Dose-dependent mesothelioma induction by intraperitoneal administration of multi-wall carbon nanotubes in p53 heterozygous mice

Our plain-English summary of Dose-dependent mesothelioma induction by intraperitoneal administration of multi-wall carbon nanotubes in p53 heterozygous mice, by A. Takagi, A. Hirose, M. Futakuchi, et al (Cancer Science, 2012).

The study

• Authors: A. Takagi, A. Hirose, M. Futakuchi, H. Tsuda, J. Kanno
• Journal: Cancer Science
• Published: 2012;103(8):1440-4
• Cited by: 131 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Among various types of multi-wall carbon nanotubes (MWCNT) are those containing fibrous particles longer than 5 μm with an aspect ratio of more than three (i.e. dimensions similar to mesotheliomagenic asbestos). A previous study showed that micrometer-sized MWCNT (μm-MWCNT) administered intraperitoneally at a dose of 3000 μg/mouse corresponding to 1 × 10(9) fibers per mouse induced mesotheliomas in p53 heterozygous mice. Here, we report a dose-response study; three groups of p53 heterozygous mice (n = 20) were given a single intraperitoneal injection of 300 μg/mouse of μm-MWCNT (corresponding to 1 × 10(8) fibers), 30 μg/mouse (1 × 10(7)) or 3 μg/mouse (1 × 10(6)), respectively, and observed for up to 1 year. The cumulative incidence of mesotheliomas was 19/20, 17/20 and 5/20, respectively. The severity of peritoneal adhesion and granuloma formation were dose-dependent and minimal in the lowest dose group. However, the time of tumor onset was apparently independent of the dose. All mice in the lowest dose group that survived until the terminal kill had microscopic atypical mesothelial hyperplasia considered as a precursor lesion of mesothelioma. Right beneath was a mononuclear cell accumulation consisting of CD45- or CD3-positive lymphocytes and CD45/CD3-negative F4/80 faintly positive macrophages; some of the macrophages contained singular MWCNT in their cytoplasm. The lesions were devoid of epithelioid cell granuloma and fibrosis. These findings were in favor of the widely proposed mode of action of fiber carcinogenesis, that is, frustrated phagocytosis where the mesotheliomagenic microenvironment on the peritoneal surface is neither qualitatively altered by the density of the fibers per area nor by the formation of granulomas against agglomerates.

© 2012 Japanese Cancer Association.

In plain English

This animal experiment tested a multi-wall carbon nanotube (Mitsui MWCNT-7), not asbestos. The authors noted that a considerable share of its particles resemble asbestos in length and width. Eighty male mice with one damaged copy of the p53 gene were split into four groups of 20. Three groups received one injection into the abdominal cavity of 300, 30 or 3 micrograms of nanotubes (about 100 million, 10 million or 1 million fibers per mouse). Controls received only the carrier liquid. Mice were followed for one year. Peritoneal mesothelioma developed in 19 of 20 high-dose, 17 of 20 middle-dose and 5 of 20 low-dose mice, and in no controls. The other 15 low-dose mice survived to the end and had small atypical mesothelial growths, which the authors regarded as precursor lesions. Scarring, adhesions and granulomas increased with dose, but estimated tumor onset times appeared similar across doses. Single fibers reached organs including the liver, kidney, lung and brain. The authors concluded that the nanotubes induced mesothelioma in this mouse model in a dose-dependent way down to 3 micrograms per mouse. They also noted that injection is not a realistic human exposure route.

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 (dose-response study): a single intraperitoneal injection in mice, followed for 1 year
• Who was studied: 80 male p53 heterozygous mice aged 9–11 weeks, randomly divided into four groups of 20 (three dose groups and one vehicle control), housed at the National Institute of Health Sciences, Tokyo
• Exposure: Multi-wall carbon nanotube (Mitsui MWCNT-7), the same lot as the authors' previous study, given by single intraperitoneal injection at 300, 30 or 3 micrograms per mouse (approximately 1 x 10^8, 1 x 10^7 and 1 x 10^6 fibers per mouse). Controls received vehicle solution only. No asbestos was tested.
• Main results:
  • High-dose group (300 micrograms per mouse): total mesothelioma incidence of 19/20 (95%). Of these, 14/20 were lethal and 5 were small incidental tumors in mice that died of ileus.
  • Middle-dose group (30 micrograms per mouse): 17/20 (85%) had lethal mesothelioma.
  • Low-dose group (3 micrograms per mouse): overall mesothelioma incidence of 5/20 (25%), made up of 4 lethal tumors and 1 non-lethal tumor found at the terminal kill on day 365.
  • Vehicle control group: no mesotheliomas were found.
  • The other 15 low-dose mice, which survived until the terminal kill, showed focal mesothelial atypical hyperplasia. The authors considered this a precancerous lesion.
  • Peritoneal fibrosis, peritoneal adhesion and foreign body granulomas were dose dependent and minimal in the low-dose group.
  • Estimated tumor onset times were 126 days for the previous study's data and 146, 148 and 138 days for the three doses of the present study. The authors described onset as apparently dose independent.
  • Single fibers were found in organs beyond the abdominal cavity, including the liver, mesenteric and pulmohilar lymph nodes, the choroid plexus of the brain, kidney glomeruli and lung alveoli.
• The authors' conclusion: The authors concluded that this micrometer-sized MWCNT caused mesothelioma in the p53 heterozygous mouse peritoneal cavity model in a dose-dependent manner from as low as 3 micrograms (about 10^6 fibers) per mouse. They said the findings might be consistent with the concept of frustrated phagocytosis and with the view from human asbestos epidemiology that there would be no practical threshold.
• Limitations the authors state:
  • The authors state that injection into the abdominal cavity is not a realistic route of exposure for humans.

Topics

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

Medical terms in this study, explained in our Lexicon: Mesothelioma, Aspect Ratio (Length-to-diameter ratio), Dose-response relationship, Granuloma, Atypical Mesothelial Proliferation, Macrophage, Epithelioid, Fibrosis.

Related studies

• Induction of mesothelioma in p53+/- mouse by intraperitoneal application of multi-wall carbon nanotube — A. Takagi, A. Hirose, et al. (2008)
• Re: Induction of mesothelioma in p53+/- mouse by intraperitoneal application of multi-wall carbon nanotube — G. Ichihara, V. Castranova, et al. (2008)
• 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)
• Intraperitoneal administration of tangled multiwalled carbon nanotubes of 15 nm in diameter does not induce mesothelial carcinogenesis in rats — H. Nagai, Y. Okazaki, et al. (2013)
• Genotoxicity and cytotoxicity of multi-wall carbon nanotubes in cultured Chinese hamster lung cells in comparison with chrysotile A fibers — M. Asakura, T. Sasaki, et al. (2010)

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