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

to crocidolite fibers and TNF-α caused greater
damage than fibers alone. Antioxidant enzymes
did not reduce the DNA damage, suggesting a
mechanism of damage other than by free radicals
[Ollikainen et al. 1999]. Crocidolite fibers
were also very cytotoxic to the cells; presumably,
cell death may prevent the observation of cell
transformation. In vitro challenge to mesothelial
cells and to fibroblast cells by crocidolite fibers,
but not by glass wool, induced dose-dependent
cytotoxicity and increased DNA synthesis activity
[Cardinali et al. 2006]. Crocidolite fibers were
found to induce TNF-α secretion and receptors
in human mesothelial cells, and TNF-α reduced
cytotoxicity of crocidolite fibers by activating
NF-κB and thus improving cell survival and permitting
expression of cytogenetic activity [Yang
et al. 2006]. Erionite fibers transformed immortalized
nontumorigenic human mesothelial cells
in vitro only when exposed in combination with
IL-1β or TNF-α [Wang et al. 2004]. Erionite fibers
were poorly cytotoxic but induced proliferation
signals and a high growth rate in hamster
mesothelial cells. Long-term exposure to erionite
fibers resulted in transformation of human
mesothelial cells in vitro, but exposure to asbestos
fibers did not transform those cells [Bertino
et al. 2007]. In vitro challenge of mesothelial cells
to asbestos fibers induced cytotoxicity and apoptosis
but not transformation. In vitro challenge
of human mesothelial cells to asbestos fibers induced
the ferritin heavy chain of iron-binding
protein, an anti-apoptotic protein, with decrease
in H 2O 2 and other ROS and resistance to apoptosis
[Aung et al. 2007]. This was seen also in a human
malignant mesothelial cell line.
The question of a co-carcinogenic effect of asbestos
fibers with a virus has been raised. Most
malignant mesotheliomas are associated with
asbestos exposures, but only a fraction of exposed
individuals develop mesothelioma, indicating
that other factors may play a role. It has
54
been suggested that simian virus 40 (SV40) and
asbestos fibers may be co-carcinogens. SV40 is
a DNA tumor virus that causes mesothelioma
in hamsters and has been detected in several
human mesotheliomas. Asbestos fibers appear
to increase SV40-mediated transformation
of human mesothelial cells in vitro [Carbone
et al. 2002]. In an in vivo demonstration of
co-carcinogenicity of SV40 and asbestos fibers,
mice containing high copy numbers of SV40
viral oncogene rapidly developed fast-growing
mesothelioma following asbestos challenge.
Transgenic copy number was proportional to
cell survival and in vitro proliferation [Robinson
et al. 2006].
Various mechanisms protect cells and tissues
against oxidants, and it is conceivable that genetic
and acquired variations in these systems
may account for individual variation in
the response to oxidative stress [Driscoll et al.
2002]. Similarly, species differences in antioxidant
defenses or the capacity of various defenses
may underlie differences in response to
xenobiotics that act, in whole or part, through
oxidative mechanisms. Oxidative mechanisms
of response to xenobiotics are especially relevant
to the respiratory tract, which is directly
and continually exposed to an external environment
containing oxidant pollutants (e.g.,
ozone, oxides of nitrogen) and particles that
may generate oxidants as a result of chemical
properties or by stimulating production of
cell-derived oxidants. In addition, exposure to
particles or other pollutants may produce oxidative
stress in the lung by stimulating the recruitment
of inflammatory cells. For example,
the toxicity of asbestos fibers likely involves the
production of oxidants, such as hydroxyl radical,
SO, and H 2O 2. Studies have also shown that
asbestos fibers and other mineral particles may
act by stimulating cellular production of ROS
and reactive nitrogen species. In addition to
NIOSH CIB 62 • Asbestos