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
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
ii

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.
iii

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?
iv

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
v

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
vi

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, Procter & 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).
vii

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
viii

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
ix

ACRONYMS

AHS Agricultural Health Study

ATSDR Agency for Toxic Substance and Disease

Registry

BBDR Biologically based dose response modeling

CDC Centers for Disease Control and Prevention

CHEHSIR Children’s Environmental Health and Safety

Inventory of Research

DART Developmental and Reproductive Toxicology

Database

DNA Deoxyribonucleic Acid

EPA U.S. Environmental Protection Agency

FDA U.S. Food and Drug Administration

FIFRA Federal Insecticide, Fungicide, and

Rodenticide Act

FQPA Food Quality Protection Act

GPRA Government Performance and Results Act

HUD U.S. Department of Housing and Urban

Development

IEUBK Integrated Exposure, Uptake, Biokinetic Model

IRIS Integrated Risk Information System

ITC Interagency Testing Committee

NAAQS National Ambient Air Quality Standards

NAS National Academy of Sciences

NCEA National Center for Environmental Assessment

(EPA/ORD)

NCER National Center for Environmental Research

(EPA/ORD)

NCEH National Center for Environmental Health

(CDC)

NCHS National Center for Health Statistics (CDC)

NCI National Cancer Institute

NERL National Exposure Research Laboratory

(EPA/ORD)

NHANES National Health and Nutrition Examination

Survey

NHEERL National Health and Environmental Effects

Research Laboratory (EPA/ORD)

NHEXAS National Human Exposure Assessment Survey

NHLBI National Heart, Lung, and Blood Institute

NIAID National Institute of Allergy and Infectious

Diseases

NIDCR National Institute of Dental and Craniofacial

Research

NICHD National Institute for Child Health and Human

Development

NIEHS National Institute of Environmental Health

Sciences

NIH National Institutes of Health

NIOSH National Institute for Occupational Safety and

Health

NOAEL No observed adverse effect level

NOEL No observed effect level

NRMRL National Risk Management Research Laboratory

(EPA/ORD)

NTP National Toxicology Program

OCHP Office of Children’s Health Protection (EPA)

OPP Office of Pesticide Programs (EPA/OPPTS)

OPPTS Office of Prevention, Pesticides, and Toxic

Substances (EPA)

ORD Office of Research and Development (EPA)

OSWER Office of Solid Waste and Emergency Response

(EPA)

PBPK Physiologically based pharmacokinetic modeling

PCB Polychlorinated biphenyl

PM Particulate matter

PM10 Particulate matter less than 10 :m in diameter

RFA Request for applications

RfC Reference concentration

RfD Reference dose

SDWA Safe Drinking Water Act

STAR EPA/ORD Science To Achieve Results

extramural grants program

TSCA Toxic Substances Control Act
x

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

(NRC 2000).

Biologicallybased 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) prior to conception, during prenatal development,

or from postnatal development to the time 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 biologicallyeffective dose for that 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, or biological agent

with the outer boundary of an organism. Exposure is quantified

as the concentration of the agent in the medium over time.

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, or dermal 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 of the 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 of the

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
xi

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.
EX-1

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 higher food 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 by the

Office of Research and Development (ORD).

The primary objective of the ORD Children’s Health

program is to conduct the research and provide the 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-2

Research Questions

Children’s risk is a topic as broad and varied as

human health risk assessment. Groups of experts have

identified dozens if not hundreds of research issues and needs,

addressing various age groups, subpopulations, disease

endpoints, biomarkers of disease, mechanisms of action,

exposure pathways, environmental contaminants, and

physiological and biological characteristics affecting doses.

A strategy for research in children’s environmental

health must be broad enough to address diverse environmental

contaminants, endpoints, and special groups such as children

living on farms and urban children. Priorities may shift rapidly

as more becomes known about the impact of environmental

agents on children’s health.

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 disruptors

# Specific compounds such as lead, mercury, PCBs, vinyl chloride

# Mixtures of pollutants

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 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? 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-3

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 shortand 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-4

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 Assessment

(§§4.3.1.1, 4.3.2.1, 4.3.3.1)

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 firstgeneration 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.

# 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-5

# 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 under the 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.

# 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 new sampling 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-6

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 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.
1

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 differ from 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 risks to 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

patterns, diet, and physiological characteristics will also help

define developmental phases of interest. The scope includes

effects that are 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 mediaspecific 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 Children’s

Health Program

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 for the 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 or windows 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 or functional maturity. Physical growth and functional

maturation continue through adolescence, with the rates

varying among the different tissues, 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

1

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 prior to

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....”
2

1981, Langston 1983, Anderson et al. 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. Agerelated 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. For example, 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

(NRC 1993).

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

other chemicals 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
3

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

answer the 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

program in Human Health Risk Assessment under Goal 8. 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 disruptors), 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 (EPA 2000a).

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.
4

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.
5

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 of topics and 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 Regulatory

Approach

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 populationspecific data are not available and cannot be collected,

extrapolation methods and default assumptions are used to

complete the assessment.3

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 order to 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 doseresponse 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 DNA mutations. 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 (no3

EPA 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).
6

observed-adverse-effect level) or the NOEL (no-observedeffect 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 longterm 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 for the 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 doseresponse (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
7

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 for cancer

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.
8

3. IMPLEMENTATION OF LEGISLATION AND POLICY ON

CHILDREN’S ENVIRONMENTAL HEALTH

In 1996, Congress enacted two statutes requiring that

EPA consider children 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 Factor will be made by

considering together the 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 whether to 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

4

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.gov/scipoly/sap/
9

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 under the 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 under the 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.
10

4. RESEARCH DIRECTIONS

In 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 howexposure 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 disorder and disease. The Federal

public health agencies of the 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 for Child 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 of the Federal program investigates the specific

role of environmental agents in causing adverse effects in

children. This section describes some of the 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 Internet (EPA 2000b), 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 longterm 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
11

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 disruptor 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
12

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 pesticidespecific 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 particular age 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
13

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 geneenvironment 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 how to 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
14

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 other environmental 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. For this 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
15

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 for children. 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 doseresponse 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 (EPA 2000d). 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 new technologies to control emissions that

disproportionately affect children. This research includes

development of drinking water treatment technologies that

reduce Cryptosporidium oocysts in water, indoor air treatment

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
16

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 water supplies 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

difficult to 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.

After developing 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
17

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 or models for assessing 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 for the 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, DNA repair, cell viability, and receptor-mediated

alterations in gene expression. The biologic bases for agerelated 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.
18

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

lowexposure levels, over various 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 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. 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 firstgeneration 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 Exposure to 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, but would

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, similar to 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 (NHLBI 2000). 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.
19

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 over time. 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 difficult to 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 doseresponse 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, as well 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-ofaction 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.

Other studies, such as the 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
20

STAR program.

# 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, Multipathway 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 fewer subjects. In NHEXAS, EPA sponsored studies

of the 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

per study.

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 over time?

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 for entire classes of chemicals.

Exposure studies should be directed toward

chemicals of high concern because of their known or
21

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 or whether 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 new sampling 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 indoor breathing zone through 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 lick or suck

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 under the STAR program. For example an 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

number of 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 under the 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
22

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 Methods and

Models

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 shortterm 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-ofaction 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 intramurally so that ORD has

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. High. The rationale is

presented in Section 4.3.1.1.

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,
23

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, and toxicological 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 for children’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
24

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 schoolage children will be adapted for use in younger subjects. In

other cases, such as measures of sensory function (e.g., vision

and hearing), available methods require further validation 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 under the 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 for the 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
25

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 effort to 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, other than specific cancer biomarker work 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 support the 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 risk than 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 water or food, 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 treatment technologies, 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
26

problems. Research in control technology for water, air, and

hazardous waste is conducted at the NRMRL.

Priority and Rationale. Low for the 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 under the

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 air and 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 risk occurring 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 chemicalspecific 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 EPAsponsored 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 risks to their children. 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
27

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. In any future 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 costeffective 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 under the 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 under the 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
28

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 of

Research Areas

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 of the research to EPA’s risk assessments and risk

management decisions, and its relation to other research

areas.
Table 2. Summary of Research Areas

Description

Contribution to Risk Assessment or

Management Links to Other R

Biology of Toxicant-Induced Tissue and Organ Damage in the Developing Organism (§4.3.1.1) High Pr

Investigate absorption, metabolic pathways andrates, distribution and storage in the body, andelimination in sensitive age groups. Investigatebiologic basis for age-related differences in targetorgan development, detoxification, repair, andcompensation. Link effects at tissue, organ, andsystem level with underlying effects at cellularand molecular levels. Identify common modes ofaction for multiple developmental endpoints andchemicals.

Identification of more appropriate animal modelsfor critical ages and endpoints. Improvedextrapolation from animals to children. Improvedrisk assessment models relying less on data fromwhole animal toxicity testing and able toincorporate biologic data specific to children.Identification of classes of chemicals with thesame modes of action.

The necessary data to develop biologi(§4.3.2.1) will be developed under th

studies will help identify pollutants thstudies and may develop biomarkers t(§4.3.1.2). Development, validation, a

(§4.3.3.1) will be needed to conduc

research also provides some of the bto understand the complicated issues groups (§4.3.5.1) and cumulative risk 

pollutants (§4.3.5.2).

Relationship Between Exposure to Environmental Agents and Adverse Health Effects in Human Populations (§4.3.

Conduct studies of the relationship betweenexposure and effects in human populations.Explore feasibility of interagency longitudinal birthcohort enrolling children at birth and continuingthrough childhood or adolescence. Conducthypothesis-based analysis of existing data sets toinvestigate relationship between exposure andeffects in children.

Identification of hazards and important sourcesand pathways of exposure. Opportunities to testhypotheses related to human exposure andeffects and the ability of animal testing and riskassessment methods to predict exposure andeffects in children. Testing of intervention andrisk reduction techniques. Collection of data fordose-response assessments.

Studies in humans will be indicated biological bases of adverse effects (§4of response in children and to aid in between animals and children (§4.3

exposure field studies (§4.3.1.3) are 

explore opportunities to combine theobjectives of both types of studies are and exposure in humans (§4.3.3) will b

developed in the context of these studwith communities and participants populations and will need communicat

intervention methods to offer to indepartments to deal with problems tHuman studies designed to consipotential to provide information on var

and responses to complex mixtures (
Table 2. Summary of Research Areas (continued)

Description

Contribution to Risk Assessment or

Management Links to Other R

Multimedia, Multipathway Exposures in Human Populations (§4.3.1.3) High Priority

Measure exposure in various age groups in thenational population and selected subgroupshypothesized to be more highly exposed. Collectenvironmental concentration data, personalexposure data, biological samples, andquestionnaire data.

Determination of when children are exposed andwhich age groups are more highly exposed andshould be subjects of further study andassessment. Development of baseline data anddata on distributions of exposure in the generalpopulation and highly exposed subgroups.Development of data for risk assessment ofchemicals in study and data on activity patternsand other exposure variables for direct use inEPA risk assessments. Identification of importantsources and pathways of exposure for riskmanagement decisions. Collection of data foruse in model development and predictions ofexposure.

Information on the most highly exposeexposure is useful in selecting relevant mode-of-action studies (§4.3.1.1), desiwith actual exposure patterns (§4.3.2

of the relationship between exposu

epidemiologic and complexexposure swhere it is possible to do so without studies’ objectives. Multimedia, multioften be designed to collect informatioand for use in designing and testing e

for use in many risk assessmentsmethods of measuring exposure a(§4.3.3.2) be developed in the cou

Investigators will need to work with conduct exposure studies and will n(§4.3.4.3) and practical methods to 

public health departments to deal with (§4.3.4.2). Studies designed to con

potential to provide information on groups (§4.3.5.1) and exposures to c

Analysis of Factors Contributing to Exposure (§4.3.1.4) High Priority

Develop data on distributions of values of keyexposure variables within critical age groups,including activity pattern data, intake rates, andother factors that may cause higher exposures forchildren.

Development of data on exposure variables thatintroduce the greatest uncertainty into EPA riskassessments as identified by EPA ProgramOffices and Regions and ORD analysis.

Multipathway studies (§4.3.1.3) often cin risk assessment to evaluate exposua secondary objective of such studiesfactors influence each other is key (§4.3.2.2). Measurement methods ar

context of studying particular exposurof critical exposure variables, such as fdust, can provide insight into variabil(§4.3.5.1).
Table 2. Summary of Research Areas (continued)

Description

Contribution to Risk Assessment or

Management Links to Other R

Methods and Models for Using Biological Data in Risk Assessment (§4.3.2.1) High Priority

Develop integrated biological models of theexposure-dose-response continuum that routinelyuse pharmacokinetic and mode-of-action data inrisk assessments for children. Develop modelsincorporating biological data to aid inextrapolation between animals and children.

Risk assessment models that take into accountage-related differences in size, absorption,metabolism, distribution, and storage, andresponse to exposure at the cellular andmolecular level. Improved ability to identify ageappropriate animal models and extrapolate fromanimals to children.

Data for model development are gresearch (§§4.3.1.1, 4.3.3.1). Human for model validation and extrapolati(§4.3.1.2). Exposure studies (§4.3.1

uptake, body burden, and elimination

biological models are connected throuobjective of chemical-specific modelinBBDR models that can be linked to through the PBPK model. With a suffmodels will be useful in predicting distrwithin an age range, allowing for esti

Exposure Modeling and Use of Exposure Data in Risk Assessment (§4.3.2.2) High Priority

Develop models for important pathways ofchildhood exposure, models of total dose viamultiple pathways, and probabilistic assessmentscombining exposure data on multiple pathways.

Identification and quantification of exposure anddose in the risk assessment. Identification andquantification of sources and pathways in order todevelop appropriate risk management options.Estimation of child-specific exposures andaggregate exposures for children in EPAassessments where measurements must besupplemented with modeling approaches to filldata gaps.

Data for model development are prov

variables (§4.3.1.4). Human studies (data to evaluate model variables amodels. Exposure models and biologicthrough PBPK modeling. It should bmodeling to develop exposure, PBPlinked to connect effects with exposura sufficient input database, probabilistdistributions of exposure within an agvariability (§4.3.5.1). Probabilistic mo

distributions of dose from multiple (§4.3.5.2)

In Vivo/In Vitro Methods for Hazard Identification (§4.3.3.1) High Priority

Develop methods for identifying and modelingmechanisms of toxic action in children.

Development of animal models and protocols thatwill provide information on mode of action to beused in risk assessment.

Predictive tests will be developed as biological basis of risk (§4.3.1.1) abetween animals and children (§4.3.2
Table 2. Summary of Research Areas (continued)

Description

Contribution to Risk Assessment or

Management Links to Other R

Methods for Measuring Exposures and Effects in Infants and Children and to Aid in Extrapolations between Animals and Child

Develop measurement methods suitable for usein infants and toddlers, such as biologicalsampling methods and cognitive testing methods.Develop biomarkers of effect and exposure inyoung subjects.

Improved methods for collecting data on childrenthat, when applied in a study, contribute to betterdata for risk assessment.

Some of these methods are likely tlaboratory studies and other human s

and 4.3.1.4)

Multimedia Control Technologies (§4.3.4.1) Low Priority

Develop control technologies for releases ofsubstances to which children are believed to beexposed, including drinking water treatment forCryptosporidium, control of air emissions,bioremediation of chemicals at waste sites, andcontrol of pesticide releases in point sources andnonpoint source runoff.

Reduced risks to children and adults throughcontrol of a substance at its source.

Risk assessments based on the resuresearch areas help identify substanneeded. Risk assessments also help effluent control, and other risk manaassess the efficacy and benefits of th

Methods for Reducing Exposure Buildup of Contaminants in Indoor Environments (§4.3.4.2) High Prio

Cleanup and remediate children’s environments

that have unacceptable environmentalconcentrations. Engineer consumer and buildingproducts to reduce release of environmentalagents to the indoor environment.

Reduced risks to children in their homes andschools through remediation and pollutionprevention.

Risk assessments based on the resuresearch areas will help identify substaneeded. Risk assessments also help and pollution prevention options and tcan be used in conjunction with huma

assist residents and local public health levels are found.

Communication of Risks and Development of Risk Reduction Techniques Through Community Participation (§4.3.

Investigate intervention and education methodsthat enlist members of the community to worktogether to reduce risks to their children.

Reduced risks to children through intervention byparents, schools, medical personnel, and othersin the community.

Risk assessments based on the resuresearch areas help identify substancare needed. Risk assessments also hbased intervention. Intervention methhuman studies (§§4.3.1.2 and 4.3.1.3health departments when high expos
Table 2. Summary of Research Areas (continued)

Description

Contribution to Risk Assessment or

Management Links to Other R

Variability in Susceptibility and Exposure in Children (§4.3.5.1) Medium Priority

Investigate impact of factors on variability inresponse or exposure within the critical agerange. Factors include preexisting disease,lifestyle and nutrition, genetic characteristics, sex,and ethnicity.

Identification and quantification of risk insusceptible and highly exposed subpopulations.

Many factors that influence variability assessed as part of studies to identify that age range is critical. Studies of consider genetic and other susceptibias risk assessments often focus on sbe more susceptible or more highly 4.3.1.4).

Cumulative Risks to Children (§4.3.5.2) Medium Priority

Investigate simultaneous exposures to multipleenvironmental agents and other stressors in achild’s environment.

Data for assessment of risk of simultaneousexposures, including chemicals by the sameroute, chemicals with common modes of actionby multiple routes, and all environmental agentsand other stressors found in the child’senvironment.

The results of mode-of-action studie

understanding effects of mixtures. E(§4.3.1.2 and §4.3.1.3) often provid

(although only a small fraction of achildren are exposed. Dose-responssimultaneous exposures are criticaassessment methods for summing m
34

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

for extramural 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 for ORD 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.

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.

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

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.

Figure 3: Pesticides and Children in Minnesota:

A NHEXAS Study and a STAR Grant

Under the 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 for a 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.
35

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.
36

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A-1

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 alter the 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

emphasize that a physiological or functional 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 include the "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 enter the 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 glomerular function 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
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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 agerelated 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 I and 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 adult size

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 (Schull et al. 1990, Chakraborti et al. 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 of the newborn and young animal, there are

data that indicate the vulnerability of the 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 over a lifetime. It was also

indicated that the nervous, immune, and reproductive systems

were of particular importance for testing given the existing

database (NRC 1993). For example, 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).

References:

Amin-Zaki, L., S.B. Elhassani, M.A. Majeed, T.W. Clarkson,

R.A. Doherty, and M.R. Greenwood. 1980.

Methylmercury poisoning in mothers and their suckling

infants. Dev. Toxicol. Environ. Sci. 8:75-78.

Andersson, U., A.G. Bird, B.S. Britton, and R. Palacios. 1981.

Humoral and cellular immunity in humans studied at the

cell level from birth to two years of age. Immunol. Rev.

57:1-38.

Barraclough, C.A. 1966. Modification in the CNS regulation of

reproduction after exposure of prepubertal rats to steroid

hormones. Recent Progr. Horm. Res. 22:503-539.

Bellinger, D., A. Leviton, C. Waternaux, H. Needleman, and M.

Rabinowitz. 1987. Longitudinal analyses of prenatal and

postnatal lead exposure and early cognitive development.

N Engl J Med. 316:1037-1043.

Besunder, J.B., M.D. Reed, and J.S. Blumer. 1988. Principles

of drug biodisposition in the neonate. A critical evaluation

of the pharmacokinetic-pharmacodynamic interface (Part

I). Clin. Pharmacokinet. 14:189-216.

Braunlich, H. 1981. Excretion of drugs during postnatal

development. Pharmacol. Ther. 12:299-320.

Chakraborti, T., J. Farra, and C. Pope. 1993. Comparative

neurochemical and neurobehavioral effects of repeated

chlorpyrifos exposure in young and adult rats. Pharmacol.

Biochem. Behav. 46:219-224.

Colten, H.R. 1977. Development of host defenses: the

complement and properdin systems, In: Development of

Host Defenses, (M.D. Cooper and D.H. Dayton, Eds.), pp.

165-171. New York, NY: Raven Press.

Dean, R.F.A. and R.A. McCance. 1947. Inulin, iodine,

creatinine, and urea clearance in newborn infants. J.

Physiol. 106:431-439.

de Mauralt, G. 1978. Maturation of cellular and humoral

immunity, In: Perinatal Physiology, (W. Stave, Ed.), pp.

267-315. New York, NY: Plenum Press.

Dobbing, J. and J. Sands. 1973. Quantitative growth and

development of human brain. Arch. Dis. Child. 48:757-

767.

EPA. (U.S. Environmental Protection Agency). 1992. Dermal

Exposure Assessment: Principles and Applications.

Interim report. Washington, DC: Office of Research and

Development.

Faith, R.E and J.A. Moore. 1977. Impairment of thymusdependent immune functions by exposure of the

developing immune system to 2,3,7,8-tetrachlorodibenzop-dioxin (TCDD). J. Toxicol. Environ. Health 3:451-646.

Gehrs, B.C. and R.J. Smialowicz 1999. Persistent

suppression of delayed-type hypersensitivity in adult F344

rats after perinatal exposure to 2,3,7,8-tetrachlorodibenzop-dioxin. Toxicology 134:79-88.

Gershanik, J., B. Boecler, H. Ensley, S. McCloskey and W.

George. 1982. The gasping syndrome and benzyl

alcohol poisoning. N. Engl. J. Med.. 307:1384-1388.

Gilbert, S.G. and K.S. Grant-Webster. 1995. Neurobehavioral

effects of developmental methylmercury exposure.

Environ. Health Perspect. 103 (Suppl 6):135-142.

Hay, A. 1982. Hexachlorophene. In: The Chemical Scythe

(E. Hay, Ed.), pp. 69-76. New York, NY: Plenum Press.

Heise, E.R. 1982. Diseases associated with

immunosuppression. Environ. Health Perspect. 43:9-19.

Herbst, A.L., R.J. Kurman, and R.E. Scully. 1972. Vaginal and

cervical abnormalities after exposure to diethylstilbestrol

in utero. Obstet. Gynecol. 40:287-298.

Hill, J.R. 1964. The development of thermal stability in the

newborn baby. In: The Adaptation of the Newborn to

Extrauterine Life, pp. 223-228. Netherlands: H.E. Stenfert

Kroese NV.

Hoar, R.M. and I.W. Monie. 1981. Comparative development

of specific organ systems. In: Developmental Toxicology

(C.A. Kimmel and J. Buelke-Sam, Eds.), pp. 13-33, New

York, NY: Raven Press.

Igata, A. 1993. Epidemiological and clinical features of

Minamata disease. Environ. Res. 63:157-169.

ILSI. (International Life Sciences Institute). 1996. Research

Needs on Age-Related Differences in Susceptibility to
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Chemical Toxicants. Report of an ILSI Risk Science

Institute Working Group. Washington, DC: ILSI Risk

Science Institute.

Jacobson, J. and S. Jacobson. 1996. Intellectual impairment

in children exposed to polychlorinated biphenyls in utero.

New Engl. J. Med. 335:783-789.

Kacew, S. 1992. General principles in pharmacology and

toxicology applicable to children. In Similarities and

Differences Between Children and Adults, (P.S. Guzelin,

C.J. Henry and S.S. Olin, Eds.), pp. 24-42. Washington,

DC: ILSI Press.

Klinger, W. 1982. Biotransformation of drugs and other

xenobiotics during postnatal development. Pharmacol.

Ther. 16:377-429.

Kostial, K., D. Kello., S. Jugo, I. Rabar, and T. Maljkovic.

1978. The influence of age on metal metabolism and

toxicity. Environ. Health Perspect. 25:81-86.

Langston, C. 1983. Normal and abnormal structural

development of the human lung. In: Abnormal Functional

Development of the Heart, Lungs and Kidneys:

Approaches to Functional Teratology (R.J. Kavlock and

C.T. Grabowski, Eds.) pp.75-91. New York, NY: Alan R.

Liss.

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.

Maturation of B-cell differentiation ability and T-cell

regulatory function in infancy and childhood. Immunol

Rev. 57:61-87.

Nau, H., W. Luck, and W. Kuhnz. 1984. Decreased serum

protein binding of diazepam and its metabolite in the

neonate during the first postnatal week relate to increased

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

Perspect. 103 (Suppl. 6):77-80.

NRC. (National Research Council). 1993. Pesticides in the

Diets of Infants and Children. Washington, DC: National

Academy Press.

Owen, J.J.T. 1972. The origins and development of

lymphocyte populations. In: Ontogeny of Acquired

Immunity, (R. Porter and J. Knight, Eds.), pp. 35-54, New

York, NY: Elsevier.

Peters, H.A. 1976. Hexachlorobenzene poisoning in Turkey.

Fed. Proc. 35:2400-2403.

Roder, P.M. 1995. The role of the environment in injuries to

the developing nervous system.. Environ. Health

Perspect. 103 (Suppl. 6):73-76.

Roder, P.M. 1980. Chronology of neuron development:

animal studies and their clinical implications. Dev. Med.

Child Neurol. 22:525-545.

Saenz de Rodriguez, C.A. and M.A. Toro-Sola. 1982.

Anabolic steroids in meat and premature telarche. Lancet.

1:1300.

Schull, W., S. Norton, and R. Jensh. 1990. Ionizing radiation

and the developing brain. Neurotoxicol. Teratol. 12:249-

260.

Sutherland, J.M. 1959. Fatal cardiovascular collapse of infants

receiving large amounts of chloramphenicol. J. Dis. Child.

97:761-767.

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

absorption: neonate compared to the adult. In:

Environmental Factors in Human Growth and

Development, Banbury Report No.2, (V.R. Hunt., M.K.

Smith, and D. Worth, Eds.), pp. 73-84, New York, NY:

Cold Spring Harbor Laboratory.

WHO. (World Health Organization). 1986. Principles for

Evaluating Health Risks from Chemicals During Infancy

and Early Childhood: The Need for a Special Approach.

Environmental Health Criteria 59. Geneva, Switzerland:

World Health Organization.

Ziegler, E.E., B.B. Edwards, R.L. Jensen, K.R. Mahaffey, and

S.J. Fomon. 1978. Absorption and retention of lead by

infants. Pediatr. Res.12:29-34.
1

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/ORD/WebPubs/final/

B-1

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 four fundamental research areas: (1) ecosystem monitoring,

(2) ecological processes and modeling, (3) ecological risk assessment, and (4)

ecological risk management and restoration.

Research Plan for Arsenic in Drinking Water

(EPA 1998b)

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

Disruptors (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 disruptors.

Pollution Prevention Research Strategy

(EPA 1998d)

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 (EPA 1999a) 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: (1) groundwater at contaminated sites, (2) soils and the vadose

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.
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APPENDIX B. ORD RESEARCH PLANS AND STRATEGIES (continued)

Name Description

ORD Strategy for Research on

Environmental Risks to Children (EPA

2000).

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). The strategy presents the goals and scientific questions and associated

research areas and shapes the agenda for EPA’s mercury research program.

Airborne Particulate Matter Research

Strategy (EPA 1999d)

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/ORD/WebPubs/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/R98/042.

EPA. 1998c. Strategic Research Plan for Endocrine Disruptors. 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

NRC.(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 Age-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 DNA repair capacity in various tissues from birth through adolescence and for rodent
C-2

models in normal populations and populations with heritable DNA 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 disruptor 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 risk of 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 disruptors 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-3

# 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 DNA 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 support to 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-4

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 lest than 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 (GIS) studies of infant health status.

#

Immunology and Pulmonary Work Group

Endpoints:

# Upper respiratory infections.

# Acute bronchitis.
C-5

# 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.”
D-1

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 in the 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 allergic diseases that

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, geneenvironment 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-2

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

Human Malformations (ORD STAR

program with NICHD, NIDCR, and

NIEHS).

Cosponsor of 8 Centers for Children’s

Environmental Health and Disease

Prevention Research. (ORD STAR

program).

Agricultural Health Study (with NCI and

NIEHS).

Environmental Genome Project -

identification and establishment of a

database of polymorphisms of

environmental disease susceptibility

genes.

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.

NHANES IV 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).

.
APPENDIX E. CROSS TABULATION OF RESEARCH QUESTIONS

AND RESEARCH AREAS

1. What are the adverse effects in

children that are different from

effects in adults?

2. What are the periods of

development when adverse health

effects in children can occur?

3. What are the best in vitro and

animal models for identifying

hazards to children?

4. To what environmental

substances are children more

highly exposed?

5. What are the relationships

between exposures to children and

adverse health effects?

6. How can laboratory and human

data be used to predict responses in

children?

7. What is the variability within

members of the same age group?

8. What mixtures are children

exposed to and what are the

adverse effects?

9. What are the best methods for

characterizing the uncertainties in

risk assessments for children?

10. What are the most effective

methods for communicating and

reducing children’s risk?

Mode-of-action research UUU UUUUEpidemiology and clinical studies UU UUUUUUUExposure field studies U UUUUActivity pattern and exposure factor studies U UMethods and models for using mode-of-action data inrisk assessment

UUU UUUUU

Methods and models for using exposure data in riskassessment

U U

Methods for studying mechanisms of actions UUUMethods for measuring exposure and effects in childrenand to aid in extrapolation between animals andhumans

UUUUU

Multimedia control technologies

U

Reduction of exposure buildup of contaminants indoors U UEducation and communication of risk and risk reductiontechniques

U

Variation in human susceptibility and exposure UUUUU U UUMixtures and cumulative risk UUUU U UUU
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARC

Research areas(priority)

Importance of theresearch to reducinguncertainty in riskassessment andprotecting childrenfrom environmentalhealth threats

Feasibility ofconducting theresearch in the ORDintramural or STARprograms

The capacities andcapabilities of ORD’slaboratories andcenters

Opportunities todevelop and maintainscientific expertise inORD to enable use ofresearch results inEPA risk assessments

Opportuniticollaboratioother Federagencies another ORD programs

4.3.1.1 Biology ofToxicant-InducedTissue and OrganDamage in theDeveloping Organism(High)

HighA greaterunderstanding of thepharmacokinetics andmode(s) of actionunderlying agentinduced developmentalabnormalities willfacilitate theinterpretation andextrapolation of animaland human data for riskassessment. Thisresearch will lead tomore refined riskassessmentapproaches by linkageof environmentalexposure withbiologically effectivedose at the cellular andmolecular level.

HighThis research area isvery feasible. Eventhough ORD’sintramural program hasthe expertise to performthe pharmacokineticsand mode(s)-of-actionresearch and apply it tochildren’s riskassessment, theseactivities need to beexpanded. Also, thesuccess of thisresearch area relies onlinkage to theapplication of the datato model doseresponse for riskassessment (4.3.2.1)and the validation andapplication of state-ofthe-science methods(4.3.3.1).

MediumAlthough ORD hasfunded intramuraldevelopmentaltoxicology researchover the years, theresearch in Section4.3.1.1 goes wellbeyond what iscurrently being done.As such, it will requirenot only an increase inresources but also along-term commitmentto this research area.The STAR program hassupported extramuralresearch in this areaand should continue todo so.

HighORD has excellentexperimental researchcapabilities in this area;however, considerationshould be given tobolstering the expertiseof existing principalinvestigators in cuttingedge cellular andmolecular biology andrecruiting investigatorswith these skills. Also,ORD must maintain itsscientific expertise forapplying the data to riskassessment.

HighThere are seongoing collwith other FeorganizationNIEHS, NICCDC) and wORD prograundoubtedly expanded thsupport of tharea.
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AR

Research areas(priority)

Importance of theresearch to reducinguncertainty in riskassessment andprotecting childrenfrom environmentalhealth threats

Feasibility ofconducting theresearch in the ORDintramural or STARprograms

The capacities andcapabilities of ORD’slaboratories andcenters

Opportunities todevelop and maintainscientific expertise inORD to enable use ofresearch results inEPA risk assessments

Opportuniticollaboratioother Federagencies another ORD programs

4.3.1.2 RelationshipBetween Exposure toEnvironmentalAgents and AdverseHealth Effects inHuman Populations(High)

HighHuman studies arecrucial to understandingwhether children aremore susceptible thanadults, to identify andconfirm adverse effectsin human, to improveextrapolation betweenanimals, and to developdata for use in riskassessments.

Medium to High

Feasibility depends on

the endpoints beingstudied and theavailability of exposuredata. Feasibilitydecreases for lesscommon endpointsbecause studies mustbe very large toobserve relationshipsand the large number ofconfounding factors.

Medium to HighORD has expertise inclinical andepidemiology studies,having sponsored andconducted manystudies both in-houseand through the STARprogram. ORD alsohas expertise inexposure research.Size of studies may belimited by currentamount of extramuralresources available forthis program.

HighORD is moving towardthe integration ofexposure andepidemiologic researchin studies such asNAFTA and theLongitudinal CohortStudy. This directionwill improve the utility ofhuman study data forrisk assessmentthrough better exposuredata.

HighThrough the Force, ORD participating feasibility stulongitudinal as well as pain collaboratthrough NHAthe Inner-CitStudy. Manopportunities other studies to arise.
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AR

Research areas(priority)

Importance of theresearch to reducinguncertainty in riskassessment andprotecting childrenfrom environmentalhealth threats

Feasibility ofconducting theresearch in the ORDintramural or STARprograms

The capacities andcapabilities of ORD’slaboratories andcenters

Opportunities todevelop and maintainscientific expertise inORD to enable use ofresearch results inEPA risk assessments

Opportuniticollaboratioother Federagencies another ORD programs

4.3.1.3 Multimedia,MultipathwayExposures in HumanPopulations(High)

HighMultimedia,multipathway exposurestudies will reduceuncertainty by: (1)delineating sources andpathways of exposure;(2) replacing defaultassumptions with actualmeasured data; (3)determining which agegroups are more highlyexposed to certainenvironmental agents;and, (4) obtainingbaseline data onchildren’s exposures tocharacterize highlyexposed subgroups andevaluate status andtrends.

HighORD has the capabilityto conduct suchstudies as intramuraland extramuralprograms, as evidencedby experience withTEAM, NHEXAS andNAFTA studies andSTAR grants.

Medium to HighIn the short term,resources are sufficientto support limited workin this area, such asanalysis of data fromcurrent studies, but notsufficient to support anew study in theintramural program andalso conduct the otherhigh-priority researchdescribed in thisstrategy. Resourcesare available in theSTAR program tosupport field studies.

HighThis research providesopportunities to developand maintain scientificexpertise in designing,implementing, andanalyzing multimedia,multipathway humanexposure studies withthe purpose of reducinguncertainty in riskassessments.

HighOpportunitiepartnerships extremely imbecause reslimited. HowFederal agesimilar intereCDC, NIEHSetc.), makingpartnerships addition, ORleverage othresearch prosuch as the program and Human HeaAssessment 
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AR

Research areas(priority)

Importance of theresearch to reducinguncertainty in riskassessment andprotecting childrenfrom environmentalhealth threats

Feasibility ofconducting theresearch in the ORDintramural or STARprograms

The capacities andcapabilities of ORD’slaboratories andcenters

Opportunities todevelop and maintainscientific expertise inORD to enable use ofresearch results inEPA risk assessments

Opportuniticollaboratioother Federagencies another ORD programs

4.3.1.4 Analysis ofFactors Contributingto Exposure(High)

HighAnalysis of factorscontributing to exposurewill reduce uncertaintyin risk assessments byreplacing defaultexposure factors withactual measuredexposure variables andfactors including microenvironmental andmacroenvironmentalactivity patterns forchildren (time spent invarious environmentsand frequency ofoccurrence), dermaltransfer rates,inadvertent ingestion(hand-to-mouth activity,pica), inhalation ratesby age and activitylevel, and ingestionconsumption levels byage group.

MediumIt is feasible to conductsome of these studiesunder both the STARand intramuralprograms. However,innovative methods andtechniques may berequired to collectcertain data, e.g.,dermal exposure andnondietary ingestion.Some of these studieswill need to beconducted by ORDintramural programs toobtain data needed forEPA risk assessments.

HighResources areavailable to conductsome of these studiesunder the STARprogram, which can besupplemented withstudies in other mediaspecific ORD programs.ORD is capable ofdeveloping an in-houseprogram to developexposure factors andvariables, as evidencedby the production of theExposure FactorsHandbook.

HighThis research providesopportunities to developand maintain scientificexpertise in developinganalysis of factorscontributing to exposurewith the purpose ofreducing uncertainty inrisk assessments.

HighOpportunitiepartnerships extremely imbecause reslimited. HowFederal agesimilar intereNIEHS, ATSmaking partnfeasible. In aORD can levother ORD rprograms, sFQPA to stuimportant exvariables in Standard OpProcedures.
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AR

Research areas(priority)

Importance of theresearch to reducinguncertainty in riskassessment andprotecting childrenfrom environmentalhealth threats

Feasibility ofconducting theresearch in the ORDintramural or STARprograms

The capacities andcapabilities of ORD’slaboratories andcenters

Opportunities todevelop and maintainscientific expertise inORD to enable use ofresearch results inEPA risk assessments

Opportuniticollaboratioother Federagencies another ORD programs

4.3.2.1 Methods andModels for UsingBiological Data inRisk Assessment(High)

HighBiologically based,dose-response modelswill lead to refined riskassessmentapproaches that nolonger rely solely onwhole-animal toxicitytesting, but incorporatethe growing knowledgeof molecularmechanisms and theirinvolvement in a toxicresponse. Based onthese models,children’s riskassessment will be ableto better address suchissues as complexmixtures, varyingexposure patterns, andcritical periods ofsusceptibility.

HighThe feasibility is veryhigh. EPA’s intramural

research capability isvery strong in this areaand is recognized bythe larger researchcommunity.Extramurally, there area great manylaboratories alreadyworking in this area. Apotential limitation ofthe STAR program isthat the researchcannot be done in acooperative mannerwith EPA investigatorsand may lack thenecessary focus forultimate application inrisk assessment.

High

This children’s research

strategy is significantstep in defining aprogram specificallyfocused on children.The research in 4.3.2.1will require a long-termcommitment ofresources. ORD hasalready madecommitments throughthe general funding ofits laboratories and theSTAR program. Acommitment to thisspecific program shouldbe made, andopportunities toleverage the resourcesof similar programs inother Federal agenciesand extramural groupsshould be identified.

Medium

This is an area of majorconcern. ORD has astrong researchcapability in this area,but it must alsomaintain the scientificexpertise to enable theuse of the data in riskassessment. This willrequire an experiencewith traditional testingand risk assessment,coupled with anunderstanding ofmodeling and newerapproaches intoxicology.

HighIn 2000, Fedhealth agencconcerned wof environme(e.g., NIEHSfocusing on of action restopics such environmentinteractions. be many oppfor developmuse of modeassess envirisks to childcollaboration
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AR

Research areas(priority)

Importance of theresearch to reducinguncertainty in riskassessment andprotecting childrenfrom environmentalhealth threats

Feasibility ofconducting theresearch in the ORDintramural or STARprograms

The capacities andcapabilities of ORD’slaboratories andcenters

Opportunities todevelop and maintainscientific expertise inORD to enable use ofresearch results inEPA risk assessments

Opportuniticollaboratioother Federagencies another ORD programs

4.3.2.2 ExposureModeling and Use ofExposure Data inRisk Assessment(High)

HighThe development ofmultimedia models anduse of exposure datawill improve the qualityof children’sassessments byreducing the uncertaintyof the relationshipbetween environmentalmeasurements,biomarkermeasurements, humanactivities andtoxicologicalparameters. Bydeveloping/evaluatingmultimedia models withactual exposure datamore realisticpredictions of exposureand risk are possible.

HighThe feasibility ofconducting thesestudies is high. ORDhas the capability toconduct such studies asintramural andextramural programs,as evidenced byexperience with STARgrants and theintramural modelingprogram.

HighResources areavailable to fundintramural and STARprograms. ORD hasdemonstrated in-houseexpertise with universitypartnerships andmodeling centers.

HighThis research providesopportunities to developand maintain scientificexpertise indeveloping, evaluating,and refining exposuremodels, and theanalysis of exposuredata with the purpose ofreducing uncertainty inrisk assessments.

HighOpportunitiepartnerships extremely imsince resourlimited. Otheorganizationsimilar intereATSDR, ACmaking partnfeasible. In ORD can levother ORD rprograms, sFQPA, to stuimportant exscenarios suOPP StandaOperating P
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AR

Research areas(priority)

Importance of theresearch to reducinguncertainty in riskassessment andprotecting childrenfrom environmentalhealth threats

Feasibility ofconducting theresearch in the ORDintramural or STARprograms

The capacities andcapabilities of ORD’slaboratories andcenters

Opportunities todevelop and maintainscientific expertise inORD to enable use ofresearch results inEPA risk assessments

Opportuniticollaboratioother Federagencies another ORD programs

4.3.3.1 In Vivo/InVitro Methods forHazard Identification

(High)

HighDevelopment,validation, andapplication of state-ofthe-science methodsare essential to carryingout mode-of-actionresearch (§4.3.1.1) anddeveloping models andrisk assessmentmethods incorporatingmode of action(§4.3.2.1).

HighThis research area isvery feasible. Eventhough ORD’sintramural program hasthe expertise to developmethods for studyingmode of action, theseactivities need to beexpanded as part of anintegrated program tosupport researchdescribed in §4.3.1.1.Also, the success ofthis research area relieson linkage to theapplication of the datato model doseresponse for riskassessment (§4.3.2.1).

MediumAlthough ORD hasfunded intramuraldevelopmentaltoxicology researchover the years, theresearch in §4.3.3.1.goes well beyond whatis currently being done.As such, it will requirenot only an increase inresources but also along-term commitmentto this research area.The STAR program hassupported extramuralresearch in this areaand should continue todo so.

HighORD has excellentexperimental researchcapabilities in this area;however, considerationshould be given tobolstering the expertiseof existing principalinvestigators in cuttingedge cellular andmolecular biology andrecruiting investigatorswith these skills. Also,ORD must maintain itsscientific expertise forapplying the data to riskassessment.

HighMost of the mdevelopmengenomics/ pis taking plaIt is expectewill collaborathese agencapplying theto research related to risassessmentThere are oncollaborationmethods devand validatioother organiNIEHS, WHwith industryundoubtedly continue.
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AR

Research areas(priority)

Importance of theresearch to reducinguncertainty in riskassessment andprotecting childrenfrom environmentalhealth threats

Feasibility ofconducting theresearch in the ORDintramural or STARprograms

The capacities andcapabilities of ORD’slaboratories andcenters

Opportunities todevelop and maintainscientific expertise inORD to enable use ofresearch results inEPA risk assessments

Opportuniticollaboratioother Federagencies another ORD programs

4.3.3.2 Methods forMeasuring Exposuresand Effects in Infantsand Children and toAid in Extrapolationsbetween Animals andHumans. (Medium)

MediumBetter methods ofsampling, analysis ofsamples, and testprotocols for infants andchildren supports betterdata for riskassessment. Methodsdevelopment is oftenconducted in concertwith a field or laboratorystudy. A separateprogram in methodsdevelopment, althoughvaluable, is somewhatless directly related toanswering questionsabout risk than thestudies themselves.

HighPrograms indevelopment of testprotocols for bothanimals and humansand methods ofexposure sampling andanalysis are part ofORD’s core expertise.

MediumORD’s laboratories andthe academiccommunity have thecapability and capacityto support thesestudies. The resourcesto devote to a programstanding alone from aparticular study arecurrently lacking.

HighMethods developmentwill continue to be a keycomponent of ORD’seffects and exposureprogram, throughORD’s core HumanHealth RiskAssessment programand as part of specificstudies conductedunder the Children’sHealth program.

HighORD often wagencies ansuch as CDC in developinprotocols.

4.3.4.1 MultimediaControl TechnologiesThat Account for theSusceptibilities ofChildren(Low)

LowControl technologiessuch as removingmicrobes from waterand pollutants in indoorair will reduce risks.However, controltechnologies do notspecifically addresschildren’s risk andtherefore for thisprogram are rated low.

HighVery feasible, and theNRMRL has a strongcapability to developthese technologies.

MediumORD laboratories havethe capability andcapacity to perform thisresearch. Extramuralresources under theChildren’s Health

program are notcurrently available.

Low

The results of controltechnology researchare not directlyapplicable toassessment ofchildren’s risks.

LowCollaboratioarea is not 
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AR

Research areas(priority)

Importance of theresearch to reducinguncertainty in riskassessment andprotecting childrenfrom environmentalhealth threats

Feasibility ofconducting theresearch in the ORDintramural or STARprograms

The capacities andcapabilities of ORD’slaboratories andcenters

Opportunities todevelop and maintainscientific expertise inORD to enable use ofresearch results inEPA risk assessments

Opportuniticollaboratioother Federagencies another ORD programs

4.3.4.2 Methods forReducing ExposureBuildup ofContaminants inIndoor Environments(High)

HighThis research areaaddresses remediationand prevention ofexposure to children inindoor environments. Itdirected at the types ofissues important withrespect to thepesticides 10X factor,for example.

HighVery feasible, and theNRMRL has a strongcapability to developthese technologies .

HighThe NRMRL has both acapability and capacityto conduct thisresearch.

MediumAn important element ofthe EPA riskassessment process isthe evaluation ofcompeting riskmanagement optionsand the analysis of theefficacy of control andcleanup methods.Supporting thisresearch will help ORDto maintain the scientificexpertise to perform arisk-based evaluation ofmanagement options.

HighOpportunitiecollaborate wORD researsuch as the and the riskassessment evaluating thof this researeducing riskCollaboratioand local gois also likely

4.3.4.3Communication ofRisks andDevelopment of RiskReductionTechniques throughCommunityParticipation (High)

HighEffectivecommunication of risksand risk interventionmethods is an importantway to reduce risks, aswell as becoming anincreasingly importantpart of human studies(§§4.3.1.2 , 4.3.1.3).

MediumORD has little expertisein conducting researchin risk communication.However, ORD doesconduct many studiesin communities. TheSTAR program hassupported riskcommunicationresearch.

MediumCapabilities forresearch reside mainlyin the STAR program.The Intramural programapplies communicationapproaches but has nocurrent capability toconduct such research.

HighORD should develop anexpertise for riskcommunication andintervention if needed,as this is an importantcomponent ofcommunity-basedresearch studies.

HighOpportunitiecross-laboracollaboration collaboration and local goagencies anagencies suATSDR.
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AR

Research areas(priority)

Importance of theresearch to reducinguncertainty in riskassessment andprotecting childrenfrom environmentalhealth threats

Feasibility ofconducting theresearch in the ORDintramural or STARprograms

The capacities andcapabilities of ORD’slaboratories andcenters

Opportunities todevelop and maintainscientific expertise inORD to enable use ofresearch results inEPA risk assessments

Opportuniticollaboratioother Federagencies another ORD programs

4.4.5.1 Variability inSusceptibility andExposure in Children(Medium)

MediumSome of this researchis integral to studyingmechanisms of actionand multipathwayexposure. Otherresearch relatedspecifically todifferences amongchildren in the sameage group is lessimportant at this timethan differencesbetween age groups.

MediumThis is one of thestrategic directions ofthe ORD Human HealthRisk Assessmentprogram.

Medium to LowThere are effortsunderway in ORD thataddress variability insusceptibility andexposure issues;however, this effort isminimal.

MediumThis research area mayserve as a catalyst toincrease interest inpursuing research thataddresses variability insusceptibility andexposure. Expertise forthis research area willbe developed andmaintained throughresearch under§§4.3.1.1, 4.3.2.1, and4.3.3.1.

Medium to HOpportunitiein mode-of-aresearch/gepolymorphiswill be conduresearch prodescribed in 4.3.2.1, and Other opporcollaboration such as imppreexisting dstyles factorto varying de
APPENDIX F. APPLICATION OF RANKING CRITERIA TO RESEARCH AR

Research areas(priority)

Importance of theresearch to reducinguncertainty in riskassessment andprotecting childrenfrom environmentalhealth threats

Feasibility ofconducting theresearch in the ORDintramural or STARprograms

The capacities andcapabilities of ORD’slaboratories andcenters

Opportunities todevelop and maintainscientific expertise inORD to enable use ofresearch results inEPA risk assessments

Opportuniticollaboratioother Federagencies another ORD programs

4.4.5.2 CumulativeRisks to Children(Medium)

MediumResearch to developinformation onmechanisms of actionand methods toinvestigate age-relateddifferences is needed toform a basis forresearch intocumulative risk.

Medium to LowMethods and data forconducting cumulativerisk assessments forboth children and adultsare currently lacking.ORD is developingguidelines forcumulative riskassessment that willprovide researchrecommendations. Asmore is learned aboutchildren’s risk and workproceeds under theORD HHRA Researchprogram, feasibility ofthis research willincrease.

MediumSome research is beingconducted under theSTAR program.Intramural researchcapabilities shouldincrease as cumulativerisk program growsunder the human healthrisk assessmentresearch program.

MediumExpertise for thisresearch area will bedeveloped andmaintained throughresearch under§§4.3.1.1, 4.3.2.1, and4.3.3.1. Research inthis area is a next stepafter basic questionsare answered.

MediumCollaboratiothe area of emeasureme(e.g., measumultiple chebiological sa