CAAT Newsletter: Vol. 13, No. 3, Summer 1996

OECD Workshop on Harmonization of Validation and Acceptance Criteria for Alternative Toxicological Test Methods

Summary of OECD Working Group 3: Validation of Testing Strategies and Proposed Strategies for Eye and Skin Irritation and Phototoxicity

By Katherine Stitzel, D.V.M.

This group was chaired by Drs. Katherine Stitzel, (Procter & Gamble) and Phil Botham (Zeneca). Rapporteurs were Drs. Nils-Gunnar Lindquist (Swedish National Chemicals Inspectorate) and Wolfgang Pape (Beyersdorf AG).

This working group first spent nearly a full day developing a set of general principles for the development and validation of testing strategies. The term testing strategies referred in general to an orderly sequence of tests used to determine the hazard of a new material. Beginning with a very long list of suggestions, the group agreed on the following general principles:

• Testing strategies should be carefully thought through and organized to provide a reasoned flow of studies, maximize the use of existing knowledge, minimize use and suffering of animals, optimize use of resources and ensure that data and information are mutually supportive and internally consistent. In addition, as new and better test methods are developed, older guidelines should be deleted as they become outdated or redundant.
• Strategies must be developed with risk assessment and regulatory needs in mind.
• The tests within a testing strategy should each be validated for the specific endpoints the test will address. For each test within the strategy, the variability and predictive capacity must be defined. A tier testing strategy does not need to be, nor should it be, validated but the entire strategy should be carefully peer reviewed.
• Whenever possible toxicity tests, including those used in a testing strategy, should be based on known and relevant mechanisms of action.
• Include consideration of all existing information including structure activity and structure property data before doing any animal testing. The group believed that SAR and SPR programs could be validated. Validated programs could be used to determine both negative and positive endpoints without further testing.
• Give preference to tests that relate specifically to the target species. For human endpoints, this includes validation based on human results and the use of human tissue for in vitro assays.
• Perform tests so that in addition to predicting adverse effects they also provide dose-response information that may be used in risk assessment.
• Give preference to those procedures that are less stressful and use fewer animals. Whenever possible valid non-animal alternatives should be used.
• Where ethically possible, encourage testing in humans at an appropriate point in the test strategy. Human testing must be governed by the principles of the Helsinki Agreement.
• Development of testing strategies by OECD will be aided by harmonization of classification schemes.
• Tests within a strategy may be valid for only certain classes of materials. Where possible different tests covering all classes of materials should be identified. Where this is not possible, the strategy may be different for different classes of materials depending upon the validated tests that are available. The group identified the process of defining classes of chemicals as an unmet need that should be addressed by the entire scientific community in the near future.
• The use of empirical tests should not be excluded especially as screens.

After developing these principles and recommendations the workshop developed possible tier testing strategies for eye irritation, skin irritation and phototoxicity. The group strongly believed all tests within each strategy must be validated; this principle must be applied to any animal test as well as to non-animal tests. The strategies also reflected our belief that appropriately validated non-animal methods can be used to identify both negative and positive results and no confirmatory animal testing is necessary after using an appropriately validated non-animal method. Each strategy included consideration of the use of valid non-animal alternative methods, but since no such methods have yet been identified the strategies also include limited, but necessary, animal testing.

Dr. Stitzel is associate director, Miami Valley Laboratories, Procter & Gamble.