A mechanistic review of particle overload by titanium dioxide

Chronic exposure to titanium dioxide (TiO2) induces slight but significant pulmonary inflammation in experimental animals, and among potential mechanisms, particle overload is likely. Although mechanisms of particle overload are poorly understood, excess accumulation of dust particles in dust containing macrophages (dust cells) can impair their mobility, resulting in reduced clearance ability. Accordingly, retention half-times of inhaled TiO2 increase linearly with lung burden in rodents, and mathematical (Michaelis-Menten-like) models for pulmonary clearance rates of TiO2 as a function of lung burden have suggested an alternative mechanism for particle overload, involving excess accumulation of macrophages in the translocation pathway due to the narrow exit to the ciliated airway region, and leading to reduced pulmonary TiO2 clearance rates. This mechanism is consistent with observations showing that TiO2 retention half-times in the lungs of rats and mice show no change from the initial value until the lung burden exceeds around mass burden of 3mg or surface area burden of 1000cm(2). In addition, excess accumulation of macrophages is consistent with several particle overload-associated pathological changes, including accelerated neutrophilic inflammation, elevation of lymph node burden, and epithelial cell hyperplasia. Because excessive alveolar accumulation of macrophages may accelerate interstitialization of macrophages (including dust cells) and subsequent migration into lymph nodes, alveolar macrophages and dust cells likely migrate into interstitial spaces and escape to the luminal side of the ciliated airway region.