Uptake and Effects of Carbon Nanotubes - Safety of Nanomaterials along Their Lifecycle - page 212

human health effects that could result as a consequence of occupational, consumer,
or environmental exposure.
10.2 LUNG DEPOSITION AND TRANSLOCATION OF NANOTUBES
The deposition of inhaled CNTs is determined by a number of factors including
particle size, shape, electrostatic charge, and agglomeration state. Published stud-
ies that document the fate and effects of inhaled CNTs are extremely valuable,
because these studies much more closely model “real world” exposures and there-
fore more accurately model the true nature of deposition patterns for particles and
fibers. Inhalation exposure results in deposition of CNTs in the distal regions; that
is, alveolar duct bifurcations and alveolar epithelial surfaces, of the lungs of mice
or rats (Ma-Hock et al. 2009; Pauluhn 2010; Mitchell et al. 2007; Shvedova et al.
2008; Ryman-Rasmussen et al. 2009a, 2009b). Most of the CNTs deposited in these
regions are avidly taken up by alveolar macrophages. Although the majority of CNTs
are engulfed by macrophages, some individual CNTs or small aggregates evade
phagocytosis or uptake by macrophages and can be found within epithelial cells or
mesenchymal cells (Ryman-Rasmussen et al. 2009a).
Aggregation of CNTs, alternatively referred to as state of dispersion, is an impor-
tant factor that determines the pathologic response following exposure. The state of
dispersion depends on electrostatic charge, functionalization, or suspension of CNTs
in surfactant-containing media. As illustrated in Figure 10.1, dispersed CNTs are
deposited throughout the lower lung with a relatively uniform distribution pattern,
causing interstitial fibrosis that increases the thickness of airway and alveolar walls.
Macrophages exposed to dispersed CNTs release growth factors [e.g., platelet-derived
growth factor (PDGF) and TGF-β1], which stimulate fibroblast proliferation and colla-
gen deposition that culminates in fibrosis and alveolar wall thickening. Agglomerated
CNTs tend to cause granuloma formation, characterized by focal accumulation of
macrophages and lymphocytes, followed by walling off of the CNT agglomerate with
fibrotic scar tissue produced by fibroblasts. Figure 10.2 shows a lung fibroproliferative
response to relatively well-dispersed multi-walled CNTs (MWCNTs) delivered by a
single nose-only inhalation exposure (Ryman-Rasmussen et al. 2009b).
CNTs also reach the subpleural region of the lungs after inhalation exposure,
either via macrophage-dependent or -independent processes, and remain embedded
within the subpleural tissue or within macrophages for up to three months (Ryman-
Rasmussen et al. 2009b). Some of these CNT-bearing macrophages exit the lung via
the pleural lymphatic system and enter the pleural space or can be found in lung-
associated lymph nodes (Ma-Hock et al. 2009; Pauluhn et al. 2010).
The majority of published studies on the pulmonary effects of CNTs have used
intratracheal instillation (IT) or oropharyngeal aspiration (OPA) techniques for
delivery to the lungs of rats or mice, respectively. Although studies using IT or OPA
are important for determining biological effects, these studies rely on an aqueous
bolus delivery and therefore do not precisely reproduce the deposition patterns that
can be achieved by using inhalation exposure with dry aerosolized or nebulized
suspensions of CNTs. Nevertheless, improvements have been made in dispers-
ing CNTs in aqueous suspension, and the use of surfactant-containing media has