CARCINOGENICITY STUDIES OF OXAZEPAM IN MICE

Oxazepam is a benzodiazepine widely used as a sedative-hypnotic and an tianxiety drug. In chronic studies, groups of 60 male and 60 female Sw iss-Webster (SW) or B6C3F(1) mice received oxazepam in feed at concent rations of 0, 2500, or 5000 ppm. Additional groups of 60 male and fema le B6C3F(1) mice received 125 ppm in feed to allow for study of mice w ith serum concentrations of oxazepam similar to those achieved in huma ns taking a therapeutic dose. At 57 weeks, treatment-related mortality of exposed SW mice caused the study to be terminated. Enhanced system ic amyloidosis contributing to heart failure was considered the princi pal cause of death. Hepatocellular adenomas and carcinomas were increa sed in exposed SW mice. Survival of B6C3F(1) mice receiving 2500 and 5 000 ppm oxazepam was also lower than that of controls. Early deaths we re due to increased incidences of hepatoblastoma and hepatocellular ca rcinoma, and nearly all mice receiving 2500 or 5000 ppm developed hepa tocellular neoplasia. An increase in follicular cell hyperplasia of th e thyroid gland occurred in all exposed groups of B6C3F(1) mice, and t hyroid gland follicular cell adenoma was increased in exposed females. Further studies of the capacity of oxazepam to induce liver cell mito genesis and an evaluation of the frequency of activated H- and K-ras o ncogenes in the liver tumors of B6C3F(1) mice has shown that many of t he neoplastic and nonneoplastic responses of mice to oxazepam resemble those observed with phenobarbital. (C) 1994 Society of Toxicology.