silicosis morbidity were also well above 1 case per 1,000 workers at
the previous PELs, with a substantial reduction at the revised PEL.
2. Summary of the Review of Health Effects Literature
    In its Review of Health Effects Literature, OSHA identified the
adverse health effects associated with the inhalation of respirable
crystalline silica (Document ID 1711). OSHA covered the following
topics: Silicosis (including relevant data from U.S. disease
surveillance efforts), lung cancer and cancer at other sites, non-
malignant respiratory diseases (NMRD) other than silicosis, renal and
autoimmune effects, and physical factors affecting the toxicity of
crystalline silica. Most of the evidence that described the health
risks associated with exposure to silica

consisted of epidemiological studies of worker populations; animal and
in vitro studies on mode of action and molecular toxicology were also
described. OSHA focused solely on those studies associated with
airborne exposure to respirable crystalline silica due to the lack of
evidence of health hazards from dermal or oral exposure. The review was
further confined to issues related to the inhalation of respirable
dust, which is generally defined as particles that are capable of
reaching the pulmonary region of the lung (i.e., particles less than 10
microns ([mu]m) in aerodynamic diameter), in the form of either quartz
or cristobalite, the two forms of crystalline silica most often
encountered in the workplace.
a. Silicosis
i. Types
    Silicosis is an irreversible, progressive disease induced by the
inflammatory effects of respirable crystalline silica in the lung,
leading to lung damage and scarring and, in some cases, progressing to
complications resulting in disability and death. Exposure to respirable
crystalline silica is the only known cause of silicosis. 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 more than 20 years
(Becklake, 1994, Document ID 0294; Balaan and Banks, 1992, 0289). In
both the accelerated and chronic forms 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, Document ID 0289). 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,
Document ID 0294). There is no specific treatment for silicosis (Davis,
1996, Document ID 0998; Banks, 2005, 0291).
    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. Prospective studies that follow the exposed cohort
over a long period of time with periodic examinations can provide the
best information on factors affecting the development and progression
of silicosis, which has a latency period (the interval between
beginning of exposure to silica and the onset of disease) from 10 to 30
years after first exposure (Weissman and Wagner, 2005; Document ID
0481).
ii. Diagnosis
    The scarring caused by silicosis can be detected by chest x-ray or
computerized tomography (CT) when the lesions become large enough to
appear as visible opacities. The clinical diagnosis of silicosis has
three requirements: Recognition by the physician that exposure to
crystalline silica has occurred; the presence of chest radiographic
abnormalities consistent with silicosis; the absence of other illnesses
that could resemble silicosis on a chest radiograph (e.g., pulmonary
fungal infection or tuberculosis) (Balaan and Banks, 1992, Document ID
0289; Banks, 2005, 0291). A standardized system to classify opacities
seen in chest radiographs was developed by the International Labour
Organization (ILO) to describe the presence and severity of silicosis
on the basis of size, shape, and density of opacities, which together
indicate the severity and extent of lung involvement (ILO, 1980,
Document ID 1063; ILO, 2002, 1064; ILO, 2011, 1475; Merchant and
Schwartz, 1998, 1096; NIOSH, 2011, 1513). The density of opacities seen
on chest radiographs is classified on a 4-point category scale (0, 1,
2, or 3), with each category divided into three, giving a 12-
subcategory 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. 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. The bottom
number can deviate from the top number by 1. At the extremes of the
scale, a designation of 0/- or 3/+ may be used. Subcategory 0/-
represents a radiograph that is obviously absent of small opacities.
Subcategory 3/+ represents a radiograph that shows much greater
profusion than depicted on a standard 3/3 radiograph.
    To address the low sensitivity of chest x-rays for detecting
silicosis, Hnizdo et al. (1993, Document ID 1050) 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. A 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, Document ID 1110).
iii. Review of Occupation-Based Epidemiological Studies
    The causal relationship between exposure to crystalline silica and
silicosis has long been accepted in the scientific and medical
communities. OSHA reviewed a large number of cross-sectional and
retrospective studies conducted to estimate the quantitative
relationship between exposure to crystalline silica and the development
of silicosis (e.g., Kreiss and Zhen, 1996, Document ID 1080; Love et
al., 1999, 0369; Ng and Chan, 1994, 0382; Rosenman et al., 1996, 0423;
Churchyard et al., 2003, 1295; Churchyard et al., 2004, 0986; Hughes et
al., 1998, 1059; Muir et al., 1989a, 1102; Muir et al., 1989b, 1101;
Park et al., 2002, 0405; Chen et al., 2001, 0332; Chen et al., 2005,
0985; Hnizdo and Sluis-Cremer, 1993, 1052; Miller et al., 1998, 0374;
Buchanan et al., 2003, 0306; Steenland and Brown, 1995b, 0451). In
general, these studies, particularly those that included retirees,
found a risk of radiological silicosis (usually defined as x-ray films
classified as ILO major category 1 or greater) among workers exposed
near the range of cumulative exposures permitted by current exposure
limits. The studies' methods and findings are presented in detail in
the Preliminary QRA (Document ID 1711, pp. 316-340); those studies on
which OSHA relied for its risk estimates are also discussed in the
Summary of the Preliminary QRA, below.
    OSHA's review of the silicosis literature also focused on specific
issues associated with the factors that affect the progression of the
disease and the relationship between the appearance of radiological
abnormalities indicative of silicosis and pulmonary function decline.
From its review of the health literature, OSHA made a number of
preliminary findings. First, the size of opacities apparent on initial
x-ray films is a determinant of future disease

progression, with subjects exhibiting large opacities more likely to
experience progression than those having smaller opacities (Hughes et
al., 1982, Document ID 0362; Lee et al., 2001, 1086; Ogawa et al.,
2003, 0398). Second, continued exposure to respirable crystalline
silica following diagnosis of radiological silicosis increases the
probability of disease progression compared to those who are not
further exposed (Hessel et al., 1988, Document ID 1042), although there
remains a likelihood of progression even absent continued exposure
(Hessel et al., 1988, Document ID 1042; Miller et al., 1998, 0374;
Ogawa et al., 2003, 0398; Yang et al., 2006, 1134).
    With respect to the relationship between radiological silicosis and
pulmonary function declines, literature findings are mixed. A number of
studies have reported pulmonary function declines among workers
exhibiting a degree of small-opacity profusion consistent with ILO
categories 2 and 3 (e.g., Ng and Chan, 1992, Document ID 1107).
However, although some studies have not found pulmonary function
declines associated with silicosis scored as ILO category 1, 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 (Cowie, 1998, 0993; Cowie and Mabena, 1991, 0342;
Ng et al., 1987(a), 1108; Wang et al., 1997, 0478). Thus, OSHA
preliminarily concluded that at least some individuals will develop
pulmonary function declines absent radiological changes indicative of
silicosis. The Agency posited that this may reflect the relatively poor
sensitivity of x-ray films in detecting silicosis or may be due to
pulmonary function declines related to silica-induced chronic
obstructive pulmonary disease (see Document ID 1711, pp. 49-75).
iv. Surveillance
    Unlike most occupational diseases, surveillance statistics are
available on 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 (NIOSH, 2008c,
Document ID 1308). Other sources are detailed in the Review of Health
Effects Literature (Document ID 1711). Mortality data are compiled from
death certificates reported to state vital statistics offices, which
are collected by the National Center for Health Statistics (NCHS), an
agency within the Centers for Disease Control and Prevention (e.g.,
CDC, 2005, Document ID 0319).
    Silicosis-related mortality has declined in the U.S. over the time
period for which these data have been collected. From 1968 to 2005, the
annual number of silicosis deaths decreased from 1,157 to 161 (NIOSH,
2008c, Document ID 1308; http://wwwn.cdc.gov/eworld). The CDC cited two
main factors that were likely responsible for the declining trend in
silicosis mortality since 1968 (CDC, 2005, Document ID 0319). First,
many deaths during the early part of the study period were among
workers whose main exposure to respirable crystalline silica probably
occurred before introduction of national silica standards established
by OSHA and the Mine Safety and Health Administration (MSHA) (i.e.,
permissible exposure limits (PELs)); these standards likely led to
reduced silica dust exposure beginning in the 1970s. Second, employment
has declined in heavy industries (e.g., foundries) where silica
exposure was prevalent (CDC, 2005, Document ID 0319).
    Despite this decline, 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 (the end of
a working life), there were 3,045 years of life lost up to age 65, with
an average of 9.9 years of life lost from a working life (NIOSH, 2008c,
Document ID 1308).
    Surveillance data on silicosis morbidity, primarily from hospital
discharge records, are available only from the few states that have
administered disease surveillance programs for silicosis. For the
reporting period 1993-2002, these states recorded 879 cases of
silicosis (NIOSH 2008c, Document ID 1308). Nationwide hospital
discharge data compiled by NIOSH (2008c, Document ID 1308) and the
Council of State and Territorial Epidemiologists (CSTE, 2005, Document
ID 0996) indicate that, for the years 1970 to 2004, there were at least
1,000 hospitalizations that were coded for silicosis each year, except
one.
    Relying exclusively on such passive case-based disease surveillance
systems that depend on the health care community to generate records is
likely to understate the prevalence of diseases associated with
respirable crystalline silica (Froines et al., 1989, Document ID 0385).
In order to diagnose occupational diseases, health care professionals
must have information about occupational histories and must be able to
recognize occupational diseases (Goldman and Peters, 1981, Document ID
1027; Rutstein et al., 1983, 0425). The first criterion to be met in
diagnosing silicosis is knowing a patient's history of exposure to
crystalline silica. In addition to the lack of information about
exposure histories, difficulty in recognizing occupational illnesses
like silicosis, that manifest themselves long after initial exposure,
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, Document ID 0420)
estimated that silicosis mortality and morbidity were understated by a
factor of between 2.5 and 5, and estimated that between 3,600 and 7,300
new cases of silicosis likely occurred in the U.S. annually between
1987 and 1996.
b. Lung Cancer
    i. International Agency for Research on Cancer (IARC)
Classification
    In 1997, the IARC determined that there was sufficient evidence to
regard crystalline silica as a human carcinogen (IARC, 1997, Document
ID 1062). This finding was 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). NIOSH also determined that crystalline
silica is a human carcinogen after evaluating updated literature (2002,
Document ID 1110).
    ii. Review of Occupation-Based Epidemiological Studies
    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. OSHA's review included approximately 60 primary
epidemiological studies. Based on this review, OSHA preliminarily
concluded that the human data provides ample evidence that exposure to
respirable crystalline silica increases the risk of lung cancer among
workers.
    The strongest evidence for carcinogenicity came from studies in
five industry sectors:
     Diatomaceous Earth Workers (Checkoway et al., 1993,
Document ID 0324; Checkoway et al., 1996, 0325; Checkoway et al., 1997,
0326;

Checkoway et al., 1999, 0327; Seixas et al., 1997, 0431);
     British Pottery Workers (Cherry et al., 1998, Document ID
0335; McDonald et al., 1995, 0371);
     Vermont Granite Workers (Attfield and Costello, 2004,
Document ID 0285; Graham et al., 2004, 1031; Costello and Graham, 1988,
0991; Davis et al., 1983, 0999);
     North American Industrial Sand Workers (Hughes et al.,
2001, Document ID 1060; McDonald et al., 2001, 1091; McDonald et al.,
2005, 1092; Rando et al., 2001, 0415; Sanderson et al., 2000, 0429;
Steenland and Sanderson, 2001, 0455); and
     British Coal Miners (Miller et al., 2007, Document ID
1305; Miller and MacCalman, 2009, 1306).
    OSHA considered these studies as providing the strongest evidence
for several reasons. They 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. In general,
these studies were of sufficient size and had adequate years of follow
up, and had 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.
    In the diatomaceous earth industry, Checkoway et al. developed a
``semi-quantitative'' cumulative exposure estimate that demonstrated a
statistically significant positive exposure-response trend between
duration of employment or cumulative exposure and lung cancer mortality
(1993, Document ID 0324). The quartile analysis with a 15-year lag
showed an increasing trend in relative risks (RR) of lung cancer
mortality, with the highest exposure quartile having a RR of 2.74 for
lung cancer mortality. Checkoway et al. 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 (1996, Document
ID 0325). Rice et al. (2001, Document ID 1118) conducted a re-analysis
and quantitative risk assessment of the Checkoway et al. (1997,
Document ID 0326) study, finding that exposure to crystalline silica
was a significant predictor of lung cancer mortality. OSHA included
this re-analysis in its Preliminary QRA (Document ID 1711).
    In the British pottery industry, excess lung cancer risk was found
to be associated with crystalline silica exposure among workers in a
proportionate mortality ratio (PMR) study \4\ (McDonald et al., 1995,
Document ID 0371) and in a cohort and nested case-control study \5\
(Cherry et al., 1998, Document ID 0335). In the former, 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.
---------------------------------------------------------------------------

    \4\ A PMR is the number of deaths within a population due to a
specific disease (e.g., lung cancer) divided by the total number of
deaths in the population during some time period.
    \5\ A cohort study is a study in which the occurrence of disease
(e.g., lung cancer) is measured in a cohort of workers with
potential for a common exposure (e.g., silica). A nested case-
control study is a study in which workers with disease are
identified in an occupational cohort, and a control group consisting
of workers without disease is selected (independently of exposure
status) from the same cohort to determine whether there is a
difference in exposure between cases and controls. A number of
controls are matched to each case to control for potentially
confounding factors, such as age, gender, etc.
---------------------------------------------------------------------------

    In the Vermont granite cohort, Costello and Graham (1988, Document
ID 0991) and Graham et al. (2004, Document ID 1031) in a follow-up
study found that workers employed prior to 1930 had an excess risk of
lung cancer. Lung cancer mortality among granite workers hired after
1940 (post-implementation of controls), however, was not elevated in
the Costello and Graham study and was only somewhat elevated (not
statistically significant) in the Graham et al. study. Graham et al.
(2004, Document ID 1031) 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,
Document ID 0285) developed a quantitative estimate of cumulative
exposure (8 exposure categories) adapted from a job exposure matrix
developed by Davis et al. (1983, Document ID 0999). They found a
statistically significant trend between lung cancer mortality and log-
transformed cumulative exposure to crystalline silica. 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. 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. OSHA expressed its belief that
the study by Attfield and Costello (2004, Document ID 0285) was of
superior design in that it used quantitative estimates of exposure and
evaluated lung cancer mortality rates by exposure group. In contrast,
the findings by Graham et al. (2004, Document ID 1031) were based on a
dichotomous comparison of risk among high- versus low-exposure groups,
where date-of-hire before and after implementation of ventilation
controls was used as a surrogate for exposure. Consequently, OSHA used
the Attfield and Costello study in its Preliminary QRA (Document ID
1711). In its Supplemental Literature Review of Epidemiological Studies
on Lung Cancer Associated with Exposure to Respirable Crystalline
Silica, OSHA also discussed a more recent study of Vermont granite
workers by Vacek et al. (2011, Document ID 1486) that did not find an
association between silica exposure and lung cancer mortality (Document
ID 1711, Attachment 1, pp. 2-5). (OSHA examines this study in great
length in Section V.F, Comments and Responses Concerning Lung Cancer
Mortality.)
    In the North American industrial sand industry, studies of two
overlapping cohorts found a statistically significant increased risk of
lung cancer mortality with increased cumulative exposure in both
categorical and continuous analyses (Hughes et al., 2001, Document ID
1060; McDonald et al., 2001, 1091; McDonald et al., 2005, 1092; Rando
et al., 2001, 0415; Sanderson et al., 2000, 0429; Steenland and
Sanderson, 2001, 0455). McDonald et al. (2001, Document ID 1091)
examined a cohort that entered the workforce, on average, a decade
earlier than the cohorts that Steenland and Sanderson (2001, Document
ID 0455) 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, Document ID 0455) cohort worked in 16
plants, 7 of which overlapped with the McDonald, et al.

(2001, Document ID 1091) cohort. McDonald et al. (2001, Document ID
1091), Hughes et al. (2001, Document ID 1060), and Rando et al. (2001,
Document ID 0415) had access to smoking histories, plant records, and
exposure measurements that allowed for historical reconstruction and
the development of a job exposure matrix. The McDonald et al. (2005,
Document ID 1092) study was a later update, with follow-up through
2000, of both the cohort and nested case-control studies. Steenland and
Sanderson (2001, Document ID 0455) 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, Document ID 1060; McDonald et al., 2005, 1092;
Steenland and Sanderson, 2001, 0455) showed 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, Document ID 1060) study in its
Preliminary QRA, as it allowed for individual job, exposure, and
smoking histories to be taken into account.
    OSHA noted that Brown and Rushton (2005a, Document ID 0303; 2005b,
0304) found no association between risk of lung cancer mortality and
exposure to respirable crystalline silica among British industrial sand
workers. However, a large portion of the cohort had relatively short
service times in the industry, with over one-half the cohort deaths and
almost three-fourths of the lung cancer mortalities having had less
than 10 years of service. Considering the apparent high turnover in
this industry and the absence of prior occupational histories,
exposures from work experience other than in the industrial sand
industry could be a significant confounder (Document ID 1711, p. 131).
Additionally, as Steenland noted in a letter review (2005a, Document ID
1313), the cumulative exposures of workers in the Brown and Ruston
(2005b, Document ID 0304) study were over 10 times lower than the
cumulative exposures experienced by the cohorts in the pooled analysis
that Steenland et al. (2001a, Document ID 0452) performed. The low
exposures experienced by this cohort would have made detecting a
positive association with lung cancer mortality even more difficult.
    In British coal miners, excess lung cancer mortality was reported
in a large cohort study, which examined the mortality experience of
17,800 miners through the end of 2005 (Miller et al., 2007, Document ID
1305; Miller and MacCalman, 2009, 1306). 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 were 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 Cox regression provided strong evidence that,
for these coal miners, although quartz exposures were associated with
increased lung cancer risk, simultaneous exposures to coal dust did not
cause increased lung cancer risk. Because of these strengths, OSHA
included this study in its Preliminary QRA (Document ID 1711).
    In addition to the studies in these cohorts, OSHA also reviewed
studies of lung cancer mortality in metal ore mining populations. Many
of these mining studies, which showed mixed results, were subject to
confounding due to exposure to other potential carcinogens such as
radon and arsenic. IARC noted that only a few ore mining studies
accounted for confounding from other occupational carcinogens and that,
when confounding was absent or accounted for, an association between
silica exposure and lung cancer was absent (1997, Document ID 1062).
Many of the studies conducted since IARC's review, however, more
strongly implicate crystalline silica as a human carcinogen (1997,
Document ID 1062). Pelucchi et al. (2006, Document ID 0408), in a meta-
analysis of studies conducted since IARC's (1997, Document ID 1062)
review, reported statistically significantly elevated relative risks of
lung cancer mortality in underground and surface miners in three cohort
and four case-control studies. Cassidy et al., in a pooled case-control
analysis, showed a statistically significant increased risk of lung
cancer mortality among miners (OR = 1.48), and demonstrated a linear
trend of increasing odds ratios with increasing exposures (2007,
Document ID 0313).
    OSHA also 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. IARC previously made a similar determination
in reference to the foundry industry. However, with respect to the
construction industry, Cassidy et al. (2007, Document ID 0313), in a
large European community-based case-control study, reported finding a
clear linear trend of increasing odds ratios with increasing cumulative
exposure to crystalline silica (estimated semi-quantitatively) after
adjusting for smoking and exposure to insulation and wood dusts.
    In addition, an 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, Document ID 0309). A national records and death certificate study
was also conducted in Finland by Pukkala et al., who found a
statistically significant excess of lung cancer incidence among men and
women with estimated medium and heavy exposures (2005, Document ID
0412).
    One of the more compelling studies OSHA evaluated and used in the
Preliminary QRA (Document ID 1711) was Steenland et al.'s (2001a,
Document ID 0452) pooled analysis of 10 occupational cohorts (5 mines
and 5 industrial facilities), which demonstrated an overall positive
exposure-response relationship between cumulative exposure to
crystalline silica and lung cancer mortality. These 10 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 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.
iii. Confounding
    Smoking is known to be a major risk factor for lung cancer.
However, OSHA maintained in the Preliminary QRA that it is unlikely
that smoking explained the observed exposure-response trends in the
studies described above (Document ID 1711). Studies by Hnizdo et al.
(1997, Document ID 1049), McLaughlin et al. (1992, Document ID 0372),
Hughes et al. (2001, Document ID 1060), McDonald et al. (2001, Document
ID 1091; 2005, 1092), Miller and MacCalman (2009, Document ID 1306),
and Cassidy et al. (2007, Document ID 0313) 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, Document ID 1051) and in the follow-up
nested case-control study (Hnizdo et al., 1997, Document ID 1049), the
combined effect of exposure to respirable crystalline silica and
smoking was greater than additive, suggesting a multiplicative effect.
This effect 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 (McLaughlin et al., 1992, Document
ID 0372), 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 (Hughes et al., 2001, Document ID 1060) and
British coal workers (Miller and MacCalman, 2009, Document ID 1306)
found positive exposure-response trends after adjusting for smoking
histories, as did Cassidy et al. (2007, Document ID 0313) in their
community-based case-control study of exposed European workers.
    Given these findings of investigators who have accounted for the
impact of smoking, OSHA preliminarily determined that the weight of the
evidence reviewed identified respirable crystalline silica as an
independent risk factor for lung cancer mortality. OSHA also determined
that its finding was further supported by animal studies demonstrating
that exposure to silica alone can cause lung cancer (e.g., Muhle et
al., 1995, Document ID 0378).
iv. Lung Cancer and Silicosis
    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 (see Document ID 1711, pp.
171-172). This has led some researchers to 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
inflammation (and concomitant oxidative stress) and increased
epithelial cell proliferation associated with the development of
silicosis. However, other researchers have noted additional genotoxic
and non-genotoxic mechanisms that may also be involved in
carcinogenesis induced by silica (see Section V.H, Mechanisms of
Silica-Induced Adverse Health Effects, and Document ID 1711, pp. 230-
239). IARC also noted that a direct genotoxic mechanism from silica to
induce a carcinogenic effect cannot be ruled out (2012, Document ID
1473). Thus, OSHA preliminarily concluded 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.
    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, Document ID
1084; Tsuda et al., 1997, 1127) showed no association with increasing
lung cancer mortality, while Lacasse et al. (2005, Document ID 0365)
demonstrated a positive dose-response for lung cancer with increasing
ILO radiographic category. A number of other studies found increased
lung cancer risk among exposed workers absent radiological evidence of
silicosis (Cassidy et al., 2007, Document ID 0313; Checkoway et al.,
1999, 0327; Cherry et al., 1998, 0335; Hnizdo et al., 1997, 1049;
McLaughlin et al., 1992, 0372). For example, the diatomaceous earth
study by Checkoway et al. showed a statistically significant exposure-
response relationship for lung cancer among persons without silicosis
(1999, Document ID 0327). Checkoway and Franzblau, reviewing the
international literature, found that all epidemiological studies
conducted to that date were insufficient to conclusively determine the
role of silicosis in the etiology of lung cancer (2000, Document ID
0323). OSHA preliminarily concluded that the more recent pooled and
meta-analyses do not provide compelling evidence that silicosis is a
necessary precursor to lung cancer.
c. Non-Malignant Respiratory Diseases (Other Than Silicosis)
    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), chronic bronchitis, and emphysema. COPD is a disease
state characterized by airflow limitation that is usually progressive
and not fully reversible. In patients with COPD, either chronic
bronchitis or emphysema may be present or both conditions may be
present together.
    As detailed in the Review of Health Effects Literature, OSHA
reviewed several studies of NMRD morbidity and preliminarily concluded
that exposure to respirable crystalline silica may increase the risk of
emphysema, chronic bronchitis, and pulmonary function impairment,
regardless of whether signs of silicosis are present (Document ID
1711). Smokers may be at an increased risk relative to nonsmokers.
    OSHA also reviewed studies of NMRD mortality that focused on causes
of death other than silicosis. Wyndham et al. found a significant
excess mortality for chronic respiratory diseases in a cohort of white
South African gold miners (1986, Document ID 0490). 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 exposure to silica-containing dust. A
multiplicative effect of smoking and cumulative dust exposure on
mortality from COPD was found in another study of white South African
gold miners (Hnizdo, 1990, Document ID 1045). 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.
    Park et al. (2002, Document ID 0405) analyzed the California
diatomaceous earth cohort data originally studied by Checkoway et al.
(1997, Document ID 0326), 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 at least partial adjustment for smoking. Using the exposure
estimates developed for the cohort by Rice et al. (2001, Document ID
1118) in their exposure-response study of lung cancer risks, Park et
al. (2002, Document 0405) evaluated the quantitative exposure-response
relationship for LDOC mortality and found a strong positive
relationship with exposure to respirable crystalline silica. OSHA found
this study particularly compelling because of the strengths of the
study design and availability of smoking history data on part of the
cohort, as well as the high-

quality exposure and job history data. The study authors noted:

    Data on smoking, collected since the 1960s in the company's
radiographic screening programme, were available for 1171 of the
subjects (50%). However, smoking habits were unknown for 45 of the
67 workers that died from LDOC (67%). Our Poisson regression
analyses for LDOC, stratified on smoking, have partially rectified
the confounding by smoking issue. Furthermore, analyses performed
without control for smoking produced slightly smaller and less
precise estimates of the effects of silica, suggesting that smoking
is a negative confounder. In their analysis of this cohort,
Checkoway et al. applied the method of Axelson concluding that it
was very unlikely that cigarette smoking could account for the
association found between mortality from LDOC and cumulative
exposure to silica (Document ID 0405, p. 41).

    Consequently, OSHA used this study in its Preliminary QRA (Document
ID 1711, pp. 295-298).
    Based on this evidence, and the other studies discussed in the
Review of Health Effects Literature, OSHA preliminarily concluded that
respirable crystalline silica increases the risk for mortality from
non-malignant respiratory disease (not including silicosis) in an
exposure-related manner. The Agency also preliminarily concluded that
the risk is strongly influenced by smoking, and opined that the effects
of smoking and silica exposure may be synergistic.
d. Renal Disease and Autoimmune Diseases
    In its Review of Health Effects Literature, OSHA described the
available experimental and epidemiological data evaluating respirable
crystalline silica exposure and renal and/or autoimmune effects
(Document ID 1711). In addition to a number of case reports,
epidemiological studies have found statistically significant
associations between occupational exposure to silica dust and chronic
renal disease (Calvert et al., 1997, Document ID 0976), subclinical
renal changes (Ng et al., 1992c, Document ID 0386), end-stage renal
disease morbidity (Steenland et al., 1990, Document ID 1125), chronic
renal disease mortality (Steenland et al., 2001b, Document ID 0456;
2002a, 0448), and granulomatosis with polyangitis, a condition that can
affect the kidneys (Nuyts et al., 1995, Document ID 0397). In other
findings, silica-exposed individuals, both with and without silicosis,
had an increased prevalence of abnormal renal function (Hotz et al.,
1995, Document ID 0361), and renal effects have been reported to
persist after cessation of silica exposure (Ng et al., 1992c, Document
ID 0386). Possible mechanisms suggested for silica-induced renal
disease include a direct toxic effect on the kidney, deposition of
immune complexes (IgA) in the kidney following silica related pulmonary
inflammation, and an autoimmune mechanism (Calvert et al., 1997,
Document ID 0976; Gregorini et al., 1993, 1032).
    In a pooled cohort analysis, Steenland et al. (2002a, Document ID
0448) combined the industrial sand cohort from Steenland et al. (2001b,
Document ID 0456), the gold mining cohort from Steenland and Brown
(1995a, Document ID 0450), and the Vermont granite cohort studies by
Costello and Graham (1988, Document ID 0991). In all, the combined
cohort consisted of 13,382 workers with exposure information available
for 12,783. 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 500 [micro]g/m\3\ or more
(Steenland et al., 2002a, Document ID 0448).
    OSHA noted that other studies failed to find an excess renal
disease risk among silica-exposed workers. Davis et al. (1983, Document
ID 0999) found elevated, but not statistically significant, 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, Document ID 0363) among Finnish granite workers,
where there were 4 deaths due to urinary tract disease compared to 1.8
expected. Both Carta et al. (1994, Document ID 0312) and Cocco et al.
(1994, Document ID 0988) reported finding no increased mortality from
urinary tract disease among workers in an Italian lead mine and zinc
mine. However, Cocco et al. (1994, Document ID 0988) commented that
exposures to respirable crystalline silica were low, averaging 7 and 90
[micro]g/m\3\ in the two mines, respectively, and that their study in
particular had low statistical power to detect excess mortality.
    OSHA expressed its belief that there is substantial evidence,
particularly the 3-cohort pooled analysis conducted by Steenland et al.
(2002a, Document ID 0448), on which to base a finding that exposure to
respirable crystalline silica increases the risk of renal disease
mortality and morbidity. The pooled analysis by Steenland et al.
involved a large number of workers from three cohorts with well-
documented, validated job-exposure matrices; it found a positive,
monotonic increase in renal disease risk with increasing exposure for
both underlying and multiple cause data (2002a, Document ID 0448).
However, there are considerably less data available for renal disease
than there are for silicosis mortality and lung cancer mortality. The
findings based on these data are, therefore, less robust. Nevertheless,
OSHA preliminarily concluded that the underlying data are sufficient to
provide useful estimates of risk and included the Steenland et al.
(2002a, Document ID 0448) analysis in its Preliminary QRA.
    For autoimmune effects, OSHA reviewed epidemiological information
suggesting an association between respirable silica exposure and
autoimmune diseases, including scleroderma (Sluis-Cremer et al., 1985,
Document ID 0439), rheumatoid arthritis (Klockars et al., 1987,
Document ID 1075; Rosenman and Zhu, 1995, 0424), and systemic lupus
erythematosus (Brown et al., 1997, Document ID 0974). However, there
were no quantitative exposure-response data available on which to base
a quantitative risk assessment for autoimmune diseases.
e. Physical Factors Affecting Toxicity of Crystalline Silica
    OSHA also 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, Document ID 1072; Wagner et al., 1980, 0476). 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, Document ID
0298; Guthrie and Heaney, 1995, 1035). Furthermore, a difference in
toxicity between cristobalite and quartz has not been observed in
epidemiological studies (tridymite has not been studied) (NIOSH, 2002,
Document ID 1110). In an analysis of exposure-response for lung cancer,
Steenland et al. found similar exposure-response trends between
cristobalite-exposed workers and other cohorts

exposed to quartz (2001a, Document ID 0452).
    OSHA also discussed other physical factors that may influence the
toxicologic potency of crystalline silica. A number of animal studies
compared the toxicity of freshly fractured silica to that of aged
silica (Porter et al., 2002, Document ID 1114; Shoemaker et al., 1995,
0437; Vallyathan et al., 1995, 1128). These studies have demonstrated
that although freshly fractured silica is more toxic than aged silica,
aged silica still retains significant toxicity. There have been no
studies comparing workers exposed to freshly fractured silica to those
exposed to aged silica. However, similarities between the results of
animal and human studies involving freshly fractured silica suggest
that the animal studies involving aged silica may also apply to humans.
For example, 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, Document ID 1294; Goodman et al., 1992, 1029). 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, Document ID 1128).
    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 (see Document ID 1711,
pp. 247-258). Aluminum has been shown to decrease toxicity (Castranova
et al., 1997, Document ID 0978; Donaldson and Borm, 1998, 1004; Fubini,
1998, 1016). Silica coated with aluminosilicate clay exhibits lower
toxicity, possibly as a result of reduced bioavailability of the silica
particle surface (Donaldson and Borm, 1998, Document ID 1004; Fubini,
1998, 1016). Aluminum as well as 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, Document ID 1016).
An epidemiological study found that the risk of silicosis was less in
pottery workers than in tin and tungsten miners (Chen et al., 2005,
Document ID 0985; Harrison et al., 2005, 1036), 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.
    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 investigated the surface characteristics of
crystalline silica particles and their influence on fibrogenic
activity, NIOSH 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
(2002, Document ID 1110). Thus, OSHA preliminarily concluded that while
there was considerable evidence that several environmental influences
can modify surface activity to either enhance or diminish the toxicity
of silica, the available information was insufficient to determine in
any quantitative way how these influences may affect disease risk to
workers in any particular workplace setting.
3. Summary of the Preliminary QRA
    OSHA presented in the Preliminary QRA estimates of the risk of
silica-related diseases assuming exposure over a working life (45
years, from age 20 to age 65) to the revised 8-hour time-weighted
average (TWA) PEL of 50 [micro]g/m\3\ respirable crystalline silica,
the new action level of 25 [micro]g/m\3\, and the previous PELs. OSHA's
previous general industry PEL for respirable quartz was expressed both
in terms of a particle count formula and a gravimetric concentration
formula; the previous construction and shipyard employment PELs for
respirable quartz were only expressed in terms of a particle count
formula. For general industry, as the quartz content increases, the
gravimetric PEL approached a limit of 100 [micro]g/m\3\ respirable
quartz. For construction and shipyard employment, OSHA's previous PELs
used a formula that limits exposure to respirable dust, depending upon
the quartz content, expressed as a respirable particle count
concentration. There was no single mass concentration equivalent for
the construction and shipyard employment PELs; OSHA reviewed several
studies that suggest that the previous construction/shipyard PEL likely
was between 250 and 500 [micro]g/m\3\ respirable quartz. In general
industry, for both the gravimetric and particle count PELs, OSHA's
previous PELs for cristobalite and tridymite were half the value for
quartz. Based upon these previous PELs and the new action level, OSHA
presented risk estimates associated with exposure over a working life
to 25, 50, 100, 250, and 500 [micro]g/m\3\ respirable silica
(corresponding to cumulative exposures over 45 years to 1.125, 2.25,
4.5, 11.25, and 22.5 mg/m\3\-yrs).
    To estimate lifetime excess mortality risks at these exposure
levels, OSHA implemented each of the risk models in a life table
analysis that accounted for competing causes of death due to background
causes and cumulated risk through age 85. For these analyses, OSHA used
lung cancer, NMRD, or renal disease mortality and all-cause mortality
rates to account for background risks and competing risks (U.S. 2006
data for lung cancer and NMRD mortality in all males, 1998 data for
renal disease mortality, obtained from cause-specific death rate tables
published by the National Center for Health Statistics (2009, Document
ID 1104)). OSHA calculated these risk estimates assuming occupational
exposure from age 20 to age 65. The mortality risk estimates were
presented in terms of lifetime excess risk per 1,000 workers for
exposure over an 8-hour working day, 250 days per year, and a 45-year
working life.
    For silicosis morbidity, OSHA based its risk estimates on
cumulative risk models used by various investigators to develop
quantitative exposure-response relationships. These models
characterized the risk of developing silicosis (as detected by chest
radiography) up to the time that cohort members (including both active
and retired workers) were last examined. Thus, risk estimates derived
from these studies represented less-than-lifetime risks of developing
radiographic silicosis. OSHA did not attempt to estimate lifetime risk
(i.e., up to age 85) for silicosis morbidity because the relationships
between age, time, and disease onset post-exposure have not been well
characterized.
a. Silicosis and NMRD Mortality
i. Exposure-Response Studies
    In the Preliminary QRA, OSHA relied upon two published quantitative
risk studies of silicosis and NMRD mortality (Document ID 1711). The
first, Mannetje et al. (2002b, Document ID 1089) conducted a pooled
analysis of silicosis mortality in which there were 18,634 subjects,
150 silicosis deaths, and 20 deaths from unspecified pneumoconiosis.
Rates for silicosis adjusted for age, calendar time, and study were
estimated by Poisson regression and increased nearly monotonically with
deciles of cumulative exposure, from a mortality rate of 5/100,000
person-years in the lowest exposure category (0-0.99

mg/m\3\-yrs) to 299/100,000 person-years in the highest category
(>28.10 mg/m\3\-yrs).
    As previously discussed, the second, Park et al. (2002, Document ID
0405) analyzed the California diatomaceous earth cohort data from
Checkoway et al. (1997, Document ID 0326), and examined mortality from
chronic lung disease other than cancer (LDOC; also known as non-
malignant respiratory disease (NMRD)). 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, Document
ID 0405) to partially adjust for smoking. Estimates of LDOC mortality
risks were derived via Poisson and Cox proportional hazards models; a
variety of relative rate model forms were fit to the data, with a
linear relative rate model selected for estimating risks.
ii. Risk Estimates
    As silicosis is only caused by exposure to respirable crystalline
silica (i.e., there is no background rate of silicosis in the unexposed
population), absolute risks of silicosis mortality rather than excess
risks were calculated for the Mannetje et al. pooled analysis (2002b,
Document ID 1089). These risk estimates were derived from the rate
ratios incorporating simulated measurement error reported by
ToxaChemica (Document ID 0469). OSHA's estimate of lifetime risk of
silicosis mortality, for 45 years of exposure to the previous general
industry PEL, was 11 deaths per 1,000 workers for the pooled analysis
(Document ID 1711). At the revised PEL, the risk estimate was 7 deaths
per 1,000.
    OSHA also calculated preliminary risk estimates for NMRD mortality.
These estimates were derived from Park et al. (2002, Document ID 0405).
For 45 years of exposure to the previous general industry PEL, OSHA
preliminarily estimated lifetime excess risk at 83 deaths per 1,000
workers. At the revised PEL, OSHA estimated 43 deaths per 1,000
workers.
    OSHA noted that, for exposures up to 250 [micro]g/m\3\, the
mortality risk estimates based on Park et al. (2002, Document ID 0405)
are about 5 to 11 times as great as those calculated for the pooled
analysis of silicosis mortality (Mannetje et al., 2002b, Document ID
1089). These two sets of risk estimates, however, are not directly
comparable, as the endpoint for the Park et al. (2002, Document ID
0405) analysis was death from all non-cancer lung diseases, including
pneumoconiosis, emphysema, and chronic bronchitis, whereas the pooled
analysis by Mannetje et al. (2002b, Document ID 1089) included only
deaths coded as silicosis or other pneumoconiosis. Less than 25 percent
of the LDOC deaths in the Park et al. analysis were coded as silicosis
or other pneumoconiosis (15 of 67), suggesting that silicosis as a
cause of death may be misclassified as emphysema or chronic bronchitis.
Thus, Mannetje et al.'s (2002b, Document ID 1089) selection of deaths
may tend to underestimate the true risk of silicosis mortality, and
Park et al.'s (2002, Document ID 0405) analysis may more completely
capture the total respiratory mortality risk from all non-malignant
causes.
    Since the time of OSHA's analysis, NCHS has released updated all-
cause mortality and NMRD mortality background rates from 2011 (http://wonder.cdc.gov/ucd-icd10.html); OSHA's final risk estimates for NMRD
mortality, which incorporate these updated rates (ICD10 codes J40-J47,
chronic lower respiratory diseases; J60-J66, J68, pneumoconiosis and
chemical effects), are available in Section VI, Final Quantitative Risk
Assessment and Significance of Risk.
b. Lung Cancer Mortality
i. Exposure-Response Studies
    In 1997, when IARC determined that there was sufficient evidence to
regard crystalline silica as a human carcinogen, it also noted that
some epidemiological studies 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 (Document ID
1062). These findings led Steenland et al. (2001a, Document ID 0452) to
conduct a comprehensive exposure-response analysis--the IARC multi-
center study--of the risk of lung cancer associated with exposure to
crystalline silica. This study relied on all available cohort data from
previously-published epidemiological studies for which there were
adequate quantitative data on worker silica exposures to derive pooled
estimates of disease risk. In addition, as discussed previously, OSHA
identified four more recent studies suitable for quantitative risk
assessment: (1) An exposure-response analysis by Rice et al. (2001,
Document ID 1118) of a cohort of diatomaceous earth workers primarily
exposed to cristobalite; (2) an analysis by Attfield and Costello
(2004, Document ID 0285) of U.S. granite workers; (3) an exposure-
response analysis by Hughes et al. (2001, Document ID 1060) of U.S.
industrial sand workers; and (4) a risk analysis by Miller et al.
(2007, Document ID 1305) and Miller and MacCalman (2009, Document ID
1306) of British coal miners. OSHA thoroughly described each of these
studies in its Preliminary QRA (Document ID 1711); a brief summary of
the exposure-response models used in each study is provided here.
    The Steenland et al. pooled exposure-response analysis was based on
data obtained from ten cohorts of silica-exposed workers (65,980
workers, 1,072 lung cancer deaths) (2001a, Document ID 0452). The
pooled analysis cohorts included U.S. gold miners (Steenland and Brown,
1995a, Document ID 0450), U.S. diatomaceous earth workers (Checkoway et
al., 1997, Document ID 0326), Australian gold miners (de Klerk and
Musk, 1998, Document ID 0345), Finnish granite workers (Koskela et al.,
1994, Document ID 1078), U.S. industrial sand employees (Steenland and
Sanderson, 2001, Document ID 0455), Vermont granite workers (Costello
and Graham, 1988, Document ID 0991), South African gold miners (Hnizdo
and Sluis-Cremer, 1991, Document ID 1051; Hnizdo et al.,1997, 1049),
and Chinese pottery workers, tin miners, and tungsten miners (Chen et
al., 1992, Document ID 0329).
    Steenland et al. (2001a, Document ID 0452) performed a nested case-
control analysis via Cox regression. There were 100 controls chosen for
each case randomly from among cohort members who survived past the age
at which the case died; controls were matched on age (the time variable
in Cox regression), study, race/ethnicity, sex, and date of birth
within 5 years. Steenland et al. found that the use of any of the
following continuous exposure variables in a log linear relative risk
model resulted in positive statistically significant (p <= 0.05)
exposure-response coefficients: (1) Cumulative exposure with a 15-year
lag; (2) the log of cumulative exposure with a 15-year lag; and (3)
average exposure (2001a, Document ID 0452). The models that provided
the best fit to the data used cumulative exposure and log-transformed
cumulative exposure. Models that used log-transformed cumulative
exposure also showed no statistically significant heterogeneity among
cohorts (p = 0.36), possibly because they are less influenced by very
high exposures. At OSHA's request, Steenland (2010, Document ID 1312)
also conducted a categorical analysis of the pooled data set and
additional analyses using linear relative risk models (with and without
the log transformation of cumulative exposure) as well as a two-piece
spline model (see Document ID 1711, pp. 276-278).

    Rice et al. (2001, Document ID 1118) applied a variety of exposure-
response models to the California diatomaceous earth cohort data
originally studied by Checkoway et al. (1993, Document ID 0324; 1996,
0325; 1997, 0326) and included in the Steenland et al. (2001a, Document
ID 0452) pooled analysis. The cohort consisted of 2,342 white males
employed for at least one year between 1942 and 1987 in a California
diatomaceous earth mining and processing plant. The cohort was followed
until 1994, and included 77 lung cancer deaths. Rice et al. reported
that exposure to crystalline silica was a significant predictor of lung
cancer mortality for nearly all of the models employed, with the linear
relative risk model providing the best fit to the data in the Poisson
regression analysis (2001, Document ID 1118).
    Attfield and Costello (2004, Document ID 0285) analyzed the U.S.
granite cohort originally studied by Costello and Graham (1988,
Document ID 0991) and Davis et al. (1983, Document ID 0999) and
included in the Steenland et al. (2001a, Document ID 0452) pooled
analysis. The cohort consisted of 5,414 male granite workers who were
employed in the Vermont granite industry between 1950 and 1982 and who
had received at least one chest x-ray from the surveillance program of
the Vermont Department of Industrial Hygiene. The 2004 report by
Attfield and Costello extended follow-up from 1982 to 1994, and found
201 deaths (Document ID 0285). Using Poisson regression models, the
results of a categorical analysis showed a generally increasing trend
of lung cancer rate ratios with increasing cumulative exposure.
    As mentioned previously, however, the rate ratio for the highest
exposure group in the Attfield and Costello analysis (cumulative
exposures of 6.0 mg/m\3\-yrs or higher) was substantially lower than
that for other exposure groups (2004, Document ID 0285). The authors
reported that the best-fitting model had a 15-year lag, untransformed
cumulative exposure, and the omission of this highest exposure group.
The authors argued that it was appropriate to omit the highest exposure
group for several reasons, including that the exposure estimates for
the highest exposure group were less reliable, and there was a greater
likelihood of cohort selection effects, competing causes of death, and
misdiagnosis (Document ID 0285, p. 136).
    McDonald et al. (2001, Document ID 1091), Hughes et al. (2001,
Document ID 1060) and McDonald et al. (2005, Document ID 1092) followed
up on a cohort study of North American industrial sand workers included
in the Steenland et al. (2001a, Document ID 0452) pooled analysis. The
McDonald et al. cohort included 2,670 men employed before 1980 for
three years or more in one of nine North American (8 U.S. and 1
Canadian) sand-producing plants, including 1 large associated office
complex (2001, Document ID 1091). A nested case-control study based on
90 lung cancer deaths (through 1994) from this cohort was conducted by
Hughes et al. (2001, Document ID 1060). A subsequent update (through
2000, 105 lung cancer deaths) eliminated the Canadian plant, following
2,452 men from the eight U.S. plants (McDonald et al., 2005, Document
ID 1092). These nested case-control studies, Hughes et al. (2001,
Document ID 1060) and McDonald et al. (2005, Document ID 1092), allowed
for individual job, exposure, and smoking histories to be taken into
account in the exposure-response analysis. Hughes et al. (2001,
Document ID 1060) found statistically significant positive exposure-
response trends for lung cancer for both cumulative exposure (lagged 15
years) and average exposure concentration, but not for duration of
employment. With exposure lagged 15 years and after adjusting for
smoking, increasing quartiles of cumulative silica exposure were also
associated with lung cancer mortality (p-value for trend = 0.04).
McDonald et al. (2005, Document ID 1092) found very similar results,
with increasing quartiles of cumulative silica exposure (lagged 15
years) associated with lung cancer mortality (p-value for trend =
0.006). Because McDonald et al. (2005, Document ID 1092) did not report
the medians of the exposure categories, and given the similar results
of both case-control studies, OSHA chose to base its risk estimates on
the Hughes et al. (2001, Document ID 1060) study.
    Miller et al. (2007, Document ID 1305) and Miller and MacCalman
(2009, Document ID 1306) continued a follow-up mortality study, begun
in 1970, of coal miners from 10 British coal mines initially followed
through the end of 1992 (Miller et al., 1997, Document ID 1304) and
extended it to 2005. In the analysis using internal controls and Cox
regression methods, the relative risk of lung cancer mortality,
adjusted for concurrent dust exposure and smoking status, at a
cumulative quartz exposure (lagged 15 years) equivalent of
approximately 55 [mu]g/m\3\ for 45 years was 1.14 (95% C.I., 1.04 to
1.25).
ii. Risk Estimates
    In the Preliminary QRA, OSHA presented estimates of excess lung
cancer mortality risk from occupational exposure to crystalline silica,
based on data from the five epidemiology studies discussed above
(Document ID 1711). In its preliminary analysis, OSHA used background
all-cause mortality and lung cancer mortality rates from 2006, as
reported by the National Center for Health Statistics (NCHS) (Document
ID 1104). These rates were used in life table analyses to estimate
lifetime risks at the exposure levels of interest, ranging from 25 to
500 [mu]g/m\3\ respirable crystalline silica.
    OSHA's preliminary estimates of lifetime excess lung cancer risk
associated with 45 years of exposure to crystalline silica at 100
[mu]g/m\3\ (approximately the previous general industry PEL) ranged
between 13 and 60 deaths per 1,000 workers, depending upon the study
used. For exposure to the revised PEL of 50 [mu]g/m\3\, the lifetime
risk estimates were in the range of between 6 and 26 deaths per 1,000
workers, depending upon the study used. For a 45 year exposure at the
new action level of 25 [mu]g/m\3\, OSHA estimated the risk to range
between 3 and 23 deaths per 1,000 workers. The Agency found that the
results from these preliminary assessments were reasonably consistent
despite the use of data from different cohorts and the reliance on
different analytical techniques for evaluating dose-response
relationships.
    OSHA also estimated the lung cancer risk associated with 45 years
of exposure to the previous construction/shipyard PEL (in the range of
250 [mu]g/m\3\ to 500 [mu]g/m\3\) to range between 37 and 653 deaths
per 1,000 workers, depending upon the study used. OSHA acknowledges
that the 653 deaths is the upper limit for 45 years of exposure to 500
[mu]g/m\3\, and recognizes that actual risk, to the extent that workers
are exposed for less than 45 years or intermittently, is likely to be
lower. In addition, exposure to 250 or 500 [mu]g/m\3\ over 45 years
represents cumulative exposures of 11.25 and 22.5 mg/m\3\-yrs,
respectively. This range of cumulative exposure is well above the
median cumulative exposure for most of the cohorts used in the
preliminary risk assessment. Thus, OSHA explained that estimating lung
cancer excess risks over this higher range of cumulative exposures of
interest to OSHA required some degree of upward extrapolation of the
exposure-response function to model these high exposures, thus adding
uncertainty to the estimates.
    Since the time of that original analysis, NCHS has released updated
all-cause mortality and lung cancer mortality background rates from
2011.

OSHA's final risk estimates, which incorporate these updated rates, are
available in this preamble at Section VI, Final Quantitative Risk
Assessment and Significance of Risk.
c. Uncertainty Analysis of Pooled Studies of Lung Cancer Mortality and
Silicosis Mortality
    In the Preliminary QRA, OSHA recognized that risk estimates can be
inherently uncertain and can be affected by confounding, selection
bias, and measurement error (Document ID 1711). OSHA presented several
reasons as to why it does not believe that confounding or selection
bias had a substantial impact on the risk estimates for lung cancer or
silicosis mortality (Document ID 1711, pp. 299-302). However, because
it was more difficult to assess the importance of exposure measurement
error, OSHA's contractor, ToxaChemica, Inc., commissioned Drs. Kyle
Steenland and Scott Bartell to perform an uncertainty analysis to
examine the effect of uncertainty due to measurement error in the
pooled studies (Steenland et al., 2001a, Document ID 0452; Mannetje
2002b, 1089) on the lung cancer and silicosis mortality risk estimates
(ToxaChemica, Inc., 2004, Document ID 0469).
    There are two main sources of error in the silica exposure
measurements. The first arises from the assignment of individual
workers' exposures based on either exposure measurements for a sample
of workers in the same job or estimated exposure levels for specific
jobs in the past when no measurements were available, via a job-
exposure matrix (JEM) (Mannetje et al., 2002a, Document ID 1090). The
second arises from the conversion of historically-available dust
measurements, typically particle count concentrations, to gravimetric
respirable silica concentrations. ToxaChemica, Inc. conducted an
uncertainty analysis using the raw data from the IARC multi-centric
study to address these sources of error (2004, Document ID 0469).
i. Lung Cancer Mortality
    To examine the effect of error in the assignment of individual
exposure values in the cohorts studied by Steenland et al. (2001a,
Document ID 0452), ToxaChemica, Inc. used a Monte Carlo analysis (a
type of simulation analysis that varies the values of an uncertain
input to an analysis--in this case, exposure estimates--to explore the
effects of different values on the outcome of the analysis) to randomly
sample new values for each worker's job-specific exposure levels from a
distribution that they believed characterized the variability in
exposures of individual workers in each job (see Document ID 1711, pp.
303-305). That is, ToxaChemica created a distribution of values for
each member of each cohort where the mean exposure for each member was
equal to the original exposure value and the distribution of exposure
values was based on a log-normal distribution having a standard
deviation that was based on the exposure variation observed in
industrial sand plants observed by Steenland and Sanderson (2001,
Document ID 0455). From this distribution, new sets of exposure values
from each cohort member were randomly drawn for 50 trials. This
simulation was designed to test whether sets of exposure values that
were plausibly different from the original estimates would lead to
substantially different results of the exposure-response analysis.
Except for the simulated exposure values and the correction of a few
minor errors in the original data sets, the simulation analysis used
the same data as the original analyses conducted by Steenland et al.
(2001a, Document ID 0452).
    When an entire set of cumulative exposure values was assembled for
all workers based on these randomly sampled values, the set was used in
a conditional logistic regression to fit a new exposure-response model.
The extent to which altering the exposure values led to changes in the
results indicated how sensitive the previously presented risk estimates
may have been to error in the exposure estimates. Among the individual
cohorts, most of the mean regression coefficients resulting from the
simulation analysis were consistent with the coefficients from the
exposure-response analyses reported in Steenland et al. (2001, Document
ID 0455) and ToxaChemica, Inc. (2004, Document ID 0469) (following
correction for minor data entry and rounding errors). An exception was
the mean of the simulation coefficients based on the South Africa gold
cohort (0.26), which was lower than the previously calculated exposure
coefficient (0.582). ToxaChemica, Inc. (2004, Document ID 0469)
concluded that this error source probably did not appreciably change
the estimated exposure-response coefficient for the pooled data set.
    To examine the effect of error in estimating gravimetric respirable
crystalline silica exposures from historical dust concentration data
(i.e., particle count data), ToxaChemica, Inc. (2004, Document ID 0469)
used a procedure similar to that used to assess uncertainties in
individual exposure value assignments. ToxaChemica, Inc. assumed that,
for each job in the dataset, a specific conversion factor existed that
related workers' exposures measured as particle concentrations to
gravimetric respirable silica exposures, and that this conversion
factor came from a normal distribution with a standard deviation
[sigma] = \1/2\ its mean [mu]. The use of a normal distribution was a
reasonable choice in that it allowed the sampled conversion factors to
fall above or below the original values with equal probability, as the
authors had no information to suggest that error in either direction
was more likely. The normal distribution also assigned higher
probability to conversion values closer to the original values. The
choice of the normal distribution therefore reflected the study
authors' judgment that their original conversion factors were more
likely to be approximately correct than not, while allowing for the
possibility of significant error in the original values.
    A new conversion factor was then sampled for each job from the
appropriate distribution, and the complete set of sampled conversion
factors was then used to re-run the risk analysis used by Steenland et
al. (2001a, Document ID 0452). The results were similar to the
coefficients originally derived from each cohort; the only coefficient
substantially affected by the procedure was that for the South African
cohort, with an average value of 0.350 across ten runs compared to the
original value of 0.582 (see Table II-5, Document ID 1711, p. 307).
This suggests that the results of exposure-response analyses conducted
using the South African cohort are sensitive to error in exposure
estimates; therefore, there is greater uncertainty due to potential
exposure estimation error in an exposure-response model based on this
cohort than is the case for the other nine cohorts in Steenland et al's
analysis.
    To explore the potential effects of both kinds of random
uncertainty described above, ToxaChemica, Inc. (2004, Document ID 0469)
used the distributions representing the error in job-specific exposure
assignment and the error in converting exposure metrics to generate 50
new exposure simulations for each cohort. A study-specific coefficient
and a pooled coefficient were fit for each new simulation, with the
assumption that the two sources of uncertainty were independent. The
results indicated that the only cohort for which the mean of the
exposure coefficients derived from the 50 simulations differed
substantially from the previously calculated exposure

coefficient was the South African gold cohort (simulation mean of 0.181
vs. original coefficient of 0.582). For the pooled analysis, the mean
coefficient estimate from the simulations was 0.057, just slightly
lower than the previous estimate of 0.060. Based on these results, OSHA
concludes that random error in the underlying exposure estimates in the
Steenland et al. (2001a, Document ID 0452) pooled cohort study of lung
cancer is not likely to have substantially influenced the original risk
estimates derived from the pooled data set, although the model
coefficient for one of the ten cohorts (the South African gold miner
cohort) appeared to be sensitive to measurement errors (see Table II-5,
Document ID 1711, p. 307).
    Drs. Steenland and Bartell also examined the effects of systematic
bias in conversion factors, considering the possibility that these may
have been consistently under-estimated or over-estimated for any given
cohort. They addressed possible biases in either direction, conducting
simulations where the true silica content was assumed to be either half
or double the estimated silica content of measured exposures. For the
conditional logistic regression model using log cumulative exposure
with a 15-year lag, doubling or halving the exposure for a specific
study resulted in virtually no change in the exposure-response
coefficient for that study or for the pooled analysis overall. This is
due to the use of log-transformed exposure metrics, which ensured that
any multiplicative bias in exposure would have virtually no effect on
conditional logistic regression coefficients (Document ID 0469, p. 17).
That is, for this model, a systematic error in exposure estimation for
any study had little effect on the lung cancer response rate for either
the specific study or the pooled analysis overall.
ii. Silicosis Mortality
    Following the procedures described above for the lung cancer
analysis, Toxachemica, Inc. (2004, Document ID 0469) combined both
sources of random measurement error in a Monte Carlo analysis of the
silicosis mortality data from Mannetje et al. (2002b, Document ID
1089). Categorical analyses were performed with a nested case control
model, in contrast to the Poisson model used previously by Mannetje et
al. (2002b, Document ID 1089). The nested case control model was
expected to control more effectively for age. This model yielded
categorical rate ratio results using the original data (prior to
simulation of measurement error) which were approximately 20-25 percent
lower than those reported by Mannetje et al. (2002b, Document ID 1089).
The silicosis mortality dataset thus appeared to be more sensitive to
possible error in exposure measurement than the lung cancer dataset,
for which the mean of the simulation coefficients was virtually
identical to the original. OSHA notes that its risk estimates derived
from the pooled analysis (Mannetje et al., 2002b, Document ID 1089),
incorporated ToxaChemica, Inc.'s simulated measurement error (2004,
Document ID 0469). More information is provided in the Preliminary QRA
(Document ID 1711, pp. 310-314).
d. Renal Disease Mortality
i. Exposure-Response Studies
    Steenland et al. (2002a, Document ID 0448) examined renal disease
mortality in a pooled analysis of three cohorts, as discussed
previously. These cohorts were chosen because data were available for
both underlying cause mortality and multiple cause mortality. The
combined cohort for the pooled analysis (Steenland et al., 2002a,
Document ID 0448) consisted of 13,382 workers with exposure information
available for 12,783 (95 percent). SMRs (compared to the U.S.
population) for renal disease (acute and chronic glomerulonephritis,
nephrotic syndrome, acute and chronic renal failure, renal sclerosis,
and nephritis/nephropathy) were statistically significantly elevated
using multiple cause data (SMR 1.29, 95% CI 1.10-1.47, 193 deaths) and
underlying cause data (SMR 1.41, 95% CI 1.05-1.85, 51 observed deaths).
ii. Risk Estimates
    As detailed in the Preliminary QRA, OSHA estimated that exposure to
the previous (100 [mu]g/m\3\) and revised (50 [mu]g/m\3\) general
industry PELs, over a 45-year working life, would result in a lifetime
excess renal disease mortality risk of 39 and 32 deaths per 1,000
workers, respectively. For exposure to the previous construction/
shipyard PELs, OSHA estimated the lifetime excess risk to range from 52
to 63 deaths per 1,000 workers at exposures of 250 and 500 [mu]g/m\3\,
respectively. These risks reflect the 1998 background all-cause
mortality and renal mortality rates for U.S. males. Background rates
were not adjusted for the renal disease risk estimates because the CDC
significantly changed the classification of renal diseases after 1998;
they are now inconsistent with those used by Steenland et al. (2002a,
Document ID 0448) to ascertain the cause of death of workers in their
study.
e. Silicosis Morbidity
i. Exposure-Response Studies
    OSHA summarized, in its Preliminary QRA, the principal cross-
sectional and cohort studies that quantitatively characterized
relationships between exposure to crystalline silica and the
development of radiographic evidence of silicosis (Document ID 1711).
Each of these studies relied on estimates of cumulative exposure to
evaluate the relationship between exposure and silicosis prevalence.
The health endpoint of interest in these studies was the appearance of
opacities on chest radiographs indicative of pulmonary fibrosis. Most
of the studies reviewed by OSHA considered a finding consistent with an
ILO classification of 1/1 to be a positive diagnosis of silicosis,
although some also considered an x-ray classification of 1/0 or 0/1 to
be positive. OSHA noted its belief, in the Preliminary QRA, that the
most reliable estimates of silicosis morbidity, as detected by chest
radiographs, come from the studies that evaluated radiographs over
time, included radiographic evaluation of workers after they left
employment, and derived cumulative or lifetime estimates of silicosis
disease risk. OSHA also pointed out that the low sensitivity of chest
radiography in detecting silicosis suggests that risk estimates derived
from radiographic evidence likely underestimate the true risk.
    Hnizdo and Sluis-Cremer (1993, Document ID 1052) described the
results of a retrospective cohort study of 2,235 white gold miners in
South Africa. A total of 313 miners had developed silicosis (x-ray with
ILO 1/1 or greater) and had been exposed for an average of 27 years at
the time of diagnosis. The average latency for the cohort was 35 years
(range of 18-50 years) from the start of exposure to diagnosis. The
average respirable dust exposure for the cohort overall was 290 [mu]g/
m\3\ (range 110-470), corresponding to an estimated average respirable
silica concentration of 90 [mu]g/m\3\ (range 33-140). The average
cumulative dust exposure for the overall cohort was 6.6 mg/m\3\-yrs
(range 1.2-18.7). Silicosis risk increased exponentially with
cumulative exposure to respirable dust in models using log-logistic
regression. Using the exposure-response relationship developed by
Hnizdo and Sluis-Cremer (1993, Document ID 1052), and assuming a quartz
content of 30 percent in respirable dust, Rice and Stayner (1995,
Document ID 0418) estimated the risk of silicosis to be 13 percent for
a 45-year exposure to 50 [mu]g/m\3\ respirable crystalline silica.

    Steenland and Brown (1995b, Document ID 0451) studied 3,330 South
Dakota gold miners who had worked at least a year underground between
1940 and 1965. Chest x-rays were obtained in cross-sectional surveys in
1960 and 1976 and used along with death certificates to ascertain cases
of silicosis; 128 cases were found via death certificate, 29 were found
by x-ray (defined as ILO 1/1 or greater), and 13 were found by both.
OSHA notes that the inclusion of death certificate diagnoses
complicates interpretation of the risk estimate from this study since,
as noted by Finkelstein (2000, Document ID 1015), it is not known how
well such diagnoses correlate with ILO radiographic interpretations; as
such, the risk estimates derived from this study may not be directly
comparable to others that rely exclusively on radiographic findings to
evaluate silicosis morbidity risk. The mean exposure concentration was
50 [mu]g/m\3\ for the overall cohort, with those hired before 1930
exposed to an average of 150 [mu]g/m\3\. The average duration of
exposure for workers with silicosis was 20 years (s.d. = 8.7) compared
to 8.2 years (s.d. = 7.9) for the rest of the cohort. This study found
that cumulative exposure was the best disease predictor, followed by
duration of exposure and average exposure. Lifetime risks were
estimated from Poisson regression models using standard life table
techniques; the results indicated an estimated risk of 47 percent
associated with 45 years of exposure to 90 [mu]g/m\3\ respirable
crystalline silica, which reduced to 35 percent after adjustment for
age and calendar time.
    OSHA used the same life table approach as described for estimating
lung cancer and NMRD mortality risks to estimate lifetime silicosis
risk based on the silicosis rates, adjusted for age and calendar time,
calculated by Steenland and Brown (1995b, Table 2, Document ID 0451).
Silicosis risk was estimated through age 85, assuming exposure from age
20 through 65, and assuming that the silicosis rate remains constant
after age 65. All-cause mortality rates to all males for calendar year
2006 were used to account for background competing risk. From this
analysis, OSHA estimated the risk from exposure to the previous general
industry PEL of 100 [mu]g/m\3\ to be 43 percent; this is somewhat
higher than estimated by Steenland and Brown (1995b) because of the use
by OSHA of more recent mortality data and calculation of risk through
age 85 rather than 75. For exposure to the revised PEL of 50 [mu]g/
m\3\, OSHA estimated the lifetime risk to be 7 percent. Since the time
of the original analysis, NCHS has released updated all-cause mortality
background rates from 2011; OSHA's final risk estimates, which
incorporate these updated rates, are available in Section VI, Final
Quantitative Risk Assessment and Significance of Risk.
    Miller et al. (1995, Document ID 1097; 1998, 0374) and Buchanan et
al. (2003, Document ID 0306) reported on a follow-up study conducted in
1990 and 1991 of 547 survivors of a 1,416 member cohort of Scottish
coal workers from a single mine. These men all worked in the mine
during a period between early 1971 and mid-1976, during which they had
experienced ``unusually high concentrations of freshly cut quartz in
mixed coalmine dust'' (Document ID 0374, p.52). Thus, this cohort
allowed for the study of exposure-rate effects on the development of
silicosis. The men all had radiographs dating from before, during, or
just after this high concentration period, and the 547 participating
survivors received follow-up chest x-rays between November 1990 and
April 1991.
    Buchanan et al. (2003, Document ID 0306) presented logistic
regression models in stages. In the first stage they compared the
effect of pre- vs. post-1964 cumulative quartz exposures on odds
ratios; this yielded a statistically significant odds ratio estimate
for post-1964 exposures. In the second stage they added total dust
levels both pre- and post-1964, age, smoking status, and the number of
hours worked pre-1954; only post-1964 cumulative exposures remained
significant. Finally, in the third stage, they started with only the
statistically significant post-1964 cumulative exposures, and separated
these exposures into two quartz bands, one for exposure to
concentrations less than 2,000 [mu]g/m\3\ respirable quartz and the
other for concentrations greater than or equal to 2,000 [mu]g/m\3\.
Both concentration bands were highly statistically significant in the
presence of the other, with the coefficient for exposure concentrations
greater than or equal to 2000 [mu]g/m\3\ being three times that of the
coefficient for concentrations less than 2000 [mu]g/m\3\. From this,
the authors concluded that their analysis showed that ``the risks of
silicosis over a working lifetime can rise dramatically with exposure
to such high concentrations over a timescale of merely a few months''
(Buchanan et al. 2003, Document ID 0306, p. 163). The authors then used
the model to estimate the risk of acquiring a chest x-ray classified as
ILO category 2/1+, 15 years after exposure, as a function of both low
(<2000 [mu]g/m\3\) and high (>2000 [mu]g/m\3\) quartz concentrations.
OSHA chose to use this model to estimate the risk of radiological
silicosis consistent with an ILO category 2/1+ chest x-ray for several
exposure scenarios; in each, it assumed 45 years of exposure, 2000
hours/year of exposure, and no exposure above a concentration of 2000
[mu]g/m\3\. The results showed that occupational exposures to the
revised PEL of 50 [mu]g/m\3\ led to an estimated risk of 55 cases per
1,000 workers. Exposure at the previous general industry PEL of 100
[mu]g/m\3\ increased the estimate to 301 cases per 1,000 workers. At
higher exposure levels the risk estimates rose quickly to near
certainty.
    Chen et al. (2001, Document ID 0332) reported the results of a
retrospective study of a Chinese cohort of 3,010 underground miners who
had worked in tin mines at least one year between 1960 and 1965. They
were followed through 1994, by which time 2,426 (80.6 percent) workers
had either retired or died, and only 400 (13.3 percent) remained
employed at the mines. Annual radiographs were taken beginning in 1963
and cohort members continued to have chest x-rays taken every 2 or 3
years after leaving work. Silicosis was diagnosed when at least 2 of 3
radiologists classified a radiograph as being a suspected case or at
Stage I, II, or III under the 1986 Chinese pneumoconiosis roentgen
diagnostic criteria, which the authors reported agreed closely with ILO
categories 0/1, Category 1, Category 2, and Category 3, respectively.
Silicosis was observed in 33.7 percent of the group; 67.4 percent of
the cases developed after exposure ended.
    Chen et al. (2001, Document ID 0332) found that a Weibull model
provided the best fit to relate cumulative silicosis risk to eight
categories of cumulative total dust exposure. The risk of silicosis was
strongly related to cumulative silica exposure. The investigators
predicted a 55-percent risk of silicosis associated with 45 years of
exposure to 100 [mu]g/m\3\. The paper did not report the risk
associated with a 45-year exposure to 50 [mu]g/m\3\, but OSHA estimated
the risk to be about 17 percent (based on the parameters of the Weibull
model).
    In a later study, Chen et al. (2005, Document ID 0985) investigated
silicosis morbidity risks among three cohorts to determine if the risk
varied among workers exposed to silica dust having different
characteristics. The cohorts consisted of 4,547 pottery workers, 4,028
tin miners, and 14,427 tungsten miners, all employed after January 1,
1950 and selected from a total of 20 workplaces. The approximate

mean cumulative exposures to respirable silica for pottery, tin, and
tungsten workers were 6.4 mg/m\3\-yrs, 2.4 mg/m\3\-yrs, and 3.2 mg/
m\3\-yrs, respectively. Measurement of particle surface occlusion
(presence of a mineral coating that may affect the biological
availability of the quartz component) indicated that, on average, 45
percent of the surface area of respirable particles collected from
pottery factory samples was occluded, compared to 18 percent of the
particle surface area for tin mine samples and 13 percent of particle
surface area for tungsten mines. When cumulative silica exposure was
adjusted to reflect exposure to surface-active quartz particles (i.e.,
not occluded), the estimated cumulative risk among pottery workers more
closely approximated those of the tin and tungsten miners, suggesting
to the authors that alumino silicate occlusion of the crystalline
particles in pottery factories at least partially explained the lower
risk seen among pottery workers, despite their having been more heavily
exposed. Based on Chen et al. (2005, Document ID 0985), OSHA estimated
the cumulative silicosis risk associated with 45 years of exposure to
100 [mu]g/m\3\ respirable crystalline silica to be 6 percent for
pottery workers, 12 percent for tungsten miners, and 40 percent for tin
miners. For 45 years of exposure to 50 [mu]g/m\3\, cumulative silicosis
morbidity risks were estimated to be 2 percent for pottery workers, 2
percent for tungsten miners, and 10 percent for tin miners.

ii. Risk Estimates

    OSHA's risk estimates for silicosis morbidity ranged between 60 and
773 per 1,000 workers for a 45-year exposure to the previous general
industry PEL of 100 [mu]g/m\3\, and between 20 and 170 per 1,000
workers for a 45-year exposure to the revised PEL of 50 [mu]g/m\3\,
depending upon the study used. OSHA recognizes that actual risk, to the
extent that workers are exposed for less than 45 years or
intermittently, is likely to be lower, but also recognizes that
silicosis can progress for years after exposure ends. Also, given the
consistent finding of a monotonic exposure-response relationship for
silicosis morbidity with cumulative exposure in the studies reviewed,
OSHA continues to find that cumulative exposure is a reasonable
exposure metric upon which to base risk estimates in the exposure range
of interest.

D. Comments and Responses Concerning Silicosis and Non-Malignant
Respiratory Disease Mortality and Morbidity

    In this section, OSHA focuses on comments pertaining to the
literature used by the Agency to assess risk for silicosis and non-
malignant respiratory disease (NMRD) mortality and morbidity. As
discussed in the Review of Health Effects Literature and Preliminary
QRA (Document ID 1711) and in Section V.C, Summary of the Review of
Health Effects Literature and Preliminary QRA, of this preamble, OSHA
used two studies (ToxaChemica, 2004, Document ID 0469; Park et al.,
2002, 0405) to determine lifetime risk for silicosis and NMRD mortality
and five studies (Buchanan et al., 2003, Document ID 0306; Chen et al.,
2001, 0332; Chen et al., 2005, 0985; Hnizdo and Sluis-Cremer, 1993,
1052; and Steenland and Brown, 1995b, 0451) to determine cumulative
risk for silicosis morbidity. OSHA discussed the reasons for selecting
these scientific studies for quantitative risk assessment in its Review
of Health Effects Literature and Preliminary QRA (Document ID 1711, pp.
340-342). Briefly, OSHA concluded that the aforementioned studies used
scientifically accepted techniques to measure silica exposures and
health effects in order to determine exposure-response relationships.
The Agency believed, and continues to believe, that these studies, as a
group, provide the best available evidence of the exposure-response
relationships between silica exposure and silicosis morbidity,
silicosis mortality, and NMRD mortality and that they constitute a
solid and reliable foundation for OSHA's final risk assessment.
    OSHA received both supportive and critical comments and testimony
regarding these studies. Comments largely focused on how the authors of
these studies analyzed their data, and concerns expressed by commenters
generally focused on exposure levels and measurement, potential biases,
confounding, statistical significance of study results, and model
forms. This section does not include extensive discussion on exposure
measurement error, potential biases, thresholds, confounding factors,
and the use of the cumulative exposure metric, which are discussed in
depth in other sections of this preamble, including V.J Comments and
Responses Concerning Biases in Key Studies and V.K Comments and
Responses Concerning Exposure Estimation Error and ToxaChemica's
Uncertainty Analysis. OSHA addresses comments on general model form and
various other issues here and concludes that these comments do not
meaningfully affect OSHA's reliance on the studies discussed herein or
the results of the Agency's final risk assessment.
1. Silicosis and NMRD Mortality
    There are two published studies that report quantitative risk
assessments of silicosis and NMRD mortality (see Document ID 1711, pp.
292-298). The first is an exposure-response analysis of diatomaceous
earth (DE) workers (Park et al., 2002, Document ID 0405). Park et al.
quantified the relationship between cristobalite exposure and mortality
caused by NMRD, which includes silicosis, pneumoconiosis, emphysema,
and chronic bronchitis (Park et al. refers to these conditions as
``lung disease other than cancer (LDOC),'' while OSHA uses the term
``NMRD''). Because NMRD captures much of the silicosis
misclassification that results in underestimation of the disease and
includes risks from other lung diseases associated with crystalline
silica exposures, OSHA believes the risk estimates derived from the
Park et al. study reasonably reflect the risk of death from silica-
related respiratory diseases, including silicosis (Document ID 1711,
pp. 297-298). The second study (Mannetje et al. 2002b, Document ID
1089) is a pooled analysis of six epidemiological studies that were
part of an IARC effort. OSHA's contractor ToxaChemica later conducted a
reanalysis and uncertainty analysis using these data (ToxaChemica,
2004, Document ID 0469). OSHA believes that the estimates from the
pooled study represent credible estimates of mortality risk from
silicosis across a range of industrial workplaces, but are likely to
understate the actual risk because silicosis is under-reported as a
cause of death.
a. Park et al. (2002)
    The American Chemistry Council (ACC) submitted several comments
pertaining to the Park et al. (2002, Document ID 0405) study, including
comments on the cohort's exposure concentrations. In its post-hearing
brief, the ACC noted that the mean crystalline silica exposure in
Park's DE cohort was estimated to be more than three times the former
general industry PEL of 100 [mu]g/m\3\ and the mean estimated exposure
of the workers with silicosis could have been close to 10 times that
level. According to the ACC, extrapolating risks from the high exposure
levels in this cohort to the much lower levels relevant to OSHA's risk
assessment (the previous general industry PEL of 100

[mu]g/m\3\ and the revised PEL of 50 [mu]g/m\3\) is ``fraught with
uncertainty'' (Document ID 4209, pp. 84-85).
    OSHA acknowledges that there is some uncertainty in using models
heavily influenced by exposures above the previous PEL due to potential
deviance at areas of the relationship with fewer data points. However,
OSHA believes that the ACC's characterization of exposures in the Park
et al. (2002) study as vastly higher than the final and former PELs is
incorrect. The ACC focused on mean exposure concentrations, reported by
Park et al. as 290 [mu]g/m\3\, to make this argument (Document ID 0405,
p. 37). However, in the Park et al. study, the mean cumulative exposure
of the cohort was 2.16 mg/m\3\-yrs, lower than what the final rule
would permit over 45 years of exposure (2.25 mg/m\3\-yrs) (Document ID
0405, p. 37). Thus, whereas some participants in the Park et al. study
had higher average-8-hour exposures than were typical under the
previous PEL, they were quite comparable to the exposures workers might
accumulate over their working lives under the final PEL of 50 [mu]g/
m\3\. In addition, as discussed in Section V.M, Comments and Responses
Concerning Working Life, Life Tables, and Dose Metric, OSHA believes
that the evidence in the rulemaking record, including comments and
testimony from NIOSH (Document ID 3579, Tr. 127), Kyle Steenland, Ph.D.
(Document ID 3580, Tr. 1227), and OSHA peer reviewer Kenneth Crump,
Ph.D. (Document ID 1716, p. 166), points to cumulative exposure as a
reasonable and appropriate dose metric for deriving exposure-response
relationships. In sum, OSHA does not agree that the Park study should
be discounted based on the ACC's concerns about the estimated exposure
concentrations in the diatomaceous earth cohort.
    The ACC also criticized the Park study for its treatment of
possible confounding by smoking and exposure to asbestos. The ACC
commented in its pre-hearing brief that data on smoking was available
for only half of the cohort (Document ID 2307, Attachment A, p. 108).
The Panel also wrote that, ``while Park et al. dismissed asbestos as a
potential confounder and omitted asbestos exposure in their final
models, the situation is not as clear-cut as they would have one
believe'' (Document ID 2307, Attachment A, p. 109). The Panel
highlighted that Checkoway et al. (1997), the study upon which Park
relied to dismiss asbestos as a potential confounder, noted that
``misclassification of asbestos exposure may have hindered our ability
to control for asbestos as a potential confounder'' (Document ID 0326,
p. 685; 2307, Attachment A, p. 109).
    OSHA has reviewed the ACC's concerns, and maintains that Park et
al. adequately addressed the issues of possible confounding by smoking
and exposure to asbestos in this data set. Smoking habits of a third of
the individuals who died from NMRD were known in the Park et al. (2002)
study. Based on that partial knowledge of smoking habits, Park et al.
presented analyses indicating that confounding by smoking was unlikely
to significantly impact the observed relationship between cumulative
exposure to crystalline silica and NMRD mortality (Document ID 0405, p.
41). Specifically, Park et al. (2002) performed internally standardized
analyses, which tend to be less susceptible to confounding by smoking
since they compare the mortality experience of groups of workers within
the cohort rather than comparing the mortality experience of the cohort
with an external population (such as by using national mortality
rates); the authors found that the internally standardized models
yielded only slightly lower exposure-response coefficients than
externally adjusted models (Document ID 0405; 1711, p. 302). These
results suggested that estimates of NMRD mortality risks based on this
cohort are not likely to be exaggerated due to cohort members' smoking
habits. Park et al. also stated that the authors' findings regarding
possible confounding by smoking were consistent with those of Checkoway
et al., who also concluded there it was ``very unlikely'' that smoking
could explain the association between mortality from NMRD and silica
exposure in this cohort (Document ID 0405, p. 41; 0326, p. 687). NIOSH
noted that ``[r]esidual confounding from poorly characterized smoking
could have an effect,'' but that effect could be either positive or
negative (Document ID 4233, pp. 32-33). While OSHA agrees that
comprehensive smoking data would be ideal, the Agency believes that the
approach taken by Park et al. to address this issue was reasonable.
    Asbestos exposure was estimated for all workers in Park et al.,
which enabled the researchers to directly test confounding. They
``found no confounding by asbestos'' and, accordingly, omitted asbestos
exposure in their final modeling (Document ID 0405, p. 41). As
discussed in the Review of Health Effects Literature and Preliminary
QRA (Document ID 1711, pp. 301-302), exposure to asbestos was
particularly prevalent among workers employed prior to 1930; after
1930, asbestos was presumably no longer used in the process (Gibbs,
1998, Document ID 1024, p. 307; Checkoway et al., 1998, 0984, p. 309).
Checkoway et al. (1998), who evaluated the issue of asbestos
confounding for the same cohort used by Park et al., found that the
risk ratio for the highest silica exposure group after excluding the
workers employed before 1930 from the cohort (Relative Risk (RR) =
1.73) was almost identical to the risk ratio of the high-exposure group
before excluding those same workers (RR = 1.74) (Document ID 0984, p.
309). In addition, Checkoway's reanalysis of the original cohort study
(Checkoway et al., 1993) examined those members of the cohort for whom
there was quantitative information on asbestos exposure, based on a
mixture of historical exposure monitoring data, production records, and
recorded quantities of asbestos included in mixed products of the plant
(Checkoway et al., 1996, Document ID 0325). The authors found an
increasing trend in lung cancer mortality with exposure to crystalline
silica after controlling for asbestos exposure and found only minor
changes in relative risk estimates after adjusting for asbestos
exposure (1996, Document ID 0325). Finally, Checkoway et al. (1998)
reported that the prevalence of pleural abnormalities (indicators of
asbestos exposure) among workers hired before 1930 (4.2 percent) was
similar to that of workers hired after 1930 who presumably had no
asbestos exposure (4.9 percent), suggesting that asbestos exposure was
not a confounder for lung abnormalities in this group of workers
(Document ID 0984, p. 309). Therefore, Checkoway et al. (1998)
concluded that asbestos was not likely to significantly confound the
exposure-response relationship observed between lung cancer mortality
and exposure to crystalline silica in diatomaceous earth workers.
    Rice et al. also utilized Checkoway's (1997, Document ID 0326) data
to test for confounding by asbestos in their Poisson and Cox
proportional hazards models. Finding no evidence of confounding, Rice
et al. did not include asbestos exposure as a variable in the final
models presented in their 2001 paper (Document ID 1118, p. 41). Based
on these numerous assessments of the effects of exposure to asbestos in
the diatomaceous earth workers cohort used by Park et al. (2002), OSHA
concludes that concerns about asbestos confounding in this cohort have
been adequately addressed and that the additional analyses performed by
Park et al. on this issue confirmed the findings of prior researchers
that

confounding by asbestos exposure was not likely to have a large effect
on exposure-response relationships.
    The ACC also expressed concern about model selection. Louis Anthony
Cox, Jr., Ph.D., of Cox Associates, on behalf of the ACC, was concerned
that the linear relative rate model was not appropriate because it is
not designed to test for exposure-response thresholds and, similarly,
the ACC has argued that threshold models are appropriate for
crystalline silica-related diseases (Document ID 2307, Attachment 4,
pp. 91). The ACC claimed that the Park et al. (2002) study is ``fully
consistent'' with a threshold above the 100 [mu]g/m\3\ concentration
for NMRD, including silicosis, mortality (Document ID 2307, Attachment
A, p. 107).
    In its post-hearing comments, NIOSH explained that categorical
analysis for NMRD indicated no threshold existed with cumulative
exposure corresponding to 25 [mu]g/m\3\ over 40 years of exposure,
which is below the cumulative exposure equivalent to the new PEL over
45 years (Document ID 4233, p. 27). Park et al. did not estimate a
threshold below that level because the data lacked the power needed to
discern a threshold (Document ID 4233, p. 27). OSHA agrees with NIOSH's
assessment. In addition, as discussed extensively in Section V.I,
Comments and Responses Concerning Thresholds for Silica-Related
Diseases, OSHA has carefully reviewed the issue of thresholds and has
concluded, based on the best available evidence, that workers with
cumulative and average exposure levels permitted under the previous PEL
of 100 [mu]g/m\3\ are at risk of silica-related disease (that is, there
is unlikely to be an exposure-response threshold at or near 100 [mu]g/
m\3\). For these reasons, OSHA disagrees with Dr. Cox's criticism of
Park et al.'s reliance on the linear relative rate model.
    The ACC then questioned the use of unlagged cumulative exposures as
the metric in Park et al. (2002). Dr. Cox noted that ``[u]nlagged
models are not very biologically plausible for dust-related NMRD deaths
(if any) caused by exposure concentrations in the range of interest.
Unresolved chronic inflammation and degradation of lung defenses takes
years to decades to manifest'' (Document ID 2307, Attachment 4, p. 92).
OSHA considers this criticism overstated. Park et al. considered a
range of lag periods, from two years to 15. They found that
``[u]nlagged models seemed to provide the best fit to the data in
Poisson analyses although lagged models performed almost as well''
(Document ID 0405, p. 37). Based on those findings, as well as
acknowledgments that NMRD effects other than silicosis (e.g., chronic
bronchitis) may be observable without a relatively long lag time
(unlike cancer) and that the majority of deaths observed in the cohort
were indeed NMRD other than silicosis, the researchers decided to use
an unlagged model. Because Park found the differences between the
lagged and unlagged models for this cohort and the NMRD endpoint to be
insignificant, OSHA finds that Park's final choice to use an unlagged
model does not detract from OSHA's decision to utilize lagged models in
its risk assessment.
    The ACC was also concerned about the truncation of cumulative
exposures in the Park et al. (2002) paper. Peter Morfeld, Dr. rer.
medic, stated that Park et al.:

suffers from a methodological drawback. . . . The authors truncated
the cumulative RCS dust exposures before doing the final analyses
based on their observation of where the cases were found. The
maximum in the study was 62.5 mg/m\3\-years but exposures were only
used up to 32 mg/m\3\-years because no LDOC deaths occurred at
exposures higher than that level. Such a selection distorts the
estimated exposure-response relationship because it is based on the
outcome of the study and on the exposure variable. Because high
exposures with no effects were deliberately ignored, the exposure-
response effect estimates are biased upward (Document ID 2307,
Attachment 2, p. 27).

    OSHA acknowledges this concern about the truncation of data in the
study, and asked Mr. Park about it at the public hearing. Mr. Park
testified that there were good reasons to truncate the part of the
exposed workforce at the high end of cumulative exposure. He noted
several plausible reasons for the drop-off in the number of cases at
high exposures (attenuation), including random variance in
susceptibility to disease among different people and the healthy worker
survivor effect \6\ (Document ID 3579, Tr. 242-243). He also stated
that this attenuation is a common occurrence in studies of workers
(Document ID 3579, Tr. 242). Mr. Park then emphasized that how one
describes the higher end of the exposure-response relationship is
inconsequential for the risk assessment process because the
relationship at the lower end of the spectrum, where the PEL was
determined, is more important for rulemaking (Document ID 3579, Tr.
242-243). He also stated, in a post-hearing comment, that ``[f]or the
purpose of low exposure extrapolation, adding a quadratic term [to
better describe the entirety of the exposure-response relationship]
would result in loss of precision with no advantage [gained] over
truncation of high cumulative exposure observation time'' (Document ID
4233, p. 26). To summarize, Mr. Park stated that there are good
scientific reasons to expect attenuation of exposure-response at the
high end of the cumulative exposure range and that use of higher-
exposure data affected by healthy worker survivor effect or other
issues could reduce precision of the exposure-response model at the
lower exposures that are more relevant to the final silica standard.
OSHA finds that Mr. Park's approach in his study, along with his
explanations in the rulemaking record, are reasonable and that he has
fully responded to the concerns of the ACC.
---------------------------------------------------------------------------

    \6\ Briefly, if individuals cease working due to illness, then
those individuals will not be represented in cohort subgroups having
the highest cumulative exposures. That exclusion may enable
individuals with greater physiological resilience to silica
exposures to be overrepresented in cohorts exposed to greater
amounts of silica. Further discussion on the healthy worker survivor
effect can be found in Section V.F, Comments and Responses on Lung
Cancer Mortality.
---------------------------------------------------------------------------

    Dr. Morfeld also noted that alternative techniques that do not
require truncation are available to account for a healthy worker
survivor effect (Document ID 2307, Attachment 2, pp. 27-28). OSHA
believes such techniques, such as g-estimation, to be relatively new or
not yet in standard use in occupational epidemiology. As discussed
above, OSHA finds Mr. Park's approach in his study to be reasonable.
    Finally, Dr. Cox stated in his comments that:

key studies relied on by OSHA, such as Park et al. (2002), do not
correct for biases in reported ER [exposure-response] relations due
to residual confounding by age (within age categories), i.e., the
fact that older workers may tend to have both higher lung cancer
risks and higher values of occupational exposure metrics, even if
one does not cause the other. This can induce a non-causal
association between the occupational exposure metrics and the risk
of cancer (Document ID 2307, Attachment 4, p. 29).

    Confounding occurs in an epidemiological study when the
contribution of a causal factor cannot be separated from the effect of
another variable (e.g., age) not accounted for in the analysis.
Residual confounding occurs when attempts to control for confounding
are not precise enough (e.g., controlling for age by using groups with
age spans that are too wide), or subjects are misclassified with
respect to confounders (Document ID 3607, p. 1). However, the Park et
al. (2002) study of non-malignant respiratory disease mortality, which
Dr. Cox cited as not

considering residual confounding by age, actually addressed this issue
by using 13 five-year age groups (<25, 25-29, 30-34, etc.) in the
models (Document ID 0405, p. 37). Further discussion on residual
confounding bias is found in Section V.J, Comments and Responses
Concerning Biases in Key Studies.
    The inclusion of Park et al. (2002) (Document ID 0405) in OSHA's
risk assessment has additional support in the record. OSHA's expert
peer-review panel supported including the Park et al. study in the risk
assessment, with Gary Ginsberg, Ph.D., stating that it ``represents a
reasonable estimate of silica-induced total respiratory mortality''
(Document ID 3574, p. 29). In addition, as OSHA noted in its Review of
Health Effects Literature and Preliminary QRA (Document ID 1711, pp.
355-356), the Park et al. study is complemented by the Mannetje et al.
multi-cohort silicosis mortality pooled study, which included several
cohorts that had exposure concentrations in the range of interest for
this rulemaking and also showed clear evidence of significant risk of
silicosis and other NMRD at the previous general industry and
construction PELs (2002b, Document ID 1089).
b. Mannetje et al. (2002b) and ToxaChemica (2004)
    The ACC also submitted several comments on the Mannetje et al.
(2002b) study of silicosis mortality; the data from Mannetje et al.
were used in the ToxaChemica (2004) re-analysis. As noted above, the
Mannetje et al. (2002b) study was a pooled analysis of silicosis
mortality data from six epidemiological cohorts. This study showed a
statistically significant association between silicosis mortality and
workers' cumulative exposure, as well as with average exposure and
exposure duration. The ACC's pre-hearing brief stated that the study
``provided no justification for the relative rate model forms [Mannetje
et al.] used to evaluate exposure-response'' (Document ID 2307,
Attachment A, p. 113). The concern expressed was that the study may not
have considered all potential exposure-response relationships and was
unable to discern differences between monotonic and non-monotonic
characteristics (Document ID 2307, Attachment A, p. 113-114).
    Mannetje et al. (2002b, Document ID 1089) did not discuss whether
models other than relative rate models were tested. However, Mannetje's
data was reexamined by ToxaChemica, Inc. on request from OSHA and the
reexamined data was used by OSHA to help estimate lifetime risk for
silicosis mortality (2004, Document ID 0469; 1711, pp. 310-314). The
ToxaChemica reanalysis of the data included a categorical analysis and
a five-knot restricted spline analysis, in addition to a logistic
model, using the log of cumulative exposure (Document ID 0469, p. 50).
ToxaChemica also corrected some errors found in the original data set
and used a nested case-control approach, which they stated would
control more precisely for age than the Poisson regression approach
used by Mannetje et al. (Document ID 0469, p. 18). As shown in Figure 5
of ToxaChemica's report, the restricted spline model (which has
considerable flexibility to represent non-monotonic features of
exposure-response data) appeared to be monotonic, while the categorical
analysis appeared largely monotonic but for one exposure group
(Document ID 0469, p. 40, 50). When not adjusted for measurement error,
the second highest exposure group deviated from the monotonic
relationship existing between the other groups. However, the deviation
was resolved when two sources of measurement error were accounted for
(Document ID 0469, p. 40). The categorical analysis, restricted spline
model, and logistic model yielded roughly similar exposure-response
curves (Document ID 0469, p. 50). OSHA concludes that the ToxaChemica
reanalysis addresses the concerns raised by the ACC by finding similar
exposure-response relationships regardless of the model as well as
providing greater validation of a monotonic curve.
    The ACC next questioned the odds ratios generated in the Mannetje
et al. (2002b) study (Document ID 2307, p. 114; 4209, p. 88). The Panel
noted that ``the exposure-response relationship is not even fully
monotonic'' and that the silica odds ratios in the pooled analysis have
overlapping confidence intervals, suggesting no statistically
significant difference (Document ID 2307, p. 114). The Panel concluded
that ``the data indicate that there is no clear effect of exposure on
odds ratios over the entire range considered by the authors; hence, the
study provides no basis for concluding that reducing exposures will
reduce the odds ratio for silicosis mortality'' (Document ID 4209, p.
88). Essentially, the ACC argued that the data do not appear to fit a
monotonic relationship and that the confidence intervals for each
exposure level overlap too much to discern any differences in risk
ratios between those exposures.
    OSHA believes that the ACC overstated its contention about
confidence interval overlap between groups in the Mannetje et al.
(2002b) paper. Although the original data set reported in the study
lacks a monotonic relationship on the upper end of the exposure
spectrum (>9.58 mg/m\3\-yrs) (possibly due to a healthy worker survivor
effect, as explained above), OSHA notes that the 95 percent confidence
intervals reported do not contradict the presence of a monotonic
relationship (Document ID 1089). First, the confidence intervals of the
lower exposed groups did not overlap with those of the higher exposed
groups in that study (Document ID 1089). Second, even if they did,
overlap in confidence intervals does not mean that there is not a
significant difference between those groups. While it is true that, if
95 percent confidence intervals do not overlap, the represented
populations are statistically significantly different, the converse--
that, if confidence intervals do overlap, there is no statistically
significant difference--is not always true (Nathaniel Schenker and Jane
F. Gentleman. ``On Judging the Significance of Differences by Examining
the Overlap Between Confidence Intervals.'' The American Statistician.
55(3): 2001. 182-186. (http://www.tandfonline.com/doi/abs/10.1198/000313001317097960).
    Finally, as discussed above and in detail in Section V.K, Comments
and Responses Concerning Exposure Estimation Error and ToxaChemica's
Uncertainty Analysis, the ToxaChemica et al. (2004) re-analysis of the
corrected Mannetje et al. (2002b) data adjusting for two sources of
measurement error resulted in a monotonic relationship for the risk
ratios (Document ID 0469).
2. Silicosis Morbidity
    OSHA relied on five studies for determining risk for silicosis
morbidity: Buchanan et al., 2003 (Document ID 0306), Chen et al., 2001
(Document ID 0332), Chen et al., 2005 (Document ID 0985), Hnizdo and
Sluis-Cremer, 1993 (Document ID 1052), and Steenland and Brown, 1995b
(Document ID 0451). OSHA finds that the most reliable estimates of
silicosis morbidity, as detected by chest radiographs, come from these
five studies because they evaluated radiographs over time, included
post-employment radiographic evaluations, and derived cumulative or
lifetime estimates of silicosis disease risk. OSHA received several
comments about these studies.
a. Buchanan et al. (2003)
    Buchanan et al. (2003) reported on a cohort of Scottish coal
workers (Document ID 0306). The authors found a statistically
significant relationship

between silicosis and cumulative exposure acquired after 1964 (Document
ID 0306). They also found that the risks of silicosis over a working
lifetime can rise dramatically with exposure to high concentrations
over a timescale of merely a few months (Document ID 0306). In the
Preliminary QRA, OSHA considered this study to be of the highest
overall quality of the studies relied upon to assess silicosis
morbidity risks, in large measure because the underlying exposure data
was based on modern exposure measurement methods and avoided the need
to estimate historical exposures. The risk estimates derived from this
study were lower than those derived from any of the other studies
criticized by the ACC. One reason for this is because Buchanan et al.
only included cases with chest x-ray findings having an ILO score of 2/
1 or higher, whereas the other studies included cases with less damage,
having a lower degree of perfusion on x-ray (ILO 1/0 or 1/1) (Document
ID 0306). Thus, OSHA considered the risk estimates derived from the
Buchanan et al. study to be more likely to understate risks.
    Dr. Cox commented that age needed to be included for modeling in
Dr. Miller's 1998 paper, the data from which were used in the Buchanan
et al. (2003) paper (Document ID 2307, Attachment 4, p. 97). However,
the Miller et al. (1998) study explicitly states that age was one of
several variables that were tried in the model but did not improve the
model's fit, as was time spent working in the poorly characterized
conditions before 1954 (Document ID 0374, p. 57). OSHA concludes that
the original paper did assess these variables and how they related to
the exposure-response relationship. Buchanan et al. (2003) also noted
their own finding that differences in age and exposure both failed to
improve fit, in agreement with Miller et al.'s conclusion (Document ID
0306, p. 161). OSHA therefore finds no credible reason that age should
have been included as a variable in Miller et al. (1998).
    Dr. Cox also questioned the modeling methods in the Buchanan paper,
which presented logistic regression in progressive stages to search for
significance (Document ID 2307, Attachment 4, pp. 97-98; 0306, pp. 161-
163). Dr. Cox claimed that this is an example of uncorrected multiple
testing bias where the post hoc selection of data, variables, and
models can make independent variables appear to be statistically
significant in the prediction model. He suggested that corrections for
bias are needed to determine if the reported significance is causal or
statistical (Document ID 2307, Attachment 4, pp. 97-98). OSHA peer
reviewer Brian Miller, Ph.D., stated that Dr. Cox's claim that the
model was affected by multiple testing bias is unfounded (Document ID
3574, pp. 31-32). He noted that the model was based on a detailed
knowledge of the history of exposures at that colliery, and represented
the researchers' attempt to build ``a reality-driven and `best-fitting'
model,'' (Document ID 3574, p. 31, quoting 2307, Attachment 4, p. 4).
Furthermore, none of OSHA's peer reviewers raised any concerns about
the approach taken by Buchanan et al. to develop their exposure-
response model and none suggested that corrections needed to be made
for multiple testing bias; all of them supported the study's inclusion
in OSHA's risk assessment (Document ID 3574). Finally, the cumulative
risk for silicosis morbidity derived from this study is similar to
values from other papers reported in the QRA (see OSHA's Final
Quantitative Risk Assessment in Section VI). Therefore, for the reasons
discussed above, OSHA is not convinced by Dr. Cox's arguments and finds
no credible reason to remove Buchanan et al. (2003) from consideration.
b. Chen et al. (2001, 2005), Steenland and Brown (1995), and Hnizdo and
Sluis-Cremer (1993)
    The ACC also commented on several other studies used by OSHA to
estimate silicosis morbidity risks; these were the studies by Chen et
al. (2001, Document ID 0332; 2005, 0985), Steenland and Brown (1995b,
Document ID 0451), and Hnizdo and Sluis-Cremer (1993, Document ID
1052). The ACC's comments focus on uncertainties in estimating the
historical exposures of cohort members (Document ID 2307, Attachment A,
pp. 117-122, 124-130, 132-136). Section V.K, Comments and Responses
Concerning Exposure Estimation Error and ToxaChemica's Uncertainty
Analysis, discusses the record in detail with respect to the general
issue of uncertainties in estimating historical exposures to respirable
crystalline silica in epidemiological studies. The issues specific to
the studies relied upon by OSHA in its risk estimates for silicosis