MECHANISTIC CONSIDERATIONS IN BENZENE PHYSIOLOGICAL MODEL DEVELOPMENT

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, pancytopenia, an d acute myelogenous leukemia. However, the risks of leukemia at low ex posure concentrations have not been established. A combination of meta bolites (hydroquinone and phenol, for example) may be necessary to dup licate the hematotoxic effect of benzene, perhaps due in part to the s ynergistic effect of phenol on myeloperoxidase-mediated oxidation of h ydroquinone to the reactive metabolite benzoquinone. Because benzene a nd its hydroxylated metabolites (phenol, hydroquinone, and catechol) a re substrates for the same cytochrome P450 enzymes, competitive intera ctions among the metabolites are possible. In vivo data on metabolite formation by mice exposed to various benzene concentrations are consis tent with competitive inhibition of phenol oxidation by benzene. In vi tro studies of the metabolic oxidation of benzene, phenol, and hydroqu inone are consistent with the mechanism of competitive interaction amo ng the metabolites. The dosimetry of benzene and its metabolites in th e target tissue, bone marrow, depends on the balance of activation pro cesses such as enzymatic oxidation and deactivation processes such as conjugation and excretion. Phenol, the primary benzene metabolite, can undergo both oxidation and conjugation. Thus the potential exists for competition among various enzymes for phenol. Zonal localization of p hase I and phase II enzymes in Various regions of the river acinus als o impacts this competition. Biologically based dosimetry models that i ncorporate the important determinants of benzene flux, including inter actions with other chemicals, will enable prediction of target tissue doses of benzene and metabolites at low exposure concentrations releva nt for humans.