United States
Environmental Protection
Agency
Office of Research and
Development
Washington DC 20460
EPA/600/R-00/068
August 2000
www.epa.gov
Strategy for Research on
Environmental Risks to
Children

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                                  EPA/600/R-00/068
      STRATEGY FOR RESEARCH
ON ENVIRONMENTAL RISKS TO CHILDREN
   U.S. Environmental Protection Agency
    Office of Research and Development
            Washington, DC

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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 1997 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 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 topics is to better understand environmental risks to children.

        A team of scientists from ORD and other EPA offices, including the  Office of Prevention,
Pesticides and Toxic Substances; the Office of Water; and the Office of Children's Health Protection,
prepared the Strategy for Research on Environmental Risks to Children.  The ORD Science Council
completed an internal review of the strategy in May 1999. Following revisions based on the Science
Council review, the draft was reviewed by scientists outside EPA. The outcome of these reviews is
a strategy that establishes EPA's long-term program goals and objectives for research in children's
risk and documents the rationale for the chosen program direction.

        The key scientific questions this strategy sets out to address are:

#       What are the adverse effects from children's exposures to environmental agents that are
        qualitatively or quantitatively different from effects in similarly  exposed adults? What are
        the near-term and delayed effects of childhood exposures? What are the characteristics of
        the environmental agents associated with these effects?

#       What are the specific  periods of development when exposure to environmental substances
        can cause adverse health effects?

#       What are the best in vitro models and in vivo animal models for screening for and identifying
        hazards to children?

#       To what environmental substances are children  more highly exposed? How do exposures
        differ with age?  What factors contribute to higher exposures?

#       What are the relationships between exposures to children and  adverse  health  effects
        observed in childhood or later? What factors in the child's environment can increase risks?

#       How can laboratory and human data be used to predict responses to childhood exposures?

#       What is the variation in exposure and susceptibility within members of the same age group,
        and what are the factors that contribute to this variation?

#       What adverse effects from children's exposures to mixtures are quantitatively or qualitatively
        different from effects  in similarly exposed adults?

#       What are the uncertainties in estimating environmental risks to children and how can they
        be characterized  in  risk  assessment?   What are the  most  effective  methods  for
        communicating results, data, and risks to risk assessors,  risk  managers, and the public?

#       What are the specific environmental agents  and  pathways of exposure where risk
        management research will be effective in addressing known risks to children? What are the
        most effective methods for reducing environmental risks to children?
                                           in

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        To answer these questions, this strategy groups its research priorities into the following five
areas: (1) development of data for risk assessment, (2) development of risk assessment methods and
models, (3) experimental methods development, (4) risk management and risk communication, and
(5) cross-cutting issues including variation in susceptibility and cumulative risk.

        This research strategy is an important planning tool because it makes clear the rationale
for, and the intended products of, EPA's research on children's environmental health and helps EPA
effectively communicate its program to clients, stakeholders, and the public.  This research strategy
is also  an important accountability tool, enabling EPA to clearly track progress toward achieving its
research goals as required by the 1993 Government Performance and Results Act.
                                                E. Timothy Oppelt
                                                Acting Deputy Assistant Administrator
                                                 for Science, ORD
                                           IV

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  EPA AUTHORS, CONTRIBUTORS, AND REVIEWERS


Executive Lead
       William H. Farland, Director, National Center for Environmental Assessment (NCEA), Office of Research
       and Development (ORD), U.S. Environmental Protection Agency

       The strategy was developed by a science team with representatives from ORD's laboratories and centers
and from the Office of Prevention, Pesticides, and Toxic Substances (OPPTS); the Office of Water; and the Office
of Children's Health Protection (OCHP).  The following are the members of the science team:

Authors
       John Cicmanec, ORD/National Risk Management Research Laboratory (NRMRL)
       Karen Hammerstrom (Chair), ORD/NCEA
       Stephen Hern, ORD/National Exposure Research Laboratory (NERL)
       Gary Kimmel, ORD/NCEA
       William Nelson, ORD/NERL
       Ralph Smialowicz, ORD/National Health and Environmental Effects Research Laboratory (NHEERL)

Contributing Science Team Members
       Andrew Avel, ORD/NRMRL
       Karl Baetcke, OPPTS/Office of Pesticide Programs (OPP)
       David Chen, OCHP
       Amal  Mahfouz, Office of Water
       Suzanne  McMaster, ORD/NHEERL
       Chris Saint, ORD/National Center for Environmental Research (NCER)
       Jennifer Seed, OPPTS/Office of Pollution Prevention and Toxics (OPPT)
       William Steen, ORD/NERL
       Karen Whitby, OPPTS/OPP

       The following ORD managers and scientists contributed to the development of this strategy through their
careful review and insightful comments on the ORD Science Council (Internal)  Review Draft:

ORD Science Council Members
       Harold Zenick, Lead Reviewer, ORD/NHEERL
       Judith Graham, ORD/NERL
       Robert Kavlock, ORD/NHEERL
       Hugh McKinnon, ORD/NRMRL
       Vanessa Vu, ORD/NCEA

Other ORD Reviewers
       Larry Claxton, ORD/NHEERL
       Elaine Francis, ORD/NCER
       Hillel Koren, ORD/NHEERL
       Martha Moore, ORD/NHEERL
       Jennifer Orme-Zavaleta, ORD/NHEERL
       Hugh Tilson, ORD/NHEERL

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                    PEER REVIEW AND COMMENTS


       An external peer review of the Strategy for Research on Environmental Risks to Children was organized by the
Eastern Research Group (ERG). A peer review workshop was held on November 9 and 10, 1999, in Washington, DC.

Peer Review Chair
       John De Sesso, Ph.D., Director, Biomedical Research Institute, Mitretek Systems, McLean, VA

Peer Review Members
       Edward Avol, M.S., Associate Professor, Department of Preventive Medicine, University of Southern California
           School of Medicine,  Los Angeles, CA
       Cynthia Bearer, M.D., Ph.D., Assistant Professor, Department of Pediatrics and Department of Neurosciences,
           Division of Neonatology, Case Western Reserve University, Cleveland, OH
       Joan Cranmer, Ph.D., ATS, Professor of Pediatrics and Toxicology, Department of Pediatrics, University of
           Arkansas for Medical Sciences and Arkansas Children's Hospital, Little Rock, AR
       George Daston, Ph.D., Research Fellow, Miami Valley Laboratories, Procters Gamble, Ross, OH
       Warren Foster, Ph.D., Associate Director/Director of Research, Center for Women's Health, Cedars-Sinai
           Medical Center, Beverly Hills, CA
       Howard Morrison, Ph.D., Chief, Behavioural Risk Assessment, Cancer  Bureau,  Health Canada, Ottawa,
       Ontario
       Rossanne Philen, M.D., M.S., Acting Associate Director for Science, Health Studies Branch, National Center
           for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA
       William Slikker, Ph.D., Director, Division of Neurotoxicology, National Center for Toxicology Research, Food
           and Drug Administration, Jefferson, AR

Other External Review and Comment
       EPA Children's Health Protection Advisory Committee (Reigart, J.R.  2000. Letter to Carol M. Browner,
           Administrator, U.S. EPA, dated January 21, 2000, from J. Routt Reigart,  M.D., Chair, Children's Health
           Protection Advisory  Committee)
       Andy Breslin, Physicians Committee for Responsible Medicine (Observer comment at Nov. 9-10, 1999, Peer
           Review Workshop)
       Keith Harrison, Michigan  Environmental Science Board (Observer comment at Nov. 9-10, 1999, Peer Review
           Workshop)
                            ACKNOWLEDGMENTS
        The external peer review was administered by ORD's Office of Science Policy (OSP) through a contract
with the Eastern Research Group (ERG).  The authors would like to thank the ERG Work Assignment Manager,
Edward Washburn, OSP, who was the EPA lead in organizing the peer review. The authors would also like to
thank OSP Director Dorothy Patton, Donna Witherspoon and Elaine Francis of OSP, and J. Deanna Easley (Office
of Administration and Resource Management) for their help in the administration of the peer review.  Kate Schalk of
ERG managed the peer review, assisted by Jan Connery, Naida Gavrelis, Melanie Russo, Laurie Stamatatos, and
Meg Vrablik, all of ERG.

        The cover of the strategy was designed by Stephen E. Wilson (ORD/NRMRL).
                                                VI

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                            TABLE  OF CONTENTS
ACRONYMS 	ix

GLOSSARY	 x

EXECUTIVE SUMMARY  	  EX-1

1.  INTRODUCTION  	 1
        1.1. Scope and Definitions	 1
        1.2. Rationale for the Children's Health Program  	 1
        1.3. Research Questions 	 3
        1.4. Goals and Objectives  	 3
        1.5. ORD Research Strategies and Plans	 3
        1.6. Organization	 3

2.  APPROACHES TO RISK ASSESSMENT 	 5
        2.1. The Standard Regulatory Approach	 5
        2.2. Future Directions in EPA Risk Assessment 	 6

3.  IMPLEMENTATION OF LEGISLATION AND POLICY ON CHILDREN'S ENVIRONMENTAL HEALTH 	 8

4.  RESEARCH DIRECTIONS	  10
        4.1. Research Needs and Recommendations	  10
        4.2. Current Research 	  10
           4.2.1.   National Testing Programs  	  10
           4.2.2.   Modes of Action and Modeling of Physiological/Biological Processes	  10
           4.2.3.   Studies in Human Populations	  13
           4.2.4.   Exposure-Dose-Response Modeling and Risk Assessment  	  14
           4.2.5.   Risk Management and Risk Communication  	  15
        4.3. Research Areas and Priorities	  16
           4.3.1.   Laboratory Studies and Surveys  	  17
                  4.3.1.1.  Biology of Toxicant-Induced Tissue and Organ Damage
                          in the Developing Organism 	  17
                  4.3.1.2.  Relationship between Exposure to Environmental Agents
                          and Adverse Health Effects in Human Populations	  18
                  4.3.1.3.  Multimedia, Multipathway Exposures in Human Populations	  20
                  4.3.1.4.  Analysis of Factors Contributing to Exposure	  21
           4.3.2.   Risk Assessment Methods and Models 	  22
                  4.3.2.1.  Methods and Models for Using Biological Data in Risk Assessment	  22
                  4.3.2.2.  Exposure Modeling and Use of Exposure Data in Risk Assessment 	  23
           4.3.3.   Methods for Studying Effects and Exposure in Humans and Animal Models	  23
                  4.3.3.1.  In Vivo/In Vitro Methods for Hazard Identification	  23
                  4.3.3.2.  Methods for Measuring Exposures and Effects in Infants and Children
                          and to Aid in Extrapolations between Animals and Humans 	  24
           4.3.4.   Risk Management Research and Risk Communication  	  25
                  4.3.4.1.  Multimedia Control Technologies that Account for the Susceptibilities
                          of Children	  25
                  4.3.4.2.  Methods for Reducing Exposure Buildup of Contaminants
                          in Indoor Environments  	  26
                  4.3.4.3.  Communication of Risks and Development of Risk Reduction Techniques
                          Through Community Participation  	  26
           4.3.5.   Cross-Cutting Issues	  27
                  4.3.5.1.  Variation in Susceptibility and Exposure in Children	  27
                  4.3.5.2.  Cumulative Risks to Children	  28
        4.4. Linking and Summary of Research Areas  	  28

5.       GUIDANCE FOR IMPLEMENTATION  	  34

6.       REFERENCES	  36
                                               VII

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APPENDIX A. GROWTH AND DEVELOPMENT FROM BIRTH THROUGH ADOLESCENCE	  A-1

              TABLE  OF CONTENTS (continued)

APPENDIX B. ORD RESEARCH PLANS AND STRATEGIES	  B-1
APPENDIX C.  RESEARCH RECOMMENDATIONS	  C-1
APPENDIX D. FEDERAL RESEARCH IN CHILDREN'S ENVIRONMENTAL HEALTH	  D-1
APPENDIX E. CROSS TABULATION OF RESEARCH QUESTIONS AND RESEARCH AREAS	  E-1
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS 	F-1

                         LIST OF  FIGURES
Figure 1.        Objectives of the ORD Strategy for Research on Environmental Risks to Children	 4
Figure 2.        Pesticides in Young Children: A NERL/NHEERL Collaboration  	 34
Figure 3.        Pesticides and Children in Minnesota: A NHEXAS Study and a STAR Grant 	 34
Figure 4.        Guiding Principles for Implementation	 35

                          LIST  OF TABLES
Table 1.    Research Recommendations and Needs	 11
Table 2.    Summary of Research Areas	 29
                                     Vlll

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                                          ACRONYMS
AHS       Agricultural Health Study                       NHEXAS
ATSDR     Agency for Toxic Substance and Disease         NHLBI
               Registry                                 NIAID
BBDR      Biologically based dose response modeling
CDC       Centers for Disease Control and Prevention        NIDCR
CHEHSIR   Children's Environmental Health and Safety
              Inventory of Research                       NICHD
DART      Developmental and Reproductive Toxicology
              Database                                 NIEHS
DNA       Deoxyribonucleic  Acid
EPA       U.S. Environmental Protection Agency            NIH
FDA       U.S. Food and Drug Administration               NIOSH
FIFRA      Federal Insecticide, Fungicide, and
              Rodenticide Act                            NOAEL
FQPA      Food Quality Protection Act                    NOEL
GPRA      Government Performance and Results Act        NRMRL
HUD       U.S. Department of Housing and Urban
              Development                              NTP
IEUBK      Integrated Exposure, Uptake, Biokinetic Model     OCHP
IRIS       Integrated Risk Information System               OPP
ITC        Interagency Testing Committee                  OPPTS
NAAQS     National Ambient  Air Quality Standards
NAS       National Academy of Sciences                  ORD
NCEA      National Center for Environmental Assessment    OSWER
              (EPA/ORD)
NCER      National Center for Environmental Research       PBPK
              (EPA/ORD)                               PCB
NCEH      National Center for Environmental Health         PM
              (CDC)                                    PM10
NCHS      National Center for Health Statistics (CDC)        RFA
NCI        National Cancer Institute                       RfC
NERL      National Exposure Research Laboratory          RfD
              (EPA/ORD)                               SDWA
NHANES   National Health and Nutrition Examination         STAR
              Survey
NHEERL   National Health and Environmental Effects        TSCA
              Research Laboratory (EPA/ORD)
National Human Exposure Assessment Survey
National Heart, Lung, and Blood Institute
National Institute of Allergy and Infectious
   Diseases
National Institute of Dental and Craniofacial
   Research
National Institute for Child  Health and Human
   Development
National  Institute  of  Environmental  Health
   Sciences
National Institutes of Health
National Institute for Occupational Safety and
   Health
No observed adverse effect level
No observed effect level
National Risk Management Research Laboratory
   (EPA/ORD)
National Toxicology Program
Office of Children's Health Protection (EPA)
Office of Pesticide Programs (EPA/OPPTS)
Office of Prevention,  Pesticides,  and  Toxic
   Substances (EPA)
Office of Research and Development (EPA)
Office of Solid Waste and Emergency Response
   (EPA)
Physiologically based pharmacokinetic modeling
Polychlorinated biphenyl
Particulate matter
Particulate matter less than 10 • m in diameter
Request for applications
Reference concentration
Reference dose
Safe Drinking Water Act
EPA/ORD Science  To  Achieve  Results
   extramural grants program
Toxic Substances Control Act

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                                             GLOSSARY
Aggregate exposure:   The  combined  exposure of an
individual or defined population to a specific agent or stressor
via all relevant routes, pathways, and sources.

Aggregate risk: The risk resulting from aggregate exposure to
a single agent or stressor.

Biological markers (biomarkers):  Indicators signaling events
in biological systems or samples. There are three classes of
biomarkers-exposure, effect, and susceptibility. A marker of
exposure is an  exogenous substance or its metabolite(s) or
the product of an interaction between a xenobiotic agent and
some  target  molecule  or cell  that  is  measured  in  a
compartment  within an organism.  A marker of effect is a
measurable biochemical, physiological,  or other alteration
within an organism that, depending on magnitude, can be
recognized as an established or potential health impairment or
disease.  A marker of susceptibility is an  indicator of an
inherent or acquired  limitation of an organism's ability  to
respond to the challenge of exposure to a specific xenobiotic
(NRC2000).

Biologically based dose response (BBDR) model:  A model
that  describes  biological  processes  at  the  cellular and
molecular level linking  the target organ dose  to the adverse
effect.

Cumulative  risk:  The   combined  risk  from  aggregate
exposures to multiple agents or stressors.

Developmental toxicology: The study of adverse effects on
the developing organism that might result from exposure (of
either parent) priorto conception, during prenatal development,
orfrom postnatal developmenttotheti me of sexual maturation.

Deoxyribonucleic Acid  (DNA): A complex macromolecule
that is composed of nucleic acids (adenine, guanine, cytosine,
and thymine) and is found in cellular organisms. DNA carries
all the genetic information necessary to determine the specific
properties of an  organism.

Dose:  The amount of  a substance available  for interactions
with metabolic processes or biologically significant receptors
after crossing the outer  boundary of an organism.  The
potential dose is the amount ingested, inhaled, or applied to
the skin. The applied dose is the amount presented to an
absorption barrier and  available for absorption (although not
necessarily having yet crossed the outer boundary of the
organism).  The absorbed dose  is the amount crossing a
specific absorption barrier (e.g., the exchange boundaries of
the skin, lung, and digestive tract) through uptake processes.
Internal dose is a more general term denoting the amount
absorbed without respect to specific absorption barriers  or
exchange boundaries.  The amount of the chemical available
for interaction by any particular organ or cell is termed the
delivered or biologically effective dose forthat organ or cell.

Dose-response  assessment:   The  determination of the
relationship between the magnitude of administered, applied,
or internal dose and a specified biological response.
Exposure: Contact of a chemical, physical, orbiological agent
with the outer boundary of an organism. Exposure is quantified
as the concentration of the agent in the medium overtime.

Exposure assessment: The determination or estimation of the
magnitude, frequency, duration, and route of exposure.

Exposure pathway: The physical course an environmental
agent takes from the source to the individual exposed.

Exposure route: The way an environmental agent enters an
organism (e.g., by ingestion, inhalation, ordermal absorption).

Hazard identification: A description of the potential adverse
health effects attributable to a specific environmental agent and
the mechanisms by which agents exert their toxic effects.

Lowest observed adverse effect level (LOAEL): The lowest
exposure  at which  there is  a  statistically  or biologically
significant increase in the frequency of an adverse effect when
compared with a control group.

Mechanism of action: The complete sequence of biological
events that must occur to produce the toxic effect.

Mode of action (MOA): A less-detailed description  of the
mechanism of action in which some but not all ofthe sequence
of biological events leading to a toxic effect is known.

No observed adverse  effect level (NOAEL): The highest
exposure  at which there  is  no statistically or biologically
significant increase in the frequency of an adverse effect when
compared with a control group.

No observed effect level (NOEL): The highest exposure at
which there is no statistically or biologically significant increase
in the frequency of any effect, adverse or not, compared with
a control group.

Nonthreshold effect: An effect for which it is assumed that
there is no dose, no matter how low, for which the probability
of an individual's responding is zero.

Pharmacodynamics: The determination and quantitation of
the sequence of events  at the cellular and molecular levels
leading to a toxic response to  an environmental agent (also
called Toxicodynamics).

Pharmacokinetics: The determination and quantitation ofthe
time  course of absorption, distribution, biotransformation, and
excretion of chemicals (also called toxicokinetics).

Physiologically based pharmacokinetic (PBPK) model: A
model that estimates the dose to a target tissue or organ by
taking into account the rate  of absorption into the body,
distribution among target organs and tissues, metabolism, and
excretion.

Program Office: An EPA organizational unit that administers
a major EPA program (Air and Radiation; Water; Prevention,
Pesticides, and Toxic Substances; and  Solid Waste and

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Emergency Response)

Reference concentration (RfC): An estimate of a continuous
inhalation exposure  to  the  human  population  (including
sensitive subgroups) that is likely to be without an appreciable
risk of deleterious noncancer effects during a lifetime.

Reference dose (RfD):  An estimate of a daily dose to the
human population (including sensitive subgroups) that is likely
to be without an appreciable risk of deleterious noncancer
effects during a lifetime.

Risk:  The probability of  adverse effects resulting from
exposure to an environmental agent.

Risk  characterization:  The  integration of information on
hazard, exposure, and dose-response to provide an estimate
of the likelihood that any of the identified adverse effects will
occur in exposed people.

Risk assessment: The evaluation of scientific information on
the hazardous properties of environmental agents and on the
extent of human exposure to those agents. The product of the
risk assessment is a statement regarding the probability that
populations or individuals so exposed will be harmed and to
what degree.

Susceptibility:  Increased likelihood  of an adverse  effect
related to an individual's developmental stage.

Threshold effect: An effect for which  there is some dose
below which the probability of an  individual's responding is
zero.

Uncertainty Factor: One of several factors used to calculate
an exposure level that will not cause toxicity from experimental
data. Uncertainty factors are used to account for the variation
in susceptibility among  humans, the uncertainty in extrapolating
from experimental animal data to humans, the uncertainty in
extrapolating from data from studies in which agents are given
for less than a lifetime, and other uncertainties such as using
LOAEL data instead of NOAEL data.

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   OFFICE OF  RESEARCH AND  DEVELOPMENT
                 STRATEGY FOR  RESEARCH
    ON  ENVIRONMENTAL  RISKS TO  CHILDREN
                           EXECUTIVE SUMMARY
      The U.S. Environmental Protection Agency (EPA) is
committed to promoting a safe and healthy environment for
children by ensuring that  all EPA regulations, standards,
policies, and risk assessments consider special childhood
vulnerabilities to environmental pollutants.

      Windows of vulnerability exist during development,
particularly during  early  gestation, but  also throughout
pregnancy, infancy, childhood, and adolescence,  when
toxicants may permanently alter the function  of a system.
Children may also be more vulnerable than adults because of
differences in absorption, metabolism, storage, and excretion,
resulting in higher biologically effective doses to target tissues.
Children can be more highly exposed than adults because of
proportionately higherfood intake and breathing rates, different
diets, and activities such as playing on floors that result in
greater contact with environmental contaminants.

      These health threats to children are often difficult to
recognize and assess because of limited understanding of
when and why children's exposures and responses  are
different from those of adults. Research is needed to address
these issues and find opportunities and approaches for risk
reduction. This document provides the strategic direction for
EPA's research program in children's health, conducted bythe
Office of Research and Development (ORD).

      The primary objective of the ORD Children's Health
program is to conduct the research and providethe methods to
reduce uncertainties in EPA risk assessments for children,
leading to effective measures for risk reduction.
                           Objectives of the Strategy for
                  Research on Environmental Risks to Children

 #     Establish direction for a long-term, stable core research program in children's environmental health that leads to
        sustained risk reduction through more accurate, scientifically based risk assessments for children.

 #     Identify research to answer the key questions about children's environmental health risks and increase our
        understanding of when children  respond differently from adults to toxic agents and why.

 #     Identify research that will help to reduce children's risks.

 #     Provide a research agenda that identifies research priorities for the ORD intramural and extramural research
        programs.

 #     Inform EPA scientists, risk assessors, and risk managers of the research related to children at EPA and other Federal
        agencies.

 #     Provide guiding  principles for implementation.
                                          EX-1

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                                      Research Questions

        Children's risk is a topic as broad  and varied as    endpoints, biomarkers  of disease,  mechanisms  of action,
human health risk assessment.  Groups of experts have    exposure  pathways,   environmental  contaminants,   and
identified dozens ifnothundredsofresearch issues and needs,    physiological and biological characteristics affecting doses.
addressing  various age  groups, subpopulations, disease
                                      Children's Risk Topics

                                              Health Endpoints
                         #      Cancer
                         #      Neurotoxicity
                         #      Immune system effects
                         #      Asthma and other respiratory effects
                         #      Reproductive effects
                         #      Other birth defects (e.g., death, malformation, growth alteration)

                                        Environmental Health Threats
                         #       Outdoor and indoor air pollution
                         #      Pesticides
                         #      Environmental tobacco smoke
                         #      Microbes and other drinking water contaminants
                         #      Endocrine disrupters
                         #      Specific compounds such as lead, mercury, PCBs, vinyl chloride
                         #      Mixtures of pollutants
        A strategy for research in children's environmental    living on farms and urban children. Priorities may shift rapidly
health must be broad enough to address diverse environmental    as more becomes known about the impact of environmental
contaminants, endpoints, and special groups such as children    agents on children's health.
                                       Research  Questions

 #      What are the effects from children's exposures to environmental agents that are different from effects in adults?

 #      What are the periods of developmentwhen exposure to environmental substances can cause adverse health effects?

 #       What are the best in vitro models and in vivo animal models for screening for and identifying hazards to children?

 #      To what environmental substances are children more highly exposed? What factors contribute to higher exposures?

 #      What are the relationships between exposures to children and adverse health effects observed in childhood or later?

 #      How can laboratory and human data be used to predict responses to childhood exposures?

 #      What is the variation  in exposure and susceptibility  within members of the same age group?

 #      What are the adverse effects from children's exposures to mixtures?

 #      What are the uncertainties in estimating environmental risks to children?

 #      What are the most effective methods for communicating and reducing environmental risks to children?
                                                    EX-2

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                                      Research  Approach
        The strategy was developed by a  science team
composed of members from ORD; the Office  of Prevention,
Pesticides, and Toxic Substances (OPPTS); the Office of
Water; and the Office of Children's Health Protection (OCHP).
The strategy is organized into 5 main topics encompassing 13
research areas. The science team ranked each research area
as high,  medium, or low.  The areas ranked high were those
judged to have the greatest  potential to improve EPA risk
assessments or to address directly the reduction of risks
specific to children.  Feasibility based on the current state of
scientific knowledge, ORD's capacity and capability to perform
the research,  opportunities  to  build  upon  the  research
conducted in other agencies, development and maintenance of
needed expertise within ORD, and the balance between short-
and long-term research were also considered in the rankings.
                                        Research  Priorities

  #      Development of data to reduce uncertainties in risk assessment

         S       Mode-of-action research (High)
         S       Epidemiology and clinical studies (High)
         S       Exposure field studies (High)
         S       Activity pattern and exposure factor studies (High)

  #      Development of risk assessment methods and models

         S       Methods and models for assessing dose-response relationships in children (High)
         S       Methods and models for using exposure  data in risk assessments for children (High)

  #      Experimental methods development

         S       Methods for hazard identification and studying mode of action (High)
         S       Methods for measuring exposure and effects in children and to aid in extrapolations between animals and
                 children (Medium)

  #      Risk management and risk communication

         S       Multimedia control technologies (Low)
         S       Reduction of exposure buildup of contaminants  indoors (High)
         S       Communication of risk (High)

  #      Cross-cutting research

         S       Variation in human susceptibility (Medium)
         S       Cumulative risk (Medium)
                                                    EX-3

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                                           Implementation
        Implementation of the strategy will be accomplished
through detailed  research  plans  developed  by  ORD's
laboratories and centers.  To assist in the development of
these plans, the strategy provides long-term outcomes and
short-term results for each of the highly ranked research areas
and guiding principles for implementation.
Mode-of-Action   and   Dose-Response
(§§4.3.1.1,4.3.2.1,4.3.3.1)
Assessment
        Long-Term Outcomes

#       Mechanism-of-action experimentation facilitates the
        extrapolation of animal and experimental model data
        to humans, enhancing ability to predict and study
        adverse effects in humans. Mode of action becomes
        an integral component of risk assessment. Advances
        in genomics/proteomics are incorporated into EPA's
        risk assessment methodologies.

#       Broadly   applicable   physiologically   based
        pharmacokinetic  (PBPK)  models and  biologically
        based dose-response (BBDR) models are routinely
        used to produce more accurate risk assessments for
        children,  making  full  use of pharmacokinetic and
        mode-of-action data.

        Short-Term Outputs

#       Develop better quantitative characterizations of dose
        to target tissue in developing organisms to replace
        default assumptions in children's risk assessments.

#       Link developmental effects at the tissue, organ, and
        system  levels with the  underlying  effects at  the
        cellular  and  molecular  levels.    Develop  first-
        generation biologically based predictive models.

#       Develop  and  validate  sensitive  and   predictive
        methods using laboratory animalsto determine mode
        of action  by  linking developmental effects at the
        tissue, organ, and system levels with the underlying
        effects at the cellular and molecular levels.

#       Validate in vitro assays (using either animal or human
        biological  material) for inclusion in the  overall  risk
        assessment process.

#       Validate and apply currently available test methods
        and emerging methods in genomics/proteomics and
        molecular  biological  approaches,  useful  for
        understanding and elucidating  mode of  action, in
        developmental toxicity testing.
#       Evaluate the appropriateness of the assumptions in
        current EPA risk assessment approaches and how
        they may be supported or modified by biological data.

#       Develop and refine PBPK models applied to the
        developing   animal, with  the intent  of eventual
        extrapolation to embryos,  fetuses,  infants, and
        children.

#       Develop and refine BBDR models applied to the
        developing animal with the intent of extrapolation to
        embryos, fetuses,  infants and children.

#       Identify biological  pathways, environmental factors,
        and  their   interactions  that  are   important  to
        understanding normal  and abnormal  development,
        with a focus on incorporation of such information into
        predictive models  of developmental toxicology and
        not solely on the generation of basic information on
        child development.

#       Define how experimental animal models mirror child
        development and  develop appropriate  correction
        factors for species differences.

#       Incorporate   information   from   dose-response,
        pharmacokinetic,  and   mode-of-action  studies  in
        animals  into models that more accurately  predict
        children's risks.

#       Develop first-generation methods, guidance, and data
        for  broad application   of  modes  of action and
        pharmacokinetics  in  EPA risk  assessments for
        children

Exposure and Epidemiologic Research (§§4.3.1.2,4.3.1.3,
4.3.1.4,4.3.2.2)

        Long-Term Outcomes

#       Environmental agents and other factors contributing
        to adverse effects in children are identified, status and
        trends   in  children's   health  and   exposure  to
        environmental  agents  are characterized, and risk
        reduction methods are  successfully implemented.

#       Status   and  trends in  children's  exposures  to
        environmental   agents  are  characterized  using
        baseline data  developed in this program.  Highly
        exposed subpopulations of children are identified,
        important  sources  and pathways  of  children's
        exposures are  delineated,  and risk  management
        interventions are successfully implemented.
                                                      EX-4

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#       Residential  exposure  factors  for  children  are
        characterized  by age  and  sex for  the  national
        population, regional  populations,  highly  exposed
        groups,  and susceptible groups.  Factors include
        activity patterns (time spent in a given activity and
        frequency of occurrence),  soil  and dust ingestion
        rates, factors  reflecting transfer of environmental
        agents from objects and surfaces children commonly
        touch, and factors  related to ingestion of chemical
        residues on surfaces.

#       A  broadly  applicable  probabilistic total-exposure
        model capable  of linking to a PBPK model is available
        to  estimate children's exposure  to pesticides,
        producing more accurate assessments of children's
        exposure and  reducing use  of default values and
        safety factors in the assessment when sufficient input
        data are available.

        Short-Term Outputs

#       Analyze relationships between childhood exposures
        to  air pollutants and respiratory effects under the
        ORD Science To Achieve Results (STAR) extramural
        grants program.

#       Analyze relationships between childhood exposures
        to pesticides and neurological effects underthe STAR
        program.

#       Develop, refine, and pilot methods for conducting a
        hypothesis-based longitudinal study of developmental
        disorders in a large birth cohort underthe U.S. Task
        Force on Children's Environmental Health and Safety.

#       Conduct analysis of existing data from the National
        Human Exposure Assessment Survey (NHEXAS), the
        National Health and Nutrition Examination Survey
        (NHANES), and the STAR grants to provide answers
        to the extent possible on whether children are more
        highly exposed, which age groups are more highly
        exposed, and important sources and pathways.

#       Develop newsampling protocols, questionnaires, and
        study designs based on previous studies of children's
        exposure.

#       Design and initiate field studies to answer questions
        about children's exposure,  with  Federal  partners
        where feasible.

 #      Identify  high-priority exposure variables for study
        through  preliminary exposure analysis.
 #      Design  and    complete  activity  pattern survey
        addressing high-priority issues for children.

 #      Complete two studies on other high-priority exposure
        variables for children.

#       Assess children's total pesticide exposure and refine
        existing  exposure  models  based  on  data  from
        NHEXAS,  NHANES, and the STAR program.

#       Analyze  models  in  EPA's   Office  of  Pesticide
        Programs (OPP) Standard Operating Procedures for
        estimating exposure of children to pesticides, identify
        important  pathways  of  exposure,  and   provide
        assessment support.

Risk Management and Risk Communication  (§§4.3.4.2,
4.3.4.3)

        Long-Term Outcomes

#       Broadly applicable methods for removing chemicals
        from residential environments and for  preventing
        exposure in the residential environment (e.g., through
        encapsulation) are used by the Superfund program,
        EPA Regional Offices, State and local public health
        and environmental agencies, and others to achieve
        cost-effective  cleanup to safe levels for children.

#       Through  implementation of  better  methods of
        communicating scientific information about risk and
        working  with  communities  to reduce  risk,  EPA
        strengthens its  community-based risk assessment
        and risk management programs.

        Short-Term Outputs

#       Develop a method  to remove  pesticides and other
        chemicals from building structures and carpets or to
        prevent exposure (e.g., through encapsulation), using
        methyl parathion as a prototype.

#       Implement  risk intervention  programs  in  several
        communities  and   publish  journal  articles   on
        effectiveness  of risk intervention approaches (output
        of  STAR  program's  Centers  for  Children's
        Environmental Health and Disease Prevention).

#       Compare  methods for communicating  risks of
        pesticides on foods  (output of current STAR program
        grant).
                                                      EX-5

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                          Guiding Principles for Implementation

#       When designing a research study, investigators should considerthe impact of the results on EPA risk assessments
        for children. Requests for Applications (RFAs) in ORD intramural and STAR programs should ask investigators to
        specify the potential impact of results on the EPA risk assessment process.

#       A multidisciplinary research program that is coordinated across the ORD laboratories and centers is encouraged.
        RFAs for cross-laboratory/center intramural projects and fostering of contact between extramural grantees and ORD
        scientists are encouraged.

#       Outreach, coordination, and partnership with other Federal agencies is essential, particularly in the areas of human
        studies and biological mechanisms of action.

#       Toxicologists, epidemiologists, clinicians, and exposure scientists are encouraged to work collaboratively during all
        phases of research planning, development, and implementation.

#       ORD needs to develop and maintain intramural expertise to be able to incorporate new data and methods into EPA
        risk assessments. Use of biological data in risk assessment is a high priority. A stable intramural research program
        with adequate support is essential to achieving this capability.

#       Research across more than one endpoint is encouraged where possible, such as research on mechanisms that can
        lead to multiple endpoints and endpoints affecting the same target organ.

#       Risk reduction research and risk management goals should be considered throughout the course of this program.
                                                   EX-6

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            OFFICE  OF  RESEARCH AND DEVELOPMENT
                          STRATEGY FOR  RESEARCH
             ON  ENVIRONMENTAL  RISKS  TO CHILDREN
                                     1.  INTRODUCTION
        The U.S. Environmental Protection Agency (EPA) is
committed to promoting a safe and healthy environment for
children  through regulations, standards, policies,  and risk
assessments that consider special childhood vulnerabilities to
environmental  agents (EPA  1996a).   Many environmental
health threats to children may not be recognized because we
do not have a complete understanding of when and why
children's exposures and responses differfrom those of adults.
This may affect EPA's ability to identify environmental hazards,
assess risks, and act to protect children.

        EPA's Office of Research and Development (ORD) is
responsible for conducting research to provide the scientific
foundation for risk assessment and risk management at EPA.
In  1998, ORD initiated the  Children's Health program to
support research on environmental risksto children. ORD and
the Office of Prevention, Pesticides, and Toxic Substances
(OPPTS) charged a team of ORD and OPPTS scientists with
developing the  Strategy for Research on Environmental Risks
to Children (EPA 1997a)1 to provide strategic direction for the
Children's Health program.

1.1.   Scope and Definitions

        This strategy  addresses  adverse effects  on the
developing  organism that may result from  exposure to
environmental  agents, starting with preconception exposures
to parents and continuing through gestation and postnatally up
to the time of maturation of all organ systems.2 Because organ
systems  reach maturity at  different  times, developmental
phases of interest will  vary by organ system.  Variation in
exposure resulting  from age-related  differences  in activity
       Representatives of the EPA Office of Water and the
EPA Office of Children's Health Protection (OCHP)  were
added to the team at the request of those offices.

       2 In the Guidelines for Developmental Toxicology Risk
Assessment  (EPA  1991), EPA  defined  developmental
toxicology, in part, as follows: "The study of adverse effects on
the developing organism that may result from exposure priorto
conception (either parent), during  prenatal development, or
post natally to the time of sexual maturation.   Adverse
developmental effects may be detected at any point in the life
span of the organism...."
patterns, diet, and physiological characteristics will also help
define developmental phases of interest. The scope includes
effects that a re not observed until adulthood. For convenience,
the terms "childhood," "child," and "children" are used to refer
to all the individuals within the scope of the strategy.

        The  Children's Health program began as part of an
Administrator's Initiative aimed at ensuring that risks to children
are considered in all EPA actions. An expanded program of
research  in  children's issues  is  part  of the Initiative.
Historically, ORD has conducted research in male and female
reproductive toxicity, embryo and fetal toxicity, and postnatal
functional deficits. ORD research supporting the Air, Water,
Waste, and Pesticides and Toxics programs deals with media-
specific issues, such as the impact of air pollution on childhood
asthma and the effects of lead on small children. This strategy
builds upon the ongoing research program.
1.2.   Rationale   for  the
        Health Program
Children's
       There is evidence  of age-related differences in
exposure and susceptibility to some environmental agents that
warrants  further investigation (ILSI 1992,  ILSI 1996, NRC
1993,  WHO 1986).  Depending on the agent, age-related
differences may increase, decrease, or have little impact on the
risk to children.

       As a rationale forthe Children's Health program, this
section provides a brief description of some of the documented
vulnerabilities of children. A more detailed  description of
potential postnatal vulnerabilities is contained in Appendix A.

       There are specific periods orwindows of vulnerability
during development, particularly during early gestation but also
throughout  pregnancy  and  early  childhood  through
adolescence, when toxicants might permanently  alter the
function of a system (Rodier 1980, Bellinger et al. 1987).  At
birth, most organs and systems of the body have not achieved
structural orfunctional maturity. Physical growth and functional
maturation continue through adolescence,  with  the  rates
varying among the differenttissues, organs, and systems of the
body.   Organs  and  systems that continue to  undergo
maturation during infancy and childhood include the lungs,
kidneys,  and liver,  and the  immune,  nervous,  endocrine,
reproductive, and gastrointestinal systems (Hoar and Monie

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1981, Langston 1983, Anderson etal. 1981). A physiological
or functional perturbation resulting from  exposure to an
environmental agent during a critical period of development
may increase  risk.   Children  may  be more susceptible
qualitatively, suffering adverse effects  not  experienced by
adults, or quantitatively  in that  effects occur at a  lower
exposure level or are more severe at the same exposure level
(Faith and Moore 1977).

        Children   may  be  more  vulnerable  to  specific
environmental pollutants because of differences in absorption,
metabolism, and excretion. Elevated rates of gastrointestinal
absorption of nitrates in infants and lead in young children are
well known.  Percutaneous absorption is elevated  during the
first few days of life until keratinization of the skin occurs. Age-
related differences  in  both  the  rates and  the pathways of
metabolism affect excretion rate and the half-life of a chemical
in the body. Young children have higher resting metabolic and
oxygen consumption rates than do adults. These higher rates
are related to a child's rapid growth and larger cooling surface
area per unit of body weight.  Developmental regulation of
metabolic  pathways  can  result  in  the   activation  and
deactivation of a pathway as individuals pass through life
stages, affecting internal dosages (Bearer 1995).

        Children's exposures to environmental pollutants are
often different from those of adults because of different diets
and different activities, such as playing on floors and in soil and
mouthing of their hands, toys, and other objects, that can bring
them into greater contact with environmental pollutants (Bearer
1995).  Because children consume proportionately more food
and fluids, have a greater skin surface area relative to their
body weight, and breathe more air per unit body weight than
adults, they may receive  greater exposure to environmental
substances. Forexample, an infant weighs about one-tenth as
much as a typical adult, but consumes about one-third as much
water daily (Goldman 1995).  The diets of infants and young
children are very different from adult diets. Certain food types,
such as juices, for example, can make up a  larger proportion
of the child's diet, resulting in a higher exposure to pesticides
(NRC1993).

        The causes  of  most developmental  effects and
childhood diseases  are unknown, but there is evidence that
environmental agents play a role in some adverse outcomes.
Exposure to environmental agents affecting development both
in utero and postnatally can result in a wide array of adverse
developmental  endpoints, such as spontaneous  abortions,
stillbirths, malformations,  early postnatal mortality, reduced
birth weight,  mental retardation,  sensory  loss,  and  other
functional  or   physical   changes  (NRC  1993).   Lead,
methylmercury,  polychlorinated  biphenyls  (PCBs),  ethyl
alcohol, and ionizing radiation have been implicated in human
studies as causes of developmental effects (EPA 1991), while
otherchemicals have been implicated in animal studies. Lead
and methyl mercury exposures in children are  related to a
variety of neurological problems  that do not occur in adults
exposed at comparable levels, including reading and learning
disabilities, IQ deficiencies, impaired hearing, reduced attention
spans, antisocial behavior, and hyperactivity.  Prenatal and
perinatal exposure to PCBs has been associated with delayed
development and learning disabilities in children (Jacobson et
al. 1990).

        Childhood exposure to air pollutants, including ozone,
sulfur dioxide, particulate matter (PM), and nitrogen dioxide,
has been associated with decreased lung function, increased
incidence of bronchitis, increased respiratory illness, increased
hospital admissions for respiratory causes, and exacerbation
of asthma (Bates 1995).

        The self-reported  prevalence   rate  for  asthma
increased 75% from 1980 to 1994, with the greatest increase
occurring among children aged 0-4 years (160% from 22 per
1,000 to 57.8 per 1,000) and aged 5-14 years (74% from 42.8
per 1,000 to 74.4 per 1,000). The estimated annual number of
physician office visits for asthma more than doubled from 4.6
million to 10.4 million between 1975 and 1995 for all age, sex,
and racial groups.  Asthma-related hospitalization increased
between   1979-80  and  1993-94,  while  the  rate  of
hospitalizations remained constant. Hospitalization rates were
consistently higher among African Americans. Children aged
0-4 years had the highest hospitalization rate of any age group.
Rates of death with asthma as the underlying cause decreased
between 1960-62 and 1975-77 and then gradually increased.
Most deaths occur in people over 65 (Mannino et al. 1995).

        Currently, the most important factor associated with
asthma is a genetic susceptibility to become allergic.  Indoor
allergens including cockroaches, dust mites, and animal dander
have been identified as the most common triggers of asthma
symptoms. Environmental tobacco smoke,  upper respiratory
tract viral infections, ozone, sulfur dioxide, and PM have also
been suggested as asthma triggers  (Etzel 1995).

        In children, exposure to environmental tobacco smoke
is  causally  associated with  an increased  risk  of lower
respiratory tract infections such as bronchitis and pneumonia,
an increased prevalence of fluid in the middle ear, symptoms
of upper respiratory tract irritation,  small reductions  in lung
function, and additional episodes and increased severity of
symptoms of asthma. Maternal smoking is considered a high
risk factor for Sudden Infant Death Syndrome (EPA 1992).

        These  examples  show  a  relationship  between
exposure to environmental agents and adverse health effects
in children.  However, most causes of adverse developmental
effects and the  reasons for the increase in asthma rates in
children are unknown.   It has been  hypothesized that the
thousands  of   man-made chemicals  introduced  into  the
environment in  recent years,  most  of which have  not been
tested for developmental  effects, may be precipitating  or
contributing factors in some cases.  Another unknown is the
extent to which the biologically effective dose differs between

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children and adults. The response to a chemical could be
identical for children and adults at a given dose at the target
site, but a child could receive a higher dose than an adult in the
same environment.  These uncertainties make it difficult to
answerthe question of whether EPA's health-based standards
are protective of children, and they provide the impetus for a
research program on children's health.

1.3.   Research Questions

        This strategy outlines a research program that will
address questions about children's vulnerabilities to adverse
effects from exposure to environmental agents, the quantitative
risk from exposure to environmental agents, and how the risk
can  be reduced.  The following  research  questions are
addressed in the  strategy:

        1.  What are the adverse effects from children's
exposures to environmental  agents that are qualitatively or
quantitatively different from effects in similarly exposed adults?
What are  the near-term  and delayed effects of childhood
exposures? What are the characteristics of the environmental
agents associated with these effects?

        2. What are the specific periods of development when
exposure to environmental substances can cause adverse
health effects?

        3.  What are the best in vitro models and in  vivo
animal models for screening  for and identifying  hazards to
children?

        4.  To what environmental substances are children
more highly exposed?  How  do exposures differ with age?
What factors contribute to higher exposures?

        5. What are the relationships between exposures to
children and adverse health effects observed in childhood or
later? What factors in the child's environment can increase
risks?

        6.  How  can laboratory and human data be  used to
predict responses to childhood exposures?

        7. What is the variation in exposure and susceptibility
within members of the same age group,  and what  are the
factors that contribute to this variation?

        8.  What are the adverse effects from children's
exposures to mixtures that are quantitatively  or qualitatively
different from effects in similarly exposed adults?

        9.   What are   the uncertainties  in  estimating
environmental  risks to children  and how  can they be
characterized in risk assessment? What are the most effective
methods for communicating  results, data, and risks to risk
assessors, risk managers and the public?

        10.  What are the specific agents and pathways of
exposure where risk management research will be effective in
addressing  known risks to children?  What are the most
effective methods for reducing environmental risks to children?

1.4.   Goals and Objectives

        This strategy was developed within the framework
established in the EPA and ORD strategic plans (EPA 1997b,
c).  EPA developed its  strategic plan in compliance with the
Government Performance and Results Act (GPRA) passed by
Congress in  1993.  The EPA strategic plan lists ten broad
GPRA goals that serve as a framework for EPA's planning and
resource allocation. This strategy addresses Goal 8: Provide
sound science to improve the understanding of environmental
risk and develop and implement approaches for current and
future environmental problems. The EPA program has been
arrayed under the GPRA goals as a series of objectives,
subobjectives, and annual milestones for purposes of reporting
under GPRA.  The ORD Children's  Health program, which is
the topic of this strategy,  is part of the ORD Sound Science
programin Human Health RiskAssessmentunderGoalS. The
objectives of this strategy are shown in Figure 1.

1.5.   ORD  Research   Strategies  and
        Plans

        The ORD strategic  plan identifies six high-priority
research topics: safe drinking water (with a near-term focus on
microbial pathogens, disinfection by-products, and arsenic),
high-priority air pollutants (with a near-term focus on particulate
matter), emerging environmental issues (with a near-term focus
on endocrine disrupters),  research to improve ecological risk
assessment,  research to  improve human  health  risk
assessment, and pollution prevention and newtechnologies for
environmental  protection.   Research strategies  are being
developed for  the six high-priority areas  and for specific
subtopics (see Appendix B), including children's health.  ORD
is developing a strategy for research on  asthma, which will
include research on childhood asthma (EPA2000a).
1.6.   Organization
         Section  2 provides  a  brief overview of the risk
assessment/risk management framework within which ORD
organizes its human health risk assessment research and a
discussion of new directions in risk assessment.  Section 3
discusses the legislative, regulatory, and policy decisions that
encouraged development of the strategy and the relevant EPA
Program and Regional Office activities. Section 4 summarizes
research recommendations from many sources, and outlines
the research program.   Section  5 presents guidance for
implementation.

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                   Figure 1.  Objectives of the ORD Strategy for

                   Research  on Environmental Risks to Children


#      Establish direction for a long-term, stable core research program in children's environmental health that leads to
       sustained risk reduction through more accurate, scientifically based risk assessments for children.


#      Identify research to answer the  key questions about  children's  environmental health risks and increase our
       understanding of when children respond differently from adults to toxic agents and why.


#      Identify research that will help to reduce children's risks.


#      Provide a research agenda that identifies research priorities  for the ORD intramural and extramural research
       programs.


#      Inform EPA scientists, risk assessors, and risk managers of the research related to children at EPA and other Federal
       agencies.


#      Provide guiding principles for implementation.

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                    2.  APPROACHES TO RISK ASSESSMENT
        This strategy was developed within the framework of
the risk assessment-risk management paradigm proposed by
the National Academy of Sciences (NRC 1983) and covers a
wide range oftopicsand disciplines. Readers will have varying
degrees  of familiarity with the use  of  quantitative  risk
assessment  to  support  environmental risk management
decisions. A  brief description of the EPA risk assessment
process is presented here  to help  readers understand the
potential  impact of the research outlined in this strategy on
EPA programs.

        Risk assessment is the process used to evaluate the
hazards of and exposures to environmental agents to produce
estimates of the probability that populations or individuals will
be harmed and to what degree.  It is one component of the
process by which EPA and many other organizations recognize
a potential risk and decide how to respond.  Risk assessment
has been defined by the National Academy of Sciences (NAS)
to consist of four  steps:  hazard  identification, exposure
assessment,   dose-response   assessment,  and  risk
characterization (NRC 1983).

        The hazard assessment describes the likelihood that
an environmental agent will  produce adverse  effects and the
mechanisms by which agents exert their toxic effects. The
exposure assessment  specifies populations that might be
exposed, identifies  routes  of exposure (usually inhalation,
ingestion, and dermal contact), and estimates the magnitude,
duration,  and  timing  of the  doses received.  The exposure
assessment may also determine the sources of exposure and
the contribution of each source  to the  total exposure.  The
dose-response assessment describes the relationship between
dose  level  and  degree of toxic  response.   The  risk
characterization integrates information from the first three steps
to develop estimates  of the likelihood that any of the identified
effects will occur in exposed people (NRC 1994).
2.1.   The     Standard
        Approach
Regulatory
        The  standard  regulatory risk  assessment of an
environmental agent is organized according to the four steps
of the NAS paradigm and is based on the available data most
relevant to the population being evaluated.   If population-
specific  data  are  not available and cannot be collected,
extrapolation methods and default assumptions are used to
complete the assessment.3
        3EPA assessment methods are described in a series
of assessment  guidelines  for exposure  and cancer and
noncancer endpoints  (e.g., EPA 1996b, EPA 1996c,  EPA
1991).
        The exposure assessment links environmental and
personal exposure measurements with activity patterns using
exposure models to estimate dose. Exposure models may be
as simple as an estimate of inhalation dose as the product of
concentration, breathing rate, and time of exposure. Or they
may be complex, with many exposure pathways and dozens of
variables. Understanding the sources of exposure and howthe
environmental agent is transported from its sources to the
exposed individual may be critical to estimating concentrations
in the air, water, soil, dust, and food to which individuals are
exposed. It is also important to know the sources of exposure
in orderto identify, evaluate, and implement risk management
options.

        Estimates of exposure or dose from the exposure
assessment are combined with information on toxic response
to produce estimates of risk. The process for determining the
likelihood of an adverse effect at a particular exposure or dose
is the dose-response assessment.  Human  data suitable for
developing dose-response relationships are usually obtained
from groups that have been highly exposed in the workplace,
by accident, through diet, and the like.  Studies of groups
outside the United States that have been  historically exposed
to high levels of environmental pollution are sometimes used.
Even when such  highly exposed groups exist, however, the
difficulty in determining and quantifying individuals' exposure
histories as well  as the presence of other possible causes of
the adverse effect can prevent even the  observation of a
cause-effect relationship.   Therefore, the quantitative  dose-
response assessment is usually based on data from controlled
laboratory studies where effects on animals are evaluated and
the results extrapolated to humans.

        Under the current EPA default approach to hazard
and dose-response assessment, cancer is thought of as the
consequence of chemically induced DNAmutations. Because
a single chemical-DNA interaction  may lead to a mutation and
since cancer is thought to arise from single cells, any dose, no
matter how low, is assumed to have the potential to cause the
adverse effect.  This is referred to as a nonthreshold effect.
Nonthreshold effects  are modeled as  linear relationships
between response and dose across the entire dose-response
curve. Dose-response relationships observed at the relatively
high doses administered in the laboratory are assumed to hold
true at the lower doses usually experienced by humans in the
environment (ERG 1997,  1998).

        Effects  other than cancer (threshold effects) have
been assumed to result from multiple chemical reactions within
multiple cells. EPA's policy is to assume that, for noncancer
effects, there is a safe exposure, and that no adverse effects
are likely to occur below that threshold.  The threshold is
estimated based on the highest exposure at which no  effect
was observed in an  experimental study—the NOAEL (no-

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observed-adverse-effect level) or the NOEL (no-observed-
effect level) (NRC 1994). To establish a safe limit for human
exposure,  the  NOAEL  is divided by  uncertainty factors to
account for differences in  susceptibility  among humans,
differences between test species and humans,  and other
uncertainties resulting from lack of key data such as a long-
term dosing study or a NOAEL. A typical assessment uses a
factor of 10 to account for variability in human response and a
factor of 10 to account for interspecies differences.  At EPA,
this quotient is termed Reference Dose (RfD) when derived for
ingestion exposure and Reference  Concentration (RfC) for
inhalation exposure (NRC 1994).

        The standard regulatory approach is extremely useful
in that it has allowed EPA to assess and make regulatory
decisions on thousands  of chemicals, often with limited data,
while providing  some  assurance that  the  decisions  are
protective  of public health. However, questions often arise
about whether the current approaches accurately account for
the  many  uncertainties introduced  when assessments  are
based on data from the laboratory. Available dose-response
data must be extrapolated from the  high exposures used in
laboratory experiments to the lower exposures usually found in
the  environment.  The  internal dose to the target tissue in
humans is usually unknown.  The frequency and duration of
exposure in the laboratory study is often different from what
can be expected in the environment.  It is often difficult to find
an appropriate animal model forthe substance and endpoint of
concern or to  predict differences in the magnitude  of the
response between animals and humans.  There  is a major
difficulty in extrapolating from  immature laboratory animals to
children because growth rates and the level of development
and maturation of organs and systems at and after birth can be
considerably different  across animal species,  as well as
between animals and humans. Current default approaches do
not  easily  allow for incorporation  of all relevant data in  the
dose-response assessment. Factors that can cause significant
age-related differences in exposure  and  toxicity, such as
metabolic pathways and rates, distribution in the body, dose to
target organ, excretion, DNA repair, and growth and  cell
proliferation are not accounted for except through uncertainty
factors.

2.2.   Future  Directions  in EPA Risk

        Assessment

        The exposure-dose-response relationship can be
envisioned as a continuum of events in which exposure to a
substance occurs, the substance enters and  moves through
the body and may be chemically transformed, and interacts to
cause changes in molecules, cells, and tissues,  leading to
disease. The series of events by which a substance exerts its
toxic effects is referred to as a mechanism of action. The term
"mechanism of action"  will  be used here to  refer to  the
complete sequence  of biological events that must occur to
produce the adverse effect. Typically, only partial information
on the mechanism of action is available. In such a case the
term "mode of action" will be used to refer to mechanisms for
which some but not all of the steps are known. In many cases,
exposures and early effects in the biological sequence can be
measured through biological  markers. An  assessor is often
able to describe qualitatively many of the processes that lead
from exposure to effect, but lacks the data and methods to use
the information in the quantitative risk assessment.

        Better  understanding  of the sequence of  events
leading to adverse effects and availability and use of biological
data will increase EPA's ability to assess risks. Early biological
effects are more prevalent in the population than is  actual
disease, and biomarkers of early effects may sometimes be
more specific to environmental agents. A better understanding
of the pharmacokinetics  and toxic  modes of action  of
environmental agents will improve hazard  identification and
reduce  uncertainties  in  extrapolation  from  laboratory
measurements of the dose-response relationship to events in
the  environment  (e.g.,  see  EPA  1996b).    Expanded
development  and  use  of biological  data is  essential to
quantifying variability in  human susceptibility, understanding
responses to mixtures of chemicals,  and  harmonizing  risk
assessment methods for cancer and noncancer endpoints.

        One method of incorporating information on the mode
of action in the dose-response assessment is the  use of
biological  models.   Physiologically based pharmacokinetic
(PBPK) models address the exposure-dose relationship in an
organism taken as a whole, estimating the dose to a target
tissue or organ by taking into account rates of absorption  into
the body, metabolism, distribution among target organs and
tissues, storage, and elimination.  Biologically  based dose-
response  (BBDR)  models  describe  specific biological
processes at the cellular and molecular levels that link the
target-organ dose to the adverse effect (Faustman and Omenn
1996). PBPK and BBDR models are useful in extrapolating
between animals and humans and between children and adults
because they allow consideration of species- and age-specific
data on physiological factors affecting dose levels and data on
biological  responses that are different  or more intense in
children.

        With advances in the ability to measure and model the
biological events in the exposure-dose-response continuum,
the  science  of risk assessment  is  moving  toward  a
harmonization of the  methodology  of cancer and noncancer
assessments and away from a consideration of endpoints in
isolation.   Carcinogenesis  is now recognized to embody
changes in key genes that regulate the cell replication cycle
and that can be influenced by mutagenic and nonmutagenic
modes of action. When direct mutagenic events do not pertain
and other modes of action apply,  the likelihood exists that
cancer is secondary to other events (e.g., stimulation of cell
division) and that a potential for cancer exists only at doses
sufficient to produce the  events.   Thus,  in some  cases,
thresholds could apply. Conversely, it is now recognized that

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threshold  considerations may not apply to  all  noncancer
effects.  For example, effects of lead exposure are manifested
at existing environmental exposure levels, and no apparent
NOAEL exists (ERG 1997, 1998).

        Thus, the current scientific database indicates that
automatic separation of dose-response relationships forcancer
and noncancer effects may not be justified. A focus on modes
of action of carcinogenesis directs attention away from tumors
toward earlier biological and toxicological responses critical in
the carcinogenesis process. Such  responses are relevant to
both cancer and noncancer effects and serve as a bridge to
link their  risk  assessments.   Use of biological data and
harmonization of assessment methods may also provide new
means by which to study relationships between environmental
agents and rare endpoints such  as the various childhood
cancers.  If it  could  be demonstrated, for  example, that
childhood cancer and birth defects of a particular target organ
result from similar modes of action, these endpoints might be
combined in an epidemiology study. The higher percentage of
cases  in the  population resulting from combining  cases
involving different endpoints would  increase the  ability  to
observe  relationships  between the  adverse effects  and
exposure to environmental agents hypothesized to produce the
effects by the common mode of action.

        New directions in  risk assessment at EPA  also
include more emphasis on total exposure via all pathways,
consideration of cumulative risks when individuals are exposed
to many chemicals at the same time, and use of probabilistic
modeling methods such as Monte Carlo analysis to provide
better estimates of the  range of exposure, dose,  and risk in
individuals in the population.

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        3.   IMPLEMENTATION OF LEGISLATION AND POLICY ON
                     CHILDREN'S ENVIRONMENTAL HEALTH
        In 1996, Congress enacted two statutes requiring that
EPA considerchildren and other potentially susceptible groups
when  setting  health-based standards:  the  Food  Quality
Protection Act of 1996 (FQPA) and the Safe Drinking Water Act
(SDWA) Amendments of 1996.

        Because  of the risk assessment  requirements  in
FQPA,  EPA's Office of Pesticide Programs (OPP) is very
active in addressing children's risk issues.  FQPA calls for a
reassessment of pesticide tolerances and registrations  to
ensure that they  are protective of children.   The  statute
provides that in making a finding of reasonable certainty of  no
harm  for threshold effects, "an additional tenfold margin  of
safety for the pesticide chemical residue and other sources of
exposure shall be applied for infants and children to take into
account potential pre- and postnatal toxicity and completeness
of data with respect to the exposure and toxicity of infants and
children."  The Administrator may use a different margin  of
safety "only if, on the basis of reliable data, such margin will  be
safe for infants and children" (FQPA, section 405, amending
the Federal  Insecticide, Fungicide, and  Rodenticide Act,
section 408(b)(2)(C)).

        OPP has developed a draft policy on application of the
tenfold margin of safety (the 10X Factor) (EPA 1999a), which
identifies a core set of toxicity tests that will  be accepted as a
complete toxicity database for  infants and children. OPP will
consider the completeness of the toxicity data as part of RfD
development.  If one  or more of the key studies in the core is
missing or inadequate, an  Uncertainty Factor for database
uncertainty will be used in deriving the  RfD.  Decisions on the
completeness of the exposure database will be made as part
of the exposure assessment, based on whether sufficient data
exist either to accurately determine exposure or to assure that
exposures to infants and children are not underestimated. If for
some  reason, the RfD process does not consider all possible
uncertainties related  to toxicity, residual uncertainties will  be
considered in the risk characterization.

        The final decision on the 10X  Factorwill be made  by
considering togetherthe use of Uncertainty Factors to account
for database uncertainty and potential toxicity to infants and
children in developing the  RfD, the recommendations in the
exposure assessment regarding the  need to account for
incompleteness in the exposure  database,  and any residual
uncertainties   and  concerns   identified  in   the  risk
characterization.  On the weight of the evidence, OPP may
decide to retain the 10X Factor, or remove, reduce, or raise it.4
        ORD supported OPP's development of toxicity and
exposure data requirements for the  10X Factor through
leadership  of  and participation  in  EPA working  groups
addressing  these issues (EPA 1999b,  c). The FQPA data
requirements were considered in developing this strategy.

        In other activities related to implementation of FQPA,
OPP  has developed standard operating  procedures for
assessing exposure by multiple routes (Versar 1997) and
methods  for  conducting  aggregate  exposure   and  risk
assessments (EPA 1999d).  These methodologies consider
dietary and  drinking water exposures using intake values for
young  age  groups.   They  also consider such  childhood
exposure pathways as contact with dust and soil followed by
ingestion, exposure to pesticides on toys, and ingestion of
pesticide  pellets.

        The SDWA Amendments of 1996 require that EPA
take into account the effect of contaminants  on sensitive
subpopulations, including infants and children, when deciding
which drinking water contaminants present the greatest public
health concerns and whetherto regulate contaminants.  Office
of Water activities are focused on  protecting infants and
children from contaminants such as microbes and chemicals in
drinking and recreational water and fish. The Drinking Water
Health Advisory program develops  guidance for  short-term
exposures to drinking water contaminants to protect children
against noncancer health effects.

        In addition to implementing these statutes, EPA has
a policy of specifically considering children throughout its
programs. U.S. Executive Order No. 13045 requires that each
Federal agency shall make it a high priority to ensure that its
policies,  programs,  activities,  and  standards   address
disproportionate risks to children that result from environmental
health risks or safety  risks (US Executive Order No. 13045
1997).  In 1995, the EPA Administrator established a policy to
explicitly take into account health risks to children and infants
from environmental hazards when conducting assessments of
environmental risks (EPA 1995a). The announcement of the
policy was followed by a 1996 EPA Administrator's report,
Environmental Health Threats to Children and EPA's National
Agenda to  Protect Children's  Health  from  Environmental
Threats (EPA 1996a). The National Agenda calls for an
evaluation of all EPA standards to ensure sufficient protection
for  children, expansion of scientific research  on childhood
susceptibilities and exposures, and an emphasis on outreach
to parents and communities through education  and other
measures to reduce and prevent childhood risks.  All EPA
        "There are many important issues related to the FQPA
Safety Factor that cannot be addressed here.  OPP  may
change some parts of its draft policy before it is finalized. The
latest information can be found at the Internet site of the OPP
Science Advisory Panel:  http://www.epa.qov/scipoly/sap/

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Program Offices and Regions have programs to implement
these policies.

        OPPTS  is  authorized  by  statute  to  require
manufacturers to test new and existing pesticides and other
toxic substances and submit data for evaluating safety.  Much
of the toxicity testing in the United States is performed by the
private sector underthe Toxic Substances Control Act (TSCA).
OPPTS provides test protocols and recently issued an updated
set of testing guidelines that will provide better information on
health effects  in  children,  particularly  reproductive  and
developmental effects.  Guidelines have  been updated and
expanded  to  include  chemical  effects on  metabolism,
developmental neurotoxicity, and reproductive and prenatal
developmental  toxicity (EPA 1998a).   New guidance  is
provided for testing for toxic effects on the immune system.

        Part 50 of the Clean  Air Act and  its supporting
legislative history require that EPA establish National Ambient
Air Quality Standards (NAAQS) to protect the  health, with an
adequate margin of safety, of susceptible subpopulations. The
innate developmental and physiologic characteristics and the
activity patterns leading to higher exposures that make children
susceptible to these air pollutants have been considered in
every NAAQS promulgated underthe Clean Air Act.

        The Office of Solid Waste and Emergency Response
(OSWER) routinely considers children's exposure  at waste
sites through dermal contact and ingestion of contaminants in
dust and soil. OSWER is expanding its efforts through such
actions as conducting consistent, comprehensive assessments
to evaluate  the  impact  on  children  of lead-contaminated
hazardous waste sites.

        The  EPA Regional   Offices are  leading  and
participating in outreach, risk assessment, risk intervention,
and community educational projects, often in cooperation with
State and local governments, private organizations such as the
American   Lung   Association   and   the  Parent-Teacher
Association, and members of local communities. The Regions
address important environmental problems, including children's
risks from proximity to hazardous waste sites,  asthma in
children  and its  relationship  to  allergens   and  other
contaminants in indoor environments, and lead and pesticides
in residences.

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                               4.  RESEARCH  DIRECTIONS
        I n developing this strategy, the science team followed
the approach outlined in the ORD Strategic Plan (EPA 1997c).
Research recommendations of conferences, workshops, and
scientific reports  on children's environmental  health were
reviewed.  Comments were sought from the ORD national
laboratories  and  centers.   The  ORD Science  Council,
composed of the ORD Deputy Assistant Administrator for
Science, the ORD Associate Directors for Health and Ecology,
and other  ORD science managers,  was consulted.  EPA
Program Offices and the Office of Children's Health Protection
(OCHP) contributed recommendations through membership on
the science team.  The science team formulated the set of
research questions in Section 1.3 and a set of research areas
to address the questions.  Criteria were developed and  the
research areas were assigned a priority of high, medium, or
low.     Section  4.1  discusses   research   needs  and
recommendations. Section 4.2 summarizes current research
sponsored by EPA and other Federal agencies. Section  4.3
describes possible research areas for  the ORD Children's
Health  program, the feasibility of conducting the research at
EPA, and the priority of the research. Section 4.4 discusses
the impact  of the  research  on  risk assessment  and
management and the relationships   between the research
areas.

4.1.   Research Needs  and

        Recommendations

        Over the past two decades, many groups of experts
have considered how exposure to environmental agents affects
children.  Hundreds of research issues have been defined,
addressing   numerous  age groups,  disease  endpoints,
biomarkers of disease, modes of action, exposure pathways,
environmental  agents,  physiological   and  biological
characteristics affecting  dose,  and   methods  of  risk
communication and risk reduction.  Research on children's
environmental  health is performed by members of many
disciplines,  among whom  are physicians;  classical  and
molecular  epidemiologists;  developmental   toxicologists,
including  specialists in neurotoxicity,  immunotoxicity,  and
childhood cancer; environmental scientists; engineers; and
statisticians.

        The   sources   of   research  recommendations
considered by the science team and the topic areas covered
are shown in Table 1 and Appendix C.

4.2.   Current Research

        ORD  conducts   research   on   exposures  to
environmental agents and related adverse effects in children.
Other Federal agencies also study the occurrence and causes
of childhood developmental disorderand disease. The Federal
public health agencies ofthe Department of Health and Human
Services, especially the National Cancer Institute (NCI), the
National Institute of Environmental Health Sciences (NIEHS),
the National Institute of Allergy and Infectious Disease (NIAID),
the National Institute forChild Health and Human Development
(NICHD), and the Centers for Disease Control and Prevention
(CDC),  support much of the Federal research, surveillance,
and data collection on children's health in the United States.
Although much of this research is relevant to EPA's mission,
only a fraction ofthe Federal program investigates the specific
role of  environmental agents  in causing adverse  effects  in
children. This section describes some ofthe Federal programs
directed at children's environmental risks and gives examples
of projects underway at EPA.  The Children's Environmental
Health and Safety Inventory of Research (CHEHSIR), which is
available via the lnternet(EPA2000b), reports relevant Federal
research at the project level. Appendix D describes the roles
of the Federal research  programs that are most relevant to
children's environmental health.

4.2.1.  National Testing Programs

        The Federal Government develops testing protocols
and tests pesticides and other chemicals in animals to identify
potential hazards to humans. Under programs administered by
OPPTS (Section 3),  EPA may  require  manufacturers to test
substances  in  commerce to  identify those that  may  be
hazardous to human health. ORD supports the OPPTS testing
program through research in improved methods of chemical
testing. The National Toxicology Program (NTP) also conducts
toxicity testing.  NTP consists of relevant activities of NIEHS,
the National Institute of Occupational Safety and  Health
(NIOSH), and the U.S. Food and Drug Administration (FDA).
NTP develops and conducts in  vitro and in vivo tests for long-
term carcinogenesis, reproductive and developmental effects,
genotoxicity, teratogenicity, immunotoxicity, neurotoxicity, and
other disease endpoints. NTP is responsible for one-third of
all toxicity testing performed world-wide (NIEHS 2000a). EPA
is  a voting member of the Interagency Testing Committee
(ITC), through which chemicals are nominated and selected for
NTP toxicity testing.

4.2.2.  Modes of Action   and  Modeling of
        Physiological/Biological Processes

        In addition to routine chemical testing to  identify
substances of concern, the Federal Government sponsors
research to investigate the biological processes by which toxic
effects, including effects in children, occur. ORD is developing
methods to  evaluate hazards  for  noncancer human  health
endpoints,  including new and refined test methods for
neurotoxicity, immunotoxicity,  and reproductive toxicity, and
predictive models to improve the biological basis for human
                                                     10

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                       Table 1.  Research Recommendations and Needs
Source
             Description
                  Topic Areas
ILSI(1992)
•EPA-sponsored workshop conducted by
International Life Sciences Institute (ILSI):
Similarities and Differences Between
Children & Adults
•Invited investigators
•Development and genetics
•Physiological and biochemical differences between
children and adults
•Animal models for developmental toxicology
•Age-related responses in cancer bioassays
•Drug case studies
•Environmental case studies (ionizing radiation, lead,
vinyl chloride,  polyhalogenated biphenyls)
•Pesticide case studies
NRC(1993)
•NRC panel report:  Pesticides in the
Diets of Infants and Children
•Differences between infants, children, and adults
•Selection of appropriate animal models
•Toxicity
•Methods of toxicity testing
•Food and water consumption
•Estimating exposures
•Estimating risks
ILSI (1996)
•EPA-sponsored workshop: Research
Needs on Age-related Differences in
Susceptibility to Chemical Toxicants:
Report of an ILSI Risk Science Institute
Working Group
•Invited experts
•Cancer
•Neurotoxicity
•Immune system effects
CEHN(1997)
•Children's Environmental Health Network
conference:  1st National Research
Conference on Children's Environmental
Health: Research, Practice, Prevention,
Policy
•Invited speakers
•Asthma and respiratory effects
•Childhood cancer
•Neurodevelopmental effects
•Endocrine disrupter effects
•Exposure
•Risk prevention and reduction through community
involvement and education
EPA(1998b)
•EPA interim final guidance:  Guidance for
Considering Risks to Children During
Establishment of Public Health-Related
and Risk-Related Standards
•Hazard considerations
•Dose-response/susceptibility considerations
•Exposure considerations
EPA(1998c)
•EPA-sponsored conference:
Preventable Causes of Cancer in Children
•Invited speakers
•Epidemiology & prevention of childhood cancer
•Susceptibility factors for childhood cancer
•Molecular markers of exposure and effect for
childhood cancer
•Quantitative measurement of exposure to potential
childhood cancer agents
NRDC(1997)
•National Resources Defense Council
report:  Our Children at Risk: the 5 Worst
Environmental Threats to Their Health
•Lead
•Air pollution
•Pesticides
•Environmental tobacco smoke
•Drinking water contamination
                                                     11

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                 Table 1.  Research Recommendations and Needs (continued)
       Source
             Description
                   Topic Area
 EPA(1998d)
•EPA workshop: Assessment of Health
Effects of Pesticide Exposure in Young
Children
•Invited experts from many disciplines
•Focus on identification of health effects
associated with exposure to pesticides
and how to measure those effects in
children
•Neurotoxicity
•Developmental toxicity
•Carcinogenicity
•Immunological effects
•Respiratory effects
 EPA(1998e)
•Annual EPA Regional risk assessor's
meeting: session on risk assessment
issues related to children's health
assessments
•EPA Regional risk assessors and
interested EPA Program Office and ORD
representatives
•Consistent approaches to toxicity assessment for
children
•Consistent approaches to exposure assessment for
children
•Default assumptions for children's risk assessments in
absence of data
•Childhood cancer and childhood exposure resulting in
adult cancer
•Effects of children's exposure to mixtures
•Risk communication to the public on children's issues.
 EPA 10X Task
 Force (EPA 1999a,
 b, c)
•Task Force reports providing
recommendations on application of FQPA
10X Factor:
 -Toxicology Data Requirements for
Assessing Risk of Pesticide Exposure to
Children's Health
 - Exposure Data Requirements for
Assessing Risk from Pesticide Exposure
of Children
 - The Office of Pesticide Programs
Policy on Determination of the
Appropriate FQPA Safety Factor(s) for
Use in the Tolerance Setting Process
•Toxicity
•Exposure
•Integration (decisionmaking on 10X Factor based on
all toxicity and exposure considerations)
 U.S. Task Force
 established under
 Executive Order
 13045
•U.S. Task Force established four working
groups to develop Government-wide
initiatives for FY2000 on children's
environmental health and safety issues
•Developmental disorders
•Childhood cancers
•Childhood asthma
•Unintentional injury
health  risk assessment.  This research includes pesticide-
specific studies to determine  long-term health  effects of
exposures during  development.  At issue are reproductive
competency   and  function,   neurobehavioral  changes,
neurochemistry, neural growth and differentiation, allergic
response, and immune function. Some of the ongoing studies
attempt to understand and  characterize the mechanisms by
which toxicants interact at the cellular and molecular levels to
produce adverse effects. As we obtain more  data on these
modes of action,  we will be able  to  test the assumptions
underlying our risk assessment methodologies and to develop
new methods that will more accurately predict children's risks.
Research in the pharmacokinetics of toxicants and modes of
toxic action are providing results that will help develop PBPK
and  BBDR  models  for target organs  (e.g.,  respiratory,
                                     reproductive, and  nervous systems) leading  to  improved
                                     hazard identification and methods of extrapolation between
                                     animals and humans.

                                            The ORD extramural grants program, Science To
                                     Achieve Results (STAR), is supporting grants to investigate the
                                     biological  and physiological characteristics of  different age
                                     groups, variability in response within particularage groups, and
                                     the biological basis for instances of increased susceptibility to
                                     environmental contaminants in children.

                                            At ORD's National Health and Environmental Effects
                                     Research  Laboratory (NHEERL),  batteries  of cellular and
                                     molecular markers, as well as functional tests, are being
                                     developed to aid in the  identification  and characterization of
                                                       12

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toxicant-induced   alterations  in   the   ontogeny  of  the
reproductive, immune and central nervous systems. Studies
are underway to determine if there are long-term, persistent, or
latent effects in animals exposed to environmental toxicants
during development and,  if so, to  identify the mechanisms
responsible for these effects. Scientists at NHEERL are also
investigating the toxicodynamic and toxicokinetic mechanisms
that underlie age-dependent responses to toxicants.

        NIEHS's research program is closely allied with that
of ORD in studying the impact of environmental contaminants
on public health.  Under their extramural programs, EPA and
NIEHS  jointly  sponsor   eight  Centers   for   Children's
Environmental Health and Disease Prevention Research (EPA
2000c). The centers conduct research to improve detection,
treatment, and prevention of environmentally related diseases
in children. The NIEHS Intramural Division conducts basic and
applied research  on how environmental  exposures  affect
biological systems and human health, on the identification of
susceptible subpopulations, and on the interaction between the
environment,  genes, and  age.  NIEHS is sponsoring the
Environmental Genome Project, which will  investigate the
interaction  of  genes and environmental  contaminants  in
causing human disease (NIEHS 2000b).  The role  of gene-
environment interactions on human development and childhood
disease could be studied  under the Environmental Genome
Project.

        NCI is the primary sponsor of research on the biology
of cancer.   Investigations are focused  on  identifying and
understanding the genes whose activity allows DNA changes
that result in a normal cell becoming a cancer cell.  NCI is
developing  and using experimental biological models that
mimic the wide variety of human cancers (NCI 2000).

        NICHD  supports research on  the reproductive,
neurobiological, developmental, and behavioral processes that
determine and maintain the health of children  and  adults
(NICHD 2000). The NICHD program includes research  on the
effects of exposure to  environmental  agents  on human
development. In 1999, EPA and NICHD sponsored a Request
for Applications (RFA) for research  on genetic susceptibility
and variability of human malformations. EPA's efforts  in this
area focus on identifying environmental agents that cause birth
defects and other developmental  disorders,  the molecular
mechanisms of birth  defects, and howto use mechanistic and
other data in the risk assessment process (EPA 2000c).

4.2.3. Studies  in Human Populations

        Five  of the  EPA/NIEHS-sponsored Centers for
Children's Environmental Health and Disease Prevention are
studying the influence of the environment on asthma and other
respiratory diseases in groups of children hypothesized to be
highly exposed to airborne contaminants and devising ways to
prevent or  reduce exposures where  necessary.   ORD is
participating in the Inner-City Asthma Study, a prevention trial
led  by NIAID aimed at developing intervention  methods to
reduce  high  asthma  morbidity  in  inner-city children and
adolescents.  The Inner-City Asthma Study identified factors
associated with asthma severity, including high levels of indoor
allergens, high levels of smoking among family members and
caretakers, and exposure to high levels of nitrogen dioxide, a
respiratory irritant (Fauci 1997).

         Some studies are conducted in cities where high
levels  of  air  pollution  increase  the  ability  to  observe
relationships between pollutants and respiratory effects. ORD
is studying the relationship between air pollution and children's
respiratory health in four Chinese cities. An ORD study is also
underway to determine whether children are more susceptible
than adults to nasal metaplasia and whether biochemical tests
can detect morphological alterations caused by high ambient
ozone and PM10 pollutants in Mexico City (EPA 2000b).

         Three of the EPA/NIEHS Centers  for Children's
Environmental Health and Disease Prevention are examining
the  relationship   between   developmental  disorders  and
exposure  to  neurotoxicants  such  as  organophosphate
pesticides in groups of children believed to be highly exposed.
ORD  is also sponsoring studies of children's exposures to
pesticides in Minneapolis-St. Paul under the National Human
Exposure Assessment  Survey (NHEXAS);  along the U.S.-
Mexico border in Arizona and Texas; and under STAR grants
in Arizona, Washington State, and Minnesota.  Depending on
the  study,  measurements include levels of pesticides in air,
water, food, dust, and soil;  personal biomarkers  of exposure
such as pesticide levels in blood, breath, and urine; and activity
information   (questionnaire,   diary,   observation,  and
videotaping).   Some of these studies  will  focus  on  total
exposure,  sources of exposure, and differences  in exposure
between children and adults, and some  also investigate the
relationship between exposure and health endpoints.

        ORD has recently  begun to investigate  exposure of
pre-elementary   school  children   to   persistent  organic
compounds through ingestion, inhalation, and dermal contact.
Targeted   compounds   include   polycyclic  aromatic
hydrocarbons, pesticides,  phthalate esters,  phenols, and
polychlorinated biphenyls.   Environmental samples will  be
collected in homes, classrooms, and outdoor  play areas.
Children will be videotaped  to determine activity patterns and
urine samples will be collected. Children and adult caregivers
in approximately 450 households will be studied.

        ORD and CDC are supporting a number of studies to
evaluate health and environmental conditions along the U.S.-
Mexico border in the context of risk to children. The goals of
one such  study  are to determine whether children are at
increased  risk of adverse  health effects from exposure to
pesticides, to identify risk factors, and to develop intervention
and prevention strategies.   Another  study  deals with the
identification of lead exposure sources  and risk reduction.
Associations between ambient air quality and acute pediatric
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respiratory  health are being evaluated in a retrospective
epidemiologic study. A case-control study of risk factors for
neural tube defects is underway.  The potential association of
neural tube and cardiac defects and exposure to disinfectant
byproducts in drinking water is also under examination. A
separate study in Chile  is investigating the relationship of
chronic  arsenic  exposure in drinking  water to  congenital
abnormalities and fetal, neonatal, and maternal morbidity and
mortality.

        Examples of  other  current ORD studies  include
determination of the ability to link recent pesticide exposure
and   elevated  cholinesterase   levels   to  defined
symptomatologies  of   young   children   in  agricultural
communities; evaluation  of  arsenic metabolic  profiles in
children and adults  in order to  determine if differences in
metabolism  are  age-related  or  are  due  to differences in
ingestion habits; and application of test methodologies for
evaluating  associations   between   estimated   insecticide
exposure and  immunologic, developmental,  and enzymatic
endpoints.

        Many  Federal agencies  conduct surveillance of
childhood disease and sponsor population-based studies of
exposure and disease in children. These programs produce
data and results vital to EPA's risk-based programs.  CDC's
National Center for Environmental Health (NCEH) tracks
asthma emergency room visits, asthma hospitalizations, and
asthma mortality on a  national level and in four geographic
regions  in  partnership with State and local  governments.
Hospitals and clinics routinely report obvious birth defects.
NCEH surveys  children aged 3 to 10 in metropolitan Atlanta to
document  developmental  disabilities  that require time to
appear,  including mental  retardation,  vision and hearing
impairment, and cerebral palsy, and conducts surveillance and
epidemiology studies of human exposure to  lead, radiation, air
pollution, and other  toxicants. A major focus of the NCEH
Strategic Plan is the incorporation of advances in genetics into
its research, epidemiology studies, and disease  prevention
programs (CDC 2000a). NCEH has a laboratory with expertise
in   analyzing   biological  samples  for  environmental
contaminants, which is developing improved analytical methods
for blood and urine samples from children (CDC 2000b).

        CDC's National Center for Health  Statistics (NCHS)
is  conducting  the  fourth National  Health   and Nutrition
Examination Survey (NHANES IV), a national survey of health
and nutrition. NHANES IV will have about 30,000 respondents
and will include sufficient numbers of children in selected age
ranges to  allow statistical inferences about their  health,
nutrition, and food intake, and  the concentrations of some
environmental contaminants in their blood and urine.  ORD is
collaborating with NCHS to collect information on children's
exposure to pesticides and otherenvironmental contaminants.
NHANES has  been  conducted since  1971,  and data  from
NHANES III are now available (CDC 2000c).
        NCI   conducts   population-based   research   on
environmental and genetic causes of cancer and on the role of
biological, chemical,  and physical agents in the initiation,
promotion, and inhibition of cancer. NCI's Agricultural Health
Study (AHS) is a large epidemiology study of cancer in farm
workers and their families. ORD is participating in the AHS
through an exposure study of a subgroup of participants. NCI
also supports human-subject research aimed at understanding
the molecular causes of specific cancers in children and the
reasons for  treatment failure. The pediatric Clinical Trials
Cooperative  Groups  (Children's  Cancer Group, Pediatric
Oncology Group, National Wilms' Tumor Study Group, and
Intergroup  Rhabdomyosarcoma  Study Group)  develop
research protocols used  in the treatment of the  majority of
children with cancer  in the  United States and represent a
significant portion of the U.S. clinical  research on childhood
cancers.  A significant portion of children with cancer in the
United States are enrolled in Federal programs.  NCI also
supports grants including laboratory and  epidemiological
studies of pediatric cancer survivors.  To date, these studies
have  not  focused on possible environmental  causes  of
childhood cancer (NCI 2000).

        NIEHS is conducting a study in Norway investigating
the hypothesis that the interaction between environmental
agents and genetic polymorphisms makes the fetus more
susceptible to cleft palate. Forthis study, both genetic samples
and data on  environmental exposure of mothers and infants
are being collected (NIEHS 2000c).

        The National Survey of Lead and Allergens in Housing
is  a joint effort of the Department of Housing and  Urban
Development (HUD) and NIEHS.   HUD is studying the
prevalence of lead-based paint, lead in house dust, and lead in
soil (HUD 2000).  NIEHS  is  studying the  prevalence  of
allergy-inducing materials  in house dust.  This study  involves
visits to more than 8,000  homes from 75 areas selected to
reflect the national housing stock, collection of environmental
samples, and interviewing of occupants (NIEHS 2000d, e).

4.2.4.  Exposure-Dose-Response Modeling
        and  Risk Assessment

        The   number  and  types   of direct  exposure
measurement studies are  limited by their relatively high cost
and the difficulties in studying children.  Another type of
exposure study design uses a mathematical model to combine
spatial and temporal information on pollutant concentrations
with population distributions of time-activity and location data
and  other  exposure-related data to  estimate  exposure.
Variables in the models are evaluated using existing data from
many sources.   ORD is using the  results of  data from
completed and ongoing  studies to  develop age-specific
exposure models. ORD also sponsors research to understand
and quantify factors,  such as intake and contact rates and
durations and frequencies of exposures, that contribute to
estimates of total exposure. Children's exposures to pesticides
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via the dermal route, through nondietary ingestion of pesticides
on surfaces and in soil and dust, and  through contact with
pesticide-treated pets  are being studied.   Transport of
pesticides from  outdoors  to  indoors  and movement  and
persistence in the indoor environment are also being studied.
Existing data are being analyzed to  determine children's
activities and dietary and nondietary exposures. Measurement
protocols and models are  being developed to account for
exposures that occur when children eat food they have placed
on floors recently treated with pesticides.

        Exposure-to-dose  models are  being developed for
estimating concentrations of contaminants in biological media
(blood and urine) and doses of contaminants to target organs.
These models take  into account age-related differences in
absorption, metabolism, distribution,  and elimination  and
differences in the  structure, composition, and function of
organs  and systems.  ORD,  OPPTS, and the  Office of
Emergency and Remedial Response (Superfund) developed
the  Integrated  Exposure Uptake Biokinetic (IEUBK)  model
(EPA 1995b), which estimates children's  blood lead levels from
environmental concentrations of lead,  taking  into  account
physiologic characteristics of a small child.  The IEUBK model
is used to assess risk at Superfund sites and was used in an
EPA risk assessment to determine lead  cleanup levels in
residences (EPA1998f).   Work  is ongoing to  develop a
modeling framework and an integrated  group of models that
can be easily modified for a variety of environmental agents
and exposure scenarios forchildren.  The models will describe
transport in microenvironments and contact with and uptake
into the body by multiple routes of entry.  Another research
effort is focused on  collecting child-specific data  on lung
structure and  respiration  and incorporating it into  dose-
response methods  for estimating exposures and risks from
inhalation of contaminants.  This project will be expanded to
include the ingestion and dermal routes.

        Long-term research is being conducted to design a
BBDR model for developmental toxicity. Thus far, research
has focused on prenatal development and chemicals for which
metabolic pathways, cellular mechanisms of action, and toxicity
profiles  are known.  In the  shorter term, ORD is working on
BBDR models that will incorporate differences in carcinogenic
effects resulting  from childhood and adult exposures to permit
estimation of cancer risk from partial lifetime exposure of any
given duration beginning at any given age.

        EPA develops  and  distributes  risk assessment
information through the Integrated Risk Information System
(IRIS), including oral RfDs and inhalation RfCs for chronic
noncarcinogenic health effects and slope factors or unit risks
for carcinogenic effects (EPA2000d).  Information on children
is included in IRIS where data are available.  ORD guidance
documents such as the Exposure Factors Handbook (EPA
1997d)  provide  analyses of  existing data on  children  and
recommendations for evaluation of exposure variables for use
in  risk assessments.  A companion project examines the
differences in  exposure to  environmental contaminants  in
children by racial, ethnic, and socioeconomic groups.  ORD
supports the  Developmental and  Reproductive Toxicology
(DART) Database in collaboration with the National Institutes
of Health (NIH) and FDA.  DART is  an  online bibliographic
database  containing about 80,000  references.   Ongoing
maintenance by the  National Library of Medicine includes
adding 3,500 to 4,000 references per year and improving the
search capability.

4.2.5. Risk Management  and Risk
        Communication

        A basic tenet of risk management is that public health
problems   resulting  from  exposures  to   environmental
contaminants can be more efficiently corrected by preventing
the exposures than by administering medical treatment after
the effects occur.  The U.S. Government's most highly visible
action   relating to children's health  is  the  control  of lead
exposure through removal of lead from gasoline and paint and
the accompanying rapid reduction in blood concentrations  of
lead in the nation's children.

        One  way to reduce risk  is  by using engineering
controls and treatment  and cleanup methods to reduce the
amount of a substance released to the environment. Currently,
ORD is developing newtechnologies to control emissions that
disproportionately affect children.  This research includes
development of drinking water treatment technologies that
reduce Cryptosporidium oocysts in water, indoor airtreatment
procedures that remove fine particulates, and development of
efficient and  cost-effective particulate  controls for  large
industrial combustors and incinerators.

        Controls  at the source often  require disposal  of
pollutants  and  may simply transfer the problem from one
environmental medium to another. Pollution prevention avoids
this problem by  reducing the amount of contaminant available
for release to the environment through increased efficiency in
the use of raw  materials, energy, water, or other resources
(EPA 1998g). ORD is developing processes and products that
will generate or release lower levels of substances that have a
disproportionate impact on children.   Pollution prevention
research projects  aimed at reducing exposure to particulate
matter include  development of better consumer products  to
mitigate indoor air problems originating from  indoor sources,
development of better construction techniques to reduce the
infiltration  of outdoor pollutants to the indoor environment,
studies on emissions from several types of oil and coal under
differing combustion conditions and  with different pollutant
controls, testing of emissions from new and older designs for
diesel engines, and improved choice of materials and design of
automobile and truck tires to reduce creation of fine particulate
during use.

        EPA  is  exploring  ways  to  address  children's
environmental   health  risks  through  partnerships with
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communities.  NIEHS requires that all of its centers develop
and maintain community outreach and participation programs.
All of the EPA/NIEHS Centers for Children's Environmental
Health  and Disease Prevention have projects in which the
grantees work closely with parents and other members of the
community to  mitigate  unacceptably  high exposures  to
environmental  contaminants.  In another ORD study, the
impact of improved community drinking watersupplies is being
evaluated  by assessing the occurrence of microbial  enteric
disease in  children 2 to 10 years old before and after changes
in  drinking water supplies  or treatments  are implemented.
ORD is investigating pesticide poisoning reports in children six
years and younger in  the Lower  Rio Grande Valley  to
determine  whether they  are at increased risk  of pesticide
poisoning,  identify risk factors, and develop intervention and
prevention strategies.

        EPA's Regional Offices are working with communities
to  address environmental  health threats to children.  For
example,  Region  5 is conducting intervention  studies on
childhood asthma in Milwaukee and working to improve indoor
air quality in Chicago schools. Regions 2 and 7 are planning
to  develop an instructional video for urban poor populations
recommending techniques for controlling asthma by reduction
of  children's exposure to cockroach  and dust mite allergen,
pesticides, molds,  pet dander, and secondhand smoke.  The
Chippawa  Cree Tribe  and  Region  8 have entered  into a
cooperative agreement to identify and reduce environmental
health threats to the Tribe's children in north-central Montana,
initially focusing on lead hazards, unsafe drinking water, and
second hand smoke.  The Office of Air and Radiation (OAR)
has developed and implemented the EPA SunWise  School
program to mitigate  children's  health  risks  related  to
overexposure to ultraviolet radiation.  Descriptions of more
EPA community-based projects can be found in the CHEHSIR
database (EPA 2000b).

        The Agency for Toxic Substances and  Disease
Registry (ATSDR), created to deal with  hazardous waste
issues, has a major role  in communicating and working with
individuals and communities.  ATSDR  advises  community
members and others of the health impacts of Superfund sites,
identifies communities where people might be exposed  to
hazardous  substances,  conducts  health   studies   in
communities, determines hazards, and recommends actions to
safeguard  health (ATSDR 2000).

4.3.   Research  Areas and Priorities

        A strategy for research in  children's risk  must be
broad enough to address diverse environmental contaminants,
endpoints, and special groups such as farm children and urban
children. The relative importance of research areas may shift
rapidly  as more  becomes  known  about the impact  of
environmental  contaminants on  children's health and  new
methods become  available to study the gene-environment
interactions that lead to adverse effects. The science team
decided  that  a  research  strategy  directed  at  specific
environmental  problems  and endpoints  would  not provide
sufficient flexibility and might impede the development of new
approaches to risk assessment. Issues surrounding children's
environmental health are too numerous to address individually
in this strategy, and current knowledge is limited, making it
difficultto foresee emerging issues and future directions. Other
EPA groups are developing research recommendations for
addressing children's environmental health, including the U.S.
Task Force, the EPA 10X Task Force,  the Office of Children's
Health Protection,  and ORD programs under GPRA goals 1
through  5 (Clean  Air, Clean Safe Water, Safe Food, Safe
Communities, and Safe Waste Management). The strategy is
organized into 5 main topic areas encompassing 13 research
areas that cut across all environmental problems and address
the research questions presented in Section 1:

#       Development of  data for risk  assessment
        S     Mode-of-action research
        S     Epidemiology studies
        S     Exposure field studies
        S     Activity pattern and exposure factor studies

#       Development  of risk  assessment  methods  and
        models
        S     Methods and models for using mode-of-action
              data in risk assessments
        S     Methods and models for using exposure  data
              in risk assessment

#       Experimental methods development
        S     Methods for hazard identification
        S     Methods for measuring exposures and effects
              in  children  and to  aid  in  extrapolations
              between animals and  humans

#       Risk management and  risk communication
        S     Multimedia control technologies
        S     Reduction   of   exposure   buildup   of
              contaminants indoors
        S     Education and communication of risk and risk
              reduction  techniques

#       Cross-cutting issues
        S     Variation in human susceptibility and exposure
        S     Mixtures/cumulative risk

Appendix E contains a cross tabulation showing relationships
between the research areas and the research questions.

        Afterdeveloping the research  areas, the science team
considered how the research might be conducted.  ORD has
intramural and extramural research programs. The intramural
program  is organized into three national laboratories and a
national center: NHEERL, the National Exposure Research
Laboratory (NERL), the National Risk Management Research
Laboratory  (NRMRL),   and  the   National  Center   for
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Environmental Assessment (NCEA). The extramural Science
to Achieve Results (STAR) program is administered by the
National  Center for Environmental Research (NCER). The
science  team  considered  the  following  possibilities  for
conducting research:

#      ORD scientists as principal investigators, often  in
        collaboration with scientists in government, academia,
        and private firms through interagency agreements,
        cooperative  agreements,  and   contracts  (the
        intramural program);

#      academic scientists as principal investigators under
        grants  funded through the STAR program; and

#      scientists  supported  by other  Federal agencies
        without active ORD collaboration or support.

        Priorities were determined for both the intramural and
the STAR programs. In setting priorities, the science team first
considered using the criteria set out in the ORD Strategic Plan
(EPA 1997c). The ORD criteria were found to be specific to
particular health effects, methods ormodelsforassessing risk,
or risk management techniques.  They are problem-specific
and difficult to apply to research areas that are more broadly
defined. Therefore, the science team developed and used the
following criteria to rank the topic  areas:

#      importance of the research to reducing uncertainty in
        risk  assessment  and  protecting children from
        environmental health threats;

#      feasibility of conducting the research  in the ORD
        intramural or STAR programs;

#      availability of resources, including the capacities and
        capabilities of ORD's laboratories and centers and the
        extramural  resources;

#      opportunities  to develop  and maintain scientific
        expertise in ORD to enable use of research results in
        EPA risk assessment;

#      opportunities  for collaboration with  other  Federal
        agencies and with other ORD  research programs;
        and

#      maintenance  of  a balance  between  short-term
        research that will reduce major uncertainties in risk
        assessment  and  long-term,  more   speculative
        research that may identify hazards and exposures to
        children  or change  EPA's  way of  doing  risk
        assessments and  ultimately produce more accurate
        and less costly assessment procedures.

        This section  describes  each  research area and
discusses the feasibility of conducting the  research in ORD.
Each research area is rated as high, medium, or low; and a
rationale is provided for the rating. For the high-priority areas,
long-term outcomes and short-term outputs forthe next 5 years
are also provided.  Appendix F shows the application of the
criteria to each research area.

4.3.1. Laboratory Studies and Surveys

        This section describes the laboratory  and  field
research that will provide the database to identify and assess
environmental health threats to children.  It includes human,
animal, and in vitro studies, and studies of sources, pathways,
and other factors influencing exposure.

4.3.1.1. Biology of Toxicant-Induced  Tissue and Organ
        Damage in the Developing Organism

        Description. Sound biological data are needed to
facilitate the interpretation and extrapolation of animal and
human data for risk assessment. Even though certain agents
have been identified as causing developmental abnormalities,
current understanding of the pharmacokinetics and modes of
action underlying these alterations is minimal. In this research
area, data will be developed to link environmental exposures
and doses with biologically effective doses at the cellular and
molecular levels.

        Data on absorption,  metabolic pathways and rates,
distribution and storage in the body, and elimination will be
developed for sensitive age groups. Hypothesis-based studies
will be  conducted to study modes of action with the goal of
linking  developmental effects at the tissue, organ, and system
levels with the underlying effects at the cellular and molecular
levels.   Investigation of modes of action may include, for
example, examination of disturbances resulting from alterations
in metabolism, DMA repair, cell viability, and receptor-mediated
alterations in gene  expression.  The biologic bases for  age-
related differences in target organ development, detoxification,
repair,  and compensation will be investigated using in vivo and
in vitro experimental models.  At a minimum, studies will be
conducted during the period of development that is the most
sensitive to perturbation by the toxicant in question.  Data are
also needed  to determine  if the pharmacokinetics and modes
of action of a toxicant are  similar across different age groups
and across different species.  The ideal study would include
more than one age group so that an overall model at various
developmental stages could be produced.

        A critical review of studies of prescription drugs to
elucidate what mechanisms of action might be expected to
produce the  greatest age-related susceptibilities might  be a
useful  exercise to  help  design studies  of environmental
contaminants.  A first exercise might be to explore whether
appropriate models have been developed for organ systems of
concern and how well existing models match up across organ
systems.
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        Feasibility.   ORD has the expertise to study the
pharmacokinetics and modes of action that result in adverse
effects in  children.   As discussed in Section 4.2.2, ORD
supports ongoing research in this area in both the intramural
and  the  STAR  program.   The  current  effort  directed at
children's issues needs to be expanded, however, particularly
in the intramural program.  NIEHS also supports research
aimed at identifying the underlying modes of action by which
toxicants affect  biological  systems,  and  it is important to
continue collaborations and make full use of results from the
NIEHS program.

        Priority and Rationale. High. These studies and the
methods and models described under Sections 4.3.2.1 and
4.3.3.1 are critical to  increasing the use of biological  data in
children's   risk  assessments,  particularly  in   selecting
appropriate animal models and endpoints and for improving
extrapolations from animals to children.  Current approaches
in risk assessment rely on assumptions that in many cases
have only  limited explanations based  on biology.  These
include  assumptions  that  are made in extrapolating (or
interpolating) from laboratory animals to humans, from high to
low exposure levels, overvarious exposure durations, and over
changing critical periods of susceptibility, especially in the case
of the developing child. Biologically  based dose-response
models should lead to refined riskassessment approaches that
no longer rely  solely on whole-animal  toxicity testing,  but
incorporate the growing knowledge of molecular mechanisms
and their involvement in a toxic response.  It  should be
possible to develop testing paradigms using in vivo and in vitro
approaches that are more biologically based and that address
such issues as complex mixtures, varying exposure patterns,
and critical periods of susceptibility. This  research can be
conducted in both the STAR and intramural programs and will
require a long-term commitment of resources. It is essential to
maintain and  expand ORD   capability through  a  strong
intramural program to support the focused research necessary
to improve EPA assessments.

        Long-Term   Outcomes.     Mechanism-of-action
experimentation  facilitates  the extrapolation of animal and
experimental model  data to humans, enhancing  ability to
predict and study adverse effects in humans. Mode of action
becomes an integral component of risk assessment. Advances
in  genomics/proteomics are  incorporated into  EPA's  risk
assessment methodologies.

        Short-Term Outputs. ORD will

#       Develop better quantitative characterizations of dose
        to target tissue in developing organisms to replace
        default assumptions in children's risk assessments.

#       Link developmental effects at the tissue, organ, and
        system levels with the  underlying effects  at  the
        cellular and molecular  levels  to  develop  first-
        generation biologically based predictive models.
#       Develop  and  validate  sensitive  and  predictive
        methods using laboratory animals to determine mode
        of action by  linking  developmental effects at  the
        tissue, organ, and system levels with the underlying
        effects at the cellular and molecular levels.

#       Validate in vitro assays (using either animal or human
        biological material) for inclusion  in the overall  risk
        assessment process.

4.3.1.2. Relationship Between Exposureto Environmental
        Agents and  Adverse Health Effects in  Human
        Populations

        Description.   Well-designed epidemiological and
clinical studies are needed to evaluate associations between
prenatal  and   postnatal   toxicant  exposure  and  altered
development,  maturation  of  organs  and systems,  and
developmental disorders such as childhood cancer,  asthma,
neurotoxic  effects,  reproductive effects,  and  birth  defects.
These studies will improve our ability to identify, characterize,
and quantify toxicant-induced alterations in the structure and
function  of organs  and  systems   during  growth  and
development.  A variety of criteria could  be used to identify
candidate populations.  These criteria would include, butwould
not be limited to, inadvertent or accidental exposure to a known
toxicant, exposure of a number of different age groups,  the
likelihood of obtaining  useful dosimetric information  (i.e.,  the
ability to obtain data useful for quantifying age-specific external
and internal dose), and availability of sensitive and predictive
test methods for the  target organ or system of concern.

        One such study is a case-control study of a  group of
children with health effects that are known or suspected to be
related to exposure to environmental pollutants.  Based on the
existing human and animal database for neurotoxicity of lead,
certain pesticides, and PCBs, individuals with neurological
diseases would be  an  appropriate group for  such  studies.
Retrospective data on cases and controls could be collected
through questionnaires, and both biological and environmental
samples might be appropriate. It would be advantageous  if
subjects could also be monitored through  early adulthood to
test for persistent and latent effects.

        Alternatively,   prospective  studies   of  childhood
exposures to environmental contaminants and their associated
effects in  juvenile  populations could be undertaken.   A
longitudinal study, similarto the 50-year-old Framingham Heart
Study,  sponsored by the National  Heart, Lung, and Blood
Institute, has been recommended by some experts to attempt
to  clarify the connection  between  childhood  exposures to
environmental  agents and adverse health effects in childhood
or adulthood (NHLBI2000). In such a study, individuals would
be enrolled at an early age, perhaps at birth, and followed  into
adulthood.  Data on health and nutrition would be collected, as
well as exposure data.
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        Feasibility.  Human studies of the cause-effect and
dose-response   relationships   between   environmental
contaminants and adverse health endpoints are most feasible
for ambient contaminants, such  as  air and drinking water
pollutants, and for easily observed effects associated with a
single route and pathway of exposure, such as respiratory
distress and enteric disease.  The ORD intramural and STAR
programs have experience in conducting human studies. Many
of the  current ORD-supported  human studies of children
involve  respiratory  endpoints.   The  impact of pesticide
exposure on children, which can occur by multiple routes and
have more than one source,  is an expanding research area
(see the discussion of EPA 1998b, in Appendix C).    As
discussed in Section 4.2.3, the STAR program is funding eight
centers, each of which includes an epidemiology/intervention
study.

        One of  the  problems in conducting  epidemiology
studies  of  environmental agents is  obtaining an accurate
estimate of exposure levels overtime. ORD, with a research
laboratory  (NERL) devoted  to  exposure science,  is  well
positioned to address this issue. For example, as discussed in
Section  4.2.3, NERL and NHEERL are collaborating in an
exposure and epidemiology study of health effects in children
along the U.S.-Mexico border.

        ORD is collaborating with other Federal agencies in
pilot studies to investigate the feasibility of a longitudinal birth
cohort  study under  the  auspices  of the  Developmental
Disorders  Working  Group of the U.S. Task Force.   The
proposed study would enroll as many as 100,000 mothers
during  pregnancy and follow the children over time. EPA,
NICHD,  and CDC are the lead agencies in this effort.

        A longitudinal study is expensive and would require a
long-term commitment of resources and partnerships with other
agencies.  Relationships between exposure to environmental
agents and adverse health  effects  are usually difficult  to
observe.   If only a small   percentage of  the  population
experiences an effect, a large sample size is a prerequisite for
testing  hypotheses   related  to  environmental exposures.
Exposure levels are often difficultto quantify and other possible
causes of the adverse effect are  usually present.

        More focused epidemiological and clinical studies will
have varying costs  and chances for  successful  outcome.
Studies  conducted in human  populations should be carefully
designed to ensure the maximum potential for identifying
hazards  and  developing   dose-response   relationships.
Collection  of exposure  data adequate to  develop dose-
response  relationships  is essential.   One  less costly  and
potentially effective study would  be to test hypotheses using
existing  databases such as NHANES.

        Priority and Rationale. High. Human studies are
crucial to understanding whether children are more susceptible
to environmental contaminants than are adults. The results of
current Federal research into the causes of childhood asthma
and the effects of exposure to organophosphates and PCBs,
for example, may  provide  ORD with  insights to guide the
design of future studies of children.

        Hypothesis-based human epidemiologic and clinical
studies are necessary to confirm that adverse effects  occur in
humans,  to  improve  extrapolations  from animal  data  to
humans,  and  to  develop  data to  incorporate into  risk
assessments. Human studies should be conducted as needed
for high-priority environmental  agents  and to assist in model
development and validation.  It is expected that human studies
will  be  supported  for particular high-priority  agents  and
populations under program-specific research, aswell as under
the  STAR program.  Factors that improve the probability of
observation of cause-effect and dose-response relationships,
such as existence of sensitive biomarkers of effect, would also
raise the priority of a human  study.   The strategy for the
intramural Children's Health  program is to focus on mode-of-
action research and modeling and to incorporate clinical and
epidemiology studies as necessary to reach this primary goal.
Such studies should be hypothesis based and the biological
basis for conducting the study should be clearly defined.

        As  discussed in  Section  4.2.3,  several  Federal
agencies in addition to EPA, including  CDC, NCI, NIAID, and
NIEHS, support epidemiologic and surveillance programs.  A
major objective of some of these studies (e.g., the Inner-City
Asthma Study) is to identify relationships between exposures
to environmental contaminants and adverse effects in children.
Otherstudies, such asthe CDC surveillance and epidemiology
studies of developmental disorders in children in Atlanta, have
not  yet focused on environmental  agents as  risk  factors.
Through the Developmental  Disorders Working Group of the
President's Task Force on Children's  Environmental Health
and Safety, EPA, CDC, and several of the Institutes of NIH are
exploring the feasibility of an  interagency longitudinal birth
cohort study to address children's environmental health and
safety issues. The study would have a core protocol that would
be followed for each member of the cohort and special studies
that would allow for collection  of additional data addressing
specific issues of participating agencies.  It is recommended
that   ORD  continue   with  this  process  and  explore
implementation  through the STAR program or through a
proposal for an Initiative in FY2003.

        Long-Term Outcome. Environmental agents and
other factors contributing to adverse effects in  children are
identified, status and trends in children's health and exposure
to environmental agents are characterized, and risk reduction
methods are successfully implemented.

        Short-Term Outputs.  By 2005, ORD will

#      Analyze relationships between childhood exposures
        to air pollutants and  respiratory  effects  under the
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        STAR program.
per study.
#       Analyze relationships between childhood exposures
        to pesticides and neurological effects under STAR
        program.

#       Develop, refine, and pilot methods for conducting a
        hypothesis-based longitudinal study of developmental
        disorders in a large birth cohort under the U.S. Task
        Force on Children's Environmental Health and Safety.

4.3.1.3. Multimedia, MuIt!pathway Exposures in Human
        Populations

        Description. Exposure studies are closely related to
the epidemiological studies described in the preceding section.
Epidemiology studies examine the link between exposure and
disease.    Exposure  studies quantify   exposure   levels,
investigate the  reasons for  exposure, identify sources of
exposure, and provide information needed to devise strategies
to  reduce  the risk.  Ideally,  epidemiological and exposure
studies are combined.  However, as the number of  issues
being studied increases, the number of measurements taken,
questions asked, and time required can become intolerable to
respondents, who will refuse to participate or drop out of the
study. Consequently, human studies are carefully designed to
limit respondent burden to an acceptable level and sometimes
address only the exposure questions.

        In a typical exposure study, samples  of the  child's
environment  (e.g., air, soil, dust), biological samples (e.g.,
blood,  urine, feces, breath,  hair),  and personal exposure
samples (e.g.,  personal air samples  taken by a collection
device worn by the child, samples of food and drinking water)
are collected, as well as questionnaire  data  on activities,
sources of exposure, and sometimes health status. Analysis
is performed on  the samples for suites of chemicals in  one or
more chemical classes.

        Some current studies target the national population,
but more  typically, exposure studies  focus on subgroups
hypothesized to be highly exposed or on  a city or region.
National studies tend to have  larger numbers of people in the
sample, but to  collect fewer samples per individual.  The
NHANES-IV study of children's exposure to pesticides, for
example, will provide a  urinalysis  and responses to a few
questions about pesticide exposure for about 1,800 subjects.
More targeted studies collect and analyze samples from many
media on fewersubjects.  InNHEXAS, EPAsponsored studies
ofthe general population and special subgroups in regional and
local areas, including a six-State study in the Midwestern Great
Lakes Region with a special study of children in Minnesota, a
State-wide study in Arizona with a special study of people living
along the U.S.-Mexico border, and a five-county study in and
around Baltimore to  test temporal variability  in exposure.
These studies asked more than 300 questions and collected
thousands of samples on approximately 60 to 300 respondents
        Some critical questions can best be answered through
probability-based  exposure  studies:   What  are  children
exposed to? Are particular age group, such as toddlers, more
highly  exposed?    If  so, what  are the  most  important
contaminants and exposure pathways for these age groups?
What are the most highly exposed groups of children (e.g.,
farm children, inner-city children)?  Does exposure vary with
climate and region?  How does exposure vary overtime?

        Feasibility. ORD has extensive experience in both
the  intramural  and STAR  programs in  conducting and
supporting exposure studies.

        Priority and Rationale. High. It has been repeatedly
hypothesized that children  are  more  highly exposed  to
chemicals in the environment than are adults and that some
age  groups, such as toddlers may be more highly exposed
than other children. However, data to test these hypotheses
are  limited.  Probability-based  exposure  studies,  where
respondents are randomly selected to represent the  study
population, can  be used to:

#       document exposures and determine whether certain
        age  groups are more  highly exposed to certain
        environmental agents;

#       provide baseline data on children's exposures  by age
        to determine national exposure levels, evaluate status
        and  trends,  and  identify and characterize  highly
        exposed  subgroups;

#       assess exposure and risk for specific populations of
        children;

#       assess total exposure  to  multiple chemicals  via
        multiple  pathways  and  determine  the relative
        importance of  the  sources  contributing  to the
        exposure;

#       develop models to estimate multimedia, multipathway
        exposures; and

#       evaluate  exposure variables in models,  such  as
        children's activity patterns.

        Some  exposure questions  may be answered  for
specific chemicals through an analysis of existing data or data
that will soon be available from NHEXAS, NHANES, and the
STAR grants.  As the questions  are answered for specific
chemicals,  the  information  can  be  generalized  to  other
chemicals to which children might be exposed by the  same
pathways, reducing uncertainty forentire classes of chemicals.

        Exposure studies  should   be  directed  toward
chemicals  of high  concern  because of  their known  or
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suspected hazards. In designing studies, investigators should
consider the research questions of interest, the various types
of information  (health,  exposure,  source)  that  could  be
collected, and the uses of that information in risk assessment
and risk management before deciding whether health data
should be collected orwhether health data should be foregone
in favor of more data on sources, exposures, and exposure
factors.

         Because of the high cost of exposure studies, ORD
should explore partnerships with other Federal agencies and
the possibility of conducting  some of  this work under other
ORD research programs such as the Safe Food program and
Human  Health Risk Assessment program.

        Long-Term  Outcomes.   Status  and   trends  in
children's exposures to environmental agents are characterized
using baseline data developed in this program. Highly exposed
subpopulations of children are identified, important sources and
pathways  of children's  exposures are delineated, and risk
management interventions are successfully implemented.

        Short-Term Outputs.  By 2005, ORD will

#       Conduct  analysis of existing data from  NHEXAS,
        NHANES, and STAR grants to provide answers to the
        extent  possible on whether children are more highly
        exposed, which age groups are more highly exposed,
        and important sources and pathways.

#       Develop newsampling protocols, questionnaires, and
        study designs based on previous studies of children's
        exposure.

#       Design and initiate field studies to answer questions
        about  children's exposure,  with Federal partners
        where feasible.

4.3.1.4.  Analysis of Factors Contributing  to Exposure

        Description. Exposure models allow risk assessors
to generalize from existing data and estimate exposures  to
subpopulations  and environmental agents for which data are
not available.  This capability is crucial  to EPA's  regulatory
programs, where thousands  of assessments  are performed
yearly,  often for subgroups, locations,  and  environmental
agents for which there  are few data.  Questionnaire-based
surveys and laboratory studies are used to develop data for
evaluation of exposure variables used  in risk assessments.

        For key exposure variables and factors, exposure
measurement studies  help to characterize distributions  of
values by age groups in the U.S. population  and in important
subgroups. Key variables include duration and frequency  of
exposure, dietary intakes, physiologic parameters,  and many
others.  Some pathways of interest for children are exposure
through  pollutants on floors, in household dust, and in the small
child's indoorbreathingzonethrough inhalation, ingestion.and
dermal contact; exposure to pollutants in soil (inadvertent
ingestion, pica, inhalation while playing sports); exposure away
from the home; and exposure  to pollutants in  water  and
sediment during swimming and wading through dermal contact
and ingestion. It  is especially important to determine how,
when, and for how long children come in contact with media
that have  higher  concentrations of toxic chemicals.  For
example, does baby food have  more contaminants than a
frozen dinner? How does the breathing zone for indoor air in
a day care center compare to that in a typical residence? How
often do children touch contaminated surfaces and lickorsuck
on their fingers,  toys,  and  other  objects?  What  is the
distribution of ingestion rates of soil and dust among children
in various age ranges? What are typical transfer rates of soil,
dust, and  pollutants from hand to mouth and what factors
determine  transfer rates?

        Feasibility.  It is  feasible to conduct some of these
studies underthe STAR program. Forexamplean investigator
working under an EPA grant,  is treating dogs with pesticides
and measuring the dislodgeable residue over a period of time
to address transfer of pesticides in flea treatments from pets to
children. It is feasible to design and conduct studies to collect
data on children's activities that parents and caretakers can
easily observe.  Some types of activities, however, such as
ingestion of dust and soil by young children or trespassing by
older children on waste sites are very difficult to  document.
Studies to collect  data on dermal  exposure and  nondietary
ingestion are  difficult to design because of lack of validated
measurement methods and models for these pathways.

        Priority and Rationale. High.  EPA needs data that
can be used to improve risk assessments for children in  the
short term.  Data on one or two key factors could have a
substantial impact on reducing  uncertainty in hundreds of
assessments as well as in helping to design future studies.
The variables need to be selected to maximize the reduction of
uncertainty. For example, by studying the exposure pathways
that are common to many chemicals and are highly applicable
to children's activities, uncertainties could be reduced for a
numberof assessments through a single study. This approach
could have a higher information return on investment than a
detailed study of all pathways for one chemical. Some studies
will need to be conducted within the ORD intramural program
to obtain data for EPA  risk assessments. Others could be
conducted underthe STAR program and under media-specific
ORD programs. For example, FQPA resources could be used
to study important exposure variables in the OPP Standard
Operating  Procedures (Versar 1997).

        Long-Term Outcomes. Residential exposure factors
for children will be characterized  by age and sex for the
national population,  regional populations, highly exposed
groups, and susceptible  groups.   Factors include activity
patterns (time spent in a given activity and frequency of
occurrence), soil and dust ingestion  rates, factors reflecting
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transfer of environmental agents from objects and surfaces
children commonly touch, and factors related to ingestion of
chemical residues on surfaces.

         Short-Term Outputs. By 2005, ORD will

 #      Identify high-priority exposure variables for study
        through preliminary exposure analysis.

 #      Design  and  complete an  activity pattern survey
        addressing  high priority activity pattern issues for
        children.

 #      Complete two studies on other high-priority exposure
        variables for children.
4.3.2.  Risk   Assessment
        Models
Methods   and
        In order to  make  full  use of  research  in  risk
assessments, EPA needs methods and models that will help
generalize the results. This section discusses development of
methods and models for using biological and exposure data in
risk assessments for children.

4.3.2.1.  Methods and Models for Using Biological Data in
        Risk Assessment

        Description.   Although there is a  considerable
amount  of research directed  at the biology of normal  and
abnormal development, these data have not been fully used in
EPA assessments, in  part because agreed-upon  biological
assessment methods do not exist. This research area is aimed
at developing methods and models for routine use of biological
data in risk assessment.  A major focus is to develop models
linking developmental effects at the tissue, organ, and system
levels with the underlying interactions  at the cellular  and
molecular levels. A second focus is to link PBPK and BBDR
models  to provide an integrated biological  model of the
exposure-dose-response continuum for children.  Additional
focus is  on improving extrapolations of laboratory data to the
human condition. The research area will consist of both short-
term research to improve existing methods and models and
long-term research to develop better, biologically based models
that are  able to make use of pharmacokinetic and mode-of-
action data to relate exposures and effects.  There is a need to
develop  exposure-dose-response models for vulnerable ages
from conception through adolescence that reflect the effects of
toxicant  exposure during early development.  This research
area is closely related to the development of biological data for
risk assessment (Sections  4.3.1.1  and 4.3.3.1).   Existing
biological data and the results of the laboratory program will
provide the basis for the development of biological methods
and models. As the assessment methods evolve, hypotheses
will be generated and  data gaps highlighted to help design
future laboratory studies.
        Feasibility. Although some prototype models could
be developed through the STAR program, the greater part of
this research will need to be done intramurallysothatORDhas
the ability to direct the research toward EPA's risk assessment
needs. The resources required to address the above issues
will be extensive.  A suggested approach is to begin expanding
ORD's capabilities in several  critical areas (developmental
toxicology,  neurotoxicology,  immunotoxicology,  respiratory
toxicology)  with  the  specific aim  of building from  the
considerable expertise that EPA has developed in these areas.
Realistic financial and scientific resources should be made
available, based on how current efforts in the critical areas can
be expanded to the periods of child development of interest.
These  efforts should  be coordinated  with ORD's STAR
program. The science team noted that a critical  mass of
scientists dedicated to this  research  area and maintained
consistently over a long-term  period is necessary  to make
progress in this area. An accompanying program of laboratory
experiments as  described  above  in  Sections 4.3.1.1  and
4.3.3.1 must also be maintained.
                               Priority and Rationale.
                       presented in Section 4.3.1.1.
                                High.  The  rationale  is
                               Long-Term Outcome. Broadly applicable PBPK and
                       BBDR models will be routinely used to produce more accurate
                       risk  assessments  for  children,   making   full   use  of
                       pharmacokinetic and mode-of-action data.

                               Short-Term Outputs. By 2005, ORD will

                       #       Evaluate the appropriateness  of the assumptions in
                               current EPA risk assessment  approaches and how
                               they may be supported or modified by biological data.

                       #       Develop and refine PBPK models applied to the
                               developing animal,  with  the intent  of  eventual
                               extrapolation  to  embryos, fetuses,  infants,  and
                               children.

                       #       Develop and refine BBDR models applied to the
                               developing animal with the intent of extrapolation to
                               embryos, fetuses, infants and  children.

                       #       Identify biological pathways, environmental factors,
                               and  their interactions  that  are   important  to
                               understanding normal and abnormal development
                               with a focus on incorporation of such information into
                               predictive models of developmental toxicology and
                               not solely on the generation of basic information on
                               child development.

                       #       Define how experimental animal models mirror child
                               development  and  develop appropriate  correction
                               factors for species differences.

                       #       Incorporate  information   from   dose-response,
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        pharmacokinetic,  and mode-of-action  studies  in
        animals into models  that more accurately predict
        children's risks.

#       Develop first-generation methods, guidance, and data
        for  broad application of  modes  of action  and
        pharmacokinetics  in  EPA risk  assessments for
        children.

4.3.2.2.  Exposure Modeling and Use of Exposure Data in
        Risk Assessment

        Description.  Exposure models are needed when it
is not possible to measure exposure directly, either because
there is currently no way to make the measurement (e.g.,
concentration in target organs) or the measurement is too
costly or too burdensome on the  study  subjects.   Most
exposure assessments for children  at EPA rely on models
rather than direct measurements of exposure.

        Exposure  models are used  in  research to  help
understand the relationships between exposure variables and
to  generate  hypotheses to be tested in  the field  or the
laboratory. They are used in risk assessments to identify and
quantify risks that may require risk management actions. And
they are used to identify sources of exposure for the purpose
of developing and evaluating  risk  management options and
regulations that reduce  risk  through  approaches such as
testing for adverse effects, limiting releases to the environment,
and banning chemicals from commerce.

        Models will be  developed  to assess pathways  of
exposure important to children. Models capable of estimating
total absorbed dose via multiple  pathways and  predicting
variability of  individual  exposures  in  a population whose
members are simultaneously exposed to multiple chemicals via
multiple pathways are needed to estimate children's exposure.
Models need to be capable of performing probabilistic analysis
and taking into account correlations among input variables.
Exposure  models that estimate  dose  by  accounting for
bioavailability need to  be developed in concert with PBPK
models  (see  Section 4.3.2.1) so  that the continuum  from
exposure through disease can  be assessed.

        Feasibility.  ORD has expertise and a program in
exposure modeling that is turning its  efforts toward children's
issues. There are opportunities to combine resources from the
Children's Health program with ongoing activities.  Exposure
modeling is  also appropriate  for  the  STAR program.  An
intramural effort is required to ensure that ORD addresses the
specific issues of concern to EPA and to maintain the expertise
to perform exposure modeling.

        Development    and   testing   of   multipathway,
multichemical models require large  amounts of data. Accuracy
depends heavily on the quality and representativeness of the
data used to evaluate the input variables. This research area
is dependent to a large extent on the current field studies being
completed and  the data made available to  modelers and
assessors in  a  timely fashion.  Model development  using
literature and other existing data is feasible now.

        Priority and Rationale. High. EPA is moving toward
assessment of total exposure for pesticides and other toxic
chemicals that are found in many environmental media - food,
drinking water, breast milk, ambient air, indoor air, soil, and
house dust, for example. The use of a multimedia exposure
assessment  process  will  improve the quality of children's
assessments by reducing the uncertainty of the relationships
among   environmental   measurements,   biomarker
measurements, human activities, andtoxicological parameters.
Distribution of exposures in populations is also of increasing
concern to risk assessors and managers. Computer modeling
approaches and consideration of multiple pathways is thus of
high priority forchildren's research because these approaches
are required to identify and quantify risks to children.

        Long-Term  Outcomes.   A broadly  applicable
probabilistic,  total exposure model,  capable  of linking to a
PBPK model, will be available to estimate children's exposure
to  pesticides,  producing  more  accurate assessments  of
children's exposure and reducing  use of default  values and
safety factors in the assessment when sufficient input data are
available.

        Short-Term Outputs. By 2005, ORD will

#       Assess children's total pesticide exposure and  refine
        existing exposure models using data from NHEXAS,
        NHANES, and the STAR program.

#       Analyze  models  in   OPP  Standard  Operating
        Procedures (Versar 1997) for estimating exposure of
        children to pesticides,  identify important pathways of
        exposure, and provide assessment support.

4.3.3.  Methods  for  Studying  Effects  and
        Exposure  in  Humans  and  Animal
        Models

        This section includes research to develop in vivo and
in  vitro  methods of hazard identification for children and
methods for measuring effects  and exposure in children.

4.3.3.1  In Vivo/In Vitro Methods for Hazard Identification

        Description.     Research  is   needed  on the
development and validation of  more sensitive and predictive
test methods for identifying perturbation of normal development
by environmental  toxicants.   The fields  of  developmental
biology  and  toxicology  are  rapidly  progressing  to  a  more
sophisticated  understanding of the  basic mechanisms  of
normal development  and the  way  in which  these can be
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altered. EPA is focusing more on the use of mode-of-action
considerations in risk assessment  and has  included the
harmonization  of cancer and  noncancer approaches  in its
research strategies.  Most recently,  the  National  Research
Council released a  report entitled  Scientific Frontiers in
Developmental Toxicology and Risk Assessment (NRC 2000),
which points up the importance of developing and incorporating
methods that can help in defining and modeling mechanisms
of developmental toxicity. These methods will not only reveal
important information on the underlying mechanisms of toxicity,
but will also  provide a  more  complete  analysis of the
quantitative dose-response relationship of the exposure and
effect.

        This section should be viewed together with Sections
4.3.1.1, Biology of  Toxicant-Induced Tissue  and Organ
Damage in the Developing Organism, and 4.3.2.1,  Methods
and Models for Using Biological Data in Risk Assessment.
There will  be overlap  among these three areas in developing
future risk assessment methodology. In addition, there should
be careful coordination between these three areas and the
research  developed  under Section  4.3.1.2,  Relationship
Between Exposure to Environmental Agents  and Adverse
Health Effects in Human  Populations,  to  ensure that the
emerging technology  provides the most benefit to the human
population and that human studies are developing databases
compatible with laboratory databases.

        Feasibility.  This research is very  feasible. ORD's
intramural program has the expertise, and has been involved
over the years, in the development and validation of sensitive
and predictive  test methods for agent-induced organ/system
alterations. The STAR program also has supported this effort.

        Priority and Rationale. High. Methods development
has been and is an important part of EPA's overall research
program. As  noted  above, viewed together with  Sections
4.3.1.1,4.3.1.2, and 4.3.2.1, this research will be important for
EPA to continue its  leadership  in risk assessment and to
maintain a current understanding of the databases that will be
created with the emerging technology.

        Long-Term   Outcomes.   Mechanism-of-action
experimentation  facilitates the  extrapolation of animal and
experimental  model data to humans, enhancing ability to
predict and study adverse effects in humans. Mode of action
becomes an integral component of risk assessment. Advances
in  genomics/proteomics  are incorporated  into EPA's risk
assessment methodologies.

        Short-Term Output.  By 2005, ORD will

#       Validate and apply currently available test methods
        and emerging methods in genomics/proteomics and
        molecular   biological  approaches,   useful   for
        understanding and elucidating mode of  action, in
        developmental toxicity testing.
4.3.3.2. Methods for Measuring Exposures and Effects in
        Infants and Children and to Aid in Extrapolations
        Between Animals and Humans

        Description. This research will provide measurement
methods suitable  for application in very young children  to
predict  health effects currently not  detected  until  later  in
development  (i.e., school age).  Earlier detection, when
combined with exposure data, will facilitate the establishment
of cause-and-effect relationships  and  provide information
needed  to develop intervention strategies.  Development  of
supplemental work in laboratory animals for  purposes  of
extrapolation and elucidation of underlying modes of action is
also included. The research includes tests where the subject
actively  participates and tests where samples, x-rays, or other
measurements are taken.

        In  some  cases,  such  as evaluation  of cognitive
effects,  methods currently available for application in school-
age children will be adapted for use in younger subjects.  In
othercases, such as measures of sensory function (e.g., vision
and hearing), available methods require furthervalidation prior
to use in risk assessment.  Other research will involve the
application of available techniques, such as eye-blink response
and visual contrast, to compare responses of human infants
and neonatal laboratory animals.  Establishment of strong
predictive relationships between animal tests and outcomes in
humans may lead to the incorporation of additional evaluative
endpoints in  the  standard test batteries used to evaluate
pesticides and other chemicals underthe Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA) and TSCA.

        There is a need to develop biomarkers of effects that
occur either only in young individuals (i.e., developmentally
mediated)  or  with  the  first   exposure  (e.g.,  vaccination
response).  This research will focus  on  the development  of
biomarker assays for effects expected only in  children  and
adaptation  of general biomarker assays for use in young
subjects. Laboratory animals will be used forthe development
of the assays. Validation will require samples from both animal
and human subjects.  Evaluation of biomarkers allows rapid
and relatively inexpensive determination of potential effects
following known exposure as  well  as general  screening  of
selected populations for exposure and effect.  For example,
biomarkers of immune system development and competency
may be  useful in the prediction of increased susceptibility to
asthma  or allergy in very young children.

        There is  also a need  to revise currently available
biomarker assays for use in epidemiology studies focused on
young children.  In many assays, the  medium (e.g., serum  or
urine) or needed quantity of the sample (e.g., 100 ml_) makes
a standard biomarker assay unsuitable for use in infants and
young children. Methods adapted to provide data with minimal
intrusiveness  and  discomfort are needed for young children,
such as breath measurements and analytical methods for small
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quantities of blood obtainable from a finger prick.

        In addition, new methods are required for a range of
exposure-related research issues. Because of the high cost of
field studies, it is important to develop the most accurate and
cost-effective methods of sampling and chemical analysis and
of conducting questionnaire surveys.   Consideration of the
successes and limitations of past and current field studies and
questionnaire surveys will lead to better methods.  Issues such
as the ability to detect and quantify substances above levels of
concern in environmental and biological samples, the ability to
analyze for speciation and metabolites, and the ability of
sampling protocols to capture intermittent  high  exposures,
longer-term average exposures, and personal total exposures
need to be addressed. Cost-effective screening methods using
questionnaires and simple sampling methods are also needed.
Dermal  exposure methods are needed for surface transfer,
adhesion, adsorption, and ingestion from hand-to-mouth and
object-to-mouth  transfers  of  contaminants.   Methods  for
improving survey response rates and for collection of activity
data are needed. Development of a cost-effective, feasible
protocol for biological and residential environmental sampling
for children is needed.

        Feasibility. Expertise to conduct biomarker research
is  available  in  the  NHEERL  Experimental  Toxicology,
Neurotoxicology, Reproductive  Toxicology, Environmental
Carcinogenesis,  and Human Studies Divisions. ORD currently
has a small program investigating the development of immune
system biomarkers. An effortto develop cholinesterase assays
requiring smaller quantities of blood, and therefore suitable for
use in children, is in the pilot phase in NHEERL under the
Sensitive Subpopulation program.  Other agencies, such as
CDC and NIEHS, have an interest in the application of  this
work but, otherthan specific cancer biomarkerwork underway
at NCI,  no  focused research program is funded.   CDC  is
developing methods to screen for multiple pesticides in smaller
serum samples suitable for use in children.  NERL develops
methods for survey design and implementation and methods
to measure contaminant concentrations in environmental
media. The STAR program solicited proposals for research on
biomarkers for the assessment of exposure and toxicity of
children and will award grants in 2000.

        Priority and Rationale. Medium. Better methods of
sampling, analysis of samples, and test protocols for infants
and children will supportthe collection and generation of better
data for risk assessment. A separate  program in methods
development, although valuable, is somewhat less directly
related to answering questions about riskthan are the studies
in  which the methods will be used. In the Children's Health
program, methods development needs to take place within a
larger study with broader objectives.  For example, methods
development  in  exposure  measurements,  recruitment  and
retention  of  study  participants,  and   assessment  of
neurobehavioral toxicity is being conducted as part of the pilot
studies for the Longitudinal Cohort Study.
4.3.4.  Risk Management Research and Risk
        Communication

        This  section   discusses  research  to   reduce
environmental risks to children through development of control
and cleanup technologies, prevention of risk, and approaches
to community education and intervention.

4.3.4.1.  Multimedia Control Technologies That Account
        for the Susceptibilities of Children

        Description.  This research  area will build upon
existing  methodologies, which range  from  drinking water
treatment  to air emission controls  to bioremediation  and
phytoremediation. The new focus on  children's health issues
highlights the dichotomy that often exists in risk management.
Frequently, EPA must  respond to a crisis caused  by an
environmental  agent without having a risk assessment to
provide the quantitative goals for risk reduction.  For example,
recent outbreaks of cryptosporidiosis, an infection caused by
exposure to the  Cryptosporidium  microbe, usually through
ingestion of contaminated drinking waterorfood, have required
immediate efforts to  remove the microbe from drinking water.
Children, the elderly, and those with compromised immune
systems are particularly  susceptible to cryptosporidiosis, even
to the  extent  of  being  at  risk  of  death.    Acceptable
concentrations of Cryptosporidium in drinking water for children
and  other  susceptible  subpopulations have  not yet been
determined through  risk assessment.  Until such levels are
established and the  technology is available to  achieve them,
efforts will continue to refine and modify existing methods of
drinking water treatment so that devastating outbreaks do not
occur and  children  are protected.  For example,  ORD is
working  toward the goal of having  water treatment methods
that  will reduce concentrations of  protozoan oocysts and
bacterial spores in raw water by six orders of magnitude.

        Children  are   hypothesized  to  be  particularly
susceptible  to pesticides, and  nonpoint  source  runoff
containing pesticides often contaminates  areas attractive to
children,  such  as streams  and ponds.   Research will be
conducted on utilization  of microorganisms and plants to treat
nonpoint source  contamination resulting  from  spray  drift of
pesticides and residual pesticides.  Strategic  placement of
selected  plants can offer means  to interdict water flows
contaminated with pollutant chemicals occurring as  part of
runoff or contaminated  subsurface waters.  Use of selected
plants or microorganisms may result in reduction of chemical
pollutants and  provide active land restoration options.

        In addition to these treatmenttechnologies, particular
attention will be directed to air treatment  methods including
treatments  for the indoor environments in which children's
inhalation exposure may be different from that of adults.

        Feasibility. ORD has expertise in the development
of engineering solutions to respond  to  children's  health
                                                       25

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problems. Research in control technology for water, air, and
hazardous waste is conducted at the NRMRL.

        Priority and Rationale. Lowforthe Children's Health
program.  Although it will  contribute  to  reducing  risks  to
children,  research  in  control  technology is not a  specific
children's issue and is more appropriately conducted underthe
ORD research programs for Air, Water, Hazardous Waste, and
Pesticides and Toxics.

4.3.4.2. Methods  for Reducing  Exposure  Buildup  of
        Contaminants in Indoor Environments

        Description.   Children spend most of their time in
indoor environments. Contaminants in airand on surfaces are
expected  to   result  in  significant childhood exposures.
Consumer products that are used indoors, such as pesticides,
cleaning products, building materials, and floor coverings, may
release toxic  agents  into a child's environment,  causing
exposure. This exposure can be reduced by cleaning up the
contaminants after they have been released.  It may also  be
reduced by designing consumer products that use or release
smaller amounts of toxic materials.

        Recent occurrences  of  household applications  of
methyl parathion, in which residents, particularly children, were
placed at risk, serve  as  useful examples of  the  need  for
development of methods and processes to remove pesticides
and  other toxic compounds from structures.   Children,
especially infants  and  toddlers,  may be highly exposed  to
chemicals that accumulate in carpets and construction joints
and cracks near the floor.  Accumulations of methyl parathion
resulted in the demolition and disposal of many structures,
including homes and day care centers,  because no methods
exist for  the removal  of  chemicals from  structures.  High
exposures can also  be discovered during epidemiology and
exposure studies, and ORD must be able to provide individuals
and public health  departments with assistance in  reducing
exposures where possible.  This research area will focus  on
methods to reduce exposure to indoor contaminants through
cleaning, encapsulation,  chemical  deactivation, and  other
approaches that will be more cost effective than demolition and
disposal.

        Feasibility. It is  feasible to conduct this research in
the ORD intramural  program.  Although no work is currently
being done in this area, research in the areas of reactive gates
and iron-sediment washing may be directly applicable.

        Priority and  Rationale.   High.   The impact  of
developing and applying specific procedures for dealing with
accidental methyl parathion applications within homes will  be
highly significant.  Recent episodes involving children have
occurred  in urban settings,  primarily as the result of illegal
application in homes by unlicensed  pesticide applicators.  In
this specialized setting, the only appropriate solution was to
evacuate the  homes  and destroy  them.   In a large-scale
outdoor  setting,  chemical  oxidation  and  neutralization
methodologies have been successfully applied at the Gila River
site in  Arizona for treatment of methyl parathion,  and it is
feasible that these methodologies could be modified for use in
a domestic setting.

        In addition to these specific child-related problems
with methyl parathion, recent studies in agricultural States have
indicated that farm children are exposed within their homes to
levels of  pesticides that are seven to  ten times higher than
outdoors,  specifically  chlorpyrifos and  endosulfan.   Even
though the most pressing need is for specialized techniques for
treating methyl parathion in the confined setting of homes,  it is
quite  plausible that  these technologies could  be  further
modified for use with other pesticides.

        Development of cost-effective methods for reducing
exposure and riskoccurring via child-specific pathways such as
dermal and hand-to-mouth contact has several advantages that
make it a high priority for ORD. It will help the EPA Regions to
provide solutions to the public for known and possible health
risks to children  in indoor environments.  On a chemical-
specific basis where  risk reduction methods can  remove
exposure, such research may even avoid the need for further
risk assessment research.  In addition, ORD needs to be able
to advise  and assist  individual study  subjects  in EPA-
sponsored epidemiology and exposure studies who are found
to be highly exposed within their residences, day care centers,
and schools.

        Long-Term Outcome.  Broadly applicable methods
for removing chemicals from residential environments and for
preventing  exposure  in the residential  environment (e.g.,
through encapsulation) are used by the Superfund program,
EPA Regional Offices, State and  local  public health  and
environmental agencies, and others to achieve cost-effective
cleanup to safe levels for children.

        Short-Term  Output.  By 2005, ORD will

#      Develop a method to remove pesticides and other
        chemicals from building structures and carpets or to
        prevent  exposure (e.g.,  through  encapsulation),
        using methyl parathion as a prototype.

4.3.4.3. Communication  of Risks and Development of
        Risk Reduction Techniques Through Community
        Participation

        Description. ORD will support research on methods
of education and  intervention  that  encourage and offer
assistance to members of communities  working together to
reduce riskstotheirchildren. Examples include projects where
researchers work with the community to reduce children's
exposure to pesticides at home and at school,  intervention
programs to  help parents reduce  the likelihood of asthma
attacks in their children, community-based studies to determine
                                                       26

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which types of intervention are most successful, dissemination
of information to medical personnel, and studies of how to
communicate risks and risk reduction methods most effectively
to diverse groups of people. For example, dialogue could be
initiated between  scientists and the community regarding
infectious disease threats to children such as E. coli strain
O157.

        An  effective exposure  or epidemiology study will
involve the community being studied.  Through civic  and
religious groups, teachers and day care workers, primary care
physicians, and other community members, researchers can
enlist the community in study design and implementation,
advertise the study and recruit participants, and communicate
results. It is important for researchers to understand and to be
sensitive to cultural practices, to address anxiety related to the
study or to  real or perceived environmental hazards, and to
assist local public health departments in dealing with problems
that are found, such as the need for alternate food or water
sources or for remediation and treatment interventions.

        Feasibility.    The  eight  Centers  for  Children's
Environmental Health and Disease Prevention have projects in
risk communication, intervention, and reduction. There is little,
if any,  expertise in  this area within the  ORD  intramural
program,  except to the extent  that individual scientists have
dealt with some of these issues in epidemiology and exposure
studies. Inanyfuture  studies of children, ORD will provide for
community involvement, communication of study results to the
respondents,    advice   about  lowering  exposures,  and
cooperation with  local public health  departments to reduce
risks where necessary.

        Priority and Rationale.  High.   Developing cost-
effective methods for reducing  children's exposures and risks
through education and community involvement has several
advantages that make it a high priority for ORD.  It will help
EPA Regions to provide solutions to the public for both known
and possible health risks to children. This research will also
improve ORD's ability to  advise and assist individual study
subjects who are found to be highly exposed in EPA-sponsored
epidemiology and exposure studies.  It is recommended that
research in this area continue to be conducted underthe STAR
program.  Any intramural efforts should be planned as part of
an exposure or epidemiology  study, rather than a separate
research  program.

        Long-Term  Outcome.  Through implementation of
better methods of communicating scientific information about
risk and  working  with  communities to reduce risk,  EPA
strengthens  its community-based  risk assessment and risk
management programs.

        Short-Term Outputs. By 2005, ORD will

#      Implement  risk  intervention programs in  several
        communities  and  publish journal  articles   on
        effectiveness of risk intervention approaches (output
        of  STAR  program  Centers   for   Children's
        Environmental Health and Disease Prevention).

#       Compare  methods for communicating  risks  of
        pesticides on foods (output of current STAR program
        grant).

4.3.5.  Cross-Cutting Issues

4.3.5.1.  Variation  in  Susceptibility and  Exposure  in
        Children

        Description. Variation in susceptibility and exposure
within an age group may be as important as  variation between
groups.  Factors such as genetic traits, pre-existing disease,
nutrition, behavioral traits, medications, coexisting exposures,
sex, and ethnicity may result in great variation in risk within an
age  group.   Epidemiological and  clinical studies, animal
toxicology studies, and in vitro assays are important methods
to identify and assess factors that may contribute to observed
variability in susceptibility. Exposure studies that first identify
scenarios and pathways of greatest concern and then perform
the research to fill the data gaps will also be useful.

        This research area is closely related to the laboratory
and field studies described in Section 4.3.1.  Two exposed age
groups  might exhibit the same  means, but their statistical
variation may be different. Researchers need to look at the
individuals in the high ends of distributions  within age groups
for clues to toxic mechanisms, adverse health effects, and high
exposures.

        This research area covers issues related to variation
in  susceptibility and exposure  that  are  unlikely  to  be
systematically examined underthe research areas in Section
4.3.1, although they  may be part of a study of a particular
environmental  agent or endpoint.

        Feasibility. Variation in susceptibility and exposure
to  environmental agents is a major focus  of ORD's Human
Health Risk Assessment  program.  Many  of the  issues that
might be addressed here are also being addressed in other
research areas.  Current and planned ORD exposure and
epidemiology studies, for example, address exposure and
sometimes effects  in groups of children hypothesized to be
highly exposed, including children living in  agricultural areas
and  inner cities.   Research  into modes  of action  will  of
necessity examine why some individuals respond to exposure
while other individuals exposed at the same level do not. For
example, a  compromised immune system in the form  of
allergies to environmental pollutants is being studied as a
potential major cause  of asthma.   Interactions between
environmental  agents and genes will be important in studying
modes of action and in using such data to assess risk.

        Priority and Rationale. Medium.  Given the  limited
                                                       27

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knowledge about which are the vulnerable ages and how and
why individuals in these age ranges tend to be vulnerable, and
the fact that many issues related to variability will be addressed
in other research areas, the science team concluded that this
area was not of as high a priority as other areas in its potential
contribution to reducing uncertainty in risk assessment. Some
of the research described in this area, such as variation related
to genetic traits and high exposures, will be carried out under
other research areas.  As more becomes known about how
children's vulnerabilities and exposures differ from those of
adults,  the priority of issues such  as the impact of nutrition,
behavior,  and  co-existing  disease on  susceptibility  will
increase.

4.3.5.2. Cumulative Risks to Children

        Description.    Children  are  exposed to many
environmental  compounds  simultaneously.   Mixtures  of
chemicals indoors,  in the  air, and on surfaces come from a
variety of sources,  including outdoor air and outdoor dust,
indoor  heating sources, building  materials,  and consumer
products. Volatile organic air pollutants occur in mixtures with
ozone.   Mixtures of heavy metals and organic pollutants at
waste sites can contaminate ground water, surface water,
drinking water, and  residential areas both indoors and out.

        Historically, toxicity testing, mechanistic research,
human  studies,  risk assessments, and  many of EPA's
regulations have been directed at single chemicals. There is
little information on the effects on children of simultaneous
exposure to  many  environmental  agents,  let alone  any
information on  the toxicokinetics  and  toxicodynamics  of
chemical interactions in this population group. As a first step,
research is needed to compare the individual toxicokinetics and
toxicodynamics of known developmental toxicants to those of
simple  mixtures of two  or three of the same chemicals in
animal models. The selection of chemicals should be made on
the basis of the availability of similar information on  mature
animals.
        Methods of estimating both aggregate exposure to
mixtures and dose-response relationships are not generally
available and need to be developed.

        Feasibility.  EPA is starting to address the issue of
cumulative risk, but methods are not well developed. EPA's
Risk  Assessment  Forum  is  developing  guidelines  for
cumulative risk assessment. ORD has sponsored studies of
exposure to multiple chemicals and chemical classes under
NHEXAS.  Research  on the effects of exposure to mixtures
and how such data can  be used in risk assessment will be a
major focus of ORD's  Human Health Risk Assessment
program. The STAR program and NIEHS are co-sponsoring
a research program on chemical mixtures  in environmental
health.    OPP  is   developing  a  risk  assessment  of
organophosphate pesticides with like modes of action. These
efforts are not focused on children's  issues, but rather on
learning as much as possible about health effects of mixtures.
Methods  for  cumulative  risk assessment  are  not  well
developed.

        Priority and Rationale. Medium. Given the current
lack of knowledge about which are the vulnerable ages and
how and why  individuals  in these age  ranges tend to be
vulnerable, as well as the general lack of knowledge about the
biological effects of exposure to mixtures, this area is a lower
priority for the Children's Health Program..
4.4.   Linking    and     Summary
        Research Areas
of
        The  preceding  sections  have focused  on each
separate research area. Table 2 is an overview of Section 4.3
containing a short  description  of each  research area,  the
contribution ofthe research to EPA's riskassessments and risk
management  decisions,  and its relation to other research
areas.
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                Description
    Contribution to Risk Assessment or
               Management
                 Links to Other Research Areas
                          Biology of Toxicant-Induced Tissue and Organ Damage in the Developing Organism (§4.3.1.1) High Priority
Investigate absorption, metabolic pathways and
rates, distribution and storage in the body, and
elimination in sensitive age groups. Investigate
biologic basis forage-related differences in target
organ development,  detoxification, repair, and
compensation. Link effects at tissue, organ, and
system level with underlying effects at  cellular
and molecular levels.  Identify common modes of
action for multiple developmental endpoints and
chemicals.
Identification of more appropriate animal models
for  critical  ages  and  endpoints.    Improved
extrapolation from animals to children.  Improved
risk assessment models relying less on data from
whole  animal  toxicity  testing   and   able  to
incorporate biologic data  specific to children.
Identification of classes of chemicals with the
same modes of action.
The necessary data to develop biologically based dose-response models
(§4.3.2.1) will be developed under this research area.  Mode-of-action
studies will help identify pollutants that are good candidates for human
studies and may develop biomarkers that could be used in human studies
(§4.3.1.2). Development, validation, and application of newtest methods
(§4.3.3.1) will  be  needed to conduct mode-of action research.  This
research also provides some of the basic science that will be necessary
to understand the complicated  issues of variability within susceptible age
groups (§4.3.5.1) and cumulative risk resulting from exposure to multiple
pollutants (§4.3.5.2).
              Relationship Between Exposure to Environmental Agents and Adverse Health Effects in Human Populations (§4.3.1.2) High Priority
Conduct studies  of the  relationship between
exposure  and effects  in  human  populations.
Explore feasibility of interagency longitudinal birth
cohort enrolling children at birth  and continuing
through childhood or adolescence.  Conduct
hypothesis-based analysis of existing data sets to
investigate relationship between exposure and
effects in children.
Identification of hazards and important sources
and pathways of exposure. Opportunities to test
hypotheses  related to  human  exposure  and
effects and the ability of animal testing and risk
assessment methods  to predict exposure  and
effects in children.  Testing  of intervention  and
risk reduction techniques. Collection of data for
dose-response assessments.
Studies in  humans will  be indicated by results of research into the
biological bases of adverse effects (§4.3.1.1) in order to verify predictions
of response in children and to aid  in developing models to extrapolate
between animals and children (§4.3.2.1).  Epidemiology studies and
exposure field studies (§4.3.1.3)  are closely related, and ORD should
explore opportunities to  combine these studies in such a way that the
objectives of both types of studies are met. Methods of studying effects
and exposure in humans  (§4.3.3) will be used in  human studies and often
developed in the context  of these studies.  Investigators will need to work
with  communities  and  participants  in conducting studies in  human
populations and will need communication methods (§4.3.4.3) and practical
intervention  methods to offer to  individuals  and  local public  health
departments to deal with problems that may be uncovered (§4.3.4.2).
Human studies designed to   consider  multiple chemicals  have the
potential to provide information on variability within age groups (§4.3.5.1)
and responses to complex mixtures (§4.3.5.2).

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Description

Contribution to Risk Assessment or
Management



Links to Other Research Areas
Multimedia, Multipathway Exposures in Human Populations (§4.3.1.3) High Priority
Measure exposure in various age groups in the
national population and selected subgroups
hypothesized to be more highly exposed. Collect
environmental concentration data, personal
exposure data, biological samples, and
questionnaire data.















Develop data on distributions of values of key
exposure variables within critical age groups,
including activity pattern data, intake rates, and
otherfactors that may cause higher exposures for
children.




Determination of when children are exposed and
which age groups are more highly exposed and
should be subjects of further study and
assessment. Development of baseline data and
data on distributions of exposure in the general
population and highly exposed subgroups.
Development of data for risk assessment of
chemicals in study and data on activity patterns
and other exposure variables for direct use in
EPA risk assessments. Identification of important
sources and pathways of exposure for risk
management decisions. Collection of data for
use in model development and predictions of
exposure.






Analysis of Factors Contributing to Exposure
Development of data on exposure variables that
introduce the greatest uncertainty into EPA risk
assessments as identified by EPA Program
Offices and Regions and ORD analysis.





Information on the most highly exposed age groups and their patterns of
exposure is useful in selecting relevant chemicals for pharmaco kinetic and
mode-of-action studies (§4.3.1 .1 ), designing biological models compatible
with actual exposure patterns (§4.3.2.1.), and designing human studies
of the relationship between exposure and effect (§4.3.1.2). Ideally,
epidemiologic and complex exposure studies would be combined in cases
where it is possible to do so without sacrificing the ability to obtain the
studies' objectives. Multimedia, multipathway measurement studies can
often be designed to collect information on exposure variables (§4. 3. 1.4)
and for use in designing and testing exposure models (§4.3.2.2) suitable
for use in many risk assessments. The strategy recommends that
methods of measuring exposure applicable to infants and toddlers
(§4.3.3.2) be developed in the course of conducting these studies.
Investigators will need to work with communities and respondents to
conduct exposure studies and will need both communication methods
(§4.3.4.3) and practical methods to offer help to individuals and local
public health departments to deal with problems that may be uncovered
(§4.3.4.2). Studies designed to consider multiple chemicals have the
potential to provide information on variability in exposure within age
groups (§4.3.5.1) and exposures to complex mixtures (§4.3.5.2).
(§4.3.1. 4) High Priority
Multipathway studies (§4. 3. 1.3) often collect data that can be used directly
in risk assessment to evaluate exposure factors. However, this is usually
a secondary objective of such studies. Data on exposure factors and how
factors influence each other is key to developing exposure models
(§4.3.2.2). Measurement methods are often developed (§4.3.3.2) in the
context of studying particular exposure pathways and variables. Studies
of critical exposure variables, such as food intake and ingestion of soil and
dust, can provide insight into variability in exposures within age groups
(§4.3.5.1).

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Description
Methods
Develop integrated biological models of the
exposure-dose-response continuumthat routinely
use pharmacokinetic and mode-of-action data in
risk assessments for children. Develop models
incorporating biological data to aid in
extrapolation between animals and children.

Contribution to Risk Assessment or
Management


Links to Other Research Areas
and Models for Using Biological Data in Risk Assessment (§4.3.2.1) High Priority
Risk assessment models that take into account
age-related differences in size, absorption,
metabolism, distribution, and storage, and
response to exposure at the cellular and
molecular level. Improved ability to identify age-
appropriate animal models and extrapolate from
animals to children.
Data for model development are generated through mode-of-action
research (§§4.3.1.1, 4.3.3.1). Human studies also provide relevant data
for model validation and extrapolation between animals and humans
(§4.3.1.2). Exposure studies (§4.3.1.3) often provide relevant data on
uptake, body burden, and elimination. Exposure models (§4.3.2.2) and
biological models are connected through PBPK modeling. It should be an
objective of chemical-specific modeling to develop exposure, PBPK, and
BBDR models that can be linked to connect effects with exposures
through the PBPK model. With a sufficient input database, probabilistic
models will be useful in predicting distributions of exposure, dose, and risk
within an age range, allowing for estimates of variability (§4.3.5.1).
Exposure Modeling and Use of Exposure Data in Risk Assessment (§4.3.2.2) High Priority
Develop models for important pathways of
childhood exposure, models of total dose via
multiple pathways, and probabilistic assessments
combining exposure data on multiple pathways.

Develop methods for identifying and modeling
mechanisms of toxic action in children.
Identification and quantification of exposure and
dose in the risk assessment. Identification and
quantification of sources and pathways in orderto
develop appropriate risk management options.
Estimation of child-specific exposures and
aggregate exposures for children in EPA
assessments where measurements must be
supplemented with modeling approaches to fill
data gaps.
In Vivo/In Vitro Methods for Hazard Identification
Development of animal models and protocols that
will provide information on mode of action to be
used in risk assessment.
Data for model development are provided through studies of exposure
variables (§4.3. 1 .4). Human studies (§§4.3.1 .2 and 4.3. 1 .3) may provide
data to evaluate model variables and to develop and test exposure
models. Exposure models and biological models (§4.3.2. 1 ) are connected
through PBPK modeling. It should be an objective of chemical-specific
modeling to develop exposure, PBPK, and BBDR models that can be
linked to connect effects with exposures through the PBPK model. With
a sufficient input database, probabilistic models will be useful in predicting
distributions of exposure within an age range, allowing for estimates of
variability (§4. 3. 5.1). Probabilistic models will also be helpful in predicting
distributions of dose from multiple chemicals via multiple pathways
(§4.3.5.2)
(§4.3.3.1) High Priority
Predictive tests will be developed as part of a program investigating the
biological basis of risk (§4.3.1.1) and provide data for extrapolation
between animals and children (§4.3.2.1).

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Contribution to Risk Assessment or
Description Management


Links to Other Research Areas
Methods for Measuring Exposures and Effects in Infants and Children and to Aid in Extrapolations between Animals and Children (§4.3.3.2) Medium Priority
Develop measurement methods suitable for use Improved methods for collecting data on children
in infants and toddlers, such as biological that, when applied in a study, contribute to better
sampling methods and cognitive testing methods, data for risk assessment.
Develop biomarkers of effect and exposure in
young subjects.
Multimedia Control Technologies (§4.3.4
Develop control technologies for releases of Reduced risks to children and adults through
substances to which children are believed to be control of a substance at its source.
exposed, including drinking water treatment for
Cryptosporidium, control of air emissions,
bioremediation of chemicals at waste sites, and
control of pesticide releases in point sources and
nonpoint source runoff.
Some of these methods are likely to be developed in the context of
laboratory studies and otherhuman studies (§§4.3.1.1., 4.3.1.2, 4.3.1.3,
and 4.3.1. 4)
1) Low Priority
Risk assessments based on the results of research described in other
research areas help identify substances for which control methods are
needed. Risk assessments also help set numerical targets for cleanup,
effluent control, and other risk management options, and are used to
assess the efficacy and benefits of the options.
Methods for Reducing Exposure Buildup of Contaminants in Indoor Environments (§4.3.4.2) High Priority
Cleanup and remediate children's environments Reduced risks to children in their homes and
that have unacceptable environmental schools through remediation and pollution
concentrations. Engineerconsumerand building prevention.
products to reduce release of environmental
agents to the indoor environment.
Risk assessments based on the results of research described in other
research areas will help identify substances forwhich control methods are
needed. Risk assessments also help identify and evaluate remediation
and pollution prevention options and their efficacy. Intervention methods
can be used in conjunction with human studies (§§4. 3. 1.2 and 4. 3. 1.3) to
assist residents and local public health departments when high exposure
levels are found.
Communication of Risks and Development of Risk Reduction Techniques Through Community Participation (§4.3.4.3) High Priority
Investigate intervention and education methods Reduced risks to children through intervention by
that enlist members of the community to work parents, schools, medical personnel, and others
together to reduce risks to their children. in the community.
Risk assessments based on the results of research described in other
research areas help identify substances forwhich intervention methods
are needed. Risk assessments also help evaluate efficacy of community-
based intervention. Intervention methods can be used in conjunction with
human studies (§§4.3. 1 .2 and 4.3.1 .3) to assist residents and local public
health departments when high exposure levels are found.

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Description

Contribution to Risk Assessment or
Management


Links to Other Research Areas
Variability in Susceptibility and Exposure in Children (§4.3.5.1) Medium Priority
Investigate impact of factors on variability in
response or exposure within the critical age
range. Factors include preexisting disease,
lifestyle and nutrition, genetic characteristics, sex,
and ethnicity.

Investigate simultaneous exposures to multiple
environmental agents and other stressors in a
child's environment.
Identification and quantification of risk in
susceptible and highly exposed subpopulations.
Cumulative Risks to Children (§4.3.5.2)
Data for assessment of risk of simultaneous
exposures, including chemicals by the same
route, chemicals with common modes of action
by multiple routes, and all environmental agents
and other stressors found in the child's
environment.
Many factors that influence variability within a critical age range will be
assessed as part of studies to identify the age range and determine why
that age range is critical. Studies of mode of action (§4.3.1.1) will often
consider genetic and other susceptibility factors. Human studies as well
as risk assessments often focus on special groups that are expected to
be more susceptible or more highly exposed (§§4.3.1.2, 4.3.1.3, and
4.3.1.4).
Medium Priority
The results of mode-of-action studies (§4.3.1.1) will be important in
understanding effects of mixtures. Epidemiology and exposure studies
(§4.3.1.2 and §4.3.1.3) often provide data on the multiple chemicals
(although only a small fraction of all chemicals) to which infants and
children are exposed. Dose-response methods for assessing toxicity of
simultaneous exposures are critical to development of models and
assessment methods for summing multichemical exposures and risks.

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                       5.  GUIDANCE FOR  IMPLEMENTATION
        The strategy will be  implemented  by ORD's three
national laboratories and two national centers. Approximately
75% of the extramural  resources of the Children's Health
program are expected to be dedicated to investigator-initiated
grants under the STAR program. The intramural program will
be conducted by ORD scientists supported by the remaining
25% of the extramural funding. Research on children's issues
performed to  address  specific concerns of EPA Program
Offices, such as epidemiology studies conducted for the air
program and exposure studies conducted for the pesticides
program, will continue.

        Criteria for selection of research projects and topics
forextramural RFAs have been adapted from criteria proposed
in the ORD Ecological Research Strategy (EPA, 1998h).  ORD
will undertake projects that meet the following criteria:

#       The project is directly related to assessing or reducing
        risks to children.

#       Intramural projects address research areas identified
        as of high priority in this strategy.

#       Extramural STAR projects address research areas
        identified as of high or medium priority in this strategy.

#       The project  is consistent with a short- or long-term
        need of an EPA program. Long-term needs include
        the development of data, models, and methods  for
        using biological information in risk assessment.

#       The project  allows ORD to establish or maintain a
        core competency and ability to meet future needs.

        The expertise needed for this research program is
distributed throughout ORD. Interdisciplinary research across
a diverse and geographically dispersed organization such as
ORD is a challenge.  Collaborations across ORD laboratories
and centers are essential to successful implementation. Figure
2 shows an example of the type of collaborations  that the
strategy encourages-a combined exposure and epidemiology
study of children in a  population along the U.S.-Mexico border
conducted by NERL and NHEERL

        ORD scientists are also encouraged to  become
familiar with relevant research in the  STAR program. There
are opportunities forORD scientists to participate in developing
RFAs for extramural grants, reviewing proposals that are highly
rated   in   external  peer  review, attending   meetings  of
investigators, and  even collaborating with investigators  in
appropriate situations.   Figure  3 shows an  example  of a
collaboration between ORD, the Minnesota Department of
Public  Health,  a  nonprofit consortium  operating under
NHEXAS, and a grantee under the STAR program.
  Figure 2. Pesticides in Young Children along the
  U.S.-Mexico   Border:   A  NERL/NHEERL
  Collaboration

          This project assesses the relationship between
  health outcomes in young children along the U.S.-Mexico
  border and  repeated pesticide exposures via multiple
  sources  and pathways.  NERL and NHEERL formed a
  partnership with a co-chair from each laboratory and joint
  planning, implementation, participation of staff, and peer
  review and publication.

          Preliminary studies included review of existing
  data,  development  of geographic information  system
  maps  of the area, and a workshop to identify relevant
  health endpoints and appropriate epidemiology studies.
  Methods of screening  of infants and children  are  now
  being  identified  and  implemented.   More extensive
  exposure screening will then take place, and if warranted
  by the results, an epidemiology study will be conducted to
  assess the relationship between  exposures and specific
  health endpoints.
        Coordination and collaboration with  other Federal
agencies are  keys  to  successful implementation.   One
mechanism for collaborating with other Federal agencies is
EPA's continued  leadership of and participation in the U.S.
  Figure 3: Pesticides and Children in Minnesota:
  A NHEXAS Study and a STAR Grant

         Underthe NHEXAS Program, ORD sponsored a
  study  under cooperative  agreement  with  Research
  Triangle Institute and the Environmental and Occupational
  Health  Sciences  Institute  in which  environmental,
  personal,  and biological samples were collected and
  analyzed  for  pesticides  and a questionnaire  was
  administered fora sample of children in Minneapolis-St.
  Paul.  The State of Minnesota also participated.  An
  investigator at the University of Minnesota proposed a
  study under the STAR program for a population of the
  same age in rural Minnesota. At the grantee's instigation,
  the two studies used similar protocols so that the results
  can be compared.
Task Force on Children's Environmental Health Risks and
Safety  Risks.   The Task  Force,  chaired  by the  EPA
Administrator  and  the  Secretary  of  Health  and  Human
Services, was established by Executive Order in 1997 (U.S.
Executive Order No. 13045 1997). The members of the Task
                                                      34

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Force are Federal agencies with programs  that address
children's environmental health and safety, including EPA; ten
Institutes of  NIH; CDC; ATSDR;  FDA;  the Departments  of
Education,  Labor,  Justice,  Energy, Housing and  Urban
Development, Agriculture, and Transportation; the Consumer
Product Safety Commission; and  the Office of Science and
Technology Policy.

        Through the efforts of the Task Force Working Group
on Developmental Disorders,  EPA, NICHD, NIEHS, and the
National Institute of Dental and Craniofacial Research (NIDCR)
are sponsoring  a  joint RFA to study susceptibility  and
mechanisms of human  congenital malformations,  including
research on the  contribution  of genetic and environmental
factors,  identified at  the  molecular  level,  to the  etiology,
distribution, and  prevention of disease within families and
across populations. As discussed in Section 4.3.1.2, the
working group is also  actively exploring the feasibility  of
establishing a longitudinal  birth cohort, as a joint effort of the
concerned Federal  agencies.  Through the Task Force,  EPA
and the Department  of Health and  Human Services  also
developed a  national strategy to address childhood  asthma.

        Other examples of EPA's collaborations include the
Centers for  Children's  Environment Health  and  Disease
Prevention cosponsored with NIEHS, sponsorship of special
exposure studies in  CDC's  NHANES  on  urine  levels  of
pesticides in  children  and adults and levels of persistent
organic compounds in adolescents, and collaboration with CDC
and FDA in the NHEXAS study of children in Minneapolis-St.
Paul.

        Information  on Federal research and EPA activities
can now be  found on  the Internet.  The ORD home page
provides electronic copies of publications, including research
strategies. The  OPP home  page posts issue papers and
deliberations of the OPP Science Advisory Panel on children's
risk issues. Several agencies, including NIEHS, CDC, NCI,
and the ORD STAR program, publish current budget requests
and descriptions of their research programs and initiatives and
provide  lists of their intramural and  extramural research.
CHEHSIR, which reports on Federal research on children's
environmental health and safety risks   at a project level, is
online (EPA 2000b).   ORD managers and scientists are
encouraged to consult these online sources to learn about
Federal  research and  activities on children and to provide
similar information on their Internet home pages.

        Figure 4 summarizes principles for implementation of
the strategy.
                    Figure 4.  Guiding Principles for Implementation

  #      When designing a research study, investigators should consider the impact of the results on EPA risk
         assessments for children. Requests for Applications (RFAs) in ORD intramural and STAR programs should ask
         investigators to specify the potential impact of results on the EPA risk assessment process.

  #      A multidisciplinary research program that is coordinated across the ORD laboratories and centers is encouraged.
         RFAs for cross-laboratory/center intramural projects and fostering of contact between extramural grantees and
         ORD scientists are encouraged.

  #      Outreach, coordination, and partnership with other Federal agencies is essential, particularly in the  areas of
         human studies and biological mechanisms of action.

  #      Toxicologists, epidemiologists, clinicians, and exposure scientists are encouraged to work collaboratively during
         all phases of research planning, development, and implementation.

  #      ORD needs to develop and maintain intramural expertise to be able to incorporate new data and methods into
         EPA risk assessments.   Use of biological data in risk assessment is a high priority.  A stable intramural research
         program with  adequate support is essential to achieving this capability.

  #      Research across more than one endpoint point is encouraged where possible, such as research on mechanisms
         that can lead to multiple endpoints and endpoints affecting the same target organ.

  #      Risk reduction research and risk management goals should be considered throughout the course of this program.
                                                      35

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Faith,  R.E.  and  J.A.  Moore.  1977.  Impairment of thymus-
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    developing immune system to 2,3,7,8-tetrachlorodibenzo-
    p-dioxin (TCDD). J. Toxicol. Environ. Health 3:451-464.
Fauci, A.S.  1997. New insights spark optimism at NIAID. U.S.
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Faustman,  E.M. and  G.S. Omenn.  1996.   In:  Casarett &
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Goldman,  L.   1995.  Children  - unique  and  vulnerable:
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Hoar, R.M. and I.W. Monie.  1981. Comparative development
    of specific organ systems. In: Developmental Toxicology
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    http://www.hud.gov:80/lea/leaoutre. html
ILSI. (International Life Sciences Institute). 1996.  Research
    Needs on Age-related Differences in  Susceptibility to
    Chemical Toxicants.  Report  of  an  ILSI Risk Science
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    Adults: Implications for Risk Assessment. (P.S. Guzelian,
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Jacobson,  J.L.,  S.W. Jacobson, and H.E. Humphrey.  1990.
    Effects of in utero exposure to polychlorinated biphenyls
    and related contaminants on cognitive functioning in young
    children.  Pediatrics 116:38-45.
Jacobson,  J.L., S.W. Jacobson, and H.E. Humphrey.  1990.
    Effects of in utero exposure to polychlorinated biphenyls
    and related contaminants on cognitive functioning in young
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Langston,  C.   1983.   Normal  and  abnormal  structural
    development of the human lung. In: Abnormal functional
    development of the heart, lungs, and kidneys: approaches
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    Liss, Inc.
Mannino, D.M., D.M. Homa, C.A. Pertowski, A. Ashizawa, L.L.
    Nixon, C.A. Johnson, L.B. Ball, E. Jack, and D.S. Kang.
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    1995.    Morbidity   and  Mortality  Weekly  Report.
    Surveillance Summaries.  April 24, 1998/47 (SS-1); 1-28.
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    www.cancer.gov/.
NHLBI. (National Heart, Lung, and Blood  Institute).  2000.
    Framingham    Heart   Study   home   page.
    http://www.nhlbi.nih.gov/about/framingham/index.html.
NICHD.   (National  Institute  of  Child  Health and  Human
    Development). 2000. Home page:  www.nih.gov/nichd/.
NIEHS.  2000a.  (National Institute of Environmental Health
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    http://ntp-server.niehs.nih.gov/
NIEHS.  2000b.  Environmental Genome Project home page.
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NIEHS.  2000c.  Research initiatives: children's health - cleft
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NIEHS.   2000d.   First national survey shows Americans'
    bedding can make them sick: allergens the culprit. Press
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NIEHS.   2000e.    Asthma  and  allergy prevention:  risk
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    in Developmental Toxicology and Risk  Assessment.
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    The White House, April 21, 1997. EPA.600-R-97-915.
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Evaluating Health Risks from Chemicals During Infancy and
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Environmental Health Criteria 59. Geneva, Switzerland: World
Health Organization.
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      APPENDIX A.   GROWTH AND  DEVELOPMENT FROM BIRTH
                                THROUGH  ADOLESCENCE
        At birth, most organs and systems of the body have
not achieved structural or functional maturity. Physical growth
and functional maturation continue through adolescence, with
the rates of growth and functional maturation varying among
the different tissues, organs, and systems of the body.  There
are specific  periods or windows of vulnerability during
development when toxicants can permanently alterthe function
of a system (Bellinger et al.  1987, Roder 1995).  Although
these  critical  periods often  occur during gestation,  some
systems that continue to  mature postnatally may be adversely
affected by exposure to toxicants after birth.  Organs and
systems that continue to undergo maturation during infancy
and childhood include the lungs,  kidneys,  and liver, and the
immune, nervous, endocrine, reproductive, and gastrointestinal
systems (Dobbing and Sands 1973, Hoar and Monie 1981,
Andersson et al. 1981,  Langston 1983).  It  is important to
emphasizethata physiological orfunctional perturbation during
a critical period of development increases the overall risk
associated  with childhood  environmental exposure.   For
example, exposure to a neurotoxicant that adversely impacts
cognitive function is integrated over a lifetime when applied to
a child (Gilbert and Grant-Webster 1995).

        Differences  in  susceptibility between  children and
adults  may  be due to either  qualitative or  quantitative
differences in the  toxicity  of  an environmental agent.
Qualitative differences in toxicity between children and adults
are a result of structural or functional alterations that occur as
a consequence of exposure during a particularly vulnerable
period of organ or system development. On the other hand,
quantitative differences are  due  in  part to  age-related
differences  in  pharmacokinetic  and  pharmacodynamic
processes.   The alterations induced  may be immediately
apparent or may manifest as delayed toxicity later in life as a
result  of short-term or low-level exposure during development.
An example of delayed toxicity, due to enhanced susceptibility
during development, is the increased incidence of vaginal and
cervical  cancers in  the daughters of mothers who took
diethylstilbestrol  (DES) to   prevent  miscarriage  during
pregnancy (Herbst et al. 1972).    Another example  is the
exposure of newborns to chloramphenicol which resulted in
cyanosis,  progressive  circulatory collapse,  and ultimately
death, and which was attributed to decreased clearance of this
chemical (Weiss et  al.  1960).   Decreased  metabolic and
excretory capacity of newborns has also been associated with
the increased  toxicity of  other chemicals during the postnatal
period. These includethe"gasping syndrome" associated with
benzol alcohol-preserved drugs (Gershanik et al. 1982) and
neurological  damage and  death  as  a  result  of dermal
application of hexachlorophene-contaminated talcum powder
(Hay  1982).   Cases  of  infant  poisoning  and death by
hexachlorobenzene  have also  been  reported  following
ingestion of highly contaminated human milk (Peters 1976).
The consumption  of mercury-contaminated fish by nursing
mothers resulted in  severe  neurological disorders in their
breast-fed infants  (Amin-Zaki et al. 1980).   The antibiotic
tetracycline  produces  tooth  discoloration  and  enamel
hypoplasia as well as interfering with bone growth in infants
prior to first dentition  and in children  prior  to permanent
dentition (Kacew 1992).

        The lungs are the major portal of entry of volatile and
airborne chemicals.  The lungs are structurally immature in
neonates and continue to mature during early childhood. Not
until several years after birth is the full complement of mature
cells in the lungs achieved (Langston 1983).  There is little
information available on the pulmonary  absorption and
bioavailability of inhaled chemicals in infants and children.

        Ingestion  is  a  major route by which  infants and
children are exposed to environmental chemicals. Absorption
of chemicals from  the gastrointestinal tract is influenced  by
factors such as the total mucosal surface area, pH, perfusion
rate, blood  supply, and the gastric emptying and intestinal
transit  time.  All of these factors change during  postnatal
development (WHO 1986).  Consequently, the absorption of
some chemicals is greater in infants than in adults.  For
example, lead  is absorbed better  by infants than by  adults
(Ziegler et al. 1978).  The rates of activation and deactivation
of chemicals are also related to the stages of maturation and
development of enzyme activity (Besunder et al. 1988).

        Chemicals also enterthe body via absorption through
the skin.  The surface area to body weight ratio of children is
much greater than that of adults.   As  such, the total body
dermal dose to a chemical for a young child can be as much as
two to three times  greater, on a per-unit body-weight  basis,
than for an adult (Wester and Maibach 1982). The EPA interim
report on dermal exposure assessment (EPA 1992) indicates
that this may be the primary difference between adults and
children with respect to dermal absorption. The data available
on childhood or comparable laboratory animal exposures via
the dermal route are limited (NRC 1993).

        The  structure  and  function of the  kidneys are
immature at birth  (Dean and McCance 1947).  This  is  an
important consideration,  given that the  elimination of most
chemicals from the body occurs primarily via renal excretion.
Both glomerular and tubular function increase with age in the
infant, with glomerularfunction somewhat more advanced than
renal   tubular  function  in   the   neonate  (NRC  1993).
Reabsorption of chemicals from the tubular lumen into tubular
cells also varies with age.  Weak organic acids are  more
readily reabsorbed by the infant than the adult. Some metals
                                                     A-1

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(i.e., cadmium, mercury, and manganese)  depend  on the
kidneys for their elimination. The elimination of these metals
by neonatal rats is less than that in adults (Kostial et al. 1978).
Smaller proportions of absorbed lead are also excreted via the
renal  route  in  infants compared to adults (WHO  1986).
Because chemical excretion  by the  kidneys  is dependent
primarily  on  glomerular filtration,  tubular  secretion, and
reabsorption, a decrement  due to the immaturity of any of
these functions in the infant may result in delayed clearance of
a chemical from the body. Consequently, an increased risk of
toxicity may ensue from the prolonged  presence in the body of
a  chemical  or its  active  metabolite(s) (Braunlich  1981).
Unfortunately, there  is only limited information about age-
related differences in elimination of environmental chemicals in
experimental  animals, let alone in humans (NRC 1993).

        As  with  other  organs,  development of the liver
involves  a  series  of integrated structural  and  functional
changes that continue postnatally.  This includes tissue cell
composition, hepatocyte differentiation, and the appearance of
hepatic enzyme activity.  After  birth the parenchymatous cells
outnumber all other types of cells in  the liver  (WHO 1986).
Another  important  cell  type  in  the  neonatal liver  is the
hemopoietic cell, as the liver is the site of hematopoiesis prior
to birth (Owen 1972). Biotransformation of organic chemicals
via phase land phase II metabolic reactions is generally slower
in the neonate than in the adult.  Consequently, degradation
and elimination of chemicals  that are dependent on these
biotransformation reactions  are generally reduced in  infants
compared with adults. Different isoenzymes and enzymes also
mature  at  different  ages.    Maturation  of  mechanisms
responsible for the  biotransformation of organic chemicals
varies  for  each  reaction  and  chemical   (Klinger  1982).
Examples  of toxicities  associated  with  the  newborn's
decreased ability to conjugate and eliminate chemicals include
chloramphenicol (Sutherland  1959),  diazepam (Nau  et al.
1984),  and hexachlorophene (Tyrala et al. 1977).

        Children are more vulnerable  because they have less
ability  to  metabolize  and  excrete  some  environmental
pollutants. Young children have higher resting  metabolic and
oxygen consumption rates than do adults, which are related to
a child's rapid growth and larger cooling surface area per unit
weight (Hill 1964).  During the first  4  to 6 months of age an
infant gains weight more rapidly than during the rest of its life
(Tanner et al. 1966). Adolescent children are also growing and
adding new tissue  at a  more rapid  rate than are  adults.
Because of  rapid  growth  during   infancy  and  puberty,
accumulation of chemicals in  the body may  be greater than
during adulthood, when growth is less  rapid.  Respiratory and
circulatory flow rates as well  as energy and fluid requirements
are greater in infants and young children than in adults, giving
rise to a greater potential for respiratory and intestinal exposure
to chemicals per unit body weight (WHO 1986).

        The nervous system is not fully developed at birth and
continues to mature  postnatally.  During the first years of life,
rapid brain growth occurs, with approximately 75% of the full
complement of brain cells of all types present by approximately
2 years. The  adult equivalent number of neurons is achieved
by 2 years; however, complete myelination does not occur until
adolescence.  The brain weight of a 6-month-old infant is
approximately 50% that of an adult's and approaches adultsize
by early childhood. In contrast, behavioral and physiological
development of the brain continues into later childhood (Roder
1980, 1995;  NRC 1993).

        Because behavioral development is dependent on
physical and functional  maturation of the nervous  system,
chemical-induced toxic effects,  which occur during critical
periods of maturation,  may  permanently alter behavioral
development.    The  various stages  of nervous  system
development,  which  include  differentiation,   proliferation,
migration, synaptogenesis and axonal growth, and myelination,
all   represent   potential  targets   for   chemical-induced
neurotoxicity (Roder 1995). For example, myelination of nerve
tracts in the spinal cord and  peripheral  nerves, which is a
process that is not complete until puberty, may be affected by
certain  chemicals.   Examples  of the  vulnerability  of the
developing  nervous  system  include  prenatal and  early
childhood exposure to lead, radiation therapy in children under
4 years old,  and  elevated serum bilirubin levels  in neonates.
Certain chemical toxicants that also have been implicated in
causing effects on the developing nervous  system include
ethanol, mercury,  polychlorinated  biphenyls,  and certain
organophosphates(Schulletal. 1990, Chakrabortietal. 1993,
Igata 1993, Needleman  1995, Jacobson and Jacobson 1996).

        The developing endocrine system may be directly
affected by  chemicals or indirectly  affected  by chemical
interactions,  with  some step of the regulating axis controlled by
the  hypothalamus,   pituitary,  or  other  part of  the  brain
(McLachlan et al. 1981). The reproductive system, as well as
other systems, can also be affected by chemical interactions
with  the neuroendocrine organs. For example,  exposure of
experimental animals  to chemicals  with  estrogenic  or
androgenic activity during the early postnatal period can alter
the sexual  dimorphic pattern (Barraclough 1966). Exposure to
chemicals with androgenic or estrogenic activity may also alter
growth and time to onset of puberty (Saenz de Rodriguez and
Toro-Sola  1982).  Altered neuroendocrine function may also
affect adrenal corticosterone release (Libertun and Lau 1972).

        The immune system  is not fully developed  at birth.
Consequently, full-term infants  are  immune  deficient as
compared  with older children and adults in essentially all
measurable  immune  parameters, resulting in their increased
susceptibility to infections (Andersson et al. 1981). Both innate
and  specific immune responses of infants and  children are
suboptimal compared to those of adults. For example, natural
killer cell activity  is at about 60% of adult levels  in newborns
(Toivanen  et al. 1981) and complement activity does not reach
adult levels until about 6 months  of age (Colten 1977). As for
specific immune responses, certain T helper cell functions only
reach adult levels by  6 months of age (Miyawaki et al. 1981).
Whereas the ability of B cells to produce antibodies of the IgG
and  IgA classes increases  with age, adult levels are reached
only  by 5 and 12 years of age, respectively (de Mauralt 1978).
In addition, external factors play a role in the maturation of the
immune system.  For example, immune responsiveness and
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maturation  of  newborns  is  influenced  by  active  (i.e.,
vaccination) and passive (i.e., food, environment) exposure to
antigens  during  perinatal  development.   Defects in the
development of the immune system due to heritable alterations
in lymphoid elements have provided clinical and experimental
examples   of  the   consequences   of  impaired  immune
development (Heise 1982).

        While information on developmental toxicity following
in utero exposure far exceeds that of developmental toxicity
following exposure ofthe newborn and young animal, there are
data that indicate the vulnerability ofthe developing animal to
toxic-induced perturbations. It was recently recommended that
testing be performed in appropriate animal models during the
postnatal developmental period and that adverse effects that
might become evident be monitored overa lifetime. Itwasalso
indicated that the nervous, immune, and reproductive systems
were  of particular importance for testing given the existing
database (NRC1993).  Forexample, certain organophosphate
and  carbamate  cholinesterase-inhibiting  pesticides  affect
learning and behavioral development as well as development
of the visual  system.  Other  chemicals that  affect the
developing  nervous system include methyl  mercury, ethanol,
methylazoxymethanol, hydroxyurea, phenytoin.trimethadione,
retinoids,  cadmium, tellurium, triethyltin, glutamate, and 6-
hydroxydopamine (ILSI 1996).  Rats exposed  perinatally to
2,3,7,8-tetrachlorodibenzo-p-dioxin  had   reduced  immune
function that persisted  through puberty  and into adulthood
(Faith and Moore 1977, Gehrs and Smialowicz 1999). A wide
variety of  drugs and toxic chemicals cause birth defects,
abnormal   reproductive development,  and  infertility  in
experimental animals following exposure during critical periods
of development.  Because sexual differentiation is dependent
upon  hormones and growth factors,  a variety  of drugs and
chemicals with androgenic and estrogenic  activity as well as
adrenergic, serotonergic, and opiate activity can alter sexual
differentiation.  Examples of drugs and chemicals that cause
developmental reproductive effects in experimental animals
include DES,  TCDD, o,p-DDT, methoxychlor, certain fungal
mycotoxins, tamoxifen, chloredecone, certain  PCBs, nitrofen,
neuroactive drugs,  and hexachlorophene (WHO 1986,  NRC
1993, ILSI 1996).

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Barraclough, C.A. 1966. Modification  in the CMS regulation of
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Faith, R.E and J.A.  Moore.  1977.  Impairment of thymus-
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Gehrs, B.C.  and  R.J.  Smialowicz    1999.    Persistent
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Gershanik,  J., B. Boeder, H. Ensley, S.  McCloskey and W.
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Gilbert, S.G. and K.S. Grant-Webster. 1995. Neurobehavioral
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Hay, A.  1982.  Hexachlorophene.  In: The Chemical Scythe
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Heise,   E.R.     1982.     Diseases   associated   with
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Herbst, A.L., R.J. Kurman, and R.E. Scully. 1972.  Vaginal and
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Hill, J.R.  1964. The  development  of thermal stability in the
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Hoar, R.M. and I.W. Monie.  1981. Comparative development
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Igata, A.   1993.  Epidemiological and  clinical features of
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    Chemical  Toxicants.  Report of an ILSI Risk Science
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Jacobson, J. and S. Jacobson. 1996. Intellectual impairment
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Kacew, S.  1992.  General principles in pharmacology and
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Klinger,  W.  1982.  Biotransformation of drugs and  other
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Kostial,  K., D.  Kello., S. Jugo, I. Rabar, and T. Maljkovic.
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Langston,  C.    1983.   Normal  and  abnormal  structural
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Libertun, C.  and C. Lau.  1972.  Adrenocortical function  in
    prepubertal  rats: neonatal effects on  testosterone.  J.
    Endocrinol. 55:221-222.
McLachlan, J.A., R.R. Newbold, K.S. Korach, J.C. Lamb, and
    Y.  Suzuki. 1981.   Transplacental toxicology:  prenatal
    factors influencing  postnatal fertility.  In: Developmental
    Toxicology.  (C.A. Kimmel and J. Buelke-Sam, Eds.) pp.
    213-232.  New York, NY: Raven Press.
Miyawaki, T., N. Moriya, T. Nagaoki, and N. Toniguchi. 1981.
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Nau, H., W.  Luck, and W.  Kuhnz.  1984.  Decreased serum
    protein binding of  diazepam and  its metabolite in the
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    free fatty levels. Br. J.  Clin. Pharmacol. 17:92-98.
Needleman, H.L. 1995.  The role of the environment in injuries
    to  the  developing  nervous system.   Environ. Health
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NRC.  (National Research Council). 1993. Pesticides in the
    Diets of Infants and Children.  Washington, DC: National
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Owen,  J.J.T.  1972.    The  origins and  development  of
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    York, NY:  Elsevier.
Peters, H.A. 1976. Hexachlorobenzene poisoning in Turkey.
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Roder, P.M. 1995. The role of the environment in injuries to
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Roder, P.M.   1980.   Chronology of neuron development:
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    Child Neurol.  22:525-545.
Saenz de  Rodriguez, C.A.  and  M.A. Toro-Sola.   1982.
    Anabolic steroids in meat and premature telarche. Lancet.
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Schull, W.,  S. Norton, and R. Jensh. 1990. Ionizing radiation
    and the developing brain.  Neurotoxicol. Teratol. 12:249-
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Sutherland, J.M. 1959. Fatal cardiovascularcollapse of infants
    receiving large amounts of chloramphenicol.  J. Dis. Child.
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Tanner, J.M.,  R.H. Whitehouse, and  M. Takaishi.  1966.
    Standards from birth to maturity for height, weight, height
    velocity, and weight velocity, Part II British children. Arch.
    Dis. Child. 41:613-635.
Toivanen, P., J. Uksila, A. Leino, O. Lassila, T. Hirvonen, and
    O.  Rewskanen.  1981.    Development  of mitogen
    responding T cells and natural killer  cells in the human
    fetus.   Immunol. Rev. 57:89-105.
Tyrala, E.E., L.S.  Hillman, R.E. Hillman,  and W.E. Dodson.
    1977.    Clinical pharmacology of hexachlorophene  in
    newborn infants. J. Pediatr. 91:481-486.
Weiss,  C.F.,  A.J. Glazko,  and  J.K.  Weston.   1960.
    Chloramphenicol in the newborn infant:  a physiological
    explanation of its toxicity when given in excessive doses.
    N. Engl. J. Med. 252:787-794.
Wester, R.C.  and H.I.  Maibach.  1982.    Percutaneous
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    Cold Spring Harbor Laboratory.
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      APPENDIX B.  ORD RESEARCH PLANS  AND STRATEGIES1
                  Name
                           Description
                                           Final Plans and Strategies
 Final Research Plan for Microbial Pathogens
 and Disinfection By-Products in Drinking
 Water (EPA 1997a)
This research plan was developed to describe research to support EPA's
drinking water regulations concerning disinfectants, disinfection by-products,
and microbial pathogens, focusing on key scientific and technical information
needed. The research plan was developed by a team of scientists from EPA's
national laboratories and  centers  within  the  Office of  Research and
Development and from the Office of Water.  The plan is intended to provide
guidance to both the  intramural research program and the extramural grants
program in terms of research priorities and sequencing of research.
 Ecological Research Strategy (EPA 1998a)
The  program goal is to provide  the scientific understanding required to
measure, model, maintain, and/or restore, at multiple scales, the integrity and
sustainability of ecosystems now and in the future. The research strategy is
organized around fourfundamental research areas: (1) ecosystem monitoring,
(2) ecological processes and modeling, (3) ecological riskassessment, and (4)
ecological risk management and restoration.
 Research Plan for Arsenic in Drinking Water
 (EPA1998b)
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 regulatory requirements.
 Strategic Research Plan for Endocrine
 Disrupters (EPA 1998c)
The plan addresses research needs in the areas of biological effects (both for
human health and wildlife) and exposure assessment. Importantly, it also
contains a "linkage" section  that strives to integrate effects and exposure
research to provide a more complete analysis of the risks than has generally
been done in the past for endocrine disrupters.
 Pollution Prevention Research Strategy
 (EPA1998d)
The four long-term goals offered in the research strategy address: (1) tools
and  methodologies for making  improved  decisions related to pollution
prevention, (2) technologies and approaches that are preventive or far less
polluting than those currently in use, (3) verification of the performance of
pollution prevention alternatives, and (4) economic, social,  and  behavioral
issues related to pollution prevention.
 Waste Research Strategy (EPA1999a)
The goal of the EPA Office of Research and Development Waste Research
Strategy is to set forth an effective research program to understand and
reduce human and  ecological exposure to toxic materials released during
waste management, and to assess and remediate contamination that has
occurred because of improper waste management. Focus is directed toward
research on:  (l)groundwater at contaminated sites, (2)soilsandthevadose
zone at contaminated  sites, (3) active waste management facilities, and (4)
emissions from waste combustion facilities.  Associated technical support
activities to assist EPA Program Offices, Regions and other stakeholders are
also described.
 Action Plan for Beaches and Recreational
 Waters (1999b)
The Beach Action Plan identifies  EPA's multiyear strategy for monitoring
recreational water quality and communicating public health risks associated
with potentially pathogen-contaminated recreational rivers, lakes, and ocean
beaches.
        1This list contains final and draft ORD research plans and strategies as of July 31,2000. Final reports and external review
drafts can be found on http://www.epa.gov/ORDAA/ebPubs/final/
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Name
ORD Strategy for Research on
Environmental Risks to Children (EPA
2000).
Description
The strategy describes the research directions that EPA's Office of Research
and Development (ORD) will follow in its Children's Health program. The
primary objective of the Children's's Health program is to conduct research to
reduce uncertainties in EPA risk assessments for children, leading to effective
measures to prevent/reduce risk.
Draft Plans and Strategies
Mercury Research Strategy (EPA 1999c).
Airborne Participate Matter Research
Strategy (EPA 1999d)
The strategy presents the goals and scientific questions and associated
research areas and shapes the agenda for EPA's mercury research program.
The strategy describes ORD's PM research in the areas of health, exposure,
risk assessment, and risk management. The scope of the strategy
corresponds to the dual responsibility of EPA to review the adequacy of the
National Ambient Air Quality Standards (NAAQS) every 5 years and to achieve
attainment of the NAAQS to protect public health and welfare. The EPA health
effects and exposure research supports NAAQS review by providing scientific
methods, models, and data needed for assessment of health risks from PM
exposures. The EPA research to support implementation of PM standards is
focused similarly on improving the methods, models, and data for attainment
decisions.
Under Development
Human Health Risk Assessment Research Strategy
Global Change Research Strategy
Air Toxics Research Strategy
Environmental Monitoring and Assessment Program (EMAP) Research Strategy
Drinking Water Contaminants Candidate List (CCL) Research Plan
Asthma Research Strategy
Source:  This list contains final and draft ORD research plans and strategies as of July 31, 2000. Final reports and external review
drafts can be found on http://www.epa.gov/ORDAA/ebPubs/final/.

EPA. (U.S.  Environmental Protection Agency).  2000.   ORD Strategy for Research  on Environmental Risks to Children.
    Washington,  DC: Office of Research and Development. EPA/600/R-00/068.
EPA. 1999a. Waste Research Strategy. Washington, DC: Office of Research and Development.  EPA/600/R-98/154.
EPA. 1999b. EPA Action Plan for Beaches and Recreational Waters. Washington, DC:  Office of Research and Development,
    Office of Water.  EPA/600/R-78/079.
EPA. 1999c. Mercury Research Strategy. Workshop review draft. Washington, DC: Office of Research and Development.
EPA. 1999d. Airborne Particulate Matter Research Strategy. External draft. Research Triangle Park, NC: Office of Research
    and Development.  EPA/600/R-99/045.
EPA. 1998a. Ecological Research Strategy. Washington, DC: Office of Research and Development.  EPA/600/R/98-066.
EPA. 1998b. Research Plan for Arsenic in Drinking Water. Washington, DC: Office of Research and Development. EPA/600/R-
    98/042.
EPA.  1998c.  Strategic Research Plan for Endocrine Disrupters.  Washington,  DC: Office of Research and Development.
    EPA/600/R-98-087.
EPA. 1998d. Pollution Prevention Research Strategy.  Washington, DC: Office of Research and Development.
EPA. 1997a. Final Research Plan for Microbial Pathogens and Disinfection By-products in Drinking Water.  Washington, DC:
        Office  of Research and Development.
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              APPENDIX C.   RESEARCH RECOMMENDATIONS

NRG.(National Research Council).  1993. Pesticides in the Diets of Infants and Children. Washington. DC: National
Academy Press.

Differences Between Children and Adults
#       What are the structural and functional differences between neonates, children of various ages, and  adults that can
        potentially influence toxicity of pollutants?
#       What are the specific periods  of development when toxicity can permanently alter the function of a system at maturity?
        What systems continue to mature after birth?
#       What are the developmental stages of individual biochemical systems, tissues, or organs that enhance, diminish, or alter
        the infant's or child's sensitivity to the toxic effects of specific pesticides?

Selection of Appropriate Animal Models
#       Compare age-related physiological changes in humans and immature animals of various ages.
#       Develop appropriate organ-specific functional measures of adverse effect that take into account variable rates of organ
        development within and between species.

Toxicity
#       Are mechanisms of action comparable across species and between neonates, infants, children, and adults?
#       What are the differences in magnitude of response between juvenile test animals and infants/children?
#       How are neurodevelopmental effects and effects on the immune system in infants and young children measured and
        assessed?
#       What are the differences in metabolism and deposition in the infant, adolescent, and young adult?
#       How can physiologic pharmacokinetic modeling be used to forecast how information about metabolism in infant animals
        could be extrapolated to infant humans?
#       What is the comparison of toxicity in several representative classes of chemicals between adult and immature animals?

Estimating Exposures
#       What are the diets and drinking  water consumption of infants and children and how do they differ from adult diets?
#       What are the foods most commonly consumed by young children?
#       What data are available to develop probability distributions of exposure factors for children?
#       What are the contributions of exposures from sources other than food and drinking water?

Estimating Risks
#       Consider physiological and biological characteristics of infants and children that influence metabolism and disposition and
        develop PBPK models for infants and children.
#       Develop biologically based models of carcinogenesis for  infants and children.
#       Use benchmark dose for risk assessments for infants and children.
#       Use risk distributions rather than point estimates..


ILSI.  (International Life Sciences Institute). 1996.  Research Needs on Acie-related Differences in  Susceptibility to
Chemical Toxicants. Report of an ILSI Risk Science Institute Working Group. Washington. DC:  ILSI Risk Science
Institute.

        This workshop summarized current knowledge and provided lists of research needs in three areas: cancer, immune
system effects, and neurotoxicity.

Cancer
#       Make better use of existing information on physiological differences between children and adults and information derived
        from common animal models.
#       Develop appropriate dose metrics for infants and children for given routes and exposure modes. Use PBPK models in
        understanding age-related effects on absorption and distribution in experimental animals and humans.
#       Develop a comprehensive profile of age-dependent changes in key metabolic enzyme systems of importance in activation
        and deactivation of carcinogens. Perinatal period and time around puberty and adolescence should be high priority.
#       Perform systematic collection data on changes in cell proliferation rates in various tissues as a function of age in humans
        and relevant experimental animals.
#       Study age-dependent changes in DMA repair capacity in various tissues from birth through adolescence and for rodent

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        models in  normal populations and populations with heritable DMA defects.
#       Find biomarkers of carcinogenicity in children as compared with adults.
#       Conduct more studies of age-dependent effects of nongenotoxic compounds focusing on mechanisms.
#       Focus in future epidemiology studies on  methodologies designed to increase the likelihood of detecting susceptibility
        differences between children and adults. Develop a better understanding of critical time periods for exposure, either for
        certain tumor types or for certain classes of carcinogens.
#       Examine well-characterized exposures associated with carcinogenesis for age-related differences in the effect. Consider
        feasibility of retrospective studies with data for chemotherapy regimes and appearance of second cancers.

Immune System Effects
#       Do chemicals that are known to be immune suppressive or elicit hypersensitivity in adult rodents have similar effects in
        immature animals? (Highest priority).
#       Assess the responses of children to known protein and/or chemical allergens.
#       Development of clinical laboratory procedures with sufficient sensitivity to detect changes in measures of immune status.
#       Wherever possible, identify and characterize genes important in immune ontogeny and immune response.

Neurotoxicity
#       Seek consistency with other reproductive /developmental study protocols.
#       Streamline current tests including neurotoxicity guidelines.
#       Seek understanding of basic developmental neurobiology and its application in risk assessment.
#       Develop ability to connect neurobiological function with neurobiological substrates is incomplete:  Major categories of
        effects include deficits in cognitive, sensory, autonomic, affective, and motor functions.
#       Understand the relationship of the neuroendocrine system to the developing nervous system.


CEHN. (Children's Environmental Health Network). 1997. 1st National Research Conference on Children's Environmental
Health: Research, Practice, Prevention, Policy. Conference Report. Washington, DC: Children's Environmental Health
Network.
        This 3-day  conference  was organized  into six sessions:  asthma  and respiratory effects, childhood cancer,
neurodevelopmental effects, endocrine  disrupter effects, exposure,  and  risk prevention and reduction through community
involvement and education. The recommendations listed below are recommendations of the plenary group. Individual speakers
also made research recommendations, which are summarized in the conference report. Most of the individual recommendations
have been captured in the general recommendations.

General Recommendations
#       Study developmental processes and identify critical periods of vulnerability.
#       Study environmental exposures in early life and their relationship to the riskof adult disease and transgenerational effects.
#       Debate ethical and social issues associated with use of genetic and biomarker information.
#       Include communities in research agreements that incorporate respect, equity, and empowerment.

Asthma and Respiratory Disease
#       Conduct epidemiologic/biologic studies that address the role of environmental exposure to understand why asthma is
        increasing and why incidence is higher in urban minority children.
#       Develop methods to measure air and tissue levels of molds  and mycotoxins and investigate their role in pulmonary
        hemorrhage  among infants (recommendation of Ruth Etzel in paper on acute pulmonary hemorrhage).

Endocrine Disruptors
#       Continued focus on the relationship  between  endocrine disrupters  and cancer,  reproductive and developmental
        alterations, and neurological and immunological effects.
#       Improved understanding of basic endocrine function throughout all stages of human development.
#       Increase studies of exposure to  environmental hormones and their effects at all stages of human development.

Childhood Cancer
#       Large biomarker-based  case-control studies to evaluate suspect exposures.
#       Prospective longitudinal studies of children exposed to known or suspected carcinogens, including exposures in utero.
#       Study cancer susceptibility in children and the interaction between genetic alterations and environmental exposures in
        cancer etiology.

Neurodevelopmental Effects
#       Mechanisms of action of toxicants.

                                                      C-2

-------
#       Health effects of mixtures of neurotoxins, especially pesticides.
#       Multigenerational studies of neurotoxicity.
#       Techniques to study gene-environment interactions of neurotoxicity.
#       Continue studies of neurotoxicity of mercury and PCBs using sensitive outcome measures.


EPA.   (U.S. Environmental Protection Agency).  1998a.  U.S. EPA Conference on Preventable Causes of Cancer in
Children.  Conference report. Washington, DC: Office of Children's Health Protection.
        Four work groups, each chaired by two experts in the work group topic, developed research recommendations.  The
research recommendations appearing below are from the reports of the four work groups as published in EPA (1998c).

Epidemiology and Prevention
#       Establish a National  Cancer Registry for Childhood Cancers,  including information on exposures, especially pesticide
        exposure and dietary intake.
#       Expand  large studies of childhood disease outcomes currently underway.
#       Develop improved techniques for analyzing clusters by redefining cancer occurring before age 5 as a birth defect.
#       Examine role of infection/viruses in childhood cancer.
#       Involve communities, families, and other stakeholders in designing and conducting studies.
#       Deliver results of research to physicians, nurses, teachers, communities.

Susceptibility Factors
#       Investigate differences in carcinogenic metabolism between children and adults, and differences among individuals that
        may predispose some to cancer.
#       Identify  differences  in DMA  repair that are age-related or  genetic.   Differential organ development and cancer
        susceptibility. Why are only certain organs the sites of most childhood cancers? Why are there windows of opportunity
        for tumors to form in children?
#       Determine relationship between diet/obesity in children and cancer development.
#       Determine whether animal models appropriately reflect exposures  and disease.
#       Increased supportto clinical studies supporting prospective registries collecting social, dietary, and exposure factors, and
        stratification  of disease subtypes by exposure and molecular marker studies.

Molecular Markers
#       Examine more closely the role of environmental exposures that occur preconception,  transplacentally, and in the early
        years.
#       Develop sensitive biomarkers and validate in the laboratory.
#       Understand mechanisms reflected by biomarkers, their relationship to external exposure, and marker differences between
        children and  adults.
#       Develop noninvasive, painless methods for collecting specimens from children.
#       Include application of biomarkers in  hypothesis-testing studies in conjunction with  exposure assessment, personal
        biomonitoring, and validated questionnaires.
#       Use biomarkers to identify exposed and sensitive populations.
#       Validate biomarkers  for risk assessment.

Quantitative Measures of Exposure
#       More closely link exposure  data and surrogates/endpoints.
#       Determine critical metrics researchers should be using (dose, range of dose).
#       Study children's activities by age,  biology, or function.
#       Existing data needs to be used as baseline. IRIS-type National Tumor Registry needs to be created as a clearinghouse
        for cancer information.
#       Conduct exposure studies specifically for children.


NRDC.  (Natural Resources  Defense Council).  1997.  Our Children at Risk: the 5 Worst Environmental Threats to Their
Health.  San Francisco. CA: Natural Resources Defense Council.
        This document is directed toward legislators and regulators and toward  parents, school systems, medical professionals,
and communities. Most recommendations are for actions that can be taken now to reduce risks.   However, it provides a few
general  research recommendations, which are as follows:
#       Food consumption surveys  should include adequate sample sizes of children in the following groups: under 12 months,
        13-24 months, 25-36 months, 37-48 months, 49-60  months, 5-10 years, and 11-18 years.
#       Measure levels of chemicals  in food,  air, water, homes, and schools.  Identify exposure routes and  develop effective

                                                       C-3

-------
        interventions.
#       Monitor toxic substances in humans (blood and urine). Develop less costly methods of biomonitoring.
#       Identify which toxins have a greater impact on children than on adults.
#       Identify critical windows of vulnerability and study developmental processes during periods of vulnerability.
#       Improve existing toxicity testing protocols.


EPA. 1998b. EPA Workshop on the Assessment of Health Effects of Pesticide Exposure in Young Children. Draft report.
Research Triangle Park. NC:  National Health and Environmental Exposure Laboratory.
         Participants were assigned to workgroups corresponding to the disciplines considered relevant for pesticide research
in children: neurobehavioral disorders, developmental disorders, pulmonary and immune system disorders, and childhood cancer.
Participants were asked to recommend appropriate endpoints and study designs for human studies.

Neurobehavioral Work Group
Endpoints and Tests:
#       Cognitive skills - Bayley Scales of Infant Development Mental Development Index.
#       Motor skills - Bayley Scales of Infant Development Psychomotor Development Index.
#       For older children, a wide range of intelligence, memory, learning, and motor skill tests are available.
#       Sensory function tests - visual acuity, visual contrast sensitivity, tactile sensitivity.

Proposed Studies:
#       Retrospective Acute, High-Exposure Study: Conduct a retrospective cohort study of a fairly small group of children with
        clearly defined, high-level exposure to determine unequivocally whether or not pesticide exposure at acutely toxic levels
        produces neurotoxic effects in young children. The study would address children who had been poisoned by pesticides.
#       Cross-Sectional Chronic, Low-Exposure Study: If the  first  study indicates that acute high exposure causes neurotoxic
        effects, further study is warranted.  Three chronically-exposed groups - high, medium, and low exposure - would be
        selected based on questionnaire responses with a total of 100 children, age  1.5 to 2.5 years. Purpose is to test whether
        children exposed at lestthan acute levels have measurable adverse neurologic effects on psychometric neurologic testing.
#       Longitudinal cohort study: If chronic low-level exposure is shown to affect neurobehavioral function, administer Bayley
        test and collect urine samples every 3 months starting at 1.5 to 2.5 years.


Developmental Work Group
        This workgroup decided that in the absence of a clear understanding of the likely pathway and  mechanisms by which
pesticide exposure might influence child development, it would recommend health  endpoints for study. Nine endpoints were
identified.

Endpoints:
#       Birth defects, stillborns, spontaneous abortions (priority ranking 1).
#       Mental, motor, adaptation (priority ranking 1).
#       Acute poisoning developmental sequelae (priority ranking  1.5).
#       Growth (priority ranking 1.5).
#       Language (priority ranking 1.5).
#       Birth weight, gestational age (priority ranking 2).
#       Social development (priority rank 4).
#       Infant mortality, neonatal and postnatal (priority ranking 5).
#       Puberty, age at menarche, secondary sex characteristics (priority ranking 5).
#       Hearing (no  ranking).

Proposed Studies:
#       Prospective  prenatal cohort study.
#       Prospective  case-control study of symptomatic children.
#       Correlation between maternal  and infant biologic  samples.
#       Geographic  Information System (CIS) studies of infant health status.
#

Immunology and Pulmonary Work Group
Endpoints:
#       Upper respiratory infections.
#       Acute bronchitis.

                                                       C-4

-------
#       Asthma (reactive airway disease).
#       Interstitial lung disease.
#       Allergic diseases (allergic rhinitis, eczema, allergic bronchopulmonary aspergillosis).
#       Immunodeficiency.
#       Contact dermatitis.
#       Autoimmune disease.
#       Inflammatory bowel disease (added because of hypothesis of relation to disorder of immunological system; no known
        association with pesticide exposure).
#       Infectious disease (associated with immune disorders).
#       Adverse reproductive endpoints (Hypothesis that immunopathology in adult female may contribute to adverse reproductive
        outcomes).

Proposed Studies:
#       Pilot study of immunologic status and development of infants exposed to pesticides.
#       Longitudinal study of a birth cohort.
#       Survey of border families.
#       Case-control study of children exposed to pesticides.
#       Case-control study of children with hyper reactive airways.

Cancer
        This work group focused  on childhood cancer and considered several possible types of studies: (1) using existing
databases,  (2) performing an ecological study that would geographically compare pesticide usage and cancer incidence, (3)
performing a case-control study that would identify cases and then determine if the cancers were associated with pesticide cancer,
(4) conducting a prospective cohort study that might link exposure to a biomarker and then to cancer, (5) conducting a study that
could link cancer-relevant biomarkers with pesticide exposure.

        The work group's conclusion was as follows:
        ".... In all cases, the questions associated with the exposure assessment compromised the conclusions that might
        be done from the study....The workgroup...concluded and strongly recommended that the issues associated with
        proper exposure information be solved prior to conducting an analysis of the health outcome....
        "....the group strongly  recommended that resources be focused first on improving the  approaches  to  exposure
        assessment.  Also, other efforts are already underway investigating childhood cancers, developing databases, and
        evaluating approaches to using biological markers....Once the exposure assessment can be more adequately conducted,
        and the information about the cancer studies is  available, it should be possible to revisit and make recommendations
        concerning studies to investigate the association of childhood cancers and exposures to pesticides."
                                                       C-5

-------
         APPENDIX D.   FEDERAL RESEARCH ON CHILDREN'S
                             ENVIRONMENTAL HEALTH
             Agency
  Examples of Collaborations with
 EPA on Children's Health Research
 Other Major Programs of Interest
Department of Health and  Human
Services (DHHS)  National Institutes
of Health - conducts research in its own
laboratories; supports the research of
scientists  in  universities,   medical
schools,  hospitals,  and  research
institutions  throughout the U.S.  and
abroad; helps inthe training of research
investigators;    and   fosters
communication of medical information.
All Institutes of Health that are members
of the U.S. Task Force on Children's
Environmental Health and  Safety are
participating in an investigation  of the
feasibility of a  federally  sponsored
longitudinal birth cohort study.
See the components of DHHS.
DHHS/NIH, National Cancer Institute -
sponsors  and conducts research on
prevention, detection, and treatment of
cancer, including research on biological,
genetic, and environmental causes of
cancer and clinical trials of treatments.
Agricultural Health Study - The goal is to
establish a large prospective cohort of
agricultural workers, their spouses, and
dependents, that can be followed for 10
or more years, to evaluate the role of
agricultural and related exposures in the
development of  cancer,  neurologic
diseases,     reproductive   and
developmental  outcomes,  and  other
chronic diseases.
Clinical trials of treatment methods for
childhood cancer (Children's Cancer
Group,   Pediatric  Oncology Group,
National Wilms' Tumor Study Group,
and  Intergroup  Rhabdomyosarcoma
Study Group)
DHHS/NIH,   National  Institute  of
Allergy and Infectious Diseases -
provides the major support for scientists
conducting  research  aimed  at
developing better ways to  diagnose,
treat, and prevent the many infectious,
immunologic, and allergicdiseasesthat
afflict people worldwide.
Inner-City Asthma Study - This study
examines respiratory  symptoms and
pulmonary function levels in children with
moderate to  severe asthma in  seven
communities.    EPA  is   sponsoring
monitoring   of  indoor  and  outdoor
particulate matter and co-pollutants.

Genetic Susceptibility and  Variability of
Human Malformations (STAR program
with NICHD, NIDCR, and NIEHS) - This
study examines relationships between
genetic  polymorphisms,   gene-
environment  interactions,  and  birth
defects.
DHHS/NIH, National Institute of Child
Health and Human  Development -
conducts  and  supports  laboratory,
clinical, and epidemiological research
on  the  reproductive, neurobiologic,
developmental,   and  behavioral
processes that determine and maintain
the health of children, adults, families,
and populations.
Genetic Susceptibility and Variability of
Human  Malformations  (ORD  STAR
program  with  NICHD,  NIDCR, and
NIEHS).
DHHS/NIH,   National  Institute  of
Dental and  Craniofacial Research -
improves oral, dental and craniofacial
health  though science and  science
transfer.
Genetic Susceptibility and Variability of
Human  Malformations  (ORD  STAR
program  with  NICHD,  NIDCR, and
NIEHS)
                                                 D-1

-------
        APPENDIX D.  FEDERAL RESEARCH  ON CHILDREN'S
                   ENVIRONMENTAL HEALTH (continued)
            Agency
  Examples of Collaborations with
 EPA on Children's Health Research
 Other Major Programs of Interest
DHHS/NIH   National  Institute  of
Environmental  Health  Sciences -
investigates the role and  interaction of
environmental  factors,  individual
susceptibility, and age in human illness
and   dysfunction   through
multidisciplinary biomedical  research
programs, prevention and intervention
efforts, and communication strategies.
Genetic Susceptibility and Variability of   Environmental   Genome  Project  -
Human  Malformations  (ORD  STAR   identification and establishment of a
program with  NICHD,  NIDCR, and   database  of   polymorphisms  of
NIEHS).                            environmental  disease susceptibility
                                  genes.
Cosponsor of 8 Centers for Children's
Environmental  Health  and  Disease
Prevention  Research.   (ORD  STAR
program).

Agricultural Health Study (with NCI and
NIEHS).
DHHS, Centers for Disease Control
and Prevention  - conducts medical
surveillance,  reports  public  health
statistics, seeks causes for public health
emergencies, and conducts research.
Study exposure to  pesticides and
potential adverse  effects in children
living along the U.S.-Mexico border.

NHANESIV study of children's exposure
to pesticides and adolescents' exposure
to persistent, bioaccumulative toxins.
Surveillance of childhood asthma and
birth defects.

NHANES  IV - collection  of data on
health  and  nutrition  in  the   U.S.
population, including several thousand
children and adolescents.

NHANES  study of lead exposures  in
children (with HUD).
DHHS, Agency for Toxic Substances
and Disease Registry - advises EPA
and others on public health impacts of
hazardous  waste  sites,  determines
levels of public health hazard, conducts
health studies in communities near
sites, and supports research.
ATSDR conducts  evaluations of the
health of children and  adults  near
Superfund sites and other hazardous
waste  sites.     ATSDR   makes
recommendations  to  EPA on  public
health issues.
Department of Housing and Urban
Development - protects children in
the home through regulations dealing
with hazards such as lead-based paint
and supports research on exposures
and remedial actions.
                                  NHANES study of lead exposures in
                                  children (with CDC).
                                                D-2

-------






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APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS






Research areas
(priority)
4.3.1.1 Biology of
Toxicant-Induced
Tissue and Organ
Damage in the
Developing Organism
(High)



















Importance of the
research to reducing
uncertainty in risk
assessment and
protecting children
from environmental
health threats
High
A greater
understanding of the
pharmacokinetics and
mode(s) of action
underlying agent-
induced developmental
abnormalities will
facilitate the
interpretation and
extrapolation of animal
and human data for risk
assessment. This
research will lead to
more refined risk
assessment
approaches by linkage
of environmental
exposure with
biologically effective
dose at the cellular and
molecular level.





Feasibility of
conducting the
research in the ORD
intramural or STAR
programs
High
This research area is
very feasible. Even
though ORD's
intramural program has
the expertise to perform
the pharmacokinetics
and mode(s)-of-action
research and apply it to
children's risk
assessment, these
activities need to be
expanded. Also, the
success of this
research area relies on
linkage to the
application of the data
to model dose-
response for risk
assessment (4.3.2.1)
and the validation and
application of state-of-
the-science methods
(4.3.3.1).




The capacities and
capabilities of ORD's
laboratories and
centers
Medium
Although ORD has
funded intramural
developmental
toxicology research
over the years, the
research in Section
4.3.1.1 goes well
beyond what is
currently being done.
As such, it will require
not only an increase in
resources but also a
long-term commitment
to this research area.
The STAR program has
supported extramural
research in this area
and should continue to
do so.






Opportunities to
develop and maintain
scientific expertise in
ORD to enable use of
research results in
EPA risk assessments
High
ORD has excellent
experimental research
capabilities in this area;
however, consideration
should be given to
bolstering the expertise
of existing principal
investigators in cutting-
edge cellular and
molecular biology and
recruiting investigators
with these skills. Also,
ORD must maintain its
scientific expertise for
applying the data to risk
assessment.









Opportunities for
collaboration with
other Federal
agencies and with
other ORD research
programs
High
There are several
ongoing collaborations
with other Federal
organizations (e.g.,
NIEHS, NICHD, NIAID,
CDC) and with other
ORD programs, which
undoubtedly will be
expanded through
support of this research
area.












Maintenance of a
balance between
short-term research
that will reduce major
uncertainties in risk
assessment and long-
term, more
speculative research
High
Initially, information will
be gained on
pharmacokinetics with
linkage to the
underlying effects at the
cellular and molecular
levels for agent-induced
developmental
dysfunction. Overtime,
the data will be applied
in risk assessment.
This area will require a
long-term commitment
in resources (i.e.,
funding, equipment,
personnel, etc.) in both
the experimental and
risk assessment arenas
for it to be successful.





-------
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS (continued)






Research areas
(priority)
4.3.1.2 Relationship
Between Exposure to
Environmental
Agents and Adverse
Health Effects in
Human Populations
(High)










Importance of the
research to reducing
uncertainty in risk
assessment and
protecting children
from environmental
health threats
High
Human studies are
crucial to understanding
whether children are
more susceptible than
adults, to identify and
confirm adverse effects
in human, to improve
extrapolation between
animals, and to develop
data for use in risk
assessments.







Feasibility of
conducting the
research in the ORD
intramural or STAR
programs
Medium to High
Feasibility depends on
the endpoints being
studied and the
availability of exposure
data. Feasibility
decreases for less
common endpoints
because studies must
be very large to
observe relationships
and the large number of
confounding factors.







The capacities and
capabilities of ORD's
laboratories and
centers
Medium to High
ORD has expertise in
clinical and
epidemiology studies,
having sponsored and
conducted many
studies both in-house
and through the STAR
program. ORD also
has expertise in
exposure research.
Size of studies may be
limited by current
amount of extramural
resources available for
this program.


Opportunities to
develop and maintain
scientific expertise in
ORD to enable use of
research results in
EPA risk assessments
High
ORD is moving toward
the integration of
exposure and
epidemiologic research
in studies such as
NAFTA and the
Longitudinal Cohort
Study. This direction
will improve the utility of
human study data for
risk assessment
through better exposure
data.




Opportunities for
collaboration with
other Federal
agencies and with
other ORD research
programs
High
Through the U.S. Task
Force, ORD is currently
participating in a
feasibility study for a
longitudinal birth cohort
as well as participating
in collaborations
through NHANES and
the Inner-City Allergy
Study. Many
opportunities to join
other studies are likely
to arise.


Maintenance of a
balance between
short-term research
that will reduce major
uncertainties in risk
assessment and long-
term, more
speculative research
High
Studies can be
designed with both
short-term and long-
term goals. The same
study could both gather
information on issues of
immediate concern to
Program Offices, test
more speculative
hypotheses, and
generate hypotheses
for future study.




-------
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS (continued)






Research areas
(priority)
4.3.1.3 Multimedia,
Multipathway
Exposures in Human
Populations
(High)

















Importance of the
research to reducing
uncertainty in risk
assessment and
protecting children
from environmental
health threats
High
Multimedia,
multipathway exposure
studies will reduce
uncertainty by: (1)
delineating sources and
pathways of exposure;
(2) replacing default
assumptions with actual
measured data; (3)
determining which age
groups are more highly
exposed to certain
environmental agents;
and, (4) obtaining
baseline data on
children's exposures to
characterize highly
exposed subgroups and
evaluate status and
trends.



Feasibility of
conducting the
research in the ORD
intramural or STAR
programs
High
ORD has the capability
to conduct such
studies as intramural
and extramural
programs, as evidenced
by experience with
TEAM, NHEXAS and
NAFTA studies and
STAR grants.















The capacities and
capabilities of ORD's
laboratories and
centers
Medium to High
In the short term,
resources are sufficient
to support limited work
in this area, such as
analysis of data from
current studies, but not
sufficient to support a
new study in the
intramural program and
also conduct the other
high-priority research
described in this
strategy. Resources
are available in the
STAR program to
support field studies.






Opportunities to
develop and maintain
scientific expertise in
ORD to enable use of
research results in
EPA risk assessments
High
This research provides
opportunities to develop
and maintain scientific
expertise in designing,
implementing, and
analyzing multimedia,
multipathway human
exposure studies with
the purpose of reducing
uncertainty in risk
assessments.











Opportunities for
collaboration with
other Federal
agencies and with
other ORD research
programs
High
Opportunities for
partnerships are
extremely important
because resources are
limited. However, other
Federal agencies have
similar interests (NIH,
CDC, NIEHS, ATSDR,
etc.), making
partnerships feasible. In
addition, ORD can
leverage other ORD
research programs,
such as the FQPA
program and the
Human Health Risk
Assessment program.



Maintenance of a
balance between
short-term research
that will reduce major
uncertainties in risk
assessment and long-
term, more
speculative research
High
This research provides
opportunities to develop
and maintain scientific
expertise in designing,
implementing, and
analyzing multimedia,
multipathway human
exposure studies with
the purpose of reducing
uncertainty in risk
assessments.










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APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS (continued)






Research areas
(priority)
4.3.1.4 Analysis of
Factors Contributing
to Exposure
(High)






















Importance of the
research to reducing
uncertainty in risk
assessment and
protecting children
from environmental
health threats
High
Analysis of factors
contributing to exposure
will reduce uncertainty
in risk assessments by
replacing default
exposure factors with
actual measured
exposure variables and
factors including micro-
environmental and
macroenvironmental
activity patterns for
children (time spent in
various environments
and frequency of
occurrence), dermal
transfer rates,
inadvertent ingestion
(hand-to-mouth activity,
pica), inhalation rates
by age and activity
level, and ingestion
consumption levels by
age group.



Feasibility of
conducting the
research in the ORD
intramural or STAR
programs
Medium
It is feasible to conduct
some of these studies
under both the STAR
and intramural
programs. However,
innovative methods and
techniques may be
required to collect
certain data, e.g.,
dermal exposure and
nondietary ingestion.
Some of these studies
will need to be
conducted by ORD
intramural programs to
obtain data needed for
EPA risk assessments.











The capacities and
capabilities of ORD's
laboratories and
centers
High
Resources are
available to conduct
some of these studies
under the STAR
program, which can be
supplemented with
studies in other media-
specific ORD programs.
ORD is capable of
developing an in-house
program to develop
exposure factors and
variables, as evidenced
by the production of the
Exposure Factors
Handbook.










Opportunities to
develop and maintain
scientific expertise in
ORD to enable use of
research results in
EPA risk assessments
High
This research provides
opportunities to develop
and maintain scientific
expertise in developing
analysis of factors
contributing to exposure
with the purpose of
reducing uncertainty in
risk assessments.

















Opportunities for
collaboration with
other Federal
agencies and with
other ORD research
programs
High
Opportunities for
partnerships are
extremely important
because resources are
limited. However, other
Federal agencies have
similar interests (CDC,
NIEHS, ATSDR, etc.)
making partnerships
feasible. In addition,
ORD can leverage
other ORD research
programs, such as
FQPA to study
important exposure
variables in the OPP
Standard Operating
Procedures.






Maintenance of a
balance between
short-term research
that will reduce major
uncertainties in risk
assessment and long-
term, more
speculative research
High
This research area
maintains a balance
between short-term
research and long-term,
more speculative
research. Short-term
projects will emphasize
the analysis of extant
data including
environmental media
concentrations,
personal exposure
measurements,
questionnaires, and
biomarkers while long-
term projects include
development of future
studies, e.g.,
inadvertent ingestion of
soil, dermal contact
rates and transfers, etc.




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APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS (continued)






Research areas
(priority)
4.3.2.1 Methods and
Models for Using
Biological Data in
Risk Assessment
(High)




















Importance of the
research to reducing
uncertainty in risk
assessment and
protecting children
from environmental
health threats
High
Biologically based,
dose-response models
will lead to refined risk
assessment
approaches that no
longer rely solely on
whole-animal toxicity
testing, but incorporate
the growing knowledge
of molecular
mechanisms and their
involvement in a toxic
response. Based on
these models,
children's risk
assessment will be able
to better address such
issues as complex
mixtures, varying
exposure patterns, and
critical periods of
susceptibility.




Feasibility of
conducting the
research in the ORD
intramural or STAR
programs
High
The feasibility is very
high. EPA's intramural
research capability is
very strong in this area
and is recognized by
the larger research
community.
Extramurally, there are
a great many
laboratories already
working in this area. A
potential limitation of
the STAR program is
that the research
cannot be done in a
cooperative manner
with EPA investigators
and may lack the
necessary focus for
ultimate application in
risk assessment.






The capacities and
capabilities of ORD's
laboratories and
centers
High
This children's research
strategy is significant
step in defining a
program specifically
focused on children.
The research in 4.3.2.1
will require a long-term
commitment of
resources. ORD has
already made
commitments through
the general funding of
its laboratories and the
STAR program. A
commitment to this
specific program should
be made, and
opportunities to
leverage the resources
of similar programs in
other Federal agencies
and extramural groups
should be identified.


Opportunities to
develop and maintain
scientific expertise in
ORD to enable use of
research results in
EPA risk assessments
Medium
This is an area of major
concern. ORD has a
strong research
capability in this area,
but it must also
maintain the scientific
expertise to enable the
use of the data in risk
assessment. This will
require an experience
with traditional testing
and risk assessment,
coupled with an
understanding of
modeling and newer
approaches in
toxicology.








Opportunities for
collaboration with
other Federal
agencies and with
other ORD research
programs
High
In 2000, Federal public
health agencies
concerned with impacts
of environmental agents
(e.g., NIEHS, CDC) are
focusing on mechanism
of action research on
topics such as gene-
environment
interactions. There will
be many opportunities
for development and
use of models to
assess environmental
risks to children through
collaboration.







Maintenance of a
balance between
short-term research
that will reduce major
uncertainties in risk
assessment and long-
term, more
speculative research
High
ORD has already
begun moving its
research in this area
into risk assessment
(e.g., benchmark dose
modeling). Although
this research area will
take a long-term
commitment, there will
be short-term results
that will be applicable to
such issues as complex
mixtures, varying
exposure patterns, and
critical periods of
susceptibility, as well as
to EPA's interest in
harmonizing all
approaches in risk
assessment.




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APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS (continued)






Research areas
(priority)
4.3.2.2 Exposure
Modeling and Use of
Exposure Data in
Risk Assessment
(High)


















Importance of the
research to reducing
uncertainty in risk
assessment and
protecting children
from environmental
health threats
High
The development of
multimedia models and
use of exposure data
will improve the quality
of children's
assessments by
reducing the uncertainty
of the relationship
between environmental
measurements,
biomarker
measurements, human
activities and
toxicological
parameters. By
developing/evaluating
multimedia models with
actual exposure data
more realistic
predictions of exposure
and risk are possible.



Feasibility of
conducting the
research in the ORD
intramural or STAR
programs
High
The feasibility of
conducting these
studies is high. ORD
has the capability to
conduct such studies as
intramural and
extramural programs,
as evidenced by
experience with STAR
grants and the
intramural modeling
program.













The capacities and
capabilities of ORD's
laboratories and
centers
High
Resources are
available to fund
intramural and STAR
programs. ORD has
demonstrated in-house
expertise with university
partnerships and
modeling centers.















Opportunities to
develop and maintain
scientific expertise in
ORD to enable use of
research results in
EPA risk assessments
High
This research provides
opportunities to develop
and maintain scientific
expertise in
developing, evaluating,
and refining exposure
models, and the
analysis of exposure
data with the purpose of
reducing uncertainty in
risk assessments.












Opportunities for
collaboration with
other Federal
agencies and with
other ORD research
programs
High
Opportunities for
partnerships are
extremely important
since resources are
limited. Other
organizations have
similar interests (CMA,
ATSDR, ACPA, etc.),
making partnerships
feasible. In addition,
ORD can leverage
other ORD research
programs, such as
FQPA, to study
important exposure
scenarios such as the
OPP Standard
Operating Procedures.



Maintenance of a
balance between
short-term research
that will reduce major
uncertainties in risk
assessment and long-
term, more
speculative research
High
This research area
maintains a balance
between short-term
research and long-term,
more speculative
research. Short-term
projects will emphasize
the refinement of
current models
(SHEDS, OPP's
exposure scenarios,
etc.), whereas long-tern
projects include
development of future
models for multimedia
cumulative exposure.






-------
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS (continued)






Research areas
(priority)
4.3.3.1 In Vivo/In
Vitro Methods for
Hazard Identification
(High)


















Importance of the
research to reducing
uncertainty in risk
assessment and
protecting children
from environmental
health threats
High
Development,
validation, and
application of state-of-
the-science methods
are essential to carrying
out mode-of-action
research (§4.3.1.1) and
developing models and
risk assessment
methods incorporating
mode of action
(§4.3.2.1).











Feasibility of
conducting the
research in the ORD
intramural or STAR
programs
High
This research area is
very feasible. Even
though ORD's
intramural program has
the expertise to develop
methods for studying
mode of action, these
activities need to be
expanded as part of an
integrated program to
support research
described in §4.3.1.1.
Also, the success of
this research area relies
on linkage to the
application of the data
to model dose-
response for risk
assessment (§4.3.2.1).





The capacities and
capabilities of ORD's
laboratories and
centers
Medium
Although ORD has
funded intramural
developmental
toxicology research
over the years, the
research in §4.3.3.1.
goes well beyond what
is currently being done.
As such, it will require
not only an increase in
resources but also a
long-term commitment
to this research area.
The STAR program has
supported extramural
research in this area
and should continue to
do so.




Opportunities to
develop and maintain
scientific expertise in
ORD to enable use of
research results in
EPA risk assessments
High
ORD has excellent
experimental research
capabilities in this area;
however, consideration
should be given to
bolstering the expertise
of existing principal
investigators in cutting-
edge cellular and
molecular biology and
recruiting investigators
with these skills. Also,
ORD must maintain its
scientific expertise for
applying the data to risk
assessment.






Opportunities for
collaboration with
other Federal
agencies and with
other ORD research
programs
High
Most of the methods
development related to
genomics/ proteomics
is taking place at NIH.
It is expected that ORD
will collaborate with
these agencies in
applying these methods
to research questions
related to risk
assessment.
There are ongoing
collaborations in
methods development
and validation with
other organization (e.g.,
NIEHS, WHO, CRADAs
with industry), which
undoubtedly will
continue.
Maintenance of a
balance between
short-term research
that will reduce major
uncertainties in risk
assessment and long-
term, more
speculative research
High
In the short term,
application of existing
test methods and
developmental-specific
test methods will
provide important
information for
children's risk
assessment. But much
of this research will
involve a long-term
effort that will
fundamentally change
the risk assessment
paradigm.






-------
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS (continued)






Research areas
(priority)
4. 3. 3.2 Methods for
Measuring Exposures
and Effects in Infants
and Children and to
Aid in Extrapolations
between Animals and
Humans. (Medium)












4.3.4.1 Multimedia
Control Technologies
That Account for the
Susceptibilities of
Children
(Low)







Importance of the
research to reducing
uncertainty in risk
assessment and
protecting children
from environmental
health threats
Medium
Better methods of
sampling, analysis of
samples, and test
protocols for infants and
children supports better
data for risk
assessment. Methods
development is often
conducted in concert
with a field or laboratory
study. A separate
program in methods
development, although
valuable, is somewhat
less directly related to
answering questions
about risk than the
studies themselves.
Low
Control technologies
such as removing
microbes from water
and pollutants in indoor
air will reduce risks.
However, control
technologies do not
specifically address
children's risk and
therefore for this
program are rated low.



Feasibility of
conducting the
research in the ORD
intramural or STAR
programs
High
Programs in
development of test
protocols for both
animals and humans
and methods of
exposure sampling and
analysis are part of
ORD's core expertise.










High
Very feasible, and the
NRMRL has a strong
capability to develop
these technologies.











The capacities and
capabilities of ORD's
laboratories and
centers
Medium
ORD's laboratories and
the academic
community have the
capability and capacity
to support these
studies. The resources
to devote to a program
standing alone from a
particular study are
currently lacking.








Medium
ORD laboratories have
the capability and
capacity to perform this
research. Extramural
resources under the
Children's Health
program are not
currently available.





Opportunities to
develop and maintain
scientific expertise in
ORD to enable use of
research results in
EPA risk assessments
High
Methods development
will continue to be a key
component of ORD's
effects and exposure
program, through
ORD's core Human
Health Risk
Assessment program
and as part of specific
studies conducted
under the Children's
Health program.






Low
The results of control
technology research
are not directly
applicable to
assessment of
children's risks.







Opportunities for
collaboration with
other Federal
agencies and with
other ORD research
programs
High
ORD often works with
agencies and programs
such as CDC and NTP
in developing testing
protocols.













Low
Collaboration in this
area is not likely.









Maintenance of a
balance between
short-term research
that will reduce major
uncertainties in risk
assessment and long-
term, more
speculative research
Medium
Research in methods
development in ORD is
expected to be problem
driven and directed at
issues relevant to a
particular ongoing
study.











Medium
By design, risk
management research
is mostly long-range.









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APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS (continued)






Research areas
(priority)
4.3.4.2 Methods for
Reducing Exposure
Buildup of
Contaminants in
Indoor Environments
(High)










4.3.4.3
Communication of
Risks and
Development of Risk
Reduction
Techniques through
Community
Participation (High)




Importance of the
research to reducing
uncertainty in risk
assessment and
protecting children
from environmental
health threats
High
This research area
addresses remediation
and prevention of
exposure to children in
indoor environments. It
directed at the types of
issues important with
respect to the
pesticides 1 0X factor,
for example.





High
Effective
communication of risks
and risk intervention
methods is an important
way to reduce risks, as
well as becoming an
increasingly important
part of human studies
(§§4.3.1.2,4.3.1.3).




Feasibility of
conducting the
research in the ORD
intramural or STAR
programs
High
Very feasible, and the
NRMRL has a strong
capability to develop
these technologies .











Medium
ORD has little expertise
in conducting research
in risk communication.
However, ORD does
conduct many studies
in communities. The
STAR program has
supported risk
communication
research.




The capacities and
capabilities of ORD's
laboratories and
centers
High
The NRMRL has both a
capability and capacity
to conduct this
research.











Medium
Capabilities for
research reside mainly
in the STAR program.
The Intramural program
applies communication
approaches but has no
current capability to
conduct such research.




Opportunities to
develop and maintain
scientific expertise in
ORD to enable use of
research results in
EPA risk assessments
Medium
An important element of
the EPA risk
assessment process is
the evaluation of
competing risk
management options
and the analysis of the
efficacy of control and
cleanup methods.
Supporting this
research will help ORD
to maintain the scientific
expertise to perform a
risk-based evaluation of
management options.
High
ORD should develop an
expertise for risk
communication and
intervention if needed,
as this is an important
component of
community-based
research studies.




Opportunities for
collaboration with
other Federal
agencies and with
other ORD research
programs
High
Opportunities exist to
collaborate with other
ORD research program
such as the exposure
and the risk
assessment program in
evaluating the efficacy
of this research in
reducing risk.
Collaboration with State
and local governments
is also likely.



High
Opportunities exist for
cross-laboratory/center
collaboration as well as
collaboration with State
and local government
agencies and Federal
agencies such as
ATSDR.


Maintenance of a
balance between
short-term research
that will reduce major
uncertainties in risk
assessment and long-
term, more
speculative research
High
This research area will
have an impact in the
short term by providing
cleanup methods for
particular chemicals,
such as pesticides. In
the long term, it will
lead to more general
technologies.






Low
This is a very applied
area of research that,
while key to a
Children's Health
program, is not likely to
involve any long-term,
speculative research.




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APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS (continued)
Research areas
(priority)
4.4.5.1 Variability in
Susceptibility and
Exposure in Children
(Medium)
Importance of the
research to reducing
uncertainty in risk
assessment and
protecting children
from environmental
health threats
Medium
Some of this research
is integral to studying
mechanisms of action
and multipathway
exposure. Other
research related
specifically to
differences among
children in the same
age group is less
important at this time
than differences
between age groups.
Feasibility of
conducting the
research in the ORD
intramural or STAR
programs
Medium
This is one of the
strategic directions of
the ORD Human Health
Risk Assessment
program.
The capacities and
capabilities of ORD's
laboratories and
centers
Medium to Low
There are efforts
underway in ORD that
address variability in
susceptibility and
exposure issues;
however, this effort is
minimal.
Opportunities to
develop and maintain
scientific expertise in
ORD to enable use of
research results in
EPA risk assessments
Medium
This research area may
serve as a catalyst to
increase interest in
pursuing research that
addresses variability in
susceptibility and
exposure. Expertise for
this research area will
be developed and
maintained through
research under
§§4.3.1.1,4.3.2.1, and
4.3.3.1.
Opportunities for
collaboration with
other Federal
agencies and with
other ORD research
programs
Medium to High
Opportunities are high
in mode-of-action
research/genetic
polymorphisms, which
will be conducted under
research programs
described in §§4.3.1.1,
4.3.2.1, and 4.3.3.1.
Other opportunities for
collaboration in areas
such as impact of
preexisting disease, life
styles factors, etc., exist
to varying degrees.
Maintenance of a
balance between
short-term research
that will reduce major
uncertainties in risk
assessment and long-
term, more
speculative research
Medium
This is an area that
should be largely
deferred until more
basic questions on
causes of qualitative
and quantitative
differences between
age groups are
answered.

-------
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AREAS (continued)






Research areas
(priority)
4.4.5.2 Cumulative
Risks to Children
(Medium)

















Importance of the
research to reducing
uncertainty in risk
assessment and
protecting children
from environmental
health threats
Medium
Research to develop
information on
mechanisms of action
and methods to
investigate age-related
differences is needed to
form a basis for
research into
cumulative risk.












Feasibility of
conducting the
research in the ORD
intramural or STAR
programs
Medium to Low
Methods and data for
conducting cumulative
risk assessments for
both children and adults
are currently lacking.
ORD is developing
guidelines for
cumulative risk
assessment that will
provide research
recommendations. As
more is learned about
children's risk and work
proceeds under the
ORD HHRA Research
program, feasibility of
this research will
increase.




The capacities and
capabilities of ORD's
laboratories and
centers
Medium
Some research is being
conducted under the
STAR program.
Intramural research
capabilities should
increase as cumulative
risk program grows
under the human health
risk assessment
research program.










Opportunities to
develop and maintain
scientific expertise in
ORD to enable use of
research results in
EPA risk assessments
Medium
Expertise for this
research area will be
developed and
maintained through
research under
§§4.3.1.1,4.3.2.1, and
4.3.3.1. Research in
this area is a next step
after basic questions
are answered.










Opportunities for
collaboration with
other Federal
agencies and with
other ORD research
programs
Medium
Collaborations exist in
the area of exposure
measurement with CDC
(e.g., measurement of
multiple chemicals in
biological samples).












Maintenance of a
balance between
short-term research
that will reduce major
uncertainties in risk
assessment and long-
term, more
speculative research
Medium
Short-term research
opportunities are in the
area of exposure,
mainly analysis of data
from field studies where
multiple chemicals have
been analyzed in many
media. Most of the
program is long-term
and should be deferred
until more basic
questions on methods
and impacts of multiple
chemicals on health
outcomes have been
answered.



-------