Mouse pulmonary dose- and time course-responses induced by exposure to multi-walled carbon nanotubes

Porter, Dale W.; Hubbs, Ann F.; Mercer, Robert R.; Wu, Nianqiang; Wolfarth, Michael G.; Sriram, Krishnan; Leonard, Stephen S.; Battelli, Lori; Schwegler‐Berry, Diane; Friend, Sherry; Andrew, Michael E.; Chen, Bean T.; Tsuruoka, Shuji; Endo, Morinobu; Castranova, Vincent

doi:10.1016/j.tox.2009.10.017

Cited by 463 publications

(782 citation statements)

References 45 publications

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“…15 Aspiration of purified MWCNTs in mice caused a similar spectrum of pulmonary responses as SWCNTs, that is, rapid but transient damage and inflammation, granulomatous lesions, and interstitial fibrosis. 16 Short-term inhalation (4 days) of MWCNTs induced pulmonary responses in mice similar to those reported after aspiration. 17 Morphometric analysis indicates that a greater fraction of alveolar MWCNTs are phagocytized than SWCNTs, while a greater fraction of SWCNTs enter the alveolar interstitium.…”

Section: A Pulmonary Responsesmentioning

confidence: 54%

“…37,38 Purified CNTs have been reported to generate low levels of reactive species in a cellular system yet remain bioactive in vivo. 16,39 Low doses of SWCNTs, representative of CNT lung burdens and alveolar epithelial cell surface area achieved after aspiration of 40 μg/mouse, exhibit low cytotoxicity. Rather, low dose SWCNT exposure of lung fibroblasts increases proliferation rate and collagen production.…”

Section: In Vitro Responses To Cntsmentioning

confidence: 99%

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Occupational Nanosafety Considerations for Carbon Nanotubes and Carbon Nanofibers

2012

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CONSPECTUSCarbon nanotubes (CNTs) are carbon atoms arranged in a crystalline graphene lattice with a tubular morphology. CNTs exhibit high tensile strength, possess unique electrical properties, are durable, and can be functionalized. These properties allow applications as structural materials, in electronics, as heating elements, in batteries, in the production of stain-resistant fabric, for bone grafting and dental implants, and for targeted drug delivery. Carbon nanofibers (CNFs) are strong, flexible fibers that are currently used to produce composite materials.Agitation can lead to aerosolized CNTs and CNFs, and peak airborne particulate concentrations are associated with workplace activities such as weighing, transferring, mixing, blending, or sonication. Most airborne CNTs or CNFs found in workplaces are loose agglomerates of micrometer diameter. However, due to their low density, they linger in workplace air for a considerable time, and a large fraction of these structures are respirable.In rat and mouse models, pulmonary exposure to single-walled carbon nanotubes (SWCNTs), multi-walled carbon nanotubes (MWCNTs), or CNFs causes the following pulmonary reactions: acute pulmonary inflammation and injury, rapid and persistent formation of granulomatous lesions at deposition sites of large CNT agglomerates, and rapid and progressive alveolar interstitial fibrosis at deposition sites of more dispersed CNT or CNF structures.Pulmonary exposure to SWCNTs can induce oxidant stress in aortic tissue and increases plaque formation in an atherosclerotic mouse model. Pulmonary exposure to MWCNTs depresses the ability of coronary arterioles to respond to dilators. These cardiovascular effects may result from neurogenic signals from sensory irritant receptors in the lung. Pulmonary exposure to MWCNTs also upregulates mRNA for inflammatory mediators in selected brain regions, and pulmonary exposure to SWCNTs upregulates the baroreceptor reflex. In addition, pulmonary exposure to MWCNTs may induce levels of inflammatory mediators in the blood, which may affect the cardiovascular system.

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Section: A Pulmonary Responsesmentioning

confidence: 54%

Section: In Vitro Responses To Cntsmentioning

confidence: 99%

Occupational Nanosafety Considerations for Carbon Nanotubes and Carbon Nanofibers

2012

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“…The increased colony formation of the carbon nanotube exposed cells in vitro indicates that low doses induce cellular proliferation. Given that epithelial hyperplasia and cellular atypia were noted in mice exposed to SWCNT and MWCNT in vivo [8,72,73], the potential for carcinogenicity is particularly concerning. Intraperitoneal injection of 3 mg of MWCNT with a mean length of at least 5 μm results in mesotheliomas in 87% of p53+/− transgenic mice [74] while a similar incidence of mesotheliomas was observed in rats following an intrascrotal injection of 240 μg of the long MWCNT with a median diameter of 4.5 μm [75].…”

Section: Discussionmentioning

confidence: 99%

“…When cell proliferation occurs prior to repair of damaged DNA, the genetic damage is passed on to subsequent generations. Given the observation that carbon nanotubes induce epithelial hyperplasia and cellular atypia in cancer resistant mice, the potential for carcinogenicity is particularly concerning [72,73,82].…”

Section: Discussionmentioning

confidence: 99%

Single-walled carbon nanotube-induced mitotic disruption

Sargent

Hubbs

Young

et al. 2012

Mutation Research/Genetic Toxicology and Environmental Mutagene

148

123

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Carbon nanotubes were among the earliest products of nanotechnology and have many potential applications in medicine, electronics, and manufacturing. The low density, small size, and biological persistence of carbon nanotubes create challenges for exposure control and monitoring and make respiratory exposures to workers likely. We have previously shown mitotic spindle aberrations in cultured primary and immortalized human airway epithelial cells exposed to 24, 48 and 96 μg/cm 2 single-walled carbon nanotubes (SWCNT). To investigate mitotic spindle aberrations at concentrations anticipated in exposed workers, primary and immortalized human airway epithelial cells were exposed to SWCNT for 24-72 h at doses equivalent to 20 weeks of exposure at the Permissible Exposure Limit for particulates not otherwise regulated. We have now demonstrated fragmented centrosomes, disrupted mitotic spindles and aneuploid chromosome number at those doses. The data further demonstrated multipolar mitotic spindles comprised 95% of the disrupted mitoses. The increased multipolar mitotic spindles were associated with an increased number of cells in the G2 phase of mitosis, indicating a mitotic checkpoint response. Nanotubes were observed in association with mitotic spindle microtubules, the centrosomes and condensed chromatin in cells exposed to 0.024, 0.24, 2.4 and 24 μg/cm 2 SWCNT. Three- Conflict of interest statementThe authors declare that there are no conflicts of interest. Appendix A. Supplementary dataSupplementary data associated with this article can be found, in the online version, at doi:10.1016/j.mrgentox.2011.11.017. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript dimensional reconstructions showed carbon nanotubes within the centrosome structure. The lower doses did not cause cytotoxicity or reduction in colony formation after 24 h; however, after three days, significant cytotoxicity was observed in the SWCNT-exposed cells. Colony formation assays showed an increased proliferation seven days after exposure. Our results show significant disruption of the mitotic spindle by SWCNT at occupationally relevant doses. The increased proliferation that was observed in carbon nanotube-exposed cells indicates a greater potential to pass the genetic damage to daughter cells. Disruption of the centrosome is common in many solid tumors including lung cancer. The resulting aneuploidy is an early event in the progression of many cancers, suggesting that it may play a role in both tumorigenesis and tumor progression. These results suggest caution should be used in the handling and processing of carbon nanotubes.

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“…In addition to the landmark study by Maynard and colleagues in 2004 which estimated workers within a CNT manufacturing plant to be exposed to 53 µg/m 3 of aerosolized CNTs [5], only a recent NIOSH report has managed to suggest a human CNT exposure limit of 1 µg/m 3 (previously considered as 7 µg/m 3 [14]). These limits however, were founded upon on a number of high-profile studies using, debatably, overload doses in vivo [15][16][17][18][19][20][21][22]. It is imperative therefore that these findings are confirmed within a realistic occupational setting (i.e., CNT manufacturing plant).…”

Section: Introductionmentioning

confidence: 99%

Assessing the impact of the physical properties of industrially produced carbon nanotubes on their interaction with human primary macrophages in vitro

et al. 2013

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Abstract:Currently it is not fully understood how carbon nanotubes (CNTs) may affect human health. Despite this, CNTs are produced at a tonne mass scale yearly. Due to their large production and intended use within a variety of applications it is imperative that a clear understanding of the hazard potential of CNTs is gained. The aim of this study therefore was to assess the impact of five different industrially produced CNTs which varied in their physical properties on the viability of human monocyte derived macrophages (MDM), and subsequently, at sub-lethal concentrations (0.005-0.02 mg/mL), their ability to cause oxidative stress and a pro-inflammatory response in these important immune cells over a 24-h period. None of the CNTs caused significant cytotoxicity up to 0.02 mg/mL after 24 h. Only the long multi-walled CNTs (MWNCTs) caused a significant, dose-dependent (0.005-0.02 mg/mL) reactive oxygen species production, whilst bundled MWCNTs showed a significant tumor necrosis factor alpha release after 24 h exposure at 0.02 mg/mL. No effects were observed for either tangled MWCNTs or short MWCNTs. It can be concluded from the findings of the present study that the industrially produced CNTs studied can cause hazardous effects in vitro that may be associated with their physical properties.

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Mouse pulmonary dose- and time course-responses induced by exposure to multi-walled carbon nanotubes

Cited by 463 publications

References 45 publications

Occupational Nanosafety Considerations for Carbon Nanotubes and Carbon Nanofibers

Occupational Nanosafety Considerations for Carbon Nanotubes and Carbon Nanofibers

Single-walled carbon nanotube-induced mitotic disruption

Assessing the impact of the physical properties of industrially produced carbon nanotubes on their interaction with human primary macrophages in vitro

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