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

esponse, and time-course data would enable
risk assessment.
Implicit in any new or revised occupational
health policy for EMPs would be the need to
conduct appropriate assessments of risk. Risk
assessments for lung cancer, mesothelioma,
and asbestosis have been conducted on worker
populations exposed to various asbestos minerals.
These risks have been qualitatively confirmed
in animals, but no adequate quantitative
multidose inhalation studies with asbestos have
been conducted in rodents that would permit
direct comparisons to lung cancer and mesothelioma
risks determined from exposed human
populations. Given the availability of risk
estimates for lung cancer in asbestos-exposed
humans, chronic studies with rats exposed to
asbestos (e.g., chrysotile) fibers would provide
an assessment of the rat as a valid “predictor”
of human lung cancer risks associated with exposure
to asbestos fibers and other EMPs.
3.4.1 Conduct In Vitro Studies to
Ascertain the Physical and
Chemical Properties that
Influence the Toxicity of
Asbestos Fibers and Other EMPs
Although in vitro studies may not be appropriate
for toxicology screening tests of EMPs, they
can help clarify the mechanisms by which some
EMPs induce cancer, mesothelioma, or fibrosis,
as well as the properties of EMPs and conditions
of exposure that determine pathogenicity.
In vitro studies allow specific biological and
mechanistic pathways to be isolated and tested
under controlled conditions that are not feasible
in animal studies. In vitro studies can yield data
rapidly and provide important insights and confirmations
of mechanisms, which can be confirmed
with specifically designed in vivo studies.
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With the exception of in vitro genotoxicity
testing of asbestos fibers, little testing information
is available on the potential genotoxicity
of EMPs. In contrast to standard genotoxicity
testing of soluble substances, the results from
testing EMPs can be influenced by dimension,
surface properties, and biopersistence. The
mechanisms of asbestos-induced genotoxicity
are not clear, but direct interaction with the
genetic material and indirect effects via production
of ROS have been proposed. A combination
of the micronucleus test and the comet
assay with continuous treatment (without exogenous
metabolic activation) has been reported
to detect genotoxic activity of asbestos fibers
[Speit 2002]. However, further research is needed
to determine whether this approach is applicable
for genotoxicity testing of other EMPs.
Before conducting such studies, the following
EMP interactions should be addressed:
• initial lesions evoking cell damage or response
(e.g., direct or indirect cytotoxic
or genotoxic events or induction of toxic
reactive intermediate materials);
• subsequent multistage cellular response
(e.g., intracellular signaling through a kinase
cascade to nuclear transcription of
factors for apoptosis, cell transformation,
and cell or cell system proliferation or remodeling
and initiation or promotion of
neoplasia or fibrosis); and
• critical time-course events in those processes
(e.g., cell-cycle-dependent EMP interactions
or EMP durability under different
phagocytic conditions).
Capabilities for conducting these studies improved
during the 2000s, including
• advancement in analytical methods for
physico chemical characterization of
EMP properties (e.g., for resolving small
NIOSH CIB 62 • Asbestos