United States     Office of Water     EPA 815-R-00-015
  Environmental Protection (4607)        December 2000
  Agency        Washington, DC 20460  www.epa.gov/safewater
  Report to Congress

  EPA Studies on Sensitive
       Subpopulations
             and
Drinking Water Contaminants

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                                EXECUTIVE SUMMARY

       The Safe Drinking Water Act (SDWA) requires the U.S. Environmental Protection
Agency (EPA) to establish national drinking water standards that protect the health of the 250
million people who get their water from public water systems.  These standards are intended to
protect the general public as well as those groups of individuals who may be more sensitive than
the general population to the harmful effects of contaminants in drinking water. The high priority
assigned to studies of sensitive subpopulations and to the drinking water research program in
general reflects the Agency's commitment to ensuring that regulatory decisions on
microbiological and chemical contaminants in drinking water have a strong scientific foundation
for public health protection.

       The 1996 SDWA Amendments (Section 1458(a)) include the following requirements for
conducting studies on sensitive subpopulations:

              (1) The Administrator shall conduct a continuing program of studies to identify
       groups within the general population that may be at greater risk than the general
       population of adverse health  effects from exposure to contaminants in drinking water. The
       studies shall examine whether and to what degree infants, children, pregnant women, the
       elderly, individuals with a history of serious illness, or other subpopulations that can be
       identified and characterized are likely to experience elevated health risks,  including risks of
       cancer, from contaminants in drinking water.
              (2) Not later than 4 years after the date of enactment of this subsection, and
       periodically thereafter as new and significant information becomes available, the
       Administrator shall report to the Congress on the results of the studies.

       This document is the first Report to Congress on the status, results and future  directions
of studies conducted by the EPA to identify and characterize sensitive subpopulations  that may be
at greater risk from exposure to drinking water contaminants than the general population.
Sensitive subpopulations are defined in this report as groups of individuals who respond
biologically at lower levels of exposure to a contaminant in drinking water or who have more
serious health consequences than the general population. EPA is conducting a program of studies
to identify such groups  which may include infants, children, pregnant women, the elderly, or
individuals with a history of chronic illness  and to evaluate whether and to what degree they are
likely to experience elevated health risks.

       The studies conducted or supported by EPA have been guided by the Agency's research
plans and strategies, expert workshops on special topics, and consultations with other  agencies,
research organizations, and the drinking water community.  Partnerships with Federal  agencies,
the water industry, universities and other research entities have been essential to the successful
implementation of the Agency's program to address this issue.  EPA studies of sensitive
subpopulations involve multidisciplinary research and assessments to identify the scope of possible

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health outcomes, including cancer, reproductive toxicity, gastrointestinal illness, and other
adverse health effects.  Approaches being used to address sensitive subpopulation issues include:

      !      Population-based epidemiology studies to identify potentially harmful contaminants,
            risk factors and sensitive subpopulations;
      !      Clinical studies to evaluate the effects of specific contaminants and the host factors
            that influence the disease process;
      !      Studies in laboratory animals to provide hazard identification and dose-response
            data, as well as to elucidate how contaminants cause their effects;
      !      The development and validation of standardized test methods for the evaluation of
            contaminants that may be of special concern to certain subpopulations;
      !      The development of improved methods and data bases to better estimate total
            exposures to drinking water contaminants from all relevant sources and routes (i.e.,
            oral, dermal and inhalation);
      !      The compilation of existing data to assist in characterizing specific sensitive
            subpopulations; and
      !      The development of improved risk assessment methods that will permit better use of
            all available information on health effects and exposure.

       Important factors that are being investigated include life stage (i.e., fetuses, infants and
children, the elderly), gender, genetic traits, health status and exposure.  Research has  focused on
the highest priority waterborne pathogens and chemicals from a public health and regulatory
perspective. The parasite Cryptosporidium, for example, has been reported to be the cause of
over 14 outbreaks in the U.S. since 1985, including one in Milwaukee in 1993 that involved an
estimated 400,000 illnesses and over 50 deaths. A large number of these deaths occurred in
individuals with weakened immune systems. Data from the laboratory and field suggest that
exposure to disinfection by-products  (DBFs), which are formed when chlorine and other
disinfectants react with naturally occurring materials in the water, may pose  a risk of certain types
of adverse health effects. The 1996 SDWA Amendments specifically identify these and several
other contaminants as high priorities  for research and regulatory determinations.

       Highlights from the EPA program of studies on sensitive subpopulations are described
below:

       Waterborne pathogens. The results of an analysis of physiological and exposure-related
characteristics of infants and children suggest that these groups may be more sensitive than the
general population to waterborne pathogens.  This is consistent with data collected on the
demographics of foodborne illnesses, but the data from waterborne disease outbreaks in the U.S.
are less conclusive.  The results of several epidemiology studies and surveys that are currently
underway should provide important information on the risks that pathogens in drinking water
pose to infants, children, and other age groups. Individuals with pre-existing disease, particularly
those with weakened immune systems, are known to be at increased risk following exposure to

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opportunistic pathogens such as Cryptosporidium. EPA is conducting research in the laboratory
and field to further evaluate the impact of host immune status on sensitivity to these agents.

       Chemicals.  Studies conducted by EPA and others have raised concerns about a potential
risk of adverse reproductive outcomes following maternal exposure to DBFs.  EPA research has
also shown that exposure of laboratory animals to high levels of certain pesticides can cause
adverse developmental effects. Current laboratory research on pesticide modes of action, along
with epidemiology studies of childhood sensitivity to pesticides, will contribute to a better
understanding of the potential risks of these contaminants to subpopulations of special concern.
In studies to evaluate the health effects of sulfate, EPA researchers and collaborators found that
piglets (as a model for human infants) and previously unexposed adults were not particularly
sensitive to the effects of this contaminant in drinking water.

       Considerable progress has been made in the development of improved methods for
evaluating toxicity, assessing exposures, and conducting risk assessments of contaminants and
subpopulations of special concern.  These new tools will enable Agency scientists to generate
critical data and conduct scientifically sound risk assessments in support of the requirements of
SDWA and other regulatory statutes.

       Future priorities include studies of DBF exposures and adverse reproductive outcomes,
risks to infants and children from exposure to waterborne pathogens, and risks to individuals
whose health status is compromised.  The Agency will continue to support studies that further
characterize risks to the elderly and that evaluate the role of genetic factors in environmentally-
induced disease.  Emphasis will also be placed on the development of improved methods for
assessing toxicity, exposure and risk.
                                            in

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                                  CONTRIBUTORS
Principal Author:    Fred Hauchman, Office of Research and Development

Steering Committee:  Joyce Donohue, Office of Water
                    Ken Elstein, Office of Research and Development
                    Karl Jensen, Office of Research and Development
                    Amal Mahfouz, Office of Water
                    Dan Olson, Office of Water
                    Robin Oshiro, Office of Water
                    Sherri Umanski, Office of Water
                                          IV

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                             TABLE OF CONTENTS

EXECUTIVE SUMMARY	i
CONTRIBUTORS 	 iv
1.     INTRODUCTION	1
2.     BACKGROUND	2
      2.1    Definition of Sensitive Subpopulations	2
            2.1.1  Intrinsic Factors  	3
            2.1.2  Acquired Factors  	4
      2.2    Contaminants of Concern	4
            2.2.1  Waterborne Pathogens 	4
            2.2.2  Chemicals	6
3.     OVERVIEW OF RESEARCH PROGRAM	7
      3.1    Risk Assessment Framework 	7
      3.2    Identification and Prioritization of Research Needs	7
      3.3    Research Approach  	8
4.     EPA STUDIES ON SENSITIVE SUBPOPULATIONS 	9
      4.1    Life Stages	9
            4.1.1  Fetuses	9
            4.1.2  Infants and Children 	11
            4.1.3  The Elderly	13
      4.2    Gender	13
      4.3    Genetic  Traits	14
      4.4    Health Status 	16
      4.5    Exposure  	17
5.     CONCLUSIONS	18
6.     REFERENCES   	20

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1.     INTRODUCTION

       Studies to identify and characterize sensitive subpopulations are an important component
of the U.S. Environmental Protection Agency's (EPA) drinking water research and assessment
program.  These studies provide scientific information to support current Safe Drinking Water
Act (SDWA) rule making activities (e.g., the Stage 2 Disinfectants/Disinfection By-Product Rule)
as well as future regulatory decisions on microbiological and chemical contaminants in drinking
water.  Sensitive subpopulation research that is conducted in support of other regulatory statutes
is also relevant to drinking water issues. For example, both the Food Quality Protection Act of
1996 (FQPA) and 1996 Amendments to SDWA require the development of a screening and
testing program to determine whether substances may have  adverse effects on the endocrine (i.e.,
hormonal) system in the body.  Collectively, these efforts provide critical information to ensure
that public health standards for drinking water (e.g., Maximum Contaminant Levels, or MCLs)
protect both the general population and subpopulations of special concern.

       Section  1458(a) of the 1996 Amendments to SDWA requires the Administrator to
conduct "...a continuing program of studies to  identify groups within the general population that
may be at greater risk than the general  population of adverse health effects from exposure to
contaminants in drinking water. The studies shall examine whether and to what degree infants,
children, pregnant women, the elderly,  individuals with a history of serious illness, or other
subpopulations that can be identified and characterized are likely to experience elevated health
risks, including risks of cancer, from contaminants in drinking water. Not later than 4 years after
August 6, 1996, and periodically thereafter as new and significant information becomes available,
the Administrator shall report to the Congress  on the results of the studies."

       This report summarizes the status,  results and future direction of the Agency's studies to
identify and characterize sensitive  subpopulations that may be at a greater health risk from
exposure to drinking water contaminants than the general public.  The focus of this report is on
studies conducted or supported by  EPA's Office of Research and Development and the Office of
Water. Relevant sensitive subpopulation studies from other programs within the Agency are also
summarized. To fully identify and characterize subpopulations that may be more sensitive than
the general population to contaminants in drinking water, the results of EPA studies need to be
considered in the context of the larger body of scientific literature on this topic.

       Section 2 provides a definition of sensitive subpopulations and an overview of waterborne
pathogens and chemicals of special concern. Section 3  describes the risk assessment framework
and research approach used by EPA to address sensitive subpopulation issues.  The status and
results of EPA studies in the areas  of health effects, risk assessment and exposure are described in
Section 4. Section 5 includes a summary of the report and a discussion of future research
directions. References are found in Section 6.

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2.     BACKGROUND

2.1    Definition of Sensitive Subpopulations

       Sensitive Subpopulations are defined in this report as groups of individuals who respond
biologically at lower levels of exposure to a contaminant in drinking water or who have more
serious health consequences than the general population. This definition also includes those
individuals who have a greater level of exposure than the general population as a consequence of
biological factors that are characteristic of the group to which they belong. As there is no
universally accepted definition of the term "sensitive subpopulation," the definition used above is
intended only for the purposes of this report.

       Sensitive Subpopulations may be considered in the context of various intrinsic (e.g., age,
gender, genetic traits) or acquired (e.g., pre-existing disease, exposure) characteristics that may
modify the risk of illness or disease.  Some characteristics of Subpopulations may directly
influence the underlying processes involved in the response of an individual to a contaminant, such
as when a pre-existing medical condition may make an individual less resistant to infection. Other
factors, such as socioeconomic status or lifestyle, may have indirect effects.  People with low
incomes, for example, may not have the same access to health care as those in higher
socioeconomic groups.  The studies described in this report focus primarily on intrinsic and
acquired factors that may directly influence sensitivity.

       In some instances, sensitivity factors may be closely linked to each other. For example,
the incidence of certain  types of chronic disease appears to be related to age or gender.
Additionally, people may cycle in and out of being more sensitive than the general population,
depending upon their age or health status at a particular point in time. While intrinsic and
acquired factors are therefore not entirely independent or fixed for the lifetime of an individual,
they provide a useful basis for classifying and studying sensitive Subpopulations.

       Data on the number and percentage of individuals in some of the major subgroups  in the
U.S. are shown in Table 1.  The data indicate that a significant portion of the population belongs
to groups with characteristics that could make them more sensitive than the general population to
the effects of environmental contaminants.

       Among the many factors that may either directly or indirectly influence sensitivity, those
discussed below are considered by EPA to be of greatest relevance for studying sensitive
Subpopulations exposed to  drinking water contaminants.

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Table 1. Selected Subpopulations1 in the United States










Siihpopulation
Life Stage
Pregnant women2
Infants and children (<10 years)3
Elderly (65+ years)3
Number of
Individuals

6,240,000
38,704,000
34,817,000
Estimated % of
Population

2.4
14.1
12.6
Health Status
Diabetes (diagnosed and estimated undiagnosed cases)4
Liver impairments5
Cardiovascular disease6
AIDS7
15,700,000
595,000
59,700,000
400,500
5.8
0.2
21.7
0.2
1 Categories of subpopulations are not mutually exclusive.
2 Ventura et al, 1999.
3 U.S. Census Bureau, 2000.
4 CDC, 1998.
5 EPA, 1998a.
6 National Heart, Lung, and Blood Institute, 2000.
7 CDC, 1999.

2.1.1   Intrinsic Factors

       Life stage. This category includes groups that may be at increased risk because of
inherent physiological factors or exposure characteristics that are unique to the particular period
of development or age of the individual. These groups include:

              Fetuses, who may be at increased risk if exposure of the pregnant woman to a
              toxic agent occurs during critical developmental stages;
              Infants and children, whose defense mechanisms against microbial and chemical
              contaminants may not be fully developed;
              The elderly, who may be less able to mount an effective defense against microbial
              or chemical contaminants because of a weakened immune system or pre-existing
              disease.
       Gender. Adult females or males may be more sensitive to the effects of certain
contaminants because of gender-specific physiological factors or differences in the prevalence of
certain types of diseases. For example, men appear to have a greater likelihood of liver
impairments, whereas women are more prone to kidney and thyroid disorders.  Pregnancy causes

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changes in the endocrine system and metabolism, which may in turn influence the body's response
to a toxic  substance.

       Genetic traits. The human body's ability to detoxify and eliminate a chemical agent or
mount an  effective defense against a microbial pathogen is related, in part, to the genetic make up
of the individual.  Groups of individuals who share certain genetic characteristics, such as the
altered ability of a gene to produce a critical  enzyme involved in the metabolism and detoxification
of chemical toxicant, may therefore be at greater risk than the general population. As a practical
matter, however, genetic influences are complex and still poorly understood. It is unclear to what
extent individuals with heightened sensitivities due to genetic factors meet the statutory criterion
of "subpopulations that can be identified and characterized."

2.1.2  Acquired Factors

       Health status.  Groups of individuals with certain pre-existing diseases or clinical
conditions may be more sensitive to the effects of chemicals or microbes present in drinking
water.  For example, people with impairments of the liver, kidney or immune system may be less
able to prevent or eliminate the effects of a contaminant due to weakened natural defenses or
detoxification mechanisms. Immunocompromised individuals, including organ transplant patients,
cancer patients being treated with immunosuppressive drugs, and those whose immune system is
weakened by the virus that causes acquired immunodeficiency syndrome (ADDS), are also at
increased risk following exposure to certain infectious and chemical agents.

       Exposure. Some groups of individuals share certain biological characteristics that result
in a greater level of exposure than that experienced by the general populations.  For example,
although infants consume less water than adults, they may have a higher likelihood  of being
exposed to toxic levels of a chemical contaminant because their water ingestion rate is three to
four times greater when calculated on the basis of volume consumed per kilogram of body weight
(EPA, 2000).

2.2     Contaminants of Concern

2.2.1  Waterborne Pathogens

       The disinfection of public water supplies has been one of the most successful public health
interventions of the 20th century, dramatically reducing the incidence of waterborne disease
outbreaks throughout the world. Despite the historic success of modern drinking water treatment
techniques, the continued occurrence  of waterborne disease outbreaks demonstrates that
contamination of drinking water with  pathogenic bacteria, viruses, and parasites still poses a
potentially serious health risk when treatment is inadequate or when there is contamination in the
distribution system. The level of exposure, as well as the characteristics of both the microbe and
the host, influence the outcome of infection. The most common health effect that occurs when a
susceptible individual is exposed to an infectious dose of a waterborne pathogen from drinking
water is an acute form of gastrointestinal disease.  Infections are typically mild and transient, but

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they may also result in more serious illness or even death in the most extreme cases. Some
pathogens may cause longer-term effects, such as heart disease or liver failure.

       The pathogenic bacteria most commonly associated with foodborne outbreaks and
waterborne outbreaks from public and private water systems are Escherichia coli, Salmonella,
Campylobacter andShigella (Gerba et al, 1996). Recently, E. coli O157:H7 was implicated as
the cause of outbreaks in the U.S. and Canada in which several people died.  The most commonly
reported cause of waterborne viral gastroenteritis is Norwalk virus.  This virus  or other members
of the calicivirus family are believed to account for a significant portion of the outbreaks for
which a causative agent has not been determined. Hepatitis A virus and  rotavirus have also been
found to cause waterborne disease outbreaks, whereas the extent to which viruses such as
coxsackievirus and echovirus may pose a
risk following contamination of drinking
water is unclear.  The protozoan parasites
Giardia lamblia and Cryptosporidium
parvum are among the most threatening
microbiological contaminants found in
drinking water. Giardia has been
responsible for about half of the outbreaks
of disease where the causative agent was
identified.  Cryptosporidium has been
                                                    Drinking Water Contaminants and
                                                        Health Effects of Concern

                                             Pathogens
                                               Bacteria (e.g., Mycobacterium avium complex, E.
                                                coli O157:H7)
                                               Viruses (e.g., Norwalk virus)
                                               Parasites (e.g., Cryptosporidium, Giardia lamblia)
                                              Chemicals
                                                Disinfection by-products (e.g., trihalomethanes)
                                                Arsenic
                                                Sulfate
                                                Pesticides
                                                Other inorganic and organic contaminants
responsible for at least 14 outbreaks in the
U.S. since 1985, including a 1993 outbreak
in Milwaukee which caused an estimated
400,000 illnesses and over 50 deaths.  A
large number of these deaths occurred in
individuals with weakened immune systems.

       "Opportunistic" pathogens are
microorganisms that normally do not pose a
serious risk to healthy individuals but are
more likely to cause disease (often severe) in
individuals with weakened immune systems.
Cryptosporidium and microsporidia are
opportunistic protozoans that can cause life
threatening illnesses in immunocompromised individuals. Opportunistic bacterial pathogens of
concern include Mycobacterium avium, Legionella species and Pseudomonas aeruginosa.  These
microorganisms are able to grow and persist as biofilms on pipes in the distribution system.
                                             Health Effects
                                               Gastrointestinal illness
                                               Cancer
                                               Adverse reproductive outcomes
                                               Immune system effects
                                               Neurotoxicity

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2.2.2  Chemicals

       A wide variety of naturally occurring and man-made chemicals may contaminate drinking
water.  These substances vary considerably in terms of the types and severity of effects that they
elicit in both the general population and in groups that may be more sensitive. The extent to
which a substance may be harmful is a function of exposure, the chemical and physical properties
of the agent, and the inherent sensitivity of the host. At sufficiently high levels of exposure,
chemicals may affect different organ systems and may cause a range of effects (e.g., irritation,
liver disease, adverse reproductive outcomes, cancer). For some chemicals, the parent compound
is responsible for the toxic effect, and the biochemical process called biotransformation (involving
metabolism) is required to detoxify the substance.  In other cases, the biotransformation process
itself is responsible for the production of the toxic form of the contaminant.

       A considerable  amount of information exists on the special sensitivities of certain
subgroups, particularly infants and children, to the drinking water contaminants lead, nitrate/nitrite
and fluoride.  Prenatal and postnatal exposures to lead have been shown to increase the risk of
neurodevelopmental damage in infants and children.  Nitrate and nitrite are known to pose a risk
to infants whose immature enzyme systems  cannot adequately protect hemoglobin,  the oxygen
carrying pigment in the red blood cells, from oxidation. The oxidized form of hemoglobin, called
methemoglobin, does not carry oxygen effectively and can be life threatening without immediate
medical attention. Fluoride can cause discoloration of the tooth enamel in children  if exposure
occurs during the period of tooth formation. EPA has developed National Primary  Drinking
Water Standards (MCLs) for lead and nitrate/nitrite that protect infants and children from harmful
levels of these contaminants in drinking water.  A secondary standard has been established for
fluoride to protect children from discoloration of tooth enamel.

       In the 1970s, scientists determined that a number of biologically active chemical
substances, referred to  as disinfection by-products (DBFs), are formed when chlorine and other
chemical oxidants used to treat drinking water react with  naturally occurring materials in the
water.  It is now known that disinfected water may contain hundreds of different DBFs, including
trihalomethanes, haloacetic acids, haloacetonitriles, and a number of other types of  chlorinated
and/or brominated compounds.  Some DBFs have been found to cause adverse health effects in
laboratory animals exposed to high concentrations of these compounds.  Epidemiology and
toxicology studies have raised concerns over potential risks of cancer and, more recently, adverse
reproductive effects.

       Arsenic has been found to cause different types of cancer and noncancer effects in
populations from various locations throughout the world.  As noted by the National Research
Council in their recent  report on arsenic in drinking water (NRC, 1999), a variation in
susceptibility to arsenic-induced effects may exist between population groups and individuals.
The extent to which genetic background, gender and  diet  may influence sensitivity to this source
water contaminant is unclear.  Laboratory animal research on certain pesticides (e.g., chlorpyrifos)
has suggested that the fetus and young animals may not have  the same capacity as adults to
detoxify and eliminate these substances from the body. Chemicals known as endocrine disrupters

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affect the natural hormones in the body that are responsible for the maintenance of normal body
function and the regulation of developmental processes. Small disturbances in endocrine function,
especially during certain stages of the life cycle (e.g., development, pregnancy and lactation) can
lead to profound and lasting changes.

3.     OVERVIEW OF RESEARCH PROGRAM

3.1    Risk Assessment Framework

       The process of risk assessment, as described by the National Academy of Sciences (NAS)
in 1983, provides the framework used by EPA to identify key issues, information gaps and
research needs for sensitive subpopulations (NRC, 1983).  The NAS risk assessment paradigm,
which was developed primarily for the assessment of chemical risks, has four main steps: hazard
identification, dose-response assessment, exposure assessment and risk characterization.
Although there  are some features of microbiological risk assessment that make it distinct from the
assessment of chemical risks (e.g., pathogen viability, infectivity and secondary spread), the NAS
framework may be used as a guide for both types of contaminants.  This Report to Congress
focuses primarily on the first three steps of the risk assessment process.  Health effects studies
cover the first two steps (hazard identification and dose-response assessments), whereas exposure
studies cover the third step. The Agency will conduct formal risk characterizations (step four) as
part of the regulatory development process for specific contaminants of concern.

3.2    Identification and Prioritization of Research Needs

       Studies  conducted by EPA to address sensitive subpopulation issues have been guided by
the Agency's research plans and strategies (EPA, 1997; 1998b;  1998c; 1999b), expert workshops
on special topics (e.g., EPA, 1993; 1998d), and consultations with other Federal agencies and
research organizations. In addition, a special series of meetings on sensitive subpopulations was
held with drinking water stakeholders as part of the SDWA 25th Anniversary Futures Forum
activities.  Participants in these meetings emphasized the need for better information to
characterize sensitive subpopulations, the contaminants that pose special risks, and the exposure
levels at which  the effects may occur.

       EPA has placed considerable emphasis on research to address sensitive subpopulation
issues for waterborne pathogens and chemicals on the current drinking water regulatory agenda
(e.g.,  Cryptosporidium, DBFs).  Studies are increasingly focusing on pathogens and chemicals
that may be candidates for future regulations, including those on the EPA's Contaminant
Candidate List1 (EPA, 1998e).
3.3    Research Approach
       lrThe EPA was required by SDWA to establish a list of contaminants, called the Contaminant Candidate
List (CCL), to aid in priority setting for the Agency's drinking water program. The CCL contains 60
microbiological and chemical contaminants that are currently not subject to any proposed or promulgated national
primary drinking water regulation, are known or anticipated to occur in public water systems, and may require
regulation under SDWA.

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       Studies of sensitive subpopulations typically involve multidisciplinary research and
assessments to identify a range of possible health outcomes, including cancer, reproductive
toxicity, gastrointestinal illness, and other adverse health effects. EPA is using several approaches
to address sensitive subpopulation issues:  1) population-based epidemiology studies to identify
potentially harmful contaminants, risk factors and sensitive subpopulations; 2) clinical studies to
evaluate the effects of specific contaminants and the host factors that influence the disease
process; 3) studies in laboratory animals to provide hazard identification and dose-response data,
as well as to elucidate how contaminants cause their effects; 4) the development and validation of
standardized test methods for the evaluation of contaminants that may be of special concern to
certain subpopulations; and 5) the development of improved methods and data bases to better
estimate total exposures to drinking water contaminants from all relevant sources and routes (i.e.,
oral, dermal and inhalation). EPA is also compiling existing data to assist in characterizing
specific sensitive subpopulations, and is developing improved risk assessment methods that will
permit better use of all available information on health effects and exposure.

       To address the broad scope of sensitive subpopulation research issues, EPA has
established partnerships to leverage resources and capabilities with various Federal and state
agencies, universities, the  water industry and other public or private research entities.
Collaborations have been established with the Department of Health and Human Services' Centers
for Disease Control and Prevention (CDC) and National Institute of Environmental Health
Sciences (NIEHS) to address several high priority epidemiology and toxicology research needs.
For example, EPA, CDC and NIEHS established eight Centers of Excellence in Children's
Environmental Health and Disease Prevention Research.  The Centers are conducting basic and
applied research in combination with community-based prevention efforts.  EPA and the
American Water Works Association Research Foundation (AWWARF) are co-funding several
important drinking water research studies under the auspices of the Microbial/Disinfection By-
Products Research Council2.  The Agency's extramural grants program supports research on
waterborne pathogens, chemicals in drinking water and endocrine disrupters in universities and
non-profit research organizations throughout the country.  In addition, EPA has worked on
endocrine disrupter testing and research issues in close collaboration with international
organizations and advisory groups, particularly the Organization of Economic Cooperation
(OECD) and Development and the Endocrine Disrupter Screening and Technical Advisory
Committee (EDSTAC).
        The Microbial/Disinfection By-Product Research Council was established in 1995 by the EPA and
AWWARF for the purpose of making funding decisions on cooperative research. The Council is composed of
three EPA representatives, three members of the AWWARF Board of Trustees, and three representatives of the
Disinfectant/Disinfection By-Product Rule Regulatory Negotiation group.

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4.
EPA STUDIES ON SENSITIVE SUBPOPULATIONS
       Studies conducted or supported by EPA to
identify and characterize sensitive subpopulations can be
described in the context of the various intrinsic and
acquired factors described in Sections 2.1.1 and 2.1.2.
While many of the studies are still in progress, those that
have been completed are providing important insights to
improve risk assessments and guide future research
activities. A description of EPA research  and assessments
on sensitive subpopulations is found below.

4.1    Life Stages

4.1.1   Fetuses
                                                   Factors Considered in Studies of
                                                      Sensitive Subpopulations

                                                    Life stage
                                                       Fetuses
                                                       Infants and children
                                                       Elderly
                                                    Gender
                                                    Genetic traits
                                                    Health status
                                                       Pre-existing diseases
                                                       Immune system deficiencies
                                                    Exposure
       Disinfection by-products  One of the most
important investigations to draw attention to the issue of DBFs and adverse reproductive
outcomes was a prospective epidemiology study, funded in part by EPA, of 5,144 pregnant
women in California (Waller et a/., 1998). The authors of this study reported an association
between exposure to high levels of trihalomethanes and the incidence of miscarriage. The
potential for DBFs to cause adverse reproductive outcomes was also examined in an EPA-funded
study in Colorado, in which the authors reported an association between high trihalomethane
levels and low birth weight (Gallagher et a/., 1998). These studies and a small number of other
published reports have provided some clues suggesting that fetuses could be sensitive to DBF-
induced toxic effects. However, the uncertainties in the epidemiologic data, particularly with
respect to the exposure assessment, preclude a more definitive conclusion about the possible
association between DBFs and adverse reproductive outcomes.

       EPA is supporting several studies to address the need for additional information on this
issue, including:  1) a reanalysis of the California spontaneous abortion study using improved
exposure data; 2) an ongoing prospective pregnancy study in California to which information on
DBF levels from selected drinking water utilities is being added; 3) a major new spontaneous
abortion study in North Carolina, Virginia and Texas, co-funded with AWWARF; and 4) birth
defects studies that are being conducted in conjunction with CDC's Centers for Birth Defects
Research and Prevention in locations throughout the country. Efforts to improve the exposure
assessment component of epidemiology studies are discussed in Section 4.5 of this Report.

       To further explore the relationship between DBF exposures and adverse reproductive
outcomes, EPA has developed an extensive extramural and in-house toxicology research
program. A key  feature of the extramural effort is a collaborative research  project with the
National Toxicology Program (NTP) of the National Institute of Environmental Health Sciences.
NTP conducts screening studies in rodents using a standardized protocol to evaluate the effects of

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DBFs on both male and female reproductive systems, as well as on fetal development.  Studies
have been conducted on a number of individual DBFs, and an evaluation of a mixture of four
haloacetic acids is now underway. Sodium bromate and bromochloroacetic acid have been shown
to exhibit selective reproductive toxicity at high experimental exposure doses (NTP, 1996; 1998).
Additional studies are being conducted to follow up on these results in more detail.

       EPA scientists are currently conducting animal studies on the potential for two DBFs,
dibromoacetic acid and bromochloroacetic acid, to delay puberty and alter male reproductive
competence in the offspring.  Other ongoing studies are evaluating the effects of exposure to
mixtures of DBFs on reproductive outcomes. A multigeneration study has been initiated to
evaluate the potential effects  of a priority DBF (bromochloroacetic acid) following long-term, low
dose exposure throughout the life cycle of the experimental animal.

       In 1998, EPA published a report that evaluated the available data for each  of the
disinfectants and DBFs, for which Maximum Residual Disinfectant Level Goals (MRDLGs) and
Maximum Contaminant Level Goals (MCLGs), respectively, were developed in support of the
final Stage 1 D/DBP Rule (EPA, 1998f). These nonenforceable health goals are set at exposure
levels for which no known or anticipated adverse health effects occur, including an adequate
margin of safety. On the basis of this analysis, EPA concluded that the MRDLGs  and MCLGs for
all the D/DBPs in the Stage 1 Rule were protective of fetuses, infants and children.

       Arsenic.  EPA scientists and collaborators are studying sensitive subpopulation issues for
arsenic in regions of the world where the drinking water is highly contaminated. A study in Chile
evaluated the potential association between exposure to arsenic in drinking water and the risk of
mortality to the fetus and newborn infants  (Hopenhayn-Rich et a/., 2000).  While the results were
suggestive of a possible association at high exposure levels, the data are still insufficient to allow
firm conclusions. A second Chilean study  is examining the possible association of low level
exposure to arsenic with low birth weight, prematurity, and indicators of maternal  health.  A study
to evaluate the health effects  of arsenic has also been initiated by EPA researchers and
collaborators in Inner Mongolia.  A variety of health endpoints, including adverse  reproductive
outcomes, will be examined in an area with a wide range of arsenic concentrations in the drinking
water supply.

       Pesticides/endocrine disrupters.  Under the EPA's research programs on pesticides and
endocrine disrupters, a wide  range of studies are  being conducted to provide insights into risks
that these chemicals pose to the developing fetus and to other life stages. EPA researchers have
demonstrated that selected organophosphate, triazine and dithiocarbamate pesticides can cause
adverse effects on the development of animals when exposure to high experimental doses occurs
during critical periods of development (Cooper et a/., 1999).  Current research on the mode of
action of some of these agents is being conducted to help evaluate the extent to which these
effects may be relevant to humans at the lower exposure concentrations that may occur in
drinking water.
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       In support of both Food Quality Protection Act (FQPA) and SDWA, significant progress
has been made in the development of standardized and validated methods for testing of chemicals
that may have estrogenic or other endocrine effects in humans. Research has focused on the
development of mammalian, non-mammalian and in vitro (i.e., cell culture) screening assays. The
assays will be used to help identify chemicals that will require further testing, to provide
information on the mechanisms by which they may cause their effects, and to help understand the
stages of the life cycle that may be most susceptible to toxic insult with these substances.  Some
of these screening assays have reached the pre-validation stage.  EPA estimates that all of the
assays under development will be validated by 2003.

4.1.2  Infants and Children

       Water borne pathogens. To evaluate the factors that may result in a greater sensitivity of
infants and children following exposure to waterborne pathogens, EPA is conducting a review of
data on various physiological  and exposure-related characteristics of these groups that can
influence infection and disease outcome. The immaturity of the child's organ systems, particularly
the  immune system and gastrointestinal tract, is a factor that can increase the likelihood of
infection and the severity of the illness. Inherent exposure-related physiological factors (e.g., a
higher water ingestion per unit body weight compared to adults) may also contribute to a greater
risk.

       The issue of whether children are more likely than adults to experience waterborne
gastrointestinal illness is being examined as part of a series of studies being conducted or
supported by the Agency in different parts of the U.S. Researchers are evaluating the health
status of families in three communities before and after the local water utilities upgrade their
treatment systems. The results of the first of these "community intervention" studies will  be
available in FY2001. As part of the EPA/CDC program of waterborne disease occurrence studies
(required by the  1996 SDWA Amendments), researchers from the University of California at
Berkeley are conducting a large epidemiology study in a Midwestern community that may provide
additional information on the  extent to which children and other demographic groups are  more
sensitive to waterborne infectious disease. Beginning in 1998, EPA supported the addition of a
water component to the CDC's Foodborne Diseases Active Surveillance Network (FoodNet).
This multi-state gastrointestinal illness  surveillance program is collecting information on the risks
to children and other demographic groups from exposure to microbiological contaminants in food,
drinking water and recreational water.

       To determine the influence of age and other demographic parameters on sensitivity to
microbial diseases and mortality, EPA conducted an analysis of data from FoodNet (prior to the
inclusion of the water component) and from waterborne disease outbreaks that were reported
through 1994 (EPA, 1998g).  Information from FoodNet indicated that there have been many
more cases of foodborne illnesses in infants and children than in other age groups.  The
waterborne disease outbreak data generally did  not reflect a greater sensitivity of infants and
children. These results should be interpreted with  caution due to the incomplete nature of the
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information examined and the possible influence of biases in reporting data for certain age groups
(e.g., there may be a greater frequency of reporting cases in the very young and elderly by adult
caregivers).

       Chemicals. Several assessment-related activities are being conducted by the Agency to
better characterize the risks to children following exposure to chemicals in drinking water. EPA
will soon publish the results of a workshop in which experts reviewed information on critical
"windows" of exposure during which time the developing organism (fetus, newborn, child and
adolescent) may be particularly sensitive to the effects of selected chemicals.  Other EPA projects
that are underway include an assessment of the potential risk of childhood cancers associated with
exposure to chemicals in drinking water, and an analysis of the potential relationship between
early-life exposures and lifetime cancer risks. In addition to these efforts, EPA is evaluating
innovative statistical approaches (i.e., Benchmark Dose and Categorical Regression)  to determine
their applicability in assessments of the dose-response in children for two drinking water
contaminants, chloral hydrate and nitrate/nitrite.

       In response to concerns about the potential sensitivity of infants to sulfate-induced
diarrhea, the EPA supported a study using neonatal piglets as a model to evaluate the effects of
inorganic sulfate in drinking water on bowel function in human infants (Gomez et a/., 1995).  The
results of this study did not indicate that infants may be  particularly sensitive to sulfate, as the
presence of sulfate in drinking water at levels of up to 1200 mg/L (as sodium sulfate) produced
minimal or no adverse health effects. A similar absence of effects was observed in EPA-
sponsored studies with adult volunteers who had no previous exposure to sulfates in drinking
water (Heizer et a/., 1997). The results suggest that transient populations may not have a greater
sensitivity to sulfate as had been previously suggested (EPA,  1999a).

       EPA is supporting an epidemiology study of childhood sensitivity to pesticides in which
several routes of exposure (i.e., ingestion, dermal and inhalation) to persistent organic compounds
are being evaluated.  In another study conducted as part of the National  Health and Nutrition
Examination Survey (NHANES), EPA is supporting data collection and analysis of serum or urine
levels of several organochlorine, organophosphate and pyrethroid pesticides, as well as selected
polychlorinated biphenyls (PCBs).  Samples are being taken from approximately  1,000 children
and young adults between 6 to 19 years of age, of which a subset will be assessed for deficits in
thyroid function.

       Finally,  the Border XXI Program is a cooperative binational effort between several
Federal agencies of the U.S. and Mexico to help ensure  human and environmental health along the
U.S.-Mexico border. As part of this program, EPA is conducting multimedia studies to
characterize exposures of children to various pesticides and metals. The data will provide a basis
to validate age-dependent exposure models that incorporate activity patterns, water consumption,
diet and nutritional status.
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4.1.3  The Elderly

       As people age, sensitivity may change due to alterations in the way the body responds to a
contaminant.  Altered biochemical processes (e.g., metabolism) that are responsible for the
detoxification or activation of a toxic agent may impact sensitivity to a chemical contaminant. A
less active immune system or an increased likelihood of pre-existing disease may be risk factors
for disease caused by waterborne pathogens. To obtain information on pre-existing diseases that
are most common in the elderly, EPA collected data from several national surveys on the
prevalence of chronic disease in the U.S. The surveys indicated that osteoporosis, cardiovascular
disease, diabetes and hypertension are more prevalent in individuals over 65 years of age than in
the remainder of the population (EPA, 1998a).

       EPA's waterborne disease occurrence studies are examining the extent to which the
elderly and other subgroups may be more susceptible than the general population following
exposure to waterborne pathogens. With regard to chemical exposures, EPA researchers are
developing a special animal model that can be used in studies to evaluate if older rodents may be
at greater risk than other age groups from exposure to chemical contaminants. Results obtained
to date indicate that the model may be a good tool for studying age-related toxic effects on the
liver.

4.2    Gender

       Adult males and females show distinct differences in the incidence of certain chronic
disorders, the presence of which may reduce the ability  of the affected individual to mount an
effective defense against subsequent exposure to a waterborne pathogen or toxic chemical.
Females appear to be more prone to anemia, osteoporosis, kidney problems and thyroid disorders,
while males have a higher reported incidence of liver disease (EPA, 1998a).

       EPA research has shown that exposure of adult female rodents to certain pesticides (e.g.,
atrazine) can cause changes in the regulation of reproductive function (Cooper et a/., 2000).  To
determine if similar results can be observed for DBFs, Agency researchers are examining if DBF
exposures can impact hormonal cycles in nonpregnant female rodents.  An EPA-funded study at
Colorado State University is following up on findings by EPA scientists that sperm production in
rodents exposed to high concentrations of selected DBFs may be adversely affected.  These new
studies are being conducted in rabbits, which have a longer period of reproductive development
than that of rodents.

       EPA studies with the haloacetic acid family of DBFs have demonstrated that certain
brominated by-products can cause decreases in the sperm quality of male rodents following
exposure to high experimental doses (Linder et a/., 1995). Studies are now underway to
determine if these effects can be observed at lower exposure levels. In the course of these
investigations, EPA researchers made an important scientific finding that could lead to the
development of a sensitive biological marker, or biomarker, of male fertility (Klinefelter et al.,
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1997). The specific protein on the sperm membrane (SP22) that is correlated with sperm fertility
may serve as an invaluable tool for determining if low level exposures to DBFs are associated
with adverse  male reproductive effects. Furthermore, this biomarker could have public health
implications that extend well beyond the original drinking water context for the research.

4.3    Genetic Traits

       With  the tremendous growth over the past decade in research related to the Human
Genome Project, interest and knowledge regarding the genetic underpinnings of disease and
susceptibility have greatly increased. As described below, EPA scientists have begun evaluating
and applying new tools to study sensitive subpopulation issues for both waterborne pathogens and
chemical contaminants in drinking water.  The genetic influences on sensitivity to environmental
contaminants are  complex and only  beginning to be understood.  As a practical matter, it is
therefore not clear to what extent such factors can be used to define groups that meet the
statutory criterion of "subpopulations that can be identified and characterized."

       Waterborne pathogens.  Sensitivity to infection and disease caused by pathogenic
bacteria, viruses or parasites is based in part on host susceptibility or resistance factors that may
be under genetic control. Changes in sensitivity may  be due to alterations in genes that are
involved in the body's immune defense system or that code for certain receptors on the surface of
host cells that are attacked by the infectious agent. Genetically induced changes in patients with
an unrelated disease may predispose these patients to infections by waterborne pathogens.

       The presence of these genes  provides an opportunity to identify biomarkers of
susceptibility. As described in a report that will soon  be finalized by  EPA, a review of the
literature was conducted to identify potential biomarkers of susceptibility in animals and/or
humans for ten waterborne pathogens: Mycobacterium species, Helicobacter pylori,
Pseudomonas species, Legionella species, coxsackievirus, adenovirus, hepatitis A, Entamoeba
histolytica, Cryptosporidium, and Toxoplasma gondii. Due to the highly complex nature of this
issue, additional studies are necessary  to determine the extent to which these biomarkers are
useful in identifying subpopulations  that may be more sensitive to infection with waterborne
pathogens.

       Chemicals.  Metabolism, which is mediated by enzymes that are under genetic control, is
known to play an important role in the toxicity of chemicals.  Individuals with either a lower
capacity to detoxify chemicals or a greater capacity to activate chemicals, due to variability in the
quantity or activity of metabolic enzymes, may be at greater risk of cancer or other adverse health
effects.  EPA is conducting an analysis of genetic and other factors that may play a role in the
metabolic detoxification or activation of chemical contaminants.  This project involves an
evaluation of data on the impact of age, gender, ethnicity, diet, common pharmaceuticals and
behavioral  characteristics (smoking, alcohol ingestion) for two important enzyme systems, the
cytochrome P-450 isoforms and the glutathione-S-transferases. Related to this effort is a research
project to determine the extent of human interindividual variability (adults and children) in the
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expression of cytochrome P-450 isoforms in samples of human liver cells derived from organ
donors. The ultimate goal is to develop a tool for identifying subpopulations that may be more
sensitive because of inherent differences in the ability to metabolize chemical toxicants.

       EPA investigators are conducting animal studies on one aspect of how genetic make-up
may predispose some individuals to DBF-induced cancer.  Specifically, efforts are being directed
toward determining whether individuals whose blood cells express different forms or amounts of
glutathione-S-transferases vary in sensitivity to the genotoxic effects of selected DBFs. This type
of study could have broad applicability, since the glutathione-^-transferase family of enzymes
comprises a fundamental detoxification mechanism for several classes of toxic substances.

       EPA researchers are also using a rat model of hereditary kidney cancer to evaluate the
influence of genetic predisposition  on the risk posed by exposure to DBFs.  The objectives are to
determine whether this genetically-altered strain of rat is more sensitive to the effects  of exposure
to trihalomethanes, and if the resulting tumors share critical features of cancers that may be linked
with human exposure to DBFs.

       This line of investigation is  being extended to other chemical contaminants.  The
metabolism of arsenic by enzymes under genetic control is believed to be an important
determinant of its toxicity and carcinogenicity. Some data from the published literature suggest
that the pattern and extent of arsenic metabolism may differ among individuals. Results of a study
conducted by EPA researchers in an arsenic-exposed population in Utah showed no differences in
the amounts of the various forms of arsenic found in the urine of adults and children (Calderon et
a/., 1999), suggesting that arsenic may be metabolized in a similar manner in both of these
subgroups. The data are being further analyzed to develop gender-related metabolic profiles.
Related research in rodents includes efforts to develop an animal model for investigating
genetically determined variations in the metabolism of arsenic, and studies to evaluate the
influence of dietary constituents (e.g., folate and selenium) on this process.

       Along with the increased interest in the genetic  foundation of disease has come
tremendous innovation in the tools  for investigating gene expression. Two complementary
techniques that are rapidly becoming essential for such research are DNA microarrays and genetic
engineering. Microarrays are glass slides or nylon filters onto which are spotted thousands of
genes (DNA).  When complementary DNA obtained from a tissue sample is overlaid onto the
spotted template, it binds to the arrayed genes and can  be detected through the use  of fluorescent
probes or a radioactive label.  In such a manner,  investigators are able to rapidly screen how
toxicants can influence the expression  of thousands of genes at a time.  Over the past year, EPA
investigators have been collaborating with Federal, academic, and industry researchers to develop
methods for applying this powerful technology to elucidate the genetic mechanisms of action of
environmental toxicants, including DBFs. Once affected genes are identified, investigators can
use genetic engineering techniques  to further study how specific genetic abnormalities alter the
risk posed by exposure to drinking  water contaminants.
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4.4    Health Status

       As discussed earlier, individuals with a pre-existing medical condition may have reduced
resistance to subsequent infection or toxic insult.  Most of the studies conducted by EPA relating
to health status have focused on individuals with weakened immune systems.  The immune system
is complex, involving a variety of different types of cells and processes that comprise an
individual's defense system against infection or disease.  Because of this complexity, many
different approaches are used to test immune status following exposure to a toxic or pathogenic
agent.  To assist risk assessors in evaluating the results of these tests, EPA compiled information
on the various assays and prepared a compendium that describes their strengths and weaknesses
(EPA, 1998h).

       EPA is conducting several different types of studies in the laboratory,  clinic and field to
evaluate the impact of host immune status on sensitivity. For individuals with weakened immune
systems, particularly those with acquired immunodeficiency syndrome (ADDS) and patients on
immunosuppressive drugs, infections with the pathogen Cryptosporidium can be life-threatening.
EPA scientists and grantees are conducting research on various animal models to examine the
impact of compromised host immune condition on infection with this parasite. Pilot epidemiology
studies are evaluating the role of drinking water as a source of Cryptosporidium infections in a
hospital setting and in a population that is positive for the virus that causes AIDS.  EPA
researchers and collaborators have  also studied the role of drinking water as a source of another
opportunistic pathogen that poses a special risk to people with weakened body defenses.  In a
recently published study (Aronson et a/., 1999), investigators foundMycobacterium avium in
potable water from selected homes, large buildings and hospitals. Many  of the isolates from the
water and from immunocompromised patients were found to share  similar patterns of genetic
material. The methodology used in this study was inadequate for establishing a clear link between
M. avium infections and exposure through the drinking water, but the results  do provide a basis
for additional studies being planned by EPA to further evaluate this issue.

       EPA has supported several  studies to determine the infectious dose and role of protective
immunity in healthy human volunteers exposed to the pathogens Cryptosporidium and Norwalk
virus. This research has suggested that a low number of pathogens is required to establish
infections in healthy adults, and that (at least for Cryptosporidium)  the immune system plays an
important role in protecting people who have been exposed previously (Chappell et al, 1999).
These results further highlight the special risks that some pathogens can pose to individuals whose
defense systems are compromised.

       It has been well established that an individual with a weakened immune system is at
greater risk of infection and serious illness following exposure to a microbial  pathogen. If a
chemical in drinking water is immunotoxic, this could render the individual more sensitive to
infection with a waterborne pathogen.  In the collaborative EPA/NTP toxicity screening program,
researchers are evaluating the potential of five DBFs (dibromoacetic acid, sodium bromate,
sodium chlorite, dichloroacetic acid and chloroform) and the disinfectant chloramine to cause
immunotoxic effects in experimental animals.  Screening studies have been completed on two of

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the DBFs to date. Dibromoacetic acid was found to alter the immune response in an initial high
dose study, and additional tests are now being conducted to further evaluate if effects can be
observed at lower doses (NTP, 1999).  Sodium bromate did not alter the immune responsiveness
of treated animals (NTP, 2000).

4.5    Exposure

       A critically important area of research to help identify sensitive subpopulations in DBF
epidemiology studies is the development of improved data and methods for estimating exposures.
Several approaches are being used, including: 1) developing and applying geographic information
systems to better manage exposure and health data; 2) incorporating lifestyle questions (e.g.,
water consumption and use) into survey questionnaires to better gauge exposures to DBFs by the
oral, dermal and inhalation routes; 3) using distribution system modeling techniques to estimate
DBF exposures at or near the homes of study participants; and 4) determining concentrations of
DBFs in blood samples for comparison with levels found in drinking water taken from the
distribution system and home. EPA is also merging activity pattern data with existing multiple
route exposure models to better estimate the variability in total exposure to DBFs for different
population groups.

       EPA is coordinating several studies to characterize multiple-source, multiple-route
exposures to environmental contaminants across seven states. This effort involves a consortium
of research organizations in the National Human Exposure Assessment Survey (NHEXAS). Two
of the studies include representative samples of the general population, and a third study will
compare urban and rural populations.  Classes of contaminants being evaluated include pesticides,
volatile organic compounds, and metals.

       In conducting risk assessments on special populations of interest, it is important to
consider information on levels of drinking water intake that may be specific to that particular
group of individuals.  Several approaches are being used to develop these intake data. EPA has
conducted an extensive review of data on drinking water intake rates from the U.S. Department
of Agriculture's Continuing Survey of Food Intake by Individuals (EPA, 2000). Intake of tap
water, bottled water and water from other sources was evaluated. Water consumed directly as
well as water used in the preparation of juices, coffee, reconstituted soup mixes and other similar
foods were considered. The data were found to generally support the Agency's use of 2  L/day
for adults and 1 L/day for children as  upper-percentile tapwater intake rates.  Pregnant women do
not differ significantly in their water ingestion compared to women of child-bearing age.
However, lactating women ingest significantly more water than pregnant or control (non-
pregnant, non-lactating) women. When considering water ingestion in units of milliliters of water
ingested per kilogram  of body weight  per day, babies younger than one year old have an ingestion
rate that is approximately three to four times higher than that of the general population.  It is
reasonable to assume individuals who engage in vigorous  work or exercise, particularly in warmer
climates, have a higher daily intake of water than the general population. An analysis of
consumption according to the source of the water indicates that community water supplies
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account for 75% of the water consumed, followed by bottled water (13%) and spring, well and
cistern water combined (10%).

       Data on drinking water consumption patterns for various age groups and on the
contribution of contaminants from drinking water exposures are also being evaluated from the
NHEXAS project and other data sources. The results will be compiled into an updated childhood
exposure factors data base.  In addition, methods are being developed to better scale physiological
parameters for children versus adults, which will lead to improved quantitative estimates of risk
for children.

       To assess total dietary exposure to contaminants, EPA has developed a PC-based Dietary
Exposure Potential Model (DEPM).  The model can help identify food and drinks that are
relatively high contributors to contaminant exposure by consumption, and it can provide a relative
exposure estimate for the consumption of tapwater only or tapwater used in food/drink
preparation and food.  The DEPM can also provide an estimate of exposure for populations based
on age, ethnic origin, and region for contaminants included in various residue surveys. Currently,
EPA is using the model in its risk assessment of arsenic to identify foods high in total arsenic
content.

5.     CONCLUSIONS

       EPA is conducting and supporting a wide range of studies to identify and characterize
groups that may be at greater health risk than the general  population following exposure to
contaminants in drinking water. Important factors that are being investigated include life stage
(i.e., fetuses, infants and children, the elderly), gender, genetic traits, health status and exposure.
Research to date has emphasized waterborne pathogens and chemicals from a public health and
regulatory perspective, with efforts now expanding to address "emerging" contaminants that may
be considered in future regulatory decision making. Because of the importance and broad scope
of this issue, EPA has established collaborations and has leveraged funding for research with
various Federal agencies,  the water industry and other research entities.

       The EPA studies that have been completed to date are providing important data to
improve risk assessments  and guide future research activities on sensitive subpopulations. New
insights are expected within the next few years as the results of ongoing studies become available.
To fully identify and characterize groups that may be more sensitive than the general population
to contaminants in drinking water, the results of EPA studies need to be considered in the context
of the larger body of scientific literature on sensitive subpopulations.

       Major highlights of EPA's sensitive subpopulation studies on waterborne pathogens and
chemicals in drinking water are summarized below:

       Waterborne pathogens. The results of an analysis of physiological and exposure-related
characteristics  of infants and children suggest that this subpopulation may be more sensitive than
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the general population to waterborne pathogens. This is consistent with data collected on the
demographics of foodborne illnesses, but the data from waterborne disease outbreaks in the U.S.
are less conclusive.  The results of several epidemiology studies and surveys that are currently
underway should provide important information on the risks that pathogens in drinking water
pose to infants, children, and other age groups.  Individuals with pre-existing disease, particularly
those with weakened immune systems, are known to be at increased risk following exposure to
opportunistic pathogens such as Cryptosporidium. EPA is conducting research in the laboratory
and field to further evaluate the impact of host immune status on sensitivity to these agents.

       Chemicals.  Studies conducted by EPA and others have raised concerns about a potential
risk of adverse reproductive outcomes following maternal exposure to DBFs.  EPA research has
also shown that exposure of laboratory animals to high levels of certain pesticides can cause
adverse developmental  effects. Current laboratory and field research on pesticides will contribute
to a better understanding of the potential risks of these contaminants to subpopulations of special
concern.  In studies to evaluate the health effects of sulfate, EPA researchers and collaborators
found that piglets (as a  model for human infants) and previously unexposed adults were not
particularly sensitive to the effects of this contaminant in drinking water.

       Considerable progress has been made since the enactment of the 1996 SDWA
Amendments in the development of improved methods for evaluating toxicity, assessing
exposures, and conducting risk assessments of contaminants and subpopulations of special
concern.  These new tools  will enable Agency scientists to generate critical data and conduct
scientifically sound risk assessments in support of the requirements of SDWA and  other
regulatory statutes.

       Based on a consideration of potential public health risks and the findings of studies to
date, near-term research priorities include studies of DBF exposures and adverse reproductive
outcomes, risks to infants and children from exposure to waterborne pathogens, and risks to
individuals whose health status is compromised.  A greater emphasis will be placed on research to
examine the elderly as a possible sensitive subpopulation.  Efforts will be made to take advantage
of new advances in molecular biology to study genetic factors involved in environmentally-
induced disease.  The development and application of improved methods for toxicity evaluations,
exposure assessment and risk assessment will also continue to be priorities.  The results of these
studies will help to provide a sound scientific basis for regulations and guidance to protect the
public health of the 250 million people, including sensitive subpopulations, who get their water
from public water systems.
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6.     REFERENCES

Aronson, T., A. Holtzman, N. Glover, M. Boian, S. Froman, O.G.W. Berlin, H. Hill, and G.
Stelma, 1999.  Comparison of large restriction fragments of Mycobacterium avium isolates
recovered from AIDS and non-AIDS patients with those of isolates from potable water.  J. din.
Microbiol, 37(4): 1008-1012.

Calderon, R.L., E. Hudgens, X.C. Le, D. Schreinemachers, and DJ. Thomas, 1999. Excretion of
arsenic in urine as a function of exposure to arsenic in drinking water. Environ. Health Perspect.,
107(8):663-667.

CDC, 1998. National diabetes fact sheet: National estimates and general information on
diabetes in the United States, Revised edition. U.S. Department of Health and Human Services,
Centers for Disease Control and Prevention, Atlanta,  GA.

CDC, 1999. HIV/AIDS surveillance report. 11:2. U.S. Department of Health and Human
Services, Centers for Disease Control and Prevention, Atlanta, GA.

Chappell, C.L., P.C. Okhuysen, C.R.  Sterling, C. Wang, W. Jakubowski, and H.L. Dupont, 1999.
Infectivity of Cryptosporidium parvum in healthy adults with pre-existing anti-C. parvum serum
immunoglobulin G. Am. J. Trop. Med. Hyg., 60(1): 157-164.

Cooper, R.L., J.M. Goldman, and I.E. Stoker, 1999.  Neuroendocrine and reproductive  effects of
contemporary-use pesticides.  ToxicolInd. Health, 15(l-2):26-36.

Cooper, R.L., T.E.  Stoker, L. Tyrey, J.M. Goldman, and W.K. McElroy, 2000. Atrazine disrupts
the hypothalamic control of pituitary-ovarian function.  Toxicol. Sci., 53(2):297-307.

EPA, 1993.  Report of the panel on reproductive effects of disinfection by-products in drinking
water.  U.S. Environmental Protection Agency/International Life Sciences Institute, September,
1993.

EPA, 1997.  Research plan for microbial pathogens and disinfection by-products in drinking
water.   EPA 600-R-97-122, December  1997.  Office of Research and Development, U.S.
Environmental Protection Agency.

EPA, 1998a. Demographic distribution of sensitive population groups. Office of Science and
Technology/Office of Water, U.S. Environmental Protection Agency.  Prepared by SRA
Technologies, Inc. (O'Day, R., J. Rench, R. Oen, and A. Castro), Falls Church, VA.

EPA, 1998b. Research plan for arsenic in drinking water. EPA 600-R-98-042. Office of
Research and Development, U.S. Environmental Protection Agency.
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EPA, 1998c. Research plan for endocrine disruptors. EPA 600-R-98-087. Office of Research
and Development, U.S. Environmental Protection Agency.

EPA, 1998d. EPA panel report and recommendations for conducting epidemiological research
on possible reproductive and developmental effects of exposure to disinfected drinking water.
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection
Agency, February 12, 1998.

EPA, 1998e. Announcement of the drinking water contaminant candidate list. Federal Register,
63(40): 10274-10287.

EPA, 1998f. Health risks to fetuses, infants, and children (final Stage 1 D/DBP Rule).  Office of
Science and Technology/Office of Water, U.S. Environmental Protection Agency, October 1998.

EPA, 1998g. Morbidity and mortality demographics for foodborne andwaterborne  microbial
disease.  Office of Science and Technology/Office of Water, U.S. Environmental Protection
Agency.  Prepared by SRA Technologies, Inc. (Rench, J.,  R. O'Day, H. Vandermer, and J.
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