ToxSci Advance Access originally published online on May 15, 2007
Toxicological Sciences 2007 98(2):348-365; doi:10.1093/toxsci/kfm119
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An Age-Dependent Physiologically Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat
Battelle Pacific Northwest Division, Center for Biological Monitoring and Modeling, Richland, Washington 99352
1 To whom correspondence should be addressed at Battelle Pacific Northwest Division, Center for Biological Monitoring and Modeling, 902 Battelle Boulevard, Richland, WA 99352. Fax: (509) 376-9064. E-mail: charles.timchalk{at}pnl.gov.
Received January 5, 2007; accepted May 8, 2007
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Abstract |
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Juvenile rats are more susceptible than adults to the acute toxicity of organophosphorus insecticides like chlorpyrifos (CPF). Age- and dose-dependent differences in metabolism may be responsible. Of importance are CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (B-est) and PON-1 (A-esterase) detoxification of CPF-oxon to TCP. In the current study, a physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue B-est levels for rats was developed. In this model, age was used as a dependent function to estimate body weight which was then used to allometrically scale both metabolism and tissue cholinesterase (ChE) levels. In addition, age-dependent changes in brain, liver, and fat volumes and brain blood flow were obtained from the literature and used in the simulations. Model simulations suggest that preweanling rats are particularly sensitive to CPF toxicity, with levels of CPF-oxon in blood and brain disproportionately increasing, relative to the response in adult rats. This age-dependent nonlinear increase in CPF-oxon concentration may potentially result from both the depletion of nontarget B-est and a lower PON-1 metabolic capacity in younger animals. The PBPK/PD model behaves consistently with the general understanding of CPF toxicity, pharmacokinetics, and tissue ChE inhibition in neonatal and adult rats. Hence, this model represents an important starting point for developing a computational model to assess the neurotoxic potential of environmentally relevant organophosphate exposures in infants and children.
Key Words: chlorpyrifos; PBPK/PD; preweanling rat; age-dependent sensitivity.
2 Current address: TargeGen Inc., 9380 Judiccial Dr., San Diego, CA 92121.
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