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

ISONICOTINIC ACID HYDRAZIDE (ISONIAZID)
(Group 3)

For definition of Groups, see Preamble Evaluation.

Supplement 7: (1987) (p. 227)

CAS No.: 54-85-3

A. Evidence for carcinogenicity to humans (inadequate)

Several early studies showed no significant excess of cancer among patients treated with isoniazid [ref: 1]. A study of 3842 tuberculosis patients followed for 16-24 years showed slight excesses of deaths from malignant neoplasms of the bronchus, lung and pleura in 2041 patients treated with isoniazid during 1953-1957 and followed through to 1973 (relative risk, 1.6 [95% confidence interval, 1.2-2.1], but none in 655 treated for tuberculosis in 1950-1952 when isoniazid was not generally available (0.7 [0.1-1.5]). An excess of all malignant neoplasms was also seen in patients treated in 1953-1957 (1.4 [1.2-1.7]), but also in 145 patients not treated with isoniazid over the same period (1.8 [0.7-2.9]). Again, no excess was observed in those treated for tuberculosis in 1950-1952. No dose-response effect was seen either for total consumption or for maximum daily dose of isoniazid [ref: 2]. Additional studies of cancer incidence and mortality among patients treated with isoniazid have shown no excess of lung cancer, or of cancer as a whole, that could be attributed to treatment [ref: 3-6]. A cancer incidence study in patients with tuberculosis, involving heavy smokers, showed an excess of lung cancer among men exposed to isoniazid (3.4, based on 88 cases observed, 26.2 expected) but also among those not exposed (2.6, based on 18 cases observed, 7.0 expected). The difference between the two ratios was not statistically significant. The corresponding figures for women were 4.6, based on 14 cases exposed, and 0.5, based on one case not exposed [ref: 7]. In a preliminary analysis of one-year case records, 72 (4.9%) cancer patients had healed tuberculosis compared with 26 (2%) noncancer patients [ref: 8]. Four case-control studies concerning bladder and kidney cancers [ref: 9], bladder cancer [ref: 10,11] and cancer in children [ref: 12] have provided no conclusive evidence of a risk associated with isoniazid therapy. A single case of mesothelioma has been reported in a nine-year-old child whose mother was treated with isoniazid for a positive tuberculin skin test in the second and third trimesters of pregnancy [ref: 13].

B. Evidence for carcinogenicity to animals (limited)

Isoniazid produced lung tumours in mice after its oral, intraperitoneal or subcutaneous administration [ref: 1,8,13-16]. Studies in rats were considered inadequate for evaluation [ref: 1]. No tumour was produced in hamsters after given oral administration of isoniazid [ref: 1].

C. Other relevant data

In the one available study, isoniazid did not induce chromosomal aberrations in lymphocytes of treated patients [ref: 17].

Isoniazid did not induce dominant lethal mutations in mice, or chromosomal aberrations, sister chromatid exchanges or DNA damage in rodents treated in vivo. Results for chromosomal aberrations and sister chromatid exchanges in human cells in vitro were inconclusive; it did not induce unscheduled DNA synthesis. In cultured rodent cells, it induced chromosomal aberrations and sister chromatid exchanges, but not DNA damage. It did not induce transformation of Syrian hamster embryo cells. It did not induce gene conversion in yeast. Isoniazid was mutagenic to Salmonella typhimurium but not, in a single study, to Escherichia coli [ref: 17].

Overall evaluation

Isonicotinic acid hydrazide (Isoniazid) is not classifiable as to its carcinogenicity to humans (Group 3).

For definition of the italicized terms, see Preamble Evaluation.

Also see previous evaluation: Vol. 4 (1974)

References

1. IARC Monographs, 4, 159-172, 1974

2. Stott, H., Peto, J., Stephens, R., Fox, W., Sutherland, I., Foster-Carter, A.F., Teare, H.D. & Fenning, J. (1976) An assessment of the carcinogenicity of isoniazid in patients with pulmonary tuberculosis. Tubercle, 57, 1-15

3. Glassroth, J.L., White, M.C. & Snider, D.E., Jr (1977) An assessment of the possible association of isoniazid with human cancer deaths. Am. Rev. respir. Dis., 116, 1065-1074

4. Howe, G.R., Lindsay, J., Coppock, E. & Miller, A.B. (1979) Isoniazid exposure in relation to cancer incidence and mortality in a cohort of tuberculosis patients. Int. J. Epidemiol., 8, 305-312

5. Boice, J.D. & Fraumeni, J.F., Jr (1980) Late effects following isoniazid therapy. Am. J. publ. Health, 70, 987-989

6. Costello, H.D. & Snider, D.E., Jr (1980) The incidence of cancer among participants in a controlled, randomized isoniazid preventive therapy trial. Am. J. Epidemiol., 111, 67-74

7. Clemmesen, J. & Hjalgrim-Jensen, S. (1979) Is isonicotinic acid hydrazide (INH) carcinogenic to man? A 24-year follow-up of 3371 tuberculosis cases. Ecotoxicol. environ. Saf., 3, 439-450

8. Bhide, S.V., Maru, G.B., Mate, N.B., Menon, M. & Gangadharan, P. (1981) Metabolic studies on the possible mode of action of isoniazid tumorigenicity. J. Cancer Res. clin. Oncol., 99, 153-166

9. Glassroth, J.L., Snider, D.E. & Comstock, G.W. (1977) Urinary tract cancer and isoniazid. Am. Rev. respir. Dis., 116, 331-333

10. Miller, C.T., Neutel, C.I., Nair, R.C., Marrett, L.D., Last, J.M. & Collins, W.E. (1978) Relative importance of risk factors in bladder carcinogenesis. J. chron. Dis., 31, 51-56

11. Kantor, A.F., Hartge, P., Hoover, R.N. & Fraumeni, J.F., Jr (1985) Tuberculosis chemotherapy and risk of bladder cancer. Int. J. Epidemiol., 14, 182-184

12. Sanders, B.M. & Draper, G.J. (1979) Childhood cancer and drugs in pregnancy. Br. med. J., i, 717-718

13. Tuman, K.J., Chilcote, R.R., Berkow, R.I. & Moohr, J.W. (1980) Mesothelioma in child with prenatal exposure to isoniazid. Lancet, ii, 362

14. Maru, G.B., Sawai, M.M. & Bhide, S.V. (1980) Prevention of isoniazid tumorigenicity by antitoxicants of isoniazid in Swiss mice. J. Cancer Res. clin. Oncol., 97, 145-151

15. Maru, G.B. & Bhide, S.V. (1982) Effect of antioxidants and antitoxicants of isoniazid on the formation of lung tumours in mice by isoniazid and hydrazine sulphate. Cancer Lett., 17, 75-80

16. Menon, M.M. & Bhide, S.V. (1983) Perinatal carcinogenicity of isoniazid (INH) in Swiss mice. J. Cancer Res. clin. Oncol., 105, 258-261

17. IARC Monographs, Suppl. 6, 347-350, 1987

Synonyms


Last updated: 9 March 1998


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       Toxicological Abbreviations