Integration of NAMs in risk assessment: The read-across approach of the EU-ToxRisk project

Abstract

The integration of NAMs, new approach methodologies, into a comprehensive risk assessment framework is challenging, in particular for complex endpoints such as repeated dose or reproductive toxicity. In EUToxRisk, scientists with different types of expertise develop integrated approaches to testing and assessment (IATAs) for these two endpoints. We believe that the in vitro and ex vivo models selected from the EUToxRisk toolbox will provide a better understanding of adverse outcome pathways moving human toxicology towards mechanistic risk assessment. In this talk, we present the concept and outcomes of the read-across case studies from the EUToxRisk programme. We report on the recent results and limitations of integrating cellular and molecular physiology, system biology and high-content technologies (omics, HCI) using computational modelling to uncover the causal relationships with apical findings arising from traditional in vivo. We will set a focus on the analysis and comparison of transcriptomic data within and between the case study compounds. This data integration will be illustrated by one case study based on structural analogues and one case study in which structurally diverse compounds share a common mode of action. In both case studies the IATA will predict the hazard of the target compound(s) after repeated low dose exposure. Besides qualitative hazard assessment EUToxRisk aims to derive threshold values, below which compounds are considered to be safe. Therefore, we will show the application of the newly developed “in vitro distribution model” that estimates the intracellular concentration of compounds in the tested cell or tissue model. The intracellular concentration is the starting point to model the oral equivalent dose with IVIVE-PBPK models, which are also under development in EUToxRisk