Oxymetholone has been identified as a suspected nongenotoxic
carcinogen and has recently completed testing in a conventional National Toxicology Program (NTP) 2-yr rodent bioassay program. As a
synthetic androgen with a limited historical database in toxicology,
oxymetholone is an ideal candidate for prospective examination of the performance of short-term transgenic mouse models in the detection of carcinogenic activity. In the present series of 3 articles, studies are described where
oxymetholone was evaluated prior to disclosure of the results of the NTP 2-yr bioassay. The accompanying articles provide evidence showing that
oxymetholone is devoid of mutagenic activity yet elicits a positive carcinogenic response in the Tg.AC transgenic mouse model. In the present study,
oxymetholone was administered by oral gavage to p53 heterozygous male and female mice for 26 wk at doses of 125, 625, and 1,250 mg/kg/day. The vehicle was 0.5% aqueous
methylcellulose. Positive 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 showed significantly increased
body weight gain and clitoral enlargement attributable 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 either 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 response with
oxymetholone is consistent with the selectivity of the p53-/- mouse model for detecting
carcinogens that act by genotoxic mechanisms.