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

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.

Acute toxicity, subchronic dermal toxicity, and delayed contact sensitization evaluations of dicyclopentenyloxyethyl methacrylate in rabbits and guinea pigs.

The subchronic dermal toxicity of dicyclopentenyloxethyl methacrylate (DPOMA) was evaluated in young adult New Zealand White rabbits, and its potential to produce delayed contact sensitization was evaluated in Harley guinea pigs by a modified Buehler's closed patch technique. In addition, studies were conducted to evaluate the acute systemic toxicity of DPOMA in rats (oral) and rabbits (dermal), and its eye and skin irritancy in rabbits. In the subchronic dermal toxicity study, 4 groups of rabbits were treated percutaneously with DPOMA at 0 (acetone), 10, 107, and 1067 (undiluted) mg/kg X day in a volume of 1 ml/kg, over a 4-wk period. The application sites were unoccluded. No deaths occurred, and no signs of systemic toxicity were observed. No treatment-related effects were seen on body weights, hematology, clinical chemistry, urinalysis, organ weights, or histopathology (except the treated skin). The only treatment-related effect was slight to moderate skin irritation in the mid- and high-dose groups. The severity of skin irritaton was dependent on the number of applications and the concentration of DPOMA. Maximal skin irritation occurred after 1 wk. No skin irritation was seen in the control and low-dose group. In the DCS study, guinea pigs received 6 induction doses of 0.5 ml 100% DPOMA and were challenged with 0.5 ml of 50% (w/v) DPOMA in acetone 2 wk after the last induction treatment. No erythema or edema was observed in any of the challenged guinea pigs in either the treated and control groups. These acute toxicity studies indicate that DPOMA is practically nontoxic by a single exposure via both oral and dermal routes (the oral LD50 in rat and dermal LD50 in rabbits were greater than 5.0 g/kg body weight), slightly irritating to the skin, and inconsequentially irritating to the eyes. The no-observed-effect level (NOEL) for systemic toxicity of DPOMA applied repeatedly to rabbits skin is at least 1067 mg/kg X d. DPOMA is not a strong or moderate skin sensitizer in guinea pigs.