Tobacco Documents Online

SPECIAL ARTICLE THE REEMERGENCE OF SMOKELESS TOBACCO GREQOR~" N. CONNOLLY, D.M.D., M.P.H., DEBORAH M. ~'INN, PH.D., STEPHEN S. HECHT, PH.D., JACK E. HENNINGFIELD, PH.D., BAILUS WALKER, JR., PH.D., M.P.H.. AND DIETRICH HOFFMANN, PH.D. Abstract Smokeless tobacco (snuff and chewing tobac- co) is reemerging as a popular form of tobacco, particular- ly among male adolescents. In different regions of the United States, from 8 to 36 percent of male high-school students are regular users. The use of smokeless tobacco has been shown to cause oral-pharyngeal cancer. The strongest link is with cancers of the cheek and gum. White mucosal lesions (leukoplakia) are found in 18 to 64 per- cent of users, often at the site where the tobacco was held. Other associations have been suggested for cancers of the esophagus, larynx, and pancreas. Nitrosamines, found in high concentrations in smokeless tobacco, most likely have a role in its carcinogenicity. Other health prob- lems include periodontal disease, acute elevations of blood pressure, and dependence. In early 1986, after action at the state level, Con- gress enacted a federal law requiring health-warning labels on packages of smokeless tobacco and a ban on electronic advertising. Other regulatory measures under consideration include raising state and federal excise taxes, tightening controls on advertising, and prohibit- ing sales to minors. In view of the recent growth of this problem, policy makers are taking the opportunity to in- tervene with preventive measures to protect a new gen- eration of tobacco users. (N Engl J Med 1986; 314: 1020-7.) T.WO types of sm.okeless tobacco, snuff and chew- ~ng tobacco, are ~.n common use. Snuff is a cured, ground tobacco that is produced in three forms: dry. snuff, moist snuff, and fine-cut tobacco. Chewing to- bacco also comes in several forms, including the popu- lar loose-leaf variety, plug tobacco, and the less popu- lar twist chewing tobaccoJ"~ The most common way of using smokeless tobacco in the United States is either plating a pinch of snuff between the gum and cheek or chewing the leaf or plug. The tobacco mixes From the Massachusetts Dcpanmem of PublicHealth. Boston: the Division of Health Examination Statistics. National Center for Health Statistics (U.S. Depan- i~ent ~" Heakh and Human Services). Hyattsville, Md.; the Naylor Dana Institute for Disease Prevention. American Health Foundation, Valhalla. N.Y.; and the National lnstitate on Drug Abuse. Bethesda. Md. Address reprint requests to Dr. Connolly at the MassachuscnS Depanmem of Public Health, 1.50 Tremont St., Boston, MA 02111. The studies at the American Health Foandation were supported by grants (CA- 29580 and CA-21393l from ~e National Cancer Institute. The opinions or assertions contained herein are those of the authors and are not to b¢ construed as reflecting the official views of the Massachusetts Department of Public Health. the U.S. Dcpanmem of Health and Human Services. or American Health Foundation. No official support or endorsement by the Depart- ment of Health and Human Services is intended or should bc inferred. with the saliva, and the nicotine is absorbed through the oral mucosa into the bloodstreamJ"~ At the beginning of this centu~', smokeless tobacco was the most popular form of tobacco used in the United States. Consumption of chewing tobacco fell from 1.8 kg (4 lb) per person per year at the start of the century to 0.2 kg (0.5 lb) by the early 1960s. A less dramatic, 50 percent, decline in the use of snuff" began later.7 In contrast, per capita consumption of ciga- reues rose from 150 cigarettes per person in 1910 to a high of 4200 by the mid-1960s.~ An upswing in the use of smokeless tobacco, espe- cially of moist snuff, began early in the 1970s. Sales of moist snuff rose dramatically from 10.7 million kg (23.7 million lb) in 1978 to 16.7 million kg (37.1 mil- lion lb) in 1984, a 55 percent increase, and sales of chewing tobacco also rose, from 36 million to 39 rail- lion kg (80 million to 87 million lb).~,~° Heavy promotion of moist snu. ff by the tobacco in- dustry has been cited as one of the main reason~ for the great rise in sales.~ In 1983, one manufacturer spent $6.8 million on promotion of a new brand of Reprinted with permission N Engl J Med: Vol. 314

Vol. 314 No. 16 SMOKELESS TOBACCO -- CONNOLLY ET AL. I021 moist snuff sold in small "tea-bag" pouchesJ t,v:, This low-nicotine product has been marketed as a clean, neat introduction to snuff use and as an alternative to smoking. It is being promoted particularly in areas of the country not known for snuff use, such as the urban Northeast]s In a 1983 survey, this product was ranked as the third most recognized brand-name to- bacco product in the United States -- the first time a non-cigarette achieved such statusJ2 Promotional ef- forts have included television advertisements that fea- ture professional athletes, a college marketing pro- gram, distribution of free samples, and sponsorship of sporting events. Twelve recent surveys have found that 8 to 36 percent of male high-school and college students throughout the United States are regular users.~-25 It is estimated that there are at least 10 million users in the countrT, of whom 3 million are under the age of 21.2 The highest use rates are in the South and West. Nevertheless, in Massachusetts, a state with no recent previous tradition of use by adults or adolescents, 28 percent of male high-school students reported trying smokeless tobacco at least once during the previous yearfl~ These surveys geiaerally find less than 1 per- cent use by girls. Most surprising is the use by very young children; an 11 percent rate of use in eight-to-nine-year-olds was reported in one study)6 The use of smokeless tobacco products seems to be increasing over time. In a Louisiana study, snuff use among white 12-to-13- year-old boys rose from 7 to 98 percent between 1975 and 1982Yg Product advertising, peer pressure, and restrictions against smoking have been cited as rea- sons for use at an early age.~6 There is concern that many young users of smokeless tobacco may switch to cigarette smoking as the)' grow older. In a Washington State survey of 1281 elementary-school children, two thirds of th~ smokeless-tobacco users took up smoking over a two-year period.2'~ After the discover)," that tuberculosis was transmit- r " ted through expecto atton, it became both illegal and socially unacceptable to spit in public placesfl~ The tobacco chewer in the later years of the 19th century may have felt many of the pressures that today's smoker feels when smoking publicly, h is possible that man)" young people took up the smoking habit in the belief that it was a safe alternative to tobacco chewing. As history may be repeating itself, there is new scien- tific evidence to be considered in evaluating the health risks associated with smokeless tobacco. Oral-pharyngeal cancer accounts for 3 percent of a]| cancers in the United States and is the seventh most common cancer.''~ Eleven of every 100,000 persons in the United States eventually l~ax'e some form of oral cancer, which resulted in 28.950 new cancer cases and 9500 deaths from oral cancer in 1985.2~.Mthough smoking habits probably account for many of these cancers, segments of the population using smokeless tobacco are at an increased risk. as the following epidemiologic and laboratory, evidence shows. EPIDEMIOLOG|C EVIDENCE The first case report linking the use of tobacco in any form to cancer, published over 200 years ago, de- scribed nasal tumors in several patients who had a long histoW of inhaling snuff.:a9 Later case reports, especially from the southern United States, noted that a relatively high proportion of patients with oral can- cer used smokeless tobacco,ao-4~ Numerous reports have described the cancer as arising preciseIy where the tobacco was placed,a7'4~'49 The description of a tumor in the ear of a Minnesota farmer who had placed snuff there for 42 years is a case in point.4s In the United States, most (90 percent) of the can- cers occurring in the oral cavity are squamous-cell carcinomas.2a Some investigators have reported that verrucous carcinomas, slow-growing wart-like lesions, are very common cancers among smokeless tobacco users,a~,sa.4s However, recent evidence suggests that they account for only a small proportion of carcino- mas in such users.4~ In th~ absence of control groups, these reports are hard to interpret, but analytic studies confirm the as- sociation between smokeless tobacco and cancer. To investigate high rates of death from oral cancer among white women in the southern United States,~°,5~ the National Cancer Institute and the University of North Carolina have initiated a case-control stud,,- of oral and pharyngeal cancers of women in l'(ortl~ Caroli- na.~2 White women with oral or pharyngeal cancer were four times more likely to have used snuff than were controls. The association between snuff dipping and oral cancer was somewhat weaker among blacks, probably because of the shoi'ter duration of use or lower consumption (or both). Among the women with cancer of the cheek and gum, the relative excesses of cancer increased from about 1 $-fold among those with 1 to 24 or 25 to 49 years of snuff use to 50-fold among those with 50 or more years of use. No other variable could eliminate snuff as a risk factor, including smok- ing, age, area of residence, denture status, or the use of proxy respondents.~'~ These findings were also consistent with other case- control studies in the United States and Scandina- via.~6"s6"6~ A study in Georgia,~ for example, showed that snuff use was far more common in women with oral or pharyngeal cancer than in controls in most age groups. The difference in use was particularly striking among rural women; 75 percent of those with oral or pharyngeal cancer dipped, in contrast to 20 percent or less in the three control groups. The rural cases in- cluded only a few smokers (about 7 percent), so that smoking habits could not account for the association. Two cohort studies described a twofold to threefold increase in the risk of oral cancer among users as corn-

I022 THE NEW ENGLAND JOURNAL OF MEDICINE April 17, 1986 pared with nonusers of smokeless tobacco.6s One study involved 1 7,000 U.S. men followed for 15 years; the-other involved 12,000 Norwegians traced for 12 years. Several reports did not show a significant associ- ation,66"69 in two cases because of problems in design. In one cohort study,~s'69 1751 snuff dippers with non- malignant oral lesions were followed over a 10-year period; no cases of cancer were reported, but the fol- low-up method, which failed to find 201 persons, prob- ably missed many patients hospitalized with oral can- cer or dying from it. As in the study in North Carolina,52 a dose- response relation between the extent of smokeless to- bacco use and cancer was demonstrated in a large study based on interviews with a sample of cancer patients diagnosed from 1969 to 1971 in 10 areas of the United States, as part of the Third National Can- cer Survey.~ Adjusting for other risk factors for oral cancer, the investigators found that among men, mod- erate users of smokeless tobacco had a fourfold in- crease in the risk of oral cancer and heavy users had almost a sevenfold increase. There is limited evidence regarding a relation be- tween smokeless tobacco use and cancer outside the oral cavity. Weak to moderate positive associations between smokeless tobacco use and cancer of the esophagus have. been described in three case-control studies61,~6,7o and two cohort studies,6~ and associ- ations with cancer of the larynx were noted in two studies,~'~6 but alternative explanations could not al- ways be ruled out. Oral snuff use has been linked to certain types of nasal-sinus cancer,71 and smokeless tobacco use has been linked to pancreatic cancer in two cohort studies.~5'7~ In India, parts of Central Asia, and Southeast Asia, oral cancer is far more frequent than in the United States. In fact, it is the most common cancer in that area, accounting in some regions for 40 percent or more of all cases.5':~'~6 Smokeless tobacco .taken oral- ly, alone or together with such ingredients as areca nut and piper betel leaf and lime, has been shown to in- crease the risk of mouth cancer greatly,=7'~8 and the use of quids containing smokeless tobacco no doubt explains why some of these regions have the world's highest rate of mouth cancer. Although oral cancer may also occur in the absence of white mucosal lesions (leukoplakia), such lesions are common in the mouths of patients with oral cancer who have a histo~" of smokeless tobacco use.41'4~'44'45 The Center for Oral Precancerous Lesions of the World Health Organization has labeled smokeless to- . 79 ~ bacco a cause of oral leukoplakm. The severi~ of the condition has been found to be directly proportional to the duration of exposure,~-~'s°'s~ and remission may occur when use stops)~62"69~° Oral examinations of smokeless tobacco users often reveal a high prevalence of leukoplakia (18 to 64 percentLss-8°.s-~ Lesions termed "white patches" but not specifically described as leukoplakia were noted in 43 to 62 percent of ado- lescents using smokeless tobacco who were examined in two Colorado surveys.~'~'s~ Most of the leukoplakias are reported to have arisen at the site where the smokeless tobacco was held.6~'a°'a~ In three biopsy series, epithelial dysplasia was found in 5 to 18 percent of patents with leukoplakia and a longstanding smokeless tobacco habit.62,a~,a5 Limited cancer data have been reported among smokeless tobacco users with leukoplakia, probably because of the difficulty of long-term follow-up of large numbers of users with lesions. In each of two small positive studies, however, one new oral cancer in users was found over a variable follow-up period, yielding malignant-transformation rates of 3.1 and 4.5 percent.6~.s6 According to the 1978 Report of the World Health Organization and a recent report from the United States,79,a7 between i.8 and 17.5 percent of leukoplakias ultimately become malignant. The latter study involved primarily older patients with several different forms of extensive leukoplakia. Epidemiologic findings from different geographic areas consistently show that exposure to smokeless tobacco increases the risk of mouth cancer, especially at or near the site of placement, and that this risk increases with. the degree of exposure.. Therefore, it must be concluded that smokeless tobacco is a cause of oral cancer. This conclusion parallels observa- tions about the relation of tobacco smoke to oral can- cer. It is strongly supported by the experimental evi- dence that follows, and is in line with the findings of the International Agency for Research on Cancers and the evidence reviewed at a recent Consensus Develop- ment Conference on Health Implications of Smokeless Tobacco.~ EXPERIMENTAL EVIDENCE Experiments to test the potential for snuff to induce oral tumors in Syrian golden hamsters exposed for I0 weeks to 18 months have been uniformly negative, possibly because of the relative insensitivity of the hamster's oral cavity to the carcinogens present in snuff.8s'93 More recently, however, application of snuff to the cheek pouches of hamsters infected with herpes simplex virus was reported to result in epithe- lial dysplasia and invasive squamous-cell carcinoma in more than 50 percent of the animals.94 Application of snuff for 9 to 22 months to a surgical- ly created test canal in the lip induced I squamous-cell carcinoma among ~2 rats, as compared with none in control rats.95 In a similar study, rats exposed to snuff alone or in combination with herpes simplex virus Type I had a higher incidence of tumors or tumor-like conditions than control rats or"rats exposed to the virus alone.96 Short-term treatment of mouse labial mucosa with both snuff extract and herpes simplex virus Type I produced more epithelial dysplasia and other changes than did either treatment alone,9~ indi- cating that interactions between the virtu and carcino

Vol. 314 No. 16 SMOKELESS TOBACCO -- CONNOLLY ET AL. 102q gens present in snuff may have a role in the induction of tumors. Three types of chemical carcinogens have been de- tected in commercial snuff products: benzo[a]pyrene, a representative polynuclear aromatic hydrocarbon; 2'°Po, an a-particle-emitting metal; and a variety of nitrosamines. Levels of benzo[a]pyrene, which may occur as a contaminant of the tobacco, range from less than 0.1 to 63 ng per gram (parts per billion) of tobac- co. Amounts of 2'°Po are between 0.16 and 1.22 pCi per gram of dry snuff.98 The ot radiation emitted by 2mPo in snuff that is repeatedly focused on a relatively small area of the cheek and gum may be important in snuff-induced carcinogenesis.gs Nitrosamines occur at high levels in snuff. Because of their known carcino- genicity, these agents are considered to be importaht risk factors for cancer.99'1°° Over 300 nitrosamine compounds have been shown to produce cancer in animals .99,101 The four most common tobacco-specific nitrosa- mines found in snuff are N'-nitrosonornicotine, N'- nitrosoanabasine, N'-nitrosoanatabine, and 4--(methyl- nitrosamino)-l-(3-pyridyl)-l-butanone (NNK). In addition, nitrosomorpholine and some other nitrosa- mines can also be present)°° NNK and nitrosomorpholine have been shown to be potent carcinogens in animals. N-nitrosonornico- fine is moderately active, ~nitrosoanabasin~ is weak- ly active, and N-nitrosoanatabine has been found to be inactive in one animal studyJ°2''°4 When metabo- lized, these compounds form biologically active in- termediates that can initiate the carcinogenic proc- ess.1°511~ Of particular interest is the formation from NNK of methyldiazohydroxide, which has been shown to methvlate DNA in vivo.1°7'111 One of the products of DI~A methylation is O6-methylguanine, which is capable of miscoding DNAJ°gJ 1o -. Fourteen studies in three different animal specms have shown that exposure to tobacco-specific nitrosa- mines through a variety of routes, including the oral, subcutaneous, and intraperitoneal, produces benign and malignant tumors in a number of differ- ent organ sites, including the oral cavity, esopha- gus, nasal cavity, lung, and liver of rats; the trachea, lungs, and nasal cavity of hamsters; and the lungs of mice.5,~02.1o4,~ t3-1~4 A number of reports show that nitrosamines can induce tumors locally in the mouths of animals. One study noted the formation of oral tumors in female F34~ rats after 50 weeks of oral administration of 0.45 oppm of nitrosomorpholine-~ Two other reports dem- nstrated that NNK2~ and N-nitrosonornicotine1'6 could produce oral tumors in hamsters and rats, even when the lung and esophagus were the major target organs. In a recent study, long-term administration of N-nitrosonornicotine and NNK to the oral cavitT in- duced tumors in 8 of 30 rats (Hecht SS: et al.: unpub- lished data). The total concentration of tobacco-specific nitros- amines in commercial snuff ranges from 5280 to 141,000 ppb,~'1°°'It~ which is 10 to 100 times higher than the levels in the inhaled smoke of one cigarette and 500 to 14,000 times higher than the level allowed by the Food and Drug Administration and the Depart- ment of A.~riculture in consumer products such as beer, baeon~ and baby-bottle nipple~.~2~'~s (Congress has restricted both agencies from regulating the health effects of tobacco.~7) On the basis of lifetime expo- sure, the levels of these nitrosamines, encountered by a snuff dipper are similar to the doses that produce can- cer in laboratory animals. This high exposure level pres.ents an unacceptable health risk to humans. PERIODONTAL DISEASE AND OTHER HEALTH CONCERNS The oral problems other than leukoplakia that are frequently reported among smokeless tobacco users include gingival recession and gingivitis. A number of case reports~2~'~4 as well as smaller studies~4'~°'8~ have described gingival recession among long-term snuff users. In one study of 14 male college students, 8 had gingival recession of the teeth adjacent to where the tobacco was held. In two surveys of 173 adolescent oral tobacco users in Colorado, gingivai recession was reported in one quarter of the users.~'s~ Among 500 Atlanta~schoolchildren, no significant difference in the prevalence of gingival recession or gingivitis, was found between users and nonusers of smokeless tobacco as long as the mouths of the adoles- cents were clean and free of gum inflammation)~5 However, this study did not employ standard meas- ures to determine changes in gingival health or expo- sure to tobacco. A recent study of Swedish schoolchil- dren used standard periodontal indexes and showed that smokeless tobacco produced gingival inflamma- tion regardless of oral hygiene.l~6 In one study of several brands of chewing tobacco, the sucrose content averaged 15 percentJ~7 Chewing- tobacco extract has also been found to enhance the growth of two forms of streptococci implicated in the production of cariesJ~8 In the only survey addressing this issue, of 565 teenage boys, the prevalence of de- cayed, missing, and filled teeth was slightl.v higher in those who used smokeless .tobacco, although the differ- ence between users and nonusers was not statistically significant.~s5 Some investigators have suggested that the use of smokeless tobacco may be associated with a lower incidence of dental caries, possibly because of increased salivation and the fluoride content of the product. ~ s9 Blood-pressure elevation in users of smokeless to- bacco may be a consequence of the sodium content of the products, of their nicotine content, or of both. An analysis of six brands of snuff yielded an average of 845 mg of sodium per 34 g of tol~accoJ4° In two small studies, users experienced an acute increase in systolic blood pressure, averaging 8 to 18 mm Hg, and ~n one of the reports a 12 mm Hg increase in diastolic pres-

]024 THE NEW ENGLAND JOURNAL OF MEDICLN'E Ap~I 17. 1986 sure was obser~ccd.14]'149 Whether smokeless tobacco could contribute to sustained hypertension is un- known. SMOKELESS TOBACCO AND DEPF.,NVV-NCE Drug dependence is broadly defined as the compul- sive use of a substance and a high tendency to relapse • 143,144 ~ • • " after absunence. The Nauonal lnsutute on Drug Abuse Addiction Research Center uses the objective criteria discussed below to assess the potential for a substance to produce drug dependence,t~ The crite- ria are based on the "psychoactiviw" of the drug, its "euphoriant" properues, and whether its use "re- inforces" further use of the drugJ4~'~46 Studies in humans and animals have shown that nicotine produces dose-related changes in mood and feeling, which are mediated by central nicotine recep- tors- i.e., nicotine is psychoactive)47 Nicotine also proved to be a euphoriant according to objective measures used to evaluate other drugs known to be abused,, such as morphine and amphetamines. 248 Fi- nally, studies in both humans and animals have shown that nicotine serves as a reinforcer and is voluntarily self-administered in several ways, including smoking and intravenous deliver).... 249 The vast body of data on the properties of nicotine has led the National Insti- tute-on Drug Abuse~° and~he L~S. Public Health Service25~ to conclude that nicotine is a prototypical dependence-producing drug, comparable in critical respects to cocaine, .morphine, and ethanol. Promotion by industry reflects the similarities be- tween initiation into the use of smokeless tobacco and the abuse of dependence-producing drugs. One indus- try advertisement advises new users that gum irrita- tion may initially occur but may pass after a few weeks of use.~ A company's brochure instructs new users to hold the tobacco in the mouth for a minute at first and then to increase exposure over time, comparing the experience to the initial use of an alcoholic bever- age.25~ A "graduation process" has been reported as part of industry promotion in the Northeast. Pouches of low-nicotine snuff are initially promoted with the implication that new users will move on to stronger brands of smokeless tobacco over time.~3 There is evidence that smokeless tobacco itself is dependence producing. In one study the mean con- centration of nicotine in moist snuff sold in the United States was found to range from 4.6 to 15.0 mg per gram.98 In addition, two other studies have shown that the use of smokeless tobacco produces serum nic- otine levels similar to those achieved when dependent smokers smoke cigarettesJ54"1~ Patterns of smokeless tobacco use often meet the criteria set bv the American Psychiatric Association for tobacco ciependenceJ~6 Since smokeless tobacco provides an effective means of delivering nicotine to the central nervous system, one must conclude that its use can represent a form of drug dependence and can result in addictive behawior. REGULATORY MEASURE.S TO CURB SMOKELESS ToBacco Us~ The above data demonstrate that the reemergence of smokeless tobacco poses a serious threat to public health and that the use of smokeless tobacco is not a safe alternative to smoking. If the newer brands of snuff had been subject to the same federal regulations that exist for other nitrosamine-containing substances,. their introduction into the United States would prob- ably have been prohibited, as in IrelandJs7 Neverthe- less, there have been increased efforts to impose laws on smokeless tobacco like those governing smoked products. In 1985, five states enacted laws requiring an excise tax on both types of smokeless tobacco, bring- ing the number of states with such taxes to 22 (50 states have excise taxes on cigarettes25S). Con- gress had repealed the federal excise tax on smokeless tobacco in 1965, citing declining sales as a reason. In 1985-1986, one state (Massachusetts) required warn- ing labels on snuff, and 25 others considered similar legislation. In response to these actions, indust~" re- luctantly sought a uniform national labeling law.~59 The bill passed both houses of Congress and was signed into law (P.L. 99-252); it also .included a - ban-on electronic advertisin~ and health warnings- - on printed advertisements that are more striking to the consumer than the warnings on printed cigarette advertisements. Public 'education at the turn of the century helped reduce, the use of smokeless tobacco in this country and should be the cornerstone of today's efforts. In addition, policy makers should continue efforts to sub- ject smokeless tobacco to the same measures that exist for cigarettes. Federal and state excise taxes should be raised so that smokeless tobacco and cigarettes are taxed to the same extent, and sales to minors should be prohibited. Congress has already placed stricter advertising re- strictions on smokeless tobacco than on cigarettes, possibly to set a precedent that will later be applied to smoked products. This activity should be continued. In particular, either a complete ban on advertising smokeless tobacco or a tax on the cost of advertis- ing and promotion should be instituted, as well as a ban on free distribution of products. Public policy makers have an excellent opportunity to halt the re- emergence of smokeless tobacco and in doing so to protect the health of this new generation of young tobacco users. , We are indebted to Dr.Joseph F. Fraumeni, Jr., of the Nation- al Cancer Institute for his suggestions about the section on epide- miology. ]~FERENCES Christen AG. Swaa¢,~ BZ. Gk~er ED. Hende~soa.AH. Smokeless tobac. ¢0: the folk.k~e and socx~l hisu~." of smff~, sneezing:. ~. and ¢:~-wiag..1 Am Dear ~ 1982z 105:$21-9.

VoL ~l~ No. 16 SMOKELESS TOBACCO ~ CONNOLLY ET AL. I025 2. National Insdmres of Health. Consensus Development Conference state- ment: health implicatiom of smokeless tobacco use. Bethesda, Mr.: Na- tional Institutes of Health, 1986:1-8. 3. Voges E. Tobacco encyclopedia. Mainz, West Germany: Tobacco Janmal lntematiooal, 1984:293. 4. United States Department of Agriculture. Tobacco in the United States. Washington. D.C.: United States Department of Agriculture, 1979. (Misc. publication no. 867 [Agricultural Marketing Service].) 5. International Agency for Research on Cancer. Evaluation of the careino- gemc risk of chemicals to humans: tobacco habits other than smoking, betel-quid and areca-nut chewing, and some related nitmsamines. Vol. 37. Lyon: World Health Organization, 1985:1-291. 6. Shut:on A. Smokeless sales continue to climb, Tub Rap 1982; 109(8):42-4. 7. Schuman LM, Patterns of smoking behavior. Natl lust Drug Abuse R~ Monogr Set 1977: 17:36-66. 8. The Tobacco Institute. 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