Development of Alternatives to Animal Use for Safety Testing and Hazard Assessment, continued.

Summary Problem Background/History Animal protection Toxicology and Safety Testing The Process of Change Implementation Definition	Motivation to Adopt In Vitro Testing and SAR: Two Models Obstacles to Implementation Validation International Controversy Current Challenges Literature Review/Bibliography
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Validation

A final, but necessary, obstacle to the implementation of alternative methodologies has been the need to validate new tests. Validation is an important theoretical construct which has proven difficult to translate into practical terms. The generally accepted definition of validation is “the process by which the credibility of a candidate test is established for a specific purpose with reliability and reproducibility verified.” The key words in this definition are “reliability,” and “reproducibility.” In order to be accepted as a replacement for an animal model, a validated non-animal test must be shown to be easily implemented in a variety of laboratories, and able to produce consistent credible results with few false positives or negatives. In other words, companies and regulatory agencies must feel certain that the new test or tests will provide them with trustworthy data that they can use to assess hazard and risk. Although this appears on first glance to be a relatively simple endeavor, creating a process through which the reliability and reproducibility of new tests can be established has proven a complex and difficult task.

As early as 1990, John M. Frazier, Associate Director of the Johns Hopkins Center for Alternatives to Animal Testing, was asked by the OECD to prepare a report on “Scientific Criteria for Validation of In Vitro Toxicity Tests” (Frazier, 1990). Later that year, CAAT and the European Research Group for Alternatives to Animal Testing (ERGATT) conducted a workshop January 8-12, 1990 in Amden Switzerland. The report published following the meeting identified validation as an issue “of crucial significance.” Recognizing that “although most scientists have an inherent concept of what constitutes the validation of test procedures, the scientific basis and the necessary components of this process have never been fully described in a formal exposition,” participants at the workshop reiterated key elements of the Frazier monograph, identifying essential features of the validation process. Even at that early stage, many of the issues which were to hamstring future efforts to validate alternative tests were recognized as potential problems. The workshop’s first three recommendations in particular were only superficially addressed over the next six years in various validation studies, some of them quite ambitious and expensive.

1) The purpose of a validation study should be fully defined, particularly in relation to the level of assessment (toxic potential, toxic potency, hazard or risk) and in relation to the type of test required (screening, adjunct or replacement), the type of toxicity to be evaluated, and the chemical spectrum of interest.

2) Tests should only be considered for inclusion in validation studies, if the specific purposes for which they have been developed are well-defined and are consistent with the overall objectives of the validation study.

3) Tests must have been adequately developed, standardized and documented, and a need for them in relation to the availability of other tests must exist, before they should be considered eligible for validation. (Balls, Blaauboer, Brusick et al., 1990)

As academic toxicologists, regulatory officials and industry attempted to work out a process which could prove the efficacy and efficiency of newly developed tests, political pressures began to build for legislative bans on animal testing. In Europe the pressures were particularly intense and in 1993, the Council of Ministers to the European Communities passed a piece of legislation commonly known as the “Cosmetics Directive” which banned “the marketing in Europe of cosmetic products or ingredients tested on animals after January 1, 1998, unless alternative methods are insufficiently validated.” At around the same time, the European Union (EU) established the European Center for the Validation of Alternative Methodologies (ECVAM) in Ispra, Italy to facilitate the process of validation.

These developments in Europe were greeted with apprehension in the U.S. and Canada. Both regulatory officials and scientists in industry and academia in North America thought that the European ban was premature--an attempt to force science to conform to politics. Validation studies in progress were methodologically flawed, critics charged, because they failed to conform to the rigorous standards which were established as early as the Amden meeting. Pressured by the Cosmetics Directive and the rapidly looming deadline, companies and national governments labored to validate acceptable tests and failed -- partially because the validation studies were indeed flawed and partially because the science of in vitro toxicology was in its infancy and the first generation of tests proposed for validation were incapable of fulfilling the ambitious role in safety testing promised by their advocates. For five years, expensive validation projects in Europe produced profoundly ambiguous results. In the end, the Cosmetics Directive fell victim to GATT, the international trade agreement, and was never implemented. The ban on animal tests was ruled an example of a trade restriction that unfairly favored certain nations and so despite its strong support by EU nations, it could not be implemented.

The focus on validation then shifted to the U.S., where a more cautious, scientifically- based approach has prevailed. An ad hoc group of regulatory officials who called themselves IRAG, (the Interagency Regulatory Alternatives Group), had by 1995 been succeeded by ICCVAM (the Interagency Coordinating Committee on the Validation of Alternative Methods). While IRAG was composed of self-nominated members from only 3 federal agencies--the Food and Drug Administration (FDA), Environmental Protection Agency (EPA) and the Consumer Product Safety Commission (CPSC)--ICCVAM by federal mandate includes members from 13 regulatory and research agencies. Its goals are to encourage the development of improved testing methods that will generate data more useful for risk assessment; lead to the scientific evaluation/validation of new and revised test methods; increase the likelihood of acceptance of scientifically valid new and revised test methods; and 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.

By late 1999, two methods had been evaluated by ICCVAM and subsequently accepted by the U.S. Food and Drug Administration, Environmental Protection Agency, Consumer Product Safety Commission, and Occupational Safety and Health Administration. The methods re the local lymph node assay for guinea pig hypersensitization and Corrositex, a biochemical assay. Both tests are replacements for the Draize test for skin irritation.