Oxymetholone: III. Evaluation in the p53(+/-) transgenic mouse model

Oxymetholone has been identified as a suspected nongenotoxic carcinogen and has recently completed testing iri a conventional National Toxicology Prog ram (NTP) 2-yr rodent bioassay program. As a synthetic androgen with a limi ted historical database in toxicology, oxymetholone is an ideal candidate f or prospective examination of the performance of short-term transgenic mous e models in the detection of carcinogenic activity. In the present series o f 3 articles, studies are described where oxymetholone was evaluated prior to disclosure of the results of the NTP 2-yr bioassay. The accompanying art icles provide evidence showing that oxymetholone is devoid of mutagenic act ivity yet elicits a positive carcinogenic response in the Tg.AC transgenic mouse model. In the present study, oxymetholone was administered by oral ga vage to p53 heterozygous male and female mice for 26 wk at doses of 125, 62 5, and 1,250 mg/kg/day. The vehicle was 0.5% aqueous methylcellulose. Posit ive controls consisted of mice treated daily by oral gavage with 200 or 400 mg/kg/day of p-cresidine in corn oil. The oxymetholone-treated females sho wed significantly increased body weight gain and clitoral enlargement attri butable to drug treatment. In addition, significant alterations in kidney, liver, and testis weights were attributable to oxymetholone. However, there were no neoplastic lesions that were attributable to oxymetholone in eithe r sex, p-Cresidine produced unequivocal bladder neoplasms in both sexes at the high dose and in males at the lower dose. The absence of a neoplastic r esponse with oxymetholone is consistent with the selectivity of the p53(+/- ) mouse model for detecting carcinogens that act by genotoxic mechanisms.