Boobis Alan R, Daston George P, Preston R Julian, Olin Stephen S
Department of Experimental Medicine and Toxicology, Imperial College London, London W12 0NN, UK.
Crit Rev Food Sci Nutr. 2009 Sep;49(8):690-707. doi: 10.1080/10408390903098673.
The existence of thresholds for toxicants is a matter of debate in chemical risk assessment and regulation. Current risk assessment methods are based on the assumption that, in the absence of sufficient data, carcinogenesis does not have a threshold, while noncarcinogenic endpoints are assumed to be thresholded. Advances in our fundamental understanding of the events that underlie toxicity are providing opportunities to address these assumptions about thresholds. A key events dose-response analytic framework was used to evaluate three aspects of toxicity. The first section illustrates how a fundamental understanding of the mode of action for the hepatic toxicity and the hepatocarcinogenicity of chloroform in rodents can replace the assumption of low-dose linearity. The second section describes how advances in our understanding of the molecular aspects of carcinogenesis allow us to consider the critical steps in genotoxic carcinogenesis in a key events framework. The third section deals with the case of endocrine disrupters, where the most significant question regarding thresholds is the possible additivity to an endogenous background of hormonal activity. Each of the examples suggests that current assumptions about thresholds can be refined. Understanding inter-individual variability in the events involved in toxicological effects may enable a true population threshold(s) to be identified.
在化学物质风险评估和监管中，有毒物质阈值的存在是一个有争议的问题。当前的风险评估方法基于这样的假设：在缺乏足够数据的情况下，致癌作用没有阈值，而非致癌终点则假定有阈值。我们对毒性潜在事件的基本理解取得的进展，为解决这些关于阈值的假设提供了契机。一个关键事件剂量反应分析框架被用于评估毒性的三个方面。第一部分说明了对啮齿动物中氯仿肝毒性和肝癌致癌作用作用模式的基本理解如何能够取代低剂量线性假设。第二部分描述了我们对致癌作用分子方面理解的进展如何使我们能够在关键事件框架中考虑遗传毒性致癌作用的关键步骤。第三部分讨论内分泌干扰物的情况，在这种情况下，关于阈值的最重要问题是对激素活性内源性背景的可能叠加性。每个例子都表明，当前关于阈值的假设可以得到完善。了解毒理学效应所涉及事件中的个体间变异性，可能有助于确定真正的群体阈值。
