Most pigment-grade titanium dioxide (TiO(2)) samples that have been tested in pulmonary toxicity tests have been of a generic variety-i.e., generally either uncoated particles or TiO(2) particles containing slightly hydrophilic surface treatments/coatings (i.e., base TiO(2)). The objectives of these studies were to assess in rats, the pulmonary toxicity of inhaled or intratracheally instilled TiO(2) particle formulations with various surface treatments, ranging from 0-6% alumina (Al(2)O(3)) or alumina and 0-11% amorphous silica (SiO(2)). The pulmonary effects induced by TiO(2) particles with different surface treatments were compared to reference base TiO(2) particles and controls. In the first study, groups of rats were exposed to high exposure (dose) concentrations of TiO(2) particle formulations for 4 weeks at aerosol concentrations ranging from 1130-1300 mg/m(3) and lung tissues were evaluated by histopathology immediately after exposure, as well as at 2 weeks and 3, 6, and 12 months postexposure. In the second study, groups of rats were intratracheally instilled with nearly identical TiO(2) particle formulations (when compared to the inhalation study) at doses of 2 and 10 mg/kg. Subsequently, the lungs of saline-instilled and TiO(2)-exposed rats were assessed using both bronchoalveolar (BAL) biomarkers and by histopathology/cell proliferation assessment of lung tissues at 24 h, 1 week, 1 and 3 months postexposure. The results from these studies demonstrated that for both inhalation and instillation, only the TiO(2) particle formulations with the largest components of both alumina and amorphous silica surface treatments produced mildly adverse pulmonary effects when compared to the base reference control particles. In summary, two major conclusions can be drawn from these studies: (1) surface treatments can influence the toxicity of TiO(2) particles in the lung; and (2) the intratracheal instillation-derived, pulmonary bioassay studies represent an effective preliminary screening tool for inhalation studies with the identical particle-types used in this study.

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The aim of this study was to evaluate the acute lung toxicity in rats of intratracheally instilled TiO2 particles that have been substantially encapsulated with pyrogenically deposited, amorphous silica. Groups of rats were intratracheally instilled either with doses of 1 or 5 mg/kg of hydrophilic Pigment A TiO2 particles or doses of 1 or 5 mg/kg of the following control or particle-types: 1) R-100 TiO2 particles (hydrophilic in nature); 2) quartz particles, 3) carbonyl iron particles. Phosphate-buffered saline (PBS) instilled rats served as additional controls. Following exposures, the lungs of PBS and particle-exposed rats were evaluated for bronchoalveolar lavage (BAL) fluid inflammatory markers, cell proliferation, and by histopathology at post-instillation time points of 24 hrs, 1 week, 1 month and 3 months. The bronchoalveolar lavage results demonstrated that lung exposures to quartz particles, at both concentrations but particularly at the higher dose, produced significant increases vs. controls in pulmonary inflammation and cytotoxicity indices. Exposures to Pigment A or R-100 TiO2 particles produced transient inflammatory and cell injury effects at 24 hours postexposure (pe), but these effects were not sustained when compared to quartz-related effects. Exposures to carbonyl iron particles or PBS resulted only in minor, short-term and reversible lung inflammation, likely related to the effects of the instillation procedure. Histopathological analyses of lung tissues revealed that pulmonary exposures to Pigment A TiO2 particles produced minor inflammation at 24 hours postexposure and these effects were not significantly different from exposures to R-100 or carbonyl iron particles. Pigment A-exposed lung tissue sections appeared normal at 1 and 3 months postexposure. In contrast, pulmonary exposures to quartz particles in rats produced a dose-dependent lung inflammatory response characterized by neutrophils and foamy (lipid-containing) alveolar macrophage accumulation as well as evidence of early lung tissue thickening consistent with the development of pulmonary fibrosis. Based on our results, we conclude the following: 1) Pulmonary instillation exposures to Pigment A TiO2 particles at 5 mg/kg produced a transient lung inflammatory response which was not different from the lung response to R-100 TiO2 particles or carbonyl iron particles; 2) the response to Pigment A was substantially less active in terms of inflammation, cytotoxicity, and fibrogenic effects than the positive control particle-type, quartz particles. Thus, based on the findings of this study, we would expect that inhaled Pigment A TiO2 particles would have a low risk potential for producing adverse pulmonary health effects.

Since toxicological testing of inhaled materials frequently requires utilization of several species, we have investigated pulmonary macrophage (PM) functional responses and compared the rat model with other rodents. Two strains of rats, three strains of mice, and one strain each of hamster and guinea pig were used in this study. The numbers of recovered cells by bronchoalveolar lavage generally correlated with animal body weight. The one exception was the Syrian Golden hamster from which increased numbers of macrophages were recovered. Cellular differential data obtained from lavaged cytocentrifuge preparations demonstrated that PM's account for greater than 97% of recoverable free lung cells for all species except the guinea pig, which contains a resident population of eosinophils. Cell morphology studies indicated that hamster PM exhibited the highest proportion of ruffled PM and demonstrated the highest phagocytic activity, whereas mouse PM phagocytic activity was significantly reduced compared with the other three species. In addition, chemotaxis studies showed that rat PM migrated best to zymosan-activated, complement-dependent chemoattractants, whereas hamster PM demonstrated an enhanced chemotactic response to N-formyl peptides. The results of these studies suggest that the rat may be the most efficient species for clearing inhaled particles, whereas hamsters and guinea pigs may best respond to bacteria.

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