Approach to risk assessment for genotoxic carcinogens based on data from the mouse skin initiation-promotion model.
Approach to risk assessment for genotoxic carcinogens based on data from the mouse skin initiation-promotion model.
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基于小鼠皮肤引发促进模型数据的遗传毒性致癌物风险评估方法。
DOI：
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发表时间：
1983
影响因子：
10.4
通讯作者：
E. Morris
中科院分区：
文献类型：
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作者：
F. Burns;R. Albert;B. Altshuler;E. Morris
在小鼠皮肤启动-促进系统中的肿瘤诱导数据被发现符合二次函数，其中线性项的系数依赖于启动剂的剂量。该模型暗示，在低剂量的致癌物质中，启动子的存在可能比在进行大多数测试的高剂量时更重要。实验表明，致癌化学物质，如苯并(A)芘、7，12-二甲基苯并(A)菲、氧化硝基喹啉和β-丙内酯，在低剂量下以不可逆的线性方式累积。即使当7，12-二甲基苯并(A)蒽被灌胃给怀孕的雌性时，暴露的子代的皮肤中也发现了大约与所用剂量和处于危险状态的细胞数量成比例的启动活性。启动的细胞本质上代表了在启动子存在下表达的可能性很高的癌症的可能性。然后，风险可以用引发剂的累积剂量来解释，这本身就是一个很小的癌症风险。然而，启动子可能会通过克隆扩增启动的细胞来显著扩大总体风险。促销需要持续，因为如果促销提前结束，癌症风险就会降低。一些组织，如小鼠膀胱，可能比其他组织更容易被促进，因此当内部促进和对外部促进的反应的组合具有可比性时，组织之间和物种之间的比较是最好的。
Tumor induction data in the mouse skin initiation-promotion system were found to be consistent with a quadratic function where the coefficient of the linear term depended on the dose of the promoter. The model implies that the existence of promoters may be more important at low doses of the carcinogen than at high doses where most testing is performed. Experiments are described showing that the initiating effect of carcinogenic chemicals, such as benzo(a)pyrene, 7,12-dimethyl-benz(a)anthracene, nitroquinoline oxide and beta-propiolactone, accumulates in a linear, irreversible manner at low doses. Even when 7,12-dimethylbenz(a)anthracene was applied intragastrically to pregnant females, initiating activity was found in the skins of exposed offspring about in proportion to dose applied and number of cells at risk. The initiated cells essentially represent a potential for cancer that has a high probability for expression in the presence of a promoter. Risk then can be interpreted in terms of the accumulated dose of initiator which alone presents a small risk of cancer. However, a promoter may substantially expand the overall risk, possibly by clonally expanding the initiated cells. Promotion needs to be sustained since there is a reduction of cancer risk if promotion is ended early. Some tissues, such as mouse bladder, may be intrinsically promoted more than others so that comparisons between tissues and between species are best made when the combination of intrinsic promotion and response to extrinsic promotion are comparable.