Phillips J C, Gibson W B, Yam J, Alden C L, Hard G C
British Industrial Biological Research Association, Carshalton, Surrey, UK.
Food Chem Toxicol. 1990 May;28(5):375-94. doi: 10.1016/0278-6915(90)90112-z.
Quantitative structure-activity relationship (QSAR) studies and in vitro studies in which correlations with LD50 have been sought are reviewed. QSAR methods have shown some success in relating LD50 to certain physicochemical properties of the compound, particularly lipophilicity, but have been less successful in correlating LD50 with electronic properties of molecules (related to reactivity) or structural variables. It is concluded that insufficient evidence is available to determine whether QSAR methods can be of general use in predicting the acute toxicity (LD50) of chemicals, and that until further work is undertaken to develop QSARs for a much wider range of homologous series of compounds, this situation is unlikely to be resolved. New chemical descriptors that are more directly relevant to the mechanism of toxic action of the chemical should be identified. Cytotoxicity in vitro is poorly correlated with LD50, but good correlations have been obtained between toxicity in vivo and in vitro, using systems in which the toxic endpoint reflects the probable mechanism(s) of acute toxicity of the test chemical (e.g. the assessment of neurotoxins using neural cell systems). Therefore, it seems that the successful application of in vitro methods requires a better understanding of the mechanisms of acute toxicity in vivo and the development of mammalian cell culture systems that can model more closely the metabolic fate of the chemicals in vivo.
本文综述了定量构效关系（QSAR）研究以及寻求与半数致死剂量（LD50）相关性的体外研究。QSAR方法在将LD50与化合物的某些物理化学性质（特别是亲脂性）相关联方面已取得了一些成功，但在将LD50与分子的电子性质（与反应性相关）或结构变量相关联方面则不太成功。得出的结论是，尚无足够证据确定QSAR方法是否可普遍用于预测化学品的急性毒性（LD50），并且在开展进一步工作以针对更广泛的同系物系列开发QSAR之前，这种情况不太可能得到解决。应确定与化学品毒性作用机制更直接相关的新化学描述符。体外细胞毒性与LD50的相关性较差，但使用毒性终点反映受试化学品急性毒性可能机制的系统（例如使用神经细胞系统评估神经毒素），已在体内和体外毒性之间获得了良好的相关性。因此，似乎体外方法的成功应用需要更好地理解体内急性毒性机制，并开发能够更紧密模拟化学品在体内代谢命运的哺乳动物细胞培养系统。
