Use of Cytochrome P450-Specific Parameters and Human Biomarker Data To Develop a Human Physiologically Based Pharmacokinetic/Pharmacodynamic Model for Dermal Chlorpyrifos Exposure

摘要

Chlorpyrifos (CPF), a widely used organophosphorus pesticide, is metabolized by cytochrome P450s (CYPs) to either an inactive metabolite, trichloro-2-pyridinol (TCPy), or to chlorpyrifos oxon (CPF-oxon), which is a potent cholinesterase inhibitor. Urinary TCPy levels are a reliable biomarker for CPF exposure while blood cholinesterase activity is an indicator of CPF toxicity. Previous work with Egyptian agricultural workers involved in CPF application to cotton fields measured urinary TCPy (daily) and blood butyrylcholinesterase and acetylcholinesterase activities (every 7-8 days) as biomarkers of CPF exposure and effect. The urinary TCPy levels and cholinesterase inhibition values reported for this group of workers exceeds previous published reports of occupational exposure to CPF. A human physiologically based pharmacokinetic/pharmacodynamic (PBPK7PD) model for dermal CPF exposure was developed using the available human biomarker data, CYP-specific kinetic rate constants and other CPF-specific parameters. Human PBPK/PD modeling simulations for a dermal CPF exposure were able to accurately simulate the human exposure and effect biomarker data.