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INTRODUCTION, OVERVIEW, AND CONCLUSIONS DEVEIAPMENT 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 consequences of using smokeless'tobacco. The content of this report is the work of numerous erperts 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 written by scientists who are recognized for their understanding of the specific 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 re- port and an "Introductioa, Overview, and Conclusions." The body of the report consists of the following four chapters: • Chapter 1-Prevalence and Trends of Smokeless Tobacco Use in the United States • Chapter 2-Carcinogenesis Associated With Smokeless Tobacco Use Chapter 3--Noacancerous Oral Health Effects Associated With Smokeless Tobacco Use • Chapter 4-Nicotine Exposure: Pharmacokinetics, Addiction, and Other Physiologic Effects HISTORICAL PERSPECTIVE The use of smokeless tobacco is a worldwide practice with numerous vari- ations in the nature of the product used as well as in the customs associated with its use. In the United States, smokeless tobacco consists of chewing tobacco and snuff. The predominant 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. 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 Rolfe in 1611 (1). Evidence of tobacco chewing, however, was not found until a century later in 1704 (2). The use of tobacco, including smokeless tobacco, has been controversial 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 2581258014 XV

appears that people who frequently lacked sufficient food alleviated their hunger pains by chewing tobacco (3). Smokeless tobacco was also thought to have several medicinal uses. Among Native Americans, for example, chewing tobacco was used to alleviate toothaches, disinfect cuts, and relieve the effects of snake, spider, aad insect bites (4). Moreover, during the 19th and early 20th centuries in America, dental snuff was advertised to relieve toothache pain; to cure neuralgia, bleeding gums, and scurvy; and to pres-erve and whiten teeth and prevent decay (1). _ On the other hand, the history of tobacco use has had numerous adversaries, including the following (1): • In 1590 in Japan, tobacco was prohibited. Users lost their property and were jailed. • King James VI of Scotland in the early 1600's was a strong antismoking advocate who increased taxes on tobacco 4,000 percent in an attempt to reduce the quantity imported to England. • 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. • 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. • A Chinese law in 1683 threatened that anyone possessing tobacco would be beheaded. • 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. • 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 Tsai Li sect of China, and some Ethiopian Christian sects forbade the use of tobacco. • Frederick the Great, King of Prussia, prevented his mother, the Dowager Queen of Prussia, from using snuff at his coronation in 1790. • Louis XV, ruler of France from 1723-1774, 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 consequence of tobacco snuff use (sniffing). 2501250015 a xvi

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 (7). 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 smokeless 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 pri- marily in the past two decades. A brief review of the health consequences of smokeless tobacco was presented 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 smok- ing 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 condition's under examination were likely to be causal in aature: • Consistency of the association-similar observations by multiple investigators in different locations and situations, at different times, and using different methods of study. • Strength of the association-high ratio of disease rate for the population exposed to the suspected risk factor compared to the population unexposed to the risk factor. • 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. • Temporal relationship of the association-exposure tq the suspected etiologic factor precedes the disease. • Coherence of the association-epidemiologic observations are conso- nant with all else that is known about the disease. 2501250016 XVil

In addition to these criteria, the general principles employed by the Inter- national Agency for Research on Cancer (IARC)* in evaluating the carcinogenic risk of chemicals or complex mixtures (table 1) were used as needed to supple- ment the primary causation criteria (11). OVERVIEW The use of smokeless tobacco products in the United States was widespread 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 national 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, seri- ous 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 tobacco into geno- toxic agents; the consistency of the oral cancer-smokeless tobacco association across epidemiologic investigations conducted in diverse locations; the trend in increasing 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 tobaccoo exposures are the greatest. In addition, a number of clinical observations and studies show an asso- ciation 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 ex- posure, and a number of studies now suggest that some snuff-iaduced leukoplakias can undergo transformation 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 IARC was established in 1965 by the World Health Assembly as an indepen- dently financed organization within the framework of the World Iieaith Orga- nization. It conducts a program of research concentrating particularly on the epidemiology of cancer and the study of potential carcinogens in the human environment. 2501259017 t , xviii

The magnitude of blood nicotine levels resulting from smokeless tobacco use has been shown to be similar to that from cigarette smoking. Therefore, the nicotine-related health consequences of smoking would also be expected to result from smokeless tobacco use. Given the nicotine content of smokeless tobacco, the users ability to sustain elevated blood levels of nicotine, and the well-established data implicating 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 contribu- tory or supportive role in the development of coronary artery and periphera]i vascular disease, hypertension, peptic ulcer disease, and fetal mortality and morbidity. . The conclusions in this report on the relationship between smokeless to- bacco 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) Consensus Development'Confer- ence on the Health Implications of Smokeless Tobacco 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 approxi- mately 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 one-third to one-half of these used smokeless tobacco at least once a week. Use by females of all ages is consistently le'ss 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 percent of adolescent males have indicated current use of smokeless tobacco. 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 frequently 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. 2501258018 XLX

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 increased 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, polycyclic aromatic hydro- carbons, and radiation-emitting polonium. The tobacco-specific nitrosamines N-aitrosoaornicotine and 4-(methylnitrosamino)-l-(3-pyridyl)-l-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 nitrosamines, at levels approximating those thought to be accumulated during a human life- time by daily smokeless tobacco users, have developed an excess of a variety of tumors. The nitrosamines 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 tested 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 portion 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 pro- duct used, frequency and duration of use, predisposing factors, cofactors (such as smoking or concomitant gingival disease), and other factors not yet determined. 2. Dose response effects have been noted by a number of investigators. Longer use of smokeless tobacco results in a higher prevalence 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 transformation 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 periodontis has not been confirmed. 2501258019 XX

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 individuals with existing gingivitis may increase the prevalence of dental caries compared to 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 dependence or addiction. 2. An examination of the pharmacokinetics of nicotine (i.e., nicotine absorp- tion, distribution, and elimination) resulting from smoking and smokeless tobacco use indicates that the magnitude of nicotine 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 central 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 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 +iser 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 on 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 dose-related increases in scores on standard measures of euphoria. It is a reinforcer (or reward) in both human and animal intravenous self-administration paradigms, functioning as do other drugs of abuse. Additionally, nicotine through smoking produces the same effects, and it causes neuroadaptation leading to tolerance and physiologic dependence. 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. 2501250020 XXL

6. The evidence that smokeless tobacco is addicting includes the pharma- cologic role of nicotine dose in regulating tobacco intake; the common- alities between nicotine and other prototypic dependence-producing sub- stances; the abuse liability and dependence potentia]l 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,'including smokeless tobacco, may function to enhance further the number of persons who are afflicted by nicotine dependence: nicotine-delivering products are widely available and relatively inexpensive; and the self-administra- tion of such products is legal, relatively well tolerated by society, and produces minimal disruption to cognitive and behavioral performance. Nicotine produces a variety of individual-specific therapeutic actions such as mood and performance enhancement; and the brief effects Qf nico- tine ensure that conditioning occurs, because the behavior is associated with numerous concomitant environmental stimuli. 8. All commonly marketed-and consumed smokeless tobacco products 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). 9. Since the exposure to nicotine from smokeless tobacco is similar in magnitude to nicotine exposure from cigarette smoking, the health consequences 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 folklore and social history of snuffing, sneezing, dipping, and chewing. J. Am. Dent. Assoc. 105: 821-829, 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 all 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 Medical Journal 102: 1-2, 1915. 2501258021 Xxll

7. Ahblom, H.E. Predisposing factors for epitheliomas of the oral cavity, larynx, pharynx, and esophagus. Acta Radiol. 18: 163-185, 1937 (in Swedish). 8. Friedell, 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 Proehl, 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, Office on Smoking and Health (DHEW Publication No. PHS 79-50066). Washington, D.C., U.S. Govt. Printing Office, 1979, pp. 13-38 to 13-41. 11. International Agency for Research on Cancer. Monographs on the evaluation of the carcinogeaic risk of chemicals to humans. Tobacco habits other than smoking; betel-quid and areca-nut chewing and some related nitro- samines. 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. xxiii

Table 1 General Principles in Evaluating Carcinogenic Risk of Chemicals or Complex Mixtures (International Agency for Research on Cancer) . Evidence for carcinogenicity in experi:tental animals: --Qualitative aspects: (a) Experimental parameters under which chemical was tested. (b) Consistency with which chemical shown to be carcinogenic. (c) 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. • 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. • Evidence of carcinogenicity in humans: -For studies showing positive association: (a) Existence of no identifiable positive bias. (b) Possibility of positive confounding considered. (c) Association unlikely to be due to chance alone. (d) Association is strong. N (e) Existence of dose-response relationship. Ca9 a -For studies showing no association: (a) Existence of no identifiable negative bias. (b) Possibility of negative confounding considered. (c) Possible effects of misclassification of exposure or outcome have been weighed. xxiv