Comparing fate and effects of three particles of different surface properties: nano-TiO(2), pigmentary TiO(2) and quartz.

The fate of nano-TiO(2) particles in the body was investigated after inhalation exposure or intravenous (i.v.) injection, and compared with pigmentary TiO(2) and quartz. For this purpose, a 5-day inhalation study (6h/day, head/nose exposure) was carried out in male Wistar rats using nano-TiO(2) (100mg/m(3)), pigmentary TiO(2) (250mg/m(3)) and quartz dust DQ 12 (100mg/m(3)). Deposition in the lung and tissue distribution was evaluated, and histological examination of the respiratory tract was performed upon termination of exposure, and 2 weeks after the last exposure. Broncho-alveolar lavage (BAL) was carried out 3 and 14 days after the last exposure. Rats were also injected with a single intravenous dose of a suspension of TiO(2) in serum (5mg/kg body weight), and tissue content of TiO(2) was determined 1, 14 and 28 days later. The majority of the inhaled nano-TiO(2) was deposited in the lung. Translocation to the mediastinal lymph nodes was also noted, although to smaller amounts than following inhalation of pigmentary TiO(2), but much higher amounts than after exposure to quartz. Systemically available nano-TiO(2), as simulated by the i.v. injection, was trapped mainly in the liver and spleen. The (agglomerate) particle size of lung deposited nano-TiO(2) was virtually the same as in the test atmosphere. Changes in BAL fluid composition and histological examination indicated mild neutrophilic inflammation and activation of macrophages in the lung. The effects were reversible for nano- and pigmentary TiO(2), but progressive for quartz. The effects observed after 5-day inhalation exposure to nano-TiO(2) were qualitatively similar to those reported in sub-chronic studies.

Development of a short-term inhalation test in the rat using nano-titanium dioxide as a model substance.

Evidence suggests that short-term inhalation studies may provide comparable prediction of respiratory tract toxicity to 90-day studies, presenting the opportunity to save time and resources in screening inhalation toxicity of test substances. The aim of this study was to develop a short-term inhalation test that could be employed to provide early evidence on respiratory tract effects which might occur from long-term exposure to aerosols of nano-materials. Male Wistar rats were exposed to aerosols of 0 (control), 2, 10 and 50 mg/m(3) nano-titanium dioxide (TiO2) by inhalation for 6 h/day for 5 days. Necropsies were performed either immediately after the last exposure or after 3 and 16 days post exposure (study days 5, 8 and 21, respectively). Treatment with nano-TiO2 resulted in morphological changes in the lung, with 50 mg/m(3) nano-TiO2 producing an increase in lung weight. Lung inflammation was associated with dose-dependent increases in bronchoalveolar lavage fluid (BALF) total cell and neutrophil counts, total protein content, enzyme activities and levels of a number of cell mediators. No indications of systemic effects could be found by measurement of appropriate clinical pathology parameters. Cell replication (determined by incorporation of 5-bromo-2'-deoxyuridine) was increased at all nano-TiO2 dose levels in large/medium bronchi and terminal bronchioles. The effects on the parameters measured were most prominent either on study day 5 or 8, with some endpoints returning to control levels by day 21. Overall, the pulmonary effects of nano-TiO2 observed in this short-term study were comparable to those previously reported in subchronic inhalation studies.

Zonal distribution of cell proliferation in the liver of untreated B6C3F1 and C57BL mice.

To determine the lobular distribution of hepatocellular proliferation, S-phase response was measured in untreated adult male B6C3F1 and C57BL mice at ages 11, 14, and 23 weeks. The percentage of cells in S-phase (labeling index, LI) was evaluated using immunohistochemical detection of 5-bromo-2'-deoxyuridine (BrdU). The BrdU was delivered either by a single ip injection 2 hr prior to sacrifice or via an osmotic minipump implanted subcutaneously for 3 or 7 days. Mitotic and apoptotic indices were determined on H&E stained sections. Animals of both strains and all ages revealed highest LI in the intermediate compartment of the liver acinus (zone 2) irrespective of the length of BrdU application. Cell proliferation in this zone was at all time points significantly higher than elsewhere in the liver. The mitotic index confirmed the data obtained by the S-phase response study. Apoptosis was rarely observed. With regard to rodent data in chemical carcinogenesis and the way they should be evaluated, this study proved that the acinar distribution of proliferating cells in liver of mice is different from that in rats, since, according to the literature, rats reveal highest cell proliferative activity in the periportal zone.