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

doi:https://doi.org/10.1093/toxsci/kfm119

Title: An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat

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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 is CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (cholinesterase; ChE) and A-esterase (PON-1) detoxification of CPF-oxon to TCP. In the current study, a modified physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue ChE 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 ChE levels. 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 the depletion of non-target B-esterases, and a lower PON-1 metabolic capacity in younger animals. These results indicate that 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 modelmore »« less

Authors:: Timchalk, Chuck; Kousba, Ahmed A; Poet, Torka S

Publication Date:: 2007-08-01

Research Org.:: Pacific Northwest National Lab. (PNNL), Richland, WA (United States)

Sponsoring Org.:: USDOE

OSTI Identifier:: 915707

Report Number(s):: PNWD-SA-7680
Journal ID: ISSN 1096-6080; TOSCF2; TRN: US200816%%169

DOE Contract Number:: AC05-76RL01830

Resource Type:: Journal Article

Journal Name:: Toxicological Sciences, 98(2):348-365

Additional Journal Information:: Journal Volume: 98; Journal Issue: 2; Journal ID: ISSN 1096-6080

Country of Publication:: United States

Language:: English

Subject:: 59 BASIC BIOLOGICAL SCIENCES; ADULTS; ANIMALS; BLOOD; BRAIN; CAPACITY; CHILDREN; CHOLINESTERASE; DETOXIFICATION; INSECTICIDES; JUVENILES; METABOLISM; TOXICITY; Chlorpyrifos; PBPK/PD; Preweanling rat; Age-dependent sensitivity

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                    Timchalk, Chuck, Kousba, Ahmed A, and Poet, Torka S. An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat.  United States: N. p., 2007. 
        Web.  doi:10.1093/toxsci/kfm119.

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                    Timchalk, Chuck, Kousba, Ahmed A, & Poet, Torka S. An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat.  United States.  https://doi.org/10.1093/toxsci/kfm119

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                    Timchalk, Chuck, Kousba, Ahmed A, and Poet, Torka S. Wed .  
        "An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat".  United States.  https://doi.org/10.1093/toxsci/kfm119.

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@article{osti_915707,

  title        = {An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat},

  author       = {Timchalk, Chuck and Kousba, Ahmed A and Poet, Torka S},

  abstractNote = {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 is CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (cholinesterase; ChE) and A-esterase (PON-1) detoxification of CPF-oxon to TCP. In the current study, a modified physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue ChE 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 ChE levels. 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 the depletion of non-target B-esterases, and a lower PON-1 metabolic capacity in younger animals. These results indicate that 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.},

  doi          = {10.1093/toxsci/kfm119},

  url          = {https://www.osti.gov/biblio/915707},
  journal      = {Toxicological Sciences, 98(2):348-365},

  issn         = {1096-6080},

  number       = 2,

  volume       = 98,

  place        = {United States},

  year         = {2007},

  month        = {8}

}

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