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IARC Working team on the review of Carcinogenic risks to Humans. Smokeless Tobacco and also Some Tobacco-specific N-Nitrosamines. Lyon (FR): International company for study on Cancer; 2007. (IARC Monographs ~ above the review of Carcinogenic threats to Humans, No. 89.)


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2.1. Introduction

Studies that have actually investigated the association between the usage of smokeless tobacco and cancer have actually often faced a difficulty of small numbers that cases, i beg your pardon has regularly precluded an evaluation of details and appropriate subgroups; alternatively, as soon as such analyses were lugged out, they brought about imprecise family member risk estimates. This is of certain concern in relationship to certain cancer sites, and additionally to an evaluation of categories of smokeless tobacco use and to stratification for tobacco smoking and also alcoholic beverage consumption. As an example, associations through smokeless tobacco use should preferably have been analysed in never ever smokers. In make its evaluation, the functioning Group provided greatest weight to studies that adequately handle potential confounding by smoking. In addition, that the studies that were reviewed formerly (IARC, 1985), just those that addressed such potential confounding have been included and also re-evaluated in this monograph.

The working Group additionally considered the opportunity of confounding by person papillomavirus (HPV), due to the fact that there is sufficient evidence in people that HPV 16 causes cancer the the dental cavity and also oropharynx (IARC, 2007). In a systematic review of the detection that HPV DNA in squamous-cell carcinoma that the head and neck, the pervasiveness of HPV was just 24% in oral and 36% in oropharyngeal cancer (Kreimer et al., 2005), which borders the relationship of instances that can be attributed to this virus. Moreover, negative asso-ciations in between HPV DNA, tobacco smoking and also alcoholic beverage intake (Gillison et al., 2000) and between HPV, tobacco smoking and also pan chewing (Herrero et al., 2003) have actually been observed. Therefore, the Working team concluded that optimistic confounding through HPV is unlikely to account for a strong association of this cancers with tobacco chewing.

In this section, case collection studies are generally consisted of only if no analytical research studies were available from that an ar or as soon as cancer at the website where the smokeless tobacco was inserted was considered.


2.2.1. Cancer that the dental cavity and pharynx

The qualities of cohort studies space summarized in Table 69 and results indigenous these studies on oral and pharyngeal cancer space presented in Table 70.


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(i) Cohort studies

The us Veterans cohort consisted of 293 958 veterans who served in the US equipped Forces throughout 1917–40, to be aged 31–84 year in 1953 and also held US government life insurance plans in 1953 (Zahm et al., 1992). Many policy holders were men (99.5%) and almost all to be white. The outcomes on smokeless tobacco were based on 248 046 (84%) veterans that responded come the questionnaire mailed in 1954 or the questionnaire mailed in 1957 come 1954 non-respondents. The cohort was adhered to up for critical status native 1954 (or 1957) through to 1980, and follow-up to be 96% complete; death certificates were easily accessible for 97% that the deceased cohort members and also identified 129 deaths from dental cancer. The family member risk for dental cancer (ICD-7 140-144) to be 3.0 (95% CI, 2.0–4.5) for customers of chewing tobacco or snuff and also those for infrequent use and frequent usage were 1.9 (95% CI, 1.0–3.5) and also 3.4 (95% CI, 2.1–5.6), respectively. The equivalent relative threats for the pharynx to be 8.7 (95% CI, 4.1–8.3), 4.5 (95% CI, 1.7–11.7) and 11.2 (95% CI, 5.0–25.0), respectively. For early age at very first use (≤ 14 year of age), the relative risk to be 20.7 (95% CI, 8.0–53.7).

NHANES i was a national probability sample survey of the non-institutionalized US populace that oversampled the elderly, poor and also women of childbearing age (Accortt et al., 2002). A complete of 14 407 adults, age 25–74 years, underwent health examinations in between 1971 and also 1975. Of the participants, 13 861 persons (96%) were successfully traced in at the very least one of the NHANES i Epidemiological Follow-up research studies (NHEFS) in 1982–84, 1986, 1987 or 1992. Fatality certificates were obtainable for 98% the the decedents. A random sample the 3847 that the cohort to be asked around smokeless tobacco use at baseline. In the 1982–84 follow-up, info on smokeless tobacco usage was obtained to infer baseline action for examine participants who were not part of the initial random sample. Attendees were taken into consideration to be users of smokeless tobacco if they right now used smokeless tobacco in ~ baseline or had ever used it follow to the 1982–84 question-naire. The analysis was restricted to the 6805 black and white subjects, age 45 year and over for whom data ~ above tobacco were available. Two dental cancers were observed in ever users that smokeless tobacco and also 1.9 to be expected based upon US rates. No dental cancers were observed amongst exclusive customers of smokeless tobacco, but only 0.8 were expected.

The cohorts of the American Cancer culture comprised volunteers, aged 30 year or above, who responded to a mailed questionnaire and also resided in a family in i beg your pardon at the very least one member to be aged 35 year or more (Chao et al., 2002; Henley et al., 2005). The CPS-I cohort included 456 487 men and also 594 544 women, and the CPS-II cohort included 508 351 men and 676 306 women. At enrolment in 1959 (CPS-I) or 1982 (CPS-II), cohort members were wondered about on use of smokeless tobacco. Because that CPS-I, crucial status to be followed-up with to 1972; 6.7% were lost to follow-up and follow-up was truncated because that logistic reasons in 1965 for another 4.9%. Death certificates were 97% complete and were coded come ICD-7. Because that CPS-II, crucial status was followed-up v to 1996 (Chao et al., 2002) or 2000 (Henley et al., 2005). Death certificates to be 99.8% complete and were coded come ICD-9. Analyses were minimal to males who had actually had no previous cancer (except for non-melanoma skin cancer) in ~ enrolment. Chao et al. (2002) further minimal the evaluation to males for whom info on tobacco was accessible (n = 467 788) and Henley et al. (2005) limited the evaluation to males who had actually never used any type of other tobacco. In the CPS-I cohort, the hazard ratio because that oral and also pharyngeal cancers (ICD-7 140-148) for present users that smokeless tobacco was 2.02 (four deaths; 95% CI, 0.53–7.74), readjusted for potential confounders such as alcoholic beverage consumption and also dietary intake. In the CPS-II cohort, the multivariate-adjusted risk ratio because that oral and also pharyngeal cancers (ICD-9 140-148) to be 0.9 (one death; 95% CI, 0.12–6.71) for present users that smokeless tobacco. No deaths occurred among former users of smokeless tobacco.


(ii) Case–control studies

A hospital-based case–control research in Atlanta, GA, USA (Vogler et al., 1962), consisted of four groups who were enroled over a 19-month period (1956–57): 333 white patients (235 men, 98 women) who had actually cancers that the oral cavity, pharynx or larynx, 214 patients who had other diseases of the mouth consisting of leukoplakia, 584 patient who had other cancers and also 787 patients who had actually no cancer and whose mouths were no examined. Usage of smokeless tobacco to be assessed by interview or questionnaire. Among 642 metropolitan women, 40% of the 38 who had actually oral cavity cancers, however only 2%, 3% and also 1% that the 57 who had actually other mouth diseases, 170 who had other cancers and also 377 non-cancer controls, respectively, had actually used snuff. Similar findings were observed because that the 371 countryside women: 75% that the 55 instances of oral cavity cancer had used snuff orally in contrast to 11% the 37 who had other mouth diseases, 20% that 129 who had other cancers, and 11% that 150 non-cancer patients. Only 7% of mrs rural situations smoked. About 30–40% of city women smoked cigarettes, however smoking behavior were comparable in each study group. The differences in snuff use in between cases and also controls were statistically significant for many of the age strata studied. In comparison to 53 (74%) ladies who had actually oral cavity cancer, among three female lip cancer patients and also two (11%) ladies who had pharyngeal or laryngeal cancer had actually used snuff.

Williams and also Horm (1977) performed a population-based case–control study of the etiology the cancer at many different sites based on the interview responses the randomly selected incident instances of invasive cancer (n = 7518; 57% that those selected) native the 3rd National Cancer survey (1969–71). Controls because that smoking-related cancer case groups consisted of men and also women who had actually cancers the were unrelated to smoking. Among men, usage of chewing tobacco and also snuff to be strongly connected with cancer that the gum or mouth, however not through cancer of the lip and also tongue or pharynx; after controlling for age, race and also smoking habits, relative dangers were 3.9 (eight cases; p < 0.01) for moderate and also 6.7 (three cases; non-significant) for hefty use of chewing tobacco or snuff. Among women, the family member risk for use of chewing tobacco or snuff for cancer of the gum or mouth to be 4.9 (two cases; non-significant).

Winn et al. (1981a) carried out a case–control examine of cancers the the oral cavity and also pharynx among women in north Carolina, USA in 1975–78 to examine factors for the exceptionally high rates of mortality from this cancers amongst white ladies throughout the southeastern USA. A complete of 232 women (91% of eligible cases) who had actually been hospitalized v or that had passed away from cancers the the tongue (ICD-8 141), gum (ICD-8 143), floor that mouth (ICD-8 144), various other mouth (ICD-8 145), oropharynx (ICD-8 146), hypopharynx (ICD-8 148) and pharynx unspecified (ICD-8 149) were consisted of in the situation group. 2 age-, race-and region of residence-matched controls were derived for each case; one interview to be completed because that 410 of the 502 eligible controls, excluding subjects with psychological disorders or cancer that the oesophagus, larynx or other oral or pharyngeal diseases. Subjects or their following of kin were interviewed in their homes. Tobacco-related threats were approximated by utilizing a usual reference group: women who did not use tobacco. The loved one risk because that white women who offered only dental snuff was 4.2 (79 cases; 95% CI, 2.6–6.7), when the loved one risk linked with cigarette smoking amongst non-users that snuff to be 2.9 (70 cases; 95% CI, 1.8–4.7). Amongst white women, the loved one risk because that those that both used oral snuff and also smoked to be 3.3 (11 cases; 95% CI, 1.4–7.8); this women had smoked fewer cigarettes and also used snuff for fewer years than ladies who only smoked or provided snuff. Threats for black females were rather lower, however they had actually used snuff because that fewer years and had offered fewer tins per week. Return 37 women had actually chewed tobacco, all but three were likewise oral snuff users. One-third of all oral snuff users had actually started the practice by the age of 10 years, and also the average duration of use among white women was 48 years. Because that cancers that the gum and also buccal mucosa, dental snuff use among nonsmokers was regarded years that use, with relative risks of 13.8 (three cases; 95% CI, 1.9–98.0) because that 1–24 years, 12.6 (10 cases; 95% CI, 2.7–58.3) for 25–49 years and 47.5 (15 cases; 95% CI, 9.1–249.5) for 50 or an ext years that use. Because that cancer at various other sites of the mouse and also of the pharynx, the equivalent relative threats were 1.7, 3.8 and 1.3. The findings relating to dental snuff use can not be defined by poor dentition (Winn et al., 1981b) or by usage of mouthwashes (Blot et al., 1983). The usage of fruit and vegetables was associated with a reduction in hazard in the research population, and was primarily noticeable in tobacco smokers but not amongst oral snuff users (Winn et al., 1984). A subsequent extr analysis contrasted the findings on snuff use and oral and pharyngeal cancer amongst study topics who responded for themselves and those for whom following of kin responded to the concerns on tobacco use (Winn 1986). Odds ratios by cancer site and also race tended to be greater for self-interview versus next-of-kin data. Amongst non-smokers and non-alcoholic beverage drinkers, the odds proportion for oral and pharyngeal cancer was 3.8 (81 cases; 95% CI, 2.3–6.3) because that snuff use.

Stockwell and also Lyman (1986) ascertained cases and also controls indigenous the population-based cancer it is registered in the state that Florida, USA, end a 1-year duration in 1982. Cases were persons who had incident cancers that the lip, tongue, outstanding glands, gum, floor the mouth, other parts that mouth, oropharynx, hypopharynx, pharynx (unspecified) and nasopharynx (ICD-O 140-149). All instances of cancer of the colon and also rectum, cutaneous melanoma and endocrine neoplasia indigenous the same source during same duration formed the regulate group. Data top top tobacco use were obtained from clinical and registry records, and also were obtainable for 79% the the 2351 examine subjects data (82% the cases, 78% the controls). Odds ratios, readjusted for age, sex, race and also tobacco use by anatomical website were: tongue, 2.3 (95% CI, 0.2–12.9); salient gland, 5.3 (95% CI, 1.2–23.4); mouth and gum, 11.2 (95% CI, 4.1–30.7); pharynx, 4.1 (95% CI, 0.9–18.0); and also nasopharynx, 5.3 (95% CI, 0.7–41.6).

In a case–control examine in the USA, 623 patients through head and also neck cancer were recruited. Cancers the the oral cavity, the oropharynx and the hypopharynx were offered as cases and also controls were patients with cancer the the salient gland, nasopharynx and para-nasal sinuses. Among men, 3.5% had ever before used snuff or chewed tobacco regularly. The authors reported the “there to be no statistically far-reaching differences between cancer site groups on these users of tobacco” (Young et al., 1986) .

The population-based case–control research of Blot et al. (1988) enroled subjects from cancer registries in new Jersey, Atlanta metropolitan area, Santa Clara and San Mateo counties, and Los Angeles, USA. Instances included all black and also white persons aged 18–79 years v incident, pathologically evidenced cancer (coded ICD-9 141–149), not included cancer that the outstanding gland (ICD-9 142) and cancer the the nasopharynx (ICD-9 147) native 1 January 1984 with to 31 march 1985. Random-digit dialling was used to ascertain controls age 64 year or younger and also Health care Financing management (HCFA) was offered for controls aged 65 years and older; controls were frequency-matched ~ above age, sex and race to the cases. Structured questionnaires were administered through trained interviewers in homes and next of kin responded because that 22% the cases and 2% the controls. The response rate to be 75 and 76% for cases and controls, respectively, and a complete of 1114 cases and also 1268 controls were consisted of in the analysis. Amongst men, 6% that 762 cases and also 7% that 837 controls used smokeless tobacco, greatly chewing tobacco. Nearly all tobacco chewers to be smokers. Amongst women, 3% of 352 cases and also 1% of 431 controls used snuff . Among nonsmoking women, the odds ratio for snuff to be 6.2 (95% CI, 1.9–19.8), based on six cases and also four controls who provided snuff. Nonsmoking women mostly used snuff quite than chewing tobacco. Every six cases had dental cavity cancer.

Spitz et al. (1988) identified situations who had actually histologically evidenced squamous-cell carcinoma of the tongue, floor of the mouth, oral cavity, orohypopharynx and larynx in white united state residents, at the MD Anderson Hospital, Houston, TX, USA, native January 1985 with to February 1987. Laryngeal cancer accounted because that 38% of the 131 male cases. Controls to be patients in ~ MD Anderson Hospital during the same period, were randomly selected and also were frequency-matched on age (± 5 years) and also sex; patients who had actually squamous-cell carcinoma of any site to be excluded. The study consisted of 185 instances (131 men and also 54 women) and 185 controls age 29–95 years. Self-administered questionnaires were part of the it is registered procedure. The writer reported the there to be ‘no distinction in circulation of sites of malignancy for snuff users contrasted to all various other cases’. Amongst men, the rudely odds ratio for chewing tobacco was <1.0>. For women, the odds ratio for snuff use was 3.4 (95% CI, 1.0–10.9). There to be no adjustment because that smoking. Every nine snuff dipping instances drank alcoholic beverages, seven likewise chewed tobacco, eight smoked cigarettes and also one smoked cigars and pipes. 3 of 4 snuff dipping controls also smoked cigarettes.

Newly diagnosed situations were established from 3 hospitals in São Paolo, Curitiba and Goiânia, Brazil, and also comprised carcinomas that the tongue, gum, floor that the mouth and other oral cavity (ICD-9 141, 143-145) diagnosed indigenous 1 February 1986 come 30 June 1988 (Franco et al., 1989). Two controls per instance were established from same or neighbouring general hospitals, to be individually matched on sex, 5-year period group and trimester the hospital admission and excluded diagnoses the neoplasms or psychological disorder. Situations were interviewed using a structured questionnaire in hospital and controls to be interviewed privately. 4 per cent of 232 cases and 3% that 464 controls provided smokeless tobacco. The writer reported that use of smokeless tobacco and also oral cancer to be ‘not associated’. The crude odds proportion was <1.4>. They detailed that the family member risk estimates were elevation of tobacco smoking or alcoholic beverage drinking, sex or anatomical site.

A population-based case–control research by Maden et al. (1992) enroled topics from three urban counties of west Washington State, USA. Situations were males aged 18–65 years v in-situ and also invasive squamous-cell cancers the the lip, tongue, gum, floor that the mouth, unspecified mouth and oropharynx diagnosed during 1985–89. Controls ascertained through random-digit dialling to be frequency-matched to instances on age (5-year groups), sex and also year the diagnosis; 131 situations (54.4%) and 136 controls (63%) perfect in-person questionnaire interviews at house or elsewhere. That 131 cases, 15% supplied smokeless tobacco in comparison to 4% the 136 controls, which gave in an age-adjusted odds proportion of 4.5 (95% CI, 1.5–14.3).

Histologically evidenced oral and pharyngeal cancers (including cancers the the tongue, floor that the mouth, oropharynx and hypopharynx) were figured out in one research (Marshall et al., 1992) from 20 hospitals in three new York counties, USA, during the duration 1975–83. Cases of black ethnicity to be excluded. Instances were individually suitable on neighbourhood, age (± 5 years) and also sex. Of 513 situations contacted, 290 (56%) participated and 290 controls were included. The authors noted that “there was a risk associated with chewing tobacco, however it to be insignificant, through very couple of people exposed”.

Mashberg et al. (1993) determined 359 cases amongst black or white men who had actually in-situ or invasive squamous-cell carcinoma that the dental cavity or oropharynx in a Veterans hospital in new Jersey, USA, during 1972–83. A total of 2280 patient from the same series of clinical examinations who had actually no cancer or dysplasia of the pharynx, larynx, lung or oesophagus were recruited and interviewed in hospital between 1977 and 1982 and served as controls; 94% of study subjects participated. Just 52 cases and 255 controls had ever before used smokeless tobacco. Chewing tobacco (odds ratio, 1.0; 95% CI, 0.7–1.4) and also snuff (odds ratio, 0.8; 95% CI, 0.4–1.9) were not connected with oral cancer. No trend by expression of tobacco chewing was observed .

Spitz et al. (1993) established 108 white instances who had actually histologically shown cancers that the oral cavity (44), pharynx (31) and also larynx (33) at MD Anderson Hospital, Houston, TX, USA, from June 1987 to June 1991. Controls who had no history of cancer were ascertained native blood and platelet donors and were frequency-matched to situations by period (± 5 years), race and sex. Patients completed a self-administered questionnaire in the hospital. The odds proportion for chewing tobacco to be 1.2. Smoking was not managed for.

Kabat et al. (1994) ascertained situations from 28 hospitals in eight urban in the USA. Cases had histologically confirmed cancers the the tongue, floor the the mouth, gums, gingiva, buccal mucosa, palate, retromolar area, tonsil and also other pharynx throughout 1977–90. Controls to be individually matched to situations on hospital, admission within 2 months after the case, age, sex and also race, and excluded persons with conditions thought to be associated with tobacco or alcoholic beverages or prior background of tobacco-related cancers. The conditions amongst the controls were: 50% cancers (also including cancer the the stomach, endometrium and also leukaemia), 7% benign neoplasms and 43% various other diseases. A full of 1560 cases and 2948 controls to be included. In-hospital questionnaire interviews were conducted with the study subjects. Amongst men, 6.1% that 1097 cases and also 5.1% the 2075 controls chewed tobacco. Among women, less than 2% of 1336 topics chewed tobacco. Amongst never-smoking men, 4.9% the 82 situations were consistent chewers as were 2.2% of 448 controls, yielding an odds proportion of 2.3 (95% CI, 0.7–7.3). Amongst never-smoking women, there to be no tobacco chewers. Amongst never-smoking women, 3.5% that 113 used snuff in contrast to 0% the 470 controls (odds ratio, 34.5; 95% CI, 8.5–140.1). Among neversmoking men, 0% the 82 cases and also 0.9% that 444 controls were snuff users.

Patients age 21–80 year diagnosed through histologically evidenced cancer of oral cavity and also pharynx (ICD-9 141, 143–146, 148, 149) to be recruited between 1981 and 1990 from hospitals in Illinois, Michigan, brand-new York and Philadelphia, USA (Muscat et al., 1996). Hospital patients with problems unrelated to tobacco usage were suitable to instances by sex, age (± 5 years), race and also date of admission (± 3 months). Solution rates to be 91% because that cases and also 97% for controls to productivity 1009 situations (687 men, 322 women) and 923 controls (619 men, 304 women). A questionnaire interview was conducted with cases and also controls. Amongst men, 5.5% that 687 situations used chewing tobacco at the very least once a week because that 1 year or an ext as did 5.3% that 619 controls . No women supplied chewing tobacco. Amongst men, 1.3% that cases and also 1.6% the controls offered snuff at the very least once a week because that 1 or more years . For women, the crude odds ratio for snuff usage was <1.9>.

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Muscat et al. (1998) report a hospital-based case–control research on salivary gland cancer. One hundred and twenty-eight patient with freshly diagnosed histologically evidenced salivary gland cancer and also 114 age- and gender-matched controls to be interviewed. One instance reported using snuff, and also three cases and also three controls were tobacco chewers.

A population-based case–control examine was performed by Schwartz et al. (1998) that in-situ and invasive (92%) squamous-cell cancers that the tongue, gum, floor of mouth, unspecified mouth, tonsils and oropharynx in persons aged 18–65 years during 1990–95 in counties of Seattle area, WA, USA. Controls to be ascertained by random-digit dialling and were frequency-matched to the situations on sex and age in a 3:2 ratio of controls to cases; 284 situations (165 men, 119 women) and also 477 controls (302 men, 175 women) completed an in-person questionnaire interview; response rates among cases and also controls to be 63.3% and also 60.9%, respectively. Amongst men, 6.7% of 165 cases and also 5.6% of 302 controls supplied smokeless tobacco (odds ratio, 1.0; 95% CI, 0.4–2.3). Just one female control used smokeless tobacco.