BENZENE - A CASE-STUDY IN PARENT CHEMICAL AND METABOLITE INTERACTIONS

Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene in hu mans are well documented and include aplastic anemia and pancytopenia, and acute myelogenous leukemia. A combination of metabolites (hydroqu inone and phenol for example) is apparently necessary to duplicate the hematotoxic effect of benzene, perhaps due in part to the synergistic effect of phenol on myeloperoxidase-mediated oxidation of hydroquinon e to the reactive metabolite benzoquinone. Since benzene and its hydro xylated metabolites (phenol, hydroquinone and catechol) are substrates for the same cytochrome P450 enzymes, competitive interactions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consistent with com petitive inhibition of phenol oxidation by benzene. In vitro studies o f the metabolic oxidation of benzene, phenol and hydroquinone are cons istent with the mechanism of competitive interaction among the metabol ites. The dosimetry of benzene and its metabolites in the target tissu e, bone marrow, depends on the balance of activation processes such as enzymatic oxidation and deactivation processes such as conjugation an d excretion. Phenol, the primary benzene metabolite, can undergo both oxidation and conjugation. Thus, the potential exists for competition among various enzymes for phenol. However, zonal localization of Phase I and Phase II enzymes in various regions of the liver acinus regulat es this competition. Biologically-based dosimetry models that incorpor ate the important determinants of benzene flux, including interactions with other chemicals, will enable prediction of target tissue doses o f benzene and metabolites at low exposure concentrations relevant for humans.