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.
Campen
D
D
National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
Maronpot
R
R
Lucier
G
G
D000818:Animals; D002784:Cholesterol; D004052:Diethylnitrosamine; D004305:Dose-Response Relationship, Drug; D004997:Ethinyl Estradiol / Q000097:blood / Q000633:toxicity*; D005260:Female; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced*; D009929:Organ Size / Q000187:drug effects; D011230:Precancerous Conditions / Q000139:chemically induced; D011388:Prolactin / Q000097:blood; D051381:Rats; D011919:Rats, Inbred Strains; D011960:Receptors, Estrogen / Q000187:drug effects; D005723:gamma-Glutamyltransferase / Q000032:analysis
D011960:Receptors, Estrogen; D004052:Diethylnitrosamine; D004997:Ethinyl Estradiol; D011388:Prolactin; D002784:Cholesterol; D005723:gamma-Glutamyltransferase