Which form of cancer is not likely to develop in a person who uses smokeless tobacco?

Q: What kind of cancer is associated with using smokeless?

Cancers linked to the use of smokeless tobacco include: Mouth, tongue, cheek, and gum cancer. Cancer of the esophagus (the tube that connects the throat to the stomach) Pancreatic cancer.

Q: What is the main cancer causing agent in tobacco products?

1,3-butadiene and benzene are arguably the two most prevalent potent carcinogens in cigarette smoke, on the basis of toxicologic criteria (Fowles and Dybing 2003).

Q: Why do some tobacco users not get cancer?

May 12, 2022 – Some smokers might not get lung cancer because of their DNA, researchers report in a new study. These people have genes that help limit mutations, or changes, to DNA that would turn cells malignant and make them grow into tumors, the researchers say.

Q: Can chewing tobacco cause colon cancer?

Smoking (or use of other tobacco products) – Regular use of cigarettes, cigars, chewing tobacco and other tobacco-containing items can heighten a persons risk of developing colon cancer.

Smokeless tobacco was considered by a previous IARC Working Group in 2004 (IARC, 2007a). Since that time, new data have become available, these have been incorporated into the Monograph, and taken into consideration in the present evaluation.

Inhaltsverzeichnis Show

1. Exposure Data
1.1. Smokeless tobacco products
1.2. Chemical composition of smokeless tobacco
1.3. Prevalence of use
2. Cancer in Humans
2.1. Oral use
2.2. Nasal use
2.3. Synthesis
3. Cancer in Experimental Animals
3.1. Chewing tobacco, unburned cigarette tobacco, mishri and naswar
3.3. Synthesis
4. Other Relevant Data
5. Evaluation
What kind of cancer is associated with using smokeless?
What is the main cancer causing agent in tobacco products?
Why do some tobacco users not get cancer?
Can chewing tobacco cause colon cancer?

1. Exposure Data

1.1. Smokeless tobacco products

The term smokeless tobacco implies use of unburned tobacco in the finished products. A variety of smokeless tobacco products are available, for oral or nasal use. Products intended for oral use are sucked, chewed (dipped), gargled or applied to the gums or teeth, while fine tobacco mixtures are usually inhaled into the nostrils.

Table 1.1 summarizes for each smokeless tobacco product its mode of use, the main ingredients included, the WHO regions in which the product is used, and some specification of the countries is which the product is used most commonly or specifically (DHHS, 2001; IARC, 2007a; European Commission, 2008). Smokeless tobacco products that contain areca nut are commonly used in India, other countries in South Asia, and in migrant populations from these countries. These products may be mentioned here for comparison but are reviewed in the Monograph on Betel Quid and Areca Nut in this volume.

Table 1.1

Smokeless tobacco products, ingredients, and use by WHO region.

1.2. Chemical composition of smokeless tobacco

The tobacco used in a particular product has a decisive influence on its chemical composition, and varies with tobacco species, growing, curing, processing and storage. During product manufacture, tobacco is blended to achieve a specific nicotine content and pH. The pH strongly influences the concentration of unprotonated nicotine, the bioavailable form of nicotine, while the nitrite/nitrate content strongly influences the levels of carcinogenic nitrosamines in the product. Other tobacco components are alkaloids which include nicotine (85–95% of total alkaloids), terpenes, polyphenols, phytosterols, carboxylic acids, aromatic hydrocarbons, aldehydes, ketones, amines, nitriles, N- and O-heterocyclic hydrocarbons, pesticides, and metallic compounds. Flavour-type additives are also present (Bates et al., 1999). Ammonia, ammonium carbonate and sodium carbonate are applied to control nicotine delivery by raising pH and subsequently the level of unprotonated nicotine which is most readily absorbed through the mouth into the bloodstream (Djordjevic et al., 1995).

1.2.1 Nicotine content in smokeless tobacco

The majority of commercial tobacco products are made from N. tabacum species, grown throughout the world with an alkaloid content that varies greatly. In randomly cultivated varieties examined, the alkaloid content ranged between 0.17 and 4.93%.

N. rustica species is cultivated in eastern Europe, Asia Minor and Africa, and the cured leaves may contain up to 12% nicotine. Toombak from Sudan, which contains N. rustica tobacco, had the highest reported levels of nicotine (Idris et al., 1991; Prokopczyk et al., 1995). In 17 brands of moist snuff from the USA, the nicotine content ranged from 0.47 to 3.43%.The nicotine content of Swedish snus ranges from 0.5–1.7% (Idris et al., 1998; Stepanov et al., 2008).

1.2.2 Carcinogenic compounds in smokeless tobacco

Multiple carcinogens have been identified in smokeless tobacco (IARC, 2007a) including:

(a) Tobacco-specific N-nitrosamines

Tobacco-specific N-nitrosamines include the carcinogens N′-nitrosonornicotine (NNN), and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

Tobacco-specific N-nitrosamines are formed from tobacco alkaloids (nicotine, nornicotine, anatabine, anabasine, and nitrite) primarily during tobacco curing, fermentation and ageing. The nitrate or nitrite content, the mode of curing and the various steps of processing are the main determining factors for the yields of tobacco-specific N-nitrosamines in tobacco.

IARC (2007a) compiled an international comparison of the concentrations of NNN and NNK in smokeless tobacco products. The ranges vary widely and are product- and country-specific. In some moist snuff brands in the USA, the highest concentrations of NNN and NNK measured were 135 and 17.8 μg/g tobacco, respectively. In home-made toombak from Sudan, values as high as 3085 and 7870 μg/g dry wt tobacco, respectively, have been reported (Idris et al., 1991; Prokopczyk et al., 1995).

(b) N-Nitrosamino acids

The amino acids present in tobacco, and probably also the proteins with secondary amino groups, are amenable to N-nitrosation. Since 1985, numerous studies have reported the presence of N-nitrosamino acids in smokeless tobacco products (IARC, 2007a).

To date, 11 N-nitrosamino acids have been identified in smokeless tobacco: N-nitrososarcosine (NSAR), N-nitrosoazetidine-4-carboxylic acid (NAzCA), 3-(methylnitrosamino)propionic acid (MNPA), 4-(methylnitrosamino) butyric acid (MNBA), N-nitrosoproline (NPRO), N-nitrosohydroxyproline (NHPRO), N-nitrosopipecolic acid (NPIC), N-nitrosothiazolidine-4-carboxylic acid (NTCA), N-nitroso-2-methylthiazolidine-4-carboxylic acid (MNTCA), 4-(methylnitrosamino)-4-(3-pyridyl)butyric acid (iso-NNAC) and 2-(methylnitrosamino)-3-phenylpropionic acid (MNPhPA) (Ohshima et al., 1985; Tricker & Preussmann, 1988; Hoffmann et al., 1995). Of these, NSAR, MNPA, MNBA and NAzCA have been established as carcinogens in experimental animals.

The concentration of N-nitrosamino acids depends on the nitrate or nitrite content of tobacco; they are formed during prolonged storage, particularly under adverse conditions of temperature and relative humidity. The concentrations reported in USA moist snuff samples were in the range of 5.7 to 13.45 μg/g dry wt. Highest amounts of MNPA were found in Indian zarda (up to 18 μg/g) and in moist snuff (up to 70 μg/g).

(c) Volatile N-nitrosamines

These include N-nitrosodimehtylamine (NDMA), N-nitrosopyrrolidine (NPYR) and N-nitrosopiperidine (NPIP).

Levels of volatile N-nitrosamines formed from volatile amines and nitrosating agents in smokeless tobacco products worldwide have been summarized (IARC, 2007a). The highest amounts were found in moist snuff (NDMA up to 265 ng/g dry wt and NPYR up to 860 ng/g dry wt).

(d) PAHs

These include benzo[a]pyrene, benz[a]anthracene, chrysene, benzofluoranthenes, and dibenz[a,h]anthracene.

Levels of various PAHs in 23 moist snuff brands marketed in the USA were determined by Stepanov et al. (2010) and are summarized in Table 1.2.

Table 1.2

PAHs in moist snuff brands marketed in the USA.

(e) Other carcinogenic compounds and constituents

Levels of the volatile aldehydes formaldehyde, acetaldehyde, acrolein and crotonaldehyde in smokeless tobacco products ranged from 0.207–10.6, 0.97–72.3, 0.27–7.85, and 0.55–19.4 µg/g dry weight tobacco, respectively (Stepanov et al., 2010).

Uranium was reported in Indian snuff at a concentration of about 3 pCi/g tobacco (Sharma et al., 1985). Levels of polonium-210 in commercial moist and dry snuff in the USA were reported to be 0.16–1.22 and 0.23–0.39 pCi/g, respectively.

In several parts of the world, smokeless tobacco is invariably chewed with lime which is responsible for highly alkaline pH (Nair et al., 1990, 1992), facilitating absorption of nicotine in the oral mucosa.

1.2.3 Comparison of new and traditional smokeless tobacco products

Newer types of smokeless tobacco products are appearing on the market. These products are sold as small pouches and do not require spitting. Similar to Swedish snus, they have been manufactured with additional controls to inhibit nitrosamine formation, and are being promoted as reduced risk products. Levels of carcinogens in these newer products are compared to those in traditional products in Table 1.3 (Stepanov et al., 2008).

Table 1.3

Mean levels of selected carcinogens in newer and traditional smokeless tobacco products.

1.3. Prevalence of use

1.3.1 Prevalence of smokeless tobacco use among adults

Several surveys have evaluated the prevalence of smokeless tobacco use at different times and targeting different populations in the WHO regions (AFRO, African Region; AMRO, Region of the Americas; EURO, European Region; EMRO, Eastern Mediterranean Region; SEARO, South-East Asian Region; WPRO, Western Pacific Region). The major surveys that form the basis of this report are (Table 1.4):

Table 1.4

Surveys and articles used to compile the information presented*.

the Global Adult Tobacco Survey conducted during 2009–10 among adults aged 15 years or more in 14 middle and low-income countries in AMRO, SEARO, EURO, EMRO and WPRO;
the national level STEPS noncommunicable risk factor survey (2006–09) was conducted in 8 countries in AFRO, and a few countries in SEARO, EURO (Georgia), EMRO and WPRO (Mongolia), in adults aged 15–64 years, except for AFRO (age group, 25–64 years);
the Demographic and Health Surveys (2003–10) provide prevalence on smokeless tobacco use among adults aged 15–49 years in countries in AFRO (16), EURO (4), EMRO (2), WPRO (8);
some other surveys such as the Behavioural Risk Factor Survey, the National Smoking/Tobacco/Drug use Survey, health cost studies, and national health, public health or morbidity surveys.

The prevalence of smokeless tobacco use reported in the various surveys are not directly comparable because of the different methodologies and time periods; however, they provide a snapshot of the global smokeless tobacco burden. Large variations are observed between countries (Table 1.5), between sex within a country, and sometimes within a country (Table 1.6). Those countries with a high prevalence (≥ 10%) represent about 25% of the global adult population. They include, by WHO region:

Table 1.5

Highest and lowest prevalence of smokeless tobacco use by WHO regions and by sex.

Table 1.6

Highest and lowest prevalence of use of selected smokeless tobacco products in India, by State.

in AFRO: Benin (men, 13%), Madagascar (men 23%; women, 20%), Mauritania (women, 28%), South Africa (women, 11%);
in EMRO: Yemen (men, 15%);
in EURO: Norway (men, 17.0%; women, 5.0%), Sweden (men, 26%), Uzbekistan (men, 22.5%);
in SEARO: Bangladesh (men, 26%; women, 28%), India (men, 33%; women 11–18%), Myanmar (men, 51.4%; women, 16.1%), Nepal (men, 31%; women, 5%), Sri Lanka (men, 24.9%);
in WPRO: Cambodia (women, 12.7%).

A few countries have medium prevalence (between 5% and 10%); these include:

in AFRO: Benin, Cape Verde, Malawi in women; Lesotho, Mali, Mauritania, Swaziland, Zimbabwe in men;
in AMRO: USA in men;
in EMRO: Tunisia in men; Yemen in women;
in EURO: Finland, Iceland and Kyrgyzstan in men; Norway and Sweden in women;
in SEARO: Sri Lanka and Thailand in women.

In most countries, current prevalence of smokeless tobacco use is higher among men than among women. Some exceptions are found at all levels of prevalence (in women and men, respectively): Bangladesh (27.9, 26.9), Barbados (0.6, 0), Cambodia (12.7, 0.7), Cape Verde (5.8, 3.5), Malaysia (3.1, 0.5), Mauritania (28.3, 5.7), South Africa (10.9, 2.4), Thailand (6.3, 1.3) and Viet Nam (2.3, 0.3).

Demographic health survey data indicate that in countries in AFRO and SEARO smokeless tobacco is more prevalent in rural compared to urban areas, and higher among low-income compared to high-income groups. Also, prevalence generally increases with increasing age.

Some countries warrant more detailed information of their pattern of smokeless tobacco use, and are presented below.

1.3.2 Country specific data

(a) India

The India Global Adult Tobacco Survey (2009–10) revealed that 26% of all adults use smokeless tobacco in some form, 21.4% daily and 4.5% occasionally. Prevalence in men (32.9%) is higher than in women (18.4%), and is higher in rural (29.3%) than urban areas (17.7%). Large variations are observed between States, from around 5% in Himachal Pradesh, Goa and Chandigarh to 49% in Bihar (India GATS Report, 2009–10).

Khaini is the most commonly used smokeless tobacco product (11.6%), followed by gutka (8.2%). Prevalence of khaini chewing is significantly higher among men (18%) than among women (5%); 13.1% men and 2.9% women chew gutka; 6.2% (7.5% men, 4.9% women) of adults use betel quid with tobacco; 4.7% (3.3% men, 6.3% women) use tobacco products such as mishri, gul, gudakhu for oral application (dentifrice); and 4.4% uses some other products, such as snuff for nasal application and some local products. The pattern of use of smokeless tobacco products also varies widely in different States of India (Table 1.6) (India GATS Report, 2009–10).

Proportion of dual tobacco users (smoking+smokeless) is 19.4% among men and 5.3% among women (Sinha et al., 2011).

(b) Bangladesh

In Bangladesh the most prevalent form of smokeless tobacco is betel quid with tobacco (24.3%), followed by gul (5.3%), sada pata (1.8%), khaini (1.5%) and others (1.4%) (BAN GATS Report, 2009). Use decreases with increasing education and socioeconomic level in both men and women, by a steeper rate among women compared to men. Among current users, those with the highest prevalence of use of gul and khaini were labourers among men (7.5% and 2.8%, respectively) and homemaker among women (5.7% and 1.4%, respectively) (BAN GATS Report, 2009).

Proportion of dual tobacco users (smoking+smokeless) is 22.5% among men and 2.5% among women (Sinha et al., 2011).

(c) Canada

Unchanged from surveys conducted in 2008 and 2009, 8% of Canadians aged 15 years and older reported having ever tried smokeless tobacco products in 2010. In 2009, 11% of young adults aged 20 to 24 years reported ever using smokeless tobacco and 1% having used it within the past 30 days. There has been a shift in the distribution of past-30-day smokeless tobacco users from youth towards older adults: in 2003, 23% of users were aged 15–19 years and 14% were older than 45 years, whereas in 2009, 16% of smokeless tobacco users were 15 to 19 years old and 33% were aged 45 and older.

(d) USA

According to the Behavioural Risk Factor Surveillance System survey (2008), conducted in 13 States, prevalence varied from 0.5% (New Jersey) to 8.8% (West Virginia). Dual use of cigarette and smokeless tobacco products varied from 0.2% (Delaware) to 1.8% (West Virginia).

In an overall analysis of users’ demographic characteristics, prevalence of smokeless tobacco use was higher among men (6.3%) than women (0.3%); more prevalent among non-Hispanic whites (4.1%) compared to other ethnic groups; highest in the youngest age group (18–24 years) and decreased steadily with age. Users of smokeless tobacco were almost equally distributed between the sextiles of annual income (3.0 to 3.8%).

(e) Europe

In Europe, countries with a high prevalence of smokeless tobacco use are Norway, Sweden and Uzbekistan.

In Sweden, a 10-year follow-up study of smoking and snus [Swedish moist snuff] habits in a middle-aged Swedish population showed that use of snus increased from 3.1% to 6.0% among women and from 24.6% to 26.3% among men. The number of people who used both snus and cigarettes was stable: 0.5% to 0.8% from baseline to follow-up for women and 4.1% to 3.3% for men. Whereas nearly all snus users in Sweden are daily users, almost half of snus users in Norway use it only occasionally.

1.3.3 Prevalence of smokeless tobacco use among youth

The Global Youth Tobacco Survey (GYTS) is a school-based survey of students aged 13–15 years that uses a two-stage sampling design. In a first stage, schools are selected based on the probability proportional to the enrolment of students in schools. In a second stage, classes are selected randomly. It uses standard questionnaire, field methodology and analysis. The Survey has core questions that spans seven thematic areas pertinent to tobacco. In addition, countries can include country-specific questions that allow assessment of tobacco unique to the country [smokeless tobacco use may include betel quid with tobacco.]

In AFRO, all countries surveyed reported a prevalence of smokeless tobacco use among youth above 5%, ranging from 5.4% in Swaziland to 16.4% in Congo. Among boys, it varied from 5.2% in Seychelles to 18.3% in Congo, whereas among girls, from 4.8% in Togo to 15.8% in Namibia. Prevalence was higher among boys than girls in most countries, except in Uganda where it was higher among girls (9.6% versus 8.6%) (Asma et al., 2011). Four countries (Botswana, Congo, Lesotho and Namibia) are particularly noteworthy: these countries reported the highest prevalence in both sexes (11.3–16.4%), the highest prevalence in boys (11.3–18.3%), the highest prevalence in girls (11.4–15.8%), and similar prevalence in boys and girls.

In AMRO, prevalence of smokeless tobacco use among youth varied from 3.5% in Panama to 9.8% in Barbados. Among boys, it varied from 3.8% in Panama to 11.5% in Barbados, whereas among girls, it varies from 2.6% in Venezuela to 8.5% in Jamaica. Most notably, smokeless tobacco use among boys was above 10% in Barbados, Dominican Republic and Grenada. Girls in most countries used less smokeless tobacco than boys, except in Jamaica (8.5% for both) and Peru (boys, 4.3%; girls, 4.8%) where boys and girls had comparable prevalence (Asma et al., 2011).

In SEARO, all countries surveyed reported a prevalence of smokeless tobacco use among youth above 5%, ranging from 4.9% in Bangladesh to 9.4% in Bhutan. Among boys, it ranged from 5.8% in Bangladesh to 14.1% in Bhutan whereas among girls, it varies from 2.7% in Myanmar to 6% in India. In all countries more boys than girls used smokeless tobacco products (Asma et al., 2011).

In EURO, prevalence of smokeless tobacco use among youth is lower than in other WHO regions, ranging from 1.1% in Montenegro to 6.9% in Estonia. While it ranged from 1.1% in Montenegro to 9.4% in Estonia among boys, it varied from 0.7% in Serbia to 4.5% in Estonia among girls. Except for Estonia (6.9%), all countries reported a prevalence among youth below 5%. Also, in all countries boys used more smokeless tobacco than girls (Asma et al., 2011).

In EMRO, prevalence of smokeless tobacco use among youth varied from 1.6% in Oman to 12.6% Djibouti. Among boys, it varied from 2% in Libyan Arab Jamahirya to 15.2% in Djibouti, whereas among girls, it varied from 0.9% in Oman and Tunisia to 9% in Djibouti. Prevalence of smokeless tobacco use among youth was highest in Djibouti (12.6%), where it is also highest among boys and girls separately. Boys generally used more smokeless tobacco than girls, except in Libyan Arab Jamahirya and Yemen where girl users slightly outnumbered boy users (Asma et al., 2011).

In WPRO, prevalence of smokeless tobacco use among youth varies from 2.1% in Macau to 8.7% in Cook Islands. Among boys, it varies from 2.2% in Macau to 10.5% in Cook Islands, whereas among girls, it varies from 2.1% in Macau to 7.3% in Cook Islands. Prevalence of smokeless tobacco use among youth in Cook Island and Republic of Korea is above 5% for boys and girls combined, as well as separately for boys and girls. Prevalence among boys was generally higher than among girls (Asma et al., 2011).

In summary, among the countries included in the GYTS survey 2007–2010, the prevalence of smokeless tobacco use among youth aged 13–15 years exceeds 5% in all or most countries in AFRO, AMRO and SEARO, in Djibouti, Islamic Republic of Iran, Qatar, Syrian Arab Republic and Yemen in EMRO, and in the Cook Islands and Republic of Korea in WPRO (Asma et al., 2011).

In general, prevalence among boys was higher than among girls, although in several countries prevalence was similar, or higher among girls.

In several countries, smokeless tobacco use among 13 to 15 year-old men is higher than that among adult men (aged 15 years or more). These include Albania, Argentina, Brazil, the Dominican Republic, Guyana, Lesotho, Mexico, Namibia, Saudi Arabia, Tunisia and Uganda. Similarly, in Albania, Argentina, Barbados, Brazil, Dominican Republic, Guyana, Kyrgyzstan, Libyan Arab Jamahirya, Mexico, Saudi Arabia, Swaziland, Uganda and Yemen, smokeless tobacco use among 13–15 year women is higher than that in adult women.

2. Cancer in Humans

2.1. Oral use

2.1.1 Cancers of the oral cavity and pharynx

(a) Overview of the studies

Studies of smokeless tobacco and oral and pharyngeal cancer have been conducted in North and South America, Europe, Asia, and Africa. All of the studies reported here examined oral cancer risks associated with use of unsmoked tobacco that was not part of a betel quid. Evidence regarding betel quid is presented in the Monograph on Betel Quid in this volume. This section focuses on the predominant smokeless tobacco products and behaviours in the countries in which the studies were conducted, for example on chewing tobacco and snuff in North America, snus in northern Europe, shammah in Saudi Arabia and Yemen, toombak in Sudan, and a variety of types in South Asia (see Table 1.1 for their mode of use, ingredients and region of use). The studies typically examine cancers arising in intra-oral sites, which are predominantly squamous cell in origin (Canto & Devesa, 2002), but some include other sites as well, such as the oropharynx, hypopharynx, or larynx. Studies involving smokeless tobacco and nasopharyngeal cancer are discussed in another chapter.

The previous Monograph (IARC, 2007a) concluded that there was sufficient evidence in humans that smokeless tobacco causes cancer of the oral cavity. Studies published since include updates on mortality and incidence for one of the cohorts reviewed previously (Accortt et al., 2002, 2005), two new cohort studies (Luo et al., 2007; Roosaar et al., 2008); case–control studies from Sweden (Rosenquist, 2005; Rosenquist et al., 2005) and India (Sapkota et al., 2007); and three meta-analyses (Weitkunat et al., 2007; Boffetta et al., 2008; Lee & Hamling, 2009).

Because tobacco smoking is a risk factor for oral and pharyngeal cancers (IARC, 2004), and tobacco smoking is often positively correlated with smokeless tobacco use (Tomar, 2002), addressing confounding by smoking is important in the examination of causality related to smokeless tobacco. Heavy alcohol use is another important risk factor and can potentially confound the relationship between tobacco use and risk of oral and pharyngeal cancer (IARC, 2010, 2012).

While analysis restricted to non-smokers and non-alcohol drinkers eliminates the possibility of confounding due to smoking and alcohol drinking, the sample sizes can be small in study populations in regions where these behaviours are common. Adjusting statistically for smoking and alcohol can alternatively be used to address confounding by these factors in populations where these behaviours are common and can provide unbiased estimates that may be more stable if there is no residual confounding within smoking/drinking categories used in the adjustment. There is sufficient evidence that human papillomavirus (HPV) 16 causes oral cancer in humans (IARC, 2007b). Studies have shown that the prevalence of HPV DNA is negatively correlated with tobacco smoking and alcoholic beverage consumption (Gillison et al., 2000), suggesting that positive confounding by HPV is not likely to account for a spurious association between smokeless tobacco and oral cancer.

The specific name of the smokeless tobacco product will be used whenever available. In the USA, where moist snuff and chewing tobacco are both common, the term “smokeless tobacco” refers to use of either. Most publications provide data on “ever” versus “never” use of these products, usually defined as using the product or not for some minimal length of time such as a year. Due to the large body of evidence, this Monograph will focus on studies published since IARC (2007a).

(i) Cohort studies

Ever lifetime use or ever daily use of smokeless tobacco and risk of oral and pharyngeal cancers was examined in six cohort studies conducted in the USA (Zahm et al., 1992; Accortt et al., 2002, 2005; Henley et al., 2005), Sweden (Luo et al., 2007; Roosaar et al., 2008), and Norway (Boffetta et al., 2005). Mortality data were analysed in four studies (Zahm et al., 1992; Accortt et al., 2002; Henley et al., 2005; Roosaar et al., 2008), four (Accortt et al., 2005; Boffetta et al., 2005; Luo et al., 2007; Roosaar et al., 2008) analysed cancer incidence. None of the studies excluded persons diagnosed in the first 1 or 2 years of follow-up nor did they collect information on changes in behaviours, such as smokeless tobacco or smoking cessation or initiation, after the baseline (Table 2.1 available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.1.pdf).

Ever use of smokeless tobacco was associated with a statistically significant threefold increased risk of death from oral cancer and an 8.7 fold increased risk of death from pharyngeal cancer in one study from the USA (Zahm et al., 1992). Risks were greater among those with more frequent use, but adjustment was not performed for tobacco smoking and therefore this study will not be considered further in this section.

Ever use of smokeless tobacco was not associated with risk for cancer in four cohorts (Accortt et al., 2005; Boffetta et al., 2005; Henley et al., 2005; Luo et al., 2007). In one cohort the age-adjusted standardized mortality ratio for oral cancer associated with ever smokeless tobacco use was not elevated (Accortt et al., 2002) and the age-adjusted standardized incidence ratio for smokeless tobacco use and oral cancer was statistically lower than expected (Accortt et al., 2005). The expected number of oral cancer deaths among ever smokeless tobacco users in this cohort was zero, suggesting limited statistical power to detect elevated risks.

In the Cancer Prevention Study I and II cohorts (Henley et al., 2005; CPS-I and CPS-II, respectively), the hazard ratio (HR) for death from oral and pharyngeal cancer in CPS-I for current use of smokeless tobacco versus never use among men who never used any other form of tobacco was 2.0 (95%CI: 0.5–7.7), based on four deaths adjusting for alcohol consumption, fruit/vegetable intake and other factors. The corresponding HR in CPS-II was 0.9 (95%CI: 0.1–6.7), based on one death adjusting for similar factors as CPS-I.

In the Norwegian cohort (Boffetta et al., 2005), the HR for ever use of smokeless tobacco was 1.1 (95%CI: 0.5–2.4), for oral, pharynx or salivary gland cancer after adjusting for age and smoking. Among non-smokers in a cohort of 280 000 Swedish male construction workers, the relative risk of developing oral cancer was 0.8 (95%CI: 0.4–1.7), adjusting for attained age and body mass index (BMI) (Luo et al., 2007).

One cohort study in Sweden involved 9 860 men who participated in an oral examination (Roosaar et al., 2008). An elevated relative risk (RR) of 3.1 (95%CI: 1.5–6.6) was found for ever daily use of snus compared to never daily use of snus controlling for calendar period, area of residence, alcohol consumption, smoking, and an interaction variable for age and smoking. Among the never-smokers in the cohort, the relative risk for ever daily use of snus was 2.3 (95%CI: 0.7–8.3).

All cohort studies had at least 12 years of follow-up. No increased risk of oral cancer was observed for the three cohorts with 12–26 years of follow-up (Accortt et al., 2002, 2005; Henley et al., 2005; Luo et al., 2007). One study with 35 years follow-up found no association of smokeless tobacco and oral cancer risk (Boffetta et al., 2005) and another study with 27–29 years follow-up had significant positive findings among smokers only (Roosaar et al., 2008).

(ii) Case–control studies

Many case–control studies examined smokeless tobacco and oral and pharyngeal cancer (Broders, 1920; Moore et al., 1953; Wynder & Bross, 1957; Wynder et al., 1957a, b; Peacock et al., 1960; Chandra, 1962; Vogler et al., 1962; Vincent & Marchetta, 1963; Martinez, 1969; Keller, 1970; Browne et al., 1977; Jafarey et al., 1977; Williams & Horm, 1977; Wynder & Stellman, 1977; Westbrook, 1980; Winn et al., 1981a; Wynder et al., 1983; Stockwell & Lyman, 1986; Young et al., 1986; Blot et al., 1988; Spitz et al., 1988; Franco et al., 1989; Goud et al., 1990; Blomqvist et al., 1991; Maden et al., 1992; Marshall et al., 1992; Mashberg et al., 1993; Spitz et al., 1993; Kabat et al., 1994; Bundgaard et al., 1995; Idris et al., 1995a; Muscat et al., 1996; Lewin et al., 1998; Muscat & Wynder, 1998; Schildt et al., 1998; Schwartz et al., 1998; Wasnik et al., 1998; Chelleng et al., 2000; Merchant et al., 2000; Rosenquist et al., 2005; Rosenquist, 2005; Sapkota et al., 2007). Two studies were of cancer of the salivary gland (Keller, 1969; Muscat & Wynder, 1998), one reported on hypopharyngeal cancer (Sapkota et al., 2007), and one on nasopharyngeal cancer (Chelleng et al., 2000). The same study was reported on twice in two instances (Wynder & Bross, 1957; Wynder et al., 1957a; Rosenquist, 2005; Rosenquist et al., 2005). Additionally, one cross-sectional study was conducted, but the comparability of the two surveys analysed to yield risk estimates was uncertain (Sterling et al., 1992).

Nearly half the studies addressed potential confounding by tobacco smoking. In three (Broders, 1920; Stockwell & Lyman, 1986; Keller, 1970), smokeless tobacco information was probably obtained from medical records and, if ascertainment of smokeless tobacco use was more likely from cases than from controls, measurement error might account for the findings and these studies will not be considered further. The remaining 15 studies were conducted in the USA (Vogler et al., 1962; Martinez, 1969; Williams & Horm, 1977; Winn et al., 1981a; Blot et al., 1988; Mashberg et al., 1993; Kabat et al., 1994), Sweden (Lewin et al., 1998; Schildt et al., 1998; Rosenquist, 2005; Rosenquist et al., 2005), India (Chandra, 1962; Wasnik et al., 1998; Sapkota et al., 2007), Pakistan (Merchant et al., 2000), and Sudan (Idris et al., 1995a) (Table 2.2 available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.2.pdf).

Five studies were population-based (Williams & Horm, 1977; Blot et al., 1988; Lewin et al., 1998; Schildt et al., 1998; Rosenquist et al., 2005); positive findings were observed in the majority of them (Williams & Horm, 1977; Blot et al., 1988; Lewin et al., 1998) and in all of the hospital-based studies except one (Mashberg et al., 1993). One study (Winn et al., 1981a) also included death certificate cases and controls.

Several case–control studies of oral cancer addressed potential confounding by tobacco smoking either by statistically controlling for tobacco smoking or by restricting to non-smokers. Odds ratios (OR) for ever versus never use of smokeless tobacco overall, or for at least one of the major cancer subtypes, was statistically significantly elevated in eight studies, with odds ratios for oral cavity cancer ranging from 3.9 to 34.5 (Vogler et al., 1962; Martinez, 1969; Williams & Horm, 1977; Winn et al., 1981a; Blot et al., 1988; Kabat et al., 1994; Idris et al., 1995a; Wasnik et al., 1998; Merchant et al., 2000) and in one study of hypopharyngeal cancer in India (Sapkota et al., 2007). In case–control studies conducted in Sweden, there was no association with use of smokeless tobacco in 2 studies (Schildt et al., 1998; Rosenquist, 2005) or in another study (Lewin et al., 1998) that controlled for smoking and alcohol intake. However, when Lewin et al., 1998 restricted the analysis to non-smokers the odds ratio for head and neck cancer associated with ever use of smokeless tobacco was 4.7 (95%CI: 1.6–13.8). [Rosenquist (2005) was based on a relatively small sample size of 132 cases and 320 controls.]

In one case–control study conducted in the USA (Vogler et al., 1962) and another of toombak users in Sudan (Idris et al., 1995a), neither statistical adjustment for tobacco smoking nor restriction to non-smokers was done. However, confounding by smoking was not likely to have a major effect on the risk estimates from these studies. The proportions of smokers in the case and control groups were low in the rural women in the study of Vogler et al. (1962) among whom positive findings were found. In the study in Sudan less than 10–12% of the two case groups and in a hospital-based control groups smoked; in the population-based control group 21% were smokers, but most had smoked for less than one year (Idris et al., 1995a).

In a meta-analysis Boffetta et al. (2008) included studies published through 2007 that provided information about non-smokers and studies that adjusted for tobacco smoking. The summary estimate for the 11 studies of oral cancer (6 of them also including pharyngeal cancer) was 1.8 (95%CI: 1.1–2.9) overall. For the USA, it was 2.6 (95%CI: 1.3–5.2) and for northern European countries, 1.0 (95%CI: 0.7–1.3) (Table 2.3 available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.3.pdf).

Another meta-analysis included 40 studies published through May 2008 (Table 2.4 available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.4.pdf) but excluded studies in Asian or African populations (Lee & Hamling, 2009). In addition to the studies in the meta-analysis by Boffetta et al. (2008), 15 other studies were included: (Moore et al., 1953; Wynder & Bross, 1957; Wynder et al., 1957, 1983; Peacock et al., 1960; Vincent & Marchetta, 1963; Martinez, 1969; Keller, 1970; Browne et al., 1977; Wynder & Stellman, 1977; Young et al., 1986; Spitz et al., 1988; Franco et al., 1989; Blomqvist et al., 1991; Maden et al., 1992; Marshall et al., 1992; Sterling et al., 1992; Zahm et al., 1992; Spitz et al., 1993; Bundgaard et al., 1995; Muscat et al., 1996; Schwartz et al., 1998) and one unpublished study by Perry and colleagues in 1993. Among never-smokers the odds ratio was 1.72 (95%CI: 1.01–2.94) based on 9 studies; further adjustment for alcohol in the three studies where this was possible yielded an odds ratio among never-smokers of 1.87 (95%CI: 0.82–4.27). The estimate for never-smokers among the studies conducted in the USA was 3.33 (95%CI: 1.76–6.32), and decreased with additional adjustment for alcohol drinking (1.58; 95%CI: 0.52–4.81), based on two studies among never-smokers. Corresponding estimates for snuff use in never-smokers in Scandinavia were 1.01 (95%CI: 0.71–1.45; 4 studies) and 2.30 (95%CI: 0.67–7.92; 1 study) adjusted for alcohol drinking. For studies published since 1990, the corresponding estimates were 1.24 (95%CI: 0.80–1.90; 7 studies) in never-smokers and 1.87 (95%CI: 0.82–4.27; 3 studies) adjusted for alcohol drinking.

Lee & Hamling (2009) updated an earlier meta-analysis (Weitkunat et al., 2007) of 32 studies through 2005, excluding studies conducted in Asian populations. Weitkunat et al. (2007) did not include three studies (Rosenquist et al., 2005; Luo et al., 2007; Roosaar et al., 2008), but provided sex- and tobacco type- specific estimates not reported by Lee & Hamling (2009). For smokeless tobacco, the overall smoking-adjusted relative risk was 1.35 (95%CI: 1.04–1.76), and for chewing tobacco and snuff, the estimates were 1.42 (95%CI: 0.99–2.03; 6 studies) and 1.28 (95%CI: 0.76–2.14; 7 studies). For men the smoking-adjusted estimate was 1.15 (95%CI: 0.97–1.37) and for women 2.51 (95%CI: 1.73–3.64). For case–control studies with hospital-based controls, the estimates were 1.41 (95%CI: 1.18–1.68) and for studies with population-based controls 0.99 (95%CI: 0.69–1.42). Smoking-adjusted relative risks for smokeless tobacco were elevated only for studies conducted before 1980: 2.02 (95%CI: 1.28–3.20) for earlier than 1969, 2.67 (95%CI: 1.83–3.90) for 1970–1979, compared with 0.97 (95%CI: 0.71–1.31) for 1980–1989, and 1.10 (95%CI: 0.88–1.37) for 1990 or later.

(b) Dose–response evidence

In this and subsequent sections, the relative risks and odds ratios are either among non-smokers or are adjusted for tobacco smoking. Dose–response relationships were observed in several studies.

(i) Duration and intensity

Williams & Horm (1977) found that the odds ratio for oral cavity cancers in men associated with heavy use of smokeless tobacco was higher than for moderate use. Lewin et al. (1998) also reported relative risks for head and neck cancer that increased with increasing intensity of oral snuff use. Of the case–control studies that examined duration, higher risks of oral cancer with greater numbers of years of snuff use were noted for cancers of the gum/buccal mucosa, but not for other cancers of the mouth/pharynx category (Winn et al., 1981a). No increase with years of snus use was observed in two Swedish case–control studies (Lewin et al., 1998; Rosenquist et al., 2005). In a study in Sudan (Idris et al., 1995a), the odds ratio for use of toombak for more than 11 years was greater than that for fewer years of use.

(c) Comparison of types of smokeless tobacco by geographical location

(i) Northern Europe

Four studies from this area found no overall association between use of snus and oral cancer (Lewin et al., 1998; Schildt et al., 1998; Boffetta et al., 2005; Rosenquist, 2005). One case–control study (Rosenquist, 2005) examined users of fermented and not fermented snuff and observed no risk for either type. In Sweden before 1983, snuff was fermented as part of the manufacturing process, and this process is conducive to formation of tobacco-specific N-nitrosamines. In one cohort study (Roosaar et al., 2008) the relative risk for ever daily use of snus was 3.1 (95%CI: 1.5–6.6, adjusted for smoking, calendar period, area of residence, alcohol consumption and a variable to account for the interaction between age and smoking) and 2.3 (95%CI: 0.7–8.3) among non-smokers with adjustment for calendar period, area of residence and alcohol consumption. In a case–control study, among non-smokers, the odds ratio for cancers of the oral cavity, pharynx and oesophagus combined was 4.7 (95%CI: 1.6–13.8) (Lewin et al., 1998).

(ii) USA

In the USA chewing tobacco and moist snuff are the predominant forms of smokeless tobacco. In five case–control studies of oral cancer, the odds ratio for ever use of smokeless tobacco were statistically significantly elevated overall for use of one or other type, ranging from 4.2 to 34.5 (Martinez, 1969; Williams & Horm, 1977; Williams et al., 1977; Winn et al., 1981a; Blot et al., 1988; Kabat et al., 1994). No association with use of either of these products was observed in 2 cohort studies (Accortt et al., 2002; 2005; Henley et al., 2005) and one case–control study (Mashberg et al., 1993).

The odds ratio for chewing tobacco was not statistically significantly elevated in two studies (Mashberg et al., 1993; Kabat et al., 1994); but was in a third (Martinez, 1969). For snuff, one study found no association (Mashberg et al., 1993) and in three others statistically significant elevated risks were observed, ranging from 4.2 to 34.5 (Winn et al., 1981a; Blot et al., 1988; Kabat et al., 1994). In one case–control study in the southern USA positive associations were observed among non-smoking women who were snuff dippers, but a significant association was observed for white, but not black women; dry snuff was the predominant form of snuff used by women in that area (Winn et al., 1981a). Elevated odds ratios persisted with control for poor dentition (Winn et al., 1981b), use of mouthwashes (Blot et al., 1983), fruits and vegetables (Winn et al., 1984), type of respondent (self versus proxy), and alcohol consumption (Winn, 1986).

(iii) Africa, Middle East, and Asia

In Sudan the majority of a consecutively accrued series of oral cancer cases used saffa, an oral snuff, a moistened, powdered tobacco treated with sodium sesquicarbonate (Elbeshir et al., 1989). Also, in Sudan toombak use was higher in oral cancer cases with squamous cell-carcinomas in sites with direct contact with the quid (e.g. floor of mouth) than cases with less or no contact (e.g. palate) (Idris et al., 1995b). The odds ratio for toombak use was 7.3 (4.3–12.4) comparing hospital-based cases with oral cancers in direct contact with the quid versus hospital controls, and 1.4 (0.8–2.5) for cases with oral cancers not usually in direct contact with the quid (Idris et al., 1995a), adjusting for age, sex, tribe and residence. Ten to twelve percent of the cases and hospital controls smoked. Twenty-one percent of population controls smoked, although most had smoked for less than one year.

Case series from Saudi Arabia have noted a high frequency of use of shammah or al-shammah in series of oral, pharyngeal, and laryngeal cancer cases (Amer et al., 1985; Ibrahim et al., 1986; al-Idrissi, 1990; Allard et al., 1999).

In Pakistan, ever using naswar was associated with an odds ratio of 9.5 (95%CI: 1.7–52.5; adjusted for cigarette smoking and alcohol consumption) (Merchant et al., 2000). Reports based on small series of users in which potential confounding by tobacco smoking could not be ruled out also noted higher frequencies of naswar use in oral cancer cases than controls or oral cancers among naswar users (Aleksandrova, 1970; Nugmanov & Baimakanov, 1970).

In India, a case–control study of buccal mucosa cancer observed an odds ratio of [2.7] for men and [2.5] for women associated with tobacco chewing among non-smokers (Chandra, 1962). In a cross-sectional survey, the period prevalence of oral and oropharyngeal cancer among persons who used pattiwala, sun-cured tobacco leaf only, was 1.17 per 100 persons compared to 0.36 among non-chewers of tobacco (Wahi, 1968) [tobacco smoking was not accounted for]. A case–control study of oropharyngeal cancer, using a smokeless tobacco product for teeth cleaning was associated with an odds ratio of 5.2 (95%CI: 2.5–11.8), adjusted for smoking (Wasnik et al., 1998). In another case–control study in India, snuffing tobacco nasally or orally, generally using naswar, was associated with elevated odds ratios for hypopharyngeal cancer in never-smokers and in analyses adjusted for tobacco smoking and alcohol consumption (Sapkota et al., 2007). [The Working Group noted that in the Sapkota et al. (2007) study, snuff use was nasal as well as oral so the role of oral use could not be separately determined.] In the same study, odds ratios for hypopharyngeal cancer among never-smokers were significantly elevated for zarda and non-significantly elevated for khaini, after adjusting for centre, age, sex, socioeconomic status, alcohol consumption and tobacco snuffing.

(d) Interactions

In one study in the USA that provided odds ratios for smokers only, smokeless tobacco users only, and smokers who also used smokeless tobacco, each compared to non-users of either, there was no evidence of an interaction between smokeless tobacco use and smoking (Winn et al., 1981a), nor was there any evidence of an interaction between smokeless tobacco use and alcohol consumption in a similar analysis of that study population (Winn, 1986).

2.1.2 Precancerous lesions of the oral cavity

(a) Overview of the studies

Studies on the natural history of oral cancer suggest that several types of potentially malignant lesions and conditions precede the development of cancer of the oral cavity. Oral precancerous lesions of relevance are leukoplakia and erythroplakia. The term leukoplakia will be used below to describe white lesions and erythroplakia to describe red lesions. Several classification systems for the lesions have been used (Axéll et al., 1976; Pindborg, 1980, Greer & Poulson, 1983; Pindborg et al., 1996), all involving visual inspection of the oral cavity and a diagnosis based on clinical appearance of the lesions to identify the causes of the white and red oral lesions. Smokeless tobacco use has previously been identified as a risk factor for oral pre-malignant lesions (IARC, 2007a). Histological and clinical changes occur in the mucosa of snuff users in as few as 2–7 days after initiation of use (Payne et al., 1998). Furthermore, the location of the lesion in the mouth has been shown to correspond to where the smokeless tobacco is typically placed (Salem et al., 1984; Zaridze et al., 1986; Ernster et al., 1990; Tomar et al., 1997; Martin et al., 1999; Ayo-Yusuf et al., 2000).

Since IARC (2007a) one cross-sectional study has been published in the USA (Fisher et al., 2005), one from Sweden (Roosaar et al., 2008), and one from Yemen (Scheifele et al., 2007).Cross-sectional studies and case series from many parts of the world have reported that leukoplakia occurs more commonly among smokeless tobacco users and that persons with lesions are more frequently smokeless tobacco users. Many cross-sectional studies were conducted in the USA (Greer & Poulson, 1983; Poulson et al., 1984; Offenbacher & Weathers, 1985; Wolfe & Carlos, 1987; Creath et al., 1988; Cummings et al., 1989; Stewart et al., 1989; Ernster et al., 1990; Grady et al., 1990; Creath et al., 1991; Daniels et al., 1992; Sinusas et al., 1992; Grasser & Childers, 1997; Tomar et al., 1997; Martin et al., 1999; Lee et al., 2000; Shulman et al., 2004; Fisher et al., 2005; Sinusas & Coroso, 2006). The types of smokeless tobacco implicated are snus in Sweden (Salonen et al., 1990; Rolandsson et al., 2005), Finland (Jungell & Malmström, 1985), and Denmark (Roed-Petersen et al., 1972; Roed-Petersen & Pindborg, 1973; Rolandsson et al., 2005), chewing tobacco in the United Kingdom (Tyldesley, 1971) and India (Jacob et al., 2004), nass (naswar) in Uzbekistan (Zaridze et al., 1985, 1986; Evstifeeva & Zaridze, 1992), toombak in Sudan (Idris et al., 1996; Ahmed et al., 2003; Ahmed & Mahgoob, 2007), snuff (finely ground fermented tobacco leaf with the wet ash of an Amaranthus species plant) in South Africa (Ayo-Yusuf et al., 2000), shammah in Yemen (Scheifele et al., 2007) and Saudi Arabia (Salem et al., 1984; Mani, 1985).

Table 2.5 (available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.5.pdf) includes cross-sectional and case–control studies of smokeless tobacco and leukoplakia, listed by country. Eight reports from the USA adjusted for tobacco smoking, either through statistical adjustment or restriction to non-smokers, one in schoolchildren (Tomar et al., 1997) and the others in adults (Shulman et al., 2004; Ernster et al., 1990; Grady et al., 1990; Daniels et al., 1992; Greene et al., 1992; Martin et al., 1999; Fisher et al., 2005). The prevalence rate ratio or odds ratio for oral leukoplakia in current smokeless tobacco users exceeded those of non-users for smokeless tobacco overall in four studies from the USA (Ernster et al., 1990; Tomar et al., 1997; Martin et al., 1999; Fisher et al., 2005) for snuff in four studies (Ernster et al., 1990; Tomar et al., 1997; Martin et al., 1999; Fisher et al., 2005) and for chewing tobacco in two (Ernster et al., 1990; Tomar et al., 1997) but not in a third (Fisher et al., 2005).

In Uzbekistan nass (naswar) use was positively associated with oral leukoplakia in non-smokers (Zaridze et al., 1986) and after adjusting for smoking, alcoholic beverage consumption, and age (Evstifeeva & Zaridze, 1992). In India, oral precancerous lesions (oral leukoplakia, submucous fibrosis, erythroplakia, and multiple lesions) were associated with tobacco chewing after adjusting for age, sex, BMI, pack–years of smoking, and years of drinking alcohol (Thomas et al., 2003; Jacob et al., 2004).

(b) Dose–response evidence

(i) Duration and intensity

Strong dose–response relationships have been observed in studies in the USA with intensity and duration of use of smokeless tobacco, snuff or chewing tobacco. The prevalence odds ratio for mucosal lesions increased with increasing intensity (amounts used per day or week) and duration (months, years, minutes or hours per day with tobacco in the mouth; shorter time since last used) of use of smokeless tobacco (chewing tobacco and snuff) (Ernster et al., 1990; Tomar et al., 1997; Martin et al., 1999; Fisher et al., 2005). Baseball players who used smokeless tobacco only during the playing season had a lower prevalence rate of oral lesions than year-long users, but higher than non-users (Greene et al., 1992).

In Uzbekistan there was a trend of greater odds ratios for pre-leukoplakia and leukoplakia with the number of times nass was used per day, earlier age at initiation of the habit, years used, and lifetime intake (Evstifeeva & Zaridze, 1992). In Yemen, there was a dose–response relationship with number of minutes shammah was kept in the mouth and the risk was reduced if the mouth was rinsed after using the product (Scheifele et al., 2007).

(ii) Cessation

The prevalence or prevalence odds ratio for oral lesions were higher in current than in former users in studies in the USA (Ernster et al., 1990; Tomar et al., 1997; Shulman et al., 2004; Fisher et al., 2005). Former users generally had higher prevalence or prevalence odds ratio (although not always statistically significantly elevated) than never users (Ernster et al., 1990; Tomar et al., 1997; Fisher et al., 2005). In Uzbekistan, both former (OR, 3.00; 95%CI: 1.08–8.32) and current users (OR, 3.86; 95%CI: 2.60–5.72) had statistically significantly elevated odds ratios associated with nass use (Evstifeeva & Zaridze, 1992).

(c) Severity of lesions

The percentage of more severe leukoplakia lesions (degree 3 and 4) was higher with increasing amount of use, longer duration of use, shorter time since last use of snuff, and exposure time in the mouth in studies in the USA (Ernster et al., 1990; Grady et al., 1990; Daniels et al., 1992; Greene et al., 1992; Tomar et al.; 1997; Martin et al., 1999). Basal-cell hyperplasia was observed in 4% of 132 lesion biopsies from snuff users, while no hyperplasia was found in the 6 biopsies from chewing tobacco users (Daniels et al., 1992). Severe epithelial atypia was observed in toombak users (38%) in a case series in Sudan (Ahmed et al., 2003). Also in Sudan greater duration of toombak use was associated with greater severity of the lesions (Idris et al., 1996). In a South African study, lesions were more severe among those with more minutes per day of use and the users of the commercial brand compared to home-made snuff (Ayo-Yusuf et al., 2000).

(d) Types

The prevalence of lesions was higher among snuff users compared with tobacco chewers in several studies (Ernster et al., 1990; Greene et al., 1992; Tomar et al., 1997; Martin et al., 1999). Among snuff users, the prevalence of lesions and the relative risk varied depending on the brand used (Grady et al., 1990; Greene et al., 1992; Martin et al., 1999). In Yemen (Scheifele et al., 2007) the prevalence odds ratio was higher for using black shammah compared to white shammah. Greater frequency of more severe lesions has been found in users of loose snus compared to men using portion-bag snus (Andersson & Axéll, 1989; Andersson et al., 1994; Rolandsson et al., 2005).

(e) Reversal or progression of lesions

Table 2.6 (available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.6.pdf) provides information from studies that examined reversal or progression of lesions. In men with leukoplakia that were re-examined 1–21 days after the first examination, 15% of the lesions resolved and 18% improved by one degree (Grady et al., 1991). Smaller lesions were most likely to have resolved in men who decreased or stopped smokeless tobacco use, among users of chewing tobacco compared with those of snuff, among light users, and among seasonal users only. Disappearance or regression of lesions was not associated with duration of smokeless tobacco use or the number of days between the initial examination and follow-up. In a study of military recruits, 97% of the oral lesions observed at the initial examination had completely resolved six weeks after they ceased using tobacco (Martin et al., 1999). In a study in Denmark, there was a lower percentage of snuff users whose lesions transformed to dysplasia or malignancy compared to patients with leukoplakia who did not use snuff (Roed-Petersen & Pindborg, 1973).

Men in Sweden with snus-induced lesions followed over 27–29 years did not have a higher risk of oral cancer (not smoking adjusted) compared to the entire Swedish population (Roosaar et al., 2006). A subset of men had a repeat oral examination 19–22 years after the baseline. Among those who stopped snus entirely or used it less than once per day, 6.1% had a lesion at the follow-up exam. Lesions were still present with the same or lesser severity in 91% of the men who continued use of loose snuff or changed to portion-bag snuff and 8.7% had a worse lesion. Of those who used snus for more hours per day at the follow-up than at baseline, 12.1% had a worse lesion. In an earlier study, after 3–6 months, snus users with oral lesions who used portion-bag snus were more likely to have less severe lesions and users who stopped using snus or who changed to portion bags and changed the placement of the snus in the mouth had no lesions at the original site (Larsson et al., 1991). Snus users who changed to snus with a lower pH and lower nicotine concentrations had less severe lesions after 24 weeks (Andersson & Warfvinge, 2003).

In a 10 year follow up study in India, Gupta et al. (1980) reported significantly higher malignant transformation in a group of smokeless tobacco users with precancer.

2.1.3 Cancer of the oesophagus

(a) Overview of studies

Studies of smokeless tobacco and oesophageal cancer have been conducted in North America, Europe and Asia. All of the studies reported here examined oesophageal cancer risks associated with use of unsmoked tobacco that was not part of a betel quid. Evidence regarding betel quid is presented in the Monograph on Betel Quid in this volume. These studies generally focused on the predominant smokeless tobacco products and behaviours in the countries in which the studies were conducted.

Two studies (Zendehdel et al., 2008; Nasrollahzadeh et al., 2008) have been published since the previous Monograph (IARC, 2007a).

Major risk factors for oesophageal cancers are tobacco smoking, betel quid chewing, heavy alcohol consumption (only for squamous cell carcinomas of the oesophagus) (IARC, 2004, IARC, 2010) and BMI (for adenocarcinoma of the oesophagus) (Kubo & Corley, 2006), making these factors potential confounders in studies of smokeless tobacco. [The Working Group notes that betel quid chewing and smokeless tobacco use are nearly always mutually exclusive in certain geographic regions.]

In two cohort studies (Boffetta et al., 2005; Zendehdel et al., 2008) smokeless tobacco use and oesophageal cancer has been examined (Table 2.7 available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.7.pdf); both addressed potential confounding by smoking and included incident cases occurring in the first few years of follow-up.

One of the cohort studies was conducted in Norway and study participants were followed for 35 years for cancer incidence (Boffetta et al., 2005). The relative risk for oesophageal cancer was 1.4 (95%CI: 0.6–3.2) for ever use of snuff compared to never use, adjusted for age and smoking. In a Swedish cohort study (Zendehdel et al., 2008) the relative risk for squamous cell carcinoma of the oesophagus among non-smoking men who used only snuff compared to never users of tobacco was 3.5 (95%CI: 1.6–7.6) adjusting for age and BMI.

Several case–control studies in the USA have been conducted that did not include odds ratio among non-smokers or did not adjust statistically for smoking behaviours (Wynder et al., 1957; Wynder & Bross, 1961; Wynder & Stellman, 1977; Pottern et al., 1981). Of the seven case–control studies of smokeless tobacco and oesophageal cancer that did so (Table 2.8 available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.8.pdf), two were conducted in Sweden (Lewin et al., 1998; Lagergren et al., 2000), three in the USA (Martinez, 1969; Williams & Horm, 1977; Williams et al., 1977; Brown et al., 1988), one in India (Phukan et al., 2001) and one in the Islamic Republic of Iran (Nasrollahzadeh et al., 2008). Because the survival rate for oesophageal cancer is poor (Crew & Neugut, 2004), case–control studies may be susceptible to selection bias from not interviewing study cases who died before the time of interview or measurement error due to obtaining information from proxy interviews (Winn, 1986).

Three case–control studies from the USA (one from Puerto Rico) showed no association between use of smokeless tobacco and oesophageal cancer (Martinez, 1969; Williams & Horm, 1977; Williams et al., 1977; Brown et al., 1988) after adjusting for smoking or restricting the analysis to non-smokers. The proportion of proxy interviews needed to ascertain smokeless tobacco use in these studies was 45% (Williams & Horm, 1977; Williams et al., 1977), at least 69% (Brown et al., 1988), and 12% (Martinez, 1969).

Both of the Swedish case–control studies were population-based and adjusted the analyses for smoking and alcohol intake (Lewin et al., 1998; Lagergren et al., 2000). In one of them that involved both squamous cell and adenocarcinoma, no proxy interviews were permitted (Lagergren et al., 2000). The odds ratio for users of smokeless tobacco only compared to non-users of tobacco was 1.4 (95%CI: 0.9–2.3) for squamous cell carcinoma of the oesophagus and 1.2 (95%CI: 0.7–2.0) for adenocarcinoma of the oesophagus adjusting for age, tobacco smoking, alcohol drinking and other factors. In the other Swedish study (Lewin et al., 1998) on squamous cell carcinoma, most were interviewed about a month after the case’s diagnosis date. The odds ratio for ever use of snuff was 1.2 (95%CI: 0.7–2.2), adjusting for age, region, tobacco smoking and alcoholic beverages.

In a hospital-based case–control study from India an association between smokeless tobacco and oesophageal cancer was found (Phukan et al., 2001). Relative to persons who neither used smokeless tobacco nor smoked, the odds ratio for persons who used only chadha (a type of smokeless tobacco) but did not chew betel quid nor smoke was 3.2 (95%CI: 1.6–9.5) for men and 6.2 (95%CI: 2.4–12.1) for women, adjusting for alcohol. In a study in the Islamic Republic of Iran cases were interviewed at the time of diagnosis (there were no proxy interviews), and only histologically confirmed squamous cell carcinoma were included (Nasrollahzadeh et al., 2008); when use of different tobacco products was examined in a multivariate model, there was a significant positive association with nass use only compared to never users of any tobacco product, after adjustment for education, ethnicity, and total intake of fruit and vegetables.

In a meta-analysis of studies published through 2007 (Boffetta et al., 2008) (Table 2.9, available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.9.pdf), only studies from Europe and the USA that provided information about non-smokers and studies that included smokers but adjusted for tobacco smoking were included. The overall estimate of effect for the five studies of oesophageal cancer was 1.6 (95%CI: 1.1–2.3). In a second meta-analysis Lee & Hamling (2009) included studies from Europe and the USA of smokeless tobacco and oesophageal cancer through May 2008, including and two studies that did not adjust for smoking (Wynder & Bross, 1961; Wynder & Stellman, 1977) (Table 2.10, available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.10.pdf). The overall relative risk among never-smokers was 1.91 (95%CI: 1.15–3.17) and the smoking-adjusted relative risk 1.13 (95%CI: 0.95–1.36). For Scandinavian studies, the summary relative risk in never-smokers was 1.92 (95%CI: 1.00–3.68; one study) and 1.10 (95%CI: 0.92–1.33) when smoking adjusted. For studies from the USA, the relative risks restricted to never-smokers or adjusted for smoking were identical, 1.89 (95%CI: 0.84–4.25).

(b) Dose–response evidence

(i) Duration and intensity

In one case–control study (Lagergren et al., 2000), there were no significant increases in risk for years of use up to 25 years, adjusted for smoking, alcohol, and other factors. For more than 25 years of use, the odds ratio for snuff use controlling for smoking, alcohol intake and other factors was 2.0 (95%CI: 0.9–4.1) for squamous cell carcinoma of the oesophagus and 1.9 (95%CI: 0.9–4.0) for adenocarcinoma of the oesophagus. The odds ratio for use of 15–35 quids per week for squamous cell carcinoma was 2.1 (95%CI: 1.0–4.4) and for adenocarcinoma, 2.0 (95%CI: 1.0–4.3). Corresponding estimates for using more than 35 quids per week were 1.0 (95%CI: 0.4–2.4) and 0.8 (95%CI: 0.3–2.0), respectively. In another case–control study (Lewin et al., 1998), the odds ratio for smokeless tobacco users of more than 50 g per week was 1.9 (95%CI: 0.8–3.9) adjusting for smoking and alcohol intake among other factors. In the Islamic Republic of Iran study (Nasrollahzadeh et al., 2008), there were significant positive exposure-response relationships for frequency of use per day of nass, cumulative use (frequency times duration), and duration of nass use. However, these findings were not controlled for tobacco smoking.

(ii) Cessation

In one case–control study of oesophageal cancer (Lewin et al., 1998), there was no association with snuff use for former or current smokeless tobacco users compared to never smokeless tobacco users.

(c) Types

In northern Europe, the predominant form of smokeless tobacco is snus. Of the four studies from that geographic region – two cohort (Boffetta et al., 2005; Zendehdel et al., 2008) and two case–control (Lewin et al., 1998; Lagergren et al., 2000) – all of the odds ratios were greater than 1.0, but statistically significantly elevated only in one study (Zendehdel et al., 2008). The odds ratios in the three studies from the USA where snuff and chewing tobacco are used, were not statistically significantly elevated (Martinez, 1969; Williams & Horm, 1977; Brown et al., 1988).

In India, among non-smokers, statistically significantly elevated odds ratios associated with chewing chadha were reported for both men and women adjusting for alcohol consumption (Phukan et al., 2001). In a study in the Islamic Republic of Iran, nass users had a significantly increased risk of oesophageal cancer (Nasrollahzadeh et al., 2008).

It was noted in a report on a case series in Sudan that use of tobacco in the form of toombak under the tongue or in the labiodental groove was common in an area where oesophageal cancer incidence rates were high (Babekir et al., 1989).

(d) Histology

Two studies analysed squamous cell cancer and adenocarcinoma separately (Lagergren et al., 2000; Zendehdel et al., 2008); in the other studies (Brown et al., 1988; Phukan et al., 2001; Nasrollahzadeh et al., 2008), most (if not all) of the cases had squamous cell carcinomas. Statistically significantly elevated odds ratios were found for ever use of smokeless tobacco and squamous cell carcinomas in one study (Zendehdel et al., 2008), in another study (Lagergren et al., 2000) for users of 15–35 quids per week, and in a third study of predominantly squamous cell carcinomas (Phukan et al., 2001). In a fourth study from the Islamic Republic of Iran that assessed squamous cell carcinomas, nass use was found to have a significant positive association with oesophageal cancer (Nasrollahzadeh et al., 2008).

Two studies provided odds ratios for use of smokeless tobacco and adenocarcinoma of the oesophagus; in one the odds ratio was statistically significantly elevated for ever users (Zendehdel et al., 2008) and in the other (Lagergren et al., 2000) users of 15–35 quids per week had an increased risk for adenocarcinoma of the oesophagus.

(e) Population characteristics

In the study in India (Phukan et al., 2001), significantly elevated odds ratios were observed in both men and women.

(f) Subsites of cancers of the upper aerodigestive tract

In some studies smokeless tobacco-associated risks were examined only for oral cancer or provided oral cavity cancer-specific findings. Of these studies, statistically significantly elevated odds ratios for ever use of smokeless tobacco were noted in seven (Chandra, 1962; Williams & Horm, 1977; Blot et al., 1988; Idris et al., 1995a; Merchant et al., 2000) but no association in two (Schildt et al., 1998; Accortt et al., 2002, 2005; Luo et al., 2007). Some other studies provided estimates for the oral cavity plus one or more of the pharynx, lip, salivary gland, oesophagus, and larynx. Of these four had positive findings (Kabat et al., 1994; Lewin et al., 1998; Wasnik et al., 1998; Roosaar et al., 2008) and four had relative risks below one or close to approximately equal to one (Mashberg et al., 1993; Boffetta et al., 2005; Henley et al., 2005; Rosenquist, 2005). In studies providing information separately for the pharynx, estimates were positive for women with 20 or more years of snuff use in the USA (Winn et al., 1981a); for hypopharyngeal cancer, estimates were positive in one study in India (Sapkota et al., 2007) and below one in two other studies (Williams & Horm, 1977; Lewin et al., 1998).

2.1.4 Cancer of the pancreas

Three cohort studies (Zheng et al., 1993; Boffetta et al., 2005; Luo et al. 2007), three population-based case–control studies (Williams & Horm 1977; Farrow & Davis, 1990; Alguacil & Silverman, 2004) and two hospital based case–control studies (Muscat et al., 1997; Hassan et al., 2007) in North America and in Europe investigated the association between the use of smokeless tobacco and pancreatic cancer.

(a) North America

(i) Cohort study

In the Lutheran Brotherhood Insurance Society cohort with 20 years follow-up, a relative risk of 1.7 (95%CI: 0.9–3.1, based on 16 deaths) adjusted for age, alcoholic beverages and smoking was found for male ever users of smokeless tobacco (Zheng et al., 1993).

(ii) Case–control studies

No association was found with smokeless tobacco in two population-based case–control studies (Williams & Horm 1977; Farrow & Davis, 1990). In a population-based case–control study that restricted analyses to lifelong non-smokers of cigarettes, a non-significantly 40% increase in risk for pancreatic cancer (95%CI: 0.5–3.6) was found in those who used smokeless tobacco regularly compared to non-users of tobacco (Alguacil & Silverman, 2004). Among tobacco chewers who were not current cigarette smokers, an elevated risk of 3.6 (CI: 1.0–12.8) was seen when compared to never-smokers and long-term quitters (≥ 20 years) in one hospital-based case–control study (Muscat et al., 1997) and no association with chewing tobacco or using snuff was noted in an another hospital-based case–control study (Hassan et al., 2007). None of the studies adjusted for BMI or alcohol, which are potentially important risk factors for pancreatic cancer (Table 2.11, available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.11.pdf).

In a meta-analysis of four studies from the USA, the summary relative risk for pancreatic cancer among users of smokeless tobacco was 1.4 (95%CI: 0.7–2.7) (Boffetta et al., 2008).

(iii) Duration and intensity

Only a few studies assessed risk in relation to duration and intensity of use, assessing oz per week or grams per day and duration of use. In one study (Alguacil & Silverman, 2004), the odds ratio for those who used > 2.5 oz of smokeless tobacco a week compared to non-users of tobacco was 3.5 (95%CI: 1.1–10.6) and for those who used smokeless tobacco for more than 20 years was 1.5 (95%CI: 0.6–4.0), adjusted for age, sex, race, cigar smoking and study area.

(b) Europe

In the Norwegian Cohort Study followed up for 35 years the relative risk for pancreatic cancer for ever use of snuff (snus) was 1.67 (95%CI: 1.12–2.50; 45 cases), adjusted for smoking and age (Boffetta et al., 2005). Among ever users of snuff, the relative risk was 0.85 (95%CI: 0.24–3.07, based on three cases) in never-smokers. In the Swedish construction worker cohort study, analyses were restricted to never smoking men at the time of entry into the study (Luo et al., 2007). Average follow-up was 20 years and 83 pancreatic cancers were recorded. Compared to never users of any tobacco product, and after adjustment for age and BMI, the relative risk for never smoking current users of snus was 2.1 (95%CI: 1.2–3.6; 18 cases) and in never-smokers who used ≥ 10 g/day snus was 2.1 (95%CI: 1.1–3.8) (Table 2.12, available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.12.pdf).

A meta-analysis showed a summary relative risk for pancreatic cancer among users of smokeless tobacco based on the two above cohort studies of 1.8 (95%CI: 1.3–2.5) (Boffetta et al., 2008).

2.1.5 Other cancers

(a) Cancer of the stomach

Four cohort studies (Kneller et al., 1991; Chao et al., 2002; Boffetta et al., 2005; Zendehdel et al. 2008) and 4 case–control studies (Williams & Horm, 1977; Hansson et al., 1994; Ye et al., 1999; Phukan et al., 2005) investigated the association between stomach cancer and use of smokeless tobacco. Phukan et al. (2005) also reported exposure to tuibur (Table 1.1).

(i) Cohort studies

In the USA, non-significantly elevated risks associated with smokeless tobacco use were observed among never-smokers compared to men who never used tobacco in the Lutheran Brotherhood cohort study with 20 years follow-up (Kneller et al., 1991) and in the CPS-II cohort study with 18 years follow-up (Chao et al., 2002). In the cohort study from Norway (35 years follow-up), a non-significantly elevated risk for snuff use was found (Boffetta et al., 2005). A total of 343 822 men were analysed in the construction worker cohort study from Sweden (33 years follow-up) and a significant positive relative risk was seen among non-smoking snus users aged 70 and over for cancer in the non-cardia region of the stomach when compared to never users of any tobacco product (Zendehdel et al., 2008; Table 2.13, available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.13.pdf).

(ii) Case–control studies

Williams & Horm (1977), Hansson et al. (1994) and Ye et al. (1999) found no significant associations with the use of smokeless tobacco products or snuff. The study by Phukan et al. (2005) showed a significantly elevated risk for chewing tobacco alone among non-betel quid users (adjusted for tobacco smoking, alcohol drinking, tuibur, education, occupation, income) and for tuibur use (adjusted for tobacco smoking, alcohol drinking, education, occupation, income) (Table 2.14, available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.14.pdf).

(iii) Dose–response evidence

In one study, risk increased with cumulative dose of tobacco chewing and for tuibur use (p for trend < 0.001), each adjusted for other confounding factors (Phukan et al., 2005).

(iv) Cessation

Phukan et al. (2005) found that risk decreased with years of cessation of tuibur use, although the test for trend was not significant.

(b) Cancer of the colon and rectum

In the US Veterans’ cohort study with 26 years follow-up (Heineman et al., 1995), smokeless tobacco users had a relative risk of 1.2 (95%CI: 0.9–1.7; based on 39 deaths) for cancer of the colon and 1.9 (95%CI: 1.2–3.1; based on 17 deaths) for cancer of the rectum compared to those who had never used tobacco. No new data have been published since the previous IARC Monograph (IARC, 2007a).

(c) Cancer of the extra-hepatic bile duct

In a population-based case–control study in Los Angeles County, USA (Chow et al., 1994) an odds ratio of 18 (95%CI: 1.4–227.7; based on 3 cases) was found for chewing tobacco and cancer of the ampulla of Vater. [All cases of cancer of the ampulla of Vater who chewed tobacco also smoked.] There have been no new studies published since the previous IARC Monograph (IARC, 2007a).

(d) Cancers of the digestive system combined

A reduced risk with use of smokeless tobacco was seen in the case–control study by Sterling et al. (1992) and in the National Health and Nutrition Examination Survey (NHANES I) follow-up study that analysed 6805 men and women aged 45–75 years at baseline (1971–75) (Accortt et al., 2002). The entire NHANES I cohort was reassessed between 1982 and 1984 and analysed 7787 subjects aged 45 and over at baseline. The results showed non-significantly elevated risks for those aged 65 years and over in men and aged 45–64 years in women (Accortt et al., 2005). [The analysis was limited to incident diseases that required an overnight stay in health care facility. Hence, there is a possibility of underrepresentation of the actual number of cancer cases that occurred in the cohort. Analysis was based on a small sample size, 414 exclusive smokeless tobacco users, and chewing tobacco and snuff use were not analysed separately. Pipe and cigar use was not controlled for in the analysis.]

The hazard ratio for men who reported current use of smokeless tobacco and never used other tobacco products was significantly elevated after adjustment for age, race, educational level, BMI, exercise, alcoholic beverage consumption, fat consumption, fruit and vegetable intake and aspirin use in the CPS I cohort but not in the CPS II cohort (additionally adjusted for status and type of employment) (Henley et al., 2005).

(e) Cancer of the gall bladder

One case–control study in India found positive associations with chewing khaini [raw tobacco with lime] and cancer of the gall bladder (OR, 1.65; 95%CI: 0.78–3.49) or chewing tobacco alone (OR, 2.71, 95%CI: 1.22–6.02), unadjusted for other potential confounding factors (Shukla et al., 2008).

(f) Cancers of the respiratory tract

(i) Nasal cavities

Brinton et al. (1984) in a case–control study found non-significant sex-adjusted odds ratios for tobacco chewers or snuff users while Stockwell & Lyman (1986) found an odds ratio for smokeless tobacco of 3.3 (95%CI,0.4–25.9), adjusted for age, race, sex and tobacco use. [The Working Group noted that information about tobacco use was obtained from medical records and ascertainment bias cannot be ruled out.] No new studies were identified since the previous IARC Monograph (IARC, 2007a).

(ii) Larynx

In a case–control study in Florida, USA, a significantly elevated odds ratio for smokeless tobacco use, adjusted for age, race, sex and tobacco smoking was found (Stockwell & Lyman, 1986). [The Working Group noted that information about tobacco use was obtained from medical records and ascertainment bias cannot be ruled out.] From a case–control study in Sweden Lewin et al. (1998) reported no significant association for current and former use of snuff, adjusted for age, smoking and alcoholic beverages. No new studies were identified since the previous IARC Monograph (IARC, 2007a).

(iii) Lung

The NHANES follow-up study ascertained incident cases (Accortt et al., 2005) and deaths from lung cancer (Accortt et al., 2002). Never-smoking women who ever used smokeless tobacco had significantly higher mortality compared to never tobacco users. In men, no deaths from lung cancer occurred among those who were never-smokers and used smokeless tobacco. Estimates of the relative risk were adjusted for age, race, poverty index ratio, region of residence, alcoholic beverages, recreational physical exercise and fruit/vegetable intake. The results for cancer incidence (Accortt et al., 2005) showed significantly elevated risks in women aged 65 years and over, based on small numbers of cases among exclusive smokeless tobacco users (n < 4 cases). No incident cases of lung cancer occurred in men who used smokeless tobacco. Risk was adjusted for age, race and poverty index ratio. [The Working Group noted limitations to this study. See section on cancers of the digestive system (d).]

In the Cancer Prevention Study I (CPS-I) in the USA, the hazard ratio for lung cancer for current smokeless tobacco users who never used other tobacco products was non-significantly elevated and the corresponding hazard ratio in the CPS-II cohort was significantly elevated, after adjusting for age, race, level of education, BMI, exercise, alcoholic beverage consumption, fat consumption, fruit and vegetable intake, aspirin use and status and type of employment (for CPS-II only) (Henley et al., 2005). The magnitude of effect was similar for those who chewed tobacco but never used snuff and for those who used snuff but never chewed tobacco. In the Norwegian cohort study the relative risk adjusted for age and smoking was non-significantly reduced for ever users of snus compared to never users (Boffetta et al., 2005). In the Swedish construction worker cohort study with 279 897 men followed for an average of 20 years there was no significant association for snus use among never-smokers (Luo et al., 2007).

Henley et al. (2007) used CPS II data to compare mortality among former cigarette smokers who switched to smokeless tobacco (switchers) with those who quit using tobacco entirely (quitters), based on tobacco use ascertained at baseline and followed-up for 20 years. In a subset of the cohort that examined uptake of tobacco after baseline, the proportions of persons taking up cigarette smoking was very low. Compared with quitters, the relative risk of lung cancer was 1.5 (95%CI: 1.2–1.7) for all switchers, 1.3 (95%CI: 1.1–1.6) for switchers to tobacco chewing only, 1.8 (95%CI: 1.2–2.5) for snuff only, and 1.9 (95%CI: 1.2–2.9) for tobacco chewing and snuff combined. Compared with men who never used any tobacco product, the relative risk of lung cancer was 3.9 for quitters and 5.6 for switchers (statistically significant but 95% confidence intervals were not provided). Risk estimates were adjusted for age, number of cigarettes formerly smoked per day, number of years smoking cigarettes, age at which they quit smoking cigarettes, race, educational level, BMI, exercise level, alcohol consumption, employment type, employment status, fat consumption, fruit and vegetable intake and aspirin use. The analysis was restricted to men because women were not asked whether or not they used smokeless tobacco.

The case–control study of lung cancer by Williams & Horm (1977) reported non-significant risk for smokeless tobacco use in men, adjusted for age, race, and smoking.

(g) Sarcoma

In the US Veterans’ cohort, the relative risk for soft-tissue sarcomas associated with smokeless tobacco use compared to persons who never used tobacco products was 1.5 (95%CI: 0.8–2.7) (Zahm et al., 1992). In a population-based case–control study conducted in the USA, the unadjusted odds ratio for ever use of smokeless tobacco was 1.8 (95%CI: 1.1–2.9); the risk was highest for those diagnosed at age 80 years or above (3.2; 95%CI: 1.0–10.1). Risks were elevated but not significantly so when analysed by anatomical site of the soft-tissue sarcoma (upper gastrointestinal; lung, pleura and thorax; head, neck and face) or by cell type (fibromatous; adipose, myomatous) (Zahm et al., 1989). No new studies were identified since the previous IARC Monograph (IARC, 2007a).

(h) Cancer of the breast

Spangler et al. (2001, 2002) conducted a case–control study in Cherokee Native American women and reported a non-significant elevated risk of breast cancer for use of smokeless tobacco. [There was no medical verification of breast cancer and the time relationship between use of smokeless tobacco and breast cancer diagnosis was not reported.] A prospective cohort study of the US population (NHANES I) showed a positive but non-significant association with smokeless tobacco (snuff or chewing tobacco) in women aged 45 years and over based on five breast cancer cases, however the hazard ratios were below one when stratified by age (Accortt et al., 2005). [The Working Group noted limitations to this study. See Section on cancer of the digestive system, 2.1.5 (d).]

(i) Cancer of the uterine cervix

In a population-based case–control study elevated risks for cervical cancer, adjusted for smoking, age and race, for use of chewing tobacco or snuff were reported (Williams & Horm, 1977). No new studies were identified since the previous IARC Monograph (IARC, 2007a).

(j) Cancer of the prostate

In two cohort studies significantly elevated risks were found among users of smokeless tobacco compared to never users of tobacco (Hsing et al., 1990, 1991). Putnam et al. (2000) reported no association with use of snuff and chewing tobacco. [The Working Group noted that data were not presented to support this.] In one case–control study (Hayes et al., 1994) and one cohort study (Accortt et al., 2005) non-significantly elevated risks of prostate cancer associated with chewing tobacco were found.

(k) Cancer of the penis

In a case–control study of cancer and the penis in India, the relative risk for snuff users was 4.2 (95%CI: 1.6–11.3), adjusted for smoking, tobacco chewing and phimosis (Harish & Ravi, 1995). [It was not clear whether snuff was used orally or nasally.] No new studies were identified since the previous IARC Monograph (IARC, 2007a).

(m) Cancer of the kidney

Four case–control studies (Goodman et al., 1986; McLaughlin et al., 1995; Muscat et al., 1995; Asal et al., 1988) and one cohort study (Boffetta et al., 2005) evaluated the risk associated with smokeless tobacco use. The adjusted risk for chewing tobacco in non-smokers was not significantly elevated in two case–control studies (Goodman et al., 1986; McLaughlin et al., 1995) and in one cohort study in Norway (Boffetta et al., 2005). In two studies, a significant association was reported for ever use of smokeless tobacco (Asal et al., 1988; Muscat et al., 1995) but there was no adjustment for potential confounders in either study. A dose–response relationship was observed: odds ratio 2.5 (95%CI: 1.0–6.1) for chewing 10 times or fewer per week and 6.0 (95%CI: 1.9–18.7) for chewing 11 or more times per week (Muscat et al., 1995), although there was no adjustment for smoking and other potentially confounding factors.

(n) Cancer of the brain

From a population-based case–control study in the USA (Zheng et al., 2001), no significantly increased risk of brain cancer was reported for either men or women with the use of snuff or chewing tobacco. [Data to support this were not presented.] No new studies were identified since the previous IARC Monograph (IARC, 2007a).

(o) Non-Hodgkin lymphoma

Two population-based case–control studies of non-Hodgkin lymphoma in men were conducted in the USA (Brown et al., 1992a; Schroeder et al., 2002). Schroeder et al. (2002) found an increased risk for t(14;18)-positive non-Hodgkin lymphoma cases who started chewing tobacco ≤ 18 years of age, after adjusting for age and state (OR, 2.5; 95%CI: 1.0–6.0). No significant associations were observed in the study by Brown et al., (1992a) for any non-Hodgkin lymphoma subtype or overall.

Bracci & Holly (2005) from a population-based case–control study of non-Hodgkin lymphoma conducted in the USA reported significantly elevated risks for non-Hodgkin lymphoma and for follicular and diffuse large cell types in those who used smokeless tobacco. Risk estimates were adjusted for age, level of education and level of average weekly alcohol consumption. [The results are based on only seven cases and six controls.]

(p) Leukaemia

Brown et al. (1992b) conducted a population-based case–control study in the USA of chewing tobacco/snuff only and risk for leukaemia. Non-significant elevated risks were seen for all leukaemias, chronic myelogenous leukaemia, chronic lymphocytic leukaemia and myelodysplasia. In the Swedish construction worker cohort study (average follow-up 22.2 years), non-significantly elevated risks for acute lymphocytic and chronic myelogenous leukaemias and no association in men for snuff dipping and acute myelogenous leukaemia and multiple myeloma were found (Fernberg et al., 2007).

(q) Myeloma

In a population-based case–control study in the USA, Brown et al. (1992a) compared users of smokeless tobacco only with never users of tobacco and found an odds ratio of 1.9 (95%CI: 0.5–6.6; based on 5 cases). A Swedish construction worker cohort study showed no association for myeloma in men with snuff dipping (Fernberg et al., 2007).

(r) Cutaneous squamous cell carcinoma

Odenbro et al. (2005) analysed the Swedish cohort study and found a relative risk of 0.64 (95%CI: 0.44–0.95) for the association between snuff dipping and the incidence of cutaneous squamous cell carcinoma.

2.2. Nasal use

There are no cohort or case–control studies that examined the association between nasal snuff use and nasal cancer.

2.2.1 Cancers of the oral cavity and pharynx

(a) Overview of the studies

Three case–control studies from India investigated the association between nasal snuff use and cancer of oral and pharyngeal subsites (Table 2.15, available at http://monographs.iarc.fr/ENG/Monographs/vol100E/100E-03-Table2.15.pdf).

Sankaranarayanan et al. (1989a) focused on cancer of the anterior two-thirds of tongue and floor of the mouth; the age-adjusted odds ratio was 4.27 (95%CI: 1.24–14.67; men only) for occasional nasal snuff users and 3.02 (95%CI: 0.94–9.60) for daily snuff users. For cancer of the gingiva the odds ratio for regular snuff use was 3.04 (95%CI: 0.67–12.65) after adjustment for daily frequency of use of betel quid, bidi smoking and alcoholic beverage use (Sankaranarayanan et al., 1989b). For cancer of the buccal and labial mucosa, the age-adjusted odds ratio was 3.98 (95%CI: 1.53–10.34) for regular nasal snuff users and 2.28 (95%CI: 0.74–7.03) for occasional nasal snuff users (Sankaranarayanan et al., 1990a). After adjusting for daily frequency of use of betel quid, bidi smoking and alcoholic beverage use, the odds ratio associated with ever snuff use was 2.93 (95%CI: 0.98–8.77).

In a multicentre case–control study of cancer of the hypopharynx in India, Sapkota et al. (2007) found an odds ratio of 2.85 (95%CI: 1.15–7.08) for tobacco snuffing among never-smokers who did not chew tobacco or a non-tobacco product, adjusting for alcohol use, and other factors [The Working Group noted that snuff use was oral as well as nasal so the role of nasal use could not be determined separately.]

(b) Dose–response evidence

In the study of cancer of the gingiva (Sankaranarayanan et al., 1989b), the age-adjusted odds ratio for daily nasal snuff use was 3.90 (95%CI: 1.19–12.70) and that for occasional use was 3.78 (95%CI: 1.05–13.54). When categories of high versus low defective nasal snuff use were compared, the odds ratios were significantly elevated for the category of lower intensity for cancers of the tongue (Sankaranarayanan et al., 1989a) and of the buccal and labial mucosa (Sankaranarayanan et al., 1990a).

2.2.2 Other cancers

No new studies were identified since the previous IARC Monograph (IARC, 2007a) for the sites listed except for cancer of the nostril.

(a) Cancer of the oesophagus

A case–control study of oesophageal cancer form India showed an age-adjusted odds ratio for daily snuff use of 2.39 (95%CI: 0.81–7.04) and that for occasional use of 3.59 (95%CI: 1.20–10.67) (Sankaranarayanan et al., 1991). [Estimates were not adjusted for smoking or betel quid chewing.]

(b) Cancer of the paranasal sinuses

Shapiro et al. (1955) studied Bantu cases of paranasal sinus cancer from radiation therapy department records from 1949–51 of a group of hospitals in South Africa. The authors noted that a high proportion (80%) of the antral cancer cases reported ‘prolonged and heavy’ use of snuff in contrast to 34% of Bantu men with cancer at other sites. The product snuffed by Bantus typically contained powdered tobacco leaves and an ash from aloe plants or other species, with the occasional addition of oil, lemon juice and herbs; typical use was ‘one teaspoonful’ per day (Keen et al., 1955). [The Working Group noted that the source and nature of the control group was not described.]

(c) Cancer of the larynx

A case–control study from India (Sankaranarayanan et al., 1990b) of laryngeal cancer showed a non-significant risk for snuff use.

(d) Cancer of the lung

Hsairi et al. (1993) conducted a case–control study of bronchial cancer in Tunisia. The odds ratio for ever use of inhaled snuff (‘tabac à priser’), adjusted for age, sex, cigarette use, water pipe and cannabis use was 2.2 (95%CI: 0.9–5.6).

(e) Carcinoma of the nostril

Sreedharan et al. (2007) reported a case of squamous cell carcinoma in the right nostril in a 69-year-old woman in Karnataka, south India, with a history of daily snuff usage of more than 2 g for a duration of 30 years.

2.3. Synthesis

2.3.1. Oral use

(a) Oral cavity and pharynx

Smokeless tobacco was positively associated with cancers of the oral cavity in a cohort study in northern Europe and several case–control studies, some of which that adjusted for smoking and others that adjusted both for smoking and alcohol. There were elevated risks for every type of smokeless tobacco studied: snuff and chewing tobacco in the USA, snus in northern Europe, toombak in Sudan, smokeless tobacco used as a dentifrice in India and naswar in Pakistan. Case series implicate shammah used in Saudi Arabia as a risk factor for oral cancer. Not all reports were positive, namely some studies in Scandinavia and the USA, including two cohorts with small sample sizes. The evidence is strongest for the oral cavity, with some indication of increased risks for the hypopharynx, or oropharynx and hypopharynx combined. Dose–response relationships with intensity of use were noted in one study and with duration in another. It is unclear whether risks are elevated in former smokeless tobacco users. Three meta-analyses of studies from northern Europe and the USA were generally consistent. In one meta-analysis an overall relative risk of 1.8 (95%CI: 1.1–2.9) was computed for studies that adjusted for smoking or among non-smokers; in another the relative risk was 1.72 (95%CI: 1.01–2.94) among never-smokers and 1.87 (95%CI: 0.82–4.27) when further adjusted for alcohol among never-smokers. In conclusion, there is strong evidence in humans that smokeless tobacco causes cancer of the oral cavity.

(b) Precancerous lesions

Studies in many countries have observed that oral lesions are more common in smokeless tobacco users than non-users, regardless of the type of smokeless tobacco used. The types include snus, snuff, chewing tobacco, smokeless tobacco used as a dentifrice, naswar, toombak, and shammah. In many studies the oral lesions were observed to be in the place in the mouth where users in that geographic region typically place the smokeless tobacco. The prevalence of the lesions increased with various exposure metrics of increasing intensity and duration of use, such as amounts used per day, time kept in mouth, duration of use in months or years. Although some lesions in young persons resolve, the prevalence of lesions in older adult users of these products remains elevated even in former users. There is some evidence from three studies that a small proportion of the lesions among smokeless tobacco users can progress to oral cancer over a period of years, although the rates vary, are not adjusted for any medical intervention to remove the lesions, smoking has not been taken into account, and the follow-up periods are highly variable. Use of smokeless tobacco causes leukoplakia and erythroplakia, both considered precancerous, with a much higher risk of progressing to cancer than normal mucosa.

(c) Oesophagus

Nine studies evaluated the association between smokeless tobacco use and oesophageal cancer. The risks for ever use of smokeless tobacco compared to never use were statistically significantly elevated in one cohort study from Sweden and case–control studies from the Islamic Republic of Iran and India. In a Swedish case–control study, increased risks were observed with 15–35 quids used per week. Smoking could be ruled out as a potential confounder in all of the studies, as well as alcohol intake in two. No increased risk was observed in the three studies from the USA, which included a significant proportion of proxy respondents. Two meta-analyses found that, overall and for the Nordic countries, the estimates of effect for smokeless tobacco use were significantly elevated. The two studies published since the previous Monograph on Smokeless Tobacco showed a positive significant association with oesophageal cancer and were adjusted for major confounders. Four of five studies of squamous cell carcinomas and both studies of adenocarcinoma showed significantly positive results.

(d) Pancreas

In North America, 3 case–control studies showed no association, one cohort study and two case–control studies showed a non-significant increased risk and one case–control study showed a borderline significant increase in risk. While these studies accounted for smoking, none adjusted for BMI or alcohol, potentially important risk factors for pancreatic cancer. In Europe, two cohort studies showed a significant increase in risk of pancreatic cancer associated with snuff use. Both studies controlled for smoking; one study adjusted for BMI and also showed that the highest risks were seen in the highest exposure category. There is good evidence to support a causal association between smokeless tobacco use and pancreatic cancer.

(e) Stomach

One cohort study in Sweden showed a significantly higher risk among non-smoking snus users aged 70 years and over for cancer in the non-cardia region of the stomach, not adjusted for alcohol use. One case–control study in India showed significantly higher risks for chewing tobacco alone and for tuibur users, with dose-dependent increases in risk. Risk decreased with cessation of tuibur use. The risk was not statistically significant in the other studies. Despite some positive findings for chewing tobacco in two different countries and for tobacco smoke-infused water, it was not considered strong enough to conclude for a causal association.

(f) Lung

In summary, in two cohort studies significant positive associations between smokeless tobacco use and lung cancer were found while in three cohort studies and one case–control study there was no association. In one of the positive cohort studies switching from cigarette smoking to smokeless tobacco significantly increased the risk for lung cancer compared to never-tobacco users, and the risk was of greater magnitude than for quitting all together (RR, 3.9 versus 5.6).

2.3.2. Nasal use

Strong positive associations for cancers of the tongue and floor of mouth, gingiva and buccal and labial mucosa were observed in one study in India. In one positive study snuff use was oral as well as nasal so the role of nasal use could not be determined separately.

3. Cancer in Experimental Animals

Since the previous IARC Monograph on Smokeless Tobacco (IARC, 2007a), only one new study has been published. The collective evidence for the carcinogenicity of smokeless tobacco in experimental animals is summarized below.

3.1. Chewing tobacco, unburned cigarette tobacco, mishri and naswar

3.1.1 Mouse

Topical application of unburned cigarette tobacco induced skin papillomas in mice (Wynder & Wright, 1957; Table 3.1). Similar treatment with chewing tobacco extract for 95 weeks followed by croton oil increased the incidence of skin papillomas and carcinomas in mice (Ranadive et al., 1963; Table 3.2). Application of chewing tobacco extract to benzo[a]pyrene-initiated mouse skin promoted development of a few skin papillomas and carcinomas in mice (Ranadive et al., 1963). In mice initiated with 7,12-dimethylbenz[a]anthracene (DMBA) applied topically, application of a barium hydroxide extract of unburned tobacco promoted skin papilloma development (Bock et al., 1964; Table 3.2). Skin-tumour-promoting activity of unburned tobacco was reported in some DMBA-initiated mice in two additional studies (Bock et al., 1965; Van Duuren et al., 1966; Table 3.2). Application of brown or black mishri extracts to DMBA-initiated skin increased significantly the total incidence of papilloma and carcinoma in Swiss mice (Kulkarni et al., 1989; Table 3.3). Administration of chewing tobacco extracts to the oral mucosa (Mody & Ranadive, 1959), skin painting with chewing tobacco extracts (Mody & Ranadive, 1959; Ranadive et al., 1976), or intravesicular or intravaginal application of jarda (Randeria, 1972) did not induce tumours in mice.

Table 3.1

Carcinogenicity studies of application of smokeless tobacco to the skin of experimental animals.

Table 3.2

Carcinogenicity studies on administration of smokeless tobacco with known carcinogens or modifiers to the skin of experimental animals.

Table 3.3

Carcinogenicity studies of mishri alone or with known carcinogens or modifiers to the skin of experimental animals.

Inhalation of powdered tobacco leaves led to a significant increase in the incidence of tumours of the lung and liver in strain A mice (Hamazaki & Murao, 1969; Table 3.4). Mice given chewing tobacco extract by oral intubation developed lung adenocarcinoma and hepatocellular carcinoma in one study [with incomplete reporting of the distribution of different neoplasms] (Bhide et al., 1984). Adding black or brown mishri in the diet increased significantly the incidence of forestomach papilloma in Swiss mice (Kulkarni et al., 1988; Table 3.5).

Table 3.4

Carcinogenicity studies of inhalation of smokeless tobacco in experimental animals.

Table 3.5

Carcinogenicity studies of oral administration of mishri alone or with modifiers to experimental animals.

3.1.2 Rat

Administration of chewing tobacco extract by gavage to vitamin-A-sufficient rats induced benign tumours in the lung and forestomach while similarly treated vitamin-A-deficient rats developed benign tumours in the stomach and pituitary gland and “lymphoma” in the lung [extremely rare tumour in rats] (Bhide et al., 1991; Table 3.6).

Table 3.6

Carcinogenicity studies of oral administration of chewing tobacco in experimental animals.

Administration of mishri by gavage to vitamin-A-sufficient or vitamin-A-deficient rats increased significantly the proportion of tumour-bearing rats in both groups. Lung adenomas and forestomach papillomas developed in vitamin-A-sufficient animals while multiple neoplasms including lung lymphoma [an extremely rare tumour in rats] pituitary adenoma and forestomach papilloma occurred in vitamin-A-deficient animals. Control animals did not develop tumours (Ammigan et al., 1991; Table 3.5). No tumours appeared when chewing tobacco extract was applied to the oral mucosa (Gothoskar et al., 1975). Adding black or brown mishri in the diet increased significantly the incidence of forestomach papillomas in male and female Sprague-Dawley rats (Kulkarni et al., 1988; Table 3.5).

3.1.3 Hamster

Application of a chewing tobacco extract to the cheek pouch of Syrian golden hamsters produced squamous cell papillomas and/or carcinomas in a small number of animals (Rao, 1984; Table 3.7). Adding black or brown mishri in the diet significantly increased the incidence of forestomach papillomas (Kulkarni et al., 1988; Table 3.5). Implantation of chewing tobacco in the cheek pouch (Peacock & Brawley, 1959; Peacock et al., 1960; Dunham & Herrold, 1962; Summerlin et al., 1992), or application of chewing tobacco extract (Suri et al., 1971; Ranadive et al., 1976) or jarda (Kandarkar et al., 1981) to the cheek pouch did not induce tumours.

Table 3.7

Carcinogenicity studies of application of smokeless tobacco to the oral mucosa or cheek pouch of experimental animals.

Application of naswar to the cheek pouch for life increased incidence of tumours in treated hamsters compared to controls (Kiseleva et al., 1976; Milievskaja & Kiseleva, 1976; Table 3.8).

Table 3.8

Carcinogenicity studies of administration of naswar with known carcinogens or modifiers to the skin of experimental animals.

3.2. Snuff

3.2.1 Mouse

Addition of snuff (snus) to the diet induced stomach tumours in gastrin transgenic mice but not in wild-type mice unless they were infected with Helicobacter pylori (H. pylori). Feeding snuff to H. pylori-infected transgenic mice increased gastric carcinoma incidence 2-fold versus control transgenic mice (Stenström et al., 2007; Table 3.9).

Table 3.9

Carcinogenicity studies of oral administration of snuff to experimental animals.

3.2.2 Rat

Application of snuff to the oral mucosa (Chen, 1989) or swabbing of lips and oral cavity with a snuff extract (Hecht et al., 1986) did not induce tumours.

In one study, the administration of snuff in a surgically created lip canal did not induce tumours in the oral cavity (Hirsch et al., 1984) while a squamous cell carcinoma of the oral mucosa developed in one rat in another study (Hirsch & Johansson, 1983). Insertion of snuff in a surgically prepared lip canal induced a squamous cell carcinoma in the lip canal, a papilloma in the oral cavity and an olfactory tumour (Hecht et al., 1986).

Insertion of snuff in a surgically prepared lip canal induced squamous cell carcinoma in the lip, hard palate, nasal cavity and forestomach and a carcinoma in situ in the hard palate. In addition, the treated animals developed squamous cell papillomas in the lip, hard palate and nasal cavity and two undifferentiated lip sarcomas. The incidence of all squamous cell tumours, squamous cell carcinomas and the total number of tumours in the treated group were significantly greater than in controls (Johansson et al., 1989; Table 3.10).

Table 3.10

Carcinogenicity studies of snuff to the oral mucosa or cheek pouch of experimental animals.

In another independent study, the insertion of snuff in the surgically prepared lip canal induced two squamous cell papillomas in the lip, 10 lip sarcomas and three squamous cell carcinomas in the hard palate. In the control group, a lip sarcoma occurred in one rat. The total incidence of epithelial and mesenchymal tumours of the lip and oral cavity and the incidence of lip sarcoma was significantly greater in snuff-treated rats than in controls (Johansson et al., 1991; Table 3.10).

In one study, animals were repeatedly administered snuff extracts by the subcutaneous route. No local tumours developed in either treated or control groups (Schmähl, 1965).

Application of snuff to the surgically created lip canal of rats infected with HSV 1 resulted in the development of squamous cell carcinoma of the oral cavity in 2/7 (28%) rats and a retroperitoneal sarcoma developed in one rat. In the group exposed to snuff alone, one rat each developed a squamous cell carcinoma of the anus and a retroperitoneal sarcoma (Hirsch et al., 1984).

In animals whose hard palate was treated with 4-Nitroquinoline 1-oxide (4NQO), repeated application of snuff did not enhance the incidence of benign and malignant oral cavity tumours over that in animals treated with 4NQO alone (Johansson et al., 1989). However, in another study, application of snuff to a 4NQO-treated surgically created lip canal increased the incidence of lip sarcoma (Johansson et al., 1991; Table 3.10).

3.2.3 Hamster

In hamsters infected with HSV1 or HSV2, insertion of snuff in the cheek pouch increased significantly the incidence of squamous cell carcinoma over that in animals infected with HSV1 or HSV2 and not administered snuff (Park et al., 1986; Table 3.11). Application of a snuff suspension alone to the cheek pouch resulted in the development of stomach papillomas but did not increase the forestomach papilloma incidence in animals initiated with DMBA (Gijare et al., 1990). In one study, chronic feeding of snuff and calcium hydroxide induced a pancreatic carcinoid in one animal only (Dunham et al., 1975) but did not induce any tumours in another study (Homburger et al., 1976). Snuff instillation in the cheek pouch did not induce tumours in six studies (Peacock & Brawley, 1959; Peacock et al., 1960, Dunham & Herrold, 1962; Dunham et al., 1975; Homburger et al., 1976; Park et al., 1986).

Table 3.11

Carcinogenicity studies of snuff with known carcinogens or modifiers to experimental animals.

3.3. Synthesis

In animals administered various smokeless tobacco preparations, consistent increases were observed for forestomach, lung, oral cavity and nasal tumours in rats; lung, skin, forestomach and liver tumours in mice; and oral cavity (cheek pouch) and forestomach tumours in hamsters.

4. Other Relevant Data

See Section 4 of the Monograph on Tobacco Smoking in this volume.

5. Evaluation

There is sufficient evidence in humans for the carcinogenicity of smokeless tobacco. Smokeless tobacco causes cancers of the oral cavity, oesophagus and pancreas.

There is sufficient evidence in experimental animals for the carcinogenicity of smokeless tobacco.

Smokeless tobacco is carcinogenic to humans (Group 1).

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What kind of cancer is associated with using smokeless?

Cancers linked to the use of smokeless tobacco include: Mouth, tongue, cheek, and gum cancer. Cancer of the esophagus (the tube that connects the throat to the stomach) Pancreatic cancer.

What is the main cancer causing agent in tobacco products?

1,3-butadiene and benzene are arguably the two most prevalent potent carcinogens in cigarette smoke, on the basis of toxicologic criteria (Fowles and Dybing 2003).

Why do some tobacco users not get cancer?

May 12, 2022 – Some smokers might not get lung cancer because of their DNA, researchers report in a new study. These people have genes that help limit mutations, or changes, to DNA that would turn cells malignant and make them grow into tumors, the researchers say.

Can chewing tobacco cause colon cancer?

Smoking (or use of other tobacco products) – Regular use of cigarettes, cigars, chewing tobacco and other tobacco-containing items can heighten a person's risk of developing colon cancer.