Stallard N, Whitehead A
Department of Applied Statistics, University of Reading, UK.
Hum Exp Toxicol. 1995 Dec;14(12):974-90. doi: 10.1177/096032719501401206.
The fixed-dose procedure (FDP), proposed by the British Toxicology Society, and the acute-toxic-class (ATC) method, proposed by the German Federal Health Authority, provide alternatives to the LD50 test for classifying substances by their acute oral toxicity. This paper presents a mathematical model that is used to compare the two procedures in terms of their classification properties and the required numbers of animals. It is found that the classification properties of the procedures depend on the dose levels used, the number of animals tested per dose and the criteria that are used to decide whether testing should continue at a higher or lower dose. For substances with steep dose-response curves, the most likely classification is determined chiefly by the choice of the dose levels whilst the number of animals and continuation criteria used are increasingly important for substances with dose-response curves with a smaller slope. The use of toxicity as a possible endpoint as in the FDP and the use of a two-stage testing procedure at each dose as in the ATC method are both found to reduce the expected numbers of animals required with little effect on the classification properties. On the strength of these findings it is indicated that a new procedure combining the dose levels and testing approach of the ATC method with the inclusion of toxicity as an endpoint as in the FDP would be more efficient than either the FDP or the ATC method.
英国毒理学协会提出的固定剂量法（FDP）以及德国联邦卫生局提出的急性毒性分级（ATC）法，为通过急性经口毒性对物质进行分类提供了替代半数致死剂量（LD50）测试的方法。本文提出了一个数学模型，用于从分类特性和所需动物数量方面比较这两种方法。研究发现，这些方法的分类特性取决于所使用的剂量水平、每个剂量测试的动物数量以及用于决定是否应在更高或更低剂量下继续测试的标准。对于剂量反应曲线陡峭的物质，最可能的分类主要由剂量水平的选择决定，而对于剂量反应曲线斜率较小的物质，所使用的动物数量和继续测试的标准则变得越来越重要。如FDP中使用毒性作为可能的终点以及如ATC法中在每个剂量下使用两阶段测试程序，都能减少所需动物的预期数量，且对分类特性影响不大。基于这些发现表明，将ATC法的剂量水平和测试方法与FDP中包含毒性作为终点相结合的新方法，将比FDP或ATC法更有效。
