Two-year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats

Tamoxifen, a nonsteroidal antiestrogen used widely in the treatment of breast cancer, was tested in a conventional 2-year carcinogenicity bioassay in rats, a species in which tamoxifen acts variably as a partial agonist and antagonist on different target tissues. Groups of 51 males and 52 females were given 5, 20, and 35 mg/kg of tamoxifen/day by gastric intubation in 0.5% hydroxypropyl methylcellulose at 5 ml/kg dose volume. There were 102 male and 104 female controls dosed with vehicle alone. Growth rate and food consumption were reduced in all treated groups. The major finding was a dose-related increase in the incidence of hepatocellular tumors which were first observed after 31 weeks of treatment in the top dose group. The majority of the neoplasms were hepatocellular carcinomas showing a well differentiated trabecular pattern. Some tumors were glandular in type. Mortality was increased in the 20 and 35 mg/kg dose groups compared with controls as a result of these tumors. By contrast, survival was greater than controls in rats given 5 mg/kg tamoxifen despite the presence of hepatocellular tumors due to a reduction in the number of pituitary tumors in females and less chronic renal disease in males. The mechanism of hepatic tumor induction by tamoxifen in rats is unclear. In view of the lack of genotoxic activity in conventional genotoxicity studies and lack of similar effect in mice or in humans, the findings may relate to a particular constellation of effects in rats. All other drug-induced changes in this study were nonneoplastic in nature and most appeared to be the result of hormonal perturbation since they were confined to endocrine organs or have been seen previously in rats treated for long periods with tamoxifen.