CAAT Newsletter: Vol. 13, No. 1, Fall 1995

ECVAM'S Director Discusses Validation

Validation of alternative methodologies is handicapped by "excessive politeness towards vested interests which want to hang onto animal tests," said Professor Michael Balls, head of the European Centre for the Validation of Alternative Methods (ECVAM). "The most important thing, as far as I'm concerned, is that we stop talking and get on with the job...and that we do not rest until the undoubted potential of replacement alternatives becomes a reality in practice, for the benefit of humans, as well as animals." Established by the European Union (EU) specifically to coordinate the validation of alternative test methods at the European Union level, ECVAM officially opened in October 1994. However, the origins of the Centre stretch back to European legislation passed in 1986, Balls said, specifically Directive 86/609/EEC, an EU law binding on all member states. The two pertinent articles on this "Council Directive on the Approximation of Laws, Regulations and Administrative Provisions of the Member States Regarding the Protection of Animals Used for Experimental and Other Scientific Purposes," are Article 23 and Article 7.

Article 23 states that the Commission and Member States should encourage research into the development and validation of alternative techniques which could provide the same level of information as that obtained in experiments using animals, but which involve fewer animals or which entail less painful procedures, and shall take such other steps as they consider appropriate to encourage research in this field. In general terms, this statement is equivalent to the clauses of the NIH Revitalization Act which mandate replacement, reduction and refinement of animal use in publicly funded research in the United States.

Article 7 (2) of the EU law goes much farther than any U.S. legislation however, stating that an experiment should not be performed (on an animal), if another scientifically satisfactory method of obtaining the result sought, not entailing the use of an animal, is reasonably and practically available. As Professor Balls noted, "ECVAM was set up by the Commission, the European Parliament and the Member States specifically to make replacement alternatives reasonably and practically available. The ECVAM has official support in the 15 countries of the EU is very important."

Equally significant is the substantial sum of money provided to ECVAM to carry out its mission. In addition to funds for staff, infrastructure support and for the maintenance of the newly constructed ECVAM building in Ispra, Italy, ECVAM will have about 3,500,000 ECU ($4,500,000) per year during 1995-1998. These funds are to be used to support laboratory studies and other scientific investigations, workshops and other activities within ECVAM and in the Member States of the EU.

"Support for external projects is given in the form of contracts for 1-2 years. Large contracts are currently being negotiated in the areas of vaccine quality control, potency and safety testing, on the integrated use of non-animal methods in toxicity testing, and on the prevalidation of new test methods," Balls said.

By the fall of 1995, ECVAM will have seven scientists on staff, three technicians and two administrative/support staff members, plus five post-doctoral visitors, four graduate students and two temporary assistants, he reported. Current projects in ECVAM's laboratories include the development of tests for metabolism-mediated toxicity and for toxicity to the hematopoietic system, and the use of embryonal stem cell lines in reproductive toxicology. Investigations are also in progress on the use of human volunteers in cosmetic efficacy and safety testing, on the ethical, legal, scientific and safety issues raised by the production and use of transgenic animals, and on the application of laboratory animal protection laws in the Member States of the EU.

Balls feels that the establishment of ECVAM has had a great impact, not only in Europe but in the United States as well. "First, it contributed to the establishment of ICCVAM (the Interagency Coordinating Committee on the Validation of Alternative Methods), which although it has a different structure and legal basis, has very similar goals. Secondly, a very good relationship is developing between ECVAM and IRAG, both of which have a governmental base. I am sure that there have been a lot more effects, but they are not so obvious from this side of Atlantic."

Balls came to ECVAM from the Nottingham UK-based organization FRAME (Fund for the Replacement of Animals in Medical Experiments), where he served as honorary scientific director and chairman of the Board of Trustees. "I am still closely involved with FRAME and the University of Nottingham," he said. "The freedom to maintain those links was my only condition before accepting an invitation to come to ECVAM."

Balls maintains his chairmanship at FRAME and is an Emeritus Professor at the University of Nottingham. He says that his move to Ispra with its consequent switch from academic advocate for alternatives to government employee has not changed his view of the alternatives scene. "My perspective and my focus have not changed since I work for the Commission which is responsible administering Directive 86/609/EEC, with its great articles 7 and 23."

The crucial step in validating alternative methodologies, he commented, is interlaboratory assessment, which involves a prevalidation study to develop an optimized protocol and establish its transferability, followed by a blind trial with coded test materials and an independent unbiased evaluation of the outcome. The ECVAM laboratories have already been involved in validation studies on phototoxicity and tumor promotion.

Nonetheless, "ECVAM would never by itself be able to provide expertise in all the different types of tests and areas of pharmacotoxicology for which alternative tests and test batteries will be necessary in the years to come," Balls said. For that reason, "collaboration with academic and industrial laboratories, in the Member States and elsewhere, will be essential not only for prevalidation and validation studies, but also for training in the use of particular tests and test batteries and for the diffusion of the principles of validation."

Despite such collaborative efforts, Balls stressed ECVAM's neutrality, commenting that the Centre is independent of any individual, commercial, or financial interests. "ECVAM is committed to support and serve the EU Commission and thereby the EU Member States, the spirit and specific provisions of Directive 86/609/EEC, and the objectives of scientific validation and justifiable regulatory acceptance, and thereby the protection of man, animals and the environment," he said. Balls candidly discussed his perceptions of the limitations of current efforts.

"I think we are making a lot of mistakes in our attempts at validation, for two main reasons. First, we are being too theoretical and idealistic, with the result that we expect too much of the replacement alternative methods and we are being unfair to them. Secondly, we have not (yet) succeeded in persuading others just how awful (scientifically) most of the animal tests are, and how very unscientific is the way the data they provide are used in risk assessment. We must do better, but others must also be made to face up to reality as well," he concluded.

ECVAM has a Scientific Advisory Committee composed of representatives from each of the 15 Member States, COLIPA (the European Cosmetic, Toiletry and Fragrance Association), ECETOC (European Center for the Ecotoxicology and Toxicology of Chemicals), EFPIA (the European Federation of Pharmaceutical Industries Association), ERGATT (the European Research Group for Alternatives in Toxicity Testing), and EUROGROUP for Animal Welfare.

"Since not all the interested parties could possibly be represented on the Scientific Advisory Committee, ECVAM is establishing a wide network of contacts with appropriate individuals and organizations not only in Europe but throughout the world," Balls said. One of those contacts is CAAT, and Balls reported that he is pleased with the "excellent working relationship" which has developed between the two Centers.

Alan M. Goldberg, Ph.D., director of CAAT, and Professor Balls were co-organizers and co-chairs of an ECVAM workshop titled "The Three Rs--The Way Forward," held in Sheringham UK in June 1995. William Russell and Rex Burch, authors of The Principles of Humane Experimental Technique, were among the participants at the workshop. Proceedings of the meeting will be printed in the journal ATLA. More CAAT/ECVAM workshops are planned (including one on cellular and molecular mechanisms of toxicity), and collaborative research projects are being discussed.

Criteria for Determining ECVAM's Priorities

• The numbers of animals used.
• The amount of unavoidablensuffering likely to be caused to them.
• The degree of public and political concern.
• The amount of scientific concern about the relevance or reliablity of the current animal procedures.
• The needs of science and industry.
• The likely availability of potential alternative methods in the foreseeable future.
• The availability of standard test materials (backed by sufficient knowledge of sufficient high quality) for use in validating the alternative methods.
• The likely achievability and acceptability of replacement (or reduction or refinement) strategies.
• The availability of the necessary expertise for pre-validation and validation studies.
• The likely cost of the necessary pre-validation and validation studies, and the availability of the necessary funding.

What's in a Name

ICCVAM (Interagency Coordinating Committee on Validation of Alternative Methods) is an ad hoc group formed in the United States in response to the National Institutes of Health Revitalization Act of 1993. ICCVAM is composed of representatives from 13 U.S. regulatory and research agencies.

Goals:

• To establish unform processes and consistent criteria within the Federal Government that will encourage the development of improved testing methods that will generate data more useful for risk assessment.
• To lead to the scientific evaluation/validation of new and revised test methods.
• To increase the likelihood of acceptance of scientifically valid new and revised test methods.
• To encourage the refinement and reduction of animal use in testing, and the replacement of animals with non-animal methods and/or phylogenetically lower species, when scientifically feasible.