Inhaled ultrafine particles of TiO2 (TiO2-D, 20 nm particle size) lead
to a greater pulmonary inflammatory response than larger pigment-grad
e particles (TiO2-F, 250 nm). Male Fisher 344 rats were exposed for 6
hours a day, 5 days a week, for 3 months to 1) filtered air (control);
2) TiO2-F, 22.3 mg/m(3); 3) TiO2-D, 23.5 mg/m(3); or 4) crystalline S
iO2, a positive control particle (similar to 800 nm particle size, 1.3
mg/m(3)). Groups of 3-4 animals were sacrificed at 6 and 12 months fo
llowing the completion of exposure. Pulmonary effects of exposure were
evaluated using standard hematoxylin and eosin-stain sections, histoc
hemical stains for collagen, and immunohistochemical assays for cell t
urnover. Six months after animals were exposed to SiO2, they had moder
ate focal interstitial fibrosis and moderately severe focal alveolitis
. Animals exposed to TiO2-D had slightly less fibrosis. The least fibr
osis was seen in the TiO2-F group. At 1 year after exposure, fibrosis
was still present but decreased in the SiO2 group. The amount of inter
stitial fibrosis in the TiO2-D- and TiO2-F-treated animals had largely
returned to untreated control levels, although an increased number of
alveolar macrophages persisted, usually with retained particles. Ther
e was discordance between bromodeoxyuridine and proliferating cell nuc
lear antigen indices, most probably due to cytokine elaboration in the
areas of inflammation, which may have altered the expression of proli
ferating cell nuclear antigens. There was no detectable fibroblast lab
eling at the 6-month observation and only very low levels at 12 months
. Thus, although initially irritant, TiO2-induced lesions regressed du
ring a 1-year period following cessation of exposure.