Work will be continued with investigations concerned with the chemical and toxicological properties, and mode of action of O,O,S-trimethyl phosphorothioate (OOS-Me), O,S,S-trimethyl phosphorodithioate (OSS-Me) and related organophosphorus esters. These compounds are present as impurities in a wide variety of organophosphorus insecticides and are known to cause delayed mortality in rats at low dosages. The major objectives of the project are (1) to elucidate the mode of action of OOS-Me and OSS-Me and (2) to determine the degree to which commonly used organosphosphorus insecticides are converted into trialkyl phosphorothioates by the action of light. Studies on the mode of action of OOS-Me and OSS-Me are divided into two parts, the first deals with the role of metabolic activation of these compounds in their mode of action and the second is concerned with the identification of the biochemical lesion associated with poisoning. Activation studies will utilize isotopically enriched 13C phosphorus ester and 13C NMR as the means of analysis. 13C enriched OOS-Me, OSS-Me, or O,S-dialkyl alkylphosphonothioate will be allowed to react with m-chloroperbenzoic acid, a model reagent for the mixed-function oxidases, and the formation of oxidation products will be monitored by 13C NMR. This study will establish whether the S-oxide product is chemically possible from compounds of this type which contain a P-S-C moiety. Proposed work on the identification of the biochemical lesion associated with the delayed toxicity of OOS-Me and related compounds is based on the recent discovery tht a single LD50 dose of OOS-Me causes hyperamino aciduria in rats. This study will include: (a) additional work on hyperamino aciduria induced in rats by OOS-Me and related esters, e.g. identification and quantification of amino acids; (b) the effect of OOS-Me and related toxicants on different parameters relating to kidney dysfunction, e.g. determination of creatinine, urea nitrogen, uric acid and alpha 1-microglobulin, and histological examination for swan neck; (c) effect of the toxicant on malabsorption and hepatic failure; and (d) determination of the effect of the toxicants on kidney enzymes involved in amino acid transport, i.e., glutathionase, cysteinylglycinase, and related enzymes associated with the gamma-glutamyl cycle. Alteration of important commercial insecticides to the delayed toxic O,O,S-trialkyl phosphorothioates using O,O-dimethyl and O,O-diethyl insecticides will be determined after exposure to ultraviolet, actinic and sunlight. Upon completion of laboratory studies, a representative compound which is readily transformed by light into a delayed toxic phosphorothioate will be examined in the field.
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