Monte Carlo Analysis of the Human Chlorpyrifos-Oxonase (PON1) Polymorphism Using a Physiologically Based Pharmacokinetic and Pharmacodynamic (PBPK/PD) Model

Details

• Personal Author:
  Kousba A ; Poet TS ; Timchalk C
• Description:
  Susceptibility to organophosphate (OP) insecticides, like chlorpyrifos (CPF), may result from differences in the extent of metabolic detoxification of the active metabolite, CPF-oxon. A genetic polymorphism in the arylesterase (PON1; CPF-oxonase) detoxification of OPs, results in the expression of a range of enzyme activities within humans. This study utilized Monte Carlo analysis and physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) modeling to investigate the impact of human CPF-oxonase status on the theoretical concentration of CPF-oxon in the brain. At low doses ( approximately 5 microg/kg) the model is insensitive to changes in CPF-oxonase. However, with increasing dose (>0.5 mg/kg) the model suggests a dose-dependent non-linear increase in the brain CPF-oxon concentration, which is associated with CPF-oxonase activity. Following repeated high dose exposure, the model predicted brain CPF-oxon concentration was approximately 8x higher (5 mg/kg) versus a single exposure, whereas, at low doses (5 microg/kg), the brain concentrations were comparable regardless of exposure duration. This suggests that at low environmentally relevant exposures other esterase detoxification pathways may compensate for lower CPF-oxonase activity. [Description provided by NIOSH]
• Subjects:
  Blood Hematologic Tests Insecticides Nervous System Nervous System Diseases Occupational Exposure Occupational Health Organophosphates Safety
• Keywords:
  Acute-exposure Blood-samples Brain-disorders Brain-function Exposure-levels Gas-chromatography Models Neurotoxic-effects Neurotoxicity Neurotoxins Organo-phosphorus-compounds Organo-phosphorus-pesticides Pesticides Pharmacodynamics

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• ISSN:
  0378-4274
• 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:
  51-59
• Volume:
  135
• Issue:
  1
• NIOSHTIC Number:
  nn:20029607
• Citation:
  Toxicol Lett 2002 Sep; 135(1-2):51-59
• Contact Point Address:
  Battelle Pacific Northwest Division, Chemical Dosimetry, 902 Battelle Blvd., P.O. Box 999, Richland, WA 99352
• Email:
  charles.timchalk@pnl.gov
• CAS Registry Number:
  Diazinon (CAS RN 333-41-5)
• Federal Fiscal Year:
  2002
• NORA Priority Area:
  Research Tools and Approaches: Exposure Assessment Methods
• Performing Organization:
  Battelle Memorial Institute, Richland, Washington
• Peer Reviewed:
  True
• Start Date:
  20010930
• Source Full Name:
  Toxicology Letters
• End Date:
  20050929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:3f1f411b72a9f5dfbdec6a507b054e70a80573ecdf8f738c43e3e4c0ebecabbef1492e96b28c19320eeb8f3cc3a69281aaf06649c8878c9bbf5460dba4933e1a
• Download URL:
  https://stacks.cdc.gov/view/cdc/190551/cdc_190551_DS1.pdf
• File Type:
  [PDF - 260.27 KB ]