Uptake and Effects of Carbon Nanotubes - Safety of Nanomaterials along Their Lifecycle - page 218

more pronounced alveolar wall thickening (i.e., interstitial fibrosis) as compared
to instilled SWCNT, which produced more granuloma formation (Shvedova et al.
2008). These studies indicate that the degree of CNT dispersion, together with the
influence of particle mass and aerodynamic properties, contributes to the differ-
ences in potency and physiological effects observed when comparing inhalation to
other routes of pulmonary exposure such as intratracheal instillation or OPA. The
agglomeration state of CNTs is an important determinant of pathologic outcome.
As illustrated in Figure 10.1, agglomerated CNTs stimulate granuloma formation,
whereas dispersed CNTs cause diffuse interstitial fibrosis in the alveolar region and
around airways and blood vessels.
In addition to the method of pulmonary exposure and the degree of particle dis-
persion, two other major factors determine the toxicity of CNTs: (a) clearance and
(b) contamination by metal catalysts. Longer CNTs impede clearance and structures
longer than 10-15 µm (the approximate width of an alveolar macrophage) are difficult
to clear from lung tissues via macrophage-mediated mechanisms. This is especially
relevant to MWCNTs, which are more rigid than SWCNTs. Although rigidity and
length are likely important for mediating frustrated phagocytosis of macrophages,
CNT diameter has also shown to mediate toxicity. In particular, thinner (~10 nm
diameter) MWCNTs are more toxic in the lungs of mice than thicker (~70 nm diam-
eter) MWCNTs (Fenoglio et al. 2012). Long SWCNTs are more likely to fold and
be taken up by macrophages, whereas long MWCNTs are more likely to cause frus-
trated phagocytosis and impede macrophage clearance. Second, the composition of
CNTs must be carefully considered. Metals such as nickel, cobalt, and iron are com-
monly used as catalysts in the manufacture of CNTs and these same metals are well-
known to cause pulmonary diseases in humans, including pulmonary fibrosis and
asthma (Kelleher, 2000). For example, nickel is known to cause occupational asthma
and contact dermatitis, whereas iron and cobalt cause interstitial pulmonary fibrosis
in occupations related to mining and metallurgy. Metal catalysts can be removed
to some extent from CNTs by acid washing, although this process usually does not
completely remove metals.
The cellular and molecular mechanisms that cause CNT-induced lung dis-
ease have not been clearly elucidated, but it is expected that many lessons can be
learned from studies on larger particles, fibers, and metals. However, CNTs and
other engineered nanomaterials may also operate through unique and unexpected
mechanisms to cause disease given that they can interact at the molecular level
with cellular organelles, proteins, phospholipids, and nucleic acids. A variety of
soluble mediators (growth factors, cytokines, and chemokines) that play important
roles in fibrosis are induced in the lungs of rats or mice after exposure to CNTs
(Bonner 2010b). Some of these mediators and their relationship to lung region and
cell type are shown in Figure 10.5. Several studies have shown that either SWCNTs
or MWCNTs delivered to the lung by intratracheal instillation in rats or inhala-
tion in mice increase mRNA and protein levels of PDGF (Mangum et al. 2006;
Ryman-Rasmussen et al. 2009a; Cesta et al. 2010). PDGF stimulates the repli-
cation, chemotaxis, and survival of lung fibroblasts to promote the pathogenesis
of fibrosis (Bonner et al. 2004). SWCNTs delivered to the lungs of mice by OPA
or inhalation cause induction of TGF-β1 (Shvedova et al. 2005; 2008), a central