Subchronic inhalation of high concentrations of low toxicity, low solubility participates produces sustained pulmonary inflammation and cellular proliferation

Long-term inhalation exposures to high dust burdens can produce tumors or proliferative keratin cysts in the lungs of exposed rats. We hypothesized that dust burdens which overwhelm lung clearance mechanisms are associated with sustained cellular proliferation responses and pulmonary inflammation. Male rats were exposed to titanium dioxide (TiO2) or carbonyl iron (CI) particles for 4 weeks at concentrations of 5, 50 and 250 mg/m3. Following completion of exposure, the lungs of sham and dust-exposed animals were lavaged or assessed for cell proliferation or particle clearance immediately after, as well as 1 week, 1, 3 and 6 months postexposure. Exposures to TiO2 or CI at 250 mg/m3 produced persistent pulmonary inflammatory responses and increased BrdU labeling of terminal airway and pulmonary parenchymal cells. The results of this study clearly demonstrate that exposure to excessive dust concentrations of two low toxicity, low solubility particle-types produced sustained pulmonary inflammation, enhanced pulmonary cell labeling, impairment of particle clearance, and the development of pulmonary lesions.