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.
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