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Pharmacokinetics and pharmacodynamics of chlorpyrifos and 3,5,6-trichloro-2-pyridinol in rat saliva after chlorpyrifos administration.

Authors
Smith-JN; Wang-J; Lin-Y; Klohe-EM; Timchalk-C
Source
Toxicol Sci 2012 Dec; 130(2):245-256
NIOSHTIC No.
20042672
Abstract
Sensors have been developed for noninvasive biomonitoring of the organophosphate pesticide chlorpyrifos (CPF), and previous studies have suggested consistent partitioning of 3,5,6-trichloro-2-pyridinol (TCPy), a metabolite of CPF, into saliva after exposure to TCPy. The objective of this study was to quantitatively evaluate in vivo pharmacokinetics and pharmacodynamics of CPF and TCPy in saliva after CPF administration. Rats were coadministered CPF (0.5-5mg/kg) and pilocarpine (~13 mg/kg) iv. Saliva and blood were collected, and levels of CPF, TCPy, and cholinesterase (ChE) activity were quantified. Experimental results suggest that CPF is rapidly metabolized after iv administration. Formation of TCPy from administered CPF at the low dose (0.5 mg/kg) was slower than from higher CPF doses, potentially due to differences in plasma protein binding to CPF. CPF was measured in saliva only at the first time point sampled (0-15 min), indicating low partitioning and rapid metabolism. After formation, TCPy pharmacokinetics were very similar in blood and saliva. Saliva/blood TCPy concentration ratios were not affected by TCPy concentration in blood, saliva flow rate, or salivary pH and were consistent with previous studies. ChE activity in plasma demonstrated a dose-dependent decrease, and ChE activity in saliva was extremely variable and demonstrated no dose relationship. A physiologically based pharmacokinetic and pharmacodynamic model for CPF was modified and predicted the data reasonably well. It is envisioned that a combination of biomonitoring compounds like TCPy in saliva coupled with computational modeling will form an approach to measure pesticide exposure to susceptible human populations such as agricultural workers.
Keywords
Pesticides; Exposure-levels; Risk-factors; Laboratory-animals; Animals; Metabolism; Blood-samples; Models; Proteins; Protein-biochemistry; Biomarkers; Author Keywords: chlorpyrifos; 3,5,6-trichloro-2-pyridinol; trichloropyridinol; TCPy; pharmacokinetics; saliva; biomonitoring
Contact
Jordan Ned Smith, Battelle Memorial Institute, Pacific Northwest Division, PO Box 999, Richland, WA 99352
CODEN
TOSCF2
CAS No.
2921-88-2; 6515-38-4
Publication Date
20121201
Document Type
Journal Article
Email Address
jordan.smith@pnnl.gov
Funding Type
Grant
Fiscal Year
2013
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-008173; Grant-Number-R01-OH-003629
Issue of Publication
2
ISSN
1096-6080
Source Name
Toxicological Sciences
State
WA
Performing Organization
Battelle Pacific Northwest Laboratories
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