ADDUCT FORMATION IN THE TOXICITY OF DITHIOCARBAMATES

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Dithiocarbamates and bis(thiocarbamoyl) disulfides are used extensively as insecticides, fungicides and herbicides. Industrial applications include slimicides for the production of sugar, pulp, and paper; accelerators and antioxidants in the vulcanization of rubber; and metal scavengers in the treatment of waste water. Exposures to dithiocarbamates occur occupationally and through consumption of residues on treated food crops. Another source of exposure to dithiocarbamates arises through their existing and potential uses as medicinal agents. Animal studies and in vitro investigations of the toxicity of dithiocarbamates and bis(thiocarbamoyl) disulfides have shown teratogenic and mutagenic effects and decreased fertility to be associated with exposure to these compounds. Despite these recognized effects tie underlying mechanisms have not been established , and the interaction of their metabolites with biomolecules have not been delineated. Recent investigations on the mechanism of CS2 toxicity have elucidated several pathways for the covalent interaction of dithiocarbamates and bis(thiocarbamoyl) disulfides with biological macromolecules. Those studies suggested that some monoalkyl dithiocarbamates may acylate macromolecules directly through isothiocyanate and isocyanate formation and that both monoalkyl and dialkyl dithiocarbamates may exert toxicity through liberation of CS2. The proposed investigation will determine the potential of direct and indirect acylation of macromolecules as a mechanism for the toxicity of dithiocarbamates. The experiments outlined in this proposal will test the following hypotheses: l) monoalkyl dithiocarbamates exert toxic effects through decomposition to isothiocyanate with subsequent acylation of proteins and DNA and 2) monoalkyl and dialkyl dithiocarbamates exert toxicity through liberation of CS2 producing derivatization and crosslinking of proteins. These hypotheses will be tested through determination of the structural characteristics favoring decomposition of monoalkyl dithiocarbamates to isothiocyanate and isocyanate at neutral pH, determination of the acylation sites and stability of adducts formed by isothiocyanates and isocyanates with proteins and DNA in vitro and in vivo, and through determination of the ability of dithiocarbamates to generate CS2 under physiological conditions leading to monoalkyl dithiocarbamate formation with amines on proteins which could then result in covalent cross-linking.