The Health Consequences Of Smoking CANCER a report of the Surgeon Genera1 1982 U.S. DEPARTMENT OF HEALTti AND HUMAN SERVICES Pubkc Health Serwce Offace on Smoking and Health RockwIle. Maryland 20857 The !ionorable Thomas P. O'PJelll, Jr. Speaker of the tiouse of Representatives Washlnqton, D.C. 20?15 Dear Mr. Speaker: I hereby submit to you the 1982 Report on the Health Consequences of Smoking, prepared I" accordance with the Public Health Clqarette Smoklna Act of 1969 and its predecessor, the Federal Clqarerte Labellnq and Advertlsinq Act. This 1s the first report in the series to focus on a slnqle disease entity--cancer. Scientists lnslde and outslde of Govrrnmen~ have evaluated the evidence presenteo 1" this report. It )olns this Deparrment's previous reports on smoklnq and health in maklnq publicly avallabie information about one of the mayor health risks of smoklnq. These reports reflect the important responslblllty of tiovernment to Inform its citizens in order that they can make a consldered decision about whether to smoke. Rlchard S. Schwetker secretary The Honorable George Bush President of the Sena+.e Wash:nq+on, D. C. 20510 Dear Mr. President: I hereby submit to you the 1982 Report on +.he Health Consequences of Smoking, prepared in accordance with the Public Health Cigarette Smoking AC? of 1969 and its prede- cessor, the Federal Cigarette Labeling and Advertising Act. This is the first report in the series to focus on a single disease entity--cancer. Scientists inside and outslde of Government have evaluated the evidence presented in this report. It loins this Department's previous reports on smoking and health in :nakinq publicly avallable information about one of the major health risks of smoking. These reports reflect the important responsibility of Government to inform its citizens in order that they can make a considered decision about whether t-0 smoke. Sincerely, &4igLL%ia 'chard S. Schweiker FOREWORD The 1982 report on The Health C'onseyuencrs of`Sn?ofziqq presents ;I comprehensive evaluation of the relationship between cigarette smoking and cancer. - Since 1937, cancer has been the second most important cause of death in the United States and will account for an estimated 430,000 deaths this year. Surveys have shown that Americans fear dying of cancer more than any other disease. We have yet to observe, however, a decline in the cancer mortality rate as is currently occurring for other chronic diseases, such as the 30 percent decline in the cardiovascular disease mortality rate and the 50 percent decline in the cerebrovascular disease mortality rate observed over the last three decades. The mortality rate for cancer has changed little over two decades, and that change has been a small, but measurable, increase. This increase in mortality has occurred in the f'cjre of remarkable improvements in survival rates for some cancer sites through earlier or better diagnosis and treatment. Unfortunate- ly. however, these advances have failed to counter the remarkable increases in mortality from smoking-related cancers, many of which have a poor prognosis for long-term survival or cures. The Public Health Significance of this Report Cigarette smoking is the major single cause of cancer mortality in the United States. Tobacco's contribution to all c:lncer deaths is estimated to be 30 percent. This means we can expect that 129,000 Americans will die of cancer this year because of the higher overall cancer death rates that exist among smokers as c'etnpared with nonsmokers. Cigarette smokers have total cancer (lc:lth rates two times greater than do nonsmokers. Heavy smokers hirve a three to four times greater excess risk of cancer mortality. If ILlrge numbers of our population did not smoke, the cancer death rate in this countrv could be reduced, and instead of the small but continued increasedin the total cancer death rate. there could be a substantial decline. There is no single action an individual can take to reduce the risk of cancer more ef'fectively than quitting smoking, PLrrticularlv cigarettes. Cigarette smoking is a major cause of cancers of the lung, larynx, oral cavity, and esophagus, and is a contributory factor for the development of cancers of the bladder, pancreas, and kidney. The term contributory factor by no means excludes the possibility of a causal role for smoking in cancer of these sites. Lung Cancer Lung cancer. f'irst correlated with smoking over 50 years ago, is the single largest contributor to the total cancer death rate. Lung cancer alone accounts for fully 25 percent of all cancer deaths in this country; it is estimated that 85 percent of lung cancer cases are due to cigarette smoking. Overall, smokers are 10 times more likely to die f'rom lung cancer than are nonsmokers. Heavy smokers are 15 to 25 times more at risk than nonsmokers. The total number of lung cancer deaths in the United States increased from 18,313 in 1950 to 90,828 in 1977. The lung cancer death rate for women is currently rising faster than the lung cancer death rate for men, a fact that reflects the later adoption of smoking by large numbers of women. The lung cancer death rate for women will soon surpass that of breast cancer (perhaps as eariy as next. year), currently the leading cause of cancer mortality in women. This remarkable increase in lung cancer mortality for women mimics that observed among men some 30 years ago. However, since the early 196Os, ,large numbers of men have given up cigarette smoking or have not begun to smoke, whereas only recently has the prevalence of cigarette smoking by women started to decline. These differences in patterns of smoking have a decided eff'ect on lung cancer mortality trends in this country, with a decline in lung cancer mortality already apparent for younger men. These differences will clearly affect future lung cancer mortality experience by sex in the United States. The American Cancer Society estimates there will be 111,000 lung cancer-related deaths in 1982, of'which 80.000 will be in men and 31,000 in women. The 5-year survival rate for cancer of the lung is less than 10 percent. This rate has not changed in 20 years. Early diagnosis and treatment do not appreciably alter this dismal survival rate-the best preventive measure a smoker can take to reduce the risk of lung cancer is to quit smoking, and for a nonsmoker, to not take up the habit. Larynx and Oral Cavity Cancer Laryngeal and oral cancers will strike an estimated 40,000 individuals and will be responsible for approximately 13,000 deaths this ~-c':rr in the United States. These sites have 5-year survival rates 01` 60 and 40 percent. respectively. An estimated 50 to 70 percent of vi oral and laryngeal cancer deaths are associated with smoking. These cancers are strongly associated with the use of cigars and pipes in addition to cigarettes. All carry approximately the same excess relative risk of at least fivefold. The use of alcohol in conjunction with smoking acts synergistically to greatly increase the risk of these cancers. Esophageal Cancer This year, 8,300 deaths due to cancer of the esophagus are expected. Cancer of the esophagus has one of the poorest survival rates of all cancers-only about 4 percent of esophageal cancer patients live 5 years after diagnosis and most die within 6 months. Cigarette smoking is estimated to be a factor in over half of esophageal cancer deaths. Smokers have mortality ratios approxi- mately 4 to 5 times higher than nonsmokers. The use of alcohol has a synergistic interaction with smoking that greatly increases this risk. Bladder and Kidney Cancers Over 50,000 Americans are expected to develop bladder and kidney cancer this year. Bladder and kidney cancers will be responsible for a total of 20,000 deaths this year. The 5-year survival rates are approximately 50 to 60 percent. Various investigators have estimated that between 30 and 40 percent of bladder cancers are smoking related, with slightly higher estimates for males than for females. Pancreatic Cancer Approximately 24,000 people will develop cancer of the pancreas this year, and there will be an estimated 22,000 deaths. Like cancers of the lung and esophagus, cancer of the pancreas is often fatal, with a 5-year survival of less than 3 percent. While few estimates are available as to the proportion of these deaths attributable to smoking, it would appear to be about 30 percent. Pancreatic cancer appears to be increasing at a more rapid rate than most other cancer sites. Stomach and Uterine Cervix Cancer A link between smoking and stomach cancer and cancer of the uterine cervix is noted. However, no judgment can be reached on the significance of any association, because of insufficient data. vii Involuntary Smoking and Lung Cancer In recent months, the popular press has generated interest in the controversy of whether passive or involuntary smoking causes lung cancer in nonsmokers. Three epidemiological studies examined this issue in the past year. Evidence from two of the studies demon- strated a statistically significant correlation between involuntary smoking and lung cancer risk in nonsmoking wives of husbands who smoked. A third noted a positive association, but it was not statistically significant. While the nature of this association is unresolved, it does raise the concern that involuntary smoking may pose a carcinogenic risk to the nonsmoker. Any health risk resulting from involuntary smoke exposure is a serious public health concern because of the large numbers of nonsmokers in the population who are potentially exposed. Therefore, for the purpose of preventive medicine, prudence dictates that nonsmokers avoid exposure to second-hand tobacco smoke to the extent possible. Lower Tar Cigarettes This report also notes that smokers who use filtered or `lower tar cigarettes have statistically lower death rates from lung cancer than do cigarette smokers who use nonfiltered or higher tar brands. This reduced risk was also noted for laryngeal cancer. However, cancer death rates for smokers of lower tar cigarettes were still significantly higher than those noted for nonsmokers. Cessation of Smoking Since cigarette smoking is a cause of many cancers, encouraging data about cessation are presented in this Report. Quitting smoking reduces one's cancer risk substantially, compared with the continu- ing smoker, even after many years of cigarette smoking. The more years one is off cigarettes, the greater the reduction in excess cancer risk. Fifteen years after quitting cigarette smoking, the former smoker's lung cancer risk, for example, is reduced close to that observed in nonsmokers. This same reduction in cancer risk is observed for the other cancer sites associated with smoking. Part V of this Report contains a review of cessation research among adults and adolescents. In summary, many promising tech- niques are available to smokers who have been unable to quit on their own. It is nonetheless interesting to note that the vast majority of former smokers, probably close to 95 percent, quit on their own, without the aid of formal smoking cessation programs. As a physician, I encourage all health care providers, particularly other physicians, to counsel cigarette smokers to quit and to give them as much support as possible. As this Report notes, a Sew . . . Vlll minutes' discussion with patients about their smoking behavior can have a decisive impact on whether they quit smoking or continue the habit. Trends in Smoking Prevalence I am encouraged by the recent decline in cigarette smoking rates in this country. Today, only one-third of adults smoke, a decline from 42 percent in 1965. Teenage smoking, particularly among adolescent girls, also appears to be declining. While these figures are encouraging, there are still 53 million cigarette smokers in this country-about the same number of smokers as 20 years ago. Furthermore, while per capita use of cigarettes has declined to its lowest level since 1957, there has been a substantial increase in the consumption of chewing tobacco and snuff, particularly among the young. What impact the use of these products will have on future cancer mortality is unclear; knowledge of the type and extent of the health effects of these tobacco products is limited. Current evidence indicates, however, that their use is not without risk. Studies conducted in this country and others have demonstrated an in- creased risk for oral cancer and other noncancerous oral diseases. Educational Efforts This Department is committed to continuing the programs of education and information for all our citizenry regarding the adverse health consequences of smoking. There is no more important aspect of this than the health education of our young, to convince them not to start smoking, or to quit the habit before it becomes difficult to break. This problem cannot be left solely to government to solve. I call upon the rest of the health care community, the voluntary health agencies, and our schools to increase their efforts to control one of this country's most pressing health problems. Reducing smoking will reduce the devastating toll that cancer, as well as other smoking- related diseases, exacts on this Nation's health. Edward N. Brandt, Jr., M.D. Assistant Secretary for Health ix PREFACE In July 1957, Dr. Leroy E. Burney issued the Public Health Service's first statement on cigarette smoking: it identified smoking as a cause of lung cancer. Each succeeding Surgeon General has had occasion to issue additional and stronger warnings. These have linked smoking with lung cancer, with heart disease, with chronic lung disease, with other cancers, and with increases in overall mortality. With this 1982 statement on cigarette smoking and cancer, I am joining my distinguished predecessors, Drs. Burney, Luther Terry, William Stewart, Jesse Steinfeld, and Julius Richmond. Cigarette smoking, as this Report again makes clear, is the chief, single, avoidable cause of death in our society and the most important public health issue of our time. Over the years, 14 reports on the health consequences of smoking have been prepared by the Public Health Service under the Federal Cigarette Labelling and Advertising Act and its successor, the Public Health Cigarette Smoking Act of 1969. These reports have contrib- uted greatly to public understanding of the hazards that cigarette smoking poses to the health of this Nation. In contrast with previous Public Health Service reports on smoking and health, the present document examines the relation- ship between smoking and a single category of disease, cancer. The relationships between smoking and lung cancer, as well as cancer of other sites, are carefully examined. This should not distract atten- tion from the fact that smoking is related to many diseases, including cardiovascular disease, which exacts a greater toll than does cancer in disease and death. Cancer, however, was the first disease to be linked with tobacco use, and its association with smoking has been the subject of the most intense research: Much of the research within the past few years has not previously been examined in the detail presented here. As in previous years, this Report has been prepared with the aid and critical review of experts from within and outside the Govern- ment. On behalf of the Public Health Service, I express here my respect for their expertise and gratitude for their help. C. Everett Koop, M.D. Surgeon General xi ACKNOWLEDGEMENTS This Report was prepared by the Department of Health and Human Services under the general editorship of the Office on Smoking and Health, Joanne Luoto, M.D., M.P.H., Acting Director. Managing Editor was Donald R. Shopland, Technical Information Officer, Office on Smoking and Health. Consulting scientific editors were David M. Burns, M.D., Assistant Professor of Medicine, Pulmonary Division, University of California at San Diego, San Diego, California; John H. Holbrook, M.D., Associate Professor of Internal Medicine, University of Utah Medi- cal School, Salt Lake City, Utah; and Ellen R. Gritz, Ph.D., Director, Macomber-Murphy Cancer Prevention Program, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California. The editors wish to acknowledge the assistance of the National Cancer Institute, particularly the Clinical Epidemiology Branch, for making available the computer-generated three dimensional graphs of cancer mortality, and the National Center for Health Statistics, for making available the cancer mortality data extracted from the publication by A. Joan Klebba, Mortality From Diseases Associated with Smoking, United States, 1960 to 1977. The following individuals authored sections within the Parts of the Report as indicated: Part I. Introduction and Conclusions Office on Smoking and Health Part II. Biomedical Evidence for Determining Causality Richard A. Bordow, M.D., Associate Director of Respiratory Medi- cine, Brookside Hospital, San Pablo, California; and Assistant Clinical Professor of Medicine, University of California at San Francisco, San Francisco, California Abraham M. Lilienfeld, M.D., M.P.H., D.&Z., University Distin- guished Service Professor, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland Part III. Mechanisms of Carcinogenesis Dietrich Hoffmann, Ph.D., Associate Director, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York x111 Ilse Hoffmann, Research Coordinator, Naylor Dana Institute foi Disease Prevention, American Health Foundation, Valhalla, New York Stanley E. Shackney, M.D., Head, Section of Cellular Kinetics. Clinical Pharmacology Branch, Division of Cancer Treatment. National Cancer Institute, Bethesda, Maryland Elizabeth K. Weisburger, Ph.D., Assistant Director for Chemical Carcinogenesis, Division of Cancer Control and Prevention, Na- tional Cancer Institute, Bethesda, Maryland Part IV. Involuntary Smoking and Lung Cancer Aristide Y. Apostolides, D.V.M., M.P.H., Associate Professor 01 Epidemiology, Department of Preventive Medicine and Biometry, Uniformed Services University of the Health Sciences, Depart- ment of Defense, Bethesda, Maryland Michael D. Lebowitz, Ph.D., Professor of Internal Medicine, College of Medicine, the University of Arizona Health Sciences Center, Tucson, Arizona Part V. Cessation of Smoking E. B. Fisher, Jr., Ph.D., Associate Professor of Psychology, Associate Director of the Washington University Diabetes Research and Training Center, Washington University in St. Louis, St. Louis, Missouri Ellen R. Gritz, Ph.D., Director, Macomber-Murphy Cancer Preven- tion Program, Division of Cancer Control, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California; Associate Research Psychologist, Department of Psychiatry and Biobehavioral Sciences, School of Medicine, Neuropsychiatric Institute, University of California, Los Angeles, California; and Research Psychologist, Veterans Administration Medical Center, Brentwood, Los Angeles, California C. Anderson Johnson, Ph.D., Associate Professor and Director, Health Behavior Research Institute, University of Southern California, Los Angeles, California The editors acknowledge with gratitude the following distin- guished scientists, physicians, and others who lent their support in the development of this Report by coordinating manuscript prepara- tion, contributing critical reviews of the manuscript, or assisting in other ways. Elvin E. Adams, M.D., M.P.H., P.A., Huguley Medical Arts Clinic, Fort Worth, Texas Sam P. Battista, Ph.D., Senior Staff Pharmacologist, Arthur D. Little, Inc., Cambridge, Massachusetts Fred G. Bock, Ph.D., Director, Orchard Park Laboratories, Roswell Park Memorial Institute, Buffalo, New York Vincent T. DeVita, M.D., Director, National Cancer Institute, Bethesda, Maryland Hans L. Falk, Ph.D., Associate Director, Health Hazard Assessment, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina William Foege, M.D., Director, Centers for Disease Control, Atlanta, Georgia Robert A. Goyer, M.D., Deputy Director, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina Dorothy E. Green, Ph.D., Consulting Research Psychologist, Arling- ton, Virginia Michael R,. Guerin, Ph.D., Section Head, Bio-Organic Analysis Section, Analytical Chemistry Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee Sharon M. Hall, Ph.D., Associate Professor, Langley Porter Psychiat- ric Institute, University of California at San Francisco, San Francisco, California Jeffrey E. Harris, M.D., Ph.D., Associate Professor, Department of Economics, Massachusetts Institute of Technology, Cambridge, Massachusetts Arthur Hull Hayes, Jr., M.D., Commissioner, Food and Drug Administration, Rockville, Maryland Maureen M. Henderson, M.D., Professor of Medicine and Epidemiol- ogy, School of Public Health and Community Medicine, University of Washington, Seattle, Washington Harry A. Lando, Ph.D., Professor, Department of Psychology, Iowa State University, Ames, Iowa Alex Langmuir, M.D., Chilmark, Massachusetts Edward Lichtenstein, Ph.D., Department of Psychology, University of Oregon and Oregon Research Institute, Eugene, Oregon Abraham M. Lilienfeld, M.D., M.P.H., DSc., University Distin- guished Service Professor, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland Anthony B. Miller, M.D., Director, Epidemiology Unit, National Cancer Institute of Canada, University of Toronto, Ontario, Canada Kenneth M. Moser, M.D., Professor of Medicine and Director, Division of Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine, University of California at San Diego, San Diego, California Richard Peto, M.A., M.Sc., I.C.R.S., Reader in Cancer Studies Unit, Nuffield Department of Clinical Medicine, Radcliffe Infirmary, Oxford, England Richard D. Remington, Ph.D., Dean, School of Public Health, University of Michigan, Ann Arbor, Michigan xv 377-310 c - 82 - 2 Dorothy P. Rice, Director, National Center for Health Statistics, Hyattsville, Maryland David Schottenfeld, M.D., Chief of Epidemiology and Preventive Medicine, Director of Cancer Control, Memorial Sloan-Kettering Cancer Center, New York, New York; and Professor of Public Health, Cornell University Medical College, New York, New York Marvin A. Schneiderman, Ph.D., Bethesda, Maryland Irving J. Selikoff, M.D., Professor of Community Medicine and `Medicine, and Director, Environmental Sciences Laboratory, Mt. Sinai School of Medicine, City University of New York, New York, New York Saul Shiffman, Ph.D., Assistant Professor, Department of Psycholo- gy, College of Social and Behavioral Sciences, University of South Florida, Tampa, Florida Michael B. Shimkin, M.D., Professor Emeritus, Department of Community and Family Medicine, School of Medicine, University of California at San Diego, La Jolla, California Jesse L. Steinfeld, M.D., Dean, School of Medicine, Medical College of Virginia, Richmond, Virginia The editors also acknowledge the contributions of the following staff members and others who assisted in the preparation of the Report. Erica W. Adams, Copy Editor, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Richard H. Amacher, Director, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland John L. Bagrosky, Associate Director for Program Operations, Office on Smoking and Health, Rockville, Maryland Richard J. Bast, Medical Translation Consultant, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Jacqueline 0. Blandford, Secretary, Office on Smoking and Health, Rockville, Maryland Marsha Clay, Clerk-Typist, Office on Smoking and Health, Rockville, Maryland Melissa R. Colbert, Applications Manager, Publishing Services Division, Informatics Incorporated, Riverdale, Maryland Karen M. Cox, Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Joanna B. Crichton, Copy Editor, Information and Technology Transfer Department, Informatics Incorporated, Rockville, Mary- land Denise M. Cross, Data Entry Manager, Publishing Services Division, Informatics Incorporated, Riverdale, Maryland Martha E. Davis, Technical Illustrator, Informatics Incorporated, Rockville, Maryland xvi Stephanie D. DeVoe, Data Entry Operator, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Andrea L. Dykstra, Senior Technical Editor, Biospherics Incorporat- ed, Rockville, Maryland Susan H. Fenton, Table Coder, Publishing Services Division, Infor- matics Incorporated, Riverdale, Maryland Judy Fernandes, Writer-Editor, Office on Smoking and Health, Rockville, Maryland Sandy ,Gibson, Copy Editor and Indexer, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Wendy S. Goldin, Secretary, Information and Technology Transfer Department, Informatics Incorporated, Rockville, Maryland Rebecca C. Harmon, Manager, Graphics Unit, Clearinghouse Ser- vices Division, Informatics Incorporated, Rockville, Maryland Reginald V. Hawkins, M.P.H., Public Health Analyst, Office on Smoking and Health, Rockville, Maryland Douglas Hayes, Applications Manager, Information Processing Ser- vices Division, Informatics Incorporated, Riverdale, Maryland Patricia E. Healy, Technical Information Clerk, Office on Smoking and Health, Rockville, Maryland Leslie J. Headlee, Information Specialist, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Shirley K. Hickman, Data Entry Operator, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Robert S. Hutchings, Associate Director for Information and Pro- gram Development, Office on Smoking and Health, .Rockville, Maryland Lisa A. Katz, Graphic Artist, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Margaret E. Ketterman, Public Information and Publications Assis- tant, Office on Smoking and Health, Rockville, Maryland John J. Kourilo, Senior Information Analyst, Clearinghouse Services Division, Informatics Incorporated, Rockville, Maryland Julie Kurz, Graphic Artist, Clearinghouse Services Division, Infor- matics Incorporated, Rockville, Maryland William R. Lynn, Program Operations Technical Assistance Officer, Office on Smoking and Health, Rockville, Maryland Marilynn H. Meinke, Copy Editor, Clearinghouse Projects Depart- ment, Informatics Incorporated, Rockville, Maryland Jacquelene Mudrock, Technical Illustrator, Informatics Incorporat- ed, Rockville, Maryland Judith L. Mullaney, M.L.S., Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland Douglas F. Pepin, Statistical Analyst, Clearinghouse Projects De- partment, Informatics Incorporated, Rockville, Maryland xvii Raymond K. Poole, Production Coordinator, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Roberta A. Roeder, Secretary, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Linda R. Sexton, Information Specialist, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland' Carol A. Sherrer, Technical Consultant, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Scott Smith, Editor, Biospherics, Incorporated, Rockville, Maryland Linda Spiegelman, Administrative Officer, Office on Smoking and Health, Rockville, Maryland Sol Su, Sc.D., Statistician, Office on Smoking and Health, Rockville, Maryland Selwyn Waingrow, Public Health Analyst, Office on Smoking and Health, Rockville, Maryland Aileen L. Walsh, Secretary, Clearinghouse Projects Department, Informatics Incorporated, Rockville, Maryland Melissa L. Yorks, M.L.S., Technical Information Specialist, Office on Smoking and Health, Rockville, Maryland xv111 TABLE OF CONTENTS Foreword ...... .I ......................................................... v Preface .................................................................. xi Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xiii 1. Introduction and Conclusions .................................. 1 2. Biomedical Evidence for Determining Causality ....... 13 3. Mechanisms of Carcinogenesis . . . . . . . . . _. . . . . . . . . . . . 171 4. Involuntary Smoking and Lung Cancer ................. 237 5. Cessation of Smoking.. ....................................... 255 Index . . . . . . . . . . . . . . _. _. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . _ _. . . . . . . . . . 305 xix PART I. INTRODUCTION AND CONCLUSIONS Introduction Development and Organization of the 1982 Report The content of this Report is the work of numerous scientists within the Department of Health and Human Services, as well as scientific experts outside the organization. Individual manuscripts were reviewed by experts, both outside and within the Public Health Service, and the entire Report was reviewed by a broad-based panel of 12 distinguished scientists. Many of these scientists are, or have been, directly involved in research on the health effects of smoking. The 1982 Report consists of a Preface by the Surgeon General, a Foreword by the Assistant Secretary for Health of the Department of Health and Human Services, and five Parts, as follows: o Part I. Introduction and Conclusions 0 Part II. Biomedical Evidence for Determining Causality 0 Part III. Mechanisms of Carcinogenesis o Part IV. Involuntary Smoking and Lung Cancer o Part V. Cessation of Smoking Historical Perspective Tobacco use was associated with the possible development of cancer as early as 1761. According to one medical historian, Dr. John Hill (1716?-1775) should be credited with the first report document- ing an association between tobacco use and cancer for his work Cautions Against the Immoderate Use of Snuff: Hill reported on two case histories and observed that "snuff is able to produce...swellings and excrescences" in the nose, and he believed these to be cancerous. Others credit Soemmerring in 1795 for noting a relationship between cancer of the lip and tobacco use. It was not until the 1920s and 1930s that investigators began to examine scientifically the possible association of smoking and cancer. In 1928, Lombard and Doering, in the United States, found an association between heavy smoking and cancer in general. Muller and Schairer (Germany) in 1939 and 1944 respectively, and Porter (USA) in 1945, and others, noted higher percentages of smokers among lung cancer patients than among controls. The first major developments in the modern history of investigation of the effects of smoking on health occurred in 1950 with the publication of four retrospective studies on smoking habits of lung cancer patients and controls in the United States by Schrek et al., Mills and Porter, Levin et al., and Wynder and Graham. Each of these noted a consistent, statistically significant association between smoking and cancer of the lung. Other investigators proceeded to further examine the relationship by initiating prospective studies in which large numbers of healthy persons were followed over time and their subsequent mortality noted. 3 The first major prospective study encompassing total and cause- specific mortality was initiated in October 1951 by Doll and Hill in the United Kingdom among 40,000 British physicians. Hammond and Horn followed 188,000 males beginning in January 1952 in the United States. These and subsequent prospective studies conducted in the United States, Sweden, Canada, and Japan, found not only that smokers have substantially elevated cancer mortality rates, but also that smokers experience significantly elevated overall death rates. Cancer has been the second ranking cause of death in the United States since 1937. Provisional vital statistics data for 1980 indicate cancer accounted for almost 21 percent of all deaths in the United States. This compares to 17 percent of all deaths in 1970 and 14.5 percent of all deaths in 1950. Various investigators have suggested that 22 to 38 percent of these deaths can be attributed to smoking, and therefore, are potentially "avoidable" if smoking did not exist as a human behavior. Since 1950, the age-adjusted overall cancer death rate has changed little, whereas the lung cancer death rate has increased dramatically for both males and females. The male age-adjusted lung cancer rate increased 192 percent during the period 1950-1952 thru 1976-1978. Female lung cancer death rates during this same period increased even more: 263 percent. Since the 1950s lung cancer has been the leading cause of cancer death among males in the United States, `and if present trends continue, will become the leading cause of cancer death in females during this decade; the age-adjusted female lung cancer death rate is projected to possibly surpass the death rate for breast cancer next year. Today, deaths from cancer of the lung represent fully one quarter of &l deaths due to cancer in the United States. In 1962, the year when the Surgeon General's Advisory Committee on Smoking and Health began deliberating the evidence presented in its landmark report, slightly more than 41,000 persons died of lung cancer annually, compared to 18,300 lung cancer deaths in 1950. In 1982, the American Cancer Society estimates 111,000 Americans will die of lung cancer, nearly a three-fold increase in the number of deaths in a 20-year time span. The Advisory Committee's Report of 1964 judged the causal significance of the association of cigarette smoking and disease by rigid criteria, no one of which alone was sufficient for a causal judgment. The epidemiologic criteria included: a. The consistency of the association b. The strength of the association c. The specificity of the association d. The temporal relationship of the association, and e. The coherence of the association 4 Corroboration was also sought from other sources, such as clinical autopsy and experimental evidence. Significant additional scientific evidence linking smoking to cancer, as well as to other tobacco-related diseases, has accumulated since the issuance of that Advisory Committee's Report in 1964. Much of this has been collected, reviewed, and published in annual reports by the L)epartment of Health and Human Services. The purpose of this Report is to review in depth the many sources of scientific evidence relating cigarette smoking to each cancer by anatomic site, and to evaluate this evidence by the same criteria first established by the Advisory Committee in its 1964 Report, including experimental carcinogenesis and human epidemiologic studies. Conclusions of the 1982 Report Overall Cancer Mortality 1. Cigarette smokers have overall mortality rates substantially greater than those of nonsmokers. Overall cancer death rates of male smokers are approximately double those of nonsmok- ers; overall cancer death rates of female smokers are approxi- mately 30 percent higher than nonsmokers, and are increasing. 2. Overall cancer mortality rates among smokers are dose-related as measured by the number of cigarettes smoked per day. Heavy smokers (over one pack per day) have more than three times the overall cancer death rate of nonsmokers. 3. With increasing duration of smoking cessation, overall cancer death rates decline, approaching the death rate of nonsmokers. SiteSpecific Cancer Mortality Lung Cancer 1. Cigarette smoking is the major cause of lung cancer in the United States. 2. Lung cancer mortality increases with increasing dosage of smoke exposure (as measured by the number of cigarettes smoked daily, the duration of smoking, and inhalation pat- terns) and is inversely related to age of initiation. Smokers who consume two or more packs of cigarettes daily have lung cancer mortality rates 15 to 25 times greater than nonsmokers. 3. Cigar and pipe smoking are also causal factors for lung cancer. However, the majority of lung cancer mortality in the United States is due to cigarette smoking. 4. Cessation of smoking reduces the risk of lung cancer mortality compared to that of the continuing smoker. Former smokers who have quit 15 or more years have lung cancer mortality rates only slightly above those for nonsmokers (about two times 5 greater). The residual risk of developing lung cancer is directly proportional to overall life-time exposure to cigarette smoke. 5. Filtered lower tar cigarette smokers have a lower lung cancer risk compared to nonfiltered, higher tar cigarette smokers. However, the risk for these smokers is still substantially elevated above the risk of nonsmokers. 6. Since the early 195Os, lung cancer has been the leading cause of cancer death among males in the United States. Among females, the lung cancer death rate is accelerating and will likely surpass that of breast cancer in the 1980s. 7. The economic impact of lung cancer to the nation is consider- able. It is estimated that in 1975, lung cancer cost $3.8 billion in lost earnings, $379.5 million in short-term hospital costs, and $78 million in physician fees. 8. Lung cancer is largely a preventable disease. It is estimated that 85 percent of lung cancer mortality could have been avoided if individuals never took up smoking. Furthermore, substantial reductions in the number of deaths from lung cancer could be achieved if a major portion of the smoking population (particularly young persons) could be persuaded not to smoke. Laryngeal Cancer 9. Cigarette smoking is the major cause of laryngeal cancer in the United States. Cigar and pipe smokers experience a risk for laryngeal cancer similar to that of a cigarette smoker. 10. The risk of developing laryngeal cancer increases with in- creased exposure as measured by the number of cigarettes smoked daily as well as other dose measurements. Heavy smokers have laryngeal cancer mortality risks 20 to 30 times greater than nonsmokers. 11. Cessation of smoking reduces the risk of laryngeal cancer mortality compared to that of the continuing smoker. The longer a former smoker is off cigarettes the lower the risk. 12. Smokers who use filtered lower tar cigarettes have lower laryngeal cancer risks than those who use unfiltered higher tar cigarettes. 13. The use of alcohol in combination with cigarette smoking appears to act synergistically to greatly increase the risk for cancer of the larynx. Oral Cancer 14. Cigarette smoking is a major cause of cancers of the oral cavity in the United States. Individuals who smoke pipes or cigars experience a risk for oral cancer similar to that of the cigarette smoker. 15. Mortality ratios for oral cancer increase with the number of cigarettes smoked daily and diminish with cessation of smok- ing. 16. Cigarette smoking and alcohol use act synergistically to increase the risk of oral cavity cancers. 17. Long term use of snuff appears to be a factor in the develop- ment of cancers of the oral cavity, particularly cancers of the cheek and gum. Esophageal Cancer 18. Cigarette smoking is a major cause of esophageal cancer in the United States. Cigar and pipe smokers experience a risk of esophageal cancer similar to that of cigarette smokers. 19. The risk of esophageal cancer increases with increased smoke exposure, as measured by the number of cigarettes smoked daily, and is diminished by discontinuing the habit. 20. The use of alcohol in combination with smoking acts synergisti- cally to greatly increase the risk for esophageal cancer mortality. Bladder Cancer 21. Cigarette smoking is a contributory factor in the development of bladder cancer in the United States. This relationship is not as strong as that noted for the association between smoking and cancers of the lung, larynx, oral cavity, and esophagus. The term "contributory factor" by no means excludes the possibili- ty of a causal role for smoking in cancers of this site. Kidney Cancer 22. Cigarette smoking is a contributory factor in the development of kidney cancer in the United States. This relationship is not as strong as that noted for the association between smoking and cancers of the lung, larynx, oral cavity, and esophagus. The term "contributory factor" by no means excludes the possibili- ty of a causal role for smoking in cancers of this site. Pancreatic Cancer 23. Cigarette smoking is a contributory factor in the development of pancreatic cancer in the United States. This relationship is not as strong as that noted for the association between smoking and cancers of the lung, larynx, oral cavity, and esophagus. The term "contributory factor" by no means excludes the possibili- ty of a causal role for smoking in cancers of this site. 7 Stomach Cancer 24. In epidemiological studies, an association between cigarette smoking and stomach cancer has been noted. The association is small in comparison with that noted for smoking and some other cancers. Uterine Cervix Cancer 25. There are conflicting results in studies published to date on the existence of a relationship between smoking and cervical cancer; further research is necessary to define whether an association exists and, if so, whether that association is direct or indirect. Mechanisms of Carcinogenesis This overview presents evidence and observations on tobacco carcinogenesis primarily developed since 1978. 1. The biological activity of whole cigarette smoke and its tar and tar fractions can now be measured by improved inhalation assays in addition to tests for tumor-initiating, tumor-promot- ing, and cocarcinogenic activities on mouse skin. 2. Studies on smoke inhalation with the hamster now appear suitable for estimating the relative tumorigenic potential of whole smoke from commercial and experimental cigarettes. The identification of the smoke constituents that contribute to tumor induction in the respiratory tract is best achieved by fractionations of tar and by assays on mouse epidermis that determine the type and potency of the carcinogens. In combina- tion with biochemical tests, mouse skin assays should also aid in evaluating the possible role of nicotine as a cocarcinogen. 3. The identification, formation, and metabolic activation of organ-specific carcinogens have been studied which help ex- plain the increased risk to cigarette smokers of cancer of the esophagus, pancreas, kidney, and urinary bladder. In addition to certain aromatic amines, tobacco-specific N-nitrosamines appear to be an important group of organ specific carcinogens in tobacco and tobacco smoke. Little is known of the in uiuo formation of organ-specific carcinogens from nicotine and other Nicotiana alkaloids. The modification of their enzymatic activation to ultimate carcinogenic forms needs to be explored by chemopreventive approaches. 4. Transplacental carcinogenesis as it may relate to effects of cigarette smoking should be investigated more fully. It has been known for some time that inhalation of tobacco smoke activates enzymes in the placenta and fetus and the conse- quences of such changes need to be studied. 5. The continuing modification of U.S. cigarettes has led to changes in the quantitative and perhaps also the qualitative composition of the smoke. This ongoing development requires continued monitoring of the toxic and carcinogenic potential of the smoke of new cigarettes. 6. The changes in cigarette composition lead generally to reduced emission of major toxic mainstream smoke constituents as measured in analytical laboratories under machine-smoking conditions. Many smokers intensify puff volume and degree of inhalation when smoking a lower-yield cigarette. Therefore, it should be determined what effect different techniques of air dilution and filtration have in counteracting the increased smoke exposure that results from intensified smoking. 7. Snuff tobaccos are increasingly used as an alternative to cigarette smoking. More information is needed regarding the carcinogenic activity of snuff tobaccos and the presence of tumorigenic agents in these products. Involuntary Smoking and Lung Cancer 1. Mainstream and sidestream cigarette smoke contain similar chemical constituents. (Mainstream smoke is smoke that the smoker inhales directly during puffing. Sidestream smoke is smoke emitted from a smoldering cigarette into the ambient air.) These constituents include known carcinogens, some of which are present in higher concentrations in sidestream smoke than they are in mainstream smoke. Passive or involun- tary smoking differs from voluntary cigarette smoking with respect to the concentration of smoke components inhaled, the duration and frequency of smoke exposure, and the pattern of inhalation. 2. In two epidemiologic studies, an increased risk of lung cancer in nonsmoking wives of smoking husbands was found. In these studies, the nonsmoking wife's risk of lung cancer increased in relation to the extent. of the husband's smoking. In a third study, the risk of lung cancer among nonsmoking wives of smoking husbands was also increased, but the difference was not statistically significant. 3. Although the currently available evidence is not sufficient to conclude that passive or involuntary smoking causes lung cancer in nonsmokers, the evidence does raise concern about a possible serious public health problem. Cessation of Smoking 1. Ninety-five percent of those who have quit smoking have done so without the aid of an organized smoking cessation program, and most current smokers indicate a preference for quitting 9 with a procedure they may use on their own, and a disinclina- tion to enter an organized, comprehensive program. 2. Research evaluations of self-help aids have reported success rates up to 50 percent cessation at extended followups (6 to 15 months). Most estimates, however, fall below this, around 5 to 20 percent. 3. Brief and simple advice to quit smoking delivered by a physician has substantial potential for producing cessation in a cost-effective manner. 4. Televised smoking cessation clinics result in variable rates of abstinence at followup. The use of television and other mass media are a cost-effective intervention because of their large potential audiences. 5. Retrospective studies revealed greater use of self-reward and active problem-solving strategies among those who quit or reduced smoking on their own than among those who were unsuccessful in quitting or reducing smoking. 6. Until recently, the long-term outcome of intensive smoking cessation clinics has remained at 25 to 30 percent abstinence. New emphasis on techniques to improve the maintenance phase of cessation promises to improve these rates, with several reports of greater than 50 percent abstinence at followups of 6 months or longer. 7. To improve maintenance of nonsmoking after intensive treat- ment programs have ended, reinforcement should be built into the, natural environment. Smoking cessation programs in the workplace may offer an opportunity for this. 8. Comprehensive self-management packages that have been shown to boost maintenance rates include a wide variety of techniques. 9. Treatment outcome may be improved by focusing on the antecedents of relapse. These include feelings of frustration, anxiety, anger, and depression as well as social models and smoking-related cues and settings. Behavioral and cognitive skills for dealing with such antecedents should be developed. 10. Social support interventions are promising. Reliable findings link social cues, smoking friends, and smoking spouses to relapse, whereas the presence of group support, nonsmoking spouses, and professional contact decreases recidivism. 11. Spontaneous smoking cessation among regular users (approxi- mately once a week or more often) is estimated to be on the order of 25 percent during adolescence. 12. Probability of quitting was greater for those adolescent smok- ers first interviewed in 1974 who had at least started to attend college by 1979 than for those smokers who did not attend college (42.0 percent vs. 24.6 percent). 10 13. Probability of quitting decreases linearly with duration of the smoking practice, changing from 64.5 percent in the first year of smoking to 14.3 percent after 7 years. 14. Quitting "cold turkey" appears to be a more effective cessation strategy than cutting down without trying to stop entirely. 15. Success at quitting increased with the number of efforts made: about 73.4 percent of adolescents who kept trying eventually succeeded. 16. Smoking prevention programs are desirable alternatives to cessation programs aimed at youth. Successful programs have been based on social psychological theory and research, and are school based. Results have shown a 50 percent or more reduction in smoking onset. 17. The most successful programs were those emphasizing the social and immediate consequences of smoking rather than long-term health consequences. These programs have placed special emphasis on teaching skills in recognizing and resisting social pressures to smoke. 377-330 0 - 82 - 3 11 PART II. BIOMEDICAL EVIDENCE FOR DETERMINING CAUSALITY INTRODUCTION Provisional mortality data for 1980 indicate that cancer was responsible for approximately 412,000 deaths in the United States (199). It is estimated that in 1982 there will be 430,000 deaths due to cancer, 233,000 among men and 197,090 among women (2). Various investigators (70, 78, 106) have suggested that 22 to 38 percent of these deaths can be attributed to smoking, and therefore are potentially "avoidable" if smoking did not exist as a human behavior. A relationship between smoking and cancer was first suggested for neoplasms of the lung in scientific reports from the 1920s and early 1930s (203, 266). Muller (192) in 1935 and Schairer and Schoeniger (237) in 1943 reported that most lung cancer patients were smokers. Subsequently, 8 major prospective studies and more than 50 retrospective studies have examined this relationship. In 1964, the Advisory Committee to the Surgeon General of the U.S. Public Health Service (272) published a comprehensive review of the then available data. They concluded that "cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking far outweighs all other factors. Data for women, though less extensive, point in the same direction. The risk of developing lung cancer increases with the duration of smoking and the number of cigarettes smoked per day and is diminished by discontinuing smoking." Over the last 17 years, thousands of scientific investigations have confirmed the Committee's conclusion and provided additional evidence concerning the relationship of cigarette smoking to lung cancers. Smoking has been implicated as a cause of cancer of the larynx, oral cavity, and esophagus, and associated with cancer of the urinary bladder, kidney, and pancreas. This is the first report devoted exclusively to a comprehensive assessment of the associa- tions reported between smoking and various cancers. In the follow- ing sections of this Part of the Report, the nature 0%' these associations is appraised in the light of currently available knowl- edge. 15 EPIDEMIOLOGIC CRITERIA FOR CAUSALITY The concept of causality has been debated by students of philoso- phy since the days of Aristotle. David Hume (1711-1776) and John Stuart Mill (1806-1873) are credited with major contributions to contemporary insight and theory of causality. More recently, mem- bers of the Advisory Committee to the Surgeon General (272), Hill (1121, MacMahon and Pugh (1681, Susser (2601, Evans (801, and Lilienfeld (158) have examined the concept of causality in the health sciences. The ability to totally control the experimental environ- ment, to randomize exposure, and to measure discrete outcomes allows a clear experimental demonstration of causality. However, the application of these rigid laboratory techniques for establishing causality to the study of cancer in humans is clearly impossible. The idea of exposing human subjects to potentially cancer-producing agents in order to establish causality is mcrally and ethically unacceptable. Therefore, other criteria have been developed to establish causality with a very high degree of scientific probability (80, 112, 158, 260, 272, 280). In practice, epidemiologic methods have been employed to study cancer in man. These studies result in observational data that may establish a statistically significant association between variables or attributes. This association may be artifactual, indirect, or direct. The possibility of an artifactual (or spurious) result can be eliminat- ed if the design and conduct of the studies are adequate, and if studies conducted in different geographical areas and among differ- ent population groups produce the same or similar statistical associations. Once an artifactual association has been ruled out, it is then necessary to determine whether the association is an indirect or direct (causal) one. Randomization is an attempt to eliminate the effect of all variables other than the one under study. However, a personal choice behavior such as smoking is impossible to randomize (i.e., to dictate smoking behavior). Therefore, in order to establish that an association between smoking and a disease is not due to a confound- ing variable, an entire body of data must exist to satisfy specific criteria, none of which by itself is an all-sufficient basis for judgment. Thus, when a scientific judgment is made that all plausible confounding variables have been considered, an association may be considered to be direct. In this Report, the same definition of the term "cause" that was used in the Report of the Advisory Committee to the Surgeon General in 1964 has been adopted. "The word cause is the one in general usage in connection with matters considered in this study, and it is capable of conveying the notion of a significant, effectual relationship between an agent and an associated disorder or disease in the host" (272). The term "cause" should not be construed to 16 exclude other agents as causes; rather, it is used in full recognition that biological processes are complex and multiple in etiologies. In this Report, as in the earlier one, the attribution of "causality" to a disease-associated variable (e.g., smoking) includes full recogni- tion that "the causal significance of an association is a matter of judgment which goes beyond any statement of statistical probability. To judge or evaluate the causal significance of the association between an attribute or agent and the disease, or the effect upon health, a number of criteria must be utilized, no one of which is an all-sufficient basis for judgment. These criteria include: a. The consistency of the association b. The strength of the association c. The specificity of the association d. The temporal relationship of the association, and e. The coherence of the association" These criteria are utilized herein for evaluation of the reported associations between cigarette smoking and cancers of various sites in humans. Consistency of the Association This criterion implies that diverse methods of approach in the study of an association will provide similar conclusions. Consistency requires that the association be repeatedly observed by multiple investigators, in different locations and situations, at different times, using different methods of study. Such replication assures that the association is not likely to be an artifact due to bias in study methodology or subject selection, and that it is not indirect due to confounding variables such as diet, occupation, or genetics. Strength of the Association The most direct measure of the strength of the association is the ratio of cancer rates for smokers to the rates for nonsmokers. The relative risk ratio yields evidence on the size of the effect of a factor on disease occurrence and which, even in the presence of another associated factor without causal effect but coincident with the causal agent, will not be obscured by the presence of the non-causal agent. A relative risk ratio measures the strength of an association and provides an evaluation of the importance of that factor in the production of a disease. If all cases of the disease under study, but none of the controls, have a history of exposure to the suspected etiologic agent or characteristic (assuming that an adequate number of cases and controls exist in the population under study), a one-to-one correspon- dence between the disease and the factor exists, and a causal hypothesis would be credible. Most diseases are influenced by many 17 factors, however, and therefore a one-to-one correspondence would not be expected. The strength of an association is measured by relative risk ratios, incidence ratios, or mortality ratios. The greater the relative risk ratio or the mortality ratio, the stronger the relationship between the etiologic agent and the disease. Prospective studies have shown that the death rate from cancer of the lung among cigarette smokers is approximately 10 times the rate in nonsmokers, and the rate in heavy cigarette smokers is 20 to 30 times greater than in nonsmokers. To account for such high relative risk in terms of an indirect association would require that an unknown causal factor be present at least 10 times more frequently in the smokers and 20 to 30 times more frequently among heavy smokers than among nonsmokers. Such a confounding factor should be easily detectable, and if it cannot be detected or reasonably inferred, the finding of such a strong association makes a conclusion concerning causality more probable. Important to the strength, as well as to the coherence of the association, is the presence of a dose- response phenomenon in which a positive gradient between degree of exposure to the agent and incidence or mortality rates of the disease can be demonstrated. Specificity of the Association This concept cannot be entirely dissociated from the concept inherent in the strength of the association. It implies the precision with which one component of an associated pair can be utilized to predict the occurrence of the other, i.e., how frequently the presence of one variable will predict, in the same individual, the presence of another. Specificity implies t,hat a causal agent invariably leads to a single specific disease, an event rarely observed. A one-to-one relationship between the presence of an etiologic agent and disease would reflect a causal relationship. However, several points must be kept in mind in interpreting specificity in biological systems. First, an agent may be associated with multiple diseases. Second, many responses considered to be disease states have multiple causes. Congenital malformations, for example, result from prenatal radiation as well as from some drugs administered during pregnancy and other factors. Variations in the relative risk of disease may be produced by variations in the number of causal agents as well as by the specificity of a given causal agent. Third, a single pure substance in the environment may produce a number of different diseases. The experimental production of a variety of diseases in mice by exposure to X-rays is a good example of this. Fourth, a single factor may be the vehicle for several different substances. Tobacco smoke is a complex mixture of several thousand individual constituents, and therefore it would not be surprising to find that these diverse substances are able 18 to produce more than one adverse biologic response. It is also not surprising that these constituents may have possible additive, synergistic, or competitive actions with each other and with other agents in the environment. And fifth, there is'no reason to assume that the relationships between one factor and different diseases have similar explanations. The association between smoking and lung cancer, for example, is considered direct and causal, whereas that between cigarette smoking and cirrhosis of the liver is thought to be indirect, reflecting the association of cigarette smoking and heavy alcohol use by some segments of the population. In summary, despite the fact that the demonstration of specificity in an association makes a causal hypothesis more acceptable, lack of specificity does not negate such an hypothesis, since many biologic and epidemiologic aspects of the association must be considered. Temporal Relationship of the Association In chronic diseases, insidious onset and the lack of knowledge of precise induction periods automatically present problems on which came first-the suspected agent or the disease. In any evaluation of the significance of an association, exposure to an agent presumed to be causal must precede, temporally, the onset of a disease which it is purported to produce. The criterion of temporal relationship requires that exposure to the suspect etiologic factor precede the disease. Temporality is more difficult to establish for diseases with long latency periods, such as cancer. Prospective studies minimize this difficulty, although even prospective studies do not exclude the possibility that the disease was present in an undetected form prior to exposure to the agent. Histologic evidence demonstrating premalignant changes among individuals exposed to the agent, but not among unexposed controls, provides evidence that temporality is present. Experimental studies may also demonstrate a temporal association. Coherence of the Association The final criterion for the appraisal of causal significance of an association is its coherence with known facts in the natural history and biology of the disease. Coherence requires that descriptive epidemiologic results on disease occurrence correlate with measures of exposure to the suspected agent. Perhaps the most important consideration here is the observation of a dose-response relationship between agent and disease, that is, the progressively increasing occurrence of disease in increasingly heavily exposed groups. In some cases, multiple mea- sures of dosage are available. The natural history of disease would include observations on the progression of disease with continuing 19 exposure differing from its progression in those whose exposure is discontinued. In order to establish the coherence of a specific association, other possible explanations for the association must be systematically considered and excluded or taken into account. Coherence is clearly established when the actual mechanism of disease production is defined. Coherence exists, nonetheless, although of a lesser magni- tude, when there is enough evidence to support a plausible mecha- nism, but not a detailed understanding of each step in the chain of events by which a given etiologic agent produces disease. Causality for Specific Forms of Cancer The causal significance of an association is a matter of judgment which goes beyond any statement of statistical probability. In the following section, the relationship between smoking and several cancers is reappraised. Epidemiologic, pathologic, and experi- mental data form the basis for review. When a significant associa- tion between cigarette smoking and a specific cancer is noted, the nature of the association was assessed by applying the judgment criteria noted above. If all epidemiologic criteria were judged to be satisfied and pathological and experimental data are supportive, the term "causal" is applied to the association. The designation "major cause" is used when the relative risk for the cancer in cigarette smokers is high. The term "contributory factor" is used when the body of evidence is less compelling, the relative risk is lower, or the ancillary evidence (pathologic and experimental data) is not suffi- cient for a judgment of causality. The term "contributory factor" by no means excludes the possibility of a causal role for smoking in cancers of those sites. The term "association" is used when a relationship between smoking and a cancer site exists, but the data are inadequate for an assessment of the character of that relation- ship. 20 SMOKING-RELATED CANCERS BY SITE Lung Cancer Introduction Since the early 1950s lung cancer has been the leading cause of cancer death among males in the United States; among females, the lung cancer death rate is accelerating faster than all other cancer death rates and, if present trends continue, will likely surpass that of breast cancer by the mid-1980s (2) (Figure 1). Between 1950 and 1977 in the United State~,~ the total number of lung cancer deaths increased from 18,313 in 1950 to 90,828 in 1977 (the figure for 1977 includes ICD (International Classification of Diseases) Nos. 162-163.0). The American Cancer Society estimates there will be 129,000 new lung cancer cases diagnosed in 1982 and 111,000 deaths. Of this number, 80,000 will be men and 31,000 women. The age-adjusted lung cancer mortality rate for the total population nearly tripled, rising from 11.1 to 32.7. (All age-adjusted death rates, unless stated otherwise, were derived by applying the age-specific rates to the standard population distributed by age as enumerated in 1940.) Overall lung cancer mortality rates increased over this period at a decelerating pace. Thus, in the 1950-1957 interval, the average annual increase in the age-adjusted death rate was 5.2 percent; over the next 10 years, the average annual increase was 4.0 percent; and in the final lo-year interval, 1968-1977, the rate of increase was 3.1 percent. These sex-aggregated figures hide differences in the lung cancer mortality trends of males and females (Figures 2,3, and 4). In the 28 year period from 1950 to 1977, the age-adjusted lung cancer rate increased almost 200 percent for men' and over 250 percent for women. The most striking aspect of this trend is the acceleration in lung cancer mortality among females. The age-adjusted death rate of white females increased by an average of 1.0 percent per year between 1950 and 1957,5.5 percent per year between 1958 and 1967, and 6.7 percent per year between 1968 and 1977. The corresponding increases for all other females were 3.0,5.1, and 6.6 percent per year. (The term "nonwhite" represents all races other than white and is used in most graphics throughout this Report for the sake of brevity.) In contrast to this trend in females, the rate of increase slowed down in males. After climbing an average of 6.1 percent a year from 1950 to 1957, the rate among white males rose 4.0 percent annually from I958 to 1967, and 2.1 percent a year from 1968 to 1977. The rate of increase among all other males fell from 8.7 to 6.2 to 3.6 percent per year over these intervals. Even with this deceleration in the rising ' Unless otherwise stated, all cancer mortahty data cited in thrs Report were extracted from the volume "Mortality From Diseases Assocmted With Smoking: Umti States, 196677" 1200). For a detaled dlscussmn oi these data as well as trends for other diseases related to smoking the reader is referred to that volume. 21 FEMALE 90 60 MALE` 7-r FIGURE I.-Male and female cancer death rates* by site, United States, 1930-1978 * Age-adjusted to the U.S. population as enumerated in 1970. SOURCE American Cancer Society (21 22 male lung cancer rate, an examination of the age-specific rates in Figures 3 and 4 reveals that the lung cancer rates are still markedly greater in males than in females. In the white population, these trends resulted in a decrease in the sex ratio of lung cancer mortality rates between males and females. In 1950, the age-adjusted lung cancer death rate was 4.7 times higher in white males than in white females. By 1977, the mortality sex ratio had dropped to 3.6. In the white population 35 to 44 years of age, the mortality sex ratio decreased from 3.74 to 1.72 over this period. In contrast, the mortality sex ratio (male/female) of the other than white group increased from 4.11 to 4.54 from 1950 to 1977. Particularly in the early part of the study period, mortality among males other than white climbed sharply. In 1950, the ratio of the,age- adjusted death rate of all other males to that of white males was 0.77; by 1977, age-adjusted death rates of all other males had surpassed those of white males. The mortality color ratio (other- than-white/white) had risen to 1.25. Among females, the mortality color ratio shifted from 0.88 in 1950 to 1.00 in 1957, after which it remained stable. In females 35 to 44 years of age, however, rates were consistently higher in the other than white group than in the white group. When age-specific lung cancer death rates are plotted by calendar year and age, a three-dimensional graph is produced (Figures 5 and 6) which can be examined from 1950-1977, or from the reverse (back side) perspective. The broad, ascending peaks reflect the dramatic rise in lung cancer rates for men and women over this time interval. The lower age-specific lung cancer death rates seen in the oldest age group (Figures 5 and 6) reflect changing cohort patterns of exposure. Thus, what appears to be a decline in mortality rates with old age is actually an artifact arising from the combining of cohorts with different cigarette smoke exposure and mortality experiences. As will be discussed later, the age-specific mortality rate for each specific birth cohort actually continues to increase steadily with increasing age in both men and women (Figures 13 and 15). Lung cancer has a considerable economic impact. Rice and Hodgson (218) estimate that the health cost of lung cancer in 1975 was $3.8 billion in lost earnings, $379.5 million in short-term hospital charges, and $78 million in physician fees. Less than 10 percent of patients with lung cancer will survive 5 or more years. This bleak survival rate has not changed significantly over the last 15 years. Hence, the prevention of lung cancer is of paramount importance. According to a recent study.for the Congres- sional Office of Technology Assessment, approximately 85 percent of United States lung cancer deaths in 1978 were attributable to smoking, and thus were "avoidable" if individuals had not smoked cigarettes (70). 23 RRiES/lOO.OOO FIGURE L-Age-adjusted* mortality rates for cancer of the bronchus, trachea, and lung, by race and sex, United States, 1950-1977 ' This graph is ageadJusted to the U.S. population as enumerated in 1970; all rates cited withm the text of the Report, however. are adjur.kd to the popula~mn as enumerated in 1940 SOURCE. National Cancer Instkute ,198). 24 K F: I2 " : N N RATES/lOO.OOO FIGURE 3.-Age-specific mortality rates for whites in the United States for cancer of the bronchus, trachea, and lung SOURCE Nat,onalCancerInstltute,19XI. 25 0 P z : " 0 N N RRTES/lOO.OOO FIGURE 4.-Age-specific mortality rates for nonwhites in the United States for cancer of the bronchus, trachea, and lung SOURCE: Nst~onal Cancer Institute (1981. 26 I I I I 1 IIIIIIIIIII llll~llllllllllll~ ~llIIIIlIIIIIIlI Id IGO ?IGURE B.-Age-specific mortality rates by &year age groups for cancer of the bronchus, trachea, and lung for white males, United States, 1950- 1977 SOURCE: Natronal Cancer Institute ,198) The term "lung cancer" refers to a number of specific malignant iseases involving the lungs. Several systems of classifying lung ancer have been proposed (Table 1). Four cell types constitute the majority of lung cancers: epidermoid r squamous, adenocarcinoma, small cell (oat cell), and large cell. `here are differences in the frequency distribution of the different 27 377-310 0 - 82 - 4 FIGURE 6.-Age-specific mortality rates by B-year age groups for cancer of the bronchus, trachea, and lung for white females, United States, 1950-1977 SOURCE Natmnal (`ancer Instltute~ 198IHI types of lung cancer in males and females and in smokers and nonsmokers. Epidermoid carcinoma was the most common histologi- cal type of lung cancer in the male smoker, while adenocarcinoma was most common in the female smoker and in nonsmokers of both sexes in a series recently published from the Mayo Clinic (Table 2) (225). Other centers have reported similar data, although the 28 FABLE l.-Comparison of the World Health Organization (WHO), Veterans Administration Lung Cancer Chemotherapy Study Group (VALG), and Working Party for Therapy of Lung Cancer (WP-L) Lung Cancer Classifications WHO -_ I. Epidermoid carcinoma VALG WP-L 11' Small cell carcincma 1. Fusiform 2. Polygonal 1. Squamous cell carcinoma 10. Epidermoid carcinoma a. With abundant keratin 11. Well differentiated b. With intercellular bridges 12. Moderately differentiated c Without keratin or 13. Poorly differentiated bridges 2. Sma:! cell carcinoma 20. Small cell carcinoma a With oatcell structure 21. Lymphocytelike h. With polygonal cell 22. Intermediate cell structure 3. Lymphocytelike 4. Others III. Adenocarcinoma 1. Bronchogenic a. Acinar h. Papillary 2. Bronchoalveolar IV. Large cell carcinoma 1. Solid tuaor with mucin 2. Solid tumor without mucin 3. Giant cell 4. Clear cell 3. Adenwarcinoma 30. Adenocarcinoma a. Acinar 31 Well differentiated b. Papillary 32. hloderately differentiated c. Poorly differentiated 33. Poorly differentiated 34. Bronchiolopapillary 4. Iarge cell undifferentiated 40. Large cell carcinoma 41. With stratification 42. Giant cell 43. With mu& formation 44. Clear cell SOURCE: Matthews and Gordon (176). proportions by histological type vary with the pathological criteria used, the patient population, the geographic location, and other factors. Earlier epidemiologic studies suggested that cigarette smok- ers were more likely to develop squamous cell, large cell, and small cell lung carcinoma than other types (67, 148). This view has been supported by some investigators (54, 284) and disputed by others (6, 18, 19, 137, 293. 329). More recent investigations indicate that all four major histological types of lung cancer-including adenocarci- noma, which appears to be increasing in recent years-are related to cigarette smoking in both males and females (8, 284, 293). Establishment of the Association Between Smoking and Lung Cancer It is not ethical or feasible to perform a controlled experiment in humans to establish a causal relationship between tobacco smoking and lung cancer. Practically, epidemiological methods are employed to test a causal hypothesis. These methods, as discussed previously, when coupled with pathological and experimental data, provide the framework for a judgment of causality. 29 TABLE Z.-Histologic types of pulmonary cancers in smokers and nonsmokers Type TOtal Smokers Smokers Epidermoid 992 892 7 80 13 Small cell 640 533 4 100 3 Adenocarcinoma 760 492 39 128 101 Large cell 466 389 16 46 15 Bronchi&alveolar 68 35 4 13 16 TOtal 2,926 2,341 70 367 148 SOURCE: Rosenow 1225) Numerous retrospective studies have examined smoking patterns among established cases of lung cancer and a variety of matched controls. These studies have been summarized and reviewed in previous reports from the Department of Health and Human Services (270,272-281). Eight prospective studies have measured lung cancer mortality rates among smokers and nonsmokers followed over various time intervals. In October 1951, Doll and Hill (62, 63) initiated the first major prospective study of the relationship between smoking habits and mortality in a cohort of more than 40,000 male and female physicians. By 1965, seven other major prospective studies in four countries had been initiated. These studies cumulatively represent more than 17 million person-years of observation and over 330,000 deaths. The study designs are summarized below and in Table 3. The number of years of followup reported for the various major prospective studies ranges from a low of 4 years in the American Cancer Society Nine-State Study to 22 years for females in the British Physicians Study. Published reports for the varying followup periods differ substantially for each study with respect to the amount of information provided. Data from the Japanese study have been published presenting 5, 8, 10, and 13 years' results. For each followup period, site-specific cancer mortality is fragmented. Data for specific cancer sites are available only for males from the 13-year followup study; dosage analyses for other cancer sites for either males or females are intermittent among the many published reports cited. In all cases, the most current data from each of the prospective investigations are cited. In some instances, mortality rates (or ratios) for all smokers for a specific site may be from one study period while dosage information (usually expressed as the number of cigarettes smoked per day) may be from another (followup) period. The reader is referred to the references cited at the end of each study description for a complete bibliography. 30 The British Physicians Study In.1951, the British Medical Association forwarded to all British doctor% a questionnaire about their smoking habits. A total of 34,400 men and 6,207 women responded. With few exceptions, all physi- cians who replied in 1951 were followed to their deaths or for a minimum of 20 years (males) or 22 years (females). Further inquiries about changes in tobacco use and some additional demographic characteristics of the men were made in 1957,1966, and 1972 and of the women in 1961 and 1973. By 1973 more than 11,000 deaths from all causes had occurred in this population (62-66, 68, 69, 71). The American Cancer Society 25State Study In late 1959 and early 1960, the American Cancer Society enrolled 1,078,894 men and women in a prospective st.udy (97-102, 155). Although this was not a representative sample of the United States population, all segments of the population were included except groups that the planners believed could not be traced easily. An initial questionnaire was administered that contained information on age, sex, race, education, place of residence, family history, past diseases, present physical complaints, occupational exposures, and various habits. Information on smoking included type of tobacco used, number of cigarettes smoked per day, inhalation, age started smoking, and the brand of cigarettes used. Nearly 93 percent of the survivors were successfully followed for a la-year period. Early reports of this study examined lung cancer mortality in relationship to several parameters of smoke exposure, including duration of habit and age at onset, among others. Two recent reports have examined the effects of general air pollution (101), the type of cigarette smoked (155), and lung cancer mortality. Cancer mortality data for 483,000 white females and 358,006 white males for the period 1967 to 1971 were also recently reported (106). The U.S. Veterans Study The U.S. Veterans study (74, 131, 222-224) followed the mortality experience of 290,000 U.S. veterans who held government, life insurance policies in December 1953. Almost all policyholders were white males. The data for specific causes of death during a 16year period were recently reported by Rogot (224) and are similar to earlier data published after only S'/, years of observation of this population (131). Over 107,000 deaths have occurred in this popula- tion. The Japanese Study of 29 Health Districts In late 1965, a total of 265,118 men and women in 29 districts in Japan were enrolled in a prospective study (115-120). This represent- 31 ed from 91 to 99 percent of the population aged 40 and older in these districts. This study provided the unique opportunity to examine the relationship of cigarette smoking to death rates in a population with genetic, dietary, and cultural differences from previously examined Western populations. By the end of the 13th year of followup, almost 40,000 deaths had occurred, including 10,300 cancer deaths, and there were over 3,000,OOO person-years of observation. For females, the main body of published data is based on 5 to 8 years of followup. The Canadian Veterans Study Beginning in 1955, the Canadian Department of National Health and Welfare enrolled 78,000 men and 14,000 women in a study of smoking-related mortality (26, 27). Information was obtained on age, detailed smoking history, residence, and occupation. During the first 6 years of followup, 9,491 males and 1,794 females died. No more recent followup has been reported. The American Cancer Society Nine-State Study In the American Cancer Society Nine-State Study (104, 105), 187,783 white males were followed for an average of 44 months. This study began in early 1952. There were 11,870 deaths in the age 50 to 70 population. The last major report of this study was published in 1958. The California Men in Various Occupations Study This study (76, 290) examined the mortality experience of 68,153 men, 35 to 64 years of age, over a period of 482,650 person-years of observation. A total of 4,706 deaths occurred. These men were in nine occupational groups. The last published report from this study was in 1970. The Swedish Study A national probability sample (42) of 55,000 Swedish men and women was surveyed in 1963 by mailed questionnaires, to which 89 percent of the sample responded. Information was collected on smoking status at the time of the initial query and for specific intervals during the previous 9 years according to type and amount of smoking and degree of inhalation. The questionnaire identified age, sex, location (urban, nonurban), income, and occupation of subjects. A lo-year followup on smoking-related mortality was published in 1975. 32 TABLE 3.-Outlin9 of eight major prospective studies Doll Dorn Best Weir cederlof Authors Hill Hammond Kahn Himyama Joeie Hammond Dunn fiberg Pet0 Ronot Walker Horn Linden Hrubec Pike Breelow lmich Males end Total population California Probability British fern&e U.S. of Canadian White malee sample of Subjects in 29 health males in doctors in the 25 veterans districts in various pensioners nine states Swedish States Japan urupetiona population Population size w@o WW@J 2%m -2%~ 92.~ 187.ou) woo %ooo Females 6,~ 562,671 1.78 13.06 17.00 > 3.70 Comments Swedish Study Nonsmoker None Light DeeP 1.00 1.00 Female data 3.70 - based on only 7.80 7.20 9 total lung 9.20 .l.SO cancer deaths Temporal Relationship of the Association The criterion of temporality requires that cigarette smoking antedate the onset of cancer. Suppdrt for this criterion is provided by all the major prospective studies in which an enormous number of initially disease-free subjects were followed over varying time intervals. 39 LUNG CANCER I. MALES 80 70 60 xl 40 30 20 10 N: CASES CONTROLS NON F NF F NF F NF F NF F NF SMOKER l-10 11-20 21-30 3140 41+ NO. OF CtGARETTES SMOKED PER DAY xl 25 126 iz FIGURE 7.-Relative risk of lung cancer for males, by number of cigarettes smoked per day and long-term use of filter (F) or nonfilter (NF) cigarettes SOURCE: W'ynder (3271 Indirect support for the temporality of the association is provided by other studies (57, 70). One study (57) examined the relationship between per capita tobacco consumption in 1930 and male lung cancer death rates in 1950 in I.1 different countries (Figure 9). This study encompassed the era prior to the advent of filter cigarettes. Assuming that the majority of tobacco consumption in 1930 occurred among males and that there was a 20-year latency period for the development of lung cancer, there was a strong positive correlation between tobacco consumption in 1930 and lung cancer death rates in 1950. 40 LUNG CANCER I. FEMALES CASES N: CONTROLS NON F NF SMOKER l-10 F NF F NF F NF 11-20 21-30 31+ NO. OF CIGARETTES SMOKED PER DAY FIGURE 8.-Relative risk of lung cancer for females, by number of cigarettes smoked per day and long-term use of filter (F) and nonfilter (NF) cigarettes SOURCE: Wynder (327). A later study (70) examined the relationship between manufac- tured cigarette consumption per adult in 1950 and lung cancer death rates in males and females who were in the 35- to 44-year-old age group in the mid-1970s (who had entered adult life in 1950). There Was a consistent correlation between cigarette consumption and lung cancer death rates in different countries (Figure IO), a finding which WaS "better than...expected in view of the possible international differences in cigarette composition, puff frequency, style of inhala- tion, butt length, additional use of nonmanufactured cigarettes (and other forms of tobacco), and national consumption of cigarettes in intervening years between 1950 and 1975." 41 TABLE 9.-Age-adjusted lung cancer mortality ratios for males and females, by tar and nicotine in cigarettes smoked M&S Females - -. High T/N 1.00 1.00 \ Medium T/S 0.95 0.79 Low T/N 0.81 0.60 the *The mortality rstm for the category with highest risk was made 1.00 90 that the relative reductions in fia nJ use of lower T/N cigarettes could be visualiud. SOURCE: Hammond et al. c 1031 Additional evidence for the temporality of this association b advanced by a number of histological studies showing that smoke& develop histologic changes interpreted by most pathologists a premalignant lesions in bronchial epithelium in much greater proportions than nonsmokers, and that these changes progra toward cancer in continuing smokers but reverse in ex-smokers (9 14, 15) (Table 14). Coherence of the Association The final criterion is the coherence of the association betwwc smoking and lung cancer with known facts in the biology and natural history of lung cancer. Coherence of the association has been noted with the following facts: Dose-Response Relationship Between Smoking and Lung Cancer Mortality The finding of a dose-response relationship between cigarette smoking and lung cancer provides great coherence with the known facts of the disease. Regardless of the measure of tobacco consump tion employed (i.e., number of cigarettes smoked, inhalation practice, duration of smoking, age when smoking began, or type of cigarettes smoked), there was a gradierut of disease consistent with a true dose response relationship in ever:y study. Sex Differences in Lung Cancer Mortality Correlating With Corresponding Differences in Smoking Habits Males have had higher lung cancer death rates than females. This observation has been interpreted by some as contradictory to the causal role of smoking in lung cancer (8.2, 167). However, a careful examination of smoking patterns and age-specific mortality data ha 42 GREAT BkTAIN # I I I I I CIGARETTE CONSUMPTION FIGURE 9.-Crude male death rate for lung cancer in 1950 and per capita consumption of cigarettes in 1930 in various countries SOURCE. DOII 1.57, been interpreted by most observers as support for the causality of smoking in lung cancer. Historically, males began to smoke in large numbers in the World War I period, and much of the increased cigarette use noted during this period reflected switching from other forms of tobacco (e.g., smokeless tobaccos, pipes, and cigars) to cigarettes. Females began to smoke in larger numbers about 20 to 25 Years later, in the World War II era (270); at that time, a smaller Proportion of females smoked compared to males, and those who did, generally smoked fewer cigarettes per day, inhaled less, started later in life, and were more likely to smoke lower tar and nicotine and filtered cigarettes. These differences in smoking habits of males and 43 377-310 0 - 82 - 5 a Ratesbasedcmow100~~ 0 Rateabased0n25-1OOdeah 0 U.S. non-smokers 19%197p SMOKED 0` 1 t 1 1 500 1000 lWC! 2ooo 2500 3aoo MANUFACTUREIY ClGARElTES PER AWLT IN 1950 FIGURE lo.-International correlation between manufactured cigarette consumption per adult in 1959 while one particular generation was entering adult life (in 19501, and lung cancer rates in that generation as it enters middle age (in the mid-i97Os) NOTE Comparison has been restricted to developed countries (i.e.. excluding Africa, all of Asia except Japan. and all except North Amencsl. with populations > 1 million, Lo impmve the accuracy of the &sewed death certification rates aa indicators of the underlying riskn of lung cancer among people aged 3&44. `Lung cancer death certification rates per million. adults aged 3544 are from WHO 003,304l These rates are the means of the male and female rates for all yews (1973.1974. or 1975) reported in WHO (303). except for Greece (which was not reported in WHO (3031 and thus was taken from WHO (Xl0 and Norway for which the rates in WHO 130.X and WHO 1304I were based on only 11 and 14 cases, respectively; for statistical stability, these welp averaged. "Manufactured cigarettes per adult are from Lee (Jw for the year 1950 Iexcept for Italy. where consumption data are available in 5-year groups onlyl; to avoid tl'le temporary postwar shortages. data for 1951-55 have been used. This excludes handrolled cigarettes, which in most countries accounted for only a small fraction of all cigarette tobacco in 1950. `U.S. nonsmoker rates were estimated by fitting straight lines (on a double logarithmic eeale) to the relationship between lung cancer mortality and age reported for male and for female lifelong nonsmokers by Gartinkel(86) and averaging the plpdicted values at age 40. (Although the average of the male and female rati actually observed at these ages is sinular to this estimated value. thew observed rates are each based on fewer than five c~dc8 tGarfinkell(86l and so might have been inaccurate.l SOURCE: Doll and Peto( 70). females correlate well with the observed sex differences in lung cancer mortality rates. In fact, the rise in female lung cancer mortality rates observed in the late 1950s and early 1960s appears to be reproducing the phenomena noted among males 20 to 30 years earlier. If one subtracts 25 years from the female cancer death rate, as noted previously in Figure 1, the rates for women are only slightly below the rates for men. Thus, close scrutiny of these trends reveals 44 no substantial difference in the risk of developing lung cancer between men and women. Lung Cancer Mortality and Cessation of Smoking Since cigarette smoking is significantly associated with lung cancer, it is logical to expect that cessation of smoking would lead to a decrease in mortality rates from lung cancer among quitters compared to persons who continue to smoke cigarettes. In fact, all of the major studies which examined cessation showed this decrease in lung cancer risk. Data from four of the major prospective studies are presented in Table 10 for illustration. After 15 to 20 years, the ex- smoker's risk of dying from lung cancer gradually decreases to a point where it more closely approximates the risk of the nonsmoker (68, 224), whereas for the continuing cigarette smoker, the lung cancer risk is more than 10 times that of the nonsmoker. The magnitude of the residual risk that ex-smokers experience is largely determined by the cumulative exposure to tobacco prior to smoking cessation (i.e., total amount the individual smoked, age when smoking began, and degree of inhalation), and varies with number of years since quitting smoking, as well as with the reasons for quitting smoking (e.g., quitting due to symptoms of disease). Differences in Lung Cancer Mortality by Site of Residence (Urban Versus Rural) A number of studies have examined the relationship of smoking to lung cancer mortality by site of residence (urban or rural) and air quality of a community. Eight of the earlier studies were reviewed in the 1971 Report of the Surgeon General (276). More recent publica- tions include "Epidemiological Review of Lung Cancer in Man" (111) and the report of a task group, "Air Pollution and Cancer" (41). There have been studies in England and Wales (59), in 20 countries combined (40, 291), as well as in the United States (101, 146, 164, 258). The majority of these studies has found that lung cancer mortality is more common in urban than rural areas. This urban to rural gradient is primarily, but not exclusively, found among smokers. Since cigarette consumption is generally greater in urban areas than in rural areas, it is difficult to define conclusively what proportion, if any, of the excess lung cancer mortality in city dwellers can be accounted for by urban living independent of smoking. One study (164) examined the risk of several cancers by religion and place of residence in 20,379 cases in the State of Utah. Members of the Church of Jesus Christ of Latter-Day Saints (Mormons) composed approximately 70 percent of the state's population in 1970. The use of tobacco and alcohol is prohibited by religious tenets, and it is documented that Mormons have a very low proportion of 45 TABLE IO.-Lung cancer mortality ratios in ex-cigarette smokers, by number of years stopped smoking U.S. Veterans ' `Years stopped Study smoking Mortality ratio British Physicians 14 16.0 5-9 5.9 10-14 5.3 15 + 2.0 Current smokers 14.0 l-4 18.83 5-9 7.73 lo-14 4.71 15-1s 4.81 20+ 2.10 Current smokers 11.28 l-4 4.65 5-9 2.56 10 + 1.35 Current smokers 3.76 ACS 2.5-Stat.e Study (males 50-69) - 600 - 500 - g 400 - 4 ii 30.0 - i 200 - mz 2 c" 2 10.0 - 90 - 80 - 7.0 - 6.0 - 50 - 40 - 3.0 - 20 - 10 - 09 - 06 - 07 - 06 - 05 - WHlTE MEN 5054 *err FIGUflE 16.-Mortality rates for malignant neoplasm of the trachea, bronchus, and lung, for white men and white women, by birth cohort and age at death, United States, 5-year intervals during 1947-1977 SOURCE!National Center for Health Statistics 1200). 56 WWTE WOMEN ICOO - So0 - WI0 - 700 - 600 - 500 - 400 - 3Jo - M.0 - 100 - so - 6.0 - 70 - 60 - 50 - 40 - 30 - 20 - FIGURE 16, continued.-Mortality rates for malignant neoplasm of the trachea, bronchus, and lung, for white men and white women, by birth cohort and age at death, United States, Byear intervals during 1947-1977 SOURCE. Natmnal Center for Health StatistmG?GOI. 57 16 years NON- SMOKERS I I I I I I I I I I I I 0 2 4 6 0 10 12 14 16 18 20 22 24 MORTALITY RATIO FIGURE 17.-Lung cancer mortality ratios for male smokers by amount smoked, S'/,- and l&year followup, U.S. Veterans Study in 11.4 percent of sections from males who smoked two or more packs a day, and in 14.3 percent of sections from smokers who died of lung cancer. Studies by the same authors and others (7, 10, 28, 39, 51, 89, 96, 144, 206, 217, 233, 268,298, 319) have confirmed this relationship between smoking and premalignant changes in bronchial epithelium in males and females, with and without lung cancer. More recent investigations (121, which examined the histologic changes in the bronchial epithelium of male cigarette smokers who had died from causes other than lung cancer, found that changes occurred far less frequently in nonsmokers than in cigarette smokers. Changes in smokers correlated with the amount smoked. When comparing the degree of histologic changes of men who died in 58 TABLE 14.-Percent of slides with selected lesions,8 by smoking status and presence of lune cancer Group Number Number CaSeS slides Percent of slides with cilia absent and averaging 4 or more cell rows in depth No cel!s Some cells All cells atypical atypical atypic& Total Cases without lung cancer Never smoked regularly 65 Excigarette smokers 72 Cigarettes-`/, pk. a day 36 Cigarettes-V-1 pk. a day 59 Cigarette-l-2 pks. a day 143 Cigarettes-2+ pks. a day 36 Lung cancer cw 63 3,324 1.0 0.03 - 1.1 3,436 3.5 0.4 0.2 4.1 1.624 0.2 4.2 0.3 4.1 3,016 - 7.1 0.8 7.9 7.062 12.6 4.3 16.9 1,787 - 26.2 11.4 37.5 2,784 - 12.5 14.3 26.8 "In some sectmns. two or more lesmns were found. In such mstances. all of the lesions were counted and are Included in both mdiwdual columns and in the total column of the table. Lesions found at the edge of an uicer were excluded "These laions may be call& carcmoma m-situ. `Of the 63 who died of lung cancer. 55 regularly smoked cigarettes up to the time of diagnosis. 5 regularly smoked cigarettes but stopped before diagnosis. 1 smoked cigars. 1 smoked pipe and cigars. 1 was an occasional cigar smoker. SOURCE. Auerbach 19. 14. 151 the period 1955-1960 with those who died in 1970-1977, these investigators found the latter exhibited less advanced histologic changes. The authors attributed this finding to the reduced tar and nicotine yield of cigarettes smoked by this group when compared to the average tar and nicotine yield of those smoked by the earlier group (Table 15). Several investigators have examined the relationship between smoking and cytological changes in respiratory epithelial cells shed into sputum in groups of smokers and nonsmokers. These studies (171, 193, 220, 262) have generally found increased proportions of sputum specimens showing atypical cells among smokers as com- pared with nonsmokers, and these changes have progressed toward cancer with increasing duration of the smoking habit. In addition, these changes have reverted toward normal in individuals who stopped smoking. These data support the causal nature of the association between smoking and lung cancer. Experimental Studies Over the past 30 years, a number of experimental models have been developed to study tobacco-induced carcinogenesis. These data are explored in detail in the Part of this Report on the mechanisms of carcinogenesis. Lung Cancer and Non-Cigarette Tobacco Use The relationship between lung cancer and other forms of tobacco was comprehensively reviewed in reports by the U.S. Public Health 59 377-310 0 - 82 - 6 TABLE l&-Percentage of sections with each of several categories of histologic change, classified according to smoking habit * Adjusted % Adjusted % Adjusted % Adjusted % Never Smoked Smoked 1-19 Smoked 2CX39 Smoked 40+ HiSt&giC Regularly Cigarettes/ Cigarettes/ Cigarettes/ change hY DRY Day A B A B A B A B Basalcell hyperplasia: Total 6+ rcnvs IO%+ cells with atypical nuclei 30%+ cells with atypical nuclei 50%+ cells with atypical nuclei 70%+ cells with atypical nuclei Lesion with cilia absent: T&d lo%+ cells with atypical nuclei 30%+ cells with atypical nuclei 50%+ cells with atypical nuclei 70%+ cells with atypical nuclei 100% cells with atypical nuclei No. of sections No. of subjects 3.8 5.8 0 0.1 0.1 0.5 0.1 0.4 0 0.1 0 0 5.3 4.2 0 ,8 cigars per day.. . . . . Pipe smokers: < 5 pipefuls per day.. . . . . . . . . . . 5 to 19 pipefuls par day . . . . . . . > 19 pipefuis per day . . . . . . . . . Cigar and pipe: 8 or lean cigars, 19 or leas pipefuls . . . . . > 8 cigars, > 19 pipefuls . . . . . . . . . . . . . 12 11 2 1.00 78 1.14 264 207 .77 220 247 2 12 3 1.62 18 219 2 SOURCE: Kahn (131). response relationship; however, the relationship is not as strong as that noted for cigarett.e smoking. A few retrospective studies contain adequate numbers of smokers tc allow an examination of dose-response relationships between pipe and cigar smoking and lung cancer (I, 161, 215, 230). An increased risk for developing lung cancer correlated with the increased use of pipes and cigars as measured by amount smoked and depth of inhalation. 61 Several investigators have examined histological changes in lungs of cigar and pipe smokers. One study (15) examined 36,340 histologic sections for various epithelial lesions obtained from 1,522 white adults. The numbers and types of pathological findings in the bronchial epithelium of pipe and cigar smokers were compared with those found in nonsmokers and cigarette smokers. Pipe and cigar smokers had abnormalities that were intermediate between those of nonsmokers and cigarette smokers, although cigar smokers had pathological changes that in some categories approached the changes seen in cigarette smokers. Others have reported similar findings (144, 233). Several experimental investigations have been conducted to examine the relative tumorigenic activity of tobacco smoke conden- sates obtained from cigarettes, cigars, and pipes. Most of these studies were standardized in an attempt to make the results of the cigar and pipe experiments more directly comparable with cigarette data, and most used the shaved skin of mice for the application of tar. Tar from cigars, pipes, and cigarettes was usually applied on an equal weight basis so that qualitative differences in the tars could be determined. In several experiments, the nicotine was extracted from the pipe and cigar condensates in an attempt to reduce the acute toxic effects that resulted from the high concentration of nicotine frequently found in these products (50, 53, 127, 138, 221, 328). These experimental data suggest that cigar and pipe tobacco condensates have a carcinogenic activity that is comparable to cigarette conden- sates. This is supported by human epidemiologic data for those sites exposed equally to the smoke of cigars, pipes, and cigarettes. The alkaline smoke derived from pipes and cigars is generally not inhaled, and as a result there appears to be a lesser exposure of the lungs and possibly other organs to pipe and cigar smoke than that which occurs due to cigarette smoking. Further, evidence from countries where smokers tend to inhale cigar smoke to a greater degree than smokers do in the United States (I) indicates that rates of lung cancer become elevated to levels approaching those of cigarette smokers. Conclusion 1. Cigarette smoking is the major cause of lung cancer in the United States. 2. Lung cancer mortality increases with increasing dosage of smoke exposure (as measured by the number of cigarettes smoked daily, the duration of smoking, and inhalation pat- terns) and is inversely related to age of initiation. Smokers who consume two or more packs of cigarettes daily have lung cancer mortality rates 15 to 25 times greater than nonsmokers. 62 3. Cigar and pipe smoking are also causal factors for lung cancer. However, the majority of lung cancer mortality in the United States is due to cigarette smoking. 4. Cessation of smoking reduces the risk of lung cancer mortality compared to that of the continuing smoker. Former smokers who have quit 15 or more years have lung cancer mortality rates only slightly above those for nonsmokers (about two times greater). The residual risk of developing lung cancer is directly proportional to overall life -time exposure to cigarette smoke. 5. Filtered lower tar cigarette smokers have a lower lung cancer risk compared to nonfiltered, higher tar cigarette smokers. However, the risk for these smokers is still substantially elevated above the risk of nonsmokers. 6. Since the early 195Os, lung cancer has been the leading cause of cancer death among males in the United States. Among females, the lung cancer death rate is accelerating and will likely surpass that of breast cancer in the 1980s. 7. The economic impact of lung cancer to the nation is consider- able. It is estimated that in 1975, lung cancer cost $3.8 billion in lost earnings, $379.5 million in short-term hospital costs, and $78 million in physician fees. 8. Lung cancer is largely a preventable disease. It is estimated that 85 percent of lung cancer mortality could have been avoided if individuals never took up smoking. Furthermore, substantial reductions in the number of deaths from lung cancer could be achieved if a major portion of the smoking population (particularly young persons) could be persuaded not to smoke. Cancer of the Larynx Introduction Cancer of the larynx was responsible for about 1 percent of cancer deaths in the United States in 1977. It is estimated that in 1982 there will be 10,900 new cases and 3,700 deaths due to this disease (2). Males are affected more commonly than females, but the ratio of new cases and deaths in males and females (now about 6:l) has been narrowing over the last 20 years (240,312). In 1950,1,852 people died of cancer of the larynx. By 1977, this figure had nearly doubled, rising to 3,390. The age-adjusted death rate increased slightly, from 1.1 to 1.2 per 100,000 (Figure 18). There is a considerable difference in this increased death rate when examined by sex and race. Among other than white males, the age-adjusted rate climbed from 1.6'to 3.5 per 100,000 between 1950 and 1977. By contrast, age-adjusted rates of white males rose less, from 2.0 to 2.1. As is seen with lung cancer, mortality rates of females were lower than those of males throughout the study period. Ejetween 1950 and 1977, the age-adjusted mortality rate for white 63 2 +=WHITE HRLES %=UHITE FEHRLES O=NONWHITE IIRLES O II=NCtNHHITE FEllALES 1 ""`0 " 1' `1 1' ' 1" c ' I 1960 1965 1960 1965 1970 1975 CRLENDFIR YEARS females increased from 0.2 to 0.3 per 100,000, while that of other than white females increased from 0.3 to 0.6 per 100,000. Generally, there was a pattern of increasing mortality after middle age (Figures 19 and 20). Among white males 55 years of age or older, mortality rates from cancer of the larynx were higher in 1977 than in 1950. Among other than white males, this pattern was evident for those 35 years of age or older. Both white and other females 45 to 74 years of age had higher mortality rates in 1977 than in 1950. Squamous cell carcinoma is the most common cell type among laryngeal cancers. Approximately 70 percent of the cases involve the glottis and 25 percent involve the supraglottic region. In contrast to lung cancer, the 5-year survival for cancer of the larynx is at present about 60 percent (2). and has been improving over the past 15 years. As a result, the trend over time in death rates from cancer of the larynx is not an accurate reflection of the incidence of this disease. Over the last 30 years, numerous epidemiological, pathological, and experimental investigations have established a strong associa- tion between smoking and cancer of the larynx. One group of scientists (296) conducted a retrospective study of 3,924 patients attending a cancer clinic in Alberta, Canada. The authors estimated that 84 percent of laryngeal cancer among men could be attributed to smoking. Causal Significance of the Association Consistency of the Association More than 25 retrospective studies have examined the relation- ship between smoking and laryngeal cancer. These studies have employed diverse methodology and have been performed in different time periods and in different countries. Regardless of the study design, these studies have found a positive association between smoking and cancer of the larynx. Relative risk ratios for 12 studies up to 1968 (Table 18) were consistently above 2.0. Subsequent studies show similar findings (30,35, &, 52, 113, 114, 134, 142,202,254,296, 299,316,327). The TNCS study (299) and the Hawaiian Study of Five Ethnic Groups (113) have also reported a positive association. Data from studies of populations with low proportions of smokers (e.g., Mormons (165, 266,294) and Seventh Day Adventists (211)) show low laryngeal cancer rates. Six of the major prospective studies have examined the relationship between smoking and laryngeal cancer (Table 19); as in the retrospective studies, a large positive association was consistently noted. 65 fiALES Or 6 30 40 50 60 70 RGE IN YERRS ItJY S-YEAR AGE GROUPS) > I FEnRLES +=1950-1956 *=1957-1963 0 :1964-1970 [3 =1971-1977 10 20 30 40 50 60 76 RGE IN YERRS (BY 5-YEAR AGE CROUPS) 60 Ir FEHALES ? O 1950-1956 % =1967-1963 0 -1964-1970 r3=1971-1977 30 40 50 60 70 80 ROE IN YEARS (6y ~-YERR RGE GROUPSI TABLE lB.-Summary of results of retrospective studies of tobacco use and cancer of the larynx Relative risk rat& Investigator, (reference) all smoke= to nonsmokers Schrek et al., U.S.A. (2441 2.0 Valko, Czechoslovakia (28.2) 3.5 Sadowsky et al., U.S.A. (230) 3.7 Bliimlein, Germany (31) 27.5 Wynder et al., U.S.A. (309) 23.6 Wynder et al., India (309) 3.1 Schwartz et al., France (246) 4.6 Wynder et al., Sweden (3171 6.0 Wynder et al., Cuba (324) (18.9P (males only) DuttaChoudhuri et al., India (77) 4.3 Staxewski. Poland (252) (40.01 hales only) Svobcda, Czechoslovakia (261) 6.3 aComputed awording to the method of J. Cornfield (49). bFiires in parentheses represent ratios based on less than five case nonsmokers. TABLE 19.4Kortality ratios for cancer of' the larynx- prospective studies Study Population size of Cigarette deaths Nonsmokers smokers Comments ACTS S&ate Study 166,000 m&s 24 - All larynx - cancer deaths occurred in smokers British Physicians 34,ooO males 38 1.00 13.00 Includes cancer of larynx and other upper respiratory sites U.S. Veterans 230,mo males 116 1.00 ACS 25-State 356,000 males 67 1.00 Study 483,ooO females 11 100 California males 6smo males 11 - in 9 occupations 11.49 6.52 3.25 Includes buccal. pharyngeal. and laryngeal cancers >2.90 AI1 larynx cancer deaths occurred in smokew Japanese Study 122,OOQ males 38 1.00 13.59 142,800 females 6 1.M) 6.52 = Rat10 derived by comparmg smokers of half a pack with all other smokers 68 TABLE ZO.-Relative risk of laryngeal cancer for males and females bs amount smoked wx day* Number of cigarettes Per Day l-10 11-20 21-m 41+ l-20 21+ Relative NUIllbW Risk Males (N = 243) 16 4.4 a7 13.5 93 17.3 41 34.4 females (N = 48) 19 4.4 23 26.2 Coniidence Limits 1.6 - 12.6 5.3 - 33.1 6.8 - 44.2 12.3 - 96.1 * Risk relative to 1.0 ior nonsmokers. SOURCE: Wynder and Hoffmann (316-l. Strength of the Association In the retrospective studies, the relative risk of laryngeal cancer (Table 18) ranged from 2.0 in a study of 73 U.S. veterans (244) to 40.0 in,a Polish study of 207 males admitted to a chronic disease hospital (252). Two other studies (30, 316) found substantial increases in relative risk among smokers as compared with nonsmokers. Several studies have reported a strong dose-response relationship between the number of cigarettes smoked per day and laryngeal cancer mortality (299, 316). The mortality ratios for male and female cigarette smokers from one of these studies (316) are summarized by daily consumption in Table 20. One study (327) examined the impact of long-term filter cigarette usage on laryngeal cancer risk. After adjustment for duration of smoking, inhalation, and butt length, the relative risk for developing laryngeal cancer was decreased in male and female users of filter cigarettes compared to users of unfiltered cigarettes, although this risk was still substantially greater than that for nonsmokers (Figures 21 and 22). The American Cancer Society 25State Study data (155) also showed a reduced risk of laryngeal cancer among smokers of lower tar and nicotine cigarettes, but this reduction was not statistically significant. In the prospective studies, the mortality ratios for smokers ranged from over 3 among U.S. females to 13 or greater among Japanese males and British male physicians (Table 19). In two of the prospective studies, mortality ratios could not be accurately calculat- ed because all the deaths occurred in smokers, Several of these prospective studies have confirmed the strong dose-response rela- tionship reported in the retrospective studies (Table 21). Specificity of the Association The prospective studies have measured mortality data for a large number of diseases. The specificity of the association is evidenced by 69 CASES N: CONTROLS 10 5 NON F F NF F NF F NF F NF SMOKER l-10 11-20 21-30 3140 41+ 25 126 32 302 16 z FIGURE 21.-Relative risk of developing larynx cancer for males, by number of cigarettes smoked per day and use of filter (F) and nonfilter (NF) cigarettes SOURCE: Wynder (327). the mortality ratios of laryngeal cancer in comparison with other cancers (Appendix Tables A and B). Temporal Relationship of the Association This criterion is supported by the major prospective studies (Table 19) that examined the occurrence of laryngeal cancer in initially healthy groups of smokers and nonsmokers. The temporal relation- ship of the association is strengthened by data from post mortem studies that have evaluated vocal cord histology in groups of smokers and nonsmokers (II, 56, 190, 228). A spectrum of premalignant changes is seen in laryngeal tissue of smokers; this is not found in nonsmokers (see below). 70 45 35 25 15 6 N: CASES CONTROLS B ii v 61 8 NON F NF F NF SMOKER l-20 21+ FIGURE 22.~Relative risk of developing larynx cancer for females, by number of cigarettes smoked per day and use of filter (F) and nonfilter (NF) cigarettes SOURCE: Wynder (327). Coherence of the Association Dose-Response Relationship The finding of a dose-response relationship between smoking and laryngeal cancer incidence and mortality in retrospective and prospective studies strongly supports a causal association. Smoke exposure has been measured by the number of cigarettes smoked per day, the tar and nicotine content of the cigarettes smoked, the depth of inhalation, the number of years smoked, and the age at initiation (269,276), all of which support a direct causal relationship. 71 TABLE 21.-Laryngeal cancer mortality ratios, by amount smoked Population U.S. Veterans Study Japanese Study British Physicians Cigarettes/day Nonsmoker 1-9 l&20 21-39 > 40 Nonsmoker l-19 m-39 4Oi Nonsmoker l-14 15-24 2.5+ Mortality rates 1.00 5.23 9.20 14.78 32.14 ILKI 19.23 27.43 34.13 Male Female 1.00 1.00 5.00 - 7.00 4.00 33.ou 6.50 Comments `Based on less than 20 deaths Includes larynx and other respiratory sites Correlation of Sex Differences in Laryngeal Cancer With Different Smoking Habits Laryngeal cancer is predominantly a disease of males, although the mortality among females has increased over the past 20 years, A male-to-female ratio of 14.9:1 was reported in 1956 (312). The sex ratio decreased to 4.6:1 by 1976. This time trend is consistent with the later adoption of cigarette smoking by females (270) and a possible increase in female alcohol consumption, given the synergy between the two exposures. The greater alcohol consumption among males and the strong association between laryngeal cancer and alcohol consumption (see below) are considered to contribute to the excess of male to female laryngeal cancer mortality. Correlation of Laryngeal Cancer Mortality Among Populations With Different Tobacco Consumption In studies of populations with low proportions of smokers (e.g., Mormons and Seventh Day Adventists), the incidence of laryngeal cancer is substantially lower (79, 165, 166, 211, 294), supporting the causal relationship between smoking and laryngeal cancer. Laryngeal Cancer Mortality and Cessation .of Smoking A few studies have examined the relationship between cigarette smoking cessation and risk for laryngeal cancer. One retrospective study found a marked reduction in risk following cessation among males and females (Figures 23 and 24) and suggested that "10 to 15 years of cessation are required before the long-term smoker's risk approaches. that of a nonsmoker" (327). In the U.S. Veterans and British Physicians studies, ex-smokers had approximately 40 percent 72 N: CASES CONTROLS 16 12 6 4 PRESENT l-3 4-6 7-10 11+ NON SMOKER SMOKER FIGURE 23.-Relative risk of developing larynx cancer for male ex-smokers, by years of smoking tCK?SSation SOURCE: Wynder Wm. of the risk of current smokers for laryngeal cancer; however, the risk was still roughly five times that of the nonsmoker (68,224). Because data were not presented by the number of years off cigarettes, the higher relative risk may be due to higher mortality rates often observed in former smokers (even compared to continuing smokers! during the initial years of smoking cessation. Smoking and Histologic Changes in the Larynx The relationship of smoking habits to precancerous lesions of the larynx was examined in an autopsy series of 148 cases, 24 of whom were nonsmokers (190). Precancerous lesions (dysplasia and carcino- ma in situ) and carcinoma occurred least frequently among non- smokers (4.2 percent). The frequency of these lesions increased from 12.5 percent in light smokers to 22.9 percent in moderate smokers and to 47.2 p¢ in heavy smokers. Similar findings were reported 73 18 6 2 N: CASES 3 CONTROLS 72 SMOKER SMOKER 4-e 7+ NON FIGURE 24.-Relative risk of developing larynx cancer for female ex-smokers, by years of smoking cessation SOURCE. Wynder (3271 from a study of histological changes in the larynx of 942 males aged 21 to 95 (II). These findings lend support to a causal nature of the relationship. Laryngeal Cancer and Non-Cigarette Tobacco Use A few epidemiological studies have examined the relationship between other forms of tobacco use and cancer of the larynx (60, 68, 98, 131). Pipe and cigar smokers develop cancer of the larynx at rates comparable to those of cigarette smokers (i.e., several times those of nonsmokers) (Tables 22 and 23). The similarities of the mortality ratios of cancer of the larynx for smoking of non-cigarette tobacco products suggests that the carcinogenic potentials of smoke from cigars, pipes, and cigarettes are quite similar at this site. The association of smoking of non-cigarette tobacco products to histological changes in the larynx has been examined (II). Among males who smoked cigars and pipes but not cigarettes, only 1 percent 74 TABLE 22.-Mortality ratios for cancer of the larynx in cigar and pipe smokers. A summary of prospective epidemiological studies Study Smoking Type ACS BState Stud? ' British Physicians' ACS 25.State Study U.S. Veterans NOtI- Cigar Pipe Total pipe Cigarette Mixed smoker only Only and cigar only 1.00 5.00 3.50 - 5.06 1.00 - 2.00 1.00 0.60 1.00 - 3.37 36.09 - 1.00 10.33 - 7.28 11.49 `Combmesdata for oral, larynx. and esophagus ' Ratros. rehve in cigarette smokers. 3 Only mortality rata for ages 4.5 to 64 are presented. had no atypical cells and more than 75 percent of the subjects had lesions with 50 to 69 percent atypical cells. Four of the cigar and pipe smokers had carcinoma in situ. Of those who never smoked regularly, 75 percent had no atypical cells. The cigar and pipe smokers had a percentage of cells with atypical nuclei similar to that of cigarette smokers who smoked one to two packs per day. Synergistic Role of Alcohol for Laryngeal Cancer Laryngeal cancer occurs much more frequently in alcoholics than in nonalcoholics (183, 208, 239). Although part of this increased risk for laryngeal cancer among alcohol abusers may be attributed to heavier smoking by this group, there remains a substantial excess risk associated with alcohol use (227). The relative risks of laryngeal cancer by daily consumption of alcohol and cigarettes in 239 male cases and 4,725 controls (Figure 25) suggest a synergy when tobacco usage is combined with chronic alcohol consumption (179). Male smokers of from 11 to 20 and from 21 or more cigarettes per day who consumed 7 ounces or more of alcohol per day had relative risks for laryngeal cancer of 26.8 and 27.2 respectively. The corresponding risks for nondrinking smokers were 6.6 and 12.0. This synergy has also been demonstrated using the Third National Cancer Survey, which suggests that the laryngeal cancer risk for smoking drinkers is approximately 50 percent greater than the sum of the excess risks posed by either behavior alone (85). The mechanism(s) by which these two factors interact is unclear (179,226, 242). Experimental Studies The Syrian golden hamster has been found to be a suitable species for the investigation of cancer of the larynx. The distribution of malignant lesions in the upper airway of the hamster is due not to an unusual susceptibility of the larynx for tumor induction, but rather to the distribution of smoke aerosol precipitation within the upper 75 377-310 0 - 82 - 7 2 TABLE !23.-Relative risk of cancer of the larynx for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies Relative Riik Ratio and Percentage of Cams and Controls by Type of Smoking Author (Reference) Number Non- Cigar Pipe Total pipe Cigarette Mixed smoker only only and cigar only Schrek-et al. (244): cam? ...................................... Controls ................................... Sadowsky et al. (236): rhea ...................................... Controls ................................... Wynder et al. (309): cases ...................................... Controls ................................... Wynder et al. (317)~ cases ...................................... Controls ................................... Wynder et al. (324): caees ...................................... Controls ................................... Pernu f209): cases ................... . ....... ........... Contmls ................................... Staszewski (252): cases ...................................... Controls ................................... Svoboda (261): casee ...................................... Contmls ................................... St.41 L?&e cases ...................................... Contmh ................................... 73 522 273 615 209 206 60 271 142 546 713 207 912 206 320 190 loo Relative risk .................................. Percent casee ................................... Percent controls .............................. Relative risk .................................. Percent cases ................................... Percent contmls .............................. Relative risk .................................. Percent casea .................................. Percent controls .............................. Relative risk .................................. Percent cams .................................. Percent controls ........................ .:. .:. Relative risk .................................. Percent cams .................................. Percent controls .............................. Relative risk .................................. Percent cama .................................. Percent controls .............................. Relative rink .................................. Percent casea .................................. Percent controls .............................. Relative risk .................................. Percent case8 .................................. Percent controls .............................. Relative tik .................................. Percent cams .................................. Percent contrd* ...... 1.0 14 24 1.0 4 13 1.0 .5 11 1.0 5 24 1.0 1 16 1.0 7 39 1.0 .5 17 1.0 3 22 1.0 11 17 0 0 10 2.2 2 3 15.5 8 10 9.7 17 9 14.5 20 22 . . . . . . . . . . . . . . . . . . . . . . , 1.1 1 11 2.3 5 7 27.7 5 4 4.5 15 16 16.0 1 1 4.5 4 5 .... 5.9 ............ ......... .. 2 ........................ 11 ............ 2.6 ............ ............ 3 ......... .. ............ 7 ............ ............ ............ 1.3 ........................ 8 10 2.3 80 59 3.7 60 53 24.6 66 74 6.3 47 36 22.0 62 45 6.7 76 50 56.2 66 61 10.0 95 71 2.4 7.9 -d, ............ ... ........ 4.1 29 23 ....... .... ............ ............ 6.3 17 13 16.0 16 16 3.2 4 7 ............ ............ ............ ............ ............ ............ ............ ........ CASES=239 CONTROLS=4725 ClGAREl-fES PER DAY NON-SMOKERS 0 l-6 7+ OUNCES OF ALCOHOL PER DAY FIGURE 25.-Relative risks of larynx cancer by daily consumption of alcohol and cigarettes for males ' Not significant. SOURCE: McCoy et al. (I 79). respiratory tract. Several recent experiments have been performed (23, 24, 72, 73, 125, 126, 133). Cigarette smoke inhalation has not been found to induce laryngeal tumors in other rodents. Such tumors have been induced, however, by direct application of carcinogens known to be present in cigarette smoke. This is accomplished by the intratracheal instillation of benzo[a]pyrene in combination with particulates into hamster lungs. In this animal model, laryngeal tumors, as well as tumors in other parts of the respiratory tract, are induced (184, 231, 232). One study has recently reported a synergy of alcohol and benzo[a]pyrene injection (257). Conclusion 1. Cigarette smoking is the major cause of laryngeal cancer in the United States. Cigar and pipe smokers experience a risk for laryngeal cancer similar to that of a cigarette smoker. 2. The risk of developing laryngeal cancer increases with in- creased exposure as measured by the number of cigarettes smoked daily as well as other dose measurements. Heavy 77 smokers have laryngeal cancer mortality risks 20 to 30 times greater than nonsmokers. 3. Cessation of smoking reduces the risk of laryngeal cancer mortality compared to that of the continuing smoker. The longer a former smoker is off cigarettes the lower the risk. 4. Smokers who use filtered lower tar cigarettes have lower laryngeal cancer ri$s than those who use unfiltered higher tar cigarettes. 5. The use of alcohol in combination with cigarette smoking appears to act synergistically to greatly increase the risk for cancer of the larynx. Oral Cancer Introduction Cancers of the oral cavity include malignant tumors of the lip, tongue, salivary gland, floor of the mouth, mesopharynx, and hypopharynx. It is estimated that in 1982 there will be 26,800 new cases and 9,150 deaths due to these tumors (21. Males are affected more commonly than females (by about threefold). Several authors (29, 175) have reported geographic differences in mortality. In the southeast, females living in urban and rural areas have mortality rates that exceed those of northern females by 30 and 90 percent respectively. Cancer of the Buccal Cavity and Pharynx, Excluding Lip2 From 1950 to 1967, the age-adjusted rate remained stable at 2.8 per `100,000. The increase in the age-adjusted death rate from 2.8 to 2.9 per 100,000 between 1967 and 1968 resulted in part from changes in coding procedures in the International Classification of Diseases. From 1968 to 1977, the age-adjusted rate rose from 2.9 to 3.1. Total deaths from cancer of these sites increased from 1,461 in 1950 to 8,291 in 1977. While the age-adjusted death rate of white males fell slightly over the study period (Figure 261, rates of white females and of males and females of races other than white increased. The largest increases occurred among other than white males, whose mortality rates rose from 4.1 to 7.7 per 160,000 between 1950 and 1977. The white male to female.mortality ratio fell gradually over the study period, from 4.09 to 2.93. In contrast, the mortality sex ratio (male/female) in the other than white population increased from 2.56 to 3.85. The mortality ratio of other than white males to white males increased from 0.91 to 1.75, while the mortality ratio of other .than white females to white females decreased slightly, from 1.45 to 1.33. z Cancer of the lip is causally associated with smoking, particularly pipe smoking. However, because this cancer site representi so few deaths in the United States, only 163 in 1977. it is excluded from thin review. 78 +=WHITE IIRLES X=WHITE FEIIFILES O=NONWHITE MILES ~=NONWHITE FEIIALES 1965 CRLENDAR YERRS 1970 1975 The death rates of white males 35 to 54 years of age and of those at least 75 years old were lower in 1977 than in 1960 (Figure 27), but rates were higher among white males between 55 and 74 years of age, as well as among white females in the same age range. In contrast, among other than white males in every lo-year age group from 35 through 84, as well as among females between 35 and 64, death rates were higher in 1977 than in 1960; the average increase in mortality in these age groups was 60 percent (Figure 28). When age-specific death rates are plotted by calendar year and age (Figures 29 and 30), a three-dimensional graph is produced, which can be examined from 1950 to 1977, or from the reverse perspective. Squamous cell cancer is the most common histological type of oral cancer and comprises about 90 percent of these tumors. The 5-year survival for cancer of the floor of the mouth, tongue. and pharynx ranges from 25 to 45 percent. Numerous epidemiological and experimental studies have estab lished a close association between smoking and oral cancer. Alcohol has an incompletely understood but important synergistic role with tobacco in increasing disease incidence and mortality. Causal Significance of the Association Consistency of the Association More than 25 retrospective studies have examined the relation- ship between smoking and the development of cancer of the oral cavity (269,276). These studies have been done in many countries, in different areas, and have involved diverse study methods. Almost uniformly, they show an association between cigarettes and other forms of tobacco use and cancer of the oral cavity and pharynx. The TNCS study (299) and the Hawaiian Study of Five Ethnic Groups (113) reported similar findings. Six of the major prospective studies examined the relationship between smoking and oral cancer. These data, presented in Table 24, show a close association between smoking and oral cancer. Strength of the Association The relative risks for oral cancer among smokers were substantial- ly greater compared with nonsmokers in the retrospective studies. Similarly, in the prospective studies, the mortality ratios for cancer of the oral cavity among smokers ranged from 1.22 among Japanese females to over 13 in the U.S. Veterans and British Physicians studies (Table 24). A dose-response relationship was noted in many of the retrospec- tive and prospective studies (Table 25) (64, 98, 120, 131, 276). The American Cancer Society 25State Study (155) reported a reduction 80 0 10 20 30 40 50 60 70 ROE IN YEARS IBY S-YEAR ROE DROUPSI 60 b :: 30 1: - C 80 FEtlRLES + =1950-1956 * =1957-1963 ? O 1964-1970 [II :1971-1977 10 20 30 40 50 60 70 EO RGE IN YEARS IBY 5-YERR ROE QROUPSI 7! 6t j- MRLES 7: 6C 15 0 0 10 20 30 40 50 60 70 -80 01 ROE IN YEARS ISY S-YEAR ROE GROUPS) 1 0 FEHRLES +=1950-1956 * -1957-1963 0 =1964-1970 cl=1971-1977 10 20 30 40 50 60 70 80 ROE IN YEARS IBY 5-YERR RGE GROUPS) '20 FIGURE !29.-Age-specific mortality rates by 5-year age groups for cancer of the buccal cavity and pharynx for white males, United States, 1950- 1977 SOURCE: National cm~~r Institute (198). in risk for cancer of the buccal cavity and pharynx among smokers of lower tar and nicotine cigarettes, but the reduction WAS nyt statistically significant. Wynder and Hoffmann (326) reported siml- lar findings in a retrospective study of smokers of filter cigarettes versus smokers of nonfilter cigarettes. 83 30 0 FIGURE 34X-Age-specific mortality rates by 5-year age groups for cancer of the buccal cavity and pharynx for white females, United States 19!50-1977 SOURCE: National Cancer Institute (198). Specificity of the Association The prospective studies have reported mortality data for a large number of diseases. Specificity, which is related to the magnitude of the association between smoking and oral cancer, is evidenced by the differences in the mortality ratios (smokers versus nonsmokers) of oral cancer and other cancers (Appendix Tables A and B). These 84 TABLE 24.-Mortality ratios for cancer of the oral cavity- prospective studies Study NUIllbW of cigarette Population size deaths Nonsmokers smokers Comments ACS 9State Study British Physicians U.S. Veterans ACS 2!%St.at.e 358,000 males 167 Study 463,000 females 65 California males in 9 occupations 68,OOU males 19 Japan- Study 122,200 males 142,800 females Swedish stuby 55,000 males and females 43 11 15 166,cOO males 34,Mw males 55 38 61 1.00 5.06 Only 3 deaths among nonsmokers 1.00 13.00 Includes lip, tongue, mouth, pharynx, larynx, and trachea 1.00 4.22 1.00 14.05 1.00 6.52 1.00 3.25 1.00 2.76 Buccal cavity Pharynx Buccal cavity and pharynx 1.00 2.86 males Data for mouth 1.00 1.22 females only Mortality ratios not 5 deaths in pubbsbed nonsmoking males; 10 deaths in smoking males differences are even greater when comparisons are made with the mortality ratios of heavy smokers. Temporal Relationship of the Association Evidence for a temporal relationship of this association is provided by the prospective studies in which populations of apparently disease-free smokers and nonsmokers were followed over time for oral cancer mortality. In addition, the finding of premalignant oral mucosal changes in greater proportions of smokers than nonsmokers provides evidence for the temporality of the association (see below). Coherence of the Association Dose-Response Relationship The finding of a dose-response relationship between smoking and oral cancer mortality in both retrospective and prospective studies lends support to the causal nature of the association. 85 TABLE 25.-Oral cancer mortality ratios by amount smoked-prospective studies Study British Physicians Population Amount Smoked per &Y Commenb MdW Females NS 1.00 NS 1.00 Male data 1-14 5.00 l-14 - by grams 1524 7.00 l&24 4.00 of tobaaa 25+ 33.00 25+ 6.56 per day U.S. Veterans Japanese in 29 Health Districts ACS Sstate Study 188,ooO males California males in 9 occupations NS 1.00 l-9 2.92' 10-20 2.87 21-39 6.15 40+ 12.40' NS 1.00 1-19 1.20 20-29 5.50 30+ 9.10 NS 1.00 l-9 7.00 lo-20 6.00 2C+ 7.67 NS 1.00 < `12 pack 3.69 1 pack 1.17 l'/, pack 5.52 `Eked on fewer then20 deaths. Hypopharynn OdY Includes larynx and e&w- Correlation of Sex Differences in Oral Cancer With Different Smoking Habits Oral cancer is predominantly a disease of males, but the difference between male and female rates of disease is narrowing. This finding is consistent with the differences in the smoking trends of males and females noted above. As with laryngeal and esophageal cancer, there is a strong association between oral cancer and alcohol consumption. This must be considered as contributing to the excess ratio of male to female oral cancer mortality (see below). Correlation of Oral Cancer Mortality Rates Among Popylations With Different Tobacco Consumption In populations with low proportions of smokers. (e.g., Mormons and Seventh Day Adventists), the incidence and mortality rates of cancer of the gum, mouth, tongue, and pharynx are substantially reduced (79, 165, 166, 211, 294). 86 N -497 PRESENT l-3 44 7-10 11-15 16 + NON- SMOKERS SMOKERS FIGURE 31.-Relative risk of male ex-smokers for cancer of the oral cavity by years since quitting smoking SOURCE: Wynder and Stellman G'6). Oral Cancer Mortality and Cessation of Smoking In the U.S. Veterans Study (224), exsmokers had approximately 40 percent of the risk for oral cancers of current smokers. Data from the American Health Foundation study found that the risk of cancer of the oral cavity among former smokers declined with the number of years off cigarettes when compared to the risk of continuing smokers. After 16 or more years of cessation, the risk of oral cancer approaches that of nonsmokers (Figure 31). This is consistent with the causal nature of the association. Smoking and Histological Changes in the Oral Mucosa Leukoplakia is an abnormal thickening and keratinization of oral mucosa and is recognized as a precursor of malignancy of the oral cavity (124). A few studies have established a relationship between smoking in various forms and leukoplakia (269). Oral Cancer and Non-Cigarette Tobacco Use The oral cavity and pharynx are the sites most consistently exposed to tobacco smoke. A summary of the data from the prospective epidemiological studies is presented in Table 26. They demonstrate that cigar and pipe smokers experience a significant risk of developing cancer of the oral cavity compared with nonsmok- ers. This risk is approximately equal for all smokers whether an individual uses a pipe, cigar, or cigarette. Several authors have reported a relationship between chewing tobacco and/or snuff dipping (the placement'and retention of fine 87 TABLE 26.-Mortality ratios for oral cancer in cigar and pipe smokers. A summary of prospective epidemiological studies Study Smoking Type NOW Cigar Pipe Total Pipe Cigarette Mid Smoker Only Only and Cigar Only ACS S&ate Study ' 1.00 5.00 3.50 - 5.06 - British Physicians ' 1.00 - - `9.00 13.00 11.00 ACS 25-Stat.e Study 1.00 - - 4.94 M 6.52 - F 3.75 - US. Veterans Study Oral * 1.00 4.11 3.12 4.20 4.22 3.79 Pharynx 1.00 - 1.93 7.76 14.05 7.75 ' Combines data for oral. larynx, and esophagus. z Figures for all non-lung respiratory cancers. ' Mortality rati- for ages 45 to 64 only as present& o Excludes pharynx. ground or powdered tobacco in the oral vestibule between the gums and cheek) and oral cancer (36,186,. 207,234,299,301,310), A recent report found a fourfold increase in risk for oral cancer among female snuff dippers compared to nontobacco users (301). The excess risk for cancers of the cheek and gum was nearly fiftyfold among long-term users. The authors estimated 87 percent of these tumors were related to snuff use. In the Third National Cancer Survey, Williams and Horm (299) noted an excess relative risk for cancers of the gum and mouth in male and female users of chewing tobacco or snuff; However, this risk was only statistically significant for males. A few epidemiological investigations have demonstrated an associ- ation between the combined use of alcohol and pipe or cigar smoking and the development of oral cancer (135, 272, 173, 310). Heavy pipe and/or cigar smoking and heavy drinking are associated with higher rates of oral cancer than are seen with either habit alone. Synergistic Role of Alcohol and Cigarettes for Oral Cancer Oral cancer occurs more commonly in heavier users of alcohol (37, 88, 136, 227, 283, 302, 310). A recent study (179) noted an interaction (Figure 32) for oral cavity cancer in white males who use both alcohol and cigarettes. Nonsmokers who consumed 7 ounces or more of alcohol per day had a relative risk of 2.5. Those cigarette smokers who consumed 7 ounces or more of alcohol per day had a relative risk of 5.1 if they smoked one-half a pack or less daily, 20.5 if they smoked 11 to 20 cigarettes per day, and 24.0 if they smoked more than one pack of cigarettes per day. A distinct synergy (a multiplicative effect) of alcohol and cigarette smoking has been described elsewhere (271). The mechanism by which these two factors interact is unclear. 88 CASES = 304 CONTROLS=4725 CIGARETTES PER DAY NON-SMOKERS 0 14 7+ OUNCES OF ALCOHOL PER DAY FIGURE 32.-Relative risks of oral cavity cancer by daily consumption of alcohol and cigarettes for males * Not signdicant SOURCE: McCoy et al. (179). Experimental Studies A useful animal model for the experimental study of oral carcinogenesis has not been found. Cigarette smoke and cigarette smoke condensates generally fail to produce malignancies when applied to the oral cavity of mice, rabbits, or hamsters. Mechanical factors, such as secretion of saliva, interfere with the retention of carcinogenic agents. However, positive results have been obtained with benzo[a]pyrene, 20-methyl-cholanthrene, 9,1Odimethyl-1,2 ben- zanthracene, and other tobacco smoke carcinogens when applied to the cheek pouch of hamsters. The cheek pouch, however, lacks salivary glands, and its structure and function differ from those of the oral muiosa. These studies have been reviewed in previous reports of the U.S. Public Health Service (272, 276). Conclusion 1. Cigarette smoking is a major cause of cancers of the oral cavity in the United States. Individuals who smoke pipes or cigars experience a risk for oral cancer similar tQ that of the cigarette smoker. 89 2. Mortality ratios for oral cancer increase with the number of cigarettes smoked daily and diminish with cessation of smok- ing. 3. Cigarette smoking and alcohol use act synergistically to increase the risk of oral cavity cancers. 4. Long term use of snuff appears to be a factor factor in the development of cancers of the oral cavity, particularly cancers of the cheek and gum. Carcinoma of the Esophagus Introduction Carcinoma of the esophagus is a rapidly fatal neoplasm; there is a median survival of less than 6 months following diagnosis and a 5- year survival rate of 3 percent. The number of deaths caused by esophageal cancer rose from 3,866 in 1950 to 7,283 in 1977. The age-adjusted death rate increased from 2.3 to 2.6 over this period (Figure 33). In the United States in 1977, 3,924 white males and 1,520 white females died from esophageal cancer; in the other than white population, 1,404 males and 435 females died from this disease. While these figures represent only a slight increase in age-adjusted mortality in the white population, they do reflect nearly a twofold increase in the other than white population from 1950 to 1977. The ratio of the age-adjusted death rate of the other than white population to that of the white population increased over the study period. In 1977, the death rate from this cause among other than white males between the ages of 35 and 44 years was eight times that among white males of the same age. The death rate of other than white females in this age group was 13 times the corresponding rate of white females. Mortality ratios by race (white/other-than-white) decreased with age in both males and females. Among whites, the mortality sex ratio (male/female) declined slightly between 1968 and 1977. In the other than white group, there was also a greater relative increase in the age-adjusted death rate of females than in those of males. Among white males and females, age-specific death rates from cancer of the esophagus (Figure 34) increased in each succeeding lo- year age group to the end of the lifespan. In other than white males, mortality peaked between ages 65 and 74 (Figure 35). The pattern was irregular in other than white females, varying with age group and time span over the 1950-1977 period. A three-dimensional graph of age-specific death rates for white males and females for cancer of the esophagus over the period 1950- 1977 is shown in Figures 36 and 37. 90 9 + =WHITE MALES m =WHITE FEllfILES O=NDNWHITE IIALES [IIzNONWHITE FEIIRLES 6 t L..~~""~`~"""""`~"" :950 1955 1960 1965 1970 1975 CALENDAR YEARS I I tlRLES 0 10 20 30 40 50 60 70 60 ROE IN YEARS IBY 5-YERR AGE GROUPS1 FE~IRLES +=1950-1956 3lc=1957-1963 c)=1964-1970 cl:1971-1977 10 20 30 40 50 60 70 80 AGE IN YERRS IBY S-YERR ROE GROUPS) 50 40 g 30 ;;t cn k B b = 20 10 ROE IN YERRS [BY 5-YERR AGE GROUPS1 50 40 = 30 2 E 4 =: b =: 20 10 0 FEtlALES + =1950-1956 * :1957-1963 0 =1964-1970 L!l:1971-1977 10 20 30 40 50 60 70 80 ROE IN YERRS IBY S-YEAR RGE GROUPS) IIIIIIIIIIIIIIII IIIII I 90 z IIIIIIIIIIlllllllllII GO s z w FIGURE 36.-Age-specific mortality rates by Byear age groups for cancer of the esophagus for white males, United States, 1950-1977 SOURCE. National Cancer Institute (1981. It is estimated that in 1982 in the United States there will be 8,900 new cases and 8,300 deaths from this disease (2). A number of epidemiological and experimental studies have established an association between smoking and esophageal cancer. 94 FIGURE 37.-Age-specific mortality rates by 5-year age groups for cancer of the esophagus for white females, United States, 1950-1977 SOURCE: National Cancer Institute (198). Causal Significance of the Association Consistency of the Association At least 10 retrospective studies have examined the relationship between smoking and esophageal cancer (276). Regardless of method- ology, risk ratios were consistently increased. Data from the major prospective studies (Table 27) also demonstrate consistently in- creased mortality ratios for male smokers as compared with non- 95 TABLE 27.-Mortality ratios for cancer of the esophagus- prospective studies Study ACS BState Study Population size 168,000 Number of Cigarette deaths Nonsmokers smokers Comments 1 nonsmoker 1.00 5.06 Eeophagus and 33 smokers other respiratory sites British Physicians 34,000 males 65 1.00 4.70 E=phsgus and other respiratory sites U.S. Veterans 29QooO 119 1.00 6.43 ACS 25-State 398,@30 males 116 1.00 3.96 Study 483,OGfl females 48 1.00 4.89 California males 68,000 males 32 l.cm 1.82 in 9 occupations JapaneSe Study 122,200 males 215 1.00 2.35 Swedish 55,000 males 1 nonsmoker Study and females 12 smokers 1.00 - smokers. The ACS 25-&&e Study showed similar results for female smokers and cancer of the esophagus. Strength of the Association Mortality ratios in the retrospective studies ranged from 1.3 to 11.1 among heavy smokers; mortality ratios in the prospective studies ranged from 1.8 to 6.4. In four of the large prospective studies, a dose-response relationship was demonstrated (Table 28). A reduced risk for esophageal cancer among female but not male smokers of lower tar and nicotine cigarettes has also been reported (155). Specificity of the Association Specificity of the association between smoking and esophageal cancer is evidenced by substantial differences in the mortality ratios (smokers versus nonsmokers) for esophageal cancer compared to other smoking-related cancers (Appendix Tables A and B). Temporal Relationship of the Association The temporal relationship of this association is supported by the prospective studies in which populations of initially disease-free subjects were followed for the development of esophageal carcinoma. In addition, there are histological data suggesting that smoking 96 TABLE 28.-Mortality ratios for cancer of the esophagus by amount smoked-prospective studies Study Population Size Cigarettes/Day Ratio Comments British Physicians 34,ooO males Nonsmoker 1.00 1-14 4.00 E-24 4.33 %+ 10.00 Grams of tobacco per day U.S. Veterans Nonsmoker l-9 1~20 21-39 40+ 1.00 3.06' 4.34 12.42 9.20' `Based on fewer than 20 deaths Japanese in 29 Health Districts 122,200 males Nonsmoker 1.00 1-19 2.2n 20-23 2.80 30+ 3.24l California males in 9 occupations Nonsmoker 1.00 about `1. pk 1.n about 1 pk 1.69 ahout l'/* pk 1.82 antedates premalignant and malignant transformation of esopha- geal epithelium (13,16X Coherence of the Association Dose-Response Relationship There is a doseresponse relationship between smoking and esophageal cancer mortality in retrospective and prospective studies (276). Esophageal Cancer Mortality and Cessation of Smoking Several of the prospective studies noted reduced risks for cancer of the esophagus after quitting smoking. The U.S. Veterans Study found that the mortality ratio for ex-smokers decreased to 2.41 compared to 6.43 for continuing smokers. For the British Physicians Study, the corresponding ratios were 1.66 and 5.33, respectively. Thus, ex- smokers had only about one-third the risk for esophageal cancer of current smokers. Figure 38 presents data from the American Health Foundation study for esophageal cancer mortality risk by the number of years off cigarettes. After quitting smoking for 4 years or more, former smoker rates were not substantially above those of nonsmokers. 97 PRESENT l-3 44 7-10 11-15 16+ NON- SMOKERS SMOKERS FIGURE 38.-Relative risk of male ex-smokers for cancer of the esophagus by years since quitting smoking SOURCE: Wynder and Stellman c326I Correlation of Sex Differences in Esophageal Cancer With Different Smoking Habits Esophageal cancer is predominantly a disease of males. The sex differences observed for esophageal cancer mortality are compatible with the sex differences in smoking patterns. As with oral and laryngeal cancer, esophageal cancer has also been related to excessive alcohol consumption. This must be considered as contribut- ing to the excess ratios of male to female esophageal cancer mortality (see page 1011. Correlation of Esophageal Cancer Mortality Among Populations With Different Tobacco Consumption In populations with low proportions of smokers (e.g., Mormons and Seventh Day Adventists), the mortality rates from esophageal cancer are substantially reduced (79, 165, 166,211,294). 98 TABLE 29.-Mortality ratios for cancer of the esophagus in cigar and pipe smokers-a summary of prospective epidemiological studies Smoking type Study NOW Cigar Pipe Total pipe Cigarette smoker only Oh and cimr only Mixed ACS 9State Stud;l 1.00 5.00 3.50 - 5.06 British Physicians ACS 25State Study 1.00 1.00 - - - - 3.70 3.97 4.70 males 3.96* females 4.89 9.0 - - U.S. Veterans 1.00 5.33 1.99 4.65 6.43 - ' Combines data for oral. larynx. end esophagus. ' Mortality ratio for ages 45 to 64. Smoking and Histologic Changes in the Esophagus Examination of 12,598 histologic sections of esophageal autopsy tissue from 1,268 men showed histologic findings which were similar to the abnormalities generally accepted as being premalignant in respiratory tract epithelium (16). Only 2.5 percent of the slides from current smokers exhibited no atypical cells, compared with 93.5 percent of slides from nonsmokers. The finding of 60 percent or more atypical cells was rare in the tissue of nonsmokers (0.3 percent), but much more common in tissue of smokers (17.7 percent). Esophageal Cancer and Non-Cigarette Tobacco Use The esophagus is not directly exposed to inhaled tobacco smoke, but tobacco smoke constituents condense on the mucous membranes of the mouth and pharynx and are swallowed, thus contacting esophageal cells. The esophagus also receives mucous cleared from the lungs by the ciliary mechanism or by coughing which is also swallowed. Variations in the inhalation of the smoke of -different tobacco products may not appreciably alter the degree of exposure of the esophagus. This possibility is suggested by the prospective and retrospective epidemiological studies which demon@rate similar mortality rates for cancer of the esophagus in smokers of cigars, pipes, and cigarettes. These data are presented in Table 29. Several retrospective investigations have examined the association between smoking in various forms and cancer of the esophagus (Table 30). These studies suggest that cigar, pipe, and cigarette smokers develop cancer of the esophagus . at rates substantially higher than do nonsmokers and that little difference exists between these rates observed in smokers of pipes, cigars, or cigarettes. H#ologic changes in the esophagus have been related to smoking of 99 cigarettes and other forms of tobacco (16). Several retrospective studies conducted in the United States and other countries have examined the synergistic role of tobacco use and heavy alcohol intake and the risk of mortality from cancer of the esophagus. At least four of these investigations contain data on pipe and cigar smoking (33, 172, 173, 307). It appears that smoking in any form in combination with heavy drinking results in especially high rates of cancer of the esophagus. TABLE 30.~Relative risk of cancer of the esophagus for men, comparing cigar, pipe, and cigarette smokers with nonsmokers. A summary of retrospective studies Relative risk ratio and percentage of aaee Author, reference NWllhW and controls by type of smoking Non- Ci Pipe TOW pipe Ciguette Mixed smoker only only . and cigar 4Y Sadowsky (ue): caaea .................. Controls ............... wynder (sf7jl: Cpaes .................. Controls. .............. Pemu (rar) cases. ................. Controls ............... Schwartz (~40: cases. ................. Controls ............... Wynder and Bms ,mn: casea. ................. COMdS ............... Bradshaw and Shoaland (S.9: cases. ................. Controls. .............. Martine 2. (In): cases. ................. controls ............... hltiinez' (175): Cpres .................. Controls ............... 164 615 39 115 Lo2 713 239 249 150 156 117 366 126 360 346 346 Math risk 1.0 4.8 3.8 5.1 3.3 33 per~en+ w 4 5 a 6 69 la Percent controls 13 3 7 4 59 19 Relative risk 1.0 3.1 21 . 26 .4 Percent cases 13 15 18 . . 51 3 Percent controls 24 9 16 . 36 1s Relative risk 1.0 . . . . 3.0 . . percent caae3 17 I . . Percent controls 39 5 . Relative risk 1.0 26 Percent casea 2 . . 2 . . Percent controls ia . 7 . . Relative risk 1.0 3.6 9.0 6.0 Percent cases 5 19 9 4 Percent controls 15 16 3 2 Relative risk 1.0 4.8 Percent case3 15 41 Percent Contras 32 la Relative risk 1.0 20 . . . . Percent case3 a 9 . Percent controls 14 a Relative risk 1.0 20 28 Percent eases 21 10 15 Percent contmls 22 9 1 . . . 27 59 50 11.7 aa 67 28 51 55 23 66 58 1.5 31 31 1.7 a4 a6 5.9 la I 86 7 7 3.7 11 9 22 43 a4 25 34 25 1Tbk study eombinea data for oml CMKZT and cancer of the wopbagu. 100 Synergistic Role of Alcohol for Esophageal Cancer Numerous investigators have found a synergistic relationship between the use of tobacco in various forms, alcohol consumption, and the development of cancer of the esophagus (119, 132, 143, 241, 243, 263, 299, 307, 323). Some investigators report that tobacco is a more important carcinogen than alcohol, but others report that the reverse is true. Most of the studies report a synergism with the combined use of tobacco and alcohol, resulting in higher rates of cancer of the esophagus than would be observed by the addition of the two exposures. The mechanisms by which these two factors interact are not known. Alcohol may act as a solvent for carcinogenic hydrocarbons in the tobacco smoke or may alter microsomal enzymes in the mucosal cells of the esophagus (306). This hypothesis has received support from experimental observations (150). It has been noted, however, that alcoholism may be accompanied by severe nutritional deficiencies, which also may predispose an individual to certain diseases (271). Experimental Studies There is experimental evidence that benda]pyrene is able to penetrate the cell membranes of the esophageal epithelium, produc- ing papillomas and squamous cell carcinoma. These studies and others are presented in the Part of this Report on mechanisms of carcinogenesis. Conclusion 1. Cigarette smoking is a major cause of esophageal cancer in the United States. Cigar and pipe smokers experience a risk of esophageal cancer similar to that of cigarette smokers. 2. The risk of esophageal cancer increases with increased smoke exposure, as measured by the number of cigarettes smoked daily, and is diminished by discontinuing the habit. 3. The use of alcohol in combination with smoking acts synergisti- cally to greatly increase the risk for esophageal cancer mortality. Cancer of the Urinary Bladder Pntroduction It is estimated that in 1982 in the United States there will be 37,100 new cases and 10,600 deaths from cancer of the bladder (2). The average annual incidence for males is almost three times that for females. 101 Cancer of the bladder resulted in 6,401 deaths in 1950 and 9,812 deaths in 1977 in the United States. The age-adjusted rate fell from 3.7 to 2.9 per 100,000. The age-adjusted mortality rate fell in all four color-sex groups (Figure 39). The rate for white males, who had the highest mortality from this disease, decreased by 5.7 percent between 1950 and 1977. Among other than white males, who had the second highest mortality rate from this disease, mortality declined by 2.6 percent. In contrast, the age-adjusted death rate for white females decreased by 36.4 percent, and that of other than white females fell 25.9 percent. White males between 45 and 74 years of age had lower death rates from cancer of the bladder in 1977 than in 1960, but older males had higher mortality. Among white females 45 years of age and older, mortality decreased over the study period. The death rate increased in other than white males 65 years of age or older and in other than white females 75 years of age or older (Figures 40 and 41). The age-specific death rates show no significant increases in either white males or white females when plotted on a three-dimensional graph for the period 1950-1977 (Figures 42 and 43). Most cancers of the bladder are transitional or squamous cell carcinomas. Unless these produce hematuria or obstruct the bladder outlet, they remain undiagnosed until quite late, making cure less likely. Five-year survival rates range from 4 percent for individuals with distant metastasis, to 21 percent for individuals with regional involvement, and to 72 percent with localized disease (2). For patients diagnosed with bladder cancer from 1960 to 1973, the overall 5-year survival rate was approximately 60 percent for whites and 30 percent for other than white (313). Certain occupational exposures are associated with an elevated risk for bladder cancer. Many of these are related to the exposure to certain aromatic amines in the work place. The first report of an association between cigarette smoking and human bladder cancer in the United States was based on a retrospective study of 321 men with bladder cancer (157). In the ensuing 35 years, other epidemiological and experimental data have established an association between cigarette smoking and bladder cancer. Several authors have conservatively calculated the percentage of bladder cancers that can be attributed to cigarette smoking. One study (313) estimated that 40 percent of male bladder cancers and 31 percent of female bladder cancers in the United States may be attributed to smoking cigarettes. This, is in agreement with the estimate by Cole et al. (48) of 39 percent in males and 29 percent in females. A Canadian study reported a population-attributable risk of bladder cancer due to cigarette smoking of 61 percent in males and 26 percent in females (129). 102 .o - +=HHITE HALES X=HHITE FEIIRLES OzNDNWHITE tIALES Cl=NONWHITE FEtlRLES a 10950 1955 1960 1965 1970 1975 CRLENORR YERRS HRLES "t ROE IN YERRS IBY S-YEAR RGE GROUPS) `5 I FEMALES 0 t + =1950-1956 Y-1957-1963 0=1964-1970 cl =1971-1977 5 t 126 100 "0 7t s 3 :: b 8 6( I i. HALES ROE IN YERRS (BY S-YEAR AGE GROUPS) 126 I 100 . +=1950-1956 %:1957-1963 0=1964-1970 clr1971-1977 FEtlALES 26 ROE IN YERRS IBY 6-YEAR AGE GROUPS) __/.H---- _---- _--- -- I I I I I I I I I I I I I I I I I .- 0 I 150 0 FIGURE 42.-Age-specific mortality rates by &year age groups for cancer of the bladder and other urinary glands for white males, United States, 1950-1977 SOURCE: National Cancer Institute ,198). Causal Significance of the Association Consistency, Strength, and Specificity of the Association There have been numerous retrospective studies of the relation- ship between smoking and bladder cancer (3, 46, 48, 55, 75, 139, 141, 157, 159, 188, 247, 253, 267, 313, 325, 327, 330). Almost all of these studies have found an association between smoking and cancer of the 106 FIGURE 43.-Age-specific mortality rates by B-year age groups for cancer of the bladder and other urinary glands for white females, United States, 1950-1977 SOURCE Natmnal Cancer Institute (1%) bladder with relative risk ratios for the smoker averaging two to three times that of the nonsmoker (Table 31). A retrospective population-based study of 470 confirmed cases of transitional cell or squamous cell cancers of the bladder found a positive relationship between cigarette smoking and bladder cancer (48). A dose-response 107 377-310 0 - 82 - 9 relationship was demonstrated for both the number of cigarettes smoked per day and different degrees of inhalation. In the TNCS study (2991, a significant association was found between cigarette smoking and bladder cancer. The Hawaiian study of five ethnic groups (113) also disclosed a positive association between smoking and bladder cancer. In a Canadian population- based retrospective stiady of 632 case-controlled pairs (1291, the relative risk for developing bladder cancer for those who had ever used cigarettes versus those who had never used cigarettes was 3.9 for males and 2.4 for females. A dose-response relationship was demonstrated, and reduced risk was associated with the use of filter cigarettes as compared with the use of nonfilter cigarettes. Several of the retrospective studies found a dose-response relationship of cigarette smoking for bladder cancer, with the risk increasing with increased number of cigarettes smoked per day, duration of cigarette smoking, or lifetime number of cigarettes. Further, a study of successive birth cohorts in four countries, including the United States, found increasing rates of bladder cancer with increasing smoking exposure, for both males and females (128). Several of the large prospective epidemiological studies have examined the relationship between cigarette smoking and bladder cancer and are summarized in Table 32. `On the average, cigarette smokers are twice as likely to die from cancer of the bladder as are nonsmokers. Several of these studies also show a moderate dose response relationship; however, this relationship is not as strong as that noted between smoking and lung, laryngeal, oral, and esopha- geal cancers (Table 33). Comparisons of mortality ratios for selected causes of disease suggest that the specificity of the association is not as great as that noted for the above cancers (Appendix Tables A and B). The American Cancer Society !&State Study (155) reported a reduced risk for bladder cancer among smokers of lower tar and nicotine cigarettes, a reduction which was statistically significant among females but not among males. The lower order of strength and specificity for bladder cancer than for cancers of the lung, larynx, oral cavity, or esophagus suggests that factors other than smoking may also be associated etiologically with bladder cancer. Bladder Cancer Mortaiity and Cessation of Smoking Wynder and Stellman (326) reported that the risk of bladder cancer decreased almost to the level of nonsmokers after about 7 years of cessation (Figure 44). More recent data from the U.S. Veterans and British Physicians prospective studies show bladder cancer mortality ratios for ex-smokers only half those for continuing smokers (68,224). 103 TAB&E 31.-Review of literature on smoking and bladder cancer reported since 1963-retrospective studies country Years of study Authors Relative risk smokers: nonsmokers Number of subjects CaseS Controls Study population U.S.A. 1957-60 U.S.A. 1951-61 Wynder et al. (325l Cobb and Ansell (4s) 3.58 7.3 300 131 3oa 120 Male patients Male VA hospital patients Male patients Male patients Female patients Male patients Male patients Female patients Female patients Bilharzial male patients Nonbilhanial male patients Male patients Female patients Male patients; Austrian population controls Female patients; Austrian population controls Poland 1958-64 Staszewski GXII U.S.A. 1958-64 Dunham et al. (75) 2.7 150 750 1.4' 334 350 1.20 159 177 <1 381 275 1.9 360 381 2.0 106 117 1.6 135 390 1.4 278 278 1.7 87 87 U.K. U.S.A. U.S.A. EBypt 1956-67 Anthony and Thomas (4) 1967-66 Cole et al. (48) 1965-71 Simon et al. (141) 1966-71 Makhyoun (157) Canada 1972-73 Morgan and Jain (288) 6.4b 156 4.4h 74 1.6 150 Austria 1972-75 Flamm et al. (84) 3.0 40 *Recalculated from author's data. b Heavy smokers ( 2 25 cigarettes per day) compared with nonsmokers SOURCE: Wynder and Goldsmith (313). c TABLE 32.-Bladder cancer mortality ratios-prospective studies POpUl8tiOIl Study size NOW All snloIcen eiguette GJmnlentJ SdWS MS lfm= smokenof1~cigatetteJ Males in White Ineludea all winmy 9-stdt.e study Males 1.00 200 tract-. Includes Pmsbte. British Ph- woo Male Dccton 1.00 211 Canadian V&IWlS Acs 25 stat.? study U.S. Veterans mm Genitourinvy anew Male 1.00 1.40 CO~MS~group ~poo Males and 1.00 256 483,ofm 1.00 280 F~Fkk.8 z-=io@J Penon- 1.00 215 Years Wif0da 88,158 Males in 9 Males 1.00 2.89 OCCUptiOllS Japanese study SWedi Study 265,118 Malen and FW&!S WJW Males and Females 1.00 1.00 1.00 1.00 2.00 (Males) 2.55 (Fe&) 1.80 (Males) Bladder+ 1.60 (Females) other urinary OrgMs For male ex-smokers, the risk after 15 years of not smoking was less than one-half that of current male smokers (1.29). Temporal Relationship of the Association Evidence for the temporal relationship of the association is provided by the prospective studies in which populations of initially disease-free subjects were followed for the development of bladder cancer. Reliable histological studies of bladder epithelium in smok- ers compared with nonsmokers have not been reported. 110 TABLE 33.-Bladder cancer mortality ratios by amount smoked-prospective studies Amount Smoked Study Population per Day Ratio Comments U.S. Veterans =mQ Nonsmoker 1.00 l-9 1.22 `Based on E-20 2.18 less than 21-39 2.78 20 deaths 240' 2.29 British Physicians 34,m males Nonsmoker 1.00 1-14 2.20 15-24 2.20 25 + 1.40 Grams of tobacco per day California males in 9 occupations Swedish Study wx@ Nonsmoker 1.00 males about `I* pk 1.52 about 1 pk 2.81 about 1% pk 5.41 Males Females =mQ males NS 1.00 NS 1.M) and l-7 gm/day 1.50 l-7 1.20 females 8-15 1.60 a15 2.10 16 + 2.70 16 + 0.80 5 No 541 1 PRESENT 1-3 44 7-10 11-15 16+ NON- SMOKERS SMOKERS FIGURE 44.--Relative risk of male ex-smokers for cancer of the bladder by years since quitting smoking SOURCE: Wynder and Stellman 1326). Coherence of the Association Dose-Response Relationship The finding of a dose-response relationship in both retrospective 111 and prospective studies (see page 106-107) strengthens the coherence of the association of smoking and bladder cancer. Correlation of Sex Differences in Bladder Cancer With Different Smoking Habits Two investigators (128, 185), reporting 10 years apart, found an association between time trends in smoking patterns and bladder cancer mortality among both males and females. Each found an increasing risk of bladder cancer with increasing smoking exposure. Correlation of Bladder Cancer Among Populations With Different Tobacco Consumption Coherence of the association is also illustrated by data showing a low prevalence of this disease in groups with small proportions of smokers (e.g., Mormons and Seventh Day Adventists) (79, 165, 166, 211,294). Bladder Cancer Mortality and Cessation of Smoking Cessation of smoking decreases the risk of bladder cancer com- pared to that of continuing smokers. A study of male ex-smokers (129) found a risk of less than one-half that of continuing smokers 15 years after quitting smoking; a similar finding was observed in two of the major prospective studies (68,224). Bladder Cancer and Non-Cigarette Tobacco Use Two prospective studies have noted a relationship between pipe and cigar smoking and cancer of the bladder (68, 131). In the British Physicians Study, a mortality ratio of 1.5 was observed for the combined category of pipe/cigar smokers, whereas in the U.S. Veterans Study, a relationship was noted only for pipe smokers (ratio 1,201. Synergistic Role of Other Substances for Bladder Cancer The relationship between cigarette smoking and occupational exposure(s) is complex and has not been clearly elucidated. A number of carcinogens specific for the human bladder have been identified (45). Some of .these compounds are found in cigarette smoke in very low concentrations. Cigarette smoking probably acts as an independent agent in the development of bladder cancer; however, there may also be additive or synergistic interactions between cigarette smoking and substances present in the work place. Those who work with dye stuffs, rubber, leather, print, paint, petroleum, and other organic chemicals are at higher risk for bladder cancer than workers not exposed. 112 Conclusion 1. Cigarette smoking is a contributory factor in the development of bladder cancer in the United States. This relationship is not as strong as that noted for the association between smoking and cancers of the lung, larynx, oral cavity, and esophagus. The term "contributory factor" by no means excludes the possibili- ty of a causal role for smoking in cancers at this site. Cancer of the Kidney Introduction Over the period 1950-1977, the age-adjusted mortality rate for kidney cancer rose from 2.2 to 2.6. The annual number of deaths due to cancer of the kidney increased from 3,643 to 7,373. It is estimated that in 1982 there will be 18,100 new cases and 8,300 deaths due to kidney and other urinary tract cancers in the United States (other than bladder cancer) (2). The death rate of white males was higher than that of the other three color-sex groups (Figure 45). While age-adjusted death rates increased, although at a decelerating pace, among white males throughout this period, rates among other than white males actually decreased slightly after 1967. Among white females, the age-adjusted rate increased between 1950 and 1957, when it stabilized. Among other than white females, who had the lowest age-adjusted rate of death from this disease, mortality rose from 1.2 to 1.4 per 100,000. In the white population, the mortality sex ratio (male/female) increased from 1.75 in 1950 to 2.24 in 1977, reflecting the rise in the male death rate and the relative stability of the female rate. In the other than white populations, the mortality sex ratio was slightly lower during the 2&year period. White males and white females were at greater risk from this disease than were their counterparts, although the white to other- than-white differential narrowed throughout the study period. In all four color-sex groups, death rates moved generally upward in the population between 45 and 84 years of age (Figures 46 and 47). In 1977, both white and other than white males had higher death rates from this disease than did white and other than white females in the 10-year age group from 35 to 44. The age-specific death rates for cancer of the kidney show an upward trend in the older age groups, without a significant increase in the rates for the younger age groups when plotted on a three- dimensional graph for the period 1950-1977 (Figures 48 and 49). There are four primary histological types of kidney cancer: (1) renal cell carcinoma, (2) nephroblastoma (Wilm's tumor), (3) sarco- 113 5` w p ps* E 80 c Y - s: z P , a2n 1965 ,--- 1970 1975 CALENDRR YERRS --.- CHLtNUHK YERRS AGE IN YEWS (BY S-YERR RGE GROUPS1 30 . 24 10 12 6 FEMRLES +=1950-1956 ?#=1967-1963 cl =1964-1970 (II -1971-1977 0 10 20 30 40 50 60 70 80 RCE IN YERRS IflY 5-YERR RGE GROUPS1 D- 4 . I KRLES 3 2, 2 II ii 7 0 0 10 20 30 40 50 60 70 80 RGE IN YEARS 181 S-YERR RCE CROUPS1 O- 4 FEhRLES + =1950-lY56 H-1957-1963 O-1964-1970 cl:1971-1977 B 8 b 8 12. 0 0 10 20 30 40 50 60 70 80 AGE IN YERRS (BY 5-YEfIR ROE GROUPS1 llllllll1lllliIIIIIIIIlIIl FIGURE 48.-Age-specific mortality rates by byear age groups for cancer of the kidney for white males, United States, 1950-1977 SOURCE: National Cancer Institute (198). ma, and (4) epithelial tumors of the renal pelvis. Renal cell carcinomas comprise about 90 percent of kidney tumors and generally affect individuals after age 40 (average 55 to 60) (197). This tumor may be silent until far advanced. The median survival time for kidney cancer in the adult is about 2.7 years for those aged 35 to 54 at the time of diagnosis and 1 year for those 65 or older (197). 117 FIGUFtE 49.-Age-specific mortality rates by 5-year age groups for cancer of the kidney for white females, United States, 195&1977 SOURCE: Natienal Cancer Institute ( 198). Epidemiological studies have established an association between cigarette smoking and kidney cancer. Causal Significance of the Assoqiation Consistency, Strength, and Specificity of the Association Several retrospective studies have examined the relationship between smoking and kidney carcinoma. Data from these studies 118 (Table 34) show a positive association between smoking and kidney cancer with relative risks ranging from 1.06 to over 5, with one study of renal pelvis cancer reporting a tenfold risk for heavy cigarette smokers. Other studies also reported an increasing relative risk of renal adenocarcinoma and cancer of the renal pelvis in cigarette smokers (20, 21, 130, 238); the increase of relative risk of renal adenocarcinoma among cigarette smokers was found for both males and females (320). A significant positive association between ciga- rette smoking and renal cancer was noted in the TNCS study (299) and in the Hawaiian Study of Five Ethnic Groups (113). In most of the prospective studies, cancer of the kidney refers to tumors arising from the renal parenchyma as well as to tumors in the renal pelvis and ureter. In several of the large prospective studies (Table 34), an association was found between cigarette smoking and cancer of the kidney. The mortality ratios for all cigarette smokers varied from 1.20 to almost 3, compared with nonsmokers. Four of the prospective studies have noted a dose- response relationship as measured by the number of cigarettes smoked per day for kidney cancer (68, 105,224,290). Data from these studies are presented in Table 35. Generally, heavy smokers have mortality ratios two to three times greater than nonsmokers. In the U.S. Veterans Study, Rogot and Murray observed a decline in kidney cancer mortality among ex-cigarette smokers with a mortality ratio of 1.21 versus 1.41 for continuing smokers. Thus, the strength of the association of cigarette smoking related to kidney cancer risk is less marked than that for cancer of the other sites discussed above. Chemical elements such as lead and cadmium, hormones, ionizing radiation, genetic susceptibilities, as well as tobacco smoke have each been suggested as potential etiologic factors in this disease (322). Several studies (21, 32, 130, 214) have shown that a substance present in tobacco smoke, di-methylnitrosamine, causes kidney tumors in rats. Temporal Relationship The prospective studies provide support for the temporal relation- ship of the association. Coherence of the Association Dose-Response Relationship The dose-response relationship noted in four of the prospective studies lends support to the coherence of the association between smoking and cancer of the kidney. 119 TABLE 34.-Kidney cancer mortality, ratios and relative risks, prospective and selected retrospective studies Number of kidney Mortality ratio or relative risk ratio Comments Population Study size cancer Non- Cigarette deaths smokers smokers Prospective Studies ACS 9State 188,000 54 Study white males ACS 25-Stat.e Study 440,558 males 104 u. s. VetL?lXlIs 290,ocm 257 1.00 California males in 9 occupations 68,153 males 27 1.00 Japanese 122,281 30 Study males British Physicians 34,ooo 48 1.00 males Bennington renal adenocarcinoma 100 Laubscher 100 casea (20. 21) 190 controls Schmauz and 43 caes of renal Cole pelvis or ureter we) 451 controls 18 1.00 Armstrong GO) Wynder 202 adenocarcinoma 1.00 et al. of kidney (322) 394 controls 1.00 1.00 1.00 1.00 Retmspactive Studies 1.00 106 adenocarcinoma 106 1.00 of kidney 30 carcinoma of 30 1.00 renal pelvis 139 controls 1.58 Based on 54 microscopically proved cases 1.42 1.57 1.41 2.48 1.20 2.88 AH smokers 5.1 10.0 Riik ratio for pipe - 10.3 cigar - 12.9 For smokers of more than 2% pks/day 1.06 1.80 2.00 1.50 (males) (females) Correlation of Sex Differences in Kidney Cancer With Different Smoking Habits There has been an increase in the white male to female ratio of deaths from kidney cancer. This trend does not demonstrate an 120 TABLE 35.-Kidney cancer mortality ratios by amount smoked per day-prospective studies Amount per Day Study/Ratio Comments Nonsmoker 1-9 l&19 m-39 40+ All smokers Nonsmoker 1-14 lb24 25+ All smokers Nonsmokers l-9 10-20 21+ All smokers Nonsmoker about 10 about 20 Over 30 All smokers U.S. Veterans 1.M) 0.95 1.32 1.63 2.59' 1.41 British Physwians" 1.00 2.66 3.00 3.00 2.66 ACS S-State Study"' 1.00 1.90 1.8 2.94 1.90 California Males in Various Occupations 1.00 0.86 3.30 2.57 2.46 `Less than 20 deaths "Grams of tobacco per day "`Includes genitourinary effect of the later initiation of smoking by females as evidenced so clearly by the recent increases in female lung and laryngeal cancer risks. Correlation of Kidney Cancer Mortality Among Populations With Different Tobacco Consumption The relative risk of kidney cancer is reduced in populations with a low proportion of smokers (79, 16.5, 166, 212, 294), although this reduction is not as great as that observed for lung, larynx, esophageal, and oral cancer. Smoking and Histologic Changes in the Kidney No human autopsy studies have been published which examine histologic changes in the kidney among smokers compared to nonsmokers. 121 Kidney Cancer and Non-Cigarette Tobacco Use An elevated relative risk of from tenfold to twelvefold has been reported for smokers of pipes or cigars in one study (21). The U.S. Veterans Study noted an association for pure pipe smokers (ratio 1.32) and for mixed smokers of pipe and cigars (ratio 1.52) and kidney cancer, but not for pure cigar smokers. Conclusion Cigarette smoking is a contributory factory in the development of kidney cancer in the U.S. The term "contributory factor" by no means excludes the possibility of a causal role for smoking in cancers of this site. Carcinoma of the Pancreas Introduction In 1982, it is estimated that there will be 24,800 new cases and 22,300 deaths from carcinoma of the pancreas in the United States (2). Pancreatic cancer caused the deaths of 8,953 persons in 1950 and 20,465 persons in 1977 (the data for 1977 include deaths coded under ICD No. 157). The age-adjusted death rate rose from 5.3 per 100,000 in 1950 to a peak of 6.8 in 1968, and has remained stable since, at about 6.7. After 1968, the age-adjusted death rate from this disease actually decreased slightly from 6.8 to 6.7 per 100,000. Increases in the age-adjusted rate between 1950 and 1967 resulted from increases in the mortality rates of all four color-sex groups (Figure 50), with white females showing the smallest increase and other than white males showing the largest. In 1950, white males and females had higher death rates from this disease than did males and females of other races. By 1977, the age-adjusted rate for whites was 22 percent lower than the rate for others. The age-adjusted death rate of white males increased from 6.4 to 8.3 per 100,000 over the study period, and that of white females rose slowly from 4.3 to 5.2. Rates nearly doubled in the other populations, rising from 3.4 to 6.6 in females and from 5.3 to 10.5 in males. Among white males 25 to 84 years of age, there was an increase in mortality from 1950 until 1967 (Figure 51). Thereafter, this trend was reversed, except in males 75 or older. Among other than white males, rates rose steadily during the 1950s and early 1960s and then leveled off or declined, except among those 55 or older, whose mortality rates continued to increase through 1977 (Figure 52). Both white and other females of most ages had increasingly higher mortality rates over the entire 1950-1977 period. Generally, the mortality sex ratio decreased with advancing age in both the vvhite and the other than white populations. The age- specific death rates over time show an increase in the older age 122 " - - 6 + =WHITE HALES ^ *m 31 %=WHITE FEHALES ". if zo D=NONWHITE HRLES $ Ek III=NONWHITE FEHALES 3 f if: K W ; #" o.*a* * * -a - *a - * *.a........,.., 1950 1956 1960 1965 1970 1976 m CRLENOAR YEARS URLES 3. I FEMRLES +=1950-1956 m =1957-1963 (3 -1964-1970 R=1971-1977 f = 150 3 I /F 0 0 10 20 30 40 50 60 70 80 RGE IN YEARS (BY 5-YEAR AGE GROUPS) 250 200 50 IIRLES ROE IN YEARS IBY S-YERR ROE GROUPS1 FEtlALES + =1950-1966 * =1967-1953 0 =1964-1970 cJ=1971-1977 AGE IN YEARS IBY S-YERR RGE GROUPS) FIGURE 53.-Age-specific mortality rates by 5-year age groups for cancer of the pancreas for white males, United States, 1950-1977 SOURCE: Natxmal Cancer Institute (198). groups without significant increases in the rates of the younger age groups, as is readily apparent when age-specific death rates for white males and females are plotted on a three-dimensional graph (Figures 53 and 54). Pancreatic carcinoma is generally undetected until late in its course, due to difficulties in diagnosis and the nonspecific nature of the presenting symptoms. Metastasis occurs relatively early in the 126 -----T------ IlllIllIlIlIlIIIIIIIIIIII 1 FIGURE 54.-Age-specific mortality rates by 5-year age groups for cancer of the pancreas for white females, United States, 1950-1977 SOURCE: National Cancer Institute W8b course of this disease, contributing to the poor S-year survival rate of 2 percent (194) and a mean survival time after diagnosis of less than 6 months (187). The most common form of pancreatic cancer is adenocarcinoma. Pancreatic cancer is more common among men than among women in the United States, but the male to female ratio has been decreasing steadily from 1.6:1 during the period of 1940-1949 to 1.2:1 estimated in 1960 (27G). 127 Several epidemiological studies have `established an association between cigarette smoking and pancreatic cancer. Causal Significance of the Association Consistency, Strength, and Specificity of the Association A number of retrospective studies have examined the relationship between smoking and pancreatic cancer. In the Third National Cancer Survey (299) and in the Hawaiian Study of Five Ethnic Groups (1131, there was a significant positive relationship between smoking and pancreatic cancer. An earlier retrospective case control study of 81 cases of pancreatic cancer (3.201 found a dose-response relationship with a relative risk of 5.0 for males smoking more than two packs of cigarettes per day (Figure 551. A recent report found a positive association for both males and females who had ever smoked and cancer of the pancreas (relative risk of 1.41, but not for pipe or cigar smokers. They also reported a significant dose-response rela- tionship for females. A similar but not significant dose-response relationship was noted for males (169). Several of the large prospective investigations have reported mortality ratios of approximately 2.0 for smokers as compared with nonsmokers. These data are presented in Table 36. The dose- response relationships from four of the major prospective studies are presented in Table 37. Smokers consuming more than one pack of cigarettes per day had mortality ratios two to three times greater than those of nonsmokers. These data consistently support an association between smoking and pancreatic cancer, although the strength of the association is less than that noted for smoking and cancer of the lung, larynx, oral cavity, and esophagus. Temporal Relationship of the Association Support for the temporal relationship of the association is provided by the prospective studies that observed subjects over varying periods of time for the development of pancreatic cancer. Support for the temporality of the association is advanced by a histological study showing a greater frequency of premalignant changes in pancreatic tissue of smokers when compared with tissue of nonsmokers (1621, and by cohort analysis showing correlation between trends in smoking patterns and pancreatic cancer mortality (22, 128). 128 5, 4 - 3 - 2 - l- O- N: CASES CONTROLS 13 5; -0 e-w- NEVER SMOKED l-10 11-M 2140 41* NO. OF CIGARETTES SMOKED PER DAY FIGURE BEi.--Relative risk of pancreatic cancer in males, by number of cigarettes smoked SOURCE: Wynder (320). Coherence of the Association Dose-Response Relationship The coherence of the association is supported by the dose-response relationship noted above, although it is not as marked as those noted for smoking and other cancers. Correlation of Pancreatic Cancer Among Populations With Different Tobacco Consumption The finding of a low incidence of pancreatic cancer in special groups (e.g., Mormons and Seventh Day Adventists) with a small proportion of smokers (79, 165, 166, 211, 294) is consistent with a causal relationship. 129 TABLE 36.-Pancreatic cancer mortality ratios-prospective studies Study Size of Population Nonsmokers All Cigarette * Smokers Comments ACS 9.State Study 188000 white males Canadian 78,000 Veterans males ACS 25Stat.e Study 358,000 males 483,ooO females U.S. Veterans 290,000 males Japanese Study 122,OlXl males 143,COO females California occupations 68,OflO males Swedish Study 55,ooo males and females 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 3.1 males 1.00 2.5 females 1.50 Based on 117 microscopically proved cases 1.96 2.14 1.42 1.79 1.57 males 1.94 females 2.43 British Physicians 34,000 males 1.M) 1.60 TABLE 37.-Mortality ratios for cancer of the pancreas by amount smoked-prospective studies Study Swedish Study Population 5waJ males and females Amount Smoked per Day Comments Males Females NS 1.00 NS 1.00 l-7 1.60 l-7 2.40 8-15 3.40 8-15 2.50 15 + 5.90 15 + 3.00 British Physicians 40,ooo NS 1.00 NS 1.00 Males based 1-14 1.35 1-14 0.44 on grams of 15-24 1.42 15-24 2.66 t&WC0 25 + 2.07 25 + 1.77 per day Japanese 265,ooO NS 1.00 NS 1.00 Study males and l-19 1.42 l-19 1.M) females 20-39 1.57 20-29 1.60 40 + 0.69 30+ 1.90 U.S. Veterans 290,ooo NS 1.00 n-G&S 1-9 1.60 lG20 1.71 21-39 2.00 40 + 2.20 NOTE NS Nonsmoker 130 Correlation of Sex Differences in Pancreatic Cancer With Different Smoking Habits The declining male to female mortality ratio discussed above is consistent with the delayed initiation of cigarette smoking by women as compared to men. Two studies have performed cohort analyses of the relationship of time trends in smoking patterns among males and females and mortality rates from carcinoma of the pancreas. Bernard and Weiss (22) examined the relationship in the United States for the period of 1939 to 1969; Moolgavkar and Stevens (185) examined these relation- ships in England and Wales for the period of 1941 to 1975. Both studies found a positive association between changes in smoking habits in males and females and pancreatic cancer death rates. Smoking and Histologic Changes in the Pancreas A recently reported study (162) found evidence for premalignant changes in pancreatic tissue of smokers. The authors collected 108 specimens of pancreatic tissue. In 44 percent of the series, there were some focal acinar cell abnormalities, which the authors state were similar to atypical acinar cell nodules in carcinogen-treated animals. These findings were more common in tissue from patients with a history of smoking as compared with tissue from nonsmokers. Tissue from heavy smokers (67 to 100 pack-years) showed a 1.8 times higher incidence of such nodules than tissue from all smokers. Pancreatic Cancer and Non-Cigarette Tobacco Use The U.S. Veterans Study found an elevated risk of 1.5 for pancreatic cancer in cigar, but not pipe, smokers. Experimental Studies Dietary factors, the presence of underlying diseases, such as chronic pancreatitis and diabetes mellitus, and chemical exposures have been suggested as potential determinants for this disease (187). The pathogenic mechanisms by which tobacco smoking influences the development of pancreatic cancer are obscure. It has been suggested that a carcinogen derived from tobacco smoke (either directly or after metabolism by the liver) ts excreted into the bile (321). It is then refluxed into pancreatic ducts and induces cancer. One group of investigators (145) has reported that nicotine inhibits pancreatic bicarbonate secretion in the dog by direct action on the organ. This has led to speculation that inhibition of duct cell secretion of bicarbonate could lead to intracellular pH changes and subsequently play a role in carcinogenesis. It has also been suggested that a protease-antiprotease imbalance may be capable of promoting carcinogenesis. Cigarette smoke is known to affect the protease- 131 antiprotease balance in vivo and in vitro. In a study of beagle dogs smoking 12 cigarettes per day for 600 days, the authors reported significant changes in pancreatic proteases as compared with their sham-exposed controls (189). Conclusion Cigarette smoking is a contributory factor in the development of pancreatic cancer in the U.S. The term "contributory factor" by no means excludes the possibility of a causal role for smoking in cancers of this site. Stbmach Cancer It is estimated that in the United States there will be 24,200 new cases of stomach cancer and 13,800 deaths in 1982 (2). For unknown reasons, mortality rates and the number of deaths have fallen dramatically over the last 28 years. The age-adjusted mortality rate for stomach cancer has continued to decline for both males and females. Since the period of 1951-1953 through 1976-1978, the age-adjusted rate has decreased by 59 percent in males and 65 percent in females. Rates for both males and females adjusted to the 1970 population are presented in Figure 56. Figures 57 and 58 give age-specific death rates for cancer of the stomach for four separate time periods by race and sex. In 1950, cancer of the stomach was fatal to 24,257 persons; in 1977, 14,440 died from this cancer in the United States. Death rates are higher for races other than white than for whites; other males have higher death rates than any of the other color sex groups. The age-adjusted rate for other than white males was 31.16 in 1950 compared to 23.86 for white males. The corresponding rates for females were 16.05 and 13.13, respectively. By 1977, the rate for other than white males had decreased to 15.18; the corresponding rate for white males was 8.25. The age-adjusted rate for females other than white was 7.46 in 1977 compared to 3.83 for white females. These differences may represent variations in exposure to undeter- mined dietary and other environmental factors or genetic differ- ences. A limited number of epidemiological studies have examined the relationship between smoking and stomach cancer. The data are not consistent, but overall, the evidence points to a possible association between cigarette smoking and stomach cancer. Olearchyk (204) noted that alcoholism (26.7 percent) and smoking (26 percent) were common habits of 243 patients with stomach cancer. In the popula- tion-based Third National Cancer Survey (299), there was a signifi- cant positive association between smoking and stomach cancer. A few other retrospective studies have also reported a statistical association between smoking and stomach cancer (122,151,302). 132 +=HHITE flALES 3~ rWHITE FEllALES O=NONWHSTE HRLES IJl =NONWHITE FEMRLES 4 1970 1975 0' * ' 1955 1960 1965 1960 CALENORR YERRS AGE IN YEFlRS (BY S-YERR AGE CROUPS1 FEMWES +=1950-1956 L 21957-1963 0=1964-1970 c1=1971-1977 / * MRLES AGE IN YEnRS IBY 5-YERR RGE GROUPS1 FEllfILES + =1960-19.56 Ill =1967-1963 0=1964-1970 [II =1971-1977 10 20 30 40 50 60 70 SO AGE IN YERRS IBY S-YEAR ROE DROUPSl TABLE 38.-Stomach cancer mortality ratios-prospective studies Population Study size NO"- smokers All cigarette smokers Comments ACS O-State 186,OKJ Study white males U.S. Veterans Swedish Study Japanese Study California males in 9 occupations ACS 25&&e Study British Physicians 55,ooo males and females mifm males and females 358,400 males woo0 1.00 1.00 (men) 1.00 (women) 1.00 (men) 1.00 (women) 1.00 1.00 45-64 1.00 6.579 1.M) 1.00 1.61 1.52 Jbed on 176 micrascopically proved cases 1.30 Cigarette and 2.30 pipe smokers 1.59 1.31 1.04 1.42 1.26 1.39 All current smokers TABLE 39.-Stomach cancer mortality ratios by amount smoked-prospective studies Amount smoked Study Population size per day Mortality ratio Comment U.S. Veterans 290.000 males Nonsmoker 1.00 l-9 1.47 10-20 1.49 21-39 1.55 40+ 1.83 British 34,ooO males Nonsmoker Physicians l-14 15-24 25+ California males in 9 occupations Nonsmoker about `I1 pk about 1 pk about 1 `I? pk 1.00 1.20 1.65 1.39 1.00 1.09 0.94 1.25 Japanese Study 122,OCKl males Nonsmoker 1.00 l-19 1.46 20-39 1.53 40+ 1.76 Baaed on grams of t&XX0 per day In contrast with the above investigations, the Hawaiian Study of Five Ethnic Groups failed to show a statistically significant associa- tion between smoking and stomach cancer (123). Haenszel et al. (91) 136 reported an increased relative risk for stomach cancer among smokers in a series of 783 patients living in the Hiroshima and Miyagi prefectures of Japan; however, these findings were not statistically significant. In a similar study of Japanese living in Hawaii, these same authors (92) found a statistically significant increased risk among Issei smokers but not among Nissei. The absence of a significant association between cigarette smoking and gastric cancer has been reported by other authors (236,318). The relationship between smoking and stomach cancer was examined in several prospective studies (Table 38). Although mortal- ity ratios were increased for smokers as compared with nonsmokers, these increases were small. Three of the four major prospective studies noted a consistent dose-response relationship as measured by the number of cigarettes smoked per day. However, the magnitude of these relationships was moderate compared to that between smoking and other cancer sites (Appendix Tables A and B). Conclusion 1. Epidemiological studies have noted an association between cigarette smoking and stomach cancer. The association is small in comparison with that noted for smoking and some other cancers. Cancer of the Uterine Cervix Slightly over 8,300 women died of cancer of the uterine cervix in 1950. By 1977, the total number of deaths attributed to this site had decreased to 5,165. The age-adjusted rate for white females is only about one-third that observed for races other than white (3.53 versus 9.63) (Figure 59). The age-specific rate for races other than white was 17.92 in. 1950 and decreased to 7.99 by 1977. The agespecific rate for white females decreased from 10.12 to 4.12 over the same time period (Figure 60). Squamous cell carcinoma is the major cell'type. The overall 5-year survival for patients with carcinoma of the cervix is 60 percent, but survival ranges from 86 percent for those with localized disease, to 50 percent for those with regional involvement, and to 22 percent for those with distant metastases (2). Cervical cancer appears to be more common among women who have early and frequent coitus, who have early or multiple mar- riages or partners, and who become pregnant at an early age or frequently (140, 264). In addition, a number of other variables have been studied that may affect the risk for cervical cancer, including 137 25 20 15 10 5 0 Cb %=WHITE FEtlALES l?l=NONNHITE FEtlALES - 4 1950 1955 1960 1965 1970 1975 CRLENORR YEARS WHITE FEIIALES 0 L 0 10 20 30 40 SO 60 70 60 RGE IN YEARS IBY 5-YEAR RGE GROUPS1 j NONWHITE FEMRLES + z1950-1956 X=1957-1963 D -1964-1970 c!l=1971-1977 ,,-., I . . L--L---_L1 IO 20 30 40 50 60 70 60 ROE IN YERRS IBY S-YEAR AGE GROUPS1 venereal infections, circumcision status of consort, and exogenous hormones (264). A limited number of studies have attempted to identify an association between cigarette smoking and cervical cancer. One study (192) reported a relationship between smoking status (never smoked, ex-smokers, present smokers) and suspicious or positive cervical cytology. Thomas (264) administered a home questionnaire to 324 females with abnormal cervical cytology and reported that the prevalence of smoking was 70 percent in cases with carcinoma in situ and 58 percent in controls (0.02 5 p 16 3.40 All smokers 3.00 diseases and matched for age, race, hospital, and hospital status (semi-private versus ward). Socioeconomic status was determined by the subject's education and occupation and by the husband's occupation. Their analysis showed an overall positive association between cigarette smoking and cervical cancer. However, after Mantzel-Haenszel adjustment for age and socioeconomic status, the authors did not find a statistically significant association. The authors suggest that the association between smoking and cervical cancer is highly confounded and not consistent with a causal hypothesis. This study also, however, failed to include direct measures of potential confounding variables, such as sexual activity. It should be noted that in the Swedish (42) and German (201) studies, differences in socioeconomic status did not affect cervical cancer incidence. The associations described between cervical cancer and many other variables, in addition to the variation in results of studies of. the possible association of cigarette smoking and cervical cancer, do not permit a conclusion on the character of this relationship at this time. Conclusion 1. There are conflicting results in studies published to date on the existence of a relationship between smoking and cervical cancer; further research is necessary to define whether an association exists and, if so, whether that association is direct or indirect. 141 Smoking and Overall Cancer Mortality Introduction Several investigators have estimated the proportion of all cancer deaths attributable to tobacco use in the United States to range from 22 percent to 38 percent of all cancer deaths (70, 78, 106). The authors of a recent review of cancer causes (701, commissioned by the Congressional Office of Technology Assessment, conclnded that 30 percent of all U.S. cancer deaths are attributable to tobacco use ~Appendix Table 0. These estimates reflect a growing consensus that smoking is the single largest contributor to cancer mortality in the United States. Overall Cancer Mortality As early as 1928, Lombard and Doering (160), in a study of 217 cancer patients and 217 controls in Massachusetts, identified an association between heavy smoking (defined as all types of smokers) and cancer in general. This study is of historical significance in light of our present day knowledge about the relationship, between smoking and specific cancer sites. Over the last two decades, four of the eight major prospective studies have examined the relationships between smoking to overall and site-specific cancer mortality. Two of these studies (98, 120) included observations on females as well as males. Male smokers, regardless of the amount smoked, have approxi- mately twice the risk of dying from cancer than do their nonsmoking counterparts (Table 41). Data from these studies also showed a gradient increase in overall cancer mortality with the amount smoked. These data are presented in Table 42. Males who consumed more than one pack of cigarettes daily had overall cancer mortality rates almost three times greater than did nonsmokers. Mortality TABLE 4l.-Smoking and overall cancer mortality ratios- prospective studies Smokers Study Nonsmokers Male Female ACS 25State Study 1.00 1.79 1.18 pipe and cigar 1.21 U.S. Veterans Japanese Study ACS 9-State Study 1.00 1.00 1.00 2.12 1.32 cigars 1.29 pipes 1.62 1.41 1.97 cigarettes 1.44 pipe 1.34 cigar 142 TABLE 4Z.--Smoking and overall cancer mortality ratios in males by amount smoked Study Amount smoked per day Mortality ratio ACS S&ate Study Nonsmoker 1.00 l-9 1.87 lo-20 1.92 20+ 2.94 All smokers 1.97 U.S. Veterans Japanese Study Nonsmoker 1.00 1-9 1.42 x-20 1.95 21-39 2.66 40+ 3.31 All smokers 2.12 Nonsmoker 1.00 1-19 1.53 20-39 1.81 40+ 2.06 All smokers 1.62 A B C D E Em Current cqaretle smokers n Ex-cigarette smokers . FIGURE 61.-Mortality ratios for all cancer sites for ex- cigarette smokers by number of years of smoking cessation, U.S. Veterans Study NOTE: A: Stopped less than 5 years. B: Stopped 5-9 years C:Stopped1&14yean. D: Stopped 15-19 years. E: stopped 20 or more years. SOURCE: Roget and Murray 122~. ratios for male pipe smokers and male cigar smokers were 1.44 and 1.34, respectively (224). Female smokers had overall cancer mortali- ty rates 20 to 40 percent greater than female nonsmokers. Hammond (106) calculated that 34.5 percent of all cancer deaths in males were smoking related. These are in close agreement with estimates made by other investigators (70,216). Rogot and Murray (224) examined overall cancer mortality in ex- cigarette smokers compared to continuing cigarette smokers and 143 1 Ex- smokers Current smokers FIGURE 62.-Mortality ratios for all cancer sites for current and ex-smokers by number of cigarettes smoked daily, U.S. Veterans Study SOURCE Roqt and Murray 1Z4) found declining cancer mortality ratios for ex-smokers by the number of years off cigarettes. For those former smokers who had quit for. 20 years or more, the overall cancer mortality rate was approximately 25 percent above those of nonsmokers but substan- tially below those of continuing smokers (1.27 versus 2.12) (Figure 61). These investigators also noted that cancer mortality. among former cigarette smokers was correlated to the number of cigarettes smoked per day. A clear gradient by the amount smoked is evident for ex-smokers as well as continuing smokers for overall cancer mortality (Figure 62). Overall cancer mortality rates for former cigarette smokers were 40 peEcent greater than for nonsmokers. Conclusion 1. Cigarette smokers have overall mortality rates substantially greater than those of nonsmokers. Overall cancer death rates of male smokers are approximately double those of nonsmok- ers; overall cancer death rates of female smokers are approxi- mately 30 percent higher than nonsmokers, and are increasing. 2. Overall cancer mortality rates among smokers are dose-related as measured by the number of cigarettes smoked per day. Heavy smokers (over one pack per day) have more than three times the overall cancer death rate of nonsmokers. 3. With increasing duration of smoking cessation, overall cancer death rates decline, approaching the death rate of nonsmokers. 144 Summary 1. Cigarette smoking is the major cause of lung cancer in the United States. 2. Lung cancer mortality increases with increasing dosage of smoke exposure (as measured by the number of cigarettes smoked daily, the duration of smoking, and inhalation pat- terns) and is inversely related to age of initiation. Smokers who consume two or more packs of cigarettes daily have lung cancer mortality rates 15 to 25 times greater than nonsmokers. 3. Cigar and pipe smoking are also causal factors for lung cancer. However, the majority of lung cancer mortality in the United States is due to cigarette smoking. 4. Cessation of smoking reduces the risk of lung cancer mortality compared to that of the continuing smoker. Former smokers who have quit 15 or more years have lung cancer mortality rates only slightly above those for nonsmokers (about two times greater). The residual risk of developing lung cancer is directly proportional to overall life-time exposure to cigarette smoke. 5. Filtered lower tar cigarette smokers have a lower lung cancer risk compared to nonfiltered, higher tar cigarette smokers. However, the risk for these smokers is still substantially elevated above the risk of nonsmokers. 6. Since the early 1950s lung cancer has been the leading cause of cancer death among males in the United States. Among females, the lung cancer death rate is accelerating and will likely surpass that of breast cancer in the 1980s. 7. The economic impact of lung cancer to the nation is consider- able. It is estimated that in 1975, lung cancer cost $3.8 billion in lost earnings, $379.5 million in short-term hospital costs, and $78 million in physician fees. 8. Lung cancer is largely a preventable disease. It is estimated that 85 percent of lung cancer mortality could have been avoided if individuals never took up smoking. Furthermore, substantial reductions in the number of deaths from lung cancer could be achieved if a major portion of the smoking population (particularly young persons) could be persuaded not to smoke. 9. Cigarette smoking is the major cause of laryngeal cancer in the United States. Cigar and pipe smokers experience a risk for laryngeal cancer similar to that of a cigarette smoker. 10. The risk of developing laryngeal cancer increases with in- creased exposure as measured by the number of cigarettes smoked daily as well as other dose measurements. Heavy smokers have laryngeal cancer mortality risks 20 to 30 times greater than nonsmokers. 145 11. Cessation of smoking reduces the risk of laryngeal cancer mortality compared to that of the continuing smoker. The longer a former smoker is off cigarettes the lower the risk. 12. Smokers who use filtered lower tar cigarettes have lower laryngeal cancer risks than those who use unfiltered higher tar cigarettes. 13. The use of alcohol in combination with cigarette smoking appears to act synergistically to greatly increase the risk for cancer of the larynx. 14. Cigarette smoking is a major cause of cancers of the oral cavi.ty in the United States. Individuals who smoke pipes or cigars experience a risk for oral cancer similar to that of the cigarette smoker. 15. Mortality ratios for oral cancer increase with the number of cigarettes smoked daily and diminish with cessation of smok- ing. 16. Cigarette smoking and alcohol use act synergistically to increase the risk of oral cavity cancers, 17. Long term use of snuff appears to be a factor in the develop- ment of cancers of the oral cavity, particularly cancers of the cheek and gum. 18. Cigarette smoking is a major cause of esophageal cancer in the United States. Cigar and pipe smokers experience a risk of esophageal cancer similar to that of cigarette smokers. 19. The risk of esophageal cancer increases with increased smoke exposure, as measured by the number of cigarettes smoked daily, and is diminished by discontinuing the habit. 20. The use of alcohol in combination with smoking acts synergisti- cally to greatly increase the risk for esophageal cancer mortality. 21. Cigarette smoking is a contributory factor in the development of bladder, kidney, and pancreatic cancer in the United States. This relationship is not as strong as that noted for the association between smoking and cancers of the lung, larynx, oral cavity, and esophagus. The term "contributory factor" by no means excludes the possibility of a causal role for smoking in cancers of these sites. 22. In epidemiological studies, an association between cigarette smoking and stomach cancer has been noted. The association is small in comparison with that noted for smoking and some other cancers. 23. There are conflicting results in studies published to date on the existence of, a relationship between smoking and cervical cancer; further research is necessary to define whether an association exists and, if so, whether that association is direct or indirect. 146 24. Cigarette smokers have overall mortality rates substantially greater than those of nonsmokers. Overall cancer death rates of male smokers are approximately double those of nonsmok- ers; overall cancer death rates of female smokers are approxi- mately 30 percent higher than nonsmokers, and are increasing. 25. Overall cancer mortality rates among smokers are dose-related as measured by the number of cigarettes smoked per day. Heavy smokers (over one pack per day) have more than three times the overall cancer death rate of nonsmokers. 26. With increasing duration of smoking cessation, overall cancer death rates decline, approaching the death rate of nonsmokers. Technical Notes Age-Adjusted Death Rates Age-adjusted death rates show what the level of mortality would be if there were no changes in the age composition of the population from year to year. The age-adjusted death rates for the U.S. as a whole presented in this Report were computed by the Direct Method, that is, by applying the age-specific death rates for all causes of death or for deaths for a given cause to the standard population distributed by age. The total U.S. population as enumerated in 1940 is used as the standard population by the National Center for Health Statistics for presentation of mortality statistics. Standard popula- tions other than 1940 have been used by other agencies, organiza- tions, and researchers in presenting mortality data. This introduces some problems of comparability in the presentation of the statistical findings drawn from a variety of sources. Cause-of-Death Classification National mortality statistics from the National Center for Health Statistics for the U.S. presented in this Report are classified in accordance with the World Health Organization (WHO) Regulations, which specify that member nations classify causes of death in accordance with the International Statistical Classification of Dis- eases, Injuries, and Causes of Death. The deaths are tabulated and presented in Vital Statistics of the United States, Volume II, Mortality by cause-of-death categories that are consistent with WHO recommendations. Other organizations and researchers whose work is cited in this Report may use different cause-of-death categories. This introduces some problems of comparability in the presentation of the statistical findings drawn from a variety of sources. Another problem of comparability in mortality rates is introduced when comparisons are made over time for specific causes of death. This is because of the practice to periodically revise the Internation- al Classification of Diseases (ED) by which causes of death are 147 classified and tabulated. The ICD has been revised approximately every 10 years since 1900 to keep abreast of medical knowledge. Each decennial revision has produced breaks in the comparability of cause-of-death statistics. For many of the causes of death described in this Report, the reader may refer to the NCHS report (199) for information about comparability in cause of death statistics due to revisions in the ICD during 1950-1977. Appendix Tables APPENDIX TABLE A.-Mortality ratios (smokers vs. never smoked regularly) for smoking-related cancers among females-ACS 25-State Study and Japanese Study Underlying cause of death Mortality ratios Cancer (total) ACS JlZpWW 1.21 1.41 Lung (excl. trachea. pleura) Buccal cavity, pharynx, larynx, and esophagus Pancreas Uterus Uterine cervix Esophagus Stomach , Bladder 3.56 2.03 3.25 6.52 1.42 - 1.18 - - 1.72 4.89 - 1.21 1.31 2.56 2.00 APPENDIX TABLE B.-Mortality ratios (smoker vs. never smoked regularly) for smoking-related cancers among males-ACS 25-State Study and U.S. Veterans Study Underlying cause of death Mortality ratios Cancer (total1 ACS U.S. Veteran.5 Bee- &e 65-79 All 2.14 1.76 2.12 Lung (excl. trachea, pleura) Buccal cavity, pharynx Larynx E-Www Bladder and other urinary Kidney PEState Pancreas Liver. biliary passages 7.64 11.59 9.90 2.93 6.09 8.99 4.17 1.74 2.00 2.96 1.42 1.57 1.04 1.01 2.69 2.17 2.64 1.34 1.42 1.26 11.28 4.22 11.49 6.43 2.16 1.41 1.31 1.79 - 1.52 148 APPENDIX TABLE C.-Cancer deaths caused by tobacco: United States, 1978 Number of deaths Certified cause of deatha Observed Estimated, had Americans not smoked Approximate excess number and percent of deaths attributed to tobacco (percent m parentheses] Cancer, males Lung Mouth, pharynx, larynx, or esophagus Bladder Pancreas Other specified sites Unspecified sites Total, males Cancer, females Lung Mouth, pharynx, larynx, or esophagus Bladder Pancreas Other specified sites Unspecified sites Total. females Total, males and females 71.006 6.439" 64.567 (90.91 14.282 6.771 11,010 loo.799 14,469 218,337 24.080 5.454h 16.626 177.4) 5.100 3,078 9,767 127,642 13,951 183,618 401,955 1.79" . 2 2.9601) 6.585'* - 8,18% 1.458x 2c 2,170'* 7,291b 11.879 10.698 174.91 3,811 (56.3) 4,425 (40.21 5.oood I 5.01 6,281 143.4) 94.782' (43.41 2,184 t42.81 908 (29.51 2,476 125.41 1.m - 2,072 (14.9, 27,266' (14.8l 122,048' (30.41 "Site of origin oicancer bNumber estimated by opplymg the nonsmoker mortality rates reported by Carfinkel (861 to the U.S population of 1978. ~Double the number estimated by the procedure descr&d in footnote b This number was doubled to allow ior the possibility that the subjects in the ACS prospective study were less exposed to alcohol or to some other cause(s) of cancer of the upper respiratory or &grstlve tracti than were average people m the United States. j Some evidence that this was mdeed the case is that even the cigarette smokers I" the ACS study had mortality rates ior these types of cancer that were somewhat below the netional US rates l9H) ) However. it makes IntIe difference to our grand totals whether the small number of cancers of the mouth and throat "expected" irom the ACS nonsmokerexperrence we leit unaltewd. are doubled, or are trebled. dOther specified sites include some. such as ludney. that may truly be aiiected by tobacco, and some, such as stomach or liver, that include a proportion of misdiagnosed cases ofcigarette-mduced cancer of the lung, pancreas, and other organs Some iractio" oi the cancers certified as being of other specified sates IS thus due to smoking, which in part explains the excess mortality among smokers I" the aggregate of all such cancer that IS iound in the American prospective studies (Appendix Tables A and BI. 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For example, the World Health Organization (WHO) (291, the Interna- tional Agency for Research on Cancer (IARC) ($1, the Environmental Protection Agency (31, the Food and Drug Administration (4), the National Cancer Institute - National Toxicology Program (221, Health and Welfare of Canada (21, and the Health Council of the Netherlands (13), as well as others, have issued guidelines for the testing of compounds for different aspects of acute and chronic toxicity. Chemicals As a first step in the testing of any material for possible carcinogenicity, the researcher should obtain a complete physic+ chemical characterization of the material. Examinations by such techniques as thin-layer, gas-liquid, or high performance liquid chromatography should afford some idea of whether the material is homogeneous or a mixture of components. If the last is the case, identification of the individual components and determination of the level of each in the mixture are highly desirable. Otherwise, the validity and significance of the results may be questioned. Factors Influencing Carcinogenicity In tests for possible carcinogenicity, several factors influence the outcome of any study. Those relevant to the compound are the route of administration and the dose and frequency of administration. Factors relating to the animal are the species, strain, sex, age, diet, spontaneous tumor incidence, and immunological status. Route of Administration Oral administration In addition to being a logical technique for testing compounds that may be ingested by humans, oral administration is also useful for compounds that may be inhaled as dusts, cleared from the airways by ciliary action, and then swallowed. Compounds may be mixed in the feed, given as aqueous solutions instead of normal drinking water, given by gavage at appropriate intervals, or even given in capsules. If the compound is mixed with the feed, the uniformity of 173 mixing, the stability in the diet, and the nonreactivity with the feed are factors of concern. Volatile compounds should not be given in the diet, for the resultant loss will lead to inaccuracies in dose levels. If given in the drinking water, solubility and stability must be considered. Dermal The dermal route simulates exposure of the skin as it occurs in occupational situations or in the use of cosmetics, and has been used as a standardized carcinogenicity assay. Application of a solution of the test-material by means of a pipet should be made in an area that cannot be reached by the animal. Otherwise, the animal will lick the treated area so that oral ingestion occurs. To avoid the animals' licking each other, single caging is desirable. In this type of test, mice, hamsters, rabbits, and sometimes rats are used. For cutaneous application, mice of the BALB/c, CSHf, or DBA strains or the non- inbred Swiss strain are most responsive. SENCAR mice have been especially bred for sensitivity in initiation-promotion assays. The skin should be clipped before'application of the test compound, but abrasion or mechanical injury of the skin should be avoided. Implantation: Subcutaneous and Intramuscular Although subcutaneous injection of polycyclic aromatic hydrocar- bons in mice has proved to be quite reliable as a test system, the use of this test in other species has led to controversial results. The induction of tumors at the implantation site, especially in rats, by inert materials of the proper size, by saline solutions, or by oily solvents has indicated the limitation of this test. Injection: lntraperitoneal and Intravenous Intraperitoneal and intravenous injections may be used to test drugs, but for various reasons are not suitable for repeated dosing. They are useful for administering a single dose or a few doses of potent carcinogens for model experiments. With this technique, exposure of personnel to carcinogens, is minimized. Inhalation Inhalation is the major route by which persons are exposed to cigarette smoke. For laboratory study, complex installations, such as pumps or metering devices, are needed to allow uniform delivery of the test material to the experimental animals. Scrubbers and other devices are required to prevent exposure of any personnel working in the area. A test by the inhalation route usually costs much more than studies using other routes of administration. 174 In lieu of using large inhalation chambers in which animals are exposed, it is possible to use chambers into which the head and nose of individual animals are fitted. The test material is then forced into the chamber, resulting in an inhalation exposure. Relatively few animals can be treated with a given chamber by this method, however. Factors that should be considered in evaluating the results of the test are effects on secretion of mucous, alteration of pulmonary ventilation, and possible toxicity to the cilia in the respiratory tract. The dilemma is that in rodents the anatomy and physiology of the respiratory tract and the biochemistry of the lung differ from that of humans and that animals anatomically resembling the human most closely are too expensive and have lifespans too long to permit their use in routine tests. For inhalation tests of the carcinogenicity of tobacco smoke and various fractions of tobacco smoke, hamsters are preferable to rats and mice because they respond with a higher incidence of airway tumors (6). Higher dose levels, greater frequency of administration, and longer periods of observation are required for weak carcinogens than are needed for potent ones. For example, potent carcinogens such as 7,12-dimethylbenz[a]anthracene or nitrosomethylurea can induce cancers in certain animals after a single dose. On the other hand, a single or very low dose of compounds such as N-2-fluorenylacetam- ide, safrole, and dioxane may not lead to tumors within the lifespan of the animal. Animal Factors Species The choice of species rests on several factors, including lifespan, size, sensitivity to a specific class of compound, and availability. Early studies on skin painting of benzo[a]pyrene showed that mice and rabbits were responsive, while the few other species tested were less responsive. Guinea pigs are not suitable for testing aromatic `amides and amines or their precursors. They either lack the enzyme system that activates aromatic amines or degrade the activated metabolite so rapidly that there is no effect. Overall, mice are the most useful animals for skin painting bioassays; rats are useful for test material that might be fed, especially with nitroso compounds or aromatic amines; and hamsters seem better suited for inhalation studies on tobacco smoke or its components. Larger species including the rabbit, dog, and primate require a longer time to obtain results; they are expensive to purchase, to maintain, and to test; and they are not always readily available. 175 Strain Within a given species, there are likely to be sizable strain variations in response to any specific carcinogen. In the more than 10 strains of rats that have been tested with N-24luorenylacetamide, the response in a given target organ varied from zero to almost 100 percent, depending on the strain. Similarly, ethionine causes liver tumors in some strains of rats but not in others; a single oral dose of 7, 12dimethylbenz[a]anthracene leads to a high incidence of mam- mary tumors in Sprague-Dawleyderived virgin female rats and none in some other strains. Mouse strains also exhibit considerable variation in their response to ethyl carbamate and other carcinogens (28). The spontaneous incidence of tumors of particular organs varies with the strain of animal used for the test. This factor will determine the number of animals required for a meaningful assay. Strains with a high spontaneous incidence of tumors may be particularly sensi- tive to exposure to test compounds, a characteristic that will also affect the numbers of animals needed for the assay. Species variation in spontaneous tumor incidence does not, however, predict sensitivi- ty to a specific agent. Before initiating any bioassay, thorough study of the literature is needed to select the proper strain of animal for the types of compounds under test. sex There are appreciable differences in the response of male and female animals to some known carcinogens. Examples are the higher incidence of skin tumors in male mice after painting with 7, 12- dimethylbenz[a]anthracene and the greater number of liver tumors in male rats after feeding 2diacetylaminofluorene. With o-aminoazo- toluene, however, female mice were affected more than males. The differences may reside in the role sex hormones play in determining the levels of certain activating enzymes. Male mice of many strains fight among themselves, causing skin wounds and deaths. The males of such strains should not be used for dermal assays unless they are individually housed or acclimated to each other when young. In routine tests, animals that are a few weeks' post-weaning are preferred so that they may be exposed to the test agent for the major part of the life span. If the animals are too old when the tests begin, they may die of other causes before tumors have time to develop. Neonatal animals are more susceptible to many carcinogens than are young adults. A striking example is the induction of liver tumors 176 in mice treated on day l-7 of life by aflatoxin Bl(AFB1); much larger doses of AFBl administered to weanlings or young adult mice did not induce liver tumors (25). Similar results were noted with vinyl chloride (12). However, the difficulties in using neonatal animals are such that this method is hardly used for routine testing of com- pounds. Diet Both the total calories available from the diet and the type of diet influence the outcome of carcinogenicity studies. Restriction in calories may decrease not only the incidence of spontaneous tumors in animals but also the response to a carcinogen (20, 24). Diets deficient in protein, vitamins, or other essential factors may enhance the action of certain carcinogens (II). On the other hand, high levels of some vitamins increase the activity of detoxifying enzymes, thus depressing or inhibiting a carcinogenic effect. High levels of fats enhance the action of certain carcinogens (14, 19); indications are that high fat levels lead to production of bile acids (17), which may have a cocarcinogenic effect. Adventitious dietary factors that may affect carcinogenesis assays include traces of nitrosamines, mycotoxins, and pesticides. Many nitrosamines and some mycotoxins are highly active carcinogens. Traces of pesticides may induce enzymes that activate or detoxify carcinogens. Similarly, vegetable material, usually a component of the processed rodent diets sold in pellet form, and antioxidants act as enzyme inducers and may influence the outcome of carcinogenicity trials. Sponta'neous Tumor Incidence Since many experiments will extend over most of the lifespan of the experimental animals, it is necessary to know what spontaneous tumors might be expected. The many literature references on tumors in various rat or mouse strains should be consulted (5, 7, 16, 21, 27). These furnish background information on spontaneous tumor inci- dence that allows the researcher to avoid a strain with a very high tumor incidence that may complicate the interpretation and evalu- ation of bioassay data. However, tumor incidence in an inbred strain may shift over a period of years. Furthermore, specific laboratory conditions such as feed, water, lighting, housing, and handling procedures may affect the "spontaneous" tumor incidence, Adequate numbers of untreated control animals must be included in the experimental design. 177 Immune Status The immune status of animals influences their response to the carcinogenic action of viruses or ultraviolet radiation (1, 10, 18, 23). The same may be true for chemical carcinogens. Although immuno- suppression increases the likelihood of tumor development or successful transplantation (9), even from allogeneic tumors, few carcinogenicity studies have been done on immunosuppressed ani- mals. Procedures Planning Any long-term bioassay must be thoroughly planned. Consider- ation should be given to delineating responsible personnel and their specific duties, obtaining and analyzing the test substance, selecting the animal species and strain, and deciding on dose, route of administration, length of exposure, animal group size, randomiza- tion, what observations should be made, animal husbandry, data acquisition, processing, storage and retrieval, data analysis or statistical methods, diet, safety measures, working protocol, and quality control measures (8,15,26'). Conduct of Experiments During the actual conduct of the experiment, the following points should be considered: quarantine of newly received animals; surveil- lance for disease; proper caging, general environment, lighting, temperature, ventilation, and handling; health monitoring of test animals; clinical examination; biochemical studies of blood, urine, and feces; proper necropsy procedures; histopathological techniques, diagnosis, and statistical analysis; and report preparation (3,8). Such attention to detail, although costly, is necessary to avoid discrepancies that may compromise or invalidate the results of the study. 178 References (I) BURNET, F.M. The concept of immunological surveillance. Progress in Experimental Tumor Research 13: l-27,1970. (2) CANADA. The testing of chemicals for carcinogenicity, mutagenicity and teratogenicity. Department of Health and Welfare of Canada, 1973. (3) ENVIRONMENTAL PROTECTION AGENCY. Scientific Rationale for the Selection of Toxicity Testing Methods: Human Health Assessment. Report #ORNLEIS151,1980. (41 FOOD AND DRUG ADMINISTRATION, ADVISORY COMMITTEE ON PROTOCOLS FOR SAFETY EVALUATION. Panel on carcinogenesis report on cancer testing in the safety evaluation of food additives and pesticides. Toxicology and Applied Pharmacology 20(3): 419-438, November 1971. (5) GOODMAN, D.G., WARD, J.M., SQUIRE, R.A., CHU, K.C., LINHART, M.S. Neoplastic and nonneoplastic lesions in aging F344 rata. Toxicology and Applied Pharmacology 48f2): 237-248, April 1979. (6) HOMBURGER, F. Chemical carcinogenesis in Syrian hamsters. Progress in Experimental Tumor Research 16: 152-175,1972. (7) HOMBURGER, F., RUSSFIELD, A.B., WEISBURGER, J.H., LIM, S., CHAK, S., WEISBURGER, E.K. Aging changes in CDR-1 HaM/ICR mice reared under standard laboratory conditions. Journal of the National Cancer Institute 55(l): 37-46, July 1975. (8) INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. Long-term and short-term screening assays for carcinogens: A critical appraisal. ZARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Supplement 2. International Agency for Research on Cancer, Lyon, France, 1980,430 pp. (9) KAMO, I., FRIEDMAN, H. Immunosuppression and the role of suppressive factors in cancer. Advances in Cancer Research 25: 271-315,1977. (10) KRIPKE, M.L. Immunologic mechanisms in UV radiation carcinogenesis. Advances in Cancer Research 34: 69-106,198l. (II) LOMBARDI, B., SHINOZUKA, H. Enhancement of 2-acetylaminofluorene liver carcinogenesis in rats fed a choline-devoid diet. International Journal of Cancer 284): 565-570,1979. (12) MALTONI, C. Recent findings on the carcinogenicity of chlorinated olefins. Environmental Health Perspectives 21: l-5, December 1977. (13) THE NETHERLANDS. Health Council of the Netherlands. The evaluation of the carcinogenicity of chemical substances, 1978. (14) NEWBERNE, P.M. Influence on pharmacological experiments of chemicals and other factors in diets of laboratory animals. Federation Proceedings 34(2): 209-218,1975. (15) PAGET, G.E. (Editor). Quality Control in Toxicology. Baltimore, University Park Press, 1977,128 pp. (16') PREJEAN, J.D., PECKHAM, J.C., CASEY, A.E., GRISWOLD, D.P., WEIS- BURGER, E.K., WEISBURGER, J.H. Spontaneous tumors in Sprague- Dawley rata and Swiss mice. Cancer Research 3301): 2768-2773, November 1973. (17.l REDDY, B.S., COHEN, L.A., MCCOY, G.D., HILL, P., WEISBURGER, J.H., WYNDER, E.L. Nutrition and its relationship ta cancer. Advances in Cancer Research 32: 237-345,1980. (18) RICHARDS, V. Cancer immunology: An overview. Progress in Experimental Tumor Research 25: l-60,1980. (19) ROGERS, A.E. Variable effects of a lipotrope-deficient high-fat diet on chemical carcinogenesis in rata. Cancer Research 3x9): 2469-2474, Septem- ber 1975. 179 (20) ROSS, M.H., BRAS, G. Tumor incidence patterns and nutrition in the rat. Journal ofNutrition 87(3): 245-260, November 1965. (21) SHER, S.P. .Mammary tumors in control rats: Literature tabulation. Toxicolo- gy and Applied Pharmacology 22(4): 562588, August 1972. (22) SGNTAG, J.M., PAGE, N.P., SAFFIO'ITI, U. Guidelines for carcinogen bioassay in small rodents. Carcinogenesis, National Cancer Institute Techni- cal Report Series #l, NCICG-TR-1, National Cancer Institute, February 1976,65 pp. (23) STUTMAN, 0. Immunological surveillance. In: Hiatt, H.H., Watson, J.D., Winsten, J.A. (Editors). Origins of Human Cancer. Book A, Volume 4, Cold Spring Harbor, New York, Cold Spring Harbor Laboratory, 1977, pp. 729- 750. (24) TUCKER, M.J. The effect of long-term food restriction on tumors in rodents. International Journal of Cancer 23(6): 80=7,1979. (25) VESSEWNOVITCH, S.D., MIHAILOVICH, N., WOGAN, G.N., LOMBARD, L.S., RAO, K.V.N. AfIatoxin BI, a hepatocarcinogen in the infant mouse. Cancer Research 32(11): 2289-2291, November 1972. (26) WARD, J.M., GOODMAN, D.G., GRIESEMER, R.A., HARDIS'I'Y, J.F., SCHUELER, R.L., SQUIRE, R.A., STRANDBERG, J.D. Quality assurance for pathology in rodent carcinogenesis tests. Journal of Environmental Pathology and Toxicology 2(2): 371378. November-December 1978. (27) WARD, J.M., GOODMAN, D.G., SQUIRE, R.A., CHU, K.C., LINHART, M.S. Neoplastic and nonneoplastic lesions in aging (C57BL/6N x C3H/HeN)Fi (B6C3Fi) mice. Journal of the National Cancer Institute 63: 849-654, September 1979. (28) WEISBURGER, J.H., WEISBURGER, E.K. Tests for chemical carcinogens. In: Busch, H. @ditor). Methods in Cancer Research I, New York, Academic Press, 1967, pp. 307-398. (29) WORLD HEALTH ORGANIZATION. Assessment of the Carcinogenicity and Mutagenicity of Chemicals. Technical Report Series No. 546, Geneva, World Health Organization, 1974,21 pp. 180 EXPERIMENTAL CARCINOGENESIS WITH TOBACCO SMOKE Introduction Tobacco carcinogenesis exemplifies a meaningful and successful interaction between epidemiology and laboratory studies. The impe- tus for the development of experimental tobacco carcinogenesis came from large-scale epidemiologic studies between 1950 and 1960 (2, 46, 64, 120, 201) that indicated a causal association between cigarette smoking and cancer (see the Part in this Report on biomedical evidence). The Physicochemical Nature of Tobacco Smoke During the last three decades, major progress has been achieved in our knowledge about tobacco smoke, its formation, its physicochemi- cal nature, and its composition. This new knowledge has contributed significantly to biologists in their study of the pharmacology, toxicity, and carcinogenicity of tobacco smoke. The, composition of tobacco smoke is a function of the physical and chemical properties of the leaf or of the tobacco blend, the wrapper, and the filter, as well as the way the tobacco is burned. A variety of chemical and physical processes occur in the oxygen-deficient, hydrogen-rich environment of the burning cone of the cigarette at temperatures up to 950oC. The majority of the more than 3,600 smoke components are formed in a pyrolysisdistillation zone just behind the heat-generating combustion zone (6, 61). The smoke is called mainstream smoke if it is generated during a puff and exits from the butt end and is called sidestream smoke if it arises mainly from the passive burning of the tobacco product and is released into the environment. Smoking Conditions The composition of the mainstream and sidestream smoke depends greatly on the smoking conditions and the methods of collection and analysis. This has long been realized; more than 20 years ago, standardized smoking conditions were established for machine measurements of cigarette smoke (199). Since then, the Federal Trade Commission (FTC), research institutions, and the U.S. ciga- rette industry have used the same standardized parameters for cigarette smoking (9, 152): one 2-second puff per minute with a volume of 35 ml and a butt length of 23 mm. For filter cigarettes, the butt length is given by the length of the filter tip plus overwrap plus 3 mm. For the analysis of sidestream smoke, a cigarette is placed in a watercooled glass vessel with a free inner volume of 250 ml. The cigarette is smoked under the standard conditions applied for the 181 analysis of the mainstream smoke, but for the collection of the sidestream smoke, an air flow of 1.5 liters per minute is sent through the glass vessel (28). The standard cigarette smoking conditions reflect the average smoking habits of a male smoker of nonfilter cigarettes as deter- mined 25 years ago (32). Today, however, fewer than 10 percent of all U.S. smokers appear to follow this pattern (130). The average smoking parameters recently recorded for filter cigarette smokers were one puff of 1.94 to 2.06 seconds duration, repeated every 26.9 to 30.0 seconds, with a puff volume of 35.9 to 47.8 ml (75). Nevertheless, FTC-standard cigarette smoking conditions continue to be used for comparisons of tar and nicotine yields in the smoke of present cigarettes and for comparisons between present cigarettes and those made years and even decades ago. The values discussed in this introduction were obtained under the standard smoking conditions, except where otherwise noted. For cigar smoking, the following conditions have been widely used: a 1.5-second puff every 40 seconds, a puff volume of 20 ml, and a butt length of 33 mm (99u). The conditions used for sidestream smoke collection of cigars are the same as those for cigarettes (28). Conditions for pipe smoking have not been standardized, although conditions of a a-second puff every 18 seconds and a puff volume of 50 ml have been repeatedly used (134). Temperature Profiles The temperature profiles of the burning cigarette are affected by the length and circumference of the cigarette, the nature of the tobacco type or blend, the amount and nature of the processed tobacco "stems," the width of the tobacco shreds, the packing density and the moisture content of the tobacco, the porosity and ingredients of the cigarette paper, and the design of the filter (including the filter material and plasticizer, draw resistance, construction, and perforation). During smoking, the temperature of the burning cone reaches up to 950oC; hot spots on the periphery of the burning zone may reach 1050oC (148, 202). In a cigarette with paper of medium porosity, the temperature falls,from 800oC to 40oC over the 30 mm of the tobacco column adjacent to the burning cone (185). The highest temperatures of cigars may reach slightly' above 900oC and those of pipes may go slightly above 800oC; however, the temperature gradient away from the burning cone is not as steep as that in cigarettes, primarily because of the larger diameter of the burning cone and the very low porosity of the cigar wrapper and of the pipe bowl (202). On the basis of the temperature profiles, three zones are defined in a burning cigarette during puffing: the high temperature zone @OO- 6OO"C), which is very low in free oxygen and contains up to 8 volume 182 percent of hydrogen and 15 volume percent of carbon monoxide; the oxygen-depleted pyrolysisdistillation zone (600-100oC); and the low temperature zone (< lOO"C), with up to 12 volume percent of oxygen. The actual generation of mainstream smoke occurs in these three zones by hydrogenation, pyrolysis, oxidation, decarboxylation, dehy- dration, reactions between freshly generated chemical species, distillation, and sublimation. The exit temperature of the main- stream smoke ranges from 25" to 5O"C, depending on the butt length. The previously cited temperature profiles do not apply to cigarettes with perforated filters. In this case, the smoke is diluted by air drawn through the filter wrapper. This lowers the velocity of the air drawn through the burning cone. The result is a more complete combustion of the tobacco. Smoke Analyses About 30 percent of the total weight of the mainstream smoke originates from the tobacco; the remainder comes from the air drawn into the cigarette. Five to eight percent by weight of the total effluent from a nonfilter cigarette is made up of moist particulate matter; about 55 to 65 percent are nitrogen, 8 to 14 percent are oxygen, and the remainder consists of other gas phase components generated during smoking (107). Undiluted cigarette smoke, as it leaves the mouthpiece, contains up to 5 x 109 heterogeneous particles per ml, with round and spheric forms ranging in diameter between 0.2 and 1.0 p and a median particle size of about 0.4 p (36,107). In the case of filter cigarettes, the median particle size> of the smoke is somewhat smaller (between 0.35-0.4 p). For cigarettes with perforat- ed filter tips, the number of particles generated is significantly lower than for unfiltered cigarettes (36). The smoke particles that are inhaled are slightly charged with about 1012 electrons per gram of smoke (equivalent to two or three cigarettes). Since the smoke is partially generated in the oxygen deficient zone, the aerosol leaving the mouthpiece has reducing activity that increases with the number of puffs drawn and that disappears completely only minutes after smoke generation (166). Thus, freshly generated tobacco smoke as inhaled may affect the redox balance of respiratory tract tissues. The pH of tobacco smoke is of major significance since it influences its inhalability by the smoker and the availability of unprotonated nicotine (3). Figure 1 depicts the percentage of diprotonated, monoprotonated, and unprotonated nicotine in aqueous solution at various pH. For a blended U.S. cigarette, the pH of the mainstream smoke varies between 5.5 and 6.2; cigarettes made exclusively from Burley or black tobacco, and cigars yield mainstream smoke with pH ranges between 6.5 and 8.5, reaching the highest pH with the last 183 pH =pKa log + (HENDERBON-HASSELBACH) PH FIGURE I.-Protonation of nicotine SOURCE: Brunnemann and Hoffmann (28). 8.0 I I . ~-- 6.0 I ---------- 5.5 L. . -- -. -. ., , , LITTLE CIGAR II CIGAR KENTUCKY FILTER (85 mm) OLAIN 185 mm1 b W' .~~ . . . . 3 4 5 6 7 8 9 10 11 12 13 14 * 20 25 30 35 40 PUFFS FIGURE 2.-pH of individual puffs of total mainstream smoke of various tobacco products SOURCE: Brunnemann and Hoffmann (28). puffs (28). Figure 2 shows the pH of .individual puffs of the mainstream smoke of some tobacco products (6). Bioassays Inhalation Studies Ideally, a suspected carcinogen should be tested using the route of administration corresponding to the exposure of humans. The experimental induction of respiratory cancer with tobacco smoke is 184 beset with major difficulties because of toxicity introduced by high carbon monoxide concentrations (generally 3.5 to 5 volume percent), and high levels of nicotine. Furthermore, laboratory animals are not willing to inhale aerosols very deeply and are especially reluctant to inhale tobacco smoke. Inhalation studies have been explored by training Rhesus monkeys and baboons to smoke cigarettes. This approach does not produce respiratory neoplasms because of insuffi- cient exposure time and because of the tendency of the animals merely to puff rather than to inhale (102, 156~~). Invasive and noninvasive bronchoalveolar tumors developed in several of 78 dogs that were trained to smoke through a tracheosto- ma and that smoked cigarettes daily for about 2l/, years. In a group of 24 dogs that smoked nonfilter cigarettes, 2 animals developed early invasive squamous cell carcinoma in the bronchi (4). However, this observation has not been repeated so far (137). A number of inhalation studies have been conducted with rats. Recently they have yielded tumors of the respiratory tract (43, 137). In 1980, investigators at the Oak Ridge National Laboratory succeeded in obtaining tumors of the respiratory-tract of rats using a highly developed smoke inhalation device (43, 126). On 5 days each week over their entire lifespan, 80 rats were exposed to air-diluted smoke (10 percent) of seven cigarettes (one cigarette per hour). At the end of the experiment, a large number of rats had developed hyperplasia or metaplasia in the epithelium of the nasal system, the larynx, or the trachea. Seven of the eighty smoke-exposed rats had tumors of the respiratory tract, including five animals with pulmo- nary adenomas, two with alveologenic carcinomas, one with a squamous carcinoma of the lung, and one with adenocarcinoma and squamous cell carcinoma in the nasal cavity. One alveologenic carcinoma was observed in 30 sham-exposed control rats; no respiratory tract tumors were seen in 63 untreated control rats (43). At present, the most promising animal for tobacco smoke inhala- tion studies appears to be the Syrian golden hamster. This animal is more resistant to respiratory infections than are mice and rats and is also more tolerant of cigarette smoke (52). Dontenwill et al. developed the first smoke inhalation device and bioassay methodolo- gy-for the chronic exposure of hamsters to cigarette smoke (51). For 5 days per week and for the duration c' I' +eir lifetime, the hamsters were exposed once, twice, or three times daily for 10 minutes to air- diluted cigarette smoke (1:15). In the 3 groups of 80 hamsters, 11.3, 30, and 30.6 percent of the animals developed pre-invasive carcino- ma, and 0.6, 10.6, and 6.9 percent had invasive carcinoma of the upper larynx (51). Laryngeal tumors were not observed in the control group nor in the animals exposed only to the gas phase of cigarette smoke. Trachea and bronchi of all animals were free of neoplastic growth. Tumors that developed in other organs of the exposed 185 hamsters were not different from those in the control group. This inhalation assay represents the first reproducible method for the induction of tumors in the respiratory tract of animals exposed to tobacco smoke. Dontenwill and his group have successfully applied this method to the evaluation of the carcinogenic potential of experimental cigarettes with and without reduced activity as measured in mouse skin bioassays (48). Bernfeld et al. (II) improved the inhalation model primarily by using an inbred hamster strain that is susceptible to carcinogenic inhalants. The smoking schedule called for exposure for 59 to 80 weeks to a 22 percent cigarette smoke aerosol twice daily for 12 minutes with cigarettes made entirely from flue-cured tobacco, such as those used in the United Kingdom. This induced carcinoma of the larynx in 27 out of 57 hamsters at risk (~47 percent). Three of the animals developed papilloma of the trachea; none had tumors of the lung. In tests with an 11 percent smoke aerosol, only 3 out of 44 hamsters at risk (7 percent) developed laryngeal carcinoma, indicat- ing a possible dose-response for the induction of carcinoma of the larynx with cigarette smoke. Thus, it appears that this hamster inhalation model is a promising bioassay system for estimating the relative carcinogenic potential of total, unaged smoke of various cigarettes. Why these inhalation experiments with hamsters did not induce carcinoma of the lung remains to be elucidated. Two investigations have examined this question using tracer studies with decachlorobi- phenyl (DCBP) (11,861. In one study, DCBP was added to cigarettes and the concentration of the tracer in the mainstream smoke was determined for the appropriate exposure for each animal. DCBP is not volatile and is, therefore, not found in the gas phase, but rather is an integral part of the smoke particulate phase. Bernfeld.et al. (II) determined that 180 I.L~ tar3 reached the lung of a hamster and that 15 pg tar were deposited in the larynx after each exposure' of a hamster to DCBP-spiked mainstream cigarette smoke. In another study with a different smoke inhalation device, 88 pg tar were found to reach the lungs and 2.8 pg tar were traced to be deposited in the larynx (86). Considering the relative surface area of both larynx (0.1 to 3.0) and lung (l,OOO), Bernfeld et al. calculated that, per surface area unit, 300 to 900 times more tar is deposited in the larynx than in the lungs. In the other study (86), the relative deposition per surface area unit was calculated to range from 110~1 to 32O:l. This high density of tar deposits in the larynx suggestsan explanation of the occurrence of a high yield of laryngeal cancers in hamsters exposed to cigarette smoke but a lack of lung tumors in the same experiments. `Throughout this section the term "tar" is wed as a descriptive noun only; it is realized that the terms "smoke particulates" or "smoke condensates" are often nwre correct. ' 186 Assays With Smoke Particulates The gaseous phase of tobacco smoke does not induce tumors of the respiratory tract in laboratory animals (51, 2021, except for lung adenomas in certain sensitive strains of mice (119). This suggests that the carcinogenic activity of smoke requires the particulate phase. Benign and malignant tumors have been induced with tobacco tar in the skin and ear of rabbits, in the connective tissue of rats, and by intratracheal instillation, in the bronchi of rats (137, 202). However, the most widely used methodology for the induction of tumors in epithelial tissues has been topical application to mouse skin. Detailed studies have shown that the effect of a tumor initiator is irreversible, but promoter activity will cease upon termination of treatment (193, 195). It appears likely that the metabolically activated form of a tumor initiator is bound to the DNA of a target cell, but the promoter effect is not directly linked with cellular DNA damage and can, therefore, be repaired. Single applications of a low dose of 7,12dimethylbenz[a]anthracene (DMBA) or benzo[a]pyrene (BaP) have served as initiators in chemical carcinogenesis studies that demonstrate initiation and promotion as two successive stages. Most model experiments utilize repeated application of 2.5 pg or lower doses of tetradecanoyl phorbol acetate (TPA) as a promoter (192). In another setting, mouse skin is treated 10 times with a very low dose of BaP or another tumor initiator and is subsequently treated with TPA (72, 116). A cocarcinogen is defined as an agent that potentiates the activity of a carcinogen when both substances are coadministered. The cocarcinogen by itself may exert little or no carcinogenic activity. The merit of the mouse skin assay lies in its sensitivity and reproducibility as a method for the identification of tumor initiators, tumor promoters, and cocarcinogens in tobacco smoke. By definition, a tumor initiator is an agent that does not elicit a significant tumor response in mouse skin or in other epithelial tissue, but suffices to bring about benign and malignant tumors when its application is followed by repeated treatments with a tumor promoter. Reversal of the order of application produces few tumors. The mouse skin assay has been employed to establish a clear dose response for carcinoge- nicity of tars. It has been most useful in evaluating the relative potential for the induction of benign and malignant tumors by contact carcinogens. The relative activity of the smoke particulate matter of commercial and experimental cigarettes has been com- pared on mouse skin (50, 2021, and the response was found to be in good agreement with results from the bioassays in which inhalation of tobacco smoke led to carcinoma of the larynx in hamsters (48,491. The mouse skin assay has been helpful in evaluating the relative tumorigenic potential of the smoke particulates of cigarettes made from different tobacco varieties, reconstituted tobacco sheets, lami- 187 377-310 0 - 82 - 1`4 na, stems, and tobacco substitutes (88, 143). Bioassays &onducted with standardized methods on the same strain of mice have indicated a gradual decline of the carcinogenic potential of the smoke particulates of a leading U.S. cigarette brand during the last 20 years. This reflects the changes in the. makeup of commercial cigarettes (188). Fractionation Experiments Assessments have been made for the materials derived primarily from two major separation schemes employed for the identification of tumorigenic agents. One system begins with fractionation of the smoke particulates into neutral, acidic, basic, and insoluble portions, followed by column chromatographic subfractionation schemes for further delineation of tumorigenic constituents (17, 90). The other system consists of the partitioning of the particulates with solvent systems and of the subsequent chromatographic separations (59). Both methods have clearly established that the tar subfractions, which contain the bulk of polynuclear aromatic hydrocarbons (PAH), are the only portions that elicit carcinoma on mouse skin when applied in high concentrations. These subfractions harbor the majority of the tumor initiators. Intratracheal instillation in rats also led to carcinomas only with those subfractions that were highly enriched in PAH. However, the PAH subfractions also contain neutral cocarcinogens. These are non-carcinogenic PAH, which nevertheless potentiate the activity of carcinogenic PAH. The chemical identification of still other cocarcinogens in these neutral subfractions points to nonvolatile ketones and tobacco terpenes (165). The weakly acidic portion of smoke particulates and its subfrac- tions have also been shown to contain tumor promoters as well as important cocarcinogens, including phenolic compounds and cate- chols (18, 67). Transplacental Carcinogenesis In the 1979 report Smoking and Health: A Report of the Surgeon General, several questions were raised in respect to transplacental effects of cigarette smoking (189). Activation of enzymes that induce metabolic activation of benzo[a]pyrene (BaP) in the foreskin of human newborns of smoking mothers has been interpreted as one indication of possible transplacental migration of smoke constituents (41, 123). Several experimental studies suggest that tobacco smoke has transplacental carcinogenic effects. Intraperitoneal injections of tobacco tar in olive oil during the 10th to 14th day of gestation of Syrian golden hamsters led to tumors in 2 of 58 females and to benign and malignant tumors in 17 of 51 transplacentally exposed offspring, within 15 to 25 months of observation. The tumors in the 188 offspring were primarily located in the adrenal glands, pancreas, female sex organs, and liver. Untreated control animals, or those whose mothers were injected with olive oil alone, did not develop any tumors during the course of this experiment. This experiment should be repeated, in order to establish the reproducibility of the transplacehtal effects. Its results are in line with general observations of transplacental carcinogenesis. These include pronounced prenatal susceptibility, expressed in a far higher lifetime tumor yield in the offspring, as compared with their mothers (156). In that direct-acting alkylating agents are generally the most effective transplacental carcinogens, the high tumor incidence in the offspring of hamsters treated with tobacco tar is remarkable. Compounds requiring metabolic activation to ultimate active forms of carcinogenic species, however, are also transplacental carcino- gens, though of a lesser potency than direct alkylating carcinogens. Enzymes necessary for activation are known to, exist in the fetus only at low levels, if at all, until just prior to birth (110). A number of tobacco Smoke constituents, which need metabolic activation in order to acquire carcinogenic properties, are known transplacental carcinogens. Among these are voiatile N-nitrosamines, BaP, o-tolui- dine, ethyl carbamate, and vinyl chloride (156). The role of nicotine in regard to possible transplacental effects of tobacco smoke also requires further elucidation, since its transpla- cental migration into the animal fetus has long been known (184). A smoker of 20 cigarettes daily is exposed to 20 to 30 mg of nicotine, and in a pregnant woman it is to be expected that some of this nicotine reaches the fetus. Enzymatic oxidation to cotinine in the fetus is very slow, because of low enzyme activities. Thus, nitrosa- mine formation from the unmetabolized nicotine may occur. Such considerations suggest the need for further experimental studies of the transplacental effects of tobacco products. Syncarcinogenesisz Occupational Carcinogens and Smoking In the United States, cigarette smoking is generally more preva- lent among blue-collar workers than among the white-collar work force (42). Thus, smokers are more likely to be in occupational environments with chemicals, dusts, and fumes than are their nonsmoking counterparts (56). This indicates the need to examine the role of smoking as a confounding variable to occupational exposure and raises the question whether tobacco smoke acts synergistically with other factors in respiratory tract carcinogenesis. In 1979, Hammond et al. (65) evaluated the smoking history relating to 276 deaths from lung cancer among asbestos workers. The calculated mortality ratios (the ratio of death rates in smokers compared with death rates in nonsmoking men of a similar age 189 distribution) for lung cancer were 87.36 for workers who smoked more than 20 cigarettes per day, 50.82 for those who smoked less than 20 cigarettes per day, and 5.33 for asbestos workers who had never smoked regularly. The authors also reported that exposure to asbestos dust in the absence of smoking may have little or no influence on death r&es from cancer of the esophagus, larynx, pharynx, or buccal cavity. Several carcinogenesis experiments were designed to measure the combined effects of tobacco smoke and the various types of asbestos fibers (189). In one such study, 500 pg of asbestos were instilled in the trachea of hamsters, prior to exposure to diluted cigarette smoke, 10 times weekly over a period of 18 months. Since no more than about 1 percent of the smoke particulates reached the hamsters' lungs in such experiments, the smoke exposure alone did not produce tumors in the lower respiratory tract, nor did it potentiate the subthreshold dose of the carcinogenic asbestos (511. In contrast, synergistic action of tobacco smoke and asbestos were indicated when asbestos fibers were first incubated with cigarette tar and then added to human lymphocyte cultures. This resulted in significantly increased induc- tion of aryl hydrocarbon hydroxylase (AHH) compared with the enzyme induction in the lymphocyte cultures with either agent alone (I 71). This finding suggests that a surface (and chemical) interaction between asbestos and cigarette smoke may have occurred with formation of a product having higher carcinogenic activity than is inherent in either agent alone. An elucidation of the mechanisms involved in syncarcinogenic effects of tobacco smoke and asbestos fibers requires further experimental studies. A substantial excess of lung cancer has been reported among uranium miners who smoke cigarettes (189). Archer et al. (2) calculated that the lung cancer rate for U.S. uranium miners who smoked was 42.2 per 10,000 persons/years compared with 4.4 for nonminers who smoked two or more packs of cigarettes a day. There is also some evidence that cigarette smoking may change the latent period for lung cancer development following radiation exposure among uranium miners (2). As will be discussed later, polonium 210 (21OPO) is present in tobacco and cigarette smoke (0.03 to 1.0 pCi/cigarette); however, it is unlikely that these traces represent a major risk for the smoker. Beagle dogs were exposed to radon daughters in uranium ore dust (group 1) or to the same uranium ore dust, together with cigarette smoke (group 2). After more than 40 months, all dogs showed areas of epithelial changes, including large areas of adenomatosis, and squamous metaplasia of the alveolar epithelium with atypical cells. After more than 50 months of exposure, lungs from 50 percent of the dogs in groups 1 and 2 contained large cavities within the paren- chyma surrounded by bands of hyperplastic adenomatous epithelial 190 cells. These changes were not seen in dogs exposed only to cigarette smoke (178). Little and his group (124) tested the hypothesis that 21OPo a- radiation acts synergistically with polynuclear aromatic hydrocar- bons (PAH) present in cigarette smoke. Syrian golden hamsters were given intratracheal instillations of low levels of both 2lOPo and BaP simultaneously or in sequence. Upon simultaneous intratracheal instillation of 21OPo and BaP on ferric oxide, the induction of peripheral lung tumors was simply additive. Sequential application of a single dose of 2'OPo (0.04 pCi) and repeated dosage of BaP (0.3 mg x 7 weeks), however, produced syncarcinogenic effects. Among 139 animals at risk in the group receiving a single dose of 210P0, only 1 animal (0.7 percent) had a lung tumor. The sequential application of 2lOPo and BaP to 135 animals induced lung tumors in 23 of them (17 percent), and BaP alone gave tumors in less than 4 percent of the hamsters (132). Although other occupational environments may provide addition- al cancer risk factors for workers who smoke, epidemiological and experimental studies have not documented such occurrences to date. It has been suggested that synergistic carcinogenic effects may occur in cigarette smokers who work in factories producing or handling chloromethyl ether (59), vinyl chloride (34i, nickel (47), or 2-naph- thylamine (189). Alcohol and Tobacco Products Epidemiological data have indicated that the combination of chronic alcohol and tobacco consumption greatly increases the risk for cancer of the oral cavity, esophagus, and larynx, but not of the lung (157, 189). Several possible mechanisms have been proposed in regard to synergistic effects of tobacco smoke and alcohol. Alcohol serves as a solvent for tobacco carcinogens, or it alters the liver metabolism of tobacco carcinogens and, thus, has an indirect influence on tobacco carcinogenesis at distant organs. Chronic alcohol consumption sometimes leads to deficiencies in essential micronutrients, making the target cells more susceptible to carcino- gens. Also, alcohol induces changes in metabolism of the tobacco carcinogens in target tissues. It has been shown in the experimental setting that alcohol, as a solvent, increases the carcinogenic effect of PAH, which are the major tumor initiators in smoke (177) and of the distillation residues of alcoholic spirits that contain carcinogens (114). .Chronic alcohol consumption, among other effects, enhances the drug metabolism capabilities of liver microsomes in both men and animals (136). The metabolism in the liver of the tobacco carcinogen N-nitrosopyrroli- dine (NPYR), for example, was enhanced in ethanol-consuming 191 hamsters (137). Excessive alcohol consumption is also known to lead to various other cellular injuries that influence carcinogenesis (236). Vitamin A deficiency, which frequently accompanies alcohol abuse, increases susceptibility to carcinogens of the PAH type in laboratory animals (175). Vitamin Bz deficiency has been shown to potentiate effects of carcinogens in mouse skin (37). Rats on a zinc- deficient diet are more susceptible to the esophageal carcinogen, N- nitrosobenzylmethylamine (55). The carcinogenicity of NPYR in Syrian golden hamsters is enhanced when the animals are on a high alcohol diet, yet this enhancement has not been observed for the tobacco-specific N'-nitrosonornicotine (131). Further studies of bio- chemical changes and bioassays with coadministration of alcohol and tobacco smoke or its constituents may provide a better under- standing of the increased cancer risk of consumers who use both alcohol and tobacco. Tumorigenic Agents In Tobacco Products Vapor Phase Components The definition of the vapor phase components is arbitrary and does not represent the true physicochemical conditions prevailing in tobacco smoke. In carcinogenesis, the tobacco chemist's definition has been widely accepted. For the purposes of this discussion the term "vapor phase component" includes all smoke constituents of which more than 50 percent pass through a Cambridge glass fiber filter. Collecting smoke from a single cigarette on a filter pad yields fairly reproducible data. More than 90 percent of the total weight of mainstream smoke is made up of vapor phase components, of which nitrogen and oxygen constitute more than 70 percent. Carbon dioxide and carbon monoxide make up 15 to 20 percent by weight of the total effluents of most cigarettes, unless the cigarette filter tip contains unblocked perforations that reduce this percentage. Carbon monoxide in cigarette smoke, although not a carcinogen, may contribute to respiratory carcinogenesis because of its inhibit- ing effect on the mucus clearance mechanism of the respiratory tract (10). Its most important toxic effect, however, lies in its Burden on the circulatory system because it combines with hemoglobin of the blood to form carboxyhemoglobin. The plain cigarette and the conventional filter cigarette contain 2 to 7 volume percent of carbon monoxide per puff, with the concentration increasing with the later puffs. The total carbon monoxide in the smoke of these cigarettes in the United States in 1980-1981 amounts to 3 to 5 volume percent or 13 to 26 mg/cigarette. However, air dilution of the smoke from cigarettes with a perforated filter tip reduces carbon monoxide to 0.5 to 13 mg/cigarette (27,191). It is estimated that more than 50 percent of the cigarettes currently sold on the U.S. market have perforated filter tips. The smoke of cigars and little cigars contains carbon monoxide values up to 11 volume percent (27). In the 1979 report Smoking and Health: A Report of the Surgeon General, carbon dioxide, nitrogen oxide, ammonia, hydrogen cya- nide, and volatile sulfur compounds and nitriles have been discussed in addition to carbon monoxide (189). Since that time no significant new information has been published in respect to the contribution of these vapor phase components to the overall toxicity and carcinoge: nicity of tobacco smoke. It should be noted that the gradual reduction of tar and nicotine was accompanied by a gradual decrease of most vapor phase components in the smoke of the sales-weighted average U.S. cigarette (89). This reduction does not apply to the level of nitrogen oxides (NO,), of which more than 95 percent are nitric oxide (NO). The NO, content of the smoke `of the sales-weighted average U.S.- cigarette has remained at a level of 270 to 280 pg per cigarette (89). One reason for this appears to be the use of increasing percentages of Burley tobacco and of "stems" in the cigarette blend. Burley tobacco and "stems" are richer than Bright tobacco in nitrate, a main precursor for NO, in the smoke. A major reduction in smoke NO, can be achieved by high smoke dilution (146). As discussed before, these observations apply to the smoke generated by standard machine smoking schedules and do not allow for the fact that many smokers of low tar cigarettes smoke more intensely. It has been demonstrated that a high percentage of the ciliatoxic agents, which inhibit the lung clearance, are present in the vapor phase (10,44). These are chiefly hydrogen cyanide (280 to 550 p.g/cig), acrolein (10 to 140 p.g/cig), ammonia (10 to 150 pg/cig), nitrogen dioxide (0 to 30 pg/cig), and formaldehyde (20 to 90 p.g/cig). Squamous cell carcinomas were induced in the nasal cavities of rats exposed in chambers for 30 hours a week to 15 ppm of formaldehyde for 18 months (182). The mechanism of its action is unknown; metabolically, it is rapidly oxidized further to formic acid. The vapor phase, i.e., that portion of the smoke passing through a glass fiber filter, does not by itself induce tumors in laboratory animals, except in certain strains of mice (119). The carcinogenic effects of low levels of volatile smoke constituents may currently escape detection by means of bioassays because of the low doses used and the low sensitivity of models available at present (100). Table 1 lists the major components of the vapor phase and whether the agent is reported to be toxic or tumorigenic. The volatile N-nitrosamines are largely retained by the smoke particulates in the glass fiber filters and will be discussed in the section on organ-specific carcino- gens. In general, our understanding of the mechanisms of carcino- genesis by other volatile smoke components is scanty. 193 TABLE l.-Major toxic and tumoripenic agents in the vapor phase* of cigarette smoke (unaged)** Agent Biologic Concentration/ciearette activity' Range reported U.S. cigarette@ Carbon monoxide Nitrogen oxides (NO,) Hydrogen cyanide Formaldehyde Acrolein Acetaldehyde Ammonia Hydrazine Vinyl chloride Urethane 2INitropropane Quinoline T T CT. T m, c CT CT T? C C C C C 0.5 - 25 PL: 16 -ml% 28 - 550 pg 20 - goI% 10 - 14ow 18 -1,400 pg 2.5 - 250 pg 24 - 43 ng 1 - 16 ng 10 =I% 0.73 - 1mw 0.8 - 2.0 pg 17 wz 350 pg 110 pg 30 6% 70 w ml% 10 w 32 M 12 w 30 I% 1.2 pg 1.7 pg `Volatile nltrcsamines are listed in Table 4 "Cigarettes contam mext likely also carcinogens such as nickel carbonyl and possibly amine. volatile chlorinated &fins and n~tro-olefins. `,T notes toxic agent; CT. cilia toxic agent: and C. carcinogenic agent. b&5 mm cigarettes without lilter tips. ' NO. i9570 NO. rst NOz. d Not toxic in smoke of blended U.S cigarettes because pH; 6.5. therefore ammonia and pyridlnes are present in protonated form. SOURCE. Hoffmann et al. (87.901 Hydrazine or its salts are most effective as carcinogens in mice. Metabolic transformation of hydrazine in some animals yields acetyl and diacetyl derivatives, although ammonia is formed in dogs (40). Numerous studies on the toxicity and carcinogenicity of hydrazine have been reported (125), but few on its metabolic transformation and the mechanism of its action. Indications are that hydrazine may disrupt normal methylation processes in the organism, since methyl- ated guanines were noted in liver DNA after exposure. The cytochrome P-450 enzyme system forms a halogenated epox- ide from vinyl chloride (8, 205). In turn, this epoxide may yield halogenated aldehydes or alcohols through rearrangement. Contrary to the situation with the nucleic acid adducts of most other activated carcinogenic intermediates, the epoxide from vinyl chloride ethylen- ates or adds across the N-l and N-6 of adenosine or the N-3 and N-4 of cytidine, forming new rings in these particular bases (21). The presence of these additional structures would probably interfere in the normal base pairing between adenosine-thymidine and guano- sine-&dine. Urethane is not a potent carcinogen, in terms of dose, except in neonatal mice. Although it is metabolized to N-hydroxyurethane, which acylates cytosine (1441, there still remains a question whether urethane or N-hydroxyurethane is the active material (135). 194 T-or Initiators The carcinogenic activity of the particulate matter of tobacco smoke in epithelial tissues of laboratory animals is greater than the sum of the effects of the known carcinogens present. Large scale fractionation studies in a number of laboratories have shown that the total carcinogenic activity also results from the effects of tumor initiators, tumor promoters, and cocarcinogens in the tar. Large-scale tar fractionation studies in a number of U.S. and foreign laboratories have shown that the tumor initiators reside in those neutral subfractions in which the polynuclear aromatic hydrocarbons (PAH) are enriched (87). So far, at least two dozen PAH and a few neutral aza-arenes have been identified to serve as tumor initiators at the dose levels found in tobacco tar. It is likely that the PAH concentrates of smoke particulates contain additional tumor initiators that may yet be identified by detailed capillary GC- MS analysis (172). All of these .PAH tumor initiators are formed during smoking by similar pyrosynthetic mechanisms (5, 853. More recent observations showed, surprisingly, that tumor initiators are also found among dimethylated or polymethylated three-ring aro- matic hydrocarbons in which the formation of bay region dihydrodiol epoxides is favored, but the detoxification to phenols is reduced. An example is 1,4dimethylphenanthrene (117). These methylated three- ring aromatic hydrocarbons may be present in tobacco smoke in much higher concentrations than the corresponding parent PAH. Table 2 lists tumor-initiating PAH and aza-arenes identified in tobacco smoke. These compounds are secondary or procarcinogens since they require metabolism to show an effect. Metabolic activation is generally mediated through the mixed-function oxidase system of enzymes. The metabolic activation of polycyclic aromatic hydrocar- bons, as typified by benzo[a]pyrene (BaP), has been reviewed within the past 2 years (58). In brief, BaP is metabolized by means of the mixed-function oxidase system to the 2,3-, 4,5-,, 7,8-, and 9,10- epoxides, of which only the 4,5epoxide is stable enough to permit isolation and thus to exist in the environment. The various epoxides can be converted to phenols, which in turn may be conjugated through glucuronyl transferase or sulfotransferase to water-soluble glucuronides or sulfates. The phenols may also be oxidized to quinones such as the 1,6-, 3,6-, and 6,12quinones derived from BaP. The original epoxides are good substrates for the glutathione-S-transferase system that forms glutathione conjugates and premercapturic and mercapturic acids from the epoxides. In addition, the epoxide hydrolase system converts the epoxides to dihydrodiols with the (-)-tram configuration. However, an additional activation step is required, i.e., the further oxidation of the dihydrodiols, also mediated by the mixed-function 195 TABLE 2.-Tumor-initiating agents in the particulate phase of tobacco smoke' Compound Relative activity a9 complete carcinogen' ng/cig BenzdaJpyrene 5Methylchrysene Dibenz(a,hJanthracene BenzdbJfluoranthene Benzdjfluoranthene Dibenzda,h)pyrene Dibenzda.i)pyrene Dibenz(a j)acridine Indendl,2,3-cd)pyrene BenzoWphenanthrene BenzWanthracene Chrysene BenzdeJpyrene 2.. and SMethylchrysene l- and 6Methylchrysene 2-Methylfluoranthene BMethylfluoranthene Dibenz(a.c)anthracene Dibenz(a.h)acridine Dibenzde,gkarbazole +++ +++ ++ ++ ++ ++ ++ ++ + + + i? f? f? + ? (+) (+) (+) 10-50 0.6 40 30 60 Pra P? 3-10 4 Pr3 40-70 4G-60 5-40 7 10 34 40 3 Efi 0.7 ' Incomplete list; all listed compounds are active as tumor initiators on mouse skin. z Relative carcinogenic actiwty on mouse skin as measured in our laboratory on Swiss albino tHa/ICR/Mil) mice; ?: Carcinogenicity unknown; (+ I: not tested in own laboratory. ' pr: present. but noquantitative data given. SOURCE: Hoffmann et al. 1881. oxidase system. For BaP, the trans isomer of the S,Sdihydrodiol-9,10- expoxide thus formed appears to be the active intermediate, capable of reacting with nucleic acids, proteins, and other cellular constitu- ents. In the nucleic acid adducts, the lo-position of the diol epoxide was linked to the amino group in the 2-position of guanosine, although some reaction with the phosphates of the DNA backbone also occurred. Various enzymatic and radioimmunoassays have been devised to measure the level of the BaP-DNA adduct in biological materials (93). Although the actual biological consequences resulting from the BaP-DNA adduct have not been exactly delineated, there are indications that the adduct can interfere in elongation of the nucleic acid during replicative processes. No studies on the mechanism of carcinogenesis by metabolic products of polycyclic heterocyclics have been reported. On the premise that they may be activated through a similar mechanism as the polycyclic aromatic hydrocarbons, some of the dihydrodiols of benz[a]- and [clacridine have been synthesized as model compounds (161). The possible metabolic transformation to N-oxides should also be considered. 196 Tumor Promoters The water extract of processed tobacco and the particulate matter of tobacco smoke contain tumor-promoting agents (16, 20). Pretreat- ing mouse skin with 125 pg of DMBA, Bock and collaborators (19) found that the tumor-promoting activity of tobacco extracts requires the concurrent presence of two agents, one of large molecular weight (LM), insoluble in organic solvents, and the other of small molecular weight (SM), soluble in organic solvents. They suggest that the SM agent could be nicotine (20). Bock and Clausen (15) fractionated the portion with the LM agent by dialysis. A subfraction with a presumptive molecular weight greater than 13,000 exhibited the highest copromoting activity when tested together with nicotine. It appears likely that the LM fraction with the highest activity consists of tobacco leaf pigments (14). Certain compounds used or suggested as sucker control agents or pesticides were active as tumor promoters on mouse skin when tested in concentrations between 0.3 and 1.0 percent. Certain fatty acid esters and fatty alcohols proposed as agricultural chemicals were also tumor promoting agents in concentrations of 3 percent or greater. Among the active tumor promoters were a 0.3 percent solution of dodecyldimethylamine, suggested as a sucker growth inhibitor; Tween 20 and Tween 80, used as surfactants; 1 percent of the insecticides DDD and DDT; and 3 percent mixtures of fatty acid esters and fatty alcohol proposed as sucker growth inhibitors (20). The very small residual amounts of these agricultural chemicals found in tobacco make it unlikely that they are of consequence in the tumor-promoting activity of tobacco extract or tar. The total smoke condensates of cigarettes, cigars, and pipes act as tumor promoters. The active agents are found primarily in the weakly acidic portion and in certain neutral subfractions. Certain fatty acids, especially oleic acid, and phenols have been identified as weakly acidic tumor promoters. Tumor promoters in the neutral subfractions were DDD, DDT and its major pyrolysis product 4,4'- dichlorostilbene, and N-methylated indoles and carbazoles (165, 189). The majority of the tumor promoters in tobacco tar remain to be identified. These include certain high molecular weight components in the most polaric neutral fraction or in the insoluble portion. Cocarcinogens Fractionation studies of tobacco smoke particulates have shown that coadministration of the neutral and weakly acidic portions raises the tumor yield in mouse skin experiments significantly above the number of tumors obtained from each fraction alone (67,87,203). Benzo[a]pyrene (BaP) at 0.005 percent concentration applied togeth- er with a 5 and 10 percent solution of the weakly acidic portion of tobacco smoke particulates also yields tumors in greater proportion 197 than expected on the basis of the additive effects of the individual materials. Some subfractions of the weakly acidic portion are inactive when tested alone, yet they potentiate the carcinogenic activity of 0.003 percent Bal? when coadministered with the carcino- gen. Van Duuren et al. (194) were the first to demonstrate that catechol, the major phenolic compound in tobacco smoke (20 to 460 w/cigarette), is a powerful cocarcinogen. Systematic fractionation studies monitored with bioassays have illustrated that the catechols are in fact a major group of cocarcinogens in cigarette smoke (67). A considerable number of other components have been identified in the cocarcinogenic weakly acidic subfractions. None of these, however, are known cocarcinogens (67, 163). They are either inactive or not as yet tested. The levels of the catechols alone cannot account for the cocarcinogenic activity observed for the weakly acidic fraction, but catechol values serve as a fairly reliable indicator of the cocarcino- genie potential of this portion of the smoke particulates. The polyphenols of the leaf apparently serve as important precursors for the catechols (35, 162). Subfractions of the neutral portion that contain concentrates of PAH are also active as cocarcinogens in studies on mouse skin (165). So far, a number of methylated naphthalenes, indoles, carbazoles, and PAH that have no tumor initiator activity have been identified as cocarcinogens in neutral subfractions (165, 196,200,202). Further fractionations and bioassays have demonstrated that both PAH- containing and PAH-free subfractions have cocarcinogenic activity (165). The PAH-free material was shown to contain several unsatu- rated hydrocarbons as well as oxygenated terpenes, which remain to be bioassayed as potential individual cocarcinogens. In model studies, GO-CM paraffin hydrocarbons as vehicles for carcinogenic PAH are potent cocarcinogens (13, 92). However, the normal paraffinic and the iso-paraffinic hydrocarbons in tobacco and tobacco smoke are waxy solids with chain lengths of C25-C~ and with n-&Ha as the predominant paraffin (174). The neutral subfraction that consists primarily of paraffin hydrocarbons has no demonstra- ble cocarcinogenic activity. In mouse skin bioassays of cigarette smoke condensates mixed with BaP, increased paraffin levels of the smoke condensates apparently inhibited tumor development (202). The basic fraction of cigarette tar contains 60 to 80 percent nicotine and other alkaloids. Since nicotine is highly toxic, only the nicotine-free basic portion has been assayed for tumorigenic activity and has been found to be inactive (90, 202). However, when nicotine is given in low doses together with TPA and BaP, it acts as a cocarcinogen. Such cocarcinogenic activity is not found for cotinine and nicotine-N'-oxide, the two major metabolites of nicotine. In fact, nicotine-N'-oxide inhibits the cocarcinogenic activity of TPA (14, 188). The concept of nicotine as a cocarcinogen in tobacco products is TABLE 3.-Cocarcinogenic agents in the particulate matter of tobacco smoke' Gxarcinogenic Compound* activity3 Ng/cig I. Neutral Fraction Pyrex (-) + 50-2-200 Methylpyrenes (?) ? 5K300 Fluoranthene (-I f lW260 Methylfluoranthenes (+;?I 7 180 Benzdghibperylene (-I + 60 BenzdeJpyrene ( + ) + 30 Other PAH (+) ? ? Methylnaphthalenes (-1 + 360-6300 1-Methylindoles (-) + 830 9-Methylcarbazoles (-1 + 140 4 and I'-Dichlorostilbene (-1 + 1500' Other or unidentified neutral compounds (?I ? ? II. Acidic Fraction Catechol (-) + 40.006350,000 SMethylcatechol (-) + 11,cGfx20,c@O 4-Methyl&echo1 (-) + 15.003-21,ooO I-Ethylcatechol C-J + 10,00&24,OOG I-n-Propylcatechol (?) ? = 5,000 Other or unidentified catechols and phenols (?) ? ? Other or unidentified acidic agents (?) ? 9 ' Incomplete list. `In parenthesiseompletecarcinogenic activity on moue skin; I?) unknown. 3 + =active;?=unknown. ' Value from 1966 U.S. cigaretti today's values will be lower, because DDT and DDD decreased in the U.S. bhaccos. SOURCE: Hoffmann et al. (88). supported by the observation that the concentration of the alkaloids is closely correlated with the carcinogenic activity of the tested tars in four large-scale mouse skin bioassays (14, 143). More research is needed to elucidate the cocarcinogenic activity of nicotine, especially since it may also be correlated with the risk of tobacco chewers and snuff dippers for cancer of the oral cavity (189,200). Table 3 lists the identified cocarcinogens and their concentrations in cigarette smoke. Although certain PAH and catechols represent two major groups of tobacco cocarcinogens, others may be identified. Organ-Specific Carcinogens Cigarette smokers have an increased risk of cancer of the esophagus, pancreas, kidney, and urinary bladder (189). Since cigarette smoke does not directly come in contact with these organs, except for the esophagus, mechanisms other than contact carcino genesis are involved in the pathogenesis of these cancers. Several hypotheses can be postulated for such mechanisms. Cigarette smoke contains organ-specific carcinogens and also agents that give rise to in uiuo formation of carcinogens (189). Cigarette smoking may also 199 shift the metabolism of dietary components toward in uiuo formation of carcinogenic metabolites (log), or may induce enzymes that convert environmental carcinogens to their ultimate active forms (41). Another concept relates to the presence in cigarette smoke of cocarcinogens that potentiate the activity of trace amounts of the carcinogens from environmental sources or of those formed in uiuo (189). Epidemiological and experimental studies have documented the occurrence of organ-specific carcinogens in certain occupational settings. Classic examples for these are 2naphthylamine, 4-aminobi- phenyl, and benzidine in dye factories (149); vinyl chloride in the chemical industry is a more recent example (98). Tobacco smoke, as a plant-combustion product containing more than 3,600 compounds (611, also contains organ-specific carcinogens which have been identified and studied by a number of groups. N-Nitrosamines N-Nitrosamines are formed in vitro and in uiuo by nitrosation of amines. More than 50 of the approximately 100 N-nitrosamines which have been tested have various degrees of carcinogenic potency in laboratory animals (127). There is a lack of direct evidence that these compounds are also human carcinogens. Nonetheless, many scientists concur with the International Agency for Research on Cancer (97) that, for practical purposes, these nitrosamines should be regarded as carcinogenic in humans. Tobacco and tobacco smoke contain three types of N-nitrosamines; namely, volatile nitrosamines (VNA), nitrosamines derived from residues of agricultural chemicals on tobacco, and the tobacco- specific nitrosamines (TSNA). These compounds are formed during tobacco processing and during smoking from precursors such as primary, secondary, and tertiary amines and quaternary ammonium salts (97), reacting with N-nitrosating agents such as nitrogen oxides, nitrite, and some C-nitro compounds (149, 195). It is also possible that the oxidation of certain amines can lead to nitrosamine formation (147). Volatile N-Nitrosamines A number of volatile N-nitrosamines (VNA) are present in tobacco products and tobacco smoke. Practically all of the VNA appear to be retained by the respiratory system upon inhalation of cigarette smoke (38). N-nitrosodimethylamine (NDMA) and N-nitrosopyrroli- dine (NPYR) occur in the highest concentrations (Table 4) (97, 1.58). NDMA, N-nitrosoethylmethylamine, and N-nitrosodiethylamine (NDEA) are among the most potent environmental carcinogens in this class of compounds (97). Tumors of the respiratory tract were 200 TABLE 4.-Volatile N-nitrosamines in tobacco and tobacco products Nitrosamine Tobacco wb Chewing tobacco or snuff wb cigarette smoke ng/cigarette Nitrosodimethylamine 7-190 (33) 2-56 (120.33) 4-180 (33,?9,13oo~ Nitrosoethylmethylamine l-40 (33,13oa, Nitroscdiethylamine O-15 (33) 8.6 (120) 0.1-28 (79,13&x) Nitrosodi-n-propylamine O-l 113ool Nitrosodi-n-butylamine o-3 f1300) Nitrosopyrrolidine 0.0X2.0 l120.30) O-110 t33,13oal Nitrosopiperidine o-9 (3oaJ Nitrosomorpholine 2&700 (30, 113&l) SOURCE. Hoffmann and Adams (77) induced in 29 of 36 Syrian golden hamsters given only 6 mg of NDEA (138). The other identified VNA are strong to moderate organ- specific carcinogens (97). Although the hydrophilic VNA are primari- ly found in the vapor phase of fresh cigarette smoke, they are retained by a Cambridge filter. This glass fiber filter has been chosen arbitrarily to separate the gas phase from the smoke particulates and has been utilized for smoke gas phase inhalation studies. The selective retention of hydrophilic VNA from smoke by cellulose acetate filter tips of cigarettes can also be explained by the fact that moisture and the moist smoke particulate act as retainers. This selective retention can remove more than 80 percent of the VNA from mainstream cigarette smoke (33, 139). Recent evidence has incriminated snuff dipping for an increased risk of cancer of the oral cavity (77, 200). Since fine cut tobacco and snuff contain high levels of VNA (Table 4) and other nitrosamines, special efforts should be made to reduce these quantities in tobaccos used for snuff dipping. The high concentration of VNA is a consequence of the high nitrate levels in these tobacco varieties, which range from 2 to 5 percent, and of long fermentation times under anaerobic conditions. N-nitrosomorpholine (NMOR) was also detected in relatively high concentrations (30) in several snuff samples. Protein and amino acids serve as major precursors for most VNA in processed tobacco and in smoke, but the origin of the precursor for NMOR remains unknown. NMOR is a relatively potent animal carcinogen (97), inducing primary liver tumors in mice and rats and tumors of the larynx, trachea, and lung in Syrian golden hamsters. Metabolic activation of the simplest member of -this group, dimethylnitrosamine (DMN), is presumed to involve a-hydroxylation of one methyl group, followed by loss of formaldehyde, to yield a monomethylnitrosamine. In turn, this unstable intermediate loses 201 OH- and nitrogen to form a methylating moiety that reacts with proteins and nucleic acids. In the latter, the N-7 and O-6 positions are attacked. Both adducts were detected relatively soon after adminis- tration of DMN (151). The demethylative enzyme is a cytochrome P- 450-dependent microsomal mixed-function oxidase that requires NADPH and 02 and can be inhibited by CO or by pretreatment of the animal with CoCL which inhibits the synthesis of cytochrome P-450. Since ethanol is often consumed in conjunction with smoking, it is pertinent to note that in rats chronic consumption of ethanol enhanced the metabolism of DMN and the formation of mutagenic substances therefrom (57, 131). This observation is of special interest in view of human data showing an increased incidence of cancer of the oral cavity and esophagus in smokers who also drink large amounts of alcohol (199). Diethylnitrosamine, the next higher member of the series, is also metabolized by a-oxidation to acetaldehyde and an ethylating species. In contrast, w-oxidation of the alkyl chain of longer chain dialkylnitrosamines yielded hydroxy, keto, and carboxylic acid derivatives. Some of these metabolites, for example, N-nitroso-n- butyl-(4-hydroxybutylamine), were more active as bladder carcino- gens than the parent N-nitrosodi-n-butylamine (53). Like other acyclic and cyclic carcinogenic nitrosamines, NMOR undergoes metabolic a-hydroxylation to electrophilic diazohydroxide intermediates that may act as ultimate carcinogens (73, 127). N-Nitrosodiethanolamine Among the agricultural chemicals used for the cultivation of tobacco crops are found several amines, amides, and carbamates. These include dimethyldodecylamine (Penar), maleic hydrazide diethanolamine, and carbaryl (Sevin) as a representative of the ethyl urethanes (Figure 3) (186, 2021. Small residual amounts of these agents were found on harvested tobacco (1691. Diethanolamine has been studied as a possible precursor for nitrosodiethanolamine (NDELA), a carcinogen found in tobaccos (0.1 to 6.8 ppm) that were treated with the sucker growth inhibitor maleic hydrazide diethano- lamine. The smoke of tobaccos thus treated contained 10 to 40 ng per cigarette of NDELA. Snuff contains especially high levels of 3.2 to 6.8 ppm of NDELA (31). This nitrosamine induces carcinoma of the kidney and liver of rats (97, 123) and carcinoma of the trachea of hamsters following subcutaneous injection, painting the skin, or swabbing the oral cavity (83, 97). NDELA penetrates rat (122) and human skin (54) and is primarily excreted via the urinary tract (122, 153). 202 CH3 CH3 \/ : t HOOC-CH3 FH2 (CHZ),O AH3 DIMETHYLDODECYLAMINE -ACETATE ( PENAR 1 OH CAREARYL (SEWN 1 + HN:CH2-cH2-OH 0 CH2-CH2 -OH MALEIC HYDRAZIDE - DIETHANOLAMINE ( MH-301 FIGURE S.-Agricultural chemicals for tobacco cultivation SOURCE Tso t lH6). and Wynder and Hoffmann (2027). Tobacco-Specific N-Nitrosamines Commercial tobaccos in the United States contain 0.5 to 2.7 percent alkaloids, 85 to 95 percent of which is nicotine. Important minor alkaloids are nornicotine, anatabine, anabasine, cotinine, and N'-formylnornicotine (Figure 4). Several of these alkaloids are secondary and tertiary amines and, as such, are amenable to N- nitrosation. Tobacco and tobacco smoke were shown to contain N'- nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-l-bu- tanone (NNK), N'-nitrosoanatabine (NAT), and N'-nitrosoanabasine (NAB). In model experiments, nitrosation of nicotine also yielded 4- (methylnitrosamino)-4-(3-pyridyl)butanal (NNA), which has not as yet been identified in tobacco nor in the smoke (71, 78). In experiments with `%-labeled nicotine, 0.009 percent of this alkaloid is nitrosated to NNN during the curing of Burley tobacco (68). Of the NNN in cigarette smoke, 41 to 46 percent originates from the NNN in tobacco by transfer, and the remainder is pyrosynthes- ized primarily from nicotine (80). Table 5 presents data for tobacco-specific N-nitrosamines (TSNA) in the tobacco and smoke of cigarettes and cigars (80). In addition, it must be noted that cigarette smoke contains traces of NAB (up to 0.015 pg/cig). Recent studies carried out on popular snuff tobaccos from the United States, Denmark, Germany, and Sweden revealed 5.5 to 106 ppm of TSNA in these materials, the highest levels of 203 377-310 0 - 82 - 15 NICOTINE COTININE NORNICOTINE N'-FORMYLNOANICOTINE ANABASINE ANATABINE FIGURE 4.-Common tobacco alkaloids in tobacco and tobacco smoke SOURCE Hoffmann et al 1801 TABLE B.-Tobacco specific N-nitrosamines in tobacco products Nitrosamines Tobacco wm Chewing tobacco or snuff pm Cigarette smoke pgfcigarette Cigar smoke N/cigar N'-Nitrosonornicotine NNK.8 N'-Nitrosoanabasine N'-Nitrowanatabine 0.2 - 45 3.5 - 77 0.2 - 3.7 3.2 - 5.5 0.1 35 0.8 - 4.7 0.12 - 0.44 1.9 - 4.2 0.0 - 0.01 0.04 1.9 0.0 - 0.15 n.d.b 0.6 13 0.8 - 44 0.15 . 4.6 1.7 1.9 aNNK = 4imethylnitrosamlnocI-t3-pyrldyltl-butanone "n.d. = nit determined SOURCE, Hoflmann et al (7X. 791. carcinogenic nitrosamines reported in a consumer product that is taken into the body. The saliva of snuff dippers yielded TSNA levels at concentrations of 0.02 to 0.9 ppm (77). These observations are of relevance to the epidemiological findings of increased risk for cancer of the oral cavity in snuff dippers (200). The importance of the carcinogenic TSNA is underscored in that these compounds can also be formed &thin the oral cavity during snuff dipping (68). At this time, there is no experimental evidence on the formation of TSNA in the lung upon inhalation of cigarette smoke. However, a smoker of one or two packs of cigarettes daily retains 20 to 60 mg of nicotine, 1 to 4 mg of nornicotine, 1.5 to 6 mg of anatabine, and 0.2 to 0.8 mg of anabasine, and inhales 0.3 to 24 mg of NO,. Thus, in uiuo formation af tobacco-specific N-nitrosamines is a real possibility. 204 TABLE 6.-Carcinogenic activity of tobacco-specific nitrosamines Compounds Speck MOUW Apphcation Principal organ affected I.P. Lung (Adenoma, Adeno- carcinoma) Salivary glands (7) NNN Rat S.C. Nasal cavity iCarcinoma) P.O. Esophagus ~Papilloma. (W&d Carcinoma) Pharynx (Papillomal Nasal cavity (Carcinoma) SC. Trachea (Paptllomal Nasal cavity (Carcinoma) MOUSe I.P. Lung (Adenoma, Aden@ carcinoma) Flat HaItBter NNK S.C. Nasal cavity (Carcinoma) Liver tHepatocarcinoma1 Lung (Adenoma, Carcinoma) S.C. Lung (Adenoma, Adeno- carcinoma) Trachea (Papillomal Nasal cavity Kkcinoma) P.O. Esophagus (Carcinoma) (WaterJ SC. Esophagus (Papilloma) Pharynx (Papilloma) NAB HZWlSt`X SC. Inactive (375 mg/hamster) The data for the carcinogenicity of NNN, NNK, and NAB are summarized in Table 6 (23, 70, 84); NAT assay results are not as yet reported. NNK is by far the most potent carcinogen of the TSNA. In the Syrian golden hamster, NNK has about the same carcinogenic potency as N-nitrosomorpholine and about twice the activity of N- nitrosopyrrolidine, but it has only about one-tenth of the activity of N-nitrosodiethylamine, which is the most potent carcinogenic nitro- samine in hamsters. The influence of alcohol as a dietary component on NNN carcinogenicity was assayed in the Syrian golden hamster at two dose levels. The data did not show an accelerating effect of the alcohol on NNN carcinogenicity in the test animals whose total caloric intake was equal to that of the control animals (131). The metabolic pathways of NNN and NNK have been studied in rats and hamsters (73, 74, 84). As was seen with other acyclic and cyclic nitrosamines, the metabolic activation of these TSNA involves most likely also uia a-hydroxylation (73, 127). Figures 5 and 6 depict the 205 FIGURE 5.-Metabolism of NNN in rats and Syrian golden hamsters SOURCE: Hecht et al. (73). metabolic pathways of NNN and NNK (73, 74). Among the stable metabolites, NNN-N'-oxide and NNK-N'-oxide, as well as the secon- dary alcohol formed by reduction by NNK (Figure 6, formula 2), are most likely also carcinogens, based on induction of lung adenomas in strain A mice. The electrophilic diazohydroxide intermediates of NNN (Figure 5, formulas 7 and 8) and of NNK (Figure 6, formulas 7 and 9), respectively, or the resulting carbonium ions are probably the ultimate carcinogenic forms of these tobacco-specific nitrosamines. Assays of NNN metabolites obtained by incubation of the carcinogen with human liver microsomes showed that five out of six human liver specimens tested contained the enzymes that effected NNN activation by a-hydroxylation (69). Two autoradiographic studies and one biochemical report on the distribution of [2'-W]NNN and [l-W]NNK in mice and hamsters, respectively, have shown that the metabolites of these labeled nitrosamines are bound to macromolecules of the tracheobronchial and nasal mucosa and to kidney, liver, sublingual and submaxillary glands, esophagus, and melanin of the eye (25, 84, 196). These data indicate that the binding of metabolites to the tissues of specific organs does not by itself explain the organ-specificity of the TSNA. 206 FIGURE 6.-Metabolism of NNK in rats and Syrian golden hamsters SOURCE. Hecht et al. 1741. Other aspects such as the DNA repair of the affected cells must be considered. Aromatic Amines and Aromatic Nitrohydrocarbons The incomplete combustion of organic matter yields C,H-radicals, which serve as precursors for benzene, naphthalene, or PAH (5). In the burning cone of a cigarette, the aromatic hydrocarbons or their radicals react with nitrogen oxides to form nitrobenzene, nitrona- phthalenes, or nitro-PAH (85, 150). These can be reduced to aromatic amines in the oxygen deficient zones. Aromatic amines may also be formed directly from proteins and amino acids (129). The presence of both aromatic nitrohydrocarbons and aromatic amines and their dependence on the nitrate concentration in the tobacco is thus not surprising (85, 150). Tables 7 and 8 list the data available at present on these compounds in cigarette smoke. 4-Nitrocatechol and other nitrophenols are also present in cigarette smoke. The reported values of 200 ng/cigarette of 4-nitrocatechol and also the values for other nitrophenols require verification, since they were obtained without the precautions that prevent artifacts during smoke collec- tion and analysis (106, 111). Epidemiological data from dye workers have documented that certain aromatic amines such as 2-naphthylamine and I-aminobi- phenyl are human bladder carcinogens (149). Some o-aminotoluenes induce cancer in animals (39). On the basis of quantitative data for aromatic amines in cigarette smoke, an etiological significance of these traces of carcinogenic amines in human bladder cancer is 207 TABLE 7.-Nitroarenes and nitrophenols in cigarette smoke Nitro compound pg/cigarett.e+ Nitrobenzene 2.Nitrotoluene 3.Nitrotoluene 4.Nitrotoluene 2.Nitr~l,4dimethylbenzene 4.Nitro-1.2dimethylbenzene 4.Nitro-1,3dimethylbenzene 4-Nitrocumene 2.Nitrophenol SNitrophenol I-Nitrophenol 2-Nitrc+3methylphenol 2.Nitro-4.methylphenol 4.Nitro-3-methylphenol 2.Nitrc&,6dimethylphenol I-Nitrocatechol 25.3 21.4 10.4 19.6 6.5 18.5 5.3 35 + 20 30 90 + + 200 *+ =present SOURCE: Schmeltz and Hoffmann (164) questionable, even if one were to consider the total of the aromatic amines and their active metabolites, which may be formed in uiuo from aromatic nitrohydrocarbons of the smoke. However, Doll (45) concluded that 2-naphthylamine (together with other aromatic amines) may suffice to explain the increased bladder cancer risk for cigarette smokers working in gasification plants. Although the importance of traces of aromatic amines in smoke for the increased bladder cancer risk of smokers is disputed, there may be reason for concern about the increasing levels of nitrate in present-day cigarettes (1.2 to 1.5 percent). Twenty years ago, these levels were only about 0.5 percent. The increased potential for formation of aromatic amines and of N-nitrosamines should be studied carefully. The metabolic detoxification and activation of 2-naphthylamine (2- NA) have been studied intensively (22, 155). Many detoxification products have been identified; most are. hydroxylated derivatives that can also be excreted as sulfuric acid or glucosiduronic acid conjugates. Premercapturic and mercapturic acids have also been identified. However, the evidence points toward an N-hydroxy derivative of 2-NA as the active carcinogen rather than the parent compound. Furthermore, an N-glucuronide appeared to be the transport form. 2-NA or the N-hydroxy derivative form adducts with guanine in nucleic acids (1031, and other adducts have also been identified (105). By analogy to the situation with l-hydroxynaphthy- lamine, the O-6 position of guanine is arylaminated (104). The 208 TABLE &-Aromatic amines in cigarette smoke Aromatic amine Aniline P-Toluidine 3.Toluidine 4.Toluidine 2,bDimethylaniline 2,4-Dimethylaniline 2,BDimethylaniline 2,BDimethylanilme 3,CDimethylaniline 3,5-Dimethylaniline 2.Ethylaniline SEthylaniline 4.Ethylaniline 2,4,6Trimethylaniline 2.Methylaniline 3.Methylaniline 5Methoxyaniline 4.Methoxyanilme Diphenylamine 1.Naphthylamine 2.Naphthylamine 2.Methyl-1-naphthylamine ZAminobiphenyl BAminobiphenyl CAminobiphenyl 2-Aminostilbene "g/cigarette ' loo 1.200 32 15 14 8 14 1; + + + + + + + + + + + 4.3 27 1.0 22 5.8 1.8 2.7 2.4 + * + = present SOURCE: Patrmnakos and Hoffmann (150) and Schmeltz and Hoffmann (164. biological significance of the different adducts has not been delin- eated as yet. Altbough N-hydroxylation also occurs during metabolism of 2- aminostilbene (14.9, the N-hydroxy group does not participate in formation of nucleic acid adducts. Instead, the ethylenic bond of the stilbene forms adducts at the N-l and N-6 of adenosine or similar adducts with the nitrogens in other bases (167, 168). A definitive experiment on the metabolism of o-toluidine showed that acetylation of the amino group and hydroxylation at the 4- position of the ring were the major pathways during metabolism (I 73). Mainly sulfate and to a lesser extent glucuronide conjugates of the cresols thus formed were also excreted. There was some oxidation of the methyl group to a hydroxymethyl or carboxylic acid. Another minor pathway was oxidation of the amino group, since azoxytoluene and nitrosotoluene were identified. Whether these metabolites were derived from an N-hydroxy-o-toluidine was not delineated. Poloniun-210 In 1964, Radford and Hunt (154) suggested that bronchogenic carcinoma in cigarette smokers could be induced by the a-particle emitter polonium-210 (ZloPo). Since then, a number of studies have reported varying quantities of 21OPo in the smoke (0.03 to 1.0 pCi per cigarette) (66, 202). Harley et al. (66) gathered data for 2lOPo in cigarette tobaccos from many countries and calculated 0.45 pCi of the radioactive element per gram tobacco as a median value. Major sources for 2lOPo in tobacco are airborne particles, taken up by the glandular hair of the tobacco leaf, as well as lead-210 (21OPb) and 2lOPo from soil that is fertilized with certain phosphates (128, 187). Thirty to fifty percent of ZloPo in the cigarette tobacco were reported to be transferred into the mainstream smoke of cigarettes; up to 90 percent of ZlOPo can be retained by filter tips (24). Upon inhalation, ZlOPo produces tumors of the lung in rats (204). Tests with multiple intratracheal instillations of 21oPo in Syrian golden hamsters revealed a dose-response relationship in regard to bronchocarcinoma and adenocarcinoma in the peripheral lung (108). Simultaneous multiple instillations of benzo[a]pyrene (total dose 4.5 mg) and 21OPo (total dose 50,000 pCi) on the same carrier induced about twice the number of tumors expected from the additive effect of the two carcinogens (124). Lead-210 (21'JPb), the grandparent of 210P0, is found in all environ- mental atmospheres (0.01 pCi 210Pb/m3 and 0.003 pCi 210Po/m3). The daily exposure of a cigarette smoker to 2loPb has been estimated to be 2.5 to 3.0 times greater than that of a nonsmoker (66). Harley et al. (66) reviewed 12 studies that had determined 2lOPo in the paren- chyma of the lungs and in the bronchial tissues of cigarette smokers, ex-smokers, and nonsmokers. The studies showed general agreement that 2l'JPo is stored in the parenchyma of smokers at three times higher levels than in nonsmokers and that it also persists in the bronchial mucosa of smokers in higher concentrations than in nonsmokers. From comparisons of radon-daughter exposure of underground miners with their relative risk of lung cancer, Harley et al. deduced that 2lOPo is a questionable risk factor for lung cancer in cigarette smokers. They recommend, nevertheless, that methods for lowering 2loPo levels in tobacco should be considered (66). Nickel A large number of studies from the United States and from other countries have shown that the tobacco of one cigarette contains 2 to 14 pg of nickel (141, 202). Analyses have determined that 10 to 20 percent of the nickel in cigarettes is transferred into the mainstream smoke (241). In one study, it was found that an average of 84 percent 210 3f the nickel is present in the gas phase (1831, indicating that cigarette smoke may contain nickel carbonyl. The possible existence and relative stability of nickel carbonyl in zigarette smoke is indirectly supported by several observations. Sunderman et al. (181) found nickel carbonyl in the exhaled air as well as in the blood of man. Stably (I 76) reported that passing carbon monoxide through an unlit cigarette column removed much of the nickel from the tobacco. Nickel has also been found in pipe tobacco 0.5 to 10 pg/cig), cigars (1.9 to 15 Kg/cigar), and in U.S. snuff (2 to 3 .Lg/g) (141). The presence of nickel in tobacco smoke is an important finding regardless of whether it is in the form of nickel carbonyl or in other forms, because nickel itself and several nickel compounds are carcinogenic in laboratory animals, inducing sarcomas by subcuta- neous injection and rhabdomyosarcomas upon intramuscular injec- tion. It appears that nickel subsulfide (NiS2) is a strongly sarcogenic agent (96, 141). Intrarenal injection of a single dose of 5 mg NiS2 induced a high rate of renal carcinomas in rats (180). Exposure of rats for 30 minutes three times weekly for 1 year to an atmosphere containing 30 to 60 pg of nickel carbonyl produced pulmonary carcinoma in two of six animals (I 79). Workers in nickel refineries in England and Canada were reported to have excessive rates of cancer of the nasal cavity and of the lung. Studies from Japan, the U.S.S.R., and the German Democratic Republic also reported increased incidences of lung cancer among nickel workers. The International Agency for Research on Cancer r96) concluded on the basis of epidemiological studies that workers in nickel refineries have an increased risk for cancer of the nasal cavity and of the lung. Although it is not likely that nickel plays a significant role in the etiology of lung cancer in cigarette smokers (1411, prudence dictates that efforts should be made to reduce the amount of this metal in tobacco and to avoid contamination of tobacco with nickel during cutting and other processes in cigarette manufacture. Arsenic Extensive studies have been conducted on paired soil residues in tobacco. From 1932 to 1951, arsenical pesticides were used on tobacco in the United States. During this time, the arsenic content of U.S. cigarettes rose from 12.6 to 42 pg/cigarette (63). In 1952, arsenicals were removed from the list of recommended insecticides for control of hornworms on tobacco. Since then, a sharp decrease in the arsenic content of cigarette tobacco has occurred. Guthrie (62) concluded in 1968 that arsenic residues in U.S. cigarettes do not exceed 2 ppm and are normally about 1 ppm or less and that tobacco is no greater source of arsenic for consumers than food. The last reported data for 211 U.S. tobacco range between 0.5 and 0.9 ppm. The arsenic now found in tobacco appears to come primarily from natural sources (63). Between 7 and 18 percent of the total arsenic on tobacco leaves is recovered in the mainstream smoke of cigarettes. Studies with 74As- labeled cigarettes have shown that, depending on the individual's smoking pattern, 2.2 to 86 percent of the arsenic in cigarette tobacco is transferred to the respiratory tract. About 50 percent of the inhaled arsenic is eliminated within 10 days, primarily in urine, the remainder is either deposited in tissues, exhaled or otherwise eliminated (91). Skin cancers have been reported to be particularly prevalent among people exposed to arsenicals through drugs, drinking water, or pesticides. The anatomic sites of these tumors suggest that they are causally associated with exposure to arsenic. Lung cancer has been associated with inhalation exposure to arsenicals in copper smelters, workers in pesticide manufacturing plants, Mosel vine- yards, and Rhodesian gold mines (99, 142). The International Agency for Research on Cancer (99) concluded in its review, "There is sufficient evidence that inorganic arsenic compounds are skin and lung carcinogens in humans." The U.S. National Academy of Sciences (142) arrived at a similar conclusion, but also mentioned that exposure to arsenicals or other metals and to sulfur dioxide may constitute carcinogenic cofactors for an increased risk for lung cancer of miners and metal workers. The view that inorganic arsenicals cause cancer of the skin and .lung has not been widely accepted, since these compounds have riot produced cancers in experimental animals (101, 118, 142, 170). Ivankovic et al. (101) reported in 1979 the induction of lung carcinomas in rats after a single intratracheal instillation of an arsenic-containing pesticide mixture, such as those formerly used by vineyard workers. Of the 15 rats exposed, 7 developed bronchogenic adenocarcinoma and 2 had bronchioalveolar carcinoma following a single instillation of 0.07 mg of arsenic as calcium arsenate. Cadmium Several forms of cadmium (Cd) are carcinogenic in experimental animals (95). Two studies indicate that occupational exposure to cadmium oxide is associated with an increased risk for prostatic cancer. It has been suggested that a heavy smoker who is exposed by inhalation to 70 to 90 ng Cd per cigarette retains 1.5 pg of Cd per day and may accumulate up to 0.5 mg (95). In Table 9 is summarized the present knowledge of the presence of organ-specific carcinogens in cigarette smoke. Special importance in this group of carcinogens should be given to the tobacco-specific N- nitrosamines, since these are found only in the Nicotiana varieties, and appear in high concentrations in tobacco products. They are 212 TABLE 9.-Organ-specific carcinogens in cigarette smoke Smoke carcinogen Amount per cigarette LNitrosodimethylamine N~trosoethyhnethylamine Nitrosodiethylamine Nitrosodl-n-butylamme Nitrosopyrrolidine Nitrosopiperidine N'-Nitrosonornicotine NNKa N'-Nitrosoanabasine N'-Nitrosoanatabine 2.Naphthylamine 4.Aminobiphenyl Polonium-210 Nickel 4 180 ng 1 40 ng 0.1 28 ng 0 - 3 "g 0 - 110 ng 0 9 ng 0 40 ng 0.2 - 3.7 pg 0.12 - 0.44 pg 0 0.15 pg 0.15 4.6 pg 4.3 27 ng 2.4 - 4.6 ng 0.03 1.0 pCi 0 3pg "NNK = 4-(methyln,trosam,no~l~Bpyr,dyl~l-butanone. SOURCE. Brunnemann and Hoffmann lZ9). Brunneman et al. (33). and Patrianakos and Hoffmann 11501 moderately active animal carcinogens or, as in the case of NNK, a potent animal carcinogen. Sidestream Smoke The sidestream smoke (SS) is a composite,of effluents generated in different ways during the burning and smoking of a tobacco product. While the product smoulders in between puff taking, smoke is freely emitted into the air; during puffing a little smoke escapes from the burning cone, and vapor phase components diffuse partially through the cigarette paper. The SS, generated between puffs, originates from a hydrogen-enriched, strongly reducing atmosphere. It con- tains, therefore, combustion products formed by thermal cracking and compounds that result from reactions involving nitrates in greater proportions than are found in mainstream smoke (MS). These compounds include nitrogen oxides, nitrosamines, ammonia and amines, and total particulate matter. Table 10 lists the known SS/MS ratios for major toxic and tumorigenic agents. The SS/MS ratios are especially high for volatile nitrosamines and for the nitrogen oxides, which constitute major precursors for in vitro and in vivo formation of nitrosamines. The relevance of this finding in regard to the SS exposure of nonsmokers in closed environments has been repeatedly discussed (26, 29, 158, 189). The SS components are diluted by air prior to being inhaled and the particulates settle rather quickly on environmental surfaces. Deep and intentional inhalation of MS delivers a far greater burden of 213 TABLE lO.-Toxic and tumorigenic agents of cigarette smoke; ratio of sidestream smoke (SS) to mainstream smoke (MS) A. Gas phase Carbon dioxide Carbon monoxide Nitrogen oxides (NO,) Ammonia Hydrogen cyanide Hydrazine Formaldehyde Acetone Acrolein Acetonitrile Pyridine 3-Vinylpyridine N-Nitrosodimethyl- amine N-Nitrosoethyl- methylamine N-Nitrwodiethylamine N-Nitrosopyrrolidine Amount/cigarette SUMS 10 - 80 w 8.1' 0.5 - 26 mg 2.5' 16 - 600 w 4.7 - 5.8 10 - 130 w 44 - 73 280 - 550 Pi? 0.17 - 0.37 32 w 3 20 - 90 w 51 loo - 940 l%z 2.5 - 3.2 10 - 140 I% 12 60 . 160 w 10 32 w 10 23 R 28 4 - 180 "II 10 - 830 1.0 - 40 "g 5 - 12 0.1 - 28 "g 4-25 0 _ 110 ng 3 - 76 B. Particulate phase Amount/cigarette ss/Ms Total particulate phase Nicotine Toluene Phenol Catechol Stigmasterol Total phytosterols Naphthalene 1.Methylnaphbhalene P-Methylnaphthalene Phenanthrene Benz(a)anthracene PyR"e 5enzda)pyrene Quinoline Methylquinoline Harmane Norharmane Aniline *Toluidine 1-Naphthylamine 2.Naphthylamine I-Aminobiphenyl N'-Nitrosonornicotine NNKZ N'-Nitrosoanatabine N-Nitrcsodiethanol- 0.1 0.06 20 40 2.0 10 15 M 1.1 3.2 100 1.0 4.3 2.4 0.2 0.12 0.15 0 40 2.3 108 150 280 53 130 2.8 1.2 1.0 80 70 90 40 1.7 6.7 3.1 8.1 1.200 32 22 27 4.6 3.7 0.44 4.6 40 w 1.3 - 1.9' w 2.6 - 3.3l w 5.6 w 2.6 w 0.7 w 0.8 I47 0.8 w 16 w 26 w 29 "IT 2.1 "g 2.7 "g 1.9 - 3.6 "g 2.7 . 3.4 Pi? 11 Irg 11 M 0.7 - 2.7 wz 1.4 - 4.3 "k? 30 w 19 "iz 39 "g 39 "g 31 w 1-5 MT l-8 I% 1-7 "is 1.2 I In cigarettes with perforated lilter tips the SSlMS ratio rises with increasing air dilution. In the case of smoke dilution with air to 17 percent. the SS/MS ratios for TPM rise to 2.14, CO> 36.5, CO 23.5. end nicotine to 13.1 z NNK = 4 99 percent plain cigarettes) delivered under standard smoking condi- tions 32.9 mg tar, 2.0 mg nicotine, and 18.6 mg carbon monoxide (197). In contrast, in 1979 the average cigarette in the United Kingdom (9 percent plain tobacco, 77 percent unventilated filter brands, and 14 percent ventilated filter cigarettes) delivered 16.8 mg tar, 1.39 mg nicotine, and 16.6 mg carbon monoxide. The authors also point out that there was a sizeable decrease since 1934 in delivery of tar (49 percent) and nicotine (31 percent), but only an 11 percent decrease in carbon monoxide delivery. The average U.K. unventilated filter cigarette of 1979 delivered 18.1 mg carbon monoxide and the average ventilated filter cigarette delivered 12.0 mg carbon monoxide (197). This finding and the values of Table 12 support the concept that filter perforation is the most important development for the reduction of carbon monoxide in cigarette smoke. The reported data are based on measurements obtained by machine smoking of cigarettes under standard conditions. As discussed before, these conditions may have reflected the average smoking habits of individuals 25 years ago, but today they appear to be representative of less than 10 percent of U.S. smokers. Russell and coworkers (160), as well as others (75, 76), reported that some smokers of lower tar, lower nicotine cigarettes will intensify smoking and inhalation in order to satisfy a physiological need for nicotine and cotinine. A statistical reevaluation (113) of the data of Russell et al., however, showed that the nicotine blood serum levels of smokers of cigarettes with perforated filt,er tips were, in fact, lower than those of other cigarette smokers. On the basis of model studies, it also appears unlikely that a smoker of perforated filter cigarettes can increase his smoking intensity to such a degree that he can fully compensate for the loss in nicotine delivery without significantly TABLE la.-Carbon monoxide in smoke of cigarettes Commercial product Carbon monoxide (mg/cigarette) NOdLIter Regular PWhated filter filter U.K. (1975)' 9.0-16.0 13.CL18.0 (N=9) (N = 10) UK. (1979)" 10.9 18.1 12.0 Germany (19751 16.0-21.0 15622.5 - IN=71 (N=17) Germany (19781 14.519.9 8.EL18.5 2.2-13.8 (N=16) (N= 151 tN=91 U.S.A. (90% of av. 1977178 ll.ls17.0 14.4-20.0 2.b12.8 sales)`*' (N=8) (N = 231 IN=91 U.S.A. IFTC - 1981) 13.&22.0 13.c26.0 0.s13.0 (N= 18) (N-87) (N=82) * Average values for nonfilter cigarettes, 12.5 mg; for filter cigarettes, 16 1 mg `* Saleswelghted average carbon monoxide yields, average of all U.K brands, 16.6 mg Wald et al 1200) *`* Average values for nonfilter cigarettes, 14.9 mg; for regular filter cigarettes. 17 1 mg; for perforated filter cigarettes. 6.9 mg. SOURCE- Hoffmann et al. (89) increasing his daily cigarette consumption (81). The increase in smoking intensity by the smoker of perforated filter cigarettes may lead to an increase in the delivery of carcinogenic tar. In addition to these changes in the pattern of smoking, smokers of lower tar and nicotine products may increase their actual dose of smoke constituents over that predicted by machine measurements through voluntary or involuntary blocking of the ventilation holes in filtbrs. Kozlowski et al. (112) examined the effect of partial and total occlusion of perforations on machine measurement of tar, nicotine, and carbon monoxide in one brand of lower tar cigarettes. With full occlusion, he found that the nicotine yield increased 118 percent, the tar yield increased 186 percent, and the carbon monoxide yield increased 293 percent. He reported survey results of from 32 to 69 percent (95 percent confidence limits) of lower tar smokers had blocked holes with fingers, lips, or tape. Further research is necessary to define the actual impact of occlusion of ventilations in filters on actual smoker exposure. The development of the low-tar cigarette required enrichment of smoke flavors in order to make the product acceptable to the consumer. The flavor is enhanced by the addition of undescribed materials that may include concentrates of flavor precursors ob- tained from tobacco, licorice, extracts from other plants, or semisyn- thetic or fully synthetic flavor components. Because these additives 217 have not been identified, no judgment can be made as to whether they result in new compounds or in higher concentrations of hazardous components in the smoke. The practice of flavor enrich- ment requires detailed toxicological studies that are not available at present for scientific evaluation of their health impact (I 16a, 189). Research Needs and Priorities Tobacco carcinogenesis has been intensively studied for more than 25 years by epidemiologists, chemists, biochemists, toxicologists, and pathologists. As a result, there is a much expanded knowledge of the major factors contributing to the toxicity and carcinogenicity of cigarette smoke. Nonetheless, significant gaps in that knowledge remain. Benign and malignant tumors have been induced in the larynx of hamsters by long-term exposure to diluted cigarette smoke. At- tempts to induce significant numbers of bronchogenic carcinoma in laboratory animals were negative in spite of major efforts with several species and strains. Neither rata nor hamsters nor baboons inhale cigarette smoke as deeply and as intensely as the cigarette smokers who have provided the data with the consequences of their "experiment" in the form of clinical evidence gathered by epidemiol- ogists. In view of this compelling evidence, it appears that the experimental induction of bronchogenic carcinoma should receive limited priority as a research goal. However, major efforts should be devoted to the elucidation of the steps involved in the formation of lung tumors. Such investigations must attempt to answer the following questions: Does cigarette smoke induce enzymes that activate tumor initiators and carcino- gens to their ultimate active forms? Are certain carcinogens, such as tobacco-specific N-nitrosamines, formed from smoke components in the lungs? Can the in viva formation of such carcinogens in the lung be prevented? Is it feasible to inhibit metabolic activation and DNA binding of tobacco smoke carcinogens by chemopreventive mea- sures? Both prospective and retrospective studies have indicated that cigarette smokers with low serum vitamin A levels have an increased risk for lung cancer compared with cigarette smokers with normal or high vitamin A levels (133, 198). Evidence from in uiuo and in vitro studies in carcinogenesis has supported the protective role of vitamin A (11.5). Studies of the specific effects of vitamin A and retinoic acid on the induction of lung tumors by tobacco carcinogens are thus needed. So far, only limited attention has been given to mechanisms of induction of cancer of the esophagus, pancreas, kidney, and urinary bladder by tobacco smoke. Initial experiments support the concept that certain nutritional deficiencies such as those of zinc and 218 vitamin A may increase the susceptibility of the esophageal epitheli- urn to insults from tobacco smoke constituents. Whether tobacco smoke as an enzyme inducer may be indirectly responsible for increased metabolic activation of organ-specific carcinogens in the esophageal epithelium needs to be determined. Only a few studies have been concerned with the effect of tobacco smoke and its nicotine level on the biochemistry and function of the pancreas in smokers and in laboratory animals (7,140). It needs to be determined whether nicotine has a direct influence on the induction of pancreatic cancer in cigarette smokers or whether it gives rise to an organ-specific N-nitrosamine or a carcinogenic metabolite of the latter. The elucidation of these questions should have high priority, since pancreatic cancer is associated with cigarette smoking, and since its incidence in the United States has increased steadily between 1950 and 1970. An earlier Part of this Report dealt with the various concepts on the correlation of cigarette smoking and bladder cancer. Currently, the most valid theory relates to the likelihood that the urine of smokers contains traces of bladder carcinogens that derive from inhaled smoke constituents either directly or via precursors. Wheth- er urine of smokers does in fact contain precursors that lead to the formation of carcinogens in the presence of infectious agents or under the influence of other pathologic conditions or whether the urine of smokers contains cocarcinogens needs to be explored. The identification of cocarcinogenic agents in the neutral and weakly acidic portions of tobacco smoke will also require much more detailed investigation as to chemical nature, precursors, and biologi- cal interactions of such compounds. In view of repeatedly expressed concerns regarding the possible transplacental effects of cigarette smoke inhalation (188, 289, 1901, intensive research in this area is urgently needed. The concern is based in part on the observation that the foreskin of newborn infants of smoking mothers contains enzymes that metabolize ben- zo[a]pyrene (41, 121). Furthermore, it is known that nicotine crosses the placenta (184) and may thus give rise to formation of carcinogen- ic nitrosamines in the fetus. The hamster appears to be a suitable model for smoke inhalation studies designed to examine various aspects of transplacental carcinogenesis (II, 51). The ongoing modifications of tobacco products offer constant challenges to the analytical chemists and toxicologists who monitor the characteristics of these products. The increasing nitrate content of cigarettes raises concerns regarding the possibility of higher yields of volatile and tobacco-specific N-nitrosamines in the smoke and regarding possible formation of aromatic nitrohydrocarhons and amines. 219 377-3-O 0 - 82 - 16 The changes in flavor composition or changes in tobacco that affect the "flavor bouquet" of tobacco products may conceivably be responsible for mutagenic, tumorigenic, or, otherwise toxic smoke constituents. Monitoring and identifying such biological activity and associated chemical characteristics remain a constant responsibility of the tobacco health research scientist. Although the published epidemiologic data regarding a possible effect of sidestream smoke on lung cancer induction in nonsmokers are not in total agreement (see the Part of this Report on involuntary smoking), the release of carcinogens from the burning cigarette into enclosed environments warrants a detailed study of this problem. Subsequent approaches toward a reduction of risks by inhibiting or ,altering the release of certain sidestream smoke components may need to be developed. Summary This overview presents evidence and observations on tobacco carcinogenesis primarily developed since 1978. 1. The biological activity of whole cigarette smoke and its tar and tar fractions can now be measured by improved inhalation assays in addition to tests for tumor-initiating, tumor-promot- ing, and cocarcinogenic activities on mouse skin. 2. Studies on smoke inhalation with the hamster now appear suitable for estimating the relative tumorigenic potential of whole smoke from commercial and experimental cigarettes. The identification of the smoke constituents that contribute to tumor induction in the respiratory tract is best achieved by fractionations of tar and by assays on mouse epidermis that determine the type and potency of the carcinogens. In combina- tion with biochemical tests, mouse skin assays should also aid in evaluating the possible role of nicotine as a cocarcinogen. 3. The identification, formation, and metabolic activation of organ-specific carcinogens have been studied which help ex- plain the increased risk to cigarette smokers of cancer of the esophagus, pancreas, kidney, and urinary bladder. In addition to certain aromatic amines, tobacco-specific N-nitrosamines appear to be an important group of organ specific carcinogens in tobacco and tobacco smoke. Little is known of the in viva formation of organ-specific carcinogens from nicotine and other Nicotiana alkaloids. The modification of their enzymatic activation to ultimate carcinogenic forms needs to be explored by chemopreventive approaches. 4. Transplacental carcinogenesis as it may relate to effects of cigarette smoking should be investigated more fully. It has been known for some time that inhalation of tobacco smoke 220 activates enzymes in the placenta and fetus and the conse- quences of such changes need to be studied. 5. The continuing modification of U.S. cigarettes has led to changes in the quantitative and perhaps also the qualitative composition of the smoke. This ongoing development requires continued monitoring of the toxic and carcinogenic potential of the smoke of new cigarettes. 6. 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Determination of particu- late matter in concentrated aerosols. Application to analysis of cigarette smoke. Analytical Chemistry 31(10): 17051709, October 1959. 12001 WINN, D.M., BLOT, W.J., SHY, C.M., PICKLE, L.W., TOLEDO, M.A., FRAUMENI, J.F., Jr. Snuff dipping and oral cancer among women in the Southern United States. New England Journal of Medicine 304f13): 745-749, March 26,198l. (201) WYNDER, E.L., GRAHAM, E.A. Tobacco smoking as a possible etiologic factor in bronchogenic carcinoma. A study of six hundred and eighty-four proved cases. Journal of the American Medical Association 143(4): 329-336, May 27,195O. (202) WYNDER, E.L., HOFFMANN, D. Tobacco and Tobacco Smoke. Studies in Experimental Carcinogenesis. New York, Academic Press, 1967,730 pp. 234 ,203) WYNDER, E.L., WRIGHT, G. A study of tobacco carcinogenesis. I. The primary fractions. Cancer lOt2): 255-271, March-April 1957. 204) YUILE, C.L., BERKE, H.L., HULL, T. Lung cancer following Polonium-210 inllalation in rats. Radiation Research 31(41: 760-763, August 1967 20,Si ZAJDELA, F., CROISY, A., BARBIN, A., MALAVEILLE, C., TOMATIS. L., BARTSCH, H. Carcinogenicity of chloroethyiene oxide, an ultimate reactive metabolite of vinyl chloride, and bistchloromethyliether after subcutaneous administration and in initiation-promotion experiments in mice. Cancer Research 4Ot21: 352-356, February 1980. 235 377-313 0 - 82 - Ii PART IV. INVOLUNTARY SMOKING AND LUNG CANCER 237 INVOLUNTARY SMOKING AND LUNG CANCER Introduction The social pressure to limit smoking in public places (6) reflects concern for protecting nonsmokers from the annoyances of others' cigarette smoke, as well as concern about the possible adverse health effects of involuntary smoking, or secondhand exposure to others' cigarette smoke. A recent publication presented the scientific evidence linking involuntary smoke exposure to adverse health effects (44). Children of smoking parents had more bronchitis and pneumonia during the first year of life (17); and acute respiratory disease accounted for a higher number of restricted activity days (1.1 days) and bed disability days (0.8 day) in children whose families smoked than in those whose families did not (3). A reduction in exercise tolerance with exposure to sidestream cigarette smoke has been demonstrated in patients with angina pectoris (I), and a decrease in small airway function of the lung equivalent to that observed in light smokers (1 to 10 cigarettes a day) has been reported in adults who never smoked themselves nor lived with smokers, but who were exposed to cigarette smoking in the workplace (49). Only recently has attention focused on the possibility that lung cancer may be caused by involuntary inhalation of tobacco smoke. This concern is based upon: (1) the occurrence of similar chemical constituents in sidestream smoke (smoke released from the cigarette between active puffs) and mainstream smoke (smoke actively inhaled); (2) the established dose-response relationship between voluntary cigarette smoking and lung cancer, and the absence of evidence establishing a threshold for effect; and (3) the recent epidemiologic studies that examined lung cancer mortality in nonsmoking spouses of cigarette smokers. Smoke Constituents The average person spends most of the time indoors where there may be significant exposure to tobacco smoke generated by others (32). For various reasons, the exposure of nonsmokers is more difficult to quantitate than that of the smoker. The constituents of the particulate and gas (vapor) phases of tobacco smoke have been quantitatively analyzed in several studies (8, 22, 37, 38). As is shown in Table 1, many of the chemical constituents of mainstream smoke are also found in sidestream smoke. Some constituents occur in markedly higher concentrations in sidestream than in mainstream smoke (note SS to MS ratio); however, sidestream smoke is released into the ambient air, resulting in dilution of constituents. The resulting concentration of smoke is dependent upon the amount of 239 TABLE l.-Constituents of cigarette smoke.' Ratio of sidestream smoke (SS) to mainstream smoke (MS) Carbon Dioxide Carbon Monoxide Methane Acetylene Propane Propene Methylchloride Methylfuran Propio+dehyde %Butan0ne Acetone A. GAS PHASE MS WMS MS SSMS 8.1 Nitrogen Oxides (NOx) 25 Ammonia 3.1 Hydrogen cyanide 0.8 Acetonitrile 4.1 f'yridine 2.1 3-Picoline 3.4 SVinylpyridine 2.4 Dimethylnitrosamine 2.9 Nitmspyrmlidine 8. PARTICULATE PHASE MS SS/MS MS WMS "Tar" Water Toluene Stigmasterol Total Phytostemls Phenol Catechol Napthalene Methyln~phthalene Pyrene Benzo(4wene 1.7 2.4 5.6 0.8 0.8 2.6 0.7 16 28 3.6 3.4 Quinoline 1.7 Irg 11 Methylquinolines 0.7 pg 11 Aniline 360 w 30 %Naphthylamine 2% 39 4-Aminobipheny! 5 m3 31 Hydrazine 32% 3 N'-Nitrownornimtine lo&x@ ng 5 NNKZ mmng 10 N&tine l-2.5 mg 27 `Nonfiltereigarette ZNNK - ~N-methyl-N-ni~mino)-1~5pyridgl~l-butanone(tobrcm c.pecificcarcinogenk nitmumim) SOlIH~`E I: S lkrwrtment 01 Health. Educatmn. and Welfaretlll smoke generated, the volume of ambient air, and the type and amount of the ventilation of that space (2, 4, 24, 34, 44). In addition, the chemical composition of smoke changes with the passage of time (24~). Further complicating factors include the continuous low-dose exposure of involuntary smokers contrasted with the intermittent high-dose exposure of the active smoker. Thus, many factors complicate the theoretical extrapolation of machine measurements of smoke constituents to the biologic effects to be expected with exposure of nonsmokers. The actual absorption of smoke c0nstituent.s by nonsmokers in smoke-filled spaces has not been completely characterized. A few studies have examined the absorption of carbon monoxide by measuring carboxyhemoglobin levels in exposed nonsmokers (44); however, the absorption of most other constituents has not been studied. Furthermore, the pattern of involuntary inhalation proba- bly differs from that of voluntary inhalation of smoke by the smoker, affecting the pattern and amount of deposition or absorption of 240 chemical constituents in nonsmokers compared to smokers. Differ- ences in the carcinogenicity of sidestream and mainstream smoke may also exist; sidestream smoke condensate is more tumorigenic per unit weight in mouse skin assays than is mainstream smoke condensate (50). Some evidence exists that suggests, however, that involuntary exposure to cigarette smoke does result in deposition or absorption of constitutents. Involuntary inhalation of cigarette smoke has been shown to produce tracheobronchial epithelial metaplasia and dyspla- sia in animals (23). The applicability of these data to human exposures is not clear, however, since the levels of smoke exposure used in this animal study were substantially higher than those normally encountered by humans in enclosed spaces where smoking is allowed (38). In a smoke-filled, unventilated, unoccupied room, the concentrations of several smoke constituents, including several volatile gases, total particulate matter, and nicotine, remained constant and were higher than when humans were present. Further, several vapor phase constituents such as nitrogen oxide, acrolein, and aldehydes were observed to decrease continuously over 3 hours when humans were placed in the room, despite fresh sidestream smoke being generated to keep the ambient carbon monoxide level stable (24). The difference in absolute levels and the continuing decrease in constituent concentrations despite the continuing addi- tion of smoke to the environment suggest absorption by humans, although the actual site(s) of deposition has not been determined. Dose-Response Relationships Examination of the dose-response relationship for voluntary smokers suggests an increased risk with any level of regular cigarette smoking (43). No threshold level of exposure for the development of lung cancer has been established and, therefore, any level of exposure is of concern. Figure 1 reflects the data that led to the scientific consensus that there is no threshold level. This absence of a clear threshold level of exposure raises the issue of whether the levels of exposure reached through involuntary smoking may also produce an increased risk of lung cancer. Epidemiologic Studies The use of epidemiologic techniques to search for an association between involuntary smoke exposure and lung cancer has a number of methodologic difficulties. 241 10 20 30 10 CURRENT NUMBER OF CIGARETTES SMOKED PER DAY 0 0 Bnttsh Physictans )6----$( Canadmn Veterans .a . . . . . . . . . . . . u s veterans v----q u s. men I" 25 states FIGURE l.-Mortality ratios of deaths from lung cancer in men. Data from four large prospective studies SOURCE Rn)al College of Physictans of London t&Y51 242 Exposure An individual's actual smoke exposure dose is difficult to quantify, even for an acute exposure. For the longer exposure periods, as in chronic disease epidemiologic studies, the exposure quantification problems are magnified. Dosage is dependent upon the amount of smoking by those around the nonsmoker, the spatial distance between the nonsmoker and smoker, the duration and frequency of exposure, and a number of other factors that complicate the quantification of involuntary smoke exposure in either retrospective or prospective studies. Several studies have used the smoking habits of the spouse of the nonsmoker as a means of identifying two groups (nonsmokers with smoking or nonsmoking spouses). This estimate of exposure is subject to misclassification, as the nonsmoker may be a former smoker. This may be true for either the nonsmoker being followed or the nonsmoking spouse in the control group. In addition, in societies with a high rate of divorce or multiple marriages, the smoking habits of the current spouse may not approximate the actual exposure. Further, there is a demonstrable correlation between the smoking habits of spouses that decreases the proportion of couples available for study who are discordant for smoking. Long Latency Periods Lung cancer follows exposures experienced over decades and, therefore, it is necessary to observe nonsmokers over an extended time in order to estimate their actual exposure. Other Carcinogenic Exposures Exposure to cigarette smoke may occur in conjunction with exposure to other occupational or environmental carcinogens. Epide- miologic studies should control for or investigate possible interac- tions with other environmental exposures as far as possible, but limitations clearly exist here as well. Accurately assessing lifetime exposures and attempting to control for such exposures are difficult, if not impossible. Current Epidemiologic Evidence To date, three epidemiologic studies have been published that examine the lung cancer risk of involuntary smoking. Two of these studies (19, 42) were conducted in the relatively traditional societies )f Greece and Japan; the third analysis was conducted in the Unit,ed states by Garfinkel (IZ), based on data originally collected by Hammond (14). Trichopoulos et al. used the case-control method of study over the oeriod of September 1978 through June 1980. They identified 51 243 Caucasian female lung cancer patients and 163 adult female orthopedic patients in Athens. All subjects were questioned on their personal smoking habits, and husbands were classified as nonsmok- ers (never smoked or quit more than 20 years prior), ex-smokers (stopped smoking 5 to 20 years prior), and current smokers (current- ly smoking or smoked within 5 years prior to interview). Single women were classified with the group having nonsmoking husbands. The cases and controls did not differ in age, duration of marriage, occupation, education, or place of residence, although specific matching on these characteristics was not performed. Involuntary exposure of the wife was estimated from her husband's daily consumption, from the date of marriage until their divorce, her husband's death, or change in his smoking habits; multiple mar- riages were also considered. Excluding 11 voluntary smokers from the 51 female lung cancer cases, and 14 smokers from the 163 controls, the remaining 40 nonsmoking lung cancer patients and 149 nonsmoking control women were compared by their husband's current smoking status, and estimated total cigarettes smoked by the husband by the time of interview. The results are shown in Tables 2 and 3 respectively. Compared with the control group, at interview the lung cancer cases showed l.&fold greater probability of being married to an ex-smoker; 2.4-fold greater odds of being married to a light or moderate smoker (20 or fewer cigarettes per day); and 3.4-fold greater odds of being married to a heavy smoker (more than 20 cigarettes per day). The trend observed in these findings was statistically significant, with a p value less than 0.02. Exclusion of single women from this analysis modified the relative risks only slightly. Table 3 shows a similar trend of increasing relative risks in nonsmoking wives with increas- ing (estimated) total number of cigarettes smoked by the husband prior to the interview. Some limitations and strengths of this study were recognized and discussed by the authors. Among the limitations were: the number of cases was small; 35 percent of the tumors lacked histologic confirma- tion; controls were chosen from a different hospital than were the cases; a single unblinded interviewer was used for both cases and controls. On the other hand, the authors suggested that the conservative social setting for this study may be less subject to errors of misclassification resulting from the exposure of nonsmoking wives of nonsmokers to the smoke of others outside the home. The number -of cases of adenocarcinoma that were excluded from the analysis is not given. Analysis including such cases would be of interest (16), as many investigators have found cigarette smoking to be a cause of adenocarcinoma of the lung as well 2s of other histologic types of lung cancer (45). Additional control groups for comparison to the cases might have enhanced the findings of this study. 244 TABLE 2.-Smoking habits of husbands of nonsmoking women with lung cancer and of nonsmoking control women Cigarettes per day lcurrent smokers1 Diagnostic group Nonsmokers Exsmokers l-10 1 l-20 21-30 31+ Total Lung cancer 11 6 2 13 4 4 40 COntr& 71 22 Q f-2 149 RRa 1.0 1.8 2.4 3.4 RRb 1.0 1.5 2.0 3.0 * Relatwe r-k-the ratio of the risk of lung cancer among women whose husbands belong to a particular .mokmg category to that among women whose husbands are nonsmokers X1=6.45. p(Z-talI~ 0 02 bAnalys~s excluding single women arbrtrardy clasafied as nonsmokers X'llrnear trendi=4.6. px 0 03 SOURCE Tnchopoulos et al (42) TABLE 3.-Distribution of nonsmoking women with lung cancer and of nonsmoking control women according to the estimated total number of cigarettes smoked by their husbands by the time of the interview Total number of cigarettes (in thousands) Diagnostic group 0 l-99 lOS199 200-299 3oLx399 400+ Total Lung cancer 8 4 6 9 6 7 40 controls 56 21 L-2 ,`2 149 RRa 1.0 1.3 2.5 3.0 `Relative risk-the ratio of the risk of lung cancer among women whose husbands belong to a particular smokmg category to that among women whose husbands are nonsmokers X2-6 50, p(2-tail]< 0.02. SOURCE: Trichopoulos et al. t1981l. Hirayama (19) used a prospective design in 29 health districts in Japan over 14 years, from 1966 to 1979, in which 91 to 99 percent of the census population was interviewed. He analyzed interview data from 265,118 adults aged 40 years and older, and found that 72.3 percent of the couples had data on the smoking habit of both spouses. Among 91,540 married women, 245 deaths from lung cancer were recorded, of which 174 were nonsmokers. He reported 2 statistically significant excess rate of lung cancer among nonsmoking wives of smokers 2s compared to nonsmoking wives of nonsmokers. Table 4 shows the standardized mortality rates for lung cancer in non- smoking wives, adjusted for age and occupation. There is an apparent dose-response relationship in each of the analyses present- ed. Certain methodologic details (e.g., the definition of an ex-smoker 245 husband, the method of age and occupation standardization, and the technique or extent of histologic confirmation) were not presented. Hirayama also examined the effects of I voluntary smoking in relationship to involuntary exposure and nonexposure. The stand- ardized annual mortality rate for nonsmokers who were not involun- tarily exposed was 8.7 per 100,000. For women who reported being exposed to cigarette smoke only involuntarily, the standardized annual mortality rate was 15.5 per 100,000. For women who voluntarily smoked, the standardized annual mortality rate was 32.8 per 100,000. He concluded that the effect of involuntary smoking was approximately one half to one third that of active or voluntary smoking. The age and, occupation standardized risk ratios in this population failed to show ,any statistically significant effect of spousal smoking on nonsmoking women's standardized risk ratios for deaths from other causes, including emphysema (although the trend in relative risk was in the same direction as for lung cancer mortality), cervical cancer, stomach cancer, or ischemic heart disease (Table 5); no significant role of spousal alcohol consumption was demonstrated for any of the above diseases. The public press has reported a possible error in Hirayama's computation of the chi square test of statistical significance (33). However, the scientist to whom this finding was attributed has subsequently stated that he raised questions about the study but denied reaching any conclusion (29u). Harris and DuMouchel (18) recalculated the chi square using the originally presented data of Hirayama by combining Tables 1 and 2. The calculated chi square of 8.09 yielded a statistically significant two-sided p value of 0.0004. In a subsequent, more detailed tabular presentation, Hirayama (21a) confirmed the statistically significant excess in lung cancer death rates in wives of smokers when adjusted for husband's age, occupation and smoking habits. In this subsequent analysis, Hiraya- ma restricted his analysis to data from one prefecture for a possible dose-response relationship of involuntary smoking and lung cancer mortality. The exposure of nonsmoking wives was calculated by multiplying the hours of the day the husband was at home by the number of cigarettes smoked per hour, assuming that the number of cigarettes smoked per hour remained constant over waking hours. There was a clear dose-response observed (Tabie 6) for each of three categories for length of hours and for number of cigarettes smoked per day. The risk of death from lung cancer in nonsmoking women increased with either the time of exposure or increasing daily number of cigarettes. In that set of analyses, the relative mortality risk (as. measured by the standardized mortality ratio) observed 246 TABLE 4.-Standardized mortality for lung cancer in women by age, occupation, and smoking habit of the husband (patient herself a nonsmoker) Husband's smoking habit Nonsmoker Ex-smoker or l-19iday > 20:day Population of wves No of deaths from lung cancer Occupation-standardized mortality/1OO,CKKl Population of wwes No. of deaths from lung cancer Occupation-standardi~d mortalityilWXKl 14,020 30.676 20.584 11 40 36 5 64 9 34 13.14 7,875 13.508 4,877 21 46 20 15 79 24 44 29 60 Standardized risk ratio far all ages 1.00 1.61 2.08 Population of wives No. of deaths from lung cancer .Age-standardized mortality/100,O(Xl 10,406 20.044 9,391 17 52 24 9.54 17.02 16.40 Population of wives No of deaths from lung cancer Age-standardized mortal~ty/1OO.OCG 11,489 24.140 16.070 15 34 32 9.13 10.46 17 78 Standardized risk ratlo for all occupations 1.00 1 43 1.90 among nonsmoking wives of smoking husbands was markedly lower than that observed for women who actively smoked (Figure 2). The observed differences between wives of smokers and wives of nonsmokers were evident for each of the four socioeconomic status classes. Hirayama's article has stimulated much discussion, which has been published as Letters to the Editor of the British Medical Journal (5, 13, 25a, 27, 27a, 30, 36, 40, 42~). In three replies to the same journal (20, 21,21a), the reader is referred to the specific issues raised and responded to in these letters. 247 TABLE 5.-Age-occupation standardized risk ratio for selected causes of death in women by smoking habit of the husband (patient herself a nonsmoker) Cause of death - Husband's smoking habit Nonsmoker Ex-smoker, 2 20/dsy p value or I-19/day * Lung cancer (n = 1741 Emphysema, asthma in-66) Cancer of cervix cn = 2501 Stomach cancer ln=716) Ischaemic heart disease ln =406) YkJlineartrendl W"RCE H,rnyama G ,.Y, 1.00 1.61 2.08 0.0001 1.00 1.29 1.49 0.474 1.00 1.15 i.14 0.249 1.00 1.02 0.99 0.720 1.00 0.97 1.03 0.393 TABLE 6.430~ often wives with smoking husbands inhale cigarette smoke passively in Japan (calculation based on a study in Aichi Prefecture, Japan) - Length of contact in a day 15 h 4h 15.0 h No. cigarettes FIX- No cigarettes FW No. cigarettes FR- No. cigarettes smoked by quency ta which they quency to which they quency to which they husband/day 1%l were exposed' (961 were exposed' (%I were exposed' 1-19 (average 101 11.8 (0.88 14.2 (2.55) 6.8 (8.821 20-29 (average 251 19.8 (2.21 I 25.4 (5.881 8.6 (22.06) 30-60 (average 451 5.6 (3.971 5.2 (10.59) 2.6 (39.71) `Length alcontact multlplwd by number smoked in an hour(numbersmoked in an hourequalsaverage number ofclyarcttessmoked I" a day divided by total hours awake) SOURCE HirayamatPll Nonetheless, the applicability of such results to the U.S. popula- tion remains to be established. Garfinkel (12) published an analysis of data from the American Cancer Society's prospective study conducted from 1960 through 1972. He reported results on 176,739 nonsmoking women who were then married (a) to men who never smoked, (b) to men who currently smoked less than 20 cigarettes per day, or (c) to men who currently smoked 20 or more cigarettes per day. In an analysis that did not attempt to control for possible confounding variables, the observed to expected lung cancer mortality ratio (expected numbers were derived from the lung cancer rates of women married to nonsmokers by s-year age groups) was 1.27 for women married to smokers of less than 20 cigarettes per day and 1.10 for women married to smokers of 20 or more cigarettes per day. These increases in mortality ratios over those of wives of nonsmokers were reported to be not statistical- 248 o FIGURE 2.-Active and passive smoking and standardised mortality rates for lung cancer: relative risks (RR) with 95 percent confidence intervals- prospective study, 19661979, Japan `Includrh o.xa~,nal smoktv~ and rx smokers SOURC'E Hway;,ma~L',u~ TABLE 7.-Observed versus expected* lung cancer deaths among nonsmoking women with cigarette- smoking husbands, ACS study, 1966-1972** Husband Husband Husband smoked 20 smoked 120 Parameter did not cigarettes cigarettes smoke per day per day - Observed deaths 65 39 49 Expected deaths 65.00 311.67 44.67 Mortality ratio 1.00 1.27 1 10 ly significant (p value not specified) (Table `7), and no dose-response effect was evident. The same three groups of nonsmoking women were compared in another analysis. In an attempt to eliminate possible confounding 249 TABLE K-Matched group study: Adjusted lung cancer deaths among women -with nonsmoking husbands matched* with women with smoking husbands GTWp Nonsmoking husband Husband smoked 20 cigarettes/day Number of adjusted lung cancer deaths 25.6 35.0 Ratio p" 1.00 1.37 NS Nonsmokmg husband 34.5 1.00 Husband smoked 120 cigarettes/day 35.8 1.04 NS variables, pairs of women were matched on multiple factors. The number of deaths in each matched diad was "adjusted" as described in a prior publication (15). The results of this analysis are shown in Table 8. Neither group of nonsmoking wives of smokers showed a statistically significant difference (p > 0.05); there is no dose-response pattern apparent. The actual size and composition of the matched study population, however, were not shown. The author concluded that any effect passive smoking had on lung cancer mortality would be small. The author presented the limitations of this analysis. The study was not designed to examine the question of effects of passive smoking and, therefore, there were difficulties with the accurate assessment of exposure. The appropriateness of this analysis of the ACS data has been questioned (16) for this reason. The difficulties include the measurement of involuntary exposure t.o smoke from persons other than the husband, and an inability to adjust for changes in husband's smoking subsequent to actual interview or for exposure(s) from previous husbands. A study should be specifically designed to measure exposure, as neither the Japanese (19) nor the ACS study met that criterion. Additionally, among 564 cases of lung cancer in nonsmoking women, the husband's smoking status was available for-only 153 (27 percent). Thus, each of the three epidemiologic studies published to date shows an increased risk of lung cancer with involuntary smoke exposure (Table 9). The results.were statistically significant in two of the three studies, which also found a dose-response effect. The evidence currently available suggests that involuntary smoke expo- sure may increase the risk of lung cancer in nonsmokers, but 250 TABLE 9.-Observed and expected deaths from lung Cancer in nonsmoking women with smoking husbands ObseWZd Expected Difference Ratio X' Japan (Hirayamal U.S. IGarfinkell Greece (Trichopoulos et al.) 142 85.8 +56.2 + 65.5% 36.81 S+gdutnt 88 75.3 -12.7 + 16.9% 2.14 Not signifxant 29 12.1 + 16.9 + 139.7% 23 60 Significant Total 259 1732 i 85.8 + 49.5% 42.50 Slymticant SOURCE Hirayama 1211 limitations in data and study design do not allow a judgment on causality at this time. Summary 1. Mainstream and sidestream cigarette smoke contain similar chemical constituents. (Mainstream smoke is smoke that the smoker inhales directly during puffing. Sidestream smoke is smoke emitted from a smoldering cigarette into the ambient air.) These constituents include known carcinogens, some of which are present in higher concentrations in sidestream smoke than they are in mainstream smoke. Passive or involun- tary smoking differs from voluntary cigarette smoking with respect to the concentration of smoke components inhaled, the duration and frequency of smoke exposure, and the pattern of inhalation. 2. In two epidemiologic studies, an increased risk of lung cancer in nonsmoking wives of smoking husbands was found. In these studies, the nonsmoking wife's risk of lung cancer increased in relation to the extent of the husband's smoking. In a third study, the risk of lung cancer among nonsmoking wives of smoking husbands was also increased, but the difference was not statistically significant. 3. Although the currently available evidence is not sufficient to conclude that passive or involuntary smoking causes lung cancer in nonsmokers, the evidence does raise concern about a possible serious public health problem. 251 377-3:o 0 - 82 - 18 References I I) ARONOW, W.S.. KAPLAN, M.A., JACOB, D. Tobacco: A precipitation factor in angina pectoris. Annals of Znternal Medicine 69(3): 529-536, September 1968. 12) ARTHUR D. LI'ITLE. INC. Energ,v Conservation in New Building Design. An Impact Assessment of ASHRAE /American Society of Heating, Refrigeration and Air Conditioning Engineers Inc.] Standard 9@75. Cambridge, Massa- chusetts: Arthur D. Little, Inc., 1976. (S) BONHAM, G.S., WILSON, R.W. Children's health in faynilies with cigarette smokers. American Journal of Public Health 71(3): 290-293, March 1981. (4) BRUNNEMANN, K.D., HOFFMANN, D. Chemical studies on tobacco smoke. LIX. Analysis of volatile nitrosamines in tobacco smoke and polluted indoor environments. In: Walker, E1.A.. 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Lung cancer and passive smoking. Inlemafional Jo~mal of Cancer 27(l): 1-4, January 15, 1981. (+`&I TSOKOS. C.P. Letter to the Edit.or. British Medica/ ~Journal 283(6304~: 1464- 1465, November 28,198l. (Letter) (-/2h) IJNIFORMED SERVICES UNIVERSITY OF THE HEALTH SCIENCES. Department of Preventive Medicine and Biometry, personal communica- tion. (-131 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES. The Changing (`lgczrc~f1c: A Report of the Surgeon General. U.S. Department of Health and Human Services. Public Health Service, Office of the Assistant Secretary for Health, Office on Smoking and Health, DHHS Publication No. (PHSB- 50156. 1981.252 pp. (441 IJ.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE. Chapter 11, Involuntary smoking. In: Smoking and Health: A Report of the Surgeon (&cr24/day 29.5 2634/day 22.2 2 35lday 48.4 SOURCE: From the NIE-sponsored Chilton Survey: Green (14 demands or stressors (38). Either would predict greater cessation difficulty for "pattern" smokers. Recent Devebptnents in Smoking Prevention Programs Smoking prevention has been espoused as a desirable alternative to cessation programs aimed at youth. This position is based on the arguments that (1) more young $ople can be reached in prevention than in cessation programs, (2) preventing the onset of smoking is easier than eliciting and maintaining cessation, (3) smoking of even short duration may be harmful to some, and (4) even if programs only delay rather than truly prevent the onset of smoking, there will be substantial health benefits to the population for whom the delay has occurred. Recently a number of researchers have developed and tested adolescent smoking prevention programs (4, 5, 11, 12, 13, 18, 20, 21, 28, 29, 40). Critical reviews of these recent prevention programs are Johnson (191, Flay et al. (13), and Evans (9). The programs that have met with consistent success share a number of features in common. All have been based on social-psychological theory and research, most notably on attitude change theory (311, social learning theory (Z), and attribution theory (25). All have been school-based programs targeted for the most part at seventh grade students. Evans (8) developed the first of several recently tested social- psychological strategies for deterrence of cigarette smoking in youth. Although t.he original study (12) did not show experimental interven- tions to be superior to just monitoring smoking behavior periodical- ly, it did establish the rationale and feasibility of several social- psychological principles for an adolescent prevention program. Emphasis was on the short-term consequences of smoking; films were used extensively to demonstrate typical pressures to smoke from peers, parents, and media, and to depict role models resisting smoking pressures. Students were encouraged to develop counter- 296 arguments against smoking in order to strengthen themselves against future persuasion attempts (30). Evans (9) has been especial- ly interested in developing social modeling films that would provide a standard and easily transportable medium for the prevention message. Although the effectiveness of standard films used alone is not yet established (191, the general approach to role model presentation employed by Evans has been used in other social- psychological prevention research efforts of this type. A methodologi- cal contribution was the use of saliva sample collection (for nicotine analysis) to augment the validity of self-reports about smoking. Evans et al. (10) found that persons were twice as likely to report smoking when self-reports were preceded by saliva collection for analysis than when not. McAlister and others (28, 29, 36, 37) of Stanford and Harvard also used role models to teach smoking resistance skills. Their role models were live, rather than on film, and consisted of a team of five to seven students from a nearby high school recruited and trained to conduct six sessions in seventh grade classrooms. Skills training was more active as well, employing role-playing of resistance techniques. Although at the start of the sessions in the fall more persons in the treatment school (2 percent) than in the control school (0.9 percent) said "yes" to the question "Have you smoked in the last week?," by spring, 10.3 percent in the control condition and 5.3 percent in the treatment condition reported smoking in the previous week. In May 1980, 2 years after termination of the program, 15.1 percent and 5.2 percent, respectively, said they had smoked in the previous week (36). Program effects seem to have endured for at least 2 years beyond the end of the program. McAlister et al. (281, report an extension of the smoking preven- tion model to prevent alcohol and marijuana abuse as well. There was a 4.7 percent increase and a 0.1 percent decrease in regular or experimental smoking by end of year among sixth and seventh grade students in the five control schools and five experimental schools, respectively. Finally, Perry et al. (37) have reported a successful replication of the 7th grade smoking program for 10th grade students, with college students acting as peer leaders. The authors report a 21 percent overall reduction in the number of self-reports of smoking in the last week, compared with the baseline number. Johnson and Luepker at the University of Minnesota developed a similar strategy for smoking prevention in adolescents (I, 18, 22). Experimental adaptations of social-psychological theory were based on systematic interviews with Twin Cities seventh and eighth grade students, and scenarios for role model films and for active role playing were distilled from these interactions. As a result, the emphasis on immediate negative consequences took on a decidedly social aspect (e.g., yellow teeth, bad breath). This research program, 297 which was developing independent of the research at Stanford, also used peer leaders, but with two important differences. First, peer leaders were defined as same-age persons aiready in the classroom who are "natural" opinion leaders. Leaders were selected by peer nomination, recruited into prevention leadership status, and brought to the university for leadership training. Second, the peer leader component was tested quasi-experimentally with the prevention program implemented in one school without peer leader recruitment and in another school with peer leader recruitment. Each school was then compared with a control school in which traditional health. oriented smoking prevention was taught in compulsory health education classes by school heaith educators. Approximately an equal number of class sessions (five) were devoted to all three curricula. As in the Houston and Stanford programs, all sessions in the experimental schoois were supervised by nonschool personnel who were members of the research team. Finally, public commit- ment was tested experimentally by having students in a random number of classrooms in the peer-led school give a public speech on why they would not smoke. In the fall of 1977, baseline measure students in the three schools did not differ in mean number of cigarettes smoked in the past week: 0.89, 0.46, and 0.29 in the control, social consequences curriculum, and peer-led social curricu- lum, respectively. By May, the average number of cigarettes smoked in the past week were 2.50, 1.47, and 0.40, respectively. By May of the following year, controls were smoking five times as many cigarettes per week as were students in the peer-led school--5.86 versus 1.02. By this time, smoking in the social consequences school (5.71) had ceased to differ from the control school. Two years after program termination, the mean number of cigaretttes smoked in the previous week were i0.97, 10.60, and 4.61 in the control, social consequences, and peer-led schools, respectively (26). As in the Stanford study, the effects of a peer-led prevention program endured for at least 2 years. An important finding from the Minnesota study was that prevention effects of an equivalent program led by adults rather than pee:*s were weak in the short run and not measurable at 1 year. The preventive advantage of a peer-led program was particularly great for females; only with peer leader involvement, was the experimental program effective with females, both in the short and long run (22). A conceptual replication of the initial Minnesota smoking preven- tion study was begun by the Minnesota researchers in 1979. All seventh grade students in two schools were assigned to a peer-led, short-term consequences treatment, and a standard media package was used in conjunction with other activities. Students in two other schools received the same peer-led, short-term consequences pro- gram without the media package. Students in two additional schools received the media-augmented social program taught by health educators rather than by peer leaders. Students in the final two schools received an equivalent health-oriented curriculum taught by the health educators brought in for that purpose. End-of-year data (I) indicate that all four programs were effective compared with an external control group consisting of seventh grade students not receiving a program in the previous year. By spring of the following year, the peer-led program with media appeared to be most effective, and the teacher-led health program was least effective in preventing onset of regular (weekly or more) cigarette smoking. Currently, a replication is underway with school health educators teaching or supervising in the various schools. In addition to theory-based experimental tests of program effects, the Minnesota group has developed biochemical assays for indepen- dent validation of self-reports (27). The Minnesota group has found that post-treatment saliva thiocyanate levels are greater in control groups than in treatment groups and, like Evans et al. (101, that self- reports of smoking are twice as likely when saliva samples are collected prior to self-reports. Botvin et al. (4, 3 have reported a more general approach to life- skills training for prevention of cigarette smoking. This program consists of 10 weekly sessions designed to teach skills necessary to resist social pressures to smoke, to develop students' autonomy and thereby reduce their susceptibility to indirect social pressures to smoke, to develop self-esteem and self-confidence, and to provide a means of coping with anxiety. Hence, the approach begun by Botvin at the American Health Foundation and continued at Cornell goes beyond teaching the skills specific to smoking avoidance. The original program was implemented by allied health professionals and a followup program was implemented by older peer leaders. Three-month followup data in the original study and 6-month followup data in the second study indicate that significantly fewer students began smoking in the experimental group compared with the nontreatment control group (6 versus 18 percent onset at ,6- month followup in the second study). Botvin is replicating these studies with a program conducted by classroom teachers. Flay et al. (13) have filled a large methodological gap created by the quasi-experimental methodology employed in each of the previ- ously reported prevention research programs. In each of these programs, researchers opted to devote whole schools to interven- tions, with the number of schools per group ranging from one to five. Consequently, random assignment of participants was not possible, raising questions about what one can infer from any one study (61. Strictly speaking, the unit of analysis in these studies ought to be school, a practical impossibility because of limited degrees of freedom. Flay et al. (13) were able to find multiple schools in the 299 Waterloo (Ontario, Canada) area, each with a single classroom per grade. Eleven schools were randomly assigned to either prograh Or control conditions. The strength of this methodo&y is that it permits random assignment of classrooms and, appropriately, the use of the classroom as the unit of analysis. The Waterloo program was administered in sixth grades, except for two booster sessions given in seventh and eighth grades. The program is similar to thos, at Stanford and Minnesota. Smoking-related information is elicited from students rather than told to them; there is a focus on social influences; decision-making skills are taught; and a public commit. ment is obtained. By seventh grade, differences in experimental smoking were beginning to emerge between treatment and control groups. If these trends continue, this methodologically tight study will lend experimental support for the consistent pattern of findings to date. The weight of data available to date consistently supports the finding that smoking prevention programs with certain identifiable components can be successful in preventing the -onset of smoking in adolescence. Summary 1. Spontaneous smoking cessation among regular users (approxi- mately once a week or more often) is estimated to be on the order of 25 percent during adolescence. 2. Probability of quitting was greater for those adolescent smok- ers first interviewed in 1974 who had at least started to attend college by 1979 than for those smokers who did not attend college (42.0 percent vs. 24.6 percent). 3,. Probability of quitting decreases linearly with duration of the smoking practice, changing from 64.5 percent in the first year of smoking to 14.3 percent after 7 years. 4. Quitting "cold turkey" appears to be a more effective cessation strategy than cutting down without trying to stop entirely. 5. Success at quitting increased with the number of efforts made: about 73.4 percent of adolescents who kept trying eventually succeeded. 6. Smoking prevention programs are desirable alternatives to cessation programs aimed at. youth. Successful programs have been based on social psychological theory and research, and are school based. Results have shown a 50 percent or more reduction in smoking onset. 7. The most successful programs were those emphasizing the social and immediate consequences of smoking rather than long-term health consequences. These programs have placed 300 special emphasis on teaching skills in recognizing and resisting social pressures to smoke. 301 References (I) ARKIN. R.M., ROEMHILD, H.F., JOHNSON, C.A., LUEPKER, R.V., MUR. RAY, D. The Minnesota smoking prevention program: 7th grade health curriculum supplement. Journal of School Health pp. 611-616, November 1981. (21 BANDURA, A. Social Learning Theory. Englewood Cliffs, New Jersey, Prentice-Hall, 1977. (31 BORLAND, B.L., RUDOLPH, J.P. Relative effects of low socioeconomic status, parental smoking and poor scholastic performance on smoking among high school students. Social Science and Medicine 9(l): 27-30, 1975. (41 BOTVIN, G.J., ENG, A. A comprehensive school-based smoking prevention program. Journal of School Health 50(4) 209-213, April 1980. (5) BOTVIN, G.J., ENG, A., WILLIAMS, C.L. Preventing the onset of cigarette smoking through life skills training. Preventive Medicine 9(l): 135-143, January 1980. (6) CAMPBELL, D.T., COOK, T.D. Quasi-Experimentation: Design and Analysis for Field Settings. Chicago, Illinois, Rand McNally College Publishing Company, 1979. (7) DONAHUE, F.J., CAPSHAW, V. The great smoking survey! American Lung Association Bulletin 63(7): 2-5, September 1977. (81 EVANS, R.I. Smoking in children: Developing a social psychological strategy of deterrence. Journal of Preoentioe Medicine 5(l): 122-127, March 1976. (91 EVANS, RI. Control prevention of smoking in adolescents: A psychosocial perspective, in press. (IO) EVANS, R.I., HANSEN, W.E., MI'ITELMARK, M.B. Increasing the validity of self-reports of smoking behavior in children. Journal ofApplied PsychoZo. gy 62(4): 521-523, April 1977. (II) EVANS, RI., ROZELLE, R.M., MAXWELL, S.E., RAINES, B.E., DILL, CA., GUTHRIE, T.J., HENDERSON, A.H., HILL, P.C. 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Teenage Smoking, National Pat. terns of Cigarette Smoking, Ages 12 through 18, in 1972 and 1974. U.S. Department of Health Education, and Welfare, Public Health Service, National Institutes of Health, DHEW Publication No. (NIHl76931, 1975, 123 pp. (35) PECHACEK, T.F. Modification of smoking behavior. In: Krasnegor, N.A. (Editor). The Behavioral Aspects of Smoking. National Institute on Drug Abuse Research Monograph No. 26, U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute on Drug Abuse. DHEW Publica- tion No. (ADMl79-882, August 1979, pp. 127-162. (36) PERRY, C.L., KILLEN, J., SLINKARD, L.A., McALiSTER. AL. Peer teaching and smoking prevention among Junior High students. -4dolescence 15(58): 277-281, Summer 1980. (37) PERRY, CL., KILLEN, J., TELCH, M., SLINKARD, L.A., DANAHER, B.G. Modifying smoking behavior of teenagers: A school-based intervention. American Journal of Public Health 70(7): 722-725, July 1980. (381 POMERLEAU, O., ADKINS, D.. PERTSCHUK, M. Predictors of outcome and recidivism in smoking cessation treatment. Addictive Behaviors 3(2): 65-70, 1978. (39) ,RUSSELL, M.A.H. Tobacco smoking and nicotine dependence. In: Gibbons, R.J., Israel, Y., Kalant, H., Popham, R.E., Schmidt, W., Smart, R.G. (Editors). Research Advances in Alcohol and Drug Problems. Volume 3. New York, John Wiley and Sons, 1976, pp. l-47. (40) SEVERSON, H., JEWE'IT, J., BIGLAN, A., NAUTEL, P., BAVRY, J., MCCONNELL, S., GRANVIN, A., LICHTENSTEIN, E., KNISKERN, J. Oregon Project: Smokers of Path Project Program for Primary Intervention and Cessatiun. Paper presented at the 33th Annual Meeting of the American Psychological Association, Montreal, 1980. (41) SPIELBERGER, C.D., JACOBS, G.D., CRANE, R.S., RUSSELL, S.F. On the relation between family smoking habits and the smoking behavior of college students. International Review ofApplied Psychology, in press. (42) U.S. PUBLIC HEALTH SERVICE. Use of Tobacco, Practices, Attitudes, Knowledge, and Beliefs, United States-Fall 1964 and Spring 1966. U.S. Department of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Clearinghouse for Smoking and Health,, July 1969, 807 pp. (43) U.S. PUBLIC HEALTH SERVICE. Adult Use of Tobacco, 1970. U.S. Depart- ment of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Clearinghouse for Smoking and Health, June 1973. (44) U.S. PUBLIC HEALTH SERVICE. Adult Use of Tobacco, 1975. U.S. Depart- ment of Health, Education, and Welfare, Public Health Service, Center for Disease Control, National Clearinghouse for Smoking and Health, June 1976. 304 INDEX ACROLEIN ciliatoxic agent, 193 ACS See AMERICAN CANCER SO- CIErY ADOLESCENTS age and sex factors in spontaneous smoking cessation, 291 predictors of spontaneous smoking cessation, 291-296 prospective attitudinal predictors of smoking cessation, 291, 292 smoking prevention programs, 2S6- 300 social influences on smoking cessa- tion, 2X-296 spontaneous smoking cessation rates, 289-291,300 ADVISORY COMMITTEE TO THE SURGEON GENERAL (1964) definition of' "cause", 16 epidemiologic criteria for causality, 4 lung cancer and smoking associa- tion, 15 AGE FACTORS age-adjusted death rates defined, 147 bladder cancer-age-specific mortal- ity, 102, 104-107 bronchial, tracheal, and lung canc- ers-age-specific mortality, 25-28 buccal cavity plus oral pharynx cancer-agespecitic mortality, cervical cancer-age-specific mortal- ity, 137, 139 esophageal cancer-age-specific mortality, SO, 92-95 kidney cancer-age-specific mortali- ty, 113, 115-118 laryngeal cancer-age-specific mor- tality, 65-67 AGE FACl'OHS-ConM. lung cancer-age-specific mortality and smoking patterns, 5058, 145 pancreatic cancer-age-specific mor- tality, 122, 124127 responsiveness of animals to known carcinogens, 176, 177 smoking initiation age and cessa- tion probability for adolescents, 293 spontaneous smoking cessation by adolescents, 291 stomach cancer-age-specific mor- tality, 132, 134, 135 AGRICULTURAL CHEMICALS carcinogen precursor, 202 tumor promoters, 197 AIR POLLUTION lung cancer mortality relationship, 46, 47 ALCOHOL CONSUMPTION dimethylnitrosamine metabolism enhancement, 202 esophageal cancer-synergistic role with smoking, 7, 100, 101, 146 influence on N'-nitrosonornicotine carcinogenicity, 205 laryngeal cancer-synergistic effect with smoking, 6, 72, 75, 77, 78, 146 oral cancer--synergistic role with smoking, 7, 80, 86, 88, 90, 146 smoking cessation relationship, 267 synergistic effects with smoking re- lative to cancer risks, 191, 192 ALKALOIDS tobacco content, 203 AMERICAN CANCER SOCIETY (AC3 "I Quit Kit" effectiveness, 258, 259 lung cancer mortality and morbidi- ty estimates for 1982, 21 305 INDEX ACS-C'onM. lung cancer mortality for nonsmok- ing wives of smokers, 24%250 the Great American Smokeout, 262 AMERICAN CANCER SOCIETY 9- STATE STUDY bladder cancer mortality ratio, 110 esophageal cancer mortality ratio, 96 AMERICAN CANCER SGC~ 25STATE STUDYantd, lung cancer mortality ratio, smok. ers vs. nonsmokers, 36, 38, 39 mortality ratios for smokingrelated cancers among females and males, 148 occupational exposure and lung cancer, 47 esophageal cancer mortality ratio in cigar and pipe smokers, 99 kidney cancer mortality ratio and relative risk, 120, 121 laryngeal cancer mortality ratio, 68 laryngeal cancer mortality ratio in cigar and pipe smokers, 75 lung cancer mortality ratio, 36, 38 oral cancer mortality ratio, 65, 86 oral cancer mortality ratio in cigar and pipe smokers, 88 overall cancer mortality ratio, 142, 143 oral cancer mortality ratio, 85 oral cancer mortality ratio in cigar and pipe smokers, 88 oral cancer risk and lower tar ano nicotine cigarettes, 80, 63 overall cancer mortality ratio, 142 pancreatic cancer mortality ratio, 130 stomach cancer mortality ratio, 136 summary, 31, 33 AMERICAN HEALTH M)UNDA. TION STUDY pancreatic cancer mortality ratio, 130 esophageal cancer mortality risk in male ex+.mokem, 97, 98 oral cancer risk in ex-smokers, 87 AMMONIA stomach cancer mortality ratio, 136 summary, 32, 33 AMERICAN CANCER SGCIETY 25 STATE STUDY air pollution effect on lung cancer, 46, 47 bladder cancer mortality ratio, 110 bladder cancer risk and lower tar and nicotine cigatettes, 108 esophageal cancer mortality ratio, 96 ciliatoxic agent, 193 ANGINA PEZI'DRIS involuntary smoking effect on pa- tients' exercise tolerance, 239 ANIMAL MODELS (See also DOGS; RODENTS; SY- RIAN GOLDEN HAMSTRRS) carcinogenicity testing factors, 17% 178 esophageal cancer mortality ratio in cigar and pipe smokers, 99 female smokers and esophageal cancer, 96 kidney cancer mortality ratio and relative risk, 120 iaryngeal cancer mortality ratio, 68, 72 inhalation studies, 184-186, 220 involuntary smoking effects, 241 laryngeal cancer research, 75, 77 lung carcinomas in rats following arsenic exposure, 212 metabolism of nitrosamines in rats and Syrian golden hamsters, 205, 206 laryngeal cancer mortality ratio in cigar and pipe smokers, 75 laryngeal cancer risk and lower tar and nicotine cigarettes, 69 lung cancer mortality among males vs. females, 55 lung cancer mortality ratio in ex- smokers, 46 lung cancer mortality ratio in male smokers, 61 nickel compounds and carcinoma development, 211 ord cancer research, 89 polonium-210 effects, 210 ANTISMORING MATRRIAI smoking prevention films for ado lescents, 296, 297 AROMATIC AMINRS cigarette smoke content and their carcinogenic activity, 207-209 guinea pigs nonsuitability for teat- ing, 175 306 INDEX AROMATIC HYDROCARBONS tumor initiators, 195 AROMATIC NITROHYDROCAR- BONS cigarette smoke content and their carcinogenic activity, 207-209 ARSENIC tobacco content and carcinogenic activity, 211, 212 ASBESTOS syncarcinogenic effects with smok- ing, 189, 190 ASBESTOS WORRERS lung cancer mortality, smokers vs. nonsmokers, 189, 190 AVERSIVE THERAPY focused smoking and smoking ces- sation maintenance relationship, 273 intensive smoking effectiveness, 10 reciprocal aversion among spouses, effectiveness, 279, 280 BEHAVIOR smoking cessation relapse relation- ship, 276-279 BENZO[A]PYRENBS animal responsiveness to skin painting, 175 esophageal cancer-experimental studies, 101 metabolic activation, 195, 196 oral cancer+xperimental studies, 89 syncarcinogenic effect with poloni- um-210, 191, 210 BLADDER CANCER aromatic amines presence in cigar- ette smoke relationship, 207, 208 carcinogens and cocarcinogens in urine of smokers, 219 causal significance of the associa- tion with smoking--coherence, 111, 112 causal significance of the asocia- tion with smoking--consistency, strength, and specificity, 106-110 causal significance of the associa- tion with smoking-temporal re lationship, 110 cigarette smoking a contributory factor, 7, 102, 146 dose-response relationship with smoking, 107, 108, 111, 112 BLADDER CANCBR-C'onM. histologic types, 102 hypothesis on mechanisms involved in pathogenesis, 199, 200 morbidity and mortality estimates for 1982, 101 mortality in populations with dif- ferent smoking habits, 48, 50 mortality rates, 102-112 occupational exposure risks, 102, 112 pipe and cigar smoking relation- ship, 112 prevalence in populations with dif- ferent smoking habits, 112 prospective epidemiological studies of relationship with smoking, 108, 110, 111 retrospective studies of relationship with smoking, 106-109 risks among ex-smokers, 108, 110, 111, 112 sex factor and smoking habits rela- tionship, 108, 112 survival rate, 102 BRITISH PHYSICIANS STUDY bladder cancer mortality for pipe and cigar smokers, 112 bladder cancer mortality ratio, 110. 111 esophageal cancer mortality ratio, 96, 97 esophageal cancer mortality ratio for ex-smokers, 97 esophageal cancer mortality ratio in cigar and pipe smokers, 99 kidney cancer mortality ratio and relative risk, 120, 121 laryngeal cancer mortality ratio, 68, 72 laryngeal cancer mortality ratio in cigar and pipe smckers, 75 laryngeal cancer risks among ex- smokers, 72, 73 lung cancer mortality ratio in ex- smokers, 46 lung cancer mortality ratio in male smokers, 61 lung cancer mortality ratio, smok- ers vs. nonsmokers, 36, 38, 39 oral cancer mortality ratio, 85, 86 oral cancer mortality ratio in cigar and pipe smokers, 88 307 INDEX BRITISH PHYSICIANS STUDY-Contd pancreatic cancer mortality ratio, 130 stomach cancer mortality ratio, 136 summary, 31, 33 Bronchial cancer See LUNG CANCER BRONCHLAL EPITHELIUM premalignant changes among cigar and pipe smokers, 62 premalignant changes and cigarette smoking relationship, 42, 55, 58 60 BRONCHITIS incidence in children of smoking parents, 239 CADMIUM carcinogenic activity, 212 kidney cancer relationship, 119 CALIFORNIA OCCUPATIONS STUDY bladder cancer mortality ratio, 110, 111 esophageal cancer mortality ratio, 96, 97 kidney cancer mortality ratio and relative risk, 120, 121 laryngeal cancer mortality ratio, 68 lung cancer mortality ratio, smok- ers vs. nonsmokers, 36, 38 oral cancer mortality ratio, 85, 86 pancreatic cancer mortality ratio, 130 stomach cancer mortality ratio, 136 su,mmary, 32, 33 CANADIAN VETERANS STUDY (See also DEPARTMENT OF HEALTH AND WELFARE OF CANADA) bladder cancer mortality ratio, 110 lung cancer mortality ratio in male smokers, 61 lung cancer mortality ratio, 36, 38 pancreatic cancer mortality ratio, 130 summary, 32, 33 CANCER (See also BLADDER CANCER; CERVICAL CANCER, ESO- PHAGEAL CANCER; KIDNEY CANCER; LARYNGEAL CANCER; LUNG CANCER; NASAL CANCER; ORAL CANCER-Contd. CANCER; PANCREATIC CANCER; PROSTATIC CANC ER; RENAL CANCERS; SEIN CANCER; STOMACH CANG ER; TRACHEAL CANCER) deaths caused by tobacco, 1978, 149 historical perspective, ti mortality for smoking-related canc- ers among females, 148 overall mortality and smoking rela- tionship, 4, 5, 15, 22, 142-144, 147 CARBAZOLES cocarcinogen role, 198 CARBON MONOXIDE absorption by nonsmokers, 240 content in cigarette smoke, 215-217 content in cigarettes, cigars, and little cigars, 192, 193 toxic effect, 192 cARcINOGENES1s alcohol consumption influence, 192 animal studies factors, 175-178 criteria and guidelines for carcino genicity tests, 173-178 dermal administration factors, 174 inhalation administration factors, 174, 175 intraperitoneal and intravenous in- jections, 174 mechanisms related to tobacco, 8, 9 oral administration factors, 173, 174 physicochemical characterization of the material requirement, 173 planning and conduct of carcino- genicity experiments, 178 research needs and priorities, 218 220 subcutaneous and intramuscular implantation, 174 synergistic effect of occupational exposure and smoking, 189, 190 tobacccqwcific nitrosamines, 205, 206 transplacental migration of smoke constituents, 188, 219-221 CARCINOGENS aromatic amines and aromatic ni- trohydrocarbons, 207-209 cadmium, 212 inorganic arsenic compounds, 212 308 INDEX CARCINOGENS-Contd. N-nitrosomorpholine in animals, 201 nickel, 210, 211 nitrosodiethanolamine, 202 organ-specific carcinogens in cigar- ette smoke, 199-213, 220 polonium-210, 210 CARDIOVASCULAR DISEASE C&e also ISCHEMIC HEART DI- SEASE) MRFIT intervention program, 280, 281 CATECHOL cocarcinogen role, 198 CERVICAL CANCER cigarette smoking relationship, 8 contributing factors, 137, 138 dose-response relationship with smoking, 140, 141 mortality, 137-141 nonsmoking wives of smokers, risk, 244 retrospective and prospective scu- dies of relationship with smok- ing, 140, 141 squamous cell carcinoma, 137 survival rate, 137 CESSATION OF SMOIUNG age and sex factors in spontaneous cessation by adolescents, 291 antecedents of relapse, 10, 276-279, 285 bladder cancer risk reduction, 108, 110-112 cessation clinics improvement re- commendations, 283, 284 esophageal cancer mortality and risk reduction, 97, 98, 101 kidney cancer mortality effect, 119 laryngeal cancer mortality and risk effect, 6, 72, 73, 78, 145 lung cancer mortality effect, 5, 6, 45, 46, 63, 146 maintenance procedures, 10; 271- 261, 285 manuals comparison, -266 minimal intervention approaches, 10, 260-266 most effective strategy, 293, 300 oral cancer risk reduction, `7, 87, 90 predictors of outcome, 264-268, 281-263 CESSATION OF SMGRING--Contd. predictors of spontaneous cessation in adolescence, 10, 291-296 preferred approach by adults, 9, 10, 257, 268 prospective attitudinal predictors in adolescents, 291, 292 reinforcement of maintenance tech- niques, 10, 271-273, 285 repeated cessation at+&mpta in ado- lescents and success probability, 11, 293295, 300 self-help approaches review, 10, 258-260, 267, 268 "self-help" defined, 258 self-management techniques for maintenance, 10, 273, 285 social influences on adolescents, 10, 292-296 social support in maintaining absti- nence; 279-281, 285 spontaneous cessation rates in adolescence, 10, 289-291, 300 tailoring treatments to individual characteristics relationship to maintenance, 274-276 therapist contact relationship to maintenance, 274 Chemicals See AGRICULTURAL. CHEMICALS CHILDREN respiratory illness incidence related to parental smoking, 239 CHURCH OF JESUS CHRIST OF LATTER-DAY SAINTS (MOR- MONS) cancer risks compared with non- Mormons, 45, 46 laryngeal cancer rates, 65, 72 lung cancer mortality, 48, 50 CIGAR SMOKE carbon monoxide values, 193 mainstream smokc+pH content, 183,184 standardized parameters for collec- tion and analysis, 182 temperature profile, 182 CIGAR SMORING bladder cancer relationship, 112 cancer mortality ratios, 143 esophageal cancer relative risk and mortality rate, 7, 99-101, 146 kidney cancer relationship, 122 309 INDEX CIGAR SMOIUNG-Xontd. laryngeal cancer relative risk and mortality rate, 6, 74-77, 145 lung cancer relative risk and mor- tality rate, 5, 60-62, 63, 145 oral cancer relative risk and mor- tality rate, 6, 7, 87-89, 146 pancreatic cancer risk, 131 synergistic role with alcohol for oral cancer risk, 88 CIGARETTE SMOKE analysis, 183, 184, 220 aromatic amines and aromatic ni- trohydrocarbons, 207-209 arsenic content, 212 biological activity measurement, 8 cadmium content, 212 changes in composition of U.S. ma- nufactured cigarettes, 9, 215, 216 flavor enhancement, 217-219 hypotheses on mechanisms involved in pathogenesis of pancreatic, kidney, and bladder cancers, 199, 200 nickel content, 210, 211 organ-specific carcinogens, 212, 213 polonium-210 content, 210 standardized parameters for collec- tion and analysis, 181, 182 tobacco-specific N-nitrosamines, 203 US. sales-weighted average tar and nicotine yields, 215 CIGARETTES nickel content, 210, 211 polonium-210 content, 210 temperature profiles, 182, 183 CIGAREXTES, LOW YIELD bladder cancer risk, 108 esophageal cancer risk, 96 laryngeal cancer risk, 6, 69, 78, 146 lung cancer risk, 6, 37, 42, 63, 145 oral cancer risk, 80, 83 smoking compensation, 216, 217, 221 CIRRHOSIS smoking association, 19 COCARCINOGENS definition, 187 identification in tobacco smoke, 219 PAH subfractions, 188 tobacco smoke particulates, 197-199 COFFEE CONSUMPTION smoking cessation relationship, 267 310 CONGRESSIONAL OFFICE OF TECHNOLOGY ASSESSMENT cancer mortality attributable to to bacco use, 142 lung cancer mortality and smoking association, 23 DEPARTMENT OF HEALTH AND WELFARE OF CANADA criteria and guidelines for carcino genicity tests, 173 DIET carcinogenicity studies in animals, relationship, 177 DOGS inhalation studies, 185 nicotine inhibition of pancreatic bi- carbonate secretion, 131 pancreatic proteases change from cigarette smoking in beagles, 132 syncarcinogenic effect of radon daughters and cigarette smoke in beagles, 190, 191 ECONOMICS lung cancer impact, 6, 23, 63, 145 EDUCATIONAL FACTORS adolescence smoking initiation and cessation effect, 293, 300 smoking cessation relationship, 267 EMPHYSEMA nonsmoking wives of smokers, risk, 246 ENVIRONMENTAL PROTECTION AGENCY (EPA) criteria and guidelines for carcino- genicity tests, 173 EPIDEMIOLOGY "association" defined, 20 "causal" defined, 20 "contributory factor" defined, 20 criteria for causality, 4, 16-20 "major cause" defined, 20 ESOPHAGEAL CANCER causal.significance of the associa- tion with smoking-coherence, 97-99 I causal significance of the associa- tion with smoking-consistency, 95, 96 causal significance of the associa- tion with smoking-specificity, 96 causal significance of the associa- tion with smoking---strength, 96 ESOPHAGEAL CANCRR-Contd. causal significance of the associa- tion with smoking-temporal re lationship, 96, 97 dose-response relationship with smoking, 96-98, 101, 146 experimental studies, 101 lower tar and nicotine cigarettes and risk in females, 96 mortality rates, 96-98 mortality rates and relative risk for cigar and pipe smokers, 9% 101, 146 mortality risk among ex-smokers. 97, 98, 131 retrospective and prospective stu- dies findings, 95-97, 99 smoking as causal factor, 7, 146 survival rate, 90 synergy of alcohol and smoking, 166, 101, 146, 191, 202 zinc deficient diet relationship, 192 ESOPHAGEAL EPITHRLIUM nutritional deficiency and suscepti- bility to smoke, 218, 219 EXSMORERS bladder cancer risk, 108, 116-112 esophageal cancer mortality and relative risk, 97, 98, 101 kidney cancer mortality, 119 laryngeal cancer mortality and re- lative risk, 6, 72, 73, 78, 146 lung cancer mortality, 5, 6, 45, 46, 63, 146 oral cancer relative risks, 7, 87, 96 overall cancer mortality compared to smokers, 5, 143, 144, 147 FATTY ACIDS tumor promoters, 197 FDA See FOOD AND DRUG AD- MINISTRATION FEDERAL TRADE COMMISSION m-c) standard cigarette smoking condi- tions, 181, 182 FILTERED CIGARETTES bladder cancer risk relationship, 108 laryngeal cancer risk relationship, 69-71, 78, 146 lung cancer mortality relationship, 37, 40, 41, 63, 145 oral cancer risk relationship, 83 FILTERED CIGAREXTESContd. perforation and carbon monoxide reduction, 216 polonium-210 retention, 210 temperature profiles of burning ci- garettes, relationship, 182 volatile N-nitrosamines retention by cellulose acetate filter tips, 201 FOOD AND DRUG ADMINISTRA- TION (FDA) criteria and guidelines for carcino- genicity tests, 173 FORMALDEHYDE induction of carcinomas in rata, 193 FTC See FEDERAL TRADE COM- MISSION GAS PHASE COMPONENTS OF SMORE smoke analysis, 183 Genetics See HEREDITY GEOGRAPHICAL FACTORS lung cancer mortality in urban vs. rural areas, 45-47 oral cancer mortality, 78 GREECE lung cancer mortality for nonsmok- ing wives of smokers, 243-245 HAWAIIAN STUDY OF FIVE ETHNIC GROUPS bladder cancer and smoking associ- ation, 108 laryngeal cancer and smoking asso ciation, 65 lung cancer and smoking associa- tion, 34 oral cancer and tobacco use associ- ation, 80 pancreatic cancer and smoking re- lationship, 128 renal cancer and cigarette smoking association, 119 stomach cancer and smoking asso ciation, 136 HEALTH COUNCIL OF THE NETHERLANDS criteria and guidelines for carcino- genicity teats, 173 HEREDITY genetic susceptibilities as potential atiologic factor in kidney cancer, 119 311 INDEX HEREDITY-Co&d. Swedish Twin Registry Study relat- ed to smoking and lung cancer, 34, 35 HORMONES potential etiologic factor in kidney cancer, 119 HORN'S REASONS FOR SMOK- ING SCALE self-control cessation techniques re- lationship, 262, 283 HYDRAZINE metabolic transformation, 194 HYDROGEN CYANIDE ciliatoxic agent, 193 IARC See INTERNATIONAL AGENCY FOR RESEARCH ON CANCER ICD See INTERNATIONAL CLAS- SIFICATION OF DISEASES INDOLES cocarciriogen role, 198 INDUSTRIAL INHALANTS carcinogenicity, epidemiological and experimental evidence, 49 INTERNATIONAL AGENCY FOR RESEARCH ON CANCER (IARC) criteria and guidelines for carcino- genicity tests, 173 inorganic arsenic compounds and skin and lung cancer, 212 nickel workers and cancers of the nasal cavity and the lung, 211 nitrosamines as carcinogens in hu- mans, 209, 201 INTERNATIONAL CLASSIFICA- TION OF DISEASES (ICD) revisions, 147 INTERNATIONAL STATISTICAL CLASSIFICATION OF DI- SEASES, INJURIES, AND CAUSES OF DEATH WHO regulation, 147 INVOLUNTARY SMOKING chemical constituents of sidestream smoke, 239-241 dose-response relationship with lung cancer, 241 epidemiologic studieemethodologic difficulties, 24, 243 health effects, 239 312 INVOLUNTARY SMOKING.-Q,~~, lung cancer mortality for nonsmok- ing wives Of smokers-Greek study, 243-245 lung cancer mortality for nonsmok. ing wives of smoke&apaneae study, 245-249 lung cancer mortality for nonsmok. ing wives of smoke-U.S. stu. dy, 248-256 lung cancer risk, 9, 256, 251 ISCHEMIC HEART DISEASE nonsmoking wives of smokers, risk, 246 JAPANESE STUDY bladder cancer mortality ratio, 119 cervical cancer mortality ratio, 141 esophageal cancer mortality ratio, 96. 97 kidney cancer mortality ratio and relative risk, 126 laryngeal cancer mortality ratio, 68, 72 lung cancer mortality among non* moking wives of smokers, 245- 249 lung cancer mortality ratio in ex- smokers, 46 lung cancer mortality ratio in male smokers, 61 lung cancer mortality ratio, smok- ers vs. nonsmokers, 36, 38 mortality ratios for smoking-related cancers among females, 148 oral cancer mortality ratio, 85, 86 overall cancer mortality ratio, 142, 143 pancreatic cancer mortality ratio, 136 stomach cancer mortality ratio, 136 summary, 3133 KAISER PERMANENTE subscribers who had or had not quit smoking, 267 KIDNEY CANCER causal significance of association with smoking-zoherence, 119 121 causal significance of association with smoking-consistency, strength, and specificity, 118, 119 INDEX KIDNEY CANCER-Contd. causal significance of association with smoking-temporal relation- ship, 119 chemical elements as potential etio logic factors, 119 cigarette smoking as contributory factor, 7, 122 doseresponse relationship with smoking, 119, 121 histological types, 113, 117 hypotheses on mechanisms involved in pathogenesis, 199, 200 mortality among ex-smokers, 119 mortality rates, 113-118 pipe and cigar smoking relation- ship, 122 prevalence in populations with dif- ferent smoking habits, 121 prospective studies of relationship with smoking, 119-121 retrospective studies of relationship with smoking, 116-120 sex factor and smoking habits rela- tionship, 120, 121 survival rate, 117 LARYNGEALCANCER animal studies, 75, 77 causal significance of association with smoking-coherence, 71-74 causal significance of association with smoking+onsistency, 65-66 causal significance of association with smoking-specificity, 69, 70 causal significance of association with smoking--strength, 69 causal significance of association with smoking-temporal relation- ship, 70 cigarette smoking as causal factor, 6, 65, 77. 145 common cell type and site, 65 dose-response relationship with smoking, 69, 71, 72, 77, 78, 145 incidence, 6, 63 mortality among ex-smokew, 72-74, 78, 146 mortality rates, 6, 63-65 mortality ratio and relative risk in cigar, pipe, and cigarette smok- er%, 6, 74-76, 145 LARYNGEAL CANCER&ntd. prospective studies of mortality among smokers and nonsmokers, 65, 68, 69 relative risk in smokers vs. nons- mokers, 69 retrospective studies of smoking re- lationship, 65, 68 risk ratios for males and females, 69-71 sex factor vs. smoking habits and alcohol consumption relationship, 72 survival rate, 65 synergy of smoking and alcohol, 72, 75, 77, 78, 146, 191 LARYNX precancerous lesions in smokers, 70, 73, 74 LEAD potential etiologic factor in kidney cancer, 119 LEAD-210 cigarette smoker exposure, 210 LEUKOPLAKIA smoking relationship, 87 LITI'LE CIGAR carbon monoxide values, 193 tobacco carcinogen metabolism en- hancement by alcohol, 191, 192 LUNG CANCER age-specific smoking patterns and mortality, 50-58, 145 arsenic exposure association, 212 causal significance of association with smoking+herence, 42-59 causal significance of association with smoking~nsistency, 3, causal significance of association with smoking-specificity, 37-39 causal significance of association with smoking-strength, 35-73 causal significance of association with smoking-temporal relation- ship, 3942 cigarette consumption/adult in 1950 vs. death rates in mid- 1970s. 41, 44 cigarette smoking as causal factor, 5, 19, 62 dose-response relationship with smoking, 36-42, 62, 145 313 INDEX LUNG CANCERContd. economic impact, 23, 63. 145 histological types in smokers and nonsmokers, 27-30 involuntary smoking risk, 9, 239, 243251 latency periods, 243 mortality among ex-smokers, 45, 46, 63, 145 mortality for nonsmoking wives of smokers-Greek study, 243-245 mortality for nonsmoking wives of smokers-Japanese study, 245 249 mortality for nonsmoking wives of smokers-U.S. study, 248250 mortahty by site of residence (ur- ban vs. rural). 45-47 mortality rates, 4, 18, 21-28, 42-48, 50-58, 145. 241 nickel relationship, 211 occupation and mortality, 47-49 polonium-210 as a risk factor, 210 premalignant changes in bronchial epithelium and smoking relation- ship, 55, 58-60 prospective studies of mortality among smokers and nonsmokers, review, 3633 risk among pipe and cigar smok- ers, 60-62, 63, 145 sex factors vs. smoking habits in relation to mortality, 4245 survival rate, 23 tobacco consumption/capita in 1930 vs. death rates in 1950, 40, 43 vitamin A level relationship to risk, 218 MASS MEDIA televised smoking cessation pro- grams, 10, 263-266, 268 MATERNAL SMOKING transplacenial carcinogenesis, 188, 189, 219 MORBIDITY bladder cancer incidence estimates for 1982, 101 laryngeal cancer incidence esti- mates for 1982, 63 pancreatic cancer incidence esti- mates for 1982, 122 stomach cancer incidence estimates for 1982, 132 314 Mormons See CHURCH OF JFYUS CHRIST OF LA'ITER-DAY SAINTS MORTALITY age-adjusted rates defined, 147 American Cancer Society Nine- State Study, 32 American Cancer Society 25-Stak Study, 31 bladder cancer, 101-112 British Physicians Study, 31 bronchial, tracheal, and lung cant. er, 24-28 California Men in Various Occupa- tions Study, 32 Canadian Veterans Study, 32 cancer death rates, 4, 5, 15, 22 cancer deaths caused by tobacco, 149 cancer of the buccal cavity and pharynx, 78-84 cause-f-death classification prob lems. 147 cervical cancer, 137-141 esophageal cancer, 90-99 Japanese Study of 29 Health Dis- tricts, 30, 31 kidney cancer, 113-119 laryngeal cancer, 6, 63-69, 71-73 lung cancer, 4-6, 18, 21-28, 36-59, 145 lung cancer among asbestos work- ers, 189, 190 lung cancer among uranium min- ers, 190 oral cancer, 6, 7, 78-88 overall cancer mortality and smok- ing relationship, 142-144, 147 pancreatic cancer, 122-131 smoking-related cancers among fe- males, 148 smoking-related cancers among males, 148 stomach cancer, 132136 Swedish Study, 32 U.S. Veterans Study, 31 MOTIVATION health risks of smoking informa- tion effect, 260 interaction with internal vs. exter- nal locus of control and smoking cessation treatment, 274-276 predictors of smoking cessation pro- gram outcome, 264, 265, 268 MULTIPLE RISK FACTOR INTER- VENTION TRIAL (MRFIT) cigarettes smoked/day and cessa- tion success relationship, 282 intervention/maintenance program for smoking cessation, 280, 281 MYCOTOXINS dietary content effect on carcino- genesis assays in animals, 177 INDEX NAPHTHALKNES cocarcinogen role, 198 NASAL CANCER snuff association, 3 NATIONAL CANCER INSTITUTE (NCI) criteria and guidelines for carcine genicity tests, 173 NATIONAL INTERAGENCY COUNCIL ON SMOKING AND HEALTH activities of American companies in employee smokmg cessation pre grams, survey, 272, 273 NEONATES benzo[a]pyrene activation in fores- kin, 188. 219 Neoplasms See CANCER NEUROTICISM smoking cessation and maintenance success relationship, 262 NICKEL cigarette tobacco and smoke con- tent and carcinogenic activity, 210. 211 NICKEL WORKERS nasal cavity and lung cancers inci- dence, 211 NICOTINE cocarcinogen role, 198, 199 pancreatic cancer induction rela- tionship, 219 t~ansplacental effects, 189 NICOTINE CONTENT bladder cancer risk relationship, 108 esophageal cancer risk relationship, 96 laryngeal cancer risk relationship, 69 lung cancer mortality relationship, 37, 42 oral cancer risk relationship, 80, 83 NICOTINE CONTENTanM. U.S. cigarettes sales-weighted aver- age, 215 NITROGEN smoke content, 1133 NITROGEN DIOXIDE ciliatoxic agent, 193 NITROGEN OXIDES content of cigarette smoke, 193 NITROSAMINES content in snuff, 201 di-methylnitrosamine caused kidney tumors in rats, 119 dietary content effect on cvrcincF genesis assays in animals, 177 N-nitrosamines in tobacco and tc+ bacco smoke, 20%206 N-nitrosodiethanolamine, 202 tobacco-specific N-nitrosamines, 203-207, 220 volatile N-nitrosamines, 200-202 NONSMOKERS lung cancer mortality among wives of smokers, 243-251 lung cancer risks, 9, 250, 251 smoke constituents absorption, 240, 241 NORTH KARELIA (FINLAND) PROJECT televised smoking cessation clinic effectiveness, 265, 266 OCCUPATIONAL FACTORS (See also INDUSTRIAL INHA- LANTS) bladder cancer risk, 102 cadmium exposure and prostatic cancer, 212 lung cancer mortality, 4749 smoking cessation and maintenance programs at the workplace, 10, 272, 273 syncarcinogenesticupational car- cinogens and smoking, 189-191 synergistic role with smoking in bladder cancer, 112 ORALCANCER causal significance of association with smoking-coherence, 85-87 causal significance of association with smoking--consistency, SO, 85 causal significance of association with smoking-specificity, 84, 85 315 INDEX ORAL CANCERantd. causal significance of association with smoking--strength, 80, 83, 85, 86 causal significance of association with smoking--temporal relation- ship, 85 dose-response relationship with smoking, 80, 85, 86, 90, 146 experimental studies, 89 geographical factors, 78 lip cancer and tobacco use relation- ship, 3 morbidity and mortality estimates for 1982, 73 mortality, 6, 7, 78-85 mortality rates for cancer of the buccal cavity and pharynx, 78- 84 most common histological type, 80 nicotine as cocarcinogen, 199 retrospective and prospective stu- dies, 80, 85, 86 risk among ex-smokers, 87, 90 risk related to non-cigarette tobac- co use, 87-90, 145 sex factors, 78, 86 smoking association, 6, 7, 80, 89, 145 snuff-dipping relationship, 201 survival rate for cancer of the floor of the mouth, tongue, and pharynx, 80 synergy of alcohol and smoking, 80, 86, 88, 90, 146. 191, 202 ORAL CAVITY prenlalignant oral mucosal changes in smokers vs. nonsmokers, 85 PAH See POLYNUCLEAR ARO- MATIC HYDROCARBONS PANCREAS premalignant changes in smokers vs. nonsmokers, 128, 131 PANCREATIC CANCER causal significance of the associa- tion with smoking--coherence, 129-131 causal significance of the associa- tion with smoking-consistency, strength, and specificity, 128 causal significance of the associa- tion with smoking-temporal re- lationship, 128 316 PANCREATIC CANCER+,,a. cigar smoking relationship, 131 cigarette smoking as contributory factor, 7 dose-response relationship with smoking, 128-130 experimental studies, 131, I32 hypotheses on mechanisms involved in pathogenesis, 199, 206 incidence in populations with dif- ferent smoking habits, 129 morbidity and mortality estimak for 1982, 122 mortality, 122-131 most common form, 127 nicotine's role in induction, 219 prevalence in men vs. Women, 127 prospective studies of relationship with smoking, 128, 136 survival rate, 126, 127 PARAFFIN HYDROCARBONS tumor development inhibition, 198 PARENTAL SMOKING adolescence smoking initiation and cessation effect, 292, 293 respiratory illness in children rela- tionship, 239 Passive smoking See INVOLUN- TARY SMOKING PEER GROUPS adolescent pear modeling for smok- ing prevention programs, 297- 300 adolescent smoking initiation and cessation effects, 293 PERSONALITY abstinence violation effect, 278, 279 internal vs. external locus of con- trol, motivation and smoking cessation treatment interactions, 274-276 self-perception relationship to maintenance of smoking cessa- tion, 283 PESTICIDES dietary content effect on carcinw genesis assays in animals, 177 PHYSICIANS smoking cessation direction to pa- tients, effect, 10, 260-262. 268 PIPE SMOKING bladder cancer relationship, 112 cancer mortality ratios, 143 INDEX PIPE SMOEING-Contd. esophageal cancer relative risk and mortality rate, 7, 99-101, 146 kidney cancer relationship, 122 laryngeal cancer relative risk and mortality rate, 6, 74-77, 145 lung cancer relative risk and mor- tality rate, 5, 60-62, 63, 145 oral cancer relative risk and mor- tality rate, 6, 7, 87-89, 146 smoke collection and analysis methods, 182 synergistic role with alcohol for oral cancer risk, 88 temperature profile, 182 PIPE TOBACCO nickel content, 211 PNEUMONIA incidence in children of smoking parents, 239 POLONIUM-210 cigarette tobacco and smoke con- tent and carcinogenic activity, 210 syncarcinogenic effect with ben- xolalpyrene, 191 POLYNUCLEAR AROMATIC HY- DROCARBONS (PAH) alcohol enhancement of carcinogen- ic effect, 191 cocarcinogen role, 198 tumor initiators, 188, 195, 196 PREVENTION OF SMOKING adolescent programs review, 11, lung cancer mortality relationship, 6 PROSPECTIVE STUDIES (See also AMERICAN CANCER SOCIETY SSTATE STUDY; AMERICAN CANCER SOCIE TY 25STATE STUDY; BRIT- ISH PHYSICIANS STUDY; CALIFORNIA OCCUPATIONS STUDY; CANADIAN VETER- ANS STUDY; JAPANESE STUDY; SWEDISH STUDY; U.S. VETERANS STUDY) bladder cancer mortality ratios, 110, 111 cervical cancer mortality ratios, 141 esophageal cancer mortality ratios, 96, 97 PROSPECTIVE STUDIES-Contd. esophageal cancer mortality ratios in cigar and pipe smokers, 99 kidney cancer mortality ratios and relative risk, 120, 121 laryngeal cancer mortality ratios, 68, 72 laryngeal cancer mortality ratios in cigar and pipe smokers, 75 lung cancer mortality ratios in ex- smokers, 45, 46 lung cancer mortality ratios in male smokers, 61 lung cancer mortality ratios, smok- ers vs. nonsmokers, 35-39 oral cancer mortality ratios, 85, 86 oral cancer mortality ratios in ci- gar and pipe smokers, 88 overall cancer mortality ratios, 142, 143 pancreatic cancer mortality ratios, 130 stomach cancer mortality ratios, 136 summaries, 30-33 PROSTATIC CANCER occupational exposure to cadmium oxide relationship, 212 RACE FACTORS bladder cancer mortality, 102-107 brenchus, trachea, and lung cancer mortality, 24-28 cancer of the buccal cavity plus oral pharynx mortality, 78-84 cervical cancer mortality, 137, 138 esophageal cancer mortality, 90-96 kidney cancer mortality, 113-118 laryngeal cancer mortality, 63-65 lung cancer mortality, 21, 23 pancreatic cancer mortality, 122 127 stomach cancer mortality, 132-135 RADIATION potential etiologic factor in kidney cancer, 119 RADON DAUGHTERS syncarcinogenic effect with smok- ing, 190, 191 RECIDMSM antecedents of relapse, 10, 276-279 negative moods relationship, 282 pretreatment cigarettes smoked/day relationship, 282 317 INDEX REDUCTION OF SMOKING buddy system effectiveness, 279 RELIGIOUS FACTORS cancer risks among Mormons vs. non-Mormons in urban vs. rural areas, 45, 46 lung cancer mortality among Mor- mons and Seventh Day Adven- tists, 48, 50 RENAL CANCERS cigarette smoking-relative risk, 119 RESPIRATORY TRACT DISEASES incidence in children of smoking parents, 239 RESPIRATORY TRACT EPITHE LIUM abnormalities in smokers vs. nons- mokers, 99 RODENTS (See also SYRIAN GOLDEN HAMSTERS) carcinogenic activity of N-nitroso morpholine, 201 carcinoma induction by nitroso diethanolamine, 202 induction of laryngeal tumors, 77 inhalation studies, 185. 186 metabolism of nitrosamines. 205, 206 responsiveness to different routes of administration of carcinogens, 174, 175 tumorigenic activity of sidestream smoke condensate in mouse skin assays, 241 SEVENTH DAY ADVENTISTS laryngeal cancer rates, 65, 72 lung cancer mortality, 48, 50 SEX FACTORS age-specific lung cancer mortality and smoking patterns, males vs. females, 56-57 bladder cancer and smoking habits relationship, 108, 112 bladder cancer incidence, 101 bronchus, trachea, and lung canc- ers mortality, 24. 27, 28 cancer mortality estimates for 1982, 15 cancer mortality trends, 22 cancer of the buccal cavity plus oral pharynx mortality, 7884 318 SEX FACI'ORS-Contd doseresponse relationship between pancreatic cancer and smoking, 128 esophageal cancer mortality, ~96 kidney cancer and smoking habits relationship, 120, 121 kidney cancer mortality, 113-118 laryngeal cancer morbidity and mortality, 6365, 69-71 laryngeal cancer, smoking habits and alcohol consumption rela- tionship, 72 lung cancer mortality, 4, 6, 21, 23, 36, 63, 145 lung cancer mortality vs. smoking habit differences, 42-45 lung cancer risk relationship to ci- garettes smoked/day and use of filter-males vs. females, 40, 41 mortality among male smokers VS. nonsmokers, 142-144, 147 mortality for smoking-related canc- ers, 148 oral cancers incidence, 78, 86 pancreatic cancer-male to female ratio, 127, 131 pancreatic cancer mortality, 122- 127, 136 responsiveness of anhal to known carcinogens, 176 spontaneous smoking cessation by adolescents, 291 stomach cancer mortality, 132-135 SIBLINGS adolescence smoking initiation and cessation effect, 292, 293 SKIN CANCER arsenic exposure association, 212 SMOKE INHALATION, ANIMALS studies and species suitability, 184 186, 220 tumorigenic potential of whole smoke, 8 SMOKE STREAMS collection and analysis methods, 181, 182 description, 9, 181, 213 mainstream smoke content, 183 sidestream/mainstream ratio for major toxic and tumorigenic agents, 213. 214 INDEX SMOKE STREAM~nM. side&ream/mainstream ratio of ci- garette smoke constituents, 240, 251 sidestream smok-hemical consti- tuents, 239-241 Smoking See CIGAR SMOKING; MATERNAL SMOKING; FA- RENTAL SMOKING; PIPE SMOKING SMOKING PATTERNS age-specific lung cancer mortality, 5055,58 bladder cancer mortality associa- tion in males and females, 112 bladder cancer prevalence in differ- ent populations, 112 cessation and maintenance success relationship, 262 cigarettes smoked/day and cessa- tion probability in adolescents, 294-296 cigarettes smoked/day and cessa- tion success relationship, 282 consumption vs. lung cancer death rate, 40, 41. 43, 44, 62 dose-response relationship of lung cancer mortality in nonsmoking wives of smokers, 243-251 dose-response relationship with bladder cancer, 107, 108, 111, 112 dose-response relationship with cer- vical cancer, 140, 141 dose-response relationship with eso- phageal cancer, 7. 96-98, 101, 146 dose-response relationship with kid- ney cancer, 119, 121 dose-response relationship with lar- yngeal cancer, 6, 69-72, 145 dose-response relationship with lung cancer, 5, 3641, 62, 145 dose-response relationship with oral cancers, 7, 80, 83, 85, 86, 146 dose-response relationship with ove- rall cancer mortality, 142-144, 147 dose-response relationship with pancreatic cancer, 126-130 dose-response relationship with sto math cancer, 137 duration of smoking and probabili- ty of quitting, 293, 294, 300 SMOKING PA'ITERNS-ConM. esophageal cancer mortality among different populations, 98 histories of those who quit vs. those who did not, 267 kidney cancer prevalence in differ- ent populations, 121 laryngeal cancer mortality among different populations, 72 lower tar and nicotine cigarettes, 9, 216, 217 lung cancer mortality among differ- ent populations, 48, 50 lung cancer mortality relationship in males vs. females, 42-45 lung cancer subjects-retrospective studies, 34, 35 oral cancer mortality among differ- ent populations, 86 pancreatic cancer incidence among different populations, 129 premalignant changes in bronchial epithelium correlation, 55. 5%60 regularity and cessation probability in adolescents, 294296 tobacco-specific N-nitrosamines re- tention relationship, 204 SNUFF cancer association, 3, 9 nickel content, 211 nitrosamines content, 201 nitrosodiethanoiamine content, 202 tobacco-specific N-nitrosamines, 203, 204 SNUFF-DIPPING lung cancer risk, 60 nicotine as cocarcinogen in oral cancer, 199 oral cancer relationship, 201 oral cancer risk, 7, 87, 88. 90, 146 tobaccospecific N-nitrosamines in saliva, 204 SOCIAL FACTORS social pressure and smoking cessa- tion relapse relationship, 276 279 social support and smoking cessa- tion maintenance, 279-281, 265 STANFORD HEART DISEASE PREVENTION PROGRAM mass media encouragement of smoking cessation, 265 STOMACH CANCFR cigarette smoking association. 8 319 INDEX STOMACH CANCER-Contd. dose-response relationship with smoking, 137 morbidity and mortality estimates for 1982, 132 mortality, 132135 nonsmoking wives of smokers, risk, 246 prospective studies of relationship with smoking, 136, 137 retrospective studies of relationship with smoking, 132, 136, 137 STRIi!S!S antecedents of smoking cessation relapse, 277, 278 SWEDISH STUDY bladder cancer mortality ratio, 110, 111 cervical cancer mortality ratio, 141 esophageal cancer mortality ratio, 96 lung cancer mortality ratio, smok- ers vs. nonsmokers, 36, 38, 39 oral cancer mortality ratio, 85 pancreatic cancer mortality ratio, 130 stomach cancer mortality ratio, 136 summary, 32, 33 SWEDISH TWIN REGISTRY genetic predisposition toward smok- ing and lung cancer, study, 34, 35 SYRIAN GOLDEN HAMSTERS inhalation studies suitability, 185, 186, 220 laryngeal cancer research suitabili- ty, 75, 77 respiratory tract tumor induction by N-nitrosodiethylamine, 200, 201 syncarcinogenic effects of polonium- 210 and benzo[a]pyrene, 191 transplacental migration of tobacco tar, 188, 189 TAR CONTENT bladder cancer risk relationship, 108 cigars vs. pipes vs. cigarettes, carci- nogenic activity, 62 esophageal cancer risk relationship, 96 laryngeal cancer risk relationship, 69, 78, 146 320 TAR CONTENT-ConM. lung cancer mortality relationship, 37, 42, 63, 145 oral cancer risk relationship, &-J, 83 U.S. cigarettes sales-weighted aver. age, 215 TARS, TOBACCO transplacental migration, 188, 189 tumor induction in skin of ani- mals, 187, 188 Television See MASS MEDIA THIRD NATIONAL CANCER SIJR. VEY (TNCS) bladder cancer and cigarette smok- ing relationship, 108 cervical cancer and smoking rela- tionship, 140 chewing tobacco and snuff use and risk for cancers of the gum and mouth, 88 laryngeal cancer and smoking - c&ion, 65 lung cancer and smoking associa- tion, 34 oral cancer and tobacco use associ- ation, 80 pancreatic cancer and smoking re- lationship, 128 renal cancer and cigarette smoking association, 119 stomach cancer and smoking asso ciation, 132 TNCS See THIRD NATIONAL CANCER SURVEY TOBACCO (See also PIPE TOBACCO; SNUFR arsenic content, 211, 212 flavor enhancers, 217-219 nitrosation of nicotine during cur- ing, 203 TOBACCO. CHEWING lung cancer risk, 60 nicotine as cocarcinogen in oral cancer, 199. oral cancer risk, 87, 88 TOBACCO SMOKE (See also CIGAR SMO- CI- GARETTE SMOKE; GAS PHASE COMPONENTS OF SMOKE) assays with smoke particles, 187, 188, 226 INDEX TOBACCO SMORE-Contd. carbon monoxide content, 192, 193 cocarcinogen identification need, 219 fractionation experiments, 188, 220 N-nitrosamines, 200-206 nickel content, 211 nitrosodiethanolamine content in maleic hydraside treated tobacco, 202 process for determining chemical and physical nature, 181-184 synergistic effects with alcohol re- lative to cancer risks, 191, 192 transplacental carcinogenesis, 188, 189, 219-221 tumor initiating agents in the par- ticulate phase, 195, 196 tumor promoters, 197 vapor phase components, 192-194 TRACHEAL CANCER mortality, 24-28, 56, 57 TUMORS initiating agents in tobacco smoke, 195, 196 polonium-210 effects, 210 promoters in tobacco smoke, 197 tumorigenic constituents of smoke particulates, 188 tumorigenic potential of smoke par- ticulatas, 187, 188 TWINS Swedish Twin Registry Study, 34, 35 UNITED STATES lung cancer mortality for nonsmok- ing wives of smokers, 248-250 URANIUM MINERS lung cancer mortality, smokers vs. nonsmokers, 190 URETHANE carcinogenicity, 194 U.S. DEPARTMENT OF HEALTH AND HUMAN SRRVICRS 1982 Report organization, 3 U.S. NATIONAL ACADEMY OF SCIENCES inorganic arsenic compounds and skin and lung cancer, 212 U.S. VETERANS STUDY bladder cancer mortality ratio, 110, 111 U.S. VETERANS STUDY-ConM. esophageal cancer mortality ratio, 96, 97 esophageal cancer mortality ratio for ex-smokers, 97 esophageal cancer mortality ratio in cigar and pipe smokers, 99 kidney cancer mortality among ex- smokers, 119 kidney cancer mortality ratio and relative risk, 120, 121 laryngeal cancer mortality ratio, 68, 72 laryngeal cancer mortality ratio in cigar and pipe smokers, 75 laryngeal cancer, relative risk, 69 laryngeal cancer risk among ex- smokers, 72, 73 lung cancer mortality by amount smoked, 38, 55, 58 iung cancer mortality ratio in ex- smokers, 46 lung cancer mortality ratio in male smokers, 61 lung cancer mortality ratio, smok- ers vs. nonsmokers, 36, 38, 39 mortality for smoking-related canc- ers among males, 148 oral cancer mortality ratio, 85, 86 oral cancer mortality ratio in cigar and pipe smokers, 88 oral cancer risks in ex-smokem, 87 overall cancer mortality ratio, 142, 143 pancreatic cancer and cigar smok- ing relationship, 131 pancreatic cancer mortality ratio, 130 pipe smoking and bladder cancer mortality, 112 pine smoking and kidney cancer association, 122 stomach cancer mortality ratio, 136 summary, 31, 33 UTAH cancer risk among rural vs. urban Mormons vs. non-Mormons, 45, 46 321 INDEX Uterine cervix cancer See CRRVI- CAL CANCER VETERANS ADMINISTRATION LUNG CANCER CHEMOTHER- APY STUDY GROUP (VALG) lung cancer classifications, 29 VINYL CHLORIDE carcinogenicity, 194 VITAMIN A deficiency relationship to increased carcinogen susceptibility, 192 lung cancer risk relationship, 218 VITAMIN kk deficiency relationship to carcino gens effects, 192 WEST GERMANY behavioral treatment manual effec- tiveness in smoking cessation, 258 WHO See WORLD HEALTH OR- GANIZATION WITHDRAWAL SYMPTOMS relapse relationship, 277 WOMEN bronchus, trachea, and lung cancer mortality, 28 cancer mortality estimates for 1982, 15 cervical cancer mortality, 137 WOMEN-Contd. esophageal cancer and smoking, 93 lower tar and nicotine cigarettes and esophageal cancer risk, 96 lung cancer mortality among nons- moking wives of smokers, 243 251 lung cancer mortality trends, 195& 1977, 21-23 mortality for smoking-related canc- ers, 148 overall cancer mortality rates, smokers vs. nonsmokers, 5, 143, 144, 147 WORKING PARTY FOR THERA- PY OF LUNG CANCER t.WP-L) lung cancer classifications, 29 WORLD HEALTH ORGANIZA- TION (WHO) cause-of-death classification regula- tion, 147 criteria and guidelines for carcino- genicity tests, 173 lung cancer classifications, 29 WY-L See WORKING PARTY FOR THERAPY, OF LUNG CANCER ZINC deficiency in diet relationship to esophageal carcinogen suscepti- bility, 192 322 U.S. GOVERNMENT "RINTING OFFICE : 1982 0 - 377-310