United States
Environmental Protection
Agency
Office of Research and
Development
Washington, DC 20460
EPA/600/R-98/042:
February ji|pa;'
"
Research Plan for
Arsenic in Drinking
Water
Inorganic soluble Arsenic
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EPA/600/R-98/042
February 1998
Research Plan for Arsenic in Drinking Water
Office of Research and Development
National Center for Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
Printed on Recycled Paper
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Notice
This document has been reviewed in accordance with U.S. Environmental
Protection Agency policy and approved for publication. Mention of trade names
or commercial products does not constitute endorsement or recommendation
for use.
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Foreword
The 1996 Strategic Plan for the Office of Research and Development (ORD) sets
forth ORD's vision, mission, and long-term research goals. As part of this strategic
process, ORD used the risk paradigm to identify EPA's top research priorities for the
next several years. The ORD Strategic Plan thus serves as the foundation for the
research strategies and research plans that ORD has developed, or is in the process
of developing, to identify and describe individual high-priority research topics. One of
these high-priority research topics is arsenic in drinking water.
The Research Plan for Arsenic in Drinking Water was developed through a
process involving EPA-wide research activities and research partnerships with
stakeholders. In 1992 EPA's Science Advisory Board (SAB) reviewed EPA's 1991
Arsenic Research Recommendations, and advised EPA to consider several addi-
tional research projects. In 1995, an Expert Workshop on Arsenic Research Needs
was sponsored by the American Water Works Association (AWWA) Research
Foundation, the AWWA. Water Industry Technical Fund, and the Association of
California Water Agencies; the workshop's final report prioritized research in mecha-
nisms, epidemiology, toxicology, and treatment. In addition, the 1996 Safe Drinking
Water Act Amendments directed EPA to develop a research plan to reduce the
uncertainty in assessing health risks from low levels of arsenic, and to conduct the
research in consultation with the National Academy of Sciences, Federal agencies,
and interested public and private entities. EPA held arsenic in drinking water
stakeholder meetings in 1997 that addressed, among other things, research activities
for arsenic.
A research plan is different from a research strategy. While a research strategy
provides the framework for making and explaining decisions about program purpose
and direction, a research plan defines the research program that EPA is pursuing.
The research strategy, as an overarching view of research needs and priorities, thus
forms the basis for the research plan and provides a link between the ORD Strategic
Plan and the individual research plan. In turn, the research plan links the research
strategy to individual laboratory implementation plans (which serve as the blueprints
for work at ORD's national laboratories and centers) by defining the research topic(s)
at the project level.
This research plan describes the research that can contribute to the development
of an arsenic drinking water regulation. Areas covered in the plan include both short-
term and long-term studies to:
improve our qualitative and quantitative understanding of the adverse
human health effects of arsenic;
understand mechanisms of arsenic health effects, using a variety of
research tools, including PBPK and BBDR models;
measure exposures of the US population to arsenic from various sources
(particularly diet), thereby permitting better definition of cumulative expo-
sures to arsenic;
development of biomarkers of effects and exposure;
improve methods for assessing and characterizing the risks from arsenic
exposures and health effects; and
refine treatment technologies for the removal of arsenic from water
supplies.
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To address these issues, the plan prioritizes arsenic research within the
following broad research areas: analytical methods, exposure assessment, risk
assessment, metabolism, health effects and dose-response for cancer and non-
cancer endpoints, mechanisms of action, human susceptibility characteristics, and
potable water treatment modalities.
This research plan is an important tool for measuring accountability because it
makes clear the rationale for, and the intended products of, EPA's arsenic in
drinking water research. By specifying up front how EPA will manage its scientific
data and information products, EPA can effectively communicate the results of its
aresenic in drinking water research to its clients, stakeholders, and the public. This
research plan is also an important budget tool, enabling EPA to clearly track
progress toward achieving its arsenic in drinking water research goals, as required
by the 1993 Government Performance and Results Act.
Lawrence W. Reiter, Ph.D.
Acting Deputy Assistant Administrator
for Science, ORD
IV
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Peer Review
Peer review is an important component of research plan development. The
peer review for the Research Plan for Arsenic in Drinking Water was conducted
by an Ad Hoc Subcommittee of ORD's Board of Scientific Councilors (BOSC)
during January 1997. In addition, the draft research plan was discussed with
stakeholder groups prior to the plan's finalization.
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Document Development
Executive Lead:
William H. Farland, Director
National Center for Environmental Assessment
ORD Lead Authors:
Jack Creed, NERL
Jennifer Orme-Zavaleta, NHEERL
Lynn Papa, NCEA
Bruce Peirano, OSP
Gail Robarge, OSP
Tom Sorg, NRMRL
Bob Thurnau, NRMRL
Paul White, NCEA
Contributing Scientists:
Rebecca Calderon, NHEERL
Herman Gibb, NCEA
Elaina Kenyon, NHEERL
Kirk Kitchin, NHEERL
Marc Mass, NHEERL
David Thomas, NHEERL
Sheila Rosenthal, NCERQA
Office of Water Reviewers:
Charles Abernathy, OST
Jeff Kempic, OGW/DW
Joyce Donohue, OST
Irene Dooley, OGW/DW
Jim Taft, OGW/DW
VI
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Research Plan Peer Reviewed by the
Ad Hoc Subcommittee on Arsenic
Research of the Board of Scientific
Counselors (BOSC)
January 22-23, 1997
Jerald I. Schnoor, Ph.D., Foundation Distinguished Professor, Department of
Civil and Environmental Engineering, University of Iowa, Iowa City, I A
Consultants
Judy Bean, Ph.D., Professor of Biostatistics, Department of Epidemiology, Uni-
versity of Miami, Miami, FL
Gary Carlson, Ph.D., Professor of Toxicology, Purdue University, School of
Health Sciences, West Lafayett, IN
Janet Hering, Ph.D., Professor, Department of Environmental Engineering, Cali-
fornia Institute of Technology, Pasadena, CA
Richard Monson, Ph.D., Professor of Epidemiology, Harvard School of Public
Health, Boston, MA
Edo Pellazzari, Ph.D., Vice President, Analytical'and Chemical Sciences, Re-
search Triangle Institute, Research Triangle Park, NC
Dr. Henry Pitot, Ph.D., M.D., Professor of Oncology and Pathology, University of
Wisconsin, Madison, Wl
Verne Ray, Ph.D., Senior Technical Advisor, Pfizer, Inc., Groton, CT
Rhodes Trussell, Ph.D., Senior Vice President, Montgomery Watson Consulting
Engineers, Pasadena, CA
Bernard Weiss, Ph.D., Professor of Environmental Medicine, University of Roch-
ester, Rochester, NY
Subcommittee Staff
Edward S. Bender, Ph.D., Designated Federal Official, Office of Science Policy,
U.S. EPA, Washington, DC
Rose Lew, M.S., M.P.H., Science Associate, Office of Science Policy, U.S. EPA,
Washington, DC
Pam Pentz, Program Analyst, Office of Science Policy, U.S. EPA, Washington,
DC
Pat Jones, Staff Assistant, Office of Research and Development, U.S. EPA,
Washington, DC
VII
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Research Plan for Arsenic in Drinking Water
EPA/600/R-98/042
Abstract
The U.S. Environmental Protection Agency's (EPA) Office of Research and
Development (ORD) develops research plans to guide its research direction
pertaining to specific environmental issues over a 5- to 10-year time frame. This
research plan addresses opportunities to enhance the scientific basis for under-
standing the health risks associated with arsenic in drinking water as well as
research to support improved control technologies for water treatment. Better
understanding of arsenic health risks will provide an improved science base for
arsenic risk assessment and regulatory decisions in the U.S. Further evaluation of
control technologies will support cost-effective implementation of future regulatory
requirements.
For more information, contact: Lynn Papa, National Center for Environmental
Assessment, Cincinnati, OH; telephone: 513-569-7587; fax: 513-569-7916; e-
mail: papa.lynn@epa.gov
viii
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Table of Contents
Introduction , 1
Purpose 1
Background on Arsenic '. 1
Regulatory Background '. 2
Risk Management Decisions Required for Arsenic in Drinking Water.. 2"
Scope of this Research Plan , 3
Research Planning and Implementation Process 3
Prioritization Criteria..... 5
1. Arsenic Risk Assessment/Characterization , 5
1.1. Background 5
1.2. Characterization of Arsenic Risks: State of the Science .....5
1.2.1. Current Exposure Data 6
1.2.2. Current Health Risk Estimates . 6
1.3. What are the Research Opportunities to Improve/Refine Current
Risk Assessments? 9
1.3.1. Exposure Assessment 10
1.3.2. Cancer Assessments 10
1.3.3. Noncancer Assessment 11
1.3.4. Risk Management Research 11
1.3.5. Research Needs.. 11
1.4. Risk Characterization Research: Health and Exposure Assessment 12
1.4.1. Risk Assessment/Characterization 12
1.4.2. Ongoing Activities... r..13
1.5. Proposed Risk Assessment Research and Risk Assessments 13
Summary Tables .....15
2. Exposure to Arsenic Species: Analysis Methods and Human Exposures 14
2.1. Background 14
2.2. What Analytical Methods are Needed for Determining Arsenic in Exposure
Assessment Media? 16
2.2.1. State of the Science 16
2.2.2. Ongoing EPA Research 17
2.3. What Data are Required to Adequately Assess Arsenic Exposure in Human -•'.
Populations? 17
2.3.1. State of the Science ....17
2.4. How Can Biomarkers and Bioayailability Data be Effectively Used to
Estimate Arsenic Exposure and Uptake? 18
2.4.1. State of the Science 18
2.5. Proposed Exposure Research 19
Summary Tables 23
ix
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Table of Contents (cont.)
3. Health Effects: Hazard Identification and Dose-Response 22
3.1. Background 22
3.2. What are the Health Effects Associated with Arsenic Exposure? 22
3.2.1. State of the Science 22
3.3. What are the Characteristics of Dose-Response for Various Toxic
Endpoints? 27
3.3.1. State of the Science 27
3.4. What are the Mechanisms Associated with Arsenic Carcinogenicity
andToxicity? 28
3.4.1. State of the Science 28
3.4.2. Ongoing EPA Research 29
3.5. What are the Modifiers of Human Susceptibility? 29
3.5.1. State of the Science 29
3.5.2. Ongoing EPA Research 29
3.6. Proposed Health Effects Research » 29
Summary Tables 30
4. Risk Management Research for Arsenic in Water 34
4.1. Background • 34
4.2. State of the Science for Arsenic Control 34
4.2.1. How Effective are Available Technologies for Meeting a Lower
Arsenic MCL? 34
4.2.2. Are There Cost-Effective Technologies for Small Systems? 35
4.2.3. How Can the Residuals be Effectively Managed? 35
4.2.4. Ongoing EPA Research 36
4.3. Risk Management Reseasrch 36
Summary Tables 37
5. Cross Linking and Summary of Arsenic Research 36
Summary Tables 39
6. References 48
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Introduction
Purpose
The Environmental Protection Agency's (EPA) Office of
Research and Development (ORD) develops research
plans.to guide its research direction pertaining to spe-
cific environmental issues over a 5- to 10-year time
frame. This research plan addresses opportunities to
enhance the scientific basis for understanding the health
risks associated with arsenic in drinking water as well as
research to support improved control technologies for
water treatment. Better understanding of arsenic health
risks will provide an improved science base for arsenic
. risk assessment and regulatory decisions in the United
States! Further evaluation of control technologies will
support cost-effective implementation of future regula-
tory requirements. This research plan is expected to be
of interest to scientists, risk managers and decision
makers in government, industry, and academia as well
as members of the public interested in arsenic expo-
sure. The issue of arsenic research needs and the basis
for current risk assessments have been the subject of
several reviews and expert panels (AWWARF, 1995;
U.S. EPA, 1988, 1991, 1992, 1996c). Therefore, this
document stresses the implications of recent research
findings and emphasizes identification of key strengths
and sources of uncertainty and variability1 in the arsenic
risk assessment. This document will also explain how
information gained through research can:
impact the methods used in new investigations
to assess the risks of arsenic, and
support or suggest changes in the assumptions
and methods used in arsenic risk assessments.
The risk assessment/risk management paradigm was
chosen as the format for the plan because risk assess-
ment provides a systematic approach to analyze sources
of scientific uncertainty and variability which can influ-
ence research directions more effectively (NRC, 1994).
The risk assessment/risk management paradigm in-
volves four types of scientific analyses followed by risk
management decisions. The risk assessment analyses
consists of hazard identification, dose-response assess-
ment, exposure assessment and risk characterization
(NRC, 1983, 1994). Hazard identification involves de-
scriptions of the potential adverse effects (e.g., short-
term illness, cancer, reproductive effects) that might
occur due to exposure to the environmental stressor
(e.g. arsenic). Dose-response assessment determines
the toxicity or potency of the stressor by describing the
quantitative relationship between the amount of expo-
sure to a stressor and the extent of injury or disease in
1 The terms uncertainty and variability, as used here, have distinct meanings
(NRC, 1994). Uncertainty refers to gaps in knowledge, and variability to
interindi vidual differences (heterogeneity) in both exposure and personal dose-
response relationships (susceptibility).
humans. Exposure assessment describes the nature
and size of the populations exposed to a stressor and
the magnitude and duration of exposure. Exposure
assessment also includes descriptions of the pathways
(e.g. air, water, food supply) by which the stressor
travels through the environment along with the potential
routes of exposure (oral, dermal, or inhalation). Risk
characterization uses the data collected from the three
preceding analyses which are integrated to convey the
overall conclusions about potential risk, as well as the
rationale, strengths and limitations of the conclusions. It
provides an estimate of the likelihood that individuals in
a population will experience any of the adverse effects
associated with the stressor, under known or expected
conditions of exposure. Risk management decisions for
drinking water involve setting maximum contaminant
levels (MCLs), based on minimizing adverse health
effects considering the available technologies. In the
context of this plan, risk management research involves
identifying treatment technology options and evaluating
their performance, cost, and effectiveness.
This Arsenic Research Plan addresses the protection of
human health, especially the research needed to imple-
ment the 1996 Safe Drinking Water Act Amendments
(SDWAA). It is intended to serve as a blueprint that will
be discussed with parties interested in addressing key
strengths and uncertainties in the arsenic risk assess-
ment. The research needs are broader than those that
EPA can address alone, and it is anticipated that other
entities will be involved in conducting some of the
needed research.
Background on Arsenic
Arsenic occurs widely in the earth's crust and is a
natural contaminant of water. Elevated levels of arsenic
in water and soil can be found in certain areas of the
country as a result of leaching from rock into ground
water and possible geothermal activity, depending on
the geologic make-up of the area. In addition, nonfer-
rous mining and smelting operations, refining opera-
tions, wood preservative use, contaminated pesticide
manufacturing sites, and past use of pesticides on
crops (e.g., cotton) may add to elevated concentrations
of arsenic in water and soils. Humans are exposed to
arsenic in a variety of forms from sources such as food
and water. Arsenic has also been used for medicinal
purposes.
Arsenic is a transitional, reactive element that forms
complexes with other metals, as well as carbon and
oxygen (Gorby, 1994). There are three biologically
important arsenic valence states: elemental arsenic
As(0), arsenite As(lll) and arsenate As(V). Arsine gas
1
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is considered the most acutely toxic; inorganic arsenic
compounds are generally considered to be more toxic
than organic arsenic compounds. Elemental arsenic is
the least toxic. The inorganic arsenicals are the pre-
dominant forms found in water.
Although the general toxicity of arsenic is widely known
through poisoning incidents and its medical use, epide-
miological reports of arsenic-related cancers in Taiwan
and other populations have raised public health con-
cerns about effects arising from chronic exposure. In
Taiwan, an association between arsenic levels in drink-
ing water and increased skin cancers and internal can-
cers in the exposed populations was observed (Tseng
et al., 1968; Tseng, 1977; Chen et al., 1986). Effects
other than cancer were also noted in this population
such as effects on the peripheral vasculature leading to
Blackfoot's disease and noncancerous skin lesions such
as altered pigmentation and skin thickening (hyperkera-
tosis). Animal studies suggest the possibility of other
noncancer effects occurring under certain conditions of
exposure.
Regulatory Background
EPA's authorities and responsibilities are mandated pri-
marily by a number of environmental statutes. These
statutes direct EPA to perform a wide variety of activities
with the underlying goal of protecting human health and
the environment. This research plan for arsenic specifi-
cally emphasizes research issues related to arsenic in
drinking water. Therefore, the discussion in this section
will focus on mandates under the Safe Drinking Water
Act (SDWA), with some consideration of other statutes
affected by the SDWA, in particular the Clean Water Act
(CWA). Nevertheless, it is important to consider the risk
from water in context of the total risk from exposure
resulting from other pathways to ensure that control
strategies will achieve adequate reduction in risk.
The SWDA mandates that EPA identify and regulate
drinking water contaminants that may have adverse
human health effects and that are known or anticipated
to occur in public water supplies. EPA's drinking water
standard, or maximum contaminant level (MCL), under
SDWA is 50 ng/L for arsenic. This level was developed
in 1942 by the Public Health Service and was not based
on risk assessment methodology. Since that time, revi-
sion of the drinking water standard has been considered
a number of times, but no change was made. In Febru-
ary 1995, OW decided to delay proposals for the revi-
sion of the arsenic MCL pending additional health re-
search to reduce uncertainties and to conduct research
on arsenic removed by small system treatment tech-
nologies. The 1996 Amendments of SDWA require the
development of an arsenic research plan, a proposal to
revise the MCL by January 2000, and a final rule by
January 2001.
The EPA's Office of Water (OW) has also established
guidance for arsenic under the CWA. The U.S. EPA's
1992 National Toxic Rule established a human health
water quality criterion for arsenic of 0.018 ng/L. Water
quality criteria are used as guidance to states in estab-
lishing surface water quality standards and discharge
limits for effluents. However, actual implementation of
the surface water standards has depended on measur-
ability criteria for arsenic at a level of several (ig/L.
Having two very different criteria for arsenic (0.018 jig/L
in ambient water vs. 50 jig/L in drinking water) to protect
human health is very confusing to the public. These
different values have been difficult to explain, defend,
and implement in EPA and State programs.
Treatment efficiency is another major concern for risk
managers since removal of arsenic from water and soil
can cost billions of dollars. Previous EPA estimates
indicate that national cost estimates for implementing
revisions range from $140 million to $6.2 billion, for
MCLs of 20 down to 5 jjg/L However, a variety of
strategies for implementation of an MCL could substan-
tially reduce cost. Further cost estimates will be con-
ducted pursuant to the new SDWAA provisions. Treat-
ment costs are of particular concern for small communi-
ties. Since the MCL must be set as close to the health
goal as feasible, there continues to be considerable
scrutiny placed on the health effects data and resulting
risk assessments for ingested arsenic. The potential
cost impacts of a revision of the arsenic MCL have
served to highlight the arsenic risk assessment and its
associated strengths and uncertainties.
Risk Management Decisions Required for
Arsenic in Drinking Water
To meet the January 1, 2001, target for a final arsenic
drinking water regulation, EPA's risk managers will rely
on scientific results that are available, at the latest, by
mid-1999. However, longer-term research will also be
important because every 6 years EPA must review and
revise, as appropriate, each national primary drinking
water regulation promulgated. Key issues for risk man-
agement decision-making in developing a drinking water
standard are described below.
1. Determine the Maximum
Contaminant Level Goal (MCLG)
In the development of national primary drinking water
regulations under SDWA, EPA is required to promulgate
a health-based MCLG for each contaminant. The MCLG
is set at a level that will not result in adverse health
effects, incorporating a margin of safety. In setting
MCLGs, EPA's policy has been to distinguish between
carcinogens and non-carcinogens as follows:
For contaminants with strong evidence of carcino-
genicity via drinking water, considering weight of
evidence, pharmacokinetics, potency and exposure,
the MCLG is set at zero.
For contaminants with limited or no evidence of
carcinogenicity including many Group C agents, the
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MCLG is based on noncancer effects using the
Reference Dose (RfD). The RfD is derived from a
no- or- lowest- adverse- effect level identified from a
sensitive endpoint of toxicity from a relevant human
or animal study and adjusted to account for uncer-
tainty of the findings. A relative source contribution
factor (RSC) is applied to the RfD to determine the
maximum amount of the RfD allocated to drinking
water (U.S. EPA, 1994b). If the contaminant shows
limited evidence of carcinogenicity, an additional
factor of 10 is applied to the RfD to account for
possible carcinogenicity.
2. Determine the Maximum Contaminant
Level (MCL)
An MCL is set as close to the MCLG as "feasible". The
SDWA (section 1412(b)(4)(D)) characterizes "feasible"
as follows: "feasible with the use of best technology,
treatment techniques, and other means which the Ad-
ministrator finds available (taking costs into consider-
ation) after examination for efficacy under field condi-
tions and not solely under laboratory conditions".
• When setting an MCL, EPA lists the best available
technology (BAT) as feasible technologies based on
cost assessments for large public water systems.
Under the new SDWAA , EPA must also identify
affordable technologies that will meet the MCL for
small water systems in three population size catego-
ries: 25-500; 501-3,300; and 3,301-10,000.
EPA will establish a standard analytical method(s)
to be used for compliance monitoring of the con-
taminant.
3. Determine if the Benefits of the MCL
will Justify the Compliance Costs
The new SDWA Amendments expand upon the cost-
benefit analysis previously required for drinking water
regulations. Under the Amendments, EPA must:
• Analyze quantifiable and nonquantifiable health risk
reduction benefits likely to occur as a result of
treatment of the contaminant and co-occurring con-
taminants, including health risk reduction benefits
for infants, children, pregnant women, the elderly.
and ill-
Analyze the quantifiable and nonquantifiable costs
of compliance, including monitoring and treatment
costs.
Determine if the benefits justify the costs.
If the benefits do not justify the costs, identify a
higher MCL that maximizes health risk reduction
benefits, where the costs are justified, unless the
cost to large systems would justify the benefits.
However, if the contaminant is found exclusively in
small systems that are unlikely to receive a vari-
ance, a higher MCL can be established.
Scope of this Research Plan
This research plan describes the research that can
contribute to the development of the arsenic drinking
water regulation, both in the near and longer terms.2
Areas covered in the research plan include both short-
term and long-term studies to:
improve our qualitative and quantitative understand-
ing of the adverse human health effects of arsenic;
understand mechanisms of arsenic health effects,
using a variety of research tools;
measure exposures of the U.S. population to arsen-
ic from various sources (particularly diet) thereby
permitting better definition of cumulative exposures
to arsenic;
improve methods for assessing and characterizing
the risks from arsenic exposures and health .effects;
and
refine treatment technologies for the removal of
arsenic from water supplies.
The relationship of the exposure and health effects
research to the development of the risk assessment and
integration into the final risk characterization is depicted
in Figure'1. An overview of how the arsenic research
and assessment will be implemented in developing drink-
ing water regulations is illustrated in Figure 2.
Research Planning and Implementation
Process
U.S. EPA's Office of Research and Development (ORD)
has implemented a new planning process where repre-
sentatives from each ORD research organization (cov-
ering all disciplines) meets regularly with representa-
tives of the Office of Water to discuss programmatic
needs and time-lines for needed research. EPA Re-
gional representatives also participate in these activities
to ensure that results from ORD research, and subse-
quent program office decisions, can be maximally and
practically utilized. More recently ORD, working with all
EPA program offices, has prioritized its entire research
program from top to bottom using a two-step process of
first making a difference with the best science only
perspective and then modifying the rankings because of
programmatic needs/deadlines, Congressional man-.
2However, this plan does not describe all the regulatory assessment and
monitoring studies needed to support arsenic regulation. Such assesments
would include studies of the prevalence of different levels of arsenic contami-
nation in water supplies in the US and economic evaluations of regulatory costs.
Such data collection and analysis falls outside the scope of resesarch planning
and is addressed directly by EPA's Office of Water.
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1—
Emission Sources
-Pollutant Type
-Amount Released >
-Geographic Location
— _
Uncertainty is associated
with each aspect of the
risk assessment process.
• • RisK Assessrfient/RisK
Environmental Human Exp
Concentrations . Route
-Air > -Magnitud
-Water -Duration
-Soil -Frequenc
-Food
^-- —
—- — -
Exposure Assessment
- Level
- Distribution
-Number of People
-Susceptible Subpopulations
-Source Apportionment
-Target Dose
" '''•" /'*- , ' V *-' ' }'-''-, ' ,-. " / " , '. ,'•••'- , -
-- , ',--•' - '<*'* ", '"''•' -*~ ''""•' '''-/''-
/I '**•''/ ""' ' ' ' ,' < '"
osure Internal Dose M Health Effects
-Absorbed Dose ;;.;.; :' -Cancer
-Biomarkers ' 'Damage/Disease
y ' • Signs/Symptons
Hazard Identification and
Dose-Response Assessment •
-Intrinsic Hazard ' '
-Type of Effect
- Dose-Response
", ," ; -Mechanisms of Action
- Modifiers of Susceptibility
Adapted from: Sexton et al. (1992)
Figure 1. Risk Assessment/Characterization: Relationship of Exposure and Effects Research.
./ Water
Extraction
Exposure from Food
Amount in
Water
"~~ • — Extraction
from Tissues
Forms
Food
Celii
Forrr
in
lar
is
X
Amount in
Food
\
PQL
RSC
Biomarkers
Metabolism
Enzymes
Cofactors
Effectiveness
Water
Treatment
Key: PQL
RSC
- Practical Qua
= Relative Sour
Applicable
Techniques
L_ • I
^\ '
ntiation Limit ^""---v
ce Contribution
Cost
Waste Disposal
^
\
Cost-Benefit
RA = Risk Assessment
BAT - Best Available Technology
Figure 2. Arsenic Research to Support Regulation Development.
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dates, etc. This has resulted in an ordinal ranking of nine
broad arsenic research areas being developed. This
activity allowed EPA to further develop the prioritization
of the arsenic projects found within this revised research
plan into three broad categories. These categories are
High, Medium, and Low. The Arsenic Research Plan
contains project priority rankings using this approach.
The research implementation process involves utilizing
the results of the research planning for identification of
arsenic related High Priority Research and comparing
these priorities to other High Priority Research Needs
identified by EPA. Decisions on when and to what levels
EPA will conduct research related to these arsenic
research needs will be made on a yearly budgetary
basis. Ultimately, decisions to implement planned re-
search depend on the priority set from within this re-
search plan, the relative priority of arsenic research
compared to other EPA High Priority Research Needs,
and the resources provided to EPA to conduct research.
The ability for EPA to leverage the research interest of
other parties to conduct portions of this arsenic research
also plays an important part in the implementation pro-
cess.
Prioritization Criteria
Decision-making criteria for use in priority-setting within
this research program have been developed. The pri-
mary arsenic specific prioritization criteria involves meet-
ing the following short-term and long-term criteria. In
addition, the sequence of needed research and feasibil-
ity of accomplishing research goals was taken into ac-
count in prioritizing tasks. Through application of these
criteria, resources have been and will be allocated in the
most effective and efficient manner.
Short-Term Criteria
1. Will the research improve the scientific basis for risk
assessments needed to propose a revised arsenic
MCLG by January 1, 2000?
2. Will the research improve the scientific basis for risk
management decisions needed for proposing a re-
vised arsenic MCL by January 1, 2000?
Long-Term Criteria
1. Will the research -improve the scientific basis for risk
assessment and risk management decisions needed
to review and develop future MCLs beyond the year
2001?
2. Is the research essential to improving our scientific
understanding of the health risks of arsenic?
Within each proposed research area, the plan summa-
rizes the primary focal area for the research, indicates
whether the activity is targeted primarily toward the
intramural or extramural (or both) components of the
EPA research program and to the extent possible other
research programs, and the planning year in which the
research is proposed to be undertaken. The arsenic re-
search plan also specifies whether the research area will
satisfy the short-term or long-term needs of the Agency.
While, in general, EPA has given the highest priority to
meeting shortTterm objectives, longer-term high-priority
research has been initiated in order to address require-
ments for future regulations in 2006. In some cases, EPA
expects the research to be conducted by other entities.
While these tables also propose the research sequence,
this strategic plan is likely to be refined as the program
progresses and new research results emerge. The full
scope of the program will likely exceed available re-
sources. In this context, it is anticipated that selections of
particular projects within the scope of the issues will be
determined by scientific peer reviews and programmatic
relevancy reviews. Peer review will help ensure the high
quality of projects selected, which is of critical importance
to both the regulatory application of the resulting informa-
tion and the overall credibility of the Agency. Additionally,
EPA will coordinate its efforts with other interested parties.
After further peer review of this research plan, EPA will
prepare more laboratory-specific implementation plans for
selected areas of research. This plan has been used and
will continue to be used to guide the development of
solicitations under EPA's extramural grants program as
well as other interested parties.
1. Arsenic Risk Assessment/
Characterization
'1.1. Background
The research plan is broadly organized according to a
modified risk assessment/ risk management paradigm in
which the risk characterization serves to formulate the
critical questions, identifies uncertainties and research
needs and provides a bridge from the scientific data to risk
management options. The Risk Assessment/Character-
ization Chapter is intended to provide a broad perspective
on the scope and nature of the problem. It provides a
discussion of the current risk assessments for ingested
inorganic arsenic. This discussion also describes the
strengths and uncertainties and identifies data gaps sur-
rounding these assessments. Secondly, this chapter out-
lines research opportunities that can improve the scientific
basis for refining the current risk estimate and its sources.
The research projects to address data gaps are discussed
in the subsequent chapters on Exposure, Health Effects
and Risk Management Research/Thirdly, this chapter
discusses the ongoing and future risk assessment re-
search, models, and assessments that should be devel-
oped in order to fully understand the risks associated with
ingestion of arsenic and support refinement of existing
regulations.
1.2. Characterization of Arsenic Risks:
State of the Science
This section reviews the risk assessment foundations of
the current regulatory standards for arsenic in water and
discusses the strengths and uncertainties in the interpretation
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of our current knowledge about arsenic exposures, health
effects, and risks. It also summarizes the approaches used to
develop existing exposure and health risk assessments to
support existing regulations and guidance under the Safe
Drinking Water Act (SDWA), Clean Water Act (CWA), Com-
prehensive Environmental Response, Compensation and
Liability Act (CERCLA) and Resource Conservation and
Recovery Act (RCRA). The overarching risk assessment
issue is determination of the risk associated with levels of
arsenic to which people in the United States are exposed in
drinking water. The evaluation of these risks includes consid-
eration of the following issues:
Regulatory levels for arsenic in drinking water and ambi-
ent water;
• Data on levels of human exposure to arsenic through
drinking water and other major pathways;
Exposure levels at which adverse effects are observed
and the closeness of those levels to levels found in U.S.
drinking water;
• An understanding of the variety of cancer and noncancer
effects induced by arsenic;
• Supporting biological and mechanistic data that may aid
in understanding arsenic risks; and
• Quantitative risk estimates and their strengths and uncer-
tainties.
1.2.1. Current Exposure Data.
1.2.1.1. Arsenic in Drinking Water — Presently,
water utilities are only required to report arsenic concentra-
tions that exceed the MCL of 50 pg/L To develop a national
picture of arsenic exposures from public drinking water sup-
plies, data have been derived from four national surveys: 1)
Community Water Supply Survey, 2) Rural Water Survey, 3)
National Organics Monitoring Survey, and 4) National
Inorganics and Radionuclides Survey (U.S. EPA, 1983,1989,
1988). Detection limits ranged from 2-5 jog/L Arsenic was
detected in both groundwater and surface waters. Concentra-
tions ranged from 0-100 jjg/L However, there is uncertainty
associated with the analytical methods used for these mea-
surements and the analytical detection limits. In less-compre-
hensive surveys, results were more variable; for example,
concentrations ranging up to 393 jjg/L in Hidden Valley, CA,
have been reported. The Metropolitan Water District of South-
em California has estimated that about 2% of the U.S.
population is exposed to arsenic drinking water concentra-
tions exceeding 10 jig/L, about 5% is exposed to concentra-
tions above 5 jig/L, and about 15% is exposed to concentra-
tions above 2 ng/L (Davis et al., 1994). The U.S. EPA is
currently evaluating and analyzing new databases received
from states, public water utilities and associations and will
establish revised occurrence and exposure distributions be-
fore beginning to draft the MCL. Additional data from ORD's
National Human Exposure Assessment Survey will be avail-
able in early 1999.
1.2.1.2. Dietary Arsenic Exposures — Dietary
exposures are also of concern because diet may con-
tribute significantly to arsenic exposure. Since 1961, the
U.S. FDA has systematically collected and analyzed
food for arsenic as part of the Total Diet Study, also
known as the Market Basket Study. Most recent data
sets include food analyses conducted from April 1982 to
April 1988 and June 1988 to April 1990 (U.S. FDA,
1992). A total of 234 foods were analyzed for arsenic
content; foods were classified into one of 11 separate
categories and total dietary intake averaged for three
age groups (infant, toddler and adult). Using average
daily consumption rates for each food group, total ar-
senic intakes of 21.5, 27.6. and 52.6 |ig/day were esti-
mated for infants, toddlers, and adults respectively. These
data address total arsenic content of foods. Because
some common organic forms of arsenic are thought not
to present toxicity concerns, this data should not be
directly compared with drinking water intake information.
Using some limited data on inorganic arsenic in foods
(which can be more directly compared with water in-
take), Borum and Abernathy (1994) estimated that inor-
ganic arsenic comprises about 20-25% of total dietary
intake of arsenic.
1.2.2. Current Health Risk Estimates.
Arsenic has been recognized as a potent human toxi-
cant since ancient times, and reports of human cancers
associated with ingestion date to the last century. In
recent decades, arsenic has been found to be carcino-
genic by both ingestion and inhalation routes in multiple
epidemiological studies (U.S. EPA, 1980a, 1984, 1993;
Tseng, 1977; Tseng et ai., 1968). Indeed, arsenic is the
only known substance for which there is adequate evi-
dence of carcinogenic risk by both inhalation and inges-
tion routes of exposure. Arsenic is also the only carcino-
gen where exposure through drinking water has been
clearly demonstrated to cause human cancer. Thus U.S.
EPA has classified arsenic as a Group A carcinogen,
i.e., a known human carcinogen, based on the 1986
Cancer Assessment Guidelines. This designation is used
when there is sufficient evidence, generally from epide-
miologic studies, to support a causal association be-
tween exposure to an agent and cancer in humans.
1.2.2.1. Foundations of the Current Arsenic
Regulations in Water — As discussed previously, the
regulatory and guidance levels under the SDWA and
CWA vary widely. In 1975, EPA adopted 50 n.g/L as a
maximum contaminant level (MCL) for arsenic in drink-
ing water under the SDWA. This level was developed by
the Public Health Service in 1942 based on the acute or
short-term toxicity associated with consuming high lev-
els of arsenic (U.S. EPA, 1995). The arsenic MCL is not
supported by a health-based risk assessment; rather it
was adopted from the U.S. PHS standard with the
consideration of water intake of arsenic relative to total
intake of arsenic from food. Using the information that
was available then (dietary arsenic was estimated to
average 900 |ig/day), a consumption of 2 L/day of
drinking water containing 50 fig/L was estimated to
contribute -10% of the total ingested arsenic (U.S. EPA,
1975). Controlling water intake to less than 10% of the
total intake was considered public health protective. As
discussed above, more recent FDA data indicate much
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lower dietary arsenic intake than was assumed in this
calculation.
More recently, a water quality criterion (WQC) of 0.018
ng/L for arsenic was established to protect humans
consuming arsenic-contaminated water and 6.5 g of fish
and shellfish/day under the CWA (U.S. EPA, 1980a,
1989, 1992). The WQC was calculated based on the
recommendations and findings from U.S. EPA Risk
Assessment Forum Technical Panel (1988) and the
Ambient Water Quality Criteria Methodology (U.S. EPA,
1980b). It represents an intake associated with an upper
bound incremental cancer risk of on-in-a-million. The
WQC reflects the dose-response data for skin cancer
from the Taiwan study (Tseng, 1977; Tseng et al.,
1968), use of age-specific prevalence rates for dose,
and a linear-quadratic dose-response model to estimate
lifetime risk of cancer. The use of a one-in-a-million risk
level represents an EPA policy decision.
1.2.2.2 Weight of Evidence Discussion of the
Cancer Data— EPA has identified arsenic as a group A
"known" human carcinogen (U.S. EPA, 1993, 1998)
Other organizations such as the International Agency for
Research on Cancer (IARC) have also classified arsenic
as a human carcinogen (IARC, 1987). This classification
is based on sufficient evidence of carcinogenicity from
human data involving occupational and drinking water
exposures. This Tseng et a!. (1968) epidemiological
study in Taiwan has played a central role in the current
EPA and IARG cancer assessments. The Tseng et al.
(1968) Taiwan study evaluated a large population (over
40,000), in comparison to other studies. Each partici-
pant was evaluated by a physician to identify skin le-
sions. Pathology was conducted on tissues collected
from a affected individuals. Older individuals were deter-
mined to have had long-term exposure, and there was a
large control population for comparison. The population
studied was characterized by age and covered a full
range. Drinking water arsenic levels in the population
studied by Tseng et al. (1968) were classified into three
concentration strata 0-290 ^g/L, 300-600 fxg/L, and 600
ng/L over) and showed a clear dose-response, relation-
ship with elevated skin tumor prevalence rates in all
three strata. Skin tumor prevalence rates were elevated
in both males and females, with the males showing a
larger increase. With regard to the U.S. regulatory con-
cern with drinking water, the Tseng et al- (1968) study
provide data on risks for levels much closer to those of
regulatory concern. In the Risk Forum report, an estima-
tion of skin cancer in a Mexican population exposed to
arsenic was consistent with the results observed in the
Taiwan study and supported the credibility of the risk
estimates based on the Taiwanese data (Cebrian et al.,
1983).
The EPA Risk Assessment Forum report upon which
EPA's current risk assessment is based was prepared by
a Technical Panel convened in 1986 (U.S. EPA, 1988).
The purpose of the panel was to address issues relating
to the qualitative and quantitative carcinogenic risk as-
sessment for ingested arsenic. In particular, the panel
examined issues relating to the validity of the Taiwan
study and its application to U.S. populations, use of
arsenic-induced skin lesions and the role of arsenic in
human nutritional status (i.e., essentiality). The panel
also evaluated information on genotoxicity, metabolism,
body burden, tissue distribution, and the possibility for a
cancer threshold. With regard to the Taiwan data, the
panel evaluated validity of the study and applicability of
the dose-response assessment to the U.S. population,
the interpretation and use of arsenic-associated skin
lesions, and the role of arsenic in human nutrition. The
panel concluded that: 1) the epidemiologic studies dem-
onstrated that arsenic was a human carcinogen by the
oral route; 2) the Taiwan studies provided a reasonable
basis for quantifying the risks of skin cancers associated
with the ingestion of inorganic arsenic in U.S. popula-
tion; 3) an estimated unit risk range for water is 3-7x10'5/
ng/L; 4) the slope of the dose-response curve at doses
below the range of observation may be less than linear,
therefore the calculated unit risk could overestimate the
true risks3; and 5) arsenic may be a possible but not
proven nutritional requirement in humans. Based on the
peer-reviewed findings of this panel, the Risk Assess-
ment Council recommended and EPA adopted the group
A classification for ingested inorganic arsenic with a
potency estimate of 0.0015/jo.g/kg/day and a unit risk for
water of 5x10-5/ng/L
There continues to be debate among the scientific com-
munity on the shape of the dose-response curve at low
doses. Scientific information has been developed that
supports both linear, i.e., shallow slopes at very low
doses, and nonlinear responses. ORD is working through
its own research program and in cooperation with the
grants program to gather more information relevant to
the dose-response assessment. To further address this
issue, on May 21 and 22, 1997, EPA convened an
expert panel and workshop to evaluate the body of
available data regarding arsenic's mode of action and
recommend whether data are sufficient to support a
linear versus nonlinear response. The charge to the
panel was: 1) examine the data on the .direct and indi-
rect effects of arsenic and its metabolites on DNA, DNA
repair, DNA methylation and regulation, mutagenesis
and carcinogenicity; 2) comment on possible mecha-
nisms and modes of action, including whether there is
clear evidence for a mode of action; 3) comment on the
confidence level for any one particular mode of action
and 4) provide guidance on the weight of evidence
supporting the use of linear or nonlinear responses in
extrapolating to low-dose arsenic exposures. The panel
concluded that more than one mode of action for arsenic
may be operating at different dose levels or even at the
same dose level. It also stated that although there does
not appear to be any direct interaction of arsenic with
DNA, this does not rule out a linear dose-response
relationship at lower doses. The panel concluded that
the modes of action they considered would lead to
nonlinear responses for cancer. However, the panel
'Additionally, at should by noted that a Maximum Liklihood Estimate (MLE)
rather than upper bound linear quadratic model was fit to the Taiwan data: thus
there was also potential for underestimation of the true low-dose slope.
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also observed that at very low doses the curve might
effectively be linear. The panel stated that the low-dose
linear component of response would likely be very
shallow. However, data to allow an evaluation of the low
dose-response were not identified because the mode of
action for arsenic is still uncertain and an area of
needed research. It should be noted that in using the
term "linear models", EPA has focused on the low-dose
region and what is more precisely described as "models
that are linear at low doses". As discussed, EPA has
shared the findings of this panel with National Academy
of Science (NAS) for consideration in its risk assess-
ment of arsenic.
As can be anticipated with a large and complex epide-
miological study, a number of specific issues have
arisen concerning the evaluation and interpretation of
the Tseng et al. (1968) study. Several of these issues
have been identified as areas of uncertainty and further
research to improve the risk characterization of arsenic.
Water concentration estimates in the Tseng study were
made at the village, rather than the individual level.
Grouped measurements are commonly employed in
epidemiological studies (for example, use of area con-
centration rather than personal measurements in many
occupational studies). However, arsenic concentrations
in individual wells varied within villages; person-specific
concentration data, were they available, might have
allowed increased resolution of dose-response patterns.
Similarly, well concentrations exhibited temporal vari-
ability, and a larger number of measurements per well,
using an improved analytical method that can reliably
measure low concentration (i.e., <50 ja.g/L), would have
increased the precision of exposure estimates.
The potential for concomitant exposures to other con-
taminants in the Taiwan drinking water study has also
received attention. The arsenical water in Taiwan also
contained humic substances. It has been speculated
that these substances may be carcinogenic. However,
humic substances are found in water supplies in many
areas of Taiwan without observed elevations of cancer
rates, and the data for Taiwan show that cancer preva-
lence was correlated with arsenic concentrations in well
water.
In a nutritional study, Yang and Blackwell (1961) sug-
gested that the Taiwanese diet in the endemic Blackfoot
area was deficient in methionine and fat. However, a
recent reexamination of these data by Engel and
Recevuer (1993) reported that the Taiwanese intakes
for protein and methionine were within the now-current
recommended levels. It has been suggested that indi-
viduals with low intake of methionine may be less able
to methylate arsenic and are potentially at higher risks
of cancer.4 However, diets low in animal fat are widely
recommended as a preventative measure to reduce
cancer risks. This suggests that the risks observed in the
Taiwanese population (including internal cancer mortality
reported in later studies) might have been higher if they
consumed a more typically western diet. There also exists
uncertainty regarding the contribution of arsenic in food to
total arsenic intake for individuals in the arsenic endemic
areas.
The U.S. and Taiwanese populations differ in genetic
characteristics, diet, and exposures to other environmen-
tal chemicals. Therefore, there is some uncertainty in the
quantitative extrapolation of arsenic risks from one popu-
lation to the other. However, for perspective, these uncer-
tainties need to be compared with the greater degree of
uncertainty involved when experimental animal results are
applied to estimate human risks.
At the time of the 1988 Risk Forum report, the available
data addressed primarily skin tumors resulting from the
ingestion of arsenic. While some data on the relationship
between arsenic and internal cancers were available in
1988, that data had not been fully assimilated into Agency
risk assessment or management discussions. The fact
that arsenic skin cancers are usually nonfatal led to Agency
discussions of whether cancer risk estimates for arsenic
should be managed less stringently. However, further
data on arsenic carcinogenesis at internal organ sites has
become available in the intervening years.
More recent studies in the same area of Taiwan have
reported a strong association between arsenic ingestion
and increased mortality and incidence of internal cancers
including cancers of the liver, bladder, kidney, colon, and
lung (Chen et al., 1986). Chen et al. (1986) calculated
standardized mortality ratios (SMRs) for each of these
cancers. The authors found the SMR for cancers of the
liver, lung, colon, bladder and kidney to be significantly
elevated (p<0.05). A recent study in Argentina (Hopenhayn-
Rich et al., 1996) has provided evidence that arsenic
exposures in drinking water are associated with bladder
cancer in a population that is very different from that
studied in Taiwan. The contrast between the Argentine
and Taiwanese studies in terms of ethnic background,
dietary patterns, and potential for other constituents to be
present in drinking water also serves in resolving concerns
that some special characteristics of the Taiwan population
or environment might have been responsible for the find-
ings in the Tseng et al. (1968) study. Specifically,
Hopenhayn-Rich et al. (1996) observed elevated rates of
bladder cancer in an arsenic exposed population that
consumed large amounts of animal protein and where
humic substances were not identified in the water. Studies
in England (Cuzik et al., 1992) and Japan (Tsuda et al.,
1990) also contribute to the weight of evidence that in-
gested arsenic causes bladder cancer. Studies conducted
in the United States have not demonstrated an associa-
tion between arsenic in drinking water and skin or internal
cancers. While there was no demonstrated elevated can-
cer incidence in some limited U.S. populations, the popu-
lation sizes were too small and/or exposure times too
short to expect to detect an effect.
4Hsueh et al. (1995) also found for individuals in the arsenic endemic area an
association with high consumption of sweet potatoes with chronic carriers of
hepatitis B surface antigen liver disfunction and an increased risk of skin cancer.
The relevance of these findings for arsenic risk assessment is not clear.
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While there are a number of relevant issues that warrant
consideration regarding quantitative extrapolation of the
Taiwanese findings, there are also considerable strengths
that provide validity to the data. As noted in U.S. EPA
(1988), the study and comparison group were large enough
to provide reliable estimates of skin cancer prevalence
rates. The skin cancer risks were statistically, significantly
increased many years after the initial exposures in the
exposed group versus the comparison group. These in-
creases were dose-related. The exposed and comparison
groups were matched by occupation and socioeconomic
status. Finally, the observed skin cancer were confirmed
by clinical pathology in over 70% of the reported cases.
1.2.2.3. Noncancer Assessment — In addition to
the cancer effects observed in epidemiologic studies, arsenic
exposures have also been reported to result in adverse
noncancer health effects in humans. These effects include
skin lesions such as hyperpigmentation and hyperkeratosis
and cardiovascular effects. A risk assessment for noncancer
effects associated with exposures to inorganic arsenic has
been developed using data from the Tseng (1977) study
considering the drinking water and potential dietary arsenic
intake for that population. An oral RfD of 0.3 pg/kg for
inorganic arsenic was developed based on the absence of
hyperpigmentation, keratosis or documented vascular com-
plications in the study control group (U.S. EPA, 1997). The
RfD was based on a no-observable-adverse-effect level
(NOAEL) of 0.8 (og/kg-day that included intakes of 9 |og/l_ of
arsenic in water and 2 ng/day in food. The RfD was calculated
using the NOAEL of 0.8 pg/kg-day and applying an uncer-
tainty factor of 3 and medium confidence. This confidence
ranking reflected a weakness in the data regarding actual
exposure levels from water. Agency risk assessors identified
a range of values as candidates for the RfD, depending on the
particular assumptions made about arsenic exposures in the
study group where adverse effects were not observed and
with different potential choices of a data base uncertainty
factor. There was not a consensus among workgroup scien-
tists on a single value for an RfD. The EPA Risk Assessment
Council selected a RfD of 0.3 jjg/kg/day for total inorganic
intake and concluded that strong scientific arguments could
be made for various values within a factor of 2 or 3 of the
recommended RfD value, i.e., 0.1 to 0.8 jog/kg/day. If expo-
sures were solely from water, this would amount to 28 pg/day
for adults (or 14.0 jjg/L, assuming consumption of 2 Uday).
The discussion on dietary exposures above in Section 1.2
suggests that background dietary exposures are already 50-
100% of that value.
The risk assessments for arsenic that are discussed above
have been peer reviewed, adopted by the Agency, and
appear as Agency consensus opinions on IRIS (U.S. EPA,
1997).
1.2.2.4. Metabolic and Mechanistic Data — Cur-
rent Contribution to Risk Assessment — In recent years,
research has provided significant information about the bio-
logical effects of arsenic, including its genotoxicity (chromo-
somal and DNA changes) and metabolism. The "state of the
science" of our current understanding of arsenic mechanisms
is addressed in some detail in Chapter 3. Our understanding
of the mechanism of action of arsenic carcinogenesis (and
other toxicity) is very limited. See the discussion of the expert
panel report regarding mode of action in Section 1.2.2.2. The
recommendations from this workshop are expected to help
shape future research directions.
Some scientists, including a panel of the EPA SAB, have
focused on evidence for dose-dependent methylation as
potentially supporting changes in the dose-response model-
ing for arsenic or suggesting that "apparent thresholds" exist.
Currently, our understanding of the role that methylation plays
in the induction of toxicity is limited; methylation may either
reduce or potentiate toxicity. Data indicate that substantial
quantities of both inorganic and methylated arsenic are ex-
creted in urine at both high- and low-exposure levels. This
observation suggests that potential dose dependencies in
metabolism may not be of a magnitude to support major
revisions to the arsenic risk estimate. Further research is
being conducted to determine if the toxicity of arsenic at low
doses is reduced or potentiated.
Further research into the mechanisms of arsenic toxicity may
make important contributions to arsenic risk assessment, as
suggested by EPA's recently proposed cancer risk assess-
ment guidelines (U.S. EPA, 1996d). Mechanistic information
has application in both hazard identification and understand-
ing dose-response relationships, potentially reducing the reli-
ance on the use of default assumptions. However, the current
U.S. standard for drinking water is within an order of magni-
tude of concentrations at which cancers and other health
effects have been seen in epidemiological studies. The close-
ness of arsenic "effect levels" and levels of regulatory concern
limits, untilfurther data are available, the potential changes in
current regulatory and treatment options resulting from slight
alterations in risk estimates. Data identifying nonlinear effects
in fundamental biological processes will provide additional
information on the range of arsenic risks. Such an assess-
ment must take into account the expected diversity of human
responses to arsenic and the substantial "background" dietary
exposures to arsenic. These factors suggest that mechanistic
findings may support refinements to the arsenic risk charac-
terization within the range of current regulatory concern.
1.3. What are the Research
Opportunities to Improve/Refine
Current Risk Assessments?
This section identifies and briefly discusses the research
opportunities associated with improving the existing risk
and exposure assessments and potential significance in
refining the current assessment. The information is orga-
nized by key research questions that relate to the uncer-
tainties in the risk assessments previously described.
Research has been delineated as being either short-term
or long-term research. In general, higher priority has
been given to research that has the potential to be
completed by 2000. While there seems to be general
recognition that substantial changes (order of magni-
tude or greater) to the fundamental health risks assess-
ment for arsenic are not to be expected for the proposal
in 2000, useful short-term research has been identified
on arsenic health effects, and exposure and treatment
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technology. It is anticipated that this short-term re-
search could lend additional support for arsenic expo-
sure and risk assessment currently being undertaken
and would impact treatment options and risk policy
decisions especially for small systems. In addition, long-
term studies have been identified and initiated to de-
velop data for future risk assessments. This section
identifies key research opportunities in order to set the
direction for both the short-term and long-term research
that is discussed in the following chapters on Exposure,
Health Effects and Risk Management Research.
1.3.1. Exposure Assessment.
Most available data on arsenic address total arsenic
concentrations and do not distinguish between arsenic
valence states or inorganic versus organic forms of
arsenic (U.S. FDA, 1982, 1990, 1992). In a number of
the research efforts discussed in this plan, it is impor-
tant to distinguish between different chemical forms of
arsenic, that is to "speciate" arsenic during chemical
analysis. This is important for assessing risks because
the arsenic species can influence the dose-response
and exposure assessments. The importance of data on
the chemical form of arsenic depends on the environ-
mental media being addressed and the intended appli-
cation of the data. Arsenic present in water is primarily
in the form of inorganic arsenic (III and V); arsenic (111) is
oxidized during water treatment to arsenic (V). In this
research strategy, distinguishing between the inorganic
forms of arsenic in water is not considered to be impor-
tant for assessing arsenic risks, but can be important for
treatment removal. However, a particular concern is the
need to distinguish between inorganic and organic ar-
senic forms in assessment of dietary exposure. To be
comparable with data on drinking water (which contains
inorganic arsenic), dietary assessments need to mea-
sure levels of inorganic arsenic present in food, and
differentiate them from organic arsenic. Food and water
are thought to be the main contributors to arsenic
exposures; dermal exposures from soil and water and
inhalation exposures are believed to be minor contribu-
tors to arsenic exposure (ATSDR, 1993; Borum and
Abernathy, 1994).
More recently, concern has been raised regarding some
specific forms of organic arsenic (i.e., mono- and di-methyl
forms) found in some foods (ATSDR, 1993) and for which
toxicity issues may exist. Pharmacokinetic research also
requires data to distinguish between the organic and
inorganic forms of arsenic found in biological samples.
The strategy for exposure assessment research includes
improving methods for the reliable speciation of arsenic. A
primary challenge of this research is the reliable extraction
of arsenic compounds from complex dietary and biological
samples in order to adequately assess intake and tissue
levels.
Research Opportunities:
Arsenic speciation: Improvements in analytical meth-
ods for arsenic, particularly for food and biological
materials. A primary concern is distinguishing be-
tween inorganic and organic arsenic, with specific
organic forms of arsenic also warranting attention
(short-term). Significance for risk assessment: Im-
prove exposure assessment, improve dose-response
assessment, improve risk characterization and aid
in design and conduct of future epidemiologic stud-
ies.
Measurement of background exposures to arsenic
in U.S. population (general population and suscep-
tible population), particularly addressing inorganic
arsenic intake in the U.S. diet. This research should
address both the cumulative intake of arsenic and
its bioavailability (long-term). Significance for risk
assessment: Provide information for interpreting to-
tal risks due to arsenic exposure and the contribu-
tion that arsenic in drinking water makes to the total
risks.
Development and evaluation of biomarkers of expo-
sures (long-term). Significance for risk assessment:
In the assessment of levels of human exposures
and contribution to the assessment of arsenic
bioavailability.
1.3.2. Cancer Assessments.
Although epidemiologic studies have clearly shown a
causal relationship for increased cancer risks in individu-
als having exposures to arsenic in drinking water, there are a
number of areas where further empirical data could broaden
and strengthen our ability to assess arsenic risks.
Research Opportunities:
Further development of data on the several types of
internal cancers that have been associated with ar-
senic exposures (long-term). Significance for risk as-
sessment: Aid in hazard identification and dose-re-
sponse assessment.
Dose-response data on hyperkeratosis as a likely
precursor to skin cancer, which, due to a higher rate of
incidence among arsenic-exposed individuals, can be
studied at lower exposure levels (long-term). Signifi-
cance for risk assessment: Biomarker of effect, define
dose-response at lower doses, provide insight into
mechanisms of toxicity.
Research on factors influencing human susceptibil-
ity including age, genetic characteristics and dietary
pat-terns (long-term). Significance for risk assess-
ment: Provide information on susceptible popula-
tions.
Metabolic and pharmacokinetic studies that can iden-
tify the presence of dose dependent metabolism and
aid in the evaluation of mechanistic data.
Mechanistic studies for arsenic-induced genotoxicity
and carcinogenicity (for example, induction of genetic
damage and tumor promotion in some experimental
systems) (long-term). Significance for risk assess-
10
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ment: Mechanistic data, if reliably linked to human
carcinogenesis by arsenic, can provide insight into
susceptibility and dose-response.
Laboratory model systems to test dose-response as-
sumptions for cancer.
1.3.3. Noncancer Assessment.
Several epidemiologic studies have observed that arsenic
exposures result in adverse effects in addition to cancer.
Clear associations were observed for hyperkeratosis, hy-
perpigmentation, peripheral vascular effects, and a study
with a U.S. population reported neurological effects. Other
potential effects such as gastrointestinal and liver effects
and diabetes have not been clearly defined. Additional
studies can better define the potential risks associated
with these health effects. In addition, studies can address
the influence of other factors on arsenic toxicity.
Research Opportunities:
Development of human dose-response data for hy-
perkeratosis, cardiovascular disease, neurotoxicity,
and developmental effects (long-term). Significance
for risk assessment: Provide data for dose-response
assessment.
Development of additional health effects and hazard
identification data on other noncancer endpoints such
as diabetes and hematologic effects (long-term). Sig-
nificance for risk assessment: Provide data for hazard
identification and assessment.
1.3.4. Risk Management Research.
Further development of treatment options for the removal of
arsenic from drinking water will contribute to informed deci-
sion making and can support the development of regulatory
standards that are protective of public health. Uncertainty
exists as to effectiveness and costs of control technologies for
removal of arsenic to levels being considered. Of particular
concern is the development of cost-effective treatment op-
tions for small systems. Also of high concern for both large
and small systems is the increase in costs of residual man-
agement that is likely to result from more stringent residual
disposal requirements triggered by the lowering of the arsenic
MCL.
Research Opportunities:
Identification of limitations of treatment technologies
and impacts on water quality
Development of treatment technologies for small
water systems
Development of data on cost and performance ca-
pabilities of various treatment options
Consideration of residuals management issues, in-
cluding disposal options and costs (short-term).
Significance of risk management research: Improve
controls for implementation of standards, provide
cost-benefit information
1.3.5. Research Needs.
Exposure Analysis
Short-Term Research:
Speciation methods for separation of arsenite from
arsenate to support water treatment decisions in
large and small utilities
Refined and evaluated analytical approaches for the
speciation of arsenic in urine
Extraction methods for inorganic and organic ar-
senicals for separation and detection of individual
arsenic species in foods '
National database on arsenic occurrence and con-
centrations in water constituents
Long-Term Research:
Exposure studies of populations with high dietary
intake of foods associated with toxic species of
arsenic
Biomarkers of exposure in biological media and
bioavailability of arsenic
Speciation methods for biological matrices to support
exposure analysis, bioavailability and biomarker re-
search '
Liquid and solid species specific standard reference
material for arsenic in water, foods, urine, and tissues
Health Effects
Short-Term Research:
Feasibility study on various endpoints associated with
arsenic exposure
Directed epidemiologic research on the health effects
associated with arsenic exposures
Long-Term Research:
Factors influencing human susceptibility including
age, genetic characteristics and dietary patterns
Metabolic and pharmacokinetic studies and other
laboratory model systems
Mechanistic studies for arsenic-induced genotoxicity
and carcinogenicity and other adverse effects
Health endpoints in animals
Biomarkers of effects
Full-scale epidemiologic studies
11
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Risk Management
Short-Term Research:
Laboratory and field testing on different arsenic con-
trol technologies
• Cost evaluations of arsenic control technologies for
small systems
Arsenic control residual management
Long-Term Research:
• Treatment modifications to reduce residuals and re-
sidual disposal options to meet more stringent re-
sidual disposal requirements
Risk Assessment
Short-Term Research:
Risk characterization guidance for States and local
communities
Assessment of arsenic mode of action for under-
standing biological mechanisms and future research
needs
• NAS reassessment of arsenic data
Long-Term Research:
Predictive tools and statistical models for assessing
bioavailability, interactions, and dose-response
Assessment of exposure levels and incorporation of
data into risk estimates
• Assessment of noncancer risks and appropriate
modeling tools for quantitative estimation of
noncancer risks
1.4. Risk Characterization Research:
Health and Exposure
As noted above, there are several strengths, issues, and
uncertainties associated with the arsenic database and
current risk assessments. In particular, issues exist with
the interpretation of human studies, shape of the dose-
response at doses below the range of observed effects,
toxicity of specific arsenic species, and extrapolation of dose
to arsenic exposures in food and water of U.S. populations.
Concern also exists regarding the level of protection associ-
ated with the drinking water MCL of 50 nQ/L which was
developed from presumed high exposure to "total" arsenic in
the 1940s.
This section discusses the research issues and activities that
address improving the current health and exposures assess-
ments and risk estimates. In addition, it describes research
projects in the areas of risk assessment methods and model
development that are either ongoing or needed to address
data gaps in developing or refining current risk assessments
for arsenic (i.e., risk estimates). It also identifies projects that
are needed to better characterize the risk associated with
exposures to arsenic (i.e., integration of health and exposure
data).
This section and the following section will cover only risk
assessment research, since more discussion of exposure,
health effects, and risk management research will be ad-
dressed in Chapters 2,3 and 4, respectively.
1.4.1. Risk Assessment/Characterization.
The risk assessment/characterization consists of a compre-
hensive evaluation and integration of the health effects (can-
cer and noncancer) induced by arsenic; the evaluation of
dose-response data, including the development of quantita-
tive risk estimates; and the identification of strengths and
uncertainties. This process considers both direct data on
arsenic toxicity as well as supporting biological and mechanis-
tic data. The preceding discussion has highlighted a number
of issues and research questions that can be addressed to
better refine and strengthen risk estimates. Risk assessment
methods should address the integration of newer scientific
information and data for risk assessment and risk character-
ization. Agency risk characterization guidance stresses the
need for analyses to address central and high-end estimates
of individual risk as well as population risks. Better character-
ization of exposures, including identification of populations
with high exposures will contribute to informed decision mak-
ing for arsenic risks. EPA is also faced with the dilemma of
providing guidance to State and local communities on the
health risk associated with exposures to arsenic from drinking
water while the regulation is in a stage of transition.
Refinement of the quantitative risk assessment is intended to
provide a clarification of the dose-response and biological
relationship for arsenic induced skin cancers and the develop-
ment of risk assessment tools for interpreting the dose-
response relationship in humans. Data exist on internal can-
cers from several published studies, in addition a number of
epidemiologic studies have been initiated to further investi-
gate the risks for internal cancers. Dose-response assess-
ments for internal cancers are needed. These assessments
would aid in defining the magnitude of risks from internal
cancers and serve as the basis for comparison to skin cancer
risks.
In addition to dose-response assessments, exposure assess-
ments are required to evaluate the relative magnitude of
population exposed to arsenic from diet and water. Previous
dietary estimates assumed a balanced diet and average
nutritional status and did not take into account ethnic, cultural,
or economic impacts on food consumption patterns. Im-
proved exposure assessment of background rates will allow
for the better risk characterization and comparative risks.
Research Opportunities to Strengthen Risk
Assessment:
Development of risk characterizations to provide
support to decision making and assist Regions,
States and local communities on health risks associ-
12
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ated with the exposures to arsenic contaminated drinking
water (short-term). Significance to risk assessment: Pro-
vide guidance to risk managers and regulators on risk
levels.
An assessment and analysis of existing and new data on
risks of internal cancers, including consideration of quan-
titative dose-response models (long-term). Significance
to risk assessment: Provide basis for refining risk esti-
mates.
Development of predictive tools and statistical models for
assessing bioavailability, interactions, and dose-response
as better mass balance data become available (long-
term). Significance to risk assessment: Provide basis for
refining dose-response estimates.
Assessment of exposure levels and incorporation of data
into risk estimates for better characterization of actual
risks associated with arsenic exposure (long-term). Sig-
nificance to risk assessment: Improve exposure assess-
ment and risk characterization.
Assessment of current information on arsenic mode of
action (short-term). Significance to risk assessment: Pro-
vide a greater understanding of biological mechanisms
and factors that may impact the shape of dose-response
curve. Significance to risk assessment: Consideration of
implications of these factors for risk assessment in hu-
man populations, provide insight for dose-response as-
sessment.
Assessment of noncancer risks and consideration of
appropriate models for quantitative estimation of
noncancer risks (long-term). Significance to risk assess-
ment: Aid in dose-response assessment.
• Assessment of existing information on arsenic interac-
tions with other metals to predict if response is additive or
departures (i.e. synergism, antagonism) from additivity
can be estimated (long-term). Significance to risk assess-
ment: Aid in dose-response assessment, mechanism of
action and refinement of risk characterization.
1.4.2. Ongoing Activities.
EPA is in the process of reevaluating the risk assess-
ments for arsenic as part of IRIS Pilot Program. This
reevaluation will cover both cancer and noncancer risks,
will include data not previously reviewed and will include
application of proposed revisions to the Agency's Can-
cer Risk Guidelines. As part of this reassessment, the
Agency has conducted a Workshop on biological mecha-
nisms for arsenic-induced carcinogenicity and implica-
tions for extrapolating below the observed dose-response
range.
1.5. Proposed Risk Assessment
Research and Risk Assessment
Risk Assessment Issue 1. Risk assessment and risk char-
acterization for arsenic — short-term efforts
1a. Workshop on Mode of Action for Arsenic
The workshop held May 21-22, 1997, examined current
information on the mechanisms by which arsenic induces
carcinogenicity and discussed implications for dose-response
assessment. The results from this workshop, a joint effort of
OW and ORD, can contribute to a further definition of re-
search needs in the area of mechanistic studies and provide
input to be addressed in arsenic risk characterization.
High priority; intramural and extramural. Completed.
1 b. Synthesis of Data to Support Arsenic Risk Ass-
essment and Risk Characterization
EPA's Health assessment documents for arsenic are based
on data available in the late 1980s. The current dose-re-
sponse estimate for arsenic is based on human data from the
Taiwan study. Low-dose risk estimates were developed by
applying age-specific prevalence rates for dose and a linear-
quadratic dose-response model to estimate lifetime risk of
cancer. Since the completion of the EPA assessment, addi-
tional studies addressing arsenic risks have become avail-
able. Additionally, EPA has received a report from an expert
panel addressing arsenic mechanisms and expects to re-
ceive a report from the National Research Council on issues
in arsenic risk assessment. This effort will synthesize newer
information relevant to arsenic risks in a form that will support
Agency management decisions for arsenic. Several studies
have been published that indicate arsenic exposures induce
internal cancers. These findings will be examined and quanti-
tative information on rates of occurrence of internal neo-
plasms will be evaluated in relationship to the current risk
estimate for skin cancer.
Based on information currently available data and assess-
ments (including the IRIS summary and the mechanisms
workshop report), ORD will work with OW to develop risk
information to assist OW, the Regions, States, and local
communities in dealing with arsenic-contaminated drinking
1 water and permitting issues. The focus of this effort will be
information to assist in the evaluation of risks from arsenic
concentrations in the 2-50 jig/L range of regulatory interest.
High priority; intramural and extramural.
1 c. Assessment of Exposure Data
This effort will focus on the development of a risk assessment
of existing exposure data to investigate background expo-
sures and speciation, and will examine relationships between
intake/blood/urine levels. This information will also be inte-
grated with hazard and dose-response information to address
integrated risks from arsenic exposures. The goal is to provide
a range of risk estimates for various exposed populations and
compare relationships for adult and child levels and media,
i.e., diet and water. Data from an ongoing EPA cooperative
study with Harvard will be analyzed, as well as data from
exposure databases such as NHEXAS and NHANES 3. A
risk characterization summary will be developed for use in
risk characterization for drinking water exposures. This
research links with exposure task 5a.
High priority; intramural and extramural.
13
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Risk Assessment Issue 2. Innovative approaches in
arsenic risk assessment —Long-term
2a. Evaluation, integration, and modeling of new
data on arsenic health effects and mechanisms
The goal of this effort is to integrate future data on arsenic
epidemiology and mechanistic research into the hazard
and dose-response assessment for arsenic. As appropri-
ate, this effort would include evaluation of the feasibility
and development of new risk models. Revised health
effects evaluations and decisions regarding model devel-
opment would build upon additional studies addressing
arsenic effects, metabolic rate, tissue dosimetry, and/or
arsenic mechanisms. Research directions for human or
animal studies are described in the Health Effects chapter.
This research is medium priority pending development of
new Information and therefore will be given a higher
priority in out years.
Medium priority; intramural.
2b. Development of Predictive Risk Assessment
Models and Tools for Assessing Arsenic Inter-
actions
There are several studies suggesting a strong interrela-
tionship between arsenic and various trace minerals and
essential elements. These studies indicate that arsenic
interacts~with these elements both environmentally and
biologically. Interactions with selenium and zinc have
shown a reduction in arsenic-induced toxicity, while inter-
actions with lead and cadmium may increase toxicity. The
goal of these studies would be synthesize data on interac-
tions and, where feasible, develop predictive models to
assess the potential interactions of arsenic with other
elements in drinking water. This project would address
mechanistic issues regarding arsenic interactions, e.g.,
additivity of arsenic toxicity for noncancer toxic effects
based on the possible interactions. Information can con-
tribute to biologically-based risk assessment by taking into
account interactions of arsenic with trace minerals and
essential elements. Development of assessment depen-
dent on data feasibility.
Medium priority; intramural and extramural.
Specific projects and products relating to these issues and
their status, use and time frame are outlined in Tables 1-1
and 1-2.
2. Exposure to Arsenic Species: Analysis
Methods and Human Exposures
2.1. Background
Arsenic in surface and ground water originates from both
geological and anthropogenic sources. The geographic distri-
bution of arsenic in surface and ground waters in the United
States has been estimated (Frey and Edwards, 1997). Based
on a national survey of 140 utilities, representing 36% of the
U.S. population, it has been projected that -15% of the U.S.
population is exposed to arsenic in drinking water at levels
greater than 2 jig/L (ppb). These estimates drop to 5% and
2% for arsenic concentrations of 5 ng/L and 10 ng/L, respec-
tively (Davis et al., 1994). The reliability of this estimate at 2
pg/L is of some concern given the detection limits of the
analytical methods used and the variability associated with
analytical measurements near the detection limit. Much higher
levels in drinking water (i.e., in excess of 80 pg/L) have been
reported in isolated areas in the western United States. These
elevated concentrations are commonly, but not exclusively,
associated with ground waters (Frey and Edwards, 1997).
Arsenic in drinking water is predominately inorganic and is
comprised of arsenate (arsenic (V)) and arsenite (arsenic
(III)). These inorganic species can interconvert, depending on
the oxidative or reductive nature of the water. Inorganic
arsenic occurs in drinking water mainly in the form of arsen-
ate, although arsenite has been reported in waters that are
anaerobic or very low in dissolved oxygen (ATSDR, 1993). Air
levels of arsenic in the United States5 have a reported range
of average site concentrations of 0.01 to 0.45 jog/m3 (Borum
and Abernathy, 1994).
Arsenic is extremely mobile in the aquatic environment.
Naturally occurring and anthropogenic arsenic compounds
are assimilated into many foods with the highest concentra-
tions found in fish, shellfish, meats, and grains. Arsenic in the
environment is metabolized, resulting in a transformation
(biological methylation) of some of the arsenic to organic
forms (i.e. monomethylarsionic acid (MMA), dimethylarsinic
acid (DMA), arsenosugars, arsenobetaine and arsenocholine)
that are found in certain foods. This biotransformation can
influence the toxicity of the arsenic. For instance, marine fish
and shellfish are high in forms of arsenobetaine that are
considered to be essentially nontoxic (ATSDR, 1993). Using a
'total" arsenic content of foods to evaluate dietary exposure
(jog/day) is not an accurate risk indicator because of the
toxicity differences of the various arsenic species, which are
merely added together in a nonspeciated arsenic exposure
assessment. The arsenic species, in at least organic and
inorganic fractions, need to be determined to adequately
characterize risk.
Arsenic physiologically found in the form of arsenate is first
nonenzymatically reduced to arsenite and then undergoes
enzymatic methylation to MMA and DMA in the liver (Styblo et
al., 1996). Methylated metabolites, arsenate and arsenite
are primarily excreted in urine. The concentrations of
these metabolites in urine are generally accepted as the
most reliable and toxicologically relevant indicator of re-
cent or ongoing arsenic exposure. Arsenic in hair and
fingernails is considered a better indicator of past expo-
sure. Blood concentrations of arsenic species are also
relevant indicators of recent high-dose arsenic exposure,
are less susceptible to contamination during collection,
and provide greater likelihood of maintaining the arseni-
cals in their ingested forms.
Problems in quantifying environmental exposure contrib-
ute to uncertainties in the exposure-dose-response chain
in human epidemiologic studies and arsenic risk assess-
5Data from the Aerometric Information Retrieval System (AIRS) air monitor-
ing database of the EPA Office of Air Quality Planning and Standards
(OAQPS) for the years 1980-91; based on a reporting limit of 0.01 ng/m3,
arsenic was detected at 118 of 257 sampling sites.
14
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Table 1-1. Risk Assessment Research Strategy Matrix for Arsenic
Issue Task
Product
Use*
RA. Issue 1. Risk assessment
and risk characterization
of arsenic—Short-term
RA. Issue 2. Innovative
approaches in arsenic risk
assessment—Long term
RA Task 1 a. Mode of
action workshop
High Priority
RA Task 1 b. Synthesis
of data to support arsenic
risk assessment and risk
characterization
High Priority
RA Task 1 c. Assessment
of exposure data
High Priority
RA Task 2a. Evaluation,
integration and modeling of
new data on arsenic health
effects and mechanisms
Medium Priority
RA Task 2b. Development
of predictive risk assessment
models for arsenic
interactions
Medium Priority
Refinement of risk estimate
for arsenic, revise IRIS summary,
provide information for
mechanistic studies
Improved risk characterization
of arsenic assessment, revised
IRIS summary
Determination of existing
exposure information for
risk assessment
Assessment of new data,
refinement of risk estimates
and characterization
Improved risk characterization
and revised assessments
Development of MCL-OW,
States and local communities,
ORD, OSWER
Support for MCL-OW, OSWER,
DOE
Development of MCL-OW,
States and local communities,
ORD, OSWER
Research planning in ORD,
Regions, States
States and Regions, DOE,
OSWER development of
regulations and permits. May
impact future MCL
*OW = Office of Water; ORD = Office of Research and Development; OSWER = Office of Solid Waste and Emergency Response;
DOE = Department of Energy
Table 1-2. Risk Assessment Task Summary, Current Activities and Proposed Sequence for Studies
Task1 Ongoing Priority Time Frame2
Short Study Title
I
Y/N
Priority
FY97
FY98
FY99 FYOO
FY01
FY02
RATask 1a. Mode of
action workshop—
Short-term
I
RA Task 1 b. Synthesis of I
existing and new data—
Short-term
RA Task 1 c. Assessment I
of exposure data—
Long-term
RA Task 2a. Evaluation I
and integration and
modeling of new data—
Long-term
RA Task 2b. Development I
of predictive models for
interaction—Long-term
E Completed High
High
High
Medium
Medium
EPA
EPA EPA EPA
EPA EPA
EPA EPA
EPA EPA
EPA
EPA
1I = Intramural (EPA inhouse research), E = Extramural (EPA sponsorship through grant or coop)
2EPA = EPA has ongoing studies or plans'to address this task in future years; some tasks may require additional research beyond EPA's
planned effort
15
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ment. For example, measuring As species is basic to
improved exposure assessment in future epidemiologic
studies as well as for exposures studies to be used for the
exposure assessment portion of the risk assessment/
characterization. This chapter describes key exposure-
related issues and research needed to address arsenic
exposure and risk assessment. These research issues
include estimating species-specific arsenic exposure from
environmental media (water, soils, diet) and estimating the
bioavailability of arsenic species from various media in-
cluding biomarkers of exposure.
2.2. What Analytical Methods are
Needed for Determining Arsenic in
Exposure Assessment Media?
2.2.1. State of the Science.
The word total could be a point of confusion in the
following sections because total in an exposure study
often refers to the consideration of all possible exposure
routes. In an analysis context, as used below, the word
total refers to chemical analysis of the total arsenic content
in a sample. When discussing all possible exposure routes,
the term "multipathway" will be used. Speciation is another
word which can lead to confusion. Speciation is defined as
the separation, identification, and quantification of the
chemical forms of arsenic. This separation can be as
simple as inorganic arsenic from organic arsenic or as
complex as complete separation into individual arsenicals.
The appropriate degree of speciation is often dependent
on the application.
Analytical methodologies which are used for arsenic moni-
toring under the Safe Drinking Water Act, Clean Water
Act, and Resource Conservation and Recovery Act all
report "total" arsenic. 'Total" arsenic is defined as the
solubilized arsenic within the sample after a digestion with
hot mineral acids (U.S. EPA, 1971). The digestion oxi-
dizes the matrix (soil, food, biological), solubilizing the
available arsenic species without regard to the chemical
form or oxidation state of the arsenic. These analytical
methodologies, written by EPA (1994a, 1986a), ASTM
(1995), SM (1995), NIOSH, and USGS, include guidance
on sample preservation, laboratory sample handling, and
sample digestion. Atomic spectroscopy is the foundation
of these analytical methodologies for determining total
arsenic in air, water, soils, foods, and biological fluids. For
instance, total arsenic in the FDA's market basket of
common foods is determined using an aggressive digestion
followed by hydride generation coupled to an atomic absorp-
tion spectrometer. These methods provide detection limits as
low as 100 ppt (ng/L) by direct analysis using an inductively
coupled plasma mass spectrometer (ICP-MS).
Virtually all the data available for arsenic exposure assess-
ment is based on total arsenic determination. Total arsenic
concentration is a relatively poor indicator of the risk associ-
ated with an arsenic exposure because the chemical form of
the arsenic strongly influences its toxicity (ATSDR, 1993). The
total arsenic digestion used in EPA, USGS, NIOSH, FDA,
ASTM, and SM, methodologies changes the chemical form of
the arsenic, resulting in a complete loss of species-based
toxicity information. Therefore, certain aspects of character-
ization of arsenic exposure require species-specific analytical
methodologies capable of providing reliable individual arseni-
cal concentrations.
Speciation-based arsenic analysis partitions the total arsenic
into at least inorganic vs. organic fractions prior to detection.
The analytical difference between total and speciation-based
methodologies is that the speciation-based methods preserve
the chemical form and separate the individual arsenic species
prior to detection. This analytical difference implies the need to
ensure species-specific integrity from sampling to detection.
In terms of instrumentation, an interface to chromatographic
techniques (liquid chromatography (LC), ion chromatography
(1C), capillary electrophoresis (CE)) is required. In this respect,
a speciation-based method is analytically very different from a
total arsenic determination. To date, these differences have
nor been adequately addressed in the form of arsenic specia-
tion methodology by the EPA, FDA, USGS, NIOSH, ASTM,
or SM. In speciation-based analysis, separation schemes (1C,
HPLC, CE) have been interfaced to hydride atomic absorp-
tion (Gailerand Irgolic, 1994; Hasegawaetal., 1994; Lopez et
al., 1993; Haswell et al., 1985); inductively coupled plasma
atomic emission spectrometer (ICP-AES) (Albert! et al., 1995;
Low et al., 1986; Valez et al., 1995); and inductively coupled
plasma mass spectrometer (ICP-MS) (Beauchemin et al.,
1989; Hansen et al., 1992; Thomas and Sniatecki, 1995;
Story et al., 1992; Hwang et al., 1994; Branch et al., 1994;
Larsen et al., 1993a,b; Le et al., 1994a; Magnuson et al.,
1996a) for the speciation of arsenic in a variety of matrices.
These manuscripts demonstrate a particular aspect of an
analytical approach or a unique capability in the area of
arsenic speciation. They represent the state-of-the-art in chro-
matographic technology and innovative detection schemes,
but they seldom address all the aspects necessary to formu-
late an analytical methodology. A complete methodology
should address the following questions: 1)What sampling
protocol will assure species-specific integrity? 2) How can the
matrix be eliminated without the destruction of speciation-
based information? 3) What components of a matrix cause
spectral and chromatographic interferences?
The peer reviewed literature contains references for the
speciation of arsenic in water (Hasegawa et al., 1994;
Haswell et al., 1985; Hwang et al., 1994; Thomas et al.,
1995; Magnuson et al., 1996a); biologicals (Arbinda et al.,
1995; Heitkemper et al., 1989; Larsen et al., 1993b; Low et
al., 1986; Story et al., 1992); and foods (Albert! et al.,
1995; Beauchemin et al., 1989; Branch et al., 1994;
Larsen et al., 1993a; Le et al., 1994a; Lopez et al., 1993;
Velez et al., 1995). While these manuscripts represent the
technical framework for a method, considerable research
will be required before they can be adopted as exposure
assessment tools by the Agency. The major analytical
challenge will be assuring that the arsenic species within
the sample are the same as those detected, i.e., that the
extraction, preparation, separation, and detection do not
alter the distribution of arsenic species.
The following research issues provide some general di-
rection and time frames for refinement of arsenic specia-
tion methods that are needed in all aspects of arsenic
16
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research. Research should focus on refinement of, the
existing analytical capability, followed by method valida-
tion. The ideal approach would be to develop an extraction
and sample preparation scheme that is compatible with a
flexible and cost-effective separation and detection scheme.
Finally, emphasis in developing a speciation method should
be placed on demonstrating the procedure's capability of
assuring species-specific integrity from sampling through
detection. This preservation procedure must be compat-
ible with the analytical detection scheme and allow for field
implementation. The integrity of the species is critical to
exposure, epidemiologic, toxicologic, and pharmacokinetic
investigation.
Sample Preservation and Preparation: Many liquid
samples can be analyzed with little preparation, but the
extraction of species-specific information from solid samples
is a relatively new area (Albert! et al., 1995; Larsen et al.,
1993a; Le et al., 1994a; Valez et al., 1995). Therefore,
solids (foods) and tissue-based matrices requiring specia-
tion information are longer term projects (3-5 years), as
opposed to the speciation of arsenic in water (Hwang and
Jiang, 1994; Hasegawa et al., 1994; Haswell et al., 1985;
Thomas and Sniatecki, 1995; Magnuson et al., 1996a)
and urine (Larsen et al., 1993b; Low et al., 1986; Story et
al., 1992) (1-3 yeaYs).
Separation Techniques: The separation system (LC, !C,
CE) should provide relatively short analysis times, tolerate
diverse matrices, e.g., drinking water and urine, and be
compatible with sensitive but conventional detectors. Given
the current state of the science in the separation of
arsenicals, 1C demonstrates a good balance of the above
attributes (Arbinda et al., 1996; Martin et al., 1995;
Magnuson et al., 1996a). An 1C separation for arsenite,
arsenate, MMA, and DMA has been demonstrated
(Magnuson et al., 1996a) in the literature, making its
evaluation a short-term project (1 year). On the other
hand, CE has shown some initial capability (Magnuson et
al., 1996b), but this approach has sample injection and
matrix limitations, which would require considerable re-
search, making it a long-range goal (3 years).
Detection: The cost-effectiveness of speciation will be driven
by the capability of the separation scheme to be interfaced to
existing instrumentation such as atomic absorption, ICP-
AES and ICP-MS. These detector interfaces are similar
to those used in total arsenic methods, making-their
adaptation easier and less research intensive (short-
term, 2 years). The applicability of atomic absorption
and ICP-AES to the detection of environmentally signifi-
cant concentrations of arsenic species would be limited
without the use of hydride generation to improve sensi-
tivity. Hydride generation affords some freedom in choos-
ing a mobile phase for the chromatographic separation
but adds to the instrumental complexity. The use of
hydride generation will require an on-line digestion prior
to detecting the .highly derivatized arsenicals, i.e.,
arsenobetaine.
2.2.2. Ongoing EPA Research.
The ongoing research in the area of arsenic speciation has
focused on utilizing a membrane gas liquid separator with
ICP-MS detection. This work has evaluated separation
schemes (LC and CE) for the speciation of arsenic in saline
matrices. These saline matrices have some of the same
analytical difficulties associated with biological matrices
(blood and urine), therefore, the initial use of saline matri-
ces represent a logical analytical progression towards
biological media. This approach will produce a more sen-
sitive method for exposure measurement purposes.
2.3. What Data are Required to
Adequately Assess Arsenic
Exposure in Human Populations?
2.3.1. State of the Science.
Arsenic exposure assessment requires evaluation of the
relative contribution of (1) media (e.g., water, food, dust),
(2) pathways (e.g., drinking water, diet, hand-to-mouth)
and (3) routes (e.g., oral, inhalation, dermal) of exposure.
For. non-occupationally exposed individuals, studies have
indicated that uptake of arsenic via dermal exposures
from soil and water and inhalation are minor contributors
to total exposure; whereas intake from food and water are
the most significant environmental arsenic exposure
(ATSDR, 1993; Borum and Abernathy, 1994). The major
exception to this might be populations in the vicinity of
arsenic emitting industrial facilities or areas where soils
are contaminated with arsenic. Food is generally esti-
mated to be the major contributor to total arsenic expo-
sure. However, estimates for the contribution of drinking
water to total human arsenic exposure vary between 63%
and 22%, depending on the assumptions used in the
analysis, and could be up to 99% in some areas in the
western United States where there is low consumption of
fish and shellfish (Borum and Abernathy, 1994). For ex-
ample, Native American and Alaska Native studies have
indicated average seafood consumption rates up to ten
times greater than the U.S. EPA average estimate of 6.5
gram/day (CRITFC, 1994; Wolfe and Walker, 1987; George
and Bosworth, 1988; Nobmann et al., 1992; Tulalip Tribe,
1996). For these populations, total arsenic derived from
seafood and other foods may be important exposure
sources in addition to drinking water. Such exposure
assessments need to consider species-specific toxicity of
the various arsenic forms to accurately assess the risk.
In most epidemiologic studies used for quantitative risk
estimation of ingested arsenic, only nonspecialized ar-
senic intake data are available for drinking water and
food. This may not be a serious limitation in situations
where drinking water (predominately inorganic arsenic)
can be verified to be the major source of arsenic expo-
sure. The degree to which this is a limitation in the
United States is difficult to determine because of the
lack of a national occurrence database for arsenic in
drinking water. However, the contribution of diet to hu-
man exposure of arsenic should be considered a poten-
tially important issue for any population because less
than half of the water ingested is in the form of drinking
water. Drinking water is also ingested as part of foods or
beverages (e.g., coffee, tea, juices). Where arsenic
levels in public drinking water supplies are relatively low,
the contribution of food to total arsenic exposure be-
17
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comes a more important factor. Estimates of total ar-
senic ingested from foods and beverages often exceed
the EPA RfD which is based on inorganic arsenic. The
assessment of risk associated with this dietary ingestion
-will depend on the distribution of arsenicals in various
foods and their relative toxicities (i.e., arsenobetaine vs.
arsenite). Efforts to estimate arsenic intakes from food
compared to drinking water have been limited given the
lack of data.
The critical issue for arsenic in foods is whether the form of
arsenic is organic or inorganic. Certain organoarsenicals
found mainly in seafoods are considered to be virtually
nontoxic (arsenobetaine) and others (e.g., methylarsonic
acid, DMA) have markedly different toxicologic properties
compared to inorganic arsenicals. A recent report from
U.S. EPA Region 10 indicates that marine seafood con-
tains predominately arsenobetaine, while inorganic ar-
senic, MMA, and DMA are found at lower concentrations
(U.S. EPA, 1996a). Species-specific data for arsenic (inor-
ganic vs. organic) in food are limited. Inorganic arsenic is
found in meats, poultry, dairy products and cereals, whereas
the organic forms are predominantly found in fruit, veg-
etables, marine fish, shellfish, and seaweed (U.S. EPA,
1988; Velez et al., 1996; U.S. EPA, 1996a). Currently
systematic, comprehensive studies have not been con-
ducted to evaluate the forms of arsenic in typical U.S.
diet(s). Current market basket surveys conducted by FDA
analyze only total arsenic (Gunderson, 1995a,b), as have
the more comprehensive diet studies reported from other
countries (e.g., Dabeka et al., 1993). NHEXAS6 does a
thorough job of evaluating multimedia/multipathway expo-
sures; however, it measures only total arsenic. This will be
especially useful in identifying the most significant path-
ways. Several U.S. EPA Office of Water databases also
provide useful arsenic occurrence data for drinking water
but are also limited to total arsenic. These databases are
the National Inorganic and Radionuclide Survey (NIRS),
the National Organic Monitoring Survey (NOMS) and the
Federal Reporting Data System (FRDS).
Both EPA and other federal food regulatory agencies
must have improved information on toxic forms of ar-
senic in both specific foods as well as in the foods that
comprise the normal daily diets of the U.S. population or
its specific high-risk subpopulations. Therefore, analyti-
cal methods must be established that perform well for
both individual food items (i.e., fish) and for broader food
groups and diets that represent total daily ingestion.
Species-specific arsenic data on specific foods provides
the EPA with an accurate risk assessment tool for
supporting its regulatory activities, such as fish adviso-
ries, and to identify populations at risk. Species-specific
analytical procedures for broader food groups and total
daily diets will allow evaluation of information obtained in
EPA's measurements programs.
'NHEXAS is the National Human Exposure Assessment Survey being con-
ducted via three consortia in the U.S. in which one of the main goals is to
evaluate multipathway, multimedia exposure and relative source contribution
by analysis of chemicals of interest in drinking water, tap water, indoor and
outdoor air, dust, soil, biological samples and food.
Bioavailability of arsenic species from foods is a related
issue. The bioavailability of inorganic arsenic from foods
compared to water has not been systematically evalu-
ated, although soluble forms of inorganic arsenic are
generally assumed to be highly bioavailable (U.S. EPA,
1984). Overestimation of inorganic arsenic exposure
from foods will result in overestimation of risk from
arsenic in food. Another related issue is bioavailability of
arsenic from soils, which can be an important issue for
populations where soils have been contaminated as a
consequence of agricultural or industrial activity (Bhumbla
and Keefer, 1994). Soil ingestion can be an important
risk factor for young children. Soil bioavailability of ar-
senic can be considerably lower than its bioavailability
from water and is impacted by factors such as water
solubility of arsenic compounds found in soil (Davis et
al., 1996; U.S. EPA, 1996b). The issue of bioavailability
from food (and soil depending on the study population)
is one that requires formal consideration in any study in
which the contribution of food to total exposure is evalu-
ated. This will be discussed in the next section.
2.4. How Can Biomarkersand
Bioavailability Data be Effectively
Used to Estimate Arsenic Exposure
and Uptake?
2.4.1. State of the Science.
Arsenic levels in blood, hair, nails, and urine have all
been used as bioindicators of exposure. Blood arsenic is
used in poisoning cases as an indicator of acute high
level exposure. Poor correlations have been reported
between arsenic concentrations in drinking water and
blood arsenic levels because arsenic is cleared rapidly
from the blood. Arsenic in nails and hair is considered a
reliable indicator of exposures that occurred 1 to 10
months earlier, assuming that external contamination of
the samples has been eliminated. However, studies that
quantitatively correlate past levels of arsenic exposure with
arsenic in hair and nails are lacking and are needed for
epidemiological studies.
Total urinary arsenic and speciated metabolites in urine are
used as indicators of more recent arsenic exposure. It is
highly desirable to determine the different arsenic metabolites
(arsenite, arsenate, MMA and DMA) in urine, rather than
simply using total urinary arsenic. Essentially nontoxic
organoarsenicals (e.g., arsenobetaine) found in certain
seafoods and excreted in the urine could otherwise lead to
overestimation of arsenic exposure when only total urinary
arsenic is measured (Klaassen and Eaton, 1993). A major
issue that arises with the use of speciated arsenic metabolites
in urine is the potential for misinterpretation of data due to the
presence of MMA and DMA in urine that is not derived from
the metabolism of inorganic arsenic. The issue arises be-
cause certain marine fish and shellfish, as well as seaweeds,
contain both MMA and DMA, which are excreted in the urine
when these foods are consumed (Velez et al., 1996; Le et al.,
1994; Buchet et al., 1994, U.S. EPA, 1996a). Various means
that have been used to address this issue include: obtaining
diet histories from study participants, prohibiting the consump-
18
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tion of certain foods prior to the study, and collecting and
analyzing duplicate diet samples. It has also been pointed out
that further investigation is needed to identify other arsenic-
containing foods in the diet and assess their effect on urinary
excretion of arsenicals (Vahter, 1994).
Other than arsenic levels in.hair, nails, and blood, there are
few biological markers of arsenic exposure. Biomarkers emerg-
ing from the research described in Chapter 3 have the
potential to improve the sensitivity and specificity of exposure
measurements. In addition, biomarkers may make it possible
to determine the impacts of various factors such as genotype
that could impact human susceptibility to arsenic exposures.
One promising biomarker is using blood cell chromosomal
mutations as an indicator of arsenic exposure.
As indicated above, the amount of each arsenic species
absorbed is very important to the overall determination of risk.
The bioavailability of each arsenic species found in water and
food constituents is an extremely important component of
determining the relative source contribution of arsenic expo-
sure from water and diet. The relative source contribution is
used to determine an MCLG based on noncancer health
effects (U.S. EPA, 1994). Bioavailability studies need to be
conducted on each of the arsenic species found in the
exposure media of water, soils, and food.
2.5. Proposed Exposure Research
The following exposure issues are not listed based on
research priority. They are listed based on the progres-
sion within the chapter. The temporal analytical needs of
certain tasks have been considered in assigning priority.
Exposure Issue 1. Develop Arsenic Speciation Methodology
to Separate Arsenite From Arsenate to Support Water Treat-
ment Decisions in Large and Small Utilities
1a. Evaluate Analytical Techniques for Inorganic Ar-
senite and Arsenate Speciation in Water
The ability to speciate the valence states of
inorganic arsenic may be significant because
the treatment processes remove arsenate
more efficiently than arsenite, and therefore,
it could be beneficial to determine the oxidation
state prior to devising a treatment approach
for arsenic. However, in normal operation most
treatment approaches will tend to convert arsenite
to arsenate, and it may not be important to
differentiate arsenite from arsenate routinely.
This technique will help to establish the best
available treatment for drinking waters which are
found to contain arsenite. This work could be
utilized in the revised arsenic rule in 2000.
(1 a High Priority; Short-term)
1b. Evaluate Sample Preservation Techniques for
Arsenic Species
The preservation of the individual arsenicals
* from sampling to detection is a concern in all
aspects of the analytical methods. Preservation •
is not listed as a subtask within other issues but
it should be understood that it is of primary
; concern within all Speciation based analysis.
This work could be utilized in the revised arsenic
rule in 2000.
(1b High Priority; Short-term)
This research will enable measurement of major As species
to support decision making to evaluate the best available
treatment technology and provide analytical monitoring capa-
bility for MCL compliance. Development of analytical methods
for water will provide the technological basis for proceeding
with development of methods for analysis of more complex
matrices.
Exposure Issue 2. Develop Extraction Methods for Inorganic
and Organic Arsenicals in Foods to Allow for the Separation
and Detection of Individual Arsenic Species in Foods
The primary need is for analytical methods that will allow
measurement of the inorganic and organic fractions of arsenic
in food. A secondary priority is the ability to distinguish the
specific organic forms (e.g., MMA and DMA) that may be of
toxicological concern.
2a. Methods for Speciation in Target Food Items
(e.g., seafood)
The ability to speciate arsenic in certain foods
provides the EPA with an accurate method for
supporting its regulatory activities, such as fish
advisories. Speciation based methods also are
required in research to identify foods and food
groups that are associated with the more toxic
forms of arsenic so that exposure evaluations
accurately reflect the relative importance of foods
as compared to other media and exposure .
pathways.
(High Priority; Short-Term/long-term)
2b. Methods for Speciation in Composite Daily Diet
(i.e., duplicate diets)
EPA measurements of human exposure from
multiple pathways requires collecting,
compositing, and analyzing 24-hour duplicate
diet samples for direct comparisons of dietary
exposure to other concurrent pathways of
exposure. Speciation- based analysis will allow
population exposure assessments which
accurately quantify the risk associated with diet.
The ability to speciate the arsenic in duplicate
diet samples will also provide the basis for
assessing the bioavailability of ingested arsenic.
(Medium Priority; Long-term)
2c. Impact of Food Preparation on the Distribution
of Individual Arsenicals
Develop methodologies to evaluate the effects
of preparation and cooking on the distribution of
19
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arsenicals in ready-to-consume foods. The
thermal and chemical environments that the
organic and inorganic arsenic species are
exposed to during cooking may cause an
interconversion of the arsenic species. To
date, this interconversion in prepared foods
has not been reported in the chemical
literature. If this conversion is documented,
the priority of this task may require some
reconsideration.
(Low Priority; Long-term)
These research areas will address the relative source
contribution of arsenic ingestion via diet and improve
mass balance data for humans including all ingestion
routes. This information could be useful in Effects Issue 3a
and Exposure Issue 5, 6 and 8. Research and develop-
ment of species specific analytical methods must be shared
by EPA and other federal food regulatory agencies such
as FDA and USDA. EPA research should focus on the
analytical procedures that directly support its programs,
namely evaluation of dietary intake in ORD total human
exposure monitoring programs and risk evaluations for
regulatory programs.
Exposure Issue 3. Development of Arsenic Speciation Meth-
odologies in Biological Matrices to Support Exposure Assess-
ment, Bioavailability, and Biomarker Research
3a. Refine and Evaluate an Analytical Approach for
the Separation of Arsenite, Arsenate, MMA, DMA
and Arsenobetaine in Urine
3b. Refine and Evaluate an Analytical Approach for
the Separation of Arsenite, Arsenate, MMA, DMA,
and Arsenobetaine in Blood
3c. Refine and Evaluate Analytical Approaches for
Speciation of Arsenic to Support Bioavailability
Investigations
3d. Refine and Evaluate Analytical Approaches for
Speciation of Arsenic in Tissues
The capability of speciating arsenic in biological fluids pro-
vides a means of measuring recent exposures to arsenic.
This speciated information may indicate the source of
the exposure, for instance, high arsenobetaine concen-
tration may indicate a diet high in seafood. The ability to
speciate arsenic in all exposure routes provides a unique
capability to address the bioavailability (Exposure Issue
8) of the arsenic from the various routes. In addition,
this speciation information can be used in identifying a
biomarker Exposure Issue 7, Effects Issue 2a) for ar-
senic.
(3a High Priority; Short-Term, 3b, 3c, 3d, Medium Prior-
ity; Long-term)
In pharmacokinetic and mechanistic studies of arsenic,
it will be important to be able to distinguish between
inorganic arsenic, MMA, and DMA. Ideally, analysis
would also differentiate between arsenite and arsenate,
although this may be more difficult to achieve and is
therefore a longer term priority. Current toxicological
studies are proceeding with the use of radiolabeled
arsenic; the eventual availability of non-radio-labeled
species-specific methods for biological matrices will be
a valuable research tool. These areas have been iden-
tified by AWWARF (1995) as high priority projects in
arsenic research. The priority assigned above is an
indicator of short-term analytical achievability and the
use of urine as a primary arsenic exposure indicator.
Exposure Issue 4. Development of Liquid and Solid
Species Specific Standard Reference Material for Ar-
senic in Water, Foods, Urine, and Tissues
4a. Refine and Evaluate a Standard Reference Ma-
terial for Foods that Provides Species Specific
Concentrations of Arsenic
4b. Refine and Evaluate a Standard Reference Ma-
terial for Biological Tissues that Provides Spe-
cies Specific Concentrations of Arsenic
4c. Refine and Evaluate a Standard Reference Ma-
terial for Water, Blood and Urine that Provides
Species Specific Concentrations of Arsenic
The development of standard reference materials (SRM)
for arsenic that are species specific is an area of re-
search which is fundamental to all speciation based
analytical methodology. This research will provide the
analytical community the capability of evaluating the
developed methodologies accuracy in terms of species
specific concentration and provides a means of assuring
species specific integrity. This work has an impact on all
species specific exposure issues.
(4b Medium Priority; Long-term, 4a, 4c High Priority;
Long-term)
This research area will provide the necessary QA/QC
materials for speciation based exposure assessment.
This research will be conducted primarily by NIST
and NRCC. The priority assignments are made based
on analytical feasibility and temporal consistency with
Exposure Issue 3 and Exposure Issue 2.
Exposure Issue 5. Dietary Exposure Assessment Stud-
ies for Populations with High Dietary Intake of Foods
Associated with Toxic Species of Arsenic
5a. Dietary Exposure Assessment Studies of Arsenic
Species for Typical U.S. Diets and Highly Ex-
posed Subpopulations
High dietary total arsenic exposure can occur because of
low levels of arsenic in many foods consumed or because
of very high levels in a few foods. The later is usually
associated with'unique populations whose dietary habits
differ from the norm. Studies are needed to evaluate the
species of arsenic in the array of foods in the typical U.S.
diet and to identify diets containing high levels of the toxic
forms of arsenic. The amount and variability of exposure
20
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from food and beverages needs to be quantified for
various populations, taking into account demographic char-
acteristics. This could be accomplished by modeling and/
or by direct measurement. Neither procedure can be
accomplished until analytical methods for speciation of
foods are available and a database is created on species-
specific arsenic levels in foods. Modeling will utilize spe-
cies-specific information for food groups and items com-
bined with information on dietary consumption to identify
high risk populations. Measurements consistent with mar-
ket basket collections of the foods consumed by the U.S.
populations and specific high risk subpopulations will be
used in this modeling. Inclusion of biomarkers in these
studies will aid in addressing the species specific adsorp-
tion rates of arsenic from ingested food.
(High Priority; Long-term)
This research will address relative source contribution
issues with dietary ingestion of arsenic while targeting
subpopulations which may have evaluated risk factors
associated with dietary ingestion. This information may be
helpful in future epidemiology studies and could be used
as a relative source contribution estimate for exposure
assessment of subpopulations. This is consistent with
Exp. Task 4a.
Exposure Issue 6. Development of National Database on
Arsenic Occurrence and Concentrations in Water for Use
in Epidemiologicai Studies and Agency Regulatory Activi-
ties
6a. Development of a National Database on Arsenic
Occurrence and Concentrations in Water.
Present databases do not report occurrence and concentra-
tions of arsenic by specjes in the various media/Also, large
amounts of the data on arsenic in drinking water only report
arsenic levels that exceed the current MCL of 50 jog/L As
speciation and low-level arsenic detection data continues to
be developed in water supplies, there will be a need to
assemble this evolving data into a national database on
arsenic. This work will act as a refinement of the near-term
need to evaluate the currently available databases for use in
epidemiological studies and Agency risk assessments/risk
characterizations/risk management activities. The research
on arsenic occurrence and concentration in water will be
primarily conducted by OW with some ORD collaboration.
Future work may be done in soils and diet. This work is
of lower immediate priority because it relies on the devel-
opment and implementation of other research before be-
ing feasible.
(High Priority in Water; short-term, Medium Priority in Diet;
long-term)
The Office of Water is required to establish a national
contaminant occurrence database, which will include ar-
senic. However, this effort is due to be established by
August 1999, which is too late for use in the short-term
arsenic proposal. For the proposal; OW is assessing data
from many sources for exposure and occurrence projec-
tions and. regulatory decisions.
Exposure Issue 7. Biomarkers of Exposure in Biological
Media
7a. Development of Biomarkers of Exposure in Bio-
Media for Use in Epidemiological Studies
The exposure in most drinking water epidemiological stud-
ies has been based on the concentration of arsenic in
drinking water and food. The analytical measurements
used before 1970 to measure arsenic have questionable
precision at low concentrations. The use of biomarkers of
exposure that would potentially measure the dose and
reduce misclassification bias would be desirable in epide-
miological studies. Development of these biomarkers tools
will improve the precision of the risk estimate.
(High Priority if feasible; long-term)
This exposure issue is related to the analytical develop-
ment of speciation in Exposure Issue 3a and the QA/QC
Exposure Issue 4c. The support of future epidemiology
within this exposure issue is related to Effects Issue 2a
and 3a.
Exposure Issue 8. Bioavailability of Arsenic
8a. Conduct Research to Determine the Bioavailability
of All Arsenic Species Found in Water, Soils, and
Food Constituents
Arsenic species are only a systemic risk if the ingested
arsenic is absorbed from the gastrointestinal tract in a
form that is biologically relevant. The question of how
much inorganic arsenic vs. organic arsenic found in
urine came from the exposure media and how much is a
result of biotransformation in the body is also important
for assessing exposure risks. Bioavailability studies
using newly evolving analytical techniques to speciate
arsenic will greatly enhance our ability to assess the
relevant risks from each arsenic containing media and
allow for more precise estimation of the relative source
contribution that arsenic levels in water have to the
overall arsenic exposure. The priority of the research is
Medium for the near-term because the analytical meth-
ods are not available and need to precede this re-
search.
(Medium Priority based on sequencing with other re-
search products; long-term)
Specific projects and products relating to these issues
and their status, use and time frame are outlined in
Tables 2-1 and 2-2.
3. Health Effects: Hazard Identification
and Dose-Response
3.1. Background
This chapter discusses the research questions that
address hazard identification and dose- response as-
sessment associated with arsenic exposure. Hazard
identification research involves the development and
application of methods that demonstrate a qualitative
relationship between exposure and effect. Dose-re-
sponse research then characterizes this relationship to
link dose with incidence and severity of effect consider-
21
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ing the mechanism(s) by which arsenic exerts its toxic-
ity. Factors that influence dose-response are also evalu-
ated. This information is then used to develop quantita-
tive models for estimating risk. The arsenicals dis-
cussed here include inorganic and organic forms.
3.2. What are the Health Effects
Associated with Arsenic Exposure?
Unlike most environmental contaminants, there is a
large human database available for inorganic arsenic.
The health effects of ingested inorganic arsenic include
skin and internal cancers and npncancer-related effects
on skin, vascular and gastrointestinal systems, and
liver. Inorganic arsenic has also been linked with devel-
opmental toxicity. Numerous epidemiologic investiga-
tions have consistently reported an association be-
tween arsenic exposure in drinking water and cancer. It
is interesting to note that this effect has not been
demonstrated in arsenic ingestion studies with animals.
Having a comparable experimental model system would
be useful to better understand the mechanisms of ar-
senic-induced health effects. While there is a substan-
tial human database for inorganic arsenic, there are a
number of uncertainties over the interpretation of these
data and their application in risk assessment. Experi-
mental data on the effects of organic forms of arsenic
are not as well characterized and thus may be a subject
for future research. Limited data in animals indicate that
some organic forms of arsenic also produce cancer and
noncancer health effects.
3.2.1. State of the Science.
Available information on the health effects of inorganic
arsenic and other arsenic species has been discussed
in several documents (U.S. EPA, 1988, 1993; ATSDR,
1993).
3.2.1.1. Carcinogenic Effects in Humans — Epi-
demiological studies conducted in several countries including
Taiwan, Mexico, Chile, Hungary, England, Japan, and Ar-
gentina have reported an increased incidence of skin
cancer in exposed populations (Tseng et al., 1968; Chen
et al., 1986; Cebrian et al., 1983; Tsuda et al., 1990; Cuzik
et al., 1992). Several of these studies have also reported
and analyzed an association between inorganic arsenic
ingestion and increased mortality from internal cancers
such as liver, bladder, kidney, and lung (Chen et al.,
1986; Tsuda et al., 1990; Hopenhayn-Rich et al., 1993;
Smith et al., 1992). Studies conducted in the United
States have not demonstrated an association between
inorganic arsenic in drinking water and skin cancer. The
design of the U.S. studies were limited, having insuffi-
cient statistical power to detect the effects of concern.
The largest epidemiology study is the Taiwan study
(Tseng et al., 1968), which also serves as the basis for
the current EPA cancer risk assessment (see Chapter
1). In this study, an increased prevalence of skin cancer
was observed among approximately 40,000 Taiwanese
consuming arsenic contaminated water (up to 1,200 ng/
L arsenic) from artesian wells as compared with ap-
proximately 7,500 residents from Taiwan and a neigh-
boring island, Matsu, consuming "arsenic free" (0-17
ng/L arsenic) water.
3.2.1.1.1. Ongoing EPA Research. Currently,
ORD is conducting a cohort mortality study on approxi-
mately 4,000 individuals in Utah. Individuals living in
areas with historically high background levels of arsenic
will be compared with others living in an area where
arsenic concentrations fall within the MCL limit for ar-
senic. Specific cause of death for cohort members will
be compared with deaths for the State of Utah. The
cohort was originally ascertained through the historic
Mormon Church (Church of Jesus Christ of Latter-day
Saints) records. Due to the Mormon lifestyle, risk fac-
tors such as smoking, second hand smoke, and alcohol
consumption are expected to be minimal. In addition,
the use of water rights data, individual well survey and
town records have allowed for the development of
individual exposure assessments for the cohort mem-
bers. This U.S. study will evaluate incidences of cancer
and noncancer effects and may add to the weight of
evidence determination for arsenic and provide insight
as to the feasibility of evaluating the incidence of impor-
tant toxic and carcinogenic endpoints such as cardio-
vascular effects and internal cancers.
ORD is also developing a report that will describe the
feasibility of conducting epidemiologic studies in the United
States that will contribute to an improved quantitative risk
assessment of the health effects of arsenic in drinking
water. This will include a description of possible study
sites, numbers of individuals exposed, levels of exposure,
and preliminary power calculations concerning the feasi-
bility to evaluate different health endpoints such as cardio-
vascular, reproductive, derrnatologic and cancer.
Along with these studies, ORD is conducting studies on
arsenic urinary metabolic profiles. This project will provide
information on baseline data at exposures typically
found in the United States. Diet as a source of exposure
will be examined along with variability of arsenic meta-
bolic profiles in individuals. It is hoped that the informa-
tion gained from this study can facilitate the extrapola-
tion of study results from one population to another and
allow for standardization of biomarkers for exposure
and effect for arsenic that can be used in future epide-
miology studies.
Finally, ORD is collaborating with ongoing investigations in
other countries such as Chile and India to evaluate the
internal carcinogenic, reproductive, and derrnatologic effects
of arsenic exposure in drinking water. For example in Chile,
there are two studies nearing completion.
One is a case control study of lung and bladder cancers
examining arsenic exposure in. air, water, and food. The
second study is an ecologic study of cancer mortality with air
and drinking water arsenic exposures. Results from these
studies may provide further information on dose-response
that can be used in the near term to refine the arsenic risk
assessments.
22
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Table 2-1. Exposure Research Strategy Matrix for Arsenic
Issue Task
Product
Use
EXP. Issue 1. Develop
arsenic speciation
methodology to separate
As(lll) from As(V) to
support water treatment
decisions in large and small
utilities.
EXP. Issue 2. Develop
extraction methods for
inorganic and organic
arsenicals to allow for the
separation and detection of
individual arsenic species
in foods.
EXP. Issue 3. Development of
arsenic speciation methodologies
in biological matrices to support
exposure assessment,
bioavailability, and biomarker
research.
Exp. Issue 4. Development
of liquid and solid species
specific standard reference
material (SRM) for arsenic in
water, foodstuffs, urine, tissues.
Exp. Task 1 a. Evaluate
analytical techniques for
Inorganic As(lll) and As (V)
speciation in water.
High Priority, Short-term
Exp. Task 1b. Evaluate
sample preservation
techniques for Arsenic
species.
High Priority, Short-term
Exp. Task 2a.-Speciation in
target food items (i.e.
seafood).
High Priority, Short-term/
Long-term
Exp. Task 2b. Speciation in
composite daily diet (i.e.
duplicate diets).
Medium Priority, Short-term/
Long-term
Exp. Task 2c. Impact of food
preparation on the
distribution of individual
arsenicals.
Low Priority, Long-term
Exp. TaskSa. Refine and
evaluate an analytical
approach to the separation
ofAs(lll),As(V), MMA, DMA
and arsenobetaine in urine.
High Priority, Short-term
Exp. Task 3b. Refine and
evaluate an analytical
approach to the separation of
As(lll),As(V), MMA, DMA
and arsenobetaine in blood.
Medium Priority, Long-term
Exp. Task 3c. Refine and
evaluate analytical approaches
to speciate arsenic to support
bioavailability investigations".
Medium Priority, Long-term
Exp. Task 3d. Refine and
evaluate analytical approaches
to speciation in tissues.
Medium Priority, Long-term
Exp. Task 4a. Develop a SRM
for foods which provide
species specific concentrations
of arsenic
As speciation method for
drinking water
Preservative for asenic
speciation methods
As speciation method and
improved information on As
species for target foods/groups
As speciation method to
determine inorganic forms in
composite samples
Improved information on As
speciation for prepared foods
Analytical method capable of
separating inorganic arsenic III
from MMA, DMA and
arsenobetaine in urine
Analytical method capable of
separating inorganic arsenic II
from MMA, DMA and
arsenobetaine in blood
Speciation method in a variety
of sample types foodstuffs,
drinking water, biologicals
Speciation method for tissue
samples.
SRM to evaluate methods
development in food
Treatment evaluation in
NRMRL, individual water
treatment plant, AWWA
Application to all speciation
based methods
Exposure assessment by
NCEA, NERL, FDA, USDA, OW
Exposure assessment by
NCEA, NERL, FDA, USDA
Exposure assessment by
NCEA, NERL, FDA, USDA
Support of exposure monitoring
and bioavailability studies in
NHEERL or NCEA, NIOSH
Support of exposure monitoring
and bioavailability studies in
NHEERL or NCEA, NIOSH
Analytical support for
bioavailability studies
Non-radio based analytical
support for NHEERL
NERL, Method validation for
NCEA exposure assessment,
EPA, FDA, USDA, NIST, OW.
Method validation in Exp 2&5.
23
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Table 2-1. (cont.)
Issue
Task
Product
Use
Exp. Task 4b. Develop a
SRM for biological tissues
which provides species
specific concentrations of
arsenic
Medium Priority, Long-term
Exp. Task 4c. Develop a SRM
for water, blood and urine which
provides species specific
concentrations of arsenic
High Priority, Long-term
SRM to evaluate methods
development in tissues
SRM to evaluate methods
development in water, blood
and urine
NERL, method validation for
NCEA exposure assessment,
EPA, NIOSH, NIST. Method
validation of Exp. 3
NERL, method validation for
NCEA exposure assessment,
EPA, NIOSH, NIST. Method
validation of Exp. 3
EXP. Issue 5. Dietary
exposure monitoring studies
which address a selected
populations exposure to
arsenic from a high dietary
EXP. Issue 6. Development of
National Database on arsenic
occurrence and concentrations
In water, soil and dietary
constituents for use in
epidemiological studies and
Agency regulatory activities.
EXP. Issue 7. Biomarkers of
Exposure in Biological Media
EXP. Issue 8. Bioavailability
of Arsenic
Exp. Task 5a. Dietary exposure Database on speciated arsenic
monitoring studies of arsenic in typical U.S. foods and for
species in the typical U.S. diet diets of targeted highly
and highly exposed sub-populations, exposed populations.
High Priority, Long-term
Exp. Task 6a. Development of
a National Database on arsenic
occurrence and concentrations
in water, soils, and dietary
constituents
High Priority in water, Short-
term/Long-term
Exp. Task 7a. Development
of biomarkers of exposure in
biological media for use in
epidemiological studies.
High Priority (if feasible),
Long-term
Exp. Task 8a. Conduct
research to determine the
bioavailability of all arsenic
species found in water, soils
and food constituents.
Medium Priority based on
sequencing with other research
products, Long-term
National Database on
Speciated Low-Level arsenic
levels in water, soils and
dietary constituents
Standardized biomarkers to
assess exposure or arsenic
species from various media.
Empirically derived
bioavailability (oral absorption)
factors will be determined for
each arsenic species from
water, soils and various food
constituents.
National and regional arsenic
diet data for improved EPA risk
assessment and risk
management decisions. FDA
and USDA will also utilize these
data. Related to Exp. 2a & 2b
Arsenic exposure information
for epidemiological studies and
for Agency risk assessment/risk
management activities.
Research and results primarily
used by OW
Standardized biomarkers
protocols will be used for
assessing exposures in
epidemiological studies and
for improving the precision of
the risk assessments
Improvements in the quantitative
precision of the arsenic risk
assessments and improvements
in the determination of the
relative source contribution of
arsenic in water vs. arsenic in
water vs. arsenic in other
exposure media.
3.2.1.2. Carcinogenic Effects in Animals—There
is limited evidence of inorganic arsenic-induced carcinogenic-
ity in animal studies. Standard experimental animal mod-
els do not demonstrate the carcinogenic effects of arsenic
seen in humans. However, there are emerging animal
models such as transgenic mice that may have utility for
arsenic effects research.
There are also limited data concerning the carcinogenic
effects of organic arsenic forms in animals. A slight in-
crease in pancreatic tumors was observed in male rats
following oral exposure to 4-hydroxy-3-nitrobenzene arsonic
acid or roxarsone (NTP, 1989). Male rats that had been
initiated with diethylnitrosamine and then exposed to
dimethylarsinic acid (DMA) had an increased incidence of
basophilic foci (a precancerous lesion) in the liver, suggesting
that DMA could be a promoter (Johansen et al., 1984; see
also discussion in mechanisms section, below). DMA has
also been demonstrated to be a promoter of cancer in multiple
organs such as urinary bladder, kidney, liver and thyroid in
rats and lung in mice (Yamamoto et al., 1995; Yamanaka et
al., 1996). A few studies indicate that organic arsenicals, DMA
and roxarsone, may be able to cause mutations and DNA
strand breaks (ATSDR, 1993).
3.2.1.2.1. Other Data Related to Carcinogenicity.
From studies conducted in animals, it can be concluded that
inorganic arsenic induces genetic damage. Experimental
evidence suggests that inorganic arsenic does not act to
damage DNA directly as a point mutagen, but produces
damage at the chromosomal level inducing chromosomal
aberrations, micronuclei and sister chromatid exchange in
mammalian cells, and neoplastic transformations in Syrian
hamster embryo cells (ATSDR, 1993; U.S. EPA, 1993). The
24
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Table 2-2. Exposure Task Summary, Current Activities and Proposed Sequence for Studies
Task - Short Study Title
Task Type1 Ongoing Priority
Time Frame2
E/O
Y/N
Priority
FY97 FY98
FY99 FYOO FY01
FY02
Exp. Task 1a. Evaluate
analytical techniques for
Inorganic As(lll) and As(V)
speciation in water
Exp. Task 1 b. Evaluate
sample preservation
techniques for Arsenic
species
Exp. Task 2a. Speciation
in target food items
(i.e. seafood)
Exp. Task 2b. Speciation
in composite, daily diet
(i.e. duplicate diets)
Exp. Task 2c. Impact of
food preparation on the
distribution of individual
arsenicals.
Exp. Task 3a. Refine and
evaluate an analytical
approach to the separation
ofAs(lll),As(V), MMA,
DMA, and Arsenobetaine in
urine
Exp, Task 3b. Refine and
evaluate an analytical
approach for the separation
of As(lll), As(V), MMA,
DMA and Arsenobetaine in
blood
Exp. Task 3c. Refine and
evaluate analytical
approaches to speciate
arsenic to support
bioavailability investigations
Exp. Task 3d. Refine and
evaluate analytical
approaches to speciate
arsenic in tissues
Exp. Task 4a. Develop a
standard reference
material for foods which
provide species specific
concentrations of arsenic
Exp. Task 4b. Develop a
standard reference material
for biological tissues which
provides species specific
concentrations of arsenic
Exp. Task 4c. Develop a
standard reference material
for water, blood and urine
which provides species
specific concentrations of
arsenic
O
O
O
High
High
High
Medium
Low
High
EPA EPA
EPA EPA
EPA EPA
EPA EPA
Medium
Medium
Medium
High
Medium
High
EPA EPA X
X X X
XX X
25
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Table 2-2. (cont.)
Task-Short Study Title
Task Type1
Ongoing Priority
Time Frame2
I
E/0
Y/N
Priority
FY97 FY98 FY99 FYOO FY01 FY02
Exp. Task 5a. Dietary
exposure assessment
studies of arsenic species
for typical U.S. diets and
high exposed sub-
populations
Exp. Task 6a, Development
of a National Database on
concentrations in water, soils,
and dietary constituents
Exp. Task 7. Development
of Biomarkers of Exposure
in biological media for use in
epidemiological studies
Exp. Task 8. Conduct
research to determine
the bioavailability of all
arsenic species found in
water, soils, and food
constituents
High
Y High/water
Medium/
dietary
High
Medium
EPA EPA
(pilot)
EPA EPA EPA EPA
EPA
EPA EPA
EPA
'I « Intramural (EPA inhouse research), E = Extramural (EPA sponsorship through grant or coop), O = other federal, state or private
organizations
*EPA » EPA has ongoing studies or plans to address this task in future years; some tasks may require additional research beyond EPA's
planned effort
X « EPA resources insufficient to address these tasks, need external effort
mechanism(s) for these effects is not known at present.
Depending on the mode of action, the dose-response curves
could be linear or nonlinear.
3.2.1.2.2. Ongoing EPA Research. Research ef-
forts have been initiated to develop an animal model for
testing arsenic-induced carcinogenesis using genetically al-
tered mice. Transgenic p53 knockout mice will be exposed to
4 arsenic species in drinking water: sodium arsenite and
sodium arsenate, monomethyl arsonic acid (MMA) and DMA.
This limited study will evaluate the animals for the presence of
common cancer lesions. Results from this study will be used
in the development of an animal model and could allow for a
better understanding of mechanism from the determination of
the active form for arsenic carcinogenesis. Other studies on
carcinogenesis focus on the actions of arsenicals in multi-
stage carcinogenesis, an evaluation of arsenic as a tumor
promoter, interactions between arsenic and genetic material
(DMA methylation) and the mechanistic aspects associated
with variations in susceptibility within the human population.
3.2.1.3. Noncarcinogenic Effects in Humans
— Exposure to inorganic arsenic may result in adverse
effects other than cancer in humans. Dermal changes
including variations in skin pigments, thickening of skin
(e.g., hyperkeratosis) and ulcerations, peripheral neuro-
toxicity (e.g., tingling and loss of feeling in arms and
legs) and auditory nerve damage, peripheral vascular
and cardiac effects, goiter, gastrointestinal and liver
effects, developmental toxicity, and diabetes have been
observed. These effects are seen at various levels in the
range of exposures reported in the epidemiology studies
(U.S. EPA, 1993; ATSDR, 1993).!
n humans, acute oral poisoning with inorganic arsenic
leads to gastrointestinal irritation accompanied by diffi-
culty in swallowing, thirst, abnormally low blood pres-
sure, and convulsions (Gorby, 1994). Both acute and
chronic exposures to inorganic arsenic result in capillary
damage to target tissues which exacerbates the dam-
age observed in these tissues (Clarkson, 1991). Signs
of chronic exposure to arsenic in drinking water are
dermal changes such as variations in skin pigments,
hyperkeratoses, and ulcerations. Blackfoot disease, a
peripheral vascular disease leading to peripheral tissue
necrosis, has been observed in humans consuming
arsenic contaminated drinking water in Taiwan (Tseng
et al., 1968) and India (Bagla and Kaiser, 1996). Human
studies have reported peripheral and central neurologic
effects after exposure to inorganic arsenic (Morton and
Dunnette, 1994). Enlargement of the liver was noted in
populations in India. Ischemic heart disease and diabe-
26
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tes were observed in Taiwanese where Blackfoot dis-
ease is endemic.
Some human studies have reported an association between
arsenic exposure and adverse reproductive outcomes and
developmental impacts (Rogers, 1996). The types of effects
noted in occupationally exposed humans include spontane-
ous abortion, congenital malformations and low birth weight.
Exposure to inorganic arsenic was associated with decreased
maternal blood glutathione levels indicative of maternal oxida-
tive stress.
When considering the range of noncancer effects associated
with inorganic arsenic exposure, hyperkeratosis observed in
the Taiwanese population (Tseng et al., 1968) is considered
the most sensitive endpoint of toxicity and serves as the basis
for EPA's current noncancer risk assessment.
3.2.1.4. Noncarcinogenic Effects in Animals •—
Signs of acute inorganic arsenic poisoning in animals
include vomiting and diarrhea, weakness, trembling,
tachycardia and collapse (U.S. EPA, 1993). Like hu-
mans, target organs appear to include liver, kidney, and
the developing organism.
In animal studies, arsenite and arsenate have greater potency
as developmental toxins than the methylated, organic forms
(Willhite, 1981). Types of malformations observed include
exencephaly, encephalocele, cleft palate-and lip, and malfor-
mations of the eye and ear, skeleton, kidney and urogenital
system as observed in hamsters, mice, rats and rabbits
(Rogers, 1996). In vivo studies in animal models indicate that
these teratogenic effects are not secondary to maternal
toxicity (Golub, 1994). There is some evidence to support a
variety of different mechanisms, similar to those associated
with carcinogenicity, including alteration of DNA methylation,
inactivation of methyltransferases, modulation of protein phos-
phorylation and production of reactive oxygen species. Signifi-
cantly, the dose-response relationships for arsenite and ar-
senate are very different, and recent evidence suggests that
the mechanisms responsible for induction of malformations of
these two inorganic arsenicals may be different (Tabacova et
al., 1996).
Limited toxicity data on organic forms of arsenic suggest
that irritation of the gastrointestinal tract, mild effect on
liver, tubular damage to kidneys and some neurological
effects may result following oral exposure in animal
studies. The limited nature of these data make it difficult
to quantitatively compare these effects with those result-
ing from inorganic arsenic exposure (ATSDR, 1993).
3.2.1.4.1. Ongoing EPA Research. ORD is
conducting several developmental toxicity studies that
evaluate the effects of metals, such as zinc and sele-
nium, and antioxidants on the prevention of arsenic-
induced malformations and the mechanisms related to
arsenic-induced malformations. This line of research
addresses questions related to mechanism(s) of action
and modifiers of susceptibility that could impact the
assessment of risk for potentially sensitive members of
the population. Further, these data may provide dose-
response information for effects other than cancer. In
addition, the Utah study, discussed above, will examine
noncarcinogenic endpoints.
3.3. What are the Characteristics of Dose-
Response for Various Toxic End-
points?
3.3.1. State of the Science.
The risk assessment process relies on scientific data charac-
terizing the effects of contaminants on human health, and
models that extrapolate existing data to estimate internal dose
and effects where data are lacking. Physiologically based
pharmacokinetic (PBPK) modeling links environmental expo-
sures with target tissue dose and provides a basis for extrapo-
lation among chemical classes. Development of biologically
based dose-response (BBDR) models integrate information
on toxicant distribution and mechanisms by which a chemical
may cause an adverse effect to relate exposure with effects.
The arsenical doses associated with the effects described
above are summarized in ATSDR (1993) and U.S. EPA
(1993).
3.3.1.1. Pharmacokinetic and Biologically-
Based Models — The shape of the dose-response
curve for arsenic-induced cancer and noncancer effects
relating the range of observation to the range of extrapo-
lation is a source of uncertainty in arsenic risk assess-
ment. This uncertainty influences both selection of a
dose-response model and high to low dose extrapola-
tion. There are several factors that can influence dose-
response, including metabolism, tissue dosimetry,
mechanism of action, and other factors that may modify
toxicity and individual susceptibility. Arsenic undergoes
a complex cycle of reduction and oxidative methylation
in humans and other species. This cycling contributes to
the mechanism for arsenic-induced toxicity and perhaps
its carcinogenic effect. Development of PBPK models
using experimental animal data and/or metabolic data
from observational human studies can provide insight
into the kinetics of substances through a quantitative,
biologically based description between exposure and
target tissue dose of the active chemical species. Hu-
man data usually include exposure and excretion infor-
mation. Therefore, use of animal models would compli-
ment the human data to provide further information
concerning exposure and target tissue dose. This is
particularly important because there are multiple target
tissues (e.g., skin, lung, liver, bladder, kidney), and the
target tissue dose of arsenate, arsenite and their methy-
lated metabolites is a balance between competing pro-
cesses of reduction, methylation, binding, and excretion.
Additional advantages of these models include the evalu-
ation of different exposure scenarios on cumulative tis-
sue dose and body burden, helping to prioritize areas for
further study, providing a link with other models that may
be developed (e.g., BBDR) to assess toxicological ef-
fects, and studying the impacts of a variety of host
factors on toxicity in humans.
27
-------
Establishing a model(s) may assist in the evaluation of
the dose-response relationship for arsenic-induced health
effects. When appropriate human data are not available,
there may be potential to utilize animal models or other
laboratory models to understand dose-response rela-
tionships for arsenic induced health effects. For some
adverse effects, studies in animal models can provide
evidence to confirm the effects associated with arsenic
exposure in human epidemiologic studies, and thus also
provide a basis for mechanistic research.
Research with laboratory model systems can also facili-
tate the dose-response evaluation of noncancer effects
such as developmental toxicity described above or in
the area of vascular effects. For example, recent in vitro
work with cultured human vascular endothelial cells
suggests that the arsenic-induced cardiovascular ef-
fects could arise from toxicant induced injury to vessel
walls (Chen et al., 1990; Chang et al., 1991). Develop-
ment of animal models to study dose dependency and
mechanistic aspects of these and other noncancer ef-
fects would complement epidemiological evaluations for
noncancer effects and subsequent dose-response evalu-
ations.
Further discussion on the role of mechanism and modi-
fiers of susceptibility in dose-response is given below.
3.3.1.2. Ongoing EPA Research — Current
ORD research efforts focus on improving our under-
standing of arsenic metabolism, factors that may influ-
ence arsenic metabolism, arsenic effects on cellular
enzymes (e.g., heme oxygenase, arsenic methylation
and research that will support the development of a
PBPK model for humans and animals. Metabolism work
is important in the development of biomarkers of expo-
sure for use in epidemiologic studies. Current efforts are
evaluating the utility of arsenic metabolic profiles as
markers of exposure for human epidemiologic and PBPK
studies.
Research on PBPK model development of arsenic is
underway using the mouse as the animal model. The rat
has been excluded from the studies because of the
unique accumulation of arsenic in red blood cells. The
rabbit has been suggested as a model for PBPK model
development relevant to humans based on somewhat
similar urinary metabolic profiles. However, the utility of
the rabbit as a model has not been adequately evalu-
ated. The mouse was selected since mice methylate
arsenic and excretes inorganic and organic forms in
urine. The physiologic parameters for mice for PBPK
models are well known, and thus enables an easier
"scale up" of the model to humans. Arsenic tissue do-
simetry studies currently being conducted with the mouse
can be used in conjunction with BBDR model develop-
ment for biomarkers of exposure or effect.
Mechanistic research combined with information from
metabolism studies and studies evaluating the modifica-
tion of toxicity and susceptibility can eventually be used
in the development of a BBDR model. This information
can improve risk estimation for arsenic induced toxicity
and carcinogenicity by improving our understanding of
"dose" and its relationship to effect.
3.4. What are the Mechanisms Associated
with Arsenic Carcinogenicity and
Toxicity?
3.4.1. State of the Science.
Mechanistic research conducted to refine arsenic risk
assessment encompasses the range of events from expo-
sure to target tissue dose associated with adverse health
effects and can impact all phases of risk assessment,
particularly dose-response. A major challenge in this area
is the limitation in sensitivity and specificity of current
analytical techniques used to measure arsenicals in tis-
sues, body fluids and other media (see Chapter 2). This
has had a major impact on pharmacokinetic and toxico-
logical mechanistic studies because it is difficult with
current methodologies to extract and distinguish between
arsenite and arsenate and their metabolites in biological
and environmental samples. This is important because
different forms of arsenic exhibit differences in disposition
and toxicity, and they act by different mechanisms at the
biochemical level.
It has long been known that arsenate is reduced to
arsenite and subsequently methylated to form MMA and
DMA in humans and experimental animals. The methy-
lated metabolites of arsenic are also the predominant
forms excreted in the urine of most species. Historically,
the operative assumption has been that arsenite is the
active or carcinogenic form of arsenic and that methylation
is simply or solely a mechanism of detoxification and
excretion. The basis for this assumption is that the methy-
lated forms of arsenic are far less acutely toxic than either
arsenite or arsenate (ATSDR, 1993). Recently, an alterna-
tive interpretation has been proposed. Brown and Kitchin
(1997) suggest that DMA may be an arsenic metabolite of
importance in carcinogenesis, and thus methylation of
arsenic to DMA may be a toxification pathway.
Until lately, there were no studies that had directly tested
the assumption of methylation as a simple detoxification
mechanism. However, DMA has recently been shown to
increase the enzyme activity of a rat kidney enzyme,
ornithine decarboxylase (ODC) (Yamamoto et al., 1995),
which has been shown as a biological indicator of cell
proliferation and promoter activity (Brown and Kitchin,
1996). As mentioned previously, DMA has also been
demonstrated to be a promoter of cancer in multiple
organs such as bladder, kidney, liver, and thyroid in rats,
and lungs in mice (Yamamato et al., 1995; Yamanaka et
al., 1996). In addition, arsenite has been shown to
produce a dose-dependent increase in rat liver ODC
activity (Brown and Kitchin, 1996). It has been postu-
lated, therefore, that arsenic may act as a promoter
rather than an initiator of carcinogenesis and affect
28
-------
some but not all elements of multistage carcinogenesis
(Brown and Kitchin, 1996). There are insufficient data on
the shape of the dose-response curve for other promot-
ers (Kitchin et al., 1994). Epidemiological, evidence that
arsenic acts at a later stage in the development of
cancer, as noted with increasing risk of lung cancer
mortality with increasing age of initial exposure, inde-
pendent of time after exposure ceased (Brown and Chu,
1983), provides some support to the hypothesis that
arsenic may act as a promoter of carcinogenesis. Fur-
ther studies are needed to clarify the mechanism of
arsenic carcinogenesis and the dose-response of ar-
senical promotion. These studies may provide insight on
the nature of the dose-response relationship for arsenic
carcinogenicity and the role of methylation as a
toxification/detoxification mechanism.
The mechanism for arsenical carcinogenesis may be
related to arsenic biotransformation. Arsenic is methylated
by an arsenic methyltransferase utilizing S-
adenosylmethionine (SAM) as the methyl donor. Arsenic
may perturb the utilization of methyl donor groups needed
for normal DNA methylation by interacting with the sub-
strate, SAM, or the methyltransferases. Depending on the
conditions, this perturbation could result in hypo- or
hypermethylation of DNA. High doses of arsenic were
thought to compete for the methyl donor pool during
detoxification, leading to hypomethylation (Mass, 1992).
Since arsenic interacts with methyltransferases, it may
inhibit or enhance other methyltransferases that could
lead to hypermethylation. Mass and Wang (1997) found
that exposure to arsenite and to a lesser extent, arsenate,
but not DMA, produced significant hypermethylation of
cytosine residues in the 5' promoter region of the p53
tumor suppressor gene in human lung adenocarcinoma
cells. They postulated that this hypermethylation could
result in suppression of the expression of tumor suppres-
sion genes and lead to cancer. An effect of arsenic on p53
or some other tumor suppressor gene by alteration of
DNA methylation provides a heritable mechanism whereby
arsenic appears to act as a nongenotoxic agent. Yet
inhibition of tumor suppressor gene function (or even
enhancement of oncogene expression) is known to lead to
genetic instability. This would endow arsenic with proper-
ties of both a genotoxic and nongenotoxic agent; it would
also provide a mechanism whereby arsenic can act as an
initiator and/or promoter/progressor.
Additional considerations for arsenic methylation include
saturation of this enzyme process in humans and the
effects of preexisting disease on the capacity for humans
to methylate arsenic. Saturation of_arsenic methylation
has been suggested as a hypothesis for low dose
nonlinearity (U.S. EPA, 1988; Petito and Beck, 1991;
Carlson-Lynch et al., 1994). There is uncertainty, how-
ever, regarding the dose at which saturation might occur.
Other researchers have concluded that the data do not
support a nonlinear mechanism for methylation
(Hopenhayn-Rich et al., 1993; Smith et al., 1995).
In an evaluation of Taiwanese populations, Hsueh et al.
,(1995) identified chronic liver disease as a risk factor
that increases the development of skin cancer. In a
separate study comparing healthy individuals to those
with liver disease, it was noted that preexisting disease
did not change the cumulative excretion of arsenic in
urine but did alter the ratio of the MMA and DMA
metabolites (Buchet et al., 1984; Geubel et al., 1988).
Studies in animals suggest that liver disease may re-
duce the availability of the methyl donor group, SAM,
necessary for arsenic methylation.
3-4.2. Ongoing EPA Research.
One focus for mechanistic research on arsenic carcinoge-
nicity and toxicity at EPA focuses on arsenic methylation
and the enzymes involved in that process. This, includes
the interaction between arsenic and DNA methylation
which could explain whether arsenic suppresses expres-
sion of certain genes from their function. Questions on
whether arsenic acts as a carcinogenic promoter are also
being addressed. The two hypotheses that DMA is an
active metabolite of arsenic in the carcinogenic process
and that free radicals may contribute to arsenic carcino-
genesis may contribute to arsenic carcinogenesis are
being evaluated. With respect to noncancer effects, the
mechanism by which arsenic perturbs the cell cycle and
induces cell death is being investigated in animal em-
bryos. Information .from these studies will reduce the
uncertainty in selection of dose-response models for can-
cer and developmental effects. Mechanistic information
will also be of use in the development of a BBDR model
relating tissue dose with response. ,
3.5. What are the Modifiers of Human
Susceptibility?
3.5.1. State of the Science.
Susceptibility is influenced by the magnitude and spe-
cies of exposure and by the characteristics of the ex-
posed organism. These modifiers can range from envi-
ronmental factors to those that are characteristic to the
organism. Environmental factors include diet or concur-
rent exposure to other toxicants. Diet and other environ-
mental factors can affect arsenic methylation. Methyla-
tion of arsenic requires the availability of a methyl group
donor (SAM). A low protein diet or diet deficient in the
amino acid methionine can result in decreased availabil-
ity of SAM. (However, a low fat diet is also considered to
lower the risk for developing some forms of cancer.)
Further, diets low in cysteine, choline, folate, and vita-
min B12 can minimize the methyl groups available for
transmethylation (Montgomery et al., 1990). In addition,
it has been shown that selenium, a related metal, inhib-
its the methylation of arsenic in vitro (Styblo et al., 1996).
The role of diet and environmental factors in arsenic
methylation can be studied in animals where these
factors can be manipulated. Such studies would be
useful in the design of human epidemiological studies to
determine the influence of dietary arid nutritional factors
on the capacity for arsenic methylation. Environmental
29
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factors that influence either exposure to arsenic or the
effects of arsenic need to be identified for incorporation
into the design of epidemiologic studies.
Characteristic modifiers include variation in susceptibil-
ity within the human population reflective of genotypic
differences, age of the individual exposed (e.g., chil-
dren, elderly), pregnancy, gender differences, and
whether the individual is predisposed to susceptibility
due to co-occurrence with another disease. Evaluation
of arsenic metabolites excreted in urine from chronically
exposed individuals suggest that there may be differences in
the pattern and extent of arsenic methylation among the
human population (Vahter et al., 1995b). Such differences
could reflect genetic polymorphisms for the enzymes involved
in arsenic methylation. Polymorphisms for enzymes that
catalyze other methylation processes have been observed
(Weinshilboum, 1989). Its also been observed that some
nonhuman primates and the guinea pig have limited or no
methylation capacity (Vahter and Marafante, 1985; Vahter et
al., 1995a; Healy et al., 1997).
In addition to the above potential modifiers, there is evidence
suggesting that arsenic is an essential trace element for
goats, chickens, minipigs, and rats (NRC, 1989). However, no
comparable data are available for humans, and demonstra-
tion of arsenic essentiality in humans is hampered by the lack
of a postulated mechanism. The possibility of arsenic as an
essential element could affect the interpretation of arsenic risk
at low-doses.
3.5.2. Ongoing EPA Research.
Current research is being conducted by EPA to evaluate
the Impact of micronutrient status on arsenic metabo-
lism and toxicity. In addition, studies are being com-
pleted on the preventive effects of zinc, selenium and
antioxidants on arsenic induced malformations in rodent
embryos. Results from these studies may be used in the
evaluation of dose-response relationships for arsenic
induced toxicity and carcinogenicity.
3.6. Proposed Health Effects Research
Proposed research topics and current activities are summa-
rized in Tables 3-1 and 3-2. Rgure 3-1 diagrams the relation-
ship between exposure and effects research and the types of
studies needed.
Effects Issue 1. What are the Health Effects and Dose-
response Associated with Arsenic Exposure?
Future epidemiological studies should be designed to im-
prove exposure analysis, provide information on arsenic spe-
ciation, reduce confounding factors and bias, and utilize
biomarkers if possible. Use of biomarkers can help reduce
uncertainty in the interpretation of epidemiological studies.
Biomarkers may be developed as indicators of exposure,
effect, or susceptibility. Chapter 2 discussed development of
biomarkers of exposure. This chapter focuses on biomarkers
of effect and susceptibility. In a long-term research plan,
biomarkers identified from mechanistic research in experi-
mental model systems can be used to help design future
epidemiology studies to improve the sensitivity and specificity
of exposure measurements (see also Chapter 2), provide
insight into the shape of the low-level dose-response curve,
and indicate the potential for a biological effect in humans. In
addition, biomarkers may make it possible to determine the
effect of various factors such as genotype that could impact
human susceptibility to arsenic exposures.
Based on current information, biomarkers such as hy-
perkeratoses and chromosomal alterations in human
blood cells are technically feasible and have potential for
success. Additional biomarkers may include but are not
limited to DNA methylation (see mechanism section,
below) and micronuclei in exfoliated bladder cells.
1 a. Conduct Feasibility Study on Important Health
Endpoints Resulting from Arsenic Exposure
This research will determine the feasibility of conducting
an epidemiologic study in the United States or other
appropriate populations focusing on important health end-
points. Research in this area would be used to determine
if the conduct of an epidemiology study in the United
States or other location would reduce the uncertainty in
the existing risk assessment. Further research, for ex-
ample, on the incidence of internal cancers, reproduc-
tive, dermatologic, neurologic and vascular effects may
provide the data that can contribute to the evaluation of
dose-response relationships at low arsenic doses and
quantify the corresponding risks. This research has
been initiated; results are expected in the near term.
(High priority; intramural and extramural tasks)
1 b. Directed Epidemiologic Research on the Health
Effects Associated with Arsenic Exposures
(i) To address uncertainties associated with the current
risk assessments for arsenic, this research would build
upon ongoing studies of appropriate study design to
evaluate the human health effects of arsenic at low
doses and determine the dose-response relationship for
important health effects attributed to arsenic exposure.
This research would expand the scope of ongoing stud-
ies in China, Chile, and India, for example, in order to
estimate the level of exposure to individuals and follow
these individuals over a period of time. Since this re-
search builds on existing studies, it could be completed
in the near term.
(High Priority, intramural and extramural)
ii) Pending the outcome of the feasibility study (1 a), a
new long-term epidemiologic study would be initiated.
This study would be developed in areas where expo-
sures could be well defined and would support the
development of a dose-response curve. These studies
are long-term in design and would be resource inten-
sive. This research might be developed through or in
collaboration with other groups such as the National
Institutes of Health or the World Health Organization on
study design and data analysis.
(High Priority, if feasible; intramural and extramural task)
30
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Table 3-1. Effects Research Strategy Matrix for Arsenic
Issue Task
Product
Use
EFF. Issue 1. What are the
health effects and dose-response
associated with arsenic exposure?
EFF. Issue 2. What are the
dose-response relationships
at low doses? - ,
EFF. Issue 3. What are the
modifiers of susceptibility?
1 a. Determine feasibility
study on important health
endpoints for carcinogenic
effects for epidemiologic
studies.
High Priority, Short-term
1b. Directed epidemiologic
research on arsenic health
effects utilizing ongoing
studies of following outcome
of feasibility study
High Priority, if feasible
1c. Research on important
health endpoints in animals.
Medium Priority
2a. Develop biomarkers of
effect and susceptibility
High Priority, Short-term .
2b. Research to support
refinement of a PBPK model
High Priority, Long-term
2c. Develop laboratory model
systems to assess mechanism
of arsenic induced
carcinogenicity and toxicity.
Medium Priority, Long-term
2d. Determine mechanisms
by which arsenic exerts its
carcinogenic and
noncarcinogenic effects.
High Priority, Long-term
3a. Factors that affect human
susceptibility
High Priority, Long-term
Determination if epidemiologic
study with improved design is
feasible.
Epidemiology studies that
determines relationship (linear
or nonlinear) between arsenic
exposure and effect
Results from animal studies on
developmental, reproductive,
cardiovascular, neuro- and
. other endpoints of arsenic
toxicity.
Biomarkers to assess biologic
effect and susceptibility
Relevant species-specific
parameters for development of
PBPK model.
Animal model utilizing
transgenic mice or other
appropriate organism or model
system.
Results from in vitro and
in vivo studies on mechanisms
of arsenic-induced carcinogenicity
and toxicity
Refined PBPK and BBDR
models
Determine health endpoint and
dose-response for use in full
scale epidemiologic study.
Basis for improved risk
assessment and derivation
ofMCL.
Determine appropriate endpoint
for future study design and
serve as basis for risk
assessment.
Standardize protocol for
assessing effects and utilize
tools for improving the precision
of the risk assessment. Relates
to Exposure Task 7
Incorporation into PBPK model
(RAtaskla).
Understand cause and effect
relationship between arsenic
exposure and effect.
Reduce uncertainty in low-dose
extrapolation in arsenic risk
assessment.
Necessary component of PBPK
and BBDR models, and improve
understanding of human
susceptibility.
1c. Research on Important Health Endpoints in Ani-
mals
This research would complement epidemiologic investi-
gations concerning the health effects and dose-response
analysis of arsenic exposures. This research would
include evaluations on developmental, reproductive, car-
diovascular, neuro- and other endpoints. Use of animal
models may enable this question to be answered more
easily or practically than human studies. Research in
these areas should combine in vitro and in vivo tech-
niques in animals to determine dose-response to further
characterize the toxicity of various arsenic species and
help target endpoints for study in epidemiologic studies.
(Medium priority; intramural and extramural task)
Effects Issue 2: What are the Dose-Responses Rela-
tionships at Low Doses?
Research in this section includes those studies that can
be used to support the assessment of health endpoints
for characterizing risks.
2a. Develop Biomarkers of Effect
Use of biomarkers can help reduce uncertainty in the
interpretation of epidemiologic studies and provide in-
sights into the shape of the dose-response curve, and
mechanism of action. Biomarkers such as hyperkera-
toses may provide insight into such factors such as
human variability and early markers of effect. These
studies would further develop biomarkers like the cellu-
lar genetic markers or DNA methylation or micron uclei
from exfoliated bladder cells to be used as measures of
biologic effect and susceptibility. This research would
develop and evaluate additional biomarkers of effect for
use in epidemiologic studies. Development of this tool
could facilitate the development of a human biologically
31
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Table 3-2. Risk Assessment Task Summary, Current Activities and Proposed Sequence for Studies
Task1 Ongoing Priority Time Frame2
Task-Short Study Title I E
Y/N
Priority
FY97 FY98 FY99 FYOO FY01
FY02
Short-term RESEARCH
Task 1a. Feasibility study I
on important health endpoint
(Utah eohort; feasibility study)
Task 1b. Directed I
epidemiology study (i) - ongoing
study collaboration (Chile,
China, India), EPA grant-India
Task 2a. Develop biomarkers of I
effect (Urinary Metabolic Profile)
Task 2c. Develop laboratory I
model systems for arsenic
mechanistic evaluation - p53
deficient mice
Task 3a. Impact of micronutrient I
status on arsenic metabolism
and toxicity
Task 3a. Prevention of arsenic I
induced malformations by
antioxidants, selenium and zinc
Long-term RESEARCH
Task 1b. Directed epidemiology I
study (ii) - long-term development
Task 1 c. Research on important I
health endpoints in animals.
—Tumor studies in p53 mice
AWWARF/ACWA
Task 2b. Refinement of PBPK I
model
—Biomethylation and disposition I
of arsenic
—Determine toxicodynamics I
of arsenic in mice
Task 2d. Arsenic mechanism - I
Arsenicals, oxidoreductases,
and cellular redox status
—Arsenic mechanism (free I
radicals)
—Arsenic mechanism I
(Enzymology of arsenic
methylation)
—Arsenic mechanism (Action I
of arsenicals in multistage
carcinogenesis)
— As-GSH interactions and
skin cancer, EPA grant
Y High
Y High
Y High
Y Medium
Y High
Completed Medium
EPA EPA
EPA EPA
EPA EPA
EPA EPA
EPA EPA
EPA
EPA
EPA EPA
EPA
EPA
High if feasible
Medium
Medium
Medium EPA
EPA
Medium EPA
X
X
EPA
EPA
X
EPA
X
X
EPA
EPA
X
EPA
X X
X X
X X
EPA EPA
EPA
X X
EPA
X
X
EPA
EPA EPA
EPA EPA
EPA EPA
EPA EPA EPA
EPA EPA
EPA EPA
High
32
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Table 3-2. (cont.)
Task - Short Study Title
Task1 Ongoing Priority
Time Frame2
Y/N
Priority
FY97 FY98
FY99 FYOO FY01
FY02
—Arsenic mechanism
(Mechanistic basis of alteration
of DNA methylation by arsenic)
—Arsenic mechanism
Identification of human arsenic
methyltransferase gene)
—Arsenic mechanism
(Arsenic perturbation of cell cycle
and induction of cell death in
embryos)
Task 3a. Impact of macronutrient
status on arsenic metabolism and
toxicity
—Genetic biomarkers of
methylation in humans
—GSH reductase and cellular
redox, EPA grant
Y
EPA EPA EPA \ EPA
XX X
High
High
High
EPA EPA EPA EPA
X X
X X
1I = Intramural (EPA inhouse research), E = Extramural (EPA sponsorship through grant or coop)
2EPA = EPA has ongoing studies or plans to address this task in future years; some tasks may require additional research beyond EPA's
planned effort
X = EPA resources insufficient to address these tasks, need external effort
Epidemiology
Exposure
Dose
Biological Effect
Disease
Metabolism
PBPK
Mechanism
BBDR
Susceptibility
Figure 3-1.
based dose-response model and improve our understand-
ing of dose-response relationships for estimating risk.
(High priority; intramural task)
2b. Research for Development of a PBPK Model
Refinement of a PBPK model (and the studies necessary
for model development) for arsenicals would provide a
better understanding of the metabolism and relevant tar-
get tissues subject to arsenic toxicity. Included in this
area are human and animal in vivo and in vitro
studies that would characterize arsenic metabolism
in humans and improve mass balance data on typical
human metabolism of arsenic at various doses, by
different routes of exposure and with different chemi-
cal forms. Development of a PBPK model provides
information relating exposure with target tissue does,
thereby reducing uncertainty in the arsenic risk as-
sessment for cancer and noncancer effects. This
long-term research would identify appropriate
biomarkers that could improve the uncertainty asso-
ciated with exposure assessment in epidemiologic
studies.
(High priority; intramural and extramural task)
2c. Develop Laboratory Model Systems to Under-
stand Mechanisms of Arsenic Toxicity and
Carcinogenicity
This research would encompass the development of labo-
ratory model systems such as an animal model utilizing
transgenic mice or other appropriate organisms or in vitro
systems to better understand arsenic mechanism of
action. Mechanistic research is long-term in nature. In
order to understand how arsenic causes cancer or
other toxic effects, it may be useful to develop a
model system to potentially generate hypotheses con-
cerning the molecular mechanism of carcinogenesis
and toxicity in humans. Understanding the mecha-
33
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nism can often be used to identify biomarkers that
would be useful for developing dose-response relation-
ships, for detecting human populations sensitive to
arsenic. A better understanding of the mechanism of
action for arsenic induced carcinogenicity and toxicity
can lead to the future development of a biologically
based dose-response model for arsenic. Pilot studies
have been initiated to determine the feasibility of devel-
oping a model system. Pending results, the overall
priority of this research area may be reconsidered.
(Medium priority; intramural and extramural task)
2d. Determine Mechanisms by Which Arsenic
Causes Cancer and Noncancer Effects
This long-term research effort will utilize in vitro and in
vivo techniques to evaluate mechanisms for cancer and
noncancer effects induced by arsenicals. Mechanistic
research further refines the link between exposure and
effect. Areas for investigation include: enzymology of
arsenic methylation; action of arsenicals in multistage
carcinogenesis or as tumor promoters; free radical
involvement in carcinogenesis, mechanistic basis of
alteration of DNA methylation by arsenic; identification
of the human arsenic methyltransferase gene; effects
on methyl dependent recombination repair, and investi-
gation of noncarcinogenic mechanisms of action. The
results from these studies may provide insights regard-
ing the mode of action for arsenic and assist in the low-
dose evaluation in arsenic risk assessment through the
incorporation of biological data in the assessment
model.(High priority; intramural and extramural task)
Effects Issue 3: What are the Modifiers of Susceptibil-
ity?
3a. Factors that Affect Human Susceptibility
Variation is known to exist in human exposure re-
sponse to environmental toxicants and may be due to
such factors as age, lifestyle, genetic background, sex
and ethnicity. This area of research would involve
studies evaluating genetic polymorphisms, differences
in metabolism and other aspects associated with fac-
tors affecting human susceptibility to disease. The
objective of this research would be to evaluate the
variation in arsenic metabolism as reflected in varia-
tions in urinary metabolites or other biomarkers of
exposure. In addition, this research area would com-
pare biomarkers of arsenic metabolism in individuals
exposed to varying levels of arsenic with differences
that include nutritional status, age, sex and genetic
variations. This research may involve epidemiologic
studies, clinical or animal studies and is long-term in
nature.
(High priority; intramural and extramural task)
Specific projects and products relating to these issues
and their status, use and time frame are outlined in
Tables 3-1 and 3-2.
4. Risk Management Research for
Arsenic in Water
4.1. Background
When EPA establishes an MCL, the Agency must
define best available technology (BAT) for large pub-
lic water systems and identify affordable technologies
for small systems. Therefore, treatment options ca-
pable of removing arsenic from drinking water sup-
plies must be identified and tested. The goal of this
part of the Plan is to assure that the desired final
drinking water arsenic concentration be technically
achievable, and the control technology(ies) reliable
and cost effective, while not significantly increasing
residual management problems. At this time, consid-
erable uncertainty exists on whether known arsenic
control technologies will function effectively if lower
arsenic levels are promulgated. Additional data are
needed to determine the effectiveness of arsenic
treatment and control. In the pursuit of an achievable
arsenic MCL, EPA is mindful that arsenic removal
technologies must not adversely impact the treatment
of other water quality parameters, but need to build
on those technologies wherever possible.
Arsenic exists in water supplies as several chemical
species usually encompassing two oxidation states (ar-
senic III and arsenic V), with arsenic (V) being more
easily removed. The common soluble species of arsenic
(V) are forms of arsenic acid: H3AsO4, H2AsO4-1, HAsO4-
2 and AsO4'3. The common soluble species of arsenic
(111) are: H3AsO3 and H2AsO3'1. In the pH range of 5 to 9,
equilibrium data indicate that the predominant arsenic
(V) species will be H2AsO4- and arsenic (111) species will
be H AsO . In addition to soluble arsenic species, there
is increasing evidence (Chen et al., 1994) that particu-
late arsenic is a common constituent in the water sup-
plies. A recent arsenic survey (Edwards et al., 1997) of
domestic water systems showed significant levels of
particulate arsenic, averaging 17% of the total. A third
component for drinking water arsenic could be organi-
cally bound, but levels reported on this component were
rarely greater than 1 ng/L (Anderson and Bruland, 1991).
For this analysis only soluble inorganic arsenic and
particulate arsenic will be considered as the species
requiring control.
A number of control technologies can remove arsenic:
coagulation/filtration (CF), lime softening (LS), activated
alumina (AA), ion exchange (IE), reverse osmosis (RO),
nanofiltration (NF) and electrodialysis reversal (EDR).
Iron removal processes, such as manganese greensand
adsorption, have also been found to remove arsenic. All
of these technologies have been applied to water sup-
plies containing arsenic and demonstrated to work. A
new, lower MCL, however, would push the required
performance of some of these technologies beyond
reported levels opening up areas of uncertainty in per-
formance, reliability and impact on other treatment op-
erations.
34
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Historically, the level of treatment chosen for arsenic
has been closely correlated to the MCL of 50 pg/L.
Improvements in analytical techniques plus the statu-
tory requirements in the SDWA of 1996 may establish a
substantially lower limit. If the MCL for arsenic is low-
ered, a parallel evaluation of available treatment tech-
nology capability must also be carried out to document
required performance and/or identify areas where addi-
tional research is necessary.
4.2. State of the Science for Arsenic
Control
4.2.1. How Effective are AvailableTechnologies
for Meeting a Lower Arsenic MCL?
As discussed above, there are. numerous treatment
technologies that can be brought to bear on removing
arsenic from drinking water. The AWWARF Research
Needs Report (1995) and Malcolm Pirnie's Report on
Treatment and Occurrence of Arsenic in Potable Water
Supplies (1993) indicate that little is known about the
performance of these processes for treatment of ar-
senic concentrations in the less than 50 |o.g/L range.
The key risk management issues are
(1) what are the performance limitations on treatment
technologies that could be applied for arsenic control,
(2) how does this treatment impact small systems, and
(3) what impact is there on the management of process
residuals?
Table 4-1 shows the performance of eight arsenic con-
trol technologies, which have the capability of meeting
the current MCL. Table 4-1 also projects the level of
performance that may be required of these technolo-
gies if the MCL is lowered. In some instances, control
technologies have performed efficiently and approached
a concentration that might be expected under a more
stringent MCL, but in the overwhelming number of
cases the required performance was not documented,
particularly at the field scale level and for a sustained
period of time. Performance data gaps exist and the
proposed research under this Plan would address those
gaps by collaborating with existing studies, conducting
independent performance studies, and initiating basic
research on arsenic's interactions with chemicals/addi-
tions. :
AWWARF is presently conducting arsenic treatment
removal efficiency research for lime softening and co-
agulation/filtration. Although most of this research is
bench scale, some full scale performance data will be
collected that will reduce some of the uncertainty asso-
ciated with arsenic control (Edwards, 1994; McNeill and
Edwards, 1997; Hering et al., 1996). Because arsenic-
containing ground water and surface water varies in
composition, it would be prudent for EPA to investigate
additional water quality parameters before casting final
judgement on lime softening and coagulation/filtration.
Adsorptive media (ion exchange resin and activated
alumina) and membranes are also being studied, but
using a fairly high natural organic material raw water
(Total Organic Carbon « 3 mg/L) which is not represen-
tative of most ground waters. Since ground water sys-
tems are the most likely candidates for the adsorptive
technologies like activated alumina, research would be
required to determine key performance and cost factors
for a source water with lower total organic carbon (TOC).
The proposed research in this Plan would build on,
augment, and validate the arsenic control data avail-
able, generate additional treatment information and ad-
vance the understanding of the control technologies
(BAT) necessary to achieve a new arsenic standard for
drinking water.
The regulation of arsenic by a more stringent MCL may
impact other treatment operations. Because significantly
higher removals can be achieved with As V than As III,
a preoxidation step in the selected treatment process
may be frequently necessary, to optimize removal effi-
ciency. In some cases a specific oxidation step in the
treatment process will need to be added to optimize
removal efficiency, but in others only optimization of
existing unit processes like softening or filtration may be
sufficient to improve arsenic control. Although oxidation
of As III to As V is not difficult with commonly used
oxidants, the oxidation kinetics of the available oxidants
has not been well characterized to provide adequate
information to design reliable facilities. The kinetics for
the oxidation of arsenic by the various oxidants needs
to be more adequately characterized. Furthermore, short
or long-term storage and aeration, while not as effective
as chemical oxidants, may be adequate in some situa-
tions and preferable because of confounding problems
associated with chemical oxidants. While researching
the performance aspects of arsenic control, this re-
search effort will also look at the entire water treatment
system and make recommendations on leveraging ex-
isting options for arsenic control.
4.2.2. Are There Cost Effective Technologies
for Small Systems?
Small water supply systems (<10,000 customers) pose
special problems for regulation and a change in the
arsenic MCL could cause significant operational/com-
pliance problems for these systems. Table 4-1 illus-
trates the arsenic removal gap that exists between
current control technologies and the projected future
need. In some cases the optimization of the control
technique may be technically insufficient or too costly
for a small system to implement. In addition, potential
changes in residual disposal regulations triggered by
a lower arsenic MCL could add substantial costs to
the total costs of arsenic treatment. In situations
where technology or economics fail for small sys-
tems, alternative compliance approaches must be
developed, such as point-of-use treatment.
4.2.3. How Can the Residuals be Effectively
Managed?
While the treatment of source water for arsenic removal has
been widely documented, efficiency, reliability and cost effec-
tiveness are topics slated for additional research. The im-
35
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Table 4-11. Arsenic Control Technology Performance (100 ng/L Influent)
Technology
1 . Coagulation Filtration
2. Lime Softening
3. Activated Alumina
4. Ion Exchange
5. Reverse Osmosis
6. Nanofiltration
7. Electrodialysis Reversal
8. Iron Removal Processes
Performance2
Currently
Required, %
50
50
50
50
50
50
50
50
Reported
Treatment
Performance, %
90 to 99
40 to 99
43 to 94
75 to 96
96 to 99
95 to 98
Not reported
95 to 98
ProjectedS
Performance
Needed, %
98
98
98
98
98
98
98
98
'Adopted from Malcolm Pirnie, 1993
sBased on current MCL of 50(ig/L
3Based on treatment requirements significantly less than 50p.g/L
proved treatment efficiency will produce a residue with el-
evated arsenic concentrations, which might affect disposal
options and cost of residual management. Currently
residuals subjected to the toxicity characteristic leaching
procedure (TCLP) are characteristically a hazardous
waste due to arsenic if the TCLP extract contains 5 mg/
L or more of arsenic. The TCLP procedure defines a
TCLP hazardous waste as producing an extract contain-
ing greater than 10Ox the referenced MCLs of specified
chemicals. Lowering the MCL for drinking water might
initiate a new regulatory requirement under the Re-
source Conservation and Recovery Act (RCRA) in which
case the TCLP arsenic trigger value will also be low-
ered. Thus, the strengthening of the arsenic drinking
water MCL could have a multiple regulatory impacts on
a utility and contribute to unfavorable economics for
various arsenic removal technologies. All of the re-
search projects initiated under this plan will require
residuals management to be an evaluation factor. Iden-
tification, characterization, and minimization of the vol-
ume of arsenic containing sludges and other types of
residuals and the degree of arsenic mobility will be a
research topic. If recycling is not a technical option, the
minimization of the volume of arsenic containing slud-
ges and degree of arsenic mobility will be a research
topic.
4.2.4. Ongoing EPA Research. EPA sponsored re-
search has been recently completed on the evaluation
of ion exchange and coagulation-microfiltration tech-
nologies for removal of arsenic from ground water.
Laboratory and pilot plant studies have shown that ion
exchange treatment with brine regeneration reuse (over
20 cycles) can effectively reduce arsenic V to less than 2
ng/L and significantly reduce the quantity of brine re-
sidual for disposal. A coagulation (iron coagulant)-
microfiltration process was also successfully piloted to
reduce arsenic V to less than 2 p.g/L. Both of these
technologies will have full scale demonstration con-
ducted by the utility that co-sponsored part of the pilot
studies with in the next 2 years.
4.3. Risk Management Research
The reliable control of arsenic at levels below 50 jig/L by
currently available treatment technologies has not been
completely demonstrated. In addition to the overall perfor-
mance problem there are special technical and economic
concerns raised by application of arsenic control to small
drinking water systems. Thirdly, additional arsenic re-
moval from drinking water may result in an enriched
residual and possibly generating a new regulated waste
stream.
Risk Management Issue 1 (RM 1). How Effective are
Available Technologies for Meeting a Lower Arsenic MCL?
RM 1 a. Laboratory and Field Testing on Different Arsenic
Control Technologies
A reduction in the MCL for arsenic in the near future is
going to require that control technology be capable of
meeting the technical requirements of the revised limit.
Currently, there are at least eight different types of
control technology applicable to arsenic control and a
significant amount of laboratory and pilot plant work on
the performance/reliability has been completed and
shown to achieve levels below the current MCL. The
main focus of the research has been on the CF and LS
methods for surface waters with high levels of TOC and
on IE and AA methods for ground waters. Short-term
research conducted in RM 1a. will verify the sustained
performance of full scale proven arsenic control tech-
nologies to achieve 10 ng/L or less of arsenic in treated
waters. Long-term research will involve studies to opti-
mize and improve efficiency of proven control technolo-
36
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gies to consistently achieve levels lower than 10 ng/L of
arsenic. Lab and pilot plant research will also be carried
out under RM 1a. to investigate the impact of TOG and
other water quality parameters on the performance and
capability of the technologies. To help define the specific
research needs and gaps, a workshop will be conducted
with leading experts in the field of arsenic research tech-
nology. This state of the science workshop will review past
work and provide guidance for new research. The SDWA
Amendments of 1996 call for promulgation of a new arsenic
MCL and this research directly supports that requirement by
determining the availability of reliable control technologies.
High Priority for activated alumina, ion exchange, conven-
tional coagulation/filtration, lime softening and iron removal
processes. Medium Priority for Reverse Osmosis,
Nanofiltration, and Electrodialysis Reversal
Risk Management Issue 2 (RM 2). Are There Cost Effective
Technologies Available for Small Systems?
RM 2a. Cost Evaluations for Laboratory and Field Testing of
Arsenic Control Technologies
Small drinking water treatment and distribution systems pose
several additional challenges to regulators. The economic
impact of a lower MCL for arsenic could be significant. As part
of the technical evaluation for the various arsenic treatment
technologies studied in RM 1a., the economics of each
system will also be evaluated using existing OW cost equa-
tions and models and other available costs information. Appli-
cability of the control technologies to point of use (POU)
considerations will also be part of the technical/economic
evaluation.
Medium Priority
Risk Management Issue 3 (RM 3). How can Residuals
From Arsenic Control be Managed Most Effectively?
RM 3a. Arsenic Control Residual Management
A reduced MCL for arsenic will result in the production of
more arsenic enriched residual material. The disposal of
this material will likely be impacted by a lower arsenic
TCLP value and trigger regulation under RCRA. Residu-
als associated with RM 1a. and other arsenic removal
projects will be evaluated for quantity and arsenic con-
tent and mobility with emphasis being on reducing the
environmental impact of its disposal. Short-term re-
search will characterize the residuals produced by all
arsenic control technologies and identify acceptable dis-
posal options considering existing and potentially modi-
fied residual disposal regulations. Long-term research
will involve studies to optimize treatment to reduce the
quantity of residuals for disposal and to develop meth-
ods to reduce cost of disposal assuming more stringent
residual disposal regulations will occur. Residuals are
important from a total arsenic management standpoint,
and have not received sufficient attention in past stud-
ies. High Priority
Specific projects and products relating to these issues and
their status, use and time frame are outlined in Tables 4-2 and
4-3.
5. Cross Linking and Summary of Arsenic
Research
The preceding chapters have presented research op-
tions and priorities for arsenic. Each chapter focused on
a particular aspect of the standard risk assessment/risk
management paradigm and associated research needs.
Accordingly, the chapters did not always provide a glo-
bal perspective on the total plan.
A series of tables were developed for this chapter in
order to assist the reader in forming a comprehensive
picture of the arsenic research plan. Tables dealing with
research initiatives on the following topics are included:
Analytical Methods
Exposure Assessment
Metabolism/ Biomarkers/PBPK Model Develop-
ment
Health Effects and Dose-response
— Cancer endpoints
— Noncancer endpoints
• Mechanisms of Action
Human Susceptibility Characteristics
• Potable Water Treatment Modalities
The tables integrate the various components of the
research plan; they illustrate the importance of specific
research opportunities, interaction of components of the
plan and limitations on what can reasonably be accom-
plished in a limited time span. Each table highlights the
contributions of the proposed activity to the arsenic risk
assessment, presents a priority for the activity and tar-
gets a time frame for its accomplishment The projected
responsibility for ORD is also delineated.
-37
-------
Table 4-2. Exposure Research Strategy Matrix for Arsenic
Issue Task
Product
Use
RM Issue 1
How effective are the
available arsenic
treatment technologies
for meeting a lower MCL
RM Issue 2
What are the technical
and economic
considerations of
arsenic control for small
systems
RM Issue 3
How can arsenic
enhanced residuals
be effectively managed
RM Task 1a. Conduct laboratory
and field tests on arsenic control
technologies including As III
oxidation.
High Priority (CF, LS, AA,
IE, Fe/MnP)
Medium Priority (NF, RO, ER)
RM Task 2a. Complete cost
evaluations for arsenic control
technologies in RM 1 a.
Medium Priority
RM Task 3a. Conduct studies
on the arsenic characteristics of
the residual material generated
by testing in RM 1a.
High Priority
RM Task 3b. Conduct studies
to modify treatment methods to
reduce quantity of residuals and
to develop residual disposal
methods to reduce costs under
more stringent regulations
Series of reports describing
the technical performance of
the different arsenic control
technologies
Report describing the economic
considerations associated with
the operation of each treatment
technology studies in RM 1 a.
Reports on the quantity and
the composition of arsenic
containing residuals and
disposal options for each
treatment technology
considering existing and more
stringent residual disposal
regulations
Report on treatment
modifications to reduce
residuals and more cost-
effective disposal methods
Will be use in the rule making
process to demonstrate the
capabilities and performance of
arsenic control technologies to
Achieve revised MCL
Will be used to determine any
adverse economic considerations
that will arise from small systems
complying with the revised MCL
for arsenic
Used to determine the recycle/
disposal options for the residual
material generated by the
technologies tested in RM 1 a and
to determine total costs of arsenic
treatment for large and small
systems
Will be used to provide guidance
to utilities on residual disposal
options and residual costs
Table 4-3. Risk Management Task Summary, Current Activities and Proposed Sequence for Studies
Task1 Ongoing Priority Time Frame2
Task - Short Study Title 1 E/O
RM Task 1 a. Bench field I E
Y/N Priority
Y High for CF,
LS, AA, IE and
Fe/MnP Medium
for NF, RO and
ER
FY97 FY98 FY99 FYOO FY01 FY02
EPA EPA EPA
RM Task 2a. Technical and
economic considerations of
arsenic control for small systems
RM Task 3a. effective
management of arsenic
enhanced residues
RM Task 3b. Treatment
modification to reduce
arsenic residuals
Medium
High
Medium
EPA EPA
EPA EPA EPA EPA
EPA EPA EPA
'I = Intramural (EPA inhouse research), E = Extramural (EPA sponsorship through grant or co-op)
!EPA « EPA has ongoing studies or plans to address this task in future years; some tasks may require additional research beyong EPA's
planned effort.
NOTE: RM Tasks 2a. and 3a. are to be carried out as subtasks under the technology performance research in RM Task 1a.
38
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Table 5-3. Summary of Tasks and Priority
Task
RA 1a
1b
1C
2a
2b
Exp 1a
1b
2a
2b
2c
3a
3b
3c
3d
4a
4b
4c
5a
6a
7a
8a
Eff 1a
1b
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2a
2b
2c
2d
3a
RM 1a
2a
3a
3b
Short-Term Long-Term
X
X
X
X
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X
X
X
X X
X
X
X
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x
X
X
X
X
X X
X
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X
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X
X
X
X
X
X
X
X
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X
Priority
High
High
High
Medium
Medium
High
High
High
High (short-term) Medium (long-term)
Low
High
Medium
Medium
Medium
High
Medium
Medium
High
High (water) Medium (diet)
High
Medium
High
High
Medium
High
Medium
Medium
High
1 High (long-term) Medium (short-term)
High
Medium
Medium
Medium
47
-------
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