Periodic Reporting for period 4 - EU-ToxRisk (An Integrated European ‘Flagship’ Program Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st Century)
Berichtszeitraum: 2020-07-01 bis 2021-12-31
Current approaches assessing chemical safety for humans are expensive, time-consuming and error-prone. Moreover, there are ethical concerns (animal use). Therefore, there is an urgent need for modern and reliable toxicological approaches that use non-animal methods. The vision of the EU-ToxRisk project is to transform toxicology towards mechanistic, animal-free safety assessment, applicable across industry sectors and acceptable for regulatory purposes. This will improve safety for European citizens by providing more robust toxicological predictions. The project aimed to develop toxicity testing strategies that integrate state-of-the-art in-silico and in-vitro technologies. So-called adverse outcome pathways (AOPs) were developed to integrate all molecular and physiological knowledge relevant for predictive safety assessment. EU-ToxRisk performed a broad range of case studies (CSs) in the areas of repeated dose toxicity and developmental/reproductive toxicity, supported and evaluated by regulatory professionals to assess the readiness of the novel strategies and new approach methods (NAMs) for practical application. The ambition was to provide guidance for the universal application of animal-free testing concepts. The validated EU-ToxRisk testing and assessment strategies will fit current regulatory frameworks as well as needs of various industry sectors. Moreover, they will serve the further development of safety sciences, and thus advance science-based regulatory risk assessment.
The first reporting period of EU-ToxRisk established the scientific and technical groundwork and involved the development of CSs to test the strength of NAMs for a number of endpoints. The second project period ensured the full maturation of the scientific toolbox for chemical safety assessment and its extensive deployment in testing batteries for the first set of project CSs. Moreover, a direct link was created between the project’s scientific innovations and regulatory practice through the establishment of a regulatory advisory board. In the third reporting period, several CSs were fully finalised, reported on, and reviewed. Novel mechanism-based human-relevant test systems were deployed, including new fluorescent stress-responsive reporter assays in human induced-pluripotent stem cells, toxicity screening in diseased 3D spheroid models of the liver, four-organ microfluidics chip test systems, and high-throughput transcriptomics. Advanced in-silico prediction tools and PBPK models were made fully fit for purpose. New CSs deploying these technologies were initiated in close collaboration with international experts, and practical testing was started. Importantly, regulatory readiness of the testing toolbox for read-across approaches was now demonstrated, and the project’s commercialisation platform aiming to exploit the toolbox was inaugurated. The final reporting period brought all project expertise together to maximise scientific and regulatory impact of the project. All project CSs were experimentally finalised. They provided new tools and information on NAM-based read-across, with several CSs also addressing uncharted areas, like how to test chemicals with little or no-observed adverse effects, or with multi-target organ toxicity, or the involvement of metabolism, or chemicals without any prior knowledge of their in-vivo effects and without known structurally similar molecules. The output was assessed by regulatory experts and learnings were condensed in the EU-ToxRisk Advisory Document on NAM-based read-across to assist regulatory toxicologists in all sectors. Several EU-ToxRisk CSs have now also been published at the OECD. All project CSs comprise biokinetics information and high-throughput transcriptomics data on all CS chemicals. Also, the fully sponsored industry CS, based on the project’s NAMs and read-across strategy, further proved its value. The commercialisation efforts were expanded and further consolidated in the joint Commercialization Platform. Training of the next generation of toxicology scientists came to its effective conclusion, yielding a workforce of young researchers with not only proven scientific excellence in non-animal toxicology approaches, but also trained in awareness of the regulatory context, much adding to their value beyond the walls of academia. Lastly, EU-ToxRisk partners made their findings sustainable and useful for others by establishing new long-term international initiatives, such as the ASPIS research cluster (including the RISK-HUNT3R project) and the PARC partnership. This will ensure that EU-ToxRisk results (data, knowledge, and methodology) will be taken up by the community.
EU-ToxRisk aimed to transform human safety evaluation of chemicals. Five distinct impacts were identified to reach this overall project objective.
i) EU-ToxRisk showed that it can integrate toxicological in-vitro and in-silico test systems more effectively, faster, and cheaper to assess chemical safety and meet regulatory needs. The project learned how to optimise test strategies to effectively target regulatory questions and how to report on them for safety assessment. New CSs challenged the approaches further by focusing on test strategies to provide conclusions from NAM data on the human safety of substances that have no or low toxic concerns, paving the way for new initiatives on next-generation risk assessment.
ii) EU-ToxRisk has improved the application of toxicological knowledge to encourage and improve read-across procedures. Extensive reviewing of the project’s read-across CSs by international regulatory experts, saw several championing as exemplars of chemical risk assessment using NAM-based read-across through endorsement and publication by the OECD IATA Case Study Project. Strategies developed in EU-ToxRisk also aided revision of the OECD considerations document to IATA approaches.
iii) Exploitation was expanded and further consolidated in the joint Commercialization Platform, which will now also operate independently and sustainably outside the EU-ToxRisk context, offering in-vitro and in-silico NAMs in an integrated fashion for both safe design as well as regulatory toxicology purposes.
iv) The project has advanced the international co-operation in the field of toxicology and safety testing through continuous feedback on its CSs from international regulatory experts from ECHA, EFSA, EMA, and OECD. EU-ToxRisk has remained actively engaged with the US Tox21 consortium on high-throughput screening technologies. EU-ToxRisk also engaged with Health Canada and NIHS Japan in the area of risk assessment in read-across CSs.
v) Successful demonstration in EU-ToxRisk CSs of the application of NAMs for safety assessment will support the reduced use of laboratory animals in safety testing. The improved read-across procedures and IATAs for RDT and DART started to lead to non-animal test studies for real industry cases. The CSs on prioritizing compounds of low or no toxicity already showed how to steer away from performing animal testing of likely safe compounds.
i) EU-ToxRisk showed that it can integrate toxicological in-vitro and in-silico test systems more effectively, faster, and cheaper to assess chemical safety and meet regulatory needs. The project learned how to optimise test strategies to effectively target regulatory questions and how to report on them for safety assessment. New CSs challenged the approaches further by focusing on test strategies to provide conclusions from NAM data on the human safety of substances that have no or low toxic concerns, paving the way for new initiatives on next-generation risk assessment.
ii) EU-ToxRisk has improved the application of toxicological knowledge to encourage and improve read-across procedures. Extensive reviewing of the project’s read-across CSs by international regulatory experts, saw several championing as exemplars of chemical risk assessment using NAM-based read-across through endorsement and publication by the OECD IATA Case Study Project. Strategies developed in EU-ToxRisk also aided revision of the OECD considerations document to IATA approaches.
iii) Exploitation was expanded and further consolidated in the joint Commercialization Platform, which will now also operate independently and sustainably outside the EU-ToxRisk context, offering in-vitro and in-silico NAMs in an integrated fashion for both safe design as well as regulatory toxicology purposes.
iv) The project has advanced the international co-operation in the field of toxicology and safety testing through continuous feedback on its CSs from international regulatory experts from ECHA, EFSA, EMA, and OECD. EU-ToxRisk has remained actively engaged with the US Tox21 consortium on high-throughput screening technologies. EU-ToxRisk also engaged with Health Canada and NIHS Japan in the area of risk assessment in read-across CSs.
v) Successful demonstration in EU-ToxRisk CSs of the application of NAMs for safety assessment will support the reduced use of laboratory animals in safety testing. The improved read-across procedures and IATAs for RDT and DART started to lead to non-animal test studies for real industry cases. The CSs on prioritizing compounds of low or no toxicity already showed how to steer away from performing animal testing of likely safe compounds.