Age-Dependent Partition Coefficients for a Mixture of Volatile Organic Solvents in Sprague-Dawley Rats and Humans

Abstract

The absorption, distribution, metabolism, and excretion of volatile organic compounds (VOCs) are critically determined by a few chemical-specific factors, notably their blood and tissue partition coefficients (PC) and metabolism. Age-specific values for PCs in rats have rarely been reported or utilized in pharmacokinetic modeling for predicting dosimetry in toxicity studies with rats progressing through their lifestages. A mixture of six VOCs (benzene, chloroform, methyl ethyl ketone, methylene chloride, trichloroethylene, and perchloroethylene) was used to determine blood:air and tissue:air PCs in rats at three different ages (postnatal d 10, 60 d, and 2 yr) and blood:air PCs in pediatric and adult human blood. No differences with age in human blood:air PCs for the six compounds were observed. Rat blood:air PCs increased with age varying with compound. Tissue:air PCs showed tissue-specific changes with age. Water-soluble methyl ethyl ketone showed no age-dependent differences. Partition coefficients, particularly the blood:air PC, are key determinants of the rodent and human blood concentrations; age-appropriate values improve the accuracy of pharmacokinetic model predictions of population variability and age-specific exposures.

This work was completed, in part, under Department of the Air Force contract F33615-00-6060 and was sponsored and funded by the U.S. Environmental Protection Agency under Interagency Agreement DW-57-93960601-0. While this text is coauthored by employees of the U.S. EPA, the views and opinions expressed herein are those of the respective authors and editors and do not represent those of the U.S. EPA. The authors thank Richard J. Godfrey for technical assistance, Charles D. Goodyear for statistical expertise, and Teresa R. Sterner for technical expertise in the preparation of this article.

The animals used in these studies were handled in accordance with the principles stated in the Guide for the Care and Use of Laboratory Animals, prepared by the Committee on Care and Use of Laboratory Animals Resources, National Research Council, DHHS, and the Animal Welfare Act of 1966, as amended.