Fraunhofer Institute for Toxicology and Experimental Medicine, Hannover, Germany.
Regul Toxicol Pharmacol. 2010 Nov;58(2):259-74. doi: 10.1016/j.yrtph.2010.06.009. Epub 2010 Jun 23.
The thresholds of toxicological concern (TTCs) define limit values for substances of unknown toxicity below which dietary intake is considered to be of no concern to human health. The TTC concept has already been used for risk assessment of e.g. food contaminants or flavoring substances and is in discussion to be applied to other classes of compounds such as cosmetic ingredients, household products, non-relevant metabolites in drinking water, and impurities in pharmaceuticals. The present publication aimed to evaluate whether the current TTC concept can also be applied to define limit values for inhalation exposure, using a data set of 203 industrial chemicals from the database RepDose. It has been shown, that the NOEC values in classes 1, 2, and 3 are distributed over six orders of magnitude resulting in a considerable overlap between the distribution curves for the three classes. Inhalation thresholds for Cramer classes 1 (compounds likely to be of low-toxicity), 2 (compounds likely to be of moderate toxicity), and 3 (compounds suspect for high toxicity) were analyzed close to the approach described by Munro for oral TTCs. The 5th percentiles NOEC of Cramer classes 1-3 result in thresholds of 1.5×10(-3) ppm for Cramer class 1 and 2.2×10(-5) ppm for Cramer class 3. A threshold could not be derived for class 2 because of the small number of compounds available. If calculated as body doses, the inhalation thresholds for classes 1 and 3 (71 and 4 μg/person/d, respectively) are considerably lower than the oral thresholds derived by Munro (1800 and 90 μg/person/d). It has been shown that one reason for this difference is the high sensitivity of the respiratory tract to local effects. In a next step, the values obtained were further refined. If organophosphates or compounds with structural alerts for genotoxicity are excluded, the TTC in Cramer class 1 increases, whereas the TTC in Cramer class 3 remains the same. Based on these analyses two inhalation TTCs for non-genotoxic compounds are proposed: 3.6×10(-3) ppm (180 μg/person/d) for Cramer class 1 and 2.4×10(-5)ppm (4 μg/person/d) for Cramer class 3.
毒理学关注阈值(TTC)定义了未知毒性物质的限值,在此限值以下,膳食摄入量被认为不会对人类健康造成危害。TTC 概念已被用于例如食品污染物或调味物质的风险评估,并正在讨论将其应用于其他化合物类别,如化妆品成分、家用产品、饮用水中非相关代谢物和药品中的杂质。本出版物旨在评估当前的 TTC 概念是否也可用于定义吸入暴露的限值,使用了来自 RepDose 数据库的 203 种工业化学品数据集。结果表明,1 类、2 类和 3 类的 NOEC 值分布在 6 个数量级,导致这 3 个类别分布曲线之间存在相当大的重叠。Cramer 1 类(低毒性化合物)、2 类(中等毒性化合物)和 3 类(高毒性化合物)的吸入阈值,采用 Munro 用于口服 TTC 的方法进行了分析。Cramer 1-3 类的第 5 个百分位 NOEC 得出的阈值分别为 Cramer 1 类的 1.5×10(-3)ppm 和 Cramer 3 类的 2.2×10(-5)ppm。由于可用化合物数量较少,因此无法为 2 类推导出阈值。如果按体剂量计算,1 类和 3 类的吸入阈值(分别为 71 和 4μg/人/d)远低于 Munro 推导出的口服阈值(1800 和 90μg/人/d)。结果表明,造成这种差异的一个原因是呼吸道对局部效应的高度敏感性。在下一步中,进一步优化了获得的值。如果排除有机磷酸酯或具有遗传毒性结构警示的化合物,则 Cramer 1 类的 TTC 会增加,而 Cramer 3 类的 TTC 保持不变。基于这些分析,提出了两种非遗传毒性化合物的吸入 TTC:Cramer 1 类为 3.6×10(-3)ppm(180μg/人/d),Cramer 3 类为 2.4×10(-5)ppm(4μg/人/d)。