Print Email Facebook Twitter Combining in vitro embryotoxicity data with physiologically based kinetic (PBK) modelling to define in vivo dose-response curves for developmental toxicity of phenol in rat and human Title Combining in vitro embryotoxicity data with physiologically based kinetic (PBK) modelling to define in vivo dose-response curves for developmental toxicity of phenol in rat and human Author Strikwold, M. Spenkelink, B. Woutersen, R.A. Rietjens, I.M.C.M. Punt, A. Publication year 2013 Abstract In vitro assays are often used for the hazard characterisation of compounds, but their application for quantitative risk assessment purposes is limited. This is because in vitro assays cannot provide a complete in vivo dose-response curve from which a point of departure (PoD) for risk assessment can be derived, like the no observed adverse effect level (NOAEL) or the 95 % lower confidence limit of the benchmark dose (BMDL). To overcome this constraint, the present study combined in vitro data with a physiologically based kinetic (PBK) model applying reverse dosimetry. To this end, embryotoxicity of phenol was evaluated in vitro using the embryonic stem cell test (EST), revealing a concentration-dependent inhibition of differentiation into beating cardiomyocytes. In addition, a PBK model was developed on the basis of in vitro and in silico data and data available from the literature only. After evaluating the PBK model performance, effective concentrations (EC x) obtained with the EST served as an input for in vivo plasma concentrations in the PBK model. Applying PBK-based reverse dosimetry provided in vivo external effective dose levels (EDx) from which an in vivo dose-response curve and a PoD for risk assessment were derived. The predicted PoD lies within the variation of the NOAELs obtained from in vivo developmental toxicity data from the literature. In conclusion, the present study showed that it was possible to accurately predict a PoD for the risk assessment of phenol using in vitro toxicity data combined with reverse PBK modelling. © 2013 Springer-Verlag Berlin Heidelberg. Subject LifeQS - Quality & SafetyEELS - Earth, Environmental and Life SciencesBiomedical InnovationBiologyHealthy LivingAlternative for animal testingEmbryonic stem cell test (EST)In vitro-in vivo (IVIV) extrapolationPhenolPhysiologically based kinetic (PBK) modellingRisk assessment To reference this document use: http://resolver.tudelft.nl/uuid:2776b338-8a51-48d8-80a8-1600bfad9fb0 DOI https://doi.org/10.1007/s00204-013-1107-4 TNO identifier 478813 ISSN 0340-5761 Source Archives of Toxicology, 87 (9), 1709-1723 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.