Peer Review Summary Report External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese


External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

FINAL

PEER REVIEW SUMMARY REPORT

External Letter Peer Review of the
Inhalation Health Effect Reference Value Array and
Summary Document for Manganese

Prepared for:

George M. Woodall, Ph.D.
U.S. Environmental Protection Agency
Office of Research and Development
National Center for Environmental Assessment
109 T.W. Alexander Drive (B243-01)
Research Triangle Park, NC 27711

Prepared by:

Versar, Inc.
6850 Versar Center
Springfield, VA 22151

Contract No. EP-C-07-025
Task Order 157

Peer Reviewers:

Donald E. Gardner, Ph.D., Fellow ATS
Peter R. McClure, Ph.D., DABT
Robert D. Sills, MPH

May 29, 2012

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

TABLE OF CONTENTS

I.	INTRODUCTION	1

II.	CHARGE TO REVIEWERS	2

III.	WRITTEN COMMENT SUMMARY	4

GENERAL IMPRESSIONS	5

RESPONSE TO CHARGE QUESTIONS	6

General Charge Questions:	6

Charge Question 1:	6

Charge Question 2:	7

Charge Question 3:	8

Charge Question 4:	9

Accompanying Tables of Data:	10

Charge Question 5:	10

Charge Question 6:	12

SPECIFIC OBSERVATIONS	13

IV.	INDIVIDUAL REVIEWER COMMENTS	15

Review by: Donald E. Gardner, Ph.D., Fellow ATS	16

Reviewed by: Peter R. McClure, Ph.D., DABT	20

Review by: Robert D. Sills, MPH	25

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

I. INTRODUCTION

EPA's National Center for Environmental Assessment (NCEA) is currently developing a
graphical array of available inhalation health effect reference values (e.g., Reference
Concentrations - RfCs) for Manganese, and is in need of an expedited, yet thorough, review. The
array for manganese provides a summation of the available inhalation health effect reference
values developed for a variety of needs (i.e., emergency response, worker protection, and general
public health protection) and across durations ranging from less than one hour up to a 70-year
expected lifespan. This effort builds upon the 24 arrays previously included in a 2009 EPA
Report entitled, "Graphical Arrays of Chemical-Specific Health Effect Reference Values for
Inhalation Exposures (Final Report)" U.S. Environmental Protection Agency, Washington, DC,
EPA/600/R-09/061, 2009, and available on-line at the following URL:
http://cfpub. epa.gov/ncea/cfm/recordisplay. cfm?deid=211003

The subject summary document has been developed by NCEA to support the EPA Office of Air
Quality Planning and Standards (OAQPS), and may also be useful for other EPA Program
Offices. This summary document will be posted on the NCEA web site and will be used in
support of regulatory decision-making. Introductory material describing the design and purpose
of the various values has been provided in Section 1 of the previously mentioned 2009 EPA
Report.

Peer Reviewers:

Donald E. Gardner, Ph.D., Fellow ATS

Inhalation Toxicology Associates
Savannah, GA 31411

Peter R. McClure, Ph.D., DABT

SRC, Inc.

North Syracuse, NY 13212
Robert D. Sills, MPH

Michigan Department of Environmental Quality (MDEQ)

Air Quality Division
Lansing, MI 48909

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

II. CHARGE TO REVIEWERS

The U.S. EPA's National Center for Environmental Assessment (NCEA) has undertaken a
project to develop a summary of manganese inhalation health effect reference values (e.g.,
reference concentrations or RfCs, and Acute Exposure Guideline Levels or AEGLs) across
durations, populations (e.g., general public vs. healthy workers), and purposes (e.g., general
public vs. emergency response vs. repeated occupational vs. occupational ceiling values). A
number of program offices within the Agency, as well as other agencies, have stated an interest
in having these types of arrays available. The manganese summary, which includes a graphical
array and table of derivation details for the reference values, are intended to complement and add
to an existing EPA report, which should also be used as a reference: Inhalation Exposures (Final
Report). U.S. Environmental Protection Agency, Washington, DC, EPA/600/R-09/061, 2009.
Available on-line at http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=211003. Additionally,
reviewers should keep in mind that the document under review is a summary of a number of
secondary sources (i.e., the supporting documents for the various reference values), and
references to primary literature is limited only to the study reports used as the basis for those
values.

Charge Questions:

Below are a series of charge questions, first of a general nature, then with questions specific to
the arrays and tables. These charge questions are provided to help focus the review, but
reviewers are also encouraged to provide any additional input that may be helpful to the
development of these comparative arrays of reference values.

General Charge Questions:

1.	Please comment on the completeness and sufficiency of the data sources used in developing
the array.

2.	Is there adequate direction for a user to obtain access to the source materials from which the
reference values were drawn? Note that the general public will not have access to PDF files,
but will have the full citation available as presented in HERO.

3.	An overview for the manganese array provides background on the chemical and a summary
of available reference values. Please comment on the completeness and sufficiency of the
overview information.

4.	Is the graphical array of reference values readily understandable and accurate in its depiction
of the underlying values being displayed?

Accompanying Tables of Data:

5.	The summary tables for each chemical include information on the duration, reference values,
health effects, point of departure, uncertainty factors, notes on reference value derivation, and
a summary on the level of peer review (ranging from none to National Academy of Sciences
review). Please comment on the extent to which the information presented in the summary

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

table is necessary and sufficient for interpretation of the data array and identify any other
information that may be useful to include.

6. Links to the source/supporting document and the citation(s) for the critical study(ies) for the
value have been included in the references. Does this provide useful reference points for a
user to delve deeper into these reference materials?

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

III. WRITTEN COMMENT SUMMARY

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

GENERAL IMPRESSIONS
Donald E. Gardner

This is a well-written and well-organized reference document that will provide valuable
information not only to the sponsors but also to public health specialists or advocates, regulatory
agencies, and the scientific community. This document provides health risk reference value
summaries for assessing inhalation health risk following exposure to manganese. The document
fully meets the challenge of insightfully summarizing and critically reviewing the established
exposure limits for this substance. While several public and private groups have established
exposure limits for manganese, under certain exposure conditions, and for certain populations,
this document is of special interest since this summary document will allow users to make
comparisons between values previously established for emergency responders, occupational
hazards, and the general public. It is important to note that while the general public will not have
access to the supporting PDF files, they will have the full citation available as presented in
EPA's HERO database.

Peter R McClure

Overall, the document clearly presents accurate information about reference values for
manganese, and the figure provides a means of visually comparing reference values across
exposure durations, populations, and agencies. Important information for understanding the
basis and derivation of the numerical values is provided in preliminary descriptive text and the
table. More explanation should be added about the basis and derivation of the occupational
values and the Texas Commission reference values. See additional comments and suggestions
for improvement in responses to Charge Questions and Specific Observations.

Robert D. Sills

Overall, this is a very good draft product. The inclusion of relevant information is very good, the
summaries are very good, and the presentation of the information is very understandable and
useful. I would not say there is a "conclusions" section to comment upon; the document presents
summaries of the risk assessments derived by various parties, but does not integrate the findings
or present separate conclusions (and I don't think it is intended to). Some information could be
clarified, and I present those suggestions below.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

RESPONSE TO CHARGE QUESTIONS
General Charge Questions:

Charge Question 1:

Please comment on the completeness and sufficiency of the data sources used in developing
the array.

Donald E. Gardner

The summary data presented for manganese were responsive to the stated needs expressed by
EPA's National Center for Environmental Assessment. This review of the reference values for
this substance was complete, and accurately and fully reflected the inhalation health effects
reference values for manganese established by several organizations.

Peter R. McClure

The sources appear complete and sufficient. I am unaware of additional sources which provide
emergency response values, occupational exposure limits, or general population reference values
for manganese.

The inclusion of the interim Texas Commission reference values in Table 1 and Figure 1 without
explanation of the basis for, and derivation of, the values should be reconsidered. Without this
information, it is impossible to meaningfully compare the values to the other general population
reference values.

Robert D. Sills

The first sentence of the document states that it presents chronic noncancer health effect
reference values. However, it does not include all available reference values for Mn, so more
inclusion, or a clarification, would be appropriate. As a clarification, perhaps it should say that it
presents peer-reviewed values from regulatory agencies and ACGIH, and emergency response
values. This would clarify why non-peer-reviewed values from regulatory agencies are not
included (e.g., Minnesota Department of Health uses a value of 0.3 |ig/m ), and published peer-
reviewed values that are not from regulatory agencies are not included (e.g., Bailey, L.A., J.E.
Goodman and B.D. Beck. 2009. Proposal for a revised Reference Concentration (RfC) for
manganese based on recent epidemiological studies. Reg Tox Pharm 55: 330-339). This paper
was also peer reviewed by TERA for the ITER database in a June 29, 2011 report. So, to be
more accurate, the document should clarify the criteria used for inclusion (and for exclusion).

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Charge Question 2:

Is there adequate direction for a user to obtain access to the source materials from which the
reference values were drawn? Note that the general public will not have access to PDF files,
but will have the full citation available as presented in HERO.

Donald E. Gardner

The list of reference source material clearly identifies the key studies. This is critical since these
values are derived from an enormous amount of data used in establishing the various values. The
bibliography at the end of the document provides additional information for readers who wish to
explore the subject further. In is important that the readers will be able to access the
accompanying reference sources and/or access the computerized database provided in the
document.

Peter R McClure

I was supplied with a "public" draft of the document in which the hyperlinks to HERO were
functional, and for those references with URLs, the links in HERO were also functional.

Some additional introductory text describing how to open the hyperlinks and explaining the
limitation of sharing copyrighted material through HERO (i.e., pdfs) may be helpful.

Specific comments:

•	Hero link for EPA, 1993 (IRIS RfC) should have a URL link to the IRIS website, but
does not.

•	The URL link to DOE, 2010 in HERO did not provide a readable document.

•	Is there a way that HERO could provide pdfs to the public for material that is not
copyrighted (e.g., a pdf for the 1993 IRIS summary for manganese)?

Robert D. Sills

Some of the reference citations lack an internet link, and I believe they are available via the
internet (e.g., MOE, 2011; Texas Commission, 2009; EPA, 2008). All available links should be
provided in the reference list. The Roels et al. (1992) citation appears to be wrong; I believe the
journal is Br JIndMed, rather than Occup Environ Med. Also, the citation for the EPA RfC
does not state that it came from the IRIS database, and it does not provide the link; it should do
that.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Charge Question 3:

An overview for the manganese array provides background on the chemical and a summary of
available reference values. Please comment on the completeness and sufficiency of the
overview information.

Donald E. Gardner

This comprehensive review presents sufficient array of reference values focusing on the critical
health effect, point-of-departure, uncertainty factors and reference sources. The scientific and the
public community depends on regulatory agencies to provide valid data to improve our ability to
predict and to assess human health risk associated with exposure to airborne substances. For
readers who seek more information on the toxicity of airborne metals, a number of relevant
reviews are suggested.

Peter R. McClure

I think the introductory material is sufficiently concise and accurate to be useful to the reading
public.

Unlike the reference values for the general public, there are inadequate descriptions of the basis
for, and derivation of, the occupational values. To the extent possible, this section should be
amended to describe how each of these numbers was derived.

A description of the basis and derivation of the Texas Commission general population reference
values was not included and should be added, if it continues to be included in Figure 1 and
Table 1.

Robert D. Sills

The background paragraph states that Mn occurs in soil. Much more relevant would be a
statement about background levels of Mn in ambient air, since this is a document about
inhalation. Data on Mn levels in relatively unimpacted ambient air and in urban environments
are available and would provide a useful context and comparison to the reference values.

The Texas values are the only ones in the graph and table that are not discussed in the text. Why
not?

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Charge Question 4:

Is the graphical array of reference values readily understandable and accurate in its depiction
of the underlying values being displayed?

Donald E. Gardner

In general, the graphical array of the critical information provided was well organized and
adequately provided useful and necessary information not only to the sponsors but also to public
health specialists or advocates, regulatory agencies, first responders and the scientific
community. The information presented in the summary tables is necessary and sufficient for
interpretation of the data array and identifies other information that may be useful and needed. I
have made one suggestion for Figure 1 under Specific Observations.

Peter R McClure

Generally, yes. The plotting of the values on the y-axis appeared accurate for the ones I spot
checked.

An explanation of the depiction in Figure 1 of the ATSDR MRL applying to exposures between
1 year and 70 years should be added (to the table or to the text describing the MRL derivation).
Is this related to an ATSDR determination that the chronic MRL could also be applied to
intermediate-duration exposures?

Robert D. Sills

Yes, with the exception of the EPA RfC and HC values, which could be clarified as discussed
above.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Accompanying Tables of Data:

Charge Question 5:

The summary tables for each chemical include information on the duration, reference values,
health effects, point of departure, uncertainty factors, notes on reference value derivation, and
a summary on the level ofpeer review (ranging from none to National Academy of Sciences
review). Please comment on the extent to which the information presented in the summary
table is necessary and sufficient for interpretation of the data array and identify any other
information that may be useful to include.

Donald E. Gardner

The information provided was well-written, organized and adequately referenced, providing
useful information not only to the sponsors but also to public health specialists or advocates,
regulatory agencies, first responders and the scientific community. This summary document
presented excellent graphical arrays and tables useful in comparing emergency response
reference values to occupational limits and to general public health values. These documents
fulfill a unique niche by providing key studies, excellent tables clearly identifying the problem,
and presenting issues that are important for adequate assessment.

Peter R. McClure

Although there is some overlapping information in the preliminary descriptions of the reference
values and the summary table, the table provides a good format for more readily comparing the
numerical values and their basis/derivations. I would keep the table and the preliminary
descriptions.

Specific comments on the table:

• Consider renaming the "Source" column in Table 1 to "Principal Study."

• If the Texas Commission reference values stay in the figure and table, additional effort
should be made to understand and explain their basis and derivation. Alternatively,
consider deleting them.

• In the Review status column, four words are used to describe review status: "Final",
"Interim", "Draft", and "Rev.26." What is meant by "Rev.26" is not clear. The other
three words do not clearly inform the level of peer review, but do provide some
ambiguous information about the status of the numbers. Additional consideration should
be given to how to capture the review status of the numbers.

• The row for the chronic ATSDR inhalation MRL lists the value derived in the 2000
ATSDR profile, but cites ATSDR 2008 and 2010 in the Review Status column. A more
accurate depiction might be to include a row for the 2000 value, which is still being used,
and a row for the proposed 2008 value (with explanation of its derivation), which is
currently under review. See Specific Observations about the accuracy of other statements
made about the proposed 2008 MRL.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Robert D. Sills

The tabular information encompasses the necessary and sufficient details. For the ACGIH TLV,
the POD is given as 1 mg/m3, with the sources listed as Roels et al. (1992; 1987). However,
based on the summary in the 1991 ACGIH Documentation of TLVs, that POD was provided in
Roels et al. (1987), while Roels et al. (1992) found that the LOAEL was actually much lower
(although the POD was not clearly identified according to this secondary reference). I do not
have access to ACGIH (2012), which is also a cited reference; did that clarify the POD and the
source that could be cited here? Please clarify.

The footnotes should clarify what is meant by NA (Not Available or Not Applicable?) and NR
(Not Reported?).

For the entry for Chronic RfC, in the column, "Notes on Derivation," the "5" should be
superscripted.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Charge Question 6:

Links to the source/supporting document and the citation(s) for the critical study(ies) for the
value have been included in the references. Does this provide useful reference points for a
user to delve deeper into these reference materials?

Donald E. Gardner

These inhalation health effect reference values for manganese are based on comprehensive
literature reviews and the scientific opinions of knowledgeable investigators who work in
relevant areas of science and medicine. The appropriate supporting references listed are essential
for readers who need to explore the original documentation further.

Peter R McClure

Yes, but see comments to Charge Question 2.

Robert D. Sills

See the response to Charge Question 2 above.

I think the document does a reasonable job of providing links to additional and supporting
sources of information, within reason. Some users will not understand much of what is
presented in this document (e.g., what is BMCLi0; how can a BMCLi0-adj be a lower
concentration than a BMCLos-adj derived by a different agency from the same key study; why do
different agencies have such different applications of adjustment factors and uncertainty factors,
even when starting with the same key study?). However, it may simply be beyond the scope of
this document to delve into such discussions, as relevant and important as they may be to risk
assessors and risk managers

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

SPECIFIC OBSERVATIONS

Donald E. Gardner

Page

Paragraph
or Line #

Comment or Question

Regarding the statement about PMi0: PMi0 represents the size fraction
of a measured aerosol in either the environment or in the workplace for
which the 50% cut point of the sampler is 10 microns. That means that
the sampler collects only 1/2 of the particles in the air that are 10
microns in aerodynamic diameter. And obviously, the sampler collects
a much greater percentage of the particles that are smaller than 10
microns, approaching 100% as you get down below particles 5 microns
in aerodynamic diameter.

I would say... 10 for going from a LOAEL to a NOAEL.

I would say... a modifying factor of 10 for uncertain database.

Regarding the deposition in neonates: It depends on which region you
are taking about, conducting airways or alveolar region airways. And it
depends on whether you normalize to body surface area or to the lung
volume. For particles > 1 micron, the lung deposition fraction is
always about 2.5 times greater in the infant than it is in the adult.
However, if you adjust for the volume of air inhaled by the infant and
the adult, the deposition fraction is always about 80 times greater in
infants compared to adults. This is why epidemiology studies typically
find effects in children more easily than they identify effects in adults.

Fig. 1

Need to expand the legend... explain the various data points.

10-11

Table 1

In some places you define "chronic" and in other places you do not.

Peter R. McCIure

Page

Paragraph
or Line #

Comment or Question

3-21

Add more explanation of the basis for, and derivation of, the
occupational values.

Sentence ending on line 8. Refer reader to Figure 1 and Table 1.

Sentence ending on line 13. Refer reader to Figure 1 and Table 1.

18-20

What was the basis of the magnitude of the proposed change and what
triggered the concern that the current value is not protective enough?

Roels et al., 1992 is the principal study, not Roels et al., 1987.

24-25

Roels et al., 1992 is the principal study, not Roels et al., 1987

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Page

Paragraph
or Line #

Comment or Question





The statement that the proposed 2008 ATSDR MRL value was
withdrawn based on public comment and on the recommendation of a
peer review is not accurate. It would be more accurate to state that the
2008 value is under review.

5

28-29

In February 2012, a proposed chronic MRL value of 0.3 |ig/m was still
under review by ATSDR. This value was based on a BMCLio of 142
|ig/m3 (from BMD analysis of data from Roels et al., 1922). The
BMCLio was duration adjusted and divided by an UF of 100 (10 for
human variability and 10 for database deficiencies).

CONTACT MALCOLM WILLIAMS at ATSDR for current
status: mxw7@cdc.gov

7

After 7

Add description of basis and derivation of the Texas Commission's
general public reference values. If they are important enough to
include in Figure 1 and Table 1, a descriptive summary of their basis
should be provided here.

8

Figure 1

Somewhere in the document, provide explanation of why the ATSDR
MRL applies to exposure durations between 1 and 70 years.

10

Chronic
AT SDR
MRL

The "Review Status" entry references ATSDR 2008 and 2010, but lists
the value derived in ATSDR 2000.

Robert D. Sills

Page

Paragraph
or Line #

Comment or Question

5

3

This sentence is not a complete sentence.

7

12-13

I agree that these values/sources cannot be discerned, and that is a
problem. To clarify it, I suggest that they be combined in the key so
that there is a single symbol representing both agencies' values, for this
specific document.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

IV. INDIVIDUAL REVIEWER COMMENTS

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Review by: Donald E. Gardner, Ph.D., Fellow ATS

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Peer Review Comments on EPA's Draft Document

Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Donald E. Gardner, PhD., Fellow ATS
Inhalation Toxicology Associates
May 10, 2012

I.	GENERAL IMPRESSIONS

This is a well-written and well-organized reference document that will provide valuable
information not only to the sponsors but also to public health specialists or advocates, regulatory
agencies, and the scientific community. This document provides health risk reference value
summaries for assessing inhalation health risk following exposure to manganese. The document
fully meets the challenge of insightfully summarizing and critically reviewing the established
exposure limits for this substance. While several public and private groups have established
exposure limits for manganese, under certain exposure conditions, and for certain populations,
this document is of special interest since this summary document will allow users to make
comparisons between values previously established for emergency responders, occupational
hazards, and the general public. It is important to note that while the general public will not have
access to the supporting PDF files, they will have the full citation available as presented in
EPA's HERO database.

II.	RESPONSE TO CHARGE QUESTIONS
General Charge Questions:

1.	Comment on the completeness and sufficiency of the data sources used in developing the
arrays.

The summary data presented for manganese were responsive to the stated needs expressed by
EPA's National Center for Environmental Assessment. This review of the reference values for
this substance was complete, and accurately and fully reflected the inhalation health effects
reference values for manganese established by several organizations.

2.	Is there adequate direction for a user to obtain access to the source materials from which
the reference values were drawn? Note that the general public will not have access to PDF
files, but will have the full citation available as presented in HERO.

The list of reference source material clearly identifies the key studies. This is critical since these
values are derived from an enormous amount of data used in establishing the various values. The
bibliography at the end of the document provides additional information for readers who wish to
explore the subject further. In is important that the readers will be able to access the
accompanying reference sources and/or access the computerized database provided in the
document.

3.	An overview for the manganese array provides background on the chemical and a
summary of available reference values. Please comment on the completeness and
sufficiency of the overview information.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

This comprehensive review presents sufficient array of reference values focusing on the critical
health effect, point-of-departure, uncertainty factors and reference sources. The scientific and the
public community depends on regulatory agencies to provide valid data to improve our ability to
predict and to assess human health risk associated with exposure to airborne substances. For
readers who seek more information on the toxicity of airborne metals, a number of relevant
reviews are suggested.

4.	Is the graphical array of reference values readily understandable and accurate in its
depiction of the underlying values being displayed?

In general, the graphical array of the critical information provided was well organized and
adequately provided useful and necessary information not only to the sponsors but also to public
health specialists or advocates, regulatory agencies, first responders and the scientific
community. The information presented in the summary tables is necessary and sufficient for
interpretation of the data array and identifies other information that may be useful and needed. I
have made one suggestion for Figure 1 under Specific Observations.

Accompanying Tables of Data:

5.	The summary tables for each chemical include information on the duration, reference
values, health effects, point of departure, uncertainty factors, notes on reference value
derivation, and a summary on the level of peer review (ranging from none to National
Academy of Sciences review). Please comment on the extent to which the information
presented in the summary table is necessary and sufficient for interpretation of the data
array and identify any other information that may be useful to include.

The information provided was well-written, organized and adequately referenced, providing
useful information not only to the sponsors but also to public health specialists or advocates,
regulatory agencies, first responders and the scientific community. This summary document
presented excellent graphical arrays and tables useful in comparing emergency response
reference values to occupational limits and to general public health values. These documents
fulfill a unique niche by providing key studies, excellent tables clearly identifying the problem,
and presenting issues that are important for adequate assessment.

6.	Links to the source/supporting document and the citation(s) for the critical study(ies) for
the value have been included in the references. Does this provide useful reference points
for a user to delve deeper into these reference materials?

These inhalation health effect reference values for manganese are based on comprehensive literature
reviews and the scientific opinions of knowledgeable investigators who work in relevant areas of science
and medicine. The appropriate supporting references listed are essential for readers who need to explore
the original documentation further.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

III. SPECIFIC OBSERVATIONS

Page

Paragraph
or Line #

Comment or Question

I would say... 10 for going from a LOAEL to a NOAEL.

I would say... a modifying factor of 10 for uncertain database.

Fig. 1

Need to expand the legend... explain the various data points.

10-11

Table 1

In some places you define "chronic" and in other places you do not.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Reviewed by: Peter R. McClure, Ph.D., DABT

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Peer Review Comments on EPA's Draft Document

Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Peter R. McClure, Ph.D., DABT
SRC, Inc.

May 17, 2012

I. GENERAL IMPRESSIONS

Overall, the document clearly presents accurate information about reference values for
manganese, and the figure provides a means of visually comparing reference values across
exposure durations, populations, and agencies. Important information for understanding the
basis and derivation of the numerical values is provided in preliminary descriptive text and the
table. More explanation should be added about the basis and derivation of the occupational
values and the Texas Commission reference values. See additional comments and suggestions
for improvement in Section II and III below.

II. RESPONSE TO CHARGE QUESTIONS
General Charge Questions:

1. Please comment on the completeness and sufficiency of the data sources used in
developing the array.

2. Is there adequate direction for a user to obtain access to the source materials from which
the reference values were drawn? Note that the general public will not have access to PDF
files, but will have the full citation available as presented in HERO.

I was supplied with a "public" draft of the document in which the hyperlinks to HERO were
functional, and for those references with URLs, the links in HERO were also functional.

Some additional introductory text describing how to open the hyperlinks and explaining the
limitation of sharing copyrighted material through HERO (i.e., pdfs) may be helpful.

Specific comments:

• Hero link for EPA, 1993 (IRIS RfC) should have a URL link to the IRIS website, but
does not.

• The URL link to DOE, 2010 in HERO did not provide a readable document.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

• Is there a way that HERO could provide pdfs to the public for material that is not
copyrighted (e.g., a pdf for the 1993 IRIS summary for manganese)?

3. An overview for the manganese array provides background on the chemical and a
summary of available reference values. Please comment on the completeness and
sufficiency of the overview information.

I think the introductory material is sufficiently concise and accurate to be useful to the reading
public.

A description of the basis and derivation of the Texas Commission general population reference
values was not included and should be added, if it continues to be included in Figure 1 and
Table 1.

4. Is the graphical array of reference values readily understandable and accurate in its
depiction of the underlying values being displayed?

Generally, yes. The plotting of the values on the y-axis appeared accurate for the ones I spot
checked.

An explanation of the depiction in Figure 1 of the ATSDR MRL applying to exposures between
1 year and 70 years should be added (to the table or to the text describing the MRL derivation).
Is this related to an ATSDR determination that the chronic MRL could also be applied to
intermediate-duration exposures?

Accompanying Tables of Data:

5. The summary tables for each chemical include information on the duration, reference
values, health effects, point of departure, uncertainty factors, notes on reference value
derivation, and a summary on the level of peer review (ranging from none to National
Academy of Sciences review). Please comment on the extent to which the information
presented in the summary table is necessary and sufficient for interpretation of the data
array and identify any other information that may be useful to include.

Specific comments on the table:

• Consider renaming the "Source" column in Table 1 to "Principal Study."

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

6. Links to the source/supporting document and the citation(s) for the critical study(ies) for
the value have been included in the references. Does this provide useful reference points
for a user to delve deeper into these reference materials?

Yes, but see comments to Charge Question 2.

III. SPECIFIC OBSERVATIONS

Page

Paragraph
or Line #

Comment or Question

3-21

Add more explanation of the basis for, and derivation of, the
occupational values.

Sentence ending on line 8. Refer reader to Figure 1 and Table 1.

Sentence ending on line 13. Refer reader to Figure 1 and Table 1.

18-20

What was the basis of the magnitude of the proposed change and what
triggered the concern that the current value is not protective enough?

Roels et al., 1992 is the principal study, not Roels et al., 1987.

24-25

Roels et al., 1992 is the principal study, not Roels et al., 1987

The statement that the proposed 2008 ATSDR MRL value was
withdrawn based on public comment and on the recommendation of a
peer review is not accurate. It would be more accurate to state that the
2008 value is under review.

28-29

In February 2012, a proposed chronic MRL value of 0.3 |ig/m was still
under review by ATSDR. This value was based on a BMCLio of 142
|ig/m3 (from BMD analysis of data from Roels et al., 1922). The
BMCLio was duration adjusted and divided by an UF of 100 (10 for
human variability and 10 for database deficiencies).

CONTACT MALCOLM WILLIAMS at ATSDR for current
status: mxw7@cdc.gov

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Page

Paragraph
or Line #

Comment or Question

7

After 7

Add description of basis and derivation of the Texas Commission's
general public reference values. If they are important enough to
include in Figure 1 and Table 1, a descriptive summary of their basis
should be provided here.

8

Figure 1

Somewhere in the document, provide explanation of why the ATSDR
MRL applies to exposure durations between 1 and 70 years.

10

Chronic
AT SDR
MRL

The "Review Status" entry references ATSDR 2008 and 2010, but lists
the value derived in ATSDR 2000.

24

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Review by: Robert D. Sills, MPH

25

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

Peer Review Comments on EPA's Draft Document

Inhalation Health Effect Reference Value Array and Summary Document for Manganese
Robert D. Sills, MPH

Michigan Department of Environmental Quality (MDEQ)

Air Quality Division
May 15, 2012

I. GENERAL IMPRESSIONS

Overall, this is a very good draft product. The inclusion of relevant information is very good, the
summaries are very good, and the presentation of the information is very understandable and
useful. I would not say there is a "conclusions" section to comment upon; the document presents
summaries of the risk assessments derived by various parties, but does not integrate the findings
or present separate conclusions (and I don't think it is intended to). Some information could be
clarified, and I present those suggestions below.

II. RESPONSE TO CHARGE QUESTIONS
General Charge Questions:

1. Please comment on the completeness and sufficiency of the data sources used in
developing the array.

included (e.g., Minnesota Department of Health uses a value of 0.3 |ig/m ), and published peer-
reviewed values that are not from regulatory agencies are not included (e.g., Bailey, L.A., J.E.
Goodman and B.D. Beck. 2009. Proposal for a revised Reference Concentration (RfC) for
manganese based on recent epidemiological studies. Reg ToxPharm 55: 330-339). This paper
was also peer reviewed by TERA for the ITER database in a June 29, 2011 report. So, to be
more accurate, the document should clarify the criteria used for inclusion (and for exclusion).

Some of the reference citations lack an internet link, and I believe they are available via the
internet (e.g., MOE, 2011; Texas Commission, 2009; EPA, 2008). All available links should be
provided in the reference list. The Roels et al. (1992) citation appears to be wrong; I believe the
journal is Br JIndMed, rather than Occup Environ Med. Also, the citation for the EPA RfC
does not state that it came from the IRIS database, and it does not provide the link; it should do
that.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

3. An overview for the manganese array provides background on the chemical and a
summary of available reference values. Please comment on the completeness and
sufficiency of the overview information.

The Texas values are the only ones in the graph and table that are not discussed in the text. Why
not?

4. Is the graphical array of reference values readily understandable and accurate in its
depiction of the underlying values being displayed?

Yes, with the exception of the EPA RfC and HC values, which could be clarified as discussed
above.

Accompanying Tables of Data:

The tabular information encompasses the necessary and sufficient details. For the ACGIH TLV,
the POD is given as 1 mg/m3, with the sources listed as Roels et al. (1992; 1987). However,
based on the summary in the 1991 ACGIH Documentation of TLVs, that POD was provided in
Roels et al. (1987), while Roels et al. (1992) found that the LOAEL was actually much lower
(although the POD was not clearly identified according to this secondary reference). I do not
have access to ACGIH (2012), which is also a cited reference; did that clarify the POD and the
source that could be cited here? Please clarify.

The footnotes should clarify what is meant by NA (Not Available or Not Applicable?) and NR
(Not Reported?).

For the entry for Chronic RfC, in the column, "Notes on Derivation," the "5" should be
superscripted.

See the response to Charge Question 2 above.

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External Letter Peer Review of the Inhalation Health Effect Reference Value Array and Summary Document for Manganese

I think the document does a reasonable job of providing links to additional and supporting
sources of information, within reason. Some users will not understand much of what is
presented in this document (e.g., what is BMCLi0; how can a BMCLi0-adj be a lower
concentration than a BMCLos-adj derived by a different agency from the same key study; why do
different agencies have such different applications of adjustment factors and uncertainty factors,
even when starting with the same key study?). However, it may simply be beyond the scope of
this document to delve into such discussions, as relevant and important as they may be to risk
assessors and risk managers.

III. SPECIFIC OBSERVATIONS

Page

Paragraph
or Line #

Comment or Question

5

3

This sentence is not a complete sentence.

7

12-13

I agree that these values/sources cannot be discerned, and that is a
problem. To clarify it, I suggest that they be combined in the key so
that there is a single symbol representing both agencies' values, for this
specific document.

28

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