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ToxSci Advance Access originally published online on October 10, 2007
Toxicological Sciences 2007 100(2):360-373; 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

Mary Sue Marty*,1, Jeanne Y. Domoradzki*,2, Steven C. Hansen*, Charles Timchalk{dagger}, Michael J. Bartels* and Joel L. Mattsson{ddagger}

* Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, Michigan 48674 {dagger} Battelle Pacific Northwest Laboratories, Richland, Washington 99352 {ddagger} Dow AgroSciences, Limited Liability Company, Indianapolis, Indiana 46268

1 To whom correspondence should be addressed at Toxicology and Environmental Research and Consulting, The Dow Chemical Company, 1803 Building, Midland, MI 48674. Fax: 989-638-9863; E-mail: mmarty{at}dow.com.

Received April 24, 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 versus divided doses. Blood concentrations of CPF and its primary metabolite, trichloropyridinol, were measured at multiple times through 24 h. Groups included were single gavage bolus versus divided gavage doses in corn oil (one vs. three times in 24h), single gavage bolus versus divided gavage doses in rat milk, and sc administration in dimethyl sulfoxide (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 4 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 CPF. 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.

2 The Dow Corning Corporation, Auburn, Michigan 48611.


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