The tables are fine as far as I am concerned

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.

Response:

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

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.

Response:

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.

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.

Response:

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.

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.

Response:

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.

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.

Response:

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.

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.

Response:

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.

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?

Response:

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.

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

University of Washington, Seattle, WA

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

Review Comments: Noah Seixas, PhD, CIH

December 13, 2009

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

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

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

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

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

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

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

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

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?

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

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

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

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

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

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

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

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?

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

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

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

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

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

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

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

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

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.

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?

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?

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.

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.

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.

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.

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.

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.

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.

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.

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 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.

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?

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.

Technical Charge to External Peer Reviewers

Peer Review of OSHA’s Preliminary Quantitative Risk Assessment for
Silica

ERG Contract No. GS-10F-0125P

BPA No. DOLQ059622303

ERG Task No. 0<IP_ADDRESS>

Instructions to Peer Reviewers

You have been selected to participate in an external peer review of the
OSHA preliminary quantitative risk assessment for silica.  The risk
assessment section will be part of a proposed rule that would amend the
existing regulation for occupational exposure to silica.  The
quantitative risk assessment is the primary analysis upon which the
Agency must rely when making its determination that employees exposed to
silica at the current permissible exposure limit face a significant risk
of material impairment to their health and that the proposed standard
will substantially reduce that risk.  It is not meant to include all
adverse effects that result from silica exposure.  Other sections of the
proposed rule discuss these health hazards and the evidence that
supports their association with silica.

The chosen data set(s) and dose metric(s) for exposure-response analysis
should be applicable to occupational exposures and adequately
demonstrate that silica influences the selected health effect.  The risk
model(s), assumptions and statistical treatments should be reasonable,
sound, and consistent with the underlying science.

Keep in mind that OSHA’s responsibility is to protect worker health
and the Agency may choose conservative assumptions where appropriate.
OSHA may also consider animal and experimental studies, where relevant.
The overriding goal of the peer review is to ensure that the data and
methodologies used to estimate risk are clear and scientifically
credible.  OSHA has provided the following questions to guide and focus
your review on issues of importance to OSHA.  Your review should, at a
minimum, address each question, providing a discussion and rationale for
any “yes” or “no” responses, and providing other comprehensive
comments to clarify your comments and/or recommendations.

Charge Questions

The draft report evaluates exposure-response data from several
occupational studies as to their suitability for quantitative assessment
of lung cancer and silicosis risk resulting from airborne exposures to
silica.  Are the strengths and limitations of the selected data sets
adequately discussed and appropriately evaluated?  Are you aware of
other study data that are better suited for quantifying lung cancer or
silicosis risk from occupational exposure to silica?  If yes, inform
OSHA of the other data.

 The draft assessment relies on quantitative uncertainty analysis and
sensitivity analysis of exposure measurement error in key studies of
lung cancer and silicosis.  Are these analyses clearly explained and
evaluated?  Is this a reasonable approach for evaluating silica-induced
lung cancer and silicosis in exposed workers?  Is there a more
appropriate approach?  If so, explain.

The draft assessment evaluates the use of a physiologically-based
pharmacokinetic model that predicts silica lung burdens in individuals
exposed to particulates through inhalation for estimating risk from lung
cancer and silicosis.  Are these analyses clearly explained and
evaluated?  Is this a reasonable approach for evaluating silica-induced
lung cancer and silicosis in exposed workers?  Is there a more
appropriate approach? If so, explain.

The draft assessment summarizes several published risk assessments that
use a variety of models and statistical methodologies employed by the
various analysts to fit the featured data sets.  Are the models and
approaches used by these investigators adequately explained and
evaluated?  If not, let OSHA know what needs to be added to the
presentation.

The draft report identifies and describes several key areas of
uncertainty with regard to the estimates of risk.  Were the major
uncertainties in the risk assessment adequately characterized?  If not,
explain what should be included.

The draft assessment relies on the use of cumulative exposure (or a
transformation of cumulative exposure) as the principal dose metric on
which lung cancer and silicosis risks are evaluated.  The draft also
contains a discussion of studies that are suggestive of a dose-rate
effect.  Given this discussion, is cumulative exposure a reasonable
exposure metric for silica-induced lung cancer and silicosis in exposed
workers?  Is there a more appropriate exposure metric?  If so, explain.

OSHA’s estimates of lung cancer and silicosis mortality are
represented as a range of estimates with those derived from the
diatomaceous earth and U.S. granite studies considered to be plausible
upper bound risk estimates.  OSHA also acknowledges that the risk may be
lower such as suggested by the results of the IARC multi-centric study,
which relied on pooled data from several epidemiological studies.  Is
this a sound and reasonable estimation of risk from the available data?
Is this decision adequately explained?  Should the risk estimates based
on one data set be preferred over the other?  Is there a more
appropriate representation of the lung cancer risk from silica exposure?
 If so, explain.

	The cumulative risk of silicosis morbidity is preliminarily considered
to be best represented by a range (approximately 3- to 4-fold) that is
based on results from four published exposure-response assessments.
Does this range reflect a sound and reasonable estimation of risk from
the available data?  Is this decision adequately explained?  Should the
risk estimates based on one data set be preferred over the other?  Is
there a more appropriate representation of the silicosis morbidity risk
from silica exposure?  If so, explain.

OSHA estimated the risk of lung cancer mortality, silicosis mortality,
and silicosis morbidity for 45-year exposures to 0.25 and 0.5 mg/m3
respirable crystalline silica; these represent a range of exposures
consistent with OSHA’s current standards for construction and maritime
industry sectors, but are above OSHA’s current general industry
standards (approximately 0.1 mg/m3 for respirable quartz).  The
cumulative exposures corresponding to these higher exposure levels are
at or above the cumulative exposures of most of the more highly exposed
workers included in the studies that underlie the risk estimates.  Is
OSHA’s approach for extrapolating risk above the observed range
reasonable?  Is it clearly explained?  Is there a more appropriate
approach that should be considered to estimate risk at cumulative
exposures that are generally above the observed range of the underlying
epidemiological studies?

External Peer Review of OSHA’s

“Preliminary Quantitative Risk Assessment for Silica”

Peer Review Comments

Specific Questions

The draft report evaluates exposure-response data from several
occupational studies as to their suitability for quantitative assessment
of lung cancer and silicosis risk resulting from airborne exposures to
silica.  Are the strengths and limitations of the selected data sets
adequately discussed and appropriately evaluated?  Are you aware of
other study data that are better suited for quantifying lung cancer or
silicosis risk from occupational exposure to silica?  If yes, inform
OSHA of the other data.

Bruce Allen	In general, I found the discussion of the strengths and
weaknesses of the selected studies to be adequate.  Because such
discussions can be very discursive, I might suggest that a tabular
summary of the strengths and weaknesses be presented.  In such a summary
table, the criteria for evaluating strengths and weaknesses could be
laid out (say in the rows) and then for each study (one per column), a
brief point or two could be presented.  This would allow the more
in-depth discussions of the strengths and weaknesses in the text to be
tied back to this summary and would allow a clearer appreciation of how
the studies compared to one another with respect to the criteria under
consideration.

If anything, the weaknesses of all the studies with respect to
reconstruction of exposure histories (both with respect to the
atmospheric concentrations and the job-specific features that lead to
worker exposures to those concentrations) may not have been presented
with enough emphasis to convey just how limiting and problematic that
process can be.  There is some discussion of the “reasonableness of
the exposure assessment” on p. 10, where silicosis mortality odds
ratios are compared across exposure categories from the pooled cohorts
of Steenland et al.  The values presented do not give me a very strong
sense that exposure misclassification was negligible, since the odds
ratios presented hardly differ (the highest three are almost identical)
and I am not sure that a formal test would reject the hypothesis that
the odds ratios were the same, i.e., would not reject the hypothesis
that would hold if all individuals were randomly allocated to the four
groups regardless of their cumulative exposure level.  I have to wonder
if this is the best evidence that is available to OSHA to make the
desired point about impact of exposure misclassification.

I am not aware of any other data that are better suited for quantifying
the lung cancer and silicosis health risks.

Kenny Crump	The strengths and limitations of the selected data sets
appear to be adequately discussed and evaluated.  Areas that could be
improved in some relatively minor ways are discussed below.  I am not
aware of any other studies that are better suited for quantifying lung
cancer or silicosis risk from occupational exposure to silica.

Murray Finkelstein	I think that the strengths and limitations of the
selected data sets were adequately discussed and appropriately
evaluated. I am not aware of other study data that are better suited for
quantifying risk.

Gary Ginsberg

Gary Ginsberg	The variety of exposure-response studies are generally
well described in terms of numbers of subjects, exposure
characterization, statistical analysis, potential confounders, and where
applicable, dose response modeling.  The report however is lacking in
terms of providing a critical appraisal of each study and its relative
merit, power or weighting for the purposes of risk assessment.  The risk
assessment section relies upon 4 studies which conducted their own
quantitative dose response assessment, accepting those cohorts as the
basis for the OSHA evaluation. However, there are numerous other studies
which might lend themselves to quantitative assessment by virtue of
their exposure and outcome measurement.  For example, Section V.C.
describes many studies which might be suitable for quantitative
assessment (e.g., Guenel et al. 1989 of Danish stone cutters) but which
are not critically appraised for this purpose.  Further, the Cassidy
2007 European multi-center analysis is promoted in Section V.C. as
particularly useful (even “compelling” – numerous positive
qualities including exposure assessment) but yet is not included in the
Section VI quantitative risk assessment.  One wonders whether any bias
is introduced into the assessment by the omission of one or more
potentially useful studies.  The lack of a critical appraisal of the
quantitative utility of such studies or the potential bias introduced by
their omission, weakens the Section VI analysis.

Brian Miller	As far as I am aware, the studies are in the main well
described and evaluated.  It’s worth noting that the choice of
radiological opacities grade 2/1+ for analysis in the Buchanan et al.
(2003) paper was driven by the use of that level being required for
compensation in the UK systems.  The radiographs from the follow-up
study were all classified on the full ILO scale just as the earlier PFR
ones had been, and there are fuller descriptions of the studies and
descriptions and analyses of the distributions at lower levels e.g. 1/0+
in earlier publications.  The 1998 paper gives logistic regression
analyses only for 2/1+, but the 1995 research report (available to
download) also has detailed analyses of a 1/0+ response.

Miller BG, Kinnear AG.  (1988).  Pneumoconiosis in coalminers and
exposure to dust of variable quartz content.  Edinburgh: Institute of
Occupational Medicine.  (IOM Report TM/88/17).
http://iom-world.org/pubs/IOM_TM8817.pdf

Miller BG, Hagen S, Love RG, Cowie HA, Kidd MW, Lorenzo S, Tielemans
ELJP, Robertson A, Soutar CA.  (1995).  A follow-up study of miners
exposed to unusual concentrations of quartz.  Edinburgh: Institute of
Occupational Medicine.  (IOM Report TM/95/03).                 HYPERLINK
"http://iom-world.org/pubs/IOM_TM9503.pdf"
http://iom-world.org/pubs/IOM_TM9503.pdf

Miller BG, Hagen S, Love RG, Soutar CA, Cowie HA, Kidd MW, Robertson A.
(1998).  Risks of silicosis in coalworkers exposed to unusual
concentrations of respirable quartz.  Occupational and Environmental
Medicine;  55: 52-58.

There are some new data on the risk of lung cancer with respect to
respirable silica exposure, from an extended follow-up of the British
PFR mortality study:

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	The studies considered are adequately described and
evaluated.  In particular, the U.S. studies and the IARC meta-analysis
for lung cancer are described in sufficient detail and carefully
evaluated.  However, the discussion of silicosis and choice of key
studies is somewhat less convincing.  The consideration of other
possible datasets, particularly the data on South African gold miners,
receive somewhat more cursory treatment.  The recent paper by Churchyard
et al. (2004) describing silicosis morbidity in black gold miners is
important both for the high level of effect seen in these workers and
the use of gravimetric exposure measures.  However, although this paper
was briefly noted elsewhere by OSHA, it is not considered in this
section.  The existence of analyses other than those performed by OSHA
and its regular collaborators is not consistently acknowledged.  This is
unfortunate since some of these analyses do to some extent address the
question of dose-response at lower levels, which is not adequately
discussed in this section (See for instance Collins et al., 2005 and
OEHHA, 2005), analyzing the data of Hnizdo and Sluis-Cremer, 1993;
Steenland and Brown, 1995; Chen et al., 2001 and Churchyard et al.,
2004).  The focus on extreme endpoints is illustrated by the extensive
coverage devoted to analysis of silicosis mortality, which is a good
technical analysis but from a public health standpoint feels like an
admission of failure!  Also, the choice of the Scottish mining study
(Miller et al., 1998) as a key study for silicosis dose-response
analysis is colored by this perspective.  This is undoubtedly an
excellent study from the technical standpoint, but its choice of a more
severe cut-point (ILO 2/1) for the radiographic diagnosis sets it apart
as being less sensitive than most of the other studies in the field, in
spite of evidence discussed here and in the section on health effects
showing that even an ILO 1/1 radiographic level substantially
under-diagnoses silicosis as assessed by later follow-up or other
methods e.g. histology.  There appears to be no discussion of the
complicating fact that these coal miners were also exposed to other
pneumoconiosis-inducing dusts, notably coal dust.  Miller and his
co-authors spend some time addressing this point in the paper, but it is
not referenced in OSHA’s narrative.

Evaluation of the dose-response relationships for disease endpoints
related to low-dose silica exposure will require evaluation of different
studies and dose-response models from those used in the existing
assessment, since those presented here (e.g. the study by Miller et al.,
1998 and linear or log-linear models) were selected for their
informative value at the pre-defined levels of interest rather than for
any information on dose-response at lower levels.  The appropriate
models would need to be selected and justified on the basis of the data
available in the lower exposure ranges, including the likelihood of a
threshold at least for non-cancer effects, as discussed above.  This
different approach is necessary to obtain a realistic evaluation of the
responses seen in the lower dose range.

Noah Seixas

Noah Seixas	The selected datasets represent as comprehensive a set as
available, to my knowledge.  The inclusion of the various cohorts is
appropriate, given the data quality needs for a robust assessment.  In
describing exclusions, (p8) it is noted that studies of coal workers and
foundry workers were excluded for good reasons.  However, it also notes
that 3 additional cohorts were excluded for ‘data unavailability or
incompatibility.’  These exclusions should be described in more
detail.

The studies included in the risk assessment are very thoroughly
described and appropriately interpreted.  While limitations of each
study are described and considered, the strengths of the studies are not
described study by study.  The general strengths are evident from the
descriptions, so it may not be important to do so in any more detail.  A
brief summary of the strengths of the selected studies could help
support their use for this risk assessment.  Furthermore, published
critiques of the studies are also included in this discussion, and OSHA
has responded to these criticisms with thoughtful consideration and
clear conclusions. I am not aware of any key studies that were not
considered.

The draft assessment relies on quantitative uncertainty analysis and
sensitivity analysis of exposure measurement error in key studies of
lung cancer and silicosis.  Are these analyses clearly explained and
evaluated?  Is this a reasonable approach for evaluating silica-induced
lung cancer and silicosis in exposed workers?  Is there a more
appropriate approach?  If so, explain.

Bruce Allen	In contrast to my comments above about the
less-than-convincing presentation related to exposure misclassification,
I did like the analysis that was presented to examine the quantitative
effects of uncertainties about the exposure reconstruction and the
individual worker exposures within that reconstruction.  The Monte Carlo
analysis approach that was applied is a reasonable way to address this
question.  My only comment related to that is that a typical Monte Carlo
analysis usually includes many more than 50 iterations (the maximum
number if simulations run in the uncertainty analyses for lung cancer
and silicosis mortality).

Note also that the analyses were performed by selecting some fixed
values for the variabilities considered.  Although the variability was
based on some observations (see bottom of p. 50 and bottom of p. 52 to
top of p. 53), those observations were themselves limited and may not be
the best reflections of the variability that is needed here.  It would
be informative to determine just how much variability is required to
result in a substantial change in the risk estimates.  If that amount of
variability can be deemed unreasonable, then there is stronger support
for the risk estimates that OSHA presents.  Or, another way of thinking
about it: if, even when there is very large variability (representing
uncertainty in the exposures), the calculated risks are still considered
substantial, then there is very strong support for the conclusion that
workers are at risk at the exposure levels under consideration.

Kenny Crump

Kenny Crump	This question refers to the analysis of exposure measurement
error in Toxichemica, Inc. (2004).  These analyses are well designed,
clearly explained and evaluated.  Evaluating and adjusting for exposure
measurement error is a very difficult issue.  The analysis of error
conducted by Toxichemica, Inc. is a very strong effort.  The assumptions
are clearly described and the data upon with they are based appear to be
appropriate and appropriately applied.  However, there are questions, as
there will always be with such an analysis, regarding the form(s)
assumed for the errors, the assumptions used in modeling the errors, and
in the completeness of the sources of errors modeled.

For the Berkson component of the error, it would seem reasonable to
consider a multiplicative error model, i.e.,

		Exposuretrue = Exposureobserved * ε

where ε has a log-normal distribution.  In this form, both the mean and
the variance of the true exposure increases with the observed exposure,
which seems reasonable.  Also, unlike the additive error model, this
model does not produce negative exposures (to avoid this problem is
presumably why the distribution was truncated in the Toxichemica, Inc.
analysis).  This model might produce significantly different results
from the additive model, including modifying the shape of the dose
response curve (Carroll et al. 2006).

It could also be assumed that silica concentrations differed randomly by
work area rather than by job.  Workers in same area of a facility will
breathe the same air even if they are doing different jobs.  Resampling
randomly by job within work area rather than by work area may tend to
average out variations by work areas and underestimate uncertainty.

The method for evaluating error in converting from dust measurements to
quartz measurements appropriately based on data and well-designed and
implemented.  However, other important sources of error do not appear to
be accounted for.

A major source of error that apparently was not accounted for is in
assuming that the average measure of exposure assigned to a job is the
true average.  But it is not always clear how representative the
underlying measurements were.  E.g., were some measurements taken at
times when it was believed there was a particular problem with high
exposures?  Moreover, some of these averages (particularly, those that
pertain to earlier times and which are likely the more influential since
they probably represent the highest exposures) were not based on direct
measurements, but were projected based on judgments of persons familiar
with the operations.  There is possibly considerable error in such
estimates.  Another source of uncertainty in the averages stems from the
need to convert from one measurement method to another (e.g., from
particle counts to gravimetric measurements).

Based on these considerations, it seems likely that the effects of
exposure errors could have been larger than predicted by the
Toxichemica, Inc. analysis.  It would also be useful to evaluate the
effect of errors in exposure using other exposure metrics than log
cumulative exposure.  Risk models based on other exposure metrics are
likely to be more sensitive to exposure error.  (Also, see response to
Question 4 regarding the use of log cumulative exposure as the exposure
metric.)

Murray Finkelstein	The use of uncertainty and sensitivity analysis by
the Toxichemica team is well explained. I think that this is an
excellent approach for evaluating uncertainty.

Gary Ginsberg

Gary Ginsberg	I am not a statistician and don’t normally get involved
with quantitative uncertainty assessment.  Therefore, I cannot comment
directly on the detailed presentation of this work.  It does appear that
the major areas of measurement uncertainty have been identified and
dealt with in some manner by the extra effort to characterize these
uncertainties.   An area of concern however is the treatment of
potential confounding by smoking.  Page 44 assumes that the only issue
with smoking as an uncontrolled variable is the potential for smoking
rate to correlate with silica exposure in such manner to bias the
disease risk high.  The text goes on to assert that this is unlikely
from the available evidence and study design.  However, this rationale
excludes the possibility that when smoking is an uncontrolled variable
it will lead to elevated cancer risk in both the reference and
silica-exposed population leading to a high and variable baseline that
will tend to bias the results towards the null hypothesis and weaken
associations between silica and lung cancer.  I could not find any
explanation or substantiative evidence that such confounding by smoking
may not have occurred given the lack of smoking history and control for
smoking present in the underlying data.   The net result may be an
underestimation of silica-induced cancer risk relative to a non-smoking
population unless there is evidence that smoking potentiates
silica-induced lung cancer.    A similar potential exists for
underestimating cancer risk in diatomaceous earth workers simultaneously
exposed to asbestos and silica (page 46).  Once again, the concern
expressed in this document is the potential for additive risk across
these exposures to inflate the potency factor.  However, the rate of
mesothelioma in the asbestos exposed workers is not discussed.  If this
were a significant intercedent cause of mortality, it would curtail the
silica-induced cancer rate.   In addition, this report would be well
served to view radon and other uncontrolled exposure variables through
this lens of potential weakening of dose response relationships.

Brian Miller	Where there is error in exposure assessment, it is
important to assess the extent to which this may affect the estimation
of the exposure-response coefficient, and to correct for that if
necessary and possible.  Other sources of uncertainty may also be
important. The approach used is a reasonable one for assessing,
describing and allowing for such sources of uncertainty within the
approach taken for quantifying the expected or average risk, which needs
to be discussed separately (see below).

Andrew Salmon	The approach used is reasonable to address uncertainty in
exposure estimation.  Indeed, given OSHA’s recognized expertise in
this area it is unsurprising that they and their contractor
(Toxichemica) have done a thorough, indeed exhaustive, job on this
aspect.  The ultimate conclusion that there is some uncertainty, but
that it does not undermine the basic conclusions of the quantitative
analysis, is reassuring, although perhaps a little underwhelming given
the amount of effort that was applied to this topic.

Noah Seixas

Noah Seixas	Selection bias and confounding are addressed very well, and
convincingly suggest that these potential biases do not unduly affect
the risk estimates derived from these studies.  On p 42, it is stated
that the confidence intervals presented in Table VI-2 represent
uncertainty due to the sample of studies used for the analysis.  This
statement should be qualified by the uncertainty due to the systematic
biases that also may be present in the selected studies.  That is, the
confidence intervals represent uncertainty due to the sample of the
universe that the selected studies represent, given that the
observations in those studies are without error, themselves.

The simulation of exposure measurement error in assessing the degree of
bias that may have been present is a reasonable approach to assessing
this source of uncertainty. However, I have several comments about the
presentation of these results.  I will preface this by saying that
although I have thought about measurement error issues in occupational
exposure assessment and epidemiology for a long time, I am not an expert
in the statistical concepts, nor the application of these concepts to
assessing uncertainty.  Therefore, I raise these questions for
consideration, without claiming to know how this analysis should be
improved.

On p48, the statement that the metric conversions apply equally to
diseased and non-diseased subjects and therefore represent Berkson type
error, is incorrect.  Errors that are applied to cases and controls are
called ‘non-differential errors,’ but do not imply a Berkson error
structure.

While the discussion of Berkson error models is generally correct, I
don’t believe the simulation has actually modeled a Berkson error, but
rather, a classical error model.  The typical Monte Carlo simulation,
which is what appears to have been done, would introduce classical
error.  I don’t think the report should repeatedly state that the
simulation produces coefficients “adjusted for Berkson error” as I
don’t believe this is Berkson, nor that the simulation actually
adjusts for it.

I think that the introduction of random error to the assigned exposures
essentially adds error to that already present.  Thus, you are taking
the results of a model based on exposure estimates which include error,
and simulating additional error on top of it.  I’m not sure what the
results of this simulation then produces. In fact, the results produced
in Table VI-4- VI-6 almost all went down (toward the null), which is
what is generally expected by adding random (classical) error into the
exposure variable.

At the bottom of page 51, the changes in coefficients with introduction
of error are reported, however, no explanation or even speculation about
why some of these estimates were greatly reduced is provided.  Although
the associated table provides the SE associated with the coefficients
for the ‘adjusted’ effects, it should also present the SE for the
‘unadjusted’ values.

I remain unconvinced that the conclusion on page 52, that measurement
error “did not have a meaningful effect on the estimate of the
exposure-response coefficient” is well supported by this analysis.  I
would believe that a statement such as “addition of random error to
the estimated exposures in the pooled analysis did not appreciably
change the estimated exposure response relationship” would be correct.
 However, I don’t believe that the analyses conducted prove that
measurement error in the selected studies did not substantially affect
the observed relationships.

There is no mention of measurement error generally reducing the effect
of exposure response relationships, and that this principle indicates
that the estimated risks are most likely to be underestimates, or
conservatively estimating risk. This is an important aspect of
measurement error with significant implications for risk assessment and
should not be overlooked.

The draft assessment evaluates the use of a physiologically-based
pharmacokinetic model that predicts silica lung burdens in individuals
exposed to particulates through inhalation for estimating risk from lung
cancer and silicosis.  Are these analyses clearly explained and
evaluated?  Is this a reasonable approach for evaluating silica-induced
lung cancer and silicosis in exposed workers?  Is there a more
appropriate approach? If so, explain.

Bruce Allen

Bruce Allen	The use of a kinetic model to estimate lung burdens that
would then lead to inflammation, fibrosis, etc. is a very reasonable
approach.  However, the methods and approaches used by Kuempel et al.
for their assessment are not well explained or presented in the OSHA QRA
document.

I am particularly troubled by the description starting in the middle of
p. 25 that says that Kuempel et al. used the dose coefficients that had
been previously derived for the two cohorts they analyzed.  Why would
they use those coefficients that were derived without consideration of
the lung burden metric, i.e., that considered simple cumulative
exposure, to estimate lifetime risks based on the lung burdens
associated with various exposure scenarios?  This is either an error in
their methodology or an incomplete and misleading reporting of their
analysis in the OSHA document.

The discussion on p. 27 (first full paragraph) describes the analysis
using the lung burden metric with the 10-cohort study data.  Although
the conclusion is that the lung burden metric does as good a job as
cumulative exposure, the risk estimates derived from that analysis are
not presented (neither in the text nor in Table VI-2, where the summary
of all the risk estimates is presented).  My impression is that OSHA has
not fully considered the lung burden-based risk estimates and perhaps
does not consider them to be “on a par” with the other estimates.
The discussion of the Kuempel et al. study appears to be the most
cursory of the discussions of the various studies.  If it is the case
that this study is not considered as relevant or it is thought of as
secondary (perhaps because it was not an epidemiology study in and of
itself but relied on the response data of two of the other studies
cited), then there should be some discussion of that and the
inter-relationships between the estimates from that “study” and the
others.

Kenny Crump	This refers to an analysis in Toxichemica, Inc. (2004).
Exposure metrics based on lung burdens can provide reasonable
alternatives to the more empirical metrics emphasized in the papers
reviewed by OSHA (lagged or unlagged cumulative exposure or log
cumulative exposure).  The lung cancer and silicosis analyses are
adequately explained as far as they go.  Whereas the silicosis analysis
considered several metrics based on lung burden, the lung cancer
analysis only considered one exposure metric – lung burden lagged 15
years.  However, both the lung cancer and silicosis analyses stopped
short of estimating risks using this approach.  Even if a fit to data
using a metric based on lung burdens is similar to the fit provided by
an empirical metric such as log cumulative exposure, that doesn’t
imply that the estimated risks from 45 years of exposure will be
similar.  Without estimating risk using the metrics based on lung
burden, the effect of these metrics upon the estimated risk will not be
known.  If workers in the epidemiological studies predominately were
exposed for only a short time (e.g., a few months), different exposure
metrics could predict significantly different risks from 45 years of
exposure even if they provided equivalent fits to the epidemiological
data.

Murray Finkelstein	The analyses are clearly explained. I think that this
would be a reasonable approach for evaluating silica-induced risk only
in the absence of human epidemiologic data. I think that the application
of dust doses and inflammatory effects in rats to the prediction of
mortality in humans is too great a leap. I think that the appropriate
approach is risk assessment based upon human epidemiologic data.

Gary Ginsberg

Gary Ginsberg	The “PBPK” lung burden model is not well explained and
pretty much just mentioned in passing as this line of evidence is not
given substantiative weight.  PBPK usually refers to a mathematical
description of chemical fate within systemic compartments that have
parameters for organ size, blood flow and clearance processes, with QC
check conducted to ensure mass balance.  I haven’t read Kuempel et al
(2001) but it sounds more like an inhalation deposition/dosimetry model
that a PBPK model.  The model description on Pages 24-27 could be
enhanced by showing the model structure, a table of parameter values for
both species (breathing rate, respiratory tract surface areas; clearance
rates in various lung compartments), how is the model affected by
breathing rate and particle size, whether clearance is a static
parameter or allowed to vary (decrease) with increased silica burden,
and how is the threshold for critical quartz lung burden (0.39 mg/g)
set.  Also, the description of the human model at the top of Page 25 is
vague – how many coal workers, are central estimates used or are all
the data used to create a statistical distribution, how was the rat
model adapted for a standard human adult?

The lung burden model has potential utility as it defines a threshold
for lung cancer.  However, it is not explained well and this concept is
not used in the remainder of the report to assess risks from low dose
exposure.

Brian Miller	Where no epidemiology exists, it may be that the only
approach that can be used for predicting risk is extrapolation from an
animal model.  In the present context, much use is made of the concept
of lung burden.  This may be the correct target organ dose metric, but
epidemiological data on it is very sparse; hence the normal focus on
exposure experienced as a surrogate for dose.  The extrapolation
involved requires many more assumptions than assessing risk from
epidemiological studies, and it may not be prudent to place the same
degree of reliance on the model-based estimates as on those from
epidemiological observation.  Having said that, one advantage of the
animal model is that the exposure is usually rather better characterized
than in humans.

Andrew Salmon	The description of the lung-burden analysis by Kuempel et
al. (2001), and the further analysis by Toxichemica (2004), is quite
brief and limited mainly to describing the overall conclusions of this
work.  It is not sufficiently detailed to allow a reader to determine
exactly what was done, or whether the implicit assumptions are
reasonable.  What is presented sounds reasonable and interesting, but
Toxichemica’s eventual conclusion appears to be that it does not
improve the analysis of Steenland’s pooled cancer data relative to the
simpler cumulative exposure model.  It seems relatively unlikely that
the available data on lung cancer or silicosis are of sufficient
precision to directly support use of this or any other complex dose
metric.  Toxichemica (2004) also note that the effect of the lung burden
calculation is to build a lag time into the dose-response model.  While
this is a reasonable assumption, and there is limited evidence that this
is appropriate for the silicosis data, there are a number of
explanations besides dependence on silica lung burden for this effect.

Noah Seixas	It is not clear to me what the importance of this
presentation is.  The studies by Kuempel that adopted a toxicokinetic
model for lung deposition to estimate silica lung burden ‘were
similarly good predictors of lung cancer risk’ as cumulative exposure.
 It appears that these studies did not contribute to the risk analysis,
other than to note that these more complex models didn’t produce any
different results, and it is unclear to me that this is an important
observation.

The draft assessment summarizes several published risk assessments that
use a variety of models and statistical methodologies employed by the
various analysts to fit the featured data sets.  Are the models and
approaches used by these investigators adequately explained and
evaluated?  If not, let OSHA know what needs to be added to the
presentation.

Bruce Allen	I think that a summary table showing the approaches and
models used by the various investigators could improve the presentation
somewhat.  Table VI-2 does have some of that information (which model
was used for the risk estimation – although there appears to be an
error there in that the Attfield and Costello analysis appears to have
used a linear, not log-linear, relative risk model).

It is difficult to determine how much information to include in a
summary of the studies.  But seeking consistency in the presentation of
the methods and results across studies (as opposed to just reflecting
the perhaps-idiosyncratic information presented by the original authors)
is a desirable goal.  So, the presentation for each study could include
the same, “standardized” information: models considered, lag times
considered, how fitting was done and evaluated, special concerns about
model fit (e.g., nonmonotonicities in observed response rates or odds
ratios), etc.

Here are a few examples of questions that I had in reading the summaries
and evaluating what had been done.

p. 20, line 7: it says Attfield and Costello used unlagged exposure.
But how is that possible if they did not update work histories beyond
the original 1982 follow-up (p. 20, line 4) when they extended mortality
follow-up to 1994?

p. 21, line 6: how did Attfield and Costello evaluate “best-fitting”
among all their dose-response analyses, especially when some of them
were on different data (i.e., some with and some without the
high-exposure category)?

If Graham et al. (2004) “concluded that dust control measures were
shown to be effective in reducing lung disease and mortality” (p. 23,
lines 3-4), how could they conclude that the results “did not support
a causal relationship between exposure to quartz and lung cancer” (p.
23, lines 4-5)?

Kenny Crump

Kenny Crump

Kenny Crump

	The reasons given for emphasizing analyses of the pooled data on lung
cancer (Steenland et al. 2001a) that use log-transformed cumulative
exposures are faulty.  There are several reasons for preferring analyses
based on untransformed exposures.  Using untransformed exposure with a
15 year lag gave a considerably better fit to the data than
log-transformed exposure with a 15 year lag (log-likelihood of 21.4
versus 18.8—what is referred to as the likelihood in Steenland et al.
(2001a) is presumably the log-likelihood).  The fact that the model
based on log-transformed exposure did not show significant improvement
in fit when the interaction terms were added (i.e., did not show
significant heterogeneity) should be viewed as more of a disadvantage of
this model in comparison to the one based on untransformed exposures
rather than an advantage: The model based on untransformed exposures not
only fit better that the model based on untransformed exposures, but
adding interaction terms significantly improved the fit of the already
better-fitting model, but did not significantly improve the fit of the
poorer-fitting model.

Figure 1 provides a simple illustration of this point.  This figure
depicts data from two studies, Study 1 (blue points) and Study 2 (red
points).  There is an apparent study effect as exposure shows a stronger
effect in Study 1 than in Study 2.  Two models are used to analyze these
data, Model 1 (orange lines) and Model 2 (green lines).  The solid lines
indicate the fits of the models to the combined data and the dashed
lines indicate the fit of the models to the data from the individual
studies.  The fit of Model 2 to the combined data (solid green line) is
clearly better (i.e., larger log-likelihood) than the fit of Model 1
(solid orange line).  However, there is a significant improvement in fit
when Model 2 is fit separately to the two studies (dotted green lines).
Thus, this model detects significant heterogeneity.  However, with Model
1 the improvement in fit is not significant; hence there is no
significant heterogeneity identified by this model.  By the decision
logic described above, Model 2 would be ruled out in favor of Model 1
even though Model 2 is clearly superior.  This example has the same
characteristics as the fits to the lung cancer data in the pooled data,
with Model 2 playing the role of the model using untransformed exposure
and Model 1 playing the role of the model using log-transformed
exposure.

There are several procedures for choosing the best model based on the
value of the likelihood (e.g., AIC (Akaike information criterion, Akaike
1974)).  Each of these procedures would identify the model based on
untransformed exposures as better than the one based on log-transformed
exposures.  The fact that the significant heterogeneity was found for
this model suggests that this model could be improved, but it does not
indicate that the model using log-transformed exposures is better.

Dose responses for the same effect (e.g., lung cancer from silica) would
not be expected to have fundamentally different forms in different
studies (e.g., derived from log-transformed exposure in one study and
untransformed exposure in another).  It would assist in comparing
results across studies to present risk estimates from the three studies
in Table VI-2 using a common exposure metric.  Similarly, it would
assist in comparing the effect of different exposure metrics, by
computing risk from single study using different exposure metrics.  Both
of these goals could be accomplished by adding to Table VI-2 risk
estimates derived from the analysis of the pooled cohorts (Steenland et
al. 2001) based on a linear relative risk model.  If the model is truly
linear in the exposure variable, use of the log-transformed exposures
will tend to underestimate risks at lower exposures and overestimate
risks at higher exposures.

More consideration needs to be given in the document to model selection
and its effect upon risk estimates.  Although log-linear models are
relied upon extensively, such models are generally selected for
convenience (since this is the model generally used in Cox regression
(Cox 1972)) rather than for biological plausibility.  Such models are
supralinear when applied to untransformed exposure (increase at a rate
faster than linear with increasing exposure).  OSHA states that it does
not believe that a supralinear response “is biologically plausible and
believes that it is more reasonable to assume that the exposure-response
relationship remains linear …”  This argues for using a linear model
(like the linear relative rate model used in Rice et al. (2001)) instead
of a log-linear model.  It also argues against using a log-linear model
with log-transformed exposure, since such models are sublinear, as
illustrated by the very slow increase in risk with increasing exposure
exhibited by the lung cancer model implemented by Toxichemica Inc.
(2004) (Table VI-12).  To more fully evaluate the effect of model
selection, it would useful to reanalyze the data from one or more of the
key studies, such as the data from the pooled cohort, using a truly
linear model, and perhaps other models, and compare risk estimates
obtained from these models.

It is claimed that the Attfield and Costello (2004) log linear model
becomes supralinear at cumulative exposures above 4.5 mg/m3-years.  How
OSHA arrived at this conclusion is not explained.  As noted above such a
model is actually supralinear at all values of cumulative exposure.

Murray Finkelstein	These models are adequately explained and evaluated.

Gary Ginsberg

Gary Ginsberg	The description of the published risk assessments is
generally adequate.  As described above, more information regarding why
certain studies were excluded from the meta analysis or not
quantitatively described would be helpful.  The issue of threshold is
not given proper attention in these descriptions.  The sense one gets is
that these studies and associated models generally find a dose response
in the range of current OSHA standards (0.05 to 0.1 mg/m3 and higher),
with a threshold possibly existing at lower concentrations:  e.g. $0.036
mg/m3 for 45 yrs based upon critical lung burden.   The issue of
possible thresholds should be systematically evaluated for each study
– was it statistically investigated by the study authors?  Were the
data sufficient to allow such an analysis?  Do the studies agree
regarding where a threshold might lie for lung cancer and silicosis and
how would such a threshold affect OSHA’s risk assessment?

Also meriting greater description are the physical characteristics of
the silica in each study.  Given that features such as the manner in
which it was mined/produced/fractured, whether it has surface coatings,
its mineral content (quartz, cristobalite, tridymite) and its age all
appear to influence its reactivity, this should be described for each
industry studied.

The 10 cohort study reported by Steenland et al. (2001a) shows general
agreement amongst 9 of the studies but one study (South African gold
miners) showed approximately 10 fold higher potency for lung cancer
(Page 15 and Table VI-1).  OSHA reports that Steenland reports that
exclusion of that dataset was not influential in the overall
meta-analysis (likely because it contained only 77 cases out of a pooled
analysis of over a thousand).  However, that is not the end of the
story.  In toxicology and risk assessment, one should consider whether
the most sensitive study and endpoint is of high enough quality to be
the source of risk calculations or whether the entire risk range should
be presented (e.g. the gold miners representing one end of a reported
potency range) or whether some central tendency potency estimate should
be used.  It may be that the South African gold miner study is more
potent for a good reason (e.g., least confounded by smoking, most potent
form of silica) and should be given serious consideration as a stand
alone data point for potency estimation and risk calculations.  Or
perhaps that study is no better or even inferior or less relevant than
the others.  The combination of Sections V and VI provide no analysis of
this but rather just accepts the Steenland treatment of the data.

OSHA focuses on cancer potency in the range of current standards and
also on higher exposures (pp 28-32).  The rationale for this is unclear.
 Is OSHA contemplating raising the standard to make it less strict?  Why
not focus as well on the dose response at lower levels of exposure just
in case there might be a desire to lower the standards (more strict).
It strikes me that the lower end of the dose response curve may be more
interesting given the potential for thresholds (e.g., the lung burden
model; potential that silicosis is needed for lung cancer to occur) and
the potential that lowering the standard might be desirable given the
high cancer risks associated with the current standards.

Brian Miller	The studies from which the risk coefficients are derived
are based on outcomes (mortality, diagnosis of silicosis) at different
lengths of follow-up from the exposures.  In a situation where the
effect of an exposure on the progression of risk may be time-dependent
(see 6 below), these coefficients may not be comparable.  There should
be more discussion of the possible effects of this disparity.

Andrew Salmon	The description of the models used and statistical methods
are in general adequately described.  OSHA relies on the models used by
the published analysts although these are in most cases very simplistic,
e.g. linear with cumulative dose.  These simple models are adequate to
fit the data in the observed ranges of the specific studies considered
(indeed, many of the studies lack the precision and/or cover an
insufficient range of different exposures to support anything more
complex).  OSHA describes these models well and confirms their validity
for prediction of response at the PELs, but makes no effort to determine
whether more informative models could be developed which would be useful
in critical exposure ranges such as those below these arbitrarily
pre-defined PELs.

Noah Seixas	The report discusses many alternative models including the
form of the linkage function, alternative exposure metrics, and
different latency periods.  These are well explained for each study, and
reasonable decisions are made as to which form of the model is most
useful and robust for the risk analysis.

The draft report identifies and describes several key areas of
uncertainty with regard to the estimates of risk.  Were the major
uncertainties in the risk assessment adequately characterized?  If not,
explain what should be included.

Bruce Allen	As stated above, although I think the uncertainty associated
with historical exposure reconstruction was under-characterized, I like
the Monte Carlo approach to addressing exposure uncertainties (with some
possible extensions suggested in response to question 2.)  The
discussions of possible selection bias, confounding, and bias in
conversion factors were adequate to dispel major concerns about their
having any negative impact on the findings.

Kenny Crump	The potential for selection bias and for bias due to
confounding are adequately addressed.  As explained in response to
Question 2, some aspects of uncertainty in risk due to uncertainty in
exposures are addressed but others probably are not.  In addition, the
effect upon risk of the exposure uncertainty that was quantified is
possibly underestimated due to the use of log-transformed exposures, as
risk estimates based upon log-transformed exposures tend to be relative
insensitive to changes in exposures.  As discussed in response to
Question 4, there needs to be additional evaluation of the uncertainty
due to the risk models used.

Murray Finkelstein	I think that the major uncertainties were adequately
characterized.

Gary Ginsberg	As described above, I believe the major uncertainties in
the estimate of risk not adequately dealt with are the potential for
confounding by smoking to decrease the strength of associations, and the
uncertainty regarding the existence of thresholds for cancer and
non-cancer endpoints.

Brian Miller	I have no other areas of uncertainty to suggest.  (We have
quite enough to deal with already.)

Andrew Salmon	Given that so much thoughtful analysis was devoted to
uncertainty in the exposure measurements, it is unfortunate that the
same level of investigation was not directed to determining the
uncertainty in determination of the other half of the dose-response
relationship.  There is some useful qualitative discussion of the
limitations of death certificates and the reliability, but low
sensitivity, of the ILO radiographic method of diagnosing silicosis in
the health effects section.  However, there is no quantitative analysis
of uncertainty in determination of health endpoints beyond the usual
statistical tests reported in epidemiological studies.  The overall
uncertainties in determining health endpoints could easily be as great
as, or greater than, the uncertainties in exposure assessment,
especially for silicosis morbidity and mortality.  An initial attempt at
quantifying uncertainties in health endpoints could be obtained by
reviewing confidence limits on measures such as SMRs for specific
endpoints, and the distribution of severity or response at different
dose levels. The latter consideration might be helpful in reviewing the
impact of reliance on measures of higher severity such as mortality,
higher-grade radiographic diagnosis, or eligibility for workers’
compensation, in some studies.   However, there is an underlying problem
in that although specific quantitative endpoints such as cancer
incidences or specific radiographic grades of silicosis are well
defined, the overall disease process is not well characterized by any
established integrative measures, so estimates of the overall disease
burden are subject to substantial qualitative as well as quantitative
uncertainties.

Noah Seixas	Yes and no – see answer to 2, above.

6. 	The draft assessment relies on the use of cumulative exposure (or a
transformation of cumulative exposure) as the principal dose metric on
which lung cancer and silicosis risks are evaluated.  The draft also
contains a discussion of studies that are suggestive of a dose-rate
effect.  Given this discussion, is cumulative exposure a reasonable
exposure metric for silica-induced lung cancer and silicosis in exposed
workers?  Is there a more appropriate exposure metric?  If so, explain.

Bruce Allen	It seems that the dose-rate effect may be related to the
lung burden metric predicted by the kinetic model of Kuempel et al.  If
that idea could be explored then there may be a way to provide further
support for the risk estimates that have been presented, especially
those based on that lung burden metric.  This is important given the
fact that, apparently, the lung burden metric did as well as cumulative
exposure (or log-cumulative exposure) in fitting the data.

On the other hand, I was not bothered by the fact that a dose-rate
effect might be present, given the indications that it may occur at
concentrations clearly above levels that OSHA needs to be concerned
about for reducing workers’ health risks.  Given the information about
where (at what concentrations) significant dose-rate effects appear to
be occurring, I am satisfied with the use of cumulative exposure for the
determination of concentration levels associated with the lower levels
of risk of concern for regulatory decision making.

Kenny Crump

Kenny Crump

	First it needs to be clear about what is meant by a “dose-rate
effect”.  My interpretation of that concept is that there is a
non-linearity in the exposure-response whereby a given increase in
intensity of exposure will cause a greater than proportional increase in
risk.  An example would be if risk varies as the integral over time of
the square of the exposure level.  Thus, there are dose metrics other
than cumulative exposure that do not incorporate a dose-rate effect.
Since OSHA is relying on cumulative exposure to estimate risk, I
interpret this question as whether cumulative exposure is an appropriate
metric, or is some other metric that incorporates a dose-rate effect
more appropriate.

Estimating risk based on an “incomplete” exposure metric like
average exposure is not recommended.  It is highly implausible that such
a metric could apply over an extended range of exposure patterns that
are likely to exist in a study.  E.g., exposure to a particular air
concentration for one week is unlikely to carry the same risk as
exposure to that concentration for 20 years, although the average
exposures are the same.

Finding a significant relationship between average exposure and risk in
itself is not evidence of a dose-rate effect.  In general, even if risk
is truly a function of cumulative exposure, there with likely also be a
significant relationship between risk and average exposure, since
cumulative exposure and average exposure are likely to be correlated.
For example, if all exposures are for the same duration, average
exposure is totally confounded with cumulative exposure.  On the other
hand, demonstration of a significant relationship with cumulative
exposure does not rule out a dose-rate effect, since cumulative exposure
will possibly be correlated with a metric that incorporates such an
effect.

To demonstrate evidence for a dose-rate effect that is not captured by
cumulative exposure, it would be most convincing to show some effect of
dose rate that is in addition to the effect of cumulative exposure.  To
demonstrate such an effect one would need to model both cumulative
exposure and some effect of dose rate, and show that adding the effect
of dose rate makes a statistically significant improvement to the model
over that provided by cumulative exposure alone.  I am not aware of any
such analysis that has been conducted for lung cancer from silica or for
silicosis mortality.  However, as discussed below, two studies conducted
such analyses for silicosis morbidity.

Most of the analyses of for silicosis morbidity did not examine exposure
metrics other than cumulative exposure.  Of the eight cumulative risk
studies summarized by OSHA (Table VI-11), only Hughes et al. (1998)
specifically tested for a dose-rate effect.  This study found that,
after controlling for cumulative exposure, workers exposed to ≥ 0.5
mg/m3 crystalline silica had a significantly higher risk than workers
exposed to lower levels.  A similar dose-rate effect was found by
Buchanan et al. (2003).  Although Steenland and Brown (1995a) found that
average exposure did not describe the morbidity in their cohort nearly
as well as cumulative exposure, this is not as specific a test for a
dose-rate effect as was conducted by Hughes et al. and Buchanan et al.
The remaining six studies used to summarize risk of silicosis morbidity
(Table VI-11) considered only cumulative exposure as an exposure metric.
 So the two studies that looked carefully for a dose-rate effect found
evidence for such an effect.  In addition, Park et al. (2002) found a
13-fold higher incidence of silicosis during 1942-52 than in subsequent
years after controlling for cumulative exposure.  Although they
attributed this possibly to a change in surveillance, it could also be
due to high exposures during this early period and a dose-rate effect.

The OSHA report states that a dose-rate effect for silicosis is
biologically plausible.  And if such an effect is present for silicosis
morbidity, it would presumably also be present for silicosis mortality.
The report also states that even if there is such an effect it may not
exist at concentrations in the range of the current PEL.  However, even
if this is the case, risks in the range of the current PEL are being
estimated from studies that involved higher air concentrations.  Not
accounting for a dose-rate effect, if one exists, could overestimate
risk at lower concentrations.

Having noted that there is evidence for a dose-rate effect for
silicosis, it may be difficult to account for it quantitatively.  The
data are likely to be limited by uncertainty in exposures at earlier
times, which were likely to be higher.  Perhaps rather than identifying
an alternative dose metric to cumulative exposure, it would be better to
retain cumulative exposure but use data from lower exposures where any
dose-rate effect would be less severe.  One possible approach that might
could be used to adjust existing estimates for a potential dose-rate
effect is to use either the coefficients estimated by Hughes et al.
and/or Buchanan et al. for low exposures (e.g., equation (1) of Hughes
et al 1998 with con = 0, or equation (2) of Buchanan et al. 2005).
Another possibility is to reanalyze data from some of the better studies
using an approach similar to the approaches used by Hughes et al. (1998)
and Buchanan et al. (2003).

The analysis by Toxichemica, Inc. (2004) that investigated several
exposure metrics based on lung burden, although it investigated exposure
metrics different from cumulative exposure, did not address a dose-rate
effect per se.

Murray Finkelstein	I am skeptical of the observation of a dose-rate
effect because I think that exposure assessment and assignment to
individual workers is too uncertain. I think that cumulative exposure is
reasonable for the risk assessment of chronic diseases such as silicosis
and lung cancer.

Gary Ginsberg	The studies suggesting that silica risk is driven by
exposure rate more so than cumulative exposure are not particularly
numerous or compelling and I agree with the current analysis.  Further,
the cumulative exposure metric ties into the critical lung burden I
mention above.  However, one cannot rule out the potential for dose-rate
to have an influence on disease rate and so it is appropriate to treat
this as an uncertainty.  In this regard, more could be done to describe
the possible ramifications of a dose-rate model on silica risk
assessment and more mechanistic information could be brought forth
regarding why dose-rate should (or should not) be considered relevant.
For example, what non-linearities in the biological response might exist
that would be sensitive to dose rate (e.g., threshold phenomena such as
exceedance of defense mechanisms or damage requirement needed for
excitation of immune/inflammatory processes).

Assuming cumulative exposure is the best metric for silica risk
assessment, it brings up an interesting assessment/intervention
question.  It raises the possibility that the OSHA standard should be
based upon worker cumulative exposure (in mg/m3-yrs) rather than a set
number (e.g. 0.05 ug/m3).  For example, it may be determined that to
reach a particular cancer risk target (e.g., 1 in a thousand), the
cumulative lifetime exposure should be no greater than xx mg/m3-years.
Some workers may get this faster (higher exposure, shorter period) while
for others it may take longer.  Akin to radiological worker protection,
it may be possible to have a running tally of cumulative silica exposure
and to limit further exposure once the “acceptable risk” level has
been superceded.  This approach would seem compatible with the
cumulative exposure assessments in this document and allow the “bright
line” to be a particular risk target (e.g., 1 in a thousand).  From
the current document, it is unclear what OSHA’s target or acceptable
risk level is.  While the cumulative exposure approach would require
more record keeping, affected industries might find it attractive in
that it might allow short –term occupations to have higher exposure
levels while limiting the cumulative exposure for any given worker.

Brian Miller

Brian Miller

	Cumulative exposure has been widely used in studies of occupational
health risks, and it has been shown theoretically that it is an
appropriate metric in circumstances where the exposure acts over a short
period of time after it is experienced.   This is true of e.g. ionizing
radiation exposures, and has been found to be a reasonable fit for
exposure to respirable coal dust (in which the whole dust rather than
the silica component has usually appeared to drive the risk).
Additionally, in most coalworker epidemiology, to a good approximation,
pneumoconiosis does not progress after exposure ceases.

With silica exposure the responses are rather different.  High exposures
can precipitate severe or accelerated reactions, and silicosis, once
well established, is likely to progress even without further exposure.
The data of Miller et al (1998), in the reanalysis of Buchanan et al
(2003), showed higher silicosis risks, mass for mass, from exposures
derived from higher concentrations.  This might be described as a
dose-rate effect, although that would not specifically address the
mechanism by which it derives, which is likely to be due to the
overloading of the human body’s defence and clearance mechanisms.

Thus there is good reason to believe that cumulative exposure, with no
allowance for the rate at which it accumulated, and no consideration of
persistence of its effects over time, may not be the most appropriate
metric, and that a metric that allowed for these aspects would be
preferred.  However, to be useful for risk assessment, such a metric
would require a more complex formula for its calculation, and would need
quantitative estimates of the coefficients for that formula.  Such
estimation would need very good exposure data.  Buchanan et al (2003)
had some success in this area, notably in establishing the relative
increase in risk from exposures at higher concentrations, but were
unable to obtain a reliable coefficient for the effect of persistence.
This was assumed to be because the high silica exposures were
accumulated over a relatively short time period, so the follow-up time
varied little across the study group, and the power to estimate an
effect of elapsed time was accordingly very low.  It may be that other
studies with a wider range of follow-up lengths might be informative on
this aspect through re-analysis.

Andrew Salmon	It appears that cumulative exposure is the most
appropriate dose metric, and that this is adequate to correlate with the
observed response data in all the major studies examined.  It is
certainly possible that there are dose rate effects, especially at
extremely high (or low) doses, but the studies considered do not, it
seems, provide clear and unequivocal evidence to demonstrate or quantify
these effects.  Similarly, it is possible that lung residence time is a
factor in the development of silicosis and other health endpoints, but
the study which evaluated this metric did not show that it materially
improved the correlation with health effects beyond what was obtained
with the cumulative exposure metric.

Noah Seixas	Cumulative exposure, or the log of cumulative exposure is,
without doubt, the correct measure of exposure for the chronic diseases
under consideration in this risk assessment.  The alternative metrics
discussed, are appropriately considered; however both by the fact that
cumulative exposure is theoretically the most appropriate measure, and
because it fits the data best in most cases, it is selected
appropriately.  More complex models that are considered including
threshold models and dose-rate effects models are interesting
explorations which may shed light on mechanisms of disease, and may in
some cases provide better fits to the data.  However, such models rarely
outperform cumulative exposure to the extent that they should be adopted
for risk assessment purposes.  Even more importantly, policies based on
such models are extremely difficult to formulate as practical exposure
limits or guidelines.  Cumulative exposure is the correct measure from
various perspectives for this assessment.

Further, I would be very skeptical of adopting dose-response estimates
from the limited data we have looking at dose rate effects.  In
particular, the existing data on dose-rate effects are limited by likely
confounding between exposure level and time – that is, all high level
effects are derived from earlier time periods.  While the papers have
done a good job of trying to separate out these two potential aspects of
risk, they are insufficiently robust to allow adoption of differential
response rates in a quantitative manner.  I recommend using the average
risk estimate associated with cumulative exposure, without regard to
exposure level, for estimation of risk.

OSHA’s estimates of lung cancer and silicosis mortality are
represented as a range of estimates with those derived from the
diatomaceous earth and U.S. granite studies considered to be plausible
upper bound risk estimates.  OSHA also acknowledges that the risk may be
lower such as suggested by the results of the IARC multi-centric study,
which relied on pooled data from several epidemiological studies.  Is
this a sound and reasonable estimation of risk from the available data?
Is this decision adequately explained?  Should the risk estimates based
on one data set be preferred over the other?  Is there a more
appropriate representation of the lung cancer risk from silica exposure?
 If so, explain.

Bruce Allen	I think it is appropriate to present a range of risk
estimates and to consider the differences in the estimates when making
decisions about regulatory limits. As discussed in the document, there
are various differences among the cohorts of individuals exposed to
silica, including the physical properties of the silica itself, that are
potentially important considerations and which may account for the range
of risk estimates. Given those differences, it is important to show the
range as a reflection of what those differences may entail (in addition
to the fact that no two sets of results will be exactly alike or give
exactly the same estimates, even if everything was identical).

The only reason that I can see to prefer one set of estimates to another
would be if that one set was based on a substantially superior study,
say in terms of sample size, relevance of exposure, measurement of
exposure, representativeness of the cohort members in relation to the
workers for whom regulatory limits are being set, etc.  The 10-cohort
study is larger than the other two cohorts alone, and its exposure
contexts clearly cover a wider spectrum.  It might be justified to base
decisions solely on the results of that study, but it is not clear that
those results should be presented to the exclusion of the others.

Kenny Crump	Other things being equal I would recommend emphasizing risks
estimated from the multi-centric study, since it incorporates data from
many studies and is less likely to be unduly influenced by exposure
errors from a single study.  However, I would not recommend emphasizing
risks from this study as currently estimated using log-transformed
exposures.  The lower risk estimated from the multi-centric study is
likely to be an artifact due to the use of log-normal transformed
exposure.  As pointed out earlier, untransformed exposure provided a
better fit to these data than log-transformed exposure.  The limited
increase in risk projected by this model to result from a 10-fold
increase in exposure (0.05 mg/m3 to 0.5 mg/m3) doesn’t seem plausible.
 OSHA could consider calculating risk from the multi-center using
untransformed exposures and a linear model.

Murray Finkelstein	I believe that the best estimate is that derived from
the IARC multi-centric study because it averages over study
uncertainties. In so doing, it is possible that the heterogeneity and
uncertainties blunt the dose response relationship. Nevertheless, I
think that individual study uncertainties are sufficiently large that
pooling is the best approach. I am particularly impressed by the
sensitivity analysis conducted by Steenland and colleague. I have
examined and worked with the raw exposure data from the US granite
study. I think that these data are much too weak to be used on a
stand-alone basis.

Gary Ginsberg	OSHA’s risk range is based upon the limited number of
studies which have received quantitative treatment.  As discussed above,
there may be others which would be suitable for quantitative assessment
if they were formally considered for this application, but this document
does not do so.  For example, as stated above, one study in the
Steenland et al 2001 analysis, South African gold miners, yielded a
potency that was approximately 10 times greater than the remainder of
the studies.  Perhaps that is an appropriate upper bound for lung cancer
risk.  Without further discussion of the merits of that study relative
to the others, one cannot determine how much weight to put on it.

Further, the assumption is made that this risk range applies equally to
quartz and other polymorphs such as cristobalite, and with respect to
non-cancer endpoints, that it refers specifically to silicosis.  In
lumping quartz and cristobalite potency information, OSHA should provide
better support that this is appropriate.  The quartz/cristobalite
distinction is brought up in passing on Page 41 and more detailed
explanations are supposedly provided in Sections VI-B and VI-E.  I
couldn’t find this discussion in VI-B and in a later section of VI
titled “Physical Factors that may Influence ….. (page 97-98, I guess
VI-E but unclear)” two paragraphs are given to this distinction, with
rather unconvincing result.  For example, the statement is made that a
difference between these polymorphs has not been seen in epidemiologic
studies but only a limited dataset is being referred to here, and it
evidently does not include the Park et al. 2002 data which showed 8-9
times higher silica-related mortality in diatomaceous earth workers
(cristobalite) than in the multi-center study.  Clearly some of this
difference is due to the broader case definition in Park et al. 2002,
but that doesn’t seem to account for all of the difference as a large
number (percentage undefined) of the LDOC deaths were likely silicosis.

A review by Bolsaitis and Wallace (1996) is cited as supporting no
difference in terms of hemolysis or fibrosis between cristobalite and
quartz but from the abstract that review appears to focus mostly on
surface properties rather than polymorph.  The OSHA document would be
benefited from further documentation along these lines especially since
there is at least some epidemiology of increased risk in association
with cristobalite.

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	The calculation and presentation of risk estimates needs
further elucidation and discussion.

The section on risk assessment for lung cancer mortality displays
several different estimates of what it calls ‘lifetime’ risks of 45
years’ exposure to silica at chosen average concentrations, starting
from age 20.  These risks are based on predicting numbers of deaths,
allowing for intercurrent mortality from other causes, but it is not
clear exactly how this is done.  The commissioned report summarizing
these estimates (ToxaChemica, 2004) does not spell this out, merely
referring to a paper from 1974; the paper references Chiang, a standard
reference on life table methods.  Different estimates for mortality and
morbidity are quoted that predict over different periods, variously up
to and truncated at ages 65, 75 and 85.  None of these can claim to be
‘lifetime’ risks, although that to age 85 comes closest.  Certainly,
if silica exposure has an effect on lung cancer risk, it would be
expected to produce excess cases from the rising background risks way
beyond age 65, particularly since the data suggest no reduction of
excess risk on cessation of exposure.  So summation to 65 must produce a
considerable underestimate of the total impact.  To tabulate these
together as if they are comparable, as in Table VI-9, seems unwise
unless accompanied by carefully-worded warnings.

How large is the underestimation of lifetime risk depends on exactly how
the calculation was done.  If I interpret it correctly, the text
suggests that the risk is for 45 years’ exposure starting at age 20,
so follow-up from the end of exposure to age 65 has zero duration, and
therefore should have zero risk.  However, non-zero risks to age 65 are
shown in e.g. Table VI-9, suggesting that the life-table calculation is
done differently.  It is possible that the calculation proceeds stepwise
through the years, introducing excess risk as exposure cumulates, in
which case excess cases could be predicted to occur from 15 years after
exposure began (to allow for latency), but then those that die before
age 65 do not experience 40 years’ exposure.

The process of predicting excess cases using life-table methods is a
purely arithmetic process, easily done with standard spreadsheets, but
the answers produced depend critically on various assumptions. Whether
to allow time-dependent exposure effects, and for how long to calculate
a follow-up are among these, and need to be described carefully and
accurately.  It is not difficult to produce estimates up to advanced
ages, which might truly be considered ‘lifetime’, so it is not clear
why any estimate so labeled should be truncated at age 65.

Andrew Salmon	In my opinion the presentation of the lung cancer and
silicosis mortality risk for the exposure range considered is well
handled in this section.  The IARC multi-center study probably
represents a reliable median estimate, but by its nature is likely to
underestimate the upper bound on risk in a situation where individual
cohorts show real variation in risks due to differences in the nature
and intensity of the exposure and the effectiveness in determining
health endpoints.  The description in this section describing and
characterizing the range of available estimates is therefore
appropriate.

Noah Seixas	OSHA has presented a thorough and well reasoned discussion
of risks from three substantial exposure-response studies for lung
cancer.  In general, the estimates made are reasonable, and remarkably
consistent in their results, especially within the exposure range
included in the original studies.  It is not clear why OSHA is
characterizing these estimates as ‘upper bound risk estimates.’
Because the estimates are based on the coefficient, and upper and lower
bounds are put on each estimate, these are ‘best estimates’ rather
than upper bounds.

I would agree with putting more emphasis on the pooled study estimate
would make sense, given the size and heterogeneity of this study.
Although somewhat more weight may be given to it, the analysis of the
two other cohorts, showing remarkably similar risk estimates, actually
adds to the overall weight of evidence presented.  Also, note that the
pooled study only presents lower estimates as exposure increases –
thus at the low end of exposure, the estimate is almost the same as the
Granite workers, and somewhat higher than the DE study results.

It would be useful to clarify why the OSHA analyses provide different
estimates than the original study results, and are in fact consistently
higher than the original estimates.  In what ways were the analyses
different, and why did those differences result in higher estimates?

The cumulative risk of silicosis morbidity is preliminarily considered
to be best represented by a range (approximately 3- to 4-fold) that is
based on results from four published exposure-response assessments.
Does this range reflect a sound and reasonable estimation of risk from
the available data?  Is this decision adequately explained?  Should the
risk estimates based on one data set be preferred over the other?  Is
there a more appropriate representation of the silicosis morbidity risk
from silica exposure?  If so, explain.

Bruce Allen	The decision to limit quantitative risk estimates to the
studies that included retirees as well as current workers was a good
one.  Cross-sectional studies are particularly problematic, and the
cumulative risk studies that excluded retired workers lose a segment of
the population that may have a different (higher) response rate than
those who were able to continue work.

The decision to present estimates from those five studies appears
reasonable.  OSHA has indicated a slight preference for the estimates
derived from Miller et al. based on the quality of the exposure indices.
 That is a reasonable position, but the variations across study are
informative and largely corroborative.  Again, given the differences
that might occur across current and future work places subject to
regulation, it is appropriate to consider as many different reasonable
estimates of risk as possible.

Kenny Crump	As discussed above, studies that have tested for a dose-rate
effect have found evidence of such an effect.  Given this, it would be
reasonable to take such an effect into account in the risk estimates.
Some suggestions are made above about how this might be accomplished.

Murray Finkelstein	I agree with OSHA that the relevant cohorts are those
that include extended follow-up, including the experience of retirees. I
agree that it is important to acknowledge a sizeable range in the risk
estimates, due primarily to sampling variability, length of follow-up,
and exposure uncertainties. I think that the range presented reflects a
sound and reasonable estimation of risk from the available data. I think
that the decision is adequately explained. Because of uncertainties, I
favor the use of as many studies as are relevant, rather than relying on
single studies.

Gary Ginsberg	OSHA appropriately narrowed the field of potential
morbidity studies to those which employed retirement follow up and did a
good job of describing the pros and cons of each study.  Given the wide
disparity in exposures, exposure measures, and diagnostic procedures, it
is surprising that the potency estimates fall into a fairly narrow
range.  OSHA’s characterization of this range appears to be
appropriate.  However, the statement on Page 82 regarding autopsy
results in the 1993 study is troubling, suggesting a high rate of false
negatives.  This implies that autopsy results are more sensitive and
that there may be some systemic under-reporting of silicosis.  While the
uncertainty in this study regarding the possible underestimation of
exposure is mentioned in summary on Page 89, the possibility of
underestimation of disease is not.  The uncertainty created by this
possible source of underestimation should be further described.

Brian Miller	There is ample evidence that the morbidity risks from
silica vary widely across industries and across exposures that differ in
nature and in composition.  For that reason alone, different studies are
likely to produce a range of estimates.  All other things being equal,
for purposes of regulation one might want to focus on the highest risk
estimates.  However, all other things may not be equal.  For example, it
should be clear that much of the risk of silicosis from the Miller et al
(1998) study was from short exposures at concentrations well above the
target concentrations considered here.

Although the Miller study is highlighted as having the
best-characterised exposures, the most recently published analyses
(Buchanan et al.) were of a response at ILO category 2/1+, and therefore
fewer than if all responses at 1/0+ had been taken.  It would of course
be possible to use from these data the results of analyses with a 1/0+
response, if that were required:  see the publications listed in answer
to Q1.  Whatever response is considered, interpretation needs to bear in
mind that the radiological responses were taken at a particular point in
time, and that it is both possible and likely that the abnormalities in
at least some of the workers studied would have progressed further, even
though no longer exposed.  With a progressive disease process,
quantitative lifetime risk estimates must take into account the rate of
progression over time.

Andrew Salmon

Andrew Salmon	A range of risk estimates is presented for the specific
concentrations previously identified as OSHA PEL values.  This is
obviously of interest in the specific context of this assessment, but it
does not provide an evaluation of the overall relationship between
exposure and effect, especially for an effect such as silicosis where
the dose-response relationship is not necessarily linear at low doses.
The charge question refers to four studies chosen for principal
evaluation, but the summary description (page 112 and page 114) refers
to five studies (Chen et al., 2001; Chen et al., 2005; Hnizdo and
Sluis-Cremer, 1993; Miller et al., 1998 and Steenland and Brown, 1995b)
as useful in

estimating long-term risk of silicosis.  This dichotomy needs to be
clarified as to exactly which sources OSHA is using as the basis of its
range of estimates.

At several points in the discussion OSHA notes concerns with the
exposure measures used in the South African studies (specifically Hnizdo
and Sluis-Cremer, 1993 in this context).  It should be noted that
although obviously there is some uncertainty in any process of
conversion of exposure measures from one basis to another these data
have in this case been thoroughly explored (Beadle and Bradley, 1970;
Page-Shipp and Harris, 1972), providing reasonable confidence in the
results.  The assertion of Gibbs and duToit (2002) that, based on the
assumed silica content of the dust, exposure was underestimated by
Hnizdo and Sluis-Cremer (1993) has been shown to be incorrect (OEHHA,
2005).  Other sources (e.g. Kielblock et al., 1997) suggest that if
anything the uncertainty is in the other direction.  The more recent
report by Churchyard et al. (2004) is also useful to compare with the
earlier South African results, since these authors used gravimetric
exposure measurements in similar situations to the earlier
particle-based data.  This data set is also worth consideration in
providing additional estimates of silicosis morbidity, although the size
of the cohort is not as large as that examined by Hnizdo and
Sluis-Cremer (1993).  The large size and inclusion of job classes with a
substantial range of different exposure levels make the study by Hnizdo
and Sluis-Cremer (1993) important for determining the overall dose
response for silicosis.  Health endpoint determination used a relatively
sensitive endpoint (ILO 1/1) and exposure measures although not by the
latest preferred method appear to have been systematic and consistent.
This is a significant contrast to the study (Miller et al., 1998) chosen
by OSHA as the “most reliable overall”, which although of excellent
quality in all respects used a less sensitive endpoint (ILO 2/1) and
thus is bound to provide a lower estimate of the risk.  This study also
involved a cohort size of little more than half that of Hnizdo and
Sluis-Cremer (1993) and apparently a narrower range of exposure
concentrations (most of the interindividual variation in cumulative
exposure within the two groups compared appears to be based on
differences in duration rather than exposure concentration.).  Thus,
although it has considerable power to determine risk at cumulative
exposures in the middle range comparable to the OSHA PELs, it is less
informative about the overall shape of the dose-response curve.

If OSHA wishes to examine the overall dose-response relationship for
silicosis morbidity as opposed to merely single-point estimates they
would do well to examine analyses such as that published by Collins et
al. 2005) which attempt to address the response relationship in the
lower cumulative exposure range.

Noah Seixas	Yes – the approach and rationale for selecting the studies
used, and the interpretation of the range of results, is well explained
and sound.  It is of great importance that the range of findings is
presented, rather than relying on any one study or estimate.
Identifying a study that OSHA thinks  perhaps provides the strongest
results, and the fact that that study (Miller, Coal workers) has risk
estimates near the middle of the range, provides good evidence of the
reasonableness of the presented range of risks.

As with the lung cancer risk estimates discussed below, OSHA must
consider how to address the clearly unacceptable level of risk estimated
to occur at 0.05 mg/m3.  Whether one chooses the Miller results (8 per
100) or the range presented by the other studies (2 – 13 per 100
workers), this risk level is clearly unacceptable.

OSHA estimated the risk of lung cancer mortality, silicosis mortality,
and silicosis morbidity for 45-year exposures to 0.25 and 0.5 mg/m3
respirable crystalline silica; these represent a range of exposures
consistent with OSHA’s current standards for construction and maritime
industry sectors, but are above OSHA’s current general industry
standards (approximately 0.1 mg/m3 for respirable quartz).  The
cumulative exposures corresponding to these higher exposure levels are
at or above the cumulative exposures of most of the more highly exposed
workers included in the studies that underlie the risk estimates.  Is
OSHA’s approach for extrapolating risk above the observed range
reasonable?  Is it clearly explained?  Is there a more appropriate
approach that should be considered to estimate risk at cumulative
exposures that are generally above the observed range of the underlying
epidemiological studies?

Bruce Allen	I consider these questions to be moot.  If the analyses show
substantial risk associated with concentrations lower than those in
question, ones that do not require extrapolation above the cumulative
exposures observed in the studies themselves, then it is entirely
reasonable to presume that higher concentrations (i.e., the 0.25 and 0.5
mg/m3 values) will be associated with even higher risks.  In that sense,
there need not be a detailed explanation of (nor angst about) methods
for extrapolation above the levels where there are observed increased
risks.

Kenny Crump	OSHA evaluated this issue by comparing cumulative exposures
corresponding to exposure levels of 0.25 and 0.5 mg/m3 to the median
exposures and third quartile exposures in various cohorts.  Such
comparisons are not particularly indicative of whether risks have been
extrapolated beyond the range of the data.  The important issue is
whether there are sufficient numbers of cohort members with exposures in
the range of interest.  Irrespective of the median of third quartile
exposures, there still could be significant numbers of cohort members
with exposures in the range of interest.  For example, adding many
additional cohort members with low exposures would lower both the median
and third quartile exposure, but would not reduce the ability to
quantify risk at higher exposures.  To explore this issue further, OSHA
could evaluate the potential numbers of cohort members in the various
studies with exposures in the range of interest.  My expectation is that
the pooled analysis will contain a significant number of cohort members
with exposures in this range.  (However, the pooled analysis may
underestimate risks in this range due to use of log-transformed
exposures – see response to Question 4.)

Murray Finkelstein	Extrapolation beyond the observed range depends on
the adoption of a risk model. The selection of the linear or log-linear
models is clearly explained. The approach adopted by OSHA is reasonable.
An alternative approach is simply to say that the risk is greater than
X, where X is the risk observed at the maximum exposure category in the
underlying epidemiologic studies.

Gary Ginsberg

Gary Ginsberg	The issue of extrapolation to cumulative exposures higher
than the majority of the empirical data is a concrete issue.  The lung
cancer high exposure analysis (pp 28-32) seems to be contradictory in
that OSHA argues that a linear relationship with cumulative dose is
likely (page 29) but then prefers the estimates derived from the log
cumulative exposure model which flattens out the dose response at high
dose.  OSHA argues that other forms of mortality or healthy worker
effect may be behind this flattening.  Given that the US granite worker
data show an apparent flattening at cumulative exposures below the range
of concern in this question (Attfield and Costello 2004 study described
on page 20), it would appear that a model that reflects a response
plateau may be appropriate.  OSHA focused on the high dose in Attfield
and Costello 2004 as a possible outlier.  I agree with this
interpretation but believe that a more appropriate focus would be on the
entire dose-response curve in this study and the others.  Is there
evidence from the other studies of flattening as well?  Are there cases
of a superlinear response at the high end of cumulative dose?  It would
appear that OSHA could make more complete use of the underlying data to
support model choice.

Brian Miller	The mechanism of the approach is clearly explained; the
appropriateness of the methodology depends on cumulative exposure being
the correct metric, and this is discussed above.  A different metric
would presumably produce a different set of differentials between the
average concentrations.

Andrew Salmon	Any extrapolation outside the range of exposures for which
sound quantitative data are available is subject to uncertainty, and
this is especially true here where there are suspicions of possible dose
rate effects and/or different pathological responses (e.g. acute
silicosis) at very high doses.  OSHA does not examine these
possibilities very thoroughly, but it is unclear what could be done
about them given the nature of the data for higher exposures (typically
including case studies and early investigations with uncertain or
non-existent exposure measurements, but no systematic large-scale
studies).  Overall the approach at least for these moderately higher
pre-defined exposure levels is reasonable, although there is no effort
to describe an overall dose-response curve which would characterize the
expected response at both low and high levels.  This alternative would
be useful in considering various questions about mechanism of causation
for various health endpoints, as well as informing a health-protective
standards-setting procedure.

Noah Seixas	Yes. The approach and rationale for this extrapolation is
well explained, and reasonable.  Further, it is not clear to me that the
precise estimates for risk in these higher levels of exposure are of any
consequence.  At the higher range of exposure, OSHA needs only to
demonstrate that a substantial risk exists, which is established using
any means of extrapolation chosen.  The precision of the risk estimates
at the lower end of exposure is much more important for the risk
analysis.

Additional Comments/References

Bruce Allen	None.

Kenny Crump

Kenny Crump

Kenny Crump

Kenny Crump

Kenny Crump

	Page 6

“OSHA’s current general industry PEL for quartz is the gravimetric
formula 10 mg/m3/(%quartz + 2) expressed as the concentration of
respirable dust.  For quartz concentrations exceeding 5 percent, the PEL
expressed as the concentration of respirable quartz exceeds 0.07 mg/m3
and approaches 0.1 mg/m3 as the quartz content increases.”

An example could perhaps make this clearer.

Page 12

“the log of cumulative exposure”

This should be the log of cumulative exposure plus 1.  This is an
important distinction that should be made throughout the document.  In a
log linear model that uses log-transformed exposure, the relative risk
approaches zero as exposure approaches zero, rather than approaching
1.0.  However, when 1 is added to cumulative exposure, the relative risk
approaches 1.0 as it should.

Page 15

“Steenland et al. (2001a) estimated excess lifetime risk of lung
cancer based on rate ratios from the spline and log-linear models
(15-year lagged log-cumulative exposure for both),”

“Spline” refers to how exposure is modeled.  “Log-linear refers to