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An age-dependent physiologically based pharmacokinetic/pharmacodynamic model for the organophosphorus insecticide chlorpyrifos in the preweanling rat.

Authors
Timchalk C; Kousba AA; Poet TS
Source
Toxicol Sci 2007 Aug; 98(2):348-365
NIOSHTIC No.
20032613
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 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.
Keywords
Insecticides; Laboratory-animals; Animal-studies; Animals; Organophosphorus insecticides; Chlorpyrifos; Metabolism; Detoxification; Pharmacodynamics; Models; Age factors; Toxins; Blood; Brain function; Drugs; Enzymology; Author Keywords: chlorpyrifos; PBPK/PD; preweanling rat; agedependent sensitivity
Contact
Charles Timchalk, Battelle Pacific Northwest Division, Center for Biological Monitoring and Modeling, 902 Battelle Boulevard, Richland, WA 99352
CODEN
TOSCF2
CAS No.
2921-88-2
Publication Date
20070801
Document Type
Journal Article
Email Address
charles.timchalk@pnl.gov
Funding Amount
246279
Funding Type
Grant
Fiscal Year
2007
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629; Grant-Number-R01-OH-008173
Issue of Publication
2
ISSN
1096-6080
Priority Area
Research Tools and Approaches: Exposure Assessment Methods
Source Name
Toxicological Sciences
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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