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Abstract
There were "miracle materials" at the time that were later banned. Most of them were "biopersistent" and had "mild acute toxicity but nasty chronic toxicity". This toxicity gap had given time to allow for mass use before ban. Most carbon-based nanomaterials are taught to be biopersistent and therefore we investigated their chronic inhalation toxicity as a part of particulate matter toxicology. We developed a universal dispersion method and a small-scale cheap and easy inhalation system named "Taquann". The first sample was Mitsui-7 multiwall carbon nanotube (MWCNT) donated by the company. Based on its size and shape, we referred to the asbestos and performed the intraperitoneal injection studies. Meanwhile, we started monitoring the inhaled mouse lung for the mechanism of lung fibrosis and carcinogenesis. The responses against inhaled particles were monitored in three studies (A) 2hr/day x 5days of inhalation (Mitsui-7) with monitoring at 0, 13w, 26w, 52w, (B) 2hr/day/week x 5weeks (Mitsui-7, TiO2 , MWCNT-N) at 0, 1w, 4w, 8, and (C) 6hr/day/4weeks x 104weeks (Mitsui-7) at 26w, 52w, 104w. There were responses common and different among rigid fiber, tangled fiber and non-fiber particles. Alveolar macrophages tend to phagocytize at its full capacity and relocate to a certain position in the lung, and/or die off, releasing the particles to be re-phagocytized. Type II cell proliferation and interstitial fibrosis may be related to the level of "frustrated phagocytosis" which may be maximized by rigid fibers. More detail including immune responses and lymphatics will be presented. (Health and Labour Science Research Grants).

Abstract

Background
The toxicological effects of nanomaterials, such as multi-walled carbon nanotubes (MWCNTs), on the immune system are considerably understood. However, the precise relationship between long-term exposure to MWCNTs and chronic inflammation remains unclear.


Methods and Finding
In this study, exposure to Taquann-treated MWCNTs (T-CNTs) was performed using aerosols generated in an inhalation chamber. At 12 months after T-CNT exposure, alveolar inflammation with macrophage accumulation and hypertrophy of the alveolar walls were observed. The fibrotic lesions were enhanced by T-CNT exposure. The cell surface phenotype of macrophages in the bronchoalveolar lavage fluid was shifted to the M1 macrophage phenotype. In addition, the alveolar macrophages of T-CNT-exposed mice produced matrix metalloprotinase-12 (MMP-12). By contrast, a mouse model of chronic peritonitis was also established using intraperitoneal injection of T-CNTs with high dispersion efficiency. Chronic peritonitis with fibrosis was observed in T-CNT-injected mice, but not in Taquann-treated TiO2-injected mice. In vivo and in vitro experiments showed that MMP-12 of macrophages was upregulated by T-CNT to enhance fibroblast activation and profibrotic molecule expression in fibroblasts. In addition, T-CNT-induced peritonitis reduced MMP-12 expression in Nfκb1−/− mice, suggesting that MMP-12-producing macrophages play a key role in chronic inflammation due to T-CNT exposure though NF-κB activation.


Conclusion
These results using the two models suggest that T-MWCNT exposure promoted chronic inflammation and fibrotic lesion formation in profibrotic macrophages via MMP12 for prolonged periods. The results of this study could be helpful in understanding the molecular toxicity of nanomaterial and chronic inflammation.

Abstract
Multi-walled carbon nanotubes (MWCNTs) are composed of multiple coaxially arranged graphene cylinders. MWCNTs range in diameter from 1 to over 100 nm depending on the number of constituting graphene cylinders. MWCNTs can be divided into two general subtypes, straight and tangled: increasing the number of constituent graphene cylinders increases the number of layers that compose the carbon nanotube wall, and as the number of wall layers increase, the wall thickness increases and the MWCNT becomes more rigid and straight. MWCNTs with a low number of wall layers are flexible and can assemble into tangled agglomerates. We initially showed MWCNT-N, a straight-type MWCNT with 30-40 walls, induced lung tumors and mesotheliomas after administration by intra-tracheal intra-pulmonary spraying (TIPS): rats were administered a total dose of 1mg/rat during the initial 2 weeks of the study, and animals were observed for 2 years without any further treatments. Using this short-term dosing and 2-year observation method we conducted carcinogenicity tests for other MWCNTs with different cylinder wall layers. We found that both straight type MWCNTs, MWCNT-7 (40 layers), MWCNT-A (150 layers), and tangled type MWCNTs, MWCNT-B (15 layers) and double-walled CNT (DWCNT) (2 layers) induced lung tumors and/or pleural mesotheliomas. In contrast to these results, we found carbon nanohorns, carbon nanostructures composed of single-walled carbon nanotubes (SWCNT), and carbon nanobrushes, a fibrous aggregate of carbon nanohorns, were not carcinogenic. Data on foreign body radical production, microarray and mutational signature analyses, and gene alterations will be presented.

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. ; BACKGROUND In their safety evaluations of bisphenol A (BPA), the U.S. Food and Drug Administration (FDA) and a counterpart in Europe, the European Food Safety Authority (EFSA), have given special prominence to two industry-funded studies that adhered to standards defined by Good Laboratory Practices (GLP). These same agencies have given much less weight in risk assessments to a large number of independently replicated non-GLP studies conducted with government funding by the leading experts in various fields of science from around the world. OBJECTIVES We reviewed differences between industry-funded GLP studies of BPA conducted by commercial laboratories for regulatory purposes and non-GLP studies conducted in academic and government laboratories to identify hazards and molecular mechanisms mediating adverse effects. We examined the methods and results in the GLP studies that were pivotal in the draft decision of the U.S. FDA declaring BPA safe in relation to findings from studies that were competitive for U.S. National Institutes of Health (NIH) funding, peer-reviewed for publication in leading journals, subject to independent replication, but rejected by the U.S. FDA for regulatory purposes. DISCUSSION Although the U.S. FDA and EFSA have deemed two industry-funded GLP studies of BPA to be superior to hundreds of studies funded by the U.S. NIH and NIH counterparts in other countries, the GLP studies on which the agencies based their decisions have serious conceptual and methodologic flaws. In addition, the U.S. FDA and EFSA have mistakenly assumed that GLP yields valid and reliable scientific findings (i.e., "good science"). Their rationale for favoring GLP studies over hundreds of publically funded studies ignores the central factor in determining the reliability and validity of scientific findings, namely, independent replication, and use of the most appropriate and sensitive state-of-the-art assays, neither of which is an expectation of industry-funded GLP research. CONCLUSIONS Public health decisions should be based on studies using appropriate protocols with appropriate controls and the most sensitive assays, not GLP. Relevant NIH-funded research using state-of-the-art techniques should play a prominent role in safety evaluations of chemicals.