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The carcinogenic effect of various multi-walled carbon nanotubes (MWCNTs) after intraperitoneal injection in rats

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Rittinghausen, Susanne, Hackbarth, Anja, Creutzenberg, Otto, Ernst, Heinrich, Heinrich, Uwe, Leonhardt, Albrecht, Schaudien, Dirk·2014·Particle and Fibre Toxicology
DOI 10.1186/s12989-014-0059-zPMC PMC4243371
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Abstract

BACKGROUND: Biological effects of tailor-made multi-walled carbon nanotubes (MWCNTs) without functionalization were investigated in vivo in a two-year carcinogenicity study. In the past, intraperitoneal carcinogenicity studies in rats using biopersistent granular dusts had always been negative, whereas a number of such studies with different asbestos fibers had shown tumor induction. The aim of this study was to identify possible carcinogenic effects of MWCNTs. We compared induced tumors with asbestos-induced mesotheliomas and evaluated their relevance for humans by immunohistochemical methods. METHODS: A total of 500 male Wistar rats (50 per group) were treated once by intraperitoneal injection with 10⁹ or 5 × 10⁹ WHO carbon nanotubes of one of four different MWCNTs suspended in artificial lung medium, which was also used as negative control. Amosite asbestos (10⁸ WHO fibers) served as positive control. Morbid rats were sacrificed and necropsy comprising all organs was performed. Histopathological classification of tumors and, additionally, immunohistochemistry were conducted for podoplanin, pan-cytokeratin, and vimentin to compare induced tumors with malignant mesotheliomas occurring in humans. RESULTS: Treatments induced tumors in all dose groups, but incidences and times to tumor differed between groups. Most tumors were histologically and immunohistochemically classified as malignant mesotheliomas, revealing a predominantly superficial spread on the serosal surface of the abdominal cavity. Furthermore, most tumors showed invasion of peritoneal organs, especially the diaphragm. All tested MWCNT types caused mesotheliomas. We observed highest frequencies and earliest appearances after treatment with the rather straight MWCNT types A and B. In the MWCNT C groups, first appearances of morbid mesothelioma-bearing rats were only slightly later. Later during the two-year study, we found mesotheliomas also in rats treated with MWCNT D - the most curved type of nanotubes. Malignant mesotheliomas induced by intraperitoneal injection of different MWCNTs and of asbestos were histopathologically and immunohistochemically similar, also compared with mesotheliomas in man, suggesting similar pathogenesis. CONCLUSION: We showed a carcinogenic effect for all tested MWCNTs. Besides aspect ratio, curvature seems to be an important parameter influencing the carcinogenicity of MWCNTs.

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Figure 1 Mortality curves in % of all rats of the study comprising all animals which died or were humanely killed due to a bad clinical condition. A group was terminated when 80% mortality was reached.
Figure 1 Mortality curves in % of all rats of the study comprising all animals which died or were humanely killed due to a bad clinical condition. A group was terminated when 80% mortality was reached.CC BY · PubMed Central
Figure 2 Animals with malignant mesotheliomas over time in %. A group was terminated when 80% mortality was reached.
Figure 2 Animals with malignant mesotheliomas over time in %. A group was terminated when 80% mortality was reached.CC BY · PubMed Central
Figure 3 Non-neoplastic histopathological findings in the abdominal cavity. A: High-power view of anti-podoplanin immunohistochemistry showing single MWCNT A (high dose) nanotubes in the tissue (arrows). B: High-power view of anti-podoplanin immunohistochemistry showing single asbestos fibers in the tissue (arrows). C: H & E, high-power view of granuloma induced by MWCNT A (low dose) nanotubes including single nanotube (arrow, 25×). D: H & E, high-power view of granuloma induced by asbestos including single fiber (arrow, 40×).
Figure 3 Non-neoplastic histopathological findings in the abdominal cavity. A: High-power view of anti-podoplanin immunohistochemistry showing single MWCNT A (high dose) nanotubes in the tissue (arrows). B: High-power view of anti-podoplanin immunohistochemistry showing single asbestos fibers in the tissue (arrows). C: H & E, high-power view of granuloma induced by MWCNT A (low dose) nanotubes including single nanotube (arrow, 25×). D: H & E, high-power view of granuloma induced by asbestos including single fiber (arrow, 40×).CC BY · PubMed Central
Figure 4 Histological typing of malignant mesotheliomas occurring in the study. The most frequent type of mesothelioma was the sarcomatoid type, followed by mesotheliomas of the biphasic type. Mesotheliomas of the epithelioid type were rare.
Figure 4 Histological typing of malignant mesotheliomas occurring in the study. The most frequent type of mesothelioma was the sarcomatoid type, followed by mesotheliomas of the biphasic type. Mesotheliomas of the epithelioid type were rare.CC BY · PubMed Central
Figure 5 Sarcomatoid-type malignant mesothelioma observed in the MWCNT B high-dose group. A: H & E, low magnification of tumor tissue invading the diaphragm (20×). B and C: H & E, high-power view (40×). D: High-power view of anti-vimentin immunohistochemistry showing a strongly positive result (40×). E: High-power view of anti-pan-cytokeratin immunohistochemistry showing several positive cells (40×). F: High-power view of anti-podoplanin immunohistochemistry revealing positively stained cytoplasm of many cells (40×).
Figure 5 Sarcomatoid-type malignant mesothelioma observed in the MWCNT B high-dose group. A: H & E, low magnification of tumor tissue invading the diaphragm (20×). B and C: H & E, high-power view (40×). D: High-power view of anti-vimentin immunohistochemistry showing a strongly positive result (40×). E: High-power view of anti-pan-cytokeratin immunohistochemistry showing several positive cells (40×). F: High-power view of anti-podoplanin immunohistochemistry revealing positively stained cytoplasm of many cells (40×).CC BY · PubMed Central
Figure 6 Biphasic-type malignant mesothelioma observed in the MWCNT D low-dose group. A: H & E, low magnification of tumor tissue found on the surface of the omentum (20×). B and C: H & E, high-power view (40×). D: High-power view of anti-vimentin immunohistochemistry showing a strongly positive result (40×). E: High-power view of anti-pan-cytokeratin immunohistochemistry showing positive staining of the majority of cells (40×). F: High-power view of anti-podoplanin immunohistochemistry revealing positively stained cytoplasm of many cells (40×).
Figure 6 Biphasic-type malignant mesothelioma observed in the MWCNT D low-dose group. A: H & E, low magnification of tumor tissue found on the surface of the omentum (20×). B and C: H & E, high-power view (40×). D: High-power view of anti-vimentin immunohistochemistry showing a strongly positive result (40×). E: High-power view of anti-pan-cytokeratin immunohistochemistry showing positive staining of the majority of cells (40×). F: High-power view of anti-podoplanin immunohistochemistry revealing positively stained cytoplasm of many cells (40×).CC BY · PubMed Central
Figure 7 Biphasic-type malignant mesothelioma observed in the amosite asbestos group. A: H & E, low magnification of tumor tissue found on the liver surface (10×). B: H & E, higher magnification (20×). C: H & E, high-power view (40×). D: High-power view of anti-vimentin immunohistochemistry showing a strongly positive result (40×). E: High-power view of anti-pan-cytokeratin immunohistochemistry showing positive staining of many cells (40×). F: High-power view of anti-podoplanin immunohistochemistry revealing positivity in distinct parts of the tumor.
Figure 7 Biphasic-type malignant mesothelioma observed in the amosite asbestos group. A: H & E, low magnification of tumor tissue found on the liver surface (10×). B: H & E, higher magnification (20×). C: H & E, high-power view (40×). D: High-power view of anti-vimentin immunohistochemistry showing a strongly positive result (40×). E: High-power view of anti-pan-cytokeratin immunohistochemistry showing positive staining of many cells (40×). F: High-power view of anti-podoplanin immunohistochemistry revealing positivity in distinct parts of the tumor.CC BY · PubMed Central
Figure 8 Scanning electron microscopic photographs of carbon nanotubes and asbestos fibers in suspension. Photographs were taken from liquid formulations of CNT in medium according to Porter (physico-chemical characterization in pre-trials). CNT agglomerates occurred infrequently and are not visible here. A: MWCNT A (left: 10,000×, right: 30,000×). B: MWCNT B (left: 10,000×, right: 30,000×). C: MWCNT C (left: 10,000×, right: 30,000×). D: MWCNT D (left: 10,000×, right: 30,000×). E: Long amosite asbestos (left: 2,000×, right: 7,000×).
Figure 8 Scanning electron microscopic photographs of carbon nanotubes and asbestos fibers in suspension. Photographs were taken from liquid formulations of CNT in medium according to Porter (physico-chemical characterization in pre-trials). CNT agglomerates occurred infrequently and are not visible here. A: MWCNT A (left: 10,000×, right: 30,000×). B: MWCNT B (left: 10,000×, right: 30,000×). C: MWCNT C (left: 10,000×, right: 30,000×). D: MWCNT D (left: 10,000×, right: 30,000×). E: Long amosite asbestos (left: 2,000×, right: 7,000×).CC BY · PubMed Central

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Research works printed but not linked: 2

  1. Recommendation from the Scientific Committee on Occupational Exposure Limits for man-made mineral fibres (MMMF) with no indication for carcinogenicity and not specified elsewhere SCOEL/SUM/88 2012, 2012: 1–17.
  2. Technical rules for hazardous substances 905. Technical Rules (TRGS) established by the Committee on Hazardous Substances (AGS). Verzeichnis krebserzeugender, erbgutverändernder oder fortpflanzungsgefährdender Stoffe German Federal Institute for Occupational Safety and Health (BAuA) 2014, 24: 3–4.

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Metadata

Authors
Rittinghausen, S., Hackbarth, A., Creutzenberg, O., Ernst, H., Heinrich, U., Leonhardt, A., & Schaudien, D.
Affiliations
  • Fraunhofer Institute for Toxicology and Experimental Medicine (DE)
  • Leibniz Institute for Solid State and Materials Research (DE)
Corresponding author
Rittinghausen, Susanne
ORCID
Venue
Particle and Fibre Toxicology
Publisher
Springer Science and Business Media LLC
Published
2014-11-20
Volume
11
Issue
1
Pages
59-59
ISSN
1743-8977 (ISSN-L)
DOI
10.1186/s12989-014-0059-z
PMC
PMC4243371
OpenAlex
W2152314477
Cited by
193
References
61
Citations by year
2026: 5 · 2025: 8 · 2024: 16 · 2023: 15 · 2022: 16 · 2021: 21 · 2020: 25 · 2019: 17 · 2018: 24 · 2017: 22 · 2016: 13 · 2015: 11
FWCI
12.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Particle and Fibre Toxicology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion, other-oa)
  • Fraunhofer-Publica (Fraunhofer-Gesellschaft) (submittedVersion)
Funders
Bundesministerium für Bildung und Forschung (03X0109A)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
  • Physical Sciences › Engineering › Biomedical Engineering › Graphene and Nanomaterials Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
Keywords
multi-walled carbon nanotubes, carcinogenicity, malignant mesothelioma, intraperitoneal injection, asbestos, amosite, nanotube curvature, aspect ratio, podoplanin, pancytokeratin, vimentin, rats, nanotube toxicity
MeSH terms
Abdominal Neoplasms, Animals, Carcinogens, Dose-Response Relationship, Drug, Immunohistochemistry, Injections, Intraperitoneal, Male, Mesothelioma, Microscopy, Electron, Scanning, Neoplasm Invasiveness, Neoplasm Proteins, Particle Size, Serous Membrane, Carcinogenicity Tests, Survival Analysis, Rats, Wistar, Nanotubes, Carbon

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