recommended standards for addressing the hazards of crystalline silica,
and the Building and Construction Trades Department, AFL-CIO also has
recommended a comprehensive program standard. These recommended
standards include provisions for methods of compliance, exposure
monitoring, training, and medical surveillance. The National Industrial
Sand Association has also developed exposure assessment, medical
surveillance, and training guidance products.
    In 1997, OSHA announced in its Unified Agenda under Long-Term
Actions that it planned to publish a proposed rule on crystalline
silica ``because the agency has concluded that there will be no
significant progress in the prevention of silica-related diseases
without the adoption of a full and comprehensive silica standard,
including provisions for product substitution, engineering controls,
training and education, respiratory protection and medical screening
and surveillance. A full standard will improve worker protection,
ensure adequate prevention programs, and further reduce silica-related
diseases.'' (62 FR 57755, 57758, Oct. 29, 1997). In November 1998, OSHA
moved ``Occupational Exposure to Crystalline Silica'' to the pre-rule
stage in the Regulatory Plan (63 FR 61284, 61303-304, Nov. 9, 1998).
OSHA held a series of stakeholder meetings in 1999 and 2000 to get
input on the rulemaking. Stakeholder meetings for all industry sectors
were held in Washington, Chicago, and San Francisco. A separate
stakeholder meeting for the construction sector was held in Atlanta.

    OSHA initiated Small Business Regulatory Enforcement Fairness Act
(SBREFA) proceedings in 2003, seeking the advice of small business
representatives on the proposed rule (68 FR 30583, 30584, May 27,
2003). The SBREFA panel, including representatives from OSHA, the Small
Business Administration (SBA), and the Office of Management and Budget
(OMB), was convened on October 20, 2003. The panel conferred with small
entity representatives (SERs) from general industry, maritime, and
construction on November 10 and 12, 2003, and delivered its final
report, which included comments from the SERs and recommendations to
OSHA for the proposed rule, to OSHA's Assistant Secretary on December
19, 2003 (OSHA, 2003).
    Throughout the crystalline silica rulemaking process, OSHA has
presented information to, and has consulted with, the Advisory
Committee on Construction Safety and Health (ACCSH) and the Maritime
Advisory Committee on Occupational Safety and Health (MACOSH). In
December of 2009, OSHA representatives met with ACCSH to discuss the
rulemaking and receive their comments and recommendations. On December
11, ACCSH passed motions supporting the concept of Table 1 in the draft
proposed construction rule and recognizing that the controls listed in
Table 1 are effective. (As discussed with regard to paragraph (f) of
the proposed rule, Table 1 presents specified control measures for
selected construction operations.) ACCSH also recommended that OSHA
maintain the protective clothing provision found in the SBREFA panel
draft regulatory text and restore the ``competent person'' requirement
and responsibilities to the proposed rule. Additionally, the group
recommended that OSHA move forward expeditiously with the rulemaking
process.
    In January 2010, OSHA completed a peer review of the draft Health
Effects analysis and Preliminary Quantitative Risk Assessment following
procedures set forth by OMB in the Final Information Quality Bulletin
for Peer Review, published on the OMB Web site on December 16, 2004
(see 70 FR 2664, Jan. 14, 2005). Each peer reviewer submitted a written
report to OSHA. The Agency revised its draft documents as appropriate
and made the revised documents available to the public as part of this
Notice of Proposed Rulemaking. OSHA also made the written charge to the
peer reviewers, the peer reviewers' names, the peer reviewers' reports,
and the Agency's response to the peer reviewers' reports publicly
available with publication of this proposed rule. OSHA will schedule
time during the informal rulemaking hearing for participants to testify
on the Health Effects analysis and Preliminary Quantitative Risk
Assessment in the presence of peer reviewers and will request the peer
reviewers to submit any amended final comments they may wish to add to
the record. The Agency will consider amended final comments received
from the peer reviewers during development of a final rule and will
make them publicly available as part of the silica rulemaking record.

IV. Chemical Properties and Industrial Uses

    Silica is a compound composed of the elements silicon and oxygen
(chemical formula SiO2). Silica has a molecular weight of
60.08, and exists in crystalline and amorphous states, both in the
natural environment and as produced during manufacturing or other
processes. These substances are odorless solids, have no vapor
pressure, and create non-explosive dusts when particles are suspended
in air (IARC, 1997).
    Silica is classified as part of the ``silicate'' class of minerals,
which includes compounds that are composed of silicon and oxygen and
which may also be bonded to metal ions or their oxides (Hurlbut, 1966).
The basic structural units of silicates are silicon tetrahedrons
(SiO4), pyramidal structures with four triangular sides
where a silicon atom is located in the center of the structure and an
oxygen atom is located at each of the four corners. When silica
tetrahedrons bond exclusively with other silica tetrahedrons, each
oxygen atom is bonded to the silicon atom of its original ion, as well
as to the silicon atom from another silica ion. This results in a ratio
of one atom of silicon to two atoms of oxygen, expressed as
SiO2. The silicon-oxygen bonds within the tetrahedrons use
only one-half of each oxygen's total bonding energy. This leaves
negatively charged oxygen ions available to bond with available
positively charged ions. When they bond with metal and metal oxides,
commonly of iron, magnesium, aluminum, sodium, potassium, and calcium,
they form the silicate minerals commonly found in nature (Bureau of
Mines, 1992).
    In crystalline silica, the silicon and oxygen atoms are arranged in
a three-dimensional repeating pattern. Silica is said to be
polymorphic, as different forms are created when the silica
tetrahedrons combine in different crystalline structures. The primary
forms of crystalline silica are quartz, cristobalite, and tridymite. In
an amorphous state, silicon and oxygen atoms are present in the same
proportions but are not organized in a repeating pattern. Amorphous
silica includes natural and manufactured glasses (vitreous and fused
silica, quartz glass), biogenic silica, and opals which are amorphous
silica hydrates (IARC, 1997).
    Quartz is the most common form of crystalline silica and accounts
for almost 12% by volume of the earth's crust. Alpha quartz, the quartz
form that is stable below 573 [deg]C, is the most prevalent form of
crystalline silica found in the workplace. It accounts for the
overwhelming majority of naturally found silica and is present in
varying amounts in almost every type of mineral. Alpha quartz is found
in igneous, sedimentary, and metamorphic rock, and all soils contain at
least a trace amount of quartz (Bureau of Mines, 1992). Alpha quartz is
used in many products throughout various industries and is a common
component of building materials (Madsen et al., 1995). Common trade
names for commercially available quartz include: CSQZ, DQ 12, Min-U-
Sil, Sil-Co-Sil, Snowit, Sykron F300, and Sykron F600 (IARC, 1997).
    Cristobalite is a form of crystalline silica that is formed at high
temperatures (>1470 [deg]C). Although naturally occurring cristobalite
is relatively rare, volcanic eruptions, such as Mount St. Helens, can
release cristobalite dust into the air. Cristobalite can also be
created during some processes conducted in the workplace. For example,
flux-calcined diatomaceous earth is a material used as a filtering aid
and as a filler in other products (IARC, 1997). It is produced when
diatomaceous earth (diatomite), a geological product of decayed
unicellular organisms called diatoms, is heated with flux. The finished
product can contain between 40 and 60 percent cristobalite. Also, high
temperature furnaces are often lined with bricks that contain quartz.
When subjected to prolonged high temperatures, this quartz can convert
to cristobalite.
    Tridymite is another material formed at high temperatures (>870
[deg]C) that is associated with volcanic activity. The creation of
tridymite requires the presence of a flux such as sodium oxide.
Tridymite is rarely found in nature and rarely reported in the
workplace (Smith, 1998).
    When heated or cooled sufficiently, crystalline silica can
transition between the polymorphic forms, with specific transitions
occurring at different temperatures. At higher temperatures the
linkages between the silica

tetrahedrons break and reform, resulting in new crystalline structures.
Quartz converts to cristobalite at 1470 [deg]C, and at 1723 [deg]C
cristobalite loses its crystalline structure and becomes amorphous
fused silica. These high temperature transitions reverse themselves at
extremely slow rates, with different forms co-existing for a long time
after the crystal cools.
    Other types of transitions occur at lower temperatures when the
silica-oxygen bonds in the silica tetrahedron rotate or stretch,
resulting in a new crystalline structure. These low-temperature, or
alpha to beta, transitions are readily and rapidly reversed as the
crystal cools. At temperatures encountered by workers, only the alpha
form of crystalline silica exists (IARC, 1997).
    Crystalline silica minerals produce distinct X-ray diffraction
patterns, specific to their crystalline structure. The patterns can be
used to distinguish the crystalline polymorphs from each other and from
amorphous silica (IARC, 1997).
    The specific gravity and melting point of silica vary between
polymorphs. Silica is insoluble in water at 20 [deg]C and in most
acids, but its solubility increases with higher temperatures and pH,
and it dissolves readily in hydrofluoric acid. Solubility is also
affected by the presence of trace metals and by particle size. Under
humid conditions water vapor in the air reacts with the surface of
silica particles to form an external layer of silinols (SiOH). When
these silinols are present the crystalline silica becomes more
hydrophilic. Heating or acid washing reduces the amount of silinols on
the surface area of crystalline silica particles. There is an external
amorphous layer found in aged quartz, called the Beilby layer, which is
not found on freshly cut quartz. This amorphous layer is more water
soluble than the underlying crystalline core. Etching with hydrofluoric
acid removes the Beilby layer as well as the principal metal impurities
on quartz.
    Crystalline silica has limited chemical reactivity. It reacts with
alkaline aqueous solutions, but does not readily react with most acids,
with the exception of hydrofluoric acid. In contrast, amorphous silica
and most silicates react with most mineral acids and alkaline
solutions. Analytical chemists relied on this difference in acid
reactivity to develop the silica point count analytical method that was
widely used prior to the current X-ray diffraction and infrared methods
(Madsen et al., 1995).
    Crystalline silica is used in industry in a wide variety of
applications. Sand and gravel are used in road building and concrete
construction. Sand with greater than 98% silica is used in the
manufacture of glass and ceramics. Silica sand is used to form molds
for metal castings in foundries, and in abrasive blasting operations.
Silica is also used as a filler in plastics, rubber, and paint, and as
an abrasive in soaps and scouring cleansers. Silica sand is used to
filter impurities from municipal water and sewage treatment plants, and
in hydraulic fracturing for oil and gas recovery. Silica is also used
to manufacture artificial stone products used as bathroom and kitchen
countertops, and the silica content in those products can exceed 93
percent (Kramer et al., 2012).
    There are over thirty major industries and operations where
exposures to crystalline silica can occur. They include such diverse
workplaces as foundries, dental laboratories, concrete products and
paint and coating manufacture, as well as construction activities
including masonry cutting, grinding and tuckpointing, operating heavy
equipment, and road work. A more detailed discussion of the industries
affected by the proposed standard is presented in Section VIII of this
preamble. Crystalline silica exposures can also occur in mining, and in
agriculture during plowing and harvesting.

V. Health Effects Summary

    This section presents a summary of OSHA's review of the health
effects literature for respirable crystalline silica. OSHA's full
analysis is contained in Section I of the background document entitled
``Respirable Crystalline Silica--Health Effects Literature Review and
Preliminary Quantitative Risk Assessment,'' which has been placed in
rulemaking docket OSHA-2010-0034. OSHA's review of the literature on
the adverse effects associated with exposure to crystalline silica
covers the following topics:
    (1) Silicosis (including relevant data from U.S. disease
surveillance efforts);
    (2) Lung cancer and cancer at other sites;
    (3) Non-malignant respiratory disease (other than silicosis);
    (4) Renal and autoimmune effects; and
    (5) Physical factors affecting the toxicity of crystalline silica.
    The purpose of the Agency's scientific review is to present OSHA's
preliminary findings on the nature of the hazards presented by exposure
to respirable crystalline silica, and to present an adequate basis for
the quantitative risk assessment section to follow. OSHA's review
reflects the relevant literature identified by the Agency through
previously published reviews, literature searches, and contact with
outside experts. Most of the evidence that describes the health risks
associated with exposure to silica consists of epidemiological studies
of worker populations; in addition, animal and in vitro studies on mode
of action and molecular toxicology are also described. OSHA's review of
the silicosis literature focused on a few particular issues, such as
the factors that affect progression of the disease and the relationship
between the appearance of radiological abnormalities indicative of
silicosis and pulmonary function decline. Exposure to respirable
crystalline silica is the only known cause of silicosis and there are
literally thousands of research papers and case studies describing
silicosis among working populations. OSHA did not review every one of
these studies, because many of them do not relate to the issues that
are of interest to OSHA.
    OSHA's health effects literature review addresses exposure only to
airborne respirable crystalline silica since there is no evidence that
dermal or oral exposure presents a hazard to workers. This review is
also confined to issues related to inhalation of respirable dust, which
is generally defined as particles that are capable of reaching the gas-
exchange region of the lung (i.e., particles less than 10 [mu]m in
aerodynamic diameter). The available studies include populations
exposed to quartz or cristobalite, the two forms of crystalline silica
most often encountered in the workplace. OSHA was unable to identify
any relevant epidemiological literature concerning a third polymorph,
tridymite, which is also currently regulated by OSHA and included in
the scope of OSHA's proposed crystalline silica standard.
    OSHA's approach in this review is based on a weight-of-evidence
approach, in which studies (both positive and negative) are evaluated
for their overall quality, and causal inferences are drawn based on a
determination of whether there is substantial evidence that exposure
increases the risk of a particular effect. Factors considered in
assessing the quality of studies include size of the cohort studied and
power of the study to detect a sufficiently low level of disease risk;
duration of follow-up of the study population; potential for study bias
(such as selection bias in case-control studies or survivor effects in
cross-sectional studies); and adequacy of underlying exposure
information for

examining exposure-response relationships. Studies were deemed suitable
for inclusion in OSHA's Preliminary Quantitative Risk Assessment where
there was adequate quantitative information on exposure and disease
risks and the study was judged to be sufficiently high quality
according to the criteria described above. The Preliminary Quantitative
Risk Assessment is included in Section II of the background document
and is summarized in Section VI of this preamble.
    A draft health effects review document was submitted for external
scientific peer review in accordance with the Office of Management and
Budget's ``Final Information Quality Bulletin for Peer Review'' (OMB,
2004). A summary of OSHA's responses to the peer reviewers' comments
appears in Section III of the background document. Since the draft
health effects review document was submitted for external scientific
peer review, new studies or reviews examining possible associations
between occupational exposure to respirable crystalline silica and lung
cancer have been published. OSHA's analysis of that new information is
presented in a supplemental literature review and is available in the
docket (OSHA, 2013).

A. Silicosis and Disease Progression

1. Pathology and Diagnosis
    Silicosis is a progressive disease in which accumulation of
respirable crystalline silica particles causes an inflammatory reaction
in the lung, leading to lung damage and scarring, and, in some cases,
progresses to complications resulting in disability and death. Three
types of silicosis have been described: an acute form following intense
exposure to respirable dust of high crystalline silica content for a
relatively short period (i.e., a few months or years); an accelerated
form, resulting from about 5 to 15 years of heavy exposure to
respirable dusts of high crystalline silica content; and, most
commonly, a chronic form that typically follows less intense exposure
of usually more than 20 years (Becklake, 1994; Balaan and Banks, 1992).
In both the accelerated and chronic form of the disease, lung
inflammation leads to the formation of excess connective tissue, or
fibrosis, in the lung. The hallmark of the chronic form of silicosis is
the silicotic islet or nodule, one of the few agent-specific lesions in
pathology (Balaan and Banks, 1992). As the disease progresses, these
nodules, or fibrotic lesions, increase in density and can develop into
large fibrotic masses, resulting in progressive massive fibrosis (PMF).
Once established, the fibrotic process of chronic silicosis is thought
to be irreversible (Becklake, 1994), and there is no specific treatment
for silicosis (Davis, 1996; Banks, 2005). Unlike chronic silicosis, the
acute form of the disease almost certainly arises from exposures well
in excess of current OSHA standards and presents a different
pathological picture, one of pulmonary alveolar proteinosis.
    Chronic silicosis is the most frequently observed type of silicosis
in the U.S. today. Affected workers may have a dry chronic cough,
sputum production, shortness of breath, and reduced pulmonary function.
These symptoms result from airway restriction and/or obstruction caused
by the development of fibrotic scarring in the alveolar sacs and lower
region of the lung. The scarring can be detected by chest x-ray or
computerized tomography (CT) when the lesions become large enough to
appear as visible opacities. The result is restriction of lung volumes
and decreased pulmonary compliance with concomitant reduced gas
transfer (Balaan and Banks, 1992). Early stages of chronic silicosis
can be referred to as either simple or nodular silicosis; later stages
are referred to as either pulmonary massive fibrosis (PMF),
complicated, or advanced silicosis.
    The clinical diagnosis of silicosis has three requisites (Balaan
and Banks, 1992; Banks, 2005). The first is the recognition by the
physician that exposure to crystalline silica adequate to cause this
disease has occurred. The second is the presence of chest radiographic
abnormalities consistent with silicosis. The third is the absence of
other illnesses that could resemble silicosis on chest radiograph,
e.g., pulmonary fungal infection or miliary tuberculosis. To describe
the presence and severity of silicosis from chest x-ray films or
digital radiographic images, a standardized system exists to classify
the opacities seen on chest radiographs (the International Labor
Organization (ILO) International Classification of Radiographs of the
Pneumoconioses (ILO, 1980, 2002, 2011; Merchant and Schwartz, 1998;
NIOSH, 2011). This system standardizes the description of chest x-ray
films or digital radiographic images with respect to the size, shape,
and density of opacities, which together indicate the severity and
extent of lung involvement. The density of opacities seen on chest x-
ray films or digital radiographic images is classified on a 4-point
major category scale (0, 1, 2, or 3), with each major category divided
into three subcategories, giving a 12-point scale between 0/0 and 3/+.
(For each subcategory, the top number indicates the major category that
the profusion most closely resembles, and the bottom number indicates
the major category that was given secondary consideration.) Major
category 0 indicates the absence of visible opacities and categories 1
to 3 reflect increasing profusion of opacities and a concomitant
increase in severity of disease. Biopsy is not necessary to make a
diagnosis and a diagnosis does not require that chest x-ray films or
digital radiographic images be rated using the ILO system (NIOSH,
2002). In addition, an assessment of pulmonary function, though not
itself necessary to confirm a diagnosis of silicosis, is important to
evaluate whether the individual has impaired lung function.
    Although chest x-ray is typically used to examine workers exposed
to respirable crystalline silica for the presence of silicosis, it is a
fairly insensitive tool for detecting lung fibrosis (Hnizdo et al.,
1993; Craighead and Vallyathan, 1980; Rosenman et al., 1997). To
address the low sensitivity of chest x-rays for detecting silicosis,
Hnizdo et al. (1993) recommended that radiographs consistent with an
ILO category of 0/1 or greater be considered indicative of silicosis
among workers exposed to a high concentration of silica-containing
dust. In like manner, to maintain high specificity, chest x-rays
classified as category 1/0 or 1/1 should be considered as a positive
diagnosis of silicosis.
    Newer imaging technologies with both research and clinical
applications include computed tomography, and high resolution
tomography. High- resolution computed tomography (HRCT) uses thinner
image slices and a different reconstruction algorithm to improve
spatial resolution over CT. Recent studies of high-resolution
computerized tomography (HRCT) have found HRCT to be superior to chest
x-ray imaging for detecting small opacities and for identifying PMF
(Sun et al., 2008; Lopes et al., 2008; Blum et al., 2008).
    The causal relationship between exposure to crystalline silica and
silicosis has long been accepted in the scientific and medical
communities. Of greater interest to OSHA is the quantitative
relationship between exposure to crystalline silica and development of
silicosis. A large number of cross-sectional and retrospective studies
have been conducted to evaluate this relationship (Kreiss and Zhen,
1996; Love et al., 1999; Ng and Chan, 1994; Rosenman et al., 1996;
Hughes et al., 1998; Muir et al., 1989a, 1989b; Park et al., 2002; Chen

et al., 2001; Hnizdo and Sluis-Cremer, 1993; Miller et al., 1998;
Buchanan et al., 2003; Steenland and Brown, 1995b). In general, these
studies, particularly those that included retirees, have found a risk
of radiological silicosis (usually defined as x-ray films classified
ILO major category 1 or greater) among workers exposed near the range
of cumulative exposure permitted by current exposure limits. These
studies are presented in detail in OSHA's Preliminary Quantitative Risk
Assessment (Section II of the background document and summarized in
Section VI of this preamble).
2. Silicosis in the United States
    Unlike most occupational diseases, surveillance statistics are
available that provide information on the prevalence of silicosis
mortality and morbidity in the U.S. The most comprehensive and current
source of surveillance data in the U.S. related to occupational lung
diseases, including silicosis, is the National Institute for
Occupational Safety and Health (NIOSH) Work-Related Lung Disease
(WoRLD) Surveillance System; the WoRLD Surveillance Report is compiled
from the most recent data from the WoRLD System (NIOSH, 2008c).
National statistics on mortality associated with occupational lung
diseases are also compiled in the National Occupational Respiratory
Mortality System (NORMS, available on the Internet at http://webappa.cdc.gov/ords/norms.html), a searchable database administered by
NIOSH. In addition, NIOSH published a recent review of mortality
statistics in its MMWR Report Silicosis Mortality, Prevention, and
Control--United States, 1968-2002 (CDC, 2005). For each of these
sources, data are compiled from death certificates reported to state
vital statistics offices, which are collected by the National Center
for Health Statistics (NCHS). Data on silicosis morbidity are available
from only a few states that administer occupational disease
surveillance systems, and from data on hospital discharges. OSHA
believes that the mortality and morbidity statistics compiled in these
sources and summarized below indicate that silicosis remains a
significant occupational health problem in the U.S. today.
    From 1968 to 2002, silicosis was recorded as an underlying or
contributing cause of death on 16,305 death certificates; of these, a
total of 15,944 (98 percent) deaths occurred in males (CDC, 2005). From
1968 to 2002, the number of silicosis deaths decreased from 1,157 (8.91
per million persons aged =15 years) to 148 (0.66 per
million), corresponding to a 93-percent decline in the overall
mortality rate. In its most recent WoRLD Report (NIOSH, 2008c), NIOSH
reported that the number of silicosis deaths in 2003, 2004, and 2005
were 179, 166, and 161, respectively, slightly higher than that
reported in 2002. The number of silicosis deaths identified each year
has remained fairly constant since the late 1990's.
    NIOSH cited two main factors that were likely responsible for the
declining trend in silicosis mortality since 1968. First, many of the
deaths in the early part of the study period occurred among persons
whose main exposure to crystalline silica dust probably occurred before
introduction of national standards for silica dust exposure established
by OSHA and the Mine Safety and Health Administration (MSHA) (i.e.,
permissible exposure limits (PELs)) that likely led to reduced silica
dust exposure. Second, there has been declining employment in heavy
industries (e.g., foundries) where silica exposure was prevalent (CDC,
2005). Although the factors described by NIOSH are reasonable
explanations for the steep reduction in silicosis-related mortality, it
should be emphasized that the surveillance data are insufficient for
the analysis of residual risk associated with current occupational
exposure limits for crystalline silica. Analyses designed to explore
this question must make use of appropriate exposure-response data, as
is presented in OSHA's Preliminary Quantitative Risk Assessment
(summarized in Section VI of this preamble).
    Although the number of deaths from silicosis overall has declined
since 1968, the number of silicosis-associated deaths reported among
persons aged 15 to 44 had not declined substantially prior to 1995 (CDC
1998). Unfortunately, it is not known to what extent these deaths among
younger workers were caused by acute or accelerated forms of silicosis.
    Silicosis deaths among workers of all ages result in significant
premature mortality; between 1996 and 2005, a total of 1,746 deaths
resulted in a total of 20,234 years of life lost from life expectancy,
with an average of 11.6 years of life lost. For the same period, among
307 decedents who died before age 65, or the end of a working life,
there were 3,045 years of life lost to age 65, with an average of 9.9
years of life lost from a working life (NIOSH, 2008c).
    Data on the prevalence of silicosis morbidity are available from
only three states (Michigan, Ohio, and New Jersey) that have
administered disease surveillance programs over the past several years.
These programs rely primarily on hospital discharge records, reporting
of cases from the medical community, workers' compensation programs,
and death certificate data. For the reporting period 1993-2002, the
last year for which data are available, three states (Michigan, New
Jersey and Ohio) recorded 879 cases of silicosis (NIOSH 2008c).
Hospital discharge records represent the primary ascertainment source
for all three states. It should be noted that hospital discharge
records most likely include cases of acute silicosis or very advance
chronic silicosis since it is unlikely that there would be a need for
hospitalization in cases with early radiographic signs of silicosis,
such as for an ILO category 1/0 x-ray. Nationwide hospital discharge
data compiled by NIOSH (2008c) and the Council of State and Territorial
Epidemiologists (CSTE, 2005) indicates that there are at least 1,000
hospitalizations each year due to silicosis.
    Data on silicosis mortality and morbidity are likely to understate
the true impact of exposure of U.S. workers to crystalline silica. This
is in part due to underreporting that is characteristic of passive
case-based disease surveillance systems that rely on the health care
community to generate records (Froines et al., 1989). Health care
professionals play the main role in such surveillance by virtue of
their unique role in recognizing and diagnosing diseases, but most
health care professionals do not take occupational histories (Goldman
and Peters, 1981; Rutstein et al., 1983). In addition to the lack of
information about exposure histories, difficulty in recognizing
occupational illnesses that have long latency periods, like silicosis,
contributes to under-recognition and underreporting by health care
providers. Based on an analysis of data from Michigan's silicosis
surveillance activities, Rosenman et al. (2003) estimated that the true
incidence of silicosis mortality and morbidity were understated by a
factor of between 2.5 and 5, and that there were estimated to be from
3,600 to 7,300 new cases of silicosis occurring in the U.S. annually
between 1987 and 1996. Taken with the surveillance data presented
above, OSHA believes that exposure to crystalline silica remains a
cause of significant mortality and morbidity in the U.S.
3. Progression of Silicosis and Its Associated Impairment
    As described above, silicosis is a progressive lung disease that is
usually first detected by the appearance of a

diffuse nodular fibrosis on chest x-ray films. To evaluate the clinical
significance of radiographic signs of silicosis, OSHA reviewed several
studies that have examined how exposure affects progression of the
disease (as seen by chest radiography) as well as the relationship
between radiologic findings and pulmonary function. The following
summarizes OSHA's preliminary findings from this review.
    Of the several studies reviewed by OSHA that documented silicosis
progression in populations of workers, four studies (Hughes et al.,
1982; Hessel et al., 1988; Miller et al., 1998; Ng et al., 1987a)
included quantitative exposure data that were based on either current
or historical measurements of respirable quartz. The exposure variable
most strongly associated in these studies with progression of silicosis
was cumulative respirable quartz (or silica) exposure (Hessel et al.,
1988; Hughes et al., 1982; Miller et al., 1998; Ng et al., 1987a),
though both average concentration of respirable silica (Hughes et al.,
1982; Ng et al., 1987a) and duration of employment in dusty jobs have
also been found to be associated with the progression of silicosis
(Hughes et al., 1982; Ogawa et al., 2003).
    The study reflecting average exposures most similar to current
exposure conditions is that of Miller et al. (1998), which followed a
group of 547 British coal miners in 1990-1991 to evaluate chest x-ray
changes that had occurred after the mines closed in 1981. This study
had data available from chest x-rays taken during health surveys
conducted between 1954 and 1978, as well as data from extensive
exposure monitoring conducted between 1964 and 1978. The mean and
maximum cumulative exposure reported in the study correspond to average
concentrations of 0.12 and 0.55 mg/m\3\, respectively, over the 15-year
sampling period. However, between 1971 and 1976, workers experienced
unusually high concentrations of respirable quartz in one of the two
coal seams in which the miners worked. For some occupations, quarterly
mean quartz concentrations ranged from 1 to 3 mg/m\3\, and for a brief
period, concentrations exceeded 10 mg/m\3\ for one job. Some of these
high exposures likely contributed to the extent of disease progression
seen in these workers; in its Preliminary Quantitative Risk Assessment,
OSHA reviewed a study by Buchanan et al. (2003), who found that short-
term exposures to high (>2 mg/m\3\) concentrations of silica can
increase the silicosis risk by 3-fold over what would be predicted by
cumulative exposure alone (see Section VI).
    Among the 504 workers whose last chest x-ray was classified as ILO
0/0 or 0/1, 20 percent had experienced onset of silicosis (i.e., chest
x-ray was classified as ILO 1/0 by the time of follow up in 1990-1991),
and 4.8 percent progressed to at least category 2. However, there are
no data available to continue following the progression of this group
because there have been no follow-up surveys of this cohort since 1991.
    In three other studies examining the progression of silicosis,
(Hessel et al., 1988; Hughes et al., 1982; Ng et al., 1987a) cohorts
were comprised of silicotics (individuals already diagnosed with
silicosis) that were followed further to evaluate disease progression.
These studies reflect exposures of workers to generally higher average
concentrations of respirable quartz than are permitted by OSHA's
current exposure limit. Some general findings from this body of
literature follow. First, size of opacities on initial radiograph is a
determinant for further progression. Individuals with large opacities
on initial chest radiograph have a higher probability of further
disease progression than those with small opacities (Hughes et al.,
1982; Lee, et al., 2001; Ogawa et al., 2003). Second, although
silicotics who continue to be exposed are more likely to progress than
silicotics who are not exposed (Hessel et al., 1988), once silicosis
has been detected there remains a likelihood of progression in the
absence of additional exposure to silica (Hessel et al., 1988; Miller
et al., 1998; Ogawa, et al., 2003; Yang et al., 2006). There is some
evidence in the literature that the probability of progression is
likely to decline over time following the end of the exposure, although
this observation may also reflect a survivor effect (Hughes et al.,
1982; Lee et al., 2001). In addition, of borderline statistical
significance was the association of tuberculosis with increased
likelihood of silicosis progression (Lee et al., 2001).
    Of the four studies reviewed by OSHA that provided quantitative
exposure information, two studies (Miller et al., 1998; Ng et al.,
1987a) provide the information most relevant to current exposure
conditions. The range of average concentration of respirable
crystalline silica to which workers were exposed in these studies (0.12
to 0.48 mg/m\3\, respectively) is relatively narrow and is of
particular interest to OSHA because current enforcement data indicate
that exposures in this range or not much lower are common today,
especially in construction and foundries, and sandblasting operations.
These studies reported the percentage of workers whose chest x-rays
show signs of progression at the time of follow-up; the annual rate at
which workers showed disease progression were similar, 2 percent and 6
percent, respectively.
    Several cross-sectional and longitudinal studies have examined the
relationship between progressive changes observed on radiographs and
corresponding declines in lung-function parameters. In general, the
results are mixed: some studies have found that pulmonary function
losses correlate with the extent of fibrosis seen on chest x-ray films,
and others have not found such correlations. The lack of a correlation
in some studies between degree of fibrotic profusion seen on chest x-
rays and pulmonary function have led some to suggest that pulmonary
function loss is an independent effect of exposure to respirable
crystalline silica, or may be a consequence of emphysematous changes
that have been seen in conjunction with radiographic silicosis.
    Among studies that have reported finding a relationship between
pulmonary function and x-ray abnormalities, Ng and Chan (1992) found
that forced expiratory volume (FEV1) and forced vital
capacity (FVC) were statistically significantly lower for workers whose
x-ray films were classified as ILO profusion categories 2 and 3, but
not among workers with ILO category 1 profusion compared to those with
a profusion score of 0/0. As expected, highly significant reductions in
FEV1, FVC, and FEV1/FVC were noted in subjects
with large opacities. The authors concluded that chronic simple
silicosis, except that classified as profusion category 1, is
associated with significant lung function impairment attributable to
fibrotic disease.
    Similarly, Moore et al. (1988) also found chronic silicosis to be
associated with significant lung function loss, especially among
workers with chest x-rays classified as ILO profusion categories 2 and
3. For those classified as category 1, lung function was not
diminished. B[eacute]gin et al. (1988) also found a correlation between
decreased lung function (FVC and the ratio of FEV1/FVC) and
increased profusion and coalescence of opacities as determined by CT
scan. This study demonstrated increased impairment among workers with
higher imaging categories (3 and 4), as expected, but also impairment
(significantly reduced expiratory flow rates) among persons with more
moderate pulmonary fibrosis (group 2).
    In a population of gold miners, Cowie (1998) found that lung
function

declined more rapidly in men with silicosis than those without. In
addition to the 24 ml./yr. decrements expected due to aging, this study
found an additional loss of 8 ml. of FEV1 per year would be
expected from continued exposure to dust in the mines. An earlier
cross-sectional study by these authors (Cowie and Mabena, 1991), which
examined 1,197 black underground gold miners who had silicosis, found
that silicosis (analyzed as a continuous variable based on chest x-ray
film classification) was associated with reductions in FVC,
FEV1, FEV1/FVC, and carbon monoxide diffusing
capacity (DLco), and these relationships persisted after
controlling for duration and intensity of exposure and smoking.
    In contrast to these studies, other investigators have reported
finding pulmonary function decrements in exposed workers independent of
radiological evidence of silicosis. Hughes et al. (1982) studied a
representative sample of 83 silicotic sandblasters, 61 of whom were
followed for one to seven years. A multiple regression analysis showed
that the annual reductions in FVC, FEV1 and DLco
were related to average silica concentrations but not duration of
exposure, smoking, stage of silicosis, or time from initial exposure.
Ng et al. (1987b) found that, among male gemstone workers in Hong Kong
with x-rays classified as either Category 0 or 1, declines in
FEV1 and FVC were not associated with radiographic category
of silicosis after adjustment for years of employment. The authors
concluded that there was an independent effect of respirable dust
exposure on pulmonary function. In a population of 61 gold miners,
Wiles et al. (1992) also found that radiographic silicosis was not
associated with lung function decrements. In a re-analysis and follow-
up of an earlier study, Hnizdo (1992) found that silicosis was not a
significant predictor of lung function, except for FEV1 for
non-smokers.
    Wang et al. (1997) observed that silica-exposed workers (both
nonsmokers and smokers), even those without radiographic evidence of
silicosis, had decreased spirometric parameters and diffusing capacity
(DLco). Pulmonary function was further decreased in the
presence of silicosis, even those with mild to moderate disease (ILO
categories 1 and 2). The authors concluded that functional
abnormalities precede radiographic changes of silicosis.
    A number of studies were conducted to examine the role of
emphysematous changes in the presence of silicosis in reducing lung
function; these have been reviewed by Gamble et al. (2004), who
concluded that there is little evidence that silicosis is related to
development of emphysema in the absence of PMF. In addition, Gamble et
al. (2004) found that, in general, studies found that the lung function
of those with radiographic silicosis in ILO category 1 was
indistinguishable from those in category 0, and that those in category
2 had small reductions in lung function relative to those with category
0 and little difference in the prevalence of emphysema. There were
slightly greater decrements in lung function with category 3 and more
significant reductions with progressive massive fibrosis. In studies
for which information was available on both silicosis and emphysema,
reduced lung function was more strongly related to emphysema than to
silicosis.
    In conclusion, many studies reported finding an association between
pulmonary function decrements and ILO category 2 or 3 background
profusion of small opacities; this appears to be consistent with the
histopathological view, in which individual fibrotic nodules
conglomerate to form a massive fibrosis (Ng and Chan, 1992). Emphysema
may also play a role in reducing lung function in workers with higher
grades of silicosis. Pulmonary function decrements have not been
reported in some studies among workers with silicosis scored as ILO
category 1. However, a number of other studies have documented declines
in pulmonary function in persons exposed to silica and whose radiograph
readings are in the major ILO category 1 (i.e. 1/0, 1/1, 1/2), or even
before changes were seen on chest x-ray (B[eacute]gin et al., 1988;
Cowie, 1998; Cowie and Mabena, 1991; Ng et al., 1987a; Wang et al.,
1997). It may also be that studies designed to relate x-ray findings
with pulmonary function declines are further confounded by pulmonary
function declines caused by chronic obstructive pulmonary disease
(COPD) seen among silica-exposed workers absent radiological silicosis,
as has been seen in many investigations of COPD. OSHA's review of the
literature on crystalline silica exposure and development of COPD
appears in section II.D of the background document and is summarized in
section V.D below.
    OSHA believes that the literature reviewed above demonstrates
decreased lung function among workers with radiological evidence of
silicosis consistent with an ILO classification of major category 2 or
higher. Also, given the evidence of functional impairment in some
workers prior to radiological evidence of silicosis, and given the low
sensitivity of radiography, particularly in detecting early silicosis,
OSHA believes that exposure to silica impairs lung function in at least
some individuals before silicosis can be detected on chest radiograph.
4. Pulmonary Tuberculosis
    As silicosis progresses, it may be complicated by severe
mycobacterial infections, the most common of which is pulmonary
tuberculosis (TB). Active tuberculosis infection is a well-recognized
complication of chronic silicosis, and such infections are known as
silicotuberculosis (IARC, 1997; NIOSH, 2002). The risk of developing TB
infection is higher in silicotics than non-silicotics (Balmes, 1990;
Cowie, 1994; Hnizdo and Murray, 1998; Kleinschmidt and Churchyard,
1997; and Murray et al., 1996). There also is evidence that exposure to
silica increases the risk for pulmonary tuberculosis independent of the
presence of silicosis (Cowie, 1994; Hnizdo and Murray, 1998;
teWaterNaude et al., 2006). In a summary of the literature on silica-
related disease mechanisms, Ding et al. (2002) noted that it is well
documented that exposure to silica can lead to impaired cell-mediated
immunity, increasing susceptibility to mycobacterial infection. Reduced
numbers of T-cells, increased numbers of B-cells, and alterations of
serum immunoglobulin levels have been observed in workers with
silicosis. In addition, according to Ng and Chan (1991), silicosis and
TB act synergistically to increase fibrotic scar tissue (leading to
massive fibrosis) or to enhance susceptibility to active mycobacterial
infection. Lung fibrosis is common to both diseases and both diseases
decrease the ability of alveolar macrophages to aid in the clearance of
dust or infectious particles.

B. Carcinogenic Effects of Silica (Cancer of the Lung and Other Sites)

    OSHA conducted an independent review of the epidemiological
literature on exposure to respirable crystalline silica and lung
cancer, covering more than 30 occupational groups in over a dozen
industrial sectors. In addition, OSHA reviewed a pooled case-control
study, a large national death certificate study, two national cancer
registry studies, and six meta-analyses. In all, OSHA's review included
approximately 60 primary epidemiological studies.
    Based on its review, OSHA preliminarily concludes that the human
data summarized in this section

provides ample evidence that exposure to respirable crystalline silica
increases the risk of lung cancer among workers. The strongest evidence
comes from the worldwide cohort and case-control studies reporting
excess lung cancer mortality among workers exposed to respirable
crystalline silica dust as quartz in various industrial sectors,
including the granite/stone quarrying and processing, industrial sand,
mining, and pottery and ceramic industries, as well as to cristobalite
in diatomaceous earth and refractory brick industries. The 10-cohort
pooled case-control analysis by Steenland et al. (2001a) confirms these
findings. A more recent clinic-based pooled case-control analysis of
seven European countries by Cassidy et al. (2007) as well as two
national death certificate registry studies (Pukkala et al., 2005 in
Finland; Calvert et al., 2003 in the United States) support the
findings from the cohort and case-control analysis.
1. Overall and Industry Sector-Specific Findings
    Associations between exposure to respirable crystalline silica and
lung cancer have been reported in worker populations from many
different industrial sectors. IARC (1997) concluded that crystalline
silica is a confirmed human carcinogen based largely on nine studies of
cohorts in four industry sectors that IARC considered to be the least
influenced by confounding factors (sectors included quarries and
granite works, gold mining, ceramic/pottery/refractory brick
industries, and the diatomaceous earth industry). IARC (2012) recently
reaffirmed that crystalline silica is a confirmed human carcinogen.
NIOSH (2002) also determined that crystalline silica is a human
carcinogen after evaluating updated literature.
    OSHA believes that the strongest evidence for carcinogenicity comes
from studies in five industry sectors. These are:
     Diatomaceous Earth Workers (Checkoway et al., 1993, 1996,
1997, and 1999; Seixas et al., 1997);
     British Pottery Workers (Cherry et al., 1998; McDonald et
al., 1995);
     Vermont Granite Workers (Attfield and Costello, 2004;
Graham et al., 2004; Costello and Graham, 1988; Davis et al., 1983);
     North American Industrial Sand Workers (Hughes et al.,
2001; McDonald et al., 2001, 2005; Rando et al., 2001; Sanderson et
al., 2000; Steenland and Sanderson, 2001); and
     British Coal Mining (Miller et al., 2007; Miller and
MacCalman, 2009).
    The studies above were all retrospective cohort or case-control
studies that demonstrated positive, statistically significant exposure-
response relationships between exposure to crystalline silica and lung
cancer mortality. Except for the British pottery studies, where
exposure-response trends were noted for average exposure only, lung
cancer risk was found to be related to cumulative exposure. OSHA
credits these studies because in general, they are of sufficient size
and have adequate years of follow up, and have sufficient quantitative
exposure data to reliably estimate exposures of cohort members. As part
of their analyses, the authors of these studies also found positive
exposure-response relationships for silicosis, indicating that
underlying estimates of worker exposures were not likely to be
substantially misclassified. Furthermore, the authors of these studies
addressed potential confounding due to other carcinogenic exposures
through study design or data analysis.
    A series of studies of the diatomaceous earth industry (Checkoway
et al., 1993, 1996, 1997, 1999) demonstrated positive exposure-response
trends between cristobalite exposures and lung cancer as well as non-
malignant respiratory disease mortality (NMRD). Checkoway et al. (1993)
developed a ``semi-quantitative'' cumulative exposure estimate that
demonstrated a statistically significant positive exposure-response
trend (p = 0.026) between duration of employment or cumulative exposure
and lung cancer mortality. The quartile analysis showed a monotonic
increase in lung cancer mortality, with the highest exposure quartile
having a RR of 2.74 for lung cancer mortality. Checkoway et al. (1996)
conducted a re-analysis to address criticisms of potential confounding
due to asbestos and again demonstrated a positive exposure response
risk gradient when controlling for asbestos exposure and other
variables. Rice et al. (2001) conducted a re-analysis and quantitative
risk assessment of the Checkoway et al. (1997) study, which OSHA has
included as part of its assessment of lung cancer mortality risk (See
Section II, Preliminary Quantitative Risk Assessment).
    In the British pottery industry, excess lung cancer risk was found
to be associated with crystalline silica exposure among workers in a
PMR study (McDonald et al., 1995) and in a cohort and nested case-
control study (Cherry et al., 1998). In the PMR study, elevated PMRs
for lung cancer were found after adjusting for potential confounding by
asbestos exposure. In the study by Cherry et al., odds ratios for lung
cancer mortality were statistically significantly elevated after
adjusting for smoking. Odds ratios were related to average, but not
cumulative, exposure to crystalline silica. The findings of the British
pottery studies are supported by other studies within their industrial
sector. Studies by Winter et al. (1990) of British pottery workers and
by McLaughlin et al. (1992) both reported finding suggestive trends of
increased lung cancer mortality with increasing exposure to respirable
crystalline silica.
    Costello and Graham (1988) and Graham et al. (2004) in a follow-up
study found that Vermont granite workers employed prior to 1930 had an
excess risk of lung cancer, but lung cancer mortality among granite
workers hired after 1940 (post-implementation of controls) was not
elevated in the Costello and Graham (1988) study and was only somewhat
elevated (not statistically significant) in the Graham et al. (2004)
study. Graham et al. (2004) concluded that their results did not
support a causal relationship between granite dust exposure and lung
cancer mortality. Looking at the same population, Attfield and Costello
(2004) developed a quantitative estimate of cumulative exposure (8
exposure categories) adapted from a job exposure matrix developed by
Davis et al. (1983). They found a statistically significant trend with
log-transformed cumulative exposure. Lung cancer mortality rose
reasonably consistently through the first seven increasing exposure
groups, but fell in the highest cumulative exposure group. With the
highest exposure group omitted, a strong positive dose-response trend
was found for both untransformed and log-transformed cumulative
exposures. Attfield and Costello (2004) concluded that exposure to
crystalline silica in the range of cumulative exposures typically
experienced by contemporarily exposed workers causes an increased risk
of lung cancer mortality. The authors explained that the highest
exposure group would have included the most unreliable exposure
estimates being reconstructed from exposures 20 years prior to study
initiation when exposure estimation was less precise. Also, even though
the highest exposure group consisted of only 15 percent of the study
population, it had a disproportionate effect on dampening the exposure-
response relationship.
    OSHA believes that the study by Attfield and Costello (2004) is of
superior design in that it was a categorical analysis that used

quantitative estimates of exposure and evaluated lung cancer mortality
rates by exposure group. In contrast, the findings by Graham et al.
(2004) are based on a dichotomous comparison of risk among high- versus
low-exposure groups, where date-of-hire before and after implementation
of ventilation controls is used as a surrogate for exposure.
Consequently, OSHA believes that the study by Attfield and Costello is
the more convincing study, and is one of the studies used by OSHA for
quantitative risk assessment of lung cancer mortality due to
crystalline silica exposure.
    The conclusions of the Vermont granite worker study (Attfield and
Costello, 2004) are supported by the findings in studies of workers in
the U.S. crushed stone industry (Costello et al., 1995) and Danish
stone industry (Gu[eacute]nel et al., 1989a, 1989b). Costello et al.
(1995) found a non-statistically significant increase in lung cancer
mortality among limestone quarry workers and a statistically
significant increased lung cancer mortality in granite quarry workers
who worked 20 years or more since first exposure. Gu[eacute]nel et al.
(1989b), in a Danish cohort study, found statistically significant
increases in lung cancer incidence among skilled stone workers and
skilled granite stone cutters. A study of Finnish granite workers that
initially showed increasing risk of lung cancer with increasing silica
exposure, upon extended follow-up, did not show an association and is
therefore considered a negative study (Toxichemica, Inc., 2004).
    Studies of two overlapping cohorts in the industrial sand industry
(Hughes et al., 2001; McDonald et al., 2001, 2005; Rando et al., 2001;
Sanderson et al., 2000; Steenland and Sanderson, 2001) reported
comparable results. These studies found a statistically significantly
increased risk of lung cancer mortality with increased cumulative
exposure in both categorical and continuous analyses. McDonald et al.
(2001) examined a cohort that entered the workforce, on average, a
decade earlier than the cohorts that Steenland and Sanderson (2001)
examined. The McDonald cohort, drawn from eight plants, had more years
of exposure in the industry (19 versus 8.8 years). The Steenland and
Sanderson (2001) cohort worked in 16 plants, 7 of which overlapped with
the McDonald, et al. (2001) cohort. McDonald et al. (2001), Hughes et
al. (2001), and Rando et al. (2001) had access to smoking histories,
plant records, and exposure measurements that allowed for historical
reconstruction and the development of a job exposure matrix. Steenland
and Sanderson (2001) had limited access to plant facilities, less
detailed historic exposure data, and used MSHA enforcement records for
estimates of recent exposure. These studies (Hughes et al., 2001;
McDonald et al., 2005; Steenland and Sanderson, 2001) show very similar
exposure response patterns of increased lung cancer mortality with
increased exposure. OSHA included the quantitative exposure-response
analysis from the Hughes et al. (2001) study in its Preliminary
Quantitative Risk Assessment (Section II).
    Brown and Rushton (2005a, 2005b) found no association between risk
of lung cancer mortality and exposure to respirable crystalline silica
among British industrial sand workers. However, the small sample size
and number of years of follow-up limited the statistical power of the
analysis. Additionally, as Steenland noted in a letter review (2005a),
the cumulative exposures of workers in the Brown and Ruston (2005b)
study were over 10 times lower than the cumulative exposures
experienced by the cohorts in the pooled analysis that Steenland et al.
(2001b) performed. The low exposures experienced by this cohort would
have made detecting a positive association with lung cancer mortality
even more difficult.
    Excess lung cancer mortality was reported in a large cohort study
of British coal miners (Miller et al., 2007; Miller and MacCalman,
2009). These studies examined the mortality experience of 17,800 miners
through the end of 2005. By that time, the cohort had accumulated
516,431 person years of observation (an average of 29 years per miner),
with 10,698 deaths from all causes. Overall lung cancer mortality was
elevated (SMR=115.7, 95% C.I. 104.8-127.7), and a positive exposure-
response relationship with crystalline silica exposure was determined
from Cox regression after adjusting for smoking history. Three of the
strengths of this study are the detailed time-exposure measurements of
both quartz and total mine dust, detailed individual work histories,
and individual smoking histories. For lung cancer, analyses based on
the Cox regression provide strong evidence that, for these coal miners,
quartz exposures were associated with increased lung cancer risk but
that simultaneous exposures to coal dust did not cause increased lung
cancer risk. Because of these strengths, OSHA included the quantitative
analysis from this study in its Preliminary Quantitative Risk
Assessment (Section II).
    Studies of lung cancer mortality in metal ore mining populations
reflect mixed results. Many of these mining studies were subject to
confounding due to exposure to other potential carcinogens such as
radon and arsenic. IARC (1997) noted that in only a few ore mining
studies was confounding from other occupational carcinogens taken into
account. IARC (1997) also noted that, where confounding was absent or
accounted for in the analysis (gold miners in the U.S., tungsten miners
in China, and zinc and lead miners in Sardinia, Italy), an association
between silica exposure and lung cancer was absent. Many of the studies
conducted since IARC's (1997) review more strongly implicate
crystalline silica as a human carcinogen. Pelucchi et al. (2006), in a
meta-analysis of studies conducted since IARC's (1997) review, reported
statistically significantly elevated relative risks of lung cancer
mortality in underground and surface miners in three cohort and four
case-control studies (See Table I-15). Cassidy et al. (2007), in a
pooled case-control analysis, showed a statistically significant
increased risk of lung cancer mortality among miners (OR = 1.48).
Cassidy et al. (2007) also demonstrated a clear linear trend of
increasing odds ratios for lung cancer with increasing exposures.
    Among workers in Chinese tungsten and iron mines, mortality from
lung cancer was not found to be statistically significantly increased
(Chen et al., 1992; McLaughlin et al., 1992). In contrast, studies of
Chinese tin miners found increased lung cancer mortality rates and
positive exposure-response associations with increased silica exposure
(Chen et al., 1992). Unfortunately, in many of these Chinese tin mines,
there was potential confounding from arsenic exposure, which was highly
correlated with exposure to crystalline silica (Chen and Chen, 2002;
Chen et al., 2006). Two other studies (Carta et al. (2001) of Sardinian
miners and stone quarrymen; Finkelstein (1998) primarily of Canadian
miners) were limited to silicotics. The Sardinian study found a non-
statistically significant association between crystalline silica
exposure and lung cancer mortality but no apparent exposure-response
trend with silica exposure. The authors attributed the increased lung
cancer to increased radon exposure and smoking among cases as compared
to controls. Finkelstein (1998) found a positive association between
silica exposure and lung cancer.
    Gold mining has been extensively studied in the United States,
South

Africa, and Australia in four cohort and associated nested case-control
studies, and in two separate case-control studies conducted in South
Africa. As with metal ore mining, gold mining involves exposure to
radon and other carcinogenic agents, which may confound the
relationship between silica exposure and lung cancer. The U.S. gold
miner study (Steenland and Brown, 1995a) did not find an increased risk
of lung cancer, while the western Australian gold miner study (de Klerk
and Musk, 1998) showed a SMR of 149 (95% CI 1.26-1.76) for lung cancer.
Logistic regression analysis of the western Australian case control
data showed that lung cancer mortality was statistically significantly
associated with log cumulative silica exposure after adjusting for
smoking and bronchitis. After additionally adjusting for silicosis, the
relative risk remained elevated but was no longer statistically
significant. The authors concluded that their findings showed
statistically significantly increased lung cancer mortality in this
cohort but that the increase in lung cancer mortality was restricted to
silicotic members of the cohort.
    Four studies of gold miners were conducted in South Africa. Two
case control studies (Hessel et al., 1986, 1990) reported no
significant association between silica exposure and lung cancer, but
these two studies may have underestimated risk, according to Hnizdo and
Sluis-Cremer (1991). Two cohort studies (Reid and Sluis-Cremer, 1996;
Hnizdo and Sluis-Cremer, 1991) and their associated nested case-control
studies found elevated SMRs and odds ratios, respectively, for lung
cancer. Reid and Sluis-Cremer (1996) attributed the increased mortality
due to lung cancer and other non-malignant respiratory diseases to
cohort members' lifestyle choices (particularly smoking and alcohol
consumption). However, OSHA notes that the study reported finding a
positive, though not statistically significant, association between
cumulative crystalline silica exposure and lung cancer, as well as
statistically significant association with renal failure, COPD, and
other respiratory diseases that have been implicated with silica
exposure.
    In contrast, Hnizdo and Sluis-Cremer (1991) found a positive
exposure-response relationship between cumulative exposure and lung
cancer mortality among South African gold miners after accounting for
smoking. In a nested case-control study from the same cohort, Hnizdo et
al. (1997) found a statistically significant increase in lung cancer
mortality that was associated with increased cumulative dust exposure
and time spent underground. Of the studies examining silica and lung
cancer among South African gold miners, these two studies were the
least likely to have been affected by exposure misclassification, given
their rigorous methodologies and exposure measurements. Although not
conclusive in isolation, OSHA considers the mining study results,
particularly the gold mining and the newer mining studies, as
supporting evidence of a causal relationship between exposure to silica
and lung cancer risk.
    OSHA has preliminarily determined that the results of the studies
conducted in three industry sectors (foundry, silicon carbide, and
construction sectors) were confounded by the presence of exposures to
other carcinogens. Exposure data from these studies were not sufficient
to distinguish between exposure to silica dust and exposure to other
occupational carcinogens. Thus, elevated rates of lung cancer found in
these industries could not be attributed to silica. IARC previously
made a similar determination in reference to the foundry industry.
However, with respect to the construction industry, Cassidy et al.
(2007), in a large, European community-based case-control study,
reported finding a clear linear trend of increasing odds ratio with
increasing cumulative exposure to crystalline silica (estimated semi-
quantitatively) after adjusting for smoking and exposure to insulation
and wood dusts. Similar trends were found for workers in the
manufacturing and mining industries as well. This study was a very
large multi-national study that utilized information on smoking
histories and exposure to silica and other occupational carcinogens.
OSHA believes that this study provides further evidence that exposure
to crystalline silica increases the risk of lung cancer mortality and,
in particular, in the construction industry.
    In addition, a recent analysis of 4.8 million death certificates
from 27 states within the U.S. for the years 1982 to 1995 showed
statistically significant excesses in lung cancer mortality, silicosis
mortality, tuberculosis, and NMRD among persons with occupations
involving medium and high exposure to respirable crystalline silica
(Calvert et al., 2003). A national records and death certificate study
was also conducted in Finland by Pukkala et al. (2005), who found a
statistically significant excess of lung cancer incidence among men and
women with estimated medium and heavy exposures. OSHA believes that
these large national death certificate studies and the pooled European
community-based case-control study are strongly supportive of the
previously reviewed epidemiologic data and supports the conclusion that
occupational exposure to crystalline silica is a risk factor for lung
cancer mortality.
    One of the more compelling studies evaluated by OSHA is the pooled
analysis of 10 occupational cohorts (5 mines and 5 industrial
facilities) conducted by Steenland et al. (2001a), which demonstrated
an overall positive exposure-response relationship between cumulative
exposure to silica and lung cancer mortality. These ten cohorts
included 65,980 workers and 1,072 lung cancer deaths, and were selected
because of the availability of raw data on exposure to crystalline
silica and health outcomes. The investigators used a nested case
control design and found lung cancer risk increased with increasing
cumulative exposure, log cumulative exposure, and average exposure.
Exposure-response trends were similar between mining and non-mining
cohorts. From their analysis, the authors concluded that ``[d]espite
this relatively shallow exposure-response trend, overall our results
tend to support the recent conclusion by IARC (1997) that inhaled
crystalline silica in occupational settings is a human carcinogen, and
suggest that existing permissible exposure limits for silica need to be
lowered (Steenland et al., 2001a). To evaluate the potential effect of
random and systematic errors in the underlying exposure data from these
10 cohort studies, Steenland and Bartell (Toxichemica, Inc., 2004)
conducted a series of sensitivity analyses at OSHA's request. OSHA's
Preliminary Quantitative Risk Assessment (Section II) presents
additional information on the Steenland et al. (2001a) pooled cohort
study and the sensitivity analysis performed by Steenland and Bartell
(Toxichemica, Inc., 2004).
2. Smoking, Silica Exposure, and Lung Cancer
    Smoking is known to be a major risk factor for lung cancer.
However, OSHA believes it is unlikely that smoking explains the
observed exposure-response trends in the studies described above,
particularly the retrospective cohort or nested case-control studies of
diatomaceous earth, British pottery, Vermont granite, British coal,
South African gold, and industrial sand workers. Also, the positive
associations between silica exposure and lung cancer in multiple
studies in multiple sectors indicates that exposure to crystalline

silica independently increases the risk of lung cancer.
    Studies by Hnizdo et al. (1997), McLaughlin et al. (1992), Hughes
et al. (2001), McDonald et al. (2001, 2005), Miller and MacCalman
(2009), and Cassidy et al. (2007) had detailed smoking histories with
sufficiently large populations and a sufficient number of years of
follow-up time to quantify the interaction between crystalline silica
exposure and cigarette smoking. In a cohort of white South African gold
miners (Hnizdo and Sluis-Cremer, 1991) and in the follow-up nested
case-control study (Hnizdo et al., 1997) found that the combined effect
of exposure to respirable crystalline silica and smoking was greater
than additive, suggesting a multiplicative effect. This synergy
appeared to be greatest for miners with greater than 35 pack-years of
smoking and higher cumulative exposure to silica. In the Chinese nested
case-control studies reported by McLaughlin et al. (1992), cigarette
smoking was associated with lung cancer, but control for smoking did
not influence the association between silica and lung cancer in the
mining and pottery cohorts studied. The studies of industrial sand
workers by Hughes et al. (2001) and British coal workers by Miller and
MacCalman (2009) found positive exposure-response trends after
adjusting for smoking histories, as did Cassidy et al. (2007) in their
community-based case-control study of exposed European workers.
    In reference to control of potential confounding by cigarette
smoking in crystalline silica studies, Stayner (2007), in an invited
journal commentary, stated:

    Of particular concern in occupational cohort studies is the
difficulty in adequately controlling for confounding by cigarette
smoking. Several of the cohort studies that adjusted for smoking
have demonstrated an excess of lung cancer, although the control for
smoking in many of these studies was less than optimal. The results
of the article by Cassidy et al. presented in this journal appear to
have been well controlled for smoking and other workplace exposures.
It is quite implausible that residual confounding by smoking or
other risk factors for lung cancer in this or other studies could
explain the observed excess of lung cancer in the wide variety of
populations and study designs that have been used. Also, it is
generally considered very unlikely that confounding by smoking could
explain the positive exposure-response relationships observed in
these studies, which largely rely on comparisons between workers
with similar socioeconomic backgrounds.

    Given the findings of investigators who have accounted for the
impact of smoking, the weight of the evidence reviewed here implicates
respirable crystalline silica as an independent risk factor for lung
cancer mortality. This finding is further supported by animal studies
demonstrating that exposure to silica alone can cause lung cancer
(e.g., Muhle et al., 1995).
3. Silicosis and Lung Cancer Risk
    In general, studies of workers with silicosis, as well as meta-
analyses that include these studies, have shown that workers with
radiologic evidence of silicosis have higher lung cancer risk than
those without radiologic abnormalities or mixed cohorts. Three meta-
analyses attempted to look at the association of increasing ILO
radiographic categories of silicosis with increasing lung cancer
mortality. Two of these analyses (Kurihara and Wada, 2004; Tsuda et
al., 1997) showed no association with increasing lung cancer mortality,
while Lacasse et al. (2005) demonstrated a positive dose-response for
lung cancer with increasing ILO radiographic category. A number of
other studies, discussed above, found increased lung cancer risk among
exposed workers absent radiological evidence of silicosis (Cassidy et
al., 2007; Checkoway et al., 1999; Cherry et al., 1998; Hnizdo et al.,
1997; McLaughlin et al., 1992). For example, the diatomaceous earth
study by Checkoway et al. (1999) showed a statistically significant
exposure-response for lung cancer among non-silicotics. Checkoway and
Franzblau (2000), reviewing the international literature, found all
epidemiological studies conducted to that date were insufficient to
conclusively determine the role of silicosis in the etiology of lung
cancer. OSHA preliminarily concludes that the more recent pooled and
meta-analyses do not provide compelling evidence that silicosis is a
necessary precursor to lung cancer. The analyses that do suggest an
association between silicosis and lung cancer may simply reflect that
more highly exposed individuals are at a higher risk for lung cancer.
    Animal and in vitro studies have demonstrated that the early steps
in the proposed mechanistic pathways that lead to silicosis and lung
cancer seem to share some common features. This has led some of these
researchers to also suggest that silicosis is a prerequisite to lung
cancer. Some have suggested that any increased lung cancer risk
associated with silica may be a consequence of the inflammation (and
concomitant oxidative stress) and increased epithelial cell
proliferation associated with the development of silicosis. However,
other researchers have noted that other key factors and proposed
mechanisms, such as direct damage to DNA by silica, inhibition of p53,
loss of cell cycle regulation, stimulation of growth factors, and
production of oncogenes, may also be involved in carcinogenesis induced
by silica (see Section II.F of the background document for more
information on these studies). Thus, OSHA preliminarily concludes that
available animal and in vitro studies do not support the hypothesis
that development of silicosis is necessary for silica exposure to cause
lung cancer.
4. Relationship Between Silica Polymorphs and Lung Cancer Risk
    OSHA's current PELs for respirable crystalline silica reflects a
once-held belief that cristobalite is more toxic than quartz (i.e., the
existing general industry PEL for cristobalite is one-half the general
industry PEL for quartz). Available evidence indicates that this does
not appear to be the case with respect to the carcinogenicity of
crystalline silica. A comparison between cohorts having principally
been exposed to cristobalite (the diatomaceous earth study and the
Italian refractory brick study) with other well conducted studies of
quartz-exposed cohorts suggests no difference in the toxicity of
cristobalite versus quartz. The data indicates that the SMRs for lung
cancer mortality among workers in the diatomaceous earth (SMR = 141)
and refractory brick (SMR=151) cohort studies are within the range of
the SMR point estimates of other cohort studies with principally quartz
exposures (quartz exposure of Vermont granite workers yielding an SMR
of 117; quartz and possible post-firing cristobalite exposure of
British pottery workers yielding an SMR of 129; quartz exposure among
industrial sand workers yielding SMRs of 129, (McDonald et al., 2001)
and 160 (Steenland and Sanderson, 2001)). Also, the SMR point estimates
for the diatomaceous earth and refractory brick studies are similar to,
and fall within the 95 percent confidence interval of, the odds ratio
(OR=1.37, 95% CI 1.14-1.65) of the recently conducted multi-center
case-control study in Europe (Cassidy et al., 2007).
    OSHA believes that the current epidemiological literature provides
little, if any, support for treating cristobalite as presenting a
greater lung cancer risk than comparable exposure to respirable quartz.
Furthermore, the weight of the available toxicological literature no
longer supports the hypothesis that cristobalite has a higher toxicity
than quartz, and quantitative

estimates of lung cancer risk do not suggest that cristobalite is more
carcinogenic than quartz. (See Section I.F of the background document,
Physical Factors that May Influence Toxicity of Crystalline Silica, for
a fuller discussion of this issue.) OSHA preliminary concludes that
respirable cristobalite and quartz dust have similar potencies for
increasing lung cancer risk. Both IARC (1997) and NIOSH (2002) reached
similar conclusions.
5. Cancers of Other Sites
    Respirable crystalline silica exposure has also been investigated
as a potential risk factor for cancer at other sites such as the
larynx, nasopharynx and the digestive system including the esophagus
and stomach. Although many of these studies suggest an association
between exposure to crystalline silica and an excess risk of cancer
mortality, most are too limited in terms of size, study design, or
potential for confounding to be conclusive. Other than for lung cancer,
cancer mortality studies demonstrating a dose-response relationship are
quite limited. In their silica hazard review, NIOSH (2002) concluded
that, exclusive of the lung, an association has not been established
between silica exposure and excess mortality from cancer at other
sites. A brief summary of the relevant literature is presented below.
a. Cancer of the Larynx and Nasopharynx
    Several studies, including three of the better-quality lung cancer
studies (Checkoway et al., 1997; Davis et al., 1983; McDonald et al.,
2001) suggest an association between exposure to crystalline silica and
increased mortality from laryngeal cancer. However, the evidence for an
association is not strong due to the small number of cases reported and
lack of statistical significance of most of the findings.
b. Gastric (Stomach) Cancer
    In their 2002 hazard review of respirable crystalline silica, NIOSH
identified numerous epidemiological studies and reported statistically
significant increases in death rates due to gastric or stomach cancer.
OSHA preliminarily concurs with observations made previously by Cocco
et al. (1996) and the NIOSH (2002) crystalline silica hazard review
that the vast majority of epidemiology studies of silica and stomach
cancer have not sufficiently adjusted for the effects of confounding
factors or have not been sufficiently designed to assess a dose-
response relationship (e.g., Finkelstein and Verma, 2005; Moshammer and
Neuberger, 2004; Selikoff, 1978, Stern et al., 2001). Other studies did
not demonstrate a statistically significant dose-response relationship
(e.g., Calvert et al., 2003; Tsuda et al., 2001). Therefore, OSHA
believes the evidence is insufficient to conclude that silica is a
gastric carcinogen.
c. Esophageal Cancer
    Three well-conducted nested case-control studies of Chinese workers
indicated an increased risk of esophageal cancer mortality attributed
by the study's authors to respirable crystalline silica exposure in
refractory brick production, boiler repair, and foundry workers (Pan et
al., 1999; Wernli et al., 2006) and caisson construction work (Yu et
al., 2005). Each study demonstrated a dose-response association with
some surrogate measure of exposure, but confounding due to other
occupational exposures is possible in all three work settings (heavy
metal exposure in the repair of boilers in steel plants, PAH exposure
in foundry workers, radon and radon daughter exposure in Hong Kong
caisson workers). Other less well-constructed studies also indicated
elevated rates of esophageal cancer mortality with silica exposure
(Tsuda et al., 2001; Xu et al., 1996a).
    In contrast, two large national mortality studies in Finland and
the United States, using qualitatively ranked exposure estimates, did
not show a positive association between silica exposure and esophageal
cancer mortality (Calvert et al., 2003; Weiderpass et al., 2003). OSHA
preliminarily concludes that the epidemiological literature is not
sufficiently robust to attribute increased esophageal cancer mortality
to exposure to respirable crystalline silica.
d. Other Miscellaneous Cancers
    In 2002, NIOSH conducted a thorough literature review of the health
effects potentially associated with crystalline silica exposure
including a review of lung cancer and other carcinogens. NIOSH noted
that for workers who may have been exposed to crystalline silica, there
have been infrequent reports of statistically significant excesses of
deaths for other cancers. A summary of these cancer studies as cited in
NIOSH (2002) have been reported in the following organ systems (see
NIOSH, 2002 for full bibliographic references): salivary gland; liver;
bone; pancreatic; skin; lymphopoetic or hematopoietic; brain; and
bladder.
    According to NIOSH (2002), an association has not been established
between these cancers and exposure to crystalline silica. OSHA believes
that these isolated reports of excess cancer mortality at these sites
are not sufficient to draw any inferences about the role of silica
exposure. The findings have not been consistently seen among
epidemiological studies and there is no evidence of an exposure
response relationship.

C. Other Nonmalignant Respiratory Disease

    In addition to causing silicosis, exposure to crystalline silica
has been associated with increased risks of other non-malignant
respiratory diseases (NMRD), primarily chronic obstructive pulmonary
disease (COPD). COPD is a disease state characterized by airflow
limitation that is not fully reversible. The airflow limitation is
usually progressive and is associated with an abnormal inflammatory
response of the lungs to noxious particles or gases. In patients with
COPD, either chronic bronchitis or emphysema may be present or both
conditions may be present together. The following presents OSHA's
discussion of the literature describing the relationships between
silica exposure and non-malignant respiratory disease.
1. Emphysema
    OSHA has considered a series of longitudinal studies of white South
African gold miners conducted by Hnizdo and co-workers. Hnizdo et al.
(1991) found a significant association between emphysema (both
panacinar and centriacinar) and years of employment in a high dust
occupation (respirable dust was estimated to contain 30 percent free
silica). There was no such association found for non-smokers, as there
were only four non-smokers with a significant degree of emphysema found
in the cohort. A further study by Hnizdo et al. (1994) looked at only
life-long non-smoking South African gold miners. In this population, no
significant degree of emphysema or association with years of exposure
or cumulative dust exposure was found. However, the degree of emphysema
was significantly associated with the degree of hilar gland nodules,
which the authors suggested might act as a surrogate for exposure to
silica. The authors concluded that the minimal degree of emphysema seen
in non-smoking miners exposed to the cumulative dust levels found in
this study (mean 6.8 mg/m\3\, SD 2.4, range 0.5 to 20.2, 30 percent
crystalline silica) was unlikely to cause meaningful impairment of lung
function.

    From the two studies above, Hnizdo et al. (1994) concluded that the
statistically significant association between exposure to silica dust
and the degree of emphysema in smokers suggests that tobacco smoking
potentiates the effect of silica dust. In contrast to their previous
studies, a later study by Hnizdo et al. (2000) of South African gold
miners found that emphysema prevalence was decreased in relation to
dust exposure. The authors suggested that selection bias was
responsible for this finding.
    The findings of several cross-sectional and case-control studies
were more mixed. Becklake et al. (1987), in an unmatched case-control
study of white South African gold miners, determined that a miner who
had worked in high dust for 20 years had a greater chance of getting
emphysema than a miner who had never worked in high dust. A reanalysis
of this data (de Beer et al., 1992) including added-back cases and
controls (because of possible selection bias in the original study),
still found an increased risk for emphysema, although the reported odds
ratio was smaller than previously reported by Becklake et al. (1987).
Begin et al. (1995), in a study of the prevalence of emphysema in
silica-exposed workers with and without silicosis, found that silica-
exposed smokers without silicosis had a higher prevalence of emphysema
than a group of asbestos-exposed workers with similar smoking history.
In non-smokers, the prevalence of emphysema was much higher in those
with silicosis than in those without silicosis. A study of black
underground gold miners found that the presence and grade of emphysema
were statistically significantly associated with the presence of
silicosis but not with years of mining (Cowie et al., 1993).
    Several of the above studies (Becklake et al., 1987; Begin et al.,
1995; Hnizdo et al., 1994) found that emphysema can occur in silica-
exposed workers who do not have silicosis and suggest that a causal
relationship may exist between exposure to silica and emphysema. The
findings of experimental (animal) studies that emphysema occurs at
lower silica doses than does fibrosis in the airways or the appearance
of early silicotic nodules (e.g., Wright et al., 1988) tend to support
the findings in human studies that silica-induced emphysema can occur
absent signs of silicosis.
    Others have also concluded that there is a relationship between
emphysema and exposure to crystalline silica. Green and Vallyathan
(1996) reviewed several studies of emphysema in workers exposed to
silica. The authors stated that these studies show an association
between cumulative dust exposure and death from emphysema. IARC (1997)
has also briefly reviewed studies on emphysema in its monograph on
crystalline silica carcinogenicity and concluded that exposure to
crystalline silica increases the risk of emphysema. In their 2002
Hazard Review, NIOSH concluded that occupational exposure to respirable
crystalline silica is associated with emphysema but that some
epidemiologic studies suggested that this effect may be less frequent
or absent in non-smokers.
    Hnizdo and Vallyathan (2003) also conducted a review of studies
addressing COPD due to occupational silica exposure and concluded that
chronic exposure to silica dust at levels that do not cause silicosis
may cause emphysema.
    Based on these findings, OSHA preliminarily concludes that exposure
to respirable crystalline silica or silica-containing dust can increase
the risk of emphysema, regardless of whether silicosis is present. This
appears to be clearly the case for smokers. It is less clear whether
nonsmokers exposed to silica would also be at higher risk and if so, at
what levels of exposure. It is also possible that smoking potentiates
the effect of silica dust in increasing emphysema risk.
2. Chronic Bronchitis
    There were no longitudinal studies available designed to
investigate the relationship between silica exposure and bronchitis.
However, several cross-sectional studies provide useful information.
Studies are about equally divided between those that have reported a
relationship between silica exposure and bronchitis and those that have
not. Several studies demonstrated a qualitative or semiquantitative
relationship between silica exposure and chronic bronchitis. Sluis-
Cremer et al. (1967) found a significant difference between the
prevalence of chronic bronchitis in dust-exposed and non-dust exposed
male residents of a South African gold mining town who smoked, but
found no increased prevalence among non-smokers. In contrast, a
different study of South African gold miners found that the prevalence
of chronic bronchitis increased significantly with increasing dust
concentration and cumulative dust exposure in smokers, nonsmokers, and
ex-smokers (Wiles and Faure, 1977). Similarly, a study of Western
Australia gold miners found that the prevalence of chronic bronchitis,
as indicated by odds ratios (controlled for age and smoking), was
significantly increased in those that had worked in the mines for 1 to
9 years, 10 to 19 years, and more than 20 years, as compared to
lifetime non-miners (Holman et al., 1987). Chronic bronchitis was
present in 62 percent of black South African gold miners and 45 percent
of those who had never smoked in a study by Cowie and Mabena (1991).
The prevalence of what the researchers called ``chronic bronchitic
symptom complex'' reflected the intensity of dust exposure. A higher
prevalence of respiratory symptoms, independent of smoking and age, was
also found for granite quarry workers in Singapore in a high exposure
group as compared to low exposure and control groups, even after
excluding those with silicosis from the analysis (Ng et al., 1992b).
    Other studies found no relationship between silica exposure and the
prevalence of chronic bronchitis. Irwig and Rocks (1978) compared
silicotic and non-silicotic South African gold miners and found no
significant difference in symptoms of chronic bronchitis. The
prevalence of symptoms of chronic bronchitis were also not found to be
associated with years of mining, after adjusting for smoking, in a
population of current underground uranium miners (Samet et al., 1984).
Silica exposure was described in the study to be ``on occasion'' above
the TLV. It was not possible to determine, however, whether miners with
respiratory diseases had left the workforce, making the remaining
population unrepresentative. Hard-rock (molybdenum) miners, with 27 and
49 percent of personal silica samples greater than 100 and 55 [mu]g/
m\3\, respectively, also showed no increase in prevalence of chronic
bronchitis in association with work in that industry (Kreiss et al.,
1989). However, the authors thought that differential out-migration of
symptomatic miners and retired miners from the industry and town might
explain that finding. Finally, grinders of agate stones (with resulting
dust containing 70.4 percent silica) in India also had no increase in
the prevalence of chronic bronchitis compared to controls matched by
socioeconomic status, age and smoking, although there was a
significantly higher prevalence of acute bronchitis in female grinders.
A significantly higher prevalence and increasing trend with exposure
duration for pneumoconiosis in the agate workers indicated that had an
increased prevalence in chronic bronchitis been present, it would have
been detected (Rastogi et al., 1991). However, control workers in this
study may also have been exposed to silica and the study and control
workers both

had high tuberculosis prevalence, possibly masking an association of
exposure with bronchitis (NIOSH, 2002). Furthermore, exposure durations
were very short.
    Thus, some prevalence studies supported a finding of increased
bronchitis in workers exposed to silica-containing dust, while other
studies did not support such a finding. However, OSHA believes that
many of the studies that did not find such a relationship were likely
to be biased towards the null. For example, some of the molybdenum
miners studied by Kreiss et al. (1989), particularly retired and
symptomatic miners, may have left the town and the industry before the
time that the cross-sectional study was conducted, resulting in a
survivor effect that could have interfered with detection of a possible
association between silica exposure and bronchitis. This survivor
effect may also have been operating in the study of uranium miners in
New Mexico (Samet et al., 1984). In two of the negative studies,
members of comparison and control groups were also exposed to
crystalline silica (Irwig and Rocks, 1978; Rastogi et al., 1991),
creating a potential bias toward the null. Additionally, tuberculosis
in both exposed and control groups in the agate worker study (Rastogi
et al., 1991)) may have masked an effect (NIOSH, 2002), and the
exposure durations were very short. Several of the positive studies
demonstrated a qualitative or semi-quantitative relationship between
silica exposure and chronic bronchitis.
    Others have reviewed relevant studies and also concluded that there
is a relationship between exposure to crystalline silica and the
development of bronchitis. The American Thoracic Society (ATS) (1997)
published an official statement on the adverse effects of crystalline
silica exposure that included a section that discussed studies on
chronic bronchitis (defined by chronic sputum production). According to
the ATS review, chronic bronchitis was found to be common among worker
groups exposed to dusty environments contaminated with silica. In
support of this conclusion, ATS cited studies with what they viewed as
positive findings of South African (Hnizdo et al., 1990) and Australian
(Holman et al., 1987) gold miners, Indonesian granite workers (Ng et
al., 1992b), and Indian agate workers (Rastogi et al., 1991). ATS did
not mention studies with negative findings.
    A review published by NIOSH in 2002 discussed studies related to
silica exposure and development of chronic bronchitis. NIOSH concluded,
based on the same studies reviewed by OSHA, that occupational exposure
to respirable crystalline silica is associated with bronchitis, but
that some epidemiologic studies suggested that this effect may be less
frequent or absent in non-smokers.
    Hnizdo and Vallyathan (2003) also reviewed studies addressing COPD
due to occupational silica exposure and concluded that chronic exposure
to silica dust at levels that do not cause silicosis may cause chronic
bronchitis. They based this conclusion on studies that they cited as
showing that the prevalence of chronic bronchitis increases with
intensity of exposure. The cited studies were also reviewed by OSHA
(Cowie and Mabena, 1991; Holman et al., 1987; Kreiss et al., 1989;
Sluis-Cremer et al., 1967; Wiles and Faure, 1977).
    OSHA preliminarily concludes that exposure to respirable
crystalline silica may cause chronic bronchitis and an exposure-
response relationship may exist. Smokers may be at increased risk as
compared to non-smokers. Chronic bronchitis may occur in silica-exposed
workers who do not have silicosis.
3. Pulmonary Function Impairment
    OSHA has reviewed numerous studies on the relationship of silica
exposure to pulmonary function impairment as measured by spirometry.
There were several longitudinal studies available. Two groups of
researchers conducted longitudinal studies of lung function impairment
in Vermont granite workers and reached opposite conclusions. Graham et
al (1981, 1994) examined stone shed workers, who had the highest
exposures to respirable crystalline silica (between 50 and 100 [mu]g/
m\3\), along with quarry workers (presumed to have lower exposure) and
office workers (expected to have negligible exposure). The longitudinal
losses of FVC and FEV1 were not correlated with years
employed, did not differ among shed, quarry, and office workers, and
were similar, according to the authors, to other blue collar workers
not exposed to occupational dust.
    Eisen et al. (1983, 1995) found the opposite. They looked at lung
function in two groups of granite workers: ``survivors'', who
participated in each of five annual physical exams, and ``dropouts'',
who did not participate in the final exam. There was a significant
exposure-response relationship between exposure to crystalline silica
and FEV1 decline among the dropouts but not among the
survivors. The dropout group had a steeper FEV1 loss, and
this was true for each smoking category. The authors concluded that
exposures of about 50 ug/m\3\ produced a measurable effect on pulmonary
function in the dropouts. Eisen et al. (1995) felt that the ``healthy
worker effect'' was apparent in this study and that studies that only
looked at ``survivors'' would be less likely to see any effect of
silica on pulmonary function.
    A 12-year follow-up of age- and smoking-matched granite crushers
and referents in Sweden found that over the follow-up period, the
granite crushers had significantly greater decreases in
FEV1, FEV1/FVC, maximum expiratory flow, and
FEF50 than the referents (Malmberg et al., 1993). A
longitudinal study of South African gold miners conducted by Hnizdo
(1992) found that cumulative dust exposure was a significant predictor
of most indices of decreases in lung function, including
FEV1 and FVC. A multiple linear regression analysis showed
that the effects of silica exposure and smoking were additive. Another
study of South African gold miners (Cowie, 1998) also found a loss of
FEV1 in those without silicosis. Finally, a study of U.S.
automotive foundry workers (Hertzberg et al., 2002) found a consistent
association with increased pulmonary function abnormalities and
estimated measures of cumulative silica exposure within 0.1 mg/m\3\.
The Hnizdo (1992), Cowie et al. (1993), and Cowie (1998) studies of
South African gold miners and the Malmberg et al. (1993) study of
Swedish granite workers found very similar reductions in
FEV1 attributable to silica dust exposure.
    A number of prevalence studies have described relationships between
lung function loss and silica exposure or exposure measurement
surrogates (e.g., duration of exposure). These findings support those
of the longitudinal studies. Such results have been found in studies of
white South African gold miners (Hnizdo et al., 1990; Irwig and Rocks,
1978), black South African gold miners (Cowie and Mabena, 1991), Quebec
silica-exposed workers (Begin, et al., 1995), Singapore rock drilling
and crushing workers (Ng et al., 1992b), Vermont granite shed workers
(Theriault et al., 1974a, 1974b), aggregate quarry workers and coal
miners in Spain (Montes et al., 2004a, 2004b), concrete workers in The
Netherlands (Meijer et al., 2001), Chinese refractory brick
manufacturing workers in an iron-steel plant (Wang et al., 1997),
Chinese gemstone workers (Ng et al., 1987b), hard-rock miners in
Manitoba, Canada (Manfreda et al., 1982) and Colorado (Kreiss et al.,
1989), pottery workers in France (Neukirch et al., 1994), potato
sorters exposed to diatomaceous earth containing crystalline silica in
The Netherlands

(Jorna et al., 1994), slate workers in Norway (Suhr et al., 2003), and
men in a Norwegian community (Humerfelt et al., 1998). Two of these
prevalence studies also addressed the role of smoking in lung function
impairment associated with silica exposure. In contrast to the
longitudinal study of South African gold miners discussed above
(Hnizdo, 1992), another study of South African gold miners (Hnizdo et
al., 1990) found that the joint effect of dust and tobacco smoking on
lung function impairment was synergistic, rather than additive. Also,
Montes et al. (2004b) found that the criteria for dust-tobacco
interactions were satisfied for FEV1 decline in a study of
Spanish aggregate quarry workers.
    One of the longitudinal studies and many of the prevalence studies
discussed above directly addressed the question of whether silica-
exposed workers can develop pulmonary function impairment in the
absence of silicosis. These studies found that pulmonary function
impairment: (1) Can occur in silica-exposed workers in the absence of
silicosis, (2) was still evident when silicosis was controlled for in
the analysis, and (3) was related to the magnitude and duration of
silica exposure rather than to the presence or severity of silicosis.
    Many researchers have concluded that a relationship exists between
exposure to silica and lung function impairment. IARC (1997) has
briefly reviewed studies on airways disease (i.e., chronic airflow
limitation and obstructive impairment of lung function) in its
monograph on crystalline silica carcinogenicity and concluded that
exposure to crystalline silica causes these effects. In its official
statement on the adverse effects of crystalline silica exposure, the
American Thoracic Society (ATS) (1997) included a section on airflow
obstruction. The ATS noted that, in most of the studies reviewed,
airflow limitation was associated with chronic bronchitis. The review
of Hnizdo and Vallyathan (2003) also addressed COPD due to occupational
silica exposure. They examined the epidemiological evidence for an
exposure-response relationship for airflow obstruction in studies where
silicosis was present or absent. Hnizdo and Vallyathan (2003) concluded
that chronic exposure to silica dust at levels that do not cause
silicosis may cause airflow obstruction.
    Based on the evidence discussed above from a number of longitudinal
studies and numerous cross-sectional studies, OSHA preliminarily
concludes that there is an exposure-response relationship between
exposure to respirable crystalline silica and the development of
impaired lung function. The effect of tobacco smoking on this
relationship may be additive or synergistic. Also, pulmonary function
impairment has been shown to occur among silica-exposed workers who do
not show signs of silicosis.
4. Non-malignant Respiratory Disease Mortality
    In this section, OSHA reviews studies on NMRD mortality that
focused on causes of death other than from silicosis. Two studies of
gold miners, a study of diatomaceous earth workers, and a case-control
analysis of death certificate data provide useful information.
    Wyndham et al. (1986) found a significant excess mortality for
chronic respiratory diseases in a cohort of white South African gold
miners. Although these data did include silicosis mortality, the
authors found evidence demonstrating that none of the miners certified
on the death certificate as dying from silicosis actually died from
that disease. Instead, pneumoconiosis was always an incidental finding
in those dying from some other cause, the most common of which was
chronic obstructive lung disease. A case-referent analysis found that,
although the major risk factor for chronic respiratory disease was
smoking, there was a statistically significant additional effect of
cumulative dust exposure, with the relative risk estimated to be 2.48
per ten units of 1000 particle years of exposure.
    A synergistic effect of smoking and cumulative dust exposure on
mortality from COPD was found in another study of white South African
gold miners (Hnizdo, 1990). Analysis of various combinations of dust
exposure and smoking found a trend in odds ratios that indicated this
synergism. There was a statistically significant increasing trend for
dust particle-years and for cigarette-years of smoking. For cumulative
dust exposure, an exposure-response relationship was found, with the
analysis estimating that those with exposures of 10,000, 17,500, or
20,000 particle-years of exposure had a 2.5-, 5.06-, or 6.4-times
higher mortality risk for COPD, respectively, than those with the
lowest dust exposure of less than 5000 particle-years. The authors
concluded that dust alone would not lead to increased COPD mortality
but that dust and smoking act synergistically to cause COPD and were
thus the main risk factor for death from COPD in their study.
    Park et al. (2002) analyzed the California diatomaceous earth
cohort data originally studied by Checkoway et al. (1997), consisting
of 2,570 diatomaceous earth workers employed for 12 months or more from
1942 to 1994, to quantify the relationship between exposure to
cristobalite and mortality from chronic lung disease other than cancer
(LDOC). Diseases in this category included pneumoconiosis (which
included silicosis), chronic bronchitis, and emphysema, but excluded
pneumonia and other infectious diseases. Smoking information was
available for about 50 percent of the cohort and for 22 of the 67 LDOC
deaths available for analysis, permitting Park et al. (2002) to at
least partially adjust for smoking. Using the exposure estimates
developed for the cohort by Rice et al. (2001) in their exposure-
response study of lung cancer risks, Park et al. (2002) evaluated the
quantitative exposure-response relationship for LDOC mortality and
found a strong positive relationship with exposure to respirable
crystalline silica. OSHA finds this study particularly compelling
because of the strengths of the study design and availability of
smoking history data on part of the cohort and high-quality exposure
and job history data; consequently, OSHA has included this study in its
Preliminary Quantitative Risk Assessment.
    In a case-control analysis of death certificate data drawn from 27
U.S. states, Calvert et al. (2003) found increased mortality odds
ratios among those in the medium and higher crystalline silica exposure
categories, a significant trend of increased risk for COPD mortality
with increasing silica exposures, and a significantly increased odds
ratio for COPD mortality in silicotics as compared to those without
silicosis.
    Green and Vallyathan (1996) also reviewed several studies of NMRD
mortality in workers exposed to silica. The authors stated that these
studies showed an association between cumulative dust exposure and
death from the chronic respiratory diseases.
    Based on the evidence presented in the studies above, OSHA
preliminarily concludes that respirable crystalline silica increases
the risk for mortality from non-malignant respiratory disease (not
including silicosis) in an exposure-related manner. However, it appears
that the risk is strongly influenced by smoking, and the effects of
smoking and silica exposure may be synergistic.

D. Renal and Autoimmune Effects

    In recent years, evidence has accumulated that suggests an
association between exposure to crystalline silica and an increased
risk

of renal disease. Over the past 10 years, epidemiologic studies have
been conducted that provide evidence of exposure-response trends to
support this association. There is also suggestive evidence that silica
can increase the risk of rheumatoid arthritis and other autoimmune
diseases (Steenland, 2005b). In fact, an autoimmune mechanism has been
postulated for some silica-associated renal disease (Calvert et al.,
1997). This section will discuss the evidence supporting an association
of silica exposure with renal and autoimmune diseases.
    Overall, there is substantial evidence suggesting an association
between exposure to crystalline silica and increased risks of renal and
autoimmune diseases. In addition to a number of case reports,
epidemiologic studies have found statistically significant associations
between occupational exposure to silica dust and chronic renal disease
(e.g., Calvert et al., 1997), subclinical renal changes (e.g., Ng et
al., 1992c), end-stage renal disease morbidity (e.g., Steenland et al.,
1990), chronic renal disease mortality (Steenland et al., 2001b,
2002a), and Wegener's granulomatosis (Nuyts et al., 1995). In other
findings, silica-exposed individuals, both with and without silicosis,
had an increased prevalence of abnormal renal function (Hotz et al.,
1995), and renal effects have been reported to persist after cessation
of silica exposure (Ng et al., 1992c). Possible mechanisms suggested
for silica-induced renal disease include a direct toxic effect on the
kidney, deposition in the kidney of immune complexes (IgA) following
silica-related pulmonary inflammation, or an autoimmune mechanism
(Calvert et al., 1997; Gregorini et al., 1993).
    Several studies of exposed worker populations reported finding
excess renal disease mortality and morbidity. Wyndham et al. (1986)
reported finding excess mortality from acute and chronic nephritis
among South African goldminers that had been followed for 9 years.
Italian ceramic workers experienced an overall increase in the
prevalence of end-stage renal disease (ESRD) cases compared to regional
rates; the six cases that occurred among the workers had cumulative
exposures to crystalline silica of between 0.2 and 3.8 mg/m\3\-years
(Rapiti et al., 1999).
    Calvert et al. (1997) found an increased incidence of non-systemic
ESRD cases among 2,412 South Dakota gold miners exposed to a median
crystalline silica concentration of 0.09 mg/m\3\. In another study of
South Dakota gold miners, Steenland and Brown (1995a) reported a
positive trend of chronic renal disease mortality risk and cumulative
exposure to respirable crystalline silica, but most of the excess
deaths were concentrated among workers hired before 1930 when exposures
were likely higher than in more recent years.
    Excess renal disease mortality has also been described among North
American industrial sand workers. McDonald et al., (2001, 2005) found
that nephritis/nephrosis mortality was elevated overall among 2,670
industrial sand workers hired 20 or more years prior to follow-up, but
there was no apparent relationship with either cumulative or average
exposure to crystalline silica. However, Steenland et al. (2001b) did
find that increased mortality from acute and chronic renal disease was
related to increasing quartiles of cumulative exposure among a larger
cohort of 4,626 industrial sand workers. In addition, they also found a
positive trend for ESRD case incidence and quartiles of cumulative
exposure.
    In a pooled cohort analysis, Steenland et al. (2002a) combined the
industrial sand cohort from Steenland et al. (2001b), gold mining
cohort from Steenland and Brown (1995a), and the Vermont granite cohort
studies by Costello and Graham (1988). In all, the combined cohort
consisted of 13,382 workers with exposure information available for
12,783. The exposure estimates were validated by the monotonically
increasing exposure-response trends seen in analyses of silicosis,
since cumulative silica levels are known to predict silicosis risk. The
mean duration of exposure, cumulative exposure, and concentration of
respirable silica for the cohort were 13.6 years, 1.2 mg/m\3\-years,
and 0.07 mg/m\3\, respectively.
    The analysis demonstrated statistically significant exposure-
response trends for acute and chronic renal disease mortality with
quartiles of cumulative exposure to respirable crystalline silica. In a
nested case-control study design, a positive exposure-response
relationship was found across the three cohorts for both multiple-cause
mortality (i.e., any mention of renal disease on the death certificate)
and underlying cause mortality. Renal disease risk was most prevalent
among workers with cumulative exposures of 0.5 mg/m\3\ or more
(Steenland et al., 2002a).
    Other studies failed to find an excess renal disease risk among
silica-exposed workers. Davis et al. (1983) found an elevated, but not
a statistically significant increase, in mortality from diseases of the
genitourinary system among Vermont granite shed workers. There was no
observed relationship between mortality from this cause and cumulative
exposure. A similar finding was reported by Koskela et al. (1987) among
Finnish granite workers, where there were 4 deaths due to urinary tract
disease compared to 1.8 expected. Both Carta et al. (1994) and Cocco et
al. (1994) reported finding no increased mortality from urinary tract
disease among workers in an Italian lead mine and a zinc mine. However,
Cocco et al. (1994) commented that exposures to respirable crystalline
silica were low, averaging 0.007 and 0.09 mg/m\3\ in the two mines,
respectively, and that their study in particular had low statistical
power to detect excess mortality.
    There are many case series, case-control, and cohort studies that
provide support for a causal relationship between exposure to
respirable crystalline silica and an increased renal disease risk
(Kolev et al., 1970; Osorio et al., 1987; Steenland et al., 1990;
Gregorini et al., 1993; Nuyts et al., 1995). In addition, a number of
studies have demonstrated early clinical signs of renal dysfunction
(i.e., urinary excretion of low- and high-molecular weight proteins and
other markers of renal glomerular and tubular disruption) in workers
exposed to crystalline silica, both with and without silicosis (Ng et
al., 1992c; Hotz et al., 1995; Boujemaa, 1994; Rosenman et al., 2000).
    OSHA believes that there is substantial evidence on which to base a
finding that exposure to respirable crystalline silica increases the
risk of renal disease mortality and morbidity. In particular, OSHA
believes that the 3-cohort pooled analysis conducted by Steenland et
al. (2002a) is particularly convincing. OSHA believes that the findings
of this pooled analysis seem credible because the analysis involved a
large number of workers from three cohorts with well-documented,
validated job-exposure matrices and found a positive and monotonic
increase in renal disease risk with increasing exposure for both
underlying and multiple cause data. However, there are considerably
less data, and thus the findings based on them are less robust, than
what is available for silicosis mortality or lung cancer mortality.
Nevertheless, OSHA preliminarily concludes that the underlying data are
sufficient to provide useful estimates of risk and has included the
Steenland et al. (2002a) analysis in its Preliminary Quantitative Risk
Assessment.
    Several studies of different designs, including case series,
cohort, registry linkage and case-control, conducted in a variety of
exposed groups suggest an association between silica exposure and

increased risk of systemic autoimmune disease (Parks et al., 1999).
Studies have found that the most common autoimmune diseases associated
with silica exposure are scleroderma (e.g., Sluis-Cremer et al., 1985);
rheumatoid arthritis (e.g. Klockars et al., 1987; Rosenman and Zhu,
1995); and systemic lupus erythematosus (e.g., Brown et al., 1997).
Mechanisms suggested for silica-related autoimmune disease include an
adjuvant effect of silica (Parks et al., 1999), activation of the
immune system by the fibrogenic proteins and growth factors released as
a result of the interaction of silica particles with macrophages (e.g.,
Haustein and Anderegg, 1998), and a direct local effect of non-
respirable silica particles penetrating the skin and producing
scleroderma (Green and Vallyathan, 1996). However, there are no
quantitative exposure-response data available at this time on which to
base a quantitative risk assessment for autoimmune diseases.
    Therefore, OSHA preliminarily concludes that there is substantial
evidence that silica exposure increases the risks of renal and
autoimmune disease. The positive and monotonic exposure-response trends
demonstrated for silica exposure and renal disease risk more strongly
suggest a causal link. The studies by Steenland et al. (2001b, 2002a)
and Steenland and Brown (1995a) provide evidence of a positive
exposure-response relationship. For autoimmune diseases, the available
data did not provide an adequate basis for assessing exposure-response
relationships. However, OSHA believes that the available exposure-
response data on silica exposure and renal disease is sufficient to
allow for quantitative estimates of risk.

E. Physical Factors That May Influence Toxicity of Crystalline Silica

    Much research has been conducted to investigate the influence of
various physical factors on the toxicologic potency of crystalline
silica. Such factors examined include crystal polymorphism; the age of
fractured surfaces of the crystal particle; the presence of impurities,
particularly metals, on particle surfaces; and clay occlusion of the
particle. These factors likely vary among different workplace settings
suggesting that the risk to workers exposed to a given level of
respirable crystalline silica may not be equivalent in different work
environments. In this section, OSHA examines the research demonstrating
the effects of these factors on the toxicologic potency of silica.
    The modification of surface characteristics by the physical factors
noted above may alter the toxicity of silica by affecting the physical
and biochemical pathways of the mechanistic process. Thus, OSHA has
reviewed the proposed mechanisms by which silica exposure leads to
silicosis and lung cancer. It has been proposed that silicosis results
from a cycle of cell damage, oxidant generation, inflammation, scarring
and fibrosis. A silica particle entering the lung can cause lung damage
by two major mechanisms: direct damage to lung cells due to the silica
particle's unique surface properties or by the activation or
stimulation of alveolar macrophages (after phagocytosis) and/or
alveolar epithelial cells. In either case, an elevated production of
reactive oxygen and nitrogen species (ROS/RNS) results in oxidant
damage to lung cells. The oxidative stress and lung injury stimulates
alveolar macrophages and/or alveolar epithelial cells to produce growth
factors and fibrogenic mediators, resulting in fibroblast activation
and pulmonary fibrosis. A continuous ingestion-reingestion cycle, with
cell activation and death, is established.
    OSHA has examined evidence on the comparative toxicity of the
silica polymorphs (quartz, cristobalite, and tridymite). A number of
animal studies appear to suggest that cristobalite and tridymite are
more toxic to the lung than quartz and more tumorigenic (e.g., King et
al., 1953; Wagner et al., 1980). However, in contrast to these
findings, several authors have reviewed the studies done in this area
and concluded that cristobalite and tridymite are not more toxic than
quartz (e.g., Bolsaitis and Wallace, 1996; Guthrie and Heaney, 1995).
Furthermore, a difference in toxicity between cristobalite and quartz
has not been observed in epidemiologic studies (tridymite has not been
studied) (NIOSH, 2002). In an analysis of exposure-response for lung
cancer, Steenland et al. (2001a) found similar exposure-response trends
between cristobalite-exposed workers and other cohorts exposed to
quartz.
    A number of studies have compared the toxicity of freshly fractured
versus aged silica. Although animal studies have demonstrated that
freshly fractured silica is more toxic than aged silica, aged silica
still retains significant toxicity (Porter et al., 2002; Shoemaker et
al., 1995; Vallyathan et al., 1995). Studies of workers exposed to
freshly fractured silica have demonstrated that these workers exhibit
the same cellular effects as seen in animals exposed to freshly
fractured silica (Castranova et al., 1998; Goodman et al., 1992). There
have been no studies, however, comparing workers exposed to freshly
fractured silica to those exposed to aged silica. Animal studies also
suggest that pulmonary reactions of rats to short-duration exposure to
freshly fractured silica mimic those seen in acute silicosis in humans
(Vallyathan et al., 1995).
    Surface impurities, particularly metals, have been shown to alter
silica toxicity. Iron, depending on its state and quantity, has been
shown to either increase or decrease toxicity. Aluminum has been shown
to decrease toxicity (Castranova et al., 1997; Donaldson and Borm,
1998; Fubini, 1998). Silica coated with aluminosilicate clay exhibits
lower toxicity, possibly as a result of reduced bioavailability of the
silica particle surface (Donaldson and Borm, 1998; Fubini, 1998). This
reduced bioavailability may be due to aluminum ions left on the silica
surface by the clay (Bruch et al., 2004; Cakmak et al., 2004; Fubini et
al., 2004). Aluminum and other metal ions are thought to modify silanol
groups on the silica surface, thus decreasing the membranolytic and
cytotoxic potency and resulting in enhanced particle clearance from the
lung before damage can take place (Fubini, 1998). An epidemiologic
study found that the risk of silicosis was less in pottery workers than
in tin and tungsten miners (Chen et al., 2005; Harrison et al., 2005),
possibly reflecting that pottery workers were exposed to silica
particles having less biologically available, non-clay-occluded surface
area than was the case for miners. The authors concluded that clay
occlusion of silica particles can be a factor in reducing disease risk.
    Although it is evident that a number of factors can act to mediate
the toxicological potency of crystalline silica, it is not clear how
such considerations should be taken into account to evaluate lung
cancer and silicosis risks to exposed workers. After evaluating many in
vitro studies that had been conducted to investigate the surface
characteristics of crystalline silica particles and their influence on
fibrogenic activity, NIOSH (2002) concluded that further research is
needed to associate specific surface characteristics that can affect
toxicity with specific occupational exposure situations and consequent
health risks to workers. According to NIOSH (2002), such exposures may
include work processes that produce freshly fractured silica surfaces
or that involve quartz contaminated with trace elements such as iron.
NIOSH called for further in vitro and in vivo studies of the toxicity
and pathogenicity of alpha quartz compared with its polymorphs, quartz

contaminated with trace elements, and further research on the
association of surface properties with specific work practices and
health effects.
    In discussing the ``considerable'' heterogeneity shown across the
10 studies used in the pooled lung cancer risk analysis, Steenland et
al. (2001a) pointed to hypotheses that physical differences in silica
exposure (e.g., freshness of particle cleavage) between cohorts may be
a partial explanation of observed differences in exposure-response
coefficients derived from those cohort studies. However, the authors
did not have specific information on whether or how these factors might
have actually influenced the observed differences. Similarly, in the
pooled analysis and risk assessments for silicosis mortality conducted
by Mannetje et al. (2002b), differences in biological activity of
different types of silica dust could not be specifically taken into
account. Mannetje et al. (2002b) determined that the exposure-response
relationship between silicosis and log-transformed cumulative exposure
to crystalline silica was comparable between studies and no significant
heterogeneity was found. The authors therefore concluded that their
findings were relevant for different circumstances of occupational
exposure to crystalline silica. Both the Steenland et al. (2001a) and
Mannetje et al. (2002b) studies are discussed in detail in OSHA's
Preliminary Quantitative Risk Assessment (section II of the background
document and summarized in section VI of this preamble).
    OSHA preliminarily concludes that there is considerable evidence to
support the hypothesis that surface activity of crystalline silica
particles plays an important role in producing disease, and that
several environmental influences can modify surface activity to either
enhance or diminish the toxicity of silica. However, OSHA believes that
the available information is insufficient to determine in any
quantitative way how these influences may affect disease risk to
workers in any particular workplace setting.

VI. Summary of OSHA's Preliminary Quantitative Risk Assessment

A. Introduction

    The Occupational Safety and Health Act (OSH Act or Act) and some
landmark court cases have led OSHA to rely on quantitative risk
assessment, to the extent possible, to support the risk determinations
required to set a permissible exposure limit (PEL) for a toxic
substance in standards under the OSH Act. A determining factor in the
decision to perform a quantitative risk assessment is the availability
of suitable data for such an assessment. In the case of crystalline
silica, there has been extensive research on its health effects, and
several quantitative risk assessments have been published in the peer-
reviewed scientific literature that describe the risk to exposed
workers of lung cancer mortality, silicosis mortality and morbidity,
non-malignant respiratory disease mortality, and renal disease
mortality. These assessments were based on several studies of
occupational cohorts in a variety of industry sectors, the underlying
studies of which are described in OSHA's review of the health effects
literature (see section V of this preamble). In this section, OSHA
summarizes its Preliminary Quantitative Risk Assessment (QRA) for
crystalline silica, which is presented in Section II of the background
document entitled ``Respirable Crystalline Silica--Health Effects
Literature Review and Preliminary Quantitative Risk Assessment''
(placed in Docket OSHA-2010-0034).
    OSHA has done what it believes to be a comprehensive review of the
literature to provide quantitative estimates of risk for crystalline
silica-related diseases. Quantitative risk assessments for lung cancer
and silicosis mortality were published after the International Agency
for Research on Cancer (IARC) determined more than a decade ago that
there was sufficient evidence to regard crystalline silica as a human
carcinogen (IARC, 1997). This finding was based on several studies of
worker cohorts demonstrating associations between exposure to
crystalline silica and an increased risk of lung cancer. Although IARC
judged the overall evidence as being sufficient to support this
conclusion, IARC also noted that some studies of crystalline silica-
exposed workers did not demonstrate an excess risk of lung cancer and
that exposure-response trends were not always consistent among studies
that were able to describe such trends. These findings led Steenland et