For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p. 330)
CAS No.:
Chem. Abstr. Name: Yohimban-16-carboxylic acid, 11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-,
methyl ester (3b,16b,17a,18b,20a)-
A. Evidence for carcinogenicity to humans (inadequate)
Sixteen case-control and three cohort studies on the relationship between reserpine and breast cancer were available to the Working Group [ref: 1-6]. Between and within studies, estimates of relative risk for different degrees of reserpine use varied from 0.6 to over 3. Many of the positive findings were not coherent with one another; and the studies considered to be most satisfactory methodologically showed little or no evidence of increased risk. However, a recent, large case-control study of breast screening participants showed that, although use of rauwolfia (reserpine) was not significantly associated with an overall increase in risk (odds ratio, 1.2; 95% confidence interval, 0.9-1.8), users for ten years or more had a risk ratio of 4.5 [2.3-11.6] [ref: 7]. A study of prolactin levels in 15 women who had taken reserpine for five years or longer showed only 50% greater elevation of levels than in 15 women taking non-reserpine-containing medications and in 15 women taking no hypertensive medication. Elevated prolactin levels have been postulated as the mechanism for increased breast cancer risk following reserpine use, and the authors postulated that the increase in prolactin observed would probably cause only small increases in breast cancer risk [ref: 8].
B. Evidence for carcinogenicity to animals (limited)
Reserpine was tested for carcinogenicity in three experiments in mice by oral administration; in two experiments, it induced malignant mammary tumours in females, and in one experiment it induced carcinomas of the seminal vesicles in males [ref: 1,9]. It was tested in four experiments in rats by oral administration; in two, it increased the incidence of phaeochromocytomas [ref: 1,9]. An increase in tumour incidence was observed after repeated subcutaneous injections to mice and rats [ref: 9].
When reserpine was administered either prior to and concurrently with or following treatment with 3-methylcholanthrene orally, it had a protective effect against the induction of mammary tumours in rats [ref: 10]. Concurrent subcutaneous administration of reserpine reduced mammary tumour multiplicity and increased the percentage of well-differentiated tumours induced in rats by N-methyl-N-nitrosourea given intravenously [ref: 11]; its intravenous administration decreased skin tumour growth in 3-methylcholanthrene-treated mice [ref: 12].
C. Other relevant data
No data were available on the genetic and related effects of reserpine in humans.
Reserpine did not induce dominant lethal mutations in mice in vivo. In human cells in vitro, it did not induce chromosomal aberrations or sister chromatid exchanges. It did not induce chromosomal aberrations in cultured rodent cells or unscheduled DNA synthesis in rat hepatocytes. Reserpine was not mutagenic to bacteria [ref: 13].
Overall evaluation
Reserpine is not classifiable as to its carcinogenicity to humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluations: Vol. 10 (1976); Vol. 24 (1980)
References
1. IARC Monographs, 24, 211-241, 1980
2. Labarthe, D.R. & O'Fallon, W.M. (1980) Reserpine and breast cancer. A community-based longitudinal study of 2000 hypertensive women. J. Am. med. Assoc., 243, 2304-2310
3. Kewitz, H., Jesdinksy, H.-J., Kreutz, G. & Schulz, R. (1980) Reserpine and breast cancer. Arch. int. Pharmacodynam. Ther., Suppl., 22-24
4. Danielson, D.A., Jick, H., Hunter, J.R., Stergachis, A. & Madsen, S. (1982) Nonestrogenic drugs and breast cancer. Am. J. Epidemiol., 116, 329-332
5. Curb, J.D., Hardy, R.J., Labarthe, D.R., Borhani, N.O. & Taylor, J.O. (1982) Reserpine and breast cancer in the hypertension detection and follow-up program. Hypertension, 4, 307-311
6. Horwitz, R.I. & Feinstein, A.R. (1985) Exclusion bias and the false relationship of reserpine and breast cancer. Arch. intern. Med., 145, 1873-1875
7. Stanford, J.L., Martin, E.J., Brinton, L.A. & Hoover, R.N. (1986) Rauwolfia use and breast cancer: a case-control study. J. natl Cancer Inst., 76, 817-822
8. Ross, R.K., Paganini-Hill, A., Krailo, M.D., Gerkins, V.R., Henderson, B.E. & Pike, M.C. (1984) Effects of reserpine on prolactin levels and incidence of breast cancer in postmenopausal women. Cancer Res., 44, 3106-3108
9. Muradyan, R.Y. (1986) A study of possible carcinogenicity of reserpine (Russ.). Vopr. Onkol., 32, 76-81
10. Gerard, S.S., Gardner, B., Patti, J., Husain, V., Shouten, J. & Alfonso, A.E. (1980) Effects of triiodothyronine and reserpine on induction and growth of mammary tumors in rats by 3-methylcholanthrene. J. surg. Oncol., 14, 213-218
11. Verdeal, K., Ertürk, E. & Rose, D.P. (1983) Effects of reserpine administration on rat mammary tumors and uterine disease induced by N-nitrosomethylurea. Eur. J. Cancer clin. Oncol., 19, 825-834
12. Lupulescu, A. (1983) Reserpine and carcinogenesis: inhibition of carcinoma formation in mice. J. natl Cancer Inst., 71, 1077-1083
13. IARC Monographs, Suppl. 6, 485-487, 1987
Synonyms
See Also:
Toxicological Abbreviations
Reserpine (PIM 467)
Reserpine (IARC Summary & Evaluation, Volume 10, 1976)
Reserpine (IARC Summary & Evaluation, Volume 24, 1980)