INHALATION OF HIGH-CONCENTRATIONS OF LOW TOXICITY DUSTS IN RATS RESULTS IN IMPAIRED PULMONARY CLEARANCE MECHANISMS AND PERSISTENT INFLAMMATION

This study was carried out to assess the time course of pulmonary clea rance impairment and persistence of inflammation following high-dose i nhalation exposures to titanium dioxide (TiO2) or carbonyl iron (CI) p articles. Male rats were exposed to air, TiO2 or CI particles 6 hr/day , 5 days/week, for 4 weeks at concentrations of 5, 50, and 250 mg/m(3) and evaluated at selected intervals through 6 months postexposure. In dices of pulmonary inflammation as well as alveolar macrophage clearan ce functions (i.e., morphology, in vivo and in vitro phagocytosis, and chemotaxis), cell proliferation, and histopathology endpoints were me asured at several postexposure time periods through 6 months. In addit ion, amounts of TiO2 or CI in lungs and tracheobronchial lymph nodes w ere measured to allow an evaluation of particle clearance and transloc ation patterns. Four-week exposures to Ti-2, or CI particles at concen trations of 250 mg/m(3) resulted in lung burdens of 12 mg titanium and 17 mg iron, respectively, with particle retention half-times ranging from 68 days for 5 mg/m(3) TiO2 to approximately 330 days for 250 mg/m (3). The impact of this TiO2 dust load and similar lung burdens of CI particles produced a sustained pulmonary inflammatory response measure d through a period of 3-6 months postexposure concomitant with increas es in BrdU cell labeling of terminal airway and pulmonary parenchymal cells. The impairment of particle clearance mechanisms was accounted f or by deficits in in vitro phagocytic and chemotactic potential of alv eolar macrophages recovered from the lungs of high-dose, TiO2- or CI-e xposed rats. Free granular pigment (TiO2 or CI) was present on the hyp ertrophic mucosal surfaces of bronchioles and bronchi, and particle-la den macrophages, found individually, were numerous throughout alveoli and within lymphoid tissues immediately after exposure. Aggregates of particle-laden macrophages were present within alveoli and alveolar du cts from 1 week postexposure through the entire 6-month recovery perio d. Macrophage accumulations increased in size and number from 1 week t hrough 1 month postexposure and then appeared to remain constant throu gh the remaining 5-month postexposure period. Minimal cellular hypertr ophy and hyperplasia were evident at alveolar duct bifurcations adjace nt to macrophage aggregates, and this effect was most prominent at 3 t o 6 months postexposure. The results of this study clearly demonstrate that exposure to high dust concentrations of two different innocuous particle types produced sustained pulmonary inflammation, enhanced pro liferation of pulmonary cells, impairment of particle clearance, defic its in macrophage function, and the appearance of macrophage aggregate s at sites of particle deposition. In addition, the mass deposition ra te determination appears to be a less sensitive indicator of ''overloa d'' when compared to biomarkers of pulmonary toxicity, such as macroph age function and cellular inflammation and proliferation indices. (C) 1997 Academic Press.