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Notes From the April 16, 1998 ITER Peer Review Meeting
April 16, 1998
Conference Call
A reference concentration (RfC) for hexavalent chromium was
reviewed by a panel of risk assessment experts on December 16,
1996. At that meeting the panel raised a number of issues and
concerns which it asked the authors (ChemRisk Division of
McLaren/Hart) to address in a revised document. This same panel
of reviewers discussed this revised document in a conference call
on April 17, 1998. This conference call was organized by
Toxicology Excellence for Risk Assessment (TERA), a non-profit
organization dedicated to the best use of toxicity data in risk
assessment. Expert peer reviewers donated their time and talents
to provide an independent review of the assessment. For a complex
assessment such as this, each reviewer brought to the review his
or her particular expertise, which when combined, provided a
comprehensive overall review of the assessment document.
The peer review conference call began with a discussion of
conflict of interest. Prior to the first meeting in December 1996
each reviewer certified that he or she did not have a conflict
(real or apparent) with the chemical under review, or with the
sponsor. Reviewers represent their own personal scientific
opinions, and not those of their employers. Possible conflicts
were discussed with the reviewer to determine if measures were
needed to manage the conflict (or appearance). Options include
excluding the reviewer from that chemical's discussion and
consensus, or allowing the reviewer to participate in the
discussion, but not be polled for consensus. The peer review
panel discussed the original certifications again, and agreed
upon how to manage any potential conflicts. This discussion is
documented in Attachment A.
These reviews follow a standard format, beginning with a close
examination of the supporting documentation and important
references several weeks prior to the meeting. At the meeting or
conference call, a discussion of conflict of interest and
decision by the panel occurs, followed by a briefing by the
authors of the assessment. The panel then systematically
discusses the assessment. For this conference call the
outstanding issues identified at the December 16, 1996 meeting
formed the basis for the discussions. Full discussion and
participation are encouraged and agreement is reached by
consensus. Consensus for the purpose of these meetings is defined
as "an opinion held by all or most, or general
agreement."
The conference call was open to the public and an individual from
the U.S. Environmental Protection Agency took part.
Reference Concentration for Hexavalent Chromium
Sponsor:
ChemRisk Division of McLaren/Hart for:
Elementis Chromium, Corpus Christi, TX
Chemical Land Holdings, Dallas, TX
PPG Industries, Inc., Pittsburgh, PA
Presenter:
Ms. Deborah Proctor, ChemRisk Division of McLaren/Hart
Chair:
Dr. Michael Dourson, Toxicology Excellence for Risk Assessment
Review Panel:
Dr. Stuart Baxter*, University of Cincinnati
Dr. Robert Benson, U.S. EPA
Dr. Matthew Bogdanffy, Haskell Laboratory, DuPont
Dr. John Christopher, California EPA
Dr. Gary Diamond, Syracuse Research Corporation
Dr. Michael Dourson, Toxicology Excellence for Risk Assessment
Dr. Linda Erdreich, Bailey Research Associates, Inc.
Dr. Marvin Friedman*, Cytec Industries, Inc.
Dr. Michael Gargas*, ChemRisk Division of McLaren/Hart
Dr. Kenneth Poirier, Procter and Gamble
Dr. Andrew Renwick*, University of Southampton
* These reviewers were not able to participate in this conference
call due to scheduling difficulties and therefore, their opinions
are not reflected in this document. They were present at the
first meeting.
Dr. Michael Dourson, as Chair, began the meeting by suggesting a
process for conducting the conference call that would facilitate
an efficient discussion. The panel agreed to follow a process
whereby each of the six issues identified from the first meeting
would be discussed in order. Dr. Dourson called upon a different
individual peer reviewer to begin each issue's discussion with
his or her opinion on whether or not ChemRisk answered the
question or issue as identified, and whether he or she agreed
with the ChemRisk position. The discussion was then opened to
others, with an alphabetic roll call used to solicit each
reviewer's opinion. Opportunity for ChemRisk to respond to the
peer reviewers' comments was also provided. Observers were
offered the opportunity to present technical comments.
ISSUES FROM THE DECEMBER 16, 1996 MEETING
Issue 1. Provide a clearer distinction of the different forms of
chromium the RfC is for and perhaps consider developing different
RfCs for acid mists and dust containing hexavalent chromium.
Issue 2. Add a more complete discussion of all available animal
and human studies, as well as ongoing research.
Issue 3. Investigate further the upper respiratory tract toxicity
and attempt to obtain raw data from Glaser.
Issue 4. Consult with an immunologist regarding the significance
of the immune effects observed in Glaser et al. (1985).
Issue 5. Determine which deep lung effects should or should not
be combined in order to use as basis of critical effect.
Acknowledge that both the lactate dehyrogenase (LDH) and lung
weight endpoints have weaknesses.
Issue 6. Use the default uncertainty factor of 10 for use of a
subchronic study, unless better support for reducing this to
three can be provided. The uncertainty factors for intra- and
interspecies are appropriate as proposed. An uncertainty factor
for database may not be needed, but needs better justification.
PRESENTATION
Deborah Proctor of the ChemRisk Division of McLaren/Hart
presented the revised assessment of hexavalent chromium to the
panel, focusing on the changes made in the document in response
to the issues raised at the December 1996 meeting.
Issue 1. Provide a clearer distinction of the different
forms of chromium the RfC is for and perhaps consider developing
different RfCs for acid mists and dust containing hexavalent
chromium.
The documentation package was revised to indicate that the
proposed RfC is only for hexavalent chromium present in the
environment as chromate salts, which are stable in the
environment. Even though chromic acid is likely to be the most
toxic form of hexavalent chromium, it is not stable in the
environment and not thought to result in environmental exposures.
Therefore, chromic acid is not the basis for the RfC.
Issue 2. Add a more complete discussion of all available
animal and human studies, as well as ongoing research.
In response to this issue, the documentation package was revised
to include a comprehensive Hazard Identification section and
tables which summarize all human and animal studies available on
the health effects of hexavalent chromium exposure.
Issue 3. Investigate further the upper respiratory tract
toxicity and attempt to obtain raw data from Glaser.
In response to this issue, Dr. Glaser was contacted to determine
if any additional data regarding upper airway irritation were
collected, but not reported in Glaser et al. (1986), the 18-month
cancer bioassay. Dr. Glaser indicted that the only upper airway
irritation observed was reported in the manuscript. In addition,
the revised documentation package now provides a focused
discussion of all information regarding upper respiratory tract
toxicity.
Issue 4. Consult with an immunologist regarding the
significance of the immune effects observed in Glaser et al.
(1985).
In response to this issue, Dr. Alice Wong, an immunologist at the
University of California, Davis, was contacted to assist in
interpreting the immune effects observed in Glaser et al. (1985).
Dr. Wong stated that the immune effects observed could indicate a
Type I allergic reaction, such as asthma, or they could be a
normal immune response to a foreign body or inflammation. The
revised documentation includes a discussion of the hexavalent
chromium levels which induce asthma. In addition, the effects on
total serum immunoglobins observed in Glaser et al. (1985) were
included in the benchmark dose analysis for the revised RfC.
Issue 5. Determine which deep lung effects should or
should not be combined in order to use as basis of critical
effect. Acknowledge that both the LDH and lung weight endpoints
have weaknesses.
The revised RfC was calculated based on the arithmetic average of
the individual RfCs for several endpoints which represent the
critical effect, lung inflammation. The endpoints averaged
include lung weight, spleen weight, protein in bronchio-alveolar
lavage fluid (BALF), albumin in BALF, total immunoglobins, and
lactate dehydrogenase (LDH) in BALF. The benchmark dose analysis
was conducted using both a polynomial mean response model and a
power mean response model. LDH in BALF fit both models well;
therefore, this endpoint was retained for RfC derivation as a
relative endpoint suggestive of inflammation.
Issue 6. Use the default uncertainty factor of 10 for use
of a subchronic study, unless better support for reducing this to
three can be provided. The uncertainty factors for intra- and
interspecies are appropriate as proposed. An uncertainty factor
for database may not be needed, but needs better justification.
In considering the appropriate uncertainty factor for
extrapolating from a less than chronic study, the following
factors should be considered: accumulation/cumulative damage,
pharmacokinetics/pharmacodynamics, severity of effect, recovery,
duration of study, and consistency of effect within duration. For
hexavalent chromium, only the accumulation and potential
cumulative damage suggest that subchronic data may not be
representative of chronic exposure. An uncertainty factor of 3 is
justified to account for this uncertainty because fibrosis, the
ultimate outcome of inflammation, was not observed in the
18-month bioassay and because none of the endpoints showed an
increased in effect between the 30 and 90 day exposure periods at
the lower dose groups.
DISCUSSION
Issue 1. Provide a clearer distinction of the different
forms of chromium the RfC is for and perhaps consider developing
different RfCs for acid mists and dust containing hexavalent
chromium.
The panel unanimously agreed that this issue was completely
resolved and that the package clearly indicated that the RfC
applies only to environmental exposure to hexavalent chromium
salts and not to occupational exposure to chromic acid. Some
reviewers disagreed with the statement that chromic acid is not
an environmentally relevant form of hexavalent chromium. The
panel recommended that the documentation should state that the
RfC is protective of exposure to both mono- and dichromate salts.
Reviewers noted that the documentation states that the RfC is
also protective of exposure to both soluble and insoluble salts
because the insoluble salts are less toxic; however, the
documentation should include the evidence to support this
statement.
Issue 1 is resolved. The documentation can be strengthened by
clearly showing the support for the statement that the RfC is
protective of exposure to insoluble salts because they are less
toxic than the soluble salts.
Issue 2. Add a more complete discussion of all available
animal and human studies, as well as ongoing research.
Overall, the panel reached unanimous consensus that this issue
has been resolved and that the documentation package adequately
describes all of the human and animal studies on hexavalent
chromium. One reviewer suggested that the discussion of the human
studies could be strengthened by improving the evaluation of the
quality of the human studies. In addition, this reviewer noted
that the discussion of some of the immunotoxicity data was
misleading because case reports of single patients are not
necessarily reflective of effects in the entire population.
Another reviewer suggested addressing this by adding a column to
Table 1 which shows the number of study subjects.
Issue 2 is resolved. The documentation can be strengthened by
providing an introductory statement for the human studies as was
done for the animal studies and by including a discussion of the
quality of the human studies.
Issue 3. Investigate further the upper respiratory tract
toxicity and attempt to obtain raw data from Glaser.
The panel reached unanimous consensus that no additional data are
available on upper respiratory tract irritation and that the
upper respiratory tract is not a critical target organ following
exposure to hexavalent chromium salts. This issue has been
resolved.
Issue 3 is resolved. No additional work is recommended for this
issue.
Issue 4. Consult with an immunologist regarding the
significance of the immune effects observed in Glaser et al.
(1985).
The panel reached unanimous consensus that the issue of
immunotoxicity was satisfactorily resolved for the purposes of
this RfC development. The comments of the immunologist were
helpful in interpreting the immune effects observed by Glaser et
al. (1985). However, several reviewers felt that the immune
system may be of some concern; although the data are not
available to answer this question conclusively. The panel noted
that the Glaser et al. (1985) study was not designed to detect
immune effects and the absence of histopathology precludes
conclusions regarding immunotoxicity as a critical effect. The
panel agreed that it is accurate to state that the LOAEL for
immunotoxicity observed in Glaser et al. (1985) is higher than
the LOAEL for lung inflammation. Reviewers discussed the
appropriateness of using sensitization/asthma as a critical
endpoint, but concluded that the data available for this endpoint
are not strong enough to use quantitatively. The LOAEL identified
for asthma (from a case study in a single person) could be widely
variable in a population because it is not known if the person
was sensitive to the effects of hexavalent chromium.
Issue 4 is resolved. No additional work is recommended for this
issue.
Issue 5. Determine which deep lung effects should or
should not be combined in order to use as basis of critical
effect. Acknowledge that both the LDH and lung weight endpoints
have weaknesses.
The panel reached unanimous consensus that the endpoints of
spleen weight and total immunoglobin should not be used for
estimating the RfC because they are not of equal value in
describing pulmonary inflammation. The remaining discussion of
this issue focused on the appropriateness of choosing the single
endpoint that is most sensitive and biologically relevant to lung
inflammation as the basis of the RfC, compared with the
appropriateness of combining several endpoints that are all
related to each other and all indicative of lung inflammation for
estimating the RfC.
The reviewers noted that LDH in BALF was the most biologically
relevant endpoint because it would not be present unless cells
were being damaged. However, there was disagreement on whether
this was the most sensitive endpoint and whether it is
appropriate to use this endpoint alone as the basis of the RfC.
Reviewers noted that when comparing the maximum likelihood
estimates for the various endpoints, LDH was the least sensitive;
however when comparing the benchmark doses, LDH was the most
sensitive. The reviewers noted that the LDH data were not highly
variable. One reviewer suggested that the probable reason for
this discrepancy was that the models were designed to fit data
that increased monotonically, which does not happen with the LDH
data. Therefore, the model did not fit the LDH data as well as it
fit the other data. The reviewers agreed that there was not a
compelling biological reason to use only the LDH in BALF
benchmark dose as the basis of the RfC. Therefore, the panel
recommended that the benchmark doses for four endpoints from
Glaser et al. (1990) (lung weight, protein in BALF, albumin in
BALF, and LDH in BALF) be combined as the basis of the RfC. The
panel also recommended that the results of either the polynomial
model or the power mean response model be used, but that they
should not be combined. Several reviewers recommended that the
polynomial model be used; the remaining reviewers had no
preference and suggested that ChemRisk choose a model.
Issue 5 is resolved. However, the RfC should be revised so that
it is based on the combined benchmark doses of four endpoints
indicative of lung inflammation as the critical effect: LDH in
BALF, protein in BALF, albumin in BALF, and lung weight. The BMDs
for these four endpoints should be combined prior to the
estimation of the RfC. ChemRisk should not combine the estimates
from the polynomial and the power mean response models to
estimate the RfC. More reviewers preferred the polynomial model.
Issue 6. Use the default uncertainty factor of 10 for use
of a subchronic study, unless better support for reducing this to
three can be provided. The uncertainty factors for intra- and
interspecies are appropriate as proposed. An uncertainty factor
for database may not be needed, but needs better justification.
The panel did not reach consensus on the appropriate choice of
uncertainty factors for development of this RfC. The overall
uncertainty factor discussed was either 100 or 300. All reviewers
agreed on the use of an uncertainty factor of 3 to account for
extrapolation from animals to humans and on the use of an
uncertainty factor of 10 to protect sensitive individuals.
Several reviewers felt that a full 10 uncertainty factor was
needed to account for the uncertainty of extrapolating from a
subchronic study; however several other reviewers felt that an
uncertainty factor of 3 was adequate. One reviewer felt that a 3
was adequate for the use of subchronic data, but that an
additional 3 was needed to address database inadequacies.
The following arguments were discussed in favor of requiring a
full 10 uncertainty factor for use subchronic data:
· Data from Glaser et al. (1985) indicate that chromium is still
accumulating in the lung at the end of the exposure period.
· Data from Glaser et al. (1990) on LDH and protein in BALF show
that there is increasing toxicity with increasing exposure time
from 30 to 90 days at the two higher dose groups (200 and 400
ug/cu.m.), and there is no histopathologic data from organs other
than the lungs in this study.
· Although the Glaser 18-month study did not demonstrate
fibrosis, it did not look for evidence of progression to more
severe inflammation as demonstrated by histiocytosis data.
The following arguments were made to support the adequacy of an
uncertainty factor of 3 to account for the use of a subchronic
study:
· The 18-month study by Glaser used higher doses and did not
demonstrate any evidence of fibrosis or other histopathological
damage to lungs.
· A study by Nessel et al. (1995) evaluated several inhalation
studies and found that in general the difference between 90-day
NOAELs and 2-year NOAELs was only a factor of 2.5.
· Data from Glaser et al. (1990) show that for all endpoints
examined there is no increasing toxicity with increasing exposure
from 30 to 90 days at the two lower doses (50 and 100 ug/cu.m.).
· The endpoints selected as the basis of the RfC are very
sensitive precursors of inflammation; therefore they are only a
signal event, not the actual adverse effect.
The panel made several recommendations to help resolve the issue
of uncertainty factor.Ffor the reviewers who felt that a total
uncertainty factor of 300 was required, the arguments made in the
current documentation package do not provide adequate support for
an uncertainty factor of 100. The revised document should rely
more on the observations of the 18-month study and, in
particular, focus on a comparison of those endpoints that were
measured in both the 90-day and 18-month studies to determine the
potential for progression of toxicity. The revised document
should include data, if available, on the accumulation of
hexavalent chromium in the lung following exposure to lower
doses. Finally the work of Nessel et al. (1995) and perhaps a
similar study by Gary Foureman of U.S. EPA, which looked
specifically at the lung, can be included in the documentation as
supporting evidence for a reduced uncertainty factor.
Issue 6 is not resolved. Reviewers might agree to a total
uncertainty factor of 100 if stronger support were provided. This
support would have to rest primarily on the Glaser 18-month study
and data showing the potential for accumulation of lower doses in
the lungs. Studies by Nessel et al. (1995) and Gary Foureman
might also provide support.
REFERENCES:
Glaser, U., D. Hochrainer, et al. 1985. Low level chromium (VI)
inhalation effects on alveolar macrophages and immune functions
in Wistar rats. Arch Toxicol. 57:250-256.
Glaser, U., D. Hochrainer, et al. 1986. Carcinogenicity of sodium
dichromate and chromium (VI/III) oxide aerosols inhaled by male
Wistar rats. Toxicology. 42:219-232.
Glaser, U., D. Hochrainer, et al. 1990. Investigation of
irritating properties of inhaled Cr(VI) with possible influence
on its carcinogenic action. In: Environmental Hygiene II. N.a.
W.H. Seemayer, ed. New York. p. 239-245.
Nessel, C., S. Lewis, K. Stauber, and J. Adgate. 1995. Subchronic
to chronic exposure extrapolation: Toxicological evidence for a
reduced uncertainty factor. Human and Ecological Risk Assessment.
1: 516.
Managing Potential Conflicts of Interest
Hexavalent Chromium RfC
(Approved April 16, 1998)
TERA peer reviewers donate their time and talents to this effort.
They are selected based upon their expertise and qualifications
and are employed by many types of organizations. TERA strives to
create a balance of expertise and affiliations. However,
individual peer reviewers are representing their own expertise
and views, not those of their employer.
TERA requested that each peer reviewer identify potential
conflicts of interest related to the review of the hexavalent
chromium inhalation reference concentration. Each reviewer signed
a statement indicating that he or she does not have a conflict of
interest with these chemicals, with the following exceptions
noted below. The following statements in reference to the
hexavalent chromium review were agreed to by the December 1998
panel and were presented at the beginning of the April 16, 1998
meeting. These statements were agreed to by all.
Stuart Baxter -- Dr. Baxter for the University of Cincinnati. He
does not have a specific conflict with this assessment and may
participate fully; however, Dr. Baxter was not able to make the
conference call.
Robert Benson -- Dr. Benson works for the U.S. Environmental
Protection Agency. He does not have a specific conflict with this
assessment and may participate fully.
Matthew Bogdanffy -- Dr. Bogdanffy works for DuPont. DuPont has
conducted limited DNA-protein crosslink studies on chromium,
under contract to ChemRisk, and also produces chromium dioxide
magnetic tapes; however, these activities do not pose a conflict
with the evaluation of the hexavalent chromium RfC. Dr. Bogdanffy
may participate fully in the chromium discussions.
John Christopher - Dr. Christopher is toxicologist with the
California Environmental Protection Agency (Cal EPA). Cal EPA
regulates various aspects of production, use, sale or disposal of
many chemicals, including chromium. However, Dr. Christopher does
not have a specific conflict of interest and may participate
fully in all discussions.
Gary Diamond -- Dr. Diamond works for Syracuse Research
Corporation. Dr. Diamond may participate fully in the chromium
discussions.
Michael Dourson - Dr. Dourson is the Director of TERA. TERA has
performed work for the City of Kearny, New Jersey which was paid
for by Chemical Land Holdings, one of the chromium sponsors, on
dermal issues related to exposure to chromium. This work does not
create a conflict with the inhalation RfC for hexavalent chromium
and therefore, Dr. Dourson may participate fully in the chromium
discussions.
Linda Erdreich -- Dr. Erdreich works for Bailey Research. She has
no conflicts and may participate fully.
Marvin Friedman - Dr. Friedman formerly worked for CYTEC
Industries. Dr. Friedman may participate fully in the chromium
discussions; however, he was not able to make the conference
call.
Michael Gargas -- Dr. Gargas works for ChemRisk. Dr. Gargas has
worked extensively on chromium and for the chromium RfC sponsors.
In December 1996 Dr. Gargas was approved to participate in the
discussion of the chromium assessment, but not be polled for a
recommendation. Dr. Gargas cannot make this conference call.
Andrew Renwick -- Dr. Renwick is on the faculty of the University
of Southampton. Dr. Renwick does not have a conflict with the
chromium assessment. Dr. Renwick may participate fully in the
discussions. Dr. Renwick is not able to make the conference call.
Kenneth Poirier -- Dr. Poirier works for The Procter and Gamble
Company. He has no conflicts and may participate fully.
© 2003 Toxicology Excellence for Risk Assessment
2300 Montana Avenue, Suite 409,
Cincinnati OH 45211
Phone: 513-542-7475
Fax: 513-542-7487
Email: TERA@TERA.org