Pulmonary toxicity from multi-walled carbon nanotube (MWCNT) inhalation exposure is well described and includes lung epithelial hyperplasia, inflammation, and fibrosis. However, at levels relevant to workplace exposures the contributing molecular mechanisms are not well described. To address this question, a 19d inhalation exposure to MWCNT in C57BL/6J mice with daily alveolar depositions of 2340 ng (=1000 d of human exposure), 234 ng (=100 d), and 23.4 ng (=10d) was conducted. Cumulatively, these doses represent 76, 7.6, and 0.76 yr for the high, middle, and low dose, respectively, for a worker exposed to an inhalable concentration of 10 mg/m3 (average exposure from worker sampling at 8 different MWCNT sites; MMAD 5.5 mm) for 8 h/d for 250 d/yr. Mice were sacrificed at 0, 28, and 84 d post-exposure. RNA was isolated from left lung lobes and global expression analysis was performed with subsequent Ingenuity Pathway Analysis (IPA). Results indicated marked inflammation at the high dose that was sustained through 84 d post-exposure. Markers associated with pathological changes, such as fibrotic growth factors (TGFb, EGF, PDGF), were also a feature of the high dose. The middle dose was also associated with markers of inflammation (e.g. IL-6, IL-1b) but to a lesser extent and not as sustained when compared to the high dose. The middle dose showed indications of increased fibrotic markers at 0 and 28 d by BioProfiler analysis, but the response was not sustained and was absent at 84 d. The low dose showed minimal expression changes that did not form any major networks of activation. These results confirm the potential of MWCNT to induce molecular mechanisms associated with a marked inflammatory and pathological response in exposed mice. Based on exposure predictions, considerable years of exposure may be necessary at facilities operating at an inhalable concentration of 10 mg/m3 or below to elicit marked molecular changes.
Toxicology; Cell-function; Cellular-function; Cell-damage; Nanotechnology; Exposure-levels; Pulmonary-disorders; Pulmonary-function; Pulmonary-system; Pulmonary-system-disorders; Molecular-structure; Molecular-biology; Fibrosis; Exposure-levels; Laboratory-animals; Animals; Pathology; Toxic-effects; Toxins; Lung; Lung-disorders; Lung-irritants; Lung-function
The Toxicologist. Society of Toxicology 53rd Annual Meeting and ToxExpo, March 23-27, 2014, Phonex, Arizona