IMMUNOTOXIC EFFECTS OF ORGANOPHOSPHORUS PESTICIDES

拟议研究的总体目标是 有机磷化合物对小鼠免疫功能的影响 如初步研究中所述。待研究的原型化合物 是广泛使用的杀虫剂马拉硫磷和几种杂质 该农药的O、O、S三甲基等技术配方 O，S，S-三甲基二硫代磷酸和O，O，O-三甲基 硫化磷酸盐。年龄和性别匹配的C57B1/6小鼠将 在急性和亚急性研究中口服这些化合物 将对这些化合物的影响进行评估，包括：一般毒性 影响、组织的病理变化和特定的免疫改变。 待研究的免疫参数包括：细胞介导型(~(51)Cr释放) 抗体(杰恩空斑试验)自然杀伤(51Cr释放试验) 有丝分裂原反应(~3H胸腺嘧啶核苷摄取试验)。我们还将研究细胞 用流式细胞术检测特征良好的小鼠的种群变化 细胞表面标记Ly1、Ly2、3、Ig和Thyl。此外，研究还将 对分离的细胞群体进行体外实验以评估细胞 参与免疫抑制的人群。B细胞、T杀伤细胞、T辅助细胞 将测试细胞、T抑制细胞和巨噬细胞的功能。I don‘我不能帮忙 将通过IL-2的产生和米歇尔-达顿培养进行评估。B类 细胞功能将在米歇尔-达顿培养中进行测试。T杀手 激活将在体外敏化中进行检测。T抑制器 激活将通过混合实验进行评估，处理后的 未经处理的细胞在体外致敏。巨噬细胞的功能将 通过IL-1的产生，Mishell-duton和 同种异体致敏培养和吞噬实验。一种模型系统 已经建立了用有机磷直接治疗淋巴细胞的方法 用肝上清液活化后的化合物。这个系统 使我们能够完全在体外进行实验，并治疗分离出来的 细胞群。有机磷的免疫毒性可能是一个重要的 在初步研究中显示的剂量范围内对健康的危害 免疫抑制大约比所需的低10-100倍 表现出其他毒性作用。

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.