Final Peer Review Report

Evaluation of OSHA’s Disposition of 2009 Reviewer Comments

and

Reviewer Responses to Oral and Written Testimony Presented at OSHA’s
Informal Hearings on the Proposed Rule on Respirable Crystalline Silica,
March 2014

Contract No.  DOLJ129F32859

Task Order 16

Submitted to:

David O’Connor

Directorate of Standards and Guidance

Occupational Safety and Health Administration

200 Constitution Avenue, NW

Washington, DC  20210

Submitted by:

Eastern Research Group, Inc.

110 Hartwell Avenue

Lexington, MA  02421-3136

April 7, 2014TABLE OF CONTENTS

Introduction	1

  HYPERLINK \l "_Toc251578075"  Bruce Allen, Bruce Allen Consulting,
Chapel Hill, NC 	3

  HYPERLINK \l "_Toc251578076"  Kenneth Crump, Louisiana Tech University
Foundation, Inc., Ruston, LA	 15

  HYPERLINK \l "_Toc251578078"  Gary Ginsberg, Connecticut Department of
Public Health, Hartford, CT 	19

  HYPERLINK \l "_Toc251578079"  Brian Miller, IOM Consulting Ltd.,
Scotland, UK 	27

  HYPERLINK \l "_Toc251578080"  Andrew Salmon, Private Consultant,
Lafayette, CA 	33

Introduction

Introduction

In 2009, under contract to OSHA, Eastern Research Group, Inc. (ERG)
coordinated an independent, scientific peer review of two draft
documents prepared by OSHA: 1) Preliminary Health Effects Section for
Silica; and 2) Preliminary Quantitative Risk Assessment for Silica.
These documents were developed by OSHA to provide the Agency with
quantitative information on these risks to support development of a
proposed rule governing exposure to crystalline silica in general
industry, construction, and maritime.

2009 Peer Review Process

ERG conducted a search for nationally recognized experts in occupational
epidemiology, biostatistics and risk assessment, animal and cellular
toxicology, and occupational medicine who had no conflict of interest
(COI) or apparent bias in performing the review. Interested candidates
submitted evidence of their qualifications and responded to detailed COI
questions. ERG also searched the Internet to determine whether qualified
candidates had made public statements or declared a particular bias
regarding silica regulation. From the pool of qualified candidates, ERG
selected seven to conduct the review.

Reviewer	Affiliation	Reviewed Health Effects Section	Reviewed
Quantitative Risk Assessment

Bruce Allen	Bruce Allen Consulting	(	(

Kenneth Crump	Louisiana Tech University Foundation

(

Murray Finkelstein	McMaster University, Ontario	(	(

Gary Ginsberg	Connecticut Department of Public Health	(	(

Brian Miller	IOM Consulting Ltd., Scotland	(	(

Andrew Salmon	Private Consultant	(	(

Noah Seixas	University of Washington, Seattle	(	(

Reviewers were provided with a letter of instruction, the charge, review
documents, and hundreds of relevant references to conduct the review.
The experts submitted their individual written reviews, which were
submitted as received.  ERG also compiled the comments by charge
question in preparation for a follow-up conference call.  ERG
facilitated the call with the reviewers and OSHA, during which reviewers
provided clarifications and  answered any questions OSHA had regarding
their comments.  After the conference call, reviewers submitted their
final peer review comments which were compiled as submitted into ERG’s
final peer review report.

At the close of the peer review, ERG informed the experts that OSHA
would be addressing and incorporating comments received from the peer
review and the public, with the intent of proposing the rule in the fall
of 2009.  At that time, OSHA would hold informal public hearings on the
proposed rule on respirable crystalline silica.  Through its OSHA
contract with ERG, the peer reviewers would be invited to attend the
hearings in Washington, DC, to listen to oral testimony as it applied to
the health effects and quantitative risk assessment sections, read
additional written comments, and provide any additional comments on
scientific issues presented in written or oral testimony at during the
public hearings.  In addition, the reviewers would be asked to read the
revised health effects and quantitative risk assessment sections and the
summary of these sections in the proposed rule, and provide comments to
OSHA on whether they felt that OSHA had or had not adequately addressed
and/or considered their peer review comments when revising the rule, and
to reiterate any concerns or issues that they felt were still
outstanding and should be addressed as OSHA moves forward to finalize
the rule.

2014 Completion of Peer Review

In 2014, under contract to OSHA, ERG completed the last phase of the
peer review of OSHA’s Preliminary Health Effects and Preliminary
Quantitative Risk Assessment sections for Silica, which entailed the
tasks described above.

Of the seven original peer reviewers, five (5) were available to conduct
the pre-hearing work and attend the two days of public hearings in
Washington, DC, on March 19-20, 2014.  The five reviewers included Bruce
Allen, Kenneth Crump, Gary Ginsberg, Brian Miller, and Andrew Salmon.
ERG secured their services and sent them a letter of instruction with
guidance on accessing the written comments in the docket, the revised
sections of the health effects and quantitative risk assessment sections
in the rule, and the summary of same, copies of the oral testifiers’
written comments, and their original peer review comments in preparation
for attending the public hearings and completing the last step of the
peer review.

This report provides the peer reviewers’ comments on the disposition
of their original peer review comments in the proposed rule, as well as
comments peer reviewers provided in response to written and oral
testimony presented at OSHA’s Informal Public Hearings on the Proposed
Rule on Occupation Exposure to Respirable Crystalline Silica on March 19
and 20, 2014, held at the Department of Labor, Washington, DC.  The
appendix consists of the original peer review report from 2009.

Bruce Allen

Bruce Allen Consulting, Chapel Hill, NCFrom: Bruce Allen

Sent: Wednesday, April 02, 2014 7:43 PM

To: Kate Schalk

Subject: RE: OSHA Silica - Final comments

Attachments: Comments on OSHA Docket-2010-0034_Allen.docx

Kate:

My comments are attached.

I have reviewed the original review materials, my 2009 peer review
comments and their disposition by OSHA in the current proposed
rulemaking. I feel that OSHA has adequately addressed my comments in
their updated Health Effects and QRA sections. I have included my
comments on these areas in my attached submission. I have also read the
written testimony of the public commenters and heard their oral
testimony. I have included comments on some of the commenters’
testimony as it applies to the QRA.

Bruce Allen

Comments on Docket OSHA-2010-0034

Submitted by Bruce Allen

April 2, 2014

Response to Peer-Review Comments (2009)

I have read OSHA’s responses to the peer-review comments that were
submitted in 2009.  I am satisfied with the manner in which OSHA
responded to those comments, and particularly to the ones that I
submitted.  I continue to believe that the low-exposure studies by Brown
and Rushton (2005a, 2005b) and Ulm et al. (1999) can be useful, but
probably mostly if a formal meta-analysis were to be conducted.  I am
satisfied that, for the analyses that have been done and reported in the
QRA section, the exclusion of those studies is acceptable.

Observations and Responses Related to Written and Oral Testimony

The following comments are provided in response to the public comments
that were submitted to the docket and which were espoused in oral
testimony on March 19-20, 2014.  The following comments are organized by
discussion point rather than specific written or oral testimony.  Many
of the discussion points were raised by various commenters; I have
attempted to cite as many of them as possible.

Declining Silicosis Mortality

The submission, 01_OSHA-2010-0034-DRAFT-3708_Borak.pdf, has a graph of
declining silicosis mortality (Figure 1, and see below).  The written
testimony makes it clear that there are two possible contributors to
that decline, reduced exposure and declining number of exposed
individuals.  However, during oral testimony, no mention was made of the
decline in the exposed population; the graphic was proposed to show the
effect of reduced exposure levels associated with “historic
implementation” of OSHA and MSHA PELs.

The fact that this graph in no way adjusts for the declining employment
in jobs with silica exposures makes its interpretation problematic.  To
emphasize the contribution of historical declines in exposure as the
underlying cause is spurious; no information is given to allow one to
account for declining employment.  Moreover, the scale for death rate
(right-hand vertical axis) is misleading insofar as it falsely gives the
impression that the rate of silicosis deaths among exposed workers has
declined to about 1 per million.  That rate is for the entire US
population, unexposed predominantly, not for the workers who are the
population of concern with respect to OSHA regulations.

Figure 1: Silicosis: Number of deaths, crude and age-adjusted death
rates, US residents age 15 and over, 1968-2004 (Source: (2))

Thresholds

The issue of thresholds in dose-response modeling and risk assessment is
a contentious one.  On the one hand, biologists and toxicologists often
assume that thresholds for toxic responses exist, based on arguments
that “a single molecule” of a substance would not be enough to
trigger such responses.  On the other hand, it is essentially impossible
to distinguish between dose-response patterns that represent a threshold
and those that do not.  Any observations that are consistent with no
dose-related change in response are also consistent with a slight,
nonzero dose-related change.

Several written and oral testimonies discussed the potential existence
and effect of thresholds for either silicosis or lung cancer (see
03_OSHA-2010-0034-2230_Long-Valberg.pdf,
08_OSHA-2010-0034-2307_attachment6_Cox.pdf, and associated oral
testimony from Drs. Valberg and Cox, among others).  The common theme of
these testimonies was that there is a threshold for silica-related
health effects and that the modeling by OSHA, which did not include a
threshold parameter, was therefore flawed.

During the oral testimony, when asked about the assumption that a
proposed threshold was constant across individuals, several of the
presenters acknowledged that such a threshold would vary in a
population; even if the concept of a threshold is accepted, then not all
individuals would have the same threshold for response.  When
considering a diverse population with variations in exposures to various
substances, physiological states, and genetics, it makes little sense to
suppose that every individual would be identical with respect to a
threshold exposure level.

Yet, in the written testimony and throughout the oral testimony, the
presenters continued to refer to “a threshold” as if such a
non-varying entity existed (see, for example,
03_OSHA-2010-0034-2230_Long-Valberg.pdf, Figure 2).  The claim was made
that models without a threshold could not “reveal threshold
concentrations” (03_OSHA-2010-0034-2230_Long-Valberg.pdf, p. 20).

My following response suggests that the critiques in those testimonies
are misguided at best.  Let us take silicosis morbidity as an example.
And let us assume that the dose-response relationship, for individual j
in a population, is given by

			P(d) 	= 0				if d < th(j)

				= 1-exp(-beta*(d-th(j)))		if d > th(j)			Eq. 1

where P(d) is the lifetime probability of silicosis morbidity, d is the
exposure level, th(j) is the exposure threshold for that individual, and
beta is a parameter to be estimated.  Once the idea of a varying
threshold value (individual th(j) values, for all individuals in the
population), then one must consider a distribution of such thresholds.
For this example we assume the distribution is lognormal with some
specified mean and variance.  One could even assume that there is some
absolute value above which all the individual thresholds must fall
(analogous to frequently heard arguments that “a single molecule” of
a substance would not cause a toxic response in any individual).  Thus,
the distribution of thresholds could be characterized as

			[th(j) – α] ~ LN(μ, σ2)

where α is that absolute minimum for any individual threshold, and
LN(μ, σ2) represents a lognormal distribution with mean μ and
variance σ2.  From these assumptions, we can derive what the population
level (frequency of response) pattern would be.

To complete this example, let us set some specific values for the
distribution of thresholds.  Let us make this correspond to the claims
made by various presenters that there was no evidence of increased
response (and therefore a “threshold”) at 100 μg/m3.  Since we must
admit varying thresholds, let us make the mean of the distribution equal
to 100.  If we let α= 5 (arbitrary small value) then the mean of th(j)
is actually 105.  Let the GSD be 1.5 (only 50% variation in the
threshold distribution, which corresponds to a log-scale variance of
0.16).  The resulting distribution of thresholds is shown here:

Note that the individual thresholds can be quite large (above 100
μg/m3) but all are greater than or equal to 5 μg/m3.

To complete the example, let the estimate of beta be such that, at 500
μg/m3, the risk of silicosis morbidity is the smallest of the values
presented in Table VI-2 of the Proposed Rules published in the Federal
Register (Vol. 58, No. 177, p. 56321), which is 626 per 1000 workers.
That value is chosen because the presenters expressed no concerns about
estimates of risk for such high exposure levels, and because it is the
lowest (leading to least protective) value for silicosis morbidity
presented by OSHA for that exposure level.  Given the values of the
other parameters, a beta value of 0.0025 (per μg/m3) achieves that
match.  The following graph shows the resulting population-level dose
response curve:

If we focus on the lower end of the dose and response curve, we observe
the following:

Even with a mean threshold at 100 μg/m3, the predicted response rate at
50 μg/m3 is 0.6 per 1000.  The 1 per thousand risk level is exceeded at
54 μg/m3.  The expected frequency of response at 100 μg/m3 is 32 per
1000 workers.

The major points illustrated by this example are as follows:

It 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.

It is NOT, therefore, inappropriate to model the population-level
observations using a non-threshold model.  The population-level
dose-response curves shown in the previous two graphs do NOT have a
threshold (except at a meaninglessly small exposure level; here, for
example, at 5 μg/m3).  Since such small exposure levels are not
included in the epidemiological data used for modeling, such vanishingly
small thresholds can be ignored when fitting models to aggregated
dose-response data.  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 population dose-response behavior is theoretically and
practically the optimal approach.

One additional set of comments about thresholds and their detection is
warranted.  Several presenters claimed there was a clear “threshold”
evidenced in the dose-response pattern estimated by Steenland et al.
(2001) (their Figure 1, and Figure 3 in
03_OSHA-2010-0034-2230_Long-Valberg.pdf, p. 21).  It is well known that
presenting the x-axis (dose) on a log-scale enhances the visual
appearance of threshold-like behavior.  The presenters made no attempt
to go beyond visual examination, and therefore misconstrue the results.

Fallacious Analogies by Dr. Cox

The written and oral testimonies by Dr. Cox are replete with
misrepresentations of various aspects of OSHA’s risk assessment.  I
will make note of several of them here.  They reflect poorly on his
reliability as an expert suited to comment on, let alone conduct, a
meaningful risk assessment.

First, consider his use of the phone vs. CHD mortality plot (Figure 1 of
his written testimony).  While no one would suggest that per capita
phone ownership is causally linked to CHD mortality, the association is
still not without value.  The plot shows results for 15 countries.  If a
per capita phone data point was found for a 16th county, I contend that
it would still be appropriate to use the graph in his Figure 1 to
predict CHD mortality in that country (in the absence of better, causal
data).

His rejoinder is that if you changed the phone ownership in one of those
countries, you would not expect the CHD mortality to change in that
country.  True.  But that is not analogous to the situation faced by
workers exposed to silica.  The observational units in the phone example
are countries; the observational units in a silica exposed population
are the individual workers.  Unlike with the countries, where phone
ownership could be changed and the effect on the CHD mortality in that
country could be monitored, the workers exposed to silica cannot be
tracked, even with a change in exposure levels,  for changes from dead
to alive, or silicosis-diseased to disease-free.  Unfortunately for
them, the response variable is not “changeable” from the state of
having the adverse event (death or silicosis) to a state of being
without such an event.

In fact, that is the problem with Dr. Cox’s entire argument in favor
of causal analysis over standard dose-response modeling.  There is no
identifiable “change” that can be tracked in the observation units
following a change in the exposure conditions.  The effects of previous
exposures are not separable from those of the changed (presumably lower)
exposure conditions.  Therefore his entire criticism of the standard
dose-response approach is erroneous.  We are trying to predict the
effects of various exposure scenarios on hypothetical, future workers
who would spend their working lives under new exposure conditions.  The
best basis for doing that is to examine what has occurred in workers
exposed to historical levels, and use model-based extrapolations as
needed to predict what would happen under revised circumstances.  I.e.,
one is not predicting what would happen to the observational units if
exposure changed, but rather predict what would happen to new
observational units under different (lower) exposure conditions.

In the case of silica and its associated diseases, the extrapolation
mentioned above is not that far below what has occurred historically.
Dr. Borak, in his oral testimony, acknowledged that so-called
“over-exposures” in the range of 120 to 480 μg/m3 – i.e., not
that much greater than the proposed PEL – do pose health hazards.  And
those acknowledged hazardous levels were more likely than not determined
to be hazardous based on durations of exposure less than, often much
less than, the assumed OSHA scenario of 45 years of exposure.  I saw no
recognition on the part of the Chamber-of-Commerce- or ACC-sponsored
presenters that the demonstrated hazards occurred usually with exposure
durations less than the rule-based 45 years.

Another fallacious analogy presented by Dr. Cox relates to Figure 2 of
his written testimony.  He states that linear modeling of absolute risk
gives spurious associations even when the relationship between the x and
y variables is random.  In his oral testimony, he further clarified that
that result was achieved by fixing the intercept to be zero
(constraining the model to pass through the origin).  The problem is
that this misrepresents the process of the risk assessments that OSHA
has done.

No modeling, linear or otherwise, for silica-related health effects has
been done on risk per se.  The modeling was performed with probability
of response or relative risk as the effect.  Neither of those effect
measures should be (or were, to my knowledge) constrained to pass
through the origin; it would be ridiculous to do so, especially for
relative risk, which should be at or around 1 for zero exposure.  It is
only by computation from more fundamental relationships that one
estimates absolute risk: from relative risk one computes lifetime
probability of response using life tables; from lifetime probability of
response one computes risk by subtracting the prediction for 0 exposure
from the probability for the dose of interest.  The fact that the
absolute risk curve passes through the origin is a (necessary)
by-product of those computations, regardless of assumptions about or
estimates of the background relative risk or probability of response.

Therefore, his claims about model misspecification (top of p. 21 of his
written testimony) simply do not apply.  The “linear absolute risk
model” he proposes as misspecified is a fiction.  It is therefore
inappropriate on that basis to claim, as Dr. Cox does, that this has
resulted in a false positive association between silica exposure and
silicosis or lung cancer.

Related to that mistake are claims that Dr. Cox makes about apparent
positive associations being more generally erroneous.  He cites an
article by Dr. Ioannidis and claims that it shows that most published
research findings are wrong.  An examination of that manuscript reveals
that under certain circumstances, the predictions of Dr. Ioannidis,
which are model-based rather than empirical, of the likelihood of a
correct finding can reach or exceed 80%.  Dr. Cox has done no analysis
to suggest where the silica studies fall with respect to the variables
used to estimate the proportion of correct results.  Apparently Dr. Cox
prefers to just use the spector of a false result as a scare tactic
rather than doing an investigation that would put the silica data base
in the correct context with respect to its predicted likelihood of a
true or a false result.

One last issue relates to the claim made by that Dr. Cox that a Monte
Carlo analysis of exposure uncertainty is inappropriate and is just
repeating the same mistake many times over.  His claim is that only by
using an errors-in-variables approach can one correctly characterize the
effect of uncertainty in the exposure metrics.  In that approach, the
independent variable(s) are assume to have an error structure and this
is factored directly into the analyses and parameter estimates.  In
contrast, I contend that the Monte Carlo approach that OSHA has used is
analogous to a parametric bootstrap analysis.  That is, rather than
specifying the error structure for the independent variables and
analytically solving for model parameter estimates and corresponding
confidence intervals (a classical statistical approach),  the bootstrap
approach relies on sampling observations (in this case independent
variable values via Monte Carlo sampling) and characterizing the
uncertainty via the resulting distribution of estimates.  In both
approaches, a good representation of the structure of the variance
(uncertainty) is required.  But given that, I see no reason why the
Monte Carlo approach would be less satisfactory than the analytical
approach.  It may in fact be advantageous especially if analytical
solutions are difficult to obtain or require assumptions that are
inappropriate for the data under consideration.

  HYPERLINK \l "_Toc251578066"  Kenny Crump

Private Consultant, Ruston, LA  Final Peer Review Comments on OSHA’s
Health Effects Analysis and Quantitative Risk Assessment for Crystalline
Silica

Kenny Crump

March 2014

Comments on OSHA’s response to my comments made in 2009 on the earlier
draft of OSHA’s Quantitative Risk Assessment

I believe that my comments have been fairly taken into account in the
current draft and I have no further comments to make.

Comments based on listening to testimony presented during March 19-20,
2014 at the OSHA Hearings

OSHA, in its Preliminary Quantitative Risk Assessment (OSHA 2014),
stated that "available information cannot firmly establish a threshold
exposure for silica-related effects." At the OSHA Hearings “For the
Proposed Rule on Occupational Exposure to Respirable Crystalline Silica
Hearings” March 19 – April 4, 2014, a number of commenters
recommended that OSHA reevaluate this conclusion.  E.g., Dr. Jonathan
Borak stated “OSHA has failed to adequately consider the evidence of a
threshold response function for silicosis and silica-related lung
cancer” and Dr. Peter Valberg stated that “there is a need for OSHA
to carefully test whether the available epidemiologic data allow for the
identification of a threshold.”

However, OSHA is on very solid ground in the statement that "available
information cannot firmly establish a threshold exposure for
silica-related effects."  In fact, in response to Dr. Valberg’s
suggestion, data (and particularly epidemiologic data) can never allow
one to conclude that a threshold has been identified, not just for
silica effects on lung cancer or silicosis but for any effect of any
contaminant.  Scientific data never permit the conclusion that a
threshold has been identified.  (Any data set is consistent with a
different response at a particular dose than the background response.)
Thus, 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.  (If
a response is confirmed at a particular dose, there could always be a
threshold at a lower dose.).  The scientific method has been described
as posing falsifiable hypotheses and using data to test those
hypotheses.  Thus, accordingly, an attempt to distinguish between
threshold and non-threshold dose responses is not even a scientific
exercise (Crump 2011).  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.

Nevertheless, it has been claimed that some dose response analyses
appearing in the OSHA docket have statistically identified a threshold.
To illustrate the fallacy of these claims I will consider an analysis
that is in the OSHA docket and has been published in the peer reviewed
literature.  From fitting a threshold dose response model to data from
an epidemiological study of quartz dust exposure and silicosis
incidence, Morfeld et al. (2013) concluded that their analysis
“indicates a respirable quartz dust exposure … concentration
threshold … possibly as high as 0.25 mg/m3,” which was the threshold
estimate obtained from the model that provided the smallest AIC out of
several alternative threshold models applied.  The Morfeld et al. (2013)
modelling approach was quite elegant and involved defining a threshold
in terms of concentration in air but assuming that silicosis incidence
was a function of the resulting (possibly lagged) cumulative exposure.
At OSHA’s public hearing to gather information to assist in revising
the exposure standard, a number of presenters recommended that OSHA use
the Morfeld et al. results, or a similar threshold modelling exercise,
to set an occupational standard for quartz dust exposure (OSHA, 2014).

 However, the Morfeld et al. threshold modeling effort suffers from the
same limitation that all such attempts statistically to estimate a
threshold must – the results are not reliable because the threshold
estimates so obtained are highly unstable.  In fact, it is easy to see
that there is always a dose response model that has no threshold which
will fit the underlying data essentially as well as a particular
threshold model.  For example, one can always simply add a linear
exposure term (or any one of many other non-threshold exposure terms) to
the threshold model, and by making the size of the linear term
sufficiently small (i.e., making the exposure coefficient sufficiently
small but greater than zero), make the modified model virtually
indistinguishable from the original model.  However the modified model
will have no threshold and consequently will predict a positive risk at
every exposure.

To make this argument specific to the Morfeld et al. analysis, the
Morfeld threshold model for relative risk can be written as (using their
terminology)

  otherwise.  However, it is clear that the slightly modified model,

 , could even be larger than OSHA would deem allowable.  Consequently
the threshold identified by Morfeld et al. is model dependent in the
extreme and consequently should not be used by OSHA to set an exposure
standard.   Of course there is nothing necessary about the specific
modification I have made to the Morfeld et al. model as many other
modifications could be made that would lead to the same conclusion.
Similarly there is nothing specific to the Morfeld et al. model in this
argument, as a similar conclusion could be reached for any other
threshold estimate obtained by fitting a threshold model to
dose-response data.

References

Crump KS. 2011. Use of Threshold and Mode of Action in Risk Assessment.
Critical Reviews in Toxicology 41(8): 637–50.

Morfeld P, Mundt KA, Taeger D, Guldner K, Steinig O, Miller BG.  2013.
Exposure and Silicosis Incidence among Workers in the German Porcelain
Industry, JOEM 55(9): 1027-1034.

OSHA (Occupational Safety and Health Administration) 2014.  Health
Effects Analysis and Quantitative Risk Assessment for Crystalline
Silica.  Docket OSHA-2012-0030, Room N-2625, U.S. Department of Labor,
200 Constitution Avenue, NW., Washington, DC 20210.

  HYPERLINK \l "_Toc251578067"  Gary Ginsberg

Private Consultant, Hartford, CT

Comments of Gary Ginsberg, Ph.D.

On The

Revised (2013) OSHA Silica Health Effects Review and Quantitative Risk
Assessment

Docket: OSHA 2010-0034

March 27, 2014

I have reviewed my comments from 2009 in relation to the original draft
Silica Health Effects and QRA documents prepared by OSHA and have
reviewed the OSHA response.  Further I have reviewed the updated OSHA
health effects and QRA synthesis available in docket OSHA 2010-0034 and
have read submissions to the document and heard testimony during the
March 19 & 20th hearings.  Outstanding issues with respect to my initial
comments remain in the areas of addressing the potential for a threshold
and on the potential for underestimation of silicosis rate based upon
radiographic evidence.  Regarding the underestimation of silicosis from
radiographic evidence, OSHA’s response was to view that as a
qualitative “significance of risk” issue.  I understand that OSHA
must make its determinations based upon the available data and that
there is no way to estimate across the breadth of epidemiological
literature on this subject the amount of silicosis that goes
undiagnosed.  However, OSHA should consider this potential
underestimation of cases as a significant uncertainty in its
quantitative risk assessment.  Thus in addition to the potential
influence of measurement error, as discussed extensively at the
hearings, diagnostic error may have also influenced non-cancer dose
response and estimation of risk.

Analysis of Potential for a Threshold in Silica-Related Cancer,
Morbidity and Mortality

Regarding my second concern, there is a natural question as to whether a
threshold exists in the silica dose response, especially  for noncancer
endpoints.  Non-cancer endpoints are often conceived of as having a
threshold below which exposure is not expected to create a tangible
risk.   A number of commenters during the March 19-20th hearing
questioned the linear approach for both cancer and non-cancer endpoints
and urged OSHA to consider modeling forms that include the possibility
of threshold.  Some of their comments relative to measurement error
tending to blur a threshold and thus lead to statistically significant
coefficients in linear or log-linear regressions (Drs. Cox and Long)
have some merit.  OSHA may want to acknowledge this point but also
recognize that measurement error can also weaken associations and
decrease the significance of regression coefficients such that those
studies in which the regression coefficients are significant may be
because they had less measurement error (or other confounders) or in
which the dose response is strong enough to overcome the hurdle of
measurement error.  OSHA may also want to acknowledge that a
statistically significant linear regression coefficient  may come about
for three other reasons which have nothing to do with measurement error:
 1) there is no threshold for the toxic mechanism as it involves direct
attack on cellular protein, lipid or DNA such that there is a finite
probability of adverse consequence on the biomolecular level that has
the potential to propagate through amplification phenomena (e.g.,
secondary messengers and altered gene expression at the level of hormone
receptors and oxidant signaling to clonal growth of initiated cells at
the level of DNA mutation).  This type of mechanism is usually
considered most plausible for direct-acting carcinogens and although it
may also be possible for other types of agents, the general belief is
that cellular defenses, homeostatic mechanisms, biological redundancy
(e.g., numerous receptors or enzymes that do the same thing) and tissue
repair generally act to create a threshold for the adverse effect.  2)
there is a threshold but it is below the dose levels tested.  In this
case, the linear-appearing regression reflects the fact that the
exposure is capable of producing the effect through the range of
observation.  3) there is a threshold at the individual level but each
individual has their own threshold 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.  For example, of
relevance to silica is that obesity is a systemic inflammatory state
which has been demonstrated to cause exaggerated responses to inhaled
particulate matter and ozone in rats (Moon et al. 2014) and humans
(Mancuso 2010).  Additionally, pre-existing respiratory disease  such as
emphysema, chronic bronchitis, COPD or asthma may theoretically enhance
the crystalline silica effect as these are lung inflammatory conditions
to which silica-induced inflammation would be additive.  Even if these
diseases are not clinically present but the pre-clinical condition is
(lung diseases are understood to be a gradual process that have various
stages), this may create increased vulnerability and caused a greater
number of individuals to be higher risk on the population level.  The
National Academy of Sciences report Science and Decisions (NAS 2009)
describes these concepts and their relevance to dose response assessment
of non-cancer endpoints, particularly with respect to the lack of
threshold at exposure levels in population studies.  Given the multiple
sources of vulnerability that may exist in a population of workers
(including smoking which was often poorly controlled for in silica
studies) it is logical for OSHA to strongly consider inter-subject
variability in vulnerability (the third alternative to the explanation
of measurement error) as the reason for linearly-appearing regression
slopes in silica-related non-cancer and cancer studies.  This
explanation does not imply an artifact 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
(e.g., silica-induced cancer, silicosis or other non-malignant diseases)
may occur in some individuals at doses well below what might be a
threshold in others.  This biological variability is important to
consider in criteria development and use of a population regression
coefficient avoids the use of NOAELs and somewhat arbitrary uncertainty
factors.

There are other reasons to decrease emphasis on the measurement error
explanation for linear-appearing dose response for silica.  A
cornerstone of the measurement error hypothesis is the Brauer et al.
2002 demonstration that error in particulate matter (PM) measurements
are capable of washing out a built in threshold in PM dose response for
mortality.  Brauer et al. took personal monitoring measurements for 16
individuals for both particulate matter and sulphate and compared these
measurements to pollution measurements at regional monitors.  The PM
measurement error was large when relying on central monitoring locations
indicating that local and personal factors play a large role in the
value obtained.  Brauer et al (2002) then go on to demonstrate that the
degree of measurement error in their PM data was sufficient to smooth
out the dose response and obscure a threshold they had built into their
dose response model for PM-induced mortality.    Rhomberg et al. (2011)
reviewed the cases of PM, nitrogen oxide and ozone measurement
variability with respect to obscuring thresholds in air pollution
epidemiology studies.  Dr. Long who testified at the silica hearings
about measurement error was co-author on this review and mentioned this
paper in his testimony.  The Rhomberg review points out the importance
of indoor/outdoor difference in pollutant measures that could create
considerable measurement error when basing personal exposure on central
monitors, given the amount of time people spend indoors.  While there
may be numerous sources of measurement error in silica workplaces, the
source of error focused upon by Rhomberg et al (2011) – indoor/outdoor
differences, would not apply.  But beyond this, Rhomberg et al (2011) do
not consider the example of sulphate pollution even though this is a key
part of the Brauer et al. (2002) study.  In contrast to the particulate
matter results, sulphate measures from personal monitors correlated
quite well with central outdoor air monitors across the 16 subjects.
This led Brauer et al. to demonstrate that given the small measurement
error for sulphate it is easy to show a threshold in population studies
should one exist (they simulated 3 different thresholds, each reliably
reproduced for sulphate when the sulphate measurement error was built
into the model).  This suggests that unlike PM, measurement error should
not substantially mask population thresholds for sulphate or sulphur
dioxide, which total sulphate is a surrogate measure for.  Looking back
at the population dose response for sulphate -related mortality  relied
upon by Brauer et al. (2002) (WHO 1999), and an update of that in WHO
2006, it is clear that many sulphate population studies are associated
with linear-appearing dose response.  The author of the sulphur dioxide
chapter of the WHO 2006 report, Dr. Morton Lippman synthesized the
sulphur dioxide evidence by saying that: “As with ozone and PM, no
obvious threshold levels have so far been identified in these
population-based studies. “  According to the Brauer et al. 2002
analysis, measurement error is unlikely to explain the lack of threshold
for sulphur dioxide increased mortality in the population studies
reviewed by Lippman.  The sulphate example makes the case that other
factors besides measurement error can cause a linear dose response down
to low dose in population studies for inhaled irritants.  These other
factors (e.g., inter-human variability) are summarized above for the
general case.

With respect to the body of silica epidemiology literature, perhaps the
case with the least amount of measurement error is of US industrial sand
workers wherein many measurements were made with filter samples and XRD
determination of crystalline silica and in which there was very careful
estimation of historical exposure for both silica and smoking (Macdonald
et al. 2005; Steenland and Sanderson 2001; Hughes et al. 2001).  In
categorical analysis these studies demonstrated what appears to be a
monotonic dose response (increasing odds ratio with increasing category
of exposure) for silicosis and what might reflect a threshold for lung
cancer as the two lowest categories of exposure had similar cancer odds
ratio which then became significantly elevated along a dose response
pattern at higher doses (MacDonald et al. 2005).  If the lung cancer
data does evidence a threshold, it was thru the >300-<1,100 ug/m3-yrs
group, which is well below the current OSHA PEL (100 ug/m3 for 45 years
is 4,500 ug/m3-yrs).  In fact, the dose category in which the cancer
risk became elevated (OR= 2.24) was still below the current PEL
equivalent (>1,100 – 3,300 ug/m3-yrs).

Beyond air pollutants, there are numerous examples of population studies
in which linear slopes occur down to low levels of exposure without
evidence of threshold.  In many of these cases measurement error is
unlikely to explain the lack of threshold since the index of exposure is
biomonitoring data.  Examples include linear appearing slopes for
arsenic-induced cancer and non-cancer effects in relation to urinary
inorganic arsenic (NAS, 2013),  for mercury-induced neurodevelopmental
deficits in relation to maternal hair mercury (USEPA, 2001, NAS, 2000)
which has been modelled as a linear relationship by Axelrad et al.
(2007), cadmium-induced decline in GFR which has been found to have
significant linear regression to low levels of urinary cadmium (Akesson
et al 2005) and lead-induced neurodevelopmental deficits in relation to
childhood blood lead (Bellinger 2008).  In the last case, the lack of a
demonstrable threshold has caused USEPA to not develop a threshold type
toxicity target (reference dose or RfD) for lead.

It may be argued that there is still some error in the biomonitoring or
XRD silica results and that epidemiology studies will always have issues
of exposure misclassification or other types of error that may create
uncertainty when it comes to model specification.  However, these types
of error will also bias correlations to the null such that if they were
sufficiently influential to obscure a threshold they may also
substantially weaken regression results and underestimate the true risk.
  Further, the arguments for measurement error as the explanation have
not considered the influence that inter-subject variability in response
can have on the lack of a threshold at the population level as discussed
above and highlighted in NAS’s Science and Decisions (NAS 2009).

Animal evidence for thresholds in silica response is also important to
consider to the extent that such data exist.  Perhaps the most relevant
study is from Kuempel et al. (2001) in which a constant dose of silica
(15 mg/m3) was delivered to rats by inhalation 6 hrs/day, 5 days per
week for varying lengths of time.  Even though only one dose level was
applied, this represents a dose-response study in terms of silica lung
loading relative to the emergence of initial (inflammation) and
secondary (fibrotic) lung damage.  While OSHA already describes this
study, its importance to the threshold concept may merit additional
discussion in a revised OSHA document.

The critical loading of lung tissue with quartz required for PMN
infiltration and impairment of macrophage clearance in this study was
0.39 mg silica/g lung.  Kuempel et al. (2001) considered this to be a
threshold for silica-induced inflammation in their animal model system
although the actual data did not exhibit a threshold for PMN
infiltration (lowest dose used was a LOAEL) and the critical loading
dose was an extrapolation from a toxicodynamic model.   Taking this
reported threshold loading dose at face value leads to a threshold
inhaled dose of 0.036 mg/m3 for a 45 year occupational span of exposure.
 Kuempel et al. (2001) recognized that this critical loading value is
variable such that some workers may be more sensitive and estimated the
lower 95% confidence limit on the critical threshold dose as 0.049 mg
quartz/g lung which corresponds to an inhaled concentration for 45 years
of 0.005 mg/m3 (Kuempel et al. 2001).   In a followup analysis this same
research group recognized that the toxicokinetics of inhaled quartz will
vary across humans particularly with regard to lung clearance rates and
estimated a 2.5 fold variability in silica loading (95th% to median) for
a given inhaled concentration (Kuempel et al. 2001b).  Thus 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
OSHA PEL and that in those who are more sensitive either because of
toxicokinetic or toxicodynamic factors (or both), the threshold may be
an order of magnitude or more below the PEL.  In terms of what this
threshold represents (inflammatory response), Kuempel et al. (2001)
projected this threshold loading out to cancer risk based upon a
combination of rat and human silica cancer data.  While more data
describing thresholds in rats and humans for various silica-related
outcomes would be helpful, the little direct evidence that does exist
suggests that the threshold for the initial stages of lung pathology
(inflammation, disruption of macrophage function) may occur below the
current PEL.

In summary, OSHA may consider incorporating a section on Model
Specification for Low Dose Extrapolation that explicitly describes the
choices relative to the threshold concept for the silica dose response
dataset.  This section could include discussion of 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.

High Dose Saturation of Response

Several studies (e.g., Park et al. 2002, diatomaceous earth workers, Lui
et al 2013, Chinese pottery workers and miners; Vacek et al. 2013,
Vermont granite workers) found evidence of silica effect at lower doses
but response at high dose was attenuated in some manner.  OSHA can
consider pulling such studies into a section that describes this type of
non-linearity, the reasons why it appears repeatedly in the silica
literature, and the modeling approaches to address it.  Measurement
error may be considered as a key reason for this apparent saturation of
effect as the highest doses in these studies are associated with the
oldest datasets in which there was the greatest opportunity for
measurement error (inexact job descriptions and work histories, older
methods of silica measurement).  Another possibility is that at high
dose various intercurrent causes of mortality related to silica exposure
are more likely to eliminate subjects before completing the latency
period for cancer than at lower dose.   Other explanations put forward
by various authors (e.g., healthy worker/survivor effect) may also be
described.  The value of this section is that it would more clearly
describe the statistical and biological rationale for either excluding
high exposure groups or using log conversions of the data.  The current
OSHA draft mentions the high dose problem in the data and exclusion of
some data without complete explanation.

IARC 2012 Monograph

The current OSHA document describes the IARC 1997 review of crystalline
silica.  The updated IARC review should be highlighted particularly with
respect to its reliance on the numerous meta-analyses and their
consistent showing of a cancer risk.  Further, IARC 2012 can be cited
for mechanism of action information and for data regarding the
requirement (or lack thereof) of silicosis for the induction of
silica-related lung cancer.  Along these lines, the Lui et al. 2013
study should also be highlighted.

References not cited in the OSHA 2013 Draft Document

Axelrad DA, Bellinger DC, Ryan LM, Woodruff TJ. 2007. Dose-response
relationship of prenatal mercury exposure and IQ: an integrative
analysis of epidemiologic data. Environ Health Perspect. 115(4):609-15.

Bellinger DC. 2008. Very low lead exposures and children's
neurodevelopment. Curr Opin Pediatr. 20(2):172-177.

Brauer M, Brumm J, Vedal S, Petkau AJ. 2002. Exposure misclassification
and threshold concentrations in time series analyses of air pollution
health effects. Risk Anal. 22(6):1183-93.

Kuempel ED, Tran CL, Smith RJ, Bailer AJ. 2001b. A biomathematical model
of particle clearance and retention in the lungs of coal miners. II.
Evaluation of variability and uncertainty. Regul Toxicol Pharmacol.
34(1):88-101.

Mancuso P. 2010. Obesity and lung inflammation. J Appl Physiol
108(3):722-8.

Moon KY(1), Park MK, Leikauf GD, Park CS, Jang AS. 2014. Diesel Exhaust
Particle-Induced Airway Responses are Augmented in Obese Rats.  Int J
Toxicol. 33(1):21-28.

NAS 2000.  The Toxicological Effects of Methyl Mercury.  National
Academy Press, Washington, DC.

NAS (National Acad Science) 2009.  Science and Decisions.  Advancing
Risk Assessment.  National Academy Press, Washington DC.

NAS 2013. Critical Aspects of EPA’s IRIS Assessment of Inorganic
Arsenic.  Interim Report.  National Academy Press, Washington DC.

Rhomberg LR, Chandalia JK, Long CM, Goodman JE.  2011. Measurement error
in environmental epidemiology and the shape of exposure-response curves.
 Crit Rev Toxicol. 41(8):651-71.

USEPA 2001.  IRIS Profile for Methyl Mercury.  Available at:   HYPERLINK
"http://www.epa.gov/iris/subst/0073.htm"
http://www.epa.gov/iris/subst/0073.htm

WHO (World Health Org) 1999. Air Quality Guidelines.

WHO 2006. Air quality guidelines: global update 2005: particulate
matter, ozone, nitrogen dioxide, and sulfur dioxide. Copenhagen,
Denmark; World Health Organization, 2006, pg 395.

  HYPERLINK \l "_Toc251578068"  Brian Miller

IOM Consulting Ltd., Scotland, UK From: Brian G Miller

Sent: Tuesday, April 01, 2014 10:11 AM

To: Kate Schalk;

Subject: RE: OSHA Silica - Reminder - Final comments due no later than
Wed, April 2nd

Dear Kate

I have reviewed the original review materials, my 2009 peer review
comments and their disposition by OSHA in the current proposed
rulemaking.  I feel that OSHA has adequately addressed my comments in
their updated Health Effects and QRA sections.  I have included one
correction in my attached submission.  I have also read the written
testimony of the public commenters and heard their oral testimony.  I
have included comments on some of the commenters’ testimony as it
applies to the strength of the evidence for causality and/or effects at
exposures to low concentrations.

Best wishes

Brian Miller

Principal Epidemiologist

Institute of Occupational Medicine

Research Avenue North

Riccarton

Edinburgh

EH14 4AP

Web:   HYPERLINK "http://www.iom-world.org"  http://www.iom-world.org

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Brian Miller - Comments on Docket OSHA-2010-0034

Comments on Docket OSHA-2010-0034

I am satisfied that my comments on the 2009 drafts were taken on board
in the redraft.

On P321, last paragraph, the sentence ‘Normal radiographs are
categorized as 0/-.’ is both incorrect and superfluous, and should be
deleted.  It may be that other parts of this paragraph are made
redundant by the more detailed descriptions above.

General comments

During the testimony, it was good to see that both industry and others
expressed the need to avoid exposures that would lead to health risks.

Industry made strong representations on a number of points that, in
their view, implied that a reduction in the PEL is unnecessary,
unwarranted on the available evidence and/or unachievable. I have no
opinion on achievability, but have comments on other aspects.

Much was made of the paucity of evidence on lung cancer risks at
concentrations at or below the proposed PEL, and it is hard to disagree
with that assessment.  In addition, there was discussion of whether
silicosis is a prerequisite for increased lung cancer risk. I consider
this issue unanswerable, given that we cannot investigate for early
fibrotic lesions in the living, but must rely on radiographs.  However,
there is no doubt that silica is causal for silicosis, and regulating to
eliminate that disease is the sensible starting point.  It is to be
expected that reducing exposure to that end will have side-benefits in
reducing cancer risks.

That expectation is predicated on a belief that silica exposure is
causal for cancer.  The testimony of Dr LA Cox emphasised strongly that
association does not necessarily imply causality, and illustrated this
with some trite (and irrelevant) pathological examples.  He also listed
a series of potential biases that could affect epidemiological studies
if not adjusted for.  However, in epidemiology we are often limited to
observational studies from which associations of health outcomes with
prior exposures are observed and quantified.  Some of the studies on
which OSHA relies are not simply cross-sectional, but show responses to
changing patterns of exposure.  This brings much greater assurance that
causality is at work.  When challenged on the issue of causality in
silicosis, Dr Cox accepted that silica was causal, but questioned
whether there was evidence for increased risks at low concentrations;
i.e. whether there was a threshold.  The Morfeld paper was quoted, which
points at a threshold around 0.25 mg/m3 of respirable quartz.  While
that analysis is consistent with the possibility of a true threshold in
the porcelain industry, it is based on very low prevalence, which may be
a reflection of the mediating effect of clay minerals; and its results
rest on some of the observed cases having developed at zero relevant
(above-threshold) exposure concentrations.  It remains to be seen
whether the same effect can be demonstrated in other industries can be
replicated in other industries, for example in the absence of clay
minerals.

Dr Cox also had many criticisms of studies of the health effects of
quartz. On P97 of his written submission, he deals with IOM papers on
effects in Scottish coal workers. He states ‘excluding age increases
the effects of age-related confounder, … undermining causal
interpretation…’. This ignores the fact that there are no
confounders, age-related or otherwise, of silicotic changes at the 2/1
level, which are caused by silica alone. He then criticises the detailed
model-building and testing that the papers describe, characterising them
as biased from ‘uncorrected multiple testing’, a criticism that I
would refute.  The various model steps were taken in the data-based
knowledge of the history of exposures at that colliery, in an attempt to
build a reality-driven and ‘best-fitting’ model, which Cox describes
on P4 as ‘standard practice’. Finally, he characterises the final
model of the Buchanan reanalysis as biased by ‘dichotomizing a
continuous variable’.  This misrepresents the final model entirely,
which does not dichotomise but fits a change-point model with dual
slopes on exposures experienced at concentrations above and below the
change-point of 2mg/m3. It is not clear how these misrepresentations
have arisen, but they do not inspire confidence in the acuity of Cox’s
criticisms of other studies.

In the end of the day, it’s true that there is little current
scientific evidence of what risks will be experienced by workers exposed
under the current or proposed PEL.  On all existing evidence, it seems
likely that those risks will vary by industry, e.g. by whether exposure
can be mediated by clay minerals. However, it would seem that OSHA has
little choice but to regulate for the highest risks, e.g. in industries
with exposure to pure respirable quartz.  In my own view, whether to
adopt a 0.1/0.05 regulatory regime or a 0.05/0.025 one is a matter for
OSHA’s judgment, but whichever is adopted it must include regular
monitoring and health surveillance.  In addition, I agree with several
of those giving testimony that a ban on sandblasting in the US is long
overdue.

Dr Brian G Miller

Institute of Occupational Medicine

Edinburgh, UK

1 April 2014

  HYPERLINK \l "_Toc251578069"  Andrew Salmon

Private Consultant, Lafayette, CA

March 31, 2014

Dear Sir,

Re: Proposed Rule: Occupational Exposure to Respirable Crystalline
Silica

“I have reviewed the original review materials, my 2009 peer review
comments and their disposition by OSHA in the current proposed
rulemaking.  I feel that OSHA has, with one minor exception, adequately
addressed my comments in their updated Health Effects and QRA sections.
I have included my comments on that area in my attached submission.  I
have also read the written testimony of the public commenters and heard
their oral testimony.  I have included comments on some of the
commenters’ testimony, specifically as it relates to thresholds,
latency, causality, new epidemiological analysis published by Liu et al.
(2013) and measurement error vs. variability.”

Yours sincerely,

Andrew G. Salmon M.A., D.Phil., C.Chem. M.R.S.C.

Proposed Rule: Occupational Exposure to Respirable Crystalline Silica

Analysis of responses to 2009 peer review and 2014 public comments

A.G. Salmon M.A., D.Phil.

Responses to 2009 Peer review

For the most part OSHA has addressed my comments on the earlier draft of
the Health Assessment and QRA sections thoroughly and adequately.  The
improved description and consideration of the South African studies of
silicosis (Hnizdo and Sluis-Cremer, 1993; Churchyard et al., 2004) is
particularly welcome.

The only area which remains somewhat less than completely resolved is
the question of the shape of the dose-response curve (for silicosis
particularly) in the lower-dose range.  I understand that OSHA’s
interest for the purpose of the rulemaking is the shape and steepness of
the dose response over the range of exposures corresponding to the
current and proposed PELs and action level.  In this respect the
analysis resembles that used for instance by US EPA’s criteria air
pollutant standards, where health effects are clearly demonstrable at
the concentrations currently observed and under consideration as
standards.  This is in contrast to the usual approach for toxic
substances where it is usual to attempt to define a “safe”
concentration below which health effects are either absent or
negligible.  Under the circumstances of the proposed silica regulation
and the difficulties (noted by OSHA) of control and measurement at
levels much below the proposed action level, this is entirely
reasonable.  However it does not replace the need to consider the
dose-response curve in the lower ranges, as illustrated by several of
the public comments presented on the issues of thresholds and the
relationship between clinical silicosis and lung cancer.  This aspect of
the debate will be addressed in the section on my consideration of some
of the public comments.

Analysis of 2014 public comments

A number of commenters drew attention to the question of whether there
is a threshold dose for the induction of silicosis.  These comments
varied from essentially anecdotal claims that silicosis had not been
observed in occupational groups with exposures generally within the
current PEL, to more analytical analyses of the epidemiological data
(e.g. Morfeld).  However it is important to understand what is implied
by this supposed “threshold” concept.  Many of the so-called
thresholds seen in epidemiological studies represent thresholds of
observability rather than thresholds of disease incidence.  The
appearance of silicosis is progressive with both dose and time since
first exposure, so 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.  This effect is also
clearly seen for studies which use more severe radiographic criteria to
define a positive response, since it has been established in the OSHA
analysis that radiographic diagnosis of silicosis is in fact a
relatively insensitive measure, and again the severity of response is a
function of both dose and timing of observation.  The best illustration
of the impact of these factors in seen in the risk assessment for
chronic inhalation of crystalline silica by California’s Office of
Environmental Health Hazard Assessment (OEHHA, 2005 in the references
listed by OSHA).  In that report a benchmark dose analysis was used to
identify a point of departure based on the data on South African gold
miners (referenced by OSHA as Hnizdo and Sluis-Cremer, 1993).  The
averaged and time-weighted concentration at this point was 11.4 μg/m3,
significantly below the proposed PEL, let alone the existing one.  This
analysis also illustrates a further important feature of these so-called
“thresholds”.  The point of departure identified by the benchmark
dose analysis can be regarded as a threshold of observability, and is
usually chosen to have roughly similar properties to the NOAEL
identified by more traditional risk assessment procedures.  However, it
is clearly established as a statistically based measure with a
distribution of plausible values reflecting both measurement uncertainty
and actual variability in the population being analyzed.  It is
definitely not a single specific value below which it can be confidently
asserted that no cases will be observed, as appears to be implied in
some of the public comments.  Another peer reviewer (Crump) has
eloquently argued that these observational thresholds are essentially
artifacts of certain types of analysis rather than genuine features of
the data.  The observational threshold or point of departure is also
quite explicitly not a statement about a possible mechanism involving a
threshold response.  If this is to be established it needs substantial
additional mechanistic information such as identification of the nature
and dose-response characteristics of precursor effects.

In a somewhat similar vein, several commenters referred to the
“latency” for appearance of silicosis or lung cancer some
considerable time after the causative exposure to crystalline silica.
This term is often used to describe a delay term included in the
equations used to fit time of incidence data in epidemiological
analysis.  However, similarly to the point of departure used in
dose-response analysis, it is an error to describe this as a cutoff
point before which no cases will be observed.  It is in fact a best-fit
estimate of the median value for a parameter in a very simplistic
equation used to describe time dependence.  As such it represents a
distribution of possible values reflecting both uncertainty and
variability, as well a random variation in the time of appearance of the
disease, rather than a single value.  The type of time dependence
implied by use of this value is not necessarily a particularly good
representation of the actual dependence in the data, although it is
often used as a mathematically convenient approximation.  Where the data
are of sufficient quality and quantity to permit, epidemiologists have
often used more sophisticated models of the time dependence for
incidence of observable effects, which make clear the distributional
nature of parameters such as “latency”.

Some commenters (notably Cox) appeared to question the causality of the
association between silicosis or lung cancer and exposure to respirable
crystalline silica.  Cox’s argument in both written and oral testimony
appears to be that, from a statistical standpoint he is unable to
establish the causality of a relationship, which he illustrates with a
trivial example involving cell phone use and coronary heart disease
mortality.  This point is both true and obvious: it could have been made
more succinctly without any loss of effectiveness.  The identification
of causality as opposed to statistical association is, as described by
Bradford Hill in his well-known criteria, based mainly on
non-statistical considerations such as consistency, temporality and
mechanistic plausibility:  the role of statistics is mostly limited to
establishing that there is in fact a quantitatively credible association
to which causality may (or may not) be ascribed.  OSHA correctly cites
the substantial body of evidence supporting the association and
causality for silicosis and lung cancer following silica exposure, and
also quotes previous expert reviews (such as IARC).  The causal nature
of these associations has already been established beyond any reasonable
doubt, and OSHA’s analysis sufficiently reflects this.  Cox also
appears to suggest that even if the causal association is proven at high
dose levels it may not be present at lower dose levels.  The assumption
of continuity in scientific hypotheses (such as that effects at one dose
level would be consistent with those at other doses, and connected by
continuous quantitative relationships without singularities) is usually
treated as a “hard” assumption which would not be questioned unless
there were actual data providing evidence to the contrary.  No such
evidence was offered in this case.  Cox also asserts that there is a
bias towards finding a positive association even if the actual data are
randomly distributed, showing a field of points with all positive, but
randomly distributed x and y values, and a least squares fitted line
(his figure 2 and slide).  This argument is irrelevant on two counts: a)
the least squares fit he uses forces the assumption y = 0 at x=0.  OSHA
does not make any such assumption in its model fits, instead fitting to
actual measured data points within the range of observation.  Indeed
models such as the spline and logarithmic fits explicitly exclude that
zero-point assumption.  b)  If indeed the data shown in this figure were
independent observations of effect at specific real doses, and the
incidence at zero dose were known to be zero (or some positive but much
lower effect incidence), a statistical analysis would correctly conclude
that the data showed a positive association between exposure (x) and
effect (y), although the data clearly do a poor job of estimating the
value of the actual slope factor.

The paper (Liu et al., 2013) cited in Steenland’s written testimony,
and commented on by several others, is an important extension of the
earlier work on the Chinese cohorts exposed in various industries to
crystalline silica.  The major difference between this and previous
analyses is the exclusion of workers considered to have substantial
confounding exposures to polycyclic aromatic hydrocarbons or arsenic,
both of which are known causes of lung cancer.  The details of this
censoring are stated as being based on measurements in the previously
published studies of thee workers.  Exact details would only be
accessible by a line-by-line analysis of the source data which is
unlikely to appear in a published paper.  However the overall conclusion
is important, in that with the exclusion of these confounders (likely
substantial if not complete) the association of silica exposure with
lung cancer is maintained with similar magnitude to that reported in the
earlier studies.  This implies that although these earlier studies were
potentially susceptible to these confounders their effect is probably
relatively small both in the earlier studies and in Liu et al (2013).
An important new conclusion in the new analysis the near multiplicative
interaction of silica exposure and smoking in the induction of lung
cancer.  This is consistent with observations on the interaction of
smoking with other dusts and fibers, such as asbestos, and has
significant implications for public health policy and education.  Also
significant is the apparently clear finding that although both lung
cancer and silicosis are correlated with silica exposure, they appear
independently, i.e. the clinical observation of silicosis is not a
prerequisite for the appearance of lung cancer.  This point has been
subject to extensive debate, with some results supporting the hypothesis
that silicosis is a necessary precursor to lung cancer and others
suggesting the opposite.  The study by Liu et al. (2013), by virtue of
its size and finding on this point is a strong argument for the
independent appearance of lung cancer.  This does not of course argue
that the initiating events for lung cancer and silicosis are not part of
a common adverse outcome pathway, but it reinforces the perception that
radiographically observable silicosis is a separate and relatively late
event.  In any event, this new publication is an important addition to
the literature which in some respects clarifies and reinforces earlier
conclusions, and OSHA should include consideration of this in its final
determination.  It is unlikely that this would result in any change to
the numerical recommendations, but it would help to resolve some of the
qualitative and mechanistic uncertainties.

Several comments addressed actual or potential uncertainties in
measurement, both in epidemiological studies used as the basis of
evidence and in workplace measurements to establish compliance with new
or existing PELs and action levels.  While this discussion is
interesting and important, it appears that in general OSHA has sound and
data-based analyses of these questions.  However an additional source of
variation in outcome which was given less attention in public comments
and discussions is interindividual variations between members of the
workforce.  This applies both to variations which can affect exposure,
such as behavior, exact location etc., and to variations in individual
susceptibility to the effects, which may be genetic or related to age
and health status inter alia.  In general these variations, which are
real features of the population and its response rather than
“errors”, are likely to be at least as large as uncertainties in
measurement.

APPENDIX A

External Peer Review of OSHA’s Draft

“OSHA Preliminary Health Effects Section for Silica”

and

 “Preliminary Quantitative Risk Assessment for Silica”

Peer Review Comments

Contract No.  GS-10F-0125P

OSHA BPA No. DOLQ059622303

Submitted to:

David O’Connor

Directorate of Standards and Guidance

Occupational Safety and Health Administration

200 Constitution Avenue, NW

Washington, DC  20210

Submitted by:

Eastern Research Group, Inc.

110 Hartwell Avenue

Lexington, MA  02421-3136

January 13, 2010

TABLE OF CONTENTS

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc251578060"  Introduction
PAGEREF _Toc251578060 \h  1

Health Effects

  HYPERLINK \l "_Toc251578061"  Technical Charge to External Peer
Reviewers For Review of

OSHA’s Preliminary Health Effects Section for Silica	  PAGEREF
_Toc251578061 \h  3

  HYPERLINK \l "_Toc251578062"  External Peer Review of OSHA’s Draft
“OSHA Preliminary Health Effects Section for Silica”

Peer Review Comments	  PAGEREF _Toc251578062 \h  7

  HYPERLINK \l "_Toc251578063"  Additional Comments/References	  PAGEREF
_Toc251578063 \h  39

  HYPERLINK \l "_Toc251578064"  Individual Review Comments	  PAGEREF
_Toc251578064 \h  41

  HYPERLINK \l "_Toc251578065"  Bruce Allen Bruce Allen Consulting,
Chapel Hill, NC	  PAGEREF _Toc251578065 \h  43

  HYPERLINK \l "_Toc251578066"  Murray Finkelstein McMaster University,
Thornhill, ON Canada	  PAGEREF _Toc251578066 \h  53

  HYPERLINK \l "_Toc251578067"  Gary Ginsberg Connecticut Department of
Public Health, Hartford, CT	  PAGEREF _Toc251578067 \h  63

  HYPERLINK \l "_Toc251578068"  Brian Miller IOM Consulting Ltd.,
Scotland, UK	  PAGEREF _Toc251578068 \h  71

  HYPERLINK \l "_Toc251578069"  Andrew Salmon Private Consultant,
Lafayette, CA	  PAGEREF _Toc251578069 \h  83

  HYPERLINK \l "_Toc251578070"  Noah Seixas University of Washington,
Seattle, WA	  PAGEREF _Toc251578070 \h  95

Quantitative Risk Assessment for Silica

  HYPERLINK \l "_Toc251578071"  Technical Charge to External Peer
Reviewers Peer Review of

OSHA’s Preliminary Quantitative Risk Assessment for Silica	  PAGEREF
_Toc251578071 \h  107

  HYPERLINK \l "_Toc251578072"  External Peer Review of OSHA’s
“Preliminary Quantitative Risk Assessment for Silica”

Peer Review Comments	  PAGEREF _Toc251578072 \h  109

  HYPERLINK \l "_Toc251578073"  Additional Comments/References	  PAGEREF
_Toc251578073 \h  139

  HYPERLINK \l "_Toc251578074"  Individual Peer Review Comments
PAGEREF _Toc251578074 \h  147

  HYPERLINK \l "_Toc251578075"  Bruce Allen Bruce Allen Consulting,
Chapel Hill, NC	  PAGEREF _Toc251578075 \h  149

  HYPERLINK \l "_Toc251578076"  Kenneth Crump Louisiana Tech University
Foundation, Inc., Ruston, LA	  PAGEREF _Toc251578076 \h  159

  HYPERLINK \l "_Toc251578077"  Murray Finkelstein McMaster University,
Thornhill, ON Canada	  PAGEREF _Toc251578077 \h  177

  HYPERLINK \l "_Toc251578078"  Gary Ginsberg Connecticut Department of
Public Health, Hartford, CT	  PAGEREF _Toc251578078 \h  183

  HYPERLINK \l "_Toc251578079"  Brian Miller IOM Consulting Ltd.,
Scotland, UK	  PAGEREF _Toc251578079 \h  191

  HYPERLINK \l "_Toc251578080"  Andrew Salmon Private Consultant,
Lafayette, CA	  PAGEREF _Toc251578080 \h  201

Introduction

In 2009, Eastern Research Group, Inc. (ERG), under contract to the
Occupational Safety and Health Administration (OSHA), conducted an
independent, scientific peer review of two draft documents prepared by
OSHA:

Preliminary Health Effects Section for Silica.

Preliminary Quantitative Risk Assessment for Silica.

This report documents the review process and provides the reviewers’
final comments and recommendations.

Background

OSHA developed two documents to support development of a proposed rule
governing exposure to crystalline silica in the general, construction,
and maritime industries: 1) a scientific assessment of the literature
and other information on the health effects of silica, and 2) a
quantitative risk assessment for silicosis, lung cancer, and other
diseases resulting from occupational exposure to crystalline silica. To
ensure a sound scientific basis for decision making, the Agency
contracted with Eastern Research Group, Inc. (ERG) to conduct a letter
peer review of these two documents.

Peer Review Process

Using selection criteria provided by OSHA, ERG conducted a search for
nationally recognized experts in occupational epidemiology,
biostatistics and risk assessment, animal and cellular toxicology, and
occupational medicine who had no conflict of interest (COI) or apparent
bias in performing the review. Interested candidates submitted evidence
of their qualifications and responded to detailed COI questions. ERG
also searched the Internet to determine whether qualified candidates had
made public statements or declared a particular bias regarding silica
regulation.

From the pool of qualified candidates, ERG selected seven to conduct the
review, based on:

Their qualifications, including their degrees, years of relevant
experience, number of related peer-reviewed publications, experience
serving as a peer reviewer for OSHA or other government organizations,
and committee and association memberships related to the review topic.

Lack of bias and lack of any actual, potential, or perceived conflict of
interest.

The need to ensure that the panel collectively was sufficiently broad
and diverse to fairly represent the relevant scientific and technical
perspectives and fields of knowledge appropriate to the review.

OSHA reviewed the qualifications of the candidates proposed by ERG and
verified that the range of the candidates’ qualifications met the
technical selection criteria. ERG then contracted with the following
reviewers to perform the review. Six experts reviewed both documents;
Dr. Crump reviewed only the quantitative risk assessment:

Reviewer	Affiliation	Reviewed Health Effects Section	Reviewed
Quantitative Risk Assessment

Bruce Allen	Bruce Allen Consulting	   (	(

Kenneth Crump	Louisiana Tech University Foundation

(

Murray Finkelstein	McMaster University, Ontario	(	(

Gary Ginsberg	Connecticut Department of Public Health	(	(

Brian Miller	IOM Consulting Ltd., Scotland	(	(

Andrew Salmon	Private Consultant	(	(

Noah Seixas	University of Washington, Seattle	(	(

Reviewers were provided with the charge, review documents, and hundreds
of relevant references and given six weeks to conduct the review.

Early in the review schedule, ERG organized and facilitated a briefing
call to ensure that reviewers understood the peer review process. OSHA
representatives were available on the call to respond to technical
questions of clarification. Reviewers were invited to submit any
subsequent questions of clarification to ERG via email.

ERG checked reviewers’ written comments to ensure that each reviewer
had clearly responded to all charge questions and then submitted the
individual reviewer comments, unedited, to OSHA. ERG also organized the
comments by charge questions for both documents and submitted this
version to OSHA and the reviewers in preparation for a follow-up
conference call.

The conference call, organized and facilitated by ERG, provided an
opportunity for OSHA to seek clarification of individual reviewer’s
comments. After the call, ERG directed reviewers to revise their written
comments to include their clarifications. ERG submitted the revised
comments to OSHA, organized by charge question, and prepared this final
peer review report. Section 2 of this report provides peer review
comments for the health effects section and Section 3 provides reviewer
comments for the quantitative risk assessment. Both sections first
present the charge to reviewers and then provide reviewer comments
organized by charge question and, subsequently, by individual reviewer.

Technical Charge to External Peer Reviewers

For Review of OSHA’s Preliminary Health Effects Section for Silica

ERG Contract No. GS-10F-0125P

BPA No. DOLQ059622303

ERG Task No. 0<IP_ADDRESS>

Instructions to Peer Reviewers

You have been selected to participate in an external peer review of the
OSHA preliminary health effects section for silica that will be part of
a proposed rule that would amend the existing regulation for
occupational exposure to silica.  The health effects section includes a
discussion of the adverse effects that result from silica exposure and
the evidence that supports those associations.  The health effects
section is not a quantitative risk assessment, but rather the primary
analysis upon which the Agency must rely when making its determination
that employees exposed to silica at the current permissible exposure
limit (PEL) face a significant risk of material impairment to their
health and that the proposed standard will substantially reduce that
risk.  The quantitative risk assessment is based on a more limited set
of health endpoints than is discussed in the health effects section.
The quantitative risk assessment is discussed in Section VI, which you
are also reviewing under this task, addressing a different set of charge
questions.

In the discussion of the health effects and their association with
silica exposure, the interpretations of studies and conclusions drawn
should be reasonable, sound, and consistent with the underlying science.
 The overriding goal of the peer review is to ensure that the
presentation of the studies, interpretations of the study results, and
preliminary conclusions drawn are clear and scientifically credible.
OSHA has provided the following questions to guide and focus your review
divided into two types: 1) general questions that apply to all parts of
the health effects section; and 2) specific questions that apply to
individual sections/topics in the health effects section of the proposed
rule.  Your review should, at a minimum, address each question,
providing a discussion and rationale for any “yes” or “no”
responses, and providing other comprehensive comments to clarify your
comments and/or recommendations.

General Questions

The draft health effects section reviews and summarizes a number of
studies.  Are the studies described in sufficient detail for the reader
to understand how the studies were done?  Are the descriptions of the
studies and results accurate?  Are the strengths and limitations of the
studies adequately discussed and appropriately evaluated?  Are OSHA’s
interpretations of the study results reasonable and explained
adequately?  Are discussions of studies clear and easy to follow?  If
not, let OSHA know what needs to be added to improve the information and
the manner in which it is presented.

The draft health effects section covers a selection of studies in each
topic area.  The discussion does not cover every study ever done on the
topics.  Do you think that OSHA should have discussed additional or
different studies on a specific health endpoint?  Are you aware of
significant studies that were omitted?  If yes, inform OSHA of those
studies.

The draft health effects section covers a number of health endpoints.
Are you aware of additional significant health endpoints affected by
exposure to crystalline silica that should be discussed?  If so, inform
OSHA of the additional health endpoints and studies that address them.

The draft heath effects section contains conclusions for each topic area
as well as an overall conclusion.  Are these conclusions reasonable in
light of the available data?  Is it clear in the discussion how OSHA
arrived at those conclusions based on the studies discussed?

Questions on Section A. Introduction

A-1.	Is OSHA’s review of the history of dust exposure monitoring
helpful to the reader in understanding the needs and limitations of
exposure conversions to a modern mass per volume metric in reference to
the exposure-response relationship?

Questions on Section B. Silicosis

B-1.	OSHA presents background information on the use of radiography,
imaging techniques, pulmonary function studies, and other diagnostic
tools used in clinical settings and for in epidemiological studies.
Does OSHA correctly present the benefits and shortcomings of these
techniques?  Are you aware of any additional information that would
either strengthen this discussion or contradict what is written?

B-2.	OSHA attempted to describe the available silicosis surveillance
data.  In your opinion, were any important topics left uncovered?  Any
data sources not discussed?  Is the subject of under-reporting
sufficiently covered?  Are the conclusions supported by the discussion
and stated succinctly?  Are you aware of any important studies in this
area that OSHA did not cover?

B-3.	For the discussion of progression of silicosis, OSHA did not review
every study that addressed this issue.  Are you aware of additional
studies that OSHA should consider, especially any studies that
illustrate progression in a cohort exposed to silica in the range of
OSHA’s current PEL (0.1 mg/m3)?

B-4.	Results of studies covered in the PFT section are not always
consistent.  Did OSHA do a fair job of presenting these results and
drawing conclusions?  Are there any important studies that you are aware
of that would strengthen this section or the conclusions of this
section?

Questions on Section C. Carcinogenic Effects of Silica (Cancer of the
Lung and Other Sites)

C-1.	With such a large amount of epidemiological literature to review,
OSHA may be subjected to criticism of selection bias.  Is the selection
criteria used by OSHA clear?  Have we missed any important studies that
have good or at least reasonable exposure estimates?  Do you recommend
any alternate or additional selection criteria?

C-2.	OSHA concludes that the studies involving four cohorts among the
20+ cohorts and case controls reviewed were the strongest in terms of
several criteria in record availability and data quality (exposure,
smoking, worker and facility history) as well as data treatment and
analyses?  Do you agree with this conclusion?  Would you add or delete
any of these studies?

C-3.	Do the tables add to the text presentation?  Do you have any
recommendations to improve their content or presentation?  Would you add
or delete another table?  Provide an explanation for any proposed
deletion or a mock-up of any proposed addition.

C-4.	OSHA has reviewed a number of studies that examined the
relationships between exposure to silica and cancer at sites other than
the lung, including larynx and nasopharynx, stomach, and esophagus.
Have we missed any important studies of cancer at other sites? If yes,
inform OSHA of those studies.

C-5.	OSHA has preliminarily concluded that an association has not been
established between silica exposure and excess mortality from cancer at
sites other than the lung.  Do you agree with this interpretation of the
data?  If not, please provide a detailed rationale for your different
interpretation.

Questions on Section D. Other Nonmalignant Respiratory Disease

D-1.	This draft section discusses COPD, NMRD, bronchitis, emphysema,
airways disease, etc.  Is it clear in the discussion how these health
endpoints are related or distinct entities?  If not, tell OSHA how to
improve the presentation.

Questions on Section E. Renal and Autoimmune Effects

E-1.	OSHA has preliminarily concluded that studies on renal and
autoimmune effects have not provided sufficient data (in quality or
amount) to support quantitative estimates of risk.  From your knowledge
and understanding of these studies, do you agree with OSHA’s
conclusion?  If you believe that there is sufficient data to support
quantitative estimates of risk, please tell OSHA specifically what data
you think could be used.

Questions on Section F. Physical Factors that May Influence Toxicity of
Crystalline Silica

F-1.	The draft “Physical Factors…” section contains a discussion
of proposed mechanisms of action by which silica causes silicosis and
lung cancer.  Does the discussion of the mechanism of action reflect the
most recent thinking on this subject?  If not, tell OSHA what the most
recent thinking is, as you understand it.

F-2.	The draft Mechanism of Action section contains a discussion on the
possible role of silicosis as a precursor or prerequisite for lung
cancer.  Does this discussion accurately reflect the current scientific
opinion on this issue?  If not, tell OSHA what the current scientific
opinion is on this issue, as you understand it.

F-3.	In the draft “Physical Factors…” section OSHA preliminarily
concludes that the available information on the physical factors that
may influence crystalline silica toxicity cannot be used at this time to
refine quantitative estimates of the lung cancer and silicosis
mortality.  Does this seem to be an appropriate conclusion based on the
information presented?  Is it clear in the discussion how OSHA arrived
at this conclusion?  Would you arrive at a different conclusion based on
the information presented?  If so, tell OSHA what your conclusion would
be and explain how you arrived at it?

External Peer Review of OSHA’s Draft

“OSHA Preliminary Health Effects Section for Silica”

Peer Review Comments

Specific Questions

The draft health effects section reviews and summarizes a number of
studies.  Are the studies described in sufficient detail for the reader
to understand how the studies were done?  Are the descriptions of the
studies and results accurate?  Are the strengths and limitations of the
studies adequately discussed and appropriately evaluated?  Are OSHA’s
interpretations of the study results reasonable and explained
adequately?  Are discussions of studies clear and easy to follow?  If
not, let OSHA know what needs to be added to improve the information and
the manner in which it is presented.

Bruce Allen	In general, the descriptions of the studies appear to be
sufficient for understanding what has been done and I have no reason to
suspect that they have been misrepresented.  By way of more succinct
summary of strengths and weaknesses, I would suggest a summary table
cross-classifying the studies with major items that affect strengths and
weaknesses (e.g., study size, length of follow-up, issues related to
measuring effects, etc.).  This would allow readers to appreciate the
major differences among the studies and their relative strengths and
weaknesses for those issues that OSHA considers of primary importance.
Just having such a succinct list of what OSHA considers important would
provide a more transparent means to evaluate those items and to
determine if that list corresponds to what informed readers would
consider important.

From a formatting perspective, it was sometimes difficult to follow when
discussion of one study or one topic ended and another began.  I would
suggest more extensive use of headers and sub-headers (bolded,
italicized or something, with perhaps section numbering and subsection
numbering) to delineate the sections and make it easier to find the
summary conclusions for each issue.

Murray Finkelstein	I think that the studies are, in general, well
described and that OSHA’s interpretations are reasonable and
adequately explained. The mass of text makes it difficult, however, to
locate specific studies and results. I think that the presentation could
be improved by including summary tables of results. As an example of one
possible layout, see the tables in the Text and Appendices of the
Institute of Medicine review “Asbestos: Selected Cancers”	ISBN-10:
0-309-10169-7 and  ISBN-13: 978-0-309-10169-1

Gary Ginsberg

Gary Ginsberg

	The descriptions of studies are well developed and provide good
background information for the risk assessment.  The conclusions about
silica-induced diseases and the variables that can lead to inconsistency
or modify dose response are generally well founded.  However, this
document is disconnected from the risk assessment in that the study
descriptions are not tied to the overall purpose of developing a
quantitative analysis.  Most study descriptions lack critical evaluation
of whether that particular study has sufficient exposure assessment,
numbers of subjects, outcome measures and quality control for inclusion
in quantitative dose-response models.  OSHA’s identification of
industries which are least confounded and thus most useful is helpful
and seemingly accurate.  However, for the most part, the critical
sorting stops at that level.   For example, it is unclear why the 1989
Danish stone cutter study is not incorporated into quantitative models
while other studies are.  The stone cutting and sand industries are
identified as having little confounding and studies from these cohorts
are not included in Section VI.  There may be good reason for that, but
without those reasons explained, one does not know whether the
quantitative assessment could be more robust or is in some manner biased
by the exclusion of useful cohorts.  The description of the Italian
brick workers (pg 138) is an example where OSHA discusses study
limitations that help the reader understand why it might not have been a
good candidate for quantitative analysis.  However, this is the
exception rather than the rule and it appears that OSHA is relying upon
study selection made by others (e.g., NIOSH, 2002; IARC 1997; the
various meta analyses; pre-existing quantitative analyses).  A
study-by-study critique (not just review, as is now presented) is needed
to sort out the value of individual studies for quantitative analysis
and to document that the array of studies relied upon in Section VI is
reasonably complete.

Better use of tables would greatly facilitate use of this document.
V-C-1 is a good start in terms of laying out key studies, but a 2nd
(perhaps 3rd as well) table is/are needed which log key information for
each study in terms of study design (cohort size, measurements made,
exposure range, etc.), results and most importantly utility for
quantitative analysis.  Also, tables would be more useful if organized
in a discrete section in the back of the report and if they were listed
in the TOC.

Brian Miller	In the main, the descriptions seem good.  I have annotated
some corrections, suggestions and comments by page number within each
section of this document.  There were some studies whose size made the
lack of statistically significant results almost a foregone conclusion:
the concept of power of a study was not prominent, and could perhaps
have been emphasized more.

Andrew Salmon	The format used for descriptions of studies in the health
effects section is appropriate, and effectively lays out the content,
methodology, strengths and weaknesses of the studies described.  In
general the section is well written and clearly explains OSHA’s
interpretation of the available data.  There are a few cases where
studies have been either ignored completely, or given less consideration
than they deserve, (or, alternatively, over-emphasized), but these
difficulties are isolated and will be identified below where
appropriate.  The level of detail given in this section is sufficient
for its purpose, which is mainly a qualitative description of the health
effects of silica exposure: more details, including report of the
detailed quantitative evaluations of the studies by Toxichemica Inc.
(2004), are appropriately deferred to the section on quantitative risk
assessment.  The section represents a commendable attempt to reduce an
enormous literature to manageable proportions.  This is most successful
in the consideration of lung cancer, where the previously published
review by IARC (1997) and the meta-analysis by Steenland et al. (2001a)
provide an overall perspective.

Noah Seixas	In sum, yes.  OSHA has clearly and thoroughly evaluated the
extensive literature relating silica exposure to the key health effects
known or suspected to be related to this exposure.  The review is
extensive, covers all of the major studies to my knowledge, and provides
an appropriate level of discussion of each study.  In particular, the
methods, results, limitations and strength of the evidence are
considered for each study reviewed. Most of the document is clearly
written.

However, I think the document is lacking an adequate “Introduction.”
 The section labeled introduction is a detailed discussion of sampling
methods.  While this is relevant, I don’t believe it should be labeled
as introductory material.  In particular, I think the document as a
whole is lacking clear definitions of many of the concepts and
terminology used throughout the document.  There is even no clear
definition of the terms silica, crystalline silica, quartz, etc.  These
terms should be clearly defined at the beginning of the document, and
used consistently throughout.

The draft health effects section covers a selection of studies in each
topic area.  The discussion does not cover every study ever done on the
topics.  Do you think that OSHA should have discussed additional or
different studies on a specific health endpoint?  Are you aware of
significant studies that were omitted?  If yes, inform OSHA of those
studies.

Bruce Allen	I believe the selection of studies was adequate for the
purpose of conveying the important issues and conclusions about exposure
to silica.  I am not aware of any significant studies that were omitted.

Murray Finkelstein	The literature on silica health effects is
voluminous. I think that OSHA has identified and discussed the major
reports. I am aware of no significant studies that were omitted.

Gary Ginsberg	The selection of studies reviewed appears to be broad and
extensive.  Not starting from a background in silica
toxicology/epidemiology, I can’t really say whether important studies
have been omitted from this review.  As mentioned above, the selection
of studies for quantitative assessment needs better justification.

Brian Miller	No, I am not aware of other studies.  Those I was familiar
with were included, along with many others that were new to me.

Andrew Salmon

Andrew Salmon

	The discussion of silicosis morbidity and mortality starts from the
premise that silicosis is the inevitable and unique result of exposure
to respirable crystalline silica particles, and provides only a very
brief mention of some of the historical reports underlying this
conclusion.  It then proceeds to review further only those studies which
the authors consider to provide information on specific topics
qualifying that association, such as the precision, repeatability and
sensitivity of the ILO radiographic method for diagnosis, the
association with other diseases such as tuberculosis, the probability
and rate of progression after initial diagnosis, etc.  While this is
somewhat reasonable in view of the large literature, it results in an
unbalanced view of the literature and produces some odd results.  Thus
this section does not describe some of the key studies used for
quantitative analysis in the following section, or only refers to them
in the context of some subsidiary point, without laying out the main
findings of a dose relationship between exposure to respirable dust
containing crystalline silica and observation of silicosis as defined by
radiography, lung function and/or pathological criteria.  It would
improve the overall perspective of this part of the narrative if these
important studies were described here, in addition to the analysis of
surveillance data.  I understand the logic of keeping a discussion of
the dose-response characteristics to the following section where they
are treated in detail.  However this section would be improved by a
demonstration that such a relationship does exist.  It would also help
the discussion of important qualitative differences such as the
distinction between acute silicosis (a high-dose effect) and the
longer-term responses.

The surveillance data which are reviewed certainly support the
assumption of a relationship between silicosis and exposure to silica,
but provide a somewhat strange perspective due to their individual and
clinical, rather than statistical, perspective.  Additionally they may
seriously understate the prevalence of the disease.  Not only is
mortality a severe endpoint which may not affect more than a minority of
those affected in less extreme ways, but as succinctly demonstrated in
the analysis presented here is prone to substantial under-reporting.
Much of the surveillance data cited here provides a limited perspective.
 For a start it is largely confined to United States data which of
itself ignores the international dimension of the problem, and may
produce other weaknesses resulting from the peculiarities of the United
States health care system.  In general, apart from special projects
following pre-defined cohorts, United States data are significantly
lacking compared to those in other countries (especially Scandinavia and
the EU) where population-wide health care systems exist.  With regard to
morbidity statistics, in the case of silicosis these are mainly related
to workers’ compensation systems, which include an element of bias
towards a negative diagnosis (thus avoiding payment) unless the evidence
is overwhelming: thus these reports are likely to show a high degree of
accuracy but low sensitivity compared to an analysis without this bias,
even if the same nominal criteria are used.

Noah Seixas	I am not aware of any significant studies on silica and
health effects that were not reviewed in this document. There are
studies which consider alternative dose metrics for silica, but these
are more appropriately addressed in the risk assessment document.  There
is a substantial literature on exposures, and exposure control
techniques for silica in various industries.  These studies are not
reviewed here, I think appropriately given the goals of the Health
Effects document.

The draft health effects section covers a number of health endpoints.
Are you aware of additional significant health endpoints affected by
exposure to crystalline silica that should be discussed?  If so, inform
OSHA of the additional health endpoints and studies that address them.

Bruce Allen	I am not aware of other health endpoints that were omitted
from the discussion.

Murray Finkelstein	I am not aware of any additional significant health
endpoints.

Gary Ginsberg	The selection of health endpoints appears to be inclusive
and it is hard to imagine that other endpoints exist that would
materially add to the quantitative assessment.  However, my knowledge
base in this area is very limited.

Brian Miller	This section covered all the effects that I was aware of as
being potentially related to silica.

Andrew Salmon	I am not aware of any additional endpoints which should be
considered.

Noah Seixas	The document addresses silicosis, lung function limitation
including obstructive lung disease, lung cancer, cancers other than
lung, renal and immunological endpoints.  These are known health effects
associated with silica exposure.  I am not aware of other significant
health effects of silica exposure.

The draft heath effects section contains conclusions for each topic area
as well as an overall conclusion.  Are these conclusions reasonable in
light of the available data?  Is it clear in the discussion how OSHA
arrived at those conclusions based on the studies discussed?

Bruce Allen	It appears that OSHA’s conclusions are reasonable in light
of the data that they presented.  The basis for those conclusions does
appear to be clear.

Murray Finkelstein	The discussion is clear and the conclusions are
reasonable.

Gary Ginsberg	The conclusions for the various topic areas appear to be
supported by the data.  However, in some cases the conclusions are not
complete thoughts or do not tie to the quantitative assessment.  For
example, Page 396 states that many cases of silicosis may be missed with
standard radiographic and CT techniques.  This connects to the evidence
I alluded to above regarding false negatives being discovered when
autopsies are performed.  OSHA does not provide any perspective on how
false negative outcomes might influence their analysis.  On the next
page, associations between pulmonary function decrements and x-ray
evidence of silicosis are discussed with doubt raised about whether
functional declines can be seen at the earlier stages of pathology.
While the conclusion drawn may be reasonable, how this makes a
difference to the quantitative assessment is unclear.  Does this affect
OSHA’s case definition of silicosis (e.g., only if there is associated
functional decline)?  Does it affect the way OSHA interprets the
epidemiology? Does OSHA have a degree of silicosis it is trying to
prevent – i.e., does the minimal ILO grade constitute an adverse
effect that is in need of prevention through regulation.  This decision
affects how the epidemiology is interpreted and risk assessment
conducted.  For example, if the dose response is from a study whose
sensitivity was for mild to moderate silicosis, OSHA may not want to
weigh that study as heavily as one with a more sensitive case
definition.  It would appear that the effort OSHA spends in Section V
(page 18 and further) to define silicosis would be a good place to
discuss how it approaches the issue of case definition when interpreting
the epidemiology and in building the quantitative risk assessment.

Brian Miller	In the main, I believe the discussions balanced the
strengths of the studies convincingly, although as mentioned above some
discussion of statistical power might have helped here.

Andrew Salmon	The health effects summaries are clear and reasonable.

Noah Seixas	Yes.  I think OSHA has made very reasonable summaries and
interpretations of the various aspects of health effects associated with
silica.  The literature reviews are comprehensive, clear and adequate
for making the determinations provided in this section.

A-1 	Is OSHA’s review of the history of dust exposure monitoring
helpful to the reader in understanding the needs and limitations of
exposure conversions to a modern mass per volume metric in reference to
the exposure-response relationship?

Bruce Allen	Yes, this section is important for understanding the
uncertainties that are associated with exposure reconstruction and the
conversion factors (and their potential biases) that might be present in
that reconstruction.

Murray Finkelstein	OSHA’s review is helpful in providing a historic
perspective and in providing context for the retrospective-prospective
epidemiologic studies.

Gary Ginsberg	The introductory material regarding dust exposure
monitoring is useful for understanding the epidemiology, how the quality
of studies has changed over time, and how certain measurement variables
can be a source of uncertainty.

Brian Miller	Given the disparity in measurement methods over the years,
this is necessary.  However, I’d suggest not describing these as
exposures, but as concentrations or intensities, and reserving the word
‘exposure’ for subjects’ interaction with those intensities, i.e.
including duration.  This is a subtle distinction, but a useful one to
maintain.  It is exposure, not concentration, that engenders risk.

P5  para 2 Replace ‘measure of exposure’ with  ‘airborne
concentration’.

P8 para 3 spans -> span.  Give ref(s) for methods?

P12 para 1 last sentence contains extra text.

P14 para 1 explain more fully what ‘respirable’ means?

Andrew Salmon

Andrew Salmon

	This section provides a summary of the major types of measurement
technology which have been used for estimating exposure to respirable
silica.  While accurate as far as it goes, this provides a rather
limited perspective.  OSHA decided some time ago that the ideal method
for measuring exposures to silica dust involves personal sampling using
a cyclone to remove non-respirable particles and a filter to collect the
respirable particles for gravimetric and X-ray crystallographic
analysis.  There are good reasons for choosing this methodology, but
this section does not do a very good job of explaining what these are.
The section is somewhat dismissive of the various methods based on
particle counting equipment, characterizing these as “historical”
and mainly addressing how their results could be converted to the
OSHA-preferred gravimetric data.  It is not that the gravimetric measure
is intrinsically technically superior, but rather that the availability
of particle counts and size- or surface-area measurements as well as
gravimetric analyses made an important contribution to the eventual
conclusion that 1) long-term cumulative exposure was the chief
determinant of chronic silicosis and 2) the gravimetric measure is the
appropriate dose metric to be related to health effects.  It is curious
that the authors of this section chose to report conversion factors used
in the analysis of various US studies (Table V-A-1), but did not include
any quantitative analysis of the various reports on dust exposures in
the South African gold mines, which represent an important cohort for
study of health effects and for which there are a number of publications
presenting such comparative analysis (Beadle and Bradley, 1970;
Page-Shipp and Harris, 1972; DuToit 1991 and others).  I also do not see
any description of modern electronic particle-counting systems, some of
which are capable of providing a gravimetric description of the
distribution of particle sizes in an atmosphere, on a continuous basis.
While these may be unsuitable for personal monitoring of workers, they
may provide important data especially for outdoor environments where
dust exposures are a concern.  More detailed consideration of particles
size and surface measures might further inform the later discussion of
factors potentially affecting the potency of specific types of silica
dust.

Noah Seixas

Noah Seixas

	This section of the document is important, given the historical changes
in dust monitoring techniques that have occurred, and the relevance of
these changes to estimating dose for chronic conditions associated with
silica.  I think that this discussion is important to the integrity and
interpretability of the document as a whole.  However, I find this
particular section poorly organized and presented. I think it could be
presented in both simpler and clearer terms.

In particular, there are several issues within the context of
measurement technique and definitions, that are frequently confused.
First, the duration of exposure monitoring should be discussed.  Grab
samples, or instantaneous samples should be distinguished from
short-term samples, from full-shift samples (called erroneously, TWA
samples).  Further, the duration of measurement is frequently confused
with the exposure metric – typically cumulative exposure.  These are
not the same issue and should not be confused.  Although some direct
reading instruments (DRI) are now available, they are not discussed.
Although DRI are generally not relevant to historical exposure datasets,
they are increasingly in use and may be important in future studies –
their use and limitations should at least be addressed briefly.

Second, particle counts vs. mass concentrations should be discussed –
as it is.  The discussion of the conversion of mppcf to mg/m3 is useful
and thorough.  However, the rationale for the superiority of mass
concentration is not addressed adequately.  My understanding is that the
choice of mass fraction is primarily dependent on the relative
simplicity (and lower expense), rather than a biological
appropriateness.  While mass fraction may be a superior metric
biologically, the evidence for this is not presented. This issue should
be considered separately from how to convert between the two measures of
exposure.

Third, the rationale and definitions of particle size fractions are not
well described.  Because different studies, and different periods in
time have used different particulate size fraction measurement systems,
and because they may have different implications for different health
endpoints, this should be addressed more clearly.

Fourth, the differences in measurement of dust, vs. silica, vs.
crystalline silica should be more clearly explained.

Fifth, in the context of describing each of these issues, the use of
different sampling and analytic devices is also relevant and should be
described.  Sampling methods are substantially different over time and
between different countries.  Each of these sampling devices or
techniques have implications in terms of the issues discussed above, and
are therefore, relevant to the comparability of the data derived from
them.

Finally, the choice of a standard based on crystalline silica
concentration in air, rather than the currently used formula combining
mass concentration and silica content of the dust should be explained.
I believe this is a defensible approach, but given its shift from
historical practice, it would be useful to point out the limitations of
the earlier standard, and OSHA’s position on the superiority of the
new method of quantification.

B-1	OSHA presents background information on the use of radiography,
imaging techniques, pulmonary function studies, and other diagnostic
tools used in clinical settings and for in epidemiological studies.
Does OSHA correctly present the benefits and shortcomings of these
techniques?  Are you aware of any additional information that would
either strengthen this discussion or contradict what is written.

Bruce Allen	This is not my area of expertise; I am not able to assess
whether or not the presentation correctly assesses benefits and
shortcomings of the techniques.

Murray Finkelstein	I think that the section on Diagnostic Tools requires
revision. In particular:

CT and HCRT: The study by Begin needs to be revisited by OSHA. There
were only 58 subjects and only 6 did not have radiographic silicosis.
The relevant question is: does CT find silicosis when X-ray does not?
There were 6 in Category 0 by X-ray and 12 in Category 0 by CT.

The Talini paper studies only 27 subjects. There was substantial
disagreement between CT and CXR at low profusions.

I think that the literature search needs to be updated for the
comparison of CT and CXR. The references in the document are old and my
own search on PubMed found additional references.

Gary Ginsberg	I do not have the technical expertise to comment on
whether OSHA descriptions of radiological and pulmonary function tests
are accurate.

Brian Miller

Brian Miller

	I’d like to see the description of the ILO conventions for describing
the abnormalities on chest x-rays spelt out early, around PP14-16,
because that informs a large part of what we mean by ‘silicosis’.
It appears too late at present.

I’d also suggest that this section might give more of an impression
that ‘chronic’silicosis, like all pneumoconiosis, is an evolving
damage process and that decisions about when a subject has the
‘disease’ involve arbitrary distinctions of severity along a
continuum.  This would also be a good place to have the (currently
later) material on reader variation.

P18 para 4 The ILO system standardizes the description of chest x-rays,
not their ‘interpretation’.

P19 para 4 however -> but

P23 para 2.  The authors used multiple regression, not multivariate
analysis.

P32 para 1.  kappa  0.49 may be ‘better’ than 0.29, but it’s still
not very good.  Note kappa does not inform about the direction of
disagreement.  Might the relationship between HRCT and ILO be shown in a
table?

P34 para 1.  Note other lung function measurements can be very variable
too.

P35 para 2  Note that values below the 5th percentile may in fact be
perfectly normal?

P37 para 1 (and/or elsewhere in this section).  ?Make more explicit that
the high inter-individual variation in lung function values implies high
variation in %predicted, and that is why (1) %predicted should be used
only as an initial screening measurement and (2) rate of loss over time
in an individual is a much more sensitive marker.?

Andrew Salmon	This chapter provides a good summary of the available
methods for recognition and evaluation of silicosis and related lung
diseases.  It makes an important point about the relatively low
sensitivity of radiography, as shown by Hnizdo et al. (1993), Craighead
and Vallyathan (1980) and others.  This point is important in evaluating
the prevalence of silicosis as reported in the various epidemiological
studies considered.  The discussion of the lung function test results in
patients affected by silicosis (however diagnosed or suspected) is also
useful.

Noah Seixas	The discussion of diagnostic tools, X-ray, CT, HRCT and
pulmonary function tests is appropriate, clear and adequately complete
for assessing their relations to silica-induced disease.  The discussion
is useful in terms of understanding the literature on silica risks,
however, there are no summary or conclusions with based on this
discussion that could be used for designing screening or surveillance
systems for silica-exposed workers.  Presumably, this discussion would
appear elsewhere before OSHA enters into recommendations for medical
surveillance requirements.

B-2	OSHA attempted to describe the available silicosis surveillance
data.  In your opinion, were any important topics left uncovered?  Any
data sources not discussed?  Is the subject of under-reporting
sufficiently covered?  Are the conclusions supported by the discussion
and stated succinctly?  Are you aware of any important studies in this
area that OSHA did not cover?

Bruce Allen	I am not familiar with surveillance data collection and
reporting so I cannot evaluate whether any important topics/data sources
have been left uncovered.  It does appear that the subject of
under-reporting has been sufficiently discussed.  It appears the
conclusions are supported by the data presented.

Murray Finkelstein	I think that the section on surveillance was
adequately done. I am not aware of overlooked studies.

Gary Ginsberg	The surveillance data review and underreporting issue
appear to be adequately described and of relevance to the remainder of
the document as general background information.

Brian Miller	I’m not close to these schemes, so I don’t have any
others to suggest.  The topic of ‘under-reporting’ is linked to the
definition of the minimum severity required to classify a subject as
having silicosis, and that might be brought out a little more clearly.

P48 para 1.  Presumably deaths in the young are from ‘acute’
silicosis?

P48 para 2.  I think YPLL is a misnomer, and capable of
misinterpretation.  Why not Years of Working Life Lost, YWLL, which is
what is meant.

P49 para 2.  Reword last sentence?  Workers in industries without silica
exposure are not likely to die of silicosis at all.

P52 para 2  Define ‘latency’?

P56 para 3.  If the three states are getting their silicosis cases from
hospital discharge records, presumably they are at the more serious end
of profusion or ‘acute’, or…, certainly not matching a definition
of ILO categories 1/0+.  There could be thousands of case that meet the
ILO definition that never go to hospitals. This highlights the necessity
of keeping it clear that not all uses of the word ‘silicosis’ mean
the same thing.

P61 para 1 ‘Silicosis’ at ILO 1/0 is unlikely to be symptomatic.
Such cases are only found if actively sought, e.g. with a radiographic
workplace surveillance program.  The conclusion in P62 para 3 is
therefore not at all surprising.

P68 para 3 Says there is no system that collects silicosis deaths, then
describes NORMS, which (I thought) does just that. But it’s true that
no system collects new live cases.

Andrew Salmon

Andrew Salmon	This description of surveillance data is sufficient as far
as it goes in describing the U.S. data.  There may be reasons why other
sources of this type of data, which certainly exist in various parts of
the world (U.K. in particular, many others), were not considered, but
these reasons are neither presented nor defended.  Specific problems
relating to under-reporting are identified and discussed.  However, as
noted previously in the general comments, the limitations in the
surveillance approach generally and in particular the concentration on
only the most severe effects (mortality, substantial disability and
high-grade radiographic diagnoses) limit the usefulness of this data
source for anything beyond the qualitative identification of disease
end-points.

There is an additional, recently published study that OSHA should
consider, which is related to those using surveillance data by its
objective of examining the prevalence of silicosis in certain population
groups.  This is the study of pneumoconiosis in Californian agricultural
workers exposed to silica and silicate-containing dust, by Schenker et
al. (2009).  Instead of using reported illness or death certificates,
these authors used histological analysis and measurements of accumulated
particles, using lung specimens obtained at coroner’s autopsy.
Significant degrees of pneumoconiosis and other pulmonary disease
indications were apparent in agricultural workers compared to others not
exposed to the mineral dusts prevalent in dry farming activities.  This
result is interesting both as an indicator of silicosis-type disease in
an occupational group not considered in the OSHA report and as a
possible contribution to the debate about aged vs. fresh silica
particles, surface occlusion by clays and so on.

Consideration of studies from outside the U.S. describing prevalence of
silicosis is entirely lacking: this is a substantial omission if the
objective was to provide a balanced view of the subject.  Some of the
key studies from the U.K., Asia, South Africa etc. are described in the
subsequent discussion of silicosis progression in this section, or in
the dose-response section, but their omission here is peculiar.  And
some important studies are omitted in both places.  It is a downright
eccentricity that the authors refer briefly to the study by Churchyard
et al. (2004) in the lung cancer chapter as a source of gravimetric
measurements of silica in South African mines, but this study is nowhere
mentioned either in this section or the dose-response section for its
presentation of data on the prevalence and dose-response of silicosis in
black South African miners, which is its primary subject.

Noah Seixas	The surveillance information presented is an excellent
summary, covering silicosis mortality and morbidity, silica exposure
surveillance, and estimates of under-reporting of these data.  Lessons
learned from these data systems, along with their limitations, are well
discussed.  However, one comes away with an important question.  Given
the rapid and consistent reduction in mortality, and the continuing
exposure levels over the current PEL, one must ask if the remaining
disease observed is not completely due to illegal (i.e., > PEL)
exposures, rather than the inadequacy of the current standard.  I think
some additional discussion of this, in particular the limitations in
assessing non-silicosis outcomes (e.g. COPD and Lung CA) in relation to
silica exposures, is warranted.  That is, just because there is a large
reduction in silicosis identified through the various surveillance
systems, does not suggest that there is little remaining risk, other
than that where exposures exceed the standard.

Given the limitations of the various surveillance data sources (both
exposure and outcomes), it should be pointed out that the best
information about the true risk of disease must come from well
constructed epidemiologic studies where the cohort can be adequately
defined, exposure can be sufficiently quantified, and outcomes can be
thoroughly ascertained.

On p 63, I assume the quote from Windau should read…”pneumoconiosis
due to other inorganic dusts.”

B-3	For the discussion of progression of silicosis, OSHA did not review
every study that addressed this issue.  Are you aware of additional
studies that OSHA should consider, especially any studies that
illustrate progression in a cohort exposed to silica in the range of
OSHA’s current PEL (0.1 mg/m3)?

Bruce Allen	I am not aware of any such studies.

Murray Finkelstein	I am not aware of additional studies that OSHA should
consider.

Gary Ginsberg	Not having background in this area, I cannot offer any
additional studies regarding progression of silicosis.  This section is
of general relevance but its unclear how it assists with the
quantitative assessment in Section VI.

Brian Miller	I’m not aware of any other studies that should be
considered.

P79 para 5  Is it worth pointing out that the problems in the Scottish
colliery were spotted as a rapid and atypical burst of radiological
progression?  If so, reference Seaton et al (Lancet, 1981)?

P80 para 2 ‘occupational history since leaving the colliery’ was
particular to the 1990/91 follow-up survey.  (regular PFR surveys did
not include retirees.)

P81 para 1.  delete ‘, as well as the mean and maximum of the non-zero
exposure estimates’?  (That looks out of place.)

P83 para 4.  Should that say ‘it progresses quickly once
established’?

P84 para 4 silicosis defined how?

P102 para 3 presumably the incidence rate what was compared, not the
ratio.

P105 para 2 odd -> odds

P108 para 3 where part of the study cohort was exposed…for a period of
some years.

P109 What does ‘sufficient data were not provided’ mean?  Should
this be ‘there have been no follow-up surveys of this cohort since
1991’?

P109 para 2 determinate -> determinant

Andrew Salmon	This part of the report does a good job of distilling what
is certainly a very large body of published data.  The key point, that
progression occurs both in the presence and absence of continuing
exposure to crystalline silica dust, is well made.  I do not have any
suggestions for additional studies that should be considered.

Noah Seixas	No.  the discussion is well organized and to the extent of
my knowledge, accurate and complete.  The conclusions concerning
progression, and determinants of progression seem well founded.

B-4	Results of studies covered in the PFT section are not always
consistent.  Did OSHA do a fair job of presenting these results and
drawing conclusions?  Are there any important studies that you are aware
of that would strengthen this section or the conclusions of this
section?

Bruce Allen	I am not familiar with the literature on silicosis and PFT.
However, based on the results of the studies as presented in the
document, it appears that the conclusions reasonably reflect the
information that is available, including the uncertainties associated
with sometimes inconsistent findings.

Murray Finkelstein	OSHA did a fair job of presenting the studies.
However, most of these studies were small, and of low statistical power.
I suggest that OSHA consider pooling the results (meta-analysis) of
comparable studies in order to increase the ability to draw conclusions
from the data.

I am not aware of important omitted studies.

Comments with respect to: PRELIMINARY CONCLUSIONS: SILICOSIS AND DISEASE
PROGRESSION (Pg 107)

Pg 111: “Both of these studies report progression in terms of
percentage of workers whose chest x-ray categories progress, and their
results are close (2 percent to 6 percent). Based on these data, one can
estimate an annual progression rate of 2-6 percent for this exposure
range. This means that every year approximately 2 to 6 percent of
workers exposed to respirable silica dust in the range of 0.12 to 0.48
mg/m3 are expected to progress at least 1 sub-category on the ILO
scale.”

This statement omits to mention one crucial factor: latency. Progression
will depend upon the time from onset of exposure. It is almost certainly
not true, for example, that in the first 10 years of exposure every year
approximately 2 to 6 percent of workers exposed to respirable silica
dust in the range of 0.12 to 0.48 mg/m3 are expected to progress at
least 1 sub-category on the ILO scale.” The OSHA authors need to bring
the time frame (latency) into the discussion.

Gary Ginsberg	The pulmonary function test results section appears to be
a reasonable discussion on the evidence surrounding PFT changes and