Polycyclic Aromatic Hydrocarbons (PAHs) are persistent and toxic organic pollutants to which humans are exposed via inhalation, dermal absorption, and ingestion, increasing cancer risk, particularly among smokers and occupationally exposed individuals. This research aims to expand current knowledge by identifying the oral mucosae as an additional gateway for PAHs, owing to their high lipophilicity and the greater permeability of oral mucosae to xenobiotics, a finding that is particularly relevant given the established correlation between tobacco-derived PAHs and oral, head, and neck cancers. Here, ex vivo permeation studies were carefully designed using vertical Franz diffusion cells and porcine buccal and sublingual mucosae, a widely used ex vivo model for permeability studies. Five PAHs congeners were selected as representative of those highlighted from the US EPA as priority control pollutants: fluorene, acenaphthene, phenanthrene, pyrene and benzo(a)pyrene. The studied PAHs were found to permeate the oral mucosae, likely via passive diffusion (permeation ∝ logP), suggesting a potential relevant contribution to the overall systemic PAHs burden and thus toxicity, especially for individuals with pronounced oromucosal exposure, such as smokers. Additionally, all PAHs exhibited significant retention in the mucosal tissues, suggesting possible loco-regional toxicity. Specifically, the observed BaP accumulation in the buccal and sublingual mucosae (1781.27±397.64 and 1338.78±269.47 ng/cm 2 , respectively) may support its correlation with oral cancers. Despite the experimental model not fully mimic the complexity of living system (e.g., enzymatic activity, active transport processes, blood perfusion, real-life exposure scenario), these findings address a major gap in the literature by identifying the oral mucosae as a previously unrecognized entry route for PAHs, a key point since the oral cavity is part of both the gastrointestinal and respiratory systems, already recognized PAHs exposure routes. The evidence reported here provides both a foundation for further multidisciplinary investigations as well as a rationale for developing cosmetic/medical devices aimed at detoxifying the oral cavity from PAHs. This study aims to expand knowledge on PAHs permeation and accumulation through oral mucosal tissues. Demonstrating PAHs permeation and accumulation through this route would have major clinical and toxicological implications, including identifying a new exposure route, refining toxicokinetic, elucidating mechanisms linking tobacco-derived PAHs to head and neck carcinogenesis, and guiding preventive interventions to limit oral exposure (e.g., development of PAHs-sequestering cosmetics or medical devices). • Oral cavity: an unexplored entry route for PAHs absorption by ingestion/inhalation • From 10- to 150-fold PAHs aqueous solubility increase with cosolvents (e.g. PEG200) • PAHs permeate oral mucosae (K p ∝ aqueous solubility) leading to systemic toxicity • PAHs accumulate into oral tissues (Ac ∝ aqueous solubility) causing local toxicity • BaP (IARC group n. 1–carcinogenic to humans) shows high affinity for oral mucosae
Mantia et al. (Sun,) studied this question.