外源化合物在鱼体内生物半减期的QSAR模型

生物半减期(t1/2)是评价外源化合物在鱼体内蓄积效应的重要参数。实验测定t_(1/2)的速度慢、成本高,难以满足化学品生态风险评价的需求,需要发展替代实验的模型预测方法。本研究搜集了653种化合物t1/2实测值,采用多元线性回归(MLR)和支持向量机(SVM) 2种方法,建立了鱼体logt1/2的定量构效关系(QSAR)预测模型。MLR模型的校正决定系数(R(adj)~2)为0.751,均方根误差(RMSE_(train))为0.587,去一法交叉验证系数(Q_(LOO)~2)为0.735,外部验证系数(Q_(ext)~2)为0.682,这表明模型具有较好的拟合度、稳健性和预测能力。SVM模型具有更好的拟合和预测能力(R_(adj)~2=0.839,RMSE_(train)=0.457,Q_(ext)~2=0.708)。采用Williams法对模型的应用域进行表征。所建模型可用于预测多环芳烃、多氯联苯、多溴联苯醚、有机磷农药、药物等典型化合物,以及其他烷烃、环烷烃、烯烃、醇、醚、酸、酯、酮、含卤素化合物、芳香族化合物、含硫、氮、磷化合物的在鱼体内的logt1/2值。     

Retention of PCDDS and PCDFS in the liver of the rat and hamster after oral administration of a municipal incinerator fly ash extract

A single dose of an extract from 16 and 5 grams fly ash was administered orally to male rats and hamsters. In the rat 1,2,3,7,8‐PnCDD had the highest retention (41%) in the liver. The congener with the highest retention in the liver of the hamster was 2,3,4,7,8‐PnCDF (70.9%). In two oral multiple dose experiments with rats, highest liver retentions were found for 1,2,3,7,8‐PnCDD (51.7%) and 1,2,3,6,7,8‐HxCDD (59.8%). With the exception of 2,3,4,6,7‐PnCDF, all PCDDs and PCDFs retained in the liver of rat and hamster had a 2,3,7,8 chlorine substitution pattern. In both types of experiments with rats the retention of 2,3,7,8‐TCDF in the liver was very low, 1.1–2.8% of the total dose. In the liver of the hamster retention of 2,3,7,8‐TCDF was almost equal to that of 2,3,7,8‐TCDD, indicating that the hamster is probably metabolizing 2,3,7,8‐TCDF Jess efficiently than the rat. In all experiments 1,2,3,7,8‐PnCDD and 2,3,4,7,8‐PnCDF were retained in the liver more efficiently than 2,3,7,8‐TCDD. Based on first order pharmacokinetic calculations, it was found that the earlier published k_e value of 0.55 for 2,3,7,8‐TCDF in the liver of the rat was also applicable. Using the same calculations for 2,3,7,8‐TCDD (k_e = 0.029) a 30% difference was found between calculated and actual measurements, but calculated results were still within the 95% confidence limits of the actual measurements.     

Quantitative structure‐activity relationships of hydrophobic organic chemicals 1

Quantitative structure‐activity relationships of hydrophobic organic chemicals were studied based on equations we established. Results showed that observed toxicity of hydrophobic organic chemicals were correlated to two physical‐chemical parameters: reaction equilibrium constant of target molecule‐organic chemical; octanol/water partition coefficient. Regression results showed that the molecular connectivity index of first‐order was an ideal parameter instead of the equilibrium constant. Good relationships between toxicity data and the two parameters were found for three aquatic organisms with a wide range of chemicals.     

QSAR技术对高关注化学物质生态环境毒理风险预测

将国外先进的QSAR技术应用于高关注化学物质(SVHC)的生态环境毒理风险预测中,以促进QSAR技术在生态环境毒理学领域的发展和应用. 采用国外先进的经科学验证的ECOSAR预测模型,对欧洲化学品管理署(ECHA)于2008年10月28日正式公布的15种SVHC的生态环境毒理风险进行了预测. 结果显示,对于蒽,4,4′-二氨基二苯甲烷和邻苯二甲酸二丁酯等9种化学物质,ECOSAR模型的预测结果与试验结果较为接近. 危害性分级标准预测结果显示,这9种化学物质为极高风险化学物质,这与ECHA将它们列为SVHC的结论一致. 对于另外6种化学物质(二水合重铬酸钠、三乙基砷酸酯、二氯化钴、五氧化二砷、三氧化二砷和砷酸氢铅),ECOSAR模型预测结果可信度不高. 对于15种SVHC和ECOSAR的预测结果准确率达到60%. ECOSAR预测模型在一定程度上能够提供与试验结果接近的化学物质生态环境毒理风险评价结果,作为一种重要的非试验科学技术手段,能够在一定程度上满足化学品管理的需要.      

取代联苯的定量结构活性相关及联合毒性研究

测定了18种取代联苯对大型蚤(Daphnia magna)24h的单一毒性(24h-EC₅₀)及其混合物联合毒性.对单一毒性进行了定量结构活性相关(QSAR)分析,建立了辛醇-水分配系数(lgK_ow)模型,理论线性溶剂化能相关(TLSER)模型及量子化学参数模型,表明量子化学参数模型能很好地预测取代联苯的单一毒性.混合物联合毒性研究表明,取代联苯的联合毒性机制为浓度相加效应,并且根据浓度相加预测了混合物半数抑制浓度(EC_50mix),预测值与实验值非常吻合.     

部分酯类化合物对四膜虫毒性的全息QSAR分析

全息定量结构活性相关分析(HolographicQSAR或HQSAR)能快速而简便的产生高统计质量和预测能力的QSAR模型。采用HQSAR分析了30个酯类化合物对四膜虫的毒性与分子结构之间的关系,及分子碎片大小和全息长度对QSAR模型的影响,得到的最佳QSAR模型的R2为0.981,Q2为0.912。此外还应用色码讨论了离群值产生的可能原因。