Review Biopersistent fiber-induced inflammation and carcinogenesis: Lessons learned from asbestos toward safety of fibrous nanomaterials Hirotaka Nagai a,b , Shinya Toyokuni a, * a Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Aichi, Japan b Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Kyoto, Japan article info Article history: Received 5 April 2010 and in revised form 10 June 2010 Available online xxxx Keywords: Asbestos Carbon nanotube Mesothelioma Inflammation Macrophage abstract Nano-sized durable fibrous materials such as carbon nanotubes have raised safety concerns similar to those raised by asbestos. However, the mechanism by which particulates with ultrafine structure cause inflammation and ultimately cancer (e.g. malignant mesothelioma and lung cancer) is largely unknown. This is partially because the particulates are not uniform and they vary in a plethora of fac- tors. Such variances include length, diameter, surface area, density, shape, contaminant metals (including iron) and crystallinity. Each of these factors is involved in particulate toxicity both in vitro and in vivo. Thus, the elicited biological responses are incredibly complicated. Various kinds of fibers were evaluated with different cells, animals and methods. The aim of this review is to con- cisely summarize previous reports from the standpoint that activation of macrophages and mesothe- lial injury are the two major mechanisms of inflammation and possibly cancer. Importantly, these two mechanisms appear to be interacting with each other. However, there is a lack of data on the inter- play of macrophage and mesothelium especially in vivo. Since fibrous nanomaterials present potential applications in various fields, it is necessary to develop standard evaluation methods to minimize risks for human health. Ó 2010 Elsevier Inc. All rights reserved. Introduction Malignant mesothelioma (or simply mesothelioma), derived from mesothelial cells covering somatic cavities, is a highly malig- nant tumor with a poor prognosis [1]. In most cases in humans, this tumor is thought to be caused by asbestos inhalation. However, this disease presents an extremely long incubation period, and may not become apparent until 30–40 years after persistent asbes- tos exposure [2]. Asbestos has been proven carcinogenic in animal experiments (Fig. 1). Previous studies demonstrated that asbestos fibers longer than 8–20 lm and thinner than 0.25 lm more readily induce mesothelioma [3,4]. Carbon nanotubes (CNTs) 1 [5] are man- ufactured materials which have the potential to be used in numerous applications in the field of engineering and materials science. How- ever, two recent papers reported that CNTs caused mesothelioma in rodents using very sensitive models for carcinogenesis [6,7]. These findings suggest that CNTs may cause cancer in a similar fashion to asbestos [8,9] and have had a negative impact on the industry. Asbestos and CNTs share similar physical characteristics as fi- brous particulate matter with a high-aspect ratio. In 1987, the IARC designated asbestos fibers as a Group 1 (definite) carcinogen for hu- mans (http://monographs.iarc.fr/ENG/Classification/crthgr01.php). Consequently, asbestos fibers were banned in many Western coun- tries in the 1990s [2,10]. However, at present there is no global agreement reached for the risk of CNTs on human health. This is partly because each CNT grown from carbon vapor is intrinsically different [4]. This has caused a confounding problem for toxicolo- gists as described later. In this review we summarize the difficulty in using these fibers for assessing their toxicological features, intro- duce important findings from previous studies and discuss future perspectives. Basic characteristics of asbestos and carbon nanotubes Asbestos is a naturally occurring mineral whose major constit- uent is silica. Asbestos species are conventionally divided into two mineralogic groups: amphiboles and serpentines. The amphiboles include crocidolite (blue asbestos), amosite (brown asbestos), tremolite, anthophyllite and actinolite. Among the amphiboles, only crocidolite and amosite have widespread commercial utiliza- tion. The non-commercial amphiboles are primarily contaminants of other minerals, such as chrysotile [11]. The second group of 0003-9861/$ - see front matter Ó 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.abb.2010.06.015 * Corresponding author. Fax: +81 52 744 2091. E-mail address: toyokuni@med.nagoya-u.ac.jp (S. Toyokuni). 1 Abbreviations used: CNF, carbon nanofiber; CNT, carbon nanotube; MWCNT, multi-walled carbon nanotube; SWCNT, single-walled carbon nanotube; TNF-a, tumor necrosis factor-a. Archives of Biochemistry and Biophysics xxx (2010) xxx–xxx Contents lists available at ScienceDirect Archives of Biochemistry and Biophysics journal homepage: www.elsevier.com/locate/yabbi Please cite this article in press as: H. Nagai, S. Toyokuni, Arch. Biochem. Biophys. (2010), doi:10.1016/j.abb.2010.06.015