EU-ToxRisk – An Integrated European ‘Flagship’ Programme Driving Mechanism-based Toxicity Testing and Risk Assessment for the 21st century

The vision of EU-ToxRisk is to drive the required paradigm shift in toxicological testing away from ‘black box’ animal testing towards a toxicological assessment based on human cell responses and a comprehensive mechanistic understanding of cause-consequence relationships of chemical adverse effects. EU-ToxRisk will integrate advancements in cell biology, omics technologies, systems biology and computational modelling to define the complex chains of events that link chemical exposure to toxic outcome. The consortium will provide proof of concept for such a mechanism-based chemical safety testing strategy. The focus of this project is on two areas: repeated dose systemic toxicity, using the lung, kidney, liver and nervous system as examples of potential target organs; and developmental and reproductive toxicity. It will also provide guidance for its universal application, allowing to push the entire field forward in an integrated manner. The ultimate goal is to deliver testing strategies to enable reliable, animal-free hazard and risk assessment of chemicals.


Mechanism-based test methods will be integrated in testing batteries that are in line with the regulatory framework and that will be suitable for industrial implementation. The project will directly address two complementary critical regulatory needs:

  1. Pragmatic, solid “read-across” procedures between chemicals as the most important data gap filling and hence animal saving method at present, and
  2. Ab initio hazard and risk assessment strategies of chemicals with little background information.

The EU-ToxRisk work plan is structured along a broad spectrum of case studies, driven by the cosmetics, (agro)-chemical, and pharma industry together with regulators and specialists from academia. Different human tiered test systems are integrated to balance speed, cost and biological complexity. The project’s methodology can be summarized under the four following themes, which the Work Packages (WPs) – that make up the project – respectively feed into:

  1. Datababase requirements & design: The project combines in silico tools and in vitro assays by computational modelling approaches to provide quantitative data on the activation of Key Events (KE) of Alternative Outcome Pathways (AOPs). This information, together with detailed toxicokinetics data, and in vitro-in vivo extrapolation algorithms forms the basis for improved hazard and risk assessment.
  2. Systems toxicology/biology, AOPs: EU-ToxRisk extensively integrates the AOP-based toxicity testing concept, by identifying and quantitatively describing the AOPs which link the effects of EU-ToxRisk test compounds to apical endpoints and to adverse effects in humans. Established and novel assays will generate concentration and time course responses for all project chemicals to ultimately derive the Point of Departure (PoD). The in vitro data obtained in WP5-WP9 will provide WP11 (see below) with AOP-based thresholds and/or PoDs for individual chemicals.
  3. Test system evaluations: Advanced technologies, including high-throughput transcriptomics, RNA interference, and High Content Imaging, will provide quantitative and mechanistic underpinning of AOPs and KE. The approach involves iterating training, testing, optimisation and validation phases to establish fit-for-purpose integrated approaches to testing and assessment with key EU-ToxRisk methodologies.
  4. Risk assessment and uncertainties: The project integrates input from relevant stakeholders (i.e. risk assessors working in different regulatory contexts like cosmetics, pesticides, drugs and chemicals) so as to evolve modern theoretical concepts underpinning the approach for risk assessment in order to achieve practical applications fit for risk assessment. Hazard assessment will be performed by the use of Integrated Approaches to Testing and Assessment (IATAs) comprising in silico and in vitro methods.

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