Characterizing dose-response relationships in multiple cancer bioassays.
Characterizing dose-response relationships in multiple cancer bioassays.
复制标题
表征多种癌症生物测定中的剂量反应关系。
DOI：
10.1111/0272-4332.211092
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发表时间：
2001
期刊：
影响因子：
--
通讯作者：
Williams,PL
中科院分区：
文献类型：
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作者：
French,JL;Williams,PL
在评估化合物的致癌风险时，美国环境保护署和国家毒理学计划（NTP）等监管机构传统上将剂量反应模型与啮齿动物生物测定数据拟合，然后使用拟合模型估计实际安全剂量或与背景风险非常小的增加（通常为10−6）相对应的剂量。最近人们的兴趣主要集中在将关于正在调查的特定化学品的特性的更多科学信息纳入风险评估过程，包括癌症诱发的生物机制、代谢途径以及化学结构和活性。尽管监管机构目前准备允许使用基于非遗传毒性化学品潜在阈值概念的非线性剂量反应模型，但很少尝试研究剂量反应曲线形状与致突变性之间的总体关系。使用NTP癌症生物测定历史数据库中的数据，作者对拟合扩展Weibull剂量反应曲线的估计形状进行了重复测量分析。得出的结论是，遗传毒性化学品的剂量反应曲线比非遗传毒性化学品更接近线性，但平均而言，两种类型的化合物的剂量反应曲线都是凸形的，遗传毒性的影响很小。
In the evaluation of chemical compounds for carcinogenic risk, regulatory agencies such as the U.S. Environmental Protection Agency and National Toxicology Program (NTP) have traditionally fit a dose‐response model to data from rodent bioassays, and then used the fitted model to estimate a Virtually Safe Dose or the dose corresponding to a very small increase (usually 10−6) in risk over background. Much recent interest has been directed at incorporating additional scientific information regarding the properties of the specific chemical under investigation into the risk assessment process, including biological mechanisms of cancer induction, metabolic pathways, and chemical structure and activity. Despite the fact that regulatory agencies are currently poised to allow use of nonlinear dose‐response models based on the concept of an underlying threshold for nongenotoxic chemicals, there have been few attempts to investigate the overall relationship between the shape of dose‐response curves and mutagenicity. Using data from an historical database of NTP cancer bioassays, the authors conducted a repeated‐measures analysis of the estimated shape from fitting extended Weibull dose‐response curves. It was concluded that genotoxic chemicals have dose‐response curves that are closer to linear than those for nongenotoxic chemicals, though on average, both types of compounds have dose‐response curves that are convex and the effect of genotoxicity is small.