Biodistribution and toxicity following a single or repeated pharyngeal aspiration of titanium dioxide nanoparticles: Determination of maximum allowable dose level

Establishing reasonable exposure conditions is crucial for maximizing the potential benefits of nanomaterials while ensuring their safety. We first identified the effects of overdose on lung tissue damage and deposition levels under different exposure scenarios (50 μg four times, 100 μg twice, and 200 μg once). Blood levels of IP and K changed significantly in the group that received a single 200 μg dose. In all TiONP-treated groups, the amount of TiONPs remaining in the lung tissues increased dramatically, accompanied by an increase in the total number of pulmonary cells and a decrease in the proportion of macrophages. A type I helper T cell-dominant inflammatory response was observed across all TiONP-treated groups, and the accumulation of pigmented macrophages was most notable in the lung tissue of mice exposed to a single dose of 200 μg of TiONPs. We then investigated biodistribution and clearance levels over time after a single dose (25 and 50 μg/lung). The amount of TiONPs remaining in the lung decreased over time. However, approximately32.6 % and 58.3 % of the amounts detected on Day 1 after a single dose persisted until Day 28 in the lungs of mice given 25 μg and 50 μg, respectively. Translocation to other tissues was more notable in mice exposed to the highest dose, and more interestingly, the TiONPs that moved to the liver showed limited clearance by Day 28 after a single dose. In conclusion, overdosed TiONPs may facilitate tissue accumulation and translocation by affecting the function of alveolar macrophages. Additionally, considering the high tissue deposition rate, we suggest that the maximum allowable dose level for the respiratory tract should be carefully determined.