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An Integrated European ‘Flagship’ Program Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st Century

Periodic Reporting for period 3 - EU-ToxRisk (An Integrated European ‘Flagship’ Program Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st Century)

Reporting period: 2019-01-01 to 2020-06-30

Current approaches assessing chemical safety for humans are expensive and time-consuming and can be error-prone and therefore bear uncertainties concerning their predictions, while there are also ethical concerns (animal use). Therefore, there is an urgent need for more 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 consumer safety by providing more robust toxicological predictions. The project is developing toxicity testing strategies that integrate state-of-the-art in silico and in vitro technologies. So-called adverse outcome pathways are being developed to integrate all molecular and physiological knowledge relevant for predictive safety assessment. EU-ToxRisk is performing 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 new strategies and new approach methods (NAMs) for practical application. The project will provide guidance for the universal application of novel animal-free testing concepts. The EU-ToxRisk validated testing and assessment strategies will fit both current regulatory frameworks as well as the needs of various industry sectors. Moreover, they will serve the further development of safety sciences, and thus improve 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, novel mechanism-based human relevant innovative test systems came to fruition, e.g. establishment of novel 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 large-scale deployment of high-throughput transcriptomics. Importantly, regulatory readiness of the testing toolbox for read-across approaches was demonstrated. This resulted in a full NAM-based read-across strategy. Work from read-across CSs was favourably assessed by international experts in a workshop and in the OECD IATA Case Studies Project. All learnings will deliver an advisory report on NAM-based read-across to assist regulatory toxicologists in all sectors. This will contribute to an acceptance of non-animal safety science in practice. CSs undergo further scrutiny through in vitro biokinetics measurements and high-throughput transcriptomics analysis. New CSs started on challenging regulatory and scientific questions, e.g. 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 similar looking molecules. CSs with industry partners also proved successful, with one seeing their OECD publication and another one being extended beyond its original scope. A commercialisation platform was launched offering NAMs in an integrated fashion and an in-silico read-across support tool is being finalised.
EU-ToxRisk aims to transform human safety evaluation of chemicals. Five distinct impacts were identified to reach this overall project objective. Firstly, EU-ToxRisk has established how to integrate more effective, faster, cheaper toxicological in silico and in vitro test systems 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 challenge 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. Secondly, EU-ToxRisk has improved the toxicological knowledge to encourage and improve read-across procedures. Through extensive reviewing of the project’s panel of read-across CSs by international regulatory experts, including the OECD IATA Case Study Project, the project found consensus on read-across testing strategies that integrate mechanistic toxicological information. In particular, innovation involved the integration of high-throughput transcriptomics approaches for implementation for read-across. Thirdly, EU-ToxRisk established a commercialization platform to exploit the developed toxicological tests, products and services. This platform will offer NAMs in an integrated fashion from case design to risk assessment. Business development will be further enhanced, continuing engagement with industry and seeking new opportunities. Fourthly, 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 is actively engaged with the US Tox21 consortium on high-throughput screening technologies. EU-ToxRisk also engaged with Health Canada and JaCVAM in the area of risk assessment in read-across CSs. Fifthly, the successful demonstration in EU-ToxRisk CSs of the application of NAM 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. Ambitious new, ongoing CSs on prioritizing compounds of low or no toxicity should show how to steer away from performing animal testing of likely safe compounds.