MODULATION OF BENZENE METABOLISM BY EXPOSURE TO ENVIRONM

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DESCRIPTION Environmental exposures occur as mixtures, while most toxicologic and pharmacokinetic studies have been done on single compounds. Benzene is a widespread contaminant that occurs as part of environmental mixtures. It has an extensive data base on toxicity based on single compound exposure or dose. The applicants propose to study benzene in mixtures using in vivo and in vitro experiments. The hypotheses to be tested are: 1) the same fraction of benzene is eliminated as the ring hydroxylated and ring opened metabolites by humans when inhaled at environmental levels alone or as part of a mixture of methyl tertiary-butyl ether (MTBE) or metals that can generate reactive oxygen species (ROS), such as iron, and 2) the toxicity of environmental pollutant mixtures, such as benzene and MTBE, iron or chromium, is due, in part, to interactive cellular effects induced by the reactive intermediates of the individual components of the mixture. The specific aims and goals to test these hypotheses are: 1) expose humans in vivo to binary mixtures of benzene and MTBE or benzene and iron with and without antioxidant ingestion; 2) expose HL-60 cells in vitro to the toxic benzene metabolites muconaldehyde and hydroquinone, the toxic MTBE metabolite formaldehyde, and Cr(VI) or Fe(II) singly and in combination; and 3) relate the pharmacodynamic effects observed in the controlled exposures in the in-vivo studies to the effects observed in the in-vitro experimental studies. The in vivo studies will be done in a Controlled Environmental Facility at environmentally relevant concentrations and durations using isotopically labeled benzene. The goals of the study include: compare the fraction of total inhaled benzene by humans excreted as ring hydroxylated metabolites, hydroquinone, and phenol, ring opened metabolite, trans, trans muconic acid, and unmetabolized benzene by human subjects following exposure to benzene alone and as binary mixtures of benzene and MTBE or iron with and without antioxidant ingestion; determine the Michaelis-Menten constants for the elimination of benzene and the formation rate of benzene metabolites; in I-IL-60 cells, examine the effects of the benzene metabolites muconaldehyde and hydroquinone, the MTBE metabolite formaldehyde, iron (as Fe(II)) and chromium (as (Cr(Vl)) singly and in combination on AP-I and NF-kB DNA binding activity, cell cycle analysis, apoptosis, and DNA strand breaks; develop response surfaces for each of the toxicological endpoints; and compare significant differences in pharmacodynamic effects between the in vivo and in vitro studies.