This report is based on data relating oral cancer risk to the consumption of chewing tobacco and snuff as used in Western countries. Our main analyses, based on results for smokers and nonsmokers combined where possible, considers 53 individual effect estimates based on 32 studies published from 1920 to 2005. This represents 11 more studies than considered in the previous most recent quantitative review of the evidence[16
]. 16,540 cases of oral cancer were included in studies of different design, size, and quality. Many of the 32 reports have limitations and present less information than is ideal for a meta-analysis. Shortcomings include small numbers of cases (particularly exposed cases), lack of histological confirmation, lack of division by cancer site, as well as an unclear description of inclusion and exclusion criteria, details of case and control selection, and methods of exposure assessment. Furthermore, exposure details such as type of smokeless tobacco, duration and frequency of use were often not considered. At the analysis level the main weaknesses were failure to adjust results for important potential confounders and to present results separately for major subgroups, particularly by sex, smoking and alcohol. These weaknesses inevitably limit the inferences that can be drawn. Nevertheless some conclusions can be drawn from the present results.
Apart from the diversity of designs, samples, procedures, methods, and types of smokeless tobacco investigated, the individual effect estimates were themselves highly variable, particularly for snuff, where the I2
statistic for the 15 estimates was 94.9 (see also Figure ). Given the well-known strong relationships of smoking and alcohol consumption to oral cancer risk [52
], and given that 33 of the 53 estimates were unadjusted for either smoking or alcohol, it was perhaps unsurprising that this heterogeneity was highly reduced, and indeed essentially eliminated (I2
= 0 for each of the types of smokeless tobacco) by restricting attention to estimates adjusted for these two variables. Not only did such adjustment remove the substantial heterogeneity, but it removed the association, with an overall estimate for all smokeless tobacco use of 1.87 (1.40–2.48) reducing to 1.02 (0.82–1.28). The latter estimate is consistent with risk of oral cancer being independent of smokeless tobacco use, though a small increase cannot of course be totally excluded.
The lower effect estimates seen in studies that adjust for alcohol and smoking need not wholly be due to the adjustment. For example, unadjusted estimates may derive from studies which are methodologically weaker, perhaps because smokeless tobacco was not a central issue. As such it is important to look at other information which may cast light on the role of confounding by alcohol or smoking. One way of attempting to eliminate potential confounding effects of smoking is to restrict attention to study of the effects of smokeless tobacco use in never smokers. Unfortunately only six studies provided effect estimates for oral cancer or data from which these could be calculated. Although the data are suggestive of an association, the meta-analysis estimates (see Table ) are inconclusive and the data are heterogeneous. They are also no doubt open to publication bias, since many researchers would not present null results based on very limited data. These data involve very few exposed cases. Any data available for subjects who have never smoked and never used alcohol would be even sparser. As can be seen from Table , one additional study [64
] provided results that were not for oral cancer specifically, but included other forms of head and neck cancer. Inclusion of these results do not affect the above conclusions. Another study [65
] also seemed at first glance to provide possibly relevant results, with significant increases noted for some oral sites and not others. However this study only asked about the primary type of tobacco used, comparing smokeless tobacco users, who may well also have smoked, with subjects who never used any tobacco product at all. These results are clearly not restricted to never smokers and are open to confounding.
To further assess possible effects of adjustment, it is helpful to consider in more detail those studies which provide both adjusted and unadjusted estimates. Lewin et al. [64
] saw no effect of snuff before or after adjustment for alcohol and smoking, but did observe a clear dose-response relationship both with alcohol and smoking. Henley et al. [66
] found that the non-significant association of oral cancer with smokeless tobacco use seen in never smokers was further reduced after adjustment for alcohol consumption. Perry et al. (Attributable oral cancer risk due to smokeless tobacco use based on a case-control study at Sinai Hospital in Detroit; unpublished) found that additional adjustment for alcohol and smoking reduced risk estimates adjusted only for sex, race, and age from 2.51 to 1.86 and from 1.30 to 0.93 in groups with, respectively lower and higher smokeless tobacco use. Sterling et al. [67
] found that a significant sex, race, and age-adjusted association (2.42) in ever as compared to never smokeless tobacco users was virtually eliminated after additional adjustment for alcohol consumption, smoking and occupation. These authors emphasized the strong dose-response for alcohol consumption (as seen also in other studies considered [68
]) as compared to the lack of association for smokeless tobacco use. Although the evidence is limited, the findings are consistent with the notion that confounding by smoking and particularly by alcohol consumption, clearly shown to be a major risk factor in oral cancer [70
], is an important consideration.
Unfortunately, the number of estimates adjusted for both smoking and alcohol consumption was rather limited. Overall estimates of the risks associated with chewing tobacco and snuff which can reasonably be compared with each other could therefore be based only on those study-specific estimates (six and seven, respectively) which were adjusted at least for smoking. However, the corresponding estimates of 1.42 (0.99–2.03) and 1.28 (0.76–2.14) have quite low precision and provide little useful information on whether the associations truly differ. Anyway, they are likely to be biased upward by uncontrolled confounding by alcohol.
For confounding to occur it is necessary for smokeless tobacco users and non-users to differ in their smoking and alcohol consumption. However relevant data seem quite limited and somewhat variable. The evidence seems more consistent for smoking where data indicating a positive relationship with smokeless tobacco use are seen in published studies in the USA [59
] and in Sweden [73
] and also in unpublished data provided by Statistics, Sweden (I Sjöberg, personal communication). For alcohol consumption, one study in Sweden [73
] and one in the US [43
] report a strong association, consistent with the possibility of substantial confounding, but such an association is not clearly evident in other studies. Thus data for men in CPS I and CPS II [66
] and from the first National Health and Nutrition Examination Survey [NHANES I][41
] show only a weak association, and, in women, reported alcohol consumption in NHANES I is clearly lower in smokeless tobacco users than in non-smokeless tobacco users, both in smokers and nonsmokers. In a study in North Carolina Winn et al. [13
] reported that "most women who dipped snuff did not smoke cigarettes or consume alcoholic beverages," though Nilsson [14
] suggested that alcohol consumption may not have been considered proper behaviour for women when the study was conducted, and that this may have led to it being substantially underreported. Whether smokeless tobacco users are more likely to underreport alcohol consumption is unclear.
The importance of confounding by alcohol consumption cannot, however, be fully resolved from the data available. Not only are the available data on the association of alcohol and smokeless tobacco very limited, they are unadjusted for age and race and usually for smoking or sex. Anyway the association may vary by type of smokeless tobacco, type of alcohol, country and period. It certainly seems to us that, at least in some studies, observed differences in risk of oral cancer associated with use of smokeless tobacco and type of tobacco used may be due to confounding by alcohol. In this context it should be noted that other potential sources of confounding are not even mentioned by most authors, like exposure to sunlight (being relevant for lip cancer) which might (as might the use of smokeless tobacco) show a social gradient due to an association with the type of occupation.
Although conclusions based on adjusted estimates seem more convincing than those based on unadjusted ones, they are still not very reliable. One reason is the small number of available estimates. A second reason is the limited nature of the adjustment – thus many of the studies that adjusted for smoking did not take into account amount smoked (e.g. [13
]) and one of those that did [68
] combined never and light smokers into a single category. Simple adjustment for smoking in broad groups, e.g. never/former/current, may bias risk estimates for smokeless tobacco downwards if in fact smokers who also use smokeless tobacco smoke fewer cigarettes than smokers who do not. The evidence here seems somewhat conflicting, with some studies [73
] reporting similar cigarette consumption in the two groups, two studies [77
] reporting somewhat lower consumption in the smokers who also use smokeless tobacco, and one study [41
] reporting somewhat higher consumption (here measured by pack-years). Though it would clearly have been better had all studies adjusted for daily cigarette consumption, any bias from this source is likely to be modest. Adjusting for whether or not the subject is a smoker seems to be of more importance.
A third reason for unreliability of the adjusted estimates is the variability of the findings. As the heterogeneity analysis revealed, study period was a major source, with smaller risks found in more recent studies. In fact, those studies which reported very large relative risk estimates for specific sites [13
] are rather old. Despite methodological limitations, the strength of these site-specific effects indicates that use of oral snuff in the USA at that time was associated with an increased oral cancer risk, especially at locations where the snuff was held. The secular decline in relative risk is encouraging and suggests that even if current use of Western smokeless tobacco poses some risk, it is substantially less than it was decades ago. This decline, and also the decline in US oral cancer rates, may relate to the fact that levels of tobacco-specific nitrosamines [TSNAs] in American smokeless tobacco products, historically much higher than in their Swedish counterparts, have declined by more than 70 percent in the last 25 years [52
]. However we note that there is no definitive evidence linking TSNAs in smokeless tobacco products with oral cancer risk, and that the available data are insufficient to take into account reliably the time lag between smokeless tobacco use and possible development of oral cancer.
Our analyses of smoking adjusted risks seemed to suggest that, compared to non-users, female users of smokeless tobacco might be at higher risk than male users, with fixed-effect relative risks of 2.51 vs 1.15. The result for females is, however, based on only two studies, of which only the Winn et al. study [13
] found an excess risk. Random-effects estimates are similar for women (1.25) and men (1.19), and though one cannot rule out the possibility of an increased effect in women, one cannot infer this from the limited data.
Our analyses showed some indications of publication bias, a finding supported by others [80
]. Specific indices of publication bias can also be found in the literature we studied. For example in two studies [32
] negative results were reported, but no details given.
Our review is consistent with a general trend in appraising the potential risk of oral cancer from use of smokeless tobacco. In the mid 1980s smokeless tobacco was assessed as a risk factor for oral cancer by IARC and the US Surgeon General [10
]. Although, according to an advance report on a forthcoming monograph [81
] IARC seems to maintain this view, more recent reviews have reached different conclusions. Whereas tobacco chewing seems to be a major risk factor for oral and pharyngeal cancer in Asia [7
] it is now considered unlikely to incur a substantial risk among users of smokeless tobacco products in the United States or Europe (e.g.[82
]). The difference in risk between Western smokeless tobacco products and those used in developing countries may be related to tobacco species, fermentation and ageing [83
]. Also, the addition of ingredients other than tobacco like betel quid, ash and lime might play a role[12
]. For Western tobacco, various reviewers [84
] have emphasized that any risk of life-threatening diseases in general that is associated with smokeless tobacco use is very much less than that associated with smoking. For example, Bates et al. [84
] conclude that "on average Scandinavian or some American smokeless tobaccos are at least 90% less hazardous than cigarette smoking."
These reviews have led to discussion as to whether smokeless tobacco might be a less dangerous alternative to smoking for those who do not quit [87
]. Unlike in the US, tobacco for oral use has been banned in all EU countries, except for Sweden, and a ban also exists in Switzerland. Fagerström and Schildt [90
] refer to the low (and declining) prevalence of smoking and the high (and increasing) use of smokeless tobacco in Sweden, and suggest this may be responsible for Sweden having the lowest incidence of tobacco-related disease among developed countries (see [89
]). Fagerström and Schildt [90
] report that 47% of current snus users were former smokers and 28% of ex-smokers used snus at their last attempt to stop smoking. An effect of snus use on smoking cessation was also suggested by Gilljam & Galanti [91
], who found that the proportion of Swedish men that had ever used snus was larger in former than current smokers (55 vs. 45%). Discussing whether snus might be a gateway to smoking, Fagerström and Schild [90
] report that only 6% of daily smokers had started tobacco consumption with snus. They concluded that "on balance, there is reason to believe that having snus available to the Swedish population has been of benefit to public health." Whether or not smokeless tobacco use can play a role in helping smokers quit and reducing population risk overall has been fiercely debated in recent years (e.g. [76