NTP Database Summarization And Evaluation

本项目的目标是总结、评价和解释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。本项目的目标是总结、评价和解释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鉴定中的作用。评估了涉及三种最广泛使用的转基因小鼠模型-Trp 53 +/-、Tg/AC和RasH 2-的99个实验的数据。研究了这些模型（单独或组合使用）预测人类致癌性（根据NTP致癌物报告和/或IARC专论确定）的能力。尽管转基因模型与已知/可能的人类致癌性具有良好的总体一致性（范围为74-81%），但错误倾向于缺失已知或疑似人类致癌物（即，“假阴性”）。当使用转基因模型结合大鼠生物测定的“混合策略”时，该性能有所改善（约85%的正确测定，无“假阴性”）。总的来说，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，以允许其监管接受和人类风险评估中的使用。 博士Shyamal Peddada和我最近完成了经济合作与发展组织（OECD）子宫营养生物测定验证计划第二阶段的参与。该生物测定法旨在鉴定疑似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，以进行进一步检测。对未成年雌性大鼠和成年去卵巢大鼠两种模型系统进行了测试和比较。来自十九个参与实验室的数据，使用七种不同的化学品，以及盲态和非盲态的协议进行了评估（每一个导致的文件，将出现在环境健康的观点）。总体结论是，两种模型系统均表现出稳健性、可重复性和跨实验室可转移性，并且能够检测弱雌激素激动剂。

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.