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ToxSci Advance Access published online on May 15, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm119
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic (PBPK/PD) Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat

C Timchalk*, AA Kousba and TS Poet*

* Battelle Pacific Northwest Division, Center for Biological Monitoring and Modeling, 902 Battelle Boulevard, Richland WA., USA 99352 Current Address: TargeGen Inc., 9380 Judiccial Dr., San Diego, Ca., USA 92121

Correspondence: Charles Timchalk Ph.D., Ph#: (509) 376-0434, Fax#: (509) 376-9064, E-mail: charles.timchalk{at}pnl.gov, Torka Poet Ph.D., E-mail: torka.poet{at}pnl.gov, Ahmed Kousba Ph.D., E-mail: akousba{at}targegen.com

Received January 5, 2007; revision received May 4, 2007; accepted May 8, 2007


  Abstract

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 non-linear increase in CPF-oxon concentration may potentially result from both the depletion of non-target 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.


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M. S. Marty, J. Y. Domoradzki, S. C. Hansen, C. Timchalk, M. J. Bartels, and J. L. Mattsson
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[Abstract] [Full Text] [PDF]


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