Dose-response relationships in promotion of rat hepatocarcinogenesis by 17 alpha-ethinylestradiol

One of the critical issues in risk assessment for chemical carcinogens is the evaluation of dose-response relationships for tumor promoters. In the studies reported here we have systematically investigated dose-response relationships for the liver tumor-promoting actions of 17 alpha-Ethinylestradiol (EE2) following a single injection of diethylnitrosamine (200 mg/kg) to ovariectomized female rats. Parameters measured included tumor incidence, gamma-glutamyltranspeptidase (GGT) positive foci, serum prolactin and serum EE2. The length of tumor promotion ranged from 30 to 60 wk. Results showed a linear increase in GGT-positive foci between doses of 16 and 90 micrograms EE2 kg/d for 30 wk. This was associated with corresponding increases in liver tumor incidence at 60 wk. Seventy-five percent of the animals had either hepatocellular adenoma or hepatocellular carcinoma in the group promoted with 90 micrograms EE2/kg for 60 wk. No liver tumors were evident in either controls or animals receiving estrogen only. Serum prolactin concentrations were elevated in all estrogen-treated groups. In summary, our studies have evaluated dose-response relationships for GGT-positive foci and tumor incidence in a two-stage model for hepatocarcinogenesis using EE2 as the promoting agent.