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

some genotoxic activities. However, modifying
the surface of a well-characterized sample
of chrysotile fibers by depleting surface Mg
while retaining fiber length did not result in a
significant quantitative difference for in vitro
micronucleus induction between the native
and surface-modified materials, both of which
were positive in the assay [Keane et al. 1999].
The surface of mineral fibers and other EMPs
also might be an indirect but critical factor in
the manifestation of pathogenic activity. EMP
surfaces may be principal determinants of EMP
durability under conditions of in vivo dissolution
in biological fluids. As such, they would
be a controlling factor in biopersistence, critical
to the suggested mechanisms of continuing
irritation or inflammatory response in causing
fibrosis or neoplastic transformation.
2.9.4 Animal and In Vitro
Toxicity Studies
Over the last half-century, in vivo animal
model studies have explored induction of lung
cancer, mesothelioma, and pulmonary fibrosis
by asbestos fibers and other EMPs following
intrapleural, intraperitoneal, or inhalation challenge.
Numerous cell-free, in vitro cellular, and
in vivo short-term animal model studies have
been pursued, attempting to (1) examine tissue
and cellular responses to EMPs and impact of
EMP conditioning on these responses; (2) identify
and evaluate interactions and mechanisms
involved in pathogenesis; and (3) seek morphological
or physicochemical EMP properties controlling
those mechanisms. These short-term
studies provide an evolving basis for design or
interpretation of higher- tier chronic exposure
studies of selected EMPs.
Some of the short-term studies have addressed
the following:
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• the general question of extrapolating human
health effects from in vivo animal
model studies;
• the physiological relevance of in vitro cellular
studies of EMP toxicities;
• the association of EMP dimensions with
pathology demonstrated in animal model
studies;
• the potential mechanisms and associated
EMP properties responsible for initiating
cell damage;
• the extensive information now available on a
“central dogma” of subsequent intracellular
biochemical pathway stimulation leading to
toxicity or intercellular signaling in disease
promotion; and
• the use of these mechanistic paradigms to
explain specific questions of
ȣ differences between the activities of asbesti
form and nonasbestiform EMPs,
including seemingly anomalous differences
between some in vitro and in vivo
EMP activities;
ȣ differences between the activities of
erionite fibers and amphibole asbestos
fibers; and
ȣ the possibility of EMP-viral co-carcinogenesis.
Several reviews and recommendations for animal
model and cellular studies on these issues
have been developed by expert workshops and
committees. Early studies on the carcinogenicity
of asbestos and erionite fibers were reviewed
by IARC [1977, 1987a,b], and SVFs
were reviewed more recently [IARC 2002].
Short-term in vivo and in vitro studies to elucidate
mechanisms of fiber-induced genotoxicity
and genetic mechanisms affecting fiber-induced
lung fibrosis have been extensively reviewed.
NIOSH CIB 62 • Asbestos