Probing the relevance of synergistic lipid membrane disruption to the eye irritation of binary mixed nonionic surfactants

Nonionic surfactant aerosols play a crucial role in many industries, but they can cause acute irritation to users' eyes during spraying. This cytotoxic process is associated with corneal cell necrosis causing cell membrane disruption. Industrial grade surfactants are typically polydisperse mixtures described by their nominal chemical structure but how the polydispersity affects their interactions with cell membrane, remains largely unexplored. A better understanding could benefit product formulations to maximise their efficiency whilst minimising their toxicity to the users. In this study, poly-oxyethylene glycol monododecyl ethers (C12E4, C12E23) were used to form ideal binary surfactant mixtures. The cytotoxicities of mono and polydispersed surfactants towards human corneal epithelial cells were examined, followed by a series of biophysical characterisations of interactions between surfactants and model cell membranes. Notably, to probe the journey of individual C12E4 and C12E23 surfactant molecules across the cell membrane from a binary surfactant mixture, "two-colour" neutron reflection measurements were achieved via Hydrogen/Deuterium substitution. The relative distributions of C12E4 and C12E23 across cell membranes and their nanostructural conformations revealed a synergistic membrane-lytic ability initiated by surfactant mixing, with the more hydrophobic C12E4 exhibiting stronger membrane binding potency than the hydrophilic C12E23. The exact molar ratio of C12E4 against C12E23 in the mixture determined how the mixed surfactant interacted with the cell membrane, and how the process directly impacted cytotoxicity and eye irritation. Thus, the cytotoxicity of polydisperse surfactants is not the same as monodisperse surfactant of the same average structure. This work provides a useful basis for the assessment of surfactant mixing by balancing their efficiency and toxicity.