SUPPORT CONTRACT FOR THE NTP INTERAGENCY CENTER/VALIDATION OF ALT METHODS

NTP 跨机构中心的支持合同/替代方法的验证

• 批准号: 8328465
• 负责人: DAVID ALLEN
• 金额: $ 355.17万
• 依托单位: INTEGRATED LABORATORY SYSTEMS, LLC
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-16 至 2012-04-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8328465
• 关键词: Academy; Accidents; Acute; Address; Adopted; Adoption; Adverse effects; Agreement; Air; Allergic Contact Dermatitis; American; Analgesics; Anesthetics; Animal Testing; Animals; Area; Authorization documentation; Biological Assay; Biological Markers; Canada; Carcinogenicity Tests; Categories; Cattle; Cavia; Charge; Chemicals; Chickens; Chronic; Classification; Collaborations; Communication; Computer Simulation; Consultations; Contracts; Corneal Opacity; Corrosion; Data; Dermal; Development; Distress; Dose; Drug Administration Schedule; Educational workshop; Endocrine Disruptors; Ensure; Environment; Environmental Exposure; Environmental Health; European; European Union; Evaluation; Exposure to; Eye; Eye Injuries; Five-Year Plans; Food; Food Additives; Fostering; Future; Goals; Guidelines; Hazard Assessment; Health; Home environment; Household; Household Products; Housing; Human; In Vitro; Informatics; Injury; Interagency Coordinating Committee on the Validation of Alternative Methods; International; International Cooperation; Irritants; Japan; Japanese Population; Laboratory Animals; Laws; Leadership; Life; Link; Local Lymph Node Assay; Medical; Medical Device; Medicine; Methods; Mission; Mus; National Institute for Occupational Safety and Health; National Institute of Environmental Health Sciences; National Toxicology Program; Occupations; Ophthalmology; Oral; Oryctolagus cuniculus; Pain; Peer Review; Permeability; Pesticides; Protocols documentation; Public Health; Publications; Published Comment; Recommendation; Research; Risk Assessment; Role; Safety; Science; Scientific Advances and Accomplishments; Scientist; Screening procedure; Skin; Source; Specific qualifier value; Support Contracts; Techniques; Technology; Testing; TimeLine; Toxic effect; Toxicity Tests; Translating; Translations; United States; United States Environmental Protection Agency; Vaccines; Validation; Vision; Visual impairment; Water; Weight; Work; Workplace; absorption; animal pain; antimicrobial; authority; base; chorioallantoic membrane; consumer product; design; disorder prevention; egg; hazard; high throughput screening; humane endpoint; immunotoxicity; improved; in vitro testing; in vivo; innovation; irritation; meetings; member; method development; new technology; outreach; potency testing; programs; reproductive; research and development; response; safety testing; sound; validation studies; web site; working group

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 NICEATM-ICCVAM 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 that 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. In the United States, the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM) coordinates interagency issues on alternative toxicological test method development, validation, regulatory acceptance, and national and international harmonization. The committee is responsible for coordinating Federal interagency technical evaluations of new, revised, and alternative safety testing methods and forwarding test method recommendations to U.S. Federal agencies. The National Institute of Environmental Health Sciences originally established ICCVAM in 1997. In 2000, ICCVAM was established by law as a permanent interagency committee of the National Institute of Environmental Health Sciences under the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods. ICCVAM is composed of representatives from the 15 U.S. Federal regulatory and research agencies that require, use, or generate toxicological testing data and information. NICEATM administers ICCVAM and provides scientific and operational support for ICCVAM activities. NICEATM also conducts and coordinates international validation studies to evaluate the usefulness and limitations of potential new alternative test methods. NICEATM and ICCVAM work together to evaluate and promote the validation and regulatory acceptance of scientifically valid toxicological test methods based on sound science that will protect human and animal health and the environment, while reducing, refining (decreasing pain and distress), and replacing animal use where scientifically feasible. NICEATM and ICCVAM provide an essential framework for translating advances in science and technology into standardized and adequately validated safety testing methods that can be used to protect and advance public health. Since its establishment in 1997, ICCVAM has coordinated or contributed to the evaluation of 27 alternative test methods that have been accepted or endorsed by national and international authorities. The types of safety testing and available alternatives include: eye irritation and injury, acute systemic toxicity, dermal absorption, dermal corrosivity and irritation, allergic contact dermatitis, pyrogenicity, and vaccine potency. The alternative methods accepted by Federal agencies include 17 non-animal methods and 10 methods that use fewer animals and/or provide for refinement by reducing or avoiding potential discomfort. Most of the in vitro methods do not require the use of animals when positive results are obtained. Recommendations for additional alternatives for allergic contact dermatitis and ocular irritation are in development. In response to requests from the Appropriations Committees of the U.S. House of Representatives and U.S. Senate, ICCVAM and NICEATM prepared a five-year plan to describe goals and objectives for the years 2008 through 2012. This plan was developed in conjunction with Federal agency program offices and describes how NICEATM and ICCVAM will promote the research, development, translation, validation, and regulatory acceptance of alternative test methods that reduce, refine, and replace the use of animals in testing while maintaining scientific quality and protecting human health, animal health, and the environment. The plan identified four key challenges that NICEATM and ICCVAM will address in conjunction with agency programs. The first challenge is to identify priority toxicity testing areas for the next five years and to conduct and facilitate activities in those areas. Currently, the four highest priority areas are ocular toxicity, dermal toxicity, acute systemic toxicity, and biologics potency and safety testing. These are based on the potential for these tests to cause animal pain and distress and the fact that these are the most commonly conducted safety tests. Other priority areas include immunotoxicity, endocrine disruptors, pyrogenicity, reproductive and developmental, and chronic toxicity/carcinogenicity testing. The second challenge is to identify and promote research initiatives that are expected to support future development of innovative alternative test methods. These new methods might incorporate techniques such as high throughput screening, computer modeling, informatics, and biomarkers. The third challenge is for NICEATM and ICCVAM to foster the acceptance and appropriate use of alternative test methods through outreach and communication. This will be accomplished by sponsoring and participating in workshops, NICEATM-ICCVAM website communications, and the development and publication of standardized test method protocols. Lastly, ICCVAM and NICEATM will develop partnerships and strengthen interactions with stakeholders to facilitate meaningful progress. These efforts are expected to facilitate research, development, translation, validation and regulatory acceptance of alternative methods that will reduce, refine, and replace animal use while maintaining scientific quality and the protection of human health, animal health, and the environment. In June 2009, ICCVAM and NICEATM released an Implementation Plan for the NICEATM-ICCVAM Five-Year Plan. This working document describes how ICCVAM and NICEATM are implementing the strategies outlined in the Five-Year Plan and includes goals, specific objectives, and planned activities for implementation. The Implementation Plan also describes NICEATM and ICCVAM accomplishments since February 2008 that relate to the goals and objectives outlined in the Implementation Plan. NICEATM and ICCVAM recently created an alternative test methods milestones page on the NICEATM-ICCVAM website to provide a comprehensive overview of available alternative methods and a quick summary of current validation and evaluation activities, (http:// http://iccvam.niehs.nih.gov/methods/milestones.htm.). The page provides a comprehensive summary of the status of ongoing and completed NICEATM-ICCVAM alternative test method evaluation projects and projects to which NICEATM, ICCVAM, and agency scientists are contributing. The page also provides timelines for each project with links to more detailed information and relevant documents. Additional information about NICEATM and ICCVAM test method evaluation activities can be found at http://iccvam.niehs.nih.gov/. On April 27, 2009, representatives of the United States, the European Union, Canada, and Japan signed a Memorandum of Cooperation for International Cooperation on Alternative Test Methods (ICATM). The agreement provides a framework for enhanced international cooperation, collaboration, and communication in three critical areas: (1) test method validation studies, independent peer review of the validation status of test methods, and the development of harmonized formal test method recommendations for regulatory authorities The initial participating validation organizations are the NICEATM and ICCVAM, the Japanese Center for the Validation of Alternative Methods (JaCVAM), the European Centre for the Validation of Alternative Methods (ECVAM), and the Environmental Health Science and Safety Bureau within Health Canada. The cooperation among these organizations facilitated by this agreement is expected to accelerate international adoption of scientifically valid alternative test methods. NICEATM and ICCVAM convened an international independent scientific peer review panel in 2008 and 2009 to review several new versions and applications of the murine local lymph node assay (LLNA), an alternative test method for assessing the allergic contact dermatitis potential of chemicals and products. ICCVAM originally evaluated the scientific validity of the LLNA in 1998. U.S. Federal agencies accepted the ICCVAM recommendations that the LLNA was a valid substitute for the current guinea pig test method used to assess the allergic contact dermatitis and that it could be used to evaluate most but not all types of substances. ICCVAM also concluded that the LLNA has many advantages over the traditional test methods, including using fewer animals, eliminating the potential discomfort that can occur from substances that are sensitizers, and providing dose-response information. The LLNA was subsequently incorporated into national and international test guidelines for the assessment of skin sensitization. Accidental eye injury is a leading cause of visual impairment in the U.S., and many of these injuries occur due to contact with workplace or household chemicals. According to the National Institute of Occupational Safety and Health (NIOSH), each day about 2000 U.S. workers have a job-related eye injury that requires medical treatment. Even more eye injuries occur in the home; with about 125,000 eye injuries a year caused by accidents involving common household products such as oven cleaner and bleach (source, American Academy of Ophthalmology). Federal agencies require safety testing to determine whether consumer products or other substances may cause temporary or permanent damage to the eye. In October 2003, the U.S. Environmental Protection Agency (EPA) nominated four in vitro ocular toxicity test methods for evaluation as potential screening methods for eye corrosion or severe irritation. Ocular safety testing is one of ICCVAM's top four priorities because it is one of the four most common safety tests required and therefore involves significant number of animals. Such testing also has the potential to cause significant unrelieved pain and distress when chemicals and products cause eye damage. In 2008, two ICCVAM-recommended in vitro safety testing methods, the bovine corneal opacity and permeability (BCOP) and isolated chicken eye (ICE) test methods, were accepted by U.S. Federal agencies for identifying substances with the potential to cause severe or permanent damage to eyes without using live animals. The OECD Council formally adopted TGs for these test methods in 2009, with the BCOP described in TG 437 and the ICE in TG 438. These methods can now be used worldwide to identify substances that may cause severe or irreversible eye damage. Positive results can be used for hazard classification without the need to use live animals, thereby avoiding the pain and distress that may have resulted if animals had been required. NICEATM and ICCVAM organized an international independent scientific peer review panel that met in May 2009 to evaluate nine alternative methods and strategies for ocular safety testing. These included: ¿ The routine use of topical anesthetics, systemic analgesics, and humane endpoints to avoid and minimize pain and distress during in vivo ocular irritation testing. ¿ The use of the BCOP, the Cytosensor(R) Microphysiometer (CM), the ICE, the isolated rabbit eye, and the hen's egg test ¿ chorioallantoic membrane test methods for identifying moderate and mild ocular irritants and for identifying substances that do not cause sufficient eye injury to require ocular hazard labeling (non-labeled category). ¿ The in vivo low volume eye test. ¿ Non-animal testing strategies using the BCOP, CM, and/or EpiOcular¿ test methods to assess the eye irritation potential of antimicrobial cleaning products and to determine their appropriate U.S. Environmental Protection Agency ocular hazard classification. Highlights of the Panel's conclusions and recommendations include: ¿ Topical anesthetics and systemic analgesics should routinely be used prior to all in vivo ocular irritancy testing. The Panel recommended an enhanced protocol of specific pain-relieving drugs and schedule of administration to effectively avoid or minimize discomfort. ¿ The BCOP and CM test methods could be used as screening tests to identify some products and substances that would not require hazard labeling for eye irritation. These methods will now be recommended for use in a ¿bottom-up testing approach¿ to identify substances that are not expected to cause sufficient injury to require classification as an ocular irritation hazard. ¿ Proposed non-animal testing strategies using three in vitro test methods to assess the eye irritation potential of antimicrobial cleaning products for EPA ocular hazard classification and labeling purposes appear promising. The Panel recommended that studies should be conducted to further characterize the in vitro test methods and that testing strategies should be designed in coordination with ICCVAM.

该合同的目标是为国家毒理学计划 (NTP) 危害评估活动提供支持，旨在预防因环境暴露于化学或物理制剂而引起的疾病或不利影响。 总体目标是国家毒理学计划的替代毒理学方法评估机构间中心 (NICEATM) 和替代方法验证机构间协调委员会 (ICCVAM) 在促进研究、开发、翻译、验证方面发挥更大的领导作用以及对替代测试方法的监管认可 NICEATM-ICCVAM 五年计划建立在 ICCVAM 促进开发、验证和监管认可的使命之上。新的和修订的监管测试方法，减少、改进和取代动物测试的使用，同时保持和促进科学质量以及保护人类健康、动物健康和环境的使命、愿景和战略重点将有所帮助。 NICEATM 和 ICCVAM 取得了更大的进展，并向公众通报了他们的计划和方法，该计划还建立在 NTP 21 世纪路线图的基础上，其中包括开发和验证改进的测试方法的目标，并在科学上可行的情况下确保这些方法的有效性。减少，该路线图还规定，根据 NTP 路线图开发的活动和检测将与 ICCVAM 合作和协商进行，以最大限度地提高其对监管机构的价值。 美国监管机构负责保护人类和动物健康和环境，作为其使命的一部分，机构需要确定接触农药、消费品、药品、医疗器械、工作场所化学品、食品等物质是否可能造成不利影响。根据联邦机构的规定，目前许多用于评估接触此类物质的危害和风险的测试方法都应基于可靠的科学。 ICCVAM 授权法2000 年，新的、修订的和替代的测试方法必须 在机构将其用于监管目的之前，需要对其提议的用途进行验证，以确定与现有方法或方法相比，使用替代测试方法是否可以为人类和动物健康提供同等或更好的保护。环境。 在美国，替代方法验证机构间协调委员会（ICCVAM）负责协调替代毒理学测试方法开发、验证、监管接受以及国家和国际协调方面的机构间问题。国家环境健康科学研究所最初于 1997 年成立了 ICCVAM。 2000 年，ICCVAM 依法成立，作为国家环境健康科学研究所的常设机构间委员会，隶属于国家毒理学计划替代毒理学方法评估中心，由来自 15 个美国联邦监管和研究机构的代表组成。要求、使用或生成毒理学测试数据和信息。 NICEATM 管理 ICCVAM 并为 ICCVAM 活动提供科学和运营支持，NICEATM 还开展和协调国际验证研究，以评估潜在的新替代测试方法的有效性和局限性，并共同评估和促进科学验证和监管接受。基于可靠科学的有效毒理学测试方法，将保护人类和动物健康和环境，同时在科学可行的情况下减少、精炼（减少疼痛和痛苦）并取代动物使用。 NICEATM 和 ICCVAM 提供了一个重要框架，将科学技术的进步转化为标准化且经过充分验证的安全测试方法，可用于保护和促进公众健康。 自 1997 年成立以来，ICCVAM 已协调或协助评估了 27 种已被国家和国际当局接受或认可的替代测试方法。安全测试和可用替代方法的类型包括：眼睛刺激和损伤、急性全身毒性、皮肤吸收、皮肤腐蚀性和刺激性、过敏性接触性皮炎、热原性和疫苗效力 联邦机构接受的替代方法包括 17 种非动物方法和 10 种使用较少动物的方法。和/或通过减少或避免潜在的不适来进行改进。当获得阳性结果时，大多数体外方法不需要使用动物。针对过敏性接触性皮炎和眼部刺激的其他替代方案的建议正在开发中。 应美国众议院和参议院拨款委员会的要求，ICCVAM 和 NICEATM 制定了一项五年计划，描述 2008 年至 2012 年的目的和目标。该计划是与联邦机构项目办公室联合制定的并描述了 NICEATM 和 ICCVAM 将如何促进替代测试方法的研究、开发、翻译、验证和监管接受，以减少、改进和取代动物在测试中的使用，同时保持科学质量，保护人类健康、动物健康和环境。 该计划确定了 NICEATM 和 ICCVAM 将与机构计划一起解决的四个关键挑战。第一个挑战是确定未来五年的优先毒性测试领域，并在这些领域开展和促进目前的四个最高优先领域的活动。包括眼毒性、皮肤毒性、急性全身毒性以及生物制剂效力和安全性测试，这些测试是基于这些测试引起动物疼痛和痛苦的可能性，以及这些是最常进行的安全性测试的事实。免疫毒性，内分泌干​​扰物、热原性、生殖和发育以及慢性毒性/致癌性测试。 第二个挑战是确定和促进有望支持创新替代测试方法未来发展的研究计划，这些新方法可能会结合高通量筛选、计算机建模、信息学和生物标志物等技术。 第三个挑战是 NICEATM 和 ICCVAM 通过推广和沟通促进替代测试方法的接受和适当使用，这将通过赞助和参与研讨会、NICEATM-ICCVAM 网站通信以及标准化测试方法的开发和发布来实现。协议。 最后，ICCVAM 和 NICEATM 的合作伙伴关系将发展并加强与利益相关者的互动，以促进有意义的进展，预计这些努力将促进替代方法的研究、开发、转化、验证和监管接受，从而减少、改进和替代动物使用，同时保持不变。科学质量和保护人类健康、动物健康和环境。 2009 年 6 月，ICCVAM 和 NICEATM 发布了 NICEATM-ICCVAM 五年计划的实施计划 该工作文件描述了 ICCVAM 和 NICEATM 如何实施五年计划中概述的战略，包括目标、具体目标和计划活动。实施计划还描述了自 2008 年 2 月以来 NICEATM 和 ICCVAM 取得的与实施计划中概述的目的和目标相关的成就。 NICEATM 和 ICCVAM 最近在 NICEATM-ICCVAM 网站上创建了替代测试方法里程碑页面，以提供可用替代方法的全面概述以及当前验证和评估活动的快速摘要（http://http://icccvam.niehs）。 nih.gov/methods/milestones.htm.）该页面提供了正在进行和已完成的 NICEATM-ICCVAM 替代测试方法评估项目以及 NICEATM、 ICCVAM 和机构科学家正在做出贡献。该页面还提供了每个项目的时间表，以及更多详细信息和相关文件的链接，请访问 http://iccvam.niehs.nih。政府/。 2009年4月27日，美国、欧盟、加拿大和日本的代表签署了替代测试方法国际合作备忘录（ICATM），该协议为加强国际合作、协作和沟通提供了框架。三个关键领域：（1）测试方法验证研究、测试方法验证状态的独立同行评审以及为监管机构制定统一的正式测试方法建议。 最初参与验证的组织是 NICEATM 和 ICCVAM、日本替代方法验证中心 (JaCVAM)、欧洲替代方法验证中心 (ECVAM) 以及加拿大卫生部合作下的环境健康科学与安全局。在该协议的推动下，这些组织预计将加速国际上采用科学上有效的替代测试方法。 NICEATM 和 ICCVAM 于 2008 年和 2009 年召集了一个国际独立科学同行评审小组，审查小鼠局部淋巴结测定 (LLNA) 的几个新版本和应用，LLNA 是一种最初评估化学品和产品的过敏性接触性皮炎潜力的替代测试方法。 1998 年评估了 LLNA 的科学有效性。美国联邦机构接受了 ICCVAM 的建议，认为 LLNA 是当前豚鼠的有效替代品ICCVAM 还得出结论，LLNA 比传统测​​试方法有许多优点，包括使用更少的动物，消除了潜在的不适。 LLNA 可以从致敏物质中产生，并提供剂量反应信息，随后被纳入国家和国际皮肤致敏评估测试指南。 在美国，眼睛意外受伤是导致视力障碍的主要原因，其中许多伤害是由于接触工作场所或家用化学品而造成的，每天约有 2000 名美国工人遭受眼睛意外伤害。与工作相关的眼部损伤需要就医，每年约有 125,000 起眼部损伤是由烤箱清洁剂和漂白剂等常见家用产品造成的。联邦机构要求进行安全测试，以确定消费品或其他物质是否可能对眼睛造成暂时或永久性损伤。2003 年 10 月，美国环境保护署 (EPA) 提名了四种体外眼毒性测试方法进行评估。作为眼睛腐蚀或严重刺激的潜在筛查方法。 眼部安全测试是 ICCVAM 的四大优先事项之一，因为它是所需的四种最常见的安全测试之一，因此涉及大量动物，当化学品和产品造成眼睛损伤时，此类测试也有可能造成严重的无法缓解的疼痛和痛苦。 2008年，ICCVAM推荐的两种体外安全性测试方法，牛角膜混浊和渗透性（BCOP）和离体鸡眼（ICE）测试方法被美国联邦机构接受OECD 理事会于 2009 年正式通过了这些测试方法的 TG，其中 TG 437 中描述了 BCOP，TG 438 中描述了 ICE。在全球范围内用于识别可能导致严重或不可逆转的眼睛损伤的物质，阳性结果可用于危险分类，而无需使用活体动物，从而避免需要动物时可能导致的疼痛和困扰。 NICEATM 和 ICCVAM 组织了一个国际独立科学同行评审小组，于 2009 年 5 月举行会议，评估眼部安全测试的九种替代方法和策略，其中包括： ¿常规使用局部麻醉剂、全身镇痛剂和人道终点，以避免和尽量减少体内眼刺激测试期间的疼痛和痛苦。 ¿使用 BCOP、Cytosensor(R) 微生理计 (CM)、ICE、离体兔眼和鸡蛋测试 ¿绒毛尿囊膜测试方法，用于识别中度和轻度眼部刺激物，以及识别不会造成足够眼损伤而需要眼部危险标签（非标签类别）的物质。 ¿体内低容量眼部测试。 ¿使用 BCOP、CM 和/或 EpiOulous 的非动物测试策略¿评估抗菌清洁产品对眼睛的潜在刺激性并确定其适当的美国环境保护局眼部危害分类的测试方法。 专家组的结论和建议的要点包括： ¿在进行所有体内眼部刺激性测试之前，应常规使用局部麻醉剂和全身镇痛剂，专家组建议采用增强的特定止痛药物方案和给药时间表，以有效避免或最大程度地减少不适。 ¿ BCOP 和 CM 测试方法可用作筛选测试，以识别一些不需要对眼睛刺激进行危险标签的产品和物质。这些方法现在建议用于 ¿自下而上的测试方法¿识别预计不会造成足够伤害而需要分类为眼部刺激危害的物质。 ¿拟议的非动物测试策略使用三种体外测试方法来评估抗菌清洁产品对眼睛的刺激潜力，用于 EPA 眼部危害分类和标签目的，该小组建议进行研究以进一步表征体外测试方法和标签。测试策略的设计应与 ICCVAM 协调。