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

Details

• Personal Author:
  Kousba AA ; Poet TS ; Timchalk C
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Age Factors Animals Blood Energy Metabolism Hazardous Substances Insecticides Laboratories Occupational Health Safety
• Keywords:
  Agedependent Sensitivity Age Factors Animal-studies Author Keywords: Chlorpyrifos Brain Function Chlorpyrifos Detoxification Drugs Enzymology Laboratory-animals Metabolism Models Organophosphorus Insecticides PBPK/PD Pharmacodynamics Preweanling Rat Toxins

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• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 10 ; Washington
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  348-365
• Volume:
  98
• Issue:
  2
• NIOSHTIC Number:
  nn:20032613
• Citation:
  Toxicol Sci 2007 Aug; 98(2):348-365
• Contact Point Address:
  Charles Timchalk, Battelle Pacific Northwest Division, Center for Biological Monitoring and Modeling, 902 Battelle Boulevard, Richland, WA 99352
• Email:
  charles.timchalk@pnl.gov
• CAS Registry Number:
  Chlorpyrifos (CAS RN 2921-88-2)
• Federal Fiscal Year:
  2007
• NORA Priority Area:
  Research Tools and Approaches: Exposure Assessment Methods ; Agriculture, Forestry and Fishing
• Performing Organization:
  Battelle Memorial Institute, Richland, Washington
• Peer Reviewed:
  True
• Start Date:
  20010930
• Source Full Name:
  Toxicological Sciences
• End Date:
  20050929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:14d47e00ecf5570f1b05e0aed7c7a815f5fdeb31e353c7d321d6f127851bd0d6d8e50f6d588491ebd0f831a9fddcee009d3ba4d03faaaf7738da149b1a259138
• Download URL:
  https://stacks.cdc.gov/view/cdc/186524/cdc_186524_DS1.pdf
• File Type:
  [PDF - 660.07 KB ]