SOURCES OF VARIABILITY IN TUMOR INCIDENCE IN LONG TERM RODENT STUDIES

该项目的目的是确定和评估可能影响实验室啮齿动物肿瘤发病率的因素。我们继续研究体重差异对肿瘤发病率的影响。我们发现，如果对照组比给药组需要更多的食物限制，那么限制给药组和对照组的动物达到理想体重可能会产生假阳性结果。我们还发现，如果给药组和对照组的体重有很大差异，那么给药组和对照组同样的食物限制可能会产生假阴性结果。我们还研究了F344雄性大鼠慢性进行性肾病（CPN）的严重程度与肾上腺嗜铬细胞瘤的发生率之间的关系。在对照动物中，嗜铬细胞瘤的发病率在CPN更严重的动物中始终较高。然而，这种相关性在给药组中并不一致。例如，在28项国家毒理学规划研究中，报告了化学相关的CPN严重程度增加，只有3项报告了嗜铬细胞瘤的显著增加。另一方面，5/6嗜铬细胞瘤发病率增加的NTP研究中，CPN严重程度有一定程度的增加。我们的结论是，这种关联可能是解释一些国家毒理学规划研究的一个因素。——可变性;肿瘤发病率;啮齿动物致癌性生物测定；体重;饮食限制。肾病，肾上腺嗜铬细胞瘤

The goal of this project is to identify and evaluate factors that may influence tumor incidence in laboratory rodents. We continued to investigate the impact of body weight differences on tumor incidence. We found that food restricting dosed and control animals to achieve idealized body weights in both 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. We also investigated the association between the severity of chronic progressive nephropathy (CPN) and the incidence of adrenal pheochromocytoma in male F344 rats. In control animals the incidence of pheochromocytoma was consistently higher in those animals with the more severe CPN. However, this correlation was not consistently observed in dosed groups. For example, among 28 NTP studies reporting a chemically-related increased severity of CPN, only three had a significant increase in pheochromocytoma. On the other hand, 5/6 NTP studies with increased incidence of pheochromocytoma had some degree of increased CPN severity. We concluded that this association may be a factor in the interpretation of some NTP studies. - Variability; tumor incidence; rodent carcinogenicity bioassays; body weight; dietary restriction. nephropathy, adrenal pheochromocytoma