Pulmonary toxicity study in rats with three forms of ultrafine-TiO2 particles: Differential responses related to surface properties (original) (raw)
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Environmental Toxicology and Pharmacology, 2007
The acute pulmonary toxicity induced by 3-nm TiO 2 primary particles was preliminary investigated after they were intratracheally instilled at doses of 0.4, 4 and 40 mg/kg into lungs of mice. The biochemical parameters in bronchoalveolar lavage fluid (BALF) and pathological examination were used as endpoints to assess their pulmonary toxicity at 3-day postexposure. As such, the pulmonary toxicity assessment of 20-nm TiO 2 primary particles was performed using the same method. It was found that the 3-nm TiO 2 primary particles induced no pulmonary toxicity at dose of 0.4 mg/kg, moderate toxicity at 4 mg/kg and lung overload at 40 mg/kg, and this kind of particles did not produce more pulmonary toxicity than the 20-nm ones at any instilled doses. As regards physicochemical characteristics of the two TiO 2 particles, their pH values in medium, other than particle size, surface area and aggregation, may play important role in affecting their pulmonary toxicity.
Toxicology and Applied Pharmacology
A B S T R A C T Nanomaterial (NM) characteristics may affect the pulmonary toxicity and inflammatory response, including specific surface area, size, shape, crystal phase or other surface characteristics. Grouping of TiO 2 in hazard assessment might be challenging because of variation in physicochemical properties. We exposed C57BL/6 J mice to a single dose of four anatase TiO 2 NMs with various sizes and shapes by intratracheal instillation and assessed the pulmonary toxicity 1, 3, 28, 90 or 180 days post-exposure. The quartz DQ12 was included as benchmark particle. Pulmonary responses were evaluated by histopathology, electron microscopy, bronchoalveolar lavage (BAL) fluid cell composition and acute phase response. Genotoxicity was evaluated by DNA strand break levels in BAL cells, lung and liver in the comet assay. Multiple regression analyses were applied to identify specific TiO 2 NMs properties important for the pulmonary inflammation and acute phase response. The TiO 2 NMs induced similar inflammatory responses when surface area was used as dose metrics, although inflammatory and acute phase response was greatest and more persistent for the TiO 2 tube. Similar histopathological changes were observed for the TiO 2 tube and DQ12 including pulmonary alveolar proteinosis indicating profound effects related to the tube shape. Comparison with previously published data on rutile TiO 2 NMs indicated that rutile TiO 2 NMs were more inflammogenic in terms of neutrophil influx than anatase TiO 2 NMs when normalized to total deposited surface area. Overall, the results suggest that specific surface area, crystal phase and shape of TiO 2 NMs are important predictors for the observed pulmonary effects of TiO 2 NMs.
The Scientific World JOURNAL, 2011
installation in mice. The role of the type of compound, polymorphism, and size of the particles was investigated. Studied compounds were the two micro-size reference quartzes, SRM1878a and DQ12, a micro-and nano-size rutile titanium dioxide (TiO 2 ), a nano-size anatase, and an amorphous TiO 2 . Particles were administered by a single i.t. instillation in mice at a fixed dose of 5, 50, and 500 μg, respectively. Inflammation was evaluated from the bronchoalveolar lavage fluid (BALF) content of inflammatory cells, the cytokines tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), as well as from lung histology. Evaluations were at 24 h (acute effects) and 3 months (subchronic effects) after instillations. Both types of quartz induced a dose-dependent acute increase of neutrophils, IL-6, and total protein in BALF. Limited subchronic inflammation was observed. All types of TiO 2 induced a dose-dependent acute increase of neutrophils in BALF. In the acute phase, micro-and nano-size rutile and nano-size amorphous TiO 2 induced elevated levels of IL-6 and total protein in BALF at the highest dose. At the nanosize rutile and amorphous TiO 2 , subchronic lung inflammation was apparent from a dosedependent increase in BALF macrophages. Histology showed little inflammation overall. The two types of quartz showed virtually similar inflammatory effects. Nearly similar effects were observed for two sizes of rutile TiO 2 . Differences were seen between the different polymorphs of nano-size TiO 2 , with rutile being the most inflammogenic and amorphous being the most potent in regard to acute tissue damage.
Toxicology Letters, 2007
The development of a risk management system for nanoscale or ultrafine particle-types requires a base set of hazard data. Assessing risk is a function of hazard and exposure data. Previously, we have suggested "parallel tracks" as a strategy for conducting nanoparticle research. On the one hand, mechanistic studies on "representative" nanoparticles could be supported by governmental agencies. Alternatively, with regard to commercial nanoparticles, the environmental, health and safety (EHS) framework would include a minimum base set of toxicity studies which should be supported by the companies that are developing nano-based products. The minimum base set could include the following criteria: substantial particle characterization, pulmonary toxicity studies, acute dermal toxicity and sensitization studies, acute oral and ocular toxicity studies, along with screening type genotoxicity, and aquatic toxicity studies.
Asian Pacific Journal of Cancer Prevention, 2014
Two types of nanosized titanium dioxide, anatase (anTiO 2) and rutile (rnTiO 2), are widely used in industry, commercial products and biosystems. TiO 2 has been evaluated as a Group 2B carcinogen. Previous reports indicated that anTiO 2 is less toxic than rnTiO 2 , however, under ultraviolet irradiation anTiO 2 is more toxic than rnTiO 2 in vitro because of differences in their crystal structures. In the present study, we compared the in vivo and in vitro toxic effects induced by anTiO 2 and rnTiO 2. Female SD rats were treated with 500 mg/ml of anTiO 2 or rnTiO 2 suspensions by intra-pulmonary spraying 8 times over a two week period. In the lung, treatment with anTiO 2 or rnTiO 2 increased alveolar macrophage numbers and levels of 8-hydroxydeoxyguanosine (8-OHdG); these increases tended to be lower in the anTiO 2 treated group compared to the rnTiO 2 treated group. Expression of MIP1a mRNA and protein in lung tissues treated with anTiO 2 and rnTiO 2 was also significantly up-regulated, with MIP1a mRNA and protein expression significantly lower in the anTiO 2 group than in the rnTiO 2 group. In cell culture of primary alveolar macrophages (PAM) treated with anTiO 2 and rnTiO 2 , expression of MIP1a mRNA in the PAM and protein in the culture media was significantly higher than in control cultures. Similarly to the in vivo results, MIP1a mRNA and protein expression was significantly lower in the anTiO 2 treated cultures compared to the rnTiO 2 treated cultures. Furthermore, conditioned cell culture media from PAM cultures treated with anTiO 2 had less effect on A549 cell proliferation compared to conditioned media from cultures treated with rnTiO 2. However, no significant difference was found in the toxicological effects on cell viability of ultra violet irradiated anTiO 2 and rnTiO 2. In conclusion, our results indicate that anTiO 2 is less potent in induction of alveolar macrophage infiltration, 8-OHdG and MIP1a expression in the lung, and growth stimulation of A549 cells in vitro than rnTiO 2 .
J Nanopart Res, 2011
This study presents a novel exposure protocol for synthesized nanoparticles (NPs). NPs were synthesized in gas phase by thermal decomposition of metal alkoxide vapors in a laminar flow reactor. The exposure protocol was used to estimate the deposition fraction of titanium dioxide (TiO 2 ) NPs to mice lung. The experiments were conducted at aerosol mass concentrations of 0.8, 7.2, 10.0, and 28.5 mg m -3 . The means of aerosol geometric mobility diameter and aerodynamic diameter were 80 and 124 nm, and the geometric standard deviations were 1.8 and 1.7, respectively. The effective density of the particles was approximately from 1.5 to 1.7 g cm -3 . Particle concentration varied from 4 9 10 5 cm -3 at mass concentrations of 0.8 mg m -3 to 12 9 10 6 cm -3 at 28.5 mg m -3 . Particle phase structures were 74% of anatase and 26% of brookite with respective crystallite sized of 41 and 6 nm. The brookite crystallites were approximately 100 times the size of the anatase crystallites. The TiO 2 particles were porous and highly agglomerated, with a mean primary particle size of 21 nm. The specific surface area of TiO 2 powder was 61 m 2 g -1 . We defined mice respiratory minute volume (RMV) value during exposure to TiO 2 aerosol. Both TiO 2 particulate matter and gaseous by-products affected respiratory parameters. The RMV values were used to quantify the deposition fraction of TiO 2 matter by using two different methods. According to individual samples, the deposition fraction was 8% on an average, and when defined from aerosol mass concentration series, it was 7%. These results show that the exposure protocol can be used to study toxicological effects of synthesized NPs.
Toxicology and Applied Pharmacology, 2007
Inhaled ultrafine particles show considerably stronger pulmonary inflammatory effects when tested at equal mass dose with their fine counterparts. However, the responsible mechanisms are not yet fully understood. We investigated the role of particle size and surface chemistry in initiating pro-inflammatory effects in vitro in A549 human lung epithelial cells on treatment with different model TiO 2 particles. Two samples of TiO 2 , i.e. fine (40-300 nm) and ultrafine (20-80 nm) were tested in their native forms as well as upon surface methylation, as was confirmed by Fourier transformed infrared spectroscopy. Radical generation during cell treatment was determined by electron paramagnetic resonance with 5,5dimethyl-1-pyrroline-N-oxide or 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl. Interleukin-8 mRNA expression/release was determined by RT-PCR and ELISA, whereas particle uptake was evaluated by transmission electron microscopy. TiO 2 particles were rapidly taken up by the cells, generally as membrane bound aggregates and large intracellular aggregates in vesicles, vacuoles and lamellar bodies. Aggregate size tended to be smaller for the ultrafine samples and was also smaller for methylated fine TiO 2 when compared to non-methylated fine TiO 2 . No particles were observed inside nuclei or any other vital organelle. Both ultrafine TiO 2 samples but not their fine counterparts elicited significantly stronger oxidant generation and IL-8 release, despite their aggregation state and irrespective of their methylation. The present data indicate that ultrafine TiO 2 , even as aggregates/agglomerates, can trigger inflammatory responses that appear to be driven by their large surface area. Furthermore, our results indicate that these effects result from oxidants generated during particle-cell interactions through a yet to be elucidated mechanism(s).
Journal of Nanoparticle Research, 2011
This study presents a novel exposure protocol for synthesized nanoparticles (NPs). NPs were synthesized in gas phase by thermal decomposition of metal alkoxide vapors in a laminar flow reactor. The exposure protocol was used to estimate the deposition fraction of titanium dioxide (TiO 2 ) NPs to mice lung. The experiments were conducted at aerosol mass concentrations of 0.8, 7.2, 10.0, and 28.5 mg m -3 . The means of aerosol geometric mobility diameter and aerodynamic diameter were 80 and 124 nm, and the geometric standard deviations were 1.8 and 1.7, respectively. The effective density of the particles was approximately from 1.5 to 1.7 g cm -3 . Particle concentration varied from 4 9 10 5 cm -3 at mass concentrations of 0.8 mg m -3 to 12 9 10 6 cm -3 at 28.5 mg m -3 . Particle phase structures were 74% of anatase and 26% of brookite with respective crystallite sized of 41 and 6 nm. The brookite crystallites were approximately 100 times the size of the anatase crystallites. The TiO 2 particles were porous and highly agglomerated, with a mean primary particle size of 21 nm. The specific surface area of TiO 2 powder was 61 m 2 g -1 . We defined mice respiratory minute volume (RMV) value during exposure to TiO 2 aerosol. Both TiO 2 particulate matter and gaseous by-products affected respiratory parameters. The RMV values were used to quantify the deposition fraction of TiO 2 matter by using two different methods. According to individual samples, the deposition fraction was 8% on an average, and when defined from aerosol mass concentration series, it was 7%. These results show that the exposure protocol can be used to study toxicological effects of synthesized NPs.
Mutagenesis, 2017
The influence of surface charge of nanomaterials on toxicological effects is not yet fully understood. We investigated the inflammatory response, the acute phase response and the genotoxic effect of two different titanium dioxide nanoparticles (TiO2 NPs) following a single intratracheal instillation. NRCWE-001 was unmodified rutile TiO2 with endogenous negative surface charge, whereas NRCWE-002 was surface modified to be positively charged. C57BL/6J BomTac mice received 18, 54 and 162 µg/mouse and were humanely killed 1, 3 and 28 days post-exposure. Vehicle controls were tested alongside for comparison. The cellular composition and protein concentration were determined in bronchoalveolar lavage (BAL) fluid as markers for an inflammatory response. Pulmonary and systemic genotoxicity was analysed by the alkaline comet assay as DNA strand breaks in BAL cells, lung and liver tissue. The pulmonary and hepatic acute phase response was analysed by Saa3 mRNA levels in lung tissue or Saa1 mR...