For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p. 250)
CAS No.:
Chem. Abstr. Name: 2-Methyl-5-nitro-1H-imidazole-1-ethanol
A. Evidence for carcinogenicity to humans (inadequate)
Two epidemiological studies [ref: 1,2] of women treated with metronidazole showed some excesses of cancers of the uterine cervix, a neoplasm that has risk factors in common with vaginal trichomoniasis, the main indication in women for treatment with this drug. In one study [ref: 1], a greater excess of cervical cancer was observed in women with trichomoniasis who were not exposed to metronidazole than in those who were (relative risk, 2.1 versus 1.7). An excess of lung cancer (4 observed, 0.6 expected) seen in one of these studies [ref: 1] was not found in the other (2 observed, 2.6 expected) [ref: 3]. In the former, the excess was mainly of adenocarcinoma (3/4 cases) and was concentrated after at least ten years from first use of metronidazole (3 observed, 0.3 expected) [ref: 4]. Further follow-up and analysis of these data have suggested that the excess could be explained entirely by confounding with smoking [ref: 5]. Another study in which 12 280 users of metronidazole were followed up for two and one-half years gave a relative risk of 0.89 (95% confidence interval, 0.45-1.9) for all cancers [ref: 6].
B. Evidence for carcinogenicity to animals (sufficient)
Metronidazole has been tested for carcinogenicity by oral administration in mice and rats. It significantly increased the incidences of lung tumours in mice of each sex, of lymphomas in female mice [ref: 7,8] and of mammary, pituitary, testicular and liver tumours in rats [ref: 7,9,10]. It increased the incidence of colonic tumours induced in rats by subcutaneous administration of 1,2-dimethylhydrazine [ref: 11,12].
C. Other relevant data
Studies on bone-marrow cells and lymphocytes from a series of patients treated with metronidazole showed no increase in the incidence of chromosomal damage. Metronidazole was active in body fluid assays using sweat, faeces and urine from humans exposed in vivo and urine from rodents exposed in vivo [ref: 13].
Metronidazole did not induce micronuclei in bone-marrow cells of mice or rats, sister chromatid exchanges in bone-marrow cells of Chinese hamsters or unscheduled DNA synthesis in germ cells of male rabbits treated in vivo. Human cells exposed to metronidazole in vitro did not show increased incidences of chromosomal aberrations, whereas results with respect to sister chromatid exchanges were inconclusive. Metronidazole did not induce sister chromatid exchanges in cultured hamster cells; conflicting results were reported for the induction of mutation and DNA damage in rodent cells in vitro. It did not induce sex-linked recessive lethal mutations in Drosophila or recombination in yeast. It induced mutation in fungi and bacteria and induced prophage in bacteria [ref: 13].
Overall evaluation
Metronidazole is possibly carcinogenic to humans (Group 2B).
For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluation: Vol. 13 (1977)
References
1. Beard, C.M., Noller, K.L., O'Fallon, W.M., Kurland, L.T. & Dockerty, M.B. (1979) Lack of evidence for cancer due to use of metronidazole. New Engl. J. Med., 301, 519-522
2. Friedman, G.D. & Ury, H.K. (1980) Initial screening for carcinogenicity of commonly used drugs. J. natl Cancer Inst., 65, 723-733
3. Friedman, G.D. (1980) Cancer after metronidazole. New Engl. J. Med., 302, 519
4. Beard, C.M. (1980) Cancer after metronidazole. New Engl. J. Med., 302, 520
5. Beard, C., Noller, K. & O'Fallon, W.M. (1985) Metronidazole and subsequent malignant neoplasms (Abstract). Am. J. Epidemiol., 122, 529
6. Danielson, D.A., Hannan, M.T. & Jick, H. (1982) Metronidazole and cancer. J. Am. med. Assoc., 247, 2498-2499
7. IARC Monographs, 13, 113-122, 1977
8. Cavaliere, A., Bacci, M., Amorosi, A., Del Gaudio, M. & Vitali, R. (1983) Induction of lung tumors and lymphomas in BALB/c mice by metronidazole. Tumori, 69, 379-382
9. Rustia, M. & Shubik, P. (1979) Experimental induction of hepatomas, mammary tumors, and other tumors with metronidazole in noninbred Sas:MRC(WI)BR rats. J. natl Cancer Inst., 63, 863-868
10. Cavaliere, A., Bacci, M. & Vitali, R. (1984) Induction of mammary tumors with metronidazole in female Sprague-Dawley rats. Tumori, 70, 307-311
11. Sloan, D.A., Fleiszer, D.M., Richards, G.K., Murray, D. & Brown, R.A. (1983) Increased incidence of experimental colon cancer associated with long-term metronidazole therapy. Am. J. Surg., 145, 66-70
12. A-Kareem, A.M., Fleiszer, D.M., Richards, G.K., Senterman, M.K. & Brown, R.A. (1984) Effect of long-term metronidazole (MTZ) therapy on experimental colon cancer in rats. J. surg. Res., 36, 547-552
13. IARC Monographs, Suppl. 6, 399-402, 1987
Synonyms
See Also:
Toxicological Abbreviations
METRONIDAZOLE (JECFA Evaluation)
Metronidazole (PIM 347)
Metronidazole (IARC Summary & Evaluation, Volume 13, 1977)