PROTEIN AND DNA ADDUCTS FOLLOWING LOW DOSE EXPOSURE BY ACCELERATOR MS

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The scope of this proposal is to study the extent of benzene and trichloroethylene (TCE) macromolecular adduct formation, metabolism,a and interaction with other solvents at concentrations equivalent to human exposure levels outside the workplace. Benzene and TCE are important toxicants in the workplace and are ubiquitous in the environment. Most importantly, they are carcinogenic and are often found in combination with other potential carcinogens at wastesites and the behavior of chemicals in mixtures may differ substantially from pure compounds. Our goal for this project is to understand the relationship between chemical dose, the dose reaching the target issues and the resultant levels of macromolecular adducts that are formed at doses equivalent to those encountered around superfund waste sits. A second goal is to determine feasibility of measuring benzene and TCE metabolism in humans. Specifically, we will: 1. develop and validate methodology for ultra-low level measurement of TCE and benzene metabolism in rodents by accelerator mass spectrometry (AMS) in combination with HPLC and electrophoresis:" 2. identify the specific protein targets for benzene and TCE adduct formation in animal lymphocytes, hepatocytes, and plasma; 3. evaluate how xylene and toluene influence 14C-benzene metabolism in a murine model at low doses by AMS. The influence of these solvents on formation of DNA and protein adducts by AMS in target and non-target tissues will also be investigated: 4. compare how benzene and phenol, when administered in vivo, at low doses are metabolized. The extent of DNA and protein binding by these two compounds will be evaluated as well; and 5. determine how arsenic exposure influences 14C-benzene metabolism and macromolecular binding at exposure concentrations relevant for human environmental exposure. The results of this research project will be important for calculating the risk posed to humans by these compounds in the environment and will help pinpoint protein or DNA adducts that can be used for exposure assessments. This work will also lead to development of protocols for determining how benzene is metabolized at low dose and physiologically-based pharmacokinetic models relevant to determining the risk these compounds pose to the American public.