NTP Database Summarization And Evaluation

该项目的目标是总结、评估和解释NTP啮齿动物致癌性数据库和其他大型数据库中包含的数据。该项目的目标是总结、评估和解释NTP啮齿动物致癌性数据库和其他大型数据库中包含的数据。 最近的一项数据库评估调查了转基因小鼠模型在致癌物识别中的作用。评估了涉及三种最广泛使用的转基因小鼠模型-Trp53+/-、TG/AC和RasH2-的99个实验的数据。研究了这些模型(单独使用或联合使用)预测人类致癌性的能力(由NTP致癌物报告和/或IARC专著确定)。尽管转基因模型与已知/可能的人类致癌性有很好的总体一致性(范围从74-81%)，但错误倾向于遗漏已知或可疑的人类致癌物(即“假阴性”)。当使用转基因模型的“混合策略”与大鼠生物测定相结合时，这一性能得到了一定程度的改善(大约85%的正确检测没有“假阴性”)。总体而言，转基因模型表现良好，但验证和标准化的重要问题需要进一步关注，以允许它们被监管机构接受并用于人类风险评估。 Shyamal Peddada博士和我最近完成了经济合作与发展组织(OECD)子宫营养生物检测验证计划的第二阶段的参与。这一生物测定旨在鉴定被怀疑为雌激素激动剂或拮抗剂的化合物的体内活性，并帮助确定阳性化合物的优先顺序，以便进一步测试。对幼年雌性大鼠和成年去卵巢大鼠两种模型系统进行了检测和比较。对来自19个参与实验室的数据进行了评估，这些实验室使用了七种不同的化学品，以及盲法和非盲法方案(每种方案都导致了将发表在《环境健康展望》上的论文)。总体结论是，这两个模型系统看起来都很健壮，可重复性和可跨实验室移植，并能够检测到微弱的雌激素激动剂。

The goal of this project is to summarize, evaluate, and interpret data contained in the NTP rodent carcinogenicity database and other large databases. The goal of this project is to summarize, evaluate, and interpret data contained in the NTP rodent carcinogenicity database and other large databases. One recent database evaluation investigated the role of transgenic mouse models in carcinogen identification. Data from 99 experiments involving the three most extensively used transgenic mouse models - Trp53+/-, Tg/AC and RasH2 - were evaluated. The ability of these models (used singly or in combination) to predict human carcinogenicity (as determined by the NTP Report on Carcinogens and/or the IARC Monographs) was investigated. Although the transgenic models had good overall concordance (ranging from 74-81%) with known/probable human carcinogenicity, the errors tended to be in the direction of missing known or suspected human carcinogens (i.e., "false negatives"). This performance was improved somewhat (approximately 85% correct determinations with no "false negatives") when a "mixed strategy" of a transgenic model in conjunction with the rat bioassay was used. Overall, the transgenic models performed well, but important issues of validation and standardization need further attention to permit their regulatory acceptance and use in human risk assessment. Dr. Shyamal Peddada and I recently completed our participation in the second phase of an Organization for Economic Co-operation and Development (OECD) validation program for the uterotrophic bioassay. This bioassay is intended to identify the in vivo activity of compounds that are suspected agonists or antagonists of estrogen, and to assist the prioritization of positive compounds for further testing. Two model systems, the immature female rat and the adult ovariectomized rat, were tested and compared. Data from nineteen participating laboratories using seven different chemicals, and both a blinded and unblinded protocol were evaluated (each leading to papers that will appear in Environmental Health Perspectives). The overall conclusions were that both model systems appear robust, reproducible and transferable across laboratories and able to detect weak estrogen agonists.