Assessment of methyl methanesulfonate using the repeated-dose liver micronucleus assay in young adult rats.

A repeated-dose liver micronucleus assay using young adult rats was conducted with methyl methanesulfonate (MMS) as a part of a collaborative study supported by the Collaborative Study Group for the Micronucleus Test/the Japanese Environmental Mutagen Society-Mammalian Mutagenicity Study Group. MMS is a classical DNA-reactive carcinogen, but it is not a liver carcinogen. In the first experiment (14-day study), MMS was administered per os to 6-week-old male Crl:CD (SD) rats every day for 14 days at a dose of 12.5, 25, or 50mg/kg/day. In the second experiment (28-day study), 6-week-old male SD rats were treated with MMS at 7.5, 15, or 30mg/kg/day for 28 days, because the highest dose used in the 14-day study (50mg/kg/day) caused mortality. Hepatocyte and bone marrow cell specimens were prepared on the day after the final dose. The frequency of micronucleated hepatocytes (MNHEPs) in the liver and that of micronucleated immature erythrocytes (MNIMEs) in the bone marrow were evaluated. Exposure to 50mg/kg/day MMS for 14 days resulted in an increased frequency of MNHEPs, but MMS had no effect on the frequency of MNHEPs in the rats exposed to the chemical for 28 days at doses up to 30mg/kg/day. MMS induced MNIMEs production at doses of 25 and 50mg/kg/day in the 14-day study and at doses of 15 and 30mg/kg/day in the 28-day study. Overall, the effect of MMS on the frequency of MNHEPs was considered to be equivocal.

Assessment of 8-methosypsoralen, lomefloxacin, sparfloxacin, and Pirfenidone phototoxicity in Long-Evans rats.

Phototoxicity has a strong impact on drug development. Although several animal models have been developed to quantitatively assess human risks, none have been validated for standardized use. In this study, we validated an in vivo phototoxicity model using Long-Evans (LE) rats treated with 4 well-known phototoxic drugs, namely 8-methoxypsoralen, lomefloxacin, sparfloxacin, and pirfenidone. Daily macroscopic observations of skin and eyes, ophthalmological examinations 4 days after dosing, and blood sampling for toxicokinetics (TKs) were performed after exposure of treated animals to ultraviolet, and dose-dependent eye and/or skin reactions were noted for all compounds. Margins of safety were calculated when possible and correlated well with known relative phototoxicity of the 4 compounds. We conclude that the present in vivo phototoxicity assay using LE rats with TK analysis can be used to quantitatively predict the risk of pharmaceutical phototoxicity in humans.