Systems biology tools for quantitative AOPs

Abstract : While hazard assessment can make use of descriptive adverse outcome pathways (AOPs), risk assessment requires quantitative relationships from exposure to effect timing and magnitude. Such relationships can be made predictive using combinations of physiologically-based pharmacokinetic (PBPK) and systems biology modeling. However, the latter are typically very complex and data hungry. Could “quantitative” AOPs be an intermediate route for in vitro data integration and fast risk assessment? This question is being investigated by the EU-ToxRisk project and we report here on its progress in that area. First, going from qualitative (descriptive) AOPs to quantitative AOPs is not so straightforward. The primary data collected are typically molecular markers or phenotypic measurement, which can directly inform systems biology models’ “variables”, while AOPs are defined in terms of initiating, intermediate and key “events”. In the systems biology reference framework, AOPs can be seen as elementary paths between molecular species, but focusing on the links rather than on the species themselves. So, AOP events must be turned into measurable markers prior to quantifying the AOP. Yet, this should not make it too complex or too different from its qualitative original, otherwise the benefit of simplicity and scientific consensus on the original AOP will be lost. Given a suitable adaptation, there are then several ways to derive relationships between measurable markers: from empirical dose-response modeling to actual systems biology modeling. We are exploring those various alternatives in the context of EU-ToxRisk case studies and illustrate our presentation with data and models for oxidative stress.
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Conference papers
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Submitted on : Friday, August 3, 2018 - 2:02:07 PM
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Frédéric Y. Bois. Systems biology tools for quantitative AOPs. 53. Congress of the European Societies of Toxicology (EUROTOX 2017), Sep 2017, Bratislava, Slovakia. pp.S67, ⟨10.1016/j.toxlet.2017.07.170⟩. ⟨ineris-01853532⟩

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