Monte Carlo analysis of the human chlorpyrifos-oxonase (PON1) polymorphism using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model

Abstract

Susceptibility to organophosphate (OP) insecticides, like chlorpyrifos (CPF), may result from differences in the extent of metabolic detoxification of the active metabolite, CPF-oxon. A genetic polymorphism in the arylesterase (PON1; CPF-oxonase) detoxification of OPs, results in the expression of a range of enzyme activities within humans. This study utilized Monte Carlo analysis and physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) modeling to investigate the impact of human CPF-oxonase status on the theoretical concentration of CPF-oxon in the brain. At low doses (∼5 μg/kg) the model is insensitive to changes in CPF-oxonase. However, with increasing dose (>0.5 mg/kg) the model suggests a dose-dependent non-linear increase in the brain CPF-oxon concentration, which is associated with CPF-oxonase activity. Following repeated high dose exposure, the model predicted brain CPF-oxon concentration was ∼8× higher (5 mg/kg) versus a single exposure, whereas, at low doses (5 μg/kg), the brain concentrations were comparable regardless of exposure duration. This suggests that at low environmentally relevant exposures other esterase detoxification pathways may compensate for lower CPF-oxonase activity.