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Pharmacokinetics of the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCPy) in rat saliva.

Authors
Smith-JN; Wang-J; Lin-Y; Timchalk-C
Source
Toxicol Sci 2010 Feb; 113(2):315-325
NIOSHTIC No.
20036505
Abstract
Biological monitoring (biomonitoring) to quantify systemic exposure to the organophosphorus insecticide chlorpyrifos (CPF) has historically focused on the quantitation of major CPF metabolites in urine. Noninvasive techniques are being advocated as novel means of biomonitoring for a variety of potential toxicants, including pesticides (like CPF), and saliva has been suggested as an ideal body fluid. However, in order to be acceptable, there is a need to understand salivary pharmacokinetics of CPF metabolites in order to extrapolate saliva measurements to whole-body exposures. In this context, in vivo pharmacokinetics of 3,5,6-trichloro-2-pyridinol (TCPy), the major chemical-specific metabolite of CPF, was quantitatively evaluated in rat saliva. Experimental results suggest that TCPy partitioning from plasma to saliva in rats is relatively constant over a range of varying physiological conditions. TCPy pharmacokinetics was very similar in blood and saliva (area under the curve values were proportional and elimination rates ranged from 0.007 to 0.019 per hour), and saliva/blood TCPy concentration ratios were not affected by TCPy concentration in blood (p = 0.35) or saliva flow rate (p = 0.26). The TCPy concentration in saliva was highly correlated to the amount of unbound TCPy in plasma (r = 0.96), and the amount of TCPy protein binding in plasma was substantial (98.5%). The median saliva/blood concentration ratio (0.049) was integrated as a saliva/blood TCPy partitioning coefficient within an existing physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for CPF. The model was capable of accurately predicting TCPy concentrations in saliva over a range of blood concentrations. These studies suggest that saliva TCPy concentration can be utilized to ascertain CPF exposure. It is envisioned that the PBPK/PD can likewise be used to estimate CPF dosimetry based on the quantitation of TCPy in spot saliva samples obtained from biomonitoring studies.
Keywords
Biochemical-tests; Biochemistry; Biodynamics; Biological-effects; Biological-monitoring; Biological-transport; Biostatistics; Exposure-assessment; Exposure-levels; Exposure-methods; Insecticides; Laboratory-animals; Laboratory-testing; Metabolic-study; Organo-phosphorus-compounds; Pesticides; Pesticides-and-agricultural-chemicals; Pharmacodynamics; Quantitative-analysis; Risk-analysis; Risk-factors; Toxic-effects; Toxins; Author Keywords: chlorpyrifos; 3,5,6-trichloro-2-pyridinol; trichloropyridinol; pharmacokinetics; saliva; biomonitoring
Contact
Charles Timchalk, Battelle Memorial Institute, Pacific Northwest Division, PO Box 999, Richland, WA 99354
CODEN
TOSCF2
Publication Date
20100201
Document Type
Journal Article
Email Address
charles.timchalk@pnl.gov
Funding Amount
246279
Funding Type
Grant
Fiscal Year
2010
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629; Grant-Number-R01-OH-008173
Issue of Publication
2
ISSN
1096-6080
Priority Area
Research Tools and Approaches: Exposure Assessment Methods; Agriculture, Forestry and Fishing
Source Name
Toxicological Sciences
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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