0145     S (119 mttrplasir)
                                        Neutrsl "fe.r" frnction  . ,, ,. .      14/100     3 (2116 carcinomne.
                                                                         t/14 pap~ll.ry rdrnomal.
                        I
    `This ErouD oI~J received on'e injection of urethsne intrr,ptri~o~~r~b'.


Author.
YPbT.
cuuntly.
rcfcrcllrc

Animal     A. Type ol cxpo,"re
R"d      II. nurntion                          nrsulc$                       Commrnlr
Blrnin     c. hlnterinl

Mlihlbock.      Hybrid (020 x    A. Chamber.         Percer~l will, all'colur corcilfumua                   No other ,Y,,P nf
L95.5,        DBA) mice:    5. 2 hours per day for    c. 31.0                                   ,"nU ,i,m,,,n \\<`TP
Nelhvrlsnds    C. 32.           UP LO GR4 dnys.     E. 79.0                                   found
(195).       E. 29.        C. Cigaretle smoke.

Lcuchtenbergcr  CF, albino mice:   A. Chamber.        23 of fhc crpcrimn\t~:imice ahoxcd:
cl .I..        C. and E. 27.6.   0. To R cig~rettu       15 b~irol cell hynerDlnfiin.
1YSB.                      DCI day from       lb ntsi\icn\ bnanl ccl1 hypcrplubis.
U.S.A. (Jb6).                 11-201 dnye.        1 dysplasia.
                      C. Cignrette smoke.       2 B~~U~~UUO ~rll mrtn~larin.

      1959,         strain rai3.    B. 45 minutes         c. 2.4 "errrnt of 39 c.UNI"OIS.
      France (Joa,.   c. IO.           wr dnu from      E. 6.1 percent of 68 aurvivora.
                E. 100.
c*,                             2-G months.
2: -                    C. Cigarette smoke.



TABLE Al&--Ezperimenta conccmng the elfect of the inhalation of cigarette smoke
    or it8 conalituenls upon the respiratory tract of ani7nuls (cont.)
       (Figurn In parenthun rcprercnt total number murvivon in opecific f~roup)

Author.
ye.*.
C0Unlt-Y.
rffrrenec

Donlenwill and   Golden hamsters.   A. Chamber.         Number of           DLliIU
Wicbeckc.      c. -        B. ur, to , cigarcttca     animal4           ovcrogf
11166.         E. 320          per dsy for up      dead at           crpoaurc
Germrny                    lo 2 ye.rIl.        510 dnya          (ciuar~llcr)
(771.                  C. Cigarette smoke.        40  ...I . . . . . . . . . .     1
                                        40  . . . . . . . . . . . . t,     2
                                        80  . . . .    l-2

              MET des = drsqusma-
    Htitoiogic      live mctaplusin.
    findinoa in     MET branch = Irron-
   drnd animalr      chini pnpillnry
81 40 MET dea        mclaylasio.
8/ 40 MET drs       PAP trach = trschrnl
44/ 80 MET de3 (3 hIET   popillomals or
branch. 2 PAP trach)    lntensc truchenl
b7/143 MET dn (13 MET mctnvlaaia.
branch. 8 PAP trach)

      Lcuchtenberrer  CF, mice.       A. Chamber.
       and                   B. Up lo 1,000 hours.
       Leuchtcn.                C. Cigarette smoke.              Marked aauamovr
       bcrger 1966.                  exvrxurt lo in-              ccl1 mclaplnaio
       Switzerland                  nuenra virus                 (percent)
       (160.                     (PM).         Cunlrol, (100) :
                                              Male ,. ,.    -
                                              Fcmnlr ,..., -
                                           Smoke en~osd (S.9) :
                                             Mule .,    -
                                              Frmnle     -
                                          Vinw exr>ascd (59, :
                                              hlalc   11.0
                                             Fwnt~le ,,... -
                                           Smoke snd
                                            virus exposed (68) :
                                              >lulr    9.0

w                                             Femnle   29.0

-
-

6.0
-

21.0

43.0
64.0

-
-

3.0
-

13.0
5.0

113.0
133.0


                              -~
Hsri i> and     C57BL mice:     A. Chamber.
Nearun~.      c. 200.       II. Smuke-12 ciga-
1967.        E. 1,437.         rcttes per `20
Pnalnnd                    mice fur I2
(121).                     minutes every
                         uthrr dny for
                         lifetime.
                    C. CiKnrelte smoke,
                         influenza virus
                         ae1.,,1u1, bcnr-
                         "Yrene c.ertrsol.


Author,
yefar.
c0""tl-i.
rrferencr

A. Type 01 expos"re
B. Duration
C. Material

Kcsults

Comment8

Wyndcr Cl al..   Male C57BL6     A. Chamber.         Conclusions: t                              tRcvuit3 not prub id4
186s.          mice:       B. UP to 315          No squamous ccl1 respiratory cancer noted. This is attributed in tabular form.
U S.A. tJ.`l).    C. snd E.-        ciR.alettes.         to the limitation 01 inhalation time (CO and nicotine acute
             more than 40.  C. Cigarette smoke.       e!Tccts) and to the ~nuton~w~lly and ahysiologicolly intricotc
                         nitrogen dioxide,      nasnl prss!aue dclenw system.
                         volntiic acids     ktxpusure to c!gu~~`tte smoke. N02. or volatile acide snd aldr
                         and aldehydes        hydes lead:, to reactive hypcrplnria and metaplasia, both of
                         fuund in ciua-        which WPVC noted to be reversible.
                         rette smoke.       Swine inl~uenru virus exposure produced hyperplsstic and
                         swine influenza       mctnplastic cflccts which could not be enhanced by aubrc-
                         \.il.US,             qurnt ~XPOSUI'C tu ciunrrttr smoke.


cc,
cu
0

.----
   huthur.

TABLE AZl.-01rlhc of .wO.ospcc1itv shtdies of tobacco ILSC and cancc~ O/ tile larpz
         _.

   Y4'kT,                     CDScl
  "`~,`\1,)`. -            ----_-
  rt,l,,rcnrc St,\  Numhcr         hlcthod ul aclcctiun
- _.....  .---             ___-.__-_

                                                                    _._---.-~
M.-F   i!?C   Clinic wticntn with canecr of the Jup/u:    108   Clinic nuticnts of ~nrne BIC P~DUD with   Medical hiaturv and QUCI-


TABLE A21.-Outline of sehxspcc~ivc sludies of tobacco use and cancer 01 the laqmz (cont.)

               Cn3-3                             Controls                  Collwtion of data
SC%  Number         Method of selection        Number         Method of selection

hl.    241   Clinic patients with enncer of Inrynx:     200   Patients wi!h no laryngeal disease:    Personal history taken In

Wyndcr ct al..     hl.    209   White mnie inpatiente hlemorinl Cancer   200   Paticnta with other than epidcrmoid   TraIned lay inlervtcwera.
1056.                   Research Center during 1952 to 1954.         cnnccr,  individually matched controls
U.S.A. (512).             with benign or malignant epidermoid          in wme institutions:
                      tumors of larynx:
                                        Prrccnl                           Pcrcrnl
                       Nonsmokers  I. .,. I,.  0.6           Nonsmokers  ,. . ..*..... 10.6
                       Cigarettes  ,,. .,, ,,, 86.0           Cigarettes  .,, .,, ,. ._, 13.7
                       Cigars ,. ,. ,,, ,. ., ,,  7.6           Cigars  .,.. .  10.1
                       PiDM .I.. ,. I.,  6.0           ripea  ,...... ......II.,.....  3.8
                       CigRts/pipCS  ., ., .I., ,.  1.0          Clynla/plpc3 I. . . . . ,. ,.  1.9


Wynder et al..     hl.    60   Patients at Rndiumhrmmst with squam-
1957,                   ous-cell etlncer of larynx. from 1952
Sweden (~2).             through 1'355:
                                        PCrCCllt
                       Nonsmokers  . . . . . . ._   6
                       CiKnrettee  ., ,,  41
                       Cimrs  ,, ., ,,  17
                       ripes  ,,  16
                       Mixed  .., ., ,,  17

Wynder et al..     hl.    142   Clinic yntients in Havann during 1956.67.   220   Same IOUTCC nnd time: aooarentlv DLL-   Interview of Dntirnts



384


1.1       14    12.1
II.4       1 ,I    11.2
4.5       I     .`J
--       2    1.7
-       0     -
-       0     -

-       v     -
- .       0     -.

04   100.0      125   100.0      :1:9   100.0      130

I     1.1       I     .H       0     -       0
4    43       25    20 0       `    1.2       0
50    63.0       54    432       Xl    26.4       21
23    24.5       21    II; n      IIG    35.3       ib
0    0.G       1    1.2       44    13.4       33
    2.1       2    1.6       I !I    6.H       II
1    1.1       0     --       5    I G       0

:oo 0
..-.
-

I'(,
I I


TAELE A24.-Number and percent distribution, 611 highest number of cell TOWS in the
   basal layer of the true vocal cord, of men classi/icd Ly smoking cutcgoty

T<>lal  . . . , . . . .   HH   100.0      116   100.0      04   100.0      125   100.0      329   100.0      190   100.0

Lcr. than 5 ccl1 row, . .   . ,,,.I .   311    34.1       7    6.0       4    4.3       3    2.4       1    0.3       0    
5 cell rows  ,. .         2'J    33.0       21    23.9      20    21.3      27    21.6       9.8    11.6       20    10.6
6 cc,, rows ,  ,  . . ,,, .,, ,   x    9.1       15    12.9      15    6.0      25    20.0       61    IS.4       24    12.6
7 cell rows      . . ., . . . .   6    6.8       12    10.3      IR    19.1       12    9.6       39    11.6       19    10 0
n cell r"wB . . .  *. .  ,   , . ,, .   6    9.1       la    12.1       9    9.6      13    10.4       30    9.1       23    12.1
3 cell rows   . .   ,. ,.    1    1.1       7    6.0       7    7.4       6    4.8       ZG    7.9       I4    1.4
10 or m"re cell row3 . . . .    .    6    6.R       34    29.4      ?I    22.3      39    31.2      146    44.1       90    47.4

-

Source: Auerbnch, 0. et al. (9).




                                                                           ----
-.   .-_- -_.-.-            ____-.----




TABLE A28.-&lhc of retrospective studies of tolmcco use and cancer of the oral cavils (cont.)

(Data~oblsincd from patient interview and otbrr auurce.)

Author,
year.
CO"ntTy,
refercncc

               CllWS                              Co"trob                     Commcnlc
SC%  Number          Melbod ol selwtlon        Number         bletbod of selection

Sbsnta and       Xl.    662   Patient> with oral and phnryngenl cancer   300
Krisbnwnurthi, F.    20t   (unsure of conflrmstion) :            100
1964.                                                    PerCCtlt
India (~66).                                     Buccal    At1teriOT   Posteri.Jr
                     MtllCll:             LiJJ     nLllcod*    touguc    tongue
                        No tobacco habit . .   -      2.0      7.2      2.0
                        Smokcw  60.0      46.7      66.6      76.0
                        Numberofcwcs ,,., (12)     (213)      (69)      (481
                      Femnlca:
                        No tobncco habit , a, ,  14.3      11.0      33.3       -
                        Smokers . ., ,, . .   -       4.7              -
                        Number of eaws .  (7)     (162)             (0

Controls residing in
~&me area matched
for age, vex, and
    ClilBa:
Phat-unz   Nlolta
  6.3      99.1
72.8      62.7
(130)     (300)
       FRndCI
40.0      RR.8
  8.8
(26)     (100)

Wnhi et al.,
1965.
lndla (302).

hl.
F.

IA0   Pnticnts with oral and pharvngeal car-   689   Patients matched for age, sex. religion.
232   Cl"Ol"a:                        232    and wcial class.
                         PeTCCTlL           PC7CC7ll
      Nonsmokers  . . . . . . . . . . .  9.62             C6.6
       Smokers  . . . . . . . . . . . . . . . . . . . 17.05             21.2
      Chewers (Betel nut)  . ., , 35.44              6.9

Hirayama.
1966.
Central and
South East
Asia (124).

           Both
       I        . . . . ,.. ,. . . 37.88              6.4

Bl    3c9   Patients with oral and pharyngenl cnrci-   277   Patients with other (unspecified) dls-   Found only a suggnllve

F.

176 noma:                         163 eases:                        association between
                       PCTCCTlt                PCrCCVlt                 hlcohol-drinking and
                     Malt Fcmolc            Malt Fcmalc                oral crlnccr In non-
      Nonusers  . . . . . ,.  1.~    2.6              11.0   33.0                 chcwcm only.
      Smokers . . . 17.1    2.6              23.8 1.2               t UN-Iletcl nut.
       Smokers, tBN nnd
        tobncco chewers . . . 46.7    6.6              24.9    1.6


TABLE AZ&-Outline of retrospective studies o/ tobacco me ad cancer o/ the oral cauilu (cont.)

(Datr obtalnrd from patient interview and other sources)

   Author,
    yerr.                    CUCU                            controla
   country,                                                                          Comments
  reference    Sex Number         Method of aelection        Number         Method of selectlo"

Keller,         M    4on   Patienta with s~usmous cell carclnomn al   408   Next mule patient admitted to same hos-   Excessive ulcohol LO"-
1967.                  oral cavity and orophsrynx connrmed         pit01 within 6 year hw range.         aumotiun noted lur
U.S.A. (I40).              hiatolonieally. Three New York Cite VA                                  cbscs invulving flour.

PIrCCnt
14.2
56.4 (D<o.o001)
2.9
6.1

mr3olhsrY"x, and
ton*uc.
Findinvs indlcatcthe
awxmtiun of hcnvy
drinking with cn"ccr
indcpcndenf of the
amount of LObUCCO uatd.

Mfid"Cl.       M.        Patients with eyidcrmoid carcinoma of   345   116 mnlc and 38 frmalc hoapilsl or clinic   Casc~ fuund to eo"suv"c
1968.         F.    38   ornl c&viLY and phurunx:             II4    vftt~cttls without c~"ccr: 330 mnlc and    "lure 111c0110llc hvcr.
I'ucrlo Rleo                                            76 fawalc rcaidvnb of slime region.    r&YES ttiun C"llltlllJ.
(Ias).                                               age and BCX mntrhcd.
                                        Pcrcctlt                Pcrrcnt
                       Nonsmokera  . . I,I, 13.7                  II).2
                       Heavy tobacco uaer8  ,. ,. 24.8                  12.2~11<0.0001)

Keller.         !A    304   Paticnc4 with primary basal or ~o~nrnuu~   304   l'n!icnla Irum ~lwnc hospilol matcbcd for
1970.                  cc11 carcinoma of liv:                   OPC and rote.
U.S.A. 1141).                                Pcrcrnl                PCTCCflt
                       Nonsmokers  . . . . . . ,....,.,.  7.3                  16.6 ( p<O.OOl )
                      Ckarclccs only  . . . . . ., 60.2                  62.8
                     Pine only  . . . . ,,, I.. .,. ,.,  6.0                   3.4
                    Pipe. other . . . . . ,,  6.3                 0.4 (D<o.ol)              -.~- ---


TADLE A28a.--Smnmary of resdts of retrospective studies O/ ,moking by type and ord cancer o/ delailctl sites



TABLE AZSa.-Summrwy of results of retrospective studies of smoking bu lupe and oral cnncer of detailed sites (cot~t.)

Keller (140). . . . . ..Allsiten (-t-j, ,. ,......,..........~.., Ailsites C-J... . .All aitcs (-) .,.. . . . ,., .All tyvcs smoking
                                                                           combined. bcnvy
                                                                           --floor of
                                                                           moulli and
                                                                           tunLuv C-t).

' Only in Individuala of low economic ntatus and over 60 years old.
  Symbols: (+) = significant association.
        I-) = asuciation absent or not xignihcant.
        ( o ) = rasoeialion of doubtful signlflcrnce.


              TALILE AZS.-Expcti,ue?ilnI sltctlics conccming oral carcit~ogcncsh

  Author,                                              -
                      A. Method.
   YV.1.        Animal     Lt. Frrwrncr and/
  country,        and       or dur.tion.                                 llwulta
  rrfcrrncr        ltral"      C. Mrtcrlal.

Krtshovrr.    7R Swh and      A. raIntIne of lower    No macrw.cuaic or microscopic chnlrgse In controlr or experlmet\~nl anlmrb.
IQKZ.        C57 mlcr.          lip mucocutaneou~
U.S.A.                     rPgIwl.
(/Sfl.                 B. 10 time8 In 76 daya.
                     C. Cigarette smoke
                         "concentrale".

SlllW.       36 Syrian        A. Paintinz of check
1054.                                                    Number of
           hnmstrra.                                                         Numbrr with     N'urnbrr witi
                         pouch.         Trenbnent:
I1.S A.                                                         IYNIUOI,      bcnipn tumorr      carcinoma
                    B. 3 per week lor 16       Ac<Cone solvcnL .    5
IPJS).                                                                        1            2
                         weeks.            ncnrenc salvent ~. ~.    4
                    C. Benr(a)Dyrene I"                                                      -


                        acetone or benrc"e.

Hobti and     60 Albino mice     A. Paintinp of lipa    No oral or lnbial chanam seen In controla or experlmrntrl anlmab.
Ermah.      I40 controla),       nnd oral cavily.
1955.                   13. 140 times In 12
Finland                    months.
(130).                  C. Tobacco "tar".

hlmrc rnd     so Surian       A. Material waked onto
MillCT.       Golden hamaten.                                                                 InTiommnlion
                         wad and sccurcd
1958.                                                   On'uiw1    Sunriuinu    Num brr   and boral rtll
                      in cheek pouch.     Treatment:
[J.S.A.                                                        number    m!e7 I ycor    1umorr    hyytryluia
                    B. Wads replaced 8
(19.oI.                                    Controls ,. .   30        29                 1
                       times in 2 yeara.                                              
                                       Smoke condmante   80        56
                     C. Smoke condensate                                              I        92
                                  Bcnzla)pyrcnc . . . . . . . . . . . . .,   20        16                 9
                      Benz I a) py~e"e.                                              


Currin.      Strain IC and     A. Chamber Jnhrlution
1959.                                             On'ginnl
           strain W rat.                                                              Burro1
                         01 tobacco awake.
France                                               number        Surviuorc            tumai,
                     B. Daily (?).        Controh ..,.,.,.,,,. 40
(108).                                                             39              o/39
                   C. UP to 6% months.    Expcrlmental . ,.   100            68              K/68 (31'5 deflnlk
                                                                           rli,lllt~llunrs,


TABLE A29.-Experimental studies comx~t~i~~~ oral carcinogenesis (COIL)

  Author.                 A. Method.
   ycIIr'.         Animal     11. Frcaucncy and/
  counwY,         and        or duration.                                  Results
  rercrcncc        strain      C. Materiot.

Peecock ct al..  124 Syrian       A. Packing of cheek     No tumors noted in nny oi the 42 nnimnls surviv/n~ over 1 year.

1060.
U.S.A.
(210).

Golden hamsters.      pouch.
           11. 1 year.
           C. S~UIT. Tobneco.
              Ulnnd mntcril\l.

Dunhsm and   Syrian Golden      A. Puking ul check                                            Hupcrpfaaia ?J,lliyru7nl
lierrold,      hamsters.          pouch.                            Oril?inol                   awllo? ;n-   pouch
19G2.                   B. Normal litepnn or    Tren(ment:             numbn        Survivor8      jfn7umaLion  1umur.
U.S.A.                      6-30 mo"ths.      Betel quid  . ,. . . .   376     9oc;o 0oCr 1 year          15
(84).                   C. Uetel quid ingredlents  Dhil)A and MCA . . .   71      56171 over%30 months      -     23'6G
                      `7-12 dimethylbenz(a)-
                      anthracene fDhlUA),
                        hlcthylcholsnthrene
                        (MCA) in bceswnx
                        DehtS.

Moore and
Chriata-
phtraon.
l[iGZ,
U.S.A.
(191).

Albino hamster
extcriorired
oral pouch.

A. Painting oral mucosa.                                          Animnlr with
B. 3 ~,er week for 683     Treatment:                                  Ic,ioi~s (lime1
   days.           Conlrols  *.. ..# .*. .,. . . . .I. ,. ,. . . . . ** . . . . .a.   OIIR ,flt 312 hY3).
C. Cixnwtte smoke      Smoke contlensa(e  . , ,. . , . . .   O/20 (rr 331 dn>u) (IO shu\%cd h>wr-
   co"de"sate.                                        kerntosis).
   D>lBA in 0.6%     DMBA . . . . . . . . . . . . . . ,a,...,, . . . . . . . . . . ..a.. 0.8   14/21 microscopic cancers (at 00 daya)
   petrolatum.                                    (invaaivc ~puatnous conccr 0riKinntinz
                                              in the skjn at Ihc WIED of the vouch).

Salley.
19c3,
U.S.A.
(239).

CAFI strain
mice.

A. Ultraviolet light
   exjmsure to nnd
   pninting of lips.
B. 3 ~)er week for 08
   weckr.
c. D(8)P in ncetone
  Cigarette smoke
   WV llnht.


Uock et al..    1CR Swiss        A. Pointing mouse
1864.        mice.             skin.
U.S.A.                  D. See results 36 wwka.
(JO).                   C. Various extract3 of    Trentmrnt:
                          unburned t&am,    DhlBA once then:
                          DhlBA.          Acetone benzene extmct
                            Conccntratnl na(OH)pextroct .,.
                            Diiuteil Un(Oll)Zcxtrnct ,.. ,,,,,
                                       DMllA only  
                                       Aectnnc bvnzene EXtl'sCt
                                    Concentrnctcd Un(OH), ~xtrrict .,
                            Diluted Bn(OIil 2 cxtrnct
                                        None  ,.  :.


5
0

h.matera.'

                 07ipind   Aforlolify   Number      utilh      wlh
Treatment:            number     rn1c     animals     1umorr     CL?"CO
DhlUA   Alcohol   Smoke 2'J       41.0       II       100.0       60.0
DMnA   Alcohol   . . ,    29       6G.0       10       60.0       40.0
DhlllA   ,.   Smoke    29       42.0       14       100.0       10.0
DMIlh   . , .,   . . . . .    28       4R.O       16       100.0       80.0
. . . . . .   Alcohol   Smoke    29       42.0       14
. . . , .   . . , . .   Smoke    28       42.0       14        -        -


Sanghvi et al.,
1365.
India (P(l),

M

                                                                       --
13   Conseculive clinic admirrions to Tats me-   2RB   Consecutive clinic admisaiona of vnticnta   ny menns of "dctnilcd
    morinl Hospital. Bombay.                 without c~nccr.                 queationary." No otbcr
                               107   Consecutive admissions of patients wilh    details given.
                                    cnnccrs other than intraoral or cw-

Wynder et sl..
1351.

           M    39   Patlents admitted to Radiumhemmet,   115   Pstientr ndmittcd LO ~arne hospital with
           F.     35    Stockholm, during 1962-66.           ICC    cancer of akin, hrnd and neck region
swcden (Jze)                                            other than IQUB~OUB cell cancer. lcu.
                                                    kemie. colon.  and other altee. No
                                                    matching.

Sra3rewski,
1960.
Polund (160).

hl

24   Patient3 admitted to Oncological Institute   912   Olhcr p~lients sent to Inatltute with   No drtnll, glvcn o"
     during 135749.                                                method ,I! dstu coJlw-
                                  aym,~loms probably not ctiologlenliy
                                  conncctcd eithsr with smoking or with    lion. No arc ~~JIIJ~-
                                 direasw of caophaguua, atomnch or du-    mcnt or mntching. hv*
                                    odrnum.                     eragc .ge of c.nrcr
                                                      vrtienla, 60.6: contm~.
                                                               63.


TABLE A3l.--hnamary of methods used in retrospective stitdics of tobacco USC and cancer of t/ie CSoPha!7us (co7if.)

Wynder rnd
Bros9.
1961,
U.S.A. (SJO).

m.    160   Cancer ~stienh awn in Memodal Hospl-   160   Psticnts neen in lame hospitals during   Data coilcctcd by trriucd
         181. New York City, and Kingsbridge        ~lnme time period with other tumors.    intrr\iewcrs.
        and Brooklyn VA Nospitnla during        64%malignant tumor: 36%benign can-
          1950-69 (86% white).                 ditions. Matched by age with et.n~cr
                                        pe.tiet2ts.
F.    37   Same hospitals, and same time period r.s    37   Same IS with rcgnrd to male controls.
         mule patienh (86% white).               43% had malignant and 67% benign
                                         l"lTOr8.

Wynder and      M.

67   Admitted to Tsts hlemorial Hospital Ilom-   13b   I'nticnls with other iorm~ al cancer ex-   Intcrvicwcd bv one DCT-


   Author.
    YPL11.                    Crises
   CO"ll,i-Y,                                                  CClntr0k

   relarenc.?    sex  Number         Method of selection        Nllmbcr         hlcthod of ~clcction           Callecllan of dot-3

Drndahnw end     hl.    on   Patients with esophoscal cnnc~r.        341
Schonlnnd.                                             l's!icntn with non-mahgnnnt diacase.     lloapitnl Lntcrvirwa by

1969.                                                                           trained Airicon doclol

South Africa                                                                      workers.

Ill).

blnrlincr,       hl    120   Patients with confirmed epidermoid eso-   360   120 male. SO female patients In snrnc has-
1969.         I.     59                                                           lnlcrviews by Irrinvl
                    phwcal cancer diagnosed In 1966.      177    pita1 with non-conccrou9 diaanoser.     pcrsonncl.
Puerto Rico
(1.93).                                               240 male. 118 female mcmbere from s&me
                                                    cummunity.                              -


TABLE Mln.Summarg oj results of vctrospcctiw studies of tobacco we and cancer of the eaophaguz

-
Sanovhi et al.                                                                           .---- .-
                                   6.6      11.3       Ar'cruor l,limLcr ol       -.     -        3.6     -

Wynder et sl.,          M                  13.0      24.0

1067,
Sweden fd91).

SI~lzewakl.
1960.
Poland (280).

F              (nbout)ELO  (about)`JZ.o         -                    -        21     -
                                    -     -                       2 0     -

                   -      18.0        95.8    59.0        87.6    80.0        -

Schwsrtr et al,,
1861.
Frrnce (PIo).

WYndcr knd Dross.
1961. U.S.A. ."d
India 1510).

--
Takano et &I..

1963.
Japan 1972).

Amrtlcsn malrs
American IcmnlpJ
Indian males
Indian females

3.0




G.0
41.0
13.0
78.0

11.0

17.0




IK.0
7M.0
2H.0
94.0

23.0

To101 t,mou,,l smokrd
dnifv (rlgar~ltot
  16.X    16.0

  48.0    33.0
  27.0    16.0
   -     -
   -     -

   -

39.0    3H.0        C.6     -




-     -        3.4     4.4
-             5.1     3.2
              2.6
-             4.6     -

-             1.3     -

Brfiduhaw and Schonlsnd.
1969,
South Africa (AI).

                                                     - -.
16.3      31.7        3l.G     6.9              -        2.6    11.1

Martinez. IOG9,                                                                    -.             -
                                   14.0      23.6        ]?.!I     X.G         -     -        LB     3.6

Pup130 Rico (188).                                                                        _-__---


100.0
33.1
6.C
0.3

-
100.0
85.2
14.8
-

-        445      -        I O'J
100.0       3.b53    IOU.0        053
98.4        b3      2.2        4Gl
1.1       2,915     iS 6        452
0.5        h55     22.2         40

7i9      -        IRl
6,762     100.0       1.5X6
lG7      2.5        170
S.38!,     19 H        1 ris
1.106     17.1         iI

-
100.0
34
YU.0
G.6

2R
25s
56
175

-
100.0
37.4
GO 1
10

loo.u
1.S
YG n
61

-
1oo.c
2n.9
61.b
1.6

.-
100.0
GI `,
41.7
14




hl
F.

163
29

Patients with bladder cnnccr.

ICI     "Comparison casm."
60

Dunham et al..       ?f     334    Admisalonr to New Orlcann hosnitnln with hir-     350     Admissions to same hosnitalr with non*nc*plns-
I'J6R.            F.     158    tolugic diagnosis of blnddcr cnrcinuma.         Ii7      tic diseaaea and discues unrelated to i?cnl-
U.S.A. (8s).                                                         tourinnry tr.c,.
--
Anthony and Thorn&a.    M.     381    Patienta with prpillumn and cancer of blnddrr     275    Sur~lcnl Datient. wllhout c.ncrr ~rcvlouslY In-
1970,                         nt Leeds betweecn 1868-67.                     trrvirwed for lunx cancer study.
Ynnlhnd (3).
-


TADL.~ A36n.Summry of results of retrospective studies of smoking and cancer of the bladder

                                             I'etccnt clKnrc!tcr    Rclatlve rink rwtio:
  Author,           Prrccnt nonamokcn   Percenl hcrvr amoken      nmukcd     All amokcrs to nonamokera
   )`cer.                                    -         -
  E"U"trY,                                                    All
  rclcrmcc     SCX    C68M                                          Huaw Ciuarclle         Commenla
                       CO"lrOl8     CIW8  CO"ld8     CWM   Controla smokers smokcra amokerr
-_ .-
Lllirnfvld ct al..    M.     16.0     2Q.0                   61.0    44.0       2.8    ,..    2.7     ClgwrtLe nnd otbcr.
196G.         F.      87.0     83.0                   II,            1.4    . ,    . . ,
U.S.A.. (171).

---
Schwvnrtr et al.,    hf.     11.0     20.0       .,.     .       83.0    70.0       2     ,    2.2     CLparette only.
1961.
Frnncc (P/O).
-
Lockw.ood.       nl.      9.0     13.4       30.0    16.0       ao.0    16.0       1.6    8.0    8.0     Clewdtrs maln male of
1961.         F.      16.0     GG.0       4.0     4.0                   1.6    12    ,..      amoklng.
Denmark (176).

Wyndtr PI Al.,     M.      7.0     18.0       41.0    23.0       86.0    63.0       2.9    6.2    3.s     Phues A snd II com-
llG3.         F.      61.0     86.0       6.0     ,..            . . .       a.9    , . .    . , ,      blncd.
U.S.A. (306).

Cobb nnd Ansell,    M.      4.6     26.8       79.4    43.5       . . .     . . .       7.9    10.3    1..
1366,
U.S.A. (67).
-.
Stiurewaki,       hl.      6.7     16.0       86.7    66.7       87.1    72.2       2.1    9.1    2.9
19GC.                                                                     Clgrrettm only.

l'olnnd (P61).

DeeIcy and Cohen.   hf.      2.4      1.1            . . .       .     .       3.1    .    . . .
1966.
Ennland (6s).
-.


TABLE A35a.--Sunm.ur~ of results of retrospective shdics of smoking and ca?lcer of the bhddcr (cont.)

SCX

Percent nonsmokers


C**CS   CO"ltlOl

               Pcrccnt CiXnrcllus    Rclntivc ribk rullu:
Percent heavy arnokers      smuked     All smoker3 to nonsmokers

                           All   Iienvv Cinorctte         COt"t"?"ll
Cnscs  ControLv     Cnsur   Cuncrol. $mokcrs hmukcrs amokcrs           -.-

Yorhido CL al.,     hl.      H.0     22.7       43.4    33.0        -     -       3.4    3.7     -
IOGA.         F.      62.1     66.4        -     -        -     -       -     -     -
Jnnnn (330).

Kida et 01..       hl.     11.0     11.0       32.0    29.0             -       1.0     -     -
IUG8,         E'      lG.O     21.0             .-                     1.4     -     -
Jnwn (144).

Dunham et aI,,
IOGR.
U.S.A. (85),

Anthony nnd
Thomas.
1110.
England (3).

hf.
F.


F.

8.6
G2.2


6.3

14.6
61.6


6.3

-
-


-

48.4
32.0


36.5

46.4
2R.2


21.1

1.8
1.0


1.0

-
-


-

1.8
1.1


1.3


Chapter 5
       Pregnancy

%uroe: 19i3 Rewrt. Chaoter 4, pages 97 _ 149

411


Contents

P3ge

Introduction _ . . . . _ _ _ _ _ _ . . _ _ _ . . . . . . _ . . . _ . _ .417

Smoking and Birth Weight
Epidemiological Studies

Cigarette Smoking and the Low-Birth-Weight Infant _ . . _ . _ . . . . 419
Evidence for a Causal Association Between Cigarette
  Smoking and Small-for-Dater Infants _ . . _ . . . _ _ _ _ _ _ _ _ . _ .420
Evidence for an indirect Association Between Ciga-
  rette Smoking and Small-for-Dates Infants  . _ . _ _ . _ . . _ _ . . .424
Experimental Studies
Studies in Animals

TobaccoSmoke _._____._.___.. . .._ . . _. __._. ._. -428
Nicotine _ _ _ . _ _ _ _ _ _ . _ _ _ _ _ . _ . _ _ . . _ _ _ . _ _ . . _ . _ . _ _ 429
CarbonMonoxide _ _ _ _. _ _ _ _. _ _. _. . _ _. _. _ _. _. . . _ -430
Polycyclic Hydrocarbons . _ _ . . . _ _ _ _ . . _ _ _ _ _ _ _ . . . . _ _ 43 1
Studies in Humans

Carbon Monoxide _ _ _ _ _ _ _ _ _ . _ _ _ . . . . . _ . _ . . . . . . . . . . 432
Polycyclic Hydrocarbons . _ _ _ _ _ _ _ . . . . . . _ _ _ . _ _ . . . . . _ 433
Vitamin Bl2 and Cyanide Detoxification . _ . . _ _ _ _ . . _ 433
VitaminC....................................433
Possible Mechanisms _ . _ . _ _ _ . . . . . . . . . _ . . . _ . . . . . . . 433
Timing of the Influence of Cigarette Smoking on Birth
Weight . . . . . . . . . . ..~.........................434
Site of Action at the Tissue and Cellular Level . _ . _ _ . _ _ . . . . . . 435
Significance of the Association _ _ _ _ _ _ . . . . _ _ _ _ . . . . . . . . .435
Birth Weight Summary _ _ _ _ . . . _ . . . . . . . . . . . . . . . .436

Cigarette Smoking and Fetal and Infant Mortality
Introducrion _ _ . _ _ _ . _ _ _ _ _ _ _ _ _ _ _ _ . , _ . . _ . . _ _ . . _ . _ _ _ _ .437
Spontaneous Abortion  _ . _ _ _ . _ . . . . _ _ . . _ . _ _ _ _ . . . _ _ . . . _ _ 437
  Spontaneous Abortion Summary . _ _ _ _ . _ _ . _ _ _ _ . _ _ _ _ _ . . _ . 438
Stillbirth _ _ _ . _ _ _ _ _ _ _ _ _ _ _ _ . _ _ . _ . . _ . _ _ _ _ _ . _ _ _ _ . . _ _ 438
  Stillbirth Summary . _ . _ . _ _ _ _ _ . _ _ . _ . . . _ _ _ _ . . . . . . . . .439
Late Fetal andNeonatal Deaths  _ _ . . . _ . _ . . _ . . _ . _ _ _ _ . . . . MO__
Epidemiological Studies _ _ _ _ _ . . . . . . . _ _ _ . _ _ _ _ . . . . . . _ .446
   Comparisons of the Mortality Risks of Low-
    Birth-Weight Infants Born to Smokers and
     Nonsmokers . . _ _ _ _ _ _ . . . _ . _ . . . . . . _ _ . . . . . . . . . . 440
   Recent Studies . _ _ _ _ . _ _ _ . . .' _ _ . . _ _ _ . . _ . . . . . . . . . . 442
   Analysis of Previously Reported Studies _ . _ . . _ _ _ _ . _ . . _ . . 444
   Factors Which Influence Perinatal hlortality
    OtherThanSmoking........ _..____..._. . . . . . . .445

413


Page

Experimental Studies

    Studies in Animals . . _ . _ . _ . . . . _ _ _ . _ _ . . J-16
    Studies in Humans . . . . . . . _ . . . . _ _ . _ _ . _ . . . -U7
  Significance of the Association . . . . _ . . _ _ . . . . . . . -U7
Cigratte Smoking and Infant Mortality - Cont.
  Late Fetal and Neonatal Death Summary . . . . _ . _ _ . . _ 418
Sex R3tio . . . . . _ . . . . . . . . _ . . . . _ . _ _ . . . . . _ _ . _ . _ _ . _ 419
Summary . . . _ . . . . . . . . . . _ . . . _ . _ . _ . _ _ _ _ _ . _ _ _ . _ _ . _ _ 449
Congenital Malformations . . . . . . . . _ _ . . _ . . _ _ _ _ . _ _ _ . . . . 450
Congenital ilfulformatiorl Summary . _ . . . . . _ . _ . . _ _ . _ _ _ _ . . _ . 4.5 I
Lactation

Introduction _ . _ _ _ . . _ . . . _ _ _ . . . . . . . _ _ _ _ . _ _ _ 452
Epidemiologkal Studies . . . _ _ . _ . _ . _ _ . _ . . _ . _ . _ _ . _ . . . 452
Experimental Studies . . . . . . . . . _ _ _ . . . _ . . _ . . _ . . . . _ 45 2
Studies in Animals

Nicotine ____.__ _._.__ . . . .._.._ ..__ ____ ._ .._ 452
Influence on the Lactation Process  _ _ . , _ _ _ . _ . _ _ . . _ _ 457,
Presence of Nicotine in the Milk . . . . _ _ _ . . _ _ . _ _ . . . 453
Evidence for an Effect Upon the Nursing Off-
  spring _ . . _ . . _ . . . . . . _ . . _ . . . . . . .453
Nitrosamines _ . _ . _ _ _ _ _ . . . . . . . . . . . . . . 4.53
Studies in Humans

   Nicotine and/or Tobacco Smoke . . _ _ . . . . . . . . . . . 453
    Influence on the Lactation Process  . . . _ . . . . . . . . . 453
   Presence of Nicotine in the hlilk . . . . . . . . 454
   Evidence for a Clinical Effect Upon the Off-
     spring..................................... 454
   Vitamin C _ _ _ _ _ _ _ . _ _ . . . _ _ . . . . . . . . . . . .455
Lactation Summary _ . . _ . . _ _ . _ . . . . . . . . 455
P reeclampsra  . _ . . . . _ . _ _ . . . . . . . . . . . . . . . . . . . 456
Sf~nvnary -.......................................456
References . _ _ . _ _ _ . _ . _ _ . . _ . . . . . . . . . . . . . . . .456

414


List of E-`igurcs

Figure l.-\Iea11 birth ucisht for \vcck of ,qcitn!ion according
to rnnternsl rmoking habit : control wwk 5in~lctorl5.~-~~ _ . . .
FigtIre ?.-Percentape di<trihlltion by birth twiFht of infants of
rnothcr~ u.ho did not smoke during ~~rr,nnnncy anti of the-e
\\-ho smoked 1 pack of cigarettei or more per day- -_ _- _ - - - -
Fiyllre 3.-Percentage of lqpancics \\ith infant \~cighing ICSS
thnn ?,500 grams, by cigarette smoking category---_--_____
Figure 4.-;\\-erage birth weight by maternal smoking habit
(n) before current prcgnnnq- and (b) during current preg-
nnnc~-_____..____-_____-__-__-~_-__-__--__--__-_--__--
Fi/llrc 5.-Percent ol Ion- birth wright white infants by smok-
inr itaru5 of their rr~ottrers--__---__-- -- -- _____ -__ ___ --_
Fiprc 6.--Sconatal mortality rate5 nrnong single x hite births
in hnipitslz thy tletuiled birth weight and specified gestation
yro:1ps: L-Grrti ~tate;)__-_------.-~~~----~~- _._________
Fiirurc 7.-Pcxrinutal mortality rnte per 1,000 total births by
ci?arettc crnokin~ catc~or~-__-_----~--__--_-_--__------

List of Tables

T:~hle 1 .-Infant birth wciyht h_v mntcrnal and paternal smok-
in~jlnt~it;~-- ____ ~-~-~ .__.____ -___~  -__-.-_--_--_--~_-
Table Z.-Effect of carbon monoxide expo5;ure of pregnnnt
rabbit5 on birth weigllt--__ _ _. _ _. _. _ _. _ ___ .-~ _ -_ ___ __ _ _
Tt~ble I<.---Comparison of the perinntal mortalit>- for infants
15 ciching le-s than 2,500 grnms, of smokers and nonsmokers-
Table J.-Effect of carbon monoxide esl)osurc of pregnnnt rab-
bit5 on birth xeipht and neonatal mortality-________-______
Tnble AS.-Proportion of male infants deli\-ered to smoking nnd
non5mokjir.rr mother~-_--_-__-_-_----~--~-~-~--~~-~---~~
Tsble C.-Relative ri;k of congenital malformation for infants
of riqarette smokcr~ nnd nonsmokers, compnring available
studies nith rerard to stwlv desip, study population, samI)le
size, number of infants with mniformation~, and dtfinirioll of
mallorrnation __.__. -_--_--_-_-_--_----_-~-~---~----~--

425


431


441


447


450

451

r3w


418

419

422

424

427

442

443

415


Introtluction

Ci,nnrette smoking is a common ltahit among n-omen of chiltl-bearing
age in the [-nited Stntcs. In 1970, ap1)roxitnntcl~ one-third of --\mer-
icnn women of child-bearing age were cigarette smokers. The percent-
age of r-.S. !I-ontett who s~uokctl tlirort~hortt pregttxncy is not definitely
known, hut is presttrtt;~l~ly lo~rrr. pt-obabl~- in tl~e ttci~ltltorltood of 20
to 25 percent. \Vith n large fetal popttlntiort at potcntinl. but prewnt-
able, risk, the relationship betxectr ci,. vrctte smoking anti the out-
come of prrpattcy 11:ts Iwen the focus of considrrablc and continuing
research.

l`hc follr)\vittr is a t,evic%\v of n-014; previously rcportecl and recent
stnctics xrItic.11 lw:~r ott t lw rrlat ionsltips bet n-cm cigarette smokittg and
dilT0t cant otttcfltiws of I)rc,siinncy. In addition, the chapter includes a
revicw of tltc rrl:ttiortlliil) bet\Yccn cigarette smoking and lactation.

Smoking and Birth Weight

In 19.57. Simpsott (an), using n retrosprctire study dcsip. tleter-
tt~ittc~l tlt:rt nittong 7.499 women itt . y z=3ti Rcrtrxrdino CotititJ-. (`alif.. the
tlelivcrJ- of infants wet, .qrliinfl less tlran 2.500 grams was ncnrlv t \I-ire as
                     r

                                    417


frequent among cignrctte smol;crs as nmons nonsmol;cr;. Suhseqrlcntly,
hue (&) studied fLtH'7 women in Birmingham, England, and dem-
onstrated in his retrospective stud? that the infants of smoking
mothers u-err. deli\-ered only slightly earlier (1.4 days on the a\-erage)
than those of nonsmokers. He further noted that for gestations of 260
days and over, the infants of smokers were consistently lighter in
weight during each lx-eek of gestation than those of the nonsmokers.
This finding has been confirmed since, and figure 1 from the British
Perinatal Mortality Study (13) provides illustration of this
relationship.

Given the nearly constant disparity present bet!\-een the birth
rreigllts of the infants of smokers and nonsmokers for gestations of 260
days atid over, but absent prior to that time, and given t.he similar
birth weights of infants of nonsmokers and of lvornen m-ho gave ur>
smoking early in pregnancy and did not begin to smoke again, 1,oxv-e
inferred tllnt the influence of smokin g upon birth weight might lie
mainly in the later months of pre?Fnncy. He emphasized the tentative
nature of this conclusion, since the number of infants with 3 gestation
of less than 260 &J-S and the nunrber of WOIIWI~ who gave up smoking
early in the pregnancy and did not begin to srno!~e again were both
small.

Figure I.--Mean birth weight for week of gestation according to maternal smok-
     ing habit: control week slftgletons.'
                                               3650

125 -                        ,---o---7 3400
                             2
                         - 3150 5
                                                  -r
                   - 29oog
                                 r"
                      - 2650 5
                                                     2

85 -                                       - 2400



75 .                                  * 12150

   36    37 38 39 40 41 42    43+

           Gestation in completed weeks

`This term refers to singleton births In England. Scotland. and Wales occurring duting the
week of March 3-9. 1958. which are included in the Psrmatal Morfaltty Survey. There
com~nsd 97 percent of all births not,fied in England and Wales or registered in~Scotland
during ul,r wcJa*.

SOURCE: Butler. N. R.. Alberman, E D. (131.

418


LoKe found that the infants whose mothers smoked throuChout
pregnancy ~ci~hetl~ on the averxgr, 1iO ~I~:~IIIS Ir.s.3 than tlrojc n-hose
mothers did not Smoke. In addition, 11~2 notrtl t!int the c1itir.c tli5trih-
tion of weight5 of infant5 of 5rnoliers u.36 shifted to tlx left (t0w3rd
lower n-eights) relatise to that for tile infants of ~~on~mokets. This
finding, too, has been confirmed bv other investigators. Figure 2 olfcrs
an illustration from IUacJIahon, et al. ($I).

Given thnt the infants of snrokcrs and non.;nokeIs diRerrd only
slightly rrith respect to the duration of gestation, Lowe concluded that
the lower birth weight of smokers' infants must be attributed to a
direct retardation of fetal growth. In other words, on the basis of his
data, the infants of smokers were small-for-dates rather than truly
premature.

Many investigators have subsequently confirmed this point (12, 1-5,
%.~?5,65,78,85, 11.3). Buncher (I2), in a study of 49.63i births among
U.S. naval wives, in the same population studied by Underwood, et al.
(I&I), found that the infants of smokers were, on the average, de-
livered only 1 day earlier than those of nonsmokers. This finding
accounted for only 10 percent of the discrepancy in birth weight be-
tween the t\ro groups of infants. The remainder of tire studies resulted
in the detection of either similar variations in gestntionnl Icngth or
no average difference. In a recent study, JIulcahy and Murphy (56),

Figure 2.-Percentage distribution by birth weight of infants of mothers who did
     not smoke during pregnancy and of those who smoked 1 pack of
      cigarettes or more per day.
        INFANT WEIGHT AND PARENTAL SMOKlNG HABITS

            ,`.*,".,`","`,.`~,`~`I"`~

10 -  - Nonsmokers
    ----- Smokers
8-

4-

2-

0

,"',"~I...~'.'I~"I"'I".I
4 5 6 ; 8 9 10 11

   BIRTH WEIGHT (SCALE IN POUNDS; INTERVALS OF 4 OZ.)
SOURCE: UacMahan. et al. (49).

419


in - L sample of 5.099 Irish mothers, concluded that although the babies
born to cigarette smokers were delivered slightI\- earlier tllnn those
of nonsmokers, independent of age and parity, the direct ehcct of
smoking in retarding fetal grolvth It-as more significant.
The foilon-ing points, based upon the results from many different
studies, can be made about the relationship betrreen cigarette smoking
during pregnancy and lov+-er infant birth weight:
1. Tfomen who smoke cigarettes during pregnancy hare a higher
  proportion of low-birth-weight infants than do nonsmokers. This
  excess of low-birth-rveight infants among cigarette smokers pre-
  dominantly consists of infants who are small-for-gestationnl nge
  rather than gestatioually premature.

2. The entire distribution of birth x-eights of the infants of cign-
rette smokers is shifted toward lower xveights compared to the
birth reights of the infants of nonsmokers.
3. The birth xv-eights of the infants of cigarette smokers are con-
sistently lighter than those of the infants of nonsmokers when
the birth rreights of the t-so sets of infants are compared n-ithin
groups of similar gestational age beyond the 36th \veek of
gestation.

The results of the studies which have been considered so far identify
a relationship betxeen cigarette smoking and lorrer infant birth
weight and illustrate some aspects of that relationship, but do not
indicate whether the association is causal or indirect. The succeeding
two sections of this chapter contain evaluations of the available evi-
dence which bears upon the nature of the association between cigar-
ette smoking during pregnancy and the incidence of small-for-dates
infants.

EVIDENCE FOR A Carssa~ -\SSOCL~TION BE-ITZES CIGARETTE SXOKING
          ASD SMALL-FOR-DA= INFANTS

Evidence previously reriexved in the 1971 and 1972 reports on the
health consequences of smoking (201, 102). suggests that cigarette
smoking is causallv associated with the delivery of small-for-dates
infants. The follow& is a summary of this evidence:

1. The results from all 30 studies in xvhich the relationship between
smoking and birth xveight was examined have demonstrated a strong
association between maternal cigarette smoking and delivery of IOK-
birth-xveight infants. On the average. the smoker has nearly twice the
risk of delivering a lox-birth-weight infant as that of a nonsmoker

420



Figure

3.-Percentage of pregnancies with infant weighing less than 2,500
  grams, by cigarette smoking category.

5.0



4.0



3.0



2.0



1.0


0.0

Nonsmoker

Number of
infants weighing
<2,500 grams:   1.322         1.186

21 pack
per day

793

Total births:     28,358

   15,328

(P <O.OOl)

6,581

SOURCE; Ontario Department of Hdth (66).

422


r\,lsll alld I\n~j (S), in 3. prospective :tl~ll~. of 1.040 pregn:1ncics in
Boston, JIassachusetts; Domagala. ct al. ( 1.3). in a retrospectiw study
of 1.~3~ ljregnancies in Poland; and Jlukhcrjw and Xukhrrjee (54))
in 3 retrospccti\x2 study of t$SSG 1,rcgnnilciv.i in India. each found a
_+iFliticantlx higlier incidence of low-bil.tl~-\\-eight infants among
ciprette snrokers.

J3utlpr, ct al. (1.5) have further analyzed the I%ritish Perinntal Jlor-
t:llir- stud1 d;\ta. A1nalj.sis of tile 16,994 qlw5t ionnnires revealed tlI:lL
4O.S l)ercent of tllc wonlen were cigarette .-illoktrs before pregnancy.
.\fter tile fourt11 n~ontlt, tllis pewclltage liac1 decreased to 27.4 lwr-
cent. Given tlw large number of \vomrn in the study, and the siz-
nificnlrt chnn~es ill snioking belrnrior wlti~~li occurred, I3utlcr, et al.
found it l)os:-itIle to corlsidcr tlie vtrect of :I cl~~nge in smoking be-
hnl-ior on birtll neight. I)ct\\-een tlie beginnilig of the prtgnanq and
the fourth nlonth (after which srnokirtq bclinvior was repol.tellly
stable). TIK nltthors stated, "If snlokin~ itself (rather than the
type of wonmu who smokes) has a deleterious effect on the fetus,
it would be reasonable to expect tile mot tiew who gave up smoking
during pregnancy to shox differences in tllv birth weigllt and pcri-
natal mortality of their offspring comparecl \\.itli tliose who continued
to ~molw." Their results are prcscntetl in fig1Lr.e 4. Tile birth \\-eights
by ~nloliillg categories wt're estinlxted by u.,iiq a mait effect. motlcl
xvltho~it mediating variables. IIolrevvr, ttle alltliors rel)orted tllat \vilen
tile mcdinting \-ariables (social class, ntatcl-ll;li age, parity, nlaternal
height, scs of infant , gcstntional age, and lxrinxtal nlortnlitJ-) \rere
allowed for. the results of tile anal?-sis n-ew \-cry similar. The egect
of cigarette smoking before pregnancy \\`a~ ill-i;l:iticant compared to
that Of Smoking rtgu~arly after the fourtll nmnth of gestation. Tile
authors concluded, "The finding that a cha~\ae in maternal smoking
habits during pregnancy had the effect of plttting the baby intna-
birth wight and perinntal mortality rategory associated \vith the ne\v
smoking habits points toward some kind of cause-effect relationship.
* * * This finding is further strengtiwned t,y tile birtll \veigIlt analysis
lxl~ich S~OKS that the diminution in birtil \vcigIlt of tile otFspring of
smoking rnotlwrs persists 2nd is inclced littlr ~hnnge~ II-lle~~ ;llIolynnce
has been made for a number of other social and obstetric lnediating
factors."

423


Figure 4.dverage birth-weight by maternal smoking habit (a) before current
     pregnancy and (b) during current pregnancy.                  .
                                                        /

                            Number of clgaretteS/da!
                                 in current pregnancy,
                                 after the fourth month
3,400 - IJ         o--

3,100 -

I          I

0       1-I

I

5-9

  I         I

lo-19     2&30    Total

Number of cigarettes/day before current pregnancy

brths:
21.671

SOURCE Adapted from Butlar. o t ml. (15).

EWDESCE FOR AN INDIRECT Assocurros BETWEEN CIGARETTE SXOEINO
          AND SMALL-FOR-DATES INFANTS

Yerushalmy (113,114,115) has suggested that smoking is an index
to a particular type of reproductive outcome and thus does not play a
causa1 role in the production of small-for-dates infants. He has de-
veloped several lines of support for this hypothesis, from an analysis
of data from the prospective investigation of 13,083 mothers in the
Oakland Child Health and Development Study. He has emphasized
that ineffective randomization and the phenomenon of self-selection
complicate the development of appropriate inferences with regard
to causality. Such difficulties do not prevent the identification of
causal associations, but they demand careful and critical analysis of
the data. Yerushalmy has questioned the causal nnture of the relation-
ship between cigarette smoking and small-for-dates infants because
of: (a) The relationship between the smoking habit of the father'
and low birth n-eight of the infant, (b) behavioral differences between
smokers and nonsmokers, and (c) comparison of the birth tveights

424


of a moman'~ infants born during tile periotls when slle snloked ciga-
rettes and when she did not.

`t-erushnln Iy (II-$) llns stated thnt tile smoking hnhit of the fxther
could not, reasonably be related to the birtll w3yht of tlw infxnt. From
prelimin:lry data derived from tile stuclx, ho\rcwr, he dctcrnlined
tllat there KX 311 increased incidence of lo~r-bitlll-\~cigllt inf:lrlts
when the fnthers smoked rind, nlorcorer, there was xi npI>arent doie-
response relationship as found for mater.n;tl smoking. Ilorwcr, he
noted that on1y lrhen both the husband :III~[ the wiEc sr11olm1 WC the
incidence of lo~~~--birtl~-~~eifil,t babies incrr;\sed. Ire felt thnt these
findings supported the conclusion that snwking AXIS :I mxrkrr of
t?-pes of individuals and not a cnusai f;lctor for low birth \I-ei,eht.
Other investigators have since csamined this relationship ($9, I&I),
but none llns confirnicti an inrle~~endcu~ nssocixtion for ptcrnxl
smoking. Tlw association between paternal snloking and birth wipht
:\ppwrs to be nn indirect enc. Paternal and maternal smokin,rr be-
Il3\-inr :ire I~ifihly correl;\ted :~nd mnternat sinckity is stron,$y related
to illi;lnt birth vieight. Undern-ood, et al. (100) studird J8.505 women,
tllcil- Ilr~sbnntls' Smoking bcllnrior, ant1 tllc wlntion wit11 birtll KriFllt
(table 1). If the JIlOtllC'l' \<-as n lionslriolir~~, then the father's smoking
hat1 no influcrirc 011 the Girth weight of tllc infnnt.

T.IBLE l.--llLfant birth weight by ?Jlo/el`JLd and paiernal smoking habits

425


Ounsted ((8) offered evidence that the best predictor of thr tjirth
xveight of a mother`s future offspring TWS the birth weight of her
previous children. Hcrriott: et al. (3.5) found prcmnturit_v rates for
prex-ious prepnncics among smokers to be markedly 1Iiplrer than
among nonsmokers, independent of parity, height, and social class.
Evidently n woman \Tlioze previous infants lin~t: been small trntls to
roritiniie to have relatix-cl\- srnaller tlran avcrn~e infants in srlbaequfnt
prepxncies. The question is- will those infants be even sm:lllcr than
expected if 511~ smokes?

Goldstein, et al. (I'S). in a comprehrnsiw re~icw, proposed a research
dcsi? in which :I u-omen ~~oultl sewe as her own control to compare
outcomes of l>rewIancics tlririn_rr \rhich she sInoked with those during
             .:
\rhich she did not, xitli consideration of the effect of parity on the
outcome. Terushnlrtiy (213) has recently tested this type of research
design. using data from his O:Ikland Growth Study. \\`ith information
on the aye ;It wlIjclI a \I~ornnn Iwpn to .srnoke ci,carcttes, her smoking
status during the prr,yancx- nctunllv studied, her prior rcproductir-e
experience. and the outcome of her present pregnancy, the author
compared the outcomes of pre-gnancx during periods of smoking and
nonsmoking using the Toman as her orrn control. -AS the author noted,
"If smoking cnuer; tlIe increase in lo\~--birtli-~~ei,nlIt infants. then the
incidence of low birth n-eight for infants born to smoking mothers
during the period before they acquired the smoking habit. should be
relatirelv lo\\-. If, on the other hand, the high incidence of Ior birth
weigf>t is due to the snooker. then it should behigh for infantsof future
smokers also rrhen they rrere born before their mothers started to
smoke."

Yerushalmy then proceeded to compare the reproductive experiences
of four groups of women: (a) Those n-110 smoked in none of their
.pregnancies, (b) those who smoked in all of their pregnancies. (6)
those x-ho n-ere smoking no-x but preriously had not smoked during
some pregnancies (future smokers), and (d) those who mere ex-
smokers norm but had prrviouslr smoked during some pregnancies.
These outcomes are shorrn in fi-pre 5. The incidence of lox--birth-
weight infants in the pre;qancips of the future smokers. before they
started to smoke, was similar to that for n-omen who smoked in every
prepancy, which rws significantly higher than that of infant-s from

426


There at-e se\-cral considerations which limit the interpretations
rrilicl1 ran be dra\rn from this study. The information on smoking
bcli:~~ior of the ~vottwtt (luring past prcgttnticies was nppnrently de-
riwd from the lvomntt's :tee x-hen she began to smoke, her smoking
bcllnvior carI~- in the stuc!v pregnancy, and the age at which she hnd
Ilcr prior prcgn3ncics. `I`! 1~. if t.he wotnnn reported that site began
smokitt~ at :I ccr-taitt age, and that she vns still smoking at Ihe time of
the study. it \vns apparently inferred that ahe hnd smoked during ali of
her pt-cgttnncirs. Since no questions wx-e specificnlly asked about actual
sntokinr behavior during ench previous pregnancy, it is possible that
tlw woulnn indeed had not smoked duritq erery pregnancy or that
the amount or wny she smoked had differed from current smoking

Figure L-Percent of low birth weight white infants by smoking status of their
        mothers.

Gravidas' smoking habits
in previous pregnancies

Nonsmoker
(during all pregnancies)

Percent low birth weight infants



   .               2,529

Nonsmoker
(future smoker)

9.5               o           210

Smoker                                .*
(during all pregnancies) .  8.9                    2,076

Smoker
(future ex-smoker)

. .                651

                   2 4 6 8 10
                        Percent
*Difference is statistically significant (P <O.Ol).
**Difference is statistically significant (P <O.OZ).
SOURCE: Adapted fmm Yarurhalmy. J. (:Iz).

427


habits. This \rould 1~ important to know gil-en the stron? don-
response relntiowhip xThich has been established Lxtween cl,pnrette
smoking and Ion- birth wright, and xould tend to make the rcproduc-
tive outcomes for es-smokers similar to those of nonsmokers, and
different from those of women x-ho smoked in all prcgnanries.

For es-smokers, the age at which smoking began wns not elicited.
Hence, some of the infants of ex-smokers may have been born Ixfore
their mothers acquired the smoking habit. This would also tend to
make the reproductive experiences of eu-smokers more like those of
nonsmokers and different from those of women who smoked in all
pregnancies.

So direct adjustment for age, parity, and other vnriablrs was
reported, although Yerushalmg stated that the study population was
limited to the births that occurred to women at nge 25 yenrs or less.
He noted t.hat, "In order to adjust for parity, the same comparisons
\vere performed for firstborn infants only. The numbers were reduced
considerably, but the same tendencies as found abore xere noted."
Hoxwver, no data were presented. Primiparous births and births in
teenagers are strongly associated with the delirery of low-birth-rreight
infants. If the pregnancies which occurred among future smokers
included a predominance of veq young v-omen and prirniparous
births, the reproductive experiences of future smokers would tend to
be similar to those of xromen rrho smoked during all pregnancies, and
diserent from those of nonsmokers. In the absence of more precise
information on actual smoking behavior during pregnancy and more
rigorous adjustment for maternal age, this study does not provide
a critical test of the hypothesis that it is the smoking during pregnancy
Khich is responsible for the high proportion of small-for-dates in-
fants born to women who smoke.

Experimcntd Studies

STUDIES IN ANIMALS

Tobacco Smoke

Several investigators have demonstrated that exposure of prepant
rats or rabbits to tobacco smoke leads to a reduction of birth wlght
in the offspring, as compared to controls (%`A', 87,127). Younoszai, et aI.
(127) reported data from studies in rats which indicntcd that some
agent pre.vnt in cigarette smoke other than nicotine was responsible
for the reduction in birth Keight observed. The authors suggested thnt
carbon monoxide might also not be responsible for the retardation of

428


fetal grolrth; however, the evidence presented ~3s inadequate to
support 3 firm conclusion.

IIaworth and Ford (33) rccentlp extended the experiments of
Younoszai. A group of pregnant rats was csposed to cigarette tobacco
smoke for 6 to 8 minutes, five times a day, from days 3 to CO of ges-
tation. These rats were compared lvith another group those food
intake was restricted to the amount actunlly consumed by the tobacco-
exposed rats, and both were compared to R well-fed control group.
Tile animals in both experiments were killed on the 21st day of
gestation, and weights of the entire body, the liver, and the kidney
of each fetus were recorded. The total average fetal weight of the
group exposed to tobacco smoke was significantly lower than that of
both the food-restricted and control groups. The fetal weigl~ts of the
latter two groups wzre quite similar. Protein and DNA analyses wre
performed separately on the entire forebrains and hindbrains of the
fetuses and on the entire carcass. 130th DSA and protein were sig-
nificantly and proportionately reduced in the carcass and hindbralns
of the animals exposed to tobacco smoke. This itnplies that cell number
\ras reduced and cell size was normal, and suggests that the exposure
to tobacco smoke either inhibited cellular proliferation or accelerated
cellular destruction.

Nicotine

Several xvorkers have demonstrated that chronic injections of large
doses of nicotine into pregnant rats resulted in a reduction of birth
IL-eight of the offspring ( 7, 8, 9, 23, 40). Other investigators have de-
termined that tritiuIn-labelled nicotine injected into pregnant rabbits
and C"-1abelled nicotine injected into pregnant mice crossed the
placenta to the developing embryo and fetus (89, 98). Kirschbaum,
et al. (41) found no significant acute effects of small doses of nicotine,
injected intravenously into near-term sheep, on blodd gas composition,
pH, blood pressure, or heart rate in either the evzes or their fetuses.
The authors concluded that the influence of maternal smoking upon.
                                                      -
the fetus must result from chronic effects or through the effects of
other variables which they did not study.
Recently, Suzuki, et al. (94) evaluated the short-term effects of in-
jected nicotine on the cardiovascular performance, acid-base status,
nnd oxygenation of pregnant female Rhesus monkeys and their infants
during the second half of gestation using the mothers as'their ovn
controls. Nicotine was administered either as a single intravenous
dose of 0.5 to 1.0 mg. or as a continuous infusion of 100 pg./kg. over
    49>~0230-i3-9

429


a X-minute period. The injection of nicotine in the larger, single dose
into the mother produced a rise in maternal blood pressure and a
fall in maternal heart rate, and an immediate fall in both fetal hlno(l
pressure and fetal heart rate followed by pcrsistcnt hypotcnsion and
tachpcardia in the fetus. Subsequent to the injection of 1.0 mg./kg. of
nicotine into pregnant monkeys, in a single dose, significant chnnqcs
in the arterial blood of the older fetuses included a fall in pII, a rise
in base deficit, and a fall in oxvgen tension. Carbon dioside tension
remained unchanged. Sicotine injected directly into the fetus prompted
an immediate rise in fetal blood pressure and a fall in fetal heart
rate. These responses were similar to those previously seen in the
mot,hers follorring a direct injcct.ion of nicotine. The changes mere more
prominent in older rather than in younger fetuses. The authors sum-
marized their findings by stating that: (a) fetuses in different ges-
tational stages are difrerentially responsive to a given dose of nico-
tine, probably because of the different stages of development of the
autonomic nervous system; (b) diminished intervillous space per-
fusion resulting from vnsotonstriction in the uterine circulation np-
pears to be mainly responsible for the fetal asphyxia following the
injection into the mother, because fetal hypotension and bradycnrdin
were not preceded by the transient hypertension seen following the
direct administration of nicotine to the fetus; (c) the differences he-
tween the results obtained hy Kirschbaum and by Suzuki, et al. may
reflect either the considerable dosage differences or species differences:
and (d) the doses xhich the authors empioyed were much larger than
those which a human mother would absorb from usual cigar-ette smok-
ing, but that differences in tolerance to nicotine between tile Rhesus
monkey and humans would imply that the dosages were, in fact, com-
parable and that, "Hence, it can be envisaged that the concentration
of nicotine which could be reached in the organism of a smoking
mother xould reduce oxygen availability to the fetus."

Carbon Monoxide

Long0 ($5) has reviewed the work of several investigators which
has demonstrated the transplacental passage of carbon monoxide from
mother to fetus in animals. A recent study n-hich related CO to birth
xeight was published by Astrup (2). He found that continuous es-
posure throughout gestation of pregnant rabbits to different levels
of ambient carbon monoside resulted in a statistically significant dose-
related reduction in birth weight (table 2). The actual significance
level was not reported.

430


Sumber of pregnnrlt rabbits __________      17         14          17
Total number of babies .___.__________     116        Sl        123
Xwrnge weight uf babies in grams.. _ _.      53. 7       5 1 0        44. 7

SOC`RCE: Astrup, P. (f).

PoIpc\-cIic nromntic ~~yd~xxxr~ons (I'-IH) such 3s bcnzo(:l)pyrene
(B_IP) nre const,ituents of cigarette smoke which have been impli-
cated in the generat,ion of cancers in many animal species (112). So
studies presently available relate brnzo(n)p~rcne to a reduction in
birth n-eight. of esposed offspring. Evidence wggests, however, that.
UAP does reach and cross the placenta. Xryl I~>-drocarbon hydrosylase
(.~HH) is a part of the cytochrome P-GO- containing microsomal
enzyme system, present in many tissues of different species. This
enzxrnc system is induced to hydroxylate pol~cyclic aromatic hydra-
carbons after exposure of cells to PdH. Several investigators have
utilized the inducibiiity of the enzyme system to demonstrate indirectly
that benzo(x)pyrene and other polycyclic IIydrocnrbons reach the
plncenta and fet,us.

IreIch, et al. (108) extended this work by administering the poly-
cyclic hydrocarbon, 3-metlly~cholnnthrene (3-MC), to rats during late
gestation. The metabolism of t)enzo(ajpyrene ~-as studied in viva (us-
ing t.ritium-labelled benzo(a)pyrene) and in vitro. AHH activity KLS
increased in fetal livers to adult levels by pretreatment with 3-NC
Since B relatively high dose of polycyclic hydrocarbon was requird
to stimulate enzyme activity in the fetus, compared to the dose which
stimulated placental enzyme activity, the authors suggested that the
placenta may protect. the fetus from esposure to polycyclic hydro-
carbons. However, immaturity of the fetal rnzvme qstenl rni,nIlt aiso
account for its apparent rclntive insensiti\-ity to pal!-q-clic llydro-
carbons. Thwefore, an exposure of the fetus to levels of poly-
cyclic h>-drocnrbon similnr to those experienced b- tile motllcr cannot
bo ruled out by the available data.

431


Schlede and Merker (86) hare studied the effect of benzo(a) pyrene
administration on nryl hydrocnrbon hydroxylnse nctivity in the mnter-
nal lir-er, placenta, and fetus of the rat during the latter half of
gestation. The pregnant animals were treated with large oral doses
of benzo(u)p\-rene 24 hours prior to sacrifice. Co!ltrol rats had no
detectable levels of aryl hydrocarbon hydrosylnse in their plnccnt*?s.
Treatment with benzo(a) pyrene resulted in barely detectable plnccntal
levels on gestation day 13, but steadily rising values until day 15, and
then constant levels thereafter. No activity was detected in the fetuses
of untreated controls. In the treated animals, the fetal enzyme activity
rose steadily from the 13th to the 16th day of gestation. The authors
concluded that the stimulatory effect of benzo (a) pyrene treatment on
aryl hydrocarbon hydroxylase activity in the fetus demonstrates that
benzo (a) pyrene readily crosses the rat placenta.

STUDIES IN IImraxs

Carbon Monoxide

Smokers and their newborn infnnts have significantly elevated levels
of carbon monoxide as compared with nonsmokers and their infants
(31,3.j, 88,116). Recently, Raribaud, et al. (5) studied 30 nonsmokers
and 27 ciF"rette smokers and their newborns. All smokers inhaled. The
authors found that the mean level of CO content in the blood of non-
smokers was 0.211 volumes percent compared with 0.679 volumes per-
cent in the blood of smokers. The values for blood samples from the
umbilical cords of tlleir ne\vborns were 0.352 and 0.949 volumes per-
cent, respectively. Moreover, a definite dose relationship was found
between CO levels and number of cigarettes smoked.

Younoszai, et al. (116) found, in addition to elevated cnrbosyhcmo-
globin levels among the infants of smoking mothers, significant
elevation of mean capillary hemotocrits and significant reduction of
standard bicarbonate levels, as compared to the infants of nonsmoking
mothers. Since no evidence for nicotine effects upon blood glucose,
serum FFA levels, or urinary catecholamines, or for hypoxia was
present, they concluded that the higher hematocrit levels in the infants
of smoking mothers may have represented a compensatory response
TV the decreased oxygen-carrying capacity of the blood due to the
presence of csrboxyhemoglobin.

Long0 (45) pointed out that a level of 9 percent carboxyhemoglobin
in the fetus is the equivalent of a 41 percent decrensc in fetal blood
flow or fetal llemoglobin concentration. In reviewing tllc studirs of
CO lewls in human mothers and their newborns, llc made the follolr-

432


inp comments: "Tlicse samples xrerc obtained at the time of vaginal
delivery or Cfsnrenn section 2nd rnnv not accurntelv rcHect the normal
values of (COIIb) F for several rcason~. T!ie nrimber of cigarettes
sm0ked by the mothers during labor niay be less than their normal
consumption and was not specified in these studies. The blood snm-
pies were collrrtetl :it I-arving time periods folloxing the cessation
of smoking. In addition, JW111y of the samples were probably taken
early in the day beforr C'OIIb le\-els had built up to the levels reached
after prolonged periods of smoking. Thus actual lcl-els of (COHb),,
and ( COIlb) E. may be higher than the report4 values."

Polgcyclic Hydrocarbons

The results of several studies concur that cigarette smoking is
strongly associated with the induction of ar-yl hydrocarbon hydros-
y-lnse in the human placenta (Z&38, 61,99? 109). This finding implies
that benzo (a) p~rcne or other polycyclic hydrocarbons reach the
placenta. To date. evidence to support the pnssa,ge of polycyclic hydro-
carbons through the placent,z to the human fetus has not been
published.

         Vitamin B ,? and Cyanide Detoxification
McGarry and ,Andrews (48) determined serum vitamin B,, levels
in 8% women at their first prenatal clinic visit. The\- found that the
                                          _
serum levels for smokers were significantly lower than for nonsmokers.
Sfter adjustnwnt for gestatioiial age, parity, social class, hemoglobin
levell hypertension, and maternal weight, smokers still had signifi-
cantly Ion-cr levels of B,?. They also found a direct. statistically sig-
nificairt dose-respoirse relatioiiship betrreen cigarettes smoked and
serum vitamin B,, level. They again confirmed the relationship be-
tween smoking and lox birth weight. The authors suggested that the
lowered vitamin B,, levels reflect a disorder of cyanide detoxification.
Cyanide is a demonstrable ingredient in cigarette smoke (39, 6'0, 62,
64:68,74,91).

Vitamin C

Penulet (105, 10.6, IO?`) has demonstrated that the vitamin C level
is significantly lovrer in the serum of xvomen xv110 smoke cigarettes
during pregnancy, compared to values for their nonsmoking counter-
pa&i.

The following mechanisms have been proposed for the production
of low birth weight and other unfavorable outcomes of pregnancy
follo~ringevposuretocignrettesmoke:

433


1. A dirwt toxic influence of constituentsof cignrettc smokeupon
the fetus (2, $5, 50, 51, 217).

2. Decreased placent31 perfusion (94).
3. Decreased maternal appetite and diminislrcd mnternnl wright
gain xvith secondnry effects upon the fetus (G, 33, 36, 65, 75: 9%
117).

4. A direct effect upon the placenta (x,Lz', 65,110).
5. An omytocic effect on uterine nctivity (d$).
6. A disturbance of vitamin B,, metabolism (48).
7. A disturbance of vitamin C metabolism (1/X,106, IW).
Of the potential mechanisms, available evidence suggests that
neither decreased maternal appetite and decreased maternal weight
gain nor a direct effect upon the placenta are responsible for a sig-
nificant reduction in birth weight. Existing evidence does not permit
firm conclusions concerning the relative significance of the remnining
mechanisms.

Timing of the Injlucnce of Cigarette Smoking on Birth Weight

Several investigators have published results which bear on the time
period during which exposure to cigarette smoke most affects fetal
grolvth. Lowe (46) and Zabriskie (118) have offered evidence which
suggests that cigarette smoking influences fetal growth most during
the second half of pregnancy. Butler, et al. (15) found that the birth
weights of infants of xomen who did not smoke after the fourth
month of pregnancy were. essentially the same as those of the infants of
nonsmokers. This implies that the influence is most probably exerted
after the fourth month of pregnancy. Herriott, et al. (35), however,
found that women in louver socioeconomic classes w-ho gave up smoking
early in pregnancy tended to have intermediate weight babies as com-
pared with nonsmokers and persistent smokers, but his numbers of
women Ivere small and the results were not atat.istically significant.
Cndern-ood, et al. (ZOO) found that cigarette smoking in any single
trimester was associated xvith a louver birth weight. of the infant,
although the difference between the birth xveiglrts of infants of
-omen n-ho smoked only during a single trimester and infants of non-
smokers was not statistically significant because of srnnll numbers.
Several investigators have detected a nearly constant difference be-
tween the birth weights of the infants of smokers and nonsmokers.
delivered during the last month of pregnancy, follnvrinp gestations
of comparable length [fig. 1, (zI)]. Although this observation is

434


compatible rrith the suggestion that the infurnce of cignrrtte smoking
upon the fetus occurs prior to tile last month of pr-e,~n:~nc>-. it is b:~-ed
upon data derived from cross-sectionnl r;\tllcr ti~nn longitudinal
studies. The results of many human epidemiol<~gicni studies suggest
that maternal smoking prior to pregnancy does not influence fetal
weight gain (1$25,46,@, 113).

Site of Action at the Tissue and Celldar Level

The use of labelled nicotine (98) and the preparations of autoradio-
grnms have permit.ted the localization of nicotine within the tissues
of the fetus and mother. Tjalve, et al. (95') found high levels of nico-
tine in the respiratory tract, adrenal, kidney, and intestine of 16- to 1%
day mice fetuses. The use of other labelled constituents during various
parts of gestation might. further the understanding of horn certain
ingredients in cigarette smoke produce an impact upon birth lveight.
Haworth and Ford (33) have reported data which suggest that the
reduction of birth weight of rat fetuses caused by the action of the
ingredient(s) of tobaccosmoke results from a reduction in celi number,
but not in cell size.

Signifinnce of the Association

Among nil women in the United States, cigarette smokers are
nearly twice as likely to deliver lowbirth-n-eight infants as are non-
smokers. Assuming that 20 percent of pregnant women in the fi:nited
States smoked cigarettes through the entire pregnancy (estrapolated
from data on changes in smoking behavior during pregnancy collected
for the British Perinatal Mortality Study), taking into account the
apparently different risks of delivering a small-for-dates infant for=
Caucasian and non-Caucasian women who smoke during pregnancy,
and considering the number of infants with a birth neight less than
2,500 grams born to Caucasian and non-Caucasian n-omen, an excess
of nearly 43,000 occurred in the 286,000 low-birth-weight infants
among the 3,500,000 infants born in the United States in 1968, because
of the increased risk among women who smoke of having smxll-for-
dates infants.

Since neonatal mortality is higher for lov-birth-weigth infants,
with gestational age held constnnt, the excess of small-for-dates infants
among smoking moth& would imply a significant excess mortality
risk as well.

435


Birth Il-tight Summury

A causal association betxwtn cigarette smoking nnd fetsl growth
retardation is supported by the following evidence:

1. The results of all 12 studies in xv-hi& the relationship betrreen
smoking and birth weight ~cas examined have demonstrated a
strong association betrreen cigarette smoking and delir-cry of
small-for-dates infants. On the nverage, the smoker has nearly
twice the risk of delivering n lov-birth-lveight infant as that of
a nonsmoker.

2. This association has been cotirmed by both retrospective and
prospective study designs.

3. A strong dose-response relationship has been established betxveen
cigarette smoking and the incidence of low-birth-weight infants.
Available evidence suggests that the effect of smoking upon fetal
growth reflects the number of cigarettes smoked daily during a
pregnancy, and not the cumulative effect of cigarette smoking
which occurred before the pregnancy began.

4. When a variety of known or suspected factors which also exert
an influence upon birth weight have been controlled for, cigarette
smoking has consistently been shorn to be independently related
to low birth weight.

5. The association has been found in many different countries,
among different populations, and in a variety of geographical
settings.

6. New evidence suggests that if a woman gives up smoking by the
fourth month of pregnancy, her risk of delivering a lore-birtb-
weight infant is similar to that of a nonsmoker.

`7. The infants of smokers experience a transient acceleration of
growth rate during the first 6 months after delivery, compared
to infants of nonsmokers. This finding is compatible with viewing
birth as the removal of the smoker's infant from a toxic influence.
8. The results of experiments in animals have shown that exposure
to tobacco smoke or some of its ingredfents results in the delivery
of low-birth-weight offspring. New evidence demonstrates that
chronic exposure of rabbits to carbon monoxide during gestation
results in a dose-related reduction in the birth weight of their
offspring.

9. Data from studies in humans have demonstrated that smokers'
fetuses are exposed directly to agents within tobacco mloke, such
as carbon monoxide, at levels comparable to those vrhich have
been shown to produce low-birth-weight offspring in animals.

436


Cigarette Smoking nrld Fetal and Tnfarlt ;\Iortalit>

Introduction

Sex-era1 previous studies of-the relationship betrreen cigarette smok-
ing and higher feta1 and infant mortality among the infants of smokers
have been revie\red in the 1971 and 1972 reports on the health con-
sequences of smoking (201, 102). In many of these studies, the authors
combined two or more categories of fetal and infant mortality. Diifer-
ent mortality outcomes, such as spontaneous abortion, stillbirth, and
neonatal death, are influenced by different sets of factors. Among
other factors, the frequency of abortion is influenced by congenital
infections, hormonal deficiencies, and cervical incompetency. In adtli-
tion to other factors, the frequency of stillbirth is influenced by prc-
mature separation of the placenta, uterine inertia, and dyst.ocia. .Ilong
with other factors, the frequency of neonatal denth is influenced by
gestational maturity, birth injuries, and delivery room and nurses-y
care. Separate analysis of the relationship of cigarette smoking to
each different mortality outcome, with control of the unique set of
factors xyhich influences it., may facilitate understanding of the
relationship.

Spontaneous Abortion

Previous epidemiological and experimental studies of the relation-
ship between spontaneous abortion and cigarette smoking reviewed in
the 1971 and 19i2 reports on the health consequences of smoking (101,
10.2) form the basis of the following statements:

The results of several studies, both retrospective and prospective,
have demonstrated a statistically significant association bettreen ma-
ternal cigarette smoking a~rd spontaneous abortion (4~7, 65, 70, 99,
118). Data from some of these studies hare documented a strong dose-
response relationship between the number of cigarettes smoked and
the incidence of spontaneous abortions (`iO,99, 118). In general, rari-
ables other than cigarette smoking (e.g.: maternal age, parity, health,
desire for the pregnancy, and use of medication), which may influence
the incidence of spontaneous abortions, have not been controlled. The
results of the one study, in n-Irich adjustment for the xroman'n desire
for the pregnancy was performed, indicated that after such adjust-
ment cigarette smoking during the pregnancy retained an association
with spontaneous abortion of borderline significance (4s). The time
period during which cigarette smoking might exert an influence on
the incidence of spontaneous abortions has not been determined. Abor-

437


tions have been produced in animals only with large doses of nicotine
(A?,%, 20;) ; t 1 le rc!er-ante of the3 studies for humans is uncertain.

-1Ithough several investigators have found a significantly higher,
dose-related incidence of spontaneous abortion among cigarette
smokers as compared to nonsmokers, the lack of control of significant
a-ariables other than cigarette smoking doe.s not permit a firm con-
clusion to be drarrn about the nsturoof the relationship.

Epidemiological studies of the association bet,r;een cigarette smok-
ing and stillbirth previously reviewed in the 1971 and 19-;2 reports on
the health consequences of Emoking (101,102) form the basis for the
follorringstatements:

In one group of retrospective and prospective studies, a higher stiII-
birth rate ~WS found for the infants of smokers as compared to those
of nonsmokers (14, 2.5, $3). In another group of retrospective and
prcqective studies, co significant difference eras detected in the still-
birch rate among the infants of smokers and nonsmokers (16,20,85,99, .
100). Differences in stud\- size, numbers of cigarettes smoked, or the
presence or absence of control of variables, such as age and parity,
which may influence stillbirth rates, were probably not sufficient to
explain the differences in results obtained.

Several recent epidemiological studies have added to our under-
standing of the relationship between cigarette smoking and stillbirth.
Siswander and Gordon (63) have reported data from 39,215 preg-
nancies followed prospectively and collected between 1959 and 1966
at 12 university hospitals in the United States. d random sample of
rromen who presented to hospital prenatal clinics were enrolled in the
study. The authors reported no increase in stillbirths among white
smokers as compared rrith Khite nonsmokers. -4 higher incidence of
stillbirths was found among black women xho smoked than among
nonsmoking black Komen. and a dose-response relationship Kith
ciprettcs smoked xvas suggested, although the findings did not attain
statistical si3qificnnce. The results rrere not adjusted for other vari-
ah&. FL&~ and Kass (82) found, in a prospective study of 3,296
prepancies at, Boston Cit- I%ospital, a nonsignificant hCre3Se in

438


stillbirths among white Tomen who smoked, but a statistically signifi-
cant increase in dillbirths among black women who smoked (P<O.OZ).
These findings are consistent rrith those previously outlined by
Frazier, et al. (2.5) and Underwood. et al. (99).

Rumeau-Roquette (81)) in a prospective study of i,S-31 pregnancies
in Paris. demonstrated thnt the risk of stillbirth was signiticantly
higher for cigarette smoker; than for nonsmokers (P<O.OOl). The
authors also presented evidence that a woman with either a previous
stillbirth or at least one prior infant weighing less than 2,500 grams
at birth was significantly more likely to have a future stillborn infant
thnn a woman Gthout such an obstetrical history. After previous
obstetrical history was controlled, smokers still retained a statistically
significant increased risk of subsequent stillbirth as compared to non-
smokers (P<O.Ol). Of further interest was the finding t.hat among
women rrho previously had delivered only living infants, rreighing
over 3$00 grams, cigarette smoking had no influence on the stillbirth
rate.

Previous experimental studies xere reviewed in the 1971 and 1972
reports on the health consequences of smoking (202,102). The authors
demonstrated that exposure of pregnant rabbits to tobacco smoke and
prepant rats tc large doses of injected nicotine resulted in a signifi-
cnnt increase in stillbirths (7,8, .S, 6').

1. The results of recent studies suggest that cigarette smoking is
most strongly associated with a higher stillbirth rate among
women who possess less favorable socioeconomic surroundings or
an unfavorable previous obstetrical history. In the United States,
black Tomen have higher stillbirth rates than white xvomen. The
finding that cigarette smoking is associated with an even greater
difference betlwen the stillbirth rates of the two groups merits
special attention. These findings may provide at least a partial
explanation for the lack of a significant difference in stillbirth
rates between smokers and nonsmokers, which some investigators
have found.

2. The results of experiments in animals demonstrate that csposure
to tobacco smoke and some of its ingredients, such as nicotine,
can result in a significant increase in stillbirth rate.

439


Late Fetal and ,\`eonatal Dcdh

Considerable variation has occurred in the definition of the study
population among the studies in which the relationship of cigarette
smoking to fetal mortality (other than abortion) nnd early infant
mortality was examined. The most commonly identified study populn-
tions have been perinatal deaths, nconutal deaths, and late fetal plus
neonatal deaths. Pfrinatal deaths are ~3 combination of Intc frtal tlcaths
(i.e., . stillborn infants) and deaths occurring within the first week of
life. Xeonntal deaths include all deaths of liveborn infants within the
first 28 days of life.

Jiost of the earlier epidemiologic4 studies of the association bctwen
cigarette smoking and late fetal plus neonatal mortality were reviewed
in the 1971 and 192 reports on the health consequences of smoking
(102. I&?). A review of previously unreported studies (C7. 76)) as well
as mouamination of previously cited studies, forms the basis of the
follo~vingstatements:

The results of several prospective and rctrospcctiw studies indicate
a statistically significant hi&r late fetal and/or nconatnl mortality
for the infants of smokers compared to those of nonsmokers (I$. 17,
Z-5, $3). The results of othrr prospective and retrospective studies idcn-
tified no significant difference in the mortality rates between the in-
fants of smokers and nonsmokers (20, 65, 73,&S, flk3, 11.5).

If mortality rates xl-ere compared for those infants of smokers nnd
nonsmokers weighing less than 2.500 grams, the infants of nonsmokers
apparently had a considerably higher risk than did those of smoker;.
The results of recent studies, coupled with a critical rerirw of the
desikm and analysis of preGous studies, and a reexamination of esist-
ing data, may provide at least a partial esplanation of discrepancies
between the results of previous studies.

Comparisons of the 3Iortalitv Risks of r,o~~---~il-th-~\`ci~l~t Infants
       Born to Smdkers and Xonsmokers

The perinatal mortality risk for infants weighing less thnn ?.NO
grams appears to be lover for those infants born to ~vomcn KIIO
smoke during pregnancy than for those born to nonsmokers (tnblc

440


3). Elo~ewr, available evidence shoxs that cigarette smokers' infants
tend to be small-for-gestntional age ratlier tlinn gestationally pre-
mature. Hence, within a giJ-en birth wight group, the infants of
smokers are, on the average, gestationally moremature than those of
nonsmokers. Data collected by the Sational Center for Health Stn-
tktics (203) demonstrate that Athin a given birth xveight group: the
more gestationally mature an infant, the lower is its mortality risk
(fig. 6). Thus, the difference in pet-it&al mortality risks experienced
by tile infants of cigarette smokers and nonsmokers, within comparable
birth weight classes, reflects the facts that the tx7-o sets of infants are
not of the same average gestational age, and that gestational age is
LI major factor influencing late fetal and neonatal mortality. ~111 accu-
rate estimate of comparative mortality risks for the infants of cig-
arette smokers and nonsmokers requires adjustment for gestational
age.

For infants of comparable gestational age, loner birth xl-eight is as-
sociated x-ith higher mortality (fig. 6). Since infants of cigarette
smokers ha\-e, on the average, lower birth weights than the infants of
nonsmokers, within groups of comparable gestational age, cigarette
smokers infants should experience higher mortality rates than non-
smokers infants of similar gestational ages. In a recent revierr, Never
and Cornstock (51) provided a more cstensire discussion of these
points.

TABLE 3.-ComparirmL of the perinatal mortality jar infants weighing
    less than 2,500 grams, of smokers and nonsmokers

Perinatal mortalfty rate (deaths per 1.~03
        lire birth5)

Smokers      h'omokers

Underwood, et nl. (100)___--- _.__.._____. ~_._     187          269
Ontario Depnrtment of Health (67)._----------     232          300
Kullander and Kiillen (43)-------------------.     129          139
Haotaksllio (7~)~~---~~----------~--~~-..---~     288          344
Yen1shalmy ' (II):
   Black women-------~--- ______._.___..__     114          202
   White a-omen- __...__..___ -__----___-_-_     114          218
Butler and Alberman (f4)------------ ______     269          284

441


Figure 6.-Neonatal mortality rates among sngle white births in hospitals (by
     detalled birth weight and speclfvxi gestation groups: Unlted States).

100

80

60

10

8

6

JANUARY 1 TO MARCH 31. 1950

SOURCE: U.S. Public Health Service, National Center for Health Statistics (103).

Recent Studies

The Ontario Perinatnl JIortality Study (66, 67) was conducted
among 10 teaching hospitals during 1960 and 1061. In this retrosp-
live study of 51.190 prrgnancies. a statistical]?- significnrlt increase
in the perinatnl mortality rate ~-as demonstrated for smokers' in-
fants as compared with those of nonsmokers; the infants of smokers
experienced an o\-era11 relati\-e risk of 1.2i (P<O.Of~l). Jloreo\`er, the
investigators found a statistically significant dose-rt_;ponrt relationship
between the amount of cigarettes smoked and the perinatal mortality
rate (P<O.OOl) (fig. 7).

442


Figure 7.-Perinatal mortality rate per 1.~320 total births by cigarette smoktng
       category.

Nonsmoker

<l pack of
cigarettes     z,l pack of
            cigarettes
per day        per day

Number of
pennatal deaths:   659            425             220

Total births:     28.358         15,328          6,581

(P <O.ool)

SOURCE: Ontario Oapatimant of Health (66).

Recently Butler, et al. (15) fu T th er analyzed the British Perinatal
Mortality Study. They found a highly significant association between
maternal smoking after the fourth month of pregnancy and both
late fetal and neonatal deaths. Infants of smokers had an increase in
the late fetal mortality rate of 30 percent, and an increase in the neo-
natal mortality rnte of 26 percent, compared to the infants of non-
smokers. The overall mortality ratio of late fetal plus neonatal deaths
=a~ 1.28 (P<O.OOl). Given the large number of women in the study,
and the significant changes in smoking behavior which occurred,
they found it possible to consider the effect, of a change in smoking

443


behavior between the beginning of pregnant: and the Iollrln lllon[n
on late fetal and neonatal mortality. .L statistically sipniiicnnt and
dose-related increase in mortality occurred among the infants of
mothers who continued to smoke after the fourtfl month of prc&mmnncy,
as compared with the infants of nonsmokers and those of \\-omen who
smoked prior to the prek?ancy but gal-e up smoking by tile fourtlr
month of gestation.

Niswander and Gordon (6s) reported data from the prospective
Collnborntiw. Perinatal Study of the Xational Institute of Seurologi-
cal Disense and Stroke. The 39,P15 pregnancies registered nt 12 uni-
versity iiospitals in the United States were almost equally divided
between black and white women. They found a nonsignificant increase
in perinatal mortality among the infants of whitesmokers as Gvmpared
to those of white nonsmokers; the overall mortality ratio was 1.13
(P>O.l). The infants of black smokers, however, had a significantly
higher mortality risk than did those of black nonsmokers; the mor-
tality ratio was 1.15 (P<O.O2). Moreover, a definite dose-response re-
lationship between cigarettes smoked by pregnant mothers and
mortality risk was shorrn for black infants. Black women xere noted to
smoke significantly fewer cigarettes, on the average, than white
women.

Rush and Kass (82) found, in a prospective study of 3."i'6 preg-
nancies followed at Boston City Hospit.al, a nonsignificant increase
in late fetal plus neonatal mortality rate among the infants of xvhite
women who smoked as compred to those of xhite nonsmokers. How-
ever, the infants of black xx-omen who smoked had a statistically sig-
nificant increase in mortality rate compared to the infants of black
nonsmokers (P<O.Ol). The overall mortality ratio for black women
who smoked was 1.86. The difference in frequency of stillbirth among
the infants of smokers and nonsmokers n-as the primary factor \chich
contributed to the significance of the difference in mortality rates.

Analysis of Previously Reported Studies

Previously reported studies can be divided into two groups: A group
in which the late fetal plus neonatal mortality rates for infants born
to cigarette smokers were significantly higher than those for the
infants born to nonsmokers, and a group in which no significant
differences wen? detected in the mortality rates for the infants born
to smokers and nonsmokers. The results of several studies (I-5. 17, 2.5,
~$2, .$3, 55, 84, 92) yielded mortality ratios rarrgirq from 1.38 to 1.X
The results of other studies (ZU, 65, 76,85,1m, 115) Fielded mortality
rntios ranging from 1.01 to 1.66. Roth groups contained retrospectiw
and prospective studies of comparable size. The two groups did differ

444


significantly, however, with recrard to control of variables other t.llnn
cigarette smoliing n-hi& influence perin2tal mortality.

Factors \Yhich Influence Pcrinntal JIortality Other Tllan Smoking

Butler acd -1lberrnan (I.?), on data from the British Pcrinatal
Mortalit>- StUd~~,emplo~-ed n. log-it transformation analysis of variance,
and demonxrated that maternal height, age, parity, social class, and
sewre preeclampsia all had a signiticsllt independent clfect on late
fetal and neonatal mortality. Rumeau-Roquette (81) provided cvi-
dence that a previous stillbirth or lo\\---birth-weight infant significantly
increased the risk of a future stillbirth. Meyer and Comstock (51)
pro\-ided examples of 110~ the ditfercntisl distribution of smoking and
other factors which arc related to perinatal mortality, in a population
of \vomenl can bias data (e.g., black women have higher perinatal
mortality ratei than do white women, but black women smoke less
than white n-omen do. Hence, nonsmokers will tend to include more
black Komen. and smokers more \vhite womell. This will tend to
reduce any differences between the groups in mortality rates.) Meyer
and Comstock concluded, "Comparisons of mortality rates of smokers'
and nonsmokers' babies should be made within subgroups according
to parity, socioeconomic status, and other appropriate risk factors,
and not xparated by birth n-ei$t."

In three of the studies in which a significantly higher mortality risk
wx demonstrated for the infants of smokers, adjustment for other
variables was performed. The result s indicated that, after such ad-
justment, a significant. independent association between cigarette
smoking and infant mortality persisted (13 and 15, 17, 82). Of the
studies rrhich rei-ealed no significant increase in mortality risks for
smokers' infants, one (115) controlled for race alone. Hence, at least
part of the discrepancy in results between the two groups of studies
may be explained by a lack of control of variables other than smoking.

-bother possible, at least partial, esplanation of th,: discrepancy
                                                       -
in results obtained by the two sets of studies is that cigaret.te smoke
may be more harmful to the fetuses of certain viomen than others.
Se\-era1 de\-eloping lines of evidence suggest that t.his may be the case:
1. Cigarette smoking and socioeconomic background.
DutIer. et al. (15) noted that IThen data from the British PeAnatal
JlortnIity Study are grouped by social class of the mother's husband,
the late fetal plus neonatal mortality ratio for infants of smokers and
nonsmokers in the upper social classes I and II is 1.10; the mortality
ratio for the entire sample was 1.28. Rush and Kass (82) reviewed the
British Perinatal lfodality Study, along xx-ith several other studies,
nnd noted that a]] have shoEn the strongest aSSO&hn betxrwn excess
infant mortality and cigarette smoking among the infants of those


mothers rrith loser socioeconomic status. Comstock and Lundin (16)
found t.~~e.ss martalit>- among smokers' infants almost entirety con-
fhd to those whose fathers had a grammar school education or 1~s.
Several of the studies which revealed no significant diderence in mor-
tality among the infants of smokers and nonsmokers nsere conducted
in predominately middle class populat.ions (20, ZOO, 115).

2. Cigarette smoking and previous obstetrical experience.
Peterson, et al. (72) had rigid criteria for entry into his study
population of 7,7-N women. He included only those women who pre-
viously had healthy infants with a birth weight greater than 2,500
grams. He found a significant decrease in birth weight among smokers'
infants, but no significant increase in mortality rates. Rumeau-
Roquette (81) found that nmong women who previously had delivered
onIy healthy infants rreighing more than 2,500 grams, cigarette smok-
ing was not associated rrith an increased risk of stillbirth ; among those
women with a previous stillbirth, smoking was significantly associated
with incre,ased risk of a future stillbirth.

3. Cigarette smoking and gtnetic differences.

The consistent finding that the mortnlity risk for the infants of black
smokers is higher than the risk for the infants of v.-hite smokers, even
when the socioeconomic background for both is ostensibly similar,
suggests that genetic factors also may interact with smoking to pro-
duce enhanced risk (SZ? 99, 11.5).

Available eridence suggests that if those women, Kho ate already
likely to have small infants for reasons other than smoking, smoke
during pregnancy, their infants ~-ill be most unfavorably affected.
This means that the women in the United Ststfs whose infants Trill
be most affected by cigarette smoking are those who have an unfnvor-
able socioeconomic situation, have a history of previously unsuccessful
pregnancies, and are bIack.

Studies in Animals

Studies previously reviewed in the 1971 and 1972 reports on the
health consequences of smoking (101, 102) demonstrate that exposure
of rabbits and rats to tobacco smoke and to injections of large dose2
of nicotine resulted in significantly increased late fetal and neonatal
mortality. Astrup (9) has recently studied the effect of continuous
exposure of pregnant rabbits to carbon monoxide on stillbirth rates.
He found a sipificantly higher, dose-related incidence of stillbirths
and deaths within the first 21 hours of life among the offspring of the
experimental rabbits (table 4).

446


T.IBLE 4.-Ejfcct qf rnrbon monnride erpowre nf pregnant rabbits on
        birth weight and neorlcltal mortality
                                          -___

Sumber of prepnent rabbits--. ._.______
Total number of babies--.-_-. -- _. _.
Stillborn and babies died within first 24
hou~~.~.~--~---~~-~~~~~~---~~~-~~.

17         14         17
116         Sl         123


' 1        `8        1 44

(P<O.OOl)

1 1 prrent.
110 $wrent.
1% percent.
6ouKx: ASVUP. P. 0).

Studies in Ruman.

Some investigators have examined the causes of death among the
infants of smokers as compared with those of nonsmokers. Comstock,
et al. (17') found that infants of smokers died more frequently of as-
phyxia, atelectasis, and immaturity. I<ullantler and IGllen (I&?) found
abruptio placentae significantly increased as a cause of death among
smokers' infants. Butler and Alberman (14) found little difference in
the death rates for the infants of smokers and nonsmokers from iso-
immunization and malformntions? but higher rates were found for
smokers' infants in the groups in which death occurred before or dur-
ing labor, or in which death resulted from massive pulmonary hemor-
rhage, or pulmonary infection. As the authors noted, "The lat.ter three
are conditions known to be associated wit,h small-for-dates babies."
They pointed out that distribution of causes of death in the smoking
group could be accounted for almost entirely by the excess of low-bitih-
weight babies. This supports the conclusion that the mechanism which
affects birth weight also influences mortality.

SIGSIFICANCE OF THE ASSOCIATION

The following calculat ion is offer-cd to gi\-e some itlcn of the order of
magnitude of increased late fetal and neonatal mortality associated
witI1 ciprctte srnoiii~~~ (IllrinK IJI-~~~I:LII~-\-. If wm1~`11 \\-IIo srwlicd tl~~r-

447


ing prqnancg in the United States had an elevation in risk of 5 Jwr-
cent for late fetal nnd Ilconntnl nrortnlit)-. as (Jrfllotl~tr`:ltC(1 I)\- J<utlcr.
ct al. (15) for Britain. Scotland, and \\`nlcs, antI if L'O pt\rwrIt of
pregnant rromen smoked throughout the prqwnnc~,' tile I!iciwr risk
of stillbirth and neonatal deatll for the infants of nrothrrs 1~1~0 smoke
cigarettes during pregnancy would account for nJ)proximatel>- -!lG~~O of
t,he 87,2F3 stillbirth and neonatal deaths in the Cnitcd States in JNX.

LATE FETAL ASD SEOSATAI, DEATIE SUXJIARY

A strong, probably causal association between cignrctte smoking
and higher late fetal and infant mortality among smokers' infants is
supported by the following evidence :

1. Twelre retrospective and prospective studies hare revealed a sta-
tistically significant relationship betiveen cicnrrttc smoking and
an elevated mortality risk amon, n the infants of smokers. In three
of these studies, of sufficient size to permit adjustment for other
risk factors, a highly significant independent association between
smokng and mortality was established. Part of the discrepancy in
raults between these studies and those in XThich a significant
association between smoking and infant mortality was not dem-
onstrated may be explained by a lack of adjustment for risk fac-
tors other than smoking.

2. Evidence is converging to suggest that cigarette smoking rnaF be
more harmful to the infants of some women than others; this may
also, in part, explain the discrepancies between the results of the
studies in which a significantly higher mortality risk was shown
for the infants of smokers compared to those of nonsmokers and
the results of those studies in which significant differences in
mortality risk were not found.                         --
3. Within groups of similar birth weight, the infants of nonsmokers
appear to have a higher mortality risk than do the infants of ciga-
rette smokers. This results from the fact that the infants of non-
smokers within such similar birth rreight groups are on the
ax-ernge gestationally less mature than the infants of cigarette
smokers. Available evidence indicates that within groups of sim-
ilar cestational age, infants of lower birth weight experience a
higher mortality risk. Since the infants of cigarette smokers are

`Ras~d on ~xtmpolatlon of data on smoking behnrlor chance durlnr prrgnancr from
the Brltlsh Perlnatnl Mortality Studs. which probably rlelds R conscrratlre esttmnte.

448


small-for-gcst:~tion:lI age. onoshould eslwct thnt if the infants of
cigarette smokers and non~mokcrs HTC compared within similar
geGnti*nal sge cIssces, the infants of ci y:rrctte SIrlOliCr5 trollId
have the higher nrortnlitv rete.

-1. The results of recent studies hnvc documented a stntisticnlly sig-
nificant dose-response rclntionship between the number or nmount
of cignrettes smoked and late fetal and nconzrtal mortality.
5. Sew data suggest that if 3 Roman gives up smoking by the fourth
month of pregnancy: she will 11nve tile s:rrne risk of incurring n
fetal or neonatal loss 3s n nonsmoker.
6. --Imilable evidence strongly supports cigarette smoking as one
cause of fetal growth retardation. The causes of excess deaths
among the infants of smokers arc those associated with snnril-
for-d:rtes babies.

7. I>nta from experiments in animnls have demonstrated thnt espo-
sure to tob:rcro smoke or some of its ingrcdicnts, such 2s nicotine
or cxrbon monoxide. results iri a significant incrfzrse in late fetal
and or neonatal deaths.

S. Tire results of studies in humans lrnre shown that the fetus of
3 snrnking niottlrr mnv be tlirectlv exposed to ngclltS Such X3
c:jrbnn nionositlc wit bin tobacco smoke, at levels conipamble to
tlrose xhich haw been shown to produce stillbirth in cspcrimrntnl
animnls.

Sex Ratio

.\lt!rough n number of small studies have found a slight, usually
5t:rtistically nonsignificnnt, increase in the proportion of female infants
born to smokers, tire tlrrre Inrgest studies of Underwood, et al. (46,505
preLgnanries), Butler (15,791 pregnancies), and Aiac3lahon (12,155
pregnancies) have found similar infant sex ratios among both Smok-
ing and rrorismoking r;rotlrer-s, with the cspected slight excess of males
~II~OII~~ZIC~I (table j)*

.I\-nilxl,le evidence strongly indicates that mnternal cignrette smok-
ing do:~s not inffucncc tltr SW r:ltio of newborn infants.

449


TABLE 5.-f'roportion of mob infants delivered to smoking and non-
           smokinmg mothers

Underwood, et al. (100) ___. ---__----_._ 48,505
Butler and Albennan (14)-------- ______ 15, 791
hlachfahon, et al. (49) _____________ -__- 12, 155
Kullander and Kiillen (43) - - _ _ _ _ - - -_ _ _ _  6,363
Reinke and Henderson `(78)__- ____ --__-  3, 156
Frazier, et al.1 (26) .___.________________  2, 915

Kizer (:.2)-- ___.___ - _.___ ---_.- __.____  2,095
Herriott, ct al. (36)_.-- ____ -- ____ - _____  2,745
Rnvenholt, et al (77). __-_ _ _______._____  2,052
Lowe (46)--_.-.-.---__-----------.--- 2,042
Russell, ettd. (83)_--- _..____ - -____ -_--  2,002

_ 518
.518
.>I3
515
: 498
_ 472

_ 502
.492
-501
.532
.513

-519
- 516
.512
_ 501
_ 517
. 305

_ 493
. 517
.533
. 529
.512

sane.
Do.
DO.
DO.
Do.
DO.
(p>O.OS)
NOW.
Do.
P<O.O5
Sone.
Do.

Congenital MaIformations

Previous epidemiological stud& xrhich examined the relationship
between cigarette smoking and congenital malformations rrere I+
viewed in the 1971 and 1972 reports on the health consequences of
smoking (101, 10.2). Recently, the authors of the Ontario Perinatal
Mortality Study (66, U), a retrospective study of 51,490 births, re-
ported no difference in malformation rate for the infants of smokes+
and nonsmokers. The vhrious studies of the association betxeen ciga-
rette smoking and congenital malformation have differed significantly
TX-ith rrgard to study des&, the type of population sampled, sample
size and number of infants with malformations, the definition of mal-
formation, and results (table 6).

Previous experimental work was reviewed in the 1971 and 1972
reports on the health consequences of smoking (IOIl IB). The chick
embryo has been employed in recent studies. The direct application of
nicotine to the embryo results in cephalic hematomas (26). malforma-
Cons of the cervical vertebrae (93), and anomalies of the heart (fl),
depending upon dose of nicotine and period of incubation in =-hich
exposure occurs. Anomalies of the limbs of chicken embqos can aI=
be induced by exposure of the eg- n to high levels of carbon monox-
ide (4).

450


T.luLE G.---Rclatix rirk q/ congenital Ina!formation -for irl~fants qf
cigarette smoX-cr.7 and nonsmokers, comparing ai-ailablc stilr1ie.s with
regard to study cfcsign, s/~tly popltiat;on, sample si:e. number 0-f
injants urith ma!formations, and dcjnition of malformation

I (b) Survlvlng Infants
   lnsg.31.
I (a) ' Elffliwrn plus
   neonntnl deaths 1
   and deaths to

I    7.
Cb) Neomtal deaths 1
   (3-mooth
   study).

?3

37

59

1.744



1,382

43





700

88







204

I. 36 >fnJor.

.31 >IoJor. cnuse of
   den&.
.b7 >le]or.

.97

I. 19 >If$x. Cz."SD of

1.07 (1)

Congenital Xalformafion Summary

Given the considerable variation in study design, st-udy population,
sample size, number of affected infants, definition of malformation,
and results, no conclusions can be drawn about any relationship
between maternal cigarette smoking and conge.nitai malformation at
the present time.

451


Lactation

Introduction

The following section is a review of available e\-idence which bears
upon any interaction betxveen cl, `oarette smoking and lactation. Emphn-
sis is placed upon the relationship of cigarette smoking to the quantity
of milk produced, to the presence of constituents of cigarette smoke
within the milk, and to eirects upon the nursing infant mediated
through changes in either the quantity of milk available or the sub-
stances within the milk.

Epidemiological Studies

cnderx-ood, et al. (99), in a stud1 of 2.000 rromen from various
social and economic strata, observed a definite but statisticall? insig-
nificant trend toward more frequent inadequacy of breast milk pro-
duction among those smoking mother; Kho attempted to nurse
compared to nonsmokers.

Mills (Z), in a study of 520 women. found that among women who
indicated either a desire to nurse or no desire to nurse yet continued
to nurse, beyond 10 days, and riho had delivered their first live-born
infant? the average period of nursing for mothers who smoked was
significantly shorter than for nonsmokers. Moreover, among the W
mothers who had given up smoking during at least the final 3 months
of their pregnancies, the average length of nursing was identical to
that of the nonsmokers. There was no significant difference between
smokers and nonsmokers with regard to complete inability to nurse
their offspring. This study is difficult to interpret because the author
did not determine the reason(s) for the discontinuation of nursing
among the women.

Experimental Studies

Nicotine

Influence on the Lactation Process

Blake and Sawyer (II) studied the influence of subcutaneously
injected nicotine (4 mg. total over a s-minute period) upon lactation
in the rat. They found that nicotine inhibited the suckling-induced

452


rise in prolactin. So ctfcct of injected nicotine was dcmonstratcd for
ox>-tocin secretion since milk release was not, blocked.

T\`ilson (110) examined the etfcc:s of nicotine supplied throcg'n
drinking water (0.5. 1.0. and 2.0 mg. daily) on the weight rain of
nursing rats. -\pp`arently: the nicotine had been avnilablc throughout
gestation as well! because theauthor commented on a reduction in litter
size among the experimental groups. more or less proportionate to the
dose of nicotine; hence. a prenatal efrect could not have been dis-
tinguished from a postnatal one. Average birth weight was similar for
ex-pcrimtntal and control groups. Ko difference in weight gain wasseen
for any of the groups. The lack of impact on birth weight suggests
thnt dose was loser than that used in other studies.

Presence of Nicotine in the Nilk

Hatcher and Crosby (A??), using a frog bioassay, reported traces of
nicotine in cotr? milk ?I hours after the intramuscular injection of
5.0 mg./kg. and 5 hours after the injection of 0.5 mg./kg.

Evidence for an Effect Upon the Nursing Offspring

Hatcher and Crosby (3;3).found that 0.5 mg./kg. nicot.ine injected
into nursing cats had no apparent harmful effect upon the kittens.
Apparently 4.0 mg./kg. suppressed Iactation. Kittens fed the miik
from the cow trhich had been injected with 5.0 mg./kg. nicotine rrere
also apparently unaffected.

Nitrosamines

Bohr (53) found that diethglnitrosamine and dibutylnitrosamine:
when administered to lactating hamsters, were associated -with the
deL*elopnwnt of typical trachea1 papillary tumors in the -oung? SU,O-
gesting passage df these compounds in.;he milk. Although diethyl-
nitrosamine and dibutvlrlitrosanline have not been identified in ciga-
rette smoke, manv X-nitrosamines are potent carcinogens, and some-
of them are present in cigarette smoke (37, 79).

Sicotine and/or Tobacco Smoke

Infiuence on the Lactation Process

Emanuel (22') noted no reduction in milk production among 10 rret
nurses who xere encouraged to smoke seven to 15 cigarettes daily;

453


some were observed to inhale the smoke. Hatcher and Crosby (39)
noted that after a mother smoked seven cigarettes vSthin 2 hours, it
was dificult to obtain a specimen of breast, milk. PerIman, et al. (71)
found that of 55 women smokers with an adequate milk suppiy at t.he
beginning of his study, 11 (20 percent) of the women had an inade-
quate supply at the time of discharge from the hospital. No relation-
ship was reported between the number of cigarettes smoked and the
likelihood of developing an inadequate milk supply. The authors' im-
pression was that there was no greater proportion with an inadequate
milk supply among smokers than among nonsmokers, but no cur-
roborating data were supplied.

Presence of h'icotine in the hiilk

Hatcher and Crosby (33) found, using a frog bioassay, that the
milk of a woman collected after she had smoked seven cigarettes in 2
hours contained approximately 0.6 mg./liter nicotine. Emanuel (D?),
using a leech bioassay, studied excretion of nicotine in the milk of wet
nurses who were encouraged to smoke for the experiment. -1fter the
subjects had smoked six to 15 cigarettes over a l- to 2-hour period, the
author found nicotine in their milk 4 to 5 hours after smoking, with a
maximum concentration of 0.03 mg./liter. Bisdom (10) demonstrated
nicotine in the milk of a mother who smoked 20 cigarettes a day.
Thompson (97) found approximately 0.1 mg./liter of nicotine in the
milk of a mother who smoked nine cigarettes a day (plus three pipe-
fuls). Perhnan, et ai. (71), using a Daphnia bioassay, demonstrated
nicotine in the milk of all women who smoked in their study. Moreover,
they found a direct. dose-relationship between concentration of nicotine
and the number of cigarettes smoked. No comment is made by the
authors on the possible inaccuracy introduced by examining only the
residual milk following nursing, but it is well known that the composi-
tion of the fore milk and hind milk is different and perhaps the
concentration of nicotine also differs.

Evidence for a Clinical Effect Upon the Offspring

Emanuel (99) noted that among the infants in his study, loose stools
were observed only in the one N-hose wet nurse had smoked 20 ciga-
rettes in the previous 4 hours. Bisdom (10) observed a case of "nico-
tine poisoning" in a 6-week-old infant -hose mother smoked 20 ciga-
rettes a day. The symptoms included : restlessness, vomiting. diarrhea,
and tachycardia. Nicotine was demonstrated in the milk, and the
symptoms abated when smoking was stopped. Greiner (30) also de-
scribed a case of possible nicotine poisoning in a 3-week-old nursling

454


~1~os.e mother smoked 35 to JOcigarettes a dav. Thr symptoms incliitlcd
vomiting and loose stools. Folloxvin~~ the curtailment of smoliinr. the
symptoms gradually abated over a 3-da>- period. l'crlninn. et nl. (71)
noted no etfect of smoking on the weight ~ train of the infants of the
smokers in their study. Furthermore. no untoward symptoms wx-e
obserr-ed. They therefore doubted an efcct of smoking on lactation.
They noted that the dose received by the infants xas beneath the toxic
level as computed from adult experience. and this accorded vcith their
clinical observations. The fact that they admitted to the study only
women with an apparently adequate milk supply mnp 11ave affected
their results. The authors su ggested that perhaps the lack of effect of
smoking upon lactation might represent the development of tolcrnnce
to nicotine, as both the mother and the offspring had been exposed
throughout the pregnancy.

VITAMIX C

Venulet (105, 106, 107), in a series of studies, demonstrated that
the level of vitamin C was reduced in the milk of smoking mothers as
compared with nonsmokers. The clinical si:nificnnce of this observa-
tion has not been evaluated.

1. The t-rro pertinent epidemiologiczil studies suggest a possible in-
fluence of smoking upon the ndequnc>- of milk supply However,
with only limited numbers of women and without control of other
potentially significant variables, no conclusions can be drax-n.
2. Studies in rats leave demonstrated that nicotine can interfere with
suckling-induced rise iii prolnctin. The relet-ante for humans
is uncertain.

3. Evidence exists that nicotine passes into breast milk. No clear
evidence for an acute effect upon the nursing infant is available.
I'otential chronic ctfccts have not been studied.
4. Sew cl-idcnce from esperimcnts wit]: niice suggests that nitros-
amines. liuo\vn cnrcino~rns, pass througIr the milk to suckling
pIIll-`.

455


Preeclampsia

Previous epidemiologic4 studies of the relationship betxwen cig-
arette smoking and preeclampsia were revielred in the 1971 nnd 13Z
reports on t.he health consequences of smoking (~01,102) and form the
basis of the following statements:

The results of several large prospective and retrospective studies
indicate a statistically significant lorrer incidence of prceclampsia
among smoking women (I-6, @`,100). The results of one large retro-
spective study demonstrated a significant inverse relationship between
the incidence of preeclampsia and the number of cigarettes smoked
(ZOO). When other risk factors, such as parity, social class; maternal
weight before the pregnancy, and maternal weight gain during the
pregnancy Kere controlled, smokin, n women retained a significantly
decreased risk of prerclampsia (22). The lower risk of preeclampsia
for cigarette smoking Tomen has been demonstrated in Britain and
Scotland (14, 21, 46: 83), The United States (100, 228), Venezuela
(@) , and Sweden (@) . If a maternal smoker does develop preeclamp-
sia, however, available data suggest that her infant has a higher mor-
tality risk than does the infant of a nonsmoker with preeclampsia
(21,83).

1. Available evidence indicates that maternal cigarette smokers
have a significantly loxrer risk of developing preeclampsia as
compared to nonsmokers.

2. If a rroman who smokes cigarettes during pregnancy does develop
preeclampsia, her infant has a higher mortality risk than the
infant of a nonsmoker rrith preeclampsia.

Pregnancy References

(I) ABEBNATHY. J. R.. GBEENBEW, B. G., WELLB, H. B., Fruzroc. T. 11.
   Smoking as an independent rariahle in a multiple regression analysis
   upon birth weight and gestation. American Journal of Public Health and
   the Xintion's Health 56(4) : 62-3, April 1966.
(2) ASTBUP, P. Patbologische Wirkuogen miissiger Koblenmonoxid-Konzen-
   trationen. (Pathological effects of moderate carbon monoxide concentra-
   tions.) Staub-Reinhnltongder Luft 32(4) : 146-150.1972.
(S) BAILEY, R. R. The effect of maternal smoking on the infant birth n-eight.
   New Zealand Medical Journal 71(456) : 293-294, May 1970.

456


(4) BAKEa. F. D.. T~MA~OXI~. C. F. Carbon monoxide and avlan embryo-
   genesis. Archires of EZnrlronmental EIcalth 24(l) : X%61, January 192.
(5) B=IBALD. L.. Yac0c-s. 11.. FALTBE. .I.. XALIXM. Y.. C.&v, G. L'oxyacar-
   bonemie de l'enfant ne de mere fumeuse. (Presence oC carbon monoxide
   ln the blood of a child born of a smoking mother.) Mwlecine Legale et
   Dommage Carpore 3(3) : 272-274. July-August-September 1970.
(6) Bm, v. A. Nutritional studies during pregnancy. Journal of the Amerl-
   can Dietetic Association 58(4) : 321-326, April 1971.
(7) BECK% R. F.. &SO. J. E. Studies on nicotine absorption during preg-
   nancy. II. The effects of acute heary doses on mother and neonates.
   American Journal of Obstetrics and Gynecology 93(3) : 515-522, June
   15.1966.

(8) BECKEB. R. F.. LII-TLK, C. R D.. 61x0. J. E. Experimental studies on
   nicotine absorption in rats during pregnancy. III. Effect of subcutaneous
   injection of small chronic doses upn mother. fetus, and neonate. Ameri-
   can Journal of Obstetrics and Gynecology lOCl(7) : 937-968, Apr. 1, 1968.
(9) BECK=. R.. F., .\IARTIS, J. C. Vital effects of chronic nfcotine absorption
   and chronic hypoxic stress during pregnancy and the nursing period.
   American Journal of Obstetrics and Gynecology llO(4) : 522-533, June
   15,1971.

(10) BI~DOY. C. J. W'. Alcohol nnd nicotine poisoning in infants (sucklings),
   Jlnandshrift roar Kindergeneeskunde G : 3X-341, 1937.
(11) B~-*lce C. A.. SAWVYER. C. II. Nicotine blocks the suckling-induced rise
   in circulnting prolactin in lactating rats. Science 177(4(X9) : 6IM21,
    Aug. 18. 19i2.

(1-O) BCNCHES. C. R. Cigarette smoking and duration of pregnancy. American
   Journal of'obstetrics and Gynecology 103(y) : 942-946. Apr. 1, 1969.
(IS) BUTLER. X. R. ALBERTAN, E. D. (Editors). Perinntal Problems. The Sec-
   ond Report of the 19% British Perinatal Mortality Survzg. London, E.
   and S. Li\-ingsrone. Ltd., 1969, 395 pp.

(14) BUTLW S. R., A\LBER\IAN. E. D. (Editors). The effects of smoking in
  pregnancy. Chapter 5. In: Perinatal Problen?s. Edinburgh, E. and 5.
   Liringstone. Ltd., 1969. pp. 72-84.

(15) BUTLER, X. R., GOLDSTEIN, H.. Ross, E. M. Cigarette smoking in preg-
   nancy: Its influence on birth weight and perinatal mortality. British
    Medical Journal 2: 127-130, Apr. 15. 1972.
(16) COMSTOCK. G. IV., LUXDIN, F. E.. Jr. Parental smoking and perinatnl
   mortality. American Journal of Obstetrics and Gyucology 98(5) : 708-
    718. July 1.1967.

(17) Cous~ocs, G. IV., SHAH, F. K., METEB, Il. B., ABBEY. H. Low-birth weight
   and neonatal mortality rate related to maternal smoking and Socio-
   economic status. American Journal of Obstetrics and GynecologY
    111(l) : 53-59, Sept. 1.1971.

(18) COSSEY, A. H., XFLCH, R.. KCNTZMAN, R., CEANO. R.. JACOBEON, Jf.,
   ~ICTROFAGRE, A. D., PECK. A. W., BE. A., POLAND, A.. POPPER% P. J..
   RXSTER, 11.. WOLF+. J. A. Erects of environmental chemicals on the
   metabolism of drugs. carcinogens, and normal body constituents in
   man. Annals of the Sew Pork Academy of Sciences 179: 155-172, July
    G. 1971.

(19) DOM~~ALA, J., DOHAGALA. L. ZarhoTanie sie magi UrOdZeniOwej oraz
  cwstosc ,vxstepowonia xvczesniactwa I wad wrodzonrch u noworodkow
  kobiet palacxch tyton. (Birth weight and incidence of prematurity and
  congenital anomalies in newborns of mothers smoking tobacci.) Pedi-
   atria Polska T. 47(6) :735-538.1972.

457


C-99) E~GESBERO, J. 11.. SCHWISD, J. V.. PA-I-U& A. R. The effects of nicotine
    3ad cigprette Smuke on pregn3nt female albino nfs and their off-llrings.
    J0urn31 of Lzlborntory and Clinical Medicine 2%: iO,Sili. I'WO.
(34) FEDRICK, J.. ALBERXAS. E. D.. GOLDSTEIX, II. Possible tentogenic effect
    of cigarette smoking. Sature 231: 52WX30. June 23, 1971.
(0.5) FRAZTER, T. .\I., DAVIS. G. B., G0~~srer.u. H.. COWBULQ. I. D. Cignrette
    smoking and prematurity: h prospective studF. .Imerimn Journal of
    Obstetrics and Crnecology Pl(5) : 11669!X. May 1961.
(,QG) GAILISG. R. R. Effect of nicotine on chick emttryo. Archires of Patholon
    i8 : ti?L'-F.?7. Dffemb+r 136-I.

(27) Grr~sr. S. H. Sicotine and cardiogenesis. An experimentn1 study. I'nthol-
   oFi3 et Microbiologia 3i (5) : 353-X+?, 1971.
(28) GOLDSTUS. Ii.. GOLDIIEEC. 1. D., E'a~zrut. T. 11.. DAVIS. G. E. Cigarette
    :mokinc and t,rcm:tlurity. .Joun~~l of the .\ulcric-an Obteopstbic .Isso-
    c-intiou 64 : :+41-.X!). Jnntx1r.r 136.X

(.?Z) II.xor#~s. IV., Jr.. .\`.~snrr. R. E. I,., G~acra, R. Smoking and prcfnaacy:
   (`:~rl~~~~ I~~~III)\II~~. in I~l~~od during festzttion and nt term. Obstetrics and
    G~-wT.1lloC\. lS(3) : x-"ci. Srprenlbcr ISGI.
l.i?~ 11.~rc.11~~ R. .L., C'p.os~r. H. The elimination of nicotia in the milk. Journal
   of I'lr;rrmn~rntir:~l nnd Experimental Therapy 321 1) : 1-G. 1'327.
(3.7) II.~wo~rrr. J. C.. FORD. .T. D. Comparison of the effects of maternal under-
   nutriri~~n and r~l~~ure to cigarette smoke on the cellular Fro\\-th of the
   rat fc*ttrs. .~rnericaa Journal of Obstetrics and Gwemlogr 112(S): %3-
    GX, 113r. 1. 1952.

(33) JJmos. H. J. The effects of smoking during pregnancy: A review Kitb n
   I're!-iv!\-. Xe\v Zr~l;~nd Medical Journal 61 : X&54& Sor~mkr 1962.
(S) ~IERRIOTT, -1.. BILLEIIICZ. I\`. Z., HTTTEN, F. E. Cigarette smoking in PW?
    m*nry. r.3ncet I : ZI 77.3. .4pr. 1.4. 1962
(JG;) J.\R\IxJ. I?. -1.. OSTERLUND, K. Effect of smoking during Pregnancy on
   tbe fetus. placenta snd delivery. Annales Pscdiatriae Fenniae S: 18-2%
    lOG3.

(3;) JOIIXSOX. D. E.. I~~o.%DE~. J. V. N-nitrosamines in smoke condensate
   from sevenI vnrietiei of tobacco. Journal of the Sationnl Cancer In-
    .i-titntr4.C;(G) : lS41,1547. .Junr 1972.

($8) .IU~IIAV, M. R. rrumnn placental hydroxylstlon of 3.+henw~renc during
   early gcstntiabrr and nt term. ToxiwlogF and -%pplied Phnrmacolo0
    IS(S) : rx.x;;3. .\hrcb 1371.

(59) KEITlr. C. iI.. TF^s~I. P. G. Xessurement of the tot31 smoke issuing from
   3 burning ciysrrrtr. Tt)lurn, lGO(1.i) : 1&Z!?. .\pr. S, 196.5.

458


(f!)) Krs-0. J. E., BECKER R. F. Studies on nicotine nbsorption during PWVancy.
   I. LD, for pregnant and nonpregnant rats. .\mericnn Journal of Cb-
   stetrics and Gynecu111~y n.?(4) : ;oS-.Y14. June 1%;. 1966.
($I) ~SCEEAUU. T. H., DILTS, P. V., Jr., BILIXKUAX, C. R., III. Some acute
   effects of smoking in sheep rind their fetuses. Obstetrics nnd GynecnlogY
   33 (4) : 5"i-536. April 13iO.

(I) KIZEX S. Influencis de1 habit0 de fumar sobre el embarazo, Parto J reclen
   nacido. (Effect of the smoking habit on pregnancy. deiirery. and the
   newborn.) Revista de Cbstetricia y Ginecologia de Venezuela 27(a) :
    59S3.1967.

(JJ) I~CLUSDEE, S.. K&EN, B. A prospective study of smoking and PregnanW.
   Acta Cbstetricia et Gy-necologica Scandinnlicn 50(l) : ,S%9i,. 1971.
(44) Kcu- D., Zot-ALAS, P. A. Studies on human premature births. II. In
   rlro effect of smoking and In vitro effect of nicotine on human uterine
   wntiactility. American Journal OC Obstetrics nnd Gynecology 87(3) :
    41Mli. Oct. 1.1963.

(cj) Losco. L. D. Carbon monoxide in the pregnant mother nnd fetus, and
   its eschange across the placenta. Annals of the sew York ACadfmY of
    Science3 174(l) : 313341. Oct. 6,197O.

(46) LOWE. C. R. Effect of mothers' smoking habits on birth weight of their
    children. British Jtedical Journal 2 : 6736i6. Ort. 10.1%9.
($7) McDoxvarn, R. L., LAX~BD, C. F. Effects of smoking on selected cllniml
   obstetric factors. Obstetrics and Gynecology 26(4) : 47&-l?& October
    1!365.

(48) JICGARBY. J. X, ANDEEWS. J. Smoking In pregnancy and vitamin Bu
   metabolism. British Medical Journal 2: 7&i7, Apr. 8, 1972.
(49) Mac~~ao~. B., ALPE.ET. hf.. SALBI~~. E. J. Infant weight and parental
   smoking habits. Americnn Journal of Epidemiology 8z(3) : 247-261.
    November 1965.

(50) Jiax~m.~, C. D. Smoking in pregnancy: The role played by carbonic anhy-
    draw. Sew Zealand Medical Journal 63: 601603, September 1964.
(51) Mm M. B.. COYBTOCK. C. W. Maternal cigarette smoking and perinatnl
   mortality. American Journal of Epidemiology 96(l) : l-10, July 1972.
(52) MILL% C. A. Tobacco smoking: Some hints of its biologic hazards. Ohio
   State Medical Journal 46(12) : 11651170, December 1950.
(3) Mona, U., XLTHOFF. J. Carcinogenic activity of aliphatic nitro.samines via
   the mother's milk in the offspring of Syrian Golden hamsters. Proceed-
   lngs Oe the Society for Experimental Biology and Medicine 136(3) :
    lC07-1099. March 1971.

(54) lICKK= S., bfURHEBTEE. E. N. A study of premature births. Indlan
   Journal of Pediatrics 38(285) : 389-392, October 1971.
(55) MmAnr. R. KNA~W J. F. Effect of age, parity, and cigarette smokle
   on outcome of pregancy. Americnn Journnl of Obstetrics and Gynecology
   101(6) : Mk849, July 15.1968.

(56) ~1mdA~r. R. M~Jw~Y, J. Xatemal smoking and the timlng of delirery.
   Journal of the Irish Medical Association 65(i) : 175177, Apr. 1, 19i2.
(57) McrcAnr. R.. MUBPIIY. J.. MARTIN, F. Placental changes and maternal
  weight in.smoking and nonsmoking mothers. American Journal of Ob-
   stetric-sand Gynecology 106(5) : 703704. .liar. 1,197o.
(58) Jtua~u. D. E. Birth aeight and smoking. Nebraska State Medical Jour-
   nal 48 (11 I : 60-6. November 1%.

(") >lWPHY. J- F., J_~WAXY. Il. The effwt of age, parity, and cigarette smok-
   ing on baby WeQht. American Journal of Obstetrics and Gynecology
   111(l) : 22-25, Sept. 1,197l.

459


(60) ~AU, J. F. Complexed cyanide in collected cigarette smoke. Abstracts of
   20th `robaceo Chemists' Research Conference. SOV. l-3. 1966. \Vtnston-
    Salem, S.C.. 1966. pp. 2627.

(61) SEBEBT, D. \$-., JYIXKEB, J.. GELBOIN. H. V. Xryl hnirocarbon hydrosylase
   activity in human placenta from cigarette smoking and n~nsmoktng
   -omen. lancer Research 29(10) : 176%li69. October 1969.
(62) ~EtVt30~~ J. R.. NOELIAN, v.. KEITH, c. H. vapor phase analysis of tobac-
    co smoke. Tobacco Science 9: 162-116. July 23. 19%
(63) SISWAXDER, K. R., Gonoon, II. Sectlon 1. Demographic characteristics.
   Cigarette smoking. In: The Women and Their Pregoanctes. The Cot-
   laborative Perinatal Study of the h'ational Institute of NeurOlOgiCal Dts-
   eases and Stroke. Philadelphia. W. B. Saunders CO., 1972. PP. 72-86
(64) SOR~AX V.. SEwsox% J. R., KEITH, C. H. Smoking mnchlnes for the
   analysis of the vapor phase of cigarette smoke. Tobacco Science 12:
    216221.1968.

(65) @uxE. J. 51. Some fetal effects of maternal Cigarette smoking. Obstetrks
    and Gynecology 22 (2) : 181-184. August 1963.
(66) ONTARIO DEPARTMENT OF HEALTH. Second Report of the Perinatal Ifor-
   tality Study in Ten University Teaching Hospitals. Toronto, Cnnoda.
    Ontnrio Department of Health, Ontario Perinatal Mortality Study Com-
    mittee. vol. I.. 1967, 275 pp.

(67) ONTARIO DEPARTMENT OP HEILTR. Supplement to the Second Report of the
    Perinotal Mortality Study in Ten University Teaching Hospitals. Toron-
    to, Canada, Ontario Department of Health, Ontario Perinatal Jlortnllty
    Study Committee, vol. II, 1967, pp. 9.5-275.
(63) Oaa~rth-~, J. S.. ADAMEK, S.. Hosna. 5f. E. Some components of gas phnse of
    cigarette smoke. Analytical Chemistry 28(2) : 211-215. February 1956.
(69) OITN~TED, JI. Maternal constraint of foetal growth in man. Developmental
   Medicine and Child Neurology 7: 479491, October 1965.
(70) PAZX~GEEN, B.. WA~.LANDER. B. Cigarettrokning och abort. Konsekutiv pros-
   pekttv undersokning av 4312 graoiditeter. (Cigarette smoking and abor-
   tion. Consecutive prospective study of 4,312 pregnancies.) Lakarrtid-
    ningen 68(22) : 2611-2616, May 26. 1971.
(71) ~EBLXAX, H. H., DANNENBERO. A. Bf., SOKOIX)FF. N. The excretion of nicotine
   in breast milk and urine from cigarette smoking. Journal of the American
   Medical Association 12O( 13) : 1003-1069, Nov. 28.1942.
(72) PEIKuON, W. F.. niORESI% R. N.. KALTBEIDER. D. F. Smoking and pre
    maturity. A preliminary report based on study of 7.740 Caucasians.
   Obstetrics and Gynecology 26(6) : 7757iB. December 1965.
(75) ~EBMON, F. Medtcinska skadeverkningar av rokoing. Riikning och by-
   nekologiskobstetriska tillstand. (Harmful clinical effects of smoking.
   Smoking and g.vn~~logicaI-obstetrical condition.) Social-Medirinsk
   Ttdskrlft 2 (Special No.) : 78-82. February 1971.
(74) P~~UPPE R. J.. y~oaa6. hf. E. Some components of the gas phase of
   cigarette smoke. Analytical Chemistry 28(12) : 2662-2005. December
     1956.

(75) GWRoSE. T., HIWINB, A. A stndy in human antepnrtum nutrition.
   Journal of Reproductive Medicine 7(6) : 257-264. December 1971.
(76) RA~TAKALLIO. P. Groups at Risk in Low Birth Weight Infants and Perinn-
   tat hfortality. A prospective study of the biological characteristics and
   8OCiOeCOnOmiC rtrcumstances of mothers in 12.666 deliveries in North
   FInland 1966. A dtscrfminant function analysis.' Acta Paediatrtca
   Scandtnavica (Supplement 193) : 1969.71 pp.

460


(77) RA\`ES~OLT. R. T., LEYISBKI, 31. J.. SEXLIST. D. J., TAKESAGA. 11. Effects
    Of S~lukirll: U]I(~II rrprodncti~~~~. .\nitrican Jvuru:il c,f Qtvhlctrics and
    G~-nPcolo.qr !I(;(?) : L'c;-31. sq,t. 15, I!,&
(78) REISI(E. \V. .\.. IIESLIERSOY, 11. SmclkinC and I~rrmnturif>- in tlic prcwnce
   of Other rnriables Archives of Ewrironmentnl Ilcnltl~ l,(S) : 1;OW.W.
     31:1>- I%;&
(79) RHO.*DES. J. TV., JOllN60S. D. E. Method for the determination of S-nitro-
    SAmines in tobacco-smoke condensatr. Journnl of the Sational Cancer
    Institute4S(G) : X-11-1M3, June 1971.
(SO) ROBISSOS. I'. `Txh\rn nshym B\vr:nm~-wt rzmn hhr~xx-n whshp'tw `I h'm
   Il'wbr ~11~1~d. (Smokillg by Burmese women during pregnancy nnd its
    influence on the mother, the fetus and rhe newborn.) Wnrefunh
    fxl ( 2) : 3733. 196.5.
(81) RU~IEAU-ROUQUETTE. C., GouJARLI, J., Kaw~ss~x, 11.. SCIIXVAR~Z, D.
    Mortnlite perinntnle en relation avec les antecedents obstetricnuz et
    l'usage du tabnc. (I'erinstnl mortality in relation to obstetric antecedents
    and tobacco usage.) Pnpcr presented at the Third European Congress
    of Perinatnl 1Iedicine. Lausannr, Apr. 19-22, 1372, 8 PP.
(82) RL`sII. D., KASS. E. H. Maternal smoking: A reassessment of the assocla-
    tion with perinatnl mortality. American Journnl of Epidemiolon OO(3) :
    183-196. September 1972.
(83) RCSSELL, C. S.. TAYLOR, R., L.kw, C. E. Smoking in pregnancy. maternal
    blood pressure, pregnancy outcome, baby weight nnd growth, and other
   related factors. A prospectire study. British Journnl of Preventire and
    Social Medicine 22(3) : 119-126. July 3363.
(ej) RCS~~ZLL, C. S.. TAYLOR, R., Jlann~sos. R. S. Some effects of smoking in
   Pregnancy. Journal of Obstetrics and Gynecology of the British Common-
    wealth 73 : 7-12-746, October 1966.
(85) SavFz, L. E., RVIH, E. Effects of smoking in pregnancy: -4 continutng
   retrospectire study. Obstetrics and Gl-necology 20(3) : 313-316 SePtem-
     her 1962.
(86) SCIILEDE, E., JIERKER, H.-J. Effect of benzo(a)pyrene treatment on the
   benzo(a)Pyrrne hydrosylase activity in maternnl liver, placenta. and
   fetus of the rat during day 13 to day 18 of gestation. Naunyn-Schmlede-
   berg's Archives of Pharmacology Z?(l) : 69-100. Dec. 21.1971.
(87) SCIIOESECK, F. J. Cigarette smoking in pregnancy. P*`ew York State
   Journal of Medicine 41: 196-1948. Oct. I. 19-i].
(88) SCOFTETTA. Y. Sul contenuto di ossido di carbonio nel sarwe circohte
   di gestanti fumatrici. (Carbon monoxide content in the blood circulating
   in pregnant smokers.) Archirio di Ostetricin e Ginecologia 73(3) : 36%
    375. Mar-June 1963.
(89) SIEBER. S. 11.. FABRO, S. Identiftcation of drugs in the PreimPlantation-
   bIastoc)-st and in the plasma, uterine secretion and Urine of the Pregnant
   rabbit. Journal of Pharmacology and Experimental Therapeutics 176(l) :
    f3.%75.1971.
(go) SIMPSON. IV. J. A preliminary report on cigarette smoking and the
  incidence of prematurity. American Journal of Obstetrics and Gone-
   colom 5314) : SO.%Rl.X April 195'7.
(91) SPEARS. A. \I-.. ROUTES, w. F,. A combined approach to the wantitatire
  ana)rsis of the rir,tatiIe comtwnents of cigarette smoke. Paper presented
   nt the ~,c,th Tol,acco rtlemists Research Confewnce. Raleigh. N.C..
     1964.

   49~wzS O-73-11


                                        461


(98) TJ~LVE. H.. H~sseo?i, E.. SCR>r1TERLijn-. C. G. Pascnge of "C-nicotine and
    its metnholitrs info mice foetnws and ldnrentfie. .%ctn Phnrrnnrolo,cicz et
    Toxicolo~icn 3?(G) : .X%-5.55. l!H.

(103) U.S. PUBLIC HEALTH SERVICE. SATIOS`IL CESTER FOR HEMXK STATISTICS.
   .Weight at birth and survival of the nen-l>orn--Z'nitrd States. earl? 1950.
    Washinfiton. U.S. Department of Health. Education. and lvelfare. Public
    Health Service Publication so. 1000. Series 21, So. 3. July 1965. 33 PP.
(fOJ) VABA. J?.. KINVUNEN, 0. The effect of nicotine on the female rabbit and
   developing foetus. An expwimrntal study. Annals Medicinae Eswri-
    mentalis et Biolntica Fenniae 2 : LX)?-1'31. 1951.
(105) VETOLET. F. Nastcpstxv-a niedohoru vitamin? c u palnczy. (Consequences
   of vitamin C deficiency In smokers.) Polskie hrchiwum Jledx.mY
    Kerrnetrznej 2G : 393-402. 1%6.

(106) VESIXFT. F., T,avsz. H. Uhytek witaminr c R narzndnch mb poddsn?ch
    dzialnniu dcmu tytonion-ego. (Influence of tobacco smoke on ascorbic
    acid content in mothers' milk.) Acta Physiologica I'olonica 4(4) : %I-
    Xi6, 1954.

(197) VESCLLTT. F.. n.tsrsz. A. \Vp'lrw Palenin Wtoniu nfl poziom n-itamiw C R
    mleku Kobiccym. (The influence of tobacco smoking on the k?vfi of
    vitamin C in human milk.) Pediatria Polska 3Of9) : 811-817. 19%

462


(103) WELTII. R. ~1.. E~.\RRISOS. T. E.. GOMQI. II. W.. Porrrxs. P. J.. FITSTER \I..
     COSXEY. -4. H. Stimulntory effect of cicarette smoking on the hrtlroxrla-
    tion of 3.Nwnq1~rene and the S-dcn~rthrlntion of 3-methFl--l-mono-
    met2l~laminoazohenzene bS enzymes in human placentn. Clinicn\ Phar-
    mncologp and Thrr:lpeutics 10( 1) : 100-109. Jnnuarl--Fehrunc- 1969.
(ff0) U~ILSOT. E. IV. The effect of smoking in prcgnanc>- on the placental coeffi-
    cient. Sew Zealand Medical Journal 74 (-475) : 38&X%5, lOi-3.
(111) \VYXDFR. E. I,., HOFFX%XS. D. Tobncco nnd Tobacco Smoke. Studies in
    Experimental Cnrcinogenesis. Sew York. Academic Press. 1967. 530 pp.
(112) TERUSRALMY. J. Infants with low-birth n-eight born before their mothers
    started to smoke cigarettes. Americau .Journnl of Obstetrics and Grne-
    colog~ 112(1?) : Xi-2R1, Jnn. 15, 1972.

(213) TERCSX.~LXY. J. Mother's cignrctte smoking nnd surrirnl of infant. Amerl-
    can Journal of Ollstetrics and G.~necolo=y S(4) : SOS-518. Feb. 1.5, 136%
(11-I) YERUSHALYY, J. Statistical considerntious and ernluntion of rpiden~iolo.&
     cal eridcncr. Ix: .Jnmes. G.. Rosenthxl. I'. (Editors). Tobacco and Wenlth.
    Spriuqtield. Charles C. Thomas, 1362. pp. 20%230.
(Ifs) YERCGHAL~W. J. The relationship of parents' ciprette smoking to outcome
    of pre.~ancc-im~licntions as to the prol,lcm of inferring causation from
     obserred nssocintions. American Joun~nl of Epidemiology- 93 (6) : +X3-
     -1.56. June 19X.

(1215) ~O~SOSZAI. 11. Ii.. KACIC. A., I~AWORTII. J. C. Cigarette smoking dnring
     pre~wncy: The effect upon the hemntocrit and acitl-base balance of
     the nelrborn infant. Canadian Medical ?\ssocintion Journal 99(S) :
    lOi-200, -411;. 3. 19GS.

463


Chaprer 6
     Peptic Ulcer Disease

Source: 1973 Reporl, Chapter 5, pager 151 - 164

46.5


Contents

Introduction___-__-.-----_-------------------------------   469
Epidemiolo$xl and Clinical Studies--- _ -_ _- _-_ _- -_ -_ _ _ __ - -   469
Esperimental Studies

  G~str2cSecretion_-_~ _______ _-___---_--_-___-_-_______   471
  Pancreatic Secretfon-- -___-_____ ---_---- ____________- -   473
Summnry of Recent Peptic Ulcer Disease Findings- _ _ _ _ - _ _ _ _   476
Refcrcnces ___-__-____ __-__-_____ -- ___-___ --__-__-___--   477

List of Figures

I.`i,qre I.-Gastric ulcer tiortality ratios of Japanese (men and
women combined) by age at initiation bf cigarette smoking
(19GF-70)_-____-____________-__-__-_--_------~--~----   470
Figure Z.-Effect of cigarett.e smoking on volume of secretin-
stimulated pancreatic secretion in humans_--___--_-__-__-   474
Figure S.-Effect of cigarette smoking on secretin-stimulated
pancreatic bicarbonnte output in humans-_-__-____-__-___   475

467


Introdriction

Preriouu epidemiological and erpcrimental studies of the relat.ion-
sliip between cigarette smoking and peptic ulcer disease were review-ed
in the 19i1 and 1972 reports on the health consequences of smoking
(17,18) sntl form the basis of the folloxving summary :
The results of epidemiological studies indicate that cigarette smok-
ing males have an increased prevalence of pept.ic ulcer disease and a
greater mortality from peptic ulcer as compared to nonsmoking males.
_Ytnong mnlcs, the association betn-een cigarette smoking and peptic
ulcer disease is stronger for gastric than for duodenal ulcer, but sig-
nificant for both. For males, ciprette smoking appears to reduce the
ctfcctiwness of standard peptic ulcer treatment and to slow the rate of
peptic ulcer healing. The relationship between cigarette smoking and
the prevalence of and mortality from peptic ulcer disease is less clear
for females than for males.

Experimental studies of the effect of cigarette smoking in man, and
of the effect of injection and infusion of nicotine in animals, on gastric
secretion and motilitv ha\-e produced conflicting results. In dogs, an
infusiori of nicotine has been found to inhibit pancreatic and hepatic
bicarbonate secretion, thus demonstrating a possible link between
cirarctte snroking and duodenal ulcer.

Recently, additional epidemiological, clinical, autopsy, and esperi-
mental studies have confirmed the association between cigarette smok-
ing and gastric ulcer mortality and have clarified a mechanism through
which cigarette smoking might be linked to duodenal ulcer.

Epidemiological and Clinical Studies

Previous studies of the relationship between peptic ulcer- disease and
cigarette smoking haw been conducted in predominantly white, We.+
em populations. A large prospective epidemiological study is currently
being conducted in .Japan. From this study, Hirayama (6) reported
5-J-e3r folIowup data on 265,llS men and women, aged 40 years and
older, reprcsentinF St to 99 percent of the total population in the area
of the 3 health districts in xvhich thestudy was conducted. Both male


and female cigarette smokers cq)erienced higher death rates from
gastric ulcer as coml~awci with nonsmokers. The mortality ratio for
ciznrctte smokers was 1.81 for males (r)<O.OOI) and 2.15 for fernaks
(P<O.OS). The mortality rntio for smokers (males and females com-
billed) was dose-dependent as measured by age at initiation of smoking
(fig. 1). The results of this study, in the contc.xt of the genetic and cul-
tural differences between Japanese and Western populations, provide
a significant confirmation of the association between cigarette smoking
ftnd gastric ulcer mortality.

Figure I.--Gastric ulcer mortality ratios of Japanese (men and women combined)
    by age at initiation of cigarette smoking (1966-1970).

  5.00

Nonsmoker

>25       <=        <I9
Age at initiatlon of cigarette smoking (years)

SOURCE: Hirayama. T. 161.

470


Alp, et al. (1) conducted a retrospective survey of 63s patients,
admitted to txvo -Lustralinn teaching lrospitals between 135-1 and 1963,
with chronic gastric ulcer confirmed by rorntgcnogrxpl~ic, rntloscopic,
or surgical examination. The findings in the patients were compared
with information a\-ailable about the South -1ustrali:in population
obtained at census in 1331 and 1961, and with a control group of 233
subjects matched for age and sex with the ulcer patients. Cigarette
use, a family history of peptic ulcer, domestic stress, and aspirin and
alcohol intake occurred significantly more frequently among ulcer
patients. Alp, et al. (Z) found that after surgical treatment, recurrence
of the ulcer WLS significantly more likely to recur among those patients
who continued to smoke, drink, and use aspirin (P<O.OOl).

Fingerland, et al. (5) compared the autopsy findinbr; from 76.5 males
rrith their smoking history. Th e autopsies xet-c performed without
selection during 1965 and 1966 at the University of Hradec Kralov6,
Czechoslovakia. Peptic ulcer -~-as significantly more frequent among
male es-smokers and male lifelong smokers than among male non-
smokers (P<O.O;?). Among males, a dose-response relationship was
found between estimated total cigarette consumption and the presence
of peptic ulcer at autopsy.

Cooper and Tolins (4) reported results from a retrospective study
of the relationship between cigarette smoking and postoperative com-
plications among 2:9SS males, admitted to I9 Veterans Administration
hospitals, for the surgical treatment of duodenal ulcer. Smoking his-
tory xas obtained for 1,441 of the men. and of these 273 were non-
smokers, 1,015 smoked cigarettes only, and 93 smoked cigarettes plus
a pipe and/or cigars. The authors found no evidence of an association
betrreen either the number of cigarettes smoked per day, or the number
of years of cigarette smoking, and postoperative complications, opera-
tive mortality, or length of hospital stay. They emphasized that their
results must be viewed Kith considerable caution and listed several
potential sources of bias. In addition, they noted, "* * * that these
results apply only to the immediate postoperative findings and do not
apply to the long-range effects of smoking upon the patient after
surgery for duodenal ulcer disease."

Experimental Stu&ee

Gastric Secretion

S-I-L-DIES IS Hrix~xs

Morales, et al. (IO, II) studied the effect of cigarette smoking on
gastric secretion in a group of 312 patients. The patients included 138

471


with duodenal ulcer, 93 with gastric ulcer, and Sl with other gastro-
intestinal disorders, who served as controls. Cigarette smoking was
significantly more frequent among the patients \Cth peptic ulcer than
among the controls.

The chronic eflect of smoking on gastricsecretion -was quite variable.
Male smokers among the controls and in the group with duodenal
ulcers had a significantly increased baseline acid output as compared
with nonsmokers in the same groups (P<O.O5). -%fter a subcutaneous
injection of histamine, only the group of male smokers with gastric
ulcers had a significant increase in acid output over the values obtained
for nonsmokers in the same group (P<O.O5). Among the smokers in
the control group, the relationship between gastric acid out.put and the
number of cigarettes smoked daily was dose dependent. No such rela-
tionship was obtained for either of the trro groups with peptic ulcers.

In these experiments, the acute effect of smoking on gastric secre-
tion was slight. In one set of experiments, n group of eight smokers
served as its o=n control. The smoking of two cigarettes prior to
collection of gastric juice had no significant effect on acid output as
compared to baseline values. After smoking two cigarettes and also
receiving a subcutaneous injection of histamine, the patients experi-
enced no significant change in gastric acid output as compared to
baseline values; 21 male patients, including members from the groups
with ulcers and controls, smoked one cigarette 1 hour after an intra-
venous infusion of histamine. A transient depression of gastric acid
output was noted as compared with the values obtained from nine
patients who did not smoke.

STUDIES IN AXMALS

Konturek, et al. (8) studied the effect of intravenous infusion of
nicotine on the formation of acute, experimental duodenal ulcers in
cats. The authors infused nicotine intravenously in doses comparabIe
to the smoking of four, eight, and 16 cigarettes per hour into catsin
whom near maximal gastric acid output had been stimulated with
intravenous pentagastrin. The investigators. found that nicotine in the
two lower doses had no effect upon the gastric acid output stimulated
by pentagastrin, but that the highest dose produced a significant de-
crease in response, due to a fall in both volume and acid concentration.
Nicotine alone failed to alter a negligible basal gastric secretion. In
control animnls (pentagastrin alone), duodenal ulcers were found in
eight of 10 animals. Nicotine at the txvo lower doses, in combination
with pentagastrin, produced ulcers in all 26 animals. At the inter-
mediate dose of nicotine, the mean ulcer area was twice that found in

472


the control group . At the hi,Thcst (lose of nicotine. peptic ulcers np-
peared in only two of six animals and the area of ulcer was reduced
compared to controls.

Shaikh, et al. (I$) studied th e acute and chronic ctfccts of sub-
cutaneously injected nicotine on gastric secwtion in rats. Under bnsai
conditions, the volume of gastric secretion eras initially depressed,
then stimulated, and depressed again as the dose of nicotine KEG
increased. Xcid output eras decreased over the entire range of nicotine
dosage. Pepsin output reflected a similar triphasic response to in-
creasing nicotine doses as did gastric secrebry volume. In the absence
of nicotine, pentagastrin stimulated gastric volume, acid, and pepsin
output. The injection of nicotine, in increasing doses, administered
simultaneously with pentxgastrin, resulted in a gradual decrease in
response for all parameters. Volume of gastric juice, acid output, and
pepsin output were all increased significantly by chronic exposure to
nicotine aIone. Based on an average smoking dose of nicotine, the dose
of nicotine employed in the chronic experiments corresponded to the
smoking of three to fire cigarettes per day.

Thompson, et al. (16) extended the study of rats described above
b_v studying the cflects of chronic nicotine injections in vngotomized
rats and rats with discrete lesions in the hypothalamus. In sham-
operated animals, chronic nicotine injections significantly increased
baseline volume of gastric juice, acid output, and pepsin output. FoI-
lowing vagotorny, the nicotine response was completely suppressed.
Caudal hypothalamic lesions did not influence the response to nicotine
in the presence of intact vagus nerves. Anterior hypothalamic lesions,
ranging from the anterior hypothalamic area to the ventromedial
h>-pothalamus, blocked the nicotine-induced gastric secretory stimula-
tion in the presence of intact vagi. The authors concluded that chronic
nicotine-induced gastric secretory stimulation is mediated via anterior
hypothalamic activation and intact ragus nerves. The importance of
local effects remained uncertain.

Pancreatic Secretion

Bpnum, et al. (3) studied the effect of cigarette smoking upon pan-
creatic secretion in -23 healthy young males and females. Five control
male nonsmokers xere compared with seven male and t\ro female light
smokers (Iess than one pack of cigarettes per day for less than .7 years)
and eight male and one female heavy smokers (more than one pack of

473


cigarettes per day for more than 3 years). Pancreatic secretion n-as
measured by the double secretin test, using Boots secretin. The experi-
ment was divided into two parts for the SJrlOk0~3: A basal collection
period and an experimental period during which the subjects smoked
seven nonfiltered cigarettes at the rate of four per hour. Light smokers
had basal values for pancreatic secretory volume and bicarbonate out-
put in response to secretin which were not significantly different from
controls. After the subjects had smoked, significant depression of both
pancreatic volume and bicarbonate output was noted (P<.oOl).
Heavy smokers had basal values that were significantly less than in the
control subjects (P<O.Ol). Smoking, horrever, did not further depress
the response to secretin (figs. 2 and 3).

Solomon and Jacobsen (15) reviexed some possible mechanisms
whereby the increased prevalence and mortality from duodenal ulcer
among cigarette smokers might be produced. They concluded that
evidence from studies in animals, coupled with the findings of Bynum,
et al. (a), supported the hypothesis that the mechanism active in
humans involves impaired neutralization of acid secondary to the
inhibition of pancreatic bicarbonate secretion.

Figure 2.-Effect of cigarette smoking on volume of secretin-stimulated pancre-
       atic secretion in humans.

MeanOY'"me
MeanOY'"me  2.5
         2.5
paff"ucrw;c 2.0
paff"ucrw;c 2.0
milliliters 1.5
milliliters 1.5
per kilogram
per kilogram
body weight 1.0
body weight 1.0

1       2.4

1 ~~gnlflc.ntly dinerant from nonsmoking test within group of light smokers (P <O.OOl).
I Signmc.ntiy different from nonrmoklng controls (P <O.Ol).

SOURCE l3ynUm. o ? ai. 0)

474


Figure 3.-Effect of cigarette smoking on secretin-stimulated pancreatic blear.
      bonate output in humans.

12

10

Mean hourty a
output of
bicarbonate 6
    in
milliequiva- 4
tents per hour
          2

0

i

a.4

1 Sqnifbcantly dufferent from nonsmoksng test wilhin group of light smokers (P <O.oOl).
1 Significantly different from nonsmoking conlrols (P 40.01).

SOURCE Eynum. at al. (3).

Konturek, et al. (7) extended his research on the mechanism of
nicotine-induced inhibition of pancreatic secretion in the dog, using
the design previously employed (9). Infused secretin alone led to a
sustained increase in pancreatic bicarbonate output. Intravenous nico-
tine, at all four doses of infused secretin, produced a significant in-
hibition of pancreatic volume and bicarbonate output (P <0.05).
                                                       -
Infused nicotine appeared to inhibit competitively the elect of secre-
tin on pancreatic secretion of fluid and bicarbonate. Topical (intraduo-
denal) nicotine failed to affect significantly the response to infused
secretin. Stimulation of endogenous secretin by an acid infusion into
the duodenum produced the expected pancreatic secretory response.
Sicotine either applied to the duodenal mucosa or injected intra-
venously significantly inhibited the pancreatic secretory response to
rndogcnous secretin. Sicotine had no significant effect on total pancrea-
tic protein output. Nicotine did not alter the cholecystokinin-induced
stimulation of pancreatic secretion. The authors concluded that nico-
tine may inhibit pancreatic secretion of fluid and bicarbonate both

475


by a direct effect on pancreatic secretory mechanisms. ;wting a~ a com-
petitive inhibitor of secretin, and by a secondary edect on the duodenal
mucosa, depressing the endo-mnous release of secretin by acid.

Robert (~2) studied the potentiation of active duodenal ulcers by
nicotine administration in the rat. Subcutqneous infusion of pentagas-
trin nnd carbachol resulted in the dose-dependent formation of duo-
denal ulcers within 24 hours. Sicotine alone produced no ulcers
Increasing doses of subcutaneously infused nicotine, in combination
with the other t\vo agents, resulted in a steadily increasing dose-related
incidence and severity of the duodenal ulcers. Robert noted that
Konturek, et al. (9) found that nicotine inhibited pancreatic and
biliary bicarbonate secretian in dogs, and that Thompson, et al. (26)
found that acute dose-s of nicotine in rats eit.her depressed or did not
alter gastric secretion. He concluded that the most. probilble mechsnism
by which nicotine potentiated acute duodenal ulcer formation in the
rat was via a suppression of pancreatic secretion.

Robert, et al. (13) further tested this hypothesis b\- infusing acid
via the esophagus of rats in doses found to cause duodenal ulcers in
one-third of the experimental animals. One group of rats also received
a subcutaneous infusion of nicotine. Another received nicotine, but
only water was infused via the esophagus; 31 percent of the animals
receiving acid but no nicotine had duodenal ulcers; 93 percent of the
nicotine-acid group had duodenal ulcers, while none of the nicotine-
water group had ulcers. The ulcers in the nicotine-ncid group rere
more numerous, extensive, and deeper than those in the animals which
received acid alone.

Summary of Recent Peptic Ulcer Disease Findings

In addition to the findings relating cigarette smoking to peptic ulcer
disease, summarized in previous reports on the health consequences of
smoking (27, 18) and cited in the introduction to this chapter, recent
studies have c0nt.ribute.d further to our understanding of the
association:

1. The finding of a significant dose-related excess mortality from
gastric ulcers among both mnle and female Japan- cigarette
smokers, in a large prospective study, and in the context of the
genetic and cultural differences between the Japanese and pre-
viously investigated IVestern populations, confirms and edends
the association between cigarette smoking and gastric ulcer
mortahty.

476


2. Data from experiments in several different animal species sug-
gest that nicotine potentiates acute duodenal ulcer formation by
mans of inhibition of pancreatic bicarbonate output.
3. Cigarette smoking has been demonstrated to inhibit pancreatic
bicarbonate secretion in healthy young men and women.

Peptic Ulcer Disease References

(1) ALP, X. H, HIS~OP, I. G., GH~NT. A. K Gastric nicer In South Anstralla,
   1954-4X L Epldemlologlcal factors, MedIcal Jonrnal of Australia 2(24) :
   lX%1132, Dee l2,1970.

(0) ALP, M. H., HISLOP, I. G., GBANT, & K. Gastric ulcer ln South AnstralIa.
   BXX-~~. 2. Symptomatology and response to treatment. MedIcal Journal
   of Austrrdh 1 (i) : 372-374, Feb. 13,197L
(9) Brrrola, T. E, SOLOMON, T. E., Jomvson, L. R, ~AcOS8ON, E. D. InhIbition
   of pancreatic secretlon in man by cigarette smoking. Gut 13(5) : 361-385,
   ?dny 19i2.

(4) Cco~4 P., TCLINB. S. II. Relatlonshlp between smoking history and complt-
   cations lmmedlately following surgery for duodenal ulcer. Xount Stnal
   Journal of JledIcine 39(3) : 267-292, MayJune 1072.
(5) FLXG~XD. A., HU~AE, T.. BENLIMVA, J. Contribution to the investigation
   of the effect of cignrette smoking. Sbornlk Vedeckych Pracl Lekarske
   Faknlty Karlovy University v Hradcl Krluove 14(a) : 221-234, 1071.
(6) HIRAYAXA, T. Smoking in relation to the death rates of 265,118 men and
   women in Japan. A report of 5 years of followup. Presented at the Amer-
   lcan Cancer Society's 14th Science Writers' Seminar, Clear-water Beach,
   FlE. Alar- 27.1972.15 pp.

(7) KOST~ZFX, 3. J., DALE, J., J~~~oason, E. D., Joaasoiv. I& R. hIechanlsms of
   nicotlneinduced lnhibltlon of pancreatic secretion of bicarbonate in the
   dog. Gastroenterology 62(3) : 425429, 1972.
(8) Ko~.~uamc, S. J, Raoecxr, T., THOR, P., D~MBIX~EI, A., JACOBSON, El. D.
   Effects of nicotine on gastric secretion and ulcer formation in cnts. Pm
   ceedhg~ of the Society for Experimental Biology and Medtclne 138(2) :
   674-67i. November 1971.

(9) Kox~uarx, 9. J, SOLOMON, T. E, MCCBEIOHT, W. G., JOHNSON, IA R,
    JACXXMN. E. D. Edects of nicotine on gastrointestinal secretions. Gastro
   enterology 60(6) : 1093-1105. June 1971.
(lo) MORALES, &, S~LVA, S., &.CALDE, J., WaJSSELUTH, J., &MOB, J., BEY, I%,
   Sdxz. R. Cigarrillo y sec&on gastrica. I. Analisis de la secrecldn-
   gastrica en pacientes digestlvos fumadores p no fumadores. (Clgarettea
   and gastric secretion. I. Analysis of gastric secretion In smoking and non-
   smoking ulcer patients.) Rerista Aledlca de Chile 90(-l) :271-274, Apxll
    197L

(11) MoaaLEa, b. SILYA, S., OEOBIO. G., ALCAJBI; J, WAIB~~LUTR, J. Clgarrlllo y
   secrrdon gastric% II. Efecto de1 clgarrlllo sobre la secreclbn gAstrIca.
   (Cigarettes and ga6trlc secretion. II. Etfect of clgarettes on gastric sea-e-
   Uon) Rwista lkdica de Chile 99(4) : 275-2i9, April 1971.

477


(12) ROBIN. A. Potentlntlon. by nicotine, of duodenal ulcers in the rat. Pro-
    ceedings of the Society for Experimental Biology and Medicine 139( 1) :
    31CL3?2. Jaouan 1972.

(1.9) ROBERT, .I., STOW& D. F.. SEZASIIS, J. E. Possible relationship hetrreeo
    smoking and peptic ulcer. Xature 233(5?20) : 497-493, Ott 15. 19il.
(1-t) SXAIKH. 31. I.. THOMPSOX. J. H.. ALYRES. D. Acute and chronic effects of
    nicotine on nt gastric secretion. Proceedings of the Kestern I'harma-
   cology Society 13: 178-184. 1970.

(1.5) So~ouoa. T. E.. Jacossorv. E. D. Cigarette smoking and duodenal-ulcer dis-
    ease. Sew England Journal of Medicine 286(2'1) : 1012-1~13. June I, 192.
(IG) TI~OSJPSOS, J. H.. GEOEOE, R.. Axarr~o, &I. Some effects of nicotine on gastric
    secretion in rats. Proceedings of the Western Pharmacology Society
   14 : 1X-177. 1971.

(17) U.S. PIXLIC HEALTIX Searxcz. The Health Consequences of Smoking. A Re-
   port of tbe Surgeon Genernl : 1971. U.S. Depnrtmeot of Henltb, Education.
    and Welfare. Washington. DHEW Publication No. (HSN) 71Li513.
   1971, 455 pp.

(18) U.S. PIXILIC HWLTII SEWICE. The Health Consequences of Smoking. A
    Report of the Surgeon General : 1972. U.S. Department of Health, Educa-
   tion, and Welfare. Washington. DHEW Publication No. (HSM) 72-6516,
   1972. 158 pp.

478


Chapter 7
      Involuntary Smoking

Source: 1975 Report. Chapter 4. pages 83 - 112.

479


Con tents

Introduction . _ _ . _ _ _ _ _ . _ _ _ _ . _ _ _ _ . _ . _ _ _ _ _ . _ . _ . . _ . . .   483

Constituents of Tobacco Smoke . . _ . . . . . _ _ _ _ _ _ _ . . . _ _ _ . . _ _ _ _   484
   Carbon hlonoxide . _ _ _ _ _ . . . . _ . _ . . . _ _ _ . . . _ _ _ . . . . _ _   486
   Nicotine . _ . . _ _ _ _ _ . _ . _ _ . . _ . . _ _ _ . . . _ _ _ . . , . _   493
   Other Substances . . _ _ _ _ . . _ _ _ _ . _ . . . _ . _ _ . . _ _ . _ _ _ _ . .   494

Effects of Exposure to Cigarette Smoke _ . . . . . . . _ _ . . . _ _ . . . . . .  494
  Cardiovascular Effects of Involuntary Smoking _ _ . . _ _ . _ . _ _  494
  Effects of Carbon Monoxide on Psychomotor Tests _ . . . . _ _ _  495
  Pathologic Effects of Exposure to Cigarette Smoke _ . _ . _ . . _  495

Summary of Involuntary Smoking Findings . . . . . _ . . _ _ . _ _ _ . . _ _ _ _  504

Bibliography _ . . . _ _ . . _ _ _ _ _ . _ _ _ . . . _ _ _ _ _ _ _ _ _ _ . . . _ . _ . _  505

481


List of Tables

Table I.-Comparison of mainstream and sidestream             Pqe
   cigarette smoke . . . . _ . L . _ . _ . . . . . _ _ . . . _ _ _ . . . _ _ _ . . _   485

Table 2.-Measurements of constituents released by
  the combustion of tobacco products in various
   situations _ _ _ _ _ . _ . _ . _ . _ . _ . . . _ _ _ . . _ _ _ . . . . _ . .  4 87-490

Table 3.-Median percent carboxyhemogiobin (COHb)
  saturation and 90 percent range for nonsmoker
  by location . . . _ . _ _ _ . _ . . . _ . . . . _ _ _ . . _ . . . _ _ . . . _ _ _ .    492

Table 4.-Effects of carbon monoxide on psychomotor
   functions . . . . . . . . _ . . . . . . . . . . . . _ . . . . . . . . , . . . . 496-497

Table S.-Admission rates (per 100 infants) by
  diagnosis, birth weight, and maternal
  smoking _ ._. _ ____. _..____ _ _.._ .._.__...........   500

Table 6.-Pneumonia and bronchitis in the first
  5 years of life by parents' smoking habit
  and morning phlegm . _ _ . . _ _ _ . _ . . . . . . . . . . . . . . . .   502

482


INTRODUCIION

    The effects of smoking on the smoker have been extensively
studied, but the effects of tobacco smoke on nonsmokers have
  received much less attention. The 1972 Health Consequences of
Smoking (4Y) reviewed the effects of public exposure to the air
pollution resulting from tobacco smoke. This exposure has been
called "passive smoking" by many authors, but will be referred to in
this report as "Involuntary Smoking." The term involuntary smoking
  will be used to mean the inhalation of tobacco combustion products
  from smoke-filled atmospheres by the nonsmoker. This type of
exposure is, in a sense, "smoking" because it provides exposure to
many of the same constituents of tobacco smoke that voluntary
smokers experience. It is also "involuntary" because the exposure
  occurs as an unavoidable consequence of breathing in a smoke-filled
  environment.

  The chemical constituents found in an atmosphere filled with
tobacco smoke are derived from two sources - mainstream and
sidestream smoke. hlainstream smoke emerges from the tobacco
product after being drawn through the tobacco during puffing.
Sidestream smoke rises from the burning cone of tobacco. Main-
stream and sidestream smoke contribute different concentrations of
many substances to the atmosphere for several reasons: Different
amounts of tobacco are consumed in the production of mainstream
and sidestream smoke; the temperature of combustion differs for
tobacco during puffing or while smouldering; and certain substances
are partially absorbed from the mainstream smoke by the smoker.
The amount of a substance absorbed by the smoker depends on the
characteristics of the substance and the depth of inhalation by the
smoker. As discussed in the 1972 Report, when the smoker does not
inhale the smoke into his lungs, the smoke he exhales contains less
than half its original amount of water-soluble volatile compounds,
four-fifths of the original. nonwater-soluble compounds and
particulate matter, and almost all of the carbon monoxide (15).
When the smoker inhales the mainstream smoke, he exhales into the
atmosphere less than one-seventh of the amount of volatile and
Particulate substances that were originally present in the smoke and
also reduces the exhaled CO to less than half its original conce'ntra-
tion (16). As a result, different concentrations of substances are
found ih exhaled mainstream smoke depending on the tobacco
product, composition of the tobacco, and degree of inhalation by the
smoker.

483


  Several minor symptoms (conjunctival irritation. dry throat.
etc.) are caused by levels of cigarette smoke encountered in everyday
life, and serious allergic-like reactions to cigarette smoke may occur
in some sensitive individuals. A major concern, however, about
atmospheric contamination by cigarette smoke has been due to ihe
production of significant levels of carbon monoxide. Cigarette
smoking in poorly ventilated enclosed spaces may generate carbon
monoxide !eveIs above the acceptable g-hour industrial exposure
limits (50 ppm) - set by the American Conference of Government
Industrial Hygienists (I). Exposure to this level of carbon monoxide
even for short periods of time has been shown to reduce significantly
the exercise tolerance of some persons with symptomatic cardio-
vascular disease. There is also some evidence that prolonged exposure
to this level of carbon monoxide in combination with a high
cholesterol diet can enhance experimental atherosclerosis in animals
(Chapter I, Cardiovascular Diseases).

  In the present chapter, the effects of cigarette smoke on the
environment and on the nonsmoker in that environment will be
examined by reviewing data on (I) the constituents of cigarette
smoke measured under various conditions, and (2) the physiologic
effects of this "involuntary smoking" on individuals.

CONSTITUENTS OF TOBACCO SXlOKE

  In a recent workshop on the effects of environmental tobacco
smoke on the nonsmoker (41), Corn (14) presented a compilation
adapted from Hoegg (32) of some of the substances in mainstream
cigarette smoke and the ratio of sidestream to mainstream levels for
some of these substances (Table 1). The actual numerical value of the
sidestream to mainstream concentration ratio will vary with different
types of tobacco tested, but Table 1 gives values generally consistent
with those found by others (34, 42). Many of these substances
including nicotine and carbon monoxide are found in much higher
concentrations in sidestream smoke than in mainstream smoke,
establishing that the smoke exposure received by both the smoker
and nonsmoker due to breathing in a smoke-filled environment
differs qualitatively as well as quantitatively from the smoke
exposure received by the smoker who inhales through a lighted
cigarette. A more comprehensive recent review of the constituents of
mainstream and sidestream smoke has also been provided by
Schmeltz, et al. (42) and Johnson, et al. (34).

484


TABLE 1. - Camparisorr of ntaitrstreuttt atrtl sidesrrearrt cigarerte smoke ' l2

Compound

hfainstream
big/c@

Sidestream
(mg/ck)

Ratio
Sidesbeam/
hfainslrcam

Commcnf

A    Gcncrul charuclcrr~tic\
   Dur.llion of smoke production     20 set         550 KC          27
    1 ooJccu burnt              337          411            1.2
   P,irticulote>, no. cigarette
              per           1.05 x IO"     3.5 x 1o'2         3.3

B   Particulate phase
  2Tar (chloroform extract)        20.8
                          10.2

44.1             2.L
34,s             3.4
I .6Y            1.8
I.27            2.8
13.5 x 10        3.7
39 x 1o-s         3.0
0.603            2.6
4s x 1o-5         3.6

Nrcotine

Benzo(a)pyrene
Pyrene
Total phenols
Cadmium

0.92
0.46
3.5 x 10-s
13 x 1cs
0.228
12.5 x 1cs

Filter cigarette

C   Cases and vapors
    Water                    1.5          295            39.7

Ammonia                 0.16          1.4            46
Carbon mon+ide            31.4          148             4.7
Carbon dioxide              63.5          79.5             1.3
Oxides of Nitrogen           0.014         0 OS1           3.6


  A number of other researchers have sttcmpted to measure the
Ir-:els of some of the substances in ci$!iJKtk smoke encountered in
everyday situations (Table 2). They have also tried to determine the
factors controlling the atmospheric concentrations of these
substances as well as the amount absorbed by nonsmokers under
these conditions. Carbon monoxide, nicotine, benzo(a)pyrene,
acrolein, and acetaldehyde have been of particular concern.

  Levels of carbon monoxide (CO), a major product of tobacco
combustion, have been studind in a variety of situations, and
concentrations ranging from 2 to 1 10 ppm have been measured
(Table 2). The major determinants of the CO levels in these
situations are size of the space in which the smoking occurs (dilution
of CO). the number and type of tobacco products smoked (CO
production), and the amount and effectiveness of ventilation (CO
removal).

  The type of tobacco product smoked is important as a
determinant of CO exposure  because it has been found that
mainstream smoke from regular and small cigars contains more CO
pre puff and per gram of tobacco burned than filtered or unfiltered
cigarettes (S). Tllis greater production of CO by cigars was confirmed
by Harke (23). He measured the CO produced by 42 cigarettes, 9
cigars. and 9 pipefuls of tobacco, each product evaluated separately
but under the same room conditions. The cigars produced the highest
CO level (60 ppm).

  In addition to the effect of type of tobacco product on CO
levels. data on the effects of room size, amount of tobacco burned,
and ventilation are included in Table 2. Only under conditions of
unusually heavy smoking and poor ventilation did CO levels exceed
the haximum permissible, &hour industrial exposure limit of--f0
ppm CO (I); however, even in cases where the ventilation was
adequate,  the measured CO levels did exceed the maximum
acceptable ambient level of9 ppm (18).

  Harke (-37) also showed that in small enclosed ventilated spaces
(an automobile) the CO level is determined more by the number of
cigarettes being smoked at one given time than by the cumula\ive
number of cigarettes that have been smoked; also the CO level
decreases rapidly once the smoking stops.

486


Rcfcrcncc, Location, and
Dlmenslons If Known

VcnlilJtion

Conslilllcnls

Ilarkc, IL-P., Cl 31. (7)
hlid-size European cur,
cng~ne off, in wind
tunnel at so km/h1
wind speed

Nvne

Air jets open Sr
blower off

9 c,g

6 cig

30 ppm CO

20 ppm CO

Air jets open &
blou'er on

6 cig

10ppmCO

Mid-size European car,
engine off, in wind
tunnel al zero km/hr
wind speed

None


NOW

Air jets open &
blower on

9 cig

6 cig

6 cit.

llOppmC0

80 ppm CO

8-10 ppm CO

Ilarke, H.-P., Peters, H. (28)
Car in trafl'tc

Srch. hf. (a)
Car, en Tine off-
   $
2.09 n,

NOllC              4 cig



None              10 cig in I hr

21.4 ppm CO


90 ppm CO, Smokers  I O'I (`Ollh
       ?ionvnokcrr 5'): UIllb

Scilf, I1.E. (~4)
   Intcrcity busts

23 cig
(burning conlinuou\ly)


fs
0)   TABLE 2. - Measuremenrs of constiruenfs released by rhe combustion of tobacco products in various sirlrarions - COnrilrfled
02                 [ Cig = cigare t (es; - = unknown; TPhl = total particulate matter]

Reference, Location, and
Dimensions If Known

Ventilation

Amount of
Tobacco Burned

Constituents

U.S. Dept. Transportation,
et al. (48)
Airplane flights:
   Overseas-100% filed
   Domestic-66% filled

15-20 air changes per hr
do.

2-S ppm CO < 120 mg/m3 TPM
<2 ppm CO: <:I20 mg/m3 TPhf

Cano, J.P., et al. (I 1)
Submarines-66 m3


Godin, G, et al. (21)
Ferry boat compartments:
   Smoking
   Nonsmoking

Yes

157 cig per day
94-103 cig per day

<40 ppm CO, 32 up/m3 Nicotine
<40 ppm CO, 15-35 pg/rn3 Nicotine




18.4 i8.7 ppm CO
3.Oi2.4 ppm CO

`Iheater:
Foyer
Auditorium

3.4tO.8 ppm CO
1.4iO.8 ppm CO

Bridge, D.P., Corn, M. (7)
Party rooms:
  145 m3
  101 m3

7 air changes per hr
1) 10.6 air changes per hr      50 cig & 17 cigars in 1.5 hr
               63 cig & 10 cigars in 1.5 hr

7 ppm CO
9 ppm CO


TABLE 2. - Measurements of constituents released by the combustion of tobacco products in various situations - Continued
                                                                           
            [ Cig = cigarettes; - = unknown; TPM = tot31'pa~ticthte matter]

Rcfcrence, Location, and
Dimensions If Known

Ventilation

Amount of
Tobacco Burned

ConstiWents

llarke, H.-P., et al. $ 25)
  Room-38.2 m              None             30 cig per 13 min (by machine)    64 ppm CO, 510 ug/m3 Nicotine
                                   .46 mg/m3 Acrolein
                                       6.5 mg/m3 Acctaldehydc

5 cig per 13 min (by machine)

Il.5 ppm CO, 60 rg/m3 Nicotine,
..07 mg/m3 Acrolcin,

1.3 mn/m3 Acctaldchydc

Harkc. H.-P. (24)
Office Bldg
ofrlcc Illdg
Roum-78.3 m3

Air conditioned
Not air conditioned

3 smokers

<5 ppm CO
<5 ppm co
! 5.6 ppm CO

   Harkc, IL-P., (23,
    Room-57 m3              None              42 cig (by machine)
                      7.2 air changes per hr       42 cig     do.      50 ppm CO, 530 pg/rn: Niculinc
                     8.4 air charlgcs per hr       42 cig     do.     < ;; ;;; ;;I :-:",;y;,,3";;.;;::;lc

                          None              9 cigars do.         60 ppm CO, 1040 tig/rn3 Nlcorinc
                     7.2 air changes per hr      9 cigxr do.         20 ppm CO, 420 pg/rn' NILU~IIIE


                           None              9 pipes do.         10 ppm CO, S20 pg/m3 Nicolinc
E                      7.2 air changes per hr      9 pipes    do.        <lO ppm CO, <IO0 lip/m3 Nicollne
Q



  Several investigators have tried to determine the amount of
carbon monoxide absorbed in involuntary smoking situations by
measuring changes in carbosyhrmozjobin 1-.2vels in nonsmokr:rs
exposed to cigarette smoke-filled environments. Anderson and
Dalharnn (3) were unable to find any change in the COHb levels of
nonsmokers in a well ventilated room where the CO level \vas 4.5
ppm. \Vhen Harke (23) studied nonsmokers under similar condltrons
(good ventilation and less than 5 ppm CO), he w;ts able to show an
increase in COHb level from I, I to I .6 percent: without ventilation
the CO levels rose to 30 ppm and the COHb level increased from .9
to 2.1 percent in 2 hours. Russell, et at. (40) also found that COHb
levels increased from 1.6 to 3.6 percent in nonsmokers exposed to a
smoke-filled room where the CO !~rl was measured at 35 ppm:
however, he cautioned that nearly ail pzrsons in the room felt that
the conditions were worse than those experienced in most social
situations.

  Stewart, et al. (46) measured COHb levels in a group of
nonsmoking blood donors from several cities and found that 45
percent exceeded the Clean Air Act's Quality Standard of 1.5
percent with the 90 percent range as high as 3.7 percent for
individual cities (Table 3). These levels represent the total CO
exposure from all sources, involuntary smoking, and other sources of
pollution as well as establishing the levels which would be added to
any new involuntary smoking exposure.

  Increases in the COHb Ic~els of this magnitude are probably
functionally insignificant in the healthy adult. but in persons
with angina pectoris, any reduction of oxygen-carrying capacity is of
great importance. In this disease, the volume of blood able to be
pumped through the diseased coronary artery is already unabk to
meet the demands of the heart nluscle under exercise stress. Aronow,
et al. (4) examined the effect of exposure to carbon monoxide on
persons with angina pectoris. They exercised persons with angina

491


TABLE 3. -Median percent carboxyhemoglobh (COHb) saturation and 90 percent
         range for nonsmokers by location

Location

Anchorage
Chicago
Denver
Detroit
Honolulu
Houston
Los Angeles
Miami
Milwaukee
New Orleans
New York
Phoenix
St. Louis
Salt Lake City
San Francisco
Seattle
Vermont,
New Hampshire
Washington. D.C.

I /

T

Nonsmokers

hledian      Range

No. of
Nonsmokers

Pcrccnl of
Nonsmokers
With COtlb
> 1.5%

1.5        0.6 - 3.2             152              56
1.7        1.0 - 3.2            401              74
2.0        0.9 - 3,7            144              76
1.6        0.7 - 2.7          1,172              42
1.4        0.7 - 2.5            503              39
1.2        0.6 - 3.5           240             30
1.8        1.0 - 3.0         2,886              76
1.2        0.4 - 3.0            398              33
1.2        0.s - 2.5         2,720              26
1.6        1.0 - 3.0            159              59
1.2        0.6 - 2.5         2,291             35
1.2        0.5 - 2.5            147              24
1.4        0.9 - 2.1            671             35
1.2        0.6 - 2.5            544              27
1.5        0.8 - 2.7           660             61
1.5        0.8 - 2.7           53s              55

1.2
1.2

!

0.8 - 2.1            959
0.6 - 2.5            850

18
35

I-

Source: Stewart, R.D., et al. (46).


pectoris before and after rxposure to carbon monoxide. `TII? sverase
amount of exercise that was able to be performed before a person
developed chest pain was significantly shortened from 226.7 sc~onds
before exposure to 157.6 seconds after CO exposure. This change:
occurred after a Z-hour exposure to SO ppm CO and with an increase
in COFIb level from I .03 percent to 2.68 percent: these COHb levels
are within the range produced by involuntary smoking.

  These data indicate that exposure to CO at levels found in some
involuntary smoking situations may well have a significant impact on
the functional capacity of persons with angina prctoris. Carbon
monoxide has also been shown to decrease cardiac contractility in
persons with coronary heart disease at COHb levels similar to those
produced due to involuntary smoking situations (5). It is reasonable
to assume that any significant CO exposure to the diseased heart
reduces its functional reserve.

h'icotirle

  Nicotine in the atmosphere differs from CO in that it tends to
settle out of the air with or without ventilation (thereby decreasing
its atmospheric concentration), whereas the CO level wilt remain
constant until the CO is removed. The concentrations of both
substances are decreased substantially by ventilation. As can be seen
from data in Table 2, under conditions of adequate ventilation
neither exceeds the maximum threshold limit values for industrial

exposure (nicotine, 500 pg/m'; CO, 50 ppm, I): whereas in
conditions without ventilation, smoking produces very high con-
centrations of both (nicotine, up to 1,040 Pg/m3 : CO, 1 10 ppm).

   Nicotine in the environment is of concern because nicotine
absorbed by cigarette smokers is felt to be one factor contributing to
the development of atherosclerotic cardiovascular disease. Several
researchers have attempted to measure the amount of nicotine
absorbed by nonsmokers in involuntary smoking situations. Cane, ef
at. (II) studied urinary excretion of nicotine by persons on a
submarine. Despite very low levels measured in the air (I 5 to 32
pg/m3), nonsmokers did show a small rise in nicotine excretion;
however, the amount excreted was still less than I percent of the
amount excreted by smokers. Harke (23) measured nicotine and its
metabolite cotinine in the urine of smokers and nonsmokers exposed
to a smoke-filled environment and reported that nonsmokers
excreted less than I percent of the amount of nicotine and cotinine
excreted by smokers. He feels that at this low level of absorption
nicotine is unlikely to be a hazard to the nonsmoker.

493


  Acroleill and acetafdcflycl~ fuve also been measurctf in hrnoke-
lill~d rooms (2.5. Table 2) and may contnbute to tl~e eye irritation
commonly experienced in tfirse sitiutlons.

EFFECTS OF EXPOSURE TO CIGARETTE SIIOKE

   Tfle effects of cis;rrct tc` ~1rloki11~ on tflr c;ll-rtio\~~~~~~ltar syhtem of
tile 5moher are well cstablihlicd. fut very littfc is kno\vn about tire
cardiovascril2r response 01` tfle nonsmohcr to ci~;ireffc aruoke. ffarke
and Bl~icllcrt (Z'6) studied IS adults ( I I smokers antI 7 nonsmokers)
in 3 room I70 m3 larzit in which I50 cigarettes \vcrc` smoked or
allowed to bL1r11 in ashtrays for 30 minutes. Tfl<y noted that the
subjects wflo smoked during  tfle experiment fud 3 significant
lowering of skin ternpt:rattlre and a rise in bfoocf pressure. Non-
smokers who were exposed  to the same smoke-contaminated
environment showed no cltarl_ge in ei tlier of tlirse parameters.
Luquetts. et 31. (36;) p2rformd a 5iIIlifar exfwrifllenf witfl 40
cltildren exposed afterfutefy to smote-contalninatctl and clean
stmospfteres. but otflerwise under identical experimtY1 taf conditions.
T11ey found that exposure to tile smoke causecf i~lrrsaes in lleartra te
(5 beats per minute) an11 in systolic (4 mm 11:) 3lld cliahlOlk r> Inn1
HF) hfood pressure. Tfle cfiffer-erlces i11 results betwecrl tf~e\c httldit`s
may be due, in part. to tile ase of IlIe subject5 - i.e.. cfiildrcii may IW
Inore s2nsjtjv2 to tile ~.frcfior~r~cufar effects of il~~0l~rJlt:ll)' SlllOkill~
ill311 3tJults. or tile incrrahe in lIt23rt rutc and I~lOo~f pl-hburc Il1.l) fW
dus to a difference bct\vre~~ cflifdren atlcf aLl~~fr\ ill 111~ )~~!<flL~fO:lC
response to being in 2 ~mo~z-t~ifl4 .ltmO~f~fkhr~~.

494


  Carbon monos~de from tobclccn <nioke. ~utornollil~ ~sll;~ust.
and industr~nl pollurion is 2n important component 01`air pollution.
There 113s been some concern over the ellct of rcl;lt~v?ly low Icvels
of carbon monoxide on psychomoror functions t tll? aljllit]: to
perceive and ri`3cf to stimuli). especially those functions rzlatzcl to
driving an automobile (Table 4).

  Carbon monoxide levels occasionally reached in some involun-
tary smoking situations result in measurable cosnitii.e and motor
effects, but these effects generally are measurable only at the
threshold of stimuli perception. One study (Wright. t`t al.. (JO))
found that the safe driving habits me3surrd on a tlri\*iil_r simulator
did not improve as much with practice in a group expo5cd to CO 3s
did the habits of a control group. Another study (37) with a
different experimental design but at the same levels of` CO did not
find any effect on complex psychomotor activity such as driving a
car. Tllus, the role of CO alone in motor vehicle accidents remains
unclear. The effect on judgernent and reactions of CO in combina-
tion with factors such as fatigue and alcohol. conditions known to
influence judgement and reaction time, has not been determined.

P~tlrologic Effects of Exposure to Cigarette Smoke

  The effect of involuntary  smokin g on an individual is deter-
mined not only by the qualitative and quantitative aspects of the
smoke-filled environment, but also largely by (lie cl\aracteristics of
the individual. Reactions may vary with age as well as with tile
sensitivity of an individual to the components of tobacco smoke. The
severity of possible effects range from minor eye and throat
irritations experienced by most people in smoke-filled rooms, to the
angina1 attacks of some persons with cardiovascular disease.

  The minor symptomatic irritation experienced by nonsmo_kers
in a smoke-tilled environment is influenced by the humidity of the
air as well as the concentration of irtitating substances found in the
atmosphere. lohansson and Ronge (33) have shown tllat irritation
due to cigarette smoke is maximal in warm, dry air and decreases
with a small rise in relative llumidity. A change frown acceptable to
unpleasant was reported at 4.7 m_E/m3 of particulate matter for
nonsmokers and eye irritation was noted at 9 mg/m3 for both
smokers and nonsmokers. The authors concluded that a ventilation
rate of I?_ m'/hr/cig was necessary to avoid eye irritation and 50
m3 /hr/cig was necessary to avoid unpleasant 0Jors.

495


TABLE 4.- Effects of carbon rnorloxide on psychomotor ftlnctions

Reference

Test or
Measurement

co
level
(mm)

COllb
level
(Percent)

Effect

hfcF.uland. R.A.
(3 7)

Abdify of drivers to stay                        6       None
between two-lane markers                       II       N 0 n c
while being permiflcd only                      17       NOilC
brick glimpsx of the ro;ld

Ray, A.hf.,
Rockwell, T.H.
(39)

hlcFarland, R.A
(38)

Reaction time to
car tdllllglll>

IO

Prolonpcd

Pcrformancc of two tasks at        700             17       None

sune time

Dark adaptallon and glare
rrcovery
Peripheral vision at IO0
and 30"

700



700

17       None

17       None

Stewart, R.D., et al.
(47)     I

Peripheral vision at 20"          700            17       l)L'uc;I\cd

Depth perception             700             17       Nnnc

Time perception              500           20       None


IIcndcr, W., el al.       Tllre>llold for trrnpordl
(6)               ICbolullorl of vi\u.il rllmull

100          7.25        K~iwl


  Tnfo rovernmell t q~~nsor~d ~tt~diz\ II;IL.T ;IIICJII~~C~I to L~t.:~~~~.l~~
tile degree of minor irritation due to ciyJrc'ttc \mokc ~\peri~niz~l I>\
bus and plane passengers. TIw U.S. Ikp~rt~n~~~~r ol Tr.ln\porr;,tlo;l
t-C-!) studied the environment on t\vo venr~l.ttcd IJII~Y -~ 011~` w1t11
simulated unrestricted smokin: and anotiter wit11 ~imul2tzd srnokirlg
limited to the rear 20 pcrccnt of tlls seats. In one bus. l~~litc'il
cigarettes were placed at every otllcr seat (23 c1~3rette5) to simulate ;I
bus filled wit11 smokers. In tlic otller bus. cis.irettcs were placed 0111).
in [lie rear 20 percent of tile bus (five ciprzttcs) to simulate ;I bus
where smoking waslimited to the r&ar 10 percent of the sests. \\`llen
smoking was limited. the CO level at the driver's seat was only IS
pprn (ambient air I3 ppm) compared to l11e level of 33 ppm
(ambient air 7 ppni) nira5ured in the nnrestrictcd sniokin: situation.
Four of tf~e 5i.x Lubjects seated in tile bus reported eye irritation
durln_r tile unrr5tricted smokin: simulation. None of tile six subjects
reported any eye irritation in the restricted sniokin_c situation (not
even tllose se3tetl in the rear 70 percent of the bus).

  Several Federal agencirs (4s) cooperated to survey tile symp-
toms experienced by travelers on botli military and commercial
aircraft. They distributed 3 questionnaire to passengers 011 20
military and S commercial fligltts; 57 percent of the passengers on
tile military fli$if5 and 45 percent of the passcn_cers on the
commercial tli$jth were smokers. The planes were well ventilated
and C-0 levels were always bciow 5 ppm witll low levels of other
pollutants as well. In 5pile 01. tile low level of measurable pollution,
over GO percent ot' tile nonsmoking passengers and IS to 12 percent
of tile smokers reported being annoyed by tile other passengers'
smoking. Seventy-tllree percent of the nonsmoking passengers on the
commercial flights and 67 percent of the nonsmoking passengers on
tlla military tlights sug_rested that some remedial action be taken; 84
percent of tl,ore su~,uestin, 0 remedial action felt that segregatjng the
smokers from nonsmokers would be a satisfactory solution. These
feelings were even more prevalent amon, 0 those nonsmokers who had
a history of respiratory disease.

  Children have been found to have a higher incidence of
respiratory infections than adults and are thou$t to be more
sensitive to tile effects of air pollution due to their greater minute
ventilation per body wei$t than adults. Several researchers have
investigated the effects of parental smokinr on the health of
children. Cameron. ct al. conducted two telephone surveys of Detroit
families to determine tile relationship bet!v<crt cllildren's respiratory
illness arid parental smoking habits. III IIK fir\t \urvc`y (0) 01ey found
a statistically significant rrlation~l~ip lJclwc'~*n 111~* ;\~~-v;r/~`llce Of`

498


  Colley (12) also found 3 relationsllip between parental stnokin:
habits and the prevalence of respiratory il!ness in the chlicircn. iIe
found an even stronger relationship between parental cough and
phlegm production and respiratory  infections in children. tie
postulates this latter relationship to result from the :reatsr infcc-
ti\.lty of these parents due to their cough and plll<:rn production.
Ths relationship between parental cigarette smokin: and respiratory
ir.t`ection in thsir children would then occur because cigarette
smoking caused the parents to cough and produce phlegm and would
not be indicative of a direct effect of cigarette smoke-filled air on the
ClllldI?Il.

  Harlap and Davies (29) studied infant admissions to Hadas~ah
Hospital in West Jerusalem and found a relationship between
admissions for bronchitis and pneumonia in the firs1 !`ear of life and
marernal smoking habits during pregnancy. Data on maternal
smoking habits after the birth of the child were not obtained, but it
can be assumed that most of the mothers who smoked during
preynancy continued to smoke durin g the first year of the infant's
life. 3, relationship between infant admission and maternal smoking
habits was demonstrable only between the sixth and ninth months of
iniant life and was more pronounced during the winter months
(when the effect of cigarette smoke on the indoor environment
would be greatest). Ifothers who smoke during pregnancy are known
to have infants with a lower average birth weight than the infants of
nonsmoking mothers. The relationship between maternal smoking
and their infants' admission to the hospital found in this study was
greater ior low birth weight infants, but was also found for normal
birth \veight infants (Table 5) (3). Harlap -and Davies (139)
demonstrated a dose-response relationship for maternal smoking and
infant admission for bronchitis and pneumonia; however, they also'
found a relationship between maternal smoking and infant admis-
sions for poisoning and injuries. This may indicate a bias in tllr study

499


TABLE 5. - Admission rates (per IO0 infants) by diagnosis, birth weight, and maternal smoking

Diagnosis

<2,999

Birth weight(g)
3,000 - $499

3,500+

   Total
(including unknown)

Bronchitis and
pneumonia

All other

Total

s       NS       s       NS       S       NS           S       NS
(297)    (2,326)    (415)    (4,098)   (264)   (3,195)        (986)    (9,686)



19.2      12.3      9.6      8.2      12.1      9.0          13.1       9.5


22.6      19.9      14.5      14.6      15.2      13.3          16.9      15.5

41.8      32.2      24.1      22.8      27.3      22.3          30.0      24.9

NOTE. - S=Smokers; NS=Nonsmokers.
Source: Harlap, S., Davies, A.M. (29).


  Coltey, et al. (13) studied the inctdcnce oi pnzLr1nor~i~1 2nd
t,ronchitis in 2.705 cllildren over the first 5 ye3rs Of life ill Jt'l3liOil 10
tll< smoking hhits ot` both parents. Tiwy found 111at :I relationsllip
b2t\LYerl p3rentnl smoking  habits and respirator), infection in
children occurred only Turin, 0 the first years of life (Table 6). Tlrey
also showed a relationship between parental cough 2nd phlqm
production and infant infection (Table 6) whiclt was found to 1~
independent of the effect of parental smoking habits. The relation-
ship between parental smokin,.
                         0 and infant infection was greater when
both parents smoked and increased with increasing number ot
cigarettes smoked per day. The relationship persisted after social
class and birth \veight had been controlled for.

  Titus. respiratory infections during the first year of life are
closely related to smoking habits independent of parental symptoms.
social class, and birth weight. Because of the dose-response relation-
ship between parental smoking and infant respiratory infection
established by Colley. et al. (13). it is reasonable to suspect tltat
ci?zrettc smoke in the atmosphere of tl1e home may be tire caL1se of
thess infections; however, other factors such as parental neglect may
               '
3150 pl3y a role.

  The shove stdies examrned the effects of involLrnt3ry smoking
on relatrvely healtliy people. A substantial proportion of the U.S.
population suffers from chronic cardiovascular and pulmonary
diseases. however. and they represent the segment of the population
most seriously jeopardized by conditions found in involuntary
smoking situations. In Chapter 1 of this report (Cardiovascular
Diseases) evidence was presented which showed that levels of CO
sometimes experienced in smoke-filled environments (50 ppm) are
capable of significantly decreasing the exercise tolerance of- persons
with angina pectoris and intermittent claudication. In addition, these
levels of CO have been shown to decrease cardiac contractility and to
raise left ventricular end-diastolic pressure (an indication of heart
fatlure) in persons with cardiovascular disease.

  Persons with chronic bronchitis anti emphysema have consider-
able excess mortality under conditions oi severe air pollutton. In
smotie-filled environments levels of CO and several other pollulants
may be 3s high or hi&her tlian OccLIr during dir pollution rmer_rerlcies.
TIK effects of short-term exposure of persons wittt chronic obstruc-

501


TABLE 6. - Pnelrmonio and bronchitis irt fire first 5 yews of rife hy parerlfs'srnakir~g /labif ad rnorrlirzg phlegm

Annual incidence of pneumonia and bronchitis per 100 children
      (Ahsolute number, in parentheses)

                          Both ex-smokers

Year of
Followup I  Both nonsmokers i    One smoker /   Both smokers I  or one c*-smoker
                                       or smoking habit I       All

changed

N     O/O      N     O/B      N     O/B      N     O/B       N      O/B

1.6      10.3     10.4     i4,a     15.3     23.0     8.2      13.2     10. I      16 1
(343)    (29)    (324)    (118)    (339)    (139)    (546)    (I?'))    (I ,652)    (42s)
8.1      8.3            15.5     x.7      9.2     65      10.7     1.4       I I.3
(322)    (36)  :;kS,    (129)    (286)    (152)    (599)    (159)    (1.572)    (476)
6.9      8. I     10.5     94      7.9      1 I .o     8.2      11.6     8.4       10.6
(305)    (37)    (353)    (107)    (242)    (154)    (661)    (173)    (1,561)    (471)
8.0      I I.1     7.5      10.8     1.6      II 6     8.2      9.1      7.9       10.3
(287)    (36)    (306)    (102)    (236)    (121)    (695)    (187)    (1.524)    (4461
6.7      14.7    5.6      9.4      3.9      10.6     6.4      7.3      5.9       9.1
(285)    (34)    (267)    (107)    (208)    (132)    (737)    (219)    (1,497)    (492)

NOTI<. - N=nr~~hrr with winter morning phlegm, O/B=one 01 both with winter morning phlegm.
Source: Colley. J.K.T.. et al. (13).


ti\e bronchopulmonnry disease (COPDI to these conditions Ila1.e not
been evaluated. Persons with COPD dre ;~lso possibly at ~ncre~rcd risk
to CO exposure because of their low alvc`olar PO* Dur: to tl~e
reduced amount of oxygen av3il3bie to compete with the CO for
hemoglobin binding sites. these persons nii$~t experience 3 carbosy-
hemoglobin to oxyhemoglobin ratio higher than those in healthy
subjects under the same conditions of CO exposure. The retention of
CO may also be prolonged due to both this increased binding ofC0
to hemoglobin under low alveolar Paz and decreased ventilator-y
capacity to excrete CO.

  in summary,  the effects of cigarette smoke on healthy
nonsmokers consists mainly of minor eye and throat irritation.
However, people with certain heart and lung diseases (angina
pectoris, COPD, allergic asthma) may suffer exacerbations of their
symptoms as a result of exposure to tobacco smoke-filled environ-
ments. These effects are dependent on the degree of individual
exposure to cigarette smoke which is determined by proximity to the
source of the tobacco smoke, the type and amount of tobacco
product smoked. conditions of room size and ventilation as well as
the amount of time the individual spends in the smoke-lilled
environment, and his physiologic condition at the time of exposure.

503


  I. Tobacco smoke can be 3 si_Wificant source of atmospheric
pollution in enclosed areas. Occasionally under conditions of he3v)
smoking and poor venttlation. the maximum limit for an &hour
work exposure to carbon monoxide (SO ppm) may be exceeded. The
upper limit for CO in ambient air (9 ppm) may be exceeded even in
cases where ventilation is adequate. For an individual located close to
a cigarette that is being smoked by someone else. the pollution
exposure may be greater than would be expected from atmospheric
measurements.

  2. Carbon monoxide, at levels occasionally found in cigarette
smoke-filled environments,  has been shown to produce slight
deterioration in some tests of psychomotor performance. especially
attentiveness and cognitive function. It is unclear whether these
levels impair complex psychomotor activities such as driving a car.
The effects produced by CO may become important when added to
factors such as fatigue and alcohol which are known to have an effect
on the ability to operate a motor vehicle.

  3. Unrestricted smoking on buses and planes is reported to be
annoying to the majority of nonsmoking passengers, even under
conditions of adequate ventilation.

  4. Childien of parents who smoke are more likely to have
bronchitis and pneumonia durin, 0 the first year of life, and this is
probably at least partly due to their being exposed to cigarette
smoke in the atmosphere.

  5. Levels of carbon monoxide commonly found in cigarette
smoke-filled environments have been shown to decrease the exercise
tolerance of patients with angina pectoris.

504


RILlLIOGRAPHY

.A\lERICAN COSFERESCE OF COVERSMENT ISDC&TRIAL IiYGENlSTS.
   TLVS" rhrelhold hmlt values for chem!cal subsuncec 111 workroom 311 adopted
  b:/ the AmerlcJn conference of ~o%rrnmenr industrlzl hypen~str for 1973. J0urn9
  or- Occupar~onal .\ledlcme 16(l): 3949. January 1974.

ANDERSON. E. W.. ANDELhlAN. R. J.. STRAUCfI. J. hf.. FORTUIN. N. J.. KNEL-
  SON. I. H. Effect of low-level carbon monolidr exposure on onset and duratron
  of angns pcctorls. A study of ten patients wlrh ixhernlc heart dlseate. Annals of
  Internd \ledicme 79(l): 46-50. July 1973.

ANDERSON. G.. DALHAMN. T. The risks to health of passive smoking. L3kxtid-
  niqen 70: 2833-2836. August 15. 1973.

ARONOW. w. s.. CASSIDY. 1.. VANGROW. J. S.. hlARCH, tl.. KERN, J.C..
  GOLDSMITH, 1. R.. KHEMKA. hf.. PACANO. 1.. VA\VfER. hi. Effect of
  cigrette smohing and breathing carbon monoxide on cardiovnsculzr hemo-
  dynamics in angrnal patients. Circulation SO(2): 340-347. August 1974.

AROSOW. W. S.. ISBELL. hl. W. Carbon monoxide effect on exercise-induced angina
  pectoris. Annals of tnternal hfedlcine 79(3): 392-395. September 1973.

BESDER. W.. GOTHERT, M. MALORNY, C. Effect of low carbon monoxide
  concentrartlons on psychological functions. Staub Reinhaltung der Luft 32(4):
  5460. April 1972.

BRIDGE. D. P.. CORN, Xl. Contribution to the assessment of exposure of nonsmokers
  to air poilutmn from cigarette and cigar smoke in occupied spaces. Environmental
  Research S:l92-209. 1972.

BRC.VNE>lANN. K. D.. HOFFMANN. D. Chemical studies on tobxco smoke. XXIV.
  A quantitauve method for carbon monoxide and carbon dloxlde in cigarette and
  cigar smoke. Jourrwl of Cbromatographic Science 12(2): 70-75, February 1974.

CAMERON. P.. KOSTIN. J. S.. ZAKS. J. %l., WOLFE. 1. H., TIGHE, G., OSELETT.
  B.. STOCKER, R.. WINTON. I. The health of smokers' and nonsmokers' chddien.
  Journal of Al:ergy 43(6): 336-341. June 1969.

CASIERON. P.. ROBERTSON, D. Effect of home environment tobacco smoke on
  famdy health. Journal of Applied Psychology 57(2): 142-147. 1973.

CASO. J. P.. CXTALIN, J.. BADRE, R.. DUMAS, C., VIALA. A.. GUILLEMlE, R.
  Determination de la nlcotme par chromatographie en phase gazeuse. II
  Applications Ann&s Pharmaccutiques Francaises 28(1 I): 633-640. 1970.

COLLEY. J. R. T. Respiratory symptoms in children and parental smoking and phlegm
  production. British !&dtcal Journal 2: 201.204, April 27, 1974.

COLLEY. J. R. T.. IIOLLAND. W. W. CORKHILL, R. T. Influence of passive smoking
  and parental phlegm on pneumonia and bronchitis in early chddhood. Lancet
  2(7888): 1031-1034, November 2, 1974.

CORN. hf. Characteristics of tobacco sidestream smoke and factors Influencing its
  CoDcentiatlOn and distrtbution in occupied spaces. Scandinavian Journal of
  Respiratory Diseases (Supplementurn 91): 21.36, 1974.

D.-\wA\lN. T.. EDFORS. Sl.. RYLANDER. R. hfouth absorption of vprious
  compounds in c@rette smoke. ArchIves of Environmental Hed:h I6(6):
  831-835. June 1968.

I

2

3



4

5



6





. 7

8





9





10



11




12



13





14

IS

505


18 t-.SVIKOS\It.NTAL PROTECTION ACESCY. Natiorul prlmxy and wconddr)
    ambvznt sir quality sczmd3rds. Federal Regstcr 36(X--Part 113:8186-8201. Aprd
      30.1971.

19 I ODOR. G G.. \\`IKSTKE. C. Effect of tow CO concrnrnlions on rcvx~~ncc to
     monotony and  on prychomotor c~paaly. Staub Keinhaltung der Luft
     32(4).46-54. Aprd 1972.

20 C.~LUSEINOVA. V. 3.4 - Benrpyrcne determ~nz~t~on in the smoky xtrnosph~re of
    SOWI mcetnne rooms and rcsuurz~nts. A conrrlbution to the problems ot to-called
    ~JTXI\I` Tmohtn:. Scoplxma t 1 :465-168. 1964.

21  GODIS. G.. \\RlGlIT. C.. SIlLPttARD. R. J. ItrbJn e\po%ure 10 carbon mono\tde.
     ,\rchives of Environmenf31 tlcalth 25(j)-3OS-313. November 1972.

22  (;ROLL-KS';\PP. E.. WACSLR. 11. tlAL!CK. II.. ItAtDER. .\I Efftxtr of tow carbon
    ,,w,no\~d~ conccntr~t~on~ on w$~nce xnd computer-x~aly~d brun potentnls.
    S~:,ub Rcmtutfun~ der Lul-t 32(-1).6468. Aprd 1972.

2-t  Ii-\RKl-:. tt. -P. The pri,t&m of ~J\"Y' \mokine. I. The ir~tlurnue of smokin< on rhe
    (`0 ~~,nc~ntr.~l~w ,n otlice rooms. Inrerru~wnatri Arch~v iur Arbrlltmedizin
     3313): 199.2r16. 1974.

2s  HARKE. ii. -P.. IrAARS. A. t-RAHXl. B.. PETtRS. H.. SCtILUTZ. C. Zum Problem
    dec P.~xx~vr.~ucbcn\ (7 he problem of passive smoking.) lnlerna~ronales Archiv fur
     Arbclt,rnrdizin 79-333-339. 1972.

26  Ft.-IRKt<. H. -P.. BLEICtll:RT. A. Zurn Problem des P3ssivrwchens (The problem of
   pacsi\e \Inoking.) In~~:rrut~on~les Archiv fur Arbeitsmedtzln 29:31 2-322. 1972.

27  HARKE. H.-P.. LIEDL. W., DENKER, D. The problem of' passive smoking. II.
    Invrxriea:lons of CO level in the automobile after cigarette smoking. Inler-
    nalmn;le~ Archiv fur Arbeitsmedirin 33(3):207-220, 1974.

28  IIARKE. H. -P.. PETERS. H. The problem of passive smoking 111. The influence of
   smoklne on the CO concentration in driving automobiles. Internalionales Archiv
    fur Arhrltsmedirln 33(3):221-229, 1974.

29 IIARLAP. S.. DAVIES. A. hf. Infant a4mitsions to hospital and matern& smoking.
    L3ncer 1(7857):529-532. hlarch 30, 1974.

30  HARMSEN. t4.. EFFENBERGER. E. Tobacco smoke in transportation vehicles. living
   and working rooms. Archw fur Hygiene and Baklenolo:ic 14I(5):383400, 1957.

31 HOEGC. U. R. The slgniticance of cigarette smoking in confined >pacec. Thesis.
   Unlverslty of Cmcinnati. Diwsion of Graduate SItidle-.. D~parlment of EnCiron-
     mental Health. 1972 137 pp.

32  HOEGG, U. R. Cigsrelte smoke rn closed spaces. Entironrr~~nt~l Ilc.~l[t~ Pcnpecfivet
    2:1 I 7-128. October 1972.

506


3s

36

37

38

39

10

41



42



43



44

45

46

41

JOH\SOS. \I R. tlALL. J \V. NEDLOCK. J n'.. GRCUBS. II. J WI\ t I.1 1) 11
  7hc ,bsrnhu:~on ot products bctu-<en ,".~,",tr<z~m .i"d \dc~trc~m \r"ol.c-. Torxco
  175121):-13-16. October 12. 1973.

LAWTHER. P. J.. CO!.l\lINS. B. T. Cigarette smoklnF 2nd cxpoxure to cz~rbo"
  monoxide. Ann& of the I\`ew York Audemy of Science\ 17J:I 35.117. Octuhrr
  5.19iO.

LUQCEI-IE. A. J.. LANDISS. C. W., MERKI. D. J. Some Imrnedutc ellects oi a
sm~krns UI~~XXI~IKIII WI chlldre" of clementxy school ZI:~. nle Jour".d oi
  School Hsslth 40(10):533-536. December 1970.

\lcFARL;\SD. R. A. A study of the etfecrs of low lcvclc of carbon mono\~dr q`on
humans pxformmz dr~wng tssks at Ihr Hxrwrd School of Publtc IleJllh 1373
  Auromotl\e AU Follut~on Resexch Sgmpo?ium. Wa%hinston. D C . \ljrch 7 9.
   1973.

\fcFARLASD. R. A. Low level exposure to carbon monoxide :md drlxlne pcrfor-
  m~ncc. ArchIves oi Environment31 Health 27(6):355-359. Dsccmber 1973.

R.\Y. .A. 51.. ROCKWELL. T. H. An e&ploratory $tudy of 3uturnobde d:kv~nz
performance under the innuence of low levels of c~rbo\yhen~o~lob~n. A"n,ds 01
  the hew York Academy of Sciences 174:396-108, October 5. 1970.

RIISSELL. \I. A. H., COLE. P. V., BRO\W. E. Absorption by "on-v"okrrx ofc~rbon
  monoxide irom loom air polluted by tobacco smoke. bncet 1(7503):576-579,
  March 17, 1973.

RYLXSDER, R. (EdItor). Environnrcntnl tobacco smoke effeclr on the non->m~k~r.
  Scand~na\un Journal of Respuatory Diseases (Supplcmrn~u"~ 91 ): I-90. 197-t.

SCH!.tELTZ. I.. HOFFMANN, I)., WYNDER. E. L. The intluence oi tohzcca <make on
  Indoor atmospheres. 1. An ovewew. Prcvent~ve Xledicme4:66-82. 1975.

SCHL'LTE. J. H. Effects of mild carbon monoTide into\wztion. Archivrs of
  Envlronmenul Health 7(5):30-36, November 1963.

SEIFF. H. E. Carbon monoxide ;1c 3" indicator of cigrettecaused pollutmn levels in
  inrerclty buses. U.S. Department of Transportntion, Federal HI$wxy Adminztm
  lion. Burwu of lrlotor Carrier Safety, April 1973, I1 pp.

SRCH, \I. LXxr due Eedeutunp des Kohlenoxyds heim Zi:~rcttcnrauchenim Fersonen-
  kr3ftuagenmnern. Deutsche Zeitsrhrift fur grrichtltchc \lcdirin 60:80-89. 1967.

STEWART. R D.. BARE~TA, E. D, PLATTE. L. R.. STtWART. E. B.. KALB-
  TLEISCH. I. H.. VAN YSERLOO. B.. RI\l\l. A. A. C~rho\)~hcmo$ob~n levels in
   Amencan blood donors.  Journal of the Amertcan hledlcal Xssoclation
  2?9(9): 1187-l 195. Aucust 26, 1974.

STEU'4RT. R. D.. SEWTON, F. E.. HOSKO. J. J.. PETERSON. J. E. Eiiect 01 carbon
  monoxide on tlmr perceptlo". Archives of EnwronmentdI tltJlth 27t3)-155-160.
  September 1973.

507


48 U.S. DEPARTMENT OF TRANSPORTATION. ItDtR:!L X\`I:\TIOS \D\lt\lS.
    TRATIOS. U.S. DEPARTMENT OF HtALTIi. EDLXIATIOS. ASD \IP.Ll--\Rt
     NATIONAL INSTI TmE FOR OCCUPATIOSAL SAILTY AXLI Ht Al.TfI.
     Healrh ~specfs of smoking in trxnrport a~rcr~l~. Rockv~llr. .\lJ AD-i34c)97.
     December I97 I. 85 pp.

49  U.S. PL'ULIC HEALTH SERVICE. The Halth Conwqurncrs or Smnkine. A Report of
    the Surgeon Grner~. 1972. U.S. Department oi flralth. Education. and \\`eIf3re.
    Washington, DHEW Publication No. (HS\I) 726516. 1972. 158 pp.

50  WRIGHT. G.. RANDELL. P.. SHEPHERD. R. J. Carbon monoxide 2nd drwine skulls.
     Archives of Environmental Heallh 27(6): 349-354. December 1973.

508


Chapter 0
      Allergy

Source: 1972 Report, Chapter 7. pages 99 116

509


Contents

                                       PUQC3
Introduction  .......................................    513
Antigenic Properties  ................................   514
Skin Testing  ......................................   515
Additional Immunological Effects  ....................   517
Effect on the Immune Response  ......................   518
Irritant and Pharmacologic Effects  ...................   519
Clinical Allergy  ....................................   520
Summary .-...-.................: .................   521

References  ........................................    522

511


ISTRODUCTION

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 criticisni 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

513

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

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 extracts
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 polysaccharidea 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-

514


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.

RQsen (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 immunere-
action (64) largely mediated by IgE. Patterson (48) recently pro-
posed a simplified model explaining the mechanism of action of the
akin sensitizing antibody (SSA). "Subsequent to stimulation of the
ammal by antigen, SSA are produced by cells of the lymphoid sys-
tem possibly located in the alimentary andrespiratory tract. . . . The
SSA SO produced are secreted in such a way that they reach the cir-
culation, where circulating cells, predominantly basophilic leuko-
V'~J.% 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 eelis in tissues. The tissue cells are pri-
marily mast cells . . . The immediate-type allergic reaction occurs

515


when antigen iz introduced into the individual sensitized by SSA,
either by transfer of antigenic molecules through the respiratory or
alimentary mucosal surface or by injection into the skin or vascular
ayatem. 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 cIinica1 pictures as hay fever, asthma,
and generalized anaphylaxiz.

Until recently, direct skin testing and the passive transfer test
(Prausnitz-Kiistner 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
aite 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 (42). Lowell
(4.9) 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 (29) biopsied urticarial wheals after intradermal injec-
tion of tobacco extract and found a local eosinophilia. He feIt that
this heIped confirm the allergic mechanism of the positive skin test.
He also biopzied the site of a delayed skin reaction to tobacco and
found an eczematous type of rezponse.

The delayed type hypersensitivity reaction is manifested by ip-.
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 ariArthus reaction, which ie
alzo a slowly evolving allergic response. Serum antibodies are not
involved in the initiation of delayed type hypersensitivity; rather,
the initial etep iz thought to involve interaction of antigen and spec-
ialized lymphocytes (10, 21). Contact dermatitis is thought to be
very nearly a pure type, delayed hypersensitivity reaction (10, II).

The foregoing dizcuzzion haz highlighted the studies concerning
C~~MMXM senzitivity to tobacco extracts. Despite the complexities
and contradictiona, numerouz workerz agree that tobacco extract

516


(leaf or smoke) is antigenic and can sensitize (2, 7,9,fs, e6,4s, 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 (4s) 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 (SZ) , 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, 4.9) have considered patients with multiple sensitivities,
inchrding that to tobacco. Atopic individuaIs 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. (I.?), Fontana (17), and Redisch (53)
have reported that patients with positive skin tests to tobaccoex-
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

517


Cohen (2) , Chu. et al. (7)) Harkavy and Perlman (.?I ), 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 62.6 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 remain9 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-
phiiia 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 Ievels were reported by
Kameswaran, et al. (~8) 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 denicotiniz+%l
tobacco extracts. The abnormalities found in the three rabbits, re-
spectively, &luded: 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 ve9-
se1 ; 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-

518


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 vh-0
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-
optima1 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 re-
sponse of lymphocytes to phytohemagglutinin were significantly
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 A2
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). The inhalation of tobacco smoke

519


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,
65) 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 (80) cited experimental data distinguishing allergic
effects from pharmacoIogic 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 roIe 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 clinica
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-

520


bacco among tobacco workers and noted that because of I`.. . the small
proportion of exposed individuals who develop such lesions, and the
tendency for it to cIear compIetely 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, 72).

Harkavy's (28) early reports of a greater number of reactors to
tobacco extract among patients with thromboangiitis obliterans
(TAO) than among controls drew attentiqn 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, 7.3) 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 T-40 to tobacco allerg)l 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 e-xacerbation 01
   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.

521


ALLERGYREFERENCES

(1) ALLI%X, R. D., ROTH, G. NI. Central and peripheral vascular effects
   during cigarette smoking. Archives of Environmental Health 19(2) :
   189-198, August 1969.

(2) ARXEN. R. N.. COHEN, S. The effect of forced inhalation of tobacco
   smoke on the electrocardiogram of normal and tobacco-sensitized rab-
   bits. Diseases of the Chest 35(6) : 663-676, June 1959.
(3) AUSTEN, K. F. Disorders due to hypersensitivity and altered immune
   response. IN: Wintrobe, M. M., Thorn, G. W., Adams, R. D., Bennett,
   I. L., Jr., Braunwald, E.. Isselbacher, K. J., Petersdorf, R. G. (Editors).
   Harrison's Principles of Internal Medicine. Sixth Edition. New York,
   McGraw-Hill Book Company, 1970. p. 342.
(4) BLUE, J. A. Cigarette asthma and tobacco allergy. Annals of Allergy
   28(3) : 110-115. March 19'70.

(5) BRUNI. A. Influenza dell'awelenamento da fumo di tabacco sulla fngo-
    citosi. (Effect.of tobacco smoke poisoning on phagocytosis.) Speri-
   mentale 85: 523543, 1931.

(6) CH~IAL, G., JOSEPH, J., COLIN. L., Ducuux, C. Les dermites chez les
   travailleurs du tabac (B propos de 9 observations). (Dermatitis in
   tobacco workers. Nine observations.) Bulletin de la Societi? Francaise
   de Dermatologie et de Syphiligraphie 77 (2) : 281-283, July 1970.
(7) CHU, Y. b'f.,PARLETT. R. C., WRIGHT, G. L.. JR A preliminary investi-
   gation of some immunologic aspects of tobacco use. American Review
   of Respiratory Disease 102(l) : 118-123. July 1970.
(8) COHEN, A. B., CLINE. hi. J. The human alveolar macrophage: Isolation,
   cultivation in vitro, and studies of morphologic and functional char-
   acteristics. The Journal of Clinical Investigation KO(7) : 1399-1398,
   July 1971.

(9) COLTOIU, A., bIATEESCU, D., LEEE. V. Consideratii privind sensibilizarea
   la tatun. (Considerations concerning sensitization to tobacco.) Vista
   hIedicala 16(l) : 2937, January 1969.
(IO) COOMBS, R. R. A. The basic types of allergic reactivity producing disease.
   Triangle 9(2) : 43-46, 1969.

(11) COOMBS, R. R. A., GFZLL, P. G. H. Classification of allergic reactions re-
   sponsible for clinical hypersensitivity and disease. Chapter 20. IN:
   Gell, P.G.H., Coombs, R.R.A. (Editors). Clinical Aspects of Immu-
   nology. Second Edition. Philadelphia, F. A. Davis Company, 1968. pp-
     675596.

(12) CORMIA. F. E., DEGAIU, P. F. Vesiculobullous dermatitis from tobscco
    smoke. Journal of the American Medical Association 193(6) : 391-392,
    August 2, 1965.

(13) DECRINIS, K, REDISCH, W., FONTANA, V., Lgwrs, A., SUL.ZBERCE& M.
   B., STEELE, J. M. Vascular responses to smoking tobacco compared
   with responses to skin testing of tobacco extracts. Annals of Internal
   Medicine 62(6) : 1035-1041, May 1960.

(14) DONXLLI, F. Influenza sulle aggiutinine dell'awelenamento da fumo
   di tabacco. (Effect of tobacco smoke poisoning on agglutinins.) Gior-
   nale di Batteriologia e Immunologia 11: 1012-1018, 1933.
(15) FERSIL, A. Die bedeutung der tabakrauchallergie bei erkrankungen
   des Gaftisssystems. (The importance of allergy to tobacco in diseases
   of the vascular system) Weiner Zeitschrift fiir Innere Medizin und
   Ihre Grenzgebiete 43: 455-458, 1962.

(16) FIN- J. F., HASSELBLAD, V., RIGCAN, W. B., NELSON, W. C., HAM-
   MEX, D. I., NEWILL, V. A. Cigarette smoking and hemagglutination

i22


inhibition response to influenza after natural disease and immunize-
tion. American Review of Respiratory Disease 104 (3) : 368-376. Sep-
tember 1971.

(17) FONTAYA, V. J. Tobacco hypersensitivity. Annals of the New York
   Academy of Sciences 90(l) : 138-141, September 27, 1960.
(18) FONTMA. V. J., REDISC~, W.. NEMILR. R. L., SMITH. M. K.. D~Cmsrs.
   K., S~L~BER~E~ hi. B. Studies in tobacco hypersensitivity. III. Reac-
   tions to skin tests and peripheral vascular responses. Journal of
   Allergy 30(3) : 241-249, May-June 1959.
(19) FRIEDLANDER, N.. SILBERT, S., LXXEY. N. Toe lesions following tobacco
   injections in rats Proceedings of the Society for Experimental Biology
    and Medicine 34: 156157, 1936.

(20) GREEN, G. M., CAROLIN, D. The depressant effect of cigarette smoke on
    the in vitro antibacterial activity of alveolar macrophages. New
   England Journal of Medicine 276: 422-427, February 23. 1967.
(21) HARWW, J. Cardiac manifestations due to hypersensitivity. Annals of
    Allergy 28(6) : 242-251, June 1970.
(ze) HARJU~Y, J1 Cardiovascular manifestations due to hypersensitivity.
    New York State Journal of Medicine 69(21) : 2757-2765, November
    1, 1969.

(~3) HAXKAW, J. Hypersensitiveness to tobacco and biopsy studies of skin
   reactions in vascular disease. Journal of Allergy 9:47b88, 1938.
(2~) HARKAW, J. Tobacco allergy. Chapter 13. IN: Vascular Allergy and
   its Systemic Manifestations. Washington, Buttenvorths, 1963. pp.
     101-116.

(2.5) HARKAYY, J. Tobacco albergy in cardiovascular disease: A review.
   Annals of Allergy 26(8) : 447-459, August 1968.
(26) HARWW, J. Tobacco allergy in vascular diseases. Review of Allergy
   and Applied Immunology 11: 189-212. March 1957.
(~7) HARKA~Y, J. Tobacco sensitiveness in angina pectoris and coronary
   artery disease. Proceedings of the Society for Experimental Biology
    and Medicine 30: 683-684, 1933.

(28) HARKAYY, J. Tobacco sensitiveness in thromboangiitis obliterans, mi-
   grating phlebitis and coronary artery disease. Bulletin of the New
   York Academy of Medicine 9: 318-322, 1933.
(29) HAXKAW, J. Tobacco sensitization in rats. Journal of Allergy 9: 275-
   277,1938.

(JO) HARKAW, J. Tobacco skin reactions and their clinical significance. The
   Journal of Investigative Dermatclogy 2: 257-279, 1939.
(31) HARKAW, J., PERLMAN, E. Tobacco allergy in coronary artery disease.
   Annals of the New York Academy of Sciences 90(l) : 327-332, Sep-
   tember 27, 1960.

(32) HARKAW. J.. &KLMAN. E. Tobacco allergy in coronary artery disease.
   New York State Journal of hIedicine 64 (11) : 1287-1296, June 1, 1964.
(JJ) HARKAW. J., ROMANOFF, A. Skin reactions to tobacco and other aller-
   gens in normal men and women smokers. Journal of Allergy 6: 62-
    70, 1934.

(34) HARKAW. J., WITEBSKY, E. Studies of specificity in multiple hyper-
   sensitiveness by quantitative titration and absorption of reagins.
   Journal of Allergy 6: 437-44'7, 1935.

(35) HARRIS, J. O., SWENBON, E. W., JOHNSON, J. E. III. Human alveolar
   macrophages: Comparison of phagocytic ability, glucose utilization,
    and ultrastructure in smokers and nonsmokers. The Journal of Clini-
   cal Investigation 49: 2086-2096, 1970.

523


(ST) HEIS~~E~L, c. L., NILLEX, J. N.. ALDRICH. a. J., CARPENTRY C. M. Smok-
  ing and serologic abnormalities. Journal of the American Medicai
   Association 181(8) : 6'7-77. August 25, 1962.
(17) ISHLWCA, K. The identification and significance of Gamma K. Hospital
   Practice: `/ml, September 1969.

(~8) KAMESWARAN, L., K,WAKAMW., IL.. VIJAYASEKARAN, V. Studies on
  plasma histaminase levels in normal and allergic individuals. Indian
   Journal of Physiology and Pharmacology 12(4) : X9-166, October
     1968.

(39) KREB, B., PELTER, A., FOWWAUD. S., DUPIN-GIROD. S. Reaction de
  precipitation entre certains serums humains et des extraits solubles
   de tabae (Precipitation reaction between certain human sera and
   soluble tobacco extracts.) Annales de Medecine Inteme 121(4) : 437-
    440, April 1970.

(40) ms, D. hf., LAPP, N. LER., B-L, R. Quantitation of secretory
   immunoglobulin A in chronic pulmonary disease. American Review
   of Respiratory Disease lOl( 1) : 65-61, January 1970.
(U) LIP A. 0.. R~CHA, G. Cutaneous reactions to tobacco antigen in aller-
   gic and nonallergic children. Annals of Allergy `f(4) : 628-631, July-
   August 1949.

(.&) LOUNSBURY, J. B., OUGHTEFSON. A. W. Specificity of tobacco antigen.
   Yale Journal of Biology and Medicine `7(4) : 306316, March 1935.
(43) Lo-. F. C. Allergy. IN: Wynder, E. (Editor). The Biologic Effects
   of Tobacto. Boston, Little, Brown, and Company, 1966. pp. 161-170.
(44) MAUKEII, M. L., SPAIN, W. C. The allergic response to tobacco. Journal
   of the American Geriatric Society 2: 278-283, 1954.
(45) MAXWELL, K. W., MARCUS, S., RENZFITI, A. C., JR. Effect of tobacco
   smoke on the phagocytic and cytopeptic activity of guinea pig alveolar
   macrophages. American Review of Respiratory Disease 96(l) : 156,
     1967.

(46) MEYEX, D. H., CROSS, C. E., IBRAHIM, A. B., MIJSTAFA, M. G. Nicotine
   effects on alveolar macrophage respiration and adenosine triphos-
   phataae activity. Archives of Environmental Health 22(3) : 362-366,
    March 1971.

(47) PAPA+ C. M., SHELL=, W. B. Menthol hypersensitivity. Diagnostic
   hasophil response in a patient with chronic urticaria, flushing, and
   headaches. Journal of the American Medical Association 189(7) :
   646-648, August 17.1964.
(48) PATTFXRO N, R. Skin-sensitizing antibodies. Advances in Internal Medi-
   cine 16: 361371, 1970.

(4P) PAYI.IK, I., CERMAKOVA, Z. Casna komi reakce na tabakovy extra&u
   chorob dychadel. (Early skin reaction against tobacco extract in res-
   piratory system disease.) Rozhledy v Tuberkulose av Nemocech
   Plknich 24(9) : 629-635, 1964.

(50) I'fZEKlX, M. M, IANDAY, L. H. Cutaneous reactions to tobacco antigen
   in allergic and nonallergic children with the direct and indirect (local
   passive transfer) methods of testing. Journal of Allergy 10: 241-246,
     1939.

(61) m. D. hi. Allergy to tobacco smoke. Annals of Allergy 28(3) : 277-
   282, July-August 1946.

(at) pO=X'J. 1. G., PAUN, R., MOLNEB. C., O~ARU, c., GH~RCEIU, T,, IOTA.
   C. G. Contributii la studio1 alergiei la tatun. (Contributions to the

stndy of tobacco allergy.) Revue Roumaine de Medecine Intema l(6) :
427-436, 1964.

524


(63) R~Ix~, W- Tobxco allergy and vascular responses. IN: James, G.,
    Rosenthal. T. (Editors). Tobacco and Health. Springfield, C. C.
    Thomas, 1962. pp. 352359.
(5-h) ROSEN, F. L. Studies in tobacco allergy. Journal of the Bfedical Society
    of New Jersey 61(3) : 109-114, March 1964.
(55) ROSEN. F. L., LZVY, A. Bronchial asthma due to allergy to tobacco smoke
    in an infant. A case report. Journal of the American Medical Asso-
    ciation 144(8) : 620-621, October 21.1960.
(55) ROTE, G. M., SCHICK, R. M. The effects of smoking on the peripheral
    circulation. Diseases of the Chest 37(Z) : 203210, February 1960.
(57) ROYAL COLLEXE OF PHYSICIA??S. Smoking and Health Now. London,
    Pitman Medical and Scientific Publishing Company, Ltd., 1971.148 pp.
(58) SNNDELLE, A.. RUFF, F., Fuvuu. N.. PARUM. J.-L. Liberation d'his-
    tarnine par des aldGhydes B courte chaine. (Liberation of histamine
    by short-chain aldehydes.) Comptes Rendus Hebdomadaires des
    Seances de I'Academie des Sciences Paris. Series D 266(Z) : 139-141,
    January 8, 1968.
(59) SAYEL, H. Clinical hypersensitivity to cigarette smoke. Archives of En-
    vironmental Health 21(2) : 146148, August 1970.
(50) SCHOEN, I.. PIZFX, M. Eosinophilia apparently related to cigarette smok
    ing. New England Journal of Medicine 270(25) : 1344-1347, June 18,
     1964.
(61) SHEUXIN. J. M., LOWXL. R. G., BfATrxws, K. P. (Editors). House dust
    and miscellaneous allergens. IN: A Bfanual of Clinical Allergy. Sec-
    ond Edition. Philadelphia, W. B. Saunders Co., 1967. pp. 437-456.
(62) SIIEXMAN, W. B. (Editor). Agents causing atopic diseases. IN: Hyper-
    sensitivity. BIechanisms and Management. Philadelphia, W. B. Saun-
    ders Company, 1968. p. 130.
(65) SHUFZ, N., HARRIS, M C. Distribution of commonplace inhalant aller-
    gens. Chapter 4. IN: Harris, M. C., Shure, N. (Editors). Sensitivity
    Chest Diseases. Philadelphia, F. A. Davis Company, 1964. pp. 62-97.
(64) Sx~vxnx, H., LAMON, P. S., HAAG, H. B. Immunological aspects of
    tobacco and smoking. American Journal of the Medical Sciences
    234 (6) : 661-689, November 1957.
(65) SPEZK, F. Tobacco and the nonsmoker. A study of subjective symptoms.
    Archives of Environmental Health 16(3): 443-446, March 1968.
(88) S~LZSERI.XIZ, M. B. Studies in tobacco hypersensitivity. I. A comparison
    between reactions to nicotine and to denicotinized tobacco extract.
    Journal of Immunology 24(l) : S&91, 1933.
(87) SKJL~~ER.~E~, M. B., FEIT, E. Studies in tobacco hypersensitivity. II-
   Thromboangiitis obliterans with positive urticarial skin reactions and
   negative reagin findings. Journal of Immunology 24(b): 425-432,
     1933.
(68) `I-IUSOFF, A., BLUMSl'EIN, G., B~ARKs, M. The immunologic aspect Of
   tobacco in thromboangiitis obliterans and coronary artery disease.
    Journal of Allergy 7: 260-253`1936.
(85) U.S. PUBLIC HE~L~TH SERVICE. Smoking and Health. Report of the Ad-
   visory Committee to the Surgeon General of the Public Health Service.
   Washington, U.S. Department of Health, Education, and Welfare,
   Public Health Service Publication NO. 1103, 1964. 387 PP.
(70) U.S. R,TILIC HEALTE SERVKX The Health Consequences of Smoking-
   A &port of the Surgeon General: 1971. Washington, U.S. Depart-
   ment of Health, Education, and Welfare, DHEW Publication No.
   (HSM) 71-7613. 1971. 468 PP-

                                       525


(71) VOS-BUT, C., RUMKE, P. IrnmunoglobuIin concentrations, PHA reac-
    tions of lymphocytes ilr vitro, and certain antibody titers of healthy
    smokers. Jaarboek Karkerondenoek Kankerbestruding 19: 49-53,
     1969.
(72) WFARY, P. E.. WOOD, B. T. Allergic contact dermatitis from tobacco
    smoke residues. Journal of the American Medical Association 208(10):
    1905-1906. June 9, 1969.
(75) WESTCC~~~, F. H., WFUGHT, I. S. Tobacco allergy and thromboangiitis
   obliterans. Journal of Allergy 9: 555-564, 1938.
(74) YEAG~ H., JR Alveolar cells: Depressant effect of cigarette smoke on
   protein synthesis. IN: Proceedings of the Society for Experimental
    Biology and Medicine 131: 247-250. December 26, 1968.
(75) ZUSSM~, B. Ed. Atopic symptoms caused by tobacco hypersensitivity.
    Southern Medical Journal 61(11) : 1175-1179, November 1968.
(76) ZUSSMAN. B. M. Tobacco sensitivity in the allergic patient. Annals of
    Allergy 28(8) : 3713'77, August 1970.


Chapter 9
      Tobacco Amblyopia

Source: 1971 ReDOrl, Chapter 7, ,,ages 431 - 438.

527


Contents

Summary and conclusions . _ . _ . . . . _ . . . . . . _ . . . . . . . . . . . .   532

References . ..___._.__..............................   532

529


TOBACCO AnmLyom

Tobacco amblyopia (tobacco-alcohol amblyopia) is that syn-
drome of visual failure occurring in association with the use of
tobacco, with or without the concurrent use of alcohol, and with or
without concurrent nutritional deficits. The disease has a subacute
onset, leading to a loss of visual acuity and coIor perception (12).
It is characterized by centrocecal scotomas which are bilateral but
not necessarily symmetrical and which have sloping diffuse edges
and by the presence of nuclei of denser visual loss within the large
scotomas (22,~`). Such visual impairment is not unique to tobacco
amblyopia. as it is also seen in neurodegenerative disorders, such
as Leber's hereditary optic atrophy (7, 25).
Clinical information on tobacco amblyopia has appeared in nu-
merous articles throughout the past century. This information has
been reviewed by Silvette, et al. (17) and, more recently, by
Dunphy (5) _ Pure tobacco amblyopia (TA), that is amblyopia
unassociated with excessive alcohol intake or the exposure to other
toxins, is rarely seen in the United States today (12). Walsh, et al.
(23) have observed that when TA is found it is usually present in
association with nutritional or idiopathic vitamin deficiencies.
Victor (29) recently observed that the type of visual defect seen in
tobacco amblyopia may be found in clinical circumstances in which
tobacco is clearly not a causative factor. He questions whether TA
is distinguishable from other forms of ambIyopia.
The prevalence of this disorder has been variously estimated in
the past at from 0.5 to 1.5 percent of all eye clinic patients (20,23).
However, currently in the United States, it appears to be a rare
condition. Silvette, et al. (17) have observed that the incidence of ~~
tobacco amblyopia appears to have decreased substantially during
the past decades. Other authors (3, 15) have also commented on
this trend. Although reference has been made to the increased fre-
quency of certain types of tobacco usage in patients with this dis-
order, adequate popuiation studies with proper controls have yet to
be performed. The association of this disorder with the use of
tobacco is strengthened by the frequent clinical observations of
improvement following the cessation of smoking although improve-
ment has been noted by some to occur without cessation.
Research into the pathogenesis of tobacco amblyopia has cen-

531


tered upon the interrelationships of cyanide metabolism, vitamin
B II, and other vitamin deficiencies. Three reviews of this material
have recently appeared (I, 12, ~`2 ). Xumerous studies reviewed in
these articles suggest that tobacco amblyopia may result from the
incomplete detoxification of the cyanide present in tobacco smoke.
This failure of detoxification may stem from or be intensified by
inadequate dietary intake of necessary nutritional factors. This
may be the reason for the association of this disorder with exces-
sive alcohol intake and with its related nutritional deficits (2, A, 6,
8,9,10,11,13,1~,16,1S, 19,91,2:,96,27,"8).

SUMhIARY AND CONCLUSIONS

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

REFERENCES

(I) CASADIXG MEDICAL XSSOCI~TION JOURNAL. Tobacco amblyopia. (Edi-
   torial) Canadian hIedica1 Association Journal lOZ(4) : 420, February
   28. 1970.

(2) CHI~HOLX, I. A., BROSTE-STEWART. J., FOULDS, W. S. Hydroxocobalamin
   versus cyanocobalamin in the treatment of tobacco amblyopia. Lancet
   2(7513) : 450451, August 26, 1967.

(3) DARBY, P. IV.. WILSON, .J. C>-anide, smoking, and tobacco amblyopia.
   Observations on the cyanide content of tobacco smoke. British Journal
   of Ophthalmology 51(5) : 336-338, May 196'7.
(4) DREYFL'S, P. M. Blood transketolase levels in tobacco-alcohol amblyopia
   Archives of Ophthalmology 74(S) : 617-620, November 1965.
(5) DU.VPHY. E. B. Alcohol and tobacco amblyopia: A historical survey.
   American Journal of Ophthalmology 68(4) : 569-578, October 1969.
(6) FOULDS, IV. S., BROKTE-STEWART. J. M., CHIsHoLhl, I. A. Serum thio-
   cyanate concentrations in tobacco amblyopia. Nature 218(5141) : 586,
   May 11. 1968.

(7) Foows. W. S.. CANT, J. S., CHISHOLM, r. A., BRONTE-STEWART J.,
   WILSOS. J. Hydrorocobalamin in the treatment of Leber's hereditary
   optic atrophy. Lancet l(7548) : 896-897, April 27, 1968.
(8) FOIXX. W. S., CHISHOLM, I. A.. BRONTE-STEWART, J., WILSON, T. M.
    Vitimin B ,:' absorption in tobacco antblyopia. British Journal of
   Ophthalmology 53 (6) : 393-397, June 1969.
(9) FOULDS. W. S., CHisHoLhl, I. A., BRON?E-STEWART, J., WILSON, T. ai.
  The optic neuropathy of pernicious anemia. Archives of Ophthalmol-
   ogy 63(4) : X7-432, October 1969.

(10) FE'JIAG, A. G., HEXTOS, J. 31. The aetiology of retrobrrlbar neuritis in
   Addisonian pernicious anaemia. Lancet l(7183) : 90%911, April 29,
     1961.

532


(II) HEATON, J. M., MCCORMICK, A. J. A., FREE~IAY. A. C. Tobacco ambly*
   pia: A clinical manifestation of vitamin-B,, deficiency. I,ancet
    Z(7041) : 286290, August 9, 1958.
(1") KNOX, D. L. Neuro-ophthalmology. Archives of Ophthalmology 83(l) :
    103-127, January 1970.
(13) LINDSTRAND, K., WILSON, J., Ma-rra~ws, D. M. Chromatography and
   microbiological assay of vitamin B,, in smokers. British Medical
    Journal 2 (5520) : 988-990, October 22, 1966.
(14) LINNELL, 3. C., Sarrw. A. D. M., SMITH, C. I,.. WILSOS. J., MATTHEWS,
    D. M. Effects of smoking on metabolism and excretion of vitamin B,?.
    British Medical Journal Z(5599) : 215-216, April 27, 1968.
(15) SCIIEPENS. C. L. Is tobacco amblyopia a deficiency disease- Transactions
   of the Ophthalmological Society of the United Kingdom 66: 309-331,
     1946.
(16) SCHIEVELBEIN, H.. WERLE, E., SCHULZ. E. K.. B~UMEJSTER. R. The influ-
    ence of tobacco smoke and nicotine on thiocyanate metabolism.
    Naunyn-Schmiedebergs Archiv fur Pharmakologie und Experimentelle
    Pathologic 262(3) : 358-365, February 5, 1969.
(17) SILVEETTE, II., HUG, H. B., LARSON, P. S. Tobacco amblyopia. The evolu-
    tion and natural history of a "tobaccogenic" disease. American Journal
    of Ophthalmology 50(l) : 71-100, January 1960.
(18) ShIITH. A. D. hr. Retrobulbar neuritis in Addisonian pernicious anae-
    mia. (Letter) Lancet l(7184) : 1001-1002, &lay 6, 1961.
(19) S~SITH, A. D. BI., DUCKETT, S. Cyanide, vitamine B,Z. experimental
    demyelination and tobacco amblyopia. British Journal of Experimen-
    tal Pathology 46(6) : 615-622, December 1965.
(20) TRAQUAIR, H. M. Toxic amblyopia, including retrobulbar neuritis. Trans-
    actions of the Ophthalmological Society of the United Kingdom 50:
     351385, 1930.
(92) VICTOR, M. Tobacco-alcohol amblyopia. A critique of current concepts of
    this disorder, with special reference to the role of nutritional deficiency
    in its causation. Archives of Ophthalmology 70(3) : 313-318, Septem-
     ber 1963.
(22) VICTOR, M. Tobacco amblyopia, cyanide poisoning and vitamin B,, de-
    ficiency. A critique of current concepts. Chapter 3. IS: Smith, J. L.
    (Editor) Neuro-Ophthlamology. Symposium of the University of
    Miami and the Bascom Palmer Eye Institute. Hallandale, Florida,
    Huffman Publishing Co., 1970. pp. 33348.
(23) VVUSH, F. B., HOYT, W. F. (Editors) Neurotoxic substances affecting   -

    the visual and ocular motor systems. Chapter 15: IN: Clinical Neuro-
    Ophthalmology. Volume 3, 3rd Edition. Baltimore, The Williams &
    Wilkins Company, 1969. pp. 2613-2616.
(fr) WATSON-WILLIAMS, E. J., BOTTOMLEY, A. C., AINL~Y, R. G., PHILLIPS,
    C. I. Absorption of vitamin B,3 in tobacco amblyopia. British Journal
    of Ophthalmology 53(8) : 549-562, August 1969.
(25) WILSON, J. Leber's hereditary optic atrophy: A possible defect of cya-
    nide metabolism. Clinical Science 29 (3) : 5055515, December 1965.
(26) WILSON, J.. MAnHEWS, D. M. Metabolic inter-relationships between
   cyanide, thioryanate and vitamin B,l in smokers and nonsmokers.
    Clinical Science 31(l) : l-7, January 1966.

                                         533


(27) Woti~s. F.. PICARD. C. W. The role of \-itsmin R,, ill human nutrition.
    Clinical Nutrition 3(5) : 3X-390. September-October 1955.
(28) WYSDFR, E. L... HOFFMASN. I). Certain constituents of tobacco products.
    Chapter 9. I<. Vapor phase of tobacco smoke. IS: \Vynder. E. I,.,
    Hoffmann, 1). (I.:diton). `l`ol~~co ;LII~ To\~~co Smoke. Studies in FIX-
   perimental Caxinogenesis. New York, Academic Press, 1367. pp.
     451453.

534


Chapter 10
       Pipes and Cigars

Source: 1973 Report, Chapter 6. pages 165 236

535


contents

Introduction- ________ ____---- ____-_-_____-_ - __-__- _ ---_--
The Prevalence of Pipe, Cigar, and Cigarette Usage __-_-_____
The Definition and Processing of Cigars, Cigarettes, and Pipe
Tobaccos_________________-____-__-_-____-------------
Chemical Analysis of Cigar Smoke-------------------------
hlortality

  Ocerall~~lortality-__- ________ --_-_--_-__-_- ____ - ______
  Mortality and Dose-Response Relationships
     AmountSrnoked~~~~~~~---..--------------------..
     Inhalation__--__--_-____________________--------
  Specijic Causes aj;Ifortality------- ____ -___-_-- ______-_
    Cancer__-__-__-_---_-_____-__---_-_----_---_-_-
    Cancer of the Lip--- _______ - ____ --__--_----___--
    Oral Cancer----_--------- _____- - __________-_-__
    Cancer of the Larq-nx_-__----_----_------ _-__ -___
    Cancer of the Esophagus---------------- _____ -_-_
    LungCancer_------- _____ -_------_--_-_-----____
    Tumorigenic Activity---_------------------------
    Experimental Studies _____ -_-_--- _________ -_-_-__
    Cardiovascular Diseases_---_ -_-_- ____ -_ _-_ ____ -_ _
    Chronic Obstructive Pulmonary Disease (COPD)-- _ _
    Gastrointestinal Disorders--_-------------- __ -_-__
Little Cigars _____ - -_____ -___- ______ -----------___-_-_---
Conclusions-_--_________________________-~----~-~----~--
References -_________-_____ -_--____---_-_ ________________

List of Figures

Figure I.--Inhalation among pipe smokers by nge- _______ -__
Figure 2.-Inhalation among cigar smokers by age--Ham-
mond______--_____-.-____________________--~---------
Figure Z.--Depth of inhalation among cigarette smokers by
age-~fammond-___-_____________________--------~----
Figure *%.-Percent distribution of 130 brands of cigarettes and
25 bmnds of little cigars by tar content------- _____ -__-_-

Page
543.
543

545
547

549

550
553
559
559
560
561
563
567
573
580
580
585
s&i
592
592
599
600

554


555

s55


595

537


Figure 5.-Percent diatribtrtion of I30 brnnds of cigrrrcttes nnd
25 brands of little cigRr3 by nicotine content- .- __ _ _ _ _ _ _ __ _

List of TubIes

TnbIe l.-Percent distribution of U.S. males nged 21 nnd older
by type of tobrrcco used for the yenrs 196-1, 1966, and 1970--
Table Z.-Percent distribution of U.S. males by t>-pe of tobucco
used nnd ngefor 1970___---_-_-__-__-_------------------
TftbIe 3.-Percent distribution of British males aged 25 nnd
older by type of tobncco used for the years 1965, 196S, nnd
  1971__________~___-__~--~----------------------------
Table 4.-Amounts of se\-ernl components of 1 grnm of par-
ticulnte mfiteriul from mainstream smoke of tobacco prod-
ucts________________~----:------------------------------
Table 5.--A comparison of se\-ernl chemicnl compounds found
in the mainstream smoke of cignrs, pipes, nnd cigarettes----
Tnble 6.-AIortaIity ratios for totnl denths by type of smoking
(mnles only) ___._______ ----___--__- __________--___----
Tnble 7.-AIortnIitv ratios for totnl denths of cigar nnd pipe
smokers by amount smoked--Hammond and Horn- _ - - _ __-
Tablr 8.--1Iortnlity ratios for total deaths of cignr and pipe
smokers by nmount smoked-Best-__- - _ - - _- _ _ -__ _ _ _ _ _ _ _ _
Table 9.-Alortnlity rrrtios for totnl deaths of cigar and pipe
smokers by age nnd nmount smokeci-~Rhn__---__-------
Table lO.--;\Iortnlitp ratios for totnl deaths of cigar and pipe
smokers by omount smoked-Hammond _ _ _ _ _ - _ _ _ - - - _ _ - - _
Tnble Il.-The extent of inhnling pipes, cignrs, nnd cigarettes
by British moles aged 16 and over in 1968 and 1971- _ _ ___ _
Table 12.-Inhalation among cigar, pipe, and cigarette smokers
by age--Doll and Hill _____. --_---_--__----_- ____ -_-___-
Table I3.--JlortaIity ratios for total deaths of cigar and pipe
smokers by nge and inhnlntion-Hammond__ _ - - _ _ ___ _ _ __ _
Tnble 14.-Percentage of British male cigar smokers who re-
ported inhnling n lot or rr fnir amount by type of product
smoked-_-._____._______________________------~--~-~
Table 15.-Percentage of individunls reporting inhnlntion of
"almost every puff" of tobncco smoke by current and pre-
vious tobacco usage and type of tobacco used-- - _ _ __ _ _ _ ___
Table !6.--Percentage of British males who reported inhaling n
lot or fair amount of cignr smoke by current and previous
tobacco usage nnd type of tobacco previously smoked
(1963) ---__ ---_-- ____ - _--- - ----------------- -_- ______

596

543


544

544

547

548


550


551


551


552


552


556


556


557
-.

557

558

558

538


Table 17.-Extent of reported inhnlation of cigar smoke by
British male cignr smokers who lvere ex-cigarette smokers in
1968, analpzcd by extent of reported inhalation of cignrctte
smoke when previouslp smoking cigarettes---_. _ _ _ _ _ __ _ _ _ _ _
Table 18.--Slortality ratios for total cancer denths in cigar nnd
pipe smokers. A summary of prospective epidemiological
studies_-_______________________________--------------
Table lg.--Kelative risk of lip cancer for men, comparing cigar,
pipe, and cigarette smokers with nonsmokers. A surnmnry of
retrospective studies-`------- ___________________________
Table PO.->Iortality ratios for oral cancer in cigar and pipe
smokers. A summary of prospective epidemiological studies- -
Table 21.--Relative risk of oral cancer for men, comparing
cigar, pipe, and cigarette smokers with nonsmokers. X sum-
mary of retrospective studies-- _ _- ________________ -_-_--
Tnble 22.--XIortality ratios for cancer of the larynx in cigar
and pipe smokers. A summary of prospective epidcmiological
studies.-_--_-_____----------------~---------~-----~--
Table 33.--Relative risk of cancer of the larynx for men, corn-
paring cigar, pipe, nnd cigarette smokers with nonsmokers.
A summary of retrospectire studies--- _- -- -_ _ _ _ __ _ - __ _ _ __
Table 24.--Jfortality ratios for cancer of the esophagus in
cignr and pipe smokers. A summary of prospective epidemio-
logical studws _____ -_-_-_____-_- ____ _ ___-_ -_---- _______
Table "S.-Relative risk of cancer of the esophagus for men,
comparing cigar, pipe, and cigarette smokers \\ith non-
smokers. ri summary of retrospective studies .____ - _-_______
Table 26.-A\Iortality ratios for lung cancer deaths in male
cigar and pipe smokers. A summary of prospective studies----
Table 27.-Lung cancer death rates for cigar and pipe smokers
byamountsmoked-DollandHill------ ______ -_- _____--
Table Pg.-Lung cancer mortality ratios for cigar and pipe
smokers by amount smoked-Kahn- ____ __-__-_-__- ____--
Table 29.-Relative risk of lung cancer for men, comparing
cigar, pipe, and cigarette smokers with nonsmokers. A
summary of retrospective sbudies-__-_---------- ____-----
Table 30.-Changes in bronchial epithelium of male cighr,
pipe, and cigarette smokers as compared to nonsmokers- _ --
Table 31.--Tumorigenic activity of cigar, pipe, and cigarette
smoke condensates in skin painting experiments on animnls--
Table 32.--Xlortalit_v ratios for cardiovascular deaths in mnie
cigar and pipe smokers. A summary of prospective epi-
     . .

demlologlcal studies _______ -_-_- ___-_______-..- ---------

Page

559

559

562

563

564

566

568



570



571


574


574


575



576


579


583



586

539


Table 33.--Iiortnlity rntios for chronic obstructi\-e pulmonnry
deaths in mnle cigar and pipe smokers. X summary ol pros-
pective epitlemiolopicnl studies- - - - _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ __ _ _ _
Table ?A.---Prey-alencc of respiratory symptoms and illness by
type of smoking--- ___________ - ______ - _______________
Table 35.--Pulmonary function values for cigar and pipe
smokers as compnretl to nonsmokers.- __- ________________
Table 36.-Jlortality rntios for peptic ulcer disense in male
cigar and pipe smokers. Summary of prospective studies__-
Table 37.4hipment of small nnd large cigars destined for
domestic consumption (1970, 1971, 1972) ____ ---___-_- ____
Table 38.-Selected compounds in mainstream smoke-------..
Table 39.-The pI1 of the mainstream smoke of selected
tobacco products_-----____----------------------------

589

590

591

592

597
598

598


Introduction

This chapter is a review of the epidemiological, pathological, and
experimental data on the henlth consequences of smoking cigars and
pipes, alone, together, and in varicus combinations with cignrettes.
Previous reviews on the health consequences of smoking have dealt
primarily with cigarette smoking. Although some of the material on
pipes and cigars pwsented in this chapter has been presented in preti-
ous reports of the Surgeon General, this is the first attempt to summ-
rize what is known about the health effects of pipe nnd cigar smoking.
Since the use of pipes nnd cigars is limited almost exclusively to men
in the United States, only dnta on men are included in this revieff.

The influence of pipe and cigar smoking on health is determined
by examining the overall and specific mortality and morbidity ex-
perienced by users of these forms of tobacco compared to nonsmokers.
Epidemilogical evidence suggests that individuals who limit their
smoking to only pipes or cigars have overall mortality rates that are
slightly higher than nonsmokers. For certain specific causes of death,
however, pipe and cigar smokers experience mortality rates that are
as great as or exceed those experienced by cigarette smokers. This
analysis becomes more complex when combinations of smoking forms
are examined. The overall mortnlity rates of those who smoke pipes,
cigars, or both in combination with cigarettes appear to be inter-
mediate between the high mortality rates of cigarette smokers and
the lower rates of thw who smoke only pipes or cigars. This might
seem to suggest that smoking pipes or cigars in combination with ciga-
retteS diminishes the harmful effects of cigarette smoking. However,
an analysis of mortality associated with smoking combinations of ciga-
rettes, pipea, and cigars should be standardized for the level of con-
sumption of each of the products smoked in terms of the amount
amoked, duration of smoking, and the depth and degree of inhalation.
For example, cigar smokers who also smoke a pack of cigarettes a day
might be expected to have mortnlity rates somewhat higher than those
who smoke omy cigarettes nt the level of a pack a day, assuming that
both groups smoke their cigarettes in the same way. Mixed smokers
who inhale pipe or cigar smoke in a manner similar to the Kay they
smoke cigarettes might be expected to have higher mortality rates
than mixed smokers who do not inhale their cigars nnd pipes and also

541


resist inhaling tliejr cigarettes. Irnfortunately, little of the published
material on mixed cignrrttt. pipe, ;III~ cigar smoking contains these
types of nnal~33 or corltr0lS.

;\ P3r3dox :eems to esi?t bet\!-ern the mortality rates of ex-smokers
of pipes and cigars and es-smokers of cigarettes. Ex-cigarettesmokers
experience a reJati\-e decline ir! orernll and certain specific causes of
mortality follo\ring cessation. This decline is important but indirect
evidence that cigarette smoking is a major cawe of the elevated mor-
tality rates experienced by current cigarette smokers. In contrast to
this finding, several prospective epidemiological investigations,
Hammond and Horn (.@a), Best (9), Kahn (50), and Hammond (38),
ha\-e reported higher death rates for ex-pipe and ex-cigar smokers
than for current pipe and cigar smokers. This phenomenon eras ann-
lyzed by Hammond and Garfinkel (39). The development of ill health
often results in a cigarette smoker giving up the habit, reducing his
daily tobncco consumption, ssitching to pipes or cigars, or choosing
a cigarette low in tar and nicotine. In many instances, a smoking-
related disease is the cause of ill health. Thus, the group of es-smokeIs
includes some people \vho.are ill from smoking-related diseases, and
death rates are high among persons in ill health.

As a result, ex-cig;lrette smokers initially have higher overall and
specific mortality rates than continuing cigarette smokers, but be-
cause of the relative decrease in mortality that occurs in those who
quit smoking for reasons other than ill health, and hecause of the
dwindling number of ill es-smokers, a relative decrease in mortality
is observed (within a few years) follo\ving cessation of cigarette
smoking. The beneficial effects of cessation nould be obvious sooner
were it not for the high mortality rates of those who quit smoking
for reasons of illness. A similar principle operates for es-pipe and ex-
cigar smokes, but because of the Iorrer initial risk of smoking these
forms and therefore the smaller margin of benefit following cessation,
the effect produced by the ill ex-smokers creates a larger and more
persistent impact on the mortality rates than is seen in cigarette
smoking.

For the above reasons R bias is introduced into the nlortality rses
of current smokers and es-smokers of pipes and cigars, so that a more
accurate picture of mortality might be obtained by combining the
ex-smokers with the current smokers and looking at the resultant
mortality experience.

B~JXLUQ? of a lack of data that would allow a precise analysis of
mortality among ex-pipe and ex-cigar smokers, a detailed analysis
of these groups could not be undertaken in this review.
For each specific cause of death, tables have been prepared m-hi&
summarize the mortality and relatire risk ratios reported in the major

542


prospective and retrospective studies which contained information
nbout pipe and cigar smokers. The smoking categories used include:
cigsr oni?, pipe only, total pipe and cigar, cigarette only, and mixed.
The tot31 pipe and cigar category includes: thw who smoke pipes
only, cigars only, and pipes and cigars. The mixed category includes:
those who smoke cigarettes and cigars; cigarettes and pipes; and
cigarettes, pipes, and cigars. Mortality and relative risk ratios were
calculnted relative to nonsmokers.

The Prevalence of Pipe, Cigar, and Cigarette Usage

The prevalence of pipe, cigar, and cigarette smoking in the United
States was estimated by the National CIearinghouse for Smoking and
Health from population surveys conducted in 1961,1966, and 1970 (98,
99,100). In each survey, about 2,500 interviews Kere conducted on a
national probability sample stratified by type of population and
geographic area. The use of these products among adults aged 21 and
older is summarized in tables 1 and 2. The prevalence of pipe, cigar,
and cigarette smoking in Great Britain for the years 1965, 196S, and
1971 is presented in table 3.

TABLE I.--Percent a!is!ribution qf U.S. n&e smokers aged 21 and Older
  by type oj tobacco used jor the years 1964, 1966, and 1970

             Forms wed        (pAI%     1x3      1970
                                          @t=PXW    (psrcent)



1. Cigar only-- ____________ - ________-__---     6. 8      5. 5      5. 6
2. Pipe only_----_-________-~~~-----~-----      1. 7      3. 0       3. 6
3. Pipe and cigar ___________________ - ______     3. 9      S-9       4.4
4. Cigarette only--- ___________________ ____     28. 6     31. 2      25. 9
5. Cigarette and cigar ____________________--     11. 3      9. 9       6. 6
6. Cigarette and pipe ______________________      5. 3      4. 9       5. 3
7. Cigarette, pipe, and cigar ________________     7. 7      6. 3       4.6
8. Nonsmoker ______ ____ ____ ____ - - ____ ____ _     34.7     34. 3      44.0


    Total ______ - __________i_________---    100.0     100.0     100.0

Number of Reasons in sample. ______________-   2,359    2,679    2,881

Total pipe users (2+3+6+7) __________-__- -    18. 7     19. 2      17. 9
Total cigar users (1-i-3+5+7) _________--_- -    29. 9     26. 7      21. 2
Total cigarette uverj (4+5+6+7) _________--    52 9     52. 4      42 3


lkwcs: U.S. De>-cat of Health, Education. and Welfam (98. PO. 100).

543


TABLE 2.-Percent distribution of U.S. male smokers by type of tobac-
           co used and age for 1.970

Forma Uspd                       A@ *ouP_
                ?I to 34    3.5 to44   4.31054   65 to M 65 to 3 +

1. Cigar only- -----__ -- _______
2. Pipe only_--- __`.______
            ____.
3. Pipeandcigar_- _____ -- _____
4. Cigarette only--- _____ _____
                  -
5. Cigarette and cigar-- ________
6. Cigarette and pipe- - ..______
7. Cigarette, pipe, and cigar- - _ _
8. Nonvmokcr __.___ ---_-__--_-

3. 7    6. 5    4. 7    6. 7     9. 3
4. 3     3. 5    3. 0     3. 2     3. 6
3. 8    3. 3    5. 2     4. 4     6. 9
28. 8    29. 0    27. 1    24. 3    13. 6
6. 8    10. 4    5. 5     5. 2     4. 2
6. 6    4. 4    5. 6    4; 0     3. 8
5.8    48    5. 0    4. 0     1. 4
40. 2    38. 1    43. 9    48. 2    57. 2

    Total- _____ --__-___-__-    100. 0   100.0   100.0   100.0    100. 0

Number of in sample- _ _
       persons           1,009     525     523     405     388
                       ~
Total pipe users .__._____.___ --     20. 5    16. 0    18. 8    15. 6     15. 7
Total cigar users. _ _____ --_- -__     20. 1    25. 0    20. 4    20. 3     21. 8
Total cigarette usem-_---_----     48. 1    48. 6    43. 3    37. 5    23. 0

Source: U.S. Deprtmeut ol Health, Education. and Welfare (100).

TABLE S.-Percent distribution of British male smokers aged 15 and
older by type of tobacco ?Lsed for the years 1965, 196S, and 1971

Forms wd                 1985      1968      1971

1. Cigars only __________________ -._- _______      1. 9      2. 8       3. 3
2. Pipeonly_--__-__-___-__-~-~-~~~-~--.~-     5. 1      5. 6       5. 9
3. Cigarettesonly__- _____ --.--_--_- _______     46. 8     45. 7      40. 8

4. Cigarettesandpipe _____ --__-_-__-_- _.__     8. 0      7. 0       6. 1
5. ~Iixedsmokers_--___--_~--_.- _______-__     7. 5      9. 1       8. 4

6. Nonsmokers- .__________ -_---_-- ______ --     30. 7     29. 9      35. 4


    Total_-_.-_-_~__.-_--~.~~--~---..--    100.0     100.0     loo. 0

Number of persons in sample-__-.--_-.-~-~-   3, 576    3, 566    3,594
                                                       -

Total pipe users _______________.__.________     13. 9     14. 3      13. 3
Totalcigar- ____.________ ~__-__-- _._._._._     9. 0    11.7 11.3
Totalcigarette _____ - _____ - _____ -__- _____._    67. 6     67. 6      61. 6



Bourcc: Todd. 0. F. (91).

544


The Definition and Proceseing of Cigm, Cigarettea, and
           Pipe Tobaccos

The U.S. Government has defined tobacco products for tax pur-
poses. Cigarettes are defined as "(1) Any roll of tobacco wrapped in
paper or in any substance not containing tobacco, and (2) any 1~11 of
tobacco Trapped in any substance containing tobacco which, &UW
of its appearance, the type of tobacco used in the filler, or its packaging
and labeling, is likely to be offered to, or purchased by, consumers as
a cigarette described in subparagraph (l)." Cigarettes are further
classified by size, but virtually all cigarettes sold in the United Stati
are "small cigarettes" which by definition weigh "not more than 3
pounds per thousand" which is not more than 1.361 grams per
cigarette (96).

American brands of cigarettes contain blends of different grades of
Virginia, Burley, Maryland, and oriental tobaccos. Several varieties
of cigarette tobaccos are flue-cured. In this process, tobacco leaves are
cured in closed barns where the temperature is progressively raised
over a period of several days. This results in "color setting," fixing,
and dryirq of the leaf. The most conspicuous change is the conversion
of starch into simpler sugars and suppression of oxidative reactions.
Flue-cured tobaccos produce an acidic smoke of light aroma (35,rZZ).

Cigara

Cigars have been defined for ta'x purposes as: "Any roll of tobacco
wrapped in leaf tobacco or in any substance containing tobacco (other
than any roll of tobacco which is a cigarette within the meaning of
subparagraph (2) of the definition for cigarette)" (112). In order to
clarify the meaning of "substance containing tobacco" the Treasury
department has stated that, "The wrapper must (1) contain a signs-
cant proportion of natural tobacco; (2) be within the range of colors
normally found in natural leaf tobacco; (3) have some of the other
characteristics of the tobaccos from which produced; e.g., nicotine
content, pH, taste, and aroma; and (1) not be so changed in the
reconstitution process that it loses all the tobacco characteristics"
{J&`j. Further, "To be a cigar, the filler must be substantially of
tobaccos unlike those in ordinary cigarettes and must not have any
added flavoring which would cause the product to have the taste or
aroma genernlly attributed to cigarettes. The fact that a product does


not resemble a cigarette (such as many large cigars do not) and has a
distincti\-e cirnr taste and aroma is of considernblc si,pificance in
making this determination" (IT/Z).

Cigars arc also cln.ssified by size. "Small cigars" xvei,nh not more
than 3 pounds per thousand and "large cigars" weigh more than 3
portnds per thousand. "Large cigars" are further divided into seven
classes for tax purposes based on the retail price intended by the
manufacturer for such cirars (96).

Cigars are made of filler, binder, and n-rapper tobaccos. hfost cigar
tobaccos are air-cured and then fermented. More recently, reconsti-
tuted cigar tobaccos have been used as wrapper, binder, or both. Cigars
are either hand-rolled or machine made. Some brands of small cigars
are manufactured on regular cigarette making machines. The aging
and fermentation processes used in cigar tobacco production produce
chemical catalytic, enzymatic. or bacterial transformations as evi-
denced by increased temperature. oxygen utilization, and carbon
dioxide generation within fermenting cigar tobaccos. In this complex
process. up to Xl percent of the dry xveipht of the leaf is lost through
decreases in the concentration of the most readily fermentable ma-
terials such as carbohydrates. proteins. and alkaloids. The flavor and
aroma of cigar tobaccos are in large measure the results of precisely
controlled treatment during the fermentation process (35,.X, 112).

Pipe Tobnccos

The definition of pipe tobacco used by the U.S. Government eras
repealed in 1966 and there is no Federal tax on pipe tobaccos. The
most popular pipe tobaccos are made of Burley; honever, many pipe
tobaccos are blends of different types of tobacco. A fern contain a
significant proportion of midrib parts that arecrushed betxveen rollers.
"Saucing" material. or casings containing licorice, sweetening agents,
sugars. and other flavoring materials are added to improve the flavo1, _
aroma. and smoke taste. These additives modify the characteristiZ
of smoke components (112).

ConclusiorL

Because of the unique curin = and procrssing methods used in the
production of cigar and pipe tobaccos. significant physical and chcmi-
cal differences esist between pipe and cigar tobaccos and those used in

546


cigarettes. The cstcnt to \\-hich t&c chnnrcs mnr alter the hcnlth
consequcnccs of sniokin~ l)ipcs n11(1 ciznrs rnn best be cstirnntcd lay nn
nn:ll\sis of tlie potcntinll\ Iinrmflll cl~fnlic:~I constitntcrits fouri(l in
the smoke of thcsc tobnccns. the turnorigcnic acti\-ity of srnnkc condcn-
sntes in tzprrirnental nnirnnls. 2nd n review of the epidcmiological
data n-hi& has nccumulntcd on the hcnlth effects of pip.2 and cigar
smoking.

Chemical Analysis of C&gar Smoke

OnIy a few studies have been conducted that compnre the chemical
constituents of cigar smoke x-ith those found in cigarette smoke.
Hotfm:lnn, et 11. (43) compnrcd the yields of several chemical com-
ponents in the smoke from 9 pklin 85 mm. cigxette, two types of
cigars, 2nd a pipe. The pflrticulnte matter, nicotine, bcnzo(a)pyrene,
and phenols were determined quantitatively in the smoke of these
tobncco products. One cigar tested ~3s 5 lL%rnm.-long, 7.6-g., U.S.-
made cigar. The other uxs n handmade Ilnvana cigar 147 mm. long
-xeighing S.6 g. The relative content of nicotine in the particulate
matter produced t.~y the cigars KE similar to that of the cigarette
tars. The benzo(a)pgrene and phenol concentrations in the cigar
condensnte xns tn`o to three times greater thnn in cigarette "tar" (t.ahle
-1). Kuhn (58) compared the nlknloid and ~~henoi content in conden-
sutes from nn SO-nun. Bright-blend cigarette sold commercially in
A1ustria -with that obtnirnd from 103'mm. cigars. These were tested

T.~BLE 4.-Amounts oj sewral components qf I g. qf pcrticulatx malerial
      from mainstream smoke of tobacco products

Tobwco product 1

Compound

            Standxd         @mm.   6.5 mm.
u 8.    II8vsns    Pipe
cigar h   cigar B   tobacco  txy~;e plain U.S. plain U.S.
                        cigarette  cigarette
(b)     (b)    In Pipe   In pipe    03)     w
             V-9

Skotine (mg.)_---- _____   46. 2    63. 6    33. 1    61. 0    65. 9    77. 4
Benzo(a)pyrene (pg.). _. _    3. 9    3. 6     6. 0    3. 6     1. 2     1. 3
Phenol (mg.)------------    8. 3    6. 7    15. 0    7. 3     2. 3     4. 1
*Crcsoi (mg.)--- ____ -__    1. 6     1. 7     1. 9     1. 4     .6      .8
n+p-Cresol (mg.).------    4. 8    3. 8    5. 6    3.4     1. 4     1. 9
d-p-EthJ-lphenol (mg.).-    I. 1     1. 5     1. 1     1.3     .7      .7

547


with and rrithout the use of a cellulose acetate filter. The concentm-
tions of total alkaloids 3nd plicnol in the cigar smoke condcnsntc wre
essentially the same as in the cigarette condensate, but pyridine values
xvere about 21,1, times higher in the cigar condensate.
Campbell and Lindsey (17) measured the polycyclic hydrocarbon
levels in the smoke of a small popular-type cigar S.8 cm. long, n-eighing
1.9 g. Si?Tificnnt quantities of anthracene, pyrene, fluoranthene, nnd
henzo(a) pvrene Kere detected in the unsmoked cigar tobacco, in con-
centrations much ,Qater than those found in Virginia ciprettes but
of the same order as those found in some pipe tobaccos. The smoking
process contributed considerably to t.he hydrocarbon content of the
smoke. Table 5 compares the concentrations in the mainstream smoke
of cigarettes. cigars, and pipes of four hydrocarbons frequently found
in condensates. The authors reported that t.he mainstream smoke from
a popular brand of small cigar contained the polycyclic aromatic
hydrocarbons; acenapht.hylene, phennnthrene, anthracene! pyrene,
fluoranthene, and benzo(a.) pyrene.. The concentrations of these hydro-
carbons in the mainstream smoke were greater than those found in
Virginia cigarette smoke:

@man. et al. (6.9) analyzed the volatile phenol content of cigar
smoke collected from a 7-g. American-made cigar with domestic filler.
:\fter quantitative anal?-sis of phenol. cresols, xylenols, ani meta and
pnn ethyl phenol. the authors concluded that the IevclGf these com-
pounds lvrcre generally similar to those reported for cigarette smoke.
&man and Bar-son (63) aIso analyzed cigar smoke for benzene,
toluene. ethyl benzene, m-, p-, and o-xylene, m- and p-ethyltoluene,
I,",~-trinret~r~lbenzen~, and dipentene, and generally found levels
within the range of those previously reported for cigarette condensates.

In summary. available evidence sugpsts that cigar smoke contains
man?- of the same chemical constit.uents, including nicotine and ot.her
aIkaIoids, phenols, and polycyclic aromatic hydrocarbons as are found

TABLE 5-A camparison oj sever& chemical compa~nds found in the
     mainstream smoke oj cigars, pipes, and cigarettes        -

COlIlpOUnd

1. 6     29. 1       5. 0
11.9     110.0      10. 9
17. 6     75. 5      12. 5
3. 4      8. 5.       .9

548


in cigarette smoke. Most of these compounds are found in conrentra
tions n-hic!l qua1 or exceed levels found in ci,rarcttc "tar." .\ more
conlplete picture of the carcinogenic potential of cigar `it313" is ob-
tained from experimental data in animals.

Mortality

OveraZ Xortdit y

Several large prospective studies have examined the health conse-
quences of various forms of smoking. The results of these invest.iga-
tions have been reviewed in previous reports of the Surgeon General
in which the major emphasis has been on cigar&to smoking and its
effect on overall and specific mortality and morbidity. The follorring
pages present a current review of the health consequences of smoking
pipes and cigars. Data from the prospe&ive investigations of Dunn,
et al. (31), Uuell, et al. (IG), Hirayama (&I), and \Veir and Dunn
(105) are not cited, because in these studies a separate category for
pipe and cigar smokers ~vas not established.

The smoking habits and mortality experience of 157,783 white men
betlveen the ages of 50 and 69 who were followed for M months were
reported by Hammond and Horn (41). The overall mortality rates of
men who smoked pipes or cigars nere slightly higher than the rates
of men who never smoked. The overall mortality rate of cigar smokers
was slightly higher than that of pipe smokers.

In a study of 41,000 British physicians, Doll and Hill (26, 27) re-
ported the overall mortality of pipe and cigar smokers as being only
1 percent greater than that among nonsmokers. Best. (9)) in a study of
78,000 Canadian veterans, reported overall mortality rates of pipe and
cigar smokers slightly nbove those of nonsmokers. Kahn (50) exam-
ined the death rates and smoking habits of more than %93,000 U.S.
veterans and Hammond (38) examined the smoking habits of and
mortality rates experienced by 440,559 men. In t.hese studies, pipe-.
smokers experienced mortality rates similar to those of men who never
smoked regularly, whereas cigar smokers'had death rates somewhat
higher than men who never smoked regularly. Table G summarizes the
results of these five studies.

Thus, data from the major prospective epidemiological studies
demonstrate that the use of pipes and cigar-s results in a small but defi-
nite increase in overall mortality. Cigar smokers have somewhat
higher death rates than pipe smokers, and mixed smokers who use
cigarettes in addition to pipes and cigars appear to experience an inter-
mediate level of mortality that approaches the mortality experience
of cigarette smokers.

495-0280--7J-13

549


TABLE 6.-&fortnlify TdiOS jar total deaths by fype of smoking (Inales
               oh)

Smoking t,-pc

Hammond and
Horn ' (&I.__  1. 00  1. 22  1. 12  1. 10    1. 36    1. 50    I. 43     1. 68
Doll and Hill
(26)_--------  1.00  ___-  __--  1.01  _-__--  _------   1. 11     1. 28
B&(9)_------  1.00  1.06  1.05   .98    1. 22    1. 26    1. 13     1. 54
Kahn (60) _.__ -_  1.00  1. 10  1.07  1.08  _--___  _______   1. 51     1. 84
Hammond *
(38)-- _______  1.00  1.25  1.19  1.01  _-___-  _____ -_   1. 57     1. 86

NortaMy and Dose-Response Relatiowhips

A consistent association exists betrreen overall mortality and the
total dose of smoke a cigar&to smoker receives. The methods most
frequently used to meaSure dosage of tobacco products are: Amount
smoked, degree of inhalation, duration of smoking experience, age
at initiation, and the amount of tar in a given tobacco product. For
cigarette smokers, the higher the dose as measured by any of these
parameters, the greater the mortality. The significance of the small
increase in overall mortality that occurs for the entire group of pipe
and cigar smokers can be analyzed by examining the mortality of
subgroups defined by similar measures of dosage as used in the study
of cigarette smokers.

hMOUXT .%lOKW

Hammond and Horn (40) reported an increase in the orerall mor-
tality of pipe and cigar smokers x4th an `increase in the amount
smoked. Individuals who smoked more than four cigars a day or more
than 10 pipefuls a day had death rates significantly higher than men
xho never smoked (PcO.05 for cigar smokers and P<O.OS for pipe
smokers) (table 7). Cigar and pipe users who smoked less than this
amount experienced an overall mortality similar to men who never

550


smoked. The study of Canadian veterans (9) also contained evidence
of a dose-response in mortality bv xwount s~noket! for cipr smokers.
So dose-response relationship was obsen-cd among pipe smokers (table
S). Kahn (50) reported a consistent increSxse in overall mortality
with an increase in the amount smoked for both pile and cigar smokers
(table 9). Hammond (38) found no consistent relationship between
overall mortality and the number of cigars or pipefuls smoked
(t.able 10).

TABLE 7.-hfortality ratios for lo!& deaths of cigar and pipe smokers by
         amount smoked-Hammond and Horn

      Number of deaths

Observed    Expected   hfannllty rsuo

Nonsmoker-~--~~~..----------------~-~~   1, 664    1,664        1. 00
Cignr only:
  TOt~l-~~~~-~-~-~~---~---~~-~--~--~~      653      593        1. 09
  1 to4 cigars-- _..___ -_----------_-_-      410      400        1. 03
  >4 cignrs- ____ -__-_-_---___-___--_-     229      185        1. 24
Pipe only:
  Total----------_-__._______________     609      560        1. 09
  1 to 10 pipefuls_--- __.. :_- _____ --_.-_     391      374        1. 05
  >10pipefllls---~-~~~-~---~~-- _-_._ --      204      172        1. 19

t3owca: Hammond. E. C.. Earn. D. (IO).

TABLE 8.-hforlality ratios for toti deaths oj cigar and pipe smokers
          by amount smoked-Best

Amount smoked

Observed

Number ol death

  Expected    Mortality ratio

Ncmmoker ___.___ ---- ________.____-
Cigar only:

Total _____ - ________ - ._.._-.--.-
1 to lOpipefuls_-_-_-- ______.___-
1010 20pipefd3-_--_- _______.-
>20pipefuls--- _____ - _______-.-

Gawa: Bat. E. W. R. (8).

90
64
23
1

570     566. 99        1. 00
374     370.09        1. 01
141     140. 84        1. 00
36      35. 90       1. 00

__-__-----       1. 00


  82.07        1. 10
  56. 05        1. 14
   19. 40        1. 19
   1. 59        . 63

551


The above evidence suggests that a dose-responx relationship map
exist between the number of cigars nnd pipefuls smoked and owrxll
mortnlit;o. However, becnuse of the high-mortnlity rate of ex-smokers
of cigars and pipes, it is difficult to interpret the data presented with-
out including this group with the continuing smokers. ll'ithout data
Fchich examines patterns of both daily rata of smoking and inhalation
at various age levels, no firm conclusions cnn be drawn ns to the nature
of this dosage relationship.

TABLE 9.---Mortdity ratios for total deaths of cigar and pipe smokers
        by age and amount smoked-Kahn

Amount smoked

Nonsmoker ______ ---__-- ________________________
cigar only:

  Total__-~__________-____________________~.-
  I to4cigarsperday _______ -_-_-- ____________
  5to8cigaraperday _______ ----__--- _________
  >S cigars per day ________ -- ________ ----_--__
Pipe only:

Total____~~~__-_________________________~-~
1 to 4 pipefuls per day _____ ---_- ______ -- _____
5ta 19pipefulsperday--_-- __.___.__ - _______
>19pipefufsperday ______ -- __._..__ - ___.___

1. 00

1. 01        1. OS
.89        1. 00
1. 14        1. 23
1. 65        1. 28

1. 08
1. 16
1. 04

1. 00

1. 06
.91
1. 10
1. 18

Boome: Kahn: H. A. (50)

TABLE lo.-Mortulity ratios for total deaths oj cigar and pipe smokers
        by amount smoked-Hammond

Amomt smoked

Amount smoked

Nonsmoker-----.-- _________   1. 00 Current pipe smokers:
Current cigar smokers:              Total __________ - _______._    1. 04
TOtal-_--- _-___ - ___.---.-    1. 09   1 to 9 pipefuls per day-__--    1. OS
1 to4cigarsperday ___.___    1. 03   >9 pipefuls per day ___.___     .92
>4 cigar3 per day__ _ __ _ _ _ _    1. 18

Boons: Hammond. E. C. (98).

552


Inhalation of tobacco smoke directly exposes the bronchi and the
lungs to smoke and results in the absorption of the soluble constituents
of the gas and particulate phases Without inhalation tobacco smoke
only reaches the oral cavity and the upper digestive nnd respirator?;
tracts and does not reach the lungs where further direct effects and
systemic absorption of various chemical compounds cln occur.

L\]thougl~ the smoker has some voluntary control over the inhalation
of smoke, the physical and chemical properties of tobacco smoke to a
degree determine its acceptability and "inhalability."

The condensate of pipe and cigar smoke is generally found to be
alkaline when the pH is measured by suspending a Cambridge filter
in CO,-free xrter. Cigarette condensate is slightly acidic as measured
by this method. Since alkaline smoke is more irritating to the respira-
tory tract, it has been assumed that the more alkaline smoke of pipes
and cigars was in part responsible for the lower levels of inhalation
reported by pipe and cigar smokers. Brunnemann and Hoffmann (15)
have analyzed the pH of whole, mainstream smoke of cigarettes and
cigar; on a putf-by-puff basis using a pH electrode suspended in main-
stream smoke. Smoke from several U.S. brands of cigarettes Kas found
to be acidic throughout the entire length of the cigarette. Of intemst
was the finding that cigar smoke also had an acidic pH for the first
two-thirds of the cigar and became alkaline only in the last 20 to M
percent of the puffs from the cigar. Available epidemiological evidence
indicates that most cigar smokers do not inhale the smoke and most
cigarette smokers do. The fact that smoke from the first half or more
of a cigar is acidic, near the range of pH values commonly found in
cigarette smoke, and becomes alkaline only toward the end of the
cigar might suggest that the pH of the smoke of a tobacco product
may not be the only factor t.hat influences inhalation patterns. Per-
haps "tar" and nicotine levels as well as the concentration of other
"irritating" chemicals also affect the degree to which a tobacco smoke
will be inhaled.

Nicotine is rapidly absorbed into the blood stream from the luns
when tobacco smoke is inhaled The amount of nicotine absorbed from
the lungs is primarily a function of the nicotine concentration in the
smoke and the depth of inhalation. Some nicotine may also be ab-
sorbed through the mucous membranes of the mouth. This is more
likely to occur under alkaline conditions rrhen nicotine is unprotonated
f3, 15, 79). This suggests that cigar smoker-s may he able to absorb
some nicotine through the oral cavity without having to inhale, par-
ticularly during the time that the smoke from the cigar is alkalme.

553


Jvith the development of sensitive measures of serum nicotine levels
(2) the extent to which nicotine is absorbed through t.he membranes
of the mouth in pipe and cigar smokers can be more awurately
determined.

Inhalation patterns of smokers Kere determined in several of the
large prospective and some of the retrospective epidemiologiul studies.
Inhalation was usually determined by the administration of n que-s-
tionnairo that required a subjective evaluation of one's orrn patterns
of inhalation. Although the accuracy of these questionnaires has not
been confirmed by an objective measure of inhalation, such as carbosy-
hemoglobin or zrum nicotine levels, their reliability is supported by
mortality data which demonstrate higher overall and specific death
rates with self-reported increases in the depth of inhalation.

Doll and Hill (26) and Hammond (38) presented information on
inhalation patterns of pipe, cigar, and cigarette smokers (figs, 1,2, 3,
and table 12). Some 80 to 90 percent of cigarette smokers reported
inhaling, Kith the majority of individuals inhaling moderately or
deeply, rrhereas most pipe and cigar smokers denied inhaling at all.
Pipe smokers reported slightly more inhalation than cigar smokers.
For each type of smoking, less inhalation n-as reported by older
smokers. This change may represent less awareness of inhalation,
differences in smoking habits of successive cohorts of smokers, or it
may reflect the operation of selective factors which favor survival of
noninhalers.

The Tobacco Research Council of the United Kingdom has, since
19.57, periodically reported the use of tobacco products by the British.

figure I.--Inhalation among pipe smokers by age.

  No
inhalation

Some
inhaiahon

      I                              I
   Age     40         50        60        70         80
SOURCEr Hammond, E C. (38).

554


Figure 2.-Inhalation among cigar smokers by age-Hammond.

c---

3"1,1C
inhalation    26.4       22.9      17.1       13.7       18.5  I

     Age 40        50        60        70        80

SOURCE: Hammond. E. C. (38).

Figure 3.-Depth of inhalation among cigarette smokers by age.-Hammond.

None

Slight
inhalation

Moderate
inhalation

Deep
inhalation

      Age 40        50         60        70        80

SOURCE: Hammond, L C. (381.

Recent reports edited by Todd h ave contained data on the inhalation
patte.rn of cigar, pip, and cigarette smokers (92, 93, 94). Table 11
shows that most, cigarette smokers inhale a "lot" of "fair amount"
whereas most pipe and cipzr smokers do not inhale at all or "just a
little." Little change is observed in the inhalation patterns of.8 given
product since 11)66.

Best (9) reported inhalation data among male cigarette smokers by
smoking intensity and age group, but did not report the inhalation

555


patterns of pipe nnd cigar smokers. The overall mortality rates of
current pipe smokers who inhaled at least slightly were reported by
Hammond (38) as being someThat higher than for men rho never
smoked regularly. The overall mortality rates of current ci.gar smokers
who reported inhaling at least slightly xrere appreciably higher than
for men who never smoked regularly (table 13).
Available evidence indicates that cigarette smokers inhale smoke
to a greater degree than smokers of cigars or pipes. Once a smoker has
learned to inhale cigarettes, however, there appears to be a tendency
to also inhale the smoke of other tobncco products. For cigars, this is
evidently true lx-hether one smokes both cigarettes and cigars or
s-x-itches from cigarettes to cigars (tables 14,15,16).
Brass and Tidings (14) examined the inhalation patterns of
smokers of large cigars, cigarettes, and those who switched from one
tobacco product to another (table 15). Nearly 75 percent of those who
were currently smoking only cigarettes reported inhaling "almost every
puff" and only 7 percent never inhaled. The opposite was true for per-
SOIIS who had always smoked only cigars among whom 4 percent re-

TABLE 1 I.-The eztiru! of inhaling pipes, cigars, and cigareties by
     British males aged 16 and over in 1968 and 1971

Tobacu, product

Inhale a lot __._____________._______   23    19    8    8    47    47
Inhale a fair amount _____ --- .______ -   16    19    10     8    31     30
Inhale just a little _________ - ________   27    27    24    26    13     15
Do not inhale at all__ ______.________   34   35   59    58    9     8
                                                      -

    Total___________~__--~-------  100   100   100   100   100    100

Soum: Todd, 0. F. (95. 9)).

TABLE I2.---l&a&ion among cigar, pipe, and cigareb smokers by
           age-DoU and HiU

smoking type

Cigar and pipe ___.____________  12. 00  10. I10   7. 00   5. 00   4. 00    4. 00
Mixed (cigarette and other)_-__ _  74. 00  60. 00  47. 00  36. 00  30.00   26. 00
Cigarette only _.______________ 90.00  85.00  75.00  66.00  58.00   41.00



8ourcr: Doll, R.. HIU, A. B. (Ib).

556


ported inhaling almost ore? puff and 83 percent said they nerer
inhaled. Cipr smokers rho also smoked cigarettes reported inter-
mediate levels of inhalation betwcn the cigar onlr and ciprette onI?
categories. Inhalation patterns wrc similar rrherher the individual
continued to smoke both products, stopped smoking cigarettes but
continued smoking cigars, or stopped smoking cigarettes  nnd
sxitched to cigars. In all three groups, about 20 percent reported
inhaling "almost every puff." This suggests that once an individual's
inhalation patterns are established on cigarettes, he mny be more likely
to inhale cigar smoke if he sxitches to cigars, or uss both cigars nnd
cigarettes, than the cigar smoker who has not smoked cigarettes.
Todd (93) reported similar data for a sample of smokers in the
United Kingdom (tabIe 16). The prevalence of inhaling a "lot" or
"fair amount" of smoke xx-as hi,nhest among cigarette smokers who were
currently smoking cigarettes (77 percent) nnd lorrest among current
cigar smokers who had previously smoked only cigars or pipes (18
percent). Indiriduals who switched from cigarettes to cigars main-
TABLE 13.-Mortality ratios jar total deaths oj cigar and pipe smokers
        by age and inhalation-Hammond


                                          Mortatltr rslb. age
                 Inhalation                    4.3 to 64     a5 to 64


Nonsmoker-__-_______---~--~----~~---~-~~--~-------     1. 00      1. 00
Cigar only:
  Totel---__-_______--____________________--~~-~~     1. 09       .98
  No inhalation _____ - _______________________ -----_     1. 02       .91
  Someinhalation~__-___-_-____________________---     1. 29      1. 37
Pipe only:
  Total---____--____-_____________________--~~-~-     1. 04       . 95
  No ihabtion ____________ --- ____._._____________     . 98      _ 87
  SOme inhalstion_-__-_-__-____________________---     1. 21      1. II


E%~: -mmond. E. C. (~8).
TABLE 14.--Percentage oj Bn'tish male cigar smokers who reported
  inhuling a lot or a jair amount by type bj product smoked



         T9ce of product                1963             1971

                            Number of   PWWnt   Sumkr of   Percent
                            In&ridu&         In&rlduals

%m only.. _ _. _____ -_ __ ____ .____._     706   23. 0
%a~ and cigarettes__--. . ___ ______._                    111     27. 0
                       1,193    42. 0      277    44. 0
CiRam and pipes.----_--- ..__________     596    35. 0      109    32. 0
cigm, cigaretteu, and pipes ._________      26    52. 0       1.5    32. 0

EOUrcC: Todd. 0. F. (0,. 04).

                                         557


tained somewhat higher levels of cigar smoke inhalation than those
cigar smokers n-ho had never smoked ci,narettes (30 percent).

Todd (93) examined further the relationship between the inhalation
of cigarette and cigar smoke. In general, cigarette smokers who
switched to cigars rrere much less likely to report illhaiing cigar
smoke than cigarette smoke; however, those who in the past reported
inhaling cigarette smoke a "lot" or "fair amount" were much more
likely to report inhaling cignr smoke to the same degree than those ex-
cigarette smokers who in the past did not inhale the smoke of their
cigarettes (table 17).

TABLE IL-Percentage of indiuidua!s reporting inhulation of "almost
erery puff' of tobacco smoke by current and previous tobacco usage and
type of tobacco used

Cigarettea only ____ Cigarettes only ____ 2, 359  Cigarette-_-  74. 8  73. 1  76. 6
Cigars only- _ _-___ Cigars only- _ _ ____   649  Cigars..----  4.5   3. 0   6. 0
Cigarettes and    Cigarette-s and      520 w-.--do ____ -  20.4  10.5  28.0
cigars.        cigara. _
Cigars- _ - - _-__ _ __ Cigarettes and       93 __.__ do-_---  18.3   9. 0  30. 0
            cigars.
None ____________ Cigarettes and      186  ____ -do----- 21.5  17.8  24.2
            cigars.
Cigars-- __ _____. _ Cigarette3 only ____    64 _____ do _____  17.2  16.0  28.0

Bourcs:Brcar. I. D.J., Tidlnpr,J.(10.

TABLE 16.-percentage of British males who reported inkding a lot or
jair amount of n'gar smoke by current and previous tobacco usage and
type of tobacco previously smoked (1968)

CigaretW only--- - _ _ _ _ Cigarettes only-_-_- -  2,`586  Cigarette.- _ __    77. 7
Cigars only __-___-.___ Nonsmoker- ____ _-__   306 Cigars------_    18. 0
Cigars only ____-_______ Cigarettes only _.___._    321 -----do-__.-.-    30. 0


&xma: Todd. 0. P. @I.

558


TABLE 17.-Extent O_r rt-ported inhafaiion qf cigar smoke by British
male cigar smokers who were ez-cigaretfe smoL-crs in I.%T, artalyzcd
by extent of reported inhalation of cigarette smoke when yrt-ciously
smoking cigareUEs

                                      or fRIT amount   or not 81 au

                                           P<rrCmLt       PClCd
Inhalealotorfairamount _____. - .____ --___- ____.      44. 0        5. 0
Inhale a little or not at all__- _______ ---- __._____._      56. 0        95. 0

Source: Todd, 0. F. (89.

Specific Causes oi

i?fortamy

Cancer

Several prospective epidemiological
              .~

studies have showr a signifi-

cantly higher overall cancer mortality among pipe and cigar smokers
compared to the cancer mortality of nonsmokers (table 18).

Pipe and cigar smokers have much higher rates of cancer at certain
sites than at others. The upper airway and upper digestive tracts
appear to be the most likely target organs. The relationship of pipe
and cigar smoking to the development of specific cancers is detailed
in the following sections.

TABLE lg.-Mortality ratios jar total cancer deaths in cigar and pipe
  smokers. A ammary of prospective epidemiological studies

            Type of smoLlng

Nonsmoker Cigar only  Pipe only  Total pipe
                      and cigar

1. 00     I. 34     1.44  __------     1. 97
1. 00     1. 13     1.38  -___--.-     2. 06
1.00   _____--  -------    1. 21      1. 76
1. 00     1. 22     1. 25     1. 25     2. 21

559


Cancer of the Lip

Approximately 11500 nerr cases of cancer of the lip are reported
each year. Because of the possibility of early detection and surgicai
accessibility of cancers in this area, there are leas than 266 deaths from
cancer of the lip each year in the United States. Some of the earliest
scientific investigations exploring the association between tobacco use
and disease examined the smoking pntterns of individunls with cancer
of the lip.

Broders (13) in 1920 examined the smoking habits of patients in
a retrospective study of 546 cases of epithelioma of the lip and 500
controIs. Of the cancer cases, 59 percent smoked pipes, whereas this
was true for only 28 percent of the controls. No association xas found
between cigar or cigarette smoking and cancer of the lip.
In a restrospective study of 439 clinic patients with cnncer of the
lip and 300 controls conducted in Sweden, Ebenius (32) reported a
significant association between pipe smoking and cancer of the lip.
A total of 61.8 percent of the lip cancer cases smoked pipes, while
only 22.9 percent of the controls smoked pipes. So associntion Kas
found between the use of cigarettes, cigars, or chewing tobacco and
cancer of the lip.

In other retrospective studies, Levin, et al. (I%) review-ed a series
of l-13 cases of cancer of the lip, and Sadowsky, et al. (77) reviewed
571 cases of cancer of the lip. In both studies, a strong association n-as
found between pipe smoking and cancer of the lip. No significant
association T<as found betlreen the use of tobacco in other forms and
cancer at this site.

In a study of environmental factors in cancer of the upper alimen-
tary tract, Wynder, et al. (113)  f ound an .association betmeen pipe
smoking, cigarette smoking, and cancer of the lip. There were only 15
cases of cancer of the lip in this study.

Staszen-ski (87) examined the smoking habits of 394 men with
carcinoma or precancerous lesions of the lips. An association eras
found between the smoking of pipes and cigars and cancer of the lip,
but this was only of doubtful significance. A significant association
was found between the use of cigarettes and cancer of the lip.

Keller (51) conducted a study of lip cancers in which he considered
a number of factors including histologic types, survival, race, occupa-
tions, hnbits, and associated diseases. A total of 301 patients with
primary basal cell or scluamous cell carcinoma of the lip and 301
controls from the same hospital matched for age and race were con-
sidered in this series. il significant association was found betxeen
smoking in all forms and combinations and carcinoma of the lip. It
\vas also found that increasing age and outdoor occupations with
exposure to the sun were equally significant factors in the etiology of
lip cancer.

560


In summary. it appears that there are several factors involved in
the etiology of cancer of the lip. 2-2mon.g the various forms of tobacco
use, pipe smoking either alone or in combiJJation with other forms of
smoking seems to be a cause of cancer of the lip. Table 19 summarizes
the results of these retrospective studies.

Oral Cancer

The lips, oral cavity, and pharynx are the first tissues exposed to
tobacco smoke d=rTvn in through the mouth. Varintions in inhalation
(Iuhng t.he smoking of various tobacco products result in different pat-
teJ-Jis of distribution of srJJoke throughout the respiratory tree. How-
ever, the oral cavity and adjacent tissues are the sites most consistently
exposed to tobacco smoke. For this reason, differences in inhalation
should result in less variation in exposum to tobacco smoke for these
sites than for t-he lower trachea and the lung. The inherent carcinogen-
icity of pipe, cigar, and cigarette smoke is most reliably compared at
those tissue sites where dosage and exposure to tobacco smoke are most
nearly equal. Data front the epidemiological studies SU~~CS~ that little
difference exists between the smoking of cigarettes, pipes, or cigars and
the J-isk of developing oral cancer.

Hammond and Horn (40) examined the association between smok-
ing in va~-ions forms and cancer of the cornbind sites of lip, mouth,
pharynx, larynx, and esophagus. The mortality ratios were 5.00 for
cigar smokers, 3.50 for pipe smokers, and 5.06 for cigarette smokers
cornpared to nonsmokers. -111 the deaths from cancer of the lip, oral cav-
ity, and pharynx reported by Doll and Hill (26) occurred in smokers.
The death rates from cancer at. these sites were 0.M per 1,000 for pipe
and cigar smokers, 0.10 per 1,000 for mixed smokers, and 0.05 per 1,000
for cigarette smokers. ,I fairlv detailed analysis of oral cancer was pre-
seJJted by Kahn (SO) who differentiated between cancer of the oral
cavity and CaJJcer of the pharynx. The mortality ratios for oral cancers
were 1.00 for those who never smoked, 3.89 for all pipe and cigar
smokers, and 4.09 for cigarette smokers. A further breakdown of thJzr
pipe and cigar smokers demonstrated a mortality r;ttio of 4.11 for
cigar smokers, 3.12 for pipe smokers, and 4.20 for smokers of pipes and
cigars For cancer of the pharynx, the mortality ratios were 1.00 for
those who never smoked. 3.06 for all pipe and cigar smokers, and 12.5
for cigarette Smokers.. So deaths occurred among those lvho smoked
oJJly Cigars. The mortality ratio was 1.98 for pipe smokers and 7.76
for sJnokem of pipes and cigars. Hammond ($8) combined cance-s of
the lip, ora1 cavity, and pharynx. The pipe and cigar smokers had a
mortnlity ratio of 4.94 and the cigarette smokers a motility J-at,io of
9.90'compared to JJoJisJnokers.

561


Brodcrv (19):
  C~CY..-...--_-_------------ 537
  CurltrulY.. _--__-_-----_---__- 500

Ebcniw (Yg) :
  CUBCYy __-_-__-----_--_------ 439
  Cuntrols ____________________ 300

Lcvin, ct rrl. (60):

cuscs-........-....--------- 143
CurltrulY _-_______----_----__ 554

Sadowaky, ct ul. (77):
  CUSCY~ - ._ ._-. -_ _____________ 671
  Cuntruly- _ _ _ _ __ _ _ ___ _ _ _. _ _ _ _ G I5

Wyndcr,' CL al. (123):
  Casts- -_---_-------- ------_-  14
  Controls-----..-.-.--------- 115

Stnszcwski (87) :
  C UY(1Y - - _ _ - - - _ - _ _ _ _ _ _ _ - _ _ _ _ _ _  394
  Cuntrols ________.____________ 912

Kcllcr: (61) :

cuscs- - - - - -- - - - _ - - -- -_ _ _ _ _ _ _  301
Controls _____________________ 2G5

Rclativc risk ____________
Percent ca~cs ___________
Percent corrtrolv .________

Rchtive rwk. __._________
Percent casts ___________
Pcrccnt controlv _________

Rclntivc risk ____________
I'crccnt CIISI:Y- _ _ _ __ _ __ _ _
Pcrccut control3 _________

Rchtivc rbk ____________
Percent cwc3 ___________
Percent controla. ________

Rcletivc risk ____________
Pcrccnt cam _______ _____
Pcrccnt controh _________

Rclntive rivk _______ _____
Pcrccnt cnscs _______ _____
Pcrccnt controlu _________

1. 0     0. 8
7      19
4      16

1. 0      7
49    6'
65      12

1. 0     1. 9
15      27
22      20

1. 0     1. 1
8       2
13      3

0       8
0    7'
24      9

1. 0  _ _ _ _ _ _ _ _ _
i   _ _ _ _ _ _ _ _ _
13 ___-____-

1. 0     1. 4
7       2
17       4

4. 3 - -- --- -
     -      -     0   - - _-. . -. -
41 --_____-_     1   __---_- _-
G   em-m...-*   2G   _ _ _. -. - - -

  4. 1 0.5  ____- __  ____ -_--_
41 4    _....__ .____--__
13 10    ____-__  ___-__-__

2. 9 _. . - - _ - -
          -      1.4  _______ __
48 -..--_--_    45   -- ._---._
24 _.______ _    46   _____ ___
                       _

  4. 3 2. 0     I. 4      0. 4
18 a      4 *1       2') *
  7 4      53       19

  1. 8 - _ - _
       - _ - _ _     I. 0      2. 2
29 - _ _ _ _ _ - _ _    36       29
16 -----____    36       13

- - - - - - _ 2. 1     2. 4  _ - - - - _ - _ -
-____-_ 12      73  _____----
-.--we-     ll      61 _________

  4.0           2. a
  I3       1      GO       G
  3 0      53       0


These studies are summarized in table 20. Ther demonstrate that
smoke.rs experience a Jar.3 and si,?ifcnnt risk of dere1opin.g cnnwr
of the oral cavity compared to nonsmokers. This risk seems to he &out
the same for all smoker; whether an indis-idusl uses a pipe, cigar, or
cigarette.

  A number of retrospective studies hnre esnmined the relationship
betwen smoking in various forms and cancer of t.he oral carit_r. The
results of these studies are pwsented in table 21. Some of the variations
in relative risk of developin g oral cancer observed in the rdrospwtive
studies is probably duo to t.he lack of suniform definition of oral cancer
by anatomical site and the various means used in select.ing and defin-
ing cases and controls. It appears, however. that R significant risk of
dereIopin,rr oral cancer exists for smokers compared to nonsmoker;
and this risk is similar for smokers of pipes, cigar;, and cigarettes.
  Several epidemiological investigations have demonstrated an asso-
ciation betrreen the combined use of alcohol and tobacco and the
dcvciopment of oral cancer. ;I few of these studies (59, 62, 63, 109)
contain data on pipe and &Far smokers. Heavy smoking and heavy
drinking are associated xTith higher rates of oral cancer than are seen
with either habit alone.

TABLE %I-Mortality ratiosjor oral cancer in cigar and pipe smokers.
    A summary of prospuztive epidemiological studies

IIammond and Horn'(40)-   1. 00    5. 00    3.50 ~_______   5.06 -: -..___
Doll and Ffill~ (PC?, .S'7)_ _ _   0.00 --.---__  ~-----   0. 80    1. 00    2. 00
Hammond (58)-_--__--__   1.00 _-__-_-_  -_-___   4 94   `9.90 -----.--
Kahn (60):
  Ora14_._____ -__-___   1. 00    4. 11    3. 12   3. 89    4.09 _- ______
  Pharynx ________ --r-   1.00 --_.----   1. 9a   3. 06   12.54  - _______

Cancer of the Larynx

The larynx is situated at t.he upper end of the trachea. Because of
its proximity to the oral cavity, the larynx probably hxs a similar
exposure to snloke drawn through the mouth as the buccal cavity and
pharynx. Tobacco smoke that is not inhaled may still reach a~ far as
the lnrj-ns and upper trachea. Pipe and cigar smokers develop cancer
of the larynx at rates compnnble to those of cigarette smokers. These

563


TABLE 21 .-Rcloriue risk of oral cancer for men, comparing cigar, pipe, and cigarelle smokers uith nonrmokers. A summary of rcfrospeclive
                                       sludies

hlillr and Porter (6G):
  CayCY~~~~.~..~.~~~~~~~~~~~~~   124
  Controls- _ _ _ _ . _ _ _ _ _ _ _ - _ _ _ _ _ _ _   185

Sadowsky, et al. (77):
Casey----..._----....._-__.- 1,136

Controls..- _ _______ ._________

615

Schwartz, et al. (89) :
  Cases.---.-.-.--------------
  Controls ____ ___ ____ __ __ ______

332
608

Wynder, et al. (109):
  CayCE..-----....-_----------
  Controls.. _ - _ - - _ _ _ _ _ _- _ _ _ _ _ _ _

Wynder, et al. (f IS):
  Cases.------..---._---------
  Conbrols ___-_______ .__ -m--m__

543
207



115

115  Percent controls __________

Relative risk _____________
Percent casc3 ____________
Percent controls.-- _ _ _____

Relative risk _____________
Percent cases- _ __________
Percent controls __________

Relative risk _____________
Percent cases- __ _________
Percent controls. _________

Relative risk _____________
Percent cuscs ___________.
Percent controls __________

Relative risk ____ _ _ _ __ __ __
Percent cnscs ____________

1.0  _-_______  _--_____    7.0
10   _-_------  _-____-_    55
38   _________  ________    30

1. 0     2. 0
8       4
13      3


1.0 ___--.___
16 _-__-_---
23      77


1. 0     3. 6
3      20
10      13


1. 0     1. 7
23      13
26      9

4.4  _________
18   _________
7   -_-______

1. 0 - - _ - - -
       - - -
3   -- -
     ----_-
3   _ - _ - _ _ _ _ _


0. 1  - - - - - - - _ -
11   _________
G   -e----e--


.9  _^______-
12   ________-
16   ----q-q--

4. 1  - - _ _ _ - - _ -
36   ____.____
32   -____-__-


1. 4      2. 1
42      28
53       23

1.5  ___------
63   _________
58   -_.-.----


3. 0      3. 3
57       8
63       8

1. 2      1. 4
37       IG
36       13


Wyndcr, ct sl. (II@:

$    C8.W! _ - _ - _ - _ _ _. _ _ - _ _ _ - _. _ _. -   178
   Controls _.__ _ _ _ _ _. . __ _ _ _ _ _ _ _ _   220

ifi
! Pcmu (73):
   Cnaev ______________._____--- 1,400
   Con trCJL_ ____ _ _ _ - _ - - _ _ ^ _ _ - - - - -   713

: Staazewski (87):
   CaSW...-----....-._.-------   383
   Controls ________ __ ___________   912

Keller (at) :
   Casea--....-..---...-.------   408
   Controls _____________________   408

hfsrtinez (08):
   Crises _ _ _ _ _ _ . . _ _. _ _ _ _ . _ _ _ _ _ _ _   170
   Controls _____________________   510

hlartinez 1 (8s) :
   Cnses. _ _ - _ _ _ _ _ - _ _ _ _ _ _ _ _ _ _ _ _ .   346
   Controls ._______ __. ____ ___ ___   346

R&live rbk _________.___
Pcrccnt cazics.. _ ___ ______
Pcrccnt controls __________

Rclutive risk _._______.___
Pcrccnt cilscs ---__-____._
Perccn t controls. _ _ _ _ _ _ _ _ _

Relative risk _____________
Percent cases ____________
Pcrccn t controls. _ _ _ _ _ _ _ _ _

Relative risk _____________
Pcrccnt casts ____________
Pcrccnt control3 ____ __.___

Rclativc risk _____________
Percent ca3c9-- _ _________
Percent controls __________

Relative risk _____________
Percent cases _______: ____
Percent controls __________

1. 0     6. 0  _ _ . _ _ _ _ _  _ _ _ _ _ _ _ _
4      33    _---.---  -_--____
10      22    _____-_-  -.-*_-__

4 0 _ _ _
    - _ - _
       _ -
4.5   _ __ _
    - - _.
        -
45   _. _ -. _ - _ -

2. 2      2. 9
50       11
60       7

3. 6  _ _ _ _ _ _ _ _ _
72   _ _ _ _ _ _ __ _
61   -________

3. 4  -. - _ _ -
      - _ _
69   _ _ _. - - - -
     _
56   _. _ _ - _
       -  - -

I. 5      23
39       34
44      25


1. 7      2. 5
34      34
3G      25


rates are several times the rates of nonsmokers. The similnritr of the
modality ratios of cancer of the larynx for srnoki~~g in \-arions forms
suggests that the carcinornznic potentials of the smoke from cigar;.
pipes, and cigarettes are quite alike at this site.

Several of the prospective epidemiological studies include data on
deaths from cancer of the larynx for pipe and cigar SII~O~~IX FIS ~~11
as for cignrette smokers. Hammond nnd Horn (40) combined data for
cancer of the larynx with cancer of the esophagus and oral cavity.
The mortality ratios compared to nonsmokers were 5.00 for cigsr
smoker;, 3.50 for pipe smokers, and 5.06 for cigarette smoker; There
Kern no deaths from carcinoma of larynx among nonsmokers in
the study of British physicians by Doll and Hill (86') ; holrevcr, the
death rate for cancer of the larynx among pipe and cignr smokers KS
0.10 per 1,000 while the death rate for cigarette smoker-s uas 0.05 per
1,000. Kahn (50) reported motility ratios for cancer of the larynx of
10.33 for cigar smokers, 9.44 for pipe and cigar smokers, 7.28 for all
pipe and cigar categories combined, and 9.95 for cigarette smokers. Xo
deaths from cancer of the larynx occurred in pipe smokers. Hammond
(38) reported a mortality ratio of 3.37 for all pipe and cigar smokers
and a mortality ratio of 6.09 for cigarette smokers in the age category
45 to 64. These studies are. summarized in table 22.

Several retrospective studies have examined the smoking habits of
pntients with cancer of the larynx and appropriately matched controls.
The small number of pipe and cigar smokers in each study results in
relative risk ratios that are quite unstable; however, it appear-s that
pipe and cigar smokers experience a risk of developing cancer of the
larynx that is similar to the risk observed among cigarette smokers
(table 18).

TABLE 22.~MurfaIity ratios for cancer of the larynz in cigar and pipe
  smokers. A ammary of prospective epidemiologid studies

Bammond and Horn 1
(f#O)-- _____.__.._____ -   1. 00    5. 00   3.50 --_-_.__   5.06 -..- ____
Doll and Hill * (es, .$7).-_   0.00 -..-~-..  -_._-_   2. 00    1. 00    0. 60
Hsmmond (Q8)- ____ - _.__   l.oo- -___ --_  -_._-_   3. 37   ' 6.09  -.---___
Kahn (60). _ _._______ _-_   1. 00   10.33   --__-_   7. 28    9.95  -.-__-._

566.


WJnder, et al. (108, 213) distinguished betxwen intrinsic and es-
trinsic larynx cancers. For smokers the relative risk of developing
cancer of the intrinsic lnrgns was similar to the relative risk of lung
cancer whereas the relative risk of developing extrinsic larynx cancer
-XBS more like the relative risk of cancer of the upper digestive tract.
fIistologic changes of the larynx in relation to smoking in various
forms were described by huerbach, et al. (5). Microscopic sections of
the larynx from 342 subjects were exnmined for the presence of
atypical nuclei and prolifemtion of cell ro\ys. Sections were t&en
from four separate areas of the larynx in each case. Among t.hose who
smoked cigars and pipes but not cigarettes, only 1 percent had no
atypical cells and more than 75 percent of the subjects had lesions
Gth 50 to 69 percent atypical cells. Four of the cigar and pipe smokers
had carcinoma in situ and in one of these four cases early invasion
Kas seen in three of the sections. Of those -ho never smoked regu-
Iariy, 75 percent had no atypical cells. The cigar and pipe smokers had
a similar pe.rcentage of cells rrith atypiwl nuclei as cigarette smokers
who smoked one to two packs per day. IVith respect to the prolifera-
tion of cell rows in the basal layer of the true vocal cord, the least
proportion of cases with eight or more cell rows E-as found in men
\Tho never smoked, and the greatest proportion was found in heavy
cigarette smokers. Pipe and cigar smokers had a distribution of cell
rows that was comparable to that of cigarette smokers who consumed
about a pack a day.

Several retrospective studies have reported an association between
the combined use of tobacco and alcohol and cancer of the larynx. A
stud? by Wynder, et al. (108) included some information on pipe and
cigar smoking in relation to drinking habits and the development of
cancer of the laryns, but. because of t,he limited number of pipe and
cigar smoking subjects this relationship could not be adequately
determined.

Cancer of the Esophagus

The esophagus is not directly exposed to tobacco smoke drawn into_
the mouth; however, the esophagus does have contact with that portion
of tobacco smoke that is condensed on the mucous membranes of the
mouth and pharynx and then swallowed. The esophagus is also ex-
posed to a potiion of tobacco smoke that is deposited in the mucus
cleared from the lung by the ciliary mechanism or by coughing. Varia-
tions in inhalntion of a tobacco product may not appreciably alter the
exposure the esophagus receir-es from smoke dissolved in mucus and
saliva. This suggestion receives support from the prospective and
retrospective epidemiological studies which demonstrate similar mor-
tality rates for ctiucer of the esophagus in smokers of cigars, pipes, and
cigarettes.

567


TABLE 23 .-Relutive risk of cancer of the larynx for men, comparing cigar, pipe, and cigarette smoker8 with nonsmokers.
                 A summary of retrospective StUdie8

Schrek, et al. (81):
  casts -___-- ________.________  73
  Controls _-___________________ 522

Sadowsky, et al. (77):
  Cases-.-..-.--_---..-------- 273
  controls _________-__*________ 615

Wynder, et al. (108):
  cases_~-.._...._~--.-~---~~~ 209
  Controls ____________.________ 209

Wynder, et al. (119):
  Cases-._.--_.--_..-.-------- 60
  Controls __________________. __ 271

Wynder, et al. (1f6):
  Cases _______________________ 142
Controls __--__________ I______ 220

Relative risk __.________ _
Percent cases- __________
Percent controls _________

Relative risk ____________
Percent cases- _ _ _ _ _ _ _ _ _ _
Percent controls _________

Relntivc risk ____________
Percent cnscs. ________. _
Percent controls _________

Relative risk ____________
Pcrccnt cases. _ _ _ _______
Pcrccnt control3 _________

Relative risk ___________
Percent cases- __________
Percent controls _________

1. 0     0       1. 1  _ - _ _ _ - _ - _
14      0      7   ----_----
24      10      11   -_.._____

2. 3  _ - - - - - - _ _
80   - _ _. _ _ _ _ -
59   _ _ _ - _ - _ _ -

1. 0     2. 2     2. 3  _ _. _ _ -
                     - - _
4       2       5   s-_-_-e_-
13      3       7   --_--____

3. 7      4. 1
GO      29
53       23

1. 0     15. 5    27. 7    11. 1
11' 5  10 8   5 4   2 1

24. 6  _ _ _ - _ _- _ -
XG   - _ _. _ - - _ -
74   _ _ _ _ _ _ _ _ .

1. 0     9. 7     4. 5  - - _ _
                   _ - _ - -    6. 3      6. 3
5      17      15   - -------_    47       17
24      9      16   - _ - - _ _ _ _ -   36      13

1. 0    14. 5     16.0  .________
1      20       1   --.--e-_-
16      22       1   .-m-_-m_-

22. 0     1G. 0
G2       16
45      16


Pernu (79) :                    Relntive risk _______.____    1.0  ______-__    45  -.-------    8.7      3. 2
  CaYeY..........--..---.-----  546    Pcrccnt cues __.________    7   ___._____    4   ____r____    78        4
  C~~nlrob ._._____________ _____ 713    Pcrccnt contrulu __-______    30   - _ _ - - - -
                                                           - -       5   --------_    50       7

Starzcwski (87):                 Rclntivc rirk ____________     1. 0  _________  _______    6. Q    50. 2 - __ - - - - - -
  Casca..-..._-..-.-..--------  207    Percent cIwes ___________      5  _________  ._____-    2      88   w-_-m-.-.
  Controls _____________________ 912    Percent control.4 _________    17  __`_._____  _______    11      01   --__--_--

Svoboda ($0) :
  C~CS...---............----.  205
  Contrh __.__________________ 320

Relative rivk ___-___.____
Percent cwey-.- ________
Percent controls--- _ _ _ _ _ _

1.0  _____-___     2. 0  - - _ _ _ _
                  _ _ _       10. 0  _-__-----
3   ____---__    3   .--------    05   _ _ -. _ - _ - -
22   ___--_-__    7   --___----    71   _- __ -----

Stell (88) :                    Rclntive risk ____________    1. 0 - - _ - _ - - _ -   - - _ - - - -    1. 3     2. 4  _ - - _ - - _ - -
  Cases-----..._.-.-.---------   190 Percent cILses.. _ _________   I1 _____ ____ ______.    8      79   - _ - _ - _ _ _ _
  Controls. ____ _ ____ ___________   190 Percent controls _________ 17 _________ _______ 10      50   - _ _ _ - - - - -


in the prospective epidemiological studies, cigar, pipe, and cigarette
smokers all had similar mortality ratios from cancer of the esophagus.
fIan\mond and lrorn (40) combined the categories of carcinoma of
the esophak?ls. i:lr~-AS, phnnnx, oral cavity, and lip and described
n~o~a~ity ratios of 3.00 for cigar smokers. 3.50 for pipe smokers, and
5.06 for ciprette smokers. Doll and Hill (26) reported an esophageal
Lancer mortality ratio of 2.0 for pipe and cigar smokers, 4.8 for mixed
smokers. and 1.5 for cigarette smokers. Kahn (30) reported the fol-
lolving mortality ratios for smoking in various forms compared to non-
smokers: cigar only, 5.33; pipe only, 1.99; pipe and cigar, 4.17; all
pipes and cigars combined, 4.05; nnd cigarettes only, 6.17. The r~~1t.s
of these prospective studies are summnrized in table 24.

Several retrospective investigations have also examined the associa-
tion betrreen smoking in various forms and cancer of the esophagus.
These studies have been summarized in table 2% The evidence sug-
gests that cigar, pipe, and cigarette smokers develop cancer of the
esophngus at rates substantially higher than those seen in nonsmokers,
and that little difference exists bet-ween these rates observed in smokers
of pipes and cigars and cigarettes.

Histologic changes in the esophagus in relation to smoking in vari-
ous forms rrerO investigated by -4uerbach, et al. (7), who looked for
atypical nuclei, disintegrating nuclei, hyperplasia, and hyperactive
esophageal glands. ,4 total of 12,598 sections were made from tissues
obtained from 1,968 subjects. For each of t.he parameters investigated,
pipe and cigar smokers demonstrated significant.ly more abnormal
histologic changes than nonsmokers; horrever, these changes were not
;LS severe or as frequent *as those seen in cigar-et te smokers.

Several retrospective studies conducted in the United States and
other countries have examined the synergistic roles of tobacco use and
heavy alcohol intake on the development of cancer of the esophagus.
Four of these investigations contain data on pipe and cigar smoking
(12, @,6s1 107). It appears that smoking in any form in combination
with heavy drinking results in especially high rates of cancer of the
esophagus.

TABLE 24.--lliorta&! ratios for cancer of th.e esophagus in cigar and
lvipe smokers. A wmmy qf prospective epidemiologica.! studies

Author, reference

ClglU
O&Y

T0W.l   Cigarette
Pfpe=d   OnJY    Mlred
cinar

Hammond and Horn 1 (JO)-   1. 00    5. 00   3.50 _---_- -_   5.06  - _____._
Doll and Hill (ES, 27) _ _ . .   1.00  -_____ -_  -__-_.   2. 00    1. 50    4. so
Hammond (38) __._ -_-__.   1.00 _--__-._  _---__   3. 97   `4.17  __---_._
Kahn (me-. _ ._.__ _-  _ _   1. 00    5. 33    1. 99    4. 05    6. 17  __;e-__-


Sndrwky, ct ul. (77):
  cllscY-*-----.--.~~.~-~--~~~- 104
  Controls __________________.__ 615

Wyndcr, CL cd. (I 13) :
  CUWY~ - - - - __- -- -___--_-___--  30
  Controls _____ _ ___ _ __- _____ __ _  116

Pcrnu (79) :

CRses-.-_------.-...-_-_~--- 202
Controls _____________________ 713

Schwartz, et al. (84) :
  cnsu- --- --__-_--__-________ 249
  Controb __-__________________ 240

Wyndcr nrd Brotls (107) :
cases-..-.--.---..-----.---- 150
  Controb _____________________ 150

Rclativc risk. ___________
Perccn!, cues. _ _ ____ _ __ _
Percent controlj _._____ _.

Rclutivc risk _______ __ ___
Pcrccn t cuscs. _ _ _ _ _ _ . _ _ _
Percent control3 _________

Rclntive risk _____- _ ___ __
Percent crises ___________
Percent controls _________

Rclntive risk ___________.
Perccllt CUSCY _-_____.___
Pcrccnt control3 _________

Rclntivo risk ____________
l'crccnt cnscn- _ _ .______ _
Pcrccnt controb _________

1. 0     4. 8
4      5
13      3

1. 0     3. 1
13      15
24      9

1. 0 _ - _ _ - _ _ _ _
17   _-_______
39   - - - _ - -
    - - _

1. 0  _ _ _ _ - - -
      _ _
2   --___ _-__
18   ___ _- __._

1. 0     3. 0
5      19
15      10

3. 8     5. 1
8      G
7       4

2. 1  _ _ _ _ _ _ - _ _
18 .________
16 -__-____.

3. 0 -. _ _ _ _ _ _ -
7   ___-__-__
5   - _ _ - _ - - - -


2. G - - - - - - - _ -
2   - _ _ - - _ - _ -

9. 0     G. 0
9       4
3       2

3. 8      3. 3
GO       18
53       13


2. 0       . 4
51       3
3G      13

2. 7      5. 0
50       18
50        7

11. 7      8. G
F8       7
67.       7


TABLE 25-Ileldive risk of cancer of the esophagus jor men, comparing cigar, pipe, and cigaretL smokers wiih nonsmokers.
             A summa y of relrospeclive sl dies.--Continued

Author rrf~rence          Number

hllred

Brndshaw and Schonland (1 E) :
  cascs_~--..-_-_~--._---~~--- 117
  Controls _____________________ 366

Martinez (68) :
  Cues...-.---...--.--------- 120
  Controls _____ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  360

Martinez 1 (69) :
  Cases...-.-----.-.---------- 346
  Controls ____________________ 346

Relative risk ____________     1. 0  _________    4. 8
Percent cases ___________    15   _______-..    41
Percent controls _________    32   _________    18

Relative risk ____________     1. 0     2.0 _____--_
Percent cases ___________    8      9   ------ --
Percent controls _________    14      8   __-_---_

Relative risk ____________     1. 0     2. 0     2. 8
Percent casts ___________    21      10      15
`Percent controls _________    22      9       1

______-_    2. 3 _ _ _ _ - - _ _ _
___-__- _    63   _ _ _ _ _ _ _ _ _
_ _ - _ _ - - -    58   _ _ _ _ _ _ _ _ -

__-mme.-     1. 5      2. 2
i - _
_ _ - - _    31       43
_-_____-    34      34

                 2. 5
- _ _ - -
-   -  -     1. 7
-_----- -    34       34
                25
_ - -
- - -  -  -    36


Lung Cancer

Abundant evidence has accumulated from epidemiologic& expeg-
men-l, and autopsy studies establishing that cigarette smoking is the
major cause of lung cnncer. Several prospective epidemiological
studies have demonstrated higher lung cancer mortality ratios for Pipe
and cigar smokes than for nonsmokerS, but the risk of developing lung
cancer for pipe and cigar smokers is less than for cignrettc smokers
Table 26 presents a summary of these prospective studies. Dose-
response relationships such as those that helped demonstrate the nature
of the ass&ation between cigarette use and Iung cancer could not be
as thororlgldy studied for pipe and cigar smokers because of the rela-
tively few smokers in these categories Although the number of deaths
were few, Doll and Hill (96) reported increased death rates from lung
cancer for pipe and cigar smokers with increasing tobacco consump
tion (table 27). Kahn (50) also demonstrated a dose-response relation-
ship for lung cancer by the amount smoked (table 28).

A few of the retrospective studies contained enough smokers to allow
an examination of dose-response relationships for pipe and cigar smok-
ing and lung canccr (I, 61, 74, 77). An increased risk of developing
lung cancer was demonstrated with the increased use of pipes and
cigars as measured by amount smoked and inhalation. The retrospec-
tive investigation of Abelin and Gsell (I) is of particular interest. The
smoking habits of 118 male patients with cnncer of the lung from a
rural area of Switzerland were compared with those reported in a sur-
vey of all male inhabitants of a town in the same region. About 20
percent of the population of this area were regular cigar smokers, the
most popular cigar being the Stiimpen, a small Swiss-made machine-
manufactured cigar cut at both ends with an average weight of 4.5 g.
In this investigation, cigar smokers experienced a risk of developing
lung cancer that was similar to the risk of cigarette smokers. A dose-
response Elationship was demonstrated for inhalation and amount
smoked. These data suggest that the heavy smoking of certain cigars
may result in a risk of lung cancer that is similar to that experienced
by cigarette smokers.

Several pathologists have reported histologic changes in the
bronchial epithelium in relation to smoking in various forms. Knudt-
aon (57) examined the bronchial mucosa of 150 lungs removed at au-
topsy and correlated the histologic changes noted with the history
of smoking, age, occupation, nnd residence. Specimens obtain& from
the six cigar and pipe smokers demonstrated basal cell hyperplasia;
however, there was no squamous or atypical proliferative metaplasia
as is frequently seen in the heavy cigarette smokers.

Sanderud (78) examined histologic sections from the bronchial tree
of 100 male autopsy cases for the presence of squamous cpithelia]

573


metaplasia. In this study, 39 percent of the population ~vre non-
smokers, 20 percent xvere pipe smokers, and 38 percent smoked cig-
arettes. A total of 80 percent of the pipe smokers and cigarette smokers
demonstrated squamous metaplasia of the bronchial tree, whereas only
54 percent of the nonsmokers had this abnormality.

Auerhach, et al. (6) examined 36,310 histologic sections obtained
from 1,522 white adults for various epithelial lesions including:
presence or absence of ciliated cells, thickness or nurnber of cell rows,
atypical nuclei, and the proportion of cells of various types. The
pathologic findings in the bronchial epithalium of pipe and cigar
smokers are compared to those found in nonsmokers and cigarette
smokers (table 25). Pipe and cigar smokers had abnormalities that
were intermediate between those of nonsmokers and cigarette smokers,
although cigar smokers had pathologic changes that in some categories
approached the changes seen in cigarette smokers.

TABLE 26.-Mortality ratios jor lung cancer deaths in male cigar and
     pipe smokers. A summary of prospectice studies

Author. rererence

Hammond and Horn (do)-   1. 00    3. 35    8.50 ____ -___  23. 12    19.71
Doll and Hill (es, 97) _ _ _ _   1.00 _____---  -_----   6. 14   13.29    7. 43
aest(9)________--_-____   1. 00    2. 94    435 __-_---_  14.91  --__-___
Hammond (S8)-----__ _ __   1. 00    1. 85    2. 24   1. 97    9. 20     7. 39
Kahn (60)--- ___________   1. 00    1. 59    1. a4    1. 67   12. 14  - . ..____

TABLE 27.-Lung cancer death rates for cigar and pipe smokers by amount
             smoked-Doll and Hill

s74


TABLE X-Lung cancer mortality rafiosjor cigar and pipe smokers by
              amount smoked-h'ahn

  <5 pipefuls per day-_ ____ -- _____._______
  5 to 19 pipefuh per day--- _____.__.______
  >I9 pipefuls per day __________________._
Cigar and pipe:

8 or less cigars, 19 or Ievs pipefulj---_-----
>8 cigars, > 19 pipefulz ______._______.___

1. 00           78

1. 14
2. Et
2. 07

.77
2. 20
2. 47

1. 62           18
2. 19            2

12
11
2

2
12
3

&mnx: Kahn. H. A. (50).

575


TABLE L?Z).-Relative risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A am-
                 manj of relrospective stwlies

Number ---

Levin, et al. (60):
  Caqca- -_______--_-___-_-____   236
  Control8 ______ ___ _______ -___ _   481

Schrck, et al. (81):
  CRsCS_-..--._...-._------.--    82
  Controls- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _   522

Wynder and Graham (111):
  CaScS--..--.-__...------__--   605
  Controls- - - _ - _ _. _ _ _ _ + _ _ _ _ _ _ _   780

Doll and Hill (%6):
Csses_.-_._.___-..---~~~---- 1,357
Controls _.___________________ I, 357

Koulumies (66) :
Cases----.------------------   812
  Controls--- _ - _ - - - - - - - - - - - _ - _   300

Sadowsky, et al. (77):
  Cases- --__-_.__-____________   477
Controls _____________ jr ______   615

Relative risk ____________
Pcrccnt cfi.qes..- _________
Percent controlv _________

Relative risk ____________
Percent cfws ___________
Percent controls _________

Relative risk ____________
Percent cases- _ _________
Percent controls _________

Relative risk ____________
Percent cases ___________
Percent controls _________

Relative risk _____.______
Percent cases ___________
Percent controls-.. _ _ _ _ _ _ _

Relative risk _______.____
Percent casc3 ___________
Percent controls _________

1. 0     0. 7
15     11
22     23


1.0      .6
15      4
22     23


1. 0     5. 1
1      4
15      8


1.0  --- .._-__
  5  --m-w_-__
5' .- -.---__

1.0  -- -______
.G ---_-_-__
18   e--v be__ _


1. 0     2. 4
4      2
13      3

0. 8  - _ - _ - - -. .
14 -_--_-___
25   _ _ _ _ _ _ _ _ _

5' 7 --.-____.
   - _ - - _ -. _ _
11 -_.._____

3.6 ____.____
4   --a----_-
12 --- --.__-

2. 1  _ I - _ - _ _ _ _
GG   - - - - - _ - _ _
44   _ - _ _ _ _ _ _ _

1. 7  - -
    _ _ - -, -. -
61   _ _- --- __-
50   - _ - _. _
     _ _.

15.7  --.---__-
91   ________.
65   --- -*-__-

9. 6  _. _ - _ _ - _ _
74   - - - - _ - _.
        -
69   . _ _ _ _ _ _ _ _

3. 7      5. 6
57      31
53       13


Wyndcr and Cornfield (I IO) :
  CIL~CS. -_ - - -- - -_ --- __________    63
  CAmtrolu ____. . ____ _ ________ _ _   133

Rnndig (74) :

  CLWS _ _ - - _ - - - - - - - - - _. _ - _ _ _ - _   415
  Controls _____________________   381

hlills and Porter (66):
  CNCS_.---.._--..-----------   444
  Controls ___-_-------- _----___   430

hlills and Porter (66) :
  Crises--.---..--..----.._-..-_   484
Controls _____________________ 1, 588

Schwartz and Dcnoix (8%) :
  Cnses.-...-.----...-~-------   430
  Controls... _ _ _ - - _ _ __-_ __ _ ____   430

Stocks (89) :

CNes~_~_-_.---.-.-~-------~ 2,101
Cuntrols ______________-______ 5, QGO

Lombard and Sncgircff (61) :
  CuJCS------.-----..------.--   500
Contruls.... ---_____-_.___.__ 1, 839

   I'ern11 (73) :

cn    GLW. - __-- __________.______ 1,477
:     Guilrols... _ _ __ __ __ _ __ i ______   713

Relative risk ____________
Pcrccnt CNCY-- _________
Pcrccnt controls ______-__

Relative risk ______ ______
Percent cases- _ _________
Percent controls _________

Relative risk ___________.
Percent cases ___________
Percent controls _________

Relative risk ____________
Percent cases ___________
Percent controls _________

Relative risk __._________
Percent case3 ___________
Percent controls _______-_

Relative risk ____________
Percent cfws ___________
Percent controls _________

Relative rivk ____________
Percent cfuea-. _________
Percent controls .________

Rclntivc risk.--* _________
Percent craw --_________
Pcrccnt control8 -_-______

1. 0     2. 5     4 0  - - - - - - _
                     _ -
4      13      6   _-__-_-__
21     27      8   - - - - - _
                  - -
                      -

1. 0     5. 3     5. 0  - - - - - -
                   -  -  -
1      21      11   -------_-
6      19      11   -----_.__

1.0  _---__--_  ---___-_    0.0
7   ------_-_  ----_-__   37
3i _________ ________    26

1.0  __--___--  _---I--_    2. 8
8   ----e-e--  ------__    13
28 _________ ________ 1G

1. 0  - - -. _
     _ -
       _  _     4. 7  - - - -
                   _ _.  _ _
1   ---- --__-    6   .__-._-__
11   --_---_-_    14   -________

1. 0 _ - - - - - _ - -    3. 1  - - _ _ _ _ _ _ -
2   --e.m-_--    9   _- ____._ _
9   -*m-----_    13   _ _ _ - _. - _ -

1.0  --_-___--  _---_--.     1. 7
2   o-_-mm-__  _-_-__--     4
10   _--.--__-  ----_-_.    15

1.0 -_----_ *_    4.2 _-__.____
7   -----em_-    4   --___-_-_
39   - - _ -
     - _  _ _ -    5   ----____-

8.5 _________
77   _ _ -_ _ _ _ _ _
4s -_--- _-__

5. 0  - _ _ _ _ - _ _ _
67   - - - - - _ _ _ _
64   - _ _ _ _ - _ _ _

5.4 _________
5s   - - - - - - _ _ _
43   _- --_ _ - - _

4. 5  _ - -. _ _ -. _
78   - _ _ - - _ _ _ -
57   _ _ - -. _ _ _ _

13. 5 _----_.__
90   _ _ _ - - _ _ _ _
78   _ _ - - - - - _ -

5. 0  - - - - - - - _ _
80   _ _ _ _ _ _ _ _ _
76   _ __ __ _ -__

8. 1 ---___- __
Qj ______ ___
75   -- _ __ --_.

9. 2     Il. 1
77       13
SO       7


TABLE 29 .-Relutive risk oj lung cancer for men, conparing cigar, pipe, and cigarette smoker8 with nomokcrs. A e-urn-
               maq of relrospective hulks--Continued

Wickcn (f&j):                .Relntive risk ____ __ _ _ ____
Cases---.-..-.--_-.~.-....---.                        1.0  ---------  -_------    2. 2     4. 3      4. 2
                       803  Percent cB9ea
  Controls                                 ___________     4   _________  ________    10      78       7
         __-__-_________________ 803  Percent controls _________ 14 _________ ________ 16      G4       G

Abelin and Cscll (I):             Relative risk ____________
Cascs--.--..---.~---~.......-.                         1. 0    30. 7    21. 8    39. 9    31. 0     24. 7
                       118  Percent ca3e9.
  Controls                                  ____-_____    2     28      7      68      25      24
        __-_---________________ 524   Percent control8 -________    35      19      G      31      17       10

Wynder, et al. (116) :
cases---..----__.........-....    Relative risk -___________    1.0  ___---__-  ---_-.--    2.0    12. 4  _ --.--___
                       210  Percent cases.
  Controls                                  _-__._____    3   ___._____  __._____    5      92   _. - - - - _ - _
        __._____._ ______FC_____ 420  Percent controls.Sm, __.__    21   ___..____  ________    15      47   - -. . . -
                                                                           - - _


TABLE 30.- Changes in bronchial epithelium of male cigar, pipe, and cigarette smokers as compared to nonsmokers

1st set (none vs. pipe vs. cigarette-matched
on 1 :I basis) :

  Nonsmoker- _ _ _ _ _ ___. _ __ _ ____ __ _ ___ ____
  Pipe only___--.--_......---------------
  Cigarette only _________________________
2d set (none vs. pipe VB. cigarette-matched
on frequency basis) :

  Nonsmoker.-- _______ _____ __ _ ___ __ _ __ _.
  Pipe only ______________________________
  Cignrcttc only-. _ ______________________
3d set (none vs. cigar va. cigarette) :
  Nonsmoker-- _ _ __ __ ___ _ __ _ _ _______ ___ _ _
  Cigar only _____________________________
  Cignrcttc only __.______________________

20
20
20

25
25
25


35
35
35

985
924
914

1, 24G
l,lG4
1, 12G

22. 9      13. 4      .7    1, 277
G8. 7      38. 7     38. 2    1, 247
96. 3      88. 7     89. 5    1, 237

1,70G      27. 4
1,733      90. 8
1,520      91. 0

21. 7
G5. 5
96. 8

11. 2      2. G    1,031       10. 3
38. 1     37. 0      079       35. 0
88. 6     95. 2      082       72. 1

12. 7      .8    1, 748
40. 0     73. G   1, 8'28
92. 7     97. 8   1, G33

11. 5
37. 9
75. 5

15. 3
52. 5
80. 2

8ourm: Auerbach et al. (8).


Tumorigcnic Activity

The tumorigenic activity of tobncco smoke can be modified in both a
quantitative and qualitative sense. Physical or chemical changes in
tobacco that. result in n reduction of total particulate matter upon
combusion of a given quantity of tobacco may result in a reduction
of carcinogenic potcntinl. Such factors as tobacco selection, treatment,
blending, cut, and additives may quantitatively alter tar production.
Wrapper porosity and filtration may also affect tar production.
Quantitative changes in the tumorigenic-activity of tobacco tar on
a gram-for-gram basis can be produced by the selection and treatment
of tobacco, the use of additives or tobacco sheets, or adjustments in the
cut and packing density.

Combustion temperature can also produce quantitative changes in
the particulate matter of tobacco smoke. Although high-temperature
burning produces less particulate matter in the smoke, it appears that
tumorigenic components occur in higher concentration xhen tobacco is
pyrolized at temperatures higher than 700" centigrade (34).
Cigars, pipes, and cigarettes 5re similar in that they are smoked
orally and have a common site of introduction to the body. The tissues
of the mouth, larynx, pharynx, nnd esophagus appear to receive np-
proximately equal exposure to the smoke of these products. Inhalation
causes smoke to be drawn deeply into the lungs and also allows for
systemic absorption of certain constituents of tobacco smoke which
then can be carried further to other organs.
Pipe tobacco and cigars vary from cigarettes in a number of charac-
teristics that can produce both quantitative and qualitative changes in
the total particulate matter produced by their combustion. Experi-
mental evidence suggests that although there is some difference in the
amount and quality of tar produced by cigars, this cannot account for
the reduced mortality observed in cigar smokers compared to cigarette
smokers.
          Experimental Studies

Several experimental investigations have been conducted to examine
the relative tumorigenic activity of tobacco smoks condenslttes obtained
from cigarettes, cigars, and pipes. Most of these studies mere standard-
ized in an attempt to make the results of the cigar and pipe experiments
more directly comparable with the cigarette dat.a and most used the
sl~aved skin of mice for the application of tar. Tars from cigars, pipes,
and cigarettes were usually applied OJI an equal n-eight. basis SO that
qunlitntire differences in the tars could be determined. In several ex-
periments. the nicotine was extracted from the pipe and cigar conden-
sates in an attempt to reduce the acute toxic effects that resulted in
nnimals from the high concentrations of nicotine frequently found in
these products.

580


JT'ynder snd ITtight (117) examined the diflerences in tumorigenic
acti\-ity of pipe and cigarette condensates. Tars mere obtained by the
SmokiIjg of 3 pop~ll3r br:~rd of king-size cignrettcs and the same +a-
rette tc)bncco snloked in 12 standard-grade briar bon-1 pipes. not11 the
cigarettes :trld pips were putfed three times a minute Ath a Q-second
putf and a 35-m]. I-oltrme. Both the cigarcttcs and pipes attnincd similar
masimum combustion zone temperzturcs, . hone\-er, the use of cigarette
tobacco in the pipe resrtlted in a combustion chamber temperature that
averaged about 150" centigrade higher thnn temperatures achieved
when pipe tobacco was used. Chemical fractionation wss accomplished
and equal concentrations of the neutral fraction were applied in t.hreo
weekly applications to the shaved skin of C-IF', and Swiss mice. The
results indicatet,hat. neutral tar obtained from cigarette tobacco smoked
in pipes is more active than that obtained in the usual manner from
cigarettes. About twice as many cancers acre obtained in both the CXF,
and the Swiss mice, and the latent period x-as about 2 months shorter.
Extending these data, Croninger, et al. (20) csamined the biologic
activity of tars obtained from cigars. pipes, and cigarettes. Each form
of tohacco was smoked as it was manufactured in a manner to simulate
human smoking or to maintain tobacco combustion. Tlw ~rlrole tar was
    .
nppired m drlutlons of one-to-one and one-to-two mith acetone to the
shaved backs of female CAF, and female Swiss mice using three
    .
npplwattonseach creek for the life-span of the animal. The nicotine was
estracted from the pipe and cigar condensates to reduce Lhe acute
toxicity of the solutions. The Swiss mice. pipe, cigar, and cigwette tars
produced both benign and malignant tumors. The incidence rates of
malignant tumors given as percents were: 44,41, and 37, respectively.
These results suggested a somewhat higher degree of carcinogenic
activity for cigar and pipe tars than for cigarette tar.
Similar results n-we reported by Kensler (53) who applied conden-
sates obtained from cigars and cigarettes to the shaved skin of mice.
The incidence of papillomas produced bv cigar smoke concentrate was
no diff'emnt from that of the cigarette"smoke condensate. Similarly,
there xas no diBerence between cigar and cigarette smoke condensates
when carcinoma incidences xrere compared.
fJombur,oer, et al. (45) prepared tars from cigar, pipe, and cigarette
tobaccos that were smoked in the form of cifarettes. In t.his way, all
tobaccos were smoked in an ident.ical manner and uniform combustion
temperatures xere achieved. Because of this standardization, differ-
ences in tumor yield could be attributed to tobacco blend and not the
manner in which the tax-s were prepared. The whole tar-s mere diluted
one-to-one with acetone and applied to the shaved skin of C.iF, mice
three times a ireek for the lifespan of the test animal. Skin cancers
XWTT produced more quickiy Kith pipe and cigar smoke condensates
than with cigarette smoke condensates. This suggests that the smoking
    495-028 Q-73-15

                                       581


of pipe and cigar tobaccos in the form of cigarettes does not alter the
condensates to any significant degree.

Davies and Day (32) prepared tars from small cigars especiallY
manufactured from a composite blend of cigar tobacco representing
small cigar ,bmnds smoked in the United Kingdom, cigarettes espe-
cially manufactured from the same tobacco used for the cigars de-
scribed above, and plain cigarettes especially manufactured from a
composite blend of flue-cured tobacco representing the major plain
cigarette brands smoked in the United Kingdom. The whole tar was
dilut& to four concentration levels and applied to the shaved backs
of female albino mice for their lifespan using four dosing regimens.
A statistically significant increase in mouse skin carcinogenicity was
shown with the cigar smoke condensate compared Kith the tars
obtained from either flue-cured or cigar tobacco cigarettes. These
results are consistent with those of the previously reported
investigations.

The effect of curing on carcinogenicity was examined by Roe, et al.
(76). Bright tobacco grown in Mexico WIS either flue-cured or air-
cured and bulk fermented. Both flue-cured and air-cured tobaccos were
made into cigarettes standardized fordraT resistance and were smoked
under similar conditions. Condensates from these cigarettes rrere ap-
plied to mouse slain three times each \yeek in an acetone solution. The
development of skin tumors was higher in mice treated with the flue-
cured condensate than in mice treated with the air-cured condensate
(P<O.Ol). The difference may have been due to the use of equal
weights of condensate rather than the use of extracts from an equal
number of cigarettes. The air-cured cigarettes produced a greater
weight of condensate than did the flue-cured cigarettes. -4 chemical
analysis of the two tobnccos and txo condensates revealed only small
differences in composition. Evidently air curing of Bright tobacco
in the method used is not associated n-it.h a loss of reducing sugars.

A more detailed analysis of these experimental studies is presented
in table 31.

These experimental data suggest that cigar and pipe tobacco con-
densates have a carcinogenic potential that is comparable to cigarette
condensates. This is supported by human epidemiological data for
those sites exposed equally to the smoke of cigars, pipes, and cigarettes.
The partially alkaline smoke derived from pipes and cigars is gen-
erally not inhaled, and as a result there appears to be a lower level
of exposure of the lungs and other systems to the harmful properties of
pipe and cigar smoke than occurs with cigarette smoking. It is antic-
ipated that niodifications in pipe tobacco or cigars which would result
in a product that eras more readily inhalable would eventually result
in elevated mortality from cancer of the lung, bronchitis and emphy-
sema, a*riosclerotic cardiovascular diseases, and the other condi-
tions =hich have been clearly associated with cigarette smoking.

582


TABLE 31 .-`hmorigenic a&wily oj cigar, pipe, and cigareh smoke condcnsatcs in skin painting experiments on animals

[Key: A-Mathod. B-Fraquoncy. C-Durotlon. D-hlntcrid.]

hnlmal

ACtlPlty

Wynder and   CAF, and     A. Painting shaved skin.
Wright       Swiss mice.   B. 3 times a week.
(117).             C. Lifcspnn (24 months).
                 D. Ncutrnl fraction tnr from
                    cignrcttcs nnd cignrcttc
                    tobacco smoked in pipes.

Croningcr, ct   Fcmnle Swiss   A. Painting shaved skin.
nl. (PO).       mice.       B. 3 times n week.
                C. Lifespnn.

D. Whole tar diluted in
   acetone.

&x&r (63)- __ Swiss mice ______ A. Painting shnvcd skin.     Cignr tnr (J) 100 mg. per neck--
                   13. 3 times n week.        Cignrcttc tnr (G) 100 mg. per
                C. Lifespan.               \vcck.

D. Whole tar diluted in
   ncetone.

Cignrctte tar (E) 100 mg. per
week.

CAF,:

I'ipc (cignrcttc tobacco)-----.
Cignrcttc--.-....-.---------
swivs:

30     GO
30     30

I'ipc (cignrcttc tobacco)- _ _ _ _ _
Cignrcttc ____ ______ __ ___ __ _ _

30     63
30     63

Cignr, nicotine free (1:l) _______    4G     05
Pipe, nicotine lrcc (1 :l) _ ____ ___    45     71
Cignr (1:2)- _ ______________.__    78     33
Pipe, nicotine free (1:2) _ _ _ _____    60     30
Cignrcttc (1 :l) _______________ _    86     47
Acctonc cohtrolr ____ _____ _ ____     23      0

100     42       41
100     40        23

100     34

20
3

50
33

4 I
4 ,I
18
IC
37
0

3.1


TABLE 31 .-Tumorigenic udivily oj cigar, pipe, and cigarette smoke condensatea in akin painting
            experiments on animads-Continued
               (Key: A-blerhcdd. D-Fre~uancy. C-Durallon. D-hlslorld.]

Homburgcr, et
al. (46).

Davies and
Day we).

Roe, et al.
(76).

CAF, mice ------ A. Painting shaved skin.
        B. 2 to 3 times a week.
        C. Lifespan (2 years).
        D. Whole tar diluted 50 per-
              cent in accttrnc.

Female albino   A. Painting shaved skin,
mice.       B. Vericd.
          c. 11G WC&s.
        D. Whole tar in 150 mg.
                acetone.

Fcmnlc Swiss   A. Painting shaved skin.
mice.       B. 3 times a week.
        C. Lifespan.

D. Whole tar diluted in
   acetone.

Cigar tobacco cigarettes 165 mg.
per week.

Pipe tobacco cignrettes r 64 mg.
per week.

Cigar&es 1 62 mg. per week- - -.
Acctonc controls- - -- .---- -----

Cigurs, smnll 83 mm. long 150
per week.

Cigar tobacco cigorcttes 150
per week.

Cignrcttcs 150 per week -------.

Flue-cured Bright tobacco 180
mg. per week.
Air-cured Bright tobacco 180
mg. per week.
Acetone controls 0.75 cc. per
week.

100     37. 5     18


100     23       20


100     15       23
100      0        0


144     44       27


72     32       14


144     28       13


400     52       30


400     68       23


400      1. 3      0. 6


The majority of deaths in the United States each yenr are due to
cardiovascular diseases. Cigarette smoking has been identified as a
major risk factor for the development of coronary heart disease
(CIID). Hoffever, pipe and cigar smokers experience OI~~Y a small
increase in mortality from coronary heart disease above the rates of
nonsmokers. Cigarette smokers have higher death rates from cerebro-
vascular disease than nonsmokers, mherens pipe and cigar smokers have
cerebrovascular death rates that are only slightly above the rates of
nonsmokers. Table 32 summarizes the major prospective epidemiologi-
cal investigations that examined the association of smoking in various
forms and total cardiovascular diseases, coronary heart disease, and
cerebrovascular disease. Doll and Hill. (28)) Best (9)) and Kahn (59)
examined dose-response relationships for pipe and cigar smokers and.
reported a slight increase in mortality from coronary heart disease
with an increase in the number of cigars or pipefuls smoked.

Other prospective epidemiological studies have also examined the
relationship of smoking in various forms to coronary heart disease and
related risk factors- Jenkins, et al. (@) in the Western Collaborative
Group Study of coronary heart disease, reported an incidence of coro-
nary heart disease in men aged 50 to 59 Kho were pipe and cigar smok-
ers that was intermediate between t.he rates seen in cigarette smokers
and nonsmokers. No increase in incidence of coronary heart disease was
seen among the pipe and cigar smokers in the younger age groups.
Shapiro, et al. (G), in a study of the health insurance plan (HIP)
population, reported incidence rates for rnyocardial infarction, angina
pectoris, and possible MI, in pipe and cigar smokers that rrere similar
to the iucidence rates seen in cigarette smokers. These rates were con-
siderably higher than those of nonsmokers. Data from the pooling
project (47) suggested that the incidence of CHD deaths, sudden
death, and the first major coronary event in pipe and cigar smokers
ras intermediate between the incidence experienced by cigarett,e smok-
ers and nonsmokers. In contrast to these-studies, Doyle, et al. (30)
reported no increase in CHD deaths, rngocardial infarction, or angina
pectoris in pipe and cigar smokers over the rates of nonsmokers in the
Framingham study.

The retrospective studies of ;Ilills and Porter (64)) Villiger and
+-den-Suchy (ZOb), Schimmler, et al. (80), and Hood, et al. (46)
contained data suggesting that pipe and cigar smokers experience
mortality rates from coronarv heart disease that are essentially similar
to those experienced by ciga;ette smokers. The retrospective study of
Spain and Sathan (86) reported lower rates of coronary heart dis-
ease in all smoking categories than mere found in nonsmokers.

Van Puchem (IOJ) and Damber, et al. (23) examined serum choles-
terol levels in groups of individuals classified according to smoking

585


habits. In these two studies. pipe and cigar smokers had serum choles-
terol levels that xere nearly identical rrith the levels found in
nonsmokers

Tibblin (9~) and Darrber, et aI. (23) investigated the effect of smok-
ing on blood pressure. The proportion of smokers decreased in groups
with higher blood pressures, although this Ka.s not as drnmntic for
pipe and cigar smokers as it was for cigarette smokers.

In an esperimental study using anesthetized dogs, Kershbaum and
Bellet (54, 55) examined the etIects of inhaled and noninhnled ciga-
rette, cigar, and pipe smoke on serum free fatty acid levels and urinary
catecholamine and nicotine excretion. In this study, inhalation of to-
bacco smoke from all these sources resulted in similar increases in
serum free fatty acids and in catecholamine and nicotine excretion.

TABLE 32.---Mol-lality rutio.s for cardiwascuhr death in male cigar and
p;pe smokers. A summary of prospectice epidmiological studies

Hammond and
Ham (&I).

Doll and HiU
(26, 27).

Hammond J
(38).

Cardiovascular 1.00  1.26  1.07 ______  1.57 -___-_
total.
Coronary ____ -- _____ 1.00  1.28  1.03 __-___  1.70 ______
Cerebrovecular _.___ I. 00  1.31  1. 23 ____ -_  1. 30  ______
cardiov~culsr 1.00 _____  ____._ 0.99  1.26 1. 13
total.
Coroaarp .__._.--._- 1.00  ----_  ___-__ .94  1.23 1. 18
Cerebrovascular _.__- 1. 00  .___  ______ . 95  1. 13 97
Cardiovascular 1. 00  1. 14   .95 ______  1.52 _____ -
total.
chronar)--~- ___---_- 1.00   . 99  1.00 ______  1.60 ___-__
Cerebravascular-, _ - . 1. 00  1.28    85 ----__
Cardiovascular 1.00 --.__ --:__- 1.06   88 ______
                  ,190  --_-__
total.
Coronary- ____._____ 1.00  1.35  1.19 -- ____  1.84 1. 58
Cerebrovascular 1.00
           _____      _____  -_-_--  1. 09  1.41 1. 40
Cardiov~cular 1. 00  1. 05  1. 06 1. 05  1. 7.5; _____ -
total.
Chmnar~--~-~-~--~~1.00  1.04  1.08 1.05  1.74 ______
Cerebravascular _____ 1.00  1.08  1.09 1.06  1.52  _--___

CHROXIC OBSTRUCTIYE PELJIOS.IRY DISEASE (COPD)

Chronic bronchitis and pulmonary emphysema account for most of
the morbidity and mortality from chronic respiratory disease in the
United States. Cigarettesmokers have higher death rates from these

586


discsses :~nd hnw more pulm6nnry symptoms and impaired pul-
monary function than ~lonsmokrn. C'il,`arcttc w~oli~~rs 31~0 hnvc more
frequent and more sewrc rcspirntoq- illfcctiolls fll:111 nonsmokers.
Tile relationship between smoking pipes and ciz:l1-; anti these discnses
is summarized in this chapter. The major prospcctiw cpiderniological
studies are surnmarizcd in table33.

In a retrospective study of 1,189 males and matched controls in
Sorthern Ireland, \Vicken (206) invrsti,rr:ltctl snloliirlz in various
forms and rnortn1it.y from bronchitis. `~`hc rcIati\-e risk ratios com-
pared to nonsmokers for mortality front chronic broncllitis were 1.9~
for all stnokrrs. 1.55 for pipe and cigar SII~O~CIY, 2.35 for cigarrttc
sr~~okers, and 1.49 for miscd smokers.

From a re\-iew of these prospective and rctrosprctil-c studies. it
appears that pipe and cigar sn~okers espcricncc mortality rntcs from
bronchitis nnd cmpl~~serna that arc higher than the rntcs of non-
smoker;. .\lthough these morality rates approach those of cigarette
smokers. iu most instances they are intcrnlcdiate bctlrccn the rates
of cignrctte smokers and nonsmokers.

Pipe and cigar smoktrs hare significantly more rrspirntory symp-
torns and illnesses than nonsmokers. Those stildics which contain dntn
on pipe and cigar smoking as related to rcspimtory symptoms are
summarized in table 34.

Only a ferr studies have examined pulmonnry function in pipe and
cigar smokers. There appeals to be little diifcrcncc in pulmonary func-
tion x-alues for pipe and cigar smokers as compared to nonsmokers
(table 35).

Xneve (67) conducted :m autopsy study on 322 L1ppa.Iachian coal
workers n-ho were classified according to the t.ypc of coal mined and
tobacco usage. Emphvserna was slightly r grenter in cigarette smokers,
3s lrere n&tomic evidences of chronic bronchitis and bronchiolitis.
Those changes found in pipe and cigar smokers were intermediate
between those of cigarette smoking miners and nonsmoking miners.

Changrs in pulmonary his%oIogy in relation to smoking habits and
age wxe examined by .Xuerbach, et al. (8). Fibrosis, alveolar rupture,
thickening of the walls of small arteries, and t,hickening of the w&
of the pnImonar~- arterioles xrerc found to be highly related to the
srnokin,rr habits of the 1,:X0 male subjects examined. The 91 pipe and
cigar smokers o\-cr the age of 60 were found to have somewhat more
al\-eolar rupture tllan the men of the same age distribution who ncvcr
smokrd rcgularl~-. Ilox\-el-cr. pipe and ciK:Rr smokers as a group had
far less rupture thn cigarette srnokcrs. Tl~snure relationsas described
above 1ve12 found for fibf-osis, thiclicning of the walls of the arterioles
and s111nl1 arteries, 21rtl padlike nttnchlllcrits to tlte al~colar scptunls-

`robacco SIIIO~C 11~1s bf2e11 sho\rn cs~vxi~lwritnll~ to hat-e a cllio5tatic
elTcct on the rcsI)inltor\- rpithelium. `I'JIc inter\-:11 Iwtwen puffs, the

587


amount of vdatile and particulate compounds in the smoke, and Ihe
exposure r-olumc ha\-c been shorrn to influrnce the tosic etfect of
tobacco smoke. Daihamn and l?>-lander (2~) exposed the upper trachea
of nnesthetized cats to the snloke of cigarettes and cigars, ohsem-inc
the etiect on ciliary acti\-ity through an incident-light microscope.
-1 chemical analysis of the was and particulntc phases revealed that
the cigar smoke was more alkaline and, in general, contained higher
concentrations of isoprenr. acetone. acetonitrile, tolurne. and total
particulate matter compared to cigarette smoke. The awrage number
of puffs required to arrest ciliaq; activity was found to be X3 for the
cigarette smoke and 11-1 for the cigar smoke. The difference is statisti-
cally significant (P <O.Ol). Of the two smokes, the smoke with the
highest concentration of volatile compounds was found to be the least
ciliosbatic. This suggests that the dcrme of ciiiotosicity of a smoke is
not necessarily correlated to tile level of one or several of thesubstances
found in the smoke.

Pnssey, ct. al. (70. 72, 72) studied the cffcct of smoke from A ue-cured
cigarette tobacco ciKnrettes and air-cured cigar tobacco cirnrettes on
the respiratory system of rats. In two separate but similar experi-
ments, a total of -IS animals were exposed to English cigarette tobacco
smoke, 48 were exposed lo air-cured cigar tobacco smoke, and 12 rrere
exposed to an air-cllr.cd I$llrlev tobacco smoke. The rats in groups rrere
exposed to the specific smoke in a smoke-filled cabinet. Animals ex-
posed to the sl~lol<e froul air-curvd tobaccos wmaincd healthy through-
out the csprriments, cwn at high lerels of smoke exposure. The three
deaths that. occurred within this group were from nonrespiratory
causes. In both experiments, the rats exposed tocigarette tobaccosmoke
began to die \\-ithiu 1 or 2 months. and in each experiment most of the
animals died withiu a week or tKo of the first deaths. At autopsy the
rats exposed to flue-cured tobacco smoke on gross examination were
found to have greatly enlarged lungs, the trachea was often full of
mucus, and there was evidence of pneumonia. On microscopic exarnina-
tion it was found that the trachea and bronchi contained purulent
cellular exudates, evidence of metaplastic changes, an absence of cilia,
and goblet cell hpyerplnsia. Typically, the cause of death was a lobar
or bronchopneumonia. The author concluded that, "the smokes of flue-
cured tobaccos are more dangerous to man and to atiimals t.han those
of air-cured tobaccos."

588


Unfortunately, few details rrere published concwning the method
used to expose the animals to the diifewnt t>.prs of smoke. The frc-
quency and duration of exposure rrcre not specific(l. x:d the cxtrnt of
actual inhalation of smoke by the different qoups of rnts was either
not determined or not reported. It is also diflicult to determine the
effect of smoke exposure on the frequency and severity of respiratory
infections when animals are exposed to smoke in groups where common
exposure occurs. The rat strain used was not identified. but it. XIS
noted that anim:& appeared to suffer from an endemic rat bron-
chiectasis. It is not knon-n to what extent epidemics of respiratory
infections occurred among these animals. Because of these difliculties,
no firm conclusion cnn be drawn concerning the effect of smoking flue-
cured or air-cured tobaccos on the incidence of respiratory infections
in rats.

TABLE 33.-hfortality ratios jor chronic obstructive pulmonary deaths
in male cigar and pipe smokers. A summary of prospective epidtmio-
logical studies

Hammond aud
Horn (40).

DoU and Hill
(es, 27).

Best (9).-----

Hammond (58)

Kahn (60)--.-

corn tot&l-_-_--_-  ----  --.-_  .----  --..-  .-----------
Emphysema_- ______  I. 00  3. 33   .7.i - _.__  5.85 _---.-
Bronchitis--___--_--  1.00  3.57  2. 11  _-___  Il.42 ______

COPDtotEL~~-----  ----  -----  -----  --_--  _-__-__--___
Emphysema__--__--  1.00 - ____  __--_  1.37 `6.55 ______-
Bronchitis._--.-_--_ .___ _____ ___-_ __-_- __--_-____-:

COPD total_ _______  1.00    79
Emphysema _____ -__  1.00 1: 24  2.36    99 10.08 ___.__
                        2. 13 1: 31  14. 17 ______
Bronchitis_--_---_-_  1.00  1.17  1.28  1.17  4.49  ._____

49SO28 S-73-16

589


Booeke (10).-e Pnrents of 59
           femilies.

Edwards, et   1,737 male
al. (3s).     outpstienta.

Ashford, et   4,014 male
d. (4).      workers in 3
           Scottish
          collieries.

Bower (If)_-_ 95 male bank
         employees.

Wynder, et al.  315 male pa-
(114).       tienta in
          New York
          and 315 male
        patient3 in
          California.

Densen, et al. 5,287 tie    Persistent cough- _
(24).      p&d and    Persistent
         7,213 male     aputum
           tramlit       production.
          workers in    Dyspne.... ______ .
          New York    Wheeze ________ --_
        City.      Chest illness-_--~-

7    11
11    16

16    19
14    21
13    16

Cederlof, et  4,379 twin pairs,  Cough- _ _ _ ___ __ __    4
al. (18).     au U.S.    Prolonged cough-_-    2
            veterans.     Bronchitis- _ _ _ __ __    2

Rimington   41,729 male
(76).       VOlUnteerS.

Cagh ____________
Sputum
production.
Chest illness~-~~~~

Chronic bronchitis-   17   `19

Bronchitis--_-----   10   ' 35    21     37
Pneumoconiosi3_~_-   11   ' 34    14     2

Cough _____ - ______
sputum
production.
Wheeze--------__-
Chest ilines_-__--

Cough (New
York).
Cough
(California).
Influenza (New
York).
Influenza
(California).
Cheat illness
(New York).
Chest illness
(California).

Chronic bronchitis_    5

32
24

5

0     0
8    15

8
1.5

14

22

11

28    24

9

7

32
I .5


4

31
54

33

30

21

10


6

7
4
3


`9

48 ______
20  ----__


5  -____-


31     14

29  -___--
33 _--_-_


33  -_-___
40 __-___


56    51


67     66


24 -_.___


31  ______


12 ___.__


11  ___---

25 ______
26 ___---

26 ______
32 --____
18  _-____

17 -_____
11  ______
10 ___---


17 ___---

590


TABLE 34.-Credence of req-iratoq symptoms and iUness by type of
           smokieontinued

Camstock, et   670 male tele-   Persistent cough.-   10    16    41  -____-
al. (19).     phone     Per$stent          13    20    42  _-__-_
         employees.     sputum.
                 Dyspnes ____ - ____   33    39    44 -___-_
                    Chest illness in      14    18    20  ----__
                   pnst 3 years.

Lcfcoc and   310 male phy-  Chronic respira-      9    18    44  ---___
rTonnncott    sicisns in      tory disease.
(69).       London,     Chronic bronchitis-    1    12    34  -__-__
            Ontario.     Obstructive lung     1     3     4 ______
                        disesse.
                    Asthma-- ________    7     3    6  __-_--
                       Rhonchi ._________    0     3     9 ._____

TABLE S5.--Pulmonary junction L&U&S for cigar and pipe smokers as
           compared to nonsmokers

FUIlCllOIl

      Ty-pe of moklng
Non-   Total pipe Clgarettt  Mixed
smoker   and cigar   OdY

A&ford, et
al. (4).

Goldsmith,
et al. (37).

3,311 active
or retired
longshore-
men.

Cornstock,
et al. (19).

Lefcoe and
Wonnecott
(69).

4,014 male
workers in
3 Scottish
collieria3.

670 male
telephone
employees.

310 male
physicians
in London,
Ontsrio.

FEV,.o--__-_m   3. 39   ' 2.59    3. 14   2. 62

Puffmeter ____  313. 63  299. 26  303.44  - _____
FEV,.o .______   2. 99    2. 80    2.91  __--_-
TVC-_-__----   3. 87    3. 68    3.88 ---___
                                -_

FEV,.e----e-e   3. 12    3. 26    2.82 ___-_-

FEV,.o .______   3. 39    3. 17    3. 11  ______
MSIFR liters    4. 09    4. 17    3.64  ______
per second.

591


GASTROISTEXTISAL DICOFCDERS

Cigamtta smokers have an increased prevalence of peptic ulcer
disease and a greater peptic ulcer mortaIity ratio thnn is found in
nonsmokers. These relationships are stronkyr for gastric ulcer than
for duodenal ulcer. Cigarette smoking a ppfars to reduce the elIectire-
ne.ss of standard peptic ulcer treatment regimens and slob-s the rate
of ulcer healing. Cigar and pipe smokers experience higher death
rates from peptic ulcer disease than nonsmokers. These rates are higher
for gastric ulcers than for duodenal ulcers but are somewhat less than
those rates experienced by cigarette smokers. Table 31 presents the
mortality ratios for ulcer disease in cigar and pipe smokers as reported
in the prospective epidemiological studies.
Retrospective or cross-sectional studies by Trovvell (.95), Allibone
and Flint (2), Doll, et al. (2.9), and Edwards, et al. (39) contain
data on ulcer disease in pipe smokers as well as cigarette smokers. So
nssocintion was found betrreen pipe smoking and ulcer disease in these
inrestigations.

TABLE 36.-Aforta&Ly ratios for peptic ulcer disease in male cigar and
     p.pe smokers. Summary of prospective studies

Type 01 smoking

Hammond and   Duodenal ulcer-_- _ _ _ 1. 00  0. 25  1. 67 _ _ . . . . 2. 16 ~. -. . -
Horn (40).
Doll and Hill   Gastriculcer~.~.---- 1.00 _____ -_-.. 4.00 7.00   5. 30
(26, 27).

Hammond (.?8)_- Gastric ulcer- __.____ 1. 00 ---- -  -___- 2.04 2.93 . ..- --
         Duodenel ulcer .____ - 1. 00 __-__ --..- .92 2.86 .-----
Kahn (60) ______ Gastric ulcer--- _____ 1.00 2.90 2.84 2. 48 4. 13 ------
        Duodenalulcer ._____ 1.00 1.58 1.59 1.39 2. 98 ------

Little Cigars

In the past year, several new brands of little cigars (vveighing 3
pounds or less per 1,000) have appeared on the national market. These
cigarette-sized products are manufactured, packaged, advertised, and
sold in R manner similar to cigarettes. Little cigars enjoy several legal
advantages over cigarettes: They have access to television ndvertising;
they are taxed by the Federal Government and by most States, at much
lower rates than cigarettes, resulting in a significant price advantage;

592


and they do not carry the rrnrning label required on cigarette pack-
ages nnd in cigarette advertising. A market appears to be developing
for the.se products, as there has recently been a sharp increase in the
shipment of little cigars destined for domestic consumption (table 37).

It is important to estimate the potentiai public health impact of
these little cigars. An adequate epidemiological evaluntion of the ef-
fect of little cigar smoking on health could take 10 or 15 years and is
probably an impractical consideration; ho\rever, a review of the epide-
mioIogicaI, autopsy, and experimental data concerning the health con-
sequences of cigarette, pipe, and cigar smoking summarized in this and
previous reports is helpful in considering the potential impact on
health of smoking little cigars. An analysis of the chemical constit-
uents suggests that both cigarettes and cignrs contnin similar corn-
pounds in similar concentrations. TKO exceptions are reducing sugars,
which nre not found in quantity in the fermented tobnccos commonly
used in cigars, and the pH of the inhaled smoke. The pH of the smoke
from U.S. commercial cigarettes is below 6.2 from the first to the Ia&.
puff, mherens the smoke from the last half of a cigar may reach as high
as pH 8 to 9. With increasing pH, nicotine is increasingly present in
the smoke as the free base. Skin painting experiments in mice indicate
that tumor yields with cigar or pipe "tars" are nearly identicnl with
those obtained with cigarettes "tars". Tn addition, the epidemiological
data suggest that depth of inhalat.ion probably accounts for the fact
that cigarettes are so much more harmful than cigars and pipes in con-
tributing to the development of lun g cancer, coronary heart disease,
and nonneoplastic respiratory disease. For such diseases ns cancer of
the oral cavity, larynx, and esophagus, where smoke from cigars, pipes,
and cigarettes is available to the target organ at comparable levels, the
mortality ratios are very similar `for all three forms of tobacco use.
Several factors, including "tar," nicotine, and the pH of the smoke,
probably operate to influence inhalation patterns of smokers. The
relative contribution of individual factors to the inhalability of a
tobacco product has not been determined.

Smoking those brands of little cigars which can be inhaled by a
significant portion of the population in a manner similar to the preg
ent use of cigarettes would probably result in an increased risk of de-
veloping those pulmonary and cardiovascular diseases which have
been associated with cigarette smoking. On the other hand, smoking
those little cigars which are used like most large cigars &ereby the
smoke is rarely inhaled would probably result in lower rates of those
Pulmonary and cardiovascular diseases than would bo found among
cigarette smokers.

OnIy a limited analysis is available comparing the chemical com-
lmunds found in little cigars, cigarettes, and large cigars. The FTC
analyzed t-he tar and nicotine content of all the little cigars (34) and
cigarettes (97) currently available on the market. Little cigars have

593


generally a higher "tar" and nicotine level than cigarettes, although
considerable o\-erlap results in some little cigar brands having "tar."
and nicotine lerels comparable to those of some brands of cigarettes
(fibs. 4 nnd j)- Hoffmann and IVynder (M) recently compared three
brands of little cigaars \vith an unfiltfrcd cigarette, a filtered c@Ssrette,
and a large cigar. They measured a number of smoke constituents, in-
cluding: "tar," nicotine, carbon monoxide, carbon dioxide, reducing
sugars, hydrogen cyanide, scetaldehyde, ncrolein, pyridines, phenols,
bcnz(a)anthracene, and benzo(a)pyrene (table 32). Cigarette -1 XX
the Kentucky reference cigarette, cignrette B was a popular brand of
filter cigarette. Cigar A eras an 8.5 mm. little cigar, cigar I3 was an
8.5 mm. little cigar, cig.w C was a 95 mm. small cigar, and cigar D was
a 112 mm. popular brand of medium sized cigar.
The smoke pH ~a2 analyzed puff by puff (table 39). Cigarette
smoke was found to be acidic (pH less than 7) for the entire cigar&a
The smoke from little cigars became alkaline only in the last. puff or
two, rrhereas about the last 40 percent of the puffs from the larger
cigar were alkaline. Although the pH of the total condensate obtained
from cigarettes is usually acidic and the total condensate obtained
from cigars is usually alkaline, the above data indicate that smoke
pH of tobacco products changes during the combustion process. Smoke
from large cigars may be acidic during the first portion of the smoke
and not become alkaline until the last half of the cigar is smoked.
Brunnemann and Hoffmann (25), using the same techniques de-
scribed above: examined the effect of 60 leaf constituents on smoke pH.
For several wrieties of cigarette tobacco, they found a high correlation
betlreen t.he total aklaloid and nitrogen content and smoke pH. Stalk
position also affected smoke pH. Tobacco leaves near the top of the
plant, n-hich contain high levels of tar and nicotine, yielded a smoke
with a much higher pH than leaves lower on the plant. At present it is
not known to ahat extent these factors influence the p1-I of the smoke
of tobacws commonly used in cigars or how these kinds of pH changes
inff uence the inhalability of tobacco smoke.
The inhalation of smoke, however, appears to be the most important
factor determining the impact a cigar will hare on overall health.
Those physical and chemical characteristics of a tobacco product
which most influence inhalation of tobacco smoke have not been
accuratel_v determined. Severtheless, it appears likely that the smoke
of some brands of cigars may be compatible rcith inhalation by a sig-
nificant. portion of the smoking population. since: (a) Little cigars
have tar and nicotine levels which, in some brands, are similar to the
le\-ek found in cigarettes, and (6) the pH of Ihe smoke of some little
cigar brands is acidic for the major portion of the little cigar and
becomes alkaline only in the last puff or two.


"tar" content.

It is rea-sonable to conclude that smoking little cigars may result in
health etfects similar to those associated \rith smoking cigarettes if
little cigars are smoked in nmounts and with patterns of inhalation
similar to those used by cigarette smokers, for the reasons cited abo\-e,
and these additional reasons: (CZ) In those littlc cigars for which pre-
liminary data are available, the concentrations of carbon monoxide,
hydrogen cyanide, acetaldehyde, acrolein, pgridine, phenol, and poly-
cyclic hydrocarbon levels are comparable to those found in cigarettes;
(b) cigarette smoker; xho switch to cigars appear to be more likely
to inhale cigar smoke than cigar smokers who have always smoked
cigars (Id) ; and (c) cigarette smokers who switch to little cigars may
he inclined to use them as they did cigarettes because of the physical
similarities between the little cigars and cigarettes, including their
size and shape, the number in a package, the burning rate, and the
time it takes to smoke them.

Figure 4.-Percent dlstrlbutmn of 130 brands of cigarettes and 25 brands of little cigars by

I

E -

I

Mg. "tar"    0     0      0   16.0    8.0   32.0   32.0    0    8.0    4.0

Cigarettts   o-4   5-9   lo-14  15-19  m-24  25-29  30-s 35-39   40-44  45-49

Little Clgan  3.1    3.1    10.0   46.2   23.1   10.0   3.9   0.8     0     0

SOURCE; " s Deparfment 0, ".Df,h. Ed"cal,on, and w.t,are (97, and FKlarsl T,M. Commllrlan ,30.

595


Figure 5.-Percent distribution of 130 brands of cigarettes and 25 brands of little

cigars by nicotine content.

CigarFnesB
Little cigars

5

cl

SOURCE: U S. Department of Health. Education. and Welfare (977) and Federal Trada Corn.
      rr,,ss~on (34).

596


TABLE 37.~Shipment of small and [urge n'gars destined for domestic
         cons-umption (1970, 1971, 1970)

Year              lml           1971           1972

January _.____-_____ ~__-    58, 328, 520    85,733,750   123, 477, 550
February-_- .______ - ____    63, 431,580    72,092,205     179,817,939
hiarch- _ _ _ __ __ _ __ __
              ___ _    85,881,860    46,542, 800    193, 165, 593
April _____ -_-_- _______._   101,613,500    59,059,920    125, 335, 740
hlay ______ -_- __________    81,093, 180    93,237,473    159, 334,565
June_________--_____-~-    82,471, 120    94,560,140    lSO,582,243

Subtotal _______ _ _ _   472, 919, 760

451,246,313

966, 713, 530
-

Jdg-_- --------_-_- -_--    62, 143, 140    70, 332, 500    127, 713, 320
August ___.___________ ~_    68,220,365    127, 709, 310    670,936,869
September.-__--_-------    79, 101,045    95,027, 340    422,534, 705
October ____________ ---_    90,752,880    109,567,900    708, 116, 830
November- ___________ __    64, 290, 600    106, 666, 107    551,326,888
December---.- _____ -___    63,806, 010    123,809, 553    485,587,014

Subtotal _____ _ _ _ _ _   428, 314,040    633, 112, 710   2,966,215,626

Yearly total._---__   901,133, so0   1,054,359,028   3,932,929,156

Large cigars

Janusry_~___-_~_-_-___-   581, 74'2,001    573,039, 120    534,565,488
February____-__.__-____   595,249,522    586,810, 844    562, 414,577
March__---_-__-_~-__.~   629, 977, 375   665, 998, 099    654,827,796
April ________ ____ _ ___ _ _ _   652,800, 200    655, 213
                            850,       554,242,048
Mey~_~_~.~~~~_~~_____-   748, 040, 796    670, 933
                            064,       719,489,529
June__-_-______________   649,539,031    692,436, 529    578, 501, 068

    Subtotal _---______  3,852,348,925  3, 844, 199,738   3, 604, 040, 506

JulY__--_______--______   647, 397,547    619, 838, 386
Auwt -_-_________ - ____                       520, 873,339
                673,082,971           148
September _________ - ____            662,970,      682, 331,630
               721,561,449
O~tobf2r- _ _ _ _ _ _ __ _ _ ____ _             680,476,418    594,843, 957
                                     968
November-           797,601,253   67.9, 420,      693,150,668
        _ _ _ _ _ _ _
            _ _ _
               _ _ _
December--- -_         696, 526,464    742,948,802    650, 746, 540
           _______ __   596,244, 159   516,879,415    437,429,996

   Subtotal --_-____ -_  4, 132, 413, 843  3, 902,534, 137   3,579,356, 130

  Yearly total- __ _- _  E, 084,762, 768  7, 746,733,875   7,183,396,636


-: 0.8. Dwnmaant of the Tw (JOJ).

597


TABLE 3S.-Selected compounds in mainstream smoke

"Tar", z~tiI~am prr cigarette.. _
Xicotine, milligram per cigarette-
Carbon monoxide, volume per-
cent_---~_-~_~---.----.-.-.
Carbon dioxide, volume percent_-
Reducing sugars, percent of
tobacco Keight- _ __._____. ___
Hydrogen cJ-snide, microgram
per cigarerle- _- - __.. ____. __ _
Aceteldchyde,  micrrgram per
cigarette-__-- ___._._.__ __-_-
Acrolein. microgram per cigar-
ette ____ - _______.______.____
Total pyridines, micrograms per
clprertc_~---__-- ______-_-..
Phenol, microgram per cigarette-.
Benz(a)anthrecene, nvnogrnm
per cigererte--- ________.___.
Benzo(a)pyrene, nanogram per
cigarette _____ _ _ __ .__. _. . ___ _

36. 1
2. 7

20. 3
1. 4

4. 6     4. 5
9. 4    9. 6


9. 3    7. 9


536.0   361. 0


iio. 0   774. 0

105.0

82. S
124.2

74. 0


47. 0

71. 0


27. 3
33. 0


31. 0


20. 0

17. 4
.G

5. 3
6. 5

1. 5


351.0


630. 0

41. 0


58. 0
35. 1


34. 0


18. 0

  31. 3     40. 6
   1. 8     3. 1


  Il. 1     7. 7
  13. 3     12. 7


   2. 9     2. 7


G97. 0  1, 029. 0


I, 238. 0  1, 150. 0


  54. 0     66. 0


  85. 3     80. 3
  63. 4     94. 1


  25. 0     39. 0


  22. 0    30. 0

Bourn: KoL7zann. D.. Wynder. E. L. C&l).
TABLE SY?.--Th.e pH of the mainstream smoke of selected tobacco products
          [Ntmben In pruenthesu lndlcale number OZ last puff.1

.4wuga pE?   Cl?xretle A  C!garette B    LllLl8     LIttIe     9mall     Cigar D
        (nondlter)    alwr1     cigar A     cigar B     ctgar c

3d puff-----
5th pufY_-_-
7th put?----
9th puf-_--
13th puff_--
18th puff---
23d pufi-T-e
28th puff_--
33d PUB-_--
38th puff_--
L-t puff---

G. 19
6. 14
6. 09
6. 02

_--_--_-
- - _ - _ _ - -
__- ____-
___--___
5.96(11)

6. 15     6. 44
6. 12     6. 34
6. 01     7. 03
5.83     _.___.__

--______ --_-_---
_-_.-___ _-_-_---
____--__ ___-_---
__--_--_ -______-
5. 76(10) 7.73 (8)

6. 55     6. 53
6. 46     6. 49
6. 51     6. 56
6. 98     6. 59

6. 47

____-- .-

6. 27
6. 39
6. 41
6. 81
7. 22
7. 53
7. 78
7. QG(43)

8oarce: HoUmmn. D.. Wynder. E. L. (u).

598


Conclusions

Pipe and cigar smokers in the United Stntes as n group experience
overall mortality rntes that are slightiy higher than those of nonsmok-
ers, but these rates are subs&ntially lower than those of cignrette
smoker-s. This appears to be due to the fact thnt the total exposure to
smoke that a pipe or cigar smoker receives from these products is
relatively low. The typical cigar smoker smokes fexvcr than five cigars
n day and the typical pipe smoker smokes less than 20 pipefuls a day.
Most pipe and cigar smokers report that they do not inhale the smoke.
Those who do inhale, inhale infrequently and only slightly. As a
result, the harmful etfects of cigar and pipe smoking appear to be
largely limited to incrensed death rates from cancer at thosesites which
are exposed to the smoke of these products. Mortality rates from
cancer of the oral cavity, intrinsic and extrinsic larynx, pharynx, and
esophagus are approximately eq~ml in users of cigars, pipes, and ciga-
rettes. Inhalation is evidently not necessary to expose these sites to
tobacco smoke. Although these are serious forms of cancer. they account
for only about 5 percent of the cancer mortality among men.

Coronary heart disease, lung cancer, emphysema, chronic bronchitis,
cnncer of the pancreas, and cancer of the urinary bladder are diseases
Khich are clearly associated rrith cigarette smoking, but for cigar and
pipe smokers death rates from these diseases are not greatly elevated
above the rates of nonsmokers. These diseases seem to depend on rnod-
erato to deep inhalation to bring the srnoke into direct contact with
the issue at risk or to allow certain constituents, such as carbon mon-
aside, to be systematically absorbed through the lungs or to affect the
temporal patterns of absorption of other constituents such as nicotine
thnt can be absorbed eit.her through the oral mucoza or through the
lungs. Evidence from countries where smokers tend to consume more
cigars and inhale them to R greater de.gree than in the United States
indicates that rates of lung cancer become elevated to levels appronch-
ing those of cigarette smokers.

Available data on the chemical constituents of cigar, pipe, and
ci@rette smoke su,azest that there are rnarked similarities in the cam:-
position of these products Pipe and c&w smoke, however? tends to
be more alkaline than cigarette smoke, and fermented tobaccos com-
monly used in pipes and cigars contain less reducing sugars than the
rapidly dried I-aricties commonly used in cigarettes.
Experimental evidence suggests that little difference exists betxwzn
the tumorigenic activities of tars obtained from cigar or cigarette

599


tobaccos. Malignant skin tumors n)>penr somewhat more mpidl>- and
in larger number-s in animals whose skin has been painted with cigar
tars than in those animals painted with cigarette tars.

One must conclude that -some risk exists from smoking cigars nnd
pipes as they ate currently used in the United States, but for most
diseases this is small compwed to the risk of smoking cigarettes ns the.!
nre commonly used. Keverthcless, changes in pntterns of usqy that
would bring about increased exposure either through increased indi-
vidual use of cigars and pipes or increased inhnlation of pipe and cigar
smoke have the potential of producing risks not unlike those nom
incurred by cigarette srrtokers. Mechanical or chemical modifications
of pipe tobacco and cigars that would result in a smoke more compnt-
ible with inhalation could have this efiect.

Pipe and Cigar References

(I) -bELry. T.. G5u 0. T. Relative risk ol pulmonary cancer in cigar and
   pip smokers. Cancer X)(8) : 1288-12x. August 1%7.
(2) AUIBOSE. A.. FLISr. F. 3. Bronchitis, aspirin, smoking. and other factors
   in the aetiologY of peptic ulcer. Lancet 2: 179-182, July 28. 1958.
(9) ARXIITAGE, -4. K.. `PLXXE~. D. M. Absorption of nicotine In cigarette and
   cigar smoke through the oral mucosa. Stature 22G(%~) : 123-1232.
   June 27, 1970.

(4) A~HZY)RD. J. R., Baows. 5%. Dumtxo. D. P., SMITH. G. S.. PAY, J. 15'. J.
   The relation between smoking habits and physique, respiratory symy
   tams, rentilatorr function, and rndiological pneumoconiosis nmongst
   coal workers at three Scottish collieries. British Journal of Preventive
   and Social Medicine 15: 1W117, 1961.

(5) AUERBACEI, 0.. Ha~ruoso, E. C.. Gannx~n, L. Histologic changes in the
   larytr in relation to smoking habits. Cancer25(1) : 92-104. Januar.r 1970.
(6) AUEEBACH. 0.. Srour. A. P., HAMMOND. E. C., GARFIYKEL, L. Changes in
   bronchial epithelium in relation to sex, age. residence, smoking nnd
  pneumonia. Sew England Journal of Medicine ?67(3) : 111-119, July 19,
    l!XX.

(7) AUERBACH. 0.. STOUT, A. P.. HAMMOND. E. C., GAHFISKEL, L. Histologic
   changes in esophagus in relation to smoking habits. -4rchires of Environ-
    mental Health ll( 1) : 4-15, July 1965.
(8) AUERSACH. 0.. STOCT, A. P.. Ha~r~iox~, E. C., GARFISKEL, L. Smoking
   habits and age in relation to pulmonary changes. Rupture of alveolar
   sryt?lms. fibrosis and thickening of walls of small arteries and arterioles.
   Sew England Journal of Medicine 269(20) : 1045-10.54. Nov. 14. 1963.
(9) BEST. E. W. R. -1 Canadian Study of Smoking and Health. Ottawa. Depart-
    ment of Sational FIenlth and.\Yelfare. 1%X, 137 pp.
(IO) Boarcr IV. C. A studF of illness in a group of Cleveland families. S\`III.
   Tobacco smoking and respiratory infections. Sew England Journal of
    ltedicine 2.X+(:!) : 124.~~1249. Dec. 23. 1958
(II) BOWER. G. Respiratory symptoms and ventilatorr function In 172 ndults
   employed in a bank. American Review of ResplrntorF Diseases 83:
    ts&ao. 1961.

600


(12) m.406~~~. E.. scaoxtam. x. Oesophageal and lung cancers in x*tal
    ue-fin mhin relation t0~tiin ~odoecno~k ract0Is.~ anOds
   or 4s inter~kws. British Journal 0r cancer 23(2) : 275-28-t June 19GD.
(f8) Bso~nrs, A. C. Squamouscell epithelioma of the lip. A study of 537 cases.
    Journal of the American Medical Assoclatlon 74: 058-e% Mar. 6, 1920.
(14) Baosa, I. D. J.. RDINOE, J. Switching from cigarettes to small cigar+-
   is it llkely to reduce the health hazards of smoking? In press: Proceed-
   ings of the American Association for Cancer Research. March 1813.
(f5) BBU?~&-EMAHN, K. D.. HOFFMAN?~. D. On the pH of tobamo smoke. Paper
   prrmented at the CORESTA/TCRO meeting, Williamsburg, Va.. tit. 23.
    1972,lS pp.
(16) Bonnb P.. DUXN. J. E, Jr.. B-how, L Cancer of the long and Joa
   Angeles-type air pollution. Prospective study. Cancer 20(12) : 21392147.
     December 1967.
(17) CAMP- J. N.. L~XDSFP, A J. Polgcpclic hydrocarbons in cigar smoke.
    British Journal of Cancer 11: lQ2-lQ5,1957.
(18) CEDEBK~F, R., Fanmao, L.. HBUBEC. 2. Cardlovascnlar and respiratory
   symptoms in mlstlon to tobacco smoking. A study on American twina
    Archives of Environmental Health 18(6) : Q34-Q40. June 1960.
(19) COXSTOCK. G. IV., Baow~x.ow. W. J., STONE, R. W., Saarw~u, P. E.
    Cigarette smoking and changes in respiratory findings. Archives of
    Environmental Health 21(l) : 5&57, July 1970.
(20) CBOXINGEB, A. B.. GMHAX, E. A., WYXDE~ E. L Experimental produc-
    tlon of carcinoma with tobacco products. V. Carcinoma InductIon in
    mice with cigar, pipe, and all-tobacco cigarette tar. Cancer Research
    18: lml271, December 1958.
(82) D~LHAMN. T., R~w?in~a, R. Ciliotoxidty of cigar and cigarette smoke.
    Archives of Environmental Health ZO(2) : 252-253, February 19iO.
(28) Davrss, R. F., DAY, T. D. A study of the comparative carcinogenidty of
    cigarette and cigar smoke condensate on mouse skin. British Journal
    of Cancer 23 (2) : 363368. June 1989.
(23) DA~~EK. T. R., ICANNEL W. B., RFP~~~EIE, N., STOKES, J.; &oan'. A.,
   GORDON, T. Some factors associated with the development of coronary
   heart disease. Six years' followup experience in the Framingham study.
   American Journal or Public.&alth and the Nation's Health 49(10) :
    13491356. October 1959.
(24) DENsEN, P. N.. Jones, E. W., BAES, H. E., Brmuna, J. A survey of respira-
   tory disease among New York City postal and transit workerj I.
   Prevalence of symptoms. Environmental Research l(3) : 262-266, No-
     vember 1967.
(es) &Lq R., H&L. A. B. A study of the aetiology of carcinoma of the lung.
   British Medical Journal 2: 1271-1286, Dec. 13.1952
(28) DoLL. R, HILL, A. B. Mortality in relation to smoking: Ten years' ob-
   servations of British doctors. (Part 1). British Medical Journal
   l(5395) : 1399-1410. May 30,1%X
(m) Donr, R.. HILL, A. B. Mortality in relation to smoklng: Ten years' ob-
   servations Or British doctors. (Concluded). British Medical Journal
   1( SEft?) : 141;0-1467, June 6,1Q64.
(28) Do% R., Hrrt A. B. Mortality of British doctors in relation to smoking:
   Observations on coronary thrombosis. In: Haenszel. w. (EXitor). Epi-
   demiotogicat Approaches to the Study of Cancer and Other Chronic
   Diseases. Bethesda. hid.. U.S. Public Health Service, National Cancer
   Institute ~Ionograph No. 19. January lQ66, pp. 205215.
(") DoU. R-9 JWQW F. A., Py~~rr, F. Edect of smokfng on the productton
   and maintenance oC gastric and duodenal ulcers. 7,ancet 1: 657-2.
    Mar. 29.1958                               601


(JO) &,\-E J. T.. D\WBER. T. R.. KASX~EI.L, W. B.. Krscn. S. H.. K.rr1.u. H. .I.
   The rvlatinnchip of ciEnrrtte smokinr to coronarT heart dlseaw. The
   smnd rrport OP the combined experience of tbe -%lbanr S.T.. and
   Franlinrham. Xnss.. studies. Journal of the ArnerlcaD MediCal Ak~xci~-
    tion l!w) (IO) : &Y%. Dec. 7.1!Mx

(jf) Dust. J. E.. Jr.. LITDEN, C.. BEERLOT. L. Lung cancer mortality czw-
   fiene of men in certain occupations In California. Americnn Journal oC
    Public IIeslth and the Katloo's Health X(10) : 1475-i-1187. October 1%X
(3) ERESICR. U. Cancer of the lip. A clinical study of 778 cases with pfltiiculnr
   regard to predirmsinq factors and radium therapy. .1ctn Rodloltica
    (Supplement 4s) : 1-2X. 1313.

(33) I%WhRDS. F.. JIrK~owx. T., 1Vlrln-K&D. A. G. w. Associntion between
   smoking: nnd dlsense in men over sixty. Lancet 1: 196-200. Jnn. `& l!Mi.
(34) F~DLR~L T~.wE Couurssro-u. Rc~wrt of tar and nicotine content of the
    smoke of 25 varieties ol small cignrs. In: Federal Trade Commission
    Sews. 14l703. Jul 3 1972.2 pp.

(3.7) FX%SK~HCRO. W. G. Chemicnl changes In the ban-ested tobacvo leaf.
    I. Cbemlcal and enzymlc conversions during the curing process. Ad-
    vances In Enz~moIogy0:3O%387.1946

(36) FR%XKESBURO. \V. G. Chemical changes in the harvested tobacco leaf.
    II. Chemical and enzymic conversions during fermentation nnd aging.
    Adrances in EozymoIogy 10 : 32%441.1950.

(.?Y) GOLDSMITH. J. It., HECHTER. H. H.. PERKISS. S. 11.. BORI~AXI. N. 0.
    Pulmonary function nnd respirntory findings among longshoremen.
    American Review of Respiratory Diseases 86(G) : 867-874. December
     1362.

(33) H.~u~oso. E. C. Smokillg iu relntion to the death rates of one million
    men and women. III: Haenszel. W. (Editor). Epidemiological hp-
   proaches to the Study oP Cancer and Other Chronic Diseases. Bethesda,
    3rd.. U.S. Public Health Service. Sational Cancer Institute Monograph
    So. 19. January 1966. pp. 127-20%

(39) H.~stztoso. E. C., GARFISKEL L. The influence of health on smoking habits.
    In: Haenszel, IV. (Editor). Epidemiological Approaches to the Study of
   Cancer and Other Chronic Dikenses. Bethesda, Md., U.S. Public Health
   Sen-ice, Sational Cancer Institute Monograph No. 19. January 1966,
    pp. "w-285.

(JO) Ha\r>rOs~. E. C., HORS, D. Smoking and death rates-Report on 44 months
   of follow-up of 187.783 men. 1. Total mortality. Joumnl of the American
   Medical Association 166( 10) : ll5%1172, Nar. 8. 1958.
( if) H.x\tz~oso. E. C.. HORS, D. Smoking and death rates-Riport on 44 months
   of followup of 187,X7 men. II. Death rates by cause. Journal of the
    American Medical Association 166(11) : 12%-1308, Mar. 15, 1958.
i $2) HIRIY.\\~A. T. Smoking in relation to the death rates of 265.118 men and
   women in Japan. A report of 5 years of followup. Presented at the
    Americnn Cancer Society`s Fourteenth Science Writers' Seminar, Clear-
    water I%each. Fin.. Mar. 57. 197". 1.5 pp.

(!,l)aH~FFsfA~;n, n., RATHKAMP, C.. \VYSDER E. L. Comparison of the rieI&
   of fiereral selected mmponmts in the smoke from different tobamo
   products. Journal of the Satinnal Cnncer Institute 31(3) : 627-637,
    Srptcmlwr 1963.

(4$i HoFF\f.~311, D., WYSD~ E. I,. Smoke of cigarettes and IIt& cj@m. An
   analrtical comparison. Science liS(4066) : 1197-1199. Dec. 15. 1972.
(4.5) IIoIla~~RGER. F.. TRFZG~R. A.. R.\KE~ J. R. Mouse-skin painting \\ith smoke
   Co~~den.xlte~ from CIKarC'ttrs made of pipe, cigar, and cigarette tobaccos.

602


     Journal of the Sational Cancer Institute 31(6) : 1~>1459. December
      1963.
($6) Hoon. B.. TIE~LI~. C.. Wm. G., OBNDA~~, G., K~RSSA.V-BEXGN~~. E
     Myocardial infarction In early axe. iII. Coronar- risk factors and their
    detlcient control. Acta Medlca Scandinarica l%(i) : 241-251. April
      1969.
(47) INTEB-Socm Co?ddu~ssros ma HEART Drseas~ R~sormc~e. Atheroxlero-
    sis Study Group and Epidemiology Study Group. Primary prerentlon of
     the atherosclerotic dlsesses. Circulation 42( 6) ; A-&A-9$ December
     1970.
(48) ISAAC, P. F., RMW. XI. J. Cigarette smoking and plasma lerels of nlco-
    tine. Piature 236(5345) :30%310, April 7.1972.
(49) JFNGIXB. C. D., ROBESHAS, R. H.. ZYZAN~KZ. 9. J. Cigarette smoklog.
    Its relationship to mronary heart disease and related risk fncrors in
    the Western Collaborative Group Study. Circulation 38(6) : 1140-1155.
     December 19668.
(50) KAHN, H. A. The Darn study of smoking and mortality among U.S.
    veterans: Report on SYg years of observntlon. In: EIaenszel. W. (Editor).
    Epldemiological Approaches to the Study of Cancer and Other Chronic
    Diseases. Bethesda, Xd.. U.S. Public Health Service. Xational Cancer
    Institute Monograph X0.19, January 1906. pp. 1-125.
(51) I&L- A. Z. Cellular types. surviral, race. nativity. occupations, habits,
    and associated diseases in the pathogenesis of lip cancers. American
    Journal of Epidemiology 91(5) : 48-99. ,Uay 1970.
(52) -8, A. Z. Cirrhosis of the liver. alcoholism, and heavy smoking asso-
    ciated with cancer of the mouth and pharynx. Cancer 20(G) : lOl~lO22.
     June 1967.
(5s) EESBLEB. C. J. The pharmscology of tobacco smoke effects of chronic
    exposure. In: James, G., Rosenthal, T. (Editors). Tobacco and Health,
    Springfield, C. C. Thomas, 1962, pp. 5-20.
(54) Ii~8s~rlavlr, A. A. comparatire study of cigarette, cigar, and pipe smoking
    elfects on blood lipids, catecholamine excretion. and nicotine content of
    the urine. Acta Cardiologica 23(4) : 317-329.1968.
(55) K~ssasauac, A., BELLET, S. Cigarette, cigar, and pipe smoking. Some
    differences in biochemical effects. Geriatrics 23(3) : 12G-134. Xarch 196.X
    25%260,1953.
(56) KOOLUMIE~. M. Smoking and pulmonary carcinoma. Acta Radiologica 39:
    255-260, 1953.
(57) Ksco~sox. I(. P. The pathologic effects of smoking tobacco on the trachea
    and bronchial mucosa. American Journal of Clinical Pathology 33(4) :
    310317, April 1960.
(58) KUHN. Ef. A comparatire study of cigarette and cigar smoke. In: Prc-
    *dings of the Fourth International Tobacco Scientitlc Congress. The
    liational Tobacco Board of Greece, Athens, Sept. ls26.1966, pp. X7-971.
(59) LEFCOE. S. .\I., \VONXACOTT. T. H. The prevalence of chronic respiratory
    disease in the male physicians of London, Ontario. Canadian .Uedlcal
    Association Journal 102: 381-3s. Feb. 23.1970.
(60) LEYIN. M. L.. GOZ.DSTEIS. II., GERHIARDT. P. R. Cancer and tobacco smoking.
   A preliminaq report. Journal of the American Nedical Association
    143(-l) :3xX338. May 37.1950.
(61) LOMBARD. H. L., SSE~~KFF, L. S. Ati epidemiologlcal study of lung cancer.
    Cancer 12( 2) : 40-13. March-April 1959.
(6-7) .\f~~ns~z, I. Factors associated with cancer of the esophagus. mouth. and
   pharJ-nr in Puerto Rico. Journal of the Natlonal Cancer Institute 42(e) :
    1069-1034. June 1969.                       603


(69) J~ARTISEZ. I. Rctrospwtive and l~rospxtive study of carcinoma of the
     esophagus. mouth. and yhnrynx in Puerto Rico. Boletin de In ;\sociacion
     Uedica de Puerto Rico t?:(O) : 17&liS, June 13iO.
(64) JI~Ls. C. A.. I'OaTE& JI. Jl. Tobacco smoking and automobiledriving stress
      In relation to deaths from cardiac and vascular causes. American Journal
     ol the Jledical Sciences 234 : 3-3. .Jul~ 1957.
(65) JInrs, C. A., POETEE. 11. II. Tobacco smoking hablts and cancer OC the
     mouth and respiratory sj-stem. Cancer Research 10: 539542. 19-50.
(66) MEL& C. A.. Posrur, Xl. Jf. Tobacco smoking, motor eybaust fumes. and
     general air pollution in relation to lung cancer incidence. Cancer Re-
     search 17 : 981-999.1957.
(67) Nay% K L. Structural features in Appalnchian coal workers, In: KeF.
     X1. >I.. Kerr, L. E., BundJ-, &I. (Editors). Pulmonary Reactions to
     Coal Dust. A Review of U.S. Experience. New York, Academic Press.
     1971. pp. 93-110.
(68) OSMAN. 8. Ba~sorr. J. H~drocnrbons of cigar smoke. Tobacco 159 (24) :
     3032. Dec. 11.1964.
(69) OBMAN. S.. SCE~~ELTZ, I., HI~XAN, H. C.. Sranu~n. R. L. Volatile phenols
     of cigar smoke. Tobacco 157 (9) : 3932, Aug. 30.1963.
(70) PASREY. R. D.. BUCKXOR& M. Biological effects of cigar and cigarette
     smoke. British Empire Cancer Campaign for Research. Annual Report
     @(Part 2) : 6.1966.
(71) PABSEY. R. D.. B~acxrroae. M. The causation of lung cancer. Some experi-
     mental blological effects of cigar and cignrette smoke. (Abstract)
     Thorax 23(3) : -W. >fay 1967.
(73) PAE~EP R. D.. BLACKMORE. M.. WAR~EICE-Sarrrrr, D.. JONES. R. Smoking
    risks of different tobaccos. British Medical Journal 4( 5781) : 19%201.
     Ott 23, 1971.
(79) P&axu. J. An epidemiological study on cancer of the digestive orgnns and
     respiratory system. A study based on 7.078 cases. Annales 3Iedicinae
    Internae Fenniae 4Q(Supplement 33) : 1960.117 pp.
(74) RA~DIO. K Untersuchungen zur Atiologle des Bronchlalkarzinoms. (In-
    restigatlons on the etiology of bronchial carcinoma,) Offentliche Cesun-
    deheitsdienst 16(B) : 395-313, December 1954.
(7.5) RrSCINaION. J. Chronic bronchitis, smoking and social class. A study among
    working people in the towns of Mid and East Cheshire. British Journal
     of Diseases of the Chest 63(4) : 193-205, October 1969.
(76) ROX, F. J. C.. CLACK. .I. C.. BISHOP, D., PEIO. R. Comparative circinogenicitg
    for mouse-skin of smoke condensates prepared from cigarettes made from
    the snme tobacco cured by t%o processes. British Journal of Cancer
    24(l) : 107-121, March 1970.
(77) SmrnsKY, D. A.. GI~IAM, A. G., COEN~ELD, J. The statistical nssociat&
    between smoking and carcinoma of the lung. Journal of the National
    Cancer Institute 13: 1237-1258, 1053.
(78) SASbEEI% K. Squamous metnplasia of the respiratory tract eplthelium:
    an autopsy study of 214 cases. II. Relation to tobacco smoking, occupa-
    tion nnd residence. Acta Pathologica et MIcrobiologica Scandinavica 43:
    47-81, 19x
(79) SCHIEW~X, H., E~EKEAWT. R. Cardlorascular actions of nicotine and
    smoking. Journal of the NatIonal Cancer Institute 48(6) : 1785-17Qf,
      June 1972.
(80) SCHIMMI.% W., N:EFF, C., SCHIME~T. G. Rlsikofaktoren und Herzlnfarkt.
    Elne retrospektive Studie. (Risk factors and mpocardial infarct. A retro-
    spective study.) Miinchener 3fedizIoIsche Wochenschrift 110 (27) : 15s
    16Q4, July 5.1968.
604


(81) SCHBEK. R., BA- L. A., Bm. G. P.. Doux)~p, 3. Tobacco smoking as
   an etiologic factor in disease. I. Cancer. Cancer R~sF~K~ 16: -1Ka. 193.
(82) sCnwABT2, D.. DESOIX. P.-F.. L'enquete Francaise sur l'etiolgie du Cancer
   bronch*pulmonaire. Role du tabac. (French LnwstiCation on the etiology
   of bronchopulmonary caner. Role OI tobacco.) Semsine des Hopi&us de
    Paris 33(62/7) : 3630-?&l-13, Oct. 30.1957.
(83) SCHW?.Xn, D.. D~soxs. P.-F., Asac~uh. G. I&her&e des locallsatlons
   du cancer asswi&es aux facteurs tabac et alcool chez L'homme. (Re-
   search on the locallzations of cancer associates tith tobacco and al-
    coholic factors in man.) Bulletin de I'Association Franaise pour
    I'Etude do Cancer 44 : 33&361,l957.

(84) Scawaam. D.. FLauasr. R., Lwnca. J., DEHORN, P.-F. Restics of a
   French survey on the role of tobacco, particularly inhalation. ln dlITerent
   cancer sites. Journal of the National Cancer Institute 26(5) : 10%5-110%
    May 1961.

(8.5) SH~PIBO, S., FPE~XBUTT. E.. Faane, C. YV., SAEE, R V. Incidence of core-
   nary heart disease in a population insured for medical care (HIP).
    Myocardial infarction. angina pectoris. and possible myocardlal ln-
    tarctlon. American Journal of Public EIealth and the Xatton's Health
   59(6. Supplement Part 2), June 1969.101 pp.
(%) SPAIX, D. hl., NATHAS. D. J. Smoking habits and coronary atherosclerotic
   heart disease. Joumnl of the American Medical Association l?i(lO) :
    6S3488. Sept. 9. X%61.

(67) Srasz~wexr, J. Palenle a rah wargi. jamy ustnej, mlgda~kow I ktini.
   (Tobacco smoking and its relation to cancer of the mouth, tonsils and
    larynx.) XoxvotworJ 10(O) : 121-132,196O.
(85) STEW P. 11. Smoking and lamngeal cancer. Lancet l(7751) : 617-818,
    Mar. 18.1972.

(s9) STOCK& P. Cancer incidence In Xorth wales and Liverpool region in
   relation to habits and environment. British Empire Cancer Campaign
   35th Annual Report, Supplement to Part II. 1957. 156 pp.
(90) S~OBDOA, V. An aoaIFsis of some possible epidemiological factors involved
   In Carcinoma of the larynx. Xeoplasma 15 (6) : 677-681, 1968.
(91) TIBBLIN. G. High blood pressure in men aged 6&-A population study of
   men born In 191% Acta Medica Scandinatica (Supplementurn 470) : I-&%,
    1967.

(92) Toon. G. F. (Editor). Statistics of Smoking in the Unfted Kingdom.
   London, Tobaw Research Council, Research Paper I, Fourth Edition,
   1988,103 pp.

(93) Too& G. F. (EdItor). Statistics of Smoking in the United Kingdom.
   London. Tobacco Research Council, Research Paper I, Fifth Edition,
   1969,124 pp,

(94) ToDo.. G. F. (Editor). Statistics of SmokJng In the United Blngdom.
   London, Tobacco Research Council. Research Paper I, Sixth Edition.
   ~Q72.132 pp.

(95) ~OWIILL. 0. h The relation of tobawo smoking to the incidence of chronic
   duodenal clcer. Lancet 1: 60%809. Apr. 14, 1934.
cgs) UsITm SKATED COPE OF F%EDEUL Rut~l'rOxa. Title 26 (Internal Rerenue
  Serrlcel Part 27@-Manufacture of Cigars and Clgarcttcs. (As adopt&
  at 33 F.R. 8173. effectire Oct. 1, 1981). B(270)3-B(270)5, Oct. 31, 1970.
fw) U.S. DEPARTMENT OF HULTH. EDECATIOX. AND WXWARE, Tar and Sjcotfne
   Content of Cigarettes. `Orashlngton, Federal Trade Commission, .\fay 1972.
   DHEW Publication SO. (HSM) 72-7510. 2 pp.

                                   605
u+bo?S o--73----17


(98) U.S. Dzr~~~~srrr OP Btzurrr. Eovcanos, tin WELFABE. Satlooal Clcar-
    in&muse for Smoking and Eealtb. Survey conducted by National
    bal~sts. Inc.. Philadelpbla, Pa., fall 1981.
(99) U.S. D~XPP~JITMENT OP HEALTR. EDUCATION. *SD 5Vm.z~aa.n Kational Clear-
   Inghoose for Smoking and Health. Survey conducted by Sotional
   AnalFsta, Inc.. Philadelphia, Pa.. and Oplnlon Research Corp.. Princeton,
    NJ.. spring 1966.

(100) U.S. DEPABTUEXT OF HEALTR, EDUCATIOX. dxn Wnsm. h'atlonal Clear-
    inghouse for Smokl~g and Health. Survey conducted by the Chllton
    Research Services. Philadelpbin. Pa.. January 1970.
(101) U.S. DEPABIYE~PT OF THE TEEA~L~Y, Bus~au 01 AXOHOL. TOBACCO *SD
    FIBEABUS. Statistical Release: Cigarettes nnd Cigars, 1970, 1971, 1972.
(IO?) U.S. DZPA~TXERT OF TEE TEF~RWY. Internal Revenue Cumulatire Bnlle-
    tin. 1969-l. Revenue Ruling +X+105, p. 359.
(105) VAX Bncne~, F. S. P. Serum lIpids, nutrition and atherosclerotic compli-
    cations in man. Acta Medica Scandlnavlca 181(4; 403-430. April 1087.
(104) Vwcix., U.. HGTDEN-STUCKY, S. Das Infarktprofll. Unterschiede zwlecben
    Xnferktpatlenten und Kontrollpersonen tn des Ostschmeiz. (The infarct
    pronle. Differences between infarct patients and control persons in East
    Switzerland.) Schwelzerische Medlzlnische Wochenxhrlft 90(23) :
     748-738, June ll, 1966.

(105) Wms. J. 11.. DCNN, J. E., Jr. Smoking and mortality : A prospective study.
    Cancer Z(1) : 105-112. January 1970.

(146) WICKEX. A. J. Environmental and Personal Factors In Lung Cancer and
    Bronchitis Mortality in Northern Ireland, 1960X72. Research Paper No. 9,
    London, Tobacco Research Council. 1906, 84 pp.
(107) WYSDEE, E. L., BROBB, I. J. A study of etiologlcal factors in cancer of the
    esophagus. Cancer 14(Z) : 384-413, March-April 1961.
(108) ~VYNDEB, E. L, Bsoss, I. J., DAY. E. A study of environmental factors in
    cancer of the larynx. Cancer D(1) : 86110. January-February 1956.
(109) Wyxorx, E. L.. Baoss. 1. J., FELDMAN, R. M. A study of the etlological
    factors in cancer of the mouth. Cancer lO(6) : 1399-1323, November-
     December 1957.

(Ilo) mY!VDw a L, tiBNFIEU), J. CanCer Of the ltxig in phyBiCian8. 6ew
    England Journal of Medicine !&48(11) : 441-444, Mar. 12, 1953.
(111) WYXDEB, E. L., Gaaaa~, E. A Tbbacro smoking 88 B posalble etlologlc
    factor in bronchiogenic carcinoma ; a study oi 634 proved cases. Journal
    of the American Medical Assoclatlon 143(4) : 328-329, May 27, 1950.
(If,?) WYXD~~. E. L, HOETMANR, D. Tobacco and Tobacco Smoke. Studies In
    Experimental Carcinogenesis, New York, Academic Press, 1997, 730 pp.
(IIS) WY~D% E. L., Hu~yssso, S., JACO~S~ON, F., Bsoss, I. J. Enyironmental
    factors fn cancer Or the upper alimentary tract A Swedlsb study w-lth
   sp&ial reference to Plummer-Vinson ( Patterson-EelIg) syndrome. Can-
    cer 10 ( 3 ) : 47@-487, MayJune 1937.

(`14) wYXD4 El L, tiMON. F. R., NANTEZ, N. E@demiology of persistent
    cough American Review of Respiratory Mseasee 91(5) : f37%709, May
     1955.

(115) mYXm% E. L., Marcooar. K.. B~~rmr; E. J., Jr. The epidemiology of
    lnng cancer. Jonrnal of the Amerlaan hiedicai Association 213(13) :
    2221-2228, Sept. 2&1970.

(216) lV~xD4 E. L. NAVABBETTE, A., Asosre~t~r. G. E., LLAMBE~, J. L. Study
    of mn+-onmental factor8 in cancer of the respiratory tract in Cuba.
   Journal of the National Cancer Institute 20(4) : -73, Aprjl 1~s.
(f17) TVyrrm~. E. L.. WIUOHT. G. A study of tobacco carclnogenesls. I. The p+
    mary fractions Cancer lO(2) : 256-271. Mati-April 1967.

506


Chapter 1 I
        Exercise Performance

Source: 1973 Report. Chapter 7. pages 237 - 249.

607


Contents

Introduction___---______________________----------------
Studies of Smokers- _ _ ____ _____ -___ ___ __ _ ___ ______ _ __ _ __-
Studies Comparing Smokers to Nonsmokers:
  A&tie& Petyformance---- _____ -__---__-_- ____ -_-------
  Bicycle Ergometer Performance_- __ _ _ _ _ __ __ _ _ _ _ __ _ : ____ _
  Treadmill Performance_----- ______ -__-_-- ______ ---__--
  Perjormance in Other Tests of Fitness-_--_--------------
Discussion-_-___-___-_____---_-__-__------_______-------
Biomechanisms _--__-_____-_--_____ --_- ______- -_---_-___
summary--_-______---____________________-------------
References____--_____-__-___-___________-______________

rage
611
611

613
614
615
6U
616
616
617
618

609


Introduction

Although it has long been held by athletes nnd coaches that cigarette
smoking is associated with "shortness of wind" and impaired perform-
ance, until recently there has been little scientific evidence to support
this view. In the past few years, a variety of studies have appeared
dealing with the effect of cigarette smoking on the response of man
to exercise. The follolving is a revielr of these studies.
Age, sex, training, health, weight, and other factors are known to
influence exercise performance. Because most of the investigations
n-we carried out in healthy, youn g male volunteers, the groups rrere
quite comparable with regard to age, sex, and health ; ho\rever, weight,
training, and other factors were often inadequately controlled.
Furthermore, problems in study design and statistical analysis limit
the value of several of these studies.                  \
Many forms of exercise mere performed in these experiments, in-
cluding: pedaling a bicycle ergometer, running on a treadmill, running
on a track, swimming, stelj climbing, gripping a hand dynamometer,
and doing sex-era1 different exercise activities as part of a battery of
tests. Small to maximum amounts of work were carried out in the
various studies revelred.

Studies of Smokera

Most of the studies of habitual cigarette smokers followed a similar
format vzith respect to smoking: (a) The subjects refrained from
smoking for a few hours prior to testing, and (6) two test runs mere
performed, one without smoking and one in which smoking imme-
diately preceded the exercise or was incorporated with the exercise
protocol.
Several investigators (I, 1.5, 28) studied the effect of smoking on
maximum grip strength. Willgoose (28) reported a greater mean per-
cent. recovery of grip strength after the nonsmoking trial than after
the smoking trial. Kay and Karporich (15) and -tinderson and Brown
(I) all followed a protocol similar to that of Willgoose except that
they randomized the smoking and nonsmoking trials, and substituted

611


a "placebo" cigarette for the nonsmolring trial. In neither of these
studies =-ere statisticaIIy significant ditference3 obsen-cd between the
grip SCOM for the smoking and nonsmoking trials.

Reexs and Morehouse (24) administered a battery of tests to 15
colleges students. The tests mere: A tapping test, a strength test. a
jumping test, and the short form of the Harvard step test. h-o statis-
tically significant differences in performance Tere noted under con-
ditions of smoking or nonsmoking.

A total of 32 college students from intermediate swimming classes
abstained from smoking for 15 minutes, 2 hours, and 12 hours in astudy
conducted by Pleasants, et al. (23). Following the abstinence, they
sxam distances of 100 and 200 yards Although actual swimming times
were not published, the authors reported no statistically significant
differences between the mean srrimming times after the different
periods of abstinence for either distance.

In 1%6, Juurup and Muido (23) carried out several experiments
in rrhich three young cigarette smokers exercised on a Krogh's bi-
cycle ergometer. Smoking was found to increase the pulse rate at
rest as Tell as during exercise. Although the effect was less con-
sistent than on the heart rate, smoking was also associated rrit.h
elevated blood pressure. Smoking had no effect on oxygen consump
tion. Henry and Fitzhenry (13): in 1949, using the bicycle ergometer,
also found t.hat smoking exerted no et?& on oxygen consumption.
In the same year, Karpovich and Hale (I$) studied bicycle ergometer
performance in eight young men. In all subjects, the average riding
time was better in nonsmoking tests than in smoking tests; how-
ever, the results Eere statistically significant for only three of the
eight. subjects.

Kerr&an, et al. (16) more recently measured direct arterial blood
pressure, heart rate, and cardiac output in 25 habitual smokers at
rest and after exercise. Smoking two cigarettes produced statistically
significant (P<O.Ol) increases in cardiac index, heart rate, and arter-
ial mean pressure compared to the immediately preceding control
period. Exercise after smoking-resulted in an increase in cardiac in-
dex ore? either the resting period or the exercise period mhich fol-
lowed abstinence; the resultant cardiac index appeared to be approsi-
mately the sum of the exercise and smoking effects. Exercise tests
preceded by smoking were also associated mtih @nificantly higher
(P<O.Ol) and more prolonged elevations of blood pressure than those
not preceded by smoking.

In the study by Goldbarg, et al. (II) of nine habitual smokers
performing submaximal exercise on a bi&ycIe ergometer, car&was-
cular responses \vere measured via pulmonary and subclavian artery
catheters. -it rest, after smoking, the mean cardiac index and mean
heart, rate increased. During successively increasing levels of exercise,
the heart, mte \~as greater and stroke index Iolrer than values for

612


comparable work before smoking. The net etfect of smokinr KS to
decrease the efiiccncy of the lwnrt clurin~ rzcr~isc in thec\rprifht
position by causing a smaller stroke volume arrd a higher heart.
rate.

Rode and Shephard (26) in\-estigated near mnrimal treadmill eser-
cise performance in sis habitual smokers. -1 l-day abstinence from
cigarette smoking \ras associated with a 1% to %-percent decrease in
the oxygen cost of breathing. Yibstinence \ras also follo\red by a slave-
ing of the heart rate and a decrease in espirntory minute volume after
exercise.

The study of Krumholz, et al. (18) is different from those cited pre-
viously in that bicycle ergometer exercise performance was measured
in habitual smokers both before and after 3 to 6 seeks of abstinence.
Among the 10 subjects n-ho abstained from smoking for 3 weeks, there
was a statistically significant (P<O.O5) decrease in heart rate, oxygen
debt, and ratio of oxygen debt to total increase in oxygen uptake pro-
duced by the 5 minutes of esercise.

Using a "double 9-inch progressive st.ep test" Rode and Shephard
(25) studied several hundred participants of a smoking withdrawal
clinic at the time of entry and at a l-year followrp. Xmong those
who returned for the follo\wp and who gave up smoking, absolute
aerobic po"rer increased insignificantly ; hoxverer, the relative aerobic
po\ver diminished in both sexes among those who quit smoking because
of theIreight gain experienced.

Studies Comparing Smokers to Nonsmokers

Athletic Perfomance

In 1968 Cooper, et al. (6) evaluated 419 airmen during their initial
6 weeks on active duty in the USAF. A 12-minute maximum running
test was performed at, least 1 hour after cigarette smoking. The mean
distance covered in 12 minutes by the nonsmokers ~GEG significantly
greater (P<O.O5) than that covered by the smokers at the beginning,
the middIe, and the end of training. A11 categories of smokers and non
smokers improved their performance at the end of training; ho!\-ever,
the maximum change in performance of those smoking 10 to 30 cig-
arettes per day was significantly (P<O.OOl) less than that of non-
smokers.

David (7) administered a battery of tests to 88 military personnel,
aged 19 to 39 years. ;\. l-mile run was included in the testing, and cig-
arette smoking was associated with a significant decrease in perform-
ance in this event.

613


Some 45 special forces soldiers were investigated at sea level and
13,000 feet above sea level by Fine (8). The subjects were randomly
assigned to a placebo group or an acetazolnmide treated group. Cig-
arette smoking vzrs positively correlated to decrements in 600-y-ard
running performance from sea level to altitude in both groups.

Pleasants (E?) studied 106 students from intermediate university
swimming classes. Swimming times were measured for lOO- and 200-
yard distances before and after training and for BOO-yard distances
after training. The mean swimming times of nonsmokers were less
than those of smokers in six of seven listed categories, but these dif-
ferences were not statistically si,@icant.

Bicycle Ergometer Perfmnank

Chevalier, et al. (5) investigated cardiovascular parameters in 32
young physicians after a standard 5-minute ergometer test. Oxygen
debt accumulation among srnokers was significantly (P<O.Ol) greater
than among nonsmokers. The heart rate at rest and 3 minutes after
exercise was significantly (P<O.O2) faster in smokers than in non-
smokers.

using a 5-minute ergometer test: IS housestaff physicians, half of
whom smoked, vrere investigated by Krumholz, et al. (17') _ They noted
the following: Oxygen debt accumulation after exercise was signifi-
cantly (P< 0.@2) greater in smokers than non-smokers, the ratio of the
oxygen debt to total increased oxygen uptake during exercise was sig-
nificantly (P<O.OOl) greater in smokers than in nonsmokers, and
the diifusing capacity at rest and with exercise was significantly
(P<O.O5) decreased in smokers compared to nonsmokers.

Kerrigan, et al. (16) studied cardiovascular parameters in smokers
and nonsmokers at rest, during, and after a B-minute bicycle ergometer
ride. Cardiac index and bIood pressure values obtained during exercise
performed immediately after smoking rrere greater than those found
in nonsmokers performing the same exercise. Similarly, heart rate and
blood pressure remained elevated for longer periods in those who
exercised immediately after smoking than in nonsmokers performing
the same task.

Aerobic capacity scores were examined in 60 university student vol-
unteers by Peterson and Kelley (29) _ Subjects worked at submaximal
levels on a bicycle ergometer before, during, and after a training
Program. At all of these intervals, nonsmokers had significantly
(P<O.O5) high er mean aerobic capacity scores than smokers. Both
groups increased their aerobic capacity during training but non-
smokers consistently performed better throughout training.

614


Treadmill Performance

In 1360 Blackbum, et al. (4) carrictl out .sevrml measurements of
cardiovascular function after different nrno\ints of tirntlmill exercix
were performed bv 233 professional mtn. I>!) Ilnivcrjity students. and
414 railroad workers. The ditferenccs betn-ccn the smokc~s and non-
smokers were of small magnitude. Basal oxygen consumpt.ion was
slightly higher in smokers than in nomxnokcts. L~lso. resting pulse
rates were higher in smokers of most groups.

Cooper. et al. (6) studied 17 out of 419 airmen with treadmill tcst-
ing. Cardiopulmonary indices measured on the tmndmiil. including
maximum indices, were comparable in smokers and nonsmokers ex-
cept for a significant (P<O.Ol) reduction in the maximum minute
volumo among the smokers.

A total of l?ii prospective Canadian fircmcn performed the Balke-
l\var-e test of work capacity in treadmill studies carried out by Glass-
ford :lncl 1Ioxwll (10). The mcnn ~wrformancr scores of nonsmokers
were significantly (P<O.Ol) greater than thoxof smolicrs.

The effect of Gtnmin C su~)~)lcll~entntio~~ on treadmill exercise per-
formance was investigated in 40 male volunteers by Bailey, et al. (3).
Sigiificant ~lift'rrtwxs in ox)-gcn utilization and ventilatory function
bct.weeil smokcts and nonsmokers were noted in only two of the 24
separate anal>-ses of variance performed.

JZasimnl oxygen intake durin, n treadmill escrcise was examined by
JIcDonough, ct. al. (13) in 86 hralthy, middle-aged male volunteers.
Cigarette smoking was one of six variables which together provided
3 mllltiplo correlation coellicient of 0.X3.

Performnnce in Other Tests of Fitness

When physical fitness tests were administered to 88 military per-
~onnel bv David (7). cigarette smoking was found to be associated
wit11 a significant. (1'<0.001) decrease in performance in the dad@
and jump test. and a significant (P<O.O2) decrease in performance in
the crawling test.

I-sing -a step test, :I breath holding test. anti an ergometer test,
Franks (9) esnnlined x middIe-aged 111~11. So~w~~okcis were able to
11ohl tlrcbir breath longer and hat1 prcatrr \-ital capacity residual after
t!w stqb trst thn the slIlokels.

III I!)iI. \\`ysokinski (9) stlutlied 200 ~~oung Polish soldiers using
I,etulrov's test \vllicli iiicludccl 20 lime-hldillg cscrcises, a fast run for
"0 ~rcolltls. a1rtl ;I 1'1111 for :: milrutes. Ciqrrct te sntokillg was associated
witlr a significant (I'<O.Ol) reduction irr the \-ital capacity and a

615


marked rise in the pulse rate at rest and after exercise. Intense exer-
cise also caused a greater rise in the systolic blood pressure in smokers
than in nonsmokers.

Discussion

Most of the studies in habitual cigarette smokers compared exercise
performance in "smoking" and "nonsmoking" runs after only a few
hours of abstinence. In some studies, smoking adversely affected per-
formanm (II, 13,.24,16,18,96,28), while in others it did not (1,12,
16,93,24). Some of these apparently discrepant results are due to dif-
ferences in methodology and in amounts and types of work performed.
In all of the more recent studies of habitual smokers in which moderate
to near maximal amounts of work were performed and sophisticated
measurements of oxygen transport and cardiopulmonary function
were made, impairment of f&&ion during smoking trials was found
(II, 16,149s).
The data of Krumholz, et al. (18) a 1 so raise the question of whether
residual effects of cigarette smoking influence "nonsmoking" trials per-
formed after a few hours of abstinence; they found statistically sig-
nificant decreases in heart rate and oxygen debt produced by exercise
after 3 weeks of cessation.

The work of Rode and Shephard (25) suggests that physical fitness
improves with cessation, but this improvement may be negated if the
subject gains a substantial amount of weight after giving up smoking.

Several investigators compared exercise performance or postexer-
cise cardiopulmonary function of smokers to nonsmokers. Although
only minor differences betvzeen smokers and nonsmokers mere found
in a few of these studies (3,4,22), in most of them (5,6,7,8, 20,16,
27,20,29) the performance or function of the nonsmokers was better
than that of the smokers. Both nonsmokers and smokers improved
their performance with training, but nonsmokers maintained their ad-
vantage throughout training (6,ZU).

Biomechanisms

The cited studies indicate that cigarette smoking exerts its adverse
effect on exercise performance through several mechanisms. Cigarette
smoking appears to impair cardiac performance during exercise by
increasing the heart rate and exerting a variable effect on cardiac

616


output (5, 12, ZJ,I~, IS. X, 29). Cigarette smoking is associated mith
an increased oxygen debt after esercise (5. 18). Alsoo: one study indi-
cated that the osxgsn cost of hyperventilation was greater among
smokers than among nonsmoker; (3).

Some of these adverse edects of smoking on osidative metabolism
are mediated by the elevated cnrbosyhemoglobin levels found in
smokers. CO exerts these effects through one or more of the follo-cFing
mechanisms: (a) Reduction of the amount of hemoglobin available for
ox)-gen transport, (6) shift of the oxygen-hemoglobin dissociation
curve to the left with consequent interference in osygen release at
the tissue level, (c) induction of arterial hypoxemia, and (d) possible
interference with the homeostatic mechanism by which 2,3,CPG
controls the affinity of hemoglobin for oxygen (97). Because carbosy-
hemoglobin has a half life in the body of at least 3 to 4 hours, its influ-
ence may still be measurable sex-era1 hours after abstinence from
smoking (97).

-1 recent investigation of maximal muscular exercise during CO in-
toxication in five male volunteers demonstrated reduced maximal 0,
consumption in spite of a much higher heart rate and a relative hyper-
ventilation (22).

Xstrand and Rodahl (2) commented recently on the adverse effect
of cigarette smoking on oxygen transport: "All other factors being
equal, a reduction in the oxygen-transporting capacity is associated
with a corresponding reduction in physical performance capacity dur-
ing heavy or maximal stork * * *. Because a regular physical train-
ing program only increases the maximal oxygen uptake by some 10 to
20 percent, a 5 to lo-percent reduction in maximal aerobic power due
to smoking may play a significant role in many types of athletic events
and in very heavy work."

Other studies cited in this review document the adverse effect of
smoking on pulmonary diffusing capacity (18) <and on pulmonary
function with exercise (6: ~9).

Summary

Clinical studies in healthy, youn g men have shorrn that cigarette
smoking impairs exercise performance, especially for many types of
athletic events and activities in\-ol\.ing masimal work capacity. Some
of these etfects are medi;lted by reduced oxygen transport and reduced
cardiac and pulmonarv function.

617


Exercise Performance Keferences

(1) ASDEEYO~, J. V.. BBDW~. C. WV. A. study o! the erects of amoklnq upon @P
   strength and recupwaffon from local muscular fatfgue Research Quar-
    terly 22 (1) : 102-108, March 1951.

(2) ASTEASD, P.-O., RODARL, K. Factors affecting performance. In: Textbook
   of Work Physiology. New York, McGraw-Hill Book Co.. 1970, 689 pp.
(S) Bantr, D. A., CARRON. A. V., -, R. Q.. WEHTEB H. J. Vitamin C
  snpplementntton related to physiologfeal response to exercise in smoking
   and nonsmoking subjects. American Journal Of CbdCd KUtIifiOn 23(7) :
   9cG9l2, July 1970.

(4) Br&xmm, H., Bsoz~x, J., TAYLOE, H. L. Common circulatory measore-
   menta in smokers and nonsmokers. Circulation 22: 1112-1124. December
    1960.

(5) CBEVAZIEB, R. B., BOWEEE. J. A., BO~D~EANT, 9.. Ross. J. C. CircUlatOry
   and ventilatory effects of exercise In smokers and nonsmokers. Journal
   of Applied Physiology 18(Z) : 357-360, bfarch 1963.
(6) COOPEB, K. H.. GEY, G. O., BOTTENBER~, R. A. Effects of clgarette smoking
   on endurance performance. Journal of the American Xedlcal Association
   203 (3) : 189-192. Jan. 15.1968.

(7) DAVID, K. H. Age. cfgarette smoking. and tests of physIca fitness. Journal
   of Applied Psychology 52 (4) : 296-298. August 1968
(8) FINE, B. J. Personality traits as related to symptomatology and running
   performance at altitude under normal and drug (acetazoleamide) condi-
    tions. Perceptual and Motor Skills 27: 975-990. 1968.
(9) FEAXSS, B. D. Smoking and selected cardiowscular-respiratory measures.
   Research Quarterly 41(2) : l-10-144, May 1970.
(10) GLAS~FORD. R. G., HOWELL. JI. L. Smoking and physical Btness: A prelim-
    innry report. Canadian Family Physician 15(10) : 6@Xi2. October 1969.
(21) GOLDB.~G. A. S.. KRONE. R. J.. RESNEKOY. L. Effects of cigarette smoking
    on bemodJnamics at rest and during exexise. I. Kormal subjects. Chest
   60(6) : 531-536, December 1971.

(IZ) HENRY. F. hl., FITZHEXEY, J. R. Oxygen metabolism of moderate exercise,
    with some observations on the effects of tobacco smoking. Journal of
   Applied Physiology 2: 41X-468. February 19.50.
(1s) JUURUP, A, Jfuroo. L. On acute effects of cigarette smoking on oxygen
   consumption, pulse rate. breathing rate and blood pressure fn working
   organisms. Acta Physiologica Scandinavica 11 : 48-60, 1946.
(1)) ~XWICE. P. V., HAU, C. J. Tobacco smoking and physical performance.
   Journal of Applied Physiology 3: 616621, April 1951.
(15) KAY. Ff. `N.. KARPOVICH, P. V. Effect of smoking upon recuperation fromlo:
   ~a1 muscular fatigue. Research Quarterly 20: 250-256. 1949.
(is) K~IGAS, R.. JAIX, A. C.. DOYLE. J. T. The circulatory response to ciga-
   rette smoking at rest and after exercise. American Journal of the Jfedi-
   cal Sciences 25.5: 113-119, February 1968.
(17) -UMHoLz, R. A.. CHEVAL.~ R. B.. Roes, J. C. Cardiopulmonary function
   In young smokers. A comparison of pulmonary iunctIon measurements
   and some cardiopulmonary resgonis to exercise betn-een a group of young
   smokers and a comparable group of nonsmokers. Annals of Internal Uedi-
   tine W(4) : 603-610, April 1964.

(18) KRL'~\IHOLZ, R. A., c:HEVALIEtS R. n., ROSE. J. C. Changes in cardiopuf-
   monary fWctions related to abstinence from smoking. Studies in young
   cigarette smokers at rest and exercise at 3 and 6 weeks of abstinence.
   Annals of Internal Medicine 62(2) : 197-207, February 19&

618


(19) ~cDo.uocc~, J. R., Knauur. F.. Recce. R. A. Variations in mar&oat
    OXYgen intake with phy-sical actirIty In middle-aged men. Circulntlon
    41(5) : 743-751. May 1970.

(20) Pmssos. F. J.. hTELzEy. I). L Tbe erect of cigarette smoking upon the
   acquisition Of physical fitness during training 8s measured by aerobic
   capacity. Journal of the American College Uealth Association 17(3) :
    2.50-W. February 1969.

(PI) -AT. F.. DUJAEIJIN, J., DEZ~AXN~. R.. Parrr. J. M. Muscular exerdse
   during intoxication by carbon monoxlde. Journal of Applied Physiology
    M(4) : 5X%575. October 1971.

(22) PwEas~a. F.. Jr. Pretrainlng and post-tralnlng swimming endurance of
    smokers and nonsmokers. Research Quarterly 40(4) : 779-782. 1999.
(-OS) P~~aaaa18. F., Jr.. Genoarr. J.. RATL~F-F, J. XV., Jr. Effects of short perlods
    of abstinence from cignrette smoking on swimming endurance of chronic
    smokers. Research Quarterly 33(3) : 474479. 1966.
(24) RCE~FS, K. E.. ,\IOREHOUEE. L. E. The acute effect of smoking upon the physi-
    cal performance of habitual smokers. Research Quarterly 21: 24%2-18.
    1950.

(25) Root. A. S~~pndno. R. J. Smoking withdrawal and changes of cardiores-
   plratory tltness. American Review of Respiratory Disease 10-l(6) : 9X3-
    933. Decwnber 1971.

(26) Row, A, SEEPHW. R. J. The influence of cigarette smoking upon the oxy-
   gen cost of breathing in near-maximal exercise. Medicine and Science in
    Sports 3(Z) : 51G5. summer 1971.

(27) U.S. Prmmc Hrxrxn Smwrcn. The Health Consequences of Smoking. A Re-
   port of the Surgeon Geneml : 1972. U.S. Department of Xealth. Education,
   and Welfare. Washington, DHEIV Publication No. (7XS.U) 7%751F, 1972,
    158 pp.

(28) W~~looox, C. E. Tobacco smoking, strength, and muscular endoraoce. Re-
    search Quarterly 18: 219225.1947.

(29) WYBOH~~~GKI. 2. Effects of tobacco smoking on certain parameters reflecting
    the condition oP the circulatory system at rest and during exercise. Polish
    Medical Science and History 14(Z) : 73-76. April 1971.

619


Chapter 12

Harmful Constituents of Cigarette Smoke

Sourca: 1972 Report. Chapter 9, pager 137 - 150.

621


              Contents

                                      Page
The Dose Relationship . . . . . . _ _ . .   625
References .._.............._._...-.................   630

LIST OF TABLES

Table 1 .-Compounds in cigarette smoke judged most likely
to contribute to the health hazards of smoking . . . _ . . . . _ .   627
Table 2.-Compounds in cigarette smoke judged as probable
contributors to the health hazards of smoking . . . . . . . . . .   628
Table 3.-Compounds in cigarette smoke judged as suspected
contributors to the heaith hazards of smoking  . . . . . . . . . _   629

623


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 equiIibrium, 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 sfi
ficient to present hazards to health. Other compounds appear in


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 Irhen they
interact with other substances in the smoke.
Substances and classes of substances in cigarette smoke lrhich
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. Nany 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 availabIe.*
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,

626


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 health hazards of smoking.

Campound

RCiCPXlC~

Carbon Monoxide      6g4o-21,coo       G      (1. 10, 23.26, 29,
                                34, 35, 37, 42, 46.
                                 49, 61, 63)

Nicotine            20@-2,400        P      (9)

I "Tar"            3.000-33,000       P      (9)

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 tesult 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-

627


TABLE 2.--Compounds in cigarette smoke judged as probable COR-
tributors to the hcnith hazards of snzoking.

Compound


Acrolein

             Pr,mar~ phuc
Conccntr*tioo in    cl..s,ncatKm
cigsrette amokc    csu
microgr~ms/ctp~rcrtc P--pnrticulate      ?kfCrCnC"


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

Cresol (all isomers)       68-97         P     120. 40)

Hydrocyanic Acid

100-400

G     (26,38,43.45.46,
     49,53)

Nitric Oxide


Nitrogen Dioxide

Phenol

C600        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 considewd likely to be involved in the he&h 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

628


TDLE 3.--Compoun& in cigarette smoke judged as suspected con-
tributors to the health hazards of smoX-ing.

Comaaond

Acetaldehyde          ISO-1,440

Acetone

Acetonitrile            140-200

Acrylonitrile            l&l5

Ammonia              60330

Benzene

2J-Butadione           43-200

Butylamine               3

1 Carbon Dioxide      23,1OCL78,300

Crotononitrile             4
Dimethylamine           lo-11

DDT                  cu.77

Endrin                 0.06
Ethylamine             10-11

Formaldehyde           2c-41

Furfural              45-110

Hydrogen Sulphide        12-35

Hydroquinone          83

Methacrolein            9-11

Methyl Alcohol          90-300
Methylamine            2&22

Nickel compounds         a-O.58

Pyridine              25-218

LB-650

12-100

c


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,
45,43,49, 53.59)
(12, 21. 27, 36, 43,
45, 48. 49, 53)

(12, 43)

(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)

(67)
(12, 43)
(12, 21, 43, 46. 49)
(22,31,40,41)
(5, 8, 47. 55, 56)
(4% 62)

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.

629


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.

REFERENCES ON HARMFUL CONSTITUENTS

(1) ROKHOYEN, C., NIESSEN, H. F. Amounts of oxides of nitrogen and carbon
   monoxide in cigarette smoke, with and without inhalation. Nature
   192(4801) : 458-459, November 4, 1961.
(2) BRADFORD, J. A., HARLOW, E. S., HARLAN, W. R., HANMER, H. R. Sature
   of cigarette smoke. Volatile bases and acids. Industrial and Engi-
   neering Chemistry 29 (1) : 45-50, January 1937.
(3) BROADDUS, G. ,)I. YORK, J. E., JR, MOSELEY, J. M. Factors affecting the
   levels of nitrate nitrogen in cured tobacco leaves. Tobacco Science 9:
   149-157, 1965.

(I) BUYSKE. D. A., OWEN, L. H., WILDER, P., HOBBS, >I. E. Chromatography
   of the 2,tiinitrophenylhydrazones of some aldehydes and ketones in
   tobacco smoke. Analytical Chemistry 28(5) : 910-913, .\Iay 1956.
(5) COGBILL, E. C., HOBBS, M. E. Transfer of metallic constituents of ciga-
   rettes to the main-stream smoke. Tobacco 144 : 2429, JIay IO, 1957.
(6) COMMINS, B. T., LIKDSEY. A. J. Some phenolic constituents of cigarette
   smoke. British Journal of Cancer lO(3) : 501506, September 1356.
(7) COMMINS. B. T., LINDSEY, A. J. The determination of phenols by chro-
   matography and spectrophotometry of their methyl ethers. IV. The
   determination of phenols in cigarette smoke. Analytica Chimica Acta
   15 (6) : 557-558, December 1956.

(8) DAY, J. M., BATEMAN. R. C., COGBILL, E. C. Determination of trace
    amounts of nickel in tobacco by neutron activation and anal>-sis.
    (abstract) Paper presented at the 145th American Cancer Society
    Meeting, New York, N.Y., 1963.
(9) FEDERAL TRADE COMMISSION. Tar and nicotine content of cigarettes.
    Washington, U.S. Department of Health, Education, and Welfare,
    DHEW Publication NO. (HSM) 72-7510, August 1371.
(IO) FISHEL, 3. B., HASKINS, J. F. Composition of cigarette smoke, the
   gaseous phase. Industrial and Engineering Chemistry 41(7) : 137-L
     1376, 1949.

(II) GROB, K. Gas chromatography of cigarette smoke. Part III. Separation
   of the overlap region of gas and particulate phase by capillary col-
   umns. Journal of Gas Chromatogr-aphy 3( 2) : 52-56, February 1365.
(12) GROE, K. Zur Gaschromatographie des Cigarettenrauchrs. 2 Teil. Ver-
   feinerte Trennung mit Hilfe van Kapillarkolonnen. (Gas chromatog-
   raphy of cigarette smoke. Part 2. Improved separation with the aid
   of capillary columns.) Beitr;ige zur Tabakforschung l(9) : 31-L523,
    December 1962.

(I$) GROB, K. Zur Gewinnung und Behandlung frischer- Gasphase aus Ciga-
   rettenrauch. (Preparation and treatment of fresh gas phase of ciga-
   rette smoke.) Beitrage zur Tabakforschung 3(J) : 2-13-250, October
     1965.


(14)

(15)



(16)



(17)

(18)



(19)



(00)

(25)



(26)

(47)



(f8)



(29)

($0)

(31)

G~ITIIRIE, F. E., BOFVFRY, T. G. Pesticide residues on tobacco. Residue
Review 19: 31-56, 1967.

HA,UXN-ST.~IT, A. J., RRUXELLE. ai. F., HARA. J. Nitrogen oxide content
of smokes from di:ferent types of tobacco. A.M.A. Archives of Indus-
trial Health 20 (5) : 399-tO0, November 1959.
HOFFMAXS, D., MASUOA. Y.. WYNDEX, E. L. Alpha-naphthylamine and
beta naphthylamine in cigarette smoke. Nature 221(6177) : 254-256,
January 18. 1969.

HOFFMANN, D., RATHKAMP. G.. WYNDER. E. L. Chemical studies on
tobacco smoke. IX. Quantitative analysis of chlorinated hydrocarbon
insecticides. Beitrage zur Tabakforschung 5 (3) : 140-148, December
1969.

HOFF>~ANN, D., VNS, J. Analysis of volatile N-nitrosamines in unaged
mainstream smoke of cigarettes. Paper presented at the 25th Tobacco
Chemists' Research Conference. Louisville, Ky., October 68, 1971.
HOFFMANN, D., WYNDEX, E. L. Die Filtration van Phenolen aus Ciga-
rettenrauch. (The filtration of phenols from cigarette smoke.) Beit-
rage zur Tabakforschung 2(2) : 61-66, June 1963.
HOFFM~CNN, D., WYSDEX, E. L. Die quantitative Bestimmung von
Phenolen im Tabakrauch. (The quantitative determination of phenols
in tobacco smoke.) Beittige zur Tabakforschung l(3) : 101-106,
August 1961.
IP.BY, R. >I., JR, HA~OW, E. S. Cigarette smoke. I. Determination of
certain vapor constituents. Tobacco 146(16) : 2-6, April 17, 1959.
IZAWA. 31.. KOBASHI, Y. Fractionation of cigarette smoke components
and some low boiling points--nitrogenous compounds (I) _ Bulletin of
the Agricultural and Chemical Society of Japan 21(6) : 35'7363, 1957.
JARRELL. J. E., de la BURDE, R. A study of the major gaseous constituents
in the mainstream smoke of a cigarette. Tobacco Science 9: 5-11,
January 8.1965.

JO~KSON, A E.. REIOADES, J. W. N-nitrosamines in smoke condensate
from several varieties of tobacco. Paper presented at the Second World
Conference on Smoking and Health. London, England, September 20-
24,1971.x pp.
JOHNSTONE, R. A. W., QUAN, P. M., CARRUTI~~, W. Composition of
cigarette smoke: Some low-boiling components. Nature 195 (4948) :
1267-1269. September 29, 1962.

KEITH, C. H., TESH, P. G. Measurement of the total smoke issuing from
a burning cigarette. Tobacco 160(15): 2629, April 9, 1966.
hL!RiZNE, A. H., LYERLY, L. A., Yovxic, G. W. Direct vapor chromato-
graphic determination of acetaldehyde, acrolein, and acetone in ciga-
rette smoke. Tobacco 159 (22) : 34-37, November 27, 1964.
MSAJDA, Y.. HOFFMAKN, D. Quantitative determination of l-naphthy-
barnine and Lnaphthylamine in cigarette smoke- Analytical Chem-
istry 41(4) : 6.50-652, April 1969.
MILLER, .J. E. Determination of the components of pipe tobacco and
cigar smoke by means of a new smoking machine. IN: Proceedings
of the Third World Tobacco Scientific Congress, Salisbury, Southern
Rhodesia, February 18-26, 1963. pp. 684-595.
MILLER, R. L., STEINAN, R. L. Essential absence of beta-naphthylamine
in cigarette smoke condensate. Tobacco 165(B) : 32, August 25, 1967.
M~KHNACHEV, I. G., KANEXHEVA, I. S. Kolichestvennyy sostav aminov
tabachnogo dyma. (I. Qualitative composition of tobacco smoke
amines.) Izvestiia Vysshikh Uchebnykh Zavedenii. Pischevaia Tek-
nologiia (56) : 62-63, 1967.

631


(~2) ~IOKHNACHEV, I. G., LATAYEXA, D. S. Kolichestvennoe opredeleniye
   letuchikh fenolov tabachnogo dyma. (Quantitative determination of
   volatile phenols of tobacco smoke.)  Izvestiia Vysshikh Uchebnykh
   Zavedenii. Pischevnia Teknologiia (57) : 4i-49, 1367.
(33) MOKHNACHEV. I. G., P~SI;LOV, V. P. Gszovyye uglevodorody tabachnogo
   dyma. (II. Research into the gaseous hydrocarbon of tobacco smoke.)
   Izvestiia Vysshikh Uchebnykh Zavedenii. Pischevaia Teknologiia (56):
    64-67, 196'7.

(94) hfOKHNACHEV, I. G., PlsKrOv, V. P. Issledovanie gazovoy fazy tabach-
   nogo dyma. (Study of the gas phase of tobacco smoke.) Tabak 4:
    31-34, 1966.

($5) MOKHNACHEV, I. G., POPOVA, L. P., DUUN. L. A.. SIROT~NKO. A. A.,
   KAMENSTCHIKOVA, S. V., Korru~ov, V. S., LATAYEVA. D. N.. PISKLOV.
    V. P., SERDJUK, L. G. The gas phase of smoke and the influence of
   the neutral part of tobacco resin on its composition. IN: Proceedings
   of the Fourth International Tobacco Scientific Congress. Athens,
    Greece, September 19-26, 1966. pp. 1040-1061.
(96) MOLD, 3. D.. MCRAE. M. T. The determination of some low molecular
    weight aldehydes and ketones in cigarette smoke as the Z,&dinitro-
   phenylhydrazones. Tobacco Science 1: 40-46, 1957.
(37) MUMPOWER, R. C.. LEWIS, J. S., TOLTY, G. P. Determination of carbon
   monoxide in cigarette smoke by gas chromatography. Tobacco Science
    6: 142-145, 1962.

(S8) N&L, J. F. Complexed cyanide in collected cigarette smoke. Abstracts of
   20th Tobacco Chemists' Research Conference, November l-3, 1966,
   Winston-Salem, N. C., 1966. pp- 26-27.
(39) NESEMANN, E., SCHRODER. R., SEEHOFEX, F. Slethoden zur quantitativen
   Bestimmung van Insektiziden in Tabak und Tabakrauch. I. Mittei-
   lung: Zur Bestimmung van Organs-Chlor-Insektiziden. (Methods for
   the quantitative determination of insecticides in tobacco and tobacco
   smoke. I. Report: Determination of chlorinated hydrocarbon insecti-
    cides.) Beitrlge zur Tabakforschung 4 (4) : 182188, May 1968.
(40) NEUFCATH, G. Stickstoffverbindungen des Tabakrauches. (Nitrogen com-
    pounds in tobacco smoke.) Reitrage zur Tabakforschung 5(3) : 115-
    133, December 1969.

(4f) NEURATH. G., DUNGER, M.. Gm, .I., LUTTICH, W., WICHERN, H. Un-
   tersuchung der Fliichtigen Basen des Tabakrauches. (Volatile bases
   of tobacco smoke.) Beitrage zur Tabakforschung 3(9): 563-569,
    December 1966.

(42) NEWSOME, J. R., KEITH, C. H. Variation of the gas phase composition
   within a burning cigarette. Tobacco Science 9: 65-69, April 16, 1965;
(43) NEWSOME, J. R., NORMAN, V., KEITH. C. H. Vapor phase analysis of
   tobacco smoke. Tobacco Science 9: 102110, July 23, 1965.
(44) NORMAN, V., KEITH, C. H. Nitrogen oxides in tobacco smoke. Nature
   205(4974) : 915-916, February 27, 1965.
(45) NORMAN. V., NEWSOME, J. R., KEITH, C. H. Smoking machines for the
   analysis of the vapor phase of cigarette smoke. Tobacco Science 12:
    216221, 1968.

(46) OSBORNE, J. S., ADA.IMEK. S., HOBBS. M. E. Some components of gas
   phase of cigarette smoke. Analytical Chemistry 28 (2) : 211-215, Feb
    wary 1956.

(47) PAILER, hf., KUHN, H. Kurzer Rericht iiber das Vorkommen vbn Nickel
   im Zigarettenrauch. (Short report on the occurrence of nickel in
   cigarette smoke.) Fachliche Mitteilungen der Osterreichischen Taba-
   kregie (4): 61-63, 1963.

632


(!+a) Pm, N., KL`HN, H., GK~~NHEXCF.R I. ilber Quantitative Unterschiede
    im Xuftreten van niedermolekularen Carbonylverbindungen im Rauch
   von Zigaretten verschiedener Tabahmischung und verschiedenen
   Feuchtigkeitsgehsltes. (Quantitative differences in the occurrence of
   low-molecular carbonyl compounds in the smoke of cigarettes having
    different tobacco mixtures and different moisture contents.) Fach-
   lithe Mitteilungen der Osterreichischen Tabakregie 3: 3x9, s!arch
     1962.

(49) PHILIP~E. R. J.. HOBBS, M. E. Some components of the gas phase of
   cigarette smoke. Analytical Chemistry ZS(l2) : 2002-2005. December
     1956.

(50) RAYLWRN, C. H., HA~~v, W. R., HANhER, H. R. Determination of
   volatile phenols in cigarette smoke. Analytical Chemistry 2519) : 1419,
   September 1953.

i51) SCSIOLLER, R. Uber den Gehalt des gasformigen und des festflussigen
   Anteils des Tabakrauches an Cyanwasserstufl. (The content of hydro-
   gen cyanide in the gaseous and stable liquid portions of tobacco
   smoke.) Fachliche Mitteilungen der Osterreichischen Tabakregie 1:
    7-10, 1938.

(52) SPEARS, A. W. Quantitative determination of phenol in cigarette smoke.
   Analytical Chemistry 35(3) : 320-322, March 1963.
(53) SPURS. A. W., ROUTH, W. E. A combined approach to the quantitative
   analysis of the volatile components of cigarette smoke. Paper pre-
   sented at the 1Sth Tobacco Chemists Research Conference, Raleigh,
    N. C., 1964.

(54) STEDMAN. R. L. The chemical composition of tobacco and tobacco smoke.
   Chemical Reviews 68(Z) : 153-207, April 1968.
(55) SUNDERMAN, F. W., SUNDERMAN. F. W., JR. Nickel poisoning. XI. Im-
   plication of nickel as a pulmonary carcinogen in tobacco smoke. Ameri-
   can Journal of Clinical Pathology 35(3) : 203-209, March 1961.
(5C) SZM)~OWSKI, D., SCHUL~~E. H., SwAurx, K.-H., LEHN~. G. Zur
   okologischen Bedeutung des Schwermetallgehalts von Zigaretten.
   Blei-, Cadmium- und Nickelanalysen des Tabaks sowie der Gasund
   Partikelphase. (Oncological significance of heavy metal content of
   cigarettes. Lead-, cadmium-, and nickel analyses of tobacco as well
   as of the gas- and particulate phase.) Archiv fur Hygiene und Bak-
   teriologie 153(l) : l-8, February 1969.

(57) TADA, 0. Determination of nitrogen oxides in the air. Report of the
   Institute of Science and Labor (Japan) No. 60: 7-26, October 1962.
(58) TOTH, J. Uber Schwefelwasserstoff im Rauch des ungarischen Tabaks.
   (Hydrogen sulfide in the smoke of Hungarian tobacco.) Chemiker-
   Zeitung 37: 897-898,1913.

(59) Tow, G. P. Gaseous phase of cigarette smoke. Isolation and analysis
   for total aldehydes. Analytical Chemistry 27: 1788-1790, 1955.
(60) U.S. SENATE, 90TH CONGRESS, 1s~ SESSION. Public Health Service tech-
    nical report on "tar" and nicotine. Hearings before the Consumer
   Subcommittee of the Committee on Commerce. August 23-25. 1967.
    pp. 7-8.

(61) Wan, P., HAUSER~N, M. Betrachtungen iiber die VerLnderung des
   Gesamtwasser, Pyridin, Nikotin,  Ph enol, Brenzcatechin, Scopoletin
   und Kohlenoxid im Cigarettenrauch in Abhlngigkeit von der Zugnu-
   mmer und vom Rauchfilter. (Considerations on the variations in to-
   bacco smoke of cigarettes. The yield of crude condensate, total water,
   pyridine, nicotine, phenol, pyrocatechol, scopoletin, and carbon mon-

633


   oxide in cigarette smoke depending on the puff number and smoke
   filter.) Beittige NT Tabakforschung 3(3) : 169-202, -4ugust 1965.
(62) WALTZ. P., HAUSFAMANN, &I., hfosnr, F. Zur Bestimmung des Pyridins
   im Rauch von Cigaretten im Rahmen der Bestimmung der Gesamt-
   alkoloide. (On the determination of pyridines in cigarette smoke in
   the scope of the determination of smoke alkaloids.) Beitrage zur Tab-
   akforschung 2 (6) : 283-293, October 1964.

(6~) WATANABE. M., KOBASHI, Y. Tabako kemuri seibun no bunsekiho ni
   kansuru kenkyu. I. Gasukuromatogurafi ni yoru tabako kemurichu
   no itsusanka tanso oyobi tansan gasu no teiryo. (Analytical methods
   of chemical components in tobacco smoke. I. Determination of carbon
   monoxide and carbon dioxide in cigarette smoke by gas chromato-
   graphy.) Nippon Senbai Kosha Chuo Kenkyushu Kenkyu Hokoku So.
    10'7: 177-180, 1965.

(6~) WILLIAMS, J. F., HUNT, G. F. Ammonia in mainstream and sidestream
   cigarette smoke. Abstracts of Zlst Tobacco Chemists' Research Con-
   ference, Durham, N.C., October 19-20,1967. p. 14.

634


AborIlOrl

effect of marernzl rmoking. 437. 438
Accnaphthylenc

in cigar. pipe, and cagaxtt~ woke. 548
AcrUldchyde

Icvclr. effects of IODI" size. amount of
tobacco burned. and venUlatmn.
487490,494

2s suqxctcd conulbutor to health haz-
   ards of smokmg. 629
ACClO"C

as suspected contilbutor to health
   hazards of smokmg. 619
ACctOfllldC

a, surpbctcd conmbutor to health
   hazards of unokmg. 629
ACIOlCl"

cffccu of mhalatlon of. I" rats. 151
as urrtant ,n tobacco smoke. 51 I
levels. cffccts of room UC. anlounl of
tobacco burned. and venularion.
487-190.494

as probable contributor 10 health haz-
   ard$ of smoking. 628
AClylO"ltdC
as  surpcacd contiibutor IO health
   hazards of smoking. 629
Adcnocucmoma

prevalence WI male and female mlokcrs
   and nonrmokerr. 216
relstronxhlp of c&ret:c smoking 10.
   272-275.322
Adcnuma

papdIary. inductIon m rats by exposure
   to ClgaJctlc firs.. 374
pulmonary. mductmn I" mice by c~ga-
   rctw Imoke mhalatlon. 375
renal. rclationsh~p of smoking to. 322
Adrcnai glands

calccholaminc release from, nicotine
effects on. 32

Advisory Commrttce on Smoking and
Health

rcporl on c~garcttc smoke and conden-
   YlCS effects on oral cavity of
   animdr. 314
Aerobic capaary

effect of cc~xa`,o" of smoking. 613
e~cC:Jof CXCI`IY and smoking. 613,614
.Agc

atypical nuclei in esophageal eprrhelium
   arranged by rmoklng and. 405406
cl-feels on CHD, 23-35
Air poUuUo"

II ~a"% of COPD. 178.201.242-243
in cl~olog~ of lung "coplarmr. 302
and human CO burden. 142
relationshIp 0f lung n~~phns. rmoking

and place of rcr~dcncc. 278.281
rummary of ICCC"I Iindmgr. 5134

A:cohol
crhx.nol.  pcnrtrablllty of  d1550lvcd
   bcnzo(a)pyrcnc I" m,ce crophqcal
   cplthcbum. 319

Alcohol consumption
cffec1 on  crophacxl ncoplarms in
   smokar. 31s. 319
cffcct on laryngeal neoplasn~r in tobacco
   USCII. 306

effect on tobacco amblyopla. 531.532
and heavy ynokmg, effect on oral
ncophrmr. 314
smoking and. in esophageal ncopljrm
ct~olo~`. 64,66.67.570
smoking and.  in laIyngea1 ne0pbr.n
etiology. 567

smoking and, u1 oral ncoplavn e:~ology.
563

smoking and. in neoplasm development.
   570
Aicohohsm

paucnrr. smokmg 3nd ventilator func-
   ton in. 239
Allergy

effect on cardlovawular abnormah:ler.
   521
tobacco and. 5 13.521
tobacco smoke ~lr,ta"ts and. S20
Alpha-1-anutryps," delicrency
COPD prcdqovno" from. 176
determinal:on  USl"g  rmmunocleclro-
   phorcns. 177
in emphysema etwlogy. 520
smoki"g and, 520
Amblyopta, tobacco
alcohol conrumptm" effect on. 53 I-532
characteruarlon of, 531
incidence oi. 531
American Heart Arsoc~atlon
poolmg project on Cf1D. 19. 24. 26. 35
Ammonia
as  suspected contributor to health
   hazards of smoking. 629
Angina pectonr
effects of mcreased carboxyhemoglobin
   levels, in passwe smokers. 491, 497
incidence t" pipe and cl&v smokers.485

A"U"alS

esophageal neoplarmr I". induction by

niuoummer. 3 18
reqwarory tract of. neoplastic changes
foliowng cigarette smoke mhalatro".
  264.265

ski" of, carcinogcmclty of tobacco tars.
   264.293
A"lhIXC"C

in ciga. pipe, and c~garctte smoke. 548
Anthrantic acid. 3hydroxy-
urmary cxcretton of, rmokmg effects on.
   322

635


AnIleen-anlibody rcattlonl
a"crgya"d.S13-517
~,mokcr~ vs. nanrmokcrr. 515. SZl
tobacco and. 514-517
Aorllc ~ncuwrm
,mokmg and. 63.67.71
Aromatrc compounds
carclnogcnlc propcrues i"  cgdIcctc
   xmokc from. 290.29 I
dctecuon in ~rme usmg chcmdummcs-
   ccncc techmque. 323
&omat,c hydrocarbons. polycyctic
cffccc dorm8 prcenancy I" laboratory
   nnimalr.431.432
matcm&fctal exchange and. 433
Anhythmlar

formatIon in  NCOti"e  srlmuhtcd
   damaged myocadium. 54
hscnic

lung neoplasm monabcy i" smeller
   workers exposed to. 283
rcsplrarory tract carcinoma m workers
   cxpowd to. 282, 283
ArtWitS

aneurysm in aortic. cwaetrc rmokmg
eifectr on. 63,67.71
nrherosclcrortc.  increased by ti~arctte
smokmg. 59

now of c;uot>d. c$a~ct~c s"wkm8 effects
on.63

occlunonr of. cigarette rmoklng effects
on, 69
walls of.  mecharosm of lipoprorcin
infiltration. 59

walls of, mcotme-induced necrosis, 59
Artenorcleroslr
in aorta and coronary artcncr. cigarette
   smokingeffects 0".41.48-52
development of. carbon monoxrde cf-
   fects 0". 59

development of, effects of nicotme on,
34

lesion development in. ynoking cnhance-
mcnt. 32

peripheral. cigarette smoking effects on.
68-69

see also Cardlovavular diseases; Core
  nxy diseases

Aryl hydrocarbon hydroxylax
effect of bcnzo(a)pyrenc UI pregnant
   rats. 433
Ada

Central and Southeast, relationship of
   tobacco use and neoplabnr of oral
   cavity. 392
Asthma

bronchzd, cigareIIc smoking effects on,
   201
Alherosclcrovs

aortic, long term smoking effects. 48-52
Athlcbc pcrformancc
ru"ni"g.effcctof smoking.613.614
smokers vs. nonsmokers. 613.614
swimmmg. effect of smoking. 614
Atxopme

effects on bro"chocon~(llclion in dog%
  189

COPD mo~badrty rn smokers VI. 229
Iuyngul "caplaun~ m. relauonshq 10
  tobacco use. 583

lung neoplavnr m. ~cuo~ecove Itudlcr
of, 3s3

Bx:cna

cifcct of c~axltc smoie on axion of
   maccophagcs on. 191
pncumo*. mice rc~~s(;ulce following
   nguccta inhalation, 199
Bc"zfc)xcphcnanLhryhrylcnc
c.uElnogc"lc properws in cigarclIc
   smoke from. 290.291
l?cnz(a)a"tiace"c
alcoholic soluuon oi. pencaabihfy of
   mice crophagcal epahclium. 318
Bcn~bhnthracenc. 7.1 Zduncthyl
carcinoma inducuon in hamsters follow-
   ing innillauon of. 372
skin pamtmg wvrch, papdloma and
   rarcmoma induction in mxx by, 367
Benzcnc

as ruspccred contributor to health
   huudr of smokmg, 629
BcnzoO')fluoranthcne
c.ucinogenic propen,es in cigarc1tt
   smoke from. 291

Bcnzo(c)phcnanthre"e
carcmogcn~c properties in cigarette
   smoke from. 291
Bcnzofajpyrcnc

alcoholic x&~bon of. pcnetratio" of
mice csopha8eal cprthchum. 318
carcinogenic propcmer  in  cigaIc,le
smoke from. 290.291
caxmogcnialy of, m relation to asbestos
in hamsters. 283

in cyv. pope. and cigaretfc smoke, 491,
492

dctoxficatlo" by lung aryl hydroxylase.
283

effects during pregnancy in Laboratory
animafr, 431.432
errecLs of i"stdJation 0, implantaiion i"
?."lC".ll   tracheobronchiaI  UCC,
312.373

clTecls on awnal tissue and organ
cultures tn. 369.371
effecls with mfluenza virus on cigarette
inhalation by m~cc, 378
levels. effects of room six. amou*o(
tobacco burned, and ventilation.
487490,494

sarcoma induction in rats fouowing
   intidlation of, 372
skin painting with, papillama induction
   in mice by. 363.364
BcLel nut chewing
oral nwplarmr from, 392.395-396
Bicarbonare

in pancreatic sarctionr. effect of smoke
ing. 473.474

Bicycle crgomclcr performance
cudiovavulaz plramcrcrr m smokers vs.
   nonsmokers.612614

636


5u:h uc,ght

cffecf cl maternal rmokms. 417428.
433436

effect of matcrml smokmnp before and
durmg cunent prcrnancy by cqa~,tc
conrdnptlon.421423
effect  of maternal smokmg dunng
p,r"*our prrgna"ilc5.426418
efiect of paternal smokme. 424.4 25
effect of tobacco woke, n,co"nc. or
carbon  monoudc in  bboratory
ammalr. 428432

gestatton duar,on in smokcn VT. non-
rmokerr. 417420
mor,ality risk of low birth wqht ,nfxnts
of smok,ng vs. nonsmokmg morhers.
440-146

timing of influcnccof Smoking. 434.435
Bladder neoplasmr
frequency ,n smokers vs. nonmokcrs.
   264. 319-321

monal,ty rater. 319. 320
rebtlonsb,p of c,yuerte smokme to. 325
rcuospecwe stud,es of. and smokmg.
319.407410

and tryptophan metabohtcr in unnc.
  322-323

Blood cholexterol ICICIS
and coronay dwase. 17.18. 19-20. 39
effect of cabon monoxldc u1 rabb,tr.
   LSO

effect of smokme. 37. 39
eilect of smokmg m penpheral vascular
d,,ea>e. 68

and hyps:,ens,on. ,n smokers vs. non-
smoker,, 137

in p,pe and r,gx smokers, SSS. 586
m xmokerr vs. nommoker>, 94.98
Blood cucula,,on
eitec, of wnat~ons in hem%lobln and
   hemat. 62

Blood coagulation
etfect 0i smokmg. 32
Blood hpid,

ctfect of vnoking. 6142. 119-I 24
smoker, vs. nonsmokeri, 37
Blood platelet,

effccl of ,,,,oking, 62, 71
Blood preswre

coronz~y d,,eaw and smokmg. 39.43
du,toLLc. c,g.+~et,e r:nok,ng &ecu. 19
dlaxtohc. ,n smokers wrh CHD, 17-18.
20.38

effect of cxc,c,~c and smokmg. 611.
  614-616

cffrct of n,co*me. 32
effect of p,pe and c,gar rmokmg. 586
h,gh rash in mortahty from CVD.63
hypertenuve vs. nonhypertsnuvc. mor-
tabty rate, of CHD ,n. 38
rtsk _actorr m arter,o;clerons obhtcranr,
  68
in  rmohcrt.  nonsmokers.  and ex-
mokerr. 137-139
in smokers vs. nonsmokers. 37. 38.
99-100

systok. rnomhry from elevated. u,th
CHD. 38

Body wclghr

and hypcrtcnuon. ,n snokc,~. r.o"-
   rmokcrr. and cxsmokcrs. 137-l 39
Bxadycardra

dcvclopmcnt ,n dogs g,vcn n~oDne. 5 3
Bronchnl cplthclwm
h,r,olog,cal chlngcr ,n c.<ar. PiPC.
  c,pKrtc sloh~rr "I. r.onsr.oicrr.
   573.514.579
B,onchit,r

development ,n infants of maternal
   smokcrr. 499
inc,dcncc  in  children  of paJcnti
   rmokerr. 501.502
,nortal,ty rat,o~ ,n male p,pe and `WI
   smokers. 587.589
in pawve smokers, summary of rcccnt
   fmdmgs. 504
prcvalcncc in pipe and cigar unokcts.
   590.591
Bronchitis. chronic
delio,t!on of. 165
mortahty rn c,gare,te mokcrr. 201
mortahty rater. 165
smokers VI. nonsmokers. 221-231
Bronchopncumonia
development ,n dcgs follov!tie n8arctte
   sr,~okc ,nhalzr!on 297
Bronchopulmonary diseases. d~ron,c ob-
Stl"`IIY~
  all  pollution  relationship in.  178.
    242.343
characteruatlon of. 165
cpmrte smokmg effects on develop
   "lent. 201
grnctrc factors in pathoecncsls of. 174.
   176.178. 231
increased prevzdence of hetcrozygotes in.
    177-178
mortal,ty rates, 165-I 71
morta~rty rater in p,pe, c,:ar. and
   c,pare,te smokers, 201
morrahty ,~t,os ,n mr~le p'pe and crgar
   smokers. 586.587. S89
2.3.Butadione
  as  mspecled contributor  to health
   hazards of smoking. 629
Butylamme
  as  suspected contributor  to health
   hazards of smoking. 629
Butylaminc, N-methylnltroro
suspected cxcmogemc propenles in
   cqarrtlc woke from, 291

Cadmium

in cigarette smoke. relation to patho-
  genes~r of emphyrema. 180
Canada

COPD morb,d,ty of rmokcrs m. 230
mfectrous rerplratory &ease 111. rel3tiow
sh,p to smokin_e, 254
kidney  and bladder neoplasmr in
smokers ,n. 320

mortahty ra,es from COPD. 165-167.
  171

mortahty ratio\ from COPD. 169

637


rhrombovs in, rmokl"; rehtmnJl,p, 128
Ca"3d,ln veterans xtudy
lung  llCOpb,l"  nlon~l,ty ~.l"OS In.
   smokers vs. nonsmokers. 267
Cxbaole. 9i"c,hyl-
porrrble ,mpor,a"ce rn lobacco carcmo-
   gcner~~. 292
Carbon-14

Lbzled smoke parr,cul!e depo,,lion Ln
   hamster resplralory ,1x,.307-308
Carbon d,ox,de
as  suspected contnbutor to health
   hazards of smokmg. 629
Carbon monoxide

cholesterol levels i" rabb,ts. after ex-
**sure to. 150

and decrelw m exercise time before
claudlcatlon. 150

effect dur,ng pregnancy in laboratory
anmdr.430.431.446.447
effecr on aortas I" animals. IS0
effect on birth we,sht and neonatal
mortahty in 3nunals. 447
effect on cholerrerolird rabb,ts. 6 142
clfect on halthy m,okerr "I. "on-
smokers. 148

effect on human physmlogy. 56-58
effect on myocardrum. 151
rxposure to,  and human abwrpt,on,

143-150

as most bkely conrnbutor to hzllh
hazards of smoiamz. 627

su,,,mary of previous liindmfr on reh-
t,o"rh,p to pzs~,ve anoking. 483.
484.504

summary of recent lindmgr. lS5
from tobacco smoke. effects on psycho-
motor performance. ,ncludq aten-
tlYenes  and cogrut,on func~,on,
495497

Carbon monox,de levels
  m cigarette smoke. 55
effect of room size, amount of tobacco
   burned and vent,lat,on. 486.591
effect on exercise performance, 493
from smokers m burr and planes. 498
Carboxyhemoglobln
formawn in blood of smokers, 56.71
Carboxyhrmoglob,n levels
in oga~ette smokers. one hour after last
   clg"`etle, 147.148
and CO burden m m,okers vs. "on-
   smokers. 147, I48
effect on CO sbsorptlon. ,n paswe
   smokers. 591. 592
cffwt on exe*c,,e perfonn~"ce. 493.
   616.617

In re1u\es. 148. I49
in neonates of Ynok,ng mothers. 432,
433

I" ,mokerr vs. nonunokerr. by xx. race.
employment ~~10s or urban locrlmn.
  144-146

rummary of recent findmgr. IS5
L~I workers exposed to exhaur, gases. 143

eltea oi robacio cuing mcchodr. 582
CaIclnogc"r

lCt,On on or31 cavity. effect of salw3,
  314

c,pr. pipe. and cyarectc rmokc condcn-
sale. I" Sk!" palnllng cxpenmrnu In
anunals. 580-584

lirung of.,n `rg"e~te vnoke. 291.292
tobacco smoke const,tuc"tr IS. 580.584
Carc,"o,d tumor

prevalence in male and fern& unokcrr
   And nonsmokers. 276
CLlICillO"l3

fomlatlo" fouowing animal s!wl paintrIg
wlh smoke condensates, 363-368
induction in rats exposed to cigarette
tars. 374

und,fferentiated. relationship 10 ciga-
   re~tc snokmg, 274-175
Carcinoma. 2lveolx ceU
,nducuon ,n m,ce by cyarctte smoke
   ,nhak.r,on. 375

Carcinoma, anaplart,c
prevalence III male and female mokerr
   and nonsmokerr. 276
Carcinoma, bronchogenlc
development ," dogs following clflrette
   smoke mhslat,on. 295.298.2S?
morality irom. xelarionshipr to soak-
   I":, JLI pdlutjon and reudexc. 279
mortali,y UI rmok,ng vs. nc-mokmg
   asbestos workers. 283
Carcinoma. epldcrmoid
mortality from, reht,onsh~p to smoking.
   air poUu,,on and reudence, 250
prcvalencc u, male and female snokers
   and nonvnokers. 276
relat,ontiip of c,garettc rmoklng to.
   272-27s

Carcmoma, sp~rhchal
inductIon m m,ce by cigarette vnokc
   inhalx,on. 376

Carcinoma. oat cell
relationship of cigaette smohmg to. 173
Carcinoma. squamous cell
development I" mice drinking alcoholic
   benzo(a)pyrene. 3 18
in oral cw,~y. relationship to tobacco
   "se. 392-393

Carcinoma. tracheobronchial
induction ,n hamsters by cigarelte smoke
   inrtillar,on. 372-373
Cxdiac index

effect of cwxcke and smokmg, 6 124 14
Cardiovawuhr daeaser
atherosclerotic. effects of CO, 149. 150
morrabty ratios in male p,pe and cigar
   smokers. 58s. S86
pathogenests of, 1 SO. 15 I
summary of prorpeccive ep,dem,olog,cd
  stud,es for agar and p,pe unokers.
   586

ICC dso Artcrlosclerorir
Cudmvawuht ryrtem
cffccl of c,garettc rmoke on, 52.54.
   103-I 14

effect of ",cot,ne on. 52-54, 103.1 14

638


G:ciCohmLlrr
e!!ccx of nl`ollne orI rcIc3sc of. 32. 53.
    115

effect on blood clicnlar~on in coronary
   azzcr.er. 54
C3fS

cdury function in, effccl of cigarcrx
rrnokc on. 247

Ccnuai neT"O"S rystem
effect of carbon monoxldc in smoke on.
   56

Ccrcbro~xscular di,eascr
Ccfimllon of. 62
cp;dcmlologlcal studies. 149. 150
morlahty rates by rgc, sex and smokmg
   cll~rdicatlon. 151
moraitty rarcs, smokers VI. nongnokerr.
    6266
zlcrta!lry  ratlox in pipe and c:gar
   smokers. 585.586
Ccss.x!,on of smoking
cozpzred benefits in cipuctlc vs. pipel-

::<u smokers, 542.543
cEs:t on absolute aerobic oowcr. 613
c:Jeir on COPD dcvclopm~nt. 166
eYc:t on COPD development in British
yh~wclans. 168

cffrcr on COPD morbrdlzy and mor-

rallty. 201

effect on COPD morbidlty in smokers vs.
conrmokerr. I72

CIJCCI on coronary disease mortality
  rare. 28.4244, 102
cffccr on Infant bulb weighf. 421423,
  426428

inprowmcn!s in respnatory syslcm,
  174.175

rcht!on to incidence of CHD. 28.4244,
  102

prcvz!encc of. in pipe and cigar smokers,
  590.591

Chickcnr

diary funit~on m. effec: oi cigarctre
  rmoke on. 249

cffccl of cigarette smoke on embryos.
   370
ClxIdrcn

of smokcrr. incndence of pncumonla and
   bronrI+&& 502
of smokers. prevalence of rcsppuatory
   vmpiomr. 501.502
Chile

arherowlcrosis autopsy studier m.5 I. 52
ChOlCSICrOl

rabbm [cd.. -ubon monoxjde effects on.
6162

ryncrgxt~c rclationshrp of carbon mon-
oudc in coronary a[hctomatoGs. 59

deIini:lon and proccrrtn~.S4S
dcvclopmenr of crophqjul ncoplzrms.
  319

sirmlanr~cs wrth Irltlc c$wr. 594. 595
tar and nicoune content. 626.62;
tar levels of,  rclatmnrhlp to lury
   ncoplrrm dcvclopmcnt. 301,302
CigueIIc5, !ilter

summary oi prenour findings. 4
Cigars

definlrlonand procesring.545.546
Cigars. Illtlc

chcmlcal compontion of. 594, SYS. 5Y8
enluar~on oi potential pubbc health
impact. 592-598

shipment for domcrtlc consumption
   (1970.1972).592-594.597
simllarlry to ci~arctfes, 594.595
sugar and pti dilfcrences uith hrre
   crgxrr and c,~arcrres. 592.594
far and n~otinc co",cx.(. 594.596. 598
Cdiary actlvlly

effect of pipelc~qr ,moke vs. cigare~tc
   smoke m cats. 567.588
Clofibrate

and rcductlon in risk of sudden death in
   c~_earctfe rmokerx. 154
Cofiee dunkme

myocaldrsl rnfarction. smoking and. rn
   rmoke:i vs. nonsmokers. 141. I42
Comburrmn tempera!ure
cffcct on turnor~gcn~ actwity of p~pc
   and c~garerte robacco. 580,581
Congenital malformalmns
maternal smokmg and, JSO, 45 1
Connect:cuf Cancer Re31stry
figures on ageadJusted larynx neoplasm
   inadence, 303

figurer on mcidence of oral neoplarms.
310

Constitutional hypotheus
relationship to CHD and rmoking.4445.
   101-102
Cornsilk

smokmg. lack of arterial cpinephrinc
   lcvcl increase. 53
Coronary dlseaser
age-adjusted rater in smokers, 19
artcr~orclerolic, mortahty rater m U.S..
   17

arherorclerosls. effects of smokmg on.
59

blood prerrure of smokers Vs. "on-
smokers. 39.43

caboq dtoxide effects on oxygen upcake
in.58

death ratios of paired combinations of
high nrk. 21

cffccr of coffee drirzkmg and cigarcUe
rmokmg. I42

cprdemmlogul rludlcr. 136. 137

639


inadcncc and mortabty rates in former
smokcrr.42.4344
lnndcncc I" p:pc and c~gu rmokcn.585.
566

oral ncoplamr m. relauomhip of tobac-
   coua.390
Cyamde,

infarcuon in NYC pipe and cigar
  smokers. 28.3-1-35
infarction. rclat~onxhip to physical act-
ivlly, smokers vs. nonmrokers. 40
morbidily, relationship of rmoking to.
2X-31.33.35.8993
mortalrty and morbidity rctrospcct~ve
sludlcr, 36, 8993
mortabty rates in hypertcnrivcs vs.
nonhypcrtcnsivcs. 38
mortally rates in obcsc vs. nonobcr. 4 1
morlahty rates in snokcrs vs. "on-
smokers, 17-18. 20. 22-25
morrahry rater in. with i"cTcused carbon
monoxldc, 58

dctoticrtmn. m ~rcgnx" nokcrr "I.
nanmok~rs.433

in tobacco amblyopu etrology. 531.532
Crcchollonkm

Luyngcll "mplasmr m. relationship lo
tobacco use. 380.383
xcrum hpld dlffercnce tn smokers vs.
nolt~ 97

DDT
ar  ruqxcrcd contnbutor to hart"
   hazards of smokme. 629

Deaths. sudden

mortahy ra,cs of cigarette rmokers
from, AHA pooling project, 24, 26,
35

inadencc in p~pc and cigx rmokerr. 585
rcducuon  of risk of, in cigarette
   smokers. using clofibratc. 154
Denmark

mortzbly rates of pared combmatmns
of high rlrk. 2 I

athcrogenic effect of carbon monoxtdc
and hypoua. 60

mnrtahty rater of U.S. wtennr. 22. 34
mortahly rater. relationship to elcctro-
cardionaphx findmgr, 38
mortality ratios in p~pc and cigar
smokers. 585.586
n~otine effccl on coronary blood flow
I". 54
rchtiorlshlp  of blood pressure a"d
rmolmg.41.43

bladder ncoplarmr in. mctt&& and
rcwlts m retrospective fitudter of
smoking and. 407,409
carbon monoudc effects on human
blood tipxtr m. 12s
carbon mononldc effects on rabbit blood
!lpldr L". 12s

relationship of hext rate and smokmg,
41.43

~emm hpad dlflerenccs in smokers vs.
   nonsmokcrr in. 98
twins in. an_sna pcctoris in smokers vs.
   nonsmokers. 47
Delmarltis

relacmnshlp of physical actway and
smokmg. 37.39,40
relationshIp of Lrlglycendes to, 61
rclat~onsh~p to conrt~tut~,n~ makeup
and smoking.4445.101-102
rclatmnshlp to ECG abnormalities and
smokrng. 41.43

rclatmnrhrp to obcdIy and rmokmg.
  3941

among tobacro workers, 521
Diabetes mclhtus
effect on CHD i? smokers. 20
rclatronsh~p ullh crgarctte smoking I"
   pcnpheral rascular disease. 68
risk m mortahry from CVD, 67
Dibenz(a.h)acndmc
carclnogcmc properties in cigarette
   smoke from. 291

risk factors, 19.20. 36-37
smokers' age effects on development. 23.
35

in smokers with prcdtsposmg factors, 20
sudden death. and smoking,48
summary of previous findings, 4, 7
lee olzo Arleriosclerosis; hlyocardtal in-
   farct
CO!&

of paxnlal rmokerr. and rerpiratory
   symptoms in chJdrc". 499,501
p~evalcncc in pxpc and cigar onokcn.
   590.591
Crcsols

in cigar. pipe. and cigarette smoke. 547
as probable conlrtbufors to health
   hazards of smokm_e, 628
suspected caxinogenlc agent of c~garettc
   smoke, 292
Crolononitrdc
as  suspected conrrtbutor to health
   hazards of smoking. 629
Cuba

Dibcnz(aJ)airidme
  carclnoecruc properties  in  cigarette
    smoke from. 291
Diethylnltroomme
suspected cuclnogcnic properties in
   c~garetrc smoke from. 291
DimclhyLmmc                --
  as  suspected contrlburor to health
   hazards of smoking. 629
Dlmcthylnuxaamlne
suspected ~ar~~rag~nic propertrcs in
   ciperrc smoke from. 291
2,3-Diphosphoglycrnte
effects of carbon mo"ox,de OS. S6-U
DNA

inacaper m vnokcrs' oral cpithctial cells.
314

levels I" mouse lung exposed to cigaettc
   smoke. 187
Dogs

arhcropcnic clTectr of nicotine m. L k6
bladder "eopksmr in. fed 2-naphthy-
Imum. 322 .

laryngeal ncoplasms in. relation&p 10      bradycardu 2nd txhycardia in, TOIJOW-
`obacco use. 382                  mg mcotmc mjccuon. 53.54

640


641


cud,ac index, crfccr of smokmg. 612.
613

effect of smokzng znd tmokmg absu-
nencc.611.612.616.617
cffa,, of CO <.\po>urc Jnd lncrcsrcd
cubo\)hcl"oflobi" Icr*lx. 491, 493
influencing ixtorr.61 I. b16.617
summary ol tindIng, and mcchrnlrm of
ICUO". 616. 617 -

on trcadmti. cffat of smokmg. 613.

cffecls of ~rutton on body wcytht.
blood prc,,urc. and hypcncwon
development. 138-14 I
IOU- b,rth uaght ,nf*ntr of. 326428
mortlllty rate\ III. COPD. 201
tnorulny r~tc, in. coronary dl,ca*.
4244

NIIIWIY oi prwou, tindlngs o" hedlth
   ~~~nscqucncc~ oi CC~~I~IO". 6
Eye ,rr,t~t,o"

effects of exposure to c~pars~tc smoke.
I" p3uw rmokcr,. 495.496

cfTect of maternal imokmg.437449
cp!dcmioloncai rtud~er. I" u"oken v\.
   nonsmokcrr. 440446
I=lllCr?

advantages in reduction of part~culates.
   295. 301
Finland

blood pre<\urc drffercncer in rmoker5 vi.
nommoken. 99

COPD morhlday a" smokers. 226
lung ncopldw~ mon.ility in. rclatlnn+ip
   to tobacco uw. 271. 272
lunp ncopla$mr tn. rctrmpccttvc rtudy
   of. mahods. 351. 353
wrum llpld dlfferenwx in vnokcn vs.
   "on3mokcrx I". 94.95
\mokq ad "~cot~nc effect, on human
   blood h,wi\. I20
rltncrr texts

\mokcrr vs. nommoken. 6 IS
1 luoranthene

Formaldchydc
1,  wrpcrtcd conrr,butor to hul:h
   hsrardr of rmokmg, 6 29
F0rlX0Sd

ILUIC effect of cqarcttc vlokc on
   human pulmonvy functmn I". 195
rrnmm~hrm Study
cffcct of coficc drmklng on morrahty in
   Lmokcrs vs. "onrmokcrr. 142
FIl"CC

bkddcr ncoptumr m. mcthcdr and
rc,ultr in rctro,pectwe ,tudlrs of
rmohnp.407-409

CHD mortabty and morbjdrty I". 90. 93
ctgarettc smoke effects on animal tlrsuc
in. 369.370. 375

COPD mortabty of lmokerr I". 227
crophngcdl "roplaxmr I". rctrorpcctwc
   studzr of tobacco "szc. 404
laryngeal ncoplasmr I". rch\ionrhlp to
   tobacco u\e. 381.383
lung neoplasmr in. mcthodx of rctrospcc-
   we study of smokmg I". 352
oral ncopbrms I". rclalmn%hlp of tobac-
   couwa"d.389
Funqcadcs

concentration in cigarette bmokc. 291.

   292
FUIfUIA
15  surpccted contributor
   haurd, of smoking, 629

Gas phaw. cigarcttc xmokr
hdrmful con\t,tucnts I". 627
Gar1rtc xcretron

to health

effect of nlcotinc in laboratory dn~mxl\.
472,473

elfat of unukirq i" ul~cr pdtic"t\. 47 I
472

Gartroinrtwin~l disorders
prevalcncc tn ciparette and prpclcigar
   rmokrrr, 592
Genetic factor5

COPD pathogc"c+ and. 174. 176-I 78.
231

twin stud&. cl-feet\ of \mokm~. 4548.
   95
Germany

CHD morbidrty and mortality in. 91-92.
93

ciprcttc smoke inhaldrion cffcctr on
animal respiratory lract in. 376
lxynpeal ncoplarmr in. rclatiomhlp to
tobacco uy`. 381

lung ncoplasmr in, mclhodc of rctroqxc-
tivc xrudy of smokmp I". 349. 351.
3S2

polomum- IO k~clr in lungs of smokers
tn. 362

smoklnp and nicotme cffcctc on human
   blood hptds. I21
Gce3tl0n.4 ;rsr

eCTcc1 on pcrinrtal mortAty r;ltcs in
w"okinp YC. rmnsmokmg morhcr,.
440446

and lowhwth-wclphl infd"t\. cffccr of
mfcrnal \mokl"p. 4 I74 20

642


terms ured in smokmg and rentdatory
function. 241

Glucose mctabobsm
and insuhn revonw. sltcrption effects
   on myocarod response. 62
ClYCOgCll

lcvelr in mice lun_n e.vowd to ngarettc
   smakc. 187
Graphttc

    rcspmtory tract carcinoma m workers
      expoxd to. 282
Grip strength
    elfcct of smoking,611.612
   Cuanerhldrnc
    blockage of nicotine cardnc stimuLtian
       by. 53
  Gumea pigs
    lung neoplasm dcvelopmcnt followinp
       chronic  nickel carbonyl or dust
       inhalation. 282
    lungs of, cigarette smoke effects on
       sudactant activdy, 281
     rclpuatory  changes in, exposed to
      c,gxe:tc smoke. I88

H1mstcrs

bcnzo(a)pyrene inhalation by. cifect of
arbcrroy dust on carcinoma mduc-
tion. 188

bladder nroplas~~~r in, fed 2-naphthy-
laminc. 322

cigmtte smoke instillation or implsn-
   tation eifects on tncheobronchial
   tree of. 294,372.374
larynx of, efiect of cigarette smoke
   inhalation on, 307. 310
lung and embr/or. effects of cigarette
   smoke tarr on. 369-370
pulmonary changes from chronic nitro-
  gen dionde mhalat&. 246
rerpuatoty tract of, C-14 labeled particu-
   fates depositton in, 307-308
respiratory tract of. cigarette smoke
   inhalation effects on, 294, 377
ticalth Insurance Plan
myocardial infarction in pipe and cigar
   smokers under. 28.34-35
Heart

effect of nicotine, 32
Heart rate

cfiect of ~XCICW and smoking. 612616
cffec: cd rmokmg and coronary disease.
   41.43
Hematite
dust.  rcrplratory tract neoplasms in
   hamsters exposed to. 374
Hematocnt

un~tmns in. effect on coronary blood
   flow. 62
Hcmoglobm

aftinnty for oxygen. CO effects on
2.3dtphorphoglyceratc contxol of.
56-57

variations m. effect on coronary blood
now. 62

car`lrio?enK propenxs In clgarctte
   smukc. 290. 291
Hcxamcthomum
blockage of nic~ofme ard~lc >t~nuh':on
   by.53
Hook>hs

rmokcrr of, latyrgeal neoplasm induc-
   tmn in. 382
Humidity

and pathologic cffccts oi crporure to
   cprcnc smoke, 495
Hunguy

methods used for tcuospcctwc studier of
   lung ncopbrmr in. 354
Hydrocyanic 2nd
as probable contnbutor to hralth haz-
   ards of rmokmg. 628
Hydrogen cyamde
in clgarctte smoke. effects on body
   oxldatwe metabolism. 58
Hydrogen sulfide
as suspected contributor to health
   hazards of rmokmg. 629
Hydroqulnanc
a,  ruypcccled contr6utor to health
   hazards oi rmokmg. 629
3.Hydroxykynurcnmc
cxc:cmn of. smokmg effects on, 322
Hydroxyprotinc

level m m~cc lung exposed to cigaret!e
   smoke. 187
Hypertension

smokme eifcctr in. 137-141
summary of recent findmax. 15s
Hypoxemla

carbon dioxide effects on. 57. 7 I
Hypoxia

aortic arheromarosls development in
rabbits expored to. 60
portoperatwe. m smokers. 200. 256
postural, mechanism m asymptomatic
smokers vs. nonsmokers. 173
tissue. cxbon monoxtde effects on, 57

Iceland

lung neoplasms in. relationship to
   tobacco smoking. 270
Indeno(l,2,3<d)pyrene
carcinogenic properties in smoke. 291
India

esophageal neoplasms in. relrospectlve
srudles of tobacco use with. 404
laryngeal ncoplasms in. relatIonship to
tobacco "se. 381.382
oral neoplarmr in. trlationship of tobac-
co use. 388,392

relationshtp oi smoking to thrombosis
tn. 127

relationship of rmoklng to tuberculosis
tn. 253

smokmg and nicotine effects on human
   cardmvarcular rystem. 113
Indole. l-methyl-
posrlblr ~nitutor in tobacco carcmogenc-
   sis. 291

643


Sndurnlal hazards
effect ol dust on COPD dcvclopmcnt,
   201
cffcct on  COPD dcvclopncnt u1
   smokers. 179.150.244.245
Infant martahty
black vs. uh~tc nnokmg mothers. 443.
   446

effect of gcneoc differences and mnok-

ing. 446

effect of materrul vnohng. 437.449
effect of previous obstctncJ c~e"c"cc

and unokmg. 446
effect of saonocconomic background and
mmkina. 445.446

epidemrolopcal studier in snokcn vs.
nonsmokers. 440.446

factors othex th-m anoking. 445,446
risk of low-buth-weight mfants of
  smokmg v~ nonrmolclng mothers.
   440.446
Inrants

development of bro"ch!tis and pneum~.
  nu, and maternal rmokmg, 499
Influenza

rncidencc from aritlbody detici1 in
rmokmx. 5 19

prevalence m p,pe and cigar snoken.
490.491

Idlurnza "UUYI
effect on dogs mhaling ckarettc smoke.
   377

resistance of mice fouowing cIgarem
smoke mhaLxion. 199

Inhalation

efiect of previous smoking habits on
patterns of, 556.559
frcquencyper-puff in cigar and cigarette
smokers. 556.559
pipe. agas, and cigarette smokers, 554,
559

powble determiGng factors in patterns
of,553.554

summary oi previous fmdings on. 4
Intermittent cL?udicauoo
denease in c~erctse 1ime after exposure
   to co. 150

effects of coffee drinking and cigarette
smokiq. 142

rmokerrvs. nonsmoken, 144.148
Ireland

acute effect of cigarette smoke on
human pulmonvy function m. 194
CHD mortahty md morbidity m. 9 2
CHD mortahty and morbidW in.
smokcrr and "onrmokcn ip Q"

., _-

lung "eoplarms in. methods of rctrospcc-
tivc r,tudy of smokrng in, 354
maternal smoking and mfant weight in.
425

methods used in study of rmoking and
human pregnxwy. 420.422
Northern. monahty rater from COPD.
  170

occupar~onal exposure and smoking
rehtlonrhrpr to COPD in. 244
rclatwnlh~p of lung neopkvm to unok-
ing. a~ pollutron and rcudcnce m.
244

~crurn llpzd dliferencer in smokers Q.
   nonmokrrs I". 95
,mokmg and mcoune effects on human
  pcnphcral vascular system. 129
mokmg reLxt!onship to thrombau in.
   126
rure1

crgarc~rc smoke cffccts on animal cm-
bryor I". 369

monabty mtcs from COPD in. 166
Italy

strum lipid differcnocr in snokcn VS.
nonsmokers in, 96

txachcobronchial tree changes in smokers
and nonsmokers in. 289

lapa"

bladder neoplasm% in. methods and
results I" reuorpcctive srudJcr of
smokmg. 408.410
CHD monalrty and morbidity in.92
clgarctte smoke effects on human letal
lung t,v.uc J". 369

csophageA ncopLasms I" rcUorpcctwe
xtudles ol tobxcco use m, 404
kidney  and bladder neoplaonr of
smokers in, 321

lung neoplasmr, mortality of vnokcn
and nonsmokers in. 269
hmg neoplarms. retrospective smoking
study. methodsof. 352,354
mortality ratios. esophageal "eoplasms
in, 317

mortality ratios, pancreatic neoplarms I*
cigarette smokers. 324
rclatmnship of lung ncopksms to smok-
,ng, air polluuon, and residence in,
281

Kidney neoplxms
morrllity rates in U.S., 322
relationship of tobacco USA and. 325
in  rmakcrr and  nonsmoken.. 264,
   32&321

Korea

relation of human pulmonary histology
and smoking in, 281        -
tracheobronchel tree changes in mmkers
and nonvnokerr of. 285

Lactacmn

cff~ct of maternal smoking, 452455
cfkct of maternal smoking, sunmary of
fidingr. 455

cpldemialogical studies. 452
expertmental studlcr. 452.453
Lxtono

suspected carcmogenic agents in ciga-
   rette smoke. 291
Laparotomy

postopcratwe pulmonary compbcatio"s
followrng. in smokcrr VI. oon-
smokcrr. 200

644


Laryngeal ncoplasllu
devclopmcnt I" hamsters followmg qa-
   rctte smoke inhalacm". 265
development L" smokers. 307
inhdat~on parttmr and. 563
mortahty nrer.  in smokers \1. "on-
   smokers. 263-264
mortality r&s. 303.305
mortality ratios for pipe. cigu, and
   c~guettc smokers vs. nonunoken.
   563.566.561

rel3tlonship of tobacco use and develop-
mcnt of. 380-383
rehtlve risk for cigar. p,pe. and c,ga~~rtc
smokers. Ml-569
relawe risk rams from tobacco UY.
303.384

summary of retrospective studier. 568.
   569
L=Yn*

eplthelial changer in, clawfieafm" of,

307.309

hamster. C-14 labeled part~cuble depw-
r,on I". 307.308

halolo& chances I" cxgar. prl'r. and
   ctguerre smokers VI. "onmtokerr.
   567
IJp neoplarms

cigarette smoking m ecology of. S60.
561

ctgaar smokmg in eliolosy of. 560.5 61
p,pe mokmg m euology of. 315. 560.

561

r&twe nsk in p'pe. c+ir, and c~arctte
smokers vs. nonsmokers. 560.561



summary of ietmspcc~~ve stud,c,. 562
tobacco use rclat~on to. 387, 38X, 391.
   393
Lipoprotems

infdtratmn in arterial walls. carbon
   monoxide efiectr on. 59
III smokers vs. nonsmoker\. 95-98
Lummerccncc

tcchmques of, u,e in determining aro-
   matic hydrocarbons m urmc, 323
Lung ncoplasms

development I" dogs followmg cyareue
smoke inhalaoon. 265
cnnronmental and armaphetic factors,
278.28 I

group charactenstics of tobacco ore in
smoker, and nonsmokers, 266, 270,
355.359

groupmgs 272. 360
hatology of, and smokmg. 272-275
inhtlacmn patterns and. 573
mort~bty from chrommm compounds,
  283-284

morlalaty rafes expected I" U.S. m 1970.
  263.265
morfdhly  rates in \meller workers
expwed 10 arsen,c, 283
mortahty rater in smokers and non-
smokers. 266.269
mortahty rater in smokers m Norway
and I'mland. 271-272
mortahry rates m Unltcd Staler. 265
mortality rater. rmoklng dura"o" and,
266.270

mortallly rauos for cigar, pipe. and
c,&xrc,rc vnokcrr YI. nonpnokcn.
573-575

prcv;llcncc in mJlcr and females by
tumor type. 272. 276
reducuon m number uong filter-type
clglrercer. 301

relatmnrh~p of asbestos and smoking to.
283

reklivc nrk in cigar. pipe, and cigarette
smokers vs.  nonunokcrr,  573.
576.578

rctrorpcctwe study methods for smoking
relatmmhips. 266. 349-354
smoking m elmlo~y of. 263. 302
and smoking in women. 272,277
summary of prenour findings. 3.5-8
s"mmary of  retrospectwe  studier.
576-578

types lmpbcated in rmokmg. 263
Lungs

arterioles. effect of pipe/cigar smoking
vs. agarelte smoking on. 587
effect of clgarecre snake on tissue.
369-371

hamrfer. C-14 lab&d parbculales drp+
slllon in. 307-308

hufology of p!pc/agar smokers vs.
ag;lre,re mokerr. S8J

Macrophqcr. ~lveoL,r
effect of c~garccte smoke on. 191
hlamm3ls

rffect of cigarette smoke tars on cells.
  369

Maternal-fetal exchange
polycychc hydrocarbons and.433
hlethxrolcm
as  suspected contributor to  health
   hazard, of smokmg. 629
Methyl alcohol

as suspected contributor to health
   hazards of smoLmg, 629
3-hielhylcholanthrrne
effects during pregnancy in IJboralory
   animals, 43 I

N-Methylmrotmun~de
unnary excretron, effect of gnokmg.
   323
Mice

bladder ncoplasmr in. inductIon by
tryptophan metabohtes, 322
esophageal eprthchum of. alcohohc benr-
o(d)pyrene pcnetrdbdily of. 3 18
esophageal epithelium of, ml&swlved
benzo(a)pyrcne pcnctrability of. 318
lung neoplasm mcidence in. from chro-
mum oxide durr exposure. 284
lungs of. effects of cigarette smoke on.
  185. 369,370

pulmonary carcmoma induclmn in, fol-
lowng asbestos dust inhaldllon. 283
pulmonary changer from chrome nitro-
gen orlde mhalatlo". 187.246
pulmonary clearance I", clgsrette unoke
cffec[r on. 196

645


I"hALlllOll  cffcct on.  :94-195.
37s.379

,kin pzntmg of.  szokc cor.dcnutcs
   cficcts on. 295. 363-368
S~ouusks

clluuy runclmn 1". effect of cigarette
   smoke on. 249
.Honkcys

athcrogcnic effects of carbon monoxide
and hypoxu. 60

cdiary function "3. effccr of cigarctre
smoke on. 248

fetal bronchul tubes of. cffccts of
   cigxcttc smoke on, 371
rhesus. devclopmcnt of bladder nco-
   plssms from 2-naphthyLnunc. 322
squlrrcl.  muogen  o.udc effects on
   ICslS~P"cc to pncum"cocc"s. 199
Sforbldiry ra,,os

coronary dierws. smotcn with prcdu-
povng factors. 20
coronzry diseases, smokmg and. 28.31.
33.35

coronary diseases. rc~orpccuvc stwdicr.
36. 89-93

in Danuh twins. smokmg effects on.
45-17

development of COPD in smokers vs.
   nonsmokers. 171.221.231
Slorldlly rates

from blJddcr nsoplasms m L'.S. for
  1967.319
from  bronchopulmorary  d:seaw.
167.171

ccrcbrovawuLr dwxscs. cnokcn vs.
nommoker,. 62-63.6446
in chronx bronchopulmonary dircaw.
cigar/pLpc  smokers VI.  CI~arICllE
smokers and nonsmokers. 586. 587
compared rate< for cyarrttc VI. plpe/ci-
par er;+mokcrs. 542.543
coronary d!scaws, 17. 136
coronary d~,cdses. and age. 136
coronary dlscases. paxed combinations
of high rllk characten\tirs in. 21
coroxuy d&ass. retrospectwe studies.
36.8993

coronary diseases.  smokers vs. non-
smokers, 20.21-25
in Dnmrh twns. smokmp effects on. 47
csophagcal neoplasms. 3 I5
in former smokers, rclatton to CHD. 42.
4344

from kldncy neopksms m US. for 1967.
322

from lung ncoplasms expcctcd in 1970.
263.265

from I;ng ncoplasms for 1939 vs. 1967
in U.S.. 265

from lung nxplasms in uncltcr worken
cxpovd to aIscn,c. 233
from myocudul infarcrmn. 136
from oral ncopkrmr III 1967.3 I1
omrall mcs for ngu smokers VI. pipe
smokers. 54.9. 550

overall ,atcr for p.~+c'npa! srnoken and
dore-rcsaonsc ~~iaoons~zps. 550.559
ovcnu tata i0r p1pciclgar rmokcrs YS.
nonsmokcn. 549.550
overall raw from cancer in pipe and
cqa~ vmokcrr. 559
in SucOlsh rums. noksrs n. non-
smokers. 47

summary of prwious findtip, 36. 135
U.S. male vcwran, from CHD. 22. 34
Mortahty ratios

coronary deeaws. wth hiqh risk charac-
   tcristrcs. rsrlmawd. 24
esophageal neoplasmr. prospective and
   retrospective studies. 315.317
laryngeal ncoplasms. 303-30s
lung ncopllsms. tn male% by cigarette
   smoktng duntlon. 266.270
lung neoplasms in smokers in Norway
   and Fmland. 272
from pancrc~ric neophsms m nokcn
   and nonsmokers. 315-32s
in p~pc and cigar smokcrr by age and
   inhalation. 5S4.557
smokers ~5. nonsmokers. from lung
   ncoplams. 266.269
Mouth ncoplasms
frequency m smokers and nonsmokers.
   264

Mucopolysaccharidcs
funcuon as wrfactants m lung tissue.
   198
5!usscls

clliary functmn in. effects of cigaretlc
   smoke on. 247.248
hfyocardml infgc1
cofice drlnkinp. smokmg and, 141. I42
damare to rabbits after exposure to
   carbon monoxldc. 151
incidence in pipe and CI~X smokers. 585
martaht~-. in smokers vs. nonvnokers.
   136

. . .

sumrn~ry of previous tindings. 4. 135
in S,\edllh ~ornen smokers vs. non-

smokrrs. I36

se dro Coronary diwares
Xlyocardwm

cfrecrs oi hydrogen c);amde in smoke
on, 58

oxygen consumption in nicotine rtimula-
ted. 55

oxygen demand of nicotine effects, 34

2.Naphthylamme

development of bladder carcinomas and
paplllomas m dogs. hamsters. and
monkcyr. 322

suspcctcd bladder carcinogen in tobacco
smoke. 29 I

National Center ior Health Statistics
suwcy on rclaw~nsh~p of smokmg and
   incidence of rerpnatory disease. 199
Narmnal Coopcratwe Pooling Project
mortality statxstm from coronary dis-
   ease. 17-1 a
Natural gas

rcspuatory tracl carcinoma in workers
exposed to. 282

646


Ncoplzsms

adcnomalous, Ir:ducrmn m mice by c!ga-
ICI~E smoke ~nhaiaUon. 376
dcvclopmrnr m smokmg dogs. pcrcenr-
ages of. 300

rummary of previous tindmgs on rcla-
   uonrhlp to unokmg. 3-8
h'etherlands

cigarette smoke inhahlion cffxtr on
   mice Icxpxatory tract in. 315
lung nmplasms. methods oi relrospec-
   WC study oi smoking I", 349
serum lipid difference. m smokers vs.
   "onwnokersm.97
New York City

m)-ocardldl infarctions in cigar and pipe
smokers in, 28,34-35

Nickel
compounds,  surpcctcd  carcinogenic
   agcntr m c,garette smoke. 291. 629

antlpenlc propcrtlcs. 5 I4
atherogE"lc effects of. 116-l 18
m ctgx, pp. and cigarette smoke, 547
ch"~cal effects on ofispr~ng of smokmg
molherr. 454.455
I" duodenal ulca mduclion in cats. 472,
473

effect durmg prcgn~ncy in I3boratory
animals. 429,430
effect on blood lipldr. 119-l 24
effect on blood pressure. 32
effect on :ardlac rhythm. 32
effccc on cardiovascular system. 52-54.
  103-I 14

cffcct on cAtccholamme release. 32. 1 IS.
  151

effect on gartrw secretion in cats. 412.
  413

cffcct on gastr~ rccretion in ralr, 473
cffcc! on heart rate, 32
cffcct on ~mmunc response in man. 5 19
clfccr on lactation I" laboratory anlmalr.
4S2.453

cffcc: on lactauo" m smokers vs. non-
smokers. 453.454
cffcct on myocardium oxygen demand,
  34

cflcct on pancreat~ secretions in ani-
mllr.475.476

effect on pcrlpheral varculx system. 68.
  71.129-130

cffcct on p~pc/cigar smoke inhalatmn.
553.554

crncmn. by passwe smokers. 493
Inductlo" of necrorls rn .uterlal walls. 59
ncurogcmc cfkctr oi. 53
as potcnr,ator of duodenal ulcers m
  m1malr.475-477

sccrct~on. cflcct of cigar. pipe. and agu-
   me smoke an dogs. 586
Nlcollnc con!ent

effects of room IIZC. amount of tobacco
burned and \~cnuIac~on. 487-190.493

in htfle c~puur comyxrcd to CI~.~ICIICI and
   `L:UI. 593-596.598
I" mdk of Lborlrory xnlmalr. 4S2. 453
in milk of rmokmg morhcrr. 453
N~lric ox,dc

3% probable contributor 10 health hu-
   ads of rmokmg. 628
Nitrogen dtorzde
a, probable contributor to health bar-
   ardr of smokmg. 625
pulmonary chsnges in rodents chroni-
   cally Inhaling. 187.246
Nitrogen oxides

effects on resistance of squirrel monkeys
   10 pncumococcw, 196
4.N!troquinoh"c l-axrdc
alcoholic solutmn of. dcvclopmcnt of
   papdlomar in ma drmking. 318
Nitrorammes

effect on lactating hamsters. 4S3
N-N,trowmmcr

carclnogcnlclly  in  cigarette  smoke.
290-292

ewphagcal neoplasms Induced in annals
   by.318
Nonsmokers

allergrc rymptomr in. from robacco
   smoke exporurc. 520,521
carboxyhcmoglobm efieclr on oxygen
   uptake, 57
h'orcpmcphcne

effects of "acotine, I51
Norway

lung neop!asms I". for pope smokers. 270
lung neoplasms mortality I". relationship
to tobacco use. 271.212
tracheobronchlal tree changes in smokers
and nonsmokers of. 285

Obesity

relationship to smoking and CHD. 39-4 I
relationship to smoking L" peripheral
   arleriorclcroslr. 68
Occupational hazards
carboxyhemoglobm levels in workers ex-
   posed to exhaust gases. 143
Occupations

asbestos workers. lung ncoplarm mortal-
sty and smokmg. 283
asbestos workers. respnatory tract car-
cinoma, 282

bank employcer. smoking and COPD,
224

coal muters. impaired pulmonary func-
tmn in rmokmg, 189
coal miners, ropuatoty tract carcinoma.
282

coal mmerr. smoking and COPD. 179,
113.144-245
call mulcrr.  smoking and venillatory

I-uncrron. 233

flax mrll workers. smoking and COPD.

  22s
government employees. blood pressure
d~ffcrenccs  tn smokers vs. non-
smokers. 95

647


longrhorcmen, mortSry Gom rmoklng.
rclrcd ccrcbrovascular d&au. 66
lorqsholcmcn. momhry ram from CHD
:n, 24

longshorcmcn. smokmg and COPD. 24
longsnarcmcn. mokmg and rcnulatory
hmzuon. 234

mtdxxl srudcnts. xrum bpld d$fcrcnccs
  in sl"okcls vs. "onsmokcrr. 94
mcdul ,rudcnu. smokm~ and "lcotinc
effects on blood lipld icvclr. I20
mcdul students. xmokmg and thrombo-
ns rctat~onsh~ps. 126
mcdud students. rmoking and rent~la-
tory funcoon. 235-236
nickel workers. lung ncoplaons in. 282
phywanr. bladder and kidney "co-
piasmr m smoking. 319.320
phyuctanr. cersat,on of smoking effect
on COPD. 168

phyncrans. COPD mortahty rates. 17s
phyocuns. dcclmc m c~&~rttc smoking
I2lCS. 44

phywcians. mortahty from smoking-
rclawd ccrebrcvawular disease. 64
ph)-sxizns. morubty rates Gom CHD.
22

phyrrclans, mortality ratios from esopha-
gcal neoplarms. 316
physliixns. pulmonary funcr~on follow-
~n_e ccssauon of smokmg. 175
physxlans.  smoking and vent&tory
funcuon. 235.236, 739
plant wrkcrs.  occupauo"al exposure
and rmokmg relationshrps to COPD.
179.244.245

p!ant workers. xmoki"g and venlilatory
function. 232.2?-l

post oiticc workers. blood pressure dif-
fcrenccs in smokers vs. nonsmokers,
  100

post office workers. smokmg and venlila-
rary iuncuo". 235

post ofJicc workers, smoking and COPD.
  226.228
ptiners. YIUrn  lipid differences in
smokers vs. nonrmokers. 96
prisoners, smoking and njcotme effects
on peripheral vascular system. I29
railroad employees, mortahty and mor-
bu+ty. CHD and smokmg. 24, 30.93
smdtcs workers, lung neoplasm mortal-
ity from arsenic exposure. 283
soldiers. smoking and COPD. 223
steel rwrkers. COPD dcvclopmenl from
dust exposure. 119

stodcnts. carbon monoxide erieas on
blood Iiu,ds. 12s

studmts. mfcctious respiratory dlseaw in
smokers vs. nonsmokers. 254-255
students, morrahty from smoktng~elatcd
cexbrovascular disease. 64
students. monabty rarer from CHD. 24
rtudcnts. smoktng and COPD. 227
studcnrs. smokmg md mco~ne cflects
on blood hpld level, I21
students. &"okmg and thrombosis rcla-
uonsh:pr. 126

rrudcnts. rmoL.mg and vcntdaro~ iunc-
r~on. 237

tclcphonc company cmployccr. smoking
and COPD. 226

texrdc uorkccs. occupJtionll e\porure
and vnoking rclatlonril~p to COW.
244-24s

tranrportat,o" workers, XII poUuuon re-
laoon~!up to COPD. 22.l. 228
transportauo" workers. vnoking and
COPD. 224.228

trmsportatmn workers. smoking and
   vcrmlatory functson. 233,238
  uramum miners.  lung "cophxms I"
   smokers and nonsmokers. 282
uulity company employox. CHD mor-
   bidity in smokmg. 320-321
Oleic acid

suspected carcinogenic agent in cigarette
   smoke, 292
olive oil

pcnetrabllity of benzo(a)pyrene I" mlcc
   esophageal cpuhclium, 318
Oral neoplasms

alcohol consumption and smoking in
cuology of. 563
cstunatcd incldencc in U.S. for 1970.
310

inhalation patterns and. 561
mortality rates in, 31 I
mortabty rauos for pipe. ct_ear. and
cigarette smokers vs. nonunokcrs.
561-563

relal~onshrp of tobacco use. 311. 315.
387.393

rclat~vc nsk of development in pipe.
   cigar. and cigarette smokers vs. "on-
   smokers.561.564.565
smoking in etiology of. 315
summary of retrospective studies. 564,
   565
Organ CUltuIeS

agarette smoke effects on cell growth
   and reproduction in. 293.369-371
Orophxyngeal "eoplasms
frequency in smokers and nonsmokers.
   264
Oxygen

debt, effect of smokrng. 616.6 17
debt. exercise performance and. 616,
617

myocardial consumption of, folIowing
nicotme stzmulatio". 54, 7 1
transport in body. cubon monoxide
effects. 56.71

uptake in nonsmokers with specdic car-
boxyhemoglobl" levels. 57. 71

Palate

hamster. C-14 labeled smoke particul3t.x
   dcpovtm" in. 307.308
Pancreatic "eoplasms
rclallonshlp of smoking to mortality
   from, 324-325

smokmg and. 264.324-325

648


Pancreaclc sccrctions

brabonatc content. effect of smoking.
473.414

elfect oi ntcotmc in ammJlr.475.476
Papal"

pu!momy cflccts on rats expoxd to
   agarette smoke wrth, 189
Papdlomar

development in mtcc drinking alcohohc
bcnzopyrene. 318

formation followtng skin pintmg with
smoke tars. 363.365, 367
inducuon in hamsters exposed to bcnzo-
(alpyrenc, 372-373

Parents

incxdencc of pneumonia and bronchitis
in children of smokers. 501, SO2
prevalence of rerplratoty symptoms in
children of smokers. 498,499
smokers cough and phlegm producuon.
and respiratory symptoms in chil-
dren, 499

Particulate phase. cigarette smoke
  harmful conrtltuents I". 621
Parve smokers

patholo@c studies. 495
summary of prevtous findings. 483.484
summary of recent findIngs. 503,504
Passwe smokmg

CO, nicottnc. benro(a)pyrene. acrolein.
and aceraldehyde levels. 486-191
effects of carboxyhcmo$obin levels. in
permns wth angzna pectorlr. 491.
493

effects of carboxyhemo@obin levels on
CO absorption. 491,492
clfcLt> of CO in tobacco smoke on
pbychomotor performance. 495-191
eiiect\ of exposure to cigarette smoke.
in parive smokers. 495
effects of tobacco smoke constituents.
484494

effect, on bus and plane pa,se"gers. 498
c\cretlo" of "Kot"e, 493
cxpo,ure to clgarctte \mokc, and dcvcl-
opment oi eye dnd throat irrltauonr.
495.496

mcadcncc of pneumonia and bronchitis
I" chddrcn of parental smokers. 501,
502

matcrnrl unoking. and developmrnr of
bronch&s and pneun~onu I" mf~nls,
499.500

prrcnul cough and phlegm production,
2nd rcspnatory ,ymptoms in chil-
dren. 499

Peoples GA Light and Coke Co.
study of CHD. xer"m cholesterol and
   rmoLmg rclauomhlps, 39
Peptrc ulcer

cltn~cal studio. 469471
cpzdcmloloFwA studies, 469471
gdbtric secrctmn I" smokers M. "on-
~mokers.471.472

incrrasrd mottality m Japancrc rmokers
vs. nonsmokers. 469.470
matably tacos m Japancu adults by
age started ,mokmg. 469.470

momhty ratms I" mdc crgax and p,pc
rnokcrr. 592

predlspoung factors. 411
ICCU~C"EC t" smokers VI. nonsmokers.
471

smokmp and. 469
Pcrinatal stud,es
effect of maternal smoking on mortality,
   summary of findings. 448.449
Pcroxldcr

suspected carcinogenic agent tn crgucttc
smoke. 291

Personnhty charactcrislicx
iclatlonti!p to CHD and smoking. 4445.
   101-102
Pcaicldcs

content tn cigarette smoke, 291.292
PH

ptpclc~gat smoke inhalation and.553
of smoke m ciparcttes, cigars. and little
   crearr. 593.594.598
Phz~ocytostr

ciiect of c!$uctte wnoke i? rabbits. 5 19
pulmonary alveolarI. m smokers vs. "on-
rmokcrr. 191

Pharynced neoplarms
frequency I" smokers vs. nonrnokcrr.
   264

rclatmnrtxp to tobacco use. 388-390.
   392
Phenols

m ctcar. pope. and cigarette smoke. 547
ar probable. contrrbutorr to health haz-
rrdr of rmokm_e. 628
suspected carctnogenic agent of cigarette
smoke. 292

Phlecm productlo"
by parental smokers. and development
   of re,puatory symptoms m chiidren.
   499

by parent31 smokers. and incldenw of
   pneumonia and bronchitis in chil-
   drcn, 501.502
Phosphohprd,

function as surfactants in lung tissue.
198

smokers vs. nonsmokers. 95-96.98
Physxal actwiry

rcktronship lo myocardial infarction.
smokers "3. nonvnokers, 40
smollng 2nd tela(lonship to CHD. 37,
39.40

Piperidrne. nitrobo-
suspected rsranogenic properties in ciga-
   rette smoke from, 291
P"eUmO"la

inctdence in children of smokers. 501.
502

matern;ll smokme. and development in
infants. 499

m pawe rmokcrr. summary of recent
   l<ndi"gr. SO4
Poland

bltddm neoptasms in. methods and IC-
sultr in rctrospeclwc slud~er of unok-
ing and. 408.409

CHD mortahty and morbidity in.92
cwphagcal neoplasms in, retrospective
rtudles of tobacco UY with, 404


surpcrtcd c.ucmo~~n~ agent I" c@arclle
    smoke. 291-293.361-362
Port-ope~atrve comphcarxons
in duodenal ulcer removJ1. smokers vs.
    nonsmokers. 471
pulmonary.  smokers vs. nonsmokers.
    200-201
Potatium40

pre~nt I" tobacco leaf. 292
Preecl3npr1a

maternal rmokmg and. 456
I" rmokmg vs. nonxnokmg &omen, 456
Pregnancy

cuboxyhemoglobin levels in fetuses.

  IJK. 149
effccr  of smokmg durmg.  78-83.
417-156

effect of smoking dorm!, and develop-
ment of bronchltis and pneumon,a m
infanrs. 499.500

effect of lobacco smoke, n~cotme. and
carbon monoxide in laboratory an,-
mah. llS432

and prewous smokmg hoblts. effect on
rnfAnr burh ucqht. 426128
summary of prewour lindmes. 5.6
c!m~ng oi ~nllucnce of rmo&ng on birth
weight. 434,435

ree n/so Smokmg. maternal
Premalunly

rnd ma!ernal rmokmg. 426
PrOt"Z"J

cdlary function I", effect of cig.ircrte
   smoke on. 191.250
Psychomotor performance
cffecls ofC0 I" tobacco smoke. 495497
m pasivc unoker,. summary of recent
   hnding,. 504

Pubhc tranrportat,on
cffeclr of pawve smoking on bus and
   pIale pauengcrr, 498
F'ucrro RICO

erophdgral nroplrsms in. re~ro~pecwc
   audler of tobacco u,e wh, 404
rehtmnsh~p of tobacco use Jnd new
   pIam> of oral cwty in. 393
Pulmonq alvcoh

xuplurc. m p~pelc~r smokrn vs. cigu-
   e~te smokers and nommokerr. 587
F'ulmonay fibrow
in p~pclqar ,mokcrr VI. cqwette uno-
   kcrl and nonxmokcr,, 587
smoker, YJ. nonsmokers. 187
Pulmonary iunwon
effect on  exerted pcrformdnce in
   smokers 13. nonmoken.616
in p~pc/c~gar maker, vs. nonvnokcrr.
   587.591

Rabbits

arhrrogenic effects of carbon monoxrdc
and hypoxia. 60

atherogemc effects of nicotmc. 116-l 18
blood bpids in. rmokmg and mcotme
cffec:rr on. 123

cardlovarular function I". vnoking and
nicotine effeclr. 104. LOS
cholesterol fed. carbon monoxldc effects
on. 6162

cilmry function in. cig~rc~tc rmokc ef-
fect on. 247.248

pulmonary changes in cigarette >molung,

185

pulmonary clearance in. cigarette bmokc
effect on, 190. 196. 197

rkm painting. smoke condensate effects
   on. 293.364
Race

as a factor in perinatal mortahty in
rmokmg VI. nonsmoking molher,.
443446

ax a factor I" rtlllbirrh rater. 438,439
Rat5

blood hpids in.  nicotine and smoke
eliecu. I?4

cihary function m, cgarette smoke on,
247, 248

lung neopl.wns, from inuabronchial km-
plantkng of chromium compounds,
2R4

lung neoplasms, from nickel carbonyl
and dust inhalauon, 282
lungs. c~garctfe smoke effects on surfac-
tan, IC~IYI~Y. 198. 25 1

pulmonary ca&oma inducrmn follow-
ing asbestos dust mhalauon, 283
pulmonary changes from chronic mtro-
gen dioxide mhalation, 187, 246 _
respiratory tract, ci:arelte smoke inhale-
1x0" effeclr. 294. 375. 379

skin painting, smoke condensates effect,
293. 366

trachea; cigarette smoke effects on, 369
tracheal ligalion. agarette vnoke and
   pdpain effccls on. 189
tracheobronchul tree, cigarette smoke
   eifecls on. 294.312-375
Rewrpinc

n~cotmc cardiac rumulalion blockage by.
53

Rop~ra!ory function tests
vnokcrr. 172-i 73. 232.240
Rcrplrdlory symptoms
prcv;llrncc rn children of parcntd
   smokers. 498.499

650


anmd. ngarettc rmokc instrlla~~on or     S.5comas
impiantatio"  ellects on,  293.      formauon followmg ammal skm pannng
  372-374                         ulth smoke condenutcs. 364.366

a"imxI, effect of c;garette smoke tnhala-
t,on on, 294.295. 375-379
crfect of cigarette and qu smoke on
b:onchul reactw~ty. 190
dfect of cigarcttc smoke on human
cdiary luncuon. 191. 247-250
effect of cigarette rmokc on human
pulmonary clearance. 190.196
g~orrary of tcrmr used L" testing. 241
histological changes I" smokers, 180-183
,.mpro"eme"ts  in function followmg
rmokmg cersatlo". 174. 175
pathological  changer I"  clgmrte
smokers, 201

portoperatwe complicatlo" I". of
   srnokeir vs. nonsmokers. 200 202.
   256
pulmonary  alveolar phagocytorls I"
   rmokers VI. nonvnokerr. 19 1
pulmonary ,ntarcr,on I" dogs Inhaling
   c,gzuette smoke. 297
surface penman of. effect of cigaicrte
   smoke on. 198.25 I
surfacmnt actwty of. in smokers VI.
   nonsmokers. 198. 25 1
surLacta"rr I". definition. 198
Rcsprratory tract diseases
infecrmnr. prevJence UI smokers. 202
~"fecuons. smoking and, 202, 252-255
patholoelcal and cytological chaneer I".
   of smokers vs. nonsmokers. 284.269
vcntdatory function in. vnokeir VI "on-
   smokers. 201

Rctrospatwc studaes
lung neoplasms. and unokmg. methods.
   349.354
Rhodcsra

methods uwd in rewospective studxr of
   smoking in relatmn to lung neo-
   pLumr, 3S4
Rubtdlum-84

traOng Capdhry now in coronary blood
   now. 5s
RlJ""lJI~

effect of smoklnp. 613,614
Rural areas

lung neoplasm mctdcnce UI. in Switzcr-
Ilnd. 270

relatlonch#ps of lu": "eoplarm to vnok-
   ing. au pollution. and. 278-281
Rurxl populatmnr
lung "eoplasmr I". suspected ctlology of
   uweaxd. 302
RUWI

atherogcnlc effects of twotine on rabbrts
m. I lb

inductmn m rats by agarettc smoke
   in]ecuon. 372.373
sex

efiect of. I" alpha-1 antltrypr," defici-
ency emphysema, 177
effect of. in lung neoplasmr and tobacco
use, 270.355-359
efiect of.  in mortahty in cigarette
smokers. 302

cffcct of, on laryngeal neoplasm inci-
dence development, 303
rarm. eifect of maternal rmokmg on,

449.4so
I.allO.  m lung "eopL,m morullly u1
Sorway and Ftnland, 271.272

erTe:t oCtobacco e\tractr. 5 IS-517
tobacco anugcnr and. 5 14.5 IS
six lertr,g

chemrll co",t,tuc"ts I". 547-549
cd;oroxlcity. 588
eiiscr of curing methods. 558,589
effect of pH on mhdauo" of. 55 3
Ilrrlc, pH, compued to c!garttte and
   cigar smoke.S_4. 59X
tumongemc actiwty in laboratory a"~-
   mais. 580-584
S.xokc. cl<xette

alrerat~on of coronary blood flow, 54
bronchogenrc carcinoma lnductlon in

dog, mhahng, 295, 296
cadrnum levels I". 180
cubon monoxide levels in, 55
carclnogematy of components to ani-

mals. 303

cause of death in dogs from inhalation.
297

chemh-al constituents in. compared to
pqr/agai smoke. 547.548
ahan- mhlbltm". 293
effect of cunng methods, 588.589
efiect of nxkel on induction of lung xyl
h>dio\ylase. 282-283
effect on phqocytorir in rabbtts, 5 19
effect on rat and mouse fetus. site of
actKIn. 43s

effect on t,r,ue cultures. 293. 369-371
harmful cons~rtuents of. 625-630
~"hAwon by dogs. lung neoplasm dcvcl-
opmenr. 294-29s. 298.300
inhalahon cfCecls on ammal re~-puatory
trx,. 294-295.37s. 379
mhhuon effects on hamster Larynx.
307.310

651


hsting of Idcntrficd or surpcctrd turnon-
   eeruc qents. 290-293
2-"aphthylxn,nc tdcntlfied I". 291
"coplast~c chrngcr i" anun& mhzhng,
   261-26s
  tobacco  Jmblyopu  JelJtlonrhlp ,*
   cyanide mrtaballsm in.531.532
Smoke, pqlc

chcmtcal constituents I". 547.548
~~~~~~~~~~~~ of. 588
cffcct of pH on mhalatwn of, 553
turnongemc acuvity in laboratory ani-
   mals. 580-584
Smokers

COPD morbidity in. 172. 223.224.
221-228.230-231
effects of smoke on bronchul rcactivlty.
  190

esophageal ncoplxun mortahty ratio.
316

krdncy neoplasmr in. 320-321
lack of risk m CVD, 63
laryngeal neoplasm induction in.
380.383

laryngeal neoptasms I". 307
lung nsoplasms. lncldsnce in rural Swit-
zerland, 270

long neoplasms. mortahty in. 266.269
mortahty ratios from COPD in, 168-I 69.
  171

morlahty ratios from pancreat~ "eo-
plasms I". 324

myocardial mfa~ctron I". 28. 34-35
rcLtlonshlp of neopLsms of oral canty
with. 387-391.393-397
relatlonshlp to mfectious resplratoty dir-
CIYS. 253

rela!ive risk in laryngd neoplapn devel-
   opment. 302
Smokers. cigar

atypical nuclei in male esophageal epith-
clium. 405

bladder neoplasm, in, 3 19-3 20
cell rows and atyplcal cells in vocal cords
of, 306.385-386

Smokers, cigarefte
arterial occlusions in, 69
atherorclerosls in aortlc and coronary
   arteries, 48-52

atypical nucla in male esophageal epith-
clum. 405-106

bhdder neoplasms I". 319-321
cell tows and atypical cells tn vocal cords
of. 306.385-386

cessatmn of smokmg, effects on COPD
morbidrty, 172. 223. 225. 229-230
changes m ventllatory function and pub
monary histology. 201
comparattve nsk ior lung ncophsmr. 263
coronary diseases I". AIlA poolmg pro-
ject. 24, 26.35

coronary dwases usk by. 19-21
decline I". Brtttsh physrcians. 44
development of esophageal neopkuns.
319

dcvclopment of second pnmuy oral
ncoplasms r" conunumg. 313
effect of filters on emphysema develop
mcnt. 188

652

esophageal neopLxuns. murtably rlt~os
in, 316.317

h,staloqy and smokmg rclrt,o"shrp of
lung ncoplasnu in, 272-275
inhalatmn cifects on human pulmonary
functl"". 189.192-195
kldncy neoplasms in. 320-322
laryngeal  ncopLsm mductlo" I".
NO-383

lung "eophsmr. etiology. 265
lung neopbrms, mortality in, 266.
269.270

mortality from ccrebrovascular ducase,
6366

mortality ratios from COPD. 168.170
morta[lty *attos from +ncrcauc "eo-
plasms I". 324

postoperative pulmonary compbcatrons.
200.256

pulmonary surfactant actwity I", 198.
251

relationship in coronary and lower hmb
arter~osckros~s. 68
rclationshlp of asbestos in lung ncoplaun
mortabty, 283

rclationshlp lo mfectlous respiratory dis-
c.ues. 198. 252-25s
relatIonship to laryngeal neoplasm dcvrl-
opment Ml. 307

relatmnshlp to Ilp or oral c~v,ty "eo
olasms. 387-396

rela'tio"sh;p to lung neoplasms. 301.302
relatlonshlo with bladder "eoolasms in

mtn. 3i5

rclattonshlp with dult on COPD develop-
nlent, 179

risk of COPD in. 166
Smokers. pipe

atypical nuclei in male esophageal epith-
chum. 405

bladder neoplssms in. 319.320
cdl ~owsond alyptcal ceUr rn vocal cords
of. 306.385-386
COPD morbtdlty in. 172. 223-224,
22-i-231

development of esophageal neoplasms.
319

esophageal neoplarms, mortabty ratios,
316

kidney neopiarms in. 320.321
lack of risk in CVD. 63
laryngeal neoplasms. induction, 380.383
lung ncoplasms. incidence m Norway.
270

lung ncoplasmr. inctdence in rutal Switz-
erland. 270

lung neoplawns. mortaltty in, 350-353
mortahty tales from COPD, 168.169.
  171

mortalw ratios from pancreatic new
plarms. 324

myocardlal Infaxctm" I". 28.34-35
rclationshlp to k"f.xtious respiratory dis-
caYs. 253


rclat~onship to Iaryngcal ncoplavn dcvcl-
opmc"t, 307

relaconrn1p to lip ncoplms. 315
rclarlonrhlp to 01x1 cavrry ncopkrms.
337-390.393

rcLtivc rusk in laryngeal "eopiarm dcvel-
opmcnt. 63

relative nrk in lung ncopLwn dcvelop-
mcnt.302

;mokcrs ~3. nonsmokers
bladder "coplasms in, 319-321, 407310
cell rows and rtyp~cal cells in vocal cords
   of.306.385.386
ccrcbrovasakar disease mortality rates.
   6346

coronary disease morbidity ratios. 20
coronary dncare moitahty. 17-16. 20,
  22-25

coronary disease mortality. by sex.
  24-27

coronary drrcaw monahty. in Swdlrh
Wl"S.47

development of COPD in. 167. 171.
221-231

dJfcrenccr in emphysema Iypcs in. 180.
  IfI2

esophageal eplrhehal cells with alypicti
nuch in. 318

crophageal neoplasm morrality ratios,
  316-317

ericre"o" of tryptophan mc!abobter I".
  323

frequency of esophageal neoplasmr in.
  264

frequency of kidney neoplasms in. 264
frequency oimourh and phuyyngeal "co-
plssmr 1". 264

frequency of ""nary bladder ncoptauns.
264

group characteristxs in lung neophrms
and smoking in, 266, 270, 355-359
laryn_ecal ncopkrm mortality rates.
  263-264
laryngeal  neoplasm mortality ratios,
304-30s

laryngeal neoplasmr in. relationship to
tobacco "se. 380.383
lung fibrosis development m. 187
lung neoplasm mortality in uranium
miners.282

lung neoplasm mortality rater, for wo-
men.266-269

morrahty ratios from pancreatic "co-
plarmr I". 324

mortahry raftas al COPD in, 168-l 70
myocardul mfarctlo" relationshrpr to
phyrrcal actwity, 40
pathological and cytolo_eical changer in
rcsplratory tract of. 284.289
patoperative hypowmia I". 200. 256
portoperatwc pulmonary complications
1".200-201.256

Postural hypoxcmia mechanism in
rymptomauc. 173

ptdmonary alveolar phagocytorls in. 191
tcIa11on between CHD and rerum chol-
cm01 iA, 39

rclalmnrhip to mfectious respiratory dti-
CRY. 198.252-255

rcrum ltpldr I". 37.9498
surfacrant xuwty m !xng, of. 198. 251
type of lung ncoplamr m mdc and
   fcmdc. 276
Smoke r(rcams

CO lcvch ,n na~nsrcam cigar mokc.
486

c~nrtltucnts of tobacco smoke. 484494
rummay' oi previous findmg>, 483, 484
Smoke, tobacco

cffcct dunng pregnancy I" laboratory
anunalr. 428.429

CffCCI of conrutucnts on ptivt vno-
ken.484494

effect on stillbirth rate in l&xatory
animals.439

imtantsm.519.520
pH of, effect of leaf constituents. 594
summary of prcnour findmgs on rck-

llonship to parswe smokmg. 483.484
summsry of recent findings, 504
tumorigenic actwty. 580-584

Smoking

cficct of abstinence in cxercbe ocrfor-
mmcc.611.612.616.617 '
health hazards of, vmdaritwx of cigar-
cites wth little cigar. 594. 595
prevalence of m U.S. and Great Britain.
543.544

see also Passwe rmokmg
Smokmg. cpr

CO levels in mainstream smoke. 486
effect on morl&ly and morbldlty com-

pared to cigarette smoking. 541-543
in esophageal neoplasm developmenr.
567.570-572

garrromtertmal dlrorders and. 592
health consequences of. 549
histolo~al effects on bronchial eplth-

elw".573,574.579
histological effects on esophagus. S;O
histological effects on larynx. 5 67
histologtcal effects on lungs. 587
inhalation patterns and. 554-559
in laryngeal neoplasm development,

567-569

in lung neoplasm development. 553.516
and lung neoplasm mortalrty ratms,
573-57s

mortality ratios from cardiovarular dk
easer and. 585.586
mortality ratios from COPD and. 587.
589

mortality ratios from esophageal nc*
FkS"M and.567.570
mortality ratios from latyngcal nco
plarmr and. 563.566.567
mortahty ra:ior from oral ncoplarml
and.561.563
oral  neoplasm development and.
563-565
overall  mortality rater by amount
smoked. 550-552

overall mortality ratel from ncoplxsms.
559

pr.evaJcncc in Great Britain. 543,544
prevalence I" Umted States. 543,544
summary of previous Gndlngr on cffc~ti.
4.135              :


con~cnml rr-~!mimtmnr and. 450. 45 1
and derclopmcnr of bronchrrir and pncu-
monw I" mimu. 499.500
effect dunn~ pregnmcy. 417456
cffcctonbulh ucighl.4174`8.433436
cffccr on fetal mortahry. 438.439
effect on gcsut,o" dunuon. 417420
cfkct on tacuuon. 452455
effect on "cona~al caboxyhemoglobin
Icrclr.432.433

cffca on sex ratio. 449.450
precclampsu and. 456
sclccrivc acuon on fetus of CcItam wD
men vs. other. 445
timing of ~"flucncc on burh ueehl. 434,
435

SEC olro Prcgmncy
Smokmg. patcrnsl
efrect on Inisnt birth wclghr. 424, 425
Smokmp. pipe

cffei: on mortrhty and morbidity corn--
plrcd to c,~xc,,c rmokmg. 541-543
I" esoph~crJ neoplxm dcvrlopmcnr.
567.510-571

pstromtclliml dlrordcrs and.592
health consequencer of. 549
hi,lologtcal efirctc on bronchhl eplth-
ehurn.513.574.S79
h,srologml effects on ewnhqur. 570
hrrtoiogxal effects on Iu)`"x, 5 67
inhalalmn p&terns and. 554-559
in Ixyngcal ncoplasr~ development.
567-569

in lung neoplasm etiology by r"ou"t
smoked, 573-576

and lung neoplasm mortality rarior.
573-57s

mortzhry rattos from COPD and. 587.

589

mortality ratios from Lvyn@ "eo-
plarmr and. 563.566.567.570
mortahty rat101 from oral ncoplasms,
  561,563
orai  neoplarmr development and,
  563.565
overall  mortahty rates by amount
smoked. 5X-552
overall mortality rates fror" neoplasms
and, 559

pre%alencc m Great Brllain. 543.544
prevdlcnce I" UnIted States. 543.544
pu!momry hlstolopical changes and.587
summ.uy of prewous findmgs on cffecrs
   on smokers. 4.135
Snuff

ord lcslonr from, 313.387.390-391
Socioeconomxr

inCOPV. 178-179.242-243
South Afnca

csophqxal neoplasmr in, reuorpeclive
studier of tobacco "se.404
methods of retrorpeccwe sfudlcs of lung
neopl3rmr I". 354

occupational cxposurc and smoking I&-
tlonrhlr, 10 COPD in. 245

xruu~" l,pld dlffcrenccr 1" smoicrr vs.
   "onsmokers I". 95
SptlJ"l

prcv~lcnce I" pipe and cigu rmokcn.
   590.591
Steam acid

ruspccrcd cuc,nogcn,c agent of c$axrte
smoke, 292

Sttibirrhs

effects of maternal smoking. 438,439
ntts 1" blacks "I. uhltcs. 438.439
in smokers VI. nonrmokcrr. 438,439
Swcdcn

acute effect, of cigearctte smoke on
human pulmonary function. 194
blood pressure differences tn smokers YI.
nonsmokers. 100

CHD mortality and morbidity m. 93
CHD morbadiry in smokers in. 229. 231
effect of c~rcrtc smoke on 3nunals
ciliary function in. 247-250
genetic studies of twrns in. snokang
effcc(s on, 46. 95

laryngeal ncopl~rms in rslationshlp lo
tobacco "se, 382

relatmnrhlp of tobacco use and lip "KY
plasms I". 387

relatlonrhlp of tobacco "se and oral
   cav,ty neoplarms, 390
retrospective studies of esophageal "co-
   plarmr. by tobacco "se. 404
serum lipId dlffcrenccr I" smokers vs.
   nonsmokers of. 95
rmokwg and nicotine effects on human
   cardmvascula system, 11 I
rmohrng and nicotine effecrs on human
   per!phcral varcul~r system, 129
tracheobronchial wee changes I" smokers
   and nonsmokers in. 289
Swimming

effect of smoking, 612.614
Swrzerland

CHD morbidity and mortality I",
smokers vs. nonsmokers, 91
cigarette smoke effects on mice lung and
kidney [issue in, 370
cigarette smoke iohalation effects on
mice respiratory tract. 377
lung neoplasm incidence in cigar and
pipe smokers ofrural. 270
lung ncoplasmr. methods of retrospec-
twc study of smoking m. 351
serum lipld differences in smokers vs.
nonsmokers of. 96

Tachycardia

development in dogs induced by nice-
   tine, 53
Tars. c~garettc

carcmogenlc effect on animal oral cnvi-
tier. 314

carcmogen,cr,y. 290. 291
caranogentc properties on animal skin,
363-368.580-584
Cffect Of lnstlUallOn or implantation in
animal  lracheobronchral  tree.
372-374

effecl on "IIUC md organ cultures,
369-370

654


as hmful component of cigalcrtc
    rmokc. 626.427
summvy of prcvlous lindin3r on effects
   on smokers. 5
Tan. tobacco
dzfi",tlon. 627
in lrttic agus. compared to &~ctte~
   and cigars, 593-596. S98
sarcoma mducnon in mu following in-
    stdlation. 372
  skin  "~OphSl"  induction by, 264,
   363-368.580-584
Tctracthylammonium chloride
blockage of "icotinc cardiac slimu~tion
   by. 53
Throat

effect of cxpowrc to cigarette smokc.in

   pawvc rmoken. 495
ThromboanPut~ obliterans

ccssa~o~ of smoking. and remission. 70
dcfimtion. 69

fobacco allergy and. 521
mombosis

rmokmg znd, 62. 1X-128
ThIombus *oImatlOn
and smokxg. 154
Tlssuc ctiturer

effect of cigarette smoke on. 293.
   369-371
Tobacco

anr~gemuc properties of. 5 14
antigens, in smokers VI. nonsmokers, 5 17
curmg methods. and mcidence of respira-
tory infections in rats. 588, S89
effect on immune rcsponwr. 517-5 19
tluesued vs. air<ured. effect on rcspua-
tory system m animals, 587,588
pharmacolo@c. uritafive. and allergic ef-
fects, 5 19.521

Tobacco chewing
lip ncophsmr from. 387-3k9.391.392
oral ncoplasms from. 387-389.391-392
Tobacco extracts
anugenic properties, 5 14.5 IS
effect on skm. 5 IS-5 17
irr1tantsm.514.515
thromboan@tls obhterann and. 521
Tobacco Icafcomponcnts
anugcn1c properucr, 514.515
prcwnce of potassium, 292
Tobacco. pipe
dcfmttion and proccuing, 546
Tongue
hamster. C-14 ldbcled particulate dcposr-
   Lion m. 307-308

Trachu

hamncr. C-14 Lbelcd part~cuL~.c dcpos,.
tmn L". 307.308

Trcadmdl poformancc
clrdrovluutax puamctcrs in smokers VI.
   nonrmoicrr, 269-21 I
effect of \,camm C. 271
oxygen mtakc in smokcn vs. "OR
   smokers. 27 I
Tiiglyccndcr

coronary dlwaw relationship to. 61
smokers vs. nonsmokers, 95-96. 98
Twptophan mcubolirm
altcratio~~ by smoking, 323

carcmogc:cruc,ty i" nuce bladders. 322
rcl.al~on of CXCICEO,, ,n mokzr, and
   nanrmokcrs. 323
Tubcrculor,,
in  smokers VI.  nonsmokrn.  198.
   252-254
T-A-i",

nngma pcctoris development in. rmoklng
cflccu on, 46-47
gcnctrc studies of xmoldng cffccts on,
4S48

monality from CHD. in mokcn vs.
nonsmokers, 136.137
smoking effect% on morttity and morbi-
dity in, 41

United Kingdom

bhdder ncoplasms in. mcthods i? rcuo-
spawc studies of smokmg and.
408-410

blood prcrsurc differcnccr in Ynokcn VI.
nonsmokers in. 99, 100
cicrette smoke effects on animal cdtarv

ciguette smoke effects on huma" fetal
lung and mlcc trachea. 370
ciguettc smoke effects on human pul-
monaxy funcuon, 194.195
cipre!re smoke eifccts on mice respira-
tory tract. 378

cigarette smoke implantation effects on
rat t:achcobro"chwl ucc in. 372-373
COPD morbtdlly r" smokers m. 221-223.

229. 230

kidney and bladder ncoplasms in

smokers in, 320

lury "eoplasms mortality in males in
England and Wales. 266
methods of rcuorpcctivc study of lung
neoplasms and smokmg I", 350, 352
mortality from cerebrovawular disease
related to snokmg in. 64
mortality rates from COPD in. kck of
increaw, 166

mortality ratios from esophageal nc*
pkrmr in, 316

mortality ratios rrom laryngeal "co-
pLsms in. 304

occupational exposure and smokingrek-
tlonships to COPD in, 244-245
physicians m. decline in cigarette smok-
ing rater, 44

physiaans in. mortality from lung new
pksms in smokers and nonsmoken,
267

pulmonary function in. c$arette smoke
effects on, 194

relauonshlp of lung neopksms to smok-
ins. au poiluuon, and rcudencc in,
279-2HO

rel~bonshrp of smoking and tuberculosis
in, 252

scmm bpld diffcrenccr in smokers vs.
nonrmokcrs I". 91.98
rmokmg and "lcotmc elfccts on animal
cardlovarcular funcho" in, 103
rmokmg and "~cotmc &ecu on human
blood hplds m. 122

655


acute cffcct of clguette smoke on hu-
rn." pulmonary funcuon m.
  192.193.195

blood prcl,urc diffcrcnccr in nnokcrs n.
nonsmokers in, 99.100
CHD mortnhty and morbidity in
smokers vs. nonmokcrr in, 26-31.
33,89-91

cigarcue smoke effccu on antial diary
funcnon in. 247-250

crgarene smoke cffccts on animal tiwucl
in. X69-371

cigarette smoke cffect~ on pulmonary
surfaaanu and surface tension, 198.
251

ciparcttc smoke implantation effects on
animal  tracheobronchial txc,

372.374

cigarrtrc rmokc inhalaiion effects on
animal msptia1ory tract,, 375-376.
378.380

COPD morbidity in smokers. 221. 222,
224-226.227-228,231

esophageal neopksrns in, retrospective
studier of tobacco use. 404

csophqeal oeoplasmr mortity in. in
  1967.315

human pulmonary function following
ccssaoon of smoking in. 175
kidney and bladder neopksms in
smokers in. 319-321

laryngeal neoplasms incidence in 1967,
303

laryngeal ncopksms in, rclationshipr to
  tobacco "se. 304-305.380-381
lung neopkumr mortality rates in,
smokers and nonsmokers in. 266269
methods of retrospective study of lung
neoplasm, and smoking in. 349.354
mortality from sonic aneurysm r&ted
to rmokulg in, 67

mmtdity from cercbrovnwular d&s
related to smoking. 6466
mortality rater for bladder neoplamrs in

1967.319

mortiiy rates for COPD, 165-l 66
mortiity rater for kidney neophrms in
  1967.322

mortality raics for lung ncoplarms ex-
pested in 1970,263,265
mortahty rates for lung neoplarmr in
1939 vs. 1961.2b.S

mortality ratios for COPD, 166-l 71
mortality ratios for elophagcal nce
plzmr in. 3 16-320

mondiry ratbar for laryngcd neopbm~,
  304-305

mortality ratios for pancreatic nropksmr
in rmokur md nonrmokerr rn. 324

,,o~on,um-210 `svcb in lung of nokas
in. 361-362

r&co&up of human pul~oruy hitcl-
ogy and smoking in. 181-153
relationxhip of lung neoplamu to mok-
ing. au poUution. and rctidcnce i%
279-280

rck3tionship of noking to i-Jccuow
rcspuatory disca.ws in. 253-25s
rclatiodup of tobacco use md lip nc*
plzsml. 387-391,393
relationship of tobacco use and MC-
phsmr of oral awn. 387-391. 393
ICN~ hpid dlffercnca in anoken v).
nonrmokcn in. 94.96,97
smokmg and nrcotinc effects on anlnll
cudiovauu~ function ~1. 103.lC8
smoking and mcotmc effects on humln
blood lipids, 119-122
smoking and nicotmc cffccts on human
cardiovawukr system. 109-110. 112,
  113-115

,mokmg and nicoti,c effects on human
catccholammc levch, IIS
smoking and nrcofix effects on hurra
pcnpheral varulx system, 129-135
smokmg relationshIp to rhrombosir LT.
126. I27

trachcobronchial tree change3 in mokcn
   and nonsmokers in. 205-289
Uramum miners
lung neophsms in, 282
Urban =rcu

lung neoplasm raies in. 302
relationship of lung neoplasms. smoking,
   air pollution to, 278-281
Urban populat]onx
lung neoplarmr in. suspected etiology of
   innewd. 302

periphcr& rmoking and nicotine effect
   on.6849, 71.129-130
VCtltildtiO~

effectl on constituents of tobwxl
smoke, 486-lPl

Ventilatory function
effect of exercise and smoking. 614.6 15
Ventricular fibrillation
death from. nicotme effects on, 32
Venticular premature beats
effect of cigarctle smoking. 142
ViruSCS

hflucnza. cigarcrte rmokc effects on
   resistance of mtce wth. 199
innucnra,  niti~e:en oxide effects on
   squlnel monkey resxtance to. 199
Vitamin B 12

in pregnant smoken VL nonsmoker,, 433
Vitamin C

cffcct on treadmill pafomw,ce i,,
smokers YI. nonanokcn. 615


in milk of smokmmq mothcrr. 455          sumrn~~y of prcrious fiidings on effects
in prqmnt smokers VI. mnvnoiers, 433        of smokmg. 5-7

657