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Comparative chlorpyrifos pharmacokinetics via multiple routes of exposure and vehicles of administration in the adult rat.

Authors
Smith-JN; Campbell-JA; Busby-Hjerpe-AL; Lee-S; Poet-TS; Barr-DB; Timchalk-C
Source
Toxicology 2009 Jun; 261(1-2):47-58
NIOSHTIC No.
20035585
Abstract
Chlorpyrifos (CPF) is a commonly used organophosphorus pesticide. A number of toxicity and mechanistic studies have been conducted in animals, where CPF has been administered via a variety of different exposure routes and dosing vehicles. This study compared chlorpyrifos (CPF) pharmacokinetics using oral, intravenous (IV), and subcutaneous (SC) exposure routes and corn oil, saline/Tween 20, and dimethyl sulfoxide (DMSO) as dosing vehicles. Two groups of rats were co-administered target doses (5 mg/kg) of CPF and isotopically labeled CPF (L-CPF). One group was exposed by both oral (CPF) and IV (L-CPF) routes using saline/Tween 20 vehicle; whereas, the second group was exposed by the SC route using two vehicles, corn oil (CPF) and DMSO (L-CPF). A third group was only administered CPF by the oral route in corn oil. For all treatments, blood and urine time course samples were collected and analyzed for 3,5,6-trichloro-2-pyridinol (TCPy), and isotopically labeled 3,5,6-trichloro-2-pyridinol (L-TCPy). Peak TCPy/L-TCPy concentrations in blood (20.2 micromol/l), TCPy/L-TCPy blood AUC (94.9 micromol/lh), and percent of dose excreted in urine (100%) were all highest in rats dosed orally with CPF in saline/Tween 20 and second highest in rats dosed orally with CPF in corn oil. Peak TCPy concentrations in blood were more rapidly obtained after oral administration of CPF in saline/Tween 20 compared to all other dosing scenarios (>1.5 h). These results indicate that orally administered CPF is more extensively metabolized than systemic exposures of CPF (SC and IV), and vehicle of administration also has an effect on absorption rates. Thus, equivalent doses via different routes and/or vehicles of administration could potentially lead to different body burdens of CPF, different rates of bioactivation to CPF-oxon, and different toxic responses. Simulations using a physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for CPF are consistent with these possibilities. These results suggest that exposure route and dosing vehicle can substantially impact target tissue dosimetry. This is of particular importance when comparing studies that use varying exposure paradigms, which are then used for extrapolation of risk to humans.
Keywords
Biological-effects; Biological-factors; Biological-systems; Chemical-hypersensitivity; Chemical-reactions; Exposure-assessment; Exposure-limits; Exposure-methods; Laboratory-animals; Laboratory-testing; Pesticides; Pharmacodynamics; Author Keywords: Chlorpyrifos; 3,5,6-Trichloro-2-pyridinol; Pharmacokinetics; Trichloropyridinol
Contact
Charles Timchalk, Battelle, Pacific Northwest Division, P.O. Box 999, Richland, WA 99354
CODEN
TXCYAC
CAS No.
2921-88-2
Publication Date
20090630
Document Type
Journal Article
Email Address
mmarty@dow.com
Funding Amount
246279
Funding Type
Grant
Fiscal Year
2009
NTIS Accession No.
NTIS Price
Identifying No.
Grant-Number-R01-OH-003629; Grant-Number-R01-OH-008173
Issue of Publication
1-2
ISSN
0300-483X
Priority Area
Research Tools and Approaches: Exposure Assessment Methods; Agriculture, Forestry and Fishing
Source Name
Toxicology
State
WA
Performing Organization
Battelle Memorial Institute, Richland, Washington
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