NTP DATABASE SUMMARIZATION AND EVALUATION

该项目的目标是总结、评估和解释国家毒理学项目啮齿动物致癌性数据库中包含的数据。除了发表对照Fischer 344大鼠和B6C3F1小鼠的最新肿瘤发病率外，我们还在NTP数据库中发现了10种增加F344大鼠脑肿瘤发病率的化学物质。由于肿瘤发病率低和/或缺乏剂量反应趋势，这些增加大多被认为是模棱两可的。Glycidol是国家毒理学规划评估的唯一一种有明确证据表明能诱发脑肿瘤的化学物质。另一个数据库评估记录了NTP研究中肿瘤发病率显著化学相关下降趋势的频率。虽然这些减少的频率超出了偶然预期，但许多与剂量组体重减轻和/或靶器官毒性有关。结果表明，在先前发表的对NTP数据库的评估中，未能遵循四个重要的科学原则，导致统计学上显着的肿瘤下降趋势的频率被大大夸大。导致这些错误的因素包括未能调整生存差异，评估不适当的肿瘤组合，未能达到报告的显著性水平（p<0.01），重复计算相同的肿瘤减少效应，以及使用科学上不充分的研究。-啮齿动物致癌性、肿瘤发生率；脑肿瘤;转基因小鼠，历史对照数据，肿瘤下降趋势

The goal of this project is to summarize, evaluate, and interpret data contained in the NTP rodent carcinogenicity database. In addition to publishing updated tumor rates in control Fischer 344 rats and B6C3F1 mice, we identified ten chemicals in the NTP database that increased the incidence of brain tumors in F344 rats. Most of these increases were considered to be equivocal because of the low tumor incidences, and/or the lack of dose response trends. Glycidol was the only chemical evaluated by the NTP for which there was clear evidence of brain tumor induction. Another database evaluation documented the frequency of significant chemically-related decreasing trends in tumor incidence in NTP studies. While the frequency of these decreases exceeds chance expectation, many are related to reduced body weight and/or target organ toxicity in the dosed groups. It was demonstrated that a failure to follow four important scientific principles in a previously published evaluation of the NTP database led to greatly exaggerated frequencies of statistically significant decreasing tumor trends. The factors contributing to these errors included failure to adjust for survival differences, evaluating improper tumor combinations, failure to achieve the reported level of significance (p<0.01), multiply counting the same decreasing tumor effect, and using scientifically inadequate studies. - Rodent carcinogenicity, tumor incidence; brain tumors; transgenic mice, historical control data, decreasing tumor trends