radiographic evidence of pathology.  I have no studies to add.

Brian Miller	This section might go a little further to emphasize how the
inter-individual variation on lung function measurements between healthy
subjects of the same height and age makes it difficult to detect
abnormality cross-sectionally.  The idea of the lower 5% being
automatically accepted as ‘abnormal’ is reported rather
uncritically.

Andrew Salmon	I think this section is reasonable and well-considered.
The conclusions drawn are cautious and defensible.  Given the complex
and conflicting nature of the data I think this chapter does an
excellent job of the analysis.  I am not aware of any additional
relevant studies (although I have to say that since I am not an expert
in clinical lung function testing I defer to others for a definitive
judgment on that point).

Noah Seixas	My reading of this presentation would suggest that OSHA has
been overly conservative in it’s conclusion concerning the association
of pulmonary function with the progression of silicosis.  Independent of
the role of emphysema, the literature supports a finding of decreased
lung function with progression of radiological silicosis.  The evidence
is most convincingly presented by the strongest study designs – those
with longitudinal follow-up of the cohorts.  The statement on page 101,
that, “it is plausible that exposure to silica impairs lung function
in at least some individuals at an earlier point in time than can be
detected on chest radiograph,” is unduly conservative.

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?

Bruce Allen	The selection criteria are fairly well laid out on pp.
237-238.  It might have been better to establish the criteria “up
front” in Section C so that as the reader is considering what is
written about each study, s/he can have those criteria as a frame of
reference.  Here, as elsewhere in my comments, I suggest that a summary
table showing how the studies compare to one another with respect to
these criteria would be a useful addition.

Murray Finkelstein	I believe that the selection criteria used by OSHA
are clear. I am not aware of any important studies that have been
missed.

Gary Ginsberg	The selection of studies for this review is described on
Page 115, bottom paragraph.  This description is vague and doesn’t
really describe a selection process with defined criteria.  Rather, it
just states what OSHA reviewed and how this builds on previous reviews.
If there were selection criteria for inclusion in the review or in the
quantitative analysis, this should be made explicit.

Brian Miller	This section of the literature has been reviewed fairly
extensively, and the criteria for inclusion seem reasonable.

Andrew Salmon	This section does a good job of presenting an overview of
the large and complex topic, which is helped by the earlier reviews by
IARC and NIOSH. Unlike the previous section which dealt with silicosis,
this section does present an overview of the various studies not only in
the U.S. but worldwide.

I do not have any specific suggestions as to additional reports to
include.  OSHAs independent review is certainly comprehensive as regards
both the inclusion of relevant studies, and the breadth of different
industries with silica exposure which were considered.  In response to
the question about selection criteria it would appear that OSHA has
taken the inclusive approach of at least describing any possibly
relevant studies, although obviously giving weight in the final analysis
to those offering reasonable determinations of exposure to crystalline
silica, without complicating concurrent exposures to other potentially
carcinogenic materials.

Noah Seixas	While I believe that the review conducted is comprehensive,
and to the degree that I am aware, has not missed any significant
studies, I don’t see a clear presentation of study selection criteria
for the studies reviewed.  I think it would be useful to state in the
beginning of this section how individual studies were selected.
Further, I would be useful to identify any studies that were not
included and provide the rationale for why they were not.

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?

Bruce Allen	This question basically follows on from the question above.
And my answer relates to two studies that were reviewed but excluded,
for reasons that are not entirely clear.  The Brown and Rushton study of
British industrial sand workers was apparently not selected because of
“the low cumulative exposure profile” (p. 179, line 8).  A similar
comment is made about the Ulm et al. study of German stone and ceramic
workers (p. 191, line 4).  There is some discussion of other limiting
factors for these two studies, but it is not clear how those limitations
relate to the selection criteria on pp. 237-238.  In particular, I would
argue that inclusion of studies with low exposures as part of a
dose-response analysis is very useful precisely because such studies
help constrain and define the low-dose (low-exposure) shapes that can be
considered to be consistent with the data and which are particularly
relevant for determining how low exposure must be to be consistent with
non-significant risk levels.

It may be that these two studies have some fatal flaws that the selected
studies do not have, but that is not made clear enough.  In particular,
it needs to be shown that, based on the selection criteria listed, these
two studies are not adequate (or the selection criteria need to be
expanded or refined to truly reflect the selection process that OSHA
used).  Again, a summary tabulation of the studies cross-classified
against the criteria would facilitate such an assessment.

Murray Finkelstein	I believe that, given the abundance of studies, it is
appropriate to weight most highly those studies with the least
confounding (due to the presence of other known carcinogens or the
absence of smoking histories). There has been discussion of
heterogeneity. Little mention was made of exposure misclassification as
a cause of heterogeneity. Of all the silica studies, I have seen the raw
exposure data only for the Vermont granite sheds. In this data set there
are many years in which there was no sampling at all, and a number of
jobs for which very few dust measurements were obtained. It is my
opinion that these data are sparse and much interpolation of uncertain
data is required. These data can certainly be used for quantitative risk
assessment, but the resulting risk estimates will have a large measure
of uncertainty attached. I would not be surprised if the same were true
of most of the other cohorts. Nevertheless, I believe that it is
important to make the best use of whatever data are available. I thus
support the pooling of data from individual studies. I recognize that
the pooling of poor quality data will tend to obscure any relations
between exposure and response. Should an exposure-response relationship
emerge from these analyses, despite the weaknesses, then I believe that
this supports the existence of a real association between exposure and
disease.

Gary Ginsberg	I agree that the 4 industries identified by IARC 1997
(Page 114) and highlighted by OSHA appear to be the most useful for
studying the effects of crystalline silica on workers.

Brian Miller	I agree that these appear the strongest at the time of
review.  There is a new paper on mortality in British coalminers that
has results on respirable quartz and lung cancer, just available online.
 This has among the best-characterised exposures of any studies.

Miller BG, MacCalman L. (2009). Cause-specific mortality in British coal
workers and exposure to respirable dust and quartz. Occup. Environ. Med.
(Published Online First: 9 October 2009. doi:10.1136/oem.2009.046151.

The above paper is summarised from:

Miller BG, MacCalman L, Hutchison PA. (2007). Mortality over an extended
follow-up period in coal workers exposed to respirable dust and quartz.
Edinburgh: Institute of Occupational Medicine.  (IOM Report TM/07/06).
 HYPERLINK "http://www.iom-world.org/pubs/IOM_TM0706rev.pdf"
http://www.iom-world.org/pubs/IOM_TM0706rev.pdf

Andrew Salmon

Andrew Salmon

	I’m not sure exactly which part of the report this charge question is
referring to – the chapter on lung cancer reviews about one hundred
studies in total, with 23 occupational cohort studies, 5 case-control
studies and 5 silicosis cohorts analyzed in detail.  The preliminary
conclusions (on page 237) cite five cohort studies as being “of the
best quality to evaluate exposure to crystalline silica as a risk factor
for lung cancer”.  These were

Diatomaceous Earth Workers (Checkoway et al. 1993, 1996, 1997 and 1999;
Seixas et al. 1997)

British Pottery Workers (Burgess et al., 1997 and 1998; Vherry et al.,
1998; McDonald et al., 1995)

Vermont Granite Workers (Applebaum et al., 2007; Attfield and Costello,
2004; Costello and Graham, 1998; Davis et al., 1983)

North American Industrial Sand Workers (Hughes et al., 2001; McDonald et
al., 2001, 2005; Rando et al., 2001)

North American Industrial Sand Workers (Sanderson et al., 2000;
Steenland and Sanderson, 2001)

This list certainly identifies a selection of key studies with adequate
statistical power and reliability, and reasonable exposure and health
endpoint determination.  It seems to me that the omission of the South
African gold-mining studies is a mistake, particularly with regard to
the more recent reports (Hnizdo and Sluis-Cremer, 1991; Hnizdo et al.,
1997), about which OSHA comments somewhat favorably (page 236).  While
there are some questions about the exposure measurements used and
possible confounding by radon exposure it appear that most of these have
been addressed by related studies.  This group of miners has been an
important source of data on silica effects over the years and
historically these studies have contributed greatly to the worldwide
concern about, and understanding of, silica exposures and health
effects.  The fact that a modern epidemiological study finds a positive
association with lung cancer in this group is an important and
persuasive part of the whole jigsaw-puzzle.  In the last analysis
however the most persuasive part of the argument is not any one of the
single study reports, but the meta-analysis by Steenland et al. (2001a).

Noah Seixas	I think the selected studies are among the most useful and
complete available. Again, I don’t think that OSHA has clearly stated
the criteria for inclusion, and demonstrated that the selected studies
did conform to these criteria, or that they were necessarily superior
with respect to the criteria than other studies which may not have been
included.

Further, OSHA has selected 5 studies in four industries as the most
useful studies available.  While the attributes which are used to make
this judgment are provided, it is not until all the other studies are
reviewed that these criteria a stated (on page 237-8).  Stating these
criteria, and reviewing the literature with them as an explicit goal
could make a more convincing argument that the best studies were in fact
selected.

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.

Bruce Allen	The inclusion of tables appears to be rather hit-or-miss.
For some study summaries a table is given, while for others the odds
ratio results are just presented in the text.  I would rather see a more
consistent presentation and would tend to prefer one that includes more
tables.  This should enhance the comparability of the assessments if the
tables are as consistent as possible across studies.  I have already
mentioned that summary tables of studies cross-categorized against
selection criteria would also be a useful addition.

Murray Finkelstein

Murray Finkelstein	I like Table V-C-1.

Tables V-C-2, V-C-3, and V-C-4 are orphans. It is not clear why results
from only these studies should be presented in tabular format. I would
delete these tables.

Additional Tables:

1) I think that a summary Table describing the characteristics of each
study, such as:

Type of industry

Cohort or case-control

Other confounders?

Adjustment for smoking?

Quantitative exposure estimates?      would be very helpful as an
overview.

2) I think that much of the material in the text could be usefully
summarized in results tables. These would replace the tables mentioned
above and summarize all the data in one place.

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

(  HYPERLINK
"file:///\\\\ERG-LEX-B\\DATA3\\SHARED\\conf\\Projects\\OSHA%20Silica%202
014\\2014%20Peer%20Review%20Report\\(http:\\www.nap.edu\\catalog.php%3fr
ecord_id=11665)"  http://www.nap.edu/catalog.php?record_id=11665)

Gary Ginsberg	See my previous comment (under general comments) regarding
potential improvements to the tables.

Brian Miller

Brian Miller	P113 para 1 delete ‘of’

P129 para 5 i.e. -> e.g.

P130 para 2 participants -> participants’

P141 para 2 base -> based

P141 para 2 Is it correct to describe an ‘elevated risk’ for gastric
cancer with a lower CL of 78?

P142 para 1 The cohort comprised white…

P144 para 1 …from regression models including …

P144 para 1 …exposure to dust could cause death from COPD only …

P156 para 5 …mineworkers who were employed…

P164 para 4  I don’t accept as valid a test of significance for a
pneumoconiosis SMR.  The general population does not contract any
pneumoconiosis, so arguably an SMR for this cause is meaningless;  the
implied null hypothesis is untenable.

P169 para 2 …quartile analysis of average respirable silica
concentration…

Table V-C-2 Average exposure -> Average concentration (throughout)

P183 para 4.  Confusing.  If ‘observed number of cases differed
significantly from expectation’, why is it that the ‘SMR based on
local rates barely missed being statistically significant’?  Are these
not the same, or is one using a different set of comparison rates?

P199 para 2 ‘decreased’ does not seem a good summary of the pattern
here.

P200 para 1 Should ‘a modest non-monotonic trend’ not read ‘no
trend’?  Presumably the ORs are in comparison with the lowest exposure
group, assumed at 1.0.  Did this really yield a p-value of 0.007?

P201 para 2 Follow-up was to 1996, not 1966.

P213 Table V-C-4  The column headed ‘Low/no’ puzzled me, because in
a case-control study it’s common to compare other exposure groups with
the lowest, and set this to an arbitrary level of 1.  However, the
column is simply mislabelled, following a typo in the original paper. In
Table 4 of Calvert et al (2003) the column is headed ‘Ever* low/no’,
and the asterisk leads to a footnote ‘*Ever =medium, high, and super
high categories combined’.  This makes it clear that this column is an
average OR for the exposed categories, and the heading in Table 4 should
have been rendered as ‘Ever* v low/no’.  Perhaps here the heading
should be ‘Ever v low/no’.

P213 Table V-C-4.  The ‘trend’ for lung cancer is not very
convincing, and the increases claimed are not large; a reminder that any
difference can be declared statistically significant with large enough
numbers.

P215 para 3  Variables are not ‘correlated in models’;  their
effects may be, i.e. demonstrate confounding.

P217 para 2.  ‘Gender’ (i.e. sex) was matched for. The analysis
method was unconditional; was gender not adjusted for?

P220 para 1 …range of relative risk estimates was…

P220 para 2 SIR is not an ‘incident rate’ but a ‘Standardized
Incidence Ratio’.

P223 para 1 …supplemented by stepwise multiple regression analysis
using proportional hazards modelling.

P223 para 2 SMRs are ‘Standardized Mortality Ratios’, not
‘standard mortality rates’.  The notions that SMRs were
‘elevated’, ‘there were trends’ that ‘became more
pronounced’, but then none of this was statistically significant,
seems like serious over-claiming.  Another way to put it is that there
was no convincing evidence of a relationship.

P224 para 2 explain what the ‘computer simulations’ were doing here?
 Trying to compensate for an absence of data?

Andrew Salmon	The tables are fine as far as I am concerned

Noah Seixas	Yes, however, there is no table summarizing the strength of
the evidence.  Although it might be more appropriate in the Risk
Assessment section, it might be possible to construct a table
identifying the strengths or weaknesses of each reviewed study (e.g.,
size of cohort, strength of exposure characterization, number of cases,
control of confounding, etc.) and the summary of results in terms of RR
or OR, etc. Such a table could provide an easier way of summarizing the
strength of the evidence, unless the permutations become too unwieldy
for a simple table.

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.

Bruce Allen	I am not aware of any other studies of cancer at other
sites.

Murray Finkelstein	I am not aware of any important studies that have
been missed.

Gary Ginsberg	I am not aware of any additional cancer sites or studies
suitable for this review.

Brian Miller	I’m not aware of any additional studies regarding these
or other sites.

P252 Something wrong with the reference dates?

P258 para 3 …greater than one hundred times…

Andrew Salmon	I am not aware of any additional studies that should be
considered.

Noah Seixas	I am not aware of any other cancer sites of importance with
respect to silica exposure.

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.

Bruce Allen	From the data that have been presented, I would agree that
the risk of cancer at sites other than the lung appears to be much less
well-established and probably less in magnitude (if they exist at all),
compared to the risk of lung cancer.  For that reason I can support
OSHA’s implied decision not to pursue a risk assessment based on
cancers at other sites.

Murray Finkelstein	I agree that definitive associations between silica
exposure and excess mortality from cancer at other sites have not been
established. I think that a potential association between silica
exposure and stomach cancer is provocative, and additional work should
be conducted exploring this connection in a quantitative fashion.

Gary Ginsberg	I agree that the data describing cancer at other target
sites are too limited and in some cases too contradictory to allow OSHA
to make these sites a focus of the risk assessment.

Brian Miller	I agree that the evidence is not convincing for increased
risks at any of these other sites.

Andrew Salmon	I think that is a reasonable conclusion.  There may be
grounds for suspicion of such effects, but they do not reach the level
of certainty to establish such a connection.

Noah Seixas	Given the studies reviewed by OSHA, I would agree with the
assessment that these other cancer sites are not clearly associated with
silica exposure, and if there is an underlying association, there are
insufficient data to provide any strong conclusions at this time.

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.

Bruce Allen	It is not clear from the discussion exactly how these health
endpoints are related to one another.  I am not sure it really matters
that much, since OSHA’s conclusion is that silica exposure (probably)
affects all of them, but a simple flow-chart or other visual, graphical
display of the relationships should suffice.

Murray Finkelstein	Pg 264.  Chronic bronchitis and emphysema are NOT
either/or.  Both conditions may be present together.

Gary Ginsberg

Gary Ginsberg	The non-malignant respiratory disease (NMRD) section reads
well and makes a number of important points regarding the ability of
silica to induce these diseases without the need for silicosis to occur.
 Once again, this information is not tied to the risk assessment, in
particular, how the additional disease entities may add to the number of
silicosis cases or add to the cumulative respiratory disease burden.  In
this regard, the OSHA assessment has the potential to underestimate
silica-related non-cancer risks.

D-1 – OSHA clarification request to Ginsberg: You state that OSHA has
not tied the information on NMRD to the risk assessment, in particular,
“how the additional disease entities may add to the number of
silicosis cases or add to the cumulative respiratory disease burden.”
Could you clarify?

Ginsberg Clarification: My intention with this comment is to point out
the disconnect in the two documents whereby respiratory disease not
classified as silicosis is understood to be related to cumulative silica
exposure in these worker cohorts in a dose response fashion, and yet
there is little analysis of how this additional respiratory disease
burden could be included in a quantitative risk assessment.  The Park et
al. 2002 diatomaceous worker study is included in this section and is
highlighted in the quantitative risk assessment.  Its definition of lung
diseases other than cancer (LDOC) includes the silicosis cases as well
as other diseases logically related to silica exposure to derive a total
lung burden of disease.  The dose response for this endpoint is roughly
10 times more potent than for the pooled silicosis mortality estimate.
This study (Park) attempts to correct for smoking and has other positive
features (high quality exposure assessment; reasonable sample size).
In Table VI-12 and associated text, OSHA considers this as an upper
bound on silicosis-related mortality.  Perhaps the better way to view
the issue is that the Park et al.study represents a reasonable estimate
of silica-induced total respiratory mortality and keep that as a
separate outcome relative to the pooled analysis of silicosis mortality.
 This suggestion is also responsive to the followup question regarding
D-1 posed by OSHA. My relevant comments in response to the quantitative
risk assessment charge are provided below.

“OSHA may want to evaluate whether the LDOC mortality (lung disease
other than cancer, as defined by Park et al., 2002) is the more
appropriate endpoint for silica-induced non-cancer mortality risk.
Right now the focus is on silicosis, which as stated in the document,
can be an underreported condition, sometimes called emphysema or other
lung conditions as a cause of death.  Further, as documented in Section
V, silica can induce a wide variety of lung conditions in addition to,
and without the necessary occurrence of, silicosis.  Therefore, an
additive or more inclusive approach to silica-induced non-cancer risk
assessment (as suggested by the Park et al. 2002 approach) may be more
appropriate.  It is useful that Table VI-12 pulls that data point out
separately but its unclear how much weight will be given to this potency
value.”

Brian Miller	It would be useful to define these terms clearly when they
are first used, including how they are usually defined in both clinical
and epidemiological contexts. It would then be clearer which are subsets
of others. Note that there are several different health endpoints here,
and it may not be appropriate to add together the numbers of cases of
different sorts.

P274 para 1.  Insert a definition of chronic bronchitis at beginning.

P275 para 2 ’reflected’ is vague. Chronic sputum production is a
defining symptom of bronchitis.

P275 para 3 explain “survivor” effect?

P286 para 2  Both ‘dust’ and ‘silica’ exposures are mentioned.
Are these the same?   If so, maybe use ‘silica’ throughout?  If this
section is addressing both silica and mixed dust, don’t jump between
them so much, deal with them separately.

P289 para 1 multivariate analyses -> multiple regression

P292 para 2 delete ‘In a bivariant analysis,’

P293 para 1 multivariate -> multiple regression

P298 para 2 spell out COPD

P308 para 2  Do the ‘overall conclusions’ need to distinguish those
findings related to silica exposure from those associated with
‘dust’?

Andrew Salmon	This section provides a clear and reasonable discussion of
the presence and relationship between these disease endpoints in those
exposed to silica dust.  It is important to emphasize that these
different pulmonary disease manifestations, plus the radiographic
diagnosis of silicosis, are all reflections of an underlying disease
process related to silica exposure, and no single diagnosis includes all
possible individual responses.  It is therefore important to look at all
these diseases entities in assessing the overall disease burden from
exposure to silica dust.

Noah Seixas	This section has a high degree of overlap with section B3,
in which respiratory impairment associated with the appearance of
silicosis is discussed.  It is not clear to me why this section is
presented separately.  Nevertheless, the endpoints discussed a
reasonable, well defined and appropriately reviewed.  Integration of
these studies with those on impairment in silicosis would make more
sense to me.

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.

Bruce Allen	It is clear from the OSHA document itself that there are
data that would support a quantitative risk assessment for at least some
renal or autoimmune diseases (see pp, 320-321, for example).  The
document even states (p 323, lines 20-21) that some of the
exposure-response analyses that have been completed are “credible.”
Coupled with the general tenor of the review of all the studies,
including those for which no quantitative analysis can be completed, I
would conclude that the “sufficiency” of the data (certainly in
terms of amount) is adequate.  I think it is not appropriate to base a
determination of whether or not there are sufficient data for a
quantitative risk assessment of renal or autoimmune disease on a
comparison to what is known about silicosis or lung cancer (p. 344,
lines 14-16).  Certainly, other compounds have been subjects of
quantitative risk assessments with much less data than what is available
for silicosis and lung cancer, and they have been considered adequate
for some level of quantitative evaluation.  One might ask oneself if, in
the absence of the silicosis or lung cancer data, one would use the
renal and/or autoimmune data for silica as the basis of a quantitative
risk assessment and determination of regulatory levels.  I suspect that
one would.

Murray Finkelstein	I agree that there is reasonable evidence to support
an association between silica exposure and renal and autoimmune effects.
I also agree that the data are insufficient in quality to support
quantitative estimates of risk.

Gary Ginsberg	I agree with the OSHA analysis that the data are
insufficient for quantitative risk assessment on these non-cancer
endpoints.

Brian Miller	I agree that a full quantitative assessment is not yet
possible.

Andrew Salmon	OSHA comments in the description of the available studies
that the evidence is convincing for an association between renal disease
and exposure to silica.  This certainly seems to be the case, in that
there are a substantial number of positive epidemiological studies
finding such an effect, as well as a large number of case reports.  The
plausibility of a causal association is enhanced by various laboratory
studies, finding of silica particles in kidney tissues, etc., which lay
the foundation for a reasonable mechanistic explanation of how such an
effect might occur.  The existence of a few “negative” (i.e.
non-positive) reports is not a convincing counter-argument, since these
observations could easily be explained by low power, misclassification
of exposures, competing effects and various other features of those
studies.  In general, one or more good positive epidemiological studies
are much more convincing than any number of studies which failed to find
any clear result.

OSHA’s chapter on this topic also specifically describes at least two
recent and major studies (McDonald et al., 2005 and the pooled analysis
by Steenland et al., 2002a) which explicitly determine a quantitative
relationship between silica exposure and renal disease.  Although
McDonald et al. do not argue in favor of a causative explanation for
their observation, this may be simply a case of those authors confining
their comments to a conservative interpretation of their own data,
rather than attempting to consider the implications of the whole body of
published evidence on the topic.  OSHA’s reluctance to consider a
quantitative analysis of renal disease and mortality therefore seems
unjustified.  It would be entirely reasonable to endorse the existing
quantitative analysis by Steenland et al. (2002a), particularly as many
aspects of this cohort and the accompanying exposure data have been
extensively validated in the consideration of silicosis and lung cancer.
 OSHA’s conclusion on page 345 states that there are “only two
studies on renal disease provide quantitative exposure-response data”
– this in itself is something of an understatement, but even as it
stands it contradicts the following sentence which asserts that the data
are “insufficient”.  OSHA does not define what it means by a
“robust” estimate, but seems to be using this nebulous desideratum
to hide behind in this case.

The data on rheumatoid arthritis and other autoimmune conditions also
include some published quantitative analyses, so it is somewhat
disingenuous of OSHA to contend that the data will not “support
quantitative estimates of risk” when that is precisely what some
authors have successfully provided.  However, the issue is not whether
such estimates can be made, but what level of confidence should be
placed in them and whether they have any implications for setting
health-protective policy.  In the case of the arthritis and autoimmune
responses obviously the data are somewhat less convincing and
comprehensive, due at least in part to the complexity and variability of
this type of disease.  It could certainly be argued that the
quantitative estimates available for these health endpoints are somewhat
uncertain, and the links required to confidently assume causality are
not as well established as for the other endpoints discussed in this
section.  This is not in itself a good argument for dismissing the
effort to apply a quantitative analysis even where substantial
uncertainties are present, although obviously the associated
uncertainties would need to be addressed when considering the results.
Indeed, it is particularly important to pursue an appropriate
quantitative analysis where possible in such a case, because it is only
by use of quantitative analytical techniques that the situation can be
properly defined, including identification of the sources and extent of
uncertainty, and estimation of confidence limits as well as measures of
central tendency for key dose-response parameters.

Noah Seixas	While the data appear to be sufficient to associate silica
exposure with these endpoints, I would agree that there are insufficient
data for a quantitative risk assessment at this time.  If one required
quantitative estimates of the risk of renal disease and silica exposure,
it would be feasible, given the available studies.  However, I don’t
see a compelling reason to do so, given the much more robust data
resources on silicosis and lung cancer.  Nevertheless, the clear
association of renal and autoimmune disease endpoints with silica
exposure is an important piece of the overall health effects assessment.

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.

Bruce Allen	I have no independent knowledge of what recent thinking has
been on the topic of proposed mechanisms, so I have no way of addressing
this question.

Murray Finkelstein	I am not competent to discuss mechanisms.

Gary Ginsberg	The proposed mechanisms of action for silicosis and lung
cancer are not spelled out in any detail and I would more refer to these
as “Mode of Action” descriptions (overall process rather than
detailed biochemical explanation).  As a MOA description, the current
document appears to adequately cover the potential pathways involved.  I
would have liked to have seen more about silica accumulation in the lung
and what governs deposition and retention.

Brian Miller	My knowledge and experience do not qualify me to comment on
the biological mechanisms proposed.

P360 para 1 Other work has also shown agreement with surface area as a
metric.  Include references?

P360 para 2 then -> than

P366 para 2 then -> than

P378 para 2 quart -> quartz

P396 para 1 This refers to more severe silicosis, and not to the milder
definitions sometimes used elsewhere (e.g. ILO 1/0+)

Andrew Salmon	As far as I am aware this discussion reflects current
thinking on this topic.  The various identified markers of inflammatory
response, and the likely involvement of reactive oxygen toxicity are
widely thought to play a role in both silicosis and lung cancer,
although obviously at this point there is no absolute and complete
description of the mechanism of action for either endpoint.

Noah Seixas	I am not qualified to discuss physical factors in any depth.
 The data presented by OSHA concerning these aspects of silica exposure
and risk appear to be well documented, thorough, and support the
conclusions made in the document.

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.

Bruce Allen	I have no independent knowledge of what the current
scientific opinion is on the topic of the role of silicosis as a
precursor for lung cancer, so I have no way of addressing this question.

Murray Finkelstein	I believe that this discussion does accurately
reflect the current scientific opinion on this issue.

Gary Ginsberg	This section makes a major point that silicosis is not a
prerequisite for lung cancer induction as there are mechanisms
independent of tissue damage that can instigate the oncogenic process.
However, what is unclear from this description and the underlying cited
papers is the extent to which silicosis can enhance or synergize the DNA
damaging effect of silica.   Thus, while there is substantial evidence
that silicosis is not required for oncogenic potential, the degree of
enhancement and how this affects the dose response and risk assessment
is unclear.

Brian Miller	P401 para 2 Silicosis cannot be a ‘prerequisite for lung
cancer’ - many people contract lung cancer without either silicosis or
silica exposure - and so this phrase should never be used unqualified.
Whether any excess silica-related lung cancer risk operates through
fibrosis or other aspects of the silicotic response is a difficult
question, and the text reflects this.

Andrew Salmon

Andrew Salmon

	This discussion presents several key points on this question, which I
believe reflect current thinking.  It seems likely that both silicosis
and lung cancer share some common mechanistic steps at the beginning of
the processes which lead to these responses, but it is simply unknown
how far up the chain of events this commonality extends.  One key
difficulty with the underlying question is what initial stages can be
properly called “silicosis” in this context.

As has been eloquently described elsewhere in this section, the standard
indicators used to diagnose silicosis are X-radiography and post-mortem
histology, both of which are “late” indicators and will certainly
not serve to identify initial stages of the disease which might, or
might not, be required steps in the eventual  development of lung
cancer.

Noah Seixas	I am not qualified to discuss the biological basis of silica
toxicity in any depth.  The data presented appear well documented,
relevant to our understanding of silica health effects, and
appropriately interpreted.

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?

Bruce Allen	It appears from the discussion that there are several and
various factors that could modify the toxicity of silica, both for lung
cancer and silicosis.  At this time, the manner in which they act
(individually or in combination) does not appear to be well understood
(although there are some ideas) and certainly does not appear to be
quantifiable.  Thus, I conclude that an overall (“average”) measure
of risk is all that can be derived and applied at this point in time.
Basing any regulatory decisions or limits on a range of risk estimates
(as OSHA appears to be doing in the quantitative risk section) should
reflect at least some of the variation that could be associated with the
physical characteristics.  That appears to be a satisfactory approach at
the current time, pending accumulation of additional relevant
information that might allow a more context-specific set of risk
estimates.

Murray Finkelstein	I agree that it is not possible, at the present time,
to include information on physical factors in quantitative risk
assessment. I think that the OSHA discussion is clear.

Editorial Comments on the Text

1. Page 12 Paragraph 1: There is a typo in the last sentence... a phrase
is duplicated

2. The word “data” is plural. Thus, for example, Page 13, last
sentence paragraph 2, “The modern data was” should be “The modern
data were”

3. Pg 16 first sentence and Pg 21.  “Ends of the lung tissue” is a
poorly chosen phrase.

4. Pg 16 Para 4 line 2: “infrequently” should be replaced by “in
low density”.  “Frequency” is not an appropriate word in this
paragraph.

5. Pg 71: “In considering the exposure-response relationship with a
progressive condition like silica, the effect variable (in this case
silicosis) takes on a more continuous and less discrete nature.”.... I
don’t understand what this sentence means.

Gary Ginsberg	The document spends considerable effort to explain various
physical factors and how they may influence crystalline silica potency
in the lung.  This would appear to create a substantial uncertainty in
the risk assessment as the most relevant study for a given occupation
may not be known.  It might be tempting to have a separate potency
factor for each industrial sector based upon prior studies of that
sector.  In theory, the surface properties at play in the published
study may still be present in today’s workers and may differ
substantially from other industrial sectors.  Therefore, to address this
issue, OSHA may want to either select the highest potency factor across
the board to cover the possibility that the workers might be exposed to
the most aggressive form in any given occupation.  Alternatively, OSHA
may apply a potency value specific to the industrial sector in the hopes
of capturing the silica properties specific to that industry.  It is
unclear how the OSHA risk range will in practice be applied, so I
don’t necessarily endorse this approach.

F-3 – OSHA clarification request to Ginsberg:  You suggest OSHA could
assign industry-specific potency values to account for differences in
quartz particle toxicities, but that you don’t necessarily endorse
“this” approach.  Do you mean the estimation of industry-specific
potency factors?

Ginsberg Response: I do not necessarily endorse industry-specific
potency factors.  Given how the physical state of crystalline silica may
vary across industries in a manner that could affect risk, ideally it
would be possible to make such distinctions.  However, this may not be
feasible for a number of reasons.  Rather, I raise the suggestion that
OSHA evaluate whether individual industries show a greater dose
response.  If so, they should decide whether it makes sense to identify
a plausible upper end of the potency range based upon a robust data set
from a specific industry which has defined silica physical
characteristics.  The discussion of this issue in the current draft
represents an uncertainty that is not really dealt with.

Brian Miller	Experiments in vitro and in vivo suggest that the toxicity
of silica varies between samples from different sources, and that some
external factors can modify the response to either reduce or intensify
the effects.  It’s difficult to see how those results could be
generalized from present knowledge.  The prudent approach is to regulate
for those situations where at is most toxic; I don’t see how you could
adjust the regulation across different industries or situations where
the toxicity differs.

Andrew Salmon	I consider that the description presented here is a clear,
fair and reasonable analysis of an admittedly complicated situation.  It
seems to be the case that different samples of crystalline silica dust
do present quantitatively (although probably not qualitatively)
different hazards  Differences between samples appear to be of basically
unknown origin.  Factors such as recent cleavage, occlusion by other
minerals, surface contaminants and so on may well influence potency, but
it has not been possible to consistently or quantitatively establish
these connections.  The only physical characteristic which does seem to
have been established as definitive is particle size – the particles
need to be respirable to cause the effect.

Noah Seixas	Given the historical suggestion that polymorphs other than
quartz had higher toxicity, this is an important discussion.  I agree
that there is insufficient evidence available to suggest that this is
true, and in fact, most of the evidence presented suggests that the
polymorphs are of comparable toxicity.  Further, the evidence concerning
freshly fractured silica and silica in mixed moiety (e.g. clay) have
lower toxicity is important and compelling.  However, I think OSHA has
presented the evidence as completely as possible, and made reasonable
conclusions based on the evidence.  I agree with OSHA that there is
insufficient evidence or consistency in the data to provide guidance on
differential control of exposure based on physical and surface
characteristics.

Additional Comments/References

Bruce Allen	None.

Murray Finkelstein	None.

Gary Ginsberg	None.

Brian Miller	None.

Andrew Salmon	References

(other than those cited in the Health Effects document)

Beadle DG, Bradley AA. 1970. The composition of airborne dust in South
African gold mines. In: Shapiro HA (ed). Pneumoconiosis. Proceedings of
the International Conference. Johannesburg 1969. Cape Town: Oxford
University Press. pp. 462-6.

Page-Shipp RJ, Harris E. 1972. A study of dust exposure of South African
white gold miners. South Afr Inst Mining Metall. 73:10-24.

Schenker MB, Pinkerton KE, Mitchell D, Vallyathan V, Elvine-Kreis B,
Green FHY (2009).  Pneumoconiosis from Agricultural Dust Exposure among
Young California Farmworkers.  Environmental Health Perspectives 117(6):
988–994.

Noah Seixas	None.

Individual Review Comments

Bruce Allen

Bruce Allen Consulting, Chapel Hill, NC

Review of OSHA’s Preliminary Health Effects Section for Silica

Comments from Bruce Allen

General Questions

1.	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.

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 subheaders (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.

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.

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.

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.

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

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?

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.

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?

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.

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?

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.

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?

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.

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)?

I am not aware of any such studies.

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?

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.

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?

The selection criteria are fairly well laid out on pp. 237-238.  It
might have been better to establish the criteria “up front” in
Section C so that as the reader is considering what is written about
each study, s/he can have those criteria as a frame of reference.  Here,
as elsewhere in my comments, I suggest that a summary table showing how
the studies compare to one another with respect to these criteria would
be a useful addition.

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?

This question basically follows on from the question above.  And my
answer relates to two studies that were reviewed but excluded, for
reasons that are not entirely clear.  The Brown and Rushton study of
British industrial sand workers was apparently not selected because of
“the low cumulative exposure profile” (p. 179, line 8).  A similar
comment is made about the Ulm et al. study of German stone and ceramic
workers (p. 191, line 4).  There is some discussion of other limiting
factors for these two studies, but it is not clear how those limitations
relate to the selection criteria on pp. 237-238.  In particular, I would
argue that inclusion of studies with low exposures as part of a
dose-response analysis is very useful precisely because such studies
help constrain and define the low-dose (low-exposure) shapes that can be
considered to be consistent with the data and which are particularly
relevant for determining how low exposure must be to be consistent with
non-significant risk levels.

It may be that these two studies have some fatal flaws that the selected
studies do not have, but that is not made clear enough.  In particular,
it needs to be shown that, based on the selection criteria listed, these
two studies are not adequate (or the selection criteria need to be
expanded or refined to truly reflect the selection process that OSHA
used).  Again, a summary tabulation of the studies cross-classified
against the criteria would facilitate such an assessment.

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.

The inclusion of tables appears to be rather hit-or-miss.  For some
study summaries a table is given, while for others the odds ratio
results are just presented in the text.  I would rather see a more
consistent presentation and would tend to prefer one that includes more
tables.  This should enhance the comparability of the assessments if the
tables are as consistent as possible across studies.  I have already
mentioned that summary tables of studies cross-categorized against
selection criteria would also be a useful 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.

I am not aware of any other studies of cancer at other sites.

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.

From the data that have been presented, I would agree that the risk of
cancer at sites other than the lung appears to be much less
well-established and probably less in magnitude (if they exist at all),
compared to the risk of lung cancer.  For that reason I can support
OSHA’s implied decision not to pursue a risk assessment based on
cancers at other sites.

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.

It is not clear from the discussion exactly how these health endpoints
are related to one another.  I am not sure it really matters that much,
since OSHA’s conclusion is that silica exposure (probably) affects all
of them, but a simple flow-chart or other visual, graphical display of
the relationships should suffice.

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.

It is clear from the OSHA document itself that there are data that would
support a quantitative risk assessment for at least some renal or
autoimmune diseases (see pp, 320-321, for example).  The document even
states (p 323, lines 20-21) that some of the exposure-response analyses
that have been completed are “credible.”  Coupled with the general
tenor of the review of all the studies, including those for which no
quantitative analysis can be completed, I would conclude that the
“sufficiency” of the data (certainly in terms of amount) is
adequate.  I think it is not appropriate to base a determination of
whether or not there are sufficient data for a quantitative risk
assessment of renal or autoimmune disease on a comparison to what is
known about silicosis or lung cancer (p. 344, lines 14-16).  Certainly,
other compounds have been subjects of quantitative risk assessments with
much less data than what is available for silicosis and lung cancer, and
they have been considered adequate for some level of quantitative
evaluation.  One might ask oneself if, in the absence of the silicosis
or lung cancer data, one would use the renal and/or autoimmune data for
silica as the basis of a quantitative risk assessment and determination
of regulatory levels.  I suspect that one would.

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.

I have no independent knowledge of what recent thinking has been on the
topic of proposed mechanisms, so I have no way of addressing this
question.

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.

I have no independent knowledge of what the current scientific opinion
is on the topic of the role of silicosis as a precursor for lung cancer,
so I have no way of addressing this question.

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?

It appears from the discussion that there are several and various
factors that could modify the toxicity of silica, both for lung cancer
and silicosis.  At this time, the manner in which they act (individually
or in combination) does not appear to be well understood (although there
are some ideas) and certainly does not appear to be quantifiable.  Thus,
I conclude that an overall (“average”) measure of risk is all that
can be derived and applied at this point in time.  Basing any regulatory
decisions or limits on a range of risk estimates (as OSHA appears to be
doing in the quantitative risk section) should reflect at least some of
the variation that could be associated with the physical
characteristics.  That appears to be a satisfactory approach at the
current time, pending accumulation of additional relevant information
that might allow a more context-specific set of risk estimates.

Murray Finkelstein

McMaster University, Thornhill, ON Canada

  SEQ CHAPTER \h \r 1 	Peer Review Comments on Silica Health Effects
Document

General Questions

1.	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.

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

	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 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.

3. 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.

I am not aware of any additional significant health endpoints.

4. 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?

The discussion is clear and the conclusions are reasonable.

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?

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

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?

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.

B-2 Surveillance

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?

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

B-3 Progression

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)?

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

B-4 PFT

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?

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.

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?

I believe that the selection criteria used by OSHA are clear. I am not
aware of any important studies that have been missed.

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?

I believe that, given the abundance of studies, it is appropriate to
weight most highly those studies with the least confounding (due to the
presence of other known carcinogens or the absence of smoking
histories). There has been discussion of heterogeneity. Little mention
was made of exposure misclassification as a cause of heterogeneity. Of
all the silica studies, I have seen the raw exposure data only for the
Vermont granite sheds. In this data set there are many years in which
there was no sampling at all, and a number of jobs for which very few
dust measurements were obtained. It is my opinion that these data are
sparse and much interpolation of uncertain data is required. These data
can certainly be used for quantitative risk assessment, but the
resulting risk estimates will have a large measure of uncertainty
attached. I would not be surprised if the same were true of most of the
other cohorts. Nevertheless, I believe that it is important to make the
best use of whatever data are available. I thus support the pooling of
data from individual studies. I recognize that the pooling of poor
quality data will tend to obscure any relations between exposure and
response. Should an exposure-response relationship emerge from these
analyses, despite the weaknesses, then I believe that this supports the
existence of a real association between exposure and disease.

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.

I like Table V-C-1.

Tables V-C-2, V-C-3, and V-C-4 are orphans. It is not clear why results
from only these studies should be presented in tabular format. I would
delete these tables.

Additional Tables:

1) I think that a summary Table describing the characteristics of each
study, such as:

Type of industry

Cohort or case-control

Other confounders?

Adjustment for smoking?

Quantitative exposure estimates?

would be very helpful as an overview.

2) I think that much of the material in the text could be usefully
summarized in results tables. These would replace the tables mentioned
above and summarize all the data in one place.

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

(  HYPERLINK
"file:///\\\\ERG-LEX-B\\DATA3\\SHARED\\conf\\Projects\\OSHA%20Silica%202
014\\2014%20Peer%20Review%20Report\\(http:\\www.nap.edu\\catalog.php%3fr
ecord_id=11665)"  http://www.nap.edu/catalog.php?record_id=11665)

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.

I am not aware of any important studies that have been missed.

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.

I agree that definitive associations between silica exposure and excess
mortality from cancer at other sites have not been established. I think
that a potential association between silica exposure and stomach cancer
is provocative, and additional work should be conducted exploring this
connection in a quantitative fashion.

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.

Pg 264.  Chronic bronchitis and emphysema are NOT either/or.  Both
conditions may be present together.

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.

I agree that there is reasonable evidence to support an association
between silica exposure and renal and autoimmune effects. I also agree
that the data are insufficient in quality to support quantitative
estimates of risk.

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.

I am not competent to discuss mechanisms.

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.

I believe that this discussion does accurately reflect the current
scientific opinion on this issue.

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?

I agree that it is not possible, at the present time, to include
information on physical factors in quantitative risk assessment. I think
that the OSHA discussion is clear.

Editorial Comments on the Text

1. Page 12 Paragraph 1: There is a typo in the last sentence... a phrase
is duplicated

2. The word “data” is plural. Thus, for example, Page 13, last
sentence paragraph 2, “The modern data was” should be “The modern
data were”

3. Pg 16 first sentence and Pg 21.  “Ends of the lung tissue” is a
poorly chosen phrase.

4. Pg 16 Para 4 line 2: “infrequently” should be replaced by “in
low density”.  “Frequency” is not an appropriate word in this
paragraph.

5. Pg 71: “In considering the exposure-response relationship with a
progressive condition like silica, the effect variable (in this case
silicosis) takes on a more continuous and less discrete nature.”......
 I don’t understand what this sentence means.

Gary Ginsberg

Connecticut Department of Public Health, Hartford, CT

Response to Charge Questions

OSHA’s Preliminary Health Effects Section for Silica

ERG Task # 0<IP_ADDRESS>

Reviewer:  Gary Ginsberg

November 4th 2009

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.

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.

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.

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.

A-1.  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.

B-1.  I do not have the technical expertise to comment on whether OSHA
descriptions of radiological and pulmonary function tests are accurate.

B-2.  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.

B-3.  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.

B-4.  The pulmonary function test results section appears to be a
reasonable discussion on the evidence surrounding PFT changes and
radiographic evidence of pathology.  I have no studies to add.

C-1.  The selection of studies for this review is described on Page 115,
bottom paragraph.  This description is vague and doesn’t really
describe a selection process with defined criteria.  Rather, it just
states what OSHA reviewed and how this builds on previous reviews.  If
there were selection criteria for inclusion in the review or in the
quantitative analysis, this should be made explicit.

C-2.  I agree that the 4 industries identified by IARC 1997 (Page 114)
and highlighted by OSHA appear to be the most useful for studying the
effects of crystalline silica on workers.

C-3.  See my previous comment (under general comments) regarding
potential improvements to the tables.

C-4.  I am not aware of any additional cancer sites or studies suitable
for this review.

C-5.  I agree that the data describing cancer at other target sites are
too limited and in some cases too contradictory to allow OSHA to make
these sites a focus of the risk assessment.

D-1.  The non-malignant respiratory disease (NMRD) section reads well
and makes a number of important points regarding the ability of silica
to induce these diseases without the need for silicosis to occur.  Once
again, this information is not tied to the risk assessment, in
particular, how the additional disease entities may add to the number of
silicosis cases or add to the cumulative respiratory disease burden.  In
this regard, the OSHA assessment has the potential to underestimate
silica-related non-cancer risks.

D-1 – OSHA question to Ginsberg: You state that OSHA has not tied the
information on NMRD to the risk assessment, in particular, “how the
additional disease entities may add to the number of silicosis cases or
add to the cumulative respiratory disease burden.”  Could you clarify?

Response:  My intention with this comment is to point out the disconnect
in the two documents whereby respiratory disease not classified as
silicosis is understood to be related to cumulative silica exposure in
these worker cohorts in a dose response fashion, and yet there is little
analysis of how this additional respiratory disease burden could be
included in a quantitative risk assessment.  The Park et al. 2002
diatomaceous worker study is included in this section and is highlighted
in the quantitative risk assessment.  Its definition of lung diseases
other than cancer (LDOC) includes the silicosis cases as well as other
diseases logically related to silica exposure to derive a total lung
burden of disease.  The dose response for this endpoint is roughly 10
times more potent than for the pooled silicosis mortality estimate.
This study (Park) attempts to correct for smoking and has other positive
features (high quality exposure assessment; reasonable sample size).
In Table VI-12 and associated text, OSHA considers this as an upper
bound on silicosis-related mortality.  Perhaps the better way to view
the issue is that the Park et al. study represents a reasonable estimate
of silica-induced total respiratory mortality and keep that as a
separate outcome relative to the pooled analysis of silicosis mortality.
 This suggestion is also responsive to the followup question regarding
D-1 posed by OSHA.

My relevant comments in response to the quantitative risk assessment
charge are pasted below.

“OSHA may want to evaluate whether the LDOC mortality (lung disease
other than cancer, as defined by Park et al., 2002) is the more
appropriate endpoint for silica-induced non-cancer mortality risk.
Right now the focus is on silicosis, which as stated in the document,
can be an underreported condition, sometimes called emphysema or other
lung conditions as a cause of death.  Further, as documented in Section
V, silica can induce a wide variety of lung conditions in addition to,
and without the necessary occurrence of, silicosis.  Therefore, an
additive or more inclusive approach to silica-induced non-cancer risk
assessment (as suggested by the Park et al. 2002 approach) may be more
appropriate.  It is useful that Table VI-12 pulls that data point out
separately but its unclear how much weight will be given to this potency
value.”

E-1.  I agree with the OSHA analysis that the data are insufficient for
quantitative risk assessment on these non-cancer endpoints.

F-1.  The proposed mechanisms of action for silicosis and lung cancer
are not spelled out in any detail and I would more refer to these as
“Mode of Action” descriptions (overall process rather than detailed
biochemical explanation).  As a MOA description, the current document
appears to adequately cover the potential pathways involved.  I would
have liked to have seen more about silica accumulation in the lung and
what governs deposition and retention.

F-2.  This section makes a major point that silicosis is not a
prerequisite for lung cancer induction as there are mechanisms
independent of tissue damage that can instigate the oncogenic process.
However, what is unclear from this description and the underlying cited
papers is the extent to which silicosis can enhance or synergize the DNA
damaging effect of silica.   Thus, while there is substantial evidence
that silicosis is not required for oncogenic potential, the degree of
enhancement and how this affects the dose response and risk assessment
is unclear.

F-3.  The document spends considerable effort to explain various
physical factors and how they may influence crystalline silica potency
in the lung.  This would appear to create a substantial uncertainty in
the risk assessment as the most relevant study for a given occupation
may not be known.  It might be tempting to have a separate potency
factor for each industrial sector based upon prior studies of that
sector.  In theory, the surface properties at play in the published
study may still be present in today’s workers and may differ
substantially from other industrial sectors.  Therefore, to address this
issue, OSHA may want to either select the highest potency factor across
the board to cover the possibility that the workers might be exposed to
the most aggressive form in any given occupation.  Alternatively, OSHA
may apply a potency value specific to the industrial sector in the hopes
of capturing the silica properties specific to that industry.  It is
unclear how the OSHA risk range will in practice be applied, so I
don’t necessarily endorse this approach.

F-3 – OSHA question to Ginsberg:  You suggest OSHA could assign
industry-specific potency values to account for differences in quartz
particle toxicities, but that you don’t necessarily endorse “this”
approach.  Do you mean the estimation of industry-specific potency
factors?

	Response:  Right, I don’t necessarily endorse industry-specific
potency factors.  Given how the physical state of crystalline silica may
vary across industries in a manner that could affect risk, ideally it
would be possible to make such distinctions.  However, this may not be
feasible for a number of reasons.  Rather, I raise the suggestion that
OSHA evaluate whether individual industries show a greater dose
response.  If so, they should decide whether it makes sense to identify
a plausible upper end of the potency range based upon a robust data set
from a specific industry which has defined silica physical
characteristics.  The discussion of this issue in the current draft
represents an uncertainty that is not really dealt with.

Brian Miller

IOM Consulting Ltd., Scotland, UK

Response to Technical Charge to External Peer Reviewers

ERG Contract No. GS-10F-0125P

BPA No. DOLQ059622303

ERG Task No. 0<IP_ADDRESS>

Review of OSHA’s Preliminary Health Effects Section for Silica

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.

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.

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.

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

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.

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

The draft health 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?

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.

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?

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?

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?

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.?

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?

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.

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)?

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

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?

This section might go a little further to emphasise how the
inter-individual variation on lung function measurements between healthy
subjects of the same height and age makes it difficult to detect
abnormality cross-sectionally.  The idea of the lower 5% being
automatically accepted as ‘abnormal’ is reported rather
uncritically.

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?

This section of the literature has been reviewed fairly extensively, and
the criteria for inclusion seem reasonable.

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?

I agree that these appear the strongest at the time of review.  There is
a new paper on mortality in British coalminers that has results on
respirable quartz and lung cancer, just available online.  This has
among the best-characterised exposures of any studies.

Miller BG, MacCalman L. (2009). Cause-specific mortality in British coal
workers and exposure to respirable dust and quartz. Occup. Environ. Med.
(Published Online First: 9 October 2009. doi:10.1136/oem.2009.046151.

The above paper is summarised from:

Miller BG, MacCalman L, Hutchison PA. (2007). Mortality over an extended
follow-up period in coal workers exposed to respirable dust and quartz.
Edinburgh: Institute of Occupational Medicine.  (IOM Report TM/07/06).
 HYPERLINK "http://www.iom-world.org/pubs/IOM_TM0706rev.pdf"
http://www.iom-world.org/pubs/IOM_TM0706rev.pdf

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.

P113 para 1 delete ‘of’

P129 para 5 i.e. -> e.g.

P130 para 2 participants -> participants’

P141 para 2 base -> based

P141 para 2 Is it correct to describe an ‘elevated risk’ for gastric
cancer with a lower CL of 78?

P142 para 1 The cohort comprised white…

P144 para 1 …from regression models including …

P144 para 1 …exposure to dust could cause death from COPD only …

P156 para 5 …mineworkers who were employed…

P164 para 4  I don’t accept as valid a test of significance for a
pneumoconiosis SMR.  The general population does not contract any
pneumoconiosis, so arguably an SMR for this cause is meaningless;  the
implied null hypothesis is untenable.

P169 para 2 …quartile analysis of average respirable silica
concentration…

Table V-C-2 Average exposure -> Average concentration (throughout)

P183 para 4.  Confusing.  If ‘observed number of cases differed
significantly from expectation’, why is it that the ‘SMR based on
local rates barely missed being statistically significant’?  Are these
not the same, or is one using a different set of comparison rates?

P199 para 2 ‘decreased’ does not seem a good summary of the pattern
here.

P200 para 1 Should ‘a modest non-monotonic trend’ not read ‘no
trend’?  Presumably the ORs are in comparison with the lowest exposure
group, assumed at 1.0.  Did this really yield a p-value of 0.007?

P201 para 2 Follow-up was to 1996, not 1966.

P213 Table V-C-4  The column headed ‘Low/no’ puzzled me, because in
a case-control study it’s common to compare other exposure groups with
the lowest, and set this to an arbitrary level of 1.  However, the
column is simply mislabelled, following a typo in the original paper. In
Table 4 of Calvert et al (2003) the column is headed ‘Ever* low/no’,
and the asterisk leads to a footnote ‘*Ever =medium, high, and super
high categories combined’.  This makes it clear that this column is an
average OR for the exposed categories, and the heading in Table 4 should
have been rendered as ‘Ever* v low/no’.  Perhaps here the heading
should be ‘Ever v low/no’.

P213 Table V-C-4.  The ‘trend’ for lung cancer is not very
convincing, and the increases claimed are not large; a reminder that any
difference can be declared statistically significant with large enough
numbers.

P215 para 3  Variables are not ‘correlated in models’;  their
effects may be, i.e. demonstrate confounding.

P217 para 2.  ‘Gender’ (i.e. sex) was matched for. The analysis
method was unconditional; was gender not adjusted for?

P220 para 1 …range of relative risk estimates was…

P220 para 2 SIR is not an ‘incident rate’ but a ‘Standardized
Incidence Ratio’.

P223 para 1 …supplemented by stepwise multiple regression analysis
using proportional hazards modelling.

P223 para 2 SMRs are ‘Standardized Mortality Ratios’, not
‘standard mortality rates’.  The notions that SMRs were
‘elevated’, ‘there were trends’ that ‘became more
pronounced’, but then none of this was statistically significant,
seems like serious over-claiming.  Another way to put it is that there
was no convincing evidence of a relationship.

P224 para 2 explain what the ‘computer simulations’ were doing here?
 Trying to compensate for an absence of data?

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.

I’m not aware of any additional studies regarding these or other
sites.

P252 Something wrong with the reference dates?

P258 para 3 …greater than one hundred times…

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.

I agree that the evidence is not convincing for increased risks at any
of these other sites.

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.

It would be useful to define these terms clearly when they are first
used, including how they are usually defined in both clinical and
epidemiological contexts. It would then be clearer which are subsets of
others. Note that there are several different health endpoints here, and
it may not be appropriate to add together the numbers of cases of
different sorts.

P274 para 1.  Insert a definition of chronic bronchitis at beginning.

P275 para 2 ’reflected’ is vague. Chronic sputum production is a
defining symptom of bronchitis.

P275 para 3 explain “survivor” effect?

P286 para 2  Both ‘dust’ and ‘silica’ exposures are mentioned.
Are these the same?   If so, maybe use ‘silica’ throughout?  If this
section is addressing both silica and mixed dust, don’t jump between
them so much, deal with them separately.

P289 para 1 multivariate analyses -> multiple regression

P292 para 2 delete ‘In a bivariant analysis,’

P293 para 1 multivariate -> multiple regression

P298 para 2 spell out COPD

P308 para 2  Do the ‘overall conclusions’ need to distinguish those
findings related to silica exposure from those associated with
‘dust’?

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.

I agree that a full quantitative assessment is not yet possible.

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.

My knowledge and experience do not qualify me to comment on the
biological mechanisms proposed.

P360 para 1 Other work has also shown agreement with surface area as a
metric.  Include references?

P360 para 2 then -> than

P366 para 2 then -> than

P378 para 2 quart -> quartz

P396 para 1 This refers to more severe silicosis, and not to the milder
definitions sometimes used elsewhere (e.g. ILO 1/0+)

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.

P401 para 2 Silicosis cannot be a ‘prerequisite for lung cancer’ -
many people contract lung cancer without either silicosis or silica
exposure - and so this phrase should never be used unqualified. Whether
any excess silica-related lung cancer risk operates through fibrosis or
other aspects of the silicotic response is a difficult question, and the
text reflects this.

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?

Experiments in vitro and in vivo suggest that the toxicity of silica
varies between samples from different sources, and that some external
factors can modify the response to either reduce or intensify the
effects.  It’s difficult to see how those results could be generalized
from present knowledge.  The prudent approach is to regulate for those
situations where at is most toxic; I don’t see how you could adjust
the regulation across different industries or situations where the
toxicity differs.

Andrew Salmon

Private Consultant, Lafayette, CA

Review of OSHA’s Preliminary Health Effects Section for Silica

General Questions

1.	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.

Response:

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.

2.	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.

Response:

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.

3.	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.

Response:

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

4.	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?

Response:

The health effects summaries are clear and reasonable.

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?

Response:

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.

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?

Response:

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.

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?

Response:

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.

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)?

Response:

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.

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?

Response:

I think this section is reasonable and well-considered.  The conclusions
drawn are cautious and defensible.  Given the complex and conflicting
nature of the data I think this chapter does an excellent job of the
analysis.  I am not aware of any additional relevant studies (although I
have to say that since I am not an expert in clinical lung function
testing I defer to others for a definitive judgment on that point).

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?

Response:

This section does a good job of presenting an overview of the large and
complex topic, which is helped by the earlier reviews by IARC and NIOSH.
Unlike the previous section which dealt with silicosis, this section
does present an overview of the various studies not only in the U.S. but
worldwide.

I do not have any specific suggestions as to additional reports to
include.  OSHAs independent review is certainly comprehensive as regards
both the inclusion of relevant studies, and the breadth of different
industries with silica exposure which were considered.  In response to
the question about selection criteria it would appear that OSHA has
taken the inclusive approach of at least describing any possibly
relevant studies, although obviously giving weight in the final analysis
to those offering reasonable determinations of exposure to crystalline
silica, without complicating concurrent exposures to other potentially
carcinogenic materials.

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?

Response:

 I’m not sure exactly which part of the report this charge question is
referring to – the chapter on lung cancer reviews about one hundred
studies in total, with 23 occupational cohort studies, 5 case-control
studies and 5 silicosis cohorts analyzed in detail.  The preliminary
conclusions (on page 237) cite five cohort studies as being “of the
best quality to evaluate exposure to crystalline silica as a risk factor
for lung cancer”.  These were

Diatomaceous Earth Workers (Checkoway et al. 1993, 1996, 1997 and 1999;
Seixas et al. 1997)

British Pottery Workers (Burgess et al., 1997 and 1998; Vherry et al.,
1998; McDonald et al., 1995)

Vermont Granite Workers (Applebaum et al., 2007; Attfield and Costello,
2004; Costello and Graham, 1998; Davis et al., 1983)

North American Industrial Sand Workers (Hughes et al., 2001; McDonald et
al., 2001, 2005; Rando et al., 2001)

North American Industrial Sand Workers (Sanderson et al., 2000;
Steenland and Sanderson, 2001)

This list certainly identifies a selection of key studies with adequate
statistical power and reliability, and reasonable exposure and health
endpoint determination.  It seems to me that the omission of the South
African gold-mining studies is a mistake, particularly with regard to
the more recent reports (Hnizdo and Sluis-Cremer, 1991; Hnizdo et al.,
1997), about which OSHA comments somewhat favorably (page 236).  While
there are some questions about the exposure measurements used and
possible confounding by radon exposure it appear that most of these have
been addressed by related studies.  This group of miners has been an
important source of data on silica effects over the years and
historically these studies have contributed greatly to the worldwide
concern about, and understanding of, silica exposures and health
effects.  The fact that a modern epidemiological study finds a positive
association with lung cancer in this group is an important and
persuasive part of the whole jigsaw-puzzle.  In the last analysis
however the most persuasive part of the argument is not any one of the
single study reports, but the meta-analysis by Steenland et al. (2001a).

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.

Response: