SOURCES OF VARIABILITY IN TUMOR INCIDENCE IN LONG TERM RODENT STUDIES

工作总结：对NTP饮食限制数据的评估 研究表明，限制进食的动物数量显著减少 与同等大小的广告相比，在许多特定部位的肿瘤中 Libitum喂动物。这些结果表明，限制饮食 专注于在剂量和剂量上实现相似体重的战略 如果控制组的数量大大增加，则可能产生假阳性结果 与给药的动物相比，对照组需要限制食物。 我们还发现，与给药和控制动物一样，对食物的限制 如果由此产生的体重是 剂量组和对照组有很大的不同。对…的评价 发现部位特异性肿瘤的发生之间的相关性 除了强烈的负相关外，几乎没有什么有意义的关联 F344男性脑下垂体和睾丸肿瘤发病率之间的关系 老鼠。给出了机械论的论点来解释 笼养方案可能是造成这种观察到的阴性的原因 肿瘤反应的相关性。我们用化学方法评估了- NTP研究中肿瘤发病率的相关下降。 这些减少中的许多与体重的减轻有关 在给药组中经常观察到。与化学有关的 大鼠白血病发病率的降低似乎与脾有关 损害，即与化学有关的脾毒性对大多数人来说都是明显的 显示出降低白血病发病率的化学物质。我们的结论是 NTP研究中观察到的大多数与化学相关的肿瘤减少是由于 与体重有关的随机变异性，或(在 白血病病例)脾毒性。

Summary of Work: An evaluation of data from the NTP Dietary Restriction Study indicates that food restricted animals show a significant reduction in a number of site-specific tumors relative to equivalently-sized ad libitum fed animals. These results suggest that a dietary restriction strategy that focuses on achieving similar body weights in dosed and control groups may produce false positive outcomes if substantially more food restriction is required for control groups than for dosed animals. We also found that equal food restriction to dosed and control animals may produce false negative outcomes if the resulting body weights are substantially different in dosed and control groups. An evaluation of correlations between the occurrence of site-specific tumors revealed little meaningful associations except for a strong negative correlation between the incidences of pituitary gland and testis tumors in male F344 rats. Mechanistic arguments were given to explain how differences in caging protocols may have been responsible for this observed negative correlation in tumor response. We evaluated the frequency of chemically- related decreases in tumor incidence in NTP studies. Many of these decreases are associated with the reduced body weights frequently observed in the dosed groups. The chemically-related decreased incidences of leukemia in rats appear to be related to spleen damage, i.e., chemically-related splenic toxicity is evident for most chemicals showing decreased incidences of leukemia. We concluded that most chemically-related tumor decreases observed in NTP studies are due to either random variability, associations with body weight, or (in the case of leukemia) splenic toxicity.