Sodium arsenite, potassium arsenite, and Fowler's solution (arsenic trioxide dissolved in potassium bicarbonate) are equally active in the mouse bone marrow micronucleus assay ( 1 10 mg/kg by IPijection). The natural ore orpment (principally AS2S3) was inactive despite blood levels of arsenic of 300 to 900 ng/mL in treated mice at 24 hr. Sodium arsenite was active in three strains ofmice. It is suggested that the human lung cancer observed among arsenic ore smelters and the skin cancer among people exposed therapeutically to Fowler's solution, have, as their common origin, the genotoxic arsenite ion AsO;-. The difficulty experienced when attempting to demonstrate rodent carcinogenicity for derivatives of arsenic suggests that the bone marrow micronucleus assay may act as a useful assay for potentially carcinogenic arsenic derivatives.

Bisphenol A (BPA) is active in inmaur AP rat uterotrphic asa when evduated using either the oral or the subcutaneous (sc) injection routes of eposure (de daily ta of 400-800 mg/kg BPA). Prmatue vaginal opening was sen for 8 of 14 animals eposed to 600 and 800 nm/kg BPA by sc injection. Vaginal openng was not produced by BPA in the gavage studies. Thes results are consistent with those ofDodds and Lawson [Nawue 137:96 (1936)1 who found that BPA induces persistent vain comnfication in ovariectomized rats exposd to the twice-daily injections of85 mg/kg BPA (totl daily dose 170 mg/kg), but they conflict with the reported inctivity of BPA in the imm mouse uterorophicaay. The uterotroplicacvity ofdiehilbestrol in the rat is also estabbished (0.04 mg/kg/day for three days). Key word bisphenol A, endocrine, estrogen, uterus.Despite extensive interest in the endocrine toxicity of bisphenol A (BPA) to mammals (1-5), only one report of its activity in the rodent uterotrophic assay exists (4). In that study, Coldham et al. (4) exposed immature (18-day-old) CFLP mice to 0.05, 0.5, and 5 mg BPA per mouse by subcutaneous (sc) injection on 3 successive days. The 5 mg dose of BPA was toxic, and the treated mice were withdrawn from the study. No uterotrophic activity was observed for the two lower dose levels, and it was concluded that BPA was inactive in the mouse uetrotrophic assay. This condusion is important, given that reliance is currently placed on the rat/mouse uterotrophic assay as a primary screen for estrogens. We therefore decided to evaluate this chemical in the immature rat uterotrophic assay with a view to establishing if it is inactive in this assay using both species of rodent. Materials and MethodsBPA was obtained from Aldrich Chemical Company (Poole, Dorset, UK) and diethylstilbestrol (DES) from Sigma Chemical Company (Poole, Dorset, UK). The vehicle, arachis oil, was as previously described (6). Immature female Alpk:AP rats (21-22 days old), with body weights in the range 38-48 g, were obtained from the breeding unit at Zeneca, Alderley Park. Animals were housed in wire mesh cages with solid bottoms. Humidity was controlled and a 12 hr/12 hr light/dark cycle was maintained.Animals were weaned on R&M no. 1 diet at 19-21 days old and maintained on R&M no. 3 diet from 21 days onward (both diets obtained from Special Diet Services Ltd., Witham, Essex, UK). Diet and water were available ad libitum. All animals were acclimatized for 24 hr before being dosed. The uterotrophic activities of BPA and DES were evaluated in three separate experiments using the test protocol described earlier (6). The test agents were dissolved (DES) or homogeneously suspended (BPA) (6) in arachis oil and dosed by either oral gavage or sc injection. The dosing volume for both routes of exposure was 5 ml/kg body weight. Animals received three daily doses of the test compound and were killed by an overdose of Fluothane (Zeneca Pharmaceuticals) 24 hr after the final dose. The dose levels shown in Table 1 are the daily dose levels. Presence or ...

The potent rat liver carcinogen 6-p-dimethylaminophenylazobenzthiazole (6BT) and its reported noncarcinogenic analogue 5-p-dimethylaminophenylazobenzthiazole (5BT; evaluated for carcinogenicity under the similar limited bioassay conditions used for 6BT) have been studied in order to seek an explanation for their different carcinogenic activities. Both compounds act as DNA-damaging agents to the rat liver, and both have now been shown to induce lacI (-) gene mutations in the liver of Big Blue(trade mark) transgenic rats. Both compounds were mutagenic following ten daily gavage doses or following administration in diet for 10 days. Neither chemical induced cell proliferation in the liver following repeat gavage administrations. In contrast, dietary administration of 6BT, and to a lesser extent of 5BT, induced hepatic cell proliferation. The carcinogen 6BT, but not the noncarcinogen 5BT, caused proliferation of oval stem cells in the livers by both routes of administration. It is possible that mutations induced in oval cells by 6BT are responsible for its potent carcinogenicity, and that the comparative absence of these cells in 5BT-treated livers may account for the carcinogenic inactivity of 5BT. Equally, the proliferation of the oval cells may reflect changes in liver homeostasis associated with the liver toxicity observed at the dose level of 6BT used (which was, nonetheless, the dose level used in the positive cancer bioassays). It is concluded that the new data presented cannot explain the differing carcinogenic activities of 5BT and 6BT, and that the reported noncarcinogen 5BT may also be carcinogenic when adequately assessed for this activity.