In aerosol research, particle size has been mainly considered in the context of the role it plays in particle deposition along the respiratory tract. The possibility that the primary particle size may affect the fate of particles after they are deposited was explored in this study. Rats were exposed for 12 wk to aerosolized ultrafine (approximately 21 nm diameter) or fine (approximately 250 nm diameter) titanium dioxide (TiO2) particles. Other rats were exposed to TiO2 particles of various sizes (12, 21, 230, and 250 nm) by intratracheal instillation. After the rat lungs were extensively lavaged, analysis of particle content in the lavaged lungs, lavage fluid, and of lymphatic nodes was performed. Electron and light microscopy was also performed using unlavaged lungs. Both acute instillation and subchronic inhalation studies showed that ultrafine particles (approximately 20 nm) at equivalent masses access the pulmonary interstitium to a larger extent than fine particles (approximately 250 nm). An increasing dose in terms of particle numbers and a decreasing particle size promoted particle access into the interstitium. The translocation of particles into the interstitium appeared to be a function of the number of particles, and the process appeared to be related to the particle size, the delivered dose, and the delivered dose rate. A net effect of the preferential translocation of the smaller particles into the interstitium was a prolongation in their lung retention. After the 12-wk inhalation exposure, pulmonary clearance of ultrafine particles was slower (t1/2 = 501 days) than of larger particles (t1/2 = 174 days). Particles not phagocytized by alveolar macrophages in the alveoli were taken up by alveolar type I epithelial cells, which was probably the first step for interstitial access of particles. The two distinct pathways for alveolar clearance of highly insoluble particles-via the airways and via the interstitial-lymphatic route-seem to be interconnected by bronchus-associated lymphoid tissue in rats. TiO2 particle translocation into the interstitium was accompanied by an acute inflammatory response, as indicated by polymorphonuclear leukocyte (PMN) increases among lavaged cells. In the postexposure period, although the lung burdens were still substantially elevated, the lavaged PMN numbers decreased to almost control values. This suggests that inflammation was affected by the processes occurring during exposure and less by the lung burden or by particle redistribution after exposure.
