The Health Consequences of Using Smokeless Tobacco A Report of the Advisory Committee to the Surgeon General 1986 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Bethesda, Maryland 20992 NIH Publication No. 96-2874 April 1996 CONTENTS Foreword ......................................... ..v Preface ........................................... . Acknowledgments ................................. ..ix Introduction, Overview, and Conclusions ................ xvii Chapter 1. Prevalence and lbnds of Smokeless lbbaccoUsei.ntheUnitedStates . . . . .l Chapter 2. Carcinogenesis Associated With Smokeless Tobacco Use . . . . .29 Chapter 3. Noncancerous and Precancerous Oral Health Effects Associated With Smokeless Tobacco Use . . . . . . . .95 Chapter 4. Nicotine Exposure: Pharmacokinetics, Addiction, and Other Physiologic Effects . . ,137 Index..................... . . . . . . . . . . . . . ...187 . . . 111 FOREWORD This report on The Health Consequences of Using Smokeless lbbamo completes the Public Health Service's initial examination of smokeless tobacco's role in the causation of cancer, noncancerous and precancer- ous oral diseases or conditions, addiction, and other adverse health effects. Almost 30 years after the Public Health Service's first state ment on the health effects of cigarette smoking, it is now possible to issue the first comprehensive, indepth review of the relationship between smokeless tobacco use and health. Ironically, while cigarette smoking has declined during the past 20 years, the production and apparent consumption of smokeless tobacco products have risen significantly. These increases are in marked con- trast to the decline in smokeless tobacco use in the United States during the first half of this century. Indeed, smokeless tobacco products, par- ticularly chewing tobacco and snuff, have recently emerged as popular products for the first time since the turn of the century. National esti- mates indicate that at least 12 million Americans used some form of smokeless tobacco during 1985 with use increasing especially among male adolescents and young male adults. The increased use and appeal of this product assume major public health significance because the evidence reveals that smokeless tobacco can cause oral cancer, can lead to the development of oral leukoplakias and other oral conditions, and can cause addiction to nicotine. The strength of the association between these conditions and smokeless tobacco use combined with the upward trend in this behavior incites the same alarm as was true with the knowledge that spitting spread tuber- culosis. That concern led to the original public rejection of tobacco chewing and dipping as unsanitary and antisocial. It is critical that our society prevent the use of this health hazard and avoid the tragic mistake of replacing the ashtray with the spittoon. This report is the work of numerous experts within the Department of Health and Human Services and in the non-Federal scientific com- munity. I express my gratitude for their contributions. C. Everett Koop, M.D. U.S. Surgeon General PREFACE This report discusses the health consequences of smokeless tobacco use. It constitutes a comprehensive review by an Advisory Committee to the Surgeon General of the available scientific literature to determine whether using smokeless tobacco increases the risk of cancer and non- cancerous oral diseases and effects, leads to addiction and dependence, and contributes to other health consequences. AFTER A CAREFUL EXAMINATION OF THE RELEVANT EPIDEMIOLOGIC, EXPERIMENTAL, AND CLINICAL DATA, THE COMMITTEE CONCLUDES THAT THE ORAL USE OF SMOKELESS TOBACCO REPRESENTS A SIGNIFICANT HEALTH RISK. IT IS NOT A SAFE SUBSTITUTE FOR SMOK- ING CIGARETTES. IT CAN CAUSE CANCER AND A NUMBER OF NONCANCEROUS ORAL CONDITIONS AND CAN LEAD TO NICOTINE ADDICTION AND DEPENDENCE. The major overall conclusions of this report are the following: 1. It is estimated that smokeless tobacco was used by at least 12 million people in the United States in 1985 and that half of these were regular users. The use of smokeless tobacco, particularly moist snuff, is increasing, especially among male adolescents and young male adults. 2. The scientific evidence is strong that the use of snuff can cause cancer in humans. The evidence for causality is strongest for cancer of the oral cavity, wherein cancer may occur several times more frequently in snuff dippers compared to nontobacco users. The excess risk of cancer of the cheek and gum may reach nearly fiftyfold among long-term snuff users. 3. Some investigations suggest that the use of chewing tobacco may also increase the risk of oral cancer, but the evidence is not so strong and the risks have yet to be quantified. 4. Experimental investigations reveal potent carcinogens in smoke less tobacco. These include nitrosamines, polycyclic aromatic hydrocarbons, and radiation-emitting polonium. The tobacco- specific nitrosamines often have been detected at levels 100 or more times higher than Government-regulated levels of other nitrosamines permitted in foods eaten by Americans. vii 5. Smokeless tobacco use can lead to the development of oral leuko- plakias (white patches or plaques of the oral mucosa), particularly at the site of tobacco placement. Based on evidence from several studies, a portion of leukoplakias can undergo transformation to dysplasia and further to cancer. 6. Gingival recession is a commonly reported outcome of smokeless tobacco use. 7. A number of studies have shown that nicotine exposure from smoking cigarettes can cause addiction in humans. In this regard, nicotine is similar to other addictive drugs such as morphine and cocaine. Since nicotine levels in the body resulting from smokeless tobacco use are similar in magnitude to nicotine levels from cigarette smoking, it is concluded that smokeless tobacco use also can be addictive. Besides, recent studies have shown that nicotine administered orally has the potential to produce a physiologic dependence. 8. Some evidence suggests that nicotine may play a contributory or supportive role in the pathogenesis of coronary artery and periph- eral vascular disease, hypertension, peptic ulcers, and fetal mortal- ity and morbidity. . . . Vlll ACKNOWLEDGMENTS This report was prepared by the Department of Health and Human Services under the direction and general editorship of Joseph W. Cullen, Ph.D., Chairman of the Advisory Committee on the Health Conse quences of Using Smokeless lbbacco. The following individuals were members of the Advisory Committee: Catherine S. Bell, M.S., Acting Chief, Prevention Research Branch, Division of Clinical Research, National Institute on Drug Abuse, Rockville, Maryland William Blot, Ph.D., Chief, Biostatistics Branch, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland James P. Carlos, D.D.S., M.P.H., Associate Director, Epidemiology and Oral Disease Prevention Program, National Institute of Dental Research, Bethesda, Maryland Joseph W. Cullen, Ph.D., Chairman of the Advisory Committee, Dep- uty Director, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland J. David Erickson, D.D.S., M.P.H., Ph.D., Chief, Birth Defects and Genetic Diseases Branch, Centers for Disease Control, Atlanta, Georgia Manning Feinleib, M.D., Dr.P.H., Director, National Center for Health Statistics, Hya ttsville, Maryland Jerome Jaffe, M.D., Director, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Michael McGinnis, M.D., M. A., M.P.P., Deputy Assistant Secretary for Health, Director, Office of Disease Prevention and Health Promo tion, United States Public Health Service, Washington, D.C. Robert Mecklenburg, D.D.S., M.P.H., Assistant Surgeon General, Chief Dental Officer, United States Public Health Service, Rockville, Maryland Susan Sieber, Ph.D., Deputy Director, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland Sumner J. Yaffe, M.D., Director, Center for Research for Mothers and Children, National Institute of Child Health and Human Develop- ment, Bethesda, Maryland The Advisory Committee was supported by the following technical experts in the areas listed below: ix Carcinogenesis William Blot, Ph.D. (Coordinator), Chief, Biostatistics Branch, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland Gayle Boyd, Ph.D., Research Psychologist, Division of Cancer Preven- tion and Control, National Cancer Institute, Silver Spring, Maryland Virginia L. Em&r, Ph.D., Associate Professor of Epidemiology, Uni- versity of California, San Francisco, California Curtis Harris, M.D., Chief, Laboratory of Human Carcinogenesis, Divi- sion of Cancer Etiology, National Cancer Institute, Bethesda, Maryland Dietrich Hoffmann, Ph.D., Associate Director, Chemistry and Bio- chemistry, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York Kenneth Rothman, Dr.P.H., Professor of Family and Community Medicine, University of Massachusetts Medical School, Worcester, Massachusetts David Schottenfeld, M.D., Chief, Division of Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, New York Steven R. Tmnenbaum, Ph.D., Professor of Toxicology and Food Chemistry, Department of Applied Biological Sciences, Massachu- setts Institute of Technology, Cambridge, Massachusetts David B. Thomas, M.D., Dr. PH., Head Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington Non-Cancer Od Effects Arden G. Christen, D.D.S., M.S.D., M.A., Chairman, Department of Preventive Dentistry, Indiana University Dental School, Indianapo lis, Indiana Stephen B. Corbin, D.D.S., M.P.H., Chief, Dental Disease Prevention Activity, Center for Preventive Services, Centers for Disease Control, Rockville, Maryland Robert 0. Greer, Jr., D.D.S., Sc.D., Professor, Division of Oral Pathol- ogy and Oncology, University of Colorado Health Sciences Center, Denver, Colorado Lireka P. Joseph, Dr.P.H., Medical Radiation Specialist, Food and Drug Administration, Rockvihe, Maryland Stephen S. Kegeles, Ph.D., Professor, Department of Behavioral Sci- ences and Community Health, University of Connecticut Health Center, Farmington, Connecticut Matthew Kinnard, Ph.D., Health Science Administrator, Periodontal and Soft Tissue Diseases Research Branch, National Institute of Dental Research, Bethesda, Maryland Dushanka Kleinman, D.D.S., M.Sc.D., Special Assistant to the Asso ciate Director for Program Coordination, Epidemiology and Oral Disease Prevention Program, National Institute of Dental Research, Bethesda, Maryland X Robert Mecklenburg, D.D.S., M.P.H. (Coordinator), Assistant Surgeon General, Chief Dental Officer, United States Public Health Service, Rmkdle, Maryland Kathleen L. Schroeder, D.D.S., M.S., Assistant Professor, Department of Oral Biology, Ohio State University College of Dentistry, Columbus, Ohio Addiction and Dependence Catherine S. Bell, M.S. (Coordinator), Acting Chief, Prevention Re search Branch Division of Clinical Research, National Institute on Drug Abuse, RockviRe, Maryland Neal Benowitz, M.D., Associate Professor of Medicine, Chief of Clinical Pharmacology and Experimental Therapeutics, University of Cali- fornia, San Francisco, california Anthony Biglan, Ph.D., Research Scientist, Oregon Research Institute, Eugene, Oregon John Grabowski, Ph.D., Associate Professor, Department of Psychiatry, School of Medicine, Louisiana State University, Shreveport, Louisiana Steven Gust, Ph.D., Reseaxh Associate, Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota Jack Hennmgfield, PhD., Chief, Biology of Dependence and Abuse Potential Assessment Laboratory, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Lynn Kozlowski, PhD., Senior Scientist, The Smoking Research Pro gram, Addiction Reseamh Foundation, Toronto, Ontario, Canada Norman A. Krasnegor, PhD., Chief, Human Learning and Behavioral Branch, Center for Research for Mothers and Children, National Institute for Child Health and Human Development, Bethesda, Maryland Ovide Pomerleau, PhD., Chief of Psychology Service, Veterans Admin- istration Medical Center, Newington, Connecticut The following individuals prepared draft chapters or portions of the report as indicated: Chapter I. Prevalence and Fends of Smokeless lbbacco Use in the United States Gayle Boyd, PhD., Research Psychologist, Division of Cancer Preven- tion and Control, National Cancer Institute, Silver Spring, Maryland Rebecca Cline, PhD., Senior Associate, Prospect Associates, Rockille, Maryland Charles Darby, M.A., `Ikhnical`Support Staff Coordinator for Addic- tion and Dependence Experts, Senior Associate, Prospect Associates, RmkvilIe, Maryland Margaret Mattson, Ph.D., Special Assistant for Science, Office of the Director, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland Chapter II. Carcirwgenesis Associated With Smokeless Tbbacco Use William Blot, Ph.D., Chief, Biostatistics Branch, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland Virginia L. Ems&, Ph.D., Associate Professor of Epidemiology, University of California, San Francisco, California Curtis Harris, M.D., Chief, Laboratory of Human Carcinogenesis, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland Stephen S. Hecht, Ph.D., Division of Chemical Carcinogenesis, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York Dietrich Hoffmann, Ph.D., Associate Director, Chemistry and Bio chemistry, Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York Kenneth Rothman, Dr.P.H., Professor of Family and Community Medi- cine, University of Massachusetts Medical School, Worcester, Massachusetts David Schottenfeld, M.D., Chief, Division of Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, New York Steven R. Xannenbaum, PhD., Professor of Tbxicology and Food Chemistry, Department of Applied Biological Sciences, Massachu- setts Institute of %chnology, Cambridge, Massachusetts David B. Thomas, M.D., Dr.P.H., Head, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, Washington Deborah M. Winn, Ph.D., Epidemiologist, Survey Planning and Devel- opment Branch National Center for Health Statistics, Hyattsville, Maryland Chapter III. Noncancerous and Precancerous Oral Health Effects Associated With Smokeless llbbacco Use Stephen B. Corbin, D.D.S., M.P.H., Chief, Dental Disease Prevention Activity, Center for Preventive Services, Centers for Disease Control, RmkvilIe, Maryland Lireka I? Joseph, Dr.P.H., Medical Radiation Specialist, Food and Drug Administration, Rockvihe, Maryland Dushanka Kleimnan, D.D.S., M.Sc.D., Special Assistant to the Asso ciate Director for Program Coordination, Epidemiology and Oral Disease Prevention Program, National Institute of Dental Research, Bethesda, Maryland Chapter IV. Nicotine Exposure: Pharmacokinetics, Addiction, and Other Physiologic Effects Neal Benowitz, M.D., Associate Professor of Medicine, Chief of Clinical Pharmacology and Experimental Therapeutics, University of Cali- fornia, San Francisco, California Anthony Biglan, PhD., Research Scientist, Oregon Research Institute, Eugene, Oregon xii Jack Henningfield, Ph.D., Chief, Biology of Dependence and Abuse Potential Assessment Laboratory, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Margaret Mattson, PhD., Special Assistant for Science, Office of the Director, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland The Advisory Committee and authors acknowledge with gratitude the following distinguished scientists, physicians, and others who lent their support in the development of this report by contributing critical reviews of the manuscript or assisting in other ways: John Bailar, M.D., Ph.D., Lecturer, Department of Biostatistics, Har- vard School of Public Health, Boston, Massachusetts Enriqueta C. Bond, PhD., Director, Division of Health Promotion and Disease Prevention, Institute of Medicine, Washington, D.C. Lester Breslow, M.D., M.P.H., Professor Emeritus, School of Public Health, University of California, Los Angeles, California David M. Burns, M.D., Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Diego Medical Center, San Diego, California Greg Connolly, D.M.D., M.P.H., Director, Division of Dental Health, Massachusetts Department of Public Health Boston Massachusetts D. Layten Davis, PhD., Director, University of Kentucky, Ylbbacco and Health Research Institute, Lexington, Kentucky Miriam Davis, PhD., Program Analyst, Office of Health Planning and Evaluation, Office of the Assistant Secretary for Health, Washing- ton, D.C. Vincent T. DeVita, Jr., M.D., Director, National Cancer Institute, Bethesda, Maryland Joseph F. Fraumeni, Jr., M.D., Associate Director for Epidemiology and Biostatistics, Division of Cancer Etiology, National Cancer Insti- tute, Bethesda, Maryland Thomas J. Glynn, PhD., Program Director for Smoking Research, Division of Cancer Prevention and Control, National Cancer Insti- tute, Bethesda, Maryland Peter Greenwald, M.D., Dr.P.H., Director, Division of Cancer Preven- tion and Control, National Cancer Institute, Bethesda, Maryland Ellen R. Grits, PhD., Director, Division of Cancer Control, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, Cahfornia Dianne G. Lindewall, Ph.D., Program Analyst, Office of Health Plan- ning and Evaluation, Office of the Assistant Secretary for Health, Washington, D.C. Marilyn M. Massey, M.P.H., `Ikchnical Support Staff Coordinator for the Advisory Committee, Senior Associate, Prospect Associates, lbdwille, Maryland . . . XlJl Gardner C. McMillan, M.D., Associate Director for Etiology, Arterio sclerosis, and Hypertension, National Heart, Lung, and Blood Insti- tute, Bethesda, Maryland Jens J. Pindborg, D.D.S., Dr. Odont., Professor of Oral Pathology, Royal Dental College, Copenhagen Panum Institute, Copenhagen Denmark John M. Pinney, Executive Director, Institute for the Study of Smoking Behavior and Policy, John F. Kennedy School of Government, Har- vard University, Cambridge, Massachusetts Earl S. Polk&, Sc.D., President, Pollack Associates Ltd., Bethesda, Maryland Richard J. Riseberg, Chief Counsel United States Public Health Ser- vice, Rochille, Maryland Thomas L. Robertson, M.D., Chief, Cardiac Diseases Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland Beatrice A. Rouse, PhD., Epidemiologist, Division of Epidemiology and Statistical Analysis, National Institute on Drug Abuse, Rock- vilIe, Maryland Donald R. Shopland, Acting Director, Office on Smoking and Health, United States Public Health Service, Rockvile, Maryland Sol Silverman Jr., M.A., D.D.S., Professor and Chairman of Oral Medi- cine, University of California, San Francisco, California Chester Slaughter, M.A., Deputy Regional Inspector General for Analy- sis and Inspections, Office of the Inspector General DaIlas, Texas K. W. Stephen, D.D.Sc., H.D.D.R.C.P.S., Head of Oral Medicine and Pathology, University of Glasgow, Glasgow, Scotland Ronald W. Wilson, M.A., Director, Division of Epidemiology and Health Promotion, National Center for Health Statistics, Hyattsville, Maryland Ernst L. Wynder, M.D., President, American Health Foundation, New York, New York Mar& Zitans, M.&z., Program Analyst, Office of the Inspector General Washington, D.C. The Advisory Committee and authors also acknowledge several organizations for their contributions in identifying relevant literature and/or in offering critical reviews of the manuscript. Institute of Medicine, National Academy of Sciences, for providing through its Board on Health Promotion and Disease Prevention a cri- tique of the Advisory Committee's review methods and drafts of the report. International Agency for Research on Cancer (IARC), Lyon, France, for providing IARC Monograph No. 37 on the Evaluation of the Carcino genie Risk of Chemicals to Humans: Tobacco Habits Other Than Smoking Betel-Quid and Areca-Nut Chewing and Some Related Nitrosammes, September 1985. National Center for Health Statistics and National Institute on Drug Abuse, for providing data on the prevalence and trends of smokeless tobacco use in the United States. Office on Smoking and Health, for bibliographic citations and other documents pertinent to the literature review. Smokeless Tobacco Council, Inc. (Michael J. Kerrigan, President), for providing approximately 15,000 citations considered relevant by a number of the smokeless tobacco companies, including the collection of testimonies representing the smokeless tobacco industry's position concerning the health consequences of smokeless tobacco. The Advisory Committee and authors also acknowledge the contribu- tions of the following staff members and others who assisted in the preparation of the report: Kathy Bauman, Editorial Assistant to the Deputy Director, Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland Julie Begtm, Research Assistant, Prospect Associates, Rockville, Maryland Barbara Clark, M.S., M.P.H., Technical Support Staff Coordinator for Non-Cancer Oral Effects Experts, Prospect Associates, Rockvihe, Maryland Shelley Clark, Conference Coordinator, Prospect Associates, Rockvihe, Maryland Nancy Cowan Conference Coordinator, Prospect Associates, Rockvihe, Maryland Kathleen Edmunds, Library Besearch Assistant, Prospect Associates, RockviUe, Maryland Robyn Ertwine, Librarian-Information Specialist, Prospect Associates, RockviNe, Maryland Catherine Fisher, Secretary, Prospect Associates, Rockvihe, Maryland Barbara Hayden, Secretary, Prospect Associates, Rockvihe, Maryland Douglas Hunter, Library Assistant, Prospect Associates, Kockvihe, Maryland Karen Jacob, Editor, Prospect Associates, Rockvihe, Maryland Margaret Johnson, `Typist, Prospect Associates, Rockville, Maryland Mary Johnson, Typist, Prospect Associates, Rockvihe, Maryland Virginia Knill, Typist, Prospect Associates, RockviIle, Maryland Solomon Levy, M.P.H., Associate Director, Office of the Surgeon General, Rockvihe, Maryland Paula Margus, Library Research Assistant, Prospect Associates, Rock- ville, Maryland Nancy McCormick-Picket& M.A., %&nicsl Support Staff Coordinator for Carcinogenesis Experts, Prospect Associates, Rockvihe, Maryland Lee McPherson, Typist, Prospect Associates, Rockvihe, Maryland xv Robbie Morsel&, Library Assistant, Prospect Associates, Rockville, Maryland Elizabeth Mugge, Secretary to the Deputy Director of the Division of Cancer Prevention and Control, National Cancer Institute, Bethesda, Maryland Arthur Nelson, Library Research Assistant, Prospect Associates, Fhkville, Maryland Ro NemethCoslett, Ph.D., Visiting Scientist, Biology of Dependence and Abuse Potential Assessment Laboratory, Addiction Research Center, National Institute on Drug Abuse, Baltimore, Maryland Simon Plog, l)pist, Prospect Associates, Rockvihe, Maryland Nancy Rudner, M.S.N., M.P.H., 7hchnicaI Support Staff Assistant, Prospect Associates, Rockvihe, Maryland Estelle Schwalb, `Ilxhnical Writer-Editor, Prospect Associates, Rock- ville, Maryland Barbara Shapiro, Editor, Prospect Associates, Rockville, Maryland John Shea, Ph.D., Technical Writer-Editor, Prospect Associates, Rock- ville, Maryland Dorritt Silber, Secretary, Prospect Associates, Rockvihe, Maryland Dori Steele, Proofreader, Prospect Associates, Rockville, Maryland Deborah S. Swansburg, Program Officer, Institute of Medicine, National Academy of Sciences, Washington, D.C. Xvi INTFlODlJC'TlON, OVERVIEW, AND CONCLUSIONS DEVELOPMENT AND ORGANIZATION OF THE REPORT This report from the Surgeon General's Advisory Committee on the Health Consequences of Using Smokeless Tobacco represents the first comprehensive assessment of the biomedical and behavioral literature describing experimental and human evidence on the health conse quences of using smokeless tobacco. The content of this report is the work of numerous experts within the Department of Health and Human Services as well as distinguished scientists outside the organization. Each chapter of the report was prepared based on manuscripts writ- ten by scientists who are recognized for their understanding of the spe cific content areas. Manuscripts were subjected to extensive peer review by a large number of experts in the specific areas of interest. The report includes a "Preface" that presents the essence of the entire report and an "Introduction, Overview, and Conclusions." The body of the report consists of the following four chapters: o Chapter l-Prevalence and Trends of Smokeless Tobacco Use in the United States o Chapter 2-Carcinogenesis Associated With Smokeless ?bbacco Use o Chapter 3-Noncancerous and Precancerous Oral Health Effects Associated With Smokeless Tobacco Use o Chapter 4-Nicotine Exposure: Pharmacokinetics, Addiction, and Other Physiologic Effects HJSTORICAL PERSPECTIVE The use of smokeless tobacco is a worldwide practice with numerous variations in the nature of the product used as well as in the customs associated with its use. In the United States, smokeless tobacco con- sists of chewing tobacco and snuff. The predo minant mode of use of these nonsmoked tobaccos is oral, although they may be placed in or inhaled into the nasal cavity. Tobacco sniffing, however, has been and remains a rare practice in the United States. Xvii Smokeless tobacco was used in the United States in the early 1600's when snuff made its way to the Jamestown Colony in Virginia through the efforts of John RoIfe in 1611(l). Evidence of tobacco chewing, how- ever, was not found until a century later in 1704 (2). The use of tobacco, including smokeless tobacco, has been controver- sial since its introduction. In the past, tobacco use was considered by some as beneficial As early as 3500 B.C., there are indications that tobacco was an article of established value to the inhabitants of Mexico and Peru. It appears that people who frequently Iacked sufficient food alleviated their hunger pains by chewing tobacco (3). Smokeless tobacco was also thought to have several medicinal uses. Among Native Ameri- cans, for example, chewing tobacco was used to alleviate toothaches, disinfect cuts, and relieve the effects of snake, spider, and insect bites (4). Moreover, during the 19th and early 20th centuries in America, dental snuff was advertised to relieve toothache pain; to cure neuralgia, bleed- ing gums, and scurvy; and to preserve and whiten teeth and prevent decay (1). On the other hand, tobacco use historically has had numerous adver- saries, inchiding the following (1): o In 1590 in Japan tobacco was prohibited. Users lost their property and were jaiIed o King James VI of Scotland in the early 1600's was a strong anti- smoking advocate who increased taxes on tobacco 4,000 percent in an attempt to reduce the quantity imported to England. o In 1633, the Sultan Murad IV of Turkey made any use of tobacco a capital offense, punishable by death from hanging, beheading, or starvation. He maintained that tobacco caused infertility and reduced the fighting capabilities of his soldiers. o The Russian Czar Michael Fedorovich, the first Romanov (1613-1645). prohibited the sale of tobacco, stating that users would be subjected to physical punishment and that persistent users would be killed. o A Chinese law in 1683 threatened that anyone possessing tobacco would be beheaded. o During the mid-1600's, Pope Urban VIII banned the use of snuff in churches, and Pope Innocent X attacked its use by priests in the Catholic Church. o Other religious groups also banned snuff use: John Wesley, the founder of Methodism, attacked its use in Ireland; the Mormons, Seventh-Day Adventists, Parsees and Sikhs of India, Buddhist monks of Korea, members of the Isai Li sect of China, and some Ethiopian Christian sects forbade the use of tobacco. . . . XVIU o Frederick the Great, King of Prussia, prevented his mother, the Dowager Queen of Prussia, from using snuff at his coronation in 1790. o Louis XV, ruler of France from 1723 to 1774, banned snuff use from the Court of France. Scientific observations concerning the health effects of smokeless tobacco use were first noted in 1761 by John Hill, a London physician and botanist who reported five cases of polypuses, a "swelling in the nostril that was hard, black and adherent with the symptoms of an open cancer" (5). He concluded that nasal cancer could develop as a conse quence of tobacco snuff use (sniffing). Evidence that suggested a possible association between smokeless tobacco use and oral conditions in North America and Europe was not reported until 1915 when Abbe identified several tobacco chewers among a series of oral cancer patients and commented that smokeless tobacco use may be a risk factor for this cancer (6). In the late 1930's. Ahblom observed in Sweden that more patients with buccal, gingival, and `mandibular" cancers than with other cancers reported the use of snuff or chewing tobacco (?L In the United States, case reports of oral cancer among users of snuff or chewing tobacco appeared in the early 1940's (8). The first epidemiologic study of smokeless tobacco was not conducted until the early 1950's (9). Since that time, several scientists have described a pattern of increased risk of oral cancer among smoke less tobacco users. Investigations of other possible health effects of smokeless tobacco use (e.g., noncancerous oral effects, addiction, and other physiologic consequences) are more recent subjects of scientific inquiry that have been undertaken primarily in the past two decades. A brief review of the health consequences of smokeless tobacco was pre sented in the 1979 Surgeon General's report on smoking and health (10). Since that review, the results of additional studies addressing the role of smokeless tobacco in health have become available and thus provide the basis of this current comprehensive review. REVIEW METHODS For the purpose of evaluating the scientific evidence to be included in this report, the Advisory Committee called upon the same criteria to determine causality as have been used for a number of Surgeon General's reports on smoking for the past two decades. The following criteria were used as the primary guidelines for assessing whether any associations between smokeless tobacco use and each of the disease areas or health conditions under e xamination were likely to be causal in Mtwe: xix o Consistency of the association-similar observations by multiple investigators in different locations and situations, at different times, and using different methods of study. o Strength of the association-high ratio of disease rate for thepopu- lation exposed to the suspected risk factor compared to the popula- tion unexposed to the risk factor. o Specificity of the association-associations with the exposure exist for a specific or limited set of diseases, and associations with the disease exist for a specific or limited set of exposures. o Temporal relationship of the association-exposure to the suspected etiologic factor precedes the disease. o Coherence of the association-epidemiologic observations are con- sonant with all else that is known about the disease. In addition to these criteria, the general principles employed by the International Agency for Resear& on Cancer (IARC)* in evaluating the carcinogenic risk of chemicals or complex mixtures (table 1) were used as needed to supplement the primary causation criteria (11). The use of smokeless tobacco products in the United States was wide spread until the end of the 19th century. With the advent of antispitting laws, loss of social acceptability, and increased popularity of cigarette smoking, its use declined rapidly in this century. However, recent na- tional data indicate a resurgence in smokeless tobacco habits with more than 12 million persons estimated as users of some form of smokeless tobacco in 1985. An upward trend in use is emerging, particularly among young males. Given the evidence that smokeless tobacco is regaining popularity, serious questions have been raised about its adverse health effects. Most notably, this behavior has been linked to cancer, specifically, oral cancer. Analytic epidemiologic studies now indicate that the use of oral snuff increases the risk of oral cancer several fold and that among long- term snuff dippers the excess risk of cancers of the cheek and gum may reach nearly fiftyfold. This conclusion is consistent with the judgment of a recent working group of the IARC, which assessed the carcinogenic risk associated with tobacco habits other than smoking (11). The conclusion that smokeless tobacco causes cancer results from several lines of evidence: the presence of high levels of carcinogens in smokeless tobacco; the metabolic conversion of products of smokeless * The IARC was established in 1965 b within the framework of the World Hea i the World Health Assembly as an inde th Organization. It conducts a program o P K ndentl financed organization researc concentrating particu- larly on the epidemiology of cancer and the study of potential carcinogens in the human environment. xx TABLE L-General F'rinciples in Evaluting Carcinogenic Risk of Chemicals or Complex Mixture8 (Intemational Agency for R.4wal& on Cancer) o Evidence for carcinogenicity in experimental animals: - Qualitative aspects: (a) Experimental parameters under which chemical was tested. (b)Consistency with which chemical shown to be ?????*???*??? (12) Spectrum of neoplastic response. (d) Stage of tumor formation in which chemical involved. (e) Role of modifying factors. - Hormonal carcinogenesis. - Complex mixtures. - Quantitative aspects; increasing incidence of neoplasms with increasing exposure. o Evidence for activity in short-term tests: - Use of valid test system. - Sufficiently wide dose range and duration of exposure to the agent and appropriate metabolic system employed in test. - Use of appropriate controls. - Specification of the purity of the compound, and in the case of complex mixtures, source and representativeness of sample tested. o Evidence of carcinogenicity in humans: - For studies showing positive association: (a) Existence of no identifiable bias. (b) Possibility of positive confounding considered. (c) Association unlikely to be due to chance alone. (d) Association is strong. (e) Existence of dose-response relationship. - For studies showing no association: (a) Existence of no identifiable negative bias. (b) Possibility of negative wnfounding considered. (c) Possible effects of misclassification of exposure or outcome have been ???????? tobacco into genotoxic agents; the consistency of the oral cancer- smokeless tobacco association across epidemiologic investigations con- ducted in diverse locations; the trend in increasiq oral cancer risk with duration of exposure; the strength of the association with oral cancer and the occurrence of the highest risks for cancers at the anatomic sites where the tobacco expoams are the greatest. In addition, a number of clinical observations and studies show an association between smokeless tobacco use and some noncancerous and precancerous oral health conditions. The development of a portion of oral leukoplakias in both teenage and adult users can be attributed to the use of smokeless tobacco. The risk of developing these leukoplakic lesions increases with increased exposure, and a number of studies now suggest that some snuff-induced leukoplakias can undergo transforma- tion to dysplasia and further to carcinoma. The evidence concerning the adverse health effects of smokeless tobacco use on other oral soft and hard tissues is only suggestive at this time. The magnitude of blood nicotine levels resulting from smokeless tobacco use has been shown to be similar to that from cigarette smok- ing. Therefore, the nicotinerelated health consequences of smoking would also be expected to result from smokeless tobacco use. Given the nicotine content of smokeless tobacco, the user's ability to sustain elevated blood levels of nicotine, and the wellestablished data implicat- ing nicotine as an addictive substance, it is reasonable to expect that smokeless tobacco is capable of producing nicotine addiction in users. There is also some suggestive evidence that nicotine may play a con- tributory or supportive role in the development of coronary artery and peripheral vascular disease, hypertension, peptic ulcer disease, and fetal mortality and morbidity. The conclusions in this report on the relationship between smokeless tobacco use and cancer, noncancerous and precancerous oral conditions, and addiction and dependence are substantially in agreement with those published at a recent National Institutes of Health (NIH) Consen- sus Development Conference on the Health Implications of Smokeless TRhacco use (12). CONCLUSIONS Prevalence and Trends of Smokeless Tobacco Use in the United States 1. Recent national data indicate that over 12 million persons used some form of smokeless tobacco (chewing tobacco and snuff) in 1985 and that approximately 6 million used smokeless tobacco weekly or more often. Use is increasing, particularly among young males. 2. The highest rates of use are seen among teenage and young adult males. A recent national survey indicates that 16 percent of males between 12 and 25 years of age have used some form of smokeless tobacco within the past year and that from onethird to onehalf of these used smokeless tobacco at least once a week. Use by females of all ages is consistently less than that of males; about 2 percent have used smokeless tobacco in the last year. 3. State and local studies corroborate the national survey findings. The prevalence of smokeless tobacco use by youth and young adults varies widely by region, but use is not limited to a single re gion. In several parts of the country, as many as 25 to 35 percent of adolescent males have indicated cnrrent use of smokelees tobacco. xxii Carcinogenesis Associated With Smokeless Tobacco Use 1. The scientific evidence is strong that the use of smokeless tobacco can cause cancer in humans. The association between smokeless tobacco use and cancer is strongest for cancers of the oral cavity. 2. Oral cancer has been shown to occur several times more fre- quently among snuff dippers than among nontobacco users, and the excess risk of cancers of the cheek and gum may reach nearly fiftyfold among long-term snuff users. 3. Some investigations suggest that the use of chewing tobacco also may increase the risk of oral cancer. 4. Evidence for an association between smokeless tobacco use and cancers outside of the oral cavity in humans is sparse. Some investigations suggest that smokeless tobacco users may face in- creased risks of tumors of the upper aerodigestive tract, but results are currently inconclusive. 5. Experimental investigations have revealed potent carcinogens in snuff and chewing tobacco. These include nitrosamines, poly- cyclic aromatic hydrocarbons, and radiation-emitting polonium The tobacco-specific nitrosamines N-nitrosonornicotine and 4-(methylnitrosamino)-l-(3-pyridyl)-1-butanone have been detected in smokeless tobacco at levels 100 times higher than the regulated levels of other nitrosamines found in bacon, beer, and other foods. Animals exposed to these tobacco-specific nitro samines, at levels approximating those thought to be accumu- lated during a human lifetime by daily smokeless tobacco users, have developed an excess of a variety of tumors. The nitro samines can be metabolized by target tissues to compounds that can modify cellular genetic material. 6. Bioassays exposing animals to smokeless tobacco, however, have generally shown little or no increased tumor production, although some bioassays suggest that snuff may cause oral tumors when testsd in animals that are infected with herpes simplex virus. Noncancerous and Precancerous Oral Health Effects Associated With Smokeless Tobacco Use 1. Smokeless tobacco use is responsible for the development of a por- tion of oral leukoplakias in both teenage and adult users. The degree to which the use of smokeless tobacco affects the oral hard and soft tissues is variable depending on the site of action, type of smokeless tobacco product used, frequency and duration of use, predisposing factors, cofactors (such as smoking or concomitant gingival disease), and other factors not yet determined. . . . xxm 2. Dose response effects have been noted by a number of investiga- tors. Longer use of smokeless tobacco results in a higher preva- lence of leukoplakic lesions. Oral leukoplakias are commonly found at the site of tobacco placement. 3. Some snuff-induced oral leukoplakic lesions have been noted upon continued smokeless tobacco use to undergo transforma- tion to a dysplastic state. A portion of these dysplastic lesions can further develop into carcinomas of either a verrucous or squamous cell variety. 4. Recent studies of the effects of smokeless tobacco use on gingival and periodontal tissues have resulted in equivocal findings. While gingival recession is a common outcome from use, gingivitis may or may not occur. Because longitudinal data are not available, the role of smokeless tobacco in the development and progression of gingivitis or periodontitis has not been confirmed. 5. The evidence concerning the effects of smokeless tobacco use on the salivary glands is inconclusive. 6. Negative health effects on the teeth from smokeless tobacco use are suspected but unconfirmed. Present evidence, albeit sparse, suggests that the combination of smokeless tobacco use in individ- uals with existing gingivitis may increase the prevalence of dental caries compared with nonusers without concomitant gingivitis. Reports of tooth abrasion or staining have not been substantiated through controlled studies; only case reports are available. Nicotine Exposure: Pharmacokinetics, Addiction, and Other Physiologic Effects 1. The use of smokeless tobacco products can lead to nicotine depen- dence or addiction. 2. An examination of the pharmacokinetics of nicotine (i.e., nicotine absorption, distribution, and elimination) resulting from smoking and smokeless tobacco use indicates that the magnitude of nico- tine exposure is similar for both. 3. Despite the complexities of tobacco smoke self-administration, systematic analysis has confirmed that the resulting addiction is similar to that produced and maintained by other addictive drugs in both humans and animals. Animals can learn to discriminate nicotine from other substances because of its effects on the cen- tral nervous system. These effects are related to the dose and rate of administration, as is also the case with other drugs of abuse. 4. It has been shown that nicotine functions as a reinforcer under a variety of conditions. It has been confirmed that nicotine can xxiv function in all of the capacities that characterize a drug with a liability to widespread abuse. Additionally, as is the case with most other drugs of abuse, nicotine produces effects in the user that are considered desirable to the user. These effects are caused by the nicotine and not simply by the vehicle of delivery (tobacco or tobacco smoke). 5. Nicotine is similar in all critical measures to prototypic drugs of abuse such as morphine and cocaine. The methods and criteria used to establish these similarities are identical to those used for other drugs suspected of having the potential to produce abuse and physiologic dependence. Specifically, nicotine is psychoactive, producing transient dose-related changes in mood and feeling. It is a euphoriant that produces doserelated increases in scores on standard measures of euphoria. It is a reinforcer (or reward) in both human and animal intravenous self-administration para- digms, functioning as do other drugs of abuse. Additionally, nice tine through smoking produces the same effects, and it causes neuroadaptation leading to tolerance and physiologic depen- dence. Taken together, these results confirm the hypothesis that the role of nicotine in the compulsive use of tobacco is the same as the role of morphine in the compulsive use of opium derivatives or of cocaine in the compulsive use of coca derivatives. 6. The evidence that smokeless tobacco is addicting includes the pharmacologic role of nicotine dose in regulating tobacco intake; the commonalities between nicotine and other prototypic dependenceproducing substances; the abuse liability and depen- dence potential of nicotine; and the direct, albeit limited at present, evidence that orally delivered nicotine retains the characteristics of an addictive drug. 7. Several other characteristics of tobacco products in general, in- cluding smokeless tobacco, may function to enhance further the number of persons who are afflicted by nicotine dependence: nicotinedelivering products are widely available and relatively inexpensive; and the self-administration of such products is legal, relatively well tolerated by society, and produces minimal d&-up- tion to cognitive and behavioral performance. Nicotine produces a variety of individual-specific therapeutic actions such as mood and performance enhancement; and the brief effects of nicotine ensure that conditioning occurs, because the behavior is associ- ated with numerous concomitant environmental stimuli. 8. All commonly marketed and consumed smokeless tobacco prod- ucts contain substantial quantities of nicotine. The nicotine is delivered to the central nervous system in addicting quantities when used in the fashion that each form is commonly used (or as recommended in smokeless tobacco marketing campaigns). XXV 9. Since the exposure to nicotine from smokeless tobacco is similar in magnitude to nicotine exposure from cigarette smoking, the health coIlSequences of smoking that are caused by nicotine also would be expected to be hazards of smokeless tobacco use. Areas of particular concern in which nicotine may play a contributory or supportive role in the pathogenesis of disease include coronary artery and peripheral vascular disease, hypertension, peptic ulcer disease, and fetal mortality and morbidity. REFERENCES (1) Christen, A.G., Swanson, B.Z., Glover, E.D., and Henderson, A.H. Smokeless tobacco: The folkIore and social history of snuffing, sneez- ing, dipping, and chewing. J. Am. Dent. Assoc. 105: 821829, 1982. (2) Gottsegen, J.J. Tobacco. A Study of Its Consumption in the United States. New York, Pitman, 1940, p. 3. (3) Voges, E. The pleasures of tobacco-How it ah began and the whole story. Tobacco J. Int. 1: 80-82, 1984. (4) Axton, W.F. Tobacco and Kentucky. Lexington, University Press of Kentucky, 1975, pp. 8, 25, 58-59. (5) Redmond, D.E. Tobacco and cancer: The first clinical report, 1761. N. Engl. J. Med. 282: 18-23, 1970. (6) Abbe, R. Cancer of the mouth. New York Med. J. 102: l-2,1915. (7) Ahblom, H.E. Predisposing factors for epitheliomas of the oral cavity, larynx, pharynx, and esophagus. Acta Radial. 18: 163-185, 1937 (in Swedish). (8) FriedeII, H.L.. and Rosenthal, L.M. The etiologic role of chewing tobacco in cancer of the mouth. JAMA 116: 2130-2135, 1941. (9) Moore, G.E., Bissinger, L.L., and ProehI, E.C. Tobacco and intraoral cancer. Surg. Forum 3: 685-688, 1952. (10) U.S. Public Health Service. Smoking and Health. A Report of the Surgeon General. Department of Health, Education, and Welfare, Public Health Service, Office of the Assistant Secretary for Health, Of- fice on Smoking and Health (DHEW Publication No. PHS 79-50066). Washington, D.C.. U.S. Government Printing Office, 1979, pp. 13-38 to 13-41. (11) International Agency for Research on Cancer. Tobacco habits other than smoking: Betel-quid and areca-nut chewing and some related nitrosamines. IARC Monogr. 37: 291,1985. (12) National Institutes of Health. Consensus Development Conference Statement on the Health Implications of Smokeless Tobacco Use, January 13-15, 1986. xxvi Chapter 1. PREVALENCE AND TRENDS OF SMOKELESS TOBACCO USE IN THE UNED STATES CONTENTS Introduction ..................................... ...5 Product Characteristics. .............................. .5 l'kendsinProductionandSaIes ......................... .5 Categories of Products ............................ .7 Tbmporallkends ............................... ...7 PendsinSeIf-ReportedUse: SurveyData. ............... .7 National Survey Data ............................. .7 StateandLocaISurveyData ...................... .15 Conclusions........... . ..24 ResearchNeeds.....................................25 References.........................................26 3 INTRODUCTION This chapter defines the various forms of smokeless tobacco that are used in the United States and e xamines the data that pertain to trends in prevalence and patterns of use. ?kends in smokeless tobacco produc- tion and sales and self-reported use are considered. Methodological con- siderations are discussed and research needs are identified. Tobacco was used by pre-Columbian American Indians in smokeless forms as well as smoked (1). Cultivated by American colonists, tobacco became a major commodity in trade with Europe. Until the end of the 19th century, the use of smokeless tobacco products was widespread in the United States. Its use declined rapidly in this century with the advent of antispitting laws, loss of social acceptability, and increased popularity of cigarette smoking (1,2). Use was primarily confined to rutd and agricultural areas and to occupational settings where smok- ing was not aIlowed, such as mining and some industries (3,4). In the Southeastern United States, especially in rural areas, oral use of dry snuff remained pop&r among women (5,6). PRODUCT CHARACTERISTICS T&lay, smokeless tobacco is produced in two general forms: chewing tobacco and snuff (7-10). Chewing tobacco is chewed or held in the cheek or lower lip. Three primary types of chewing tobacco are marketed: looseleaf, plug, and twist. Snuff has a much finer consistency than chewing tobacco and is held in place in the mouth without chewing. It is marketed in both dry and moist forms. Although smokeless tobacco is not subject to combustion and is usually used orally in the United States, products differ with regard to several factors, including type of tobacco plant used, parts of the tobacco plant used, method of curing, moisture content, and additives. For example, looseleaf chewing tobacco is made from aircured, cigar-type leaves from tobacco that is grown in Pennsylvania and Wisconsin In contrast, dry snuff is made primarily from firecured dark tobacco that is grown in Kentucky and `Ibnnessee. Plug tobacco and snuff come in dry and moist forms. Many smokeless tobacco products are sweetened with sugar or molasses. Many are flavored; licorice is a common additive for chewing tobacco, while mint and wintergreen often are used to flavor snuff. able 1 describes the types of smokeless tobacco and how they are used and packaged (7-101. TRENDS IN PRODUCTION AND SALES United States Department of Agriculture (USDA) records on the annual production and sales of smokeless tobacco serve as indicators of the population's consumption Changes in consumption can be inferred from changes in production and sales. Because sales figures closely resemble those for production, only production will be reported. 5 0.J TABLE l.-Characteristics of Smokeless Tobacco Products Product Description How used Packaging* Plug `I\vist CHEWING TOBACCO Made from airwred. cigar leal tobaccos of I'ennsylvan~a and Wisconsin. Consists 111 stripped and procrssed Lobacco leaves. The leaves are sttvnmtul. rut. or granulated and are loosely packed to form small strips of shredded tobacco. Most brands are sweetened and flavortxl with licorice. Made from enriched tobacco leaves (I~urlry and bright tobacco and cigar tobacco) or fragments wrapped in fine tobacco and pressed into bricks. May be firm (less than 15 percent moisture) or m&l (15 percent or greater moisture). Most plug tohacro is swwlened and flavored with licorice. Handmade of dark, air-cured leaf tobacco treated with a tarlike tobawo leaf extract and twisted into strands that are dried. Majority is sold without flavoring and sW~La"ars. A piece of tobacco. 314 Lo 1 inch in diameter, is tucked between the gum and jaw, usually Lo the back of the mouth. Pouch. typically 3 ounces. A few brands market a 1.5-ounce pouch. Chewed or held in the cheek or lower lip. May be held in the mouth for several hours. A compressed brick or flat block wrapped inside natural tobacco leaves. Packaged in clear plastic. Packages range from 7 Lo 13 ounces. Also sold by the piece. Similar to plug. A pliable but dry rope. Sold by the piece, packaged in plastic bags. No standard weight. Sold in small (approximately l-2 ounces) and larger sizes based on the number of leaves in the twist. SNUFF Moist Dry Made from air-cured and fire-cured tobacco. Consists of tobacco sLems and leaves that are processcld into fine par- ticks or strips. Some products are flavored. Has a moisture content of up to 50 percent. Most dry snuff is made from fire-curtd tobaccos of Ken- tucky and Tennessee. After initial curing. the tobacco is fermented further and processed into a dry powdered form. Products vary in strength and flavoring. tienerally has a moisture content of less than 10 percent. A small amount ("pinch") is placed between the lip or cheek and gum and is typically held for 30 minutes or longer per pinch. Same as moist snuff. May also be sniffed. Cans and plastic containers. typically 1.2 ounces. Metal cans or glass containers, vary from 1.15 to 7 ounces per container. * Product weight Iincludes moisture). Categories of Products The USDA reports production and sales by product category (i.e., chewing tobacco and snuff). The definitions of categories changed in 198 1. Prior to 198 1, total figures for chewing tobacco were derived by summing data for the subcategories of plug, twist, looseleaf, and fine cut; snuff was a separate category. However, finecut tobacco is used in moist snuff. `Ih reflect this fact, after 1981 USDA shifted fine-cut from the category of chewing tobacco to moist snuff. Tb observe and clarify temporal trends for the purposes of this review, the data presented in figure 1 reflect a uniform category system across years. In these records, finecut tobacco is counted consistently as snuff (11-17). Temporal Trends Figure 1 depicts temporal trends in the quantities of smokeless tobacco that were manufactured in the United States from 1961 to 1985. Be tween 1944 and 1968, total smokeless tobacco production declined 38.4 percent from 150.2 to 92.5 miI.Iion pounds. Subsequent increases in pro duction reached 135.6 rniIIion pounds in 1985. Between 1970 and 1985, total snuff production increased 56 percent from 31.3 to 48.7 million pounds. This increase was due to changes in the production of moist snuff; the manufacture of dry snuff dechned (3). The difference in trends in the production of moist and dry snuff is shown in figure 1 for the years 1981 through 1985. Separate production data are not available for the two types of snuff prior to 1981. Between 1970 and 1981, however, the production of finecut tobacco, used in the manufacture of some moist snuff, increased threefold from 4.8 to 15.2 miIIion pounds. Between 1970 and 1985, the production of chewing tobacco increased 36 percent from 63.9 to 86.9 miIIion pounds. This increase was due to the production of looseleaf tobacco, which increased 87.3 percent from 39.5 to 74.0 mihion pounds. The production of plug and twist tobacco declined during this period. National Survey Data National data from 1964 to 1985 are available from eight different na- tional probability surveys and a national survey of college students. The majority of the data pertain to persons over the age of 17. The prin- cipal characteristics of these surveys are shown in table 2. Office on Smoking and He&h Surveys Early data on the use of chewing tobacco and snuff are available from the 1964.1966.1970, and 1975 Adult Use of Tobacco Surveys that were FIGURE l.-Manufacturing lhdsz Quantities of Smokeless `Ibbacco Mamdactured in the United States From 1961 to 1985 Expressed in Million Pounds o ? ?? ?? ? ? ? TABLE 2.-National Prevalence of Smokeless Tobacco Use: Data Sources Number of survey * Date Respondents Respondents/ Households Products Questions Office on Smoking and Health Office on Smoking and Health Office on Smoking and Health Oifice on Smoking and Health National Health Interview Survey Supplement (National Center for Health Statistics) Simmons Study of Media Markets, Simmons Market Research Bureau, Inc. Simmons National College Study, Simmons Market Research Bureau, Inc Personal Interview Personal Interview Telephone `IbIephone Personal Interview Including Proxy Questionnaire Questionnaire Current Population Survey Personal Supplement-Census Bureau Interview for Office on Smoking I"chJdi"g and Health Proxy NIDA Household P~sO"Ed Survey Interview 1964 Adults L 21 5,794 1966 Adults L 21 Adults 2 21 Adults > 21 Persons 2 17 5,770 1970 5,200 1975 1970 12.000 77,ooo/ 37.ooo 1980 1981 1982 1983 1984 1985 1983 1985 Adults 2 18 15,ooo- 19,ooo Cdegs Students 2 18 2,011- 2,373 1985 Persons 1 16 12o.o00/ Snuff and Chewing 58,000 Tobacco Separately 1985 Persons > 12 8,ooO Snuff and Chewing Tbbacco Separately Snuff and Chewing Tobacco Separately Snuff and Chewing Tbbacco Separately Snuff and Chewing -Ibbacco separately Snuff and Chewing lbbacco Separately Snuff only Snuff only Snuff and "On the average. in the past 12 months, Chewing how often have you used chewing tobacco `Ibbacco Combined or snuff or other smokeless tobacco?" "Have you ever used-at aII regularly?" "Do you use-now?" "Have you ever used-at aII regularly?" "Do you use-now?" "Have you ever used-at all regularly?" "Do you use-now?" "Have you ever used-at alI regularly?" "Do you use-now?" Dol?S presently use any other form of smokeless tobacco, such as snuff or chewing tobacco? 1980 to 1983 "Do you use it yourself- snuff (smokeless tobacco)?" 1984 to 1985 "Do you yourself use any of the following tobacco products?" Snuff (ST) listed as an option. "Please mark which of the items listed below you yourself use." Snuff (smokeless tobacco) listed as a" option. Does presently use any other form of tobacco. such as snuff or chewing tobacco? What other forms of tobacco does presently use? TABLE 3.-Use of Smokeless Tobacco in the United States by Individuals Over 21 Years of Age* Percentage of Users Males Females Use Catesrw 1964 l!x6 1970 1975 1964 1966 1970 1915 Now Use Snuff 2.0 3.1 2.9 2.5 2.0 2.1 1.4 1.3 Used to Use Snuff 3.6 3.9 4.2 4.0 0.9 1.0 1.1 1.1 Have Ever Used Snuff t 5.7 7.2 7.1 6.4 2.9 3.1 2.6 2.4 Now Use Chewing Tobacco 5.1 7.1 5.6 4.9 0.5 0.4 0.6 0.6 Used to Use Chewing mbacco 12.0 13.2 19.1 16.1 1.0 1.1 1.8 1.2 Have Ever Used Chewing Tobaccot 17.2 20.5 24.7 21.0 1.5 1.5 2.4 1.8 * "Use" not further defined with respect to frequency. t Includes those who used to use. but did not state if they used it currently. Source: National Clearinghouse on Smoking and Health conducted by the National Clearinghouse for Smoking and Health, cur- rently the Office on Smoking and Health (OSH) (18-20). National prob ability samples of 5,700 to 12.000 individuals over the age of 21 from randomly selected households were interviewed by telephone regarding the use of tobacco products. Between 1964 and 1975, the prevalence of smokeless tobacco use remained fairly stable. Results are summ&zed in table 3. Three patterns in these data may be noted: o Less than 5 percent of the population reported using smokeless tobacco. o Nationally, use was higher among males than females. o Among males, the prevalence of use of chewing tobacco was higher than that for snuff. National Health Interview Survey In 1970, the National Center for Health Statistics included a question on current use of snuff and chewing tobacco in its National Health Interview Survey (NHIS) (21). One respondent per household provided information on alI household members age 17 and older. Data were col- lected on approximately 77,000 persons in 37,000 households. Esti- mates indicate that 1.4 percent of males used snuff and 3.8 percent used chewing tobacco (table 4). Simmons Market Research Bureau, Inc. National probability data that were coIIected annuaIIy from 1980 through 1985 for the Simmons Study of Media and Markets provide estimates of the prevalence of snuff use among adults who were 18 years of age or older. Sample size ranged from 15,000 to 19,000. Data are ed in table 5 for the years 1980 to 1985. The prevalence 10 TABLE 4.-Prevalence of the Use of Snuff and Chewing `lbbncco Among Malee by Age, 1970 NHIS and 1985 CPS Surveys* 1970 HIS 1985 CPS Product Snuff Chewing Tobacco Age 17-19 20-29 30-39 40-49 50+ Total 17-19 20-29 30-39 40-49 50+ lbtal Percentage of usf!m 0.3 0.6 0.7 1.2 2.7 1.4 1.2 1.9 2.8 3.0 6.5 3.8 Age 16-19 20-29 30-39 40-49 50+ ?btal 16-19 20-29 30-39 40-49 50+ mal Percentage of uaem 2.9 2.7 1.8 1.5 1.4 1.9 3.0 4.2 3.7 3.3 4.2 3.9 o "Use" *?? further defined with respect to frequency. Sources: National Center for Health Statistics. National Health Interview Survey, 1970 (unpublished). Office on SmoLing and Health, Current Population Survey. 1985 (unpubtiahedl. TABLE B.-National Prevalence of Current Use of Snuff by Gender, Age, and Race for 19&o Through 1985* Percentage of Ufsera Sample 1980 1961 1982 1963 1984 1985 Total 1.6 2.2 2.6 2.3 1.9 1.9 Gender Males Females 2.4 3.7 4.2 3.8 3.0 3.2 0.8 0.8 1.1 0.9 1.0 0.7 Ali!= 18-24 25-34 35-44 45-54 55-64 2 65 1.4 2.6 4.3 3.5 3.2 2.8 2.5 2.8 3.1 3.0 2.0 2.1 1.07 1.3 1.6 1.8 1.5 1.0 1.37 1.3 1.47 1.07 1.17 1.5 1.2t 1.7 1.7 2.3 1.1t 1.3 1.67 2.8 2.6 1.4 2.5 2.4 Race Black White Other 2.3t 1.6t 3.0 2.9 2.9 2.4 1.5 2.2 2.6 2.3 1.9 1.9 1.97 1.47 1.17 NA 0.4t 1.2 o Adults defined as individuals over 18 years of age. Use not further defined with respect to frequency. t Number of cases too small for reliable estimates. Source: Simmons Market Reaemch Bureau. Inc.. Study of ????? and Markets. 1980.1985. 11 TABLE 6.-Prevalence of Snuff Use Among College Students 18 Years of Age or Older by Gender and Year* Percentage of Users Sample 1983 1986 Total Gender Males Females Race Black White Other 2.7 3.5 5.4 6.7 0.17 0.2f 1.5t 1.4-f 5.1 3.6 4.97 4.37 o Current use; frequency of "se not specified. t Projection relatively unstable because of small sample. Source: Simmons Market Research Bureau, Inc.. Simmons National College Study, 1983 and 1985 rate for "current use" of snuff was 2.4 percent for males in 1980 and 0.8 percent for females. Rates for males peaked at 4.2 percent in 1982 and were 3.2 percent in 1985. Since 1982, the highest rates of use have con- sistently been observed in the age group 18 to 24 years old. Compara- tively higher rates of use were also observed in the age groups 25 to 34 years old and over age 65 (22. The Simmons National College Study reports data from a probability sample of full-time students 18 years or older who were attending baccalaureategranting colleges and universities in the coterminous United States. In 1983, 2,011 students were sampled, and 2,373 students were sampled in 1985. Five to 7 percent of males indicated use of snuff compared to 0.2 percent of females (table 6). The prevalence rate among male students exceeded that of the general adult male popula- tion (tables 5 and 6). In 1985, prevalence among college males was twice that of other adult males, while the rate for college women was less than onethird that among the general adult female population. The com- bined prevalence for male and female college students (3.5 percent) was very similar to that for 18- to 24yearolds in the general population (2.8 percent) (tables 5 and 6) (23). Current Population Survey In the fall of 1985, the Census Bureau collected health information on approximately 120,000 persons in 58,000 households in its Current Population Survey (CPS) (24). OSH sponsored a supplement to this survey, which included a question on current use of snuff and chewing tobacco. One respondent per household provided information on all members age 16 and older. Provisional estimates of smokeless tobacco use indicate that 1.9 percent of males used snuff and 3.9 percent used chewing tobacco (table 4). 12 TABLEI 7.-National Prevalence of Smokeless `Ibbaccu Use by Adult Status aud Sex, NIDA Sample, 198!5* Percentage. of Users Males Females Use Category 12OYears 2 21 Years I 20 Years r21Years Used in Past Year 16 11 2 2 Used Formerly 4 7 2 2 Never Used 79 82 96 96 o Preliminary estimates not adJusted for oversampling of blacks and Hispamcs. Source: National Institute on Drug Abuse, 1985 Natmnal Household Survey on Drug Abuse Preliminary results presented at the NIH Consensus Development Conference on the Health Implications of Smokeless lbbacco Use. January 1986. TABLE 8.-Recency of Smokeless Tobacco Use by Sex and Age Group* Percentage of Users by Age Groups 12-17 l&25 26-3s 40-t Use Categom Males Females Males Females Males Females Males Females Usedin Past Year 16 1 16 1 10 1 8 3 Used Formerly 4 2 7 1 5 1 8 2 Never Used 80 97 77 98 85 98 84 95 * P&mmary estimates not adjusted for oversampling of blacks and Hispanics Source: National Institute on Dtug Abuse, 1985 National Household Survey on Drug Abuse. Preliminary results t; resented at the NIH Consensus Development Conference on the Health Implications of Smokeless Tobacco Use. anuary 1986. National Institute on Drug Abuse Housebold Survey The recently completed 1985 National Household Survey on Drug Use provides the national probability data on current use and correlates of use of smokeless tobacco by youth It is the eighth in a series of na- tional probability surveys conducted among household residents in the coterminous United States by the National Institute on Drug Abuse (NIDA). Data are collected on the use and adverse consequences that are associated with 11 drugs or drug classes. The 1985 survey over- sampled for blacks and Hispanics and younger age groups. The total sample consists of approximately 8,000 facet-o-face interviews. The data presented here are based on a prehminary analysis of 4,564 inter- views. provisional estimates are presented in tables 7 through 9. Sixteen percent of males under the age of 21 reported using chewing tobacco or snuff within the last year, in contrast to 11 percent of older males (table 7). The decline in older age groups is seen more clearly when narrower age categories are used (table 8). An estimate of the preva- lence of weekly use may be obtained by combining the use frequency 13 TABLE 9.--Frequency of Smokeless Tobacco Use in Past Year* Percentage of Users Past Year Use of Smokeless Tobacco Age Groups for Males 12-17 18% 2&39 40+ Males and Females Age 12 and Above Most Days/Week 3 7 5 4 2 1 or 2 Days/Week 2 1 1 1 1 1 or More Days/Week 5 8 6 5 3 3-51 Days/Year 5 5 3 3 2 1-2 Days/Year 6 3 2 1 2 Not in Past Year 4 7 5 8 3 Have `Itied 20 23 15 16 10 Never 80 77 85 84 90 o Prelmnary estunates not adJusted for oversampling of blacks and Hispanics. Source National Institute on Drug Abuse. 1985 National Household Survey on Drug Abuse. Preliminary results presented ar. the N IH Consensus Development Conference on the Health Implications of Smokeless Tobacco Use. January 1986. categories of "most days a week" and "1 or 2 days a week" (table 9). Use at least once a week peaks in the 1% to 25year-old age groups at 8 per- cent. As in previous surveys, the use among females was consistently much lower than among males. Responses suggest slightly higher rates of use among women 40 years of age and older than among younger women (table 8) (25). Discussion of National Survey Data Despite varying methodologies among the national surveys (table 2), sufficient commonalities permit mean@ful comparisons. The 1970 and 1975 OSH surveys and the 1980 to 1985 Simmons Study of Media and Markets indicate that the use of snuff by adult males remained con- stant within a range of 3 to 4 percent. Use by adult females also re- mained constant at about 1 percent. During this same l&year period, the population over the age of 18 increased 32 percent from 133.5 million to 175.8 million (26). The production of all forms of smokeless tobacco increased 42 percent from 95.2 to 135.6 million pounds, and the production of finecut/moist snuff tripled. This may indicate the emergence of a new population of users. The 1970 NHIS and the 1985 CPS both relied on the use of proxy re spondents. Estimates of smokeless tobacco use are likely to be lower than the actual population prevalence because respondents may not always be aware of smokeless tobacco use by other members of the household. In fact, in 1970, the NHIS estimated that 1.4 percent of males used snuff and 3.8 percent used chewing tobacco. In the same year, the OSH Adult Survey, which did not use proxy respondents, pro vided corresponding estimates of 3 and 6 percent. Similarly, the CPS estimates that 1.9 percent of males used snuff in 1985, while the Sim- mons Study of Media and Markets estimates 3.2 percent. 14 However, comparisons between the 1970 NHIS and the 1985 CPS for the purpose of e xamining trends are appropriate. They suggest little change in the overall rate of adult male use of smokeless tobacco but indicate a marked change in the age distribution of users (table 4). In 1970, the use of smokeless tobacco was most common among older men; in 1985, the prevalence in the younger age groups had greatly increased. Both the Simmons Study of Media and Markets and the NIDA survey show the highest rates of use among young adults ages 18 to 24. The Simmons National College Study indicates that male college students are as likely to use snuff as are other 18- to 24-year-olds. The Simmons data also show a slight elevation in prevalence among persons over the age of 65, which reflects the age distribution of traditional users of smokeless tobacco. If the NIDA prevalence estimates are applied to current population figures (261, there are at present over 12 million persons in the United States ages 12 and older who have used some form of smokeless tobacco in the past year. Three million are under the age of 21, and 1.7 milhon of these are males 12 to 17 years old. An estimated 6 million persons use smokeless tobacco at least weekly. Of these, 0.5 million are males ages 12 to 17; 1.3 million are males ages 18 to 25; and approximately 780,000 are females. The 1980 to 1985 Simmons Study of Media and Markets estimated that 2 to 4 million persons over the age of 18 were users of snuff. Of these, 0.6 to 1.2 million were between the ages of 18 and 24. able 10 summar%es data on the prevalence of smokeless tobacco use by region from three national surveys conducted in 1985. Among these adult samples, use was highest in the South and lowest in the North- east, with the West and North Central/Midwest falling in between. These surveys provide self-report data only; no direct validation at- tempts were made. Because no strong social sanctions regarding smokeless tobacco use exist for adults, systematic misrepresentation by them is unlikely. However, under the conditions of a personal inter- view, as used in the NIDA study, adolescents would be more likely to underreport than over-report their use of smokeless tobacco. In addi- tion, the prehminary estimates from the NIDA survey have not been adjusted for oversampling of blacks and Hispanics. In this sample, blacks and Hispanics reported less smokeless tobacco use than whites, and their over-representation would result in underestimates of national prevalence. State and Local Survey Data State and local surveys provide much of the information after 1980 on the use of smokeless tobacco. Since most of these surveys were con- ducted in schools, often motivated by apparent increases in students' 15 TABLE lo.-Prevalence of Smokeless Tobacco Use by census Region, 1985 Prevalence Category Percentage Reporting Use Northeast North Central South West CPS Chewing Tobacco Snuff Simmons Snuff NIDA* (Snuff and/or chewing tobacco) Weekly Use or More Often Any Use in Past Year 1.6 3.7 7.0 3.9 1.2 2.3 3.1 1.6 1.5 1.3 2.9 1.3 1.0 2.0 5.0 4.0 4.0 6.0 8.0 9.0 * Preliminary estimates not adjusted for age and race Sources: Office on Smoking and Hex&b. Current Population Survey. 1985 iunpublished). Simmons Market Research Bureau. Inc., Study of Media and Markets. 1980-1985. National Institute on Drag Abuse, 1965 House- hold Survey on Drug Abuse. Preliminary results presented at the NIH Consensus Develqxnent Conference on the Health Implications of Smokeless lbbscco Use, January 1986. use of smokeless tobacco products, there may be a selection bias. However, the large and growing number of reports and the wide geographic coverage support the conclusion that smokeless tobacco use is not a localized phenomenon, Indeed, the consistency of such data sug- gests that smokeless tobacco has become a product that is used by large numbers of teenage and young adult males. Adult Use Several reports provide a tentative profile of local usage patterns of smokeless tobacco among adults. In 1979, tobacco use information was collated from 4,282 men between the ages of 21 and 84 in 10 geographic areas as part of the National Bladder Cancer Study, a population-based case control study (27). The overall prevalence for having "ever used snuff for 6 months or more" among the control subjects (randomly selected from the general population) was 5 percent; for chewing to bacco, the corresponding figure was 12 percent. A breakdown by age indicated much more use of smokeless products by older men than younger men (table 11). Glover and his colleagues conducted a random sample telephone survey of 280 persons in Pitt County, North Carolina (28). A user was defined as a person who answered "yes" to the question, "Do you dip or chew tobacco?" Forty percent of males and 9 percent of females answered positively. High rates of use are probably not a new phenome non since. there is a tradition of smokeless tobacco use among both sexes in this area, and tobacco is a major agricultural product,. 16 TABLE Il.--prevalence of Snuff and Chewing Tobacco Use by Adult Males in 10 Geographic Areaa Percentage Reporting Ever Used Sample n Snuff Chewing lbbacco All Men 4.282 5 12 Age 21-44 45-64 65-84 240 0 2 1,653 3 6 2,389 7 16 Area of Residence Atlanta Connecticut Detroit Iowa New Jersey New Mexico New Orleans San Francisco Seattle Utah 186 8 23 654 4 12 355 8 20 552 12 14 1.288 2 10 129 7 20 115 1 6 542 2 8 255 10 6 206 5 7 Race White Nonwhite 3,892 5 11 390 5 18 Source: National Bladder Cancer Study. Hartge. P.. Hoover. FL. and Kantor. A. Bladder cancer risk and pipes. cigars. and smokeless tobacco. Cancer. 55: 901-906. 1985. Research supported by the National Cancer Institute, the Food and Drug Administration. and the Environmental Protection Agency. Gritz, Ksir, and McCarthy surveyed a sample of 214 students at the University of Wyoming (29). In their sample, 27.1 percent of males and 4.1 percent of females reported "current use," with the criterion for "current use" unspecified. The vast majority of users (84 percent) used moist snuff. Glover and his colleagues reported a survey of 5,894 students in physical education classes at 72 colleges and universities from 8 States (Oregon, Arizona, Colorado, Oklahoma, Minnesota, Ohio, South Carc~ lina, and Connecticut) (30). `l%enty-two percent of the males who were surveyed reported using smokeless tobacco compared to 2 percent of the females. Combined rates of use for both sexes ranged from 15 per- cent in Oklahoma to 8 percent in Connecticut. The majority of the users reported using less than one can or pouch per week. Adolescent Use Studies of school-age youth conducted since 1980 are summarized in table 12 13145). Five different criteria for classifying use have been selected for data display: daily use, weekly use, monthly use, current use (no frequency specified), and ever used. Recent regional data on the use of smokeless tobacco have been col- lected by a number of National Cancer Institute grantees in the course 17 TABLE EL-Prevalence of Use of Smokelese lbbacco Among Youth by Gender and Grade: Regional and StateLevel Surveys Reported since 1!Bo* LOC.StiOll keference~ Grade&$ Malea Females Total I Daily Use Arkansas (31) Arkansas (32) Nebraska (33) Ohio (34) Chewing Tobacco Snuff Oregon (35) Oregon (36) wisconsin (37) lo-12 lo-12 7-12 4-12 7 9 10 7 a 9 10 7 8 9 10 11 12 lbtal 26.0 - 2.5 11.4 19.7 a.8 18.5 23.1 4.6 5.8 9.7 10.6 3.0 6.0 3.0 8.0 11.0 15.0 - - - 0.0 0.2 0.4 0.7 0.0 2.4 - - - - 0.0 0.0 0.0 0.0 0.0 0.0 - - 179 15.0 901 - 2,612 - 1.004 - 1,004 - 443 - 249 - 130 - 710 - 139 - 432 - 255 - - - - - - - - - - weekly use (Or more often) Nebraska (33) wisconsin (37) 7-12 7 8 9 10 11 12 lbtal 4.8 0.0 - 2.616 12.0 - - 18.0 - - - 15.0 - - - 24.0 - - - 25.0 - - 37.0 - - - - 1.0 - 25,000 Monthly Use (Or more often) Arizona (38) Midwestern states (39) Nebraska (33) 8-12 18.4 - - 1,080 lo-12 33.0 0.0 - 323 7-12 7.1 0.0 - 2.616 Current Use (Frequency not specified) Arkansas (31) lo-12 Arkansas (32) 10 11 12 T&al 31.8 2.2 - 179 - - 13.8 326 - - 20.6 330 - - 23.7 245 36.7 2.2 - 901 18 TABLEIl2.-Continued LOtXtiOll (reference) Grade(s) M&Ii Females Total n Current Use (Cont.) Colorado (40) lo-12 21.6 0.6 - 1,119 Colorado (4 1) 10-12 26.0 0.0 - 445 Louisiana (42)f 1976-1977 Chewing Tobacco 8-9 11.0 - - - lo-11 17.0 - - - 12-13 25.0 - - - 14-15 24.0 - - - 16-17 15.0 - - - Snuff 8-9 4.0 - - - 10-l 1 7.0 - - - 12-13 5.0 - - - 14-15 11.0 - - - 16-17 5.0 - - - Total - - - 2.880 1981-1982 Chewing Tobacco 8-9 24.0 - - - IO-11 32.0 - - - 12-13 39.0 - - - 14-15 43.0 - - - 16-17 15.0 - - - Total - - - 1.981 Snuff 8-9 21.0 - - - lo-11 26.0 - - - 12-13 32.0 - - - 14-15 30.0 - - - 16-17 14.0 - - - lbtal - - - 1,981 Pennsylvania (43) 7-12 30.0 0.0 - 538 Texas (44) 7-12 19.0 0.0 - 5,392 Wyoming (29) 7-9 24.5 1.2 - 2,408 Ever Used Arkansas (45) K Ohio (34) Chewing Tobacco 4-12 lbtal Snuff 4-12 Total Oregon (35) 7 9 10 Wisconsin(37) 7 8 9 10 11 12 Total 58.0 - 64.0 - 63.4 72.7 76.7 32.0 45.0 47.0 50.0 47.0 48.0 - 12.0 - 24.0 - 19.9 16.4 23.8 - - 21.4 112 - - - 1,007 - - - 1,007 - 445 - 249 - 133 - - - - - - 11.0 25,000 o Unless otherwise indicated, figures represent the usa been made for studies that provide for more than one c E... of chewing tobacco andlor snuff. Multiple entries have sslfrcatmn cntenon. t Age listed rather than grade. 19 of their ongoing research on tobacco use by youth (4s). Through col- laboration, these investigators have achieved more standardization in data collection than in previous studies, which makes comparisons among the different locales more meaningful. Although there were some differences in methodology, all of the studies addressed one or both of the following research questions: 1. What percentages of males and females have ever used smokeless t&lCCO? 2. What percentages of males and females have used smokeless tobacco in the last 7 days? Adolescent males may be subject to pressures that simultaneously discourage and encourage smokeless tobacco use. Underreporting of use may result from the presence of teachers and the setting in which the survey is administered. Overreporting may result from peer pressure to be seen as a smokeless tobacco user. Accurate reporting may be facilitated by collecting breath or saliva samples when surveys are completed. Respondents who believe that their se&reports can be objectively verified via biochemical testing tend to provide more accu- rate responses (47-49). Biochemical validation was used in 14 of the 17 subsamples reported in table 13. Most studies do not distinguish between snuff and chewing tobacco. In reports where the two have been separated, both substances were found to be in use (344243). Rates of smokeless tobacco use were consistently higher among males than females. This difference is especially marked when more precise classifications for regular use are employed. While substantial numbers of adolescent females report having tried smokeless tobacco at least once, very few use it on a regular basis (3335,37,39,&J. The use of smokeless tobacco by youth was generally higher in rural than urban areas, in small communities, and in areas where there is a tradition of smokeless tobacco use (Z&$37,46). However, high rates of use have also been reported in large metropolitan areas as well (37,40,46). able 14 smmm&es data on smokeless tobacco use by ethnic groups collected by investigators using standardized questions (46). lb date, lit- tle information has been available on smokeless tobacco use by non- whites, and some early research suggested that minority youth were not taking up the practice (42). In these studies, however, Hispanic youth showed rates of smokeless tobacco use comparable to whites, and Native American rates were consistently higher. In most locales, use was less common among Asians and blacks. Nationally, black college stu- dents are less likely to use snuff than are white college students Itable 6). Prevalence estimates for smokeless tobacco use by black adults, however, have equaled or exceeded those of whites (tables 5 and 11). The likelihood of using smokeless tobacco appears to increase with age as well as over time (32-35,37,42,46). Only one study has collected 20 TABLE 13.-Prevalence of Use of Smokeless lbbacca Among Youth by Gender and Grade: Local Surveys Using stana Questions Sample Males Females Grade Percentage n Percentage Il Used in Last 7 Days California Suburban/Rural Minnesota Suburban/Urban Montana Urban New York Urban New York New York City New York Suburban Oregon Suburban/Rural Oregon Suburban/Urban Southeastern unitf!d states 10 SMSA's Vermont Rural Vermont Urban Washington Rural Washington RLUal 4.7 (469) 0.7 (407) 14.8 (574) 1.4 (557) 9.2 (487) 1.6 (499) 9 18.1 (2.015) 2.4 (2.146) 9.4 (477) 2.0 (4031 11.9 (429) 1.5 (392) 13.9 (446) 3.2 (402) 3.9 (306) 2.9 1272) 10.7 (252) 0.3 it: ww (275) (243) 6 1.1 (1,488) 0.9 U.494) 7 3.0 (2,016) 0.0 (1,811) 6 ii 9 10 11 E 13:6 17.3 22.2 22.7 (602) (627) (6631 (572) (514) (440) 0.9 0.8 it: 2:3 0.5 (542) (618) 608) (567) (471) (431) 6 7 ; 1.9 (571) 0.4 625) 4.6 (570) 1.4 (575) 6.8 (514) 0.8 (533) 14.8 (588) 1.2 (575) 6 9.8 (305) 1.3 ww 7 12.1 (346) 0.6 (325) 8 10.4 v79) 1.6 (313) 9.3 mw 0.3 (317) 14.9 (328) 1.0 (289) 4 2.8 (216) 0.0 w9) 5 4.8 (207) 1.0 cw 6 5.4 (204) 0.0 (193) 4 2: 6 8.8 7 13.1 8 14.8 (45) 0.0 (47) (141) 1.3 056) W8) 2.1 (964) (521) 4.1 (514) (316) 5.2 (325) 10 23.7 (215) 0.4 (233) 21 TABLE 13.-Continued Males Females Sample Grade Percentage P Percentage n Ever Used California Suburban/Rural California pG/;pples California Los Angeles SMART California Los Angeles TVSP Minnesota Suburban/Urban Montana Urban New York Urban New York New York City New York Suburban Oregon Suburban/Rural Oregon Suburban/Urban Southeastern united states 10 SMSA's Vermont Rural Vermont Urban Wzu$inl@n Waterloo. Canada Suburban/Rural 32.6 56.2 56.7 24.9 7.8 19.6 20.0 6.7 I:;:; (504) (310) 25.3 (479) 31.9 1429) ii:: 32.0 (1,240) 6.9 (480) (418) (1,474) 62.1 (2,001) 22.9 (2,133) 41.0 56.9 68.2 17.5 19.3 24.6 23.1 (307) 3.4 33.5 (272) 5.1 47.8 (255) 7.0 i275; (24.3) 6.7 (1,488) 3.0 u,494 25.3 (2.016) 4.1 11,811) 48.3 (607) 16.2 57.9 639) 19.8 64.5 (677) 23.8 70.4 (577) 26.7 74.7 (5221 31.1 77.5 (445) 34.2 (551) I:?;; (576) (4851 (436) 32.4 (568) 44.9 (568) 54.1 (51.2) 61.3 1589) E 17:2 24.7 (528) f%J (575) 47.6 49.0 51.4 11.4 ew 13.5 (325) 15.6 (314) 38.8 1289) 8.2 (317) 54.8 (332) 7.2 (290) 17.4 (213) 26.2 (207) 39.8 (206) %!I 3.1 l%1 (193) 15.6 27.0 49.0 52.0 58.9 145) (141) 1E1 (316) 0.0 (47) 7.7 (156) 13.0 (964) 16.0 (514) 20.1 (325) 73.5 (215) 26.0 (281) 30.9 5.5 WW (444) 22 TABLE 14.-Mean Frequency of Smokeless Tihacco Use During Last 7 Days by Ethnicity of Male Respondents Sample California Suburban/Rural Grades 6-8 Ethnkity Asian Black Hispanic White Prevalence n % 192 3.7 118 6.1 188 11.2 1,046 11.4 Minnesota Asian 36 13.9 Suburban/Urban Black 201 4.0 Murray Hispanic 24 45.8 Native American 38 18.4 White 1,602 19.6 New York Asian 119 2.5 New York City Black 205 0.5 Grade 6 Hispanic 510 1.0 White 501 1.2 New York Asian 23 4.3 Suburban Black 47 2.1 Grade 7 Hispanic 39 2.6 Native American 26 3.8 White 1,796 3.3 Oregon Asian 38 5.3 Suburban/Rural Black 33 15.2 Grades 6-11 Hispanic 61 16.4 Native American 120 23.3 White 3.162 14.2 Oregon Asian 71 2.8 Suburban Black 231 3.9 Grades 6-9 Hispanic 26 0.0 Native American 48 12.5 White 1,847 7.6 Southeastern uIlited states 10 SMSA's Black 258 3.9 White 652 14.0 Washington Rural Grades 4-8 Asian Black Hispanic Native American White 148 6.1 119 1.7 111 9.0 179 30.7 1,434 9.4 23 both cross-sectional and longitudinal data. Hunter and her colleagues assessed tobacco use by children in Bogalusa, Louisiana, in 1976-77 and again in 1981-82 (az). The use of both snuff and chewing tobacco in- creased over time within age categories, within age cohorts, and across age categories (table 12). A decrease in use was observed in the oldest age category, 16-17 years old, but has not been seen in other locales (tables 12 and 13). The decrease may reflect agerelated changes in nor- mative behavior particular to that ares or a cohort effect. Peer and family members are found consistently to be important in- fluences on smokeless tobacco use by children and adolescents. Young users of smokeless tobacco have more friends who also use smokeless tobacco (343fQ9,&~ and may themselves identify friends' encourage ment as a reason for use (35,,44). Users of smokeless tobacco are also more likely to have family members who themselves use smokeless tobacco (34,3&$5) and encounter less parental disapproval of the prac- tice (31,359. In a special National Program Inspection study prepared by the Of- fice of the Inspector General of the Department of Health and Human Services, young current and former users of smokeless tobacco were interviewed in depth (So). `AVO hundred and ninety students in junior and senior high schools from 16 States volunteered to participate. AU had used smokeless tobacco on a weekly or daily basis. While this study was not designed to provide prevalence estimates, it provides useful in- formation about the attitudes and practices of some adolescent smoke less tobacco users. Over 90 percent of these respondents used snuff exclusively, and over 55 percent indicated that they would have strong cravings if they tried to quit. On the average, this group reported first trying snuff at age 10 and beginning regular use by age 12. Fifty percent cited pressure from friends as their primary reason for initiating use, but continued use was most often attributed to enjoyment of taste (64 percent) and habit strength ("being hooked," 37 percent). Over 85 percent thought that dipping and chewing can be harmful to health, but less than 55 percent considered regular use to present a moderate or severe risk. CONCLUSIONS 1. Recent national data indicate that over 12 million persons used some form of smokeless tobacco (chewing tobacco and snuff) in 1985 and that approximately 6 million used smokeless tobacco weekly or more often. Use is increasing, particularly among young males. 2. The highest rates of use are seen among teenage and young adult males. A recent national survey indicates that 16 percent of males between 12 and 25 years of age have used some form of 24 smokeless tobacco within the past year and that from onethird to onehalf of these used smokeless tobacco at least once a week. Use by females of all ages is consistently less than that of males; about 2 percent have used smokeless tobacco in the last year. 3. State and local studies corroborate the national survey findings. The prevalence of smokeless tobacco use by youth and young adults varies widely by region, but use is not limited to a single region. In several parts of the country, as many as 25 to 35 per- cent of adolescent males have indicated current use of smokeless tobacco. RESEARCH NEEDS More systematic and detailed national and local surveys on smoke less tobacco should be conducted.* National probability sample surveys need to be supplemented with surveys of suspected "hot spots" to detect the extent of high-risk areas in the country and the prevalence of use in these areas. Standard&d methods are essential to facilitate appropriate compari- sons among data. The current state of assessment is similar to the early days of research on cigarette smoking before standardized formats for assessment of prevalence and quantification of dosage became available. Accurate and reproducible dosage measurement for smokeless tobacco products is needed. Standardization may prove more difficult than for cigarette smoking because of the multiplicity of product forms. Specific items that require standardization include the following o Collection of data separately for snuff and chewing tobacco. o Definition of user classified according to the frequency of use. `Lb date, little attention has been given to finer distinctions of use, in- cluding quantity used, the appropriate unit of measurement, and time that the product is allowed to remain in the mouth o Description of use. 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A comparison of the use of smokeless tobacco in rural and urban teenagers. CA 34: 248-261, 1984. (42) Hunter, S.M., Croft, J.B., Burke, G.L., Parker, F.C., Webber, L.S., and Berenson, G.S. Longitudinal patterns of cigarette smoking and smoke less tobacco use in youth. Am. J. Public Health 76: 193-195,1986. (43) Guggenheirner, J., Zullo, T.G., Krupee, D.C., and Verbin, R.S. Chang- ing trends of tobacco use in a teenage population in western Pennsyl- vania. Am J. Public Health 76: 196-197, 1986. (44) Schaefer, S.D., Henderson, A.H., Glover, E.D., and Christen, A.G. Pat- terns of use and incidence of smokeless tobacco consumption in school- age children. Arch. Otolaryngol. (in press). (4.5) Young, M., and Williamson, D. Correlates of use and expected use of smokeless tobacco among kindergarten children. Psychol. Rep. 56: 63-66,1985. (46) Boyd, G.M.. et al. Use of smokeless tobacco among children and adolescents in the United States. Prev. Med. (in press). (47) Evans, R.I., Hansen, W.G., and Mittehnark. M.B. Increasing the valid- ity of self-reports of smoking behavior in children. J. Appl. Psychol. 62: 521-523. 1977. (48J Murray, D.M.. O'Connell, C.M., Schmiel. L.A., and Perry, C.P. The validity of smoking self-reports by adolescents: A reexamination of the logic and pipeline procedure. Addict. Behav. (in press). (49) Bauman, K.E., and Dent, C.W. Influence of an objective measure on self-reports of behavior. J. Appl. Psychol. 67: 623-638, 1982. (50) Office of the Inspector General. Youth use of smokeless tobacco: More than a pinch of trouble. U.S. Department of Health and Human Ser- vices, January 1986. 28 Chapter 2. CARCINOGENESIS ASSOCIATED WTTH SMOKELESS TOBACCO USE CONTENTS Introduction.. ................................... ..3 3 Epidemiologic Studies and Case Reports of Oral CancerinReIationtoSmokelessTbbaccoUse ............. .33 DataFromNorthAmericaandEurope .............. .33 DataFromAsia ................................ .42 summary......................................4 4 References ................................... ..4 4 Epidemiologic Studies of Other Cancers inRelationtoSmokeless'I%accoUse ................... .47 NasalCancer.................................... 8 EsophagealCancer............................... 8 LaryngealCancer................................ 0 StomachCancer ............................... ..5 1 Urinary'It-actCancer ............................ .52 Other Cancers .................................. .54 summary.. .................................. ..5 5 References ................................... ..5 6 Chemical Constituents, Including Carcinogens, of Smokeless Tobacco ............................... .58 Chemical Composition of Smokeless Tobacco .......... .58 Carcinogens in Smokeless `Ibbacco .................. .58 Summary......................................6 5 References ................................... ..6 7 Metabolism of Constituents of Smokeless Tobacco .... .70 Metabolism of NNK ........................ .71 Metabolism of NNN ........................ .73 Metabolism of NMOR ...................... .74 summary ................................ .75 References ............................... .75 Experimental Studies Involving Exposing Laboratory Animals to Smokeless `Ibbacco or Its Constituents ......... .79 Bioassays With Chewing Tobacco .................. .79 Bioassays With Snuff. ........................... .83 Bioassays With Constituents of Smokeless Tobacco .... .86 Mutagenicity Assays and Other Shoti'Ihrrn lb&s ...... .88 Summary.. .................................. ..8 9 References ................................... ..8 9 cOnclusions........................................92 ResearchNeeds.....................................93 31 This chapter presents the results of a systematic review of the world's medical literature describing experimental and human evidence perti- nent to the evaluation of smokeless tobacco as a potential cause of cancer. Five categories of research relevant to assessing the role of smokeless tobacco in cancer causation were defined: 1. Epidemiologic studies and case reports of oral cancer in relation to smokeless tobacco use. 2. Epidemiologic studies of other cancers in relation to smokeless toba~0 use. 3. Chemical constituents of smokeless tobacco. 4. Metabolism of constituents of smokeless tobacco. 5. Experimental studies involving exposing laboratory animals to smokeless tobacco or its constituents. consensus summari es of the literature in each of these categories were prepared and form the basis of this report. In addition, recommen- dations for future i-search to clarify suggestive findings or fi.lI gaps in knowledge are made. EPIDEMIOLOGIC STUDIES AND CASE REPORTS OF ORAL CANCER IN RELATION TO SMOKELESS TOBACCO USE Because smokeless tobacco products used in different regions of the world vary considerably in composition and usage patterns, this section will consider North American and European data separately from Asian data. Citations to the literature from India and other Asian coun- tries where quids containing tobacco and other ingredients are com- monly used orally focus on articles that attempt to distinguish tobacco from other ingredients in the quids as possible determinants of cancer risk. Data From North America and Europe Although about a dozen informative epidemiologic studies of smoke less tobacco use and oral cancer in North America or Europe have been reported, only a few were specifically designed to examine this relation. There are two major reasons for the relative paucity of studies. Apart from the recent increased prevalence in use of smokeless tobacco, the habit has not been widely practiced in America during this century, ex- cept in localized areas such as parts of the rural South (1,2). Further- more, cancer of the mouth is uncommon in the Western Hemisphere, 33 exacerbating the difficulty of conducting epidemiologic investigations, particularly cohort studies, into the relation between smokeless tobacco and oral cancer. The ageadjusted incidence rate for cancers of the buc- cal cavity and pharynx in the United States is approximately 11 cases per 100,000 population per year, with these tumors accounting for about 3 percent of all cancer deaths (3). Nevertheless, sufficient informa- tion is available to evaluate whether the use of smokeless tobacco increases the risk of oral cancer. case studies In their review of 566 oral cancer patients treated in two hospitals in Nashville, Rosenfeld and Callaway (4,5) noted that the proportion of women (61 percent) with buccal and gingival carcinoma was higher than the proportion of men (36 percent). Approximately 90 percent of women with buccal and gingival carcinoma used snuff for 30 to 60 years; in con- trast, 22 percent of women with cancers in other oral cavity subsites used snuff. Many of these women began practicing "snuff dipping," namely, the placement of tobacco snuff in the gingivobuccal sulcus, be tween the ages of 10 to 20 years. These reports are typical of numerous and sometimes large series of cases from the South, which reported that high percentages of patients with gingivobuccal cancers were snuff dip- pers or tobacco chewers (613). The articles describing these case series generally did not use comparison (control) groups, but the authors con- sistently commented on an apparently high prevalence of the use of snuff by the cancer patients. Clinicians also noted that the usual male predominance for epidermoid carcinomas of the oral cavity diminished or disappeared for the subgroup of gingivobuccal carcinomas occurr@ in geographic areas where there was relatively common use of snuff and chewing tobacco. Ahblom reported in the 1930's on a possible association between smokeless tobacco and cancer in Sweden (14). Among male patients with cancers of various sites seen at the Ftadiumhemmet (Stockholm), the use of snuff or chewing tobacco was reported in 70 percent with buc- cal, gingival, and "mandibuIar" cancers as compared to 26 to 37 percent with cancers in other oral subsites, the larynx, pharynx, and esophagus. Ax611 et al. reviewed medical records of male patients with squamous cell carcinoma in the oral cavity diagnosed between 1962 and 1971 and recorded in the Register of the Swedish Board of Health and Welfare (Is). The authors were only able to determine a history for the pattern of use of snuff in 25 percent of eligible patients but commented that two thirds of patients who were verified snuff users had oral cancers in regions where the snuff was generally placed. Reports of a single or a few cases, usually among male tobacco chewers, in the Northern United States and Canada also described buccal carcinomas that were often located precisely in the area where the tobacco was retained in the mouth (1619) 34 In the early 1940's, Friedell and Rosenthal associated the use of snuff or chewing tobacco with an exophytic, verrucous type of squamous car- cinoma of the oral cavity (16). Ackerman described in detail the morpho logic and clinical features of verrucous carcinoma of the oral cavity (20). Where the lesions originated in the buccal mucosa, a history of chronic use of chewing tobacco was elicited in 60 percent of the patients. The morphologic description was that of a well-differentiated, locally inva- sive, papillary squamous carcinoma, often in association with leuko plakia. In more than half of these patients, there was poor oral hygiene and carious and missing teeth. In summary, clinical and pathological reports published during the past four decades in the United States and elsewhere have commented on the use of smokeless tobacco by oral cancer patients and have described the entity known as snuffdipper's carcinoma (4,7,11), providing the basis for the hypothesis that the prolonged use of snuff or chewing tobacco is associated with an increased risk of low-grade, verrucal or squamous cell carcinoma of the buccal mucosa and gingivobuccal s&us. case control studies Most of the epidemiologic evidence comes from several case-control studies of oral cancer. The low prevalence of smokeless tobacco use in most North American populations contributes to a low statistical effi- ciency in most of these studies. Good information has been obtained, however, from studies that were either very large, conducted in an area of high prevalence of smokeless tobacco use, or analyzed according to site within the oral cavity (since the tissue affected by snuff use appears to be highly localized). One study, by Winn et al., with these characteris- tics consequently provides the most informative body of data on the carcinogenicity of smokeless tobacco in North America (21). The major concern for validity in the epidemiologic studies of smoke less tobacco and oral cancer is uncontrolled confounding. A smalI num- ber of subjects in crucial categories prevented efficient adjustment for confounding by stratification in many of these studies. Many of the studies were conducted before the advent of sophisticated epidemic logic analyses and make no attempt to control confounding. The two primary confounding factors of concern are alcohol consumption and smoking (22). Alcohol consumption is a strong risk factor for oral can- cer. It is not clear on a priori grounds, however, to what extent alcohol consumption would be correlated with smokeless tobacco use. The rela- tion between smoking, also a strong risk factor for oral cancer (2), and smokeless tobacco use may be complex. Users of smokeless tobacco may be more likely to have been smokers at some time. On the other hand, heavy users of smokeless tobacco typically cannot be heavy users of cigarettes, so that smoking is p resumably negatively correlated with smokeless tobacco use. Failure to control confounding by smoking would therefore lead to underestimates of the effect of smokeless tobacco. 35 TABLE l.-Smokeless Tobacco and Mouth Cancer, Case-Control Data From Moore et al. (23,24) Smokeless Tobacco Mouth Cancer Cases controls Users 26 12 Nonusers 14 26 Totals 40 38 Crude RR = 4.0 95%.Confidence Interval: 1.6-10 Chronologically, the first casecontrol study of smokeless tobacco was conducted by Moore et al. in Minnesota (23,24). Patients at the University of Minnesota `lhrnor Clinic with a diagnosis of cancer of the mouth were interviewed about tobacco use as part of a general inter- view procedure for clinic patients. Surgical outpatients who received the same interviews served as controls. Prom the data that were reported by these authors, one can calculate a crude relative risk estimate for mouth cancer among smokeless tobacco users of 4.0 with a 95percent confidence interval of 1.6-10 (table 1). An oddity was an ap- parent lack of effect for other forms of tobacco use. A partial explana- tion might be negative confounding between smokeless and smoked tobacco; indeed, 26 of the 40 cases of mouth cancer chewed tobacco. Still, the extent of disparity in crude effect estimates for smokeless tobacco (relative risk estimate 4.0) and smoked tobacco (all relative risk estimates < 1.0) is surprising. Wynder et al. reported on a case-control study of squamous cell cancers of the upper alimentary and respiratory tract that was con- ducted at Sweden's Radiumhemmet in 1952-55, including 33 tongue cancer patients, 14 lip cancer patients, 19 gingival cancer patients, and 8 patients with cancer of the buccal mucosa, among others (25). Con- trols were patients with cancers of the skin, head, and neck other than squamous cell carcinoma, stomach cancer, lymphoma, salivary-gland tumors, leukemia, sarcoma, cancers of the colon and rectum, and cancers of the female genital tract. A variety of risk factors was exam- ined, including the use of chewing tobacco. The authors state that the data suggested that an increased risk is associated with the duration of chewing tobacco for cancers of the gingiva and oral cavity but not for cancers of the tongue, lip, hypopharynx, esophagus, or larynx, but the data as presented do not permit an estimation of risk. In addition, data were not adjusted for other potential confounders, including cigarette smoking. Wynder and colleagues also reported in 1957 data from a similar hospital-based casecontrol study of mouth cancer conducted in New York (26). ?bbacco chewing was found to be more common among men with oral cavity cancers than among controls; but it was noted that almost all of these patients also drank alcoholic beverages and smoked and no further analyses were attempted. 36 TABLE 2.-Smokeless Tobacco and Mouth Cancer, CaseControl Data From Peacock et al. (27) Age Smokeless Tobacco User Nonuser Total 40-49 59-59 60-69 case controls case controls Case Controls 0 16 7 13 18 20 5 14 6 16 9 37 5 60 13 29 27 57 RR=0 RR = 1.4 RR = 3.7 RRMH = 2.0 95%.Confidence Interval: 1.0-4.2 Peacock et al. studied 56 cases of mouth cancer, including malignan- cies of the buccal mucosa, alveolar ridge, and floor of the mouth, and compared their tobacco histories with those of two control groups: 146 hospitalized controls with diagnoses other than cancer and 217 outpa- tients (27). Agespecific results using the hospitalized controls are sum- marized in table 2. The overall relative risk was estimated to be 2.0 (95percent confidence interval 1.0-4.2); the relative risk seemed to in- crease with age with an estimate of 3.7 for the 60 to 69 age group. The data were not reported in sufficient detail to control for confounding by smoking, which presumably led to underestimates of the relative risk. There was also insufficient detail reported to evaluate the relation be tween the risk of mouth cancer and the amount or duration of smokeless tobacco use. In Atlanta, patients with oral, pharynx, and larynx cancer were com- pared to three control groups having other mouth diseases, other can- cers, or no cancer (28. Among urban women, 40 percent of the cases used snuff compared to 3 percent or less of the controls (table 3). Among rural women, 75 percent dipped snuff compared to 20 percent or less among controls. Cigarette smoking was common in urban women and not specifically controlled for. Few rural female cases smoked cigarettes (7 percent) so confounding by smoking was minimal. The association between snuff dipping and oral, pharynx, and larynx cancer in women was generally evident in most age groups. Among the cases, the propor- tion of snuff dippers was highest among oral cancer patients: 53/72 were dippers compared to 2/18 pharynx and larynx cancer patients. Among men, insufficient information was provided to obtain precise epidemic logic estimates of the effect of chewing tobacco, although date from one of the bar charts presented indicate that urban cases were more likely to be users of smokeless tobacco than controls, that rural men with oral, pharynx, and larynx cancer or mouth disease were more likely to chew than controls, and that oral cancer patientu were more likely to chew 37 TABLE 3.-Estimated Relative Risks Associated With Snuff Use for Cancers of the Oral Cavity, Pharynx, and Larynx, Case.C!ontrol Data From Vogler et aL (2B), Females Only oral/ Other PlLSryIlXl Mouth Larynx Disease Other No ClUlCer Cancer Urban User Nonuser Crude Relative Risk Estimate RlUal User Nonuser Crude Relative Risk Estimate 15 1 5 4 23 56 165 373 60.8 1.7 2.8 1.0* 41 4 26 17 14 33 103 133 22.9 0.9 2.0 1.0* TABLE 4.-Smokeless Tobacco and Head and Neck Cancer by Anatomic Site, CaseControl Data From Vincent and Marchetta (29), Males Only Smokeless Tobacco Use User Nonuser Total Relative Risk Estimate 95%~Confidence Interval Control Larynx 5 2 95 21 100 23 1.8 0.3-9.8 oral All Head Phw Cavity and Neck 3 9 14 30 24 75 33 33 89 1.9 7.1 3.5 0.4-8.3 2.4-21 1.3-9.8 than the pharynx and larynx cancer cases. Among men, confounding by smoking could not be ruled out. Vincent and Marchetta reported the results of a case-control study of head and neck cancer according to anatomic site. Table 4 summarizes the findings for males (29). The oral cavity seems to be the anatomic site where the bulk of the effect is noted; only mild increases in risk were estimated for the larynx and pharynx, whereas users of smokeless tobacco were estimated to have a sevenfold greater risk for cancer of the oral cavity. These estimates are imprecise because of the small number of subjects and are uncontrolled for age and smoking. 38 TABLE 5.-Estimated Relative Risk for Cancer of the Head and Neck From Smokeless `lbbacco Use by Anatomic Site, Third National Cancer Survey (311, Males Only Relative Risk Estimate Anatomic Site Low Exposure High Exposure Gum-Mouth 5.6 3.9 Pharynx 0.6 - Lip-Tongue 0.3 1.1 LarYm 2.0 1.7 Martinez reported on a case-control study in Puerto Rico of risk fac- tors for cancers of the mouth, pharynx, and esophagus (XI). This population-based study included 400 cases of epidermoid carcinomas of those sites and 1,200 controls matched on age ( + 5 years) and sex to the cases. One control per case was drawn from the same hospital or clinic and two from the same community. There were 153 cases of mouth cancer (115 male and 38 female) and 68 cases of pharyngeal cancer (55 male and 13 female). The authors concluded that "Patients with cancer of the mouth did not often use chewing tobacco disproportionately. " However, calculation of the relative risks of mouth cancer that are asso ciated with chewing tobacco based on comparing the use of chewing tobacco only with no tobacco use suggests a strong effect for oral and pharyngeal cancer in males (data from table 13 in the paper). The esti- mated relative risks were 11.9 (95percent confidence interval 2.5-56.4) for oral cancer and 8.7 (95percent confidence interval 1.4-54.5) for pharyngeal cancer among chewers. These numbers do not include the experience of the many study subjects whose use of tobacco was mixed" (that is, those who used any combination of cigarette, cigar, and pipe smoking and chewing tobacco), and these calculations were based on unmatched data. Further evidence for the site specificity arose from a case-control analysis of multiple cancers using data from the Third National Cancer Survey (31). There were few female users of smokeless tobacco and scanty data by site within the head and neck region even for males; the findings do seem to indicate that the effect is greater for the site that is labeled gum-mouth as opposed to other head and neck sites (table 5). Browne et al. conducted interviews with 75 oral cancer patients, or (usually) their next of kin, and 150 living sex-, neighborhood-, and occupation-matched controls in the West Midlands area of the United Kingdom where oral cancer mortality rates were high and tobacco chewing was common among miners (32). Controls on average were born about 10 years earlier than the cases. The proportion of tobacco chewers was approximately the same among the 16 cases and 43 con- 39 trols who were miners, although data on this variable were missing for onefourth of the cases, and the authors apparently assumed that all cases with missing information were nonchewers. If the proportion of tobacco chewers among the cases with missing information was similar to those miners with known information, then the data would have shown a positive association between chewing tobacco and oral cancer. All of the miners with oral cancer who chewed tobacco also smoked pipes, further complicating interpretation of this study. Additional evidence that a carcinogenic effect of smokeless tobacco may be greatest at the anatomic site of exposure came from Westbrook et al. who compared the medical records of 55 female patients with cancers of the alveolar ridge or buccal mucosa who were treated at the University of Arkansas with those of 55 randomly selected female hospital controls (33). Fifty of the cases, but only one control, were snuff dippers, with the tumors among the cases typically appearing at the site where the snuff was usually placed. No reliable estimates of risk can be derived from this study because of the strong possibility that them was not comparable elicitation of exposum information for cases and controls. `Iwo large case-control studies were not reported in a way that enables a meaningful quantitative assessment of the effect of smokeless to. bacco in chewers and dippers compared to tobacco abstainers (34,35). The first study found that 10 percent, and the second 9 percent, of male oral cancer cases had ever chewed tobacco, while the corresponding fig- ure for controls was 9 percent. These studies, like many of the others cited here, were not undertaken specifically to evaluate the carcino genicity of smokeless tobacco. Although the data seem to indicate a weak relation, if any, between smokeless tobacco and cancer of the oral cavity, the findings are uncontrolled for age, race, geography, and smoking. The recent casecontrol study of Winn et al. is by far the most infor- mative study on the carcinogenicity of smokeless tobacco (21). The case series comprised 255 women with oral and pharyngeal cancer who were living in 67 counties in a high-risk (for oral cancer) region of North Carolina. ?tyo female controls were obtained for all but a few cases a