Our study provides several novel findings. To the best of our knowledge, these are the first data on biomarkers of tobacco exposure in a regional population of AN people. Furthermore, we provide novel data on tobacco toxicant exposure in users of the regional smokeless tobacco product iqmik, as well as dual cigarette and smokeless tobacco users.
Our measurements of nicotine and TSNAs in the tobacco products confirm prior research that nicotine concentrations are higher in general in cigarette tobacco than in smokeless tobacco (18
). Of note is that nicotine concentrations in iqmik and commercial smokeless tobacco were similar. However, because of the addition of ash that is quite alkaline, the pH is much higher in iqmik (average, 10.9) than in commercial smokeless tobacco (5.4–8.6; refs. 2
). As reported previously, the levels of NNK and other TSNAs are higher in commercial smokeless tobacco than in cigarette tobacco (18
). In contrast to commercial smokeless tobacco, TSNA levels are much lower in iqmik. Presumably, this is because iqmik is made from dried tobacco leaves that are fire cured and not fermented, resulting in less generation of NNK from nicotine. Our observation agrees with data in the IARC monograph where chewing tobacco (leaf or twist used for iqmik) has substantially lower NNN and NNK levels than the commercial moist snuff varieties sold in the United States (18
). The lower levels of NNK in iqmik might also be due to decomposition under the alkaline conditions (pH 10.9), via base-induced condensations involving the relatively acidic methylene protons adjacent to the carbonyl group of NNK.
We provide several novel observations related to nicotine exposure of AN smokers and tobacco users. First, the average plasma cotinine level of 170 ng/mL in AN smokers is only slightly lower than the 200 ng/mL average for U.S. smokers in a representative population sample (20
). However, the average number of cigarettes consumed by U.S. smokers overall is about 15 cigarettes per day, whereas the average in our AN population was 7.8 cigarettes per day. Thus the AN smokers who participated were on average taking in much more nicotine (and presumably other tobacco smoke toxicants) per cigarette than the average U.S. smoker. Similar observations have been made comparing other groups of light smokers (20
). Nicotine intake from commercial smokeless tobacco was on average similar to that of cigarette smokers, which has been observed in other U.S. and European populations (23
Nicotine intake from iqmik was strikingly higher than that from commercial smokeless tobacco. Because the nicotine content of iqmik, the number of dips used per day and duration of use was similar to commercial smokeless tobacco products, the greater systemic dose is most likely due to greater oropharyngeal absorption of nicotine from the iqmik product related to the addition of alkaline ash. Nicotine is a weak base, and in an alkaline environment more nicotine is in the free or unionized state than in the ionized state. Alkaline iqmik (pH 10.9) results in 99.9% unionized nicotine, which is expected to be absorbed more rapidly through the buccal mucosa than in nicotine from commercial smokeless tobacco which has a pH of 5.4 to 8.6 (2
). Anecdotal reports provided by our participants indicated that iqmik frequently results in very intense symptoms of nicotine effects and toxicity. Because the dose of nicotine and the rapidity of absorption of nicotine are thought to influence the risk of addiction, one would predict that iqmik would be more highly addictive than commercial smokeless tobacco products. Not only is it likely that iqmik use would be harder to quit, but iqmik addiction may also serve as a gateway to cigarette addiction (25
). Our findings are consistent with those of Hurt and colleagues, who found that among pregnant women plasma nicotine and cotinine levels were higher in iqmik users than in users of other forms of tobacco (26
Exposure to NNK, as indicated by urine levels of NNAL, was higher in smokeless tobacco users than in smokers, which has been reported by other researchers in different regions of the United States (23
). The difference reflects the higher level of NNK in commercial smokeless tobacco than in cigarette tobacco, presumably related to the smokeless tobacco curing process. NNK exposure in iqmik users was much lower than in commercial smokeless tobacco, consistent with lower levels in the product. This is most likely because iqmik is made with leaf or twist chewing tobacco with relatively low moisture content, unlike popular snuff products that contain much higher water content and are often fermented which may increase the nitrosation reactions leading to higher TSNA content. We did not observe significant differences in urinary NNN among tobacco user groups, which may be due, at least in part, to the contribution of endogenous formation of NNN to total NNN (12
NNK and NNAL are potent pulmonary carcinogens (7
). Smokeless tobacco use is not associated with increase of lung cancer, but is associated with increased risk of pancreatic cancer and for some products an increased risk of oral and esophageal cancer (27
). Presumably these cancers are caused at least in part by exposure to TSNAs. Dual cigarette smokers and smokeless tobacco users had, on average, higher exposure to NNK than cigarette smokers alone, which suggests that a combination of smoking and smokeless tobacco use might be more harmful than smoking alone. On the basis of the higher TSNA levels in smokeless tobacco than in iqmik users, one might predict a higher cancer risk from the former. However the possible contribution of components of ash to cancer risk from iqmik also needs to be considered. Thus, it would be premature to conclude that iqmik poses a lower cancer risk than commercial smokeless tobacco.
PAH analysis confirmed prior research that cigarette smokers are exposed on average to higher levels of some PAHs than nonsmokers (9
). This is particularly true of the more volatile PAHs such a naphthalene and fluorene, which are most specific to cigarette smoking (9
). Differences in urine 1-hydroxypyrene excretion between smokers and nonsmokers were much less prominent, consistent with other environmental sources of exposure to pyrene. Although smokeless tobacco made with fire cured tobacco also contains PAHs (28
), we did not observe significant differences in PAH biomarker levels comparing users of smokeless tobacco, iqmik users, or nonusers.
Analysis of within-participant correlations between self-reported product use and biomarkers of exposure revealed moderately strong correlations with number of cigarettes smoked per day and weak correlations with tins per week for commercial smokeless tobacco users, but no significant correlations between amount of iqmik use and exposures. The latter may be due to variability in the composition of the homemade product, including variability in pH. Among smokers there were strong correlations between nicotine intake and exposure to NNK and PAHs, as expected from previous studies (29
). For commercial smokeless tobacco users there was a strong correlation between nicotine intake and NNK exposures, but weaker correlations with PAH exposure. This observation is consistent with the fact that nicotine is a precursor of TSNAs, but that PAH levels in smokeless tobacco are very dependent on the nature of the curing process and the length and condition of storage of the product. Among iqmik users there were no significant correlations between nicotine intake and carcinogen exposure, most likely related to wide variability in product constituents, including pH.
There are several potential limitations of our study. Foremost with respect to generalizability is that we studied AN people in only one region, the Bristol Bay region of southwest Alaska, who volunteered to participate. Our participants were primarily Yupik. The AN people in other areas of Alaska have different ethnic backgrounds and different cultural influences which could influence smoking behavior and exposure to tobacco toxicants. Although, the number of subjects using iqmik only was relatively small, our article provides new data on exposure to carcinogens among users of this tobacco product and indicate the potential increased addiction risk among this population. There are no other published data on human exposure to nicotine and carcinogens among iqmik users, so our data are unique.
Our findings have important implications for tobacco regulation under the auspices of the U.S. Food and Drug Administration as well globally under the Framework Convention on Tobacco Control. First, the TSNA levels of commercial smokeless tobacco are high and may be contributing to the high rate of oral cancer in AN people. TSNA levels in smokeless tobacco can be controlled and reduced to substantially lower levels than those observed in the present study (30
), which could have a beneficial effect on cancer risk at the population level. Second, the very high levels of unionized (free) nicotine and the resultant high levels of nicotine absorption from iqmik is consistent with a high addiction risk. A high level of addiction is likely to increase the risk of transition to smoked products and of dual use and to impede efforts to achieve and sustain abstinence, further increasing the risk to health. Thus, the pH and levels of unionized nicotine in smokeless tobacco products need to be evaluated and potentially regulated as a way to reduce addiction and disease risk (31
). Finally, the use of iqmik raises challenges to the regulation of products that are prepared by the user or by small vendors. This is of particular importance because many people think that noncommercial products are less harmful than commercial products (2
). Research is needed on the contribution of ash to the harmful effects of tobacco, and when regulation is not feasible, public health workers and regulators need to educate the public about the risks of additives such as ash.