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ToxSci Advance Access published online on February 16, 2005
Toxicological Sciences, doi:10.1093/toxsci/kfi119
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Toxicological Sciences © The Author [2005]. Published by Oxford University Press [on behalf of the Society of Toxicology]. All rights reserved. For Permissions, please email: journals.permissions@oupjournals.org
Received October 26, 2004
Accepted February 12, 2005

Biotransformation and Toxicokinetics

DEVELOPMENT OF A PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR ETHYLENE GLYCOL AND ITS METABOLITE, GLYCOLIC ACID, IN RATS AND HUMANS

R.A. Corley 1*, M.J. Bartels 2, E.W. Carney 2, K.K. Weitz 1, J.J. Soelberg 1, R.A. Gies 1, and K.D. Thrall 1

1 Battelle Pacific Northwest Division, Richland, WA 99352, USA
2 The Dow Chemical Company, Midland, MI 48674, USA

* To whom correspondence should be addressed.
R.A. Corley, E-mail: rick.corley{at}pnl.gov


  Abstract

An extensive database on the toxicity and modes of action of ethylene glycol (EG) has been developed over the past several decades. While renal toxicity has long been recognized as a potential outcome, developmental toxicity, which has only been observed in rats and mice, has become the subject of extensive research and regulatory reviews in recent years to establish guidelines for human exposures. The developmental toxicity of EG has been attributed to the intermediate metabolite, glycolic acid (GA), which can become a major metabolite when EG is administered to rats and mice at high doses and dose rates. Therefore, a physiologically based pharmacokinetic (PBPK) model was developed to integrate the extensive mode of action and pharmacokinetic data on EG and GA for use in developmental risk assessments. The resulting PBPK model includes inhalation, oral, dermal, intravenous and subcutaneous routes of administration. Metabolism of EG and GA were described in the liver with elimination via the kidneys. Metabolic rate constants and partition coefficients for EG and GA were estimated from in vitro studies. Other biochemical constants were optimized from appropriate in vivo pharmacokinetic studies. Several controlled rat and human metabolism studies were used to validate the resulting PBPK model. When internal dose surrogates were compared in rats and humans over a broad range of exposures, it was concluded that humans are unlikely to achieve blood levels of GA that have been associated with developmental toxicity in rats following occupational or environmental exposures.

Keywords: Ethylene glycol; glycolic acid; PBPK modeling.
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