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CG 007 561

The Health Consequences of Smoking; A Report of the

Surgeon General: 1972.

Health Services and Mental Health Administration

(DHEW), Bethesda, Md.

72

151p.

Superintendent of Documents, U. S. Government

Printing Office, Washington, D. C. 20402 (Stock No.

1723-0051, $0.70)

MF-$0.65 HC-$6.58

Allergy; Cardiovascular System; Diseases; *Health;

Health Education; *Physical Health; Pollution;

Pregnancy; *Public Health; *Smoking; Special Health

Problems; *Tobacco

ABSTRACT

Six times since 1964, the Public Health Service has

issued formal reviews of the scientific evidence which links

cigarette smoking to disease and premature death. Each successive

review, including this one, has seemed to confirm and strengthen the

conclusion of the 1964 Report, that cigarettes are a major cause of

death and disease. In the first three chapters of this report, the

relationships between cigarette smoking and cancer, cardiovascular

disease, and non-neoplastic bronchopulmonary disease are reviewed and

evidence is presented which helps develop our understanding of the

mechanisms which are involved in these relationships. In the final

three chapters, information is presented on public exposure to air

pollution from tobacco, on the relationship between tobacco and

allergy, and on the harmful consituents which are found in cigarette

smoke. The chapter which discusses the harmful constituents of smoke

is a useful statement of our current knowledge in this field.

(Author)
U.S DEPARTMENT OF HEALTH.

EDUCATION WELFARE OFFICE OF EDUCATION

THIS DOCUMENT HAS BEEN REPRODUCED EXACTLY AS RECEIVED FROM

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FILMED FROM BEST AVAILABLE COPY
The

Health Consequences

of Smoking

A Report of the Surgeon General: 1972

U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE

Public Health Service

Health Services and Mental Health Administration

For sale by the Superintendent of Documents, U.S. Government Printing Office

Washington, D.C. 20402 - Price 70 cents.

Stock Number 1723-0051
hts,

Honorable Carl Albert

Speaker of the House of Representatives

Washington, D.C. 20515

Dear Mr. Speaker:

Enclosed is the 1972 report on the health consequences of smoking,

as called for by Section 8 (a) of the Public Health Cigarette Smoking

Act of 1969. As you will see, it continues and strengthens the findings of previous Public Health Service reports that cigarette

smoking is a hazard to the health of the American people.

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

As you know, it has long been the position of this Department that an adequate health warning should appear in cigarette advertisements along with listings of "tar" and nicotine. We are in support of the current efforts of the Federal Trade Commission to bring this about through the exercise of its regulatory powers. Should these

efforts fail, however, we would return to our previous recommendations that this should be accomplished through legislative action.

With kindest regards,

3

Sincerely,

Elliot L. Richardson

Secretary
Preface

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

reviews of the scientific evidence which links cigarette smoking to disease and premature death. Each successive review, including

this one, has served to confirm and strengthen the conclusion of the

1964 Report, that cigarettes are a major cause of death and disease.

In the first three chapters of this reps et, the relationships between cigarette smoking and cancer, cardiovascular disease, and

non-neoplastic bronchopulmonary disease are reviewed and evidence 'is presented which helps develop our understanding of the

mechanisms which are involved in these relationships. In the final

three chapters, information is presented on public exposure to air

pollution from tobacco, on the relationship between tobacco and

allergy, and on the harmful constituents which are found in cigarette smoke.

In the past few years, millions of Americans have stopped smoking because they have persuaded themselves that it is in their own

self-interest to do so; we must continue to encourage cessation as

the only certain way to protect both the individual and society from

the harmful effects of smoking. We must also, however, work towards reducing the dangers of smoking for those who have not

quit by developing less hazardous cigarettes and encouraging less

hazardous ways of smoking. The chapter which discusses the

harmful constituents of smoke is a useful statement of our current

knowledge in this field; it should interest not only research scientists but those who are concerned with public education and public

policy.

Research in smoking and health continues, as this report shows,

both in this country and abroad and under both public and private

auspices ; furthermore, the range of this research is widening as the

significance of cigarette smoking as a public health problem becomes

more apparent. In establishing the present series of reports, first

under Public Law 89-92 and now under Public Law 91-222, the

Congress has given us a means of encouraging the research we need

and of building a better understanding of the problem.

4

JESSE L. STEINFELD, M.D.

Surgeon General
Table of Contents

Letter of Transmittal Page

iii

PREFACE

PREPARATION OF THE REPORT AND

ACKNOWLEDGMENTS ix

Chapter 1. Introduction and Summary 1

Chapter 2. Cardiovascular Diseases 11

Chapter 3. Non-neoplastic Bronchopulmonary Diseases . 35

Chapter 4. Cancer 57

Chapter 5. Pregnancy 81

Chapter 6. Gastrointestinal Disorders 95

Chapter 7. Allergy 101

Chapter 8. Public Exposure to Air Pollution from

Tobacco Smoke .119

Chapter 9. Harmful Constituents of Cigarette Smoke 139

Index 151

v.

5

vii
Preparation of the Report and Acknowledgments

"Smoking and Health. Report of the Advisory Committee to the

Surgeon General of the Public Health Service"* was published in

1964. The following documents were subsequently published as reviews of the medical literature as called for by Public Law 89-92.

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"**

These documents reviewed the medical literature which had been

published since the original Surgeon General's Report. The format

of publishing a supplement to a supplement became unwieldy, particularly in tFe light of the lack of availability of previous reviews

to the general public. Therefore, when P.L. 91-222 was signed into

law on April 1,1970, calling for an 18-month interval between the

previous report and the new report, the entire field was reviewed

with an emphasis on the most recent additions to the literature.

The product of this review was: "The Health Consequences of

Smoking, A Report of the Surgeon General : 1971."**

The present document, "The Health Consequences of Smoking, A

Report of the Surgeon General : 1972," includes a review of the

literature which has been published since the 1971 Report was

completed. It also includes an evaluation of the state of knowledge

in three areas which have not been previously reviewed in these

reports: allergy and tobacco, public exposure to air pollution from

tobacco smoke, and harmful constituents of cigarette smoke.

The National Clearinghouse for Smoking and Health has the

responsibility for the continuous monitoring and compilation of the

medical literature on the health consequences of smoking and for

the preparation of this document. This is accomplished through several mechanisms:

Referred to in this manuscript as the Surgeon General's Report.

Referred to In this manuscript as "The Health Consequences of Smoking."

lx 6
1. An information science corporation is on contract to extract

articles on smoking and health from the medical literature of

the world. This organization provides a semi-monthly accessions list with abstracts and copies of the various articles.

Translations are called for as needed. Articles are classified

according to subject and filed by a series of code words and

phrases.

2. The National Library of Medicine, through the Medlars sys- tem, sends the National Clearinghouse for Smoking and

Health a monthly listing of articles in the smoking and health

area. These are reviewed, and articles not identified by the

information science corporation are ordered.

3. Staff members review current medical literature and identify

pertinent articles.

Initial drafts of the present review were prepared by the staff

director, assistant staff director, and consulting editors. The first

drafts of the individual chapters were sent to experts for review,

criticism, and comment with respect to the articles reviewed, articles not included, and conclusions. The drafts were then revised

until they met with the general approval of the reviewers. The final

drafts were reviewed as a whole by the Director of the National

Clearinghouse for Smoking and Health, the Director of the National

Cancer Institute, the Director of the National Heart and Lung

Institute, the Director of the National Institute of Environmental

Health Sciences, and by six additional experts both within and outside of the Public Health Service.

Acknowledgments

The NW-tonal Clearinghouse for Smoking and Health, Daniel

Horn, Ph. D., Director, was responsible for the preparation of this

report. Staff Director for the report was John H. Holbrook, M.D.,

and Assistant Staff Director was Elvin E. Adams, M.D. Daniel P.

Asnes, M.D., and David G. Cook, M.D., were Consulting Editors.

The professional staff has had the assistance: and advice ofa number of experts in the scientific and technical fields, both in and outside of the Government. Their contributions are gratefully acknowledged. Special thanks are due the following:

ANDERSON, WILLIAM H., M.D.Chief, Pulmonary Section, School of Medicine,

University of Louisville, Louisville, Kentucky.

ANTHONISEN, NICHOLAS R., M.D., Ph. D.Associate Professor, Department of

Experimental Medicine, McGill University, Montreal, Quebec, Canada. x
AUERBACH, OSCAR, M.D.Senior Medical Investigator, Veterans Administration Hospital, East Orange, New Jersey.

AYRES, STEPHEN M., M.D.Director, Cardiopulmonary Laboratory, Saint Vincent's Hospital and Medical Center of New York, New York, New York.

BAKER, CARL G., M.D.Director, National Cancer Institute, National Institutes

of Health, Bethesda, Maryland.

BING, RICHARD J., M.D.Professor of Medicine, University of Southern California, Huntington Memorial Hospital, Pasadena, California.

BOCK, FRED G., Ph. D.Director, Orchard Park Laboratories, Roswell Park

Memorial Institute, Orchard Park, New York.

BOREN, HOLLIS G., M.D.Chief, Pulmonary Disease Section, The Medical College of Wisconsin, Wood Veterans Administration Hospital, Milwaukee,

Wisconsin.

BOUTWELL, ROSWELL K., M.D.Professor of Oncology, McArdle Laboratory for

Cancer Research, University of Wisconsin, Madison, Wisconsin.

COOPER, THEODORE, M.D.Director, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland.

CORNFIELD, JettomnResearch Professor of Biostatistics, Graduate School of

Public Health, University of Pittsburgh, Biostatistics Project, Bethesda,

Maryland.

EPSTEIN, FREDERICK H., M.D.Director and Professor of Epidemiology, School

of Public Health, University of Michigan, Ann Arbor, Michigan.

FALK, HANS L., Ph. D.Associat6 Director for Program, National Institute of

Environmental Health Sciences, Research Triangle Park, North Carolina.

FARR, RICHARD, M.D.Head, Department of Allergy and Clinical Immunology,

National Jewish Hospital and Research Center, Denver, Colorado.

FERRIS. BENJAMIN G., JR., M.D.Professor of Environmental Health and

Safety, School of Public Health, Harvard University, Boston, Massachusetts.

FINKLEA, JOHN F., M.D.Acting Director, Division of Effects Research, National Environmental Research Center, Research Triangle Park, North

Carolina.

FITZPATRICK, MARK J., M.D.Obstetrician, Perinatal Biology and Infant Mortality Branch, National Institute of Child Health and Human Development,

National Institutes of Health, Bethesda, Maryland.

FRAZIER, TODD M.Assistant Director, Harvard Center for Community Health

and Medical Care, School of Public Health, Harvard University, Boston,

Massachusetts.

FaEsroN, JAMES, M.D.Associate Professor of Medicine, Head, Division of

Gastroenterology, University of Utah Medical School, Salt Lake City, Utah.

GOLDSMITH, JOHN R., M.D.Head, Environmental Epidemiology Unit, Bureau

of Occupational Health and Environmental Epidemiology, California State

Department of Public Health, Berkeley, California.

HANNA, MICHAEL G., JR., Ph. D.Director, Immunology of Carcinogenesis

Program, Oak Ridge National Laboratory, Oak Ridge, Tennessee.

HARKAVY, JOSEPH, M.D.Clinical Professor of Medicine (Emeritus), The

Mount Sinai Medical School of the University of New York, New York, New

York.

HIGGINS, IAN T. T., M.D.Professor of Epidemiology, School of Public Health,

University of Michigan, .Ann Arbor, Michigan.

HOFFMANN, DIETRICH, Pfi. D.Chief, Division of Environmental Carcinogenesis, American Health Foundation, New York. New York.

KELLER, ANDREW Z., D.M.D.Chief, Research in Geographic Epidemiology,

Veterans Administration Central Office, Washington, D.C.

xi

8
KIRSNER, JOSEPII B., M.D., Ph. D.Chief of Staff and Deputy Dean for Medical

Affairs, The Pritzker School of Medicine, University of Chicago Hospitals

and Clinks, Chicago, Illinois.

KOLBYE, ALBERT C., JR., M.D., J.D.Deputy Director, Bureau of Foods, Food

and Drug Administration, U.S. Department of Health, Education, and Welfare, Washington, D.C.

KRUMHOLZ, Mammal) A., M.D.Medical Director, Institute of Respiratory

Diseases, Kettering Medical Center, Kettering, Ohio.

LENFANT, CLAuns J. M., M.D.Associate Director for Lung Programs, National Heart and Lung Institute, National Institutes of Health, Bethesda,

Maryland.

LIEBOW, AVERILL A., M.D.Professor and Chairman, Department of Pathology,

University of California (San Diego), La Jolla, California.

LILIENFELD, ABRAHAM, M.D.Professor and Chairman, Department of Epidemiology, School of Hygiene and Public Health, The Johns Hopkins University,

Baltimore, Maryland.

LOWELL, FRANCIS C., M.D.Chief, Allergy Unit, Massachusetts General Hospital, Boston, Massachusetts.

MCLEAN, Ross, M.D.Professor of Medicine, Bowman Gray School of Medicine, Wake Forest University, Winston Salem, North Carolina.

McMiLLA ra, GARDNER C., M.D.Chief, Arteriosclerotic Disease Branch, National Heart and Lung Institute, National Institutes of Health, Bethesda,

Maryland.

MACMAIION, BRIAN, M.D.Professor of Epidemiology, School of Public Health,

Harvard University, Boston, Massachusetts.

MEYER, MARY B., MRS. Assistant Professor of Epidemiology, The Johns

Hopkins University, Baltimore, Maryland.

MITCHELL, ROGER S., M.D.Chief of Staff, Veterans Administration Hospital,

Denver, Colorado.

MURPHY, EDMOND A., M.D., Sc. D.Associate Professor of Medicine and Biostatistics, The Johns Hopkins Hospital, Baltimore, Maryland.

NEWILL, VAUN A., M.D.Chief, Health Effects Branch, Environmental Protection Agency, Washington, D.C.

PAPFENBARGER, RALPH S., JR., M.D.Chief, Epidemiology Section, Bureau of

Adult Health and Chronic Diseases, California State Department of Public

Health, Berkeley, California.

PARKER, CHARLES W., M.D.Professor of Internal Medicine, Division of Immunology, Washington University Medical School, St. Louis, Missouri.

PETERS, JOHN M., M.D.Associate Professor of Occupational Medicine, School

of Public Health, Harvard University, Boston, Massachusetts.

PETERSON, WILLIAM F., M.D.Chairman, Department of Obstetrics and Gynecology, Washington Hospital Center, Washington, D.C.

PETTY, THOMAS L., M.D.Asscciate Professor of Medicine and Head, Division

of Pulmonary Diseases, University of Colorado Medical Center, Denver,

Colorado.

RALL, DAVID P., M.D.Director, National Institute of Environmental Health

Sciences, Research Triangle Park, North Carolina.

RENzerri, ATTILIo I)., JR., M.D.Professor of Medicine, Pulmonary Disease

Division, University of Utah Medical Center, Salt Lake City, Utah.

ROBINS, MORTONChief of Study, Design, and Analysis Staff, Regional Medical

Programs Service, Health Services and Mental Health Administration,

Rockville, Maryland.

&morn, UMBERTO, M.D.Associate Scientific Director for Carcinogenesis,

Etiology, National Cancer Institute, National Institutes of Health, Bethesda,

Maryland.

xii
SCHUMAN, LEONARD M., M.D.Professor and Head, Division of Epidemiology,

School of Public Health, University of Minnesota, Minneapolis, Minnesota.

SHIMKIN, MICIIAEL B., M.D.Coordinator and Professor of Community Medicine and Oncology, Regional Medical Program, University of California

(San Diego), La Jolla, California.

STAMLER, JEREMIAH, M.D.Executive Director, Chicago Health Research

Foundation, Chicago, Illinois

VAN DUUREN, BENJAMIN L., M.D.Professor of Environmental Medicine,

Institute of Environmental Medicine, New York University Medical Center,

New York, New York.

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

New York.

The chapter on Harmful Constituents of Cigarette Smoke was

prepared somewhat differently from the rest of the report, being

the culmination of a one-day conference held in June 1970 to review

this area of knowledge and to discuss a draft report prepared in advance by staff of the National Institute of Environmental Health

Sciences and the National Clearinghouse for Smoking and Health.

Earlier in this section, some of these participants are acknowledged

as contributors to other parts of the report, namely, Dr. Daniel

Horn, who served as Chairman of the meeting, Drs. Daniel P. Asnes,

Fred G. Bock, Dietrich Hoffmann, Albert C. Kolbye, Gardner C.

McMillan, Umberto Saffiotti, Leonard Schuman, Benjamin L. Van

Duuren, and Ernest L. Wynder.

In addition, acknowledgments should be made to the following

who were also participants in the conference:

GORI, Gm BATTA, M.D.Associate Scientific Director for Program, Etiology,

National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

GRIPPITII, ROBERT, Ph. D.Director, Tobacco and Health Research Institute,

Universit7 of Kentucky, Lexington, Kentucky.

GUERIN, MICIIAEL, Ph. D.Senior Chemist, Oak Ridge National Laboratory,

Oak Ridge, Tennessee.

JAHVIK, MURRAY, M.D.Professor of Psychiatry and Pharmacology, Albert

Einstein College of Medicine of Yeshiva University, Bronx, New York.

KENSLER, CHARLES, M.D.Senior Vice President, Life Sciences Division,

Arthur 1). Little, Inc., Cambridge, Massachusetts.

KOTIN, PAUL, M.D.Vice President for Health Sciences, Health Sciences Center, Temple University, Philadelphia, Pennsylvania.

LIPTON, Monis, M.D., Ph. D.Professor and :hairman, Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina.

REMINGTON, RICHARD, M.D.Associate Dean for Research, School of Public

Health, University of Texas, Houston, Texas.

SCHMELTZ, ERWIN, Ph. D.Head, Lubricants Investigations, Eastern Utilization Research and Development Division, U.S. Department of Agriculture,

Philadelphia, Pennsylvania:

STANTON, MEARL F., M.D.Medical Officer, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Tso, TIEN C., M.D.Plant Physiologist and Leader, Tobacco Quality Investigations, Plant Science Research Division, ARS, U.S. Department of Agri- culture, Beltsville, Maryland.

10
The following professional staff of the National Clearinghouse for

Smoking and Health contributed to the preparation of this report:

Robert S. Hutchings, Emil Corwin, Elaine Bratic, Annabel W.

Hecht, Lillian Davis, Richard W. White, Richard H. Amacher,

Donald R. Shopland, Jennie M. Jennings, Dan Nemzer, Nancy S.

Johnston, and Gertrude Herrin.

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

Ritchie.

xtv

11
CHAPTER 1

Introduction and Summary
INTRODUCTION AND SUMMARY

Cigarette smoking continues to be a major health problem in the

United States today. It is still too early to tell whether the increasing rate of giving up smoking by adults during the years 1967, 1968,

1969, and early 1970 and the plateauing of this effect during the

past year have had any measurable effect on the morbidity and

mortality associated with smoking. At the same time that the major

health professions, voluntary health agencies, and public service

agencies concerned have joined with government agencies to reduce

the magnitude of this problem through education, research efforts

devoted to understanding how cigarette smoking affects biological

function to produce disease continue at a high level.

This report is largely concerned with reviewing the research reports which have become available in the past year. In this chapter,

brief summary statements are presented of the state of knowledge

in several areas. These are followed, where appropriate, by a "highlight" statement of significant additions to knowledge made as a

result of the new research presented in greater detail in the body

of the report.

The state of knowledge in three areas, which have not been reviewed previously, is also presented in the report. These areas are:

Allergy, Public Exposure to Air Pollution from Tobacco Smoke,

and the Harmful Constituents of Cigarette Smoke.

SUMMARY : CORONARY HEART DISEASE

Cigarette smokers have higher death rates from coronary heart

disease (CHD) than nonsmokers. This relationship is stronger for

men than women. Cigarette smoking markedly increases an individual's susceptibility to earlier death from CHD. Cigarette smoking,

hypertension, and elevated serum cholesterol are major risk factors

contributing to the development of CHD ; cigarette smoking acts

both independently and conjointly with these other factors to increase the risk of developing CHD. Cigarette smoking may contribute both to the development of CHD and to the exacerbation of

preexistent CHD ; both nicotine and carbon monoxide are thought

to contribute to these abnormal processes. Cigarette smoking is

associated with a significant increase in atherosclerosis of the aorta

13
and coronary arteries. Cessation of smoking is associated with a

decreased risk of death from CHD. The risk of CHD incurred by

pipe and cigar smokers is appreciably less than that incurred by

cigarette smokers.

Highlights of 1972 Report: Coronary Heart Disease

1. Recent epidemiological studies from several countries confirm

that cigarette smoking is one of the major risk factors contributing to the development of CHD. Avoidance of cigarette

smoking is of importance in the primary prevention of CHD.

2. Studies in man and animals have shown a greater myocardial

arteriole wall thickness in smokers than nonsmokers.

3. Experimental and epidemiological investigations implicate

the elevation of carboxyhemoglobin levels in smokers as a

contributor to the deielopment of CHD and arteriosclerotic

peripheral vascular disease.

4. Cigarette smoking is considered to be the major cause of pulmonary heart disease (cor pulmonale) in the United States in

that it is the most important cause of chronic non-neoplastic

bronchopulmonary diseases. Avoidance of cigarette smoking

is of importance in the primary prevention of pulmonary

heart disease.

SUMMARY: CEREBROVASCULAR DISEASE

Cigarette smokers have higher death rates from cerebrovascular

disease than nonsmokers.

SUMMARY: NONSYPHILITIC AORTIC ANEURYSM*

Cigarette smokers have higher death rates from nonsyphilitic

aortic aneurysm than nonsmokers.

SUMMARY : PERIPHERAL VASCULAR DISEASE

Cigarette smoking is a likely risk factor in the development of

peripheral vascular disease. Cigarette smoking appears to aggravate

preexistent peripheral vascular disease.

This summary statement is the same as that appearing in previous reports, because new

studies adding to the understanding of this area have not appeared. Consequently, the literature

in this area is not reviewed and the statement is only included to complete this summary chapter.

2

14
SUMMARY : NON-NEOPLASTIC

BRONCHOPULMONARY DISEASES

Cigarette smoking is the most important cause of chronic obstructive bronchopulmonary disease (COPD) in the United States. Cigarette smokers have higher death rates from pulmonary emphysema and chronic bronchitis and more frequently have impaired pulmonary function and pulmonary symptoms than nonsmokers. Excigarette smokers have lower death rates from COPD than do continuing smokers. Cessation of smoking is associated with improved

ventilatory function and decreased pulmonary symptom prevalence. For most of the United States population, cigarette smoking is a more important cause of COPD than air pollution or occupational

exposure; cigarette smoking may also act conjointly with occupational or environmental exposure to produce greater COPD morbidity and mortality. An infrequent genetic error, homozygous

alpharantitrypsin deficiency, has been commonly associated with

the early development of severe, panacinar emphysema. Whether on

not cigarette smoking acts together with the 1- ,mozygous or heterozygous deficiency states to increase the risk of developing either

panacinar emphysema or the more common forme of COPD has

not been adequately studied. Cigarette smoking exerts an adverse

effect on the pulmonary clearance mechanism. Respiratory infections are more prevalent and severe among cigarette smokers, particularly among heavy smokers, than among nonsmokers. The risk

of developing or dying from COPD among pipe or cigar smokers is probably higher than that among nonsmokers but is clearly less

1. than that among cigarette smokers.

Highlights of the 1972 Report:

Non-neoplastie Bronehopulmonatry Diseases

1. Recent epidemiological and clinical studies from several

countries confirm that men and women cigarette smokers have

an increased prevalence of respiratory symptoms and have

diminished pulmonary function compared to nonsmokers.

2. Investigations of high school students have demonstrated that

abnormal pulmonary function and pulmonary symptoms are

more common in smokers than nonsmokers.

3. Recent occupational studies confirm that cigarette smoking is

an important cause of COPD, acting both independently and

in combination with occupational exposure.

4. Recent experimental studies confirm that cigarette smoking

exerts an adverse effect on pulmonary clearance and macrophage function.

15

3
5. Pulmonary macrophages obtained from cigarette smokers exhibit characteristic morphologic differences when compared

to those obtained from nonsmokers.

SUMMARY : CANCER

Cigarette smoking is the major cause of lung cancer in men and a

significant cause of lung cancer in women. The risk of developing

lung cancer in both men and women is directly related to an individual's exposure as measured by the number of cigarettes smoked,

duration of smoking, earlier initiation, depth of inhalation, and the

amount of "tar" produced by the cigarette. The risk of developing

lung cancer diminishes with cessation of smoking. Smokers of pipes or cigars have a lower risk of developing lung cancer than cigarette

smokers. Certain occupations are associated with an increased risk

of developing lung cancer. In these occupational settings cigarette

smoking appears to exert an effect that produces much higher lung

cancer rates than those resulting either from the occupational exposure alone or from smoking alone. Factors associated with urban

living result in an increase in the risk of developing lung cancer ; this effect, however, is minor compared to the overriding effect of cigarette smoking.

The smoking of cigarettes, pipes, and cigars is a significant factor

in the development of cancers of the larynx and oral cavity. Pipe

smoking is causally related to cancer of the lip. The significant asso- ciation between smoking and the development of cancer of the

esophagus is somewhat stronger for cigarettes than for pipes or cigars and the combined exposure to alcohol and cigarettes is asso- ciated with especially high rates of cancer of the esophagus. Cigarette smoking is associated with cancer of the urinary bladder in men. There is also an association between cigarette smoking and

cancer of the pancreas.

Highlights of the 1972 Report: Cancer

1. Preliminary results from a major prospective epidemiological study in Japan demonstrate a strong association between cig- arette smoking and lung cancer. A dose-response relationship

was demonstrated for the number of cigarettes smoked. These

findings in an Asian population with distinct genetic and cultural' characteristics confirm the major importance of ciga- rette smoking in the causation of lung cancer, a conclusion which up to now has been based largely on studies of Cauca- sian populations in the United States, Canada, and Europe.

4
2. Ex-smokers have significantly lower death rates for lung cancer than continuing smokers. The decline in risk following

cessation appears to be rapid both for those who have smoked

for long periods of time and for those with a shorter smoking

history, with the sharpest reductions taking place after the

first two years of cessation.

3. The risk of developing lung cancer appears to be higher for

smokers who have chronic bronchitis. Though both conditions

are directly related to the amount and duration of smoking,

an additional risk for lung cancer appears to exist for cigarette smokers with chronic bronchitis which is independent of

age and number of cigarettes consumed.

4. Experimental studies on animals have demonstrated that the

particulate phase of tobacco smoke contains certain chemical

compounds which can act as complete carcinogens, tumor

initiators, or tumor promoters. Recently, other compounds

have been described that have no independent activity in twostage carcinogenesis but accelerate the carcinogenic effects of

polynuclear aromatic hydrocarbons in the initiator-promoter

system.

5. Additional epidemiological evidence confirms a significant association between the combined use of cigarettes and alcohol,

and cancer of the esophagus.

6. Epidemiological studies have demonstrated a significant association between cigarette smoking and cancer of the urinary

bladder in both men and women. These studies demonstrate

that the risk of developing bladder cancer increases with inhalation and the number of cigarettes smoked.

7. Epidemiological evidence demonstrates a significant association between cigarette smoking and cancer of the pancreas.

SUMMARY : PREGNANCY

Maternal smoking during pregnancy exerts a retarding influence

on fetal growth as manifested by decreased infant birth weight and

an increased incidence of prematurity, defined by weight. There is

increasing evidence to support the view that women who smoke

during pregnancy have a significantly greater risk of an unsuccessful pregnancy than those who do not.

SUMMARY : GASTROINTESTINAL DISORDERS

Cigarette smoking males have an increased prevalence of peptic

ulcer disease as compared to nonsmoking males and a greater peptic

17
ulcer mortality ratio. These relationships are stronger for gastric

ulcer than for duodenal ulcer. Smoking appears to reduce the effectiveness of standard peptic ulcer treatment and to slow the rate of

ulcer healing.

Highlights of the 1972 Report: Gastrointestinal Disorders

1. A possible link between cigarette smoking and peptic ulcer

has been demonstrated in dogs in which nicotine was found to

inhibit pancreatic and hepatic bicarbonate secretion. This

could lead to peptic disease by depriving the duodenum of

sufficient alkaline secretion to neutralize gastric acidity.

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

reflux.

SUMMARY : TOBACCO AMBLYOPIA*

Tobacco amblyopia is presently a rare disorder in the United

States. The evidence suggests that this disorder is related to nutritional or idiopathic deficiencies, in certain detoxification mechanisms, particularly in the metabolism of the cyanide component of

tobacco smoke.

SUMMARY : NON-NEOPLASTIC ORAL DISEASE*

Ulceromembranous gingivitis, alveolar bone loss, and stomatitis

nicotina are more commonly found among smokers than among

nonsmokers. The influence of smoking on periodontal disease and

gingivitis probably operates in conjunction with poor oral hygiene.

In addition, there is evidence that smoking may be associated with

edentulism and delayed socket healing. While further experimental

and clinical studies are indicated, it would appear that nonsmokers

have an advantage over smokers in terms of their oral health.

The information contained in the following three summary statements: Allergy, Public Exposure to Air Pollution from Tobacco

Smoke, and Harmful Constituents of Cigarette Smoke, is new and

appears for the first time.

This summary statement is the same as that appearing in previous rePorts, because new

studies adding to the understanding of this area have not appeared. Consequently, the literature

in this area is not reviewed and the statement is only included to complete this summary chanter.

6

18
SUMMARY OF THE 1972 REPORT : ALLERGY

1. Tobacco leaf, tobacco pollen, and tobacco smoke are antigenic

in man and animals.

2. (a) Skin sensitizing antibodies specific for tobacco antigens

have been found frequently in smokers and nonsmokers.

They appear to occur more often in allergic individuals.

Precipitating antibodies specific for tobacco antigens

have also been found in both smokers and nonsmokers.

(b) A delayed type of hypersensitivity to tobacco has been

demonstrated in man.

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

3. (a) Tobacco smoke can contribute to the discomfort of many

individuals. It exerts complex pharmacologic, irritative,

and allergic effects, the clinical manifestations of which

may be indistinguishable from one another.

(b) Exposure to tobacco smoke may produce exacerbation of

allergic symptoms in nonsmokers who are suffering from

allergies of diverse causes.

4. Little is known about the pathogenesis of tobacco allergy and

its possible relationship to other smoking-related diseases.

SUMMARY OF THE 1972 REPORT: PUBLIC EXPOSURE TO

AIR POLLUTION FROM TOBACCO SMOKE

1. An atmosphere contaminated with tobacco smoke can contribute to the discomfort of many individuals.

2. The level of carbon monoxide attained in experiments using

rooms filled with tobacco smoke has been shown to equal, and

at times to exceed, the legal limits for maximum air pollution

permitted for ambient air quality in several localities and can

also exceed the occupational Threshold Limit Value for a normal work period presently in effect for the United States as a

whole. The presence of such levels indicates that the effect of

exposure to carbon monoxide may on occasion, depending

upon the length of exposure, be sufficient to be harmful to the

health of an exposed person. This would be particularly significant for people who are already suffering from chronic

bronchopulmonary disease and coronary heart disease.

3. Other components of tobacco smoke, such as particulate matter and the oxides of nitrogen, have been shown in various

19 ;

7
concentrations to affect adversely animal pulmonary and

cardiac structure and function. The extent of the contributions of these substances to illness in humans exposed to the

concentrations present in an atmosphere contaminated with

tobacco smoke is not presently known.

SUMMARY OF THE 1972 REPORT:

HARMFUL CONSTITUENTS OF CIGARETTE SMOKE

A number of substances or classes of substances found in cigarette smoke are identified as those which are judged to be contributors to the health hazards of smoking. These constituents are

further divided into the most likely contributors to these health

hazards (carbon monoxide, nicotine, and tobacco "tar"), substances which are probable contributors, and those which are suspected contributors. The recommendations for control in this area

are to seek progressive reduction of all harmful constituents in

cigarette smoke with priority being given first to the most likely

contributors named and second to the probable contributors to the

health hazards of smoking. These judgments represent the consensus of experts based on current knowledge and are subject to modification and further elaboration as more knowledge becomes

available.

8

20
CHAPTER 2

Cardiovascular Diseases

21
Contents

Page

Coronary Heart Disease

Introduction 13

Epidemiological Studies 14

Interaction of Smoking and Other Risk Factors 16

Autopsy Studies 19

Experimental Studies 21

Nicotine and Cigarette Smoke 21

Carbon Monoxide 21

Smoking and Thrombosis 23

Cholesterol Content of Tobacco and Tobacco Smoke 24

Cor Pulmonale (Pulmonary Heart Disease) 24

Cerebrovascular Disease 24

Peripheral Vascular Disease 25

Oral Contraceptives, Thrnmbophlebitis, and Smoking 26

Highlights of Current Cardiovascular Information 27

References 27

1 LIST OF TABLES

Table 1.Incidence (1963-1970) of heart infarct in relation

to tobacco consumption in "The Men Born in 1913,"

Goteborg, Sweden 15

Table 2.Cigarette smoking at entry and subsequent 20-year

CHD incidence among Minnesota men

Table 3.Human autopsy study. Comparison of the thickness of myocardial arteriole walls in smokers and non15

smokers 19

Table 4.Average values of carboxyhemoglobin and serum

cholesterol in Danish Smokers and nonsmokers in control

group and group of patients with arteriosclerotic cardiovascular disease 23

22

11
LIST OF FIGURES

Figure 1. Canine autopsy study. Comparison of the thickness of myocardial arteriole walls in 32 smoking dogs

killed after 875 days and 8 nonsmoking dogs

12

23

.
INTRODUCTION

In the United States more people die from coronary heart disease

(CHD) than from any other disease; furthermore, CHD is the

single most important cause of excess death among cigarette

smokers (54, 57). The 1971 report, "The Health Consequences of

Smoking" (56), outlined the growing magnitude of this problem

and summarized the relationship between smoking and coronary

heart disease as follows :

1. Data from numerous prospective and retrospective studies

confirm the judgment that cigarette smoking is a significant

risk factor contributing to the development of coronary heart

disease including fatal CHD and its most severe expression,

sudden and unexpected death. The risk of CHD incurred by

smokers of pipes and cigars is appreciably less than that by

cigarette smokers.

2. Analysis of other factors associated with CHD (high serum

cholesterol, high blood pressure, and physical inactivity)

shows that cigarette smoking operates independently of these

other factors and can act jointly with certain of them to increase the risk of CHD appreciably.

3. There is evidence that cigarette smoking may accelerate the

pathophysiological changes of pre-existing coronary heart

disease and therefore contributes to sudden death from CHD.

4. Autopsy studies suggest that cigarette smoking is associated

with a significant increase in atherosclerosis of the aorta and

coronary arteries.

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

of death from CHD.

6. Experimental studies in animals and humans suggest that

cigarette smoking may contribute to the development of CHD

and/or its manifestations by one or more of the following

mechanisms :

a. Cigarette smoking, by contributing to the release of

catecholamines, causes increased myocardial wall tension,

contraction velocity, and heart rate, and thereby increases

the work of the heart and the myocardial demand for

oxygen and other nutrients.

13

24
b. Among individuals with coronary atherosclerosis, cigarette smoking appears to create an imbalance between the

increased needs of the myocardium and an insufficient increase in coronary blood flow and oxygenation. c. Carboxyhemoglobin, formed from the inhaled carbon

monoxide, diminishes the availability ofoxygen to the myo- cardium and may also contribute to the development of

atherosclerosis.

d. The impairment of pulmonary function caused by cigarette

smoking may contribute to arterial hypoxemia, thusreducing the amount of oxygen available to the myocardium.

e. Cigarette smoking may cause an increase in platelet adhesiveness which might contribute to acute thrombus formation.

Recent epidemiological, pathological, and experimental studies

add to the understanding of the relationship between smoking and CHD. These studies point to cigarette smoking as one of the major

risk factors leading to CHD and help clarify some of the biomechanisms through which this occurs.

EPIDEMIOLOGICAL STUDIES

A prospective study of 973 men born in 1913 in G8teborg, Sweden, was undertaken in 1963 (51, 52). The proportion of myo- cardial infarctions among cigarette smokers was significantly

greater than among nonsmokers (P < .05), and the incidence of

myocardial infarction rose with increasing cigarette consumption

(table 1). Of the 35 individuals who experienced a myocardial infarction between 1963 and 1970, only two had been nonsmokers; in

the whole population of men born in 1913, 56 percent were smokers.

Although angina pectoris was more common in smokers than

nonsmokers, the difference was smaller than for myocardial infarction and was not statistically significant (52). Paffenbarger, et al. (42) reported on the health experience of 3,263 longshoremen studied over the past 18 years. During this interval 1,098 were known to have died, 350 dying from CHD. Longshoremen who smoked more than 20 cigarettes a day faced a risk

of coronary death which was more than twice as great as that of

the group made up of both nonsmokers and smokers of less than 20

cigarettes a day (P < .01).

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

examined. The originally published table of results was incorrect

14

25
and the authors have supplied a corrected table which appeared

in a later issue of the same journal (table 2). The morbidity

ratio for "hard CHD" (CHD deaths plus myocardial infarctions not

resulting in death) among those smoking more than 10 cigarettes a

TABLE 1.-Incidence (1963-1970) of heart infarct in relation to

tobacco consumption in "The Men Born in 1913," GOteborg,

Sweden. n = 855

Smoking

classification Heart infarct

Number Percent

Never smoked

n = 207

( 2) 1.0

Stopped smoking

n = 168

( 2) 1.0

Cigarette smokers (13) 6.0

1-14 cig/day

n = 234

15-24 cig/day

n = 138

cig/day

n = 33

( 9)

( 4)

7.0

12.0

Pipe/cigar

n = 75

( 5) 7.0

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

TABLE 2.-Cigarette smoking at entry and subsequent 20-year CHD

incidence among Minnesota men.'

Number

Age of men Item Never Smoking habit (cigarettes /day) Stopped <10 10-19 >20

47, 48 53 % with habit 23 19 9 19 30

49, 50 51 % with habit 33 20 14 10 23

51, 52 69 % with habit 33 26 14 14 13

53, 54 53 % with habit 36 30 8 13 13

55-57 51 % with habit 24 33 8 18 17

47-57 277 Number of men 83 71 30 41 52

47-57 277 Hard CHD rate (%) 12.0 15.5 10.0 17.1 21.2

47-57 277 Hard CHD rate (SE) ± 3.6 + 4.3 ± 5.5 ± 5.9 ± 5.7

47-57 277 Hard CHD Morbidity

Ratio 1.00 1.29 .83 1.43 1.77

47-57 277 All CHD rate (%) ±21.7 ±21.1 ±16.7 ±19.5 ±26.9

47-57 277 All CHD rate (SE) ± 4.5 ± 4.8 ± 6.8 ± 6.2 ± 6.1

47-57 277 All CHD Morbidity

Ratio 1.00 .97 .77 .90 1.24

Cigarette smoking habits, by age at start of the 20-year foilow-up, 20-year ic ".nce rates

(per 100 men), and standarl errors (SE) of the rates. "Hard CHD"-CHD death and myocardial

infarcts. "All"-anglna pectoris and other CHD diagnoses. "Deaths"-from ail causes except

violence.

SOURCE: Modified from Keys, A., et al. (80).

#.-k: 26

15
day is similar to that reported from the large prospective studies.

However, with the small number of cases in each smoking category,

there are no statistically significant differences in the incidence of

CHD between the categories, either singly or combined.

Retrospective studies of CHD have recently been reported from

Czechoslovakia, Sweden, Norway, and India which corroborate

earlier studies linking cigarette smoking with excess CHD morbidity and mortality.

The Prague study (19) included 443 men between the ages of 60

and 64 years. Significantly more (P < .05) individuals with a

"probable" myocardial infarction were found among cigarette

smokers than among nonsmokers or pipe and cigar smokers.

The smoking habits of 120 patients with myocardial infarction

who were hospitalized in Goteborg were compared with those of the

entire "men born in 1913" population sample (17, 62). A significantly (P <.01) greater number of smokers and heavy smokers

(more than 15 cigarettes a day) were found in the myocardial infarction group than in the population sample.

The Bergen, Norway, cross sectional study of 2,117 women and

2,472 men documented a relationship between smoking and CHD in

men, which was most marked in the 50 to 59 year old age group

(16). No effect of smoking on the prevalence of CHD in women was

demonstrable in this study, and the effect in men did not appear

to be related to the daily number of cigarettes smoked.

In New Delhi, 100 "well documented" cases of ischemic heart

disease were compared with an equal number of control cases (8).

In this study, significantly more (P < .01) of the case group smoked

cigarettes regularly than the control group (Morbidity Ratio = 2.1). Mulcahy, et al. (40) recently found a positive association between

coronary heart disease mortality rate and calculated per capita cigarette consumption in 21 countries. He interpreted the results as

being consistent with the hypothesis that cigarette smoking is a

significant risk factor in CHD mortality.

Stamler, et al. (50) found that for both men and women the 1964

CHD mortality rates in 17 developed countries were related to average annual per capita cigarette consumption.

INTERACTION OF SMOKING AND OTHER RISK FACTORS

The Report of the Inter-Society Commission for Heart Disease

Resources summarized the evidence indicating that three risk factors (hypercholesterolemia, hypertension, and cigarette smoking)

are properly designated major risk factors for premature CHD

(28). Qther possible risk factors including obesity, physical inactivity, diabetes mellitus, elevated resting heart rate, electrocardio16
graphic abnormalities, a positive family history of premature CHD,

and psychologic and social factors have also been described (54, 55, 56) .

In the study of 973 men born in 1913 in Goteborg, Sweden, several coronary risk factors including elevated serum cholesterol, elevated serum triglyceride, low physical activity at work, and smoking were found to be related to an increased risk for the development

of coronary heart disease during the subsequent years of the study. Failure to find a relationship between hypertension and an increased risk of CHD may have been due to the fact that all patients

with hypertension in 1963 have been under treatment since that

time.

Tibblin and Wilhelmsen (52) found that as a patient accumulated

more risk factors his chance of developing CHD became substantially greater. Werko (61) reported from the same Goteborg study

that patients who were smokers, had sedentary jobs, and had both

elevated cholesterol and triglycerides experienced a 4-year incidence

of new coronary events of about 20 percent; the 4-year incidence

among those who exhibited only one or two risk factors was much

lower, ranging from 0 to 3 percent. ECG changes and anginal pain

were included in the definition of new coronary events.

Paffenbarger, et al. (42) evaluated coronary risk factors in the

study of 3,263 longshoremen. They found that, with the exception

of diagnosed heart disease, smoking was the most important factor

predictive of high risk for coronary mortality.

Keys, a al. (80) in the study of 279 Minnesota men, concluded

that a positive cold pressor test, elevated serum cholesterol, and

elevated systolic blood pressure had major predictive power for CHD death or infarction; in their analysis smoking seemed less

important.

Stamler (49) has analyzed the data on 13 deaths occurring during the first years of the Chicago Coronary Prevention Evaluation

Program, which originally consisted of 519 coronary-prone male

volunteers aged 40 to 59 who were free from clinical CHD. Eleven

of the 13 decedents had three or more coronary risk factors at entry

into the program, and at least 8 were cigarette smokers at the time

of death. Forty-three men, who were cigarette smokers at entry

into the Coronary Prevention Evaluation Program, gave up smoking and have remained active in the program. There have been no

deaths from cardiovascular ca;:q.az, in this group. Stamler (49)

commented: "Even though the number of decedents was small,

these data strongly suggest that continued cigarette smoking is associated with very high risk of premature death for very coronary-

. prone men, and that other preventive measures are by themselves

of limited value for them as long as they fail to give up cigarette

smoking."

28

17
As described in the 1971 report, "The Health Consequences of

Smoking" (56), come studies have indicated that smokers show

increased levels of serum lipids while others have not. Such contradictory results are also present in recent studies from Germany,

Poland, and Sweden (21, 39, 53).

After a patient suffers a myocardial infarction, he frequently

gives up smoking (17, 26). Only fragmentary data are available on

what effect the cessation of cigarette smoking might have on the

likelihood of a recurrent myocardial infarction (9, 34, 43). Ninetytwo survivors of a first myocardial infarction were studied over a

3-year period by Paris Chavero, et al. (43). During this time, 37

patients continued smoking, and 12 of them (32 percent) experi- enced a second myocardial infarction. The 51 patients who did not

smoke during this 3-year period included 39 ex-smokers and 12 patients who had never smoked. Eight of the nonsmokers (16 percent)

experienced a second myocardial infarction. The smoking habits of four of the patients were not known. Although the continuing

smokers experienced a greater rate of recurrent myocardial infarction than the nonsmokers, the difference was not statistically sig- nificant (P = .07).

The role of genetic factors in the development of CHD and the

difficulties associated with the use of twin studies were discussed

in the 1971 report, "The Health Consequences of Smoking" (56).

Mailed questionnaires were used to establish the diagnosis of angina

pectoris in a study by Lundman, et al. of twin pairs discordant with

respect to smoking habits and in a study by Liljefors of twins with

CHD. Lundman, et al. (36) recently investigated 69 male twins with

the diagnosis of angina pectoris established by questionnaire. Only

22 percent of these diagnoses could be verified by clinical examination.

In a study of CHD, Liljefors (35) studied 91 pairs of twins from

the Swedish Twin Registry of 1967. The twins ranged in age from

42 to 67 years, and 51 pairs were monozygotic. Smoking habits were not significantly different in pairs discordant for the probable presence of CHD. However, Liljefors noted that "... in many pairs

the smoking habits were similar and that the material included few

pairs discordant with respect to smoking, so that it does not pro- vide a suitable basis for conclusions as to the causal importance of

smoking for CHD." As observed in the 1971 report, "The Health

Consequences of Smoking" (56), it would be surprising if genetic

factors did not play a role in heart disease; however, it is open to

question whether findings from twin studies can be used to distinguish 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."

8
AUTOPSY STUDIES

In previously reported autopsy studies, Auerbach, et al. found

that aortic and coronary atherosclerosis in man were more common

and severe among smokers than among nonsmokers (5). They have

now extended their investigations to the myocardial arterioles of

men and beagle dogs (6). In a study of 1,184 men, they found that

the thickness of myocardial arteriole walls was greater, on the

average, in smokers than nonsmokers (table 3). The thickness increased with the number of cigarettes smoked per day and with

age. The thickness was less, on the average, among cigar and pipe

smokers than among cigarette smokers, but it was greater than in men who had never smoked regularly.

TABLE 3.-Human autopsy study. Comparison of the thickness of

myocardial arteriole walls in smokers and nonsmokers.'

Age

(year) Smoking Total 0 Number of Men

:Grade *Grade *Grade

1 2. 3 Total

Percent of Men

*Grade *Grade :Grade

0 1 2.3 < 45 None 22 2 19 1 100.0 9.1 85.4 4.5

Cigar. pipe 4 - 1 3 100.0 - t25.0 t75.0

Cig. 1-19 50 1 31 18 100.0 2.0 62.0 36.0

Cig. 20-39 65 4 35 46 100.0 4.7 41.2 64.1

Cig. >40 29 - 10 19 100.0 - 34.5 65.5

45-59 None 15 1 12 2 100.0 6.7 80.0 13.3

Cigar, pipe 13 - 8 5 100.0 - 61.5 38.5

Cig. 1-19 3$ - 17 16 100.0 - 51.5 48.5

Cig. 20-39 99 - 35 64 100.0 - 35.4 64.6

Cig. >40 50 - 11 39 100.0 - 22.0 78.0

60-69 None 56 4 36 16 100.0 7.1 64.3 28.6

Cigar, pipe 35 - 22 13 100.0 - 62.9 37.1

Cig. 1-19 92 - 44 48 100.0 - 47.8 52.2

Cig. 20-39 193 - 58 135 100.0 - 30.1 69.9

Cig. -40 87 - 21 66 100.0 - 24.1 75.9

70 None 32 2 18 12 100.0 6.3 56.2 37.5

Cigar, pipe 40 - 19 21 100.0 - 47.5 52.5

Cig. 1-19 30 - 12 18 100.0 - 40.0 60.0

Cig. 20-39 46 - 12 34 100.0 - 26.1 73.9

Cig. ,II) 9 - 3 6 100.0 - t33.3 t66.7

1ln the right ventricular wall of 1.020 men by age and smoking habits.

t Percentages based on less than ten cases.

2 Four Point Seale for the Thickness of Myocardial Arteriole Walls:

0-normal thickness; 1-slight thickness; 2-moderate thickness; 3-great thickness.

SOURCE: Auerbach. 0.. et al. 16).

19

30
In one experiment, beagle dogs inhaled cigarette smoke daily

through tracheostemae. Twenty-eight dogs that died between days

57 and 875 formed one group; 32 dogs that vere killed after 875

days formed another group. Eight control dogs were not exposed.

Beagle myocardial arteriole walls were found to be thicker in smoking than nonsmoking dogs, in dogs smoking many cigarettes than

in dogs smoking fewer cigarettes, and in dogs smoking nonfilter cigarettes than in dogs smoking filter-tip cigarettes (figure 1). Also,

the thickness of arteriole walls increased with the duration of

smoking.

Group N

No smoking

8 Dogs

. Group L

Nonf liter

Cigarettes

(X as many

cigarettes)

10 Does

. Group F

FilterTip

Cigarettes

10 Dogs .

. . . Group H Nonfilter

Cigarettes

12 Dogs

. Grade of

Thickness 0 1 2

Each dot represents one section. The three dots on a line represent the three

sections from a particular dog.

FIGURE 1.Canine autopsy study. Comparison of the thickness of myocardial

arteriole walls in 32 smoking dogs killed after 875 days and 8 nonsmoking

dogs.

SOURCE: Auerbach, 0., et al. (6).

20
EXPERIMENTAL STUDIES

NICOTINE AND CIGARETTE SMOKE

Schievelbein, et al. (47) investigated the effect of oral nicotine

administration over a 20-month period on lipid metabolism in 35

rabbits. Even though lipoprotein lipase levels and calcium content

of the aorta were significantly greater in the group given nicotine

than in the control group, the histological changes of arteriosclerosis were found with equal frequency in both groups. The authors

concluded that the epidemiological correlations between CHD and

cigarette smoking could not be explained by the pharmacologic effect of nicotine alone.

A study of the interaction of chronic nicotine administration and

acute hypoxia in 280 rats was performed by Wenzel and Richards

(60) . Pretreatment of the rats with nicotine increased the mortality

duriqg hypoxia, but the difference was not statistically significant.

Pretreatment with the nicotine also was associated with marked

variability of regression of hypoxic heart lesions. The interaction

of nicotine pretreatment and the hypoxic insult produced variable

effects on myocardial enzymes.

Aronow (1) recently studied the effect of cigarette smoking on

the A wave of the apexcardiogram in 20 men with CHD. The A wave

reflects the left ventricular filling wave associated with the impact

of blood upon the ventricular wall during left atrial contraction.

He found that the mean maximum increase in A wave ratio after

smoking was 34 percent for high-nicotine cigarettes, 13 percent for

the low-nicotine cigarettes, and 6 percent for the non-nicotine cigarettes. He ascribed these changes to increased myocardial ischemia

produced by cigarette smoking, which was reflected by a larger A

wave ratio in the apexcardiogram. While nicotine appears to have

produced most of these changes, the observation that a 6 percent

increase occurred in the absence of nicotine suggests the possibility

that carbon monoxide plays a role in this effect.

CARBON MONOXIDE

Because cigarette smoke contains from 2.7 to 6 percent carbon

monoxide (CO), significantly higher carboxyhemoglobin (COHb)

levels are found in smokers than nonsmokers (13, 20, 24, 63) . COHb

levels in nonsmokers are usually less than 1 percent, while those in

smokers average around 4 percent and may exceed 15 percent (4, 20, 56) . Heavy smokers and those who inhale show the highest

carboxyhemoglobin levels (20) . Haebisch (24) found that a smoker with a daily consumption of

35 to 40 cigarettes easily attains and maintains for hours an alveolar

32

21
CO concentration of 50 p.p.m., which reaches or exceeds legallyestablished ambient air quality standards (14,18, 23, 24).

Cohen, et al. (13) and Aronow, et al. (2) have shown that there

is no significant difference in mean expired air carbon monoxide

levels after patients have smoked tobacco or lettuce leaf cigarettes.

Although pipe and cigar smokers in the United States are reported

to have lower exposure to CO than cigarette smokers (20), CO intoxication has been reported in cigar smokers (25).

CO exerts its adverse effects on the cardiovascular system of

smokers through one or more of the following mechanisms: (a) reduction of the amount of hemoglobin available for oxygen transport; (b) shift of the oxygen-hemoglobin dissociation curve to the

left with consequent interference in oxygen release at the tissue

level; and (c) induction of arterial hypoxemia. CO may interfere

with the homeostatic mechanism by which 2,3-DPG controls the

affinity of hemoglobin for oxygen (56). CO has also been implicated

in experimental atherogenesis in animals (56) . Ayres, et al. (7) recently studied 41 patients during diagnostic

cardiac catheterization, at which time they inhaled either 5 percent

or .1 percent CO. Arterial and mixed venous oxygen tensions were

decreased by administration of either concentration. In patients

with CHD, coronary artery 03 extraction decreased 7.9 percent after

inhalation of .1 percent CO and 30.5 percent after inhalation of 5

percent CO. Some of the patients with CHD experienced changes in

lactate and pyruvate metabolism indicative of inadequate myocardial oxygenation. The higher level of CO inhalation in this experiment is comparable to that experienced intermittently by cigarette

smokers.

Brewer and his colleagues (11) investigated cigarette smoking

as a cause of hypoxemia in residents of Leadville, Colorado, at an

altitude of 3,100 meters. The arterial p0, of 8 smokers was significantly lower (P < .05) than that of 12 nonsmokers, but this was

reversible upon cessation of smoking. They concluded that the adverse effect of cigarette smoking on 03 transport may be especially

pronounced at high altitude and may restrict an individual's ability

to adapt to reduced 0. tensions (11, 12).

Kjeldsen (31, 32) examined 993 industrial workers, about onehalf of whom were tobacco workers. Fifty-nine cases of arteriosclerosis were documented by such clinical symptoms as angina

pectoris and intermittent claudication or by a previous history of

myocardial infarction. While 20.9 percent of the 934 "control" individuals were nonsmokers, only 2 (3.4 percent) of the 59 patients

with arteriosclerosis were nonsmokers. A significantly higher percentage of diseased workers were heavy smokers and inhaled the

smoke.

22 33
jimmi

The diseased smokers had significantly higher carboxyhemoglobin

and serum cholesterol levels than either smoking or nonsmoking

control patients. This was true after standardizing for differences

in levels of smoking between controls and diseased patients. As ex- pected, there was a gradient in carboxyhemoglobin levels from

lower levels in light smokers to higher levels in heavy smokers

(table 4).

TABLE 4.Average values of carboxyhemoglobin and serum cholesterol in Danish smokers and nonsmokers in control group and

group of patients with arteriosclerotic cardiovascular disease.

Smoking

category

Carboxyhemoglobin

(saturation percentage)

Serum cholesterol

(mg/100 ml)

controls

Id:--S.D.

patients

M±S.D. signifi- canc. controls patients

11:_-S.D.

signifiranee Smokers 4.2±3.1 7.0±3.7 p<0.001 247±44 290±33 p<0.001

(738) (57) t=5.52 (738) (57) t=4.89

Nonsmokers 0.4±0.9 0.5±0.7 n.s. 236±49 284±56 p<0.02

(196) (2) t=0.16 (196) (2) t=2.32

Light smokers 2.5=2.5 3.7±2.5 n.s. 245±38 279±67 n.s. (121) (3) t=0.76 (121) (3) t=1.45

Moderate 4.1±3.0 7.3±3.6 p<0.001 246±45 286±50 p<0.001

smokers (463) (34) t=4.95 (463) (34) t=4.52

Heavy smokers 5.1-2:3.0 7.0±4.0 n.s. 258 ±45 298±53 p<0.05

(154) (20) t=1.45 (154) (20) t=2.18

p = Probability that difference 14 not due to chance.

I Student's I calculation.

n.s. = not significant.

The number of subjects in each category is enclosed in parentheses beneath the mean (II) and

standard deviation (S.D.).

Souargt Kjeldsen. K. (Si).

Kjeldsen also observed that the COHb levels of 8 to 19 percent

seen in 40 percent of the patients with arteriosclerosis were of the

same magnitude as those provoking experimental atherosclerosis

and cardiac necrosis in animals.

SMOKING AND THROMBOSIS

Previous reports of the Surgeon General on smoking and health

have reviewed the effects of smoking on thrombus formation (54, 55, 56). The role of thrombosis in CHD remains an active area of

investigation. Recent studies have not thus far yielded a unifying

concept of the effect of smoking on thrombosis (33, 41, 48).

34 .

23
CHOLESTEROL CONTENT OF TOBACCO AND TOBACCO SMOKE

Cholesterol glucoside has not previously been reported in tobacco,

or in any other plant (10). Bolt and Clarke (10) investigated the

sterolin and sterol fraction of flue-cured tobacco and found that

cholesterol is one of the major components of the sterol fraction.

More recently, Grunwald, et al. (22) have confirmed that cholesterol accounts for 10 percent of the total sterol in cigarette tobacco.

They also found that 8.6 percent of the total sterol content of cigarette smoke condensate was cholesterol. Thirteen percent of the

cholesterol present in cigarette tobacco was transferred to the

condensate.

The biological significance of these findings remains to be

determined.

COR PULMONALE (PULMONARY HEART DISEASE)

The relationship between cigarette smoking and chronic obstructive bronchopulmonary disease (COPD) with cor pulmonale was

discussed in the 1968 Supplement to "The Health Consequences of

Smoking" (55).

Although the extent of morbidity and mortality due to cor

pulmonale and right heart failure is difficult to determine, COPD is

often complicated by these conditions (27).

The Pulmonary Heart Disease Study Group of the Inter-Society

Commission for Heart Disease Resources recently summarized the

evidence linking cigarette smoking with COPD and concluded :

"Cigarette smoking is the major cause of pulmonary heart disease

in that it is the most important cause of the chronic non-neoplastic

bronchopulmonary diseases in the United States" (28).

CEREBROVASCULAR DISEASE

The 1971 report, "The Health Consequences of Smoking" (56),

summarized the data linking smoking to cerebrevascular disease as

follows :

1. Data from numerous prospective studies indicate that cigarette smoking is associated with increased mortality from

cerebrovascular disease.

2. Experimental evidence concerning the relationship of smoking and cerebrovascular disease is at present insufficient to

allow for conclusions concerning pathogenesis. However,

some of the pathophysiological considerations discussed concerning CHD may also pertain to the relationship of smoking

and CVD, particularly cerebral infarction.

24

35
In the interim, additional reports have been published.

Dyken (15) performed a retrospective studyon 285 patients with

cerebrovascular disease in Elkhart, Indiana. Even though low cigarette consumption was noted in all groups, males who had cerebral

infarctions smoked significantly more than controls.

Paffenbarger, et al. (42) found that smokers of more than 20

cigarettes a day faced a slightly increased but not significantly greater risk of dying from a stroke than those smoking lesser

amounts.

After 16 years follow-up, male cigarette smokers in the Framingham study had more than three times the nonsmokers' risk of developing a cerebral infarction (29). However, Kannel commented : "It

is not clear that smoking actually affects the rate of cerebral atherogenesis, and some other mechanism may be involved."

PERIPHERAL VASCULAR DIJEASE

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

1. Data from a number of retrospective studies have indicated

that cigarette smoking is a likely risk factor in the development of peripheral vascular dit.eftse. Cigarette smoking also

appears to be a factor in the aggravation of peripheral vascular disease.

2. Cigarette smoking has been observed to alterperipheral blood

flow and peripheral vascular resistance.

Newly published studies add to our understanding of the effect of nicotine or tobacco smoke on the peripheral circulation and of the

significance of =molting in peripheral vessel atherogenesis.

Martz, et al. (37) observed that some of the apparently conflicting data on the effects of nicotine upon the peripheral vasculature may result from interpretations based upon indirect measurements of microcirculatory variables. Hence, they studied vascular

changes in a bat wing under direct microscopic observation. They noted a marked increase in the diameter of innervated, minute

arteries with intraperitoneal nicotine administration, but this effect

was abolished with sympathetic denervation.

Asano and Branemark (3) installed a direct, microscopic observation chamber in the connective tissue of two human volunteers.

One volunteer was a ."healthy" 20-year-old male nonsmoker. The

other volunteer was a diabetic who had been a smoker for five years and who "... had no apparent diabetic vasculopathy." The effects of tobacco smoking on the microcirculation of these volunteers in25

36
eluded: "... vasoconstriction, decrease in blood flow rate and frequency of plasma spacing, blocking of blood flow in varying numbers of nutritive capillaries, shunting of blood from arterioles to

venules...." These microcirculatory changes were said to result in

a decrease of nutritive blood flow in tissue.

As mentioned in the discussion of CHD, Kjeldsen ( 31, 32) studied several smoking patients with occlusive peripheral vascular

disease whose COHb levels were significantly higher than those of

control smokers. The levels of COHb in many of these patients were

comparable to those associated with experimental atherosclerosis

in animals. Astrup, et al. (4) have suggested that prospective studies should be performed to investigate the relationship between

COHb levels and the incidence of arterial disease.

In the Prague study (19) intermittent claudication was significantly (P < .01) more common among cigarette smokers than nonsmokers. Twenty percent of the men in the age group of 60 to 64

who were heavy smokers (more than 25 cigarettes a day) had intermittent claudication.

Raf (44) reported that all but 4 of the 98 patients admitted for

peripheral vascular surgery at the Karoline Hospital, Sweden, were

smokers.

Mathiesen, et al. (38) in Denmark followed the spontaneous

course of arterial insufficiency in 211 patients. Cessation of smoking

increased the number of patients displaying spontaneous improvement.

ORAL CONTRACEPTIVES, THROMBOPHLEBITIS,

AND. SMOKING

In two studies from Great Britain and one from the United

States, it was reported that the use of oral contraceptives was associated with a significantly increased risk of developing venous

thromboembolism (46, 58, 59). The British investigators also noted

in their initial report that the affected patients were, on the average,

heavier smokers than controls (58). However, after an additional

year of study, a similar effect was not noted and they concluded

(59) : "...the earlier difference between the smoking habits of the

two groups can thus reasonably be attributed to chance (P = 0.08)."

The American investigator (45) found "... no evidence that smoking, acting either independently or in conjunction with oral contraceptives, is a factor in idiopathic thromboembolism."

Cigarette smoking has not been clearly demonstrated to .be a factor that contributes to the risk of idiopathic thromboembolism associated with the use of oral contraceptives. Nevertheless, the

possibility that it may act to increase that risk has not yet been

completely ruled out.

26 37..
HIGHLIGHTS OF CURRENT CARDIOVASCULAR

INFORMATION

In addition to the comprehensive summary from the 1971 report, "The Health Consequences of Smoking" (56), cited earlier in this chapter, the following statements are made to emphasize the most recent developments in the field : 1. Recent epidemiological studies from several countries confirm that cigarette smoking is one of the major risk factors

contributing to the development of CHD. Avoidance of cigarette smoking is of importance in the primary prevention of CHD.

2. Studies in man and animals have shown a greater myocardial

arteriole wall thickness in smokers than nonsmokers.

3. Experimental and epidemiological investigations implicate

the elevation of carboxyhemoglobin levels in smokers as a

contributor to the development of CHD and arteriosclerotic

peripheral vascular disease.

4. Cigarette smoking is considered to be the major cause of pulmonary heart disease (cor pulmonale) in the United

States in that it is the most important cause of chronic nonneoplastic bronchopulmonary diseases. Avoidance of cigarette smoking is of importance in the primary prevention of pulmonary heart disease.

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(24) HAEBISCH, H. Die Zigarette als Kohlenmonoxydquelle. (The cigarette

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(27) INTER-SOCIETY COMMISSION FOR HEART DISEASE RESOURCES. PUID10111117

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(29) KANNEL, W. B. Current status of the epidemiology of brain infarction

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July-August 1971.

(30) KEYS, A., TAYLOR, H. L., BLACKBURN, H., BROZEK, J., ANDERSON, J. T.,

SIMONSON, E. Mortality and coronary heart disease among men studied for 23 years. Archives of Internal Medicine 128(2) : 201-214,

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(31) KJELDSEN, K. Carboxyhemoglobin and serum cholesterol levels in

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(32) KJELDSEN, K. ROkning och koronarsjukdom (12) : CO-eksposition og

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(34) LEREN, P. The Oslo diet-heart study. Eleven-year report. Circulation

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(35) LILJEFORS, I. Coronary Heart Disease in Male Twins. Hereditary and

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Medica Scandinavica (Supplementum 511), 1970. 90 pp.

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P. A. Effects of nicotine en the subcutaneous microcirculation of the

bat. Proceedings of the Society for Experimental Biology and Medicine 133 (1) : 153-159, January 1970.

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the spontaneous course of arterial vascular insufficiency. Acta Chirurgica Scandinavica 136(4) : 303-308, 1970.

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31

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CHAPTER 3

Non-neoplastic Bronchopulmonary Diseases

(I

43
Contents

Page

Introduction 37

Epidemiological Studies 38

COPD Mortality 38

COPD Morbidity 39

Cessation of Smoking 41

Occupational Hazards 42

Genetic Factors 44

Pathological Studies 45

Experimental Studies 45

Human Studies 45

Animal Studies 46

Overall Clearance 47

Phagocytosis 47

The Surfactant System 48

Other Respiratory Disorders 48

Highlights of Current Bronchopulmonary Information 48

References 49

44

35
INTRODUCTION

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

1. Cigarette smoking is the most important cause of chronic obstructive bronchopulmonary disease in the United States.

Cigarette smoking increases the risk of dying from pulmo- nary emphysema and chronic bronchitis. Cigarette smokers

show an increased prevalence of respiratory symptoms, in- cluding cough, sputum production, and breathlessness, when

compared with nonsmokers. Ventilatory function is 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 fre- quency and severity of asthmatic attacks in patients already suffering from this disease.

3. The risk of developing or dying from COPD among pipe

and/or cigar smokers is probably higher than that among

nonsmokers while clearly less than that among cigarette

smokers.

4. Ex-cigarette smokers have lower death rates from COPD

than do continuing smokers. The cessation of cigarette smoking is associated with improvement in ventilatory function

and with a decrease in pulmonary symptom prevalence.

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

6. For the bulk of the population of the United States, the im- portance of cigarette smoking as a cause of COPD is much

greater than that of atmospheric pollution or occupational

exposure. However, exposure to excessive atmospheric pollution or dusty occupational materials, and cigarette smoking may act jointly to produce greater COPD morbidity and mortality.

37
7. The results of experiments in both animals and humans have

demonstrated that the inhalation of cigarette smoke is associated with acute and chronic changes in ventilatory function and pulmonary histology. Cigarette smoking has been

shown to alter the mechanism of pulmonary clearance and

adversely affect ciliary function.

8. Pathological studies have shown that cigarette smokers who

die of diseases other than COPD have histologic changes

characteristic of COPD in the bronchial tree and pulmonary

parenchyma more frequently than do nonsmokers.

9. Respiratory infections are more prevalent and severe among

cigarette smokers, particularly heavy smokers, than among

nonsmokers.

10. Cigarette smokers appear to develop postoperative pulmonary complications more frequently than nonsmokers.

Recent epidemiological, autopsy, and experimental studies confirm and extend the foregoing statements.

EPIDEMIOLOGICAL STUDIES

COPD MORTALITY

Over a period of 4 to 8 years, Burrows and Earle (10) studied 200

patients with symptomatic COPD whose mean FEV, was 1.01*. 0.4

liter. Ninety-seven percent of these patients had a history of cigarette smoking; the average consumption for the entire group of 200

individuals was 23 cigarettes a day over a period of 41 years. Upon

entry into the study, 59 percent were still regular smokers and 38

percent had discontinued smoking. Eighty-nine percent of the group

were males and the mean age was 59.1 years.

A 47 percent 5-year mortality was observed in these 200 patients,

and most deaths were ". . directly attributable to the underlying

lung disease or one of its complications." The relationship of continued smoking to the course of the disease was difficult to interpret.

Patients who stopped smoking prior to entry into the study had a

poorer survival than those who continued to use cigarettes. This was

related to a tendency for patients to give up smoking when their

illness was severe, and ". . . the apparent advantage of smokers was

eliminated when patients with similar FEVI levels were compared."

The authors reported no reduction of mortality in the group of patients who stopped smoking, even when smokers and ex-smokers

with similar FEVI levels were compared.

38

46
Reduction of cigarette smoking was associated with a history of

reduced expectoration, smaller measured sputum volume, and 44. . . a favorable course of the vital capacity (P < .01) ... ."

The 1971 report, "The Health Consequences of Smoking" (70) , included an analysis of the variety of ways in which smoking may

be related to disease. COPD was cited as an example in which smoking probably initiates a disease process by producing progressive,

irreversible damage. The 200 patients reported by Burrows and

Earle (10, 11) may be representative of patients who have experienced progressive and irreversible pulmonary damage after many

years of exposure to cigarette smoke. In such cases, "... cessation

of smoking leaves impaired function which does not improve appreciably but does not continue to deteriorate from continued exposure

to cigarette smoke. However, such function may deteriorate through

aging or through exposure to other harmful agents" (70). COPD MORBIDITY

New reports of chronic bronchopulmonary disease prevalence

support the findings of earlier studies in which a greater prevalence

was found among smokers than nonsmokers.

A repeat study of a Berlin, New Hampshire, population sample,

which included more than 1,500 individuals, was carried out in 1967

by Ferris, et al. (27). In both this survey and the earlier 1961 survey, a greater prevalence of chronic nonspecific respiratory disease

was found in cigarette smokers than nonsmokers.

The 1967 Berlin study demonstrated that cigarette smokers who

inhaled deeply or moderately had generally higher prevalences of

chronic nonspecific respiratory disease than those who did not inhale

or inhaled only slightly.

After standardization for age, sex, and smoking habits, the prevalence of chronic nonspecific respiratory disease in the 1967 survey

sample was slightly lower than in 1961. This may be accounted for by a decrease in air pollution.

In a random sample of 609 residents of Glenwood Springs, Colorado, a high prevalence of chronic bronchitis was found to be

strongly related to smoking, particularly of cigarettes, and this relationship was independent of age, sex, or history of dust exposure at work (52). Chronic airway obstruction was found to be predominantly a disease of elderly male smokers and increased in frequency with increasing age after 49 years.

The Tecumseh study is a well-known continuing epidemiologic

investigation of the entire community of Tecumseh, Michigan. In

this study the relationship of parental longevity to ventilatory

function and prevalence of chronic nonspecific respiratory disease

47

39
among sons was recently analyzed (17). Death before age 65 of

either parent was related to low values of 1-second forced expiratory

volume among the sons. Maternal death before age 65 was also associated with increased prevalence of chronic bronchitis and emphysema among sons. Some, but not all, of these relationships were

accounted for by differences in smoking habits of the sons. The

authors also concluded : "The evidence strongly suggests that constitutional factors are involved" (17).

A higher prevalence of chronic bronchitis was found among

smokers than nonsmokers (P < .01) in a study of 710 Yugoslavian

workers (43) . There was a direct relationship between the lifetime

number of cigarettes smoked and the presence of chronic bronchitis.

Several papers have been published recently comparing respiratory symptoms such as cough and sputum production among

smokers and nonsmokers in different populations. Two of the new

studies were prospective investigations (15, 38). In all instances,

symptoms were more common among cigarette smokers than nonsmokers (1, 6, 8,15, 38, 52, 63, 75Y. In the three studies which reported on pipe and cigar smokers, the frequency of respiratory

symptoms in this group was, in general, intermediate between those

of cigarette smokers and nonsmokers (6, 15, 52).

Results of studies of pulmonary function in representative samples of different populations (6, 17, 38, 63), surveys of employees

(15, 43, 57), and normal volunteers (75) indicate that cigarette

smokers have lower average pulmonary function than nonsmokers.

Pulmonary diffusing capacity was found by Van Ganse, et al.

(72) to decrease in men and women with aging and with an increase

in current or lifetime cigarette consumption.

In general, a dose-response relationship between cigarette consumption and the development of respiratory symptoms and/or impaired pulmonary function was found in both men and women; as

cigarette consumption increased, these abnormalities were found

more frequently (6, 38, 52, 72, 75).

Woolf and Suero (75) studied the respiratory effects of cigarette

smoking in 298 normal women. The prevalence of cough, sputum

production, wheezing, and shortness of breath increased progressively with increased cigarette smoking. The results of the following tests of pulmonary function were significantly lower in smokers

than in nonsmokers : forced vital capacity, forced expiratory volume in one second, maximal mid-expiratory flow, arterialized capillary blood oxygen tension at rest, specific conductance, and pulmonary diffusing capacity and fractional uptake of carbon monoxide

during exercise.

Seely, et al. (63) examined 365 high school students in the New

Haven area. They found that students with 1 to 5 years' smoking experience had excessive cough, sputum production, and shortness of

40

48
breath. These young smokers also had lower flow rates at mid-vital

capacity and at lower lung volumes than nonsmoking students. The

authors have raised the question of whether smoking by high school students may lead to developmental arrest of the lung. They feel

that follow-up pulmonary function studies in adolescents who stop

smoking will help clarify this question.

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

capacity.

Snider, et al. (65) investigated 1,403 patients with documented

pulmonary tuberculosis for the presence of obstructive pulmonary

disease. Airway obstruction was found in 62 percent of white men,

37 percent of nonwhite men, 36 percent of white women, and 17

percent of nonwhite women. Sixty-eight percent of the patients were current smokers and 15 percent were ex-smokers. Heavy

smoking had less effect on the presence of airway obstruction than

advanced tuberculosis or older age. These data were interpreted as

showing the predominant importance of tuberculosis as a factor

leading to airway obstruction in tuberculous patients. However, the authors also concluded : "The present data suggest the possibility

of an additive effect of smoking with tuberculosis in producing air- way obstruction."

CESSATION OF SMOKING

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

A recent statement from the "Pulmonary Heart Disease Study Group" of the Inter-Society Commission for Heart Disease Resources (41) also emphasized this point: "The overwhelming cause

and effect relationship between smoking, bronchitis-emphysema and

pulmonary heart disease is such that there is little doubt that a radical reduction or elimination of the cigarette habit would result in a

greatly lowered incidence of the chronic respiratory diseases and

cor pulmonale."

In recent studies, a decrease in the prevalence of respiratory

symptoms among ex-cigarette smokers has been demonstrated (10, 15, 75). Higgins, et al. (38) interpreted data from 1957 and 1966

surveys of chronic respiratory disease in England as suggesting that

the benefits of giving up smoking on respiratory symptoms are less

in those who have smoked for many years than in those who have

smoked for shorter periods.

Baker, et al. (5) undertook a therapeutic program for previously

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49
unrecognized mild to moderate cases of COPD. One hundred thirtyfour men were included in this study. Eighty-five percent of these

men were cigarette smokers, 11 percent were ex-smokers, and 4 percent were nonsmokers. At the 6-month follow-up, 61 subjects were

still in the treatment program. Patients were encouraged to stop

smoking, and at the 6-month follow-up 34 percent of the cigarette

smokers had stopped smoking, while 34 percent decreased their

cigarette consumption by at least half. At the follow-up evaluation,

approximately two-thirds of those who either gave up smoking or

decreased their cigarette consumption showed improvement in

symptoms. Thirty percent of those whose smoking habits did not

change showed improvement in symptoms. No significant differences were found in the pulmonary function studies at the follow-up

evaluation. Alteration of smoking habits was the single factor most

closely related to symptomatic improvement.

OCCUPATIONAL HAZARDS

As observed by Bouhuys and Peters (7) , the relative contributions of cigarette smoking and industrial exposure to the loss of

lung function may at times be difficult to determine.

Recent studies in wool, textile, grain elevator, shipyard, pulp mill,

steel, and underground mining industries have documenteda higher

prevalence of chronic bronchitis among cigarette smokers than nonsmokers (9, 13,19, 20, 39, 42, 47, 50). Similar studies in steel, pulp

mill, machine shop, and welding industries indicate a greater fre- quency of respiratory symptoms and/or diminished pulmonary

function in smokers than in nonsmokers (22, 23, 30, 39).

Japanese investigators recently reported that former employees

of a poison gas factory had a high prevalence of chronic bronchitis

and expiratory slowing; a history of chronic bronchitis was obtained from 67 percent of smoking men and 47 percent of nonsmoking men who had manufactured mustard gas or lewisite (54). In recent months several articles have been published on coal

workers' pneumoconiosis. Because coal miners are not allowed to

smoke at work, they must smoke their cigarettes during a shorter

period of time than non- miners; nevertheless, the average coal miner smokes as many cigarettes a day as does the non-miner (51).

Thus, his exposure tends to be more intense during the period in

which he is smoking. Also, the documented hazard of chronic expo- sae to coal dust may be compounded by the deleterious effect of

smoking on ciliary function.

Ashford, et al. (4) studied approximately 30,000 working coal

miners in Great Britain. Their data suggest that smoking and pneumoconiosis Lct independently in the production of pulmonary symptoms.

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50
A total of 801 working, anthracite coal miners from Pennsylvania were investigated by Tokuhata, et al. (68). Twenty-four percent of

the smoking miners had pulmonary function impairment as com- pared with 11 percent of miners who did not smoke. Because the

smokers developed their pulmonary function abnormalities after a

much shorter underground work exposure, the authors suggested

that smoking may significantly accelerate the development of pneumoconiosis among coal miners.

Rasmussen and Nelson (61) studied 368 soft-coal miners from

the Southern Appalachian coal fields. All workers included in the

study had been involved in the coal industry for at least five years. Miners with a smoking history of 30 pack-years or more showed a

significant (P < .01) reduction of FEV, when compared to non- smoking miners. Impairment of oxygen transfer was greater in both

the 15 to 29.9 pack-year group and the 30 plus pack-year group than

among the lifelong nonsmokers (P < .01) . One hundred sixty-two dyspneic soft-coal miners, who gave histories of lifelong abstinence from cigarette smoking, were examined

by Rasmussen (60). Of these patients, 85.6 percent had some X-ray

evidence of pneumoconiosis. The group as a whole was "... not representative of all coal miners, nor of all symptomatic coal miners."

Even though 56 percent of these miners had "normal" ventilatory

capacities, i.e., an FEV, which was 75 percent or greater of the predicted normal vital capacity, more than 90 percent had an

alveolar-arterial oxygen gradient during exercise which exceeded

19.9 mmHg. In more than 95 percent of the "normal" group, this gradient was not associated with significant arterial oxygen denaturation during exercise. The loss of pulmonary function in the entire

group of non-cigarette smokers was somewhat less than that found

in a group of miners composed of cigarette smokers and non- smokers; nonetheless, these findings demonstrate that, in the ab- sence of cigarette smoking, coal dust exposure may be associated with abnormalities in oxygen transfer during exercise, despite the presence of a normal FEV,.

An autopsy study of 144 Appalachian coal miners was carried out

by Naeye, et al. (53) . Several parameters of cardiac and pulmonary

structure were examined with regard to the effect of smoking. The

volume of pulmonary macules and nodules containing coal dust and

the concentration of silica crystals and collagen in these macules

and nodules were unrelated to smoking. Right ventricular hypertrophy, defined according to an index developed by Naeye, was pres- ent in all groups of miners but was more severe in the bituminous

workers who smoked cigarettes. The emphysema index, which is a

measurement of the percent of lung tissue comprised of abnormal

air space, was determined only in bituminous coal miners. It was

43
significantly greater in cigarette smokers than in nonsmokers.

Goblet cell hyperplasia, which appeared to be present in the entire

group, was somewhat greater in the bituminous coal miners who

smoked than in the nonsmokers, but the differences were not statistically significant.

Several investigators have concluded that cigarette smoking by

itself is more important in the production of respiratory disease,

other than pneumoconiosis, among coal miners than is exposure to

coal dust (24, 34, 58, 68). Rasmussen questions this view (60).

There is no consensus in recent publication3 on what role cigarette

smoke may play in the development of coal workers' pneumoconiosis (24, 51, 53, 58, 68).

Weiss (73) examined 100 asbestos textile workers and found a

greater prevalence of pulmonary fibrosis among cigarette smokers

than nonsmokers. The prevalence increased with increasing amount

and duration of cigarette smoking and with increasing duration of

exposure to asbestos.

GENETIC FACTORS

An infrequent genetic error, homozygous alphas- antitrypsin deficiency, has been commonly associated with the premature development of severe, panacinar emphysema. It is postulated that alphas -

antitrypsin is essential to protect the lung against the destructive

action of naturally occurring proteinases (36).

Related questions of current interest deal with the prevalence and

significance of the heterozygous deficiency state (intermediate

serum antitrypsin deficiency) and the interaction of smoking with

the severe and intermediate deficiency states. Mittman, et al. (49)

recently reviewed the limited data available on the smoking habits of

patients with alpha, - antitrypsin deficiency; the cigarette smoke exposure of patients with the intermediate deficiency appears to be

greater than that of patients with the severe deficiency.

Cigarette smoking has been reported to be a possible precipitating

factor in the development of COPD in the homozygous deficiency

state (40). Some studies (26, 44, 49, 67) have demonstrated an

association between the heterozygous deficiency state and the development of COPD, while other studies have not (35,62). Mittman,

et al. (49) have suggested that the intermediate deficiency may

predispose to lung disease by accentuating an individual's susceptibility to the harmful erects of external irritants. Whether or not

cigarette smoking acts together with the homozygous or heterozygous deficiency states to increase the risk of developing either

panacinar emphysema or the more common forms of COPD has not

been adequately studied.

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52
PATHOLOGICAL STUDIES

In previous investigations, a correlation has been found between

cigarette smoking and the histologic changes characteristic of

bronchitis and emphysema (70) . An autopsy study of 60 patients with COPD was performed by Cullen, et al. (16). Although they did not find a correlation between

the smoking history, total emphysema score, type of emphysema, or

bronchial histologic features, the authors noted that only three patients were non-cigarette smokers. These three patients were pipe or cigar smokers. Eight patients who had stopped smoking three

years before death had the same bronchial histologic abnormalities

as those who continued smoking until death. This suggests that the

bronchial abnormalities had become irreversible at the time of

smoking cessation.

Dunnill and Ryder (21) carried out' quantitative study of the

relationship between chronic bronchitis, emphysema, and smoking.

The lungs of 353 patients were examined at autopsy, and a smoking

history was available in 179 cases. A small but significant (P < .005) difference was found between smokers and nonsmokers in the per- centage volume of bronchial mucous glands. Emphysema, mainly

the centrilobular type, was found significantly (P < .001) more frequently in men and women smokers than nonsmokers, and it occurred at a much younger age in the smokers.

EXPERIMENTAL STUDIES

HUMAN STUDIES

Anderson (3) observed in a few patients with and without COPD

that cigarette smoking can produce V/Q (ventilation/perfusion)

changes resulting in a significant average drop in Pa02 (partial pressure of oxygen in arterial blood).

Clarke, et al. (14) studied the bronchoconstrictor effect of plain

and filtered cigarettes in 16 men. Filtration of either the particulate

or vapor phase of the smoke had a similar effect in reducing the

bronchoconstrictor response to cigarette smoke inhalation.

Using a reference cigarette developed by the University of Kentucky, Diamond, et al. (18) measured pulmonary expiratory

resistance immediately after smoking. Heavy smokers, whose control resistance values were significantly higher than those of moderate or nonsmokers, had a decrease in resistance, while nonsmokers had an increase. Although selected ventilatory function tests did

not change significantly after smoking, the author noted that the

methods used in this study are probably not sensitive enough to

measure constriction in peripheral airways, where smoking is

thought to exert an adverse effect.

45
ANIMAL STUDIES

Frasca, et al. (32) made electron microscopic observations in

areas of fibrosis and emphysema of the lungs of dogs, which had

been subjected to experimental cigarette smoking as reported by Hammond, et al. (37). Details of the smoking procedure were reviewed in the 1971 report, "The Health Consequences of Smoking"

(70) . The major findings in the study of Frasca, et al. were: a complete loss or marked reduction in the number of alveolar septal capillaries, a marked thickening of the alveolar septa due to increased

amounts of collagen, thickening of the pleural stroma due to large

amounts of collagen, and the presence of increased numbers of

macrophages in both the pleura and parenchyma. Many of these

macrophages were filled with pleomorphic cytoplasmic inclusions.

Crystalline-like structures were found in membrane-bound inclusions and ferritin-like particles occurred both in large membranebound aggregates and lying free in the cytoplasm.

Flint, et al. (29) reported a significant increase in the number of

polymorphonuclear leukocytes recoverable from the lungs of guinea

pigs following exposure of these animals to cigarette smoke. Because no changes in serum alpharantitrypsin levels were found in

this setting, the authors hypothesized that an imbalance may occur between proteolytic enzymes released by polymorphonuclear

leukocytes and the inhibitors of these enzymes.

The stress effects of forced mouth-breathing and inhalation of

cigarette smoke on lung mitochondria] phosphorylation were studied

in the guinea pig by Kyle and Thesen (45). Mouth-breathing alone

was associated with impaired efficiency of phosphorylation at two

mitochondria! loci, while mouth-breathing guinea pigs exposed to

cigarette smoke lost efficiency at only one of these sites.

Aviado and coworkers have studied the effects of hormones on

the pulmonary response to cigarette smoke inhalation and intravenous nicotine injection. Subcutaneous progesterone administration, prior to nicotine or smoke exposure, reduced the bronchoconstrictor response in rats (64). A similar experiment involving

pretreatment of dogs with glucocorticoids resulted in variable bronchoconstrictor responses after exposure to cigarette smoke (12) . Nitrogen dioxide (NO2) , a gas found in cigarette smoke and some

industrially polluted air, can destroy cellular membranes and subcellular structures (25) . Continuous administration of low concentrations of NO2 in rats has produced an emphysema-like disease

(66). Falk has suggested that NO may ".. . carry a major responsibility for the high incidence of emphysema in cigarette smokers"

(25) . Stephens, et al. (66) examined ultrastructural changes in pulmonary connective tissue of rats exposed to 2 to 20 p.p.m. of NO2 for

46

54
varying periods of time. In the absence of significant cell destruction, striking alterations in both collagen fibrils and basement membranes were found.

OVERALL CLEARANCE

Pavia, et al. (55, 56) examined the effect of cigarette smoking on

the mucociliary mechanism of the human lung. A temporary slowing of mucociliary clearance was found in a group of 22 elderly

smokers (56). Eight of these subjects had mild restrictive impairment and two had airway obstruction. When percentage clearance

by elderly cigarette smokers and nonsmokers was compared, significant differences were not demonstrable (55). In the latter study,

patients with functional evidence of lung disease were not included.

Deposition and clearance of inhaled 2p, particles of iron oxide labeled with 1°8Au were studied in 19 young, normal subjects by

Lourengo, el; al. (46). While tracheobronchial clearance began immediately after inhalation in nonsmokers, it was delayed for periods

of 1 to 4 hours after inhalation in smokers.

Frances, et al. (31) studied the effect of cigarette smoke on particle transport on donkey nasociliary mucosa. This mucosa was

found to be much more resistant to the effects of cigarette smoke

than that in the donkey tracheobronchial tree. More recently, Albert,

et al. (2) published a report that in one of three donkeys tolerance

to cigarette smoke had developed in the tracheobronchial mucosa.

Weissbecker, et al. (74) examined in vivo mucus flow rates in

cats exposed to cigarette smoke gas phase of varied composition.

Several compounds, e.g., isoprene and nitrogen dioxide, when added

in combination to the gas phase, were effective in reducing the

mucus flow, compared to the effect of the gas phase alone. Other

compounds, e.g., CO, diminished the mucostatic effect of the gas

phase. Compounds producing mucostasis were ineffective when

added to cigarette smoke. These experiments indicate that effects

observed from pure compounds cannot be used to predict the effect

of cigarette smoke on mucus transport.

PHAGOCYTOSIS

The recent literature concerning the effect of tobacco smoke on

macrophage function is reviewed in the charter on sllergy of this

report.

Pratt, et al. (59) have extended their studies on the ultrastructure of human alveolar macrophages. Macrophages obtained from

smokers tend to contain more heterogeneous inclusions than those

from nonsmokers. Angular and needle-like structureswere observed

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55
only in the inclusions of smokers. The authors concluded that these

structures "... may represent undigested smoke products... ."

In an investigation of early emphysema found in patients who

were autopsied, McLaughlin and Tueller (48) found brownish, pigmented alveolar macrophages in the intact parenchyma adjacent to

areas of emphysema. Such macrophages were not found in normal

lungs, but were found in sputum specimens of "... apparently

healthy cigarette smokers." In heavy smokers many of the macrophages also contained iron particles.

THE SURFACTANT SYSTEM

Giammona, et al. (33) measured the surface tension of lung extracts and bronchial washings of dogs following exposure to cigarette smoke. Elevated minimal surface tension values were found

in bronchial washings obtained from three dogs. The values remained elevated for 48 hours after the cigarette smoke exposure ;

the values obtained one week after the cigarette smoke exposure

were normal. The surface tension measurements of lung extracts

obtained from four autopsied dogs were normal.

OTHER RESPIRATORY DISORDERS

Finklea, et al. (28) studied acute, noninfluenzal respiratory disease in military cadets and found significantly higher incidence rates

for acute upper and lower respiratory illness among cigarette

smokers than nonsmokers. Intermediate rates were found for

lighter cigarette smokers, cigar, pipe, and ex-smokers.

HIGHLIGHTS OF CURRENT BRONCHOPULMONARY

INFORMATION

In addition to the comprehensive summary from the 1971 report,

"The Health Consequences of Smoking" (70), cited earlier in this

chapter, the following statements are made to emphasize the most

recent developments in the field :

1. Recent epidemiological and clinical studies from several

countries confirm that men and women cigarette smokers have

an increased prevalence of respiratory symptoms and have

diminished pulmonary function compared to nonsmokers.

2. Investigations of high school students have demonstrated that

abnormal pulmonary function and pulmonary symptoms are

more common in smokers than nonsmokers.

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3. Recent occupational studies confirm that cigarette smoking is

an important cause of COPD, acting both independently and

in combination with occupational exposure.

4. Recent experimental studies confirm that cigarette smoking

exerts an adverse effect on pulmonary clearance and macrophage function. . 5. Pulmonary macrophages obtained from cigarette smokers exhibit characteristic morphologic differences when compared

to those obtained from nonsmokers.

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53

Contents

Page

Lung Cancer 59

Epidemiological Studies 60

Experimental Aspects 65

Other Cancers 67

Cancer of the Larynx 68

Oral Cancer .. 68

Cancer of the Esophagus 70

Cancer of the Urinary Bladder 72

Cancer of the Pancreas 74

Highlights of Current Cancer Information 74

References 75

LIST OF TABLES

Table 1.Some initiating agents in two-stage carcinogenesis 66

LIST OF FIGURES

Figure 1.Lung cancer mortality ratios of Japanese males

by amount smoked 61

Figure 2.Relative risk of lung cancer in ex-smokers of

cigarettes by length of cessation before diagnosis 63

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

smoking 64

Figure 4.Relative risk of cancer of the oral cavity, pharynx,

larynx, and esophagus associated with smoking and chewing in various forms 70

Figure 5.Death rates for cancer of the esophagus in Japanese males by smoking and drinking characteristics . . . . 71

Figure 6.Relative risk of urinary bladder cancer for males

by amount smoked 72

Figure 7.Relative risk of urinary_ bladder cancer for females by amount smoked 73

63

57
LUNG CANCER

Cigarette smoking has been established as the 11-.."ior cause of

lung cancer. The 1971 report, "The Health Consequences of Smoking" (39), in summarizing this association, concluded:

1. Epidemiological evidence derived from a number of prospective and retrospective studies coupled with experimental and

pathological evidence confirms the conclusion that cigarette

smoking is the main cause of lung cancer in men. These studies reveal that the risk of developing lung cancer increases

with the number of cigarettes smoked per day, the duration of smoking, and earlier initiation, and diminishes with cessation of smoking.

2. Cigarette smoking is a cause of lung cancer in women but

accounts for a smaller proportion of the cases than in men.

The mortality rates for women who smoke, although significantly higher than for female nonsmokers, are lower than

for men who smoke. This difference may be at least partially

attributed to difference in exposure : the use of fewer cigarettes per day, the use of filtered and low "tar" cigarettes, and

lower levels of inhalation. Nevertheless, even when women

are compared with men who apparenly have similar levels

of exposure to cigarette smoke, the mortality ratios appear

to be lower in women.

3. The risk of developing lung cancer among pipe and/or cigar

smokers is higher than for nonsmokers but significantly lower

than for cigarette smokers.

4. The risk of developing lung cancer appears to be higher among

smokers who smoke high "tar" cigarettes or smoke in such a

manner as to produce higher levels of "tar" in the inhaled

smoke.

5. Ex-cigarette smokers have significantly lower death rates for

lung cancer than continuing smokers. There is evidence to

support the view that cessation of smoking by large numbers

of cigarette smokers would be followed by lower lung cancer

death rates.

59

64 . ;
6. Increased death rates from lung cancer have been observed

among urban populations when compared with populations

from rural environments. The evidence concerning the role of

air pollution in the etiology of lung cancer is presently inconclusive. Factors such as occupational and smoking habit differences may also contribute to the urban-rural difference

observed. Detailed epidemiologic surveys have shown that the

urban factor exerts a small influence compared to the overriding effect of cigarette smoking in the development of lung

cancer.

7. Certain occupational exposures have been found to be associated with an increased risk of dying from lung cancer.

Cigarette smoking interacts with these exposures in the

pathogenesis of lung cancer so as to produce very much higher

lung cancer death rates in those cigarette smokers who are

also exposed to such substances.

8. Experimental studies on animals utilizing skin painting,

tracheal instillation or implantation, and inhalation of cigarette smoke or its component compounds, have confirmed the

presence of complete carcinogens as well as tumor initiators

and promoters in tobacco smoke. Lung cancer has been found

in dogs exposed to the inhalation of cigarette smoke over a

period of more than two years.

In the interim, additional epidemiological, pathological, and experimental studies have added to our understanding of these relationships.

EPIDEMIOLOGICAL STUDIES

The major prospective epidemiological studies to date, demonstrating associations between cigarette smoking and specific diseases, were conducted primarily in the United States, Canada, and

Great Britain in Caucasian populations. A large, prospective study

currently in progress in Japan adds to the weight of evidence supporting a causal relationship between cigarette smoking and lung

cancer. It is the first large-scale prospective study to be conducted in

a population characterized by genetic, dietary, behavioral, and cultural influences distinctively different from those in previously examined Western populations. The 8-year preliminary prospective

data for lung cancer from this population of 265,118 adults in Japan

(10) demonstrate overall effects and dose-response relationships

similar to those observed in previous studies (figure 1).

60

65
The mortality ratio for male smokers of 1 to 9 cigarettes a day was 2.7 and rose to 24.8 for smokers of more than 2 packs a day. The mortality ratio was 6.9 for ex-smokers. Of the 122,261 men in the study, 74.3 percent were daily smokers, 3.4 percent were ex- smokers, and 19.1 percent nonsmokers. The percentage of males who were daily smokers decreased with advancing age.

26

24

22

20

18 16 e 14 212

02

10

2.7 1.0

5.7

9.1

12.1

24.8

6.9

Non. 1.9 10.19 20.24 25.49 >50

Number of cigarettes smoked per day

Ex.

FIGURE 1.Lung cancer mortality ratios of Japanese males by amount smoked.

SOURCE: Hirayama, T. (10) . In a prospective study of 12,322 Czechoslovakian males, Kubik, et al. (19) analyzed various factors associated with the develop- ment of lung cancer. During the 31/2-yearfollow-up period, 61 cases of lung cancer were discovered. The incidence of lung cancer among males aged 40 to 64 was 460/100,000 among heavy cigarette

smokers (more than 200,000 lifetime cigarettes), 90/100,000 for

light cigarette smokers (less than 200,000 lifetime cigarettes) , and

10/100,000 for nonsmokers. There were no cases of lung cancer among the 222 smokers of pipes and cigars.

66

61
In the past 50 years Poland has experienced a rise in cigarette

consumption and, more recently, a sharp rise in the incidence of and

mortality from lung cancer (16, 34). In the 5-year period between

1963 and 1967, the mortality rate from lung cancer for men rose

from 33.0 to 49.1 per 100,000. This increase was more pronounced

in urban areas. Lung cancer has been the leading cause of death

from malignant neoplasms in Polish men since 1959.

Additional studies conducted in Germany (26), Lebanon (1),

Scotland (6), and Sweden (37) have demonstrated a strong association between cigarette smoking and lung cancer.

Rimington (28) examined the smoking habits and sputum production of 21,579 British males aged 40 and older who were screened

for lung cancer by X-ray examination. During the follow-up period

of 36 to 56 months, 64 new cases of lung cancer were identified.

Because chronic bronchitis and lung cancer are both associated with

cigarette smoking, the data were standardized by cigarette consumption categories. An increase in both lung cancer and chronic

bronchitis was demonstrated with increasing consumption, but for

each level of smoking there was a higher incidence of lung cancer

among the individuals with chronic bronchitis than among those

without this condition. Standardization with respect to age showed

that the differences in lung cancer incidence between those with

and without chronic bronchitis could not be accounted for by the

increase seen in these diseases with advancing age. It was concluded

that persons who smoke run a higher risk of chronic bronchitis than

nonsmokers and those smokers who develop chronic bronchitis run

a higher risk of developing lung cancer than smokers without

chronic bronchitis. The relationship between lung cancer and

chronic bronchitis was not demonstrated for pipe smokers.

Graham and Levin (7) examined the effect of cessation of cigarette smoking on the risk of developing lung cancer in a retrospective study of 700 lung cancer patients. The risk of developing lung

cancer in ex-smokers declined sharply after cessation (figure 2) .

The decline occurred both in those who smoked for less than 31

years and those who had smoked 31 years or more (figure 3) . Those

who had smoked for less than 31 years had a lower risk of lung

cancer following cessation than those with the longer smoking history in each category of time following cessation. Although there

was an appearance of a somewhat more rapid rate of decline in risk

with time following cessation for those who smoked for the shorter

period, the difference was not statistically significant. The relative

risk for the development of lung cancer for pipe and cigar smokers

was 2.6. The reduction in risk following cessation of these forms of

smoking was not examined.

The relationship of smoking to lung cancer in women has recently

been examined by several authors. The smoking patterns of 142,857

62

67
fF

I.

Japanese women were described by Hirayama (/0). Only 10.9 per- cent were daily smokers of cigarettes. Women started smoking at an older age than men and, in cwitrast to Western populations, there

was a higher percentage of smokers in the older age groups than

among younger women. The mortality rates were lower for women

than for men, but a dose-response relationship was demonstrated.

The lung cancer mortality ratio for women smokers of 1 to 9 ciga- rettes a day was 2.65 and rose to 3.14 for smokers of 20 to 24 ciga- rettes a day compared to nonsmokers.

50

40

-le 30

cc 20

10

Cases

42.20

1.00

23.30

10.00

3.33

18 65 19 12

Controls 346 31 17 23 29 30

Months Never 0-6 7.12 13-36 37-120 >120 Smoked

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

FIGURE 2.Relative risk of lung cancer in ex-smokers of cigarettes by length of cessation before diagnosis.

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

In two recent investigations (9, 13) , both similar in design, the

authors described higher rates of lung cancer among Jewish women

in Pittsburgh and Montreal than among Catholic and Protestant

controls. The proportion of epidermoid and anaplastic carcinomas

was found to be lower for the 87 Jewish women with lung cancer in

these studies than for the non-Jewish women. A survey of smoking

68

63
habits in the two cities suggested that the increased incidence of

lung cancer in Jewish women could not be entirely attributed to

variations in smoking patterns. A low incidence of lung cancer was

found among Jewish males, and this was correlated with their low

cigarette consumption.

80

70

60

50

30

20

10

Cases

74.4

Controls Yedrs

12.4

93

Smoking duration before cessation

More than 31 years

Less than 31 years

19.9

1.7 r-1

4.8

0.0

20

24 31 0-1

29 3 4 0

28 34 16 34 2.10

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

>10

Flame 3.Relative risk of lung cancer in ex-smokers of cigarettes by length of

cessation and previous duration of smoking.

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

The increased risk for the development of lung cancer among

uranium miners is well established. The 1971 report, "The Health

Consequences of Smoking" (39), summarized the recent investigations in this area. The histologic types of 121 cases of lung cancer

in American uranium miners were studied by Saccomanno, et al.

(30) using the WHO classification of lung tumors. A marked in-

. crease was noted in the small cell undifferentiated types with in64

69
creasing radiation exposure. The author examined the role of

tobacco in the etiology of these tumors stating, "... among uranium

miners, cigarette smoking is a potent co-carcinogen in the cause of

lung cancer, but exerts little, if any, influence on the cell type of

lung cancer...."

EXPERIMENTAL ASPECTS

Chemicals present in the particulate phase of tobacco smoke have

been teste3 for their carcinogenic potential in experimental animals

and/or tissue and organ cultures and have been grouped according

to the type of activity observed. On mouse skin, certain chemicals

induce tumor formation and are called complete carcinogens; others

appear to act only in conjunction with additional treatment, and

are referred to as incomplete carcinogens. They include tumor initiators and tumor promoters. Tumor initiators inclue an irreversible

change in epidermal cells which causes them to respond to subsequent applications of tumor promoters with the development of skin

tumors. This two-stage mechanism of carcinogenesis, well known

for mouse skin, has not been demonstrated in other animal speciesor

tissues under comparable conditions.

Hoffmann and Wynder (11, 44) discussed the major initiators

and promoters found in cigarette smoke and described an additional

property of acceleration possessed by N-alkylated carbazoles,

N-alkylated indoles, and Trans-4, 4'-dichlorostribene (DCS) which

is a pyrolysis product of the insecticides DDT and DDD. These

compounds are inactive as complete carcinogens, initiators, or promoters but accelerate the initiator-promoter activity of polynuclear

aromatic hydrocarbons (PAH).

The initiating activity of polycyclic aromatic hydrocarbons in

two-stage carcinogenesis was investigated and reviewed by Van Duuren, et al. (41). Several compounds previously thought to be of

little or no significance in tobacco carcinogenesis have been found

by Van Duuren and other independent investigators to be tumor

initiators. Table 1 lists a number of these compounds. Tumor promoting agents probably allow these weak carcinogens to express

their tumorigenic potential. Dibenz (a, c) anthracene which was reported by Van Duuren, et al. (41) to be an initiating agent was

found by Lijinsky, et al. (22) to also act as a complete carcinogen in mouse skin experiments.

In another investigation, Van Duuren, et al. (42) confirmed that

tobacco smoke condensate is primarily a tumor-promoting agent

with weak carcinogenic activity. They also found that benzo (a) - pyrene, a carcinogen in cigarette "tar," acts as a tumor promoter when applied to mouse skin in low doses over a long time period

70

65
TABLE 1.Some initiating agents in two-stage carcinogenesis.

Compound

f Dibenz(a,c)anthracene

t Chrysene

f Benz(a)anthracene

f 6Methylanthanthrene

Chloromethyl methyl ether

Urethan

Triethylenemelamine

1,4Dimethanesulfonoxy-2butyne

f Those found in cigarette smoke.

SOURCE: Van Duuren. et al. (41).

after the application of an initiating agent. This supports the observation that the tumor-promoting activity of cigarette "tar" may

represent the summation of carcinogenic activities of the several

carcinogenic aromatic hydrocarbons present in cigarette "tar."

In tobacco carcinogenesis research the choice of bioassay is of

major importance. Mouse and rabbit skin models have been an important source of experimental data concerning tobacco carcinogenesis (44) . Several relatively rapid screening bioassays have been

recently suggested. Major (24) examined the effects of tumor promoters and initiators on mouse skin, measuring cell numbers, cell

size, mitotic index, and epidermal thickness. Changes found during

the first five days were characteristic for different agents.

The effects of polycyclic aromatic hydrocarbons on the nonspecific

esterase activity in sebaceous glands of mice were examined by

Healey, et al. (8). The changes observed were not entirely specific

for carcinogenic activity and were probably related more to the

toxicity of the painted substances to the sebaceous gland cells. This

suggests that further improvement is needed in this system before

it can be a practical screening bioassay for potential carcinogenic

compounds.

Shabad (33) reviewed experimental studies from Russia and elsewhere relating tobacco with tumor formation, and concluded, "... it

is indicated that cigarette smoke can actually induce lung cancer in

animals."

Leuchtenberger and Leuchtenberger (21) have described adenomas and adenocarcinomas in the lungs of mice chronically exposed

to cigarette smoke. . Takayama -(36) found that subcutaneous injections of cigarette

"tar" in newborn mice produced benign and malignant tumors of

the liver, lung, and lymphoid tissue.

66
The compound 7H-Dibenz (c,g)carbazole (7H-DBC), a component of cigarette smoke, was tested for its carcinogenic potential on

the respiratory tract of Syrian golden hamsters using 15 or 30 intratracheal injections per week. Sellakumar and Shubik (32) found a

high percentage of squamous tumors of the trachea and bronchi in

the tested animals and observed that 7H-DBC appeared to be a

potent carcinogen for the respiratory system of hamsters.

Krasnyanskaya (18) has examined the effects of chronic exposure to cigarette smoke on the respiratory tract of 95 rabbits. One

group was pretreated with an intratracheal injection of benz (a)- pyrene. Although premalignant changes were found in treated animals, no malignancies were observed after four years of exposure.

OTHER CANCERS

The relationships between tobacco smoking in its various forms

and cancers of the oral cavity, larynx, esophagus, kidney, urinary

bladder, and pancreas were summarized in the 1971 report, "The

Health Consequences of Smoking" (39).

1. Cancer of the Larynx

a. Epidemiological, experimental, and pathological studies

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

b. The risk of developing laryngeal cancer among cigarette

smokers as well as pipe and/or cigar smokers is signifcantly higher than among nonsmokers.

c. The magnitude of the risk for pipe and cigar smokers is

about the same order as that for cigarette smokers, or possibly slightly lower.

d. Experimental exposure to the passive inhalation of cigarette smoke has been observed to produce premalignant

and malignant changes in the larynx of hamsters.

2. Cancer of the Oral Cavity

a. Epidemiological and experimental studies contribute to the

conclusion that smoking is a significant factor in the development of cancer of the oral cavity and that pipe smoking,

alone or in conjunction with other forms of tobacco use,

is causally related to cancer of the lip.

b. Experimental studies suggest that tobacco extracts and

tobacco smoke contain initiators and promoters of cancerous changes in the oral cavity.

67

72

1
3. Cancer of the Esophagus

a. Epidemiological studies have demonstrated that cigarette

smoking is associated with the development of cancer of

the esophagus.

b. The risk (f developing esophageal cancer among pipe

and/or cigar smokers is greater than that for nonsmokers

and of about the same order of magnitude as for cigarette

smokers, or perhaps slightly lower.

c. Epidemiological studies have also indicated an association

between esophageal cancer and alcohol consumption and

that alcohol consumption may interact with cigarette

smoking. This combination of exposures is associated with

especially high rates of cancer of the esophagus.

4. Cancer of the Urinary Bladder

a. Epidemiological studies have demonstrated an association

of cigarette smoking with cancer of the urinary bladder

among men.

b. The association of tobacco usage and cancer of the kidney

is less clear-cut.

c. Clinical and pathological studies have suggested that

tobacco smoking may be related to alterations in the metabolism of tryptophan and may in this way contribute to

the development of urinary tract cancer.

5. Cancer of the Pancreas

Epidemiological studies have suggested an association between cigarette smoking and cancer of the pancreas. The

significance of the relationship is not clear at this time.

Additional relevant epidemiological, pathological, and experimental data have been reported.

CANCER OF THE LARYNX

McNelis and Esparza (23) reported 14 cases of carcinoma in situ

of the larynx found among 387 vocal cord biopsies. Thirteen patients were men and with one exception all smoked cigarettes.

Lavelle (20) described 11 patients with carcinoma of the larynx

which occurred as a second primary cancer at least one year after

the successful treatment of an initial primary cancer of the

bronchus. "Although it was not possible to ascertain with certainty

the smoking habit of all these patients there were no definite nonsmokers among them."

68

73 . .
ORAL CANCER

Leukoplakia of the oral mucosa represents a keratinization of

surfaces normally unkeratinized. Over a 23-year period, Sugar and

Banoczy (35) observed 535 patients with leukoplakia. Of the 324

patients examined in the latest survey, 96 (30 percent) had

leukoplakia for more than 10 years. Two hundred sixty-nine patients (83 percent) were smokers. Treatment was ineffective in

those patients who continued to smoke. Oral cancer eventually developed in 13 of 48 patients (27 percent) who had severe leukopla- kia.

The initial changes in the mouth caused by smoking may not be

the hyperkeratotic lesions of leukoplakia. Meyer, Rubinstein, 4nd

colleagues (25, 29) examined the effects of smoking on the surface

cytology of clinically normal oral mucosa and, in general, found

that smoking produced changes in cytoplasm characterized by less

mature cell configurations. These changes were most pronounced

on those surfaces most directly exposed to the stream of cigarette

smoke.

Etiological aspects of squamous cancers of the head and neck

were reviewed by Wynder (43). There was an increased likelihood

of a second primary tumor forming at the site of the first cancer if

a patient had been a heavy smoker, or if he continued to smoke,

after surgical removal of the first primary. From a preventive point

of view it was observed that squamous cell cancers of the head and

neck would be comparatively rare in the absence of tobacco and excessive alcohol consumption.

Jussawalla and Deshpande (15) examined various types of smoking and chewing habits in a retrospective investigation of 2,005

patients in Bombay, India, who had histologically established cancers of the oral cavity, pharynx, larynx, and esophagus. Smokers

used either a manufactured cigarette or the Indian "bidi" which

contains a small quantity of shredded tobacco rolled in a dried leaf,

usually of the Temburni tree (Dispyros Melanoxylon). Chewers

used "pan" made with betel leaf, lime, and spices. A small quantity

of tobacco was, on occasion, added to this mixture as an optional ingredient. Smoking and chewing both resulted in an increased risk of

cancer at each site examined with a striking increase in risk observed in patients who had the combined habits of chewing and

smoking (figure 4). The independent contribution of tobacco to the

increased risk of cancer at each site could not be clearly isolated as

there was no control for chewing when smoking characteristics

were examined and vice versa.

Intra-oral smoking with the lighted end of a cigar or cigarette

inside the mouth is a custom found in parts of the Caribbean, South

America, India, and the Island of Sardinia. Morrow and Suarez

69

74
(27) examined 79 intra-oral smokers, most of whom had sought

medical attention for reasons other than symptoms associated with

smoking-related diseases. All but one patient demonstrated "nicotinic stomatitis" characterized by hyperplasia, acanthosis, hyperkeratosis, and parakeratosis. Sixteen cases of squamous cell carcinoma were found. These were located predominantly at the base of

the tongue, tonsillar fauces, and adjacent pharyngeal mucosa.

30

25

20

tnFt tu 15

4(

tutt 10

5

0 Ore! Oropha ynx NvPopharynx

CHEWING ONLY

SMOKING ONLY

221 CHEWING AND

SMOKING

Larynx Oesophagus

FIGURE 4.Relative risk of cancer of the oral cavity, pharynx, larynx, and

esophagus associated with smoking and chewing in various forms.

SOURCE: Jussawalla, D. J., Deshpande, V. A. (15).

The oral mucosa of many experimental animals appears to be

resistant to the induction of cancers. Cohen, et al. (4) failed to produce any distinctive cancerous or precancerous changes in the

mucosal lining of surgically created buccal pouches of monkeys filled

with chewing tobacco for varying lengths of time. Homburger (12)

exposed the oral mucosa of Syrian golden hamsters to snuff and

7,12-Dimethylbenz (a) anthracene (DMBA) using a bit inserted in

the mouth. Snuff alone failed to produce any changes that were not

also seen in the control animals who had a plain cotton plug inserted

in the mouth. Benzo (a) pyrene and DMBA caused a few carcinomas

of the oral mucosa, but they produced a much higher number of

cancers outside the mouth where the carcinogenic agents had spilled

onto the perioral skin. The authors observed that "... skin-painting

experiments are more sensitive indicators of carcinogenicity for the

oral mucosa than applications to the mucosa itself."

70

'75
CANCER OF THE ESOPHAGUS

Cancer of the esophagus is associated with both tobacco and alcohol consumption.

In the prospective study from Japan, Hirayama (10) found no

significant association between the use of cigarettes or alcohol alone

and cancer of the esophagus, but there were high rates of esophageal cancer among individuals using both cigarettes and alcohol

(figure 5).

30

7.6

0

4.2

5.1

0

22.5

27.9

Drinking

Daily

Smoking

Daily

Observed

Person-years ++ ++ 66,080 59,062 48,799 95,073 19,422 43,025

FIGURE 5.Death rates for cancer of the esophagus in Japanese males by smoking and drinking characteristics.

SOURCE: Hirayama, T. (10).

Schoenberg, et al. (31), using cohort analysis, examined mortality from esophageal cancer in the United States. Substantial ethnic,

geographic, and temporal variations were observed. On a state-bystate basis, mortality from esophageal cancer was correlated about

equally with urbanization, per capita cigarette sales, and per capita

71

76
alcohol sales. The correlation with urbanization was partially explained by increased sales of tobacco and alcohol in urban areas.

CANCER OF THE URINARY BLADDER

In a retrospective study of 470 confirmed cases of transitional

cell or squamous cell cancers of the bladder, Cole, et al. (5) found a

consistent positive relationship between cigarette smoking and

bladder cancer. The relative risk and standard error for the development of bladder cancer were 1.89 ± 0.22 for male smokers and

2.00 ± 0.33 for female smokers. A dose-response relationship was

demonstrated for both the number of cigarettes smoked per day

(figures 6 and 7) and various degrees of inhalation. Bladder cancer

has been shown to be associated with certain occupational categories

such as dye workers, certain textile workers, tailors, and nurses

(2, 14). Cole standardized the data with respect to occupation and

found that the risk demonstrated could not be explained by any indirect association with industrial exposure. Cole concluded: "The

3

1.00 1.03 ii_,

2.01

2.17

Observed 70 36 140 85

Expected 109.5 54.6 109.1 61.4

Number of cigarettes Nonsmoker 1.9 10.29 30-49

smoked per day

MALES

FIGURE 6.Relative risk of urinary bladder cancer for males by amount smoked.

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

72
4

3

Jg0

E0

c

2

"' N

Tocc1

0

1.97

1.52

1.00

[Observed

Expected

3.81

50 13 30 12

68.2 11.7 20.8 4.3

Number of ciga ettes smoked

per day Nonsmoker

FEMALES

10-29 30.49

FIGURE 7.Relative risk of urinary bladder cancer for females by amount

smoked.

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

present findings indicate that about 35 percent of cases of cancer of

the lower urinary tract in the study population are associated with

cigarette smoking. If this association is accepted as causal, and if it

is generalized to the entire population of the United States, smoking

is associated with about 3,100 deaths per year from cancer of the

lower urinary tract." No significant association was found between

pipe or cigar smoking and bladder cancer.

Tyrrell, et al. (88) examined several factors including smoking

history and occupation in a group of 250 patients treated for urinary bladder cancer in Ireland. No significant association between

occupation and bladder cancer was found. This may have been due

to the low concentration of high-risk industries for this cancer in

Ireland. A significant (P < 0.005) association was found in males

between cigarette smoking and cancer of the urinary bladder, but

73

78
no significant association was found for the 50 cases of bladder

cancer in females.

In an extensive review of cancer of the urinary tract, Clayson

and Cooper (3) included data that demonstrated an association between cigarette smoking and excessive mortality from bladder

cancer.

CANCER OF THE PANCREAS

Cancer of the pancreas was responsible for 9,696 deaths among

men and 7,190 deaths among women in the United States in 1967

(40). The United States age-adjusted mortality rate for carcinoma

of the pancreas has risen from 2.9 to 8.2 per 100,000 from 1920 to

1965 (17).

In the prospective Japanese study by Hirayama (10), the preliminary data showed a pancreatic cancer mortality ratio of 2.7

for male smokers and a mortality ratio of 3.0 for female smokers.

In an epidemiologic appraisal of cancer of the pancreas, Krain

(17) found that cigarette smoking and industrial exposure were

more strongly associated with this disease than either air pollution

or genetic factors.

HIGHLIGHTS OF CURRENT CANCER INFORMATION

In addition to the comprehensive summary from the 1971 report,

"The Health Consequences of Smoking" (39), cited earlier in this

chapter, the following statements are made to emphasize the most

recent developments in the field :

1. Preliminary results from a major prospective epidemiologi- cal study in Japan demonstrate a strong association between

cigarette smoking and lung cancer. A dose-response relationship was demonstrated for the number of cigarettes smoked.

These findings in an Asian population with distinct genetic

and cultural characteristics confirm the major importance of cigarette smoking in the causation of lung cancer, a conclusion which up to now has been based largely on studies of

Caucasian populations in the United States, Canada, and

Europe.

2. Ex-smokers have significantly lower death rates for lung cancer than continuing smokers. The decline in risk following

cessation appears to be rapid both for those who have smoked

for long periods of time and for those with a shorter smoking

74
history, with the sharpest reductions taking place after the

first two years of cessation.

3. The risk of developing lung cancer appears to be higher for

smokers who have chronic bronchitis. Though both conditions

are directly related to the amount and duration of smoking, an

additional risk for lung cancer appears to exist for cigarette

smokers with chronic bronchitis which is independent of age

and number of cigarettes consumed.

4. Experimental studies on animals have demonstrated that the

particulate phase of tobacco smoke contains certain chemical

compounds which can act as complete carcinogens, tumor initiators, or tumor promoters. Recently, other compounds have

been described that have no independent activity in two-stage

carcinogenesis but accelerate the carcinogenic effects of polynuclear aromatic hydrocarbons in the initiator-promoter

system.

5. Additional epidemiological evidence confirms a significant association between the combined use of cigarettes and alcohol,

and cancer of the esophagus.

6. Epidemiological studies have demonstrated a significant association between cigarette smoking and cancer of the urinary

bladder in both men and women. These studies demonstrate

that the risk of developing bladder cancer increases with inhalation and the number of cigarettes smoked.

7. Epidemiological evidence demonstrates a significant association between cigarette smoking and cancer of the pancreas.

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1970.

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(15) JussAwAttA, D. J., DESHPANDE, V. A. Evaluation of cancer risk in

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Pregnancy
Contents

Page

Introduction 83

Effect on Birth Weight 83

Effect on the Outcome of Pregnancy 83

Congenital Malformations 87

Cancer in Children Born to Smoking Mothers 87

Long-Term Effects on Children Born to Smoking Mothers 88

Experimental Studies 88

Summary 89

References 89

LIST OF TABLES

Table 1.Frequency of abortion and cigarette consumption 85

81

85
INTRODUCTION

The 1971 report, "The Health Consequences of Smoking" (23),

summarized the relationship between smoking and pregnancy as

follows :

Maternal smoking during pregnancy exerts a retarding in- fluence on fetal growth as manifested by decreased infant

birth weight and an increased incidence of prematurity, defined by weight alone. There is strong evidence to support the

view that smoking mothers have a significantly greater number of unsuccessful pregnancies due to stillbirth and neonatal

death as compared to nonsmoking mothers. There is insufficient evidence to support a comparable statement for abortions. The recently published Second Report of the 1958

British Perinatal Mortality Survey, a carefully designed and

controlled prospective study involving large numbers of patients, adds further support to these conclusions.

New epidemiological, experimental, and pathologic studies lend

support to the foregoing statements.

EFFECT ON BIRTH WEIGHT

Analysis of data from more than 100,000 births has shown that

infants of mothers who smoke during pregnancy have a mean birth

weight of 6.1 ounces (173 grams) less than infants born to nonsmoking mothers (23) . Several recent studies confirm this relationship (1, 2, 6, 7, 10, 13, 15, 18, 25).

EFFECT ON THE OUTCOME OF PREGNANCY

New studies have been published concerning the effect of maternal

smoking on the outcome of pregnancy.

Kullander and Killen (13) performed a prospective study in Sweden involving 6,363 pregnant women. These women completed

several questionnaires during the course of their pregnancy, and

in this manner specific information was obtained on smoking habits

for the entire pregnancy. Forty-four percent of the women smoked

cigarettes during pregnancy and D7 percent of these smoked during

the whole pregnancy.

86

e3
Stillbirths, neonatal deaths, and deaths occurring before one year

of age were recorded to determine a "total death risk." This risk

was approximately 60 percent higher for children born to smoking

mothers as compared to those born to nonsmoking mothers.

Deaths occurring before one week of age and also deaths taking

place between the age of one week and one year were significantly

more frequent in children born to smoking mothers. Among children

dying before one week of age, significantly more cases of abruptio

placentae were found in smoking mothers than in nonsmoking

mothers. The higher level of neonatal mortality in children born to

smoking mothers was confined to those weighing more than 2,500

grams. Live-born infants weighing less than 2,500 grams had

equally high neonatal mortality rates whether they were born to

smoking or nonsmoking mothers. The stillbirth rate was greater in

smoking mothers than in nonsmoking mothers, but the difference

was not statistically significant.

An overall increased risk of spontaneous abortion among smoking

women was found, but this was primarily due to an association between unwanted pregnancy and smoking. The authors found that

significantly (P < .001) more women with unwanted pregnancies

were smokers than women with wanted pregnancies ; in addition,

spontaneous abortions were significantly (P < .001) more frequent

among women with unwanted pregnancies than among women with

wanted pregnancies. When correction was made for the mothers'

acceptance of pregnancy, the contribution of maternal smoking to

spontaneous abortion was of only borderline significance.

Also in the Kullander and Killen study (13), a decreased frequency of preeclampsia among smoking mothers was noted. Maternal smoking had no effect on the mean Apgar score of surviving,

non-malformed children.

A prospective study from Sweden of abortions in 4,812 pregnancies was reported by Palmgren and Wallander (17). Only those

women who smoked throughout pregnancy were considered smokers.

The lowest abortion rate was found among nonsmoker3, 7.8 percent,

while the highest rate was found among heavy smokers, 14.5 percent (table 1). The difference is statistically significant (P < .001).

Heavier smokers appeared to abort earlier in pregnancy. A history

of previous abortion was obtained twice as often in heavy smokers

as in nonsmokers.

Yerushalmy reported in 1964 on pregnancies occurring in women

participating in the Kaiser Health Plan of the San Francisco-Oakland area (24). The 1971 report, "The Health Consequences of

Smoking" (23), commented in detail on that report. Recently,

Yerushalmy published data on 18,088 pregnancies occurring in this

plan between 1960 and 1967, which included the 6,800 cases previously reported (24, 25).

84

87
TABLE 1.Frequency of abortion and cigarette consumption.

Result

of the

pregnancy Nonsmokers gl0 cigarettes >10 cigarettes Total

Abortion

Delivery

Total

177 148 60 385

7.8% 9.1% 14.5% 8.95

2,087 1,486 354 3,927

92.2c 90.9% 85.5% 91.1%

2,264 1,634 414 4,312

Stumm Palmgren. B.. Wallander. B. (17)

As in the 1964 study, he again found an increase in the incidence

of low birth weight infants (less than 2,500 grams) among smoking

mothers. These small infants had a significantly lower neonatal

mortality rate and fewer congenital anomalies than the small infants born to nonsmoking mothers. The neonatal mortality rate for

single, live-born infants born to white, smoking mothers was

11.3/1000, while that for single, live-born infants born to white,

nonsmoking mothers was 11.0/1000; the difference is not significant.

Taylor analyzed Yerushalmy's data for the probability of fetal

death and found no difference between smoking and nonsmoking

mothers (22).

Some of these findings are different from those reported in the

other recent, large-scale prospective studies (5, 13, 17, 19), and

some of the differences may be a consequence of the definition of

"smoker" used. In the study of Kullander and Millen (13), multiple

interviews were performed during pregnancy which allowed more

precise separation of the pregnant women into smokers and nonsmokers. In the study reported by Palmgren and Wallander (17),

only those women who smoked throughout pregnancy were considered smokers. The British Perinatal Mortality Study (5), which

was discussed in the 1971 report, "The Health Consequences of

Smoking" (23), defined "smokers" as those women who smoked

regularly after the fourth month of pregnancy. The smoking history

was obtained shortly after delivery of the infant.

In contrast, Yerushalmy (25) defined "smokers" as women who

were smoking one or more cigarettes a day during the pregnancy,

and "nonsmokers" as women who never smoked and those who

stopped smoking either before or during the pregnancy. Because

the smoking history was obtained only once, usually early in pregnancy, some of the women who were classified as smokers could

have gone through a significant portion of their pregnancy as nonsmokers, and similarly some of the women who were classified as

85

7 88
nonsmokers could have gone through a significant portion of their

pregnancy as smokers. If smoking by pregnant women increases the

risk of an unsuccessful pregnancy, an imprecise separation of pregnant women into smokers and nonsmokers would tend to diminish

the magnitude of any differences found. One Swedish study (13) and the British Perinatal Mortality Study (5) seemed to be at variance in statements about the frequency with which smoking habits

vary from one portion of the pregnancy to another. If this is a culturally determined phenomenon, there is no way of estimating the

extent to which it applies to the patients participating in the Kaiser

Health Plan described by Yerushalmy.

Mac Mahon, et al. (14) commented on Yerushalmy's analysis of mortality rates in low birth weight infants. They observed that

there are "... factors that affect birth weight without influencing mortality ; for example, females have lower birth weights than

males but not the higher mortalities that might be predicted for

them on that account. If cigarette smoking is another such factor,

the explanation of the higher weight-specific mortalities for nonsmokers becomes immediately clear: it is an artifact of the analysis.

It is meaningful to compare category-specific rates only when the

specification of the category has the same implication for each of

the populations compared."

Perinatal mortality, rates were similar in infants born to smoking

and nonsmoking mothers in a recent prospective investigation of

1,300 pregnancies from New Zealand (/ ). Women were classified

as smokers or nonsmokers during their first "booking" at an antenatal clinic, and this was not later amended. This method of classification is similar to that used in the Yerushalmy study.

Comstock, et al. (6, 7) have reported in 1967 and 1971 on the

relationship of maternal smoking to the outcome of pregnancy. In

their studies, all perinatal deaths and samples of live births occurring during a 10-year period among children whose mothers were

residents of Washington County, Maryland, were matched against

the records of a special census based on a household interview taken

in 1963. Maternal smokers were defined as women who were smoking in 1963 and who had started to smoke prior to the pregnancy in

question; maternal nonsmokers were women who denied ever having smoked. When this study is compared to previously cited studies

(5, 13, 17), the data on the smoking status of the mothers during

pregnancy are imprecise, which limits their value.

In the 1967 study (6) , maternal smoking was associated with an

increased risk of mortality for the child, both in the neonatal period

and for several years thereafter; however, this effect was thought

to be related to factors such as adequacy of prenatal or postnatal

environment and care, rather than a direct effect of maternal smoking. Stillbirth rates were similar for smokers and nonsmokers.

e6

89
The more recently published study (7) includes a 32 ~percent

sample of live-born, low birth weight infants and a 3 percent sample of live-born, larger infants born during the 10-year period preceding the census. The total births represented by these samples

were 4,641 to smokers and 7,646 to nonsmokers. The neonatal Mon

tality rate, when adjusted for environmental and socioeconomic

factors, was approximately one-third higher among infants born to

smoking mothers than among those born to nonsmoking mothers

(7). The categories of asphyxia, atelectasis, and immaturity accounted for the greater neonatal mortality among infants born to

smoking mothers as compared to those born to nonsmoking mothers

(7).

CONGENITAL MALFORMATIONS

As noted in the 1971 report, "The Health Consequences of Smoking" (23), the possible teratogenic effect of maternal smoking has

not been adequately evaluated. Additional studies have been published in the interim, but rather than investigating congenital malformations in both stillborn and live-born infants, most of the recent

studies have dealt only with live-born infants.

Fedrick, et al. (8) analyzed data from the large British Perinatal

Mortality Study for the incidence of congenital heart disease in stillborn and live-born infants of smoking and nonsmoking mothers. An

incidence of 7.3/1000 births was found in infants born to smoking

mothers as compared to 4.7/1000 births for infants born to nonsmoking mothers, a statistically significant difference (P < .001) . Kullander and Millen (13) noted no teratogenic effect of maternal smoking in children dying before one year of age or in children

surviving one year of age. However, they observed that published

studies have been too small to exclude this possibility.

In a study of perinatal death occurring in infants weighing more

than 1,000 grams, Bailey (1) found that maternal smoking did not

lead to an increased incidence of congenital anomalies.

Yerushalmy (25) reported only on live-born infants weighing

less than 2,500 grams and found significantly fewer (P < .02)

anomalies among infants born to smoking mothers.

Comstock, et al. (7) found fewer than the expected number of

congenital anomalies among live -born infants of smoking mothers.

CANCER IN CHILDREN BORN TO SMOKING MOTHERS

Neutel and Buck (16) studied the relationship between maternal

smoking during pregnancy and the development of cancer in the offspring. The base population was obtained from the British and

Ontario Perinatal Studies and consisted of 89,302 babies who sur90

17
vived at least seven days. There were 65 cancer deaths and 32 cancer survivors in the period from birth to a minimum of 7 and a

maximum of 10 years of age. For cancer of all sites, the children

of smokers had a relative risk of 1.3. The authors concluded : "Although these results make it most unlikely that in utero exposure to

tobacco smoke has a broadly carcinogenic effect on the fetus, a response confined to one tissue or expressed over a narrow age range

cannot be ruled out."

LONG-TERM EFFECTS ON CHILDREN BORN TO

SMOKING MOTHERS

Goldstein (9) analyzed data from the British Perinatal Mortality

Study to determine factors influencing the height of 7-year-old

children. In the 1958 study, information was collected on 16,994

singleton births. In 1965, heights were measured "to the nearest

inch" on 13,127 of these children who could be followed up. The data

were analyzed for the influence of parity, birth weight, length of

gestation, maternal age, maternal height, social class, number of

younger siblings, and maternal smoking habits during pregnancy.

Allowance was made for the sex and age of the child at the time of

measurement. The author's conclusions included the following:

"After allowing for the other variables, the children of mothers who

smoked 10 or more cigarettes a day after the 4th month of pregnancy, are on average about 1.0 cm shorter at age seven than the

children of mothers who did not smoke."

EXPERIMENTAL STUDIES

Becker and Martin (3) continued their experiments concerning

the effect of nicotine on pregnant rats. Offspring of rats given nicotine weighed significantly lees at birth than saline-injected controls.

There were fewer live births among the nicotine-injected rats.

Kelly and Roy (12), using cinephotomicrography, demonstrated

that nicotine crosses the mouse placental barrier in amounts adequate to produce a measurable cardiovascular response.

Stalhandske, et al. (21) studied the in vitro metabolism of nicotine in livers of fetal, young, and adult mice. Cotinine was found to

be the major metabolite at all ages investigated.

Using radioactive compounds, Sieber and Fabro (20) identified a

variety of drugs in the preimplantation blastocyst and in uterine

secretions of pregnant rabbits. In animals receiving dose levels of

nicotine comparable to that encountered in man, significant amounts

of radioactivity were found in the preimplantation blastocyst. A

markedly higher concentration of radioactivity was observed in

uterine secretion than in maternal plasma.

88

91
Juchau (11) studied the levels of benzpyrene hydroxylase in the

placentas of smoking and nonsmoking women obtained both early in

pregnancy and at term. This enzyme hydroxylates benzo (a) pyrene,

a carcinogenic hydrocarbon found in tobacco smoke. Previous studies had shown that placentas, obtained at term from smoking

women, have a greater ability to hydroxylate benzo (a) pyrene than

the placentas from nonsmokers (23) . Juchau corroborated this, but

also found very low levels in placental tissues obtained from healthy

smokers during first trimester dilatation and curettage or hysterotomy for therapeutic abortion. This lack of significant placental

drug metabolizing activity during the first trimester was interpreted as a possible hazard to the fetus, particularly if the substance were active in the unmetabolized form. Enzyme levels were

undetectable in placental homogenates of nonsmokers at 8 to 16

weeks gestation.

The carcinogenic effect on the newborn of rats receiving benzo-

(a) pyrene during the latter half of pregnancy was studied by Bulay

and Wattenberg (4). An increased incidence of pulmonary adenoma

and skin papilloma was observed.

SUMMARY

Maternal smoking during pregnancy exerts a retarding influence

on fetal growth as manifested by decreased infant birth weight and

an increased incidence of prematurity, defined by weight. There is

increasing evidence to support the view that women who smoke

during pregnancy have a significantly greater risk of an unsuccessful pregnancy than those who do not.

PREGNANCY REFERENCES

(1) BAILEY, R. R. The effect of maternal smoking on the infant birth

weight. New Zealand Medical Journal 71(456) : 293-294, May 1970.

(2) BEM., V. A. Nutritional studies during pregnancy. Journal of the American Dietetic Association 58(4) : 321-326, April 1971.

(3) BECKEE, R. F., MARTIN, J. C. Vital effects of chronic nicotine absorption

and chronic hypoxic stress during pregnancy and the nursing period.

American Journal of Obstetri212stAfnaogy 110(4) : 522-533,

June 15, 1971.

(4) BULAY, 0. M., WATTENBERG, L. W. Carcinogenic effects of subcutaneous

administration of benzo(a) pyrene during pregnancy on the progeny.

Proceedings of the Society for Experimental Biology and Medicine

135(1) : 84-86, October 1970.

(5) BUTLER, N. R., ALDERMAN, E. D. (Editors). Perinatal Problems. The

Second Report of the 1958 British Perinatal Mortality Survey. London,

E. and S. Livingstone Limited, 1969. 395 pp.

(6) COMSTOCK, G. W., LUNDIN, F. E., JR. Parental smoking and perinatal

mortality. American Journal of Obstetrics and Gynecology 98(5) :

708-718, July 1, 1967.

92 89
(7) ComvrocE, G. W., SHAH, F. K., MEYER, M. B., ABBEY, H. Low birth weight and neonatal mortality rate related to maternal smoking and

socioeconomic status. American Journal of Obstetrics and Gynecology

111(1) : 53-59, September 1, 1971. (8) PEDRICK, J., ALBERMAN, E. D., GOLDSTEIN, H. Possible teratogenic effect of cigarette smoking. Nature 231: 529-530, June 25, 1971. (9) Go LosrEiN, H. Factors influencing the height of seven year old children

results from the National Child Development Study. Human Biol- ogy 43: 92-111, February 1971.

(10) GOUJARD, J., ETIENNE, C., EVRARD, F. Caracteristiques maternelles et

poids de naissance. (Maternal characteristics and birth weight.) Revue du Praticien 19(28, Supplement) : 54, 59-62, 65, November 1,

1969.

(11) JUCHAU, M. R. Human placental hydroxylation of 3,4-benzpyrene during early gestation and at term. Toxicology and Applied Pharmacology 18(3) : 665-675, March 1971.

(12) KELLY, M., ROY, F. H. Microcirculatory response of fetal mice to maternal nicotine. (Abstract.) Clinical Research 19(2) : 322, April 1971. (13) KULLANDER, S., KALLEN, B. A prospective study of smoking and preg- nancy. Acta Obstetricia et Gynecologica Scandinavica 50(1) : 82-94, 1971.

(14) MACMAHON, B.; ALPEirr, M., SALBER, E. J. Infant weight and parental smoking habits. American Journal of Epidemiology 82(3) : 247-261, November 1965.

(15) MURPHY, J. F., MULCAHY, R. The effect of age, parity, and cigarette

smoking on baby weight. American Journal of Obstetrics and Gynecology 111(1) : 22-25, September 1, 1971.

(16) NEUTEL, C. I., BUM, C. Effect of smoking during pregnancy on the risk

of cancer in children. Journal of the National Cancer Institute 47(1) : 59-63, July 1971.

(17) PALMGREN, B., WALLANDER, B. CigarettrOlming och abort. Konsekutiv

prospektiv undersokning av 4312 graviditeter. (Cigarette smokingand

abortion. Consecutive prospective study of 4312 pregnancies.) Likarrtidningen 60(22) r 2611-2616, 1971.

(18) PErrEassoN, F. Medicinski skadeverkningar av rokning. Rokning och

gynekologisk-obstetriska tillstand. (Harmful clinical effects of smoking. Smoking and gynecological-obstetrical condition.) Social-Medicinsk Tidskrift 2(Special No.) : 78-82, February 1971. (19) RUSSELL, C. S., TAYLOR, R., LAW, C. E. Smoking in pregnancy, maternal blood pressure, pregnancy outcome, baby weight and growth, and

other related factors. A prospective study. British Journal of Preventive and Social Medicine 22(3) : 119-126, July 1968.. (20) SIEBER, S. M., FABRO, S. Identification of drugs in the preimplantation

blastocyst and in the plasma, uterine secretion and urine of the preg- nant rabbit. Journal of Pharmacology and Experimental Therapeutics

176(1) : 65-75, 1971.

(21) STALHANDSKE, T., SLANINA, P., TJALVE, H., HANSSON, E., SCHMITERLoW,

C. G. Metabolism in vitro of 14C-nicotine in livers of foetal, newborn

and young mice. Acta Pharmacologica et Toxicologica 27(5) : 363-

380, 1969.

(22) TAYLOR, W. F. The probability of fetal death. IN: Fraser, F. C.,

McKusick, V. A. (Editors). Congenital Malformations. Proceedings

of the Third International Conference, The Hague, The Netherlands,

September 7-13, 1969. New York, Excerpta Medics, August 1970.

pp. 307-320.

90
(23) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking.

A Report of the Surgeon General: 1971. Washington, U.S. Department of Health, Education, and Welfare, DHEW Publication No.

(HSM) 71-7513, 1971. 458 pp.

(24) YERUSHALAIT, J. Mothers' cigarette smoking and survival of infant.

American Journal of Obstetrics and Gynecology 88(4) : 505-518,

February 15, 1964.

($5) YERUSHALMV, J. The relationship of parents' cigarette smoking to outcome of pregnancyimplications as to the problem of inferring causation from observed associations. American Journal of Epidemiology

93(6) : 443-456, June 1971.

91

94
CHAPTER 6

Gastrointestinal Disorders

95
Contents

Page

Highlights of Current Gastrointestinal Information 98

References 98

96

95
GASTROINTESTINAL DISORDERS

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

follows :

Cigarette smoking males have an increased prevalence of

peptic ulcer diseaae and a greater peptic ulcer mortality ratio.

These relationships are stronger for gastric ulcer than for

duodenal ulcer. Smoking appears to reduce the effectiveness of

standard peptic ulcer treatment and to slow the rate of ulcer

healing.

Studies of the effect of smoking on gastric secretion in patients

with peptic ulcer and normal controls have produced conflicting reports (4). Recently, Wilkinson and Johnston (5) reported a significant inhibition of pentagastrin-stimulated gastric acid secretion

after cigarette smoking by normal volunteers, while Debas, et al.

(1) found no significant overall change. Wilkinson and Johnston also

studied patients with gastric and duodenal ulcers in whom a significant inhibition of pentagastrin-stimulated gastric secretion was

observed after the patients smoked one or two cigarettes over a period of 10 to 15 minutes.

A study by Konturek, et al. (8) suggests that alterations in

pancreatic and biliary secretion may be responsible for the relationship between smoking and peptic ulcer. Nicotine was infused in

mongrel dogs in doses corresponding to amounts absorbed from

smoking up to four cigarettes in one hour. In the pancreas, nicotine

inhibited the secretin-stimulated secretion of both fluid and bicarbonate, and the degree of inhibition was dose-related. Spontaneous biliary secretion of bicarbonate was also depressed by the drug.

Nicotine had no effect on gastric secretion of acid, gastric mucosal

blood flow, or the mucosal barrier to hydrogen or sodium ions. This

inhibition of pancreatic and hepatic bicarbonate secretion may deprive the duodenum of sufficient alkaline secretion to neutralize gastric acidity and may be one biomechanism linking cigarette smoking

and peptic ulcer.

Dennish and Castel] (Z) noted the clinical association between

cigarette smoking and heartburn. To investigate the biomechanism

of this relationship. lower-esophageal sphincter pressure determinations were made before and after smoking in six normal male

volunteers. All of the volunteers were cigarette smokers. In each

97
subject after the onset of cigarette smoking, there was a rapid decrease in lower-esophageal sphincter pressure from the basal level.

This diminution in sphincter pressure persisted until smoking was

stopped, at which time the pressure returned rapidly toward normal. Mean basal pressure was 19.6 ± 2.1 (± 1 S.E.) mmHg. and

mean pressure during smoking was 11.4 ± 2.2 mmHg. The difference between these pressures is statistically significant (P < .001).

No changes were noted when volunteers puffed on unlit cigarettes.

Variable responses were noted when volunteers smoked cigars and

pipes. The investigators concluded that cigarette smoking decreases

the effectiveness of the lower-esophageal sphincter as a barrier

against gastroesophageal reflux.

HIGHLIGHTS OF CURRENT GASTROINTESTINAL

INFORMATION

In addition to the summary statement cited at the beginning of

this section, the following observations have been made:

1. A possible link between cigarette smoking and peptic ulcer has

been demonstrated in dogs in which nicotine was found to inhibit pancreatic and hepatic bicarbonate secretion. This

could lead to peptic disease by depriving the duodenum of sufficient alkaline secretion to neutralize gastric acidity.

2. An investigation in human volunteers has suggested that

cigarette smoking decreases the effectiveness of the loweresophageal sphincter as a barrier against gastroesophageal

reflux.

98

GASTROINTESTINAL DISORDERS REFERENCES

(1) DEBAS, H. T., COHEN, M. M., HOLUBITSKY, I. B., HARRISON, R. C. Effect

of cigarette smoking on human gastric secretory responses. Journal

of the British Society of Gastroenterology 12: 93-96, 1971.

(2) DENNISH, G. W., CASTELL, D. 0. Inhibitory effect of smoking on the

lower esophageal sphincter. New England Journal of Medicine

284 (20) : 1136-1137, May 20, 1971.

(3) KONTUREK, S. J., SOLOMON, T. E., MCCREIOHT, W. G., JOHNSON, L. R.,

JACOBSON, E. D. Effects of nicotine on gastrointestinal secretions.

Gastroenterology 60(6) : 1098-1105, June 1971.

(4) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking.

A Report of the Surgeon General: 1971. Washington, U.S. Department of Health, Education, and Welfare, DHEW Publication No.

(HSM) 71-7513, 1971. 458 pp.

(5) WILKINSON, A. R., JOHNSTON, D. Inhibitory effect of cigarette smoking

on gastric secretion stimulated by pentagastrin in man. Lancet

2(7725) : 628-632, September 18, 1971.

98
CHAPTER 7

Allergy

99
Contents

Page

Introduction 103

Antigenic Properties 104

Skin Testing 105

Additional Immunological Effects 107

Effect on the Immune Response 108

Irritant and Pharmacologic Effects 109

Clinical Allergy 110

Summary 111

References 112
INTRODUCTION

As early as 1886 reference was made to an entity called "tobacco

asthma" (64). Subsequently, controversy has arisen over whether

tobacco smoking causes clinical allergy (61) and whether such

tobacco allergy is associated with the major smoking-related diseases (25, 69).

In 1957, Silvette, et al. (64) reviewed more than 100 papers concerned 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 : ".. . virtually all reported clinical investigation has been limited to determinations of cutaneous sensitivity to tobacco extracts; and it must be

regretfully admitted that much of this published work is equivocal,

uncritical, and inadequately controlled."

Such criticism is also applicable to many studies published since

then.

Epidemiologic studies designed to determine the prevalence of

tobacco allergy have not been carried out; hence, it is difficult to

evaluate the magnitude of the problem.

Allergy may be defined as a specific alteration in response mediated by an antigen-antibody reaction. When a hereditary susceptibility to allergic illness is present, the term atopy is used. For example, hay fever and asthma are atopic diseases.

There is no single test or observation which can be used to determine whether a substance may be responsible for allergic disease ; however, fulfillment of the following criteria constitutes evidence 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 simuliting an allergic reaction are elicited which

disappear upon its removal.

3. Demonstration that the immunologic event is related to the

clinical event.

Recent advances in the understanding of immunological reactions

as well as in the Methodology of immunology are now being applied

103

101
to problems of clinical allergy. For example, Ishizaka (37), using

radioimmunoelectrophoresis, recently reported that the so-called

"allergic antibody" (reagin, skin-sensitizing antibody (SSA) , atopic antibody) belongs to a new ',lass of immunoglobulins, IgE.

Although the skin test remains a simple and definitive method of

demonstrating reagins in the allergic patient, there are many variables 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 composition result from differences in tobacco types and species, processing 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 antibody formation in rabbits. The antigens contained in the extracts

included both proteins and polysaccharides and had molecular

weights ranging from 20,000 to 60,000.

Silvette, et al. (64) reviewed several papers dealing with the

immunology of nicotine and concluded that nicotine was nonantigenic. 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, although not antigenic by itself, reacts with antibody and conveys

antigenic specificity when combined with another compound.

With pyrolysis many of the tobacco constituents undergo reactions involving oxidation, dehydrogenation, cracking, rearrangement, 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 distinct 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 to104

102
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 removing all irritants from test extracts. In a clinical setting, allergy to

tobacco additives such as menthol has also been suspected (47).

SKIN TESTING

Intracutaneous injection of test antigen is a widely used method

of skin testing. Patch tests have also been used in cases of suspected

contact dermatitis.

Rosen (54) has observed that skin testing does not accurately

duplicate the most common route ofexposure 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 extracts includes comparisons of the prevalence of positive skin reactions in different groups, such as "normal" nonsmoking adults (17, 68) , "normal" smokers (17, 33) , allergic patients (59, 76), children

(41, 50), tobacco workers (6, 9) , and patients with specific diseases,

e.g., thromboangiitis obliterans (28, 73). Harkavy reported on

tobacco skin reactions in several different groups of patients (30). Many of the apparently discordant results in some of these reports can be traced to failure to compare similar populations or to control

for differences in the test antigen or in the method of testing.

Sulzberger (66) studied the different types of skin reactions pro- duced by intracutaneous injection of denicotinized tobacco extract.

Three types of positive skin responses were observed: eczematous

reactions; immediate wheal-and-flare reactions; and late reactions,

probably of the tuberculin type. The wheal-and-flare response has been by far the predominant type (42).

This immediate wheal-and-flare response is a specific immune re- action (64) largely mediated by IgE. Patterson (48) recently pro- posed a simplified model explaining the mechanism of action of the

skin sensitizing antibody (SSA). "Subsequent to stimulation of the

animal by antigen, SSA are produced by cells of the lymphoid system possibly located in the alimentary and respiratory tract. .. . The

SSA so produced are secreted in such a way that they reach the circulation, where circulating cells, predominantly basophilic leukocytes, are sensitized by attachment of the SSA to the cell surface.

In addition, the SSA also leave the vascular compartment and sensitize mediator-releasing cells in tissues. The tissue cells are pri- marily mast cells . . . The immediate-type allergic reaction occurs

103

105
when antigen is 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

system. The antigens reach the antibody on the surface of the mast

cells and initiate the intracellular events that result in mediator release from the cells." The actions of these mediators include smooth

muscle contraction, vasodilation, and increased capillary permeability which can produce such clinical pictures as hay fever, asthma, and generalized anaphylaxis.

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

site and adjacent normal skin. In a positive response, cutaneous

reactivity is transferred to the normal subject at the injection site.

The absence of a positive response in nearby normal skin excludes

nonspecific irritation as a cause of the response and shows that the

normal subject is not himself allergic to the antigen.

Harkavy and Witebsky (34) found and selectively absorbed

tobacco reagins in patients showing multiple sensitivities. This selective 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 Rot ha (41). Lowell

(43) stated, "The individual possessing skin-sensitizing antibody

to the tobacco extract may be regarded as unequivocally allergic to

the extract...." Despite the inability of Sulzberger and Feit (67)

to demonstrate tobacco reagins in their skin test positive patients,

several investigators have found them (26, 50, 75).

Harkavy (23) biopsied urticarial wheals after intradermal injection of tobacco extract and found a local eosinophilia. He felt that

this helped confirm the allergic mechanism of the positive skin test.

He also biopsied the site of a delayed skin reaction to tobacco and

found an eczematous type of response.

The delayed type hypersensitivity reaction is manifested by induration and erythema developing within 24 to 48 hours after injection of antigen. The absence of response in the first 6 to 8 hours

after exposure to antigen helps exclude an Arthus reaction, which is

also a slowly evolving allergic response. Serum antibodies are not

involved in the initiation of delayed type hypersensitivity; rather,

the initial step is thought to involve interaction of antigen and specialized lymphocytes (10, 11). Contact dermatitis is thought to be very nearly a pure type, delayed hypersensitivity reaction (10, II).

The foregoing discussion has highlighted the studies concerning

cutaneous sensitivity to tobacco extracts. Despite the complexities and numerous workers agree that tobacco extract

106 104
(leaf or smoke) is antigenic and can sensitize (2, 7, 9, 18, 26, 43, 50,

52, 64, 66, 76). Silvette, et al. (64) concluded, "It is, indeed, beyond

question that allergy to tobacco extracts, presumably atopic in nature, is an established fact...."

Lowell (43) observed that, in most instances, skin reactivity to

an extract of tobacco actually means the presence of allergy in some

degree to something in the extract. Armen and Cohen (2), Harkavy

and Perlman (31) , and Popescu, et al. (52) observed that tobacco

extract is weakly antigenic. Armen and Cohen (2) were able to

sensitize rabbits to tobacco proteins only after absorbing the protein 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 sensitivity to a battery of antigens has been demonstrated in individuals who are entirely free from allergic symptoms upon exposure

to the antigens. Rosen (54) stated that this lack of correlation between positive skin tests and clinical symptoms is greater for tobacco 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 approximately 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 extract (33, 43) have considered patients with multiple sensitivities,

including that to tobacco. Atopic individuals have been noted to

have a greater prevalence of skin sensitivity to tobacco than nonatopics (64) ; hence, in some studies an excess of atopic patients

may account for a substantial part of the elevated prevalence of

tobacco skin sensitivity reported for smokers.

Several workers have sought to use the skin test as a screening

device for indicating an unusual susceptibility to the adverse effects

of tobacco. DeCrinis, et al. (13), Fontana (17), and Redisch (53)

have reported that patients with positive skin tests to tobacco extracts 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

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107
Cohen (2), Chu, et al. (7) , Harkavy and Perlman (31), and Zussman (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 tuberculosis or lung cancer. A precipitation reaction between the patients' sera ar, 1 a commercial tobacco extract was found in 62.5 percent 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 precipitated specificially with the tobacco antigens. Only 7 percent of a

group of nonsmokers demonstrated these antibodies.

Savel (59) studied eight nonsmoking, allergic individuals who

developed immediate upper respiratory discomfort after being exposed to cigarette smoke. As measured by the uptake of tritiated

thymidine, the lymphocytes of these individuals were stimulated by

tito smoke, while "normal" lymphocytes were depressed. The

au, :kor zi .1ted that the correlation of this test with specific forms of

rt I lergy remains uncertain.

Some investigators have observed abnormal laboratory test results in smokers as compared to nonsmokers, which may indicate

an allergic response in the former group. Schoen and Pizer (60) described a smoking woman who demonstrated a striking blood eosinophilia 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 compared to nonsmokers. Plasma histaminase levels were reported by

Kameswaran, et al. (88) 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 reactions in the sensitized animals ; however, female rats failed to demonstrate this sensitization. Harkavy (24) reported cardiac histological abnormalities in three rabbits sensitized with denicotinized

tobacco extracts. The abnormalities found in the three rabbits, respectively, included: intimal proliferation, focal fragmentation of

the internal elastic membrane, and loss of smooth muscle fibers in

the media of a branch of a coronary artery ; focal intimal proliferation and fibrinoid alterations in the media of a small coronary vessel ; and a focus of myocardial fibrosis and necrosis.

EFFECT ON THE IMMUNE RESPONSE

The effect of tobacco on the immune response nas received some

attention. Early studies in rabbits suggested that tobacco smoke re108

106
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 Caro lin (20) performed in vitro

studies in rabbit alveolar macrophages and observed that cigarette

smoke inhibited the capacity of these cells to inactivate bacteria. Harris, et al. (35) reported no differences in the phagocytic ability

of macrophages taken from human smokers and nonsmokers, but

he also concluded that his data neither contradicted nor supported Green's work. Cohen and Cline (8), while noting that macrophages

from smokers had normal phagocytic capacity, demonstrated suboptimal 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 pulmonary alveolar macrophage respiration and ATPase activity. Re- cently, Yeager (74) reported that water soluble constituents of

cigarette smoke depress protein-synthesis in rabbit alveolar macrophages 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 response of lymphocytes to phytohemagglutinin were significantly

lower in smokers than nonsmokers.

A number of investigators have reported increased rates of respiratory illnesses among cigarette smokers (70). Fink lea, 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 inhibition antibody after natural infection or vaccination with

antigens. They postulated that this antibody deficit among cigarette

smokers might be related to increased illness during influenza outbreaks.

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 (53). The inhalation of tobacco smoke

10.,

107
causes bronchial constriction, mucus hypersecretion, and ciliary

stasis (57) in man, all of which can contribute to a clinical picture

indistinguishable from an allergic reaction. Several authors (44, 61,

63) share Sherman's (62) view that "... tobacco smoke is an important 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 irritation, 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 discomfort of many individuals; they do not rule out a possible contrit ution from allergic reactions.

Harkavy (30) cited experimental data distinguishing allergic

effects from pharmacologic effects of smoking such as increased

heart rate and decreased skin temperature.

Additional studies are needed to separate the pharmacologic, irritant, and allergic effects of tobacco smoke.

CLINICAL ALLERGY

It is important to understand what role tobacco and tobacco

smoke may play in clinical allergy because many individuals are

exposed to them in varying concentrations throughout the year.

A variety of conditions have been ascribed to allergic manifestations toward tobacco leaf or smoke including: asthma, rhinitis,

urticaria, angioneurotic edema (giant hives), contact dermatitis,

migraine headache, gastrointestinal symptoms, and various cardiovascular disturbances (64) ; however, some case reports are lacking

in documentation (4, 49) . A small group of patients having cutaneous sensitivity to tobacco and showing complete disappearance of

symptoms when free from exposure to tobacco were reported by Rosen and Levy (55). Included in this group were cases of asthma and urticaria.

Studies of atopic individuals have revealed a group of nonsmoking

patients with cutaneous sensitivity to tobacco who developed clinical

symptoms upon exposure to tobacco smoke (59, 76) . In none of

these studies (54, 59, 76) have detailed immunologic investigations,

attempt. .-fto link clinical and immunologic events, been performed.

Lowell (43) reviewed case reports of contact dermatitis to to110
bacco among tobacco workers and noted that because of "... the small

proportion of exposed individuals who develop such lesions, and the

tendency for it to clear completely when contact with tobacco is

avoided and to return on reexposure, an allergic cause in certain

instances would appear to be highly probable." Recently, case reports 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 attention to the cardiovascular

system as a possible "susceptible" organ for allergic reactions (15).

Harkavy continues to be a strong proponent of the role of tobacco

allergy in a wide range of cardiovascular abnormalities, including

coronF:ry artery disease (21, 22, 25, 27, 31, 32). This view on

tobacco allergy as one of the etiological factors in coronary heart

disease (CHD) has not received much attention.

Silvette, et al. .(64) reviewed reports (28, 33, 66, 68, 73) on the

prevalence of skin sensitivity in patients with TAO as compared to

controls and cited possible reasons for a higher prevalence of positive skin tests to tobacco in these patients.

In general, the evidence relating TAO to tobacco allergy is inconclusive.

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 mechanisms 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 bc indistinguishable from one another.

(b) Exposure to tobacco smoke may produce exacerbation of

allergic symptoms in nonsmokers who are suffering from

allergies of diverse causes.

4. Little is known about the pathogenesis of tobacco allergy and

its possible relationship to other smoking-related diseases.

109 6 111
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116

114
CHAPTER 8

Public Exposure to Air Pollution

From Tobacco Smoke

115
Contents

The Extent to which the Components of Cigarette Smoke Contaminate the Atmosphere and are Absorbed by the Nonsmoker

Page

121

The Effects of Low Levels of Carbon Monoxide on Human

Health 125

Allergic and Irritative Reactions to Cigarette Smoke Among Nonsmokers 128

The Known Harmful Effects of the Passive Inhalation of

Cigarette Smoke in Animals 129

Summary 130

References

LIST OF TABLES

Table 1.Percent of COHb during and following exposure

to 50 p.p.m. of CO

131

124

Table 2.Effects of carbon monoxide 127

119
PUBLIC EXPOSURE TO AIR POLLUTION FROM

TOBACCO SMOKE

The purpose of this chapter is to summarize the present state of

evidence concerning the effects of exposure to an atmosphere containing either tobacco smoke or its constituents. Since the identification of cigarette smoking as a serious health hazard to the smoker

was based on clinical and epidemiological observations that nonsmokers have much lower mortality and morbidity rates from a

number of conditions, it is obvious that cigarette smoking is normally a greater hazard to the smoker than is the typical level of exposure to air pollutants produced by the smoking of cigarettes which

many nonsmokers experience. This would be consistent with the

voluminous data which show a dose-response relationship between

the level of exposure to smoke and the magnitude of its effect.

The research so far reported on the nature and effects of exposure

to smoke-pollutants in the atmosphere has not been as extensive and

well-controlled as that done on the health effects of smoking on the

smoker himself. Knowledge on this subject can be separated into

four major areas of concern:

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

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

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

among nonsmokers.

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

THE EXTENT TO WHICH THE COMPONENTS OF

CIGARETTE SMOKE CONTAMINATE THE ATMOSPHERE

AND ARE ABSORBED BY THE NONSMOKER

Theoretical models of this contamination have been constructed.

Owens and Rossano (44) have noted that most popular cigarettes

release into the atmosphere approximately 70 mg. of dry particulate

matter (about 60 mg. in the sidestream and slightly over 20 mg. in

the mainstream, about one-half of the latter being absorbed by the

smoker and one-half expelled into the ambient air) and 23 mg. car121

117
bon monoxide per cigarette. This material adds to the cleaning

problem of the air of any enclosed space and contritutes to residual

odors. In a recent study of particulate matter filtration in domestic

premises (35), the authors observed that the smoking of one cigar

completely overcame the effect of an electrostatic filtration device

for one hour.

Atmospheric pollutants caused by smoking are derived from two

major sources : mainstream and sidestream smoke. Mainstream

smoke emerges from the tobacco product through the mouthpiece

during puffing, whereas sidestream smoke comes from the burning

cone and from the mouthpiece during puff intermissions (60). The

tobacco smoke released into the atmosphere consists of all the sidestream smoke as well as that part of the mainstream smoke which

has been either held in the smoker's mouth or taken into his lungs

and then expelled. The actual amount of material to which individuals are exposed in the presence of smokers depends upon the

amount of smoke produced, the depth of inhalation on the part of

the smoker, the ventilation available for the removal or dispersion

of the smoke, and the proximity of the individual to the smoker. The

length of time of exposure to those pollutants is extremely important in determining how much is absorbed into the body. The pattern of smoking influences the amount procilic2.3 by altering the

content of the exhaled smoke. As shown by Dalhamn, et al. (10,

11), mouth absorption removes approximately 60 percent of the

water-soluble volatile components (e.g., acetaldehyde) , 20 percent of the nonwater-soluble volatile components (e.g., isoprene), 16

percent of the particulate matter, and only three percent of the carbon monoxide. Thus, the smoker who does not inhale "filters" a

portion of the smoke components in his mouth before expelling them

into the ambient air. On the other hand, the lungs retain from 86

to 99 percent of the volatile and particulate substances andapproxi- mately 54 percent of the carbon monoxide inhaled. Hence, the inhaling smoker "filters" the mainstream smoke rather effectively before

expelling it into the ambient air. A factor which has apparently not

been investigated is the difference in the smokers' "filtration" of

mainstream smoke when the smoke is exhaled through the nose

instead of the mouth.

Thus, the nonsmoker breathes smoke-containing air composed of sidestream smoke and mainstream smoke exhaled by smokers. The

inhaling smoker receives nearly the full amount of mainstream

smoke as well as a portion of sidestream smoke and smoke exhaled

by himself and other smokers. The smoker who does not inhale receives those compounds which are absorbed from the mainstream

smoke in his mouth, as well as absorbing the sidestream smoke and

the smoke exhaled by himself and other smokers contained in the

air he breathes.

122

118

.

4 I.
Since pipe and cigar smokers inhale less commonly than do ciga- rette smokers, their contribution to the substances in the air

breathed in exposure to smoke pollutants consists of a composite of sidestream smoke and relatively unfiltered mainstream smoke

which has been held in the mouth and then expelled. The actual effluents in the mainstream and sidestream cigarette

smoke have been considered by Pascasio, et al. (45) and Scassellati Sforzolini and colleagues (50, 51). These authors stated that "tar"

and nicotine levels in sidestream smoke may be significantly higher

than those of mainstream smoke and may be harmful to the non- smoker. Actual volume measurements were not reported, however. Actual measurements of the contamination due to cigarette smoking have been carried out by a number of research groups. A recent, well-controlled study by Harke (24) involved the smoking of 42

cigarettes in 16 to 18 minutes using German blend cigarettes of 85 mm. length, 18 mm. filter, and smoked to a 25 mm. butt length

in a room with a volume of 57 cubic meters (approximately the

equivalent of a room with a 10-foot ceiling and dimensions of 12 by

14 feet) . The author observed that in the absence of ventilation the

atmosphere contained up to 50 p.p.m. carbon monoxide and .57 mg./m.3 nicotine. With substantial ventilation, these levels fell sig- nificantly (to approximately 10 p.p.m. carbon monoxide and .10 mg./m.3 nicotine). He also found that cigar smoke (9 cigars of Clear

Sumatra tobacco smoked in 30 to 35 minutes) produced similar amounts of contamination while pipe smoke (3 grams of Navy type medium cut tobacco smoked as eight pipefuls in 35 to 40 minutes) produced much less. Other authors have made similar measurements. Galuskinova (20) found that 3,4-benzpyrene levels in a

smoky restaurant were from 2.82 to 14.4 mg./100 m.3 as compared

to outside atmospheric levels of 0.28 to 0.46 mg./100 m.3, although burning of food particles may have contributed to the presence of 3,4-benzpyrene in this setting. Kotin and Falk (38) have shown

that sidestream cigarette smoke condensate may contain more than

three times as much benzo (a)pyrene as mainstream smoke. Srch

(55) observed that the smoking of 10 cigarettes to a 5 mm. butt

length in an enclosed car of 2.09 m.3 volume produced carbon monoxide levels up to 90 p.p.m. Lawther and Commins (84), working with

a ventilated chamber, found levels of up to 20 p.p.m. of carbon mo- noxide after seven cigarettes were smoked in one hour; however,

peaks of up to 90 p.p.m. were recorded at the seat next to the smoker.

Coburn, et al. (9) recorded levels of 20 p.p.m. of carbon monoxide

in a small conference room after 10 cigarettes were "burned." Harmsen and Effenberger (25) reported up to 80 p.p.m. of carbon

monoxide in an enclosed 98 m.3 room (approximately the equivalent of a room with a 10-foot ceiling and dimensions of 18 by 20 feet) in

which 62 cigarettes had been smoked in two hours.

119

123
TABLE 1.Percent of COHb during and following exposure to 50

p.p.m. of CO.

Time during

exposure Mean Range

Number of

subjects

Preexposure

30 minutes

0.7

1.3

0.4-1.5

1.3

11

3

1 hour 2.1 1.9-2.7 11

3 hours 3.8 3.6-4.2 10

6 hours 5.1 4.9-5.5 5

8 hours 5.9 5.4-6.2 5

12 hours 7.0 6.5-7.9 3

15 % hours 7.6 7.2-8.2 3

22 hours 8.5 8.1-8.7 3

24 hours 7.9 7.6-8.2 3

Time with Iv.t exposure after

1 hour of exposure

30 minutes 1.8 1.8 3

1 hour 1.7 1.6-1.8 3

2 hours 1.5 1.4-1.5 3

5 hours 1.1 1.0-1.1 2

Time without exposure after

3 hours of exposure

30 minutes 3.7 3.4-3.9 3 1 hour 3.3 2.7-3.8 3

2 hours 2.7 2.3-3.0 3

Time without exposure after

8 hours of exposure

30 minutes 5.6 5.1-5.9 3

1 hour 5.1 4.8-5.4 3

1 % hours 4.0

11 hours 1.5 1.4-1.7 3

Time without exposure after

24 hours of exposure

30 minutes 7.5 7.2-7.8 3

1 hour 6.7 6.4-7.1 3

2 hours 5.8 5.6-6.2 3

Sousa: Stewart, et al. (66) .

Another set of contaminants probably present in a tobacco smokepolluted atmosphere are the oxides of nitrogen. These, specificially

NO and NO2, have been shown to be present in tobacco smoke although the type most likely to be present in the atmosphere is NO2.

No measurements have been reported of the amount of NO2 in

smoke-filled rooms. The importance of obtaining and evaluating this

information is stressed by the results of Freeman and Haydon and

124
their colleagues (17, 18, 19, 27, 28) and of Blair, et al. (5) who observed bronchial and pulmonary parenchymal lesions in rodents

continuously exposed to low levels of NO2.

Other experimenters have measured carboxyhemoglobin ( COHb)

levels in nonsmokers exposed to cigarette smoke pollutants. Srch (55) observed that the COHb level in two nonsmokers rose from 2

to 5 percent (that of smokers from 5 to 10 percent) when seated in

the cigarette-smoke contaminated car mentioned above (exposure

to 90 p.p.m.). Harke (24) reported that when seven nonsmokers

were exposed for approximately 90 minutes to a "smoked" room

containing 30 p.p.m. of CO there was a rise in COHb from a mean

of 0.9 percent to 2.0 percent. In 11 smokers subjected to the same

conditions, COHb rose from a mean of 3.3 percent to 7.5 percent. With improved ventilation of the experimental room, the COHb

level decreased significantly.

The CO exposures and COHb levels reported above closely approximate the results obtained following experimental chamber expo- sure of humans to various levels of CO. The uptake of CO by the

person depends on, among other parameters: CO concentration,

previous COHb level, the level of activity, and the person's state of health. Equilibrium between CO concentration in the lung and in

the blood requires over 12 hours exposure. However, as may be noted in table 1, reproduced from Stewart, et al. (56) and derived

from measures of COHb in young sedentary males who were not

smoking, over half of the equilibrium COHb level is reached within

three to four hours of the onset of exposure. The equilibrium value

associated with 100 p.p.m. is approximately 14 to 15 percent COHb. Exposure to 100 p.p.m. in the nonsmoker can lead to 3.0 percent of

COHb within 60 minutes and 6.0 percent in two hours (16). Of equal significance is that COHb has a half-life of at least three to four

hours in the body. As shown in table 1, the COHb level fell only to 2.7 percent in the two hours following cessation of exposure to 50

p.p.m. from the end exposure level of 3.7 percent. This lengthy halflife extends the period of effect of exposure to CO and provides for

a buildup of COHb concentration from fresh exposures.

THE EFFECTS OF LOW LEVELS OF

CARBON MONOXIDE ON HUMAN HEALTH

The data on the effect of low levels of carbon monoxide on human

psychological and physiological function have been summarized in

two recent publications (8, 58).

There is presently much discussion as to the physiologic and

psychophysiologic effects of exposure to levels of CO approximating 50 to 100 p.p.m. Beard and Grandstaff (4) observed that exposure

to 50 p.p.m. of CO for from 27 to 90 minutes altered auditory dis121

125
crimination, visual acuity, and the ability to distinguish relative

brightness. McFarland (40) observed that COHb levels of 4 to 5

percent caused visual threshold impairment. Ray and Rockwell

(48), reporting on a study of the driving ability of three subjects

under varying CO exposure, observed that the presence of 10 percent COHb was associated with increased response time for taillight discrimination and increased variance in distance estimation.

Schulte (52) observed that increased errors in cognitive and choice

discrimination tests were manifest at levels of COHb as low as 3

percent. Chevalier, et al. (7) have also obnerved that levels of 4

percent COHb in nonsmokers are associated with an increase in

oxygen debt formation with exercise similar to that seen in smokers. On the other hand, other investigators utilizing complex

psychomotor tasks in men and monkeys have observed no decrement

in function upon exposures to CO at 50 to 250 p.p.m. (2, 8, 28, 41,

56).

Animals exposed to low levels of CO ( 50 to 100 p.p.m.) continuously for weeks have shown varying degrees of cardiac and cerebral

damage similar to that produced by hypoxia (21, 47, 57).

Finally, the possible effects of exposure to 50-100 p.p.m. CO on

patients with coronary heart disease (CHD) were investigated by

Ayres, et al. (1) who observed a decrease in arterial and mixed

venous oxygen tensions with COHb saturations of 5 percent. Certain

patients with CHD developed altered lactate and pyruvate metabolism with COHb levels of 5 to 10 percent suggesting myocardial

hypoxia.

The evidence concerning the effect of low levels of carbon monoxide has recently been reviewed and evaluated by the National Air

Quality Criteria Committee of the National Air Pollution Control

Administration (58). The following is taken from the published

conclusions of the Advisory Committee (also see table 2) :

"Experimental exposure of nonsmokers to 58 mg/m3 (50

ppm) for 90 minutes has been associated with impairment in

time-interval discrimination.... This exposure will produce

an increase of about 2 percent COHb in the blood. This same

increase in blood COHb will occur with continuous exposure

to 12 to 17 mg/m3 (10 to 15 ppm) for 8 or more hours....

"Experimental exposure to CO concentrations sufficient to

produce blood COHb levels of about 5 percent (a level producible by exposure to about 35 mg/m3 for 8 or more hours)

has provided in some instances evidence of impaired performance on certain other psychomotor tests, and an impairment in

visual discrimination....

"Experimental exposure to CO concentrations sufficient to

produce blood COHb levels above 5 percent (a level producible

126

122
TABLE 2.Effects of carbon monoxide.

Environmental

conditions Effect Comment

58 mg./m.3 (50 p.p.m.)

for 90 minutes

Impairment of timeinterval discrimination

in non-smokers.

Blood COHb levels not

available, but anticipated to be about 2.5

percent.

Similar blood COHb levels

expected from exposure

to 10 to 17 mg./m.3 (10

to 15 p.p.m.) for 8 or

more hours.

11E mg./m.3 (100

p.p.m.) intermittently through a

facial mask

Impairment in performance of some psychomotor tests at a COHb

level of 5 percent.

Similar results may have

been observed at lower

COHb levels, but blood

measurements were not

accurate.

High concentrations

of CO were administered for 30 to 120

seconds, and then 10

minutes was allowed

for washout of

alveolar CO before

blood COHb was

measured.

Exposure sufficient to produce blood COHb levels

above 5 percent has been

shown to place a physiologic stress on patients

with heart disease.

Data rely on COHb levels

produced rapidly after

short exposure to high

levels of CO; this is not

necessarily comparable

to exposure over a longer

time period or under

equilibrium conditions.

Sougcg: Adapted from U.S. Public Health Service. Air Quality Criteria for Carbon Monoxide. Washington. D.C.. U.S. Department of Health. Education, and Welfare (5$).

by exposure to 35 mg/m3 or more for 8 or more hours) has

provided evidence of physiologic stress in patients with heart disease. .. ."

The levels of carbon monoxide found to be present in "smoked"

rooms (20 to 80 p.p.m.) are similar to the levels (30 to 50 p.p.m.) which the Advisory Committee has concluded are associated with

adverse health effects:

"An exposure of 8 or more hours to a carbon monoxide concentration of 12 to 17 mg/m3 (10 to 15 ppm) will produce a blood carboxyhemoglobin level of 2.0 to 2.5 percent in non- smokers. This level of blood carboxyhemoglobin has been associated with adverse health effects as manifested by impaired

time interval discrimination. Evidence also indicates that an

exposure of 8 or more hours to a CO concentration of 35 mg/m3

(30 ppm) will produce blood carboxyhemoglobin levels of

about 5 percent in nonsmokers. Adverse health effects as manifested by impaired performance on certain other psychomotor

727
tests have been associated with this blood ca:boxyhemoglobin level, and above this level there is evidence of physiologic

stress in patients with heart disease."

These levels of CO are also similar to that set as the timeweighted occupational Threshold Limit Value of 50 p.p.m. for a

40-hour week (five 8-hour days) which has been in effect in the

United States for the past several years (13). A further reduction

in this limit to 25 p.p.m. is now under consideration. These levels of

CO exceed those recently set by the Environmental Protection

Agency as the national primary and secondary ambient air quality

standards for CO (14). These standards are:

(a) 10 milligrams per cubic meter (9 p.p.m.)maximum 8-

hours concentration not to be exceeded more than once

per year.

(b) 40 milligrams per cubic meter (35 p.p.m.)maximum

1-hour concentration not to be exceeded more than once

per year.

ALLERGIC AND IRRITATIVE REACTIONS TO

CIGARETTE SMOKE AMONG NONSMOKERS

(A more detailed discussion of this subject is presented in the

Allergy chapter of this report.)

Several investigators have reported on the discomfort and symptoms experienced by both allergic and nonallergic individuals upon

exposure to tobacco smoke. Johansson and Ronge (31, 32) in 1965

and 1966 have observed that the acute irritation experienced by

nonsmokers in the presence of tobacco smoke is maximal in warm,

dry air and that nonsmokers experience more nasal irritation than

ocular irritation as compared with smokers exposed to similar

amounts of smoke in the atmosphere. Speer (54) studied the reactions of 441 nonsmokers divided into two groups, one composed of

individuals with a history of allergic reactions and the other of individuals without such a history. The allergic group underwent skin

testing for the presence of sensitivity to tobacco extract while the

"nonallergic" group was determined solely by questionnaire concerning subjective allergic responses. Approximately 70 percent of

both groups experienced eye irritation while other symptoms differed in their frequency from group to group (nasal symptoms : allergic 67 percent, "nonallergic" 29 percent; headache: allergic 46

percent, "nonallergic" 31 percent; cough: allergic 46 percent, "nonallergic" 25 percent; and wheezing: allergic 22 percent, "nonallergic" 4 percent). Thus, 'a significant proportion of nonsmoking individuals report discomfort and respiratory symptoms on exposure

to tobacco smoke.

128

124
Other authors have attempted to separate out those patients whu

may have specific allergies to smoke. Zussman (61) found that in a

random series of 200 atopic patients 16 percent were clinically sen- sitive to tobacco smoke, and that a majority of these were aided by

desensitization therapy. In an earlier study, Pipes (46) observed

that 13 percent of 229 patients with respiratory allergy showed positive skin tests to tobacco smoke. Savel (49) has recently reported on

eight nonsmokers observed to be clinically hypersensitive to tobacco

smoke. After in vitro incubation of their lymphocytes with cigarette

smoke, increased incorporation of tritiated thymidine was recorded ;

similar exposure of the lymphocytes of those not sensitive resulted

in depression of tritiated thymidine uptake.

Luquette, et al. (39) have recently reported on the immediate effects of exposure to cigarette smoke in school-age children. They

observed that heart rate and blood pressure rose with such exposure, although questions remain about the adequacy of their controls and the manner in which the experimental situation may have excited the subjects. Finally, Cameron, et al. (6) observed that

acute respiratory illnesses were more frequent among children from

homes in which the parents smoked than among children of nonsmoking parents. The meaning of these results is uncertain since

smoking by the children was not considered and the level of exposure to cigarette smoke in their homes was not measured. Shy, et

al. (53) in a study of second grade Chattanooga school children

failed to demonstrate a relationship between parental smoking

habits and the respiratory illness rates of their children.

THE KNOWN HARMFUL EFFECTS OF THE PASSIVE

INHALATION OF CIGARETTE SMOKE IN ANIMALS

A number of investigators have studied the effects of the passive

inhalation of high concentrations of cigarette smoke on the pulmonary parenchyma and tracheobronchial tree of animals. The results

of these investigations are listed in detail in the recent report to Congress, "The Health Consequences of Smoking," (59) in table 9

of the Bronchopulmonary chapter, and table 16 of the Cancer

chapter.

The pathologic changes observed in the respiratory tract of the

animals included parenchymal disruption, bronchitis, tracheobronchial epithelial dysplasia and metaplasia, and pulmonary adenomatous tumor formation. Leuchtenberger, et al. (36) exposed 151 mice to the smoke of from 25 to 1,526 cigarettes over a period of 1

to 23 months and observed that 20 percent of the animals developed

severe bronchitis with atypism. Working with 30 control rabbits

exposed to up to 20 cigarettes per day for two to five years, Holland, et al. (30) observed increased focal and generalized hyperplasia of

125

129
the bronchial epithelium and generalized emphysema in the exposed rabbits. Hernandez, et al. (29) observed significantly more

pulmonary parenchymal disruption in adult greyhound dogs exposed to cigarette smoke 10 times per week for approximately one

year than in nonexposed control animals.

Lorenz, et al. (38) observed no increase in respiratory tract tumor formation above that seen in controls in 97 Strain A mice exposed to cigarette smoke for up to 693 hours. Essenberg (15), however, exposed Strain A mice to cigarette smoke for 12 hours a day

for up to one year and observed significantly more papillary adenocarcinomas in the exposed than in the control group. An increased

percentage of hybrid mice were found by Miihlbock (42) to have

alveolar carcinomas among the experimental group exposed to

smoke for two hours a day for up to 684 days when compared with

a nonexposed group. Similarly, Guerin (22) observed that 5.1 percent of rats exposed to cigarette smoke for 45 minutes a day for

two to six months showed pulmonary tumors compared to 2.4 percent of the control mice.

Leuchtenberger, et al. (37), working with 400 female CF, mice,

observed only a slight increase in the presence of pulmonary adenomatous tumors among those exposed to cigarette smoke compared

with those in the control group. The authors commented that the

presence of tumors showed an age relationship independent of

smoking exposure. Otto (43) found that 11 percent of a group of

albino mice exposed to 12 cigarettes a day for up to 24 months

showed pulmonary adenomas as compared with five percent of the

control non-exposed group. Dontenwill and Wiebecke (12) found

that increasing the exposure of golden hamsters to up to four cigarettes a day for up to two years was associated with an increasing

percentage of animals showing desquamative metaplasia and bronchial papillary metaplasia. Harris and Negroni (26) exposed 200

C57BL mice to cigarette smoke for 20 minutes a day every other

day for life and found eight adenocarcinomas as compared to none

in the control group.

Because the damage observed in these experiments was seen after

prolonged exposure to high concentrations of cigarette smoke, and

because the comparability of animal exposure to smoke with that of

human exposure in smoke-filled rooms is unknown, it is presently

impossible to be certain from animal experimentation about the extent of the damage that may occur during long-term intermittent

exposure to lower concentrations.

SUMMARY

1. An atmosphere contaminated with tobacco smoke can contribute to the discomfort of many individuals.

130

126
2. The level of carbon monoxide attained in experiments using

rooms filled with tobacco smoke has been shown to equal, and at times to exceed, the legal limits for maximum air pollution per- mitted for ambient air quality in several localities and can also ex- ceed the occupational Threshold Limit Value for a normal work

period presently in effect for the United States as a whole. The pres- ence of such levels indicates that the effect of exposure to carbon monoxide may on occasion, depending upon the length of exposure, be sufficient to be harmful to the health of an exposed person. This would be particularly significant for people who are already suffering from chronic bronchopulmonary disease and coronary heart disease.

3. Other components of tobacco smoke, such as particulate matter and the oxides of nitrogen, have been shown in various concentrations to adversely affect animal pulmonary and cardiac structure

and function. The extent of the contributions of these substances to

illness in humans exposed to the concentrations present in an atmo- sphere contaminated with tobacco smoke is not presently known.

PUBLIC EXPOSURE TO AIR POLLUTION FROM TOBACCO

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CHAPTER 9

Harmful Constituents of Cigarette Smoke

132
Contents

Page The Dose Relationship 141

References 146

LIST OF TABLES

Table 1.Compounds in cigarette smoke judged most likely

to contribute to the health hazards of smoking 143

Table 2.Compounds in cigarette smoke judged as probable

contributors to the health hazards of smoking 144

Table 3.Compounds in cigarette smoke judged as suspected

contributors to the health hazards of smoking 145

139

133
HARMFUL CONSTITUENTS OF CIGARETTE SMOKE*

Cigarette smoke contains a large number and a wide variety of

compounds which may result in complex and multiple ps.thophysiological effects on various tissues and organ systems. Although the

constituents of cigarette smoke are usually divided for convenience

into the two categories of particulate and gas phases,** many of

them exist in a distribution equilibrium, that is, they are present partially in the gas phase and partially in the particulate phase.

This review concerns itself with judgments concerning the harmful

constituents of cigarette smoke whether these are found primarily

in the gas phase or in the particulate phase.

Constituents of cigarette smoke may enter the body by a variety

of routes. Theoretically, the route of entry and subsequent absorption could affect the degree to which various organs are subjected

to specific cigarette smoke constituents. Some constituents, particularly the water soluble components of the gas phase, may be absorbed by the nasal and oropharyngeal mucous membranes, or

may be dissclved in the saliva and swallowed, thus allowing for possible gastric or intestinal absorption. Other constituents are absorbed 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 sufficient to present hazards to health. Other compounds appear in

This report attempts to summarise the areas of g I consensus reached in a special oneday conference of experts in this field which met in June 1970. This is not to imply that there

was unanimous agreement on all statements contained herein. A list of participants in the meeting appears in the Acknowledgments.

It should be noted that there is, at present, no available instrumentation permitting the

separation and individual collection of the particulate and gas phases which duplicates the

precise physicochemical conditions prevailing in cigarette smoke as it is inhaled. A widely accepted arbitrary distinction between the two phases is as follows: If 50 percent or more of

given constituent is retained on a Cambridge filter (CM-I13) during standardised machine smoking of cigarette, then the compound is considered to belong to the particulate phase; if on the

other hand more than 50 percent of the compound passes through the Cambridge filter under

these conditions, then the constituent is considered to belong to the gas phase.

141

134
borderline concentrations. Still others, although potentially harmful, are probably not present in sufficient concentrations to contribute to the hazard, and some may be hazardous only when they

interact with other substances in the smoke.

Substances and classes of substances in cigarette smoke which

have been judged to contribute to the hazard of cigarette smoking

have been classified into three priority groups. Those compounds

which are judged most likely to contribute to the health hazards of

smoking are listed in table 1. Additional substances which probably

contribute to the health hazards of smoking are listed in table 2.

Those compounds which are suspected contributors to the health

hazards of smoking in the concentrations in which they are present

in tobacco smoke are listed in table 3. Many other constituents of

tobacco smoke are considered to be toxic under some conditions but

probably do not present a health hazard in the concentrations in

which they are generally found in cigarette smoke ; these are not

listed. This listing is not presented as final, and may be subject to

modification as more information becomes available.*

In 1966, the Public Health Service prepared a technical report on

"tar" and nicotine (60). Tobacco "tar" is the name given to the aggregate 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 consumed per day increases. In the studies which have reported

other measures of exposure such as pack-years, degree of inhalation, 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 cigarette smoke appears to be the most critical factor for the development 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,

Subsequent to the conference on which this report was based. several studies were published

reporting the presence of N-nitrusamines in cigarette smoke. Since these substances are accepted

u carcinogens in experimental animals, they represent another portion of the "tar" which

probably contributes to the total health hazard (18. 24).

142

135
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 content of cigarette smoke, the less harmful would be the effect." Several 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 1.Compounds in cigarette smoke judgedmost likely to contribute to the health hazards of sniiiking.

Compound

Primary phase Concentration in classification

cigarette smoke Ggas micrograms/cigarette Pparticulate References

Carbon Monoxide 5,240-21,400 G (1, 10, 23, 26, 29,

34, 35, 37, 42, 46,

49, 61, 63)

Nicotine 200-2,400 P (9)

I "Tar" 3,000-33,000 P (9)

"Tar" is defined as the total particulate matter collected by a Cambridge filter (CM -113) after

subtracting moisture and nicotine and includes the class of compounds known as polycyclic aromatic hydrocarbons (PAH). PAH are generally accepted as being responsible for a substantial portion of the carcinogenic activity of the total "tar." Although "tar" from different

cigarettes varies in its carcinogenic potential as measured by the bioassay methods In current

use, it remains the most practical single "indicator" of total carcinogenic potential. Special

mention should be made of Beta Naphthylamine which is a known human urinary bladder car- cinogen for which there is no known safe level of exposure and which has been reported present

in tobacco smoke in very low concentrations (16. 28. 30) (0.022 ppm/cigarette).

It is recognized that the substances in cigarette smoke may inter- act so that the combined pathological effects of severalsubstances

may be quite different from the sum of their effects produced in

isolation. An example of this type of interaction might be the carcinogenic effects of tobacco "tar" as a result of the combined action

of cancer initiating, cancer promoting, and cancer accelerating

agents in producing the total effect. Such interactionstheoretically

could take place among substances within the gas phase, or substances 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- nehts, judgments concerning the action or identification of harmful

substances in cigarette smoke have, of necessity, been made pri143

136
TABLE 2.Compounds in cigarette smoke judged as probable contributors to the health hazards of smoking.

Compound

Concentration in

cigarette smoke micrograms/cigarette

Primary phase

classification Cgas Pparticulate References

Acrolein 45-140 G (12, 20, 21, 27, 36,

43, 45)

Cresol (all isomers) 68-97 P (20, 40)

Hydrocyanic Acid 100-400 G (26, 38, 43, 45, 46,

49, 53)

Nitric Oxide 0-600 G (1, 3, 15, 40, 42, 44,

57)

Nitrogen Dioxide 0-10 G (1, 40, 44, 57)

Phenol 9-202 P (7, 19, 20, 32, 50,

52)

marily on the basis of the action of the individual substances. Nevertheless, 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 development 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 information to the contrary, cigarettes in which overall "tar" and

nicotine levels have been reduced present to the smoker lower concentrations of the harmful substances in the particulate phase. If,

at the same time, significant reductions are made in those gas phase

constituents which also contribute to the hazards of smoking, the

resulting product should be less hazardous to health.*

The consensus is that a progressive and simultaneous reduction

of all substances considered likely to be involved in the health hazards of smoking should be encouraged as the most promising step

available at the present time towards the development of a less hazardous cigarette. Primary emphasis should be given to the reduction of the three substances or classes of substances named in the

first table, and as a second priority to the reduction of those substances or classes of substances in the second table before reducing

An alternative point of view held by some is that smoking behavior is a response to the need

to reach a certain nicotine level and that lowering the amount of nicotine available from a

cigarette may result in an increase in the number of cigarettes smoked, the depth of inhalation.

or the number of puffs in order to maintain an accustomed level. Such an increase in smoking

might result in an increased inhalation of other hazardous substances in the smoke, thereby

potentially negating the effect of reducing the amount available in each cigarette.

144

137
TABLE 3.-Compounds in cigarette smoke judged as suspected contributors to the health hazards of smoking.

Compound

Concentration in

cigarette smoke

micrograms/cigarette

Primary phase

classification

C.--gas

P--particulate References

Acetaldehyde 180-1,440 G (4, 21, 27, 36, 43,

45, 48, 49, 53, 59)

Acetone 88-650 G (12, 21, 27, 36, 43,

45, 48, 49, 53)

Acetonitrile 140-200 G (12, 43)

Acrylonitrile 10-15 G (12, 43)

Ammonia 60-330 G (2, 22, 40, 41, 43,

64)

Benzene 12-100 G (11, 12, 25, 43, 45,

49, 53)

2,3-Butadione 43-200 G (43, 46, 49, 53)

Butylamine 3 P (31,40,41)

1 Carbon Dioxide 23,100-78,300 G (1, 10, 15, 23, 26,

29, 34, 35, 42, 46, 49,

63)

Crotononitrile 4 G (43)

Dimethylamine 10-11 P (31, 40, 41)

DDT 0-0.77 P (17, 39, 54)

Endrin 0.06 P (14)

Ethylamine 10-11 G (22, 31, 40, 41)

Formaldehyde 20-41 G (4, 36, 43, 48, 53)

Furfural 45-110 P (4, 13, 36)

Hydrogen Sulphide 12-35 G (10,43, 51, 58)

Hydroquinone 83 P (6, 7)

Methacrolein 9-11 G (12, 43)

Methyl Alcohol 90-300 G (12, 21, 43, 46, 49)

Methylamine 20-22 G (22, 31, 40, 41)

Nickel compounds 0-0.58 P (5, 8, 47, 55, 56)

Pyridine 25-218 P (40, 62)

CO: is included because of the hazard it may represent to those with CO: retention, such as

those with advanced COPD.

those named in the third table. In addition to the epidemiological

and pathological data gained from human studies, it is important to

develop better bioassay systems to evaluate cigarettes modified

by these general guidelines.

145

138
It should again be emphasized that, in addition to the variation in

chemical properties of the cigarette being smoked, procedures within the control of the individual smoker such as how many ciga- rettes he smokes, how far down he smokes the cigarette, and how

frequently and deeply he inhales are critical factors in determining

how much of the harmful substances which can be produced by the burning cigarette is given the opportunity to injure him.

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150

143
INDEX

Abortion

effect of maternal smoking, 5,84,85

frequency, and cigarette consumption,

85

Acetaldehyde

as suspected contributo' to health hazards of smoking,145

Acetone

as suspected contributor to health

hazards of smoking, 145

Acetonitrile

as suspected contributor to health hazards of smoking; 145

Acrolein

as irritant in tobacco smoke, 101

as probable contributor to health hazards of smoking, 144

Acrylonitrile

as suspected contributor to health hazards of smoking, 145

Adolescents

see Students, high school

Air pollution,

carbon monoxide from cigarette smoke,

7,121-123,125

effect on nonsmokers, 121-125

tobacco smoke as a factor, 7,121-124

Air quality

standards for carbon monoxide, 128

Alcohol consumption

effect on mortality rates from esophageal neoplasms in Japanese males, 71

smoking and, in esophageal neoplasm

etiology, 4,68,70,71

Allergy

effect on cardiovascular abnormalities,

111

tobacco and, 7,103-111

tobacco smoke irritants and, 110

Alphat -antitrypsin deficiency

in emphysema etiology, 44

smoking and, 44

Altitude,

effect on arterial oxygen tension, 22

Amblyopia, tobacco

cyanides and, 6

diet and, 6

smoking and, 6

Ammonia

as suspected contributor to health hazards of smoking, 145

Angina pectoris

smoking and, in twin studies, 18

Antigen-antibody reaction

allergy and, 103-107

smokers vs. nonsmokers, 7,105,111

tobacco and, 7,104-107

Aortic aneurysm, nonsyphilitic

mortality rates, smokers vs. nonsmokers,

2

Aromatic hydrocarbons, polycyclic

effect on tobacco carcinogenicity, 66

Arterial diseases

carboxyhemoglobin levels and, 26

smokers vs. nonsmokers, 26

smoking and, 25,26

Arteriosclerosis

autopsy studies and, 19,20

cigar smoking and, 19

experimentally induced in dogs, 19,20

pipe smoking and, 19

smokers vs. nonsmokers, 19,22,23,27

smoking classification and, 19

Asbestos

pulmonary fibrosis and, 44

Asthma

smoking and, 37

Atherosclerosis

see Arteriosclerosis

Autopsy studies

arteriosclerosis and, 19,20

coronary heart disease and, 19,20

144

Benz(a)anthracene

carcinogenicity, as component of cigarette smoke, 66

Benzene

as suspected contributor to health hazards of smoking, 145

Benzo(a)pyrene

as air pollutant from cigarette smoke,

123

carcinogenic effects during pregnancy in

rats, 89

cocarcinogenic effect on respiratory

tract in rabbits, 67

hydroxylation by the placenta, 89

in smoke streams, 123

Betel nut chewing

in Bombay, India, 69
in head and neck neoplasm etiology, 69

smoking and, 69

Birth weight

effect of ma temal smoking, 5,83.87

Bladder neoplasms

relative risk in females by amount

smoked, 73

relative risk in males by amount smoked,

7 2,7 3

smoking and, 68,72.74

smoking characteristics in etiology of, 5

Body height

effect of maternal smoking, 88

Bronchial abnormalities

in smokers vs. nonsmokers, 45

Bronchial histological changes

smoking and, 45

Bronchitis

incidence in British males by cigarette

consumption, 62

occupational diseases and, 42

prevalence in smokers in Glenwood

Springs, Colorado, 39

prevalence in smokers vs. nonsmokers in

Yugoslavia, 40

smoking in etiology of, 37

Bronchopulmonary disease, chronic obstructive

alpha i-antitrypsin deficiency and, 3,44

epidemiology in Tecumseh, Michigan,

39,40

morbidity, smokers vs. nonsmokers in

Berlin, New Hampshire, 39

mortality, smokers vs. nonsmokers,

38,39

mortality rates for ex-smokers, and

smokers vs. nonsmokers, 3

mortality rates for pipe/cigar smokers vs.

cigarette smokers, 3

occupational hazards and, 42.44

smoking in etiology of, 3,37

2,3-Bu tadione

as suspected contributor to health hazards of smoking, 145

Butylamine

as suspected contributor to health hazards of smoking, 145

Cancer see Neoplasms and specific listings, e.g.,

Lung neoplasms

Carbon dioxide

as suspected contributor to health hazards of smoking, 145

152

145

Carbon monoxide

as air pollutant from cigarette smoke,

7,121-123,125

effect on blood carboxyhemoglobin

levels, 21-23,127

effect on cardiovascular system, 22

effect on nonsmokers, 126

effect on psychomotor performance,

126

effect on vision, 126

as most likely contributor to health

hazards of smoking, 8,143

psychological and physiological effects,

125-128

Car boxyhemoglobin levels

blood cholesterol and, 23

during and following exposure to carbon

monoxide, 124,125

in nonsmokers exposed to cigarette

smoke, 125

occlusive peripheral vascular disease and,

26

smokers vs. nonsmokers, 21-23

Carcinogenesis

experimental, 65-67

initiating agents in cigarette smoke, 66

Carcinogens

effect on oral mucosa in laboratory animals, 70

Cerebrovascular disease

mortality rates, smokers vs. nonsmokers,

2

smoking and, 24,25

Cessation of smoking

effect on COPD morbidity and mortality, 41,42

effect on respiratory symptoms, 4 1,4 2

lung neoplasm development and, 62

myocardial infarct and, 17,18

as preventive measure in CHD, 17,18

as therapy in arterial diseases, 26

CHD

see Coronary heart disease

Children

effect of parental smoking, 129

passive smoking and, 129

respiratory illness and, 129

Cholesterol

in tobacco, 24

in tobacco smoke, 24

Chronic bronchitis see Bronchitis

Chronic bronchopulmonary disease

see Bronchopulmonary disease, chronic

obstructive
I

t

Chrysene

carcinogenicity, as component of cigaretie smoke, 66

Cigarette consumption

effect on mortality from lung cancer in

Poland, 61,62

Cigarettes

tar and nicotine content, 142,143

Cigarette smoking

sec Smoking

Cigar smokers

carboxyhemoglobin levels in, 21-23

myocardial arteriole wall thickness in, 19

relative risk in esophageal neoplasm

development, 68

relative risk in laryngeal neoplasm development, 67

Coal miners

pneumoconiosis and, 42-44

Congenital malformations

maternal smoking and, 87

COPD

see Bronchopulmonary disease, chronic

obstructive

Coronary heart disease

autopsy studies, 19,20

carboxyhemoglobin levels and, 27

cross-sectional study in Bergen, Norway,

16

epidemiological studies, 14-16

heredity as a factor, 18

incidence among Minnesota men by age

and smoking habit, 14-16

interaction of smoking and other risk

factors, 16-18

mortality rates and per capita cigarette

consumption in several countries, 16

mortality rates in longshoremen, 14

retrospective studies in Goteborg,

Sweden, 16

retrospective studies in Prague, Czechoslovakia, 16

smoking in etiology of, 1,2,13,14

twin studies, 18

Cor Puhnonale

see Pulmonary heart disease

Cough

smokers vs. nonsmokers, 40

Cresol

as probable contributor to health hazards of smoking, 144

Crotononitrile

as suspected contributor to health hazprds of smoking, 145

Cyanides

tobacco amblyopia and, 6

DDT

as suspected contributor to health hazards of smoking, 65,145

Dermatitis

among tobacco workers, 1 1 1

Dibenz(a,c)anthracene

carcinogenicity, as component of cigarette smoke, 66

711-Dibenz(c,g)carbozole

carcinogenicity, as component of cigarette smoke, 66,67

carcinogenic effect on respiratory tract

in hamsters, 66,67

Diet

tobacco amblyopia and, 6

Dimethylamine

as suspected contributor to health hazards of smoking, 145

7,12-D imethylbenz(a)anthracene

effect on oral mucosa in hamsters. 70

Edentulism

smoking and, 6

Emphysema

alpha' -antitry psin deficiency and, 44

experimentally induced in smoking dogs,

46

smoking in etiology of, 37

Endrin

as suspected contributor to health hazards of smoking, 145

Epidemiological studies

bronchopulmonary diseases and smoking, 38-41

coronary disease and smoking, 14-16

esophageal neoplasms and smoking,

70,71

laryngeal neoplasms and smoking, 68

lung neoplasms and smoking, 60-65

maternal smoking and outcome of pregnancy, 83-87

oral neoplasms and smoking, 68-70

pancreatic neoplasms and smoking, 74

urinary bladder neoplasms and smoking,

72-74

Esophageal neoplasms

alcohol consumption and smoking in

etiology of, 4,5,71

mortality rates in Japanese males by

smoking and drinking characteristics,

71

146

153
smoking in etiology of, 4,70,71

Esophagus

effect of smoking, 98

Ethylamine

as suspected contributor to health hazards of smoking, 145

Experimental studies

nicotine and cigarette smoke, 21

Ex-smokers

mortality rates from lung cancer, 5

Fetus

effect of maternal smoking, 5,83-89

Filtration

smoke, effect on broncho-constrictor

response in smokers, 45

Formaldehyde

as suspected contributor to health hazards of smoking, 10

Furfural

as suspected contributor to health hazards of smoking, 145

. . Gas phase, cigarette smoke

effect on mucous flow rates in cats, 47

harmful constituents in, 143

Gastric secretions

effect of nicotine, 97

Gastrointestinal disorders

smoking and, 5,6,97,98

Genetic factors

in alphas-antitrypsin deficiency, 44

smoking and, 44

Gingivitis

smoking and, 6

Heart disease

see Coronary heart disease

Heredity

alphas-antitrypsin deficiency and, 44

coronary heart disease and, 18

smoking and, 18

Hydrocyanic acid

as probable contributor to health hazards of smoking, 144

Hydrogen sulphide

as suspected contributor to health hazards of smoking, 145

Hydroquinone

as suspected contributor to health hazards of smoking, 145

Hypercholesterolemia

as a risk factor for coronary heart disease, 16,17

154

147

Hypertension

as a risk factor for coronary heart disease, 16,17

Hypoxemia

smoking and, 22

Hypoxia

effect of nicotine, 21

experimentally induced in rats, 21

Infant mortality

effect of maternal smoking, 83-87

low birth weight and, 86

Influenza

incidence from antibody deficit in smokers, 109

Intermittent claudication

smokers vs. nonsmokers, 2 2,26

Intra-oral smoking

see Reverse smoking

Ischemic heart disease

morbidity ratio from, in New Delhi,

India, 16

Laryngeal neoplasms

epidemiological studies, 68

relative risk among cigarette, pipe and

cigar smokers, 67

smoking in etiology of, 4,67,68

Leukoplakia

oral neoplasm development in smokers

and, 68,69

smoking in etiology of, 68,69

Lip neoplasms

pipe smoking as cause of, 4

Lung cancer see Lung neoplasms

Lung function

effect of smoking, 37,38

in smokers vs. nonsmokers, 40

Lung neoplasms

epidemiological studies, 60-65

etiology and epidemiology, 59,60

incidence in British males by amount

smoked, 62

incidence in Czechoslovakian males by

amount smoked, 61

incidence in Jewish vs. non-Jewish

women, 63,64

incidence in uranium miners, 64,65

mortality ratios in Japanese males by

amount smoked, 6I

mortality ratios in Japanese women, 63

prospective study in Japanese adults,

4,60,61
prospective study in Czechoslovakian

males, 61

relationship to chronic bronchitis and

smoking, 62

relative risk in :A-smokers by length of

cessation and previous duration of

habit, 62-64

smoking as cause, 4,5,59,60

Macrophages, alveolar

effect of tobacco smoke, 47,48

in sputum specimens of smokers vs. nonsmokers, 48

Maternal-fetal exchange

effect of nicotine, 88

Maternal smoking

see Smoking, maternal

Methacrolein

as suspected contributor to health hazards of smoking, 145

Methyl alcohol

as suspected contributor to health hazards of smoking, 145

6-Methylanthranthrene

carcinogenicity, as component of cigarette smoke, 66

Morbidity

from chronic bronchopulmonary disease,

39-41

Mortality

from chronic bronchopulmonary disease,

38,39

Mortality rates

esophageal neoplasms in Japanese males

by smoking and drinking characteristics, 71

lung neoplasms in Japanese women, 63

pancreatic neoplasmi in United States,

74

Mortality ratios

lung neoplasms in Japanese males by

amount smoked, 61

Mouth neoplasms

see Oral neoplasms

Myocardial arteriole walls

effect of filtered cigarettes in dogs, 20

thickness in smokers vs. nonsmokers,

2,19

thickness in smoking and nonsmoking

dogs, 2,20

Myocardial infarct

epidemiological study in Goteborg,

Sweden, 14,15

incidence among Minnesota men by age

and smoking habit, 14,15

incidence in men in Goteborg, Sweden,

by tobacco consumption, 15

incidence rates by smoking classification, 15

smokers vs. nonsmokers in Goteborg,

Sweden, 16

Neonatal death

maternal smoking and, 83-87

Neoplasms

see also Specific types of neoplasms,

e.g. lung neoplasms

smoking and, 4,5,59-75

Nickel compounds

as suspected contributors to health hazards of smoking, 145

Nicotine

antigenic properties, 104

effect on apexcardiogram, 21

effect on birth weight in rats, 88

effect on bronchoconstrictor response

in laboratory animals, 46

effect on fetus in laboratory animals,

88

effect on gastric secretions, 97

effect on gastrointestinal secretions in

dogs, 6

effect on immune response in man, 109

effect on lipid metabolism in rabbits, 21 effect on peripheral circulatory system,

25,26

effects during pregnancy in laboratory

animals, 88

experimental studies, 21

hypoxia and, 21

as most likely contributor to health

hazards of smoking, 8,143

Nitric oxide

as probable contributor to health hazards of smoking, 144

Nitrogen dioxide

effect on pulmonary tissue in rats,

46,47

in emphysema etiology, 46

as probable contributor to health hazards of smoking, 144

Nitrogen oxides

as air pollutants in cigarette smoke,

124,125

Non-nicotine cigarettes

effect on apexcardiogram, 21

Nonsmokers

allergic and irritative reactions to cigarette smoke, 128,129

148

155
allergic symptoms in, from tobacco

smoke exposure, 110,111

carboxyhemoglobin levels in, 125

passive smoking and, 121-125

Obesity

as a risk factor for coronary heart disease, 16

Occupational diseases

bronchitis, 42

chronic obstructive pulmonary disease,

3,4244

pneumoconiosis, 42 -44

pulmonary fibrosis, 44

smoking and, 3,42 -44

Occupational hazards

smoking and, 3,4,42 -44

Oral contraceptives

smoking and, 26

thrombophlebit is and, 26

Oral diseases, non-ncoplastic

smoking and, 6

Oral hygiene

smoking and, 6

Oral mucosa

effect of carcinogens in laboratory animals, 70

effect of cigarette smoke, 6,69

effect of reverse smoking, 69

effect of tobacco/bidi smoking and

chewing, 69

Oral neoplasms

pipe smoking as cause, 67

relative risk in tobacco smokers and

chewers, 70

smoking in etiology of, 4,67-70

Oxygen tension

smokers vs. nonsmokers, 22

Pancreatic neoplasms

mortality rates in United States, 74

mortality ratios in Japanese male 'and

female smokers, 74

smoking and, 5,68,74

Particulate phase, cigarette smoke

carcinogenic accelerators in, 5,65

effect on pulmonary and cardiac structure and function, 7,8

harmful constituents in, 143

Passive smoking

effect on children, 129

effect on respiratory tract in laboratory

animals, 129,130

in neoplasm induction in laboratory

animals, 130

156

149

Perinatal studies

maternal smoking and, 83-88

Periodontal diseases

smoking and, 6

Peripheral vascular diseases

carboxyhemoglobin levels and, 26

smoking and, 2,25,26

Phagocytosis

effect of cigarette smoke in rabbits,

109

effect of tobacco smoke, 47-48

Phenol

as probable contributor to health hazards of smoking, 144

Physical inactivity

as risk factor in coronary heart disease,

16,17

Pipe smokers

carboxyhemoglobin levels in, 21

myocardial arteriole wall thickness in,

19

oral neoplasms and, 67

relative risk in esophageal neoplasm

development. 68

relative risk in laryngeal neoplasm

development, 67

Pneumoconiosis

prevalence in coal miners, 4244

smokers vs. nonsmokers, 4244

Post-operative pulmonary complications

smokers vs. nonsmokers, 38

Preeclampsia

smoking and, 84

Pregnancy

effect of maternal smoking, 5,83.87

Prematurity

effect of maternal smoking, 5,83.87

Pulmonary clearance

effect of smoking, 3,47

Pulmonary fibrosis

in asbestos textile workers, 44

smoking and, 44

Pulmonary heart disease

COPD and, 24

smoking as cause, 24,27

Pulmonary macrophages

effect of smoking, 3,4,47-48

morphologic differences in smokers vs.

nonsmokers, 4,47-48

Pyridine

as suspected contributor to health hazards of smoking, 145

Radiation exposure

smoking and, in uranium miners, 64,65
Respiratory disorders, acute noninfluenzal

in smokers vs. nonsmokers, 48

Respiratory function tests

effect of smoking, 45

Respiratory infections

smoking and, 3,38

Respiratory symptoms

pipe/cigar smokers and cigarette

smokcrs vs. nonsmokers; 3,40

Reverse smoking

effect on oral mirmsa, 6,69,70

nicotinic stoma Otis and, 6,69,70

Risk factors

in coronary heart disease, 16.18

Skin

effect of tobacco extracts, 105.107

tobacco antigens and, 7,104,105

Skin testing

for reactions to tobacco, 105-107

Smoke, cigarette

carcinogenicity, 65,66

cocarcinogcnic effect on respiratory

tract in rabbits, 67

effect on apexcardiogram, 21

effect on breathing in guinea pigs, 46

effect on lung surface tension in tlogi,

48

effect on nasociliary mucosa ill donkeys, 47

effect on phagocytosis in rabbis. 109

experimental studies in laboratory animals, 21

harmful constituents of, 8,141-146

Smoke, tobacco

as air pollutant, 7,1 21,1 22

allergic and irritative ccloponents,

effect on nonsmokers, 7,128,129

antigenic properties, 104

effect on macrophages, 47

irritants in, 109,110

Smokers vs. nonsmokers

arteriosclerosis and, 19

carboxyhemoglobin levels, 21.23

cerebrovascular diseases and, 25

oral diseases and, 6

respiratory sptiptoms, 40

thickness of myocardial arteriole walls,

19

Smoke streams

benzo(a)pyrene content, 123

effect on nonsmokers, 122,123

tar and nicotine content, 123

Smoking

bladder neoplasms and, 68,72-74

effect on cardiovascular system, 6,13,14

effect on esophageal sphincter, 97,98

effect on gastrointestinal secretions in

dogs, 6

effect on leukocytes in guinea pigs, 46

effect on lungs in dogs, 46

effect on mortality rates from esophageal neoplasm in Japanese males, 71

effect on neoplasm recurrence at site of

primary, 69

effect on oxygen tension in arterial

blood, 45

effect on pen tagastrin-stimulated gastric

secretion, 97

effect on peripheral circulatory system,

25,26

effect on pulmonary clearance, 47

heartburn and, 97,98

peptic ulcers and, 6,97,98

tobacco amblyopia and, 6

Smoking, bidi

in neoplasm etiology in Bombay, India,

69

Smoking, maternal

carcinogenic effects on fetus, 88

effect on abortions, 5,84,85

effect on birth weight, 5,83-87

effect on body height of children, 88

Iffect on fetal growth rate, 5,83.87

Ofect on neonatal mortality rates,

84.87

effect on neoplasm development in offspring, 87,88

effect on placental metabolizing activity, 89

effects during pregnancy, 5,83.87

teratogenic effects, 87

unwanted pregnancy and, 84

Smoking, parental

effect on children, 129

Snuff

effect on oral mucosa in hamsters, 70

Squamous cell carcinoma

smoking in etiology of, 69

Stomatitis nicotina

reverse smoking and, 6,69,70

Stroke

smoking and, 24,25

Students, high school

effect of smoking, 40,41

pulmonary function of smokers vs. nonsmokers, 3

157
respiratory symptoms in, 40,41

Surfactants

effect of tobacco smoke, 48

Tar content as harmful component of cigarette

smoke, 142,143

Tars, tobacco

carcinogenicity, 65,66

definition, 143

Thromboangiitis oblitcrans

tobacco allergy and, 1 1 1

Thrombophlebitis

oral contraceptives and, 26

smoking and, 26

Thrombosis

effect of smoking, 23

Tobacco

cholesterol content, 24

effect on immune responses, 6,107-109

pharmacologic, irritative, and allergic effects, 7,109-111

Tobacco antigens

in smokers vs. nonsmokers, 107

Tobacco chewing

oral neoplasms and, 69

Tobacco extracts

antigenic properties, 104,105

effect on skin, 105-107

158

151

irritants in, 104,105

thromboangiitis oblitcrans and, 1 1 1

Tobacco leaf

antigenic properties, 104,105

Tobacco pollen

antigenic properties, 104

Tuberculosis

smoking and, 41

Twins

smoking and coronary heart disease in,

18

Ulcer, duodenal

smoking and, 6,97,98

Ulcer, peptic

Increased prevalence in male smokers,

97

smoking and, 5,6,97,98

smoking as cause in dogs, 97,98

Urinary bladder neoplasms

see Bladder neoplasms

Vascular disease, peripheral

carboxyhemoglobin levels and, 26

nicotine and, 25

smokers vs. nonsmokers, 26

smoking as a risk factor, 2,25,26

Vision

effect of carbon monoxide, 126

* U.S. GOVERNMENT PRINTING OFFICE: 1972 0-445.181