Cohen S M, Ellwein L B
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198.
Toxicol Appl Pharmacol. 1990 Jun 1;104(1):79-93. doi: 10.1016/0041-008x(90)90284-2.
The development of tumors in relationship to 2-acetylaminofluorene (AAF) dose and time on study has been evaluated in an experiment conducted by the National Center for Toxicological Research (NCTR) using more than 24,000 female BALB/c mice. By using a biologically based model of two-event carcinogenesis accounting explicitly for both genotoxic and nongenotoxic proliferative effects at the cellular level, we provide a unifying explanation for the apparently disparate dose-response results observed in the urinary bladder and liver. Experimental observations of dose-related DNA adduct levels in both tissues and hyperplasia in the bladder were utilized in estimation of model parameters. Analyses demonstrate that tumor prevalence in the liver can be explained entirely by the influence of AAF on the first of two genetic events, and in the bladder by the synergy between AAF genotoxicity affecting both genetic events and cellular proliferation at higher doses. These results are consistent across the entire ED01 data set.
美国国家毒理学研究中心（NCTR）使用超过24,000只雌性BALB/c小鼠进行了一项实验，评估了与研究中的2-乙酰氨基芴（AAF）剂量和时间相关的肿瘤发生情况。通过使用一种基于生物学的双事件致癌模型，该模型明确考虑了细胞水平上的遗传毒性和非遗传毒性增殖效应，我们对在膀胱和肝脏中观察到的明显不同的剂量反应结果提供了一个统一的解释。在估计模型参数时，利用了两个组织中与剂量相关的DNA加合物水平以及膀胱增生的实验观察结果。分析表明，肝脏中的肿瘤患病率完全可以由AAF对两个遗传事件中的第一个事件的影响来解释，而膀胱中的肿瘤患病率则可以由高剂量下影响两个遗传事件的AAF遗传毒性与细胞增殖之间的协同作用来解释。这些结果在整个ED01数据集中是一致的。
