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The in vivo quantitation of diazinon, chlorpyrifos, and their major metabolites in rat blood for the refinement of a physiologically-based pharmacokinetic/pharmacodynamic models.

Authors
Busby-A; Kousba-A; Timchalk-C
Source
J Undergrad Res 2004 Jun; 4:36-40
NIOSHTIC No.
20032921
Abstract
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 ~3 hours post-dosing. When given as a mixture, both DZN and CPF peak blood concentrations were not achieved until ~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.
Keywords
Organo-phosphorus-compounds; Organo-phosphorus-pesticides; Pesticides; In-vitro-studies; Models; Environmental-factors; Insecticide-poisoning; Quantitative-analysis; Laboratory-animals; Animals; Blood-serum; Blood-plasma
CAS No.
333-41-5
Publication Date
20040601
Document Type
Journal Article
Funding Amount
246279
Funding Type
Grant
Fiscal Year
2004
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629
ISSN
1547-9641
Priority Area
Research Tools and Approaches: Exposure Assessment Methods
Source Name
Journal of Undergraduate Research
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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