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

IARC MONOGRAPHS – 100C
binding to these scavenger receptors (Hamilton
et al., 2008). Other receptors expressed by
macrophages and other target cells in the lung
that bind mineral dusts include complement
receptor and mannose receptors (Gordon, 2002).
The pathological consequences of silica-induced
injury to alveolar macrophages followed by
apoptosis is impaired alveolar-macrophagemediated
clearance of crystalline silica as
discussed in Section 4.1. Lysosomal membrane
permeabilization following phagocytosis of crystalline
silica particles has been hypothesized to
enhance IL-1β secretion (Hornung et al., 2008),
and to trigger the release of cathepsin D, leading
to mitochondrial damage, and the apoptosis of
alveolar macrophages (Thibodeau et al., 2004).
Macrophage injury and apoptosis may be responsible
for the increased susceptibility of workers
exposed to silica to develop autoimmune disease
(Pfau et al., 2004; Brown et al., 2005), and pulmonary
tuberculosis (IARC, 1997; Huaux, 2007).
Persistent inflammation triggered by crystalline
silica (quartz) has been linked to indirect
genotoxicity in lung epithelial cells in rats, see
Fig. 4.1 (IARC, 1997). Rats exposed to crystalline
silica develop a severe, prolonged inflammatory
response characterized by elevated neutrophils,
epithelial cell proliferation, and development of
lung tumours (Driscoll et al., 1997). These persistent
inflammatory and epithelial proliferative
responses are less intense in mice and hamsters,
and these species do not develop lung tumours
following exposure to crystalline silica or other
poorly soluble particles (IARC, 1997). There has
been considerable discussion of whether the
response of rats to inhaled particles is an appropriate
model for the exposed response of humans
(ILSI, 2000). Comparative histopathological
studies of rats and humans exposed to the same
particulate stimuli reveal more severe inflammation,
alveolar lipoproteinosis, and alveolar
epithelial hyperplasia in rats than in humans
(Green et al., 2007). These studies suggest that
rats are more susceptible to develop persistent
lung inflammation in response to particle inhalation
than other species (ILSI, 2000).
 Chronic exposure of rats to crystalline
silica also leads to pulmonary fibrosis
(Oberdörster, 1996), and workers with silicosis
have an elevated risk of developing lung cancer
(Pelucchi et al., 2006). The causal association
between chronic inflammation, fibrosis, and
lung cancer was reviewed by IARC (2002). These
associations provide a biological plausible mechanism
between inflammation and the development
of fibrosis and/or lung cancer (Balkwill &
Mantovani, 2001).
4.3 Molecular pathogenesis of cancer
of the lung
Acquired molecular alterations in oncogenes
and tumour-suppressor genes characterize the
multistage development of lung cancer (Sato et al.,
2007). Somatic alterations, such as DNA adducts,
develop in the respiratory tract of smokers during
the early stages of carcinogenesis (Wiencke et al.,
1999). Specific point mutations in in the K-RAS
oncogene and the p53 tumour-suppressor gene
are considered as biomarkers of exposure to
chemical carcinogens in tobacco smoke (Pfeifer
et al., 2002). Only one study has investigated the
mutational spectrum of these genes that may
be used as biomarkers for exposure to crystalline
silica. Liu et al. (2000) analysed the mutation
spectra in the K-RAS and p53 genes in lung
cancers that developed in workers with silicosis
[smoking status unknown]. In a series of 36 cases,
16 mutations in exons 5, 7 and 8 of the p53 gene
were found. In contrast to non-occupational
lung cancers, seven of these mutations clustered
in exon 8. Most of the K-RAS gene mutations in
non-small cell lung carcinomas occur at codon
12. Liu et al. (2000) did not detect this mutation
in their case series of silicotics. Six mutations
were found at codon 15 in exon 1 as well
as additional mutations in codons 7, 15, 20, and
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