Pharmacokinetic and Pharmacodynamic Interaction for a Binary Mixture of Chlorpyrifos and Diazinon in the Rat

Details

• Personal Author:
  Busby AL ; Hinman MN ; Kousba AA ; Poet TS ; Timchalk C
• Description:
  Chlorpyrifos (CPF) and diazinon (DZN) are two commonly used organophosphorus (OP) insecticides and a potential exists for concurrent exposures. The primary neurotoxic effects from OP pesticide exposures result from the inhibition of acetylcholinesterase (AChE). The pharmacokinetic and pharmacodynamic impact of acute binary exposures of rats to CPF and DZN was evaluated in this study. Rats were orally administered CPF, DZN, or a CPF/DZN mixture (0, 15, 30, or 60 mg/kg) and blood (plasma and RBC), and brain were collected at 0, 3, 6, 12, and 24 h postdosing, urine was also collected at 24 h. Chlorpyrifos, DZN, and their respective metabolites, 3,5,6-trichloro-2-pyridinol (TCP) and 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMHP), were quantified in blood and/or urine and cholinesterase (ChE) inhibition was measured in brain, RBC, and plasma. Coexposure to CPF/DZN at the low dose of 15/15 mg/kg did not alter the pharmacokinetics of CPF, DZN, or their metabolites in blood. A high binary dose of 60/60 mg/kg increased the C(max) and AUC and decreased the clearance for both parent compounds, likely due to competition between CPF and DZN for CYP450 metabolism. At lower doses, most likely to be encountered in occupational or environmental exposures, the pharmacokinetics were linear. A dose-dependent inhibition of ChE was noted in tissues for both the single and coexposures, and the extent of inhibition was plasma > RBC > or = brain. The overall relative potency for ChE inhibition was CPF/DZN > CPF > DZN. A comparison of the ChE response at the low binary dose (15/15 mg/kg), where there were no apparent pharmacokinetic interactions, suggested that the overall ChE response was additive. These experiments represent important data concerning the potential pharmacokinetic and pharmacodynamic interactions for pesticide mixtures and will provide needed insight for assessing the potential cumulative risk associated with occupational or environmental exposures to these insecticides. [Description provided by NIOSH]
• Subjects:
  Animals Blood Hematologic Tests Insecticides Laboratories Nervous System Occupational Exposure Occupational Health Organophosphates Radiation Dosimeters Safety

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• Keywords:
  Acute-exposure Animal-studies Blood-samples Dosimetry Exposure-levels Gas-chromatography Laboratory-animals Models Neurotoxic-effects Neurotoxicity Neurotoxins Organo-phosphorus-compounds Organo-phosphorus-pesticides Pharmacodynamics

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• ISSN:
  0041-008X
• 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:
  31-42
• Volume:
  205
• Issue:
  1
• NIOSHTIC Number:
  nn:20029018
• Citation:
  Toxicol Appl Pharmacol 2005 May; 205(1):31-42
• Contact Point Address:
  Center for Biological Monitoring and Modeling, Battelle, Pacific Northwest Division, PO Box 999, 902 Battelle Boulevard, Richland, WA 99352
• Email:
  charles.timchalk@pnl.gov
• CAS Registry Number:
  Chlorpyrifos (CAS RN 2921-88-2) ; Diazinon (CAS RN 333-41-5)
• Federal Fiscal Year:
  2005
• 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 and Applied Pharmacology
• End Date:
  20050929
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:6d5388264a862434f52b38822b70f998df417740faf4c3a876d87d4d262ae0be5df3403360df12c04818816851d6b9011be70a639f6340b59a4a2111c1d7a288
• Download URL:
  https://stacks.cdc.gov/view/cdc/190094/cdc_190094_DS1.pdf
• File Type:
  [PDF - 557.09 KB ]