On the contribution of the phagocytosis and the solubilization to the iron oxide nanoparticles retention in and elimination from lungs under long-term inhalation exposure

• Rats inhaled Fe2O3 nanoparticles (NPs) at a low concentration for 4 h a day, 5 days a week during 3, 6 or 10 months.
• Mathematical modeling shows that retention of the NPs in lungs is controlled by physiological and solubilization mechanisms.
• TEM images revealed NPs accumulated within alveolocytes and myelin sheaths of brain neural fibers.

The aim of our study was to test a hypothesis according to which the pulmonary clearance vs. retention of metal oxide nanoparticles (NPs) is controlled not only by physiological mechanisms but also by their solubilization which in some cases may even prevail.Airborne Fe2O3 NPs with the mean diameter of 14 ± 4 nm produced by sparking from 99.99% pure iron rods were fed into a nose-only exposure tower. Rats were exposed to these NPs for 4 h a day, 5 days a week during 3, 6 or 10 months at the mean concentration of 1.14 ± 0.01 mg/m3. NPs collected from the air exhausted from the exposure tower proved insoluble in water but dissolved markedly in the cell free broncho-alveolar lavage fluid supernatant and in the sterile bovine blood serum. The Fe2O3 content of the lungs and lung-associated lymph nodes was measured by the Electron Paramagnetic Resonance (EPR) spectroscopy.We found a relatively low but significant pulmonary accumulation of Fe2O3, gradually increasing with time. Besides, we obtained TEM-images of nanoparticles within alveolocytes and the myelin sheaths of brain fibers associated with ultrastructural damage.We have developed a multicompartmental system model describing the toxicokinetics of inhaled nanoparticles after their deposition in the lower airways as a process controlled by their (a) high ability to penetrate through the alveolar membrane; (b) active endocytosis; (c) in vivo dissolution.To conclude, both experimental data and the identification of the system model confirmed our initial hypothesis and demonstrated that, as concerns iron oxide NPs of the dimensions used, the dissolution-depending mechanisms proved to be dominant.