"ikA.Lfi*'
Boston University Medical Center
Boston University Graduate School
30 East Concord Street
Boston, Massachusetts 02118
Division of Medical and Dental Sciences
April 18, 1979
Honorable Stephen J. Gage
Assistant Administrator for Research and. Development (KD 672)
U.S. Environmental Protection Agency
Washington, D.C.' 2 04 60
Honorable David G, Hawkins
Assistant Administrator for Air and Waste Management (AW 443)
U.S. Environmental Protection Agency
Washington, D.C. 20460
Mr. Todd M. Joseph, Esq,
Office of General Counsel (A 13 3)
U.S. Environmental Protection Agency
Washington, D.C. 20460
Gentlemen:
I am pleased -to transmit to you the report of the Science
Advisory Board's Subcommittee on Arsenic as a Possible Hazardous
Air Pollutant. This report has been prepared by the Subcommittee -
to detail its deliberations and analyses following the two
review sessions of scientific documents on arsenic prepared by
EPA on May 22-23, 1978 and January 10, 1979.
Dr. Cantlon, Chairman of the Science Advisory Board, has
authorized the direct release of the Subcommittee's report so
that various groups within the EPA may use the scientific
information contained therein for purposes of preparing new or
additional documents on arsenic as a possible hazardous air
pollutant. Dr. Cantlon has requested, however, that the report
and the Subcommittee's experiences be discussed at the upcoming
meeting of the Executive Committee, probably the morning of
May 10, 1979. 1 am prepared to be present at that meeting, ana
would look forward to meeting with you concurrently or subsequently
if you wish.
Ruth R. Levine
Sincerely yours
Chairman, Graduate Division of
Medicine and Dentistry
University Professor
Chairman, Subcommittee on Arsenic
as Possible Hazardous Air
Pollutant
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U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
EXECUTIVE COMMITTEE
A Report Of
THE SUBCOMMITTEE ON ARSENIC AS A POSSIBLE HAZARDOUS AIR POLLUTANT
Dr. Ruth R. Levine, Chairman
Boston University
Boston, Massachusetts
Dr. Ursula M. Cowgill
University of Pittsburgh
Pittsburgh, Pennsylvania
Dr. Samuel S. Epstein
University of Illinois
Chicago, Illinois
Dr. Alan H. Gittelsohn
Johns Hopkins University
Baltimore, Maryland
Dr. Thomas J- Haley
National Center for Toxieological Research
Jefferson, Arkansas
Dr. Eva K. Killam
University of California
Davis, California
Dr. Harold M. Peck
Merck, Sharp, and Dohme
West Point, Pennsylvania
Dr. Karl B. Schnelle, Jr.
Vanderbilt University
Nashville, Tennessee
Ms. Anne M. Wolven
Atlanta, Georgia
Dr. Joel L. Fisher, Staff Officer
Science Advisory Board
U.S. Environmental Protection Agency
Washington, D. C.
April 18, 1979
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EPA, Notice
Thi s report was written by a Subcommittee of the Executive
Conur.ittee of the Science Advisory Board of the U.S.
Environmental Protection Agency. The Science Advisory Boarc
is a statutory advisory body to the Administrator and provides
independent scientific advice. This report has not been
reviewed by the Environmental Protection Agency and,
therefore, cannot be construed to represent official Agency
policy. Mention of any trade names, products, or commercial
items does not constitute an endorsement.
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Table of Contents
Introduction
Discussion of Conclusion One..
Discussion of Conclusion Two.
Subcommittee Conclusions and
RsconuRfindfiitiions
Discussion of Various Issues about the
Role of Arsenic as a Possible Hazardous
Air Pollutant.
A. Issue 1
B. Issue 2
C. Issue 3
D. Issue 4
£. Issue 5
F. Issue 6
G. Issue 7
H. Issue 8
I. Issue 9
Appendices
Appendix A:
Appendix B:
• *•» + »»»«•*•••••»*••««•«
Membership of Subcommittee
Subcommittee Statement,
(Corrected) June 12, 1978
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I. INTRODUCTION
The Clean Air Act Amendments of 197 7 require that the
Administrator of EPA determine whether several chemical
substances and radioactive materials are sufficiently
dangerous, at the concentrations at which they are currently
found in ambient air, to warrant special regulation.
Specifically named chemical substances were (elemental)
arsenic and (elemental) cadmium, coke oven emissions, and
polycyclic organic matter (POM). Implicit in the naming of
arsenic and cadmium are the inorganic compounds of each. The
organic compounds of arsenic may also be of concern.
To determine whether these previously named substances
need' regulation, various EPA program offices, mainly the Office
of Research and Development (ORD) and the Office of Air
Quality planning and Standards (OAQPS), were to supervise the '
preparation of several documents to assess the effects of a
given substance on human health, the exposure potential of
various airborne levels of the substance by selected
population groups at risk, and the risk of cancer production
from exposure. Hie program offices requested that the Science
Advisory Board review the scientific merits of -the documents
prior to Agency development of appropriate regulatory or
nonregulatory policies and strategies with respect to airborne
levels of the substance.
The Science Advisory Board's approach to the review of
these air pollutant documents has been to form subconunittees
of specialists to review the materials and present their
findings in discussions with the documents' authors at public
meetings. These subcommittees are asked to consider the
information presented and determine whether the analyses of
such information make a cogent, scientifically-based set of
arguments upon which a defensible regulatory or nonregulatory
policy may be based.
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This report deals with arsenic. Ttie Science Advisory
Board Subcommittee on Arsenic as a Possible Hazardous Air
pollutant (hereafter referred to as the Subcommittee) was
established under the Chairmanship of Dr. Ruth R. Levine of
the School of Medicine of Boston University. The membership
of the Subcommittee is Appendix A.
Two sets of arsenic documents are discussed herein. The
first set, prepared in spring 1978 and reviewed by the
Subcommittee in public session on May 22-23, 1978, is referred
to as the original draft set. The second set of documents,
prepared in autumn 1978 and reviewed by the Subcommittee on
January 10, 1979, is referred to as the revised draft set.
Each set of documents has three parts: a 'health effects
document, an exposure document, and a cancer risk assessment
document (referred to as either "CAG document" or "cancer risk
document") .
When the original draft set of documents was reviewed,
the Subcommittee suggested many revisions to make the
documents more scientifically useful for supporting various
EPA regulatory options. Because of the considerable interest
in those recommended revisions, the Subcommittee issued a
public statement of its findings -and recommendations,
corrected on June 12, 1978. The corrected public statement is
Appendix B,
With the exception of the exposure document, the
Subcommittee is no more satisfied with the revised set of
documents that with the original set. The exposure document
incorporated most of the Subcommittee's recommendations to
provide an updated picture of population exposure to airborne
arsenic from various arsenic sources.
A section on mutagenesis was the major revision in the
health assessment document. The majority Of the
Subcommittee's recommendations were not incorporated into the
revised health effects document.
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The cancer risk document, although completely revised in
content and analysis, incorporated very few of the
Subcommittee's suggestions. Because of problems in
statistical methodology, the Subcommittee considered this
document to be less useful to the Agency (EPA) than the
original draft version.
The Subcommittee found the revisions to be either
insufficient in scope and detail or of limited usefulness to
EPA decision makers. As a result, the set of documents failed
to address and clarify specific, still unresolved issues. EPA
decision makers tend to rely most heavily on the health
effects document; thus, most of the Subcommittee's discussions
dealt with that document. Probably the most serious problems
the Subcommittee had with the health effects document, both
the original and revised versions, were the way in which the
literature cited on arsenic was evaluated, the omission of
critical references without explanation, and the use of
secondary sources for critical data. All of these resulted in
a document which appears to obfuscate a very difficult and
controversial literature. Subcommittee Members found the
material poorly organized and found that there would be
difficulty in following the logic, argumentation, and
inferences about the meaning of the health effects data on
arsenic in humans. Furthermore, the scientific revisions were
inadequate in scope and detail. Specific inadequacies are
discussed under various issues of concern to the Subcommittee.
At the January 10, 1979 meeting, the Subcommittee
received a completely revised section of Chapter 3 of the
health effects document dealing with experimental
carcinogenesis. This additional material could only be
discussed in a cursory manner at the meeting. Substantive
review would require additional Subcommittee time once the
Members returned to their home institutions. The Subcommittee
noted, however, that this additional material exceeded in
scope, detail, and length the total of all prior revisions of
the health effects document received and reviewed by the
Subcommittee. This only reinforced the view that previous
revisions were inadequate.
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The Subcommittee was charged to base its findings and
conclusions primarily on the information presented, even
though individual Members might be knowledgeable about data or
analyses not cited in the documents. As a Member noted, one
had to trust that the document's authors chose the relevant
data, analyzed those data properly, and, drew reasoned and
scientifically supportable inferences and conclusions from
those data.
During the evaluation of the arsenic documents, the
Subcommittee was continually reminded of the difficult and
controversial nature of the literature on the environmental
problems of airborne arsenic. EPA decision makers need
documents that have clarity, focus, and a sense of direction.
With the information on arsenic as presented in the two sets
of documents, the reviewer is confronted with ambivalence,
uncertainty, and possibly even confusion. Hie Subcommittee
felt that its own conclusions must accurately reflect the
current situation. it, therefore, framed two conclusions
which are discussed in the next two sections. These
discussions provide some of the Subcommittee's reasoning and
analyses.
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II. DISCUSSION OF CONCLUSION ONE
Conclusion One, as read into the Record on January 10,
1979, follows:
"All the available data lead to a consensus that
there is a real association between exposure to arsenic
and the development of cancer, both lung and skin
cancer."
The conclusion is based on the data available in the
open literature and is not necessarily one that the
Subcommittee could draw from the selected literature cited in
the health effects document. First, it is essential to
establish the relationship between exposure to arsenic and
cancer production under some set of conditions, e.g.,
occupational exposures, before one can consider whether
environmental exposure to arsenic is a potential health
hazard.
The Subcommittee has no doubt -that -exposure to arsenic,
specifically inorganic arsenic compounds (both trivalent and
pentavalent arsenic), raises the risk of lung and skin cancer.
There may also be increased risks for liver cancer and some
lymphatic cancers, (See the Federal Register, Volume 43,
May 5, 1978, Part IV, p. 19584.) Tfre uncertainties may be the
levels of exposure, durations of exposure at various levels,
dose-time response relationships, and mechanisms of
carcinogenesis. The scientific literature provides an
overwhelming collection of evidence that overall the
association is real despite any specific deficiencies and
limitations cited for individual studies.
The Subcommittee believes that it is important to
address some other issues which have been mentioned as
possibly casting doubt on the arsenic-cancer association.
A. The Subcommittee wants to resolve some of the
problems that have resulted from responses within the
scientific community to the perceived ambivalence of the
expert committee of the International Agency for fie search
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on Cancer (IARC) in its 1972 monograph on carcinogenic risk to
humans from arsenic (International Agency for Research on
Cancer. IARC Monographs on the Evaluation of the Carcinogenic
Risk of Chem1cals to Man. Volume 2. "Some Inorganic and
Organometallic Compounds." Lyon; WHO, IARC, 1973). The I ARC
expert group evaluated studies up to 1972 on the possible
carcinogenicity of arsenic in animals and the existing
epidemiological data on human exposures to arsenic. Uiat
group expressed uncertainty as to whether the animal bioassay
data support arsenic to be a carcinogen. The IARC expert
group generally questioned cited studies, which showed a
possible carcinogenic potential for arsenic, on the basis of
inadequacies in experimental design (problems in the control
groups of animals, numbers of animals used, dosing pattern),
the small number of neoplasms detected, the very small overall
sample sizes, or ambiguities in the descriptions and
interpretations given by the original investigators.
Nevertheless, the IARC accepted a carcinogenic role for
arsenic:
"The available studies point consistently to a
"causal relationship between skin cancer and heavy
exposure to arsenic in drugs, in drinking water with a
high arsenic content, or in the occupational
environment."
The IARC group expressed -less certainty with respect to lung
cancer and thought that some observations of cancer of the
liver were possibly "coincidental."
Clearly more studies and data were needed. In the six
years since the IARC report, a large number of studies have
been or are being completed,. Based on the weight and
direction of the results of these studies, there has been a
change in the situation since 1973 with respect to the
epidemiology of lung and skin cancer associated with human
exposure to arsenic. This has been recognized by the
Occupational Safety and Health Administration (OSHA) in
rulemaking to reduce allowable airborne arsenic levels in the
workplace. OSHA's rulemaking is based on an accepted
association between exposure to inorganic arsenic and
increased cancer risk. The reader is referred to the
following major references for appropriate information and
citations of work;
Carnow, B. w. (ed,)r "Health Effects of
Occupational Lead and -Arsenic Exposure." U.S.
Department of Health, Education and Welfare.
Washington, D. C., NIOSH Publication Number 7 6-134
(1976) .
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Fowler, B, A. (ed.), "International Conference on
Environmental Arsenic: An Overview," Environmental
Health Perspectives, volume 19. U.S. Department of
Health, Education and Welfare. Publication (NIH) 77-218
{1977).
Federal Register, Volume 43, May 5, 1978, p. 19584.
(This is the final rulemaking of the Occupational Safety
and Health Administration on inorganic arsenic in the
workplace.)
Of the preceding three references, only the first two
are cited in the revised health effects document. The
proposed, rather than the final, rulemaking of OSHA is cited
in the revised health effects document despite the
availability of the final rulemaking two weeks before the
original draft version was reviewed by the Subcommittee on May
22-23, 1978. The analyses presented in the final OSHA
rulemaking were far more definitive than those in the proposed
rulemaking and clarified important issues that should have
been included in the revised health effects documents prepared
by EPA.
B. The Subcommittee feels that regardless of the
mechanism of cancer induction,' i.e., whether arsenic is a
primary carcinogen, a precursor, a promotor, or a
cocarcinogen, the statistical validity of the association
between human exposure and cancer production is real.
For risk assessment, the mechanism of cancer induction
is immaterial since statistical association, specifically
correlation as opposed to regression, does not prove cause and
effect. Correlation demonstrates only relationship. The
statistical weight of available studies, even those studies
with marginal statistical results, lends overall validity to
the association. The IARC did acknowledge cause and effect
relationships between arsenic and skin cancer. (Very simply,
the presence of arsenic elevates the risk of cancer
induction.)
C. The Subcommittee believes that, although EPA does
not regulate workplace -exposure to arsenic but only potential
ambient or environmental exposures, EPA cannot ignore the
occupational literature as a guide to assessment of
environmental hazard. Workplace exposure and worker health
records, in many instances, provide the best data from which
to develop dose-response curves for nonoccupational exposures.
Especially important, as cited in reason #1 of the
Subcommittee's supporting analyses of Conclusion One, is the
OSHA record on regulating arsenic in the workplace. In
general, the Subcommittee believes that consideration of the
occupational literature is good scientific practice.
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D. The Subcommittee believes that, although many
arsenic compounds have been claimed to exhibit antitumorigenie
or "carcinostatic" properties, this is not sufficient reason
to declare arsenic compounds noncarcinogenic. The
Subcommittee notes that some of the most potent anticancer
drugs and medical techniques are themselves carcinogenic under
different circumstances.
Several investigators have remarked about the
carcinostatic properties of' certain arsenic compounds and have
decried the abandonment of arsenical medicines in the United
States. The Subcommittee noted that most arsenical medicines
are organics. "Fowler's solution" is an exception, since it
is an inorganic arsenical medicine? the relationship between
its use and the induction of skin cancer in patients is
established. The issue of organic arsenicals as cancer causing
agents is not completely resolved at this time. The OSHA
rulemaking deals only with inorganic arsenic and exempts
organo-arsenicals~ (Organo-arsenicals are covered by other
legislation, notably, the Federal Insecticide, Fungicide, and
Rodenticide Act when the organo-arsenical is a pesticide
product.) However, the Subcommittee does not believe that a
~substance with antitumorigenic effects is a priori
noncarcinogenic.
E. The Subcommittee believes that the apparent lack of
a suitable animal model for experimentally induced
carcinogenicity does not reduce the validity of the
association between arsenic exposure in humans and cancer
production. In fact, the Subcommittee believes that this
issue may no longer be a problem if one reviews the data from
neoplasm studies in nonrodent species.
The Subcommittee is aware of the "lack" of suitable
animal species for experimental induction of cancer with
arsenic exposure. Most of.the bioassay studies have been with
rodents and the results have been equivocal. The Subcommittee
believes that for reasons as yet unclear, rodents nay not be
appropriate experimental models for arsenic studies. It is to
be noted (and appropriately cited in the revised health
effects document) that the fate of arsenic in rats is unlike
that in other mammals. Furthermore, Kraybill was cited in the
OSHA final rulemaking to the effect that the right modes of
dosing (inhalation) were not used. The citations of Halver's
work by Kraybill (noted in the revised health effects
document) in which liver hepatomas were found in trout exposed
to carbarsone, an arsenic compound, were noted by the
Subcommittee. Mawdsley-Thomas (Mawdsley-Thomas, L.E.
"Neoplasia in Fish: A Review." in: T. Cheng, ed., Topics in
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Comparative Pathobiologv, Volume 1. Academic Press, New York,
1971) has reviewed the literature on neoplasms in fishes. His
review strongly indicates the validity of using fishes as
cancer bioassay test species in pollution-related situations.
The current evidence from epidemiological studies
strongly suggests carcinogenicity in man from arsenic
exposures. Lack of an experimental non-human animal model to
show cancer production does not deny the relevance of human
cancer risk inherent in the epidemiological data. The
Subcommittee noted during its January 10, 1979 meeting that
the drug thalidomide was removed from the marketplace as a
human teratogen long before an appropriate animal model for
the teratogenic endpoint was determined or study completed.
Ill, DISCUSSION OF CONCLUSION TWO
Conclusion Two, as read into the Record on January 10,
197 9, follows:
"The data reviewed, and the manner in which these
data are analyzed do not permit making a valid or
definitive judgment at this time about the role of
arsenic as a possible (nonoccupationally) hazardous (or
nonhazardous) air pollutant."
The Subcommittee attempted to phrase Conclusion Two in
an exact and unambiguous manner, but Conclusion Two has proven
to be especially troublesome nonetheless. The Subcommittee
developed the statement on the basis of the documents
reviewed. The Subcommittee did not believe that it was
impossible, in general, to make a judgment about arsenic; only
that the documents prepared by EPA were by themselves
inadequate to permit such a judgment. The Subcommittee felt
that if its first recommendations had been incorporated into
the revised draft documents to the maximum extent possible
and, where not possible, an explicit explanation given as to
why not, a definitive judgment on the role of arsenic as a
hazardous or nonhazardous ambient air pollutant could have
been made.
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The Subcommittee did not intend to avoid making a
decision, avoid its advisory responsibilities, or become a
hindrance to Agency decision makers. As scientists asked to
review data to substantiate conclusions concerning arsenic as
a possible hazardous air pollutant, the Subcommittee could
only base a decision on what was presented by EPA for its
deliberations.
Agency officials were particularly concerned with
Conclusion Two. First, Agency officials requested at the
January 10, 1979 meeting that the conclusion be reread (four
times) into the record to assure that the statement had been
accurately heard by questioners and correctly recorded by the
meeting reporter. - Second, the Staff Officer of the
Subcommittee received nearly fifty telephone calls on January 1
1979, within the first .two hours of the working day, for
an exact reading of the conclusion and a constant stream of
requests thereafter, from both within and outside the Agency,
for an exact reading. The Subcommittee was asked by Agency
officials several times at the meeting if the Subcommittee
understood the political .ramifications of its conclusion. The
Subcommittee carefully responded that they made no political
interpretations of the conclusions, and any political
interpretations were not a consideration in their
deliberations-.
IV, SUBCOMMITTEE CONCLUSIONS AND RECOMMENDATIONS
The Subcommittee has every reason to believe that most
of the suggestions and recommendations made for revision of
the various documents are still valid and can be accommodated.
The Subcommittee also believes that, without reconsideration
of its suggestions and recommendations in further revision of
the arsenic documents, the EPA decision makers charged with
deciding whether or not to- regulate arsenic will not have an
adequate scientific basis for their decision.
Specific recommendations, as given at the January 10,
1979 meeting, follow:
(a) Collect and analyse all existing data pertinent to
the evaluation of the health effects of arsenic on
nonoccupationally exposed individuals.
(b) Collect new data on concentrations of airborne
arsenic in the vicinity of point sources and collect estimates
of absorption of airborne arsenic by exposed individuals.
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(c) Require that a statistician sit on every working
group in which data collection/analysis will occur to avoid
some of the statistical problems that have arisen in the
various existing documents.
(d) Reassess the role of arsenic as a possible hazardous
air pollutant on the basis of newly collected and analyzed
(reanalyzed) data, this reassessment to be made as
expeditiously as possible.
V. DISCUSSION OF VARIOUS ISSUES ABOUT THE ROLE OF ARSENIC AS
A POSSIBLE HAZARDOUS AIR POLLUTANT
The Subcommittee wants to be of maximum help to the
Agency but is not charged with preparation of the documents
needed to assess the role of arsenic as a hazardous air
pollutant. Nevertheless, the Subcommittee feels that, since
some important issues were not addressed in the documents
(original or revised), others were not adequately addressed,
and still others were incorrectly approached, EPA program
officials would find it beneficial to have as detailed a
picture of the Subcommittee's concern as it is possible to
provide.
The highest priority issues are the use of ambient
monitoring data, the assessment of risk for noncarcinogenic
endpoints (especially neuropathology and teratology), dose-
response analyses on teratology, and the use of incorrect
statistical procedures with misinterpretation of the results.
The various issues and a discussion of each follow:
A. ISSUE 1
To what extent are ambient monitoring data incorporated
into the exposure analysis?
Most of the exposure analysis involved modeling. A
particular model, CSTER (not an acronym but a computer code
name), was used. This model assumes a geographical grid, and,
within each grid space, a completely mixed atnosphere.
Superimposed on the grid is a Gaussian diffusional input from
and output to adjacent grid spaces. This models scales, for a
particular emission characteristic, the atmospheric
concentrations of arsenic in each grid space. When population
distributions are superimposed upon the grid, human exposure
can be estimated. A ratio of an actual emission strength to
the assumed model source strength then scales the actual
exposure.
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While the modeling is not subject to criticism per se,
the Subcommittee questioned the extent to which actual
monitoring data were used in scaling or checking the model
results. There seemed to be indications that monitoring data
were available but not used. Most of the apparently unused
data were attributable to industrial sources. The
Subcommittee understands that Agency scientists may be
somewhat hesitant to use monitoring data that are supplied by
an industrial source that is subject to regulation based on
analyses of its data submissions. Nevertheless, there should
have been more positive approaches to such data. Modeling,
while intellectually stimulating and often rewarding, loses
reality when only hypothetically scaled ambient predictions
are made and when no concordance is examined between scaled
predictions and actual data, regardless of source {e.g.,
Region X, EPA, monitoring and enforcement data and other data
available for the Tacoma, Washington area).
B. ISSUE 2
The use of statistics within all of the reports presents
serious problems'to Agency decision makers because of
incorrect or inadequate procedures. Document credibility
often hinges on how statistics are used. Hie documents in
hand are examples of poor statistical practice.
The first statistical problem, found in the health
effects document, is the presentation of data on airborne
arsenic versus urinary arsenic in exposed individuals. Since
the data are designed to show that exposures to airborne
arsenic are reflected in particular urinary levels, airborne
arsenic should be the independent variable in the regression,
and urinary arsenic becomes the dependent variable. This is
not how the document presents these data. The original
literature on the airborne/urinary arsenic cited in the_ health
effects document, exposure documents, and"other sources, have
the reverse. in the health effects document, measured values
of urinary arsenic are plotted as independent variables
against airborne levels of arsenic as dependent variables.
The Subcommittee questions whether human excretion of arsenic
is a major source of airborne pollution.
Once the presentation of the air/urine arsenic
regressions was given, the analyses proceeded along incorrect
lines. Use of the regression, as presented, to calculate what
the level of airborne arsenic must be to achieve an exposure
associated with a given urinary level requires some special
statistical procedures called "inverse prediction." Inverse
prediction requires that special confidence levels be assigned
rather than standard error estimates when the regression is
reversed. These estimates of special confidence levels
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associated with a predicted value of an independent variable
calculated from a measured value of a dependent variable, are
often larger numerically than the standard errors associated
with the original data from which the regression was created.
A second problem was a tendency in the original draft
version of the health effects document to preselect data
points for regression analysis and reject others as "outliers"
because they did not look "attractive." In the original
draft, the outliers were not outliers. Statistical
significance of the original regressions depended on these
data points being part of the set. When the recalculation of
regression was performed without these points, the results
were statistically nonsignificant. This -point is raised
because the particular practice is common within EPA and
applies to other documents reviewed by some Subcommittee
Members for Science Advisory Board groups. Such statistical
procedures must be carefully justified each tine they are
used. They cannot be used routinely, or many of the analyses
presented in pollutant criteria documents may be judged
misleading or even invalid.
A third problem, this time in the CAG document, is in
combining three studies which do not have comparable data
because of differences in experimental design and parameter
meaning, and in estimating a new parameter from these studies
as a basis for risk assessment of lifetime exposure to
arsenic. This becomes questionable when one of the component
studies has a regression and correlation with a zero
correlation coefficient (no statistical significance). The
slope of the regression line which is nonsignificant was used
as one of the numbers to calculate a geometric mean of all the
component studies as the basis risk parameter. In any
geometric mean where one term is zero, the n-th root of zero
is zero, not some positive number. This was discussed at
considerable length. A particular investigator's data were
force fit to a regression line that passed through the origin.
The variances associated with the data points relative to that
line increased, and a zero correlation coefficient resulted
from the force fit. If that is the case, then the force fit
is itself not statistically significant. The Subcommittee
believes it would have been better to treat each study
separately, make all -risk calculations required for each
study, and compare the final results for concordance or
nonconcordance. When nonconcordance was found, the authors
should have explained "the differences.
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On February 9, 1979, the Chairperson of the Subcommittee
met with EPA directors of the Cancer Assessment Group (Drs.
Albert and Anderson), At that meeting, the GAG directors
explained that the no threshold risk extrapolation policy for
cancer risk assessment presumes that the origin is a valid
datum without error or bias. Thus, if only one dose/effect
datum were available, a force fit line through the origin
could be drawn -and used by CAG for its analyses. This was
stated as EPA policy. The Subcommittee does not wish to enter
into the debate on Agency policy. What is at issue is how
statistics are misused in the step after the force fit line is
constructed. If the force fit line does not give a nonzero
statistically significant slope-or if statistical properties
of the slope cannot be calculated because of an inadequate
number of degrees of freedom (i.e., insufficient number of
data points), then that study should not be combined with
others having valid statistics to produce an invalid combined
assessment. The force fit study should be treated separately
and, as previously suggested, the results of all risk
assessments should be examined for concordance or
nonconcordance.
A fourth problem, also in the CAG document, is the
practice of merging data points, taking means of several
points, and taking means of means. This practice reduces the
number of degrees of freedom in resultant correlations.
Although individual points may appear very close, when the
number of degrees of freedom are reduced, the result may again
be a nonsignificant or misleading regression. Subcommittee
Members noted that often the data points which were combined,
although numerically close, fit a geometric scale of exposures
and thus provided a picture of several orders of magnitude in
values of arsenic concentration. A geometric scale of doses
and/or exposure is accepted practice in roost toxicological
protocols for risk assessment and dose-response relationship
analyses. The procedure of merging data points is more
prevalent at very low dose levels where scatter and
variability in the data are greatest. .But the procedures,
rather than increasing reliability, lose vital information.
Biological variabililty at low dose levels is expected and
should not be masked by the procedures of data analysis.
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C. ISSUE 3
Are there endpoints and adverse effects other than
cancer for which risk assessments associated with arsenic
exposure have to be considered?
The Subcommittee' s answer is an emphatic yes. Risk
assessment, even if only qualitative, for endpoints other than
cancer is necessary to provide a balanced health risk
assessment for regulatory purposes.
This is an important issue that arose at both
Subcommittee meetings. At the May 22, 1979 meeting, the
document authors were asked if they had reviewed data on
arsenic effects on the central nervous system. The answer was
"No, because data were unavailable." However, two relevant
references were, indeed, cited in the original draft version
of the health effects document and were also in the revised
draft of health effect document. Yet neither reference was
discussed in any detail or included in the discussion of risk
assessment. Examinations of the references, with a view
toward dose—response analyses of the data, were not provided
in the health effects document; so the question of possible
risk assessment could not be addressed and evaluated either
qualitatively or quantitatively. Moreover, the Subcommittee
Members are aware of additional data on the effects of arsenic
on cardiovascular, renal, and central nervous system
functions. A study including some of the most recently
summarized data on neuropathology was sponsored by EPA
("Epidemiology Studies —Selected Non-Carcinogenic Effects of
Industrial Exposure to Inorganic Arsenic." EPA report number
560/6-77-018, October 1977, Final Report, Office of Toxic
Substances, U.S.E.P.A., Washington, D. C. 20460).
The Subcommittee feels it is also important to address
the differential effects in the young vetsus the adult. For
this reason, considerable analysis of the Chilean data on the
children exposed to arsenic through drinking water is needed,
not just citation and summarization of the results, as in the
arsenic documents.
The issue of the paucity of analysis of the
noncarcinogenic adverse health effects data with a view toward
risk assessment was raised at the January 10, 1979; the
Subcommittee was asked to provide the references for any data
for endpoints or disease states other than cancer with respect
to arsenic exposure. Because the need for risk assessment for
noncarcinogenic endpoints is vital to EPA decision makers, the
Subcommittee includes, herein, some useful references. The
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Subcommittee expects, however, that citation of these
references will be accompanied by analyses and critical
evaluations for risk assessments. The Subcommittee, in fact
had provided references for the revised health effects
document only to find them cited in the bibliography but not
in the text. In fact, the Subcommittee noted that 107
references listed in the bibliography of the revised health
effects document were not cited in the text.
References:
Petren, K. "Etudes cliniques sur I'etiologie et les
symptomes de 1'empoissonement arsenical du a
1'habitation ou des objets de I'emploie domesticme."
Acta. Med. Scand. 58: 217-230 (1923).
Chuttani, P.N.,' Chaula, L.S., and T.S. Sharma.
"Arsenical neuropathy." Neurology 17: 269-274 (1974).
Jenkins, R.B. "Inorganic arsenic and the nervous
system." Brain 89: 479-498 (1966).
Lequesne, P.M. and J.G. McLeod, "peripheral neuropathy
following a single exposure to arsenic." J» Neurol.
Sci. 32: 437-451 (1977).
Prank, G. "Neurologische und psychiatrische
folgesymptone bei akuter arsen-wassers toff
vergiftunis." J. Neurol. 213: 59-70 (1976).
Freeman, J.W.. and J.R. Couch. "Prolonged encephalopathy
with arsenic poisoning." Neurology 28: 853-855 (1978).
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D. ISSUE 4
Are there dose-response characteristics for arsenic as
a teratogen?
Teratogenicity of inorganic arsenic compounds was
discussed briefly at the January 10, 1979 meeting. The
Subcommittee believes that significant data exist to show that
inorganic arsenic is a teratogen. Teratogenicity has been
demonstrated in mammalian species (mice, golden hamsters,
rats) and bird species (chickens, mallards). Transplacental
movement has been demonstrated in rodents and humans~ The
revised health effects document deals with teratogenicity
through citations of the relevent work of Ferm, Hood and
Bishop, and Petrokova and Puzanova. However, the revised
health effects document does not present these discussions in
terms of dose-response pharmacological and toxicological
principles. The National Academy of Sciences document on
arsenic (National Academy of Sciences- Arsenic. Washington,
D.C. 1977), from which the citations appear to be taken, also
did not present such analyses, although it cited some of the
relevant numerical data.. The Subcommittee suggests that
Perm's data and Hood and Bishop's data may lend themselves to
such an analysis and that a dose-response relationship should
be attempted.
E. ISSUE 5
Are the low levels of arsenic which appear to be present
in all individuals .important when assessing the role of
arsenic as an environmental hazard?
Although data on the environmental distribution of
arsenic are discussed at some length in the various draft sets
of documents, the issue of low levels of arsenic found in all
human tissues is not addressed in either the health effects
document or the exposure document. If individuals universally
have low body burdens of arsenic and if these body burdens are
not measurement artifacts, the correct lower limit of arsenic
concentrations in dose/risk extrapolations is not necessarily
zero, but some finite, measurable, residual value. Body
burdens of arsenic below the lower limit of this residual level
do not have the same biological significance as the residual
levels because the latter act as "backgrounds."
There is a fifty year history of scientific interest in
the body burdens of arsenic associated with "normal" or
"unexposed" individuals. The literature begins with Billeter
and Marfutt (1923), in Switzerland, and their analysis on a
"fresh weight basis" of spleen and thyroid with lower limits
of 0.03 - 0.06 ppm. Other data are those of Van Itallie
(1932), in Holland, with comparable lower limits on nails.
Wore recent data, all on a "fresh weight basis," are those of
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Katsura (1957), Gerin and de Zor2i (1961), Boylen and Hardy
(1967), Damsgaard et al (1973), and Mathies (1974), who
provide lower limits of 0.001 ppm for heart, spleen, and
brain; 0.006 ppm for liver, kidney, pancreas, blood, intestine
(wall), and stomach (wall); and 0.15 ppm for bone. Reeves
(1976) made an attempt to summarize some of these data but
emphasized hair, and nails (tissues not indicative of current
exposure but of past exposure) and urine and blood. Underwood
(1977) cited data of Smith (1967), possibly because only Smith
reported his analyses on a "dry weight basis," independent of
the size and weight of the tissue. Moisture - con4ent causes
changes in tissue size and weight, and, when 'the moisture is
blood, tissue levels may also reflect the arsenic content of
blood. Smith suggests lower levels of 0.04 - 0.09 ppm (mg/kg)
for body tissues .
Perusal of the literature shows that there is great
variability in the data. This is to be expected because
exposure levels -are unknown and extremely variable. Another
problem is the analytical methods for quantifying arsenic at
trace levels in tissues. Analytical methods for trace
quantities of arsenic have low reproducibility, as little as
+ 30% at the 1 ppm level, depending on the matrices of the
sample. This was acknowledged in the original draft of the
health effects document but omitted in the revised draft.
There seems to be little reason, therefore, to calculate and
report mean values, median values, or other statistical
parameters for these data. The range of values appears most
descriptive with a note as to the great variability.
A corollary issue of trace body burdens is the question
of whether they are of biological significance or
coincidental; is arsenic necessary or just tolerated at some
background level? Schwarz (1977) was concerned that trace
body burdens of arsenic might imply biological necessity. The
Subcommittee does not express a view on this conjecture but
notes that biological significance is not restricted to
metabolic necessity. Biological significance, however, may
involve beneficial, but not essential, effects. Because trace
levels of arsenic exist in all individuals, any health
assessment document should note this and the fact that there
is some question as to whether these levels have biological
significance either in terms of essentiality of the element or
beneficial, but nonessential, effects.
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References;
Billeter, 0. and E. Marfutt. "De la teneur normal en
arsenic dans le corps humain." Helv, Chim. Acta.
6:780-784 (1923).
Boylen, G.W. and H.L. Hardy. "Distribution of arsenic
in non-exposed persons (hair, liver, urine)." Amer.
Ind. Byg. Assoc. J. 28:148-150 (1967).
Darasgaard, E., K. Heydorn, N.H. Larsen, and B. Nielsen.
"Simultaneous determination of arsenic, manganese and
selenium in human serum by neutron activation analysis,"
Riso Report 271, Boskilde; Danish Atomic Energy
Commission (1973) 35 pp.
Gerin, C. and C. de Zorzi. "The arsenic content in the
organs of the human body." Zacchia 36 (Vol 24, Ser 2):
1-19 (1961) .
Katsura, R. "Mecicological studies on arsenic poisoning.
Report l: Arsenic contents of the visceral organs,
bone, and hair of normal human individuals." Shikoku
Acta. Med. (Shikoku Igaku Zasshi) 11:439-444 (1957)
(m Japanese).
Mathies, J.C. "x-ray spectrographic microanalysis of
human urine for arsenic." Applied Spectroscopy
28: 165-170 (1974).
Reeves, A. see B.W. Carnow (1976), p.240 (previously
referenced).
Schwarz, .K. "Essentiality versus toxicity-of metals."
Clinical Chemistry and Chemical Toxicology of
Metals. S. Brown (ed.) Elsevier, Hollana (1977).
Smith, H. "The distribution of antimony, arsenic, copper
and zinc in human tissue." Forensic Sci. Soc. J,
7: 97-102 (1967).
Underwood, E.J. Trace Elements in Human and Animal
Nutrition. 4 th Ed 'it ion" Academic Press, New York,
pp. 424-429 (1977).
Van Itallie, L. "Arsenic content of hair." Pharm.
Weekblad. 69: 1134-1145 (1932) (in Dutch).
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F. ISSUE 6
Does arsenic at low levels have any beneficial effects
on cell systems?
Most studies of arsenic metabolism in man have
emphasized the nature of arsenic excretion products as a
function of exposure to specific inorganic arsenic compounds.
Virtually none of the research has eraphasi2ed trying to
establish the form of arsenic within cells. Until the form of
arsenic and the way in which it is bound in human tissues are
ascertained, the questions of carcinogenicity of inorganic
versus organic arsenic and toxicity versus beneficial effects
will be conjectural.
Arsenic appears to have a potentially beneficial role in
a number of animal species. Ironically, it was another part
of EPh which alerted the Subcommittee to the data. In the
Federal Register announcement, "Notice ,o£ Rebuttable
Presumption Against Registration and Continued Registration of
Pesticide Products Containing Inorganic Arsenic," (Volume 4 3,
October 18, 1978, p.48267), EPA acknowledged and cited several
references about possible beneficial effects of arsenic in
mammals:
(a) Muth et al; Amer. J. of Vet. Med. 32:1621
(1971); describes that 1 ppm of sodium arsenate
reduced myopathy of lambs on a selenium deficient diet.
(b) Nielsen et al; Fed. Proceedings. 34-923
(1957); reports on possible arsenic deficiency in rats
on a 30 ppb arsenic level in the diet. The test animals
had low rates of growth, rough hair coats, splenomegaly,
decreased hematocrit, and increased osmotic fragility
of erythrocytes.
{c) Anke et al: Trace Substances in Environmental
Health, Volume-TO; D.D. Hemphill (ed. ) (1976); reports
effects similiar to Nielsen's on possible arsenic
deficiency in the diets of goats and swine.
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In addition, there is a large literature on the
importance of arsenic-selenium interactions in mammalian
systems. Selenium is a cofactor in metabolic systems
utilizing Vitamin E, is toxic in excess, is responsible for
a number of animal diseases and has been implicated in some
human diseases. In the 1930's, Moxon and his coworkers
[Moxon, A.L. "The effect of arsenic on the toxicity of
seleniferous grains" Science 88:81 (1938)? Moxon, A.L. and
K.P. DuBois. "The influence of arsenic and the other elements
on the toxicity of seleniferous grains." J. Nutrition 18:447-
459 (1939)] at the South Dakota Agricultural Station found
that arsenic, added to the drinking water and feed of
livestock, detoxified the selenium from seleniferous grains
and selenium accumulator plants consumed by the livestock.
Recently, Levander and his coworkers [Levander, O.A. and C.A.
Baumann, "Selenium metabolism." Parts V and VI. Toxicol.
Appl. Pharmacol. 9:98-105, 9:106-115 (1966).] at the
Agricultural Research Service in Beltsville, Maryland, have
examined some of the mechanisms of the arsenic-selenium
interaction. They found that selenium detoxification by
arsenic involves secretion of an arsenic-selenium complex into
the bile.
G. ISSUE 7
What effect might possible beneficial effects of arsenic
in human tissues have on the Agency's no threshold cancer risk
extrapolation policy?
EPA has a policy to prescribe how to infer the effects
of low dose exposures of a carcinogen from high dose bioassay
data. This policy uses an assumption that carcinogens have no
thresholds. This is not a question which the Subcommittee was
asked to address, and, consequently, the Subcommitee did not
address .it. At the January 10, 1979 meeting, however, Agency
officials questioned the Subcommitee on this issue,.because
they felt that perhaps the Subcommittee was recommending, in
its Conclusion Two, that EPA abandon that policy. In
addition, some scientists believe that beneficial effects of a
substance, which is carcinogenic at higher exposure levels,
might imply a threshold for the carcinogenicity.
The wording of Conclusion Two indicates only, one, that
the data presented and reviewed in the arsenic documents did
not include the possibilities that low levels of arsenic may
have some beneficial effects in some species? and second, that
the data presented on adverse health effects were insufficient
and inadequately interpreted to permit drawing conclusions
about the environmental levels at which arsenic is hazardous
to humans. At the present time, as Kraybill noted in the OSKA
rulemaking (previously cited), not enough is known about the
mechanisms of carcinogenicity to discuss thresholds for this
endpoint.
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H. ISSUE 8
What is the significance for human carcinogenicity of
equivocal results in animal bioassays of carcinogenicity?
Many of the animal studies of experimentally induced
carcinogenesis produced equivocal results. Equivocal, in the
sense used here, refers to a result which is not sufficiently
statistically significant to displace a null hypothesis but is
sufficiently marginal to be suspicious. In some instances,
statistical procedures exist which allow one to test the
combined effects of several studies with statistically
marginal data to resolve the issue of whether one can ascribe
an equivocal nature to the combined studies, or whether one
can shade the overall evidence toward positive or negative
inferences [c.f., Fisher, R, A. Statistical Methods for
Research Workers. 12th Edition. Oliver and Boyd, Edinburgh
(1954), 356 pp. (see section 21.1)]. Such techniques were
not explored in any of the documents. However, the
Subcommittee received a thoroughly revised section of Chapter
3 of the health effects document, dealing with carcinogenicity
and including a reexamination of all of the animal bioassay
studies. On the weight of the overall evidence, the authors
concluded that the equivocal nature of the animal bioassay
tests should be shaded toward a positive inference of
carcinogenicity rather than a negative inference of
noncarcinogenicity, the important issue is that equivocal
results are not automatically positive or negative. Each case
must be critically examined,* such critical analysis should be
an integral part of the assessment of 'the health effects of
any pollutant.
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I. ISSUE 9
Why have certain documents that have been published by
the EPA and -other Federal agencies and that are extremely
relevant been ignored in the preparation of the criteria
document for arsenic?
As previously indicated (ISSDE 6), the FIFRA document
published in the Federal Register, Vol., 43, October 18, 1978,
p. 4826 7 contained much data and addressed many issues that
would have been entirely appropriate for inclusion in the
Health Effects and CAG documents on arsenic. Also the OSHA
document, Federal Register, Vol, 43, May 5, 1978, p. 19584,
for example, provides analyses of data of such variables as
time to tumor death, age at time of exposure and duration of
exposures; the incorporation of assessments of risks
associated with each of these variables were recommended by
the Subcommittee in the review of the original CAG document
(see Appendix B).
The Subcommittee finds it difficult to understand why the
EPA ignored criteria documents prepared by one of its own
subdivisions or by an agency of both the IRLG and Interagency
Toxic Substances Data Committee with which the EPA is charged
to maintain liaison. Hie Subcommittee concludes that almost
one year could have been saved in the preparation of useful
criteria documents for arsenic and the expenditure of much
effort and funds been avoided, if the information in extant
documents had been utilized.
The Subcommittee wishes to suggest that in preparing
future criteria documents the EPA adhere to its broad
coordination and policy development responsibilities under
various environmental legislative authorities with particular
attention to policies it describes in the Federal Register
announcement of May 26, 1978 concerning the Interagency Toxic
Substances Data Committee.
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VI. APPENDICES
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APPENDIX A
Membership of Subcommittee
Dr. Ruth R. Levine (Chairman) *
Professor of Pharmacology
Chairman, Graduate Division of
Medicine and Dentistry
Boston University School of Medicine
Boston, Massachusetts
Dr. Ursula M. Cowgill *
Professor of Biological Sciences
Division of Biological Sciences
University of Pittsburgh
Pittsburgh, Pennsylvania
Dr, Samuel S. Epstein *
Professor of -Occupational Health
and Medicine
University .of Illinois at Chicago
Circle
Chicago, Illinois
Dr. Alan H. Gittelsohn **
Professor of Biostatistics
School of Public Health
Johns Hopkins University
Baltimore, Maryland
Dr. Thomas J. Haley **
Assistant to the Director
National Center for Toxicological
Research
Jefferson, Arkansas
Dr. Eva K. Kiilam *
Professor of Pharmacology
and Neurotoxicology
Associate Director of the Primate
Center
School of Medicine
University of California
Davis, California
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Dr. Harold M. Peck *
vice President for Safety
Evaluation
Merck, Sharp and Dohme
West Point, Pennsylvania
Dr. Karl B, Schnelle, Jr. **
Professor of Air Pollution Resources
Chairman, Department of Environmental
Engineering
Vanderbilt University
Nashville, Tennessee
Ms. Anne M. Wolven *
Consultant in Toxicology
Atlanta, Georgia
* Joined Subcommittee in May 1978
** Joined Subcommittee in December 1978
Dr. Joel L. Fisher, Staff Officer
Science Advisory Board
U.S.E.P.A.
Washington, D. C.
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APPENDIX B
U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
SUBCOMMITTEE ON ARSENIC AS A POSSIBLE HAZARDOUS AIR POLLUTAN
• Subcommittee Statement
(Corrected) June 12, 1978
Dr. Ruth R. Levine, Chairman
Boston University
Boston, Massachusetts
Dr. Ursula M. Cowgill
University of Pittsburgh
Pittsburgh, Pennsylvania
Dr. Samuel S. Epstein
University of Illinois
Chicago, Illinois
Dr. Eva K. Killam
University of California
Davis, California
Dr. Harold M. Peck
Merck, Sharp., and Dohrae
West Point, Pennsylvania
Ms. Anne M. Wolven
Private Consultant
Atlanta, Georgia
Dr. Joel L. Fisher, Staff Officer
Science Advisory Board
U.S.E.P.A.
Washington, D. C.
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INTRODUCTION
On May 22-23, 1978, the Subcommittee on Arsenic as a Possible
Hazardous Air Pollutant met in public session in Washington, D.C. to
review documents related to the EPAks proposed actions on whether or
not to "list" arsenic as a hazardous air pollutant under Section 123
of the Clean Air Act Amendments of 1978. The Subcotnmittee read into
the public record a Statement of Recommendations on May 23, 1978
which provided the' Subcommittee's consensus on the Agency's
documents.
One part of the Subcommittee's Statement indicated that the
document, Assessment of the Health'Effects of Arsenic, was "not
suitable in its present form to support the development of control
procedures for arsenic as a hazardous air pollutant." In making this
statement, the Subcommittee was not aware of the Agency's legal
choices 'with respect to the use of documents to support air pol*.Jtion
standards and criteria. Only in the case of designating a national
ambient standard for an air pollutant must the scientific documentation
be in a "final form" which can withstand appropriate challenge. In
those situations where the Agency is asked to "list" a pollutant as
na hazardous air pollntant" the decision to-"list" or "not to :ist"
does not depend on the scientific qaality of background documentation.
Theoretically the Agency could choose to "list" or "not list" without
recourse to scientific documentation.
The Subcommittee desired to be of maximum constructive assistance
to the Agency, Therefore, in order that the public record not be
clouded by any misunderstanding on the part of the Subcoirroittee with
respect to the Agency^s needs and uses of scientific documentation
on arsenic as a possible hazardous air pollutant, the Subcommittee
has issued a revision of its Statement of Recommendations (June 12, 1978).
This Statement of Recommendations, in its revised forms, has been
communicated by the Staff Director of the Science Advisory Board to
appropriate Offices of the EPA.
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STATEMENT
The Subcommittee on Arsenic, as a Possible Hazardous Air
Pollutant (of the Science Advisory Board of the U.S. Environmental
Protection Agency) has read and reviewed in detail the three
documents submitted by the EPA:
1.-Human Exposure to Atmospheric Arsenic
2* Population Risk to Arsenic Exposures
3. Assessment of the Health Effects of Arsenic
.I• Human Exposure to Atmospheric Arsenic
This is a well-written document discussing the data available
to quantify the exposure of United States populations to atmospheric
arsenic. The general summary and the summaries of each chapter
appear to be valid conclusions drawn from the assessment of the
data presented. The modeling estimates are in good accord with
the limited monitoring data available. ,
In order to make this document suitable as part of the
scientific basis upon which the EPA can develop control procedures
for arsenic, as a hazardous air pollutant, we recommend the
inclusion of a statement to the effect that:
"Data essential for determining the potential hazard
of arsenic emissions from certain point sources, such as
glass manufacturing plants and cotton ginning operations,
be collected and made available for critical analyses.
There is is also a need for additional monitoring data
from regions with primary smelters."
Also, the Subcommittee believes that the exposure assessment
needs to include information on the possible.exposure routes of
arsenic in man through water and food with consideration of
food chain relationships that may be relevant.
The Committee recommends that the final document contain
data relevant to emissions from .secondary smelters* since these
point sources have not been discussed.
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II* Population Risk to Arsenic Exposures
This is a well-prepared document given the paucity of the
data available. The authors appear to have used the best of the
data to arrive at dose-response relationships between standard
mortality ratios (SMR) and crude estimates of the lifetime
exposure to atmospheric arsenic.
The Conmittae recommends that the following additional
analyses and asseessmants be incorporated into the present .
document:
1. SMRs be estimated for regions of high ambient arsenic
concentrations for populations both occupational^ and
non-occupationally exposed. This is essential because
• the Committee points out that the statistic of 15.6
excess deaths nationally from lung cancer attributable
to arsenic exposure is not indicative of the true risk
to United States populations in high risk areas in the
vicinity of point source emissions. Indeed, the document
should contain seme statement regarding the level of
confidence of this statistic.
2. Statistical studies of such variables as time to
tumor death, age at tine of exposure, and duration of
exposure be carried out. The Committee believes that
this is necessary to provide more insight into the
problems of differential risk from arsenic exposure,
3. Recalculations be made of excess lung cancer deaths
in the smelter areas studied by Blot and Fraumeni. *
4. Assessments of the possible synergistic relationships
between arsenic and sulfur dioxide at ambient levels be
extracted from modern' and historical data.
Blot, W.J., Fraumeni, J.F. (1975)
"Arsenical Air Pollution and Lung Cancer," Lancet:
142-144; July 26, 1975
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III. Assessment of the Health Effects of Arsenic
Although this document does contain a compilation of useful
material, it does not do justice to the data available. Moreover,
this document in its present form is not as useful to EPA as it should
be to support the development of control procedures for arsenic as a
hazardous air pollutant. In order to make this document suitable, the
Committee suggests that the following revisions be made:
1. The document should be reorganized to lend itself to logical
evaluation of the data presented,
2. Since there is little or no critical analysis of the
toxicological and epidemiological studies cited,, such analyses
should be made and included.
3. Since there is a lack of consistency in the presentation of
much of the data, this deficiency should be rorrected.
4. Many important and pertinent recent as well as early
references have been omitted, and should be added.
5. Since the discussions of carcinogenesis, teratogenesis, and
mutagenesis are inadequate and sometimes confounded, these
sections need to be improved.
6. The summary should be rewritten to become an adequate
presentation of the data on health effects of arsenic.
In summary, the Committee recommends that.the document be
substantively revised under1 the direction of a qualified toxicoZoo'ist
in order to correct its deficiencies and to incorporate additional
data deemed essential.
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