Asbestos Fibers and Other Elongate Mineral Particles: State of the ...

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• Investigate mechanisms of EMP-induced
pulmonary disease; and
• Determine whether cell proliferation in
the lungs (terminal bronchioles and alveolar
ducts) can be a predictive measure of
pathogenicity following brief inhalation exposure
and use of the BrdU assay [Cullen et
al. 1997].
Exposure protocols for tracheal inhalation or
instillation in an animal model for short-term
in vivo studies using field-collected or laboratory-generated
EMPs should address possible
adulteration of EMP morphology (e.g., anomalous
agglomeration of particles). This might
be addressed in part by preconditioning EMPs
in a delivery vehicle containing representative
components of pulmonary hypophase fluids.
Exposure protocols using pharyngeal aspiration
as a delivery system should be considered,
given the observations in studies with singlewalled
carbon nanotubes that such a delivery
system closely mimics animal inhalation studies
[Shvedova et al. 2005, 2008].
Studies evaluating the roles of biopersistence
and dimension in the development of noncancer
and cancer endpoints from exposure to EMPs
are also needed. These studies should attempt to
elucidate the physicochemical parameters that
might affect bio-durability of EMPs of specific
dimensions. Although short-term animal inhalation
studies would be informative, companion
in vitro assays should also be conducted to assess
their validity for screening EMPs.
3.4.2.2 Long-Term Animal Studies
Chronic animal inhalation studies are required
to address the impacts of dimension, morphology,
chemistry, and biopersistence on critical
disease endpoints of cancer induction and
nonmalignant respiratory disease. The EPA’s
proposed testing guidelines should be considered
as the criteria for establishing the testing
parameters for chronic studies [EPA 2001].
To date, chronic inhalation studies have been
conducted with different animal species and different
types of EPs. However, it remains uncertain
which species of animal(s) best predict(s)
the risk of respiratory disease(s) for workers
exposed to different EPs. Chronic inhalation
studies should be initiated to establish exposure/
dose-response relationships for at least two animal
species. The rat has historically been the
animal of choice for chronic inhalation studies
with EPs, but the low incidence of lung tumors
and mesotheliomas in rats exposed to asbestos
fibers suggests that rats may be less sensitive than
humans. Therefore, any future consideration for
conducting long-term animal inhalation studies
should address the need for using a multispecies
testing approach to help provide solid scientific
evidence on which to base human risk assessments
for a variety of EMPs of different durabilities
and dimensions. For example, some recent
studies suggest that the hamster may be a more
sensitive model for mesothelioma than the rat.
Validation of appropriate animal models could
reduce the resources needed to perform longterm
experimental studies on other EMP types
[EPA 2001].
Multidose animal inhalation studies with asbestos
(probably a carefully selected and wellcharacterized
chrysotile, because most of the
estimates of human risk have been established
from epidemiological studies of chrysotile-
exposed workers) are needed to provide an improved
basis for comparing the potential cancer
and noncancer risks associated with other
types of EMPs and various types of synthetic
EPs. The asbestos fibers administered in these
animal studies should be comparable in dimension
to those fibers found in the occupational
NIOSH CIB 62 • Asbestos