Gubbels-van Hal W M L G, Blaauboer B J, Barentsen H M, Hoitink M A, Meerts I A T M, van der Hoeven J C M
NOTOX B.V., 5203 DL 's-Hertogenbosch, The Netherlands.
Regul Toxicol Pharmacol. 2005 Aug;42(3):284-95. doi: 10.1016/j.yrtph.2005.05.002.
Various in vitro and in silico methods without animals were applied to 10 substances listed on ELINCS with a complete VIIA base-set available at NOTOX. The hazard assessment for these substances was performed on basis of available non-animal data, QSAR, PBBK-modelling and additional, new in vitro testing was applied. Based on these data predictions on fish toxicity, acute toxicity, skin- and eye-irritation, sensitisation, and toxicity after repeated dosing were made. The predictions were compared with the outcome of the in vivo tests. Nine out of ten predictions on fish LC(50) proved to be correct. For skin- and eye-irritation 70% was predicted correctly. Sensitisation was predicted correctly for 7 out of 10 substances, but three false negatives were found. Acute oral toxicity (LD(50)) and repeated dose toxicity were less successful (5 out of 10 and 2 out of 10 correct predictions, respectively); application of the PBBK model proved successful. Acute dermal toxicity was predicted correctly in 9 out of 10 cases. In general an over-estimation of systemic toxicity was found, which can be explained by an over-prediction of cytotoxicity and worst case assumptions on absorption and binding to (plasma) proteins. This integrated approach leads to a 38% reduction of laboratory animals.
多种无动物参与的体外和计算机模拟方法被应用于欧洲现有商业化学物质目录（ELINCS）列出的10种物质，这些物质在NOTOX有完整的VIIA基础数据集。基于可用的非动物数据、定量构效关系（QSAR）、生理药代动力学（PBBK）模型以及额外的新体外测试，对这些物质进行了危害评估。基于这些数据，对鱼类毒性、急性毒性、皮肤和眼睛刺激性、致敏性以及重复给药后的毒性进行了预测。将这些预测结果与体内试验结果进行了比较。十分之九的鱼类半数致死浓度（LC(50)）预测被证明是正确的。皮肤和眼睛刺激性的预测正确率为70%。十分之七的物质致敏性预测正确，但发现了三例假阴性结果。急性口服毒性（半数致死剂量（LD(50)））和重复剂量毒性的预测成功率较低（分别为十分之五和十分之二的预测正确）；PBBK模型的应用被证明是成功的。十分之九的急性皮肤毒性预测正确。总体而言，发现存在对全身毒性的高估，这可以通过对细胞毒性的过度预测以及对吸收和与（血浆）蛋白结合的最坏情况假设来解释。这种综合方法使实验动物数量减少了38%。
