CRITICAL ISSUES IN BENZENE TOXICITY AND METABOLISM - THE EFFECT OF INTERACTIONS WITH OTHER ORGANIC-CHEMICALS ON RISK ASSESSMENT

Benzene, an important industrial solvent, is also present in unleaded gasoline and cigarette smoke. The hematotoxic effects of benzene are w ell documented and include aplastic anemia and pancytopenia. Some indi viduals exposed repeatedly to cytotoxic concentrations of benzene deve lop acute myeloblastic anemia. it has been hypothesized that metabolis m of benzene is required for its toxicity, although administration of no single benzene metabolite duplicates the toxicity of benzene. Sever al investigators have demonstrated that a combination of metabolites ( hydroquinone and phenol, for example) is necessary to duplicate the he matotoxic effect of benzene. Enzymes implicated in the metabolic activ ation of benzene and its metabolites include the cytochrome P450 monoo xygenases and myeloperoxidase. Since benzene and its hydroxylated meta bolites (phenol, hydroquinone, and catechol) are substrates for the sa me cytochrome P450 enzymes, competitive interactions among the metabol ites are possible. In vivo data on metabolite formation by mice expose d to Various benzene concentrations are consistent with competitive in hibition of phenol oxidation by benzene. Other organic molecules that are substrates for cytochrome P450 can inhibit the metabolism of benze ne. For example, toluene has been shown to inhibit the oxidation of be nzene in a noncompetitive manner. Enzyme inducers, such as ethanol, ca n alter the target tissue dosimetry of benzene metabolites by inducing enzymes responsible for oxidation reactions involved in benzene metab olism. The dosimetry of benzene and its metabolites in the target tiss ue, bone marrow, depends on the balance of activation processes, such as enzymatic oxidation, and deactivation processes, like conjugation a nd excretion. Biologically based dosimetry models that incorporate the important determinants of benzene flux, including interactions with o ther chemicals, will enable prediction of target tissue doses of benze ne and metabolites at low exposure concentrations relevant for humans.