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EUToxRisk case studies: new approach methodologies in read-across

: Escher, Sylvia E.

The Toxicologist 162 (2018), No.1, pp.394-395, Abstract W 2632
ISSN: 0731-9193
Society of Toxicology (Annual Meeting) <57, 2018, San Antonio/Tex.>
Fraunhofer ITEM ()

The integration of new approach methodologies (NAM) into a comprehensive risk assessment framework is challenging, in particular for complex endpoints such as repeated dose or reproductive toxicity. EUToxRisk is a consortium of academic and industry scientists funded by the EU Horizon 2020 research program that aims to develop scientific underpinning for replacement of in vivo testing as far as possible by in vitro, ex vivo, and in silico models. This presentation will report on several recent case studies results, and limitations of integrating cellular and molecular physiology, systems biology, high-content technologies, and computational modeling to uncover the causal relationships with apical toxicity findings observed in traditional in vivo (mainly rodent) studies. Specifically, this talk will focus on two case studies: 1) the VPA case study in which we aim to predict microvesicular liver steatosis and reproductive effects; and 2) the mitochondrial toxicity case study, which is based on a concept of biological read-across. Each case study has specific scientific questions as well as technical and modeling challenges. Differences in toxicokinetics from in vivo and in vitro investigations are one key aspect of the integrated approach for testing and assessment of EUToxRisk. PBPK models informed by in vitro methods and reverse dosimetry are also used to determine in vivo-relevant test conditions. Overall, the case-study approach is aimed at developing demonstration blueprints on how NAM data may be used in regulatory submissions.