Alternative test methods are methods that replace, reduce, or refine animal use in research and testing, a concept first described by William Russell and Rex Burch in their 1959 book The Principles of Humane Experimental Technique. Alternative test methods:
- Replace animals by substituting non-animal systems, such as computer models or biochemical or cell-based systems, for traditional animal models, or replace one animal species with a less highly developed one (for example, replacing a mouse with a worm)
- Reduce animal use by decreasing the number of animals required for testing while still achieving scientifically valid testing objectives
- Refine animal use by decreasing or eliminating pain or distress in animals or enhancing animal well-being
Chemical Safety Testing and Animal Use
Why is safety testing performed on chemical products?
Regulatory agencies require testing of consumer products, medicines, and industrial and agricultural chemicals to identify potential health and safety hazards. Testing these substances informs appropriate hazard classification and labeling, which in turn enables responsible use, storage, and disposal decisions.
Why are animals used for safety testing?
Human and animal responses to chemicals are complex and difficult to accurately assess using only biochemical or cell-based (in vitro) systems or computer models. In some areas, such as identification of eye irritants or substances that may cause allergic skin reactions, major progress has been made in reducing and replacing animal use. Identification of other hazards such as those causing cancer or birth defects is more difficult because of the biological complexity of the processes involved.
Are there requirements to consider alternative methods before using animals for testing?
Yes, but only to a limited extent. U.S. laws require that alternatives must be considered before using animals for research and testing under specific circumstances.
- The Animal Welfare Act requires that facilities using animals for research and testing have Institutional Animal Care and Use Committees. These committees review and approve proposals for animal use, and ensure that alternatives are being used whenever appropriate. However, the most commonly used species for toxicity testing—rats, mice, and birds—are not covered under the Animal Welfare Act and are therefore not subject to these requirements.
- The Public Health Service (PHS) Policy on Humane Care and Use of Laboratory Animals addresses the use of animals by NIH grantees and within NIH and other PHS institutions. The PHS Policy requires that proposals justify:
- Use of animals
- Number of animals used
- Specific procedures used
Are federal agencies required to support the development of alternative test methods?
Yes, the following U.S. laws require federal agencies to support the development of alternative test methods:
- The NIH Revitalization Act of 1993 directed NIH to support research to replace, reduce, and refine animal use in biomedical research, and to develop and validate methods that will reduce and replace animals in acute and chronic safety testing.
- The ICCVAM Authorization Act of 2000 established the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) to coordinate activities within the federal government relevant to new test method evaluation, acceptance, and use. ICCVAM is made up of representatives of 16 U.S. federal agencies that use or generate toxicity testing information.
- The Frank R. Lautenberg Chemical Safety for the 21st Century Act directed the Administrator of the Environmental Protection Agency to “reduce and replace, to the extent practicable, scientifically justified, and consistent with the policies of this title, the use of vertebrate animals in the testing of chemical substances.”
What NIEHS is Doing to Support Alternatives Development?
NIEHS is an ICCVAM member institution and supports the development and use of alternative methods by:
- Adhering to the PHS Policy requirements
- Funding grants that support development and validation of alternative methods
- Participating in the U.S. government’s Tox 21 interagency high throughput screening initiative
- Participating in the activities of the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM)
- ICCVAM member institution
What is NICEATM?
NICEATM is an office within the NIEHS Division of the National Toxicology Program. The office has three federal employees:
Warren Casey, Ph.D.
Director – NICEATM
P.O. Box 12233Mail Drop K2-16Durham, N.C. 27709
Nicole Kleinstreuer, Ph.D.
Deputy Director - NICEATM
530 Davis Dr
Durham, NC 27713
Elizabeth Maull, Ph.D.
Toxicologist; Program Administrator
P.O. Box 12233Mail Drop K2-17Durham, N.C. 27709
Additional NICEATM support is provided through a NIEHS contractor.
NICEATM’s activities include:
- Supporting NIEHS and NTP activities, especially those contributing to Tox21
- Conducting evaluations and coordinating independent validation studies of novel and high-priority alternative test methods and approaches
- Providing information to test method developers, regulators, and regulated industries through its website and email list and by sponsoring workshops on topics relevant to alternative test methods
- Providing scientific and operational support to ICCVAM
- NTP Interagency Center for the Evaluation of Alternative Toxicological Methods
- Small Business Innovation Research and Small Business Technology Transfer Grants
National Toxicology Program Website
- NTP Interagency Center for the Evaluation of Alternative Toxicological Methods
- About ICCVAM
- ICCVAM Annual and Biennial Reports
- Alternative Methods Accepted by U.S. Agencies
- NICEATM and ICCVAM Meetings and Workshops
- Strategic Roadmap: New Approaches to Evaluate the Safety of Chemicals and Medical Products
What is ICCVAM?
ICCVAM was established by the ICCVAM Authorization Act of 2000 to:
- Increase the efficiency and effectiveness of federal agency test method review
- Eliminate duplication of effort between federal agencies
- Optimize the use of scientific expertise outside the federal government
- Ensure that new and revised test methods are validated to meet the needs of federal agencies
- Reduce, refine, and/or replace the use of animals in testing whenever feasible
How does ICCVAM accomplish its mandate as articulated in the ICCVAM Authorization Act?
To accomplish its mandate, ICCVAM is charged with the following:
- Coordinate the technical review and evaluation of new, revised, or alternative test methods
- Foster interagency and international harmonization of test protocols that encourage reducing, refining, and replacing animal test methods
- Facilitate and provide guidance on validation criteria and processes
- Promote the acceptance of scientifically valid test methods
- Promote awareness of accepted test methods
- Submit ICCVAM test recommendations to appropriate U.S. federal agencies
- Consider requests from the public to review and evaluate new, revised, or alternative test methods that have evidence of scientific validity
- Make ICCVAM final test recommendations available to the public
- Prepare and make available to the public reports on ICCVAM progress and accomplishments under the Act
Who are ICCVAM’s members?
ICCVAM is made up of one or more federal employees from each of the following Federal agencies or offices.
- Agency for Toxic Substances and Disease Registry
- Consumer Product Safety Commission
- Department of Agriculture
- Department of Defense
- Department of Energy
- Department of the Interior
- Department of Transportation
- Environmental Protection Agency
- Food and Drug Administration
- National Institute for Occupational Safety and Health
- National Institutes of Health
- National Cancer Institute
- National Institute of Environmental Health Sciences
- National Library of Medicine
- Occupational Safety and Health Administration
- National Institute of Standards and Technology
Employees of these agencies are selected to serve on ICCVAM because they are knowledgeable about their agency’s activities or requirements relevant to safety testing. ICCVAM members attend monthly ICCVAM committee meetings or teleconferences and engage in other ICCVAM activities in addition to their other duties within their agencies.
Alternative Methods Research and Validation
Does ICCVAM or NICEATM conduct alternative methods research or validation studies?
No. ICCVAM is an interagency committee that meets monthly. NICEATM activities include data curation, computational method development, and test method evaluation, but NICEATM has no laboratory facilities and does not conduct validation studies. ICCVAM depends on stakeholders with appropriate capabilities and resources to carry out alternative test method research, development, and validation studies, the results of which are submitted to ICCVAM for review and comment.
Who are ICCVAM's stakeholders?
ICCVAM's stakeholders are any person or organization that uses, develops, or has an interest in toxicity testing methods or the data that is generated from toxicity testing. They include:
- U.S. federal agencies that generate or use toxicity data
- Agencies within U.S. state governments or governments of other countries that use or generate toxicity data
- Researchers and Institutional Animal Care and Use Committee members in companies or research institutions that perform toxicity testing
- Companies that develop toxicity tests for sale
- Animal welfare organizations
- Consumer protection organizations
- Any member of the public interested in human and environmental health and related animal welfare issues
What is the role of NICEATM and ICCVAM in gaining regulatory acceptance of new and alternative test methods?
When a test method is submitted to ICCVAM for a formal evaluation, NICEATM and ICCVAM work together to evaluate that method’s usefulness and limitations for specific testing purposes.
- ICCVAM develops recommendations for federal agencies regarding appropriate uses of the method. Each federal agency determines whether the test method is acceptable for its specific program.
- ICCVAM reviews and issues opinions on test methods that have been evaluated by validation organizations in other countries.
- ICCVAM agencies work together and independently to identify alternative tests or, in some cases, non-testing approaches that can replace or reduce animal use for required testing.
See “Progress and Plans” below for examples of these activities.
Outreach and Interactions
How do ICCVAM and NICEATM communicate with their stakeholders?
ICCVAM and NICEATM communicate with their stakeholders through:
- Publication of
- Federal Register notices
- ICCVAM Biennial Report (mandated by the ICCVAM Authorization Act)
- Peer-reviewed journal articles
- Pages on the National Toxicology Program’s website
- NICEATM News email list
- NTP Update email list
- Presentations of their activities at national and international scientific meetings
- Workshops and webinars on topics of relevance to alternative models and the 3Rs concept
- Interactions of ICCVAM agency members with their international counterparts through the International Cooperation on Alternative Test Methods and the Organisation for Economic Co-operation and Development
- Three annual ICCVAM-sponsored events, open to the public, which enable direct public interaction with ICCVAM:
- Communities of Practice webinars, usually held in January, feature experts presenting on current topics in alternative methods development.
- Public Forums, usually held in May, include updates from ICCVAM agencies on their activities relevant to alternative test method development.
- Meetings of the Scientific Advisory Committee on Alternative Toxicological Methods (SACATM), usually held in the fall, provide an opportunity for in-depth discussion of topics relevant to ICCVAM activities. SACATM is made up of representatives from various ICCVAM stakeholder groups and advises the NIEHS Director, NICEATM, and ICCVAM about NICEATM and ICCVAM activities.
Stakeholders are invited to ask questions and submit comments on relevant topics at the Public Forum and SACATM meeting.
Who can submit test methods for evaluation by ICCVAM?
ICCVAM welcomes submissions of relevant new, revised, and alternative test methods from any of its stakeholders. However, to maximize the potential for effective implementation of new methods or approaches, ICCVAM only evaluates and prepares recommendations for methods and approaches that align with ICCVAM agency needs and priorities. Therefore, test method developers are encouraged to consult with NICEATM and ICCVAM throughout the test method research, development, translation, and validation process, as well as during preparation of submissions. These interactions ensure that:
- The test method aligns with the needs and priorities of one or more ICCVAM agencies, and there is at least one agency willing to sponsor the test method for evaluation
- Test method validation studies adequately characterize the method’s usefulness and limitations for a specific regulatory application
- The test method submission contains the necessary data and information required by the sponsoring agencies to determine if a test method can generate information that will meet their regulatory needs
A list of funding opportunities supporting these activities is available on the NICEATM website.
Progress and Plans
How has ICCVAM's work replaced, reduced, or refined animal use in toxicity testing?
ICCVAM has evaluated many alternative methods for regulatory use and made a number of formal recommendations to federal agencies, including:
- The use of cell culture assays to inform the starting doses for animal tests, reducing the overall animal use
- An alternative approach to the standard acute oral systemic toxicity (poisoning) animal test that reduces the number of animals used
- Nonanimal models that simulate human skin to assess the potential of chemicals to cause skin burns
- Assays employing animal tissues to screen chemicals and products for their potential to cause blindness or other severe eye injuries; substances that test positive do not require testing on live animals
ICCVAM has also issued opinions on tests evaluated by the European Union Reference Laboratory for Alternatives to Animal Testing, including tests to identify substances that may cause allergic skin reactions.
ICCVAM agencies work independently or together to reduce animal use for testing.
- The Environmental Protection Agency (EPA) and NICEATM collaborated to develop and validate an approach that combines data from 18 high throughput screening assays with a computational model to identify chemicals with the potential to interact with the estrogen receptor.
- EPA and NICEATM conducted a data analysis that supported EPA guidance enabling data waivers for acute dermal studies for formulated products, reducing the numbers of animals needed for required acute toxicity testing.
Other agency activities supporting alternative methods development or reducing animal use for required testing are described in agency presentations at ICCVAM Public Forums:
- ICCVAM Public Forum: May 2017
- ICCVAM Public Forum: May 2016
- ICCVAM Public Forum: May 2015
- ICCVAM Public Forum: June 2014
What is ICCVAM doing to encourage application of new technologies to required toxicity testing?
In support of NIH Director Francis Collins’ comment that nonanimal testing approaches would replace animal safety testing of environmental chemicals and medical products within the next ten years, ICCVAM is coordinating the development of a strategic U.S. roadmap that incorporates new approaches into safety testing of chemicals and medical products. For the United States, this roadmap will lay out a plan to:
- Facilitate the development and use of new approaches for evaluating the safety of chemicals and medical products
- Increase our confidence in alternative methods
- Demonstrate the relevance of alternative methods to human health
- Maintain the commitment to replace, reduce, and refine animal use
Federal agencies, the regulated community, and interested stakeholders will work together to explore new approaches for evaluating the safety of chemicals and medical products within the United States while collaborating with international partners to facilitate global harmonization of new testing approaches.
SACATM identified the roadmap as a priority activity in 2015, and the roadmap was the primary discussion topic at the 2016 SACATM meeting. Activities are taking place throughout 2017 to solicit stakeholder input for the roadmap, which is scheduled for release in December 2017.
Environmental Factor (NIEHS Newsletter)
- Advancing Computer Models That Predict Toxicity (May 2018)
- New Cells Better Mimic Human Heart for Chemical, Drug Testing (May 2018)
- Scientists Invited to Build Computer Models That Predict Toxicity (December 2017)
- International Meeting Highlights NTP Efforts to Replace Animal Tests (September 2017)
- New Technologies Highlighted at Toxicology Meetings (August 2017)
- Public Forum on Alternatives to Animal Testing Highlights Next Steps (June 2017)
- NIEHS Grantee Validates Tissue Chips for Toxicity Testing (March 2017)
- Kleinstreuer Receives Lush Prize Young Researcher Award (December 2016)
- New Initiative to Modernize Regulatory Toxicity Testing (November 2016)
- Experts Address the Challenge of Inhalation Toxicity Testing (sidebar article, November 2016)
- Plan to Replace Animal Use Shared at Public Forum (July 2016)
- Kleinstreuer Highlights Groundbreaking Approaches to Safety Testing (June 2016)
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