Imogolite nanotube modifications impact pulmonary toxicity in mice: implications for safe and sustainable by design (SSbD).

BACKGROUND: Imogolite is a naturally occurring hollow aluminosilicate nanotube with potential for engineered applications due to its high aspect ratio, hydrophilicity, and polarization. However, these same features raise concerns about potential adverse health effects. These concerns parallel those associated with multi-walled carbon nanotubes (MWCNTs), which are known to cause inflammation, fibrosis, and cardiovascular effects. The purpose of this study was to investigate how surface functionalization of imogolite influences its toxicity and biological response, with the aim of informing safer design of nanomaterials. Female C57BL/6J mice were exposed via intratracheal instillation to 6, 18, or 54 µg of hydroxylated (Imo-OH) or methylated (Imo-CH(3)) imogolite. Toxicity was assessed at day 1, 28 and 90 post-exposure, with carbon black (Printex90) nanoparticles as a benchmark. Pulmonary inflammation and systemic acute-phase response were assessed as key indicators of chronic health effects. RESULTS: Physicochemical characterization showed that Imo-OH dispersed as single nanotubes, while Imo-CH(3) formed bundles, impacting surface accessibility. Both variants induced strong pulmonary inflammation, but Imo-OH elicited a stronger and more persistent neutrophil influx, lymphocyte recruitment, and acute-phase response. Cytotoxicity was low, though elevated total protein in bronchoalveolar lavage fluid indicated altered alveolar-capillary barrier integrity, especially for Imo-OH. Lung histopathology confirmed more severe lung lesions, macrophage aggregates, and type II pneumocyte hyperplasia in the Imo-OH group. Benchmark dose modeling revealed that Imo-OH's inflammatory potential surpassed other high aspect ratio nanomaterials. CONCLUSIONS: Both imogolite variants induced pulmonary inflammation and an acute-phase response in mice; however, these effects were markedly reduced for the methylated imogolite (Imo-CH(3)). In addition to surface functionalization, factors like bundle formation and by-product particles may also influence toxicity. These findings emphasize the pivotal role of surface chemistry-and associated structural properties-in shaping the biological response to nanomaterials, reinforcing the need for thoughtful design strategies to promote safer applications in nanotechnology.