Using membrane–water partition coefficients in a critical membrane burden approach to aid the identification of neutral and ionizable chemicals that induce acute toxicity below narcosis levels†

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.