Baumer Andreas, Bittermann Kai, Klüver Nils, Escher Beate I
Helmholtz Centre for Environmental Research - UFZ, Permoserstr. 15, DE-04318 Leipzig, Germany.
Environ Sci Process Impacts. 2017 Jul 19;19(7):901-916. doi: 10.1039/c7em00099e.
In numerous studies on the toxicity of ionisable organic chemicals, it has been shown that the toxicity was typically higher, when larger fractions of the neutral species were present. This observation was explained in some cases by slower uptake of charged species. In other cases it was suggested that the neutral species has intrinsically higher toxicity than the charged species or is alone responsible for the toxicity. However, even permanently charged and organic chemicals with multiple acid and base functional groups and zwitterions are toxic. We set out to reconcile the divergent views and to compare the various existing models for describing the pH-dependence of toxicity with the goal to derive one model that is valid independent of the type and number of charges on the molecule. To achieve this goal we measured the cytotoxicity of 18 acidic, 15 basic and 9 multiprotic/zwitterionic pharmaceuticals at pH 5.5 to pH 9 with the bioluminescence inhibition test using Aliivibrio fischeri (Microtox assay). This assay is useful for an evaluation of various models to describe pH-dependent toxicity because the majority of chemicals act as baseline toxicants in this 30 min cytotoxicity assay. Therefore baseline toxicity with constant membrane concentrations of the sum of all chemical species of approximately 200 mmol kg served for the validation of the suitability of the various tested models. We confirmed that most tested pharmaceuticals acted as baseline toxicants in this assay at all examined pH values, when toxicity was modeled with a mixture model of concentration addition between the neutral species and all charged species. An ion trapping model, that assumes that the membrane permeability of charged species is kinetically limited, improved model predictions for some pharmaceuticals and pH values. However, neither unhindered uptake nor no uptake of the charged species were ideal models; the reality lies presumably between the two limiting cases with a slower uptake of the charged species than the neutral species. For practical applications a previously developed QSAR model with the ionisation-corrected liposome-water distribution ratio as the sole physicochemical descriptor proved to be generally applicable for all ionisable organic chemicals including those with multiple charges and zwitterions.
在众多关于可电离有机化学品毒性的研究中，结果表明，当中性物种所占比例较大时，毒性通常更高。在某些情况下，这种现象被解释为带电物种的摄取速度较慢。在其他情况下，则有人认为中性物种本身的毒性高于带电物种，或者单独导致了毒性。然而，即使是永久带电的、带有多个酸和碱官能团的有机化学品以及两性离子也是有毒的。我们着手调和这些不同观点，并比较现有的各种描述毒性与pH值相关性的模型，目标是得出一个与分子上电荷的类型和数量无关的有效模型。为实现这一目标，我们使用费氏弧菌生物发光抑制试验（微毒性试验），在pH 5.5至pH 9的条件下测量了18种酸性、15种碱性和9种多质子/两性离子药物的细胞毒性。该试验对于评估各种描述pH依赖性毒性的模型很有用，因为在这个30分钟的细胞毒性试验中，大多数化学品都作为基线毒物起作用。因此，所有化学物种总和的膜浓度恒定约为200 mmol/kg时的基线毒性，用于验证各种测试模型的适用性。我们证实，当用中性物种和所有带电物种之间的浓度加和混合模型来模拟毒性时，在所有检测的pH值下，大多数测试药物在该试验中都作为基线毒物起作用。一种离子捕获模型，即假设带电物种的膜通透性受动力学限制，对于某些药物和pH值改善了模型预测。然而，带电物种的无阻碍摄取和不摄取都不是理想模型；实际情况可能介于这两种极限情况之间，带电物种的摄取比中性物种慢。对于实际应用，一个先前开发的以电离校正脂质体 - 水分配比作为唯一物理化学描述符的QSAR模型，被证明普遍适用于所有可电离有机化学品，包括那些带有多个电荷和两性离子的化学品。
