This project will develop and apply biomarkers of exposure associated with benzene, pentachlorophenol (PCP), and 2-6-dinitrotoluene (DNT). All of these compounds are metabolized to electrophilic intermediates, capable of reacting with macromolecules in the blood and other tissues. Since the Program will ultimately pursue epidemiological studies of populations exposed to benzene. PCP, and DNT, this project should provide exposure- biomarker relationships which offer the means for optimizing the assessment of exposure. Furthermore, experimental applications of the protein adducts in vitro and in vivo should provide substantial information related to the disposition of the reactive intermediates and to the ultimate mechanisms of toxicity. Significant progress was made in the first three years of Project 3 in determining the amounts to reactive intermediates which were produced by benzene in vivo. That work showed that although exposure to benzene produces adducts of the benzoquinone (BQ) species (1,2- and 1,4- BQ), the same adducts are present at high concentrations in humans, rats, and mice, with no known exposures to benzene. This result calls into question the role which these quinones can play in the carcinogenicity of benzene and suggests that benzene oxide (BO) is more likely to be responsible for such effects. This project also provided the first unambiguous evidence that PCP is metabolized to tetrachlorobenzoquinone (C14BQ) in vivo and that this electrophile reacts with proteins to produce adducts indirect evidence also suggests that C14BQ is not easily transported through membranes and may, therefore, be particularly toxic tot he hepatocyte, because of restricted egress after formation. Project 3 has 13 specific aims.
Aims 1 -5 relate to experimental studies involving genotoxic metabolites of benzene. The major thrust of these aims is to investigate the formation and disposition of BQ in vitro and in vivo and to determine whether benzene semiquinone produces significant amounts of adducts in vivo. ? 710 involve experimental investigations of adducts formed by metabolites of PCP, namely, C14BQ, tetrachlorosemiquinone (C14SQ), and related quinone species. Particular attention is given to investigating the disposition of these species in the liver and to restricted transport through membranes.
Aims 6 and 10 will investigate (in collaboration with the Epidemiology core) the exposure - biomarker relationships in selected cohorts of persons exposed to benzene (Aim 6) and PCP (Aim 10). The particular biomarkers include: levels of the parent compounds (in blood, exhaled air, and/or urine), and levels of the adducts of the reactive intermediates with hemoglobin and serum albumin. Finally, Aims 11013 will investigate the reactive intermediates associated with 2,6- DNT by identifying and characterizing the adducts formed with blood proteins in vitro and in vivo.
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