Studies in Sweden Mod&r, Lavstedt, and Ahlund studied the oral health effects of smoking and snuff use in 232 Swedish school children ages 13 to 14 years (119 boys and 113 girls) (36). Thirteen (11 percent) of the boys used snuff. The children were interviewed regarding their tobacco and tooth- brushing habits, and examin ers (blind to the interview results) clinically assessed the degree of gingival mflammation, oral hygiene, and the presence of calculus (discussed in the next section). Standardized in- dices were used to assess all oral conditions. Controlling for the presence of dental plaque, gingival inflamma tion was the only variable that was significantly different between snuff users and nonusers. Snuff use was directly correlated with the degree of gingival mflamma- tion. The gingival inflammation noted was related to the site of smoke less tobacco placement. Discussion The relationship of smokeless tobacco use and the health of gingival and periodontal tissue has received minimal study. Because of the variation in study designs and diagnostic criteria, comparisons between available studies are inappropriate. Thus the effects of smokeless tobac- co use on these tissues are not clearly understood. With regard to gingivitis, one cross-sectional study noted no differ- ence between users and nonusers (9). Another study, however, empha- sized that there was a significant difference between users and nonusers and that snuff use was directly correlated with the degree of gingival inflammation (36). Gingival recession is a common finding among users of smokeless tobacco/snuff. In the U.S. cross-sectional studies, gingival recession was found in 25.6 to 60 percent of teenage users (7-9). In the two Col- orado studies, all the gingival recession was specific to the site of to bacco placement (25.6 and 26.8 percent) (8). In the Georgia study, only 6.6 percent of the gingival recession was in the area of tobacco place ment (9). In addition, several case reports have identified gingival reces- sion at the site of habitual tobacco placement (1@13). Between 76.6 and 86.6 percent of smokeless tobacco users who had gingival recession also had concomitant mucosal pathology (7,s). These soft tissue changes were found at the site of habitual tobacco placement. Salivary Glands Smokeless tobacco or its components may contribute to degenerative changes and severe damage, such as undifferentiated carcinoma, to the salivary glands and excretory ducts of humans and mice (1&20,2437). In a study that assessed the formation of tobacco-specific nitrosamines from the major tobacco alkaloid nicotine, Hecht et al., reporting from the histologic evaluation, noted two undifferentiated carcinomas of the 126 salivary glands in two groups of mice that were given injections of nitrosonomicotine (NNN) in saline or trioctanoin (37). Because of the uncommonness of salivary tumors in strain A mice, Hecht et al. con- cluded that the tumors were probably a result of systemic administra- tion of NNN. SiaIadenitis and degenerative changes in minor salivary glands were found in 16 of 50 habitual snuff dippers with a greater number belong- ing to the groups that were classified clinically as having the most severe snuff-induced lesions (18) (table 1). The findings from this study included a decrease in oxidative enzyme activities and indications of metabolic aty-pia that were based on enzyme histochemical tests. The salivary glands appeared to manifest more damage than the oral epi- thelium from snuff use. Variations in degrees of effect may be attrib uted to the variations in snuff dipping habits and brands of snuff. In a recent study by Greer and his colleagues (20) (table l), 45 smoke less tobacco users ages 13 to 74 years were clinically and histomorpho logically assessed for the effects of smokeless tobacco on the oral tissues. Of 45 tissue specimens, 18 included salivary gland tissue. Damage in the form of sialadenitis and other degenerative changes in salivary glands was shown in 4 of the 18 specimens. A consistent pat- tern for chronic sialadenitis was not found among any of the age groups. The authors did not specify the other degenerative changes. However, four patients, ages 21,25,50, and 60 years, demonstrated either a mild, moderate, or severe salivary gland fibrosis. The most severe salivary gland fibrosis was found in the 21-year-old subject who was considered a short-term smokeless tobacco user; a definition for short-term user was not provided. Unlike the findings of Hirsch, Heyden, and ThiIander (18), salivary gland fibrosis or changes were not related to the stage (degree) of the clinical lesion. The authors concluded that there is no doubt that salivary gland fibrosis can be shown and that it is likely to be related to the damage from smokeless tobacco. They also commented that "It is likely that the degree of salivary gland fibrosis and degenera- tive change, along with sialadenitis, may be a factor that is associated with tobacco brand rather than with a generalized reaction caused by alI tobam. ' ' Included among the many questions concerning the effects of smoke less tobacco use on the salivary glands is that of changes on the flow and buffering capacity of saliva. In a sample of 48 Finnish snuff users ages 17 to 21 years (mean 18.9), the resting and stimulated salivary flow was measured (21) (table 1). The subjects refrained from the use of snuff for 1 hour before collection of saliva. The saliva of 10 nonusers was simiIarly collected. The statistically significant findings demonstrated a higher resting salivary flow of snuff users compared with controls. Although the stimulated salivary flow was also higher among the snuff users than the controls, this difference was not statistically significant. Buffering capacity was the same between the two groups. Although 127 these findings offer additional information regarding the effects of smokeless tobacco on the salivary glands, the clinical significance of these effects has not been systematically assessed, nor have the out- come differences related to the different products. Replication studies of these findings are needed before firm conclusions can be made. In contrast to the effects just cited, Archard et al. were unable to identify lesions or dysfunctions associated with smokeless tobacco use (23) (table 2). These investigators carried out histochemical tests on le sions in the oral cavity that were in close proximity to the salivary glands. These tests revealed no evidence of an mflammatory reaction associated with the glands. The interpretation of data within this general area requires caution. Limited evidence suggests a possible relationship between the use of snuff and damage to the salivary glands. Should this be the case, the loss of salivary gland function can result in the decreased production of saliva and the ultimate loss of a protective buffer for the oral epithelium and the teeth against numerous exogenous factors such as infectious agents, including dental caries. THE EFFECTS OF SMOKELESS TOBACCO USE ON TEETH Background and Definitions This section of the chapter addresses the role of various forms of smokeless tobacco in causing or contributing to diseases or conditions of the teeth. Specific effects that are examined include dental caries, abrasion, erosion, plaque and calculus buildup, and staining. For pur- poses of discussion, definitions are offered for a number of terms that are considered to represent commonly held concepts of diseases and conditions of the teeth as evidenced in the relevant scientific literature. o Dental caries-Clinically detectable cavitation of the coronal or root surfaces of the tooth that is caused by acid demineralization of colonizing bacteria on tooth surfaces. o Abrasion-Clinically evident wear of the coronal portion of teeth either generally or focally that appears excessive for a patient of a given age. This is a mechanical effect that is caused by the action of abrasive substances or objects during normal functioning or by oral habits. o Erosion-Loss of tooth structure that is attributable to a chemical agent. o Plaque-Bacterial-laden, proteinaceous material that is continu- ally deposited in the oral cavity through the proliferation of bac- terial types. 128 o Calculus-A concretion that forms on the coronal and exposed root surfaces of teeth through the calcification of bacterial plaques. o Staining-An extrinsic stain deposit that results in discoloration on tooth surfaces. Dental Caries Evidence for the effects of smokeless tobacco use on the teeth is avail- able from several cross-sectional studies (table l), from a limited number of case reports (table 2), and from a limited number of related investiga- tions of the potential for constituents of smokeless tobacco to serve as predisposing or etiologic factors in the development of dental caries. As previously mentioned, Offenbacher and Weathers reported on the oral soft and hard tissue effects of smokeless tobacco use in a study population that comprised 565 males with a mean age of 13.8 years (9). This population typifies the age group that is commonly described as "the cavity-prone years." Although caries rates expressed as decayed, missing, or filled teeth (DMFT) were higher for smokeless tobacco users without gingivitis than for nonusers without gingivitis, these differ- ences were not statistically significant. However, when DMFI' scores for smokeless tobacco users with gingivitis were compared with scores for nonusers without gingivitis, a significantly higher caries prevalence was found among users. Among students who used both snuff and chewing tobacco, the DMFT score was 6.56 + 0.71. This score is significantly elevated compared with scores of nonuser gingivitis-free students and the nonuser group that had gingivitis. There was a 2.4-fold increase in disease experience. In this study, the presence of gingivitis was presented as a cofactor with smokeless tobacco use in the increased prevalence of dental caries. This finding has not bean reported elsewhere, and the biologic explanation is unclear. The different that were noted in caries rates could not be accounted for based upon differences in oral hygiene or the frequency of dental visits-two factors that could potentially affect DMFT scores. The ex- aminers had no knowledge from the self-reported survey forms of the history of smokeless tobacco use among the group that was examined; thus, a degree of study "blindness" was attained. Absolute blindness in these types of surveys is difficult because it is likely that some evidence of smokeless tobacco use (e.g., tobacco residues, stain, odor, and soft tis- sue effects) is observable. No quantifiable doseresponse effect for smokeless tobacco use and dental caries was reported in this study. Dental caries is highly age dependent, and no age adjustment was made in the statistical analysis. A cross-sectional study by Greer and Poulson of 1,119 teenage smokeless tobacco users and nonusers from urban Colorado demon- strated neither "tobaccoassociated dental caries" nor occlusal or in- cisal abrasion of the teeth (7). This finding is not surprising because 129 abrasive effects are cumulative and would likely require a number of years to become evident. The abrasion that has been reported in smoke less tobacco users has been in adults who have used smokeless tobacco products, generally leaf and plug forms of tobacco, for years (10,13). The Greer and Poulson study reported a single case of cervical erosion on the mandibular central incisors. Some case reports have implied a causative role for smokeless tobac- co in the development of dental caries (38,39), while others have postu- lated a potential protective effect from caries (13,40). The presumed mode of protection would be through a greatly increased salivary flow that may provide a buffering action. Additionally, there is evidence that various forms of smokeless tobacco contain fluoride, from a few tenths to several parts per million, which may offer some cariostatic protection (41). At the same time, various types of smokeless tobacco contain up to five different forms of caries-promoting sugars (42). Rvo studies reported that constituents in smokeless tobacco products either cause a proliferation of caries-producing bacteria in vitro or, at the least, do not inhibit bacterial growth in vitro (43,44). The fluoride and sugar contents of smokeless tobacco vary by product type (41). This may explain the in- consistent and equivocal results obtained by different investigators. Variations in reported caries rates, if truly reflective of the larger population of smokeless tobacco users, may represent the clinical out- come of a number of antagonistic or synergistic factors that operate while smokeless tobacco is used. Other Hard Tissue Effects Plaque, calculus, and staining are extrinsic factors that may be asso &ted with smokeless tobacco use. This is clinically important because dental plaque and calculus that is coated with plaque harbor bacteria that can produce acids and toxins and thus bring about dental caries and diseases of the periodontal structures. The stainfng of teeth, restor- ations, and prosthetic appliances have been described as resulting from smokeless tobacco use (13,22,45,46). Van Wyk also reported a constant finding of chronic mflammation of tooth pulps that were extracted from oral snuff users (22). He attributed this as being "probably due to the irritation of the snuff overlying the exposed dentine and cementum." No quantifiable evidence currently documents the risk of smokeless tobacco use compared with nonuse in the development of plaque, calcu- lus, or staining or the relationship of staining to oral disease conditions. CONCLUSIONS 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 130 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. 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. 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. F&ports of tooth abrasion or staining have not been substantiated through controlled studies; only case reports are available. RESEARCHNEEDS The review of the literature for this component of the report has iden- tified the need for research in each of the areas discussed: the oral soft tissues, the periodontium, the salivary glands, and the teeth. Basically, the effects of the various types and forms of smokeless tobacco in all age groups should be investigated. Controlled studies and comparisons between users and nonusers of smokeless tobacco are needed. Estab lished criteria for assessing tissue changes and disease presence should be applied to permit comparability between studies. Studies should include the identification and control of variables that also may affect these tissues. Such variables may include alcohol use, diet, oral hygiene practices, microbial flora changes, and salivary flow rate, composition, and pH. In addition to these variables, consideration should be given to the effects of concurrent disease states. For example, 131 the effects of smokeless tobacco on dental caries in the presence or absence of gingivitis should be investigated. The natural history of smokeless tobacc&nduced lesions resulting from continued, intermittent, and discontinued smokeless tobacco use needs investigation. Histopathologic evaluations and clinical examina- tions to determine the natural history of oral leukoplakia/mucosal pathology and salivary gland pathology are desirable to understand completely the extent and severity of smokeless tobacco oral effects. In general, incidence and prevalence studies should be implemented, Prospective study designs should be pursued to dssess the temporal relationship between smokeless tobacco use and various health effects. In addition, dose-response studies are needed to assess dose in terms of both duration of use (in months and years) and daily exposure (in minutes and hours). REFERENCES (1) World Health Organization Collaborating Centre for Oral Precancerous Lesions. Definition of leukoplakia and related lesions: An aid to studies on oral precancer. Oral Surg. 46: 518-539,1978. (2) A&II, T., Hohnstrup, P., Kramer, I.R.H., Pindborg, J.J., and Shear, M. International Seminar on Oral Leukoplakia and Associated Lesions Related to Tobacco Habits. Community Dent. Oral Epidemiol. 12: 145154, 1984. (3) International Agency for Research on Cancer. Tobacco habits other than smoking Bet&quid and areca-nut chewing and some related nitro samines. IARC Monogr. Eval. Carcinog. Risk Chem. Hum37: 113,1985. (4) Moore, G.E., Bissinger, L.L., and ProehI, E.C. Tobacco and intraoral cancer. Surg. Forum 3: 685688, 1952. (5) Peacock, E.E., Jr., et al. The effect of snuff and tobacco on the produc- tion of oral carcinoma: An experimental and epidemiological study. Ann. Surg. 151: 542-549, 1960. (6) Smith, J.F., Mincer, H.A., Hopkins, K.P., and Bell, J. Snuff-dipper's lesion. A cytological and pathological study in a large population. Arch. Otokuyngol. 92: 450-456, 1970. (7) Greer, R.O., Jr., and PouIson, T.C. Oral tissue alterations associated with the use of smokeless tobacco by teenagers. Oral Surg. 56: 275~284,1983. (8) Poulson, T.C.. Lindenmuth, J.E., and Greer, R.O., Jr. A comparison of the use of smokeless tobacco in rural and urban teenagers. CA 34: 248-261, 1984. (9) Offenbacher. S., and Weathers, D.R. Effects of smokeless tobacco on the periodontal, mucosal and caries status of adolescent males. J. Oral Pathol. 14: 169-181. 1985. (10) Christen, A.G., Armstrong, W.R., and McDaniel, R.K. Intraoral leukoplakia, abrasion, periodontal breakdown, and tooth loss in a snuff dipper. J. Am. Dent. Assoc. 98: 584-586, 1979. 132 (11) Christen, A.G., McDaniel, R.K., and Doran. J.E. Snuff dipping and tobacco chewing in a group of Texas college athletes. Tex. Dent. J. 97: 6-10, 1979. (12) Hog-e, H.W., and Kirkham, D.B. Clinical management and soft tissue reconstruction of periodontal damage resulting from habitual use of snuff. J. Am. Dent. Assoc. 107: 744-745, 1983. (13) Zitterbart, P.A.. Marlin, D.C., and Christen A.G. Dental and oral effects observed in a long-term tobacco chewer: Case report. J. Indian Dent. Assoc. 62: 17-18, 1983. (14) Axell, T., Momstad. H., and Sundstrom, B. The relation of the clinical picture to the histopathology of snuff dipper's lesions in a Swedish population. J. Oral Pathol. 5: 229-236, 1976. (15) Pindborg, J.J., and Renstrup, G. Studies in oral leukoplakias, II. Effect of snuff on oral epithelium. Acta Derm. Venereol. 4.X: 271-276, 1963. (16) Pindborg, J.J., and Poulsen, H.E. Studies in oral leukoplakias, I. The influence of snuff upon the connective tissue of the oral mucosa. Preliminary report. Acta Pathol. Microbial. Immunol. Stand. 55: 412-414, 1962. (17) Axell, T. A prevalence study of oral mucosal lesions in an adult Swedish population. Odontol. Rev. (Suppl. 36) 27: l-103, 1976. (18) Hirsch, J.M., Heyden, G., and Thilander, H. A clinical histomorphologi- cal and histochemical study on snuff-induced lesions of varying sever- ity. J. Oral Pathol. 11: 387-398, 1982. (19) Frithiof, L., Anneroth. G., Lasson, U., and Sederholm, C. The snuff- induced lesion. A clinical and morphological study of a Swedish material. Acta Odontol. Stand. 41: 53-64, 1983. (20) Greer, R.O., Poulson, T.C., Boone, M.E., Lindenmuth, J., and Crosby, L.K. Smokeless tobacco associated oral changes in the juvenile, adult, and geriatric patients: Clinical and histomorphologic features including light microscopic, immunocytochemical and ultrastructural findings. Gerodontics 2: 3, 1986. (21) Jungell, P., and Malmstrom, M. Snuff-induced lesions in Finnish recruits. Stand. J. Dent. Res. 93: 442-447. 1985. (22) Van Wyk, C.W., The oral lesion caused by snuff. A clinics-pathological study. Medical Proceedings II: 531-537, 1966. (23) Archard, H.O., and Thrpley, T.M.. Jr. Clinicopathologic and histo- chemical characterization of submucosal deposits in snuff dipper's keratosis. J. Oral Pathol. 1: 3-11, 1972. (24) Smith, J.F. Snuff-dippers lesion. A ten-year follow-up. Arch. Otolaryngol. 101:276-277, 1975. (25) Brightman, V.J. Laboratory procedures. In: Malcolm A. Lynch (ed). Burket's Oral Medicine-Diagnosis and `Beatment. Philadelphia, J.B. Lippincott Company, 1977, pp. 723-724. (26) Mehta, F.S., Gupta, P.C., and Pindborg, J.J. 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BuccogingivaI carcinoma of snuff dippers. Am. Surg. 27: 442-447,196l. (34) Banndczy, J., and Sugar, L. Progressive and regressive changes in Hungarian oral leukoplakias in the course of longitudinal studies. Com- munity Dent. Oral Epidemiol. 3: 194-197, 1975. (35) Pindborg, J.J., Reibel, J., and Hohnstrup, P. Subjectivity in evaluating oral epithehal dysplasia, carcinoma in situ and initial carcinoma. J. Oral Pathol. 14: 698-708. 1985. (36) Mod&, T., Lavstedt, S., and Ahlund, C. Relation between tobacco con- sumption and oral health in Swedish schoolchildren. Acta Odontol. Stand. 38: 223-227, 1980. (37) Hecht, S.S., Chen. C.B., Hirota, N., Omaf, R.M., and `Iho, T.C. Tobacco- specific nitrosamines: Formation from nicotine in vitro and during tobacco curing and carcinogenicity in strain A mice. J. Natl. Cancer Inst. 60: 819-824, 1978. (38) Sitzes, L. On chewing tobacco. ADA News 8: 2, 1981. (39) Croft, L. Smokeless tobacco: A case report. Tex. Dent. J. 99: 15-16, 1981. (40) Shannon, I.L., and `RodahI, J.N. Sugars and fluoride in chewing tobac- co and snuff. Tex. Dent. J. 96: 6-9, 1981. (41) Going, R.E., Hsu, S.C., Pollack, R.L., and Haugh, L.D. Sugar and fluoride content of various forms of tobacco. J. Am. Dent. Assoc. 100: 27-33, 1980. (42) Hsu, SC., Pollack, R.L., Hsu, A.F., and Going, R.E. Sugars present in tobacco extracts. J. Am. Dent. Assoc. 101: 915-918, 1980. (43) Lindemeyer. R.G., Baum, R.H., Hsu, S.C., and Going, R.E. In vitro ef- fect of tobacco on the growth of oral cariogenic streptococci. J. Am. Dent. Assoc. 103: 719-722. 1981. 134 (44) Falkler, W.A., and Zimmerman, M.L. Effect of smokeless tobacco ex- tracts on the growth of streptococcus mutans. Presented at the Annual Meeting of the International Association of Dental Research, Las Vegas, Nevada, March 1985. (45) Christen, A.G. The case against smokeless tobacco: Five facts for the health professional to consider. J. Am. Dent. Assoc. 101: 464-469,198O. (46J U.S. Department of Health and Human Services. Draft report to the Surgeon General by the Inspector General on smokeless tobacco. December 20, 1985. (47) Waldron, C.A., and Shafer, W.G. Leukoplakia revisited. A clinicopatho logic study of 3,256 oral leukoplakias. Cancer 36: 1386-1392, 1975. (48) Waldron, C.A., and Shafer, W.G. Current concepts of leukoplakia. Int. Dent. J. 10: 350-367, 1960. (49) Shafer, W.A., Hine, M.K., and Levy, B.M. Oral Pathology, ed. 2. Philadelphia, W.B. Saunders Co., 1969, pp. 80-81, 85. /So) Liie, H.. and Silness, J. Periodontal disease in pregnancy. I. Prevalence and severity. Acta Odontol. Stand. 21: 533-551. 1963. 135 Chapter 4. NlCOTlNE EXPOSURF' PHARMACOKINmCS, ADDICTION, AND OTHER PHYSIOLOGIC EFFECTS CONTENTS Introduction .,,...................................141 Pharmacokinetics of Nicotine Levels of Nicotine in Smokeless Tobacco Absorption of Nicotine Distribution of Nicotine Nicotine Elimination Nicotine and Cotinine Levels in Users of Smokeless Tobacco Time Course of Nicotine `Bunover During Daily lbbacco Use References 141 141 141 142 142 143 143 143 Nicotine Addiction Associated With Smokeless lbbacco Use Background and Definitions Commonahties Between Ibbacco Use and Other Addictive Substances Experimental Studies of the Abuse Liability and Physical Dependence Potential of Nicotine Evidence That Orally Delivered Nicotine (Including Via Smokeless lbbacco) Has a Liability for Abuse and a Potential to Produce Physical Dependence References....................................... 144 144 146 157 166 168 Physiologic and Pathogenic Effects of Nicotineand Smokeless l'Uxcco Physiologic Effects of Nicotine Nicotine, Smokeless Tobacco, and Human Diseases . NonnicotineRelated Adverse Metabolic Consequences References 175 175 176 179 ,179 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...182 ResearchNeeds....................................184 139 This chqter examin es the consequences of exposure to nicotine from smokeless tobacco. It draws from the vast literature on the effects of nicotine delivered via smoking and intravenously and includes recent evidence of the effects of orally delivered nicotine. The first section describes the pharmacokinetics of nicotine, includ- ing absorption, distribution, and elimination. The data presented indi- cate that nicotine is present in smokeless tobacco in significant amounts and that users attain blood levels of nicotine similar to those produced by cigarette smoking. The second section reviews the established evidence that nicotine is an addictive and dependenceproducing substance, having a number of important characteristics in common with prototypic addictive and dependenceproducing substances, as well as substantial experimental evidence of its abuse liability and dependence potential. Given the nice tine content of smokeless tobacco, its ability to produce high and sus- tained blood levels of nicotine, and the well-established data implicating nicotine as an addictive substance, one may deduce that smokeless tobacco is capable of producing addiction in users. In addition, very re- cent studies provide direct confirmation that nicotine delivered orally from smokeless tobacco and nicotine chewing gum is addictive, produc- ing abuse liability and dependence potential. The final section of the chapter reviews the multisystem physiologic effects of nicotine and examin es the evidence pertaining to the potential contributory role of nicotine in the causation of several diseases. PHARMACOKINETICS OF NICOTINE Levels of Nicotine in Smokeless Tobacco `Ibbacco is a plant product, and therefore differences exist in nicotine content among and within different strains of tobacco. Nicotine content among smokeless tobacco products also differs: moist snuff contains 4.56 to 15.1 mg nicotine per gram (1); plug tobacco has been measured to contain 17.2 mg per gram (2). Assuming a daily consumption of 10 grams of smokeless tobacco, the habitual user can be exposed to roughly 130 to 250 mg nicotine per day, of which varying amounts may be absorbed. By comparison, cigarette tobacco averages 15 mg nicotine per gram or 9 mg nicotine per cigarette (3). A person who smokes a pack of cigarettes per day therefore can be exposed to 180 mg nicotine per day. Absorption of Nicotine Nicotine is a weak base (pKa 7.9). In its ionized form, as in the acidic environment of most cigarette smoke, nicotine crosses membranes poorly. As a consequence, there is virtually no buccal absorption of nice 141 tine from cigarette smoke. In contrast, smokeless tobacco products are buffered to an alkaline pH that facilitates absorption. The rate of absorption of nicotine from smokeless tobacco depends on the product and the route of administration. With fineground nasal snuff, blood levels of nicotine rise almost as fast as those that are observed after cigarette smoking (4). The rate of nicotine absorption with the use of oral snuff (and presumably chewing tobacco) is more gradual (5). People who use oral smokeless tobacco, particularly those who chew tobacco, generate large amounts of saliva, some of which is expecto rated and some of which is swallowed. Due to first pass metabolism in the liver following absorption from the intestines, the bioavailability of swallowed nicotine is approximately 30 percent (6). By changing how much is chewed, how much is held inside the mouth, and how much saliva is expectorated or swallowed, the user of smokeless tobacco has considerable control over the dose of nicotine that is absorbed. Distribution of Nicotine Smoking is a unique form of drug administration in that entry into the circulation is through the pulmonary rather than the portal or sys- temic venous circulations. The lag time between smoking and the appearance of nicotine in the brain is even shorter than after intrave- nous injection. Nicotine enters the brain quickly, but then brain levels decline rapidly as it is distributed to other body tissues. The rapid brain uptake of nicotine from smoking allows easy puff-topuff titration of desired nicotine effects and partly may explain the highly addictive nature of cigarette smoking. In contrast, the concentrations of nicotine that enter the brain from smokeless tobacco use are likely to be lower (6), and the pharmacologic ef- fects may differ. The rate of exposure to psychoactive drugs is an impor- tant determinan t of their effects. Thus there could be differences in the ef- fects of nicotine that is taken by smoking compared to using smokeless tobacco, even with the same average body concentrations of nicotine. Nicotine Elimination Nicotine is rapidly and extensively metabolized primarily in the liver but also to a small extent in the lung and kidney. Renal excretion depends on urinary pH and urine flow and accounts for 2 to 35 percent of total elimination (78). The half-life of nicotine averages 2 hours, although there is considerable individual variability that ranges from 1 to 4 hours (9). The major metabolites of nicotine are cotinine and nicotineN-oxide. Neither metabolite appears to be pharmacologically active (8). Because of its long half-life, cotinine is commonly used as a marker of nicotine intake in survey and cessation studies. It should be recognized, however, that first pass metabolism of swallowed nicotine 142 may result in wtinine levels that are disproportionately higher than nicotine levels with the use of smokeless tobacco compared to the use of cigarettes. Nicotine and Cotinine Levels in Users of Smokeless Tobacco Blood or plasma concentrations of nicotine in cigarette smokers who were sampled in the afternoon generally ranged from 10 to 50 ng/ml (10). The increment in blood nicotine concentration after a single cigarette is smoked ranges from 5 to 30 ng/ml, depending on how the cigarette is smoked (llJ2). In users of moist oral snuff or chewing tobacco, the levels of nicotine increase an average from 2.9 to 21.6 ngiml during 8 hours of repeated use (1). In habitual users of nasal snuff, blood levels of nicotine increased on average by 12.6 ng/ml after a single dose of snuff, and levels aver- aged 36 nglml after multiple doses (4). Similarly, blood cotinine concen- trations averaged 197 ng/ml and 411 ng/ml in groups of oral and nasal tobacco users, respectively, compared to an average cotinine level of 300 q/ml for cigarette smokers described in many studies 11,4). These comparisons indicate that the intake of nicotine and nicotine levels in habitual users of smokeless tobacco are similar to those that are ob- served in habitual cigarette smokers. Time Course of Nicotine Turnover During Daily Tobacco Use Tobacco use is commonly considered to be a process of intermittent dosing of nicotine, which in turn is rapidly eliminated from the body. Smoking produces considerable variations from highest to lowest blood nicotine levels from one cigarette to the next cigarette. However, con- sistent with a half-life of 2 hours, nicotine accumulates over 6 to 8 hours of regular smoking, and nicotine levels persist overnight, even as the smoker sleeps (13). The same accumulation is probable with repeated smokeless tobacco use. Thus as with the smoker, the smokeless tobacco user may be exposed to nicotine for 24 hours each day. References (1) Hoffmann, D., Harley, N.H., Fisenne, I., Adams, J.D., and Brunne mann, K.D. Carcinogenic agents in snuff. JNCI 76: 435-437,1986. (2) Hoffmann, D., Hecht, S.S., Omaf, R.M., Wynder, E.L., and Tso, T.C. Chemical studies on tobacco smoke. XLII. Nitrosonornicotine: Presence in tobacco, formation and carcinogenicity. In: E.A. Walker, P. Bogovski, and L. Griciute (eds.). Environmental N-Nitroso Com- pounds. Analysis and Formation (IARC Scientific Publications No. 14). Lyon, France, International Agency for Research on Cancer, 1976, pp. 307-320. 143 (3) Benowitz, N.L., Hall, S.M., H eming, R.I., Jacob, P., III, Jones, R.T., and Osman, A.L. Smokers of low-yield cigarettes do not consume less nicotine. N. Engl. J. Med. 309: 139-142, 1983. (4) Russell, M.A.H., Jarvis, M.J., Devitt, G., and Feyerabend, C. Nicotine intake by snuff users. Br. Med. J. 283: 814-817, 1981. (5) Russell, M.A.H., Jan&, M.J., West, R.J., and Feyerabend, C. Buccal absorption of nicotine from smokeless tobacco sachets. Lancet 8468: 1370, 1985. (6) Jenner, P., Gorrod. J.W., and Beckett, A.H. The absorptionof nicotine 1 `-N-oxide and its reduction in the gastrointestinal tract in man. Xeno- biotica 3: 341-349, 1973. (7) Beckett, A.H., Gorrod, J.W., and Jenner, P. A possible relation be tween pKa and lipid solubility and the amounts excreted in urine of some tobacco alkaloids given to man. J. Pharm. Pharmacol. 24: 115-120, 1972. (8) Benowitz, N.L., Kuyt, F., Jacob, P.. Jones, R.T., and Osman, A-L. Coti- nine disposition and effects. Clin. Pharmacol. Ther. .%5? 139142,1983. (9) Benowitz, N.L., Jacob, P., III, Jones, R.T., and Rosenberg, J. Inter- individual variability in the metabolism and cardiovascular effects of nicotine in man. J. Pharmacol. Exp. Ther. 221: 368-372,1982. (10) Russell, M.A.H., Jarvis, M., Iyer, R., and Feyerabend, C. Relationship of nicotine yield of cigarettes to blood nicotine level concentration in smokers. Br. Med. J. 280: 972-976, 1980. (11) Armitage, A.K., Dollery, C.T., George, C.F., Houseman, T.H., Lewis, B.J., and timer, D.M. Absorption and metabolism of nicotine from cigarettes. Br. Med. J. 4: 313-316, 1975. (12) Herning, R.I.. Jones, R.T., Benowitz, N.L.. and Mines, A.H. How a cigarette is smoked determines nicotine blood levels. Clin. Pharmacol. Ther. 33 84-91, 1983. (13) Benowitz, N.L., Kuyt, F., and Jacob, P., III. Circadian blood nicotine concentration during cigarette smoking. Clin. Pharmacol. Ther. 32: 758-764. 1982. NICOTINE ADDICTION ASSOCIATED WITH SMOKELESS TOBACCO USE Background and Definitions Clinical observations and data, historical anecdotes, and sworn testi- mony all support the conclusion that some users of smokeless tobacco are unable to abstain permanently from smokeless tobacco, even when iIl health is apparent (1). Such observations suggest that smokeless tobacco use can become a form of drug addiction or dependence.* o The terms "addictnn and dependence" will be used almost interchangeably throughout this section While man argue the value of one of these terms over the other, it is im i-tam to note that in the context of this chapter ???? B f& B dress the questkon of whether ruwtine resulting from smo or smokeless tobacco use leads an individual to lose voluntary control over bk or her use of t&acco products (i.e.. does the drug cause either dependence or addiction). 144 This section of the report will evaluate the scientific evidence that smokeless tobacco is an addictive substance whose use results in drug dependence. Drug dependence as used in this review is defined in accor- dance with the World Health Organization's Expert Committee on Drug Dependence (2) and other recognized sources (3). Drug dependence is substanceseeking behavior that is controlled by the activity of a con- stituent drug in the central nervous system and displaces other behavior such that drug seeking assumes greater priority. IUzrance and physiologic withdrawal may or may not be present (23). and the severity of dependence may vary considerably among individuals. The scientific standard for classifying a drug as likely to cause addic- tion or dependence is based on the degree to which "abuse liability" and "physical dependence potential" are present. Both terms are accepted terminology of the Committee on Problems of Drug Dependence and the Addiction Research Center (ARC) of the National Institute on Drug Abuse (4,5F and are commonly accepted to refer to drugs whose actions are mediated by the central nervous system Abuse liability refers to drug effects that contribute to compulsive self-administration, often in the face of excessive financial cost, physical and social dysfunction, and the exclusion of more socially acceptable behaviors (56). Physical dependence potenti (also referred to as physiological dependence potential) pert&s to the direct physiologic effects that are produced by the repeated administration of a drug that results in neuroadaptation (34). Neuroadaptation is characterized by demonstrated tolerance to the effects of the drug and the occurrence of physiologic withdrawal signs following the termination of drug administration. Physiologic or physical dependence, as evidenced by physiologic and behavioral rebound (withdrawal) effects, is neither necessary nor suffi- cient to define drug dependence (35). Nevertheless, the process of drug dependence and abuse entails physical components, including physical interactions between drug and tissue in the central nervous system (specific receptors in the case of some drugs such as nicotine and opioids) that are critical~ Three lines of evidence are important to assess the abuse liability and physical dependence potential of smokeless tobacco use. The first in- volves inference from the systematic comparison of tobacco use (includ- ing smokeless forms) to the use of prototypic dependenceproducing drugs (e.g., alcohol, morphine, and cocaine) to determine whether the t A concept that is central to many discussions of drug de 8" dence is that the substance reduces damage or debilitation. This asp& of tob.scco dependence will not be a dressed here because extensive 8. ta already exist in- dicnting the actual toxicity of tobacco and there is widespread recognition even by tobacco users that the sub stance I.3 harmful. 145 patterns of tobacco use, as well as the behavioral and physiologic effects of such use, are similar to those of the prototypic dependenceproducing drugs. This issue is discussed below in the section entitled "Commonali- ties Between Tobacco Use and Other Dependence-Producing Substances." The second line of evidence emerges from recent studies in which nicotine was evaluated using the same methods and criteria that have been used to evaluate any substance that is suspected of causing abuse and physical dependence. This deductive approach evaluates whether nicotine meets rigorous experimental criteria as a drug that has sub stantive liability for abuse and physical dependence potential. This issue is discussed in the section entitled "Experimental Studies of the Abuse Liability and Dependence Potential of Nicotine." The third line of evidence comes from recently completed studies that involve direct assessments of the abuse liability and dependence poten- tial of orally given nicotine. E xamination of these studies provides indi- cations of whether the consumption of nicotine through oral forms of administration delivers pharmacologically active quantities of nicotine to the bloodstream and whether smokeless tobacco itself meets specific criteria for abuse liability and dependence potential. This issue is dis- cussed in the section entitled "Evidence That Orally Delivered Nicotine (Including Smokeless Tobacco) Has a Liability for Abuse and a Poten tial to Produce Dependence. " Taken together, the first and second lines of evidence support the con- clusion that smokeless tobacco contains an addictive substance. The third line of evidence suggests that delivery of the addictive substance (nicotine) in the form of smokeless tobacco does not alter its addictive properties. Commonalities Between Tobacco Use and Other Addictive Substances The assertion that tobacco use can occur as a form of drug addiction rests firmly on the observed commonalities between the use and effects of tobacco and the use and effects of addictive substances such as alto hoi, opium, and coca. Systematic reviews of these commonalities have been published (%ll), and the major points that tobacco and addictive substances have in common are as follows: o A centrally (CNS) active substance (drug) is delivered. o Discriminative (subjective) effects are centrally mediated. o The substance (drug) is a reinforcer for animals. o The patterns of acquisition and maintenance of substance inges- tion are orderly. o The patterns of self-administration of the substance are orderly. 146 o The patterns of self-administration of the substance vary as a func- tion of the dose that is consumed. o Tolerance to the behavioral and physiologic effects of the sub stance develops with repeated use (neuroadaptation). o Therapeutic effects may be produced by the substance. o The treatment of addiction resulting from the substance (drug) involves similar strategies. The evidence concerning tobacco and these factors is presented in the following subsections. `Ibbacco Use Delivers a Centrally Active Substance-Nicotine The fundamental commonality between tobacco use and the use of known addictive substances is the delivery of a chemical to the central nervous system The primary agent in tobacco, nicotine, is delivered to the central nervous system in all commonly used forms of tobacco (12). The fact that cigarette smokers will substitute smokeless tobacco, when cigarettes are not available or when the use of combustibles is restricted, certainly suggests that different forms of tobacco use pro duce acceptably similar effects for the user (13). . . . Dmnmmative Effects of Nicotine Are Centrally Mediated Nicotine, like other drugs of abuse, produces doserelated effects in animals, which an be attenuated by centrally acting antagonists (1416). When the animals confuse these effects with other drugs (i.e., effects partially generalize to other drugs of abuse), it is more likely to be a drug like amphetamine rather than a sedativelike drug (17). These findings are also consistent with data derived from studies with humans in which the doserelated effects of intravenously given nicotine were attenuated by mecamylamine pretreatment (18). Nicotine Is a Reinforcer for Animals Most drugs that are abused by humans are voluntarily self- administered when they are made available to animals in laboratory studies; in other words, the drug serves as a reinforcer or a reward (19,20). Such findings confirm that the physiologic effects of the drug in the central nervous system are sufficient for the substance to control behavior by virtue of its reinforcing effects. Definitive studies ???? were undertaken in the early 1980's support this statement. As seen in table 1, nicotine has now been shown to function as a reinforcer for five non- human animal species and under a variety of conditions (21,227. F'urther- more, its functional behavioral effects are similar to those engendered when other drugs of abuse (e.g., cocaine) serve as reinforcers. Patterns of Acquisition and Maintenance of Tobacco Use Are Orderly The use of tobacco, like that of prototypic addictive substances, is often initiated due to peer influences (2.5). The contribution of social 147 TABLE I.-Summary of Reports in Which Nicotine Was Available Under Intravenous Drug Self-Administration Procedures Study SpC!CieS Reinforcement Schedule Main Finding Comment Deneau Rhesus and Inoki Monkey (19371 Yanagita, Rhesus Ando, Monkey OiIlUIIUl, and Ishida (1974) Lang. Hooded Latiff. Rat McQueen. and Singer (1977) Singer, Hooded Simpson, Rat andLang (1973) Fixed-ratio 1 (FR 1). Several doses of nicotine were tested. Experiment 1: FR 1. Several doses of nicotine and lefetamine and saline were t&MI. Nicotine did not - serve as a reinforcer when compared to saline or lefetamine. Experiment 2: Stable rates of No direct test of FR 1. Several nicotine S-A reinforcing doses of nicotine occurred in most efficacy was done. were continuously subjects but were available for at not clearly related least 4 weeks. to dose. Experiment 3: Progressive ratio (PR) procedures. `ho doses of nicotine and saline and three doses of cocaine were teSti. At 0.2 mg/kg nice Nicotine was tine, response marginaNy rein- rates slightly forcing when exceeded those compared to maintained by cocaine. dine or the lowest cocaine dose (0.03 mg/kg). FR 1. Nicotine and saline were tested in food- sated and food- deprived rats. Concurrent [(FR 1: nicotine). (Fixed- time 1 min.: food pellet)] in food- deprived rats. Subsequently, the rats were food- sated. Two monkeys Currently initiated self- accepted criteria administration to assess reinforc- (S-A); the others ing efficacy were required a prim- not achieved. ing procedure. In food-deprived - (but not food- sated) rats, nicotine was a reinforcer when compared to saline. Food satiation Results were simi- decreased rate of lar to those nicotine S-A, how- obtained when ever, nicotine was rats were similarly a reinforcer in tested with both conditions. ethanol. 148 TABLE l.-Continued Study Species Reinforcement Schedule Main Finding Comment Griffiths, Baboon Brady, and Bradford (1979) Hanson, Albino Rat Iveskr, and Moreton (1979) Latiff, Hooded Smith, and Rat Smith and Hooded L=% Rat (1980) Goldberg, Squirrel Speahnan, Monkey and Goldberg (1981) FR 160 followed by 3-hr. timeout. Several doses of nicotine and saline were substituted for cocaine. FR 1. Several doses of nicotine and saline were teSti. Cone (FR 1: injec- tion) (FT 1 min.: food pellet). Several doses of nicotine and saline were teSti. FR 1. One dose of nicotine and saline were tested. Second order schedule FI 1 or 2 min. (FR 10: stimulus) followed by 3-min. timeout. One dose of nico- tine and saline was tested. Number of nice- tine injections per day did not exceed that of saline. Mecamylamine (centrally acting antagonist) but not pent&km (peripherally act- ing antagonist) altered S-A behavior. Nicotine was a reinforcer relative to saline. Urine pH manipulations had mild effects on rate of S-A only during initial exposure to nicotine. Nicotine was established as a reinforcer both with and without a concurrent food delivery schedule Caffeine, ephedrine, and a variety of other similarly tested stimulants did serve as rein- forcers relative to saline in this paradigm. Group data suggest that nicotine was a reinforcer; however, there was no clear dose effect curve. Rate of S-A was inversely related to dose during initial exposure to nicotine but not after nicotine S-A was established. - in food-deprived but not food-sated rats. Nicotine main- Demonstrated the tained high rates importance of of responding. ancillary environ- Rates decreased mental stimuli in markedly when (1) maintaining high saline replaced rates of nicotine, (2) the responding. brief stimuh were omitted, and (3) subjects were pretreated with mecamylamine. 149 TABLE l.-Continued Study Species Reinforcement Schedule Main Finding Comment Ator and Baboon Griffiths (1981) Dougherty, Rhesus Miller. - Monkey Todd, and Kosten- bauder (1981) Goldberg and Spealman (1982) Singer, Wallace, and HalI (19821 Squirrel Monkey Long Evans Rat FR 2 followed by Nicotine was 15-sec. timeout. marginally rein- Several doses of forcing compared nicotine and saline to saline across a and cocaine were narrow dose tested. range. FI 16 and second order FI 1 min. (FR 4: stimulus). Several doses of nicotine and saline were tested. FI 5 min. Several doses of nicotine and cocaine and saline were tested. CONC [FR 1: nicotine) (FT 1 min.: food pellet)]. One dose of nicotine was tf?Skd. Nicotine main- tained higher rates of S-A than saline under the FI and second order schedules but was only a margjnally effec- tive reinforcer when continu- ously available. Nicotine and Initial dose response curve was inverted U-shaped, and final dose response curve was flat (from abstract of study). Establishment of nicotine as a rain- forcer required several months using procedures that typically require only a few days to establish cocaine or codeine as reinforcers. This study also cocaine were quali- showed that tatively similar nicotine could reinforcers when serveasa compared to punisher similar to saline. Cocaine electric shock. maintained higher rates of respond- ing in one of two monkeys. Meca- mylamine pre- treatment reduced rates of nicotine S-A. A group of rats Extended the with 6-OHDA range of lesions in the scheduled-induced nucleus accum- behaviors that are hens S-A nicotine inhibited by such at lower rates lesions. than a sham- lesioned group. 150