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 × 109 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 × 108 fibers), 30 μg/mouse (1 × 107) or 3 μg/mouse (1 × 106), 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. (Cancer Sci 2012; 103: 1440–1444)
Highlights
U nique properties such as persistency and electric conductivity promise a high potential for technology applications of carbon nanotubes
The present study showed a dose-dependent induction of mesothelioma by the lm-multi-wall carbon nanotubes (MWCNT) from 1/1000 of the dose of our previous study (i.e. 3 lg/mouse corresponding to 1 9 106 fibers)
It is noted that the mesotheliomas of the low-dose group were not accompanied by foreign body granulomas or fibrous scars
Summary
U nique properties such as persistency and electric conductivity promise a high potential for technology applications of carbon nanotubes (e.g. in lithium ion batteries). Marsella et al[9] has shown that development of mesothelioma by crocidolite asbestos was accelerated in this mutant mouse. We have bred this mouse and tested it as an alternative model to replace the wild-type mouse carcinogenicity test of the National Toxicology Program of the National Institute of Environmental Health Sciences/NIH of the United States.[10] As a result, spontaneous neoplastic lesions of this model have been well characterized.[11]. We applied the same fiber to p53+/À mice at doses of 1/10, 1/100, and 1/1000 of the dose used in the previous study (i.e. 300, 30 and 3 lg/mouse), which corresponds to approximately 1 9 108, 1 9 107, and 1 9 106 fibers per mouse, respectively, and monitored the mice for 1 year
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