Wageningen University, Environmental Economics and Natural Resources Group, Wageningen, the Netherlands.
BASF SE, Experimental Toxicology and Ecology, Ludwigshafen, Germany.
ALTEX. 2017;34(4):525-538. doi: 10.14573/altex.1606271. Epub 2017 Feb 23.
Test methods to assess the skin sensitization potential of a substance usually use threshold criteria to dichotomize continuous experimental read-outs into yes/no conclusions. The threshold criteria are prescribed in the respective OECD test guidelines and the conclusion is used for regulatory hazard assessment, i.e., classification and labelling of the substance. We can identify a borderline range (BR) around the classification threshold within which test results are inconclusive due to a test method's biological and technical variability. We quantified BRs in the prediction models of the non-animal test methods DPRA, LuSens and h-CLAT, and of the animal test LLNA, respectively. Depending on the size of the BR, we found that between 6% and 28% of the substances in the sets tested with these methods were considered borderline. When the results of individual non-animal test methods were combined into integrated testing strategies (ITS), borderline test results of individual tests also affected the overall assessment of the skin sensitization potential of the testing strategy. This was analyzed for the 2-out-of-3 ITS: Four out of 40 substances (10%) were considered borderline. Based on our findings we propose expanding the standard binary classification of substances into "positive"/"negative" or "hazardous"/"non-hazardous" by adding a "borderline" or "inconclusive" alert for cases where test results fall within the borderline range.
测试方法通常使用阈值标准将连续的实验读数分为是/否结论，以评估物质的皮肤致敏潜力。阈值标准规定在各自的 OECD 测试指南中，结论用于监管危害评估，即物质的分类和标签。我们可以在分类阈值周围识别一个边界范围（BR），由于测试方法的生物学和技术变异性，测试结果在此范围内不确定。我们分别在非动物测试方法 DPRA、LuSens 和 h-CLAT 以及动物测试 LLNA 的预测模型中量化了 BR。根据 BR 的大小，我们发现用这些方法测试的物质中，有 6%到 28%的物质被认为是边界物质。当个体非动物测试方法的结果组合成综合测试策略（ITS）时，个体测试的边界测试结果也会影响测试策略对皮肤致敏潜力的整体评估。对于 2 取 3 的 ITS，我们进行了分析：40 种物质中有 4 种（10%）被认为是边界物质。基于我们的发现，我们建议通过在测试结果落在边界范围内的情况下添加“边界”或“不确定”警报，将物质的标准二进制分类“阳性”/“阴性”或“危害”/“非危害”扩展为“阳性”/“阴性”或“危害”/“非危害”。
