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

In the second phase of cellular response to EMPs,
the central dogma of intracellular response is
being intensively researched. The initial extracellular
primary damage induces intracellular
signaling (e.g., by MAPK), which causes a cascade
of kinase activities that stimulate selective
nuclear transcription of mRNAs, leading to
production of TNF-α or other cytokines for extracellular
signaling of target cells. Those other
cytokines may induce cell proliferation toward
cancer or collagen synthesis toward fibrosis.
Further definition of signaling mechanisms and
analyses of their induction by different primary
EMP-cellular interactions may better define the
ultimate role of EMP properties in the overall
process. That research, again, may be facilitated
by using different specific types of EMPs, each
with relatively homogeneous morphology and
surface properties.
Although full investigation of biopersistence
of EMPs may require long-term animal model
studies, in vitro systems coupled with advanced
surface analytical tools (e.g., field emission
SEM–energy dispersive X-ray spectroscopy or
scanning Auger spectroscopy) may help guide
in vivo studies. This could be done by detailing
specific surface properties of EMPs and their
modifications under cell-free or in vitro conditions
representing the local pH and reactive
species at the EMP surface under conditions
of extracellular, intra-phagolysosomal, or frustrated
annular phagocytic environments.
3.4.2 Conduct Animal Studies to
Ascertain the Physical and
Chemical Properties that
Influence the Toxicity of
Asbestos Fibers and Other EMPs
A multispecies testing approach has been recommended
for short-term assays [ILSI 2005]
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and chronic inhalation studies [EPA 2000]
that would provide solid scientific evidence
on which to base human risk assessments for a
variety of EMPs. To date, the most substantial
base of human health data for estimating lung
cancer risk is for workers exposed to fibers
from different varieties of asbestos minerals.
There are similarities between animal species
and humans in deposition, clearance, and retention
of inhaled particles in the lungs. For
example, peak alveolar deposition fraction is
greatest for particles at an AED of about 2 µm in
humans and about 1 µm for rodents. However,
some interspecies differences have been identified.
Variations in ventilation, airway anatomy,
and airway cell morphology and distribution account
for quantitative differences in deposition
pattern and rate of clearance among species. In
addition, the efficacy of pulmonary macrophage
function differs among species. All these differences
could affect particle clearance and retention.
It has been suggested that the following
species differences should be considered in the
design of experimental animal inhalation studies
of elongate particles [Dai and Yu 1988; Warheit
et al. 1988; Warheit 1989].
• Due to differences in airway structure,
airway size, and ventilation parameters, a
greater fraction with large AED particles
are deposited in humans than in rodents.
• Alveolar deposition fraction in humans
varies with workload. An increase in the
workload reduces the deposition fraction
in the alveolar region because more of
the inhaled particulate is deposited in the
extra-thoracic and bronchial regions.
• Mouth breathing by humans results in a
greater upper bronchial deposition and
enhanced particle penetration to the peripheral
lung.
NIOSH CIB 62 • Asbestos