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In the absence of stand-alone one-to-one replacements for existing animal tests, efforts were made to integrate data from in silico, in chemico and in vitro methods to ensure sufficient mechanistic coverage of the skin sensitisation Adverse Outcome Pathway (AOP) and generate predictions suitable for hazard identification and potency sub-categorisation. A number of defined approaches (DAs), using fixed data interpretation procedures (DIP) to integrate data from multiple non-animal information sources, were proposed and documented using a standard reporting template developed by the Organisation for Economic Co-operation and Development (OECD). Subsequent international activities focused on the extensive characterisation of three of these DAs with respect to the reference in vivo data, applicability domains, limitations, predictive performances and characterisations of the level of confidence associated with the predictions. The ultimate product of this project was an OECD Guideline that provides information equivalent to that provided by the animal studies and that can be used to satisfy countries’ regulatory data requirements for skin sensitisation. This Defined Approach Guideline was the first of its kind for the OECD, and provides an important precedent for regulatory adoption of human biology-relevant new approach methodologies with performances equivalent to, or better than, traditional animal tests. This mini review summarizes the principal features of the defined approaches described in OECD guideline 497.

The annual EURL ECVAM status report describes research, development and validation activities, as well as initiatives that promote the regulatory use and international adoption of non-animal methods and approaches and their dissemination in the regulatory and research arenas. EU policies and legislation call for innovative and more efficient ways of safety testing and chemical risk assessment that do not depend on animal testing. Advanced technologies such as computational models, in vitro methods and organ-on-chip devices are being developed, evaluated and integrated to translate mechanistic understanding of toxicity into safety testing strategies. The ultimate goal is to achieve better protection of human health and the environment while supporting EU innovation and industrial competitiveness, without the use of animals. The development and use of non-animal models and methods are also essential for advancing basic, applied and translational research. Education also plays an essential role in enabling a shift to non-animal methods through the introduction of the Three Rs (Replacement, Reduction and Refinement of animal use in science) into secondary school curricula and programmes of higher education., JRC.F.3-Chemicals Safety and Alternative Methods

The European Union Reference Laboratory for alternatives to animal testing (EURL ECVAM) is an integral part of the European Commision's Joint Research Centre. The EURL ECVAM status report informs about research and development activities, test method submissions, validation and peer reviews, activities that promote the regulatory acceptance and international adoption of alternative methods and approaches and their dissemination. Replacement, reduction and refinement of animal testing (Three Rs) in basic, applied and translational research, as well as for regulatory purposes is anchored in EU legislation. Innovative technologies (e.g., computational models, in vitro methods, organ-on-chip devices) are developed, evaluated and integrated in assessment strategies for chemicals and products safety testing in order to preserve a high level of protection for human health and the environment. Important activities to promote the development and use of alternative methods and approaches are also pursued in the areas of basic and applied research as well as for education purposes., JRC.F.3-Chemicals Safety and Alternative Methods

The European Union Reference Laboratory for Alternatives to Animal Testing (EURL ECVAM) is an integral part of the European Commission's Joint Research Centre (JRC). The EURL ECVAM status report provides updates on the progress made in the development, validation and regulatory acceptance and use of alternative methods and approaches and their dissemination. The status report describes research, development and validation activities, as well as on initiatives that promote the regulatory and international adoption and use of alternative approaches and their dissemination., JRC.F.3-Chemicals Safety and Alternative Methods

Considerable progress has been made in non-animal methods and approaches for skin sensitisation assessment since the publication in 2013 of the EURL ECVAM strategy for this endpoint. This report illustrates EURL ECVAM views on the regulatory use of individual test methods, including two in vitro methods peer reviewed by ESAC, the LuSens and the U-SENS™ and on defined approaches and provides EURL ECVAM recommendations on future work to be undertaken in the area., JRC.F.3-Chemicals Safety and Alternative Methods

Every year, EURL ECVAM prepares a Status Report with the primary purpose of which is to inform its stakeholders and all interested parties (the public, press etc.) on updates on the status of alternative methods and approaches. The EURL ECVAM status report provides updates on activities since the last report published in October 2016. It reports on research and development, validation activities as well as on activities which promote the regulatory and international adoption and use of alternative approaches and their dissemination. It describes primarily, but not exclusively, all the activities that EURL ECVAM has undertaken or has been involved in since the publication of the last report., JRC.F.3-Chemicals Safety and Alternative Methods

Replacement, Reduction and Refinement of animal testing is anchored in EU legislation. Alternative non-animal approaches facilitate a shift away from animal testing. Cell-based methods and computational technologies are integrated to translate molecular mechanistic understanding of toxicity into safety testing strategies., JRC.F.3-Chemicals Safety and Alternative Methods

Significant progress has been made in the development, validation and regulatory acceptance of in chemico and in vitro test methods for skin sensitisation. Although these methods have been shown to perform relatively well (about 80% accuracy in predicting Local Lymph Node Assay (LLNA) classifications) a concern was raised on the regulatory acceptability of negative results since it was questioned whether these methods are able to predict chemicals that need to be activated to act as sensitisers. In order to inform ongoing discussions at the regulatory level in the EU, EURL ECVAM held an expert meeting on 10-11 November 2015 to analyse the extent to which in chemical and in vitro methods are able to correctly identify chemicals that need to be activated either through abiotic activation (pre-haptens) and/or through biotic (enzyme-mediated) mechanisms (pro-haptens) to acquire skin sensitisation potential. The expert group analysed a list of 127 chemicals, with available LLNA and in vitro data, 22% of which were considered to be pre- and/or pro-haptens. The pre-haptens, constituting the vast majority of chemicals requiring activation, where mostly correctly identified by both the in chemico and in vitro assays whereas the pro-haptens which represent a small subset of sensitising chemicals, were generally identified correctly by one of the cell-based assays. As a result, the expert group recommended that negative in vitro data should be accepted unless there is a compelling scientific argument that a substance is likely to be an exclusively metabolically activated pro-hapten., JRC.I.5-Systems Toxicology

The EURL ECVAM status report provides an update on the progress made in the development, validation and regulatory acceptance of alternative methods and approaches and their dissemination since the last report published in June 2014. It is informing on ongoing research and development activities, validation studies, peer reviews, recommendations, strategies and regulatory/international acceptance of alternative methods and approaches and dissemination activities. R&D activities within large European or International consortia continued in toxicity areas where 3Rs solutions are more difficult to find due to the underlying complexity of the area. On the other hand, toxicity areas where promising non-animal approaches have been developed, their validation and regulatory acceptance/international adoption could be progressed. Particular emphasis was given to the best and most intelligent combination and integration of these different non-animal approaches to ultimately obtain the required information without resorting to animal testing., JRC.I.5-Systems Toxicology

The EURL ECVAM Recommendation on the human Cell Line Activation Test (h-CLAT) provides EURL ECVAM views on the validity of the test method, advises on its possible regulatory applicability, limitations and proper scientific use and suggests possible follow-up activities in view of addressing knowledge gaps., JRC.I.5-Systems Toxicology