BENZENE--MECHANISMS OF TOXICITY AND CHEMOPROTECTION

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DESCRIPTION: (Adapted from the Investigator's Abstract) There is concern about human exposure to benzene arising from a variety of sources, including certain occupational settings, hazardous waste sites, automobiles and cigarette smoking. Exposure of humans to benzene is associated with the development of aplastic anemia and leukemia. While there is an appreciation of the bone marrow being a target organ of benzene-induced toxicity, the underlying mechanisms and determinants of toxicity are not fully understood. The hypothesis the investigators are investigating is that the susceptibility of bone marrow cell populations is determined in part by the activation of benzene-derived metabolites by CuZn superoxide dismutase and the relative protection provided by quinone reductase and glutathione. Moreover, they hypothesize that the induction of quinone reductase and glutathione by 1,2-dithiole-3-thione affords protections against benzene-induced hematoxicities both in vitro and in vivo. Accordingly the specific aims of this proposal are designed to: 1) investigate factors which regulate the biologically effective concentration and early biological effects of benzene-derived metabolites in relevant bone marrow cell populations and other cellular models; 2) assess if human peripheral blood cells can be used to screen for possible human susceptibility to benzene; and 3) conduct a mechanistically-based chemoprotection study for benzene-induced bone marrow toxicity in DBA/2 mice. These studies will utilize a spectrum of biochemical, cell and molecular biology approaches and analytical techniques, to address the hypotheses put forth in the specific aims. As a result of this project the investigators should better understand the mechanisms of benzene-induced toxicity so that this information can be applied to human risk assessment, biomarker and chemoprotection studies in susceptible individuals and exposed populations.