Akers K S, Sinks G D, Schultz T W
Department of Pathology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814-4799, USA.
Environ Toxicol Pharmacol. 1999 Mar;7(1):33-9. doi: 10.1016/s1382-6689(98)00048-9.
Toxicity to the ciliate Tetrahymena pyriformis (log(IGC(50)(-1))) for 39 halogen-substituted alkanes, alkanols, and alkanitriles were obtained experimentally. Log(IGC(50)(-1)) along with the hydrophobic term, logK(ow) (1-octanol/water partition coefficient) and the electrophilic parameter, E(lumo) (the energy of the lowest unoccupied molecular orbital) were used to develop quantitative structure-activity relationships (QSARs). Two strong hydrophobic dependent relationships were obtained: one for the haloalkanes and a second for the haloalcohols. The relationship for the haloalkanes [log(IGC(50)(-1))=0.92 (logK(ow))-2.58; n=4, r(2)=0.993, s=0.063, f=276, Pr>f=0.0036] was not different from baseline toxicity. With the rejection of 1,3-dibromo-2-propanol as a statistical outlier, the relationship [log(IGC(50)(-1))=0.63(logK(ow))-1.18; n=19, r(2)=0.860, s=0.274, f=104, Pr>f=0.0001] was observed for the haloalcohols. No hydrophobicity-dependent model (r(2)=0.165) was observed for the halonitriles. However, an electrophilicity-dependent model [log(IGC(50)(-1))=-1.245(E(lumo))+0.73; n=15, r(2)=0.588, s=0.764, F=18.6, Pr>f=0.0009] was developed for the halonitriles. Additional analysis designed to examine surface-response modeling of all three chemical classes met with some success. Following rejection of statistical outliers, the plane [log(IGC(50)(-1))=0.60(logK(ow))-0.747(E(lumo))-0.37; n=34, r(2)=0.915, s=0.297, F=162, Pr>F=0.0001] was developed. The halogenated alcohols and nitriles tested all had observed toxicity in excess of non-reactive baseline toxicity (non-polar narcosis). This observation along with the complexity of the structure-toxicity relationships developed in this study suggests that the toxicity of haloalcohols and halonitriles is by multiple and/or mixed mechanisms of action which are electro(nucleo)philic in character.
通过实验获得了39种卤素取代的烷烃、烷醇和烷腈对梨形四膜虫的毒性（log(IGC(50)(-1))）。利用log(IGC(50)(-1))以及疏水项logK(ow)（1-辛醇/水分配系数）和亲电参数E(lumo)（最低未占分子轨道的能量）建立了定量构效关系（QSARs）。得到了两个强疏水依赖关系：一个是关于卤代烷烃的，另一个是关于卤代醇的。卤代烷烃的关系为[log(IGC(50)(-1)) = 0.92 (logK(ow)) - 2.58；n = 4，r(2) = 0.993，s = 0.063，f = 276，Pr>f = 0.0036]，与基线毒性无差异。剔除1,3-二溴-2-丙醇作为统计异常值后，观察到卤代醇的关系为[log(IGC(50)(-1)) = 0.63(logK(ow)) - 1.18；n = 19，r(2) = 0.860，s = 0.274，f = 104，Pr>f = 0.0001]。对于卤代腈，未观察到疏水依赖模型（r(2) = 0.165）。然而，为卤代腈建立了一个亲电依赖模型[log(IGC(50)(-1)) = -1.245(E(lumo)) + 0.73；n = 15，r(2) = 0.588，s = 0.764，F = 18.6，Pr>f = 0.0009]。旨在检验所有三种化学类别表面响应建模的进一步分析取得了一定成功。剔除统计异常值后，得到了平面方程[log(IGC(50)(-1)) = 0.60(logK(ow)) - 0.747(E(lumo)) - 0.37；n = 34，r(2) = 0.915，s = 0.297，F = 162，Pr>F = 0.0001]。所测试的卤代醇和卤代腈的观察毒性均超过非反应性基线毒性（非极性麻醉）。这一观察结果以及本研究中建立的结构-毒性关系的复杂性表明，卤代醇和卤代腈的毒性是通过多种和/或混合作用机制产生的，这些机制具有亲电（亲核）性质。
