Institute for Clinical Pharmacology and Toxicology, Charité-Universitätsmedizin Berlin, Germany.
Arch Toxicol. 2012 Jan;86(1):17-25. doi: 10.1007/s00204-011-0732-z. Epub 2011 Jul 7.
The TTC concept employs available data from animal testing to derive a distribution of NOAELs. Taking a probabilistic view, the 5th percentile of the distribution is taken as a threshold value for toxicity. In this paper, we use 824 NOAELs from repeated dose toxicity studies of industrial chemicals to re-evaluate the currently employed TTC values, which have been derived for substances grouped according to the Cramer scheme (Cramer et al. in Food Cosm Toxicol 16:255-276, 1978) by Munro et al. (Food Chem Toxicol 34:829-867, 1996) and refined by Kroes and Kozianowski (Toxicol Lett 127:43-46, 2002), Kroes et al. 2000. In our data set, consisting of 756 NOAELs from 28-day repeated dose testing and 57 NOAELs from 90-days repeated dose testing, the experimental NOAEL had to be extrapolated to chronic TTC using regulatory accepted extrapolation factors. The TTC values derived from our data set were higher than the currently used TTC values confirming the safety of the latter. We analysed the prediction of the Cramer classification by comparing the classification by this tool with the guidance values for classification according to the Globally Harmonised System of classification and labelling of the United Nations (GHS). Nearly 90% of the chemicals were in Cramer class 3 and assumed as highly toxic compared to 22% according to the GHS. The Cramer classification does underestimate the toxicity of chemicals only in 4.6% of the cases. Hence, from a regulatory perspective, the Cramer classification scheme might be applied as it overestimates hazard of a chemical.
TTC 概念利用动物测试的可用数据来推导出无可见不良作用水平（NOAEL）的分布。从概率的角度来看，分布的第 5 个百分位数被视为毒性的阈值。在本文中，我们使用了 824 个来自工业化学品重复剂量毒性研究的 NOAEL，重新评估了目前使用的 TTC 值，这些值是由 Munro 等人根据 Cramer 方案（Cramer 等人，1978 年，食品化学毒物学 16:255-276）对物质进行分组而得出的（食品化学毒物学 34:829-867，1996 年），并由 Kroes 和 Kozianowski（毒理学快报 127:43-46，2002 年），Kroes 等人进行了改进。在我们的数据集中，包括 28 天重复剂量测试的 756 个 NOAEL 和 90 天重复剂量测试的 57 个 NOAEL，实验性 NOAEL 必须使用监管部门接受的外推因子外推到慢性 TTC。从我们的数据集中得出的 TTC 值高于目前使用的 TTC 值，证实了后者的安全性。我们通过将该工具的分类与联合国全球统一分类标签制度（GHS）的分类指导值进行比较，分析了 Cramer 分类的预测。近 90%的化学品属于 Cramer 第 3 类，与 GHS 相比，被认为是高度有毒的，占 22%。只有 4.6%的情况下，Cramer 分类法低估了化学品的毒性。因此，从监管的角度来看，Cramer 分类方案可以应用，因为它高估了化学品的危害。
