statistical approach for exposure estimates with substantial estimation
errors'' (Document ID 2307, Attachment 4, p. 75). During the public
hearing, however, Dr. Steenland explained to OSHA's satisfaction how
the data in his study was transformed, using accepted statistical
methods. Specifically, referring to his use of a log transformation to
address the heterogeneity, Dr. Steenland testified:

    [I]t reduces the effect of the very highest exposures being able
to drive an exposure-response curve because those exposures are
often [skewed] way out--skewed to the right, because occupational
exposure data is often log normal. With some very high exposures,
they are sort of extreme, and that can drive your exposure-response
curve. And you take the log, it pulls them in, and so therefore
gives less influence to those high data points. And I think those
high data points are often measured with more error (Document ID
3580, Tr. 1265-1266).

    OSHA finds this testimony to be persuasive and, therefore, believes
that Dr. Steenland's use of a log transformation to address the
heterogeneity was appropriate. The log transformation also permits a
better model fit when attenuation of the response is observed at high
cumulative exposures.
    Dr. Morfeld commented that Steenland et al. did not take into
account smoking, which could explain the observed excess lung cancer of
20 percent (SMR = 1.2). Dr. Morfeld stated, ``Thus, lung cancer excess
risks were demonstrated only under rather high occupational exposures
to RCS dust, and, even then, an upward bias due to smoking and a
necessary intermediate role for silicosis could not be ruled out''
(Document ID 2307, Attachment 2, p. 10). Dr. Steenland addressed the
concern about a potential smoking bias during his testimony:

    We concluded that this positive exposure response was not likely
due to different smoking habits between high exposed and low exposed
workers. And the reason we did that was twofold. First, workers tend
to smoke similar amounts regardless of their exposure level in
general. We often worry about comparing workers to the general
population because workers tend to smoke more than the general
population. But, in internal analyses, we don't have this problem
very often. When we have smoking data, we see that it is not related
to exposure, so a priori we don't think it is likely to be a strong
confounder in internal analyses. Secondly, a number of the studies
we used in our pool[ed] cohort had smoking data, either for the
whole cohort or partially. And when they took that into account,
their results did not change. In fact, they also found that smoking
was not related to exposure in their studies, which means that it
won't affect the exposure-disease relationship because if it is
going to do that, it has to differ between the high exposed and the
low exposed, and it generally did not (Document ID 3580, Tr. 1227-
1228).

    In addition, Brown and Rushton (2009), in their review article
submitted to the rulemaking record by Dr. Morfeld, appeared to agree
with Dr. Steenland, stating, ``This [Steenland et al.] internal
analysis removed the possibility of confounding by smoking'' (Document
ID 3573, Attachment 5, p. 150). Thus, OSHA rejects Dr. Morfeld's
assessment that the risk estimates may be biased upwards due to
smoking.
    The ACC also commented that exposure misclassification due to
uncertain exposure estimates in Steenland's pooled cohort could have
created the appearance of a monotonic relationship, in which the
response

increases with the exposure, even if the true response was not
monotonic (Document ID 2307, Attachment A, p. 76). The ACC, along with
Dr. Borak (representing the U.S. Chamber of Commerce) and others,
likewise cited OSHA's statement from the Review of Health Effects
Literature and Preliminary QRA, in which the Agency acknowledged that
uncertainty in the exposure estimates that underlie each of the 10
studies in the pooled analysis was likely to represent one of the most
important sources of uncertainty in the risk estimates (Document ID
1711, p. 292; 2376, p. 16). Dr. Borak also quoted Mannetje et al.
(2002), who developed quantitative exposure data for the pooled
analysis, as stating, ``While some measurement error certainly occurred
in our estimates, a categorical analysis based on broad exposure groups
should not be much affected by the resulting level of
misclassification'' (Document ID 2376, p. 17, quoting 1090, p. 84).
From this statement, Dr. Borak concluded that the researchers
themselves believed the data were only adequate for ``categorical
analyses which might lead to qualitative conclusions'' (Document ID
2376, p. 17).
    OSHA disagrees with Dr. Borak's interpretation of the Mannetje et
al. statement, as categorical analyses are typically quantitative in
nature, with the data being used to draw quantitative conclusions.
However, OSHA recognized the possibility for uncertainty in the
exposure estimates, and it is for this reason that OSHA commissioned a
quantitative analysis of uncertainty in Steenland's pooled study
(ToxaChemica, 2004, Document ID 0469). This analysis suggested that
exposure misclassification had little effect on the pooled exposure
coefficient (and the variance around that estimate) for the lung cancer
risk model (Document ID 1711, pp. 313-314). Given this analysis, OSHA
also disagrees with the ACC's statement that ``it is virtually certain
that substantial exposure estimation error infused the pooled analysis,
resulting in exposure misclassification that would create a false
appearance of a monotonically increasing exposure-response even where
none exists'' (Document ID 2307, Attachment A, p. 78). OSHA notes that
this statement is not supported with any evidence from the Steenland et
al. (2001) study. In addition, as discussed at length in Section V.K,
Comments and Responses Concerning Exposure Estimation Error and
ToxaChemica's Uncertainty Analysis, exposure estimation error can also
bias results towards the null (weaken or obscure the exposure-response
relationship) (Document ID 3580, Tr. 1266-67; 3576, Tr. 358-359; 3574,
p. 21). Other criticisms from the ACC concerning alleged modeling
errors and biases in the Steenland study and the alleged threshold for
the health effects of silica exposure are discussed generally in
Section V.J, Comments and Responses Concerning Biases in Key Studies,
and Section V.I, Comments and Responses Concerning Thresholds for
Silica-Related Diseases. Dr. Cox's and Dr. Morfeld's criticisms of the
uncertainty analysis performed by Toxachemica are addressed in Section
V.K, Comments and Responses Concerning Exposure Estimation Error and
ToxaChemica's Uncertainty Analysis. For the reasons stated in those
sections, OSHA is unpersuaded by these criticisms.
    The ACC concluded:

    For all these reasons, the pooled analysis by Steenland et al.
(2001) does not yield credible or reliable estimates of silica-
related lung cancer risk. But, even if risk estimates based on
Steenland et al. (2001) were not so problematic, that study would
not demonstrate that reducing the PEL from 0.1 mg/m\3\ [100
[micro]g/m\3\] to 0.05 mg/m\3\ [50 [micro]g/m\3\] will result in a
substantial reduction in the risk of lung cancer (Document ID 2307,
Attachment A, p. 81).

    The ACC then discussed the ToxaChemica report (2004), which the ACC
claimed shows that ``under the spline model (which the authors prefer
over the log cumulative model because of biological plausibility)''
reducing the PEL from 100 [micro]g/m\3\ to 50 [micro]g/m\3\ would
negligibly reduce the excess risk of lung cancer mortality from 0.017
(17/1,000) to 0.016 (16/1,000), ``risk values that are
indistinguishable given the overlapping confidence limits of the two
estimates'' (Document ID 2307, Attachment A, p. 81). In addition, the
ACC noted that the excess risk at 150 [micro]g/m\3\ and 250 [micro]g/
m\3\ in the spline model is the same as the excess risk at 50 [micro]g/
m\3\, while that at 200 [micro]g/m\3\ is lower. ``Estimates of lung
cancer risk in the neighborhood of the current general industry PEL are
hugely uncertain--with the data suggesting that a greater reduction in
lung cancer risk could be achieved by doubling the PEL to 200 [micro]g/
m\3\ than by cutting it in half to a level of 50 [micro]g/m\3\''
(Document ID 2307, Attachment A, pp. 81-82).
    OSHA notes that these risk estimates cited by the ACC were the
original estimates for the spline model provided to OSHA by ToxaChemica
in its 2004 report (Document ID 0469). These are not the risk estimates
used by OSHA. Instead, to estimate the risks published in this final
rule, the Agency used the exposure-response coefficients from the study
in an updated life table analysis using background all-cause mortality
and lung cancer mortality rates from 2006 and 2011, respectively. The
risk estimates using the 2011 background data are the most updated
numbers with which to make the comparisons ACC has suggested. With the
2011 background data, the estimated excess risk is 20 deaths per 1,000
workers at 100 [micro]g/m\3\, and 16 deaths per 1,000 workers at 50
[micro]g/m\3\, a reduction of 4 deaths. OSHA's estimated excess risk at
250 [micro]g/m\3\ is 24 deaths per 1,000 workers, an increase in 8
deaths when compared to 50 [micro]g/m\3\. Thus it is not the case, as
ACC suggested, that increasing the PEL would cause a reduction in lung
cancer mortality risk.
    In addition, the linear spline model employed by Steenland et al.
(2001) was only one of three models used by OSHA to estimate
quantitative risks from the pooled analysis. OSHA also used the log-
linear model with log cumulative exposure as well as the linear model
with log cumulative exposure (see Section VI, Final Quantitative Risk
Assessment and Significance of Risk). OSHA notes that all three models
indicated a reduction in risk when comparing an exposure level of 100
[micro]g/m\3\ to 50 [micro]g/m\3\.
    In summary, OSHA disagrees with the ACC's assertion that the
Steenland et al. pooled analysis does not yield credible risk estimates
for lung cancer mortality. Dr. Morfeld's assertion that the risk
estimates were biased upwards due to smoking is quite unlikely to be
true, given that the study was an internal (worker to worker) analysis.
The ACC's claim that exposure estimation error resulted in false
exposure-response relationships was not supported by any actual data;
as discussed in Section V.K, Comments and Responses Concerning Exposure
Estimation Error and ToxaChemica's Uncertainty Analysis, exposure
estimation error can also bias results towards the null (weaken or
obscure the exposure-response relationship) (Document ID 3580, Tr.
1266-67; 3576, Tr. 358-359; 3574, p. 21). For these reasons, OSHA
rejects the ACC's claims that the Steenland study of lung cancer
mortality does not yield credible risk estimates. Rather, based upon
its review, OSHA believes this pooled analysis to be of high quality.
As Dr. Steenland testified during the informal public hearings, this
pooled analysis, with its more than 60,000 workers and 1,000 lung
cancer deaths, involved ``a rich dataset with high statistical power to
see anything, if there was anything to see'' (Document ID 3580, Tr.
1227). In fact, OSHA believes the Steenland et al. (2001a) study to be
among the best available studies in the peer-reviewed literature on the
topic of

silica exposure and its relationship to lung cancer mortality.
d. Rice et al. (2001)
    The ACC also commented on the Rice et al. (2001, Document ID 1118)
study of diatomaceous earth workers, which found a significant risk of
lung cancer mortality that increased with cumulative silica exposure in
a cohort of diatomaceous earth workers. The ACC claimed that it had a
high likelihood of exposure misclassification. Dr. Cox contended that
the practice of ``[a]ssigning each worker a single estimated cumulative
exposure based on estimated mean values produces biased results and
artificially narrow confidence intervals (and hence excess false-
positive associations)'' (Document ID 2307, Attachment 4, p. 76). OSHA
notes that Rice et al. (2001) described the exposure estimation
procedure in their paper. There were more than 6,000 measurements of
dust exposure taken from 1948-1988; particle count data were converted
to gravimetric data using linear regression modeling. Cumulative
exposures to respirable crystalline silica were then estimated for each
worker using detailed employment records (Document ID 1118, p. 39).
OSHA concludes it is highly unlikely that the exposure estimates are
biased to such an extent, as Dr. Cox suggests, that they would produce
false-positive associations.
    The ACC also noted that the mean crystalline silica exposure in the
diatomaceous earth worker cohort was 290 [mu]g/m\3\, approximately
three times the former PEL for general industry (Document ID 2307,
Attachment A, p. 83). OSHA, however, believes that the cumulative
respirable crystalline silica dust concentration is the metric of
concern here, as that is what was used in the regression models. The
mean cumulative respirable crystalline silica dust concentration in the
study was 2.16 mg/m\3\-yrs, which is a very realistic cumulative
exposure for many workers (Document ID 1118, p. 39).
    The ACC also stated that the results of the Rice study were
confounded by smoking and possibly asbestos exposure (Document ID 2307,
Attachment A, p. 83). OSHA previously addressed the possible
confounding in this cohort in its Review of Health Effects Literature
and Preliminary QRA (Document ID 1711, pp. 139-143). Rice et al. (2001)
used the same cohort originally reported on by Checkoway et al. (1993,
Document ID 0324; 1996, 0325; 1997, 0326). The Rice study discussed the
smoking confounding analysis performed by Checkoway et al. (1997), in
which the Axelson method (1978) was used to make a worst case estimate
(assuming 20 times greater lung cancer risk in smokers compared to non-
smokers) and indirectly adjust the relative risk (RR) estimates for
lung cancer for differences in smoking rates (Document ID 1118, pp. 40-
41). With exposures in the Checkoway study lagged 15 years to account
for the latency period, the worst case effect was to reduce the RR for
lung cancer in the highest exposure group from 2.15 to 1.67. Checkoway
et al. concluded that the association between respirable silica
exposure and lung cancer was unlikely to be confounded by cigarette
exposure (Document ID 0326, pp. 684, 687). Regarding confounding by
asbestos exposure, Rice et al. (2001) stated:

    Checkoway et al. found no evidence that exposure to asbestos
accounted for the observed association between mortality from lung
cancer and cumulative exposure to silica. Our analyses of their data
also found no evidence of confounding by asbestos in the Poisson
regression or Cox's proportional hazards models regardless of lag
period; therefore, exposure to asbestos was not included in the
models presented in this paper (Document ID 1118, p. 41).

    Based upon these analyses, OSHA rejects the ACC's unsupported
assertion that the results of Rice et al. (2001) were confounded by
smoking and asbestos exposure.
    Lastly, Dr. Cox asserted that there were several biases in Rice et
al. (2001), including multiple-testing bias from testing multiple lag
periods, exposure groupings, and model forms; model specification bias;
and a lack of model diagnostics (Document ID 2307, Attachment 4, pp.
63-64, 77). OSHA addressed these issues generally in Section V.J,
Comments and Responses Concerning Biases in Key Studies, and rejects
these assertions for the same reasons. OSHA also discussed regression
diagnostics at length in the same section. In summary, despite the
criticisms directed at the Rice et al. study by the ACC, OSHA continues
to believe that the quantitative exposure-response analysis by Rice et
al. (2001) is of high quality and appropriate for inclusion in the QRA
(Document ID 1711, p. 143).
e. Hughes et al. (2001)
    The ACC, through the comments of Dr. Cox, presented a similar
critique of the study of North American industrial sand workers by
Hughes et al. (2001, Document ID 1060). This study found a
statistically significant association (increased odds ratios) between
lung cancer mortality and cumulative silica exposure as well as average
silica concentration (Document ID 1060). In this study, according to
Dr. Cox, ``The selected model form guarantees a monotonic exposure-
response relation, independent of the data. Model uncertainty and
errors in exposure estimates have both been ignored, so the slope
estimate from Hughes et al. (2001), as well as the resulting excess
risk estimates, are likely to be biased and erroneous'' (Document ID
2307, Attachment 4, p. 85). The ACC also noted that this cohort had
incomplete smoking information, with the proportion of ``ever smokers''
significantly higher in cases than in controls. In addition, the ACC
asserted that asbestos exposure may have also occurred, as three death
certificates listed mesothelioma as the cause of death (Document ID
2307, Attachment A, pp. 85-86).
    OSHA discussed the Hughes et al. (2001, Document ID 1060) study in
its Review of Health Effects Literature and Preliminary QRA,
highlighting as strengths the individual job, exposure, and smoking
histories that were available (Document ID 1711, p. 285). Exposure
levels over time were estimated via a job exposure matrix constructed
by Rando et al. (2001, Document ID 0415) utilizing substantial exposure
data, including 14,249 respirable dust and silica samples taken from
1974 to 1998 in nine plants (Document ID 1711, pp. 88, 124-128; 1060,
202). Smoking data were collected from medical records supplemented by
information from next of kin or living subjects for 91 percent of cases
and controls (Document ID 1060, p. 202). OSHA believes these smoking
histories allowed the authors to adequately control for confounding by
smoking in their analyses. Regarding the three death certificates
listing mesothelioma, McDonald et al. (2001) explained that two were
for workers not included in the case/control study because they were
hired at or after age 40 with less than 10 years of work time; the
third was for a worker hired at age 19 who then accumulated 32 years of
experience in maintenance jobs (Document ID 1091, p. 195). As such,
OSHA does not believe it likely that asbestos exposure was a large
source of confounding in typical industrial sand operations in this
study. OSHA also notes that the positive findings of this study were
consistent with those of other studies of workers in this cohort,
including Steenland and Sanderson (2001, Document ID 0455) and McDonald
et al. (2005, Document ID 1092).
    The ACC also noted that there was no consistent correlation in
Hughes et al. (2001) between employment duration

and lung cancer risk (Document ID 2307, Attachment A, p. 86), with Dr.
Cox suggesting that model specification error was to blame (Document ID
2307, Attachment 4, p. 86). OSHA believes that cumulative exposure is a
more appropriate metric for determining risk than is duration of
exposure because the cumulative exposure metric considers both the
duration and intensity of exposure. For example, some workers may have
been employed for a very long duration with low exposures, whereas
others may have been employed for a short duration but with high
exposures; both groups could have similar cumulative exposures.
    In summary, OSHA considers the Hughes et al. (2001) study to be of
high enough quality to provide risk estimates for excess lung cancer
from silica exposure, as the study is unlikely to be substantially
confounded. For these reasons, the Agency finds the assertion that the
risk estimates based on this study are erroneous to be unconvincing.
    Overall, regarding all of the studies upon which OSHA relied in its
Preliminary QRA, the ACC concluded, ``In sum, none of the studies on
which OSHA relies is inconsistent with a concentration threshold above
100 [mu]g/m\3\ for any risk of silica-related lung cancer; none
demonstrates an increased lung cancer risk in the absence of silicosis;
and none provides a sound basis for estimating lung cancer risks at RCS
[respirable crystalline silica] exposure levels of 100 [mu]g/m\3\ and
below'' (Document ID 2307, Attachment A, p. 87).
    OSHA is not persuaded that the evidence presented by the ACC
supports these conclusions. On the contrary, as OSHA discussed in the
Section V.I, Comments and Responses Concerning Thresholds for Silica-
Related Diseases, demonstrating the absence of a threshold is not a
feasible scientific pursuit, and some models produce threshold
estimates well below the PELs. Similarly, the ACC has not put forward
any study that has proven that silicosis must be a precursor for lung
cancer and, as discussed in Section V.H, Mechanisms of Silica-Induced
Adverse Health Effects, some studies have shown genotoxic mechanisms by
which exposure to crystalline silica may lead to lung cancer. The
strong epidemiological evidence for carcinogenicity, supported by
evidence from experimental animal and mechanistic studies, allowed IARC
to conclude on multiple occasions that respirable crystalline silica is
a Group I carcinogen. OSHA places great weight on this conclusion given
IARC's authority and standing in the international scientific
community. In addition, all of the lung cancer studies relied upon by
OSHA used models that allow for the estimation of lung cancer risks at
crystalline silica exposure levels of 100 [mu]g/m\3\ and below. OSHA
believes these studies (Steenland et al., 2001a, Document ID 0452, as
re-analyzed in ToxaChemica, 2004, 0469; Rice et al., 2001, 1118;
Attfield and Costello, 2004, 0284; Hughes et al., 2001, 1060; and
Miller and MacCalman, 2009, 1306) are of high quality and contain well-
supported findings. Thus, OSHA continues to rely upon these studies for
deriving quantitative risk estimates in its QRA and continues to
believe that workers exposed to respirable crystalline silica at levels
at or near the previous and new PELs are faced with a significant risk
of dying from lung cancer. As such, the Agency believes it would be
irresponsible as a scientific matter, and inconsistent with its
statutory obligations to issue standards based on the best available
evidence after conducting an extensive rulemaking, to retain the
regulatory status quo.

G. Comments and Responses Concerning Renal Disease Mortality

    OSHA estimated quantitative risks for renal disease mortality
(Document ID 1711, pp. 314-316) using data from a pooled analysis of
renal disease, conducted by Steenland et al. (2002a, Document ID 0448).
As illustrated in Table VI-1, the lifetime renal disease mortality risk
estimate for 45 years of exposure to the previous general industry PEL
(100 [mu]g/m\3\ respirable crystalline silica) is 39 deaths per 1,000
workers. However, for the final PEL (50 [mu]g/m\3\), it is 32 deaths
per 1,000 workers. Although OSHA acknowledges that there are
considerably less data for renal disease mortality, and thus the risk
findings based on them are less robust than those for silicosis, lung
cancer, and non-malignant respiratory disease (NMRD) mortality, the
Agency believes the renal disease risk findings are based on credible
data. Indeed, the Steenland et al. pooled analysis had a large number
of workers from three cohorts with sufficient exposure data, and
exposure matrices for the three cohorts had been used in previous
studies that showed positive exposure-response trends for silicosis
morbidity or mortality, thus tending to validate the underlying
exposure and work history data (see Document ID 1711, pp. 215-216).
Nevertheless, OSHA received comments that were critical of its risk
estimates for renal disease mortality. Based upon its review of the
best available evidence, OSHA finds that these comments do not alter
its overall conclusions on renal disease mortality. In addition, OSHA
notes that even if the risk of renal disease mortality is discounted,
there would remain clearly significant risks of lung cancer mortality,
silicosis and NMRD mortality, and silicosis morbidity, with more robust
risk estimates based upon a larger amount of data from numerous studies
(see Table VI-1).
    OSHA received several comments from the ACC regarding the Agency's
quantitative risk estimates for renal disease mortality. Specifically,
the ACC argued that: (1) The pooled study (Steenland et al., 2002a,
Document ID 0448) that OSHA relied upon did not provide sufficient data
to estimate quantitative risks; (2) the individual studies included in
the pooled study had several limitations; and (3) most epidemiological
studies have not demonstrated a statistically significant association
between silica exposure and renal disease mortality (Document ID 2307,
Attachment A, pp. 139-157; 4209, pp. 92-96). As explained below, and as
stated above, although the Agency acknowledges there is greater
uncertainty in the risk estimates related to renal disease than other
silica-related diseases, the best available evidence is of sufficient
quality to quantify the risk of renal disease in the final risk
assessment.
1. Pooled Study
    Some commenters expressed concern about the Steenland et al.
(2002a, Document ID 0448) pooled study of renal disease mortality,
which OSHA and its contractor, ToxaChemica, used to calculate
quantitative risk estimates. Specifically, the ACC questioned why the
analysis only used three studies (Homestake, North Dakota gold miners,
Steenland and Brown, 1995a, Document ID 0450; U.S. industrial sand
workers, Steenland et al., 2001b, Document ID 0456; Vermont granite
workers, Costello and Graham, 1988, Document ID 0991) out of the ten
originally used in the pooled study of lung cancer mortality (Steenland
et al., 2001a, Document ID 0452). Peter Morfeld, Dr. rer. medic.,
representing the ACC, wrote in his written testimony that although
Steenland et al. (2002a, Document ID 0448) indicated that the three
studies were selected because they were the only ones to have
information on multiple cause mortality, all 10 studies had information
on renal disease as an underlying cause of death (Document ID 2308,
Attachment 4, pp. 24-25). Since ToxaChemica focused on underlying cause
results in their discussion, Dr. Morfeld argued that not having used
all

10 studies in the pooled analysis ``raises a suspicion of study
selection bias'' (Document ID 2308, Attachment 4, pp. 24-25).
    OSHA finds this assertion of study selection bias by the ACC and
Dr. Morfeld to be unpersuasive because Steenland et al.'s explanation
(2002a) for including only three studies in the pooled analysis was
sound. The authors reported in their pooled study that both underlying
cause and multiple cause mortality were available for only three
cohorts of silica-exposed workers, and ``multiple cause (any mention on
the death certificate) was of particular interest because renal disease
is often listed on death certificates without being the underlying
cause'' (Document ID 0448, p. 5). The authors likewise cited a study
(Steenland et al., 1992), indicating that the ratio of chronic renal
disease mortality shown anywhere on a U.S. death certificate versus
being shown as an underlying cause is 4.75 (Document ID 0453, Table 2,
pp. 860-861). Indeed, in their pooled analysis of renal disease
mortality, Steenland et al. noted that there were 51 renal disease
deaths when using underlying cause, but 204 when using multiple cause
mortality (Document ID 0448, p. 5). As renal disease is a serious
disabling disease, the use of multiple cause mortality gives a much
better sense of the burden of excess disease than does the use of
underlying cause of death as an endpoint. As such, Steenland et al.
calculated odds ratios by quartile of cumulative silica exposure for
renal disease in a nested case-control analysis that considered any
mention of renal disease on the death certificate as well as underlying
cause. For multiple-cause mortality, the exposure-response trend was
statistically significant for both cumulative exposure (p = 0.004) and
log cumulative exposure (p = 0.0002); whereas for underlying cause
mortality, the trend was statistically significant only for log
cumulative exposure (p = 0.03) (Document ID 1711, p. 315). Thus, OSHA
believes that Steenland et al. (2002a, Document ID 0448) were justified
in including only the three cohorts with all-cause mortality in their
pooled analysis.
    Concern was also expressed about the model selection in the pooled
analysis. Dr. Morfeld noted that a statistically significant
association between exposure to crystalline silica and renal disease
mortality was only found in the underlying cause analysis in which the
model was logged (p = 0.03) (Document ID 2308, Attachment 4, p. 25).
Dr. Morfeld commented, ``The authors stated that the log-model fit
better, but evidence was not given (e.g., information criteria), and it
is unclear whether the results are robust to other transformations''
(Document ID 2308, Attachment 4, p. 25).
    OSHA disagrees with this criticism because a log transformation of
the cumulative exposure metric is reasonable, given that exposure
variables are often lognormally distributed in epidemiological studies,
as discussed in Section V.J, Comments and Responses Concerning Biases
in Key Studies. Also, while it is true that Steenland et al. (2002a)
only found a statistically significant association in the continuous
underlying cause analysis when the cumulative exposure metric was
logged (p = 0.03), OSHA notes that the authors also found a
statistically significant association in the highest quartile of
unlogged cumulative silica exposure (1.67 + mg/m\3\-yr) in the
categorical underlying cause analysis (95% confidence interval: 1.31-
11.76) (Document ID 0448, Table 2, p. 7). Thus, for the highest
cumulative exposures, there was a significant association with renal
disease mortality even without a log transformation of the exposure
metric. Dr. Morfeld also failed to mention that Steenland et al.
(2002a) found statistically significant associations in the continuous
analyses (for both untransformed and log-transformed cumulative
exposure) using any mention of renal disease on the death certificate,
which adds weight to the study's findings that exposure to respirable
crystalline silica is associated with renal disease mortality (Document
ID 0448, Table 2, p. 7). In light of this, OSHA concludes that Dr.
Morfeld's criticism of the pooled analysis is without merit.
    The ACC also noted that the authors of this study, Drs. Kyle
Steenland and Scott Bartell, acknowledged the limitations of the data
in their 2004 ToxaChemica report to OSHA. Specifically, in reference to
the 51 renal deaths (underlying cause) and 23 renal cases in the pooled
study, Drs. Steenland and Bartell wrote, ``This amount of data is
insufficient to provide robust estimates of risk'' (Document ID 2307,
Attachment A, p. 139, citing 0469, p. 27). Given this acknowledgement,
the ACC concluded that OSHA's inclusion of the renal disease mortality
risk estimates in the significant risk determination and calculation of
expected benefits was speculative (Document ID 2307, Attachment A, pp.
139-140). During the hearing, Dr. Steenland further explained, ``I
think there is pretty good evidence that silica causes renal disease. I
just think that there is not as big a database as there is for lung
cancer and silicosis. And so there is more uncertainty'' (Document ID
3580, Tr. 1245). OSHA agrees with Dr. Steenland and acknowledges, as it
did in its Review of Health Effects Literature and Preliminary QRA
(Document ID 1711, p. 357), that its quantitative risk estimates for
renal disease mortality have more uncertainty and are less robust than
those for the other health effects examined (i.e., lung cancer
mortality, silicosis and NMRD mortality, and silicosis morbidity).
However, OSHA disagrees with the ACC's suggestion that the Agency's
renal disease risk estimates are ``rank speculation'' (Document ID
4209, pp. 95-96), as these estimates are based on the best available
evidence in the form of a published, peer-reviewed pooled analysis
(Steenland et al. 2002a, Document ID 0448) that uses sound
epidemiological and statistical methods. Thus, OSHA believes that it is
appropriate to present the risk estimates along with the associated
uncertainty estimate (e.g., 95% confidence intervals) (see Document ID
1711, p. 316).
2. Individual Studies in the Pooled Study
    The ACC also identified limitations in each of the three
epidemiological studies included in the Steenland et al. (2002a,
Document ID 0448) pooled study. First, with respect to the Steenland
and Brown (1995a, Document ID 0450) study of North Dakota gold miners,
the ACC noted there was a significantly elevated standardized mortality
ratio (SMR) for chronic renal disease only in the men hired prior to
1930. It noted that there were no silica exposure measurement data
available for this early time period, such that Steenland and Brown
(1995a, Document ID 0450) instead estimated a median exposure (150
[mu]g/m\3\) that was seven times higher for men hired prior to 1930,
versus men hired after 1950 (20 [mu]g/m\3\) (Document ID 2307,
Attachment A, p. 147). The ACC maintained that these exposure estimates
were likely to be understated and not credible, while also suggesting
``the existence of an average exposure threshold >=150 [mu]g/m\3\ for
any risk of silica-related renal disease mortality'' (Document ID 2307,
Attachment A, p. 147).
    OSHA finds the ACC's suggestion of a threshold to be unpersuasive,
as the ACC provided no analysis to indicate a threshold in this study.
OSHA addresses the Steenland and Brown (1995a, Document ID 0450)
exposure assessment in Section V.D, Comments and Responses Concerning
Silicosis and Non-Malignant Respiratory Disease Mortality and
Morbidity. The ACC also

ignored the alternative explanation, that elevated chronic renal
disease mortality may have only been seen in the workers hired prior to
1930 because they had a higher cumulative exposure than workers hired
later, not because there was necessarily a threshold.
    The ACC had a similar criticism of the Steenland et al. (2001b,
Document ID 0456) study of North American industrial sand workers. The
ACC posited that the exposure estimates were highly uncertain and
likely to be understated (Document ID 2307, Attachment A, p. 149). The
ACC noted that these exposure estimates, developed by Sanderson et al.
(2000, Document ID 0429), were considerably lower than those developed
by Rando et al. (2001, Document ID 0415) for another study of North
American industrial sand workers (Document ID 2307, Attachment A, p.
149). After discussing several differences between these two exposure
assessments, the ACC pointed to OSHA's discussion in the lung cancer
section of the preamble to the Proposed Rule (78 FR at 56302) in which
the Agency acknowledged that 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 the development of a job exposure matrix,
while 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
(Document ID 2307, Attachment A, pp. 149-151). The ACC then noted that
the McDonald et al. study (2005, Document ID 1092), using the Rando et
al. (2001, Document ID 0415) exposure assessment, found no association
between end-stage renal disease or renal cancer and cumulative silica
exposure (Document ID 2307, Attachment A, pp. 149, 152).
    The ACC also noted that, based on underlying cause of death, the
SMR for acute renal death in the Steenland et al. (2001b, Document ID
0456) study was not significant (95% confidence interval: 0.70-9.86),
and the SMR for chronic renal disease was barely significant (95%
confidence interval: 1.06-4.08) (Document ID 2307, Attachment A, p.
151). In light of this, the ACC maintained that Steenland et al. based
their exposure-response analyses on multiple-cause mortality data,
using all deaths with any mention of renal disease on the death
certificate even if it was not listed as the underlying cause. The ACC
asserted that ``only the underlying cause data involve actual deaths
from renal disease'' (Document ID 2307, Attachment A, p. 152).
    OSHA does not find this criticism persuasive. For regulatory
purposes, multiple-cause mortality data is, if anything, more relevant
because renal disease constitutes the type of material impairment of
health that the Agency is authorized to protect against through
regulation regardless of whether it is determined to be the underlying
cause of a worker's death. Moreover, the discrepancy in the renal
disease mortality findings is a moot point, as only the model in the
pooled study with renal disease as an underlying cause was used to
estimate risks in the Preliminary QRA (Document ID 1711, p. 316). In
any event, OSHA notes an important difference between the Steenland et
al. study (2001b, Document ID 0456) and the McDonald study (2005,
Document ID 1092): They did not look at the same cohort of North
American industrial sand workers. Steenland et al. (2001b) examined a
cohort of 4,626 workers from 18 plants; the average year of first
employment was 1967, with follow-up through 1996 (Document ID 0456, pp.
406-408). McDonald et al. (2005) examined a cohort of 2,452 workers
employed between 1940 and 1979 at eight plants, with follow-up through
2000 (Document ID 1092, p. 368). Although there was overlap of about
six plants in the studies (Document ID 1711, p. 127), these were
clearly two fairly different cohorts of industrial sand workers. These
differences in the cohorts might explain the discrepancy in the
studies' results. In addition, OSHA notes that McDonald et al. (2005,
Document ID 1092) observed statistically significant excess mortality
from nephritis/nephrosis in their study that was not explained by the
findings of their silica exposure-response analyses (Document ID 1092,
p. 369).
    The ACC further argued that the Steenland et al. (2002a, Document
ID 0448) pooled study is inferior to the Vacek et al. (2011, Document
ID 2340) study of Vermont granite workers, which found no association
between cumulative silica exposure and mortality from either kidney
cancer or non-malignant kidney disease and which it contended has
better mortality and exposure data (Document ID 2307, Attachment A, p.
154) (citing Vacek et al. (2011, Document ID 2340). In particular, it
argued that the Vacek et al. study is more reliable for this purpose
than the unpublished Attfield and Costello data (2004, Document ID
0285) on Vermont granite workers, which Steenland et al. relied on in
finding an association between silica exposure and renal disease.
    OSHA notes that Steenland et al. acknowledged in their pooled study
that that unpublished data had not undergone peer review (Document ID
0448, p. 5). Despite this limitation, OSHA is also unpersuaded that the
Vacek et al. study, although it observed no increased kidney disease
mortality (Document ID 2340, Table 3, p. 315), negates Steenland et
al.'s overall conclusions. OSHA discussed several substantial
differences between these two studies in Section V.F, Comments and
Responses Concerning Lung Cancer Mortality.
3. Additional Studies
    The ACC also submitted to the record several additional studies
that did not show a statistically significant association between
exposure to crystalline silica and renal disease mortality. These
included the aforementioned studies by McDonald et al. (2005, Document
ID 1092) and Vacek et al. (2011, Document ID 2340), as well as studies
by Davis et al. (1983, Document ID 0999), Koskela et al. (1987,
Document ID 0363), Cherry et al. (2012, article included in Document ID
2340), Birk et al. (2009, Document ID 1468), Mundt et al. (2011,
Document ID 1478), Steenland et al. (2002b, Document ID 0454), Rosenman
et al. (2000, Document ID 1120), and Calvert et al. (2003, Document ID
0309) (Document ID 2307, Attachment A, pp. 140-145). In light of its
assertions on the limitations of the three studies in the pooled
analysis, and because the three studies ``run counter to a larger
number of studies in which a causal association between silica exposure
and renal disease was not found,'' the ACC concluded that ``the three
studies relied on by OSHA do not provide a reliable or supportable
basis for projecting any risk of renal disease mortality from silica
exposure'' (Document ID 4209, p. 94). Similarly, the AFS argued that
renal disease was only ``found in a couple of selected studies and not
observed in most others,'' including no foundry studies (Document ID
2379, Attachment 1, pp. 1-3).
    In light of the analysis contained in the Review of Health Effects
Literature and Preliminary QRA, and OSHA's confirmation of its
preliminary findings through examination of the record, OSHA finds
these claims to be lacking in merit (Document ID 1711, pp. 211-229). In
the Review of Health Effects Literature and Preliminary QRA, OSHA
presented a comprehensive analysis of several studies that showed an
association between crystalline silica

and renal disease, as well as discussing other studies that did not
(Document ID 1711, pp. 211-229). Based upon its overall analysis of the
literature, including the negative studies, OSHA concluded that there
was substantial evidence suggesting an association between exposure to
crystalline silica and increased risks of renal disease. This
conclusion was supported by a number of case reports and
epidemiological studies that 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), end-stage
renal disease incidence (Steenland et al. 2001b, Document ID 0456),
chronic renal disease mortality (Steenland et al., 2002a, 0448), and
granulomatosis with polyangitis (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 were reported to
persist after cessation of silica exposure (Ng et al., 1992c, Document
ID 0386). While the mechanism of causation is presently unknown,
possible mechanisms suggested for silica-induced renal disease included
a direct toxic effect on the kidney, deposition in the kidney of immune
complexes (IgA) following silica-related pulmonary inflammation, or an
autoimmune mechanism (Calvert et al., 1997, Document ID 0976; Gregorini
et al., 1993, 1032).
    From this review of the studies on renal disease, OSHA concluded
that there were considerably less data, and thus the findings based on
them were less robust, than the data available for silicosis and NMRD
mortality, lung cancer mortality, or silicosis morbidity. Nevertheless,
OSHA concluded that the Steenland et al. (2002a, Document ID 0448)
pooled study had a large number of workers and validated exposure
information, such that it was sufficient to provide useful estimates of
risk of renal disease mortality. With regard to the additional negative
studies presented by the ACC, OSHA notes that it discussed the Birk et
al. (2009, Document ID 1468) and Mundt et al. (2011, Document ID 1478)
studies in the Supplemental Literature Review of the Review of Health
Effects Literature and Preliminary QRA, noting the short follow-up
period as a limitation, which makes it unlikely to observe the presence
of renal disease (Document ID 1711, Supplement, pp. 6-12). OSHA
likewise discussed the Vacek et al. (2011, Document ID 2340) study
earlier in this section, and notes that Cherry et al. reported a
statistically significant excess of non-malignant renal disease
mortality in the cohort for the period 1985-2008, with an unexplained
cause (2012, p. 151, article included in Document ID 2340). Although
these latter two studies did not find a significant association between
silica exposure and renal disease mortality, OSHA does not believe that
they substantially change its conclusions on renal disease mortality
from the Preliminary QRA, given the number of positive studies
presented and the limitations of those two studies.
    Thus, OSHA recognizes that the renal risk estimates are less robust
and have more uncertainty than those for the other health endpoints for
which there is a stronger case for causality (i.e., lung cancer
mortality, silicosis and NMRD mortality, and silicosis morbidity). But,
for the reasons stated above, OSHA believes that the evidence
supporting causality regarding renal risk outweighs the evidence
casting doubt on that conclusion. Scientific certainty is not the legal
standard under which OSHA acts. OSHA is setting the standard based upon
the clearly significant risks of lung cancer mortality, silicosis and
NMRD mortality, silicosis morbidity, and renal disease mortality at the
previous PELs; even if the risk of renal disease mortality is
discounted, the conclusion would not change that regulation is needed
to reduce the significant risk of material impairment of health (see
Society of the Plastics Industry, Inc. v. OSHA, 509 F.2d 1301, 1308 (2d
Cir. 1975)).

H. Mechanisms of Silica-Induced Adverse Health Effects

    In this section, OSHA describes the mechanisms by which silica
exposure may cause silica-related health effects, and responds to
comments criticizing the Agency's analysis on this topic. In the
proposal as well as this final rule, OSHA relied principally on
epidemiological studies to establish the adverse health effects of
silica exposure. The Agency also, however, reviewed animal studies (in
vivo and in vitro) as well as in vitro human studies that provide
information about the mechanisms by which respirable crystalline silica
causes such effects, particularly silicosis and lung cancer. OSHA's
review of this material can be found in the Review of Health Effects
Literature and Preliminary Quantitative Risk Assessment (QRA), which
provided background and support for the proposed rule (Document ID
1711, pp. 229-261).
    As described in the Review of Health Effects Literature, OSHA
performed an extensive evaluation of the scientific literature
pertaining to inhalation of respirable crystalline silica (Document ID
1711, pp. 7-265). Due to the lack of evidence of health hazards from
dermal or oral exposure, the Agency focused solely on the studies
addressing the inhalation hazards of respirable crystalline silica.
OSHA determined, based on the best available scientific information,
that several cellular events, such as cytotoxicity (i.e., cellular
damage), oxidative stress, genotoxicity (i.e., damage to cellular DNA),
cellular proliferation, and inflammation can contribute to a range of
neoplastic (i.e., tumor-forming) and non-neoplastic health effects in
the lung. While the exact mechanisms have yet to be fully elucidated,
they are likely initiated by damage to lung cells from interaction
directly with the silica particle itself or through silica particle
activation of alveolar macrophages following phagocytosis (i.e.,
engulfing particulate matter in the lung for the purpose of removing or
destroying foreign particles). The crystalline structure and unusually
reactive surface properties of the silica particle appear to cause the
early cellular effects. Silicosis and lung cancer share common features
that arise from these early cellular interactions but OSHA, in its
Review of Health Effects Literature and Preliminary QRA,
``preliminarily conclude[d] that available animal and in vitro studies
have not conclusively demonstrated that silicosis is a prerequisite for
lung cancer in silica-exposed individuals'' (Document ID 1711, p. 259).
Although the health effects associated with inhalation of respirable
crystalline silica are seen primarily in the lung, other observed
health effects include kidney and immune dysfunctions.
    Below, OSHA reviews the record evidence and responds to comments it
received on the mechanisms underlying respirable crystalline silica-
induced lung cancer and silicosis. The Agency also addresses comments
regarding the use of animal studies to characterize adverse health
effects in humans caused by exposure to respirable crystalline silica.
1. Mechanisms for Silica-Related Health Effects
    In 2012, IARC reevaluated the available scientific information
regarding respirable crystalline silica and lung cancer and reaffirmed
that crystalline silica is carcinogenic to

humans, i.e., a Group 1 carcinogen (Document ID 1473, p. 396). OSHA's
review of all the evidence now in the rulemaking record, including the
results of IARC's reevaluation, indicates that silica may lead to
increased risk of lung cancer in humans by a multistage process that
involves a combination of genotoxic (i.e., causing damage to cellular
DNA) and non-genotoxic (i.e., not involving damage to DNA) mechanisms.
Respirable crystalline silica may cause genotoxicity as a result of
reactive oxygen species (ROS) produced by activated alveolar
macrophages and other lung cells exposed to crystalline silica
particles during phagocytosis. ROS have been shown to damage DNA in
human lung cells in vitro (see Document ID 1711, pp. 236-239). This
genotoxic mechanism is believed to contribute to neoplastic
transformation and silica-induced carcinogenesis. ROS is not only
produced during the early cellular interaction with crystalline silica
but also produced by PMNs (polymorphonuclear leukocytes) and
lymphocytes recruited during the inflammatory response to crystalline
silica. In addition to genotoxicity contributed by ROS, it is also
plausible that reactive molecules on the surface of crystalline silica
itself may bind directly to DNA and result in genotoxicity (Document ID
1711, p. 236). It should be noted that the mechanistic evidence
summarized above suggests that crystalline silica may cause early
genotoxic events that are independent of the advanced chronic
inflammatory response and silicosis (Document ID 1473, pp. 391-392).
    Non-genotoxic mechanisms are also believed to contribute to the
lung cancer caused by respirable crystalline silica. Phagocytic
activation as well as silica-induced cytotoxicity trigger release of
the aforementioned ROS, cytokines (e.g., TNF[alpha]), and growth
factors (see Document ID 1711, pp. 233-235). These agents are able to
cause cellular proliferation, loss of cell cycle regulation, activation
of oncogenes (genes that have the potential to cause cancer), and
inhibition of tumor suppressor genes, all of which are non-genotoxic
mechanisms known to promote the carcinogenic process. It is plausible
that these mechanisms may be involved in silica-induced tumorigenesis.
The biopersistence and cytotoxic nature of crystalline silica leads to
a cycle of cell death (i.e., cytotoxicity), activation of alveolar
macrophages, recruitment of inflammatory cells (e.g., PMNs,
leukocytes), and continual release of the non-genotoxic mediators
(i.e., ROS, cytokines) able to promote carcinogenesis. The non-
genotoxic mechanisms caused by early cellular responses (e.g.,
phagocytic activation, cytotoxicity) are regarded, along with
genotoxicity, as important potential pathways that lead to the
development of tumors (Document ID 1711, pp. 232-239; 1473, pp. 394-
396).
    The same non-genotoxic processes that may cause lung cancer from
respirable crystalline silica exposure are also believed to lead to
chronic inflammation, lung scarring, fibrotic lesions, and eventually
silicosis. This would occur when inflammatory cells move from the
alveolar space through the interstitium of the lung as part of the
clearance process. In the interstitium, respirable crystalline silica-
laden cells--macrophages and neutrophils--release ROS and TNF-[alpha],
as well as other cytokines, stimulating the proliferation of
fibroblasts (i.e., the major lung cell type in silicosis).
Proliferating fibroblasts deposit collagen and connective tissue,
inducing the typical scarring that is observed with silicosis.
Alternatively, alveolar epithelial cells containing respirable
crystalline silica die and may be replaced by fibroblasts due to
necrosis of the epithelium. This allows for uninhibited growth of
fibroblasts and formation of connective tissue where scarring
proliferates (i.e., silicosis). As scarring increases, there is a
reduction in lung elasticity concomitant with a reduction of the lung
surface area capable of gas exchange, thus reducing pulmonary function
and making breathing more difficult (Document ID 0314; 0315). It should
be noted that silicosis involves many of the same mechanisms that occur
during the early cellular interaction with crystalline silica.
Therefore, it is plausible that development of silicosis may also
potentially contribute to silica-induced lung cancer. However, the
relative contributions of silicosis-dependent and silicosis-independent
pathways are not known.
    Although it is clear that exposure to respirable crystalline silica
increases the risk of lung cancer in exposed workers (see Section VI,
Final Quantitative Risk Assessment and Significance of Risk), some
commenters claimed that such exposure cannot cause lung cancer
independently of silicosis (i.e., only those workers who already have
silicosis can get lung cancer) (Document ID 2307, Attachment A, p. 53).
This claim is inconsistent with the credible scientific evidence
presented above that genotoxic and non-genotoxic mechanisms triggered
by early cellular responses to crystalline silica prior to development
of silicosis may contribute to crystalline silica-induced
carcinogenesis. OSHA finds, based on its review of all the evidence in
the rulemaking record, that workers without silicosis, as well as those
with silicosis, are at risk of lung cancer if regularly exposed to
respirable crystalline silica at levels permitted under the previous
and new PELs. The Agency also emphasizes that, regardless of the
mechanism by which respirable crystalline silica exposure increases
lung cancer risk, the fact remains that workers exposed to respirable
crystalline silica continue to be diagnosed with lung cancer at a
higher rate than the general population. Therefore, as discussed in
section VI, Final Quantitative Risk Assessment and Significance of
Risk, OSHA has met its burden of proving that workers exposed to
previously allowed levels of respirable crystalline silica are at
significant risk, by one or more of these mechanisms, of serious and
life-threatening health effects, including both silicosis and lung
cancer.
2. Relevance of Animal Models to Humans
    Animal data has been used for decades to evaluate hazards and make
inferences regarding causal relationships between human health effects
and exposure to toxic substances. The National Academies of Science has
endorsed the use of well-conducted animal studies to support hazard
evaluation in the risk assessment process (Document ID 4052, p. 81) and
OSHA's policy has been to rely on such studies when regulating
carcinogens. In the case of respirable crystalline silica, OSHA has
used evidence from animal studies, along with human epidemiology and
other relevant information, to establish that occupational exposure is
associated with silicosis, lung cancer, and other non-malignant
respiratory diseases, as well as renal and autoimmune effects (Document
ID 1711, pp. 261-266). Exposure to various forms of respirable
crystalline silica by inhalation and intratracheal instillation has
consistently caused lung cancer in rats (IARC, 1997, Document ID 1062,
pp. 150-163). These results led IARC and NTP to conclude that there is
sufficient evidence in experimental animals to demonstrate the
carcinogenicity of crystalline silica in the form of quartz dust. IARC
also concluded that there is sufficient evidence in human studies for
the carcinogenicity of crystalline silica in the form of quartz or
cristobalite.

    In its pre-hearing comments and post-hearing brief, the ACC noted
that increased lung cancer risks from exposure to respirable
crystalline silica have not been found in animal species other than
rats, and questioned the relevance of the rat model for evaluating
potential lung carcinogenicity in humans (Document ID 2307, Attachment
A, p. 30; 4209, p. 32). Specifically, the ACC highlighted studies by
Holland (1995) and Saffiotti et al. (1996) indicating that bioassays in
respirable crystalline silica-exposed mice, guinea pigs, and Syrian
hamsters have not found increased lung cancer (Document ID 2307,
Attachment A, p. 30, f. 51).
    The ACC proposed that the increased lung cancer risk in respirable
crystalline silica-exposed rats is due to a particle overload
phenomenon, in which lung clearance of nonfibrous durable particles
initiates a non-specific response that results in intrapulmonary lung
tumors (Document ID 2307, Attachment A, p. 30, n. 51). Dr. Cox, on
behalf of the ACC, citing Mauderly (1997, included in Document ID
3600), Oberdorster (1996, Document ID 3969), and Nikula et al. (1997,
included in Document ID 3600), likewise commented that rats are
``uniquely sensitive to particulate pollution, for species-specific
reasons that do not generalize to other rodents or mammals, including
humans'' (Document ID 2307, Attachment 4, p. 83). OSHA reviewed the
three studies referenced by Dr. Cox and notes that two actually appear
to support the use of the rat model and the third does not reject it.
Mauderly (1997) noted that the rat model was the only one to correctly
predict carcinogenicity after inhalation exposure to several types of
asbestos, and highlighted the shortcomings of other models, such as
those using hamsters, which are highly insensitive to particle-induced
lung cancers (article included in Document ID 3600, pp. 1339-1343).
While Mauderly (1997) advised caution when using the rat because it is
the most sensitive rodent species for lung cancer, he concluded that
``there is evidence supporting continued use of rats in exploration of
carcinogenic hazards of inhaled particles,'' and that the other test
species are problematic because they provide too many false negatives
to be predictive (article included in Document ID 3600, p. 1343).
Similarly, Oberdorster (1996), in discussing particle parameters used
in the evaluation of exposure-dose-relationships of inhaled particles,
stated that ``the rat model should not be dismissed prematurely''
(Document ID 3969, p. 73). Oberdorster (1996) postulated that humans
and rats have very similar responses to particle-induced effects when
analyzing the exposure-response relationship using particle surface
area, rather than particle mass, as the exposure metric. Oberdorster
concluded that there simply was not enough known regarding exact
mechanisms to reject the model outright (Document ID 3969, pp. 85-87).
The remaining paper cited by Dr. Cox, Nikula et al. (1997), evaluated
the anatomical differences between primate and rodent responses to
inhaled particulate matter and the role of clearance patterns and
physiological responses to inhaled toxicants. The study noted that the
differences between primate clearance patterns and rat clearance
patterns may play a role in the pathogenesis from inhaled poorly
soluble particles but did not dismiss the rat model as irrelevant to
humans (Nikula, 1997, included in Document ID 3600, pp. 83, 93, 97).
    Thus, OSHA finds that the Mauderly (1997) and Oberdorster (1996)
articles generally support the rat as an appropriate model for
qualitatively assessing the hazards associated with particle
inhalation. OSHA likewise notes that the rat model is a common and
well-accepted toxicological model used to assess human health effects
from toxicant inhalation (ILSI, 2000, Document ID 3906, pp. 2-9). OSHA
evaluated the available studies in the record, both positive and non-
positive, and believes that it is appropriate to regard positive
findings in experimental studies using rats as supportive evidence for
the carcinogenicity of crystalline silica. This determination is
consistent with that of IARC (Document ID 1473, p. 388) and NTP
(Document ID 1164, p. 1), which also regarded the significant increases
in incidence of malignant lung tumors in rats from multiple studies by
both inhalation and intratracheal instillation of crystalline silica to
be sufficient evidence of carcinogenicity in experimental animals and,
therefore, to contribute to the evidence for carcinogenicity in humans.
3. Hypothesis That Lung Cancer Is Dependent on Silicosis
    The ACC asserted in its comments that ``if it exists at all,
silica-related carcinogenicity most likely arises through a silicosis
pathway or some other inflammation-mediated mechanism, rather than by
means of a direct genotoxic effect'' (Document ID 2307, Attachment A,
p. 52; 4209, p. 51; 2343, Attachment 1, pp. 40-44). It explained that
the ``silicosis pathway'' means that lung cancer stems from chronic
inflammatory lung damage, which in turn, ``implies that there is a
threshold for any causal association between silica exposure and risk
of lung cancer'' (Document ID 2307, Attachment A, pp. 52-53). The ACC
went on to state that a mechanism that involves ROS, growth factors,
and inflammatory cytokines from alveolar macrophages is ``most
consistent'' with development of advanced chronic inflammation (e.g.,
epithelial hyperplasia, lung tissue damage, fibrosis, and silicosis).
According to this hypothesis, silica-related lung cancer is restricted
to people who have silicosis (Document ID 2307, Attachment 2, p. 7).
Regarding this hypothesis, the ACC concluded, ``[t]his view of the
likely mechanism for silica-related lung cancer is widely accepted in
the scientific community, including by OSHA's primary source of silica-
related health risk estimates, Dr. Kyle Steenland. OSHA appears to
share this view as well'' (Document ID 2307, Attachment A, p. 54).
    The ACC statement regarding acceptance by OSHA and the scientific
community is inaccurate. It implies scientific consensus, as well as
OSHA's concurrence, that the chronic inflammation from silicosis is the
only mechanism by which crystalline silica exposure results in lung
cancer. The ACC has over-simplified and neglected the findings of the
mechanistic studies that show activation of phagocytic and epithelial
cells to be an early cellular response to crystalline silica prior to
chronic inflammation (see Document ID 1711, pp. 234-238). As discussed
previously, alveolar macrophage activation leads to initial production
of ROS and release of cytokine growth factors that could contribute to
silica-induced carcinogenicity through both genotoxic and non-genotoxic
mechanisms. The early cellular response does not require chronic
inflammation and silicosis to be present, as postulated by the ACC. It
is possible that the early mechanistic influences that increase cancer
risk may be amplified by a later severe chronic inflammation or
silicosis, if such a condition develops. However, as Brian Miller,
Ph.D., stated ``this issue of silicosis being a precursor for lung
cancer is unanswerable, given that we cannot investigate for early
fibrotic lesions in the living, but must rely on radiographs.''
(Document ID 3574, Tr. 31).
    In pre-hearing comments the ACC commented, as proof of silicosis
being linked to lung cancer, that fibrosis was linked to
adenocarcinomas (Document ID 2307, Attachment A, p. 61). This statement
is misleading. As explained

earlier, silicosis results from stimulation of fibroblast cells that
cause lung fibrosis. Adenocarcinomas, a hallmark tumor type in
respirable crystalline silica-induced lung cancer, are tumors that
arise not from fibroblasts, but exclusively from lung epithelial cells
(IARC, 2012, Document ID 1473, pp. 381-389, 392). These tumors may be
linked to the genotoxic and non-genotoxic mechanisms that occur prior
to fibrosis, not secondary to the fibrotic process itself.
    OSHA also received some comments that questioned the existence of a
direct genotoxic mechanism. Jonathan Borak, M.D., on behalf of the U.S.
Chamber of Commerce, commented, ``there is no direct evidence that
silica causes cancer by means of a directly DNA-reactive mechanism''
(Document ID 2376, p. 21). Dr. Peter Morfeld, on behalf of the ACC, as
well as Peter Valberg, Ph.D., and Christopher M. Long, Sc.D., of
Gradient Corporation, on behalf of the U.S. Chamber of Commerce, cited
a scientific article by Borm et al. (2011, included in Document ID
3573) which reported finding evidence against a genotoxic mechanism and
in favor of a mechanism secondary to chronic inflammation (Document ID
3458, pp. 5-7; 4016, pp. 5-6; 4209, p. 51). Borm et al. (2011, included
in Document ID 3573) analyzed 245 published studies from 1996 to 2008
identified using the search terms ``quartz'' and `toxicity'' in
conjunction with ``surface,'' ``inflammation,'' ``fibrosis,'' and
``genotoxicity.'' The authors then estimated the lowest dose (in units
of micrograms per cell surface area) to consistently induce DNA damage
or induce markers of inflammation (e.g., IL-8 upregulation) in in vitro
studies. They adjusted the in vitro doses for the lung surface area
encountered in vivo and found the crystalline silica dose that produced
primary genotoxicity was 60-120 times higher than the dose that
produced inflammatory cytokines (Borm et al., 2011, included in
Document ID 3573, p. 762). Drs. Valberg and Long concluded that Borm et
al. demonstrated that genotoxicity was a secondary response to chronic
inflammation, except at very high exposures at which genotoxicity
independent of inflammation might occur. They also maintained that lung
cancer as a secondary response to chronic inflammation is considered to
have a threshold (Document ID 4016, p. 6).
    OSHA reviewed the Borm et al. study (2011, Document ID 3889), and
notes several limitations. The authors examined the findings from
various genotoxic assays (comet assay, 8-OH-dG, micronucleus test)
(Borm et al., 2011, 3889, p. 758). They reported that 40 [mu]g/cm\2\
was the lowest dose in vitro to produce significant direct DNA damage
from crystalline silica. This genotoxic dose appears to be principally
obtained from a study of a specific quartz sample (i.e., DQ12) in a
single human alveolar epithelial cell line (i.e., A549 cells), even
though Appendix Table 3 cited in vitro studies using other cells (e.g.,
fibroblasts) and other types of quartz (e.g., MinUsil) that produced
direct genotoxic effects at lower doses (Borm et al., 2011, Document ID
3889, pp. 760, 769-770). This is especially pertinent since Borm et al.
state that in vitro systems utilizing single-cell cultures are
generally much less sensitive than in vivo systems, especially if
attempting to determine oxidative stress-induced effects, since many
cell culture systems use reagents that can scavenge ROS (Borm et al.
2011, Document ID 3889, p. 760). There was no indication that the
authors accounted for this deficiency. They go on to conclude that
their work shows a large-scale variation in hazard across different
forms of quartz with regard to effects such as DNA breakage (e.g.,
genotoxicity) and inflammation (Borm et al. 2011, Document ID 3889, p.
762).
    The extreme variation in response along with reliance on an
insensitive genotoxicity test system could overestimate the appropriate
genotoxic dose in human lung cells in vivo. In addition, Borm et al.
used the dose sufficient to initiate production of an inflammatory
cytokine (i.e., IL-8) in the A549 cell-line as the threshold for
inflammation. It is not clear that an early cellular response, such as
IL-8 production necessarily reflects a sustained inflammatory response.
In summary, OSHA finds inconsistencies in this analysis, leaving some
questions regarding the study's conclusion that silica induces
genotoxicity only as a secondary response to an inflammation-driven
mechanism. While the in vitro dose comparisons in this study fail to
demonstrate that genotoxicity is secondary to the inflammatory
response, the study findings do indicate that cellular responses to
crystalline silica that drive inflammation may also lead to
tumorigenesis through both genotoxic and non-genotoxic mechanisms.
    Dr. Morfeld, in his hearing testimony on behalf of the ACC,
referred to the paper by Borm et al. (2011) as reaching the conclusion
that the mechanism of silica-related lung cancer is secondary
inflammation-driven genotoxicity. As summarized by the ACC in post-
hearing comments, he observed that ``there are no crystalline silica
particles found in the nucleus of the cells. There is nothing going on
with particles in the epithelial cells inside the lung'' (Document ID
4209, p. 52). In hearing testimony, however, Dr. Morfeld acknowledged
that the Borm paper had limitations on extrapolating from in vitro to
in vivo and cited a study by Donaldson et al. (2009), which discussed
some of the limitations and the need for caution in extrapolating from
in vitro to in vivo (Document ID 3582, Tr. 2076-2077; 3894, pp. 1-2).
In considering this testimony, OSHA notes that the Donaldson et al.
(2009) study, which includes the same authors as the Borm et al. (2011)
study, acknowledged that direct interaction between respirable
crystalline silica and epithelial cellular membranes induces
intracellular oxidative stress which is capable of being genotoxic
(Document ID 3894, p. 3). This is consistent with the OSHA position as
well as the most recent IARC reevaluation of the cancer hazard from
crystalline silica dust. As IARC stated in its most recent evaluation
of the carcinogenicity of respirable crystalline silica under a section
on direct genotoxicity and cell transformation (Document ID 1473,
section 4.2.2, pp. 391-393):

    Reactive oxygen species are generated not only at the particle
surface of crystalline silica, but also by phagocytic and epithelial
cells exposed to quartz particles. . . . Oxidants generated by
silica particles and by the respiratory burst of silica-activated
phagocytic cells may cause cellular and lung injury, including DNA
damage (Document ID 1473, p. 391).

    Given the IARC determination as well as the animal and in vitro
studies reviewed herein, OSHA finds that there is no conclusive
evidence that silica-related lung cancer only occurs as a secondary
response to chronic inflammation, or that silicosis is a necessary
prerequisite for lung cancer. Instead, OSHA finds support in the
scientific literature for a conclusion that tumors may form through
genotoxic as well as non-genotoxic mechanisms that result from
respirable crystalline silica interaction with alveolar macrophages and
other lung cells prior to onset of silicosis.
4. Hypothesis That Crystalline Silica-Induced Lung Disease Exhibits a
Threshold
    It is well established that silicosis arises from an advanced
chronic inflammation of the lung. As noted above, a common hypothesis
is that pathological conditions that depend on chronic inflammation may
have a threshold. The exposure level at which silica-induced health
effects might begin

to appear, however, is poorly characterized in the literature (see
Section V.I, Comments and Responses Concerning Thresholds for Silica-
Related Diseases). The threshold exposure level required for a
sustained inflammatory response is dependent upon multiple pro- and
anti-inflammatory factors that can be quite variable from individual to
individual and from species to species (Document ID 3896).
    Discounting or overlooking the evidence that respirable crystalline
silica may be genotoxic in the absence of chronic inflammation, Drs.
Valberg and Long commented that crystalline silica follows a threshold
paradigm for poorly soluble particles (PSPs). PSPs are defined
generally as nonfibrous particles of low acute toxicity, which are not
directly genotoxic (ILSI, 2000, Document ID 3906, p. 1). Specifically,
Drs. Valberg and Long stated:

    Mechanisms whereby lung cells respond to retention of a wide
variety of PSPs, including crystalline silica, follow a generally
accepted threshold paradigm, where the initiation of a chronic
inflammatory response is a necessary step in the disease process,
and the inflammatory response does not become persistent until
particle retention loads become sufficient to overwhelm lung defense
mechanisms. This overall progression from increased but controlled
pulmonary inflammation across a threshold exposure that leads to
lung damage has been described by a number of investigators
(Mauderly and McCunney, 1995; ILSI, 2000; Boobis et al., 2009;
Porter et al. 2004) (Document ID 2330, p. 19).

    Similarly, Dr. Cox, in his post-hearing comments, discussed his
2011 article describing a quantifiable exposure-response threshold for
lung diseases induced by inhalation of respirable crystalline silica
(Document ID 4027, p. 29). Dr. Cox hypothesized the existence of an
exposure threshold such that exposures to PSPs, which he described as
including titanium dioxide, carbon black, and crystalline silica, must
be intense enough and last long enough to disrupt normal homeostasis
(i.e., normal cellular functions) and overwhelm normal repair
processes. Under the scenario he described, a persistent state of
chronic, unresolved inflammation results in a disruption of macrophage
and neutrophil ability to clear silica and other foreign particles from
the lung (Document ID 1470, pp. 1548-1551, 1555-1556).
    OSHA disagrees with these characterizations about exposure
thresholds because, among other reasons, respirable crystalline silica
is not generally considered to be in the class of substances defined as
PSPs.\7\ Specifically, regarding the comments of Drs. Valberg and Long,
OSHA notes that the two cited documents (Mauderly and McCunney, 1995,
and ILSI, 2000) summarizing workshops on PSPs did not include
crystalline silica in the definition of PSP and the lung ``overload''
concept, instead highlighting silica's cytotoxic and genotoxic
mechanisms. Mauderly and McCunney (1995) stated, ``[i]t is generally
accepted that the term `overload' should be used in reference to
particles having low cytotoxicity, which overload clearance
[mechanisms] by virtue of the mass, volume, or surface area of the
deposited material (Morrow, 1992)'' (p. 3, article cited in Document ID
2330, p. 19). Mauderly specifically cited quartz as a cytotoxic
particle that may fall outside this definition (p. 24, article cited in
Document ID 2330, p. 19). The International Life Science Institute's
(ILSI) Workshop Report (2000) intended only to address particles of
``low acute toxicity,'' such as carbon black, coal dust, soot, and
titanium dioxide (Document ID 3906, p. 1). OSHA believes that the
cytotoxic nature of crystalline silica would exclude it from the class
of rather nonreactive, non-toxic particles mentioned above. Therefore,
the Agency concludes that most scientific experts would not include
crystalline silica in the class of substances known as PSPs, nor intend
for findings regarding PSPs to be extrapolated to crystalline silica.
---------------------------------------------------------------------------

    \7\ OSHA notes that crystalline silica has many mechanistic
features in common with asbestos. They are both durable,
biopersistent mineral forms where there is sufficient evidence of an
association with lung cancer (i.e., IARC Group 1 carcinogens),
chronic lung inflammation, and severe pulmonary fibrosis (i.e.,
silicosis and asbestosis) in humans. Like crystalline silica,
asbestos has reactive surfaces or other physiochemical properties
able to hinder phagocytosis and activate macrophages to release
reactive oxygen species, cytokines, and growth factors that lead to
DNA damage, cytotoxicity, cell proliferation and an inflammatory
response responsible for the disease outcomes mentioned above (see
IARC 2012, Document ID 1473, pp. 283-290). Crystalline silica and
asbestos can trigger phagocytic activation well below the high mass
burdens required to ``overload'' the lung and impair pulmonary
clearance that is typical of carbon black and other low acute-
toxicity PSPs.
---------------------------------------------------------------------------

    During the public hearing, OSHA questioned Dr. Morfeld about the
relevance of the rat overload response and whether he considered
crystalline silica to be like other PSPs such as carbon black. Dr.
Morfeld replied that he was well aware of the literature and indicated
that crystalline silica was not considered one of the PSPs
(specifically not like carbon black) that these reports reviewed
(Document ID 3582, Tr. 2072-2074). OSHA also notes a report of the
European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC),
which was cited by the ACC (Document ID 4209, p. 32) and stated that
``particles exhibiting significant surface related (cyto)toxicity like
crystalline silica (quartz) and/or other specific toxic properties do
not fall under this definition [of PSPs]'' (Document ID 3897, p. 5).
    Respirable crystalline silica differs from PSPs because it does not
require particle overload to induce the same response typical of PSPs.
``Overload'' refers to the consequence of exposure that results in a
retained lung burden of particles that is greater than the steady-state
burden predicted from deposition rates and clearance kinetics (Document
ID 4174, p. 20). This is a result of a volumetric over-exposure of dust
in the lung, which overwhelms macrophage function. Respirable
crystalline silica does not operate on this mechanism since macrophage
function is inhibited by the cytotoxic nature of respirable crystalline
silica rather than a volumetric overload (Oberdorster, 1996, Document
ID 3969). Therefore, respirable crystalline silica does not require
particle overload to induce the same response. Studies have found that
the respirable crystalline silica exposure levels required to induce
tumor formation in some animal studies are similar to those observed in
human studies, whereas studies involving PSPs tend to show responses at
much higher levels of exposure (Muhle et al., 1991, Document ID 1284;
Muhle et al., 1995, 0378; Saffiotti and Ahmed, 1995, 1121).
    A study by Porter et al. (2004) demonstrated that pulmonary
fibrosis induction does not require silica particle overload (Document
ID 0410, p. 377). The ACC cited this study in its post-hearing brief,
stating, ``Porter . . . noted that the response of the rat lung to
inhaled crystalline silica particles is biphasic, with a below-
threshold phase characterized by increased but controlled pulmonary
inflammation'' (Document ID 4209, p. 52). OSHA notes that this biphasic
response is due in part to the cytotoxic nature of crystalline silica,
which disrupts macrophage clearance of silica particles leading to a
chronic inflammatory response at less than overload conditions. While
there are some mechanistic similarities, OSHA believes that the
argument that crystalline silica operates on the basis of lung overload
is erroneous and based on false assumptions that ignore toxicological
properties unique to crystalline silica, such as cytotoxicity and the
generation of intracellular ROS (Porter et al., 2002, Document ID 1114;
Porter et al., 2004, 0410). As previously discussed, the generation of
ROS could

potentially damage cellular DNA by a genotoxic mechanism that may not
exhibit a threshold.
    OSHA thoroughly reviewed Dr. Cox's 2011 article (Document ID 1470),
in which he proposed a threshold for crystalline silica, in its
Supplemental Literature Review (Document ID 1711, Attachment 1, pp. 37-
39). OSHA concluded that the evidence used to support Cox's assertion
that the OSHA PEL was below a threshold for lung disease in humans was
not supported by the evidence presented (Document ID 1470, p. 1543;
1711, Attachment 1). Specifically, Cox (2011) modelled a threshold
level for respirable crystalline silica using animal studies of PSPs.
This approach, according to the ILSI report (2000) and ECETOC report
(2013), is clearly not appropriate since the cytotoxic nature of
crystalline silica is not consistent with the low-toxicity PSPs
(Document ID 3906, p. 1; 3897, p. 5). Dr. Cox (2011) categorized
crystalline silica incorrectly as a PSP and ignored the evidence for
cytotoxicity and genotoxicity associated with crystalline silica. He
further failed to consider or include studies indicating a tumor
response at exposure levels below that leading to an excessive chronic
inflammatory response, such as Porter et al. (2002) and Muhle et al.
(1995) (Document ID 1114; 0378). Thus, OSHA considers the threshold
model designed by Dr. Cox (2011, Document ID 1470) and referenced by
Drs. Valberg and Long (Document ID 2330) to be contradicted by the best
available evidence regarding the toxicological properties of respirable
crystalline silica. Although OSHA acknowledges the possible existence
of a threshold for an inflammatory response, the Agency believes that
the threshold is likely much lower than that advocated by industry
representatives such as the ACC and the Chamber of Commerce (see
Section V.I, Comments and Responses Concerning Thresholds for Silica-
Related Diseases).
    OSHA concludes that a better estimate of a threshold effect for
inflammation and carcinogenesis was done by Kuempel et al. (2001,
Document ID 1082). These researchers studied the minimum human
exposures necessary to achieve adverse functional and pathological
evidence of inflammation. They employed a physiologically-based lung
dosimetry model, included more relevant studies, and considered a
genotoxic effect for lung cancer (Kuempel et al., 2001, Document ID
1082; see 1711, pp. 231-232). Briefly, Kuempel et al. evaluated both
linear and nonlinear (threshold) models and determined that the average
minimum critical quartz lung burden (Mcrit) in rats
associated with reduced pulmonary clearance and increased neutrophil
inflammation was 0.39 mg quartz/g lung tissue. Mcrit is
based on the lowest observed adverse effect level in a study in rats
(Kuempel, 2001, Document ID 1082, pp. 17-23). A human lung dosimetry
model, developed from respirable coal mine dust and quartz exposure and
lung burden data in UK coal miners (Tran and Buchanan, 2001, Document
ID 1126), was then used to estimate the human-equivalent working
lifetime exposure concentrations associated with lung doses. An 8-hour
time-weighted average (TWA) concentration of 0.036 mg/m\3\ (36 [mu]g/
m\3\) over a 45-year working lifetime was estimated to result in a
human-equivalent lung burden to the average Mcrit in rats
(Document ID 1082, pp. 24-26). OSHA peer reviewer Gary Ginsburg, Ph.D.,
summarized, ``the Kuempel et al. (2001, 2001b) rat analysis of lung
threshold loading and extrapolation to human dosimetry leads to the
conclusion that in the median case this threshold is approximately 3
times below the current [now former] OSHA PEL'' (Document ID 3574, pp.
23). This estimated threshold would be significantly below the final
PEL of 50 [mu]g/m\3\.
    In pre-hearing comments, ACC stated that some health organizations
suggested a silicosis-dependent threshold exists for lung cancer (ACC,
Document ID 2307, Attachment A, pp. 60-62). Specifically, ACC cited
Environment and Health Canada as stating:

    Although the mechanism of induction for the lung tumours has not
been fully elucidated, there is sufficient supportive mode of action
evidence from the data presented to demonstrate that a threshold
approach to risk assessment is appropriate based on an understanding
of the key events in the pathogenesis of crystalline silica induced
lung tumours (pp. 49-51 as cited by ACC, Document ID 2307, p. 62).

    In addition to the statement submitted by ACC, Environment and
Health Canada also stated that:

    While there is sufficient evidence to support key events in a
threshold mode of action approach for lung tumours, the molecular
mechanism is still not fully elucidated. Also, despite the fact that
the effects seen in rats parallel the effects observed in human
studies, additional mechanistic studies could further clarify why
lung tumours are not seen in all experimental animals . . . Thus,
the question of whether silica exposure, in the absence of silicotic
response, results in lung tumours remains unanswered.'' (pp. 51-52
as cited by ACC, Document ID 2307, pp. 59-61).

    It should be noted that the Environment and Health Canada report
was to determine general population risk of exposure to respirable
crystalline silica as a fraction of PM10. Environment and
Health Canada found that levels 0.1-2.1 [mu]g/m\3\ respirable
crystalline silica were sufficiently protective for the general
population because they represented a margin of exposure (MOE) 23-500
times lower than the 50 [mu]g/m\3\ quartz concentration associated with
silicosis in humans (pp. 50-51 as cited by ACC, Document ID 2307, pp.
59-61).
    A report by Mossman and Glenn (2013) reviewed the findings from
several international OEL setting panels (Document ID 4070). The report
cites findings from the European Commission's Scientific Committee on
Occupational Exposure Limits for respirable crystalline silica. The
findings ``acknowledged a No Observed Adverse Exposure Level (NOAEL)
for respirable crystalline silica in the range below 0.020 mg/m\3\, but
stated that a clear threshold for silicosis could not be identified''
(Mossman and Glen, 2013; Document ID 4070, p. 655). The report went on
to state that SCOEL (2002) recommended that an OEL should lie below 50
[mu]g/m\3\ (Document ID 4070, p. 655). Therefore, even if silica-
induced lung cancer were limited only to a mechanism that involved an
inflammation-dependent threshold, OSHA concludes that exposure
threshold would likely be lower than the final PEL.
5. Renal Disease and Autoimmunity
    While mechanistic data is limited, other observed health effects
from inhalation of respirable crystalline silica include kidney and
autoimmune effects. Translocation of particles through the lymphatic
system and filtration through the kidneys may induce effects in the
immune and renal systems similar to the types of changes observed in
the lung (Miller, 2000, Document ID 4174, pp. 40-45). A review of the
available literature indicates that respirable crystalline silica most
likely induces an oxidative stress response in the renal and immune
cells similar to that described above (Donaldson et al., 2009, Document
ID 3894).
6. Conclusion
    OSHA has reviewed and responded to the comments received on the
mechanistic studies of respirable crystalline silica-induced lung
cancer and silicosis, as well as comments that the mechanistic data
imply the existence of an exposure threshold. OSHA concludes that: (1)
Lung cancer likely results from both genotoxic and non-genotoxic
mechanisms that arise during early cellular responses as well

as during chronic inflammation from exposure to crystalline silica; (2)
there is not convincing data to demonstrate that silicosis is a
prerequisite for lung cancer; (3) experimental studies in rats are
relevant to humans and provide supporting evidence for carcinogenicity;
(4) crystalline silica does not behave like PSPs such as titanium
dioxide; and (5) any threshold for an inflammatory response to
respirable crystalline silica is likely several times below the final
PEL of 50 [mu]g/m\3\. Thus, the best available evidence on this issue
supports OSHA's findings that respirable crystalline silica increases
the risk of lung cancer in humans, even in the absence of silicosis,
and that lung cancer risk can be increased by exposure to crystalline
silica at or below the new OSHA PEL of 50 [mu]g/m\3\.

I. Comments and Responses Concerning Thresholds for Silica-Related
Diseases

    In this section, OSHA discusses comments focused on the issue of
exposure-response thresholds for silica exposure. In the comments
received by OSHA on this topic, an exposure-response ``threshold'' for
silica exposure typically refers to a level of exposure such that no
individual whose exposure is below that level would be expected to
develop an adverse health effect. Commenters referred to thresholds
both in terms of concentration and cumulative exposure (i.e., a level
of cumulative exposure below which an individual would not be expected
to develop adverse health effects). In addition to individual
thresholds, some commenters referred to a ``population average
threshold,'' that is, the mean or median value of individual thresholds
across a population of workers. There is significant scientific
controversy over whether any such thresholds exist for silicosis and
lung cancer, as well as the cumulative exposure level or concentration
at which a threshold effect may occur and whether certain statistical
modeling approaches can be used to identify threshold effects.
    OSHA has reviewed the evidence in the record pertaining to
thresholds, and has determined that the best available evidence
supports the Agency's use of non-threshold exposure-response models in
its risk assessments for silicosis and lung cancer. The voluminous
scientific record accrued by OSHA in this rulemaking supports lowering
the existing PEL to 50 [mu]g/m\3\. Rather than indicating a threshold
of risk that starts above the previous general industry PEL, the weight
of this evidence, including OSHA's own risk assessment models, supports
a conclusion that there continues to be significant, albeit reduced,
risk at the 50 [mu]g/m\3\ exposure limit. OSHA's evaluation of the best
available evidence on thresholds indicates that there is considerable
uncertainty about whether there is any threshold below which silica
exposure causes no adverse health effects; but, in any event, the
weight of evidence supports the view that, if there is a threshold of
exposure for the health effects caused by respirable crystalline
silica, it is likely lower than the new PEL of 50 [mu]g/m\3\.
Commenters have not provided convincing evidence of a population
threshold (e.g., an exposure level safe for all workers) above the
revised PEL. In addition, OSHA's final risk assessment demonstrates
that achieving this limit--which OSHA separately concludes is overall
the lowest feasible level for silica-generating operations--will result
in significant reductions in mortality and morbidity from occupational
exposure to respirable crystalline silica.
1. Thresholds--General
    In the Preliminary Quantitative Risk Assessment (QRA) (Document ID
1711, pp. 275, 282-285), OSHA reviewed evidence on thresholds from a
lung dosimetry model developed by Kuempel et al. (2001, Document ID
1082) and from epidemiological analyses conducted by Steenland and
Deddens (2002, Document ID 1124). As discussed in the Preliminary QRA,
Kuempel et al. (2001) used kinetic lung models for both rats and humans
to relate lung burden of crystalline silica and estimate a minimum
critical lung burden (Mcrit) of quartz above which particle
clearance begins to decline and lung inflammation begins to increase
(early steps in the process of developing silica-related disease). The
Mcrit would be achieved by a human equivalent airborne
exposure to 36 [mu]g/m\3\ for 45 years, based on the authors' rat-to-
human lung model conversion. Exposures below this level would not lead
to an excess lung cancer risk in the average individual, if it were
assumed that cancer is strictly a secondary response to persistent
inflammation. OSHA notes, however, that if some of the silica-related
lung cancer risk occurs as a result of direct genotoxicity from early
cellular interaction with respirable silica particles, then this
threshold value may not be applicable. Since silicosis is caused by
persistent lung inflammation, this exposure level could be viewed as a
possible average threshold level for that disease as well (Document ID
1711, p. 284). As 36 [mu]g/m\3\ is well below the previous general
industry PEL of 100 [mu]g/m\3\ and below the final PEL of 50 [mu]g/
m\3\, the Kuempel et al. study showed no evidence of an exposure-
response threshold high enough to impact OSHA's choice of PEL.
    Steenland and Deddens (2002, Document ID 1124) examined a pooled
lung cancer study originally conducted by Steenland et al. (2001a).
They found that a threshold model based on the log of cumulative dose
(15-year lag) fit better than a no-threshold model, with the best
threshold at 4.8 log mg/m\3\-days (representing an average exposure of
10 [mu]g/m\3\ over a 45-year working lifetime). OSHA preliminarily
concluded that, in the Kuempel et al. (2001) study and among the
studies evaluated by Steenland et al. (2001a) in the pooled analysis,
there was no empirical evidence of a threshold for lung cancer in the
exposure range represented by the previous and final PELs (i.e., at 50
[mu]g/m\3\ or higher) (Document ID 1711, pp. 275, 284). Thus, based on
these two studies, workers exposed at or below the new PEL of 50 [mu]g/
m\3\ over a working lifetime still face a risk of developing silicosis
and lung cancer because their exposure would be above the supposed
exposure threshold.
    In its prehearing comments, the ACC argued that OSHA's examination
of the epidemiological evidence, along with animal studies and
mechanistic considerations, ``has not shown that reducing exposures
below currently permitted exposure levels would create any additional
health benefits for workers. OSHA's analysis and the studies on which
it relies have not demonstrated the absence of an exposure threshold
above 100 [mu]g/m\3\ for the various adverse health effects considered
in the QRA'' (Document ID 2307, Attachment A, p. 26; also 2348,
Attachment 1, p. 33). According to the ACC, an exposure threshold above
OSHA's previous general industry PEL of 100 [mu]g/m\3\ means that
workers exposed below that level will not get sick, negating the need
to lower the PEL (Document ID 2307, Attachment A, p. 91).
    Members of OSHA's peer review panel for the Review of Health
Effects Literature and Preliminary Quantitative Risk Assessment
(Document ID 1711) rejected the ACC's comments as unsupportable. Peer
reviewer Mr. Bruce Allen stated: ``it is essentially impossible to
distinguish between dose-response patterns that represent a threshold
and those that do not'' in epidemiological data (Document ID 3574, p.
8). Peer reviewer Dr. Kenneth Crump similarly commented:

    OSHA is on very solid ground in the [Preliminary QRA's]
statement that ``available information cannot firmly establish a
threshold exposure for silica-

related effects'' . . . the hypothesis that a particular dose
response does not have a threshold is not falsifiable. Similarly,
the hypothesis that a particular dose response does have a threshold
is not falsifiable (Document ID 3574, p. 17).

    Dr. Cox, representing the ACC, agreed with Dr. Crump that ``it's
impossible to prove a negative, empirically . . . you could never rule
out that possibility'' of a threshold at a low level of exposure
(Document ID 3576, Tr. 402). However, he contended that it is possible
to rule out a threshold in the higher-level range of observed exposures
based on observed illness: ``I think that there are plenty of chemicals
for which the hypothesis of a threshold exist[ing] at or above current
standards could be ruled out because you see people getting sick at
current levels'' (Document ID 3576, Tr. 403). Other commenters stated
their belief that workers recently diagnosed with silicosis must have
had exposures above the previous general industry PEL and, based on
this supposition, concluded that OSHA has not definitively proven risk
to workers exposed below the previous general industry PEL (Document ID
4224, pp. 2-5; Tr. 3582, pp. 1951-1963).
    OSHA agrees with Dr. Cox that observation of workers ``getting sick
at current levels'' can rule out a threshold effect at those levels. As
is discussed below, there is evidence that workers exposed to silica at
cumulative or average exposure levels permitted under the previous PELs
have become ill and died as a result of their exposure. OSHA thus
strongly disagrees with any implication from commenters that the Agency
should postpone reducing a PEL until it has extensive documentation of
sick and dying workers to demonstrate that the current PEL is not
sufficiently protective (see Section II, Pertinent Legal Authority, and
Section VI, Final Quantitative Risk Assessment and Significance of
Risk).
    The ACC's and Chamber's comments on this issue essentially argue
that the model OSHA used to assess risk was inadequate to assess
whether a threshold of risk exists and, if one does exist, at what
level (Document ID 2307, Attachment A, pp. 52-65; 2376, pp. 20-22;
2330, pp. 17-21). According to OSHA peer reviewer Dr. Crump, however,
the analytical approach taken by OSHA in the Preliminary QRA was
appropriate. Considering the inherent limitations of epidemiological
data:

an attempt to distinguish between threshold and non-threshold dose
responses is not even a scientific exercise . . . The best that can
be done is to attempt to place bounds on the amount of risk at
particular exposures consistent with the available data, which is
what OSHA had done in their risk assessment (Document ID 3574, p.
17).

    A further source of uncertainty in investigating thresholds was
highlighted by Dr. Mirer, on behalf of the AFL-CIO (Document ID 3578,
Tr. 988-989) and by peer reviewer Dr. Andrew Salmon, who stated:

[m]any of the so-called thresholds seen in epidemiological studies
represent thresholds of observability rather than thresholds of
disease incidence . . . studies (and anecdotal observations) with
less statistical power and shorter post-exposure followup (or none)
will necessarily fail to see the less frequent and later-appearing
responses at lower doses. This creates an apparent threshold which
is higher in these studies than the apparent threshold implied by
studies with greater statistical power and longer follow-up
(Document ID 3574, p. 37).

    Peer reviewer Dr. Gary Ginsberg suggested that, recognizing these
inherent limitations, OSHA should characterize the body of evidence and
argument surrounding thresholds by discussing the following factors
related to whether a threshold for silica-related health effects exists
at exposure levels above the previous general industry PEL:

the choices relative to the threshold concept for the silica dose
response . . . [including] specific dose response datasets that are
consistent with a linear or a threshold-type model, if a threshold
seems likely, where was it seen relative to the current and proposed
PEL, and a general discussion of mechanism of action, measurement
error and population variability as concepts that can help us
understand silica dose response for cancer and non-cancer endpoints
(Document ID 3574, p. 24).

    Following Dr. Ginsberg's suggestion, OSHA has, in its final health
and risk analysis, considered the epidemiological evidence relevant to
possible threshold effects for silicosis and lung cancer. As discussed
below, first in ``Thresholds--Silicosis and NMRD'' and then in
``Thresholds--Lung Cancer,'' OSHA has carefully considered comments
about statistical methods, exposure measurement uncertainty, and
variability as they pertain to threshold effects. The discussion
addresses the epidemiological evidence with respect to both cumulative
and concentration thresholds. For reference, a working lifetime (45
years) of exposure to silica at the previous general industry PEL (100
[mu]g/m\3\) and the final PEL (50 [mu]g/m\3\) yield cumulative
exposures of 4.5 mg/m\3\-yrs and 2.25 mg/m\3\-yrs, respectively. Other
sections with detailed discussions pertinent to threshold issues
include Section V.H, Mechanisms of Silica-Induced Adverse Health
Effects, and Section V.K, Comments and Responses Concerning Exposure
Estimation Error and ToxaChemica's Uncertainty Analysis.
2. Thresholds--Silicosis and NMRD
    OSHA has determined that the studies most relevant to the threshold
issue in this rulemaking are those of workers who have cumulative
exposures or average exposure concentrations below the levels
associated with the previous general industry PEL (100 [mu]g/m\3\, or
cumulative exposure of 4.5 mg/m\3\-yrs). Contrary to comments that OSHA
only relied on studies involving exposures far above the levels of
interest to OSHA in this rulemaking, and then extrapolated exposure-
response relationships down to relevant levels (e.g., Document ID 2307,
Attachment A, pp. 94-95; 4226, p. 2), a number of silicosis studies
included workers who were exposed at levels close to or below the
previous OSHA PEL for general industry. For example, four of the six
cohorts of workers in the pooled silicosis mortality risk analysis
conducted by Mannetje et al. (2002) had median cumulative exposures
below 2.25 mg/m\3\-yrs., and three had median silica concentrations
below 100 [mu]g/m\3\ (Mannetje et al., 2002, Document ID 1089, p. 724).
Other silicosis studies with significant numbers of relatively low-
exposed workers include analyses of German pottery workers (Birk et
al., 2009, Document ID 4002, Attachment 2; Mundt et al., 2011, 1478;
Morfeld et al., 2013, 3843), Vermont granite workers (Attfield and
Costello, 2004, Document ID 0285; Vacek et al., 2011, 1486), and
industrial sand workers (McDonald et al., 2001, Document ID 1091;
Hughes et al., 2001, 1060; McDonald et al., 2005, 1092). In this
section, OSHA will discuss each of them in relationship to whether they
suggest the existence of a threshold above 100 [mu]g/m\3\, the previous
PEL for general industry.
a. Mannetje et al. Pooled Study and Related Analyses
    Mannetje et al. (2002b, Document ID 1089) estimated excess lifetime
risk of silicosis based on six of the ten cohorts that were part of the
IARC multi-center exposure-response study (Steenland et al., 2001a,
Document ID 0452). The six cohorts were U.S. diatomaceous earth (DE)
workers, Finnish granite workers, U.S. granite workers, U.S. industrial
sand workers, U.S. gold miners, and Australian gold miners. Together,
the cohorts included 18,634 subjects and 170 silicosis deaths. All
cohorts except the Finnish granite workers and Australian gold miners
had significant numbers of workers with median

cumulative and/or average exposures below the levels associated with
OSHA's previous general industry PEL. Checking for nonlinearities in
their exposure-response model, Mannetje et al. found that a five-knot
cubic spline model (which allows for deviations, such as thresholds,
from a linear relationship) did not fit the data better than the linear
model used in their main analysis. The result of this attempt to check
for nonlinearities suggests that there is no threshold effect in the
relationship between cumulative silica exposure and silicosis risk in
the study. Significantly, NIOSH stated that the results of Mannetje et
al.'s analysis ``suggest the absence of threshold at the lowest
[cumulative] exposure analyzed . . . in fact, the trend for silicosis
mortality risk extends down almost linearly to the lowest cumulative
exposure stratum'', in which ``the average cumulative exposure is the
equivalent of 45 years of exposure at 11.1 [mu]g/m\3\ silica''
(Document ID 4233, pp. 34-35). This level is significantly below the
new OSHA PEL of 50 [mu]g/m\3\.
    As discussed in Section V.K, Comments and Responses Concerning
Exposure Estimation Error and ToxaChemica's Uncertainty Analysis, OSHA
commissioned Drs. Kyle Steenland and Scott Bartell to examine the
potential effects of exposure measurement error on the mortality risk
estimates derived from the pooled studies of lung cancer (Steenland et
al., 2001, Document ID 0452) and silicosis (Mannetje et al., 2002b,
Document ID 1089). Their analysis of the pooled data, using a variety
of standard statistical techniques (e.g., regression analysis), also
found the data either consistent with the absence of a threshold or
inconsistent with the existence of a threshold \8\ (Document ID 0469).
Thus, neither Mannetje et al. nor Steenland and Bartell's analyses of
the pooled cohorts suggested the existence of a cumulative exposure
threshold effect; in fact, they suggested the absence of a threshold.
Given the predominance in these studies of cohorts where at least half
of the workers had cumulative exposures below 4.5 mg/m\3\-yrs, OSHA
believes these results constitute strong evidence against an exposure
threshold above the level of cumulative exposure resulting from long-
term exposure at the previous PEL of 100 [mu]g/m\3\.
---------------------------------------------------------------------------

    \8\ This analysis included a log-cumulative logistic regression
model, as well as a categorical analysis and five-knot restricted
cubic spline analysis using log-cumulative exposure. Had the spline
analysis shown a better-fitting model with a flat exposure-response
at low cumulative exposure levels, it might have suggested a
threshold effect for cumulative exposure. However, no significant
difference was observed between the parametric model and the two
other models, which had greater flexibility in the shape of the
exposure-response (Document ID 0469, p. 50, Figure 5).
---------------------------------------------------------------------------

b. Vermont Granite Workers
    As discussed in the Supplemental Literature Review of
Epidemiological Studies, Vacek et al. (2011, Document ID 1486) examined
exposures from 1950 to 1999 for a group of 7,052 workers in the Vermont
granite industry (Document ID 1711, Attachment 1, pp. 2-5). The
exposure samples show relatively low exposures for the worker
population. For the period 1950 to 2004, Verma et al. (2012), who
developed the job exposure matrix used by Vacek et al., estimated that
average exposure concentrations in 21 of 22 jobs were below 100 [mu]g/
m\3\, and 11 of the 22 job classes were at 50 [mu]g/m\3\ or below. The
remaining job category, laborer, had an estimated average exposure
concentration of exactly 100 [mu]g/m\3\ (Verma et al., 2011, Document
ID 1487, p. 75).
    Six of the 5,338 cohort members hired in or after 1940, when
Vermont's dust control program was in effect, were identified as having
died of silicosis by the end of the follow-up period (Vacek et al.,
Document ID 1486, p. 314). The frequency of observed silicosis
mortality in the population is significant by OSHA standards (1.1 per
1,000 workers), and may be underestimated due to under-reporting of
silicosis as a cause of death (see Section V.E, Comments and Responses
Concerning Surveillance Data on Silicosis Morbidity and Mortality).
This observed silicosis mortality shows that deaths from silicosis
occurred among workers hired after silica concentrations were reduced
below OSHA's previous general industry PEL. It therefore demonstrates
that a threshold for silicosis above 100 [mu]g/m\3\ is unlikely.
    In terms of morbidity, Graham et al.'s study of radiographic
evidence of silicosis among retired Vermont granite workers found
silicosis in 5.7 percent of workers hired after 1940 (equivalent to 57/
1,000 workers) (Graham et al., 2004, Document ID 1031, p. 465). OSHA
concludes that these studies of low-exposed workers in the Vermont
granite industry show significant risk of silicosis--both mortality and
morbidity--at concentrations below the previous PELs. These studies
also indicate that a threshold at an exposure concentration
significantly above the previous PEL for general industry, as posited
by industry representatives, is unlikely.
c. U.S. Industrial Sand Workers
    In an exposure-response study of 4,027 workers in 18 U.S.
industrial sand plants, Steenland and Sanderson (2001) reported that
approximately three-quarters of the workers with complete work
histories had cumulative exposures below 1.28 mg/m\3\-yrs, well below
the cumulative exposure of 2.25 mg/m\3\-yrs associated with a working
lifetime of exposure at the final PEL of 50 [mu]g/m\3\ (Document ID
0455, p. 700). The study identified fourteen deaths from silicosis and
unspecified pneumoconiosis (~3.5 per 1,000 workers) (Document ID 0455,
p. 700), of which seven occurred among workers with cumulative
exposures below 1.28 mg/m\3\-yrs. As with other reports of silicosis
mortality, this figure may underestimate the true rate of silicosis
mortality in this worker population.
    Hughes et al. (2001) reported 32 cases of silicosis mortality in a
cohort of 2,670 workers at nine North American industrial sand plants
(~12 per 1,000) (Document ID 1060, p. 203). The authors developed a
job-exposure matrix based on exposure samples collected by the
companies and by MSHA between 1973 and 1994, along with the 1946
exposure survey used by Steenland and Sanderson (2001, Document ID
0455; 2307, Attachment 7, p. 6). Job histories were available for 29
workers who died of silicosis. Of these, fourteen had estimated
cumulative exposure less than or equal to 5 mg/m\3\-yrs, and seven had
cumulative exposures less than or equal to 1.5 mg/m\3\-yrs (Document ID
1060, p. 204). Both studies clearly showed silicosis risk among workers
whose cumulative exposures were comparable to those that workers could
experience under the final PEL (Document ID 0455, p. 700; 1060, p.
204), indicating that a threshold above this level of cumulative
exposure is unlikely.
d. German Porcelain Workers
    A series of papers by Birk et al. (2009, Document ID 4002,
Attachment 2; 2010, Document ID 1467), Mundt et al. (2011, Document ID
1478), and Morfeld et al. (2013, Document ID 3843) examined silicosis
mortality and morbidity in a population of over 17,000 workers in the
German porcelain industry. Cohort members' annual average
concentrations of respirable quartz dust were reconstructed from
detailed work histories and dust measurements collected in the industry
from 1951 onward (Birk et al., 2009, Document ID 4002, Attachment 2,
pp. 374-375). Morfeld et al. observed 40 silicosis morbidity cases (ILO
profusion category 1/1 or greater), and noted that additional

follow-up of the cohort might be necessary due to the long latency
period of silicosis (2013, Document ID 3843, p. 1032).
    Follow-up time is a critical factor for detection of silicosis,
which has a typical latency of 20-30 years (see Morfeld et al., 2013,
Document ID 3843, p. 1028). As stated in Section V.C, Summary of the
Review of Health Effects Literature and Preliminary QRA, the disease
latency for silicosis can extend to around 30 years. Follow-up was
extremely limited in the German porcelain workers silicosis morbidity
analysis, with a mean of 7.5 years of follow up for the study
population (Document ID 3843). Despite the limited follow-up time, the
cohort showed evidence of silicosis morbidity among low-exposed
workers: 17.5 percent of cases occurred among workers whose highest
average silica exposure in any year (``highest annual'') was estimated
by the authors to be less than 250 [mu]g/m\3\, and 12.5 percent of
cases occurred among workers whose highest annual silica exposure was
estimated at less than 100 [mu]g/m\3\ (Document ID 3843).
    The lead author of the study, Dr. Peter Morfeld, testified at the
public hearings on behalf of the ACC Crystalline Silica Panel. In his
post-hearing comments, Dr. Morfeld stated that ``[m]echanistic
considerations imply that we should not expect to see a threshold for
cumulative exposure'' in silicosis, but that the question of whether a
threshold concentration level may exist remains (Document ID 4003, p.
3). The study by Morfeld et al. ``focused on the statistical estimation
of a concentration threshold . . . [and] simultaneously took into
account the cumulative exposure to respirable crystalline silica dust
as a driving force of the disease'' (Document ID 4003, p. 3). Morfeld
et al. applied a technique developed by Ulm et al. (1989, 1991) to
estimate a concentration threshold. In this method a series of
candidate exposure concentration values are subtracted from the
estimated annual mean concentration data. Using the recalculated
exposure estimates for the study population, regression analyses for
each candidate are run to identify the best fitting model, using the
Akaike Information Criterion (AIC) to evaluate model fit (Document ID
3843, p. 1029). According to Morfeld, the best fitting model in their
study estimated a threshold concentration of 250 [mu]g/m\3\ (AIC =
488.3) with a 95 percent confidence interval of 160 to 300 [mu]g/m\3\.
A second model with very similar fit (AIC = 488.8) estimated a
threshold concentration of 200 [mu]g/m\3\ with a 95 percent confidence
interval of 57 [mu]g/m\3\ to 270 [mu]g/m\3\. A third model with a
poorer fit (AIC=490.6) estimated a threshold concentration of 80 [mu]g/
m\3\ with a 95 percent confidence interval of 0.2 [mu]g/m\3\ to 210
[mu]g/m\3\ (Document ID 3843, Table 3, p. 1031).
    In the Final Peer Review Report, Dr. Crump stated that Morfeld et
al.'s modeling approach, like ``all such attempts statistically to
estimate a threshold,'' is ``not reliable because the threshold
estimates so obtained are highly unstable'' (Document ID 3574, p. 17).
Dr. Morfeld's co-author, Dr. Mundt, stated in the public hearings:

    I'll be the first one to tell you there is a lot of imprecision
and, therefore, say confidence intervals or uncertainty should be
respected, and that the--I'm hesitant to just focus on a single
point number like the .25 [250 [mu]g/m\3\], and prefer that you
encompass the broader range that was reported in the Morfeld, on
which I was an author and consistently brought this point to the
table (Document ID 3577, Tr. 645).

    NIOSH submitted post-hearing comments on the analysis in Morfeld et
al. (2013). NIOSH pointed out that the exposure measurements in the
analysis were based on German dust samplers, which for pottery have
been shown to collect approximately twice as much dust as U.S.
samplers. Therefore, ``when Dr. Morfeld cited 0.15 mg/m\3\ (150 [mu]g/
m\3\) as the lower 95% confidence limit for the threshold, that would
convert to 0.075 mg/m\3\ (75 [mu]g/m\3\) in terms of equivalent
measurements made with a U.S. sampler'' (Document ID 4233, p. 21).
Similarly, the U.S. equivalent of each of the other threshold estimates
and confidence limits presented in Morfeld et al.'s analysis would be
about half the reported exposure levels. NIOSH also commented that
Morfeld et al.'s analysis appears to be consistent with both threshold
and non-threshold models (Document ID 4233, p. 55). Furthermore, NIOSH
observed that Morfeld et al. did not account for uncertainty in the
values of one of their model parameters ([egr]); therefore their
reported threshold confidence limits of 0.16-0.30 are too narrow
(Document ID 4233, p. 56). More generally, NIOSH noted that Morfeld et
al. did not quantitatively evaluate how uncertainty in exposure
estimates may have impacted the results of the analysis; Morfeld agreed
that he had not performed a ``formal uncertainty analysis'' (Document
ID 4233, p. 58; 3582, Tr. 2078-2079). NIOSH concluded, ``it is our firm
recommendation to discount results based on the model specified in
[Morfeld et al. Eq. 3] . . . including all results related to a
threshold'' (Document ID 4233, p. 58). OSHA has evaluated NIOSH's
comments on the analysis and agrees that the issues raised by NIOSH
raise serious questions about Morfeld et al.'s conclusions regarding a
silica threshold.
    OSHA's greater concern with Dr. Morfeld's estimate of 250 [mu]g/
m\3\ as a threshold concentration for silicosis is the fact that a
substantial proportion of workers with silicosis in Dr. Morfeld's study
had no estimated exposure above the threshold suggested by the authors;
this threshold was characterized by commenters, including the Chamber
of Commerce (Chamber), as a concentration ``below which the lung
responses did not progress to silicosis'' (Document ID 4224, Attachment
1, p. 3). This point was emphasized by Dr. Brian Miller in the Final
Peer Review Report (Document ID 3574, p. 57) and by NIOSH (Document ID
4233, p. 57). In the study, 17.5 percent of workers with silicosis were
classified as having no exposure above Morfeld et al.'s estimated
threshold of 250 [mu]g/m\3\, (Document ID 3843, p. 1031) and 12.5
percent of these workers were classified as having no exposure above
100 [mu]g/m\3\. OSHA believes the presence of these low-exposed workers
with silicosis clearly contradicts the authors' estimate of 250 [mu]g/
m\3\ as a level of exposure below which no worker will develop
silicosis (see Document ID 4233, p. 57).
    In a post-hearing comment, Dr. Morfeld offered a different
interpretation of his results, describing his threshold estimate as a
``population average'' which would not be expected to characterize risk
for all individuals in a population. Rather, according to Dr. Morfeld
``we expect to see differences in response thresholds among subjects''
(Document ID 4003, p. 5). OSHA agrees with this interpretation, which
was similarly expressed in several comments from OSHA's peer reviewers
on the subject of thresholds (e.g., Document ID 3574, pp. 13, 21-22).
Consistent with its peer reviewers' opinions, OSHA draws the conclusion
from the data and discussion concerning population averages that these
``differences in response thresholds among subjects'' support setting
the PEL at 50 [mu]g/m\3\ in order to protect the majority of workers in
the population of employees exposed to respirable crystalline silica.
OSHA's review of the Morfeld et al. data on German porcelain workers
thus reinforces its view that reducing exposures to this level will
benefit the many workers who would develop silicosis at exposure levels
below that of the ``average'' worker.
    Dr. Morfeld's discussion of his estimate as a ``population
average'' among workers with different individual responses to silica
exposure

echoes several comments from OSHA's peer reviewers on the subject of
thresholds. In the Final Peer Review Report, Dr. Ginsberg observed that
a linear exposure-response model may reflect a distribution of
individual ``thresholds,'' such that ``the population can be
characterized as having a distribution of vulnerability. This
distribution may be due to differences in levels of host defenses that
come with differences in age, co-exposure to other chemicals, the
presence of interacting background disease processes, non-chemical
stressors, and a variety of other host factors'' (Document ID 3574, p.
21). Given the number of factors that may influence vulnerability to
certain diseases in a population of workers, Dr. Ginsberg continued:

it is logical for OSHA to strongly consider inter-subject
variability . . . as the reason for linearly-appearing regression
slopes in silica-related non-cancer and cancer studies. This
explanation does not imply an artifact [that is, a false appearance
of linear exposure-response] but that the linear (or log linear)
regression coefficient extending down to low dose reflects the
inherent variability in susceptibility such that the effect of
concern . . . may occur in some individuals at doses well below what
might be a threshold in others (Document ID 3574, pp. 21-22).

    Peer reviewer Mr. Bruce Allen agreed that ``[i]t makes no sense to
discuss a single threshold value . . . Given, then, that thresholds
must be envisioned as a distribution in the population, then there is
substantial population-level risk even at the mean threshold value, and
unacceptably high risk levels at exposures far below the mean
threshold.'' He further stated:

    It is NOT, therefore, inappropriate to model the population-
level observations using a non-threshold model . . . In fact, I
would claim that it is inappropriate to include ANY threshold models
(i.e., those that assume a single threshold value) when modeling
epidemiological data. A non-threshold model for characterizing the
population dose-response behavior is theoretically and practically
the optimal approach (Document ID 3574, p. 13).

    OSHA concludes that this German porcelain workers cohort shows
evidence of silicosis among workers exposed at levels below the
previous PELs, and that continued follow-up of this cohort would be
likely to show greater silicosis risk among low-exposed workers due to
the short follow-up time. Furthermore, the Chamber's characterization
of Dr. Morfeld's result as ``a threshold concentration of 250 [mu]g/
m\3\ below which the lung responses did not progress to silicosis''
(Document ID 4224, p. 3) is plainly inaccurate, as the estimated
exposures of a substantial proportion of the workers with silicosis in
the data set did not exceed this level.
e. Park et al. (2002)
    The ACC submitted comments on the Park et al. (2002, Document ID
0405) study which examined silicosis and lung disease other than cancer
(i.e., NMRD) in a cohort of diatomaceous earth workers. The ACC's
comments on this study are discussed in detail in Section V.D, Comments
and Responses Concerning Silicosis and Non-Malignant Respiratory
Disease Mortality and Morbidity, including comments relating to
exposure-response thresholds in this study. Briefly, the ACC claimed
that the Park et al. (2002) study is ``fully consistent'' with
Morfeld's estimate of a threshold above the 100 [mu]g/m\3\
concentration for NMRD, including silicosis, mortality (Document ID
2307, Attachment A, p. 107). However, NIOSH explained in its post-
hearing brief that categorical analysis for NMRD indicated no threshold
existed at or above a 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 attempt to 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, which indicates
that, if there is a cumulative exposure threshold for NMRD, including
silicosis, it is significantly below the final PEL of 50 [mu]g/m\3\.
f. Conclusion--Silicosis and NMRD
    OSHA concludes that the body of epidemiological literature clearly
demonstrates risk of silicosis and NMRD morbidity and mortality among
workers who have been exposed to cumulative exposures or average
exposure concentrations at or below the levels associated with the
previous general industry PEL (100 [mu]g/m\3\, or cumulative exposure
of 4.5 mg/m\3\-yrs). Thus, OSHA does not agree with commenters who have
stated that the previous general industry PEL is fully protective and
that reducing it will yield no health benefits to silica-exposed
workers (e.g., Document ID 4224, p. 2-5; Tr. 3582, pp. 1951-1963).
Instead, the Agency finds that the evidence is at least as consistent
with a finding that no threshold is discernible as it is with a finding
that a threshold exists at some minimal level of exposure. The best
available evidence also demonstrates silicosis morbidity and mortality
below the previous PEL of 100 [mu]g/m\3\, indicating that any threshold
for silicosis (understood as an exposure level below which no one would
develop disease), if one exists, is below that level. Even if the
conclusion reached by Dr. Morfeld that a population average threshold
exists above the level of the previous PEL is accurate, there will
still be a substantial portion of the population who will develop
silicosis from exposures below the identified ``threshold.'' These
findings support OSHA's action in lowering the PEL to 50 [mu]g/m\3\.
3. Thresholds--Lung Cancer
    OSHA's Preliminary QRA and supplemental literature review included
several studies that provide information on possible threshold effects
for lung cancer. OSHA has determined that the epidemiological studies
most relevant to the threshold issue are those with workers who have
cumulative exposures or average exposure concentrations below the
levels associated with the previous general industry PEL (100 [mu]g/
m\3\, or cumulative exposure of 4.5 mg/m\3\-yrs). As with the silicosis
studies previously discussed, contrary to comments that OSHA only
relied on studies involving exposures far above the levels of interest
to OSHA in this rulemaking (e.g., Document ID 2307, Attachment A, pp.
94-95; 4226, p. 2), a number of lung cancer studies included workers
who were exposed at levels close to or below the previous general
industry PEL. Five of the 10 cohorts of workers in the pooled lung
cancer risk analysis conducted by Steenland et al. (2001a) had median
cumulative exposures below 4.5 mg/m\3\-yrs (the cumulative level
associated with a working lifetime of exposure at the previous general
industry PEL); four were also below 2.25 mg/m\3\-yrs (the cumulative
level associated with a working lifetime of exposure at the revised
PEL) and three had median silica concentrations below 100 [mu]g/m\3\
(Document ID 0452, p. 775). Other lung cancer studies with significant
numbers of relatively low-exposed workers include analyses of the
Vermont granite workers (Attfield and Costello, 2004, Document ID 0285;
Vacek et al., 2011, 1486) and industrial sand workers (McDonald et al.,
2001, Document ID 1091; Hughes et al., 2001, 1060; McDonald et al.,
2005, 1092) described in the previous discussion on silicosis. In
addition to the epidemiological studies discussed here, in Section V.H,
Mechanisms of Silica-Induced Adverse Health Effects, OSHA discussed
studies that have shown direct genotoxic mechanisms by which exposure
to crystalline silica at any level, with no threshold effect, may lead
to lung cancer.

a. Steenland et al. Pooled Lung Cancer Study and Related Analyse