The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat.
Tamoxifen (TAM) is used in the treatment of breast cancer and is being given to healthy women to inhibit breast cancer. The present study examines the effects of TAM in female rats exposed for up to one year. Starting at 6 weeks of age, groups of 55-57 female Sprague-Dawley rats were given TAM by gavage daily at 2.8, 11.3 or 45.2 mg/kd body weight/day, for up to 1 year with two recovery segments, 4 weeks of recovery after 6 months of exposure, and 3 months of recovery after 12 months of exposure. Complete necropsies and histopathology were performed. Drug-related mortality was highest in the high TAM group. In the two high dose groups, hepatoproliferative lesions were present in time- and dose-related incidence, severity and multiplicity. In the high dose rats, at 6 months, hepatocellular adenomas and carcinomas were observed in 71 and 29% of rats respectively. With 1 month of recovery, at 7 months the adenomas and carcinomas were increased to 75%. At 12 months the adenomas were present in 50% and carcinomas in 75% of high dose rats. In the mid dose group, liver lesions were not found until 12 months; at this time 50% had adenomas and 10%, carcinomas. After a 3 month recovery period, 45% exhibited adenomas and 45%, carcinomas. Thus, TAM at 45.2 mg/kg/day elicited hepatocellular neoplasia sometime between 3 and 6 months of administration. At 11.3 mg/kg the neoplastic process was evident at 12 months. At 2.8 mg/kg, no hepatoproliferative changes were found. The strong hepatocarcinogenic effect of TAM in rats raises issues bearing on the prophylactic chronic administration to healthy women.
Williams
G M
GM
American Health Foundation, Division of Pathology and Toxicology, Valhalla, NY 10595.
Iatropoulos
M J
MJ
Djordjevic
M V
MV
Kaltenberg
O P
OP
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013629:Tamoxifen / Q000633:toxicity*
D002273:Carcinogens; D013629:Tamoxifen