Carcinogenicity is the major human health risk associated with the regulation of chemicals on the National Priority List. In the past, clean up standards for most of the Superfund sites used linear risk assessment based on animal cancer bioassay data. The 1996 Revised Cancer Risk Assessment Guidelines contain many important changes in how future cancer risk assessments will be performed. Paramount to these changes is the incorporation of more science regarding the mode of action and dose response of the chemical in question. The proposed research focuses on developing a sound scientific understanding of the mode of action and the observed and expected dose response relationship of several of the major hazardous chemicals on the National Priority List. These data will be suitable for use with the revised guidelines and will improve the accuracy of the risk assessments driving site remediation. We hypothesize that several aliphatic and aromatic chlorinated hydrocarbons share an important mode of action referred to as """"""""oxidative stress."""""""" Through this mechanism, Reactive Oxygen Species (ROS) cause damage to DNA and activated signal transduction pathways involved in gene regulation and cell proliferation. Little is known about the dose response relationship of oxidative stress induced by these chemicals. The proposed research will identify the most useful biomarkers for oxidative stress and use these to examine the extent and type of oxidative stress on tissues from rodents to determine if linear or non-linear models best fit the data. In addition, these markers of this research are: (1) To develop and validate a comprehensive battery of biomarkers of oxidative stress; (2) To evaluate the role of oxidative stress in the toxicity and carcinogenicity of chlorinated aliphatic hydrocarbons; (3) to evaluate the role of ROS in damage to DNA and plasma proteins of individuals with known plasma PCB characterization; and (5) to collaborate with Projects 2 and 3 in the measurement of oxidative stress and other DNA adducts.
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