The goal of this contract is to provide support of the National Toxicology Program (NTP) hazard assessment activities targeted toward the prevention of diseases or adverse effects caused by environmental exposure to chemical or physical agents. An overall goal is for the National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) and the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) to assume a greater leadership role in promoting research, development, translation, validation, and regulatory acceptance of alternative test methods. The five-year plan builds on the ICCVAM mission of facilitating the 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. The mission, vision, and strategic priorities will help NICEATM and ICCVAM achieve greater progress and inform the public of their plans and approaches. The plan also builds on the NTP's Roadmap for the 21st Century, 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. U.S. regulatory agencies are charged with protecting human and animal health and the environment. 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 to contaminants in air, food, or water. Many of the current test methods for evaluating hazard and risk assessments 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, 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. Currently, the four highest priorities are ocular toxicity, dermal toxicity, acute toxicity, and biologics. Other priority areas include immunotoxicity, endocrine disruption, pyrogen testing, reproductive/developmental toxicity, and chronic toxicity/carcinogenicity. These priorities will likely evolve over time in response to new testing needs and advances in science and technology. The inherent complexity of human and animal responses to toxicants means that it is unlikely that any single alternative test method will be able to serve all regulatory needs for a specific testing area. Rather, integrated approaches using batteries of two or more alternative test methods combined with other information about the properties of a test substance will likely be needed to significantly reduce or replace the use of animals for each type of testing. As outlined below, these integrated approaches are being investigated for a number of different toxicity testing areas. Such approaches may be critical to the development of successful hazard assessment methodologies for complex endpoints such as carcinogenicity or reproductive/developmental toxicity, which can result from effects on many different pathways. A priority for each of the areas identified below is the collection and use of available human, animal, and ecological data to assess the performance of existing and new test methods for protecting human and animal health and the environment. Ocular Toxicity Testing The evaluation of alternative methods for ocular (eye) safety testing is one of ICCVAM's four highest priorities because it is required by multiple agencies as one of the four most commonly required product safety tests and can therefore involve large numbers of animals, and because rabbits used in tests to identify ocular hazards can experience significant pain and distress when eye injuries occur. Regulatory agencies require identification of potential ocular hazards to warn consumers and workers when exposure to a chemical or product may cause blinding or other kinds of eye damage. Prevention of eye injury is of great importance to human health. Two critically important goals are the replacement of the rabbit eye test with one or more alternative assay(s) that can provide equal or greater prediction of these types of hazards, and the implementation of procedures to avoid pain and distress where animals must still be used. NICEATM and ICCVAM recently evaluated and recommended two in vitro test methods that can be used to identify certain types of substances that cause permanent and severe eye damage and that do not use animals. NICEATM and ICCVAM will carry out activities to improve the usefulness and applicability of these test methods. In addition, in collaboration with the European Centre for the Validation of Alternative Methods (ECVAM), NICEATM and ICCVAM will evaluate the use of these and other in vitro test methods for accurately identifying substances that cause reversible eye damage or that do not damage the eye. NICEATM and ICCVAM will also evaluate in vitro approaches for determining the ocular irritation potential of antimicrobial cleaning product formulations, and will facilitate the submission of in vivo reference data to be added to a database for use in expanding the development and applicability of new alternative ocular test methods for prevention of eye injury. NICEATM and ICCVAM recently organized scientific symposia on ?Mechanisms of Chemically-Induced Ocular Injury and Recovery,? and ?Minimizing Pain and Distress in Ocular Toxicity Testing.? Symposia recommendations for relevant research, development, and validation studies have been provided to the scientific and regulatory communities for consideration. NICEATM and ICCVAM will encourage stakeholders to carry out the recommended studies, and will evaluate new methods or combinations of in vitro test methods that are developed to reduce or replace animal use for corrosivity and irritation testing. In addition, a comprehensive review of the use of topical anesthetics and systemic analgesics for reducing pain and distress will be conducted to determine their applicability in ocular testing. Biologics Testing Biological products (commonly referred to as biologics) include vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, monoclonal antibodies, and recombinant therapeutic proteins that are used to treat or protect humans or animals. Biologics testing is also one of ICCVAM's four highest priorities because it can require large numbers of animals that may experience significant pain and distress during testing, and it is required by multiple agencies. As such, it is important to identify in vitro alternatives to the current in vivo tests that provide equal or greater protection of human or animal health, and to identify procedures that can be used to reduce or avoid pain and distress where animals must still be used. Alternative test methods are under development that target reduction and replacement of animal testing with in vitro test methods, as well as refinement of animal testing through modifications to the current animal tests. To facilitate the development of these types of alternatives, ICCVAM, NICEATM, and ECVAM recently co-sponsored a workshop that identified activities needed to further reduce, refine, and replace the use of mice for determining the effectiveness of a biologic product. NICEATM and ICCVAM will evaluate alternative test methods and testing strategies for vaccine potency testing and will facilitate the acceptance of adequately validated test methods and humane endpoints found to be sufficiently accurate and reliable. A priority for evaluation will be an in vitro vaccine-related potency test being developed by the USDA to reduce the numbers of animals required to evaluate the potency of a common veterinary bacterial vaccine for Leptospirosis. Dermal Toxicity Testing The evaluation and development of alternatives for dermal (skin) safety testing is also one of ICCVAM's four highest priorities because it is required by multiple agencies as one of the four most commonly required product safety tests and therefore can involve large numbers of animals, and because rabbits used in tests to identify dermal hazards can experience significant pain and distress. Regulatory agencies require identification of dermal hazards to warn consumers and workers when exposure to a chemical or product may cause skin injury (permanent scarring/burns) or irritation. This information is used to determine appropriate precautions needed to avoid such unintentional injury. Test results are also used to determine appropriate packaging to minimize dangerous spills during transport. ICCVAM's ultimate goal in this area is the replacement of the rabbit skin test for both corrosivity and irritation with alternative methods that meet the requirements of U.S. regulators. In vitro alternatives for dermal corrosivity have been developed, and several of these test methods have been recommended and accepted for regulatory use as screening methods. In appropriate circumstances, substances yielding positive results can be classified and labeled as corrosives without the use of animals. The National Toxicology Program's Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM) and ICCVAM will evaluate alternative dermal irritation test methods for their usefulness and limitations in U.S. regulatory testing. This will include an evaluation of the use of a combination of in vitro test methods for both corrosivity and irritation to reduce or replace animals. NICEATM and ICCVAM will also evaluate non-animal methods and approaches for determining the skin irritation potential of antimicrobial cleaning products.