The overall goal of the proposed research is to characterize immunosuppression in mice following exposure to organosphosphorus compounds as described in preliminary studies. Prototypic compounds to be studied are the widely used pesticide malathion and several impurities found in technical formulations of this pesticide including O,O,S-trimethyl phosphorothioate, O,S,S-trimethyl phosphorodithioate, and O,O,O-trimethyl phosphorothioiate. Groups of age and sex matched C57B1/6 mice will be administered these compounds orally in acute and subacute studies and the effects of these compounds will be assessed including: general toxic effects, pathologic changes in tissues, and specific immune alterations. Immune parameters to be studied include: cell-mediated (51Cr Relaease Assay) antibody (Jerne Plaque Assay) natural killer (51Cr Release Assay) and mitogen responses (3H Thymidine Uptake Assay). We will also study cell population changes via flow cytometry with the well characterized mouse cell surface markers Ly1, Ly2, 3, Ig and Thyl. In addition, studies will be performed in vitro with isolated cell population to assess the cell populations involved in immunosuppression. B cell, T killer cell, T helper cell, T suppressor cell and macrophage functions will be tested. T help will be assessed by production of IL-2 and in a Mishell-Dutton culture. B cell function will be tested in the Mishell-Dutton culture. T killer activation will be examined in an in vitro sensitization. T suppressor activation will be evaluated by mixing experiments with treated and untreated cells in an in vitro sensitization. Macrophage function will be assessed by IL-1 production, antigen presentation in Mishell-Dutton and allosensitization cultures and by phagocytosis experiments. A model system has been established to treat lymphocyte directly with organophosphorus compounds following activation with a liver supernatant. This system enables us to perform experiments entirely in vitro and to treat isolated cell populations. Organophosphorus immunotoxicity may be a significant health hazard in so far as the dose range shown in preliminary studies to be immunosuppressive is approximately 10-100 fold lower than is needed to demonstrate other toxic effects.
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