National Toxicology Program

Plan Overview	Preface
Executive Summary	Introduction
CHAPTER 1 - Research, Development, Translation, and Validation Activities for Priority Test Methods to Reduce, Refine, and Replace Animals in Regulatory Testing
CHAPTER 2 - Incorporating New Science and Technology
CHAPTER 3 - Fostering Acceptance and Appropriate Use of Alternative Test Methods
CHAPTER 4 - Developing Partnerships and Strengthening Interactions with ICCVAM Stakeholders
References - Acronyms and Abbreviations - Glossary	Appendices
Acknowledgements - ICCVAM Roster - About NICEATM and ICCVAM

Introduction

This document, prepared by the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) and the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), in partnership with relevant Federal agency program offices, describes a five-year plan to:

• Research, develop, translate¹, and validate new and revised non-animal and other alternative assays for integration of relevant and reliable methods into Federal agency testing programs
• Identify areas of high priority for new and revised non-animal and alternative assays or batteries of those assays to create a path forward for the replacement, reduction, and refinement of animal tests, when this is scientifically valid and appropriate

An overall goal is for ICCVAM to assume a greater leadership role in promoting research, development, translation, validation, and regulatory acceptance of alternative test methods. This five-year plan builds on the ICCVAM mission, vision, and strategic priorities (ICCVAM 2004; see Appendix A) to help NICEATM and ICCVAM achieve greater progress and to inform the public of their plans and approaches. The plan also builds on the NTP’s Roadmap for the Future, which includes the goal of developing and validating improved testing methods and, where scientifically feasible, to ensure that these methods reduce, refine, or replace the use of animals. The Roadmap also specifies that activities and assays developed under the NTP Roadmap will be conducted in cooperation and consultation with ICCVAM to maximize their value to regulatory agencies.

The Mission and Strategic Priorities of NICEATM and ICCVAM: as outlined in the “ICCVAM Mission, Vision and Strategic Priorities” (February 2004): ICCVAM’s Mission: “To facilitate development, validation and regulatory acceptance of new and revised regulatory test methods that reduce, refine and replace the use of animals in testing while maintaining and promoting scientific quality and the protection of human health, animal health and the environment.” Strategic Priorities: Set priorities for evaluating test methods and carry out the reviews Facilitate collaborative scientific validation internationally Stimulate development of priority test methods and strategies Foster appropriate use of validated test methods Strengthen ICCVAM capability and sustainability Strengthen interaction with ICCVAM stakeholders

Building on the NTP Roadmap for the 21st Century Goal 2 of the Roadmap: “Develop and validate improved testing methods and, where feasible, ensure that they reduce, refine, or replace the use of animals.” From page 7: “Activities and assays developed under the NTP Roadmap will be done in cooperation and consultation with the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) to maximize their value to regulatory agencies.

Background

U.S. regulatory agencies are charged with protecting human and animal health and the environment (Appendix B). As part of this mission, agencies need to determine whether adverse effects might result from exposures to substances such as pesticides, consumer products, medicines, medical devices, workplace chemicals, food additives, or contaminants in air, food, or water. Many of the current test methods for evaluating hazards and risks from exposure to such substances use laboratory animals. Federal agencies require that all test methods should be based on sound science. According to the ICCVAM Authorization Act of 2000 (see Appendix E), new, revised, and alternative test methods must be determined to be valid for their proposed use before agencies can adopt them for regulatory purposes. Validation is required to determine if the use of an alternative test method, compared to current methods or approaches, can provide equal or better protection of human and animal health and the environment.

U.S. laws (42 USC 289d, 7 USC 2131 et. seq.) require that alternatives be considered before using animals for research and testing². Such alternatives include new or revised test methods that:

• Reduce the number of animals to the minimum required to obtain scientifically valid data
• Refine procedures to lessen or eliminate pain and distress to animals
• Replace animals with non-animal systems or one animal species with a phylogenetically lower animal species

Reduction, refinement, and replacement alternatives are commonly referred to as “the 3Rs” of alternatives.

The U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training are the foundation for the 1985 Animal Welfare Act amendment and the Public Health Service (PHS) Policy on the Humane Care and Use of Laboratory Animals. Key provisions include: The animals selected for a procedure should be of an appropriate species and quality and the minimum number required to obtain valid results. Methods such as mathematical models, computer simulation, and in vitro biological systems should be considered. Proper use of animals, including the avoidance or minimization of discomfort, distress, and pain when consistent with sound scientific practices, is imperative. Unless the contrary is established, investigators should consider that procedures that cause pain or distress in human beings may cause pain or distress in other animals. Procedures with animals that cause more than momentary pain or distress should be performed with appropriate sedation, analgesia, or anesthesia. Surgical or other painful procedures should not be performed on unanesthetized animals paralyzed by chemical agents. Animals that would otherwise suffer severe or chronic pain or distress that cannot be relieved should be painlessly killed at the end of the procedure, or, if appropriate, during the procedure.

The Role of ICCVAM and NICEATM

ICCVAM³ is a permanent interagency committee administered by the National Institute of Environmental Health Sciences (NIEHS) under NICEATM and is composed of members from 15 Federal agencies. The mission of ICCVAM is to facilitate development, validation, and regulatory acceptance of new, revised, and alternative test methods that reduce, refine, and replace the use of animals in testing while maintaining and promoting scientific quality and the protection of human health, animal health, and the environment.

To fulfill this mission, NICEATM and ICCVAM work with a broad range of stakeholders, including Federal agencies, national and international validation and test guideline organizations, industry, academia, and the animal welfare community. Many Federal agencies and other organizations conduct research that could ultimately result in the development and validation of an alternative test method for regulatory use. Thus, ICCVAM depends on its many stakeholders to conduct and achieve successful test method research, development, translation, and validation. These test methods can then be evaluated by ICCVAM for potential regulatory use. These interactions have resulted in the review of 185 test methods by NICEATM and ICCVAM (Appendix F). To date, ICCVAM and NICEATM have developed recommendations for ICCVAM member agencies on alternative methods for the four most commonly used toxicity tests.

The following chapters outline the NICEATM-ICCVAM five-year plan by describing the ongoing and planned activities for priority areas directed at reducing, refining, and replacing animal use in regulatory testing. This is followed by a summary of new science and technology being pursued by ICCVAM member agencies as promising approaches to alternative test method development and testing strategies. Finally, the mechanisms for fostering acceptance and appropriate use of alternative test methods and developing partnerships with stakeholders are described.

Footnotes

¹ ICCVAM considers test method translation activities as those that are carried out to characterize if there is evidence of relevance and applicability of a test method for a specific testing purpose. If so, then the test method may be considered for further evaluation in a formal validation study.

² This concept is integral to the U.S. Government Principles for the Utilization and Care of Vertebrate Animals Used in Testing, Research, and Training, which are incorporated in the Public Health Service Policy on Humane Care and Use of Laboratory Animals.

³ ICCVAM, a Federally mandated interagency committee, provides recommendations to Federal agencies about the scientific validity and usefulness and limitations of proposed test methods. Agencies are required to consider ICCVAM test method recommendations and make decisions on their acceptability. ICCVAM seeks to advance test methods that will ensure the protection of human and animal health and the environment while advancing animal welfare. It does so by facilitating the research, development, translation, and validation activities for alternative methods.