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中包含的数据。除了公布对照Fischer 344大鼠和B6 C3 F1小鼠的最新肿瘤发生率外，我们还在NTP数据库中确定了10种增加F344大鼠脑肿瘤发生率的化学物质。由于肿瘤发生率较低和/或缺乏剂量反应趋势，认为这些增加中的大多数是不确定的。缩水甘油是NTP评价的唯一一种化学品，有明确的脑肿瘤诱导证据。另一项数据库评价记录了NTP研究中肿瘤发生率的显著化学相关下降趋势的频率。虽然这些降低的频率超过了偶然预期，但许多与给药组的体重降低和/或靶器官毒性相关。研究表明，在先前发表的NTP数据库评价中未能遵循四个重要的科学原则，导致统计学显著性肿瘤下降趋势的频率大大夸大。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效应，以及使用科学不充分的研究。- 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