Many of the chemicals to which humans are exposed to environmentally and occupationally contribute to the development of disease conditions. It is widely understood that in order for many xenobiotics to exert a toxic effect, they must undergo metabolic activation to a reactive intermediate. Thus, factors which can increase the activation of xenobiotics to reactive intermediates may be viewed as a potential risk factor for enhancing the development of toxicologic reactions. It is the overall goal of this project to establish that inflammatory states may be such a factor as a result of the ability of inflammatory cells to activate xenobiotics through oxidant-dependent mechanisms. Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental contaminants and their metabolism has been associated with the development of a number of toxicological processes including, lung cancer, bone marrow toxicity and immunotoxicity. In this regard, we will (1) characterize the spectrum of reactive metabolites resulting from the interaction of various derivatives of polycyclic aromatic hydrocarbons with inflammatory cells; (2) evaluate how exposure to other environmental agents such as ozone, modulate the populations of inflammatory cells in the lung and the bone marrow; and (3) develop in vivo models to establish that the inflammatory cell-mediated activation of PAHs results in enhanced risk for the development of toxicologic reactions in the lung and bone marrow. The PAH metabolism studies will utilize HPLC and chemilumigenic probing as well as examine the interaction of these intermediates with macromolecules and potential target cells. Similarly, in the in vivo toxicity studies, we are particularly interested in exploiting the inflammatory cell status of the lung and bone marrow as a means to alter the expression of toxicity between strains of mice well known for their differences in reactivity toward PAHs. These studies will provide insights into how an inflammatory state could be a risk factor for enhancing the development of toxicities elicited by not only PAHs, but other environmental toxicants.
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