Chronic toxicity and oncogenicity were evaluated in male and female Charles River Crl:CD(SD)BR rats (100/sex/group) exposed to atmospheres containing titanium dioxide dust at concentrations of 0, 10.55, 50.68, or 250.10 mg/cu m for 6 hrs/day, 5 days/week for up to 2 yrs. The mean respirable fractions were 93.7% or greater. Titanium dioxide was observed to accumulate in the upper respiratory tract airways, lungs, gastrointestinal tract, lymphatic system, liver and spleen. There were significant differences between treated and control groups of both sexes in the following: decreased body weights, increased lung weights, increased thymus weights (both sexes at high-dose level and males at 50 mg/cu m/), increased white blood cell counts, increased bilirubin levels (females at 50 and 250 mg/cu m), decreased calcium levels, phosphorus levels (decreased in males and increased in females), increased irregular respiration, and abnormal lung noises. Significant dose-related lung effects included alveolar proteinosis, cholesterol granuloma formation, focal pleurisy, collagenized fibrosis, and thickened alveolar walls impairing oxygen diffusion. Polycythemia was observed in high-dose level rats. Bronchioalveolar adenomas were significantly increased in high-dose animals and cystic keratinizing squamous cell carcinomas were observed primarily in the high-dose animals, females more affected than males. There were significant differences between treated and control animals, without clear dose-responses, in decreased absolute and/or relative liver and kidney weights.