Setting the stage for next-generation risk assessment with non-animal approaches the EU-ToxRisk project experience

Setting the stage for next-generation risk assessment with non-animal approaches the EU-ToxRisk project experience

Moné, M.J.
Pallocca, G.
Escher, S.E.
Exner, T.
Herzler, M.
Hougaard Bennekou, S.
Kamp, H.
Kroese, E.D.
Leist, M.
Steger-Hartmann, T.
van de Water, B.

2020

In 2016, the European Commission launched the EU-ToxRisk research project to develop and promote animal-free approaches in toxicology. The 36 partners of this consortium used in vitro and in silico methods in the context of case studies (CSs). These CSs included both compounds with a highly defined target (e.g. mitochondrial respiratory chain inhibitors) as well as compounds with poorly defined molecular initiation events (e.g. short-chain branched carboxylic acids). The initial project focus was on developing a science-based strategy for read-across (RAx) as an animal-free approach in chemical risk assessment. Moreover, seamless incorporation of new approach method (NAM) data into this process (= NAM-enhanced RAx) was explored. Here, the EU-ToxRisk consortium has collated its scientific and regulatory learnings from this particular project objective. For all CSs, a mechanistic hypothesis (in the form of an adverse outcome pathway) guided the safety evaluation. ADME data were generated from NAMs and used for comprehensive physiological-based kinetic modelling. Quality assurance and data management were optimized in parallel. Scientific and Regulatory Advisory Boards played a vital role in assessing the practical applicability of the new approaches. In a next step, external stakeholders evaluated the usefulness of NAMs in the context of RAx CSs for regulatory acceptance. For instance, the CSs were included in the OECD CS portfolio for the Integrated Approach to Testing and Assessment project. Feedback from regulators and other stakeholders was collected at several stages. Future chemical safety science projects can draw from this experience to implement systems toxicology-guided, animal-free next-generation risk assessment.

adverse outcome pathway
chemical safety
computer model
controlled study
drug safety
human
in vitro study
learning
letter
Organisation for Economic Co-operation and Development
outcome assessment
quality control
respiratory chain
risk assessment
toxicology

http://resolver.tudelft.nl/uuid:a0c411e7-b2c9-4a89-a431-4cf7796484f5

https://doi.org/10.1007/s00204-020-02866-4

955256

0340-5761

Archives of Toxicology, 94 (94), 3581-3592

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