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

types of health assessment studies to evaluate
the influence on toxicity of EMP dimensions
(length and width), chemical composition, biopersistence,
and other characteristics. Toxicological
testing is needed to address some of the
fundamental questions about EMP toxicity that
cannot be determined through epidemiology or
other types of health assessment studies. Irrespective
of study type or design, the full characterization
of all particulate material in a test
sample is an essential step in understanding
the mechanisms of EMP toxicity. The determination
of EMP dimensions is important, and
they are best expressed as bivariate size distributions
(i.e., width and length). Such determinations
should be made by using both relatively
simple procedures (optical microscopy)
and highly specialized techniques (e.g., TEM
or SEM with EDS), because size-specific fractions
of EMP exposures have both biological
and regulatory significance.
The chemical composition (e.g., intrinsic chemical
constituents and surface chemistry) of asbestos
fibers and other EMPs has been shown
to have a direct effect on their ability to persist
in the lung and to interact with surrounding
tissue to cause DNA damage. For example, ferric
and ferrous cations are major components
of the crystalline structure of amphibole asbestos
fibers; iron may also be present as a surface
impurity on chrysotile asbestos fibers and other
EMPs. The availability of iron at the surface
of asbestos fibers and other EMPs has been
shown to be a critical parameter in catalyzing
the generation of ROS that may indirectly
cause genetic damage [Kane 1996]. Also, attempted
clearance of long asbestos fibers from
the lung causes frustrated phagocytosis, which
stimulates the release of ROS [Mossman and
Marsh 1989]. Individual adaptive responses
to oxidant stress and the body’s ability to repair
damaged DNA are dependent on multiple
NIOSH CIB 62 • Asbestos
exogenous and endogenous factors, but few
experiments have been attempted to evaluate
these variables in animal or human model
systems. Kane [1996] has suggested that the
mechanisms responsible for the genotoxic effects
of asbestos fibers are due to indirect DNA
damage mediated by free radicals and direct
physical interference with the mitotic apparatus
by the fibers themselves. Research to address
the following questions would assist in
validating these proposed mechanisms:
• Are in vitro genotoxicity assays relevant
to carcinogenesis of asbestos fibers and
other EMPs?
• Are in vitro doses relevant for in vivo exposures?
• Can genotoxic effects of asbestos fibers
and other EMPs be assessed in vivo?
Macrophages are the initial target cells of EMPs
and other particulates deposited in the lungs
or pleural and peritoneal spaces. Phagocytosis
of asbestos fibers has been shown to be accompanied
by the activation of macrophages,
which results in the generation of ROS as well
as a variety of chemical mediators and cytokines
[Kane 1996]. These mediators amplify
the local inflammatory reaction. Persistence
of asbestos fibers in the lung interstitium or
in the subpleural connective tissue may lead
to a sustained chronic inflammatory reaction
accompanied by fibrosis [Oberdorster 1994].
The unregulated or persistent release of these
inflammatory mediators may lead to tissue
injury, scarring by fibrosis, and proliferation
of epithelial and mesenchymal cells. This response
appears to occur independently of fiber
length. In the lungs and pleural linings, chronic
inflammation and fibrosis are common reactions
following exposure to asbestos fibers, but
research is needed to understand the effects of
fiber dimension, loading, and surface reactivity
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