ID AND DEV OF BIOLOGICAL MARKERS OF HUMAN EXPOSURE TO THE INSECTICIDE PERMETHRI

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 农业工人、园丁和房主经常接触杀虫剂氯菊酯。 此外，军事 人员在使用国防部驱虫系统和非处方虱皂时暴露于氯菊酯 使用氯菊酯作为有效成分。氯菊酯尿中的一种氯菊酯代谢物，含量很高， 稳定，可能是一个理想的生物标志物暴露于该农药。 此外，一种代谢物与另一种代谢物的比率可 根据给药途径的不同而有所不同。这项研究的结果将用于确定候选人， 开发一种快速、灵敏的基于免疫化学的分析方法，可用于常规监测 人类接触氯菊酯 目的：本研究的目的是测定经皮肤给药后， 最丰富和最稳定的暴露。加速器质谱法是一种用于 测量14 C的水平比液体闪烁计数灵敏几个数量级。有了这个高 敏感性我们将在生物相关剂量下进行人体代谢研究。 方法：我们将利用三种领先的分析技术，以综合的方式来识别和开发 用于检测和定量人类接触氯菊酯的实验室和现场便携式方法。 将使用高压液相色谱法与最先进的串联质谱仪（LC/MS）联用， 并鉴定氯菊酯的尿代谢产物。加速器质谱法（AMS）是一种用于测定 测量14 C的水平比液体闪烁计数灵敏几个数量级。与此 超灵敏度，反映实际人体暴露的14 C-氯菊酯剂量将用于确定代谢物 辐射风险最小的个人资料。通过LC/MS和AMS鉴定的代谢物将用于开发快速、灵敏的 免疫测定法用于人体氯菊酯暴露的常规监测。 六名人类志愿者将暴露在 14 C-氯菊酯皮肤剂量8小时。将在7天内收集尿液和血液样本， 在最初的24小时内频繁出现。首先将利用一个受试者进行试点研究，以测试这些方法 用于分离预期的代谢物。 使用其他5名受试者的暴露研究将提供置信度 观察到的代谢物模式可以作为一般人群的预测指标。 结果：将鉴别和定量尿液代谢物。基于这些信息， 将选择代谢物或代谢物缀合物作为免疫测定开发的目标。 成功将 包括适合于常规监测的免疫测定和暴露之间的明确定量关系， 吸收剂量，并测量了6名受试者尿液中氯菊酯的代谢物。 结论：本研究结果将用于候选人的鉴定，为开发一种快速、灵敏的 可用于常规监测人类接触氯菊酯的免疫化学分析方法。的 仔细监测氯菊酯吸收剂量的存在的能力将是一个有用的工具，以防止 氯菊酯对人体健康的影响。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Agricultural workers, gardeners and homeowners are routinely exposed to the insecticide permethrin. Also, military personnel are exposed to the permethrin when using the DOD Insect Repellent System and over-the-counter lice soaps use permethrin as the active ingredient. A urinary metabolite of permethrin, that is in high abundance and is relatively stable, may be an ideal biomarker of exposure to this pesticide. In addition, the ratio of one metabolite to another may vary, according to the route of administration. The results of this study would be used to identify candidates for the development of a rapid, sensitive immunochemical based analytical method that can be used to routinely monitor human exposure to permethrin. Objectives: The purpose of this study is to determine the human metabolite(s) of permethrin in urine following dermal exposure that are in greatest abundance and are the most stable. Accelerator mass spectrometry is a method for measuring levels of 14C several orders of magnitude more sensitive than liquid scintillation counting. With this high sensitivity we will conduct human metabolism studies at biologically relevant doses. Methodology: We will utilize three leading edge analytical technologies in an integrated approach to identify and develop both laboratory-based and field portable methods for the detection and quantitation of human exposure to permethrin. High-pressure liquid chromatography coupled to a state-of-the-art-tandem mass spectrometer (LC/MS) will be used to fractionate and identify urinary metabolites of permethrin. Accelerator mass spectrometry (AMS) is a method for measuring levels of 14C several orders of magnitude more sensitive than liquid scintillation counting. With this ultrasensitivity, doses of 14C-permethrin reflective of actual human exposure will be used to determine the metabolite profile with minimal radiation risk. The metabolites identified by LC/MS and AMS will be used to develop a rapid, sensitive immunoassay for routine monitoring of human exposure to permethrin. Six human volunteers will be exposed to low dermal doses of 14C-permethrin for 8 hours. Urine and blood samples will be collected over a 7-day period with more frequent time points in the first 24 hours. A pilot study utilizing one subject will be conducted first to test the methods developed for separating anticipated metabolites. An exposure study utilizing 5 other subjects will provide confidence that the metabolite patterns observed can be a predictor for the general population. Outcome: The urinary metabolites will be identified and quantified. Based on this information the most abundant, stable metabolite or metabolite conjugate will be chosen for the target of the development of an immunoassay. Success will include an immunoassay suitable for routine monitoring and clear quantitative relation between the exposures, absorbed dose, and measured metabolites of permethrin in the urine among the six subjects. Conclusion: The results of this study will be used to identify candidates for the development of a rapid, sensitive immunochemical based analytical method that can be used to routinely monitor human exposure to permethrin. The ability to carefully monitor the presence of absorbed doses of permethrin will be a useful tool to prevent the possibility of human health effects due to permethrin exposure.