Efforts to Validate Alternatives Stall in Europe, Surge in U.S.By Deborah Rudacille In recent months, the unhurried but methodical science-based approach of U.S. regulatory authorities appears to have overtaken the dramatic legislatively-driven attempts of European Union (E.U.) officials to validate alternatives to animal testing. In the E.U., parliamentary efforts to implement a market ban on animal testing of cosmetics and their ingredients have become mired in international trade restrictions and E.U. politics, according to sources in Europe. Dr. Mark Matfield, director of the European Biomedical Research Association, told a U.S. research audience in March 1997 that the revolutionary 6th amendment to the European Cosmetics Directive (passed in 1993), which legislated a European ban on such testing after January 1, 1998, will likely be scrapped in favor of a 7th amendment, which addresses restraint-of-trade issues and evolving technology more cautiously than the sweeping 6th amendment. This assessment is echoed by animal protection groups in Europe. "The European Commission directive banning cosmetics tested on animals remains in limbo," according to the Winter 1997 National Anti-Vivisection Society (NAVS) Campaigner. "...There are problems with the future progress of the proposal because of the World Trade Organization (WTO). In previous rulings, the WTO has not allowed trade bans which are based purely on the way a product is produced." Rory Macmillan, communication and information manager for COLIPA, the European Cosmetic, Toiletry and Perfumery Association, confirmed that member states have voted for a delay in implementing the ban on animal testing of cosmetic ingredients, while also indicating that the commission is considering a 7th Amendment that may ban the testing of finished products on animals "except in cases where there is a serious safety issue." Until the commission and member states are able to craft a compromise which does not violate international trade agreements, "we're at a stalemate," he said. Meanwhile, the U.S. approach, with its rejection of legislatively-imposed deadlines and emphasis on extensive data-gathering and consensus-building, has resulted in a set of criteria for the validation of alternative methods from the Interagency Coordinating Committee for the Validation of Alternative Methods (ICCVAM), an ad hoc committee with members from 16 key U.S. scientific and regulatory agencies. The ICCVAM committee, which includes representatives from the National Institutes of Health; FDA; EPA; Departments of Agriculture, Labor, Interior, Energy, Defense, Transportation; and the Consumer Products Safety Commission, met monthly from September 1994 to October 1996 to develop a draft report on criteria for the regulatory acceptance of new test methods. ICCVAM's report was created after a thorough review of current literature on toxicology and testing methods, assistance from scientists at federal agencies and from the public (via comments in response to a Federal Register notice). A workshop on "Validation and Regulatory Acceptance of Alternative Test Methods," held in December 1995 in Arlington, Virginia to review the draft of ICCVAM's report, generated further comments and recommendations from industry, academic scientists and public interest groups. "We got a very enthusiastic response, not only within this country, but from the international community," commented William S. Stokes, D.V.M., ICCVAM co-chair. "The draft report was significantly improved as a result of the recommendations offered by those who attended the NTP workshop (at Arlington)." The draft report was also discussed at a workshop on "Harmonization of Validation Criteria for Alternative Test Methods" sponsored by the Organization for Economic Cooperation and Development (OECD), in Sweden in January 1996. The goal of OECD is to establish global testing guidelines applicable to all chemicals and exposures. The comments and recommendations of scientists attending the 1996 OECD alternatives workshop in Sweden were considered by ICCVAM in creating the final draft of its report. Stokes said that ICCVAM's work was greatly facilitated by "the enormous amount of work which had been done prior to the committee's formation by groups like CAAT and IRAG in the United States and ERGATT and FRAME in Europe, in discussing issues related to validation. The committee's job was made much easier because of those people and organizations, and we extensively referenced their work on validation in the report." Validation, a scientific process which attempts to prove the reliability and relevance of alternative tests, has proven a difficult hurdle for developers of new methodologies. Although the animal tests mandated by law throughout the world have for the most part never been formally validated or rigorously evaluated by the same standards now demanded of alternative tests, regulators say that a 50-year history of safety and protection of public health itself constitutes validation of animal testing. Results of traditional whole animal tests are mathematically evaluated and, via a series of complex calculations based upon body weight, metabolism and other variables, extrapolated to humans. Some tests, such as the now defunct LD50 and the much less commonly performed Draize eye test, were criticized by scientists for years before activist campaigns added a new impetus for change. But developing workable replacements and convincing cautious regulatory officials that new tests will protect the health and safety of the public presents a daunting series of challenges. New ingredients used in cosmetics, and finished products based upon new formulations or combinations of chemicals, may sometimes require testing for a number of endpoints, including eye and skin irritation and sensitization, systemic toxicity (effect on organ systems throughout the body), photosensitivity (effect on the skin when exposed to UV light), and percutaneous absorption (ability to penetrate skin). Larger cosmetic and personal care companies, committed to the development of new and innovative products, tend to find it more difficult to implement animal testing bans than smaller concerns, which generally use ingredients known to be safe through previous animal testing and years of use. Nonetheless, the number of companies relying on animal testing to insure product safety has steadily diminished over the past decade, with those who still use animals greatly reducing both the number of animals and the invasiveness of procedures. A strategy called "tier-testing," a multi-layered process of evaluation which includes database searches, computer modeling and in vitro or test-tube studies, is typically used by industry before animal testing is even considered. Many observers believe that the failure of the 6th amendment to the E.U. Cosmetics Directive Indicates the weakness of legislatively-driven efforts to force regulatory change. "You can't legislate good science," commented one U.S. researcher. Others believe that the effort was doomed from the start and that the European lawmakers who crafted the amendment knew that it was in violation of GATT (General Agreement on Trade and Tariffs) and would be unable to withstand pressure by the World Trade Organization. The European Union is now the biggest economic market in the world -- any legislation which reduces fair trade and competition there faces a fierce battle from multinational corporations which must carry out some animal tests to meet regulatory guidelines in other nations and from governments where federal officials are not convinced alternative tests will protect public health and insure safety. "It is true that the latest GATT agreement does make things more difficult," commented Professor Michael Balls, head of the European Center for the Validation of Alternative Methods (ECVAM). "However I don't think that the E.U. will have to be more cautious. More realistic would be a better way of putting it. If anything, the postponement of the ban will increase the urgency of the search for alternatives." ICCVAM co-chair Stokes believes that the European legislation was handicapped by the lack of a thorough assessment of existing methodologies. "When you sit back and look at the process, developing new methodologies, validating them and moving them into regulatory review...that process has typically taken at least ten years. When the legislation (6th amendment to the Cosmetics Directive) was passed in Europe, I think there was a perception that the methods were much further along than they were." ICCVAM's guidelines may offer a way to satisfy both the innate caution of regulators and the impatience of activists and those consumers who would like industry to renounce animal testing once and for all. For U.S. cosmetics and personal care companies, which have monitored events in Europe carefully, the failure of the European legislation and the success of the U.S. approach signifies the importance of science-based efforts to develop and validate alternatives. "The key to developing alternatives to animals in toxicity testing is enhancing understanding of basic biology and mechanisms of toxicity," said Alan M. Goldberg, Ph.D., director of the Johns Hopkins Center for Alternatives to Animal Testing (CAAT), which has been largely funded by the cosmetics and personal care industry since its founding in 1981. Goldberg pointed out that the recent creation of a Subcommittee on Toxicology at the U.S. Food and Drug Administration, charged with reviewing the agency's testing policies, is another sign of progress. In February 1994, an advisory science board at FDA recommended that the agency assess its toxicity and carcinogenicity testing protocols to determine if FDA practices "reflect evolving scientific understanding, and to recommend changes if necessary, to yield the best science upon which to make regulatory and consumer protection decisions." The FDA Subcommittee on Toxicology was formed in 1996 to carry out this work. "We are trying to set a model of cooperation and interaction between all interested parties, trying to eliminate the traditional barrier between the regulatory community and private sector," said Neil L. Wilcox, D.N.V., M.P.H., Special Assistant to the Associate Commissioner for Science at FDA. "There is no organization or component within the arena of hazard identification and safety testing that can work within its own box anymore. The days of these separate components working independently within the same arena are over, because shrinking resources no longer permit that kind of independence." Wilcox commented that FDA's evaluation of its testing strategies "couldn't come at a better time" because they coincide with the formalization of ICCVAM's status as a permanent committee. "With ICCVAM about to become a reality, together with FDA efforts, we have real momentum to encourage development of new methods, coupled with a strong sense and message that this will result in better predictive models," Wilcox said. "The whole approach is a pragmatic way to get better data based upon good science by targeting endpoints in the species of interest, which is usually human being." | 
