National Toxicology Program

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What does ICCVAM stand for?

ICCVAM (pronounced “ICK-vam”) is an acronym that refers to the Interagency Coordinating Committee on the Validation of Alternative Methods. ICCVAM is made up of representatives from 15 Federal agencies that generate or use toxicological data to carry out their responsibilities to protect and advance the health and safety of people, animals, and the environment.

What agencies are represented on ICCVAM?

• Consumer Product Safety Commission (CPSC)
• Department of Agriculture (USDA)
• Department of Defense (DOD)
• Department of Energy (DOE)
• Department of Health and Human Services
  
  • Centers for Disease Control and Prevention
    
    • Agency for Toxic Substances and Disease Registry (ATSDR)
    • National Institute for Occupational Safety and Health (NIOSH)
  • Food and Drug Administration (FDA)
  • National Institutes of Health (NIH)
    
    • National Cancer Institute (NCI)
    • National Institute of Environmental Health Sciences (NIEHS)
    • National Library of Medicine (NLM)
    • Office of the Director
• Department of the Interior (DOI)
• Department of Labor
  
  • Occupational Safety and Health Administration (OSHA)
• Department of Transportation
• Environmental Protection Agency (EPA)

What is ICCVAM's mission?

ICCVAM's mission is to promote the development, validation, and regulatory acceptance of new, revised, and alternative regulatory safety testing methods. Emphasis is on alternative methods that will reduce, refine (less pain and distress), 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.

The ICCVAM Authorization Act of 2000 states that the purposes of ICCVAM are to:

• Increase the efficiency and effectiveness of Federal agency test method review
• Eliminate duplication of effort between Federal agencies
• Optimize 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 where feasible

To accomplish this, ICCVAM is charged with the following functions:

• Coordinate the technical review and evaluation of new and revised test methods
• Submit ICCVAM test recommendations to appropriate Federal agencies
• Facilitate interagency and international harmonization of test protocols that encourage the reduction, refinement, and replacement of animal test methods
• Facilitate and provide guidance on validation criteria and processes
• Facilitate the acceptance of scientifically valid test methods
• Facilitate awareness of accepted test methods
• Consider petitions from the public for review and evaluation of new and revised test methods for which there is evidence of scientific validity
• Submit ICCVAM recommendations to the Secretary of Health and Human Services for transmittal to appropriate Federal agencies
• Make ICCVAM final test recommendations available to the public
• Prepare reports on ICCVAM progress and accomplishments under the Act and make these available to the public

What is NICEATM?

NICEATM (pronounced “nigh-SEA-tum”) stands for the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods). NICEATM is part of the National Institute of Environmental Health Sciences (NIEHS) located in Research Triangle Park, NC.

What does NICEATM do?

NICEATM administers and provides scientific support for ICCVAM, by:

• Coordinating and supporting meetings of the ICCVAM and its subcommittees and interagency working groups
• Evaluating new test method submissions and nominations for their completeness and adherence to ICCVAM guidelines
• Preparing technical review documents to evaluate the validity of new, revised, and alternative methods
• Working with ICCVAM to organize scientific workshops and independent scientific peer review meetings
• Assembling information about current best practices for the humane care and use of animals in toxicological research and testing
• Facilitating communication among agencies, between agencies and test method developers, and between ICCVAM and its stakeholders
• Conducting independent validation studies on high priority alternative test methods

What is the relationship between NICEATM and ICCVAM?

ICCVAM is an interagency committee that meets several times a year. ICCVAM does not conduct validation studies.

NICEATM provides assistance and coordinates the activities that ICCVAM requires to evaluate and make recommendations regarding new, revised, and alternative test methods.

What is the role of NICEATM and ICCVAM in gaining regulatory acceptance of new and alternative test methods?

NICEATM and ICCVAM assess the validation status of new, revised and alternative safety testing methods to determine their usefulness and limitations for testing purposes. ICCVAM then transmits recommendations to Federal agencies regarding appropriate uses of these methods based on their scientific validity. Each Federal agency then determines whether the test methods are acceptable for their respective programs. Agencies must respond to ICCVAM recommendations within 180 days after receiving them.

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What are alternative toxicity test methods?

Alternative toxicity test methods are test methods that, reduce, refine or replace animal use in regulatory toxicity testing. Reduction, refinement, and replacement are commonly referred to as “the 3Rs of alternatives”. The 3Rs concept was first described by William Russell and Rex Burch in their book, The Principles of Humane Experimental Technique, published in 1959.

What does "refine, reduce, or replace” or the “3Rs,” mean in terms of animal use for regulatory toxicity testing?

• A test method that refines animal use lessens or eliminates pain or distress in animals, or enhances animal well-being.
• A test method that reduces animal use decreases the number of animals required for testing while still obtaining the testing objectives.
• A test method that replaces animals substitutes animals with nonanimal systems, or replaces one animal species with a less highly developed one (for example, replacing a mouse with a fish).
• Reduction, refinement and replacement alternatives are commonly referred to as the "3Rs" of alternatives.

Why are animals still used for safety testing?

Consumer products, medicines, and industrial and agricultural chemicals must be adequately tested in order to identify potential hazards. U.S. regulatory agencies that use toxicity test data are responsible for protecting human and animal health and the environment. To carry out this mission, agencies require that all toxicity test methods used for regulatory purposes be based on sound science and be able to accurately represent hazards.

Human and animal responses to toxicants are complex, and difficult to accurately assess using in vitro systems or computer models. The term in vitro refers to experiments performed in laboratory containers, such as test tubes or petri dishes, with living tissues, organs, or cells obtained from animals or people. No single in vitro test method is currently available to serve all regulatory needs for a specific testing area. Rather, integrated approaches using alternative test methods, conventional animal testing, and other information about the properties of a test substance are used to accurately assess hazards.

Are scientists required to consider alternative methods before they use animals for testing?

Yes, U.S. laws require that alternatives must be considered before using animals for research and testing. These laws are based on 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. Institutional Animal Care and Use Committees must approve proposed animal use, and ensure that alternatives are being used where appropriate.

Are Federal agencies that use toxicity data required to support the development of alternative test methods?

Federal agencies view the reduction, refinement and replacement of animal use as a priority. Both the NTP Roadmap for the 21st Century and the National Research Council’s Vision and Strategy of Toxicity Testing in the 21st Century emphasize the goal of ensuring that new and improved test methods reduce, refine, or replace the use of animals where scientifically feasible.

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Who can make test method nominations and submissions?

NICEATM and ICCVAM welcome nominations of relevant new, revised and alternative test methods from any of its stakeholders, including government agencies, academics, companies developing new test methods and animal welfare organizations. Test method sponsors 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.

How does ICCVAM prioritize test method evaluations?

A sponsor or nominator submits a test method for evaluation to NICEATM following ICCVAM submission guidelines. NICEATM then assesses the completeness and performs a preliminary evaluation of the test method nomination or submission. This evaluation takes into consideration:

• The extent to which the proposed test method applies to the testing needs of regulatory agencies or programs
• The potential for the proposed test method to refine, reduce or replace animal use
• The potential for the proposed test method to improve the prediction of adverse health or environmental effects
• Other advantages offered by the proposed test method, such as reduced cost or performance time

ICCVAM reviews the NICEATM preliminary evaluation and makes draft recommendations regarding evaluation activities to be carried out and their priority. Draft recommendations are made available to SACATM and the public for comment.

How are alternative test methods evaluated to determine whether they are valid for use?

They are studied to determine their usefulness and limitations for a specific proposed purpose. This involves validation studies to assess their reliability and relevance. Reliability is the degree to which a test method can be performed reproducibly within and among laboratories over time. Relevance is the extent to which a test method correctly predicts or measures the biological effect of interest in humans or another species of interest. Test methods need to be sufficiently relevant and reliable in order to be used for safety testing.

What has ICCVAM accomplished in the last 10 years?

ICCVAM has evaluated over 185 test methods in the areas of acute oral toxicity, biologics testing, developmental toxicity (birth defects), endocrine disruptors, eye corrosion and irritation, pyrogenicity, skin corrosion and allergic contact dermatitis. (View a table summarizing ICCVAM's test method evaluations.) In each of these areas, ICCVAM’s evaluation has included a review of the usefulness and limitations of the test method, and recommendations about current uses, further validation studies, or further development of the test method. ICCVAM recommendations to Federal agencies have resulted or will result in the reduction, refinement and replacement of animal use in the areas of acute oral toxicity, eye corrosion and irritation, skin corrosion, and skin sensitization.

How has ICCVAM’s work reduced, refined or replaced animal use in toxicology testing?

ICCVAM’s recommendations to Federal agencies include:

• Changing the standard animal tests used to assess acute oral systemic toxicity (poisoning) to reduce the number of animals used for this purpose by over 70%
• Using toxicity assays employing cultured cells to set starting doses for the standard animal tests for acute oral systemic toxicity testing, in order to further reduce the number of animals required for each test.
• Using cellular models that simulate human skin to assess the potential of acids, bases and acid derivatives to cause chemical burns (corrosion) to skin
• Replacing a guinea pig test to assess the potential of substances to cause allergic contact dermatitis with a mouse method that uses fewer animals and refines the test method to eliminate pain and distress
• Using assays employing tissue from isolated cow or chicken eyes to screen chemicals and products for their potential to cause blindness or other severe eye injuries, rather than performing these tests on live animals; positive substances do not require testing on live animals

These recommendations have reduced the number of animals used for these types of toxicity testing, refined animal use to lessen or avoid animal pain and distress, and are expected to further reduce animal use in the future.

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Who are ICCVAM's stakeholders?

ICCVAM's stakeholders are any person or organization that uses, develops or has an interest in toxicological test methods or the data that is generated from toxicological testing. They include:

• U.S. Federal agencies that generate toxicological data
• U.S. Federal agencies that require or use toxicological data
• Agencies within governments of other countries that use or generate toxicological data
• Researchers and Institutional Animal Care and Use Committee (IACUC) members in companies or research institutions that perform toxicological testing
• Companies that develop toxicological tests
• Animal welfare organizations
• Consumer protection organizations
• The public

What is the relationship between ICCVAM and U.S. Federal agencies?

ICCVAM and its working groups are made up of representatives from 15 Federal agencies that generate or use toxicological data to carry out their functions. These scientists review and evaluate new and revised test methods, facilitate interagency and international harmonization of test methods, and coordinate cross-agency issues relating to the development, validation and acceptance of new and revised test methods.

How does ICCVAM communicate with its stakeholders?

ICCVAM announces activities and requests input from its stakeholders by publication of notices in the Federal Register, posting announcements on its website and sending emails to members of the ICCVAM-all listserv mailing list. ICCVAM also actively participates in national and international meetings by presenting results from their many different review activities.

How does the public know what ICCVAM has accomplished?

The NICEATM-ICCVAM website has pages giving overviews of all ongoing and past activities, and will soon feature a mechanism for reviewing updates for ongoing activities. More detailed information about ICCVAM's accomplishments and activities are provided in the ICCVAM Biennial Progress Reports. These reports, along with all other NICEATM publications, are available in PDF format on the website. Paper copies are also available for most reports upon request.

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Why is ICCVAM publishing a Five-Year Plan?

ICCVAM prepared the Five-Year Plan in response to requests from the Appropriations Committees of the U.S. House of Representatives and U.S. Senate. The Committees requested that ICCVAM:

• Work with relevant Federal agencies to create a five-year plan to research, develop, translate and validate new and revised non-animal and other alternative assays for integration of relevant and reliable methods into the Federal agency testing programs
• Identify areas of high priority for development of such assays
• Encourage public input in the development of the plan

What testing areas of high priority have NICEATM and ICCVAM identified in the Five-Year Plan?

Using the criteria outlined above, NICEATM and ICCVAM have identified ocular toxicity, dermal toxicity, acute toxicity, and biologics as the highest-priority testing areas for development of new and revised non-animal and other alternative assays. Other priority testing areas include immunotoxicity, endocrine disruptors, pyrogenicity, reproductive and developmental toxicity, and chronic toxicity and carcinogenicity. Neurotoxicity testing is also an area of interest. While these represent current priorities and interests, ICCVAM and NICEATM recognize that planning must be flexible in order to take advantage of advances in science and technology and to respond to new testing needs.

Does the Five-Year Plan identify emerging technologies that could be utilized to develop new test methods and approaches to reduce, refine or replace animal use in toxicity testing?

Yes. The Plan describes how the following technologies might be used to develop new test methods and approaches to toxicity testing:

• High-throughput screening
• Non-mammalian animal systems
• Computational approaches
• Toxicity biomarkers
• Development of high-quality toxicology databases

What will ICCVAM do to promote the use of alternative test methods?

NICEATM and ICCVAM will provide high quality comprehensive test method background review documents and the results of independent scientific peer reviews to support the approval of new, revised, and alternative test methods by regulatory agencies and the international community. Once an alternative test method has been accepted, ICCVAM will work to promote the use of the test method by sponsoring and participating in training workshops and scientific meetings to reach interested stakeholders who may want to use or consider data from the test method.

Does the Five-Year Plan discuss how ICCVAM can strengthen interactions with its stakeholders?

Yes. The Plan describes ICCVAM’s strategy to strengthen interaction with its stakeholders, including:

• Being proactive in identifying research needs and emerging methods that should be priorities for further development, translation, validation or ICCVAM evaluation
• Facilitating collaboration among Federal research and regulatory agencies, including opportunities for test method validation activities
• Collaborating with governmental and non-governmental organizations to co-sponsor workshops to evaluate the state-of-the-science and identify high priority activities to advance development and validation of alternative toxicological test methods
• Fostering international collaboration in the development of international best practices for test method evaluations
• Participating in the development of performance standards for international test guidelines to promote development of innovative improvements to accepted test methods

What were the opportunities for public involvement during development of the Five-Year Plan?

The process for development of the plan included three phases: information gathering, development of a preliminary draft and development of a final draft. NICEATM requested comments from the public via Federal Register notices published in the first and second phases. On June 11, 2007, after the publication of the preliminary draft, a town meeting was held specifically to allow an opportunity for public comment. Public meetings of ICCVAM’s scientific advisory committee during the first and second phases, and of the NTP Board of Scientific Counselors during the second phase, provided additional opportunities for public comment. All comments received from the public during the development of the Five-Year Plan can be viewed on the NICEATM-ICCVAM website.

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