Elsevier

The Lancet Oncology

Volume 9, Issue 7, July 2008, Pages 667-675
The Lancet Oncology

Review
Smokeless tobacco and cancer

https://doi.org/10.1016/S1470-2045(08)70173-6Get rights and content

Summary

Use of smokeless tobacco products is common worldwide, with increasing consumption in many countries. Although epidemiological data from the USA and Asia show a raised risk of oral cancer (overall relative risk 2·6 [95% CI 1·3–5·2]), these are not confirmed in northern European studies (1·0 [0·7–1·3]). Risks of oesophageal cancer (1·6 [1·1–2·3]) and pancreatic cancer (1·6 [1·1–2·2]) have also increased, as shown in northern European studies. Results on lung cancer have been inconsistent, with northern European studies suggesting no excess risk. In India and Sudan, more than 50% of oral cancers are attributable to smokeless tobacco products used in those countries, as are about 4% of oral cancers in US men and 20% of oesophageal and pancreatic cancers in Swedish men. Smokeless tobacco products are a major source of carcinogenic nitrosamines; biomarkers of exposure have been developed to quantify exposure as a framework for a carcinogenesis model in people. Animal carcinogenicity studies strongly support clinical results. Cancer risk of smokeless tobacco users is probably lower than that of smokers, but higher than that of non-tobacco users.

Introduction

Use of oral and nasal smokeless tobacco products has been common in many countries for centuries (figure 1). During most of the 20th century, use of these products has been common in India and other Asian countries, as well as in parts of Africa, but has declined in northern Europe and North America. However, during the past decades, an increase in use has been seen in the USA and some northern European countries, especially by young people.

Section snippets

Products and patterns of use

Smokeless tobacco is consumed without burning the product, and can be used orally or nasally. Oral smokeless tobacco products are placed in the mouth, cheek, or lip, and are sucked (dipped) or chewed. Chewing tobacco can be classified as loose leaf (made from cigar leaf tobacco that is air-cured, sweetened, and loosely packed), plug (made from heavier grades of tobacco leaves harvested from the top of the plant, immersed in a mixture of licorice and sugar and pressed into a plug), or twist

Carcinogens in smokeless tobacco

More than 30 carcinogens exist in smokeless tobacco, including volatile and tobacco-specific nitrosamines, nitrosamino acids, polycyclic aromatic hydrocarbons, aldehydes, metals.4 Smokeless tobacco use entails the highest known non-occupational human exposure to carcinogenic nitrosamines, which is 100–1000 times greater than exposure in foods and beverages commonly containing nitrosamine carcinogens. Every gram of commonly used smokeless tobacco contains 1–5 μg of the tobacco-specific

Oral use—studies from Europe and North America

13 separate risk estimates have been made available from 11 studies examining the risk of oral cancer (oral and pharyngeal cancer in six studies) in users of smokeless tobacco products (table 1). Summary relative risk was 1·8 (95% CI 1·1–2·9), with evidence of heterogeneity in the results (table 2). When stratified by geographic region, the increased risk was restricted to the studies from the USA, whereas no increased risk was reported in the studies from Norway and Sweden (four risk

Health effects other than cancer

Many cross-sectional studies from the USA, India, Saudi Arabia, Uzbekistan, and Sudan reported a higher occurrence of oral soft tissue lesions in smokeless tobacco users than in non-users.4 Most of the studies have accounted for tobacco smoking either by statistical adjustment or restriction to non-smokers. The lesions are described as leucoplakia, erythroplakia, snuff dipper's lesion, tobacco and lime user's lesion, verrucous hyperplasia, and submucosal deposits, and tend to be seen in the

Burden of smokeless tobacco-related cancer

The fraction attributable cancers (AF) is a measure of the burden of smokeless tobacco use on human cancer. It refers to the role of past exposure on current cancer burden, and, if exposure has changed (as has occurred in the composition of smokeless tobacco products used in North America and Europe), it cannot be applied to the effect of current exposure on future cancer. Attributable cancers can be estimated based on the relative risk due to the habit (RR) and the proportion of the exposed

Biomarkers of carcinogen exposure in smokeless tobacco users

Biomarker studies clearly show the uptake and metabolism of tobacco carcinogens by smokeless tobacco users. These studies are crucial in linking smokeless tobacco use to cancer outcomes. Human beings and laboratory animals metabolise NNK into NNAL and NNK's glucuronides (NNAL-Glucs).17 These compounds are excreted in the urine, and the total amount, known as total NNAL, is a practical and widely used biomarker of NNK exposure.59

The carcinogenic properties of NNAL are quite similar to those of

Mechanisms of carcinogenicity of smokeless tobacco

Figure 3 presents a conceptual framework for the carcinogenic mechanism by smokeless tobacco. People begin using these products generally at a young age, frequently because of effective marketing and peer pressure. These individuals become addicted to nicotine and cannot stop using the products. Nicotine is not a carcinogen, but as described above, every dip of smokeless tobacco contains more than 30 established carcinogens, with especially high amounts of the tobacco-specific nitrosamines NNK

Conclusion

We do not intend to address explicitly the use of smokeless tobacco to reduce the risk from tobacco smoking—eg, by promoting smokers to switch to smokeless products or by introducing these products in a population where the habit is not prevalent. Nevertheless, several conclusions can be reached based on the available data: use of smokeless tobacco products is widespread in many populations, but their health effects (especially with respect to cancer risk) need to be better characterised; such

Search strategy and selection criteria

We identified epidemiological studies of smokeless tobacco and cancer based on the IARC Monograph, which was prepared in October, 2004, and provides a very detailed review of the studies available at that time,4 and by searching Medline, PubMed, and references from relevant articles for reports published in any language between October, 2004, and September, 2007, using the search terms “snus”, “snuff”, or “smokeless tobacco”, and “cancer” or “neoplasm”. Meeting abstracts and reports were

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