Recent advances in the metabolism and toxicity of benzene.

Benzene is a heavily used industrial chemical, a petroleum byproduct, an additive in unleaded gas, and a ubiquitous environmental pollutant. Benzene is also a genotoxin, hematotoxin, and carcinogen. Chronic exposure causes aplastic anemia in humans and animals and is associated with increased incidence of leukemia in humans and lymphomas and certain solid tumors in rodents. Bioactivation of benzene is required for toxicity. In the liver, the major site of benzene metabolism, benzene is converted by a cytochrome P-450-mediated pathway to phenol, the major metabolite, and the secondary metabolites, hydroquinone and catechol. The target organ of benzene toxicity, the hematopoietically active bone marrow, metabolizes benzene to a very limited extent. Phenol is metabolized in the marrow cells by a peroxidase-mediated pathway to hydroquinone and catechol, and ultimately to quinones, the putative toxic metabolites. Benzene and its metabolites appear to be nonmutagenic, but they cause myeloclastogenic effects such as micronuclei, chromosome aberrations, and sister chromatid exchange. It is unknown whether these genomic changes, or the ability of the quinone metabolites to form adducts with DNA, are involved in benzene carcinogenicity. Benzene, through its active metabolites, appears to exert its hematological effects on the bone marrow stromal microenvironment by preventing stromal cells from supporting hemopoiesis of the various progenitor cells. Recent advances in our understanding of the mechanisms by which benzene exerts its genotoxic, hematotoxic, and carcinogenic effects are detailed in this review.