Application of physiologically based pharmacokinetic modeling in setting Acute Exposure Guideline Levels (AEGLs) for methylene chloride

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 hours. 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-hour exposure time range from CNS-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. PBPK-modeling was considered to be the appropriate tool to address all of 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 of 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.