Human exposure to dithiocarbamates derives from their many uses in agriculture, industry and medicine. Although the degradative pathways of dithiocarbamates are fairly well understood, there is presently little knowledge regarding the molecular targets and mechanisms underlying the observed biological effects of dithiocarbamates. One of the major decomposition products of dithiocarbamates, CS2, is a known neurotoxicant. The principal objectives of this project are to delineate the potential interactions of dithiocarbamates and their decomposition products within biological systems and to determine both the relevance of these interactions as mechanisms of toxicity and the utility of these interactions as biomarkers of exposure and effect. This investigation is guided by the following working hypotheses: 1) dialkyldithiocarbamates and bis(thiocarbamoyl) disulfides exert neurotoxicity through liberation of carbon disulfide, producing derivatization and cross-linking of proteins; and 2) that covalent modification of proteins by carbon disulfide including dithiocarbamate formation and covalent cross-linking can be used as biomarkers of exposure and effect for dithiocarbamates, bis(thiocarbamoyl) disulfides and CS2. These hypotheses will be tested through determining the morphological changes in the nervous system and the covalent modifications produced on peripheral marker proteins and putative target proteins within the nervous system by bis(thiocabamoyl) disulfides; and through determination of the dose response, sensitivity for detection and the rate of accumulation and elimination of CS2-mediated cross-linking on hemoglobin and dithiocarbamate formation on blood proteins following acute, subacute and chronic exposures to environmentally relevant levels of dithiocarbamates and CS2. Delineation of the molecular mechanisms and the development of valid biomarkers will facilitate the performance of mechanistically based risk assessments and the formulation of structure activity relationships for these widely used compounds.
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