An Adverse Outcome Pathway for Food Nanomaterial-induced Intestinal Barrier Disruption

Introduction Ingestion of nanomaterials (NMs) might impair intestinal barrier, but the underlying mechanisms remain evasive, and evidence is not systematically gathered or produced. A mechanistic-based approach would be instrumental to assess if relevant NMs disrupt intestinal barrier to support NM risk assessment in the food sector. Methods Here, we developed an adverse outcome pathway (AOP) based on biological plausibility and by leveraging existing information of an existing NM relevant AOP leading to hepatic outcomes. We then extracted the current evidence existing in the literature for a targeted selection of NMs with high food sector relevance, namely ZnO, CuO, FeO, SiO 2 , Ag NMs and nanocellulose. Results We propose a new AOP (AOP530) that starts with endocytic lysosomal uptake leading to lysosomal disruption inducing mitochondrial dysfunction. Mitochondrial impairments can lead to cell injury/death and disrupt the intestinal barrier. The evidence collected supports that those food NMs can be taken up by intestinal cells and indicates that intestinal barrier disruption by Ag, CuO, SiO 2 NMs might occur whilst only few studies support that outcome for FeO, ZnO. Lysosomal disruption and mitochondrial dysfunction are rarely evaluated. For nanocellulose, none of the studies report toxic-related events. Conclusions Collecting the existing scientific evidence supporting our AOP linking NM uptake to intestinal barrier impairments allowed us to highlight current evidence gaps but also data inconsistencies. Those latter could be associated with the variety of stressors, biological systems and KE-related assays used in the different studies, calling for further harmonized methodologies and production of mechanistic evidence in the safety regulatory assessment of NMs in the food sector.