Validation Centers

European governmental and private centers specializing in the validation of in vitro, in silico or alternative methods to reduce, refine and/or replace the use of animals in regulatory toxicology include the following:

• European Centre for the Validation of Alternative Methods (ECVAM)
• Fund for the Replacement of Animals in Medical Experiments (FRAME)
• German Center for the Documentation and Evaluation of Alternatives to Animal Experiments (ZEBET)

European Centre for the Validation of Alternative Methods (ECVAM)

ECVAM was established in 1991 pursuant to a requirement in Directive 86/609/EEC that the Commission and Member States actively support the development, validation and acceptance of methods to replace, reduce or refine the use of animals in laboratories. The specific duties of ECVAM are "to:

• Coordinate the validation of alternative test methods at the European Union level
• Act as a focal point for the exchange of information on the development of alternative test methods
• Set up, maintain and manage a database on alternative procedures
• Promote dialogue between legislators, industries, biomedical scientists, consumer organizations and animal welfare groups, with a view to the development, validation and international recognition of alternative test methods." To this end, ECVAM has organized more than 60 scientific workshops and task forces.

In addition to these core activities, ECVAM has taken on a lead role in:

• Developing internationally recognized validation and regulatory acceptance criteria of new and revised test methods
• Establishing the European Reference Laboratory for Alternative Tests (CORRELATE) and advancing, as a project manager and/or lead laboratory, several multi-year, multi-million-Euro integrated research projects aimed at moving away from animal testing for such complex endpoints as acute toxicity, skin sensitization, and reproductive toxicity
• Coordinating international validation studies, including collaborative efforts in partnership with ICCVAM in the United States, JaCVAM in Japan, and the OECD
• Supporting the development of integrated testing strategies, including serving as the Commission lead for the REACH Implementation Project 3.3
• Sponsoring independent scientific peer reviews of alternative methods/strategies and publishing statements of validity issued by the ECVAM Scientific Advisory Committee (ESAC) to encourage regulatory acceptance and use of appropriate 3Rs methods

Fund for the Replacement of Animals in Medical Experiments (FRAME)

Within a decade of Russell and Burch's proposal of the "3Rs" concept of reduction, refinement and replacement in 1959, FRAME was established as a registered charity to advance alternatives to animal experiments in the United Kingdom. Since that time, FRAME has come to be recognized as a leading national and international authority on the 3Rs and toxicology through the following activities:

• Laboratory-based research: FRAME funds an Alternatives Laboratory at the University of Nottingham, which has been involved in the development and optimization of numerous in vitro assays for endpoints such as acute toxicity, ocular and dermal irritation, phototoxicity and embryotoxicity, and has been an active participant in a number of international validation studies for these and other toxicological endpoints.
• Publications: Since the mid 1970s, FRAME has published the bimonthly, peer-reviewed journal Alternatives to Laboratory Animals (ATLA), which reports the results of original research as well as workshop and conference proceedings, news items and commentaries and other information related to the development, validation, acceptance and use of the 3Rs in toxicology and research.
• Analysis and Advocacy: "FRAME conducts literature-based scientific studies to investigate the justification for using animals in laboratory research and to promote the adoption of the Three Rs strategy wherever possible." Recent initiatives include the development integrated testing strategies for use under REACH and in the evaluation of endocrine modulating effects; identification of opportunities for the revision and deletion of OECD Test Guidelines; the potency testing and cosmetic use of Botulinum toxin; the use of dogs, cats, non-human primates and transgenic animals in testing and research; testing requirements for food additives and vaccines; and the identification of biomarkers as refinement endpoints. The results and recommendations of these analyses are regularly communicated to government authorities and other key stakeholders through FRAME's involvement in expert committees, scientific conferences and workshops, as well as through publication in ATLA and other journals.

German Center for the Documentation and Evaluation of Alternatives to Animal Experiments (ZEBET)

Established in 1989 as part of the German Federal Institute for Risk Assessment (BfR), ZEBET is a government center mandated to "bring about the replacement particularly of legally prescribed animal experiments with alternative test methods" by documenting and assessing 3Rs methods, and, as appropriate, "pushing through their recognition both nationally and internationally." Within Germany, ZEBET plays a role in the enforcement of the country's Animal Welfare Act, advising national authorities with respect to available alternatives to animal experiments, and preparing expert opinions in response to applications for authorization of animal research projects. ZEBET also maintains a publicly accessible alternatives database, which currently contains summaries of approximately 800 books, journals, laws, regulations, guidelines, pharmacopeia, dissertations, conference proceedings, etc.

ZEBET is also directly involved in the development of in vitro and other alternative toxicological testing methods, both in-house and through grants for extramural research, as well as in their validation. For example, ZEBET:

• Led the development and successful validation of the in vitro 3T3 NRU Phototoxicity Test, in which mouse fibroblast cells are exposed to a test substance in the presence and absence of UV light to evaluate the potential for sunlight-induced toxicity
• Helped to pioneer the use of mouse embryonic stem cells to screen for agents that may be harmful to developing embryos, and served as the lead laboratory for the successful ECVAM validation of the Embryonic Stem Cell Test. ZEBET is also an active participant in the related EU research initiative, ReProTect, which aims to develop an integrated, non-animal testing strategy for the endpoints of reproductive and developmental toxicity.
• Has been a leading advocate for ending one-year pesticide dosing studies in dogs
• Is represented on Scientific Advisory Committee to the European Center for the Validation of Alternative Methods (ESAC)