Smokeless tobacco (ST) is mainly used orally, chewing tobacco and snuff being the major products used in North America and Europe. There are several types of chewing tobacco and snuff, differing in their formulation and in how the tobacco is treated and used 1 2 3 . In the United States, where finely-cut moist snuff or chewing tobacco is held by users in the gingival buccal area, ST has been an important part of total tobacco consumption for many years. For example, in 2000, ST formed 12.9% of tobacco consumption by weight 4 5 , and was used by 4.5% of men and 0.3% of women 6 . Previously, sales of chewing tobacco considerably exceeded those of snuff, but since the 1980s sales of snuff have risen sharply, now exceeding those of chewing tobacco 4 5 . In Sweden, the only other economically developed country where ST forms a major part of tobacco sales (e.g. 53% in 2000), snuff ('snus') is generally placed between the gum and upper lip 2 . The Swedish population has a long history of use of snus, sales of chewing tobacco there being negligible. ST also forms a few per cent of the market in Canada and in other Scandinavian countries 4 5 . ST is also widely used in parts of Central and South-East Asia. Use occurs in various ways, with the tobacco used alone or in combination with other products, such as betel nut quid, slaked lime, areca nut and even snail shells 1 3 7 .

In 2008, a report from the European Community Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR) on the health effects of ST 8 noted that "All STP [ST products] contain nicotine, a potent addictive substance. They also contain carcinogenic tobacco-specific nitrosamines, albeit at differing levels. STP are carcinogenic to humans and the pancreas has been identified as a main target organ." The conclusion relating to the pancreas derived from a review of evidence from eight studies 9 10 11 12 13 14 15 16 , and was identical to that in a draft report published in 2007 17 . No meta-analyses were presented, but it was noted that the pancreas was identified as a main target organ in two Scandinavian studies. When detailing the results for these studies, the data cited were not complete. Notably, for the Norway Cohorts Study by Boffetta et al 10 , reference was made to a relative risk [RR] for ever use of snuff of 1.67 (95% confidence interval [CI] 1.12–2.50), which was based on results for smokers and non-smokers combined with adjustment for smoking, with no mention made of the RR of 0.85 (95% CI 0.24–3.07) specifically for never smokers. In contrast, for the study of Swedish construction workers by Luo et al 11 , reference was made to a RR of 2.00 (1.20–3.30) specifically for never smokers, with no reference made to a RR of 0.90 (0.70–1.20), based on results for smokers and non-smokers combined, with adjustment for smoking.

The previous year, in 2007, the International Agency of Research on Cancer (IARC) published a monograph entitled "smokeless tobacco and some tobacco-specific nitrosamines" 2 , an earlier indication of its findings having been made available three years before this 18 . The monograph concluded that "there is sufficient evidence in humans for the carcinogenicity of smokeless tobacco. Smokeless tobacco causes cancers of the oral cavity and pancreas." The monograph considered the same studies as had SCENIHR 8 , but did not consider the Swedish Construction Workers Study 11 and one other study 15 published in 2007, after the IARC working group had completed their deliberations. As in the SCENIHR report, the IARC report did not mention the lack of association of snuff with risk in never smokers in the Norway Cohorts Study 10 .

Given the lack of meta-analyses in either report, the apparent failure to consider all the relevant data, and the existence of other studies providing a certain amount of additional information 19 20 21 , we decided to carry out a detailed review of all the available evidence relating ST use to pancreatic cancer in North America and Europe. As in some other reviews of possible effects of ST use (e.g. 22 23 24 25 26 , results from other areas (such as South East India), where ST is often mixed with other substances, are not considered. However, it should be noted that no studies of ST and pancreatic cancer conducted outside North America and Europe were referred to in either the IARC monograph 89 2 or the SCENIHR report 8 .

Table 1 summarizes details of the four cohort studies 9 10 11 19 for which results have been reported relating ST use to pancreatic cancer incidence or mortality. The sources cited give the most recent (and comprehensive) publications, although for two of these studies earlier publications 29 30 31 32 provide more limited results from a shorter follow-up. The studies are all in males, except for a very small proportion of females in the US veterans study 33 . Two of the studies were conducted in the USA and concern unspecified ST. The other two were conducted in Scandinavia and concern snuff use. The largest study, of US veterans, has only provided limited results, for fifteen years of follow-up, in an abstract 19 . The other three studies involve follow-up periods of 20 to 36 years. All of the cohort studies use exposure data as recorded at baseline.

Table 2 summarizes details of seven case-control studies 12 13 14 15 16 20 21 , all conducted in the USA or Canada. Results for ST are available for males and females combined in four studies 14 15 20 21 and for males only in the other three studies 12 13 16 . The studies vary as to whether they report results for chewing tobacco and snuff separately 13 15 20 , for chewing tobacco only 12 21 , or for combined ST use based on chewing tobacco or snuff 14 16 . Of the seven studies, all concern incident cancer, except for one 21 that makes no such distinction. In humans, the great majority of pancreatic cancers are exocrine adenocarcinomas, endocrine (islet-cell) carcinomas being far less common, so that the stated restrictions to "carcinoma of the exocrine pancreas" in one study 14 or to "pancreatic adenocarcinoma" in another 15 should be of little consequence. One study also included cancers of the bile duct or gall bladder 21 , but these form only a small proportion of the total. Three studies used population based controls 12 14 21 , while two used hospital patients 13 20 and one hospital visitors 15 . One study 16 was based on the Third National Cancer Survey and compared pancreatic cancer cases with cancers considered not to be associated with smoking. One study 12 used only surrogate respondents, while two studies 20 21 used some. The numbers of cases studied varied from 113 16 to 808 15 .

When preference is given to overall population smoking-adjusted estimates of pancreatic cancer risk associated with ST, on the basis that these provide greater power to detect a possible association, the meta-analyses (Table 4) show no clear evidence of any increase in risk associated with ST use. In contrast, when preference is given to risk estimates for never smokers, on the basis that these avoid possible confounding by smoking, the meta-analyses (Table 5) show more indication of an increase in risk. While no increased risk is demonstrated in studies in North America or in case-control studies (all of which were in North America), there is some evidence of an increased risk in studies in Sweden or Norway and in the cohort studies. This is also suggested by an analysis excluding the unusually low estimate from the Third National Cancer Survey 16 , a study which in any case suffers from a weakness we describe later.

Of the three cohort studies contributing to the analysis in Table 5, one conducted in the USA, one in Sweden and one in Norway, the Norway Cohorts Study 10 shows no increase at all (RR 0.85, 95% CI 0.24–3.07) in never smokers, but the estimate is based on only three pancreatic cancer cases in snuff users, while the Lutheran Brotherhood Study 9 shows a non-significant increase (1.70, 0.90–3.10) based on 16 cases in ST users in an analysis for smokers and non-smokers combined adjusted for smoking (and also age and alcohol).

The major contributor to the observed increase derives from the recently reported Swedish Construction Workers Study 11 , where the RR was 2.00 (1.20–3.30), based on 20 cases of pancreatic cancer in snuff-using never smokers. In considering this report by Luo et al, a number of points should be made.

First, the study was based on follow-up until the end of 2004, based on exposure information obtained at the first health check-up of those cohort members with at least one visit in the 1978–1992 period. The authors reported that a proportion of subjects classified on their first visit as never smoking were recorded in a later visit as having smoked, and that this proportion was greater in subjects who initially reported use of snus (12% vs 7%). They stated (based on an analysis not reported in detail) that bias due to this misclassification would have had little effect on the risk estimates. However, the estimated bias may have been greater, had account been taken of the possibility of subjects taking up smoking later in the follow-up period, when data were not collected.

Second, as pointed out by Rodu 34 , the authors excluded workers enrolled in their cohort from 1971 to 1975 because of "ambiguities" in questionnaire coding, despite an earlier report on snus and cardiovascular disease from this cohort 35 being based only on workers enrolled in the years excluded by Luo et al (1971 to 1974).

Finally, the study provided no indication of an increase in the overall population of smokers and non-smokers combined, with the RR adjusted for age, smoking and body mass index estimated as 0.90 (95% CI 0.70–1.20). Though this estimate would have been based on considerably more snuff-using pancreatic cancer cases, Luo et al tended to dismiss this finding, and placed far more reliance on the estimate for never smokers, as this avoids residual confounding by smoking. They noted that "previous evidence, reinforced by observed data in the present study (not shown), suggests that individuals who combine smoking with snus use smoke less and might increase their overall chances of subsequent abstinence, compared with those who only smoke". While some bias may be present for this reason, it seems implausible that it could possibly explain the huge difference between the estimates for ever vs. never snuff use of 0.90 (0.70–1.20) for smokers and non-smokers combined and that of 2.00 (1.20–3.30) for never smokers. The same publication 11 also reports corresponding results for lung cancer of 0.70 (0.60–0.70) for smokers and non-smokers combined and of 0.80 (0.50–1.30) for never smokers. Given that smoking has a much greater effect on lung cancer risk than on pancreatic cancer risk 36 37 , any residual confounding in the estimated ever vs. never snuff use for smokers and non-smokers combined should be substantially greater for lung cancer than for pancreatic cancer. The lack of any marked difference between the two estimates for lung cancer suggests residual confounding cannot explain more than a minor part of the difference between the two estimates for pancreas cancer. The high estimate in snuff users for never smokers in the Swedish Construction Workers Study seems therefore likely to be due to other reasons, including possibly chance.

No epidemiological study is perfect, and there are weaknesses in those studies that showed no evidence of an association of ST use with pancreatic cancer (see below). However, given the reliance that has been placed on the Swedish Construction Workers Study in a recent review ( 8 ), it is not inappropriate to have focused on some particular weaknesses of this study, as well as to have pointed out that estimates for other comparisons in this study do not show an association of ST with increased pancreatic cancer risk.

Considering the evidence as a whole, there are a number of limitations which should be pointed out. These include the small number of exposed cases, with the main analysis for never smokers based on a total of only 63 exposed cases from the seven studies providing data, limited control of confounding with, for example, no study at all having taken diet into account (other than alcohol) in their analyses of risk from ST, and the very limited reporting of results relating to ST use for a number of the studies, either because only an abstract was available 19 , or because ST was not a major issue in the publication 9 12 13 15 20 .

Individual study weaknesses are also an issue. The Louisiana Study and the Quebec Study 20 21 used surrogate respondents markedly more often for cases than for controls. The analysis of the Third National Cancer Survey data 16 included in its control group of cancers not associated with smoking some (e.g. kidney cancer, stomach cancer and leukaemia) for which there is now evidence of a moderate relationship 37 . The Louisiana Study 20 used a control group where exclusions were based on whether the conditions were suspected of altering diet, rather than on grounds of an association with tobacco use. Reliance, in the four cohort studies 9 10 11 19 , all involving follow-up of at least 15 years, on exposure data recorded at baseline, as already noted for the Swedish Construction Workers Study 11 , is also a problem. In regard to the Norway Cohorts Study 10 , this issue has also been referred to by Ramström 38 , who comments on the considerable changes in snus use and smoking over the long follow-up period.

Other general points affecting the overall interpretation are the lack of evidence of any dose-response relationship, and possible publication bias, not only due to failure to publish data that show no effect, but also to failure to present data in a form suitable for meta-analysis where no relationship is seen 12 20 21 .

While it remains possible that ST may increase the risk of pancreatic cancer, more evidence is clearly needed to demonstrate this. In any event, any excess risk is highly likely to be less than that associated with active smoking, where there is clear evidence that the risk increases with daily cigarette consumption and the number of years of smoking, and RRs range from three up to five at the highest levels of smoking 36 37 .

Our conclusions are not in line with those of the SCENIHR report 8 or of IARC Monograph 89 2 . The SCENIHR report, as already noted, was limited by emphasis on specific results from the Norway Cohorts Study 10 and from the Swedish Construction Workers Study 11 without citing other relevant results from these two studies. IARC Monograph 89 2 did not include some recent studies 11 15 and based its conclusions on four studies; one of these 9 did not report a significant relationship with ST use, one of these 13 reported a marginally significant association with chewing tobacco but not snuff, one of these 14 reported no overall association with ST use, but a marginally significant trend with amount used in an analysis that, as explained above, is biased, and one of these 10 reported an association with snuff use in an analysis which effectively assumed that such use would not change over a follow-up period of over 30 years, and also found no association with snuff use in never smokers. Both reviews omitted some relevant references 19 20 21 and neither included any meta-analyses. Taking into account the limitations of the SCENIHR report 8 and of IARC Monograph 89 2 , and also the weaknesses of the available data, we consider that our analysis more accurately reflects the present evidence regarding the risk of pancreatic cancer associated with smokeless tobacco use, and indicates that an effect has not been demonstrated.

The available data relating pancreatic cancer to ST use are limited, and relatively weak. Random-effects meta-analyses based on evidence from seven studies do not show a significant relationship of ST use with pancreatic risk, whether (a) attention is restricted specifically to estimates for never smokers (RR 1.28, 95% CI 0.71–2.30, n = 5), (b) estimates for never smokers are used where available and overall population estimates used otherwise (1.14, 0.67–1.93, n = 7), or (c) overall population estimates are used where there is a choice (1.03, 0.71–1.49, n = 7). While some subgroup analyses based on the second set of estimates seem to suggest a possible association, all of these are heavily dependent on the contribution of one specific relative risk estimate from one study with known weaknesses 11 .

The data, taken as a whole, are no more than suggestive of a possible effect. More evidence is needed to determine if a true relationship exists. Any risk that may exist is highly likely to be less than that associated with active smoking.

CI: 95% confidence interval; IARC: International Agency for Research on Cancer; OR: odds ratio; PMI: Philip Morris International; RR: relative risk; SCENIHR: Scientific Committee on Emerging and Newly Identified Health Risks; ST: smokeless tobacco; STP: smokeless tobacco products.

ZS-W and RW work for Philip Morris International (PMI), R&D. Both receive their salary from PMI and both own shares in Altria, the holding company of PMI. PNL, founder of P.N. Lee Statistics and Computing Ltd., is an independent consultant in statistics and an advisor in the fields of epidemiology and toxicology to a number of tobacco, pharmaceutical and chemical companies.

PNL completed an unpublished review and meta-analysis of ST and various cancers in March 2007 and later that year prepared a further unpublished review and meta-analysis specifically for pancreatic cancer. During that year ZS-W and RW carried out their own meta-analysis of this evidence. After discussion, it was decided to publish a paper jointly. The text and meta-analyses were drafted by PNL, with the other two authors helping to check the meta-analyses and clarify the text. The figures were prepared by ZS-W. All authors read and approved the final manuscript.