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As a result of the growing potential industrial and medical applications of multi-walled carbon nanotubes (MWCNTs), people working in or residing near facilities that manufacture them may be exposed to airborne MWCNTs in the future. Because of concerns regarding their toxicity, quantitative data on the long-term clearance of pristine MWCNTs from the lungs are required. We administered pristine MWCNTs well dispersed in 0.5 mg ml(-1) Triton-X solution to rats at doses of 0.20 or 0.55 mg via intratracheal instillation and investigated clearance over a 12-month observation period. The pristine MWCNTs pulmonary burden was determined 1, 3, 7, 28, 91, 175 and 364 days after instillation using a method involving combustive oxidation and infrared analysis, combined with acid digestion and heat pretreatment. As 0.15- and 0.38-mg MWCNTs were detected 1 day after administration of 0.20 and 0.55 mg MWCNTs, respectively, approximately 30% of administrated MWCNTs may have been cleared by bronchial ciliary motion within 24 h of administration. After that, the pulmonary MWCNT burden did not decrease significantly over time for up to 364 days after instillation, suggesting that MWCNTs were not readily cleared from the lung. Transmission electron microscopy (TEM) showed that alveolar macrophages internalized the MWCNTs and retained in the lung for at least 364 days after instillation. MWCNTs were not detected in the liver or brain within the 364-day study period (<0.04 mg per liver, < 0.006 mg per brain)., (Copyright © 2015 The Authors. Journal of Applied Toxicology Published by John Wiley & Sons Ltd.)

Multi-walled carbon nanotubes (MWCNTs), dispersed in suspensions consisting mainly of individual tubes, were used for intratracheal instillation and inhalation studies. Rats intratracheally received a dose of 0.2 mg, or 1 mg of MWCNTs and were sacrificed from 3 days to 6 months. MWCNTs induced a pulmonary inflammation, as evidenced by a transient neutrophil response in the low-dose groups, and presence of small granulomatous lesion and persistent neutrophil infiltration in the high-dose groups. In the inhalation study, rats were exposed to 0.37 mg/m(3) aerosols of well-dispersed MWCNTs (>70% of MWCNTs were individual fibers) for 4 weeks, and were sacrificed at 3 days, 1 month, and 3 months after the end of exposure. The inhalation exposures delivered less amounts of MWCNTs into the lungs, and therefore less pulmonary inflammation responses was observed, as compared to intratracheal instillation. The results of our study show that well-dispersed MWCNT can produce pulmonary lesions, including inflammation.

It is important to conduct a risk assessment that includes hazard assessment and exposure assessment for the safe production and handling of newly developed nanomaterials. We conducted an inhalation study of a multi-wall carbon nanotube (MWCNT) as a hazard assessment. Male Wistar rats were exposed to well-dispersed MWCNT for 4 weeks by whole body inhalation. The exposure concentration in the chamber was 0.37 ± 0.18 mg/m³. About 70% of the MWCNTs in the chamber were single fiber. The geometric mean diameter (geometric standard deviation, GSD) and geometric mean length (GSD) of the aerosolized MWCNTs in the chamber were 63 nm (1.5) and 1.1 μm (2.7), respectively. The amounts of MWCNT deposited in the rat lungs were determined by the X-ray diffraction method and elemental carbon analysis. The average deposited amounts at 3 days after the inhalation were 68 μg/lung by the X-ray diffraction method and 76 μg/lung by elemental carbon analysis. The calculated deposition fractions were 18% and 20% in each analysis. The amount of retained MWCNT in the lungs until 3 months after the inhalation decreased exponentially and the calculated biological half times of MWCNT were 51 days and 54 days, respectively. The clearance was not delayed, but a slight increase in lung weight at 3 days after the inhalation was observed.

This paper describes a method for determination of multiwall carbon nanotubes (MWCNTs) in rat lungs after intratracheal instillation exposure. The MWCNTs were quantitatively decomposed to CO(2) by combustive oxidation and were then determined by non-dispersive infrared analysis. Samples were pretreated by acid digestion, muffle ashing and in situ preheating to remove interferences due to coexisting biological carbon from the lung tissue sample, while preserving the MWCNTs as in its their original form. The preservation was confirmed by transmission electron microscopic observation of the pretreated samples of exposed lung tissues and by the fact that the recoveries of MWCNTs spiked to the lung tissues were close to 100%. The detection limit for MWCNTs obtained by the proposed method was 0.30 μg and the repeatability as expressed by the relative standard deviation was 5.6% (n=4). The method was sufficiently sensitive and precise to apply to real samples of rat lung to investigate the in vivo persistence of intratracheally instilled MWCNTs. To our knowledge, this is the first report of this type of sample pretreatment and direct determination of pristine MWCNTs without modification or tagging. Conventional indirect methods use tagging with other compounds or metal impurities in the CNTs for detection, and the detachment of these tags can increase uncertainties in the determination of the CNTs. The tags can also change how the CNTs persist in vivo, which can lead to an incorrect understanding of the persistence of pristine CNTs in vivo., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Fullerene (carbon sixty [C(60)]) has potential industrial and medical applications. In the future, people working in or residing near manufacturing facilities may be exposed to C(60). Therefore, quantitative data on long-term C(60) clearance from the lungs are required. To estimate the clearance rate and deposition fraction of C(60) from inhalation exposure, the C(60) burden in the lungs, liver, and brain of rats was determined after intratracheal instillation and inhalation. Male Wistar rats were intratracheally instilled with different concentrations of a C(60) suspension prepared with Tween 80 (geometric mean [GM] of particle diameter based on number, 18-29 nm; geometric standard deviation [GSD] of particle diameter, 1.5; and doses, 100, 200, and 1000 micrograms per body) or exposed to a C(60) aerosol prepared with nebulizer (GM of particle diameter based on number, 96 nm; GSD of particle diameter, 2.0; and exposure level, 120 μg/m(3)). C(60) burden in the lungs, liver, and brain was determined at various time points (1 h to 6 months) by a newly developed sensitive high-performance liquid chromatography-ultraviolet absorptiometry combined with extraction and concentration of C(60) from the organs. C(60) clearance was evaluated using a 2-compartment model: fast clearance after deposition on lung surface and slow clearance after retention in the epithelium. The detection limit of our analysis method was 8.9 ng/g tissue. Pulmonary C(60) burden decreased with time and depended on the C(60) concentration administered. The concentration of C(60) in the liver and brain was below the detection limit: 8.9 ng/g tissue. The half-life of intratracheally instilled C(60) was 15-28 days. The deposition mass fraction of inhaled C(60) was 0.14. Mode evaluation revealed that most instilled particles could be eliminated by the fast clearance pathway. This finding is consistent with the transmission electron microscopy finding that many particles were present in alveolar macrophages.

Concern over the influence of nanoparticles on human health has risen due to advances in the development of nanotechnology. We are interested in the influence of nanoparticles on the pulmonary system at a molecular level. In this study, gene expression profiling of the rat lung after whole-body inhalation exposure to C(60) fullerene (0.12mg/m(3); 4.1x10(4) particles/cm(3), 96nm diameter) and ultrafine nickel oxide (Uf-NiO) particles (0.2mg/m(3); 9.2x10(4) particles/cm(3), 59nm diameter) as a positive control were employed to gain insights into these molecular events. In response to C(60) fullerene exposure for 6h a day, for 4 weeks (5 days a week), C(60) fullerene particles were located in alveolar epithelial cells at 3 days post-exposure and engulfed by macrophages at both 3 days and 1 month post-exposures. Gene expression profiles revealed that few genes involved in the inflammatory response, oxidative stress, apoptosis, and metalloendopeptidase activity were up-regulated at both 3 days and 1 month post-exposure. Only some genes associated with the immune system process, including major histocompatibility complex (MHC)-mediated immunity were up-regulated. These results were significantly different from those of Uf-NiO particles which induced high expression of genes associated with chemokines, oxidative stress, and matrix metalloproteinase 12 (Mmp12), suggesting that Uf-NiO particles lead to acute inflammation for the inhalation exposure period, and the damaged tissues were repaired in the post-exposure period. We suggest that C(60) fullerene might not have a severe pulmonary toxicity under the inhalation exposure condition.

Abstract: Concern over the influence of nanoparticles on human health has risen due to advances in the development of nanotechnology. We are interested in the influence of nanoparticles on the pulmonary system at a molecular level. In this study, gene expression profiling of the rat lung after whole-body inhalation exposure to C60 fullerene (0.12mg/m3; 4.1×104 particles/cm3, 96nm diameter) and ultrafine nickel oxide (Uf-NiO) particles (0.2mg/m3; 9.2×104 particles/cm3, 59nm diameter) as a positive control were employed to gain insights into these molecular events. In response to C60 fullerene exposure for 6h a day, for 4 weeks (5 days a week), C60 fullerene particles were located in alveolar epithelial cells at 3 days post-exposure and engulfed by macrophages at both 3 days and 1 month post-exposures. Gene expression profiles revealed that few genes involved in the inflammatory response, oxidative stress, apoptosis, and metalloendopeptidase activity were up-regulated at both 3 days and 1 month post-exposure. Only some genes associated with the immune system process, including major histocompatibility complex (MHC)-mediated immunity were up-regulated. These results were significantly different from those of Uf-NiO particles which induced high expression of genes associated with chemokines, oxidative stress, and matrix metalloproteinase 12 (Mmp12), suggesting that Uf-NiO particles lead to acute inflammation for the inhalation exposure period, and the damaged tissues were repaired in the post-exposure period. We suggest that C60 fullerene might not have a severe pulmonary toxicity under the inhalation exposure condition. [Copyright &y& Elsevier]