Environmental Engineering Reference
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cells (fused macrophages), which again are typical of a foreign-body response (Poland et al., 2008).
These are held together with extracellular matrix proteins such as collagen and together form a
persistent structure, walling off the foreign object.
Higher levels of exposure lead to a greater acute inlammatory response, ibrosis, and fur-
ther granuloma formation at sites of particle deposition. These dose-response-related effects
have led some authors to suggest a no or lowest observable effect level of 0.1 mg/m 3 for some
CNTs (Ma-Hock et al., 2009; Pauluhn, 2010a), which has formed the basis of a proposed OEL
of 0.05 mg/m 3 (time-weighted average) for a speciic Baytubes ® CNT sample (Pauluhn, 2010b).
Despite several inhalation studies being undertaken, no study has yet addressed the role of length,
in the sense that none has compared long (greater than ∼20 μm) to short (<10 μm) nanotubes.
There is a wide variability in the physicochemical characteristics between samples of CNTs, and
the understanding of how such properties inluence the toxicity observed is still emerging. Hence, it
is premature to draw conclusions on the toxicity of all CNTs from a single or even multiple studies.
This creates a problem as there are numerous different CNTs, each with different morphologies,
sizes, lengths, and surface characteristics, and inhalation studies are costly and require specialist
facilities in order to be carried out. Therefore, the more common exposure method of lung (intratra-
cheal) instillation or (pharyngeal) aspiration is used to deliver an immediate dose of particles to the
lung in a liquid bolus (Warheit et al., 2004; Lam et al., 2004). However, as the delivery of dose in
this way does not relect true exposure, the results gained are subject to further caveats and uncer-
tainty. In addition, as the particles are in solution, this in itself may further modify the dose by caus-
ing agglomeration of particles resulting in the instillation of non-respirable (and hence irrelevant)
particles into the lung. This extra uncertainty is relected in how such data may be used. Currently,
data obtained by instillation/aspiration methods are not considered suitable for extrapolation to a
HED for the purposes of deriving a human exposure limit (ECHA, 2008). Instead, these data are
useful for understanding the nature of the hazard and the resultant effects of particles in the lung.
There have now been two studies comparing exposure of the lung by CNTs using these two
methods. In the irst study, Li et al. found that exposure by instillation could lead to the presence of
large, non-respirable aggregates, resulting in typical foreign-body responses, while inhalation led
to a lower dose of smaller material in the alveolar region due to the elutriating effect of the lung.
Thus, the responses gained by each method were different possibly due to aggregation state and
lung distribution (Li et al., 2007). It was noted that exposure by inhalation generated an enhanced
cellular inlammation, protein, and LDH release over instillation (two- to fourfold increase) with
large increases in ibrosis also seen (Shvedova et al., 2008).
The next source of information on toxicity comes from in vitro assays which typically use immor-
talized cells grown in an artiicial medium supplemented with various proteins and growth factors
to stimulate their continued growth and division. The beneits of such a system are that it is very
controllable with various aspects of the experiment manipulated with relative ease both quickly and
cheaply with minimal ethical issues. When considering the caveats associated with in vitro toxicol-
ogy and its relevance to human exposure, one can see many issues relected in its use primarily as a
highly useful screening tool and a source of mechanistic information, but it is currently not suitable
for direct extrapolation to deriving a human exposure limit and is of limited use in risk assessment.
When considering HARN toxicity, the vast majority of research is directed toward CNT toxicity,
which relects the current higher usage of CNT as an industrial product as compared to other forms
of HARN. There are now numerous exposure studies to CNTs using a variety of routes, including
dermal (Murray et al., 2009), intravenous (Singh et al., 2006), and oral (Folkmann et al., 2009),
which relect the potential exposure routes and medical applications of CNT.
In relation to HARN toxicity, there may also be variability in the durability of different mate-
rials, which may result in differing toxicity. It is conceivable that a soluble nanowire, such as a
silver nanowire, will dissolve rapidly in the complex biological environment of the lung leading to
a reduction in dose. In contrast, CNTs are hypothesized to be very durable due to their structure.
There have only been a few studies which have directly addressed the issue of CNT durability,
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