Assessing the impact of human PON1 polymorphisms: sensitivity and Monte Carlo analyses using a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model for chlorpyrifos.
Timchalk-C; Kousba-A; Poet-TS
Toxicologist 2002 Mar; 66(1-S):311
A PBPK/PD model was developed for chlorpyrifos (CPF) and the active metabolite CPF-oxon. Susceptibility to organophosphate (OP) insecticides is associated with variation in pharmacokinetic/pharmacodynamic response. A genetic polymorphism in the PONI (arylesterase) detoxification of OPs results in the expression of a range of PON1 enzyme activities within humans. The objective was to identify sensitive parameters that influence the model output, and to investigate the impact of human PONI status on CPF-oxon brain concentration over a range (5 microg/kg - 5 mg/kg) of CPF doses. The model was used for parameter sensitivity analysis, and Monte Carlo simulations for PONI activity utilizing the human PONI polymorphic distributions. Based on the sensitivity coefficients (SC), the model was sensitive to the following parameters: CPF-oxon plasma protein-binding, liver partitioning, liver PONI metabolism, plasma butyrylcholinesterase (BuChE) and blood flow to the liver and brain. In addition, the SC for plasma protein binding, PON], and BuChE demonstrated a clear dose-dependency. The model simulations suggest a dose-dependent non-linear increase in the brain CPF-oxon AUC, at doses >0.5 mg/kg, which is a function of both dose and PONI activity. In contrast, at low environmentally relevant doses (-5 micro/kg) the model is relatively insensitive to the variability in PONI activity. The results suggest that other esterase detoxification pathways may adequately compensate for lower PON 1 activity; hence an increased sensitivity to low PON 1 is not observable until non-target esterases have been appreciably depleted. This response is consistent with simulations that show an increased sensitivity to PONI status at doses that significantly deplete plasma BuChE activity in humans (>90% inhibited). This study illustrates the utility of PBPK/PD modeling for determining the overall impact of parameter uncertainty and variability on risk assessment predictions for OP insecticides.
Insecticides; Pesticides; Models; Statistical-analysis; Toxicopathology; Toxic-effects; Physiological-response
Research Tools and Approaches: Exposure Assessment Methods
The Toxicologist. Society of Toxicology 41st Annual Meeting and ToxExpo, March 17-21, 2002, Nashville, Tennessee
Battelle Memorial Institute, Richland, Washington