Induction of mesothelioma in p53+/- mouse by intraperitoneal application of multi-wall carbon nanotube

Our plain-English summary of Induction of mesothelioma in p53+/- mouse by intraperitoneal application of multi-wall carbon nanotube, by A. Takagi, A. Hirose, T. Nishimura, et al (The Journal of Toxicological Sciences, 2008).

The study

• Authors: A. Takagi, A. Hirose, T. Nishimura, N. Fukumori, A. Ogata, N. Ohashi, S. Kitajima, J. Kanno
• Journal: The Journal of Toxicological Sciences
• Published: 2008;33(1):105-16
• Cited by: 491 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Nanomaterials of carbon origin tend to form various shapes of particles in micrometer dimensions. Among them, multi-wall carbon nanotubes (MWCNT) form fibrous or rod-shaped particles of length around 10 to 20 micrometers with an aspect ratio of more than three. Fibrous particles of this dimension including asbestos and some man-made fibers are reported to be carcinogenic, typically inducing mesothelioma. Here we report that MWCNT induces mesothelioma along with a positive control, crocidolite (blue asbestos), when administered intraperitoneally to p53 heterozygous mice that have been reported to be sensitive to asbestos. Our results point out the possibility that carbon-made fibrous or rod-shaped micrometer particles may share the carcinogenic mechanisms postulated for asbestos. To maintain sound activity of industrialization of nanomaterials, it would be prudent to implement strategies to keep good control of exposure to fibrous or rod-shaped carbon materials both in the workplace and in the future market until the biological/ carcinogenic properties, especially of their long-term biodurability, are fully assessed.

In plain English

This was an animal experiment by researchers in Tokyo, Japan. The authors tested whether multi-wall carbon nanotubes (MWCNT), which are fiber- or rod-shaped carbon particles, cause mesothelioma in mice with only one working copy of the p53 gene, a strain reported to be sensitive to asbestos. Groups of 19 male mice each received one injection into the abdomen of MWCNT, crocidolite (blue asbestos, the positive control), fullerene (another carbon material), or the carrier liquid alone. Each particle-treated group received 3 mg per mouse. The study ended at week 25. The authors counted mice from day 84, when the first case was found in the MWCNT group. From then on, peritoneal mesothelioma (in the lining of the abdomen) occurred in 14 of 16 MWCNT mice (87.5%) and 14 of 18 crocidolite mice (77.8%). No tumors were found in the fullerene or control groups. The authors concluded that MWCNT showed carcinogenic potential in these mice, presumably because of its size and shape and its persistence in the body. They stated that this mouse study cannot by itself predict mesothelioma in humans and applies only to MWCNT particles longer than 5 micrometers.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Animal experiment: short-term carcinogenicity bioassay using a single intraperitoneal injection in p53 heterozygous mice
• Who was studied: 76 male p53 heterozygous (p53+/-) mice aged 9 to 11 weeks, 19 per group, at the National Institute of Health Sciences, Tokyo, Japan. Additional satellite groups of 6 wild-type C57BL/6 male mice each were examined at day 10 for early responses.
• Exposure: Single intraperitoneal injection, each in 1 ml of suspension. The MWCNT group (MITSUI MWCNT-7) received 1×10^9 particles (3 mg per mouse). The positive control group received UICC-grade crocidolite at 1×10^10 fibers (3 mg per mouse). The fullerene (C60) group received 3 mg per mouse. Negative controls received 1 ml of vehicle solution only. The MWCNT had an average width of about 100 nm, 27.5% of its particles were longer than 5 micrometers, and its iron content was about 0.35%.
• Main results:
  • Counted after the first incidental case in the MWCNT group at day 84, mesothelioma occurred in 14/16 (87.5%) of the MWCNT group (11 as cause of death, 3 incidental). It occurred in 14/18 (77.8%) of the crocidolite group (8 as cause of death, 6 incidental).
  • In the control and fullerene groups there were no tumors and no deaths during the study, except for one mouse that became moribund from chronic pyelonephritis at day 152.
  • In the MWCNT group, lesions ranged from pile-ups of atypical mesothelial cells to large tumors up to 2.7 × 1.5 cm that were compatible with high-grade malignant mesothelioma.
  • Large tumors invaded the abdominal wall, diaphragm, liver and pancreas, and in some cases the chest cavity. No distant spread was observed.
  • The second major cause of death was intestinal obstruction (constriction ileus) due to severe peritoneal adhesion.
  • The fullerene group showed no peritoneal adhesion, no fibrous thickening and no tumors.
  • At day 10, the MWCNT-treated satellite mice showed slight fibrinous adhesion and a trace of ascites. Crocidolite-treated mice showed similar but lesser responses.
  • Cells containing MWCNT and crocidolite fibers were found not only in the peritoneal lesions but also in the liver and the mesenteric lymph nodes.
• The authors' conclusion: The authors concluded that intraperitoneal MWCNT showed carcinogenic potential in p53+/- mice, presumably depending on its size and shape and its persistence in the body, and that it may share carcinogenic mechanisms postulated for asbestos.
• Limitations the authors state:
  • This mouse model study cannot by itself predict whether MWCNT causes mesothelioma in humans.
  • The findings apply only to the portion of MWCNT longer than 5 micrometers.
  • The effects of pure nanometer-sized carbon nanotubes and fullerene were not assessed, and the method may not detect effects of such particles within 25 weeks.
  • The biodurability of MWCNT has not yet been rigorously tested.
  • The authors noted debate over whether rodent injection models are equivalent to human inhalation exposure.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma, Peritoneal mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelioma, Aspect Ratio (Length-to-diameter ratio), Carcinogenic, Crocidolite.

Related studies

• Re: Induction of mesothelioma in p53+/- mouse by intraperitoneal application of multi-wall carbon nanotube — G. Ichihara, V. Castranova, et al. (2008)
• Dose-dependent mesothelioma induction by intraperitoneal administration of multi-wall carbon nanotubes in p53 heterozygous mice — A. Takagi, A. Hirose, et al. (2012)
• Effects of sustained stimulation with multi-wall carbon nanotubes on immune and inflammatory responses in mice — A. Yamaguchi, T. Fujitani, et al. (2012)
• Single- and multi-wall carbon nanotubes versus asbestos: are the carbon nanotubes a new health risk to humans? — M. Pacurari, V. Castranova, et al. (2010)
• High-temperature calcined fullerene nanowhiskers as well as long needle-like multi-wall carbon nanotubes have abilities to induce NLRP3-mediated IL-1β secretion — H. Cui, W. Wu, et al. (2014)
• Aspect ratio has no effect on genotoxicity of multi-wall carbon nanotubes — J.S. Kim, K. Lee, et al. (2011)

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