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

Reporting period: 2017-07-01 to 2018-12-31

Current approaches assessing the safety of chemical substances for humans are expensive and time-consuming. Moreover, they often see high error rates and uncertainties concerning their predictions. Finally, there are 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 bring about this paradigm shift in toxicology towards mechanistic, animal-free safety assessment, applicable across industry sectors and acceptable for regulatory purposes. This will improve consumer safety in the EU by providing more robust toxicological predictions. The project is developing toxicity testing strategies that integrate state-of-the-art in vitro and in silico technologies. So-called adverse outcome pathways (AOPs) are being developed to integrate all molecular and physiological knowledge relevant for predictive safety assessment. EU-ToxRisk is performing several case studies (CSs) in the areas of repeated dose toxicity (RDT) and developmental/reproductive toxicity (DART). These CSs are supported and evaluated by regulatory professionals to assess the readiness of the new strategies and new approach methods (NAMs) for practical application. As a result, the project will provide guidance for the universal application of new animal-free testing concepts. EU-ToxRisk validated testing and assessment strategies will fit both the current regulatory frameworks and the needs of various industry sectors. Moreover, it will serve the further development of safety sciences, and thus improve regulatory risk assessment.
During the first reporting period, the scientific and technical groundwork was laid out, and case studies were developed to test the strength of NAMs for a number of endpoints. Project outreach activities to relevant stakeholders, including academia, industry, regulators, civil groups and interested lay audience, were kicked off. The second reporting period of EU-ToxRisk saw significant scientific progress: the project expanded the development and implementation of the in silico toolbox for risk assessment and uncovered chemical-target interactions at the molecular level via structural modelling. Computational models to predict cellular biokinetics of chemicals and cell stress regulatory networks were established. Novel dual-colour stress-responsive fluorescent reporter assays were generated in human stem cells (iPSC). A human-on-a-chip model featuring four human tissues was established. High-throughput transcriptomics led to a better understanding of the mode of action of toxicants. Transcriptomics was applied to evaluate individual variability to toxicant stresses. These novel technologies were integrated in the CSs. The project established 15 new AOPs linked to ongoing CSs to support the generation of relevant mechanistic data. The involvement of regulatory agencies was further strengthened through the establishment of a regulatory advisory board (RAB) that includes members from European and international regulatory agencies such as the German BfR and the European ECHA and EFSA. Scientific progress was closely monitored for all CSs. Regulatory acceptance of the approaches and technologies used in EU-ToxRisk is a key success factor. Therefore, the RAB provided a set of guidelines for the reporting of project CSs –to allow for proper regulatory assessment– and will also review “mock” submissions generated from these CSs, mimicking real-world submissions with the aim of regulatory acceptance. This will significantly push the project mission to develop NAM-based approaches for regulatory safety assessment. A second set of CSs was defined to address additional goals and questions, e.g. is it possible, using NAMs, to predict an absence of toxic effects for certain compounds (i.e. low or no toxicity)? These CSs were developed with input from the consortium and under advice from the RAB and scientific advisory board (SAB). Building on previous efforts to team up with the European Commission’s Joint Research Centre (JRC), also a joint case study on the topic of ab initio safety assessment is under development, where no upfront data is available on chemical substance toxicity. EU-ToxRisk technologies and approaches have proven highly attractive to external stakeholders. This has led to collaborative CSs between EU-ToxRisk and Cosmetics Europe as well as with Syngenta, to carry out industrial CSs deploying the project’s techniques and expertise. The industrial CSs highlight the strong efforts by the consortium to disseminate project technologies and achievements, and to collaborate with stakeholders and experts.
EU-ToxRisk aims to instigate a paradigm shift in human safety evaluation of chemicals. Five distinct impacts were identified to reach this objective. Impact 1: more effective, faster, and cheaper toxicological testing to predict human risks and meet regulatory needs. The consortium planned to achieve this by developing an Integrated Approach to Testing and Assessment (IATA) based on a systems toxicology approach. Work from CSs has informed a key publication that will detail the strategy for improved read across assessment by incorporating data from in vitro and in silico methods. Close collaboration with the RAB will ensure that EU-ToxRisk strategies are in line with regulatory needs. A read-across workshop assessing several CSs and their regulatory relevance in depth will take place in collaboration with international regulatory agencies, including ECHA, EFSA, OECD, US-EPA and US-NTP. This will culminate in a guidance document and web-based toolkit for NAM-based safety assessment. Impact 2: improved toxicological knowledge to encourage and improve read-across procedures. The initial set of CSs focused on read-across procedures supported by NAMs. CSs have generated a wealth of data utilised in “mock” submissions, where a read-across argument was prepared according to guidance by the RAB. These mock submissions are under assessment for regulatory acceptance by RAB members. The generation of more than 15 novel AOPs has supported CS read-across procedures. Impact 3: commercial exploitation of the developed toxicological tests, tools and services. The EU-ToxRisk battery of in vitro methods was defined and is currently undergoing systematic comparative testing. Testing of all project methodologies and the use of RNA sequencing has generated a deeper understanding of the test systems and their utility. These tests are now being applied in a CS funded entirely through industry, thus making a big step towards commercial exploitation of EU-ToxRisk project outcomes. Impact 4: advancement of international co-operation in the field of toxicology and safety testing. The EU-ToxRisk consortium has continued working with the US Tox21 group, and has signed a formal collaboration agreement with the European Commission’s JRC. In addition, EU-ToxRisk started to interact with the US FDA and will collaborate on state-of-the-art high-throughput transcriptomics technologies involving the US EPA as well as Tox21. Impact 5: reduced use of laboratory animals in safety testing. While first steps were made to implement animal-free hazard assessment strategies for RDT and DART, improved read-across procedures or IATAs for RDT and DART are expected to help companies fulfilling some of their regulatory requirements without additional animal experiments.
EU-ToxRisk - Test Systems Overview
EU-ToxRisk - Case Study Types & Processes
EU-ToxRisk - Model Systems