UNITED STATES ENVIRONMENTAL PROTECTfON AGENCY
WASHINGTON, D.C. 20460
EPA-SAB-EHC-89-038
September 28, 1989
OFFICE OF
THE ADMINISTR
Honorable William K. Reilly
Administrator
U.S. Environmental Protection Agency
401 M street/ s.W.
Washington, D.C. 20460
Subject: Science Advisory Board's review of the ARSENIC issues
relating to the Phase II proposed regulations from the Office of
Drinking Water
Dear Mr. Reilly:
The Drinking Water Subcommittee of the science Advisory
Board's Environmental Health Committee has.completed its review
of the arsenic related issues identified in the Phase II proposed
regulations from the Office of Drinking Water at its meeting in
Cincinnati, Ohio, June 2-3, 1988.
The major recommendations of the Subcommittee are limited to
a few specific areas concerning the health effects of arsenic and
include the following; (1) that the evidence for the essentiality
of arsenic is suggestive but should be excluded in characterizing
health risks or in the development of a drinking water standard?
(2) that the current state of scientific knowledge cannot resolve
the important question of whether or not hyperkeratosis is a
precursor of skin cancer and, thus, in establishing the MCL
should consider hyperkeratosis and skin cancer as independent
effects? (3) that the findings of the Tseng study are adequate to
conclude that ingested arsenic can cause cancer in humans? and
(4) that at dose levels below 200 to 250 ug As3+/person/day there
is a possible detoxification mechanism that may substantially
reduce cancer risk from the levels EPA has calculated using
linear-quadratic model fit to the Tseng data. We recommend that
EPA (1) develop a revised risk assessment based on estimates of
the delivered dose of non-detoxified arsenic to target tissues,
and (2) consider the potential reduction in cancer risk due to
detoxification in establishing an MCL for arsenic.
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We appreciate the opportunity to conduct this particular
scientific review. We request that the Agency formally respond
to the scientific advice provided herein.
sincerely,
Chairman, Executive Committee
Arthur Upton
Chairman
Environmental Health Committee
Gary P* Carlson
Chairman
Drinking Water Subcommittee
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ARSENIC
The Drinking Water subcommittee of the Science Advisory
Board's Environmental Health Committee met June 2-3, 1988 in
Cincinnati, Ohio to review selected issues relating to the
scientific background for regulating arsenic in drinking water.
The Subcommittee concluded that? the evidence for essentiality is
suggestive, that the current state of knowledge cannot resolve
whether or not hyperkeratosis is a precoursor of skin cancer and
that at dose levels below 200 to 250 up As^/person/day there is a
possible detoxification mechanism that may substantially reduce
cancer risk. The Subcommittee recommended that EPA? develop a
revised risk assessment based on estimates of the delivered dose
of non-detoxified arsenic to target tissues, and consider the
potential reduction in cancer risk due to detoxification in
establishing a maximum contaminant level for arsenic.
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SUBJECT: SCIENCE ADVISORY BOARD'S REVIEW OF THE ISSUES RELATING
TO ARSENIC CONTAINED IN THE PHASE II PROPOSED REGULATIONS PROM THE
OFFICE OF DRINKING WATER
SCIENCE ADVISORY BOARD COMMITTEE: DRINKING WATER SUBCOMMITTEE OF
THE ENVIRONMENTAL HEALTH COMMITTEE
DATE OF REVIEW; JUN1 2-3, 1988
PLACE OF REVIEW: EPA LABORATORY, CINCINNATI, OHIO
A. Nutritional essentiality of arsenic
Whether arsenic is an essential nutrient for humans has been
a topic of extensive scientific investigation! and for the
present, the issue remains unresolved. Admittedly numerous
studies in laboratory and domestic animals have suggested the
essentiality of arsenic in some of those species; however, the
evidence is not sufficiently persuasive to conclude unequivocally
that arsenic is essential for normal health, growth, or
reproduction. The body of evidence exploring such a role for
arsenic in humans is much more sparse and far less convincing
than for animals. Consequently, the Subcommittee concludes that
arsenic cannot now be accorded the role of essential trace
element for humans. Hence, for EPA's evaluation of health risks
from small quantities of arsenic in tap water, attributing a
prominent role to the essentiality of arsenic in human nutrition
is unfounded. We recommend that the document be revised to
acknowledge the existence of suggestive evidence but exclude the
concept of essentiality as a factor in characterizing, or
modulating, conclusions about health risk — and, further, as a
factor in establishing drinking water standards,
B. Hyperkeratosis
In some epidemiologic studies arsenic exposures were
associated with skin lesions including cancer and hyperkeratosis.
Unknown at present is whether hyperkeratosis elicited by
inorganic arsenic is a lesion independent of the initiation of
skin tumors or a step necessary in tumor formation. The
distinction is important in assessing the risks from arsenic
exposures in the following way! If hyperkeratosis were
independent of skin cancer in the same individuals, there might
continue to be a suitable justification for assuming that the
dose-response curve for cancer would have no true threshold, and
the data would be extrapolated toward zero dose/zero effect. On
the other hand, if hyperkeratosis — a lesion for which a
threshold is not only plausible but also known — were an
obligatory intermediate to skin tumor formation, then the
threshold for the first becomes the threshold for the second,
leading to an extrapolation of the dose-response curve to a
point below which there would be no likelihood of cancer
incidence. The subcommittee concludes that the issue cannot be
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resolved with our current state of knowledge? hence, we recommend
that EPA follow its traditional interpretative procedure of
assuming that the two effects are independent of one another.
Research to resolve this matter is viewed by the Subcommittee as
particularly important and timely, and the Subcommittee
encourages EPA to conduct appropriate studies aimed at resolving
this matter.
Hyperkeratosis was selected by EPA as the basis on which to
select a no-observed-adverse-effect level (NQAEL) based on
findings of Valentine (1979), Southwick (19S3), and Harrington
(1978). The NOAELs derived from those investigations ranged from
3 to 10 ug As per kg body weight per day. Using these NQAELs,
EPA applied an uncertainty factor of 5 (rather than the more
traditional 10) to derive a drinking water equivalent level
(DWEI.). While EPA's rationale for the selection and application
of an uncertainty factor of 5 is based on a reasonable
proposition that the NOAEL was derived from a considerably
sensitive group of humans, the Subcommittee favors the use of the
larger uncertainty factor of 10, because the size of the cohort
(250 individuals) from which the NOAEL was derived is
sufficiently small to contribute additional uncertainty.
C. Applicability of Tseng epidemiologic study for
estimating cancer risks for the U.S population
Of the many epidemiologic studies that explored associations
between ingested arsenic and the increased incidence of cancer,
that of Tseng et al. was selected by EPA as pivotal to estimate
cancer risks in the U.S. population. That conclusion raises two
vital questions: Does the study support a strong positive
association between ingested arsenic and skin cancer? And, if
ingested arsenic caused cancer in humans, can the Taiwanese data
extrapolatable to humans in the U.S, (perhaps due to different
eating habits)?
The Tseng study of Taiwanese populations credibly relates,
in the view of the Subcommittee, arsenic exposures via tap water
to the prevalence of skin cancer and reports a positive dose-
response relationship that is usable in estimating cancer risks
at much lower doses in tap water.
The extent to which one can confidently extrapolate the
Taiwanese findings the U.S. population is governed, in part, by
the similarities and differences between the two populations.
Among the more salient considerations are the relative
differences in water consumption, body mass, nutritional status,
and background incidence of skin cancer among members of each
country. Additional distinctions taken into some account by EPA
are sources of arsenic other than tap water and the presence of
organic and physical (i.e., UV light) carcinogens and co-
carcinogens (viz., ergot alkaloids) in tap water.
There exists an apparent discrepancy among epidemiologic
findings. The studies in Mexico and Germany support the
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associations reported by Tseng et al.; however, the few
epidemiological investigations carried out in the U.S. failed to
find any such association. The Subcommittee concludes that part
of the basis for the absence of association in the U.S. studies
is insufficient statistical power, given the magnitude of
exposure of the US cohorts.
The findings of Tseng et al. (1977), in the opinion of the
Subcommittee, are adequate to conclude that infested arsenic can
cause cancer in humans; however, the many differences between the
populations of the two countries render inconclusive a confident
determination of cancer risk at the levels ingested in the U.S.
The Subcommittee concludes that, faced with such uncertainty, EPA
is justified in considering arsenic a possible human carcinogen
for the U.S. population. However, the many differences between
the populations — particularly nutritional status of those
exposed — should be viewed as overestimating cancer risk from
relatively high doses of ingested arsenic; that is, the Taiwanese
are to be considered as much more vulnerable to the cancer-
causing property of ingested arsenic than are residents of the
U.S, On the other hand, the presence of Blackfoot disease in the
Taiwan study group could result in an underestimate of cancer
risk due to earlier mortality.
The practical outcome of such conclusions, as endorsed by
this Subcommittee, is for EPA to consider promulgating a Maximum
Contaminant Level Goal of zero based on a cautious policy of
public health protection (although as indicated below, some non-
zero concentration would likely achieve nearly the, same
objective). The setting of the MCL should, in our view, be
guided by the characterization and utilization of a non-linear
dose-response relationship for skin cancer associated with the
effective (non-detoxified) dose of inorganic arsenic*
D. Dose-response assessment for ingested arsenic at low doses
There is clear evidence that arsenic ingested at high doses
can cause cancer in humans. The risk of skin cancer at doses
encountered in U.S. tap water has not been empirically
determined. This depends in part on the ability of the human
body to efficiently detoxify relatively small doses of ingested
arsenic.
Convincing evidence of human metabolism of ingested
inorganic arsenic has been presented by the EPA (see Section VIII
of the Health Criteria Document). Specifically, conversion by
the liver of inorganic arsenic by methylation to
monomethylarsenic acid (MMA) and to dimethylarsenic acid (DMA) is
the predominant pathway of detoxification in humans. The
findings indicate that daily doses of 250 to 1000 ug
As3 /person/day or less may be largely detoxified? whereas, at
higher doses, the detoxification pathway becomes increasingly
saturated, thereby increasing the possibility of macromolecular
binding with consequent pathology such as tumor formation. As a
result, the slope of the dose-response curve for arsenic-induced
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cancer can be expected to be much steeper above intake levels of
250-1000 ug As3vperson/day than at lower levels of intake. The
risks of cancer induction at lower levels of intake are then
likely to be greatly exaggerated if the relevant pharmacokinetic
considerations are not appropriately taken into account. Whether
the concentration of As3 reaching target cells is sufficient to
pose a significant risk of carcinogenic effects at levels of
intake below 250-1000 ug As3 /person/day is problematic.
However, because the detoxification at lower doses does not
appear to be more than 80 - 90% complete, the possibility of some
risk at lower doses cannot be ignored. The Subcommittee
concludes that the metabolic evidence for at least partial
detoxification is sufficiently persuasive to incorporate it
directly into the derivation of an MCL, with appropriate
consideration of the known heterogenieity of detoxification in
the human population.
E. Arsenic exposure from drinking water and from food
The major source by far of arsenic exposure to the U.S.
population is food — principally beef, chicken, milk products,
and fin- and shellfish. Compared to that large background of
exposure, the quantity of arsenic contributed from tap water to
daily dose is quite low. Moreover, the ability to eliminate or
substantially reduce small quantities (i.e., low ppb) is
difficult and costly.
The dietary habits of some individuals may result in doses
of arsenic that are much higher than the average dose from food
products, and both food and water exposures should be considered
in assessing arsenic health risks*
F. Apportionment of reference dose across routes of exposure
Currently, EPA sets MCLs for non-carcinogens and for
substances classified by EPA as either C, D, or E in a manner
that takes explicit account of tolerable levels of exposure from
other sources such as food and air. To the extent that reliable
data characterizing contributions from other sources are
available, EPA incorporates them in the derivation of MCLs. In
the absence of such information, EPA arbitrarily assigns 20
percent of the RfD to tap water (10 percent for inorganic
substances).
The Subcommittee concludes that EPA's approach appears to be
a reasonable management tool — even for substances classified as
C — because it appears to foster the protection of public
health. The Subcommittee cautions, however, that the application
of such assumptions may lead in some cases to regulations that
are not in the best interest of the public by virtue of being
either too restrictive or inadequately protective. Consequently,
the Subcommittee, while acknowledging the practical necessity of
using default assumptions (e.g., 20% of RfD), strongly encourages
the Agency to obtain data that accurately portray human intake
from major sources and routes.
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U.S. Environmental Protection Agency
Science Advisory Board
Environmental Health Committee
Drinking Water Subcommittee Roster
June 2 & 3, 1988 Meeting
Dr. Gary Carlson - CHAIRMAN
Department of Pharmacology
and Toxicology
School of Pharmacy
Purdue University
West Lafayette, IN 47907
Dr. Robert Tardiff - VICE CHAIRMAN
1423 Trapline Court
Vienna, Va 22180
Dr. Julian B. Andelman
Graduate School of Public Health
130 Desoto Street
Parran Hall - Room A-711
University of Pittsburgh
Pittsburgh, PA 15261
Dr. Rose Dagirmanjian
Department of Pharmacology
and Toxicology
University of Louisville
Louisville, KY 402902
Dr. Charles Gerba
Department of Microbiology
and Immunology
Building #90
University of Arizona
Tucson, AZ 85721
Dr. William Glaze, Director
School of Public Health
University of California-Los Angeles
650 Circle Drive South
Los Angeles, CA 90024
Dr. J. Donald Johnson
Department of Environmental Sciences
and Engineering
University of North Carolina School
of Public Health 201H
Chapel Hill, NC 27599
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Dr. Marshall Johnson
Department of Anatomy
Jefferson Medical College
1020 Locust Street
Philadelphia, PA 19107
Dr. David Kaufman
Department of Pathology
University of North Carolina
Brinkhous-Bullitt, Room 515
Chapel Hill, NC 27514
Mr. Ramon G. Lee
System Director
Water Quality Research
American Water Works Service Company, Ine,
1025 Laurel Oak Road
Voorhees, New Jersey 08043
Dr. Verne Ray
Hedical Research Laboratory
Pfitzer Inc.
Groton, CT 06340
Dr» Harold Shechter, Professor
Chemistry Department
Ohio State University
140 West 18th Avenue
Columbus, OH 43201
Dr. Thomas Tephly, Professor
Department of Pharmacology
The Bowen Science Building
University of Iowa
Iowa City, IA 52242
Dr. R. Rhodes Trussell
Vice President, James M, Mongomery,
Consultanting and Engineers, Inc.
250 North Madison Ave.
P,O. Box 7009
Pasadena, CA 91109-7009
C. Richard Cothern, Executive Secretary
Environmental Protection Agency
Science Advisory Board
Washington, D.C, 20460
Donald G. Barnes, Director
Environmental Protection Agency
Science Advisory Board
Washington, D.C. 20460
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