Rats were exposed to TiO2 by the inhalation route at concentrations of 0, 10, 50, or 250 mg/m3 for 6 hr/day, 5 days/week for 2 years. Lung weights of rats at 10 mg/m3 were within normal limits after 2 years exposure. Lung weights increased significantly after 6 months at 50 mg/m3 and after 3 months at 250 mg/m3. After 2 years exposure, TiO2 retention in dried lung was 3.1% (26.5 mg per lung) at 10 mg/m3, 16.9% (124 mg per lung) at 50 mg/m3, and 28% (665 mg per lung) at 250 mg/m3. Lung clearance mechanisms appeared to be overloaded at 250 mg/m3. Dust particles were retained in the lung in a dose-related fashion, but there was no significant difference in lung clearance rate between 10 and 50 mg/m3. Lung response at 10 mg/m3 satisfied the biological criteria for a "nuisance dust," while adverse effects resulting from gradually accumulated particles (8.1%, 67.7 mg per lung) were found after 1 year of exposure to 50 mg/m3. An early pulmonary response indicating an overloaded lung clearance mechanism was manifested by massive accumulation of dust-laden macrophages (dust cells), foamy dust cells, free particles, or cellular debris derived from disintegrated foamy dust cells in the alveoli adjacent to the alveolar ducts. Alveolar proteinosis also appeared to be an important marker of an overloaded lung clearance mechanism and was observed at 50 and 250 mg/m3 after 1 year of exposure. Cholesterol granulomas were developed with degenerative foamy dust cells at 50 and 250 mg/m3 after 1 year of exposure. After 2 years exposure at 250 mg/m3, bronchioalveolar adenomas occurred in the alveoli showing type II pneumocyte hyperplasia, while cystic keratinizing squamous carcinomas were developed from squamous metaplasia of alveoli showing bronchiolarization in the alveolar duct region. Since the lung tumors were a unique type of experimentally induced tumors under exaggerated exposure conditions and have not usually been seen in man or animals, their relevance to man is questionable.