Influence of lung overload and exposure scenarios on recovery following inhalation of an alumina nanoparticle and HCl gas mixture

Co-exposure to alumina nanoparticles (Al₂O₃ NPs) and hydrogen chloride (HCl) can occur in combustion-related environments, particularly in aerospace and defense sectors. While acute pulmonary toxicity of these agents has been described, the impact of temporal exposure patterns on the persistence of inflammation and the link to cumulative lung burden and clearance efficiency remains poorly understood. Following nose-only inhalation in rats, we compared two exposure regimens to equivalent concentration ranges (1–20 mg/m³ Al₂O₃ with 5 ppm HClg): a short-term scenario (four consecutive days) and a long-term intermittent scenario (once a week for 8 weeks). Lung burden, clearance kinetics, inflammatory responses, molecular stress markers, as well as potential longer-term impact and recovery were assessed at 1 and 28 days post-exposure. Short term scenario induced a dose-dependent neutrophilic inflammation that resolved by day 28, consistent with partial restoration of alveolar clearance. In contrast, repeated long-term scenario resulted in significantly higher retained lung burdens, reduced clearance efficiency, and persistent neutrophilic inflammation at day 28. Surface area-based estimations indicated that the highest long-term scenario exceeded established NPs lung overload thresholds, suggesting a mechanism involving impaired clearance and sustained inflammatory signaling. Sustained parenchymal cytokine activation and altered stress-response gene expression further supported the establishment of a non-resolving inflammatory state. However, importantly, persistent inflammation was not associated with tissular damage or genotoxicity. These findings demonstrate that temporal exposure pattern is a critical determinant of lung overload and recovery capacity following inhalation of poorly soluble NPs. Repeated intermittent exposure promotes clearance impairment and persistent inflammation, underscoring the importance of dose metrics and exposure frequency in risk assessment. Not applicable. Short-term scenario shows transient and reversible inflammation. Long-term scenario induces persistent neutrophilic inflammation. Analysis of recovery profiles highlights the importance of long-term evaluation. Pulmonary inflammation and clearance are linked to overload conditions. Persistent inflammation is observed in the absence of detectable tissue remodeling or genotoxicity.