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International Agency for Research on Cancer (IARC) - Summaries & Evaluations

BETEL-QUID AND ARECA-NUT CHEWING

VOL.: 37 (1985) (p. 141)

5. Summary of Data Reported and Evaluation

5.1 Exposure data

The habit of chewing betel quid is widespread in South-East Asia and the South Pacific islands and in people of Indian origin elsewhere in the world. Betel quid usually contains areca nut, lime and catechu wrapped in a betel leaf. Tobacco is often added.

These habits result in exposure inter alia to areca-nut alkaloids, N-nitroso compounds derived from these alkaloids, polyphenols, and, when the habit includes tobacco, tobacco-specific nitrosamines.

5.2 Experimental data

Aqueous extracts of betel quid containing tobacco were tested for carcinogenicity in mice by gastric intubation, skin painting and subcutaneous injection; some malignant tumours occurred at the site of skin or subcutaneous administration. In hamsters, forestomach carcinomas occurred after painting of the cheek-pouch mucosa with aqueous extracts or implantation of a wax pellet containing powdered betel quid with tobacco into the cheek pouch; carcinomas occurred in the cheek pouch following implantation of the wax pellets.

Aqueous extracts of betel quid without tobacco were tested in mice by gastric intubation and by subcutaneous administration; an increased incidence of local tumours was observed after subcutaneous injection. In hamsters, painting of the cheek-pouch mucosa or implantation of wax pellets into the cheek pouch resulted in the induction of forestomach carcinomas; carcinomas occurred in the cheek pouch following implantation of the wax pellets.

Aqueous or dimethyl sulphoxide extracts of areca nut with tobacco were tested in mice by skin application. A low incidence of skin tumours was reported in a study lacking controls. In hamsters, applications of such extracts to cheek-pouch mucosa produced squamous-cell carcinomas of the cheek pouch and forestomach carcinomas.

Areca nut or aqueous extracts of areca nut were tested in mice by oral intubation, dietary administration, skin application, and intraperitoneal and subcutaneous injection. Local tumours were produced following subcutaneous injection. In rats, areca nut was tested by oral administration, and aqueous extracts were tested by subcutaneous injection. Studies involving dietary administration were inadequate, but local mesenchymal tumours occurred after subcutaneous injection. In hamsters, administration of areca nut and application of aqueous or dimethyl sulphoxide extracts to the cheek-pouch mucosa resulted in squamous-cell carcinomas of the cheek pouch and carcinomas of the forestomach.

Aqueous extracts of betel leaf were tested in mice by oral intubation or intraperitoneal injection and in hamsters by application to the cheek-pouch mucosa. Betel leaf was tested in rats by dietary administration and in hamsters by implantation in beeswax pellets into the cheek pouch. All these studies were inadequate for evaluation.

Arecoline (an alkaloid of areca nut) was tested in mice by oral intubation and by intraperitoneal and subcutaneous injection, and in hamsters by feeding or application to the cheek-pouch mucosa in combination with lime. The data are inadequate for evaluation.

Aqueous extracts of betel quid without tobacco induce mutations in Salmonella typhimurium but not in Chinese hamster V79 cells. They do not induce micronuclei in bone-marrow cells of Swiss mice.

Aqueous extracts of betel quid with tobacco induce mutations in Salmonella typhimurium and in Chinese hamster V79 cells. They also induce micronuclei in bone-marrow cells of Swiss mice.

Aqueous extracts of areca nut induce mutations in Salmonella typhimurium and in Chinese hamster V79 cells, gene conversion in Saccharomyces cerevisiae, as well as chromosomal aberrations in Chinese hamster ovary cells. They induce micronuclei in bone-marrow cells of Swiss mice. A tannin fraction of areca nut induces gene conversion in Saccharomyces cerevisiae.

Ethyl acetate and n-butanol extracts of areca nut induce chromosomal aberrations in Chinese hamster ovary cells. Ethyl acetate extracts do not induce mutations in Chinese hamster V79 cells, sister chromatid exchanges in human lymphoblastoid cells or transformation in Syrian hamster embryo cells.

Aqueous extracts of betel leaf are not mutagenic to Salmonella typhimurium. They induce chromosomal aberrations in human lymphocytes and in Chinese hamster ovary cells.

n-Butanol and ethyl acetate extracts of betel leaf induce chromosomal aberrations in Chinese hamster ovary cells. Ethyl acetate extracts of betel leaf do not induce mutations in Chinese hamster V79 cells, sister chromatid exchanges in human lymphoblastoid cells or transformation in Syrian hamster embryo cells.

Arecoline induces mutations in Salmonella typhimurium and Chinese hamster V79 cells, and chromosomal aberrations in Chinese hamster ovary cells. It also induces micronuclei, chromosomal aberrations and sister chromatid exchanges in bone-marrow cells of Swiss mice.

Arecaidine induces mutations in Salmonella typhimurium and Chinese hamster V79 cells. It induces sister chromatid exchanges but not micronuclei in bone-marrow cells of Swiss mice.

5.3 Human data

Chewers of betel quid in India and the Philippines had elevated frequencies of micronucleated cells in their buccal mucosa. The proportion of micronucleated exfoliated cells is related to the site within the oral cavity where the betel quid is kept habitually and to the number of betel quids chewed per day. The proportion can be reduced by administration for two to three months of vitamin A or b-carotene or a mixture of the two.

Oral leukoplakia shows a strong association with habits of betel-quid chewing in India. Some follow-up studies have shown malignant transformation of a proportion of leukoplakias. Oral submucous fibrosis and lichen planus, which are generally accepted to be precancerous conditions, appear to be related to the habit of chewing betel quid.

Many descriptive studies and reports of case series have identified an association between the habit of chewing betel quid with tobacco and oral cancer. The association has been consistent across many countries [Bangladesh, China (Taiwan), India, Malaysia, Pakistan, the Philippines, Singapore, Sri Lanka and Thailand]. Further, in case-control studies of oral cancer, whether smoking was controlled for (five studies) or not (five studies), the relative risks were high and statistically significant. However, the results are not directly comparable owing to the inclusion of different anatomical sites; most of these studies did not clearly describe the chewing habits of subjects, and some probably included a large proportion of users of tobacco-lime with or without areca nut. A significant association between the chewing of betel quid with tobacco and oesophageal cancer was reported from a case-control study in Sri Lanka.

Two case-control studies of oral cancer and one of oral and oropharyngeal cancer distinguished between different types of chewing and smoking habits. Controls were age-matched, and relative risks were statistically significant, in the range of 4 to 14, for chewing of betel quid with tobacco.

A positive dose-response relationship was found in two case-control studies.

In a population-based case-control study from Bombay, controls selected from the population were matched for age, sex and religion. Chewing habits were not precisely defined. After controlling for smoking habits, the relative risks were statistically significant for cancers of the oral cavity, oropharynx, hypopharynx, larynx and oeosophagus, but not for cancer of the nasopharynx. When habits were categorized into chewing with and without tobacco, but smoking habits were not taken into account, the relative risks remained statistically significant for all sites except the nasopharynx.

In a case-control study from Thailand, relative risks associated with chewing of betel quid with tobacco were statistically significant for oral and oropharyngeal cancers for men and women, and for laryngeal and hypopharyngeal cancer for men, after adjusting for several possible confounding variables, including smoking.

In cross-sectional surveys from India, although the number of oral cancer cases was generally small, samples were large (10 000 to100 000). Oral cancer was consistently found much more frequently among chewers and/or smokers than among those who did not chew or smoke. Two of these cross-sectional samples were subsequently followed up for two and 10 years. New oral-cancer cases were seen only among those who chewed and/or smoked.

In a large-scale prospective study, two types of chewing habit were distinguished: of Mainpuri tobacco (which contains tobacco, lime and areca nut) and 'other' tobacco usages (which very often included lime and, frequently, areca nut). After controlling for smoking and alcohol drinking (although not for age), prevalence rates of oral cancer were highest for Mainpuri-tobacco usage and generally in second rank for the 'other'-tobacco usage category, in comparison to no chewing habit. The association with oral cancer for both types combined was examined in many different ways and was found to be positive.

Several descriptive studies from Papua New Guinea indicated an association between the habit of chewing betel quid without tobacco and oral cancer. The association is consistent for different areas and different communities (without controlling for smoking); however, analysis of time trends of incidence, chewing and smoking, by sex, suggests that smoking is an important risk determinant.

One case-control study from Pakistan suggests that chewing of betel without tobacco increases the risk of oral cancer when practised alone or in combination with smoking. Another case-control study from India and Sri Lanka provides different results, showing a clear effect of chewing betel with tobacco but not of chewing betel without tobacco, taking into account smoking. A case-control study from Bombay which categorized chewing habits (presumably betel) without tobacco, but did not control for smoking, showed statistically significantly increased relative risks for cancers of the oral cavity, oropharynx, hypopharynx, larynx and oesophagus, in the range of 3 to 5.

Cross-sectional surveys in India show that the percentage of people who chew betel quid without tobacco is small. In one case-control study from India and Sri Lanka, after controlling for smoking, the relative risk for oropharyngeal cancer of the habit of chewing betel quid without tobacco was increased but not significantly so.

5.4 Evaluation

There is sufficient evidence that the habit of chewing betel quid containing tobacco is carcinogenic to humans.

There is inadequate evidence that the habit of chewing betel quid without tobacco is carcinogenic to humans.

The Working Group also concluded that, while there is sufficient evidence that the combined habits of smoking tobacco and chewing betel quid without tobacco cause oral and pharyngeal cancer, the evidence considered here does not allow an assessment of the possible contribution of betel quid without tobacco to this carcinogenic risk.

There is limited evidence that aqueous extracts of betel quid with and without tobacco are carcinogenic to experimental animals.

There is limited evidence that areca nut with and without tobacco is carcinogenic to experimental animals.

The data are inadequate to allow an evaluation of the carcinogenicity of betel leaf or arecoline to experimental animals.

For definition of the italicized terms, see Preamble Evaluation.

Subsequent evaluation: Suppl. 7 (1987)


Last updated: 21 April 1998


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       Toxicological Abbreviations