The In Vivo Quantitation of Diazinon, Chlorpyrifos, and Their Major Metabolites in Rat Blood for the Refinement of a Physiologically-Based Pharmacokinetic/Pharmacodynamic Models

Details

• Personal Author:
  Busby A ; Kousba A ; Timchalk C
• Description:
  Chlorpyrifos (CPF)(O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate, CAS 2921-88-2), and diazinon (DZN)(O,O-diethyl-O-2-isopropyl-4-methyl-6-pyrimidyl thiophosphate, CAS 333-41-5) are commonly encountered organophosphorus insecticides whose oxon metabolites (CPF-oxon and DZN-oxon) have the ability to strongly inhibit acetylcholinesterase, an enzyme responsible for the breakdown of acetylcholine at nerve synapses. Chlorpyrifos- oxon and DZN-oxon are highly unstable compounds that degrade via hepatic, peripheral blood, and intestinal metabolism to the more stable metabolites, TCP (3,5,6-trichloro-2-pyridinol, CAS not assigned) and IMHP (2-isopropyl- 6-methyl-4-pyrimidinol, CAS 2814-20-2), respectively. Studies have been performed to understand and model the chronic and acute toxic effects of CPF and DZN individually but little is known about their combined effects. The purpose of this study was to improve physiologically based pharmacokinetic/ pharmacodynamic (PBPK/PD) computational models by quantifying concentrations of CPF and DZN and their metabolites TCP and IMHP in whole rat blood, following exposure to the chemicals individually or as a mixture. Male Sprague-Dawley rats were orally dosed with 60 mg/kg of CPF, DZN, or a mixture of these two pesticides. When administered individually DZN and CPF were seen to reach their maximum concentration at approximately 3 hours post-dosing. When given as a mixture, both DZN and CPF peak blood concentrations were not achieved until approximately 6 hours post-dosing and the calculated blood area under the curve (AUC) for both chemicals exceeded those calculated following the single dose. Blood concentrations of IMHP and TCP correlated with these findings. It is proposed that the higher AUC obtained for both CPF and DZN as a mixture resulted from competition for the same metabolic enzyme systems. [Description provided by NIOSH]
• Subjects:
  Animals Blood Environmental Health Insecticides Laboratories Occupational Health Organophosphates Safety
• Keywords:
  Blood-plasma Blood-serum Environmental-factors In-vitro-studies Insecticide-poisoning Laboratory-animals Models Organo-phosphorus-compounds Organo-phosphorus-pesticides Pesticides Quantitative-analysis

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• ISSN:
  1547-9641
• 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:
  36-40
• Volume:
  4
• NIOSHTIC Number:
  nn:20032921
• Citation:
  J Undergrad Res 2004 Jun; 4:36-40
• CAS Registry Number:
  Diazinon (CAS RN 333-41-5)
• Federal Fiscal Year:
  2004
• 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:
  Journal of Undergraduate Research
• End Date:
  20050929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:20e39ab29891fdd65bf7b8a23c168766a7188d0b7152e085905a5a86958faa81806d477fab59c995138112c82a609f97d478cbcb546c93cd18c0853f1459e269
• Download URL:
  https://stacks.cdc.gov/view/cdc/186707/cdc_186707_DS1.pdf
• File Type:
  [PDF - 465.28 KB ]