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dc.contributor.authorBos, Peter Martinus Jozef
dc.contributor.authorZeilmaker, Marco Jacob
dc.contributor.authorEijkeren, Jan Cornelis Henri van
dc.date.accessioned2007-01-18T11:47:50Z
dc.date.available2007-01-18T11:47:50Z
dc.date.issued2006-06-01
dc.identifier.citationToxicol. Sci. 2006, 91(2):576-85en
dc.identifier.issn1096-6080
dc.identifier.pmid16569727
dc.identifier.doi10.1093/toxsci/kfj176
dc.identifier.urihttp://hdl.handle.net/10029/7610
dc.description.abstractAcute 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.
dc.format.extent242095 bytes
dc.format.mimetypeapplication/pdf
dc.language.isoenen
dc.titleApplication of physiologically based pharmacokinetic modeling in setting acute exposure guideline levels for methylene chloride.en
dc.typeArticleen
dc.format.digYES
refterms.dateFOA2018-12-18T15:33:05Z
html.description.abstractAcute 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.


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