Validation and Acceptance Status of Alternatives

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In the Spotlight

Validation and Acceptance Status of Alternatives

Martin L. Stephens, Center for Alternatives to Animal Testing, and Nina S. Mak, Alternatives Research and Development Foundation

Published:June 1, 2014

Editor’s note: A new book co-edited by David Allen and Mike D. Waters, “Reducing, Refining and Replacing the Use of Animals in Toxicity Testing” (Royal Society of Chemistry, 2014), provides an overview of the state of technology and policy governing the use of non-animal alternatives in toxicity testing. founder and Management Team member, Martin L. Stephens, along with co-author Nina S. Mak, contributed the opening chapter, “History of the 3Rs in Toxicity Testing: From Russell and Burch to 21st Century Toxicology.”  With the generous permission of the Royal Society of Chemistry, we are pleased to feature this excerpt (section 1.5.1, “Validation and Acceptance Status of Alternatives”) from their chapter.  A Table and references available in the text are not included in this brief excerpt.

In vitro and other alternative tests have a long history of use in corporate decision-making about chemical safety and product formulation. However, for many years such testing was not necessarily considered definitive in the regulatory context. Corporations would often follow up on their alternative testing with the historical animal-based methods. Validation – the formal assessment of the relevance and reliability of a test method for a particular purpose – came to be considered a prerequisite for regulatory use of alternatives.

Moreover, validation needed to be followed by a declaration of regulatory acceptance by the relevant government agencies, as a way of encouraging industry to use the validated tests and submit data based on them. Indeed, the need for successful validation and regulatory acceptance are written into U.S. law through the ICCVAM Authorization Act of 2000.

New and modified assays that have been validated and accepted for regulatory use are listed in Table 1.7 [note: the information in Table 1.7, omitted here, is based on AltTox’s Table of Validated and Accepted Alternative Methods]. A number of patterns can be discerned. First, most of the assessments of validation status and regulatory acceptance have occurred since 2000, following the establishment of key alternatives centers (Table 1.5) and the development of the principles and procedures of validation and regulatory acceptance (see Section 1.4.3). Second, the bulk of this effort has been invested in replacement alternatives (full or partial), with acute systemic toxicity and skin sensitization being notable exceptions. This activity has been driven, in part, by the ban on animal testing for cosmetic ingredients, pursuant to the European Cosmetics Directive.

Much of what we might term “toxicological space” has been touched by alternative methods. This is especially true for acute toxicity endpoints, where replacement alternatives have become available for skin penetration, skin corrosion, skin irritation, and phototoxicity. However, the challenge of replacing animal use for chronic endpoints is much more formidable. One prominent effort addressing the challenge of alternatives to chronic toxicity testing is the SEURAT program, a multi-million Euro partnership between the cosmetics industry and the European Union. A roadmap for replacing animals in chronic and systemic toxicity testing has been published recently.

Of course, validation and regulatory acceptance of new methods do not necessarily ensure full implementation of those methods in all cases, so the degree of implementation and any barriers to implementation would need to be addressed in a more definitive analysis of the impact of alternative methods on toxicology.

What would Russell and Burch themselves have made of the record of achievement as reflected in Table 1.7? Rex Burch died in 1996 and William Russell in 2006, but their writings and statements towards the end of their lives suggest their pride in what their pioneering book set in motion. Of course, much remains to be done, with formidable challenges ahead (see Section 1.6).

Editor’s Note: AltTox’s “Table of Validated and Accepted Alternative Methods,” the topic of the book section presented above, was originally created in 2006 and is updated several times per year to reflect the current state of alternative test methods available for regulatory use. The validation authorities, ECVAM, ICCVAM, and JaCVAM, each provide table(s) showing the status of methods they have reviewed, however, the AltTox table is the only place where information from all of the …CVAMs is integrated into one table.