""""""""Mode of Action and Metabolism of Organic Toxicants"""""""" is a concerted continuation program on pesticide chemistry and toxicology with three long-term objectives. The first is to define the chemistry and molecular toxicology of selected pesticides of concern because of actual or potential extensive human exposure with emphasis on elucidating their modes of action, biochemical target sites, and mechanisms of selective toxicity. The second objective is to design and develop chemical probes useful for furthering fundamental knowledge in the medical and agricultural sciences. The third is to improve the margins of safety for humans, other nontarget species and the environment in the essential uses of pest control chemicals.
The specific aims are embodied in five subprojects. The goals of the subproject on botanical insecticides and their analogs are to better understand the chemical toxicology of the established pyrethroids, rotenoids, ryanoids, veratridine alkaloids and isobutylamides and to devise ways of improving their potency and safety. Two subprojects focus on the toxicology and chemistry of GABA-gated chloride channel blockers. The toxicology emphasis is on the binding site of these channel blockers in mammals and insects and the physiological and metabolic aspects of their selective toxicity. The chemical studies consider the synthesis, structure-activity and degradation of many classes of insecticides acting at this site including the highly potent trioxabicyclooctanes and dithianes discovered in this Program Project. New radioligands and photoaffinity probes are also involved. The fourth subproject on organophosphorus pesticide toxicology is primarily concerned with the chemical and biological activation of the very extensively used thiophosphorus insecticides, the activated intermediates and biochemical targets of organophosphorus herbicides and fungicides, and the mechanisms and implications of sequential phosphorylation and alkylation reactions within the catalytic site of esterases important in delayed neurotoxicity and other long-term toxicological lesions. The last subproject considers the mammalian toxicology of herbicides and more specifically the acetyl CoA carboxylase target leading to a block in lipid synthesis, the glutathione-dependent processes in activation and detoxification, and the identification of the binding site of the herbicide endothall and the blister beetle toxicant cantharidin. This multidisciplinary program applies chemical, biochemical and toxicological methodologies to improving human and environmental health in the use of agricultural chemicals.
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