13989995, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.14202 by Nat Prov Indonesia, Wiley Online Library on [11/02/2023].

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| |
Received: 7 November 2019    Revised: 20 December 2019    Accepted: 8 January 2020

DOI: 10.1111/all.14202

REVIEW ARTICLE

Silica-related diseases in the modern world

Ryan F. Hoy1,2  | Daniel C. Chambers3,4

1
Department of Epidemiology and
Preventive Medicine, School of Public
Health and Preventive Medicine, Monash
University, Melbourne, VIC., Australia
2 respirable crystalline silica. Silicosis is historically a disease of miners; however, fail-
Department of Respiratory Medicine,
Alfred Hospital, Melbourne, VIC., Australia
3
School of Clinical Medicine, The University
of Queensland, Brisbane, QLD, Australia
4
Queensland Lung Transplant Program, The
Prince Charles Hospital, Brisbane, QLD,
Australia
Correspondence
Ryan F. Hoy, Department of Epidemiology
and Preventive Medicine, School of Public
Health and Preventive Medicine, Monash
University, Melbourne, VIC., Australia.
Email: ryan.hoy@monash.edu
Abstract
Silicosis is an ancient and potentially fatal pneumoconiosis caused by exposure to
ure to recognize and control the risk associated with silica exposure in contempo-
rary work practices such as sandblasting denim jeans and manufacturing of artificial
stone benchtops has led to re-emergence of silicosis around the world. This review
outlines the mineralogy, epidemiology, clinical and radiological features of the vari-
ous forms of silicosis and other silica-associated diseases. Perspective is provided on
the most recent studies shedding light on pathogenesis, including the central role of
innate immune effector cells and subsequent inflammatory cascades in propagating
pulmonary fibrosis and the extrapulmonary manifestations, which uniquely charac-
terize this pneumoconiosis. Clinical conundrums in differential diagnosis, particularly
between silicosis and sarcoidosis, are highlighted, as is the importance of obtaining a
careful occupational history in the patient presenting with pulmonary infiltrates and/
or fibrosis. While silicosis is a completely preventable disease, unfortunately workers
around the world continue to be affected and experience progressive or even fatal
disease. Although no treatments have been proven, opportunities to intervene to
prevent progressive disease, founded in a thorough cellular and molecular under-
standing of the immunopathology of silicosis, are highlighted.

KEYWORDS

autoimmune disease, macrophage, occupational, silica, silicosis

1 |  I NTRO D U C TI O N There are three forms of silicosis depending on characteristics

Occupational silica dust exposure is one of the oldest known causes
of lung disease; however, the burden of silica-associated disease
remains high and treatment options are limited. There have been
recent outbreaks of severe, progressive forms of silicosis in coun-
tries including Israel, Spain and Australia due to the introduction of
high silica-containing artificial stone material used to fabricate do-
mestic benchtops. These outbreaks highlight the need to maintain
constant vigilance to identify and control sources of occupational
silica exposure.
of silica exposure, clinical, radiological and pathological features:
(1) chronic (also known as classical) silicosis, (2) accelerated silico-
sis and (3) acute silicosis (silicoproteinosis).1 There are also several
other conditions associated with silica exposure, which result in
considerable morbidity and mortality, including autoimmune dis-
eases and tuberculosis (Table 1). This review outlines the most re-
cent advances in understanding of this ancient disease including the
mineralogy of silica and the central role of innate immune effector
cells and subsequent inflammatory cascades in propagating pulmo-
nary fibrosis.

© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Allergy. 2020;75:2805–2817.  |
wileyonlinelibrary.com/journal/all     2805
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2806       HOY and CHAMBERS
2 |  S I LI C A M I N E R A LO G Y
Silica (also known as silicon dioxide, SiO2) is a widely abundant
mineral compound. 2 It accounts for 59% of the earth's crust and is
the main constituent of over 95% of rocks. 3,4 Silica occurs in crys-
5
talline and noncrystalline (amorphous) forms. Amorphous forms
are generally considered to be of low toxicity; however, there are
limited data, especially related to amorphous silica nanoparticles
suggesting adverse health effects. 5,6 Crystalline silica has a fixed
repeating pattern of silicon-oxygen tetrahedra in comparison with
the random orientation of the amorphous form. 5,7,8 If combined
with other elements, these minerals are referred to as silicates,
such as asbestos, talc and kaolinite. There are several polymorphs
of crystalline silica: α-quartz, β-quartz, tridymite, cristobalite,
coesite and stishovite.9 The most biologically toxic and common
form is α-quartz.9
For silica particles to be biologically active, they must be small
enough to reach the distal airways and alveoli. These particles are
10
defined as “respirable” and are usually less than 5μm in diameter.
This form of silica is referred to as “respirable crystalline silica” (RCS).
RCS is generated when industrial processes, such as cutting, crush-
ing or grinding, apply pressure to silica-containing materials. RCS
may go unnoticed in a workplace as it is colourless, odourless and
nonirritating, and does not cause immediate health effects.11
The age of silica particles influences their potential toxicity.12
Crushing silica results in new cleavage planes with greater Si-
and SiO- radicals, which react with water to produce the damag-
ing hydroxyl radical (-OH).12,13 Silica particles pose piezoelectric
properties; that is, under applied pressure, the crystals acquire
7
electric polarity. This provides a means of direct cytotoxicity as
particles react with resident cells and cause lipid peroxidation
of cell membranes. The concentration of free silica in respirable
dust also influences biological potential.14 The adsorption of other
nonfibrogenic dusts onto the surface of silica particles decreas-
ing their toxicity has been referred to as the “interactive dust
7
phenomenon”.
3 |  O CCU PATI O N A L S I LI C A E X P OS U R E
The dose of cumulative respiratory exposure (a function of intensity
and duration of exposure) is the primary factor associated with de-
velopment of silicosis. Most countries regulate RCS occupational ex-
posure limits, typically expressed as a time-weighted average (TWA).
The TWA is the average airborne concentration of a particular sub-
stance permitted over an eight-hour working day and a 5-day work-
ing week. Internationally RCS exposure limits are generally in the
3 3 15
range of 0.05 mg/m to 0.1 mg/m . In 2002, the National Institute
for Occupational Safety and Health (NIOSH) noted that workers
still have a significant risk (at least 1 in 100) of developing chronic
radiographic silicosis when they are exposed for their working life-
times (40 to 45 years) at levels equal to the TWA of 0.05 mg/m3. The
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estimated risk of death up to age 65 from silicosis after 45 years of
exposure at 0.1 mg/m3 silica (the current standard in many coun-
tries) was 13 per 1000, while the estimated risk at an exposure of
0.05 mg/m3 was 6 per 1000.16
The risks of silicosis can rise markedly with high-intensity peri-
odic RCS exposure. A study of 371 men noted short-term exposure
to high concentrations of RCS (>2 mg/m3) has an effect three times as
great as a cumulative equivalent longer term exposure at lower lev-
els.17 Short-term exposure levels are not usually regulated; however,
the American Conference of Governmental Industrial Hygienists
(ACGIH) advise that the workplace RCS level should not exceed 3
times the 8-hour TWA for more than 30 minutes, and should never
exceed 5 times the 8-hour TWA.18
Due to its extensive presence in nature and low cost, occupa-
tional exposure to RCS is common (Table 2). In the United States
over 1.7 million workers are exposed to RCS in the general, mari-
time and construction industries.1,8 It is estimated that 3-5 million
workers in Europe have been exposed to silica.19 A cross-sec-
tional survey of the Australian working population noted 6.4% of
respondents were exposed to RCS at work, and 3.3% at a high
level. 20 Miners and construction workers were most likely to be
highly exposed to RCS. 20 Exposure is very common in low- and
middle-income countries. In India, around 3 million workers are at
high risk of exposure to silica, 1.7 million work in mining or quar-
rying activities. 21
Despite the large number of workers in the construction sec-
tor, there have been few studies of RCS exposure in this indus-
try. Activities likely to produce periods of short-term, possibly
high-intensity RCS exposure include cutting, demolishing and
grinding high silica-containing materials such as concrete, bricks
and cladding. 5 A study of RCS dust exposure during concrete
finishing (grinding) using hand-held grinders noted that the time-
weighted average concentration of silica dust in 69% of the sam-
ples exceeded the current recommended threshold limit value of
0.05 mg/m3 . 22
4 | PATH O LO G Y O F S I LI COS I S
Respirable silica dust deposited near or about respiratory bronchioles
and alveoli is phagocytosed by macrophages in an attempt to clear
the particles. An aggregation of dust-laden macrophages with scanty
reticulin and collagen fibres may be apparent in the earliest stages of
silicosis. 23 The silicotic nodule develops from within the macrophage
aggregate, with production of whorled concentric layers of collagen
at the centre of the lesion. A dense cuff of dust-laden macrophages
form around the enlarging collagen centre.7,14,23 Examination under
polarized light may demonstrate weakly birefringent silica particles
(Figure 1) and more strongly birefringent silicates (silicon dioxide
bound to cations such as magnesium and aluminium). 24
Silicotic nodules are usually 3-6 mm in diameter and distributed
along lymphatic routes.23 Rarely, the silicotic nodules may be found in
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HOY and CHAMBERS       2807

TA B L E 1   Diseases associated with respirable crystalline silica exposure5

Disease RCS exposure Comment

Silicosis
Chronic simple (nodular) Low level Pulmonary nodules up to 10 mm diameter
silicosis Latency greater than 10 y Usually asymptomatic
Chronic complicated Low level Pulmonary nodules and masses over 10mm diameter
silicosis (progressive Latency greater than 10 y Symptoms and progression associated with radiological severity
massive fibrosis)
Accelerated silicosis Moderate-high level More rapid disease progression than chronic silicosis.
Latency less than 10 y May have features of simple, complicated and acute silicosis
Acute silicosis Very high level Similar features to alveolar proteinosis
(silicoproteinosis) Develops within weeks to 5 y High mortality
Other pulmonary conditions
Lymphadenopathy Lowest exposure or duration not With or without co-existent parenchymal silicosis
determined Calcification may be present
Chronic obstructive   Association with chronic bronchitis, emphysema and airflow obstruction
pulmonary disease COPD association independent of smoking and silicosis24,98
Pulmonary fibrosis   Case-control studies have demonstrated association between silica exposure
and pulmonary fibrosis99,100
Sarcoidosis   Associated with RCS exposure
May be difficult to differentiate from complicated silicosis
Lung cancer Dose-response relationship with Close to multiplicative increased risk if co-existent smoking
RCS exposure May develop in the absence of silicosis
Caplan's syndrome   Combination of rheumatoid arthritis or elevated rheumatoid factor with
pneumoconiosis
Mycobacterial disease
Pulmonary tuberculosis   2.8-39 times higher risk of TB, depending on silicosis severity
Autoimmune disease
Rheumatoid arthritis   3 times increased risk compared with non-RCS exposed, especially males
Systemic lupus   Dose-response associations with increasing intensity or duration101
erythematosus
Scleroderma (Erasmus   Development of systemic sclerosis with or without silicosis
syndrome) RR 3.02 for males with RCS exposure
Greater prevalence of anti-DNA topoisomerase 1 autoantibodies
ANCA-associated   Exposure to RCS associated with OR 2.56 (95% CI 1.51-4.36)102
vasculitis
Renal disease
Chronic renal disease Elevated mortality for renal Histopathology varies from focal to crescentic and necrotizing
disease without clear dose- glomerulonephritis with aneurysm formation (72)104
response relationship103 May occur without pulmonary disease105
Suggested to be a result of a direct nephrotoxic effect by the microcrystalline
silica particles and immune-mediated processes in the context of
autoimmune disease106,107

abdominal nodes, liver, spleen, peritoneum and bone marrow.5 As the
nodules become less cellular and more hyalinized, they correspond-
ingly become more radiologically apparent. Progressive massive fibro-
sis (PMF) is present when nodules have enlarged and conglomerated
to form fibrous masses of 1 cm or more.24 Diffuse fibrosis extends
outwards from conglomerated silicotic masses as disease advances.
Upper lobes may be completely replaced, and masses obliterate in-
5
tralobar fissures and involve the apical regions of the lower lobes.
PMF lesions may develop into areas of necrosis and cavitation.
The pathology of acute silicosis is markedly different from
chronic silicosis and is characterized by severe alveolitis and alveolar
proteinosis. Alveolar filling with periodic acid-Schiff-positive mate-
rial, consisting of denatured surfactant, is present. The CT feature
of ground-glass opacities correlates with pathological findings of in-
tra-alveolar material, and septal lines with alveolar wall thickening,
dilated lymphatic and septal oedema. 25 Alveolar architecture may
be preserved with minimal fibrosis and uncommon small silicotic
nodules.5,25
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2808       HOY and CHAMBERS

TA B L E 2   Activities in which workers

Industry/occupation Specific task/operation Source material
may be exposed to respirable crystalline
Abrasive blasting Rust and paint removal, automotive Sand, sandstone, silica5,71,108
repairs abrasives
Agriculture, farming Mechanized ploughing, harvesting Soil
Cement and brick Raw material processing Clay, sand,
manufacturing limestone
China, ceramic and pottery Mixing, moulding, glaze or enamel Clay, shale, flint,
manufacturing spraying, sculpting sand, quartzite
Construction Bricklaying, concrete cutting, paving, Sand, concrete,
cement finishing, labouring, abrasive rock, soil, plaster
blasting, demolition, earthworks
Denim jean production Sandblasting Sand, abrasives
Dental material manufacturing Abrasive blasting, polishing Sand, abrasives
Excavation Earthmoving, drilling, digging Soil, rocks
Glass, fibreglass manufacturing Raw material processing Sand, quartz
Hydraulic fracking Drilling, fracking operation Rock, sand
Iron, steel mills, foundry Foundry casting production, furnace Sand, refractory
installation and repair materials
Jewellery production and Cutting, grinding, polishing gems Semiprecious
cleaning stones or gems,
abrasives, glass
Mining and related milling Most occupations (above and Ore, associated
underground mining), rock drilling rocks
Ornamental stone and Stonemasonry, sandblasting Sandstone,
tombstone repair granite, sand
Paint manufacturing Raw material handling Fillers (tripoli,
diatomaceous
earth, silica flour)
Quarrying and related milling Crushing rock, sand and gravel Sandstone,
processing granite, gravel,
slate
Road/highway construction and Sawing, breaking and grinding road Concrete, asphalt,
repair materials bitumen
Sand quarrying and processing Silica flour production Sand, silica flour
Shipbuilding and repair Abrasive blasting Sand, abrasives
Soap and cosmetic production Manufacturing or occupational use Silica flour
of abrasive soaps and scouring
powders
Stone benchtop fabrication and Cutting, grinding, polishing Artificial stone,
installation sandstone,
granite, porcelain
Tuckpointing Mortar removal, grinding Bricks, mortar
Tunnelling Blasting, drilling Soil, rock,
sandstone
Waste incineration Maintenance, cleaning Fly ash

The pathology of accelerated silicosis has not been clearly de-
scribed. As a more rapidly progressive condition, the features will
depend on the stage the disease is identified. Description of ad-
vanced pathological findings from sandblasters and artificial stone
workers has noted mixed features of both small and confluent sil-
icotic nodules, extensive interstitial fibrosis and areas of alveolar
proteinosis. 26-28
5 | PATH O G E N E S I S
The earliest steps in the pathogenesis of silicosis are relatively well
described. Silica particles that are small enough to remain airborne
until they reach the alveolar space (usually less than 5 µm) are en-
gulfed by alveolar macrophages (AM; Figure 1).10 AMs are the first
line of defence in the distal lung where they phagocytose inhaled

HOY and CHAMBERS
(A)
(B)
F I G U R E 1   (A) Birefringent crystals between 2.1 and 4.2 µm
in length are identifiable in an intracellular location in alveolar
macrophages obtained at bronchoalveolar lavage (BAL) from a
27-year-old stonemason. He had been dry-cutting engineered
stone with poor respiratory protection for 9 y. He gave a 2-y history
of breathlessness and had upper zone predominant centrilobular
nodules, but without progressive massive fibrosis. Green staining
reflects intracellular accumulation of oxidised lipid. (B) Scanning
electron microscope image of crystals purified from lysed alveolar
macrophages taken from BAL obtained from the same individual
demonstrating an alveolar macrophage with intracellular crystal.
The atomic content of the crystal was 27.9% Si and 69.6% O,
consistent with SiO2. Scale bars indicate 1 µm. Microscopy images
courtesy of Dr Simon Apte, Qld Lung Transplant Service
microbes and dusts. Usually, this key innate immune effector cell will
digest engulfed material, which is then either destroyed, removed
through lymphatic drainage to regional lymph nodes, or cleared by
the mucociliary escalator to be expectorated or swallowed.
Crystalline silica particles are recognized and scavenged by the
macrophage receptor with collagenous structure (MARCO). 29,30 If
AMs which have ingested silica particles are not cleared from the
lung, the phagocytosed particles induce the production of reactive
|
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      2809
oxygen species (ROS) and damage macrophage lysosomes (Figure 2).
Spillage of lysosomal contents into the cytoplasm provokes potent
activation of a multiprotein complex called the inflammasome,
which in turn cleaves inactive proIL-1β, leading to secretion of the
prototypic proinflammatory cytokine IL-1β (Figure 2).31,32 This in-
flammatory cascade generates further recruitment of inflammatory
cells, perpetuating the pathology. If the MARCO receptor is absent,
silica clearance is further impaired, lysosomal membranes become
more permeable, and intense inflammation results.30 Dysfunctional
AMs that remain in the alveolar space are both unable to clear al-
veolar glycoprotein or maintain surfactant homeostasis, leading
to accumulation of the PAS-positive intra-alveolar material that
characterizes alveolar proteinosis. They also stimulate a potent
profibrotic response, leading to collagen deposition, fibrosis and
eventually PMF.33 It is hence clear that AMs are central to fibrosis,
both in terms of histopathology (above) and in terms of pathogen-
esis (Figure 2).
While these early events are well defined, the steps leading
to fibrosis are less well understood. AMs have been difficult to
study due to intense autofluorescence and nonspecific surface
markers, hampering attempts to define phenotypes through sur-
face labelling and conventional flow cytometry. Recent techno-
logical developments that now allow description of the entire
transcriptome in single cells (single-cell RNA sequencing, scRNA-
seq) have overcome these obstacles, so that unprecedented
description of cellular taxonomy even in complex tissues and
disease states is now possible. 34 This technique has unveiled the
presence of an aberrant profibrotic AM, which appears central
to the pathogenesis of pulmonary fibrosis, and which is charac-
terized by overexpression of secreted phosphoprotein 1, which
encodes osteopontin. 35 Osteopontin is known to be increased
in human silicosis. 36 scRNAseq has also led to the discovery that
in patients with idiopathic pulmonary fibrosis, monocyte-de-
rived AMs are recruited to fibrotic niches where they stimulate
fibroblasts to produce collagen. 37 However, it is as yet unknown
whether similar perturbations in AM populations drive fibrosis
in silicosis.
Other currently unexplained aspects of silicosis pathogenesis in-
clude the association with several systemic autoimmune disorders, and
the inexact correlation between the level of workplace exposure and
development of disease. A recent article from an Israeli group iden-
tified the presence of nanosized silica particles, which if inhaled may
be able to bypass alveolar clearance mechanisms and enter the blood-
stream for systemic distribution, potentially triggering extrapulmonary
disease (see below).38 It is likely several factors impact on the develop-
ment of disease in any one individual, including not only the length, but
also the intensity of exposure, which may overwhelm usual AM clear-
ance mechanisms, as well as the composition of the product generating
respirable crystalline silica. It could be that resins and other materials
used in the manufacture of some products may lead to the generation
of unexpected compounds, which effectively act as adjuvants to inten-
sify the inflammatory response.39 Finally, silicosis pathogenesis should
be viewed through a lens of gene-environment interactions, with early
 |
2810       HOY and CHAMBERS
reports confirming susceptibility to silicosis in carriers of polymor-
40
phisms in the TNF-α and FAM13A genes.
6 |  C LI N I C A L PAT TE R N S O F S I LI COS I S
Chronic silicosis is the most common form and is subclassified as sim-
ple (nodular) silicosis or complicated silicosis (progressive massive
24
fibrosis). Chronic silicosis typically develops slowly with prolonged
low concentration RCS exposure, usually presenting 10 to 30 years
after first exposure. 24 Radiographic features may initially develop
many years after cessation of exposure.41 Chronic simple silicosis is
radiologically characterized by pulmonary nodules up to 10 mm in
diameter (usually 3-6 mm), typically in the upper zones. Patients with
simple silicosis may be asymptomatic and only detected by chest
radiology, such as part of an occupational health screening pro-
gramme. The severity of simple silicosis can be categorized by the
extent of nodularity in the lung fields (radiological profusion).42 With
more advanced simple silicosis, a significant proportion will have im-
paired gas transfer and restricted spirometry.42,43 Simple silicosis is
often symptomless but may be associated with cough and sputum
production.5,24
Silicosis transitions to complicated silicosis when pulmonary nod-
ules have enlarged or coalesced to be at least 1 cm in diameter.5 The
larger opacities, also known as progressive massive fibrosis (PMF),
have an upper lobe predominance and vary in shape. There is often a
background of smaller nodules.5 There may be volume loss with tra-
cheal and mediastinal distortion and development of “paracicatricial
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F I G U R E 2   Pathogenesis of silicosis.
Inhaled silica crystals are scavenged by
alveolar macrophages adorned with the
MARCO receptor. Phagosomes contain
indigestible crystal, which generates
reactive oxygen species, and induces
lysosomal swelling and damage. Lysosomal
damage and leakage of contents into
the cytoplasm trigger activation of the
inflammasome complex and ultimately
production of interleukin-1β (IL-1 β).
This and other cytokines and growth
factors (transforming growth factor β
(TGF-β), tumour necrosis factor α (TNF-α),
platelet-derived growth factor (PDGF)
and osteopontin (OPN)) drive further
inflammation, fibroblast activation,
collagen secretion and fibrosis
emphysematous” destruction (Figure 3).5 It may be difficult to dif-
ferentiate radiological features from lung cancer, tuberculosis and
sarcoidosis. Lymph node enlargement is common. Calcification may
also develop within the conglomerated masses and in lymph nodes.
Destruction of lung tissue results in impaired lung function and ele-
vated pulmonary vascular resistance. Clinically, patients experience
progressively worsening dyspnoea, hypoxaemia, cor pulmonale, re-
spiratory failure and death. Following development of pulmonary
silicosis, the disease may progress even after cessation of RCS expo-
sure. Risk of progression has been associated with cumulative RCS
exposure, younger age, lower lung function and larger size and extent
of lung opacities on chest radiology at time of initial visit and fol-
low-up duration.44-46
Accelerated silicosis develops less than 10 years after initial RCS
exposure and is associated with higher intensity RCS exposure than
chronic silicosis.24 Accelerated silicosis has similar features to the
chronic forms but is characterized by more rapid disease progression
(Figure 4).45,47 The radiological features vary depending on the stage
when the condition is identified and have not yet been well described.
In the early stages of accelerated silicosis, plain chest X-ray may not
detect diagnostic features. A study of Chinese miners noted 26.9% had
a negative result on chest X-ray screening despite findings for pneu-
moconiosis on HRCT.48 A preliminary report of artificial stone workers
in Australia noted a normal chest X-ray in 43% with CT findings of sil-
icosis, suggesting a low sensitivity of the chest X-ray in that setting.49
Acute silicosis differs significantly from chronic silicosis. Acute sil-
icosis results from very high level RCS exposure for a few weeks to
5 years.24 It has been described most commonly in sandblasters, but

HOY and CHAMBERS
also in tunnel workers and silica flour processing.5,50,51 Acute silicosis
is a progressive condition with nonspecific symptoms including dys-
7,25
pnoea, cough, fatigue, weight loss, fever and pleuritic pain. Disease
progression may be rapid, and there is high associated mortality.7,52
Radiological features are limited to small case series and reports. CT
findings include numerous bilateral centrilobular nodular opacities,
53,54
focal ground-glass opacities and patchy areas of consolidation.
Lymphadenopathy may occur in silica-exposed workers with-
out pulmonary parenchymal findings, so-called “lymph node silico-
55,56
sis”. A study of 264 deceased miners noted 20% to have lymph
node silicosis alone, 4% to have parenchymal silicosis alone and 39%
to have both.56 There are limited data currently regarding progres-
sion to pulmonary silicosis; however, the presence of lymph node
fibrosis impairs elimination of silica dust from the lungs, leading to
higher lung burden of silica and possibly increasing the likelihood of
lung damage and parenchymal silicosis.56
The diagnosis of silicosis requires a history of sufficient RCS ex-
posure, compatible radiological features and exclusion of alternate
diagnoses, such as sarcoidosis, hypersensitivity pneumonitis, tuber-
culosis and lung cancer. The diagnosis may be challenging where the
radiological features of complicated silicosis, sarcoidosis, tuberculo-
sis and lung cancer are similar. In these circumstances, further inves-
tigation, such as bronchoscopy with bronchoalveolar lavage and lung
biopsy, may be considered.
7 | S I LI C A-A S S O C I ATE D CO N D ITI O N S
Apart from silicosis, silica exposure is also associated with a range
of other respiratory and nonrespiratory conditions including sar-
coidosis, autoimmune disease, lung cancer and pulmonary infections
(Table 1).
F I G U R E 3   Advanced accelerated silicosis with paracicatricial
“emphysematous” predominantly upper lobe destruction
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      2811
Epidemiological studies have noted an association between silica
exposure and sarcoidosis.57 In one of the most systematic reports, a
study of 2187 silica-exposed iron foundry workers in Sweden noted
an excessive incidence of sarcoidosis (3.94, 95% CI 1.07-10.08), in
particular among those with high exposure to silica dust (>0.048 mg/
m3).58 Especially in the early stages, silicosis and sarcoidosis display
very similar radiological and pathological features (such as the pres-
ence of histiocytic aggregates and granulomatous inflammation) and
so may be easily confused. Importantly, since sarcoidosis is a dis-
ease with no known cause, the diagnosis requires exclusion of other
granulomatous disorders where the cause is known and especially
those, such as silicosis, triggered by environmental exposures.59 It
is hence critical that in any patient presenting with granulomatous
pulmonary disease, a very careful occupational history is obtained.
If there is potential for significant exposure to respirable crystalline
silica, silicosis, rather than sarcoidosis, should be strongly suspected
so that the opportunity to provide specific, and potentially life-sav-
ing, advice regarding ceasing further exposure is not missed. Further
diagnostic testing (eg bronchoscopy with bronchoalveolar lavage,
transbronchial or open lung biopsy) may be required to differentiate
the two conditions.
Respirable crystalline silica (α-quartz and cristobalite) has been
classified as a human carcinogen by the International Agency for
Research on Cancer since 1997, and since that time, there has been
increasing evidence of a dose-response relationship. 2,60,61 An analy-
sis of 65,980 workers from pooled cohort studies found cumulative
exposure, with a 15-year lag, was a strong predictor of lung can-
cer.61 The estimated excess risk (through age 75) of lung cancer for
a worker exposed from age 20 to 65 at 0.1 mg/m3 RCS was 1.1%-
1.7%, above background risks of 3%-6%.61 There is a significant ad-
ditive and close to multiplicative joint effect of silica exposure and
cigarette smoking with lung cancer.5,60,62 There is also increasing
evidence that the risk of lung cancer can increase in those work-
ing with RCS in the absence of radiological features of silicosis.5,60
It has been suggested through animal models that initial inflamma-
tion induced by silica exposure is followed by the development of an
immunosuppressive microenvironment that supports the growth of
lung tumours.63
Silica is associated with several autoimmune diseases such as
systemic sclerosis (SSc), rheumatoid arthritis (RA), systemic lupus
erythematosus and antineutrophil cytoplasmic antibody (ANCA)-
related vasculitis.64 A meta-analysis of 242 silica-exposed RA cases
indicated that disease risk for exposed individuals was more than
three times that of unexposed individuals (3.43, 95% CI 2.25-5.22),
and the risk appeared to be higher in males.65 Although SSc is less
common than RA, several studies have demonstrated an increased
risk of SSc in association with silica exposure. A meta-analysis of 16
studies examined the association between SSc and occupational ex-
posure to silica, noting a RR of 3.02 (95% CI 1.24-7.35) for males.66
The risks in the three cohort studies included were extremely high,
with over 15-fold higher risks.66 Patients with silica-associated SSc
had greater prevalence of anti-DNA topoisomerase 1 autoantibodies
compared with those with idiopathic disease.67,68
 |
2812       HOY and CHAMBERS
Autoantibodies (anti-DNA, anti-SS-A/Ro, anti-SS-B/La, anti-
centromere and antitopoisomerase 1) have been noted to occur at
higher frequency in silica-exposed individuals without autoimmune
disease than the general population.67 Autoimmune disease can also
occur with silica exposure, but in the absence of silicosis, suggesting
that the development of fibrosis and nodular lesions may not be re-
quired for development of autoimmunity.67-69
One of the primary causes of morbidity and mortality in sili-
ca-exposed workers is the development of Mycobacterium tubercu-
70
losis (TB) infection. The risk of a patient with silicosis developing
tuberculosis is higher (2.8 to 39 times depending on the severity of
the silicosis) than for healthy controls.70 TB rates are extremely high
in silica-exposed workers from regions with high background rates
of TB and HIV. South African gold miners have pulmonary TB rates
of 3000 per 100 000.71 TB infection is associated with increased
risk of silicosis progression and disease severity.71 The effects of TB
are also aggravated by HIV infection and smoking, which commonly
24,71
coexist, especially in developing countries, such as South Africa.
Silica exposure increases the risk of tuberculosis, even without sili-
71
cosis, and continues after exposure has ceased.
Clinical management can be difficult as the radiological features
72
of silicosis and TB frequently overlap. International guidelines rec-
ommend TB screening for silica-exposed workers (especially over
10 years of exposure) and chemoprophylaxis for latent TB in the set-
ting of silicosis.71
8 |  E PI D E M I O LO G Y O F S I LI C A-
A S S O C I ATE D D I S E A S E S
In 1995, the World Health Organization began a campaign to elimi-
nate silicosis from the world by 2030, but silicosis remains a major
13989995, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.14202 by Nat Prov Indonesia, Wiley Online Library on [11/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
F I G U R E 4   Radiological progression of
accelerated silicosis. Widespread ground-
glass opacification with small pulmonary
nodules evolves into progressive massive
fibrosis with volume loss and nodules > 10
mm
health issue internationally. In 2016, the Global Burden of Disease
Study estimated 10 400 deaths per year, and 210 000 years of life
lost due to silicosis.73
Between 1991 and 1995, there were more than 500 000 new cases
of silicosis in China.24,74 The industry with the highest contribution in
China was mining, with an estimated prevalence of 6% among all coal
miners. About 12.9% of cases came from metallurgy and 8.9% from
construction material manufacturing.74 In 2003, the South African
mining industry committed itself to eliminating silicosis, the target
being no new cases by 2013. However, there was no significant decline
in overall silicosis prevalence among a cohort of working gold miners in
1984 compared with a further study between 2004 and 2009.75
In higher income countries, due to improvements in dust control
measures (such as wet drilling and ventilation) there have been re-
ductions in the incidence of silicosis over the last 50 years. In the UK
between 1996 and 2017, there were 216 cases of silicosis reported
to a surveillance programme, and an estimated 700 cases for the
country as a whole.76 The mean age was 61 years, but the young-
est was 23.76 In the United States, there were an estimated 3600-
7300 newly recognized silicosis cases per year from 1987 to 1996.77
Death certificates between 1990 and 1996, noted 200-300 deaths
per year, contributed to by silicosis.8
In recent years, two of the worst outbreaks of silicosis have oc-
curred in industries not traditionally thought to be associated with
RCS exposures, specifically denim jean production and domestic
benchtop fabrication. The process of sandblasting denim jeans to
produce a “worn-out” look began in Turkey in the 1990s and reached
its peak in the early 2000s.78 The first case of silicosis in this industry
was identified in 2001. A study of former workers noted 77 of 143
(53%) to have silicosis at baseline. After a 4-year follow-up period,
nine (6.2%) had died with a mean age of just 24  years. Of the 74
living sandblasters available for re-examination, the prevalence of

HOY and CHAMBERS
silicosis increased from 53% to 96%, and radiographic progression
was observed in 82%.45,79,80
Since the early 2000s, artificial (also known as engineered or
reconstituted) stone has rapidly become a popular material for the
fabrication of kitchen and bathroom benchtops. Artificial stone is
a composite material made of quartz as the major filler, with the
addition of coloured glass, shells, metals or mirrors bound together
by a polymer resin. 81 The crystalline silica content of the material is
over 90%, which is far higher than traditionally used natural stone
such as granite (30%) or marble (3%).47 Slabs of artificial stone are
modified by workers based on client specifications, which includes
producing cut-outs for installation of cooktops, sinks and tapware.
Cutting and grinding the material without water dust suppression,
so-called dry-cutting, has been commonplace and is associated
with generation of potentially extreme levels of RCS 47,82 (Figure 5).
One study noted dry-cutting artificial stone produced 44 mg/m3 of
RCS over 30 minutes, close to 300 times above the recommended
30-minute exposure limit. 82 Another study noted that grinding ar-
tificial stone produced respirable dust with a silica content of up to
93%. 83
The first reported case of silicosis associated with artificial stone
was from Italy in 2010, and recently, the number of cases reported
internationally has grown rapidly from countries including Israel,
Australia, Spain and the United States.47,84-86 These reports have
noted younger age at diagnosis and more rapid disease development
than chronic silicosis, a high rate of disease progression, and resul-
tant death or requirement for lung transplantation.47,86-89 Data have
also indicated a sevenfold excess prevalence of autoimmune disease
in patients with artificial stone-associated silicosis in Israel.85 Out of
40 patients with advanced silicosis, 9 (23%) were diagnosed with au-
toimmune diseases, specifically systemic sclerosis (3), mixed connec-
tive tissue disease (2), rheumatoid arthritis (2), Sjogren's syndrome
(1) and polymyositis (1).85
9 | PR E V E NTI O N A N D M A N AG E M E NT
Silicosis is an incurable, but preventable, lung disease. Redoubled ef-
fort is required worldwide to control known and emerging sources
of silica exposure. The recent outbreak of silicosis associated with
artificial stone is a stark example of failure to maintain a high level
of caution when using silica-containing materials. Where possible,
these materials should be eliminated or substituted for safer alterna-
tives, for example by using metal grits for abrasive blasting. 24 When
available, periodic measurement of environmental RCS levels is criti-
cal to ensure the effectiveness of control measures and adherence
with regulated exposure limits. Respirators should not be utilized as
the primary means of worker protection, but used only after more
effective control measures, such as elimination, substitution and
exhaust ventilation. Guidelines detailing good practice when han-
dling and using silica-containing materials have been made available
|
13989995, 2020, 11, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/all.14202 by Nat Prov Indonesia, Wiley Online Library on [11/02/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
      2813
F I G U R E 5   Cutting of artificial stone during stone benchtop
fabrication
by the European Network on Silica at https​://www.nepsi.eu/good-
pract​ice-guide​.
Health surveillance of exposed workers is widely recommended
and generally comprises a periodic health questionnaire, physical
examination, lung function and chest radiology.5 Historically, pro-
grammes were developed to identify preclinical features of chronic
silicosis. The effectiveness and frequency of these measures, in par-
ticular use of chest X-ray, have not been sufficiently evaluated to
screen workers who have been exposed to high levels of RCS from
artificial stone and are at risk of accelerated silicosis. Preliminary re-
ports from artificial stone workers noted a significant proportion to
have a normal chest X-ray despite features of silicosis on high-res-
olution CT.49
Following the diagnosis of a silica-associated disease, removal
from further exposure is generally recommended. 5 Treatment of
co-existing conditions such as nicotine addiction or latent TB is
required. If the worker is required to leave his employment, there
is a high risk of unemployment and major economic disadvantage;
therefore, compensation is required to minimize the impact and
assist in obtaining suitable alternate employment where possible.
Compensation insurance levies may be a tool to further encourage
workplaces to control RCS exposure. Although there have been no
published studies, other general measures should include psycho-
logical support, vaccinations and exercise programmes.
10 | E M E RG I N G TR E ATM E NT O P TI O N S
Although avoiding respirable crystalline silica is obviously critical,
there is very limited evidence to guide treatment of established sili-
cosis. The first long-term (10 months) survivor of lung transplanta-
tion was a 23-year-old sandblaster with silicosis transplanted in the
early 1970s; however, transplantation is a limited resource, which
may be contraindicated in some, and has a short median survival of
 |
2814       HOY and CHAMBERS
only 6-7 years.90,91 Silicoproteinosis is characterized by intra-alveolar
protein accumulation and is similar to pulmonary alveolar proteinosis
(PAP), caused by AM dysfunction. In PAP, whole lung lavage (WLL)
clears the accumulated material from the airspaces, and a significant
body of nonrandomized evidence strongly supports the safety and
efficacy of this therapeutic approach.92 Similarities between PAP
and silicoproteinosis suggest that WLL may have therapeutic poten-
tial in the nonfibrotic forms of silicosis, a contention supported by
case reports and series.93,94
The antifibrotic drugs pirfenidone and nintedanib are known to
be effective not only in patients with IPF, but also in a wide range
of progressive fibrotic lung diseases; however, it remains unknown
whether these drugs are effective for workers with silicosis.95,96
More work is clearly required to design effective treatment strate-
gies. Due to the relatively low prevalence of silicosis in the general
population, the acquisition of high-quality evidence based on clinical
endpoints will be limited. In this situation, the identification of bio-
markers based on a thorough cellular and molecular understanding
of disease pathogenesis can provide an effective path to evidence
generation.97
11  | CO N C LU S I O N
Although silica exposure is one of the oldest known causes of lung
disease, it remains a major cause of disease internationally and is on
the rise in those workers using newer high silica content materials.
Recent outbreaks of silica-associated disease highlight the need for
constant vigilance to identify and control new and well-established
sources of silica exposure. While there are currently no effective
treatments for silicosis, it is a completely preventable lung disease.
AC K N OW L E D G M E N T S
The authors would like to thank Mr Ron Rasch from the Centre for
Microscopy and Microanalysis at The University of Queensland, and
Dr Simon Apte from the Qld. Lung Transplant Research Program for
providing microscopy imaging. The authors would also like to thank
Prof Malcolm Sim, Prof Michael Abramson and A/Prof Deborah
Glass from Monash University for their assistance with development
and review of the manuscript.
C O N FL I C T S O F I N T E R E S T
The authors declare that they have no conflict of interest.
ORCID
Ryan F. Hoy  https://orcid.org/0000-0001-9150-9440
Daniel C. Chambers  https://orcid.org/0000-0002-9553-5870
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