Carcinogenicity of diethylstilbestrol in the Wistar rat: effect of postnatal oral contraceptive steroids.

Abstract

Diethylstilbestrol (DES) has been associated with vaginal neoplasia and malformations in humans. We have studied a test population of 504 female Wistar rats given diethylstilbestrol at from 0.0 to 0.5 mg/kg maternal body weight on days 18, 19, and 20 of gestation. Animals were euthanized in extremis, or at 2 years of age. The incidence of vaginal epithelial tumors was dose related. The types of epithelial tumors of the vagina were adenocarcinoma, squamous cell carcinoma, and mixed carcinoma, containing discrete adenomatous and squamous components. The incidence of vaginal epithelial tumors was determined to be dose related: rats exposed to 0 mg DES/kg maternal weight had an incidence of 0.6% (1 of 167 rats); 0.1 mg/kg, 4.1%; and 0.5 mg/kg, 4.3% (6 of 140); 25 mg/kg, 1.6% (1 of 63); and 50 mg/kg, 11.5% (3 of 26). Tumors of other reproductive tissues (mammary gland, ovary, oviduct, cervix, or uterus) demonstrated no discernible DES dose-response relationship. There was no oncogenic effect of postnatal administration of oral contraceptives (0 oral contraceptives, 31.25 micrograms/kg diet ethynylestradiol, and 31.25 micrograms/kg diet norethindrone or 104 micrograms/kg diet ethynylestradiol and 31.25 micrograms/kg diet norethindrone). Thus, vaginal tumors can be induced in a dose-related manner in the rat following in utero DES exposure. Oral contraceptive treatment did not increase the risk of neoplasia.