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ToxSci Advance Access originally published online on March 28, 2006
Toxicological Sciences 2006 91(2):576-585; doi:10.1093/toxsci/kfj176
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Application of Physiologically Based Pharmacokinetic Modeling in Setting Acute Exposure Guideline Levels for Methylene Chloride

Peter Martinus Jozef Bos1, Marco Jacob Zeilmaker and Jan Cornelis Henri van Eijkeren

RIVM (National Institute for Public Health and the Environment), Centre for Substances and Integrated Risk Assessment, 3720 BA Bilthoven, The Netherlands

Received December 8, 2005; accepted March 9, 2006

Acute exposure guideline levels (AEGLs) are derived to protect the human population from adverse health effects in case of single exposure due to an accidental release of chemicals into the atmosphere. AEGLs are set at three different levels of increasing toxicity for exposure durations ranging from 10 min to 8 h. In the AEGL setting for methylene chloride, specific additional topics had to be addressed. This included a change of relevant toxicity endpoint within the 10-min to 8-h exposure time range from central nervous system depression caused by the parent compound to formation of carboxyhemoglobin (COHb) via biotransformation to carbon monoxide. Additionally, the biotransformation of methylene chloride includes both a saturable step as well as genetic polymorphism of the glutathione transferase involved. Physiologically based pharmacokinetic modeling was considered to be the appropriate tool to address all these topics in an adequate way. Two available PBPK models were combined and extended with additional algorithms for the estimation of the maximum COHb levels. The model was validated and verified with data obtained from volunteer studies. It was concluded that all the mentioned topics could be adequately accounted for by the PBPK model. The AEGL values as calculated with the model were substantiated by experimental data with volunteers and are concluded to be practically applicable.

Key Words: PBPK modeling; acute exposures; methylene chloride; AEGL setting.


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