Smokeless tobacco use: harm reduction or induction approach?

Preventive Medicine 38 (2004) 309 – 317 www.elsevier.com/locate/ypmed

Smokeless tobacco use: harm reduction or induction approach? Dorothy K. Hatsukami, Ph.D., a,* Charlotte Lemmonds, Ph.D., a and Scott L. Tomar, DmD, DrPH b a

b

Tobacco Use Research Center, Medical School, University of Minnesota, Minneapolis, MN 55414, USA Division of Public Health Services and Research, College of Dentistry, University of Florida, Gainesville, FL 32610, USA

Abstract Background: Smokeless tobacco (ST) substitution for cigarettes as a method to reduce harm has been actively debated. Use of ST as a smoking cessation method or as a means to reduce cigarettes has been proposed. The impact of using ST in these ways is relatively unknown. Method: A review of the different issues and studies related to using smokeless tobacco as a method to reduce tobacco toxin exposure and harm is presented. Results: The toxicity of the product itself varies by brand of ST and across countries. Of the existing studies, comparisons of consequences between cigarettes and ST show that cigarette smoking produces more negative health effects, is likely to have a higher addiction potential and more severe withdrawal, and leads to a higher rate of relapse than ST use. On the other hand, ST use facilitates the use of cigarettes, which is a deadly tobacco product. Additionally, ST is not a harmless product, and a less harmful product, medicinal nicotine, is available as an effective treatment approach. Furthermore, ST products are not under the same regulatory scrutiny as medicinal nicotine products. Conclusions: Considerably more research and product regulation is necessary prior to considering smokeless tobacco as a harm reduction method. D 2003 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved. Keywords: Smokeless tobacco; Harm reduction; Toxicity

Introduction In recent years, consideration has been given to the use of oral noncombustible or smokeless tobacco (ST) as a harm reduction method for cigarette smokers who are unable or unwilling to quit using tobacco. As defined by the Institute of Medicine report, Clearing the Smoke, Assessing the Science Base for Tobacco Harm Reduction, [1] ‘‘a product is harm-reducing if it lowers total tobacco-related mortality and morbidity even though use of that product may involve continued exposure to tobacco-related toxicants.’’ The use of ST as a harm reduction approach has been fueled by the experiences in Sweden, where the rates of tobacco-related mortality and morbidity have been reduced significantly. These reductions have been attributed to the decreasing prevalence of cigarette smoking resulting from the greater use of snus (oral snuff) among the male tobacco users [2]. Furthermore, several Swedish cohort studies suggest that most smoking cessation by men occurred with the use of ST * Corresponding author. University of Minnesota, Tobacco Use Research Center, 2701 University Avenue SE, #201, Minneapolis, MN 55414. Fax: +1-612-627-4899. E-mail address: [email protected] (D.K. Hatsukami).

[3 –6]. However, a similar reduction in smoking prevalence has been observed among females who have not used snus instead of cigarettes. Therefore, the reduction in prevalence may be a result of other significant tobacco control measures that have been implemented in Sweden [7]. Thus, this issue continues to remain controversial among scientists and tobacco control advocates. The use of ST as a method for reducing tobacco toxin exposure can occur on several levels. ST can be used as a substitute for cigarettes in situations where smoking is not allowed, when inconvenient or to reduce secondhand smoke exposure. Marketing attempts have been made by smokeless tobacco companies aimed at smokers to use smokeless tobacco in situations where they cannot smoke [8] or to switch to ST to reduce secondhand smoke (US Smokeless Tobacco Company, letter submitted to the Food and Trade Commission, 2003). These efforts to capture the market of cigarette smokers may have great economic benefit to the smokeless tobacco companies and lead to great public health harm. For example, this substitution approach would not necessarily lead to lower levels of nicotine or tobacco toxin exposure for the individual. That is, ST would be used in situations where the cigarette smoker would normally not have been able or want to smoke; thereby the use of ST

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could potentially increase overall exposure. Furthermore, this approach may lead to more harm by increasing the maintenance of smoking [8], although others have argued that use of ST products may eventually increase interest in quitting. Two other reduced exposure methods that are potentially more reasonable include the use of ST as a substitute for cigarette smoking for those who are primarily attempting to cut down on number of cigarettes. Or, ST could be used as a cessation tool, either transitionally towards cessation of all tobacco products or as a long-term substitute for cigarette smoking. The focus of this paper is the use of ST among existing cigarette smokers aimed at the latter two approaches. The pros and cons of using these purported harm reduction approaches need consideration because of the current endeavors of the tobacco industry to position ST as a safer alternative to smoking. In addition, a few members of the scientific and public health community are advocating that switching from cigarette smoking to ST use will have significant public health benefits. This paper will discuss the rationale for considering ST as a harm reduction method, the existing although limited literature that examines the efficacy of this approach, and future research recommendations. Although important, no extensive discussion will be presented as to whether public health will benefit if ST was chosen over cigarette smoking as a primary tobacco product.

Rationale Several reasons have been given for the use of ST as a harm reduction method [9]. Prominent among these reasons is the fewer negative health consequences associated with ST compared to cigarettes. Estimates have been made that ST poses about 2% of the mortality risk of cigarette smoking [9,10] and only half of the risk of oral cancer associated with continued cigarette smoking [9]. The average years of life remaining across age groups have been estimated to be the same among quitters of cigarette smoking and smokers who switched to ST [11]. To augment this argument of significant reduced disease risk associated with ST use, in a recent epidemiological survey, the mortality experienced by ever ST users was no different than nonusers of tobacco products whether related to all causes, cancer or cardiovascular outcomes after adjusting for age, race, gender and poverty status [12]. That study, however, has some methodological shortcomings. For example, few significant differences may have distinguished nonusers and ST users because the latter population was comprised of ever users, including one time users, and because ‘‘nonusers’’ also included cigar and pipe smokers, estimated at 24% of men in the United States [13]. In addition, during the time of the initial survey in that study, the primary form of ST used by men in the early 1970s was chewing tobacco [14], which contains lower levels of carcinogens than snuff [15], while female ST users were predominantly using snuff.

These factors may explain, in part, why male ST users in the Accortt et al. [12] study did not appear to be at increased risk for mortality, while female ST users had a 70% increased risk of mortality relative to nonusers. Nevertheless, the lack of combustion products from ST primarily accounts for the reduced toxicity of this product compared to cigarettes [1]. ST users as well as individuals who would otherwise be subjected to secondhand smoke are not exposed to combustion products such as catechols, which are potential human co-carcinogens, or poisonous gases such as carbon monoxide, acetone, ammonia or acrolein. Furthermore, the route of administration also affects the amount of exposure to different areas of the body. Because ST users do not inhale the product and experience less toxins, they are unlikely to experience increased risk for pulmonary disease such as chronic obstructive lung disease, emphysema and lung cancer, although one study showed that rats developed both lung and site-specific oral tumors in rats exposed to tobacco specific nitrosamines, 4-(methylnitrosoamino)-1(3-pyridly)-1-butanone (NNK) and NV-nitrosonornicotine (NNN) [16]. The main disease states associated with ST are oral pathologies including oral cancer and increased risk factors of cardiovascular disease [15,17,18]. The rate of oral cancer is highly likely to be contingent upon the level of tobacco specific N-nitrosamines (TSNAs) in the ST products. Some countries such as Sweden have ST products with relatively low nitrosamine levels compared to other nations such as the United States. In the United States, the concentrations of TSNAs ranges from 5,280 to 141,000 parts per billion (ppb), which is hundreds to a thousands times higher than allowed in food products [18]. A recent study commissioned by the Massachusetts Tobacco Control Program found TSNA levels in U.S. brands of moist snuff that were substantially higher than levels found in a popular Swedish brand [19]. For example, the total TSNA levels for Skoal (UST, Inc.) and Copenhagen (UST, Inc.), the two most popular brands of moist snuff sold in the United States, were 64.0 and 41.1 Ag/g, respectively. Those levels were 15– 23 times higher than the TSNA level of 2.8 Ag/g found in a popular Swedish snus brand, Ettan (Swedish Match). In addition, TSNA levels in Skoal and Copenhagen rose substantially after 6 months of storage at room temperature, while Ettan exhibited no change. Such differences in TSNA levels may explain why studies conducted in Sweden have shown relatively low rates of oral cancer compared to cigarette smokers and levels that are similar to nonusers of tobacco products [20 –22]. On the other hand, in the United States the rate of oral cancer in users of ST is estimated to be 3 – 11 times higher compared to nonsnuff users (e.g., Refs. [23 – 27]). Unfortunately, most of the U.S. studies have limitations since they did not control for smoking or alcohol use, both of which are established risks for oral and pharyngeal cancer. More recent studies found that ST use did not increase oral cancer [28 – 30], but these studies also

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have methodological concerns. The study by Bouquot and Meckstroth [29] was a strictly ecological analysis that compared oral cancer incidence or mortality rates for West Virginia, which is a state with a high prevalence of ST use, with rates for other states with less ST use. That study did not adjust for major confounders such as race. The study by Sterling et al. [28] was based on a very small number of cases of oral cancer deaths and measured all use of ST among persons who died from oral cancer strictly from proxies. Additionally, it used a control group that was not well matched to the case group given the changing epidemiology of ST use in the 1970s and 1980s. The Mashberg et al. study [30] was conducted in a part of the United States where ST use is quite uncommon. Some of the variability in the link between oral cancer and ST use can also be attributed to the varying levels of tobacco-specific carcinogens or nitrosamines in products sold within the United States [31]. Other countries such as Africa and India have ST products with very high nitrosamine levels [32,33]. The high nitrosamine levels may in part account the twofold increased incidence rates of oral cancer in India compared to the United States (cited in Ref. [29]). The type of ST may also account for differences in relative risk for oral cancer. In a pooled analyses of relative risks of oral and respiratory tract cancers in case control studies [34], the relative risk for cancer was significant with the use of dry snuff (RR = 5.9 [95% CI: 1.7, 20]), but minimally increased with moist snuff (RR = 1.0 [95% CI: 0.8, 1.2]) and chewing tobacco (RR = 1.2 [95% CI: 1.0, 1.4]). This analyses, however, has been criticized for including moist snuff brands that contain widely varying levels of nitrosamines and the poor quality of some of the studies, which did not control for confounding factors or which included ST users with varying levels of ST use including minimal use [35]. Other studies have also suggested that a preexisting condition such as herpes simplex virus Type 1 needs to be present to see an increase in oral tumor development associated with ST use (cited in Ref. [18]). Other than oral cancer, there are enhanced rates of oral pathologies associated with ST use including gum recession, inflammation and lesions of the oral cavity including ST keratosis (leukoplakia), tooth erosion and potentially tooth decay, and periodontal alveolar bone loss [15,36]. The prevalence of leukoplakia or oral lesions ranges from 18% to 64% [18] and is as high as 79% in ST users compared to 6% in non-ST users [37]. Even among U.S. adolescents, 38% of daily snuff users had smokeless tobacco lesions [38]. The malignant transformation of these lesions is estimated to be 2% to 18% [18,39]. Unlike cigarette smokers, these oral pathologies associated with ST use are localized to the site of tobacco placement. Although smoking cigarettes is clearly linked to cardiovascular disease, the link between ST use and cardiovascular disease has been equivocal. Some studies have shown an enhanced risk from dying of cardiovascular disease [22] and

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others have shown no increased risk of myocardial infarction [40,41]. However, it is evident that ST use does lead to increased heart rate and blood pressure [42 –44], a modestly higher relative risk ratio (1.7 –1.8) of high systolic and diastolic blood pressure [45,46], and a 2.5 times higher prevalence of hypercholesterolemia [47] compared to nonusers. The observed high blood pressure may in part be due to nicotine as well as the high sodium content in some ST products [18,48]. On the other hand, studies examining other contributors to cardiovascular risk (triglycerides, total cholesterol, HDL, LDL, fibrinogen, thromboxane A2, insulin, glucose, [22,49 – 52]) or carotid intima thickening or femoral atherosclerosis [49,53] found no difference between snuff and nonsnuff users. The risk of cardiovascular disease is often associated with an increase risk of type 2 diabetes, although the reasons for this association are unclear. An increase risk in type 2 diabetes has been found in smokers [54 –57] but to date, only one study has found an increased risk in type 2 diabetes in heavy ST users [58]. Another area of concern with the use of ST is fetal toxicity. Nicotine alone has been demonstrated in animals to be toxic and teratogenic to the fetus, including alterations in neural development [59,60]. Animal studies found that fetal exposure to gastric lavage of ST resulted in decreased birth weight and decreased bone ossification in the offspring [61,62]. Although studies of nicotine’s adverse fetal effects in humans are more difficult, with the high levels of nicotine attained through the use of ST, it is reasonable to conclude that ST has harmful effects on the fetus. The levels of nicotine obtained through ST are significantly higher than that observed with the use of medicinal nicotine products and maximum levels are as high while overall nicotine exposure are higher than that observed with cigarettes because of the prolonged exposure [63,64]. In summary, although the risk for tobacco-associated disease is lower with the use of ST compared to cigarettes, ST still is associated with some risks. The degree of these risks will be dependent on the type, composition, manner of use of the products, and perhaps whether the ST is loose or in a portion bag [65,66]. The overall health effects of ST use include periodontal disease localized to placement of the ST, a potential increase in risk contributors for cardiovascular disease (but not to the same degree as smoking), an increased risk in the development of oral cancer, which may be dependent on the levels of carcinogens in the product, and negative effects on the fetus. It is important to note that the disease risks observed both on an individual and population levels are highly dependent on the pattern of tobacco use. For example, if the individual or a significant portion of the population engages in dual use of the products, then reduced disease may not be observed [8]. The second rationale for the use of ST as a harm reduction approach is the potential for reduced abuse liability associated with ST compared to cigarettes. Reduced abuse potential is important to investigate because of the

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harms associated with ST use and the necessity for the eventual goal of cessation of all tobacco use. Should ST have less abuse potential than cigarettes, then there might be a greater ease of cessation of all tobacco use by substituting ST for cigarettes. Unfortunately, comparing abuse liability across products is difficult and differences cannot be solely attributed to the product itself. That is, the characteristics of cigarette or ST users may play an important role on the abuse potential of a drug. Therefore, comparisons between products must be interpreted with a great deal of caution. One way to determine the abuse potential of a drug is to determine how many individuals exposed to a drug become regular users of the drug. Unfortunately, limited data are available to determine whether individuals exposed to cigarette use have a greater likelihood of becoming addicted to tobacco products compared to individuals exposed to ST use. Data were analyzed from the 2000 National Household Survey on Drug Abuse (NHSDA), a national survey collected on U.S. civilians aged 12 years and older. In this analyses, the rate of individuals ‘‘ever smoking cigarettes’’ who reported cigarette use in the past year (43.8%) or past month (37.5%) was almost twice as high as individuals ‘‘ever using ST’’ and who reported ST use in the past year (24.5%) or past month (18.6%). Those figures remained essentially unchanged when age-adjusted to the 2000 U.S. population. Similar results for smokeless tobacco use were observed in a study with data derived from the 1989 Teenage Attitudes and Practices Survey, which included youth from 11 to 19 years [67]. Results showed that among those who tried ST but never regular users, about 18% reported regular use at the follow-up survey assessed 4 years later. In another study that was conducted by Tomar [68] using data from 1998 National Health Interview Survey (NHIS), 82% of current male smokers reported smoking every day compared to 56% of current snuff users who reported using snuff every day. These data would suggest that cigarette smoking has greater potential to lead to continued or daily use of tobacco than ST. However, when looking at any tobacco use, the data show a different picture. The percent of individuals ‘‘ever smoking cigarettes’’ who reported any tobacco use in the past year (50.6%) or past month (42.9%) was very similar if not slightly lower than individuals ‘‘ever using ST’’ who reported any tobacco use in the past year (61.9%) or past month (53.3%). Therefore, this finding would suggest that ever ST users are as likely to proceed on to the use of other tobacco products such as cigarettes. In fact, the data showed that 37% of the ever ST users reported past month cigarette use. Therefore, current efforts for a more aggressive campaign to market ST products as alternative reduced risk products may result in higher rates of smoking as well, particularly in a climate of competitive marketing between cigarettes and ST. The data however do suggest that ST exposure is less likely to lead to continued ST use compared to cigarette exposure leading to continued use of cigarettes. One factor that may account for this finding is the differences in

pharmacokinetics across the two products. The speed of drug delivery has been associated with abuse liability of a drug [69,70]. The rate of absorption of ST varies with the brand of ST and its pH level. In the United States, Copenhagen has the fastest rate of absorption, while Skoal Bandits has a slower rate of absorption [64]. All brands of ST have a slower rate of absorption than cigarettes. Furthermore, the arterial levels of nicotine from ST are likely to be lower than the arterial levels achieved through cigarette smoking. Although no studies have directly compared the relatively reinforcing effects of ST compared to cigarettes, Henningfield and Keenan [70] examined drug liking across tobacco products and found that ST users tend to have slightly lower liking scores than cigarette smokers. However, this result may be attributed to the use of pouched ST, which is likely to lead to a significantly slower and lower magnitude of nicotine absorption than loose ST. A second factor that may contribute to decreased abuse liability may be reduced physical dependence on ST compared to cigarettes. The studies in this area show equivocal results. One study has been conducted to compare withdrawal symptoms between cigarette smokers versus ST users among those individuals who were not interested in quitting. This study showed that more severe withdrawal symptoms are observed among cigarette smokers compared to ST users [71], even though levels and duration of nicotine exposure from each to these products were similar. However, in another study of non-treatment-seeking college-aged students, ST users and cigarette smokers were observed to experience similar severity of withdrawal symptoms [72]. Likewise, when examining a population seeking treatment, withdrawal levels tend to be very similar [73,74] between cigarette smokers and ST users. Another factor that may contribute to reduced potential for dependence on ST is a behavioral one. The number of cues associated with drug use behavior may be associated with the extent of dependence on a drug. Stimuli or cues associated with tobacco use have been associated with enhanced urges to smoke and tobacco use (e.g., Ref. [75]). Although the types of cues that are associated with ST use are similar to those associated with cigarette smoking [36], the number of cues associated with ST tends to be less. On average, ST users seeking treatment take 10 dips per day, while cigarette smokers seeking treatment tend to smoke on the average of 20 –30 cigarettes per day. Therefore, in general, there is the potential for more cues to be associated with cigarette smoking than ST use and perhaps even a greater number of cues when puffs per cigarette are taken into account. All these characteristics of ST compared to cigarettes leads the most important question when considering ST as a method to quit or reduce cigarette consumption: What is the ease of cessation from ST compared to cigarettes? When examining the results from meta-analyses conducted on medication trials for cigarettes, the results show around 18– 24% point prevalence abstinence rates in the nicotine

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patch and gum treatment conditions and 10– 17% in placebo conditions at 6 months posttreatment [76]. On the other hand with ST users, the rate of success at around 6 months is 31 –41% with the use of nicotine patch and gum versus 29 – 35% with the placebo medication [73,74,77,78]. Even with self-help ST cessation treatment, the rates of cessation were 23% and 18% in two low intensity programs offered by mail and phone [79]. In another study involving a 4-year followup of employed participants of a Working Well cancer prevention trial, ST users were more likely than smokers to quit (20% vs. 16%, respectively [80]). These findings demonstrate a greater rate of cessation with ST than cigarettes. However, the host factors associated with cigarette smokers vs. ST users can confound these results. For example, it’s possible that ST users may find it easier to quit because they experience fewer comorbid disorders compared to cigarettes smokers and these disorders have been found to be associated with greater probability of relapse [76]. One way to indirectly look at the issue of whether factors other than the product itself contributes to treatment outcome is to examine whether ST users who have had a history of smoking may have greater difficulty quitting ST use compared to ST users without a history of cigarette smoking. A reanalysis of a data of a previous study [74] showed that smoking history was a better predictor of success than no smoking history even when controlling for age (odds ratio = 1.84 [95% CI: 1.01, 3.23] at 6 months; odds ratio = 1.65 [95% CI: 0.90, 3.04] at 12 months). The results from this study suggest that cigarettes and not necessarily characteristics of smokers may be responsible for the greater difficulty in quitting its use compared to ST. On the other hand, smokers who then switch to ST products may still constitute a different population compared to smokers who have never used ST products. Based on these studies, ST products per se appear to result in lower abuse liability, possibly severity of addiction or dependence than cigarettes, and greater ease of cessation, but still a higher abuse potential than medicinal nicotine [81]. The assessment of abuse potential of nicotine containing products must also consider the accessibility of the product, the palatability (e.g., taste, the absorption of nicotine particularly among initiators) and the cost. Currently, the most toxic nicotine-containing products are the most accessible, are developed to be palatable and are less costly, than the less toxic medicinal products, which also have the least abuse potential. Therefore, the final reason for the use of ST to reduce or quit using cigarettes is the reduced cost of ST compared to nicotine replacement products. Since the lower income population has disproportionately more smokers, the issue of cost cannot be discounted. The unit purchase of snuff is approximately $4. Given the average rate of use of 3.5 tins per week [36], the cost per day would be about $2. This cost compares with the per unit cost of nicotine replacement agents of $32 for a 2-week supply of generic nicotine patches to $48 for a bottle of the nicotine nasal spray for

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1-week supply, with a per day cost of $2 to $7. The most recent product on the market is the nicotine lozenge, which costs from $38 to $47 for a box that contains 72 lozenges, with a per day cost of about $4. The cost per day of smoking is between $2 (generics) and $3 (Marlboro and Camels) per pack. These price differentials would indicate the importance of increasing the cost of tobacco products through taxation and at the same time reducing the cost of medicinal nicotine so that the cost of the least hazardous medicinal nicotine product would be less that the more hazardous nicotine-containing tobacco products and more attainable to low income individual. In summary, the results show that initiation with either cigarettes or ST will lead to an equal likelihood of continued use of any tobacco product, with a significant number of ST users smoking cigarettes. However, the likelihood and indices of addiction to the specific products tends to be slightly less with ST than cigarettes. Therefore, it may be possible that switching from cigarettes to ST would increase the potential for cessation from all tobacco products. Furthermore, since the unit cost of ST is less than the significantly safer medicinal nicotine agents, ST may be more affordable to consumers. On the other hand, ST is an addictive drug that is not devoid of harm. Furthermore, even with a potentially greater tobacco cessation rate among ST users compared to cigarette smokers, the rate of relapse to ST is 60% or greater.

The effects of smokeless tobacco use on cigarette smoking In the United States, the rate of ST use among cigarette smokers is lower than cigarette use among ST users. The proportion of current cigarette smokers who report using ST ranges from 2.6% [82] to 4.7% (2000 NHSDA). In a recent study by Tomar [68], about 20% of daily snuff users and 40% of occasional snuff users were smokers. In prior studies, about 22.9% of current ST users were current smokers [82]. Epidemiological data show that a small number of smokers use ST to quit smoking and a substantial number of ST users report a history of cigarette smoking. Survey data show that 6.4% of current and 7% of former smokers have used ST as a smoking cessation aid [83]. The percent of ST users who report having been a former smoker is 33.3% [82]. In a clinic population, about 50% of ST users report a history of cigarette smoking [74]. A couple of important questions in examining the effects of ST on cigarette use are whether ST use leads to reduction in cigarette smoking and whether ST use leads to cessation of cigarettes. Again limited data exist that have examined these areas. We undertook an analysis of the 2000 NHSDA to determine the effects of ST use on cigarette consumption. For this analysis, cigarette smokers who reported past month use of ST were compared with smokers who reported no past month of ST use on cigarette consumption in the past

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month. The results showed significantly reduced smoking among cigarette smokers who used ST compared to those smokers who did not use ST. Differences, although relatively small, were observed for number of days smoking in the past 30 days (19.86 F 12.16 vs. 23.14 F 10.92, respectively, P < 0.0001) and average number of cigarettes smoked per day on days that they smoked (3.73 F 1.59 vs. 4.01 F 1.52, P < 0.0001). The analyses undertaken with the NHIS data also showed that smokers, who used snuff on a daily basis, reported fewer cigarettes smoked than never snuff users, but no differences were observed in number of cigarettes smoked among smokers who used snuff only on some days [68]. Similarly, in another study, occasional snuff users also tended to smoke as many cigarettes as those who did not use snuff, indicating a potentially high amount of tobacco toxin exposure [80]. In an epidemiological survey study, the combined tobacco product users smoked more cigarettes compared to exclusive smokers (42.3 vs. 35.1 mean pack years, respectively). The results also showed that combined use of ST and cigarettes led to a doubling of lung cancer mortality rate compared to exclusive smokers [12]. Few studies have examined the effects of using ST as a cessation method. One way to examine this area is to determine quit success and attempts among smokers who have used ST versus smokers who have never used ST. In one analyses, among a group of ever daily Swedish male smokers who had a history of using ST, 66% have quit smoking versus 45% of ever daily smokers without a history of ST use ( P < 0.001) and the differences were particularly evident among the higher dependency smokers [84]. It is unclear, however, whether that analysis would have found significant differences if adjusted for age, which would be a major confounder of the association in light of the dramatic changes in the epidemiology of snuff use in Sweden during the past 50 years [85] and the large age differences in quitting behavior among smokers. In an analysis of the NHIS [68], male ever smokers (e.g., smokers who smoked at least 100 cigarettes in their lifetime) who currently used snuff everyday were three to four times more likely to quit smoking or to have quit within the past year than male ever smokers who never used snuff. On the other hand, although not significant, ever smokers who used snuff on some days tended to be about half as likely as never users to quit smoking. In terms of quit attempts lasting at least 1 day, the results from this survey showed that male smokers who used snuff only on some days were more likely to have tried to quit smoking in the past year than those who never used snuff. Furthermore, smokers who were ever users of snuff or daily snuff users were not deterred from making quit attempts since the rate in this population was similar to the never users of snuff. Again, this data may not necessarily reflect the efficacy of using the ST product vs. not using the product, but more a function of the characteristics of cigarette smokers who eventually choose to use snuff vs. those who do not. Of concern are the results from Tomar’s study [68] showing that the male smokers who used snuff

on some days made the greatest number of quit attempts, but they were also the least successful in quitting. This result is concordant with those observed in another study in which individuals who used both types of tobacco products were less successful in quitting than those individuals who used only a single tobacco product [80]. Therefore, the co-use of cigarettes and ST may potentially lead to greater difficulty quitting. One group of investigators prospectively examined the characteristics of a small number of smokers who used ST as a method for cessation or sustaining cessation from cigarettes [86]. These investigators found that the transition from cigarettes to ST was primarily made for health reasons and many of these individuals had already experienced adverse smoking related health effects. The transition to ST was made either immediately or after a period of abstinence from cigarettes. A similar group of investigators subsequently conducted a pilot study in this area using Skoal Bandits manufactured by US Tobacco and a lecture about the health effects of tobacco use as the method for cessation [87]. In a population of 63 smokers seeking treatment for cessation, at one year 31% of men and 19% of women had attained 4 weeks of cessation for an overall success rate of 25%. In addition, 7% reduced their smoking by at least 50%. It is notable that of the 16 abstainers, 13 of them still used ST at 1 year with an average consumption of 2.3 cans of ST per week. An additional six subjects quit without using ST products.

Future research directions Although there is sufficient rationale to suggest that ST has the potential to be used as a harm reduction method for cigarette smokers, several significant concerns are also evident. Before any recommendations can be made for the use of ST as a means for cigarette reduction and cessation, several scientific issues need to be addressed. Although ST leads to reduced mortality and morbidity compared to smoking, it is not a safe product and it is addictive. The extent to which this product imposes significantly greater risk than current or future medications for smoking cessation is unknown. Therefore, studies comparing the adverse effects and risk benefit ratio of ST products and existing medications need to be tested and determined, including the abuse liability and its effects on sustained use of the products. In addition, the use of ST as a cessation or reduced smoking aid in a randomized, placebo controlled trial using nontobacco products as a control, as well as comparing ST with current medications for the treatment of cigarette smoking is needed. Studies would need to also determine the persistence of continued use of ST, proportion that use cigarettes and ST concurrently, and consequent impact of exposure. It is possible the concurrent use of tobacco products confer greater tobacco toxin exposure [80] and risks. This area needs to be carefully examined given the

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current efforts by tobacco industry to advertise ST as a safer product than cigarettes and to advertise for the use of these products in situations where smokers cannot smoke [8]. Another area that requires more systematic and careful investigation is determining whether reduction in mortality and morbidity is observed among those who persist in the use of ST after smoking cessation or after smoking reduction, particularly given the long duration of smoke exposure before the change in tobacco products. If this tobacco substitution should prove to be effective for cessation, then consideration should be given to who should be targeted for the use of ST. Should the target population be the inveterate smoker, the low income uninsured smoker with limited resources, and or smokers who have failed at all existing treatments? Studies would need to be conducted on the methods for use of ST to optimize cessation success and minimize continued use of ST. Finally, it would be vital to examine the public health and legal implications of using these products. Total harm must be examined by looking not only at the toxicity of the product itself, the extent of absorption of these toxins and reduction in harm conferred to the individual user, it must also examine impact on the total population as well. For example, would the public be served by introducing these products as a reduced risk or cessation aid? Would use of ST in this manner increase the prevalence of tobacco use either by the uptake of ST use by former smokers, new initiates or smokers unable to quit ST use or smokers who continue to use ST because they perceive themselves as reducing disease risk? With the increase in ST prevalence, what would be the consequences in terms of health or as a gateway drug to cigarettes or other drugs? Prior studies have shown that in the United States using ST is more likely to lead to smoking than never using ST [68,88,89]. The transition from ST to cigarette smoking among new initiates would be a significant public health concern and likely to occur in a cultural setting of competitive marketing. The aggressive marketing to ST to youth and the development of ‘‘starter’’ products for the initiates are considered factors that contributed to the dramatically increased consumption of ST in the United States in the 1970s and 1980s among young males [7,90]. Consideration of legal implications may evolve around liability associated with recommending the use of a product that is known to contain carcinogens and other tobacco-related toxins and is associated with increased cardiovascular risk factors and oral pathologies, and has a potential for addiction. Of final note, ST undoubtedly is a toxin-laced nicotine delivery device, particularly in some countries. Since medicinal nicotine would not deliver these toxins, the least harmful product for situational use of nicotine and for tobacco addiction treatment would be pharmaceutical nicotine replacement products or other medicinal treatments for tobacco dependence (see Table 1). Perhaps greater efforts should be devoted to developing more effective and aggressive treatments for nicotine dependence including higher

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Table 1 Relative effects and costs across nicotine containing products Cigarettes

Smokeless tobacco

Medicinal nicotine

Health consequences Pulmonary disease Secondhand smoke Cancer Oral pathologies Cardiovascular disease Fetal toxicity

+++ +++ +++ +++ +++ +++

+ (oral) +++ ? ++

? +

Abuse liability Use to addiction Pharmacokinetics Severity of physical dependence

+++ +++ +++

++ ++ ++

+/ +/ +/

Addiction Difficulty of cessation Cost

+++ ++

++ ++

+/ +++

The number of ‘‘+’’ indicates the strength of the relationship; ‘‘ ’’ means no relationship, ‘‘?’’ means unknown.

and more rapid delivery of medicinal nicotine. Furthermore, before potential reduced exposure products (PREPS) can even be considered as harm reduction or even exposure reduction products, independent research and federal regulation of these products is essential. The lack of regulation and disclosure of toxins in ST products would induce more harm to the public health than benefit. This regulatory process must be considered on a global level, since the level of toxicity in these products can vary dramatically from one country to another. Further, in the United States, ST cannot be claimed as a method to reduce cigarette smoking or as a cessation tool unless these claims are approved by the Food and Drug Administration. The same testing that is required of pharmaceutical products should be required of oral noncombustible tobacco products that claim use as a cigarette cessation or reduction method or as a way of reducing exposure and disease risk.

Acknowledgments This review was funded by NIDA/NCI grant P50DA13333 (DH and CL) and T32 DA07239 (CL) and NCI Contract No. 263-MQ-210254 (ST).

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