Bone marrow micronucleus frequencies in the rat after oral administration of cyclophosphamide, hexamethylphosphoramide or gemifloxacin for 2 and 28 days

Abstract

Cyclophosphamide (CPA), hexamethylphosphoramide (HMPA) and gemifloxacin (GF) were administered orally to Han Wistar rats for 2 and 28 days up to their maximum tolerated doses. For CPA, the sensitivity, as measured by the increases at the lowest active dose, was greater after 28 days. However, published data show that blood levels at 28 days are the same as at 2 days. The sensitivity to HMPA was also greater at 28 days but toxicokinetic analysis showed a reduction in blood levels. Although apparently anomalous, this probably reflected increased metabolism of HMPA to its genotoxic metabolite, formaldehyde. In contrast, GF gave a clear increase in micronucleus frequency after 2 doses but not after 28 and the maximum dose tolerated for 28 days gave blood levels 80% greater than the same dose after 2 days. It is apparent that for these three compounds there are differences between responses after dosing for 2 and 28 days that cannot be ascribed simply to differences in blood levels. It is important to note that although the responses were quantitatively different, the two established rodent carcinogens gave positive results at both sampling times. Because rodent oncogenicity data are not available for GF, it is not known whether the positive or negative result in the rat bone marrow micronucleus test is predictive. The purpose of this work was not to support the use of either acute or sub-chronic dosing for the rat micronucleus assay but to point out that sampling times can give both qualitatively and quantitatively different results.