ORGANOPHOSPHORUS INSECTICIDE TOXICOLOGY

描述(改编自《调查者摘要》)：长期 目的是了解急性毒性和迟发性毒性的机制。 来自重要的有机磷(OP)和磷化氢杀虫剂。这些 化合物是人类健康的主要问题，因为它们被广泛用于 农业和对中毒事件负有最多责任的人 杀虫剂类。 第一个目标是确定OP诱导的迟发性毒性的机制 (已困扰30,000多人)与神经病有关 我们新开发的放射性配基[~3H]OBDPO和a~(2+)的靶标酯酶(NTE) 新型氨基甲酸酯生物素亲和剂在鸡脑组织中的靶向分离 结构和功能表征的活性形式。非NTE目标 [~3H]OBDPO的磷酸化和基于其他OP的放射性配体延迟 毒物将被确认为NTE本身。细胞模型将 确定OP诱导的神经生长、基本神经营养因子的变化 和离子传输。 第二个目的是了解重要的有机磷杀虫剂的作用机理。 因为植物中的系统作用和对哺乳动物的中等毒性。这个 假设是：乙酰甲胺磷的毒性是自限的，因为它的代谢物 甲胺磷抑制激活乙酰甲胺磷的酰胺酶；甲胺磷是 S的生物活性-氧化(旧假说)或N-氧化(新建议) 需要研究化学模型来解决位置和稳定性 关系；S-二甲基磷二硫代酸的甲基化 乐果代谢物对其毒理学特征有贡献，包括 延迟效应。 第三个目标是建立铝的毒性机制。 正在日益取代甲基溴(臭氧)的磷化物 消耗器)作为储存产品的主要熏蒸剂。总体假设 是1)磷化氢，一种在环境中水解释放出来的气体 磷化铝，经历自发或生物氧化以 氧化膦，以及2)这种磷酰化试剂产生急性毒性 尚未确定的靶点的影响和对DNA衍生的遗传毒性影响 导致脱氧鸟苷部分转化为 8-羟基脱氧鸟苷。这项研究对于确保安全使用是必要的。 含磷杀虫剂。

DESCRIPTION (Adapted from the Investigator's Abstract): The long-term objective is to understand the mechanisms for acute and delayed toxicity from important organophosphorous (OP) and phosphine insecticides. These compounds are major concerns for human health since they are widely used in agriculture and responsible for more cases of poisoning than any other pesticide class. The first aim is to define the mechanisms of OP-induced delayed toxicity (which has afflicted greater than 30,000 people) associated with neuropathy target esterase (NTE) using our newly-developed radioligand [3H]OBDPO and a novel carbamate-biotin affinity agent for target isolation from hen brain in active form of structural and functional characterization. Non-NTE targets phosphorylated by [3H]OBDPO and radioligands based on other OP delayed toxicants will be identified as with NTE itself. Cellular models will determine OP-induced changes in neural growth, essential neurotropic factors and ion transport. The second aim is to understand the mechanisms of important OP insecticides because of systemic action in plants and moderate toxicity to mammals. The hypotheses are: acephate toxicity is self-limiting because its metabolite methamidophos inhibits the amidase that activates acephate; methamidophos is bioactivated by S-oxidation (old hypothesis) or N-oxidation (new proposal) requiring studies of chemical models to resolve the site and stability relationships; S-methylation of dimethyl phosphorodithioic acid as a dimethoate metabolite contributes to its toxicological profile including delayed effects. The third aim is to establish the mechanisms for toxicity of aluminum phosphide which is increasingly replacing methyl bromide (the ozone depleter) as the major fumigant for stored products. The overall hypothesis is that 1) phosphine, a gas liberated on environmental hydrolysis of aluminum phosphide, undergoes spontaneous or biological oxidation to phosphine oxide, and 2) this phosphinylating agent produces acute toxic effects at a yet undefined target and genotoxic effects on derivatizing DNA leading to conversion of the deoxyguanosine moiety to 8-hydroxydeoxyguanosine. This research is necessary to ensure the safe use of phosphorus-containing insecticides.