INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT NO. 24
CRYSTALLINE SILICA, QUARTZ
INTER-ORGANIZATION PROGRAMME FOR THE SOUND MANAGEMENT OF CHEMICALS
A cooperative agreement among UNEP, ILO, FAO, WHO, UNIDO, UNITAR and
OECD
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organization, or the World Health Organization.
First draft prepared by Ms F. Rice, National Institute of Occupational
Safety and Health, Cincinnati, OH, USA
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organization, and the
World Health Organization, and produced within the framework of the
Inter-Organization Programme for the Sound Management of Chemicals.
World Health Organization
Geneva, 2000
The International Programme on Chemical Safety (IPCS),
established in 1980, is a joint venture of the United Nations
Environment Programme (UNEP), the International Labour Organization
(ILO), and the World Health Organization (WHO). The overall objectives
of the IPCS are to establish the scientific basis for assessment of
the risk to human health and the environment from exposure to
chemicals, through international peer review processes, as a
prerequisite for the promotion of chemical safety, and to provide
technical assistance in strengthening national capacities for the
sound management of chemicals.
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Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
Agriculture Organization of the United Nations, WHO, the United
Nations Industrial Development Organization, the United Nations
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field of chemical safety. The purpose of the IOMC is to promote
coordination of the policies and activities pursued by the
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WHO Library Cataloguing-in-Publication Data
Crystalline silica, quartz.
(Concise international chemical assessment document ; 24)
1.Quartz - toxicity 2.Quartz - adverse effects
3.Risk assessment 4.Occupational exposure
5.Environmental exposure 6.Epidemiologic studies
I.Programme on Chemical Safety II.Series
ISBN 92 4 153023 5 (NLM Classification: QV 633)
ISSN 1020-6167
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TABLE OF CONTENTS
FOREWORD
1. EXECUTIVE SUMMARY
2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES
3. ANALYTICAL METHODS
4. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION
6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
8.1. Single exposure
8.2. Short-term exposure
8.3. Long-term exposure and carcinogenicity
8.3.1. Interaction with other compounds
8.4. Genotoxicity and related end-points
8.5. Reproductive and developmental toxicity
8.6. Immunological and neurological effects
9. EFFECTS ON HUMANS
9.1. Case reports
9.2. Epidemiological studies
9.2.1. Silicosis
9.2.2. Pulmonary tuberculosis and other infections
9.2.3. Lung cancer
9.2.4. Autoimmune-related disease
9.2.5. Renal disease
9.2.6. Chronic obstructive pulmonary disease
9.2.7. Other adverse health effects
10. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
11. EFFECTS EVALUATION
11.1. Evaluation of health effects
11.1.1. Hazard identification and dose-response assessment
11.1.2. Criteria for setting tolerable intakes or guidance values for quartz
11.1.3. Sample risk characterization
12. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
APPENDIX 1 -- SOURCE DOCUMENTS
APPENDIX 2 -- CICAD PEER REVIEW
APPENDIX 3 -- CICAD FINAL REVIEW BOARD
APPENDIX 4 -- INTERNATIONAL CHEMICAL SAFETY CARD
RÉSUMÉ D'ORIENTATION
RESUMEN DE ORIENTACI²N
FOREWORD
Concise International Chemical Assessment Documents (CICADs) are
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Risks to human health and the environment will vary considerably
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of locally measured or predicted exposure scenarios. To assist the
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considered as representing all possible exposure situations, but are
provided as guidance only. The reader is referred to EHC 1701 for
advice on the derivation of health-based tolerable intakes and
guidance values.
1 International Programme on Chemical Safety (1994) Assessing human
health risks of chemicals: derivation of guidance values for
health-based exposure limits. Geneva, World Health Organization
(Environmental Health Criteria 170).
While every effort is made to ensure that CICADs represent the
current status of knowledge, new information is being developed
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In the event that a reader becomes aware of new information that would
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A standard outline has been developed to encourage consistency in
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1. EXECUTIVE SUMMARY
This CICAD on crystalline silica, quartz was based on the
following three extensive peer-reviewed documents on the health
effects of crystalline silica, including quartz: (1) a review of
published human studies and reports on the adverse health effects of
quartz exposure (NIOSH, forthcoming), (2) a review of the
carcinogenicity studies conducted by the International Agency for
Research on Cancer (IARC, 1997), and (3) a review of the non-cancer
health effects of ambient quartz (US EPA, 1996). The source documents
had different emphases on different end-points, and the CICAD was
developed to assess all the adverse health effects identified in these
documents. It is to be noted that despite the different emphases, the
final conclusions of all source documents were very similar. A
comprehensive literature search of several on-line databases was
conducted. Data identified as of March 1999 are included in this
review.
This CICAD considers the most common form of crystalline silica
(i.e., quartz). It does not consider experimental studies of the
effects of other forms of crystalline silica (e.g., cristobalite,
tridymite, stishovite, or coesite), coal dust, diatomaceous earth, or
amorphous silica, because their in vitro toxicities differ from that
of quartz. Differences in induction of fibrogenicity of quartz,
cristobalite, and tridymite were demonstrated in vivo in an early
rat study. However, there are virtually no experimental studies that
systematically evaluated exactly the same material to which humans are
exposed. The IARC Working Group considered the possibility that there
may be differences in the carcinogenic potential among polymorphs of
crystalline silica. However, some of the epidemiological studies
evaluated lung cancer among workers in "mixed environments" where
quartz may be heated and varying degrees of conversion to cristobalite
or tridymite can occur (e.g., ceramics, pottery, and refractory brick
industries), and exposures specifically to quartz or cristobalite were
not delineated. Although there were some indications that cancer risks
varied by industry and process in a manner suggestive of
polymorph-specific risks, the Working Group could reach only a single
conclusion for quartz and cristobalite. The CICAD reflects the
discussion and conclusion of that source document; therefore, when
considering the carcinogenicity of quartz in the occupational setting,
it does not distinguish between epidemiological studies of quartz and
those of cristobalite.
The peer review process for this CICAD was targeted to include
review by an international group of experts selected for their
knowledge about the current controversies and issues surrounding
quartz. Information on the nature of the peer review and the
availability of the source documents is presented in Appendix 1.
Information on the peer review of this CICAD is presented in
Appendix 2. This CICAD was approved as an international assessment at
a meeting of the Final Review Board, held in Sydney, Australia, on
21-24 November 1999. Participants at the Final Review Board meeting
are listed in Appendix 3. The International Chemical Safety Card
(ICSC 0808) for crystalline silica, quartz has been reproduced in
Appendix 4 (IPCS, 1993).
Quartz (CAS No. 14808-60-7) is a frequently occurring solid
component of most natural mineral dusts. Human exposures to quartz
occur most often during occupational activities that involve movement
of earth, disturbance of silica-containing products (e.g., masonry,
concrete), or use or manufacture of silica-containing products.
Environmental exposure to ambient quartz dust can occur during
natural, industrial, and agricultural activities. Respirable quartz
dust particles can be inhaled and deposited in the lung; however, no
conclusions have been made about the clearance kinetics of quartz
particles in humans.
Quartz dust induces cellular inflammation in vivo. Short-term
experimental studies of rats have found that intratracheal
instillation of quartz particles leads to the formation of discrete
silicotic nodules in rats, mice, and hamsters. Inhalation of
aerosolized quartz particles impairs alveolar macrophage clearance
functions and leads to progressive lesions and pneumonitis. Oxidative
stress (i.e., increased formation of hydroxyl radicals, reactive
oxygen species, or reactive nitrogen species) has been observed in
rats after intratracheal instillation or inhalation of quartz. Many
experimental in vitro studies have found that the surface
characteristics of the crystalline silica particle influence its
fibrogenic activity and a number of features related to its
cytotoxicity. Although many potential contributory mechanisms have
been described in the literature, the mechanisms responsible for
cellular damage by quartz particles are complex and not completely
understood.
Long-term inhalation studies of rats and mice have shown that
quartz particles produce cellular proliferation, nodule formation,
suppressed immune functions, and alveolar proteinosis. Experimental
studies of rats reported the occurrence of adenocarcinomas and
squamous cell carcinomas after the inhalation or intratracheal
instillation of quartz. Pulmonary tumours were not observed in
experiments with hamsters or mice. Adequate dose-response data (e.g.,
no-adverse-effect or lowest-adverse-effect levels) for rats or other
rodents are not available because few multiple-dose carcinogenicity
studies have been performed.
Quartz did not test positively in standard bacterial mutagenesis
assays. Results of genotoxicity studies of quartz conflict, and a
direct genotoxic effect for quartz has not been confirmed or ruled
out.
In experimental studies of particles, results may vary depending
on the test material, particle size of the material, concentration
administered, and species tested. The experiments with quartz
particles involved specimens from various sources, using various
doses, particle sizes, and species, which could have affected the
observations.
Data on the reproductive and developmental effects of quartz in
laboratory animals are not available.
The adverse effects of quartz in aquatic organisms and
terrestrial mammals have not been studied.
There are many epidemiological studies of occupational cohorts
exposed to respirable quartz dust. Silicosis, lung cancer, and
pulmonary tuberculosis are associated with occupational exposure to
quartz dust. IARC classified inhaled crystalline silica (quartz or
cristobalite) from occupational sources as a Group 1 carcinogen based
on sufficient evidence of carcinogenicity in humans and experimental
animals; "in making the overall evaluation, the Working Group noted
that carcinogenicity in humans was not detected in all industrial
circumstances studied. Carcinogenicity may be dependent on inherent
characteristics of the crystalline silica or on external factors
affecting its biological activity or distribution of its polymorphs"
(IARC, 1997).
Statistically significant increases in deaths or cases of
bronchitis, emphysema, chronic obstructive pulmonary disease,
autoimmune-related diseases (i.e., scleroderma, rheumatoid arthritis,
systemic lupus erythematosus), and renal diseases have been reported.
Silicosis is the critical effect for hazard identification and
exposure-response assessment. There are sufficient epidemiological
data to allow the risk of silicosis to be quantitatively estimated,
but not to permit accurate estimations of risks for other health
effects mentioned above. (A pooled risk assessment of epidemiological
studies of silica and lung cancer is in progress at IARC.)
The risk estimates for silicosis prevalence for a working
lifetime of exposure to respirable quartz dust concentrations of about
0.05 or 0.10 mg/m3 in the occupational environment vary widely (i.e.,
2-90%). Regarding exposure to ambient quartz in the general
environment, a benchmark dose analysis predicted that the silicosis
risk for a continuous 70-year lifetime exposure to 0.008 mg/m3
(estimated high crystalline silica concentration in US metropolitan
areas) is less than 3% for healthy individuals not compromised by
other respiratory diseases or conditions and for ambient environment
(US EPA, 1996). The silicosis risk for persons with respiratory
diseases exposed to ambient quartz in the general environment was not
evaluated.
Uncertainties exist in the evaluation of epidemiological studies
and the risk assessment of health effects related to quartz dust
exposure. The difficulties, many of which are inherent to the study of
respiratory diseases in occupational populations, include limitations
in the amount and quality of historical exposure data, deficiencies in
data on potentially confounding factors, such as cigarette smoking,
and difficulties in the interpretation of chest radiographs as
evidence of exposure. In addition, occupational exposures to quartz
dust are complex because workers are frequently exposed to dust
mixtures that contain quartz and other mineral varieties. Properties
of the dust (e.g., particle size, surface properties, crystalline
form) may differ according to geological source and can also change
during industrial processing. Such variations can affect the
biological activity of the inhaled dust. The IARC Working Group
evaluated the carcinogenicity of crystalline silica (including quartz)
and focused on epidemiological studies that were the least likely to
have been affected by confounding and selection biases and that
evaluated exposure-response relationships (IARC, 1997).
2. IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES
"Silica," or silicon dioxide (SiO2), occurs in either a
crystalline or non-crystalline (amorphous) form. Crystalline silica
may be found in more than one form (polymorphism), depending on the
orientation and position of the tetrahedra (i.e., the
three-dimensional basic unit of all forms of crystalline silica). The
natural crystalline forms of silica are alpha-quartz, ß-quartz,
alpha-, ß1-, and ß2-tridymite, alpha- and ß-cristobalite, coesite,
stishovite, and moganite (IARC, 1997). This document discusses the
most common form of naturally occurring crystalline silica -- quartz
(CAS No. 14808-60-7). Cristobalite (CAS No. 14464-46-1) and tridymite
(CAS No. 15468-32-3) exist in nature, but they can also be created
during industrial processes, such as the calcination of diatomaceous
earth, ceramics manufacturing, foundry processes, silicon carbide
manufacturing, and any other process in which quartz is heated to high
temperatures (NIOSH, 1974; Altieri et al., 1984; Virta, 1993;
Weill et al., 1994; IARC, 1997).
Quartz is a colourless, odourless, non-combustible solid and a
component of many mineral dusts (NIOSH, 1997). It is insoluble in
water (NIOSH, 1997). When quartz is cut, ground, or milled, the
crystal is fractured, and Si and Si-O radicals may be generated on the
cleavage surfaces (Castranova et al., 1996). Trace metal impurities,
such as iron and aluminium, can modify the surface reactivity of
quartz (Fubini et al., 1995; Fubini, 1997, 1998; IARC, 1997; Donaldson
& Borm, 1998).
Most of the experimental studies described in section 8 used
Min-U-Sil or DQ 12 quartz. Min-U-Sil is a trade name, and the number
that follows (e.g., Min-U-Sil 5) describes the particle size of the
sample (e.g., Min-U-Sil 5 is <5 µm in diameter). The purity is 99%
quartz (IARC, 1997). However, the geological sources of crystals have
varied; consequently, the associated impurities may have varied. The
particle size distributions of Min-U-Sil and several other reference
standards for the quantification of quartz in coal mine dust have been
investigated (Huggins et al., 1985), but a comprehensive report has
not been published on the analytical characteristics of a standard
sample of Min-U-Sil and the reproducibility of its aliquots
(Saffiotti et al., 1993). DQ 12 is a quartz sand that contains 87%
crystalline silica; the remaining proportion is amorphous silica, with
small contaminations of kaolinite. All DQ 12 samples originate from
the same source, but its particle size and composition have not been
reported recently (IARC, 1997). Furthermore, many experimental and
epidemiological studies do not state the source and properties of the
quartz that is used as a test material or collected in the workplace
(Mossman & Churg, 1998).
Additional physical and chemical properties of quartz are
presented in the International Chemical Safety Card (ICSC 0808)
reproduced in this document (Appendix 4).
3. ANALYTICAL METHODS
Mineral dust particles, such as quartz particles, are typically
described by diameter size (e.g., geometric mean diameter) and
aerodynamic diameter. Both characteristics are important in
determining whether the particle is respirable (IARC, 1997). Analysis
for airborne quartz is usually by X-ray diffraction or infrared
spectrophotometry in combination with filter collection methods
(IARC, 1997). Dust levels can be based on counts from an impinger or
on mass collected on a filter (IARC, 1997). Currently, the latter
method is more commonly used. Most countries (e.g., the USA, the
United Kingdom, Germany, Japan, and Australia) require that the sample
be restricted to the respirable fraction (IARC, 1997). The estimated
detection limit for quartz in respirable dust samples is 0.005 mg
using US National Institute for Occupational Safety and Health (NIOSH)
method 7500 (i.e., X-ray powder diffraction) (NIOSH, 1994a). The
estimated detection limit for quartz in respirable dust samples with
NIOSH method 7602 (infrared absorption spectrophotometry) is also
0.005 mg (NIOSH, 1994b).
4. SOURCES OF HUMAN AND ENVIRONMENTAL
EXPOSURE
Quartz is abundant in most rocks, sands, and soils (IARC, 1997).
The extensive natural occurrence of quartz and the wide uses of the
materials that contain quartz are directly related to potential
occupational exposures to quartz for workers in many industries and
occupations. Virtually any process that involves movement of earth
(e.g., mining, farming, construction), disturbance of
silica-containing products such as masonry and concrete, or use of
sand and other silica-containing products (e.g., foundry processes)
may potentially expose a worker to quartz (IARC, 1997).
5. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND
TRANSFORMATION
Environmental exposures to quartz can occur when ambient quartz
is emitted into the air as a component of particulate emissions
produced by natural, industrial, and farming activities
(US EPA, 1996). These activities include construction and demolition,
quarrying and mining, dust from travel on paved and unpaved roads,
electrical power generation, agricultural tilling, forest fires,
volcanic eruptions, and wind erosion (US EPA, 1996; IARC, 1997).
6. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
Ambient quartz is emitted to the environment as a component of
particulate emissions. The available data on concentrations of quartz
in the non-occupational environment (i.e., ambient air), including
data collected by the US Environmental Protection Agency (US EPA), are
limited (US EPA, 1996). The US EPA's Inhalable Particulate Network
provides a data set of quartz concentrations that were collected from
high-volume or dichotomous samples of ambient aerosols in 25 US cities
in 1980 (Davis et al., 1984). Average quartz concentrations were
highest (and most variable) in air masses in continental interior
sites. Ambient quartz concentrations collected from high-volume filter
samples of total suspended particulates in 10 US cities ranged from
0 µg/m3 (Portland, Oregon) to 15.8 µg/m3 (Akron, Ohio)
(Davis et al., 1984). Both of those findings were based on one sample
in each city (US EPA, 1996).
Non-occupational inhalation of quartz may occur while using a
variety of commercial products, such as cleansers, cosmetics,
art clays and glazes, pet litter, talcum powder, caulk, putty, paint,
and mortar (US Department of the Interior, 1992). Data representing
quantitative exposure levels of respirable quartz during
non-occupational uses of commercial products are not available.
Although quartz particles may be present in water, quantitative
data on concentrations of quartz in potable or other forms of
drinking-water are not available (IARC, 1997).
Occupational quartz dust exposure is probably one of the most
documented workplace exposures. Nearly every mineral deposit contains
some quartz (Greskevitch et al., 1992); thus, most quartz exposures
are to mixed dust with a variable quartz content that must be measured
by dust collection and analysis (Wagner, 1995). Compliance officers
for the US Occupational Safety and Health Administration measured
respirable quartz in 255 industries that were targeted for inspection,
excluding mining and agriculture. In 48% of the industries, average
overall exposure exceeded the permissible exposure level (10 mg
respirable dust/m3 divided by % silica + 2) (Freeman & Grossman,
1995).
Respirable quartz levels exceeding 0.1 mg/m3 have been reported
in many industries worldwide and are most frequently found in metal,
non-metal, and coal mines and mills; in granite quarrying and
processing, crushed stone and related industries; in foundries; in the
ceramics industry; and in construction and sandblasting operations
(IARC, 1997). IARC summarized data from the main industries for which
quantitative quartz exposure levels were available in the published
literature or where major occupational health studies were conducted
(IARC, 1997). The IARC review is condensed here and presented by
industry. Many processes in these industries include potential
exposures to other substances with known adverse health effects,
including carcinogenicity. Information about the health hazards for a
particular industry, the variability of the proportion of quartz found
in total dust samples from different industries, and the estimated
proportion of workers exposed to defined concentrations is available
elsewhere (e.g., IARC, 1984, 1987, 1997; Burgess, 1995; Linch et al.,
1998).
The mean respirable quartz level in mining operations (i.e.,
underground and surface mining, milling operations) inspected in the
USA from 1988 to 1992 was usually less than 0.10 mg/m3, but a
significant percentage of samples exceeded the permissible exposure
limit (see above) (Watts & Parker, 1995; IARC, 1997). Estimated
arithmetic mean respirable crystalline silica levels (form of
"crystalline silica" was not specified) for 1950-1959 and 1981-1987 in
20 Chinese mines (10 tungsten, 6 iron-copper, and 4 tin) decreased
about 10-fold between those periods. The estimated arithmetic mean
level of respirable silica (mg/m3) for the older period and the more
recent period, respectively, were as follows: underground mining,
4.89, 0.39; surface mining, 1.75, 0.27; ore dressing, 3.45, 0.42;
tungsten mines, 4.99, 0.46; iron and copper mines, 0.75, 0.20; and tin
mines, 3.49, 0.45 (Dosemeci et al., 1995; IARC, 1997). Respirable
quartz concentrations in underground dust from South African gold
mines ranged from 0.05 to 0.58 mg/m3 in surveys taken during
1965-1967 (Beadle & Bradley, 1970). In a copper mine in Finland, the
mean concentration of respirable quartz in the general mine air was
about 0.16 mg/m3 until 1965, 0.12 mg/m3 in 1966-1975, and 0.08
mg/m3 after 1981 (Ahlman et al., 1991).
Exposure to respirable quartz dust can occur in granite quarrying
and processing, including crushed stone and related industries.
Geometric mean air concentrations and air concentrations of quartz
from personal breathing-zone samples collected during various jobs in
the granite quarrying and processing industries and crushed stone and
related industries in Finland, the USA, and the United Kingdom ranged
from 0.03 to 1.5 mg/m3 and from not detectable to 135 mg/m3,
respectively (Donaldson et al., 1982; Eisen et al., 1984; Koskela et
al., 1987; Davies et al., 1994; Kullman et al., 1995; IARC, 1997). In
US granite quarries and sheds, control measures implemented in the
late 1930s and the 1940s resulted in 10- to 100-fold reductions of
formerly high dust levels (Davis et al., 1983; IARC, 1997).
In India, personal respirable dust levels of 0.06-1.12 mg/m3
(average 0.61 mg/m3 with a free silica content of 15%; form of silica
not specified) were generated during the manufacture of slate pencils
from natural rock. Average personal dust concentrations measured in
previous surveys in 1977 and 1982 were 10- to 100-fold higher (Fulekar
& Alam Kham, 1995; IARC, 1997).
Foundry occupations can involve exposure to quartz-containing
sands and parting powders (e.g., silica flour). The quartz content of
sands ranges from 5% to nearly 100% (IARC, 1997). Foundry occupations
with particularly high potential exposures to quartz (e.g., sand or
silica flour) are those jobs that involve sand preparation and
reclamation, knocking-out or shaking-out, cleaning of castings (i.e.,
fettling, grinding, sandblasting), and furnace and ladle refractory
relining and repair (IARC, 1997). Mean personal respirable quartz
levels in iron, steel, aluminium, brass, and other types of foundries
ranged from 0.19 to 5.26 mg/m3 in Finland (Siltanen et al., 1976;
IARC, 1997) and from 0.13 to 0.63 mg/m3 in Sweden (Gerhardsson, 1976;
IARC, 1997); in Canadian iron and steel foundries, the mean personal
respirable quartz concentration was 0.086 mg/m3 (Oudyk, 1995; IARC,
1997).
IARC presented respirable quartz dust levels for jobs in
ceramics, brick, cement, or glass industries in China (Dosemeci et
al., 1995), Italy (Cavariani et al., 1995), the Netherlands (Buringh
et al., 1990), South Africa (Myers et al., 1989; Rees et al., 1992),
the United Kingdom (Bloor et al., 1971; Fox et al., 1975; Higgins et
al., 1985), and the USA (Anderson et al., 1980; Salisbury & Melius,
1982; Cooper et al., 1993) and noted that jobs involving mixing,
moulding, glaze spraying, and finishing were associated with higher
exposure levels, often in the range of 0.1-0.3 mg/m3 (IARC, 1997). In
ceramic and pottery manufacturing facilities, exposures are mainly to
quartz, but potential exposures to cristobalite may occur where high
temperatures are used (e.g., ovens) (IARC, 1997). In refractory brick
and diatomaceous earth processing facilities, the raw materials
(amorphous or crystalline silica) are processed at temperatures near
1000°C, with varying degrees of conversion to cristobalite (IARC,
1997).
In the construction industry, drilling, sandblasting, sawing,
grinding, cleaning, and many other actions that are applied to
concrete, mortar surfaces, brick, rock, and other silica-containing
substances and products can result in the generation of a fine
airborne dust (Lofgren, 1993; Linch & Cocalis, 1994; NIOSH, 1996; IARC
1997). Concrete finishers and masons in the USA (Lofgren, 1993),
caisson workers in Hong Kong (Ng et al., 1987a), and construction site
cleaners in Finland (Riala, 1988) have had respirable quartz exposure
levels of at least 0.10 mg/m3, and some exposures were many times
higher.
Sandblasters in US steel fabrication yards were exposed to a mean
exposure of 4.8 mg/m3 of respirable free silica (type of silica not
specified). Samples were collected from the workers' breathing zones,
inside and outside protective hoods. Other yard workers had mean
respirable free silica exposures ranging from 0.06 to 0.7 mg/m3
(Samimi et al., 1974).
In the USA, average personal respirable quartz exposures ranged
from 0.02 to 0.07 mg/m3 during rice farming activities (Lawson et
al., 1995), and median airborne quartz levels during fruit harvesting
ranged from 0.007 to 0.11 mg/m3 (Popendorf et al., 1982; Stopford &
Stopford, 1995).
Exposures to respirable quartz have been noted in "miscellaneous"
operations (IARC, 1997). Studies of US waste incinerator workers
(Bresnitz et al., 1992), US wildland firefighters (Kelly, 1992;
Materna et al., 1992), and workers in Canadian silicon carbide
manufacturing plants (Dufresne et al., 1987) reported respirable
quartz levels that were generally below 0.1 mg/m3. Gemstone workers
in Hong Kong (Ng et al., 1987b), US workers involved with refuse
burning, transfer, and landfill activities (Mozzon et al., 1987), and
US maintenance-of-way railroad workers (i.e., broom operators and
ballast regulators) (Tucker et al., 1995) had exposures to respirable
quartz above 0.10 mg/m3.
7. COMPARATIVE KINETICS AND METABOLISM IN LABORATORY ANIMALS
AND HUMANS
Quartz enters the body as a particle. Usually the particle is
inhaled, and it may be deposited in the lung. Solid particulates such
as quartz are often described by size range. For example, "coarse"
particles are usually described as particles with a diameter more than
2 µm; "fine" particles are those with diameters in the range of
0.1-2.0 µm; and "ultrafine" particles are described as particles with
a diameter less than 0.1 µm. While particle size is often described as
geometric mean diameter in inhalation studies, the aerodynamic
characteristics of the particle are important, too. In humans,
inhalation of "respirable" particles involves exposure to the
particles in a mineral dust that are able to penetrate into the
alveolar spaces of the lungs. It is generally considered that
respirable particles have an aerodynamic diameter of <3-4 µm, while
most particles larger than 5 µm may be deposited in the
tracheobronchial airways and thus not reach the alveolar region (IARC,
1997). Particles deposited in the respiratory bronchioles and proximal
alveoli are cleared more slowly and are more likely to injure the
lung.
There are few data on quartz dust burdens in human lungs, and no
conclusions have been drawn about the clearance kinetics of quartz
particles in humans (IARC, 1997). It has been observed that the
deposition and clearance of quartz and other inhaled particles in
other animals vary with species (IARC, 1997; Oberdörster, 1997).
Short-term inhalation exposures (i.e., <10 days) in rats have shown
that respirable quartz particles can be deposited in the lung and
translocated into epithelial cells and to the interstitium and may
eventually accumulate in the lymph nodes (IARC, 1997). Experimental
particle inhalation studies of laboratory animals, particularly
Fischer 344 rats, have demonstrated a phenomenon known as "particle
overload," which may occur when the pulmonary defences are overwhelmed
by very high exposures (Donaldson & Borm, 1998) and which may reduce
the accuracy of linear exposure-response extrapolations to low levels
(US EPA, 1996). The implications of particle overload for non-rodent
species, such as humans, are not known, but in rats it is
characterized by the suppression of particle transport by alveolar
macrophages and the development of concurrent events such as increased
interstitial dust uptake and prolonged inflammatory response (Morrow,
1988, 1992).
8. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
The biological response to quartz particles depends on a variety
of factors. It is currently thought that the surface of the quartz
particle is of prime importance in determining its biological effects
because the surface makes contact with biological molecules and cell
surfaces (Fubini et al., 1995; Fubini, 1997; Donaldson & Borm, 1998).
Many experimental in vitro studies have investigated the surface
characteristics of crystalline silica particles, including quartz, and
their influence on fibrogenic activity and have found that a number of
features may be related to cytotoxicity (Fubini et al., 1995;
Bolsaitis & Wallace, 1996; Castranova et al., 1996; Fubini, 1997,
1998; Donaldson & Borm, 1998; Erdogdu & Hasirci, 1998). Some factors
are inherent to the quartz particle itself (e.g., particle size,
micromorphology, external surface defects, origin of the sample,
thermal treatments, and grinding, ball milling, or etching of the
particles), while other factors are external (e.g., contact,
association, contamination, or coating by substances other than
quartz) (Iler, 1979; Fubini, 1998). It has been suggested that
intimate contact between quartz and carbon or metals could modify the
nature of the surface sites (Fubini, 1998) and thus affect the
biological response to quartz. Freshly fractured surfaces are more
reactive than aged ones (IARC, 1997). Further research is needed to
associate the surface characteristics with occupational exposure
situations and health effects (Donaldson & Borm, 1998; NIOSH,
forthcoming), such as work processes that produce freshly fractured
silica surfaces (Vallyathan et al., 1995; Bolsaitis & Wallace, 1996)
or where quartz may be contaminated with trace elements such as iron
(Castranova et al., 1997). There is also a need for experimental
studies to fully describe the sources and properties of quartz in
products used in experimental studies (Mossman & Churg, 1998).
Experimental studies of the effects of other forms of crystalline
silica, such as cristobalite, tridymite, stishovite, and coesite, as
well as coal dust, diatomaceous earth, and amorphous silica, are not
discussed because their in vitro toxicities differ from that of
quartz (Parkes, 1982; Wiessner et al., 1988; Driscoll, 1995; Fubini et
al., 1995; Donaldson & Borm, 1998; Hart & Hesterberg, 1998).
Differences in induction of fibrogenicity of quartz, cristobalite, and
tridymite were demonstrated in vivo in an early rat study (King et
al., 1953).
8.1 Single exposure
No useful data are available on lethal doses of quartz in
experimental animals.
8.2 Short-term exposure
Evidence of cellular proliferation and 3-fold (or higher)
increases in the water, protein, and phospholipid content of male rat
lungs were observed within 28 days after a single 50-mg intratracheal
injection of quartz (i.e., Min-U-Sil with particle diameter less than
5 µm) (Dethloff et al., 1986a,b; Hook & Viviano, 1996). Discrete
silicotic granulomas were observed in rats (both sexes) 21-30 days
after administration of a single intratracheal instillation of 12 mg
of quartz (Min-U-Sil; particle size <5 µm in diameter)
(Saffiotti et al., 1996). When the same research team administered a
single intratracheal instillation of 10 mg of quartz (Min-U-Sil;
particle size <5 µm in diameter) to male mice, the histopathological
changes were not as pronounced on day 30 as in the experimental rats,
but silicotic nodules and some fibrosis were present
(Saffiotti et al., 1996). However, hamsters at the same facility had
silicotic granulomas, but not fibrosis or epithelial reactions,
30 days after a single intratracheal instillation of 20 mg of quartz
(Min-U-Sil; particle size <5 µm in diameter) (Saffiotti et al.,
1996).
A short-term inhalation bioassay of the pulmonary toxicity of
aerosolized quartz particles (Berkeley Min-U-Sil(R) particles with
mass median aerodynamic diameter of 3.7 µm; particle size range not
reported) in rats found that brief exposure produced a persistent
pulmonary inflammatory response and impairment of alveolar macrophage
clearance functions (Warheit & Hartsky, 1997). Progressive lesions
were observed within 1 month after a 3-day (6 h per day) aerosolized
quartz exposure of 100 mg/m3. Two months after exposure, the lesions
had progressed and developed into a multifocal, granulomatous-type
pneumonitis. Rats with a 3-day exposure (6 h per day) to 100 mg
carbonyl iron particles/m3 (negative controls) had no cellular,
cytotoxic, or membrane permeability changes at any time after exposure
(Warheit & Hartsky, 1997).
Silica-induced apoptosis (i.e., programmed cell death) was
observed in three in vivo experiments with 60 (Leigh et al., 1998a)
or 20 (Leigh et al., 1997; Wang et al., 1997a) male Wistar rats that
were divided into groups of equal size and intratracheally instilled
with 0.5 ml saline as a control or doses of Min-U-Sil 5 quartz
suspended in 0.5 ml saline and ranging from 2.5 to 22.5 mg per group.
Apoptotic cells were observed among lavaged cells (both alveolar and
granulomatous) at various time periods, ranging from 1 to 56 days
after instillation. The proportion of apoptotic cells generally
appeared to increase with increasing quartz dose (Leigh et al., 1997),
and it was proposed that apoptosis and subsequent engulfment of
apoptotic cells by macrophages may be involved in the silica-induced
inflammatory response, both acutely and chronically (Leigh et al.,
1997; Wang et al., 1997a).
8.3 Long-term exposure and carcinogenicity
Several end-points have been selected to measure the fibrogenic
potential of quartz in animals: pulmonary toxicity, lung weight,
development of fibrous tissue, collagen content, cytotoxicity, and
biochemical changes in the lungs (US EPA, 1996; Gift & Faust, 1997).
Table 1 presents critical non-cancer effects found in subchronic and
chronic quartz inhalation studies of rats and mice (US EPA, 1996; Gift
& Faust, 1997). All studies showed either fibrosis, increased
collagen, and increased elastin content of lungs or impaired
phagocytic ability of alveolar macrophages. (Table 1 also presents
estimates of human equivalent concentrations [HECs] for environmental
exposures, which are discussed in section 11.1.1.)
Tests of the carcinogenicity of quartz by different routes of
exposure have been conducted. Different quartz specimens (i.e.,
Min-U-Sil 5, Novaculite, DQ 12, hydrogen fluoride-etched Min-U-Sil 5,
Min-U-Sil with polyvinylpyridine- N-oxide, DQ 12 with
polyvinylpyridine- N-oxide, and Sikron F-300 quartz) with particle
sizes in the respirable range were tested in five experiments with
rats by inhalation (Holland et al., 1983, 1986; Dagle et al., 1986;
Muhle et al., 1989, 1991, 1995; Reuzel et al., 1991; Spiethoff et al.,
1992) and in four experiments with rats by intratracheal instillation
(Holland et al., 1983; Groth et al., 1986; Saffiotti, 1990, 1992;
Pott et al., 1994; Saffiotti et al., 1996). The results of these
experiments and others are summarized in Tables 2-4. Significant
increases in the incidence of adenocarcinomas and squamous cell
carcinomas of the lung were found in eight of the nine experiments.
Marked, dense pulmonary fibrosis was part of the response
(IARC, 1997). (The IARC Working Group noted that the experiment by
Reuzel et al. [1991], in which only one respiratory tract tumour was
observed, had a short duration and lacked information on survival;
in addition, only a small proportion of the quartz particles was
respirable by rats.) (Note: Level of statistical significance of
tumour incidence in treated animals compared with control animals was
reported only by Groth et al. [1986]. P-value was less than 0.001
for their Min-U-Sil 5 and Novaculite experiments.)
Although pulmonary granulomatous inflammation and slight to
moderate fibrosis of the alveolar septa were observed in three
experiments on hamsters that used repeated intratracheal instillation
of quartz dusts, no pulmonary tumours were observed (Holland et al.,
1983; Renne et al., 1985; Niemeier et al., 1986).
In experiments with mice, no statistically significant increase
was seen in the incidence of lung tumours in a strain A mouse (i.e.,
male A/J mice from Jackson Laboratories, Bar Harbor, ME, USA) lung
adenoma assay with one sample of quartz (McNeill et al., 1990) or with
a sample of quartz in a limited inhalation study of BALB/cBYJ female
mice (Wilson et al., 1986). Fibrosis was not observed; however, the
lungs of quartz-treated mice did have silicotic granulomas, and
lymphoid cuffing was observed around airways (IARC, 1997).
Thoracic and abdominal malignant lymphomas, primarily of the
histiocytic type, were found in several studies in rats using single
intrapleural or intraperitoneal injection of suspensions of several
types of quartz (Wagner & Berry, 1969; J.C. Wagner, 1970; Wagner &
Wagner, 1972; M.M.F. Wagner, 1976; Wagner et al., 1980;
Jaurand et al., 1987; IARC, 1997).
It is important to note the species differences observed in the
tumour response to quartz particles. In rats, quartz is clearly
carcinogenic, but there is less or no malignant tumour response in
mice and hamsters (Donaldson & Borm, 1998). Particle-induced lung
tumours have been noted in rats, but not to the same degree in mice or
hamsters (IARC, 1997). Currently, there is a limited understanding of
the mechanisms of quartz toxicity, including mechanisms of the rat
lung response (IARC, 1997). Several mechanisms for the carcinogenicity
of quartz in rats have been proposed, included the hypothetical
inflammation-based mechanism (Figure 1; IARC, 1997). The rat model is
the best model currently available for studying the effects of quartz,
because it demonstrates the carcinogenic response observed in some
human studies (Donaldson & Borm, 1998).
8.3.1 Interaction with other compounds
Other tests of carcinogenicity have been conducted using mixtures
of quartz with known carcinogens. When aerosol concentrations of
quartz (Dörentrup DQ 12) were administered by inhalation to rats for
29 days and followed by a single intravenous injection of Thorotrast
(an alpha-radiation-emitting material) at the end of the inhalation
period, there was a pronounced interactive effect of Thorotrast with
quartz (DQ 12) that included the occurrence of tumours in the lung
(i.e., bronchioloalveolar adenomas, bronchioloalveolar carcinomas, and
squamous cell carcinomas), liver, and spleen (Spiethoff et al., 1992;
IARC, 1997). In experiments with hamsters, benzo[ a]pyrene with
quartz and ferric oxide with quartz were administered by intratracheal
instillation. No pulmonary tumours were observed in hamsters given
mixtures of quartz and ferric oxide (1 : 1) (Niemeier et al., 1986).
However, the number of respiratory tract tumours in hamsters given
Min-U-Sil quartz and benzo[ a]pyrene or Sil-Co-Sil and
benzo[ a]pyrene was significantly higher (P < 0.01) than the
number found in hamsters that received saline and benzo[ a]pyrene
(Niemeier et al., 1986).
Table 1: Human equivalent concentrations (HECs) for environmental exposures and non-cancer and
non-tumour effects for LOAELsa reported in subchronic (<3 months) and chronic quartz inhalation
studies in experimental animals.b
Species, strain, Exposure, dose, LOAEL(mg/m3) LOAELHECc
number, sex duration (mg/m3) Critical effect Reference
Rat 1 mg/m3 of DQ 12 1 0.18 Subpleural and Muhle et al., 1989
Fischer 344 for 6 h/day, 5 peribronchial
50/sex days/week, for fibrosis, focal
24 months lipoproteinosis
cholesterol clefts,
enlarged lymph
nodes, and
granulomatous
lesions in the
walls of large bronchi;
doubling of lung
collagen content.
(Quantitative data were
not reported for these
effects.)
Mouse 2 mg/m3 of 2 0.36 Suppressed response to Scheuchenzuber
BALB/c Min-U-Sil aerosol of Escherichia et al., 1985
Female for 8 h/day, coli (i.e., formation
5 days/week, of plaque-forming cells
for 150, 300, in spleen) at 150, 300,
or 570 days and 570 days; reduced
ability of alveolar
macrophages to
phagocytize
Staphylococcus aureus
at 570 days; reduced
T-lymphocyte-mediated
cytolysis of allogeneic
tumour cells at 185 days.
Table 1 (cont'd)
Species, strain, Exposure, dose, LOAEL(mg/m3) LOAELHECc
number, sex duration (mg/m3) Critical effect Reference
Mouse 4932.4 + 235.4 5 0.90 Suppressed response to Burns et al., 1980
BALB/c µg/m3 of Min-U-Sil aerosol of Escherichia
Female 5 for 6 h/day, coli (i.e., formation of
5 days/week, for plaque-forming cells in
3, 9, 15, 27, spleen) at 15, 27, 33,
33, or 39 weeks and 39 weeks; increased
spleen/body ratios at
15, 21, and 27 weeks;
induced pulmonary fibrosis
(fibrotic nodules of
collagen, fibroblasts,
lymphocytes,
silica-filled
macrophages) at 39 weeks.
Rat 0, 2, 10, or 20 2 0.36 Increased collagen and Drew & Kutzman,
Fischer 344 mg/m3 of Min-U-Sil elastin content of lungs; 1984b
Both sexes 5 for 6 h/day, caused birefringent
5 days/week, for crystals in foamy
6 months cytoplasm of macrophages
that had accumulated in
end airway luminal
spaces; induced Type II
cell hyperplasia in
alveolar compartment and
intralymphatic
microgranulomas around
bronchioles in some
animals. Quartz-dependent
increases in collagen and
elastin were 110%, 111%,
and 116% for collagen
Table 1 (cont'd)
Species, strain, Exposure, dose, LOAEL(mg/m3) LOAELHECc
number, sex duration (mg/m3) Critical effect Reference
(as hydroxyproline) and
102%, 109%, and 109% for
elastin, respectively, for
each exposure group
relative to controls
(US EPA, 1996).
Rat 0, 2, 10, or 2 0.36 Increased weight and Drew & Kutzman,
Fischer 344 20 mg/m3 collagen, elastin, 1984a
Both sexes of Min-U-Sil 5 deoxyribonucleic acid,
for 6 h/day, and protein content of
5 days/week, lungs (particularly at
for 6 months, higher exposures of 10
plus 6-month and 20 mg/m3),
incubation period indicating continued
tissue proliferation and
fibrogenesis during
incubation; increased
number of silica
particles and
inflammation at end
airways, focal fibrosis
and intralymphatic
granulomata, and overall
severity and frequency of
lesions. Alveolar
proteinosis observed in
the 20 mg/m3 group.
Quartz increases in
collagen and elastin
were 116%, 128%, and
Table 1 (cont'd)
Species, strain, Exposure, dose, LOAEL(mg/m3) LOAELHECc
number, sex duration (mg/m3) Critical effect Reference
136% for collagen (as
hydroxyproline) and 107%,
119%, and 130% for
elastin, respectively,
for each exposure group
relative to controls
(US EPA, 1996).
a LOAEL = lowest-observed-adverse-effect level. No-observed-adverse-effect levels (NOAELs) were not reported.
b Adapted from Gift & Faust (1997).
c HEC calculated using methods described in US EPA (1994) and summarized in section 11.1.1.
Table 2: Summary of data on lung tumours induced in rats by quartz.a
Incidence of lung tumoursb
Treatment sample Exposure conditions Rat strain Sex Treated Controls Reference
Quartz Intratracheal instillation Sprague-Dawley not 6/36c 0/58 Holland
(Min-U-Sil 5) (suspended in 0.2 ml saline) reported et al., 1983
of 7 mg weekly for 10 weeks
Inhalation (nose only), Fischer 344 F 20/60d 0/54 Holland
12 + 5 mg/m3 for up to 2 years et al., 1986
Inhalation of 51.6 mg/m3 for Fischer 344 F 10/53e 0/47 Dagle et al.,
various durations; sacrificed M 1/47f 0/42 1986
at 24 months
Intratracheal instillation Fischer 344 M 30/67g 1/75h Groth et al.,
(volume of suspension not 1986
reported) of 20 mg in left
lung, sacrificed at 12, 18,
or 22 months or found dead
Novaculite Intratracheal instillation Fischer 344 M 21/72i 1/75h Groth et al.,
(i.e., of 20 mg (volume of 1986
microcrystalline suspension not reported)
quartz) in left lung, sacrificed at
12, 18, or 22 months or
found dead
Quartz (DQ 12) Inhalation of 1 mg/m3 Fischer 344 F 12/50j 3/100k (male Muhle et al.,
for 24 months M 6/50l and female) 1989
Inhalation (nose only) of Wistar F 62/82m 0/85 Spiethoff
6 mg/m3 for 29 days, followed et al., 1992
by lifetime observation
Table 2 (cont'd)
Incidence of lung tumoursb
Treatment sample Exposure conditions Rat strain Sex Treated Controls Reference
Inhalation (nose only) of Wistar F 69/82n 0/85 Spiethoff
30 mg/m3 for 29 days, et al., 1992
followed by lifetime
observation
Quartzo (Sikron Inhalation of 58.5 + 0.7 mg/m3, Wistar F 1/70p 0/70 Reuzel
F300 from Quartz 6 h/day, 5 days/week, M 0/70 0/70 et al., 1991
Werke, Frechen, for 13 weeks
Germany)
a Adapted from Saffiotti et al. (1996); IARC (1997).
b Number of lung tumours per number of rats observed.
c One adenoma and five carcinomas.
d Six adenomas, 11 adenocarcinomas, and three epidermoid carcinomas.
e All epidermoid carcinomas.
f One epidermoid carcinoma.
g All adenocarcinomas.
h One adenocarcinoma.
i Twenty adenocarcinomas and one epidermoid carcinoma.
j Two keratinizing cystic squamous cell tumours, two adenomas, and eight adenocarcinomas.
k Two adenomas and one adenocarcinoma.
l Two keratinizing cystic squamous cell tumours, two adenocarcinomas, one adenosquamous carcinoma,
and one epidermoid carcinoma.
m Eight adenomas, 17 bronchioloalveolar carcinomas, and 37 squamous cell carcinomas.
n Three adenomas, 26 bronchioloalveolar carcinomas, and 30 squamous carcinomas.
o IARC Working Group noted that only a small proportion of particles were respirable in rats.
p One squamous cell carcinoma, 1 year after the end of the exposure period.
Table 3: Lung tumours induced in Fischer 344 rats by a single intratracheal instillation of quartz.a
Treatment Treatment Sex Observation Incidence of Total number of Histological
sample doseb time lung tumoursc lung tumoursd types
Untreated None M Died after 0/32 0
17 months
None F Died after 1/20 (5%) 1 1 adenoma
17 months
Quartz 12 mg M Sacrificed 3/18 (17%) 37 6 adenomas,
(Min-U-Sil 5) 11 months 25 adenocarcinomas,
1 undifferentiated
Sacrificed 6/19 (32%) carcinoma, 2 mixed
17 months carcinomas, and 3
epidermoid
Died after 12/14 (86%) carcinomas
17 months
12 mg F Sacrificed 8/19 (42%) 59 2 adenomas,
11 months 46 adenocarcinomas,
3 undifferentiated
Sacrificed 10/17 (59%) carcinomas, 5 mixed
17 months carcinomas, and
3 epidermoid
Died after 8/9 (89%) carcinomas
17 months
20 mg F Died after 6/8 (75%) 13 1 adenoma, 10
17 months adenocarcinomas, 1 mixed
carcinoma, and 1 epidermoid
carcinoma
Table 3 (cont'd)
Treatment Treatment Sex Observation Incidence of Total number of Histological
sample doseb time lung tumoursc lung tumoursd types
Quartz 12 mg M Sacrificed 2/18 (11%) 20 5 adenomas,
(hydrogen 11 months 14 adenocarcinomas,
fluoride-etched and 1 mixed carcinoma
Min-U-Sil 5) Sacrificed 7/19 (37%)
17 months
Died after 7/9 (78%)
17 months
12 mg F Sacrificed 7/18 (39%) 45 1 adenoma,
11 months 36 adenocarcinomas,
3 mixed carcinomas,
Sacrificed 13/16 (81%) and 5 epidermoid
17 months carcinomas
Died after 8/8 (100%)
17 months
a From Saffiotti et al. (1993, 1996).
b As mg quartz suspended in 0.3 ml saline.
c Number of rats with lung tumours per number of rats observed.
d At all observation times.
Table 4: Incidence of lung tumours in female Wistar rats after intratracheal instillation of quartz.a
Number and percentage of rats with primary epithelial lung tumoursb
Material Surface Number of Number of Adenoma Adenocarcinoma Benign Squamous Total Other
area instillations rats CKSCTd cell (%) tumourse
(m2/g) (× mg)c examined carcinoma
Quartz
(DQ 12) 9.4 15 × 3 37 0 1z 11 1 + 1y 38 1
Quartz
(DQ 12) + PVNOf 9.4 15 × 3 38 0 1 + 3z 8 + 1x 4 + 1x + 3y + 1z 58 2
Quartz
(DQ 12) 9.4 1 × 45 40 0 1 7 1 23 2
Quartz
(Min-U-Sil) 15 × 3 39 1 4 + 4z 6 1 + 2y + 2z + 1y,z 54 3
Quartz
(Min-U-Sil)
+ PVNO 15 × 3 35 1 2 + 1x 8 5 + 1x + 1y + 1z 57 3
Quartz
Sykron (F600) 3.7 15 × 3 40 0 3 5 3 + 1z 30 1
0.9% sodium
chloride - 15 39 0 0 0 0 0 5
a From Pott et al. (1994); IARC (1997).
b If an animal was found to bear more than one primary epithelial lung tumour type, this was indicated as follows: x adenoma;
y adenocarcinoma; z benign CKSCT.
c Dusts were suspended in 0.9% sodium chloride solution with ultrasonication for 1-5 min.
d CKSCT, cystic keratinizing squamous cell tumour.
e Other types of tumours in the lung: fibrosarcoma, lymphosarcoma, mesothelioma or lung metastases from tumours at other sites
f PVNO, polyvinylpyridine-N-oxide; PVNO was administered subcutaneously in seven injections of 2 ml each of 2% PVNO in saline.
No PVNO control group was included.
8.4 Genotoxicity and related end-points
Although silica (form not specified) has not tested positive in
standard bacterial mutagenesis assays (IARC, 1987, 1997; Rabovsky,
1997), chromosomal changes, including DNA damage, have been observed
in experimental systems, both in vitro and in vivo. (Study results
are presented in Table 5.) Although the results of some studies
(Daniel et al., 1993, 1995; Saffiotti et al., 1993; Shi et al., 1994)
demonstrated that quartz caused damage (i.e., strand breakage) to
isolated DNA in acellular systems, the IARC Working Group (IARC, 1997)
stated that the relevance of these assays to assess quartz-related
genetic effects in vivo was "questionable." Uncertainties existed
because the non-physiological experimental conditions did not apply to
intracellular silica exposure and because very high doses of silica
were used in the DNA breakage assays (IARC, 1997). However, a recent
study not included in the IARC review found that by using the alkaline
single cell gel/comet assay, crystalline silica (Min-U-Sil 5) induced
DNA damage (i.e., DNA migration) in cultured Chinese hamster lung
fibroblasts (V79 cells) and human embryonic lung fibroblasts (Hel 299
cells) at concentrations ranging from 17.2 to 103.4 µg/cm2 (Zhong et
al., 1997). Since the time of the IARC review, Liu et al. (1996, 1998)
applied experimental conditions (i.e., Chinese hamster lung
fibroblasts challenged with dusts pretreated with a phospholipid
surfactant) to simulate the condition of particles immediately after
deposition on the pulmonary alveolar surface. Results of the
experiments showed that untreated Min-U-Sil 5 and Min-U-Sil 10 induced
micronucleus formation in a dose-dependent manner, but surfactant
pretreatment suppressed that activity (Liu et al., 1996). A subsequent
experiment found that surfactant pretreatment suppressed
quartz-induced DNA damage in lavaged rat pulmonary macrophages, but
DNA-damaging activity was restored with time as the phospholipid
surfactant was removed by intercellular digestion (Liu et al., 1998).
In vitro cellular transformation systems model the in vivo
process of carcinogenesis (Gu & Ong, 1996; Gao et al., 1997). The
ability of quartz to induce dose-dependent morphological
transformation of cells in vitro has been demonstrated in
experiments with Syrian hamster embryo cells (Hesterberg & Barrett,
1984) and mouse embryo BALB/c-3T3 cells (Saffiotti & Ahmed, 1995). Gu
& Ong (1996) also reported a significant increase in the frequency of
transformed foci of mouse embryo BALB/c-3T3 cells after treatment with
Min-U-Sil 5 quartz. These studies indicate that quartz can
morphologically transform mammalian cells. However, further studies
are needed to determine whether the transforming activity of quartz is
related to its carcinogenic potential.
Table 5: Genetic and related effects of silica.a
Test system Resultb Dose Reference
(LED/HID)c
DNA strand breaks, gamma-HindIII-digested DNA + 30 000d Daniel et al., 1993
DNA strand breaks, herring sperm genomic DNA + 10 000d Daniel et al., 1993
DNA strand breaks, gamma-HindIII-digested DNA + 9 500d Daniel et al., 1995
DNA strand breaks, PM2 supercoiled DNA + 9 500d Daniel et al., 1995
GIA, Gene mutation, hprt locus, rat RLE-6TN
alveolar epithelial cells in vitro - NG Driscoll et al., 1997
SIC, Sister chromatid exchange,
Chinese hamster V79-4 cells in vitro - 15e Price-Jones et al., 1980
SHL, Sister chromatid exchange, human lymphocytes in vitro - 100d Pairon et al., 1990
SIH, Sister chromatid exchange, human lymphocytes
and monocytes in vitro - 100d Pairon et al., 1990
MIA, Micronucleus test, Syrian hamster embryo cells in vitro - 18.75f Oshimura et al., 1984
MIA, Micronucleus test, Syrian hamster embryo cells in vitro + 70e Hesterberg et al., 1986
MIA, Micronucleus test, Chinese hamster lung fibroblasts
(V79) in vitro + 200g Nagalakshmi et al., 1995
CIC, Chromosomal aberrations, Chinese hamster lung
fibroblasts (V79) in vitro - 1 600g Nagalakshmi et al., 1995
CIS, Chromosomal aberrations, Syrian hamster embryo
cells in vitro - 18.75f Oshimura et al., 1984
Table 5 (cont'd)
Test system Resultb Dose Reference
(LED/HID)c
AIA, Aneuploidy, Chinese hamster lung cells (V79-4) in vitro - 15e Price-Jones et al., 1980
AIA, Aneuploidy, Syrian hamster embryo cells in vitro - 18.75f Oshimura et al., 1984
AIA, Tetraploidy, Syrian hamster embryo cells in vitro - 70e Hesterberg et al., 1986
TBM, Cell transformation, BALB/3T3/31-1-1 mouse cells in vitro + 30d,h,i Saffiotti & Ahmed, 1995
TBM, Cell transformation, BALB/3T3/31-1-1 mouse cells in vitro + 60j,k Saffiotti & Ahmed, 1995
TCS, Cell transformation, Syrian hamster embryo cells in vitro + 18e Hesterberg & Barrett, 1984
TCS, Cell transformation, Syrian hamster embryo cells in vitro + 70f Hesterberg & Barrett, 1984
TCL, Cell transformation, fetal rat lung epithelial cells
in vitro (+) NGd Williams et al., 1996
MIH, Micronucleus test, human embryonic lung (Hel 299)
cells in vitro + 800g Nagalakshmi et al., 1995
CIH, Chromosomal aberrations, human embryonic lung
(Hel 299) cells in vitro - 1 600g Nagalakshmi et al., 1995
DVA, 8-hydroxy-2'-deoxyguanosine DNA extract from
lung tissue, male Wistar rats + 50 × 1 itd Yamano et al., 1995
DVA, 8-hydroxy-2'-deoxyguanosine DNA extract from
peripheral blood leukocytes, male Wistar rats - 50 × 1 itd Yamano et al., 1995
GVA, Gene mutation, hprt locus, rat alveolar
epithelial cells in vivo + 100 × 1 it Driscoll et al., 1995
Table 5 (cont'd)
Test system Resultb Dose Reference
(LED/HID)c
GVA, Gene mutation, hprt locus, rat alveolar
epithelial cells in vivo + 5 × 2 it Driscoll et al., 1997
MVM, Micronucleus test, albino mice in vivo - 500 ip Vanchugova et al., 1985
SLH, Sister chromatid exchange, human lymphocytes in vivo + NG Sobti & Bhardwaj, 1991
CLH, Chromosomal aberrations, human lymphocytes in vivo + NG Sobti & Bhardwaj, 1991
BID, Calf thymus DNA binding in vitro + 200l Mao et al., 1994
ICR, Metabolic cooperation using 8-azaguanine-resistant
cells, Chinese hamster lung cells (V79-4) in vitro - 50 Chamberlain, 1983
a Source: IARC (1997). See Appendix 1 of IARC (1997), Test system code words, for definitions of
the abbreviations used in column 1.
b Results without exogenous metabolic system: +, positive; (+), weakly positive; -, negative.
c LED, lowest effective dose; HID, highest ineffective dose; in vitro tests, µg/ml; in vivo tests,
mg/kg body weight per day; NG, not given; it, intratracheal; ip, intraperitoneal.
d Min-U-Sil 5.
e Min-U-Sil unspecified.
f alpha-Quartz.
g Min-U-Sil 5 and Min-U-Sil 10.
h Min-U-Sil 5, hydrofluoric acid-etched.
i A Chinese standard quartz sample.
j DQ 12, a standard German quartz sample.
k F600 quartz.
l Min-U-Sil 5 or Chinese standard quartz.
Some studies have demonstrated the ability of quartz to induce
micronuclei in mammalian cells in culture (i.e., Oshimura et al.,
1984; Hesterberg et al., 1986; Nagalakshmi et al., 1995) and were
reviewed by IARC (Table 5). However, other in vitro studies did not
observe chromosomal aberration (Oshimura et al., 1984;
Nagalakshmi et al., 1995), hprt (hypoxanthine-guanine phosphoribosyl
transferase) gene mutation (Driscoll et al., 1997), or aneuploid or
tetraploid cells (Price-Jones et al., 1980; Oshimura et al., 1984;
Hesterberg et al., 1986).
Pairon et al. (1990) tested quartz (i.e., Min-U-Sil 5) particles
for their ability to induce a significant number of sister chromatid
exchanges in cultures of human lymphocytes plus monocytes or of human
purified lymphocytes. The results were not "clear cut" for any of the
three doses tested (i.e., 0.5, 5.0, and 50 µg/cm2) (Pairon et al.,
1990) (Table 5).
An in vivo treatment of rats with quartz induced mutation in
rat alveolar epithelial cells (Table 5) (Driscoll et al., 1995, 1997).
Nehls et al. (1997) reported results of tests for DNA modifications by
quartz that were not reviewed by IARC (1997). Quartz (2.5 mg of DQ 12
suspended in 0.5 ml of physiological saline) or corundum (2.5 mg), a
non-carcinogenic particle, was intratracheally instilled into the
lungs of Wistar rats (10 rats per exposure and per time period).
Control animals were exposed to saline solution or not treated. Rats
were sacrificed 7, 21, and 90 days after treatment, then lung tissue
sections were analysed with immunocytological assay to determine the
level of 8-hydroxydeoxyguanosine in DNA extracts. Reactive oxygen
species can induce 8-hydroxydeoxyguanosine and other mutagenic DNA
oxidation products, which may be converted to mutations in
proliferating cells (Nehls et al., 1997). Exposure to quartz induced
levels of 8-hydroxydeoxyguanosine in the DNA of alveolar lung cells
that were significantly higher (P-value not reported) at all time
points than levels found in cells of untreated rats or rats treated
with corundum or saline. The number of total cells in bronchoalveolar
lavage fluid was 3-4 times higher in the quartz-treated groups at all
time points than in corundum-exposed rats and control rats exposed to
saline.
Other in vivo studies not reviewed by IARC (1997) found that
quartz induced micronuclei in pulmonary alveolar macrophages of male
Wistar rats in a time-dependent (Leigh et al., 1998b) and
dose-dependent manner (Wang et al., 1997b).
In summary, results of genotoxicity studies of quartz conflict,
and a direct genotoxic effect for quartz has not been confirmed or
ruled out.
8.5 Reproductive and developmental toxicity
There are no data available on the reproductive or developmental
effects of quartz in laboratory animals (IARC, 1997).
8.6 Immunological and neurological effects
Data on the neurological effects of quartz have not been
identified. In vitro studies have shown that quartz can stimulate
release of cytokines and growth factors from macrophages and
epithelial cells, and there is evidence that these events may occur
in vivo and contribute to disease (IARC, 1997). The immunological
response to quartz in experimental animals is a complex subject with
uncertain implications for humans, and detailed reviews are available
elsewhere (i.e., Davis, 1991, 1996; Haslam, 1994; Heppleston, 1994;
Weill et al., 1994; Driscoll, 1996; Gu & Ong, 1996; Hook & Viviano,
1996; Iyer & Holian, 1996; Kane, 1996; Sweeney & Brain, 1996;
Weissman et al., 1996; Mossman & Churg, 1998).
9. EFFECTS ON HUMANS
9.1 Case reports
There are many published case reports of adverse health effects
from occupational exposure to quartz. These health effects include
silicosis (acute and chronic) and lung cancer. Case reports of
silicosis and lung cancer are not mentioned further, because these
diseases have been researched in depth in epidemiological studies
(section 9.2).
There are numerous published case reports of several autoimmune
disorders in workers or patients who had been occupationally exposed
to crystalline silica, including quartz dust (NIOSH, forthcoming). The
most frequently noted autoimmune diseases in those reports were
scleroderma, systemic lupus erythematosus (i.e., lupus), rheumatoid
arthritis, autoimmune haemolytic anaemia (Muramatsu et al., 1989), and
dermatomyositis or dermatopolymyositis (Robbins, 1974; Koeger et al.,
1991). Case reports have also described health effects that may be
related to the immunological abnormalities observed in patients with
silicosis, such as chronic renal disease (Saita & Zavaglia, 1951;
Giles et al., 1978; Hauglustaine et al., 1980; Bolton et al., 1981;
Banks et al., 1983; Slavin et al., 1985; Bonnin et al., 1987;
Osorio et al., 1987; Arnalich et al., 1989; Sherson & Jorgensen, 1989;
Dracon et al., 1990; Pouthier et al., 1991; Rispal et al., 1991;
Neyer et al., 1994; Wilke et al., 1996), ataxic sensory neuropathy
(Tokumaru et al., 1990), chronic thyroiditis (Masuda, 1981),
hyperthyroidism (i.e., Graves' disease) (Koeger et al., 1996),
monoclonal gammopathy (Fukata et al., 1983, 1987; Aoki et al., 1988),
and polyarteritis nodosa (Arnalich et al., 1989).
9.2 Epidemiological studies
9.2.1 Silicosis
Most, if not all, of the several hundred epidemiological studies
of exposure to quartz dust are studies of occupational cohorts. The
majority of studies investigated the occurrence of silicosis morbidity
or mortality. These studies have conclusively linked occupational
quartz dust exposure with silicosis. Silicosis (i.e., nodular
pulmonary fibrosis) is a fibrotic lung disease, sometimes
asymptomatic, that is caused by the inhalation and deposition of
respirable crystalline silica particles (i.e., particles <10 µm in
diameter) (Ziskind et al., 1976; IARC, 1987).
A worker may develop one of three types of silicosis, depending
on the airborne concentration of respirable crystalline silica: (1)
chronic silicosis, which usually occurs after 10 or more years of
exposure at relatively low concentrations; (2) accelerated silicosis,
which develops 5-10 years after the first exposure; or (3) acute
silicosis, which develops after exposure to high concentrations of
respirable crystalline silica and results in symptoms within a few
weeks to 4 or 5 years after the initial exposure (Ziskind et al.,
1976; Peters, 1986; NIOSH, 1992a,b, 1996). Acute silicosis is a risk
for workers with a history of high exposures from performing
occupational processes that produce small particles of airborne dust
with a high silica content, such as during sandblasting, rock
drilling, or quartz milling, or any other process with high exposures
to small particles of airborne dust with a high quartz content
(Davis, 1996).
A recent study of 67 paraffin-embedded lung tissue samples from
silicotic patients found a significant linear relationship
(P <0.001) between lung quartz concentration and silicosis severity in
gold miners; although several types of mineral particles were found in
the lungs, quartz was the only significant indicator of silicosis
severity. The silicosis cases included 39 patients without lung cancer
and 28 patients with lung cancer. All of the cases were gold miners in
Canada (Dufresne et al., 1998a,b).
The epidemiological studies of silicosis usually define the
profusion of small opacities present in the disease according to a
standard system used by trained readers and developed by the
International Labour Organization for classification of chest
radiographs of pneumoconioses (ILO, 1980). Each reader assesses the
profusion according to a 12-point scale of severity. Categories 0/-
and 0/0 are the first and second points on the scale and represent a
normal chest radiograph. The third point, category 0/1, represents the
borderline between normality and abnormality, and category 1/0, the
fourth point, represents definite, but slight, abnormality
(Love et al., 1994). The shape (rounded or irregular) and size of the opacities
can also be described by the readers.
The critical studies of chronic silicosis, a progressive disease,
are those occupational epidemiological studies where (1) quantitative
quartz exposure data were available and used for risk analysis,
(2) exposure-response relationships were investigated, or (3) the
exposure-response relationships were documented with sufficient detail
for a health effects benchmark, including (4) application of data to
mathematical models that predicted silicosis prevalence at increasing
concentrations of cumulative quartz exposure. (The predicted
prevalences reported in the studies are discussed in section 11.1.3.)
Studies that selected workers from a broad spectrum of occupations and
included many workers that were exposed to different combinations of
various minerals, such as studies of "dusty trades" workers
(i.e., Rice et al., 1986), were excluded from consideration for risk
assessment of quartz and silicosis. Epidemiological studies that
provided evidence of an exposure-response relationship for silica and
silicosis based on other kinds of exposure data (e.g., there is a
positive relationship between development of chronic silicosis and
duration of exposure) have been reviewed elsewhere (WHO, 1986;
Goldsmith, 1994; Hughes, 1995; Rice & Stayner, 1995; Seaton, 1995;
Steenland & Brown, 1995a; Davis, 1996; US EPA, 1996).
The two critical cross-sectional studies (i.e., Kreiss & Zhen,
1996; Rosenman et al., 1996 -- see Table 6) found that the prevalence
of radiographic silicosis (ILO category >1/0 or >1/1) was
dose-related. That is, the prevalence of radiographic silicosis
increased with average silica dust exposure, cumulative quartz
exposure, duration of employment, or all of these measures. The actual
prevalences varied greatly among the studies, and conclusions
concerning quartz dust concentrations that may or may not induce
silicosis cannot be drawn from simple "eyeball" analysis of the
prevalences in the following two worker populations:
* Kreiss & Zhen (1996) conducted a community-based random sample
survey of 134 male residents at least 40 years old, living in a
hardrock (i.e., molybdenum, lead, zinc, and gold) mining town in
Colorado, USA. Of the 134 residents, 100 were silica-exposed
hardrock miners (including 32 silicosis cases) and 34 were
community "controls" without occupational dust exposure. Nearly
all (97%) of the dust-exposed subjects were 20 years since first
exposure. The estimated crystalline silica content (polymorph not
reported) of the total dust was 12.3%. Exposure was assessed with
information from occupational histories, gravimetric dust
exposure data from 1974-1982, and a cumulative silica exposure
index. Pre-1974 exposure estimates were based on job-specific
gravimetric data collected after 1974. Exposures were also
estimated for mines where no exposure data were available (17.1%
of person-years of follow-up). Thirty-two per cent of the 100
dust-exposed subjects had silicosis (defined as radiological
profusion of small opacities of ILO category >1/0). Prevalence
of silicosis was related to average silica dust exposure. Among
the 94 dust-exposed subjects with data on cumulative and average
dust exposures, those subjects with average silica exposure
<0.05 mg/m3 had 10% prevalence of silicosis; subjects with
>0.05-0.10 mg/m3 had a prevalence of 22.5%; subjects with
greater than 0.10 mg/m3 average silica exposure had a silicosis
prevalence of 48.6% (P = 0.01). (See Table 6 for predicted
prevalences when silicosis was defined as radiological profusion
of small opacities of ILO category >1/1.) It is not known
whether the small sample of 134 residents was representative of
all miners or if the exposure estimates for mines where no
exposure data were available (17.1% of person-years of follow-up)
were representative.
* Rosenman et al. (1996) conducted a cross-sectional study in 1991
of 549 current, 497 retired, and 26 current salaried workers that
were former production workers in a US grey iron foundry that
produced automotive engine blocks (total workers = 1072).
Twenty-eight cases (2.9%) of silicosis, defined as rounded
opacities >ILO category 1/0, were identified by at least two
of three "B" readers of a total of 952 chest radiographs. More
than half (18/28) of the cases were found in retired workers.
Silicosis prevalence was positively related to mean silica (i.e.,
quartz) exposure (P < 0.0001). Of the workers with mean quartz
exposure less than 0.05 mg/m3, 0.8% had silicosis, while 6.3%
of foundry workers with mean quartz exposure greater than 0.45
mg/m3 had silicosis. Silicosis prevalence also increased with
years of employment at the foundry, cumulative silica exposure,
work area within the foundry, and cigarette smoking (i.e., smoker
vs. non-smoker). Exposure estimates were derived from conversions
of "early silica exposure data" collected by impingers. Quartz
content of total dust was not reported. Weighted total dust
exposure from impinger data was converted to an estimate of
silica exposure in mass units (mg/m3) by multiplying it by the
average percentage of quartz in bulk samples.
Results of cohort studies of gold miners in South Africa, Canada,
and the USA (see Table 7) also demonstrated an exposure-response
relationship for radiographic silicosis (US EPA, 1996):
* A cohort study was conducted of 2235 white South African
underground gold miners, 45-54 years old at the time of medical
examination in 1968-1971, who started working after 1938, worked
>10 years, and were followed until 1991 (Hnizdo &
Sluis-Cremer, 1993). More than 300 (n = 313) of the 2235 miners
were followed to the time when radiological signs developed, 658
miners were followed up to death, and 1264 miners were followed
to the year of the most recent radiograph. Radiographs were read
blindly by two independent readers. Silicosis was defined as the
presence of rounded opacities of ILO category >1/1.
Radiographs were read blindly by two readers initially, then one
reader was chosen because his readings more closely matched the
autopsy data. Mean respirable dust concentrations, after heat and
acid treatment, in milligrams per cubic metre per shift were
calculated for nine gold mining occupations. The concentrations
were based on a study of shift-long dust exposure that measured
the surface area of the respirable mine dust and the number of
respirable particles (i.e., incombustible and acid-insoluble dust
particles) per cubic metre in a random sample of 20 South African
gold mines (Beadle, 1965, 1971). After heat and acid treatment,
the respirable dust in South African gold mines was found to
contain about 30% quartz (Beadle & Bradley, 1970). Cumulative
dust exposure for the miners was calculated in milligrams per
cubic metre-year by using data for mean mass respirable dust
concentrations for the nine occupational categories, the average
number of hours underground, and the number of dusty 8-h shifts.
Of the 2235 miners studied by Hnizdo & Sluis-Cremer (1993),
313 developed radiologically diagnosed silicosis (rounded
opacities with profusion of ILO category >1/1) during the
follow-up period (i.e., 1968-1971 to 1991). The onset of
silicosis occurred after an average (i.e., mean) of 27 years of
Table 6: Predicted prevalence of silicosis (ILO category >1/1)
following exposure to respirable quartz dust based on modelling of cumulative exposure
at mean concentrations of 0.05 or 0.10 mg/m3 over a 45-year working lifetime.
Cross-sectional study Mean concentration of Predicted prevalence of Cohort's mean time Cohort's maximum time
and cohort respirable quartz dust silicosis, ILO category since first quartz since first quartz
(mg/m3) >1/1 (cases per exposure (years) exposure (years)
100 workers)
Kreiss & Zhen, 1996 0.05 approx. 30a silicotic miners: silicotic miners:
41.6 66
100 US hardrock 0.10 approx. 90a non-silicotic non-silicotic
miners and 34 miners: 33.5 miners: 68
community controls
Rosenman et al., 0.05 2b,c 28 >30
1996
1072 US grey 0.10 3b,c
iron foundry workers
a Based on cumulative silica exposure model with 10 years of post-employment follow-up.
b ILO category >1/0.
c Based on a 40-year working lifetime and controlling for pack-years of cigarette smoking, race,
and silica exposure other than in the foundry under study.
Table 7: Predicted number of silicosis cases (ILO category >1/1) following exposure to respirable
quartz dust based on modelling of cumulative exposure at mean concentrations of 0.05 or 0.10 mg/m3
over a 45-year working lifetime.
Cohort study Mean concentration of Silicosis cases, Mean time since first Maximum time since
and population respirable quartz ILO category >1/1, quartz exposure (years) first quartz exposure
dust (mg/m3) per 100 workers (years)
Hnizdo & 0.05 13a silicotic miners: 36 silicotic miners: 50
Sluis-Cremer, 1993
2235 South African 0.10 approx. 70
gold miners
Muir et al., 0.05 0.09-0.62a,b 18 silicotic miners: 38
1989a,b;
Muir, 1991
2109 Canadian
gold and
uranium miners
Steenland & 0.05 10c 37 73d
Brown, 1995a
3330 US gold 0.09 47c
miners
a Estimate was reported in Rice & Stayner (1995).
b No post-employment follow-up and no retired miners included. The range includes five estimates
(one for each reader).
c The predicted number of silicosis cases does not account for effects of age or calendar time
(K. Steenland, personal communication, 1997).
d K. Steenland, personal communication, 1998.
net service, at a mean age of 56 years. For more than half of the
miners (n = 178; 57%), the onset occurred an average of
7.4 years (standard deviation 5.5; range 0.1-25 years) after
their employment at the mines, at 59 years of age (range
44-74 years). For the other miners (n = 135; 43%), the onset
of silicosis occurred while they were still mining, at 51 years
of age (range 39-61 years). These results show that the majority
of the cases occurred in miners who were no longer employed at
the mine and who were at least 50 years old
(Hnizdo & Sluis-Cremer, 1993).
* Muir and colleagues conducted a study of 2109 current Ontario
miners from 21 gold and uranium mines who started working and
worked more than 5 years between 1940 and 1959 and were followed
to 1982 or to the end of their dust exposure, whichever came
first (Muir et al., 1989a,b; Muir, 1991). Any uranium miner with
more than 2 weeks of exposure was also included (Muir et al.,
1989a). The quartz content of respirable gold mine dust was 6.0%,
and that of uranium mine dust was 8.4%. Retired and former miners
were not included in the study. Sources of data for this study
were full-sized annual chest radiographs taken for all miners
after 1927 and periodic (pre-1959) and semi-annual mine dust
measurements obtained with a konimeter (which is an instantaneous
dust sampler that measures the number of particles per unit
volume of air; Verma et al., 1989). Konimeter dust measurements
taken from 1940 to 1952 were expressed in particles per cubic
centimetre of air (ppcc). Verma et al. (1989) initiated an
extensive, side-by-side comparison of the konimetric and
gravimetric (i.e., milligrams of silica per cubic metre) sampling
to derive a konimetric/gravimetric silica conversion curve. A
total of 2360 filter (i.e., nylon cyclone-filter assembly in a
constant-flow pump) samples and 90 000 konimeter samples were
taken in a 2-year period in two gold and uranium mines, in
existing conditions as well as in an experimental simulation of
the high-dust conditions of the past caused by dry drilling
(Verma et al., 1989). The results of the conversion relationship
were non-linear and may have reflected the limitations of the
konimeter in measuring high dust (i.e., high count)
concentrations and the limitations of the gravimetric sampler in
measuring low dust concentrations. There were different
relationships for the gold and uranium mines, possibly because of
the different fractional silica concentrations in the host rock.
The conversion of the historical konimeter counts to gravimetric
respirable silica equivalents was used to derive a cumulative
respirable silica dose for each miner based on the miner's
respirable silica dose for each year, mine, and task in his work
history (Verma et al., 1989).
Thirty-two of the 2109 hardrock miners studied by Muir and
colleagues were considered by at least one of five readers to
have silicosis (small, rounded opacities with profusion of ILO
category >1/1). However, the results differed among the five
readers and "complicated the analysis" (Muir et al., 1989b). One
of the five readers identified only seven cases of silicosis
(Muir et al., 1989b). The results were presented by individual
reader and by consensus. A consensus of all of the five readers
with respect to identification of silicosis was reached on only
six cases (Muir et al., 1989b). Average respirable quartz dust
exposure for the cases was not reported.
* A cohort study of 3330 white male underground gold miners from
South Dakota employed for at least 1 year between 1940 and 1965
and followed through 1990 found 170 cases of silicosis (128 cases
were identified on death certificates, 29 cases were found during
X-ray surveys of workers conducted in 1960 and 1976, and 13 cases
were identified on both X-ray and death certificate). Cases were
defined as (1) an underlying or contributing cause of death of
silicosis, silico-tuberculosis, respiratory tuberculosis, or
pneumoconiosis, and/or (2) ILO category >1/1 silicosis
identified in the 1976 radiographic survey or "small opacities"
or "large opacities" identified in the 1960 radiographic survey
(Steenland & Brown, 1995a). The miners were exposed to a median
quartz level of 0.05 mg/m3 (0.15 mg/m3 for workers hired prior
to 1930). The average length of follow-up was 37 years, and the
average length of employment underground was 9 years. Quartz
exposure was estimated by converting dust particle counts to
gravimetric measurements (i.e., mg/m3), based on an estimate of
13% quartz content of total dust. A job-exposure matrix was
created to estimate dust exposures for each job over time, then
average dust exposures for the job categories were calculated
using existing measurements for each year from 1937 to 1975. The
estimated daily dust exposures (constant over each year) were
weighted to account for daily time spent underground. Summation
of the estimated daily dust levels over time provided an estimate
of cumulative quartz exposure (Steenland & Brown, 1995a). The
risk of silicosis was less than 1% for miners with a cumulative
exposure less than 0.5 mg/m3-years. The risk increased to 68-84%
for the highest cumulative exposure category (i.e.,
4 mg/m3-years) (Steenland & Brown, 1995a). Silicosis risk
estimates could have been affected by (1) combining silicosis
deaths with silicosis cases detected by cross-sectional
radiographic surveys, (2) differences in quartz content of dust
in early years, and (3) lack of dust measurements before 1937.
A cohort study of a subcohort of the South Dakota gold
miners described above analysed cases of silicosis that were
reported as the underlying cause of death on the death
certificates. Forty cases of silicosis, as well as 49 cases of
tuberculosis, were ascertained among the 1321 miners employed for
at least 21 years and followed through 1973. There was a linear
trend in risk of about 2.4% for each 0.1 mg/m3 of silica
exposure. However, this study does not meet the criteria for a
critical study because risk by cumulative quartz exposure was not
calculated (McDonald & Oakes, 1984).
In the five critical studies described above, the number of cases
identified depended upon the definition of silicosis (radiographic
category and whether irregular opacities were included), the quality
of the evaluation of the chest radiographs (e.g., number and training
of readers), the duration of dust exposure, and the duration of
follow-up after the end of exposure. Interstudy variation exists for
each of these factors. In addition, exposure assessments in these
studies were accompanied by uncertainties, such as the use of
conversion equations (i.e., converting particle count data to mass
concentrations; application of equations from one industry to a
different industry) and estimation of quartz content of the dust. It
is not uncommon for epidemiological studies to lack characterization
of the source and properties of the mineral dusts collected in the
workplace (Mossman & Churg, 1998). Nevertheless, the critical studies
found an exposure-response relationship for respirable quartz dust
that, when modelled, predicts the occurrence of silicosis cases in
various industries at exposures close to regulatory levels.
9.2.2 Pulmonary tuberculosis and other infections
The association between tuberculosis and silicosis has been
firmly established by the results of epidemiological studies conducted
during this century (Balmes, 1990). In recent studies of silicotics,
the association was well supported by the results of a survey of
tuberculosis deaths among silicotics in the USA for the period
1979-1991 (Althouse et al., 1995), a mortality study of 590 California
silicosis claimants (Goldsmith et al., 1995a), and a retrospective
study of silicotic miners from the Freegold mines in South Africa
(Kleinschmidt & Churchyard, 1997).
In studies of workers without silicosis, there is some limited
evidence that long exposures or high cumulative exposures to quartz
dust may increase the risk of developing tuberculosis. Two
epidemiological studies reported 3-fold higher incidences of pulmonary
tuberculosis cases in 5424 non-silicotic silica-exposed Danish foundry
workers employed 25 or more years (Sherson & Lander, 1990) and among
335 non-silicotic black South African gold miners with a median
underground employment of 26 years (Cowie, 1994). Westerholm et al.
(1986) found 13 cases of tuberculosis among 428 silicotic Swedish iron
and steel workers and one case of tuberculosis in a comparison group
of 476 Swedish iron and steel workers with normal chest radiographs
(level of statistical significance not reported). Both groups had been
exposed to silica for at least 5 years.
A study of tuberculosis incidence in 2255 white South African
gold miners included 1296 miners who had an autopsy. The
smoking-adjusted relative risk for pulmonary tuberculosis in miners
without silicotic nodules on autopsy examination (n = 577) increased
slightly with quartiles of cumulative dust exposure (relative risk
[RR] = 1.38; 95% confidence interval [CI] = 0.33-5.62) for the highest
quartile of cumulative exposure). For miners without radiologically
diagnosed silicosis (n = 1934), the smoking-adjusted relative risk
increased to 4.01 (95% CI = 2.04-7.88) in the highest quartile of
cumulative dust exposure (Hnizdo & Murray, 1998, 1999). Radiological
silicosis was defined as ILO category >1/1; detailed ILO grading
was not performed (Hnizdo & Murray, 1998, 1999). Tuberculosis was
diagnosed on average 7.6 years after the end of dust exposure and
6.8 years after the onset of radiological silicosis -- a result that
supports the need for medical surveillance of workers after the end of
exposure to silica dust (Hnizdo & Murray, 1998). (Miners who developed
tuberculosis before completing 10 years of underground employment were
excluded because they were not allowed to continue working underground
after diagnosis) (Hnizdo & Murray, 1998). It is not clear whether
"dust" exposure refers to quartz exposure or exposure to gold mine
dust.
Chen et al. (1997) conducted a case-control study (8740 cases;
83 338 controls) with US National Occupational Mortality Surveillance
data for the years 1983-1992 that controlled for confounding from age,
gender, race, socioeconomic status, potential exposure to active
tuberculosis, and the presence of silicosis and other pneumoconioses.
The potential for exposure to silica was based on potential exposure
data from the National Occupational Exposure Survey (Seta et al.,
1988) and the National Occupational Health Survey of Mining