ESNATS conference - the use of human embryonic stem cells for novel toxicity testing approaches.

The main achievements and results of the ESNATS project (Embryonic Stem Cell-based Novel Alternative Testing Strategies) were presented at the final project conference that was held on 15 September 2013, the day before the traditional EUSAAT (European Society for Alternatives to Animal Testing) Congress in Linz, Austria. The ESNATS project was an FP7 European Integrated Project, running from 2008 to 2013, the aim of which was to develop a novel toxicity testing platform based on embryonic stem cells (ESCs), and in particular, human ESC (hESCs), to accelerate drug development, reduce related R&D costs, and propose a powerful alternative to animal tests in the spirit of the Three Rs principles. Altogether, ESNATS offered the first proof of concept that hESCs can be used to create robust, reproducible and ready-to-use test assays for predicting human toxicity. In the end, essentially five test systems were developed to an adequate level for entering possible pre-validation procedures. These methods are based on hESCs, and can be combined to study the possible effects, on the human embryo, of exposure to a chemical during the early stages of development. In addition to the presentations by the main project partners, external speakers were invited to give lectures on relevant topics, both in the field of neurotoxicity and, more generally, on the applicability of hESCs in the development of advanced in vitro tests.

Moving forward in human cancer risk assessment.

BACKGROUND: The current safety paradigm for assessing carcinogenic properties of drugs, cosmetics, industrial chemicals, and environmental exposures relies mainly on in vitro genotoxicity testing followed by 2-year rodent bioassays. This testing battery is extremely sensitive but has low specificity. Furthermore, rodent bioassays are associated with high costs, high animal burden, and limited predictive value for human risks. OBJECTIVES: We provide a response to a growing appeal for a paradigm change in human cancer risk assessment. METHODS: To facilitate development of a road map for this needed paradigm change in carcinogenicity testing, a workshop titled "Genomics in Cancer Risk Assessment" brought together toxicologists from academia and industry and government regulators and risk assessors from the United States and the European Union. Participants discussed the state-of-the-art in developing alternative testing strategies for carcinogenicity, with emphasis on potential contributions from omics technologies. RESULTS AND CONCLUSIONS: The goal of human risk assessment is to decide whether a given exposure to an agent is acceptable to human health and to provide risk management measures based on evaluating and predicting the effects of exposures on human health. Although exciting progress is being made using genomics approaches, a new paradigm that uses these methods and human material when possible would provide mechanistic insights that may inform new predictive approaches (e.g., in vitro assays) and facilitate the development of genomics-derived biomarkers. Regulators appear to be willing to accept such approaches where use is clearly defined, evidence is strong, and approaches are qualified for regulatory use.

Alternatives to animal experimentation: the regulatory background.

The framework, in which alternatives to animal experiments can be developed, standardized, respectively formally validated, has to be seen in a global context. The ever increasing demand of testing for hazard and risk assessment in health and environment, exemplified by the EU REACH program, subsequently triggers laboratory animal testing. This holds especially true, if no valid alternative methods agreed to by the regulatory authorities and the scientific community are available. At least for regulatory toxicity testing, the global frame and network are given by institutions such as OECD, ICH, and alike. However, due to the necessity of global consent of states, organizations, and stakeholders, the time gap between availability of a novel alternative test method and its final acceptance by authorities and implementation thereafter is widening. The lack of new technologies or opportunities for alternative method application such as, for example, the broad use of transgenic animals for refinement of existing tests, adds to the problem. The bare existence of certain in vivo tests increases also the gap between public demands for testing versus availability of alternative tests. Industries operating on a worldwide basis support the alternative test development in their respective area of research and operational business. However, a more coordinating approach such as that of the ecopa-organization (European Consensus Platform on Alternatives) is needed to exploit the existing possibilities within the current regulatory framework. This will speed up the process of acceptance and challenge the political world to feel responsible for the sequels of their demanding more testing, that is, by funding alternative method development in academia and industry.

Dialogue and collaboration with ECVAM: the view of the EFPIA.

An evaluation is presented of past experience of dialogue and collaboration of ECVAM with the European Federation of Pharmaceutical Industries and Associations (EFPIA) over the last nine years. Lessons learnt from the viewpoint of EFPIA company representatives are given. Also, proposals for the future ECVAM approach are made, such as support for other research areas for new methods to be validated, giving realistic statements to ECVAM's EU and external customers, and being open to any new technology development that might help in opening and establishing new alternative avenues. Finally, the need for proper publications on the implementation of alternatives is recommended, for example, through the existing national platforms and their umbrella organisation, ecopa.