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ToxSci Advance Access published online on September 25, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm251
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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

Physiologically-based Pharmacokinetic (PBPK) Modeling of 1,4-Dioxane in Rats, Mice and Humans

Lisa M. Sweeney*, Karla D. Thrall{dagger}, Torka S. Poet{dagger}, Richard A. Corley{dagger}, Thomas J. Weber{dagger}, Betty J. Locey{ddagger}, Jacquelyn Clarkson{ddagger}, Shawn Sager{ddagger} and Michael L. Gargas*

* The Sapphire Group, Dayton, Ohio {dagger} Battelle, Richland, Washington {ddagger} ARCADIS, Novi, Michigan

Address correspondence to: Lisa M. Sweeney, 2661 Commons Blvd., Suite 240, Dayton, OH 45431, 937-427-4293 (voice), 937-458-0050 (fax), LMS29{at}cwru.edu or LMS{at}thesapphiregroup.com (Email)

Received April 16, 2007; revision received September 17, 2007; accepted September 18, 2007


  Abstract

1,4-Dioxane (CAS No. 123-91-1) is used primarily as a solvent or as a solvent stabilizer. It can cause lung, liver and kidney damage at sufficiently high exposure levels. Two physiologically-based pharmacokinetic (PBPK) models of 1,4-dioxane and its major metabolite, hydroxyethoxyacetic acid (HEAA), were published in 1990. These models have uncertainties and deficiencies that could be addressed and the model strengthened for use in a contemporary cancer risk assessment for 1,4-dioxane. Studies were performed to fill data gaps and reduce uncertainties pertaining to the pharmacokinetics of 1,4-dioxane and HEAA in rats, mice, and humans. Three types of studies were performed: partition coefficient measurements, blood time course in mice, and in vitro pharmacokinetics using rat, mouse, and human hepatocytes. Updated PBPK models were developed based on these new data and previously available data. The optimized rate of metabolism for the mouse was significantly higher than the value previously estimated. The optimized rat kinetic parameters were similar to those in the 1990 models. Only two human studies were identified. Model predictions were consistent with one study, but did not fit the second as well. In addition, a rat nasal exposure was completed. The results confirmed water directly contacts rat nasal tissues during drinking water under bioassays. Consistent with previous PBPK models, nasal tissues were not specifically included in the model. Use of these models will reduce the uncertainty in future 1,4-dioxane risk assessments.


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