Th e Health Consequences of Smoking A Report of the Surgeon General: 1972 U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE Public Health Service Health Services and Mental Health Administration For de by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 - Price 70 cents. Stock Number 1723-0051 Honorable Carl Albert Speaker of the House of Representatives Washington, D.C. 20515 Dear Mr. Speaker: Enclosed is the 1972 report on the health consequences of smoking, as called for by Section 8 (a) of the Public Health Cigarette Smoking Act of 1969. As you will see, it continues and strengthens the find- ings of previous Public Health Service reports that cigarette smoking is a hazard to the health of the American people. Under this Act, I am also required to submit to you such recom- mendations for legislation as I deem appropriate. As you know, it has long been the position of this Department that an adequate health warning should appear in cigarette advertise- ments along with listings of "tar" and nicotine. We are in support of the current efforts of the Federal Trade Commission to bring this about through the exercise of its regulatory powers. Should these efforts fail, however, we would return to our previous recommenda- tions that this should be accomplished through legislative action. With kindest regards, Sincerely, Elliot L. Richardson Secretary iii Preface v' Six times since 1964, the Public Health Service has issued formal reviews of the scientific evidence which links cigarette smoking to disease and premature death. Each successive review, including this one, has served to confirm and strengthen the conclusion of the 1964 Report, that cigarettes are a major cause of death and disease. In the first three chapters of this report, the relationships be- tween cigarette smoking and cancer, cardiovascular disease, and non-neoplastic bronchopulmonary disease are reviewed and evi- dence is presented which helps develop our understanding of the mechanisms which are involved in these relationships. In the final three chapters, information is presented on public exposure to air pollution from tobacco, on the relationship between tobacco and allergy, and on the harmful constituents which are found in ciga- rette smoke. In the past few years, millions of Americans have stopped smok- ing because they have persuaded themselves that it is in their own self-interest to do so; we must continue to encourage cessation as the only certain way to protect both the individual and society from the harmful effects of smoking. We must also, however, work to- wards reducing the dangers of smoking for those who have not quit by developing less hazardous cigarettes and encouraging less hazardous ways of smoking. The chapter which discusses the harmful constituents of smoke is a useful statement of our current knowledge in this field; it should interest not only research scien- tists but those who are concerned with public education and public Policy. Research in smoking and health continues, as this report shows, both in this country and abroad and under both public and private auspices ; furthermore, the range of this research is widening as the significance of cigarette smoking as a public health problem becomes more apparent. In establishing the present series of reports, first under Public Law 89-92 and now under Public Law 91-222, the Congress has given us a means of encouraging the research we need and of building a better understanding of the problem. JESSE L. STEINFELD, M.D. Swgeon Geneml Table of Contents Page Letter of Transmittal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ." 111 PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..I V PREPARATION OF THE REPORT AND ACKNOWLEDGMENTS . . . . . . . . . . . . . . . , . . . . . . . . . . ix Chapter 1. Introduction and Summary . . . . . . . . . . . . . . . . . 1 Chapter 2. Cardiovascular Diseases . . . . . . . . . . . . . . . . . . . 11 Chapter 3. Non-neoplastic Bronchopulmonary Diseases . . . 35 Chapter 4. Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Chapter 5. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81 Chapter 6. Gastrointestinal Disorders . . . . . . . . . . . . . . . . . 95 Chapter `7. Allergy . . , . . . . . . . . . . . . . . . . . , . . . . . . . . . . . 101 Chapter 8. Public Exposure to Air Pollution from Tobacco Smoke . . . . . . . . . . . . . . . . . . . . . . . . . 119 Chapter 9. Harmful Constituents of Cigarette Smoke . . . . . 139 Mex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 vii Preparation of the Report and Acknowledgments "Smoking and Health. Report of the Advisory Committee to the Surgeon General of the Public Health Service"* was published in 1964. The following documents were subsequently published as re- views of the medical literature as called for by Public Law 39-92. 1. "The Health Consequences of Smoking, A Public Health Serv- ice Review : 1967"** 2. "The Health Consequences of Smoking, 1968 Supplement to the 1967 PHS Review"** 3. "The Health Consequences of Smoking, 1969 Supplement to the 1967 PHS Review"** These documents reviewed the medical literature which had been published since the original Surgeon General's Report. The format of publishing a supplement to a supplement became unwieldy, par- ticularly in the light of the lack of availability of previous reviews to the general public. Therefore, when P.L. 91-222 was signed into law on April 1, 1970, calling for an B-month interval between the previous report and the new report, the entire field was reviewed with an emphasis on the most recent additions to the literature. The product of this review was: "The Health Consequences of Smoking, A Report of the Surgeon General : 1971."** The present document, "The Health Consequences of Smoking, A Report of the Surgeon General: 1972," includes a review of the literature which has been published since the 1971 Report was completed. It also includes an evaluation of the state of knowledge in three areas which have not been previously reviewed in these reports: allergy and tobacco, public exposure to air pollution from tobacco smoke, and harmful constituents of cigarette smoke. The National Clearinghouse for Smoking and Health has the responsibility for the continuous monitoring and compilation of the medical literature on the health consequences of smoking and for the preparation of this document. This is accomplished through sev- eral mechanisms : o Referred to in this manuscript as the Surgeon General's Report. ** Referred to in this manuscript as "The Health Consequences of Smoking." ix 1. An information science corporation is on contract to extract articles on smoking and health from the medical literature of the world. This organization provides a semi-monthly acces- sions list with abstracts and copies of the various articles. Translations are called for as needed. Articles are classified according to subject and filed by a series of code words and phrases. 2. The National Library of Medicine, through the Medlars sys- tem, sends the National Clearinghouse for Smoking and Health a monthly listing of articles in the smoking and health area. These are reviewed, and articles not identified by the information science corporation are ordered. 3. Staff members review current medical literature and identify pertinent articles. Initial drafts of the present review were prepared by the staff director, assistant staff director, and consulting editors. The first drafts of the individual chapters were sent to experts for review, criticism, and comment with respect to the articles reviewed, arti- cles not included, and conclusions. The drafts were then revised until they met with the general approval of the reviewers. The final drafts were reviewed as a whole by the Director of the National Clearinghouse for Smoking and Health, the Director of the National Cancer Institute, the Director of the National Heart and Lung Institute, the Director of the National Institute of Environmental Health Sciences, and by six additional experts both within and out- side of the Public Health Service. Acknowledgments The National Clearinghouse for Smoking and Health, Daniel iHorn, Ph. D., Director, was responsible for the preparation of this report. Staff Director for the report was John H. Holbrook, M.D., and Assistant Staff Director was Elvin E. Adams, M.D. Daniel P. Asnes, M.D., and David G. Cook, M.D., were Consulting Editors. The professional staff has had the assistance and advice of a num- ber of experts in the scientific and technical fields, both in and out- side of the Government. Their contributions are gratefully acknowl- edged. Special thanks are due the following : ANDERSON, WILLIAM H., M.D.-Chief, Pulmonary Section, School of Medicine, University of Louisville, Louisville, Kentucky. ANTHONISEN, NICHOLAS R., M.D., Ph. D.-Associate Professor, Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada. x AUERBACH, OSCAR, M.D.-Senior Medical Investigator, Veterans Administra- tion Hospital, East Orange, New Jersey. AYRES, STEPHEN M., M.D.-Director, Cardiopulmonary Laboratory, Saint Vin- cent's Hospital and Medical Center of New York, New York, New York. BAKER, CARL G., M.D.-Director, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. BING, RICHARD J., M.D.-Professor of Medicine, University of Southern Cali- fornia, Huntington Memorial Hospital, Pasadena, California. BOCK, FRED G., Ph. D.-Director, Orchard Park Laboratories, Roswell Park Memorial Institute, Orchard Park, New York. BOREN, HOLLIS G., M.D.-Chief, Pulmonary Disease Section, The Medical Col- lege of Wisconsin, Wood Veterans Administration Hospital, Milwaukee, Wisconsin. BOUTWELL, ROSWELL K., M.D.-Professor of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, Wisconsin. COOPER, THEODORE, M.D.-Director, National Heart and Lung Institute, Na- tional Institutes of Health, Bethesda, Maryland. CORNFIELD, JEROME-Research Professor of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Biostatistics Project, Bethesda, Maryland. EPSTEIN, FREDERICK H., M.D.-Director and Professor of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan. FALK, HANS L., Ph. D.-Associate Director for Program, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. FARR, RICHARD, M.D.-Head, Department of Allergy and Clinical Immunology, National Jewish Hospital and Research Center, Denver, Colorado. FERRIS, BENJAMIN G., JR., M.D.-Professor of Environmental Health and Safety, School of Public Health, Harvard University, Boston, Massachusetts. FINKLEA, JOHN F., M.D.-Acting Director, Division of Effects Research, Na- tional Environmental Research Center, Research Triangle Park, North Carolina. FITZPATRICK, MARK J., M.D.-Obstetrician, Perinatal Biology and Infant Mor- tality Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. FRAZIER, TODD M.-Assistant Director, Harvard Center for Community Health and Medical Care, School of Public Health, Harvard University, Boston, Massachusetts. FRESTON, JAMES, M.D.-Associate Professor of Medicine, Head, Division of Gastroenterology, University of Utah Medical School, Salt Lake City, Utah. GOLDSMITH, JOHN R., M.D.-Head, Environmental Epidemiology Unit, Bureau of Occupational Health and Environmental Epidemiology, California State Department of Public Health, Berkeley, California. RAnN.4, MICHAEL G., JR., Ph. D.-Director, Immunology of Carcinogenesis Program, Oak Ridge National Laboratory, Oak Ridge, Tennessee. BARKAw, JOSEPH, M.D.-Clinical Professor of Medicine (Emeritus), The Mount Sinai Medical School of the University of New York, New York, New York. "looINS, IAN T. T., M.D.-Professor of Epidemiology, School of Public Health, university of Michigan, Ann Arbor, Michigan. HorrM~~~, DIETRICH, Ph. D.-Chief, Division of Environmental Carcino- genesis, American Health Foundation, New York, New York. )iELLEa, ANDREW Z., D.M.D.-Chief, Research in Geographic Epidemiology, Veterans Administration Central Office, Washington, D.C. xi KIRSNER, JOSEPH B., M.D., Ph. D.-Chief of Staff and Deputy Dean for Medical Affairs, The Pritzker School of Medicine, University of Chicago Hospitals and Clinics, Chicago, Illinois. KOLBYE, ALBERT C., JR., M.D., J.D.-Deputy Director, Bureau of Foods, Food and Drug Administration, U.S. Department of Health, Education, and Wel- fare, Washington, D.C. KRUMHOLZ, RI~IIARD A., M.D.-Medical Director, Institute of Respiratory Iliseases, Kettering Medical Center, Kettering, Ohio. LENFANT, CI.AUDE J. M., M.D.-Associate Director for Lung Programs, Na- tional Heart and I.ung Institute, National Institutes of Health, Bethesda, Maryland. LIEBOW, A~ERII.I. A., M.D-Professor and Chairman, Department of Pathology, University of California (San Diego), La Jolla, California. LILIENFELD, ABRAHAM, M.D.-Professor and Chairman, Department of Epide- miology, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland. LOWELL, FRANCIS C., M.D.-Chief, Allergy Unit, Massachusetts General Hos- pital, Boston, Massachusetts. MCLEAN, ROSS, M.D.--Professor of Medicine, Bowman Gray School of Medi- cine, Wake Forest Univei sity, Winston Salem, North Carolina. MCMILLAN, GARDNER C., M.D.-Chief, Arteriosclerotic Disease Branch, Na- tional Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland. MACMAHON, BRIAX, M.D.-Professor of Epidemiology, School of Public Health, Harvard University, Boston, Massachusetts. MEYER, MARY B., MRS.-Assistant Professor of Epidemiology, The Johns Hopkins University, Baltimore, Maryland. MITCHELL, ROGER S., M.D.-Chief of Staff, Veterans Administration Hospital, Denver, Colorado. MURPHY, EDMOND A., M.D., SC. D.-Associate Professor of Medicine and Bio- statistics, The Johns Hopkins Hospital, Baltimore, Maryland. NEWILL, VAUN A., M.I).-Chief, Health Effects Branch, Environmental Pro- tection Agency, Washington, D.C. PAFF~NBARGER, RALPH S., JR., M.D-Chief, Epidemiology Section, Bureau of Adult Health and Chi,onic Diseases, California State Department of Public Health, Berkeley, California. PARKER, CHARLES W., M.I,.-Professor of Internal Medicine, Division of Im- munology, Washington University Medical School, St. Louis, Missouri. PETERS, JOHN M., M.I).-Associate Professor of Occupational Medicine, School of Public Health, Harvard University, Boston, Massachusetts. PF,TERSOX, WIL.I IAM F., Xl).-Chairman, Department of Obstetrics and Gyne- cology, Washington Hospital Center, Washington, D.C. PETTY, THOMAS L., M.l).-Associate Professor of Medicine and Head, Division of Pulmonary I )iseasrs, University of Colorado Medical Center, Denver, Colorado. RALI., DAvII) P., M.I).---Director, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina. RENZETTI, ATTILIO I)., JR., M.D.-Professor of Medicine, Pulmonary Disease Division, University of Utah Medical Center, Salt Lake City, Utah. ROBINS, MORTON-Chief of Study, Design, and Analysis Staff, Regional Medical Programs Service, Health Services and Mental Health Administration, Rockville, Maryland. SAFFIOTTI, UMBERTO, M.D.-Associate Scientific Director for Carcinogenesis, Etiology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. xii SCHUMAN, LEONARD M., M.D.-Professor and Head, Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, Minnesota. SHIMKIN, MICHAEL B., M.D.-Coordinator and Professor of Community Medi- cine and Oncology, Regional Medical Program, University of California (San Diego), La Jolla, California. STAMLER, JEREMIAH, M.D.-Executive Director, Chicago Health Research Foundation, Chicago, Illinois VAN DUUREN, BENJAMIN L., M.D.-Professor of Environmental Medicine, Institute of Environmental Medicine, New York University Medical Center, New York, New York. WYXDER, ERNEST L., M.D., President, American Health Foundation, New York, New York. The chapter on Harmful Constituents of Cigarette Smoke was prepared somewhat differently from the rest of the report, being the culmination of a one-day conference held in June 1970 to review this area of knowledge and to discuss a draft report prepared in ad- vance by staff of the National Institute of Environmental Health Sciences and the National Clearinghouse for Smoking and Health. Earlier in this section, some of these participants are acknowledged as contributors to other parts of the report, namely, Dr. Daniel Horn, who served as Chairman of the meeting, Drs. Daniel P. Asnes, Fred G. Bock, Dietrich Hoffmann, Albert C. Kolbye, Gardner C. McMillan, Umberto Saffiotti, Leonard Schuman, Benjamin L. Van Duuren, and Ernest L. Wynder. In addition, acknowledgments should be made to the following who were also participants in the conference: GORI, GIO BATTA, M.D.-Associate Scientific Director for Program, Etiology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. GRIFFITH, ROBERT, Ph. D.-Director, Tobacco and Health Research Institute, University of Kentucky, Lexington, Kentucky. GUERIN, MICHAEL, Ph. D.-Senior Chemist, Oak Ridge National Laboratory, Oak Ridge, Tennessee. JARV~K, MURRAY, M.D.-Professor of Psychiatry and Pharmacology, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York. KENSLER, CHARLES, M.D.-Senior Vice President, Life Sciences Division, Arthur I). Little, Inc., Cambridge, Massachusetts. KOTIN, PAUL, M.D.-Vice President for Health Sciences, Health Sciences Cen- ter, Temple University, Philadelphia, Pennsylvania. LIPTON, MORRIS, M.D., Ph. D.-Professor and Chairman, Ijepartment of Psy- chiatry, University of North Carolina, Chapel Hill, North Carolina. REMINGTON, RICHARD, M.D.-Associate Dean for Research, School of Public Health, University of Texas, Houston, Texas. SCHMELTZ, ERWIN, Ph. D.-Head, Lubricants Investigations, Eastern Utiliza- tion Research and Development Division, U.S. Department of Agriculture, Philadelphia, Pennsylvania. STANTON, MEARL F., M.D.-Medical Officer, National Cancer Institute, Na- tional Institutes of Health, Bethesda, Maryland. TSO, TIEN C., M.D.-Plant Physiologist and Leader, Tobacco Quality Investi- gations, Plant Science Research Division, ARS, U.S. Department of Agri- culture, Beltsville, Maryland. . . . Xlll The following professional staff of the National Clearinghouse for Smoking and Health contributed to the preparation of this report : Robert S. Hutchings, Emil Corwin, Elaine Bratic, Annabel W. Hecht, Lillian Davis, Richard W. White, Richard H. Amacher, Donald R. Shopland, Jennie M. Jennings, Dan Nemzer, Nancy S. Johnston, and Gertrude Herrin. Special thanks are due Theresa Klotz, Rosalie Levine, and Mildred Ritchie. xiv CHAPTER 1 Introduction and Summary INTRODUCTION AND SUMMARY Cigarette smoking continues to be a major health problem in the United States today. It is still too early to tell whether the increas- ing rate of giving up smoking by adults during the years 196'7,1968, 1969, and early 1970 and the plateauing of this effect during the past year have had any measurable effect on the morbidity and mortality associated with smoking. At the same time that the major health professions, voluntary health agencies, and public service agencies concerned have joined with government agencies to reduce the magnitude of this problem through education, research efforts devoted to understanding how cigarette smoking affects biological function to produce disease continue at a high level. This report is largely concerned with reviewing the research re- ports which have become available in the past year. In this chapter, brief summary statements are presented of the state of knowledge in several areas. These are followed, where appropriate, by a "high- light" statement of significant additions to knowledge made as a result of the new research presented in greater detail in the body of the report. The state of knowledge in three areas, which have not been re- riewed previously, is also presented in the report. These areas are : Allergy, Public Exposure to Air Pollution from Tobacco Smoke, and the Harmful Constituents of Cigarette Smoke. SUMMARY: CORONARY HEART DISEASE Cigarette smokers have higher death rates from coronary heart disease (CHD) than nonsmokers. This relationship is stronger for men than women. Cigarette smoking markedly increases an individ- ual's susceptibility to earlier death from CHD. Cigarette smoking, hypertension, and elevated serum cholesterol are major risk factors contributing to the development of CHD; cigarette smoking acts both independently and conjointly with these other factors to in- Qeage the risk of developing CHD. Cigarette smoking may con- tribute both to the development of CHD and to the exacerbation of Preexistent CHD; both ni,cotine and carbon monoxide are thought to contribute to these abnormal processes. Cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and coronary arteries. Cessation of smoking is associated with a decreased risk of death from CHD. The risk of CHD incurred by pipe and cigar smokers is appreciably less than that incurred by cigarette smokers. Highlights of 1972 Report: Coronary Heart Disease 1. Recent epidemiological studies from several countries confinp! that cigarette smoking is one of the major risk factors con.! tributing to the development of CHD. Avoidance of cigaretb. smoking is of importance in the primary prevention of CHD.' 2. Studies in man and animals have shown a greater myocardial arteriole wall thickness in smokers than nonsmokers. 3. Experimental and epidemiological investigations implicate the elevation of carboxyhemoglobin levels in smokers as a' contributor to the development of CHD and arteriosclerotic peripheral vascular disease. 4. Cigarette smoking is considered to be the major cause of pul. monary heart disease (car pulmonale) in the United States in that it is the most important cause of chronic non-neoplastic bronchopulmonary diseases. Avoidance of cigarette smoking is of importance in the primary prevention of pulmonary heart disease. SUMMARY: CEREBROVASCULAR DISEASE Cigarette smokers have higher death rates from cerebrovascular disease than nonsmokers. SUMMARY: NONSYPHILITIC AORTIC ANEURYSM* Cigarette smokers have higher death rates from nonsyphilitic aortic aneurysm than nonsmokers. SUMMARY: PERIPHERAL VASCULAR DISEASE Cigarette smoking is a likely risk factor in the development of peripheral vascular disease. Cigarette smoking appears to aggravate preexistent peripheral vascular disease. o This summary statement is the same as that appearing in previous reports. because new studies adding to the understanding of this area have not ????????? Conseqxntly. the literature in this area is not reviewed and the statement is ?*o? included to complete this summary chapter. 2 SUMMARY: NON-NEOPLASTIC BRONCHOPULMONARY DISEASES Cigarette smoking is the most important cause of chronic obstruc- tive bronchopulmonary disease (COPD) in the United States. Ciga- rette smokers have higher death rates from pulmonary emphysema and chronic bronchitis and more frequently have impaired pul- monary function and pulmonary symptoms than nonsmokers. Ex- cigarette smokers have lower death rates from COPD than do con- tinuing smokers. Cessation of smoking is associated with improved ventilatory function and decreased pulmonary symptom prevalence. For most of the United States population, cigarette smoking is a more important cause of COPD than air pollution or occupational exposure; cigarette smoking may also act conjointly with occupa- tional or environmental exposure to produce greater COPD mar.- bidity and mortality. An infrequent genetic error, homozygous alphal-antitrypsin deficiency, has been commonly associated with the early development of severe, panacinar emphysema. Whether or not cigarette smoking acts together with the J- `mozygous or hetero- zygous deficiency states to increase the risk of developing either panacinar emphysema or the more common forme of COPD has not been adequately studied. Cigarette smoking exerts an adverse effect on the pulmonary clearance mechanism. Respiratory infec- tions are more prevalent and severe among cigarette smokers, par- ticularly among heavy smokers, than among nonsmokers. The risk of developing or dying from COPD among pipe or cigar smokers is probably higher than that among nonsmokers but is clearly less than that among cigarette smokers. Highlights of the 1972 Report: Non-neoplastic Bronchopulmonary Diseases 1. Recent epidemiological and clinical studies from several countries confirm that men and women cigarette smokers have an increased prevalence of respiratory symptoms and have diminished pulmonary function compared to nonsmokers. 2. Investigations of high school students have demonstrated that abnormal pulmonary function and pulmonary symptoms are more common in smokers than nonsmokers. 3. Recent occupational studies confirm that cigarette smoking is an important cause of COPD, acting both independently and in combination with occupational exposure. 4. Recent experimental studies confirm that cigarette smoking exerts an adverse effect on pulmonary clearance and macro- phage function. 3 5. Pulmonary macrophages obtained from cigarette smokers ex- hibit characteristic morphologic differences when compared to those obtained from nonsmokers. SUMMARY: CANCER Cigarette smoking is the major cause of lung cancer in men and a significant cause of lung cancer in women. The risk of developing lung cancer in both men and women is directly related to an individ- ual's exposure as measured by the number of cigarettes smoked, duration of smoking, earlier initiation, depth of inhalation, and the amount of "tar" produced by the cigarette. The risk of developing lung cancer diminishes with cessation of smoking. Smokers of pipes or cigars have a lower risk of developing lung cancer than cigarette smokers. Certain occupations are associated with an increased risk of developing lung cancer. In these occupational settings cigarette smoking appears to exert an effect that produces much higher lung cancer rates than those resulting either from the occupational ex- posure alone or from smoking alone. Factors associated with urban living result in an increase in the risk of developing lung cancer; this effect, however, is minor compared to the overriding effect of cigarette smoking. The smoking of cigarettes, pipes, and cigars is a significant factor in the d,evelopment of cancers of the larynx and oral cavity. Pipe smoking is causally related to cancer of the lip. The significant asso- ciation between smoking and the development of cancer of the esophagus is somewhat stronger for cigarettes than for pipes or cigars and the combined exposure to alcohol and cigarettes is asso- ciated with especially high rates of cancer of the esophagus. Ciga- rette smoking is associated with cancer of the urinary bladder in men. There is also an association between cigarette smoking and cancer of the pancreas. Highlights of the 1972 Report: Cancer 1. Preliminary results from a major prospective epidemiological study in Japan demonstrate a strong association between cig- arette smoking and lung cancer. A dose-response relationship was demonstrated for the number of cigarettes smoked. These findings in an Asian population with distinct genetic and cul- tural characteristics confirm the major importance of ciga- rette smoking in the causation of lung cancer, a conclusion which up to now has been based largely on studies of Cauca- sian populations in the United States, Canada, and Europe. 2. 3. 4. 5. 6. 7. Ex-smokers have significantly lower death rates for lung can- cer than continuing smokers. The decline in risk following cessation appears to be rapid both for those who have smoked for long periods of time and for those with a shorter smoking history, with the sharpest reductions taking place after the first two years of cessation. The risk of developing lung cancer appears to be higher for smokers who have chronic bronchitis. Though both conditions are directly related to the amount and duration of smoking, an additional risk for lung cancer appears to exist for ciga- rette smokers with chronic bronchitis which is independent of age and number of cigarettes consumed. Experimental studies on animals have demonstrated that the particulate phase of tobacco smoke contains certain chemical compounds which can act as complete carcinogens, tumor initiators, or tumor promoters. Recently, other compounds have been described that have no independent activity in two- stage carcinogenesis but accelel ate the carcinogenic effects of polynuclear aromatic hydrocarbons in the initiator-promoter system. Additional epidemiological evidence confirms a significant as- sociation between the combined use of cigarettes and alcohol, and cancer of the esophagus. Epidemiological studies have demonstrated a significant asso- ciation between cigarette smoking and cancer of the urinary bladder in both men and women. These studies demonstrate that the risk of developing bladder cancer increases with in- halation and the number of cigarettes smoked. Epidemiological evidence demonstrates a significant associa- tion between cigarette smoking and cancer of the pancreas. SUMMARY: PREGNANCY Maternal smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birth weight and an increased incidence of prematurity, defined by weight. There is increasing evidence to support the view that women who smoke during pregnancy have a significantly greater risk of an unsuccess- ful pregnancy than those who do not. SUMMARY: GASTROINTESTINAL DISORDERS Cigarette smoking males have an increased prevalence of peptic ulcer disease as compared to nonsmoking males and a greater peptic 5 ulcer mortality ratio. These relationships are stronger for gastric ulcer than for duodenal ulcer. Smoking appears to reduce the effec- tiveness of standard peptic ulcer treatment and to slow the rate of ulcer healing. Highlights of the 1972 Report: Gastrointestinal Disorders 1. A possible link between cigarette smoking and peptic ulcer has been demonstrated in dogs in which nicotine was found to inhibit pancreatic and hepatic bicarbonate secretion. This could lead to peptic disease by depriving the duodenum of sufficient alkaline secretion to neutralize gastric acidity. 2. An investigation in human volunteers has suggested that cig- arette smoking decreases the effectiveness of the lower- esophageal sphincter as a barrier against gastro-esophageal reflux. SUMMARY: TOBACCO AMBLYOPIA* Tobacco amblyopia is presently a rare disorder in the United States. The evidence suggests that this disorder is related to nutri- tional or idiopathic deficiencies in certain detoxification mecha- nisms, particularly in the metabolism of the cyanide component of tobacco smoke. SUMMARY : NON-NEOPLASTIC ORAL DISEASE* Ulceromembranous gingivitis, alveolar bone loss, and stomatitis nicotina are more commonly found among smokers than among nonsmokers. The influence of smoking on periodontal disease and gingivitis probably operates in conjunction with poor oral hygiene. In addition, there is evidence that smoking may be associated with edentulism and delayed socket healing. While further experimental and clinical studies are indicated, it would appear that nonsmokers have an advantage over smokers in terms of their oral health. TOP in.t'o?.ma.tion contained in the fob&g three summary state- ru~nfs: A&q~y, P&lie Exposure to Air Pollution from Tobacco Smoke. awl Harmfzl.1 Constitu.ents of Cigarette Smoke, is new and uppears for the first time. --- * This summary statement is the same as that appearing in previous reports, because new sturliei adding t<, thez understanding of this area have not appeared. Consewentb. the literature in this area is not reviewed and the statement is only included to complete this summa~`~ chapter. b SUMMARY OF THE 1972 REPORT: ALLERGY 1. Tobacco leaf, tobacco pollen, and tobacco smoke are antigenic in man and animals. 2, (a) Skin sensitizing antibodies specific for tobacco antigens have been found frequently in smokers and nonsmokers. They appear to occur more often in allergic individuals. Precipitating antibodies specific for tobacco antigens have also been found in both smokers and nonsmokers. (b) A delayed type of hypersensitivity to tobacco has been demonstrated in man. (c) Tobacco may exert an adverse effect on protective mech- anisms of the immune system in man and animals. 3. (a) Tobacco smoke can contribute to the discomfort of many individuals. It exerts complex pharmacologic, irritative, and allergic effects, the clinical manifestations of which may be indistinguishable from one another. (b) Exposure to tobacco smoke may produce exacerbation of allergic symptoms in nonsmokers who are suffering from allergies of diverse causes. 4. Little is known about the pathogenesis of tobacco allergy and its possible relationship to other smoking-related diseases. SI'JIMARY OF THE 1972 REPORT: PUBLIC EXPOSURE TO AIR POLLUTION FROM TOBACCO SMOKE 1. An atmosphere contaminated with tobacco smoke can con- tribute to the discomfort of many individuals. 3 LI. The level of carbon monoxide attained in experiments using rooms filled with tobacco smoke has been shown to equal, and at times to exceed, the legal limits for maximum air pollution Permitted for ambient air quality in several localities and can also exceed the occupational Threshold Limit Value for a nor- mal work period presently in effect for the United States as a Rhole. The presence of such levels indicates that the effect of exposure to carbon monoxide may on occasion, depending UPon the length of exposure, be sufficient to be harmful to the health of an exposed person. This would be particularly sig- nificant for people who are already suffering from chronic hronchopulmonary disease and coronary heart disease. ". Other components of tobacco smoke, such as particulate mat- ter and the oxides of nitrogen, have been shown in various 7 concentrations to affect adversely animal pulmonary and' cardiac structure and function. The extent of the contribu. tions of these substances to illness in humans exposed to the concentrations present in an atmosphere contaminated with tobacco smoke is not presently known. SUMMARY OF THE 1972 REPORT: HARMFUL CONSTITUENTS OF CIGARETTE SMOKE A number of substances or classes of substances found in ciga. rette smoke are identified as those which are judged to be con. tributors to the health hazards of smoking. These constituents are further divided into the most likely contributors to these health hazards (carbon monoxide, nicotine, and tobacco "tar"), sub. stances which are probable contributors, and those which are su.s. pected contributors. The recom,mendations for control in this area are to seek progressive reduction of all harmful constituents in cigarette smoke with priority being given first to the most likely contributors named and second to the probable contributors to the health hazards of smoking. These judgments represent the consen. sus of experts based on current knowledge and are subject to modi.. fication and further elaboration as more knowledge becomes available. 8 CHAPTER 2 Cardiovascular Diseases Contents Page Coronary Heart Disease Introduction 13 Epidemiological Studies 14 Interaction of Smoking and Other Risk Factors 16 Autopsy Studies 19 Experimental Studies 21 Nicotine and Cigarette Smoke 21 Carbon Monoxide 21 Smoking and Thrombosis 23 Cholesterol Content of Tobacco and Tobacco Smoke 24 Cor Pulmonale (Pulmonary Heart Disease) . . . . . . . . . . . . . 24 Cerebrovascular Disease . . . . . . . , . . . . . . . . . . . . . . . . . . . . . 24 Peripheral Vascular Disease . . . . . . . . . . . . . . . . . . . . . . . . . . 25 Oral Contraceptives, Thrombophlebitis, and Smoking . . . . . 26 Highlights of Current Cardiovascular Information . . . . . . . . 27 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 LIST OF TABLES Table L-Incidence (1963-1970) of heart infarct in relation to tobacco consumption in "The Men Born in 1913," Goteborg, Sweden . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table 2.-Cigarette smoking at entry and subsequent 20-year CHD incidence among Minnesota men . . . . . . . . . . . . . . . . Table 3.-Human autopsy study. Comparison of the thick- ness of myocardial arteriole walls in smokers and non- smokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table $.-Average values of carboxyhemoglobin and serum cholesterol in Danish smokers and nonsmokers in control group and group of patients with arteriosclerotic cardio- vascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15 15 19 23 11 LIST OF FIGURES Page Figure l.-Canine autopsy study. Comparison of the thick- ness of myocardial arteriole walls in 32 smoking dogs killed after 875 days and 8 nonsmoking dogs . . . . . . . . . . . 20 12 INTRODUCTION In the United States more people die from coronary heart disease (CHD) than from any other disease; furthermore, CHD is the single most important cause of excess death among cigarette smokers (54, 57). The 1971 report, "The Health Consequences of Smoking" (56)) outlined the growing magnitude of this problem and summarized the relationship between smoking and coronary heart disease as follows : 1. Data from numerous prospective and retrospective studies confirm the judgment that cigarette smoking is a significant risk factor contributing to the development of coronary heart disease including fatal CHD and its most severe expression, sudden and unexpected death. The risk of CHD incurred by smokers of pipes and cigars is appreciably less than that by cigarette smokers. 2. Analysis of other factors associated with CHD (high serum cholesterol, high blood pressure, and physical inactivity) shows that cigarette smoking operates independently of these other factors and can act jointly with certain of them to in- crease the risk of CHD appreciably. 3. There is evidence that cigarette smoking may accelerate the pathophysiological changes of pre-existing coronary heart disease and therefore contributes to sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and coronary arteries. 5. The cessation of smoking is associated with a decreased risk of death from CHD. 6. Experimental studies in animals and humans suggest that cigarette smoking may contribute to the development of CHD and/or its manifestations by one or more of the following mechanisms : a. Cigarette smoking, by contributing to the release of catecholamines, causes increased myocardial wall tension, contraction velocity, and heart rate, and thereby increases the work of the heart and the myocardial demand for oxygen and other nutrients. 13 b. Among individuals with coronary atherosclerosis, ciga. rette smoking appears to create an imbalance between the increased needs of the myocardium and an insufficient in- crease in coronary blood flow and oxygenation. c. Carboxyhemoglobin, formed from the inhaled carbon monoxide, diminishes the availability of oxygen to the myo- cardium and may also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hypoxemia, thus reduc. ing the amount of oxygen available to the myocardium. e. Cigarette smoking may cause an increase in platelet adhe. siveness which might contribute to acute thrombus for- mation. Recent epidemiological, pathological, and experimental studies add to the understanding of the relationship between smoking and CHD. These studies point to cigarette smoking as one of the major risk factors leading to CHD and help clarify some of the biomech- anisms through which this occurs. EPIDEMIOLOGICAL STUDIES A prospective study of 973 men born in 1913 in GGteborg, Sweden, was undertaken in 1963 (51,52). The proportion of myo- cardial infarctions among cigarette smokers was significantly greater than among nonsmokers (P < .05), and the incidence of myocardial infarction rose with increasing cigarette consumption (table 1). Of the 35 individuals who experienced a myocardial in- farction between 1963 and 1970, only two had been nonsmokers; in the whole population of men born in 1913,56 percent were smokers. Although angina pectoris was more common in smokers than nonsmokers, the difference was smaller than for myocardial in- farction and was not statistically significant (52). Paffenbarger, et al. (42) reported on the health experience of 3,263 longshoremen studied over the past 18 years. During this in- terval 1,098 were known to have died, 350 dying from CHD. Long- shoremen who smoked more than 20 cigarettes a day faced a risk of coronary death which was more than twice as great as that of the group made up of both nonsmokers and smokers of less than 20 cigarettes a day (P < .Ol) . Keys, et al. (30) analyzed the 20-year CHD incidence among 279 Minnesota men aged 47 through 57 years who were CHD free at entry into the study. The relationship of cigarette smoking habits at the start of the study to the subsequent incidence of CHD was examined. The originally published table of results was incorrect 14 and the authors have supplied a corrected table which appeared in a later issue of the same journal (table 2). The morbidity ratio for "hard CHD" (CHD deaths plus myocardial infarctions not resulting in death) among those smoking more than 10 cigarettes a TABLE L-Incidence (1963-l 970) of heart infarct in relation to tobacco consumption in "The Men Born in 1913," Giiteborg, Sweden. n = 855 Smoking Heart infarct classification Number Percent Never smoked n ti 207 Stopped smoking n = 168 Cigarette smokers 1-14 cig/day n = 234 15-24 cig/day n= 138 225 cigiday n = 33 Pipe/cigar n = 75 ( 2) 1.0 ( 2) 1.0 (13) 6.0 ( 9) 7.0 ( 4) 12.0 ( 5) 7.0 SOURCE: Tibblin, G.. Wilhelmsen. L. (51). TABLE 2.-Cigarette smoking at entry and subsequent RO-year CHD incidence among Minnesota men.' Number Smoking habit (cigarettes/day) Age of men Item NW`X Stopped 20 47948 53 49,50 51 51,52 69 x1,54 53 -55-57 51 J;-57 277 47-57 277 4:-w 277 47-57 277 47-57 277 ~1-51 277 47-57 277 % with habit 23 % with habit 33 % with habit 33 % with habit 36 % with habit 24 Number of men 83 Hard CHD rate (%) 12.0 Hard CHD rate (SE) -t 3.6 Hard CHD Morbidity Ratio 1.00 All CHD rate (%) "21.7 All CHD rate (SE) k 4.5 All CHD Morbidity Ratio 1.00 19 20 26 30 33 71 15.5 + 4.3 1.29 .83 1.43 1.77 221.1 516.7 k19.5 k26.9 k 4.8 ?I 6.8 2 6.2 r+ 6.1 .97 .77 .90 1.24 9 14 14 8 3: 10.0 * 5.5 19 10 14 13 18 41 17.1 2 5.9 30 23 13 13 i'z 21.2 + 5.7 ' Cigarette smoking habits, by age at start of the XI-year follow-up, ZO-year incidence rates ' per 100 men ) and standard ei-ram (SE) of the rates. `"flrCt.q. .*A,+- "Hard cxD"--CHD death and myoeardial ~iohee. angina peetoris and other CHD diagnoses. "Deaths"-from all ca"ses except SoURCE: Modified from Keys, A., et al. (30). 15 day is similar to that reported from the large prospective studies. However, with the small number of cases in each smoking category, there are no statistically significant differences in the incidence of CHD between the categories, either singly or combined. Retrospective studies of CHD have recently been reported from Czechoslovakia, Sweden, Norway, and India which corroborate earlier studies linking cigarette smoking with excess CHD morbid- ity and mortality. The Prague study (19) included 443 men between the ages of 60 and 64 years. Significantly more (P < .05) individuals with a "probable" myocardial infarction were found among cigarette smokers than among nonsmokers or pipe and cigar smokers. The smoking habits of 120 patients with myocardial infarction who were hospitalized in Goteborg were compared with those of the entire "men born in 1913" population sample (17, 62). A signif- icantly (P < .Ol) greater number of smokers and heavy smokers (more than 15 cigarettes a day) were found in the myocardial in- farction group than in the population sample. The Bergen, Norway, cross sectional study of 2,117 women and 2,472 men documented a relationship between smoking and CHD in men, which was most marked in the 50 to 59 year old age group (16). No effect of smoking on the prevalence of CHD in women was demonstrable in this study, and the effect in men did not appear to be related to the daily number of cigarettes smoked. In New Delhi, 100 "well documented" cases of ischemic heart disease were compared with an equal number of control cases (8). In this study, significantly more (P < .Ol) of the case group smoked cigarettes regularly than the control group (Morbidity Ratio = 2.1). Mulcahy, et al. (40) recently found a positive association between coronary heart disease mortality rate and calculated per capita cig- arette consumption in 21 countries. He interpreted the results as being consistent with the hypothesis that cigarette smoking is a significant risk factor in CHD mortality. Stamler, et al. (50) found that for both men and women the 1964 CHD mortality rates in 17 developed countries were related to aver- age annual per capita cigarette consumption. INTERACTION OF SMOKING AND OTHER RISK FACTORS The Report of the Inter-Society Commission for Heart Disease Resources summarized the evidence indicating that three risk fac- tors (hypercholesterolemia, hypertension, and cigarette smoking) are properly designated major risk factors for premature CHD (28). Other possible risk factors including obesity, physical inac- tivity, diabetes mellitus, elevated resting heart rate, electrocardio- 16 graphic abnormalities, a positive family history of premature CHD, and psychologic and social factors have also been described (54, 55,56). In the study of 973 men born in 1913 in Giiteborg, Sweden, sev- eral coronary risk factors including elevated serum cholesterol, ele- vated serum triglyceride, low physical activity at work, and smok- ing were found to be related to an increased risk for the development of coronary heart disease during the subsequent years of the study. Failure to find a relationship between hypertension and an in- creased risk of CHD may have been due to the fact that all patients with hypertension in 1963 have been under treatment since that time. Tibblin and Wilhelmsen (52) found that as a patient accumulated more risk factors his chance of developing CHD became substan- tially greater. Werkij (61) reported from the same Gijteborg study that patients who were smokers, had sedentary jobs, and had both elevated cholesterol and triglycerides experienced a 4-year incidence of new coronary events of about 20 percent; the 4-year incidence among those who exhibited only one or two risk factors was much lower, ranging from 0 to 3 percent. ECG changes and angina1 pain were included in the definition of new coronary events. Paffenbarger, et al. (42) evaluated coronary risk factors in the study of 3,263 longshoremen. They found that, with the exception of diagnosed heart disease, smoking was the most important factor Predictive of high risk for coronary mortality. Keys, et al. (30) in the study of 279 Minnesota men, concluded that a positive cold pressor test, elevated serum cholesterol, and elevated systolic blood pressure had major predictive power for CHD death or infarction; in their analysis smoking seemed less important. Stamler (49) has analyzed the data on 13 deaths occurring dur- ing the first years of the Chicago Coronary Prevention Evaluation Program, which originally consisted of 519 coronary-prone male volunteers aged 40 to 59 who were free from clinical CHD. Eleven of the 13 decedents had three or more coronary risk factors at entry into the program, and at least 8 were cigarette smokers at the time of death. Forty-three men, who were cigarette smokers at entry into the Coronary Prevention Evaluation Program, gave up smok- ing and have remained active in the program. There have been no deaths from cardiovascular causes in this group. Stamler (49) commented : "Even though the number of decedents was small, these data strongly suggest that continued cigarette smoking is as- sociated with very high risk of premature death for very coronary- Prone men, and that other preventive measures are by themselves of limited value for them as long as they fail to give up cigarette smoking." 17 As described in the 1971 report, "The Health Consequences of ! Smoking" (56), some studies have indicated that smokers show increased levels of serum lipids while others have not. Such contra. dictory results are also present in recent studies from Germany, Poland, and Sweden (21, 39, 53). After a patient suffers a myocardial infarction, he frequently gives up smoking (17,26). Only fragmentary data are available on what effect the cessation of cigarette smoking might have on the likelihood of a recurrent myocardial infarction (9,34, 43). Ninety- two survivors of a first myocardial infarction were studied over a S-year period by Par&s Chavero, et al. (43). During this time, 37 pati,ents continued smoking, and 12 of them (32 percent) experi- enced a second myocardial infarction. The 51 patients who did not smoke during this 3-year period included 39 ex-smokers and 12 pa- tients who had never smoked. Eight of the nonsmokers (16 percent) experienced a second myocardial infarction. The smoking habits of four of the patients were not known. Although the continuing smokers experienced a greater rate of recurrent myocardial infarc. tion than the nonsmokers, the difference was not statistically sig- nificant (P = .07). The role of genetic factors in the development of CHD and the difficulties associated with the use of twin studies were discussed in the 1971 report, "The Health Consequences of Smoking" (56). Mailed questionnaires were used to establish the diagnosis of angina pectoris in a study by Lundman, et al. of twin pairs discordant with respect to smoking habits and in a study by Liljefors of twins with CHD. Lundman, et al. (36) recently investigated 69 male twins with the diagnosis of angina pectoris established by questionnaire. Only 22 percent of these diagnoses could be verified by clinical examina- tion. In a study of CHD, Liljefors (35) studied 91 pairs of twins from the Swedish Twin Registry of 1967. The twins ranged in age from 42 to 67 years, and 51 pairs were monozygotic. Smoking habits were not significantly different in pairs discordant for the probable presence of CHD. However, Liljefors noted that ". . . in many pairs the smoking habits were similar and that the material included few pairs discordant with respect to smoking, so that it does not pro- vide a suitable basis for conclusions as to the causal importance of smoking for CHD." As observed in the 1971 report, "The Health Consequences of Smoking" (56)) it would be surprising if genetic factors did not play a role in heart disease; however, it is open to question whether findings from twin studies can be used to dis- tinguish between ". . . the hypothesis that genetic factors govern the level of host susceptibility or resistance to the effects of an exo- genous influence such as cigarette smoking and the hypothesis that genetic factors `cause' both heart disease and smoking." 18 AUTOPSY STUDIES In previously reported autopsy studies, Auerbach, et al. found that aortic and coronary atherosclerosis in man were more common and severe among smokers than among nonsmokers (5). They have now extended their investigations to the myocardial arterioles of men and beagle dogs (6). In a study of 1,184 men, they found that the thickness of myocardial arteriole walls was greater, on the average, in smokers than nonsmokers (table 3). The thickness in- creased with the number of cigarettes smoked per day and with age. The thickness was less, on the average, among cigar and pipe smokers than among cigarette smokers, but it was greater than in men who had never smoked regularly. TABLE S.-Human autopsy study. Comparison of the thickness of myocardial arteriole wa2Z.s in smokers and nonsmokers.' Age (Year) Smoking Number of Me" Percent of Men :Grade XGrade XGrade SGrade $Grade :Grade Total 0 1 2. 3 Total 0 1 2.3 < 45 None 22 2 19 1 100.0 9.1 85.4 4.5 Cigar, pipe 4- 13 100.0 - t25.0 y75.0 Cig. 1-19 50 1 31 18 100.0 2.0 62.0 36.0 Cig. 20-39 85 4 35 46 100.0 4.7 41.2 54.1 Cig. 240 29 - 10 19 100.0 - 34.5 65.5 45-59 None 15 1 12 2 100.0 6.7 80.0 13.3 Cigar, pipe 13 - 8 5 100.0 - 61.5 38.5 Cig. 1-19 33 - 17 16 100.0 - 51.5 48.5 Cig. 20-39 99 - 35 64 100.0 - 35.4 64.6 Cig. 240 50 - 11 39 100.0 - 22.0 78.0 GO-69 None 56 4 36 16 100.0 7.1 64.3 28.6 Cigar, pipe 35 - 22 13 100.0 - 62.9 37.1 Cig. 1-19 92 - 44 48 100.0 - 47.8 52.2 Cig. 20-39 193 - 58 135 100.0 - 30.1 69.9 Cig. 240 87 - 21 66 100.0 - 24.1 75.9 2 70 None 32 2 18 12 100.0 6.3 56.2 37.5 Cigar,pipe 40 - 19 21 100.0 - 47.5 52.5 Cig. 1-19 30 - 12 18 100.0 - 40.0 60.0 Cig. 20-39 46 - 12 34 100.0 - 26.1 73.9 Cig. 240 g- 3 6 100.0 - $33.3 t66.7 ' 1" the right ventricular ~111 of 1.020 me" bu age and smoking habits. ' P=="tages based on less than ten cakes. * Four Point Scale for the Thickness of bfyocardial Arteriole Walls: @-normsi thickness; l-slight thickness; 2-moderate thickness; 3-great thickness. SoURCE: Auerbacb. 0.. et al. (6). 19 In one experiment, beagle dogs inhaled cigarette smoke daily through tracheostomae. Twenty-eight dogs that died between days 57 and 875 formed one group; 32 dogs that were killed after 875 days formed another group. Eight control dogs were not exposed. Beagle myocardial arteriole walls were found to be thicker in smok- ing than nonsmoking dogs, in dogs smoking many cigarettes than in dogs smoking fewer cigarettes, and in dogs smoking nonfilter cig- arettes than in dogs smoking filter-tip cigarettes (figure 1). Also, the thickness of arteriole walls increased with the duration of smoking. Group N No smoking 8 Dogs . . i :: . . . . . . . . . . . . . . . . . . Group L Nonfilter Cigarettes (% as many cigarettes) 10 Doas . . . . . . Group F . . . . Filter-Tip : Cigarettes . 10 Dogs A----l- Group H Nonfilter Cigarettes 12 Dogs I I Grade of 0 1 Thickness :: . . .ii ::: : :: :ii . . . . . . ..* . . . . . . . . . . . . . . . . . . . . . ::: . . . . . . . . . 2 Each dot represents one section. The three d.ots on a line represent the three sections from a particular dog. FIGURE L-Canine autopsy study. Comparison of the thickness of myocardial arteriole walls in 32 smoking dogs killed after 875 days and 8 nonsmoking dogs. SOURCE: Auerbach, O., et al. (6). 20 EXPERIMENTAL STUDIES NICOTINE AND CIGARETTE SMOKE Schievelbein, et al. (47) investigated the effect of oral nicotine administration over a 20-month period on lipid metabolism in 35 rabbits. Even though lipoprotein lipase levels and calcium content of the aorta were significantly greater in the group given nicotine than in the control group, the histological changes of arteriosclero- sis were found with equal frequency in both groups. The authors concluded that the epidemiological correlations between CHD and cigarette smoking could not be explained by the pharmacologic ef- fect of nicotine alone. A study of the interaction of chronic nicotine administration and acute hypoxia in 280 rats was performed by Wenzel and Richards (60). Pretreatment of the rats with nicotine increased the mortality during hypoxia, but the difference was not statistically significant. Pretreatment with the nicotine also was associated with marked variability of regression of hypoxic heart lesions. The interaction of nicotine pretreatment and the hypoxic insult produced variable effects on myocardial enzymes. Aronow (1) recently studied the effect of cigarette smoking on the A wave of the apexcardiogram in 20 men with CHD. The A wave reflects the left ventricular filling wave associated with the impact of blood upon the ventricular wall during left atria1 contraction. He found that the mean maximum increase in A wave ratio after smoking was 34 percent for high-nicotine cigarettes, 13 percent for the low-nicotine cigarettes, and 6 percent for the non-nicotine ciga- rettes. He ascribed these changes to increased myocardial ischemia produced by cigarette smoking, which was reflected by a larger A wave ratio in the apexcardiogram. While nicotine appears to have produced most of these changes, the observation that a 6 percent increase occurred in the absence of nicotine suggests the possibility that carbon monoxide plays a role in this effect. CARBON MONOXIDE Because cigarette smoke contains from 2.7 to 6 percent carbon monoxide (CO), significantly higher carboxyhemoglobin ( COHb) levels are found in smokers than nonsmokers (j3,20,24,63). COHb levels in nonsmokers are usually less than 1 percent, while those in smokers average around 4 percent and may exceed 15 percent (4, 20, 56). Heavy smokers and those who inhale show the highest carboxyhemogldbin levels (20). Haebisch (24) found that a smoker with a daily consumption of 35 to 40 cigarettes easily attains and maintains for hours an alveolar 21 CO concentration of 50 p.p.m., which reaches or exceeds legally- established ambient air quality standards (14,18, 23, 24). Cohen, et al. (23) and Aronow, et al. (2) have shown that there is no significant difference in mean expired air carbon monoxide levels after patients have smoked tobacco or lettuce leaf cigarettes. Although pipe and cigar smokers in the United States are reported to have lower exposure to CO than cigarette smokers (20) , CO in- toxication has been reported in cigar smokers (25). CO exerts its adverse effects on the cardiovascular system of smokers through one or more of the following mechanisms : (a) re- duction of the amount of hemoglobin available for oxygen trans- port ; (b) shift of the oxygen-hemoglobin dissociation curve to the left with consequent interference in oxygen release at the tissue level ; and (c) induction of arterial hypoxemia. CO may interfere with the homeostatic mechanism by which 2,3-DPG controls the affinity of hemoglobin for oxygen (56). CO has also been implicated in experimental atherogenesis in animals (56). Ayres, et al. (7) recently studied 41 patients during diagnostic cardiac catheterization, at which time they inhaled either 5 percent or .l percent CO. Arterial and mixed venous oxygen tensions were decreased by administration of either concentration. In patients with CHD, coronary artery 0, extraction decreased 7.9 percent after inhalation of .1 percent CO and 30.5 percent after inhalation of 5 percent CO. Some of the patients with CHD experienced changes in lactate and pyruvate metabolism indicative of inadequate myocar- dial oxygenation. The higher level of CO inhalation in this experi- ment is comparable to that experienced intermittently by cigarette smokers. Brewer and his colleagues (11) investigated cigarette smoking as a cause of hypoxemia in residents of Leadville, Colorado, at an altitude of 3,100 meters. The arterial p0, of 8 smokers was signif- icantly lower (P < .05) than that of 12 nonsmokers, but this was reversible upon cessation of smoking. They concluded that the ad- verse effect of cigarette smoking on 0, transport may be especially pronounced at high altitude and may restrict an individual's ability to adapt to reduced 0, tensions (11,12). Kjeldsen (31, 32) examined 993 industrial workers, about one- half of whom were tobacco workers. Fifty-nine cases of arterio- sclerosis were documented by such clinical symptoms as angina pectoris and intermittent claudication or by a previous history of myocardial infarction. While 20.9 percent of the 934 "control" in- dividuals were nonsmokers, only 2 (3.4 percent) of the 59 patients with arteriosclerosis were nonsmokers. A significantly higher per- centage of diseased workers were heavy smokers and inhaled the smoke. 22 The diseased smokers had significantly higher carboxyhemoglobin and serum cholesterol levels than either smoking or nonsmoking control patients. This was true after standardizing for differences in levels of smoking between controls and diseased patients. As ex- pected, there was a gradient in carboxyhemoglobin levels from lower levels in light smokers to higher levels in heavy smokers (table 4). TABLE 4.-Average values of carboxyhemoglobin and serum choles- terol in Danish smokers and nonsmokers in control group and group of patients with arteriosclerotic cardiovascular disease. Smoking category Carboxyhemoglobin Serum cholesterol (saturation percentage) ba/lOO ml) controls patients signifi- controls patients signifi- M?S.D. M%S.D. canee MIS.D. MfS.D. cance Smokers 4223.1 7.043.7 p120 FIGURE Z.-Relative risk of lung cancer in ex-smokers of cigarettes by length of cessation before diagnosis. SOURCE: Graham, S., Levin, M. L. (7). In two recent investigations (9, 13) , both similar in design, the authors described higher rates of lung cancer among Jewish women in Pittsburgh and Montreal than among Catholic and Protestant controls. The proportion of epidermoid and anaplastic carcinomas Was found to be lower for the 87 Jewish women with lung cancer in these studies than for the non-Jewish women. A survey of smoking 63 habits in the two cities suggested that the increased incidence of lung cancer in Jewish women could not be entirely attributed to variations in smoking patterns. A low incidence of lung cancer was found among Jewish males, and this was correlated with their low cigarette consumption. 80 - 74.4 70 - 60 - ; I Smoking duration before cessation More than 31 years 1 Less than 31 years 1 1 01 2-10 (Smoked clgarertes only or with other forms and stopped all.) >lO FIGURE 3.-Relative risk of lung cancer in ex-smokers of cigarettes by length of cessation and previous duration of smoking. SOURCE: Graham, S., Levin, M. L. (7). The increased risk for the development of lung cancer among uranium miners is well established. The 1971 report, "The Health Consequences of Smoking" (39)) summarized the recent investiga- tions in this area. The histologic types of 121 cases of lung cancer in American uranium miners were studied by Saccomanno, et al. (30) using the WHO classification of lung tumors. A marked in- crease was noted in the small cell undifferentiated types with in- 64 creasing radiation exposure. The author examined the role of tobacco in the etiology of these tumors stating, ". . . among uranium miners, cigarette smoking is a potent co-carcinogen in the cause of lung cancer, but exerts little, if any, influence on the cell type of lung cancer. . . ." EXPERIMENTAL ASPECTS Chemicals present in the particulate phase of tobacco smoke have been tested for their carcinogenic potential in experimental animals and/or tissue and organ cultures and have been grouped according to the type of activity observed. On mouse skin, certain chemicals induce tumor formation and are called complete carcinogens; others appear to act only in conjunction with additional treatment, and are referred to as incomplete carcinogens. They include tumor initi- ators and tumor promoters. Tumor initiators induce an irreversible change in epidermal cells which causes them to respond to subse- quent applications of tumor promoters with the development of skin tumors. This two-stage mechanism of carcinogenesis, well known for mouse skin, has not been demonstrated in other animal species or tissues under comparable conditions. Hoffmann and Wynder (11, 44) discussed the major initiators and promoters found in cigarette smoke and described an additional property of acceleration possessed by N-alkylated carbazoles, N-alkylated indoles, and Trans-4, 4'-dichlorostribene (DCS) which is a pyrolysis product of the insecticides DDT and DDD. These compounds are inactive as complete carcinogens, initiators, or pro- moters but accelerate the initiator-promoter activity of polynuclear aromatic hydrocarbons (PAH) . The initiating activity of polycyclic aromatic hydrocarbons in two-stage carcinogenesis was investigated and reviewed by Van Duuren, et al. (41). Several compounds previously thought to be of little or no significance in tobacco carcinogenesis have been found bY Van Duuren and other independent investigators to be tumor initiators. Table 1 lists a number of these compounds. Tumor pro- moting agents probably allow these weak carcinogens to express their tumorigenic potential. Dibenz (a, c) anthracene which was re- ported by Van Duuren, et al. (41) to be an initiating agent was found by Lijinsky, et al. (22) to also act as a complete carcinogen in mouse skin experiments. In another investigation, Van Duuren, et al. (42) confirmed that tobacco smoke condensate is primarily a tumor-promoting agent With weak carcinogenic activity. They also found that benzo(a) - PYrene, a carcinogen in cigarette "tar," acts as a tumor promoter When applied to mouse skin in low doses over a long time period 65 TABLE L-Some initiating agents in two-stage curcinoge~. Compound - t Dibenz (a,c) anthracene t Chrysene t Benz (a) anthracene t 6-Methylanthanthrene Chloromethyl methyl ether Urethan Triethylenemelamine 1,4-Dimethanesulfonoxy-2-butyne -- - t Those found in cigarette smoke. SOURCE: Van Duuren, et al. (41). after the application of an initiating agent. This supports the obser. vation that the tumor-promoting activity of cigarette "tar" may represent the summation of carcinogenic activities of the several carcinogenic aromatic hydrocarbons present in ciggrette "tar." In tobacco carcinogenesis research the choice of `bioassay is of major importance. Mouse and rabbit skin models have been an im. portant source of experimental data concerning tobacco carcino. genesis (44). Several relatively rapid screening bioassays have b&n recently suggested. Major (24) examined the effects of tumor pro. moters and initiators on mouse skin, measuring cell numbers, cell size, mitotic index, and epidermal thickness. Changes found during the first five days were characteristic for different agents. The effects of polycyclic aromatic hydrocarbons on the nonspecific esterase activity in sebaceous glands of mice were examined br Healey, et al. (8). The changes observed were not entirely specific for carcinogenic activity and were probably related more to the toxicity of the painted substances to the sebaceous gland cells. This suggests that further improvement is needed in this system before it can be a practical screening bioassay for potential carcinogenic compounds. Shabad (33) reviewed experimental studies from Russia and else. where relating tobacco with tumor formation, and concluded, ". . . it is indicated that cigarette smoke can actually induce lung cancer in animals." Leuchtenberger and Leuchtenberger (21) have described adeno- mas and adenocarcinomas in the lungs of mice chronically exposed to cigarette smoke. Takayama (36) found that subcutaneous injections of cigarette "tar" in newborn mice produced benign and malignant tumors of the liver, lung, and lymphoid tissue. 66 The compound 7H-Dibenz (c,g) carbazole (7H-DBC) , a compo- nent of cigarette smoke, was tested for its carcinogenic potential on the respiratory tract of Syrian golden hamsters using 15 or 30 intra- tracheal injections per week. Sellakumar and Shubik (32) found a high percentage of squamous tumors of the trachea and bronchi in the tested animals and observed that 7H-DBC appeared to be a potent carcinogen for the respiratory system of hamsters. Krasnyanskaya (18) has examined the effects of chronic expo- sure to cigarette smoke on the respiratory tract of 95 rabbits. One group was pretreated with an intratracheal injection of benz (a) - pyrene. Although premalignant changes were found in treated ani- mals, no malignancies were observed after four years of exposure. OTHER CANCERS The relationships between tobacco smoking in its various forms and cancers of the oral cavity, larynx, esophagus, kidney, urinary bladder, and pancreas were summarized in the 1971 report, "The Health Consequences of Smoking" (39). 1. Cancer of the Larynx a. Epidemiological, experimental, and pathological studies support the conclusion that cigarette smoking is a signif- icant factor in the causation of cancer of the larynx. b. The risk of developing laryngeal cancer among cigarette smokers as well as pipe and/or cigar smokers is signif- cantly higher than among nonsmokers. c. The magnitude of the risk for pipe and cigar smokers is about the same order as that for cigarette smokers, or pos- sibly slightly lower. d. Experimental exposure to the passive inhalation of cig- arette smoke has been observed to produce premalignant and malignant changes in the larynx of hamsters. 2. Cancer of the Oral Cavity a. Epidemiological and experimental studies contribute to the conclusion that smoking is a significant factor in the devel- opment of cancer of the oral cavity and that pipe smoking, alone or in conjunction with other forms of tobacco use, is causally related to cancer of the lip. b. Experimental studies suggest that tobacco extracts and tobacco smoke contain initiators and promoters of cancer- ous changes in the oral cavity, 67 3. Cancer of the Esophagus a. Epidemiological studies have demonstrated that cigarette smoking is associated with the development of cancer of the esophagus. b. The risk of developing esophageal cancer among pipe and/or cigar smokers is greater than that for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly lower. c. Epidemiological studies have also indicated an association between esophageal cancer and alcohol consumption and that alcohol consumption may interact with cigarette smoking. This combination of exposures is associated with especially high rates of cancer of the esophagus. 4. Cancer of the Urinary Bladder a. Epidemiological studies have demonstrated an association of cigarette smoking with cancer of the urinary bladder among men. b. The association of tobacco usage and cancer of the kidney is less clear-cut. c. Clinical and pathological studies have suggested that tobacco smoking may be related to alterations in the me- tabolism of tryptophan and may in this way contribute to the development of urinary tract cancer. 5. Cancer of the Pancreas Epidemiological studies have suggested an association be- tween cigarette smoking and cancer of the pancreas. The significance of the relationship is not clear at this time. Additional relevant epidemiological, pathological, and experi- mental data have been reported. CANCER OF THE LARYNX McNelis and Esparza (23) reported 14 cases of carcinoma in situ of the larynx found among 387 vocal cord biopsies. Thirteen pa- tients were men and with one exception all smoked cigarettes. Lavelle (20) described 11 patients with carcinoma of the larynx which occurred as a second primary cancer at least one year after the successful treatment of an initial primary cancer of the bronchus. "Although it was not possible to ascertain with certainty the smoking habit of all these patients there were no definite non- smokers among them." 68 ORAL CANCER Leukoplakia of the oral mucosa represents a keratinization of surfaces normally unkeratinized. Over a 23-year period, Sugar and Banoczy (35) observed 535 patients with leukoplakia. Of the 324 patients examined in the latest survey, 96 (30 percent) had leukoplakia for more than 10 years. Two hundred sixty-nine pa- tients (83 percent) were smokers. Treatment was ineffective in those patients who continued to smoke. Oral cancer eventually de- veloped in 13 of 48 patients (27 percent) who had severe leukopla- kia. The initial changes in the mouth caused by smoking may not be the hyperkeratotic lesions of leukoplakia. Meyer, Rubinstein, and colleagues (25, 29) examined the effects of smoking on the surface cytology of clinically normal oral mucosa and, in general, found that smoking produced changes in cytoplasm characterized by less mature cell configurations. These changes were most pronounced on those surfaces most directly exposed to the stream of cigarette smoke. Etiological aspects of squamous cancers of the head and neck were reviewed by Wynder (43). There was an increased likelihood of a second primary tumor forming at the site of the first cancer if a patient had been a heavy smoker, or if he continued to smoke, after surgical removal of the first primary. From a preventive point of view it was observed that squamous cell cancers of the head and neck would be comparatively rare in the absence of tobacco and ex- cessive alcohol consumption. Jussawalla and Deshpande (1.5) examined various types of smok- ing and chewing habits in a retrospective investigation of 2,005 patients in Bombay, India, who had histologically established can- cers of the oral cavity, pharynx, larynx, and esophagus. Smokers used either a manufactured cigarette or the Indian "bidi" which contains a small quantity of shredded tobacco rolled in a dried leaf, usually of the Temburni tree (Dtipyros MeZunoxyEon). Chewers used "pan" made with betel leaf, lime, and spices. A small quantity of tobacco was, on occasion, added to this mixture as an optional in- gredient. Smoking and chewing both resulted in an increased risk of cancer at each site examined with a striking increase in risk ob- served in patients who had the combined habits of chewing and smoking (figure 4). The independent contribution of tobacco to the increased risk of cancer at each site could not be clearly isolated as there was no control for chewing when smoking characteristics were examined and vice versa. Intra-oral smoking with the lighted end of a cigar or cigarette inside the mouth is a custom found in parts of the Caribbean, South America, India, and the Island of Sardinia. Morrow and Suarez 69 ($3') examined 79 intra-oral smokers, most of whom had sought medical attention for reasons other than symptoms associated with smoking-related diseases. All but one patient demonstrated "nice. tinic stomatitis" characterized by hyperplasia, acanthosis, hyper. keratosis, and parakeratosis. Sixteen cases of squamous cell carci- noma were found. These were located predominantly at the base of the tongue, tonsillar fauces, and adjacent pharyngeal mucosa. 30 25 Old CHEWING ONLY I SMOKING ONLY El CHEWING AND SMOKING "X Hypcmharynx Larynx Oesophagus FIGWE 4.-Relative risk of cancer of the oral cavity, pharynx, larynx, and esophagus associated with smoking and chewing in various forms. SOURCE: Jussawalla, D. J., Deshpande, V. A. (15). The oral mucosa of many experimental animals appears to be resistant to the induction of cancers. Cohen, et al. (4) failed to pro- duce any distinctive cancerous or precancerous changes in the mucosal lining of surgically created buccal pouches of monkeys filled with chewing tobacco for varying lengths of time. Homburger (1.2) exposed the oral mucosa of Syrian golden hamsters to snuff and 7,12-Dimethylbenz (a) anthracene (DMBA) using a bit inserted-in the mouth. Snuff alone failed to produce any changes that were not also seen in the control animals who had a plain cotton plug inserted in the mouth. Benzo (a) pyrene and DMBA caused a few carcinomas of the oral mucosa, but they produced a much higher number of cancers outside the mouth where the carcinogenic agents had spilled onto the perioral skin. The authors observed that ". . . skin-painting experiments are more sensitive indicators of carcinogenicity for the oral mucosa than applications to the mucosa itself." 70 CANCER OF THE ESOPHAGUS Cancer of the esophagus is associated with both tobacco and al- cohol consumption. In the prospective study from Japan, Hirayama (10) found no significant association between the use of cigarettes or alcohol alone and cancer of the esophagus, but there were high rates of esopha- geal cancer among individuals using both cigarettes and alcohol (figure 5). 30 0 Drinking Daily Smoking Daily Observed Person-years 7.6 4 5.1 4.2 Q-47 0 - I- + 22.5 - - + 27.9 - + 1 , - + ++ - + ++ 66,080 59,062 48,799 95,073 19,422 43,025 FWJRE S.-Death rates for cancer of the esophagus in Japanese males by smok- ing and drinking characteristics. SOURCE : Hirayama, T. (10). Schoenberg, et al. (31) , using cohort analysis, examined mortal- ity from esophageal cancer in the United States. Substantial ethnic, geographic, and temporal variations were observed. On a state-by- Jbte basis, mortality from esophageal cancer was correlated about eWally with urbanization, per capita cigarette sales, and per capita 71 alcohol sales. The correlation with urbanization was partially ex. plained by increased sales of tobacco and alcohol in urban areas. CANCER OF THE URINARY BLADDER In a retrospective study of 470 confirmed cases of transitional cell or squamous cell cancers of the bladder, Cole, et al. (5) found a consistent positive relationship between cigarette smoking and bladder cancer. The relative risk and standard error for the devel. opment of bladder cancer were 1.89 * 0.22 for male smokers and 2.00 t 0.33 for female smokers. A dose-response relationship was demonstrated for both the number of cigarettes smoked per day (figures 6 and 7) and various degrees of inhalation. Bladder cancer has been shown to be associated with certain occupational categories such as dye workers, certain textile workers, tailors, and nurses (2, 14). Cole standardized the data with respect to occupation and found that the risk demonstrated could not be explained by any in- direct association with industrial exposure. Cole concluded : "Thh Observed Expected Number of cigarettes smoked per day 70 36 140 85 109.5 54.6 109.1 61.4 Nonsmoker 1-9 1 o-29 30-49 MALES FIGURE 6.-Relative risk of urinary bladder cancer for males by amount smoked. SOURCE: Cole, P., et al. (5). 72 Observed Expected Number of cigarettes smoked per day 50 13 30 12 68.2 11.7 20.8 4.3 Noosmelcer x-l 1 o-29 30-49 FEMALES FIGURE `I.-Relative risk of urinary bladder cancer for females by amount smoked. SOURCE: Cole, P., et al. (5). present findings indicate that about 35 percent of cases of cancer of the lower urinary tract in the study population are associated with cigarette smoking. If this association is accepted as causal, and if it is generalized to the entire population of the United States, smoking is associated with about 3,100 deaths per year from cancer of the lower urinary tract." No significant association was found between pipe or cigar smoking and bladder cancer. Tyrrell, et al. (38) examined several factors including smoking history and occupation in a group of 250 patients treated for uri- nary bladder cancer in Ireland. No significant association between occupation and bladder cancer was found. This may have been due to the low concentration of high-risk industries for this cancer in Ireland. A significant (P < 0.005) association was found in males between cigarette smoking and cancer of the urinary bladder, but 73 no significant association was found for the 50 cases of bladder cancer in females. In an extensive review of cancer of the urinary tract, Clayson and Cooper (3) included data that demonstrated an association be- tween cigarette smoking and excessive mortality from bladder cancer. CANCER OF THE PANCREAS Cancer of the pancreas was responsible for 9,696 deaths among men and 7,190 deaths among women in the United States in 1967 (4Q). The United States age-adjusted mortality rate for carcinoma of the pancreas has risen from 2.9 to 8.2 per 100,000 from 1920 to 1965 (27). In the prospective Japanese study by Hirayama (IO), the pre- liminary data showed a pancreatic cancer mortality ratio of 2.7 for male smokers and a mortality ratio of 3.0 for female smokers. In an epidemiologic appraisal of cancer of the pancreas, Krain (17') found that cigarette smoking and industrial exposure were more strongly associated with this disease than either air pollution or genetic factors. HIGHLIGHTS OF CURRENT CANCER INFORMATION In addition to the comprehensive summary from the 1971 report, "The Health Consequences of Smoking" (39)) cited earlier in this chapter, the following statements are made to emphasize the most recent developments in the field : 1. Preliminary results from a major prospective epidemiologi- cal study in Japan demonstrate a strong association between cigarette smoking and lung cancer. A dose-response relation- ship was demonstrated for the number of cigarettes smoked. These findings in an Asian population with distinct genetic and cultural characteristics confirm the major importance of cigarette smoking in the causation of lung cancer, a conclu- sion which up to now has been based largely on studies of Caucasian populations in the United States, Canada, and Europe. 2. Ex-smokers have significantly lower death rates for lung can- cer than continuing smokers. The decline in risk following cessation appears to be rapid both for those who have smoked for long periods of time and for those with a shorter smoking 74 3. 4. 5. 6. 7. history, with the sharpest reductions taking place after the first two years of cessation. The risk of developing lung cancer appears to be higher for smokers who have chronic bronchitis. Though both conditions are directly related to the amount and duration of smoking, an additional risk for lung cancer appears to exist for cigarette smokers with chronic bronchitis which is independent of age and number of cigarettes consumed. Experimental studies on animals have demonstrated that the particulate phase of tobacco smoke contains certain chemical compounds which can act as complete carcinogens, tumor ini- tiators, or tumor promoters. Recently, other compounds have been described that have no independent activity in two-stage carcinogenesis but accelerate the carcinogenic effects of poly- nuclear aromatic hydrocarbons in the initiator-promoter system. Additional epidemiological evidence confirms a significant as- sociation between the combined use of cigarettes and alcohol, and cancer of the esophagus. Epidemiological studies have demonstrated a significant asso- ciation between cigarette smoking and cancer of the urinary bladder in both men and women. 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The epidermis and the respiratory tract as bioassay systems in tobacco carcinogenesis. British Journal of Cancer 24 (3) : 574-587, September 1970. 78 CHAPTER 5 Pregnancy Contents Page Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Effect on Birth Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 Effect on the Outcome of Pregnancy . . . . . . . . . . . . . . . . . . . . 83 Congenital Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87 Cancer in Children Born to Smoking Mothers . . . . , . . , . . . 8'7 Long-Term Effects on Children Born to Smoking Mothers . . 88 Experimental Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 LIST OF TABLES Table l.-Frequency of abortion and cigarette consumption 85 81 INTRODUCTION The 1971 report, "The Health Consequences of Smoking" (23)) summarized the relationship between smoking and pregnancy as follows : Maternal smoking during pregnancy exerts a retarding in- fluence on fetal growth as manifested by decreased infant birth weight and an increased incidence of prematurity, de- fined by weight alone. There is strong evidence to support the view that smoking mothers have a significantly greater num- ber of unsuccessful pregnancies due to stillbirth and neonatal death as compared to nonsmoking mothers. There is insuf- ficient evidence to support a comparable statement for abor- tions. The recently published Second Report of the 1958 British Perinatal Mortality Survey, a carefully designed and controlled prospective study involving large numbers of pa- tients, adds further support to these conclusions. New epidemiological, experimental, and pathologic studies lend support to the foregoing statements. EFFECT ON BIRTH WEIGHT Analysis of data from more than 100,000 births has shown that infants of mothers who smoke during pregnancy have a mean birth weight of 6.1 ounces (173 grams) less than infants born to non- smoking mothers (29). Several recent studies confirm this relation- ship (1,2,6, 7,10,13,15,18,25). EFFECT ON THE OUTCOME OF PREGNANCY New studies have been published concerning the effect of maternal smoking on the outcome of pregnancy. Kullander and Kallen (IS) performed a prospective study in Sweden involving 6,363 pregnant women. These women completed several questionnaires during the course of their pregnancy, and in this manner specific information was obtained on smoking habits for the entire pregnancy. Forty-four percent of the women smoked cigarettes during pregnancy and 97 percent of these smoked during the whole pregnancy. 83 Stillbirths, neonatal deaths, and deaths occurring before one year of age were recorded to determine a "total death risk." This risk was approximately 60 percent higher for children born to smoking mothers as compared to those born to nonsmoking mothers. Deaths occurring before one week of age and also deaths taking place between the age of one week and one year were significantly more frequent in children born to smoking mothers. Among children dying before one week of age, significantly more cases of abruptio placentae were found in smoking mothers than in nonsmoking mothers. The higher level of neonatal mortality in children born to smoking mothers was confined to those weighing more than 2,500 grams. Live-born infants weighing less than 2,500 grams had equally high neonatal mortality rates whether they were born to smoking or nonsmoking mothers. The stillbirth rate was greater in smoking mothers than in nonsmoking mothers, but the difference was not statistically significant. An overall increased risk of spontaneous abortion among smoking women was found, but this was primarily due to an association be tween unwanted pregnancy and smoking. The authors found that significantly (P < .OOl) more women with unwanted pregnancies were smokers than women with wanted pregnancies; in addition, spontaneous abortions were significantly (P < .OOl) more frequent among women with unwanted pregnancies than among women with wanted pregnancies. When correction was made for the mothers' acceptance of pregnancy, the contribution of maternal smoking to spontaneous abortion was of only borderline significance. Also in the Kullander and Kallen study (13)) a decreased fre- quency of preeclampsia among smoking mothers was noted. Mater- nal smoking had no effect on the mean Apgar score of surviving, non-malformed children. A prospective study from Sweden of abortions in 4,312 pregnan- cies was reported by Palmgren and Wallander (17). Only those women who smoked throughout pregnancy were considered smokers. The lowest abortion rate was found among nonsmokers, 7.8 percent, while the highest rate was found among heavy smokers, 14.5 per- cent (table 1). The difference is statistically significant (P < .OOl) . Heavier smokers appeared to abort earlier in pregnancy. A history of previous abortion was obtained twice as often in heavy smokers as in nonsmokers. Yerushalmy reported in 1964 on pregnancies occurring in women participating in the Kaiser Health Plan of the San Francisco-Oak- land area (24). The 1971 report, "The Health Consequences of Smoking" (23), commented in detail on that report. Recently, Yerushalmy published data on 13,083 pregnancies occurring in this plan between 1960 and 1967, which included the 6,800 cases pre- viously reported. (24, 25). 84 TABLE L-Frequency of abortion and cigarette consumption. Result of the pregnancy Nonsmokers 510 cigarettes >lO cigarettes Total Abortion 177 148 60 385 7.8% 9.1% 14.5% 8.9% Delivery 2,087 1,486 354 3,927 92.2% 90.9% 85.5% 91.1% Total 2,264 1,634 414 4,312 SOURCE: Palmgren. B., Wallander. B. (17) As in the 1964 study, he again found an increase in the incidence of low birth weight infants (less than 2,500 grams) among smoking mothers. These small infants had a significantly lower neonatal mortality rate and fewer congenital anomalies than the small in- fants born to nonsmoking mothers. The neonatal mortality rate for single, live-born infants born to white, smoking mothers was 11.3/1000, while that for single, live-born infants born to white, nonsmoking mothers was ll.O/lOOO; the difference is not signifi- cant. Taylor analyzed Yerushalmy's data for the probability of fetal death and found no difference between smoking and nonsmoking mothers (22). Some of these findings are different from those reported in the other recent, large-scale prospective studies (5, 13, 17, 19)) and some of the differences may be a consequence of the definition of "smoker" used. In the study of Kullander and KBllen (13), multiple interviews were performed during pregnancy which allowed more precise separation of the pregnant women into smokers and non- smokers. In the study reported by Palmgren and Wallander (17)) only those women who smoked throughout pregnancy were con- sidered smokers. The British Perinatal Mortality Study (5)) which was discussed in the 1971 report, "The Health Consequences of Smoking" (El), defined "smokers" as those women who smoked regularly after the fourth month of pregnancy. The smoking history was obtained shortly after delivery of the infant. In contrast, Yerushalmy (25) defined "smokers" as women who were smoking one or more cigarettes a day during the pregnancy, and "nonsmokers" as women who never smoked and those who stopped smoking either before or during the pregnancy. Because the smoking history was obtained only once, usually early in preg- nancy, some of the women who were classified as smokers could have gone through a significant portion of their pregnancy as non- smokers, and similarly some of the women who were classified as nonsmokers could have gone through a significant portion of their pregnancy as smokers. If smoking by pregnant women increases the risk of an unsuccessful pregnancy, an imprecise separation of preg- nant women into smokers and nonsmokers would tend to diminish the magnitude of any differences found. One Swedish study (13) and the British Perinatal Mortality Study (5) seemed to be at vari- ance in statements about the frequency with which smoking habits vary from one portion of the pregnancy to another. If this is a cul- turally determined phenomenon, there is no way of estimating the extent to which it applies to the patients participating in the Kaiser Health Plan described by Yerushalmy. MacMahon, et al. (14) commented on Yerushalmy's analysis of mortality rates in low birth weight infants. They observed that there are ". . . factors that affect birth weight without influencing mortality ; for example, females have lower birth weights than males but not the higher mortalities that might be predicted for them on that account. If cigarette smoking is another such factor, the explanation of the higher weight-specific mortalities for non- smokers becomes immediately clear : it is an artifact of the analysis. It is meaningful to compare category-specific rates only when the specification of the category has the same implication for each of the populations compared." Perinatal mortality rates were similar in infants born to smoking and nonsmoking mothers in a recent prospective investigation of 1,300 pregnancies from New Zealand (1) . Women were classified as smokers or nonsmokers during their first `booking" at an ante- natal clinic, and this was not later amended. This method of classi- fication is similar to that used in the Yerushalmy study. Comstock, et al. (6, 7) have reported in 1967 and 1971 on the relationship of maternal smoking to the outcome of pregnancy. In their studies, all perinatal deaths and samples of live births occur- ring during a lo-year period among children whose mothers were residents of Washington County, Maryland, were matched against the records of a special census based on a household interview taken in 1963. Maternal smokers were defined as women who were smok- ing in 1963 and who had started to smoke prior to the pregnancy in question; maternal nonsmokers were women who denied ever hav- ing smoked. When this study is compared to previously cited studies (5, 13, 17')) the data on the smoking status of the mothers during pregnancy are imprecise, which limits their value. In the 1967 study (6), maternal smoking was associated with an increased risk of mortality for the child, both in the neonatal period and for several years thereafter; however, this effect was thought to be related to factors such as adequacy of prenatal or postnatal environment and care, rather than a direct effect of maternal smok- ing. Stillbirth rates were similar for smokers and nonsmokers. The more recently published study (7) includes a 32 percent sample of live-born, low birth weight infants and a 3 percent sam- ple of live-born, larger infants born during the lo-year period pre- ceding the census. The total births represented by these samples were 4,641 to smokers and 7,646 to nonsmokers. The neonatal mor- tality rate, when adjusted for environmental and socioeconomic factors, was approximately one-third higher among infants born to smoking mothers than among those born to nonsmoking mothers (7). The categories of asphyxia, atelectasis, and immaturity ac- counted for the greater neonatal mortality among infants born to smoking mothers as compared to those born to nonsmoking mothers (7) * CONGENITAL MALFORMATIONS As noted in the 1971 report, "The Health Consequences of Smok- ing" (zS), the possible teratogenic effect of maternal smoking has not been adequately evaluated. Additional studies have been pub- lished in the interim, but rather than investigating congenital mal- formations in both stillborn and live-born infants, most of the recent studies have dealt only with live-born infants. Fedrick, et al. (8) analyzed data from the large British Perinatal Mortality Study for the incidence of congenital heart disease in still- born and live-born infants of smoking and nonsmoking mothers. An incidence of 7.3/1000 births was found in infants born to smoking mothers as compared to 4.`7/1000 births for infants born to non- smoking mothers, a statistically significant difference (P < .OOl ) . Kullander and Killen (IS) noted no teratogenic effect of maternal smoking in children dying before one year of age or in children surviving one year of age. However, they observed that published studies have been too small to exclude this possibility. In a study of perinatal death occurring in infants weighing more than 1,000 grams, Bailey (1) found that maternal smoking did not lead to an increased incidence of congenital anomalies. Yerushalmy (25) reported only on live-born infants weighing less than 2,500 grams and found significantly fewer (P < .02) anomalies among infants born to smoking mothers. Comstock, et al. (7) found fewer than the expected number of Congenital anomalies among live-born infants of smoking mothers. CANCER IN CHILDREN BORN TO SMOKING MOTHERS Neutel and Buck (16) studied the relationship between maternal Smoking during pregnancy and the development of cancer in the off- spring. The ba+se population was obtained from the British and Ontario Perinatal Studies and consisted of 89,302 babies who sur- 87 vived at least seven days. There were 65 cancer deaths and 32 can. cer survivors in the period from birth to a minimum of 7 and a maximum of 10 years of age. For cancer of all sites, the children of smokers had a relative risk of 1.3. The authors concluded: "Al. though these results make it most unlikely that in utero exposure to tobacco smoke has a broadly carcinogenic effect on the fetus, a re- sponse confined to one tissue or expressed over a narrow age range cannot be ruled out." LONG-TERM EFFECTS ON CHILDREN BORN TO SMOKING MOTHERS Goldstein (9) analyzed data from the British Perinatal Mortality Study to determine factors influencing the height of 7-year-old children. In the 1958 study, information was collected on 16,994 singleton births. In 1965, heights were measured "to the nearest inch" on 13,127 of these children who could be followed up. The dab were analyzed for the influence of parity, birth weight, length of gestation, maternal age, maternal height, social class, number of younger siblings, and maternal smoking habits during pregnancy. Allowance was made for the sex and age of the child at the time of measurement. The author's conclusions included the following: "After allowing for the other variables, the children of mothers who smoked 10 or more cigarettes a day after the 4th month of preg- nancy, are on average about 1.0 cm shorter at age seven than the children of mothers who did not smoke." EXPERIMENTAL STUDIES Becker and Martin (3) continued their experiments concerning the effect of nicotine on pregnant rats. Offspring of rats given nico- tine weighed significantly less at birth than saline-injected controls. There were fewer live births among the nicotine-injected rats. Kelly and Roy (12)) using cinephotomicrography, demonstrated that nicotine crosses the mouse placental barrier in amounts ade- quate to produce a measurable cardiovascular response. Stalhandske, et al. (21) studied the in vitro metabolism of nico- tine in livers of fetal, young, and adult mice. Cotinine was found to be the major metabolite at all ages investigated. Using radioactive compounds, Sieber and Fabro (20) identified a variety of drugs in the preimplantation blastocyst and in uterine secretions of pregnant rabbits. In animals receiving dose levels of nicotine comparable to that encountered in man, significant amounts of radioactivity were found in the preimplantation blastocyet. A markedly higher concentration of radioactivity was observed in uterine secretion than in maternal plasma. Juchau (11) studied the levels of benzpyrene hydroxylase in the placentas of smoking and nonsmoking women obtained both early in pregnancy and at term. This enzyme hydroxylates benzo (a) pyrene, a carcinogenic hydrocarbon found in tobacco smoke. Previous stud- ies had shown that placentas, obtained at term from smoking women, have a greater ability to hydroxylate benzo (a) pyrene than the placentas from nonsmokers (23). Juchau corroborated this, but also found very low levels in placental tissues obtained from healthy smokers during first trimester dilatation and curettage or hystero- tomy for therapeutic abortion. This lack of significant placental drug metabolizing activity during the first trimester was in- terpreted as a possible hazard to the fetus, particularly if the sub- stance were active in the unmetabolized form. Enzyme levels were undetectable in placental homogenates of nonsmokers at 8 to 16 weeks gestation. The carcinogenic effect on the newborn of rats receiving benzo- (a) pyrene during the latter half of pregnancy was studied by Bulay and Wattenberg (4). An increased incidence of pulmonary adenoma and skin papilloma was observed. SUMMARY Maternal smoking during pregnancy exerts a retarding influence on fetal growth as manifested by decreased infant birth weight and an increased incidence of prematurity, defined by weight. There is increasing evidence to support the view that women who smoke during pregnancy have a significantly greater risk of an unsuccess- ful pregnancy than those who do not. PREGNANCY REFERENCES (1) BAILEY, R. R. The effect of maternal smoking on the infant birth weight. New Zealand Medical Journal 71(456) : 293-294, May 1970. (2) BEAL, V. A. Nutritional studies during pregnancy. Journal of the Amer- ican Dietetic Association 58(4) : 321-326, April 1971. (3) BECKER, R. F., MARTIN, J. C. Vital effects of chronic nicotine absorption and chronic hypoxic stress during pregnancy and the nursing period. American Journal of Obstetrics and Gynecology llO(4) : 522-533, June 15, 1971. (4) BULAY, 0. M., WATTENBERC, L. W. Carcinogenic effects of subcutaneous administration of benzo(a)pyrene during pregnancy on the progeny. Proceedings of the Society for Experimental Biology and Medicine 135(l) : 84-86, October 1970. (5) BUTLER, N. R., ALBERMAN, E. D. (Editors). Perinatal Problems. The Second Report of the 1958 British Perinatal Mortality Survey. London, E. and S. Livingstone Limited, 1969. 395 pp. (6) COMSTOCK, G. W., LUNDIN, F. E., JR. Parental smoking and perinatal mortality. American Journal of Obstetrics and Gynecology 98 (5) : 708-718, July 1, 1967. 09 (7) COMSTOCK, G. W., SHAH, F. K., MEYER, M. B., ABBEY, H. Low birth weight and neonatal mortality rate related to maternal smoking and socioeconomic status. American Journal of Obstetrics and Gynecology 111(l) : 53-59, September 1, 1971. (8) FEDRICK, J., ALBERMAN, E. D., GOLDSTEIN, H. Possible teratogenic ef- fect of cigarette smoking. Nature 231: 529-530, June 25, 1971. (9) GOLDSTEIN, H. Factors influencing the height of seven year old children -results from the National Child Development Study. Human Biol- ogy 43: 92-111, February 1971. (10) GOUJARD, J., ETIENNE, C., EVRARD, F. Caracteristiques matemelles et poids de naissance. (Maternal characteristics and birth weight.) Revue du Praticien 19(28, Supplement) : 54, 59-62, 65, November 1, 1969. (11) JUCHAU, M. R. Human placental hydroxylation of 3,Pbenxpyrene duri ing early gestation and at term. Toxicology and Applied Pharmacology lS(3) : 665-675, March 1971. (12) KELLY, M., ROY, F. H. Microcirculatory response of fetal mice to ma- ternal nicotine. (Abstract.) Clinical Research 19( 2) : 322, April 1971. (13) KULLANDER, S., KLLLEN, B. A prospective study of smoking and preg- nancy. Acta Obstetricia et Gynecologica Scandinavica 50(l) : 8%94, 1971. (14) MACMAHON, B., ALPERT, M., SALBER, E. J. Infant weight and parental smoking habits. American Journal of Epidemiology 82(3) : 247-261, November 1965. (15) MURPHY, J. F., MULCAHY, R. The effect of age, parity, and cigarette smoking on baby weight. American Journal of Obstetrics and Gyne- cology 111(l) : 22-25, September 1, 1971. (16) NEUTEL, C. I., BUCK, C. Effect of smoking during pregnancy on the risk of cancer in children. Journal of the National Cancer Institute 47 (1) : 59-63, July 1971. (17) PALMGREN, B., WALLANDER, B. Cigarettriikning oeh abort. Konsekutiv prospektiv undersokning av 4312 graviditeter. (Cigarette smoking and abortion. Consecutive prospective study of 4312 pregnancies) Llkarrtidningen 60 (22) : 2611-2616,197l. (18) PETTERSSON, F. Medicinska skadeverkningar av tikning. Rijkning och gynekologisk-obstetriska tillstand. (Harmful clinical effects of smok- ing. Smoking and gynecological-obstetrical condition.) Social-Medi- cinsk Tidskrift Z(Special No.) : 78-82, February 1971. (19) RUSSELL, C. S., TAYLOR, R., LAW, C. E. Smoking in pregnancy, maternal blood pressure, pregnancy outcome, baby weight and growth, and other related factors. A prospective study. British Journal of Pre- ventive and Social Medicine 22(3) : 119-126, July 1968. (20) SIEBFX, S. M., FABRO, S. Identification of drugs in the preimplantation blastocyst and in the plasma, uterine secretion and urine of the preg- nant rabbit. Journal of Pharmacology and Experimental Therapeutics 176 (1) : 65-75,197l. (2.2 ) STALHANDSKE, T., SL~~NINA, P., TJALVE, H., HANSSON, E., SCHMITERL~W, C. G. Metabolism in vitro of 14C-nicotine in livers of foetal, newborn and young mice. Acta Pharmacologica et Toxicologica 27(5) : 363- 380,1969. (22) TAYLOR, W. F. The probability of fetal death. IN: Fraser, F. C., McKusick, V. A. (Editors). Congenital Malformations. Proceedings of the Third International Conference, The Hague, The Netherlands, September 7-13, 1969. New York, Excerpta Medica, August 1970. pp. 307-320. 90 (28) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of the Surgeon General: 1971. Washington, U.S. Departr ment of Health, Education, and Welfare, DHEW Publication No. (HSM) 71-7513, 1971. 458 pp. (Z4) YEBUSHALMY, J. Mothers' cigarette smoking and survival of infant. American Journal of Obstetrics and Gynecology 88 (4) : 505-518, February 15, 1964. (25) YERUSRALMY, J. The relationship of parents' cigarette smoking to out- come of pregnancy-implications as to the problem of inferring causa- tion from observed associations. American Journal of Epidemiology 93(6) : 443-456, June 1971. 91 CHAPTER 6 Gastrointestinal Disorders Contents Page Highlights of Current Gastrointestinal Information . . . . . . . 98 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 95 GASTROINTESTINAL DISORDERS The 1971 report, "The Health Consequences of Smoking" (4), summarized the relationship between smoking and peptic ulcer as follows : Cigarette smoking males have an increased prevalence of peptic ulcer disease and a greater peptic ulcer mortality ratio. These relationships are stronger for gastric ulcer than for duodenal ulcer. Smoking appears to reduce the effectiveness of standard peptic ulcer treatment and to slow the rate of ulcer healing. Studies of the effect of smoking on gastric secretion in patients with peptic ulcer and normal controls have produced conflicting re- ports (4). Recently, Wilkinson and Johnston (5) reported a sig- nificant inhibition of pentagastrin-stimulated gastric acid secretion after cigarette smoking by normal volunteers, while Debas, et al. (1) found no significant overall change. Wilkinson and Johnston also studied patients with gastric and duodenal ulcers in whom a sig- nificant inhibition of pentagastrin-stimulated gastric secretion was observed after the patients smoked one or two cigarettes over a Period of 10 to 15 minutes. A study by Konturek, et al. (3) suggests that alterations in pancreatic and biliary secretion may be responsible for the relation- ship between smoking and peptic ulcer. Nicotine was infused in mongrel dogs in doses corresponding to amounts absorbed from smoking up to four cigarettes in one hour. In the pancreas, nicotine inhibited the secretin-stimulated secretion of both fluid and bi- carbonate, and the degree of inhibition was dose-related. Spontane- OUs biliary secretion of bicarbonate was also depressed by the drug. Nicotine had no effect on gastric secretion of acid, gastric mucosal blood flow, or the mucosal barrier to hydrogen or sodium ions. This inhibition of pancreatic and hepatic bicarbonate secretion may de- prive the duodenum of sufficient alkaline secretion to neutralize gas- tric acidity and may be one biomechanism linking cigarette smoking and peptic ulcer. Dennish and Caste11 (2) noted the clinical association between cigarette smoking and heartburn. To investigate the biomechanism of this relationship, lower-esophageal sphincter pressure determi- nations were made before and after smoking in six normal male volunteers. All of the volunteers were cigarette smokers. In each 97 subject after the onset of cigarette smoking, there was a rapid d+ crease in lower-esophageal sphincter pressure from the basal level. This diminution in sphincter pressure persisted until smoking was stopped, at which time the pressure returned rapidly toward nor. mal. Mean basal pressure was 19.6 -C 2.1 (C 1 S.E.) mmHg. and mean pressure during smoking was 11.4 2 2.2 mmHg. The differ. ence between these pressures is statistically significant (P < .OOl), No changes were noted when volunteers puffed on unlit cigarettes. Variable responses were noted when volunteers smoked cigars and pipes. The investigators concluded that cigarette smoking decrease the effectiveness of the lower-esophageal sphincter as a barrier against gastroesophageal reflux. HIGHLIGHTS OF CURRENT GASTROINTESTINAL INFORMATION In addition to the summary statement cited at the beginning of this section, the following observations have been made: 1. A possible link between cigarette smoking and peptic ulcer has been demonstrated in dogs in which nicotine was found to in- hibit pancreatic and hepatic bicarbonate secretion. This could lead to peptic disease by depriving the duodenum of suf- ficient alkaline secretion to neutralize gastric acidity. 2. An investigation in human volunteers has suggested that cigarette smoking decreases the effectiveness of the lower- esophageal sphincter as a barrier against gastroesophageal reflux. GASTROINTESTINAL DISORDERS REFERENCES (1) DEBAS, H. T., COHEN, M. M., HOLUBITSKY, I. B., HARMKIN, R. C. Effect of cigarette smoking on human gastric secretory responses. Journal of the British Society of Gastroenterology 12: 93-96, 1971. (2) DFNNISH, G. W., CASTELL, D. 0. Inhibitory effect of smoking on the lower esophagea! sphincter. New England Journal of Medicine 284(20) : 1136-1137, May 20, 1971. (9) KONTUREK, S. J., SOLOMON, T. E., MCCREICHT, W. G., JOHNSON, L. R., JACOBSON, E. D. Effects of nicotine on gastrointestinal secretions. Gastroenterology 60 (6) : 1098-1105, June 1971. (4) U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking. A Report of the Surgeon General: 1971. Washington, U.S. Depart- ment of Health, Education, and Welfare, DHEW Publication No. (HSM) 71-7513, 1971. 458 pp. (5) WILKINSON, A. R., JOHNSTON, D. Inhibitory effect of cigarette smoking on gastric secretion stimulated by pentagastrin in man. Lancet Z(`7725) : 628-632, September 18, 1971. 98 CHAPTER 7 Allergy Introduction ........................................ Antigenic Properties ................................ Skin Testing ....................................... Additional Immunological Effects ..................... Effect on the Immune Response ....................... Irritant and Pharmacologic Effects .................... Clinical Allergy .................................... Summary .......................................... References ...................... .................. Page 103 104 105 107 108 109 110 111 112 101 INTRODUCTION As early as 1886 reference was made to an entity called "tobacco asthma" (64). Subsequently, controversy has arisen over whether tobacco smoking causes clinical allergy (61) and whether such tobacco allergy is associated with the major smoking-related dis- eases (25, 69). In 1957, Silvette, et al. (64) reviewed more than 100 papers con- cerned with "the immunological aspects of tobacco and smoking." They concluded that inadequate animal studies had been performed in this area. Referring to clinical studies, they observed : ". . . virtu- ally all reported clinical investigation has been limited to determi- nations of cutaneous sensitivity to tobacco extracts; and it must be regretfully admitted that much of this published work is equivocal, uncritical, and inadequately controlled." Such criticism is also applicable to many studies published since then. Epidemiologic studies designed to determine the prevalence of tobacco allergy have not been carried out; hence, it is difficult to evaluate the magnitude of the problem. Allergy may be defined as a specific alteration in response medi- ated by an antigen-antibody reaction. When a hereditary suscepti- bility to allergic illness is present, the term atopy is used. For ex- ample, hay fever and asthma are atopic diseases. There is no single test or observation which can be used to de- termine whether a substance may be responsible for allergic dis- ease; however, fulfillment of the following criteria constitutes evi- dence for such a relationship : 1. Demonstration that the substance is antigenic, i.e., capable of stimulating the production of antibody and then reacting with the antibody. 2. Demonstration that, upon exposure to the substance, signs and symptoms simulating an allergic reaction are elicited which disappear upon its removal. 3. Demonstration that the immunologic event is related to the clinical event. Recent advances in the understanding of immunological reactions as well as in the methodology of immunology are now being applied 103 to problems of clinical allergy. For example, Ishizaka (37)) using radioimmunoelectrophoresis, recently reported that the so-called "allergic antibody" (reagin, skin-sensitizing antibody (SSA), atopic antibody) belongs to a new class of immunoglobulins, IgR, Although the skin test remains a simple and definitive method of demonstrating reagins in the allergic patient, there are many vari. ables involved in this technique which must be carefully Weighed when interpreting test results. In the area of tobacco skin testing, such variables include: differences in antigenic content of the test extract, differences in route of administration, and heterogeneity of test groups. ANTIGENIC PROPERTIES Tobacco leaf contains a complex mixture of chemical components including : celluloses, starches, proteins, sugars, alkaloids, pectic substances, hydrocarbons, phenols, fatty acids, isoprenoids, sterols, and inorganic minerals (69). Theoretically, relatively few of these substances should be antigenic. Tobacco extracts of different compo sition result from differences in tobacco types and species, process. ing of tobacco, and preparation of the extract. Harkavy (26) has shown in some patients a differential skin reactivity to extra& from different types of tobacco. Coltoiu, et al. (9) reported that 13 different antigens capable of inducing precipitins in rabbits have been isolated from tobacco pollen. Chu, et al. (7) prepared aqueous extracts of five commercial tobacco products which stimulated anti- body formation in rabbits. The antigens contained in the extracts included both proteins and polysaccharides and had molecular weights ranging from 20,000 to 60,000. Silvette, et al. (64) reviewed several papers dealing with the immunology of nicotine and concluded that nicotine was nonanti- genie. Harkavy (25)) who performed some of the earliest studies on the antigenicity of nicotine, could not exclude the possibility that nicotine may act as a hapten. A hapten is a compound which, al- though not antigenic by itself, reacts with antibody and conveys antigenic specificity when combined with another compound. With pyrolysis many of the tobacco constituents undergo reac- tions involving oxidation, dehydrogenation, cracking, rearrange- ment, and condensation (69). Many new compounds are formed. Pipes (51) demonstrated, through exhaustion of passive transfer reactivity in skin sites, that allergy to tobacco smoke in man is dis- tinct from that of allergy to tobacco leaf. Tobacco smoke exhausted reactivity in sites injected with tobacco smoke sensitized serum; reactivity was reduced but not exhausted with tobacco extract. The converse was true with passive transfer sites of tobacco-sensitized serum; tobacco extracts abolished allergic reactivity whereas to- 104 bacco smoke extract produced a diminution but not total exhaustion. He concluded that it would be useful to test human subjects for both tobacco leaf and tobacco smoke sensitivity. Kreis, et al. (39) have speculated that tobacco leaf antigenicity may be lost with pyrolysis. Coltoiu, et al. (9) recently emphasized the importance of remov- ing all irritants from test extracts. In a clinical setting, allergy to tobacco additives such as menthol has also been suspected (47). SKIN TESTING Intracutaneous injection of test antigen is a widely used method of skin testing. Patch tests have also been used in cases of suspected contact dermatitis. Rosen (54) has observed that skin testing does not accurately duplicate the most common route of exposure to tobacco, i.e., tobacco smoke inhalation. For those involved in the production of tobacco products, inhalation of tobacco dust or direct contact with tobacco may play important roles in sensitization (9). The extensive literature on cutaneous sensitivity to tobacco ex- tracts includes comparisons of the prevalence of positive skin reac- tions in different groups, such as "normal" nonsmoking adults (17, 68) , "normal" smokers (17,33) , allergic patients (59,76), children (41,50), tobacco workers (6,9), and patients with specific diseases, e.g., thromboangiitis obliterans (28, 73). Harkavy reported on tobacco skin reactions in several different groups of patients (30). Many of the apparently discordant results in some of these reports can be traced to failure to compare similar populations or to control for differences in the test antigen or in the method of testing. Sulzberger (66) studied the different types of skin reactions pro- duced by intracutaneous injection of denicotinized tobacco extract. Three types of positive skin responses were observed: eczematous reactions ; immediate wheal-and-flare reactions ; and late reactions, probably of the tuberculin type. The wheal-and-flare response has been by far the predominant type (42). This immediate wheal-and-flare response is a specific immune re- action (64) largely mediated by IgE. Patterson (48) recently pro- posed a simplified model explaining the mechanism of action of the skin sensitizing antibody (SSA) . "Subsequent to stimulation of the animal by antigen, SSA are produced by cells of the lymphoid sys- tem possibly located in the alimentary and respiratory tract. . . . The SSA so produced are secreted in such a way that they reach the cir- culation, where circulating cells, predominantly basophilic leuko- cytes, are sensitized by attachment of the SSA to the cell surface. In addition, the SSA also leave the vascular compartment and sen- sitize mediator-releasing cells in tissues. The tissue cells are pri- marily mast cells . . . The immediate-type allergic reaction occurs 105 when antigen is introduced into the individual sensitized by SSA, either by transfer of antigenic molecules through the respiratory or alimentary mucosal surf ace or by injection into the skin or vascular system. The antigens reach the antibody on the surface of the mast cells and initiate the intracellular events that result in mediator re- lease from the cells." The actions of these mediators include smooth muscle contraction, vasodilation, and increased capillary permeabil-' ity which can produce such clinical pictures as hay fever, asthma, and generalized anaphylaxis. Until recently, direct skin testing and the passive transfer test (Prausnitz-Ktistner reaction) were the only methods of studying IgE mediated responses. In the passive transfer test, serum from an allergic patient is injected into the skin of a normal subject. After a suitable interval the antigen is injected into the prepared site and adjacent normal skin. In a positive response, cutaneous reactivity is transferred to the normal subject at the injection site. The absence of a positive response in nearby normal skin excludes nonspecific irritation as a cause of the response and shows that the normal subject is not himself allergic to the antigen. Harkavy and Witebsky (34) found and selectively absorbed tobacco reagins in patients showing multiple sensitivities. This se- lective absorption documented the immunologic mechanism of the skin reaction. Passive transfer of the SSA was also reported by Peshkin and Landay (50) and by Lima and Rocha (41). Lowell (43) stated, "The individual possessing skin-sensitizing antibody to the tobacco extract may be regarded as unequivocally allergic to the extract. . . ." Despite the inability of Sulzberger and Feit (67) to demonstrate tobacco reagins in their skin test positive patients, several investigators have found them (.26, 50, 75). Harkavy (23) biopsied urticarial wheals after intradermal injec- tion of tobacco extract and found a local eosinophilia. He felt that this helped confirm the allergic mechanism of the positive skin test. He also biopsied the site of a delayed skin reaction to tobacco and found an eczematous type of response. The delayed type hypersensitivity reaction is manifested by in- duration and erythema developing within 24 to 48 hours after injec- tion of antigen. The absence of response in the first 6 to 8 hours after exposure to antigen helps exclude an Arthus reaction, which is also a slowly evolving allergic response. Serum antibodies are not involved in the initiation of delayed type hypersensitivity; rather, the initial step is thought to involve interaction of antigen and spec- ialized lymphocytes (10, 11). Contact dermatitis is thought to be very nearly a pure type, delayed hypersensitivity reaction (10,11) . The foregoing discussion has highlighted the studies concerning cutaneous sensitivity to tobacco extracts. Despite the complexities and contradictions, numerous workers agree that tobacco extract 106 (leaf or smoke) is antigenic and can sensitize (2, 7, 9,18, .26,43, 50, 52, 64, 66, 76). Silvette, et al. (64) concluded, "It is, indeed, beyond question that allergy to tobacco extracts, presumably atopic in na- ture, is an established fact. . . ." Lowell (43) observed that, in most instances, skin reactivity to an extract of tobacco actually means the presence of allergy in some degree to something in the extract. Armen and Cohen (2)) Harkavy and Perlman (31), and Popescu, et al. (52) observed that tobacco extract is weakly antigenic. Armen and Cohen (2) were able to sensitize rabbits to tobacco proteins only after absorbing the pro- tein to aluminum hydroxide, which served as an adjuvant. Even though a positive skin test to tobacco extract may be due to a specific allergic reaction, the interpretation of such a positive test in a given patient or group of patients poses problems, since sen- sitivity to a battery of antigens has been demonstrated in individ- uals who are entirely free from allergic symptoms upon exposure to the antigens. Rosen (54) stated that this lack of correlation be- tween positive skin tests and clinical symptoms is greater for to- bacco than for other antigens such as pollens, dusts, and feathers. He and others have emphasized that the skin test has value only when correlated with clinical evidence. Analysis of skin test studies in nonsmokers (64) shows that ap- proximately 15 percent of such "healthy" individuals give positive reactions to tobacco extracts. Some studies of smokers reporting a 30 percent or more prevalence of skin sensitivity to tobacco ex- tract (33, 43) have considered patients with multiple sensitivities, including that to tobacco. Atopic individuals have been noted to have a greater prevalence of skin sensitivity to tobacco than non- atopics (64) ; hence, in some studies an excess of atopic patients may account for a substantial part of the elevated prevalence of tobacco skin sensitivity reported for smokers. Several workers have sought to use the skin test as a screening device for indicating an unusual susceptibility to the adverse effects of tobacco. DeCrinis, et al. (13), Fontana (l7), and Redisch (53) have reported that patients with positive skin tests to tobacco ex- tracts were more likely to have an adverse vascular response to tobacco as indicated by a fall in peripheral skin temperature on smoking. More recent studies have shown that a decrease in skin temperature with smoking is a reproducible response to nicotine found in "normal" individuals and does not appear to be confined to a specific group of smokers (1,56, 70). ADDITIONAL IMMUNOLOGICAL EFFECTS Additional evidence is available to support the view that tobacco induces immunologic changes in man and animals. Armen and 107 Cohen (2) , Chu, et al. (7)) Harkavy and Perlman (31)) and Zuss- man (76) induced precipitin formation in animals sensitized to tobacco extract. Kreis, et al. (39) studied precipitation reactions in 651 hospitalized patients, many of whom were suffering from tu- berculosis or lung cancer. A precipitation reaction between the pa- tients' sera and a commercial tobacco extract was found in 62.5 per- cent of the patients. Chu, et al. (7)) using the same antigens as those employed to stimulate precipitin formation in rabbits, found serum antibodies in 40 percent of a group of smokers which precipi- tated specificially with the tobacco antigens. Only 7 percent of a group of nonsmokers demonstrated these antibodies. Save1 (59) studied eight nonsmoking, allergic individuals who developed immediate upper respiratory discomfort after being ex- posed to cigarette smoke. As measured by the uptake of tritiated thymidine, the lymphocytes of these individuals were stimulated by cigarette smoke, while "normal" lymphocytes were depressed. The author stated that the correlation of this test with specific forms of clinical allergy remains uncertain. Some investigators have observed abnormal laboratory test re- sults in smokers as compared to nonsmokers, which may indicate an allergic response in the former group. Schoen and Pizer (60) de- scribed a smoking woman who demonstrated a striking blood eosino- philia while smoking cigarettes. Upon cessation of smoking, the eosinophil count returned promptly to normal levels. Resumption of smoking was associated with a return of the eosinophilia. Heiskell, et al. (36) found a significant increase in C-reactive protein and an abnormal seroflocculant for ethyl choledienate in smokers as com- pared to nonsmokers. Plasma histaminase levels were reported by Kameswaran, et al. (38) to be elevated in smokers. Experimental animal sensitization to tobacco was reported by Friedlander, et al. (19) in male rats. Harkavy (29) confirmed these results in male rats and also obtained positive Schultz-Dale reac- tions in the sensitized animals ; however, female rats failed to dem- onstrate this sensitization. Harkavy (24) reported cardiac histo- logical abnormalities in three rabbits sensitized with denicotinized tobacco extracts. The abnormalities found in the three rabbits, re- spectively, included : intimal proliferation, focal fragmentation of the internal elastic membrane, and loss of smooth muscle fibers in the media of a branch of a coronary artery ; focal intimal prolifera- tion and fibrinoid alterations in the media of a small coronary ves- sel ; and a focus of myocardial fibrosis and necrosis. EFFECT ON THE IMMUNE RESPONSE The effect of tobacco on the immune response has received some attention. Early studies in rabbits suggested that tobacco smoke re- 108 tarded the production of agglutinins in rabbits immunized against typhoid (14). A variety of observations indicate that ingestion of antigenic material by the macrophage may be an essential step in the immune response (3). Bruni (5) found that cigarette smoke suppressed phagocytosis in rabbits. Green and Carolin (20) performed in vitro studies in rabbit alveolar macrophages and observed that cigarette smoke inhibited the capacity of these cells to inactivate bacteria. Harris, et al. (35) reported no differences in the phagocytic ability of macrophages taken from human smokers and nonsmokers, but he also concluded that his data neither contradicted nor supported Green's work. Cohen and Cline (8), while noting that macrophages from smokers had normal phagocytic capacity, demonstrated sub- optimal macrophage function in an environment of low 0, tension, a state found more frequently in smokers than nonsmokers. Max- well, et al. (45)) using guinea pigs, found that smoke exerted no effect on phagocytosis; nevertheless, smoke seemed to impair the phagocytes' ability to inactivate bacteria. Nicotine has been shown by Meyer, et al. (46) to exert a depressant effect on sheep pulmo- nary alveolar macrophage respiration and ATPase activity. Re- cently, Yeager (74) reported that water soluble constituents of cigarette smoke depress protein-synthesis in rabbit, alveolar macro- phages in vitro. Lewis, et al. (40) found that cigarette smoking had a suppressive action on secretory IgA production in normal subjects but not in subjects with chronic respiratory disorders. Vos-Brat and Rumke (71) recently reported that IgG serum concentrations and the rp- sponse of lymphocytes to phytohemagglutinin were significant11 lower in smokers than nonsmokers. A number of investigators have reported increased rates of res- piratory illnesses among cigarette smokers (70). Finklea, ,et al. (16) studied antibody response in 289 volunteers after the 1968 Hong Kong influenza epidemic. They reported a significant decrease among cigarette smokers in the persistence of hemagglutination in- hibition antibody after natural infection or vaccination with A, antigens. They postulated that this antibody deficit among cigarette smokers might be related to increased illness during influenza out- breaks. IRRITANT AND PHARMACOLOGIC EFFECTS As Lowell (43) has emphasized, the pharmacologic. irritant, and allergic effects of tobacco are difficult to distinguish. Acrolein and acetaldehyde are potent irritants found in tobacco smoke, which, as demonstrated in animal studies, are capable of releasing chemical mediators such as histamine (58). Th,e inhalation of tobacco smoke 16 causes bronchial constriction, mucus hypersecretion, and ciliary stasis (57) in man, all of which can contribute to a clinical picture indistinguishable from an allergic reaction. Several authors (44,61, 63) share Sherman's (62) view that ". . . tobacco smoke is an im- portant secondary factor in precipitating allergic symptoms through its action as a nonspecific irritant." Speer (65) recently compared the subjective responses of two groups of nonsmokers to tobacco smoke exposure. One group of 191 patients suffered from documented allergies. In one-sixth of these patients a positive skin test to tobacco extract was found, but only a few patients were seen with objective symptoms which could be traced to tobacco smoke. The other group of 250 patients had no history of allergy and was studied by questionnaire only. Eye irrita- tion, nasal symptoms, headache, and cough were common in both groups. Speer concluded that these ,effects of tobacco smoke were irritative rather than allergic in origin. The data presented in this study demonstrate that tobacco smoke can contribute to the dis- comfort of many individuals; they do not rule out a possible con- tribution from allergic reactions. Harkavy (30) cited experimental data distinguishing allergic effects from pharmacologic effects of smoking such as increased heart rate and decreased skin temperature. Additional studies are needed to separate the pharmacologic, ir- ritant, and allergic effects of tobacco smoke. CLINICAL ALLERGY It is important to understand what role tobacco and tobacco smoke may play in clinical allergy because many individuals are exposed to them in varying concentrations throughout the year. A variety of conditions have been ascribed to allergic manifesta- tions toward tobacco leaf or smoke including: asthma, rhinitis, urticaria, angioneurotic edema (giant hives), contact dermatitis, migraine headache, gastrointestinal symptoms, and various cardio- vascular disturbances (64) ; however, some case reports are lacking in documentation (4,49). A small group of patients having cutane- ous sensitivity to tobacco and showing complete disappearance of symptoms when free from exposure to tobacco were reported by Rosen and Levy (55). Included in this group were cases of asthma and urticaria. Studies of atopic individuals have revealed a group of nonsmoking patients with cutaneous sensitivity to tobacco who developed clinical symptoms upon exposure to tobacco smoke (59, 76). In none of these studies (54, 59, 76) have detailed immunologic investigations, attempting to link clinical and immunologic events, been performed. Lowell (43) reviewed case reports of contact dermatitis to to- 110 bacco among tobacco workers and noted that because of ". . . the small proportion of exposed individuals who develop such lesions, and the tendency for it to clear completely when contact with tobacco is avoided and to return on reexposure, an allergic cause in certain instances would appear to be highly probable." Recently, case re- ports have appeared identifying tobacco smoke and tobacco smoke residue as causes of contact dermatitis (6, 12, 7.2). Harkavy's (28) early reports of a greater number of reactors to tobacco extract among patients with thromboangiitis obliterans (TAO) than among controls drew attention to the cardiovascular system as a possible "susceptible" organ for allergic reactions (15). Harkavy continues to be a strong proponent of the role of tobacco allergy in a wide range of cardiovascular abnormalities, including coronary artery disease (21, 22, 25, 27, 31, 32). This view on tobacco allergy as one of the etiological factors in coronary heart disease (CHD) has not received much attention. Silvette, et al. (64) reviewed reports (28, 33, 66, 68, 73) on the prevalence of skin sensitivity in patients with TAO as compared to controls and cited possible reasons for a higher prevalence of posi- tive skin tests to tobacco in these patients. In general, the evidence relating TAO to tobacco allergy is incon- clusive. SUMMARY 1. Tobacco leaf, tobacco pollen, and tobacco smoke are antigenic in man and animals. 2. (a) Skin sensitizing antibodies specific for tobacco antigens have been found frequently in smokers and nonsmokers. They appear to occur more often in allergic individuals. Precipitating antibodies specific for tobacco antigens have also been found in both smokers and nonsmokers. (b) A delayed type of hypersensitivity to tobacco has been demonstrated in man. (c) Tobacco may exert an adverse effect on protective mecha- nisms of the immune system in man and animals. 3. (a) Tobacco smoke can contribute to the discomfort of many individuals. It exerts complex pharmacologic, irritative, and allergic effects, the clinical manifestations of which may be indistinguishable from one another. (b) Exposure to tobacco smoke may produce exacerbation of allergic symptoms in nonsmokers who are suffering from allergies of diverse causes. 4. Little is known about the pathogenesis of tobacco allergy and its possible relationship to other smoking-related diseases. 111 ALLERGYREFERENCES (1) ALLISON, R. D., ROTH, G. M. Central and peripheral vascular effects during cigarette smoking. Archives of Environmental Health 19(2) : 189-198, August 1969. (2) ARMEN, R. N., COHEN, S. 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Annals of Allergy 28(S) : 3'71377, August 1970. 116 CHAPTER 8 Public Exposure to Air Pollution From Tobacco Smoke Contents Page The Extent to which the Components of Cigarette Smoke Contaminate the Atmosphere and are Absorbed by the Nonsmoker . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 The Effects of Low Levels of Carbon Monoxide on Human Health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 Allergic and Irritative Reactions to Cigarette Smoke Among Nonsmokers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 The Known Harmful Effects of the Passive Inhalation of Cigarette Smoke in Animals . . . . . . . . . . . . . . . . . . . . . . . . 129 summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 LIST OF TABLES Table l.-Percent of COHb during and following exposure to50p.p.m.of CO . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 Table 2.-Effects of carbon monoxide . . . . . . . . . . . . . . . . . 127 119 PUBLIC EXPOSURE TO AIR POLLUTION FROM TOBACCO SMOKE The purpose of this chapter is to summarize the present state of evidence concerning the effects of exposure to an atmosphere con- taining either tobacco smoke or its constituents. Since the identifi- cation of cigarette smoking as a serious health hazard to the smoker was based on clinical and epider;iological observations that non- smokers have much lower mortality and morbidity rates from a number of conditions, it is obvious that cigarette smoking is nor- mally a greater hazard to the smoker than is the typical level of ex- posure to air pollutants produced by the smoking of cigarettes which many nonsmokers experience. This would be consistent with the voluminous data which show a dose-response relationship between the level of exposure to smoke and the magnitude of its effect. The research so far reported on the nature and effects of exposure to smoke-pollutants in the atmosphere has not been as extensive and well-controlled as that done on the health effects of smoking on the smoker himself. Knowledge on this subject can be separated into four major areas of concern : 1. The extent to which the components of cigarette smoke con- taminate the atmosphere and are absorbed by the nonsmoker. 2. The effects of low levels of carbon monoxide on human health. 3. Allergic, adverse, and irritative reactions to cigarette smoke among nonsmokers. 4. The known harmful effects of the passive inhalation of ciga- rette smoke in animals. THEEXTENTTOWHICHTHE COMPONENTSOF CIGARETTE SMOKE CONTAMINATE THE ATMOSPHERE AND ARE ABSORBED BY THE NONSMOKER Theoretical models of this contamination have been constructed. Owens and Rossano (44) have noted that most popular cigarettes release into the atmosphere approximately 70 mg. of dry particulate matter (about 60 mg. in the sidestream and slightly over 20 mg. in the mainstream, about one-half of the latter being absorbed by the smoker and one-half expelled into the ambient air) and 23 mg. car- 121 bon monoxide per cigarette. This material adds to the cleaning problem of the air of any enclosed space and contributes to residual odors. In a recent study of particulate matter filtration in domestic premises (35), the authors observed that the smoking of one cigar completely overcame the effect of an electrostatic filtration device for one hour. Atmospheric pollutants caused by smoking are derived from two major sources : mainstream and sidestream smoke. Mainstream smoke emerges from the tobacco product through the mouthpiece during puffing, whereas sidestream smoke comes from the burning cone and from the mouthpiece during puff intermissions (60). The tobacco smoke released into the atmosphere consists of all the side- stream smoke as well as that part of the mainstream smoke which has been either held in the smoker's mouth or taken into his lungs and then expelled. The actual amount of material to which individ- uals are exposed in the presence of smokers depends upon the amount of smoke produced, the depth of inhalation on the part of the smoker, the ventilation available for the removal or dispersion of the smoke, and the proximity of the individual to the smoker. The length of time of exposure to those pollutants is extremely impor- tant in determining how much is absorbed into the body. The pat- tern of smoking influences the amount produced by altering the content of the exhaled smoke. As shown by Dalhamn, et al. (10, 11) , mouth absorption removes approximately 60 percent of the water-soluble volatile components (e.g., acetaldehyde) , 20 percent of the nonwater-soluble volatile components (e.g., isoprene), 16 percent of the particulate matter, and only three percent of the car- bon monoxide. Thus, the smoker who does not inhale "filters" a portion of the smoke components in his mouth before expelling them into the ambient air. On the other hand, the lungs retain from 86 to 99 percent of the volatile and particulate substances and approxi- mately 54 percent of the carbon monoxide inhaled. Hence, the inhal- ing smoker "filters" the mainstream smoke rather effectively before expelling it into the ambient air. A factor which has apparently not been investigated is the difference in the smokers' "filtration" of mainstream smoke when the smoke is exhaled through the nose instead of the mouth. Thus, the nonsmoker breathes smoke-containing air composed of sidestream smoke and mainstream smoke exhaled by smokers. The inhaling smoker receives nearly the full amount of mainstream smoke as well as a portion of sidestream smoke and smoke exhaled by himself and other smokers. The smoker who does not inhale re- ceives those compounds which are absorbed from the mainstream smoke in his mouth, as well as absorbing the sidestream smoke and the smoke exhaled by himself and other smokers contained in the air he breathes. 122 Since pipe and cigar smokers inhale less commonly than do ciga- rette smokers, their contribution to the substances in the air breathed in exposure to smoke pollutants consists of a composite of sidestream smoke and relatively unfiltered mainstream smoke which has been held in the mouth and then expelled. The actual effluents in the mainstream and sidestream cigarette smoke have been considered by Pascasio, et al. (45) and Scassellati Sforzolini and colleagues (50, 51) . These authors stated that "tar" and nicotine levels in sidestream smoke may be significantly higher than those of mainstream smoke and may be harmful to the non- smoker. Actual volume measurements were not reported, however. Actual measurements of the contamination due to cigarette smok- ing have been carried out by a number of research groups. A recent, well-controlled study by Harke (24) involved the smoking of 42 cigarettes in 16 to 18 minutes using German blend cigarettes of 85 mm. length, 18 mm. filter, and smoked to a 25 mm. butt length in a room with a volume of 57 cubic meters (approximately the equivalent of a room with a lo-foot ceiling and dimensipns of 12 by 14 feet). The author observed that in the absence of ventilation the atmosphere contained up to 50 p.p.m. carbon monoxide and 57 mg./m.3 nicotine. With substantial ventilation, these levels fell sig- nificantly (to approximately 10 p.p.m. carbon monoxide and JO mg./m.3 nicotine). He also found that cigar smoke (9 cigars of Clear Sumatra tobacco smoked in 30 to 35 minutes) produced similar amounts of contamination while pipe smoke (3 grams of Navy type medium cut tobacco smoked as eight pipefuls in 35 to 40 minutes) produced much less. Other authors have made similar measure- ments. Galuskinova (20) found that 3,kbenzpyrene levels in a smoky restaurant were from 2.82 to 14.4 mg./lOO m." as compared to outside atmospheric levels of 0.28 to 0.46 mg./lOO m.", although burning of food particles may have contributed to the presence of 3,4benzpyrene in this setting. Kotin and Falk (33) have shown that sidestream cigarette smoke condensate may contain more than three times as much benzo(a)pyrene as mainstream smoke. Srch (55) observed that the smoking of 10 cigarettes to a 5 mm. butt length in an enclosed car of 2.09 m.3 volume produced carbon monox- ide levels up to 90 p.p.m. Lawther and Commins (3.4)) working with a ventilated chamber, found levels of up to 20 p.p.m. of carbon mo- noxide after seven cigarettes were smoked in one hour; however, peaks of up to 90 p.p.m. were recorded at the seat next to the smoker. Coburn, et al. (9) recorded levels of 20 p.p.m. of carbon monoxide in a small conference room after 10 cigarettes were "burned." Harmsen and Effenberger (25) reported up to 80 p.p.m. of carbon monoxide in an enclosed 98 m.3 room (approximately the equivalent of a room with a lo-foot ceiling and dimensions of 18 by 20 feet) in which 62 cigarettes had been smoked in two hours. 123 TABLE 1 .-Percent of COHb during and following exposure to 50 p.p.?n. of co. Time during exposure Mean Range Number of subjects Preexposure 0.7 0.4-1.5 11 30 minutes 1.3 1.3 3 1 hour 2.1 1.9-2.7 11 3 hours 3.8 3.6-4.2 10 6 hours 5.1 4.9-5.5 5 8 hours 5.9 5.4-6.2 5 12 hours 7.0 6.5-7.9 3 15 `/z hours 7.6 7.2-8.2 3 22 hours 8.5 8.1-8.7 3 24 hours 7.9 7.6-8.2 3 Time without exposure after 1 hour of exposure 30 minutes 1 hour 2 hours 5 hours Time without exposure after 3 hours of exposure 30 minutes 1 hour 2 hours Time without exposure after 8 hours of exposure 30 minutes 1 hour 1 i hours 11 hours Time without exposure after 24 hours of exposure 30 minutes 1 hour 2 hours SOURCE: stewart, et al. (56). 1.8 1.8 3 1.7 1.6-1.8 3 1.5 1.4-1.5 3 1.1 1.0-1.1 2 3.7 3.4-3.9 3 3.3 2.7-3.8 3 2.7 2.3-3.0 3 5.6 5.1-5.9 3 5.1 4.8-5.4 3 4.0 - - 1.5 1.4-1.7 3 7.5 7.2-7.8 3 6.7 6.4-7.1 3 5.8 5.6-6.2 3 Another set of contaminants probably present in a tobacco smoke- polluted atmosphere are the oxides of nitrogen. These, specificially NO and NO,, have been shown to be present in tobacco smoke al- though the type most likely to be present in the atmosphere is NO,. No measurements have been reported of the amount of NO, in smoke-filled rooms. The importance of obtaining and evaluating this information is stressed by the results of Freeman and Haydon and 124 their colleagues (17, 18, 19, 27, 28) and of Blair, et al. (5) who ob- served bronchial and pulmonary parenchymal lesions in rodents continuously exposed to low levels of NO,. Other experimenters have measured carboxyhemoglobin ( COHb) levels in nonsmokers exposed to cigarette smoke pollutants. Srch (55) observed that the COHb level in two nonsmokers rose from 2 to 5 percent (that of smokers from 5 to 10 percent) when seated in the cigarette-smoke contaminated car mentioned above (exposure to 90 p.p.m.) . Harke (2.4) reported that when seven nonsmokers were exposed for approximately 90 minutes to a "smoked" room containing 30 p.p.m. of CO there was a rise in COHb from a mean of 0.9 percent to 2.0 percent. In 11 smokers subjected to the same conditions, COHb rose from a mean of 3.3 percent to 7.5 percent. With improved ventilation of the experimental room, the COHb level decreased significantly. The CO exposures and COHb levels reported above closely approx- imate the results obtained following experimental chamber expo- sure of humans to various levels of CO. The uptake of CO by the person depends on, among other parameters: CO concentration, previous COHb level, the level of activity, and the person's state of health. Equilibrium between CO concentration in the lung and in the blood requires over 12 hours exposure. However, as may be noted in table 1, reproduced from Stewart, et al. (56) and derived from measures of COHb in young sedentary males who were not smoking, over half of the equilibrium COHb level is reached within three to four hours of the onset of exposure. The equilibrium value associated with 100 p.p.m. is approximately 14 to 15 percent COHb. Exposure to 100 p.p.m. in the nonsmoker can lead to 3.0 percent of COHb within 60 minutes and 6.0 percent in two hours (16). Of equal significance is that COHb has a half-life of at least three to four hours in the body. As shown in table 1, the COHb level fell only to 2.7 percent in the two hours following cessation of exposure to 50 p.p.m. from the end exposure level of 3.7 percent. This lengthy half- life extends the period of effect of exposure to CO and provides for a buildup of COHb concentration from fresh exposures. THE EFFECTS OF LOW LEVELS OF CARBON MONOXIDE ON HUMAN HEALTH The data on the effect of low levels of carbon monoxide on human psychological and physiological function have been summarized in two recent publications (8,58). There is presently much discussion as to the physiologic and Psychophysiologic effects of exposure to levels of CO approximating 50 to 100 p.p.m. Beard and Grandstaff (I) observed that exposure to 50 p.p.m. of CO for from 2'7 to 90 minutes altered auditory dis- 125 crimination, visual acuity, and the ability to distinguish relative brightness. McFarland (40) observed that COHb levels of 4 to 5 percent caused visual threshold impairment. Ray and Rockwell (48), reporting on a study of the driving ability of three subjects under varying CO exposure, observed that the presence of 10 per- cent COHb was associated with increased response time for tail- light discrimination and increased variance in distance estimation. Schulte (52) observed that increased errors in cognitive and choice discrimination tests were manifest at levels of COHb as low as 3 percent. Chevalier, et al. (7) have also observed that levels of 4 percent COHb in nonsmokers are associated with an increase in oxygen debt formation with exercise similar to that seen in smokers. On the other hand, other investigators utilizing complex psychomotor tasks in men and monkeys have observed no decrement in function upon exposures to CO at 50 to 250 p.p.m. (2, S, 23, 41, 56). Animals exposed to low levels of CO ( 50 to 100 p.p.m.) continu- ously for weeks have shown varying degrees of cardiac and cerebral damage similar to that produced by hypoxia (21,47,57). Finally, the possible effects of exposure to 50-100 p.p.m. CO on patients with coronary heart disease (CHD) were investigated by Ayres, et al. (1) who observed a decrease in arterial and mixed venous oxygen tensions with COHb saturations of 5 percent. Certain patients with CHD developed altered lactate and pyruvate metabo- lism with COHb levels of 5 to 10 percent suggesting myocardial hypoxia. The evidence concerning the effect of low levels of carbon monox- ide has recently been reviewed and evaluated by the National Air Quality Criteria Committee of the National Air Pollution Control Administration (58). The following is taken from the published conclusions of the Advisory Committee (also see table 2) : "Experimental exposure of nonsmokers to 58 mg/m3 (50 ppm) for 90 minutes has been associated with impairment in time-interval discrimination. . . . This exposure will produce an increase of about 2 percent COHb in the blood. This same increase in blood COHb will occur with continuous exposure to 12 to 17 mg/m3 (10 to 15 ppm) for 8 or more hours.. . . "Experimental exposure to CO concentrations sufficient to produce blood COHb levels of about 5 percent (a level pro- ducible by exposure to about 35 mg/m3 for 8 or more hours) has provided in some instances evidence of impaired perform- ance on certain other psychomotor tests, and an impairment in visual discrimination. . . . "Experimental exposure to CO concentrations sufficient to produce blood COHb levels above 5 percent (a level producible 126 TABLE 2.-Effects of carbon monoxide. E~Vi~OIlm.3Ital conditions Effect Comment 58 mgJm.3 (50 p.p.m.) Impairment of time- Blood COHb levels not for 90 minutes interval discrimination available, but antici- in non-smokers. pated to be about 2.5 percent. Similar blood COHb levels expected from exposure to 10 to 17 mg./m.J (10 to 15 1l.p.m.) for 8 or more hours. 115 mg./m.3 (100 p.p.m.) intermit- tently through a facial mask Impairment in perform- Similar results may have ante of some psycho- been observed at lower motor tests at a COHb COHb levels, but blood level of 5 percent. measurements were not accurate. High concentrations of CO were admin- istered for 30 to 120 seconds, and then 10 minutes was allowed for washout of alveolar CO before blood COHb was Exposure sufficient to pro- Data rely on COHb levels duce blood COHb levels produced rapidly after above 5 percent has been short exposure to high shown to place a physio- levels of CO; this is not logic stress on patients necessarily comparable with heart disease. to exposure over a longer time period or under equilibrium conditions. measured. SOURCE: Adapted from U.S. Public Health Service, Air Quality Criteria for Carbon Monoxide. Washington, D.C., U.S. Department of Health, Education, and Welfare (58). by exposure to 35 mg/m3 or more for 8 or more hours) has provided evidence of physiologic stress in patients with heart disease. . . ." The levels of carbon monoxide found to be present in "smoked" rooms (20 to 80 p.p.m.) are similar to the levels (30 to 50 p.p.m.) which the Advisory Committee has concluded are associated with adverse health effects : "An exposure of 8 or more hours to a carbon monoxide con- centration of 12 to 17 mg/m3 (10 to 15 ppm) will produce a blood carboxyhemoglobin level of 2.0 to 2.5 percent in non- smokers. This level of blood carboxyhemoglobin has been asso- ciated with adverse health effects as manifested by impaired time interval discrimination. Evidence also indicates that an exposure of 8 or more hours to a CO concentration of 35 mg/m3 (30 ppm) will produce blood carboxyhemoglobin levels of about 5 percent in nonsmokers. Adverse health effects as man- ifested by impaired performance on certain other psychomotor 127 tests have been associated with this blood carboxyhemoglo- bin level, and above this level there is evidence of physiologic stress in patients with heart disease." These levels of CO are also similar to that set as the time- weighted occupational Threshold Limit Value of 50 p.p.m. for a 40-hour week (five f&hour days) which has been in effect in the United States for the past several years (13). A further reduction in this limit to 25 p.p.m. is now under consideration. These levels of CO exceed those recently set by the Environmental Protection Agency as the national primary and secondary ambient air quality standards for CO (1.4). These standards are: (a) 10 milligrams per cubic meter (9 p.p.m.) -maximum 8- hours concentration not to be exceeded more than once per year. (b) 40 milligrams per cubic meter (35 p.p.m.) -maximum l-hour concentration not to be exceeded more than once per year. ALLERGIC AND IRRITATIVE REACTIONS TO CIGARETTE SMOKE AMONG NONSMOKERS (A more detailed discussion of this subject is presented in the Allergy chapter of this report.) Several investigators have reported on the discomfort and symp- toms experienced by both allergic and nonallergic individuals upon exposure to tobacco smoke. Johansson and Ronge (S1,32) in 1965 and 1966 have observed that the acute irritation experienced by nonsmokers in the presence of tobacco smoke is maximal in warm, dry air and that nonsmokers experience more nasal irritation than ocular irritation as compared with smokers exposed to similar amounts of smoke in the atmosphere. Speer (5.4) studied the reac- tions of 441 nonsmokers divided into two groups, one composed of individuals with a history of allergic reactions and the other of in- dividuals without such a history. The allergic group underwent skin testing for the presence of sensitivity to tobacco extract while the "nonallergic" group was determined solely by questionnaire con- cerning subjective allergic responses. Approximately `70 percent of both groups experienced eye irritation while other symptoms dif- fered in their frequency from group to group (nasal symptoms: allergic 67 percent, "nonallergic" 29 percent ; headache : allergic 46 percent, "nonallergic" 31 percent ; cough : allergic 46 percent, "non- allergic" 25 percent ; and wheezing: allergic 22 percent, "nonaller- gic" 4 percent). Thus, a significant proportion of nonsmoking in- dividuals report discomfort and respiratory symptoms on exposure to tobacco smoke. 128 Other authors have attempted to separate out those patients who may have specific allergies to smoke. Zussman (61) found that in a random series of 200 atopic patients 16 percent were clinically sen- sitive to tobacco smoke, and that a majority of these were aided by desensitization therapy. In an earlier study, Pipes (46) observed that 13 percent of 229 patients with respiratory allergy showed posi- tive skin tests to tobacco smoke. Save1 (49) has recently reported on eight nonsmokers observed to be clinically hypersensitive to tobacco smoke. After in vitro incubation of their lymphocytes with cigarette smoke, increased incorporation of tritiated thymidine was recorded ; similar exposure of the lymphocytes of those not sensitive resulted in depression of tritiated thymidine uptake. Luquette, et al. (39) have recently reported on the immediate ef- fects of exposure to cigarette smoke in school-age children. They observed that heart rate and blood pressure rose with such ex- posure, although questions remain about the adequacy of their con- trols .and the manner in which the experimental situation may have excited the subjects, Finally, Cameron, et al. (6) observed that acute respiratory illnesses were more frequent among children from homes in which the parents smoked than among children of non- smoking parents. The meaning of these results is uncertain since smoking by the children was not considered and the level of ex- posure to cigarette smoke in their homes was not measured. Shy, et al. (53) in a study of second grade Chattanooga school children failed to demonstrate a relationship between parental smoking habits and the respiratory illness rates of their children. THE KNOWN HARMFUL EFFECTS OF THE PASSIVE INHALATION OF CIGARETTE SMOKE IN ANIMALS A number of investigators have studied the effects of the passive inhalation of high concentrations of cigarette smoke on the pulmo- nary parenchyma and tracheobronchial tree of animals. The results of these investigations are listed in detail in the recent report to Congress, "The Health Consequences of Smoking," (59) in table 9 of the Bronchopulmonary chapter, and table 16 of the Cancer chapter. The pathologic changes observed in the respiratory tract of the animals included parenchymal disruption, bronchitis, tracheobron- chial epithelial dysplasia and metaplasia, and pulmonary adenoma- tous tumor formation. Leuchtenberger, et al. (36) exposed 151 mice to the smoke of from 25 to 1,526 cigarettes over a period of 1 to 23 months and observed that 20 percent of the animals developed severe bronchitis with atypism. Working with 30 control rabbits exposed to up to 20 cigarettes per day for two to five years, Holland, et al. (30) observed increased focal and generalized hyperplasia of 129 the bronchial epithelium and generalized emphysema in the ex- posed rabbits. Hernandez, et al. (29) observed significantly more pulmonary parenchymal disruption in adult greyhound dogs ex- posed to cigarette smoke 10 times per week for approximately one year than in nonexposed control animals. Lorenz, et al. (38) observed no increase in respiratory tract tu- mor formation above that seen in controls in 97 Strain A mice ex- posed to cigarette smoke for up to 693 hours. Essenberg (15)) how- ever, exposed Strain A mice to cigarette smoke for 12 hours a day for up to one year and observed significantly more papillary adeno- carcinomas in the exposed than in the control group. An increased percentage of hybrid mice were found by Miihlbock (42) to have alveolar carcinomas among the experimental group exposed to smoke for two hours a day for up to 684 days when compared with a nonexposed group. Similarly, Guerin (22) observed that 5.1 per- cent of rats exposed to cigarette smoke for 45 minutes a day for two to six months showed pulmonary tumors compared to 2.4 per- cent of the control mice. Leuchtenberger, et al. (37)) working with 400 female CF, mice, observed only a slight increase in the presence of pulmonary adeno- matous tumors among those exposed to cigarette smoke compared with those in the control group. The authors commented that the presence of tumors showed an age relationship independent of smoking exposure. Otto (.43) found that 11 percent of a group of albino mice exposed to 12 cigarettes a day for up to 24 months showed pulmonary adenomas as compared with five percent of the control non-exposed group. Dontenwill and Wiebecke (12) found that increasing the exposure of golden hamsters to up to four ciga- rettes a day for up to two years was associated with an increasing percentage of animals showing desquamative metaplasia and bron- chial papillary metaplasia. Harris and Negroni (26) exposed 200 C5'7BL mice to cigarette smoke for 20 minutes a day every other day for life and found eight adenocarcinomas as compared to none in the control group. Because the damage observed in these experiments was seen after prolonged exposure to high concentrations of cigarette smoke, and because the comparability of animal exposure to smoke with that of human exposure in smoke-filled rooms is unknown, it is presently impossible to be certain from animal experimentation about the ex- tent of the damage that may occur during long-term intermittent exposure to lower concentrations. SUMMARY 1. An atmosphere contaminated with tobacco smoke can con- tribute to the discomfort of many individuals. 130 2. The level of carbon monoxide attained in experiments using rooms filled with tobacco smoke has been shown to equal, and at times to exceed, the legal limits for maximum air pollution per- mitted for ambient air quality in several localities and can also ex- ceed the occupational Threshold Limit Value for a normal work period presently in effect for the United States as a whole. The pres- ence of such levels indicates that the effect of exposure to carbon monoxide may on occasion, depending upon the length of exposure, be sufficient to be harmful to the health of an exposed person. This would be particularly significant for people who are already suffer- ing from chronic bronchopulmonary disease and coronary heart disease. 3. Other components of tobacco smoke, such as particulate mat- ter and the oxides of nitrogen, have been shown in various concen- trations to adversely affect animal pulmonary and cardiac structure and function. 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Annals of Allergy 28(8) : 371-377, August 1970. 135 CHAPTER 9 Harmful Constituents of Cigarette Smoke Contents Page The Dose Relationship 141 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 LIST OF TABLES Table l.-Compounds in cigarette smoke judged most likely to contribute to the health hazards of smoking , . . . . . . . . . 143 Table 2.-Compounds in cigarette smoke judged as probable contributors to the health hazards of smoking . . . . . . . . . . 144 Table 3.-Compounds in cigarette smoke judged as suspected contributors to the health hazards of smoking , . . . . . . . . . 145 139 HARMFUL CONSTITUENTS OF CIGARETTE SMOKE* Cigarette smoke contains a large number and a wide variety of compounds which may result in complex and multiple pathophysio- logical effects on various tissues and organ systems. Although the constituents of cigarette smoke are usually divided for convenience into the two categories of particulate and gas phases,** many of them exist in a distribution equilibrium, that is, they are present partially in the gas phase and partially in the particulate phase. This review concerns itself with judgments concerning the harmful constituents of cigarette smoke whether these are found primarily in the gas phase or in the particulate phase. Constituents of cigarette smoke may enter the body by a variety of routes. Theoretically, the route of entry and subsequent absorp- tion could affect the degree to which various organs are subjected to specific cigarette smoke constituents. Some constituents, par- ticularly the water soluble components of the gas phase, may be absorbed by the nasal and oropharyngeal mucous membranes, or may be dissolved in the saliva and swallowed, thus allowing for pos- sible gastric or intestinal absorption. Other constituents are ab- sorbed along the tracheobronchial tree, and the distance which they reach before being absorbed or deposited depends on such factors as the depth of inhalation and the particle size. The absorption of gases in the tracheobronchial tree appears to be in part dependent on the adsorption of gases to particulate matter. Another factor affecting the route and degree of absorption is the adequacy of pulmonary clearance by which constituents deposited or dissolved in the mucous sheath are delivered to the pharynx and then usually swallowed. Of the hundreds of compounds identified in cigarette smoke, some occur in the smoke in concentrations which may be considered suf- ficient to present hazards to health. Other compounds appear in o This report attempts to swnmarise the areas of general consensus reached in a special one- day conference ?? experts in this field which met in June 19'70. This is not to imply that there was unanimous agreement on all statements contained herein. A list of participants in the meet- ing appears in the Acknowledgments. o * It should be noted that there is. at present, no available instrumentation permitting the separation and individual collection of the particulate and gas phases which duplicates the precise physieochemical conditions prevailing in cigarette smoke as it is inhaled. A widely ae- cepted arbitrary distinction between the two phases is as follows: If 50 percent or more of a given constituent is retained on a Cambridge Alter (CM-l 13) during standardized machine smok- ing of a cigarette, then the compound is considered to belong to the particulate phase: if on the other hand more than 60 percent of the compound passes through the Cambridge filter under these conditions, then the constituent is considered to belong to the gas phase. 141 borderline concentrations. Still others, although potentially harm- ful, are probably not present in sufficient concentrations to con- tribute to the hazard, and some may be hazardous only when they interact with other substances in the smoke. Substances and classes of substances in cigarette smoke which have been judged to contribute to the hazard of cigarette smoking have been classified into three priority groups. Those compounds which are judged most likely to contribute to the health hazards of smoking are listed in table 1. Additional substances which probably contribute to the health hazards of smoking are listed in table 2. Those compounds which are suspected contributors to the health hazards of smoking in the concentrations in which they are present in tobacco smoke are listed in table 3. Many other constituents of tobacco smoke are considered to be toxic under some conditions but probably do not present a health hazard in the concentrations in which they are generally found in cigarette smoke; these are not listed. This listing is not presented as final, and *may be subject to modification as more information becomes available.* In 1966, the Public Health Service prepared a technical report on "tar" and nicotine (60). Tobacco "tar" is the name given to the ag- gregate of particulate matter in cigarette smoke after subtracting nicotine and moisture. In that report it was stated: "It is clear that the overall risk associated with cigarette smoking increases as the average number of cigarettes con- sumed per day increases. In the studies which have reported other measures of exposure such as pack-years, degree of in- halation, and maximum level of cigarette consumption, the same type of relationship holds." Individuals may differ in their inherent susceptibility to diseases in which cigarette smoking plays a role and differ in their exposure to other factors which may increase the likelihood of these diseases. Within these groups of varying risk, the degree of exposure to ciga- rette smoke appears to be the most critical factor for the develop- ment of smoking related disease. Therefore, the general statement that the lower the dosage the lower the risk is the most useful guide available. It was also stated that : "It is possible for a cigarette to be altered in such a way that its `tar' and nicotine content is reduced but certain other harmful effects, for example the effect of the gaseous phase, may be increased. Although this is a theoretical possibility, o Subsequent to the conference on which this report was based. several studies were published reporting the presence of N-nitrosamines in cigarette smoke. Since these substances are accepted as carcinogens in experimental animals, they represent another portion of the "tar" which probably contributes to the total health hazard (18, 24). 142 there is no evidence that this has occurred to any serious degree." The consensus is that there is inadequate evidence to support a change in that view at the present time. In addition, it was concluded that "the preponderance of scientific evidence strongly suggests that the lower the `tar' and nicotine con- tent of cigarette smoke, the less harmful would be the effect." Sev- eral studies reported since that time have added strong support to this position. The present review is an attempt to identify those constituents of the "tar" as well as those constituents considered part of the gas phase which are most likely to contribute to the health hazards from cigarette smoking. TABLE L-Compounds in cigarette smoke judged most likely to con- tribute to the heaZth hazards of smoking. Compound Carbon Monoxide Nicotine I "Tar" Primary phase Concentration in classification cigarette smoke G-gas micrograms/cigarette P-particulate References 5,240-21,400 G (1, 10, 23, 26, 29, 34, 35, 37, 42, 46, 49, 61, 63) 200-2,400 P (9) 3,000-33,000 P (9) 1 "Tar" is defined as the total particulate matter collected by a Cambridge Alter (CM-113) after subtracting moisture and nicotine and includes the class of compounds known as polycyclic aromatic hydrocarbons (PAH) PAH are generally accepted as being responsible for a sub- stantial portion of the carcinogenic activity of the total "tar." Although "tar" from different cigarettes varies in its carcinogenic potential as measured by the bioassay methods in current use. it remains the most practical single "indicator" of total carcinogenic potential. Special mention should be made of Beta Naphthylamine which is a known human urinary bladder car- cinogen for which there is no known safe level of exposure and which has been reported present in tobacco smoke in very low concentrations (16. 28. 30) (0.022 &gm./cigarette). It is recognized that the substances in cigarette smoke may inter- act so that the combined pathological effects of several substances may be quite different from the sum of their effects produced in isolation. An example of this type of interaction might be the car- cinogenic effects of tobacco "tar" as a result of the combined action of cancer initiating, cancer promoting, and cancer accelerating agents in producing the total effect. Such interactions theoretically could take place among substances within the gas phase, or sub- stances within the particulate phase, or between constituents of the gas phase and constituents of the particulate phase. In the absence of data which identify the interactions of cigarette smoke compo- nents, judgments concerning the action or identification of harmful substances in cigarette smoke have, of necessity, been made pri- 143 TABLE 2.-Compounds in cigarette smoke judged as probable con- tributors to the health hazards of smoking. Compound Primary phase Concentration in classification cigarette smoke G--gas micrograms/cigarette P-particulate References Acrolein Cresol (all isomers) Hydrocyanic Acid Nitric Oxide Nitrogen Dioxide Phenol 45-140 G (12, 20, 21, 27, 36, 43, 45) 68-97 P (20,40) 100-400 G (26, 38, 43,45,46, 49,53) O-600 G (1, 3, 15, 40, 42,44, 57) O-10 G (1, 40, 44, 57) 9-202 P (7, 19, 20, 32, 50, 52) marily on the basis of the action of the individual substances. Never- theless, experimental evaluation of modified cigarette smoke should be designed to take into account the possibility of such interaction. Until there is a better understanding of the relative importance of the interaction of the constituents of cigarette smoke in the de- velopment of the diseases associated with cigarette smoking, it will be difficult to assess the significance of the reduction or elimination of one or several of the constituents named in this report. However, it is reasonable to take the position that unless there is positive in- formation to the contrary, cigarettes in which overall "tar" and nicotine levels have been reduced present to the smoker lower con- centrations of the harmful substances in the particulate phase. If, at the same time, significant reductions are made in those gas phase constituents which also contribute to the hazards of smoking, the resulting product should be less hazardous to health.* The consensus is that a progressive and simultaneous reduction of all substances considered like19 to be involved in the health haz- ards of smoking should be encouraged as the most promising step available at the present time towards the development of a less haz- ardous cigarette. Primary emphasis should be given to the reduc- tion of the three substances or classes of substances named in the first table, and as a second priority to the reduction of those sub- stances or classes of substances in the second table before reducing * An &a-native point of view held by some ia that smoking behavior is a response to the need to reach II certain nicotine level and that lowering the amount of nicotine available from a cigarette rnay result in an increase in the number of cigarettes smoked. the depth of inhalation. or the number of puffs in order to maintain an accustomed level. Such an increase in smoking might result in an increased inhalation of other hazardous substances in the smoke, thereby potentially negating the effect of reducing the amount available in each cigarette. 144 TABLE 3.-Compounds in cigarette smoke judged as suspected con- tributors to the health hazards of smoking. Compound Primary phase Concentration in classification cigarette smoke o-gas micrograms/cigarette P-particulate References Acetaldehyde 180-1,440 Acetone 88-650 Acetonitrile 140-200 Acrylonitrile 10-15 Ammonia 60-330 Benzene 12-100 2,3-Butadione 43-200 Butylamine 3 1 Carbon Dioxide 23,100-`78,300 Crotononitrile 4 Dimethylamine 10-11 DDT o-o.77 Endrin 0.06 Ethylamine 10-11 Formaldehyde 20-41 Furfural 45-110 Hydrogen Sulphide 12-35 Hydroquinone 83 Methacrolein 9-11 Methyl Alcohol go-300 Methylamine 20-22 Nickel compounds O-O.58 Pyridine 25-218 G G G G G G G P G G P P P G G P G P G G G P P (4, 21, 27, 36, 43, 45, 48, 49, 53, 59) (12, 21, 27,36, 43, 45, 48, 49, 53) (1243) (12, 43) (2, 22, 40, 41, 43, 64) (11, 12, 25, 43, 45, 49, 53) (43, 46, 49,53) (31,40,41) (1, 10, 15, 23, 26, 29,34,35,42,46,49, 63) (43) (31,40,41) (17, 39, 54) (14) (22,31,40,41) (4, 36, 43, 48, 53) (4, 13,36) (10,43,51,58) (6,7) (12,43) (12, 21, 43, 46, 49) (22,31,40,41) (5, 8, 47, 65, 56) (40,62) ' CO2 is included because of the hazard it may represent to those with CO, retention, such 8~ those with advanced COPD. those named in the third table. 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Fachliche Mitteilungen der Osterreichischen Taba- kregie (4) : 61-63, 1963. 148 (48) PAILER, M., KUHN, H., GR~~NBERGER, I. ijber Quantitative Unterschiede im Auftreten von niedermolekularen Carbonylverbindungen im Rauch von Zigaretten verschiedener Tabakmischung und verschiedenen Feuchtigkeitsgehaltes. (Quantitative differences in the occurrence of low-molecular carbonyl compounds in the smoke of cigarettes having different tobacco mixtures and different moisture contents.) Fach- lithe Mitteilungen der Osterreichischen Tabakregie 3: 33-39, March 1962. (49) PHILIPPE, R. J., HOBBS, M. E. Some components of the gas phase of cigarette smoke. Analytical Chemistry 28 (12) : 2002-2005, December 1956. (50) RAYBURN, C. H., HARLAN, W. R., HANMER, H. R. Determination of volatile phenols in cigarette smoke. Analytical Chemistry 25 (9) : 1419, September 1953. (51) SCHOLLER, R. Uber den Gehalt des gasformigen und des festflussigen Anteils des Tabakrauches an Cyanwasserstoff. (The content of hydro- gen cyanide in the gaseous and stable liquid portions of tobacco smoke.) Fachliche Mitteilungen der Osterreichischen Tabakregie 1: 7-10, 1938. (52) SPEARS, A. W. Quantitative determination of phenol in cigarette smoke. Analytical Chemistry 35 (3) : 320-322, March 1963. (58) SPEARS, A. W., ROUTH, W. E. A combined approach to the quantitative analysis of the volatile components of cigarette smoke. Paper pre- sented at the 18th Tobacco Chemists Research Conference, Raleigh, N. C., 1964. (54) STEDMAN, R. L. The chemical composition of tobacco and tobacco smoke. Chemical Reviews 68(2) : 153-207, April 1968. (55) SUNDERMAN, F. W., SUNDERMAN, F. W., JR. Nickel poisoning. XI. Im- plication of nickel as a pulmonary carcinogen in tobacco smoke. Ameri- can Journal of Clinical Pathology 35(3) : 203-209, March 1961. (56) SZADKOWSKI, D., SCHULTZE, H., SCHALLER, K.-H., LEHNERT, G. Zur okologischen Bedeutung des Schwermetallgehalts von Zigaretten. 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Abstracts of 21st Tobacco Chemists' Research Con- ference, Durham, N.C., October 19-20,196'7. p. 14. 150 INDEX Abortion effect of maternal smoking, 5,84,85 frequency, and cigarette consumption, 85 Acetaldehyde as suspected contributor to health haz- ards of smoking, 145 Acetone as suspected contributor to health hazards of smoking, 145 Acetonitrile as suspected contributor to health haz- ards of smoking, 145 Acrolein as irritant in tobacco smoke, 101 as probable contributor to health haz- ards of smoking, 144 Acrylonitrile as suspected contributor to health haz- ards of smoking, 145 Adolescents see Students, high school Air pollution, carbon monoxide from cigarette smoke, 7,121-123,125 effect on nonsmokers, 121-125 tobacco smoke as a factor, 7,121-124 Air quality standards for carbon monoxide, 128 Alcohol consumption effect on mortality rates from esopha- geal neoplasms in Japanese males, 71 smoking and, in esophageal neoplasm etiology, 4,68,70,71 Allergy effect on cardiovascular abnormalities, 111 tobacco and, 7,103-l 11 tobacco smoke irritants and, 110 Alphat -antitrypsin deficiency in emphysema etiology, 44 smoking and, 44 Altitude, effect on arterial oxygen tension, 22 Amblyopia, tobacco cyanides and, 6 diet and, 6 smoking and, 6 Ammonia as suspected contributor to health haz- ards of smoking, 145 Angina pectoris smoking and, in twin studies, 18 Antigen-antibody reaction allergy and, 103-107 smokers vs. nonsmokers, 7,105,111 tobacco and, 7,104-107 Aortic aneurysm, nonsyphilitic mortality rates. smokers vs. nonsmokers, 2 Aromatic hydrocarbons, polycyclic effect on tobacco carcinogenicity, 66 Arterial diseases carboxyhemoglobin levels and, 26 smokers vs. nonsmokers, 26 smoking and, 25,26 Arteriosclerosis autopsy studies and, 19,20 cigar smoking and, 19 experimentally induced in dogs, 19,20 pipe smoking and, 19 smokers vs. nonsmokers, 19,22,23,27 smoking classification and, 19 Asbestos pulmonary fibrosis and, 44 Asthma smoking and, 37 Atherosclerosis see Arteriosclerosis Autopsy studies arteriosclerosis and, 19,20 coronary heart disease and, 19,20 Benz(a)anthracene carcinogenicity, as component of ciga- rette smoke, 66 Benzene as suspected contributor to health haz- ards of smoking, 145 Benzo(a)pyrene as air pollutant from cigarette smoke, 123 carcinogenic effects during pregnancy in rats, 89 cocarcinogenic effect on respiratory tract in rabbits, 67 hydroxylation by the placenta, 89 in smoke streams, 123 Betel nut chewing in Bombay, India, 69 in head and neck neoplasm etiology, 69 smoking and, 69 Birth weight effect of maternal smoking, 5,83-87 Bladder neoplasms relative risk in females by amount smoked, 73 relative risk in males by amount smoked, 72,73 smoking and, 68,72-74 smoking characteristics in etiology of, 5 Body height effect of maternal smoking, 88 Bronchial abnormalities in smokers vs. nonsmokers, 45 Bronchial histological changes smoking and, 45 Bronchitis incidence in British males by cigarette consumption, 62 occupational diseases and, 42 prevalence in smokers in Glenwood Springs, Colorado, 39 prevalence in smokers vs. nonsmokers in Yugoslavia, 40 smoking in etiology of, 37 Bronchopulmonary disease, chronic ob- structive alphat-antitrypsin deficiency and, 3.44 epidemiology in Tecumseh, Michigan, 39,40 morbidity, smokers vs. nonsmokers in Berlin, New Hampshire, 39 mortality, smokers vs. nonsmokers, 38,39 mortality rates for ex-smokers, and smokers vs. nonsmokers, 3 mortality rates for pipe/cigar smokers vs. cigarette smokers, 3 occupational hazards and, 4244 smoking in etiology of, 3,37 2,3-Butadione as suspected contributor to health haz- ards of smoking, 145 Butylamine as suspected contributor to health haz- ards of smoking, 145 Cancer see Neoplasms and specific listings, e.g., Lung neoplasms Carbon dioxide as suspected contributor to health haz- ards of smoking, 145 Carbon monoxide as air pohutant from cigarette smoke, 7,121~123,125 e f fee t on blood carboxyhemoglobn, levels, 21-23,127 effect on cardiovascular system, 22 effect on nonsmokers, 126 effect on psychomotor performance, 126 effect on vision, 126 as most likely contributor to health hazards of smoking, 8,143 psychological and physiological effects, 125128 Carboxyhemoglobin levels blood cholesterol and, 23 during and following exposure to carbon monoxide, 124,125 in nonsmokers exposed to cigarette smoke, 125 occlusive peripheral vascular disease and, 26 smokers vs. nonsmokers, 21-23 Carcinogenesis experimental, 6567 initiating agents in cigarette smoke, 66 Carcinogens effect on oral mucosa in laboratory ani- mals, 70 Cerebrovascular disease mortality rates, smokers vs. nonsmokers, L smoking and, 24,25 Cessation of smoking effect on COPD morbidity and mortal- ity, 41,42 effect on respiratory symptoms, 41,42 lung neoplasm development and, 62 myocardial infarct and, 17.18 as preventive measure in CHD, 17,18 as therapy in arterial diseases, 26 CHD see Coronary heart disease Children effect of parental smoking, 129 passive smoking and, 129 respiratory illness and, 129 Cholesterol in tobacco, 24 in tobacco smoke, 24 Chronic bronchitis see Bronchitis Chronic bronchopulmonary disease see Bronchopulmonary disease, chronic obstructive 152 Chrysene carcinogenicity, as component of ciga- rette smoke, 66 Cigarette consumption effect on mortality from lung cancer in Poland, 61,62 Cigarettes tar and nicotine content, 142,143 Cigarette smoking see Smoking Cigar smokers carboxyhemoglobin levels in, 21-23 myocardial arteriole wall thickness in, 19 relative risk in esophageal neoplasm development, 68 relative risk in laryngeal neoplasm de- velopment, 67 Coal miners pneumoconiosis and, 4244 Congenital malformations maternal smoking and, 87 COPD see Bronchopulmonary disease, chronic obstructive Coronary heart disease autopsy studies, 19,20 carboxyhemoglobin levels and, 27 cross-sectional study in Bergen, Norway, 16 epidemiological studies, 14-16 heredity as a factor, 18 incidence among Minnesota men by age and smoking habit, 14-16 interaction of smoking and other risk factors, 16-18 mortality rates and per capita cigarette consumption in several countries, 16 mortality rates in longshoremen, 14 retrospective studies in Goteborg, Sweden, 16 retrospective studies in Prague, Czecho- slovakia, 16 smoking in etiology of, 1,2,13,14 twin studies, 18 Cor Puhnonale see Pulmonary heart disease cough smokers vs. nonsmokers, 40 Cresol as probable contributor to health haz- ards of smoking, 144 Crotononitrile as suspected contributor to health haz- ards of smoking, 145 Cyanides tobacco amblyopia and, 6 DDT as suspected contributor to health haz- ards of smoking, 65,145 Dermatitis among tobacco workers, 111 Dibenz(a,c)anthracene carcinogenicity, as component of ciga- rette smoke, 66 7H-Dibenz(c,g)carbozole carcinogenicity, as component of ciga- rette smoke, 66,67 carcinogenic effect on respiratory tract in hamsters, 66,67 Diet tobacco amblyopia and, 6 Dimethylamine as suspected contributor to health haz- ards of smoking, 145 7,12-Dimethylbenz(a)anthracene effect on oral mucosa in hamsters, 70 Edentulism smoking and, 6 Emphysema alphar -antitrypsin deficiency and, 44 experimentally induced in smoking dogs, 46 smoking in etiology of, 37 Endrin as suspected contributor to health haz- ards of smoking, 145 Epidemiological studies bronchopulmonary diseases and smok- ing, 3841 coronary disease and smoking, 14-16 esophageal neoplasms and smoking, 70,71 laryngeal neoplasms and smoking, 68 lung neoplasms and smoking, 60-65 maternal smoking and outcome of preg- nancy, 83-87 oral neoplasms and smoking, 68-70 pancreatic neoplasms and smoking, 74 urinary bladder neoplasms and smoking, 72-74 Esophageal neoplasms alcohol consumption and smoking in etiology of, 4,5,71 mortality rates in Japanese males by smoking and drinking characteristics, 71 153 smoking in etiology of, 4,70,71 Esophagus effect of smoking, 98 Ethylamine as suspected contributor to health haz- ards of smoking, 145 Experimental studies nicotine and cigarette smoke, 21 Ex-smokers mortality rates from lung cancer, 5 Fetus effect of maternal smoking, 5,83-89 Filtration smoke, effect on bronchoconstrictor response in smokers, 45 Formaldehyde as suspected contributor to health haz- ards of smoking, 145 Furfural as suspected contributor to health haz- ards of smoking, 145 Gas phase, cigarette smoke effect on mucous flow rates in cats, 47 harmful constituents in, 143 Gastric secretions effect of nicotine, 97 Gastrointestinal disorders smoking and, 5,697,98 Genetic factors in alphat+mtitrypsin deficiency, 44 smoking and, 44 Gingivitis smoking and, 6 Heart disease see Coronary heart disease Heredity alpha, -antitrypsin deficiency and, 44 coronary heart disease and, 18 smoking and, 18 Hydrocyanic acid as probable contributor to health haz- ards of smoking, 144 Hydrogen sulphide as suspected contributor to health haz- ards of smoking, 145 Hydroquinone as suspected contributor to health haz- ards of smoking, 145 Hypercholesterolemia as a risk factor for coronary heart dis- ease, 16 ,17 Hypertension as a risk factor for coronary heart dis- ease, 16,17 Hypoxemia smoking and, 22 Hypoxia effect of nicotine, 21 experimentally induced in rats, 21 Infant mortality effect of maternal smoking, 83-87 low birth weight and, 86 Influenza incidence from antibody deficit in rmok- ers, 109 Intermittent claudication smokers vs. nonsmokers, 22,26 Intraoral smoking see Reverse smoking Ischemic heart disease morbidity ratio from, in New Delhi, India, 16 Laryngeal neoplasms epidemiological studies, 68 relative risk among cigarette, pipe and cigar smokers, 67 smoking in etiology of, 4,67,68 Leukoplakia oral neoplasm development in smokers and, 68,69 smoking in etiology of, 68.69 Lip neoplasms pipe smoking as cause of, 4 Lung cancer see Lung neoplasms Lung function effect of smoking, 37.38 in smokers vs. nonsmokers, 40 Lung neoplasms epidemiological studies, 6065 etiology and epidemiology, 59,60 incidence in British males by amount smoked, 62 incidence in Czechoslovakian males by amount smoked, 6 1 incidence in Jewish vs. non-Jewish women, 63,64 incidence in uranium miners, 64,65 mortality ratios in Japanese males by amount smoked, 6 1 mortality ratios in Japanese women, 63 prospective study in Japanese adults, 4,60,61 154 prospective study in Czechoslovakian males, 6 1 relationship to chronic bronchitis and smoking, 62 relative risk in exsmokers by length of cessation and previous duration of habit, 6264 smoking as cause, 4,5,59,60 Macrophages, alveolar effect of tobacco smoke, 4748 in sputum specimens of smokers vs. non- smokers, 48 Maternal-fetal exchange effect of nicotine, 88 Maternal smoking see Smoking, maternal Methacrolein as suspected contributor to health haz- ards of smoking, 145 Methyl alcohol as suspected contributor to health haz- ards of smoking, 145 6-Methylanthranthrene carcinogenicity, as component of ciga- rette smoke, 66 Morbidity from chronic bronchopulmonary disease, 3941 Mortality from chronic bronchopuhnonary disease, 38,39 Mortality rates esophageal neoplasms in Japanese males by smoking and drinking character- istics, 71 lung neoplasms in Japanese women, 63 pancreatic neoplasms in United States, 74 Mortality ratios lung neoplasms in Japanese males by amount smoked, 61 Mouth neoplasms see Oral neoplasrm Myocardial arteriole walls effect of filtered cigarettes in dogs, 20 thickness in smokers vs. nonsmokers, 2,19 thickness in smoking and nonsmoking dogs, 2,20 Myocardial infarct epidemiological study in Gomborg, Sweden, 14.15 incidence among Minnesota men by age and smoking habit, 14.15 incidence in men in Goteborg, Sweden, by tobacco consumption, 15 incidence rates by smoking classifi- cation, 15 smokers vs. nonsmokers in Goteborg, Sweden, 16 Neonatal death maternal smoking and, 83-87 Neoplasms see aLsO Specific types of neoplasms, e.g. lung neoplasms smoking and, 4,5,59-75 Nickel compounds as suspected contributors to health haz- ards of smoking, 145 Nicotine antigenic properties, 104 effect on apexcardiogram, 21 effect on birth weight in rats, 88 effect on bronchoconstrictor response in laboratory animals, 46 effect on fetus in laboratory animals, 88 effect on gastric secretions, 97 effect on gastrointestinal secretions in dogs, 6 effect on immune response in man, 109 effect on lipid metabolism in rabbits, 21 effect on peripheral circulatory system, 25,26 effects during pregnancy in laboratory animals, 88 experimental studies, 21 hypoxia and, 21 as most likely contributor to health hazards of smoking, 8,143 Nitric oxide as probable contributor to health haz- ards of smoking, 144 Nitrogen dioxide effect on pulmonary tissue in rats, 46,47 in emphysema etiology, 46 as probable contributor to health haz- ards of smoking, 144 Nitrogen oxides as air pollutants in cigarette smoke, 124,125 Non-nicotine cigarettes effect on apexcardiogram, 21 Nonsmokers allergic and irritative reactions to ciga- rette smoke, 128,129 155 allergic symptoms in, from tobacco smoke exposure, 110,111 carboxyhemoglobin levels in, 125 passive smoking and, 121-125 Obesity as a risk factor for coronary heart dis- ease, 16 Occupational diseases bronchitis, 42 chronic obstructive pulmonary disease, 3,4244 pneumoconiosis, 4244 pulmonary fibrosis, 44 smoking and, 3,4244 Occupational hazards smoking and, 3,4,4244 Oral contraceptives smoking and, 26 thrombophlebitis and, 26 Oral diseases, non-neoplastic smoking and, 6 Oral hygiene smoking and, 6 Oral mucosa effect of carcinogens in laboratory ani- mals, 70 effect of cigarette smoke, 6,69 effect of reverse smoking, 69 effect of tobacco/bidi smoking and chewing, 69 Oral neoplasms pipe smoking as cause, 67 relative risk in tobacco smokers and chewers, 70 smoking in etiology of, 4,67-70 Oxygen tension smokers vs. nonsmokers, 22 Pancreatic neoplasms mortality rates in United States, 74 mortality ratios in Japanese male and female smokers, 74 smoking and, 5,68,74 Particulate phase, cigarette smoke carcinogenic accelerators in, 5,65 effect on pulmonary and cardiac struc- ture and function, 7,s harmful constituents in, 143 Passive smoking effect on children, 129 effect on respiratory tract in laboratory animals, 129,130 in neoplasm induction in laboratory animals, 130 156 Perinatal studies maternal smoking and, 83-88 Periodontal diseases smoking and, 6 Peripheral vascular diseases carboxyhemoglobin levels and, 26 smoking and, 2,25,26 Phagocytosis effect of cigarette smoke in rabbits, 109 effect of tobacco smoke, 47-48 Phenol as probable contributor to health haz- ards of smoking, 144 Physical inactivity as risk factor in coronary heart disease, 16,17 Pipe smokers carboxyhemogiobin levels in, 21 myocardial arteriole wall thickness in, 19 oral neoplasms and, 67 relative risk in esophageal neoplasm development 68 relative risk in laryngeal neoplasm development, 67 Pneumoconiosis prevalence in coal miners, 4244 smokers vs. nonsmokers, 4244 Post-operative pulmonary complications smokers vs. nonsmokers, 38 Preeclampsia smoking and, 84 Pregnancy effect of maternal smoking, 5,83-87 Prematurity effect of maternal smoking, 5,83-87 Pulmonary clearance effect of smoking, 3,47 Pulmonary fibrosis in asbestos textile workers, 44 smoking and, 44 Pulmonary heart disease COPD and, 24 smoking as cause, 24.27 Pulmonary macrophages effect of smoking, 3,4,4748 morphologic differences in smokers vs. nonsmokers, 4.4748 Pyridine as suspected contributor to health haz- ards of smoking, 145 Radiation exposure smoking and, in uranium miners, 64,65 Respiratory disorders, acute noninflu- enzal in smokers vs. nonsmokers, 48 Respiratory function tests effect of smoking, 45 Respiratory infections smoking and, 3,38 Respiratory symptoms pipe/cigar smokers and cigarette smokers vs. nonsmokers, 3,40 Reverse smoking effect on oral mucosa, 6,69,70 nicotinic stomatitis and, 6,69,70 Risk factors in coronary heart disease, 16-18 Skin effect of tobacco extracts, 105-107 tobacco antigens and, 7,104,105 Skin testing for reactions to tobacco, 105-107 Smoke, cigarette carcinogenicity, 65,66 cocarcinogenic effect on respiratory tract in rabbits, 67 effect on apexcardiogram, 21 effect on breathing in guinea pigs, 46 effect on lung surface tension in dogs, 48 effect on nasociliary mucosa in don- keys, 47 effect on phagocytosis in rabbits, 109 experimental studies in laboratory ani- mals, 21 harmful constituents of, 8,141-146 Smoke, tobacco as air pollutant, 7,121 ,122 allergic and irritative components, effect on nonsmokers, 7,128,129 antigenic properties, 104 effect on macrophages, 47 irritants in, 109,110 Smokers vs. nonsmokers arteriosclerosis and, 19 carboxyhemoglobin levels, 21-23 cerebrovascular diseases and, 25 oral diseases and, 6 respiratory symptoms, 40 thickness of myocardial arteriole walls, 19 Smoke streams benzo(a)pyrene content, 123 effect on nonsmokers, 122,123 tar and nicotine content, 123 Smoking bladder neoplasms and, 68,72-74 effect on cardiovascular system, 6,13,14 effect on esophageal sphincter, 97,98 effect on gastrointestinal secretions in dogs, 6 effect on leukocytes in guinea pigs, 46 effect on lungs in dogs, 46 effect on mortality rates from esopha- geal neoplasm in Japanese males, 71 effect on neoplasm recurrence at site of primary, 69 effect on oxygen tension in arterial blood, 45 effect on pentagastrin-stimulated gastric secretion, 97 effect on peripheral circulatory system, 25,26 effect on pulmonary clearance, 47 heartburn and, 97,98 peptic ulcers and, 6,97,98 tobacco amblyopia and, 6 Smoking, bidi in neoplasm etiology in Bombay, India, 69 Smoking, maternal carcinogenic effects on fetus, 88 effect on abortions, 5,84,85 effect on birth weight, 5,83-87 effect on body height of children, 88 effect on fetal growth rate, 5,83-87 effect on neonatal mortality rates, 84-87 effect on neoplasm development in off- spring, 87,88 effect on placental metabolizing activ- ity, 89 effects during pregnancy, 5,83-87 teratogenic effects, 87 unwanted pregnancy and, 84 Smoking, parental effect on children, 129 Snuff effect on oral mucosa in hamsters, 70 Squamous cell carcinoma smoking in etiology of, 69 Stomatitis nicotina reverse smoking and, 6,69,70 Stroke smoking and, 24,25 Students, high school effect of smoking, 40,41 pulmonary function of smokers vs. non- smokers, 3 157 respiratory symptoms in, 40,41 Surfactants effect of tobacco smoke, 48 Tar content as harmful component of cigarette smoke, 142,143 Tars, tobacco carcinogenicity, 65,66 definition, 143 Thromboangiitis obliterans tobacco allergy and, 111 Thrombophlebitis oral contraceptives and, 26 smoking and, 26 Thrombosis effect of smoking, 23 Tobacco cholesterol content, 24 effect on immune responses, 6,107-109 pharmacologic, irritative, and allergic ef- fects, 7,109-l 11 Tobacco antigens in smokers vs. nonsmokers, 107 Tobacco chewing oral neoplasrm and, 69 Tobacco extracts antigenic properties, 104,105 effect on skin, 105-107 irritants in, 184,105 thromboangiitis obliterans and, 111 Tobacco leaf antigenic properties, 104,105 Tobacco pollen antigenic properties, 104 Tuberculosis smoking and, 41 Twins smoking and coronary heart disease in, 18 Ulcer, duodenal smoking and, 6,97,98 Ulcer, peptic increased prevalence in male smokers, 97 smoking and, 5,6,97,98 smoking as cause in dogs, 97,98 Urinary bladder neoplasms see Bladder neoplasms Vascular disease, peripheral carboxyhemoglobin levels and, 26 nicotine and, 25 smokers vs. nonsmokers, 26 smoking as a risk factor, 2,25,26 Vision effect of carbon monoxide, 126 158 *U.S. GOVERNMENT PRINTING OFFICE: 1972 O-445.191