The risk assessment of thousands of chemicals used in our society benefits from adequate grouping of chemicals based on the mode and mechanism of toxic action (MoA). We measure the phospholipid membrane–water distribution ratio (D_MLW) using a chromatographic assay (IAM-HPLC) for 121 neutral and ionized organic chemicals and screen other methods to derive D_MLW. We use IAM-HPLC based D_MLW as a chemical property to distinguish between baseline narcosis and specific MoA, for reported acute toxicity endpoints on two separate sets of chemicals. The first set comprised 94 chemicals of US EPA's acute fish toxicity database: 47 categorized as narcosis MoA, 27 with specific MoA, and 20 predominantly ionic chemicals with mostly unknown MoA. The narcosis MoA chemicals clustered around the median narcosis critical membrane burden (CMB_narc) of 140 mmol kg⁻¹ lipid, with a lower limit of 14 mmol kg⁻¹ lipid, including all chemicals labelled Narcosis_I and Narcosis_II. This maximum ‘toxic ratio’ (TR) between CMB_narc and the lower limit narcosis endpoint is thus 10. For 23/28 specific MoA chemicals a TR >10 was derived, indicative of a specific adverse effect pathway related to acute toxicity. For 10/12 cations categorized as “unsure amines”, the TR <10 suggests that these affect fish via narcosis MoA. The second set comprised 29 herbicides, including 17 dissociated acids, and evaluated the TR for acute toxic effect concentrations to likely sensitive aquatic plant species (green algae and macrophytes Lemna and Myriophyllum), and non-target animal species (invertebrates and fish). For 21/29 herbicides, a TR >10 indicated a specific toxic mode of action other than narcosis for at least one of these aquatic primary producers. Fish and invertebrate TRs were mostly <10, particularly for neutral herbicides, but for acidic herbicides a TR >10 indicated specific adverse effects in non-target animals. The established critical membrane approach to derive the TR provides for useful contribution to the weight of evidence to bin a chemical as having a narcosis MoA or less likely to have acute toxicity caused by a more specific adverse effect pathway. After proper calibration, the chromatographic assay provides consistent and efficient experimental input for both neutral and ionizable chemicals to this approach.

中文翻译：

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在临界膜负荷方法中使用膜-水分配系数来帮助识别在麻醉水平以下诱导急性毒性的中性和可电离化学物质

对我们社会中使用的数千种化学品的风险评估受益于根据毒性作用 (MoA) 的模式和机制对化学品进行充分分组。我们使用色谱法 (IAM-HPLC) 测量 121 种中性和电离有机化学品的磷脂膜-水分配比 ( D _MLW )，并筛选其他方法来推导D _MLW。我们使用基于 IAM-HPLC 的D _MLW作为区分基线麻醉和特定 MoA 的化学特性，用于报告两组不同化学品的急性毒性终点。第一组包含 US EPA 的鱼类急性毒性数据库中的 94 种化学物质：47 种被归类为麻醉性 MoA，27 种具有特定的 MoA，以及 20 种主要为离子的化学物质，其中大部分是未知的 MoA。麻醉 MoA 化学物质聚集在140 mmol kg ^{-1脂质的中值麻醉临界膜负荷 (CMB} _narc ) 周围，下限为 14 mmol kg ^-1脂质，包括标记为 Narcosis_I 和 Narcosis_II 的所有化学物质。_{CMB narc}之间的最大“毒性比”（TR）因此，下限麻醉终点为 10。对于 23/28 特定的 MoA 化学品，得出 TR >10，表明与急性毒性相关的特定不良反应途径。对于归类为“不确定胺”的 10/12 阳离子，TR <10 表明这些阳离子通过麻醉 MoA 影响鱼类。第二组包含 29 种除草剂，包括 17 种离解酸，并评估了 TR 对可能敏感的水生植物物种（绿藻和大型植物浮萍和狐尾藻）的急性毒性作用浓度)，以及非目标动物物种（无脊椎动物和鱼类）。对于 21/29 除草剂，TR >10 表明至少有一种水生初级生产者具有麻醉以外的特定毒性作用方式。鱼类和无脊椎动物的 TR 大多小于 10，特别是对于中性除草剂，但对于酸性除草剂，TR >10 表明对非目标动物有特定的不利影响。推导 TR 的已建立的关键膜方法为证据权重提供了有用的贡献，将化学品分类为具有麻醉 MoA 或不太可能具有由更具体的不良反应途径引起的急性毒性。经过适当的校准后，色谱测定为这种方法提供了中性和可电离化学品的一致和有效的实验输入。