Occupational Exposure to Carbon Nanotubes and Nanofibers

3.3 SWCNT and MWCNTIntraperitoneal StudiesIntraperitoneal injection studies in rodents havebeen frequently used as screening assays for potentialmesotheliogenic activity in humans. To date,exposures to only a few fiber types are known toproduce mesotheliomas in humans; these includethe asbestos minerals and erionite fibers. Severalanimal studies [Takagi et al. 2008; Poland et al.2008; Muller et al. 2009; Varga and Szendi 2010;Murphy et al. 2011] have been conducted to investigatethe hazard potential of various sizes and dosesof MWCNT and SWCNT to cause a carcinogenicresponse. Takagi et al. [2008] reported on the intraperitonealinjection of 3 mg of MWCNT in p53+/- mice (a tumor-sensitive, genetically engineeredmouse model), in which approximately 28% of thestructures were > 5 µm in length with an averagediameter of 100 nm. After 25 weeks, 88% of micetreated with MWCNT revealed moderate to severefibrotic peritoneal adhesions, fibrotic peritonealthickening, and a high incidence of macroscopicperitoneal tumors. Histological examination foundmesothelial lesions near fibrosis and granulomas.Similar findings were also seen in the crocidoliteasbestos-treated positive control mice. Minimalmesothelial reactions and no mesotheliomas wereproduced by the same dose of (nonfibrous) C 60fullerene. Poland et al. [2008] reported that theperitoneal (abdominal) injection of long MW-CNT—but not short MWCNT—induced inflammationand granulomatous lesions on the abdominalside of the diaphragm at 1 week post-exposure.This study, in contrast to the Takagi et al. [2008]study, used wild type mice exposed to a much lowerdose (50 µg) of MWCNT. Although this studydocumented acute inflammation, it did not evaluatewhether this inflammation would persist andprogress to mesothelioma. Murphy et al. [2011]found similar findings in C57BI/6 mice that were injectedwith different types of MWCNT composed ofdifferent tube dimensions and characteristics (e.g.,tangled) or injected with mixed-length amosite asbestos.Mice were injected with a 5 µg dose directlyinto the pleural space and evaluated after 24 hours, 1,NIOSH CIB 65 • Carbon Nanotubes and Nanofibers4, 12, and 24 weeks. Mice injected with long (> 15µm) MWCNT or asbestos showed significantlyincreased granulocytes in the pleural lavage, comparedwith the vehicle control at 24 hours post exposure.Long MWCNT caused rapid inflammationand persistent inflammation, fibrotic lesions, andmesothelial cell proliferation at the parietal pleuralsurface at 24 weeks post exposure. Short (< 4 µm)and tangled MWCNT did not cause a persistent inflammatoryresponse and were mostly cleared fromthe intrapleural space within 24 hours.A lack of a carcinogenic response was reported byMuller et al. [2009] and Varga and Szendi [2010]in rats, and by Liang et al. [2010] in mice, followingintraperitoneal injection or implantation ofMWCNT or SWCNT. No mesotheliomas werenoted 2 years after intraperitoneal injection ofMWCNT in rats at a single dose of 2 or 20 mg[Muller et al. 2009] or MWCNT (phosphorylcholine-grafted)in mice when given daily doses ofeither 10, 50, or 250 mg/kg and evaluated at day28 [Liang et al. 2010]. However, the MWCNT samplesused in the Muller et al. [2009] and Liang etal. [2010] studies were very short (avg. < 1 µm inlength observed by Muller et al. [2009] and < 2 µmin length observed by Liang et al. [2010]), and thefindings were consistent with the low biologicalactivity observed in the Poland et al. [2008] studywhen mice were exposed to short MWCNT. Vargaand Szendi [2010] reported on the implantation ofeither MWCNT or SWCNT in F-344 rats (six pergroup) at a dose of 10 mg (25 mg/kg bw). Gelatincapsules containing either SWCNT (< 2 nm diameters× 4–15 µm lengths), MWCNT (10–30 nm diameters× 1–2 µm lengths), or crystalline zinc oxide(negative control) were implanted into the peritonealcavity. Histological examination at 12 monthsrevealed only a granulomatous reaction of foreignbody type with epithelioid and multinucleated giantcells in CNT-exposed animals. No information wasreported on what effect the delivery of SWCNT andMWCNT in gelatin capsules had on their dispersionin the peritoneal given the tendency of CNT toagglomerate. If SWCNT and MWCNT remainedagglomerated following delivery, this may have19