silica dust, crystalline, in the form of quartz or cristobalite - IARC ...

IARC MONOGRAPHS – 100C
(inducible nitric oxide synthase) was also found
in preneoplastic lesions, which is consistent with
a role for reactive nitrogen species in silicosis
(Porter et al., 2006).
4.4 Species differences and
susceptible populations
In rat chronic inhalation studies using crystalline
silica or granular, poorly soluble particles,
female rats are more susceptible than males to
the induction of lung tumours. Overall, rats
are susceptible to the induction of lung cancer
following the exposure to crystalline silica or
granular, poorly soluble particles, but hamsters
and mice are more resistant. The mechanistic
basis for these sex and species differences is
unknown. Mice exposed to crystalline silica by
intranasal instillation or subcutaneous injection,
as well as rats injected intrapleurally or intraperitoneally
develop lymphomas. Following inhalation
exposure to crystalline silica, lymphomas
have not been observed in any species (see
Section 3).
In some workers exposed to crystalline silica,
cytokine gene polymorphisms have been linked
with silicosis (Yucesoy et al., 2002). Specific
polymorphisms in genes encoding in TNF-α
and IL-1RA (interleukin-1 receptor antagonist)
have been associated with an increased risk for
the development of silicosis (Yucesoy & Luster,
2007). Gene–linkage analyses might reveal additional
markers for susceptibility to the development
of silicosis and lung cancer in workers
exposed to crystalline silica.
4.5 Synthesis
Three mechanisms have been proposed for
the carcinogenicity of crystalline silica in rats
(Fig. 4.1). First, exposure to crystalline silica
impairs alveolar-macrophage-mediated particle
clearance thereby increasing persistence of silica
in the lungs, which results in macrophage activation,
and the sustained release of chemokines
and cytokines. In rats, persistent inflammation
is characterized by neutrophils that generate
oxidants that induce genotoxicity, injury, and
proliferation of lung epithelial cells leading to
the development of lung cancer. Second, extracellular
generation of free radicals by crystalline
silica depletes antioxidants in the lung-lining
fluid, and induces epithelial cell injury followed
by epithelial cell proliferation. Third, crystalline
silica particles are taken up by epithelial cells
followed by intracellular generation of free radicals
that directly induce genotoxicity.
The Working Group considers the first
mechanism as the most prominent based on
the current experimental data using inhalation
or intratracheal instillation in rats, although
the other mechanisms cannot be excluded. It
is unknown which of these mechanisms occur
in humans exposed to crystalline silica dust.
The mechanism responsible for the induction
of lymphomas in rats and mice following direct
injections of crystalline silica dust is unknown.
5. Evaluation
There is sufficient evidence in humans for the
carcinogenicity of crystalline silica in the form
of quartz or cristobalite. Crystalline silica in the
form of quartz or cristobalite dust causes cancer
of the lung.
There is sufficient evidence in experimental
animals for the carcinogenicity of quartz dust.
There is limited evidence in experimental
animals for the carcinogenicity of tridymite dust
and cristobalite dust.
Crystalline silica in the form of quartz or cristobalite
dust is carcinogenic to humans (Group 1).
396