High Aspect Ratio Nanomaterials - Aerosols: Measurement, Dosimetry, and Health Effects - page 240

10.3.3 e vidence b ase For H arn
When considering the evidence for adverse effects of exposure to a material such as nanomaterials,
various resources are available within the peer-reviewed literature. Ideally, the most robust data
would be derived from large numbers of human subjects exposed within well-controlled relevant
exposure scenarios. However, this is very rarely ethically acceptable or feasible, and alternatives or
surrogates for this type of data have to be used, with all the caveats and limitations associated with
information from animals or models. These surrogates may include epidemiological information
if available but due to the early stage of much of the nanotechnology industry, there is currently
no epidemiological information available for HARN. Moreover, as epidemiological evidence is
most often retrospective (except, e.g., in the case of a prospective cohort study), its strength is in
identifying causal links and trends but is less than ideal from the point of prevention.
When trying to understand the potential health effects of a new substance, a great deal of
importance is placed upon animal data as they still provide insight into the complex interactions
which culminate in toxic responses. A great deal of in vivo toxicology focuses on rodent spe-
cies with both rats and mice being the most commonly used, and typically the basis for many
international accepted test guidelines such as the OECD guidelines for the testing of chemicals.
These species obviously have substantial differences to humans both in the mechanisms of par-
ticle deposition based primarily on differences in breathing patterns and airway morphometry
(Hofmann et al., 2000), but also in their relative sensitivities to particle-induced effects (Bermudez
et al., 2004). These differences need to be taken into account when extrapolating from the sur-
rogate back to a human equivalent dose (HED) and numerous modeling efforts and approaches
have been published to facilitate this (Anjilvel and Asgharian, 1995; Hofmann et al., 2000). When
considering lung exposure, the gold standard is inhalation exposure to an aerosol that most faith-
fully replicates real exposure, although there are still likely to be considerable differences in the
aerosol parameters (e.g., the luctuating nature of particle concentration and size distribution)
between a workplace and experimental exposure system. In addition, there is much discussion
among researchers regarding the ability to generate some forms of airborne HARN, such as CNTs,
in an industrial or consumer setting. This scepticism is driven by the observation that CNTs exhibit
a high propensity to aggregate. In order to address this question, Maynard et al. (2004) investi-
gated unreined single-walled CNTs agitated in a controlled laboratory setting, and found that such
agitation resulted in ine particle release into air. A subsequent study of four production facilities
found airborne concentrations in the vicinity of single-walled CNT production equipment to be
relatively low (<53 μg/m 3 ). While this is a low concentration when compared to the occupational
exposure limits for other nuisance particles such as TiO 2 , it is relatively high compared to ambi-
ent air pollution (associated with morbidity and mortality). Furthermore, in comparison to ibers,
exposure limits are set according to the number of ibers per cubic centimeter of air. The relation-
ship between ug/m 3 and number of CNTs per cubic centimeter is currently unknown, but is likely
to vary between different CNT types and sources.
It is important to note that it is challenging to produce inhalable or respirable aerosols of CNTs
because of the tendency of these materials to form aggregates, but efforts are being made to develop
more eficient methods for aerosolizing CNTs (Baron et al., 2008). In relation to the use of gold
standard inhalation studies to investigate the respiratory toxicity of high aspect ratio nanoparticles,
there have now been several studies, but again these are all focused on CNTs and the results of these
studies are summarized in Table 10.1.
From the results gained from inhalation exposure of rodents to CNTs, it appears that low-level
exposure (<0.5 mg/m 3 ) is associated with minimal effects such as transient lung inlammation and
the formation of small granulomas at sites of iber deposition. The formation of granulomas is
typical of a foreign-body response and is seen in many circumstances where a foreign material
cannot be removed (e.g., implanted medical device). Such granulomas are typically formed of a
collection of inlammatory cells such as macrophages and may even contain multinucleated giant