Drug safety assessment is a knowledge-intensive process that demands advancement in data handling methods and tools for facilitating data sharing, mining, analysis and predictive modelling. This need is not restricted to any specific type of data and real advancement requires integrating information of different types and from different sources (e.g. publicly available biomedical knowledge, proprietary preclinical and clinical data, evidence from post-marketing studies) for addressing drug safety assessment from a holistic perspective. The eTRANSAFE project will address these needs by developing a powerful data integration infrastructure (Knowledge Hub) and a collection of computational tools (exploitation modules) for making optimal use of these data. The proposed system will be a flexible and expandable framework, built on previous experience and applying state-of-the-art methods and technologies for providing the most advanced solutions for data sharing, interoperability and exploitation. An experienced honest broker will guarantee the confidentiality of any proprietary data. The project will develop in silico tools for data mining, visualisation, and prediction of potential toxicity, with specific attention to the assessment of the preclinical to clinical predictivity and the discovery of safety biomarkers. The CDISC-SEND format will be supported, facilitating the preparation of regulatory-compliant documentation. This infrastructure will be underpinned by development of open standards and guidelines recognised by regulatory agencies and international organisations. The eTRANSAFE consortium brings together 13 organizations that mobilize an unprecedented capacity and resources, uniquely placed to leverage the experience of eTOX and other EU projects and initiatives. The project partners are six prestigious academic institutions, six highly skilled small-medium enterprises (SME) and one European infrastructure (ELIXIR), bringing in this way a perfect balance.

The vision of EU-ToxRisk is to drive a paradigm shift in toxicology towards an animal-free, mechanism-based integrated approach to chemical safety assessment. The project will unite all relevant disciplines and stakeholders to establish: i) pragmatic, solid read-across procedures incorporating mechanistic and toxicokinetic knowledge; and ii) ab initio hazard and risk assessment strategies of chemicals with little background information. The project will focus on repeated dose systemic toxicity (liver, kidney, lung and nervous system) as well as developmental/reproduction toxicity. Different human tiered test systems are integrated to balance speed, cost and biological complexity. EU-ToxRisk extensively integrates the adverse outcome pathway (AOP)-based toxicity testing concept. Therefore, advanced technologies, including high throughput transcriptomics, RNA interference, and high throughput microscopy, will provide quantitative and mechanistic underpinning of AOPs and key events (KE). The project combines in silico tools and in vitro assays by computational modelling approaches to provide quantitative data on the activation of KE of AOP. This information, together with detailed toxicokinetics data, and in vitro-in vivo extrapolation algorithms forms the basis for improved hazard and risk assessment. The EU-ToxRisk work plan is structured along a broad spectrum of case studies, driven by the cosmetics, (agro)-chemical, pharma industry together with regulators. The approach involves iterative training, testing, optimization and validation phases to establish fit-for-purpose integrated approaches to testing and assessment with key EU-ToxRisk methodologies. The test systems will be combined to a flexible service package for exploitation and continued impact across industry sectors and regulatory application. The proof-of-concept for the new mechanism-based testing strategy will make EU-ToxRisk the flagship in Europe for animal-free chemical safety assessment.