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ToxSci Advance Access published online on October 10, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm239
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The Effect of Route, Vehicle and Divided Doses on the Pharmacokinetics of Chlorpyrifos and its Metabolite Trichloropyridinol in Neonatal Sprague-Dawley Rats

M.S. Marty*, J.Y. Domoradzki*,{dagger}, S.C. Hansen*, C. Timchalk{ddagger}, M.J. Bartels* and J.L. Mattsson§

* Toxicology and Environmental Research & Consulting, The Dow Chemical Company, Midland, MI 48674, mmarty{at}dow.com; schansen{at}dow.com; mjbartels{at}dow.com {dagger} Present address: The Dow Corning Corporation, Auburn, MI 48611 jean.domoradzki{at}dowcorning.com {ddagger} Battelle Pacific Northwest Laboratories, Richland, WA 99352 charles.timchalk{at}pnl.gov § Dow AgroSciences, LLC, Indianapolis, IN jmattsson{at}indy.rr.com

Please send all correspondence to: Sue Marty, Ph.D., D.A.B.T. , Toxicology & Environmental , Research and Consulting, The Dow Chemical Company, Building 1803, Midland, MI, USA 48674

Received April 24, 2007; revision received August 10, 2007; accepted August 25, 2007


  Abstract

There is a paucity of data on neonatal systemic exposure using different dosing paradigms. Male CD (Sprague-Dawley derived) rats at postnatal day (PND) 5 were dosed with chlorpyrifos (CPF, 1 mg/kg) using different routes of exposure, vehicles, and single vs. divided doses. Blood concentrations of CPF and its primary metabolite, trichloropyridinol (TCP), were measured at multiple times through 24 h. Groups included: single gavage bolus vs. divided gavage doses in corn oil (1 vs 3 times in 24 h), single gavage bolus vs. divided gavage doses in rat milk, and subcutaneous administration in DMSO. These data were compared with lactational exposure of PND 5 pups from dams exposed to CPF in the diet at 5 mg/kg/day for four weeks or published data from dams exposed to daily gavage with CPF at 5 mg/kg/day. Maternal blood CPF levels were an order of magnitude lower from dietary exposure than gavage (1.1 vs 14.8 ng/g), and blood CPF levels in PND 5 pups that nursed dietary-exposed or gavage-exposed dams were below the limit of detection. Single gavage doses of 1 mg/kg CPF in corn oil vehicle in pups resulted in CPF blood levels of 49 ng/g, and in milk vehicle about 9 ng/g. Divided doses led to lower peak CPF levels. A bolus dose of 1 mg/kg CPF in DMSO administered sc appeared to have substantially altered pharmacokinetics from orally administered chlorpyrifos. To be meaningful for risk assessment, neonatal studies require attention to the exposure scenario, since route, vehicle, dose and frequency of administration result in different systemic exposure to the test chemical and its metabolites.

Key Words: Neonatal rat; chlorpyrifos; trichloropyridinol; gavage; diet; SC DMSO; dose rate; vehicle.


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