Long-Term Pulmonary Responses of Three Laboratory Rodent Species to Subchronic Inhalation of Pigmentary Titanium Dioxide Particles

Abstract

Female mice, rats, and hamsters were exposed to 10, 50, or 250 mg/m(3) pigmentary titanium dioxide (p-TiO(2)) particles for 6 h per day and 5 days per week for 13 weeks with recovery groups held for an additional 4, 13, 26, or 52 weeks postexposure (46 weeks for the p-TiO(2)-exposed hamsters). At each time point p-TiO(2) burdens in the lung and lymph nodes and selected lung responses were examined. The responses studied were chosen to assess a variety of pulmonary parameters, including inflammation, cytotoxicity, lung cell proliferation, and histopathologic alterations. Burdens of p-TiO(2) in the lungs and in the lung-associated lymph nodes increased in a concentration-dependent manner. Retained lung burdens following exposure were greatest in mice. Rats and hamsters had similar lung burdens immediately postexposure when assessed as milligrams of p-TiO(2) per gram of dried lung. Particle retention data suggested that pulmonary overload was achieved in both rats and mice at the exposure levels of 50 and 250 mg/m(3). Under the conditions of the present study, hamsters were better able to clear p-TiO(2) particles than were similarly exposed mice and rats. Pulmonary histopathology revealed both species and concentration-dependent differences in p-TiO(2) particle retention patterns. Inflammation was noted in all three species at 50 and 250 mg/m(3), as evidenced by increases in macrophage and neutrophil numbers and in soluble indices of inflammation in bronchoalveolar lavage fluid (BALF; rats > mice, hamsters). In mice and rats, the BALF inflammatory responses remained elevated relative to controls throughout the entire postexposure recovery period in the most highly exposed animals. In comparison, inflammation in hamsters eventually disappeared, even at the highest exposure dose, due to the more rapid clearance of particles from the lung. Pulmonary lesions were most severe in rats, where progressive epithelial- and fibroproliferative changes were observed in the 250 mg/m(3) group. These epithelial proliferative changes were also manifested in rats as an increase in alveolar epithelial cell labeling in cell proliferation studies. Associated with these foci of epithelial proliferation were interstitial particle accumulation and alveolar septal fibrosis. In summary, there were significant species differences in pulmonary responses to inhaled p-TiO(2) particles. Under conditions in which the lung p-TiO(2) burdens were similar and likely to induce pulmonary overload, rats developed a more severe and persistent pulmonary inflammatory response than either mice or hamsters. Rats also were unique in the development of progressive fibroproliferative lesions and alveolar epithelial metaplasia in response to 90 days of exposure to a high concentration of p-TiO(2) particles.

In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitioneal injection

“…A research program to investigate inter-species differences as a result of exposure to TiO 2 and to conduct detailed epidemiological surveys of the major manufacturing sites was initiated by a consortium of TiO 2 manufacturers in Europe (under the European Chemistry Industry Council; CEFIC) and North America (under the American Chemistry Council; ACC). Some detailed results published from these studies showed distinct species differences in lung responses, particle distributions and clearance rates (Bermudez et al, 2002(Bermudez et al, , 2004.…”

The potential health risk of titania nanoparticles

“…TNP toxicity has been observed in diverse models, such as rodents [15][16][17][18], aquatic organisms [19][20][21], and human cells [22][23][24]. Female workers were reported to experience shortness of breath and pleural effusions after 5-13 months of exposure in a polyacrylic ester nanoparticle processing factory [25], raising significant doubt about the human safety of TNPs.…”

Hazard Assessments of Manufactured Nanomaterials

“…If the doses were expressed as surface area rather than mass in the experiment, the fact that the doseresponse relationship appeared as a straight line, led to the opinion that larger surface area is a factor in the strong inflammatory response to TiO 2 nanoparticles 7,27,30) . Bermudez et al 31,32) compared the results of a 13-week inhalation study of TiO 2 nanoparticles in rat, hamster and mouse with previous reports of TiO 2 microparticles. They reported, that at the same mass-based exposures, greater pulmonary inflammatory responses were seen in the groups exposed to TiO 2 nanoparticles than in the groups exposed to TiO 2 microparticles, and concluded that differences in surface area were the cause of this result.…”

“…One of the possible reasons for disagreement is that many studies have been performed using particles with different particle size, surface properties, impurities and crystal structures, involving complex interactions among many factors, and it has been difficult to separate the sole effects of particle size and surface area among many factors. For example, in the research of Bermudez et al 31,32) and Sager et al 35) the TiO 2 nano-and micro-particles used came from different sources and had different crystal structures. Both used the 80% anatase -20% rutile form of TiO 2 particles, generally known by the product name P25, made by Evonik as TiO 2 nanoparticles.…”

“…Both used the 80% anatase -20% rutile form of TiO 2 particles, generally known by the product name P25, made by Evonik as TiO 2 nanoparticles. On the other side, rutile TiO 2 particles produced by DuPont 32) or Sigma Aldrich 35) were used as TiO 2 microparticles. Also, in some studies, measurements of the particles used in the studies were insufficient, making it all the more difficult to validate the nanoparticle paradigm.…”