Kitchin K T, Brown J L, Kulkarni A P
Carcinogenesis and Metabolism Branch, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711.
Teratog Carcinog Mutagen. 1994;14(2):83-100. doi: 10.1002/tcm.1770140205.
Twenty-one chemicals carcinogenic in rodent bioassays were selected for study. The chemicals were administered by gavage in two dose levels to female Sprague-Dawley rats. The effects of these 21 chemicals on four biochemical assays [hepatic DNA damage by alkaline elution (DD), hepatic ornithine decarboxylase activity (ODC), serum alanine aminotransferase activity (ALT), and hepatic cytochrome P-450 content (P450)] were determined. Available data from seven cancer predictors published by others [the Ames test (AMES), mutation in Salmonella typhimurium TA 1537 (TA 1537), structural alerts (SA), mutation in mouse lymphoma cells (MOLY), chromosomal aberrations in Chinese hamster ovary cells (ABS), sister chromatid exchange in hamster ovary cells (SCE), and the ke test (ke)] were also compiled for these 21 chemical carcinogens plus 28 carcinogens and 62 noncarcinogens already published by our laboratory. From the resulting 111 (chemicals) by 11 (individual cancer predictors) data matrix, the five operational characteristics (sensitivity, specificity, positive predictivity, negative predictivity, and concordance) of each of the 11 individual cancer predictors (four biochemical parameters of this study and seven cancer predictors of others) are presented. Two examples of complementarity or synergy of composite cancer predictors were found. To obtain maximum concordance it was necessary to combine both genotoxic and nongenotoxic cancer predictors. The composite cancer predictor (DD or [ODC and P450] or [ODC and ALT]) had higher concordance than did any of the four individual cancer predictors from which it was constructed. Similarly, the composite cancer predictor (TA 1537 or DD or [ODC and P450] or [ODC and ALT]) had higher concordance than any of its five individual constituent cancer predictors. Complementarity or synergy has been demonstrated both 1) among genotoxic cancer predictors (DD and TA 1537) and 2) between nongenotoxic (ODC, P450, and ALT) and genotoxic cancer predictors (TA 1537 and DD).
选择了21种在啮齿动物生物测定中具有致癌性的化学物质进行研究。通过灌胃将这些化学物质以两种剂量水平给予雌性斯普拉格-道利大鼠。测定了这21种化学物质对四种生化测定指标的影响，即碱性洗脱法检测的肝脏DNA损伤（DD）、肝脏鸟氨酸脱羧酶活性（ODC）、血清丙氨酸转氨酶活性（ALT）以及肝脏细胞色素P-450含量（P450）。还收集了其他研究者发表的七种癌症预测指标的现有数据，即艾姆斯试验（AMES）、鼠伤寒沙门氏菌TA 1537突变（TA 1537）、结构警报（SA）、小鼠淋巴瘤细胞突变（MOLY）、中国仓鼠卵巢细胞染色体畸变（ABS）、仓鼠卵巢细胞姐妹染色单体交换（SCE）以及ke试验（ke），这些数据涉及这21种化学致癌物以及我们实验室已发表的28种致癌物和62种非致癌物。从得到的111种（化学物质）×11种（个体癌症预测指标）的数据矩阵中，给出了11种个体癌症预测指标（本研究的四个生化参数以及其他研究者的七个癌症预测指标）各自的五个操作特征（敏感性、特异性、阳性预测值、阴性预测值和一致性）。发现了复合癌症预测指标互补或协同作用的两个例子。为了获得最大一致性，有必要将遗传毒性和非遗传毒性癌症预测指标结合起来。复合癌症预测指标（DD或[ODC和P450]或[ODC和ALT]）的一致性高于构成它的四个个体癌症预测指标中的任何一个。同样，复合癌症预测指标（TA 1537或DD或[ODC和P450]或[ODC和ALT]）的一致性高于其五个个体组成癌症预测指标中的任何一个。互补或协同作用已在以下两个方面得到证明：1）在遗传毒性癌症预测指标（DD和TA 1537）之间；2）在非遗传毒性（ODC、P450和ALT）与遗传毒性癌症预测指标（TA 1537和DD）之间。
