Occupational Exposure to Carbon Nanotubes and Nanofibers

examined up to 60 days post-exposure [Mulleret al. 2005]. Rats that received ground MWCNT(0.7 µm) showed greater dispersion in the lungs,and fibrotic lesions were observed in the deep lungs(alveolar region). In rats treated with ungroundMWCNT (5.9 µm), fibrosis appeared mainly inthe airways rather than in the lung parenchyma.The biopersistence of the unground MWCNT wasgreater than that of the ground MWCNT (81% vs.36 %). At an equal mass dose, ground MWCNTproduced a similar inflammatory and fibrogenic responseas chrysotile asbestos and a greater responsethan ultrafine carbon black [Muller et al. 2005].Similar findings have been reported by Aiso etal. [2010], in which rats exposed to IT doses of0.04 and 0.16 mg of dispersed MWCNT (meanlength-5 µm, diameter-88 nm) caused transientinflammation, and persistent granulomas and alveolarwall fibrosis. These acute effects have alsobeen reported in guinea pigs at IT doses of 12.5 mg[Grubek-Jaworska et al. 2005] and 15 mg [Huczkoet al. 2005]; in mice at doses of 0.05 mg (average diameterof 50 nm, average length of 10 µm) [Li et al.2007], and at 5, 20, and 50 mg/kg [Park et al. 2009];and in rats [Liu et al. 2008] dosed at 1, 3, 5, or 7 mg(diameters of 40 to 60 nm, lengths of 0.5 to 5 µm). Incontrast, Elgrabli et al. [2008a] reported cell deathbut no histopathological lesions or fibrosis in rats exposedat doses of 1, 10, or 100 µg MWCNT (diametersof 20 to 50 nm, lengths of 0.5 to 2 µm). Likewise,Kobayashi et al. [2010] observed only transient lunginflammation and a granulomatous response inrats exposed to a dispersed suspension of MWCNT(0.04–1 mg/kg). No fibrosis was reported, but theauthors did not use a collagen stain for histopathology,which would have compromised the sensitivityand specificity of their lung tissue analysis.In a study of rats administered MWCNT or crocidoliteasbestos by intrapulmonary spraying (IPS),exposure to either material produced inflammationin the lungs and pleural cavity in addition to mesothelialproliferative lesions [Xu et al. 2012]. Fourgroups of six rats each were given 0.5 ml of 500 µgsuspensions, once every other day, five times overa 9-day period and then evaluated. MWCNT andcrocidolite were found to translocate from the lungto the pleural cavity after administration. MWCNTand crocidolite were also observed in the mediastinallymph nodes suggesting that a probable routeof translocation of the fibers is lymphatic flow.Analysis of tissue sections found MWCNT andcrocidolite in focal granulomatous lesions in thealveoli and in alveolar macrophages.3.2.3 Inhalation StudiesSeveral short-term inhalation studies using mice orrats have been conducted to assess the pulmonary[Mitchell et al. 2007; Arkema 2008; Ma-Hock et al.2009; Porter et al. 2009; Ryman-Rasmussen et al.2009b; Pauluhn 2010a; Wolfarth et al. 2011] andsystemic immune effects [Mitchell et al. 2007] fromexposure to MWCNT. Mitchell et al. [2007] reportedthe results of a whole-body short-term inhalationstudy with mice exposed to MWCNT (diameters of10 to 20 nm, lengths of 5 to 15 µm) at concentrationsof 0.3, 1, or 5 mg/m 3 for 7 or 14 days (6 hr/day) (although there was some question regardingwhether these structures were actually MWCNT[Lison and Muller 2008]). Histopathology of lungsof exposed animals showed alveolar macrophagescontaining black particles; however, there was noobserved inflammation or tissue damage. Systemicimmunosuppression was observed after 14 days, althoughwithout a clear concentration-response relationship.Mitchell et al. [2009] reported that the immunosuppressionmechanism of MWCNT appearsto involve a signal originating in the lungs that activatescyclooxygenase enzymes in the spleen. Porteret al. [2009] reported significant pulmonary inflammationand damage in mice 1 day after inhalation ofwell-dispersed MWCNT (10 mg/m 3 , 5 hr/day, 2–12days; mass aerodynamic diameter of 1.3 µm, countaerodynamic diameter of 0.4 µm). In addition, granulomaswere also observed encapsulating MWCNTin the terminal bronchial/proximal alveolar regionof the lung. In an inhalation (nose-only) study withmice exposed to 30 mg/m 3 MWCNT (lengths of 0.5to 50 µm) for 6 hours, a high incidence (9 of 10 mice)of fibrotic lesions occurred [Ryman-Rasmussen etal. 2009b]. MWCNT were found in the subpleuralNIOSH CIB 65 • Carbon Nanotubes and Nanofibers17