Metabolism and Age-Related Organophosphate Toxicity

描述（由申请人提供）：有机磷（OP）杀虫剂，广泛用于农业和住宅，显示多种化学成分。有机磷杀虫剂表现出广泛的急性毒性水平，这在很大程度上取决于化合物的特定解毒效率。幼虫通常比成虫更容易受到OP杀虫剂的毒性影响。幼鱼较低的未成熟外源性解毒能力导致其脆弱性增强。合乎逻辑的结论是，在成虫体内容易解毒的化合物，在幼虫体内的毒性水平相对高于不易解毒的化合物；换句话说，所谓的“安全”杀虫剂（基于对成人的低毒性水平）对婴儿和儿童的危害相对大于“不安全”杀虫剂。本应用程序的目的是确定暴露于一组具有代表性的OP化合物后，幼鼠和成年鼠对毒性影响的相对脆弱性程度，并表征解毒在这些脆弱性中的作用。假设是：在高暴露水平下观察到的成年人对OP杀虫剂毒性的脆弱性较低，主要是由于他们成熟的解毒系统更有效；对于那些对成人毒性较小的化合物，即那些传统上被认为“更安全”的化合物，对单个OP化合物的易损性的年龄相关差异将更大。这一假设来源于我们的初步发现，即成人和青少年的急性毒性水平与几种保护性酯酶的水平和效率密切相关。我们计划通过调查以下两个具体目标来检验我们的假设：1。测定了12种OP化合物在体外发育过程中关键解毒机制的效率和靶酶的敏感性；和2。确定这12种有机磷化合物的解毒机制对不同年龄群体体内有机磷毒性水平的贡献。该项目将利用我们实验室合成的新型OP化合物，这些化合物具有独特的特性-抑制效力和解毒潜力。该项目将调查肝脏和血液解毒机制的效率（保护性酯酶：羧基酯酶、非靶点乙酰胆碱酯酶、丁基胆碱酯酶、a -酯酶）和靶酶（脑和外周乙酰胆碱酯酶）对每种测试化合物的敏感性。实验将在2个幼龄大鼠（1日龄和12日龄）和成年大鼠中进行。我们预计解毒效率将是化合物特异性的，对这些保护性酯酶解毒OP的效率的测定将允许预测幼年毒性水平与成年毒性水平的差异有多大，并且在更容易解毒的化合物中存在更显着的年龄相关差异。这些结果将表明解毒对毒性水平的贡献，并将允许更准确地预测与年龄相关的毒性差异。

DESCRIPTION (provided by applicant): Organophosphorus (OP) insecticides, extensively used agriculturally and residentially, display a variety of chemistries. OP insecticides demonstrate a wide range of acute toxicity levels, which are largely dependent on the compound-specific efficiencies of detoxication. Juveniles are typically more vulnerable than adults to the toxic effects of OP insecticides. The low immature xenobiotic detoxication capacity of juveniles contributes to their enhanced vulnerability. It is logical to conclude that compounds, which are readily detoxified in adults, will display relatively higher toxicity levels in juveniles than compounds, which are not readily detoxified; in other words, the so-called "safer" insecticides (based on low toxicity levels in adults) are of relatively more danger to infants and children than are the "unsafe" insecticides. The objective of this application is to determine the relative degree of vulnerability to toxic effects following exposures to a representative group of OP compounds in juvenile and adult rats, and to characterize the role of detoxication in these vulnerabilities. The hypothesis is: The lower vulnerability of adults to the toxicity of OP insecticides observed at high exposure levels is primarily the result of (he greater effectiveness of their mature detoxication systems; the age-related differences in vulnerability to individual OP compounds will be greater for the compounds which are less toxic to adults, i.e., those traditionally viewed as "safer" This hypothesis was derived from our preliminary findings that acute toxicity levels in both adults and juveniles are strongly related to the levels and the efficiency of several protective esterases. We plan to test our hypothesis by investigating the following two specific aims: 1. Determine for 12 select OP compounds the in vitro efficiency of critical detoxication mechanisms and of target enzyme sensitivity during development; and 2. Determine for these 12 OP compounds the contribution of detoxication mechanisms to the in vivo OP toxicity levels among ages. The project will utilize novel OP compounds synthesized in our laboratories, which demonstrate unique characteristics 0 inhibitory potency plus detoxication potential. The project will investigate the efficiency of hepatic and blood detoxication mechanisms (the protective esterases: carboxylesterases, non-target acetylcholinesterase, butyrylcholinesterase, A-esterase) and target enzyme (brain and peripheral acetylcholinesterase) sensitivity for each test compound. Experiments will be conducted in rats of 2 juvenile ages (1 and 12 days) and adults. We expect that detoxication efficiencies will be compound-specific, that the determination of the efficiencies of these protective esterases to detoxify the OP's will allow a prediction of how greatly the juvenile toxicity levels will differ from those of adults, and that there will be more dramatic age-related differences in compounds which are more readily detoxified. These results will indicate the contribution of detoxication to toxicity level, and will allow more accurate predictions of age-related differences in toxicity.