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dc.contributor.authorGeraets, Liesbeth
dc.contributor.authorZeilmaker, Marco J
dc.contributor.authorBos, Peter M J
dc.date.accessioned2018-03-06T13:48:11Z
dc.date.available2018-03-06T13:48:11Z
dc.date.issued2018-01-05
dc.identifier.citationThe importance of inclusion of kinetic information in the extrapolation of high-to-low concentrations for human limit setting. 2018, 282:81-92 Toxicol. Lett.en
dc.identifier.issn1879-3169
dc.identifier.pmid29030269
dc.identifier.doi10.1016/j.toxlet.2017.10.008
dc.identifier.urihttp://hdl.handle.net/10029/621538
dc.description.abstractHuman health risk assessment of inhalation exposures generally includes a high-to-low concentration extrapolation. Although this is a common step in human risk assessment, it introduces various uncertainties. One of these uncertainties is related to the toxicokinetics. Many kinetic processes such as absorption, metabolism or excretion can be subject to saturation at high concentration levels. In the presence of saturable kinetic processes of the parent compound or metabolites, disproportionate increases in internal blood or tissue concentration relative to the external concentration administered may occur resulting in nonlinear kinetics. The present paper critically reviews human health risk assessment of inhalation exposure. More specific, it emphasizes the importance of kinetic information for the determination of a safe exposure in human risk assessment of inhalation exposures assessed by conversion from a high animal exposure to a low exposure in humans. For two selected chemicals, i.e. methyl tert-butyl ether and 1,2-dichloroethane, PBTK-modelling was used, for illustrative purposes, to follow the extrapolation and conversion steps as performed in existing risk assessments for these chemicals. Human health-based limit values based on an external dose metric without sufficient knowledge on kinetics might be too high to be sufficiently protective. Insight in the actual internal exposure, the toxic agent, the appropriate dose metric, and whether an effect is related to internal concentration or dose is important. Without this, application of assessment factors on an external dose metric and the conversion to continuous exposure results in an uncertain human health risk assessment of inhalation exposures.
dc.language.isoenen
dc.rightsinfo:eu-repo/semantics/closedAccessen
dc.subject.meshAnimals
dc.subject.meshDose-Response Relationship, Drug
dc.subject.meshEthylene Dichlorides
dc.subject.meshHumans
dc.subject.meshInhalation Exposure
dc.subject.meshMethyl Ethers
dc.subject.meshModels, Biological
dc.subject.meshRisk Assessment
dc.subject.meshSpecies Specificity
dc.subject.meshToxicokinetics
dc.titleThe importance of inclusion of kinetic information in the extrapolation of high-to-low concentrations for human limit setting.en
dc.typeArticleen
dc.identifier.journalToxicol Lett 2018; 282:81-92en
html.description.abstractHuman health risk assessment of inhalation exposures generally includes a high-to-low concentration extrapolation. Although this is a common step in human risk assessment, it introduces various uncertainties. One of these uncertainties is related to the toxicokinetics. Many kinetic processes such as absorption, metabolism or excretion can be subject to saturation at high concentration levels. In the presence of saturable kinetic processes of the parent compound or metabolites, disproportionate increases in internal blood or tissue concentration relative to the external concentration administered may occur resulting in nonlinear kinetics. The present paper critically reviews human health risk assessment of inhalation exposure. More specific, it emphasizes the importance of kinetic information for the determination of a safe exposure in human risk assessment of inhalation exposures assessed by conversion from a high animal exposure to a low exposure in humans. For two selected chemicals, i.e. methyl tert-butyl ether and 1,2-dichloroethane, PBTK-modelling was used, for illustrative purposes, to follow the extrapolation and conversion steps as performed in existing risk assessments for these chemicals. Human health-based limit values based on an external dose metric without sufficient knowledge on kinetics might be too high to be sufficiently protective. Insight in the actual internal exposure, the toxic agent, the appropriate dose metric, and whether an effect is related to internal concentration or dose is important. Without this, application of assessment factors on an external dose metric and the conversion to continuous exposure results in an uncertain human health risk assessment of inhalation exposures.


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