EVALUATION STUDIES ON THE IN-VITRO RAT HEPATOCYTE MICRONUCLEUS ASSAY

Based on a previous study with 8 chemicals (Muller et al., 1993) the a pplicability of the in vitro rat hepatocyte micronucleus assay was eva luated by testing a further 21 compounds of different chemical classes . The obtained results are in good agreement with the known genotoxic profiles of about 90% of the in total tested compounds. Several known mutagens and carcinogens, i.e., alkylating agents, aromatic amines, ni trosamines, nitro compounds, cross-linking agents, and pyrrolizidine a lkaloids gave clear positive results in this assay, whereas all of the tested non-carcinogens were negative. The hepatocyte micronucleus ass ay was shown to distinguish between carcinogenic/non-carcinogenic isom ers, such as 2- and 4-acetylaminofluorene (AAF) and 2- and 1-nitroprop ane (NP). Furthermore, the non-genotoxic nature of several hepatocarci nogens, i.e., the peroxisome proliferating agents fenofibrate, nafenop in, Wy-14,643, diethyl(hexyl)phthalate (DEHP), and the sedative phenob arbital, could be confirmed in this assay. The hepatocarcinogen coumar in exerted mitogenic but no mutagenic properties in the rat hepatocyte micronucleus assay. This compound may act as a liver tumor promoter. Benzo[a]pyrene (B[a]P) and 7,12-dimethylbenzanthacene (DMBA), both bel onging to the group of known carcinogenic and mutagenic polycyclic aro matic hydrocarbons, failed to induce micronucleus formation in rat hep atocytes. The high susceptibility of in vitro proliferating hepatocyte s to mitotic inhibition, exerted by the strong cytotoxic actions of th ese compounds, seems to be responsible for these negative results. A s trongly reduced mitotic activity can prevent the formation of micronuc lei, even when clastogenic effects may have occurred. In the present s tage, the in vitro rat hepatocyte micronucleus assay cannot be recomme nded for screening genotoxicity testing. It should rather be used for special purposes, e.g., when liver-specific mutagenic effects are expe cted.