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

Conference Highlights: NTP Workshop on Validation and Regulatory Acceptance of Alternative Toxicological Testing Methods

By William S. Stokes, D.V.M.

An NTP Workshop on Validation and Regulatory Acceptance of Alternative Toxicological Test Methods was held in Arlington, Virginia on December 11-12, 1995. The workshop was sponsored by the National Institute of Environmental Health Sciences and the National Toxicology Program, and was organized by the ad hoc Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM). The ICCVAM is composed of representatives from 15 federal regulatory and research agencies and programs that generate or use information from toxicological testing for human health or environmental risk assessment. Agencies represented include the ATSDR, USDA, CPSC, DOD, DOE, DOI, DOT, EPA, FDA, NIOSH, NIH, OSHA, NCI, NLM, and the NIEHS.

The purpose of the workshop was to receive comments and recommendations from the public and invited experts on the draft ICCVAM report, Validation and Regulatory Acceptance of Toxicological Test Methods, that was developed by representatives from the 15 Federal regulatory and research agencies. The draft report described proposed criteria and processes for the validation and regulatory acceptance of new and revised toxicological testing methods. The draft report was developed in response to directives in the NIH Revitalization Act of 1993 (Public Law No. 103-43), which also directed NIEHS to develop and validate improved alternative toxicological testing methods.

The stated goals of the ICCVAM report were to:

• Communicate the criteria and processes that Federal agencies should employ in considering new and revised test methods.
• Encourage the development of new methods and improvement of existing test methods.
• Provide effective guidance for scientists and regulatory staff for the validation and evaluation of new and revised test methods.
• Contribute to the increased likelihood of regulatory acceptance of scientifically valid new and revised test methods.
• Encourage, when scientifically feasible, the reduction and refinement of animal use in testing, and the replacement of animals with non-animal methods and phylogenetically lower species.
• Encourage the use of validated and accepted new and revised test methods.

The workshop was attended by over 130 scientists and other interested stakeholders from industry, academia, government, animal welfare and public interest organizations, and included participants from nine countries.

Forty-nine scientists from industry, academia, public interest groups, international organizations and state and federal government participated as invited expert reviewers. Dr. Kenneth Olden, director of the NIEHS and the NTP, opened the workshop by emphasizing the need for new toxicological testing methods that will provide for improved predictions of toxicity and thereby enhance the protection of public health and the environment.

He also stressed the need for test methods that can be conducted with less expense and time. Dr. George Lucier, director of the Environmental Toxicology Program at NIEHS, provided an overview of the National Toxicology Program and noted the importance of achieving regulatory acceptance of new methods in order for such methods to be used for human health risk assessment. Dr. Richard Hill, co-chair of the ICCVAM and EPA Science Advisor, reviewed current federal toxicological testing activities, which are conducted by at least 12 different agencies with widely divergent purposes and for a broad range of products, including consumer products, pesticides, industrial chemicals, pharmaceuticals and biologicals.

Dr. William Stokes, ICCVAM co-chair and associate director for alternative and animal resources at NIEHS, provided an overview of the ICCVAM process leading to development of the draft report and charged the three breakout groups to provide constructive reviews and recommendations.

The Validation Breakout Group, co-chaired by Drs. David Brusick and Warren Schaeffer, reviewed the proposed chapter on validation criteria that discussed scientific assessment of the reliability and relevance of new and revised toxicological testing methods. The Regulatory Acceptance Criteria and Processes Breakout Group, chaired by Dr. Steve Niemi, discussed the proposed process for determining the acceptability of test methods for regulatory use, and assessed the adequacy of the criteria for regulatory acceptance.

The role of groups inside and outside of government in evaluating the status of validated methods was also discussed. The Proposals for Future Directions Breakout Group, chaired by Patricia Williams, developed implementation strategies for the processes of validation and regulatory acceptance of test methods, and addressed how industry, government, academe and public interest groups can work together both nationally and internationally to more efficiently develop, validate and adopt new improved testing methods for regulatory use. Drs. Oliver Flint, Lorraine Twerdok and Penelope Fenner-Crisp served as the executive secretaries for the three breakout groups, respectively.

The groups generally agreed that the criteria and guidance for validation and regulatory acceptance of new testing methods provided in the draft report would be useful to both government and non-government scientists, including regulatory scientists. Suggestions were provided to improve the clarity and format of the document. Other selected workshop recommendations included:

1. Involvement and communication among all stakeholders (developers, users, regulators and the public) are essential at all stages of the process leading to regulatory acceptance of alternative methods, including development, validation and review.
2. The current ad hoc Interagency Coordinating Committee on Validation of Alternative Methods (ICCVAM) or its equivalent should be sustained by establishment of a standing permanent committee that would facilitate communication and provide administrative guidance to the validation and acceptance process. Proposed functions included:
   • Provide an interagency clearinghouse to coordinate review of new methods and their data submissions with appropriate agencies.
   • Provide a critical communication link to government and non-government stakeholders at various stages of the process.
   • Foster interagency as well as international harmonization.
   • Determine regulatory need and relevance of proposed new methods at all stages of development and validation.
   • Provide guidance on validation criteria and processes, and maintain a link between method developers and regulators.
   • Facilitate domestic and international communication, coordination and sharing of information during development, validation, review and acceptance of new methods.
   • Promote awareness of accepted methods. It was recommended:
     1. that the committee include official representation, technical competence and animal welfare advocacy from federal research and regulatory agencies;
     2. that the committee be established and empowered through NIEHS/NTP within two months after ICCVAM Final Report issuance; and
     3. that financial resources be provided to support the committee.
3. Alternative methods should be considered for acceptance if they are adequate in terms of biological relevance and regulatory utility, and generate data at least equivalent for hazard identification and/or dose-response assessment purposes as the established method.
4. Consideration of reduction, refinement and replacement of animal use must be formally included as regulatory acceptance criteria for proposed new test methods.
5. Existing and proposed testing regulations, test methods and alternatives should be readily available on the Internet at a single location.
6. Periodic regulatory review and revision of test methods should be established.
7. International harmonization of test methods should be sought.

Following the presentations and discussion of the conclusions and recommendations of the three workgroups, brief presentations were made by several of the attendees during the public comment session. The comments indicated broad support from all stakeholders for the workshop recommendations and conclusions. Following the NTP Workshop, the Organization for Economic and Cooperation and Development (OECD) conducted a Workshop on Harmonization of Validation and Acceptance Criteria for Alternative Toxicological Test Methods in Solna, Sweden, on January 22-24, 1996. The draft ICCVAM report and the draft NTP workshop report served as background working documents. The OECD workshop report will be available in late spring and it is anticipated that an OECD guidance document will be developed to serve as an international reference on this subject.

The recommendations and comments from both the NTP and OECD workshops will be considered by the ICCVAM in revising the draft ICCVAM report, and the NTP workshop report will be incorporated as an appendix in the final ICCVAM report. The final ICCVAM report is anticipated to be completed later this year, and availability will be announced in the Federal Register. Both the NTP workshop report and the draft ICCVAM report are available from the NTP Liaison Office; copies can be requested by contacting the Office at (919) 541-0530 Fax: (919) 541-0295 e-mail: lange@niehs.nih.gov. If you have questions or comments about the ICCVAM, you may contact the co-chairs, Dr. William S. Stokes, NIEHS at 919-541-7997, or email at stokes@niehs.nih.gov, or Dr. Richard Hill, EPA, at 202-260-2897, or e-mail at hill.richard@epamail.epa.gov.