EU-ToxRisk ponders branched vs linear AOPs

Do adverse outcome pathways (AOPs) need to include “feedback loops” to reflect biological systems? The question was a focus of debate at the first general assembly of EU ToxRisk, a six-year European Commission funded project exploring alternative approaches to chemical safety evaluation. Meeting at Egmond aan Zee in the Netherlands, EU-ToxRisk’s principal investigators had “very lively discussions about AOPs”, project partner Mardas Daneshian, CEO of the Centre for Alternatives to Animal Testing (CAAT) Europe, told Chemical Watch. To date, published AOPs have taken a linear form. However, natural biological systems tend to have positive and negative feedback loops, said Dr Daneshian. With pathways regulated by chemical intermediates or metabolites, “linearity in AOPs is something that doesn’t make much sense, biologically,” he suggests. The OECD and the EU Reference Laboratory for alternatives to animal testing (EURL-Ecvam) were both present at the meeting as observers, and the former now plans to discuss the idea of incorporating feedback loops into AOPs, said Dr Daneshian. EU-ToxRisk launched officially in January 2016, with an overall mission to develop a quantitative adverse outcome pathway (AOP) concept for regulatory purposes, integrating relevant in vitro and in silico technologies for assessing chemical safety in humans. It received €30m from the Commission’s Horizon 2020 research programme. The project centres on a number of case studies, some of which are still ongoing. Research teams are looking for biological mechanisms that may link to case studies, focusing on key events and threshold levels, as well as assessing weight of evidence for existing mechanisms. The teams are expected to begin delivering data in spring 2017. A summer school for EU-ToxRisk students, preceding the general assembly, focused on “good practice”. “The project needs to start with good practice, with the most important thing being reproducibility,” said Dr Daneshian. To achieve reproducibilty, students need to think about all possible shortcomings of experimental designs, he added. This September, ToxRisk will hold a workshop in Mainz, Germany, in collaboration with US projects ToxCast and Tox21.

Chemical Watch, 28 July 2016 ; ;