CYP-Specific PBPK/PD Models and Biomarkers of Organophosphorus Pesticides

Title: CYP-Specific PBPK/PD Models to Interpret Biomarkers for Organophosphate Pesticides

Principal Investigator: James Olson, PhD

Funding Agency: US EPA STAR Grant

Period: 09/01/07 - 08/31/12

Abstract: The primary objective of the proposed studies is to improve existing pharmacokinetic /pharmacodynamic (PBPK/PD) models to better estimate exposures, target tissue dose and resulting effects in human populations, utilizing the abundance of urinary metabolite / biomarker data for the organophosphate (OP) pesticides, chlorpyrifos, parathion, methyl parathion, and diazinon. It is hypothesized that more accurate measures of exposure, target tissue dose and subsequent effects will come from existing PBPK/PD models, which incorporate human CYP-specific kinetic parameters (Km and Vmax) for OP metabolism, CYP–specific content in the liver, and the function and content of genetic variants in key enzymes (CYP2B6, CYP2C19, PON1) which regulate OP metabolic activation and detoxification.