US governmental and private centers specializing in the validation of in vitro, in silico or alternative methods to reduce, refine and/or replace the use of animals in regulatory toxicology include the following:
Interagency Coordinating Committee on the Validation of Alternative Methods/NTP Interagency Center for the Evaluation of Alternative Toxicological Methods
The Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) was established as a temporary advisory body under the NIH Revitalization Act of 1993, which sought multi-agency input into a federal plan to "conduct or support research into the [3Rs]; for establishing the validity and reliability of [3Rs methods]; for encouraging the acceptance by the scientific community of such methods that have been found to be valid and reliable; and for training scientists in the use of such methods..." In 2000, the ICCVAM Authorization Act (42 U.S.C. 285l-3) established ICCVAM as a permanent interagency committee, administered by the NTP Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) at the National Institute of Environmental Health Sciences (NIEHS). NICEATM is charged with providing administrative and scientific support to ICCVAM, including the review of test method nominations, organization of peer reviews and workshops, and communication with ICCVAM stakeholders.
Composition: ICCVAM is comprised of the following 15 US federal regulatory and research agencies:
- Agency for Toxic Substances and Disease Registry (ATSDR)
- Consumer Product Safety Commission (CPSC)
- Department of Agriculture (USDA)
- Department of Defense (DoD)
- Department of Energy (DOE)
- Department of the Interior (DOI)
- Department of Transportation (DOT)
- Environmental Protection Agency (EPA)
- Food and Drug Administration (FDA)
- National Cancer Institute (NCI)
- National Institute of Environmental Health Sciences (NIEHS)
- National Institute of Occupational Safety and Health (NIOSH)
- National Institutes of Health (NIH)
- National Library of Medicine (NLM)
- Occupational Safety and Health Administration (OSHA)
Validation & Acceptance Criteria: ICCVAM criteria for test method validity and regulatory acceptance have been articulated in the following documents:
Statutory Mandate: ICCVAM's mandate under law is to:
- "increase the efficiency and effectiveness of Federal agency test method review;"
- "eliminate unnecessary duplicative efforts and share experiences between Federal regulatory agencies;"
- "optimize utilization of scientific expertise outside the U.S. Federal Government"
- "ensure that new and revised test methods are validated to meet the needs of Federal agencies; and"
- "reduce, refine, or replace the use of animals in testing, where feasible."
In contrast to its European counterpart, the European Centre for the Validation of Alternative Methods (ECVAM), ICCVAM is not mandated to participate directly in test method pre-validation or validation, per se. Rather, ICCVAM is responsible for coordinating the technical review and evaluation of new and revised test methods, as appropriate, and for facilitating US acceptance of scientifically valid test methods. For example, in the case of a new or revised toxicity test that has undergone validation but has not already been peer reviewed elsewhere, ICCVAM may convene a panel of expert scientists to independently evaluate the test's relevance and reliability according to ICCVAM validation criteria and provide recommendations regarding the regulatory context(s) in which it can be used to reduce, refine or replace animal use.
If the conclusions and recommendations of an expert panel favor the regulatory use of a particular alternative method, and if ICCVAM concurs, draft test method recommendations will be published in the Federal Register for public review and comment. The ICCVAM Authorization Act requires that final test recommendations be forwarded to federal agencies, which are obligated to review and respond to such recommendations within six months.
Past & Future Activities: To date, ICCVAM-NICEATM have evaluated 3Rs methods germane to the following toxicological endpoints and/or regulatory sectors: acute oral toxicity, biologics, developmental toxicity, endocrine disruption, eye corrosion/irritation, genetic toxicity, pyrogenicity, skin corrosion, and skin sensitization. In 2007, ICCVAM-NICEATM were directed by Congress to develop 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 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."
Scientific Advisory Committee: Pursuant to the ICCVAM Authorization Act, a Scientific Advisory Committee on Alternative Toxicological Methods (SACATM) was created to advise ICCVAM, NICEATM and the NIEHS Director regarding "priorities and activates related to the development, validation, scientific review, regulatory acceptance, implementation, and national and international harmonization of new, revised, and alternative toxicological test methods." SACATM operates under the rules of the Federal Advisory Committee Act, and includes representation from state government, academia, industry and the animal protection community.
Institute for In Vitro Sciences
The Institute for In Vitro Sciences (IIVS) is a technology-driven charitable organization created to advance the development, validation and use of in vitro methods in toxicology. Since its founding in 1997, IIVS has come to be recognized as a leading national and international authority on the 3Rs and toxicology through the following program activities:
- Laboratory services: IIVS contract testing services provide "rapid, high quality in vitro testing for broad sectors of industry and government" in the areas of skin and eye irritation/corrosivity, phototoxicity, embryotoxicity, percutaneous absorption, basal cytotoxicity, and other specialized areas where feasible.
- Assay development and validation: IIVS "develops custom, cell-based assays measuring efficacy/potency of specialty chemicals, drugs, and biologics" and "has experience in managing programs for optimization of assay systems ... and in managing prevalidation and validation projects for groups of companies interested in bringing a system forward for regulatory acceptance." IIVS has served as a participating laboratory in multiple prevalidation and validation efforts, and is currently a member of the EU integrated project ACuteTox, which aims to optimize and prevalidate an in vitro testing strategy for predicting acute toxicity in humans.
- Education and training: IIVS provides its clients and other stakeholders with a range of education and training opportunities, including hands-on practical demonstrations designed for new users, as well as more involved "technical workshops" and "user groups" of experts in a particular assay. The goal of all IIVS outreach efforts is "to improve and expedite in vitro method development and validation through cooperation, exchange of information, and training."
- Advocacy: IIVS also "strives to coordinate various efforts taking place in the field nationally and harmonize them with international activities." To this end, IIVS representatives have been appointed to a range of US federal advisory committees and international scientific task forces.
International QSAR Foundation to Reduce Animal Testing
Established in 2004 by a former US Environmental Protection Agency senior scientist and program manager, the International QSAR Foundation (IQF) is currently the only charitable research entity working to develop quantitative structure-activity relationship ((Q)SAR) and other in silico models as non-animal alternatives for identifying chemical hazards. The stated mission of the IQF is "to serve as a focal point on non-testing alternative methods to:
- build a scientific consensus on the best approaches to predict the outcomes of animal tests;
- make quality data from past animal tests more accessible to scientists throughout the world;
- create new methods to predict chemical hazards which currently can not be adequately predicted
- demonstrate the reliability of QSAR-based methods in setting priorities for use of testing alternatives."
Central to the Foundation's consensus-building mission is the organization of focused workshops to bring together experts from the regulatory, regulated, academic, and other stakeholder communities to identify barriers to the acceptance of alternative approaches, as well as priorities for research to overcome these barriers. To this end, IQF devotes at least half of its research budget to targeted project grants, particularly in the following key areas: inhalation toxicity, aquatic toxicity, skin and lung sensitization, reproductive toxicity, environmental persistence and bioaccumulation potential.
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