A Reference Edition Selected Chapters From 1971 Through 1975 Reports With Cumulative Index For All Reports 19641975 U.S. Department of Health, Education, and Welfare Public Health Service cmltar for Dii Control Athnta, Gewpia 30333 THE HEALTH CONSEQUENCES OF SMOKING A Reference Edition Selected Chapters From 1971 Through 1975 Reports With Cumulative Index For All Reports 1964-1975 U.S. Department of Health, Education, and Welfare Public Health Service Center far Diia50 Controi Atlanta, Georgia 30333 1976 HEW Publication Nd. (CDC) 78-8357 October 1977 Honorable Thomas P. O'Nelll Speaker of the House of Representatives Kashfngton, D.C. 20515 Dear ?fr. Speaker: As required by Section 8(a) of the Public Health Cigarette Smokfng Act of 1969 (Public Law 91-222). enclosed is the 1976 Report to Congress on the Health Consequences of Smoking. This year's report includes the "Bibliography on Smoking and Health - 1975," the official abstract bulletin of the National Clearinghouse for Smoking and Health. Bureau of Health Education. Center for Disease Control. Public Health Service. It presents the scientific information published since last year's report to Congress. Also part of this year's report is 'The Health Consequences of Smoking. a Reference Edition." a compilation of selected chapters from previous reports to Congress. This reference edition was prepared to emphasize the fact that the major health risks from smoking are know" and that recent scientific information refines the understanding of these relatlonshlps. Without doubt. cigarette smoking is a cause of cardiovascular disease. various types of cancer, and respira- tory disease. Its toll lo illness and premature death 1s needless and preventable. Because of ny strong commitment in reducing the morbidity and mortality which result from smoking. the Department 1s conducting a major review of its prograrrm 1" this field in order to introduce administrative and legislative proposals to combat this problem. Sincerely. Joseph A. Cslifano. Jr. Eoclosure PREFACE ?e health consequences of cigarette smoking are well established. ad have bee; clearly understood for several years. The causal re- k ionships between cigarette smoking and an excess risk of devel- Fing cardiovascular disease, respiratory tract cancers, and chronic 1 structive lung disease, as well as the risk to the fetus, are well cumented and accepted by the scientific and health communities. r the past several years, new additions to the literature have bstantiated i' these risks and further explained the mechanisms which smoking produces disease, disability, and death; however, search has identified no new major health risks. Therefore, it ems appropriate at this time to prepare a reference document viewing the full range of health hazards due to smoking. is reference report consists of selected chapters from previous ports to the U.S. Congress which present summations of the i own health hazards from smoking. Because the 1971 report was review of all information on smoking and health at that time, chapters were included from reports prior to that time. This `ference, coupled from the annual Bibliography on Smoking and le E alth, represents a complete description of major smoking and alth information. e scientific evidence is clear and unavoidable, and the important k now is to convert this knowledge into programs for reducing d eliminating the preventable death and disability related to the oking habit. Theodore Cooper, M.D. Assistant Secretary for Health TABLE OF CONTENTS Page PREFACE ~.._...___.___._..__________..._.......... ... 111 TABLEOFCONTENTS . . . __. . _. _ _ _. _ _. . . . . . . . . . . _. . . . . v PREVIOUS PUBLIC HEALTH SERVICE REPORTS ON SMOKING AND HEALTH _ _ . _ _ _ _ _ . . . _ . . . . . . . . . . . . . . . vii ACKNOWLEDGEMENTS . . . . _ _ . _ . _ . . . . . _ . . . _ _ _ _ _ . . . . . . . . ix CHAPTER 1 CHAPTER 2 CHAPIER 3 CHAPTER 4 CHAPTER 5 CHAPTER 6 CHAPTER 7 CHAPTER 8 CHAPTER 9 Overview (197.5 Report) _ . . . . . _ . . . . _ . _ _ . . _ . _ . . . 1 Cardiovascular Disease _ . . _ . . . . _ . . . . _ _ _ . . _ _ _ _ . . . 9 Part 1 (1971 Report, Chapter 2) _ _ . . . . . . _ . . . _ . _ . _ . 11 Part 2 (1975 Report, Chapter 1) . . _ . . . . . . . . . _ . . . . _ 131 Chronic Obstructive Bronchopulmonary Disease (1971 Report, Chapter 3) . . . . . . . _ . . . _ _ . . _ . . . . . . 161 Cancer (1971 Report, Chapter 4) . . . . _ _ _ . . . . . . . . . _ 257 Pregnancy (1973 Report, Chapter 4) . . . . . _ . _ . . . _ . . _ 411 Peptic Ulcer Disease (1973 Report, Chapter 5) . . . . . _ _ _ . 465 Involuntary Smoking (1975 Report, Chapter 4) . . . . . . . . 479 Allergy (1972 Report, Chapter 7) . _ . _ _ . . . . . . _ . . . . . 509 Tobacco Amblyopia (197 1 Report, Chapter 7) . . . . . . . 527 CI-IAPIER 10 Pipes and Cigars (1973 Report, Chapter 6) _ . . . . . . . . _ _ 535 CHAPTER 11 Exercise Performance (1973 Report, Chapter 7) . . . _ . _ . _ 607 CHAPTER 12 Harmful Constituents of Cigarette Smoke (1972 Report, Chapter 9) . _ . . . . . _ . _ . _ _ . . _ . . _ _ _ . 621 INDEX This Report . . . _ . . _ _ . . . . _ _ _ . . . _ . . . . _ . . _ _ . . . _ 635 CUMULATIVE INDEX (1964 - 1975) _ . . . . . . _ _ . _ . . . . . . . _ . . . . . 000 Previous Public Health Service Reports on Smoking and Health Reviews of the scentitic evidence linking smoking to health effects began in 1964 with Smoking and Health, Report of the Advisory Committee to the Surgeon General of the Public Health Service or as subsequently referred to "the Surgeon General's Report." After this report, Public Law 89-92 was passed requiring supplemental reports to Congress on this subject. In compliance, three reports were submitted: 1. The Health Consequences of Smoking, A Public Health Service Review: 1967. 2. The Health Consequences of Smoking, 1968 Supplement to the 1967 PHS Review. 3. The Health Consequences of Smoking, 1969 Supplement to the 1967 PHS Review. In April 1970, Public Law 91-222 amended the previous law and called for an updated report on the health effects of smoking no later than January 1, 197 1, with annual reports thereafter. The Health Consequences of Smoking, A Report of the Surgeon General: 1971, a comprehensive review of all the scientific literature available to the National Clearinghouse for Smoking and Health and with emphasis on the most recent additions to the literature was that updated report. Since then, the following annual reports on the health consequences of smoking have been submitted: 1. The Health Consequences of Smoking, A Report of the Surgeon General, 1972. 2. The Health Consequences of Smoking, 1973. 3. The Health Consequences of Smoking, 1974. 4. The Health Consequences of Smoking, 1975. Each report since the original "Surgeon General's Report" has reviewed the scientific literature relevant to the association between smoking and Vii cardiovascular diseases, non-neoplastic bronchopulmonary diseases. and cancer. Smoking as related to the following diseases and condiiions has been reviewed periodically in the reports: Pregnancy(1967.1969, 1971,1972,1973) Peptic Ulcer Disease (1967,197 1,1972,1973) Public Exposure to Air Pollution from Tobacco Smoke (1972,197s) Noncancerous Oral Disease (1969) Tobacco Amblyopia (197 1) Allergy (1972) Harmful Constituents of Cigarette Smoke (1972) Exercise Performance (1973) Pipe and Cigar Smoking (1973) Overview: The Health Consequences of Smoking (1975) . . . vlu ACKNOWLEDGMENTS Preparation of this reference edition, The Health Consequences of Smoking, was the responsibility of the National Clearinghouse for Smoking and Health; Charles A. Althafer, Acting Director; David M. Burns, Medical Staff Director; Priscilla B. Holman, Technical Editor; Donald R. Shopland, Technical In- formation Officer. Individual chapters comprisin, 0 this reference volume are from reports which were prepared under the direction of Daniel Horn, Ph.D., Director of the Clearinghouse,-currently on assignment to the World Health Organization. The following persons served as medical staff directors or consultants for the preparation of the reports whose chapters are included in this reference edi- tion: Elvin E. Adams, M.D.; Daniel P. Asnes, M.D.: David M. Burns, M.D.; David G. Cook, M.D.; John H. Holbrook, M.D.; Paul Schneiderman, M.D.; and H. Stephen Williams, M.D. The following persons provided assistance and advice for the preparation of reports whose chapters are included in this reference edition. Reviewers' AncJerson,`William H., M.D. - Chief, Pulmonary Disease Section, University of Louisville, School of Medicine, Louisville. KY. Anthonisen, Nicholas, I?., M.D., Ph.D. - Director, Respiratory Division for the Health Sciences Center, Winnipeg General Hospital, Winnipeg, Canada. Auerbach, Oscar, M.D. - Senior Medical Investigator, Veterans Hospital, East Orange, NJ. Ayres, Stephen M., M.D. - Professor and Chairman, Department of Internal Medicine, St. Louis University Medical School, St. Louis, MO. Baker, Carl, M.D. - Director, Program Policy Staff, Health Resources Ad- ministration, U.S. Department of Health, Education, and Welfare, Wash- ington, D.C. tBellet, Samuel, M.D. - Director, Division of Cardiology, Philadelphia -_ General Hospital, Philadelphia, PA. Bing, Richard .I, M.D. - Visiting Assoctie in Biomedical Engineering, California Institute of Technology, Pasadena, CA. Bock, Fred G., Ph.D. - Director, Orchard Park Laboratories, Roswell Park Memorial Institute, Orchard Park, NY. Boren, Hollis, M.D. - Professor of Medicine, University of South Florida Medical Center, Tampa, FL. Boutwell, Roswell K., M.D. - Professor of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison, WI. Brass, Irwin, M.D. - Director of Biostatistics, Roswell Park Memorial Institute, Buffalo, NY. `Current addresses. `Deceased. ix Cooper, Theodore, M.D. - Assistant Secretary for Health, U.S. Department of Health, Education and Welfare, Washington, DC. Cornfield, Jerome - Research Professor of Biostatisticr, University of Pittsburgh Graduate School of Public Health, Biostatistics Project, Bethesda. MD. Earl, Christopher J., M.D. - National Hospital, London, England. Epstein, Frederick H., M.D. - University of Zurich, Zurich, Switzerland. Falk, Hans L., Ph.D. -`Associate Director for Program, National institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. Farr, Richard, M.D. - Director, Department of Medicine, Section of Allergy and Clinical Immunology, National Jewish Hospital and Research Center, Denver, CO. Ferris, Benjamin G., Jr., M.D. - Professor, Department of Physiology, Harvard School of Public Health, Boston, MA. Finklea, John F., M.D. - Director, National Institute for Occupational Safety and Health, Center for Disease Control, Public Health Service, U.S. Department of Health, Education and Welfare, Rockville, MD. Fitzpatrick, Mark J., M.D., M.P.H. - Fairhaven Medical Associates, Inc., Fairhaven. MA. Frazier, Todd M. - Assistant Director. Harvard Center for Community Health and Medical Care. Harvard School of Public Health, Boston, MA. Freston, James, M.D. - Associate Professor of Medicine; Chairman, Divisions of Gastr.oenterology and Clinical Pharmacology, University of Utah Medical School. Salt Lake City, UT. Goldsmith, John R., M.D. - Medical Epidemiologist, Epidemiological Studies Laboratory, California State Department of Health, Berkeley, CA. Gori, Gio B., Ph.D. - Deputy Director, Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD. Hanna, Michael G., Jr., Ph.D. - Director of Basic Research, Frederick Cancer Research Center, Frederick, MD. Harkavy, Joseph, M.D. - Clinical Professor of Medicine(Emeritus1, the Mount Sinai Medical School of the University of New York, New York, NY. Harke, H. -P., Ph.D. - Forschunginstitut der Cigarettenindustrie, e.V., Hamburg, Germany. Higgins, fan T. T.. M.D., F.R.C.P. - Professor, Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, Ml. Hoffmann, Dietrich, Ph.D. - Member, and Chief, Division of Environmental Carcinogenesis, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, NY. Israel, Robert A. - Acting Deputy Director, National Center for Health Statistics, Public Health Service. U.S. Department of Health, Education, and Welfare. Rockville, MD. `Current addresses. `Deceased. X Jennings, Michael, M.D. - Epidemic Intelligence Service, Center for Disease Control located at Ohio Department of Health, Columbus. OH. Keller, Andrew Z., D.M.D., M.P.H. - Chief, Research in Geographic Epidemiology. Medical Research Service. Veterans Administration Central Office, Washington, DC. Kirsner, Joseph, M.D. - Professor of Medicine, University of Chicago School of Medicine, Chicago, IL. Knox. David L., M.D. - Associate Professor, The Wilmer Opthalmological Institute, The Johns Hopkins University School of Medicine, Baltimore. MD. - Kolbye, Albert C., Jr., M.D., J.D. - Director, Office of Sciences, Bureau of Foods, Food and Drug Administration, U.S. Department of Health, Education and Welfare, Washington, DC. Kotin, Paul, M.D. - Senior Vice President of Health, Safety, and Environ- ment Division, Johns-Manville Company, Denver, CO. Krumholz, Richard A.. M.D. - Medical Director, Institute of Respiratory Diseases, Kettering Medical Center, Kettering, OH. Lenfant, Claude, J. M., M.D., - Director, Division of Lung Diseases, National Heart and Lung Institute, National Institutes of Health, Bethesda, MD. Liebow, Averill A., M.D. - Professor and Chairman, Department of Pathology, University of California at San Diego, LaJolla, CA. Lilienfeld, Abraham, M.D. - University Distinguished Service Professor of Epidemiology, Johns Hopkins School of Hygiene and Public Health, Baltimore, MD. Lowell, Francis C., M.D. - Chief, Allergy Unit, Massachusetts General Hospital, Boston, MA. MacMahon, Brian, M.D. - Professor, Department of Epidemiology, Harvard School of Public Health, Harvard University, Boston, MA. McLean, Ross, M.D. - Professor of Medicine and Chief of Pulmonary Services, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, NC. McMillan, Gardner C., M.D. - Assistant Director for the Etiology of Arteriosclerosis and Hypertension, National Heart and Lung Institute, National Institutes of Health, Bethesda, MD. -_ - _ Manning, Kathleen M., R.N. - Department of Staff Development, Boston City Hospital, Boston, MA. Meyer, Mary 8.. Mrs. - Assistant Professor of Epidemiology, The Johns Hopkins University, Baltimore, MD. Mitchell, Roger S., M.D. - Chief of Staff, Veterans Administration Hospital. Denver, CO. Murphy, Edmond A., M.D. - Professor of Medicine and Biostatistics. The Johns Hopkins University, Baltimore, MD. Nettesheim, Paul, M.D. - Group Leader, Respiratory Cnrcinogenesis Group. Biology Division, Oak Ridge National Laboratory, Oak Ridge, TN. ' C~mnc addresses. `Deceased. xi Newill, Vaun A., M.D. - Executive Office of the President, Office of Science and Technology, Washington, DC. Paffenbarger, Ralph S., Jr., M.D. - Epidemiologist, California State Depart- ment of Health, Berkeley, CA. Parker, Charles W.. M.D. - Professor of internal Medicine, Division of Immunology. Washington University Medical School, St. Louis, MO. Peters, John M., M.D. - Associate Professor of Occupational Medicine, Harvard University School of Public Health, Boston, MA. Peterson, William F., M.D. - Chairman, Department of Obstetrics and Gynecology, Washington Hospital Center, Washington, DC. Petty, Thomas L., M.D. - Professor of Medicine; Head, Director of Pulmonary Medicine, University of Colorado Medical Center, Denver, CO. Rall, David P., M.D. - Director, National institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC. Rauscher, Frank J., M.D. - Director, National Cancer Program, National Cancer Institute, National Institutes of Health, Bethesda. MD. Reinke, William A., Ph.D. - Professor, Department of International Health, The Johns Hopkins University, 8altimore. MD. Renzetti, Attilio D. Jr., M.D. - Professor of Medicine, and Head, Pulmonary Disease Division, The University of Utah Medical Center, Salt Lake City, UT. Ringler, Robert L., Ph.D. - Deputy Director. National Heart and Lung Institute, National institutes of Health. Bethesda, MD. Robins, Morton, M.D. Health Consultant, Westat, Inc., Rockville, MD. Saffiotti, Umberto. M.D. - Associate Director, Carcinogenesis Program. Division of Cancer Cause and Prevention, National Cancer Institute, National Institutes of Health, Bethesda, MD. Schuman, Leonard M., M.D. - Professor and Head, Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, MN. Shimkin, Michael B., M.D. - Professor of Community Medicine and Oncology, School of Medicine, University of California at San Diego, LaJolla, CA. Stamler, Jeremiah, M.D. - Professor and Chairman, Community Health and Preventive Medicine and Dingman Professor of Cardiology, Northwestern University Medical School, Chicago, IL. Underwood, Paul B., Jr., M.D. - Professor, Department of Obstetrics and Gynecology, and Director of Gynecologic.Oncology, University of South Carolina Medical School. Charleston, SC. Van Duuren, Benjamin L., M.D. - Professor of Environmental Medicine, institute of Environmental Medicine, New York University Medical Center, New York, NY. Victor, Maurice, M.D. - Professor, Department Head, Neurology, Case Western Reserve, Cleveland, OH. Wynder, Ernest L., M.D. - President and Medical Director. American Health Foundation, New York, NY. xii The following staff persons at the National Clearinghouse for Smoking and Health or at the Center for Disease Control contributed to the preparation of one or more reports whose chapters are included in this report: Richard H. Arnacher, Elaine Bratic, Marjorie L. Brighman, Kathryn Carlysle. Emil Corwin, Winthrop N. Davey. M.D., Lillian Davis. Mary E. Dement. Julia M. Puller, Sandy Harris, Annabel W. Hecht, Gertrude Herrin. Priscilla B. Holman, Robert S. Hutchins, Theresa Klotz, Jennie M. Jennings. Nancy S. Johnston, Sanda Lager, Seth N. Leibler, Ed. D., Rosalie Levine. Mary Mitchell, Dan Nemzer, Mildred Ritchie. James A. Robertson. Donald R. Shopland, Kathleen H. Smith, Elsie Van Valkenburg, and Richard W. White. . . . Xl11 Chapter 1 Oveniew - The Health Consequences of Smoking Source: 1975 Report, Overwew - The Health Consequences of Smoktng. pages 1 8. 1 OVERVIEW - HEALTH CONSEQUENCES OF SMOKING The statement, "Warning: 77re Surgeon General Has Determined That Cigarette Smoking Is Dangerous to Your Health," has been required by law on cigarette packaging since 1970 as a part of the Public Health Cigarette Smoking Act of 1969. This Act was a response by the U.S. Congress to the scientific information on the health consequences of cigarette smoking summarized in reports then avaiIabIe (the Surgeon General's Report of 1964 and the subsequent 1967, 1968, and 1969 PHS Health Consequences of Smoking). This Act was passed because a series of important questions concerning cigarette smoking and health had been answered. The following discussion summarizes the basic questions, the methodology used to determine the answers, and the answers themselves. The initial question to be answered concerning the health consequences of smoking was "`Are there any harmflt/heaIth effects of smoking cigarettes?" The answer to this question was provided in two ways. First, it was demonstrated that some diseases occurred more frequently in smokers than in nonsmokers. Second, a causal relationship was established between smoking and these diseases. Concern about the possible health effects of smoking started when scientists began looking for an explanation to account for the rapidly increasing death rate from lung cancer. The early retrospec- tive studies showed a link between lung cancer and smoking. The first prospective studies, however, found that only oneeighth_of.the excess overall mortality found among smokers could be accounted for by lung cancer; the rest was 1argeIy due to coronary heart disease, chronic respiratory disease, and other forms of cancer. They also found that the effect on overall mortality was largely confined to cigarette smokers rather than the users of other forms of tobacco. However, demonstrating an association by statistical probability is not enough to establish the causal nature of a relationship. Deterpining that the association between smoking and excess death rates is cause and effect was a judgment made after a number of criteria had been met, no one of which by itself is sufficient to make this judgment. These criteria as listed in the Surge0;: General's 3 Advisory Committee Report (1964) were the consistency, strength, specificity, temporal relationship, and coherence of the association. In addition, con.vincing theories about the mechanisms whereby smoking contributes lo the various diseases responsible for the excess mortality among cigarette smokers were developed from the evidence on the biochemical, cytologic, pathologic, and pathophysiologic effects of cigarette smoking, thereby providing the necessary support for the decision that the relationship was causal. The most important specific health consequence of cigarette smoking in terms of the number of people affected is the development of premature coronary heart disease (CHD). Boih prospective and retrospective studies clearly established that cigarette smokers have a greater risk of death due to CHD and have a higher prevalence of CHD than nonsmokers. Long-term followup of healthy populations has confirmed that a cigarette smoker is more likely to have a myocardial infarction and to die from CHD than a nonsmoker. Cigarette smoking has been shown to be one of the major independent CHD risk factors and to act in combination with other major alterable CHD risk factors (high blood pressure and elevated serum cholesterol). Autopsy studies have shown that persons who smoked cigarettes have more severe coronary athero- sclerosis than persons who did not smoke. Physiologic studies and animal experiments have indicated several mechanisms whereby these effects can take place. A second major health consequence of smoking is the develop- ment of cancer in smokers. Cigarette smoking was firmly established as the major risk factor in lung cancer. The risk of developing lung cancer was found to be 10 times greater for cigarette smokers than for nonsmokers. The risk of developing lung cancer increases with the number of cigarettes smoked per day and is greater in cigarette smokers who report inhaling, who started smoking at an early age, or who have smoked for a greater number of years. Smokers of filter cigarettes have been shown to have a lower risk of developing lung cancer than smokers of nonfiiter cigarettes, but the risk remains well above that for nonsmokers. The risk of developing cancer of the larynx, pharynx, oral cavity, esophagus, pancreas, and urinary bladder.was also found to be significantly higher in cigarette smokers than in nonsmokers. Pipe and cigar smokers were found to have elevated risks for the development of cancer of the oral cavity, pharynx, larynx, and esophagus when compared to nonsmokers. Fewer pipe and cigar smokers than cigarette smokers report that they inhale. As a result lungs of pipe and cigar smokers receive much less 4 exposure to smoke than the lungs of cigarette smokers. This is probably the primary reason for the lower incidence of cancer of the lung for pipe and cigar smokers compared to cigarette smokers. Women have had far lower rates of lung cancer than men. This has been attributed to the fact that fewer women than men smoke and the fact that women smokers generally select filter and low tar and nicotine cigarettes. However, the percentage of women smokers in the United States has increased steadily in the last 30 years, and since 1955 the death rates from lung cancer in women have increased proportionately more rapidly than the rates for men, reflecting this increased proportion of women smokers. The tar from cigarette smoke has been found to induce malignant changes in the skin and respiratory tract of experimental animals, and a number of specific chemical compounds contained in cigarette smoke were established as potent carcinogens or cocarcino- gens. Malignant changes including carcinoma in situ were found in the larynx and in the sputum exfoliative cytology. of experimental animals exposed to cigarette smoke. Nonmalignant respiratory disease is a third area of smoking- induced morbidity and mortality. Cigarette smokers have been shown to have more frequent minor respiratory infections, miss more days from work due to respiratory illness, and report symptoms of cough and sputum production more frequently than nonsmokers. Retrospective and prospective studies with long-term followup have found that cigarette smoking is the primary factor in the develop- ment of chronic bronchitis and emphysema in the United States. Cigarette smokers have also been found to be more likely to have abnormalities of pulmonary function and have higher death rates from respiratory diseases than nonsmokers. Data from autopsy studies have shown that cigarette smokers were more likely to have the macroscopic changes of emphysema, and that these changes are closely related to the number of cigarettes smoked per day. MUCOUS cell hyperplasia has been found more often in cigarette smokers. Cigarette smoke aIso inhibits the ciliary motion responsible for cleansing the respiratory tract. An additional area of health concern has been the effect of cigarette smoking during pregnancy. Mothers who smoke cigarettes during the last two trimesters of their pregnancy have been found to have babies with a lower average birth weight than nonsmoking mothers In addition cigarette smoking mothers had a higher risk of having a stillborn child, and their infants had higher late fetal and 5 neonatal death rates. There are some data to show that these risks due to cigarette smoking are even greater in women who have a high risk pregnancy for other reasons. These effects may occur because carbon monoxide passes freely across the placenta and is readily bound by fetal hemoglobin, thereby decreasing the oxygen carrying capacity of fetal blood. Having established that cigarette smoking is a significant causal factor in a number of serious disease processes, two additional questions became important. They are "Can the health consequences to the individual be averted by stopping smoking or by changing the cigarette. " and "What are the overall public health consequences of cessation and of the changes made in cigarettes?" The first question is the simpler of the two to answer. In the individual, cessation of cigarette smoking results in a rapid decline of the carbon monoxide level in the blood over the frrst 12 hours. Symptoms of cough, sputum production, and shortness of breath usually improve over the next few weeks. A woman who stops smoking by the fourth month of her pregnancy has no increased risk of stillbirth or perinatal death in her infant related to smoking. The deterioration in pulmonary function tests that occurs in some smokers becomes less rapid than that of continuing smokers. The death rates from ischemic heart disease, chronic bronchitis, and emphysema also become less than those of the continuing smoker. The risk of developing cancer of the lung, larynx, and oral cavity declines relative to the continuing smoker in the first few years after cessation and IO to 15 years after stopping smoking approximates that of nonsmokers. A smoker who switches to filter cigarettes and has smoked them for IO years or longer has a lower risk of developing lung cancer than a smoker who continues to smoke nonfilter cigarettes. The risk to a filter cigarette smoker, however, still remains well above that of a nonsmoker. The public health benefits of cessation are more difficult to determine than the effects of cessation on the individual. Just as cause-specific death rates have reflected the effect of cigarette smoking on certain diseases, they should also reflect any substantial benefits to be gained by cessation or reduction in cigarette smoking. Several factors combined to produce a reduction in per capita dosage of tobacco exposure in the United States for the years 1966-1970. First, per capita consumption of cigarettes declined from 4,287 cigarettes per person in 1966 to 3,985 in 1970. Second, during this period there was a slow but significant decrease in the average tar and nicotine content of cigarettes as well as a decrease in the amount of 6 tobacco contained in the average cigarette. The decline in per cnplfa consumption during those years occurred in the face of a substantial , increase in the proportion of young women becoming smokers as cornpared to women of previous generations and SO reflected t predominantly a decrease in cigarette consumption by men. Since 1970, although the per capita consumption of cigarettes has increased. the average levels of tar and nicotine have continued to decline, making it more difficult to predict what has happened to per capita dosage. Examination of cause-specific death rates for the period of this declining per capita consumption reveals that there was a downturn in the male death rate from ischemic heart disease beginning in 1966 which reversed the upward trend that had occurred over the previous two decades. This decline in the death rate from ischemic heart disease has not occurred in women. The male death rate from chronic bronchitis has also been declining since 1967, and the male death rate for emphysema has declined since 1968 when it was first recorded as a separate category. Female death rates for these two diseases have not shown these trends. Despite the impressive coincidences of the decline in death rates among males occurring at the same time that there was a decline in per capita cigarette consumption, it is impossible to be certain of the exact cause of the decline in the death rates. These diseases are influenced by a variety of factors in addition to cigarette smoking such as blood pressure and air pollution. Some of these factors have also been subject to major control efforts which may have contributed to the decline in the death rates. In addition, there have been therapeutic advances in the treatment of these problems which may also have helped lower the death rates. A decline in male death rates from lung cancer should also follow the decline in per capita consumption. This rate would not be influenced as much by changes in other etiologic factors or changes in therapy because cigarette smoking causes from 85 to 90 percent of all lung cancer and there have been no major improvments in survival due to changes in therapy. With lung cancer, however, two additional considerations must be kept in mind. A decline in death rates from lung cancer would be expected to lag several years behind a decline in per capita consumption. In addition, the decline in consumption and switch to low tar and nicotine cigarettes occurred 7 predominantly in the younger age groups where death rates from Lung cancer are low. For these reasons, it is necessary to look at lung cancer death rates by age group rather than total lung cancer death rates. The lung cancer rates by age groups for 1971 suggest a decline in the lung cancer rates for the younger males (under 4S), but the confidence limits on these trends at present remain wide enough that it is impossible to say whether this is a real decline or merely a leveling off. The national health statistics broken down by 5-year age groups are currently available only through 1971. The data by age group from a few more years will be necessary to determine whether the changes in smoking behavior which have taken place have reversed the trend of the preceding 4.0 years of continually increasing lung cancer rates in men. In 1971, the last year for which detailed mortality statistics are available, the accumulated exposure to cigarettes reached its peak among men born between 19 I5 and 1919, a group then in their early 50's. Cumulative exposure has continued to decline with each successive S-year birth cohort born since then. The trends of the last few years offer some hope that the peak of the "lung cancer epidemic," as some have termed this phenomenon, may have been reached with this group and that future years will show a slow but consistent decline. 8 Chapter 2 cardidar~s Pan I - 1971 Rspori, Chapter 2, 15 - 174. paQa Pan I1 - 1975 Remrt, Chapter 1. 9 - 38. paws Chapter 2 Cardiovascular Diseases Part I Contents Introduction Paga Smoking and Obesity . _ . : i - . . . . . . . . _`. . . . . . ii-; `. `. : :!; 39 Smoking and Electrocardiographic Abnormalities. I.--I; 43 Smoking and Heart Rate . : .`;-:t.`: ;:i;..' i, .;- .I ..,> _, .`_*.*._`. . . . . 43 The Effect of Cessation of Cigarette Smoking on Coronary i Heart Disease.. . .";. ; ::; ::`;f: _ 1';. e5'.:1'l . , . .". `: i 1` ; 5' . . :' . . . ,-.y'T. 43 The Constitutiona] Hypothesis ;: .;~J:-~-~,~: ;:!;:Y,< ,`t.: ;:,I )y.F.> 44 Autopsy Studies Relating Smoking, ~Atheros~lerosis, and ~' "- ti Sudden CHDDeath . . . . .`;:..`; .!..`~...`.~.~.;:`....~~`~.I':i'~'):: 48 Experimenta Studies Concerning `the `Relationship of ' Coronary Heart Disease and Smoking . . `. .: : : : : . ; : . `. .`." `.' 52 Cardiovascular Effects of Cigarette Smoke and Nicotine . * - , _ , -`.":" ." I `;I,' a;;:, . . .._.............._........ 52 Coronary Blood Flow _ . . . . _ . `. .I,o.y'L'; P .:t &j.`;;:!:`! *1! !&j `<>*<..a.irTJr; ;`- . . . . . . . . . . . ..-....... ) :54 Cardiovascular Effects of Carbon Monoxide . ;i .`i; I. 5 ::f. 1 .`i'.55 Effects of Smoking on the Formation of Atherosclerotic _,`. Lesions -- .-..- I-, II-- . .I `i . . . . . . . . . . . .._. . . ...`::. . . . . . ..-.. .:;r'.. . The Effect of Smoking on Serum Lipid Levels . . J:~!:~ ;; ?:s- 59 .f 61 The Effect of Smoking on Thrombosis . i; ;:;J.:. :Y,:.,`~~~~l~`~~~ 62 Other Areas of Investigation - _L. ._ . , : ., . . ., . . . . ., . . - - .-. :. 2 - , . . . , -* , ?Z I. . Iit. i . . . . . . ,:;-, '..,,' *- . :; 62 Nonsyphilitic Aortic Aneurysm . . y.;. . `. . . .:. ;`I-. . .,;r:t:!.r.~r.- .' 63 Peripheral Arteriosclerosis . ;`.`. .: ; . .-::`;:!u. ;. ;. . . .: ::1?-:3!;.$68 -`.,:r--`:;i~ ,`) -, .,? := i ,*,-' ,r` `. Experimental Evidence.`:".~~.;.",~,~!,I^;.!;.-f!~,.: ~~~;, ,:,r-: I- .69 Thromboan.itis ObIiteran;Y :`~:x-~iif*:i?~~. f;:F:nfi- ./-:s;f :+.3 `,;Q-j . . . . . . . . . ..`................ Summary and Conclusions . . . . . . -. .- `eiIj,ure -, `!::,y-;.p::2, . . . ...* :..- . . . . . s..: . . . . -. _ _...,, W..`.`. I-.--. 13 -Coronary Heart Disease . . . . _ . _ . _ . _ . . Coronary Heart Disease . . . . _ . _ . _ . _ . . Pap Pap ..-..-....a.. ..-..-....a.. 70 70 Cerebrovascular Disease . . . . _ . . _ . _ . . . . Cerebrovascular Disease . . . . _ . . _ . _ . . . . . . . ..-...... . . . ..-...... Nonsyphilitic Aortic Aneurysm . _ . . . . . . Nonsyphilitic Aortic Aneurysm . _ . . . . . . 71 71 . . . . . . ..---. . . . . . . ..---. Peripheral Vascular Disease _ . _ . . . ; -. . . Peripheral Vascular Disease _ . _ . . . ; -. . . 71 71 . . . . . ..-.... . . . . . ..-.... 71 71 References.. _ _ . : :... . . . _ ; :;.;+;ii;;T F References.. _ _ . : :... . . . _ ; :;.;+;ii;;~ F .' .' `,............~`.""" `,............~`.""" 71 71 ,.. ,.. FIGURES FIGURES `11 National Cooperative Pooling Project, Inter-Society Com- 3 ~ssion for Heart Disease Resources, :;. `!,: .+ ..; I, ,,., i c r . . .2-i.-. ,"`+."...j_.~ 1g p Risk of coronary heart diseas;?"(l2 years) according to .-- ..&; . . cigarette smoking habit and-presence of "p&&&ing j';. factors" .(men 30-59 at entry). Framingham Heart $!. cl -\- `Study. .`:`---.`:.`:`.`::"-"`:`::.-"` " a.. . . . . :. :. . . . . . . . -s- : I . - .;,;.-.;-;,' ratio: "i'ca 17-51 2. 3. Estimated coronary heart disease'death year follow-up, and frequencies of paired combinations of six high-risk characteristics in college, for all ages at death _ . . . .I ", `_ . . . . . . . . . . . . . . . . . . . . . . . ;..ii- ,-..... . . 21 4. Relationship between smoking status and serum choles- terol level at initial examination, and incidence of chn- ical coronary heart disease in men originally age 40-59 free of definite CHD. Peoples Gas Light and Coke Company Study, 1958-1962.. . . . -1.. . . . . . . . . .,. :. . . . . . ~. -39 6. Average annual incidence of first myocardial infarction among men in relation to overall physical activity, class, and smoking habits ,,(age-adjusted rates per 1,000) . . . . ..'.~.........; . . . . . . . . . . . . ..1..~.....-.'40 . :.: 1i- 1 _,a , . . ::._a , _ .;. _-<. .; :...I _, :-. aLIST OF kABiESs' -, . . ; . J. ~..~~j'~'.-~~~;jsij~ -: , : . (A indicates tables located in Appendix at end of Chatte;? ::, ji;L2,. .._ .._ . . . L . . . . ._. ,. I 1. Sudden death and acute mortality with first major.-: coronary episodes . 1 . ; :`; . ! :.I:. .e.:. :. ; ;r:`.`.-. . . r-y:: 19 2. Coronary heart disease mortality ratios related to smoking-prospective studies. _ -mci-J; ;IJedz:i.>< ..`;`.`.=~:rc-, ,.22 3. Sudden death from coronary heart disease related to :`. - ' smoking _ ..; -. ;r - - .-; . . . . :< ;`.-; . -`. ..-i;! _ ;`: /. `$i*;;. .`.:r!-!f; 26 4. Coronary heart disease morbidity as .-related .to .<%TL?-~ smoking. _ .; :. . . . .:. . . . . . .;. . . . . . . . -; 1 :.;-:-:,:.- ;,;~&;_?~~ 5. Coronary heart disease morbidity as related to smO~~,R~~.~ &d ing-angina pectoris-prospective studies Y.`: i -.-. .rX2 33 A 6. Coronary heart disease- morbidity and modid+- r retrospective studies `. . .-. . . . .`. . .' .`.- ; y'. ;-. ::w, ~.>,:Ai.:-,.L:~t8g . . . . . : . . - A 7. Differences in serum lipids between smokers and non- r"c!l'%. smokers. .1---- --. . . . . . . . . . . . . *.......-...... . :. . . -.94 EI ~_ - -- 14 usr 0~ TABLES (CONT.) [A indicates tables located in Appendix at end of CII~~~~, ^ Page A 8. Blood pressure differences between smokers and non- i smokers . . . .-;.: 7:. m-i,;`.-,r- :- .I.. -:..;; . . . . :.:.-.r`.-.::~):.`,, 99' 9. Death rates from coronary heart disease, by systolic - +J k -L - blood pressure: ILWU mortality study, 1951-1961 38 10. Death rates from coronary heart disease, by diastolic : !:J::' -, % ..L blood pressure : ILWU mortality study, 1951-1961 38 .-II. Death rates from coronary heart disease, among hy- ..?- ;;bl: pertensives and nonhypertensives : ILWU mortality ' 1 t-j ; study, 1951-1961_. ;:..:F:': ;`I. ;;;~;;.f~.i ;+ j: F?;< :i.yi-i.>{rg ,38 ,12. Death rates from coronary heart disease among men. ,a; without abnormabties related to cardiopulmonary `diseases by weight classification in 1951: ILWU morfa1if.y study, 1951-1961. : ;":`;`!?":?~~`:?;!:?;~-I:;`-.::`;:! 41 13. Death rates from coronary heart disease, by electro- : cardiographic findings in 1951: ILWU mortality study, 1951-1961............................. 14. 1958 status with respect to heart rate, blood pressure, cigarette smoking, and ten-year mortality rates, by cause (1,329 men originally age 40-59 and free of definite coronary heart disease) Peoples Gas Com- pany Study,1958-1968....................... 15. The effect of the cessation of cigarette smoking on the incidenceof CHD . . . . . . .._.._......._........ 16. Annual probability of death from coronary heart dis- ease, in current and discontinued smokers, by age, maximum amount smoked, and age started smoking A 17. Incidence of new coronary heart disease by smoking category and behavior type for men 39-49 years of age --.........................-.~........ A 18. Incidence of new coronary heart disease by smoking -- -- 101 category and behavior type for men 60-59 years of age . . . . . _ . . .`. . _ . .3 . . _`. . . .: .-T. .`1 .: . . . ..-. _ . . 302 19. Autopsy studies of atherosclerosis _ . . _ . . . . . . . . . . . . 49 A 20. Experiments concerning the effects of smoking and nicotine on animal cardiovascular function . . . . ; . 103 A 21. Experiments concerning the effects of smoking and nicotine on the cardiovascular system of humans. . 109 A22. Experiments concerning the effect of nicotine or smoking on catecholamine levels - 115 e.......,....... A 23. Experiments concerning the atherogenic effect of nicotine administration - .- 116 . . . ..-.................. 41 41 42 42 LIST OF TABLES (CONT.) (A indicates tales located in Appendix at end of Chapter) Page 24. Experiments concerning the atherogenic effect of carbon monoxide exposure and hypoxia _ 60 425. Experiments concerning the effect of smoking and nicotine upon blood lipids (Human Studies) *' rx.-.--rclf- .----s 119 C125a.Experiments concerning the effect of smoking and.lmPKG./DAY `1,' . 1 ' `.' 196' .s , . ,: .z..A:,, ___; 37 - 12 x7 - NONE ANY ONE . 7'. P PREDISPOSING FACTORS (CHOLESTEROL > 250. HYPERTENSION. DIABETES) *SIGNIFICANTLY DIFFERENf FROM "NONSMOKER" P<.D5 ,. .$. ._ = <. , 7 ,: :; : _ + 3 _- . . .= `.- E~CURE Z-Risk of coronary heart disease (12 years) according to cigarette smoking habit and presence of "predisposing factors" (men 30-59 at entry). Framingham Heart Study. . .: SOURCE: Kannel, W. B., et al. (9.4). _ $-, f `.: ; .I< 1.. -- _- :,;: _, :. ;. ,_* :: : : _ < . . ;;.. 1, .F : -`. I * ,`< : : ;' r.. -- ., _ : ; 1 s-j ^I __ .;,` -i I . _- I +. .Y Numerous epidemiological studies have indicated that cigarette smokers have increased mortality ratios for CHD ; that is, cigarette smokers show significantly increased death rates compared with nonsmokers (table 2). The risk incurred by cigarette smoking in- creases with increasing dosage and, as measured by mortality ratios, is more marked for men in the younger age groups, under age 60, although the absolute increment in death rates experienced- by smokers over that of nonsmokers continues to increase with increasing age. Table 2 lists the mortality ratios found in the major-' studies. Certain of these studies, including those at Framingham, Massachusetts, the Health Insurance Plan of Neti York City (HIP), and at Tecumseh, Michigan, have analyzed morbidity as well as mortality from CHD and have indicated that the risk of developing fatal and nonfatal CHD is greater among -cigarette smokers than among nonsmokers (tables 3 and 4). Conflicting etidence has been published concerning the relationship of ciga- rette smoking and the incidence of angina pectoris. While some 20 CI**nttn --I 3 SF. BP 130+ --B 2.4 . 131 2 140 1.4 1.4 LO 238 201 1 324 442 373 clI!Il 644 O- I CI~."ttsl `-A 3 H,ilhl <69 -B 2.0 2 ---.. 1.5 96 I.3 124 1.0 Z?? 1 Lllllh 199 346 468 394 875 0 no rpxt-A SP. BP no+ -6 . _- :`:. I O- i C' ! . k. .1. 2 1.1 1.9 ). 7b 1.3 124 102 1.0 1.1 - 149 1 232 4`2 ,- sp. BP 130+ _A hnnl dud --II : . . ; 2.5 3 2 ' 1 10 3 .._ 2 I -0 3 _ 2 I -0 3 2 1 -0 3 /- A+ A- A+ TABIF. 2.-Cormry heart disease mortality (Ati number of dathm [SM = SmoLcn AMhOG .* __. ,a=, amnh. Nmbcr,d .~. --. `: ; pOD&tiOn " Data rcfermm cdkctIon Hunmoad 187.7BS QucaLIm- ;"I a% 6.297 NS . . . . . ..!!l.OO (709) md rhItcmrkm nab.? md __-.___ -.----.-Msmokcn .1.70 (assl) - Horn. fne.t.ba - 1968. ' c&-69 ,e*n V.SA oflpr - mate. -\ (,,, ,I). _, _. , : : t `. `(v26 . . . . . . ..*.43 (50). : : ,, ,- I .- ,, . . ,(;:, 7 stmbel a.743 male Question- e 162 NS . . . . . . ..LOO md Gc.eU eSti phy- enrim and :.. i _ -;:,..>-.c -2 1966 skiam. fOUOW-Up I.__ _, l-20 . . . . ...1.48 swit.mr- of death hnd . -7 ' ">20 ________ 1.76 (`c: 1, crrti6ute. (150). .-- i ~~ Bat. Appmri- Quatioa- 6 mat.& `. , naircmd L :-7 j _ 2.000 NS . . . . .._. 1.00 1966 Allsmoker, .I.60 (1380) Ctnadn 78,cmo fOlhLWD c- ; ,tt,;j .-is ;, `Z I;,.. ;:_- 20 ..:..::1.78 (277) --,: returns. `- r. a: ; _L;;,~ -2 ,I ,kF ., lrdm 1966 U.S.A. . (88). us. In& Qoestion- 8% 10,890 NS ________ 1.00 (2997) vctcrula nrire and Allsmokcrs .1.74 (4160) : 2.266.674 fouoov-up :, -.. :" 1-3 ..-.__-. 1.39 (43SP ; :`..`. Del-m ~I. of dalb _ry t :- ..`I IO-20 _.._. .1.78 (2102) 1' : : i Jan. I ' ecrticlute. ' PI-39 . I ; I ___.._ 1.84 (1292) ; . . 1 fl .,y.-, : ; : : 7-q ;-`,l,. c 2 . . --?>39...... . .-.f.OO (266) i. Hhw. 266,118 Rmincd in- * 1 91 NS ____ ____ 1.00 fl7) . nmks LIcdiulu- l2 62 NS ..__ .-..l.OO (27)) ratios related to smoking-prospective studies dlcmn b parentheses)' NS = Nonamokenl - _.- . . .~ __-_ Cigars I. ,... NS..l.OO .- `- : NS ..`. so-Sb 6649 6-I 6548 . . . . . 1.00 190) 1.00 (142) 1.00 (204) 1.00 (273) . rI.C : b,.?zmG SM..1.28 (420) ..AUsmokcrs .193 (765) 1.85 (962) 1.66 (921) 1.41 (718) .<., .,,,:,!;,.; Pipu . . . . . . ..I.38 (36) 1.98 (60, 1.17 (49) 127 (68) NS..l.W - -""l20 . . . . i::.Z.Kl (203) 2.47 (199) 1.92 (129) 1.66 (78) .t z -s:. :;.$> ). ,, ' Data WDIJ : . . 7. . . . : : ~. ._ or& to maks . . 4red40-49 -. md irea CucED~t entw.NS Include Dive, .___ ~. ~----. ._.-._. --- __. _.._ -..- _. -. --._-. . ~~~___~ _ -- .- ..--- eksrmd : .-I : I a:;-. I, . ..-f.. er-amoken. Sd-bb bsmb 85-64 : . NS . . . . . . . ..l.OO 1.00 1.00 :t.: . I-14 . . . . . .x73 : 1.40 1.71 ! ? _ : lb24 . _. . .4.46 1.79 1.27 . . : i.%. >26 . . . . . ...1.36 1.92 1.68 --. -..-.- _ _. _ _ _. .~ _ .- _- - _- - - NS. .I.@, sy..1.46 .I : - ;.:-.. ._, : : Tllsu 2.-Coronaty heart disease mwtdity ratios (A&ml number of dacha (SM = Smokrn 5mond :c4*!`1L- :, C..,`.". ti-.:t !N-z _' ., ;-:-- -._ : . . . . `2 t:.!iJ` . : : . . I; ,.. :.., :. c i:..Z!.- :. . . . ._ :: Paffcnbu- 60.000 m& BUClIlIIT 17-61 1.146 NS . . . . . . . . 1.00 zcr md ._ former intervIew -..--r-mddxd 24 . . . . . ...1.60 (886) (D20 . . ..z.os 1970. men 8664 screeninp U.8& Jean of and follow- (zra). m. 09 of dcnth CcrtIflc~Cs. Tad.x _,K71 m.l* lntcrvlew. 6 ,_ 46 NS . . . . . .._ 1.00 (4) ,* ., o ? ?o?? railroad md rmulqr . <20 . . . . . . . .I.97 (20) I < i. 1970.. -Db?m foollaw-up - USA 4&69 ye=n ULPL- -.: :c, (-:, ;I! >2@ . . . . . . . .S.60 (22) c: (18s). of aamat Ln.t,on. ! : `.Z. :, 1 !I,i;; <.`.I . `:-, < , .:`. Pooh T.427 white XedIcrI a- 10 239 NS ._._ me m&s . . . . .I.00 (27) unIaatlm Amdan :.,_ `. :- 20 . . . . `. . . . S.00 (68) -:,,L. ___ .- _ .--w------y--_ .: -, <-; tJ=b -_. :. _ `) - ,,.. :-., I/ 1970. ., ... * ,,, US& :.. (Jr). - : _.! , _`., + I .). `- .; ,. _.' - r. , ,:I-; ,._ .. _-. ., _, 24 related to smoking-prospective ntudies (cont.) .hom in 9.~theses)I .,s'? ' NS = Nona.a~cn] ^ A'..- --.+-.. --. .- : T, `. : - I r - - ---~ --- -,o-" as--51 ,s-4* , .`-.. ----- - ------ - .. NS . ..`...... 1.90 1.00 1.00 ,:i, `I',3 ' .;.; (DA.: :. .>t,. - __. __ ._. . .:vl_.,: "I _ 7:..:..-?,1 ,r; -:; ;ic :I -,;.'z ,l?:.z:. : .' L-c,:-..- .?I- I(: ..`i -5 . ,,' ~. . . . _~ ~. ~. -. _ SC-II b6-6b 65-d& .86-m . ..NSincluda __ `. `5 .: us _ ,....... 1.00 1.00 1.00 .`: 1.00 -, i; ?: DfDa mad : I-.. 2 &IO . . . . . ...4.22 2.06 1.41 1.17 .I>l!~.`dpsm. `: ,I .- i- l. -, r: `.(T ___ 520 . . . . . ...6.14 a.17 1.64 .i 1.26 '!I!&:&. ml inchlda ^ ,.. 7.' -_-. *Jo . . . . . . ..I357 ldl 1.66 .,r 1.86 ..rrf?,eramoktn.- ' e.2 .ro . . . . . . ..i.sa a.16 1.42 :-I 1.42 <>,I! .- . :- 7 . r-' AU . . . . . . ...6.24 2.96 l-66 i 1.24 ..' _ TMLE 3.Pudden death from coronary Project. Amcriua aart hwciation. 1970. U.SA. (88). TABLE 4.-Coro7uzry heart disease (Risk rstlos-actus1 number of CHD [S?d = Smokers NS = Nonsmokcn Dorh 2.282 nula Dctdkd 10 24a mro- NS . . . . . . . . . . . . 1.00 (62) cc al.. F~minghlm. mcdkd CSKdM AU smokers . _. .2.36(191) 1964. 3W2 yean usminn- infrrc- <20 . . . . . . . . . .I.98 (44) . USA. of Lge. tian snd tions and 20 . . . . . . ..__.._ 2.06 (64) (84). 1,913 m&s folka-up. CHD >20 . . . . . .._.. 3.04 (83) An=w. dathx. X9-66 ran of sgc. 8Lunlcr 1.329 CHD- Int.e?vicv 4 46 CHD NS . . . . . . . . . . . . 1.00 (2) ct& free mrk mnd uamio- 1666. anDlo7rn of stion 4th =`; ;ig;;t.ty: 2.92 (6) 4 USA. PcoulQ Gas clinic < 6 vbca..... (177) _ COUlD=V folbr-up. l&19 cigarette.3.67 (8) 40-59 ,an of *se. > 6 PIPCS..... 4 96 mak. Male* 92 femak 40-58 CED in- NS . . . . . . . . . . ..l.OO (1) duding EX . . . . . -. . . ...6.63 (10) deaths, Clg.rrttea . . . . .6.20 (36) msirm. and Femakm ,nyocudIII NS . . . _. . . . . . . . 1.0 (21) idsrctlon.. EX . . . . . . . ._ . . , 0.80 (1) Cfp.RtrcS . . ...1.02 (X0 26 heart disease related to smoking of death shorn fn Darentbesca) Ci~rcttesldru Clean, Dive Comment Never smoke3 ........... 1.00 (16) 1.00 (16) See t&k 1 for der.crlDthn of 210 ............... z.. .. .t.90 (23) 1.86 (13) Pooling Project. 20 . .:.: ...... . ....... .x.90 (60) z-20 .................... 5.36 (40 morbidity US related to smoking msoifstrtions shown in psrcothesea)' EX = Exxsmokcnl PROSPECTIVE STUDIES-Continued Pipes, clears Age variation cornmenb Dats include CHD deaths. only on m&s 4049 remn of we md f rrr of CHD on entry. NS includa, PIPeE. c&w% and cx-smoken. NS include cr-smokera. Includn all CHD. Mole&ntinued M.Zk. Recxrmination 80 and WdT N-59 Of pdenb 1.00 (7) SM . . ..l.SO(Z) WOJ spread l.z?(ll) 60 and over cwer 1y,.a-yar 1.96(23) SY . ...0.86(6) Femah-contlnued period. but dsta are re- 1.00(47) DOdZd in 1.11 (6) tcrma of 0.42 (2) 4-year in& dence r.tes. Actual number of CHD inci- dents derived from dsta on incidmce and tot4 In smok- ha CLsl. 27 TABLE 4.-Coronary heart disease (Rhk rrtIm--sctrul number of CHD (SM = Smokcn NS = Nonamatcm PROSPECTIVE STUDIES eAUthOr. *-. Number knd Lkt, Polkm- Number ot camtrr. t7De Of eolkctlcm UP incidenti Clgl3rtttM/&T rdcrarcc pOpllhti0n la- Jenkins. 3,lfJZ mda Initid 4% 104 m,o- NS __ . . . . ..- . ..I.00 (21) et 8L. 19-69 ,cIn m&cl1 UldLl EX ._.___ . . . . . . 1.47 (16) 1968. of sge at usmin8- hhrrtbnm. Cumnt _ ., ._. .2.78 (68) U.S.A. mtl7. uon rnd o-lS/daT ._-._. t1.as (46) (901. fol!er-up >I6 _ -.*-.. . . . . . WI6 (69) br -t aunlnr- uon8- Kmoel. 6.127 mslea Y&d l2 226 myc- kr,c,a rnforc:ifm et al.. and females crur.fnstbn UIdW M&8 1968. to-59 yt*ra end follow- Snflrc- NS . . .,* . . . . . . . 1.00 (21) U.S.A. of *pz. UP- tiorl~. AU slid . . . . . . . . 1.61(16a) (94). a80 CHD. aesvy SM . . ..I.86 (69) Ri.k of CHD (owrdI) Mdu NS .._____ _ . .._ 1.00 (61) l-10 . . . . . . . . . . . I.24 (25) II-20 . . . . . . ..__ 1.80 (90) >20 . . . . .._..._ 2.41 (76) Shapiro 110.000 male Bwelioc mcd- a Tot&l Mok. et IL. sod femak kd ioter- un*pecl- NS . . . _. . . . __ .I.OO 1969. cnr0lk3 ricr md tied. At1 cul~cnt . . . .2.14 U.S.A. of Ecmhh rxamin*ticm cigsrettea (p20 . . , . . . . . . .2.33 Greater I >40 . . . . . . . . . ..B.JC New York (HIP) a-4 le.= of .gc. K,. 9,186 m&s Iotervie~ 5 65 dcatha. NS. EX 1970 In 6 coun- and r-- 80 nwocIIr- Ytlp+ (SM <20) I. .1.00(306) tria lo-59 Isr foibw- dial in- AU current ah& Icall of np examins- f.rction% PinLnd (>20) . . . . . ..1.31(103) .*e at entrY. lion br 128 8ngir-m ItAb Lxrl NdhU- DCCti?iU. Dhysici*nr 156 other lands - C- (III). t428 totaL 28 mwbidity as related to smoking (cont.) mmnifahtioos show in p~renthmcs)' EX = Ex-emokersl PROSPECTIVE STUDIES--Continued (~o.ol) fD20 . . . . . . . . . . . 1.17 (13) myocardial infarctions. DtUIZl 13,145 male Dsta only up to 14 Total un- et rl., p*tienb in on *cur ape&&d. 1970 periodic health incidents U.S.A. examination extracted (55). clinics. from clinic recorda. POOtiIlp 7.427 while Medical 10 638 Prujtct. mrla 30-59 examination Includea Never Fmokcd .l.OO (63) American ,can of xnd follow- fatal and 20 . . . . . . . . . ..3.28(164) 1970. infarction USA. nnd audden car). death. Pmxl CL IL. 1.939 Wntcrn Screening lP63, Ekctric co. crsmination COTOMW TJmsa rmk workera and CaBCS 167) (li.4). prticipatinp history. NS .__ .__.... . 23 In. prmpcc- l- 7 _ . . . . . . . 2 tire atw3Y 8-12 . . . . . . . . _ 9 for 4% ,C.rn. la-17 . . . . . . . . - 6 18-22 .----- 41 .._..... - 23-27 , . . . . . . . a >28 ___ . . . . . . . 9 30 ,/. ,,... y. -I .`J. ~- ,J ., -1 . . , : . . . ,, , ,, -.. :' ,. . ._ .:,, .-; _ , :s. ! ,`.' .' ; 1. i, :i:;.-, . . :* ;-,2 . I,,.i: , ,.Z' `: ,_ ,>' f `., ; -' ' .; .,. , : ,I ..- ` tios JO-19 .( ; bo-bf 60-59 t Includea ; SM 1.00(26) 1.00(126) 1.00(167, NS. EX. and ." _._ I,. tHlgb <20 cigarettes/ . --: . , day. .I SM 2.17(10) 0.90 (31) 1.41 (63) :>ZOei`~a- . . . .`.d ..I )*,-J.. .iz- ._, ; , r&es/dry. ,' I :.:.* ;`.. ,_I.' -: ,`., : Include. all ' . CHD blrt __ I .._. . . .,_. _.. :.I :: :,:-* I ;-car. ,., -; `.. : - . . r `- .' czcludr. ._. 1.26(60 ' = . i . . -.. 1. . . -* . . . ..1..--- :. . .-, `. 1; ,.,., -; , =...; ,. I : ,,, +i : 1;. -*. __ .:. studies have shown an increased risk of this manifestation among smokers, others have not (see table 5). From these longitudinal studies, it has become increasingly clear that cigarette smoking is one of several risk factors for CHD and that it exerts both an independent effect and an effect in conjunc- tion with the other risk factors. The basic concept may be ex- pressed as follows: The more risk factors a given individual has, the greater the chance of his developing CHD. The importance of the constellation of coronary risk factors which include cigarette smoking, high blood pressure, and high serum cholesterol in pre- dicting the risk for CHD is illustrated in figures 1 through 3. Other risk factors are included in certain of these figures and are dis- cussed below. Knowledge of the effects of cigarette smoke on the cardiovascu- lar system has developed concurrently with the knowledge derived from the epidemiological studies. Nicotine, as well as cigarette smoke, has been shown to increase heart rate, stroke volume, and blood pressure, all most probably secondary to the promotion of catecholamine reIease from the adrenal gland and other chromaffin tissue. This release of cateeholamines is also considered to be the cause of the rise in serum free fatty acids observed upon the in- halation of cigarette smoke. Studies concerning the effect of nico- tine on cardiac rhythm have also suggested that smoking might contribute to sudden death from ventricular fibrillation. In addition, research efforts have also been directed toward the effects of smoking on blood clotting and thrombosis; since many _ cases of sudden death and myocardial infarction are associated with thrombosis in a diseased coronary artery branch. Cigarette smoking may be associated with increased plateIet aggregation in Vitro and thus might play a role in the development of such throm- bi or platelet plugs in viva. , Other mechanisms have been investigated. Because cigarette smoking has been shown in some studies to be related to the prev- alence of angina pectoris as well as to the incidence of myocardial infarction, it has been suggested that smoking enhances the de- velopment of atherosclerotic lesions. Autopsy and experimental studies have shown that cigarette smoking plays a role in athero- genesis. The administration of nicotine has been observed to in- crease the severity of cholesterol-induced atherosclerotic lesions in exper+nental animals. Attention is presently being given to carbon monoxide, which is present in cigarette smoke in such concentra- tions as to cause carboxyhemoglobin concentrations in the blood of smokers as high as 10 percent. Based on research in animals, it is reasonable to conclude that the atherosclerotic process may be enhanced, in part, by the relative arterial hypoxemia in cigarette 32 ;f .' ,;p, - -. $,,:" : 1(' -: : TABLE S.-Coronary heart disease morbidity aa related to smoking -angina pectoris+woapective atudiee .+, . (Rl#k +.l~-utu~l number of CHD mrnlfntatlon# shown In parenthesn)~ `,,. ;, ,;, -. ! [SY = Smokera NS z Nonsmokers] Cll?#M -. Clmrcttedday wd DiDC. :.-, : .I `., : AgevarIatIon ,. `t `.I " Commcntr ?`. . . NS Include ez- Malu Fmalsc M&b Male* t (PCO.01) >4o ..*,..a . . . . . . . - 4.12 - ' Unb c4h-d~ ~e~ltlcd. dlwultla between the total number of ,A , -ntf-Ulom *ad the bum OK the lndlrldurl wnoklns caegx,ries .re due to the acluslon of citbw aculonal, mLcelLne0ur. mlred. or ex-rmokrtn. smokers caused by the increased carboxyhemoglobin level. With respect to the acute event of myocardial infarction, atten- tion has been focused on the role of nicotine. Nicotine stimulates the myocardium, increasing its oxygen demand. Other experiments have demonstrated that in the face of diminished coronary flow `(due to partial occlusion from severe atherosclerosis in man or to partial mechanical obstruction in the animal), nicotine does not lead to an increase in coronary blood flow as seen in the normal individual. These effects exaggerate the oxygen deficit when the supply of oxygen has already been decreased by the presence of carboxyhemoglobin. Thus, a marked imbalance between oxygen demand (which has been increased) and oxygen supply (which has been decreased) is created by the inhalation of CO and nico- tine. This imbalance may contribute to acute coronary insufficiency and myocardial infarction. EPIDEMIOLOGICAL STUDIES Numerous epidemiological studies, bath retrospective. and pros- pective, have been carried out in various countries in order to iden- tify the risk factors associated with the development of coronary heart disease (CHD) . Many of these studies have included smok- ing as one of the variables investigated. Tables 2 to 4 present the major findings. CORONARY HEART DISEASE MORTALITY Table 2 lists the various prospective studies concerning the rela- tion of CHD mortality and smoking. These studies demonstrate the dose-related effect of cigarette smoking on the risk of deveIoping CHD. For example, the Dorn Study of U.S. Veterans as reported by Kahn (93) reveals progressively increasing mortality ratios, from 1.39 for those smoking 1 to 9 cigarettes per day to 2.00 for those smoking more than 39 cigarettes per day: Although the data are not detailed in the accompanying tables, several of these stud- ies have also shown that increased rates of CHD mortality are associated with increased cigarette dosage, as measured by the degree of inhalation and the age at which smoking began. Although not as striking, the data for females reveal the same trends. In most studies, the smokers' increased risk of dying from CHD appears to be limited mainly to those who smoke cigarettes. Some studies that have investigated other forms of smoking have shown much smaller increases in risk for pipe and cigar smokers when compared to nonsmokers. However, the recent study by Shapiro, et al. (172) of a large population enrolIed in the Health Insurance Plan (HIP) of New York City showed a significantly increased risk for the development of myocardial infarction and rapidly fatal myocardial infarction for a group consisting of both pipe and cigar smokers. Table 3 details the findings of the American Heart Association Pooling Project on sudden death. The Pooling Project, a national cooperative project of the AHA Council on Epidemiology, is de- scribed in table 1 (88). Cigarette smokers in the 30 to 59 Year age group incurred a risk of sudden death from CHD substantially greater than that of nonsmokers. Pipe and cigar smokers were observed to show a risk slightly greater than that of nonsmokers -- (table 3). The relative risk of CHD mortality is greatest among cigarette smokers (as well as among those with other risk factors) in the younger age groups and decreases among the elderly. In table 2, Hammond and Horn found that for those smoking more than one pack per day, the risk is 2.51 in the 50 to 54 year age group and 1.56 in the 65 to 69 year age group. Although the relative risk for CHD among smokers decreases in the older age groups, the actual number of excess deaths among smokers continues to climb since the differences in death rates between smokers and nonsmok- -ers continue to rise. CORONARY HEART DISEASE MORBLLIITY Tables 4 and 5 list the prospective studies carried on in a num- ber of countries to identify the risk of CHD morbidity incurred by smoking. Here, CHD morbidity includes myocardial infarction as well as angina pectoris. Certain studies, notably those of Doyle, et al. (541, Keys, et al. (III), and Taylor, et al. (185) include a number of CHD deaths in their data that could not be separated out .using the information provided in their respective reports. As noted in the discussion on CHD mortality, the CHD risk ratio increases significantly as the number of cigarettes smoked perday increases. Similarly, the HIP data of Shapiro, et al. (17.2) sha$ that the elevated morbidity ratios declined with increasing age as has been shown for mortality ratios. A recent monograph edited by Keys (111) dealt with the &year CHD incidence in males age 40 to 59 from seven countries. As summarized in table 4, cigarette smoking &as found to be associ- ated with an increased incidence of CHD in the U.S. railroad worker population, 2,571 individuals (183). None of the differences in ratio between smokers and nonsmokers was statistically sjmifi- e-ant for the 13 other population samples which varied in size from 505 m 962 individuals, from the five other countries. (Smoking was not considered in the two Japanese populations.) men more cases . . 35 become available to provide greater statistical stability to the rates, this intercultural comparison should prove illuminating. The results of those studies which have separated out angina pectoris as a manifestation of CHD are presented in table 5. Doyle, et al. (54) found no relationship between this manifestation of CHD and cigarette smoking. Both Jenkins, et al. (90) and Kannel, et al. (94) observed increased risk ratios among male cigarette smokers although these. differences were not statistically signifi- cant. More recently, Shapiro; et al. (172) found a significantly increased risk for angina among their male cigarette smokers as well as increasing risk ratios with increasing dosage among both males and females, particularly in the .younger age groups. A variety of hypothetical explanations have been advanced to account for this seeming contradiction- Among these are the relatively small number of cases, the difficulties associated with the definitive diagnosis of the syndrome, and differences in the methods of clas- sifying those cases of angina pectoris which are followed bv mvo- cardial infarction. RETROSPECTIVE STUDIES Table A6 presents data from the various retrospective studies of CHD prevalence. Most of these are case-control studies and show an increased percentage of smokers among those with clinical CHD when compared with a selected control population, usually without apparent CHD. Two of these studies include data on mortality. THE INTERACTION OF CIGARETTE SMOKING AND OTHER CHD RISK FACTORS The preceding section has reviewed the epidemiologic evidence which supports the judgment that' cigarette smoking is a signifi- cant risk factor in the development of CHD. Many of the studies discussed above have identified a number of biochemical, physio- logical, and environmental factors; other than cigarette smoking, which also increase the risk of developing CHD. These risk factors include elevated serum lipids (particularly serum cholesterol) and hypertension, which, with cigarette smoking, are considered to be of greatest importance. .Other facto&-are obesity, physical inac- tivity, elevated resting heart rate, diabetes (as we11 as asympto- matic hyperglycemia), electrocardiographi~~abnormalities, and a positive family history of premature CHD (88). A number of these studies have also found that these factors, when present in the same individual, exert a combined effect on the risk of developing CHD. Figures 1 through 3 depict this inter- action of risk factors. As may be noted in Figures 1 and 2, the 36 additional factor of smoking greatly increases the risk of develop- ing CHD among those people already at high risk because of other factors. Furthermore, these studies have shown that the effect of smok- ing on the risk of deveIoping CHD is statistically independent of the other risk factors. That is, when the effect of the other factors is statistically controlled, smoking continues to exert a significant effect on increasing the risk of developing and dying from CHD. Smoking and Serum Lipids The interaction of smoking and serum lipid Ievels in the develop- ment of CHD should be considered in the light of information con- cerning the relationship of smoking to serum lipid levels. Table A7 presents studies which deal, with the association between smoking and lipids, notably cholesterol, triglycerides, and lipoproteins (con- cerned with lipid transport) _ While some of the studies have indi- &,ed that smokers show increased serum IeveIs of these lipid con- stituents, others have not. The populations investigated and the methods of the various studies show significant variation. This lack of comparability makes interpretation of the tidings diflicult It is clear, however, that in the presence of high serum choles- terol, cigarette smoking increases the risk of. CHD. Figure 4 de- picts the data from the Chicago Peoples Gas, Light and Coke Com- pany study which show that smoking greatly `&eases the risk of CHD in each of the cholesterol groups. Smoking and Hypwtemion Some epidemiological studies have indicated that smokers tend to have lower mean systolic and/or diastolic blood pressures than nonsmokers, while other studies have not found this to be the case (table A 8). Reid, *et al. (155)) in a study of 1,300 British and American postal workers, found that the blood pressure difference between the smoking and nonsmoking groups was eliminated after controlling for body weight. Tables 9 through 11, derived from the study by Borhani, et aL (27) , demonstrate the following associations : That for both amok- ers and nonsmokers, the risk of dying from CHD increases with increasing diastolic or systolic pressure, and that the risk of mor- tality from CHD is higher among smokers than among nonsmokers in each blood pressure group. Cigarette smoking, therefore, ham been shown to elevate CHD mortality independently botb'of its effect on blood pressure and of the effect of hypertension on CL-ID. Smoking and Phyticul inactivity The recent study by Shapiro, et al. (172) of more fhan 110,00fr TABLE Q.-Dsath rate6 from coronas hem9 dineuse, b sy&& b&d $wuMc: 4664 . . . . . . . . . . . . . . . . `.:. - lO Never cig.rruc./day smoked r~~ulrb _ ._ . . .1.00l1.841) l.OO(1.841) Yale da. only CUlTCUt clemrettc amaken . _. . _ ._ l.DO(1.063) 2.66 (2.822 ) stoD,Xd 20 . . . . . . . . . ..-....... 1.08 (70) 1.06 (80) AU cx-dnardte smokers . -1.16 (263) 1.28 (6641 N Total &finite myacardial infarction ever smoked .._...._._... _ . . . . . . .._...... . . . . . . ..I.00 Current cigarcite smokers ......................... 1.87 StDPM S6 Yeara ................................. .0.78 AR CHD &aLhs Never smoked . . . ._. . . . . . . .1.00(27) >`j4 wck/dsy _ _.._.___. ._ .1.66(34) 1 wck/dq . . . _ . . . .._. . ..1.70(.66) >1 Drck/dry . . . . . . . . . .._.. 3.00(68) Exsmokcrx . . _ . . . . . . . . . . . . 0.80(19) Pirmf major CormION event 1.00 (63) See table 4 1.66 (72) for description 2.08(205) of Pmlinp 3.28 (154) PrOiKt. 1.25 (61) TAEKE 16.-Annual probability of death front coronary heart da%ease, in current and discontinued enwkers, by age, maximum amount smoked, and age started Bmoking .-e-v._ _ ..___. 0 601 - 601 - lo-20 198 608 811 661 7.149 S60 766 612 698 &`I(' -.__ . . . . . . .._ 0 1.016 - 1.016 - lo-20 1.601 1.169 1.478 1.21t 21-M l.710 l.ur 1.ma 1.0911 * For - group 66-74, ~r.,b.blUUa for dkeantlnrrsd -ken o R for 10 Or mOrr - d dh-- adinn.~cc dacc d.t. for the 64 ,err dk.zantLntunu craw .R not riven. Sxmcx: thmtldd, J, Yft&c~I. 8. (44). Bud cm da@ derived Irma IhIm. 1. A. (#I). 42 Smoking and Electrocardiographic Abnormalltzes Electrocardiographic (ECG) abnormalities such as T-wave and ST-segment changes as well as a number of arrhythmias are use- ful indicators of CHD and may, therefore, be predictive of the development of clinically overt CHD manifestations. The results summarized`in table 13, from the prospective study by Borhani, et al. (279, reflect the joint predictive value of smoking and ECG abnormalities on the death rate from CHD. Smokzng and Heart Rate Recent analysis by Berkson, et al. (25) of the data derived from the Chicago Peoples Gas, Light `and Coke Company study of middle-aged men revealed that resting heart rates of 80 or greater were associated with an increase in the risk of death from CHD. These authors found that this association was independent of the other major coronary risk factors. Table 14 presents the interaction between smoking, blood pres- sure, and elevated heart rate in increasing the risk of CHD mor- tality. This study shows that cigarette smoking increases CHD risk in the presence of elevated heart rate as well as in its absence. THE EFFECT OF CESSATION OF CIGARETTE SMOKING ON CORONARY HEART DISEASE A number of epidemiological studies have been concerned with the CHD incidence and mortality among ex-cigarette smokers as compared with current smokers (51, 76, 88, 90, 93, 172). These studies are listed in table 15. Table 16 presents the data derived by Cornfield and Mitchell (45) from the Dorn Study of U.S. Veterans (93). Ex-cigarette smokers show a reduced risk of both myocardial infarction and death from CHD relative to that of continuing ciga- rette smokers. The Pooling Project (88) and the Western CollaB orative Study Group (192) which adjusted for the other risk fac- tors of elevated serum cholesterol and blood pressure observed this relationship. Hammond and Garfinkel (76) noted that cessation of smoking is accompanied by a relative decrease in risk of death from CHD within 1 year after stopping. This decreased risk of CHD among ex-smokers further strength- ens the relationship between smoking and CHD. It must be noted, however, that the group of ex-smokers is composed of individuals who have stopped smoking for a variety of reasons. Those who stop because of ill health and the presence of symptoms are gen- erally at high risk and can bias the group results in one direction; 43 those healthy persons who stop as part of a general concern about their health and may adopt a number of self-protective health prac- tices are generally at low risk and can bias the group results in the other direction. Therefore, ex-smokers as a group are not fully representative of the entire population of smokers and may have limited value in predicting what would happen if large numbers of cigarette smokers stopped smoking purely for self-protection. Cer- tain incidence studies, such as the Pooling Project, (88)) were initi- ated with only clinically healthy individuals. The data from such studies, as well as those from the British physicians study, contain ex-smoker data less influenced by these biases. Fletcher and Horn (63) have recently presented data derived from the British physicians study of Doll and Hill. Over the past lo-16 years, cigarette smoking rates among British physicians have declined significantly in comparison with those of the general British population. The information presented by these authors concerning all cardiovascular diseases showed that for individuals between the ages of 36 and 64, the age-adjusted death rate for CHD declined by 6 percent among physicians and rose by 10 percent among the male population of England and Wales during the period from 1953-57 to 1961-65. THE CONSTITUTIONAL HYPOTHESIS The effect of smoking on the incidence of CHD has been found to be independent of the influence of the other CHD risk factors. When such risk factors as high serum cholesterol (1771, increased blood pressure (27)) elevated resting heart rate (251, physical in- activity (172), obesity (27), and electrocardiographic abnormali- ties (27) have been controlled, cigarette smokers still show higher rates of CHD than nonsmokers. It haa been suggested by some (39, f7U) that the relationship between cigarette smoking and CHD has a constitutional basis. That is peopIe with certain constitutional make-ups are more likely to develop CHD, and the same people are more likely to smoke cigarettes. This hypothesis maintains that the relationship between cigarette smoking and CHD is thus largely fortuitous and that the significant relationships are between the genetic make-up of the individual and CHD and between the genetic make-up of the indi- vidual and his becoming a cigarette smoker. Two sets of epidemic logic data bear on this hypotheeis. It has been maintained that people with a certain temperament are more likely to smoke and also more likely to develop CHD. These characteristics have been demonstrated for those with the 44 Type A behavior pattern of Rosenmann, et al. (159) which is characterized by competitiveness, excessive drive, and an enhanced sense of time urgency. The prospective study organized by the western Collaborative Group indicates that individuals who ex- hibit this type of personality are more likely to have or develop CHD than those without it (Type B), whether or not they smoke. When the incidence rates of CHD are analyzed with respect to smoking and personality types (tables A 17, A 18)) it is noted that in both Type A and Type B individuals the incidence of CUD is greater among cigarette smokers than among nonsmokers. This research indicates that both personality type, as measured in these studies, and cigarette smoking contribute independently as risk factors to the development of CHD. To what extent such behavior patterns are determined constitutionally or represent acquired characteristics is still open to question. The other type of research designed to study the genetic hypoth- esis has made use of data from registries of twins. Cederlof, et al. (37, 38, 39, 40) have utilized the Twin Registries of Sweden and the Veterans Follow-Up Agency of the U.S. National Academy of Sciences-National Research Council to investigate the relative contributions of heredity and smoking to cardiovascular and bron- chopulmonary symptom prevalence. Data obtained by mailed ques- tionnaires were analyzed for the following characteristics: zy- gosity of the same-sex twin pair, urban-rural residence differences, smoking concordance, and history of various symptoms. Compari- sons were made between smoking discordant monozygotic (iden- tical) pairs and smoking discordant dizygotic (fraternal) pairs, and between unmatched twin pairs and matched twin pairs. Smok- ing discordance has been defined somewhat differently in various reports but, in general, describes twin pairs in which the smoking habits differ between the two members of the same twin pai: Analyzing the data obtained from 9,319 Swedish twin pairs (`72.3 percent of the possible respondents), Cederlof, et al. (39) found that respiratory symptoms were more common among smok- era in both the unmatched and matched smoking discordant twin pair groups. The authors analyzed the data in two distinct man- ners. Group A analysis, which did not control for genetic factors ntihzed two groups; the first composed of all the firstborn, and the second of those listed second on the birth certificates. Group B analysis utilized MZ and DZ t&n pairs which were discordant for smoking, thereby controlling genetic factors. "Angina pedoris," a8 defined by a certain pattern of responses to the questionnaire, was found to be more prevalent among smokers in Group A, but this difference was not present when the data from Group B were an- alyzed. Males in the first group exhibited a "hypermorbidityratio" 45 of 1.6, whiIe those in the second group were found to have one of approximately 1.1. The authors concluded that this difference be- tween the two groups provides better support for the importance of constitutional factors as against the importance of cigarette smoking in the development of angina pectoris. A similar study was done using the responses of 4,379 U.S. Vet- eran twin pairs (approximately 60 percent of estimated available total) who completed the mailed questionnaires (38). Cederlof, et al. found a significantly increased prevalence of chest pain and "angina pectoris" among smokers when Group A. ~8s analyzed. Analysis of the smoking-discordant matched twin pairs (Group B) revealed no association between smoking and cardiovascular symp- tams among the monozygotic pairs. The dizygotic pair data did show a slight association. The authors concIuded that this Iack of association among the monozygotes and its presence among the dizygotes and unmatched pairs strengthens the case for a constitu- tional hypothesis. A major problem in these studies is the small number of cases available and, therefore, the statistical instability of the results. In the Swedish study, among the 274 monozygotes, only 19 smokers and 16 nonsmokers were classified as having angina pectoris while among the 733 dizygotes, 25 smokers and 25 nonsmokers were so classified. In neither group was the difference between the prev- alence ratios found in the Group A analysis and that in the Group B analysis of statistical significance. Analysis of the data on women shows a similar lack of significance. Similar criticisms may be made of the study which utiliyed the U.S. Veteran Twin Registry. In that study, the authors observed that the difference in the prevalence of angina pectoris Mween the low-cigarette-exposure and high-cigarette-exposure dizygotic groups was not present among the monozygotes. The authors ques- tioned whether the excess morbidity associated with cigarette smoking found in the dizygotic group was causal as it was not pos- sible to reproduce the association when studying monozygotic smoking-discordant twin pairs. As noted above, the numbers in this study are also small so that the differences in rates do not approach statistical significance. ~ Tibblin (188) has questioned the value of a mailed questionnaire to diagnose heart disease. The questionnaire as originalIy con- structed was used and validated by interview technique alone (157, 158). Cederlof, et al. (40) conducted a study to determine the validity of this questionnaire as a mailed instrument by personally interviewing and examining 170 of the twin pairs who had replied. Of the eight males who were diagnosed as having "angina pectoris" by the questionnaire. four were found to be free of symptoms on 46 clinical examination, while among 204 responding negatively, two were found to have angina by clinical criteria. None of the 11 women who were diagnosed as positive by questionnaire was found to be cIinicaIIy affected, and of the 136 reporting as negative, three had symptoms of angina pectoris. Other major difificulties associated with these studies include the problems of using prevalence data in the investigation of a disease (CHD) from which a significant number of those affected die shortly after the onset of symptoms, the inclusion of ex-smokers in the smoking population, and the,low numbers of heavy cigarette smokers in the Swedish population. In general, the problems of using twin registries to study the etioIogy of cardiovascular disease with mortality and morbidity ratios in the neighborhood of 2 to 1 are much more difficult than in studying the etiology of bronchopulmonary disease in which the relationships are of the order of magnitude of 4 to 1. More recently, Friberg, et al. (69) reported on mortality data from the Swedish Twin Registry. The authors suggested that part of the increased mortality observed among smokers when com- pared with nonsmokers was not due to smoking per se but to fac- tors associated with smoking. The very small numbers of total deaths presently available (47 deaths among 706 dizygotic pairs and 13 deaths among 246 monozygotic pairs) do not provide a sta- tically stable base for deriving any conclusions at the present time. huge, et al. (81) have recently reported on the influence of smoking on the morbidity and mortality observed in the Danish Twin Register. Among 762 monozygotic and same-sexed dizygotic twin pairs, angina pectoris was found to be significantly more fre- Went in those cotwins with a higher consumption of tobacco than h those with a lower or no consumption. A similar tendency was observed for myocardial infarctions but was not of statistical significance. Seltzer, who has been a proponent of the constitutional hypothe- sis, in a recent review of some of the experimental, clinical, and PothO~Ogica~ data relating smoking and CJID, concluded that the evidence from these areas has not "reasonably substantiated" the "hypothesis" of the acute effect of cigarette smoking on the coro- narY circulation, nor has the chronic effect of cigarette smoking on ihe cardiovascular system been shown to be a "clear" and eon- gist& one (170). His views are contrary to those of most re- achers in this fieid. mhough the data from the twin studies are inconclusive with regard to a role for genetic factors in heart disease, it w&Id be surprising if genetic factors did not play such a role. It is open to 47 question whether findings from twin studies can be used to distin- guish between the hypothesis that genetic factors govern the level of host susceptibility or resistance to the effects of an exogenous influence such as cigarette smoking and the hypothesis that genetic factors "cause" both heart disease and smoking. AUTOPSY STUDIES RELATING SMOKING, ATHEROSCLEROSIS, AND SUDDEN CHD DEATH A number of researchers have investigated the ci&rette smoking habits and the cardiovascular pathology of th,ose.individuaIs dying suddenly from CHD and of large populations of individuals with and without histories of overt CHD. Spain and Bradess (175) recently analyzed the smoking habits of X89 individuals who died suddenly and unexpectedly, apparently from the first acute clinical episodes of CHD. The authors nofed a close correlation of a history of cigarette smoking with this type of sudden death and also with shorter survival times following the acute episode. This association was strongest in those persons under 50 years of age. The Authors also observed that those survlvmg very short pe- riods of time showed a notable lack of intracoronary artery throm- bi at autopsy and that the frequency of thrombi present increased with increasing survival time. They suggested that thrombi found at autopsy may be the result rather than the cause of certain instances of myocardial infarction, particularly of lesions showing subendocardial necrosis. This finding is of significance in the study of the effect of smoking on myocardial metabolism and oxygen supply and demand rather than on thrombus or platelet plug formation. While the autipsy study of Spain and Bradess (175) concerned sudden death among smokers, other autopsy studies from various countries have been directed towards the relationship of cigarette amoking to the presence of atherosclerotic disease in the aorta-and .coronary arteries. These are concerned with the long-term effects .which smoking has on the cardiovascular system and are `sum- marized in table 19. The studies of Auerbach, et al. (IZ), Avtan- dilov, 8 al. (IS), Sackett, et al. (165), and Strong, et al. (~82) round that aortic and coronary atherosclerosis were more common and more severe among smokers than amongnonsmokers. Auerbach, et al. (12) .Gted that this relationship persisted when the cases were matched for both age and cause of death or when the follow- ing cases were excluded ; men.with a history of diab&; men who had died of any type of heart disease ;. and men whose hearts weighed 400 grams, or more. Sackett. et al. (165) found that the 40 TAEILE lO~Autopet( studiea o/ athsroaclaroaia (Flguta la pwmthnn an number of Indivldualc In that amoklnc ertrn0r7)~ [SM = anoken NS = nonmokcrs] AdhOt, 7*rr, Aubpr7 D&tA COUl-li~. DODUktlOC, collcctlon Comment4 odjwkd rrrulk) No othcro- NkTO6b Slight NS .;.., ,.,. 6.6 (69) --.`-. 67.8 Cumnt elgarctte <20 *.,.*1 l.6(139) 30.9 20-39 .,.,0.8(299l lg.7 >49 ,,.`.;.0.6(144) 18.1 the percentage of men with .?I o dv*need deorn of M0hub. Advonccd coronary d,herolckm~k 21.8 16.8 wu hlpbcr .mong elsn- - rette rmokcn thnn among nonrmokem and that the 873 29.2 ' pcrecntagc hcreued 42.1 87.4 with amount of elgrretts 96.4 46.9 I 8moklng. This relation- lblp DM'dlted CvCIl nhm cad" were mhtehed for age and UUI~ of death. TABIX 19.-Autopsy studies oj athumsch'osia (cm:.) (?`I- In DuSrrthC.4. w number of IndlrlduLL in that fimOkiU ukmr7)' [9X = mmken NB = noo~mekenl Ln Anthor, 0 Y-t AntaDtoprl Dab OoOMtn, DODUbtk"3 ' wnudm Ckamtta DCr dw conctuliona cornlnmta rdmu Avtandlh, 219 mab and Nat BDrChdd, fh,SDWdW #(I# of maan a,~ of athbtcrobrutb b&BU The rutbar eoncluda that Cawa of dath 9l-&mro- 1966, 141 f*mmb but there rarer in inn47 mat of covmary a.rkriar. the wont ehanga rm Acrotle, lOZ-wcldrntA, Flunrlr ~~~D~l~. 180 9X uid Rlpht COTOMY ortsru h/1 mrona.ry orby found In the left and 202varloru dlrcua. (Ia). 220 NS. srd Nf mf NS rlsklt ??????? o ?????? tT-tent for +~.lltuncr a049 ,*.tla.s(ao, Lscaz) ma 2.2 nlth h mvcra changer of hlffcrenca klwcen 40-49 . , tzs.ecao 11.6(27) tu.a 4.4 hi clreu.m.8a artery means II llgnldunt so-t.9 ..tae.a(so, 14.8(89) t27.9 9.9 &rid wti. at P26 clmrettes/day . . ..17(10) 14117) 29(12) 16(111 .-. `~IGJW dm-wlre ~~eclAed, dlsparitlcs bctwen the total number of ln- severity of aortic atherosclerosis, as measured both by intensity and duration, increased with increasing use of cigarettes and that this dose-relationship persisted when the patients were matched for the consumption of alcohol. On the other hand, VieI, et al. (200) concluded from their study of accidental deaths in Chile that "no relationship between atherosclerotic lesions and the use of tobacco was discernible." Examination of the data (provided in graph form only) indicates that heavy smokers showed consistently higher percentages of diseased areas than nonsmokers, but appar- ently these differences were not statistically significant when sub- jected to an analysis of variance. Thus, in addition to the acute effects which smoking exerts on cardiovascular physiology, cigarette smoking is associated with a significant increase in atherosclerosis. EXPERIMENTAL STUDIES CONCERNING THE RELATIONSHIP OF CORONARY HEART DISEASE AND SMOKING Several areas of interest in cardiovascular pathophysiology have been investigated in the search for the mechanisms by which ciga- rette smoking contributes to cardiovascular disease, particularly coronary artery disease. Previous Public Health Service Reviews (191, 19.2, 193, 198) have described in detail and commented on the results of experiments by many teams of researchers. Central to the discussion which follows is a concept of cardiac physiology which provides a framework for analysis and under- standing of the varied research. That concept concerns the dynamic balance between myocardial oxygen need and supply. CARDIOVASCULAR EFFECTS OF CIGARETTE SMOKE AND NICOTINE The inhalation of tobacco smoke or the parenteral administra- tion of nicotine has been found by many researchers to be asso- ciated with a number of specific acute cardiovascular responses. These responses have been observed in human as well as animal subjects; including increased heart rate, blood pressure, cardiac output, stroke volume, velocity of contraction, myocardial contrac- tile force, myocardia1 oxygen consumption, arrhythmia formation, and electrocardiographic or ballistocardiographic changes (tables A20 to A22). The effect of these responses on coronary blood flow will be discussed in a following section. That the acute effects observed following the inhalation of ciga- rette smoke are due primarily to the nicotine present in the smoke may be seen in the results of a number of experimenti. In humans, Irving and Yamamota (89) and Von Ahn (202) duplicated the 52 effects of cigarette smoking by the administration of nicotine intra- VenOUSlY. Similar results in animals were noted by Kien and Sherrod (112). The mechanism by which cigarette smoke and hence nicotine in- duces these changes has been of interest to numerous investigators. Nicotine has long been known as a stimulator of both sympathetic and parasympathetic ganglia. Research has centered, therefore, on the function of catecholamines, mainly epinephrine and norepi- nephrine, as mediators, of these responses. Using isolated rabbit atria1 myocardium, Bum and Rand (55) noted that the prior ad- ministration of reserpine to the perfusate blocked the increased rate and amplitude of contraction seen following the administra- tion of nicotine. West, et al. (208) showed that the in vivo cardiac stimulating effect of nicotine was blocked by tetraethylammonium chloride. Leaders and Long (125). Romero and Talesnik (156), and, more recently, Ross and Blesa (160) have all demonstrated this blockade in animals using agents such as pentolinium, hexa- methonium, guanethidine, and reserpine. More direct evidence of the catecholamine-releasing effect of nicotine has been found by Watts (203) and Westfall, et al. (209, 210, 221) (table A22). Among animal subjects, nicotine adminis- tration and the inhalation of the smoke of standard cigarettes caused significant increases in peripheral arterial epinephrine lev- els, while cornsi!k cigarette smoke inhalation evoked no such change. In humans, cigarette smoking was found to be associated with a significant increase in urinary epinephrine excretion. The source of these nicotine-released catecholamines, particu- larly those which mediate the immediate and local cardiac re- sponses to intracoronary injections of nicotine, is felt to be the myocardial chromaffin tissue (35, 160). The more widespread effects are most probably mediated by hormones released from the adrenal gland. According to recent research of Saphir and Rapaport, catechol- amine release may not be the sole mediator of these responses (166). These investigators reported that intra-arterial injections of nicotine into the mesenteric circulation of cats were followed within 1 to 2 seconds by enhanced myocardial performance, in- creased left ventricular systolic pressure, and increased systemic resistance. Sectioning of the mesenteric afferent nerves led to a diminished response. The authors concluded that the cardiovascu- lar response to nicotine may also be neurogenic in nature. Nadeau and James (14.2) injected `nicotine directly into the sinus node artery of dogs and noted an initial bradycardia, due probably to direct vagal stimulation, followed by tachycardia, due probably tb catecholamine release. 53 That the presence of nicotine may predispose the myocardium, particularly a hypoxic or previously damaged myocardium, to ar- rhythmia formation is suggested by the research of Balazs, et al. (161, Bellet, et al. (21), and Greenspan, et al. (74). Balazs pro- duced myocardial lesions in dogs either by pretreatment with iso- proterenol or ligation of the anterior descending coronary artery; It was found that while normal animals did not develop arrhy- thmias upon challenge with small doses of intravenous nicotine, the animals with damaged myocardiums responded with increased arrhythmia formation shortly after their spontaneous arrhythmias bad ceased. More recently, Bellet, et al. (20) studied the effect of cigarette smoke inhalation on the ventricular fibrillation threshold in anesthetized dogs. They observed a statistically significant de- crease in the threshold following smoke inhalation. Greenspan, et al. (74), using isolated dog right ventricular myocardium, ob- served that nicotine perfusion increased the automaticity of the Purkinje fibers system and decreased the conduction velocity. The authors consider that these two nicotine-induced effects probabIy predispose the myocardium to the initiation of arrhythmias. CORONARY Bmn FLOW Studies in animals and humans (tables A20, A21) have noted alterations in coronary blood flow (CBF) following the inhalation of cigarette smoke or the administration of nicotine. Generally, exposure of the normal subject to these agents results in an in- crease in flow. Kien and Sherrod (112), Leb, et al. (126), Ross and Bless (160), Travel], et al. (189), and West et al. (208)) working with normal animaIs, and Bargeron, et al. (179, working with normal humans, have demonstrated this response. As with the other cardiac responses to the administration of nicotine, it has been found that the augmentation in CBF is most probably due to the release of catecholamines. Using instantaneous coronary arte- rial flow measurement in dogs, Ross and Blesa (160) were able to reproduce the effects of intracoronary nicotine with the adminis- tration of epinephrine and were able to bIock the response to nico- tine by pretreatment with pentobnium. The direct action of catecholamines on the coronary arteries may not, however, be solely responsible for the increase in CRF seen with cigarette smoking and intravenous nicotine administra- tion. It appears that the catecholamine-induced increase in myo- cardial work and therefore in myocardial oxygen requirement is a prerequisite for the increase in CBF. Kien and Sherrod (112), using tracbeostomized dogs, found that without blood pressure and cardiac output changes CRF did not increase following either the inhalation of cigarette smoke or the administration of nicotine 54 intravenously, although CBF did increase folIowing such changes. Recent work by Leb, et al. (126) has utilized Rb8' as a radioactive marker in order to distinguish capillary flow from overall totai CBF. The authors consider that this capillary flow represents that portion of CBF which is effectively involved in nutrient and oxygen exchange. The researchers observed that the increase in effective coronary flow was almost proportional to the nicotine- induced increase in myocardial oxygen consumption. However, the increase in total coronary flow which may be due to increased myocardial shunting was far in excess. Thus, the increased work evoked by the effect of nicotine on the myocardium may induce local hormonal release in the myocardium and coronary vessels leading to coronary vasodilatation and increased CBF. This homeostatic response to increased work appears to be fully effective only in the subjects with normal coronary arteries. Bellet, et al. (22), working with normal dogs and dogs that had under- gone either coronary artery ligation or artificially-induced coro- nary artery narrowing, noted that the increase in CBF following the intravenous administration of nicotine was significantly less among the animals with coronary insufficiency. Work with humans discussed above has revealed a similar increase in CBF with smok- ing in normaIs. Regan, et al. (1.54) studied seven men with EKG- proven myocardial infarction and observed that cigarette smoke evoked slight increases in myocardial oxygen consumption in only three patients and caused no overall rise in CBF. A number of other investigators have noted that patients with overt CHD do not respond to the stimulus of cigarette smoke as readily as do normals (67,149,164). Thus, patients with compromised coronary circulation may not be capable of increasing their coronary flow in the face of the in- creased demands of a myocardium stimulated by nicotine or ciga- r&e smoke. In the normal state, the heart responds to increased oxygen demands by increasing coronary flow because even at rest oxygen extraction is almost at a maximal level. Any further in- crease in extraction may produce coronary sinus p0, values incom- Nible with proper tissue oxygenation. CARDIOVASCULAB EPFECTS OF CARBON MONOXIDE Carbon monoxide (CO) is a colorless and odorless gas, low levels of which have significant effects on human and animal physi- ok%?y which are just now beginning to be understood. According to WCjynder and Hoffmann (21.5). it is present in cigarette smoke in concentrations of approximately 2.9 to 5.1 percent. The concen- tration of CO in smoke is subject to many factors, among them 55 the type of tobacco and the porosity of cigarette paper. The con- centration of CO in smoke has been found to increase significantly toward the last puffs of the cigarette. According to Chevalier, et al. (41). a concentration of approxi- r&&ely 4 percent CO in cigarette smoke will produce alveolar levels elf around 0.04 percent which, equilibrated with hemoglobin, result in carboxyhemogIobin (COHb) concentrations of from 3 to 10 per- Cent. A number of investigators have compared COHb levels in smokers and nonsmokers. Goldsmith and Landaw (73) reported the analysis of expired air samples obtained from 3,311 longshore- men. Using a regression analysis, they calculated the concentra- tion of COHb and found that nonsmokers showed levels of 1.2 per- cent while those smoking over 2 packs per day had IeveIs of 6.8 percent and that smokers of lesser amounts had intermediate Ievels. Occupational exposure accounted for the mean nonsmokers' level being over 1.0 percent, an uriusual finding in comparison with other studies. Kjeldsen (113) interviewed and obtained blood samples from 934 CHD-free smokers and nonsmokers. The mean COHb level for 196 nonsmokers was 0.4 percent while all inhaiing emokers had a mean level of 7.3 percent. All 416 cigarette smokers, regardless of inhalation or amount smoked, showed a mean level of 4.0 percent. Carbon monoxide has many varied and significant effects on human physiology. An overall review of these effects may be found in a discussion by Lilienthal (127) or more recently in an exten- aive review by the United States Public Health Service National Air Pollution Control Administration (ISA). Apart from its effects Oti respiratory and circulatory function, CO has been found to affect certain central nervous system functions adversely. These effecta are probably due to interference by CO with the proper oxygenation and oxidative metabolism of the tissue in question. CO interferes with oxygen transport in a variety of ways. First, the affinity of hemoglobin for CO is approximately 200 times lz'reater than its afiinity for oxygen, and thus CO can easily dis- PlsCe oxygen from hemoglobin. Second, CO shifts the oxyhemo- globin dissociation curve. By increasing the avidity with which oxygen ia bound by hemoglobin, CO interferes with 0, release at the tissue level. This is of greatest importance at the tissue level where the oxygen content of the capillary blood has been reduced b Proximately 40 percent saturation: Here the shift can sub- tintially dec&e the oxygen tension supplying the tissues. Third, and of more recent note, is the possible interference by 0 with the homeostatic mechanism by which 2, 3-diphosphogly- -rate (2, 3-DPG) controls the affinity of hemoglobin for oxygen. BUM and Jandl (54) have recently reviewed the various experi- 36 merits concerning this glycolytic intermediate. The question of whether the low levels of CO present in the blood of smokers can affect this homeostasis is presently under investigation (29, l&?), and firm conclusions cannot be drawn at this time. Apart from its effect on hemoglobin affinity, CO appears to induce arterial hypoxemia, and this may act as an additional cause of tissue hypoxia. Ayres, et al. (14,15) observed unexpectedly that exposure of individuals to'C0 sufficient to raise their levels of COHb to between 5 and 10 percent was associated with a signifi- cant fall in arterial p0 Greater fall in venous pOi was noted, but this was considered secondary to increased tissue extraction. In a recent article, Brady and Coburn (30) suggested that this COHb-induced arterial hypoxemia was due to the interaction of a number of factors. These authors noted that in the presence of veno-arterial shunts or of an imbalance in the ventilation-perfu- sion ratio, the shift in the oxyhemoglobin dissociation curve in- creased the alveolar-arterial O? gradient and resulted in arterial hypoxemia. The presence of shunts as small as 2 percent of cardiac output as well as of approximately 10 percent COHb was found to cause an increase in the gradient. Such ventilation-perfusion (V/Q) abnormalities have recently been noted even in asymp- fomatic smokers (see Chapter on Chronic Obstructive Broncho- pulmonary Disease). The increased levels of COHb found in the blood of smokers may interact with these V/Q abnormalities to further decrease available oxygen. In normal individuals, coronary flow can increase to meet the increased oxygen demands of a stressed myocardium (as that under nicotine stimulation), while in `individuals with severe CHD coronary flow cannot respond as readily. In such cases, myocardial oxygen extraction must be increased above the almost maximal extraction found at rest. Any interference with arterial oxygen levels or hemoglobin affinity could very well decrease available oxygen supplies below the level required for proper tissue func- tion. That this occurs is suggested by the experiments discussed below. Chevalier, et al. (41) exposed 10 young nonsmokers to CO con- centrations sufficient to induce COHb levels of approximately 4 percent. Taking measurements from blood specimens obtained at cardiac catheterization under resting and exercise conditions, the authors noted that the ratio of oxygen debt to oxygen uptake in- creased significantly under conditions of increased COW. Accord- ing to the investigators this implied that the same work was being done at a greater metabolic cost. These same authors, (121,162) had previously noted similar findings among smokers and observed 57 that cessation of smoking was associated with a significant im- provemeat in oxygen debt accumulation. More recent work by Ayres, et al. (15) has focused on the dif- ference in response to CO exposure between 7 normals and pi pa- tients suffering from CHD (proven arteriographically). The induG tion of a COHb concentration of approximately 9 percent in the normals was followed by an increase in coronary blood flow, a decrease in hemoglobin-oxygen percent extraction and no change in myocardial oxygen consumption, coronary sinus.oxygen tension, .&id lactate and pyruvate extraction ratios. The induction of simi- Iar COW levels in the CHD patients was followed by no change in coronary blood flow, a decrease in the hemoglobin-oxygen ex- traction ratio, and no change in myocardial oxygen consumption. However, these patients did manifest a decrease in coronary sinus p0, as well as a decrease in lactate and pyruvate extraction. The latter measures indicate that the myocardium was functioning under hypoxic conditions. Because the coronary flow could not in- crease and because the myocardium couId not extract 0, from IGO, which was under the influence of CO, coronary sinus oxygen tension decreased to a point which could inactivate certain oxida- five enzyme processes. Thus, the myocardial function of persons with CHD may be unable to compensate for the stresses induced by smoking. Although COHb levels resulting from the CO present in the atmosphere during periods of high air pollution are much lower than those due to the inhalation of cigarette smoke, these concen- trations of COHb might contribute to the manifestations of CHD. Cohen, et al. (44) studied the case fatality rates for patients ad- mitted to 35 Los Angeles area hospitals with myocardial infarction in relation to atmospheric CO pollution. The authors observed an increased MI case fatality rate in areas of increased pollution, and then only during periods of relatively increased CO pollution. An area of interest which has been discussed in previous reports concerns the presence of hydrogen cyanide in tobacco smoke. According to Wynder and Hoffmann (225), the amount present ranges from 11 to 32 micrograms HCN per puff. It is known that a significant amount of this material is detoxified to thiocyanate and excreted as such in the urine or saliva. However, cyanide is a potent inhibitor of oxidative metabolism. Such inhibition of myo- cardial oxidative metabolism may be of importance when combined with f&e other factors mentioned above- which tend to decrease the oxygen supply available and increase the need for oxygen on the part of the myocardium. 58 EFFECTS OF SMOKING ON THE FORMATION OF ATHEXOSCLER~T Ic LESIONS A number of autopsy studies have demonstrated a significant association between cigarette smoking ar.d the presence of aortic and coronary artery atherosclerosis, even in men without a his- tory of clinical CHD. The possible pathophysiologic mechanisms for the atherogenic influence of cigarette smoking are discussed in this section. A number of investigators have studied the effect. of nicotine administration, either subcutaneously or intravenously, upon athe- rosclerotic changes in the aorta and coronary arteries of animals (table A23). When administered alone, nicotine induces Cedin necrotic changes in the arterial wall. However, in combination with the administration of increased amounts of cholesterol in the diet, nicotine aggravates either subendothelial fibrosis (7.5) or definite atheromatous lesions (46, 75, 80, 130, 178). Studies by Choi (AZ) and by Wenzel, et al. (207) did not demonstrate this synergism between cholesterol and nicotine. The other major cigarette smoke component under discussion in this chapter, carbon monoxide, has also been recently implicated in atherogenesis. Table 24 presents the studies which have related exposure to CO in combination with increased dietary cholesterol to both macroscopic and microscopic aortic and coronary athero- matosis. Astrup, et al. (10) exposed cholesterol-fed rabbits to CO continually over a period of up to 10 weeks. The experimental group showed increased aortic atheromatosis over that shown by the control group, also cholesterol-fed. Kjeldsen, et al. (II&) observed that exposure of rabbits to increased oxygen concentra- tions significantly reduced the amount of cholesterol-induced atheromatosis in rabbits. Most recently, Webster, et al. (204) have extended this research to primates. These investigators found that cholesterol-fed squirrel monkeys developed significantly more coronary artery atherosclerosis when exposed intermittently to CO over a T-month period than when exposed only to room air. ReceCt discussion has centered on the mechanisms whereby CO can induce these changes (9, 212). Astrup (9), referring to pre- vious experiments in humans which had shown increased vascular permeability for albumin upon chronic exposure to CO (II), con- siders it likely that this increase in permeability allows for in- creased filtration of lipoproteins into arterial walls. This, he con- siders, is a primary cause of intimal and medial lipid accumulation and, therefore, of atherosclerosis. Another point of view has been stressed by Whereat (ZIZ), who considers the filtration theory to be an inadequate hypothesis for 59 TABUS !U.-Expdmnta evncedng the athemgmic efect of carbon monde ezpoeure and hyporia Ucldrcn X4 cutrated mde hdat dlct p!U8 X WKent Tbr uDer~mcntd1 D,V"D cxpored to hYDoxl4 lboaed kaCP?6sed ttW~OD!O UHtlS et al, rlblno rabblta. cboleateml: atberomatod# over that ahown by eontml o nim& bfkroacoDk uamtnathxI rc ID68. I. (12) control. w&d mom Intlmal and sublatin lipid dcposltlon In the o ortu of the cr~mod Dcnmrrt II. (12) continub, qry~~~m. rabbit-s than In those of the noncxwaed. The total amount of ebcltiterol dt- (117). to hypoxia: Posited In tbs sort&n of the experiment&l Om"D wan tbrn tha t&her thw h 10 DWCe"t.$ for 6 weeks. chow of tbe cootrol sroup. 8 DetCWIt Ox for 2 weeks. uetdrcn x4 ca1lrrtAd male h~ulat dlst DlUS 2 percent bhOtWODkdY, the exDerhe"tll WOUD ahowed &diCl"tb feWt StbWoUMbUI et aL. albino rrbbltr. cholcsteml: changn. Micro~coDlc~ll~, tie uperlmrntal PKIUD ~hoaed ~ignlflcant~ krr rortlo 1060. I. (12) conttc1. Intimrl liDId deposItIon. Dmmwk 11. (12) CXDOIUM t0 28 DtrCmt (JJ4). O2 for 10 weeks. Webster x2 femrb lpulrrel Diet eontalnlng 0.1 percent The uprr~mtntal proup cxpoml to trrbon moaoxldr rhowad 8 prertrt maan Wr- e &I.. moakeya. chol~~ttrol rnd 26 DUCC"t fat: eentalpe of comnar~ rrtcrlar rlth rtheruclemtlc lcalon~ rnd more lumen occlu- 1970, I. (IO) control. U.S.A. don among the &ccted arteries Them wm ~lmifluntb mom CO-treat4 11. (12) eIDdme"trk!Y UpO8d t0 monkeys than control monkcn having 11 per-ant or more o ????*? athem- (W). 200400 P.P.~. errbon monoxide AerotIc rtenorlt among the wTected arterlcr. Aorttlc atbcmrclcroaL wu &PP*~- for 20 hOWa DW week for 7 cntlv not agemwkl by exposure to CO. COHb IevcL at the md of each ewaun montha. perlad averaged 18-28 percent durlw the flnrl 24 wrnkr of tbhs apsrlment mural lipid accumulation. The author notes that when the oxida- tion of the pyridine nucleotide, nicotinamideadenine dinucleotide (NAD), is impaired, the reduced form of this nucleotide (NADH) provides an essential factor for fatty acid synthesis. Fatty acid synthesis in the aorta and heart is carried out by mitochondrid enzymes whose hydrogen donor is NADH. Substances which slow or impair the reoxidation of this compound tend to increase mite- chondrial fatty acid synthesis (and decrease fatty acid utilization) in the arterial wall. Carbon monoxide prevents this oxidation proc- ess both directly and indirectly. Indirectly, it decreases the oxygen available for diffusion into the tissue. Directly, carbon monoxide can stall the process of NADH oxidation by combining with cyto- chrome oxidase. Further research is required into this problem, ParticuIarIy in view of the fact that cyanide is also a respiratory chain inhibitor and thus may also adversely affect arterial wall fat metabolism. In the discussion concerning the epidemiologica aspects of CEID, it was noted that increased serum cholesterol was a significant risk factor for the development of overt CHD. Serum triglycerides have also been related to CHD incidence. Of concern also is the immediate effect which cigarette smoking has upon blood lipid levels. The studies concerning this immediate effect are presented in tables A 25 and A 25a. The tabIe is divided into a section concem- he studies on humans (table A25) and one concerning studies utilizing animals or in vitro systems (table A 25a). Although no consistent response was noted for serum cholesterol, serum free fatty acids were found consistently to rise following smoking, As with other cardiovascular reactions to nicotine and smoking, it appears that the fatty acid response is also mediated by catechol- amine release. This relationship has been observed in a number of experiments by Kershbaum, et al. (105,106,108,109,110) and Klensch (118). That nicotine is primarily responsibIe for this rise may be seen by reference to the study by Kershbaum, et al. (105) in which lettuce-leaf cigarettes of minimal nicotine content had a negligible effect upon serum free fatty acids in comparison with that of regular cigarettes. While attention has been centered upon nicotine as the agent inducing the immediate increase in serum lipids, recent studies have been concerned with the effect of chronic exposure to carbon monoxide on serum lipid metabolism. These studies are hated in table A26. Among rabbits fed increased amounts of cholesterol, the authors observed significant increases in cholesterol and tri- glyceride concentrations in those exposed to CO versus those maintained in a normal atmosphere. TEE EFFECT OF SMOKING ON THROMBOSIS In the study of CHD, a number of investigators have turned their attention to thrombosis because myocardial infarction and sudden coronary death frequently result from thrombotic events. A thrombus may be of either gross or microscopic dimensions, and a minute thrombus at a strategic site may precipitate a fatal-ari rhythmia. However, thrombotic and prethrombotic states are dif- ficult to detect except when gross, and the emphasis has been pri- marily on factors which can be studied conveniently. Coagulation is now thought to have a secondary role in the consolidation of an arterial tbrombus and little if any in initiating the process. The prime mechanism in thrombogenesis appears to be the reaction of the platelet. Several papers have been written about platelet re- activity in v&-o but few about the effect of smoking on platelet behavior in wivo. The assay of fibrinolysis, which may also be im- portant, has received scanty treatment. The relevant studies are listed in table A27. Many of these are discussed in the 1968 sup- plement (192) and by Murphy (140). Corroborative data are still inconclusive as to whether smoking shortens platelet survival. OTHER AREAS OF IFNEXT~GATION Certain other aspects of cardiovascular pathophysiology may be of importance in the relationship of smoking to CHD. Glucose me- tabolism and insulin response, when altered, may alter myocardial response. This topic has been covered in detail in the 1968 Supple- ment to the Health Consequences of Smoking (192). Also, .varia- Finns in. blood hemoglobin and hematocrit may adversely affect coronary blood flow. A number of studies showing a possible rela- tionship of smoking to hemoconcentration have been reviewed pre piougly (192, I%?), and the reader is referred to those discussions. CEREBROVAXKJLAR DISEASE The term cerebrovascular disease (CVD) refers to a number of merent types of vascular lesions affecting the central nervous system : subarachnoid hemorrhage, cerebral hemorrhage, cerebral embolism, and thrombosis (ICD Codes 330 to 334). In 1967 in the United States; a total of 93,071 males and 109,113 females were Wed as dying from CVD as the underlying cause (196). Epidemiological studies indicate that cigarette smoking is asso- 62 ciated with increased mortality from cerebrovascular disease, whether CVD is listed as the underlying or as a contributory cause of death. Table 28 presents the results of the seven major epidemi- ological studies. The smoking of pipes and cigars does not appear to increase significantly the risk of ,dying from CVD. The impor- tance of high blood pressure and diabetes as risk factors for mor- tality from CVD has recently been noted by Hammond and Gar- finkel (76). The data from their study, as presented in table 23, also indicate that the mortality ratio for cigarette smokers is greater for persons under 75 years of age than for older individuals. Many of the pathophysiological considerations discussed in the sections concerning CHD may also pertain to the relationship of smoking and CVD, particularly cerebral infarction. In a study reported by Kuhn (~zS), 20 habitual smokers X+ frained from smoking for one-half day, and base line retrograde brachiocerebral angiograms were taken; they then smoked one cigarette, inhaling deeply, and had repeat angiograms. Those over 60 years of age failed to have significant acceleration of flow as demonstrated in carbon dioxide inhalation experiments. More recently, Miyazaki (15.2) studied the effect of smoking on the cerebral circulation of 12 moderate/heavy cigarette smokers 88 measured indirectly using an ultrasonic Doppler technique to record internal carotid artery flow. Measurements were made be- fore and after ordinary smoking and showed an increase in cere- bral blood flow and a decrease in cerebral vascular resistance in all subjects. No significant difference in response was observed between the 4 younger and 8 older (over 66 years of age) subjects. More research is needed to clarify the role of cigarette smoking in the acute pathogenesis of CVD manifestations. However, the chronic effect of smoking upon the cerebral circulation (particu- h]JT its extracranial portion) is Iikely to be similar to the effect Of smoking upon the aortic and coronary atherosclerosis. NON-SYPHILITIC AORTIC ANEURYSM Aortic aneurysm is an uncommon but not rare cause of death. In 1967 in the United States, a total of 8,448 men and 3,173 women Were listed as dying from aortic aneurysm as the underlying cause (196). Cigarette smoking appears to i_ncrease the risk of dying from this disease, perhaps by promoting the atherosclerotic proc- aaa'which underlies this type of aneurysm. As illustrated in table 29, the mortality ratios for cigarette smokers are high relative to other cardiovascular diseases in which smoking increases the risk, and the risk increases in proportion to the amount smoked. 63 TABW PL-Deaths jrma cerebruva.mdar disease related to making (Xcutdity ratIoa--actual number of death8 ahown In ~nrmthesca)~ [SM = lmokcn NS = non~mdrsnl PROSPECTIVE STUDIES Age r1rhtIon commcntr 1.060 NS . . . . . . ..l.OO (lE4) t(Pco.01). Ckarcttn SM . . . . ..tl.aO (666) Other SM . .1.26 (HO) Ciuarstter only 20 . . . . . . . 1.46 (83) Doll and ADDR~u~~Y Questlonnalrs 10 606 NS . ..,...,. 1.00 RIU 41,ObO mole md fqlIow- All SM ,,.,., 1.06 1064, Brltlsh up of death All CRlt phyrlelan~. certine*te. clgrrctta 1.12 B?ibLn l-14 . . . . ..l.lO (lob. 16-24 . ...,. 1.W >26 .,,,,... 1.26 Kmnsl 6,127 males MedICal 12 1s NS . . . .L.OO 161 Data o o~lu onlv TABLE `&I.-Deaths from cerebrovaamlar diseaee related to making (cont.) (Mortality ntlw-actual number of dwthr ahown In partnthnel)' [SM = mokcn NS = nonamokersl PROSPECTIVE STUDIES Irhn. U.S. mab Queatloonalra 6% 2,008 NS . . . . . . . . 1.00 (614) PIPU 1060. Vetm-uIl and follor- AU shl . .1.06 (82) U.S.A. 2966.674 up of death current . . . .1.60(1,894) NS . .1.00(614) (011. pmon MrufiUk Chtl-tnt CXQLW Y- dgetla . 51.62 (682) NS . .1.00(614) 1-v . . . . . , . 1.61 (88) 8M ..1.06(186) lo-20 . . ...1.42 (826) 21-89 . . . ..l.?O (216) >se .# ..*.* 1.69 (87) Elmmond 868.d64 make Quatlonn~lm 6 md 446,876 and follow- Cuflnkd, fcrmla 40-79 UP of death 196O. ,eara of we CertlIlC~tc. U.S.A. at entry. (78). 4.09D CUW#UC rcoukw duortfle 40-u Never rmoktd 1.00 l-9 . . . ...2.79 lo-18 . . ...1.14 2049 . . ...2.21 ,>40 . . . ...1.64 NeVW amoked 1.00 l-9 . . . ...1.60 IO-19 . . ...2.60 20-39 . . ...2.90 >tO . . . ..t6.70 Maksr so-se 004 1.00 1.00 1.96 1.to 1.48 tl.44 LOS 1.62' 2.40 1.72 Fcnrclkr 1.00 1.00 1.26 1.26 2.70 2.16 2.67 1.88 t6.62 - trlued on only 69 death. TO-78 1.00 0.86 0.92 1.22 to.68 1.00 0.83 to.67 1.26 T)~BLE 28.-Deaths from cerebromscular dieease veluted to smoking (cont.) (Mortrllty ratios-actual number of dtrtha ehoan In parentheses)l SY = Smoken. NS = Nonsmokers. PROSPECTIVE STUDIES Pbf?ra. 8.268 m&b IraM multi- 16 67 NSand buglt, bnoabaremhn pbdc -30, . . . . . . . ..l.OO (42) rtd. s-e4 Yea" lC~e+nltlg x0 . . . . . . . al.16 (26) 1970 of .* In and follow- U.&A. 1961. UD of death (144). ceruncrte. RETROSPECTIVE STUDY >SO,OOO male Inltlal eolleps Death Rater The 69 deaths from barper Unlvcnlty entrsnce Corer (fad, Catrok (ala) occlualvc stroke u.d ,tudrnt., medld cx- SM ,,..,.,,...,,...,..,. 46.0 81.8 (ptO per day . 20.9 11.2(P39 . . . . . . . . . . . . . . . . . 7.26 (17) Hammond 368.634 males Queationn~irc 6 337 NS . . . . . . . . . . . . 1.00 Data r~uly onlv and 446.816 femrles and follow-up 1-9 . . . . . . . . . ..2.62 toms1ec SO-69 GarRnkcl. 40-79 ye,* Of of death 10-19 .:.....,..8.86 yt.m of Lge. 1369, age at entry. certificate. 20-3s . . . . . a.... 4.64 V.S;A* >40 (76). , . . . . .._.I . ..8.00 Web ind 68,163 Callfomla Queatlannalre S-8 61 NS . . . ..,.,...* 1.00 DlInIl, tide workera and fOl!OW-Up All . . . ,. . . . . . . . .2.64 1970. E-64 ye.n ot al death Cl0 I.. ..a,. a .,.2.44 U.S.A. age at entry. crrtificste. 520 ,... * . . . . . . . 2.88 (IDS). ZSO . . . . . . . . . ...2.64 ' Unlnr ofJwrwlse 1~4fled, dl#parltlh between the total number of dsrthl and the sum of the Indlvldual cskgorlw .re due to the urclulon Sk! Include cr-amoken. NS include plge and clg~r amoken. m of elthcr oeculonrl, mlscell~neou~, mlxed, or rxamokcn. PERIPHERAL ARTERIOSCLEROSIS Peripheral arteriosclerosis represents the effects on the vascu- lature of the extremities of the pathophysiologic processes which produce coronary and aortic atherosclerosis. A number of studies have been concerned with smoking as a risk factcr in the develop- ment of this disease. Kannel, et al. (95) observed, in the Framing- ham study, that diabetes mellitus and elevated serum cholesterol, as well as cigarette smoking, were also risk factors in the develop- ment of peripheral vascular disease. Juergens, et al. (9.2) reviewed the records of and contacted 478 maIe patients with arteriosclerosis obIiterans (a severe form of peripheral arteriosclerosis), who had been patients at the Mayo Clinic between 1939 and 1948. The diagnosis of this condition was based upon certain clinical criteria: the presence of intermittent claudication, the marked diminution or absence of lower extremity arterial pulsations, and objective trophic manifestations of per- ipheral limb ischemia. Smoking information was available on 401 patients. These patients were compared with a control group of 350 Mayo Clinic patients of similar age who showed no clinical evidence of vascular disease. It was found, for males under the age of 60, that 2.5 percent of the cases and 25 percent of the con- trols were nonsmokers. However, no difference was noted between the percentages of heavy smokers in each group. The authors also impIicated high blood pressure and elevated serum cholesterol as risk factors in the occurrence of this disease. Begg (19) noted similar findings in a study of 294 male patients with intermittent claudication who were patients at the Western Infirmary in Glasgow, Scotland. .In comparing the smoking his- tories of 100 patients with this complaint with those of 116 healthy male controls, the author found that 1 percent of the patients and 21 percent of the controls had never smoked. A total of 42 percent of the patients smoked more than 20 cigarettes per day while only 24 percent of the controls had a similar history of heavy smoking. The author concluded that smoking, while not a prime cause of peripheral arterial disease, is a significant cofactor in its develop- ment in almost ali cases. The author also noted obesity, high blood Pressure, and elevated serum choIestero1 as risk factors. Schwartz, et al. (168) compared the prevalence of risk factors in four groups of subjects: 141 cases with arteriosclerotic disease of the lower limbs, 551 cases with coronary arteriosclerosis, 58 cases with both conditions, and finally an indefinite number of control individuals who h.ad been hospitalized for injuries. The in- vestigators reported that certain risk fa_ctors, including hyper- cholesterolemia, hypertension, and cigarette smoking, were signifi- 68 cant in both coronary and lower limb arteriosclerosis. The authors noted that the inhalation of cigarette smoke appeared to be an important risk factor for coronary arteriosclerosis up to age 55 while in arteriosclerosis of the lower extremities, inhalation ap- peared to increase the risk even in the older age groups. Widmer, et al. (215) compared 277 male patients with arteriaI occlusion of the limbs as demonstrated by aortography or oscilIog- raphy with 2,082 men demonstrated by oscillography to be free of arterial disease. The authors found that cigarette smoking, parti- cularly heavy smoking, was significantly more frequent among the cases with arterial occlusion than'among the controls. Increased beta-lipoproteins and systolic hypertension were also found to be more common among the cases. EXPERIMENTAL EVIDENCE A number of experimenters have investigated the acute effects of smoking or nicotine upon the peripheral circulatory system. These investigators, as listed in table A30, have measured effects in terms of alterations in skin temperature and blood flow as meas- ured by plethysmography, radioactive iodinated albumin clear- ance, or radiosodium clearance from the skin. The majority of these studies have shown significant decreases in peripheral blood flow and skin temperature upon smoking, particularly in persons without manifest peripheral vascular disease. The study of Freund and Ward (68) demonstrates the difference in peripheral vascular reactivity found between normals and patients with arterioscle- rotic changes in the vessels of their extremities. The work of Striimblad (181) on blockade of this response with automatic SYS- tern blockers indicates that the reactivity of these vessels is se& ondary to the local release of catecholamines. Most probably, the degenerative changes associated with this disease create a stiffen- ing of the vessel wall and prevent rapid alteration, particularly dilatation, in response to the catecholamines liberated by smoking or nicotine. THROMBOANGIITIS OBLITERANS Thromboangiitis obliterans (Buerger's Disease) (TAO) in an uncommon obstructive vasculitis primarily involving the arteries and veins of the extremities. Severely affected patients may even lose their limbs secondary to ischemic changes. Much discussion has centered upon the question as to whether this disease is a clin- ical and pathological entity separate froqperipheral arterioscle: r&is. McKusick, et al. (128) consider it to be a distinct entity 69 while Eisen (57) concludes that TAO is the acute inflammatory phase of severe arteriosclerosis. Clinically, it has been shown that smoking aggravates this dis- ease and cessation of smoking frequently aids in complete or par- tial remission. Razdan, et al. (153) and Brown, et al. (32) found very few nonsmokers in groups of patients diagnosed as having typical TAO. A recent study from Israel (16) involved a case- control comparison of 46 patients with TAO and 32 matched con- trols. Although the controls were found to smoke less-per day than the patients, this difference was not found to be statistically sig- nificant. However, 100 percent of the smoking patients and only 72 percent of the smoking controls were inhalers, a difference sig- nificant at the 0.02 level. CARDIOVASCULAR DISEASES SUMMARY AND CONCLUSIONS CORONARY HEART DISEASE 1. Data from numerous prospective and retrospective studies confirm the judgment that cigarette smoking is a significant risk factor contributing to the development of coronary heart disease including fatal CHD and its most severe expression, sudden and unexpected death. The risk of CHD incurred by smokers of pipes and cigars is appreciably less than that by cigarette smokers. 2. Analysis of other factors associated with CHD (high serum cholesterol, high blood pressure, and physica inactivity) shows that cigarette smoking operates independently of these other fac- tors and can act jointly with certain of them to increase the risk of CHD appreciably. 3. There is evidence that-cigarette smoking may acceIerate tfle pathophysiological changes of pre-existing coronary heart disease and therefore contributes to sudden death from CHD. 4. Autopsy studies suggest that cigarette smoking is associated with a significant increase in atherosclerosis of the aorta and coro- nary arteries. 5. The cessation of smoking is associated with a decreased risk of death from CHD. 6. Experimental studies in animals and humans suggest that cigarette smoking may contribute to the development of CHD and/ or its manifestations by one or more of the following mechanisms: a. Cigarette smoking, by contributing to the release of catechol- amines, causes increased myocardial wall tension, contraction 70 velocity, and heart rate, and thereby increases the lvork of the heart and the myocardial demand for os'gen and other nutrients. b. -among individuals \vith coronar> atherosclerosis, cigarette smoking appears to create an imbalance betlveen the increased needs of the mvocardium and an insufficient increase in coro- nary blood flow and oxygenation. c Carboxyhemoglobin, formed from the inhaled carbon mon- oxide, diminishes the a\.`ailability of oxygen to the myocardium and may also contribute to the development of atherosclerosis. d. The impairment of pulmonary function caused by cigarette smoking may contribute to arterial hyposemia, thus reducing the amount of oxygen available to the myocardium. e. Cigarette smoking may cause an increase in platelet adhesive- ness which might contribute to acute thrombus formation. CEREBROVASCULXR DISEASE 1. Data from numerous prospective studies indicate that ciga- rerte smoking is associated with increased mortalit>- from cerebro- vzscnlar disease. `3. Experimental evidence concerning the relationship of smok- ing and cerebrovascular disease is at present insufficient to allow for conc!usions concerning pathogenesis. However, some of the pathophgsiological considerations discussed concerning CHD may also pertain to the relationship of smoking and 0-D, particularly cerebral infarction. NON-SYPHILITIC XORTIC ANEURYSM Cigarette smoking has been observed to increase the risk of dying from nonsyphilitic aortic aneurysm. PERIPHERAL VASCULAR DISEASE 1. Data from a number of retrospective studies have indicated that cigarette smoking is a likely risk factor in the development of peripheral vascuiar disease. Cigarette smoking also appears to be a factor in the aggravation of peripheral vascular disease. 2. 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S?O ., ,. I.. .46.3(S) IIrnlth Survey interview. >20 . ,, .* *. *.. ,18.6 (21) U.S.A. >20 . . . . .11.6(10 with mntched (33). contm3ls from slmr I"rvCY (included there surviving Arot myocardi~l infarction). \D 0 rctrospectiuc studies (cont.) TAULE AG.-Coronaq hnrt discusc morbidity and worlulity- (Actual number OC casca ahown in pnrcnthesn)' [ SM = Smokers NS = Nonsmokers EX = Ex-smokers1 Author. year. COUntrY, rcrrrence Number nnd type of Donulntiu" Dstn collcctian Cnscs (percent) Controls (percent) Comments Rusrsk and 97 mule and 3 Interviews Tobacco ~jU cigurctkalday Psticnts Zohmrn. lcmalc coronary bs 70 percent. 35 percent. included 83 199. pntientl. Controls: authors. with chwical U.S.A. 100 healthy control3 mkucnrdiut (165). of similar "g-2. iliiairliu" sex. occupation. nnd II WlLh and ethnic origin. sngtna pcctorin. SDai" and 269 males identified 3,000 mr1es NS .,....., .30.0 (81) 29.0 (772) Nnthe", 8s hnving CHID by in New 40/day ,. .13.0 (33) 9.0 (234) (D36 . . . . . . . . . . ...21.8 (42) 2.2 (9) ciK(olrPLtc CnLcKOrir8 -Hnmburp ngr- 100.0~193) ~ 100.0(413) i"rllldP n~ihr,Ll 01 cisnr matchcvl citizens ' (only 28 were mixed (G2 wcrc mixed nr sm<,krrn ri~,ils.ulntrd selected randomly. or cigar smokers) cigar smokers1 as LLI nutnhcr cbt CLKLL. I.P~~LY No vntir,ntr or controls brnilkcd "ii'rn cxcIu5i\rly. Dbrken, 33 females up to Death cer- Cioaretlcs prr dau 1967. 44 yrnrsofngc tificotcs, 0 . . . . . . . . . . ,.... 6.1 (2) 63.?(841 (P36 . . . . ..~.. c.1 (2) of time frcam clinic without CVD or lung Lc7 CLi"CFt. P _-- TABLE A&-Coronary heasl disease morbidily and mortalily--7etro~ective studies (cont.) (Aeturl number of cum shown In ~nrenthesn)~ [Shl = Smokers NS = Nonsmokers EX = Ex.smokeral Cl3CO (pcrccnt) Cummcntl refcrcncc population Hybms 79 maln Iurvivino. Interviews NS . *... . . . . . . . 10.1 (S) 21.0 (33) et al, myocsrdial infnrc- by trained l-9 eiearettes 1967, lion. 167 age. DW3Otltl.d. perday 1.0 (6) 10.5 (13) Jkpnn matched controls lo-15 .._..., ,,,., 26.4 (18) 33.9 (42) (87). hospilalired for nan- 16-20 ,..,..., ,. .35.2 (25) 26.8 (37.) CVD but include 21-34 . . . 22.6 (1G) 17.7 (22) hypcrtenaive diaeare. >36 . 9.Y (7) 12.1 (15) AllSbl . . . . . . . . . . 100.0 (71) 100.0(1!40 - Mulcahy 100 fet"ak DSthltS Hospital sm . . . . . . . I .I., 63.0 (63) 45.6(261) Smoking on controlr et al., less than GO yesrs interviews. NS .,.....,,..,,, 33.0 (33) 45.3(2511) obtsinrd from 1967, of age admitted t0 EX . . . . . . . . . . . . . 4.0 (4) 0.1 (52) stulisticn of Ireland hospital with CHD. Total . . . ..100.0(100) 100.0(572) smoking in (IJIb. Irish I~rpulrl~c. Sudclrn dvn\h ""1 IrlCIIIIICII. Stejfa, 70 maleand Direct Plcvolcncc Of risk factora Authurs then fullowcd 19G7. female patient3 interview. Angina patient., Control DIOllD lhr 70 pnlirnts for Poland with recent onrct 60.0 3 yrnr, and rrutcd (179,. exertional angina 48,1(p>O.l) Lhnl amgaktng sinnifi. Deftotis. 54 control3 canlly inilurnr*,20 ..I. .42 0(2(13) 29.or2oiI (PI6 cigarettes .22.6 20.0 All ,, ,,. ., .EO.O 47.4 Pipe 16.5 8.8 JOUVC 1.229 CIID patients: Interview. 43.0 13.0~P<0.0001) et al., 802 malcs.427 1961. fcmsics. Controls: FranCe 743 individuals of (91). both BCXCJ: age. sex. and socinl class matcbedd. Icrst1. 275 mrde railway Interview NS . . . . . . . . . I... .ZO.O 1.55) 29.8 (82) 1969. FmploycPr UP to 65 and ex- Z-20 cigarettes or Germany years of e.gc sur- amina- UD to 6 cigars.. .32.O (88) 63.3 (82) (98). viving myocnrdial tion. >20 CigaretleS or infarction. 215 con- >S cigars. . . . . . ..48.0(132) 6.9 119) trol employees with minor circulstory diaturbanccs. ' Unless otherwise specified. disparities pween the total number of case9 and the sum of the individual smoking categories are due to the exclusion of u tither occuionrl, miacellaneoua. mixed, or ex-smokera. w - TABLE A?`.-Differences in sertcm lipids betlceen sl,iokers and nonsmokers (Aciusl number of ind\vlduslo shown in parrnthm)' [Sat = Smukcn NS = Nonsmokers] Author. year. Number and countrv. type of Results Comments Diflermcc bctu,ern S,!l and NS tSf relrrs to S~edbere ngca 90-19 Ages JO-S9 Apt-a4049 flotation unit8 of Lipid: f NS 55. SM 37) (NS 66. SM 67) (NS 17. Shl 44) centrlfugcd lil,iaproteins. tsr o-12 . . . . ,. +59.9 lJ concludu from the antl I.unrlmnn, tbvin ~:LIIS nnd of cholesterol. triRlyccridcs, and pho~pholiyid~ than nonsmokers. di!Trring 512 and DZ rc~ult~ I !I 1: G , k7 o.o5 1.362.1 I p270 ahownl significantly biphcr tng. petcni1 mg.pcrcmlt (p20 cigarettes/duy(Sll) 249.4 30.0 Van Buchem. 1967, Netherlands (19Pl. -- Quvlr ct al.. 19BM. . U.S.A. i la ) . 918 randomly chowen Strum clLolcafcrol The nuthon found no maks 40-SY yearn O-209 mg. portent PIO-249 mg. percent >250 mg. percent correlution bctwwn smokbnu of age for entry NS .,t...,.....,..... 12.4 (32) 14.0 (40 14.2 (41) and serum chokntrrol Icvela. Into prospective Ciparettc SM `lt.6(184) 67.8(213) 68.2(197) study. Other . . . . 16.0 (41) 18.2 (61) 17.6 (61) 1.10% male lnctory Snum chorcslcrd Strum Bclo-liyoprotcin Dcta-lipoprotrins were found rmaloyem 20.64 mg, pcrccllt mp. pcrccnt to increase with age. but Y*nrl Of age. NS . . . . . . . . . . . . . . . . . 243(519) smokers had hivhcr lcvcl~ SM 251(576) p26 PT~UIB 127.9 (`JO) 128.1(218) All amounta 129.1(619) 128.6 (447 I The author did notz MUX diadtoldic b&d yrcrrvrc Shf-NS blood "rcaeurr dlf- UK Lf.5.A. lcrmcm prior to 70.9 81.0 rnntrolling fur wciuht. 19.4 62.1 but nut sltcr such cuntrol. 78.6 71.3 71.6 17.1 78.7 77.8 - JS'O-J70/ Numbers in parcnthcwa Ioo-Iro(zro~ >J7sl>IJs(rs, reurewnt tatnl in blood 25.5 34.7 yrcllure group. 26.6 18.7 The nulhor noted 15.6 17.3 a stcpwiue dwrcue with 10.0 4.0 ICI,@1 01 blood pwsJ"re Tibblin. 1967. 896 m&3 In SW&tl GGtebn?, SW&J& (Jar). born in 1913. L?locd prcrr,rre J JS-145/ ~110/~70(a9) 7*95 (468) NS . . . . . . . . . . . .t. . . . . IP:O 23.0 l-14 clgaretta, *....,..... 29.2 21.2 >I6 cigar&k-a . . . . . . . . . . . 28.1 20.9 Pipe and cigar , . ,, 11.2 8.6 ditiduala and the aum cl tbc individual smoking categories are due to the excluioa of either oeeuional, mlrel+oua, mhd, or ex-smokera. TABLE A17 .-Incidence of new coronary heart disease by smoking category and behavior type for men 59-49 years of age (Numb-m in pnrentheses are number oC CHD cases in each aubnroup) Smoking group NW.3 smoked Currot and former pipe and ciynr only I-16 Cigarcttez 16-25 2C rnd over TOtAl 1.6(l) 15 8(15) 14.9(16) 9.3(461 1.3(J) 3.1 (3) 4,9 (0 3.3(18) 4.3(5) 9.3(18) 10.4(20) 6.2(63) --- -- Analysis of variance Iable Source Sum of sauark-0 d.C. `Eater nre sue-adjusted nnnual incidence per 1,000 men. *Mean SQUH~TI for "betwccm smoking groups" and "between behavior Iypea" are each computed eliminating the general mean and the other main effect but ignoring interaction. thus yicldine m eatimak al each main o f- feet unconfounded by other significant main ef?~ta. SOUKCS: Jcnkino. C. D. et al. (90). TABLE AlS.-Incidence of new coronary heart disease by smoking category and behavior type for men 50-59 years of age (Numbera in psrcntheaes are number of CHD cylea in cacb nubgroup) Former Current and Cigarettes BehaVlOr Never cigarette fOiTlCl' DiDC tYDC amokcd amoken and cigar only 1-16 16-25 26 and over TOlal A . ** . . . .~. .., . . . . . .,.. `12.4(K) 18.6(B) 21.8 (8) 16,4(6) 21.5 (9) 30.0(14) 20.4 (43; B .*....... . . . . . . . . . . ...,., 10.0(4) 6.1(I) 6.4 (3) 4.7(l) 21.1 (I) 19.1 (51 12.0(21) Total . ., . . . . , ., 11.1(g) 14.2(9) 14.9(!1) 11.6(6) 21.3116) Z&0(19) 16.8(70) - Analysis of variance table Wltbin eclb . . . . . ., ,#I......,.. ,....,. ,.. . . . . . . . . . . ..,. 63.627 911 0.070 Regreuion on age . . . . . . . . ..*..*.*..* ,..... ..,.,... . . . . . . . . . 0.117 1 0.171 2.64 0.111 Dctwctn smoking groupa: . . . ,.. . . . . . . . . . ., . . . .., , ~, . . . , 0.522 6 0.104 1.496 0.188 Between behavior typea 2 ..,...~.....,., . . . . . . . ,.,... .,..,,...... 0.296 1 0.296 4.24 0.040 hkr.ction . . . . . . . . . . . . . . . . . . . . . . . . . ..I . . . . . . I ,....,,.,..,.,, 0.129 6. 0.026 0.37 0.870 IFLaLpl are age-hdjuattd annual incidence per 1.000 men. cflect buL ignoring interaction, lhur yielding an catimate of each mnln rf- `Yew ~puarea for "between smoking groups" and "between behavior feet uncanloundL4 by other significant rn~~in ellectr. trpn" are each computed eliminating the general meon and the other msin SOURCE: Jenkins. C. D. et nl. (901. TAULE .420.-Expcrinrents concwning the cffccts of swoking ant1 nicotine on animal cardiovascttlar function West cl nl.. 33 norm01 1958, ndult rn0ngrcl U.S.A. rlous. (:`OS) COIOn&I-Y intro- ortcrinl nicotine: 1. 0.2-2.2 uz./ka. II. 0.04-i )ig./ks. Dttli"iW incrensc (ey3lolic). (Tctrnuthylammonium chloride b!ockcd CUF In- crcnsc.) The authors found no evidence of coronary YLBD. mnalriction In tbeuc healthy rnimala. TABLE ABO.--Ezperiments concerning the efects of smoking and nicotine on animal cardiovascular function (cont.) Author, YCIT. Number and Smoking Heart Blcmd Cardiac CCTO"tIW EO""tcJ, type of DKXCd"~C rate DXW"R OUtPUt blood Commenld rdcrence DoDulnlio" flow Forte 27 obscrvn- intravenous Definite No cbanw. No signlflcant change I" either left ventricular et nl., tiono on 8 nicotine up initial work or myocardlal oxygen extraction. 1060, dogs. I3 21.6 "lg. increase U.S.A. given 83 6-16 then 165). !.w./kg./ dccroase. minute. - Kicn and 21 adult doas Ciasrette Definite Definite Increase ERccts of cigarette smoke were duplicated by In- Shrrrod, 1960. U.S.A. IlIP). smoke under positive pressure via tracheostomy. Nicotine 20 pg./kg. intrs- ve"ou8Jy. Epinrphrine 6 w./kg. intra- ve"ausly. increaae. i"crea8e. followi"g trnvenous nicotine and eDi"eDbrl"C. incrcnse During cigarette smoke Inhalation. it WBI noted in blood that without blood pressure or output chanp+a, prC*s"rC coronary blood Row did not Incrrnse and tbnt and cardiac while adverse EKG changea were noted they COP 0"tD"t. related Marc claaeiv with decreued cardinc OXY- gel, utilization than with actual cardiac wGrk. TraVCll 14 norm"1 intravenous DCli"itC Nicotinc.induced coronary blood flow and heart CL RI., rabbits nnd nicotine increase rate increase in the atheroeclulotic nnlmals re- IICO. 1C rabbits 0.01-0.1 mg. in normals. auirrd 10 times and 2 timn. ~IIB~C~LIVCI~. thr U.S.A. with severe emwnta rwuircd in the norms1 animula. flS9). cholratwxzl- induced ather- sclerosis. TADLD A20.--6zpcrimcnts concerning the cflccts of smoki,tg nud nicofinc on animal cardiovnecular function (cont.) Numbrr and type oc raopulntion Smoking proccdurc Comments Dellet I. 10 narmol dose l"trevcnaus 1.126 percent The nuthors noted that: et al.. 11. 9 dous at nicotine. increase 1, The rCBPO"Se of coron.ry blood flow to "ica- 1962, varying in- 20 ug./kg./ II. 82.6 percent line resembled that of anoxtmia I" t(c Drrs- U.S.A. tervnls Iol- minute for l"CV?WX cnce of eoronsry i"3ufllciency. (22). lowing core- 15-20 mi"ute3. 111, 83.3 DE'K'Znt 2. The grater the induced coronary imwlrment nary artery increase the smaller the increment in coronary blood ligation. Row. III. 7 dogs with varying grndcn of srtificinlly- induced corcw nary artery narrowing. Leaders 16 adult Left anterior Nicotine and norcyinrphrine both ir\crcnacd corc- and mongrel descending nary vascular rcsiotance and myucnrdinl contrsc- Long. dogs. i"tracoro"nrY tile force (the formor mcanurcd by e. conalant- 196?, injection of volume variable~prcssurc rystem). The action of U.S.A. niwtinc or nicotine was blocked by prrtrcatment wilh hcx- (125). norepincphrine. amethonium, pmtolinium. rcsrrpinc. or I(U&~C tbidinc. Lk?-Wll 13 rdult Intravenous Definite Definite Systemic vnscular rrsiatnnce ond pulmonnrr nrten et al.. mongrel nicotine, incrcasc. incraw. and left atria1 ~rr~surca show4 biphnaic rr 1965. duga. 0.02 mg.lke.1 ?~ponoen of increase followed by drcrcsac. U.S.A. minute for (JZJ). IO-12 minutes. P TABLD A20.-&p&??~nt8 concerning t/te eflecls of smoki~tg wd nicotine ox anirrla~ cafdiovQscU~ar flt?Iction (cont.) 0 m Author. yr.r. Number and Smukina cuuntry, type of ptOC`%lUtC C"mlne"tl refrrencc population FOIL? 7 dog-a of 30 inveatleated et al.. (Rcmoinder expcrirnced 1966, cntbcterizntion fnilurra). U.S.A. (64). h'adcau and J&mm. 1961. U.S.A. (144). 26 dogs 1. Cigarette smoke inhnlntian to isolated left lower lobe and then blood perfused coronary srtcries. 11. Cunrctte smoke to rest of lunu and then blood pnascd to gcnrral cireullltion. III. Nicotine perfuocd directly into left coronary nrtery. Nicotine 0.01-10.0 pg. into sinus node artery. I. No change in cor~n&ry vw~lnr resistance. II. S/G show~~i increase in c~r~ne.ry va~ulor tesiatance due, actordine to the author. to gcncral aympathetlc nervou~l ayatem stimulation. IIt. 415 showed ~nrrcn~e in corunnry vascular rnisldnce. The authors eon- cldc that the cnrdiac eflcct~ of tobacco arise nlmotlt entlrcly from thr extracnl.rlinc actiona of smoking instend of the direct reaponae of the 111.nrt. HeurL rate showed initial slowing (due probably to vnaal stimulation) fol- lowed by r.ccelcrntiun (due probably to vagnl pnrnlyais and cntecholamine reluse~. No systrrnic blood pressure changes nuted~ 22 monurel dopa I. (IO Intrnvcnour nicotine cnrct. I. Nlcotinr pruduccd B dclinitc incrcnre In the force and vt~l~~city of left 50 irr./kg.lminutc fur 3-4 \L.~IIIC~II;II. c\jnt~actiun. minutes II. Prrtrcntmcnt with proprsnolol produced (r&live to rP3u1IP Of Group 1): II. (8) Prcpranolol pretreat- (a) A further increase in left vrntriculsr ayatolic prrsnlrr. ment, then 50 hK./kg./minute (b) A dccrensc in velocity of shortening. nicotine fur 3-d minutes (c) A aignificxnt incrtnae in lrft vrntrirular cnd.diwtolic prc*rurc. The authors CO~CIUIIO thnl proprnnolol probably lmpnira the no,rcpinrpbrirl~ like cfIccts of nicotine on the myocardium while cnhrnclng ita wriphrral ve.*oprcssor enecta. TASLD AZO.-Ezpetiments concerning Llle eflccts of smoking a,td nicotine on atiirttnl cardiovascdar function (cont.) Author, YC`T. Number end Smoklna cuuntry. type of ptOCCdUre Comments l-dcrcncc populntlon D1Iaza Bcaule dona with lesions 1. Normsb (3-6 per exveriment): I. (a) No evidence of arrhythmias; (b) A ainele or ~1 few ectopic brats Cl al.. Induced in myocardium by (a) 4 PK./kg. intravenous in Z/3 normal dogs. 1969. either: (1) IaavroierenOl nicotine. lb1 40 ,%/kg. II. Extrnsystoles noted in 2/3 animals during the firat dny nftcr cesantlon U.S.A. vrctrcatmcnt. or (2) intravenous nicotine. of the arrhythmia induced by the lesion alone. but not thcrenfter, (Id). ligation of the anterior II. Experimentnl (3), 4 )iK./kg. These and nicotine-induced arrhythmias wcrc of II abort clurution. descending ecmnar~ artery. intruvenoua nicotine Greensvan Cardiac muaeleisalated from Nicotine Z-100 ~~p./cc. in Nicotine perfusion produced: Cl 81.. the right vcntriele of 10 Tyrode'n solution verfuunte. (I) An increase In myocnrdlnl contractile force avusrently indrvcndrnt 1969. adult dogs. of adrcnergic innervation. U.S.A. (2) An increased automuticity of the Purkinje Aber ~ystcm ~lvpe.rently (74). due to release 01 catecholamin& from chromnmn tissue ~turn. (3) A dccresse in conduction velocity. The authors conclude that the latter two eirectn vrobnbly predispose to nr. rhythmia formation. Swhlr and RaPSPOrt. 1969. U.S.A. (166). 88 mongrel cats Nicotine 6-12 pg./kg. injcctrd lntrnarterially to mesenterie circulatio". I. hlesenteric injection of nicotine WLI followed with 1-2 secunda by: (a) Increased left ventricular ayatalic prcasure (LVSP). (b) Increased systemic resistance. (c) Enhanced myocvrdial performance. II. Left ventricular injection of nicotine WBB followed by: (a) Increased LVSP. (b) L1radycardia. (c) Enhanced myocardisl pcr!ormnnce grcnter than that wxn in mcrenterir-injected group. 111. Prctrcntmcnt with phcnoxybcnznmine diminished the incrcnlc in LVSP while pr~~pl`nnoli~l prctrrutmcnt diminiJhcd the tnhnncrmcnt of my- ocardial perfurmnncc while LVSP still showed D. niKnif~cnnt IIIC~PU~~. 1V. MNrntvrie sympsthctic ncrvc section led to a diminished rc*i,on~u. The nuthurs ctmeludc thnt the cnrdiovnsculnr IC'IPO~BCB to nlcntinc m&y be ncurogenic in nature with receptors distributed in ccrtnin abdominal srterica. TABLD A20.-Ezpsriments concerning the etfects of smoking and nicotine on animal cardiovascular function (cont.) Smoking procedure Comments Lrb ct al., 12 mon~rcl dov and Nicotine 100 u#.lkt. for Effecelive Corunary Flow (ECF) 11 that part of the totnl COTU"*T) IloW 1910. CBF measured with UIC of 2 mln!lLC Intravenously. (TCF) which il "ellcctivelr ' involved In nutria1 exchonec. U.S.A. Rb" and digital counter. Nicotine injection WM followed by: (J,6). (11 96.6 gcrccnt increase in TCF. (2) 61.1 percent lncrense in ECF. (3) 73.1 percent increase In mwcardial oxysen ccnaumption and annl~aia revealed that capillav flow increased almost ptovortimatcly to my- wardial oxygen consumption whereas the increase in TCF W~LI f&r In CXCCJ8. (4) Definite increases In cardiac output, hesrt rate. left ventricular work, and oorlic pressure. Ross rnd BIna. 1970, U.S.A. (160). 10 does undergoIng inatrntulcwJs COlO"r.ry arrerinl flow meuurement. Nicotine lC-100 BB. lntra- coronary injection. Nicotine injection was followed by: (11 Increurcd tontractilc force. (2) Decreawl myocardial cuntrnction time. (3) Dccrensed time RCCCJI~~Y to reach peak tension. (4, Dccreucd total stroke ustolic CBF. (5) Incrcwcd total stroke dirutolic CBF. (6 I Increased total stroke CBF. (7) Changes similar to intraarterial rDin&rine. (8) Changes blocked by pentolinium pretreatment. (9) No change in heart rate or blood ~r~rure. The authors conclude that eatecholamines released from the ventricular mywardium mediated thrae I~~FIOIIIFI to nicotine. TABLE A21.- Experiments concerning the efects of smoking. and nicotixc on the cardiovascular system of humana Author, Year. Nypy;;nd Smoking Heart Blood Electrocardiogram Stroke Cnrdiac %%" eounlry, procedun rate PttBY"te ballistocard~ugrsm volume OutDUt Commenta referrnee DODUhth, Row Rusaek I. 28 healthy 1 standard and 1 I. Incresae. Incrcaee. EKG: Denicotinircd cign- et al., male amokera denicotlnired I. 16/29 showed rettes evoked changes 1955. 21-60 yearn cigsrettc. significnnt of R lesser dcgrcc U.S.A. of age (aver- chnnaex. in normnle and CliD (ISi). ape 42). II. No sis- subjoeU, but in the II. 37 male patients II. Increeae. 1ncre.s.w. nineant latter group thcr'e with overt chansce. wc,s no aiguiflcnnt clinical CHD BCC : dilTcrcnce between 42-10 yeara of I. these change+.. .-ge (bvenge II. 18/37 showed 64) ( 6 were aiKnificnnt nonsmokers. chnnue. DIrgeron 14 of 30 healthy 1 cigarette Insinnilicsnt Increase. Dcnnite Coronary vrl8cIIIflr et al.. adult mnle vol- inhaled at increase. increase. re3i3tBncc fill 1967. untccr smokera intervals of si!pificelrtly. U.S.A. and nonrmokers 20 aeconda. Myacerdinl O3 fJ71. who underwent usage unllcrwc"l no BUCCeSSfUl aienlfirsnt chnnac. catheterization Pyruvnte extrnction 18-63 years fell slightly. of age. Authora conaldrr lack of incrcnw in heart rate u due to bascllne nl>prrhcnsive tschyrardia. F 0 TABLE A21.- Expriments concerning the eflects of smoking and nicotine on the cardiovascular s@?T?t of humans (cont.) Author, Y-r. cou"trY. NUt~pbc"o;"d Smoking Heart Dlood Elcctrocardiopram Stroke Cardiac prowlure rate pre49urc b@lliatocardloprrm volume output cYl"Y reference potNlstio" nOow Comment4 Repm et al.. 1860, U.S.A. (IS4). 7 mnlca with 2 standard DCA"lte Dcnnite Incrcaac. No aipnl- Myocsrdlal 0, conaump- bintory of cirarettn In Increase. increcae. licnnt tlon row sliuhtl,`in EKC.DWWl 26 minutes change. 3outof7. myocsrdial inhaled at The author considcra Inf~rctlo" minute that the EKG chsnrca undergoing Intervals. notrd on amokinw are cardiac ~a- probably due ICYS to theteriration. decreased coronor~, blood Row than to incrcawd worklond (oxygen "red) where oxygen supply dwcs not incrcwe. Noted no cvidrnce of myocardirl irchcmla during anwkinp. Thomas and 113 clinlcallu One rtandard Definite Definite Definite Definite Pulse yrcsaurc ahowed MUWhY, healthy young cigarette increase. increase. incrcaae. increase. a decrease. 1960, males. smoked at Smokers rrr~mnded U.S.A. own pace. slightly but sisnl- (166). Acantly more actively lhan "on- smokrra. BCC change were incrcnninfly common with incrraaing ale. wright, and serum ehulcaterol. TADLE AZl.--Experin~ents concerning the effects of smoking and nicotine on the cardiovascular system of humans (cont.) Author. YCBT, country. retcrencc Number nnd type of Dopulnlion Smoking Heart procedure rate Blood Electrocardiosram Stroke Cardiac lltC33"t.? bnllirtocardioyrnm v0lume output cti:o":w timmcntd now Von Ah", The author Cigarette Increase. EKG: Slight ST EKG changes more 1960. reviews * smoking. HCg"lC"t prominent in younr, SWCd?" arries of denreeaion clinicnlly healthy (POZ). expcrimenta nnd T-wnve aubjccla than /II performed nattc"i"c. older. hltbitunl IJCLWCC" amokcrs. Intro- 1944-1954. venou nicutinc end smuki"K ahuwrenses not de. (b) Non-inhalation lb) No No change. (IJ) No cbrnge. No change. dilutwn tvchniwc. Ennlnnd fined. 19-66 yesra smoking. change. (89). ol nw. all mod- (c) 2 standard (c) Definite Widened (c) DefiniLe DeAnire ernte-heavy cigarettes in increase. vulse, increaaae. increase. cisaretti smokers. 10 minutes. pressure. (d) NicotineO.6 (d) Definite Definite (d) Dcfinlt-e Dellnit- mg. intra- increase. increase. i"CV3.W. change. Ye"ousIy. TAOLE A21.--6ccpcri~~~ents concerning the efects of smoking and nicotine on the cardiovascular system of humans (cont.) Author. Year. country. rclercnce Prntrcost Nut$r;nd Smoking Heart Blood Eleclrocardiosrnm Stroke Cardiac DhXFSi!J~~ rate PRSl"W ballistocnrdloeram volume OUtDUt C"d;o,n;lY Comment.8 pODUt`,tiO" How I. 14 volunteers Single ciKarette Definite Definite I. 10 21 DerCe,,t ;b"J with clinical Shelling- CIID, 13/14 l~,ril, smokers, 11164. averape *pe U S.A. 39.6. (149). II. 6 patients with angina pCCtAri.3. &it1 smokers, ave. rage age 43.4. 111. 14 Datk"tS with history ol definite myo. cnrdinl infsrc- tlon, all smok. em *"eraBe age 64.1. smoked at own increase increase geW"t incrcaw. rate in 6-l in all in all increase, minutes. ITOUDI. !JrO"DS, II. Inter- Interme- medipte dlnte change. change. III. a DCP 1 D~rG?r,t cent incresac. decreaae. Frulikl 6 male and 3 2 rtandsrd Definite No signih- No signifi- The author contrnnta P! HI., female Datients cigarettes in incrense cant changes cant this rnponse with lcKJ5, u*ith healed 10 minute3 at al rest at rest or chnngL-3 that LI~C" amo,,p U.S.A. myocardisl inlarc- rest and under and at during at rest or hcnlthy you"&! (ti?). tion 48-69 years graded exercise. exercise. exercise. during individuals. 01 age Z/8 non- exercise. smokers. TABLE A21.- Experiments concerning the e&Tech of smoking atld nicotine on the cardiovascular system of hman8 (cont.) AUlbW, year. Number and Smoking lienrt Blood Electrocardiocrnm Stroke Csrdinc CO"IltlY, 1ype of procedure rate pWSs"rC bnllistocnrdiogram volume cK,"d"v output ^ C4mmentc reference populntion 1lLlW Allison 30 healthy male 2 standard ciga- Definite Increase. Increase fol- Definite drercnac in and Roth, aubjectr. retta smoked Increase. lowed by pulmonary blwd 1969. 1949 years of In 12-16 minute decrease wulume 83 indicated U.S.A. (3): nge. period. within 20 minutes. by impwloncc mc\boda of thorocic PUIX volume. Aronow and 10 male patienta 1 low nicotine Definite Definite All patients dcvclopcd SWltOOD. with classical cigarette in increase. increase. angina moner if 1969. fingina pectoris. 6 minutes. they amoked bclore U.S.A. 32-59 yeara of exercising. (7). aye. Aronow and 10 male patients 1 non-nleotlne No chanw. No chance. No dlfiercncr natcd Swanson. with claraical cigarette in In time or onset 1969. anpina pectaria. 6 minutea. of excrcistcinduced U.S.A. 32-69 yeara of *ngir,0 bctwe,n (6). ape. anwkina and non- rmoklng prucrdurca. Mershsll et III., 1969. U.S.A. (129). 42 normotenslvc 314 of one standard Insignificant lnsignificnnt Blood prr-srurc rrB"onle healthy male cigarette. increase. increanc. to cold prwsor teat prisoner8 noled to Lw grcntrr in 13-50 yean of heavy amokcra. a!ze. Prc5~n~opnl rcnctiona 13 nonsmokera. to 40 dcgrre bced-up 16 moderate till moi-c Irruucn1 smokers. in smokers. 13 heavy smokers. TABLE A22.-.?hpeti?ncnts concerning the cgcct of nicotine or smoking on cutcchoht~inc lcuch WMlfril 22 mongrel doga Clgnrette smoking via Ile~uler ciunrette smoke evoked a atatlatically aignlflcent incrcndc In nilrrnnl vein. md Watta, trneheal cnnnula: vena cave. and femoral artery levels of eDinepbrine. CornsIlk cigarcttc amukr woked 1063, 1 cigarette/8 minutea no chnnse. U.S.A. for 36 minutes. (ZIO). Wes1fall 21 male volunteers 3 ciunrettcs smoked in Smoking nt rnte noted for 2',4 hours evoked B signlficnnt Incrcn8c In urinnry cplnc- and Wntta. ap~roximnlely 26 SO minulca. phrinc. but not norcpincphrlne Irvels. 1ec4, yenre of n*e; U.S.A. 11 nonsmokers, (II!). 10 amokem. wmtfsll et al., MOnkTVZl dOK8 Standard cigarette amokc Smoke inhalntian cvoknl R r/Be In cardloc output. atrokc volume. blood nrrw\!rc, nnd 1966, cxwsure vin cndotrnchcnl plarmn catccholnminc levels. Prctrcntmcnt with prvprnnolol diminial~cd the cnrdinc U.S.A. tube. Smoke lnhnlntion output and ntrokc volume reeponsn but increased the blood prcsaure rrsponsc-the (209,. every third inspiration for latter cflect llue to the release of alpha-receptor activity by betn.bloekade. 3 minutes. E TABLE A23.-Experiments concerning the atherogenic eflect of nicotine administrution m Author. ye.,, couotn. Number and tyDe Procedure Results rercrciee cl mlmal~ Adler et al.. Rabblb Nlcotlne 1.6 mg. IntravenouaLv in 6 oercent The authors noted an artcrionecrosir of the aorta. anectins mainly the 1906, U.S.A. (2). mlutlo" 6 O! 7 dnya per week for more than 4 munthr. inner muscular 18ycrs. hlocrorcopicslly. early changa consisted Of ,mall nrens of calcnrcuus ridging nnd aneur~smsl dilatation without notable fatty degeneration or intimnl discontinuity. hlicroucopicnlly. rarly changes appeared in the muscle cells of the media. and "chalky" depositi wcrc noted between the elastic Rbcn. HUWW. 1943. U.S.A. (SS). I. 6 moni~el donr. Nicotine subcutaneously. lncreaaing dosage up I. O/G ~njmn1s died of infection nnd showed marked cdcmo. n!ld f0Cnl UP to 2.6 cc. 013 percent solution fur 1 hynlinizntion of the mcdin of the e.ojin and lnrgc clustic nrtvriL*. month. 216 nn,mnls wcrc sncrificed and show4 thickcninn and hynlinizo- tion of the WSH~ of the mronory artcries nnd cdcmn uf the mcllin BP well as ondothclial prulifelntion of other aIzc.ricB, II. 60 rati. Increaalne doses UP to 1 cc. of 1 percent II. Much It-15 *ortic involvement than that found in thr doga: inlrc- solution for 1 month. quent r,rteriolnr changes consisting of Rbrosia and thickcninu of the media. MS6lOVa, Rabbi& I. (10) Nicotine aubeutaneously 1 percent I. Aorlic wall---acute swelling of claxtic fibem with loco1 frognlenta- 1966, solution 0.2 cc. daily for 116 days. lion and partial disintegration-no intimal lot deposits SCC~. USSR Coronary vessels-thickening 01 thr vessel wall-no fat deposits. (130). II. (14) Nicotine ~1~s 0.2 grams cholesterol II. Aorta-"massive" deposits of "cholesterol" in the intlma nnd YLLSIL per day. vniorum with "lcmsening" of the aotiic wall. Cotonnry VMSVII- the larger vcsscl~ showed mticrntc fnt depositlou nnd the ~mllllcr ve~scls showed swelling of the cliuLicn. III. (IO) Cholesterol only. III. Aorta--i.olatd lipid deyusition in the arch snd a.vccndinv. portiune only. Coronary vessels-no fat dcpusitiun. -- Czochra- Rnbbita I. (10) 1.0 g. cholesterol/day for 100 ln~irx uf nul-tic lnion density (cholesterol inr~ltrstion): Lysanowicr dnye. I. 2.5. et al., Il. (10) Cholesterol plus 0.0015 g. nicotine/ II. 3.4. 1969. day intrnvenourly. U.S.A. 111. (4) Nicotine only. III. Nu nurtic lcsiono noted. (46). Author, year, CO""lrY. Number and type I'rllcrilurc RcvultJ rcfcrrncc of nnimnl -- Wcnzrl Pl al.. Rabbits I. (12) C,~ntwl untlcntod. Gcncrni Rn~l!n~`s: Mnrkul .sorlic nntholonic involvrmrnt w'ns noted in nil 1050. II. fl U.S.A. (frn7). III. IV. V. 12) Cs~ntrul ,licl plu3 I percent cholcstcrl,l nnd 5 ,icrccnt cuttanseed oil nddcd 12) Cnnlrol diet plus oral nicotine 2.2H mp./kC./dny. 12) Rraimen 11 plus oral nicotine 2.2R ma./ha./day. 12) Regimen 11 plus oral n&line I.42 mu./ks /~lny. Thicncs 1960, U.S.A. VI. (12) IleKimcn II plus oral nicotine 0.57 mg /ka./dey. Newborn rata nnd Nicotine subcutnncousiv un to 5 mg./kg. No nnrrini pathology noted. hledinl dwrnwntion wcn more Irn~unltiv mice. twice daily by the end of 1 month. Animals autonsied at 1 year. hlale rabbits I. (10) Nicotine subculnncounlv 0.16 Sicnilicont diflcrcncn in aorlic subrndothrilnl fibrail brtwwn control Sncrificcd at GO days. i= TABLE AZ?,.--Eccperimenls concerning the QtherOgeniC cfCct of nicotine administration (Cont.) OJ Author. year, countw, Number and type Procedure Reaulb rcfewnce of animrl Hua cl al., Male rabbits Nicolinc Diet Vilomin D 1966, I. (8) Conlrol CO"ltOl Control I. Infrwucnt medial calcific disease without llpid localization. U.S.A. 11. 17) Control Cholrsterol Cuntrol II. No medial calcific disease but Ireguent intimal atherurna formation. (80). III. (14) Nicotine CU"ttOl CO"ttUl III. Rare cnlcilic medinl degeneration; no intimal athcro"bntous dlscost. IV. (15) Nicotine Cholcslerol Control IV, The Iaw=t number of ntheromataus lesions. V. (91 Control Cholesterol Vitamin D V. No medial calcific diseaae. VI. (14) Nicotine Cholesterol Vitamin D VI. Conslrtent medial calcific disease. (Sacrificed at various times) Control-no treatment. Nicotine-subcutaneous injectiona in oil- increasing amounts 2 times per week. Vitamin D--subcutanwus injections up Lo 6-8 x 1w III. Cholesterol--260-500 mg. cholesterol sdded per 100 g. diet. Choi. Albino rabbita I. Nicotine l-5 mg./kg.lday intraperi. I. Increasing nicotine dosages were aswciatcd with dccrcnscd athcroma 1961. t0"MllY. formation (findings not statistically significant). Korea Cholesterol 1 g.1dr.y (in varying II. Nlcotinc ulone prcduccd no nthcruma formation bul WBJ usur,ciatI prOCCd"rC fatty ncidr cholrstclol triglyccridcs ottlcr Comments rerrrcnce wpulotiou hlurchiron 0 melt and 4 2 cigarettes I. Dclinitc Nu rhngc. Nu chan~c. Uoth regular nnd sham amokers and fcmnle mod- in 15 minutes. incwose. shawcd significant incrcn.4cs FYIIZ, mate smokers I. Lit-cign- II. No change. No ClLmKe. No chnnw, in conccntrntion of IcNm I'JGC. with various rc1tes. oieic acid nnd SLgnlfirnnt Scotland discnses 31- 11. Unlit-cign- dccrcnars in conuvlltrl~tion of (139). 67 ycnrs of rettcs. ~crum Pnllnitic acid. age. Kerrhbaum 6 normal et .I., heavy 106i, cipnrette U.S.A. amukcrs (105). 20-15 years of nE!e. Vnrlous types of cigarettes of known nicotine content. llrsulai. cigarcttrr. filtrr ciKnrrttes. chmcllnl-filtP, ciunlcttcs. pipe tobnccn PI\B cignreltes nil showed similnr increiw in FFA. Lcltuce Ical cimrettes hnd negligible eRect. ANIMAL AND IN VITRO STUIlIES Kerrhbaum 20 adult I. 0 reccivcd I?4 nicotine et al., 1 II c 5 , U.S.A. (107). TABLE AZ?.Smoking and thrombosis -- Author. wlmle Partial Rexaleif~ed YtiT. Numbrr and Expcrl. blood Pro- thrombc- Dlrrsma Plotrlet Platelet PlaL?let Platelet ctiuntt-y. type of mental clotting pInstin clotting adhrsive- count SUlViVal turnover Other Comments rcrcrcnte populntion conditions ' lime ":Ein tlme time "~88 -_-___- - Blnck- 16 dUlL 12 individuals PloU"U burn achizo- rmokcd 2 llypvtn et al., phlwnic hlph. time 1053. pnticntn. 8 nicotine (-) U.S.A. university atsndard (25). atud,,ntr. nil trR,id ii"!1 with cithcr IlflCr clumping Murphy. CVDur periods of time l%i3. COI'O. Dli nbstinence (-) c--j (-) (-) (-) (+) (4-l (2) U.S.A. hrn\y or cuntinua- dacrenae increase (Ill,. smokers 35- Lion of 72 YPBi-5 of smoking. aYe Ambrus 20 hoolthy Deep inhala- Thromboplaslir~ 2 studrnts and mule nr,n- tl"n of one yc,lmltlon I~~~plmc ill, Ml"k. smukinv nonfiltered 1-j (-) f--j (`c) C-J 1imr Rvomen: while filtered cxgarettrs showed respective decreesa of 11 nerwnt and 2, percrnt. Stromb!ad. 1959. Saedcn , Ii, ,. 11 mnie and femnle subjects (smokrrs and nonsmokers) were studicd for the eilect of the intra-arterial administration of nicotine (bra- chial artery) on blood flow to the hand as measured by veno~~l occlusion plpthysmozraphy. Increasing doses of nicotine were asso- ciated with increasing nombers of individuals manifesting vase- constriction. The vasoconStTxtive eKec!s of nicotine were abolished by the prior administration of either hexamethonium or Dentolinium. Bmnetr and Boake 9 male patients with intermittent clsodication (`I were heavy smokers) 1960X"srnlia 118,. were studied ior the cKect of smoking on blood flow to the leg a5 measured h,- vc11ous occlusion plethgsmogr-aphy. Smoking an un- filtered cigarette was found not to p:-educe aray consistent changes in blood Row to the caLf or foot of the affected leg. Freund and Ward. 1960. U.S.A. (68). 15 male prkon inmates (less then 35 years of age) and 14 male patients with peripheral vascular disease la~~roximatcly 65 years of ape, were studied ior the effect u: smoking on digital circulation as rwasurrd by skin temtxrsture. plc:hysmoglsphy, and radiosodium CIPP~R~CC from the skin. Smokina WRS iound to adversely affect the fib;: and third ~FISUIP~ in a stp~iricant manner (while plethva- montaphic valurs weac rsr-isb!r) only in the healthy prisoners and not at a,, in the Sargent group. Roth and Schick. 100 normal tndividuals undrruent 425 cxperlmcntal procedures con- 1960. U.S..4 (161). cerntng the eflrrt 01 srnok~~~ on the petipheznl circulation. Smak- ing II-Z, found to be as.oclsted with a drrrrxe in extremity skin tP"De**t"*C. 129 130 Chapter 2 Cardiovascular Diseases Part II 131 CONTENTS Page Coronary Heart Disease (CHD) .............................. 135 Introduction ..................................... Cigarette Smoking as 3 Major Risk Factor for -135 Coronary Heart Disease .......................... .136 Cigarette Smoking in Relation to Other Risk Factors for Coronary Heart Disease .................. .137 Hypertension ............................. .137 Cofflee Drmking _ _ _ . _ _ _ _ . , _ _ . . _ . ,141 Ventriculx Premature Beats ................... .142 Carbon hlonoxide .................................. ,142 Introduction ................................. -142 Sources of Carbon hlonoxide Esposu re and Human Absorption ......................... .143 Effects on Healthy Individuals ..................... .148 Effects on Persons With Atherosclerotic Cardiovascular Disease ....................... .I49 Studies on the Pathogenesis of Cardiovascular Disease ................................. .150 Nicotine ....................................... ..15 1 Acrolein ....................................... ..15 1 Cerebrovascular Disease ................................ .,.151 Effects of Smoking on the Coagulation System .................. .154 Summary of Recent Cardiovascular Findings .... , ... , ........... .155 Bibliography .............. _ .......................... .156 133 List of Tables Table I. - Age-standardized blood pressure changes (mm tlg) at followup for continuing cigarette smokers and quitters according to weight clrsnges _ . . . _ _ 139 Table 2. - Number of subjects who had developed hypertension at followup for continuing cigarette smokers and quitters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...140 Table 3. - Mean percent of carboxyhemoglobin saturation in smokers and nonsmokers by sex and race . _ . . _ _ . _ _ . . _ . _ _ 144 Table 4. - Alean percent of carbosybemoglobin saturation in smokers and nonsmokers by employment status _ . . _ . 14.5 Table 5. - Median percent carbo~yl~enloglobln (COHb) saturation and 90 percent range for smokers and nonsmokers by location _ . . . . . . . . . _ . _ . 146 Table 6. - Alean percent carboxyhemoglobin (COHb) saturation in cigarette smokers I hour after last cigarette . . . . 147 Table 7. - Age-standardired death rates and mortality ratios for cerebral vascular lesions for men and women by type of smoking (lifetime history) and age at start of study . . . . . . . . . . .._...____...._____._______.____ 153 134 COROXARY HEART DISE,\SE (CHD) itirrodlrcliorl Coronary Heart Disease (CHD) is the most frequent C`XUSS of death in the United States and is the most important single c3use of excess mortality among cigarette smokers. The evidence relatins smoking to CHD has been reviewed in previous reports on the health consequences of smoking (61. 62. 63. 64. 65. 66. 67. 6Sj. The following is a brief summary of the relationships between smoking and CHD presented in these reports. Cigarette smoking, hypertension, and elevated serum cholesterol are the major alterable risk factors for myocardial infarction and death from CHD. Cigarette smoking acts both independently as a risk factor and synergistically with the other CHID risk factors. The magmtude of the risk increases directly wi'th the amount smoked. The excess risk of CHD amon? smokers has been demonstrated in some Asian, Black, and Caucasian populations and is proportionately greater for younger men, especially those below age 80. Cessation of cigarette smoking results in a reduced mortality rate from CHD compared with the mortality rate for those who continue to smoke. Pipe and cigar smokers have a slightly higher risk of death from CHD than nonsmokers. but they incur a much lower risk than ciga- rette smokers. This has been attributed to the lower levels of inhala- tion that characterize most pipe and cigar smoking. Data from autopsy studies have shown coronary atherosclerosis to be more frequent and more extensive in cigarette smokers than in nonsmokers, and experimental work in humans and animals has suggested several mechanisms by which smoking may influence the- development of atherosclerosis and CHD. The formation of carboxy- hemoglobin, release of catecholamines, creation of an imbalance between myocardial oxygen supply and demand, and increased platelet .adhesiveness leading to thrombus formation have all been demonstrated in smokers and proposed as explanations for the excess CHD mortality and morbidity among smokers. 135 Cigarette Stnot?ittg as a .Ilajor Risk Facror for Corottary Heart Dherrse The evidence establishing smoking as a major risk factor in CI1D has been reviewed in previous reports (lil. 62. 63. 64. 62. 66. 67. 6s). During the last year new epidemiologic data have been published on the relationship between coronary artery disease and smoking. Bengtsson (9. 10) studied the smoking habits of women with myocardial infarction (hiI) in Goteborg, Sweden. He found that smoking w3.s significantly more common in a group of 46 women (80 percent smokers), ages 50-54, who had a myocardial infarction than in ;1 control group of 578 herllthy nonhospitalized women (37.2 percent smokers). Other investigators examined the effect of cigarette smoking on sunrival of people with acute myocardial infarction. In a study of 400 patients with documented myocardial infarction who survived to he admitted to a coronary care unit, Helmers (26, 27, 2s) found no significant difference between the percentages of smokers and nonsmokers among survivors studied after ihe first 24 hours. from 2 days until discharge, and from discharge to 3 years. Reynertson and Tzagournis (53). in a 5-year prospective study of 137 patients with documented CHD at age 50 or less, were also unable to find sny relationship between CHD mortality rates and smoking habits. Smoking habits after entrance into the study were also considered and again rio difference in mortality rates was found. The Coronary Drug Project (17) found an effect of cigarette smoking on mortality after myocardial infarction. This group studied 2,789 men ages 30-64 years for 3 years after myocardial infarction and found a statistically significant correlation between cigarette smoking determined 3 months after a myocardial infarction and mortality (t-value of 2.94). None of these studies (Z 7, 26, 27, 28, 52) were able to examine the smoking habits of the group of people who die suddenly as a first manifestation of CHD, and therefore may have excluded that group in which there is the highest excess mortality due to cigarette smoking (31). Additional data from the Swedish twin study of Friberg, et al. (23) have been reported. They found an excess CHD mortality among smokers in dizygotic twins with different degrees of smoking, but no similar excess in monozygotic twins. Although the numbers \vcrc too lrnal1 to be significant, the authors suggest that this tends to >uppc>rt the theory that both smoking and CHD are constitutionally 136 determined. These data must be viewed with caution. however, since the difference was demonstrable only in the older age group (born 1901 - 1910). \J'hen the younger age group (born 191 1 - 19?5) ~3s considered, no excess CHD mortality was seen in the dizygotic group but a small excess was noted in the monozygotic group (three CHD deaths in the high smoking group and one in the low smoking group). Also the difference in cigarette consumption between the t!igh and low smoking groups was rslativeiy small (seven cigarettes per day). Consequently, data from this study are not sufficient to warrant the conclusion that both smoking and excess CHD mortality are constitutionally determined rather than smoking being a cause-of the excess CHD mortality. Cigarette Smoking in Relation to Other Risk Factors for Coronary Heart Dbease Cigarette smoking, elevated serum cholesterol, and elevated blood pressure are generally accepted as the three major modifiable risk factors for CHD. However, there is less agreement concerning other CHD risk factors - obesity, physical inactivity, diabetes mellitus. elevated resting heart rate, psycholopic type A behavior, etc. The following studies present recent evidence on the relation- ships between smoking and hypertension, coffee drinking, and ventricular premature beats. Results from several studies have shown that smokers on the average have slightly lower blood pressure than nonsmokers. Some investigators have attributed this finding to the fact that smokers on the average weigh slightly less than nonsmokers. Three current studies (24, 36. 55) discuss this relationship. Gyntelberg and Meyer (-74), based on their evaluation of 5,249 men ages 40-59, were of the opinion that lower blood pressure in smokers could not be accounted for by differences in weight. age, or physical fitness. Kesteloot and Van Houte (36), in a study of 42.804 men, performed a multiple regression analysis on age, weight, and height and found that cigarette smokers had lower blood pressure than nonsmokers; however, When they included serum cholesterol values in the analysis, the difference in blood pressure was reduced to approxi- mately I mm Hg. Although tllis difference was statistically signifi- cant based on the large population. the actual difference in blood pressure was too small to be of clinical importance. 137 Seltzer (55) studied 794 men selected for their initial good health and normal blood pressure (below 140 systolic and 90 diastolic) and followed them for changes in cigarette smoking habits, weight. and blood pressure. During the S-year period of the study 104 men gave up smoking. For every age group except those over 55. there was a significantly greater weight gain (8 lb) among the "quitters" than among the continuing smokers (3.5 lb). Blood pressure increased 4 mm Hg systolic and 2.5 mm Hg diastolic in the quitters with no change in systolic and a slight reduction in diastolic (-1.1 mm Hg) in persons who continued to smoke. in order to examine blood pressure changes in relation to weight change, both continuing smokers and quitters were grouped according to their weight changes during the period of study (Table 1). The most significant finding was an increase in the systolic blood pressure (+ 1 .77 mm Hg) among the quitters even in that group with significant weight loss. In contrast, the continuing smokers with significant wei$t loss had a decline in systolic blood pressure (-3.28 mm Hg). Diastolic blood pressure in quitters showed an increase with weight gain and no change with weight loss, while continuing smokeys showed a decrease in diastolic pressure with weight loss and no change with weight gain. The data on subjects whose blood pressure had increased to hypertensive levels (systolic > 1.50 and diastolic > 9.5) were evaluated, and it was found that quitters had a much higher frequency of becoming hypertensive than continuing smokers (Table 2). Seltzer, in interpreting these data, suggested that cigarette smoking tends to inhibit blood pressure increases, with only minimal pressure rises occurring even in instances of substantial weight gain. When this inhibiting effect of cigarette smoking is removed as in the case of the quitters, sharp rises in blood pressure become evident. He cautioned, however, that the development of hypertension in some quitters may have been responsible for decisions to lose weight and that his data do not allow an evaluation of the degree of blood pressure changes according to how recently cigarettes were given up. The results of the ischemic fleart disease study by Kahn, et al. (34) raise additional questions about Seltzer's data. Kahn followed 10,000 Jsraeli male civil service employees for 5 years to determine what factors were associated with an increased incidence of hypertension. He presented no data concerning persons who stopped smoking, but he did show that the incidence of hypertension increased with age and that the age-adjusted incidence of hyper- tension in smokers was over twice that of nonsmokers (76.9/ 1000 for smokers versus 35.4/1000 for nonsmokers). Seltzer reported no 138 TABLE 1. - Age-standardized blood pressure changes (mm IIg)l at followup for continuing cigarette sn~nkers and quitters according to weight chofrges Weight Change (LB) Significant No Significant Modcrate Smoking Clas wt LOS Wt Cl13ngc WI Gain II) lb lb NO. -25 to -5 No. -4 lo +4 No. +5 IO +12 Mean systolic BP changes; Continuing smokers 32 -4.00 84 -1.52 71 2.85 Quitters 13 1.77 27 2.22 27 4.04 Mean diastolic BP changes: Continuing smokers 32 -3.28 84 -2.04 71 0.13 Quitters 13 -0.31 27 -1.96 27 4.30 `Standardized on basis of age distribution of current cigarette smokers. Source: Seltzer, C.C. (j-5). Significanl WI c;ain II) - No. +I3 IO +30 24 I .sll 32 3 69 24 -0.04 32 3.94 TABLE 2. - Number of subjects who hod developed hyperrensiorl at followup for contirruhg cigorettc smokers and quirters Blood preaure Continuing cigarette snnokers Quitters levels Number Percent Number Pcrccnt Systolic blood pressure lSO+ 6 2.8 9 x.7 Systolic blood pressure 160+ 2 0.9 5 4.8 Diastolic blood pressure 9S+ 3 1.4 5 4.8 Source: Seltzer, C.C. (55). data on the incidence of hypertension in nonsmokers, and the age distribution for his group of smokers (the original source of the quitters) is heavily weighted toward younger age groups .(with only 33 of 214 men age 50 years or over). According to Kahn's data, this age group would be expected to have a lower incidence of hypertension, and, in fact, Seltzer found only small numbers of men who developed hypertension (eight with diastolic hypertension) (Table 2). Making interpretations based on such small numbers is hazardous; for example, the difference between current smokers and quitters in the incidence of diastolic hypertension could have been produced by only three men quitting smoking because they developed hypertension. Coffee Drinking The Boston Collaborative Drug Study (12) recently reported a correlation between coffee drinking (> 6 cups per day) and myocardial infarction that persisted after controlling for the effect of cigarette smoking. This was a retrospective study of 276 patients with a hospital discharge diagnosis of myocardial infarction and 1,103 age, sex, and hospital-matched controls discharged with other diagnoses. In addition to the usual limitations of retrospective studies, this study has several characteristics that make interpretation difficult. In controlling for the effect of cigarette smoking, the investigators divided the smokers into those who smoked one pack or less per day and those who smoked more than one pack per day. Because cigarette consumption is highly correlated with coffee consumption (29, 39), it can be expected that within such broad smoking categories those who were heavy coffee drinkers tended to be heavier smokers than those who consumed smaller amounts of coffee. It is also possible that the hospitalized controls represented persons who drank less coffee than the general population because of serious chronic illnesses. These characteristics of the study design do not allow firm conclusions to be made concerning the extent to which the relationship between coffee drinking and myocardial infarction is independent of the relationship of both variables to cigarette smoking. The question of the independent nature of this relationship is also dealt with in a prospective study by Klatsky, et al. (39) of 464 patients with myocardial infarction who previously had had multi- phasic health checkups. Both ordinary controls and CHD risk factor-matched controls were drawn from 250,000 people who had undergone the same multiphasic health checkups. The investigators did not find an independent correlation between coffee drinking and myocardial infarction when risk-matched controls were used. 141 The Framingham Study (I$) recently published data on coffee drinking based on a I?--year followup of 5,209 mrn and women ages 30-67. An incrensed risk cfdeath from all causes was demonstrated in coffee drinkers, but this relationship was accounted for by the associ- ation between coffee consumption and cigarette smol;i,g. No association between coffee drinking and myocardial infarction or between coffee drinking and the development of CHD, stroke, or intermittent clsudication was demonstrated. Heyden, et al. (29) also found no relationship between excessive coffee consumption (> 5 cups per day) and atherosclerotic vascular disease. Vettrrictrlar Prmratrtre Beats Ventricular premature beats have been shown to be a risk factor for sudden death from CHD. Vedin, et al. (69). in a study of 793 men 111 Goteborg, Sweden, examined the frequency of rhythm and COl~dUc~iOJ~ disturbances at rest and during exercise. They found no statistically significant correlation between cigarette smoking habits and the presence of supraventricular or ventricular premature beats at rsst or during exercise. CARBON MONOXIDE Itrtrodrictiott Carbon monoxide has long been recognized as a dangerous gas, but until recently concentrations which produced carboxyhemo- globin levels below 15 to 20 percent were thought to have little effect on humans. Currently there is considerable interest in determining the effect of chronic exposure to low levels of carbon monoside (65. 66, 67, 68). Carbon monoxide is present in concentrations of 1 to 5 pelcent of the gaseous phase of cigarette smoke (II, 45). The concentr%tion varies with temperature of combustion as well as with factors which control the oxygen supply such as the porosity of the paper and packing of the tobacco. The amount of carbon monoxide produced increases as the cigarette burns down. Carboxyhemoglobin levels in smokers vary from 2 to IS percent depending on the amount smoked, degree of inhalation, and the time elapsed since smoking the lrtst cigarette. Carbon monoxide, which has 230 times the affinity of oxygen for hemoglobin, impairs oxygen transportation in at lcast Iwo ways: 142 First, it competes with oxygen for hemoglobin binding sites. Second. it increases the affinity of the remaining hemo@obin for osyfen. thereby requiring a larger gradient in Paz between the blood and tissue to dsliver a given amount of oxygen; this increased gradient is usually produced by a lowering of the tissue Po2. Carbon monoxide also binds to other heme-containing pig ments, most notably myoglobin, for which it has e\`en a greater affinity than for hemoglobin under conditions of low Paz. The significance of this binding is unclear, but may be important in tissues, such as the heart muscle, which have both high oxygen requirements and large amounts of myoglobin. Sources of Carbon hlonoxide Exposure and flumarl A bsorpriorl Several researchers (13, 32, 35. 57. 60. 70) have estimated the relative contribution of cigarette smoking and air pollution to the human carbon monoxide burden as measured by carboxyhemoglobin levels (COHb). Kahn, et al. (35), in a study of 16,649 blood donors. determined that smoking was the most important contributing factor, followed by industrial work exposure. Nonsmoking industrial workers had COHb levels of 1.38 percent, and nonsmokers without industrial exposure had levels of .7S percent. Cigarette smokers. on the other hand, had very high levels. Smokers with industrial exposure had levels of 5.01 percent, while smokers without industriai exposure had levels of 4.44 percent (Tables 3 and 4). Stewart, et al. (57) found similar results in a nationwide survey of blood donors and noted marked variation in mean COHb levels in residents of different cities measured at different times of the year (Table 5). However. in all areas, smokers still had COHb levels two to three times higher than nonsmokers and had increasing COHb levels with increasing level of cigarette consumption (Table 6). Similar findings were reported by Torbati, et al (60) in a study of 500 male Israeli blood donors. Nonsmoking workers exposed to atitomobile exhaust - London taxi drivers (32) and garage and service station operators (13) ~ have higher baseline levels of carboxyhemoglobin than nonsmokers of the general population. But even in these high exposure occupations smokers have markedly higher COHb levels (8.1 and 10.8 percent) than nonsmokers (6.3 and 5.5 percent). An extreme is represented by New York City tunnel workers who are exposed to an average of 63 ppm CO with peak exposure levels as high as 217 ppm CO: cigarette smokers still maintained much higher COHb levels (5.01 percent) than nonsmokers (2.93 percent) (8). 143 TABLE 3. -Mean percent of carbo.~yhemoglobit1 saturation in smokers and notwnokers by sex alId race Total Sample 1 Nonsmokers Smokers1 No. jz+s,- NO. x+q No. 2 +s, Total Sample 16,649 2.30 t 0.02 10,157 0.85 2 0.01 6,492 4.58 t 0.03 hlalc 10,542 2.66 + 0.03 5,888 1.00 + 0.01 4>654 4.76 + 0 04 Female 6,107 1.68 + 0.03 4,269 0.64 + 0.01 1.838 4.10 + 0.06 White 15,167 2.28 to.02 9.474 0.85 f. 0.01 5.693 4 66 + 0.04 htale 9,669 2.65 f 0.03 5,508 1.00 * o.o\ 4,161 4 tl3 * 0.04 Female 5,498 1.63 f. 0.03 3,966 0.64 * 0.01 1,532 4 19 + 0.06 Black 1,429 2.59 5 0.06 641 Male 829 2.91 *0.10 347 Female 600 2.15 c 0.09 294 `Smokers are defined as those who smoked on the day of giving blood. NOTE. - % = mean percent: ST= standard error of mean percent. Source: Kahn, A., et al. (35). 0.86 t 0.03 788 4.00 f 0.08 1.07 2 0.05 482 4.24 + O.lC 0.62 + 0.04 306 3.63 f 0 12 TABLE 4. - hfearz percerzt of carbo.~.~llzt~rnoglobin saturation in smokers arzt! Izutzwzokers by euzployrnerzt statzis I Nonsmokers Smokrrs' xiss; I No. I.38 t 0.04 I 1,738 5.01 t O.OG G.955 0.7M f 0.0 1 I 4,224 4.44 f u.u`l Persons not employed 1,678 0.6 3 +_ 0.02 531 4 24 f 0. I I `Industrial workers are employed in either durably or ~mndur,~bls good> manufacturing (craflsmen. operalives. or I~borrrs). Smokers are defined iis those who smoked on lhe day UC giving I~lood. NOTE. - i = mean percent; S, = stnnd.lrd error of mean percent. Source: Kahn, A., et al. (35). TABLE 5. - Median percent carbo~yylrerrloglobin (COHb) saturation and 90 percetrt range for smokers and wmtnokers by location Location Anchorage Chicago Denver Dciroit rlonolulu Houston Los Angeles hliami Milwaukee New Orleans NW York PhOWlX St. Louis S.111 Lake City Slin IFruncisco SeJttle Vermont. NW Ilampshire Washington, DC Cigarette Smokers Nonsmokers . Median Range 4.1 0.9 - 9.5 5.8 2.0 - 9.9 5.5 2.0 - 9.8 5.6 1.6 - IO.4 4.9 1.6 - 9.0 3.2 1.0 - 7.8 6.2 2.0 - 10.3 S.0 1.2 - 9.1 4.2 1.0 - 8.9 5.5 2.0 - 9.6 4.8 1.2 - 9.1 4.1 09 - 8.7 5.1 1.7 - 9.2 5.1 1 5 - 9.5 5.4 1.6 - 9.8 5.7 1.7 - 9.6 4.8 1.4 - 9.0 4.9 1.2 - 8.4 hlcdian K3llge 1.5 0 6 .- 3.2 I .7 I.0 - 3 2 2.0 o.!, - 3.7 1.6 0.7 - 2.7 I.4 0.7 - 2.5 1.2 06-35 1.u I.0 - 3.0 1.2 0 4 - 3.0 1.2 0.5 - 2.5 1.6 I.0 - 3 u 1.2 0.6 .- 2 5 1.2 0.5 2 5 1.4 0.9 - !.I I.? 0 G 2,s 1.5 0 h 2.1 1.5 0.M - 2 7 I.2 0 K - ?..I s 1.2 0.6 2.5 l-- Source: Stewurt, K.D., et III. (57). TABLE 6. - Mean percent carhoxyl~emoglobirr (COiIb) saturation in cigarette smokers I hour after bst cigarette Location Nonsmoker Packs of Cigucttcs Smoked Per day CK %-I I 1 5i 2 hlilwukuc Now Htimp\hirc, Vermont New York City Washington, DC LOS Angclcs Chicago 1.3 3.0 4.2 5.3 6.2 4,7 1.4 3.3 4.4 5.1 67 5.3 1.4 3.1 4.3 4.1 5.x 63 1.4 3.8 4.6 5.2 5.x 6 6 2.0 4.0 5.2 6.0 1.4 7.5 2.0 4.x 5.4 6.3 7. I 1.1 Source: Slewart, R.D.. et al. (57) Studies on the CO burden of each cigrette have determined the body burden of CO per cigarette to be 7.10-S.66 ml (40). and the increase in COHb level produced by smoking one ci_rar?tte to he .94 to I .6 percenr after I:! hours of abstinence (40. 33). The hali-life for the washout of CO in healthy college smokers (40) was catculated to be from 3 to 5 hours. Several studies have been published on the effects of carbon monoxide on healthy individuals. Small doses of CO (COZb levels 2.4-5.4 percent) were found to have no effect on heart rate (56). Raven, et al. (5f), in a study of young men exposed during exercise on a treadmill to 50 ppm CO (COlIb levels 2.5 percent in nonsmokers and 4.1 in smokers), found no decrease in maximum aerobic capacity when the subjects were tested at 25" C. In a similar experiment conducted at 35" C by the same researchers (20). there was a decrease in maximum aerobic capacity in nonsmokers exposed to SO ppm CO, but not in smokers despite an increase in the carboxyhemoglobin levels of I.5 percent in both groups. They postulated a possible physiologic adaptation of smokers to carbon monoxide. Ekblom and Huot (22) studied five young men who inhaled CO to reach given COHb levels. They reported that as COHb levels increased, there was a decrease in maximal oxygen uptake and lower heart rates at maximal treadmill exercise. Sagone, et al. (54), in a study of 9 cigarette smokers and I8 nonsmokers ages 20-32, showed significantly higher values for COHb, red cell mass, hemoglobin, and hematocrit in the smokers. Levels of 2,3 DPG were unaltered while oxyhemoglobin affinity I'50 and A'fP levels were significantly lower in the smokers. The three smokers with highest red cell mass had normal arterial blood gases and one smoker had very high values of red cell mass which returned to normal after he stopped smokin,. 0 The authors interpret these data-as evidence of tissue hypoxia. Millar and Gregory (43), in a study of both fresh heparinized blood and ACD-stored blood from a bIood bank, showed a reduction in the oxygen carrying capacity of up to 10 percent in the blood of cigarette smokers; this reduction persisted for the full 21-day storage life of blood bank blood. Cole, et al. (16), in a study of pregnant women, found COHb levels in the fetus to be 1.8 times a~ great as those in the 148 simu!taneou,ly measured bloat! ot t!1t` m0tI1rr. Fct31 l~100d \v3s exposed to carbon monoxide in vitro. and Iztd! h~mo~!ol~in \vas found to 113~2 a shift of the osyh~mo~obin disassociation curve to the left as occurs \vit!l adult !lemo_clobin. The !li$ler fetal CO!!b levels were attributed to tile lower fetal Po2 and a resultant decrease in the ability of oxygen to compete for t!X fetal I~emoglobin. It was felt by the authors that the hi& COHb levels may be responsible for the lower birth wei$t of infants born to mothers who smoke. Effecis ofi Persons wirll A rheroscleroric Carrliovascdar Disease Aronow and Isbe!! (5) and Anderson, et a!. (I) have shown a decrease in the mean duration of exercise before the onset of pain in patients with angina pectoris exposed to low levels of carbon monoxide (50 and 100 ppm). Carboxyhemoglobin levels were significantly elevated (2.9 percent after 50 ppm; 4.5 percent after 100 ppm) and the systolic blood pressure, heart rate, and product of s>.stolic blood pressure times heart rate (a measure of cardiac work) were a!! significantly lower at onset of angina pectoris. In a continuation of this work. Aronow, et al. (2. 3) studied eight patients durin: two separate cardiac catheterizations, one during which each patient smoked three cigarettes and one during Lvhich each patient inhaled carbon monoxide until the maximal coronary sinus COHb level equalled that produced by smoking during the first catheterization. All eight had angiographically demonstrated CHD (> 75 percent obstruction of at least one coronary artery). Smoking increased the systolic and diastolic blood pressure, heart rate. left ventricular end-diastolic pressure (LVEDP), and coronary sinus. arterial, and venous CO levels. No changes were noted in left ventricular contractility (dp/dt), aortic systolic ejection period. or cardiac index, and decreases were found in stroke index and coronary sinus. arterial, and venous Pq When carbon monoxide was inhaled. increased LVEDP and coronary sinus, arterial, and venous CO levels were noted; there were no changes in systolic and diastolic blood pressure, heart rate, or systolic ejection period; and decreases in left ventricular dp/dt, stroke index, cardiac index and coronary sinus. arterial, and venous Paz were found. .These data suzoest that carbon monoxide has a negative inotropic effect OR m;&ardia! tissue resulting in the decrease in contractility (dp/dt) and stroke index. \I'hen the positive effect of nicotine on contrac- tility and heart rate is added by cigarette smoking, the net effect is increased cardiac work for the same cardiac output. in the heart with 149 coronary artery disease there is a greatly restricted capacity to increase blood flow in response to this increase in cardiac work. The result is early cardiac decompensation manifested by elevation in LVEDP and angina pectoris. Aronow, et al. have also shown decreased exercise time prior to onset of angina pectoris in persons exercised after riding for 90 minutes on the Los Angeles Freeway (4). In a related study, they demonstrated a decrease in exercise time before claudication in a group of patients with intermittent claudication who were exposed to 50 ppm CO (6). Studies otr the Putlrogertesis of Curdiovascniur Disease In a review of some of their work on carbon monoxide, Astrup and Kjeldsen (7) noted that in cholesterol-fed rabbits exposed to I70 ppm carbon monoxide for 7 weeks (COHb 16 percent) and then to 310 ppm for 2 weeks, the cholesterol content of the aorta was 2.5 times higher than that of cholesterol-fed, air breathing controls. Groups of cholesterol-fed rabbits intermittently exposed to carbon monoxide for 13 or 4 hours per day produced three- to fivefold increases in the cholesterol content of their aortas. Cholesterol-fed rabbits made hypoxic at IO and 16 percent oxygen had 3 to 3.5 times tlie aortic cholesterol content, while those exposed to 26 and 28 percent oxygen had a considerable decrease in cholesterol aciumulation. Theodore, et al. (5s) studied the aortas of monkeys, baboons, dogs. rats, and mice fed a normal diet but exposed to very high levels of CO (COHb levels 33 percent) and found no atheromatous changes in their aortas. Further work by Astrup and Kieldsen (38) revealed that in rab- bits fed normal diets but exposed to 180 ppm carbon monoxide for 2 weeks, there were local areas in their hearts of partial or total necro% of myofihrils; in the arteries there was endothelial swelling, formation of subendothelial edema, and degeneration of the myocytes. When the aortas of these rabbits were examined (37), the Iuminal coats showed pronounced changes characterized by sevcrc edematous reaction with extensive swellin, 0 and formation of srrbendothelial blisters and plaques. The authors postulate that carbon monoxide increases endothelial permeability to albumin which results in formation of edema leading to changes indijtirl~Ir;il,,lt~l~ from early atherosclerosis. 150 Evidenc2 that this mecllJnism rnsy occur in Ilunlans is provided by the findings of Panins (50) \vho showed an increased trans- capillary escape rat2 for 13 1 I- labzlrd albumin in humans exposed to .-I3 percent CO (COHh 20 p2rcent) for 3 to 5 hot115. hut not in thoss mad2 hypoxic to an altituti? of -I300 mrters (I~emoglobin 75 percent saturat2d). By exposing rabbits to different conccntmtions of carbon monoxide (SO. 100, and 180 ppm) for varying periods (.S, 2. 4, 8, 24. and 48 hours), Thornsen and Kjeldsen (59) were able to show a threshold of 100 ppm of CO for myocardial damage. The demonstra- tion of damage at this level of CO (COHb 8-10 percent) is possibly explained by the ratio of carboxyrnyodobin to carboxyt~erno_elobin which is about 3 to 1 in myocardium at ambirnt POT. Thus, a COHb level of 10 percent would be accompanied by a cnrboxymyo- globin level of 30 percent in heart muscle. This ratio is even greater under hypoxic condltlons with a ratio of 6 to I when the arterial Paz is below 40 mm Hg (15). Nicotine In a study of the effects of smoking cigarettes with low and hi* nicotine content, Hill and Wynder (30) noted increasing serum epin2phrine levels with increasing nicotine content of the smoke. but serum nor2pinephrine levels were unchanged. However. increasing serum epinephrine levels with increasing number of low nicotine content cigarettes smoked were also noted. Acrolein Egle and Hudgins (21) did inhalation studies with acrolein on rats. Inhalation of this aldehyde at concentrations below those encountered in cigarette smoke resulted in a significanj increase in blood pressure and heart rate in rats. CEREBROVASCULAR DISEASE There has been conflicting evidence on whether there is an increased risk of cerebrovascular disease due to smoking (61, 62, 63, 64. 65. 66. 67, 65). A prospective study by Paffenbarger, et al. (4s) of 3,991 lon&oremen followed for I8 years showed no correlation between fatal strokes and smoking. However, both the Dot-n study of 151 U.S. veterans (3-i) and Hammond's study of one million men and women (175) showed a small but slgniticsnt increase in tile death rates from cerebrovascular disease among cigarette smokers. The Framing- ham i&year followup of men ages 45 to 54 (32) and PafTenbar~er`s study of men who entered IIarvard between 1916 and 1940 (49) also showed an excess risk of cerebrovsscular disease associated wit11 cigarette smoking. TWO recent studies provided more data on this topic. Ostfctld. et al. (46, 47), in a study of 2,748 people ages 65-74 receiving old age assistance in Cook County, Illinois, were unable to find any relation between cigarette smoking habits at the start of the study and incidence of new strokes or prevalence of transient ischemic attacks. Nomura, et al. (44), in a study of the population of Washington County, Maryland, ages 25 and older, were unable to find any relation between cigarette smoking and either mortality or morbidity from stroke. Nomura noted that "in atherosclerotic strokes the Framingham study and Paffenbarger's investigation of former college students included a great percentage of stroke cases under the age of 55. Because these two studies found an association between cigarette smoking and atherosclerotic strokes and the present study did not, it may be that the association is age-dependent." Hammond (25) provides some data which may clarify this relationship. Analysis of his data shows that the difference between cerebrovascular death rates in cigarette smokers and nonsmokers increases as persons get older except in males ages 75-84 (Table 7), indicating that the excess death rates associated with cigarette smoking increase with advancing age. The ratio of the death rates for smokers and nonsmokers (mortality ratio), however, decreases with 3ge. reflecting the fact that cerebrovascular disease death rates attributable to other causes increase with age more rapidly than death rates attributable to smoking. Cigarette smoking may well be a risk factor for stroke at all ages, but other causes of strokes become proportionally so important in older age groups that in studies not based on very large populations the risk due to cigarette smoking%' masked by the large total number of strokes due to other causes. 152 CVL Death Rates per 100,000 Person-Years hlen Never woked regulxly Pipe. cigx Clgtirctlc and other Clgarettc only 28 92 349 25 100 369 2x 129 36 I 42 130 477 Total 35 116 Never smoked regularly Clg;lrcllc Tot;11 18 38 25 57 X8 64 391 22x 315 238 1,3sti 1,371 9'10 l,lbY I.272 I .0X! I.277 I ,09 I CVL hfortalitv Ratios Never smoked regularly I 00 1.00 1.00 I .oo Pipe, cigx 0.119 I 09 I .06 I .o I Clgarelle dnd other I .oo 1.40 1.03 0.72 CigJrclle anl! 1.50 I.41 1.37 0.X6 Women Never smoked regulxrly CIprectc NOTE. - (`VL = Crruhrdl vtiscul~r Ies~ons. I .oo 1.00 1.00 I 00 2.1 I I.54 I.!X I Iii EFFECTS OF S.\lOKISG ON THE CO.AGULATION SYSTEM Several studies have contributed to an understandinq of the role of smoking in thrombogenesis. Lri,inr l-J/), in a controllc`d double blind study, showed that smoking a sin~Je cigarette increased the platelet's response to a standnrd a:_crqatin g stimulus (ADP). This phenomenon did not occur when lettuce lca11` cigarettes were smoked and was independent of a rise in free fatty acids in the plasma. The author postulates that this may be due to increasing epinephrine Jcvelr. These data may have relevancrt for two other studies. In the clinical trial of the possible prevention of heart attack by hyperlipidemic drugs in Newcastle, En~lnnd, (19) it was found that cigarette smokers were at increased risk of sudden death. This increased risk was not present in smokers treated with clotibrate. Llowrver, the researchers were unclble to relate this reduction in risk to any effect of clofibrate on st`m~n lipids. Kscfntly Carvaiho, et at. (13) evaluated 79 patients with familial i~yp~rbetslipoproteintlniia and noted that their platelets had an increased sensitivity to aggregating stimuli (ADP). Treatment with clofibrate returned the ADP sensitivity to normal without significantly altering serum lipids. This demonstrated effect of clofibrate may provide some insight into the Newcastle study. The reduction in the escess risk of sudden death could be due to a clofibratr induced reversal of increased sensitivity to aggr-egating stimuli produced by smoking. 154 SUJIhlARY OF RECEST C:\RDlO\`,ASCL'LAR FINDISCS 1. Data from one recent incidcncr: study suggest that ciCarc't;-? smokers are more likely to develop hypertension than 3ri nonsmokers. There is some evidence that suggests that stoppir.: smoking may be accompanied by a rise in blood pressure. 2. Cigarette smoking has been shown to be the major sourc< of elevated carbosyhemoglobin levels, with occupational esposnrs and air pollution being far less important in most circumstances. Carboxyhemoglobin levels in cigarette smokers are two to three times the levels in nonsmokers and increase with the amounts smoked. 3. Elevated carboxyhemoglobin levels have been shown to decrease maximal oxygen uptake in healthy people as weft 3s to decrease the exercise tolerance of persons with angina pectoris and intermittent claudication. The carboxyhemoglobin levels at which these effects take place 3re well within the range productld b!: cigarette smoking. 4. Carbon monoxide at levels of exposure commonly reachi`d by cigarette smokers has been shown to decrease cardiac contractlfitb, in persons with coronary heart disease. 5. Carbon monoxide has been shown to produce changes Iik? those of early atherosclerosis in the aortas of rabbits. 155 BlBLIOGKAPHY ANDERSON. E. W., ANDEL5IAN. K J.. 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Alherosclero~~s 16( 1): 67-82, July-August 1972. 38 KJELDSEN. E.. THOMSEN. H. K., ASTRUP, Y. Eit&ts of carbon monoxide on myocardiurn. Ultrastructural chsnrrs m rabblls sfter moderate. chronic e\powre. Clrculstion RL`search 34(3): 339.348. March 1974. 39 KLATSKY. A. L, t RILDXIAN, C. D., SIECELAUE. A. B. Coffee drinking prmr to acute myocardlal mfxction. Journ~J of the American hledrcal Association 226(S): 540-543. October 29. 1973. 40 LANDAW. S. A. The effects of cigarette smoking on total body burden and excretion r3tes of carbon monoxrde. Journal of Occupatmnal Medicine 15(3): 231.235, 5lxch i 973. 41 LE\;INE, P. H. An acute effect of cigarette smoking on platelet function. A possible hnk between smoking and arterial thrombosis. Circulation 48(3): 619-623;. September 1973. 42 \l&EE. D. Section 28. The probability of developing certain cardiovascular diseases in eight years at specified values of some characterrstics. In: Kannsl, W. B., Gordon, T. (Editors). The FramIngham Study: An cpidemiolorrcal investigation Of cardiovascul.u disease. U.S. Departmt-nt of Health. Education. and Welfare. Public Health Service. Natmnal Instrtutes of Health. Publication No. (NIH) 74-618, May 1973. 152 pp. 43 MILLAK, R. A.. GRI-,(;ORY. I. C. Reduced oxygen content in eqwhhrated fresh hrp,rrinrzed and ACD-stored blood from cigarrttc smokcrc. Bntlsh Journal of Anarsthecta44( 10): 1015.1019, October 1972. 44 NO\lURA. A.. CO\fSTOCK, G. W., KULLEK. L. TDS.\SCIA. 1. A. Qurettr making and strokes. Stroke 5(4):4X3486. July-August 1974. 158 46 OSTFELD. A. hf., SHEK;EI.LE. R. B.. K;1..\\1',\SS. H L. Tr~nwnt icchrrnlc .~llxk\ and risk of stroke m an elderly poor popul.~lion. Stroke 4(h): 9809Yh. November-December 1973. 47 OSTFELD. A. M., SHEKELLE, R. B.. KLAWANS. H , 1 U10, H. hl. Epidemloloey of stroke in an elderly welfare population. American Journal ol` Puhllc tlealth 63(S): 4SO--l58. May 1974. 48 PAFFENBARCER, R. S., Jr. Faclors predisposing to Patal stroke m long>horcmen. Preventive Medicine i(4): 522-525. December 1972. 49 PAFFENBARGER, R. S., Jr.. WING. A. L. Chronic disease in former college students, XI. Early precursors of nonfaral stroke. American Journal of Epldemlology 9-t(6): 524-530, Drcember 197 I. 50 PARVING. H. -H. The effect of hypoxia and carbon monouldr exposure on plasma volume and capillary prrmcabdity to albumin. Scandinavian Journal of Clmical and Laboratory investigation 3U( 1): 49-56. September 1972. 51 RAVEN. P. B.. DRINKWATER. B. L., RUHLING. R. 0.. BOLDUAN. N..TAGUCtll. S.. CLINER. J., HORVATH. S. ht. Effect of carbon monoxide and peroxyxetyl nitrate on man's maxmmt aerobic capacity. Journal of Applied Physiology 36(3): 288-293, hlarch 1973. 52 REYNERXON, R. H., TZACOURNIS. hl. Clinical and metabolic characterislics. Effects on mortality in coronary disease. Archives oi 1ntern.d hlediclne 132(5). 649653, November 1973. 53 RUSSELL, hl. A. H. Blood carhoxghaernoglobin changes during: tobacco \moklng. Postgraduate Medical Journal 49(576)' 684.687, October 1973. 54 SAGONE. A. L., Jr., LAWRENCE, T., BALCERZAK, S. P. Effect of smoking on tissue oxygen supply. Blood 4 l(6): 845.85 1. June 1973. 55 SELTZER. C. C. Effect of smoking on blood pressure. American lfrart Journ.rl 87(S): 558-564, May 1974. 56 SHEPHARD, R. J. The influence of small doses of carbon monoxide upon heart rate. Respiration 29(5/6): 516-521. 1972. 57 STEWART, R. D., BARETTA, E. D., PLATTE, L. R., STEWAKT, E. B.. KALBFLEISCH, J. H., VAN YSERLOO, B.. RIXlM. A. A. Csrboxyhemogobm levels in American blood donors. Journal. of the American hledlcal Association 229(9): 1187-l 195, August 26. 1974. 58 THEODORE, J., O'DONNELL, R. D., BACK, K. C. Toxicological evaluation of carbon monotlde in humans and other mammalian species. Journal of Occupstlonal hiedicine 13(S): 242-255. hfay 1971. 59 THOMSEN. H. I<., KJELDSEN. K. Threshold limit for carbon monoxide-Induced myocudlal damage. An electron muoscopic study in rabbits. ArchIves oi Environmental Health 29(2): 73-78. August 1974. 60 TORBATI. I.D.; HAR-KEDAR. I.. BEN-DAVID. A. Carbo\yhcmoglobin Icvelr in blood donors in relation to c~garel!e smoking And to orcupstlonal expowre to carbon monoxtde. Israel Journal ot blcdwal Sc~encrs lO(3): 241-244, hIarch 1974. 159 61 US. PUBLIC HtAI.TH SERVICE. %nokin~ ..d Ilralth. Kcport ot the ~d\,wry Committee to the Surgeon General of the Public tlralth Service. Wsshinpton. U.S. Department oi Health. Education, and Welfare. Pubhc IlcJlth Setvice Pubhcatwn No. 1103. 1964. 387 pp. 62 U.S. PURLIC HEALTH SERVICE. The Health Conwquences of Smoking. A Public 63 US 64 U.S Health Sew~ce Rcwew: 1967. U.S. Dcpartrncnt of Health. Education. And Welfare. Washington. Public Health Serwce Pubhcatlon No. 1696. Revised January 1968. 227 pp. PUBLIC HEALTH SERVICE. Ihe Health Consequences of Smoking 1968. Supplement IO the 1967 Public Health Scrwce R&ew. U.S. Dcpartmcnt of Health. Education. and Welfare. Washington, Public Health Service Publwation 1696, 1968. II7 pp. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking 1969. Supplement to the 1967 Public Health Sew~ce Review. U.S. Department of Health, Education. and Welfare. Warhington. Public Hrslth Servrce Publtcafion 1696-Z. 1969. 98 pp. 65 U.S. PUBLIC HEAL.rH SERVICE. The Health Consequrnces of Smokmg. A Report of lhe Surgeon General: 1971. U.S. Drputment ol Health. Educatmn. and Welfare. Washington, DHEW Publication No. (fiShi) 7 I-75 13, 1971, 458 pp. 66 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smokmg. A Report of the Surgeon General: 1972. U.S. Department of Health. Education. and Welfare. Washingron, DHEW Publication No. (HSM) 72-6516, 1972. IS8 pp. 67 U.S. PUBLIC HEALTH SERVICE. The Health Consequences of Smoking: 1973. U.S. Department of Health, Education. and Welfare. Washington. DHEW Publication No. (HSM) 73-8704. 1973. 249 pp. 68 U.S. PUBLIC HEALTH SERVICE: The Health Consequences of Smoking: 1974. U.S. Department of Health, Education. and Welfare. Washington. DHEW Publication No. (CDC) 74-8704. 1974. 124 pp. 69 VEDIN, J. A., WILHELMSSON, C. E.. WILHELhtSEN. L.. BJURE, J.. EKSTROhl- JODAL. B. Relation of restmg and exercise-induced eclopc beats IO other ischemic manifestations and to coronsry risk factors. Men born in 1913. American Journal of Cardiology 30(l): 25-3 I, July I I. 1972. 70 WALLACE, N. D., DAVIS, G. L., RUTLEDGE, R. B.. KAHN, A. Smoking and carboxyhemoglobin in the St. Louis Metropolitan population. Theoretical and empIrica considerations. Archives of Environmental Health 29(3): 136-142, September 1974. 160 Chapter 3 Chronic Obstructive Bronchopulmonq Disease source: 1971 Report, Chapter 3, pages 135 - 230. 161 Contenfs Introduction ......................................... Epidemiological Studies .............................. COPD Mortality ................................. COPD Morbidity .......................... .._... Ventilatory Function. ............................ Genetic Factors ................................. Alpha,-antitrypsin ........................... Air Pollution .................................... Occupational Hazards ............................ Cadmium. .................................. Pathological Studies ................................. Experimental Studies ................................ Animal Studies ................................. Studies in Humans .............................. Studies Concerning Pulmonary Clearance .......... Overall Clearance ........................... Ciliary Function ............................ Phagocytosis ................................ Studies Concerning the Surfactant System ......... Other Respiratory Disorders .......................... Infectious Respiratory Diseases .................... Postoperative Complications ...................... Summary and Conclusions ........................... References .......................................... FIGURES 1. Percent of lung sections with Grade IV or V fibrosis . . . 187 2. Percent of lung sections with Grade II or III emphysema 188 LIST OF TABLES (A indicates tables located in appendix at end of chapter) 1. Chronic obstructive bronchopulmonary disease mor- tality ratios.. . . _. . _. . . . . . . _. . . . . . _ . . _ . . . . . . . . Page 165 .167 167 171 172 174 176 178 179 180 180 184 184 189 190 190 190 191 198 198 198 200 201 202 168 163 LIST OF TABLES (Continued) (A indicates tsbics locstetl ~n :~ppendix at end of chapter) A2. Smoking and chronic obstructive pulmonary disease symptoms-percent prevalence. _ _ _ , . _ . . . . . . . _ _ . A3. Smoking and ventilatory function . . . . . . . _ _. _ _ . . _ AJ. GIossary of terms used in tables and text on smoking and ventilatory function.. _ . _ _ _ . . . . . . . . . . . . . . . _ 5. Cessation of smoking and human pulmonary function AG. Epidemiological studies concerning the relationship of air pollution, social class, and smoking to chronic obstructive bronchopulmonary disease (COPD) . . A7. Epidemiological studies concerning the relationship of occupational exposure and smoking to chronic obstructive bronchopulmonary disease. . . _ . . . _ . . 8. Studies concerning the relation of human pulmonary histology and smoking . . . . . . . . . . . . . . . . . . . . . . . 9. Experiments concerning the effect of the inhalation of cigarette smoke upon the tt,acheob~.o2lc)lial tree and pulmonary parenchymn of animals . . . . . . . _ _ . . . . . AlO. Experiments concerning the effect of the chronic in- halation of I\`O? upon the trncheobronchial tree and pulmonary parench>-ma of animals _ . _ . . :. . . . . . . 11. Experiments concerning the acute effect of cigarette smoke inhalation on hutnnn pulmonary function. . 12. Experiments concerning the effect of cigarette smoke on human and animal pulmonary clearance. . . . . . . A13. Experiments concerning the effect of cigarette smoke or its constituents upon ciliary function . . . . . . . . . Al4. Experiments concerning the effect of cigarette smoke on pulmonary surfactant and surface tension . . . ATS. Studies concerning the relationship of smoking to in- fectious respiratory disease in humans . . . . . . . . . . A16. Complications developing in the postoperative period in patients undergoing abdominal operations - .-. . A17. Arterial oxygen saturation before and after operation Paw 221 232 241 175 242 244 181 185 246 192 196 247 251 252 256 256 ISTI?ODLCTIOS Chronic obstructive bronchopulmonary disease (COPD) is char- acterized by chronic obstruction to airflow within the lungs. The term COPD refers to three common I-espiratory ailments: namely, chronic bronchitis, pulmonary emphysema, and reversible obstruc- tive lung disease (bronchial asthma) .* Chronic bronchitis has been defined as the chronic or recurrent excessive mucus secretion of the bronchial tree. It is characterized by cough with the production of sputum on most days for at least three months in the year during at least two consecutive years (217). Pulmonary emphysema is that anatomically defined condition of the iung characterized by an abnormal, permanent increase in the size of the distal air spaces (beyond the terminal bronchiole) ac- companied by destructive changes (217). Patients can suffer from both of these conditions simultaneously. The symptoms as well as the abnormalities in pulmonary function observed in the presence of the t1v-o ailments may be quite similar. Patients with chronic bronchitis suffer from productive cough with or without dyspnea (breathlessness both at rest or on exertion) while pulmonary emphysema is characterized mainly by dyspnea. COPD comprises a spectrum of clinical manifestations; thus, it is frequently diffleult to determine nhether a particular patient is suffering from one of the two specified diseases alone or which one predominates when both are thought to be present. COPD is responsible for significant mortality in the United States. In 1967, a total of 21,507 men and 3,885 women were re- corded as dying from chronic bronchitis and emphysema (221). This figure does not include a sizable number of individuals fol whom COPD was a contributory cause of death. During the past two decades, a major increase has taken place in the mortality from COPD in the United States. In 1949, the death rate from COPD was 2.1 per lOp,OOO resident population, Tvhile in 1960 it was 6.0 (zz?), and in 1967, 12.9 (2'1). Although 165 much of this rise is probably due to changes in certification and recording methods as well as to an increased interest on the part of the medical community, an appreciable proportion is also gen- erally accepted as reflecting a real increase in disease. Similar in- creases over the past 20 to SO years have also been observed in Canada (7) and in Israel (3L). The lack of a similar increase in Great Britain, a country with an extremely high rate of COPD, may be the result of a number of factors including improved therapy and decreased air pollution. Moreover, it is also likely that the diagnosis of COPD has been made more commonly and ac- curately in Great Britain for a longer time than in the United States, or elsewhere. Furthermore, the British definitions of bron- chitis and emphysema have differed in the past from those used in the United States. The mortality from and prevalence of COPD is probably under- estimated. In a study of death certificates, Rloriyama, et al. (170) reported that COPD is often omitted as a contributing cause of death. In a study of more than 350 autopsies, hlitchell, et al. (169) noted that the disease often goes unreported and that emphysema was occasionally found unassociated with severe cIinica1 airway obstruction. Hepper, et al. (110) observed that ventilatory test re- sults were abnormal in 10 percent of 714 patients in whom no symptoms, signs, or past history of pulmonary disease were noted. They concluded that severe degrees of ventilatory impairment may be undetected by history and physical examination alone. Boushy, et al. (40) evaluated clinical symptoms, physiologic measurements of airway obstruction, and morphologic bronchial and parenchymal changes in 90 males with bronchogenic carcinoma. The authors found that when either clinical, physiologic, or pathologic evidence of COPD was used alone, one-third to one-fourth of the patients were considered normal, but when all three criteria were used to- gether, only one patient was free of COPD. The importance of COPD as a contributing cause of mortality is now beginning to be more fully recognized. Clinicians have long observed that the `majority of their patients suffering from COPD were cigarette smokers (1, 150). Epidemio- logical studies have validated this impression by indicating that cigarette smokers are at a much greater risk of developing or dying from this disease and that the risk increases with increased dosage of cigarette smoke, reaching in the smoker of two packs or more a day a level as high as 18 times that of the nonsmokers (132). The salutary effect of giving up smoking has also been borne out by clinical observation and epidemiological studies. In a number of studies, smokers were found to suffer more fre- quently than nonsmokers from pulmonary symptoms including 166 cough, cough with production of phlegm, and dyspnea. By a variety of PUhIIOnar?- function tests, .cmokers were sho\\-Il to ltave dimin- ished function as compared to nonsmokers :ind also to have 3 steeper slope of the espected decline of function lvith age. Tests of ventilation./perfusion relationships in the lung have revealed ab- normal function in smokers. Autopsy studies have indicated that smokers dying of causes other than COPD have significnntl3~ more changes characteristic of emphysema than nonsmokers. Several recent studies have validated the clinical impression that among patients who undergo surgery, cigarette smokers run a greater risk of developing complications in the post-operative period than nonsmokers. Abundant experimental evidence of the role of smoking in bronchopulmonary disease has been obtained from experiments employing animals and tissue and cell cultures. Recent work has demonstrated, in dogs trained to inhale cigarette smoke through a tracheostoma, that emphysema, pulmonary fibrosis, and other path- ologic changes in the pulmonary parenchyma and bronchi develop and that these changes are proportional to the total dosage of cig- arette smoke inhaled. In vice and in vitro studies have sho\vn that whole cigarette smoke, or certain fractions thereof, inhibit ciliar) activity of the bronchial epithelium, adversely affect the mucous sheath, and inhibit the phagocytic activity of the pulmonary alveolar macrophage. These abnormalities lead to retarded clear- ance of inhaled foreign matter including infectious agents from the lungs, thus predisposing the individual to respiratory infec- tions. Evidence also exists that pulmonary surfactant may be ad- versely affected by cigarette smoke. The convergence of these lines of evidence, which will be de- scribed in more detail in the body of this chapter, leads to the judgment that cigarette smoking is the most important Cause of COPD in man. EPIDE31IOLOGICXL STUDIES COPD MORTALITY Numerous epidemiological studies, based on a variety of pop- ulations and carried on in a number of countries, have investi- gated the association between cigarette smoking and COPD. They have shown a greatly increased mortality and morbidity from COPD among smokers as compared to nonsmokers. Results from the major prospective studies relating smoking and CQPD mortal- ity are presented in table 1. The majority of the studies separate 167 TA~LD l.-Chronic obstructive broncltopulmonary disease mortality ratios (Actual number of deaths shown in pnrcntbewa)' SM = Smukcrs. NS = Nonsmokers PKOSFECTIVE STUDlF;S Author. yc.r. Number and Date Follow.up Number CiRnrcttcs/dry Cbr0tlk countly. type of collection Yeal.8 of deaths PlucJ. cignn bmnchitir Empbyaema Other rdcrence po9ulntion Hammond 187.783 white Queatiannaire 31/j 33s Ciporcltrr bnd maim in 3 and follow-up ShI ., ,308 NS ,. .I. .l.OO (30) Horn. e.te.te3 50-69 of death NS ., ,, 30 ?O . . . . -3.64 (40) Ail ,.. . .2.151231) Pipw h's ., .I.00 (90) sn ...I..1.77 (23) Cigar, NS ,., . ..I.00 (30) Shl . ..I 1.23 08) Doll and Approximately Qucationnnire 10 ___..-.. 292 Hill Ciporctfca 41.000 male Ciiinrt.llvY and follow-up Chronir 1964 NS , .I.00 N .s Llritish . . . ..I.00 of death bronchilit l-14 .6.80 Great 1 I4 . . ..O.GS phssicians. certificate. 111 Drilnin 15-24 ,12.80 15-24 ,l.OH Other >zs .21.20 >ZG .ucn (70). 181 All . . ...11.60 All . . . ..U.til I'ilwr art11 I'ijt,,a ct PIII Cif7orr (`i!,o ra sat .3.00 S>I ,....UiH --.---__---- _-_- --.. Author. )`cnr, Nu,m$;nd DlIln Follow-up NUttlbCt Cip.nrrttcs/doy Chronic country, eollcction YPtlTS of denths pipes, cignrs bronchitis Emphysema Other rdcrcnee 909ulntion PROSPECTIVE STUDIES net. Approximntelr Qucstionnairc 6 IOGG. 78,000 mole nncl follow-up Conndn Cnnndian of dcnth (JO). vctcrnns. certificate. Hammond. 440.568 males IntPrriews by 4 IIGG. 5li?.GiI ACS volun- U.S.A. icmnlcs twrs. (103). 35-M years of ape in 25 3taLes. 124 Cionrcttea NS , ,I.00 20 . . ..I4.G3fIZ) Al, 11.42(781 Pill0 Shl ,, ,. .2.11 (5) CipClr8 Shl 3.57 (1) Ciporcltra NS ,..... 1.00 ?O .G.03 (7) All .5,Y5(3?1 Pijlc.4 Shl ,,..,.. 0.75 (2) C10flta Shl .,...,, 3.33 (1) 380 nloicr Sbl . . . ...369 NS ., .l.OO (20) NS . . . . ..?a SM (nge 45-60 , .6.65(114) S!l! (age 65-79) .11.41(175) Kuhn. U.S. male Questionnaire S?l, Hronciiitis NS 1966. . . . ..I.oo (31) Cunc7lt cign- Currmt cigo. veterans snd Shl 64 U.S.A. AIlShI . ..6.49(348) 2,265.674 rtttcr odv rcltea ml/v fOUOW-Up NS . ..I3 Current ciga. (1J:l. NS .,..,. l.OO(l3) NS 1.00 (18) person years. of death Emphvacmo rette .10.08 (229) 1-O . . . . . 3.63 (5) l-9 ,.,.,.. 5.33 (10) certificate. ShI . . . ...284 Pipe8 IO-20 .4.61(22) 10-20 .14.04 (93) NS .,...., 18 Shl ~.2.36 (9) 21-39 .,,. 4.5i(12) 21-39 . ,. .17.04 (62) Cipora >a9 . . ...8.31 (4) >39 ,. .26.34 (171 Shl . ...,. 0.70 (6) All .I.... 4.49(43) Ail ..:...14.17(186) w m r, 0 Wickcn. 1,189 moles. Personal inter- 1,188 obtoincd 1066. view with rctrosncc. North- relntives of tiveiy. err1 individuals Shl .1,064 lrelsnd listed on NS . . . ..I24 (227). death register. `Unless otherwise specified, disparities between the total number of deaths and the mourn of the individual smoking cntcgoriea are due to the exclusion Ciyarcltcs odu NS ,...., LOO(124) I-10 ,,, .2.95(245) II-?? . . ..3.43(300) >?3 . . . ..4.44(168) hlirrd Shl . . . ..I.55 (62) I'ipca or ciynrr Shl ., . . .1.84(ZB9) - of either occasional, miscellnnwus. mixed, or ex.smokcrs. 2 NS includus aijic and cigur smokwr: SXl includes rx-rmokcra. the findings for chronic bronchitis and emphysema. Such specific VJUPing Of the mortality data should be viejved with some reser- vations in the light of the difhculties mentioned above in dis- tinguishing the two diseases clinically. The dose relationship of increased mortality ratios with increased Consumption of cigarettes is indicated by the results of all the studies which present rates for different Ievels of smoking. Kahn (13-3), for instance, noted that those smoking only 1 to 9 cigarettes per day incurred an emphysema mortality ratio of 5.33 while those smoking over 39 per day incurred one of 25.34. Pipe and cigar smokers were found in some studies to have slightly elevated mor- tality ratios in comparison with nonsmokers although other studies did not show this. The risk of dying from COPD among cigar and pipe smokers appears to be much less than that incurred by cigarette smokers but may be somewhat greater than that among nonsmokers (table 1) . The effect of stopping smoking on COPD mortality is reflected in the results of Doll and Hill (70, 71) in their study of British physi- cians. They found that during the years immediately following cessation of smoking, mortality ratios remained elevated and did not begin to decline below the level of continuing smokers until nearly a decade later. This delay in response is probably due to two factors: the presence in the ex-smokers' group of many who quit for reasons of ill health and the long-term effects of cigarette smoke on the respiratory tree, some of which are irreversible. Kahn (131') also noted that the age-specific mortality ratios for es-smokers were lower than those for continuing smokers of cor- responding amounts of cigarettes. A better estimate of the potential effect of stopping smoking on COPD mortality can be gained by studying the death rates in a population in which a high proportion of smokers have stopped smoking to protect their health rather than as a response to ill health. Among doctors age 35-64 in England and Wales, many of whom have stopped smoking cigarettes, there was a 24 Percent- reduction in bronchitis mortality between 1953-57 and 1961-65, as compared with a reduction of only 4 percent in all men of the same age in England and Wales, among whom there was no reduc- tion of cigarette smoking. (84). COPD MORBIDITY Many investigators have studied the prevalence of bronchopul- monary symptoms (including those of chronic nonspecific respira- tory disease) among smokers and nonsmokers. These studies are outlined in table AZ. Their results indicate that the cigarette 171 smoker is much more likely to suffer from respiratory symptoms such as cough, sputum production, and dyspnea than is the non- smoker. Such symptoms, particularly cough and sputum produc- tion, increase with increasing dosage of cigarette smoke. Table A2 also sholvs that pipe and cigar smokers experience COPD symptoms more frequently than nonsmokers although not to the degree found in cigarette smokers. These morbidity findings are similar to the mortality findings presented above. Similarly, cessation of cigarette smoking has been shown to be associated with a decrease in symptom prevalence. Nitchell, et al. (168) studied 60 patients who succeeded in stopping smoking and 84 continuing smokers. Among the ex-smokers, more than 70 per- cent reported improvement in their cough while less than 3 percent of the continuing smokers did so. Wynder, et al. (2.37) followed 224 ex-smokers of cigarettes and noted that 77 percent reported cessation of persistent cough and an additional 17 percent reported definite improvement. Hammond (102) reported similar results concerning cough and shortness of breath in a study of a large group of ex-smokers. VENTILATOKY FUXCTION Another type of quantification of the effects of smoking on the bronchopulmonary system has been obtained by those groups of investigators who have studied pulmonary function in various gIWUpS. Results are presented in table A3, and a glossary of the terms used in the various tests is presented in table A4. The pa- rameters investigated have included maximal breathing capacity (maximal voluntary ventilation), expiratory flow rates, forced expiratory volume, and vital capacity. Although certain of these parameters appear to be more sensitive measures of pulmonary dysfunction than others, the overwhelming majority of these stud- ies have shown diminished function among smokers. An increase in the expected age-diminution rate in smokers has been observed in those studies which employed either repeated examinations or examinations at many different age levels. Higgins, et al. (117) conducted a nine-year follow-up examination of 385 male residents of a British industrial town who were age 55-64 at the beginning of the study. Among the survivors who were tested initially and nine years later, the average decline in FEV,.;, was smallest in non- smokers, slightly greater in ex-smokers, and greatest in smokers. As with COPD mortality and symptom prevalence, the impairment of pulmonary function shows a dose-reIationship with increasing amounts of cigarettes smoked. The data contained in table XX provide two di;?erent kinds of information. The majority of the studies \vere conducted on un- selected populations, which probably include a number of individ- uals with clinically manifest COPD. Therefore, these studies re- flect the prevalence of COPD-related dysfunction (as determined by pulmonary function tests) in relation to smoking. However, some studies of younger individuals have revealed that pulmonary function tests are abnormal in clinically asymptomatic smokers. Krumholz, et al. (140) and Rankin, et al. (189) have sho\vnthat pulmonary diffusing capacity is impaired in young asymptomatic smokers when compared with age-matched nonsmokers. Similar impairment in other pulmonary function tests was noted by Peters and Ferris (182, 183) in an asymptomatic college-age group and by Zwi, et al. (241) and Krumholz. et al. (lS0, 142) in groups of young asymptomatic physicians and medical students. Several investigators have employed tests which measure the relationship of ventilation and perfusion (V/Q relationships) in the various pulmonary segments. These tests are predicated on observations that some segments of the lung may he relatively under or overperfused and that, likewise, segments may be under or over-ventilated. Anthonisen, et al. (IO) investigated pulmonary function in 10 male smokers with clinically mild chronic bronchitis, all of whom had smoked cigarettes for at least 30 years. Regional pulmonary function was studied using radioactive xenon. Despite the fact that overall pulmonary function was nearly normal in sev- eral patients, all had depressed V/Q ratios in some lung regions with the basal areas being those most commonly affected. The au- thors suggested that significant disease in the peripheral airways may exist in patients whose chronic bronchitis is clinically mild and who show no present impairment of ventilatory capacity. The radioactive xenon test may reveal severe compromise of local gas exchange when usual studies of ventilatory capacity do not reveal any impairment. Similar results concerning peripheral airway ob struction in bronchitic patients with normal, or only minimally in- creased pulmonary resistance, have been observed by Woolcock, et al. (234). These authors also noted that their patients demon- strated frequency-dependent compliance lvhich was unaffected by the administration of bronchodilator aerosols. Strieder, et al. (214) have recently investigated the mechanism of postural hypoxemia in 2.1 asymptomatic smokers and non- . smokers. They found that standard ventilatory tests and lung vol.- umes were normal in both the smoking and nonsmoking groups. However, the arterial ~0' measured in the supine position was significantly lower among the smokers and alveolar-arterial oxygen gradients, while breathing room air, were larger in smokers than in 173 nonsmokers (more so in the supine than in the erect position) _ The increase in alveolar-arterial 0: gradients I\-as rrenter for heaq than for light smokers. The authors concluded that mnltlistribution of ventilation and perfusion accounted for the observed hyposemin. They also felt that this mild diffu5.e air\\-a>- disease among asympto- matic smokers is physiologically significant mainly because of in- volvement of small bronchi, as expressed by maldistribution unac- companied by gross airway obstruction. X similar ventilatory distribution abnormality among smokers has also been observed by Ross, et al. (198) with the mere severe alterations found in the long-term smokers. Although of concern in the consideration of COPD, such dis- turbances of the V/Q relationship may also have adverse effects upon cardiac function depending upon the level of hppoxemia (213). The discussion in the section on Coronary Heart Disease noted that carbon monoxide has adverse effects on both oxygen transport and alveolar-arterial exchange as well as on osygtn debt developed with exercise (50). Further research is needed on the joint effect of these pulmonary and carbon monoxide induced h>-poxemic influences. A number of other studies have provided further evidence con- cerning the adverse effect of smoking on ventilatory function. Table 5 presents those experiments which deal with the effect of cessation of smoking on pulmonary function. Among the param- eters which have been noted to improve after stopping smoking are: diffusing capacity, compliance, resistance, maximal breathing capacity, and forced expiratory volumes. These parameters shelved improvement within 3 to -1 weeks after cessation of smoking. GENETIC FACTORS Recent interest has been shown in the possible contribution of genetic factors to the pathogtnesis of COPD. Earlier studies (127. 147) had noted the existence of kindreds with high incidenres of chronic bronchitis, emphysema, or both diseases. In addition to the presence of genetic susceptibility, Larson, et al. (1:7) also observed that all but one of the 11 symptomatic individuals in their two kindreds were smokers. They postulated that the susceptibility of some smokers to develop emphysema may be, at least partially, genetically detemined. More recently, Larson, et al. (1;8) studied 156 relatives of COPD patients and 86 control individuals. The subjects underwent pul- monary function testing, including forced espiratory volume and residual volume./total lung capacity measurements. The authors observed that pulmonary function abnormalities were most prev- alent among the relatives who smoked and least prevalent among 174 Krumhulz 10 physicians F&lowing J wecka abslincnce FoUowinp c weeks obalincxcc (6 tubjocts mily)t ! All subjcets were >E Dock eL al., 25-33 ycara Lung volumes--no significant ehnnae. Lung volumes: per ycnr smokcra 1965. or hKC. Pcnk e&pirntory flow rntl-incrensc Insplrntury rcscrvc volumcinerease (p- (.we below). In addition, nonsmoking reIati\.es and -;nroking controls were observed to sho\v approsimntely the same pre\.:llence of :tb- normalities. However. due to the large proportion of females in the nonsmoking relative group and to the clustering of tuo-thirds of the affected relatives in 10 families, firm conclusions cannot nt present be dralvn from this study concerning the relative contribu- tions of smoking and of heredity to the pathogenesis of COPD. In order to determine the relative significance of smoking and heredity in the pathogenesis of COPD, Cederlof, et al. (;;s, ;c) have used the twin-study methods on registries in both Sweden and the USA. The specific details of this method are described in the sec- tion on Coronary Heart Disease. As may be noted from a summary of their work at the end of table A 2, the authors compared the symptom prevalence among monozygotic and dizygotic twins who were both discordant and concordant for smoking habits. The\ observed that the h~~permorbidit~ for COPD symptoms related to smoking persisted even after controlling for zygosity and concluded that a causal relationship of smoking and COPD symptoms iv-as sup- ported. HoLvever, genetic factors were still found to have an appre- ciable influence. Lundmann (1.59) has applied this method to the study of pulmonary function. He studied 37 monozygotic and 62 dizygotic tlvin pairs, measuring forced expiratory voiumes and nitrogen washout gradients, and matched the various pairs for smoking discordancy. He observed that both of these parameters were adverseI>. affected in txvins ivho smoked and that these changes were correlated \vith cigarette consumption. The results are out- lined at the end of table X3. AZr,I~a-,-a,~ti~~.~~sin (X,XT) -Of more recent note and discus- sion has been the discovery of an association between a hereditary predisposition to COPD and the relative or absolute absence of alpha,-antitrypsin, a serum glycoprotein enzyme. Eriksson (78) was the first investigator to observe a relationship between the presence of markedly decreased serum trypsin inhibitory capacity and panlobular emph!-sema. Since Eriksson's paper, much added research has been published concerning many facets of this intrigu- ing area. It appears that X,-XT deficiency is inherited as an autosomal recessive trait (~8, 2IG) although Kueppers (IL') considers the transmission to be by an autosomal codominant allele. It hlis been estimated that up to 5 percent of the general population may be heterozygous for this gene (1.51) although full cross-sectional studies of the population remain to be done. Homozygous or severe deficiency of this enzyme has been asso- 176 ciated with a particular type of pulmonary emphysema. \Vhile the majority of lungs of cmphysematous patients reveal ~UIIOLIS or centrilobular deformities, particularly of the upper lobes, this hereditary disorder reveals a panncinar change, most severe in the lower lobes (101, 215. 226). Patients with emphysema who are found to have the homozygous deficiency have been observed to include a greater percentage of female patients than is usually ob- served in the general emphy-sema population. Their disease begins earlier, is more severe, is characterized by dyspnea rather than cough, and frequently is unassociated with a history of preceding bronchitis (101 , "~5, ~6) _ Radiographic studies of A,AT-deficient patients have revealed decreased vascularization of the lower lobes and increased vascularization of the upper lobes (101, 21.1). It is estimated that between 1 and 2 percent of patients with COPD have this homozygous deficiency (78 , 216). In family studies, it has been found that almost all the homozygous individuals are symptomatic by the age of -10 and that those ivho are not usually show alterations in pulmonary function studies. Guenter, et al. (38) studied 7 per- sons with homozygous deficiency. Of the five symptomatic individ- uals, .I smoked and all had abnormal timed vital capacity. Neither of the two asymptomatic individuals smoked or had this change in vital capacity. All 7, however, were noted to be hypoxemic at rest and to have decreased pulmonary diffusing capacity. It has been suggested (I.?;) that the lack of this proteinase in- hibitor in the serum of homozygous patients predisposes them t.o emphysema in the following manner: Leukocytes present in the blood contain significant amounts of proteinase enzymes as part of the overall defense mechanism against infection ; the breakdown of these cells during acute infection releases proteinases into the pul- monary tissues and these, \vithout the presence of a normal inhib- itor, may contribute to the breakdown of the structural proteins of lung tissue. Heterozygous individuals have been defined as those who show levels of X,AT intermediate between those of normals and those with homozygous deficiency. At the present time, there is much debate about whether or not heterozygotes for A,AT are at a greater risk of developing COPD than are A,AT normals. A major dificultv is the lack of a precise definition of heterozygosity. At Present, the best method for the determination of the level of A,AT appears to be that of crossed serum immunoelectrophoresis he- cause levels of trypsin inhibitory capacity (TIC) have been shown to rise acutely with infections. Welch, et al. (26) feel that heterozygotes do not show an in- creased susceptibility to COPD. The heterozygotes tvhich they studied showed symptoms of bronchitis and did not present the 177 lolver lobe perfusion defects frequentI>- noted in homozygotes. The>- also fo~~nd no difference in the number of COPD patients among the heterozygotic and the gtner:\l population. Other inve~iiigators, no- tably Lieberman, et al. (I.,;, I.;.;), Rueppers, et al. ( IAL), and L;irson, et al. (I.;$) found significantly increased percentaF;es of COPD patients among those lvith heterozpgous deficiency as com- pared with the general population. Lieberman, et al. (~55) ob- served that the percentage of heterozygdtes among a group of healthy industrial xvorkers was 1.7 percent while that among a group of patients with emphysema was 18.1 percent. In a recent re\,iew, Falk and Briscoe (79) considered that the available evi- dence points to an increased prevalence of COPD among hetero- zygotes. Of more central interest to this discussion, however, is the pos- sible relationship of smoking to the predisposition of disease among the heterozygote population. Kueppers, et al. (IL-$) studied three populations: younger controls, older controls, and a group of COPD patients. They observed that of the 25 heterozygotes with COPD, only 2 \vere over 70 years of age, both were female and non- smokers. The remaining 23 were cigarette smokers. Nevertheless, studies which adequately sort out the factors of genetic susceptibil- ity and cigarette smoke exposure have yet to be reported. An important question is to \vh.at extent the relationship between smoking and COPD is influenced by identifiable genetic factors. At present, it is possible to identify what appears to be only a very small group of susceptibles for whom genetic factors may be para- mount in the pathogenesis of their ailment. Of greater public health import is whether lesser degrees of genetically identifiable suscep- tibility interact with cigarette smoking m account for a significant proportion of the problem. AIR POLLUTION Numerous epidemiological studies have been conducted in order to examine the effect of air pollution on human nonneoplastic res- piratory disease. Three major types of studies have been utilized : observation of the mortality and morbidity due to an acute episode of increased air pollution, observation of the day-to-day variation in mortality and its relation to air pollution levels, and geographical comparisons- The majority of studies fall into the third category, and these are detailed in table A& A number of studies did not show an association among air pol- lution, respiratory symptoms, and pulmonary dysfunction (81,205). More recent studies which evaluated the factors of smoking, social class, and air pollution separately noted a greater prevalence of 178 COPD symptoms, pulmonary ds,sfunction, and COPD mortality in areas of high pollution (21, 122, l;li, 2,;s). Lambert and Reid (146) observed that in the absence of cigarette smoking the corre- lation bet\\-een COPD symptoms and air pollution was slight and suggested that the two factors may interact to produce higher rates of disease. The evidence which has accumulated in the past 7 years gives further support to the conclusion of the Surgeon General's Ad- visory Committee on Smoking and Wealth as stated in its 1964 Re- port that: "For the bulk of the population of the United States, the relative importance of cigarette smoking as a cause of chronic bronchopulmonary disease is much greater than atmospheric pol- lution or occupational exposures." Exposure to various dusty occupational environments has been shown in many studies to be associated with the development of various forms of nonneopiastic lung disease. Lowe (158)) in a re- view of the relationship of occupational exposure and chronic bronchitis, noted that among workers exposed to dust significant increases in COPD mortality were observed. These occupations included coal mining, tinning, galvanizing, riveting, and caulking. Commenting on a previously unreported study of more than 20,000 steel Jvorkers, he observed that the relationship betrveen mean dust exposure levels and COPD prevalence was much stronger among smokers than among nonsmokers. Alore recently, Bouhuys and Peters (37) reviewed those specific industrial exposures related to lung disease. COPD was found to be associated with exposure to coal dust, asbestos, bagasse dust, iso- cyanates, various irritant gases, and textile dusts (cotton, flax, or hemp). Studies which have investigated the interrelationship between smoking, industrial exposure, and COPD are listed in table A?. Act; ditional compounds, not listed in the table, but which also appear to be related to COPD, are chlorine ($9) and washing powder dust (!?7), Cigarette smoking and harmful dust exposures appear to act in a combined manner in the production of COPD. Although an increased prevalence of COPD is found with cer- tain occupational exposures, in none is the relationship as strong as that between COPD and cigarette smoking. To demonstrate an increased occupational risk, careful analysis of smoking habits is required. The relative importance of cigarette smoking appears to be much greater than occupational exposure as an etioIogic factor in COPD. 179 Cad,,zilc,)r-CC:hl.onic industrial esposure to cadmium in man has been found to induce pulmonary emphysema without significant accompanying chronic bronchitis (32, 35, 210) Nandi, et al. (177) recently investigated the contribution of the cadmium in cigarette smoke to the pathogenesis of emphysema. Analyzing \I-hole cigarettes, ash. and filters, the>- found that an average of 69 percent of the cadmium present in the cigarette (ap- proximately 16 microgram5 20 cigarettes) is inhaled in the smoke. In a related study (2.53). these investigators showed that the level of cadmium in water-soluble liver protein on autopsy was three times greater in those patients with a history of chronic bronchitis; emphysema than that found in those without such a history. Un- fortunately, no smoking histories were available. PXTHOI~OGIC~I~ STUDIES The relationship betn-een smoking habits and pathological changes in the bronchial tree and pulmonary parenchpma has been investigated by se\-era1 groups of lvorkers. Xetaplastic changes, although found in nonsmokers, are much more common in smokers (table 10, Cancer Chapter), and a dose-relationship of increasing metaplasia with increased smoking has been evident in many of the studies. Pathological studies which deal primarily with pulmonary parenchgmal and non-metaplastic bronchial changes are presented in table 8. Goblet cell distention, alveolar septal rupture, thickened bronchial epithelium, and mucous gland hypertrophy have been found to be more frequent in smokers than in nonsmokers. Auer- bath, et al. (17) noted a dose-response relationship between the amount of smoking and the degree of septal rupture. Anderson, et al. (;, 5) studied the difference in the type of emphysema shown by smokers and nonsmokers. In their study, listed in table 8, they noted that the group of patients with panlobu- lar emphysema was comprised of equal numbers of smokers and nonsmokers while of patients with centrilohular emphysema, 98 percent \vere smokers. Xore recently, the same authors studied lung macrosections from 80 nonsmokers. While most were normal, 24 demonstrated parenchymal dilatation and disruption consistent with panlobular emphysema. Thurlbeck, et aL> (217) have also ob- served that centrilobular emphysema rarely occurs in nonsmokers. 180 hlcgnhed 50 male patients Mucous eland hupcrlrophu et II.. with chronic Pcrcm& 1967. bronchitis under- NS . . . . . . . . . . . ..~........ PO Egypt (2/7) goinK bronchial ShI . ,. ,, .I., ., I 77 (33/431 (P40 cigarcltn/day (66) . . 1.3 1.4 31.6 45.3 20.6 ' Numerourr experiments dttailing changes in bronchial epithelium ore dctoilcd tnbulnrly in the Cnnccr chapter. ESPERI.\IESTXL STCDIES Xsrsrx~ STUDIES A number of investigators have studied the effect of the inhala- tion of cigarette smoke on the macroscopic and microscopic str-uc- ture of the tracheobronchial tree and Pulmonary parench>.ma of animals. Studies dealing with metaplasia and cellular atypism of the trachea and bronchi are listed in table Xl6 of the cancer chap- ter. Studies more directly concerned with the pathology of COPD are listed in table 9. They show that cigarette smoke exposure is associated with changes similar to those found in humans vvith COPD, i.e., bronchitis, parenchymai disruption, alveolar septal rupture, alveolar space dilatation, and the loss of cilia and ciliated celIs in the bronchial mucosa. The investigations of Auerbach and his coworkers (15, 16, 88) have demonstrated by the use of both light and electron microscopy that dogs \vho inhale cigarette smoke through tracheostomas de- velop progressively more severe lesions of the bronchi and paren- chyma lvith increased exposure to cigarette smoke. In electron microscopic studies of specimens taken from the lungs of dogs thus exposed to cigarette smoke, the following changes were observed : In 5 dogs sacrificed after only 44 days of smoking exposure, there was a proliferation of goblet cells as well as a partial loss of cilia in the lining cells, and in 5 dogs sacrificed after 120 days or more of esposure, the num'ber of cell layers in the bronchial epithelium was found to be twice that of the nonsmoking dogs. Goblet cells and ciliated columnar cells were no longer present; instead, the surface was lined with columnar and cuboidal cells with stubby projections in place of cilia. 3Iitotic figures were frequently observed in the basal cells. These findings may be relevant to carcinogenesis as well as to the development of COPD. In a long-term experiment, carried out by the same group, dogs were exposed to varying doses of cigarette smoke. Details of the experimental procedure have been outlined in the section on Pul- monary Carcinogenesis. The animals were separated into non- smoker, filter-tip cigarette, nonfilter-light, and nonfilter-heavy ex- posure groups. The dogs were "smoked" for 87.5 days, or approxi- mately 29 months. The animals which died during the experiment and the animals sacrificed after day 875 \vere examined for Pul- monar3' psrenchymal changes as well as for bronchial epithelial alterations. As seen in figures 1 and 2, dose-related pathological changes, including fibrosis and emphysema, were found in the lung parenchyma of the exposed dogs. These changes were similar to those seen in the lungs of humans with COPD. 184 IOO- --__- 91.7 a0 - 20 - 17.9 I.- 57 0 00 GROUP N: GROUP f: GROUP L: GROlJP H: NONSMOKING FILTER-TIP NO FILTER NO FILTER (% 25 many clpretter) as Gro"D H Several investigative groups have exposed rodents to various ambient concentrations of nitrogen dioxide over prolonged periods of time. This gas is found in cigarette smoke and in some indus- trially polluted air. The results of these studies are outlined in table A10. It is clear that chronic exposure to low levels of NO? is capable of inducing lesions in the bronchial tree although the rela- tionship between these changes, cigarette smoking, and the devel- opment of COPD remains to be determined. Rosenkrantz, et al. (196, 197) have recently undertaken experi- ments dealing with pulmonary cellular metabolism. They exposed Swiss albino mice to cigarette smoke or its vapor phase for varying lengths of time. On autopsy, animals exposed to cigarette smoke showed elevations in the levels of lung DNA, lactate, and glycogen which the authors conclude reflect hyperplnsia and macrophage infiltration. Similarly, a dose-related increase in lung hydroxypro- line was observed. This was considered to be due to increased fi- broblastic collagen synthesis. 187 GROUP N: NONSMOKING GROUP F: GROUP L: GROUP H: FILTER-TIP NO FILTER NO FILTER (`A as many cigaretb) a* Group H FIGURE Z.-Percent of lur:g sections with grade II or III emphysema. SOURCES Hammond, et al. (104). Aviado and coworkers have performed a series of experiments on live animals and in heart-lung preparations to study the effect of cigarette smoke on pulmonary physiology and structure (18, 19, 20,21, 22, 179, 180, 199, 200,201, 202). The authors observed that cigarette smoke causes acute bronchoconstriction both by the re- lease of histamine and the stimulation of parasympathetic nerve pathways in the lung. Bronchial arterial injections of nicotine were found to cause reactions similar t,o those observed after cigarette smoke inhalation. The hronchoconstriction was usually followed by bronchodilatation which the authors attributed to sympathetic stimulation. As mentioned in the Chapter on Cardiovascular Dis- eases, nicotine has been shown to induce the release of catechola- mines. Experiments by Aviado and coworkers as well as other authors (66, 99) using guinea pigs showed that exposure to cigarette smoke was associated with increased bronchopulmonary resistance and decreased pulmonary compliance. The authors related these changes to the bronchoconstriction of terminal ventilatory `units. 188 Similar experiments in dogs shelved that the increase in resistance following either cigarette smoke exposure or intravenous nicotine could be blocked by pretreatment ivith atropine. Xs a parasympa- thetic blocker, atropine would decrease the acute bronchoconstric- tive phase. Nest recently, Xviado and his colleagues (00, 130) have at- tempted to induce physiologic and anatomic changes similar to those found in the lungs of patients with emphysema. They ex- posed male rats to cigarette smoke, the introduction of the enzyme papain, as we11 as to partial tracheal ligation. In 10 rats exposed to cigarette smoke tlvice daily for 30 minutes over a period of 10 weeks, no changes in pulmonary compliance or resistance were noted. Also, no abnormal histological changes were observed in the group exposed only to cigarette smoke. However, animals who underwent tracheal ligation as well as smoke exposure showed in- creased numbers of enlarged air spaces and increased pulmonary resistance when c\ompared with animals who underwent only tracheal ligation. STUDIES IN I-TUhIhNS The acute effects of cigarette smoke inhalation on bronchopul- monary function in man have been investigated by a number of workers. The results of these studies are presented in table 11. The majority of studies, particularly the more recent ones, found that the inhalation of cigarette smoke is associated with an acute in- crease in pulmonary resistance and a decrease in pulmonary com- pliance. Chapman (&8) also observed decreases in pulmonary dif- fusing capacity and arterial 0, tension. Chiang and Wang (51) noted changes in nitrogen washout time and alveolar dilution fac- tor, alterations which reflect impaired alveolar ventilation and gas mixing. James (131) examined the effect of prior smoking on the mul- tiple breath nitrogen washout test in 41 pneumoconiotic miners and 5 normal young males. Prior smoking of a cigarette in the subject's normal manner was found to adversely affect the indices of dis- tribution in 20 percent of the miners and in all of the 5 normals who smoked within one hour of testing. The author suggests that smoking be prohibited prior to any series of pulmonary function studies. Anderson and 1ViIliams (9) studied the acute effect of cigarette smoke inhalation upon the ventilation-perfusion (V/Q) measure- ments in the lung in normals and in patients with COPD. Cigarette smoking was observed to cause acute changes in the V/Q measure- ments, and the COPD patients were found to be particularly liable to these changes. 189 Finally, Robertson, et a1. (194) studied the effect of unfiltered and filtered cigarette smoke and cigar smoke upon bronchial re- activity in 19 of the most reactive persons in a group of 91 heavy smokers. They observed that bronchial reactivity was significantly reduced by increasing the retention efficiency of the filter and that reactivity to inhaled cigar tobacco was no less than that to cigarette smoke. They concluded that differences in inhalation account for the difference in COPD prevalence observed between cigarette and cigar smokers. STUDIES CONCEKNING PULMONARY CLWRANCE Owercdl Gkarance The ability of the lqng to rid itself of inhaled particles that can- not be easily exhaled is dependent upon a number of physiologic mechanisms including ciliary activity, the mucous sheath, and the pulmonary alveolar macrophage. Studies concerning the effect of human cigarette smoking and the exposure of animals to cigarette smoke on this clearance system are presented in tabIe A13. LaBelle, et al. (145) and Bair and Dilley (23) observed no change in clear- ance following the exposure of rats, rabbits, or dogs to cigarette smoke. The latter authors noted, however, that normal clearance rates obtained prior to smoking were too low to reflect any sig- nificant change except complete cessation. Albert, et al. (3) exposed donkeys to cigarette smoke via nasal catheter and observed impairment of clearance times. Holma (185) obtained similar results in rabbits. In a related study, Albert, et al. (2) studied the bronchial ciear- ante times of 9 nonsmokers and 14 cigarette smokers in a total pop- ulation of 36 subjects. The rates of bronchial clearance were slower on the average in the cigarette smokers when compared with the nonsmokers, although a wide variation was present in each group. In relation to their study mentioned above, they also noted that the shape of the whole lung clearance curves seen in smokers (with markedly prolonged 50 percent clearance times) was similar to that developed in the donkey following acute exposures to suIfur dioxide or cigarette smoke. Numerous experiments have shown that cigarette smoke or cer- tain constituents of cigarette smoke adversely affect and can even bring about a cessation of ciliary activity in respiratory epithelium in vivo and in vitro in cultures of ciliated microorganisms. The re- sults of a number of these experiments are presented in table 12. 190 CiliarY acti\`it?: has been shown to be affected bp particulate matter as me]] a.~ by the gas phase components of cigarette smoke. The re]- ative importance of these tno large classes of components of smoke in producing ciliastasis is presently a matter of some discussion. Dalhamn and Rylander (63, 6J) consider the particulate phase to be of greater importance while Battista and Kensler (~8, 29) con- clude that gas phase components are more important in the induc- tion of ciliastasis. Studies investigating the effect of cigarette smoke on the morphology of the tracheobronchial tree in animals have noted a decrease or absence in the number of cilia in smoke-exposed ani- mals. Recently, Kennedy and Elliot (1.31) studied the effect of the direct exposure of cigarette sinoke upon the electron microscopic structure of protozoan mitochondria. After 42 minutes of exposure to mainstream smoke, they noted destruction of the internal mem- brane structure of the mitochondria. Thus, cigarette smoke has been shown to be tosic to ciliary func- tion by pathological (including electron microscopic) and physio- logical methods. Phayocytosis The effect of cigarette smoke upon pulmonary alveolar phago- cytosis, one part of the clearance mechanism, has been studied by several authors. Masin and hlasin (162) observed increased varia- tion in the size of lipid inclusions in sputum macrophages obtained from smokers as compared to those obtained from nonsmokers. They attributed these differences to a combined effect of irritation of the alveolar lining, increased turnover of alveolar cells, and in- creased injury to the macrophages. Green and Carolin (96) noted that cigarette smoke inhibited the ability of rabbit a]veo]ar macro- phages to clear cultures of S. au?-eels. This effect was noticeably reduced by filtration. Similarly, Yeager (239) exposed rabbit alveolar macrophages which had been induced by M. botiis to cigar- ette smoke and observed a dose-dependent decrease in protein syn- thesis. This alteration occurred at smoke solution concentrations that did not affect cell viability. The alteration was only partly rc- versible and was due mainly to gas phase components. LMyrvik and Evans (175) observed similar protein synthesis alterations in macrophages exposed to NO,. Roque and Pickren (19.5) obtained alveolar macrophages at thoracotomy from 17 smokers and 4 nonsmokers. They found a decrease in the activity of oxidoreductases and hydrolases in the macrophages of smokers. The reduction in the enzymatic activit? was directly proportional to the amount of stored fluorescent ma- terial present in the macrophages. This material was thought to 191 rcfcrrn-ci pop;lallon smoking Blckerman I. 66 mslc and A. Pulmonary and 26 Icmale function. Reaultd Commentd Vi&d ctlmcib (VC) I. lo/91 dccrcaae. Maximal brcafhing capacity 9/91 patient8 showed lo/e1 dccreaae. VC LIICTPLWC due to BBnzh, paLlent B. 3 cigarettes. II. No aignlficant change. No aign(flcnnt change. ClebrlnCC of apcrc- 1954. with chronic C. 30 minutes. liona. All mild cr U.S.A. nontubcrculous mdcratr enwkcra. (11). rCSpira\OV di3eam (avernge ego 601. II. 20 male snd 7 female normsl aub- jecta (average age20). Elcb. I. 31 patients with A. Esophrgwl bslloon Mc4.n uiru,ay rcriatawc Mean airwov compliancs ct al.. obxtrucllvc twhnisuc to 1. Stntiatlcolly ai~nincant No chsngc. 1917, Pllllnlmnry m~1p~s11rc Dulmonnry InCrNL?IP. U.S.A. eml'hyncma. com~~llnt~rc nnd II. No chnnuc. No change. (76). ll. 14 normul rusiatnncc. III. No chsngr. No change. subjwtd. 8. 1 cigarrttc. III. 6 patients with C. Undcfind. respiratory cumplainls. All habitual smokcn. -- Chupmon, I. 12 normal A. Pulmonarv function 1. All showed P dccrcnse In diRtwing ca~acily. lDGS, volunteer. Artcriul blood II. 4/b--aiynlficont dccrrnac in artcrinl O1 tcl~sl00. Ireland (nil smokera). atudiea. No change in vilnl cnpacily or FEV. (48,. 11. 6 pnticnla with B. I ciulrctre. chronic non- C. Undelirrcd. apccilic lung dieeaae. McDermott I. 32 normnle. A. Body Dlcthy. Afcon oirwav rcairtatwc Light amokcra ahowcd nnd II. 28 with chronic smosrnl,hy. I. Siu~iflcnnt incrcnac. prrnter chnrlu~n 1hnn COlliM. bronchitis B. Cigercttc. II. Sigoificnnt lncresse. hc.vy amokrrd. 1966. (All ciyn- C. Undefined. WDler rctte smokera (160). 3560 years of ace.) Author. A. hlcthod ' year. Number and ,3. Mnlcrinl J country. type or C. Durnliun of Result-4 COlll~Clila rcIcrmu! Dopulation emuking Miller and 10 normal A. Eaovhsuenl bnllwn DUWl77tic Inapimtory at-d Suroule, cignrcttt tcchniaue. FEVo 6 compliance cxyiratorv rcaiatanec 1966. smokcn l3. 1 cigarette. No signiicant Significant Significant U.S.A. (40 yeara C. One inhnlntion chnnge dccrcnae. increuse (166). al age). evcrY 30-60 seconds. Sterling, 11 "ormal adulta A. Body plethy- Airway rceidtance 1067, (8 smokers, smouaphy. Significant increase (Return England 3 nonsmokers). B. 16 inhalationa. to nom-al in 30 minutes). (113). C. 6 minutes. Cbiang and 7 male normal WanK. nonsmokers 1970, (c-48 yeat FWlTl03a of rae). (61). A. Pulmonary function Nitrogetr wnahout Nitrogen washout. time B. 2 cigarettes. Significant c. Undefined. iricrease. Guyatt 710 nubjecb: A. Ilodr plethy- et al., 608 smoked amograDhu. 1910. betwe?" mens- B. 1 cigarette. Englnnd urm 202 `2, Undefined. (100). did not smoke. w `All the exucriments listed concern studies of pulmonnry function b+ z iore and after smoking the epecifled number of cigarettee (unless otber- wise soeeifLd). Author. YCLI. cuunlry, rclcrcnee Subjccta Method LaUrCnXl Swiss-Webster Xlicc exposed to Significnnt incrcjbsc in S. ourcu8 rctcntion in mice cxp+8c%l to: CL nl., male mice. nermul of s. DurcuI (n) hyrruxin-retention ratio 2.5 (IO prrccnt 02). 196% and ancrificcd at (b) cignrcttc smuhc-rctintion riilio 4.5. U.S.A. Intcrvnla following (149). CXwrure 10 vilrious stimuli. LSDCIIC Albino female Silver idideor 17-30 hours uf cx~~wrc to cirrnrvttc amukc caused no change In pulmunnr/ et al.. mbbib. colloidnl gold elenrnnce ns cumjlnrcyl with controlr breathing room air. 1966. intrntrachellly. U.S.A. (1151. Bair and SpraaudJhwlw Radioactive aer&. Acute cxposurc to cignrctte smoke hnd no proo, oflect on clenrance. Chronic Dillcy. frmale rata, erl>orurc tu ciplrrctte rmukc cut) to l&20 cigarettes/7 hour day/6 dnu wwk L967. mule beogle dep. Radioactive aerwol. for "1, to 420 doye) hod no ubscrvnblc rllcctr. The authors noted, however, U.S.A. thnt normnl clrnrance rntcx were too low to rcflcct anything but complete (05). cerse.tion. so pcrcmt 90 pcrcrnt t ADproximntc villuc3. clcaronce CICOIUIICe None of `I nonamokcrs Albert 3G subjecta Radlonctive tagged Number oj "lvcraoc time time hnd GO pc~ccnl time-a et al.. undergoing 117 FeOZ particles subjcctr aoe (minulcr) (mixuterI over 200 minu(cY or 1969. uperimcnts. mensured with Nonsmekerr . 0 28 88 367 90 p~,rcmL limes over U.S.A. Scintillation All smokers ,. ,. . , , . 14 33 172 1406 600 ntinuta while (2). counter. `X+20 cigarettcs/dny ..,,,... 7 23 191 t519 6/14 am,>kws cxcwlcd 30-40 cisorettes/day ,.._,.,.. 7 36 163 1474 both thcsc limits. Uranium miners ,. 3 62 310 b80 Cigar nnd ~ipc smokrra ,..... 4 46 07 3'76 Emphywmu patients . . 2 66 330 G7G TAEZLE le.--E'zperinamts concerning the effect of cigarette smoke on human and animal pulmona~ clearance (cont.) Author. Y-r, CO""tl-7, rcfcrence Subjects MOtbOd nesuita COnlml?ntn Albert Donkey8 exwsed Radioactive tagged AVWQ7C Tmchoel franail Thmc donkeys CxDoacd et al., to CiKF,Rtte FcOz particles number lime to the KrCnl`-Bt 1969. smoke by nasnl measured wilb cigarcllca in Percent clcara?lcc Ilaltlime clmrance emount of smukc U.S.A. catheter. Scintillation z-hour period COnlrOl CiQ~rclle Cotllrol Cioarclle Conlrd Cigartile showed rczidunl (3). CO"nter. 1n-24 5.3 GO 1.2 1.9 0.G I.? Impnirmrnt of 3c 5R 64 1.0 3.4 04 6.8 clrsrnnrc fur nt h.nt 2 month3 afkr ucuk CXpW"rC. Helms. Rabbits ' CP' monodisperse Ihmsurc tu Irrsh ciaurct~c smoke (1.6 cc. nulTr, 40 puiTsl8 minxten) caured 1069, (nncsthctlrcd). PolYstYrcne n "sianificnnt" increnrc in lung retention 10 minutes followinK cessation of U.S.A. aer0301. eX,lOS"rC. (IIS). originate in tobacco smoke. The authors suggested that the tobacco smoke may have induced abnormalities in the mitochondria of the macrophage. In a study of pulmonary macrophages harvested by endobronchial lavage from smokers and nonsmokers, Pratt, et al. (187) observed that the mncrophages of smokers contained an ab- normal pigment. These studies indicate that the function of pulmonary clearance carried on by the macrophage and ciliary systems is adversely af- fected by cigarette smoke. STUDIES CONCERNING THE SURFACTANT SYSTEM The surfactant system of the lung consists of various biologically active compounds such as phosphoiipids and mucopolysaccharides which are present in the alveolar lining. Normal pulmonary func- tion is influenced and partly determined by the integrity of this system (103). The purpose of the surfactant system is to main- tain the proper amount of surface tension in the alveoli so that the expansion and contraction of the alveoli are facilitated. Studies concerning the effect of cigarette smoke upon the sur- factant system and the surface tension of the pulmonary alveoli are presented in table Al4. Exposure of rat and dog Iung extracts to cigarette smoke has been found to induce a notable decrease in the maximal surface tension demonstrated by the extracts (94, 165, 224). Cook and Webb (57) observed that surfactant activity was diminished in smokers and in patients with pulmonary disease when compared with healthy nonsmokers. Scarpelli (203) in a recent review, concluded that the lowering of maximal surface tension by cigarette smoke has been demon- strated reasonably well. The relationship of these findings to the pathogenesis of emphysema is unclear at this time. OTNER RESPIRATORY DISORDERS INFECTIOUS RESPIRATORY DISEASES Several studies have examined the question of whether ciga- rette smokers are at an increased risk of developing infectious res- piratory and bronchopulmonary disease. Table A15 presents a summary of these studies. Lowe (157) observed an excess of smokers among 705 tuberculosis patients, but Brown and Campbell (4s) in a similar study found that the difference was not present when the cases and controls were matched for alcohol intake. More recent studies have been concerned with the frequency of upper respiratory infections among groups of smokers and nonsmokers. A number of investigators (1U8,181,183) have reported increased 198 rates of respiratory illnesses among smokers. Finklea, et al. (8~) studied a male college population (prospectively) during the 1!XS-F9 influenza epidemic. They found that smokers of ail amounts experienced more clinical illness than did nonsmokers and that this r&tion was dose-dependent. Similarly, smokers required more bed rest than nonsmokers. A survey conducted by the National Center for Health Statistics (290)) involving approximately 134,000 persons, showed that male cigarette smokers reported 54 percent more cases of acute bron- chitis than males who had never smoked cigarettes, while female smokers reported 74 percent more acute bronchitis than did females who had never smoked. MaIe cigarette smokers reported 22 percent more cases of influenza than did males who had never smoked cigar- ettes, while the female smokers reported an excess of 9 percent. Experimental evidence in support of this relationship has been noted by Spurgash, et al. (211) _ Mice were tihallenged with h'lcbsiclla pneumoniae or Di$ococcw pneumoniae before or after a single exposure to cigarette smoke. They observed that those ani- mals exposed to smoke eshibited a decrease in resistance to respira- tory infection, as shown by an increase in mortality and a decrease in survival time. Preexposure to cigarette smoke was found to have no significant effect on resistance of mice to influenza infection initiated by aerosol exposure. However, exposure of infected mice to smoke resulted in significantly higher mortaiity, thus suggest- ing that cigarette smoke can aggravate an existing respiratory viral infection. In the light of the experimental evidence presented above con- cerning the effect of cigarette smoke on pulmonary clearance, phagocytosis, and ciliary function, it seems reasonable to conclude that such changes in tracheobronchial physiologic function would predispose a person to respiratory infections or aggravate already existing ones. Further evidence is derived from the work of Henry, et al. (109) and Ehrlich, et al. (75). These investigators exposed sWirr& monkeys to atmospheres containing 10 and 5 p.p.m. of nitrogen dioxide. They observed that this exposure increased the suscepti- bility of the animals to airborne Klcbsiellu pneumoniae as demon- strated by increased mortality and reduced lung clearance of viable bacteria. Infectious challenge with influenza virus 24 hours before exposure to 10 p.p.m. was fatal to all monkeys within three days. Infected controls shoxved symptoms of viral infection but did not succumb to the infection. The extent to which the various oxides of nitrogen present in cigarette smoke contribute to the increased sus- ceptibiljty to respiratory disease noted in smokers is presently undefined. 199 POSTOPERATIVE COMPLICATIONS Several studies have been published which examine the questions of whether smokers run an increased risk of developing postopera- tive PUhonarY complications over nonsmokers undergoing similar operations. Morton (173) reported on a study of more than 1,100 patients undergoing abdominal operations in which he found that cigarette and mixed smokers were significantly more likely to develop hron- chitis, bronchopneumonia, or atelectasis during the postoperative period than nonsmokers (table A16). Wiklander and Norlin (229) examined the incidence of post- operative complications in 200 patients undergoing laparotomy in the winter months when it was expected that pulmonary compli- cations would be at their maximum. These authors found no sig- nificant differences between the frequency of complications in smokers and nonsmokers. No information about the definition of a smoker and no data on dosage of tobacco smoke were reported. Piper (186) observed the prevalence of postoperative pulmonary complications in 150 patients undergoing laparotomy. Of the total sample, 66.7 percent developed pulmonary complications during the first postoperative week. All patients considered in the statis- tical analysis as having pulmonary complications had radiographic evidence of disease. Of the cigarette smokers, 73.5 percent had complications as compared to 55.5 percent of the nonsmokers. When the smokers were divided according to dosage, heavy smok- ers being those consuming more than 10 cigarettes per day for the previous six months, 55 percent of light smokers and 88 percent of heavy smokers were considered to have postoperative compli- cations. Piper also reported that stopping smoking for Up to four days preoperatively had no apparent effect on the incidence of complications. Wightman (228) reported on the incidence of postoperative pul- monary complications in 455 patients undergoing abdominal oper- ations and in 330 patients undergoing other operations. Of the cigarette smokers, 14.8 percent developed complications as com- pared to 6.3 percent of the nonsmokers. The substantial difference between these figures and those of Piper (186) is due to the latter's use of radiographic criteria alone. Wightman utilized only clinical criteria. Morton (172) has recently reported a study of postoperative hypoxemia in 10 patients, 5 of whom were cigarette smokers. Four of the smokers had chronic bronchitis. He found that the smokers had a more pronounced decrease in arterial oxygen saturation, Per- sisting into the second postoperative day CtabIe A17) -. 200 In summary, the majority of studies so far reported indicate that cigarette smokers run a higher risk of developing postopera- tive pulmonary complications than do nonsmokers, corroborating a long-held clinical impression. The risk of developing such com- plications appears to increase with increasing dosage of cigarette smoke. SUNNARY AND CONCLUSIONS 1. Cigarette smoking is the most important cause of chronic ob- structive bronchopulmonary disease in the United States. Ciga- rette smoking increases the risk of dying from pulmonary emphy- sema and chronic bronchitis. Cigarette smokers show an increased prevalence of respiratory symptoms, including cough, sputum pro- duction, and breathlessness, when compared with nonsmokers. Ventilatory function is decreased in smokers when compared with nonsmokers. 2. Cigarette smoking does not appear to be related to death from bronchial asthma although it may increase the frequency and se- verity of asthmatic attacks in patients already suffering from this disease. 2. The risk of developing or dying from COPD among pipe and/ or cigar smokers is probably higher than that among nonsmokers while clearly less than that among cigarette smokers. 4. Ex-cigarette smokers have lower death rates from COPD than do continuing smokers. The cessation of cigarette smoking is associated with improvement in ventilatory function and with a decrease in pulmonary symptom prevalence. 5. Young, relatively asymptomatic, cigarette smokers show measurably altered ventilatory function when compared with non- smokers of the same age. 6. For the bulk of the population of the United States, the im- portance of cigarette smoking as a cause of COPD is much greater than that of atmospheric pollution or occupational exposure. HOW- ever, exposure to excessive atmospheric pollution or dusty occupa- tional materials, and cigarette smoking may act jointly to produce greater COPD morbidity and mortality. `7. The results of experiments in both animals and humans have demonstrated that the inhalation of cigarette smoke is associated with acute and chronic changes in ventilator-y function and pul- monary histology. Cigarette smoking has been shown to alter the mechanism of pulmonary clearance and adversely affect ciliary function. 8. 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American Review of Respiratory Dis- eases 89(l) : 73-81, January 1964. 217 RRONCHOPTJLMONARY APPENDIX TABLES 219 TABLE AZ.-,Smoliing and c/Lronic obslrrrctiua pttlwonar~ discase su'ttptonls'-percolt prevalence (Numbcn in garcnthcwe rcprcscnt tolnl number of individusl in yatiiculnr smoking group) Shl = Smokera. NS = Nanamokcra. EX ; Ex-amokere. Author, ycllr, countl-Y, Nutt$rO;nd Drcnlhl~~snns Cowh Sputum production or dyspnea Chest illncssses Other Commenle rcfcrcnce DoPUhtiOn ____ Short 2,031 male and NS I... 1.6 (496) NS ,, .ID.O C.hril illnrssra Oswnld 3,602 male nnd Chronic Bronchilir Chronic and 2.2*12 femnle nfh brrducLllln. PhilliDe 1.274 mnle NS `2.0 (461) et al., fnctor~ workcn sm . ..Gl.O (823) 1966. wiLhout overt U.S.A. pulmonary (185). dircnsc or hcnrt failure. Higgins 301 male nnd Ccmoh and spufum Chronic Bronchilia 1957, 280 ffmnle hfolcs Malea `41&l Malts Enslnnd i-oral dwellers NS . ,, 7.1 (28) NS..........7.1 NS . . . ..I... a.6 NS I,,.... 3.6 (II?). 26-74 yeDrS of SM . ,. ,. 63.9 (222) 531 ..I. . . . ...19.8 Shl . . . . . . . . . 17.1 Sbf , ., I.. 9.9 we. FtWU21.24 Ft??7l~fGJ FO7I&# FL-?Mlt-, NS ., ,, 4.6 (176) NS .,I. . . . ...21.6 NS . 9.7 NS . ,, . ., 3.4 sm ,... 17.2 (93) sm . , . 9.1 Shf .a . . ..16.1 Shl . . . . 8.6 k r T,\nr.~ A2.-Smokhg and chronic obstructive pulmonary, disease sl/jliptotlis +m+xnt pcvalence (coral.) (Numbers in pnrcnthcvrs rcyrescnt tatnl number of individunl~ in vnrticular smoking nroUV) Sbl = Smokers. NS = Nunsmokers. EX = Ex.amokrra. and 92 frmnlcs Cochran. randomly chosen 1958. (members of an England agricullurel (114). commur*itu.) Edwards 1,131 male out- et al.. ImticntY on 1959. lists of Ennlnod lmlcral prnc- (74). titionera >60 YCPci of DBF. Cammrnta Couoh and sputum NS .,... . . . . ...33.3 NS I..,. 0.0 hlalca NS (6) S!d . . . . . . . . . ...29.3 SH 16.0 NS . . . . . . . 0.0 Sbf ., ..24.0 (151 FtWIalW Femdcs SM . . . 6.7 NS ., ,, 3.1 (G4) NS . . . . . ...46.3 NS . 10.9 FCrntllC# Shl .I ,I 3.0 (20) SH ..,.., .20.0 Shf ..I 10.0 NS . ,,,, .` 0.0 S.M ,,....I 6.0 Chronic bronchilir NS .,, ,, 1C.6 (151) Cigarette8 29.1 (778) l-9 . ...23.4 (236) lo-19 . ...31.2 (361) >20 . . . . . 33.7 (176) Pipe . . . 18.6 (340) - Flick 222 mnle NS . . . . . . . 10.0 (61) NS ..,,,.... 26.0 (49) NS . . 30.0 (47) and pntitnts not sm ,. ,. ..66.0 (167) Sbl ,, ..66.0 (1.66) SM . . . 60.0(138) Pnton, auffvrina from 1359. avert rnnlio- U.S.A. D\lllilOnF.~y (86). dincnac. ZO..OO r*rnofopc. Hiuuina 716 maln In Couoh and c~ulutn Chronic bronchitis et al., VR?/OUI SM ,. ., ., ,. 7.1 (86) NS . ,. . . . . .a.., 0.4 NS s I. . . 7.1 SM , ,,.., 14.3 106D. OCCUD~UO~~ NS ,. ., ,. 36.0 (1176) SM ,, ,, ,, ,. ,, .24.9 SM .a .a 20.2 NS . . . . . . 3.b England 26-64 yc(~rc, (IIS). of age. -- Liebnchuetr,l47 male NS ,. ,, ,. 0.0 (621 lC59, soldiers Shi ,. ., ,. 13.0 (83) Elsland 20-30 years tl.76). of ogc. - -- Ashford 4.014 male Et al., Rcnpiraloru ayrn~,lomr Rwpirntov coal workers. NS . . . . . . 103 (677) symplumn- lQC\. EX . ,. ,. 19.6 ,England (123) "bronchitis and/or (11). Cignrcttes 21 1 (1,604) Pipe only 36.1 (202) uthmn". Nu Cizarcttn duua 1.<,1>,- 3 and DIDC 37.1 (90) tionslaip AIlShI 21.7 (3,210 f"Ul-ld. t4 TAllI E A2.- .Ytt~okin~~ 117rtf chrouic obstricclilrc prtlt~lcr?rcrrl~ tliucccw .ul/~Jr/J~o~~lY'-- td ],c:rcclll /murlfcm: (CWll.) IP (N\,,,,~,Q~ ,n ,,nrcnthws rrprcucnt t,,tuI n,,n\l~cr of l,~dlvldunl~ in ~nrtlcufnr amokinv k!:ro'JD) SM z= Slnok~rr. NS ~1 Nunanwkvra. 1,:~ := Ex.smokurs. Author, YPUi-. NumLcrnnd Urcnthlc~sncas country. type uf Cough Sputum prduction 01 dyapnea Chest illnesses Other Comment.9 rrfcrrncc nnpulntion -______- -- Dnwcr. 06 malt nnd NS . . . . . . . . 4.1 (49) NS .,. . . ...20.4 NS . . . .31.7 Cheat lllnws- 1861. 11 lcmulc Shl .#. .27.0 (76) Shl . . . . . ...34.2 Sht ,,.,.I 88.2 clllY!t COllll U S.A. bnuk om~~loycoa l'lvc, clunr 1. (19) l'inc. clgor lG.4 I'il~c.cluar duringcach 01). 40.10ycnrs 63.0 01 Ilint z of I,YV. Wlr~tPIR. - Flrtchvr nnd 3G3 mnlc I.w~don -- NS . , 8 , (80) NS ..,..,.a., 8.7 NS . . . . . . . . . .I NS . . .a. 4.S Tlukcr, trQnalwrt t-14 g./dny 16.6 (1GC) I-14 a./dny ..ZI.U 1..14 n./dny *. 8.2 1-14 n./doy lOGI, Cm[ll"Yl'L* >lS . . . ...27.0 (110) >lG . . . . . . . ..aO.D >lG . . ...*.. 8.0 8.2 Ynulnnd 40 GoYchrI >lS . ...10.7 185). 01 DPB. Read 170 malcand M&a and 132 Iernnlc NS ..,..s.. 4.4 SCIIJY. indlvldunla SM . . . . . ...23.1 1961. lntervicwed EX . . . . . ...21.2 Auatdlr inanoub FHlt.llC~ (191). Datient NS , 4.9 clinic (not SM . . . . . ...18.6 all paticntsl, BIlebum 1.461rnale NS . . . . ...10.2 (263) NS..........ll.O NS.......... 9.8 et al.. llaht SM . . . . . . ..23.3(1.108) SM ., . . . . ...30.4 SM . . . . . . . ...14.6 IDVZ. Industry 60 .,. . . ,, .29.0 PO . . . ..GO.O (24) X0 *..II... 62.0 ?`,\uLE AZ.-Slnoking and chronic obstwclil~e pulmomr~ discasc' .S~III~~O~II.S `-.-pcrcoil prcunleuce (co?it.) (Numbers In ~nrentbrsw re~resrnt tutnl number ol individunls in ~nrticular smoking aroun) SM = Smokcra. NS = Nonsrnoken. EX = Ex-smokers. Author, YCPT, Number snd nrenthlcssnns countrY, type of Cough Sputum Drduction or dyspnea Chest illness- Other Commcnte refrrencc population - Boucot 6,137 mslcs NS . . 13.0 (806) et Ill.. 1862. cnroliina SM .31,6(6.331) U.S.A. in pulmonary (36). neoplasm project. Ftrria 90 male and Chraic Nonrpccific CL &I,. 71 female Reepiralory Dbcosc llC2. Rnx mill- n1a1ca Frtlld20 .63.1(32) GO.0 (4) Fenis 642 male and Chronic Irorkchilir hgc-,prcifir and 6?5 frmnle ?lrnlCI r*tm. AlldCrWn. wnidcnts of NS . . . . . . 13.8 (126) 1962. New Iinmpshire EX . ,, ,, ..lI.O (77) U S.A. town chosen Cianrcttcs 40.3 (340) IElI. by randurn l-10 . ...218 rumpling of 11-20 . .34.2 CC"S"S. 21-30 . 4?.3 31-40 G1.1 >:I ., .SG.3 F'cnlol~, NS . 0.4 (97Lo El . 10.8 (37) Cignrcttn 19.8 (208) I-10 .13.1 II-20 ..I. 22.2 21-30 31-40 .27.3 F=: >41 .` u -- (Jf6). e. Finnish 1-14 .,.., 31.6 (108) commun*l 15-24, . . . ..4O.S (191) region, >25 .,.... 42.4 (86) 40-64 yearn Femah of age. NS . . . . . ..I 4.6 (709) EX . . . ..13.3 (30) 1-14 . . ...10.4 (77) 16-24 .*,.,. 43.0 (6) >26 .,....# *. (1) TABLE AP.--Smoking and chronic obstructive pulmonary disease s~?~ipto?t~s `-percEnt prevalence (cont.) (Numben I" Qarcntbu.~ reQreaent total number of individuals in ~articulnr smokinn p.rOUD) SM = Smokers. NS = Nonsmokers. EX z Er-amokera. Author, y-2.r. Numm:ri"d Brcnthlrss"ess CO""W. Cough SQUh" prcductic.n or dyepnes Cheat Illnessw Other Commcntd refcrcnce QoQularloa Goldsmith 3,381 wtive Respiretory et al., or retired cotiditiona 1862, longahoremcn. NS U.S.A. hI"d6;;;;;h$:y (74" (9s'. smokcn 43.0 (1,298) Co&lea 1,342 male and Covgh and chronic phlcotn Current et al., 242 female NS . . . ..ll.Z (747) NS 14.7 NS . . . . 4.0 smoking 1966, Detroit poet l-14 , ..12.7 (266) (not LiK.) 1-14 .28.2(Q26 . . . 36.4 (170) (P25 . .a4.i(D26 . . . . . 26.8(Q26 . . . . . .42.4 FC7WJlC8 NS . . 4. .:-.. . 16.6 `ix . .24.8 l-14 . . . . ,* .2G.O IS-24 ,,,..... 26.2 >25 . ., .31.8 FOdC8 NS . 6.9 NS ., ,, . . 29.2 EX **.... . ..13.3 EX . . >. .33.3 l-14 . . . . . .10.4 1-14 * ,,..... 14.3 Molcl NS . . . . 6.7 EX . *. . . 16.3 1-14 , . . I 38.0 16-24 ,...41.4 >26 ,,... 40.0 FCTdU NS . . . 4.6 EX .,, . . 13.3 x-14 . 10.4 16-24 >?6 I . . .67.0 lb-26 >= . . ...67.0 Author, YCBT. Number and BreathlnsnpJs count-Y, type of Cough Sputum production or dyopneu Chest illnesses, Other Conlmvntd reference populntion Wynder 316 male New York Cily et al.. patirntr in NS I.., .14.0 (44) 19G6 Nrw York City Pipe. cigar 33.0 (64) U S.A. and 316 male Cigrrcttcs: (PSB). patient3 in l-10 . ..46.0 (44) California. 10-2.0 . .46.0 (88) >20 . ...67.0 (86) Catifornia NS .~ . . . . 22.0 (69) Pipe, cigar 30.0 (32) Cigarettes: l-10 .46.0 (64) lo-20 . ..74.0 (91) >20 . . ..`?4.0 (69; --.- FIPOID 1.066 randomlv Clinical aipna ot TABLE A2.-.%tokinn and chronic obstructive pulmonary disease syltlpto,t~s'-percent prevalence (cont.) (Numbcra in parentheses represent t&l number of individuals in particulbr smoking group) SM = Smokera. NS = Nonemokem. EX = Ex-amokera. Cough Sputum production Dreatblwsness or dyapnea Chest Illne4ace 0ti-M Commenti DCllWlI 6,ais IIW& POI(rrl PCWld Poltd Dyepnca a &I., and 7.29 1 NS ..a ,. ,. 7.0 (908) 13.1 IQ.8 rcurcscntcd 1967. fernah POStAl Pipe, clgsr 12.4 (628) 11.4 24.8 by Grade 11 U.S.A. snd ban&It Clgarettrs OIIIY. (88). worken. only . a. .27.0(2.687) 28.9 31.7 Transit Transit Tromit NS . . . 6.4(1,012) 9.6 11.7 Pipe, cigar 10.6 (766) 14.1 14.2 cigucttea onlr , . . .23.6(8,`746) 23.7 21.9 Efggins 926 white NS .I,,... 16.4 (162) NS . . . . . . . . . . . 31.1 NS , . . , , ,. 6.0 et al., de A- l-f ..a . . ..47.2 (61s) SM , ,a ., ., .4&Z snl . ., ,* . ,* ..10.7 1968. dents of EX s.,,.,. 19.9 (144) EX . . ,... 28.6 EX . . . . . . . ..16.8 U.S.A. hlatlon (116). county, West Virginia. 26-69 ycsn of age. Holland 8,788 mrlc Nolcr Fcmolcs N&I FVdC# snd and female NS . ,, . . , 8.8(1,000) 9.2(3,137) 2.4 2.1 Elliott, lChOOl SM . . . . . . . 6.3(1.038) 6.9 (664) 6.1 8.3 1968. ebildrcn. EX . , . . . . . 2.9 (1,782) 4.3(1.161) 3.9 4.2 England 5 *.,./ . . . . . . . . . . . . ..# . . . . ..9.`3(142) 18.3 Commenls Austrnlin. niminnton 41,723 mnic prcvnlrncc 01 di,WgC chronic bronchilia RlO20 , 20.6 FC,lltll~# NS .,.... 3.4(12,361) EX ,..... 38 (D69) PiDc . . 00 Cigarcttcs (8.986) 1- 9 ,.. 6.1 lo-19 . 10.6 >20 * I. 18 6 Chronic bronchilir rt al., G&54 yesra NS . . . 1.0 (88) 1IEl. of nac rnndomly EX , . . . * 3.0 (67) Swcdcn snmplcd irom l-14 grnms/ (231). Pu~~uIc.tloI\ day ., 6.0 (04) uf Guhborg. >16 ,.,., 17.0 (GO -. TAULE AZ.--Smoki?lg and chronic obstructive p~tlnmm~ discasc sutttptol,ls'-pcrcolt preuahce (co7lt.J (Numben in parentheses represent total number of individual* in wrticular amokinn `?rouP) SM = Smokers. NS = NonsmLkcrs. EX = Ex-smokers. Author, YCBT, Number and Drcnthlcssneas countw, type of Cough Sputum production or dyspnca Chest illnesses 00.X? Commcnta rctrrcnce DoPulation Pcrnistent couph otldphlcgm Mnlcr nclc rtuc Aoc Age ss-IS is-55 65-05 M-48 NS It... 7(?27) G("OU1 ll(171l 1 (01) ES . . . . . I(3031 11(3GBl 16(33G) 18(14Y) 20 . . ..27(1481 26(1X) 42(121) 26 (12) Fcmalcr NS .I.,. 31600) 4(G37) K(O26) 6 (211 EX 311271 al1281 1 (041 1 1411 <20 . . . o;mz; 13(472) 16(3OC) 11 (CGi 20 . . . . ..lC(1281 27(122) 31 (711 14 (7) izo . ...23 (22) 26 (301 43 (7) . . (11 LCfCW 310 male Agc.rlondardizcd roka Excluded from rnd Phuriciens of chronic rer~~irot~rv examokcra Wonnacott. in London dircaae nt~' thvac 1970. and Ontario, NS . . ...**. t. 1.0 (881 clgurctk Cnrda 26-74 yerAT EX ..*,,. .*.. 6.0 (61) amokcn who (151). of am. SM .,,....,.. 34.0 (101) now Bmoke Plpr, clgsr , .12.0 (aa) pipn or clnrn. ' Data collected by either dlrcct lnteylw, puntionnnirs. rcvicw of medical records and/or medical cxamlnation. TABLE A23 .-S9rloltirlg and chro~~ic f~bslr~rlcliuc lI~tltilu7ictrU tlisvclsc s~~tl~~Lo~~is'-~l~l'cc,lt prmlcncc LNumbcra In parrnthcszu rcprrscnt tutol n~~rnbcr of individunb in pal-ticunr smoking group) Shl = Smnkcra. NS = Nurlsnwkrw EX = Ex-emokcrs. Author, YCLLT. countty. Nutm$:,;nd Cough Bronchitis Commcnta rcfcrcnce popuation Ccdcrlol 9.319 twin Obacrved/ Obscrvcd Explnnotion of nnsl~nes for All ex.snrokcrs ir~cludcd et .I., paira czjectcd IIupcrmorbidilu cxllcclcd Ilyyermorhidity rc3pirotory eymplorn with smnkcrn. 136G, rcairtcrcd Croup A: C(IICII ratio COlCd ralio VNV8lCliCC: MZ--monorYKotlc Swcdcn in Swcdcn hlnlcr . . . . ...393/151.9 2.c 157/60,8 3.1 Croup A analyale-using each pPlr8 (46). 01 12,RRB FC?YIL?les . . . ..lW 49.4 2.8 a/11.2 3.8 flr~tbom twin an one proup DZ-dizynolic ueira availuble. Grau~ II Shl/NS: In sn unmntchcd relat!onshlp Author concludes thnt hlZ Males , , 14.6/1.1 1.9 G.C/ 1.1 6.0 (274) to each urcondborn twin. ~llnee hypcrmorbldltv Females . . l&6/7.6 1.8 3.0/ 2.3 1.33(264) Group I.3 annlysis-uuiop each for amsklnr pcraista DZ Mnlcs , . . 12.3/6.6 2.26 4.6/ 1.8 2.5,1(733) twin set BJ matched pair. in bmukinil-ill~rur,lrlnl Females , , . 14.6/6.? 2.67 LB/ 1.6 3.0 (663) AU compnrisons in Groups A hlZ popuIe:ion. o and B circ bctwwn smoking CBIURI rcIntio~~~tI/~ ot discordnnt pain. smokmn nnd brnnrho- DuhOt,lltY B,"lDt"",l IS luyD"rtLYl. Cederlol 4,379 twin Prevalence of reapiralceu symptoms No cx.amukcrs lnciuilcd et al.. pairs (all Group A: in Croup II an0ly~11-1. 1969. U.S. veterarls) NS . . ., ,, ,. 4.3 4.3 1.G Group A--as above. The nutliurr conclude U.S.A. in U.S. l-10 . . . . . . . . 6.4 6.4 2.7 Grouv B--n3 above. that the dntn indiente 145). National 11-30 . . . . . . . . . . . . . . 16.3 18.3 8.0 *strong probability Academy of >31 . . . . . . . .27.1 27.1 16.6 of rh cnu~al connection Sciences Twin Pipe, cigar . . 7.1 7.1 2.1 with amokinK. Even RegistrV (of Group B: NS sn1 NS snr thcsc a)`m,~t,rm~. 9,000 avial. hlZ . . . . . . . . . . . . . . . . . . . . 2.6 6.4 1.6 4.6 able), howcvcr. acem to be DZ . . . . . . . . . . ..., .,., ,..,, ,., 2.0 9.8 1.6 9.1 influvrrccd by gcnctic factors. ' Dab collccted'b~ either direct interview. questionnaire, review of medical records and/or mcdicnl examination. N (Numbers in parcnthcscs rrprcuunt total number of individuals in ynrticulrr amokinx R~QUD) NS = Nonsmokers. Shl = Smokers. EX = Ex-amokere. EFR FEV vc bliaccllancour Commcnb rorcrcncc pop"lution -_.. - Chivcl-s. 463 m.lc Ilcight-in-inchca tblrn" EFII 1069. rmlhyrcs Cigcuettes/dny: 64" 66" 680' 70" I" lltcm Ennland of olknline &rJ . . . . . . . . . . . . *. t97(28) 91 (35) 108 (91) lOl(21) par minute. (51). industry 6-20 ..~....,.......... R9(60) RR (75) 101 (112) 1w (76) RCgrl3Ul"" plnnt. >7.0 ,..... ,.. .,, ,,, 63 (6) RR.6 (9) 92.6 (9) llS(lZ) annl,als of dn~n rcvralvd L 8iPiiincsnr r* h,tionahiv bclwc-z" smuking and dc crceviny function. Hlgglnl 773 male3 26-64 65-64 cxprcsanl Et al., Invarious NS 146 (66) 101 (29) FE"o.75 DEB n>c~n indlrcct 1969, occupstionl EX 143 (31) 89 (62) MUC. England (25-34 and 1-14 grnms (116). 66-64 YeFall .140(193) 87(167) of age). >I6 Drnml ,183 (89) m(ia6) - WilSO" 28 male RV/TLC et al., residenta of NS . . . . 6.69 (14, NS . . . ,. . . 21.1 1960 nnllsa, Sbf ,..,I `4.44 (IO SM . . . . . . . `27.01 U.S.A. TCXBS. 1?32). former rural dwL4en; mntched for body aurrare. all.?. and height. TOLD A3.--Smoking and vmlilatcq function (cont.) (Numberr In parentheeca reprcscnt total number of individunls In gnrticulnr omoking group) NS :: Nonsmokers. Shl = Smokas. EX = Ex-enwkera. EFR FEV vc blleceunneoua Comment.4 Ashford 4.014 mnle et LI., coal workera Age: FNESVl .o snr lD61. at 3 Scottish co . ..2.88 (42) 2.21(297) Dnta rcprcjent reaulb nfter correction fur dtti"E hCiKht. SM lncludcs ylpc smoker. Datr on cx.amokcr not Included. FEV,,O found r,ipnlllcs"t: lower for Shl tbsn NS. Fletcher a63 male Mean peak EFR and London NS . . . . . ,.. 670 (SO) Tinker. CT!l"PPti l-14 prune 637(166) 1961, employees. >I6 grams 628(116) Ensland EX ,....,.. 666 (61) (85). Franklin 213 male llcavy smoker and factow FEV1.0 FEVo".;: y.;; LOWdl. workcra FIenVY 2.670 3,dll 2.71; Light . . 3.703 (69) rcyrcecnta 8" ListIt `2.489 amount wusl lOGI. 40-60 ycrlrs `2,666 `2.284 mnvy .~3,678(100 to or "lure U.S.A. of nw. thsn 30 pack (87). YEIIII. 240 . , I 307.63 (67) 2.90 blsrlt. 73 healthy 1962. medical per- DLC# Smukcn ,luRnrrl U.S.A. aanne with. NS . , . . ., , . a3.10(30) a* `hurt y'n"kinc (IS!). out signifi. SLI <6 yce.n .`28.40 (8) >zo ciKurcllcu/ eant we 6-lOyears . ..JZB.ZO(lO) dny for varying diflcrence >I0 YEB,S .`24.00(26) pcriuds. between smokers and nonmoken. TABLE A3.-Smoking and vmtilatory /unction (cont.) (Numberr In DatentheSer tepre~enl total number of individuals in particular smoking group) NS = Nonrmokrre. SM = Smokers, EX = Ex-smokers. AilthOr. YC@.i-. C0"thll-Y. MBC ,efCtenCe PWUltItiOtl EFR FEV vc Mfacelkneou8 Comment4 Revotakle 1,130 male et al., and 1.813 FE"I.O Data prcacntrd M&l Fmah 1862, female in tcrma of NS U.S.A. relidtnti In . . ...0.98 (66) 0X18(255) ratio of (IPI). Cigsrettes/dny: Framinp- obaervcd to ham par- l-10 .0.97 (90) 0.99 (92) 9rcdlcted 10-29 ticipating .0.91(163) O.OS(167) valuca. >30 in the pro- ..0.90 (81) 0.01 (22) spective study. KrumboL 18 physicians MEFR et al.. 24-37 yee.ra NS . en . . . . 660 (9) hftan DL lB64. or *ge. U.S.A. Shl ..,.., ,. `690 (9) NS SN Rat . . . . . . . . . 36 `81 (ILO). Excrclre: 2mlnuta ..60 `41 4 minutes ..60 148 8 mlnuks zwi 20 medical port exrrclae 39 `86 *t PI.. MNEFR ntudcnbor NS . . . 187 (lo) Authors found 1964. graduate 4.84 6.17 Sbl aa.1193 (10) a signitlcont diRercncc U.S.A. uhysicisns. `6.09 `6.63 bctwecn Shf and (P&l). NS for RV/TLC. complinnce. nnd non- CO&b, 1.342 male et al.. and 242 1966. female 9oat U.S.A. oNice (5-J). emDloYecs elastic realslance. FEV,.O Timed VC' Age: NS >25 o'oldau NS >tS/dau FEVI,/VC NS >fS/daU ID-44 `2.08(186) 2.86 (60) 3.89 3.86 `0.17 0.14 46-49 `2.96(170) 2x4 (42) 3.92 3.83 2 0.74 0.70 60-64 `2.X(116) 2.62 (22) 9.71 3.74 `0.74 0.70 2.44 (18) 3.64 8.61 `0.14 0.68 h) >roueste Of *gc. 65-59 `2.64 (64) k.i G&64 l2.36 (63) 2.30 (8) 3.30 3.33 `0.12 0.70 TADLD A3.Stnokitlg and vmlilator~ funcliotr (cont.) (Numben In percnthcacn rcprcacnr total number of lndividu8ls In patilcul~r lmDkln# E~OUPI NS = Nonsmokcre. SM = Smokcra. EX = Ex-amokera. Author, YCU, LO"lltlT. NuttAi-;nd MLIC EFR FEV vc Ml,cell*nmu Commrnta Xrumholr 20 mrls Pulmonwy cmnpftime'a Mean body surfnce et d., medlcd NS , ., ,,,, ,, .0.241(10) .rca for 2 ~1'0uUfl 1961, ltuden(a or SM , ,.., . . .~0.177(10) ~08 not hnifl- U.S.A. graduate Compliancr/FRC eanlly d,Rcrrnt. (14:). Dhyalclms. NS ,,,...,.,. 0.064 Smokcls arc those SM . ,* ,. .*. .`0.042 wit11 rc~unl to or g,ratr,' Ihhn 5 pack ycor history. RankIn 126 malea NS ,., 118.1 (68) et al.. nlthout a SM , ..`111.7 (67) FEV1.0 DL DL/ NS Includea pipe NS .,..,,.,. . ..106.6 NS . . ..Sl.l d"eo,ar .",I CiYLII. arnl)krrs 1066, P-t SM . #, *. . . *. * .`102.7 SM . .`26.9 volume snd ox-smoke~a ot U.S.A. hlatarq ~l'26 20-69 years . . . . . . . . a.ao(m) of .p?. w" w rrfrrcnec pOpil&Nl Sluia- 633 white 35-44 G-54 >SS Fh"J.O 1 cignrrtlc z CRWWr mnlc NS S63(106) 627(101) 444(H) ss-44 45-54 >Gs 1 gin",. . . . . . . . . and fflctorv Grams/day: 3.70 3.22 2.76 1 D""PC lobocco = Sichcl. workers l-14 . . . . . . 657 (2C) 619 (17) 410 (7) 3.c4 3.31 2.24 2c grrtms. 19&P. over 36 15-24 . . 632 (94) 446 (36) 401(13) 3.66 2.94 2.28 1 cigar = 2 10 6 South ycrsrs of >?5 t52a (66) t494 (31) t380(10) 3.54 3.05 12.12 grnms. AirkCl .ge. t Derivnl BIUIIPI (tw). found sunifi- ranlly dillcrcnt frurn 0. SlBlM_CU 87 male bus FE"1.o Nifrogcn gradient et 81.. drivers: Younper OIdcr YouQ?er Old&-7 Younger Older 1968. 27 anrd NS ,.I.. 4.470(14) 3.310(40) 6,126 4,?90 1.63 2.49 Rumania 20-26. 60 Shl . . . ..`4.5OOl131 `3,200(20) '6.285 '4,290 Il.47 83.77 BYIll"lQmB. DenWl 6.281 male FEV, n FEV exprcaacd 111 et &I., 1969, U.S.A. (69). postal and 7,213 mole transit workers in New York City. A." POSlOl 1Slritc 3.29 (666) 3.11t2.340) 3.14 (1.292) 3.06 (1.038) Tronait ll'hitc 3.39 (620) 3.11(2,941) 3.16(1,929) Non-white 3.05 (2041 2.04 (768) 2.96 (699) 2.93 (161) Na-vhilc 3.08 (298) 2.99(1.041) 3.00 (691) 226 gramaldey ,. ,. . . , . . . . 3.0?(1,011) 2.96 (149) (Numbers in parentheses rcprcscnt totul number of individunh in Dnrticular smoking group) NS = Nunsmukrrs. Shl = Smukcrr. EX - Ex-smokcru. EFR FEV vc Miscellanwu Commcntr PEFR vc 1963 vnlum only. NS . . . . . . . . . . . . . . . . . . . . . . . 1. 626(88) FEVl,O 3.17 4.83 EX . , . . 631tb7) 3.69 4.77 1-14 grams/day .,., . . .., 621(90 3.62 4.83 >I6 grams/day ., ,I. .., ,. 492(GO 3.31 4.66 -- NBIFR NblFR hua Lccn NS , . . 4.09 (88) ;;;I.0 ~lnnllnrdlrcd for Cignrrtte ogc nnd hciuht. amokers. 3.64(101) 3.11 EX , 3.99 (61) 3.38 Pipe, cigar 4.17 (33) 3.17 TAELE AS.--Smoking and vent&tory function (cont.) (Numbs-8 In psrenthcaea rcprcacnt total number of lndivldurb In pw-tlcular amoklnr WJuD) NS = Nonsmokers. Shl = Smokers. EX = En.smokem. AUbX, Year, countl-y, FEV Miacellsneoua Commcnta rtfcrcncs Lundmnn. 87 hlZ and FEV, n N. wanhout nndicnt hlZ = monorygotle. 62 DZ twin prim aelectcd from Swedlrh Twln.Pair Rerl1tty. Slgnlftcant dlffercnccs between smoklnp discordant twin DltIl found for: 1. G~OUD A MZ males and fern&e. 2. Group n DZ malea, 8. Gmuu ADZ nudes. Slgnlficant diFferencea between smoking dls- cordant twin pain found far: Grouu B DZ malee. DZ = dirygotlc. The author concludea that the danwe of ventllrtlon II mcssured by N, w&shout was correlated with cigarette conaumptlon. Tbr FEY,,, WBI aignlficrntly lower for amokera and tbcre wns a ecrrelstiuti with clgsrette consumutlon. Explan&tlon of rnalysea for rnplratow wnptam prevalencr: Grouu A nnrlvsls-u~lnn each Aratborn twin " ona PIO"P In .n unmatched relstlcnshlp to each wcondborn twin. Group B w~alyala-wing ekfb twin set u mstcb*d unlr. All comp~rlson~ In Grour, A rnd B are bctwetn nnoklw-dlscor dant DllrI. ' Not lignlflcnnt Cdlflerence OI trend), : DtO ye~n of age) (59). (lime md xxi- sxs ruociated with decrcued PEFR v~lua. Mb uposum~. Fiireins 300 mak miner. Miners showed incrra~ed prevalence of symptoms and de and and 300 mak creased MBC value which remained even after standard- c"cbrwne. nonminer 3-4 iration for smoking habits. 1961. yea13 of .KF. Torrl dust cxmure wm not dirvcthr correlated with these Engbnd hndiwx. (115). Wiva of miners showed similsr symr)tom nod tert changes u compmrd with -iv- of nonminen. Brinkmm 1.317 mxlt_ 4-s Incrcucd ailicl exposure wu lssociati with r+n increased md ye.?5 of LKe prcv&nce of chrnnic broacbith. cata. ritb v.rious Higbrrt prcrsknce of chronic bronchitis -xx noted in the 1962. ailiu tXpon"rC non-expowd -up: and this group wsx noti to have U.S.A. hhtorier. tie hirhea number of smoken and bisbest consumption. OX). Hyatt 267 male min,m Increued history of undewround work xvxs a%.oci~Led Witi cl d.. md tx-minen o n incrtued bmnchopulmonrv s~~tom prevd~~ce and 1964. 45-55 yc.n decreu& p"lmonSry function rahwx USA. of .OC. The impairment of pubn"n8r~ function Luociated with (**a,. undergground work wss se~rr~(c from effect of smokimx: but rmokinp md under-und work did show *dditioF &ecu. ElW"Od 2.628 mde and Preparing room worken who umoifested hmiami -P- CL *I.. fern& flu tarns *kc. .h"aed an incrPrwd prevnknce of chronic 1965. worken ""CT 35 bronchitis inderxndent of ape "I- smoking When ComP*d IrcLod Jean of .pe. with non-prepm-ing mom workers. (77). Fern... worken manifested s signib`cant wi=ti"" b tarrn byuiaosia wm~tozzu and amoking while mrk work- m did not. Sluis-Cmmcr a27 minet-3 md Those smokcn cxpoad to nold mine duJt mnnifatcd more ct al.. nonminen over s~mptomr of COPD ' Thea did noa-durt exp~cd smoken. 1961. 3s yarJ of .OC. rbik prcvmknce of swptoms. uooog nonsmoker% VU Suth .\fric. *imil*r for the two k7rouLm. 1 WY). TABLE A7.-Epidemiological studies concerning the relationship of occupational exposure and smokzng to chronic obstructive bronchop?cl,nonary dzsease (cont.) *=I=. Number and country. t-e of Result5 reference pCJIXJla50ll -__ Sluis-Cremer 827 miners and The dose rclationxhiv of c~g~rettp. and COPD' JY~P~O~U et *I.. 1967. nonminers over we.3 much more noticeable among those cxpoaed to dulL South Africa 35 years of *gc. Thr authors strnxed the syn-istIc rctiana of cisarrtte (?09). (cont.) smoking and dust exvo~urc. BOUhUYS et J.. 1969. U.S.A. (99). 455 male cotton Those exposed to dust manifested a significantly greater textile workers prevslence of byssinosilr sym~tom'~ than nonexvcsed. (214 exposed to Smoker, msntie?ted a significantly greater vrevrlmce of dust in carding byssinosia symptoms than nnnamoken. and spinnina No aignificsnt dlffcrencn in Monday morning FEV' vnlues rooms. 241 not were observed between smoker, and nonsmoken. expo3ed~. Prevalence of bysxinosis symptoms did not show any re- lstionxhip to length of employment. Bouhuys et al.. 1969. U.S.A. (38). Chester et al.. 1969. U.S.A. (49). 216 male hemp workers and 247 workers in other industries in same region. 2069 years of age. 139 male chlorine Chlorine-exposed group manifested no difference in symp- plant workers (55 with history of severe ex- pasure,. Hemp workers (especially the older ona) were noted to have different smoking hnbitn from control group-fewer heavy smokers. more light smokers. more ex-smokers due to doctor`, orders. Aged 20-49 -a. No difference in FEV, 0' values between controls and hemp &kern in cay smok- ing catel3ory. b. No di!Terence in FEV,., valum between men in different smokmg catpgorier. Ap-ed SC+69 -3. Hemp workers manifested decreased FEV,.O values in .II smoking gmuvs except for heaviest smokers. Ex-smok- ers had lowest FEVIsO values. b. Those smoking moot had lower FEV, o values 1c1 compared with Light and non- smokers. The authors conclude that: There appesn to be no synersism between smoking and hemv exposure as to effect on FEV, o although the selection D~OCCSS whereby those with sy'mptoms have L zreater tendency to stop smoking may obscure such a relationship. tams and D decreased MBC value when compared with non-exposed IJroup. Smoken in ehlorine-exvowd group had significantly de- creased MBC and FEY values at) compared with non- smokers in non-exposed group. Greenberg 121 workers in et al.. washing powder Ser.sitized group manifested lower FEV,.dFVC' valua IS comvnred with nonsensitized group even after smok- 1910. factory (48 found inp habits were controlled for. England to be sensitized (911. to $Iraduct. 73 "CA). __- Tokuhat. 801 male miners Incrensed mine cx~)osurc WRS associated with residual vol- et al.. umr and FEV abnormalities even after adjustments for 1970. .sge and smoking. U.S.A. A systematic ervosurc-impairment relationship ~a9 noted (218). only -"ml: smokers while relatively few nonxmoken showed COPD impairment. Smokrnn minen manifested more X-ray mIteration and COPD JymDtoms than nonxmakers. regardle=., of n~m- be= of Ye*- of underground exposure. 245 TaLE AIQ.-Ezpe~~ltn~ concerning the egect of the chronic inhdation of x0x upon ihe irachcobronchial tree and pulmonary parenchma of animals freeman SpragucD~sl~Y 25 D.p.m.; and rnt% (n, after 37-41 drya-moderate brDcrtrODhY md byper- Hsydon. plrsrr of bmnchisl and bronchiolar rpirhelium. 1964 (h) dter 146-157 &P-(I) Advanced ~YDC~~WD~Y md U.S.A. hyperphaim of broochis and (90). bronchiolrr epltbeIium. (2) Increucd lunp vohlmr. (3) Proliferation of coonectlve tlrsue. Rwdon et .I.. 1965 U.S.A. (107). 12.5 p.p.m. to d.z.th: (a) Hypct-tmphy and occasion=1 metapluls of bmnchial and hronchiolsr epithelium. (b) Incrtuc in number of sctivcly aecrrtlnrr roblct CCUX. Haydon et rl.. 1967 U.S.A. (106). Albino rabbita. Fr*Ul*ll SprarucDawlcr 0.8 mp.m.-2 p.p.m. for entire lifespan: et .I., rats. (a) Alveolar distention. 1968. (b) Reduction in number of da. U.5.k (cl Epithelial inactivity ("dormancy"). (91). FWCUIan et *l.. 1968. U.S.A. (89). Bhir et .I.. 1969. U.S.A. (3X). SvagucDawleu rata. Female Swiss Albino mice. 18 D.P.m. (a) 5 days-terminal bronchiolar epithclial bm?lertrophy. (b) 4 weeks-(l) Widcapread bmnchiolar epitbelial by- vs-trophr. (2) Non-necratizing emphysema. 0.5 P.D."L: (PI 6 hours/day for 3 months--pneumonitis. (b) 24 boun/day for 3 months-(l) &3Diratiw hmnchi- okr obstruction. (2) Alveolar expmsion and bronchi&r infiammstion con- sistent with early focal emphywna. Klcincrmm. Male Smi.n Golden 100 D.p.I'n. for 5% houra: 1970. hamsten. (a) thymidinc autoradiography-intense burst of pmlii- U.S.A. eration of cpithelium retUrninE to normal in 4 days (IJO). (more lxraistent distdy). (h) electron micro,copt( 1) Decrcsaed number of ICJ- CrdmY cella + mcrrto~ granules. (2) Increased number of brso- aomd structures. (3) No chmge in number of ciliated cella. 246 AUthOr. year. country. system reference and Shreeve, 1937. U.S.A. (160. Rakictcn et al.. 1942. 1J.S.A. (188). Calf trachea. In ritro: (al rabbit and rat tmcharl rings. (b) human naJal lllUCO"S membrane Method 1 I. Nicotine in 1. Caliary sctivlty dcpreued only upon er- Locke-Ringers pmurc to 100 mg. percent mlution. solution. 11. Ciliaw activity depressed after 15-20 min- II. Cisarette smoke ute exweure depending on concentration In ecdution. of smoke in soiution. Kordik In oitro: X&tine in Locke's Nicotine at ID--J g./cc had no eflecct on ciliary CL .I.. Rabbit solution. activity. 1952. trachea England (137). Hilding. In vitro: Cigarette smoke All tracbes, showed depressed or absent riliary 1956. Cow trachea (direct mtivity. U.S.A. exposure,. (120). Krueger In viva: Cisarertc smoke. Cigarette smoke decreased ciliarv activity by and Rabbit approximately 200 beata,minute. Smith. trachea 1958, U.S.A. ,199,. Dalhamn. 1~ vim: Cigarette smoke. 1: `I/IO ahowed retsstion of ciliaw activity 1959. I. Rat after one explmure. Sweden trachea II. 6/10 showed cessation of ciliary activitg (59). In vitro: after one expol"r.5 II. Rabbit III. 6/7 ahowed cation of ciliary activity trachea after one cigarme exposure. III. Humsn ciliated Dl"CO3a Fslk In vitro: Cigarette smoke. Decreased ciliam activiW noted on expaaure to et al.. Rat and rabbit cigarette smoke: 1959 tracheal (a) Repetitive exp~nure -ELU associated with U.S.A. epithelium. persistence of response user longer periods (80). of time. (b) "Tar"-rich clgarette WZY more inhibitory than "tar"-poor. cc) Filtered smoke was I- inhibitory than Wlfillcred. BIllleWCr. In vitro: Cigarette unoke Ciliary activity =su fully inhibited within 628 1960. Human in solutioa. minum of erpmure depending upon concen- U.S.A. bronchial tration of smoke in solution. (15). .nd tracheal epitbclium obtained durinr r*e.tbnla. 247 TABLE X13.-Ezp~rimmts concerning the effect of czgnrette smoke UT its co~stitzlenfs upon diary function (cont.) Krnder et rL. 1963. U.S.A. (896,. In riror Cinarrttc smoke: Unfiltered ci~~rctte smokwili~tasia bp Znd- Frab a.ter and ita fractions 5th poty mussel in solution. Acid fpbenolic) fraction solution-immedialc diata-3 ciliastlrrh. epitbelium I%%& extr*ct fraction solution--oo cililataris. Neutral fraction solution-no ciliaatasia. 1 percent phenol solutica+-immediate ciliuta- sin. D~lhunn In &-or Cig.rrtte smoke. Unfiltered eigarctte?r--ciliasstsala in 3/6 csta and cst trscbc8. after 5 cigarettes. Rylandcr. Filtered cigarettes--no ci1ieata.G after 8 ciga- 1964. rett`?_ (6 cata). SWed?fJ Controls-no cili.utasis (6 cab). (61). Balleoacr In rib-o: Nicotine in solution. Initlsl stimulation of activitT fallowed by de- ct *I.. axl3.a cline mnd complete ciliuWi8 sfter 12-24 1965. uij.ted hours of erwnure. U.S.A. mched (26). e>it0rhm obtazned d-ring. .2atbesiL Dalhamn In tirar Cigarette smoke. The longer the time interval between expo- and Cst trxter sure-s, the more puffs were required (0 ca~ae Rylandcr. ciliastasis. 1965. swwde?3 (61,. Wvnder In rim: Various compounds Formic. acetic. proDionic. benzaic acids alI et sL. FrcGl rua:R` in soluhxL more ciliatoxic than phenol. 1965, masel Oxalic acid Ins ciliatoxic than phenol. U.SA. cihted Formrldebvde. acrolein more ciliatoxic than (35). cpitbelium phenol. CBTSOIJ In R'COT Cigareltr smoke. Perccv2 dccnruc in ciiiary activity et .L.. c*r traclla Control . . . . . . . . . . . . . . . . . . . . . . . 0 1966. Unfiltered smoke . . . __ __ _... . . . . . . . . . 63 U.S.A. C4lulose aceLate filter . . _. . ._ . . . . . . . 46 (44). C.rbon cellulose ncetste filLcr . . . . . . . -. . . so D&was. In rite: Cigrrette smoke. Mean number of puffs requirrd to v&uca -- 1966. Cat rrubcl. CiIiadLG Swdm No filter . . . . . . _. . . . . . . . :. . . . 91 (60). Chnrcoal filter ._ __ _ _. _. . . . . . . . . . . . 170 Commcrrial cellulose acetate tilLer . . . . . 194 Chsrcoal and acet.tc filter . . . . . . . . . . . . 612 Cambridpc filter . . . . . . . . . . boo Ken&r III G-9: Cianrettc smoke Rabbit trachea-Total smoke condemw& of 2 and Rabbit mnd componenta cigareiten, gas phase condensate of 7 ci&%- B.ttisu. trdlcs. in Tyrode's rctte caused similar ciliastasis. 1966. cat t.chea. Yolution. Other sDeeiar--All found scnaitive to ciliaatrtic U.S.A. don trde., components of cigarette smoke. Bulk of a~- (135). monkc7 tivitg noted in gal phase (HCH. fommkk- tncba bud=-. rcrokia). I-St machcr 248 TABLE A13.--Erpen'msnts concerning the rdcct oj kgarette smoke or its comtitucnts upon diary junction (cont.) Author. ye-r. CD"3h-S. SIStem Methcd ' IkS"lb reference Kaminski In virlo: Whole md filtered Wet chamber adsrotion aignificantlrr reduced et II.. c*t trP.chea. cigarette smoke tbc cilirstaric activity of whole smoke. but 1968. er$cm?d or uler- did not affect the ciliastatic activity of smoke U.S.A. posed to "Wet previously filtered by Cambridge or cbuwal (ISJ). chamber" made filters. to stimulate oral mucoma and saliva Klrhl In viw: CiRarette amokc SimiBcant ciliastasis. reveaible. md ConmOD dissolved in BulmMb* mollusk sea water. 1968. ciiirtcd U.S.A. cpithclinm. (IN). B.ttiata and Ken&r, 1970, U.S.A. (ra). Bdtlsta md ILenskr. 1970. U.S.A. (19). In vitro: Cigrrette smoke The autban observed that: Chicken or HCN in (1) The more diluted smoke required more trxhed TYrode's puRa to cau3c ciliastasis. cpitbelium. solution. . (2) Activated rbarcoal filtered smoke wu less eiiia3tatic than ceilulose acetnte filtered smoke and ~LYO contained less HCN and acmkio. (3) HCN alone Wm ciliastatic but recovery WLS mare rapid than after cigarette smoke alone. They conclude that the ~a, phase components are more related to ciliastaeis (as particnlste matter is not aignificantb decrearred by char- coal filtration while HCN and acmlein nre). In o&m: Ciearette smoke. The authors ab,crved th.t: Hen tracha. (1) Whole smoke acuteb depressed ciliuy activity in 44 puffs. 249 Dalhamn In vim: Unfilteredcigarette Acrmor number of puda required to arrest and Cat trachea. and c,ge.r smoke. diary nctivity Rylander. Cigsrette smoke . ._. __. 73 (p4o I.,.,.....I.,..... 0.4 6.7 I amokcrr among the C,,~PI Dowllng, Indlvidurrb et al., UDOd t.0 1967, "Infectious U.S.A. cold agent" (751. and plncebo. Interview and medical cxaminatlon. Expored to placebo Ezporcd to infrcliour lioenl No stitlaticnllY Pcrcmt Pcrccnt aigniftcnnt dewloping drurloping dilTrrrnccs A'umbcr "cold" Numbnr "cold" noted. NS . . * . . . . 111 10 928 34 Shl . . , * . 78 14 248 36 TABLE AlS.-stt(die8 conceming the rck~tionsltip of smoking to in/eclio~ts respiratory disease in hwllan8 (Cont.) (Actunl numbrr of ~OIICJ ~huwn in wrrnthraca) SM = Smokers NS = Nonamokcra AUt.hX, yc*r. Number and Dnts country. type cl collection ncaults Comments rclcrcncc gopulation Bcakc. Parc"tT3 of Interview Number of No statidtlcslly 1068, 69 famillm Prrr'm- rcrpirotofy IUrutrcr/ aipnificont U.S.A. lltL%r, iuncsctc gtrrm.yrarr diflerenccu ($5). NS . ..I.. . . . . . . . ,.. (24) 120 624 6.2 natcd. Ciraretti/day: I-10 . ,...... (19) BB 629 6.8 11-20 . . . . . . . . . . . . . . . . . (26) 108 486 4.6 >20 . . . . . . . ..~............ (IQ) 89 424 4.8 Pipe, clnnr . . ..* .,.. (II) 72 804 4.2 Shah ct al., 19G9, Indla (loa). Tuberculosla Survey, X.ray, Institute and emlhyea. Interview. Author, ye&r, Number nnd colllltiy, type of Dntn rcfcrmce DOPUhtiOn collection Ilrrulls Commrnta Drown 306 mnle und - Interview Smoking habile prior lo diagnorid Data nrrscntcd only et al., irmnlc Tubcwrlour yolicnlc Controlr on Queenrlnnd 1061, tuberculosis (pcrccnl) (percent) aample. Aurtrnlia clinic NS ,...,,....._..,..,,,._..,..,.,.. 9.1 18.0 The authors noted (4). pnticnts. Cignrcttcs/dny: 1-Q . 10.6 16.4 that the 221 male and 10-11 34.3 19.6 aignihrnnt diRcrencc fcrnslc 20-29 . . ..I.. 26.3 26 a bctwecn the outpatienta. 30-39 . . . . 1.2 6.4 potienta and >10 ..,,...........,.........,.,. 6.2 9.1 mntrols ~09 not Pipc5 . . . . . . . . . . . . . .._........ 6.9 4.6 present when the gro"", were matched for alcohol intake. Haynes 191 male Interview Average number of rcapiratory iUncnrerli0 students et al.. prep school (adjurlcd Ior age) 1866. studcntd. AU .OYCIC her U.S.A. All (Joal. AU SCYC~C or combined rrapiratory rrapirotory rcapirotory cpiaodcr EpiaOde4 cpiaoder NS (99) ..,........,....,, 11.1 1.6 0.36 Sbl (92) ., ,.......,...,,,, 20.2 6.1 3.34 Pm-rlcll 41 smoking- Intcrvlew et al.. Median number o/ illnca~cclttudcnt The uthors noted nonsmoker palm and health 1966 AU All that these Of atudtnt numes service Cfintldn rcspirntory other dillercnces were mnLchcd for WC rccorda. (J~J). dirrarcrt illncsrra statistically and parrn~3' NS (47) . . . . . 2.08 2.99 rlgnlfitsnt. xcupntional Shl (47) .,................. 2.64 6.00 t Particularly CILIIS. tracbcitia, bronchitls. and pncumonl~. Author, yI'.r, Number nnd Dntn C"U"lry. WPC of collcctio" Rcvulte rrfercnrc Commcnle DOPUlntiOn rrtrrs 1.496 H~tvard Medical history. Number of viails to rtudcnt health unit for rrspirahy Plneao/atudent t e<0.001. et al.. nnd chart review. (comnic-n colda, pharyngitis. bronchitis. larynoitld, 1967. 310 Radclifle and pt~cumonia-not allrruic rhinilir) U.S.A. atudenta. questionnaire. Harvard Radclife IISY). NS . . . . . . . . . . . . . . . . . . . 1.44 (771) 1.44 (193) Sbl . . . . . . . . . . . . . . . . . . . . tz.27 (726) 2.27 (177) <2 YCRTS amoknl .,,...., 2.00 3-4 .,...,..........,,,. 2.30 >G . . . . . . . . . . . . . . . . . . . 2.60 Finklea 1,811 mule Questio""slrc Iicnw rmokcn-21 pcrccnt more clinicnl IIIIINL)R than nonsmokera: The authors .Iso Cl nl., CUllVgC prior to 20 percent mom twuirinz bed rest than nonsmokers nolcd that: 19c9 dudents. h,lliK/68 Light smokers-10 pcrccnt more clinical Illnc3ma than nonsmokers: U.S.A. (n) Smokrra epidemic ond 7 wrccnt more squiring bed rcat than nonamokcrn (BY). rrhlbltml follow.uu on BcroIwIc morbidity. cvlllPllcc of Incr,,nwd subrlitlicnl A2111KIG8 infcclion. (b) Thcrc wn& no diflcrcncc in tIkcra. N ?l TABLE A16.-Complications developing in the postoperative period in patients undergoing abdominal operations GtWUD CZLBeS Smoken ______.___.......... 300 Linbt Smok m-8 . . . . . . 180 Nmamokcm ._.._.._........ 66 Percent chest clear 41.1 68.4 92.3 PerWIlt brancho- PKCKlt PCk-Cmt p"eaunmdOnir tot*, bronchitis complication atelcctasis rllte 63.0 3.3 58.3 27.1 3.9 31.6 6.0 1.3 7.6 Smokcra _. _. __. . . 23 Light Sm 0 k em . . . . . . . . . . . 62 Nonsmokers . _.. . ._. . . . 518 Souscz: Morton. H. J. V. (172) 60.9 39.1 43.5 17.4 77.5 202 1.6 22.5 88.8 8.1 3.1 112 TABLE A17.--Arterial ozygen saturation before and after operation Arterial oxygen saturation (percentage) 1 94 93 94 . . 2 94 93 94 . . N onsmokers 94 . . . . . . 3 96 93 4 93 90 04 . . 6 94 90 93 . . 6 95 91 89 91 I 92 89 81 89 S mokem 89 . _ . . . . . . . . . . . 8 91 83 86 9 93 91 88 92 10 90 87 88 92 SOURCE: Morton. A. (17P). 256 Chapter 4 Cancer Source: 1971 Amcart, Chapter 4, pages 231 - 384. 257 Contents Introduction ...................................... Lung Cancer ....................................... Epidemiological Studies .......................... Prospective Studies .......................... Retrospective Studies ........................ Lung Cancer Trends in Other Countries ............ Histology of Lung Tumors ........................ Lung Cancer Relationships in Women .............. Lung Cancer, the Urban Factor, and Air Pollution. . _ . Lung Cancer and Occupational Hazards ........ _ ... Uranium blining ............................ Other Occupations ..... _ ... ;. ................. Nickel ...................................... Asbestos .................................... Arsenic ..................................... Chromium............-...........~......-.~. Pathological Studies. ............................. Pulmonary Carcinogenesis .. _ ..................... General Aspects of Carcinogenesis . . _ . _ _ . _ . _ _ _ . Polynuclear Aromatic Hydrocarbons . _ . _ _ _ Kitrosamine Compounds. .................. Pesticides and Fungicides ................. Radioactive Isotopes ..................... Inhibitors of Ciliary Novement _ . . _ . . _ . _ . _ Experimentai Studies ...................... Skin Painting and Subcutaneous Injection. .. Tissue and Organ Culture ............. _ .. Tracheobronchial Implantation and Instillation ...................... Inhalation .................... _ ........ Reduction in Tumorigenicity .............. Summary and Conclusions ........................ Cancer of the Larynx ................................ Epidemiological Studies .......................... Pathological Study .... :. ........................ Experimental Study ............................. Summary and Conclusions .............. _ ......... Oral Cancer _............__..._ ..................... Epidemiological Studies .......................... Experimental Studies ............................ Summary and Conclusions ........................ Page 263 265 266 266 266 270 272 277 278 282 282 282 282 283 283 283 284 284 284 290 290 292 292 293 293 293 293 294 294 301 302 303 303 304 307 307 310 311 x4 315 259 Cancer of the Esophagus ............................. Epidemiological Studies .......................... Pathological Study .............................. Experimental Studies ............................ Summary and.Conclusions ........................ Cancer of the Urinary Bladder and Kidney .............. Epidemiological Studies (Bladder) . _ ............... Epidemiological Studies (Kidney) ................. Experimental Studies ....... _ ........ _ ........... Summary and Conclusions ... _ .................... Cancer of the Pancreas ............................... Summary and Conclusions ........................ References ................. . ....................... FIGURES 1. Lung cancer, Finland and Norway . . . . . . . . . . . . . . _ _ . . . 2. Percent of smoking dogs with tumors . . . . . . . . . . . _ . . . . 3. Percent of lung lobes with tumors in smoking dogs . . . . _ 4. Effects of chronic cigarette smoke inhalation on the 271 300 300 haaster larynx . . . . . _ _ . . . . . . . . . . . . . . . . . . . . . . . . . . 310 1. 2. A3. A4. 5. 6. A7. 8. 9. Lung cancer mortality ratios . . _ _ _ . . . . . . . . . . . . . . _ Lung cancer mortality ratios for males by duration of cigarette smoking . . _ . . . _ . . . . . . . . . . _ . _ . . . . . . . Outline of methods used in retrospective studies of smoking in relation to lung cancer . . . . . . . . . . . . . Group characteristics in retrospective studies on lung cancer and tobacco use _ . . . . . . _ . . . . . . . . . . . . . . . Annual means of total lung cancer mortality and sex ratios for selected periods in Finland and Norway Epidemiologic and pathologic investigations concern- ing smoking and histology of lung cancer . . . . . . . Grouping of pulmonary carcinomas _ . _ . . . . . . . . . . . Tumor prevalence among males and females 35-69 years of age, by type of tumor and smoking category ._......__...._.................... Epidemiologic investigations concerning the relation- ship of lung cancer to smoking, air pollution, and urban or rural residence . . . . . . . . . . . . . . . . . . . . . . Pathologic and cytoIogic findings in the tracheo- bronchial tree of smokers and nonsmokers _ . . . , _ 10. LIST OF TABLES Page 315 315 318 318 319 319 319 322 322 325 325 325 325 267 270 349 355 272 273 360 276 279 285 260 LIST OF TXELES (Continued) (A indicates tcibles located in appendix at end of chapter) 11. Identified or suspected tumorigenetic agents in cigarette smoke _ . . . . _ . _ . . . . . _ . _ . _ . _ _ . . . . . . . . X12. Autopsy studies concerning the presence of radio- activity in the lungs of smokers . : . . . . . . . . . . . . . A13. Experiments concerning the effects of the skin paint- ing or subcutaneous injection of cigarette smoke condensate or its constituents upon animals . . . . . A14. Experiments concerning the effect of cigarette smoke or its constituents on tissue and organ cultures . . A15. Experiments concerning the effect of the instillation or implantation of cigarette smoke or its constitu- ents into the tracheobronchial tree of animals _ . . . X16. Experiments concerning the effect of the inhalation of cigarette smoke or its constituents upon the respiratory tract of animals . . . . . . . . . . . . . . _ _ . . 17. Data on pedigreed male beagle dogs of groups F, L, H,hand N . . . . . . . . . . . . .._.__............... 18. Summary of principal cause of death (days No. 57 through No. 875) in dogs of groups F, L, H, hand N 19. Data on dogs with lung tumors indicating type of tumor and lobe in which the tumor was found . . . _ 20. Laryngeal cancer mortality ratios - prospective studies . . . . . . .._...._.._..............-..._ A21. Outline of retrospective studies of tobacco use and cancer of the larynx . . . _ . _ . . _ . . . . . . _ . . . . _. . . _ X22. Summary of results of retrospective studies of tobacco use and cancer of the larynx _ . . . . . . . . . . . . . . . . . . A23. Number and percent distribution by relative fre- quency of atypical nuclei among true vocal cord cells, of men classified by smoking category . . . . . A24. Number and percent distribution, by highest num- ber of cell rows in the basal layer of the true vocal cord, of men classified by smoking category . . . . 25. Deposition of lGlabeled smoke particles in particu- lar regions of the respiratory tract . . . . _ . _ . . . . . 26. Classification of the five registered stages of epithe- lial changes at the larynx . . _ _ . . . . . _ . . . . . . . . 27. Oral cancer mortality ratios-prospective studies. . A28. Outline of retrospective studies of tobacco use and cancer of the oral cavity _ . . . . . . . . _ . . . . _ . . . . . . A28a. Summary of results of retrospective studies of smok- ing by type and oral cancer of the detailed sites.. PCaa 291 361 363 369 372 375 296 297 298 304 380 384 385 386 308 309 312 387 394 261 30. X31. :31. 36. LIST OF TXBLES (Continued) (=\ indicates tables located in appendix at end of chapter) Experimental studies concerning oral cnrcino- genesis __..__._..._.__......._........_.... Esophageal cancer mortality ratios-prospective studies _ . , . . _ _ _ _ . . . . _ . . . . . . . . _ _ . . . . . . . . . . . . Summary of methods used in retrospective studies of tobacco use and cancer of the esophagus . . . . . . Summary of results of retrospective studies of to- bacco use and cancer of the esophagus . _ _ . . . . . . At:-pical nuclei in basal cells of epithelium of esoph- agus of males, by smoking habits and age . . . . . . At)-pica1 nuclei in basal cells of epithelium of esoph- agus of males, by amount of smoking and age . . . . Kidney and urinary bladder cancer-prospective studies _ . . _ . . _ . . _ . _ _ _ _ . . _ _ . . . . . . . . . . . . . . . . Summar)- of methods used in retrospective studies of smoking and cancer of the bladder _ . . . . . . . . . . Summary of results of retrospective studies of smok- ing and cancer of the bladder . . . . _ _ . . . _ _ _ . _ _ Pancreatic cancer mortality ratios-prospective studies . . . . . _ . _ . . _ _ _ _ . . . . _ . _ . . . _ . _ . . . . . . _ . . Pwgc 397 316 401 404 405 406 320 407 409 324 262 INTRODUCTION During the early years of this century, a number of pathologists and clinicians reported a dramatic increase in the incidence of lung cancer. Autopsy studies and studies of lung cancer death rates re- vealed a significant increase beginning prior to World War I and continuing during the ensuing years. This epidemic of lung cancer continues to the present day, with nearly GO,000 deaths expected from this disease in the United States during 1970. Beginning in the 1920's, a number of reports appeared which suggested a relationship between lung cancer and tobacco smoking (2, 30.3 , 278). Since that time, many clinical and epidemiological studies have been published which confirm this relationship. The 19G-l Report (-391) contains a thorough review and analysis of the data available at that time as well as an excellent discussion of the considerations necessary for their evaluation. Xajor epidemiological studies have demonstrated that smokers have greatly increased risks of dying from lung cancer compared to nonsmokers. An increased risk of lung cancer has been found for every type of smoking habit investigated, but two character- istics of the risk are particularly evident: The risk is much greater for cigarette smokers than for smokers of pipes and cigars, and among cigarette smokers a dose relationship exists. That is, the more one smokes, as. measured by total pack-years of smoking, present level of smoking, degree of inhalation, or age at start of smoking, the greater is the risk. It has also been shown that the risk of lung cancer among ex-smokers decreases with time almost to the Ievel of nonsmokers; the time required is dependent on the degree of exposure prior to cessation. Pathologists have found that the squamous cell or epidermoid form of Iung cancer is the most prevalent one in cigarette smoking populations and that this form accounts for a major portion of the rise in lung cancer deaths (15~). Such studies have also indi- cated 3 lower prevalence among smokers for oat-cell and adeno- carcinomas of the lung than for the squamous form, but in most studies a higher frequency of these tumors is found among smokers than among nonsmokers. Smoking has been implicated in the deveropment of other types of cancer in humans. Among these is cancer of the larynx. A num- 263 her of epidemiological studies have demonstrated increased mar- talitY rates for laryngeal cancer in smokers, particularly cigarette smokers, compared with nonsmokers. Autopsy studies have re- vealed that a clear dose-relationship exists between smoking and the development of cellular changes in the larynx, including carci- noma in situ. Cancers of the mouth and oropharynx have been found to be more common among users of all types of tobacco than among abstainers. Although smoking is a definite risk factor in the de- velopment of malignant lesions of the oral cavity and pharynx, its relative contribution in conjunction with other factors such as poor nutrition and alcohol consumption has not been fully clarified. Similarly, although smokers are more likely to develop carci. noma of the esophagus than nonsmokers, the relative additional contribution of smoking in conjunction with nutritional factors and alcohol consumption requires clarification. Smokers have been found to be more at risk for the development of cancer of the urinary bladder than are nonsmokers, and there is evidence to suggest that some smoking-induced abnormal meta- bolic product or abnormal concentration of a metabolic product may be responsible for this increased risk. In addition, cancer of the kidney is apparently more common in smokers than in non- smokers, but the epidemiologic evidence for this relationship is not as definite as for bladder cancer. Epidemiological studies have indicated an association between smoking and cancer of the pancreas. The significance of this rela- tionship is unclear at this time. Experimental studies have demonstrated the carcinogenicity of the condensate of tobacco smoke, or "tar." This material, when painted on the skin of animals, leads to the development of squam- ous cell tumors of the skin. Researchers have shown that this condensate contains substances known as carcinogens, capable of inducing cancers. Among these carcinogens are several chemicals which have been identified as tumor initiators, that is, compounds which initiate changes in target cells and also tumor promoters, or compounds which promote the neoplastic development of initi- ated cells. Other, as yet unidentified, factors are presumably also involved because the sum of the carcinogenic effects of the known agents does not equal that of cigarette smoke condensate. Numerous experiments have been performed in which whole cigarette smoke, filtered smoke, or certain constituents of smoke, such as the "tar," are administered by varying methods to animals or to tissue and cell cultures in order to investigate the neoplastic- inducing properties of cigarette smoke. Particular difficulty has been encountered in experiments which have attempted to deliver whole cigarette smoke to the larynx and into the lungs of experi- mental animals, This has resulted in the use of other methods such as the implanting of pellets containing suspected carcinogens and the instilling into the trachea of suspected carcinogens as such, or adsorbed onto tine inert particulate matter as a carrier. The dif- ficulty with the inhalation studies has been twofold. First, the animals, particularly the smaller species such as the rat, frequently die from the acute toxic effects of the nicotine and carbon monoxide in the tobacco smoke. Second, the upper respiratory tract of experi- mental animals, particularly the nose, is much different from anal- ogous human structures, resulting in a more efficient filtration of smoke in the upper respiratory tract. Nevertheless, in rodents and canines, progressive changes apparently indicative of ultimate neo- plastic transformation have been identified in the respiratory tract. Recently, two studies in different species and in different target organs have been reported concerning the development of early in- vasive cancer following the prolonged inhalation of cigarette smoke; Auerbach and his coworkers (11) trained dogs to inhale cigarette`. smoke through a tracheostoma. After approximately 29 months of daily exposure, these investigators found a number of cancers of the lung. Dontenwill (76) in the second of these two studies, exposed ham- sters to the passive inhalation of cigarette smoke over varying and prolonged periods of time. He observed the deveIopment of pre- malignant changes and, ultimately, invasive squamous cell cancer of the larynx. LUNG CANCER Cancer of the lung in the United States accounted for 45,383 deaths among males and 9,023 deaths among females in 1967 (289). It is presently estimated that approximately 60,000 people will die of lung cancer during 1970. The alarming epidemic of lung cancer is a relatively recent phenomenon. Death rates for lung cancer (ICD Codes 162, 163) rose from 5.6 (per 100,000 resident population per year) in 1939 to 27.5 in 1967 (289, 290). This rapid increase followed the in- creased use of cigarettes among the United States population. The increase has occurred principally among males, although more re- cently females have shown a similar rising pattern. The converging evidence for the conclusion that cigarette smok- ing is the major cause of lung cancer is derived from varied types of research including epidemiological, pathological, and laboratory investigations. 265 EPIDEMIOLOGICAL STUDIES Numerous epidemiological studies, both retrospective and pros- pective, have been carried out in different parts of the world to investigate the relationship between smoking and cancer of the lung. These studies are outlined in tables 1, 2, A3, and A4. Prospective Studies The major prospective studies concerning the relationship of smoking and lung cancer are presented in table .l. In all, these investigations have studied more than a million persons from a number of different populations for up to 10 years. These studies show increased lung cancer mortality ratios for cigarette smokers of all amounts ranging from 7.61 to 14.20 among male smokers as compared to nonsmoking males. The one major prospective study of female cigarette smokers reveals an overall mortality ratio of 2.20 (118). Also uniformly present in these studies is a dose-related increase in the mortality from lung cancer with increasing amounts of cigar- ettes smoked per day. Other measures of exposure show similar trends. Hammond (118) reported increased mortality ratios asso- ciated with increased inhalation (table I) as well as with increased duration of smoking (table 2). Ex-smokers show significantly lower lung cancer death_- .rates than continuing smokers. In their study of more than 40,000 B$tish physicians, Doll and Hill (74, 75) noted a decrease in lung carricer mortality rates with increasing time since smoking stopped (table 1). During the past 20 years, half of all the physicians in Britaig who used to smoke cigarettes have stopped smoking. While the death rates from lung cancer rose by 7 percent among all men from England and Wales during the period from 1953-57 through 1961- 65, the rates for male doctors of the same ages fell by 38 percent (96). Pipe and cigar smokers have been shown in the prospective stud- ies to have lung cancer mortality rates higher than those of Bon- smokers, although these are generally substantially lower than those of cigarette smokers (table 1). Retrospective Studies More than 30 retrospective (case-control) studies have been re- ported conc&ning the relationship of smoking and lung cancer. These studies are outlined in tables A3 and A4. Table A4 presents the percent of nonsmokers and of heavy smokers among both cases and controls as well as the relative risk ratios for all smokers. 26.6 (Actual number of deaths shown in porenthcsn)' Shl= Smokcrn. NS = Nonsmukcra. Author, Number yenr. wdo'qw co'zP Follow- NUmbCr Regular cigarette I'irw EO"rlLl-Y. UP dcaok smoking only cigar Inbalntion Exsmokcrs CDmlliCnt3 reference popuL5tion YcBrl (ciBarctter/day) Hammond 187.783 Queation- 3 `h 448 Pills No dotn fIro,lchoocnic 341l.448 and white nnirc and SN 443 NS ..I.. 1.00 (16) NS .,. ;.OO (16) (Errludinp adcnocnrcinoma) drnth? with IIorn. msles interview. NS , 16 20 . . . . 23.40(\17) NS .,. 1.00 (1G) Continuing . ,,. ,, .16.94 ClUllc-3 t1w,e (110). LDCB All . ..t10.73(397) SII ,,. 1.00 (7) Duration 60-69. 1 I0 yenrs , ( 1.61 amokcrs who PrcviourlV >I pack/day ntv~ amokd Continuing , . .46.21 ply<* und Duretion uf cesrstion 1 lO year* .17.79 w\lh""t micrwcopic vrwf. - Doll and ApprOXi- QucsCion- 10 212 NS ...I 1.00 (3) Pipe and Cigar No data Cigeretlc rmokcrr Hill, mstely naire and SM , 209 l-14 ,.,. 8.14 (22) NS ., . . 1.00 (3) NS . ..I. .,.. .,..... ~. 1.00 (3) 1964, 41,OdO fOllOWUP NS . 8 16-24 ,. .19.86 (63) Groma/dav Continuing t . . . . . . . . . . 18.21(124) Grest male of dcatb >25 . . . . 32.43 (67) l-14.. 6.00 (12) Durnlion <6yettra 9.61 (b) Britnin UriLirb certificate. 15-24 ., 6.43 (G) of 6-9 years 7.00 (7) (70. physiciana >26 .13.71 (3) I c~ssi,tiun lo-20 ycara 2.67 (3) x0 ycrrs 2.11 (2) Beat. APDroxi- Queetion- 6 331 NS . . . . . 1.00 (7) Pipe No dnts 1 II, fcra 1966. mntcly nairc nnd tSM 324 no .I?.31 (63) Cigar Canadian cixorctl~~ only 6.06 (18) cixnrs tic certificate. All .14.?O(ZdG) NS ..I.00 (I) an,ilkLr!d YewranD. SM . ..2.94 (2) only. __~- -. .- TABLE l.--Lung cuttce~ mwtulity rattie (cont.) (Actud number of dcrtha rhown In DWeQthW=)' SM = Smoktn. NS = Nonsmokem. Prodpectlve studies 8% 1,266 sbi .1,118 NS . 7.6 Reguh eiwctte smoklnn only (clparettra/day) PIPS cl&x Inhalhtion Exsmokcn Cammcr NS ,*... 1.00 (78) 1-B *,.. 5.49 (46) lo-20 . , . 9.91 (am) 21-39 . . .17.41(816, >S9 . .a a23.93 (8'2) AU , ,.. .12.14(749) Pip NS . . ..l.OO (78) Nodata sbl *.. .1.84 (17) Cigar NS . . ..l.OO (78) SM . . ..I.69 (6) Pip. and cigar NS . . ..l.OO (78) SM . ...1.66 (20) NS . . . . . . ,....a 1.00 (78) Number of ciparsttoldav: l-9 .,,,. *.*... 0.96 (4) lo-20 . . . . ..I.. l.48 (89) 21-89 .,......* 9.88 (17) >a@ . . . . ...**** 8.24 (19) IU - Hum.nond.440.668 InterviewB 4 Mdu 1966, mbles by ACS 1,169 U.S.A. 662.671 voluntetn. SM .l.llO (Jl6). fer4er NS . 40 w-a4 FOlWh ,e.n of 188 .gt In 26 SM. 81 statea. NS 6 102 Cuncnt ei0aret1cc Pips oh NS . . ..l.oa (49) hfda SM . ...2.24 (21) NS a.... 1.00 (49) Cigar 1-S .*.. 4.60 (26) NS . . ..l.OO (49) lo-19 . . . 7.48 (82) Sbl . . ..1.86 (22) 20-39 . ..13.14(981) Pipe and cioar >40 ,,.. 16.61 (82) NS a... 1.00 (49) AU a.... 9.20(719) SM . ...0.90 (11) Fcmdu NS .,... 1.00(102) l-19 , ., , 1.06 (20) >20 . . . a 4.76 (60) All . . . . . 2.20 (81) Mdecr NS . . . ..s.. 1.00 (43) Slight . . . . . . 8.42(120) Moderate ,a .11.46(811) DWD . . . . . ..14.81(141) FCiVlOL~ ICD cD11c 162 only. NS ,....... 1.00(102) Slkbt ..a... 1.78 (26) 8.70 (46) TABLE I.-Lung cancer mortality ratios (cont.) (Aetusl number of deaths &own in Darcnthpsea)l SM = Smokers. NS = Nonsmokers. Prospective studies Author, Number FOUOW- Year. andoyw Data UP Regular cizzarette Pipe ~0"l-ltl-Y. collection years N"zber smoking only cigar InhalPtlon Exsmokcrs Comment.9 nferenee poPulatlcn deaths (cigarettes/day) nucu 69.868 Question. 3 a04 NS 1.00 et al., Americm naire and <20 ,.,. 2.30 1967. LcpiOW fOllOWUP 20 ,.. 3.50 U.S.A. nsirea of death >20 . . . . 4.90 (AD). 36-76 certificate. ye&l-a of out and older. Hlrw~m~.265.116 TUiW?d 1% 4s NS . . . . . 1.00 (a) rrcllmlnnrr 1067. mnlcand PIIS SM . 40 l-24 . . 2.69 (29) report. Jbpan femnle nurse >26 . . . . 6.68 (6) (lfb). adulb IntervIew 40 ye." and fol- of we and lowuu of older. death ccrtlflcate. ??o? o nd 68.169 Qumtlon- 68 BE8 NS ..a. 1.00 NY Include Dunn. mah In nnlre and 510 ., . 8.12 pipo nnd 1970, V~rloub fOllOWUP 220 , , , 8.06 cigar U.S.A. OCCUP.. of derth >a0 ,. , 9.66 amoken (roa) * tiona in certith(c. AU a.. 7.61 YJI include C~llfOn\lll. cx-amoker~. L Unlm, otbcrai~e mpecifled, disparltlcs between the total number of death8 and the bum of the Indlvldtml amoklng cbtewxies w-e due to the cxclu~l~n r-4 of clthtr ocrralonrl. mlacell~neous, mlxed, or exsmokcra. z TABLE 2,Lung cancer mortality ratios for tit% by duration of cigarette smoking (,4ctusl number of death arc sboan in parenthesa) age began cigareYe smokine 35-64 25 or older _........... 2.77 (6) *Is24 ________......... 6.83 (31) 15-19 .___............ 8.71(112) 25 ,... . . Epidrmloid (475) 0.2 (1) Nalt-l oat-ccl1 BI annplaatia (101) 0.1 (2) 2.9 (IO a.9 (12) 36.6~1c9) ZC.3~11OJ 3C.8 (176) 34.7(10GJ 24 4(lIG) 24.4 (70 Epidcrmoid (18) 61.1 (11) 6.6 (1) 22.2 (4) 6.6 (I) 6.6 (1) FCTllo(C# oat.ccu or an.aphtic (19) 31.6(12) 16.8 (6) 23.7 (0) 18.4 (7) 10.6 (4) Admocarcimmo (IO) blolc~-10G unclaui!X GO.0 (6) t"~O~. Fcmslw-13 unclwifiul 20.0 (2) tumors. 10.0 (1) .,. 20.0 (2) ti -- __.-_-_.-.. z TABLE 6. Epidemiologic and pathologic investigations concerning emokhg and the histology of hg came? (cont.) e (Actual number of can ahown In parenlbcam) Author. Number of et al.. 1967, FWlC-2 (%ll). female cases with hl~tologlcaUy Epidcrtnoid ATUlPhlic Udwwn tvps Cvlindrkd + Difference confirmed Jung crsea . . . . ~ . . . . 96.0 81.0 86.0 100.0 siyniRcant cancer. 4 matched Controls . . 79.0t 83.0t 79.0t 06.0 *t p~O.06 Icvel. control IlwUDLI. Hwn,zel 168 female Relative risk for apccified tumorr (rmokn*/wnrmokera) 134 man with nnnl st .I.. case9 or bialoloaicnl 1968, lung cnrlccr. Grmp I (Xrwbcrg) Admocarciwma determinulion. U.S.A. Adjusted for age and occupation. ,,..,.....I.. 3.0t 1.19 t Diffcrcnce from (ii%). unity aigniRcrsnt8L ll~O.Ol. Haen32el 2.181 mnlc Stnutnrdircd martdilv roliar Cuts obtslncd from t. rrrrrcncc mr, h,Nl Cohen 411 malt and .nd Icmalc CUBY Of Hossain. lung cancer with 1966, histolugic U.S.A. dingnosia 1939-63 Nonsmokera . . . (56). at one husvital. Smokers . and frmule EOHCB of DUVle& hialoloyirslly Unili~crcmlti~tcrl IDGI. dlngnurcd Nonsmokera 2.8 (4) Enulnnd lunn cancer. Pipe . 9.9 (14) (6). Cigarette . . . . . . . . . . . . 87.3(124) ro , *. . . I.. 7.1 (IO) Souvnww 2.6 (G) 9.9 (20 87.6(211) 22.4 (64) 41.6(100) 21.6 (62) 12.9 (31) 6.2 (16) clylllctlc s"wkl,iy Adcnocarcinom P,,,IParl to bc `il 3.4 (2) llronyly rclutcd to 1.7 (1) adcnocsrcillomn 113 lo 94.9(663 (he olhcr 2 tywa. 22.0(13) A~blcy'r data on `.ootul 33.9(20) number of civurcltc 16.9(10) smukrrs BTL' 8.6 (6) inconuistvnl with 6.1 (9) hi3 brcnkduwn ol TADLE 8.-Tumor prevalence among males and females 85-69 uears of age, by type of tumor and smoking catvory (Smoken conatltutcd 86 percent of popul&tlons rtudled) Sex and type of tumor TOtd Smoking category Smoking all mcthoda Non- smokera nisk rntio aml>ng smokers Total . ..a. . . ..I... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 3s 13 18.3 1.9 1 Number that would be exueeted II Incidence rate among smokers were eauI to that of nonsmokers. SOURCE: Kreyberg, L. (154) LUNC CANCER RELATIONSHIPS IN \VOXEN Lung cancer death rates for lvomen are presently much lourer than the corresponding rates for men. In addition, it has been ob- served that among certain strains of mice exposed to carcinogenic agents, the male animals show a greater tendency to develop lung tumors than do the females (200, .?07) although there are strains for which this is apparently not so. The extent of the influence of endocrine factors in the sex variation in the incidence of lung tumors is unknown. AS of 1967 in the United States, women accounted for only about one-sixth of the footal deaths from lung cancer (289). However, the lung cancer death rate in women has risen by over 400 percent in the past 40 years. From 1950 to 1967 alone, the rate per 100,000 population doubled, increasing from 4.5 to 8.9 (289, ~0). A number of retrospective studies concerning lung cancer and cigarette smoking among women have found that the difference in the prevalence of lung cancer between males and females is ac- counted for principally by those tumors classified as Kreyberg's Group I (~54,311). These, as was noted above, are the tumors, par- ticularly in males, which show the closest relationship with smok- ing. Haenszel, et al. (113). in a study of 158 women with lung cancer, observed that the sex differential for lung cancer death rates diminishes, but does not fully disappear when only non- smokers are considered. Hammond (118) found that the death rate for lung cancer in nonsmoking males was somewhat higher than for nonsmoking fe- males. However, the difference in male-female rates was much greater when smokers were compared. It appears that a substantial part of the difference in death rates between male smokers and fe- male smokers can be explained mainly by differences in their smok- ing habits. These differences in smoking habits between males and females are of two types. First, overah consumption among females is still significantly lower than that among males. In 1966 (281), 30 per- cent of males reported that they had never smoked while for fe- males the corresponding figure was 59 percent. This study also noted that nearly three times as many males as females reported consuming more than 20 cigarettes per day. Second, it ,has been shown that women smoke differently than men (303) : They begin smoking later than men (114) and do not smoke cigarettes as close to the end, where proportionaIIy more nicotine and "tar" are in- haled. Women smoke more filter-tip and "low tar and nicotine" cigar&es than men. Furthermore, cigarette smoking stiII tends to be heavily concentrated among women under the age at which lung cancer is most likely to occur. 277 Finally, analysis of the ratio of male and female lung cancer death rates (283, 284, 285, 286, 287, 288, 289, 290) reveals that since 1960 this ratio has shown a steady decline, reflecting the greater relative rise in mortality from lung cancer in the female population. LUNG CANCER, THE URBAN FACTOR, AND AIR POLLUTION A number of studies have been concerned with the relative influ- ences of smoking, urban residence, and air pollution in the etiology of lung cancer. Table 9 lists studies performed in the United States, Great Britain, and Japan which have dealt with this question. Kotin and Falk (149,150) and more recently the Royal College of Physi- cians (228) have reviewed the literature concerning the influence of atmospheric and environmental factors in the pathogenesis of lung cancer. The studies listed.in table 9 show a number of important trends. Lung cancer death rates are found to be higher among urban popu- lations than among rural populations. It is not known to what ex- tent this urban factor in the etiology of lung cancer is due to differences in the levels of air pollution. Other factors associated with urban residence which may influence the etiology of lung cancer are: differences in smoking habits between the two popula- tions, occupational differences, and possible differences in the re- porting of lung cancer deaths (228). The studies also uniformly show that within each urban/rural grouping, Iung cancer death rates increase with increased smoking. Whether air pollution acts with cigarette smoking to influence lung cancer death rates in a combined manner is presently unclear (112, 126, 264, 26.5), and the evidence concerning a separate role of air pollution in the etiology of Iung cancer is still inconclusive (228). The recent report of the Royal College of Physicians on air pollu- tion and heaIth (228) concIuded that "the study of time trends in the death rates of lung cancer in urban areas demonstrates the overwhelming effect of cigarette smoking on the distribution o? the disease. Indeed, only the detailed surveys that have taken individual smoking histories into account have succeeded in separating the relatively very small influence of the `urban factor' on the over- riding effect of cigarette smoking in the development of cancer of the lung." 278 Author. POQUhtiOn Y`,!ll-, atudird and c0untl-Y. moth& at Results Commmla re1crcnce data collection Doll. Estimated death r&ten Lung canccv morlalily (1950) PET 1,000 Authors noted that 1163, from lung c*nwr Nnlcs Fcmalcr Ncmtnokcra ce.~I:n~tL~ arc boscd on Ennlnnd in English London Olhcr urban Rural Lordott Ofhcr urbarl Rural AI1 arcad "cry few dcutha. (70). DoQulsllon and Age: ~rnons nonsmokers 26-44 ..I.,, 0.126 0.096 0.070 0.028 0.028 0.012 0.020 obtained fram 46-64 . , . , 1.612 1.264 0.861 0.194 O.lG2 0.120 0.000 general register. 65-74 .,. 3.124 2.006 1.1G4 0.440 0.326 0.288 I.219 Stocka and Death ratn in Nda lung catictr dcalh ratea 19S2-61 (PC? 100,000) (~Pc, 54-71 The authors noted the CampbeU. England and 1966, Northern Wales. Rurd (66) Mind (116) Urban (559) upward nrsdicnt amonr nonsmokers, yiyc Ewlnnd Review of Datient Nonsmokers ,~......,........,.,.,,,,,,..,.. 14 , , 131 smokers and light (266). chart or Interview Pipe . , , , . . . . . , . . 41 26 143 dgsrctt~ smokcra and the with kin or Cigarettes: Light ,. . _. 87 163 291 lack of a simllnr vhyaicisns. hloderate .~...........,,,.,,.......,,..,.. 183 132 287 gradient LrnO"Y Heavy . . ..I..I...._............,,,.,...... 363 303 304 mdcrnlc and hrsvy cigarette amokerr. Hammond 187.783 white m&s Age alandardircd dcalh rafcb due Lo bronchoonric carcinoma (mdcs) Data excluded and Horn. in 9 s!nlea. adcnocnrcinomn. when 1968, Questionnafrc Suburb Cily ol Cifv of standardized for BIL' and U.S.A. and interview. Rural 0, to*n 10,00040.000 >50.000 smoking. rural rate WLI (IN). Nonsmokers . . , , . , 4.7 (2) 9.8 (3) 14.7 (4) aHll noted to bc 26 Cigarette smokers . , . 66.2(62) 11.1(61) 70.8(58) 86.2(63) porccnt lcua than urban. Author, POlHJl~ti0n YCli-. studied and COUhY, method OC Results Comments refcrcnec data collection Hlrn3lcl 10 percent ol all ~0~. and rmokinprt.andordizcd lung conce~ rno?tiitU %%tb Standcrdircd Mortality et al., white mnle Lund (cpidermoid and undiferentiated carcinomua &VI Ratio = 100 for U.S. 1962, cancer depths in whlte males age 36 and U.S.A. U.S.A. for 19G8 Nctrovolitan countier Nonmslropditan counti Over In 1968. The authora (JJ~). for whom next of >50.000 ,,......,....119 2,EOc-50,000 , .QO rho noted I', joint kin or physiciana 10.000-60.000 . . ,151 Rural nonfarm .I4 ef?ch, cl rcaldence snd supplied smoking Z&00-10.000 ,,......... 99 Farm . .I. I.. .67 Bmokine histories in the data. 2,191 cnsee schedule of iuny-csncer with adeguate r~l-?_ far *re*ter lh" Incormatlon. those expected on the taumption of ~dliitlvity of the ser~nrutc ellectd . ." DOU and Hill, 1964. Enuland (70. 41,000 male British Slandardircd death rater for lunp CLIRCCY The authors noted that physiciana. rural marte.llty dub Questionnaire and Conurbatian(49) Large Towtu (34) Small Towtu (3P) Rurd (Jab were aKrcl*.d hy L follow-UP of death Nonamokero . . 0.03 0.00 0.11 0.12 slgnlncsnt number uf certihcate. Clearetle smokers: city reiidenla l-14 .~.,..,...,...,. 0.48 0.32 0.87 0.62 retiring to the cuulitry. 16-24 . . . . . . . . . . . . . . . 1.31 1.88 1.06 1.16 . >26 . . . . . . . . * 1.90 4.43 2.20 1.17 Wleken. 1.908 male and Lung cancw dcafh rate per IOO.OOO-age. and rmohirlo.rtand6rdizrd total number uf drIllha 1966, female luw ctincc-i- noted under mcthlid uf Northern deaths over 36 fnnn OUlC7 Ucllaa t Urban Small dat. cullcction lncludc Ireland years of L(lC from Dcl~d Dcllaat Environs Arta TOWl-4 Rural 964 conhols. (soa, * rc~i9t.m. Personal Malea . . , . . lG7(241) 139(167) 135(46) llB(185) 137 (26) 47(149) interviews with Femalea , t, 22 (38) 17 (24) 12 (6) 23 (36) 22 (6) 12 (43) kin or physicians. TABLE g,-Epidemiologic inue8ligalions concerning the relationeilip o/ lung cancer to mking, air pollution, and urban or rural reeidence (confi.) (Acted number ol death shown In prrmtbesm) Author. PODUhtlO" Year, atudlcd wd CouncrY. method of Results Commtnta relerence data collectlon BUell 804 IWO ernecr Apaadju~trd Lund cancer dsa;h ratra per IW.OOO man yrarr and moriolity ratior The authors noted the lack et d.. deaths .mong of dcath.rate dlllcrencu 1961, Amerlcm San Froncircol AU other bctwecn Loa Anaels, and U.S.A. Leglonnrlrcs Lor Anoslu Son Disoo Colifomio counlisc San Frw~claco rryiona 449). o ged26andovn. Ratr i2atio Rots Ratio RDId Ratio and concludrd thrt Quc~tlcnnalrem to Nonsmokers , . . . , , . . . . . . . 26.1 2.6 49.0 3.9 11.2 1.0 photochemlcal 8mw Ia next of kin. Smokers: not relstnl to <1 prcklday .b.*I.III,..I. C3.6 6.7 77.1 6.0 61.02 6.4 lung c.nccr. . . . . . . . . . . . . . . . . . . . ..a. 126.0 11.8 134.6 12.0 124.9 11.2 $: . . . . . . . . . . . . . . . . . . . . . . . 241.3 21.6 22G.0 20.2 131.6 12.8 Rltwugl, 186 male and Lung entlcer dsolh rats PET 100.000 The &uthOn DOBtUhtd L 1DbB. ternale lung e*ncer &llpht syner,zlatlc Japm deatha rnd 4,191 POuutim rsOion (11.4). et?rct betwan amoklog mrtcbcd controla Male* LOW Intsrmtdiati Hioh rnd .lr DOllUtlUn. aged 36-74. Dot& Nonamokcrr . . . . . . ..s.. ..,...........,....,,.., 11.6 8.8 4.9 from Smokers: aucstlonnrlrea l-14 clearettes/day . . . . . . . . . . . . . . . . . . . . . . . . . . . 10.6 14.2 28.6 and Inkrvlavs.' >I6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21.3 18.6 81.4 F4Vlnle# Nonsmokera . I,., II......I....,.......,....I... 4.6 6.9 a.0 Smokera: 1-14 clearetteslday ..,.. . . . . . . . . . . . . . . . . . . . 19.7 16.6 16.9 >16 .a,..a.a..nas....a ,,...,,................ 12.4 20.6 11.1 Ape and cmokinp.ndjustcd lung cotlcs? death rots pn 100,000 LOW Intsrmrdiok lliph MRlCl III~II~..I.....I..o...~.o..,...,.,,II,., 16.1 22.4 28.4 E Fomaln . . . . . . . . . . . . . . . . . . . . . ..l.......I....I.. 7.6 11.6 8.7 w __ LUNG CANCER AND OCCUPATIONAL HAZARDS C'ranium Mining The excess risk for the development of lung cancer among uran- ium and fluorspar miners has been known for more than 30 years. In a recent review, Bair (17) noted that radon and ridon-decay products are the only inhaled radionuclides to be epidemiologically related to lung cancer. Lundin, et al. (178), in a continuation of the work initiated by Wagoner, et al. (299, 300, 301)) have re- cently reported on a 1'7-year follow-up of 3,414 white underground uranium miners. The authors estimated that smoking uranium miners experienced an excess of lung cancer ten times greater than did nonsmoking miners. Saccomanno (2.3~ ), in recent testimony, analyzed the data of the United States Public Health Service (USPHS) Study Group a.! presented by Lundin, et al. (178) above. He reported that cigar- ette smoking uranium miners incurred lung cancer rates four times greater than those of other cigarette smokers. Of the 62 lung cancer deaths in this population, 60 occurred in smokers. He also observed that among 100,000 uranium miners 700 lung cancer deaths per year would be expected to occur among cigarette smokers compared with only 4 among nonsmokers. Other Occupations Nelson (199) has recently reviewed certain environmental and occupational hazards as they relate to inhalation carcinogenesis. He observed that cancer of the respiratory tract has been linked epidemiologically and, in some cases, experimentally with occupa- tional exposure to the following materials: chromium, nickel, arsenic, and asbestos. Doll (72) and Goldblatt (IOU), in earlier reviews, also noted an association with coal, natural gas, and graphite exposures. Nickel Morgan (194) noted that much of the nasal and lung cancer at- tributed to nickel exposure may have been due to arsenical impuri- ties found in processed nickel prior to 1925. Doll (69) found that the number of excess deaths among nickel workers under 50 years of age had declined following the change in nickel manufacturing processes. The experiments of Hueper (134) and Sunderman, et al. ( 267,268,269) have shown that both guinea pigs and rats develop lung cancer following chronic exposure to nickel carbonyl or nickel dust. Sunderman and Sunderman (270) also reported that ciga- rette smoke contains nickel and that this concentration of nickel 282 may be capable of inhibiting the induction of lung aryl hydroxylase, an enzyme lvhich is able to detoxify aromatic hydrocarbons includ- ing known carcinogens such as benzo[a]pyrene. Asbestos In 1955. Do11 (71) found that lung cancer was a definite hazard among asbestos vvorkers. In a more recent study, Selikoff, et al. (251, 252) examined the relationship of smoking and asbestos ex- posure to lung cancer. These authors followed 370 people who had been asbestos workers during the years 1942-1962. Over a 5-year follow-up period, 94 deaths occurred in this group, of which 24 were due to bronchogenic carcinoma. The authors noted that according to data obtained from Hammond (118)) only 3.16 deaths from lung cancer would have been expected among smokers, and calculated a 7.6 to 1.00 mortality ratio due to asbestos exposure. None of the 87 nonsmokers or pipe and cigar smokers died of lung cancer. When the expected number of nonsmoker deaths (0.26) is compared with the actual number (24) which occurred among the smoking asbes- tos workers, an extremely high mortality ratio of 92 to 1 is obtained, thus reflecting the possible interaction of asbestos exposure and cigarette smoking. Exposure of mice (179) and rats (106) to asbestos dust or the intratracheal injection of chrysotile asbestos dust has resulted in the production of significant numbers of primary pulmonary car- cinomas. AIiller, et al, (184) exposed hamsters to intractracheal injections of benzo[a]pyrene. These authors observed that the addi- tion of the chrysotile variety of asbestos to the injections appeared to promote benzo[a]pyrene carcinogenesis in the respiratory tract, as determined by the time of appearance and yields of papillomas and carcinomas. Arsenic A recent epidemiologic study by Lee and Fraumeni (163) Ffai indicated an excess of lung cancer deaths among smelter workers exposed to arsenic for more than one year. Cigarette smoking was not taken into account in their computations. Experimental work on the induction of cancer in animals using arsenic has yielded either negative or inconclusive results (133, 135). Chromium Exposure to industrial bichromate compounds has been associ- ated \vith an excess of lung cancer deaths (22,P55). Laskin, et al. (159) have recently reported that intrabronchial pellet implanta- 283 tion of various chromium compounds in rats is associated with the development of squamous cell carcinomas and adenocarcinomas. However, Nettesheim, et al. (ZOO) exposed mice to chromium oxide dust and observed that it had no discernible effect on lung tumor incidence. PATHOLOGICALSTUDIES Investigators who have conducted detailed autopsy studies on patients who died of lung cancer have reported the increased pres- ence, when compared to noncancer patients, of bronchial epithelial changes which they considered to be precursors of bronchogenic carcinoma (7, 8, 23, 51,. 104, 208, 220, 279, 309). Such changes include squamous metaplasia, atypical squamous metaplasia (with acanthosis, dyskeratosis, and numerous mitotic figures), and car- cinoma in situ. Cames (52) noted that carcinoma in situ was pres- ent in 119 cases or^ lung cancer but not in any of the 119 controls who were matched for age, sex, and race. Autopsy studies comparing the frequency of these cancer- related changes in the lungs of smokers and nonsmokers are pre- sented in table 10. Virtually al] the studies noted an increased prevalence of these epithelial alterations among smokers as com- pared with nonsmokers. Definite dosage-dependent relationships were evident in the results of many of the reports. Also, Auerbach, et al. (14) observed that the number of cells with atypical nuclei decreases progressively in the bronchial mucosa of ex-cigarette smokers, depending upon the number of years between cessation of smoking and death, although it usually remains above that found in nonsmokers. The cytologic studies included in this table (182, 198, 222) ali noted an increased percentage of sputum specimens showing meta- plasia among smokers as compared with nonsmokers. PULMONARYCAFLCINOGENESIS General Aspects of Carcinogenesis Agents found in cigarette smoke which have been identified as, or are suspected of being carcinogenic, are listed in table 11. The list includes certain compounds which most probably contribute to the pathogenesis of the various cancers discussed in the other sec- tions of this chapter. Many other agents have been identified in tobacco and tobacco smoke. At the present time, they do not appear to bear a direct relationship to carcinogenesis. Stedman (262) and Wynder and Hoffmann (S19) provide detailed listings and discus- sions concerning these materials. 284 1068, &uLopslcd mt Nonsmokom . . . :, , . , . , , . . , , . . . , , . . .-. . . . ,y. ,:. , . Norwn~ 84.0. (89) cludo tbas Cnde Institute Pl9e . . * , . , *, , , * . . . . * , , , , . . . . . . . , , . . . . , , , . . , . , . , , , , , 80.6 (20) amoklng Inn trio). on whom All cigarette . . sg . . . . . . . . . . an..., . . . . . . . . . . . . . ..t...... . . . . 78.0 (88) than or equal Lo smoking data Clgsrdtps per day: 6 gram. per dry. was available. 6-14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70.0 (23) ) 16-26 ..1...............III.....,I.....I........,....I....1. 90.0 (10) X6 ,.....,,,.,,.............,.,,,I..,,...,........,..,,..,. 100.0 (6) Knudtson, 100 D,ci-eOna 1960. Pncmt 01 colu with: AlVgLXl Age. occuuntlon. 23-86 yesrd No. of NO U.S.A. Baaal cell Squomour g+olilc+aliuo and site or of age PCWXl4 (147). change hvrm&da WWt&WiG mct4ula8ia rcaldencs were autwsied at Nonsmokers . . , , , . . . . . ,, . (21) 47.6 26.6 14.8 9.6 senwc Clgarettea/drr: found to hevr DO Veterans rDprccl&lls l-9 . . . , . * * . . . . , . . , . , (9) 77.0 11.1 11.1 Hospital on lo-16 eflcct. .*.*..*,......... (11) . . 18.2 18.2 64.6 9.1 whom 16-20 .*.*..*,,..,,.,,. (44) 20.4 29.6 28.6 20.6 amoklng >21 , . . . *. . . . ,. ,. ., ,. , (9) 11.1 88.8 data WLI 44.4 11.1 Pipe or clgw I....I`.,,,. (6) . . 100.0 ~Vllll~!Jl`Z. . . . . TABLE IO.-Pathologic and cytologic findings in the traclreo-bronchial tree of smokers and nonsmokers (cont.) (Actual number of cues ahown in psrenthna) Author, Y-r. NE%f countrY, method of RcauPd C0mfTlentd rofernee aelretion Auerbach 339 pcreons Number oj Percent rectionr Pcrcmt secfiow The authora noted. et al.. 22-88 ye.m Numbrr rcctimu with cilia ablent with some dcdcrrsvonse lx- 1961, U.S.A. (If). of age mJtopalcd nt Enst Orange Veterans HOSDitAl (excludes lung CUtCW), Nonamokcn: ot perswu 01 bronchial and entirclu cpithelium atypical cell4 atypical cella and cilia absent <40 yean of .ge . .*. . . . . . . . . . . a 4&69 ,.. ., ., ., . . .I .., . . ., , . . ,. 11 6049 . . . , .a . . . ,. . . . , , ., . 28 >70 .,..........,.,..,,*.,,...... 18 Smokera 70 . . . , . . . . . . . , . . . , , ., 22 Smokers >l pack/day: 70 .,..,.,`.........,. ,,.,, ,,.., 16 383 660 1,463 918 . 0.3 0.1 0.6 121 0.1 4.1 1,240 1.0 16.9 1,772 0.6 10.8 1,101 0.6 9.4 lath of smoking Lo: a, lose al clllr., b. lncrearc In number of atypical ceh. c. carcinoma in ailu. Averbgc number of aectiona per oil0 e~uald 62.3. am 1.6 12.6 3.027 4.6 11.4 4.186 6.3 20.6 766 9.8 23.7 CKW 140 personr Pcrcnlt rectiou showing chunpta in bronchi& rpilhclium (number 01 mcctionr) t The nuthOr8 noted et al.. autopeicd at S.Jl`flt?lOW AlVpicd Carcinoma that thr diflcra lP61, Iowa City Normal Ilyvcrp,liuia mct,lvla4ia rnCt4Vhlia in aitv Crrrcitwmo ence bclxccn U.S.A. VpterU!I~ Nonamoken (al) ..II,..I.. Gl(GC2) X(131) a (33) tl6(68) . . . . .a.. smokers and non. (64). iioaplt.1 Smokera (109) .,,,......... 44(670) 43(662) 16(197) 20(263) l(12) 2.6(34) amokera W~I on whom ,t~llC,liC~lllY smohinr algnlncsl~t. data WBI available. TADLE 10.~Pntlrologic and cytologic findings in the traclreo-bronchial tree of smokers and nomnokcrs (cmt.) (Aclual nurnbcr uf cose4 ahown in vnrcnttwn) Author. Numbrr of Year, CQ~ES nnd c""ntlY. method of ncsulta Commcnls reference selcclion AUCrbaCh 72 sulopsicd Nurnbcr of Pcrccnt scctim~ Pnccnt scclims Percent rrctiow Each cx-smoker et al., former ciga- acctiona Of with cilia obacnt tuitJ~ smncalvpi- with 60 gerccnt matched with a 1962. rette smokers brmtcAia1 and cnlircly U.S.A. cd ecu4 and atypical cell4 CUI~C~L smoker who had been Number epill~clium alvpical cella (II). cilia abrent and ciiia grerrnt vlua never-smoker smoking for Nonsmokers . , , , . . , 72 3,156 0.0 0.1 0.6 for ape, oceuvn- 210 years EIxx-amokerr . , , . 12 3.436 0.2 0.9 2.6 tion. and rcsl- and had Current amoken . . . 72 3,537 8.0 18.0 80.8 dcnce. There wu ceased *n llb'ernge of 26 yetll-8 .*o. GO.3 e.CCtlDna vcr subject nnd none had leas than 18 sections. TABLE lo.-Pathologic and cytologic findings in the trachea-bronchial tree of smokers and nonsmokers (cant,) (Acluul number ol CLI(CB ahown In pnrenthraca) AUthW. Number of Year. CLSCB and CO"l-htCJ. mcthnd of Ihulta Cummcnld rctcrcnce sclrclian Auerbrch 466 male and Prreed #cc- Percc?d ,CC. Percent ICC. Major llndlnrs ct al.. 302 fcmnle Number of tionr utith tion.4 with lion4 wit.4 50 lW1d: 1962, amokera rnd rccliotu 01 cilia abacnt U.S.A. 80md afypi- prtccd alylricnl Urbun nonamokcrn nonsmoken brachial and nltircly cd cell1 and (13). cdl, and ghowrd more ~u~opaled nnd Number epithetturn ulvpicol cell8 cilia abrmt cilia prrrmt lesion than rure.l. mntched for blslea: Both lmlona and we. OCC". Nonemokcrs 1. ,. . ,,`.. . 41 2,346 0.1 0.1 ._LY9iCII nuclei DatiOn, and Cigarette amokera . . . , . 1 76 3.303 62 21.2 78.6 were much lrw residence. Females: ,, 2reQucnt In nan- Nonamokcn . . . . . . , . . . . 41 2.919 . 0.1 0.6 nmokem and lcae Cisarettc smokera , , , . , 76 3,607 2.6 13.8 62.6 Ireclucnt In plvc Mlll~: snd cigar amokera Nonsmokers . .s,, , , . . . . 36 1,106 . . 0.2 0.5 thnn In clgareltc Cimr smokers , , , . , ,. , . 86 1,133 0.8 10.0 10.7 smokera. Clsaretteamokera . . . . . . 36 1,62t 12.6 27.8 89.1 K'I.I$`O of e.ara h&d 6b66 sectiona al.ayfo of cuea had 40-40 arclions 7.370 01 CBBNI had 30-s asctiona 4.6% of cn~rtl hrd 16-20 scctlwls Robbina, 103 students -^_ Percent in rwh evtolollio ctddr Smokora drilncd LLI 1ICC. 11-24 years U.S.A. Slightly Modrratclv Strongly those hnvlnu con- of aze who NOWWl (PPO. afvpicd l7!YPiCOl 4tupical #urned 210 ciye- underwent Nonamokera (46) . . . . * .*,.. ~ ..,.... 86.1 4.4 a.9 aerosol Smokers (68) rsttn n dw for I. *.* . . *.,,.......,,, 66.2 32.8 10.8 1.7 21 Ye*?. sputum induction. I Aulhar. Number of year. COHPI~ nnd cowltrY. method of rcfcrcnce srlrctlon Results Commcnla Number Pcrcmt rhmuinn mrlolrla#ia 234 41.16 189 41.09 886 61.43 93 6 I .29 38 CO.29 Nasiell. 60 nanamoklng Sputum cvlologic ehanpca Pcrcrnt ruilh t RlKilrdiYl by 19G8. wtpnlicnt~. l'crcL71t Percent with alvpicd author a8 "rcrl Sweden 398 smukera Number nra1c1 Airan aye mclnphrio mclapluriat vrcmnliununt (ISA). parMpr.ting Nonsmokers . , . . . , 60 42 67.1 18 4 chsnyc." In wneral Smokers . . . , , . . , . . 398 73 kG.6 62 27 health exam- lnation who underwent suutum induction. Spnin 167 males and Number Prrccnt with mc(apkuia The authors found et PI., 78 femsles AldeB: no evidcnrc of 1970. autopsied foL Nonamokera . ., . . . . . . . . . . . . . . . . . . . . . ., a.. , . ., , 36 60.0 carcinoma in rilu U.S.A. lowing sudden Ex-smokers . . . . . . . . . . (. . . . . . . . . . . ,. . . , . . . . . . . . , , (. . . ,. . . . 2~ 67.7 Or DrenCOVh8lk (258). or accidental <1 wck .I. . . . . . . ..t I... . . . . . . . . . . . . . . . . . ,, . . . . . . . . . . . . . 32 62.6 &LYpicnl ctinngca. dcnth for >I pack . . . . . . . . . . . . . . . . . . . . ,.....I... . . . . ,..,..,,..,,,..,,, , 68 13.6 whom smok- Females: ing data were Nonsmokera . . . . . . . . . . . . , . . . . . . . . . +. . , , , , , . 34 34.1 available (ex. l pndc . . , ,, ,. . , . . . . ., . . . ., ..~. . . . . . . . . .., 46.1 eluded from female data). In order to facilitate understanding of the relationships of the various compounds to one another, the third column presents the presently understood relative importance of each of the various groups of compounds. These compounds have been tested only in animals or tissue cultures, and it should be stressed that the rela- tive importance of one compound may not be the same in man as it is in animals. Table 11 is divided into two major sections. The first section details those compounds which are considered to be or are suspected of being cancer initiators. These are compounds which induce irreversible changes in responsive cells. In the second section are listed those compounds which are considered to be or are suspected of being tumor promoters. These compounds promote the maI%- nant reproduction of cells in which neoplastic changes have been initiated. A number of these initiators may also act as complete carcinogens in their own right. The evidence concerning the two stage initiation-promotion mechanism is still rather limited for respiratory tract carcinogenesis. The polynuclear aromatic hydrocarbons (PAH) listed are pres- ently considered to pIay a very significant role in pulmonary car- cinogenesis due to tobacco smoking. These compounds act as tumor initiators or complete carcinogens. The particular role of these agents in environmental and occupational carcinogenesis has been reviewed by Falk, et al. (93). That such hydrocarbons are pro- duced from tobacco during human smoking has been shown by Kiryu and Kuratsune (146). These authors reported the presence of benz[a]anthracene, chrysene, benzo[a]pyrene, and benzo- [blfluoranthene in the "tar" produced by normal smoking and measured in either filters or stubs. Two hydrocarbons which have frequently appeared in the litera- ture on experimental tobacco carcinogenesis may not actually be present in tobacco smoke. They have been used as representatives of carcinogenic PAH, a class which includes many constituents that have been identified in cigarette smoke condensate. They-ai-e 7,12-dimethylbenz[a]anthracene and 3-methylcholanthrene and have been frequently used as tumor initiators or complete carcino- gens, parCcuIarly in skin painting and tracheal impIantation experiments. The nitrosamine compounds listed are potent carcinogens affect- ing many organ systems, including the respiratory tract (188, 189). hlagee and Barnes (181) have presented a detailed account of experiments in this area. Nitrosamines have been identified in trace amounts in tobacco "tar" and the conditions required for their formation (the presence of secondary amines and nitric oxide) are 290 TABLE IL-Identified or suspected tumorigenic agents in cigarette smoke' I. Complete urcioantna and tumor initiators: I'olynuclar mromatic hydrocarbons ........ 1. Bcnw(~)p9rene .................... 2. Dibcnrlr.h)snthmcene .............. 3. Bcnu,(b)fluaranthene ............... 4. Bcnw( j)fluoranthenc ............... S.Dibenzo(a.i)pyrene ................. 6. Benz(a)anthracene ................. 7. Chrvsene ........................... 8. Indena(l.2.3.cd)pyrene .............. 9. Ben7.o(c)pheoanthrcne~ ............. 10. ~cthylbenra(.)pyrc"es ............. 11. MethylcblTsenea .................... X0-30 UP 3.3 0.4 0.3 0.6 Trace 0.3 2.0 0.6 TTllCC 0.1 2.0 N-heterocyclic hydrocarbons .............. 1. Dibenrls.h)acridine ................ Z.Dibenr(a.j)ncridine ................. 3.7Hdlb~zo(c.z)carbarole ........... N-nitrossmio~a ......................... 1-2 0.01 1.0 0.07 l-10 1. Dimetb~lnitrosnmine ................ 0.4 2. Diethylnicroae.mine ................. TlTLC-2 3. ~lethpl-n-butylnitro.aminc ........... TWlCTZ 4. Nitraopyrrolidine .................. 0.4 5. Nitrosopipcridine ................... T0TC.Z Epoxidea. perory compound% and lactones: 1. Eporides ........................... 2. Peroxides .......................... 3.Lkctones ........................... L. ,-Levantenolide ................ b. p-Levantenolide ................ No data Present . 20.0 2.0 N-alkyl-hcterocyclics: 1. I-methylindole ...................... Paticidn and fungicides:' l.TDE ............................... Z-c,.;-DDD ........................... 3.DDT ............................... 4. Malcic bydrrzide .................... BeLwnsphthylamine ...................... Present Possible initiator. No essential contribution sus9eetcd. 10-100 10.100 10-100 10-100 2-3 Tumor initiators. Tumor initial-am. ~uspcrted carcinonens of possible im~artance (presence in fresh smoke possible). Certain of these compounds are known carcinogens; presence in smoke condensate not established. Suspected bladder carcinosen: of doubtful significance at reported Iev&. Polonium 210 _. . . _. . . . . . . ..-- 1.60 Of .90me importance only in the gicocuriea caz.e of relatively high conix~n- trslion. but not impo&nt at reported levch. TABLE Il.-Zdentified or suspcctcd tumorigenic agents in cigorettc smoke' (cont.) II. Tumor promotinp nnenta: Neutral pmmotur (polmera) (unboan ,tructuren.) No data Of pwsible importance. VoLtilc pbm& . . . . . . . . . . . . . . . . . . . . . . . . . 20.30 my. Of porGble immxtance. 1. Phenol 2. cresc.1 Nonvolatile fatty s&da . _. . _. . . _. . . . 20-100 mu. Of minor importance. 1. St.sric acid 2. Oleic acid N-dkyl heterocfdics: Of possible imwrtancc. 1. S-mstbylcrrbarole . . . . . . . . . . . . . . . . Present found in tobacco smoke (38). However, nitrosamines may be arti- facts dependent on the method of smoke collection (201). Neurath (202) considers the `nitrosamines listed in table 11 as being present in fresh cigarette smoke (253, 254). However, con- clusive confirmation of their presence in fresh smoke is not available (38,138,155,319). Certain of the pesticides and fungicides presently in use on tobacco have been found to be carcinogenic (91,273,280). A num- ber of these, such as DDT, are now being phased out of regular domestic use. The compounds listed have been shown to be present in trace amounts in mainstream tobacco smoke (1 II, 128). A recent, extensive review by Guthrie (111) provides more detailed informa- tion concerning these agents. Radioactive isotopes can be found in tobacco and tobacco smoke (205). Potassium-40, while present in tobacco leaf, is not trans- mitted in any substantial amount to mainstream smoke (230). Polonium-210 ( PoZID) , however, is transmitted into the mainstream smoke (94, 123, 142,145, 215,217). A number of autopsy studies (table AI2) have shown that the bronchial epithelium of smokers contains significantly more Po~,~ than that of nonsmokers. Littie, et al. (172, 173, 174) have also noted that the concentration of polonium was markedly higher at sites of bronchial bifurcation. These authors stress the importance of this finding for pulmonary carcinogenesis by noting that bronchogenic carcinomas are fre- 292 quently located at bifurcations and that the polonium levels which they found in those regions probably have biologic significance (216). Other investigators (12.3, 217) have not observed this excess at bifurcations, and in a recent discussion Wynder and Hoff- mann (320) concluded that it appears unlikely that Poz10 in the amounts present in cigarette smoke plays a role in tobacco car- cinogenesis. Although not listed as a separate group, there are a number of agents in cigarette smoke which are potent inhibitors of ciliary movement. Their importance in carcinogenesis derives from the increased amount of time which they afford the known carcinogens to be present on the surface of the bronchial epithelium. These inhibitors include volatiIe aldehydes, hydrogen cyanide, nitrogen oxides, volatile phenols, and certain volatile acids such as formic and acetic (129). Expen`mental Studies In some respects, the animal and tissue culture studies detailed below apply to neoplastic transformations, not only in the lung but in other tissues in which tobacco smoke, particularly cigarette smoke, is believed to play a role. These general experiments will be presented here, however, with the experiments which bear on lung tissue directly. Skin Painting and Subcutaneous In.jection Numerous animal studies on rats, mice, and rabbits, have been performed utilizing known carcinogens, whole tobacco "tar," and various tobacco condensate subfractions, or compounds known to be present in tobacco smoke. These experiments involve the single or repeated painting of shaved or unshaved animal skin. A seIected number of these studies is presented in table A13. Numerous other studies, performed prior to and following 1953, are reviewed by Wnder and Hoffmann (319). -. The skin painting method is still considered to be a valid pro- cedure for the identification of agents suspected of participating in pulmonary carcinogenesis, as well as for the quantification of the reduction in tumorgenicity of specific agents. Tiss-ue and Organ Culture The exposure of tissue and organ cultures to cigarette smoke, its condensates, or its constituent compounds has been shown to sig- nificantly alter patterns of cell growth and reproduction. Table Al4 presents an outline of these experiments. Once again, less severe effects have been noted when filtered smoke was used (165). 293 Tracheobronchial Implantation and instillation More complex experiments concerning the carcinogenicity of cigarette and tobacco smoke are represented by those which involve the direct implantation, instillation, or fixation of suspected ma- terials into the tracheobronchial tree of animals. Certain of these experiments are outlined in table A15. Recent reviews by Saffiotti (233,2.3:) Laskin, et al. (159). and hiontesano, et al. (189) as well as that by Wynder and Hoffmann (319) provide more detailed and extensive accounts of these experiments. Of note among the results outlined in this table are the following: The enhanced carcinogenicity found when benzo[a]pyrene (B[a]P) is combined with a carrier such as hematite dust (235), and the definite increase in bronchial epithelial preneoplastic and neo- plastic changes among dogs treated with smoke condensate as com- pared with those undergoing only physical bronchial stimulation (2%). Inhalation Various species, including mice, rats, hamsters, and dogs, have been exposed to cigarette smoke or aerosols of its constituents. These inhalation experiments are outlined in table Al& It must be noted that the majority of the studies listed involve the passive inhalation of the material presented usually in a chamber. Active inhalation experiments, exemplified by the work of Rockey and Speer (223) and Auerbach and his colleagues (II, ff9) involved animals which were trained to inhale voluntarily, thus more closely simulating human smoking. Results of note among these experiments include the following: Miihlbock (195) observed that cigarette smoke inhalation en- hances the already substantial rate of spontaneous alveolar cell carcinoma formation in hybrid mice, and various investigators in- duced adenomas in experimental animals (108, 168, 206). Harris and Negroni (121) found that exposure to cigarette smoke achieved some enhancement of adenocarcinoma formation in mice but did not observe proven squamous cell carcinoma. Some of their mice had also been exposed to Swine influenza virus aerosol. In a related study, Boren (32) exposed hamsters to cigarette smoke at set inter- vals over a 48-hour period. The author observed alterations in pul- monary cell kinetics (the pattern of DNA synthesis) as demon- strated by H3-thymidine autoradiography. The pattern of the label- ing response to cigarette smoke was significantly different from that of the response to high oxygen concentrations. Auerbach, et al. (11) have reported the development of early 294 invasive squamous cell bronchogenic carcinoma in dogs following a period of direct inhalation of cigarette smoke. These investiga- tors trained beagle dogs to inhale cigarette smoke through a tracheostoma (50) and divided the anima!s into groups according to dosage as detailed in table 17. A number of dogs died during the course of the experiment which ran for 875 days, or approximately 29 months. The causes of death are listed in table 18. All of the remaining dogs, with the exception of group "h" (high exposure, heavy weight), were sacrificed shortly after day 875; the survivors among the heavier dogs are continuing to smoke. Examination of the respiratory tree of the animals revealed a number of tumors (table 19). Most of these were similar to the type of tumor which in man is referred to as bronchiole-alveolar. This tumor arises in the bronchiolar and alveolar epithelium and tends to be multicentric. Two striking characteristics of these bronchiolo- alveolar tumors were the existence of a histologic spectrum (from a tumor resembling the benign condition of adenosis to frankly malignant tumors with invasion of the pleura and surrounding parenchyma) and the marked tendency to squamous change. Inva- sive bronchiole-alveolar tumors were found in 12 dogs in the group which had been exposed to the largest dosage of cigarette smoke. Several had tumors of more than one category. Ten of these dogs had invasivee bronchiole-alveolar tumors which did not extend into the pleura, one dog had an invasive bronchiole-alveolar tumor which extended to the pleura, and four had invasive bronchiolo- alveolar tumors extending into the pieura beyond the pleural- pulmonary junctions. In addition, two bronchogenic squamous cell carcinomas \r-ere found in this group (table 19). The dosage de- pendence of tumor formation is shown in figures 2 and 3. Major findings of the study were twofold. First, that smoking filter-tip cigarettes was less harmful, both in terms of pulmonary parenchymal damage and lung tumors, than smoking identical cigarettes without filters. This supports the generally held view that total particulate matter is a meaningful indicator of the car- cinogenic potential of a cigarette. Second, lung cancer of two types found in man was produced by the inhalation of cigarette smoke. Two of the dogs were found to have early invasive squamous cell carcinoma of the bronchus, and both belonged to the high-dosage group. These carcinomas were indistinguishable from early invasive squamous cell carcinomas found in the bronchial tubes of human beings who smoke cigarettes. The majority of tumors found in the dogs lvere of a bronchiole-alveolar type, which although not as common as squamous cell cancer in man, is not rare in humans. This type is often included in the category of adenocarcinoma. A number of studies have shown an excess of these tumors among 295 TILE 17.-Data on pcdigrecd male beagle dogs of groups F, L, H, h, and N (Some of the figures (rnuly only lo doga surviving 876 dwa or longer) Filter I-E, group oroup F L 12 12 26.0 26.1 6,143 3,103 7.02 3.64 42.1 21.2 17.8 34.8 1.11 1.86 109.3 103.6 1.19 6.66 4.31 4.12 0.29 0.22 NO nikr grO"p II 2b 26.0 6.1'28 7.0 42.0 34.8 1.85 207.8 11.12 0.91 0.44 fEr Nonsmokera ETOUP YP N a0 0 al.9 SO.7 E.129 no,is 7.0 - a2.9 - 84.8 - 1.86 - 207.8 - 11.12 - 6.61 - o.aa - ' The smoking doga wetc divided Into grwDe F, L. H, and h on day No. 67. ' Dogs of gwunl L. ii, snd h amok& hltcr.tiD clgarcttcs during B training period nt the start of tbc uporlment. but amoktd nonfilter clU&retttl tbcrcaf'er. SUUHCE: Adardrd from lIammond, E. C. et hl. (110). TABLIZ l&-Summary of principal cause of death (&us No. 57 through No. 875) in dogs of groups F, L, H, h, and N (Each death clwained according to m&st scvcre condition--eome doas diad ol a combinstion uf ce,uses listed) Filter NO No tip filter nltcr n% Principal C.USC of death N~~~y;;cra Croup c TO" p C;oiuD Cr"UD Total F I, h N Pulmonwy emphysema nnd fibrosis . . . . . . . . . . . . . . . . . . . . . - 2 Cur pulmunale (pulmonary emphysema and fibrosis with - - 2 right heart enlargement) . . . . . . . . . . . . . . . . . . . . - 3 Pulmonary infarction . . . . . . . . . . , . . . . .,. - 6 8 1 1 2 Broncho~neumonla ..,.,...,..,........,......,,..,.... 6 - 9 - 3 Aauir&tion of food . . . . . . . . ., . . . . . . . . . . . . . . . . . ,... , . . - 1 - 4 1 1 VnCWtsi" - - 2 . . . . . . . . . . ..1............................... 2 Number of deatha . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . - 1 - a 2 2 12 Number surviving 876 dam 12 20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 10 Total number of dogs 12 26 0 66 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 12 24 38 8 84 SOURCE: Hammond, E. C. et al. (111). TABLETS.- Data on dogs with lung tumors indicating type of tumor and lobe in which tile tltmor wae found CIOUD %xf N%bcr &c at Early n~u~lnou dCBlb Lubcn wiLh bmnchialo-rlv~~~~i~mo~ ccl1 bmnchlnl cignrcttcs (Years) Non-invnoive CnKIrIUma 9048 904b - 6.1 4.0 LA IU 8788 6,161 6.1 879a 6.170 4.1 8868 G.224 6.2 890a 6.269 5.4 LA LA LA LA 347 1.055 3.8 LA. LC 812 2,847 6.1 I1A 876n 3,103 6.1 LA,RA 8778 3,107 6.2 LA.LC 8R2a 3.127 1.2 LA, LD Aclria 3.lh3 6.3 I.h, l(D 8lJliu 3,I'JG 6.4 l.h 6IH 2.L l.:i4:I 3..1 3.404 47 4.6nv 6.0 s.o:io 3n G.lJKH 4.2 6.970 13 G.l'LY I.9 G. I :I" 6.1 C,l47 6.3 6,1X3 6.4 6,192 4.7 C,?IO 6.0 6.246 6.0 6.255 I.9 6.?73 6.7 6.273 6.3 G.3lX 6.2 G.3lR 4.6 IIC: I.h. RA, 1tn 1.11. IlA I(1 1.A L A . LA LC.RA ItA LC - - - - - - - - LA 1.h. Ilh, IlD -_ - LA. 1.1). IlA LA LA - LA LA, KA LA - - LA, 11A - LA - - - - - - - - - - - - -. - .- -. - - LAUII - - -- L51U -- - -. - - TABLE l&-Data on dogs with lung tumors indicating type of tumor and lobe in which the tumor was found (cont.) Number of cigarettes hKC at death (Years) CrOUD h (no filter) . . ...* . . . . . . . . . . a..... h 606 3,761 4.6 LA - h 626 3,928 4.4 LA, RI - h 649 4.143 5.0 iI LA, RA - h 794 5,400 5.1 LA, RA - - LA. left apical lobe; LC, left cardiac: LD left diaphrsgmatic; RA, risht spicnl: RC. ripbt cardiac; RI, right intermediate; RD, right dinpbragmatic; LAUD. left nuical branch bronchus; LMB. left main bronchus. start of smoking. The letter "a" or "b" follows the day of dcutb of doga sacrilicetl after day #876. For smoking dopa, the day of death indicates the number of days since SOURCE: Auerbach. 0. et al. (I!), 58.3 -- - -..--- GROUP N: NONSMOKING GROUP F: GROUP L: GROUP H: FILTER-TIP NO FILTER NO FILTER (I/Z a* many ciparrtlcs) .s Group H i i ;:i TUMORS 2 4 7 19 DOGS -ii 12 i;i Fi FIGURE 2.-Percent of smoking dogs with tumors. SOURCE: Adapted from Auerbach. O., et al. (11). 60 s 4 40 b s Y 20.8 _ s & 20 0 GROUP N: GROUP F: GROUP L: GROUP H: NONSMOKERS FILTER-TIP NO FILTER NO FILTER (`A as many cigIrstta) II Grout H TUMORS 2 4 12 35 LOBES M SC sr 1-z FIGURE J.-percent of lung lobes with tumors in smoking dogs. SOURCE: Adapted from Auerbach, 0.. et al. (11). 300 cigarette smokers (6, ~2, 11.2). but the magnitude of this reiation- ship is not as great as that with squamous cell cancer in man. Reduction in Tumorigenicity The importance of reducing total particulate matter in cigarette smoke is reflected in the dose-dependent results of the Auerbach- Hammond study. A major objective of experimental tobacco car- cinogenesis must be the reduction in the tumorigenicity of cigarette smoke and other tobacco products. In a recent article (320). Wynder and Hoffmann have reviewed the various methods applied to achieve this goal. Among these methods are the modification of the tobacco itself, the modification of the conditions of tobacco pyrolysis, the use of additives, and the use of fiIters. The use of filters shouId produce a reduction of particulate matter as well as of gas phase components. Brass (14) studied 974 cases of lung cancer at Roswell Park Nemorial Institute and concluded that smokers who switched to filter cigarettes showed a decreased risk of developing lung cancer. However, even after switching, heavy smokers were still found to have a mortality risk five times that of nonsmokers. More recently, Wynder, et al. (324) reported on an interview study of 350 patients with histologically confirmed lung cancer and 552 age and sex-matched controls. They found that subjects who had switched from nonfilter to filter cigarettes ten or more years prior to the study incurred a lower relative risk of lung cancer at all consumption levels than that incurred by those who continued to smoke nonfilter cigarettes. The authors suggest that this difference in relative risk may be due to the lower "tar" content in filter cigarette smoke. Prospective studies concerning the effects of filter cigarette smoking are presently being conducted. Apart from variations in "tar" exposure due to filtration, it appears that different patterns of smoking result in the inhalation of varied amounts of "tar." Graham, et al. (103) simulated dif- ferent inhalation patterns with the use of an analytic smoking ma-- chine. He found that smoking a given number of puffs over a long period of time results in greater "tar" retrieval than smoking them over a short period. Also, he observed that taking most of the puffs at the end of the cigarette results in the highest retrieval while taking most at the beginning results in the smallest retrieval. Complementing these observations is the same author's case/con- trol study (102) of 183 men with lung cancer and 161 men with diseases not related to tobacco smoking. He found that the lung cancer patients had significantly greater high "tar" yield cigar&e smoking patterns than the controls. The risk of lung cancer was found to increase with the increase in mean number of puffs per 301 cigarette, the average length of time taken to sm.k,-t :a cign~tZc (except in the highest number of puffs category), ti:ti, ;be rAki,% of more puffs at the end of the cigarette. These findings, and those of the study of Xuerbrrhh .I: :>, !, ~.i,j, add further support to the dose-response relationsti:, i~et~c?en- Cung, cancer and total cigarette smoke condensate expo~.rr~~.r:. SUXSIARY AND CONCLUSIONS 1. Epidemiological evidence derived from a numo::?-.C nrc:~+n~:- tive and retrospective studies coupled with experimm the main cause of lung cancer in men. These stud& yz'i-,<&~-a~ -;he risk of developing lung cancer increases with the mFizr,of. cigar: ettes smoked per day, the duration of smoking, an!:e:nCier iniaia- tion, and diminishes with cessation of smoking. 2. Cigarette smoking is a cause of lung cancel 5 xmm @rrt accounts for a smaller proportion of cases than in LF:Z, Y%: ZXX- tality rates for women who smoke, although sigti:it:zr;Jp h&iier than for female nonsmokers, are lower than for r?xtn ~dcssmok;l This difference may be at least partialIy attributed :`D ~.Lf%r~nt?r ia exposure; such as, the use of fewer cigarettes per rtiy ~ t&e :rse `3s filtered and low "tar" cigarettes, and lower level3 #& irr%a!a:ion. Nevertheless, even when women are compared w&F men v&o a?- parently have similar levels of exposure to cigar&z smoke, the mortality ratios appear to be lower in women. 3. The risk of developing lung cancer among p$e aridG>or ciwr smokers is higher than for nonsmokers but signifi~l~~:~~~~~;\re~~ &-ran for cigarette smokers. 4. The risk of developing lung cancer appears to5ehighur amor.g smokers who smoke high "tar" cigarettes or smokt in- ~~uh~a.rna~~ti ner as to produce higher levels of "tar" in the inhaM smoke.. 5. Ex-cigarette smokers have significantly lower &aUr -rates-for lung cancer than continuing smokers. There is evi&nc~~%u support the view that cessation of smoking by Iarge nurnbz=, s.f &`garette smokers would be followed by lower lung cancer &a~&: CYL%& 6. Increased death rates from lung cancer ham: 4ezz ;Itlssrved among urban populations when compared with pq~~~$~~ns~ from rural environments. The evidence concerning the rzitt $2 :tir poi'iu- tion in the etiology of lung cancer is presently incolc,r&si~~ FBctitrs such as occupational and smoking habit difference may- z&o. cm- tribute to the urban-rural difference observed. D&;+d. epjdcmio- logic surveys have shown that the urban factor ~xexi;s a smalI influence compared to the overriding effect of cig~.~~:e~ ~mok;hg in the development of lung cancer. 302 7. Certain occupational esposures have been found to be asso- ciated with an increased risk of dying from lung cancer. Cigarette smoking interacts with these esposures in the pathogen&s of lung cancer so as to produce very much higher lung cancer death rates in those cigarette smokers who are also exposed to such substances. 8. Experimental studies on animals utilizing skin painting, tracheal instillation or implantation, and inhalation of cigarette smoke or its component compounds, have confirmed the presence of complete carcinogens as well as tumor initiators and promoters in tobacco smoke. Lung cancer has been found in dogs exposed to the inhalation of cigarette smoke over a period of more than two years. CANCEROFTHELARYNX Cancer of the larynx is a disease which predominantly affects males in the 55 to 70 year age group. In 1967, a total of 2,468 males and 329 females died of laryngeal cancer in the United States. With the development and application of more effective therapy during the past 30 years, the death rate for cancer of the larynx appears to he dropping slightly (288, 289) ; however, the incidence con- tinues to rise. Figures from the Connecticut Cancer Registry (88) show that the age-adjusted incidence per 100,000 population of cancer of the larynx for males rose from 3.0 in 1950 to 5.6 in 1961. EPIDEMIOLOGICALSTUDIES A number of epidemiological studies have investigated the rela- tionship between smoking habits and the development of cancer of the larynx. The major prospective studies, as outlined in table 20, show that smokers of cigarettes run an approximately six-to- tenfold risk of dying from this form of cancer as compared to non- smokers. Smokers of pipes and cigars incur a three-to-sevenfoId risk. The retrospective studies listed in table A21 uniformly show fewer nonsmokers and more smokers among cases with cancer of the larynx than among matched controls. Table A22 summarizes- the relative risk ratios derived from the retrospective studies. The wide variation is due to a number of factors, including type of pop- lation and interview technique. But, in general, the magnitude of most of these ratios is of the same order as in the prospective studies. Wynder, et al. (31.2) have distinguished between cancer of the intrinsic and extrinsic larynx. Tumors arising on the vocal cords are classified as intrinsic and constitute approximately 70 percent of the lesions. The extrinsic larynx is composed of those sections of the larynx excluding the vocal cords and may also be referred to as 303 w 0 4. TABLE 20.--Laryngeal cancer vtortalit2/ ratios (Actual number of drnths shown in pnrenthc-ses)' Shf = Smukcrs. NS = Nonsmukcra. Prospective etudica Author. Y-2&*. country, Number and Data type of collcctlon FOUOW- U" Cizarcttes/dny Plpea, cleara Comments rcfrrr"cc DOPUlUllO" y&w dr1rtha Hammond 187.763 whlta Qucntlo""nlrs n'/JJ 24 Clgnrcttc smokers 11124. Cigar Dntn rcfsrring to mortality and males 60-68 and follow- `. s,v .24 3/24 rntlo i"Cl~~dCd ennccr of Hot", ycal-8 of age UP of Jcnth NS 0 Mizcd csophagua nnd mouth. 1966, In 9 statea. certificate. 4124 U.S.A. (IrnOl. Doll and Appr0ximatd.y Qutstlonnaire 10 16 All rmokcra by amount t Includea data on BX- Hill, Pipe and cigart 41,000 male and follow- SM ..16 in gramr NS .,.. 1.00 smokem of pipes and clunra. 1964, British "P of death NS 0 NS . . . . . . . . . . a.. . . SM . 6.00 Crut No NS died of lnr~n.geo- Dhysicinna. certificate. l-14 . . . . . . . . . . . . 1.00 BriWn tracheal esnccr, therefore 16-24 ( 71) . . . . . . . . . . . 1.00 l-14 pram SbI set 08 1.00 >?G . . . . . . ,. 4. . . . 7.60 rtrndsrd. Data combinc leryn~csl md tracheal carcinoma. Kahn U.S. male PucBtlonnorre 8% 64 NS (Darn), . . . . . . . . 1.00 (8) Pipe Refers to cu~`rc"t cipurcttc veterana, and follow- Shf .61 l-9 1866, . . . . . . ..a.... 3.27 (1) NS . . . . 1.00 (3) amokera only. 2.266.674 UP of deeth NS 3 U.S.A. la-20 , ., ., ,, ** *. * 8.46(10) SM . ...10.33 (6) Pwm" yean. ccrtlflcate. 21-39 (ISO). . . . . . . . . . . . 19.62(11) Pipe 4nd cigar >39 . ., .I ., .,, . .16.85 (3) NS .a. 1.00 (3) All . . . . . . . . . . . . . . fI.D5(26) SM .,. 7.28(11) Iinmmond. 440,658 mnln Interviewa 4 G7 1966, NS Male data only. 662.671 fe . . ..I. ,... . . 1.00 (3) Pipe and cigar by ACS U.S.A. SM .64 males 35-84 SM (aw46-60 . . 6.09(923 NS .a.. 1.00 (8) Pipe and clpar d8ts refer to volunteera. (118). YeQrl of age NS..3 SM (ngc65-79) . . 8.99(18) Sbl . ,, , 8.87 (4) m&lea KG-84 ye*" of aIC. I" 26 atatea. TABLE ZO.--LarUngcal cancer mortality ratios (cont.) (Actual number of drnth3 shown I" psrcnthcses)l Shl = Smokars. NS = Nunamokcrs. Author, Y-2.-T, eou"trY, rrfurcnce Number and type of DoPulation Data collection Cigarettcs/daY Plpca, cigars Commcnta Weir and DU"", 1870, U.S.A. (sob). 68,163 mnle. Qucc.rlonnaire 6-8 11 NS . . . ., ,. ., , - No ncnsmoken died of In various snd follow- SM ..ll ?I10 . .I ,.. . . . . 1.00 hryn~rbl carcinuma. occupatio"s "D of death NS . o 220 . ,. ., . . . 6.99 tlivrcfitrc 210 ami,Lc,r set in California. certificate. >a0 a . . . ., 6.84 ~1s 1.00 standard. NY inch\dca ulve snd clxar amukcra. Shl includes rx.smohcja. ' Unless otherwise apecifwd. disparities between the total number of dcatha xnd the aum of the Lndivldual smokins categories arc due to the exclusion of either occasional. miscellaneous. mixed, or ex-smokers W s the hypopharyns. These authors noted that the percentage of hea\-> smokers among the patients \vith cancer of both the extrinsic and intrinsic larynx was significantI>- greater than that among controls. However, it is of interest that the excess risk of laryngeal cancer among cigar and pipe smokers in this study could be attributed to the extrinsic laryngeal group. As in studies of oral cancer, it appears that alcohol consumption should also be taken into account in studies of laryngeal cancer. Wynder, et al. (315) reported a significantly increased risk of extrinsic cancer among those with alcohol intake above 7 ounces of whiskey per day. With less than this amount, no increased risk was evident. Schwartz, et al. (%8), noted no effect in relation to alcohol intake. Further research into the interaction of these two variables is necessary. PATHOLOGICALSTUDY Auerbach, et al. (9) studied histological changes in the larynges of 942 men, age 21 to 95, who were autopsied at a single hospital between 1961 and 1967. Cases of primary cancer of the larynx \vere excluded from the study. Smoking histories for all cases were obtained from family members of the deceased by trained inter- viewers. The randomized histological sections were graded by one observer. Tables A23 and A?? summarize the findings in the true vocal cord. Of the men who never smoked, 75 percent had no cells with atypical nuclei, only 4.5 percent had sections with areas con- taining 60 to 69 percent of cells with atypical nuclei, and none had a higher percentage. The 116 ex-smokers had laryngeal histology similar to that of the nonsmokers, as far as atypical nuclei were concerned. However, disintegrating nuclei were found in 40.5 per- cent of the ex-cigarette smokers and in only 0.4 percent of the remaining cases. Only one of the 91 cigar and/or pipe smokers had no atypical cells. Three had carcinoma in situ, and one case had a section showing early invasive primary carcinoma. The highest percentage of atypical cells was found among the cigarette smokers. The proportion of cases with a high degree of cellular change increased with increased daily smoking. None of the pack-or-more-a-day smokers was free of atypical nuclei in the laryngeal epithelium. Of those who smoked two or more packs per day, 85 percent had lesions with 60 percent or more atypical cells as compared to 3 percent of the nonsmokers. Retween 10 and 18 Percent of the' cigarette smokers had areas of carcinoma in site, and 4 of the 644 cases showed early microscopic invasion. The thickness of the basal level of the true vocal cord was also directly related to the amount smoked. 306 Dmtenwill (76) has recently reported the development of an effective and practicable method by lvhich small rodents (ham- sters, rats, mice) can be exposed to long-term passive inhalation of cigarette smoke in a manner which circumvents the fatal effects of acute toxicity which ruined earlier attempts but allow-s for a dosage of smoke great enough to inpuce the development of chronic patho- logical changes. The Syrian Golden hamster was found to be the most suitable species for such inhalation experiments for several reasons : its resistance to pulmonary infections, its resistance to the effects of nicotine as compared to that of rats or certain strains of mice, and, especially, its susceptibility to develop tracheobronchial cancers after treatment with carcinogens, in contrast to its almost total freedom from the spontaneous development of these tumors. Dontenwifl demonstrated that the concentration of deposited cigarette smoke was greatest in the hamster's larynx as compared to the other portions of the exposed respiratory tract (table 25), and that the laryngeal epithelium was the tissue which underwent the greatest smoke-induced histological changes. In studying the changes in the larynx, the author differentiated five stages of epithelial change, using as his reference the Atlas of Tumor Pathology of the Armed Forces Institute of Pathology (5). Table 36, quoted by Dontenwill, describes the five types of change. They range from benign, such as epithefial hyperplasia, to pre- malignant, exemplified by pseudoepitheliomatous leukoplakia. The results of the inhalation experiment are presented in figure 4 in which a dosage-related increase in the severity of the epithelial changes is represented in graphic form. The author also reported, and depicted with photomicrographs, the finding of an early inva- sive squamous cell carcinoma. This form of cancer is the predomi- nant type involving the human larynx. SUMMARY AND CONCLUSlOSS 1. Epidemiological, experimental, and pathological studies sup- port the conclusion that cigarette smoking is a significant factor in the causation of cancer of the larynx. The rizk of developing laryngeal cancer among cigarette smokers as well as pipe and/or cigar smokers is significantly higher than among nonsmokers. The magnitude of the risk for pipe and cigar smokers is about the same order as that for cigarette smokers, or possibly slightly lower. 2. Experimental exposure to the passive inhalation of cigarette smoke has been observed to produce premalignant and malignant changes in the larynx of hamsters. 307 TABLE X.-Deposition of "C-labeled smoke particles in particular regions of the respiratoqj tract' He.d and pslate _. 6.11 Head. palate TODEUC ___ _. ._... . 0.41 Oral cavity in total. Larynx _. . . . 0.39 Trachea __ __ __ __ OX Luns, . . . . 695 I Total . . . . . .14.12 EStitlll3ted Deposition radio- of activity particles (nCi) (70) 5.6 37.4 1.6 10.9 7.6 (traced1 51.7 `14.1 100.0 0.1-0.3 X561-187 0.6 X62.3 1000 Xl TABLE 26.-Classification of the five registered stages of epithcliaI changes at the laru?ix',' Dyskeratosia (nre. mnture e..(yplcril Acnnthasls (thicken- Hyperkwntosis Parakeratosls (in. cornification ing of strntum increased complete corniRcn- changes In the hlito3i3 spinosum multi- cornification tion 0Cnuelel in nucleus Drolifcrn. cellulnr kwert (rtroturu comeum) the stratum corneum) lion yf)j;,bnxaI 1. Pachydermia (cpithelirrl hywrDlania) . . . . , . . . t t t t t 6. Pseudoe~ith.liomatous leucoptakia . . ,. . . . . . t -t t tt+ t f Symbols: t = negative: $ = mlnimnl; f = weak; ++ = medium; i-4-f = BtronE. 1 From Atlas of Tumor Pathology of the Arm& Forces Institute al Pathology. SOURCE: Adapted from Dontenwlll, W. (76). TOTAL 146 2 4 ii a IO 12 14 16 18 20 22-s-3 SMOKE WPOSURE. months . ZONE ANIMAL Q=AN~MAL LIVING O=lARYNX CANNIBALIZED FIGURE do--Effects of chronic cigarette smoke inhalation on the hamster larpx. Review of the results of the inhalation experiments: number of smoke-ex- posed animals with and without changes in the larynx, duration of smoke exposure, and number of animals still alive. SOURCE: Dontenwill, `8. (76). ORAL CANCER The cancers included in this category are those of the lips, tongue, floor of the mouth, hard and soft palate, gingiva, alveolar mucosa, buccal mucosa, and oropharyns. It is estimated that 15,000 of these cancers will be diagnosed in the United States in 1970, accounting for about 2.5 percent of the estimated 600,000 malignant neo- plasms reported (289). A variety of histological types of malig- nant neoplasms can affect these tissues, but squamous cell car- cinoma is by far the predominant type, accounting for about 90 percent of the cancers. The incidence of and mortality from oral cancers has remained steady over the past 20 to 30 years. The Connecticut Cancer Res- istry (88). which is a fairly reliable index of incidence, noted that the incidence among males remained between 15.8 and 16.3 per 100,000 population during the years from 1950-1961. Examination of mortality rates over the past 20 to 30 years (P&Z, 289) reveals a similar constancy. The apparent lack of change in mortality from oral cancer in 310 contrast to the sharp increase that took place in lung cancer rates in those years is probably due to several of the following factors. First, pipe and cigar smohing are both significantly related to can- cer of the oral cavity, and the increase in cigarette smoking among men, noted between $$O and 1955, has been, to a large degree, accompanied by corresponding reductions in the use of pipes and cigars. Second, aside from the various changes ivhich the Interna- tional Classification of Diseases (ICD) had undergone during that period, the diseases discussed above are recorded in ICD Codes 140-148 which include some neoplasms not found to be related to the use of tobacco. The various sites of cancer themselves do not contribute equally to the overall rate and are subject to widely dif- ferent cure rates, so that their contributions to the total incidence rate is different from their contribution to the overall mortality rate from oral cancer. Although more than 20,000 cancers of the oral cavity were estimated as newly diagnosed in 1967, the totai number of individuals recorded as dying from oral cancer during that year was only 6,718 (ZQO). Oral cancer occurs predominantly in people of the middle and older age groups. More than 90 percent of all oral cancers occur in persons over age 45, with the average age at time of diagnosis approximating GO. Although the majority of oral cancers occur in men, there is recent evidence that the ratio of males affected to females affected is decreasing (9.57). The use of tobacco in various forms has been associated with the development of cancer of the oral cavity and pharynx. The studies in this area of concern are truly international, many having been carried out in Asian nations as well as in the West. The major pro.specti\~e epidemiological studies have found in- creased rates of these cancers for cigarette smokers as well as for pipe and cigar smokers (see table 27). Pipe smoking, per se, has- - long been recognized as a cause of lip cancer (~91) _ The methodol- ogy and results of the numerous retrospective studies are sum- marized in tables A28 and A28a. These studies almost uniformly show significant relationships between the various forms of tobacco use and c-nsr:rs of the oral cavity and pharynx. Studies in Asi:ln I~`* +iqns have examined the prevalence or inci- dence of premalignatit ch:inge, such as oral leukoplakia, as well as that of cancer of the oral cavity. In many of these studies, forms of tobacco use not prevalent in IVestern countries have been investi- gated, including reverse smoking (in which the lighted end of the cigarette is kept in the mouth close to the palate) and the chewing 311 Number and tyne of population Data collection FOIIOW- up yea14 N"omIber Cipnrettea Pipea. cIgara Comment8 deaths Hemmond 187.783 white Qucntionnaire 3 1% 66 and mnlcs in 9 and follow-up tSN .61 Horn, stntc. 3a-Go of dcnth NS ..3 1068, ycllra of nKe. ccrtincnt.zo. U.S.A. (14'0). Doll and Ap~`rurlmntrly Quratlunrrnlre 10 10 llill, 41,000 mslc nnd follow-UP Shl . ,I9 1964. llrltirh of drbth NS ..a Crrnt physicinns. ccrtificntc. Dritain (71). Kahn U.S. msle Questionnaire B!/r 61 NS ._.... l.OO(ll) Pipe Data do not Include pharynx. (Darn), veterans. and follow-up Shl .60 tCigs/dsy 1-9 . . . , 0.8C (1) NS ..*.*.. l.OO(ll) t Refera to current clgarctte 10G6, 2.265.614 of dcnth NS . .I1 lo-20 ..,,,......, 2.93(13) Shl ..,.... 2.12 (4) smoken only. U.S.A. r)utsol! yesrs. certinca1c, 21-39 . . . ., ,, 3. . . . 7.34(20) Cipar IIJY). >N . ,. . . . 6.73 (3) NS *...... l.OO(ll) All . . . . . . . . . . . . . . 4.@3(37) Shl .,..,,,. 4.11 (0) Hammond. 440,LGE malra Intcrvlcws by 4 I')CG. bG%.G71 Ivmnlea ACS vuluntccm V.S,A. .15-X4 yt:arn of (JIJ). rwc in X.5 Ststca. _. Wclr end 68.1G3 males Questionnaire 6-8 Dunn, In vnlious and follow-up 1070. occupstiona of death U.S.A. in California. certlflcnte. (SOF). of "pan" or "Xass," which are mixtures of tobacco with either betel nut or lime ash, and other ingredients (2L1, 255, ,056). Snuff dipping, a habit in which snuif is placed in the gum and retained there for prolonged periods, has also been associated with the development of oral cancer (193, 210), as has the chewing of tobacco (124,193,241,998). -The risk of developing a second primary mouth or throat cancer, after the recognition of the first primary cancer, has been found to be greater in continuing smokers than in those who quit smok- ing. All of the patients studied by Moore (190) were asymptomatic for at least three years following the treatment of the first cancer. Of the 117 patients with adequate smoking histories, only 4 of 43 (9 percent) who quit smoking developed a new primary cancer. On the other hand, 27 of 74 (36 percent) who continued to smoke developed a second primary cancer. However, a study by Castigliano (53) of patients treated for oral cancer did not show a greater risk of a second primary among continuing smokers. In this study, 5 of 26 (19 percent) of those patients who did not quit smoking developed a second primary cancer as compared to 9 of 51 (IS percent) of those who did quit. The rate of quitting smoking in the two studies is markedly dif- ferent (36 percent in the Moore study and 62 percent in the Casti- gliano study) _ From the data presented in the two papers, it is not possible to evaluate the other significant ways in which the pop- ulations may have differed. Keller (140) studied 408 males with histologically confirmed squamous cell cancer of the mouth or pharynx. This author dealt with the question of recurrent tumors in a somewhat different manner. The patients were observed for the development of a sec- ond or third primary cancer at an anatomically discrete site of the mouth and pharynx within a median period of three years after the first cancer. He found that a second or third cancer (termed a coexisting cancer) developed in 28 of the 408 cases. Among these 28 cases with 33 coexisting neoplasms, 21.7 percent were heavy: -- smokers, but among their matched controls, there were no heavy smokers. Coexisting cancers were most commonly found on the soft Palate, an anatomical site that is in direct contact with the main- stream of tobacco smoke. More recently, Wynder, et al. (315) studied 63 male and 23 female patients with multiple primary cancers of the mouth and pharynx. They observed that heavy smoking prior to the develop- ment of the oral cancer was associated with a greater likelihood of developing a.second primary. Also, continued smoking after the first primary was found to have a significant association with the occurrence of a second primary. 313 IJ'ith or without smoking, use of alcohol appears to contribute to the development of oral cancer (1_7:, 120, 15'9, 297. 32). In a study of male ve6%ans, Keller (ILO) found that heavy smoking and heavy drinking were associated with cancer of the mouth and phan-nx. No studies are presently available which determine the relative contributions and possible interactions of heavy smoking, heavy drinking, and concurrent nutritional deficiencies in the etiol- ogy of these cancers. EXPERIJIENTAL STUDIES In 196-1, the Advisory Committee to the Surgeon General on Smoking and Health (291) reported that cigarette smoke and ciga- rette smoke condensates had failed to produce cancer when applied to the oral cavity of mice and rabbits or to the palate of hamsters and that the oral mucosa appears to be resistant in general to can- cer induction even when highly active carcinogens such as benzo- [alpyrene are applied. Some of the difficulties in experimental de- sign were attributed to the fact that mechanjcal factors, such as secretion of saliva, interfere with the retention of applied carcino- genic agents on the tissues of the oral cavity and pharynx. Positive results with certain carcinogens have, however, been obtained in the hamster cheek pouch. but it has also been pointed out that the cheek pouch lacks salivary glands and that its structure and func- tion differ from those of the oral mucosa. The majority of these studies are outlined in table A29. Although cigarette smoke condensate acts as a complete carcino- gen on mouse skin, the work of several authors (319) supports the concept that cigarette smoke contains cancer promoters that may be of special importance, particularly in orai carcinogenesis. Elzay (90) has reported that whole cigarette smoke is a promoting agent for the hamster cheek pouch. More importantly, regarding the chewing of tobacco, Bock, et al. (27,30), Van Duuren, et al. (29:), and Wynder and Hoffmann (321) have shown that unburned to- bacco products contain tumor promoters that might contribute to the promoting activity of the smoke. Roth, et al. (226, ,R.H') have shown that the dye-binding capacity of the DNA of oral epithelial cells is significantly enhanced in cigarette smokers in contrast to nonsmokers, probably reflecting an increase in the DNA content of oral epithelial cells in smokers. Smokers had values of dye-binding capacity intermediate between nonsmokers and 21 patients with proven oral cancer. Those smok- ers who refrained from smoking for up to six months showed a significant decrease toward more normal values. 314 I. Epidemiological and experimental studies contribu:e to the conclusion that smoking is a significant factor in the development of cancer of the oral cavity and that pipe smoking, alone or in conjunction with other forms of tobacco use, is causali>- related to cancer of the lip. 2. Experimental studies suggest that tobacco estracts and tobacco smoke contain initiators and promoters of cancerous changes in the oral cavity. CANCER OF THE ESOPHAGUS Esophageal cancer accounted for 4,306 deaths among -American males in 1967 and 1,321 deaths among females. The death rate from esophageal cancer has remained relatively constant since 1949. EPIDEMIOLOGICALSTUDIES The major prospective epidemiological studies (table 30) have indicated a significant relationship between smoking and esopha- geal cancer. Overall mortality ratios for male cigarette smokers range from 1.73 to 6.17. There are insufficient data concerning females for establishing firm conclusions. A number of retrospective studies concerning the relationship of smoking and esophageal cancer are outlined in table A31 and A31a. Smokers incur risk ratios ranging from 1.3 to 6.6 when compared with nonsmokers. As in studies of oral cancer, the effect of alcohol consumption must be taken into account in studies of esophageal cancer. Because a relationship between alcohol consumption and tobacco use is known to exist, \Vynder and Eross (810) analyzed the association between tobacco consumption and esophageal cancer after adjust- ing for alcohol intake. They found that in the absence of alcohd consumption, there was no association between the use of tobacco and esophageal cancer but that in the presence of alcohol consump- tion, an increasing relative risk with increasing number of ciga- rettes smoked \vas apparent, as well as an association bet\\-een cigar and pipe smoking and esophageal cancer. More recently, Takano, et al. (wz?), in a retrospective study of 3-00 patients with esophageal carcinoma, found an increased risk with smoking which was magnified by increased alcohol consump- tion. Martinez (28.7) analyzed the association of tobacco usage and esophageal cancer after controliing for age, sex, and alcohol consumptioir. Increasing relative risks with increasing tobacco use 315 TABLE 30.-Esophageal cancer mortdity ratios--prospective studies (Actual number of deaths shown in puenthnn)' SM = Smokera. NS = Nonsmokcn. Author, Number of ye.70 Nu,rn;:r;nd Data FOllOW. esophnae&\ countlY. collection UP yenn cllnccr Cigarette3/dny Pip-, CigIrl Commcntd rtfcrenee DoQulntlon deaths Hammond 187,783 white Quutionnairc 3 % 34 Cigarette amokcra Pipe hftied De.tn rcfcrring to and malts in 3 and follow.up NS 1 16133. z/33 cigarette mortality ratios Horn, State K&69 of death sar , 33 Cigar amokera Included cancer lOS8. ye*n of age. ccrtiflcate. 2133 13/K! al mouth U.S.A. and larynx. (190). Doll and Approximately Questionnaire 10 29 ~11 amokera bu amount tPipe and ciuar t Includes ex- Hill, 41.000 mnlc and follaw.u~ in yramr NS . . * 1.00 amaker, of pipe 1964, British of death NS . ,. 1,. 1.00 Shf . 2.00 and cigara, Great physicians. certificate. l-14 . . . . 2.00 Britrln IS-24 ,.., 3.60 (74). >25 . . 6.00 All . ., . 3.00 Kahn U.S. male Questionnaire E?`r 111 NS . . . . . l.OO(ll) Pipe t Rcfrra to (Ihrll). Yt-tel'B"9 and follow-up NS . ..I1 t1-9 . . 1.76 (2) 1.99 (3) cigarette 1966, 2.265.674 of death SM . ..lOO lo-19 . . . . 4.71(18) Cigar smokinl U.S.A. person yearn. certlflcate. 20-39 ., .11.60(24) 6.33(12) only. (139). >25 . . 7.65 (3) All . . . 6.17(47) Hammond, 440.55R male8 Interview by 4 46 NS .., . 1.00 (6) Pipe und CiQa.r 1966. 662.671 females ACS volunteers. NS ,.. 6 Shl (iire NS .._. 1.00 U.S.A. 35-84 YCBT9 or Shf 40 St4 I... 3.97(14) 45-60 4.17(32) (IIS). we in 26 States. Shl (age 65-79) 1.74 (81 TABLE SO.--Esophageal cancc?' Ino,`talitu rafios-p,`ospcctiuo studies (cont.) (Actual number of dcnthr shown in w.rcnthcs<%) Shl= Smokers, NS = Nonamokrrs. Author YCDT. country, Nuttny;nd Datn FQllOW- collection "II YCQl-3 Comments relercncc populntiun Hirnynms. 265,118 male Trained PIiS l',`r Slil _, 21 NS . . .., 1.U,O(D30 . . ., 1.82 (306). All ,. . 1.82 1 Unlcso otherwise epcciflcd. disparities between the totnl number of drolhs and the rum of the individual smoking cntegoriee are due to the exclwion of either occnsional, misceUnneoue. mixed, or ex-amokcrs. were noted. The consumption of very hot beverages was also found to be related to the development of esophageal cancer. PATHOLOGGIL STUDY Autopsy studies of smokers as compared with nonsmokers, spe- cifically observing the pathological changes in esophageal tissue, have been performed by Anerbach, et al. (15). A microscopic study was made of 12,598 sections of esophageal autopsy tissue from 1,268 men who died from causes other than esophageal cancer. The findings were strikingly similar to the abnormalities generally ac- cepted as representing premalignant tissue changes in the respira- tory tract epithelium. Esophageal epithelial cells with atypical nuclei (having an irregular distribution of chromatin) were found far more frequent.ly in cigarette smokers than in nonsmokers. Basal cell hyperplasia and hyperactive glands were also found more fre- quently in cigarette smokers than in nonsmokers. An increase in frequency with amount of cigarette smoking was noted for both epithelial cells with atypical nuclei and basal cell hyperplasia. Tables A32 and A33 summarize these findings. EXPERIMENTALSTUDIES Kuratsune, et al. (156) investigated the possibility that the car- cinogens known to be present in tobacco smoke could penetrate the esophageal epithelium more readily if dissolved in aqueous ethanol. Mice were exposed to several compounds by esophageal intubation. Tissues were then removed and studied by fluorescence microscopy. Deeper penetration and a different distribution were found when B[a]P was dissolved in aqueous ethanol as compared to B[a]P in olive oil. It was also found that benzo[a] anthracene and fluoran- thene dissolved in ethanol solution or aqueous caffeine solution could penetrate the epithelium of the esophagus. Horie, et al. (132) reported on the development of 10 papillomas and one squamous cell carcinoma of the esophagus in a group of 63 mice periodically forced to drink a solution of benzo[a]pyrene dissolved in diluted ethanol. Twenty-six papillomas and one squam- ous cell carcinoma also developed in a group of 63 mice to which 4-nitroquinoline l-oxide was administered in the same way. None of the 6'7 control animals given only diluted ethanol developed neoplasms. Several other authors have reported nitrosamine-induced esopha- geal cancer in experimental animals (56, 79, 80, 81). As noted above, the presence of nitrosamines in cigarette smoke is still a subject of debate. 318 1. Epidemiological studies ha\-e demonstrated that cigarette smoking is associated rvith the development of cancer of the esopha- gus. The risk of developing esophageal cancer among pipe and;or cigar smokers is greater than that for nonsmokers and of about the same order of magnitude as for cigarette smokers, or perhaps slightly lower. 2. Epidemiological studies have also indicated an association be- tlveen esophageal cancer and alcohol consumption and tthat alcohol consumption may interact with cigarette smoking. This combina- tion of exposures is associated with especially high rates of cancer of the esophagus. CANCER OF THE URISXRY BLADDER AND KIDNEY EPIDEMIOLOGICALSTUDIES (BLADDER) Cancer of the urinary bladder accounted for 6,019 deaths among American males and 2,743 deaths among American females in 1967 (289). Incidence rates have increased from 1949 to 1962 (88), but the death rates from bladder cancer have remained relatively stable during that period. Improvements in early diagnosis and therapy may have masked the increasing incidence of this disease. A number of epidemiological studies have indicated that smokers have an increased risk of contracting or of dying from bladder cancer (see tables 31 and A3.5). Certain of these studies include kidney cancer mortality in the results. The major prospective stud- ies, with the exception of that of British physicians, have shown bladder cancer mortality ratios among cigarette smokers ranging from 1.40 to 2.89. Smokers of more than 1 pack per day were shown to incur ratios of 3.12 to 5.41. The study by Doll and Hill (74, 75) of British physicians, on the other hand, reports death rates for smokers to be lower than those of nonsmokers based on 38 bladder cancer deaths. The mortality ratios for pipe or cigar smokers are substantially loxver than those among cigarette smokers. Pipe smokers were shown by both Hammond and Horn (120) and Kahn (13.9) to incur ratios approximating 1.50. Retrospective studies (table A35a) have also shown an increased proportion of smokers among bladder cancer patients when com- pared with matched controls. Relative risk ratios for bladder can- cer among smokers range from 1.0 to 7.3 among a11 smokers and up to 10.3 among heavy smokers of all types. 319 u N 0 TABLE 34.-Kidncu ami urinnru blatldcr cancer-prospective studies--Mortalit2/ ratios (~ctunl numlcr uf dcutha shown in ~~nrcnthescs)' Shl = Smokers. NS = Nonsmukcis. Author, )`car. Number and Data FCIIIOW. Number CO"lllTY, type Of collection "I, years of Cignretle/day Pipe. cigar Kidney Blnddcr Commcnta refcrcnce wl,ulation denlhs Hnmmund 187,183 white Questionnaire 3% 287 NS ,. 1.00(B) Pipe snd malen in 9 and 20 ,.. 3.42((l) Cipar U.S.A. NS ..l.O0(3R) (100). Shl , ..l.OG(I'i) Doll snd AnDroximatelv Questionnaire 10 38 NS . ..I.00 llill. 41,000 mule and follow. Sht ,O.dl 11c4. Llritish ua of death Crest Dhyeicinns. certificate. nritain (fb). All Sdf bv amount in ~rcarnn NS ..I.00 1-14 .0.69 16-24 . .o.c5 >25 .0.76 All I. .O.?l BCSl, Apuroximntelr Questionnaire 10 114 NS . 1.00 Pipe Rcfcrr to 1966. 18.000 mall? nnd follow- 30 .,. 1.43(16) Cigar gruu*. All ,. 1.40(10) NS . ..I.00 SM . ..1.16 (3) Hsmmond, 440,568 mules Interviews by 4 Bladder Cioarcllrc CiQCl'ClfCl hfnlc dn1n OlllY. 1966, 6GZ.G7 I ACS 13R NS ,I . . .I .* .1.00(22) 1.00(23) Blwhlcr IncluilM U.S.A. females volun1eere. SM ,116 SM (age 45-64) . ..1.42(64) Z.OO(GCJ) olher urinary (II(i). 35-R4 years NS . 23 SFll (nse 65-78) . ..1.5'7(?8) 2.96(66) tract COnLECrI. of ace in 25 Ridmu SLllbX. 104 Shl 82 NS 22 AUtllUr. yc)Lr. Nyne'yd Dnta Follow- Number roun1ry, c011cct10n "V yenre rcfcrcncc population de% Ciuarette/day Knhn U.S. nlRlc Questionnaire a',/. B!addcr (Darn), vcte:ana nnd follow. 224 196C, 2.266,674 "P of denth Shl 172 U.S.A. person certificate. NS . 62 (139). years. Kld,lcy 141 Shl ,102 NS 93 Pipe, CiBfit Kidney Bladder Comnlcnta - NS ,, ,, ,,, ,,,. .1.00(39) I'irle _. ., ,, ,. .1.32 (6) Cignr .,.. ,. .,.,. ..0.77 (6) CiKarettes/duy: l-9 ..I ,,,.... 0.97 (4) IO-19 ,...,.,.... 1.34121) 20-30 . . . . . . . .l.GB(lG) >39 .,,. ,,, ,. . ..2.76 (6) All ,.,.,... l.IG(IC) 1.00(62) Dladder includca 1.20 (8) other urinnry 0.94(10) tract CLIIICCIY. 1.10 (6) 1.93(37) 9.20(u) 2.52 (6) 2.1G(B?) - Hlraunmn. 2GG.110 mnlc Trnincd PIIS 1 `ii SM C NS 1.00 rllnddcr cn>>ccr only. lOG7. nnd fcmnle nurse intcr- Shl .lO.OO (6) ncrcm to ali Japnn adults 40 view and inrmr of swokinu. (IPJ). YCLlM of nge foilow-up nnd older. of dcnth ccrlificnte. Weir and 68.163 males Qucstionnalre 6-8 Biaddcr NS .x.1.00 NS . ..l.OO ShI include. ex- Dunn. in vnrious and follow- 27 ?lO ..0.6G 210 , . .1.82 smokcra. 1970, occupations UP of dcnth Kidmu -c20 .3.30 -e20 . .2.81 NS include ~ipc U.S.A. In California. ccrtilicnte. 27 >30 . .2.67 >30 . .6.41 snd clgor (306). All . .2.40 All . .2.89 amakcra. `Unless othrrwivc spccificd. dirpnrities between the total number of drnths nnd the sum of the individual smoking categories are due to the exclusion of rithcr occnsianal, miscelloneoua. mixed. or ex-smokers. W h, Y EPIDEMIOLOGICALSTUDIES (KIDYEY) A total of 5,53-1 Americans died of cancer of the kidney durir.:: 1967. A relationship between smoking and this type of cancer has been suggested by several epidemiological studies. The three major studies which separately examine the relationship of kidney cancer to smoking (table 34), namely those of Hammond (I I&), Kahn (139), and Weir and Dunn (~`06)~ have shown mortalit>- ratios for all cigarette smokers to range from 1.43 to L-16. Retrospective studies by Bennington, et al. (18, 13) have indicated a signilicant association between all forms of smoking and renal adenoma and adenocarcinoma. Numerous experiments have been undertaken by many invtsti- gators to elucidate the relationship of tobacco smoking to bladder carcinogenesis. The two areas of major concern have centered upon the presence of a known bladder carcinogen, beta naphth>-lam:ne. in cigarette smoke and the presence of abnormal tryptophan me- tabolism in patients with bladder cancer. By virtue of data gathered concerning industrial exposure of workers, beta naphthylamine has long been kno\vn as a bladder carcinogen. Complementing such data was the work of Hueper, et al. (136) who subjected mongrel dogs to daily subcutaneous injec- tions and oral administration of commercial beta naphthylamine. Thirteen of the 16 animals developed bladder papillomas and c21-- cinemas of the bladder. Saffiotti, et al. (236) fed hamsters a diet containing up to 1.0 percent beta naphthylamine and observed that 18 of 39 animals developed bladder tumors, almost all typical tran- sitional cell carcinomas. More recently, Conzelman, et al. (59) ad- ministered beta naphthylamine to 24 rhesus monkeys for more than 30 months. Transitional ceil carcinomas of the urinary biad- der were induced in 9 of the animals, and a dose-response relation- ship was apparent. Pailer, et al. (207) and Miller and Stedman (183) failed to End this amine in cigarette smoke. However, more recently, Hoffmann, et al. (127) identified it in cigarette smoke. The authors, noting the minute quantity present in each cigarette (2.2 x 10--g), hesi- tated to attach a biological significance to the finding. Of more recent interest have been the metabolites of tr>-ptophan present in certain patients with bladder cancer. A number of nor- mal and abnormal metabolites of tryptophan have been found to be carcinogenic when tested by implantation in the bladders of mice. These include 3-hydroxykynurenine (OHKy), 3-hy-droxyanthranilic 322 acid (OHA), 3-hydroxy-%-amino-acetophenone (all orthoamino- phenols), the S-methyl ether of santhurenic acid (CHSa), santhu- renic acid (,Ya), I>-kynurenine (KY), quinnldic acid, and Zmeth- oxyanthranilic acid (3CHO.1) (2, 36, 37, 39, $7, $8). OHKy and OHX are frequently present in human urine, as is kynurenic acid (KYA). Certain investigators have concentrated their attention on the presence of abnormal tryptophan metabolites and increased amounts of normal tryptophan metabolites in the urine of patients with bladder cancer as compared with selected controls (1, 40, $6, 97, 118, 214,243, 329). These authors have observed the increased excretion of Ky, KyA, OHKy, anthranilic acid, OHA, and acetylky- nurenine in such patients. Yoshida, et al. (329), in a recent study concerning the relationship between tryptophan metabolism and heterotopic recurrences of human urinary bladder tumors, reported that those patients with recurrences showed abnormal metabolite excretion more often than those without recurrences. The relationship of smoking to these biochemical findings is presently uncertain. Kerr, et al. (1$3), in 30 experiments on 3 smokers and 3 nonsmokers who were given large doses of trypto- phan, found that smoking increased the urinary excretion of OHKy and OHA and decreased that of N'methylnicotinamide (an end product of tryptophan metabolism). Kerr concluded that smoking interferes with the normal metabolism of tryptophan. Recently, Brown, et al. (45) studied 15 adults under smoking and abstinence conditions and found that except for the basal escretion of acetylky- nurenine, tryptophan metabolite excretion did not change with smoking or cessation. The authors also compared 13 nonsmokers and 17 regular cigarette smokers under basal and tryptophan- loaded conditions. No differences were observed in the excretion of the measured tryptophan metabolites. However, due to its instabil- ity, OHA was not measured. The authors concluded that the rela- tionship of smoking to urinary bladder cancer was probably not vk - - its effect on the kynurenine pathxvay of tryptophan metabolism. Another experimental approach to the relationship of smoking and urinary bladder cancer is reflected in the work of Schlegel, et al. (2: :, 2:~). The authors observed an elevated concentration of certain ortho-amincphenols in the urine of bladder cancer patients and cigarette smokers, when compared with nonsmokers (245). More recently (?$5), the same group compared the chemilumines- cence of the urines of smokers, nonsmokers, and bladder tumor patients. 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Journal *a dYlnR or CDnCcr of ECT uf certain other sites. the lung. Lickint, 1163. Grrmany (170). hl-F W ul hlnlcs Fcmnlcs Author. CO\C3 Controls CilYC3 Cunlrols ycnr. Rclntive Rcliitivc Cumrncnta rrrcrc"rc I'r,rcrnt rrrccnt rcrccnt Percent ritlk rcrccnr Pcrccnt risk I,,`". hrnvy non- hcitw ratio Pr1crnt 1y;t "Cl". / ll"n- hcaw wtiu Number snrukvrs rmx,kcrs' Number smokers smokers1 Sht:NS Number smokrrs smokers' Number emokcn, smokers' SM:NS' miiih, RG 3.5 G5.1 86 1c.3 36.0 `5.4 (`) (1) (1) (`I (`I (`I . 1939 (196). Schnircr nnd OR S.? 31.2 270 16.0 9.3 lG.7 (`) (1) (`1 (`) (`) (`) I6 fcrn,~lc Schunlccr. CDII(LY nr4t 1943 I?IP). Rllnl) LL.II Potter and 43 7.0 30.2 2.RO4 26.0 23.0 14.1 (1) (`) I') (1) (`1 (`I . Tully. 1945 (?I."). Milla end 444 7.2 430 30.L .I. 6.7 I') i') I'1 I') I') I') r'urlrr. 1950 (186). Wrndcr nnd 605 1.3 51.2 7HO 14.G 19.1 13.0 40 57.5 25.0 552 71.6 1.2 2.!, Crnhnm. 1350 (JJ6). hl, I*J5R ("3:). rr!,wh,~il. ---- _-_.--._ WYntlcr and GR I.1 C7.G 133 20.G 23.3 `C.l (1) (`1 (`1 (`1 (`) (`I ,.. Curlblirld. 1:15:1 ,314). ~- Kuulumtcs HI2 0.0 GR.`) 300 18.0 25.0 3c.o , (`) (`I (`) ,~,------- 1053 (121,. LickinL - _-. 2'2 4 1.8 36.X 1,000 lC.0 4.n `10.1 22 G 1.0 66 1,002 00.4 0.1 5.3 IV53 (170). Ilnndic. 415 1.2 34.2 381 6.8 17.9 35.1 33 51 G 3.0 131 70.3 0 2.2 l'J54 (.'IS). Cellond cl ul.. 32 G.3 32 c3.0 `26.3 (`I (1) (0 (1) (1) (1) 1065 19x1. - \Vyncicr ct al., 210 1.4 67.5 420 21.0 40.`) 220.8 30 lG.7 14.0 13? 57.6 23.3 6.78 li~ni~ TABLE A?`-Grouping of pulmonary carcinomas Group I: A. Epidermoid carcinoma. B. Small cell nnaplastic carcinomn ("oat-cell" carcinoma). Group II: A. Adenacarcinoms. B. Bronchi&-alveolar cell carcinoma. C. Carcinoid tumor. D. hlucous gland tumor. Extra (not included in I and II): A. Large cell undifferentiated carcinoma. B. Combined epidermoid and sdenocsrcinama. Un.uitab!e for diagnosis. 360 Little et al., Po"' 1rrcLt in vorioue liaaucr (PC/g tissue) Vcrlcbral budicY. rcnul 1961. Pcribronchia! Bronrhinl eorlcx. spleen and U.S.A. (173). lymph mdcr Lung (nvcrogc) rpilhclzutn ur,n,iry Lloilllcr stliiwcd NS ,. . . . 6 0.011 0.001-Z nrglisiblc SM no dificrencrs. . . . . . . . . . . . ..12 0.011 0.00s 0.028-I .2G TABLE AlZ.-Autopsy studies concerning the presence of radioactivity in the lunga of smoker8 (cant,) NS = Nonsmokers. SM = Smokers. Ferrl end Nran Pa"@ htlr in various ttbs~ca (PC/~ wet hue) Bnratta, LUW Liver Kidney 1866, NS , ,. ,,,,.... . ..lO 0.031 0.103 0.080 U.S.A. (98). SM . . . . . . . * . . * . * .14 0.066 0.126 0.070 Rajewasky and StAhlhOfWl. 1966, Canmy (927). hfoan PdlO levela in various ltiruo (PC/g) tData not given. Smokcrn Lung narrnchyma Uronchid trrrr Bronchial bijurcution were connldcrcd those NS . . . . . . . . . . . . . . . t 0.0026 0.0020 0.0012 using more than 1 pack SM .*. . . . . ,, ., . ..I2 0.0078 0.0017 0.0047 P dnu. The authora noted tbht thclr tln~rcs were con- nldcrablu nm.sller tbhn thoak! of LItlIe et al. (27~. 171) and alao dianereed with tbel? data on bilurcatlon. Rsdford, 1967, U.S.A. (17)). SM ............. .zs Plpe ............. 2 Ex-ekarttte .. , ... 1 Never ............ 8 Bronchial wall snd aubmucoaa .: ..;. .................. .......... 0.004 Bronchial epithelium: Trachea .................................................... 0.120 Lobar bronchi ............................................... 0.190 Segmental bifurcalion ....................................... 4.soo Wynder CAFt mice A. Painting shaved skin. ct .I, II. Jiwcck fur 2 years. 1963. C. Whole cigarette smoke U.S.A. condensate in acetone. (317). Croton oil oncc/wcek. PBlSCY 5 different A. Painting unshaven CL al.. rnO"IC akin. 1955. Strains IJ. Z/week for 9 England (101). months. (109). C. Whole "tar" or neutral fraction. w Q\ w TABLE A13.-Expetimenta concerning the ejects of the skin painting or subcutaneous injection of cigarette smoke condensate or its constituents upon animals (cmt.) Author. year. country. rcfcrcme Anlmrl and strain Commcn*a Wynder et A, 1966. U.S.A. (316). Author. Anlmrl A. Method. A. Method. year. and B. Frequency and/ B. Frequency and/ country. strain or dur~tio". or dur~tio". Resultd Resultd Commcn*a rcfcrcme C. Material C. Material Wynder Mice of 4 Mice of 4 A. Painting shaved skin. A. Painting shaved skin. Sfrain Sfrain PopiUoma4 PopiUoma4 Corc~a Corc~a No tumor8 noted with No turrrora noted with et A, acparste acparste ll. Z./week for 80 days. ll. Z./week for 80 days. C57BL . . . , . . . . . . C57BL . . . , . . . . . . lo/89 10/89 2/89 2/89 aectune alone. aectune alone. 1966. straina. straina. C. Whole condensate C. Whole condensate Swiss Swiss . . . . . . . . . . . . 22/86 22/86 12/86 12/86 strwsea strwsea U.S.A. I" ~EClO"C. I" ~EClO"C. diRcrcncc8 in diRcrcncc8 in (316). susceptibility of susceptibility of strain. strain. Hamar and Outbrrd A. Plintlng unshaved WOOdhOUW, albino skin. 1966. 8trfiin B. Varied for 18 months. U.S.A. mice. C. Whole "tar"/scetone. (IJU). IJenrLJyrene [D(a)Pl, crotun oil. Trcalmmt: P4piUomor "Tar" P/week . . l/60 "Tar" and etoton oil l/week. . . . 2130 B(a) P 3 times then "tar" `2/wwk 4130 ll(n)l' 3 time . . . . . . . . . . . . . . . . . o/30 Author, A22"' A. Method, yrnr. Il. Frn,,wncy and/ country, atrrin or durntion, Rcnulb Commcntd rcfcrc"ca C. hlntrrinl Wyndcr Swh mice A. Pnintina skin. Percrnt PCKClll ct ul,, B. Vsricd for 12 TRblmCnt: Nnmbcr pap~llomar carrinmnor 1957, months. S/week ..,.....,...,,,, ,,,,. so 12.0 8.0 U.S.A. C. Whole condensate Jiweek 50 38.0 16.0 (3?J). in acetone. Z/week 40 10.0 30 l/week ..I 40 ti.0 Wynder and CAF, or A. Painting shaved skin. Percent PL-rCClll Swiss mlcc nolcd Wright, Swiss Ll. J/week far lifespan. Trcalmcnt CAF,: Xirmbcr poplllomad carcinomor ,o br l\lOi-e I",. 1957. mice. c. whole "tar" 07 nicotine Whole "tar" I.,, 30 53.0 27 .o rrptiblr. U.S.A. free "tar" derived Nicotine free "tar" , ,, ., 40 73.0 26.0 hlnlorlty of carcino- (J?Bl. from pipe and CiKarelte "tar" ., 30 30.0 30.0 grns noted to br cigarette tobacco. ripe -tRT'* 30 60.0 20.0 in nciitral fraction Trcalmc~~t Swiar: of condenrntc. Whole "tar" ,, ,, ,, 30 63.0 10.0 Nicotine fret "tar" I, ,. 40 43.0 20 0 Cignrette "tar" ,, 30 63.0 33.0 Pipe "tar" .,... ,, ,.. .,, 30 63.0 60.0 Celihorn, Pnris R III A. Pointing shaved skin. Trcnlmcnt: Fapilfomas Carcinoma0 1358, mice B. Vnricd for l-2 years. Benrpyrcnc (twice only) _, ,, 20/529 5/%5:9 U.S.A. C. "Tnr" in acetone. Cru:on oil (516 wcrk) .., ._, ,, 4126 O/26 (991. bcnzpyrene, "Tnr" 1516 rveck) 3/551 2/5G9 croton oil. Acetone (5,`G \vcck) ,, ._ ., o/30 O/30 Bock and Swiss A. Painting skin. "Tar" and croton oil (5iG week) 101175 o/175 PCWCtll bloore. female B. S/week rol. lifespan. Group: Number liuirly ot G montha Skin tumor8 at C4 wcrl;s 1959. mice C. Whole condensate Painted 4'3 U.S.A. 13.0 irradiation. Painted and irradiated c5 44.0 (29). Irrndiated I. 36 w 2 Bock et al.. ICR Swiaa A. I'alntlna ahtved akin. 19t2. mice B. IO/week for 1 year. Trcritmcnt: U.S.A. C. Cigarette "tnr". Stnndnrd cigarette (JI). Standard cigolvtte Stnndnrd ciRarcLtc Standnrd ciKnrctte . . Pcrrcnt Skin neopla0ia 64.0 51.0 44.0 62.0 27.0 23.0 I.. IDGZ. U.S.A. (225). Druckrey and Rnte Schildbsch. 1063, Germany (82). B. J/week for 84 wcrka. C. Whole smoke "tar" withaddadB(n)P in acetone. A. Subcutaneous injection. B. l/week for 700 dsya. C. B~IIZDYEYI~ in tries rylin. Homhurscr CAFi mice A. Pointing shaved skin. (`O,"l,lClC Pcrccnt I'CICC7Il EL al.. 11. Z-3/week for 2 years. Condcnaalc: Uiit"pSiCS Pa,"ii"mol Corcirioirtna 1963. C. Various tobacco Pipe tobnccu ,. 77 U.S.A. 35.0 15.0 condenantea I" CiEnr tobacco Ml 21.5 (IS!,. 16.0 tlCeto"e. Cianrette tohncco H2 27.0 lG.O Uc"zpyrc"c 54 10.0 20.0 Acetone only . . ..I...... G2 Bock ct &I., Swiw ICR A. Painting clipped akin. - I'( TCC,IL I'crrcnt 1965. mice II IO/week for 11 wwks. Percent conccntrntion of tRr U.S.A. aurb,ii,irlg Pcrrsnt C"IICCI und C. Various smoke (WPC ciporcttc) : I I werka (IO). c0llrt-I ~~~:pillomo conaensatee in 9.2 (.3tnndlhrd) !iLO 30.0 Gi.0 neetone. 8.3 (stnndntd) ,,..,,,... ..,.. 33.0 ?7.0 61.0 7.9 (English stsndnrd) .I,..,.. 90.0 24.0 KS.0 8.7 (king) ,, 100.0 2M.O CU.0 4.0 (Rltcr) `IX.0 0.0 36 0 4.4 1 liiter) , 100.0 10.0 41.0 2.5 (filler) 07.0 4.0 16.0 Acetone control . . 94.0 Untrcstcd cmltrvl . ..I 100.0 Van Duurcn Swiss ICR/ A. Painting shaved akin. Cumulntil'c number 01 mire with t l.ll-dimclhyl- et al., Ho mice B. Initinting agent once-- Itrilinlor P'romolcr 1966, I'a],iilolriaa Corcirio,nM livlir(ll,u"ll~r,lcr"c. Promoter J/week for DXIUA ,.Ether t(ihaccn lent cxtlnct ,, ,, ., ,, U.S.A. 4/20 o/20 12-14 months. (006). 0 . . 5. .Ethcr tobacco IrnI exttnct o/20 O/20 C. DhlBAt. tobacco DhlBA . ,Chulorufurm tobacco lcof extract . l/20 O/?O extrncts cige,. 0 . , . Chuiurolorm tvbncco Ical cxtrnct . , , , O/20 o/20 rette "tar" DhlBA ,.Cimrcllc "t,ir" .~~,,.,...~....,... ..,, 11/:0 4120 0 . . . . .CiEnrette "tnr" .., .., ,, ,. ., ,,, ., o/20 o/20 TABLE A13.-Ezpcri~r1rnls conccnring the eflccts of tltc skin painting or subcutuncous injcctiott o/ ciga7.cttc smoke condensate or ifs cans~it~tenls upon animals (cont.) Author, A. Method yrnr, Animal u. Frcqucncy and/ CO""LlY, snd relersncc or duration. Results Commrnla slrnin C. Material Munaz tt al.. Swiss ICW A. Painting shaved akin. Dark tobacco "for" At risk TUmOrI Carcinoma, The aulhura noled 1868, 40. mice IS. Vnrid. 4.0 percent ,, ,. 81 50 17 & JtiurlrntYl Intent U.S.A. C. "Tar" from dark 8.0 percent I.. . . . 71 46 1G gcnud for dark and (Colombian) and Liohl tobacco for: tutJncev. Colombia light (U.S.A.) 4.0 percent . . , , . . , , ,. . . . , 95 26 6 (197). Lobaccoa. 8.0 percent . . . . 18 64 20 Acetone , . . . . . a . . , 8.. . 91 0 0 ._ Davlea and Albino A. Pslntlngahaved akin. Percent of cnrcinama-bearing attimala a( 116 wcckr Tbe suthurs concluded DlY, mice Il. Varied rcRimrn. T*CatTtlcl,l: th.t thr lnrk of 1868. (acfual number of animala in porcnthracn) C. Cinnrette and SOL) mu, 150 mo. 78 mp. 87.3 mu. diflrrrncc In rc- Crcrt cimr condensate. Uritrln Stnndrrd ci~arctte . t , a . . 20.1(20l 13.2(10) 0.7 (1) . . tiulta Ircbm the Ant Ciwr 27.1(31) (86). lI.l(lG) 2.1(3) and thlrll YFIIODI Cigar lubacco ciunrcttc 13.9(10) . . u,,dcr trrutmrnt rdvvrata that Ibc lncrrallcd turnuri- weniclly ol cluLr tobrco is duel0 physical ~race~lne Iretars. TILE Al&-Erperimenta concerning the effect of cigarette smoke or itu constituents On tiSSUe and T?an mltU?`Cs Author. yea*. countly, rclercncc Boucbard and Mw, 1960, Frmcs (95). Tiaaus or 0rg.n culrurr Mouse lung. Materlal/deUvev Tobacco amokc condensate perfusion for 24 hours and aubseauent praftinx under renal capsule of mice. Re_"ltd Increased number of mitotic abnormalitin In the treated CUhUres; vntiicula*b in the nrat 6-10 dsra after prafting. AWS et 81.. 1961. J&pan (la). Direct exposure to smoke from: a. Whole cIgareLLen. b. Tobacco alone. e. Paper alone. Paper smoke Induced the moat scvcre chanpet. conslstin'iz of CYtODlnlmiC VnrJ- olization and nuclear pyknoais. Alao noted were & decrease in the mitollc index and an incrcaac in abnormal divirionn, more L)O with paper amoke tbnn With the other two. Tharcr and Kcnaler, 196d. U.S.A. (276). KB mammslian tumor cells. Cisarctlc smoke condensate applica- tion: filtered mnd untiltercd cigarettes. SipniRcanr prowth inhibition was shown In unfiltered smoke. C~tot~xlc COmDD- nentr were noted in both the pls e.nd particulate phases. Berwald and Sscha. 19CB. Israel (PO). Cracker ct al.. 1965. U.S.A. (6-J). SWR mice and golden hamrter embryos. Suckling mt traches in oretin culture. Direct application of bcnro(n)pyrene [B(a)Pl. Application of U(a)P in acetone. ~rnro(a)pyrcnc caused lncrcastd cell trnnsformatlon M manlfrr!nl by: a. Ilcrcditary random growth pattern. h. Prusrnaivc p.rovth 81 tumor8 after rulruLrnevur injection Into adulld. C, Ability to Bruw continuously in culture. --- Treeled culture, revrolcd cellular mcteplnsia. baanl cell hypcrplaaia, izicwaoryl mitotic rate, and incrstiard HI-thumidinc incorporntiun pro@ortiun*l to t.bc con* centration of material and durstinn of spplicatiun. Dirmond. Vnriuus con- Avolication of - 196G. tinuoue cell II(n) P in either U.S.A. (68). Itrain* dimcthylsulfoxide (mammalian). (DMSOI or pnrnffin. K \o TADLE Al4.--Ezpcrimente concerning the cfect of cigarette smoke or ile consliluct~te on lireue and organ cttIL~rc8 (co?I~.) Aulhor, yr*r. CD"",tY. rcfvrcnce Burcnfrc""d et LI., Hamster luhr Application of e... lncreawd ~ppc~~rnnce of new rmrll chromoaomts and tclocrntrle ehromosomca. 1966, t1BIue. B(a)Pineither b. Incre~rcd ability tu grow in hnmsler cheek pouch and there become Bpindle- U.S.A. (33). DMSO or dimetbyl- cell s~rColn*~. Iormamldc. Cuimard. Chlcken embryo Application 01 lncrc~ecd mitotic activity and incrrlaed incidence 01 snomalou# mltoacs. 1966, muscular robaccu extract. France (110). eXphtl. Lasnitrkl. Mice nmnatal Appllcatlun of II hy. u. Incrcnscd buanl cell hypcrplarla and pleomorphlam of newly lormrd cclla. IPGR. trachea. droclrbon-enriched b. Increa~rd cyllhclial mi:oair. England (160). fraction of whole smoka condensate. Larnitzkl, Human fetal lung Application of a hy- a.. Cellular enlargement and promotion of growth of new bronchi. 1868, In orpsn culture. drocarbon-enriched b. Increased mitoae,, bronchial epithelial hyperplssia. and a~u~rnou~ mctaplnsln. England (161). fraction of whole c. Inhibition of stromal growth. smoke condensnte. Ghan et al.. hlouae lung 1969. bud embryonic U.S.A. (S4). cuIturcs, Application of D(a)P in DMSO. a. Cellular disorganization. b. Ccllul~r pyknosis: nuclear ahape and size Irrepularlties. c. lncrcaac-d cllithclinl milotic rntc and decrcrsed mcacnchymol mltotic rnlc in thorc cul~urw exposed to D(a)P ver~ua those cxpnrd to pyrcnc or DMSO. Lcuchtcnbcrger MouYe lung Exposure to fresh smoke: and and kidney a. Unfiltered. a. Decreared RNA production, pyknoslr. and death of cella. Leuehtenberger. tissue and b. Activated b. Similar rcsulh. but chanpts were of minlmal severity. 1969. orlcsn culture3. charcoal Rker. Switzerland (16s). c. Cigarette or c. Similar elects as group a., but Ins severe. cigar tobacco. Author. Y<~llT. Tirnuc or rountry. oryon culture hlntrriolldrlivcry llrrults tef,,tCr,CB Cruckcr. Various organ Apvlicntion uf Squnmoug mrtaylusls: frcqucnt plcomor~~bic CPIIO: dnliflrrcntlutlon ol cpllbrllum _-.- 1970. cult"rca: Il(u)l'in8er"m. (inhl!~ited by L'itlimin A). U.S.A. 162). n. Whole suck- ling hamster trncheer. b. Whole bron- chin1 tubes from late fetal dogn and monkws. TADLE A15.-Erperiments concerning the cflecl of the insti[[ation 01 implantation of cigarette smoke or its constituents into the tracheobronchial tree of animals Author, YCI r. COUntPI, Animal and A. Method B. Fre~uencu and/ or duration Rnults reference atrain c. nlntcrial nlacklock. CD white A. Injection into 3.4-brnrpyrcne: Number wilh lumorr/numbcr erporcd 1967. ,a,,. Lund parrnchyma .5. 3 mg. in olive oil K/6 Barcornll. crrht by tharacotomy. b :I mu. in ulive oil with dead Tb bacilli Z/4 sarcoma, 4/B sguamou~ cell carcinomr. Uritain B. Once. c. 5.15 rn~. in cholrstcml pellet l/8 ~qui1rnou8 ccl1 tarcinoms. IPO. C. 3.4-benrpyrrne Cignrctlr "tnr": in olive oil, II. In olive oil o/10. with ~lcad Tb b. In ulivc oil with dad Tb bncllll I/8 aureoma, l/8 ~pue.mou~ cell crrcinomm. bncilli or in ClllltVUlY: cholesterol, 8. U 15 cc. olive oil O/4. cigarette "tar". b. 0.15 EC. ulive oil with dead Tb bacilli O/I. c. Cholntcrol pcllcts O/4. Della Port& Syrisn golden A. Direct tracheal et al.. hamstera. instilllstlon. 1968, B. Weekly'up to U.S.A. 46 weeks. (67). C. 1 percent 7,12-dime- thylbenz(a)nnlhra- cent (DMUA). cigarette "La," concentrate. hlnterial: lYetk4 n. DMBA 50 ,,c./wek , . . ., , 46 b. "Tar" 200 /,,g./wrk 32 c. DMBA hO,,c./wcek . 12 then "tar" 200. ,,a./ NWk I.,..,...... 30 d. DhlDA 100 ug./week . . 17 e. DMDA 100 irK./wffk 1 and "tar" 500 20 ,&week ...I..*II.**I Suruivorr at t0 vwke/orioinal number erportd 10/20 11/21 9/20 - T/20 9/20 - - Ripdon. White Pekin A. Intratracheal No nronlastic chanacl noted in either the exocrimentrl or control PTOUDB. _ ducks. injecti,,rr. Control3: 99 B. Dsily for 721 days. Experimental C. Tobacco cundensate group: 62 1 In liauid petrolntum. thorncutumy. B. Once and auriflced at I week-2 YEBTB. C. Cigarette tubscco smoke condensnte In eucerin. Rockry et nl., Dupy. A. llrunchial inoeulntion SQllonlo", 19GZ. or 3:imulntion. PTC- ~~lUpl,l,lU U.S.A. B. 3-5 times/week NU"LbCr IItuosruc Carcinoma- Canccro"` W\lli al",`iascd (59, : hlalc 11.0 Fwnt~le ,,... - Smoke snd virus exposed (68) : >lulr 9.0 w Femnle 29.0 - - 6.0 - 21.0 43.0 64.0 - - 3.0 - 13.0 5.0 113.0 133.0 -~ Hsri i> and C57BL mice: A. Chamber. Nearun~. c. 200. II. Smuke-12 ciga- 1967. E. 1,437. rcttes per `20 Pnalnnd mice fur I2 (121). minutes every uthrr dny for lifetime. C. CiKnrelte smoke, influenza virus ae1.,,1u1, bcnr- "Yrene c.ertrsol. Author, yefar. c0""tl-i. rrferencr A. Type 01 expos"re B. Duration C. Material Kcsults Comment8 Wyndcr Cl al.. Male C57BL6 A. Chamber. Conclusions: t tRcvuit3 not prub id4 186s. mice: B. UP to 315 No squamous ccl1 respiratory cancer noted. This is attributed in tabular form. U S.A. tJ.`l). C. snd E.- ciR.alettes. to the limitation 01 inhalation time (CO and nicotine acute more than 40. C. Cigarette smoke. e!Tccts) and to the ~nuton~w~lly and ahysiologicolly intricotc nitrogen dioxide, nasnl prss!aue dclenw system. volntiic acids ktxpusure to c!gu~~`tte smoke. N02. or volatile acide snd aldr and aldehydes hydes lead:, to reactive hypcrplnria and metaplasia, both of fuund in ciua- which WPVC noted to be reversible. rette smoke. Swine inl~uenru virus exposure produced hyperplsstic and swine influenza mctnplastic cflccts which could not be enhanced by aubrc- \.il.US, qurnt ~XPOSUI'C tu ciunrrttr smoke. cc, cu 0 .---- huthur. TABLE AZl.-01rlhc of .wO.ospcc1itv shtdies of tobacco ILSC and cancc~ O/ tile larpz _. Y4'kT, CDScl "`~,`\1,)`. - ----_- rt,l,,rcnrc St,\ Numhcr hlcthod ul aclcctiun - _..... .--- ___-.__-_ _._---.-~ M.-F i!?C Clinic wticntn with canecr of the Jup/u: 108 Clinic nuticnts of ~nrne BIC P~DUD with Medical hiaturv and QUCI- TABLE A21.-Outline of sehxspcc~ivc sludies of tobacco use and cancer 01 the laqmz (cont.) Cn3-3 Controls Collwtion of data SC% Number Method of selection Number Method of selection hl. 241 Clinic patients with enncer of Inrynx: 200 Patients wi!h no laryngeal disease: Personal history taken In Wyndcr ct al.. hl. 209 White mnie inpatiente hlemorinl Cancer 200 Paticnta with other than epidcrmoid TraIned lay inlervtcwera. 1056. Research Center during 1952 to 1954. cnnccr, individually matched controls U.S.A. (512). with benign or malignant epidermoid in wme institutions: tumors of larynx: Prrccnl Pcrcrnl Nonsmokers I. .,. I,. 0.6 Nonsmokers ,. . ..*..... 10.6 Cigarettes ,,. .,, ,,, 86.0 Cigarettes .,, .,, ,. ._, 13.7 Cigars ,. ,. ,,, ,. ., ,, 7.6 Cigars .,.. . 10.1 PiDM .I.. ,. I., 6.0 ripea ,...... ......II.,..... 3.8 CigRts/pipCS ., ., .I., ,. 1.0 Clynla/plpc3 I. . . . . ,. ,. 1.9 Wynder et al.. hl. 60 Patients at Rndiumhrmmst with squam- 1957, ous-cell etlncer of larynx. from 1952 Sweden (~2). through 1'355: PCrCCllt Nonsmokers . . . . . . ._ 6 CiKnrettee ., ,, 41 Cimrs ,, ., ,, 17 ripes ,, 16 Mixed .., ., ,, 17 Wynder et al.. hl. 142 Clinic yntients in Havann during 1956.67. 220 Same IOUTCC nnd time: aooarentlv DLL- Interview of Dntirnts 384 1.1 14 12.1 II.4 1 ,I 11.2 4.5 I .`J -- 2 1.7 - 0 - - 0 - - v - - . 0 -. 04 100.0 125 100.0 :1:9 100.0 130 I 1.1 I .H 0 - 0 4 43 25 20 0 ` 1.2 0 50 63.0 54 432 Xl 26.4 21 23 24.5 21 II; n IIG 35.3 ib 0 0.G 1 1.2 44 13.4 33 2.1 2 1.6 I !I 6.H II 1 1.1 0 -- 5 I G 0 :oo 0 ..-. - I'(, I I TAELE A24.-Number and percent distribution, 611 highest number of cell TOWS in the basal layer of the true vocal cord, of men classi/icd Ly smoking cutcgoty T<>lal . . . , . . . . HH 100.0 116 100.0 04 100.0 125 100.0 329 100.0 190 100.0 Lcr. than 5 ccl1 row, . . . ,,,.I . 311 34.1 7 6.0 4 4.3 3 2.4 1 0.3 0 5 cell rows ,. . 2'J 33.0 21 23.9 20 21.3 27 21.6 9.8 11.6 20 10.6 6 cc,, rows , , . . ,,, .,, , x 9.1 15 12.9 15 6.0 25 20.0 61 IS.4 24 12.6 7 cell rows . . ., . . . . 6 6.8 12 10.3 IR 19.1 12 9.6 39 11.6 19 10 0 n cell r"wB . . . *. . , , . ,, . 6 9.1 la 12.1 9 9.6 13 10.4 30 9.1 23 12.1 3 cell rows . . ,. ,. 1 1.1 7 6.0 7 7.4 6 4.8 ZG 7.9 I4 1.4 10 or m"re cell row3 . . . . . 6 6.R 34 29.4 ?I 22.3 39 31.2 146 44.1 90 47.4 - Source: Auerbnch, 0. et al. (9). ---- -. .-_- -_.-.- ____-.---- TABLE A28.-&lhc of retrospective studies of tolmcco use and cancer of the oral cavils (cont.) (Data~oblsincd from patient interview and otbrr auurce.) Author, year. CO"ntTy, refercncc CllWS Co"trob Commcnlc SC% Number Melbod ol selwtlon Number bletbod of selection Sbsnta and Xl. 662 Patient> with oral and phnryngenl cancer 300 Krisbnwnurthi, F. 20t (unsure of conflrmstion) : 100 1964. PerCCtlt India (~66). Buccal At1teriOT Posteri.Jr MtllCll: LiJJ nLllcod* touguc tongue No tobacco habit . . - 2.0 7.2 2.0 Smokcw 60.0 46.7 66.6 76.0 Numberofcwcs ,,., (12) (213) (69) (481 Femnlca: No tobncco habit , a, , 14.3 11.0 33.3 - Smokers . ., ,, . . - 4.7 - Number of eaws . (7) (162) (0 Controls residing in ~&me area matched for age, vex, and ClilBa: Phat-unz Nlolta 6.3 99.1 72.8 62.7 (130) (300) FRndCI 40.0 RR.8 8.8 (26) (100) Wnhi et al., 1965. lndla (302). hl. F. IA0 Pnticnts with oral and pharvngeal car- 689 Patients matched for age, sex. religion. 232 Cl"Ol"a: 232 and wcial class. PeTCCTlL PC7CC7ll Nonsmokers . . . . . . . . . . . 9.62 C6.6 Smokers . . . . . . . . . . . . . . . . . . . 17.05 21.2 Chewers (Betel nut) . ., , 35.44 6.9 Hirayama. 1966. Central and South East Asia (124). Both I . . . . ,.. ,. . . 37.88 6.4 Bl 3c9 Patients with oral and pharyngenl cnrci- 277 Patients with other (unspecified) dls- Found only a suggnllve F. 176 noma: 163 eases: association between PCTCCTlt PCrCCVlt hlcohol-drinking and Malt Fcmolc Malt Fcmalc oral crlnccr In non- Nonusers . . . . . ,. 1.~ 2.6 11.0 33.0 chcwcm only. Smokers . . . 17.1 2.6 23.8 1.2 t UN-Iletcl nut. Smokers, tBN nnd tobncco chewers . . . 46.7 6.6 24.9 1.6 TABLE AZ&-Outline of retrospective studies o/ tobacco me ad cancer o/ the oral cauilu (cont.) (Datr obtalnrd from patient interview and other sources) Author, yerr. CUCU controla country, Comments reference Sex Number Method of aelection Number Method of selectlo" Keller, M 4on Patienta with s~usmous cell carclnomn al 408 Next mule patient admitted to same hos- Excessive ulcohol LO"- 1967. oral cavity and orophsrynx connrmed pit01 within 6 year hw range. aumotiun noted lur U.S.A. (I40). hiatolonieally. Three New York Cite VA cbscs invulving flour. PIrCCnt 14.2 56.4 (Du) (IO shu\%cd h>wr- co"de"sate. kerntosis). D>lBA in 0.6% DMBA . . . . . . . . . . . . . . ,a,...,, . . . . . . . . . . ..a.. 0.8 14/21 microscopic cancers (at 00 daya) petrolatum. (invaaivc ~puatnous conccr 0riKinntinz in the skjn at Ihc WIED of the vouch). Salley. 19c3, U.S.A. (239). CAFI strain mice. A. Ultraviolet light exjmsure to nnd pninting of lips. B. 3 ~)er week for 08 weckr. c. D(8)P in ncetone Cigarette smoke WV llnht. Uock et al.. 1CR Swiss A. Pointing mouse 1864. mice. skin. U.S.A. D. See results 36 wwka. (JO). C. Various extract3 of Trentmrnt: unburned t&am, DhlBA once then: DhlBA. Acetone benzene extmct Conccntratnl na(OH)pextroct .,. Diiuteil Un(Oll)Zcxtrnct ,.. ,,,,, DMllA only Aectnnc bvnzene EXtl'sCt Concentrnctcd Un(OH), ~xtrrict ., Diluted Bn(OIil 2 cxtrnct None ,. :. 5 0 h.matera.' 07ipind Aforlolify Number utilh wlh Treatment: number rn1c animals 1umorr CL?"CO DhlUA Alcohol Smoke 2'J 41.0 II 100.0 60.0 DMnA Alcohol . . , 29 6G.0 10 60.0 40.0 DhlllA ,. Smoke 29 42.0 14 100.0 10.0 DMIlh . , ., . . . . . 28 4R.O 16 100.0 80.0 . . . . . . Alcohol Smoke 29 42.0 14 . . . , . . . , . . Smoke 28 42.0 14 - - Sanghvi et al., 1365. India (P(l), M -- 13 Conseculive clinic admirrions to Tats me- 2RB Consecutive clinic admisaiona of vnticnta ny menns of "dctnilcd morinl Hospital. Bombay. without c~nccr. queationary." No otbcr 107 Consecutive admissions of patients wilh details given. cnnccrs other than intraoral or cw- Wynder et sl.. 1351. M 39 Patlents admitted to Radiumhemmet, 115 Pstientr ndmittcd LO ~arne hospital with F. 35 Stockholm, during 1962-66. ICC cancer of akin, hrnd and neck region swcden (Jze) other than IQUB~OUB cell cancer. lcu. kemie. colon. and other altee. No matching. Sra3rewski, 1960. Polund (160). hl 24 Patient3 admitted to Oncological Institute 912 Olhcr p~lients sent to Inatltute with No drtnll, glvcn o" during 135749. method ,I! dstu coJlw- aym,~loms probably not ctiologlenliy conncctcd eithsr with smoking or with lion. No arc ~~JIIJ~- direasw of caophaguua, atomnch or du- mcnt or mntching. hv* odrnum. eragc .ge of c.nrcr vrtienla, 60.6: contm~. 63. TABLE A3l.--hnamary of methods used in retrospective stitdics of tobacco USC and cancer of t/ie CSoPha!7us (co7if.) Wynder rnd Bros9. 1961, U.S.A. (SJO). m. 160 Cancer ~stienh awn in Memodal Hospl- 160 Psticnts neen in lame hospitals during Data coilcctcd by trriucd 181. New York City, and Kingsbridge ~lnme time period with other tumors. intrr\iewcrs. and Brooklyn VA Nospitnla during 64%malignant tumor: 36%benign can- 1950-69 (86% white). ditions. Matched by age with et.n~cr pe.tiet2ts. F. 37 Same hospitals, and same time period r.s 37 Same IS with rcgnrd to male controls. mule patienh (86% white). 43% had malignant and 67% benign l"lTOr8. Wynder and M. 67 Admitted to Tsts hlemorial Hospital Ilom- 13b I'nticnls with other iorm~ al cancer ex- Intcrvicwcd bv one DCT- Author. YPL11. Crises CO"ll,i-Y, CClntr0k relarenc.? sex Number Method of selection Nllmbcr hlcthod of ~clcction Callecllan of dot-3 Drndahnw end hl. on Patients with esophoscal cnnc~r. 341 Schonlnnd. l's!icntn with non-mahgnnnt diacase. lloapitnl Lntcrvirwa by 1969. trained Airicon doclol South Africa workers. Ill). blnrlincr, hl 120 Patients with confirmed epidermoid eso- 360 120 male. SO female patients In snrnc has- 1969. I. 59 lnlcrviews by Irrinvl phwcal cancer diagnosed In 1966. 177 pita1 with non-conccrou9 diaanoser. pcrsonncl. Puerto Rico (1.93). 240 male. 118 female mcmbere from s&me cummunity. - TABLE Mln.Summarg oj results of vctrospcctiw studies of tobacco we and cancer of the eaophaguz - Sanovhi et al. .---- .- 6.6 11.3 Ar'cruor l,limLcr ol -. - 3.6 - Wynder et sl., M 13.0 24.0 1067, Sweden fd91). SI~lzewakl. 1960. Poland (280). F (nbout)ELO (about)`JZ.o - - 21 - - - 2 0 - - 18.0 95.8 59.0 87.6 80.0 - Schwsrtr et al,, 1861. Frrnce (PIo). WYndcr knd Dross. 1961. U.S.A. ."d India 1510). -- Takano et &I.. 1963. Japan 1972). Amrtlcsn malrs American IcmnlpJ Indian males Indian females 3.0 G.0 41.0 13.0 78.0 11.0 17.0 IK.0 7M.0 2H.0 94.0 23.0 To101 t,mou,,l smokrd dnifv (rlgar~ltot 16.X 16.0 48.0 33.0 27.0 16.0 - - - - - 39.0 3H.0 C.6 - - - 3.4 4.4 - 5.1 3.2 2.6 - 4.6 - - 1.3 - Brfiduhaw and Schonlsnd. 1969, South Africa (AI). - -. 16.3 31.7 3l.G 6.9 - 2.6 11.1 Martinez. IOG9, -. - 14.0 23.6 ]?.!I X.G - - LB 3.6 Pup130 Rico (188). _-__--- 100.0 33.1 6.C 0.3 - 100.0 85.2 14.8 - - 445 - I O'J 100.0 3.b53 IOU.0 053 98.4 b3 2.2 4Gl 1.1 2,915 iS 6 452 0.5 h55 22.2 40 7i9 - IRl 6,762 100.0 1.5X6 lG7 2.5 170 S.38!, 19 H 1 ris 1.106 17.1 iI - 100.0 34 YU.0 G.6 2R 25s 56 175 - 100.0 37.4 GO 1 10 loo.u 1.S YG n 61 - 1oo.c 2n.9 61.b 1.6 .- 100.0 GI `, 41.7 14 hl F. 163 29 Patients with bladder cnnccr. ICI "Comparison casm." 60 Dunham et al.. ?f 334 Admisalonr to New Orlcann hosnitnln with hir- 350 Admissions to same hosnitalr with non*nc*plns- I'J6R. F. 158 tolugic diagnosis of blnddcr cnrcinuma. Ii7 tic diseaaea and discues unrelated to i?cnl- U.S.A. (8s). tourinnry tr.c,. -- Anthony and Thorn&a. M. 381 Patienta with prpillumn and cancer of blnddrr 275 Sur~lcnl Datient. wllhout c.ncrr ~rcvlouslY In- 1970, nt Leeds betweecn 1868-67. trrvirwed for lunx cancer study. Ynnlhnd (3). - TADL.~ A36n.Summry of results of retrospective studies of smoking and cancer of the bladder I'etccnt clKnrc!tcr Rclatlve rink rwtio: Author, Prrccnt nonamokcn Percenl hcrvr amoken nmukcd All amokcrs to nonamokera )`cer. - - E"U"trY, All rclcrmcc SCX C68M Huaw Ciuarclle Commenla CO"lrOl8 CIW8 CO"ld8 CWM Controla smokers smokcra amokerr -_ .- Lllirnfvld ct al.. M. 16.0 2Q.0 61.0 44.0 2.8 ,.. 2.7 ClgwrtLe nnd otbcr. 196G. F. 87.0 83.0 II, 1.4 . , . . , U.S.A.. (171). --- Schwvnrtr et al., hf. 11.0 20.0 .,. . 83.0 70.0 2 , 2.2 CLparette only. 1961. Frnncc (P/O). - Lockw.ood. nl. 9.0 13.4 30.0 16.0 ao.0 16.0 1.6 8.0 8.0 Clewdtrs maln male of 1961. F. 16.0 GG.0 4.0 4.0 1.6 12 ,.. amoklng. Denmark (176). Wyndtr PI Al., M. 7.0 18.0 41.0 23.0 86.0 63.0 2.9 6.2 3.s Phues A snd II com- llG3. F. 61.0 86.0 6.0 ,.. . . . a.9 , . . . , , blncd. U.S.A. (306). Cobb nnd Ansell, M. 4.6 26.8 79.4 43.5 . . . . . . 7.9 10.3 1.. 1366, U.S.A. (67). -. Stiurewaki, hl. 6.7 16.0 86.7 66.7 87.1 72.2 2.1 9.1 2.9 19GC. Clgrrettm only. l'olnnd (P61). DeeIcy and Cohen. hf. 2.4 1.1 . . . . . 3.1 . . . . 1966. Ennland (6s). -. TABLE A35a.--Sunm.ur~ of results of retrospective shdics of smoking and ca?lcer of the bhddcr (cont.) SCX Percent nonsmokers C**CS CO"ltlOl Pcrccnt CiXnrcllus Rclntivc ribk rullu: Percent heavy arnokers smuked All smoker3 to nonsmokers All Iienvv Cinorctte COt"t"?"ll Cnscs ControLv Cnsur Cuncrol. $mokcrs hmukcrs amokcrs -.- Yorhido CL al., hl. H.0 22.7 43.4 33.0 - - 3.4 3.7 - IOGA. F. 62.1 66.4 - - - - - - - Jnnnn (330). Kida et 01.. hl. 11.0 11.0 32.0 29.0 - 1.0 - - IUG8, E' lG.O 21.0 .- 1.4 - - Jnwn (144). Dunham et aI,, IOGR. U.S.A. (85), Anthony nnd Thomas. 1110. England (3). hf. F. F. 8.6 G2.2 6.3 14.6 61.6 6.3 - - - 48.4 32.0 36.5 46.4 2R.2 21.1 1.8 1.0 1.0 - - - 1.8 1.1 1.3 Chapter 5 Pregnancy %uroe: 19i3 Rewrt. Chaoter 4, pages 97 _ 149 411 Contents P3ge Introduction _ . . . . _ _ _ _ _ _ . . _ _ _ . . . . . . _ . . . _ . _ .417 Smoking and Birth Weight Epidemiological Studies Cigarette Smoking and the Low-Birth-Weight Infant _ . . _ . _ . . . . 419 Evidence for a Causal Association Between Cigarette Smoking and Small-for-Dater Infants _ . . _ . . . _ _ _ _ _ _ _ _ . _ .420 Evidence for an indirect Association Between Ciga- rette Smoking and Small-for-Dates Infants . _ . _ _ . _ . . _ _ . . .424 Experimental Studies Studies in Animals TobaccoSmoke _._____._.___.. . .._ . . _. __._. ._. -428 Nicotine _ _ _ . _ _ _ _ _ _ . _ _ _ _ _ . _ . _ _ . . _ _ _ . _ _ . . _ . _ . _ _ 429 CarbonMonoxide _ _ _ _. _ _ _ _. _ _. _. . _ _. _. _ _. _. . . _ -430 Polycyclic Hydrocarbons . _ _ . . . _ _ _ _ . . _ _ _ _ _ _ _ . . . . _ _ 43 1 Studies in Humans Carbon Monoxide _ _ _ _ _ _ _ _ _ . _ _ _ . . . . . _ . _ . . . . . . . . . . 432 Polycyclic Hydrocarbons . _ _ _ _ _ _ _ . . . . . . _ _ _ . _ _ . . . . . _ 433 Vitamin Bl2 and Cyanide Detoxification . _ . . _ _ _ _ . . _ 433 VitaminC....................................433 Possible Mechanisms _ . _ . _ _ _ . . . . . . . . . _ . . . _ . . . . . . . 433 Timing of the Influence of Cigarette Smoking on Birth Weight . . . . . . . . . . ..~.........................434 Site of Action at the Tissue and Cellular Level . _ . _ _ . _ _ . . . . . . 435 Significance of the Association _ _ _ _ _ _ . . . . _ _ _ _ . . . . . . . . .435 Birth Weight Summary _ _ _ _ . . . _ . . . . . . . . . . . . . . . .436 Cigarette Smoking and Fetal and Infant Mortality Introducrion _ _ . _ _ _ . _ _ _ _ _ _ _ _ _ _ _ _ . , _ . . _ . . _ _ . . _ . _ _ _ _ .437 Spontaneous Abortion _ . _ _ _ . _ . . . . _ _ . . _ . _ _ _ _ . . . _ _ . . . _ _ 437 Spontaneous Abortion Summary . _ _ _ _ . _ _ . _ _ _ _ . _ _ _ _ _ . . _ . 438 Stillbirth _ _ _ . _ _ _ _ _ _ _ _ _ _ _ _ . _ _ . _ . . _ . _ _ _ _ _ . _ _ _ _ . . _ _ 438 Stillbirth Summary . _ . _ . _ _ _ _ _ . _ _ . _ . . . _ _ _ _ . . . . . . . . .439 Late Fetal andNeonatal Deaths _ _ . . . _ . _ . . _ . . _ . _ _ _ _ . . . . MO__ Epidemiological Studies _ _ _ _ _ . . . . . . . _ _ _ . _ _ _ _ . . . . . . _ .446 Comparisons of the Mortality Risks of Low- Birth-Weight Infants Born to Smokers and Nonsmokers . . _ _ _ _ _ _ . . . _ . _ . . . . . . _ _ . . . . . . . . . . 440 Recent Studies . _ _ _ _ . _ _ _ . . .' _ _ . . _ _ _ . . _ . . . . . . . . . . 442 Analysis of Previously Reported Studies _ . _ . . _ _ _ _ . _ . . _ . . 444 Factors Which Influence Perinatal hlortality OtherThanSmoking........ _..____..._. . . . . . . .445 413 Page Experimental Studies Studies in Animals . . _ . _ . _ . . . . _ _ _ . _ _ . . J-16 Studies in Humans . . . . . . . _ . . . . _ _ . _ _ . _ . . . -U7 Significance of the Association . . . . _ . . _ _ . . . . . . . -U7 Cigratte Smoking and Infant Mortality - Cont. Late Fetal and Neonatal Death Summary . . . . _ . _ _ . . _ 418 Sex R3tio . . . . . _ . . . . . . . . _ . . . . _ . _ _ . . . . . _ _ . _ . _ _ . _ 419 Summary . . . _ . . . . . . . . . . _ . . . _ . _ . _ . _ _ _ _ _ . _ _ _ . _ _ . _ _ 449 Congenital Malformations . . . . . . . . _ _ . . _ . . _ _ _ _ . _ _ _ . . . . 450 Congenital ilfulformatiorl Summary . _ . . . . . _ . _ . . _ _ . _ _ _ _ . . _ . 4.5 I Lactation Introduction _ . _ _ _ . . _ . . . _ _ _ . . . . . . . _ _ _ _ . _ _ _ 452 Epidemiologkal Studies . . . _ _ . _ . _ . _ _ . _ . . _ . _ . _ _ . _ . . . 452 Experimental Studies . . . . . . . . . _ _ _ . . . _ . . _ . . _ . . . . _ 45 2 Studies in Animals Nicotine ____.__ _._.__ . . . .._.._ ..__ ____ ._ .._ 452 Influence on the Lactation Process _ _ . , _ _ _ . _ . _ _ . . _ _ 457, Presence of Nicotine in the Milk . . . . _ _ _ . . _ _ . _ _ . . . 453 Evidence for an Effect Upon the Nursing Off- spring _ . . _ . . _ . . . . . . _ . . _ . . . . . . .453 Nitrosamines _ . _ . _ _ _ _ _ . . . . . . . . . . . . . . 4.53 Studies in Humans Nicotine and/or Tobacco Smoke . . _ _ . . . . . . . . . . . 453 Influence on the Lactation Process . . . _ . . . . . . . . . 453 Presence of Nicotine in the hlilk . . . . . . . . 454 Evidence for a Clinical Effect Upon the Off- spring..................................... 454 Vitamin C _ _ _ _ _ _ _ . _ _ . . . _ _ . . . . . . . . . . . .455 Lactation Summary _ . . _ . . _ _ . _ . . . . . . . . 455 P reeclampsra . _ . . . . _ . _ _ . . . . . . . . . . . . . . . . . . . 456 Sf~nvnary -.......................................456 References . _ _ . _ _ _ . _ . _ _ . . _ . . . . . . . . . . . . . . . .456 414 List of E-`igurcs Figure l.-\Iea11 birth ucisht for \vcck of ,qcitn!ion according to rnnternsl rmoking habit : control wwk 5in~lctorl5.~-~~ _ . . . FigtIre ?.-Percentape di- for infants 15 ciching le-s than 2,500 grnms, of smokers and nonsmokers- Table J.-Effect of carbon monoxide esl)osurc of pregnnnt rab- bit5 on birth xeipht and neonatal mortality-________-______ Tnble AS.-Proportion of male infants deli\-ered to smoking nnd non5mokjir.rr mother~-_--_-__-_-_----~--~-~-~--~~-~---~~ Tsble C.-Relative ri;k of congenital malformation for infants of riqarette smokcr~ nnd nonsmokers, compnring available studies nith rerard to stwlv desip, study population, samI)le size, number of infants with mniformation~, and dtfinirioll of mallorrnation __.__. -_--_--_-_-_--_----_-~-~---~----~-- 425 431 441 447 450 451 r3w 418 419 422 424 427 442 443 415 Introtluction Ci,nnrette smoking is a common ltahit among n-omen of chiltl-bearing age in the [-nited Stntcs. In 1970, ap1)roxitnntcl~ one-third of --\mer- icnn women of child-bearing age were cigarette smokers. The percent- age of r-.S. !I-ontett who s~uokctl tlirort~hortt pregttxncy is not definitely known, hut is presttrtt;~l~ly lo~rrr. pt-obabl~- in tl~e ttci~ltltorltood of 20 to 25 percent. \Vith n large fetal popttlntiort at potcntinl. but prewnt- able, risk, the relationship betxectr ci,. vrctte smoking anti the out- come of prrpattcy 11:ts Iwen the focus of considrrablc and continuing research. l`hc follr)\vittr is a t,evic%\v of n-014; previously rcportecl and recent stnctics xrItic.11 lw:~r ott t lw rrlat ionsltips bet n-cm cigarette smokittg and dilT0t cant otttcfltiws of I)rc,siinncy. In addition, the chapter includes a revicw of tltc rrl:ttiortlliil) bet\Yccn cigarette smoking and lactation. Smoking and Birth Weight In 19.57. Simpsott (an), using n retrosprctire study dcsip. tleter- tt~ittc~l tlt:rt nittong 7.499 women itt . y z=3ti Rcrtrxrdino CotititJ-. (`alif.. the tlelivcrJ- of infants wet, .qrliinfl less tlran 2.500 grams was ncnrlv t \I-ire as r 417 frequent among cignrctte smol;crs as nmons nonsmol;cr;. Suhseqrlcntly, hue (&) studied fLtH'7 women in Birmingham, England, and dem- onstrated in his retrospective stud? that the infants of smoking mothers u-err. deli\-ered only slightly earlier (1.4 days on the a\-erage) than those of nonsmokers. He further noted that for gestations of 260 days and over, the infants of smokers were consistently lighter in weight during each lx-eek of gestation than those of the nonsmokers. This finding has been confirmed since, and figure 1 from the British Perinatal Mortality Study (13) provides illustration of this relationship. Given the nearly constant disparity present bet!\-een the birth rreigllts of the infants of smokers and nonsmokers for gestations of 260 days atid over, but absent prior to that time, and given t.he similar birth weights of infants of nonsmokers and of lvornen m-ho gave ur> smoking early in pregnancy and did not begin to smoke again, 1,oxv-e inferred tllnt the influence of smokin g upon birth weight might lie mainly in the later months of pre?Fnncy. He emphasized the tentative nature of this conclusion, since the number of infants with 3 gestation of less than 260 &J-S and the nunrber of WOIIWI~ who gave up smoking early in the pregnancy and did not begin to srno!~e again were both small. Figure I.--Mean birth weight for week of gestation according to maternal smok- ing habit: control week slftgletons.' 3650 125 - ,---o---7 3400 2 - 3150 5 -r - 29oog r" - 2650 5 2 85 - - 2400 75 . * 12150 36 37 38 39 40 41 42 43+ Gestation in completed weeks `This term refers to singleton births In England. Scotland. and Wales occurring duting the week of March 3-9. 1958. which are included in the Psrmatal Morfaltty Survey. There com~nsd 97 percent of all births not,fied in England and Wales or registered in~Scotland during ul,r wcJa*. SOURCE: Butler. N. R.. Alberman, E D. (131. 418 LoKe found that the infants whose mothers smoked throuChout pregnancy ~ci~hetl~ on the averxgr, 1iO ~I~:~IIIS Ir.s.3 than tlrojc n-hose mothers did not Smoke. In addition, 11~2 notrtl t!int the c1itir.c tli5trih- tion of weight5 of infant5 of 5rnoliers u.36 shifted to tlx left (t0w3rd lower n-eights) relatise to that for tile infants of ~~on~mokets. This finding, too, has been confirmed bv other investigators. Figure 2 olfcrs an illustration from IUacJIahon, et al. ($I). Given thnt the infants of snrokcrs and non.;nokeIs diRerrd only slightly rrith respect to the duration of gestation, Lowe concluded that the lower birth weight of smokers' infants must be attributed to a direct retardation of fetal growth. In other words, on the basis of his data, the infants of smokers were small-for-dates rather than truly premature. Many investigators have subsequently confirmed this point (12, 1-5, %.~?5,65,78,85, 11.3). Buncher (I2), in a study of 49.63i births among U.S. naval wives, in the same population studied by Underwood, et al. (I&I), found that the infants of smokers were, on the average, de- livered only 1 day earlier than those of nonsmokers. This finding accounted for only 10 percent of the discrepancy in birth weight be- tween the t\ro groups of infants. The remainder of tire studies resulted in the detection of either similar variations in gestntionnl Icngth or no average difference. In a recent study, JIulcahy and Murphy (56), Figure 2.-Percentage distribution by birth weight of infants of mothers who did not smoke during pregnancy and of those who smoked 1 pack of cigarettes or more per day. INFANT WEIGHT AND PARENTAL SMOKlNG HABITS ,`.*,".,`","`,.`~,`~`I"`~ 10 - - Nonsmokers ----- Smokers 8- 4- 2- 0 ,"',"~I...~'.'I~"I"'I".I 4 5 6 ; 8 9 10 11 BIRTH WEIGHT (SCALE IN POUNDS; INTERVALS OF 4 OZ.) SOURCE: UacMahan. et al. (49). 419 in - L sample of 5.099 Irish mothers, concluded that although the babies born to cigarette smokers were delivered slightI\- earlier tllnn those of nonsmokers, independent of age and parity, the direct ehcct of smoking in retarding fetal grolvth It-as more significant. The foilon-ing points, based upon the results from many different studies, can be made about the relationship betrreen cigarette smoking during pregnancy and lov+-er infant birth weight: 1. Tfomen who smoke cigarettes during pregnancy hare a higher proportion of low-birth-weight infants than do nonsmokers. This excess of low-birth-rveight infants among cigarette smokers pre- dominantly consists of infants who are small-for-gestationnl nge rather than gestatioually premature. 2. The entire distribution of birth x-eights of the infants of cign- rette smokers is shifted toward lower xveights compared to the birth reights of the infants of nonsmokers. 3. The birth xv-eights of the infants of cigarette smokers are con- sistently lighter than those of the infants of nonsmokers when the birth rreights of the t-so sets of infants are compared n-ithin groups of similar gestational age beyond the 36th \veek of gestation. The results of the studies which have been considered so far identify a relationship betxeen cigarette smoking and lorrer infant birth weight and illustrate some aspects of that relationship, but do not indicate whether the association is causal or indirect. The succeeding two sections of this chapter contain evaluations of the available evi- dence which bears upon the nature of the association between cigar- ette smoking during pregnancy and the incidence of small-for-dates infants. EVIDENCE FOR A Carssa~ -\SSOCL~TION BE-ITZES CIGARETTE SXOKING ASD SMALL-FOR-DA= INFANTS Evidence previously reriexved in the 1971 and 1972 reports on the health consequences of smoking (201, 102). suggests that cigarette smoking is causallv associated with the delivery of small-for-dates infants. The follow& is a summary of this evidence: 1. The results from all 30 studies in xvhich the relationship between smoking and birth xveight was examined have demonstrated a strong association between maternal cigarette smoking and delivery of IOK- birth-xveight infants. On the average. the smoker has nearly twice the risk of delivering a lox-birth-weight infant as that of a nonsmoker 420 Figure 3.-Percentage of pregnancies with infant weighing less than 2,500 grams, by cigarette smoking category. 5.0 4.0 3.0 2.0 1.0 0.0 Nonsmoker Number of infants weighing <2,500 grams: 1.322 1.186 21 pack per day 793 Total births: 28,358 15,328 (P arent doie- response relationship as found for mater.n;tl smoking. Ilorwcr, he noted that on1y lrhen both the husband :III~[ the wiEc sr11olm1 WC the incidence of lo~~~--birtl~-~~eifil,t babies incrr;\sed. Ire felt thnt these findings supported the conclusion that snwking AXIS :I mxrkrr of t?-pes of individuals and not a cnusai f;lctor for low birth \I-ei,eht. Other investigators have since csamined this relationship ($9, I&I), but none llns confirnicti an inrle~~endcu~ nssocixtion for ptcrnxl smoking. Tlw association between paternal snloking and birth wipht :\ppwrs to be nn indirect enc. Paternal and maternal smokin,rr be- Il3\-inr :ire I~ifihly correl;\ted :~nd mnternat sinckity is stron,$y related to illi;lnt birth vieight. Undern-ood, et al. (100) studird J8.505 women, tllcil- Ilr~sbnntls' Smoking bcllnrior, ant1 tllc wlntion wit11 birtll KriFllt (table 1). If the JIlOtllC'l' \<-as n lionslriolir~~, then the father's smoking hat1 no influcrirc 011 the Girth weight of tllc infnnt. T.IBLE l.--llLfant birth weight by ?Jlo/el`JLd and paiernal smoking habits 425 Ounsted ((8) offered evidence that the best predictor of thr tjirth xveight of a mother`s future offspring TWS the birth weight of her previous children. Hcrriott: et al. (3.5) found prcmnturit_v rates for prex-ious prepnncics among smokers to be markedly 1Iiplrer than among nonsmokers, independent of parity, height, and social class. Evidently n woman \Tlioze previous infants lin~t: been small trntls to roritiniie to have relatix-cl\- srnaller tlran avcrn~e infants in srlbaequfnt prepxncies. The question is- will those infants be even sm:lllcr than expected if 511~ smokes? Goldstein, et al. (I'S). in a comprehrnsiw re~icw, proposed a research dcsi? in which :I u-omen ~~oultl sewe as her own control to compare outcomes of l>rewIancics tlririn_rr \rhich she sInoked with those during .: \rhich she did not, xitli consideration of the effect of parity on the outcome. Terushnlrtiy (213) has recently tested this type of research design. using data from his O:Ikland Growth Study. \\`ith information on the aye ;It wlIjclI a \I~ornnn Iwpn to .srnoke ci,carcttes, her smoking status during the prr,yancx- nctunllv studied, her prior rcproductir-e experience. and the outcome of her present pregnancy, the author compared the outcomes of pre-gnancx during periods of smoking and nonsmoking using the Toman as her orrn control. -AS the author noted, "If smoking cnuer; tlIe increase in lo\~--birtli-~~ei,nlIt infants. then the incidence of low birth n-eight for infants born to smoking mothers during the period before they acquired the smoking habit. should be relatirelv lo\\-. If, on the other hand, the high incidence of Ior birth weigf>t is due to the snooker. then it should behigh for infantsof future smokers also rrhen they rrere born before their mothers started to smoke." Yerushalmy then proceeded to compare the reproductive experiences of four groups of women: (a) Those n-110 smoked in none of their .pregnancies, (b) those who smoked in all of their pregnancies. (6) those x-ho n-ere smoking no-x but preriously had not smoked during some pregnancies (future smokers), and (d) those who mere ex- smokers norm but had prrviouslr smoked during some pregnancies. These outcomes are shorrn in fi-pre 5. The incidence of lox--birth- weight infants in the pre;qancips of the future smokers. before they started to smoke, was similar to that for n-omen who smoked in every prepancy, which rws significantly higher than that of infant-s from 426 There at-e se\-cral considerations which limit the interpretations rrilicl1 ran be dra\rn from this study. The information on smoking bcli:~~ior of the ~vottwtt (luring past prcgttnticies was nppnrently de- riwd from the lvomntt's :tee x-hen she began to smoke, her smoking bcllnvior carI~- in the stuc!v pregnancy, and the age at which she hnd Ilcr prior prcgn3ncics. `I`! 1~. if t.he wotnnn reported that site began smokitt~ at :I ccr-taitt age, and that she vns still smoking at Ihe time of the study. it \vns apparently inferred that ahe hnd smoked during ali of her pt-cgttnncirs. Since no questions wx-e specificnlly asked about actual sntokinr behavior during ench previous pregnancy, it is possible that tlw woulnn indeed had not smoked duritq erery pregnancy or that the amount or wny she smoked had differed from current smoking Figure L-Percent of low birth weight white infants by smoking status of their mothers. Gravidas' smoking habits in previous pregnancies Nonsmoker (during all pregnancies) Percent low birth weight infants . 2,529 Nonsmoker (future smoker) 9.5 o 210 Smoker .* (during all pregnancies) . 8.9 2,076 Smoker (future ex-smoker) . . 651 2 4 6 8 10 Percent *Difference is statistically significant (P ~0230-i3-9 429 a X-minute period. The injection of nicotine in the larger, single dose into the mother produced a rise in maternal blood pressure and a fall in maternal heart rate, and an immediate fall in both fetal hlno(l pressure and fetal heart rate followed by pcrsistcnt hypotcnsion and tachpcardia in the fetus. Subsequent to the injection of 1.0 mg./kg. of nicotine into pregnant monkeys, in a single dose, significant chnnqcs in the arterial blood of the older fetuses included a fall in pII, a rise in base deficit, and a fall in oxvgen tension. Carbon dioside tension remained unchanged. Sicotine injected directly into the fetus prompted an immediate rise in fetal blood pressure and a fall in fetal heart rate. These responses were similar to those previously seen in the mot,hers follorring a direct injcct.ion of nicotine. The changes mere more prominent in older rather than in younger fetuses. The authors sum- marized their findings by stating that: (a) fetuses in different ges- tational stages are difrerentially responsive to a given dose of nico- tine, probably because of the different stages of development of the autonomic nervous system; (b) diminished intervillous space per- fusion resulting from vnsotonstriction in the uterine circulation np- pears to be mainly responsible for the fetal asphyxia following the injection into the mother, because fetal hypotension and bradycnrdin were not preceded by the transient hypertension seen following the direct administration of nicotine to the fetus; (c) the differences he- tween the results obtained hy Kirschbaum and by Suzuki, et al. may reflect either the considerable dosage differences or species differences: and (d) the doses xhich the authors empioyed were much larger than those which a human mother would absorb from usual cigar-ette smok- ing, but that differences in tolerance to nicotine between tile Rhesus monkey and humans would imply that the dosages were, in fact, com- parable and that, "Hence, it can be envisaged that the concentration of nicotine which could be reached in the organism of a smoking mother xould reduce oxygen availability to the fetus." Carbon Monoxide Long0 ($5) has reviewed the work of several investigators which has demonstrated the transplacental passage of carbon monoxide from mother to fetus in animals. A recent study n-hich related CO to birth xeight was published by Astrup (2). He found that continuous es- posure throughout gestation of pregnant rabbits to different levels of ambient carbon monoside resulted in a statistically significant dose- related reduction in birth weight (table 2). The actual significance level was not reported. 430 Sumber of pregnnrlt rabbits __________ 17 14 17 Total number of babies .___.__________ 116 Sl 123 Xwrnge weight uf babies in grams.. _ _. 53. 7 5 1 0 44. 7 SOC`RCE: Astrup, P. (f). PoIpc\-cIic nromntic ~~yd~xxxr~ons (I'-IH) such 3s bcnzo(:l)pyrene (B_IP) nre const,ituents of cigarette smoke which have been impli- cated in the generat,ion of cancers in many animal species (112). So studies presently available relate brnzo(n)p~rcne to a reduction in birth n-eight. of esposed offspring. Evidence wggests, however, that. UAP does reach and cross the placenta. Xryl I~>-drocarbon hydrosylase (.~HH) is a part of the cytochrome P-GO- containing microsomal enzyme system, present in many tissues of different species. This enzxrnc system is induced to hydroxylate pol~cyclic aromatic hydra- carbons after exposure of cells to PdH. Several investigators have utilized the inducibiiity of the enzyme system to demonstrate indirectly that benzo(x)pyrene and other polycyclic IIydrocnrbons reach the plncenta and fet,us. IreIch, et al. (108) extended this work by administering the poly- cyclic hydrocarbon, 3-metlly~cholnnthrene (3-MC), to rats during late gestation. The metabolism of t)enzo(ajpyrene ~-as studied in viva (us- ing t.ritium-labelled benzo(a)pyrene) and in vitro. AHH activity KLS increased in fetal livers to adult levels by pretreatment with 3-NC Since B relatively high dose of polycyclic hydrocarbon was requird to stimulate enzyme activity in the fetus, compared to the dose which stimulated placental enzyme activity, the authors suggested that the placenta may protect. the fetus from esposure to polycyclic hydro- carbons. However, immaturity of the fetal rnzvme qstenl rni,nIlt aiso account for its apparent rclntive insensiti\-ity to pal!-q-clic llydro- carbons. Thwefore, an exposure of the fetus to levels of poly- cyclic h>-drocnrbon similnr to those experienced b- tile motllcr cannot bo ruled out by the available data. 431 Schlede and Merker (86) hare studied the effect of benzo(a) pyrene administration on nryl hydrocnrbon hydroxylnse nctivity in the mnter- nal lir-er, placenta, and fetus of the rat during the latter half of gestation. The pregnant animals were treated with large oral doses of benzo(u)p\-rene 24 hours prior to sacrifice. Co!ltrol rats had no detectable levels of aryl hydrocarbon hydrosylnse in their plnccnt*?s. Treatment with benzo(a) pyrene resulted in barely detectable plnccntal levels on gestation day 13, but steadily rising values until day 15, and then constant levels thereafter. No activity was detected in the fetuses of untreated controls. In the treated animals, the fetal enzyme activity rose steadily from the 13th to the 16th day of gestation. The authors concluded that the stimulatory effect of benzo (a) pyrene treatment on aryl hydrocarbon hydroxylase activity in the fetus demonstrates that benzo (a) pyrene readily crosses the rat placenta. STUDIES IN IImraxs Carbon Monoxide Smokers and their newborn infnnts have significantly elevated levels of carbon monoxide as compared with nonsmokers and their infants (31,3.j, 88,116). Recently, Raribaud, et al. (5) studied 30 nonsmokers and 27 ciF"rette smokers and their newborns. All smokers inhaled. The authors found that the mean level of CO content in the blood of non- smokers was 0.211 volumes percent compared with 0.679 volumes per- cent in the blood of smokers. The values for blood samples from the umbilical cords of tlleir ne\vborns were 0.352 and 0.949 volumes per- cent, respectively. Moreover, a definite dose relationship was found between CO levels and number of cigarettes smoked. Younoszai, et al. (116) found, in addition to elevated cnrbosyhcmo- globin levels among the infants of smoking mothers, significant elevation of mean capillary hemotocrits and significant reduction of standard bicarbonate levels, as compared to the infants of nonsmoking mothers. Since no evidence for nicotine effects upon blood glucose, serum FFA levels, or urinary catecholamines, or for hypoxia was present, they concluded that the higher hematocrit levels in the infants of smoking mothers may have represented a compensatory response TV the decreased oxygen-carrying capacity of the blood due to the presence of csrboxyhemoglobin. Long0 (45) pointed out that a level of 9 percent carboxyhemoglobin in the fetus is the equivalent of a 41 percent decrensc in fetal blood flow or fetal llemoglobin concentration. In reviewing tllc studirs of CO lewls in human mothers and their newborns, llc made the follolr- 432 inp comments: "Tlicse samples xrerc obtained at the time of vaginal delivery or Cfsnrenn section 2nd rnnv not accurntelv rcHect the normal values of (COIIb) F for several rcason~. T!ie nrimber of cigarettes sm0ked by the mothers during labor niay be less than their normal consumption and was not specified in these studies. The blood snm- pies were collrrtetl :it I-arving time periods folloxing the cessation of smoking. In addition, JW111y of the samples were probably taken early in the day beforr C'OIIb le\-els had built up to the levels reached after prolonged periods of smoking. Thus actual lcl-els of (COHb),, and ( COIlb) E. may be higher than the report4 values." Polgcyclic Hydrocarbons The results of several studies concur that cigarette smoking is strongly associated with the induction of ar-yl hydrocarbon hydros- y-lnse in the human placenta (Z&38, 61,99? 109). This finding implies that benzo (a) p~rcne or other polycyclic hydrocarbons reach the placenta. To date. evidence to support the pnssa,ge of polycyclic hydro- carbons through the placent,z to the human fetus has not been published. Vitamin B ,? and Cyanide Detoxification McGarry and ,Andrews (48) determined serum vitamin B,, levels in 8% women at their first prenatal clinic visit. The\- found that the _ serum levels for smokers were significantly lower than for nonsmokers. Sfter adjustnwnt for gestatioiial age, parity, social class, hemoglobin levell hypertension, and maternal weight, smokers still had signifi- cantly Ion-cr levels of B,?. They also found a direct. statistically sig- nificairt dose-respoirse relatioiiship betrreen cigarettes smoked and serum vitamin B,, level. They again confirmed the relationship be- tween smoking and lox birth weight. The authors suggested that the lowered vitamin B,, levels reflect a disorder of cyanide detoxification. Cyanide is a demonstrable ingredient in cigarette smoke (39, 6'0, 62, 64:68,74,91). Vitamin C Penulet (105, 10.6, IO?`) has demonstrated that the vitamin C level is significantly lovrer in the serum of xvomen xv110 smoke cigarettes during pregnancy, compared to values for their nonsmoking counter- pa&i. The following mechanisms have been proposed for the production of low birth weight and other unfavorable outcomes of pregnancy follo~ringevposuretocignrettesmoke: 433 1. A dirwt toxic influence of constituentsof cignrettc smokeupon the fetus (2, $5, 50, 51, 217). 2. Decreased placent31 perfusion (94). 3. Decreased maternal appetite and diminislrcd mnternnl wright gain xvith secondnry effects upon the fetus (G, 33, 36, 65, 75: 9% 117). 4. A direct effect upon the placenta (x,Lz', 65,110). 5. An omytocic effect on uterine nctivity (d$). 6. A disturbance of vitamin B,, metabolism (48). 7. A disturbance of vitamin C metabolism (1/X,106, IW). Of the potential mechanisms, available evidence suggests that neither decreased maternal appetite and decreased maternal weight gain nor a direct effect upon the placenta are responsible for a sig- nificant reduction in birth weight. Existing evidence does not permit firm conclusions concerning the relative significance of the remnining mechanisms. Timing of the Injlucnce of Cigarette Smoking on Birth Weight Several investigators have published results which bear on the time period during which exposure to cigarette smoke most affects fetal grolvth. Lowe (46) and Zabriskie (118) have offered evidence which suggests that cigarette smoking influences fetal growth most during the second half of pregnancy. Butler, et al. (15) found that the birth weights of infants of xomen who did not smoke after the fourth month of pregnancy were. essentially the same as those of the infants of nonsmokers. This implies that the influence is most probably exerted after the fourth month of pregnancy. Herriott, et al. (35), however, found that women in louver socioeconomic classes w-ho gave up smoking early in pregnancy tended to have intermediate weight babies as com- pared with nonsmokers and persistent smokers, but his numbers of women Ivere small and the results were not atat.istically significant. Cndern-ood, et al. (ZOO) found that cigarette smoking in any single trimester was associated xvith a louver birth weight. of the infant, although the difference between the birth xveiglrts of infants of -omen n-ho smoked only during a single trimester and infants of non- smokers was not statistically significant because of srnnll numbers. Several investigators have detected a nearly constant difference be- tween the birth weights of the infants of smokers and nonsmokers. delivered during the last month of pregnancy, follnvrinp gestations of comparable length [fig. 1, (zI)]. Although this observation is 434 compatible rrith the suggestion that the infurnce of cignrrtte smoking upon the fetus occurs prior to tile last month of pr-e,~n:~nc>-. it is b:~-ed upon data derived from cross-sectionnl r;\tllcr ti~nn longitudinal studies. The results of many human epidemiol<~gicni studies suggest that maternal smoking prior to pregnancy does not influence fetal weight gain (1$25,46,@, 113). Site of Action at the Tissue and Celldar Level The use of labelled nicotine (98) and the preparations of autoradio- grnms have permit.ted the localization of nicotine within the tissues of the fetus and mother. Tjalve, et al. (95') found high levels of nico- tine in the respiratory tract, adrenal, kidney, and intestine of 16- to 1% day mice fetuses. The use of other labelled constituents during various parts of gestation might. further the understanding of horn certain ingredients in cigarette smoke produce an impact upon birth lveight. Haworth and Ford (33) have reported data which suggest that the reduction of birth weight of rat fetuses caused by the action of the ingredient(s) of tobaccosmoke results from a reduction in celi number, but not in cell size. Signifinnce of the Association Among nil women in the United States, cigarette smokers are nearly twice as likely to deliver lowbirth-n-eight infants as are non- smokers. Assuming that 20 percent of pregnant women in the fi:nited States smoked cigarettes through the entire pregnancy (estrapolated from data on changes in smoking behavior during pregnancy collected for the British Perinatal Mortality Study), taking into account the apparently different risks of delivering a small-for-dates infant for= Caucasian and non-Caucasian women who smoke during pregnancy, and considering the number of infants with a birth neight less than 2,500 grams born to Caucasian and non-Caucasian n-omen, an excess of nearly 43,000 occurred in the 286,000 low-birth-weight infants among the 3,500,000 infants born in the United States in 1968, because of the increased risk among women who smoke of having smxll-for- dates infants. Since neonatal mortality is higher for lov-birth-weigth infants, with gestational age held constnnt, the excess of small-for-dates infants among smoking moth& would imply a significant excess mortality risk as well. 435 Birth Il-tight Summury A causal association betxwtn cigarette smoking nnd fetsl growth retardation is supported by the following evidence: 1. The results of all 12 studies in xv-hi& the relationship betrreen smoking and birth weight ~cas examined have demonstrated a strong association betrreen cigarette smoking and delir-cry of small-for-dates infants. On the nverage, the smoker has nearly twice the risk of delivering n lov-birth-lveight infant as that of a nonsmoker. 2. This association has been cotirmed by both retrospective and prospective study designs. 3. A strong dose-response relationship has been established betxveen cigarette smoking and the incidence of low-birth-weight infants. Available evidence suggests that the effect of smoking upon fetal growth reflects the number of cigarettes smoked daily during a pregnancy, and not the cumulative effect of cigarette smoking which occurred before the pregnancy began. 4. When a variety of known or suspected factors which also exert an influence upon birth weight have been controlled for, cigarette smoking has consistently been shorn to be independently related to low birth weight. 5. The association has been found in many different countries, among different populations, and in a variety of geographical settings. 6. New evidence suggests that if a woman gives up smoking by the fourth month of pregnancy, her risk of delivering a lore-birtb- weight infant is similar to that of a nonsmoker. `7. The infants of smokers experience a transient acceleration of growth rate during the first 6 months after delivery, compared to infants of nonsmokers. This finding is compatible with viewing birth as the removal of the smoker's infant from a toxic influence. 8. The results of experiments in animals have shown that exposure to tobacco smoke or some of its ingredfents results in the delivery of low-birth-weight offspring. New evidence demonstrates that chronic exposure of rabbits to carbon monoxide during gestation results in a dose-related reduction in the birth weight of their offspring. 9. Data from studies in humans have demonstrated that smokers' fetuses are exposed directly to agents within tobacco mloke, such as carbon monoxide, at levels comparable to those vrhich have been shown to produce low-birth-weight offspring in animals. 436 Cigarette Smoking nrld Fetal and Tnfarlt ;\Iortalit> Introduction Sex-era1 previous studies of-the relationship betrreen cigarette smok- ing and higher feta1 and infant mortality among the infants of smokers have been revie\red in the 1971 and 1972 reports on the health con- sequences of smoking (201, 102). In many of these studies, the authors combined two or more categories of fetal and infant mortality. Diifer- ent mortality outcomes, such as spontaneous abortion, stillbirth, and neonatal death, are influenced by different sets of factors. Among other factors, the frequency of abortion is influenced by congenital infections, hormonal deficiencies, and cervical incompetency. In adtli- tion to other factors, the frequency of stillbirth is influenced by prc- mature separation of the placenta, uterine inertia, and dyst.ocia. .Ilong with other factors, the frequency of neonatal denth is influenced by gestational maturity, birth injuries, and delivery room and nurses-y care. Separate analysis of the relationship of cigarette smoking to each different mortality outcome, with control of the unique set of factors xyhich influences it., may facilitate understanding of the relationship. Spontaneous Abortion Previous epidemiological and experimental studies of the relation- ship between spontaneous abortion and cigarette smoking reviewed in the 1971 and 19i2 reports on the health consequences of smoking (101, 10.2) form the basis of the following statements: The results of several studies, both retrospective and prospective, have demonstrated a statistically significant association bettreen ma- ternal cigarette smoking a~rd spontaneous abortion (4~7, 65, 70, 99, 118). Data from some of these studies hare documented a strong dose- response relationship between the number of cigarettes smoked and the incidence of spontaneous abortions (`iO,99, 118). In general, rari- ables other than cigarette smoking (e.g.: maternal age, parity, health, desire for the pregnancy, and use of medication), which may influence the incidence of spontaneous abortions, have not been controlled. The results of the one study, in n-Irich adjustment for the xroman'n desire for the pregnancy was performed, indicated that after such adjust- ment cigarette smoking during the pregnancy retained an association with spontaneous abortion of borderline significance (4s). The time period during which cigarette smoking might exert an influence on the incidence of spontaneous abortions has not been determined. Abor- 437 tions have been produced in animals only with large doses of nicotine (A?,%, 20;) ; t 1 le rc!er-ante of the3 studies for humans is uncertain. -1Ithough several investigators have found a significantly higher, dose-related incidence of spontaneous abortion among cigarette smokers as compared to nonsmokers, the lack of control of significant a-ariables other than cigarette smoking doe.s not permit a firm con- clusion to be drarrn about the nsturoof the relationship. Epidemiological studies of the association bet,r;een cigarette smok- ing and stillbirth previously reviewed in the 1971 and 19-;2 reports on the health consequences of Emoking (101,102) form the basis for the follorringstatements: In one group of retrospective and prospective studies, a higher stiII- birth rate ~WS found for the infants of smokers as compared to those of nonsmokers (14, 2.5, $3). In another group of retrospective and prcqective studies, co significant difference eras detected in the still- birch rate among the infants of smokers and nonsmokers (16,20,85,99, . 100). Differences in stud\- size, numbers of cigarettes smoked, or the presence or absence of control of variables, such as age and parity, which may influence stillbirth rates, were probably not sufficient to explain the differences in results obtained. Several recent epidemiological studies have added to our under- standing of the relationship between cigarette smoking and stillbirth. Siswander and Gordon (63) have reported data from 39,215 preg- nancies followed prospectively and collected between 1959 and 1966 at 12 university hospitals in the United States. d random sample of rromen who presented to hospital prenatal clinics were enrolled in the study. The authors reported no increase in stillbirths among white smokers as compared rrith Khite nonsmokers. -4 higher incidence of stillbirths was found among black women xho smoked than among nonsmoking black Komen. and a dose-response relationship Kith ciprettcs smoked xvas suggested, although the findings did not attain statistical si3qificnnce. The results rrere not adjusted for other vari- ah&. FL&~ and Kass (82) found, in a prospective study of 3,296 prepancies at, Boston Cit- I%ospital, a nonsignificant hCre3Se in 438 stillbirths among white Tomen who smoked, but a statistically signifi- cant increase in dillbirths among black women who smoked (PO.l). The infants of black smokers, however, had a significantly higher mortality risk than did those of black nonsmokers; the mor- tality ratio was 1.15 (P- StUd~~,emplo~-ed n. log-it transformation analysis of variance, and demonxrated that maternal height, age, parity, social class, and sewre preeclampsia all had a signiticsllt independent clfect on late fetal and neonatal mortality. Rumeau-Roquette (81) provided cvi- dence that a previous stillbirth or lo\\---birth-weight infant significantly increased the risk of a future stillbirth. Meyer and Comstock (51) pro\-ided examples of 110~ the ditfercntisl distribution of smoking and other factors which arc related to perinatal mortality, in a population of \vomenl can bias data (e.g., black women have higher perinatal mortality ratei than do white women, but black women smoke less than white n-omen do. Hence, nonsmokers will tend to include more black Komen. and smokers more \vhite womell. This will tend to reduce any differences between the groups in mortality rates.) Meyer and Comstock concluded, "Comparisons of mortality rates of smokers' and nonsmokers' babies should be made within subgroups according to parity, socioeconomic status, and other appropriate risk factors, and not xparated by birth n-ei$t." In three of the studies in which a significantly higher mortality risk wx demonstrated for the infants of smokers, adjustment for other variables was performed. The result s indicated that, after such ad- justment, a significant. independent association between cigarette smoking and infant mortality persisted (13 and 15, 17, 82). Of the studies rrhich rei-ealed no significant increase in mortality risks for smokers' infants, one (115) controlled for race alone. Hence, at least part of the discrepancy in results between the two groups of studies may be explained by a lack of control of variables other than smoking. -bother possible, at least partial, esplanation of th,: discrepancy - in results obtained by the two sets of studies is that cigaret.te smoke may be more harmful to the fetuses of certain viomen than others. Se\-era1 de\-eloping lines of evidence suggest that t.his may be the case: 1. Cigarette smoking and socioeconomic background. DutIer. et al. (15) noted that IThen data from the British PeAnatal JlortnIity Study are grouped by social class of the mother's husband, the late fetal plus neonatal mortality ratio for infants of smokers and nonsmokers in the upper social classes I and II is 1.10; the mortality ratio for the entire sample was 1.28. Rush and Kass (82) reviewed the British Perinatal lfodality Study, along xx-ith several other studies, nnd noted that a]] have shoEn the strongest aSSO&hn betxrwn excess infant mortality and cigarette smoking among the infants of those mothers rrith loser socioeconomic status. Comstock and Lundin (16) found t.~~e.ss martalit>- among smokers' infants almost entirety con- fhd to those whose fathers had a grammar school education or 1~s. Several of the studies which revealed no significant diderence in mor- tality among the infants of smokers and nonsmokers nsere conducted in predominately middle class populat.ions (20, ZOO, 115). 2. Cigarette smoking and previous obstetrical experience. Peterson, et al. (72) had rigid criteria for entry into his study population of 7,7-N women. He included only those women who pre- viously had healthy infants with a birth weight greater than 2,500 grams. He found a significant decrease in birth weight among smokers' infants, but no significant increase in mortality rates. Rumeau- Roquette (81) found that nmong women who previously had delivered onIy healthy infants rreighing more than 2,500 grams, cigarette smok- ing was not associated rrith an increased risk of stillbirth ; among those women with a previous stillbirth, smoking was significantly associated with incre,ased risk of a future stillbirth. 3. Cigarette smoking and gtnetic differences. The consistent finding that the mortnlity risk for the infants of black smokers is higher than the risk for the infants of v.-hite smokers, even when the socioeconomic background for both is ostensibly similar, suggests that genetic factors also may interact with smoking to pro- duce enhanced risk (SZ? 99, 11.5). Available eridence suggests that if those women, Kho ate already likely to have small infants for reasons other than smoking, smoke during pregnancy, their infants ~-ill be most unfavorably affected. This means that the women in the United Ststfs whose infants Trill be most affected by cigarette smoking are those who have an unfnvor- able socioeconomic situation, have a history of previously unsuccessful pregnancies, and are bIack. Studies in Animals Studies previously reviewed in the 1971 and 1972 reports on the health consequences of smoking (101, 102) demonstrate that exposure of rabbits and rats to tobacco smoke and to injections of large dose2 of nicotine resulted in significantly increased late fetal and neonatal mortality. Astrup (9) has recently studied the effect of continuous exposure of pregnant rabbits to carbon monoxide on stillbirth rates. He found a sipificantly higher, dose-related incidence of stillbirths and deaths within the first 21 hours of life among the offspring of the experimental rabbits (table 4). 446 T.IBLE 4.-Ejfcct qf rnrbon monnride erpowre nf pregnant rabbits on birth weight and neorlcltal mortality -___ Sumber of prepnent rabbits--. ._.______ Total number of babies--.-_-. -- _. _. Stillborn and babies died within first 24 hou~~.~.~--~---~~-~~~~~~---~~~-~~. 17 14 17 116 Sl 123 ' 1 `8 1 44 (P- -!lG~~O of t,he 87,2F3 stillbirth and neonatal deaths in the Cnitcd States in JNX. LATE FETAL ASD SEOSATAI, DEATIE SUXJIARY A strong, probably causal association between cignrctte smoking and higher late fetal and infant mortality among smokers' infants is supported by the following evidence : 1. Twelre retrospective and prospective studies hare revealed a sta- tistically significant relationship betiveen cicnrrttc smoking and an elevated mortality risk amon, n the infants of smokers. In three of these studies, of sufficient size to permit adjustment for other risk factors, a highly significant independent association between smokng and mortality was established. Part of the discrepancy in raults between these studies and those in XThich a significant association between smoking and infant mortality was not dem- onstrated may be explained by a lack of adjustment for risk fac- tors other than smoking. 2. Evidence is converging to suggest that cigarette smoking rnaF be more harmful to the infants of some women than others; this may also, in part, explain the discrepancies between the results of the studies in which a significantly higher mortality risk was shown for the infants of smokers compared to those of nonsmokers and the results of those studies in which significant differences in mortality risk were not found. -- 3. Within groups of similar birth weight, the infants of nonsmokers appear to have a higher mortality risk than do the infants of ciga- rette smokers. This results from the fact that the infants of non- smokers within such similar birth rreight groups are on the ax-ernge gestationally less mature than the infants of cigarette smokers. Available evidence indicates that within groups of sim- ilar cestational age, infants of lower birth weight experience a higher mortality risk. Since the infants of cigarette smokers are `Ras~d on ~xtmpolatlon of data on smoking behnrlor chance durlnr prrgnancr from the Brltlsh Perlnatnl Mortality Studs. which probably rlelds R conscrratlre esttmnte. 448 small-for-gcst:~tion:lI age. onoshould eslwct thnt if the infants of cigarette smokers and non~mokcrs HTC compared within similar geGnti*nal sge cIssces, the infants of ci y:rrctte SIrlOliCr5 trollId have the higher nrortnlitv rete. -1. The results of recent studies hnvc documented a stntisticnlly sig- nificant dose-response rclntionship between the number or nmount of cignrettes smoked and late fetal and nconzrtal mortality. 5. Sew data suggest that if 3 Roman gives up smoking by the fourth month of pregnancy: she will 11nve tile s:rrne risk of incurring n fetal or neonatal loss 3s n nonsmoker. 6. --Imilable evidence strongly supports cigarette smoking as one cause of fetal growth retardation. The causes of excess deaths among the infants of smokers arc those associated with snnril- for-d:rtes babies. 7. I>nta from experiments in animnls have demonstrated thnt espo- sure to tob:rcro smoke or some of its ingrcdicnts, such 2s nicotine or cxrbon monoxide. results iri a significant incrfzrse in late fetal and or neonatal deaths. S. Tire results of studies in humans lrnre shown that the fetus of 3 snrnking niottlrr mnv be tlirectlv exposed to ngclltS Such X3 c:jrbnn nionositlc wit bin tobacco smoke, at levels conipamble to tlrose xhich haw been shown to produce stillbirth in cspcrimrntnl animnls. Sex Ratio .\lt!rough n number of small studies have found a slight, usually 5t:rtistically nonsignificnnt, increase in the proportion of female infants born to smokers, tire tlrrre Inrgest studies of Underwood, et al. (46,505 preLgnanries), Butler (15,791 pregnancies), and Aiac3lahon (12,155 pregnancies) have found similar infant sex ratios among both Smok- ing and rrorismoking r;rotlrer-s, with the cspected slight excess of males ~II~OII~~ZIC~I (table j)* .I\-nilxl,le evidence strongly indicates that mnternal cignrette smok- ing do:~s not inffucncc tltr SW r:ltio of newborn infants. 449 TABLE 5.-f'roportion of mob infants delivered to smoking and non- smokinmg mothers Underwood, et al. (100) ___. ---__----_._ 48,505 Butler and Albennan (14)-------- ______ 15, 791 hlachfahon, et al. (49) _____________ -__- 12, 155 Kullander and Kiillen (43) - - _ _ _ _ - - -_ _ _ _ 6,363 Reinke and Henderson `(78)__- ____ --__- 3, 156 Frazier, et al.1 (26) .___.________________ 2, 915 Kizer (:.2)-- ___.___ - _.___ ---_.- __.____ 2,095 Herriott, ct al. (36)_.-- ____ -- ____ - _____ 2,745 Rnvenholt, et al (77). __-_ _ _______._____ 2,052 Lowe (46)--_.-.-.---__-----------.--- 2,042 Russell, ettd. (83)_--- _..____ - -____ -_-- 2,002 _ 518 .518 .>I3 515 : 498 _ 472 _ 502 .492 -501 .532 .513 -519 - 516 .512 _ 501 _ 517 . 305 _ 493 . 517 .533 . 529 .512 sane. Do. DO. DO. Do. DO. (p>O.OS) NOW. Do. PfnJor. .31 >IoJor. cnuse of den&. .b7 >le]or. .97 I. 19 >If$x. Cz."SD of 1.07 (1) Congenital Xalformafion Summary Given the considerable variation in study design, st-udy population, sample size, number of affected infants, definition of malformation, and results, no conclusions can be drawn about any relationship between maternal cigarette smoking and conge.nitai malformation at the present time. 451 Lactation Introduction The following section is a review of available e\-idence which bears upon any interaction betxveen cl, `oarette smoking and lactation. Emphn- sis is placed upon the relationship of cigarette smoking to the quantity of milk produced, to the presence of constituents of cigarette smoke within the milk, and to eirects upon the nursing infant mediated through changes in either the quantity of milk available or the sub- stances within the milk. Epidemiological Studies cnderx-ood, et al. (99), in a stud1 of 2.000 rromen from various social and economic strata, observed a definite but statisticall? insig- nificant trend toward more frequent inadequacy of breast milk pro- duction among those smoking mother; Kho attempted to nurse compared to nonsmokers. Mills (Z), in a study of 520 women. found that among women who indicated either a desire to nurse or no desire to nurse yet continued to nurse, beyond 10 days, and riho had delivered their first live-born infant? the average period of nursing for mothers who smoked was significantly shorter than for nonsmokers. Moreover, among the W mothers who had given up smoking during at least the final 3 months of their pregnancies, the average length of nursing was identical to that of the nonsmokers. There was no significant difference between smokers and nonsmokers with regard to complete inability to nurse their offspring. This study is difficult to interpret because the author did not determine the reason(s) for the discontinuation of nursing among the women. Experimental Studies Nicotine Influence on the Lactation Process Blake and Sawyer (II) studied the influence of subcutaneously injected nicotine (4 mg. total over a s-minute period) upon lactation in the rat. They found that nicotine inhibited the suckling-induced 452 rise in prolactin. So ctfcct of injected nicotine was dcmonstratcd for ox>-tocin secretion since milk release was not, blocked. T\`ilson (110) examined the etfcc:s of nicotine supplied throcg'n drinking water (0.5. 1.0. and 2.0 mg. daily) on the weight rain of nursing rats. -\pp`arently: the nicotine had been avnilablc throughout gestation as well! because theauthor commented on a reduction in litter size among the experimental groups. more or less proportionate to the dose of nicotine; hence. a prenatal efrect could not have been dis- tinguished from a postnatal one. Average birth weight was similar for ex-pcrimtntal and control groups. Ko difference in weight gain wasseen for any of the groups. The lack of impact on birth weight suggests thnt dose was loser than that used in other studies. Presence of Nicotine in the Nilk Hatcher and Crosby (A??), using a frog bioassay, reported traces of nicotine in cotr? milk ?I hours after the intramuscular injection of 5.0 mg./kg. and 5 hours after the injection of 0.5 mg./kg. Evidence for an Effect Upon the Nursing Offspring Hatcher and Crosby (3;3).found that 0.5 mg./kg. nicot.ine injected into nursing cats had no apparent harmful effect upon the kittens. Apparently 4.0 mg./kg. suppressed Iactation. Kittens fed the miik from the cow trhich had been injected with 5.0 mg./kg. nicotine rrere also apparently unaffected. Nitrosamines Bohr (53) found that diethglnitrosamine and dibutylnitrosamine: when administered to lactating hamsters, were associated -with the deL*elopnwnt of typical trachea1 papillary tumors in the -oung? SU,O- gesting passage df these compounds in.;he milk. Although diethyl- nitrosamine and dibutvlrlitrosanline have not been identified in ciga- rette smoke, manv X-nitrosamines are potent carcinogens, and some- of them are present in cigarette smoke (37, 79). Sicotine and/or Tobacco Smoke Infiuence on the Lactation Process Emanuel (22') noted no reduction in milk production among 10 rret nurses who xere encouraged to smoke seven to 15 cigarettes daily; 453 some were observed to inhale the smoke. Hatcher and Crosby (39) noted that after a mother smoked seven cigarettes vSthin 2 hours, it was dificult to obtain a specimen of breast, milk. PerIman, et al. (71) found that of 55 women smokers with an adequate milk suppiy at t.he beginning of his study, 11 (20 percent) of the women had an inade- quate supply at the time of discharge from the hospital. No relation- ship was reported between the number of cigarettes smoked and the likelihood of developing an inadequate milk supply. The authors' im- pression was that there was no greater proportion with an inadequate milk supply among smokers than among nonsmokers, but no cur- roborating data were supplied. Presence of h'icotine in the hiilk Hatcher and Crosby (33) found, using a frog bioassay, that the milk of a woman collected after she had smoked seven cigarettes in 2 hours contained approximately 0.6 mg./liter nicotine. Emanuel (D?), using a leech bioassay, studied excretion of nicotine in the milk of wet nurses who were encouraged to smoke for the experiment. -1fter the subjects had smoked six to 15 cigarettes over a l- to 2-hour period, the author found nicotine in their milk 4 to 5 hours after smoking, with a maximum concentration of 0.03 mg./liter. Bisdom (10) demonstrated nicotine in the milk of a mother who smoked 20 cigarettes a day. Thompson (97) found approximately 0.1 mg./liter of nicotine in the milk of a mother who smoked nine cigarettes a day (plus three pipe- fuls). Perhnan, et ai. (71), using a Daphnia bioassay, demonstrated nicotine in the milk of all women who smoked in their study. Moreover, they found a direct. dose-relationship between concentration of nicotine and the number of cigarettes smoked. No comment is made by the authors on the possible inaccuracy introduced by examining only the residual milk following nursing, but it is well known that the composi- tion of the fore milk and hind milk is different and perhaps the concentration of nicotine also differs. Evidence for a Clinical Effect Upon the Offspring Emanuel (99) noted that among the infants in his study, loose stools were observed only in the one N-hose wet nurse had smoked 20 ciga- rettes in the previous 4 hours. Bisdom (10) observed a case of "nico- tine poisoning" in a 6-week-old infant -hose mother smoked 20 ciga- rettes a day. The symptoms included : restlessness, vomiting. diarrhea, and tachycardia. Nicotine was demonstrated in the milk, and the symptoms abated when smoking was stopped. Greiner (30) also de- scribed a case of possible nicotine poisoning in a 3-week-old nursling 454 ~1~os.e mother smoked 35 to JOcigarettes a dav. Thr symptoms incliitlcd vomiting and loose stools. Folloxvin~~ the curtailment of smoliinr. the symptoms gradually abated over a 3-da>- period. l'crlninn. et nl. (71) noted no etfect of smoking on the weight ~ train of the infants of the smokers in their study. Furthermore. no untoward symptoms wx-e obserr-ed. They therefore doubted an efcct of smoking on lactation. They noted that the dose received by the infants xas beneath the toxic level as computed from adult experience. and this accorded vcith their clinical observations. The fact that they admitted to the study only women with an apparently adequate milk supply mnp 11ave affected their results. The authors su ggested that perhaps the lack of effect of smoking upon lactation might represent the development of tolcrnnce to nicotine, as both the mother and the offspring had been exposed throughout the pregnancy. VITAMIX C Venulet (105, 106, 107), in a series of studies, demonstrated that the level of vitamin C was reduced in the milk of smoking mothers as compared with nonsmokers. The clinical si:nificnnce of this observa- tion has not been evaluated. 1. The t-rro pertinent epidemiologiczil studies suggest a possible in- fluence of smoking upon the ndequnc>- of milk supply However, with only limited numbers of women and without control of other potentially significant variables, no conclusions can be drax-n. 2. Studies in rats leave demonstrated that nicotine can interfere with suckling-induced rise iii prolnctin. The relet-ante for humans is uncertain. 3. Evidence exists that nicotine passes into breast milk. No clear evidence for an acute effect upon the nursing infant is available. I'otential chronic ctfccts have not been studied. 4. Sew cl-idcnce from esperimcnts wit]: niice suggests that nitros- amines. liuo\vn cnrcino~rns, pass througIr the milk to suckling pIIll-`. 455 Preeclampsia Previous epidemiologic4 studies of the relationship betxwen cig- arette smoking and preeclampsia were revielred in the 1971 nnd 13Z reports on t.he health consequences of smoking (~01,102) and form the basis of the following statements: The results of several large prospective and retrospective studies indicate a statistically significant lorrer incidence of prceclampsia among smoking women (I-6, @`,100). The results of one large retro- spective study demonstrated a significant inverse relationship between the incidence of preeclampsia and the number of cigarettes smoked (ZOO). When other risk factors, such as parity, social class; maternal weight before the pregnancy, and maternal weight gain during the pregnancy Kere controlled, smokin, n women retained a significantly decreased risk of prerclampsia (22). The lower risk of preeclampsia for cigarette smoking Tomen has been demonstrated in Britain and Scotland (14, 21, 46: 83), The United States (100, 228), Venezuela (@) , and Sweden (@) . If a maternal smoker does develop preeclamp- sia, however, available data suggest that her infant has a higher mor- tality risk than does the infant of a nonsmoker with preeclampsia (21,83). 1. Available evidence indicates that maternal cigarette smokers have a significantly loxrer risk of developing preeclampsia as compared to nonsmokers. 2. If a rroman who smokes cigarettes during pregnancy does develop preeclampsia, her infant has a higher mortality risk than the infant of a nonsmoker rrith preeclampsia. Pregnancy References (I) ABEBNATHY. J. R.. GBEENBEW, B. G., WELLB, H. B., Fruzroc. T. 11. Smoking as an independent rariahle in a multiple regression analysis upon birth weight and gestation. American Journal of Public Health and the Xintion's Health 56(4) : 62-3, April 1966. (2) ASTBUP, P. Patbologische Wirkuogen miissiger Koblenmonoxid-Konzen- trationen. (Pathological effects of moderate carbon monoxide concentra- tions.) Staub-Reinhnltongder Luft 32(4) : 146-150.1972. (S) BAILEY, R. R. The effect of maternal smoking on the infant birth n-eight. New Zealand Medical Journal 71(456) : 293-294, May 1970. 456 (4) BAKEa. F. D.. T~MA~OXI~. C. F. Carbon monoxide and avlan embryo- genesis. Archires of EZnrlronmental EIcalth 24(l) : X%61, January 192. (5) B=IBALD. L.. Yac0c-s. 11.. FALTBE. .I.. XALIXM. Y.. C.&v, G. L'oxyacar- bonemie de l'enfant ne de mere fumeuse. (Presence oC carbon monoxide ln the blood of a child born of a smoking mother.) Mwlecine Legale et Dommage Carpore 3(3) : 272-274. July-August-September 1970. (6) Bm, v. A. Nutritional studies during pregnancy. Journal of the Amerl- can Dietetic Association 58(4) : 321-326, April 1971. (7) BECK% R. F.. &SO. J. E. Studies on nicotine absorption during preg- nancy. II. The effects of acute heary doses on mother and neonates. American Journal of Obstetrics and Gynecology 93(3) : 515-522, June 15.1966. (8) BECKEB. R. F.. LII-TLK, C. R D.. 61x0. J. E. Experimental studies on nicotine absorption in rats during pregnancy. III. Effect of subcutaneous injection of small chronic doses upn mother. fetus, and neonate. Ameri- can Journal of Obstetrics and Gynecology lOCl(7) : 937-968, Apr. 1, 1968. (9) BECK=. R.. F., .\IARTIS, J. C. Vital effects of chronic nfcotine absorption and chronic hypoxic stress during pregnancy and the nursing period. American Journal of Obstetrics and Gynecology llO(4) : 522-533, June 15,1971. (10) BI~DOY. C. J. W'. Alcohol nnd nicotine poisoning in infants (sucklings), Jlnandshrift roar Kindergeneeskunde G : 3X-341, 1937. (11) B~-*lce C. A.. SAWVYER. C. II. Nicotine blocks the suckling-induced rise in circulnting prolactin in lactating rats. Science 177(4(X9) : 6IM21, Aug. 18. 19i2. (1-O) BCNCHES. C. R. 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Americnn Journnl of Obstetrics and Gynecology 101(6) : Mk849, July 15.1968. (56) ~1mdA~r. R. M~Jw~Y, J. Xatemal smoking and the timlng of delirery. Journal of the Irish Medical Association 65(i) : 175177, Apr. 1, 19i2. (57) McrcAnr. R.. MUBPIIY. J.. MARTIN, F. Placental changes and maternal weight in.smoking and nonsmoking mothers. American Journal of Ob- stetric-sand Gynecology 106(5) : 703704. .liar. 1,197o. (58) Jtua~u. D. E. Birth aeight and smoking. Nebraska State Medical Jour- nal 48 (11 I : 60-6. November 1%. (") >lWPHY. J- F., J_~WAXY. Il. The effwt of age, parity, and cigarette smok- ing on baby WeQht. American Journal of Obstetrics and Gynecology 111(l) : 22-25, Sept. 1,197l. 459 (60) ~AU, J. F. Complexed cyanide in collected cigarette smoke. Abstracts of 20th `robaceo Chemists' Research Conference. SOV. l-3. 1966. \Vtnston- Salem, S.C.. 1966. pp. 2627. (61) SEBEBT, D. \$-., JYIXKEB, J.. GELBOIN. H. V. 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The excretion of nicotine in breast milk and urine from cigarette smoking. Journal of the American Medical Association 12O( 13) : 1003-1069, Nov. 28.1942. (72) PEIKuON, W. F.. niORESI% R. N.. KALTBEIDER. D. F. Smoking and pre maturity. A preliminary report based on study of 7.740 Caucasians. Obstetrics and Gynecology 26(6) : 7757iB. December 1965. (75) ~EBMON, F. Medtcinska skadeverkningar av rokoing. Riikning och by- nekologiskobstetriska tillstand. (Harmful clinical effects of smoking. Smoking and g.vn~~logicaI-obstetrical condition.) Social-Medirinsk Ttdskrlft 2 (Special No.) : 78-82. February 1971. (74) P~~UPPE R. J.. y~oaa6. hf. E. Some components of the gas phase of cigarette smoke. Analytical Chemistry 28(12) : 2662-2005. December 1956. (75) GWRoSE. T., HIWINB, A. A stndy in human antepnrtum nutrition. Journal of Reproductive Medicine 7(6) : 257-264. December 1971. (76) RA~TAKALLIO. P. Groups at Risk in Low Birth Weight Infants and Perinn- tat hfortality. A prospective study of the biological characteristics and 8OCiOeCOnOmiC rtrcumstances of mothers in 12.666 deliveries in North FInland 1966. A dtscrfminant function analysis.' Acta Paediatrtca Scandtnavica (Supplement 193) : 1969.71 pp. 460 (77) RA\`ES~OLT. R. T., LEYISBKI, 31. J.. SEXLIST. D. J., TAKESAGA. 11. Effects Of S~lukirll: U]I(~II rrprodncti~~~~. .\nitrican Jvuru:il c,f Qtvhlctrics and G~-nPcolo.qr !I(;(?) : L'c;-31. sq,t. 15, I!,& (78) REISI(E. \V. .\.. IIESLIERSOY, 11. SmclkinC and I~rrmnturif>- in tlic prcwnce of Other rnriables Archives of Ewrironmentnl Ilcnltl~ l,(S) : 1;OW.W. 31:1>- I%;& (79) RHO.*DES. J. TV., JOllN60S. D. E. Method for the determination of S-nitro- SAmines in tobacco-smoke condensatr. Journnl of the Sational Cancer Institute4S(G) : X-11-1M3, June 1971. (SO) ROBISSOS. I'. `Txh\rn nshym B\vr:nm~-wt rzmn hhr~xx-n whshp'tw `I h'm Il'wbr ~11~1~d. (Smokillg by Burmese women during pregnancy nnd its influence on the mother, the fetus and rhe newborn.) Wnrefunh fxl ( 2) : 3733. 196.5. (81) RU~IEAU-ROUQUETTE. C., GouJARLI, J., Kaw~ss~x, 11.. SCIIXVAR~Z, D. Mortnlite perinntnle en relation avec les antecedents obstetricnuz et l'usage du tabnc. (I'erinstnl mortality in relation to obstetric antecedents and tobacco usage.) Pnpcr presented at the Third European Congress of Perinatnl 1Iedicine. Lausannr, Apr. 19-22, 1372, 8 PP. (82) RL`sII. D., KASS. E. H. Maternal smoking: A reassessment of the assocla- tion with perinatnl mortality. American Journnl of Epidemiolon OO(3) : 183-196. September 1972. (83) RCSSELL, C. S.. TAYLOR, R., L.kw, C. E. Smoking in pregnancy. maternal blood pressure, pregnancy outcome, baby weight nnd growth, and other related factors. A prospectire study. British Journnl of Preventire and Social Medicine 22(3) : 119-126. July 3363. (ej) RCS~~ZLL, C. S.. TAYLOR, R., Jlann~sos. R. S. Some effects of smoking in Pregnancy. Journal of Obstetrics and Gynecology of the British Common- wealth 73 : 7-12-746, October 1966. (85) SavFz, L. E., RVIH, E. Effects of smoking in pregnancy: -4 continutng retrospectire study. Obstetrics and Gl-necology 20(3) : 313-316 SePtem- her 1962. (86) SCIILEDE, E., JIERKER, H.-J. Effect of benzo(a)pyrene treatment on the benzo(a)Pyrrne hydrosylase activity in maternnl liver, placenta. and fetus of the rat during day 13 to day 18 of gestation. Naunyn-Schmlede- berg's Archives of Pharmacology Z?(l) : 69-100. Dec. 21.1971. (87) SCIIOESECK, F. J. Cigarette smoking in pregnancy. P*`ew York State Journal of Medicine 41: 196-1948. Oct. I. 19-i]. (88) SCOFTETTA. Y. Sul contenuto di ossido di carbonio nel sarwe circohte di gestanti fumatrici. (Carbon monoxide content in the blood circulating in pregnant smokers.) Archirio di Ostetricin e Ginecologia 73(3) : 36% 375. Mar-June 1963. (89) SIEBER. S. 11.. FABRO, S. Identiftcation of drugs in the PreimPlantation- bIastoc)-st and in the plasma, uterine secretion and Urine of the Pregnant rabbit. Journal of Pharmacology and Experimental Therapeutics 176(l) : f3.%75.1971. (go) SIMPSON. IV. J. A preliminary report on cigarette smoking and the incidence of prematurity. American Journal of Obstetrics and Gone- colom 5314) : SO.%Rl.X April 195'7. (91) SPEARS. A. \I-.. ROUTES, w. F,. A combined approach to the wantitatire ana)rsis of the rir,tatiIe comtwnents of cigarette smoke. Paper presented nt the ~,c,th Tol,acco rtlemists Research Confewnce. Raleigh. N.C.. 1964. 49~wzS O-73-11 461 (98) TJ~LVE. H.. H~sseo?i, E.. SCR>r1TERLijn-. C. G. Pascnge of "C-nicotine and its metnholitrs info mice foetnws and ldnrentfie. .%ctn Phnrrnnrolo,cicz et Toxicolo~icn 3?(G) : .X%-5.55. l!H. (103) U.S. PUBLIC HEALTH SERVICE. SATIOS`IL CESTER FOR HEMXK STATISTICS. .Weight at birth and survival of the nen-l>orn--Z'nitrd States. earl? 1950. Washinfiton. U.S. Department of Health. Education. and lvelfare. Public Health Service Publication so. 1000. Series 21, So. 3. July 1965. 33 PP. (fOJ) VABA. J?.. KINVUNEN, 0. The effect of nicotine on the female rabbit and developing foetus. An expwimrntal study. Annals Medicinae Eswri- mentalis et Biolntica Fenniae 2 : LX)?-1'31. 1951. (105) VETOLET. F. Nastcpstxv-a niedohoru vitamin? c u palnczy. (Consequences of vitamin C deficiency In smokers.) Polskie hrchiwum Jledx.mY Kerrnetrznej 2G : 393-402. 1%6. (106) VESIXFT. F., T,avsz. H. Uhytek witaminr c R narzndnch mb poddsn?ch dzialnniu dcmu tytonion-ego. (Influence of tobacco smoke on ascorbic acid content in mothers' milk.) Acta Physiologica I'olonica 4(4) : %I- Xi6, 1954. (197) VESCLLTT. F.. n.tsrsz. A. \Vp'lrw Palenin Wtoniu nfl poziom n-itamiw C R mleku Kobiccym. (The influence of tobacco smoking on the k?vfi of vitamin C in human milk.) Pediatria Polska 3Of9) : 811-817. 19% 462 (103) WELTII. R. ~1.. E~.\RRISOS. T. E.. GOMQI. II. W.. Porrrxs. P. J.. FITSTER \I.. COSXEY. -4. H. Stimulntory effect of cicarette smoking on the hrtlroxrla- tion of 3.Nwnq1~rene and the S-dcn~rthrlntion of 3-methFl--l-mono- met2l~laminoazohenzene bS enzymes in human placentn. Clinicn\ Phar- mncologp and Thrr:lpeutics 10( 1) : 100-109. Jnnuarl--Fehrunc- 1969. (ff0) U~ILSOT. E. IV. The effect of smoking in prcgnanc>- on the placental coeffi- cient. Sew Zealand Medical Journal 74 (-475) : 38&X%5, lOi-3. (111) \VYXDFR. E. I,., HOFFX%XS. D. Tobncco nnd Tobacco Smoke. Studies in Experimental Cnrcinogenesis. Sew York. Academic Press. 1967. 530 pp. (112) TERUSRALMY. J. Infants with low-birth n-eight born before their mothers started to smoke cigarettes. Americau .Journnl of Obstetrics and Grne- colog~ 112(1?) : Xi-2R1, Jnn. 15, 1972. (213) TERCSX.~LXY. J. Mother's cignrctte smoking nnd surrirnl of infant. Amerl- can Journal of Ollstetrics and G.~necolo=y S(4) : SOS-518. Feb. 1.5, 136% (11-I) YERUSHALYY, J. Statistical considerntious and ernluntion of rpiden~iolo.& cal eridcncr. 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Canadian Medical ?\ssocintion Journal 99(S) : lOi-200, -411;. 3. 19GS. 463 Chaprer 6 Peptic Ulcer Disease Source: 1973 Reporl, Chapter 5, pager 151 - 164 46.5 Contents Introduction___-__-.-----_------------------------------- 469 Epidemiolo$xl and Clinical Studies--- _ -_ _- _-_ _- -_ -_ _ _ __ - - 469 Esperimental Studies G~str2cSecretion_-_~ _______ _-___---_--_-___-_-_______ 471 Pancreatic Secretfon-- -___-_____ ---_---- ____________- - 473 Summnry of Recent Peptic Ulcer Disease Findings- _ _ _ _ - _ _ _ _ 476 Refcrcnces ___-__-____ __-__-_____ -- ___-___ --__-__-___-- 477 List of Figures I.`i,qre I.-Gastric ulcer tiortality ratios of Japanese (men and women combined) by age at initiation bf cigarette smoking (19GF-70)_-____-____________-__-__-_--_------~--~---- 470 Figure Z.-Effect of cigarett.e smoking on volume of secretin- stimulated pancreatic secretion in humans_--___--_-__-__- 474 Figure S.-Effect of cigarette smoking on secretin-stimulated pancreatic bicarbonnte output in humans-_-__-____-__-___ 475 467 Introdriction Preriouu epidemiological and erpcrimental studies of the relat.ion- sliip between cigarette smoking and peptic ulcer disease were review-ed in the 19i1 and 1972 reports on the health consequences of smoking (17,18) sntl form the basis of the folloxving summary : The results of epidemiological studies indicate that cigarette smok- ing males have an increased prevalence of pept.ic ulcer disease and a greater mortality from peptic ulcer as compared to nonsmoking males. _Ytnong mnlcs, the association betn-een cigarette smoking and peptic ulcer disease is stronger for gastric than for duodenal ulcer, but sig- nificant for both. For males, ciprette smoking appears to reduce the ctfcctiwness of standard peptic ulcer treatment and to slow the rate of peptic ulcer healing. The relationship between cigarette smoking and the prevalence of and mortality from peptic ulcer disease is less clear for females than for males. Experimental studies of the effect of cigarette smoking in man, and of the effect of injection and infusion of nicotine in animals, on gastric secretion and motilitv ha\-e produced conflicting results. In dogs, an infusiori of nicotine has been found to inhibit pancreatic and hepatic bicarbonate secretion, thus demonstrating a possible link between cirarctte snroking and duodenal ulcer. Recently, additional epidemiological, clinical, autopsy, and esperi- mental studies have confirmed the association between cigarette smok- ing and gastric ulcer mortality and have clarified a mechanism through which cigarette smoking might be linked to duodenal ulcer. Epidemiological and Clinical Studies Previous studies of the relationship between peptic ulcer- disease and cigarette smoking haw been conducted in predominantly white, We.+ em populations. A large prospective epidemiological study is currently being conducted in .Japan. From this study, Hirayama (6) reported 5-J-e3r folIowup data on 265,llS men and women, aged 40 years and older, reprcsentinF St to 99 percent of the total population in the area of the 3 health districts in xvhich thestudy was conducted. Both male and female cigarette smokers cq)erienced higher death rates from gastric ulcer as coml~awci with nonsmokers. The mortality ratio for ciznrctte smokers was 1.81 for males (r)25 <= -pothalamus, blocked the nicotine-induced gastric secretory stimula- tion in the presence of intact vagi. The authors concluded that chronic nicotine-induced gastric secretory stimulation is mediated via anterior hypothalamic activation and intact ragus nerves. The importance of local effects remained uncertain. Pancreatic Secretion Bpnum, et al. (3) studied the effect of cigarette smoking upon pan- creatic secretion in -23 healthy young males and females. Five control male nonsmokers xere compared with seven male and t\ro female light smokers (Iess than one pack of cigarettes per day for less than .7 years) and eight male and one female heavy smokers (more than one pack of 473 cigarettes per day for more than 3 years). Pancreatic secretion n-as measured by the double secretin test, using Boots secretin. The experi- ment was divided into two parts for the SJrlOk0~3: A basal collection period and an experimental period during which the subjects smoked seven nonfiltered cigarettes at the rate of four per hour. Light smokers had basal values for pancreatic secretory volume and bicarbonate out- put in response to secretin which were not significantly different from controls. After the subjects had smoked, significant depression of both pancreatic volume and bicarbonate output was noted (P<.oOl). Heavy smokers had basal values that were significantly less than in the control subjects (P, no. cigarette per 1.05 x IO" 3.5 x 1o'2 3.3 B Particulate phase 2Tar (chloroform extract) 20.8 10.2 44.1 2.L 34,s 3.4 I .6Y 1.8 I.27 2.8 13.5 x 10 3.7 39 x 1o-s 3.0 0.603 2.6 4s x 1o-5 3.6 Nrcotine Benzo(a)pyrene Pyrene Total phenols Cadmium 0.92 0.46 3.5 x 10-s 13 x 1cs 0.228 12.5 x 1cs Filter cigarette C Cases and vapors Water 1.5 295 39.7 Ammonia 0.16 1.4 46 Carbon mon+ide 31.4 148 4.7 Carbon dioxide 63.5 79.5 1.3 Oxides of Nitrogen 0.014 0 OS1 3.6 A number of other researchers have sttcmpted to measure the Ir-:els of some of the substances in ci$!iJKtk smoke encountered in everyday situations (Table 2). They have also tried to determine the factors controlling the atmospheric concentrations of these substances as well as the amount absorbed by nonsmokers under these conditions. Carbon monoxide, nicotine, benzo(a)pyrene, acrolein, and acetaldehyde have been of particular concern. Levels of carbon monoxide (CO), a major product of tobacco combustion, have been studind in a variety of situations, and concentrations ranging from 2 to 1 10 ppm have been measured (Table 2). The major determinants of the CO levels in these situations are size of the space in which the smoking occurs (dilution of CO). the number and type of tobacco products smoked (CO production), and the amount and effectiveness of ventilation (CO removal). The type of tobacco product smoked is important as a determinant of CO exposure because it has been found that mainstream smoke from regular and small cigars contains more CO pre puff and per gram of tobacco burned than filtered or unfiltered cigarettes (S). Tllis greater production of CO by cigars was confirmed by Harke (23). He measured the CO produced by 42 cigarettes, 9 cigars. and 9 pipefuls of tobacco, each product evaluated separately but under the same room conditions. The cigars produced the highest CO level (60 ppm). In addition to the effect of type of tobacco product on CO levels. data on the effects of room size, amount of tobacco burned, and ventilation are included in Table 2. Only under conditions of unusually heavy smoking and poor ventilation did CO levels exceed the haximum permissible, &hour industrial exposure limit of--f0 ppm CO (I); however, even in cases where the ventilation was adequate, the measured CO levels did exceed the maximum acceptable ambient level of9 ppm (18). Harke (-37) also showed that in small enclosed ventilated spaces (an automobile) the CO level is determined more by the number of cigarettes being smoked at one given time than by the cumula\ive number of cigarettes that have been smoked; also the CO level decreases rapidly once the smoking stops. 486 Rcfcrcncc, Location, and Dlmenslons If Known VcnlilJtion Conslilllcnls Ilarkc, IL-P., Cl 31. (7) hlid-size European cur, cng~ne off, in wind tunnel at so km/h1 wind speed Nvne Air jets open Sr blower off 9 c,g 6 cig 30 ppm CO 20 ppm CO Air jets open & blou'er on 6 cig 10ppmCO Mid-size European car, engine off, in wind tunnel al zero km/hr wind speed None NOW Air jets open & blower on 9 cig 6 cig 6 cit. llOppmC0 80 ppm CO 8-10 ppm CO Ilarke, H.-P., Peters, H. (28) Car in trafl'tc Srch. hf. (a) Car, en Tine off- $ 2.09 n, NOllC 4 cig None 10 cig in I hr 21.4 ppm CO 90 ppm CO, Smokers I O'I (`Ollh ?ionvnokcrr 5'): UIllb Scilf, I1.E. (~4) Intcrcity busts 23 cig (burning conlinuou\ly) fs 0) TABLE 2. - Measuremenrs of constiruenfs released by rhe combustion of tobacco products in various sirlrarions - COnrilrfled 02 [ Cig = cigare t (es; - = unknown; TPhl = total particulate matter] Reference, Location, and Dimensions If Known Ventilation Amount of Tobacco Burned Constituents U.S. Dept. Transportation, et al. (48) Airplane flights: Overseas-100% filed Domestic-66% filled 15-20 air changes per hr do. 2-S ppm CO < 120 mg/m3 TPM <2 ppm CO: <:I20 mg/m3 TPhf Cano, J.P., et al. (I 1) Submarines-66 m3 Godin, G, et al. (21) Ferry boat compartments: Smoking Nonsmoking Yes 157 cig per day 94-103 cig per day <40 ppm CO, 32 up/m3 Nicotine <40 ppm CO, 15-35 pg/rn3 Nicotine 18.4 i8.7 ppm CO 3.Oi2.4 ppm CO `Iheater: Foyer Auditorium 3.4tO.8 ppm CO 1.4iO.8 ppm CO Bridge, D.P., Corn, M. (7) Party rooms: 145 m3 101 m3 7 air changes per hr 1) 10.6 air changes per hr 50 cig & 17 cigars in 1.5 hr 63 cig & 10 cigars in 1.5 hr 7 ppm CO 9 ppm CO TABLE 2. - Measurements of constituents released by the combustion of tobacco products in various situations - Continued [ Cig = cigarettes; - = unknown; TPM = tot31'pa~ticthte matter] Rcfcrence, Location, and Dimensions If Known Ventilation Amount of Tobacco Burned ConstiWents llarke, H.-P., et al. $ 25) Room-38.2 m None 30 cig per 13 min (by machine) 64 ppm CO, 510 ug/m3 Nicotine .46 mg/m3 Acrolein 6.5 mg/m3 Acctaldehydc 5 cig per 13 min (by machine) Il.5 ppm CO, 60 rg/m3 Nicotine, ..07 mg/m3 Acrolcin, 1.3 mn/m3 Acctaldchydc Harkc. H.-P. (24) Office Bldg ofrlcc Illdg Roum-78.3 m3 Air conditioned Not air conditioned 3 smokers <5 ppm CO <5 ppm co ! 5.6 ppm CO Harkc, IL-P., (23, Room-57 m3 None 42 cig (by machine) 7.2 air changes per hr 42 cig do. 50 ppm CO, 530 pg/rn: Niculinc 8.4 air charlgcs per hr 42 cig do. < ;; ;;; ;;I :-:",;y;,,3";;.;;::;lc None 9 cigars do. 60 ppm CO, 1040 tig/rn3 Nlcorinc 7.2 air changes per hr 9 cigxr do. 20 ppm CO, 420 pg/rn' NILU~IIIE None 9 pipes do. 10 ppm CO, S20 pg/m3 Nicolinc E 7.2 air changes per hr 9 pipes do. 1.5% 1.5 0.6 - 3.2 152 56 1.7 1.0 - 3.2 401 74 2.0 0.9 - 3,7 144 76 1.6 0.7 - 2.7 1,172 42 1.4 0.7 - 2.5 503 39 1.2 0.6 - 3.5 240 30 1.8 1.0 - 3.0 2,886 76 1.2 0.4 - 3.0 398 33 1.2 0.s - 2.5 2,720 26 1.6 1.0 - 3.0 159 59 1.2 0.6 - 2.5 2,291 35 1.2 0.5 - 2.5 147 24 1.4 0.9 - 2.1 671 35 1.2 0.6 - 2.5 544 27 1.5 0.8 - 2.7 660 61 1.5 0.8 - 2.7 53s 55 1.2 1.2 ! 0.8 - 2.1 959 0.6 - 2.5 850 18 35 I- Source: Stewart, R.D., et al. (46). pectoris before and after rxposure to carbon monoxide. `TII? sverase amount of exercise that was able to be performed before a person developed chest pain was significantly shortened from 226.7 sc~onds before exposure to 157.6 seconds after CO exposure. This change: occurred after a Z-hour exposure to SO ppm CO and with an increase in COFIb level from I .03 percent to 2.68 percent: these COHb levels are within the range produced by involuntary smoking. These data indicate that exposure to CO at levels found in some involuntary smoking situations may well have a significant impact on the functional capacity of persons with angina prctoris. Carbon monoxide has also been shown to decrease cardiac contractility in persons with coronary heart disease at COHb levels similar to those produced due to involuntary smoking situations (5). It is reasonable to assume that any significant CO exposure to the diseased heart reduces its functional reserve. h'icotirle Nicotine in the atmosphere differs from CO in that it tends to settle out of the air with or without ventilation (thereby decreasing its atmospheric concentration), whereas the CO level wilt remain constant until the CO is removed. The concentrations of both substances are decreased substantially by ventilation. As can be seen from data in Table 2, under conditions of adequate ventilation neither exceeds the maximum threshold limit values for industrial exposure (nicotine, 500 pg/m'; CO, 50 ppm, I): whereas in conditions without ventilation, smoking produces very high con- centrations of both (nicotine, up to 1,040 Pg/m3 : CO, 1 10 ppm). Nicotine in the environment is of concern because nicotine absorbed by cigarette smokers is felt to be one factor contributing to the development of atherosclerotic cardiovascular disease. Several researchers have attempted to measure the amount of nicotine absorbed by nonsmokers in involuntary smoking situations. Cane, ef at. (II) studied urinary excretion of nicotine by persons on a submarine. Despite very low levels measured in the air (I 5 to 32 pg/m3), nonsmokers did show a small rise in nicotine excretion; however, the amount excreted was still less than I percent of the amount excreted by smokers. Harke (23) measured nicotine and its metabolite cotinine in the urine of smokers and nonsmokers exposed to a smoke-filled environment and reported that nonsmokers excreted less than I percent of the amount of nicotine and cotinine excreted by smokers. He feels that at this low level of absorption nicotine is unlikely to be a hazard to the nonsmoker. 493 Acroleill and acetafdcflycl~ fuve also been measurctf in hrnoke- lill~d rooms (2.5. Table 2) and may contnbute to tl~e eye irritation commonly experienced in tfirse sitiutlons. EFFECTS OF EXPOSURE TO CIGARETTE SIIOKE Tfle effects of cis;rrct tc` ~1rloki11~ on tflr c;ll-rtio\~~~~~~ltar syhtem of tile 5moher are well cstablihlicd. fut very littfc is kno\vn about tire cardiovascril2r response 01` tfle nonsmohcr to ci~;ireffc aruoke. ffarke and Bl~icllcrt (Z'6) studied IS adults ( I I smokers antI 7 nonsmokers) in 3 room I70 m3 larzit in which I50 cigarettes \vcrc` smoked or allowed to bL1r11 in ashtrays for 30 minutes. Tfl Inn1 HF) hfood pressure. Tfle cfiffer-erlces i11 results betwecrl tf~e\c httldit`s may be due, in part. to tile ase of IlIe subject5 - i.e.. cfiildrcii may IW Inore s2nsjtjv2 to tile ~.frcfior~r~cufar effects of il~~0l~rJlt:ll)' SlllOkill~ ill311 3tJults. or tile incrrahe in lIt23rt rutc and I~lOo~f pl-hburc Il1.l) fW dus to a difference bct\vre~~ cflifdren atlcf aLl~~fr\ ill 111~ )~~! IO Prolonpcd Pcrformancc of two tasks at 700 17 None sune time Dark adaptallon and glare rrcovery Peripheral vision at IO0 and 30" 700 700 17 None 17 None Stewart, R.D., et al. (47) I Peripheral vision at 20" 700 17 l)L'uc;I\cd Depth perception 700 17 Nnnc Time perception 500 20 None IIcndcr, W., el al. Tllre>llold for trrnpordl (6) ICbolullorl of vi\u.il rllmull 100 7.25 K~iwl Tnfo rovernmell t q~~nsor~d ~tt~diz\ II;IL.T ;IIICJII~~C~I to L~t.:~~~~.l~~ tile degree of minor irritation due to ciyJrc'ttc \mokc ~\peri~niz~l I>\ bus and plane passengers. TIw U.S. Ikp~rt~n~~~~r ol Tr.ln\porr;,tlo;l t-C-!) studied the environment on t\vo venr~l.ttcd IJII~Y -~ 011~` w1t11 simulated unrestricted smokin: and anotiter wit11 ~imul2tzd srnokirlg limited to the rear 20 pcrccnt of tlls seats. In one bus. l~~litc'il cigarettes were placed at every otllcr seat (23 c1~3rette5) to simulate ;I bus filled wit11 smokers. In tlic otller bus. cis.irettcs were placed 0111). in [lie rear 20 percent of tile bus (five ciprzttcs) to simulate ;I bus where smoking waslimited to the r&ar 10 percent of the sests. \\`llen smoking was limited. the CO level at the driver's seat was only IS pprn (ambient air I3 ppm) compared to l11e level of 33 ppm (ambient air 7 ppni) nira5ured in the nnrestrictcd sniokin: situation. Four of tf~e 5i.x Lubjects seated in tile bus reported eye irritation durln_r tile unrr5tricted smokin: simulation. None of tile six subjects reported any eye irritation in the restricted sniokin_c situation (not even tllose se3tetl in the rear 70 percent of the bus). Several Federal agencirs (4s) cooperated to survey tile symp- toms experienced by travelers on botli military and commercial aircraft. They distributed 3 questionnaire to passengers 011 20 military and S commercial fligltts; 57 percent of the passengers on tile military fli$if5 and 45 percent of the passcn_cers on the commercial tli$jth were smokers. The planes were well ventilated and C-0 levels were always bciow 5 ppm witll low levels of other pollutants as well. In 5pile 01. tile low level of measurable pollution, over GO percent ot' tile nonsmoking passengers and IS to 12 percent of tile smokers reported being annoyed by tile other passengers' smoking. Seventy-tllree percent of the nonsmoking passengers on the commercial flights and 67 percent of the nonsmoking passengers on tlla military tlights sug_rested that some remedial action be taken; 84 percent of tl,ore su~,uestin, 0 remedial action felt that segregatjng the smokers from nonsmokers would be a satisfactory solution. These feelings were even more prevalent amon, 0 those nonsmokers who had a history of respiratory disease. Children have been found to have a higher incidence of respiratory infections than adults and are thou$t to be more sensitive to tile effects of air pollution due to their greater minute ventilation per body wei$t than adults. Several researchers have investigated the effects of parental smokinr on the health of children. Cameron. ct al. conducted two telephone surveys of Detroit families to determine tile relationship bet!vlANN. K. D.. HOFFMANN. D. Chemical studies on tobxco smoke. XXIV. A quantitauve method for carbon monoxide and carbon dloxlde in cigarette and cigar smoke. Jourrwl of Cbromatographic Science 12(2): 70-75, February 1974. CAMERON. P.. KOSTIN. J. S.. ZAKS. J. %l., WOLFE. 1. H., TIGHE, G., OSELETT. B.. STOCKER, R.. WINTON. I. The health of smokers' and nonsmokers' chddien. Journal of Al:ergy 43(6): 336-341. June 1969. CASIERON. P.. ROBERTSON, D. Effect of home environment tobacco smoke on famdy health. Journal of Applied Psychology 57(2): 142-147. 1973. CASO. J. P.. CXTALIN, J.. BADRE, R.. DUMAS, C., VIALA. A.. GUILLEMlE, R. Determination de la nlcotme par chromatographie en phase gazeuse. II Applications Ann&s Pharmaccutiques Francaises 28(1 I): 633-640. 1970. COLLEY. J. R. T. Respiratory symptoms in children and parental smoking and phlegm production. British !&dtcal Journal 2: 201.204, April 27, 1974. COLLEY. J. R. T.. IIOLLAND. W. W. CORKHILL, R. T. Influence of passive smoking and parental phlegm on pneumonia and bronchitis in early chddhood. Lancet 2(7888): 1031-1034, November 2, 1974. CORN. hf. Characteristics of tobacco sidestream smoke and factors Influencing its CoDcentiatlOn and distrtbution in occupied spaces. Scandinavian Journal of Respiratory Diseases (Supplementurn 91): 21.36, 1974. D.-\wA\lN. T.. EDFORS. Sl.. RYLANDER. R. hfouth absorption of vprious compounds in c@rette smoke. ArchIves of Environmental Hed:h I6(6): 831-835. June 1968. I 2 3 4 5 6 . 7 8 9 10 11 12 13 14 IS 505 18 t-.SVIKOS\It.NTAL PROTECTION ACESCY. Natiorul prlmxy and wconddr) ambvznt sir quality sczmd3rds. Federal Regstcr 36(X--Part 113:8186-8201. Aprd 30.1971. 19 I ODOR. G G.. \\`IKSTKE. C. Effect of tow CO concrnrnlions on rcvx~~ncc to monotony and on prychomotor c~paaly. Staub Keinhaltung der Luft 32(4).46-54. Aprd 1972. 20 C.~LUSEINOVA. V. 3.4 - Benrpyrcne determ~nz~t~on in the smoky xtrnosph~re of SOWI mcetnne rooms and rcsuurz~nts. A conrrlbution to the problems ot to-called ~JTXI\I` Tmohtn:. Scoplxma t 1 :465-168. 1964. 21 GODIS. G.. \\RlGlIT. C.. SIlLPttARD. R. J. ItrbJn e\po%ure 10 carbon mono\tde. ,\rchives of Environmenf31 tlcalth 25(j)-3OS-313. November 1972. 22 (;ROLL-KS';\PP. E.. WACSLR. 11. tlAL!CK. II.. ItAtDER. .\I Efftxtr of tow carbon ,,w,no\~d~ conccntr~t~on~ on w$~nce xnd computer-x~aly~d brun potentnls. S~:,ub Rcmtutfun~ der Lul-t 32(-1).6468. Aprd 1972. 2-t Ii-\RKl-:. tt. -P. The pri,t&m of ~J\"Y' \mokine. I. The ir~tlurnue of smokin< on rhe (`0 ~~,nc~ntr.~l~w ,n otlice rooms. Inrerru~wnatri Arch~v iur Arbrlltmedizin 3313): 199.2r16. 1974. 2s HARKE. ii. -P.. IrAARS. A. t-RAHXl. B.. PETtRS. H.. SCtILUTZ. C. Zum Problem dec P.~xx~vr.~ucbcn\ (7 he problem of passive smoking.) lnlerna~ronales Archiv fur Arbclt,rnrdizin 79-333-339. 1972. 26 Ft.-IRKt<. H. -P.. BLEICtll:RT. A. Zurn Problem des P3ssivrwchens (The problem of pacsi\e \Inoking.) In~~:rrut~on~les Archiv fur Arbeitsmedtzln 29:31 2-322. 1972. 27 HARKE. H.-P.. LIEDL. W., DENKER, D. The problem of' passive smoking. II. Invrxriea:lons of CO level in the automobile after cigarette smoking. Inler- nalmn;le~ Archiv fur Arbeitsmedirin 33(3):207-220, 1974. 28 IIARKE. H. -P.. PETERS. H. The problem of passive smoking 111. The influence of smoklne on the CO concentration in driving automobiles. Internalionales Archiv fur Arhrltsmedirln 33(3):221-229, 1974. 29 IIARLAP. S.. DAVIES. A. hf. Infant a4mitsions to hospital and matern& smoking. L3ncer 1(7857):529-532. hlarch 30, 1974. 30 HARMSEN. t4.. EFFENBERGER. E. Tobacco smoke in transportation vehicles. living and working rooms. Archw fur Hygiene and Baklenolo:ic 14I(5):383400, 1957. 31 HOEGC. U. R. The slgniticance of cigarette smoking in confined >pacec. Thesis. Unlverslty of Cmcinnati. Diwsion of Graduate SItidle-.. D~parlment of EnCiron- mental Health. 1972 137 pp. 32 HOEGG, U. R. Cigsrelte smoke rn closed spaces. Entironrr~~nt~l Ilc.~l[t~ Pcnpecfivet 2:1 I 7-128. October 1972. 506 3s 36 37 38 39 10 41 42 43 44 45 46 41 JOH\SOS. \I R. tlALL. J \V. NEDLOCK. J n'.. GRCUBS. II. J WI\ t I.1 1) 11 7hc ,bsrnhu:~on ot products bctu-m~k~r. Scand~na\un Journal of Respuatory Diseases (Supplcmrn~u"~ 91 ): I-90. 197-t. SCH!.tELTZ. I.. HOFFMANN, I)., WYNDER. E. L. The intluence oi tohzcca -anide, smoking, and tobacco amblyopia. Observations on the cyanide content of tobacco smoke. British Journal of Ophthalmology 51(5) : 336-338, May 196'7. (4) DREYFL'S, P. M. Blood transketolase levels in tobacco-alcohol amblyopia Archives of Ophthalmology 74(S) : 617-620, November 1965. (5) DU.VPHY. E. B. Alcohol and tobacco amblyopia: A historical survey. American Journal of Ophthalmology 68(4) : 569-578, October 1969. (6) FOULDS, IV. S., BROKTE-STEWART. J. M., CHIsHoLhl, I. A. Serum thio- cyanate concentrations in tobacco amblyopia. Nature 218(5141) : 586, May 11. 1968. (7) Foows. W. S.. CANT, J. S., CHISHOLM, r. A., BRONTE-STEWART J., WILSOS. J. Hydrorocobalamin in the treatment of Leber's hereditary optic atrophy. Lancet l(7548) : 896-897, April 27, 1968. (8) FOIXX. W. S., CHISHOLM, I. A.. BRONTE-STEWART, J., WILSON, T. M. Vitimin B ,:' absorption in tobacco antblyopia. British Journal of Ophthalmology 53 (6) : 393-397, June 1969. (9) FOULDS. W. S., CHisHoLhl, I. A., BRON?E-STEWART, J., WILSON, T. ai. The optic neuropathy of pernicious anemia. Archives of Ophthalmol- ogy 63(4) : X7-432, October 1969. (10) FE'JIAG, A. G., HEXTOS, J. 31. The aetiology of retrobrrlbar neuritis in Addisonian pernicious anaemia. Lancet l(7183) : 90%911, April 29, 1961. 532 (II) HEATON, J. M., MCCORMICK, A. J. A., FREE~IAY. A. C. Tobacco ambly* pia: A clinical manifestation of vitamin-B,, deficiency. I,ancet Z(7041) : 286290, August 9, 1958. (1") KNOX, D. L. Neuro-ophthalmology. Archives of Ophthalmology 83(l) : 103-127, January 1970. (13) LINDSTRAND, K., WILSON, J., Ma-rra~ws, D. M. Chromatography and microbiological assay of vitamin B,, in smokers. British Medical Journal 2 (5520) : 988-990, October 22, 1966. (14) LINNELL, 3. C., Sarrw. A. D. M., SMITH, C. I,.. WILSOS. J., MATTHEWS, D. M. Effects of smoking on metabolism and excretion of vitamin B,?. British Medical Journal Z(5599) : 215-216, April 27, 1968. (15) SCIIEPENS. C. L. Is tobacco amblyopia a deficiency disease- Transactions of the Ophthalmological Society of the United Kingdom 66: 309-331, 1946. (16) SCHIEVELBEIN, H.. WERLE, E., SCHULZ. E. K.. B~UMEJSTER. R. The influ- ence of tobacco smoke and nicotine on thiocyanate metabolism. Naunyn-Schmiedebergs Archiv fur Pharmakologie und Experimentelle Pathologic 262(3) : 358-365, February 5, 1969. (17) SILVEETTE, II., HUG, H. B., LARSON, P. S. Tobacco amblyopia. The evolu- tion and natural history of a "tobaccogenic" disease. American Journal of Ophthalmology 50(l) : 71-100, January 1960. (18) ShIITH. A. D. hr. Retrobulbar neuritis in Addisonian pernicious anae- mia. (Letter) Lancet l(7184) : 1001-1002, &lay 6, 1961. (19) S~SITH, A. D. BI., DUCKETT, S. Cyanide, vitamine B,Z. experimental demyelination and tobacco amblyopia. British Journal of Experimen- tal Pathology 46(6) : 615-622, December 1965. (20) TRAQUAIR, H. M. Toxic amblyopia, including retrobulbar neuritis. Trans- actions of the Ophthalmological Society of the United Kingdom 50: 351385, 1930. (92) VICTOR, M. Tobacco-alcohol amblyopia. A critique of current concepts of this disorder, with special reference to the role of nutritional deficiency in its causation. Archives of Ophthalmology 70(3) : 313-318, Septem- ber 1963. (22) VICTOR, M. Tobacco amblyopia, cyanide poisoning and vitamin B,, de- ficiency. A critique of current concepts. Chapter 3. IS: Smith, J. L. (Editor) Neuro-Ophthlamology. Symposium of the University of Miami and the Bascom Palmer Eye Institute. Hallandale, Florida, Huffman Publishing Co., 1970. pp. 33348. (23) VVUSH, F. B., HOYT, W. F. (Editors) Neurotoxic substances affecting - the visual and ocular motor systems. Chapter 15: IN: Clinical Neuro- Ophthalmology. Volume 3, 3rd Edition. Baltimore, The Williams & Wilkins Company, 1969. pp. 2613-2616. (fr) WATSON-WILLIAMS, E. J., BOTTOMLEY, A. C., AINL~Y, R. G., PHILLIPS, C. I. Absorption of vitamin B,3 in tobacco amblyopia. British Journal of Ophthalmology 53(8) : 549-562, August 1969. (25) WILSON, J. Leber's hereditary optic atrophy: A possible defect of cya- nide metabolism. Clinical Science 29 (3) : 5055515, December 1965. (26) WILSON, J.. MAnHEWS, D. M. Metabolic inter-relationships between cyanide, thioryanate and vitamin B,l in smokers and nonsmokers. Clinical Science 31(l) : l-7, January 1966. 533 (27) Woti~s. F.. PICARD. C. W. The role of \-itsmin R,, ill human nutrition. Clinical Nutrition 3(5) : 3X-390. September-October 1955. (28) WYSDFR, E. L... HOFFMASN. I). Certain constituents of tobacco products. Chapter 9. I<. Vapor phase of tobacco smoke. IS: \Vynder. E. I,., Hoffmann, 1). (I.:diton). `l`ol~~co ;LII~ To\~~co Smoke. Studies in FIX- perimental Caxinogenesis. New York, Academic Press, 1367. pp. 451453. 534 Chapter 10 Pipes and Cigars Source: 1973 Report, Chapter 6. pages 165 236 535 contents Introduction- ________ ____---- ____-_-_____-_ - __-__- _ ---_-- The Prevalence of Pipe, Cigar, and Cigarette Usage __-_-_____ The Definition and Processing of Cigars, Cigarettes, and Pipe Tobaccos_________________-____-__-_-____------------- Chemical Analysis of Cigar Smoke------------------------- hlortality Ocerall~~lortality-__- ________ --_-_--_-__-_- ____ - ______ Mortality and Dose-Response Relationships AmountSrnoked~~~~~~~---..--------------------.. Inhalation__--__--_-____________________-------- Specijic Causes aj;Ifortality------- ____ -___-_-- ______-_ Cancer__-__-__-_---_-_____-__---_-_----_---_-_- Cancer of the Lip--- _______ - ____ --__--_----___-- Oral Cancer----_--------- _____- - __________-_-__ Cancer of the Larq-nx_-__----_----_------ _-__ -___ Cancer of the Esophagus---------------- _____ -_-_ LungCancer_------- _____ -_------_--_-_-----____ Tumorigenic Activity---_------------------------ Experimental Studies _____ -_-_--- _________ -_-_-__ Cardiovascular Diseases_---_ -_-_- ____ -_ _-_ ____ -_ _ Chronic Obstructive Pulmonary Disease (COPD)-- _ _ Gastrointestinal Disorders--_-------------- __ -_-__ Little Cigars _____ - -_____ -___- ______ -----------___-_-_--- Conclusions-_--_________________________-~----~-~----~-- References -_________-_____ -_--____---_-_ ________________ List of Figures Figure I.--Inhalation among pipe smokers by nge- _______ -__ Figure 2.-Inhalation among cigar smokers by age--Ham- mond______--_____-.-____________________--~--------- Figure Z.--Depth of inhalation among cigarette smokers by age-~fammond-___-_____________________--------~---- Figure *%.-Percent distribution of 130 brands of cigarettes and 25 bmnds of little cigars by tar content------- _____ -__-_- Page 543. 543 545 547 549 550 553 559 559 560 561 563 567 573 580 580 585 s&i 592 592 599 600 554 555 s55 595 537 Figure 5.-Percent diatribtrtion of I30 brnnds of cigrrrcttes nnd 25 brands of little cigRr3 by nicotine content- .- __ _ _ _ _ _ _ __ _ List of TubIes TnbIe l.-Percent distribution of U.S. males nged 21 nnd older by type of tobrrcco used for the yenrs 196-1, 1966, and 1970-- Table Z.-Percent distribution of U.S. males by t>-pe of tobucco used nnd ngefor 1970___---_-_-__-__-_------------------ TftbIe 3.-Percent distribution of British males aged 25 nnd older by type of tobncco used for the years 1965, 196S, nnd 1971__________~___-__~--~---------------------------- Table 4.-Amounts of se\-ernl components of 1 grnm of par- ticulnte mfiteriul from mainstream smoke of tobacco prod- ucts________________~----:------------------------------ Table 5.--A comparison of se\-ernl chemicnl compounds found in the mainstream smoke of cignrs, pipes, nnd cigarettes---- Tnble 6.-AIortaIity ratios for totnl denths by type of smoking (mnles only) ___._______ ----___--__- __________--___---- Tnble 7.-AIortnIitv ratios for totnl denths of cigar nnd pipe smokers by amount smoked--Hammond and Horn- _ - - _ __- Tablr 8.--1Iortnlity ratios for total deaths of cignr and pipe smokers by nmount smoked-Best-__- - _ - - _- _ _ -__ _ _ _ _ _ _ _ _ Table 9.-Alortnlity rrrtios for totnl deaths of cigar and pipe smokers by age nnd nmount smokeci-~Rhn__---__------- Table lO.--;\Iortnlitp ratios for totnl deaths of cigar and pipe smokers by omount smoked-Hammond _ _ _ _ _ - _ _ _ - - - _ _ - - _ Tnble Il.-The extent of inhnling pipes, cignrs, nnd cigarettes by British moles aged 16 and over in 1968 and 1971- _ _ ___ _ Table 12.-Inhalation among cigar, pipe, and cigarette smokers by age--Doll and Hill _____. --_---_--__----_- ____ -_-___- Table I3.--JlortaIity ratios for total deaths of cigar and pipe smokers by nge and inhnlntion-Hammond__ _ - - _ _ ___ _ _ __ _ Tnble 14.-Percentage of British male cigar smokers who re- ported inhnling n lot or rr fnir amount by type of product smoked-_-._____._______________________------~--~-~ Table 15.-Percentage of individunls reporting inhnlntion of "almost every puff" of tobncco smoke by current and pre- vious tobacco usage and type of tobacco used-- - _ _ __ _ _ _ ___ Table !6.--Percentage of British males who reported inhaling n lot or fair amount of cignr smoke by current and previous tobacco usage nnd type of tobacco previously smoked (1963) ---__ ---_-- ____ - _--- - ----------------- -_- ______ 596 543 544 544 547 548 550 551 551 552 552 556 556 557 -. 557 558 558 538 Table 17.-Extent of reported inhnlation of cigar smoke by British male cignr smokers who lvere ex-cigarette smokers in 1968, analpzcd by extent of reported inhalation of cignrctte smoke when previouslp smoking cigarettes---_. _ _ _ _ _ __ _ _ _ _ _ Table 18.--Slortality ratios for total cancer denths in cigar nnd pipe smokers. A summary of prospective epidemiological studies_-_______________________________-------------- Table lg.--Kelative risk of lip cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A surnmnry of retrospective studies-`------- ___________________________ Table PO.->Iortality ratios for oral cancer in cigar and pipe smokers. A summary of prospective epidemiological studies- - Table 21.--Relative risk of oral cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. X sum- mary of retrospective studies-- _ _- ________________ -_-_-- Tnble 22.--XIortality ratios for cancer of the larynx in cigar and pipe smokers. A summary of prospective epidcmiological studies.-_--_-_____----------------~---------~-----~-- Table 33.--Relative risk of cancer of the larynx for men, corn- paring cigar, pipe, nnd cigarette smokers with nonsmokers. A summary of retrospectire studies--- _- -- -_ _ _ _ __ _ - __ _ _ __ Table 24.--Jfortality ratios for cancer of the esophagus in cignr and pipe smokers. A summary of prospective epidemio- logical studws _____ -_-_-_____-_- ____ _ ___-_ -_---- _______ Table "S.-Relative risk of cancer of the esophagus for men, comparing cigar, pipe, and cigarette smokers \\ith non- smokers. ri summary of retrospective studies .____ - _-_______ Table 26.-A\Iortality ratios for lung cancer deaths in male cigar and pipe smokers. A summary of prospective studies---- Table 27.-Lung cancer death rates for cigar and pipe smokers byamountsmoked-DollandHill------ ______ -_- _____-- Table Pg.-Lung cancer mortality ratios for cigar and pipe smokers by amount smoked-Kahn- ____ __-__-_-__- ____-- Table 29.-Relative risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective sbudies-__-_---------- ____----- Table 30.-Changes in bronchial epithelium of male cighr, pipe, and cigarette smokers as compared to nonsmokers- _ -- Table 31.--Tumorigenic activity of cigar, pipe, and cigarette smoke condensates in skin painting experiments on animnls-- Table 32.--Xlortalit_v ratios for cardiovascular deaths in mnie cigar and pipe smokers. A summary of prospective epi- . . demlologlcal studies _______ -_-_- ___-_______-..- --------- Page 559 559 562 563 564 566 568 570 571 574 574 575 576 579 583 586 539 Table 33.--Iiortnlity rntios for chronic obstructi\-e pulmonnry deaths in mnle cigar and pipe smokers. X summary ol pros- pective epitlemiolopicnl studies- - - - _ _ _ _ _ _ _ _ _ _ _ _ _ __ _ _ __ _ _ _ Table ?A.---Prey-alencc of respiratory symptoms and illness by type of smoking--- ___________ - ______ - _______________ Table 35.--Pulmonary function values for cigar and pipe smokers as compnretl to nonsmokers.- __- ________________ Table 36.-Jlortality rntios for peptic ulcer disense in male cigar and pipe smokers. Summary of prospective studies__- Table 37.4hipment of small nnd large cigars destined for domestic consumption (1970, 1971, 1972) ____ ---___-_- ____ Table 38.-Selected compounds in mainstream smoke-------.. Table 39.-The pI1 of the mainstream smoke of selected tobacco products_-----____---------------------------- 589 590 591 592 597 598 598 Introduction This chapter is a review of the epidemiological, pathological, and experimental data on the henlth consequences of smoking cigars and pipes, alone, together, and in varicus combinations with cignrettes. Previous reviews on the health consequences of smoking have dealt primarily with cigarette smoking. Although some of the material on pipes and cigars pwsented in this chapter has been presented in preti- ous reports of the Surgeon General, this is the first attempt to summ- rize what is known about the health effects of pipe nnd cigar smoking. Since the use of pipes nnd cigars is limited almost exclusively to men in the United States, only dnta on men are included in this revieff. The influence of pipe and cigar smoking on health is determined by examining the overall and specific mortality and morbidity ex- perienced by users of these forms of tobacco compared to nonsmokers. Epidemilogical evidence suggests that individuals who limit their smoking to only pipes or cigars have overall mortality rates that are slightly higher than nonsmokers. For certain specific causes of death, however, pipe and cigar smokers experience mortality rates that are as great as or exceed those experienced by cigarette smokers. This analysis becomes more complex when combinations of smoking forms are examined. The overall mortnlity rates of those who smoke pipes, cigars, or both in combination with cigarettes appear to be inter- mediate between the high mortality rates of cigarette smokers and the lower rates of thw who smoke only pipes or cigars. This might seem to suggest that smoking pipes or cigars in combination with ciga- retteS diminishes the harmful effects of cigarette smoking. However, an analysis of mortality associated with smoking combinations of ciga- rettes, pipea, and cigars should be standardized for the level of con- sumption of each of the products smoked in terms of the amount amoked, duration of smoking, and the depth and degree of inhalation. For example, cigar smokers who also smoke a pack of cigarettes a day might be expected to have mortnlity rates somewhat higher than those who smoke omy cigarettes nt the level of a pack a day, assuming that both groups smoke their cigarettes in the same way. Mixed smokers who inhale pipe or cigar smoke in a manner similar to the Kay they smoke cigarettes might be expected to have higher mortality rates than mixed smokers who do not inhale their cigars nnd pipes and also 541 resist inhaling tliejr cigarettes. Irnfortunately, little of the published material on mixed cignrrttt. pipe, ;III~ cigar smoking contains these types of nnal~33 or corltr0lS. ;\ P3r3dox :eems to esi?t bet\!-ern the mortality rates of ex-smokers of pipes and cigars and es-smokers of cigarettes. Ex-cigarettesmokers experience a reJati\-e decline ir! orernll and certain specific causes of mortality follo\ring cessation. This decline is important but indirect evidence that cigarette smoking is a major cawe of the elevated mor- tality rates experienced by current cigarette smokers. In contrast to this finding, several prospective epidemiological investigations, Hammond and Horn (.@a), Best (9), Kahn (50), and Hammond (38), ha\-e reported higher death rates for ex-pipe and ex-cigar smokers than for current pipe and cigar smokers. This phenomenon eras ann- lyzed by Hammond and Garfinkel (39). The development of ill health often results in a cigarette smoker giving up the habit, reducing his daily tobncco consumption, ssitching to pipes or cigars, or choosing a cigarette low in tar and nicotine. In many instances, a smoking- related disease is the cause of ill health. Thus, the group of es-smokeIs includes some people \vho.are ill from smoking-related diseases, and death rates are high among persons in ill health. As a result, ex-cig;lrette smokers initially have higher overall and specific mortality rates than continuing cigarette smokers, but be- cause of the relative decrease in mortality that occurs in those who quit smoking for reasons other than ill health, and hecause of the dwindling number of ill es-smokers, a relative decrease in mortality is observed (within a few years) follo\ving cessation of cigarette smoking. The beneficial effects of cessation nould be obvious sooner were it not for the high mortality rates of those who quit smoking for reasons of illness. A similar principle operates for es-pipe and ex- cigar smokes, but because of the Iorrer initial risk of smoking these forms and therefore the smaller margin of benefit following cessation, the effect produced by the ill ex-smokers creates a larger and more persistent impact on the mortality rates than is seen in cigarette smoking. For the above reasons R bias is introduced into the nlortality rses of current smokers and es-smokers of pipes and cigars, so that a more accurate picture of mortality might be obtained by combining the ex-smokers with the current smokers and looking at the resultant mortality experience. B~JXLUQ? of a lack of data that would allow a precise analysis of mortality among ex-pipe and ex-cigar smokers, a detailed analysis of these groups could not be undertaken in this review. For each specific cause of death, tables have been prepared m-hi& summarize the mortality and relatire risk ratios reported in the major 542 prospective and retrospective studies which contained information nbout pipe and cigar smokers. The smoking categories used include: cigsr oni?, pipe only, total pipe and cigar, cigarette only, and mixed. The tot31 pipe and cigar category includes: thw who smoke pipes only, cigars only, and pipes and cigars. The mixed category includes: those who smoke cigarettes and cigars; cigarettes and pipes; and cigarettes, pipes, and cigars. Mortality and relative risk ratios were calculnted relative to nonsmokers. The Prevalence of Pipe, Cigar, and Cigarette Usage The prevalence of pipe, cigar, and cigarette smoking in the United States was estimated by the National CIearinghouse for Smoking and Health from population surveys conducted in 1961,1966, and 1970 (98, 99,100). In each survey, about 2,500 interviews Kere conducted on a national probability sample stratified by type of population and geographic area. The use of these products among adults aged 21 and older is summarized in tables 1 and 2. The prevalence of pipe, cigar, and cigarette smoking in Great Britain for the years 1965, 196S, and 1971 is presented in table 3. TABLE I.--Percent a!is!ribution qf U.S. n&e smokers aged 21 and Older by type oj tobacco used jor the years 1964, 1966, and 1970 Forms wed (pAI% 1x3 1970 @t=PXW (psrcent) 1. Cigar only-- ____________ - ________-__--- 6. 8 5. 5 5. 6 2. Pipe only_----_-________-~~~-----~----- 1. 7 3. 0 3. 6 3. Pipe and cigar ___________________ - ______ 3. 9 S-9 4.4 4. Cigarette only--- ___________________ ____ 28. 6 31. 2 25. 9 5. Cigarette and cigar ____________________-- 11. 3 9. 9 6. 6 6. Cigarette and pipe ______________________ 5. 3 4. 9 5. 3 7. Cigarette, pipe, and cigar ________________ 7. 7 6. 3 4.6 8. Nonsmoker ______ ____ ____ ____ - - ____ ____ _ 34.7 34. 3 44.0 Total ______ - __________i_________--- 100.0 100.0 100.0 Number of Reasons in sample. ______________- 2,359 2,679 2,881 Total pipe users (2+3+6+7) __________-__- - 18. 7 19. 2 17. 9 Total cigar users (1-i-3+5+7) _________--_- - 29. 9 26. 7 21. 2 Total cigarette uverj (4+5+6+7) _________-- 52 9 52. 4 42 3 lkwcs: U.S. De>-cat of Health, Education. and Welfam (98. PO. 100). 543 TABLE 2.-Percent distribution of U.S. male smokers by type of tobac- co used and age for 1.970 Forma Uspd A@ *ouP_ ?I to 34 3.5 to44 4.31054 65 to M 65 to 3 + 1. Cigar only- -----__ -- _______ 2. Pipe only_--- __`.______ ____. 3. Pipeandcigar_- _____ -- _____ 4. Cigarette only--- _____ _____ - 5. Cigarette and cigar-- ________ 6. Cigarette and pipe- - ..______ 7. Cigarette, pipe, and cigar- - _ _ 8. Nonvmokcr __.___ ---_-__--_- 3. 7 6. 5 4. 7 6. 7 9. 3 4. 3 3. 5 3. 0 3. 2 3. 6 3. 8 3. 3 5. 2 4. 4 6. 9 28. 8 29. 0 27. 1 24. 3 13. 6 6. 8 10. 4 5. 5 5. 2 4. 2 6. 6 4. 4 5. 6 4; 0 3. 8 5.8 48 5. 0 4. 0 1. 4 40. 2 38. 1 43. 9 48. 2 57. 2 Total- _____ --__-___-__- 100. 0 100.0 100.0 100.0 100. 0 Number of in sample- _ _ persons 1,009 525 523 405 388 ~ Total pipe users .__._____.___ -- 20. 5 16. 0 18. 8 15. 6 15. 7 Total cigar users. _ _____ --_- -__ 20. 1 25. 0 20. 4 20. 3 21. 8 Total cigarette usem-_---_---- 48. 1 48. 6 43. 3 37. 5 23. 0 Source: U.S. Deprtmeut ol Health, Education. and Welfare (100). TABLE S.-Percent distribution of British male smokers aged 15 and older by type of tobacco ?Lsed for the years 1965, 196S, and 1971 Forms wd 1985 1968 1971 1. Cigars only __________________ -._- _______ 1. 9 2. 8 3. 3 2. Pipeonly_--__-__-___-__-~-~-~~~-~--.~- 5. 1 5. 6 5. 9 3. Cigarettesonly__- _____ --.--_--_- _______ 46. 8 45. 7 40. 8 4. Cigarettesandpipe _____ --__-_-__-_- _.__ 8. 0 7. 0 6. 1 5. ~Iixedsmokers_--___--_~--_.- _______-__ 7. 5 9. 1 8. 4 6. Nonsmokers- .__________ -_---_-- ______ -- 30. 7 29. 9 35. 4 Total_-_.-_-_~__.-_--~.~~--~---..-- 100.0 100.0 loo. 0 Number of persons in sample-__-.--_-.-~-~- 3, 576 3, 566 3,594 - Total pipe users _______________.__.________ 13. 9 14. 3 13. 3 Totalcigar- ____.________ ~__-__-- _._._._._ 9. 0 11.7 11.3 Totalcigarette _____ - _____ - _____ -__- _____._ 67. 6 67. 6 61. 6 Bourcc: Todd. 0. F. (91). 544 The Definition and Proceseing of Cigm, Cigarettea, and Pipe Tobaccos The U.S. Government has defined tobacco products for tax pur- poses. Cigarettes are defined as "(1) Any roll of tobacco wrapped in paper or in any substance not containing tobacco, and (2) any 1~11 of tobacco Trapped in any substance containing tobacco which, &UW of its appearance, the type of tobacco used in the filler, or its packaging and labeling, is likely to be offered to, or purchased by, consumers as a cigarette described in subparagraph (l)." Cigarettes are further classified by size, but virtually all cigarettes sold in the United Stati are "small cigarettes" which by definition weigh "not more than 3 pounds per thousand" which is not more than 1.361 grams per cigarette (96). American brands of cigarettes contain blends of different grades of Virginia, Burley, Maryland, and oriental tobaccos. Several varieties of cigarette tobaccos are flue-cured. In this process, tobacco leaves are cured in closed barns where the temperature is progressively raised over a period of several days. This results in "color setting," fixing, and dryirq of the leaf. The most conspicuous change is the conversion of starch into simpler sugars and suppression of oxidative reactions. Flue-cured tobaccos produce an acidic smoke of light aroma (35,rZZ). Cigara Cigars have been defined for ta'x purposes as: "Any roll of tobacco wrapped in leaf tobacco or in any substance containing tobacco (other than any roll of tobacco which is a cigarette within the meaning of subparagraph (2) of the definition for cigarette)" (112). In order to clarify the meaning of "substance containing tobacco" the Treasury department has stated that, "The wrapper must (1) contain a signs- cant proportion of natural tobacco; (2) be within the range of colors normally found in natural leaf tobacco; (3) have some of the other characteristics of the tobaccos from which produced; e.g., nicotine content, pH, taste, and aroma; and (1) not be so changed in the reconstitution process that it loses all the tobacco characteristics" {J&`j. Further, "To be a cigar, the filler must be substantially of tobaccos unlike those in ordinary cigarettes and must not have any added flavoring which would cause the product to have the taste or aroma genernlly attributed to cigarettes. The fact that a product does not resemble a cigarette (such as many large cigars do not) and has a distincti\-e cirnr taste and aroma is of considernblc si,pificance in making this determination" (IT/Z). Cigars arc also cln.ssified by size. "Small cigars" xvei,nh not more than 3 pounds per thousand and "large cigars" weigh more than 3 portnds per thousand. "Large cigars" are further divided into seven classes for tax purposes based on the retail price intended by the manufacturer for such cirars (96). Cigars are made of filler, binder, and n-rapper tobaccos. hfost cigar tobaccos are air-cured and then fermented. More recently, reconsti- tuted cigar tobaccos have been used as wrapper, binder, or both. Cigars are either hand-rolled or machine made. Some brands of small cigars are manufactured on regular cigarette making machines. The aging and fermentation processes used in cigar tobacco production produce chemical catalytic, enzymatic. or bacterial transformations as evi- denced by increased temperature. oxygen utilization, and carbon dioxide generation within fermenting cigar tobaccos. In this complex process. up to Xl percent of the dry xveipht of the leaf is lost through decreases in the concentration of the most readily fermentable ma- terials such as carbohydrates. proteins. and alkaloids. The flavor and aroma of cigar tobaccos are in large measure the results of precisely controlled treatment during the fermentation process (35,.X, 112). Pipe Tobnccos The definition of pipe tobacco used by the U.S. Government eras repealed in 1966 and there is no Federal tax on pipe tobaccos. The most popular pipe tobaccos are made of Burley; honever, many pipe tobaccos are blends of different types of tobacco. A fern contain a significant proportion of midrib parts that arecrushed betxveen rollers. "Saucing" material. or casings containing licorice, sweetening agents, sugars. and other flavoring materials are added to improve the flavo1, _ aroma. and smoke taste. These additives modify the characteristiZ of smoke components (112). ConclusiorL Because of the unique curin = and procrssing methods used in the production of cigar and pipe tobaccos. significant physical and chcmi- cal differences esist between pipe and cigar tobaccos and those used in 546 cigarettes. The cstcnt to \\-hich t&c chnnrcs mnr alter the hcnlth consequcnccs of sniokin~ l)ipcs n11(1 ciznrs rnn best be cstirnntcd lay nn nn:ll\sis of tlie potcntinll\ Iinrmflll cl~fnlic:~I constitntcrits fouri(l in the smoke of thcsc tobnccns. the turnorigcnic acti\-ity of srnnkc condcn- sntes in tzprrirnental nnirnnls. 2nd n review of the epidcmiological data n-hi& has nccumulntcd on the hcnlth effects of pip.2 and cigar smoking. Chemical Analysis of C&gar Smoke OnIy a few studies have been conducted that compnre the chemical constituents of cigar smoke x-ith those found in cigarette smoke. Hotfm:lnn, et 11. (43) compnrcd the yields of several chemical com- ponents in the smoke from 9 pklin 85 mm. cigxette, two types of cigars, 2nd a pipe. The pflrticulnte matter, nicotine, bcnzo(a)pyrene, and phenols were determined quantitatively in the smoke of these tobncco products. One cigar tested ~3s 5 lL%rnm.-long, 7.6-g., U.S.- made cigar. The other uxs n handmade Ilnvana cigar 147 mm. long -xeighing S.6 g. The relative content of nicotine in the particulate matter produced t.~y the cigars KE similar to that of the cigarette tars. The benzo(a)pgrene and phenol concentrations in the cigar condensnte xns tn`o to three times greater thnn in cigarette "tar" (t.ahle -1). Kuhn (58) compared the nlknloid and ~~henoi content in conden- sutes from nn SO-nun. Bright-blend cigarette sold commercially in A1ustria -with that obtnirnd from 103'mm. cigars. These were tested T.~BLE 4.-Amounts oj sewral components qf I g. qf pcrticulatx malerial from mainstream smoke of tobacco products Tobwco product 1 Compound Standxd @mm. 6.5 mm. u 8. II8vsns Pipe cigar h cigar B tobacco txy~;e plain U.S. plain U.S. cigarette cigarette (b) (b) In Pipe In pipe 03) w V-9 Skotine (mg.)_---- _____ 46. 2 63. 6 33. 1 61. 0 65. 9 77. 4 Benzo(a)pyrene (pg.). _. _ 3. 9 3. 6 6. 0 3. 6 1. 2 1. 3 Phenol (mg.)------------ 8. 3 6. 7 15. 0 7. 3 2. 3 4. 1 *Crcsoi (mg.)--- ____ -__ 1. 6 1. 7 1. 9 1. 4 .6 .8 n+p-Cresol (mg.).------ 4. 8 3. 8 5. 6 3.4 1. 4 1. 9 d-p-EthJ-lphenol (mg.).- I. 1 1. 5 1. 1 1.3 .7 .7 547 with and rrithout the use of a cellulose acetate filter. The concentm- tions of total alkaloids 3nd plicnol in the cigar smoke condcnsntc wre essentially the same as in the cigarette condensate, but pyridine values xvere about 21,1, times higher in the cigar condensate. Campbell and Lindsey (17) measured the polycyclic hydrocarbon levels in the smoke of a small popular-type cigar S.8 cm. long, n-eighing 1.9 g. Si?Tificnnt quantities of anthracene, pyrene, fluoranthene, nnd henzo(a) pvrene Kere detected in the unsmoked cigar tobacco, in con- centrations much ,Qater than those found in Virginia ciprettes but of the same order as those found in some pipe tobaccos. The smoking process contributed considerably to t.he hydrocarbon content of the smoke. Table 5 compares the concentrations in the mainstream smoke of cigarettes. cigars, and pipes of four hydrocarbons frequently found in condensates. The authors reported that t.he mainstream smoke from a popular brand of small cigar contained the polycyclic aromatic hydrocarbons; acenapht.hylene, phennnthrene, anthracene! pyrene, fluoranthene, and benzo(a.) pyrene.. The concentrations of these hydro- carbons in the mainstream smoke were greater than those found in Virginia cigarette smoke: @man. et al. (6.9) analyzed the volatile phenol content of cigar smoke collected from a 7-g. American-made cigar with domestic filler. :\fter quantitative anal?-sis of phenol. cresols, xylenols, ani meta and pnn ethyl phenol. the authors concluded that the IevclGf these com- pounds lvrcre generally similar to those reported for cigarette smoke. &man and Bar-son (63) aIso analyzed cigar smoke for benzene, toluene. ethyl benzene, m-, p-, and o-xylene, m- and p-ethyltoluene, I,",~-trinret~r~lbenzen~, and dipentene, and generally found levels within the range of those previously reported for cigarette condensates. In summary. available evidence sugpsts that cigar smoke contains man?- of the same chemical constit.uents, including nicotine and ot.her aIkaIoids, phenols, and polycyclic aromatic hydrocarbons as are found TABLE 5-A camparison oj sever& chemical compa~nds found in the mainstream smoke oj cigars, pipes, and cigarettes - COlIlpOUnd 1. 6 29. 1 5. 0 11.9 110.0 10. 9 17. 6 75. 5 12. 5 3. 4 8. 5. .9 548 in cigarette smoke. Most of these compounds are found in conrentra tions n-hic!l qua1 or exceed levels found in ci,rarcttc "tar." .\ more conlplete picture of the carcinogenic potential of cigar `it313" is ob- tained from experimental data in animals. Mortality OveraZ Xortdit y Several large prospective studies have examined the health conse- quences of various forms of smoking. The results of these invest.iga- tions have been reviewed in previous reports of the Surgeon General in which the major emphasis has been on cigar&to smoking and its effect on overall and specific mortality and morbidity. The follorring pages present a current review of the health consequences of smoking pipes and cigars. Data from the prospe&ive investigations of Dunn, et al. (31), Uuell, et al. (IG), Hirayama (&I), and \Veir and Dunn (105) are not cited, because in these studies a separate category for pipe and cigar smokers ~vas not established. The smoking habits and mortality experience of 157,783 white men betlveen the ages of 50 and 69 who were followed for M months were reported by Hammond and Horn (41). The overall mortality rates of men who smoked pipes or cigars nere slightly higher than the rates of men who never smoked. The overall mortality rate of cigar smokers was slightly higher than that of pipe smokers. In a study of 41,000 British physicians, Doll and Hill (26, 27) re- ported the overall mortality of pipe and cigar smokers as being only 1 percent greater than that among nonsmokers. Best. (9)) in a study of 78,000 Canadian veterans, reported overall mortality rates of pipe and cigar smokers slightly nbove those of nonsmokers. Kahn (50) exam- ined the death rates and smoking habits of more than %93,000 U.S. veterans and Hammond (38) examined the smoking habits of and mortality rates experienced by 440,559 men. In t.hese studies, pipe-. smokers experienced mortality rates similar to those of men who never smoked regularly, whereas cigar smokers'had death rates somewhat higher than men who never smoked regularly. Table G summarizes the results of these five studies. Thus, data from the major prospective epidemiological studies demonstrate that the use of pipes and cigar-s results in a small but defi- nite increase in overall mortality. Cigar smokers have somewhat higher death rates than pipe smokers, and mixed smokers who use cigarettes in addition to pipes and cigars appear to experience an inter- mediate level of mortality that approaches the mortality experience of cigarette smokers. 495-0280--7J-13 549 TABLE 6.-&fortnlify TdiOS jar total deaths by fype of smoking (Inales oh) Smoking t,-pc Hammond and Horn ' (&I.__ 1. 00 1. 22 1. 12 1. 10 1. 36 1. 50 I. 43 1. 68 Doll and Hill (26)_-------- 1.00 ___- __-- 1.01 _-__-- _------ 1. 11 1. 28 B&(9)_------ 1.00 1.06 1.05 .98 1. 22 1. 26 1. 13 1. 54 Kahn (60) _.__ -_ 1.00 1. 10 1.07 1.08 _--___ _______ 1. 51 1. 84 Hammond * (38)-- _______ 1.00 1.25 1.19 1.01 _-___- _____ -_ 1. 57 1. 86 NortaMy and Dose-Response Relatiowhips A consistent association exists betrreen overall mortality and the total dose of smoke a cigar&to smoker receives. The methods most frequently used to meaSure dosage of tobacco products are: Amount smoked, degree of inhalation, duration of smoking experience, age at initiation, and the amount of tar in a given tobacco product. For cigarette smokers, the higher the dose as measured by any of these parameters, the greater the mortality. The significance of the small increase in overall mortality that occurs for the entire group of pipe and cigar smokers can be analyzed by examining the mortality of subgroups defined by similar measures of dosage as used in the study of cigarette smokers. hMOUXT .%lOKW Hammond and Horn (40) reported an increase in the orerall mor- tality of pipe and cigar smokers x4th an `increase in the amount smoked. Individuals who smoked more than four cigars a day or more than 10 pipefuls a day had death rates significantly higher than men xho never smoked (PcO.05 for cigar smokers and P4 cignrs- ____ -__-_-_---___-___--_- 229 185 1. 24 Pipe only: Total----------_-__._______________ 609 560 1. 09 1 to 10 pipefuls_--- __.. :_- _____ --_.-_ 391 374 1. 05 >10pipefllls---~-~~~-~---~~-- _-_._ -- 204 172 1. 19 t3owca: Hammond. E. C.. Earn. D. (IO). TABLE 8.-hforlality ratios for toti deaths oj cigar and pipe smokers by amount smoked-Best Amount smoked Observed Number ol death Expected Mortality ratio Ncmmoker ___.___ ---- ________.____- Cigar only: Total _____ - ________ - ._.._-.--.- 1 to lOpipefuls_-_-_-- ______.___- 1010 20pipefd3-_--_- _______.- >20pipefuls--- _____ - _______-.- Gawa: Bat. E. W. R. (8). 90 64 23 1 570 566. 99 1. 00 374 370.09 1. 01 141 140. 84 1. 00 36 35. 90 1. 00 __-__----- 1. 00 82.07 1. 10 56. 05 1. 14 19. 40 1. 19 1. 59 . 63 551 The above evidence suggests that a dose-responx relationship map exist between the number of cigars nnd pipefuls smoked and owrxll mortnlit;o. However, becnuse of the high-mortnlity rate of ex-smokers of cigars and pipes, it is difficult to interpret the data presented with- out including this group with the continuing smokers. ll'ithout data Fchich examines patterns of both daily rata of smoking and inhalation at various age levels, no firm conclusions cnn be drawn ns to the nature of this dosage relationship. TABLE 9.---Mortdity ratios for total deaths of cigar and pipe smokers by age and amount smoked-Kahn Amount smoked Nonsmoker ______ ---__-- ________________________ cigar only: Total__-~__________-____________________~.- I to4cigarsperday _______ -_-_-- ____________ 5to8cigaraperday _______ ----__--- _________ >S cigars per day ________ -- ________ ----_--__ Pipe only: Total____~~~__-_________________________~-~ 1 to 4 pipefuls per day _____ ---_- ______ -- _____ 5ta 19pipefulsperday--_-- __.___.__ - _______ >19pipefufsperday ______ -- __._..__ - ___.___ 1. 00 1. 01 1. OS .89 1. 00 1. 14 1. 23 1. 65 1. 28 1. 08 1. 16 1. 04 1. 00 1. 06 .91 1. 10 1. 18 Boome: Kahn: H. A. (50) TABLE lo.-Mortulity ratios for total deaths oj cigar and pipe smokers by amount smoked-Hammond Amomt smoked Amount smoked Nonsmoker-----.-- _________ 1. 00 Current pipe smokers: Current cigar smokers: Total __________ - _______._ 1. 04 TOtal-_--- _-___ - ___.---.- 1. 09 1 to 9 pipefuls per day-__-- 1. OS 1 to4cigarsperday ___.___ 1. 03 >9 pipefuls per day ___.___ .92 >4 cigar3 per day__ _ __ _ _ _ _ 1. 18 Boons: Hammond. E. C. (98). 552 Inhalation of tobacco smoke directly exposes the bronchi and the lungs to smoke and results in the absorption of the soluble constituents of the gas and particulate phases Without inhalation tobacco smoke only reaches the oral cavity and the upper digestive nnd respirator?; tracts and does not reach the lungs where further direct effects and systemic absorption of various chemical compounds cln occur. L\]thougl~ the smoker has some voluntary control over the inhalation of smoke, the physical and chemical properties of tobacco smoke to a degree determine its acceptability and "inhalability." The condensate of pipe and cigar smoke is generally found to be alkaline when the pH is measured by suspending a Cambridge filter in CO,-free xrter. Cigarette condensate is slightly acidic as measured by this method. Since alkaline smoke is more irritating to the respira- tory tract, it has been assumed that the more alkaline smoke of pipes and cigars was in part responsible for the lower levels of inhalation reported by pipe and cigar smokers. Brunnemann and Hoffmann (15) have analyzed the pH of whole, mainstream smoke of cigarettes and cigar; on a putf-by-puff basis using a pH electrode suspended in main- stream smoke. Smoke from several U.S. brands of cigarettes Kas found to be acidic throughout the entire length of the cigarette. Of intemst was the finding that cigar smoke also had an acidic pH for the first two-thirds of the cigar and became alkaline only in the last 20 to M percent of the puffs from the cigar. Available epidemiological evidence indicates that most cigar smokers do not inhale the smoke and most cigarette smokers do. The fact that smoke from the first half or more of a cigar is acidic, near the range of pH values commonly found in cigarette smoke, and becomes alkaline only toward the end of the cigar might suggest that the pH of the smoke of a tobacco product may not be the only factor t.hat influences inhalation patterns. Per- haps "tar" and nicotine levels as well as the concentration of other "irritating" chemicals also affect the degree to which a tobacco smoke will be inhaled. Nicotine is rapidly absorbed into the blood stream from the luns when tobacco smoke is inhaled The amount of nicotine absorbed from the lungs is primarily a function of the nicotine concentration in the smoke and the depth of inhalation. Some nicotine may also be ab- sorbed through the mucous membranes of the mouth. This is more likely to occur under alkaline conditions rrhen nicotine is unprotonated f3, 15, 79). This suggests that cigar smoker-s may he able to absorb some nicotine through the oral cavity without having to inhale, par- ticularly during the time that the smoke from the cigar is alkalme. 553 Jvith the development of sensitive measures of serum nicotine levels (2) the extent to which nicotine is absorbed through t.he membranes of the mouth in pipe and cigar smokers can be more awurately determined. Inhalation patterns of smokers Kere determined in several of the large prospective and some of the retrospective epidemiologiul studies. Inhalation was usually determined by the administration of n que-s- tionnairo that required a subjective evaluation of one's orrn patterns of inhalation. Although the accuracy of these questionnaires has not been confirmed by an objective measure of inhalation, such as carbosy- hemoglobin or zrum nicotine levels, their reliability is supported by mortality data which demonstrate higher overall and specific death rates with self-reported increases in the depth of inhalation. Doll and Hill (26) and Hammond (38) presented information on inhalation patterns of pipe, cigar, and cigarette smokers (figs, 1,2, 3, and table 12). Some 80 to 90 percent of cigarette smokers reported inhaling, Kith the majority of individuals inhaling moderately or deeply, rrhereas most pipe and cigar smokers denied inhaling at all. Pipe smokers reported slightly more inhalation than cigar smokers. For each type of smoking, less inhalation n-as reported by older smokers. This change may represent less awareness of inhalation, differences in smoking habits of successive cohorts of smokers, or it may reflect the operation of selective factors which favor survival of noninhalers. The Tobacco Research Council of the United Kingdom has, since 19.57, periodically reported the use of tobacco products by the British. figure I.--Inhalation among pipe smokers by age. No inhalation Some inhaiahon I I Age 40 50 60 70 80 SOURCEr Hammond, E C. (38). 554 Figure 2.-Inhalation among cigar smokers by age-Hammond. c--- 3"1,1C inhalation 26.4 22.9 17.1 13.7 18.5 I Age 40 50 60 70 80 SOURCE: Hammond. E. C. (38). Figure 3.-Depth of inhalation among cigarette smokers by age.-Hammond. None Slight inhalation Moderate inhalation Deep inhalation Age 40 50 60 70 80 SOURCE: Hammond, L C. (381. Recent reports edited by Todd h ave contained data on the inhalation patte.rn of cigar, pip, and cigarette smokers (92, 93, 94). Table 11 shows that most, cigarette smokers inhale a "lot" of "fair amount" whereas most pipe and cipzr smokers do not inhale at all or "just a little." Little change is observed in the inhalation patterns of.8 given product since 11)66. Best (9) reported inhalation data among male cigarette smokers by smoking intensity and age group, but did not report the inhalation 555 patterns of pipe nnd cigar smokers. The overall mortality rates of current pipe smokers who inhaled at least slightly were reported by Hammond (38) as being someThat higher than for men rho never smoked regularly. The overall mortality rates of current ci.gar smokers who reported inhaling at least slightly xrere appreciably higher than for men who never smoked regularly (table 13). Available evidence indicates that cigarette smokers inhale smoke to a greater degree than smokers of cigars or pipes. Once a smoker has learned to inhale cigarettes, however, there appears to be a tendency to also inhale the smoke of other tobncco products. For cigars, this is evidently true lx-hether one smokes both cigarettes and cigars or s-x-itches from cigarettes to cigars (tables 14,15,16). Brass and Tidings (14) examined the inhalation patterns of smokers of large cigars, cigarettes, and those who switched from one tobacco product to another (table 15). Nearly 75 percent of those who were currently smoking only cigarettes reported inhaling "almost every puff" and only 7 percent never inhaled. The opposite was true for per- SOIIS who had always smoked only cigars among whom 4 percent re- TABLE 1 I.-The eztiru! of inhaling pipes, cigars, and cigareties by British males aged 16 and over in 1968 and 1971 Tobacu, product Inhale a lot __._____________._______ 23 19 8 8 47 47 Inhale a fair amount _____ --- .______ - 16 19 10 8 31 30 Inhale just a little _________ - ________ 27 27 24 26 13 15 Do not inhale at all__ ______.________ 34 35 59 58 9 8 - Total___________~__--~------- 100 100 100 100 100 100 Soum: Todd, 0. F. (95. 9)). TABLE I2.---l&a&ion among cigar, pipe, and cigareb smokers by age-DoU and HiU smoking type Cigar and pipe ___.____________ 12. 00 10. I10 7. 00 5. 00 4. 00 4. 00 Mixed (cigarette and other)_-__ _ 74. 00 60. 00 47. 00 36. 00 30.00 26. 00 Cigarette only _.______________ 90.00 85.00 75.00 66.00 58.00 41.00 8ourcr: Doll, R.. HIU, A. B. (Ib). 556 ported inhaling almost ore? puff and 83 percent said they nerer inhaled. Cipr smokers rho also smoked cigarettes reported inter- mediate levels of inhalation betwcn the cigar onlr and ciprette onI? categories. Inhalation patterns wrc similar rrherher the individual continued to smoke both products, stopped smoking cigarettes but continued smoking cigars, or stopped smoking cigarettes nnd sxitched to cigars. In all three groups, about 20 percent reported inhaling "almost every puff." This suggests that once an individual's inhalation patterns are established on cigarettes, he mny be more likely to inhale cigar smoke if he sxitches to cigars, or uss both cigars nnd cigarettes, than the cigar smoker who has not smoked cigarettes. Todd (93) reported similar data for a sample of smokers in the United Kingdom (tabIe 16). The prevalence of inhaling a "lot" or "fair amount" of smoke xx-as hi,nhest among cigarette smokers who were currently smoking cigarettes (77 percent) nnd lorrest among current cigar smokers who had previously smoked only cigars or pipes (18 percent). Indiriduals who switched from cigarettes to cigars main- TABLE 13.-Mortality ratios jar total deaths oj cigar and pipe smokers by age and inhalation-Hammond Mortatltr rslb. age Inhalation 4.3 to 64 a5 to 64 Nonsmoker-__-_______---~--~----~~---~-~~--~------- 1. 00 1. 00 Cigar only: Totel---__-_______--____________________--~~-~~ 1. 09 .98 No inhalation _____ - _______________________ -----_ 1. 02 .91 Someinhalation~__-___-_-____________________--- 1. 29 1. 37 Pipe only: Total---____--____-_____________________--~~-~- 1. 04 . 95 No ihabtion ____________ --- ____._._____________ . 98 _ 87 SOme inhalstion_-__-_-__-____________________--- 1. 21 1. II E%~: -mmond. E. C. (~8). TABLE 14.--Percentage oj Bn'tish male cigar smokers who reported inhuling a lot or a jair amount by type bj product smoked T9ce of product 1963 1971 Number of PWWnt Sumkr of Percent In&ridu& In&rlduals %m only.. _ _. _____ -_ __ ____ .____._ 706 23. 0 %a~ and cigarettes__--. . ___ ______._ 111 27. 0 1,193 42. 0 277 44. 0 CiRam and pipes.----_--- ..__________ 596 35. 0 109 32. 0 cigm, cigaretteu, and pipes ._________ 26 52. 0 1.5 32. 0 EOUrcC: Todd. 0. F. (0,. 04). 557 tained somewhat higher levels of cigar smoke inhalation than those cigar smokers n-ho had never smoked ci,narettes (30 percent). Todd (93) examined further the relationship between the inhalation of cigarette and cigar smoke. In general, cigarette smokers who switched to cigars rrere much less likely to report illhaiing cigar smoke than cigarette smoke; however, those who in the past reported inhaling cigarette smoke a "lot" or "fair amount" were much more likely to report inhaling cignr smoke to the same degree than those ex- cigarette smokers who in the past did not inhale the smoke of their cigarettes (table 17). TABLE IL-Percentage of indiuidua!s reporting inhulation of "almost erery puff' of tobacco smoke by current and previous tobacco usage and type of tobacco used Cigarettea only ____ Cigarettes only ____ 2, 359 Cigarette-_- 74. 8 73. 1 76. 6 Cigars only- _ _-___ Cigars only- _ _ ____ 649 Cigars..---- 4.5 3. 0 6. 0 Cigarettes and Cigarette-s and 520 w-.--do ____ - 20.4 10.5 28.0 cigars. cigara. _ Cigars- _ - - _-__ _ __ Cigarettes and 93 __.__ do-_--- 18.3 9. 0 30. 0 cigars. None ____________ Cigarettes and 186 ____ -do----- 21.5 17.8 24.2 cigars. Cigars-- __ _____. _ Cigarette3 only ____ 64 _____ do _____ 17.2 16.0 28.0 Bourcs:Brcar. I. D.J., Tidlnpr,J.(10. TABLE 16.-percentage of British males who reported inkding a lot or jair amount of n'gar smoke by current and previous tobacco usage and type of tobacco previously smoked (1968) CigaretW only--- - _ _ _ _ Cigarettes only-_-_- - 2,`586 Cigarette.- _ __ 77. 7 Cigars only __-___-.___ Nonsmoker- ____ _-__ 306 Cigars------_ 18. 0 Cigars only ____-_______ Cigarettes only _.___._ 321 -----do-__.-.- 30. 0 &xma: Todd. 0. P. @I. 558 TABLE 17.-Extent O_r rt-ported inhafaiion qf cigar smoke by British male cigar smokers who were ez-cigaretfe smoL-crs in I.%T, artalyzcd by extent of reported inhalation of cigarette smoke when yrt-ciously smoking cigareUEs or fRIT amount or not 81 au PI9 pipefuls per day __________________._ Cigar and pipe: 8 or less cigars, 19 or Ievs pipefulj---_----- >8 cigars, > 19 pipefulz ______._______.___ 1. 00 78 1. 14 2. Et 2. 07 .77 2. 20 2. 47 1. 62 18 2. 19 2 12 11 2 2 12 3 &mnx: Kahn. H. A. (50). 575 TABLE L?Z).-Relative risk of lung cancer for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A am- manj of relrospective stwlies Number --- Levin, et al. (60): Caqca- -_______--_-___-_-____ 236 Control8 ______ ___ _______ -___ _ 481 Schrck, et al. (81): CRsCS_-..--._...-._------.-- 82 Controls- _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 522 Wynder and Graham (111): CaScS--..--.-__...------__-- 605 Controls- - - _ - _ _. _ _ _ _ + _ _ _ _ _ _ _ 780 Doll and Hill (%6): Csses_.-_._.___-..---~~~---- 1,357 Controls _.___________________ I, 357 Koulumies (66) : Cases----.------------------ 812 Controls--- _ - _ - - - - - - - - - - - _ - _ 300 Sadowsky, et al. (77): Cases- --__-_.__-____________ 477 Controls _____________ jr ______ 615 Relative risk ____________ Pcrccnt cfi.qes..- _________ Percent controlv _________ Relative risk ____________ Percent cfws ___________ Percent controls _________ Relative risk ____________ Percent cases- _ _________ Percent controls _________ Relative risk ____________ Percent cases ___________ Percent controls _________ Relative risk _____.______ Percent cases ___________ Percent controls-.. _ _ _ _ _ _ _ Relative risk _______.____ Percent casc3 ___________ Percent controls _________ 1. 0 0. 7 15 11 22 23 1.0 .6 15 4 22 23 1. 0 5. 1 1 4 15 8 1.0 --- .._-__ 5 --m-w_-__ 5' .- -.---__ 1.0 -- -______ .G ---_-_-__ 18 e--v be__ _ 1. 0 2. 4 4 2 13 3 0. 8 - _ - _ - - -. . 14 -_--_-___ 25 _ _ _ _ _ _ _ _ _ 5' 7 --.-____. - _ - - _ -. _ _ 11 -_.._____ 3.6 ____.____ 4 --a----_- 12 --- --.__- 2. 1 _ I - _ - _ _ _ _ GG - - - - - _ - _ _ 44 _ - _ _ _ _ _ _ _ 1. 7 - - _ _ - -, -. - 61 _ _- --- __- 50 - _ - _. _ _ _. 15.7 --.---__- 91 ________. 65 --- -*-__- 9. 6 _. _ - _ _ - _ _ 74 - - - - _ - _. - 69 . _ _ _ _ _ _ _ _ 3. 7 5. 6 57 31 53 13 Wyndcr and Cornfield (I IO) : CIL~CS. -_ - - -- - -_ --- __________ 63 CAmtrolu ____. . ____ _ ________ _ _ 133 Rnndig (74) : CLWS _ _ - - _ - - - - - - - - - _. _ - _ _ _ - _ 415 Controls _____________________ 381 hlills and Porter (66): CNCS_.---.._--..----------- 444 Controls ___-_-------- _----___ 430 hlills and Porter (66) : Crises--.---..--..----.._-..-_ 484 Controls _____________________ 1, 588 Schwartz and Dcnoix (8%) : Cnses.-...-.----...-~------- 430 Controls... _ _ _ - - _ _ __-_ __ _ ____ 430 Stocks (89) : CNes~_~_-_.---.-.-~-------~ 2,101 Cuntrols ______________-______ 5, QGO Lombard and Sncgircff (61) : CuJCS------.-----..------.-- 500 Contruls.... ---_____-_.___.__ 1, 839 I'ern11 (73) : cn GLW. - __-- __________.______ 1,477 : Guilrols... _ _ __ __ __ _ __ i ______ 713 Relative risk ____________ Pcrccnt CNCY-- _________ Pcrccnt controls ______-__ Relative risk ______ ______ Percent cases- _ _________ Percent controls _________ Relative risk ___________. Percent cases ___________ Percent controls _________ Relative risk ____________ Percent cases ___________ Percent controls _________ Relative risk __._________ Percent case3 ___________ Percent controls _______-_ Relative risk ____________ Percent cfws ___________ Percent controls _________ Relative rivk ____________ Percent cfuea-. _________ Percent controls .________ Rclntivc risk.--* _________ Percent craw --_________ Pcrccnt control8 -_-______ 1. 0 2. 5 4 0 - - - - - - _ _ - 4 13 6 _-__-_-__ 21 27 8 - - - - - _ - - - 1. 0 5. 3 5. 0 - - - - - - - - - 1 21 11 -------_- 6 19 11 -----_.__ 1.0 _---__--_ ---___-_ 0.0 7 ------_-_ ----_-__ 37 3i _________ ________ 26 1.0 __--___-- _---I--_ 2. 8 8 ----e-e-- ------__ 13 28 _________ ________ 1G 1. 0 - - -. _ _ - _ _ 4. 7 - - - - _ _. _ _ 1 ---- --__- 6 .__-._-__ 11 --_---_-_ 14 -________ 1. 0 _ - - - - - _ - - 3. 1 - - _ _ _ _ _ _ - 2 --e.m-_-- 9 _- ____._ _ 9 -*m-----_ 13 _ _ _ - _. - _ - 1.0 --_-___-- _---_--. 1. 7 2 o-_-mm-__ _-_-__-- 4 10 _--.--__- ----_-_. 15 1.0 -_----_ *_ 4.2 _-__.____ 7 -----em_- 4 --___-_-_ 39 - - _ - - _ _ _ - 5 ----____- 8.5 _________ 77 _ _ -_ _ _ _ _ _ 4s -_--- _-__ 5. 0 - _ _ _ _ - _ _ _ 67 - - - - - _ _ _ _ 64 - _ _ _ _ - _ _ _ 5.4 _________ 5s - - - - - - _ _ _ 43 _- --_ _ - - _ 4. 5 _ - -. _ _ -. _ 78 - _ _ - - _ _ _ - 57 _ _ - -. _ _ _ _ 13. 5 _----_.__ 90 _ _ _ - - _ _ _ _ 78 _ _ - - - - - _ - 5. 0 - - - - - - - _ _ 80 _ _ _ _ _ _ _ _ _ 76 _ __ __ _ -__ 8. 1 ---___- __ Qj ______ ___ 75 -- _ __ --_. 9. 2 Il. 1 77 13 SO 7 TABLE 29 .-Relutive risk oj lung cancer for men, conparing cigar, pipe, and cigarette smoker8 with nomokcrs. A e-urn- maq of relrospective hulks--Continued Wickcn (f&j): .Relntive risk ____ __ _ _ ____ Cases---.-..-.--_-.~.-....---. 1.0 --------- -_------ 2. 2 4. 3 4. 2 803 Percent cB9ea Controls ___________ 4 _________ ________ 10 78 7 __-__-_________________ 803 Percent controls _________ 14 _________ ________ 16 G4 G Abelin and Cscll (I): Relative risk ____________ Cascs--.--..---.~---~.......-. 1. 0 30. 7 21. 8 39. 9 31. 0 24. 7 118 Percent ca3e9. Controls ____-_____ 2 28 7 68 25 24 __-_---________________ 524 Percent control8 -________ 35 19 G 31 17 10 Wynder, et al. (116) : cases---..----__.........-.... Relative risk -___________ 1.0 ___---__- ---_-.-- 2.0 12. 4 _ --.--___ 210 Percent cases. Controls _-__._____ 3 ___._____ __._____ 5 92 _. - - - - _ - _ __._____._ ______FC_____ 420 Percent controls.Sm, __.__ 21 ___..____ ________ 15 47 - -. . . - - - _ TABLE 30.- Changes in bronchial epithelium of male cigar, pipe, and cigarette smokers as compared to nonsmokers 1st set (none vs. pipe vs. cigarette-matched on 1 :I basis) : Nonsmoker- _ _ _ _ _ ___. _ __ _ ____ __ _ ___ ____ Pipe only___--.--_......--------------- Cigarette only _________________________ 2d set (none vs. pipe VB. cigarette-matched on frequency basis) : Nonsmoker.-- _______ _____ __ _ ___ __ _ __ _. Pipe only ______________________________ Cignrcttc only-. _ ______________________ 3d set (none vs. cigar va. cigarette) : Nonsmoker-- _ _ __ __ ___ _ __ _ _ _______ ___ _ _ Cigar only _____________________________ Cignrcttc only __.______________________ 20 20 20 25 25 25 35 35 35 985 924 914 1, 24G l,lG4 1, 12G 22. 9 13. 4 .7 1, 277 G8. 7 38. 7 38. 2 1, 247 96. 3 88. 7 89. 5 1, 237 1,70G 27. 4 1,733 90. 8 1,520 91. 0 21. 7 G5. 5 96. 8 11. 2 2. G 1,031 10. 3 38. 1 37. 0 079 35. 0 88. 6 95. 2 082 72. 1 12. 7 .8 1, 748 40. 0 73. G 1, 8'28 92. 7 97. 8 1, G33 11. 5 37. 9 75. 5 15. 3 52. 5 80. 2 8ourm: Auerbach et al. (8). Tumorigcnic Activity The tumorigenic activity of tobncco smoke can be modified in both a quantitative and qualitative sense. Physical or chemical changes in tobacco that. result in n reduction of total particulate matter upon combusion of a given quantity of tobacco may result in a reduction of carcinogenic potcntinl. Such factors as tobacco selection, treatment, blending, cut, and additives may quantitatively alter tar production. Wrapper porosity and filtration may also affect tar production. Quantitative changes in the tumorigenic-activity of tobacco tar on a gram-for-gram basis can be produced by the selection and treatment of tobacco, the use of additives or tobacco sheets, or adjustments in the cut and packing density. Combustion temperature can also produce quantitative changes in the particulate matter of tobacco smoke. Although high-temperature burning produces less particulate matter in the smoke, it appears that tumorigenic components occur in higher concentration xhen tobacco is pyrolized at temperatures higher than 700" centigrade (34). Cigars, pipes, and cigarettes 5re similar in that they are smoked orally and have a common site of introduction to the body. The tissues of the mouth, larynx, pharynx, nnd esophagus appear to receive np- proximately equal exposure to the smoke of these products. Inhalation causes smoke to be drawn deeply into the lungs and also allows for systemic absorption of certain constituents of tobacco smoke which then can be carried further to other organs. Pipe tobacco and cigars vary from cigarettes in a number of charac- teristics that can produce both quantitative and qualitative changes in the total particulate matter produced by their combustion. Experi- mental evidence suggests that although there is some difference in the amount and quality of tar produced by cigars, this cannot account for the reduced mortality observed in cigar smokers compared to cigarette smokers. Experimental Studies Several experimental investigations have been conducted to examine the relative tumorigenic activity of tobacco smoks condenslttes obtained from cigarettes, cigars, and pipes. Most of these studies mere standard- ized in an attempt to make the results of the cigar and pipe experiments more directly comparable with the cigarette dat.a and most used the sl~aved skin of mice for the application of tar. Tars from cigars, pipes, and cigarettes were usually applied OJI an equal n-eight. basis SO that qunlitntire differences in the tars could be determined. In several ex- periments. the nicotine was extracted from the pipe and cigar conden- sates in an attempt to reduce the acute toxic effects that resulted in nnimals from the high concentrations of nicotine frequently found in these products. 580 JT'ynder snd ITtight (117) examined the diflerences in tumorigenic acti\-ity of pipe and cigarette condensates. Tars mere obtained by the SmokiIjg of 3 pop~ll3r br:~rd of king-size cignrettcs and the same +a- rette tc)bncco snloked in 12 standard-grade briar bon-1 pipes. not11 the cigarettes :trld pips were putfed three times a minute Ath a Q-second putf and a 35-m]. I-oltrme. Both the cigarcttcs and pipes attnincd similar masimum combustion zone temperzturcs, . hone\-er, the use of cigarette tobacco in the pipe resrtlted in a combustion chamber temperature that averaged about 150" centigrade higher thnn temperatures achieved when pipe tobacco was used. Chemical fractionation wss accomplished and equal concentrations of the neutral fraction were applied in t.hreo weekly applications to the shaved skin of C-IF', and Swiss mice. The results indicatet,hat. neutral tar obtained from cigarette tobacco smoked in pipes is more active than that obtained in the usual manner from cigarettes. About twice as many cancers acre obtained in both the CXF, and the Swiss mice, and the latent period x-as about 2 months shorter. Extending these data, Croninger, et al. (20) csamined the biologic activity of tars obtained from cigars. pipes, and cigarettes. Each form of tohacco was smoked as it was manufactured in a manner to simulate human smoking or to maintain tobacco combustion. Tlw ~rlrole tar was . nppired m drlutlons of one-to-one and one-to-two mith acetone to the shaved backs of female CAF, and female Swiss mice using three . npplwattonseach creek for the life-span of the animal. The nicotine was estracted from the pipe and cigar condensates to reduce Lhe acute toxicity of the solutions. The Swiss mice. pipe, cigar, and cigwette tars produced both benign and malignant tumors. The incidence rates of malignant tumors given as percents were: 44,41, and 37, respectively. These results suggested a somewhat higher degree of carcinogenic activity for cigar and pipe tars than for cigarette tar. Similar results n-we reported by Kensler (53) who applied conden- sates obtained from cigars and cigarettes to the shaved skin of mice. The incidence of papillomas produced bv cigar smoke concentrate was no diff'emnt from that of the cigarette"smoke condensate. Similarly, there xas no diBerence between cigar and cigarette smoke condensates when carcinoma incidences xrere compared. fJombur,oer, et al. (45) prepared tars from cigar, pipe, and cigarette tobaccos that were smoked in the form of cifarettes. In t.his way, all tobaccos were smoked in an ident.ical manner and uniform combustion temperatures xere achieved. Because of this standardization, differ- ences in tumor yield could be attributed to tobacco blend and not the manner in which the tax-s were prepared. The whole tar-s mere diluted one-to-one with acetone and applied to the shaved skin of C.iF, mice three times a ireek for the lifespan of the test animal. Skin cancers XWTT produced more quickiy Kith pipe and cigar smoke condensates than with cigarette smoke condensates. This suggests that the smoking 495-028 Q-73-15 581 of pipe and cigar tobaccos in the form of cigarettes does not alter the condensates to any significant degree. Davies and Day (32) prepared tars from small cigars especiallY manufactured from a composite blend of cigar tobacco representing small cigar ,bmnds smoked in the United Kingdom, cigarettes espe- cially manufactured from the same tobacco used for the cigars de- scribed above, and plain cigarettes especially manufactured from a composite blend of flue-cured tobacco representing the major plain cigarette brands smoked in the United Kingdom. The whole tar was dilut& to four concentration levels and applied to the shaved backs of female albino mice for their lifespan using four dosing regimens. A statistically significant increase in mouse skin carcinogenicity was shown with the cigar smoke condensate compared Kith the tars obtained from either flue-cured or cigar tobacco cigarettes. These results are consistent with those of the previously reported investigations. The effect of curing on carcinogenicity was examined by Roe, et al. (76). Bright tobacco grown in Mexico WIS either flue-cured or air- cured and bulk fermented. Both flue-cured and air-cured tobaccos were made into cigarettes standardized fordraT resistance and were smoked under similar conditions. Condensates from these cigarettes rrere ap- plied to mouse slain three times each \yeek in an acetone solution. The development of skin tumors was higher in mice treated with the flue- cured condensate than in mice treated with the air-cured condensate (P-lander (2~) exposed the upper trachea of nnesthetized cats to the snloke of cigarettes and cigars, ohsem-inc the etiect on ciliary acti\-ity through an incident-light microscope. -1 chemical analysis of the was and particulntc phases revealed that the cigar smoke was more alkaline and, in general, contained higher concentrations of isoprenr. acetone. acetonitrile, tolurne. and total particulate matter compared to cigarette smoke. The awrage number of puffs required to arrest ciliaq; activity was found to be X3 for the cigarette smoke and 11-1 for the cigar smoke. The difference is statisti- cally significant (P .prs of smoke. The frc- quency and duration of exposure rrcre not specific(l. x:d the cxtrnt of actual inhalation of smoke by the different qoups of rnts was either not determined or not reported. It is also diflicult to determine the effect of smoke exposure on the frequency and severity of respiratory infections when animals are exposed to smoke in groups where common exposure occurs. The rat strain used was not identified. but it. XIS noted that anim:& appeared to suffer from an endemic rat bron- chiectasis. It is not knon-n to what extent epidemics of respiratory infections occurred among these animals. Because of these difliculties, no firm conclusion cnn be drawn concerning the effect of smoking flue- cured or air-cured tobaccos on the incidence of respiratory infections in rats. TABLE 33.-hfortality ratios jor chronic obstructive pulmonary deaths in male cigar and pipe smokers. A summary of prospective epidtmio- logical studies Hammond aud Horn (40). DoU and Hill (es, 27). Best (9).----- Hammond (58) Kahn (60)--.- corn tot&l-_-_--_- ---- --.-_ .---- --..- .----------- Emphysema_- ______ I. 00 3. 33 .7.i - _.__ 5.85 _---.- Bronchitis--___--_-- 1.00 3.57 2. 11 _-___ Il.42 ______ COPDtotEL~~----- ---- ----- ----- --_-- _-__-__--___ Emphysema__--__-- 1.00 - ____ __--_ 1.37 `6.55 ______- Bronchitis._--.-_--_ .___ _____ ___-_ __-_- __--_-____-: COPD total_ _______ 1.00 79 Emphysema _____ -__ 1.00 1: 24 2.36 99 10.08 ___.__ 2. 13 1: 31 14. 17 ______ Bronchitis_--_---_-_ 1.00 1.17 1.28 1.17 4.49 ._____ 49SO28 S-73-16 589 Booeke (10).-e Pnrents of 59 femilies. Edwards, et 1,737 male al. (3s). outpstienta. Ashford, et 4,014 male d. (4). workers in 3 Scottish collieries. Bower (If)_-_ 95 male bank employees. Wynder, et al. 315 male pa- (114). tienta in New York and 315 male patient3 in California. Densen, et al. 5,287 tie Persistent cough- _ (24). p&d and Persistent 7,213 male aputum tramlit production. workers in Dyspne.... ______ . New York Wheeze ________ --_ City. Chest illness-_--~- 7 11 11 16 16 19 14 21 13 16 Cederlof, et 4,379 twin pairs, Cough- _ _ _ ___ __ __ 4 al. (18). au U.S. Prolonged cough-_- 2 veterans. Bronchitis- _ _ _ __ __ 2 Rimington 41,729 male (76). VOlUnteerS. Cagh ____________ Sputum production. Chest illness~-~~~~ Chronic bronchitis- 17 `19 Bronchitis--_----- 10 ' 35 21 37 Pneumoconiosi3_~_- 11 ' 34 14 2 Cough _____ - ______ sputum production. Wheeze--------__- Chest ilines_-__-- Cough (New York). Cough (California). Influenza (New York). Influenza (California). Cheat illness (New York). Chest illness (California). Chronic bronchitis_ 5 32 24 5 0 0 8 15 8 1.5 14 22 11 28 24 9 7 32 I .5 4 31 54 33 30 21 10 6 7 4 3 `9 48 ______ 20 ----__ 5 -____- 31 14 29 -___-- 33 _--_-_ 33 -_-___ 40 __-___ 56 51 67 66 24 -_.___ 31 ______ 12 ___.__ 11 ___--- 25 ______ 26 ___--- 26 ______ 32 --____ 18 _-____ 17 -_____ 11 ______ 10 ___--- 17 ___--- 590 TABLE 34.-Credence of req-iratoq symptoms and iUness by type of smokieontinued Camstock, et 670 male tele- Persistent cough.- 10 16 41 -____- al. (19). phone Per$stent 13 20 42 _-__-_ employees. sputum. Dyspnes ____ - ____ 33 39 44 -___-_ Chest illness in 14 18 20 ----__ pnst 3 years. Lcfcoc and 310 male phy- Chronic respira- 9 18 44 ---___ rTonnncott sicisns in tory disease. (69). London, Chronic bronchitis- 1 12 34 -__-__ Ontario. Obstructive lung 1 3 4 ______ disesse. Asthma-- ________ 7 3 6 __-_-- Rhonchi ._________ 0 3 9 ._____ TABLE S5.--Pulmonary junction L&U&S for cigar and pipe smokers as compared to nonsmokers FUIlCllOIl Ty-pe of moklng Non- Total pipe Clgarettt Mixed smoker and cigar OdY A&ford, et al. (4). Goldsmith, et al. (37). 3,311 active or retired longshore- men. Cornstock, et al. (19). Lefcoe and Wonnecott (69). 4,014 male workers in 3 Scottish collieria3. 670 male telephone employees. 310 male physicians in London, Ontsrio. FEV,.o--__-_m 3. 39 ' 2.59 3. 14 2. 62 Puffmeter ____ 313. 63 299. 26 303.44 - _____ FEV,.o .______ 2. 99 2. 80 2.91 __--_- TVC-_-__---- 3. 87 3. 68 3.88 ---___ -_ FEV,.e----e-e 3. 12 3. 26 2.82 ___-_- FEV,.o .______ 3. 39 3. 17 3. 11 ______ MSIFR liters 4. 09 4. 17 3.64 ______ per second. 591 GASTROISTEXTISAL DICOFCDERS Cigamtta smokers have an increased prevalence of peptic ulcer disease and a greater peptic ulcer mortaIity ratio thnn is found in nonsmokers. These relationships are stronkyr for gastric ulcer than for duodenal ulcer. Cigarette smoking a ppfars to reduce the elIectire- ne.ss of standard peptic ulcer treatment regimens and slob-s the rate of ulcer healing. Cigar and pipe smokers experience higher death rates from peptic ulcer disease than nonsmokers. These rates are higher for gastric ulcers than for duodenal ulcers but are somewhat less than those rates experienced by cigarette smokers. Table 31 presents the mortality ratios for ulcer disease in cigar and pipe smokers as reported in the prospective epidemiological studies. Retrospective or cross-sectional studies by Trovvell (.95), Allibone and Flint (2), Doll, et al. (2.9), and Edwards, et al. (39) contain data on ulcer disease in pipe smokers as well as cigarette smokers. So nssocintion was found betrreen pipe smoking and ulcer disease in these inrestigations. TABLE 36.-Aforta&Ly ratios for peptic ulcer disease in male cigar and p.pe smokers. Summary of prospective studies Type 01 smoking Hammond and Duodenal ulcer-_- _ _ _ 1. 00 0. 25 1. 67 _ _ . . . . 2. 16 ~. -. . - Horn (40). Doll and Hill Gastriculcer~.~.---- 1.00 _____ -_-.. 4.00 7.00 5. 30 (26, 27). Hammond (.?8)_- Gastric ulcer- __.____ 1. 00 ---- - -___- 2.04 2.93 . ..- -- Duodenel ulcer .____ - 1. 00 __-__ --..- .92 2.86 .----- Kahn (60) ______ Gastric ulcer--- _____ 1.00 2.90 2.84 2. 48 4. 13 ------ Duodenalulcer ._____ 1.00 1.58 1.59 1.39 2. 98 ------ Little Cigars In the past year, several new brands of little cigars (vveighing 3 pounds or less per 1,000) have appeared on the national market. These cigarette-sized products are manufactured, packaged, advertised, and sold in R manner similar to cigarettes. Little cigars enjoy several legal advantages over cigarettes: They have access to television ndvertising; they are taxed by the Federal Government and by most States, at much lower rates than cigarettes, resulting in a significant price advantage; 592 and they do not carry the rrnrning label required on cigarette pack- ages nnd in cigarette advertising. A market appears to be developing for the.se products, as there has recently been a sharp increase in the shipment of little cigars destined for domestic consumption (table 37). It is important to estimate the potentiai public health impact of these little cigars. An adequate epidemiological evaluntion of the ef- fect of little cigar smoking on health could take 10 or 15 years and is probably an impractical consideration; ho\rever, a review of the epide- mioIogicaI, autopsy, and experimental data concerning the health con- sequences of cigarette, pipe, and cigar smoking summarized in this and previous reports is helpful in considering the potential impact on health of smoking little cigars. An analysis of the chemical constit- uents suggests that both cigarettes and cignrs contnin similar corn- pounds in similar concentrations. TKO exceptions are reducing sugars, which nre not found in quantity in the fermented tobnccos commonly used in cigars, and the pH of the inhaled smoke. The pH of the smoke from U.S. commercial cigarettes is below 6.2 from the first to the Ia&. puff, mherens the smoke from the last half of a cigar may reach as high as pH 8 to 9. With increasing pH, nicotine is increasingly present in the smoke as the free base. Skin painting experiments in mice indicate that tumor yields with cigar or pipe "tars" are nearly identicnl with those obtained with cigarettes "tars". Tn addition, the epidemiological data suggest that depth of inhalat.ion probably accounts for the fact that cigarettes are so much more harmful than cigars and pipes in con- tributing to the development of lun g cancer, coronary heart disease, and nonneoplastic respiratory disease. For such diseases ns cancer of the oral cavity, larynx, and esophagus, where smoke from cigars, pipes, and cigarettes is available to the target organ at comparable levels, the mortality ratios are very similar `for all three forms of tobacco use. Several factors, including "tar," nicotine, and the pH of the smoke, probably operate to influence inhalation patterns of smokers. The relative contribution of individual factors to the inhalability of a tobacco product has not been determined. Smoking those brands of little cigars which can be inhaled by a significant portion of the population in a manner similar to the preg ent use of cigarettes would probably result in an increased risk of de- veloping those pulmonary and cardiovascular diseases which have been associated with cigarette smoking. On the other hand, smoking those little cigars which are used like most large cigars &ereby the smoke is rarely inhaled would probably result in lower rates of those Pulmonary and cardiovascular diseases than would bo found among cigarette smokers. OnIy a limited analysis is available comparing the chemical com- lmunds found in little cigars, cigarettes, and large cigars. The FTC analyzed t-he tar and nicotine content of all the little cigars (34) and cigarettes (97) currently available on the market. Little cigars have 593 generally a higher "tar" and nicotine level than cigarettes, although considerable o\-erlap results in some little cigar brands having "tar." and nicotine lerels comparable to those of some brands of cigarettes (fibs. 4 nnd j)- Hoffmann and IVynder (M) recently compared three brands of little cigaars \vith an unfiltfrcd cigarette, a filtered c@Ssrette, and a large cigar. They measured a number of smoke constituents, in- cluding: "tar," nicotine, carbon monoxide, carbon dioxide, reducing sugars, hydrogen cyanide, scetaldehyde, ncrolein, pyridines, phenols, bcnz(a)anthracene, and benzo(a)pyrene (table 32). Cigarette -1 XX the Kentucky reference cigarette, cignrette B was a popular brand of filter cigarette. Cigar A eras an 8.5 mm. little cigar, cigar I3 was an 8.5 mm. little cigar, cig.w C was a 95 mm. small cigar, and cigar D was a 112 mm. popular brand of medium sized cigar. The smoke pH ~a2 analyzed puff by puff (table 39). Cigarette smoke was found to be acidic (pH less than 7) for the entire cigar&a The smoke from little cigars became alkaline only in the last. puff or two, rrhereas about the last 40 percent of the puffs from the larger cigar were alkaline. Although the pH of the total condensate obtained from cigarettes is usually acidic and the total condensate obtained from cigars is usually alkaline, the above data indicate that smoke pH of tobacco products changes during the combustion process. Smoke from large cigars may be acidic during the first portion of the smoke and not become alkaline until the last half of the cigar is smoked. Brunnemann and Hoffmann (25), using the same techniques de- scribed above: examined the effect of 60 leaf constituents on smoke pH. For several wrieties of cigarette tobacco, they found a high correlation betlreen t.he total aklaloid and nitrogen content and smoke pH. Stalk position also affected smoke pH. Tobacco leaves near the top of the plant, n-hich contain high levels of tar and nicotine, yielded a smoke with a much higher pH than leaves lower on the plant. At present it is not known to ahat extent these factors influence the p1-I of the smoke of tobacws commonly used in cigars or how these kinds of pH changes inff uence the inhalability of tobacco smoke. The inhalation of smoke, however, appears to be the most important factor determining the impact a cigar will hare on overall health. Those physical and chemical characteristics of a tobacco product which most influence inhalation of tobacco smoke have not been accuratel_v determined. Severtheless, it appears likely that the smoke of some brands of cigars may be compatible rcith inhalation by a sig- nificant. portion of the smoking population. since: (a) Little cigars have tar and nicotine levels which, in some brands, are similar to the le\-ek found in cigarettes, and (6) the pH of Ihe smoke of some little cigar brands is acidic for the major portion of the little cigar and becomes alkaline only in the last puff or two. "tar" content. It is rea-sonable to conclude that smoking little cigars may result in health etfects similar to those associated \rith smoking cigarettes if little cigars are smoked in nmounts and with patterns of inhalation similar to those used by cigarette smokers, for the reasons cited abo\-e, and these additional reasons: (CZ) In those littlc cigars for which pre- liminary data are available, the concentrations of carbon monoxide, hydrogen cyanide, acetaldehyde, acrolein, pgridine, phenol, and poly- cyclic hydrocarbon levels are comparable to those found in cigarettes; (b) cigarette smoker; xho switch to cigars appear to be more likely to inhale cigar smoke than cigar smokers who have always smoked cigars (Id) ; and (c) cigarette smokers who switch to little cigars may he inclined to use them as they did cigarettes because of the physical similarities between the little cigars and cigarettes, including their size and shape, the number in a package, the burning rate, and the time it takes to smoke them. Figure 4.-Percent dlstrlbutmn of 130 brands of cigarettes and 25 brands of little cigars by I E - I Mg. "tar" 0 0 0 16.0 8.0 32.0 32.0 0 8.0 4.0 Cigarettts o-4 5-9 lo-14 15-19 m-24 25-29 30-s 35-39 40-44 45-49 Little Clgan 3.1 3.1 10.0 46.2 23.1 10.0 3.9 0.8 0 0 SOURCE; " s Deparfment 0, ".Df,h. Ed"cal,on, and w.t,are (97, and FKlarsl T,M. Commllrlan ,30. 595 Figure 5.-Percent distribution of 130 brands of cigarettes and 25 brands of little cigars by nicotine content. CigarFnesB Little cigars 5 cl SOURCE: U S. Department of Health. Education. and Welfare (977) and Federal Trada Corn. rr,,ss~on (34). 596 TABLE 37.~Shipment of small and [urge n'gars destined for domestic cons-umption (1970, 1971, 1970) Year lml 1971 1972 January _.____-_____ ~__- 58, 328, 520 85,733,750 123, 477, 550 February-_- .______ - ____ 63, 431,580 72,092,205 179,817,939 hiarch- _ _ _ __ __ _ __ __ ___ _ 85,881,860 46,542, 800 193, 165, 593 April _____ -_-_- _______._ 101,613,500 59,059,920 125, 335, 740 hlay ______ -_- __________ 81,093, 180 93,237,473 159, 334,565 June_________--_____-~- 82,471, 120 94,560,140 lSO,582,243 Subtotal _______ _ _ _ 472, 919, 760 451,246,313 966, 713, 530 - Jdg-_- --------_-_- -_-- 62, 143, 140 70, 332, 500 127, 713, 320 August ___.___________ ~_ 68,220,365 127, 709, 310 670,936,869 September.-__--_------- 79, 101,045 95,027, 340 422,534, 705 October ____________ ---_ 90,752,880 109,567,900 708, 116, 830 November- ___________ __ 64, 290, 600 106, 666, 107 551,326,888 December---.- _____ -___ 63,806, 010 123,809, 553 485,587,014 Subtotal _____ _ _ _ _ _ 428, 314,040 633, 112, 710 2,966,215,626 Yearly total._---__ 901,133, so0 1,054,359,028 3,932,929,156 Large cigars Janusry_~___-_~_-_-___- 581, 74'2,001 573,039, 120 534,565,488 February____-__.__-____ 595,249,522 586,810, 844 562, 414,577 March__---_-__-_~-__.~ 629, 977, 375 665, 998, 099 654,827,796 April ________ ____ _ ___ _ _ _ 652,800, 200 655, 213 850, 554,242,048 Mey~_~_~.~~~~_~~_____- 748, 040, 796 670, 933 064, 719,489,529 June__-_-______________ 649,539,031 692,436, 529 578, 501, 068 Subtotal _---______ 3,852,348,925 3, 844, 199,738 3, 604, 040, 506 JulY__--_______--______ 647, 397,547 619, 838, 386 Auwt -_-_________ - ____ 520, 873,339 673,082,971 148 September _________ - ____ 662,970, 682, 331,630 721,561,449 O~tobf2r- _ _ _ _ _ _ __ _ _ ____ _ 680,476,418 594,843, 957 968 November- 797,601,253 67.9, 420, 693,150,668 _ _ _ _ _ _ _ _ _ _ _ _ _ December--- -_ 696, 526,464 742,948,802 650, 746, 540 _______ __ 596,244, 159 516,879,415 437,429,996 Subtotal --_-____ -_ 4, 132, 413, 843 3, 902,534, 137 3,579,356, 130 Yearly total- __ _- _ E, 084,762, 768 7, 746,733,875 7,183,396,636 -: 0.8. Dwnmaant of the Tw (JOJ). 597 TABLE 3S.-Selected compounds in mainstream smoke "Tar", z~tiI~am prr cigarette.. _ Xicotine, milligram per cigarette- Carbon monoxide, volume per- cent_---~_-~_~---.----.-.-. Carbon dioxide, volume percent_- Reducing sugars, percent of tobacco Keight- _ __._____. ___ Hydrogen cJ-snide, microgram per cigarerle- _- - __.. ____. __ _ Aceteldchyde, micrrgram per cigarette-__-- ___._._.__ __-_- Acrolein. microgram per cigar- ette ____ - _______.______.____ Total pyridines, micrograms per clprertc_~---__-- ______-_-.. Phenol, microgram per cigarette-. Benz(a)anthrecene, nvnogrnm per cigererte--- ________.___. Benzo(a)pyrene, nanogram per cigarette _____ _ _ __ .__. _. . ___ _ 36. 1 2. 7 20. 3 1. 4 4. 6 4. 5 9. 4 9. 6 9. 3 7. 9 536.0 361. 0 iio. 0 774. 0 105.0 82. S 124.2 74. 0 47. 0 71. 0 27. 3 33. 0 31. 0 20. 0 17. 4 .G 5. 3 6. 5 1. 5 351.0 630. 0 41. 0 58. 0 35. 1 34. 0 18. 0 31. 3 40. 6 1. 8 3. 1 Il. 1 7. 7 13. 3 12. 7 2. 9 2. 7 G97. 0 1, 029. 0 I, 238. 0 1, 150. 0 54. 0 66. 0 85. 3 80. 3 63. 4 94. 1 25. 0 39. 0 22. 0 30. 0 Bourn: KoL7zann. D.. Wynder. E. L. C&l). TABLE SY?.--Th.e pH of the mainstream smoke of selected tobacco products [Ntmben In pruenthesu lndlcale number OZ last puff.1 .4wuga pE? Cl?xretle A C!garette B LllLl8 LIttIe 9mall Cigar D (nondlter) alwr1 cigar A cigar B ctgar c 3d puff----- 5th pufY_-_- 7th put?---- 9th puf-_-- 13th puff_-- 18th puff--- 23d pufi-T-e 28th puff_-- 33d PUB-_-- 38th puff_-- L-t puff--- G. 19 6. 14 6. 09 6. 02 _--_--_- - - _ - _ _ - - __- ____- ___--___ 5.96(11) 6. 15 6. 44 6. 12 6. 34 6. 01 7. 03 5.83 _.___.__ --______ --_-_--- _-_.-___ _-_-_--- ____--__ ___-_--- __--_--_ -______- 5. 76(10) 7.73 (8) 6. 55 6. 53 6. 46 6. 49 6. 51 6. 56 6. 98 6. 59 6. 47 ____-- .- 6. 27 6. 39 6. 41 6. 81 7. 22 7. 53 7. 78 7. QG(43) 8oarce: HoUmmn. D.. Wynder. E. L. (u). 598 Conclusions Pipe and cigar smokers in the United Stntes as n group experience overall mortality rntes that are slightiy higher than those of nonsmok- ers, but these rates are subs&ntially lower than those of cignrette smoker-s. This appears to be due to the fact thnt the total exposure to smoke that a pipe or cigar smoker receives from these products is relatively low. The typical cigar smoker smokes fexvcr than five cigars n day and the typical pipe smoker smokes less than 20 pipefuls a day. Most pipe and cigar smokers report that they do not inhale the smoke. Those who do inhale, inhale infrequently and only slightly. As a result, the harmful etfects of cigar and pipe smoking appear to be largely limited to incrensed death rates from cancer at thosesites which are exposed to the smoke of these products. Mortality rates from cancer of the oral cavity, intrinsic and extrinsic larynx, pharynx, and esophagus are approximately eq~ml in users of cigars, pipes, and ciga- rettes. Inhalation is evidently not necessary to expose these sites to tobacco smoke. Although these are serious forms of cancer. they account for only about 5 percent of the cancer mortality among men. Coronary heart disease, lung cancer, emphysema, chronic bronchitis, cnncer of the pancreas, and cancer of the urinary bladder are diseases Khich are clearly associated rrith cigarette smoking, but for cigar and pipe smokers death rates from these diseases are not greatly elevated above the rates of nonsmokers. These diseases seem to depend on rnod- erato to deep inhalation to bring the srnoke into direct contact with the issue at risk or to allow certain constituents, such as carbon mon- aside, to be systematically absorbed through the lungs or to affect the temporal patterns of absorption of other constituents such as nicotine thnt can be absorbed eit.her through the oral mucoza or through the lungs. Evidence from countries where smokers tend to consume more cigars and inhale them to R greater de.gree than in the United States indicates that rates of lung cancer become elevated to levels appronch- ing those of cigarette smokers. Available data on the chemical constituents of cigar, pipe, and ci@rette smoke su,azest that there are rnarked similarities in the cam:- position of these products Pipe and c&w smoke, however? tends to be more alkaline than cigarette smoke, and fermented tobaccos com- monly used in pipes and cigars contain less reducing sugars than the rapidly dried I-aricties commonly used in cigarettes. Experimental evidence suggests that little difference exists betxwzn the tumorigenic activities of tars obtained from cigar or cigarette 599 tobaccos. Malignant skin tumors n)>penr somewhat more mpidl>- and in larger number-s in animals whose skin has been painted with cigar tars than in those animals painted with cigarette tars. One must conclude that -some risk exists from smoking cigars nnd pipes as they ate currently used in the United States, but for most diseases this is small compwed to the risk of smoking cigarettes ns the.! nre commonly used. Keverthcless, changes in pntterns of usqy that would bring about increased exposure either through increased indi- vidual use of cigars and pipes or increased inhnlation of pipe and cigar smoke have the potential of producing risks not unlike those nom incurred by cigarette srrtokers. Mechanical or chemical modifications of pipe tobacco and cigars that would result in a smoke more compnt- ible with inhalation could have this efiect. Pipe and Cigar References (I) -bELry. T.. G5u 0. T. Relative risk ol pulmonary cancer in cigar and pip smokers. Cancer X)(8) : 1288-12x. August 1%7. (2) AUIBOSE. A.. FLISr. F. 3. Bronchitis, aspirin, smoking. and other factors in the aetiologY of peptic ulcer. Lancet 2: 179-182, July 28. 1958. (9) ARXIITAGE, -4. K.. `PLXXE~. D. M. Absorption of nicotine In cigarette and cigar smoke through the oral mucosa. Stature 22G(%~) : 123-1232. June 27, 1970. (4) A~HZY)RD. J. R., Baows. 5%. Dumtxo. D. P., SMITH. G. S.. PAY, J. 15'. J. 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Chapter 7. pages 237 - 249. 607 Contents Introduction___---______________________---------------- Studies of Smokers- _ _ ____ _____ -___ ___ __ _ ___ ______ _ __ _ __- Studies Comparing Smokers to Nonsmokers: A&tie& Petyformance---- _____ -__---__-_- ____ -_------- Bicycle Ergometer Performance_- __ _ _ _ _ __ __ _ _ _ _ __ _ : ____ _ Treadmill Performance_----- ______ -__-_-- ______ ---__-- Perjormance in Other Tests of Fitness-_--_-------------- Discussion-_-___-___-_____---_-__-__------_______------- Biomechanisms _--__-_____-_--_____ --_- ______- -_---_-___ summary--_-______---____________________------------- References____--_____-__-___-___________-______________ rage 611 611 613 614 615 6U 616 616 617 618 609 Introduction Although it has long been held by athletes nnd coaches that cigarette smoking is associated with "shortness of wind" and impaired perform- ance, until recently there has been little scientific evidence to support this view. In the past few years, a variety of studies have appeared dealing with the effect of cigarette smoking on the response of man to exercise. The follolving is a revielr of these studies. Age, sex, training, health, weight, and other factors are known to influence exercise performance. Because most of the investigations n-we carried out in healthy, youn g male volunteers, the groups rrere quite comparable with regard to age, sex, and health ; ho\rever, weight, training, and other factors were often inadequately controlled. Furthermore, problems in study design and statistical analysis limit the value of several of these studies. \ Many forms of exercise mere performed in these experiments, in- cluding: pedaling a bicycle ergometer, running on a treadmill, running on a track, swimming, stelj climbing, gripping a hand dynamometer, and doing sex-era1 different exercise activities as part of a battery of tests. Small to maximum amounts of work were carried out in the various studies revelred. Studies of Smokera Most of the studies of habitual cigarette smokers followed a similar format vzith respect to smoking: (a) The subjects refrained from smoking for a few hours prior to testing, and (6) two test runs mere performed, one without smoking and one in which smoking imme- diately preceded the exercise or was incorporated with the exercise protocol. Several investigators (I, 1.5, 28) studied the effect of smoking on maximum grip strength. Willgoose (28) reported a greater mean per- cent. recovery of grip strength after the nonsmoking trial than after the smoking trial. Kay and Karporich (15) and -tinderson and Brown (I) all followed a protocol similar to that of Willgoose except that they randomized the smoking and nonsmoking trials, and substituted 611 a "placebo" cigarette for the nonsmolring trial. In neither of these studies =-ere statisticaIIy significant ditference3 obsen-cd between the grip SCOM for the smoking and nonsmoking trials. Reexs and Morehouse (24) administered a battery of tests to 15 colleges students. The tests mere: A tapping test, a strength test. a jumping test, and the short form of the Harvard step test. h-o statis- tically significant differences in performance Tere noted under con- ditions of smoking or nonsmoking. A total of 32 college students from intermediate swimming classes abstained from smoking for 15 minutes, 2 hours, and 12 hours in astudy conducted by Pleasants, et al. (23). Following the abstinence, they sxam distances of 100 and 200 yards Although actual swimming times were not published, the authors reported no statistically significant differences between the mean srrimming times after the different periods of abstinence for either distance. In 1%6, Juurup and Muido (23) carried out several experiments in rrhich three young cigarette smokers exercised on a Krogh's bi- cycle ergometer. Smoking was found to increase the pulse rate at rest as Tell as during exercise. Although the effect was less con- sistent than on the heart rate, smoking was also associated rrit.h elevated blood pressure. Smoking had no effect on oxygen consump tion. Henry and Fitzhenry (13): in 1949, using the bicycle ergometer, also found t.hat smoking exerted no et?& on oxygen consumption. In the same year, Karpovich and Hale (I$) studied bicycle ergometer performance in eight young men. In all subjects, the average riding time was better in nonsmoking tests than in smoking tests; how- ever, the results Eere statistically significant for only three of the eight. subjects. Kerr&an, et al. (16) more recently measured direct arterial blood pressure, heart rate, and cardiac output in 25 habitual smokers at rest and after exercise. Smoking two cigarettes produced statistically significant (P!) Ilnivcrjity students. and 414 railroad workers. The ditferenccs betn-ccn the smokc~s and non- smokers were of small magnitude. Basal oxygen consumpt.ion was slightly higher in smokers than in nomxnokcts. L~lso. resting pulse rates were higher in smokers of most groups. Cooper. et al. (6) studied 17 out of 419 airmen with treadmill tcst- ing. Cardiopulmonary indices measured on the tmndmiil. including maximum indices, were comparable in smokers and nonsmokers ex- cept for a significant (P-ses of variance performed. JZasimnl oxygen intake durin, n treadmill escrcise was examined by JIcDonough, ct. al. (13) in 86 hralthy, middle-aged male volunteers. Cigarette smoking was one of six variables which together provided 3 mllltiplo correlation coellicient of 0.X3. 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(42) NEWSOME, J. R., KEITH, C. H. Variation of the gas phase composition within a burning cigarette. Tobacco Science 9: 65-69, April 16, 1965; (43) NEWSOME, J. R., NORMAN, V., KEITH. C. H. Vapor phase analysis of tobacco smoke. Tobacco Science 9: 102110, July 23, 1965. (44) NORMAN, V., KEITH, C. H. Nitrogen oxides in tobacco smoke. Nature 205(4974) : 915-916, February 27, 1965. (45) NORMAN. V., NEWSOME, J. R., KEITH, C. H. Smoking machines for the analysis of the vapor phase of cigarette smoke. Tobacco Science 12: 216221, 1968. (46) OSBORNE, J. S., ADA.IMEK. S., HOBBS. M. E. Some components of gas phase of cigarette smoke. Analytical Chemistry 28 (2) : 211-215, Feb wary 1956. (47) PAILER, hf., KUHN, H. Kurzer Rericht iiber das Vorkommen vbn Nickel im Zigarettenrauch. (Short report on the occurrence of nickel in cigarette smoke.) Fachliche Mitteilungen der Osterreichischen Taba- kregie (4): 61-63, 1963. 632 (!+a) Pm, N., KL`HN, H., GK~~NHEXCF.R I. ilber Quantitative Unterschiede im Xuftreten van niedermolekularen Carbonylverbindungen im Rauch von Zigaretten verschiedener Tabahmischung und verschiedenen Feuchtigkeitsgehsltes. (Quantitative differences in the occurrence of low-molecular carbonyl compounds in the smoke of cigarettes having different tobacco mixtures and different moisture contents.) Fach- lithe Mitteilungen der Osterreichischen Tabakregie 3: 3x9, s!arch 1962. (49) PHILIP~E. R. J.. HOBBS, M. E. Some components of the gas phase of cigarette smoke. Analytical Chemistry ZS(l2) : 2002-2005. December 1956. (50) RAYLWRN, C. H., HA~~v, W. R., HANhER, H. R. Determination of volatile phenols in cigarette smoke. Analytical Chemistry 2519) : 1419, September 1953. i51) SCSIOLLER, R. Uber den Gehalt des gasformigen und des festflussigen Anteils des Tabakrauches an Cyanwasserstufl. (The content of hydro- gen cyanide in the gaseous and stable liquid portions of tobacco smoke.) Fachliche Mitteilungen der Osterreichischen Tabakregie 1: 7-10, 1938. (52) SPEARS, A. W. Quantitative determination of phenol in cigarette smoke. Analytical Chemistry 35(3) : 320-322, March 1963. (53) SPURS. A. W., ROUTH, W. E. A combined approach to the quantitative analysis of the volatile components of cigarette smoke. Paper pre- sented at the 1Sth Tobacco Chemists Research Conference, Raleigh, N. C., 1964. (54) STEDMAN. R. L. The chemical composition of tobacco and tobacco smoke. Chemical Reviews 68(Z) : 153-207, April 1968. (55) SUNDERMAN, F. W., SUNDERMAN. F. W., JR. Nickel poisoning. XI. Im- plication of nickel as a pulmonary carcinogen in tobacco smoke. Ameri- can Journal of Clinical Pathology 35(3) : 203-209, March 1961. (5C) SZM)~OWSKI, D., SCHUL~~E. H., SwAurx, K.-H., LEHN~. G. Zur okologischen Bedeutung des Schwermetallgehalts von Zigaretten. Blei-, Cadmium- und Nickelanalysen des Tabaks sowie der Gasund Partikelphase. (Oncological significance of heavy metal content of cigarettes. Lead-, cadmium-, and nickel analyses of tobacco as well as of the gas- and particulate phase.) Archiv fur Hygiene und Bak- teriologie 153(l) : l-8, February 1969. (57) TADA, 0. Determination of nitrogen oxides in the air. Report of the Institute of Science and Labor (Japan) No. 60: 7-26, October 1962. (58) TOTH, J. Uber Schwefelwasserstoff im Rauch des ungarischen Tabaks. (Hydrogen sulfide in the smoke of Hungarian tobacco.) Chemiker- Zeitung 37: 897-898,1913. (59) Tow, G. P. Gaseous phase of cigarette smoke. Isolation and analysis for total aldehydes. Analytical Chemistry 27: 1788-1790, 1955. (60) U.S. SENATE, 90TH CONGRESS, 1s~ SESSION. Public Health Service tech- nical report on "tar" and nicotine. Hearings before the Consumer Subcommittee of the Committee on Commerce. August 23-25. 1967. pp. 7-8. (61) Wan, P., HAUSER~N, M. Betrachtungen iiber die VerLnderung des Gesamtwasser, Pyridin, Nikotin, Ph enol, Brenzcatechin, Scopoletin und Kohlenoxid im Cigarettenrauch in Abhlngigkeit von der Zugnu- mmer und vom Rauchfilter. (Considerations on the variations in to- bacco smoke of cigarettes. The yield of crude condensate, total water, pyridine, nicotine, phenol, pyrocatechol, scopoletin, and carbon mon- 633 oxide in cigarette smoke depending on the puff number and smoke filter.) Beittige NT Tabakforschung 3(3) : 169-202, -4ugust 1965. (62) WALTZ. P., HAUSFAMANN, &I., hfosnr, F. Zur Bestimmung des Pyridins im Rauch von Cigaretten im Rahmen der Bestimmung der Gesamt- alkoloide. (On the determination of pyridines in cigarette smoke in the scope of the determination of smoke alkaloids.) Beitrage zur Tab- akforschung 2 (6) : 283-293, October 1964. (6~) WATANABE. M., KOBASHI, Y. Tabako kemuri seibun no bunsekiho ni kansuru kenkyu. I. Gasukuromatogurafi ni yoru tabako kemurichu no itsusanka tanso oyobi tansan gasu no teiryo. (Analytical methods of chemical components in tobacco smoke. I. Determination of carbon monoxide and carbon dioxide in cigarette smoke by gas chromato- graphy.) Nippon Senbai Kosha Chuo Kenkyushu Kenkyu Hokoku So. 10'7: 177-180, 1965. (6~) WILLIAMS, J. F., HUNT, G. F. Ammonia in mainstream and sidestream cigarette smoke. Abstracts of Zlst Tobacco Chemists' Research Con- ference, Durham, N.C., October 19-20,1967. p. 14. 634 AborIlOrl effect of marernzl rmoking. 437. 438 Accnaphthylenc in cigar. pipe, and cagaxtt~ woke. 548 AcrUldchyde Icvclr. effects of IODI" size. amount of tobacco burned. and venUlatmn. 487490,494 2s suqxctcd conulbutor to health haz- ards of smokmg. 629 ACClO"C as suspected contilbutor to health hazards of smokmg. 619 ACctOfllldC a, surpbctcd conmbutor to health hazards of unokmg. 629 ACIOlCl" cffccu of mhalatlon of. I" rats. 151 as urrtant ,n tobacco smoke. 51 I levels. cffccts of room UC. anlounl of tobacco burned. and venularion. 487-190.494 as probable contributor 10 health haz- ard$ of smoking. 628 AClylO"ltdC as surpcacd contiibutor IO health hazards of smoking. 629 Adcnocucmoma prevalence WI male and female mlokcrs and nonrmokerr. 216 relstronxhlp of c&ret:c smoking 10. 272-275.322 Adcnuma papdIary. inductIon m rats by exposure to ClgaJctlc firs.. 374 pulmonary. mductmn I" mice by c~ga- rctw Imoke mhalatlon. 375 renal. rclationsh~p of smoking to. 322 Adrcnai glands calccholaminc release from, nicotine effects on. 32 Advisory Commrttce on Smoking and Health rcporl on c~garcttc smoke and conden- YlCS effects on oral cavity of animdr. 314 Aerobic capaary effect of cc~xa`,o" of smoking. 613 e~cC:Jof CXCI`IY and smoking. 613,614 .Agc atypical nuclei in esophageal eprrhelium arranged by rmoklng and. 405406 cl-feels on CHD, 23-35 Air poUuUo" II ~a"% of COPD. 178.201.242-243 in cl~olog~ of lung "coplarmr. 302 and human CO burden. 142 relationshIp 0f lung n~~phns. rmoking and place of rcr~dcncc. 278.281 rummary of ICCC"I Iindmgr. 5134 A:cohol crhx.nol. pcnrtrablllty of d1550lvcd bcnzo(a)pyrcnc I" m,ce crophqcal cplthcbum. 319 Alcohol consumption cffec1 on crophacxl ncoplarms in smokar. 31s. 319 cffcct on laryngeal neoplasn~r in tobacco USCII. 306 effect on tobacco amblyopla. 531.532 and heavy ynokmg, effect on oral ncophrmr. 314 smoking and. in esophageal ncopljrm ct~olo~`. 64,66.67.570 smoking and. in laIyngea1 ne0pbr.n etiology. 567 smoking and, u1 oral ncoplavn e:~ology. 563 smoking and. in neoplasm development. 570 Aicohohsm paucnrr. smokmg 3nd ventilator func- ton in. 239 Allergy effect on cardlovawular abnormah:ler. 521 tobacco and. 5 13.521 tobacco smoke ~lr,ta"ts and. S20 Alpha-1-anutryps," delicrency COPD prcdqovno" from. 176 determinal:on USl"g rmmunocleclro- phorcns. 177 in emphysema etwlogy. 520 smoki"g and, 520 Amblyopta, tobacco alcohol conrumptm" effect on. 53 I-532 characteruarlon of, 531 incidence oi. 531 American Heart Arsoc~atlon poolmg project on Cf1D. 19. 24. 26. 35 Ammonia as suspected contributor to health hazards of smoking. 629 Angina pectonr effects of mcreased carboxyhemoglobin levels, in passwe smokers. 491, 497 incidence t" pipe and cl&v smokers.485 A"U"alS esophageal neoplarmr I". induction by niuoummer. 3 18 reqwarory tract of. neoplastic changes foliowng cigarette smoke mhalatro". 264.265 ski" of, carcinogcmclty of tobacco tars. 264.293 A"lhIXC"C in ciga. pipe, and c~garctte smoke. 548 Anthrantic acid. 3hydroxy- urmary cxcretton of, rmokmg effects on. 322 635 AnIleen-anlibody rcattlonl a"crgya"d.S13-517 ~,mokcr~ vs. nanrmokcrr. 515. SZl tobacco and. 514-517 Aorllc ~ncuwrm ,mokmg and. 63.67.71 Aromatrc compounds carclnogcnlc propcrues i" cgdIcctc xmokc from. 290.29 I dctecuon in ~rme usmg chcmdummcs- ccncc techmque. 323 &omat,c hydrocarbons. polycyctic cffccc dorm8 prcenancy I" laboratory nnimalr.431.432 matcm&fctal exchange and. 433 Anhythmlar formatIon in NCOti"e srlmuhtcd damaged myocadium. 54 hscnic lung neoplasm monabcy i" smeller workers exposed to. 283 rcsplrarory tract carcinoma m workers cxpowd to. 282, 283 ArtWitS aneurysm in aortic. cwaetrc rmokmg eifectr on. 63,67.71 nrherosclcrortc. increased by ti~arctte smokmg. 59 now of c;uot>d. c$a~ct~c s"wkm8 effects on.63 occlunonr of. cigarette rmoklng effects on, 69 walls of. mecharosm of lipoprorcin infiltration. 59 walls of, mcotme-induced necrosis, 59 Artenorcleroslr in aorta and coronary artcncr. cigarette smokingeffects 0".41.48-52 development of. carbon monoxrde cf- fects 0". 59 development of, effects of nicotme on, 34 lesion development in. ynoking cnhance- mcnt. 32 peripheral. cigarette smoking effects on. 68-69 see also Cardlovavular diseases; Core nxy diseases Aryl hydrocarbon hydroxylax effect of bcnzo(a)pyrenc UI pregnant rats. 433 Ada Central and Southeast, relationship of tobacco use and neoplabnr of oral cavity. 392 Asthma bronchzd, cigareIIc smoking effects on, 201 Alherosclcrovs aortic, long term smoking effects. 48-52 Athlcbc pcrformancc ru"ni"g.effcctof smoking.613.614 smokers vs. nonsmokers. 613.614 swimmmg. effect of smoking. 614 Atxopme effects on bro"chocon~(llclion in dog% 189 COPD mo~badrty rn smokers VI. 229 Iuyngul "caplaun~ m. relauonshq 10 tobacco use. 583 lung neoplavnr m. ~cuo~ecove Itudlcr of, 3s3 Bx:cna cifcct of c~axltc smoie on axion of maccophagcs on. 191 pncumo*. mice rc~~s(;ulce following nguccta inhalation, 199 Bc"zfc)xcphcnanLhryhrylcnc c.uElnogc"lc properws in cigarclIc smoke from. 290.291 l?cnz(a)a"tiace"c alcoholic soluuon oi. pencaabihfy of mice crophagcal epahclium. 318 Bcn~bhnthracenc. 7.1 Zduncthyl carcinoma inducuon in hamsters follow- ing innillauon of. 372 skin pamtmg wvrch, papdloma and rarcmoma induction in mxx by, 367 Benzcnc as ruspccred contributor to health huudr of smokmg, 629 BcnzoO')fluoranthcne c.ucinogenic propen,es in cigarc1tt smoke from. 291 Bcnzo(c)phcnanthre"e carcmogcn~c properties in cigarette smoke from. 291 Bcnzofajpyrcnc alcoholic x&~bon of. pcnetratio" of mice csopha8eal cprthchum. 318 carcinogenic propcmer in cigaIc,le smoke from. 290.291 caxmogcnialy of, m relation to asbestos in hamsters. 283 in cyv. pope. and cigaretfc smoke, 491, 492 dctoxficatlo" by lung aryl hydroxylase. 283 effects during pregnancy in Laboratory animafr, 431.432 errecLs of i"stdJation 0, implantaiion i" ?."lC".ll tracheobronchiaI UCC, 312.373 clTecls on awnal tissue and organ cultures tn. 369.371 effecls with mfluenza virus on cigarette inhalation by m~cc, 378 levels. effects of room six. amou*o( tobacco burned, and ventilation. 487490,494 sarcoma induction in rats fouowing intidlation of, 372 skin painting with, papillama induction in mice by. 363.364 BcLel nut chewing oral nwplarmr from, 392.395-396 Bicarbonare in pancreatic sarctionr. effect of smoke ing. 473.474 Bicycle crgomclcr performance cudiovavulaz plramcrcrr m smokers vs. nonsmokers.612614 636 5u:h uc,ght cffecf cl maternal rmokms. 417428. 433436 effect of matcrml smokmnp before and durmg cunent prcrnancy by cqa~,tc conrdnptlon.421423 effect of maternal smokmg dunng p,r"*our prrgna"ilc5.426418 efiect of paternal smokme. 424.4 25 effect of tobacco woke, n,co"nc. or carbon monoudc in bboratory ammalr. 428432 gestatton duar,on in smokcn VT. non- rmokerr. 417420 mor,ality risk of low birth wqht ,nfxnts of smok,ng vs. nonsmokmg morhers. 440-146 timing of influcnccof Smoking. 434.435 Bladder neoplasmr frequency ,n smokers vs. nonmokcrs. 264. 319-321 monal,ty rater. 319. 320 rebtlonsb,p of c,yuerte smokme to. 325 rcuospecwe stud,es of. and smokmg. 319.407410 and tryptophan metabohtcr in unnc. 322-323 Blood cholexterol ICICIS and coronay dwase. 17.18. 19-20. 39 effect of cabon monoxldc u1 rabb,tr. LSO effect of smokme. 37. 39 eilect of smokmg m penpheral vascular d,,ea>e. 68 and hyps:,ens,on. ,n smokers vs. non- smoker,, 137 in p,pe and r,gx smokers, SSS. 586 m xmokerr vs. nommoker>, 94.98 Blood cucula,,on eitec, of wnat~ons in hem%lobln and hemat. 62 Blood coagulation etfect 0i smokmg. 32 Blood hpid, ctfect of vnoking. 6142. 119-I 24 smoker, vs. nonsmokeri, 37 Blood platelet, effccl of ,,,,oking, 62, 71 Blood preswre coronz~y d,,eaw and smokmg. 39.43 du,toLLc. c,g.+~et,e r:nok,ng &ecu. 19 dlaxtohc. ,n smokers wrh CHD, 17-18. 20.38 effect of cxc,c,~c and smokmg. 611. 614-616 cffrct of n,co*me. 32 effect of p,pe and c,gar rmokmg. 586 h,gh rash in mortahty from CVD.63 hypertenuve vs. nonhypertsnuvc. mor- tabty rate, of CHD ,n. 38 rtsk _actorr m arter,o;clerons obhtcranr, 68 in rmohcrt. nonsmokers. and ex- mokerr. 137-139 in smokers vs. nonsmokers. 37. 38. 99-100 systok. rnomhry from elevated. u,th CHD. 38 Body wclghr and hypcrtcnuon. ,n snokc,~. r.o"- rmokcrr. and cxsmokcrs. 137-l 39 Bxadycardra dcvclopmcnt ,n dogs g,vcn n~oDne. 5 3 Bronchnl cplthclwm h,r,olog,cal chlngcr ,n c.urc Jnd lncrcsrcd cubo\)hcl"oflobi" Icr*lx. 491, 493 influencing ixtorr.61 I. b16.617 summary ol tindIng, and mcchrnlrm of ICUO". 616. 617 - on trcadmti. cffat of smokmg. 613. cffecls of ~rutton on body wcytht. blood prc,,urc. and hypcncwon development. 138-14 I IOU- b,rth uaght ,nf*ntr of. 326428 mortlllty rate\ III. COPD. 201 tnorulny r~tc, in. coronary dl,ca*. 4244 NIIIWIY oi prwou, tindlngs o" hedlth ~~~nscqucncc~ oi CC~~I~IO". 6 Eye ,rr,t~t,o" effects of exposure to c~pars~tc smoke. I" p3uw rmokcr,. 495.496 cfTect of maternal imokmg.437449 cp!dcmioloncai rtud~er. I" u"oken v\. nonsmokcrr. 440446 I=lllCr? advantages in reduction of part~culates. 295. 301 Finland blood pre<\urc drffercncer in rmoker5 vi. nommoken. 99 COPD morhlday a" smokers. 226 lung ncopldw~ mon.ility in. rclatlnn+ip to tobacco uw. 271. 272 lunp ncopla$mr tn. rctrmpccttvc rtudy of. mahods. 351. 353 wrum llpld dlfferenwx in vnokcn vs. "on3mokcrx I". 94.95 \mokq ad "~cot~nc effect, on human blood h,wi\. I20 rltncrr texts \mokcrr vs. nommoken. 6 IS 1 luoranthene Formaldchydc 1, wrpcrtcd conrr,butor to hul:h hsrardr of rmokmg, 6 29 F0rlX0Sd ILUIC effect of cqarcttc vlokc on human pulmonvy functmn I". 195 rrnmm~hrm Study cffcct of coficc drmklng on morrahty in Lmokcrs vs. "onrmokcrr. 142 FIl"CC bkddcr ncoptumr m. mcthcdr and rc,ultr in rctro,pectwe ,tudlrs of rmohnp.407-409 CHD mortabty and morbjdrty I". 90. 93 ctgarettc smoke effects on animal tlrsuc in. 369.370. 375 COPD mortabty of lmokerr I". 227 crophngcdl "roplaxmr I". rctrorpcctwc studzr of tobacco "szc. 404 laryngeal ncoplasmr I". rch\ionrhlp to tobacco u\e. 381.383 lung neoplasmr in. mcthodx of rctrospcc- we study of smokmg I". 352 oral ncopbrms I". rclalmn%hlp of tobac- couwa"d.389 Funqcadcs concentration in cigarette bmokc. 291. 292 FUIfUIA 15 surpccted contributor haurd, of smoking, 629 Gas phaw. cigarcttc xmokr hdrmful con\t,tucnts I". 627 Gar1rtc xcretron to health effect of nlcotinc in laboratory dn~mxl\. 472,473 elfat of unukirq i" ul~cr pdtic"t\. 47 I 472 Gartroinrtwin~l disorders prevalcncc tn ciparette and prpclcigar rmokrrr, 592 Genetic factor5 COPD pathogc"c+ and. 174. 176-I 78. 231 twin stud&. cl-feet\ of \mokm~. 4548. 95 Germany CHD morbidrty and mortality in. 91-92. 93 ciprcttc smoke inhaldrion cffcctr on animal respiratory lract in. 376 lxynpeal ncoplarmr in. rclatiomhlp to tobacco uy`. 381 lung ncoplasmr in, mclhodc of rctroqxc- tivc xrudy of smokmp I". 349. 351. 3S2 polomum- IO k~clr in lungs of smokers tn. 362 smoklnp and nicotme cffcctc on human blood hptds. I21 Gce3tl0n.4 ;rsr eCTcc1 on pcrinrtal mortAty r;ltcs in w"okinp YC. rmnsmokmg morhcr,. 440446 and lowhwth-wclphl infd"t\. cffccr of mfcrnal \mokl"p. 4 I74 20 642 terms ured in smokmg and rentdatory function. 241 Glucose mctabobsm and insuhn revonw. sltcrption effects on myocarod response. 62 ClYCOgCll lcvelr in mice lun_n e.vowd to ngarettc smakc. 187 Graphttc rcspmtory tract carcinoma m workers expoxd to. 282 Grip strength elfcct of smoking,611.612 Cuanerhldrnc blockage of nicotine cardnc stimuLtian by. 53 Gumea pigs lung neoplasm dcvelopmcnt followinp chronic nickel carbonyl or dust inhalation. 282 lungs of, cigarette smoke effects on sudactant activdy, 281 rclpuatory changes in, exposed to c,gxe:tc smoke. I88 H1mstcrs bcnzo(a)pyrene inhalation by. cifect of arbcrroy dust on carcinoma mduc- tion. 188 bladder nroplas~~~r in, fed 2-naphthy- laminc. 322 cigmtte smoke instillation or implsn- tation eifects on tncheobronchial tree of. 294,372.374 larynx of, efiect of cigarette smoke inhalation on, 307. 310 lung and embr/or. effects of cigarette smoke tarr on. 369-370 pulmonary changes from chronic nitro- gen dionde mhalat&. 246 rerpuatoty tract of, C-14 labeled particu- fates depositton in, 307-308 respiratory tract of. cigarette smoke inhalation effects on, 294, 377 ticalth Insurance Plan myocardial infarction in pipe and cigar smokers under. 28.34-35 Heart effect of nicotine, 32 Heart rate cfiect of ~XCICW and smoking. 612616 cffec: cd rmokmg and coronary disease. 41.43 Hematite dust. rcrplratory tract neoplasms in hamsters exposed to. 374 Hematocnt un~tmns in. effect on coronary blood flow. 62 Hcmoglobm aftinnty for oxygen. CO effects on 2.3dtphorphoglyceratc contxol of. 56-57 variations m. effect on coronary blood now. 62 car`lrio?enK propenxs In clgarctte smukc. 290. 291 Hcxamcthomum blockage of nic~ofme ard~lc >t~nuh':on by.53 Hook>hs rmokcrr of, latyrgeal neoplasm induc- tmn in. 382 Humidity and pathologic cffccts oi crporure to cprcnc smoke, 495 Hunguy methods used for tcuospcctwc studier of lung ncopbrmr in. 354 Hydrocyanic 2nd as probable contnbutor to hralth haz- ards of rmokmg. 628 Hydrogen cyamde in clgarctte smoke. effects on body oxldatwe metabolism. 58 Hydrogen sulfide as suspected contributor to health hazards of rmokmg. 629 Hydroqulnanc a, ruypcccled contr6utor to health hazards oi rmokmg. 629 3.Hydroxykynurcnmc cxc:cmn of. smokmg effects on, 322 Hydroxyprotinc level m m~cc lung exposed to cigaret!e smoke. 187 Hypertension smokme eifcctr in. 137-141 summary of recent findmax. 15s Hypoxemla carbon dioxide effects on. 57. 7 I Hypoxia aortic arheromarosls development in rabbits expored to. 60 portoperatwe. m smokers. 200. 256 postural, mechanism m asymptomatic smokers vs. nonsmokers. 173 tissue. cxbon monoxtde effects on, 57 Iceland lung neoplasms in. relationship to tobacco smoking. 270 Indeno(l,2,3 of CO in tobacco smoke on pbychomotor performance. 495-191 eiiect\ of exposure to cigarette smoke. in parive smokers. 495 effects of tobacco smoke constituents. 484494 effect, on bus and plane pa,se"gers. 498 c\cretlo" of "Kot"e, 493 cxpo,ure to clgarctte \mokc, and dcvcl- opment oi eye dnd throat irrltauonr. 495.496 mcadcncc of pneumonia and bronchitis I" chddrcn of parental smokers. 501, 502 matcrnrl unoking. and developmrnr of bronch&s and pneun~onu I" mf~nls, 499.500 prrcnul cough and phlegm production, 2nd rcspnatory ,ymptoms in chil- dren. 499 Peoples GA Light and Coke Co. study of CHD. xer"m cholesterol and rmoLmg rclauomhlps, 39 Peptrc ulcer cltn~cal studio. 469471 cpzdcmloloFwA studies, 469471 gdbtric secrctmn I" smokers M. "on- ~mokers.471.472 incrrasrd mottality m Japancrc rmokers vs. nonsmokers. 469.470 matably tacos m Japancu adults by age started ,mokmg. 469.470 momhty ratms I" mdc crgax and p,pc rnokcrr. 592 predlspoung factors. 411 ICCU~C"EC t" smokers VI. nonsmokers. 471 smokmp and. 469 Pcrinatal stud,es effect of maternal smoking on mortality, summary of findings. 448.449 Pcroxldcr suspected carcinogenic agent tn crgucttc smoke. 291 Personnhty charactcrislicx iclatlonti!p to CHD and smoking. 4445. 101-102 Pcaicldcs content tn cigarette smoke, 291.292 PH ptpclc~gat smoke inhalation and.553 of smoke m ciparcttes, cigars. and little crearr. 593.594.598 Phz~ocytostr ciiect of c!$uctte wnoke i? rabbits. 5 19 pulmonary alveolarI. m smokers vs. "on- rmokcrr. 191 Pharynced neoplarms frequency I" smokers vs. nonrnokcrr. 264 rclatmnrtxp to tobacco use. 388-390. 392 Phenols m ctcar. pope. and cigarette smoke. 547 ar probable. contrrbutorr to health haz- rrdr of rmokm_e. 628 suspected carctnogenic agent of cigarette smoke. 292 Phlecm productlo" by parental smokers. and development of re,puatory symptoms m chiidren. 499 by parent31 smokers. and incldenw of pneumonia and bronchitis in chil- drcn, 501.502 Phosphohprd, function as surfactants in lung tissue. 198 smokers vs. nonsmokers. 95-96.98 Physxal actwiry rcktronship lo myocardial infarction. smokers "3. nonvnokers, 40 smollng 2nd tela(lonship to CHD. 37, 39.40 Piperidrne. nitrobo- suspected rsranogenic properties in ciga- rette smoke from, 291 P"eUmO"la inctdence in children of smokers. 501. 502 matern;ll smokme. and development in infants. 499 m pawe rmokcrr. summary of recent l of oral cwty in. 393 Pulmonq alvcoh xuplurc. m p~pelc~r smokrn vs. cigu- e~te smokers and nommokerr. 587 F'ulmonay fibrow in p~pclqar ,mokcrr VI. cqwette uno- kcrl and nonxmokcr,, 587 smoker, YJ. nonsmokers. 187 Pulmonary iunwon effect on exerted pcrformdnce in smokers 13. nonmoken.616 in p~pc/c~gar maker, vs. nonvnokcrr. 587.591 Rabbits arhrrogenic effects of carbon monoxrdc and hypoxia. 60 atherogemc effects of nicotmc. 116-l 18 blood bpids in. rmokmg and mcotme cffec:rr on. 123 cardlovarular function I". vnoking and nicotine effeclr. 104. LOS cholesterol fed. carbon monoxldc effects on. 6162 cilmry function in. cig~rc~tc rmokc ef- fect on. 247.248 pulmonary changes in cigarette >molung, 185 pulmonary clearance in. cigarette bmokc effect on, 190. 196. 197 rkm painting. smoke condensate effects on. 293.364 Race as a factor in perinatal mortahty in rmokmg VI. nonsmoking molher,. 443446 ax a factor I" rtlllbirrh rater. 438,439 Rat5 blood hpids in. nicotine and smoke eliecu. I?4 cihary function m, cgarette smoke on, 247, 248 lung neopl.wns, from inuabronchial km- plantkng of chromium compounds, 2R4 lung neoplasms, from nickel carbonyl and dust inhalauon, 282 lungs. c~garctfe smoke effects on surfac- tan, IC~IYI~Y. 198. 25 1 pulmonary ca&oma inducrmn follow- ing asbestos dust mhalauon, 283 pulmonary changes from chronic mtro- gen dioxide mhalation, 187, 246 _ respiratory tract, ci:arelte smoke inhale- 1x0" effeclr. 294. 375. 379 skin painting, smoke condensates effect, 293. 366 trachea; cigarette smoke effects on, 369 tracheal ligalion. agarette vnoke and pdpain effccls on. 189 tracheobronchul tree, cigarette smoke eifecls on. 294.312-375 Rewrpinc n~cotmc cardiac rumulalion blockage by. 53 Rop~ra!ory function tests vnokcrr. 172-i 73. 232.240 Rcrplrdlory symptoms prcv;llrncc rn children of parcntd smokers. 498.499 650 anmd. ngarettc rmokc instrlla~~on or S.5comas impiantatio" ellects on, 293. formauon followmg ammal skm pannng 372-374 ulth smoke condenutcs. 364.366 a"imxI, effect of c;garette smoke tnhala- t,on on, 294.295. 375-379 crfect of cigarette and qu smoke on b:onchul reactw~ty. 190 dfect of cigarcttc smoke on human cdiary luncuon. 191. 247-250 effect of cigarette rmokc on human pulmonary clearance. 190.196 g~orrary of tcrmr used L" testing. 241 histological changes I" smokers, 180-183 ,.mpro"eme"ts in function followmg rmokmg cersatlo". 174. 175 pathological changer I" clgmrte smokers, 201 portoperatwe complicatlo" I". of srnokeir vs. nonsmokers. 200 202. 256 pulmonary alveolar phagocytorls I" rmokers VI. nonvnokerr. 19 1 pulmonary ,ntarcr,on I" dogs Inhaling c,gzuette smoke. 297 surface penman of. effect of cigaicrte smoke on. 198.25 I surfacmnt actwty of. in smokers VI. nonsmokers. 198. 25 1 surLacta"rr I". definition. 198 Rcsprratory tract diseases infecrmnr. prevJence UI smokers. 202 ~"fecuons. smoking and, 202, 252-255 patholoelcal and cytological chaneer I". of smokers vs. nonsmokers. 284.269 vcntdatory function in. vnokeir VI "on- smokers. 201 Rctrospatwc studaes lung neoplasms. and unokmg. methods. 349.354 Rhodcsra methods uwd in rewospective studxr of smoking in relatmn to lung neo- pLumr, 3S4 Rubtdlum-84 traOng Capdhry now in coronary blood now. 5s RlJ""lJI~ effect of smoklnp. 613,614 Rural areas lung neoplasm mctdcnce UI. in Switzcr- Ilnd. 270 relatlonch#ps of lu": "eoplarm to vnok- ing. au pollution. and. 278-281 Rurxl populatmnr lung "eoplasmr I". suspected ctlology of uweaxd. 302 RUWI atherogcnlc effects of twotine on rabbrts m. I lb inductmn m rats by agarettc smoke in]ecuon. 372.373 sex efiect of. I" alpha-1 antltrypr," defici- ency emphysema, 177 effect of. in lung neoplasmr and tobacco use, 270.355-359 efiect of. in mortahty in cigarette smokers. 302 cffcct of, on laryngeal neoplasm inci- dence development, 303 rarm. eifect of maternal rmokmg on, 449.4so I.allO. m lung "eopL,m morullly u1 Sorway and Ftnland, 271.272 erTe:t oCtobacco e\tractr. 5 IS-517 tobacco anugcnr and. 5 14.5 IS six lertr,g chemrll co",t,tuc"ts I". 547-549 cd;oroxlcity. 588 eiiscr of curing methods. 558,589 effect of pH on mhdauo" of. 55 3 Ilrrlc, pH, compued to c!garttte and cigar smoke.S_4. 59X tumongemc actiwty in laboratory a"~- mais. 580-584 S.xokc. cldio\ylase. 282-283 effect on phqocytorir in rabbtts, 5 19 effect on rat and mouse fetus. site of actKIn. 43s effect on t,r,ue cultures. 293. 369-371 harmful cons~rtuents of. 625-630 ~"hAwon by dogs. lung neoplasm dcvcl- opmenr. 294-29s. 298.300 inhalahon cfCecls on ammal re~-puatory trx,. 294-295.37s. 379 mhhuon effects on hamster Larynx. 307.310 651 hsting of Idcntrficd or surpcctrd turnon- eeruc qents. 290-293 2-"aphthylxn,nc tdcntlfied I". 291 "coplast~c chrngcr i" anun& mhzhng, 261-26s tobacco Jmblyopu JelJtlonrhlp ,* cyanide mrtaballsm in.531.532 Smoke, pqlc chcmtcal constituents I". 547.548 ~~~~~~~~~~~~ of. 588 cffcct of pH on mhalatwn of, 553 turnongemc acuvity in laboratory ani- mals. 580-584 Smokers COPD morbidity in. 172. 223.224. 221-228.230-231 effects of smoke on bronchul rcactivlty. 190 esophageal ncoplxun mortahty ratio. 316 krdncy neoplasmr in. 320-321 lack of risk m CVD, 63 laryngeal neoplasm induction in. 380.383 laryngeal neoptasms I". 307 lung nsoplasms. lncldsnce in rural Swit- zerland, 270 long neoplasms. mortahty in. 266.269 mortahty ratios from COPD in, 168-I 69. 171 morlahty ratios from pancreat~ "eo- plasms I". 324 myocardial mfa~ctron I". 28. 34-35 rcLtlonshlp of neopLsms of oral canty with. 387-391.393-397 relatlonshlp to mfectious resplratoty dir- CIYS. 253 rela!ive risk in laryngd neoplapn devel- opment. 302 Smokers. cigar atypical nuclei in male esophageal epith- clium. 405 bladder neoplasm, in, 3 19-3 20 cell rows and atyplcal cells in vocal cords of, 306.385-386 Smokers, cigarefte arterial occlusions in, 69 atherorclerosls in aortlc and coronary arteries, 48-52 atypical nucla in male esophageal epith- clum. 405-106 bhdder neoplasms I". 319-321 cell tows and atypical cells tn vocal cords of. 306.385-386 cessatmn of smokmg, effects on COPD morbidrty, 172. 223. 225. 229-230 changes m ventllatory function and pub monary histology. 201 comparattve nsk ior lung ncophsmr. 263 coronary diseases I". AIlA poolmg pro- ject. 24, 26.35 coronary dwases usk by. 19-21 decline I". Brtttsh physrcians. 44 development of esophageal neopkuns. 319 dcvclopment of second pnmuy oral ncoplasms r" conunumg. 313 effect of filters on emphysema develop mcnt. 188 652 esophageal neopLxuns. murtably rlt~os in, 316.317 h,staloqy and smokmg rclrt,o"shrp of lung ncoplasnu in, 272-275 inhalatmn cifects on human pulmonary functl"". 189.192-195 kldncy neoplasms in. 320-322 laryngeal ncopLsm mductlo" I". NO-383 lung "eophsmr. etiology. 265 lung neopbrms, mortality in, 266. 269.270 mortality from ccrebrovascular ducase, 6366 mortality ratios from COPD. 168.170 morta[lty *attos from +ncrcauc "eo- plasms I". 324 postoperative pulmonary compbcatrons. 200.256 pulmonary surfactant actwity I", 198. 251 relationship in coronary and lower hmb arter~osckros~s. 68 rclationshlp of asbestos in lung ncoplaun mortabty, 283 rclationshlp lo mfectlous respiratory dis- c.ues. 198. 252-25s relatIonship to laryngeal neoplasm dcvrl- opment Ml. 307 relatmnshlp to Ilp or oral c~v,ty "eo olasms. 387-396 rela'tio"sh;p to lung neoplasms. 301.302 relatlonshlo with bladder "eoolasms in mtn. 3i5 rclattonshlp with dult on COPD develop- nlent, 179 risk of COPD in. 166 Smokers. pipe atypical nuclei in male esophageal epith- chum. 405 bladder neoplssms in. 319.320 cdl ~owsond alyptcal ceUr rn vocal cords of. 306.385-386 COPD morbtdlty in. 172. 223-224, 22-i-231 development of esophageal neoplasms. 319 esophageal neoplarms, mortabty ratios, 316 kidney neopiarms in. 320.321 lack of risk in CVD. 63 laryngeal neoplasms. induction, 380.383 lung ncoplasms. incidence m Norway. 270 lung ncoplasmr. inctdence in rutal Switz- erland. 270 lung neoplawns. mortaltty in, 350-353 mortahty tales from COPD, 168.169. 171 mortalw ratios from pancreatic new plarms. 324 myocardlal Infaxctm" I". 28.34-35 rclationshlp to k"f.xtious respiratory dis- caYs. 253 rclat~onship to Iaryngcal ncoplavn dcvcl- opmc"t, 307 relaconrn1p to lip ncoplms. 315 rclarlonrhlp to 01x1 cavrry ncopkrms. 337-390.393 rcLtivc rusk in laryngeal "eopiarm dcvel- opmcnt. 63 relative nrk in lung ncopLwn dcvelop- mcnt.302 ;mokcrs ~3. nonsmokers bladder "coplasms in, 319-321, 407310 cell rows and rtyp~cal cells in vocal cords of.306.385.386 ccrcbrovasakar disease mortality rates. 6346 coronary disease morbidity ratios. 20 coronary dncare moitahty. 17-16. 20, 22-25 coronary disease mortality. by sex. 24-27 coronary drrcaw monahty. in Swdlrh Wl"S.47 development of COPD in. 167. 171. 221-231 dJfcrenccr in emphysema Iypcs in. 180. IfI2 esophageal eplrhehal cells with alypicti nuch in. 318 crophageal neoplasm morrality ratios, 316-317 ericre"o" of tryptophan mc!abobter I". 323 frequency of esophageal neoplasmr in. 264 frequency of kidney neoplasms in. 264 frequency oimourh and phuyyngeal "co- plssmr 1". 264 frequency of ""nary bladder ncoptauns. 264 group characteristxs in lung neophrms and smoking in, 266, 270, 355-359 laryn_ecal ncopkrm mortality rates. 263-264 laryngeal neoplasm mortality ratios, 304-30s laryngeal neoplasmr in. relationship to tobacco "se. 380.383 lung fibrosis development m. 187 lung neoplasm mortality in uranium miners.282 lung neoplasm mortality rater, for wo- men.266-269 morrahty ratios from pancreatic "co- plarmr I". 324 mortahry raftas al COPD in, 168-l 70 myocardul mfarctlo" relationshrpr to phyrrcal actwity, 40 pathological and cytolo_eical changer in rcsplratory tract of. 284.289 patoperative hypowmia I". 200. 256 portoperatwc pulmonary complications 1".200-201.256 Postural hypoxcmia mechanism in rymptomauc. 173 ptdmonary alveolar phagocytorls in. 191 tcIa11on between CHD and rerum chol- cm01 iA, 39 rclalmnrhip to mfectious respiratory dti- CRY. 198.252-255 rcrum ltpldr I". 37.9498 surfacrant xuwty m !xng, of. 198. 251 type of lung ncoplamr m mdc and fcmdc. 276 Smoke r(rcams CO lcvch ,n na~nsrcam cigar mokc. 486 c~nrtltucnts of tobacco smoke. 484494 rummay' oi previous findmg>, 483, 484 Smoke, tobacco cffcct dunng pregnancy I" laboratory anunalr. 428.429 CffCCI of conrutucnts on ptivt vno- ken.484494 effect on stillbirth rate in l&xatory animals.439 imtantsm.519.520 pH of, effect of leaf constituents. 594 summary of prcnour findmgs on rck- llonship to parswe smokmg. 483.484 summsry of recent findings, 504 tumorigenic actwty. 580-584 Smoking cficct of abstinence in cxercbe ocrfor- mmcc.611.612.616.617 ' health hazards of, vmdaritwx of cigar- cites wth little cigar. 594. 595 prevalence of m U.S. and Great Britain. 543.544 see also Passwe rmokmg Smokmg. cpr CO levels in mainstream smoke. 486 effect on morl&ly and morbldlty com- pared to cigarette smoking. 541-543 in esophageal neoplasm developmenr. 567.570-572 garrromtertmal dlrorders and. 592 health consequences of. 549 histolo~al effects on bronchial eplth- elw".573,574.579 histological effects on esophagus. S;O histological effects on larynx. 5 67 histologtcal effects on lungs. 587 inhalation patterns and. 554-559 in laryngeal neoplasm development, 567-569 in lung neoplasm development. 553.516 and lung neoplasm mortalrty ratms, 573-57s mortality ratios from cardiovarular dk easer and. 585.586 mortality ratios from COPD and. 587. 589 mortality ratios from esophageal nc* FkS"M and.567.570 mortality ratios from latyngcal nco plarmr and. 563.566.567 mortahty ra:ior from oral ncoplarml and.561.563 oral neoplasm development and. 563-565 overall mortality rater by amount smoked. 550-552 overall mortality ratel from ncoplxsms. 559 pr.evaJcncc in Great Britain. 543,544 prevalence I" Umted States. 543,544 summary of previous Gndlngr on cffc~ti. 4.135 : con~cnml rr-~!mimtmnr and. 450. 45 1 and derclopmcnr of bronchrrir and pncu- monw I" mimu. 499.500 effect dunn~ pregnmcy. 417456 cffcctonbulh ucighl.4174`8.433436 cffccr on fetal mortahry. 438.439 effect on gcsut,o" dunuon. 417420 cfkct on tacuuon. 452455 effect on "cona~al caboxyhemoglobin Icrclr.432.433 cffca on sex ratio. 449.450 precclampsu and. 456 sclccrivc acuon on fetus of CcItam wD men vs. other. 445 timing of ~"flucncc on burh ueehl. 434, 435 SEC olro Prcgmncy Smokmg. patcrnsl efrect on Inisnt birth wclghr. 424, 425 Smokmp. pipe cffei: on mortrhty and morbidity corn-- plrcd to c,~xc,,c rmokmg. 541-543 I" esoph~crJ neoplxm dcvrlopmcnr. 567.510-571 pstromtclliml dlrordcrs and.592 health consequencer of. 549 hi,lologtcal efirctc on bronchhl eplth- ehurn.513.574.S79 h,srologml effects on ewnhqur. 570 hrrtoiogxal effects on Iu)`"x, 5 67 inhalalmn p&terns and. 554-559 in Ixyngcal ncoplasr~ development. 567-569 in lung neoplasm etiology by r"ou"t smoked, 573-576 and lung neoplasm mortality rarior. 573-57s mortzhry rattos from COPD and. 587. 589 mortality ratios from Lvyn@ "eo- plarmr and. 563.566.567.570 mortahty rat101 from oral ncoplasms, 561,563 orai neoplarmr development and, 563.565 overall mortahty rates by amount smoked. 5X-552 overall mortality rates fror" neoplasms and, 559 pre%alencc m Great Brllain. 543.544 prevdlcnce I" UnIted States. 543.544 pu!momry hlstolopical changes and.587 summ.uy of prewous findmgs on cffecrs on smokers. 4.135 Snuff ord lcslonr from, 313.387.390-391 Socioeconomxr inCOPV. 178-179.242-243 South Afnca csophqxal neoplasmr in, reuorpeclive studier of tobacco "se.404 methods of retrorpeccwe sfudlcs of lung neopl3rmr I". 354 occupational cxposurc and smoking I&- tlonrhlr, 10 COPD in. 245 xruu~" l,pld dlffcrenccr 1" smoicrr vs. "onsmokers I". 95 SptlJ"l prcv~lcnce I" pipe and cigu rmokcn. 590.591 Steam acid ruspccrcd cuc,nogcn,c agent of c$axrte smoke, 292 Sttibirrhs effects of maternal smoking. 438,439 ntts 1" blacks "I. uhltcs. 438.439 in smokers VI. nonrmokcrr. 438,439 Swcdcn acute effect, of cigearctte smoke on human pulmonary function. 194 blood pressure differences tn smokers YI. nonsmokers. 100 CHD mortality and morbidity m. 93 CHD morbadiry in smokers in. 229. 231 effect of c~rcrtc smoke on 3nunals ciliary function in. 247-250 genetic studies of twrns in. snokang effcc(s on, 46. 95 laryngeal ncopl~rms in rslationshlp lo tobacco "se, 382 relatmnrhlp of tobacco use and lip "KY plasms I". 387 relatlonrhlp of tobacco "se and oral cav,ty neoplarms, 390 retrospective studies of esophageal "co- plarmr. by tobacco "se. 404 serum lipId dlffcrenccr I" smokers vs. nonsmokers of. 95 rmokwg and nicotine effects on human cardmvascula system, 11 I rmohrng and nicotine effecrs on human per!phcral varcul~r system, 129 tracheobronchial wee changes I" smokers and nonsmokers in. 289 Swimming effect of smoking, 612.614 Swrzerland CHD morbidity and mortality I", smokers vs. nonsmokers, 91 cigarette smoke effects on mice lung and kidney [issue in, 370 cigarette smoke iohalation effects on mice respiratory tract. 377 lung neoplasm incidence in cigar and pipe smokers ofrural. 270 lung ncoplasmr. methods of retrospec- twc study of smoking m. 351 serum lipld differences in smokers vs. nonsmokers of. 96 Tachycardia development in dogs induced by nice- tine, 53 Tars. c~garettc carcmogenlc effect on animal oral cnvi- tier. 314 carcmogen,cr,y. 290. 291 caranogentc properties on animal skin, 363-368.580-584 Cffect Of lnstlUallOn or implantation in animal lracheobronchral tree. 372-374 effecl on "IIUC md organ cultures, 369-370 654 as hmful component of cigalcrtc rmokc. 626.427 summvy of prcvlous lindin3r on effects on smokers. 5 Tan. tobacco dzfi",tlon. 627 in lrttic agus. compared to &~ctte~ and cigars, 593-596. S98 sarcoma mducnon in mu following in- stdlation. 372 skin "~OphSl" induction by, 264, 363-368.580-584 Tctracthylammonium chloride blockage of "icotinc cardiac slimu~tion by. 53 Throat effect of cxpowrc to cigarette smokc.in pawvc rmoken. 495 ThromboanPut~ obliterans ccssa~o~ of smoking. and remission. 70 dcfimtion. 69 fobacco allergy and. 521 mombosis rmokmg znd, 62. 1X-128 ThIombus *oImatlOn and smokxg. 154 Tlssuc ctiturer effect of cigarette smoke on. 293. 369-371 Tobacco anr~gemuc properties of. 5 14 antigens, in smokers VI. nonsmokers, 5 17 curmg methods. and mcidence of respira- tory infections in rats. 588, S89 effect on immune rcsponwr. 517-5 19 tluesued vs. air