Genotoxicity of inhaled nanosized TiO(2) in mice.

In vitro studies have suggested that nanosized titanium dioxide (TiO(2)) is genotoxic. The significance of these findings with respect to in vivo effects is unclear, as few in vivo studies on TiO(2) genotoxicity exist. Recently, nanosized TiO(2) administered in drinking water was reported to increase, e.g., micronuclei (MN) in peripheral blood polychromatic erythrocytes (PCEs) and DNA damage in leukocytes. Induction of micronuclei in mouse PCEs was earlier also described for pigment-grade TiO(2) administered intraperitoneally. The apparent systemic genotoxic effects have been suggested to reflect secondary genotoxicity of TiO(2) due to inflammation. However, a recent study suggested that induction of DNA damage in mouse bronchoalveolar lavage (BAL) cells after intratracheal instillation of nanosized or fine TiO(2) is independent of inflammation. We examined here, if inhalation of freshly generated nanosized TiO(2) (74% anatase, 26% brookite; 5 days, 4 h/day) at 0.8, 7.2, and (the highest concentration allowing stable aerosol production) 28.5 mg/m(3) could induce genotoxic effects in C57BL/6J mice locally in the lungs or systematically in peripheral PCEs. DNA damage was assessed by the comet assay in lung epithelial alveolar type II and Clara cells sampled immediately following the exposure. MN were analyzed by acridine orange staining in blood PCEs collected 48 h after the last exposure. A dose-dependent deposition of Ti in lung tissue was seen. Although the highest exposure level produced a clear increase in neutrophils in BAL fluid, indicating an inflammatory effect, no significant effect on the level of DNA damage in lung epithelial cells or micronuclei in PCEs was observed, suggesting no genotoxic effects by the 5-day inhalation exposure to nanosized TiO(2) anatase. Our inhalation exposure resulted in much lower systemic TiO(2) doses than the previous oral and intraperitoneal treatments, and lung epithelial cells probably received considerably less TiO(2) than BAL cells in the earlier intratracheal study.

Nanosized TiO2 caused minor airflow limitation in the murine airways.

The use of nanotechnology is increasing exponentially, whereas the possible adverse health effects of engineered nanoparticles (NPs) are so far less known. Standardized mouse bioassay was used to study sensory and pulmonary irritation, airflow limitation, and inflammation potency of nanosized TiO(2). Single exposure (0.5 h) to in situ generated TiO(2) (primary particle size 20 nm; geometric mean diameters of 91, 113, and 130 nm at mass concentrations of 8, 20, and 30 mg/m(3), respectively; crystal phase anatase + brookite (3:1)) caused airflow limitation in the conducting airways at each studied exposure concentration, which was shown as a reduction in expiratory flow, being at the lowest 73% of baseline. The response was not dose dependent. Repeated exposures (altogether 16 h, 1 h/day, 4 days/week for 4 weeks) to TiO(2) at mass concentration of 30 mg/m(3) caused as intense airflow limitation effect as the single exposures, and the extent of the responses stayed about the same along the exposure days. Sensory irritation was fairly minor. Pulmonary irritation was more pronounced during the latter part of the repeated exposures compared to the single exposures and the beginning of the repeated exposures. Sensory and pulmonary irritation were observed also in the control group, and, therefore, reaction by-products (NO(2) and C(3)H(6)) may have contributed to the irritation effects. TiO(2) NPs accumulated mainly in the pulmonary macrophages, and they did not cause nasal or pulmonary inflammation. In conclusion, the irritation and inflammation potencies of studied TiO(2) seemed to be low.

Inhalation exposure to nanosized and fine TiO2 particles inhibits features of allergic asthma in a murine model.

BACKGROUND: Nanotechnology and engineered nanomaterials (ENM) are here to stay. Recent evidence suggests that exposure to environmental particulate matter exacerbates symptoms of asthma. In the present study we investigated the modulatory effects of titanium dioxide particle exposure in an experimental allergic asthma. METHODS: Nonallergic (healthy) and ovalbumin-sensitized (asthmatic) mice were exposed via inhalation to two different sizes of titanium dioxide particles, nanosized (nTiO2) and fine (fTiO2), for 2 hours a day, three days a week, for four weeks at a concentration of 10 mg/m3. Different endpoints were analysed to evaluate the immunological status of the mice. RESULTS: Healthy mice elicited pulmonary neutrophilia accompanied by significantly increased chemokine CXCL5 expression when exposed to nTiO2. Surprisingly, allergic pulmonary inflammation was dramatically suppressed in asthmatic mice which were exposed to nTiO2 or fTiO2 particles - i.e. the levels of leucocytes, cytokines, chemokines and antibodies characteristic to allergic asthma were substantially decreased. CONCLUSIONS: Our results suggest that repeated airway exposure to TiO2 particles modulates the airway inflammation depending on the immunological status of the exposed mice.

Airway exposure to silica-coated TiO2 nanoparticles induces pulmonary neutrophilia in mice.

The importance of nanotechnologies and engineered nanoparticles has grown rapidly. It is therefore crucial to acquire up-to-date knowledge of the possible harmful health effects of these materials. Since a multitude of different types of nanosized titanium dioxide (TiO(2)) particles are used in industry, we explored their inflammatory potential using mouse and cell models. BALB/c mice were exposed by inhalation for 2 h, 2 h on 4 consecutive days, or 2 h on 4 consecutive days for 4 weeks to several commercial TiO(2) nanoparticles, SiO(2) nanoparticles, and to nanosized TiO(2) generated in a gas-to-particle conversion process at 10 mg/m(3). In addition, effects of in vitro exposure of human macrophages and fibroblasts (MRC-9) to the different particles were assessed. SiO(2)-coated rutile TiO(2) nanoparticles (cnTiO(2)) was the only sample tested that elicited clear-cut pulmonary neutrophilia. Uncoated rutile and anatase as well as nanosized SiO(2) did not induce significant inflammation. Pulmonary neutrophilia was accompanied by increased expression of tumor necrosis factor-alpha (TNF-alpha) and neutrophil-attracting chemokine CXCL1 in the lung tissue. TiO(2) particles accumulated almost exclusively in the alveolar macrophages. In vitro exposure of murine and human macrophages to cnTiO(2) elicited significant induction of TNF-alpha and neutrophil-attracting chemokines. Stimulation of human fibroblasts with cnTiO(2)-activated macrophage supernatant induced high expression of neutrophil-attracting chemokines, CXCL1 and CXCL8. Interestingly, the level of lung inflammation could not be explained by the surface area of the particles, their primary or agglomerate particle size, or radical formation capacity but is rather explained by the surface coating. Our findings emphasize that it is vitally important to take into account in the risk assessment that alterations of nanoparticles, e.g., by surface coating, may drastically change their toxicological potential.