Metal Oxide Nanoparticles Induce Unique Inflammatory Footprints in the Lung: Important Implications for Nanoparticle Testing

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Abstract

Background

Metal oxide nanoparticles (NPs) have been widely used in industry, cosmetics, and biomedicine.

Objectives

We examined hazards of several well-characterized high production volume NPs because of increasing concern about occupational exposure via inhalation.

Methods

A panel of well-characterized NPs [cerium oxide (CeO ₂NP), titanium dioxide (TiO ₂NP), carbon black (CBNP), silicon dioxide (SiO ₂NP), nickel oxide (NiONP), zinc oxide (ZnONP), copper oxide (CuONP), and amine-modified polystyrene beads] was instilled into lungs of rats. We evaluated the inflammation potencies of these NPs 24 hr and 4 weeks postinstillation. For NPs that caused significant inflammation at 24 hr, we then investigated the characteristics of the inflammation. All exposures were carried out at equal-surface-area doses.

Results

Only CeO ₂NP, NiONP, ZnONP, and CuONP were inflammogenic to the lungs of rats at the high doses used. Strikingly, each of these induced a unique inflammatory footprint both acutely (24 hr) and chronically (4 weeks). Acutely, patterns of neutrophil and eosinophil infiltrates differed after CeO ₂NP, NiONP, ZnONP, and CuONP treatment. Chronic inflammatory responses also differed after 4 weeks, with neutrophilic, neutrophilic/lymphocytic, eosinophilic/fibrotic/granulomatous, and fibrotic/granulomatous inflammation being caused respectively by CeO ₂NP, NiONP, ZnONP, and CuONP.

Conclusion

Different types of inflammation imply different hazards in terms of pathology, risks, and risk severity. In vitro testing could not have differentiated these complex hazard outcomes, and this has important implications for the global strategy for NP hazard assessment. Our results demonstrate that NPs cannot be viewed as a single hazard entity and that risk assessment should be performed separately and with caution for different NPs.

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Most cited references 27

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Safe handling of nanotechnology.

Andrew Maynard, Robert J Aitken, Tilman Butz … (2006)

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Carbon nanotubes: a review of their properties in relation to pulmonary toxicology and workplace safety.

Ken Donaldson, Robert AITKEN, Lang Tran … (2006)

Carbon nanotubes (CNT) are an important new class of technological materials that have numerous novel and useful properties. The forecast increase in manufacture makes it likely that increasing human exposure will occur, and as a result, CNT are beginning to come under toxicological scrutiny. This review seeks to set out the toxicological paradigms applicable to the toxicity of inhaled CNT, building on the toxicological database on nanoparticles (NP) and fibers. Relevant workplace regulation regarding exposure is also considered in the light of our knowledge of CNT. CNT could have features of both NP and conventional fibers, and so the current paradigm for fiber toxicology, which is based on mineral fibers and synthetic vitreous fibers, is discussed. The NP toxicology paradigm is also discussed in relation to CNT. The available peer-reviewed literature suggests that CNT may have unusual toxicity properties. In particular, CNT seem to have a special ability to stimulate mesenchymal cell growth and to cause granuloma formation and fibrogenesis. In several studies, CNT have more adverse effects than the same mass of NP carbon and quartz, the latter a commonly used benchmark of particle toxicity. There is, however, no definitive inhalation study available that would avoid the potential for artifactual effects due to large mats and aggregates forming during instillation exposure procedures. Studies also show that CNT may exhibit some of their effects through oxidative stress and inflammation. CNT represent a group of particles that are growing in production and use, and therefore, research into their toxicology and safe use is warranted.

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Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles.

Christie M. Sayes, Laura Reed, D Warheit (2007)

Previous studies have reported little correlation between the relative toxicity of particle types when comparing lung toxicity rankings following in vivo instillation versus in vitro cell culture exposures. This study was designed to assess the capacity of in vitro screening studies to predict in vivo pulmonary toxicity of several fine or nanoscale particle types in rats. In the in vivo component of the study, rats were exposed by intratracheal instillation to 1 or 5 mg/kg of the following particle types: (1) carbonyl iron (CI), (2) crystalline silica (CS) (Min-U-Sil 5, alpha-quartz), (3) precipitated amorphous silica (AS), (4) nano-sized zinc oxide (NZO), or (5) fine-sized zinc oxide (FZO). Depending on particle type and solution state, these particles range in size from 90 to 500 nm in size. Following exposures, the lungs of exposed rats were lavaged and inflammation (neutrophil recruitment) and cytotoxicity end points (bronchoalveolar lavage [BAL] fluid lactate dehydrogenase [LDH] values) were measured at 24 h, 1 week, 1 and 3 months postexposure. For the in vitro component of the study, three different culture conditions were utilized. Cultures of (1) rat L2 lung epithelial cells, (2) primary alveolar macrophages (AMs) (collected via BAL from unexposed rats), as well as (3) AM-L2 lung epithelial cell cocultures were incubated with the particle types listed above, and the culture fluids were evaluated for cytotoxicity end points (LDH, 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan [MTT]) as well as inflammatory cytokines (macrophage inflammatory 2 protein [MIP-2], tumor necrosis factor alpha [TNF-alpha], and interleukin-6 [IL-6]) at one (i.e., cytokines) or several (cytotoxicity) time periods. Results of in vivo pulmonary toxicity studies demonstrated that instilled CI particles produced little toxicity. CS particles produced sustained inflammation and cytotoxicity. AS particles produced reversible and transient inflammatory responses. NZO or FZO particles produced potent but reversible inflammation which was resolved by 1 month postinstillation exposure. Results of in vitro pulmonary cytotoxicity studies demonstrated a variety of responses to the different particle types, primarily at high doses. With respect to the LDH results, L2 cells were the most sensitive and exposures to nano- or fine-sized ZnO for 4 or 24 h were more cytotoxic than exposures to CS or AS particles. Macrophages essentially were resistant and epithelial macrophage cocultures generally reflected the epithelial results at 4 and 24 h incubation, but not at 48 h incubation. MTT results were also interesting but, except for nano- and fine-sized ZnO, did not correlate well with LDH results. Results of in vitro pulmonary inflammation studies demonstrated that L2 cells did not produce MIP-2 cytokines, but CS- or AS-exposed AMs and, to a lesser degree, cocultures secreted these chemotactic factors into the culture media. Measurements of TNF-alpha in the culture media by particle-exposed cells demonstrated little activity. In addition, IL-6 secretion was measured in CS, AS, and nano-sized ZnO-exposed cocultures. When considering the range of toxicity end points to five different particle types, the comparisons of in vivo and in vitro measurements demonstrated little correlation, particularly when considering many of the variables assessed in this study-such as cell types to be utilized, culture conditions and time course of exposure, as well as measured end points. It seems clear that in vitro cellular systems will need to be further developed, standardized, and validated (relative to in vivo effects) in order to provide useful screening data on the relative toxicity of inhaled particle types.

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Author and article information

Journal

Journal ID (nlm-ta): Environ Health Perspect

Title: Environmental Health Perspectives

Publisher: National Institute of Environmental Health Sciences

ISSN (Print): 0091-6765

ISSN (Electronic): 1552-9924

Publication date (Print): December 2010

Publication date (Electronic): 20 August 2010

Volume: 118

Issue: 12

Pages: 1699-1706

Affiliations

[1 ] ELEGI (The Edinburgh Lung and the Environment Group Initiative), Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom;

[2 ] Immunology Group, Centre for Inflammation Research and

[3 ] School of Chemistry, University of Edinburgh, Edinburgh, United Kingdom;

[4 ] Free Radical Research Facility, Department of Diabetes and Cardiovascular Science, Centre for Health Science, University of the Highlands and Islands, Inverness, United Kingdom

Author notes

Address correspondence to K. Donaldson, Queens Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Telephone: 44-131-242-6580. Fax: 44-131-242-6582. E-mail: ken.donaldson@ 123456ed.ac.uk

The authors declare they have no actual or potential competing financial interests.

Article

Publisher ID: ehp-118-1699

DOI: 10.1289/ehp.1002201

PMC ID: 3002189

PubMed ID: 20729176

SO-VID: 9e23ce2c-cc56-4b7e-af44-3e98dd106214

Copyright © This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.

History

Date received : 23 March 2010

Date accepted : 20 August 2010

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Metal Oxide Nanoparticles Induce Unique Inflammatory Footprints in the Lung: Important Implications for Nanoparticle Testing

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Abstract

Background

Objectives

Methods

Results

Conclusion

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Global Health Next Generation Network

Most cited references 27

Safe handling of nanotechnology.

Carbon nanotubes: a review of their properties in relation to pulmonary toxicology and workplace safety.

Assessing toxicity of fine and nanoparticles: comparing in vitro measurements to in vivo pulmonary toxicity profiles.

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Cited by 88