title: 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 ( approximately 5 microg/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 approximately 8x higher (5 mg/kg) versus a single exposure, whereas, at low doses (5 microg/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.
authors.affiliation: Battelle Pacific Northwest Division, Chemical Dosimetry, 902 Battelle Blvd., P.O. Box 999, Richland, WA 99352, USA. charles.timchalk@pnl.gov
authors.forename: C
authors.initials: C
authors.lastname: Timchalk
authors.forename: A
authors.initials: A
authors.lastname: Kousba
authors.forename: T S
authors.initials: TS
authors.lastname: Poet
mesh_terms: D000383:Agriculture; D043303:Aryldialkylphosphatase; D001921:Brain / Q000378:metabolism; D004390:Chlorpyrifos / Q000493:pharmacokinetics* / Q000633:toxicity; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004950:Esterases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007306:Insecticides / Q000493:pharmacokinetics* / Q000633:toxicity; D009010:Monte Carlo Method; D011110:Polymorphism, Genetic
chemical_list: D007306:Insecticides; D004950:Esterases; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D004390:Chlorpyrifos